CN101917977A

CN101917977A - Formulations of nonopioid and confined opioid analgesics

Info

Publication number: CN101917977A
Application number: CN200780053839XA
Authority: CN
Inventors: J·罗森伯格; G·维尔勒; T·Y·克斯勒; J·布雷滕巴赫; S·杜拉克; F·W·里希特; S·杜塔; W·刘
Original assignee: Abert & Co KG GmbH
Current assignee: Abert & Co KG GmbH; Abbott GmbH and Co KG
Priority date: 2007-07-20
Filing date: 2007-07-20
Publication date: 2010-12-15
Anticipated expiration: 2027-07-20
Also published as: RU2010106202A; BRPI0721940A2; TW200904431A; RU2477995C2; EP2182928A1; AU2007356880A1; CA2690829A1; NZ581767A; CN101917977B; WO2009014534A1; MX2010000803A; IL202680A0; KR20100055431A; ZA200908900B; JP2010534204A

Abstract

The preferred exemplary embodiments in the present application provide formulations and methods for the delivery of drugs, particularly drugs of abuse, having an abuse-relevant drug substantially confined in the core and a non-abuse relevant drug in a non-core region. These formulations have reduced potential for abuse. In the formulation, preferably the abuse relevant drug is an opioid and the non-abuse relevant drug is acetaminophen or ibuprofen. More preferably, the opioid is hydrocodone, and the non-abuse relevant analgesic is acetaminophen. In certain preferred embodiments, the dosage forms are characterized by resistance to solvent extraction; tampering, crushing or grinding. Certain embodiments of the inventions provide dosage forms that provide an initial burst of release of drug followed by a prolonged period of controllable drug release.

Description

The preparation of the opioid analgesic drugs of non-opioid and restriction

TECHNICAL FIELD OF THE INVENTION

The present invention relates to be used for liquid preparations for oral administration.Preferably, the present invention instructs at least a anti-abuse compositions, is used to send the medicine with abuse potential, prepares the correlation technique of these dosage forms, and the method to there being this patient who needs to treat, and comprises giving this patient with compositions of the present invention.More preferably, these compositionss comprise the opioid analgesic drugs of at least a non-opioid analgesic drugs and at least a restriction.

Background of invention

The prescription drug abuse has become a kind of public health problem in many communities.A kind of common type medicine of being abused is an opioid.In the U.S., because opioid effectiveness, the easy and favourable risk and income ratio of titration, they are the analgesic that are used in the main type of moderate to the serious pain control.

One of effect of opioid administration is that these medicines have the ability that changes emotion and emotion in a certain way in some individuality, can provide a kind of like this and improve isolated on desirable " happiness " sense from treatment.Multiple illegal abuse further causes specific user habit-forming to opioid.Similar to opioid, the medicine of many other kinds is also abused, although the pattern of abuse is different with influence.

Therefore, described the whole bag of tricks and preparation in the art and reduced or eliminated various abuse patterns, as relate to alcoholic acid occasionality or intentional property dose dumping (dose dumping), pulverize and suck etc.

U.S. patent application 11/625,705 that on January 22nd, 2007 submitted to and PCT application PCT/US07/60864 are incorporated herein by reference its integral body at this, are used for all purposes, have described the whole bag of tricks and the compositions of the anti-abuse preparation that contains Drug abuse.In these patent applications, used widely the preparation screening program to identify the suitable extrudate preparation, said preparation is for anesthetics Hycodan 2.5-hydrate, in external medicine dissolution, present two stages (behind the 1h＞30%, behind the 8h＞80%).Yet, found for acetaminophen (being also referred to as acetaminophen or APAP), the medicine dissolution of second kind of medicament do not satisfy above-mentioned two stage medicine dissolution standards (behind the 1h＞30%, behind the 8h＞80%).Although two kinds of medicines of Hycodan 2.5-hydrate and acetaminophen all obtain from extruding of mixed uniformly solid mixture and calendering, the institute of resultant dosage form be there are some researches show that two kinds of active component obtain release with different speed.In the Animal Experimental Study (little boar) of using these dosage forms and clinical research, these vitro datas have also been confirmed.Obtained required kinetics although clinical research also shows for Hycodan 2.5-hydrate, lacking for acetaminophen is not like this.Therefore, for acetaminophen, must find that new preparation notion realizes two required stage medicine dissolution features.In addition, also found in most applications, according to U.S.11/625,705 and the calendering extrudate tablet of PCT/US07/60864 patent application manufacturing have coarse surface, therefore based on its outward appearance, in all situations, all do not satisfy the standard that to sell tablet.Therefore, in this respect, also need to improve.

Though exist many compositionss, preparation and method to solve drug dependence, there are certain limitation more or less in all compositionss, preparation and method.

Therefore, need provide preparation, compositions and method new and/or improvement, to prevent to have the abuse of the medicine of abusing potential.More specifically, need a kind of following oral formulations of research and development: said preparation satisfies two stage medicine dissolution features, and has and comprise that medicine prevents such feature and satisfy the desirable appearance that conduct can be sold the tablet standard.

For some Given informations that the applicant is thought may be relevant with the present invention, provide this background information.The information of any front neither should allow, also should not be construed formation prior art of the present invention.

Summary of the invention

Particular preferred embodiment of the present invention provides and has been used for delivering drugs, and particularly the dosage form of Drug abuse and method is characterized in that anti-solvent extraction; Smash (tampering) to pieces, pulverize or grind, and initial fulminant drug release is provided, follow long controlled drug release.Preferably, dosage form comprises the opioid analgesic drugs of at least a non-opioid analgesic drugs and at least a restriction.

In a preferred embodiment, the invention provides the pharmaceutical composition with core and non-core layer, it contains: (a) hydrocodone, acceptable salt or hydrate and (b) acetaminophen or ibuprofen on its materia medica.In this embodiment, all hydrocodones of at least 75%, or acceptable salt or hydrate are in core on its materia medica, and acetaminophen or ibuprofen are non-core layers.In addition, described compositions is applicable to be administered orally in the people 3 times, 2 times or 1 time every day.Preferably, be higher than 90% hydrocodone, or on its materia medica acceptable salt or hydrate in core.More preferably, whole basically hydrocodones, or on its materia medica acceptable salt or hydrate in core.In another embodiment, core also comprises acetaminophen or ibuprofen.More preferably, core also comprises acetaminophen.

In specific embodiment, during the patient of the single dose administration that will contain Hycodan five semihydrates of the 15mg that has an appointment and about 500mg acetaminophen in fasting, preferably present following pharmacokinetic characteristic.Preferably, when delivering medicine to people patient, the blood plasma feature that drug regimen deposits yields feature is following: behind the single dose, for hydrocodone, about 0.6ng/mL/mg is to the Cmax of about 1.4ng/mL/mg with for acetaminophen, the Cmax of about 2.8ng/mL/mg to 7.9ng/mL/mg.In another embodiment, the blood plasma feature that drug regimen deposits yields feature is following: for hydrocodone, about 0.4ng/mL/mg is to the Cmax of about 1.9ng/mL/mg with for acetaminophen, and about 2.0ng/mL/mg is to the Cmax of about 10.4ng/mL/mg.In another embodiment, the blood plasma feature that drug regimen deposits yields feature is following: for hydrocodone, about 0.6ng/mL/mg is to the Cmax of about 1.0ng/mL/mg with for acetaminophen, and about 3.0ng/mL/mg is to the Cmax of about 5.2ng/mL/mg.Other embodiments of dosage form comprise about 5-20mg Hycodan five semihydrates and about 400-600mg acetaminophen.Another embodiment of dosage form comprises 10-15mg Hycodan five semihydrates and about 500-600mg acetaminophen.

In specific embodiment, during the patient of the single dose administration that will contain Hycodan five semihydrates of the 15mg that has an appointment and about 500mg acetaminophen in fasting, preferably present following pharmacokinetic characteristic.When delivering medicine to people patient, for hydrocodone, dosage form produces the AUC of about 9.1ng*hr/mL/mg to about 19.9ng*hr/mL/mg, for acetaminophen, is the AUC of about 28.6ng*hr/mL/mg to about 59.1ng*hr/mL/mg.In another embodiment, for hydrocodone, dosage form produces the AUC of about 7.0ng*hr/mL/mg to about 26.2ng*hr/mL/mg, for acetaminophen, is the AUC of about 18.4ng*hr/mL/mg to about 79.9ng*hr/mL/mg.In another embodiment, for hydrocodone, dosage form produces the AUC of about 11.3ng*hr/mL/mg to about 18.7ng*hr/mL/mg, for acetaminophen, is the AUC of about 28.7ng*hr/mL/mg to about 53.5ng*hr/mL/mg.Preferably, in this embodiment, the in-vitro release rate of pharmaceutical composition has two stage release characteristics, and wherein for each stage of in-vitro release rate, for acetaminophen is zero level or one-level, and is zero level or one-level for Hycodan five semihydrates.

In specific embodiment, during the patient of the single dose administration that will contain Hycodan five semihydrates of the 15mg that has an appointment and about 500mg acetaminophen in fasting, preferably present following pharmacokinetic characteristic.For hydrocodone, dosage form produced the plasma concentration (C1) of about 0.18ng/mL/mg to about 1.51ng/mL/mg in the time of 1 hour, and for acetaminophen, the plasma concentration C1 in the time of 1 hour is that about 2.34ng/mL/mg is to about 7.24ng/mL/mg.In preferred embodiments, as preparation 15, for hydrocodone, dosage form produces the C1 of about 0.32ng/mL/mg to about 1.51ng/mL/mg, and for acetaminophen, about 2.34ng/mL/mg is to the C1 of about 5.50ng/mL/mg.

In other specific embodiments, during the patient of the single dose administration that will contain Hycodan five semihydrates of the 15mg that has an appointment and about 500mg acetaminophen in fasting, preferably present following pharmacokinetic characteristic.For hydrocodone, dosage form produced the plasma concentration (C1) of about 0.30ng/mL/mg to about 1.06ng/mL/mg in the time of 1 hour, and for acetaminophen, C1 is that about 2.75ng/mL/mg is to about 5.57ng/mL/mg.In preferred embodiments, for hydrocodone, dosage form produces the C1 of about 0.45ng/mL/mg to about 1.06ng/mL/mg, and for acetaminophen, about 2.75ng/mL/mg is to the C1 of about 4.43ng/mL/mg.

In other embodiments, when fasting, behind 15mg Hycodan five semihydrates and 500mg acetaminophen of single dose, for hydrocodone and acetaminophen, dosage form has produced the associating C1 of about 1.18 μ g/mL to about 3.63 μ g/mL.In preferred embodiments, behind 15mg Hycodan five semihydrates and 500mg acetaminophen of single dose, for hydrocodone and acetaminophen, dosage form has produced the associating C1 of about 1.18 μ g/mL to about 2.76 μ g/mL.

In specific embodiment, behind 15mg Hycodan five semihydrates and 500mg acetaminophen of single dose, for hydrocodone and acetaminophen, dosage form has produced the associating C1 of about 1.38 μ g/mL to about 2.79 μ g/mL.In preferred embodiments, behind 15mg Hycodan five semihydrates and 500mg acetaminophen of single dose, for hydrocodone and acetaminophen, dosage form has produced the associating C1 of about 1.38 μ g/mL to about 2.23 μ g/mL.

In preferred embodiments, behind 15mg Hycodan five semihydrates and 500mg acetaminophen of single dose, for hydrocodone and acetaminophen, dosage form has produced the associating C1 of 1.80 ± 0.42 μ g/mL, for falling into about 1.61 μ g/mL, has 95% confidence interval to the meansigma methods between about 2.00 μ g/mL.For preferred embodiment and contrast, be eclipsed for 95% confidence interval of the associating C1 of hydrocodone and acetaminophen.For contrast, deliver medicine to people patient according to the 15mg hydrocodone of single dose and 500mg acetaminophen after, be about 1.46 to 1.96 μ g/mL for 95% confidence interval of the associating C1 meansigma methods of hydrocodone and acetaminophen.Contrast provides the opioid and the non-opioid analgesic drugs of enough blood plasma levels, so that the reduction of pain intensity to be provided in about 1 hour after administration.

Deliver medicine to healthy North America or western's group time, particularly preparation is improved to be suitable for, or be intended for use, delivered medicine to man-hour in per as required 12 hours, in 0.01N HCl, under 50rpm, 37 ℃, the hydrocodone of about 20-45% discharges from pharmaceutical composition external in about 1 hour, and the acetaminophen of about 20-45% discharges from pharmaceutical composition external in about 1 hour.In another embodiment, in 0.01N HCl, under 50rpm, 37 ℃, the hydrocodone of about 25-35% discharges from pharmaceutical composition external in about 1 hour, and the acetaminophen of about 25-35% discharges from pharmaceutical composition external in about 1 hour.In addition, in another embodiment, in about 8 hours to about 12 hours, at least 90% hydrocodone discharges from pharmaceutical composition, with in about 6 hours to about 8.5 hours, at least 60% to about 99% acetaminophen discharges from pharmaceutical composition external.In another embodiment, in about 8 hours to about 11 hours, at least 90% hydrocodone discharges from pharmaceutical composition and in about 8 hours to about 11 hours, at least 90% acetaminophen discharges from pharmaceutical composition external.In another embodiment, in about 9 hours to about 12 hours, at least 95% hydrocodone discharges from pharmaceutical composition and in about 9 hours to about 12 hours, at least 95% acetaminophen discharges from pharmaceutical composition external.In another embodiment, in about 10 hours to about 12 hours, at least 95% hydrocodone discharges from pharmaceutical composition and in about 10 hours to about 12 hours, at least 95% acetaminophen discharges from pharmaceutical composition external.In another embodiment, in about 11 hours to about 12 hours, at least 99% hydrocodone discharges from pharmaceutical composition and in about 11 hours to about 12 hours, at least 99% acetaminophen discharges from pharmaceutical composition external.In another embodiment, be less than in about 13 hours, at least 99% hydrocodone discharges from pharmaceutical composition and is being less than in about 13 hours, and at least 99% acetaminophen discharges from pharmaceutical composition external.

Yet, the slow release formulation of preparation is improved to be suitable for, or be intended for use as required to deliver medicine to man-hour twice every day, so in about 18 hours to about 23 hours, at least 90% hydrocodone discharges from pharmaceutical composition, with in about 18 hours to about 23 hours, at least 90% acetaminophen discharges from pharmaceutical composition external.In another embodiment of slow releasing preparation, in about 20 hours to about 25 hours, at least 95% hydrocodone discharges from pharmaceutical composition and in about 20 hours to about 25 hours, at least 95% acetaminophen discharges from pharmaceutical composition external.In another embodiment of slow releasing preparation, in about 21 hours to about 22 hours, at least 95% hydrocodone discharges from pharmaceutical composition and in about 21 hours to about 22 hours, at least 95% acetaminophen discharges from pharmaceutical composition external.In another embodiment of slow releasing preparation, in about 22 hours to about 26 hours, at least 99% hydrocodone discharges from pharmaceutical composition and in about 22 hours to about 26 hours, at least 99% acetaminophen discharges from pharmaceutical composition external.In another embodiment of slow releasing preparation, be less than in about 27 hours, at least 99% hydrocodone discharges from pharmaceutical composition and is less than in about 27 hours, and at least 99% acetaminophen discharges from pharmaceutical composition external.

In preferred embodiments, the invention provides a kind of compositions, wherein core layer contain can control drug release excipient or excipient mixture, but not core layer contains the excipient that can discharge medicine immediately.In addition, in preferred embodiments, the fused mass straight forming that then will contain medicine by melt extrusion is made core layer, and non-core layer spraying is coated on the core layer.More preferably, said composition contains Hycodan five semihydrates of have an appointment 500mg acetaminophen and about 15mg.

In another exemplary, the invention provides pharmaceutical composition with core and non-core layer, it contains: (a) the relevant medicine of the abuse in the core layer, acceptable salt or hydrate on its materia medica, with acceptable salt on non-abuse related drugs or its materia medica, (b) the non-abuse related drugs in the non-core layer, acceptable salt or hydrate on its materia medica.Preferably, said composition is characterised in that at least one following feature:

I) be less than or equal in the amount of the external abuse related drugs that in 37 ℃ of next hours, comes out 1.5 times in the amount of the external abuse related drugs that in 37 ℃ of next hours, from compositions, extracts by the 0.01N hydrochloric acid extraction by 40% ethanol water,

Ii) as measuring by " Pharma Test PTB 501 " hardness analyzer, compositions is in 150 newton, preferred 300 newton, and more preferably 450 newton are not more preferably broken under 500 Newton force again,

Iii) in first hour of dissolution in vitro test process, compositions discharges at least 20% abuse related drugs and is no more than 45% abuse related drugs, and first hour of preferred test in vivo also be so in the process,

Iv) compositions discharges the non-abuse related drugs of treatment effective dose in 1 to 2 hour behind single dose,

V) discharge the non-abuse related drugs and/or the abuse related drugs of treatment effective dose when compositions behind single dose 1 hour and 12 hours,

Vi) in compositions, 20,000-50 in the time of 1 minute, compares the compositions grinding under the 000rpm with intact tablet by coffee mill, and 37 ℃ of next hours in 40% ethanol water, the release raising of the abuse related drugs after the grinding is lower than 2 to 3 times,

When vii) grinding, compositions contains following particle diameter: for about 20% part, particle diameter for about 2cm to about 355 microns, for about 66% part, particle diameter be greater than about 63 microns extremely less than about 355 microns, and for about 14% part, particle diameter is less than about 63 microns, or

Viii) compositions is slick basically, and wherein centrage meansigma methods (CLA) is about 0.1 to about 0.6, and preferred about 0.1 to about 0.4, most preferably from about 0.1 to about 0.2.

In said composition, the amount of the abuse related drugs that in 37 ℃ of next hours, from preparation, extracts by 40% ethanol water be the medicine that comes out by the 0.01N hydrochloric acid extraction in 37 ℃ of next hours amount about 70% to about 130%.In another embodiment, the amount of the abuse related drugs that in 37 ℃ of next hours, from preparation, extracts by 40% ethanol water be the medicine that comes out by the 0.01N hydrochloric acid extraction in 37 ℃ of next hours amount about 70% to about 90%.In another embodiment, the abuse related drugs that in 37 ℃ of next hours, from preparation, extracts by 40% ethanol water be the medicine that comes out by the 0.01N hydrochloric acid extraction in 37 ℃ of next hours amount about 75% to about 90%.

Another embodiment of the invention provides the pharmaceutical composition with core layer and non-core layer.In said composition, core layer comprises the mixture of being made up of following material: (a) at least a opioid; (b) acceptable polymer, copolymer or its combination on the materia medica of at least a change speed.Non-core layer contains at least a non-opioid analgesic drugs.In addition, these compositionss are applicable to be administered orally in the people 3,2 or 1 times every day.Preferably, core layer also contains at least a non-opium sample analgesic.In preferred embodiments, compositions is characterised in that at least one following feature:

When vii) grinding, as measured by sieve test, compositions contains following particle diameter: for about 20% part, particle diameter is extremely about 355 microns of about 2cm, for about 66% part, particle diameter be greater than about 63 microns to less than about 355 microns, and for about 14% part, particle diameter is less than about 63 microns, or

In one embodiment, opioid is selected from alfentanil, allylprodine, alphaprodine, anileridine, the benzyl morphine, bezitramide; buprenorphine; butorphanol; Clonitazene; codeine; cyclazocine; dihydrodesoxymorphine; dextromoramide; dezocine; diampromide; paracodin; paramorphane; dimenoxadol; dimepheptanol; dimethylthiambutene; dioxaphetyl butyrate; dipipanone; eptazocine; ethoheptazine; ethylmethylthiambutene; ethylmorphine; etonitazene; fentanyl; heroin; hydrocodone; hydromorphone; hydroxypethidine; isomethadone; ketobemidone; levallorphan; levophenacylmorphan; levorphanol; Lofentanil; dolantin; meptazinol; metazocine; methadone; metopon; morphine; Myrophine; nalbuphine; narceine; nicomorphine; norpipanone; Opium; oxycodone; oxymorphone; papvretum; pentazocine; Phenadon-X; phenazocine; phenomorphan; phenoperidine; Piminodine; disopyramide; dextropropoxyphene; sufentanil; tilidate and tramadol, and salt; hydrate and mixture.In addition, non-opioid analgesic drugs is selected from acetaminophen, aspirin, fentaynl, ibuprofen, indomethacin, ketorolac, naproxen, Phenacetin, piroxicam, new fentanyl, Su Lin acid, interferon-ALPHA, and salt, hydrate and mixture.Preferably, opioid is a hydrocodone, but not opioid analgesic drugs is acetaminophen or ibuprofen.More preferably, opioid is a hydrocodone, but not opioid analgesic drugs is an acetaminophen.

In specific embodiment, during the patient of the single dose administration that will contain Hycodan five semihydrates of the 15mg that has an appointment and about 500mg acetaminophen in fasting, preferably present following pharmacokinetic characteristic.Preferably, when delivering medicine to people patient, the blood plasma feature that drug regimen deposits yields feature is following: behind the single dose, for hydrocodone, about 0.6ng/mL/mg is to the Cmax of about 1.4ng/mL/mg with for acetaminophen, the Cmax of about 2.8ng/mL/mg to 7.9ng/mL/mg.In another embodiment, the blood plasma feature that drug regimen deposits yields feature is following: behind the single dose, for hydrocodone, about 0.4ng/mL/mg is to the Cmax of about 1.9ng/mL/mg with for acetaminophen, the Cmax of about 2.0ng/mL/mg to 10.4ng/mL/mg.In another embodiment, the blood plasma feature that drug regimen deposits yields feature is following: for hydrocodone, about 0.6ng/mL/mg is to the Cmax of about 1.0ng/mL/mg with for acetaminophen, and about 3.0ng/mL/mg is to the Cmax of about 5.2ng/mL/mg.

In specific embodiment, during the patient of the single dose administration that will contain Hycodan five semihydrates of the 15mg that has an appointment and about 500mg acetaminophen in fasting, preferably present following pharmacokinetic characteristic.When delivering medicine to people patient, for hydrocodone, dosage form produces the AUC of about 9.1ng*hr/mL/mg to about 19.9ng*hr/mL/mg, for acetaminophen, is the AUC of about 28.6ng*hr/mL/mg to about 59.1ng*hr/mL/mg.In another embodiment, for hydrocodone, dosage form produces the AUC of about 7.0ng*hr/mL/mg to about 26.2ng*hr/mL/mg, and for acetaminophen, dosage form produces the AUC of about 18.4ng*hr/mL/mg to about 79.9ng*hr/mL/mg.In another embodiment, for hydrocodone, dosage form produces the AUC of about 11.3ng*hr/mL/mg to about 18.7ng*hr/mL/mg, and for acetaminophen, dosage form produces the AUC of about 28.7ng*hr/mL/mg to about 53.5ng*hr/mL/mg.Preferably, in this embodiment, the in-vitro release rate of pharmaceutical composition has two stage release characteristics, and wherein for each stage of in-vitro release rate, for acetaminophen is zero level or one-level, and is zero level or one-level for Hycodan five semihydrates.

In specific embodiment, during the patient of the single dose administration that will contain Hycodan five semihydrates of the 15mg that has an appointment and about 500mg acetaminophen in fasting, preferably present following pharmacokinetic characteristic.Preferably, when delivering medicine to people patient, for hydrocodone, pharmaceutical composition produced the plasma concentration (C1) of about 0.18ng/mL/mg to about 1.51ng/mL/mg in the time of 1 hour, for acetaminophen, the plasma concentration C1 in the time of 1 hour is that about 2.34ng/mL/mg is to about 7.24ng/mL/mg.In preferred embodiments, as preparation 15, for hydrocodone, dosage form produces the C1 of about 0.32ng/mL/mg to about 1.51ng/mL/mg, and for acetaminophen, dosage form produces the C1 of about 2.34ng/mL/mg to about 5.50ng/mL/mg.

In specific embodiment, during the patient of the single dose administration that will contain Hycodan five semihydrates of the 15mg that has an appointment and about 500mg acetaminophen in fasting, preferably present following pharmacokinetic characteristic.Preferably, when delivering medicine to people patient, for hydrocodone, pharmaceutical composition produced the plasma concentration (C1) of about 0.30ng/mL/mg to about 1.06ng/mL/mg in the time of 1 hour, and for acetaminophen, C1 is that about 2.75ng/mL/mg is to about 5.57ng/mL/mg.In preferred embodiments, for hydrocodone, dosage form produces the C1 of about 0.45ng/mL/mg to about 1.06ng/mL/mg, and for acetaminophen, about 2.75ng/mL/mg is to the C1 of about 4.43ng/mL/mg.

In specific embodiment, behind 15mg Hycodan five semihydrates and 500mg acetaminophen of single dose, for hydrocodone and acetaminophen, dosage form has produced the associating C1 of about 1.18 μ g/mL to about 3.63 μ g/mL.In preferred embodiments, behind 15mg Hycodan five semihydrates and 500mg acetaminophen of single dose, for hydrocodone and acetaminophen, dosage form has produced the associating C1 of about 1.18 μ g/mL to about 2.76 μ g/mL.

In preferred embodiments, behind 15mg Hycodan five semihydrates and 500mg acetaminophen of single dose, for hydrocodone and acetaminophen, dosage form has produced the associating C1 of 1.80 ± 0.42 μ g/mL, for falling into about 1.61 μ g/mL, has 95% confidence interval to the meansigma methods between about 2.00 μ g/mL.For preferred embodiment and contrast, be eclipsed for 95% confidence interval of the associating C1 of hydrocodone and acetaminophen.For contrast, deliver medicine to people patient according to 15mg Hycodan five semihydrates of single dose and 500mg acetaminophen after, be about 1.46 to 1.96 μ g/mL for 95% confidence interval of the associating C1 meansigma methods of hydrocodone and acetaminophen.Contrast provides the opioid and the non-opioid analgesic drugs of enough blood plasma levels, so that the reduction of pain intensity to be provided in about 1 hour after administration.

Deliver medicine to healthy North America or western's group time, particularly preparation is improved to be suitable for, or be intended for use, delivered medicine to man-hour in per as required 12 hours, in 0.01N HCl, under 50rpm, 37 ℃, the hydrocodone of about 20-45% discharges from pharmaceutical composition external in about 1 hour, and the acetaminophen of about 20-45% discharges from pharmaceutical composition external in about 1 hour.In another embodiment, in 0.01N HCl, under 50rpm, 37 ℃, the hydrocodone of about 25-35% discharges from pharmaceutical composition external in about 1 hour, and the acetaminophen of about 25-35% discharges from pharmaceutical composition external in about 1 hour.

In addition, in another embodiment, in about 8 hours to about 12 hours, at least 90% hydrocodone discharges from pharmaceutical composition, with in about 6 hours to about 8.5 hours, at least 60% to about 99% acetaminophen discharges from pharmaceutical composition external.In another embodiment, in about 8 hours to about 11 hours, at least 90% hydrocodone discharges from pharmaceutical composition and in about 8 hours to about 11 hours, at least 90% acetaminophen discharges from pharmaceutical composition external.In another embodiment, in about 9 hours to about 12 hours, at least 95% hydrocodone discharges from pharmaceutical composition and in about 9 hours to about 12 hours, at least 95% acetaminophen discharges from pharmaceutical composition external.In another embodiment, in about 10 hours to about 12 hours, at least 95% hydrocodone discharges from pharmaceutical composition and in about 10 hours to about 12 hours, at least 95% acetaminophen discharges from pharmaceutical composition external.In another embodiment, in about 11 hours to about 12 hours, at least 99% hydrocodone discharges from pharmaceutical composition and in about 11 hours to about 12 hours, at least 99% acetaminophen discharges from pharmaceutical composition external.In another embodiment, be less than in about 13 hours, at least 99% hydrocodone discharges from pharmaceutical composition and is less than in about 13 hours, and at least 99% acetaminophen discharges from pharmaceutical composition external.

In another exemplary, the invention provides pharmaceutical composition with core and non-core layer.In said composition, core layer contains the mixture of following material: (a) at least a opioid and at least a first non-opioid analgesic drugs; (b) acceptable polymer, copolymer or its combination on the materia medica of at least a change speed.Non-core layer contains at least a second non-opioid analgesic drugs.In addition, described compositions is applicable to deliver medicine to the people 3,2 or 1 times every day.In this embodiment, preferred, opioid contains hydrocodone, and first kind and the second non-opioid analgesic drugs contain acetaminophen or ibuprofen.More preferably, opioid contains hydrocodone, and first kind and the second non-opioid analgesic drugs contain acetaminophen.In addition, in this embodiment, non-core layer contains: (a) acetaminophen; (b) acceptable polymer, copolymer or its combination on the materia medica of at least a change speed.Preferably, polymer or copolymer are selected from: hydroxypropyl cellulose, hydroxypropyl emthylcellulose, hydroxyethyl-cellulose; Polymethacrylates, polyvinyl alcohol, poly(ethylene oxide) and combination thereof.More preferably, polymer or copolymer are selected from: hydroxypropyl emthylcellulose and polyvinyl alcohol, or its combination.Again more preferably, polymer or copolymer are selected from: polyvinyl alcohol and poly(ethylene oxide) graft copolymer.In addition, in this embodiment, the ratio of acetaminophen and rate control polymer or copolymer or its combination is about 1: 1 to about 10: 1.More preferably, the ratio of acetaminophen and rate control polymer or copolymer or its combination is about 3: 1 to about 5: 1.As providing among the present invention, in a preferred embodiment,

Non-core layer has at least one following feature:

(a) under 40 ℃, 75% relative humidity in the HDPE of induction sealing bottle, do not break basically after 3 months;

(b) be (not sticking) that does basically;

In 0.01N HCl, under 37 ℃, provide quick dissolving exposing core layer, delivering medicine to the acetaminophen that people patient discharges at least 80% in the non-core layer in 20 minutes; Or

(c) provide the painted of white to preparation, and do not have other pigment.

In specific embodiment, during the patient of the single dose administration that will contain Hycodan five semihydrates of the 15mg that has an appointment and about 500mg acetaminophen in fasting, preferably present following pharmacokinetic characteristic.Preferably, when delivering medicine to people patient, the blood plasma feature that drug regimen deposits yields feature is following: behind the single dose, for hydrocodone, about 0.6ng/mL/mg is to the Cmax of about 1.4ng/mL/mg with for acetaminophen, the Cmax of about 2.8ng/mL/mg to 7.9ng/mL/mg.In another embodiment, the blood plasma feature that drug regimen deposits yields feature is following: behind the single dose, for hydrocodone, about 0.4ng/mL/mg is to the Cmax of about 1.9ng/mL/mg, with for acetaminophen, about 2.0ng/mL/mg is to the Cmax of about 10.4ng/mL/mg.In another embodiment, the blood plasma feature that drug regimen deposits yields feature is following: for hydrocodone, about 0.6ng/mL/mg is to the Cmax of about 1.0ng/mL/mg with for acetaminophen, and about 3.0ng/mL/mg is to the Cmax of about 5.2ng/mL/mg.

In specific embodiment, during the patient of the single dose administration that will contain Hycodan five semihydrates of the 15mg that has an appointment and about 500mg acetaminophen in fasting, preferably present following pharmacokinetic characteristic.Preferably, when delivering medicine to people patient, for hydrocodone, pharmaceutical composition produced the plasma concentration (C1) of about 0.18ng/mL/mg to about 1.51ng/mL/mg in the time of 1 hour, for acetaminophen, the plasma concentration C1 in the time of 1 hour is that about 2.34ng/mL/mg is to about 7.24ng/mL/mg.In preferred embodiments, as preparation 15, for hydrocodone, dosage form produces the C1 of about 0.32ng/mL/mg to about 1.51ng/mL/mg, and for acetaminophen, about 2.34ng/mL/mg is to the C1 of about 5.50ng/mL/mg.

In addition, in another embodiment, in about 8 hours to about 12 hours, at least 90% hydrocodone discharges from pharmaceutical composition, with in about 6 hours to about 8.5 hours, at least 60% to about 99% acetaminophen discharges from pharmaceutical composition external.In another embodiment, in about 8 hours to about 11 hours, at least 90% hydrocodone discharges from pharmaceutical composition and in about 8 hours to about 11 hours, at least 90% acetaminophen discharges from pharmaceutical composition external.In another embodiment, in about 9 hours to about 12 hours, at least 95% hydrocodone discharges from pharmaceutical composition and in about 9 hours to about 12 hours, at least 95% acetaminophen discharges from pharmaceutical composition external.In another embodiment, in about 10 hours to about 12 hours, at least 95% hydrocodone discharges from pharmaceutical composition and in about 10 hours to about 12 hours, at least 95% acetaminophen discharges from pharmaceutical composition external.In another embodiment, in about 11 hours to about 12 hours, at least 99% hydrocodone discharges from pharmaceutical composition and in about 11 hours to about 12 hours, at least 99% acetaminophen discharges from pharmaceutical composition external.In another embodiment, be less than in about 13 hours, at least 99% hydrocodone discharges from pharmaceutical composition and is being less than in about 13 hours, and at least 99% acetaminophen discharges from pharmaceutical composition external.

Yet, the slow release formulation of preparation is improved to be suitable for, or be intended for use as required to deliver medicine to man-hour twice every day, so in about 18 hours to about 23 hours, at least 90% hydrocodone discharges from pharmaceutical composition, with in about 18 hours to about 23 hours, at least 90% acetaminophen discharges from pharmaceutical composition external.In another embodiment of slow releasing preparation, in about 20 hours to about 25 hours, at least 95% hydrocodone discharges from pharmaceutical composition and in about 20 hours to about 25 hours, at least 95% acetaminophen discharges from pharmaceutical composition external.In another embodiment of slow releasing preparation, in about 21 hours to about 22 hours, at least 95% hydrocodone discharges from pharmaceutical composition and in about 21 hours to about 22 hours, at least 95% acetaminophen discharges from pharmaceutical composition external.In another embodiment of slow releasing preparation, in about 22 hours to about 26 hours, at least 99% hydrocodone discharges from pharmaceutical composition and in about 22 hours to about 26 hours, at least 99% acetaminophen discharges from pharmaceutical composition external.In another embodiment of slow releasing preparation, be less than in about 27 hours, at least 99% hydrocodone discharges from pharmaceutical composition and is being less than in about 27 hours, and at least 99% acetaminophen discharges from pharmaceutical composition external.

In preferred embodiments, the invention provides a kind of compositions, wherein core layer contain can control drug release excipient, but not core layer contains the excipient that can discharge medicine immediately.In addition, in preferred embodiments, the fused mass straight forming that then will contain medicine by melt extrusion is made core layer, and non-core layer spraying is coated on the core layer.Most preferably, said composition contains Hycodan five semihydrates of have an appointment 500mg acetaminophen and about 15mg.

The inventive method of describing more comprehensively below reading and wherein during the detailed content of composition therefor, it is clear that these and other targets of the present invention, advantage and feature will become to those skilled in the art.

The accompanying drawing summary:

The coating that Fig. 1 has described to extrude tablet causes tablet surface obviously smooth.

Fig. 2 has described the sketch map of the surface roughness calculating of use centrage meansigma methods (CLA) method.

Fig. 3 has described the centrage meansigma methods (CLA) of uncoated preparation.For uncoated preparation, in the time of (N=69), CLA=36.1.

Fig. 4 has described the centrage meansigma methods (CLA) of uncoated preparation.For the preparation of coating, in the time of (N=69), CLA=10.4.

Fig. 5 has described for preparation 15 and 16 and contrast 1 and continue (a) 48 hours and (b) preliminary average hydrocodone concentration-temporal characteristics of 12 hours.

Fig. 6 has described for preparation 15 and 16 and contrast 1 and continue (a) 48 hours and (b) preliminary average acetaminophen concentration-temporal characteristics of 12 hours.

Fig. 7 has described to continue 480 minutes, the vitro drug release feature of hydrocodone and acetaminophen for preparation 17 and 18, contrast 2 and uncoated preparation VM-1.

Detailed Description Of The Invention

The invention is not restricted to described ad hoc approach, experimental program, zooscopy and reagent, it can change. It will also be appreciated that the purpose that just is used for describing particular in this used technology, is not to limit the scope of the invention, and it will only limit by claims.

Must be noted that as described in this and the claims, singulative " ", " one " and " being somebody's turn to do " comprise that plural number refers to thing, unless clearly point out in addition in the literary composition. Therefore, for example, comprise multiple such compound and equivalent well known by persons skilled in the art thereof etc. about " a kind of compound ". In addition, term " " (or " "), " one or more " and " at least a " can Alternate at this. Be further noted that term " contains ", " comprising " and " having " can Alternate.

Unless otherwise defined, has the same meaning that those skilled in the art understand usually in these all used technology and scientific terminology. Although can be used for practice of the present invention and test with those any method and materials similar or that equate described here, will describe preferred method and material now. All publications are hereby incorporated by referred in this, be used for to describe and the purpose of chemical substance, animal, instrument, statistical analysis and the method that can be used in combination with the present invention that public publication is put down in writing. Anything is not interpreted as admitting that the present invention does not have right prior to formerly inventing such disclosing at this.

For known material, used the trade mark as convenient abbreviation in this description. As known to persons of ordinary skill in the art, the material shown in following trade mark represents:

The polymer of deriving from the ester of acrylic acid and methacrylic acid.

The methyl or methoxy cellulose

Polyvinyl alcohol-polyethylene glycol-graft copolymer

Polyvinyl pyrrolidone polymers or-copolymer

The propane diols laurate

Sorbitan fatty acid ester

GREMAPHOR GS32

Polyoxyethylene polyoxypropylene block copolymers or polyoxyethylene polypropylene glycol

The sorbitan ester of polyethoxylated

Hydroxypropyl cellulose

PVP all-or copolymer

(2,3,4,5) tetrahydroxy-amylalcohol

6-0-α-D-glucopyranoside-D-D-sorbite (1,6-GPS) and 1-0-α-D-glucopyranoside-PEARLITOL 25C-dihydrate (1,1-GPM-dihydrate) wait a mole composition.

Water-soluble resin based on polyethylene glycol oxide

(2,3,4,5) tetrahydroxy-amylalcohol

The oleate of polyglycereol

Polyoxyethylene polyoxypropylene block copolymer or polyoxyethylene polypropylene glycol

Ethyl cellulose

Sodium starch glycolate

The invention provides a kind of solid or solid solution of improvement, the oral dose preparation, it provides sustained release in the body that the reactive compound on the materia medica (" medicine ") and salt thereof, ester, prodrug and other medicines learn upper acceptable equivalent, and the reactive compound on the described materia medica has possibility to be abused it or shown the character of often being abused.

Term " AUC " refers to the area under the Cot curve, uses trapezoidal rule and Clast/k to calculate, and wherein Clast is that concentration and the k that observes at last is the elimination rate constant that calculates.

Term " AUCt " refers to the area under the Cot curve, the concentration of observing at last of using trapezoidal rule to calculate.

Term " Cmax " represents with ng/mL and μ g/mL respectively when referring to Tmax and the PC of described abuse related drugs, produces by oral absorption composition of the present invention. Except as otherwise noted, Cmax refers to the concentration that total maximum is observed.

Term " Cmin " refers to give formulation of the present invention for the contiguous administration time of 5 dosage intervals, the concentration that minimum in the administration time interval of appointment is observed is 12 hours administration time intervals for the preparation that mark is suitable for administration in per 12 hours or as required administration for example.

Term " ng*hr/mL/mg " refers to that the quantity of the material that every milliliter of blood is measured with nanogram multiply by hourage, again divided by with the milligram number of giving animal or human's abuse related drugs.

Phrase used herein " rate of release of rising " refers to usually the in time rate of dissolution of increase, so described medicine is dissolved in the liquid with the speed that usually increases in time under environment for use, rather than keep constant or minimizing, until formulation exhausts about 80% medicine.

Be used for above or during other treatment, can be with pure form, or in such form situation about existing, use one of The compounds of this invention for the treatment of effective dose with acceptable salt, ester or prodrug forms on the materia medica. It is to be applicable under the reasonable benefit/risk ratio of any medical treatment that phrase the present invention includes compound " treatment effective dose " meaning, the enough content of the compound for the treatment of disease. Yet the total every consumption per day that can understand The compounds of this invention and composition will be decided by the doctor in charge, in rational medical judgment scope. Specific treatment effective dose for any particular patient will depend on various factors, comprise disease to be treated and the order of severity of disease; The activity of used specific compound; Used specificity group compound; Patient's age, body weight, general health, sex and meals; The discharge rate of administration time, method of administration and used specific compound; The duration for the treatment of; The medicine of being combined or using simultaneously with used specific compound; Known similar factor in the medical domain.

In a preferred embodiment, the invention provides and suppress the formulation that medicine is extracted from preparation by conventional solvent, conventional solvent is such as, but not limited to, the ethanol water of distillation. Extract opioid ability by restriction people (wittingly or by mistake) from said preparation, said preparation is dissuaded abuse from, and so described opioid can not be concentrated to be used for parenteral easily. In addition, these anti-abuse preparations can not be broken for littler particle or powder type easily, described will be by sucking in the nose than small particle or powder type easy abuse. This anti-abuse preparation does not need to add opioid antagonists (although, opioid antagonists can be added in the said preparation with further prevention abuse). Although do not wish to be bound by any particular theory, it is believed that, add the alkylcellulose class, (but being not limited to) CMC class for example, and preferred hydroxypropyl emthylcellulose, can promote the anti-extractability of said preparation in alcohol, described alcohol is 20% or 40% ethanol water particularly. Described alkylcellulose preferably has the alkyl substituent of at least 12% substitution value, the more preferably alkyl substituent of at least 16% substitution value, and the alkyl substituent of at least 19% substitution value most preferably. In the context of the present invention, preferred described cellulosic alkyl replaces less than about 40%, is more preferably less than about 30%. In addition, described alkyl substituent C preferably₁-C ₆, be more preferably C₁、C ₂Or C₄, and most preferably be C₃, and when described alkyl substituent contains 3 or more carbon atom, can be straight or branched.

In a further preferred embodiment, the optional anti-cutting of described formulation, grinding, pulverizing etc. For this aspect of the present invention, measuring method is " fracture strength " easily, as measuring by " Pharma Test PTB 501 " hardness-testing device. Preparation of the present invention preferably has the fracture strength of at least 150 newton (150 N). More preferably, preparation of the present invention has at least fracture strength of 300N, especially more preferably the fracture strength of at least 450 N, the especially more preferably fracture strength of at least 500 N.

Can be with the tablet of 10mm diameter and 5mm width according to fracture strength of the present invention, according in European pharmacopeia 1997, p143,144, the method for disclosed mensuration tablet fracture strength is measured among the square religious name 2.9.8. The preferred apparatus that is used for the measurement fracture strength is " Zwick Z 2.5 " Material Testing Machine, Fmax=2.5kN, and maximum tension 1150mm, wherein this device comprises post and measures axle, the post gap of 100mm and test speed 0.1800mm/min. Measurement can use the pressure piston of band screw-in insert and cylinder (10mm diameter) to carry out, this is that (type 0.5 is from 10N for Fmax.1kN, diameter=8mm for a kind of force cell, Class1 is from 2N to ISO 7500-1, the total power Fmax=1.45kN of Zwick). This instrument is optional can be from Zwick GmbH ﹠ Co.KG, Ulm, and Germany obtains.

Any suitable method can be for the preparation of composition of the present invention. In a kind of preferred embodiment, described preparation is melt-processed preferably, more preferably melt extrusion, and said preparation is not ground or ground to direct forming all in both cases then. Although as mentioned above, can consider the direct forming tablet of said preparation optional with swallowing the auxiliary agent dressing, such as but not limited to, gelatine glaze. Although do not wish to be subjected to the constraint of any particular theory, it is believed that direct forming grinds the superior fracture strength that step will help said preparation to prevent forming undesirable evident characteristic at said preparation in the middle of namely not having. In addition, by using the polymer of at least two kinds of melt-processed, the extra fracture strength of the optional acquisition of the embodiment of preparation of the present invention. Although owing to any specific theory, not it is believed that, the preferential interpolymer interaction with first kind of melt-processed of the polymer of second melt-processed so that during the preparation tablet glass transition temperature of whole adjusting said composition advantageously.

In one embodiment, said preparation can use polymer or copolymer or its make up to generate melt-processed, the more preferably preparation of the direct forming of melt extrusion. Can also use pharmacology inactive and the polymer of enteric coating or said preparation sustained release curve is provided. In one embodiment, suitable polymer/copolymer comprises poly-(methyl) acrylate such as EudragitL-or S-type, and it is that pharmacology is inactive.

That some are fit in the present invention trade name that use and that be derived from the preferred polymers of acrylate and methacrylate. The performance of this EUDRAGIT polymer is mainly determined by the functional group that is attached in the EUDRAGIT polymer monomer. Each

Grade is different on the ratio of their neutrality, alkalescence or acidic-group, and therefore causes on physical and chemical performance different. Can use methacrylic acid aminoalkyl ester copolymer or methacrylate copolymer with lower general formula:

The Eufragit polymer satisfies specification standards/demand of setting among the USP. According to 2007 American Pharmacopeias, according to USP 30/NF 25 definition Eudragit.

Methacrylic acid copolymer, type A NF=Eudragit L-100

Methacrylic acid copolymer, type B NF=Eudragit S-100

Methacrylic acid copolymer, Type C NF=Eudragit L-100-55 (containing washing agent in a small amount)

Ammonium (ammonio) methacrylate copolymer, type A NF=EudragitRL-100 (particle)

The amino methyl acrylate copolymer, type A NF=Eudragit RL-PO (powder)

The amino methyl acrylate copolymer, type B NF=Eudragit RS-100 (particle)

The amino methyl acrylate copolymer, type B NF=Eudragit RS-PO (powder)

Polyacrylate dispersion 30% European Pharmacopoeia=Eudragit NE30D (=30% aqueous dispersion)

Alkalescence butylation methacrylate copolymer European Pharmacopoeia=Eudragit E-100

Wherein said functional group has quaternary ammonium (methacrylic acid (trimethyl amino-ethyl) ester) part or R=COOCH2CH2N⁺(CH ₃) 3Cl-[with

(RL or RS) buys] or described functional group be carboxylic acid, or R=COOH[with

(L) buy]. When described functional group is carboxylic moiety, described

(L) polymer be anti-stomach with enteric. Therefore, use

(L) preparation will be resistant to gastric juice and in colon release bioactive agent. When described functional group is methacrylic acid (trimethyl amino-ethyl) ester moiety, described

(RL or RS) polymer be insoluble, permeable, dispersible and pH-independently. Therefore, these

The delay medicine that (RL or RS) polymer can be used for extended release preparation discharges.

Sell with various forms, for example solid-state form (

L100/S100/L-100-55，

E PO，

RL PO, Eudragit RS PO), particle (

E100，

RL 100/RS 100), dispersion (L 30 D-55/FS 30D 30%,

NE 30 D/40 D 30%/40% polymer content,

RL 30D RS 30 D 30%) and organic solution (

L 12.5，

E12.5，

RL 12.5/RS 12.5-12.5% organic solution).

When using the polymer of at least two kinds of melt-processed, a kind of preferably cellulose derivative, more preferably hydroxyalkyl cellulose derivative, with optional hydroxypropyl methylcellulose, and independently, another kind of polymer is (methyl) acrylate polymer (such as, any suitable Eudragit polymer) preferably. In the middle of (methyl) acrylate polymer, preferred polymer is Eudragit L and Eudragit RS in the context of the present invention. In the context of the present invention, a kind of preferred polymer is Eudragit RL. Described Eudragit polymer can be used in combination, and wherein the mixture of Eudragit RS and RL is preferred.

The people's (although indeliberately) who drinks a large amount of alcoholic beverage may significantly change the composition of gastric juice contained in the stomach when taking the medicine that the doctor opens, under extreme case, these gastric juice can comprise and be up to 40% alcohol. Advantageously, the optional mixture that comprises melt-processed of the embodiment of anti-abuse preparation of the present invention, this mixture is at least a abuse related drugs, at least a cellulose ether or cellulose esters, with at least a (methyl) acrylate copolymer, wherein be less than or equal to described medicine by 0.01 N hydrochloric acid, 1.5 times in the amount of 37 ℃ of medicines lower or that obtain 25 ℃ or both extractions in 1 hour by the amount of 20% ethanol water or 40% ethanol water or the medicine that the two extracted in 1 hour under 37 ℃ from described preparation. Anti-40% alcohol extract is favourable in those situations, and wherein individuality on purpose attempts to extract the abuse related drugs from contain the medicine of abusing related drugs.

Scheme experimental section below by 20% or 40% ethanol water or 0.01 N hydrochloric acid extraction provides respectively. The amount of the medicine that was extracted from described preparation by 20% or 40% ethanol water in 1 hour in a more preferred embodiment, is less than or equal to 1.5 times of amount of the medicine that was extracted from described preparation by 0.01 N hydrochloric acid in 1 hour. In also having preferred embodiment, the amount of the medicine that was extracted from described preparation by 20% or 40% ethanol water in 1 hour is less than or equal to the amount of the medicine that was extracted from described preparation by 0.01 N hydrochloric acid in 1 hour. In also having preferred embodiment, the amount of the medicine that was extracted from described preparation by 20% or 40% ethanol water in 1 hour is less than or equal to 0.9 times of amount of the medicine that was extracted from described preparation by 0.01 N hydrochloric acid in 1 hour.

The present invention also provides the extended release preparation of at least a abuse related drugs, when extraction is carried out solvent extraction by the available extraction solvent of general family, it hinders medicine to extract from described preparation, the available extraction solvent of described general family, such as isopropyl alcohol, distilled spirit, such as vodka, light-coloured vinegar, water and ethanol water (for example, 20% ethanol). Although said preparation is anti-solvent extraction substantially, it still provides sufficient medicine to discharge in aqueous solution such as gastric juice. When pulverizing or grind, in aqueous solution such as gastric juice, this preparation also provides sufficient medicine to discharge. Fortunately, in some preferred embodiment of the present invention, will 3 ounces a kind of, more than two kinds or three kinds or three kinds above listed family solvent, be no more than 15% from beginning standing time (namely 0 hour) to the amount of placing the abuse related drugs that discharged in 1 hour, greater than in same time, swallowing the quantity that discharges by the ordinary people, or be no more than 15% greater than 1 hour amount to the abuse related drugs that discharged in about 4 hours, the quantity that discharges when being swallowed by the ordinary people in same time perhaps both has.

The exemplary preferred composition of the present invention contains cellulose ether and cellulose esters, and it can be used singly or in combination in the present invention, has 50,000 to 1,250 the preferred molecular weight in 000 dalton's scope. Cellulose ether is preferably selected from alkylcellulose, hydroxy alkyl cellulose, hydroxyalkyl alkylcellulose or its mixture, for example ethyl cellulose, methylcellulose, hydroxypropyl cellulose (NF), hydroxyethylcellulose (NF) and hydroxypropyl methylcellulose (USP) or its combination. Useful cellulose esters is, but is not limited to cellulose acetate (NF), cellulose acetate-butyrate, cellulose acetate propionate, HPMCP, acetic acid Hydroxypropyl Methylcellulose Phathalate and composition thereof. Most preferably, can use non-ionic polyalcohol, such as hydroxypropyl methylcellulose.

Substituent quantity can represent by the substituent average that is attached on the described ring on the cellulosic anhydroglucose unit, this be the known concept of cellulose chemistry man " substitution value " (D.S.). If three available positions of all on each unit are substituted, this D.S. is called as 3 so, if on average two on each ring react, this D.S. is called as 2 etc. so.

In preferred embodiments, described cellulose ether has 1.3 to 2.0 alkyl substitution value and is up to 0.85 hydroxyalkyl mole replacement.

In preferred embodiments, the alkyl replacement is methyl. In addition, preferred hydroxyalkyl replacement is hydroxypropyl. The methoxyl group with various substitution values of these types-and propoxyl-substituent polymer sum up with title " Hypromellose " and list in the pharmacopeia, USP for example.

Methylcellulose can obtain with trade name METHOCEL A. METHOCEL A has the methyl (or methoxyl group) of 1.64 to 1.92 D.S.. The polymer of these types is listed in in title " methylcellulose " pharmacopeia, for example USP.

Particularly preferred cellulose ether is hydroxypropyl methylcellulose. Hydroxypropyl methylcellulose can trade name METHOCEL E obtains that (methyl D.S. about 1.9, the hydroxypropyl mole replaces about 0.23), (methyl D.S. about 1.8 for METHOCEL F, the hydroxypropyl mole replaces about 0.13), with METHOCEL K (methyl D.S. about 1.4, the hydroxypropyl mole replaces about 0.21). METHOCELF and METHOCEL K are the preferred hydroxypropyl methylcelluloses that uses in the present invention.

Described acrylate copolymer comprises homopolymers and copolymer (this term comprises the polymer that has greater than two different repeat units) suitably, and it comprises the monomer of acrylic acid and/or alkyl acrylic and/or (alkyl (alk)) alkyl acrylate. Term used herein " (alkyl) alkyl acrylate " refers to corresponding acrylate or alkyl acrylate, and it is made by corresponding acrylic acid or alkyl acrylic respectively usually. In other words, term " (alkyl) alkyl acrylate " refers to alkyl alkylacrylate or alkyl acrylate.

Preferably, described (alkyl) alkyl acrylate is ((C₁-C ₁₀) alkyl) acrylic acid (C₁-C ₂₂) Arrcostab. Be somebody's turn to do the C of (alkyl) alkyl acrylate₁-C ₂₂The example of alkyl comprises methyl, ethyl, n-pro-pyl, normal-butyl, isobutyl group, the tert-butyl group, isopropyl, amyl group, hexyl, cyclohexyl, 2-ethylhexyl, heptyl, octyl group, nonyl, decyl, isodecyl, undecyl, dodecyl, tridecyl, myristyl, pentadecyl, cetyl, heptadecyl, octadecyl, nonadecyl, eicosyl, docosyl and isomers thereof. This alkyl can be straight or branched. Preferably, should (C₁-C ₂₂) alkyl represents as defined above (C₁-C ₆) alkyl, more preferably represent as defined above (C₁-C ₄) alkyl. Be somebody's turn to do the C of (alkyl) alkyl acrylate₁-C ₁₀The example of alkyl comprises methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, amyl group, hexyl, cyclohexyl, 2-ethylhexyl, heptyl, octyl group, nonyl, decyl and isomers thereof. This alkyl group can be straight or branched. Preferably, should (C₁-C ₁₀) alkyl represents as defined above (C₁-C ₆) alkyl, more preferably represent as defined above (C₁-C ₄) alkyl.

Preferably, should (alkyl) alkyl acrylate be ((C ₁-C ₄) alkane) acrylic acid (C ₁-C ₄) Arrcostab, most preferably (methyl) acrylic acid (C ₁-C ₄) Arrcostab.Be appreciated that term (methyl) acrylic acid (C ₁-C ₄) Arrcostab is meant acrylic acid (C ₁-C ₄) Arrcostab or methacrylic acid (C ₁-C ₄) Arrcostab.(methyl) acrylic acid (C ₁-C ₄) example of Arrcostab comprises methyl methacrylate (MMA), ethyl methacrylate (EMA), n propyl methacrylate (PMA), isopropyl methacrylate (IPMA), n-BMA (BMA), isobutyl methacrylate (IBMA), metering system tert-butyl acrylate (TBMA), acrylic acid methyl ester. (MA), ethyl acrylate (EA), acrylic acid n-propyl (PA), n-butyl acrylate (BA), isopropyl acrylate (IPA), acryllic acid isobutyl ester (IBA), and combination.

Preferably, alkyl propenoic acid monomer is (C ₁-C ₁₀) alkyl acrylic.(C ₁-C ₁₀) example of alkyl acrylic comprises methacrylic acid, ethylacrylic acid, n-pro-pyl acrylic acid, isopropylacrylic acid, normal-butyl acrylic acid, isobutyl group acrylic acid, tert-butyl group acrylic acid, amyl group acrylic acid, hexyl acrylic acid, heptyl acrylic acid and isomer thereof.Preferably, described (C ₁-C ₁₀) alkyl acrylic is (C ₁-C ₄) alkyl acrylic, most preferably methacrylic acid.

In specific embodiment, alkyl can be replaced by aryl." alkyl " is meant straight chain, side chain or cyclic, saturated or undersaturated aliphatic hydrocarbon as used in this.Alkyl has 1-16 carbon, and can be unsubstituted or replaced that substituent group is selected from halogen, hydroxyl, alkoxy carbonyl group, acylamino-, alkyl amido, dialkyl group acylamino-, nitro, amino, alkyl amino, dialkyl amido, carboxyl, sulfo-and alkylthio group by one or more group." hydroxyl " is meant the OH group." alkoxyl " is meant--the O-alkyl, wherein alkyl is as defined above." sulfo-" is meant--the SH group." alkylthio group " is meant--the SR group, wherein R is an alkyl as defined above." amino " is meant--NH ₂Group." alkyl amino " is meant--the NHR group, wherein R is an alkyl as defined above." dialkyl amido " is meant--NRR ' group, wherein R and R ' are all basic as defined above." acylamino-" is meant--CONH ₂" alkyl amido " be meant-the CONHR group that wherein R is an alkyl as defined above." the dialkyl group acylamino-" be meant-CONRR ' group that wherein R and R ' they are alkyl as defined above." nitro " is meant NO ₂Group." carboxyl " is meant the COOH group.

In specific embodiment, alkyl can be replaced by aryl.As used in this, " aryl " comprises isocyclic and heterocyclic aromatic ring, and be monocyclic and condensed multi-ring, and wherein said aromatic ring can be 5-or 6-unit ring.Representational monocyclic aryl includes, but not limited to phenyl, furyl, pyrrole radicals, thienyl, pyridine radicals, pyrimidine radicals, oxazolyl, isoxazolyl, pyrazolyl, imidazole radicals, thiazolyl, isothiazolyl etc.The fused polycycle aryl is those following aromatic groups: it comprises that in the condensed ring system 5-or 6-unit's aromatic series or heteroaromatic ring are as one or more rings.Representational fused polycycle aryl comprises naphthalene, anthracene, indolizine, indole, iso-indoles, benzofuran, benzothiophene, indazole, benzimidazole, benzothiazole, purine, quinoline, isoquinolin, cinnolines, phthalazines, quinazoline, quinoxaline, 1,8-naphthyridines, pteridine, carbazole, acridine, azophenlyene, phenothiazine, phenoxazine and azulene.Equally as used in this, aryl also comprises aralkyl.In addition, as used in this, " aralkyl " is meant the part that aromatic series wherein is connected with alkyl, as benzyl.

Preferably, acrylate copolymer is an acrylic copolymer.Preferably, acrylic copolymer comprises derived from (alkyl) alkyl acrylate as defined above, and/or the monomer of acrylic acid and/or alkyl acrylic.Most preferably, acrylic copolymer comprises and derives from (alkyl) alkyl acrylate monomer, that is, but copolymerization alkyl acrylate and alkyl alkylacrylate monomer as defined above.Especially preferred acrylic copolymer comprises acrylic acid (C ₁-C ₄But) alkyl ester monomer and copolymerization (C ₁-C ₄) alkyl acrylic (C ₁-C ₄) the Arrcostab comonomer, but the copolymer that particularly forms by the comonomer of the acrylic acid methyl ester. of methyl methacrylate and copolymerization and/or ethyl acrylate and/or n-butyl acrylate.

Preferably, (methyl) acrylate copolymer is ion-type (methyl) acrylate copolymer, particularly cationic (methyl) acrylate copolymer.Ion-type (methyl) acrylate copolymer is made with neutral (methyl) acrylic monomers combined polymerization by (methyl) acrylic monomers that will carry ion radical.Described ion radical is quaternary ammonium group preferably.

(methyl) acrylate copolymer is normally water-fast, but is expandable and permeable in aqueous solution and Digestive system.Cation group is the water-permeability of the described preparation of control with the mol ratio of neutral (methyl) acrylate.In preferred embodiments, described (methyl) acrylate copolymer is the mixture of copolymer or copolymer, and the mol ratio of wherein said cation radical and neutral (methyl) acrylate is on average within about 1: 20 to 1: 35 scope.By selecting suitable cationic (methyl) acrylate copolymer of buying, or, regulate this ratio by cationic (methyl) acrylate copolymer is mixed with neutrality (methyl) acrylate copolymer of suitable quantity.

Suitable (methyl) acrylate copolymer is available from Rohm Pharma, and its commodity are called Eudragit, preferred Eudragit RL and Eudragit RS.Eudragit RL and Eudragit RS are the copolymers of the quaternary ammonium group of acrylate and methacrylate and low content, and ammonium is 1: 20 in Eudragit RL and is 1: 40 in Eudragit RS with the mol ratio of neutral (methyl) acrylate of residue.This mean molecule quantity is about 150,000.

Except that (methyl) acrylate copolymer, acceptable polymer scale on the more materia medica can be incorporated in the preparation of the present invention, with performance of regulating said preparation and/or the easiness of improving its manufacturing.These polymer can be selected from: the homopolymer of N-vinyl lactam, especially polyvinylpyrrolidone (PVP), N-vinyl lactam and one or more can with the copolymer of the comonomer of its copolymerization, described comonomer is selected from nitrogen containing monomer and contains the oxygen monomer; Especially the copolymer of N-vinyl pyrrolidone and vinyl esters of carboxylic acids, preferred embodiment is the copolymer of N-vinyl pyrrolidone and vinyl acetate or the copolymer of N-vinyl pyrrolidone and vinyl propionate base ester; Polyvinyl alcohol-polyethylene glycol-graft copolymer (for example, with IR is by BASFAG, Ludwigshafen, Germany obtains); The polyphosphazene polymer oxyalkylene is as the copolymer of polyethylene glycol oxide and polypropylene oxide and ethylene oxide and propylene oxide; Polyacrylamide; Vinyl acetate polymer, as, the copolymer of vinyl acetate and .beta.-methylacrylic acid, the polyvinyl acetate of partial hydrolysis (being also referred to as partly-hydrolysed " polyvinyl alcohol "); Polyvinyl alcohol; Gather (hydroxy acid), as poly-(lactic acid), poly-(hydroxyacetic acid), poly-(3-hydroxybutyric acid) and poly-(3-hydroxybutyric acid-be total to-the 3-hydroxypentanoic acid); Or its one or more mixture.PVP produces hydrocodone N-oxide in extrusion, therefore, preferably do not use usually the PVP-polymer and-copolymer.Yet, when using the antioxidant of a small amount of (the total preparation of 0.2-0.6%w/w), so preferably use PVP.

" abuse related drugs " is used for being meant that its distribution is subjected to any biology of the effective ingredient of administrative organization's restriction.The Drug abuse that can be used to prepare includes but not limited to pseudoephedrine, antidepressants, strong beta stimulant, meals medicine, steroidal and NSAID (non-steroidal anti-inflammatory drug) in the context of the present invention.In the classification of strong beta stimulant, dexoxyn is a kind of medicine of generally being paid close attention to recently as Drug abuse.At present, also there are some concerns in the abuse potential to atropine, hyoscyamine, phenobarbital, scopolamine etc.The abuse related drugs of another main type is an analgesic, especially opioid.

Term " opioid " is meant a kind of material, comprises agonist, antagonist or mixes agonist-antagonist, and it reacts by endogenous opioid peptide such as the bonded acceptor site of enkephalin, endorphins and dynorphin with one or more.Opioid comprises, but be not limited to, alfentanil, allylprodine, alphaprodine, anileridine, the benzyl morphine, bezitramide; buprenorphine; butorphanol; Clonitazene; codeine; cyclazocine; dihydrodesoxymorphine; dextromoramide; dezocine; diampromide; paracodin; paramorphane; dimenoxadol; dimepheptanol; dimethylthiambutene; dioxaphetyl butyrate; dipipanone; eptazocine; ethoheptazine; ethylmethylthiambutene; ethylmorphine; etonitazene; fentanyl; heroin; hydrocodone; hydromorphone; hydroxypethidine; isomethadone; ketobemidone; levallorphan; levophenacylmorphan; levorphanol; Lofentanil; dolantin; meptazinol; metazocine; methadone; metopon; morphine; Myrophine; nalbuphine; narceine; nicomorphine; norpipanone; Opium; oxycodone; oxymorphone; papvretum; pentazocine; Phenadon-X; phenazocine; phenomorphan; phenoperidine; Piminodine; disopyramide; dextropropoxyphene; sufentanil; tilidate and tramadol, and salt and mixture.

In some preferred embodiments, preparation of the present invention comprises at least a other medicine.In a more preferred embodiment, other medicine can be, but be not limited to, be selected from non-steroidal, non-opium sample analgesic, and optional acetaminophen, aspirin, fentaynl, ibuprofen, indomethacin, ketorolac, naproxen, Phenacetin, piroxicam, sufentanil, Su Lin acid and the interferon-ALPHA of further being selected from.Particularly preferably be under the suitable supervision of country administrative organization the drug regimen that those are sold the public with the fixed dosage combining form at present as (for example) Food and Drug Administration.These medicines include but not limited to hydrocodone and acetaminophen (fixed dosage) combination, or (fixed dosage) of hydrocodone and ibuprofen combination.

One or more abuse related drugs preferably are dispersed in the substrate, and this matrix optimization forms by other optional components of cellulose ether or cellulose esters and a kind of acrylic or methacrylic acid polymer and described preparation.This description also is used for being included in the short grained system of having of matrix phase Chinese medicine, typically less than 1 μ m diameter.These system preferences do not contain the active opioid component with its crystal or crystallite form of significant quantity, and it analyzes (DSC) by heat or X-ray diffraction analysis (WAXS) proves.At least 98% (weight) of medicine total amount preferably exists with amorphous state.If other non-abuse related drugs active matter such as acetaminophen are present in the preparation of the present invention in addition, so this one or more other pharmaceutical actives can be embedded in the described preparation with the crystalline state form.

When the dispersion of component be make system chemistry and physically whole be uniform or basic homogeneity or by a thermodynamics phase composition, such dispersion is called " solid solution ".The solid solution of abuse related activity thing is preferred.

Said preparation can also comprise one or more additives, and described additive is selected from sugar alcohol or derivatives thereof, maltodextrin; Acceptable surfactant, flowing regulator, disintegrating agent, filler and lubricant on the materia medica.Useful sugar alcohol illustrates by mannitol, Sorbitol, xylitol; Useful sugar alcohol derivant includes but not limited to that hydroxyl isomaltulose, hydrogenation concentrate isomaltulose and other similarly and not similar.

Acceptable surfactant acceptable nonionic surfactant on the materia medica preferably on the materia medica.For the substrate of the active component that contains poorly water-soluble and/or in order to improve the wettability of described preparation, the adding surfactant is especially preferred.Surfactant can be realized the moment emulsifying of the active component that discharges from dosage form, and prevents that active component from precipitating in gastrointestinal is liquid, aqueous.

Some additives comprise polyoxyethylene alkyl ether, for example, and polyoxyethylene (3) lauryl ether, polyoxyethylene (5) cetyl ether, polyoxyethylene (2) octadecyl ether, polyoxyethylene (5) octadecyl ether; The polyoxyethylene alkyl aryl ether, for example, polyoxyethylene (2) nonylplenyl ether, polyoxyethylene (3) nonylplenyl ether, polyoxyethylene (4) nonylplenyl ether or polyoxyethylene (3) octyl phenyl ether; Cithrol, for example, PEG-200 monolaurate, PEG-200 dilaurate, PEG-300 dilaurate, PEG-400 dilaurate, PEG-300 distearate or PEG-300 dioleate; The aklylene glycol fatty-acid monoester, for example, PGML and dilaurate (

); Sucrose fatty acid ester, for example, sucrose monostearate, sucrose distearate, sucrose monolaurate or sucrose dilaurate; Sorbitan fatty acid list-and diester such as sorbitan monolaurate (

20), sorbitan monooleate, the sorbitan monopalmitate ( 40), or Sorbester P18, castor oil derivatives, for example, polyoxyethylene glycerol three ricinoleate esters or polyoxyl 35 Oleum Ricini (

EL; BASF Corp.) or polyoxyethylene glycerol oxygen base stearate such as Polyethylene Glycol 40 castor oil hydrogenated (

RH 40) or Polyethylene Glycol 60 castor oil hydrogenated (

RH 60); Or the block copolymer of ethylene oxide and propylene oxide, also claim polyoxyethylene polyoxypropylene block copolymer or polyoxyethylene polypropylene glycol as F68,

F127,

124, 188,

237, 388 or

407 (BASF Wyandotte Corp.); Or the mono fatty acid ester of polyoxyethylene (20) sorbitan, for example, polyoxyethylene (20) sorbitan monooleate (tween

80), polyoxyethylene (20) sorbitan monostearate (tween 60), polyoxyethylene (20) sorbitan monopalmitate (tween

40), polyoxyethylene (20) Sorbitan monolaurate (tween

20) etc., and two kinds, three kinds, four kinds, five kinds or multiple mixture.

Various other additives can be included in this fused mass, and for example, flowing regulator is as colloidal silica; Lubricant, filler, disintegrating agent, plasticizer, stabilizing agent are as the stabilizing agent of antioxidant, light stabilizer, free radical scavenger or antimicrobial attack.In addition, have the bitterness that produces by acetaminophen self, sweeting agent and/or flavoring agent etc. can be alleviated this bitterness as additive owing to contain the coating layer of acetaminophen.A kind of optimal way that alleviates bitterness is the other scumbling layer of cloth that does not contain acetaminophen.

Preparation of the present invention can obtain by any suitable melting method, for example adds hot pressing by use, and preferably prepares by melt extrusion.In order to obtain the medicine of uniform distribution and enough dispersion, during enough time of staying, the fused mass that will contain medicine remains in the thermotank of melt extruder.Fusion occurs in and carries out the transition to during liquid or the rubbery state, and wherein a kind of component might embed in another component equably.Fusion is usually directed to cellulose ether/ester or (methyl) acrylate copolymer are heated to more than the softening point.The preparation of fused mass can be carried out in every way.

Usually, this melt temperature in 70 to 250 ℃ scope, preferably at 80 to 180 ℃, most preferably 100 to 140 ℃.

When this melting method comprises melt extrusion, this fusion and/or mix and can in a device that is generally used for this purposes, carry out.Specially suitable is extruder or kneading machine.Suitable extruder comprises single screw extrusion machine, meshing spiral extruder and multi-screw extruder, preferred double screw extruder, and it can be common rotation or rotate in opposite directions and the optional kneading disc that is equipped with.Be appreciated that operating temperature also will be determined by the kind of configuration in the kind of extruder or the institute's use extruder.Can provide the required portion of energy of component in fusion, mixing and the dissolving extruder by heating element heater.Yet the friction of material and shearing also can make mixture have the energy of significant quantity in the extruder, and help to form the even molten mass of a component.

In another embodiment, the invention provides a kind of oral, sustained release forms, it is characterized in that, it has at least two following features: (a) by alcohol solvent, as 40% or 20% ethanol water or both, under 37 ℃ in 1 hour, stirring or not under the condition of stirring, the amount of the medicine that extracts from preparation is less than or equal under 37 ℃, in 1 hour, and 1.5 times of the amount of the medicine that from preparation, extracts by 0.01N hydrochloric acid, (b) the anti-sled of this dosage form and in 150 newton, preferred 300 newton, more preferably 450 newton more preferably do not have fragmentation under 500 Newton force again, as surveying by " Pharma Test PTB 501 " hardness-testing device, (c) in extracorporeal dissoluting test and optional body in the solubility test (that is, in animal or human's the digestive tract) was at 30 minutes, in first hour or the preceding two hours processes, this dosage form discharges at least 15%, more preferably 18% and optional 24% medicine, and be no more than 45%, more preferably 38% and optional 34% medicine.Although do not wish to be subjected to the constraint of any particular theory, think by in preparation, providing high drug loading to realize the high initial rate of release of acetaminophen from preparation.For the drug loading of single-activity component, as acetaminophen, in some embodiments of preparation of the present invention, can be greater than about 60%, 70%, 75%, 80%, 85% weight.The drug loading of acetaminophen can be limited to 80%.

The preferred embodiment of this dosage form is integral form or solid solution.Term " integral body " is derived from the root of the meaning for " single " and " stone ".Integral form or solid preferably have the size of one dimension at least greater than 5mm.In whole implementation scheme of the present invention, the abuse related drugs preferably is contained in single solid or the single solid solution.This integrated solid or solid solution can choose wantonly with other material outer coatings or with other material mixing.These other materials preferably do not contain the abuse related drugs of significant quantity, and these materials are preferred in vivo or at external dissolving or the rate of dispersion that has no significant effect this abuse related drugs.In the external and/or body of this one or more abuse related drugs rate of release after about first hour preferred substantial constant at least about 6,8,10,12 or 16 hours.Therefore, embodiment of the present invention provide a kind of single-phase pharmaceutical preparation, and it can change, so that breaking of one or more abuse related drugs to be provided, make its treatment level that in the blood of patient or animal, reaches medicine fast, and keep providing therapeutic dose at least about 8,12 or 24 hours.In addition, this pharmaceutical preparation preferably be suitable for repeating every day to give the human or animal once, twice or three times.

Advantageously, the preferred embodiment of the dosage form of the present invention abuse related drugs that discharges entire quantity basically is mixed in this dosage form.For example, in extracorporeal dissoluting test, in about 16 hours, and in optional 12 or 9 hours, can change dosage form of the present invention to give greater than 90% this medicine of preferred 95%.This accumulates haemoconcentration, or AUC, can not directly know by the time that from said preparation, discharges at 90% medicine, but, when this pharmaceutical preparation discharges all abuse related drugs basically in the part digestive tract, wherein said part digestive tract can reach higher AUC/mg abuse related drugs usually with drug absorption in patient's (or animal) blood system.

In another preferred embodiment of the present invention, the invention provides a kind of manufacture method of abuse resistant drugs dosage particles, this method comprises the preparation that melt extrusion comprises at least a medicine, and comprises that with the extrudate direct forming be a kind of dosage form, does not have (centre) grinding steps.This melt extrusion thing preferably comprises cellulose derivative, and preferably comprises the Eudragit polymer.Preferred Eudragit polymer comprises Eudragit L or Eudragit RS or both, and particularly preferably is the combination of Eudragit RL or Eudragit RL and Eudragit RS.

This molten mass can be at pasty state to heavy-gravity scope.Before this molten mass was solidified, this molten mass was chosen wantonly and be can be shaped as in fact any required shape.Easily, the shaping of this extrudate is optional can be undertaken by calender, this calender preferably have two that rotate in opposite directions, at their the surface cylinder depressed of coupling mutually.By the cylinder that uses the band various forms to depress, can obtain the tablet form of wide region.Perhaps, this extrudate can be cut into fragment, perhaps before curing (" thermal cutting ") or (" cold cut is cut ") after the curing or use in the mold ejector method.The melting method that relates to hot pressing randomly can also be rolled.

The molten mass of this shaping can be chosen the medicine with abuse potential of using material outer coatings, described material not to contain significant quantity wantonly.For example, the whole dosage form that contains Drug abuse can be carried out outer coatings with another layer of colored coating, swallow auxiliary agent or pharmaceutically acceptable material.The stacked material that is placed on this integral form does not preferably have significantly to change the rate of release of active component in the dosage form.

In order to help this dosage form to be absorbed by mammal, it is favourable that dosage form is made suitable shape.Therefore, the bolus that can be swallowed comfily is preferably microscler rather than circular in shape.

Film coating on the dosage form further promotes it easily to be swallowed.Film coating also improves taste and exquisite outward appearance is provided.If desired, film coating can be a casing.Film coating generally includes the polymerization film formation material, as hydroxypropyl emthylcellulose, hydroxypropyl cellulose and acrylate or methacrylate copolymer.Remove the film-forming polymer beyond the region of objective existence, film coating can also comprise plasticizer, for example, Polyethylene Glycol, surfactant, for example,

Type, and optional pigment, for example, titanium dioxide or iron oxides and/or sweeting agent or flavoring agent.Film coating can also comprise Pulvis Talci as antitack agent.Film coating accounts for this formulation weight less than about 5% usually.

Exemplary of the present invention:

The specific exemplary of the present invention provides for easy water-soluble medicine has the whole dosage formulation of two stage release characteristics, and this medicine has by extruding and roll the tablet that contains polymer of production.Said preparation preferably has the combination of discharging immediately of hydrocodone and acetaminophen compositions and controlled release formulation.These whole dosage formulation especially have anesthetics, can have abuse and hinder characteristic, make the medicine dissolution of dosage form in 40% ethanol water solution, have reduction/minimum doses dumps.Again more preferably, these preparations provide reproducible manufacture method, provide and have been transferred to large-scale selection fast.

Can obtain two stage medicine dissolutions of required acetaminophen, keep whole dosage form by active component (acetaminophen) is embedded in two preparations with different release rates simultaneously, then these two preparations be mixed producing two-layer or multilayer tablet.The method that is applicable to this purpose comprises the coextrusion method that multilayer tablet is produced that is used for described in the EP0857062, especially for the extrudate dosage form.A shortcoming of this technology is to move two extruders simultaneously, and their quality and volume flow must cooperate with very big accuracy.Especially in calender, during with the tablet molding, two fused mass must be mixed with the point-device ratio of each self-sustaining, to guarantee to comply with pharmacopeia (for example, USP, Ph.Eur.) the inclusions homogeneity requirement of the test shown in and tablet.This needs high-caliber effort.

Also can in the tablet that separates, make the acetaminophen part of rapid release, in calender line, it be mixed in the static plasticity fused mass of slow release drug moiety then.After the cooling, obtain the tablet of extruding of calendering, it contains the separately rapid release composition of embedding.Such dosage form is described in US 6,001, in 391, especially for extruding dosage form.The acetaminophen tablet that a shortcoming of this method is a rapid release must very accurately be introduced independent calender intracavity, is wrapped up by fused mass fully to prevent it.Have only when the acetaminophen composition of this rapid release is located immediately at tablet surface, could enough partly begin medicine dissolution from this tablet that separates apace during contacting hydrous medium.

Can also obtain the acetaminophen composition of rapid release in the tablet by the film coating that use contains acetaminophen.The treatment of extruding dosage form of film coated has description in various patent applications.Yet these patent applications have been described and have specially been designed the film coating that contains medicine and realize two stage medicine dissolutions.Use is according to patent application 11/625,705 and the result of the clinical research of extruding dosage form that produces of PCT/US07/60864 show that about 20% acetaminophen that contains in the tablet must change into quick-release formulation (for example to realize two required stage medicine dissolutions, behind the 1h＞about 30%, behind the 8h＞about 80%).Use total about 500mg acetaminophen content/tablet, mean that the acetaminophen of about 100mg must obtain rapid release.It is difficult that the active component of 100mg rapid release form is applied on the tablet, and only when satisfying following particular requirement ability possible:

The amount of the medicine of film-coated preparation must be very high, makes each layer can not become too sticking.

Be used for film-coatedly containing medicine solution or dispersion must have very high concentration, to avoid and to make method uneconomic long process time in addition.

Even when having big layer thickness, the film coating layer also should give enough mechanical stabilities, must not glue etc., and must be enough pliable and tough, does not break even also produce when having thick-layer.Also must guarantee extruding the lip-deep good adhesion of nuclear.

When using thick-layer, also should be (maximum approximately in preferred embodiments 1h) fast from film-coated medicine dissolution.

Use big bed thickness and store in the process of time expand section under the temperature, height or the low-down relative humidity that raise or its combination, the organoleptic attribute of film coating layer must not have big change (that is, the fragmentation of no coating, adhesion, chip etc.) yet.

Surprisingly, if had been found that now when the suitable water solublity of the acetaminophen of fine grinding and relatively small amount or water-swelling polymer one be used from the film coating layer, can satisfy above-mentioned requirements.Found to obtain such preparation with high activity component content, even and the viscosity of spray solution is obviously low when surpassing the very high total solids content of 30% weight, and can use thick film coating layer (200 microns or more) in the short relatively time, the method that makes thus is economical.In the layer that contains above the 100mg acetaminophen, medicine dissolution also is enough fast.

Therefore, can control point-device content of the acetaminophen of spraying and therefore can also control medicine dissolution feature (that is, in the process of first hour) by film-coated bed thickness.

Another surprising discovery is that the membrane according to the invention coated preparation can make the rough surface of the extruding tablet cunning that flattens very effectively, that is, film coating has sealed the impression on tablet surface very effectively.Also do not plan to have this special characteristic in view of in fact nearly all film coating of buying and the polymer that is used to produce do not have, so this is surprising.Known polymer and film-coated preparation design are reproduced one by one embossing element (logos etc.) and geosutures one by one.In other words, it is unwanted being present in conventional " filling " of making the recess in the tablet especially, and will definitely avoid (referring to, WO2006/002808; At this with particular reference to this situation among all embodiment, referring to embodiment 4, p18: " embossing is fully reproduced, and does not have smearing and bridging effect ").

The soluble polymer that is used to make film-coated preparation is an acceptable polymer on the water miscible and water-swollen materia medica, and it has been used for film-coated preparation so far.The basis require be produce sprayable, preferred pure aqueous solution or suspension, it has the total solids content (=all summations dissolved or component that suspends comprise active component) of at least 20% weight (preferred 25%, preferred especially 30% or more).The total solids content of solution or dispersion also must have at least 50% active component content (preferred 60%, preferred especially 70% or higher).If use acceptable solvent such as ethanol on nontoxic, the materia medica, non-aqueous solution or suspension also are fine.The mixture of these organic solvents and water also is fine.Yet, usually, preferred pure aqueous solution or suspension.

Even particularly preferably be the polymer that under high concentration, in aqueous solution, forms suitable low viscosity solution, maintain in certain scope with viscosity spray solution, in this scope,, still guarantee the spraying the accepted behavior of solution or suspension even when using above-mentioned high total solids content.Suitable polymers comprises: the non-ionic cellulose polymer, and as hydroxypropyl cellulose, hydroxypropyl emthylcellulose, hydroxyethyl-cellulose; The cation methacrylate, as

E, NE30D,

RL,

RS; Polyvinyl alcohol; The poly(ethylene oxide) macromolecule polyethylene glycol of 100,000 molecular weight (MW) (have＞); Polyvinyl alcohol/poly(ethylene oxide) graft copolymer (

IR).Preferably, suitable polymers be selected from hydroxypropyl emthylcellulose,

NE30D and polyvinyl alcohol, or its combination.More preferably, suitable polymers is that polyvinyl alcohol/the poly(ethylene oxide) graft copolymer (for example,

IR, BASF).

Active component is (preferred: acetaminophen) must be with above-mentioned high concentration in water-soluble or water/organic or pure organic solvent.If (as using acetaminophen) water solublity is not enough, preferably also can use drug suspension or dispersion.Yet in this case, determiner is that the particle size distribution of active component should be enough thin, because otherwise be disadvantageous, that is, the active component that has taken place to suspend in the spray solution precipitates too soon and/or the nozzle of film coating machine gets clogged.Preferred particle diameter is: the granule that is no more than 10% (especially preferably being no more than 5%) is higher than 0.25mm, and the granule that is no more than 20% (especially preferably being no more than 10%) is higher than 0.1mm, and the granule that is no more than 35% (preferably being no more than 20%) is higher than 0.063mm.In order to obtain thinner particle diameter, can be with medicine pulverizing (dry grinding and wet grinding be suitable) in mill processes.

Surprisingly, found that the membrane according to the invention coatings is not only very good with tablet adhesion ground, and do not become fragile and become sticky, and do not demonstrated fragmentation, even under up to 60 ℃ elevated temperature in the storing process.There is not the disengaging of coatings and tablet core yet.

Various exemplary embodiments have below been described.It is for illustrative purpose that these embodiment are provided, and the scope of the present invention that not will be understood that their constrictions.

Embodiment 1: be used for the manufacturing of film-coated tablet

Will be by the acetaminophen of 61.8% weight, 12.6% weight

The hydroxypropyl emthylcellulose of the xylitol of RL, 12.6% weight, 6% weight (

K100), the hydroxypropyl emthylcellulose of 6% weight (

K100M) and 1.0% weight

The 200 uniform powder mixture of forming measure to co-rotating twin screw extruder (ZSK-40) and extrude uniform to produce, white fused mass band under about 140 ℃ temperature with 20kg/h.Although still be under the plasticity state, this fused mass band to be introduced in the counter-rotating forming rolls calender, this roller has indenture in its surface, can directly form tablet from the fused mass band from this roller.Resulting tablet has the average weight of 720mg after cooling and deburring.The surface of tablet is coarse and uneven in some place.

Embodiment 2:

To have 13% particle diameter and be higher than the acetaminophen that 0.25nm and 68% particle diameter be higher than 0.063nm and suspend in water by stirring.After cutting off blender, active component precipitates very apace.This suspension is pulverized and homogenizing by colloid mill.After milling, with pulverous polymer (

IR, BASF) add in this suspension (acetaminophen/ The mass ratio of IR=75: 25), to produce the total solid concentration of 30% weight.Even after adding polymer, acetaminophen still demonstrates tangible precipitation trend.Then in film coating machine (Driam) continuous stirring limit, limit with this suspension spray (6kg) on the tablet described in the embodiment 1.Use on the film coating 30,50,70 and the 90mg acetaminophen after, obtain tablet samples.

In all situations, observe coating and tablet and adhere to very goodly, although the tablet surface of pure white film coated is still slightly coarse owing to still big relatively acetaminophen granule.For form of ownership, with afterwards, the loss when tablet is dry is 1% weight before the film coating.

The film coating procedure parameter:

6kg tablet core

Drum speed: 12rpm

Air intake: 1200m ³/ h

Inlet temperature: 65 ℃

Spray rate: 40-45g/min

Atomisation pressure: 4,5 crust

Embodiment 3:

To have 1% particle diameter greater than 0.25mm by stirring, 5% particle diameter suspends in water greater than 0.1mm and the 16% particle diameter acetaminophen greater than 0.063nm.Compare with material used among the embodiment 2, behind the cut-out blender, active component demonstrates the precipitation trend of reduction.Then with solid polymer powder (

IR BASF) adds (acetaminophen/Kollicoat in this suspension

Mass ratio=75: 25), to produce the total solid concentration of 30% weight.After adding polymer, acetaminophen does not almost demonstrate sedimentary trend.Then in the film coating machine (Driam) with this suspension spray according to described in the embodiment 1 and produce but (6kg) on the tablet that tablet geometry slightly changes (technological parameter with embodiment 2 in the same).With 30,50,70,90 with after the 120mg acetaminophen is applied on the film coating, obtain tablet samples.The coating of observing in all situations on the tablet adheres to very good.The surface of pure white film coated tablet is smooth and uniform.

Embodiment 4: the medicine dissolution of tablet

(USP dissolver II (Paddle), USP XXV in officinal device according to US; 37 ℃, 0.01M HCl, 50rpm) mensuration is according to the medicine dissolution of the tablet of embodiment 1.Measure the content that is released into the active component the moisture HCl medium from tablet by HPLC at different intervals.

The tablet that does not have the applied film coating

The medicine dissolution of after 30 minutes, measuring: 7%

The medicine dissolution of after 60 minutes, measuring: 11%

The medicine dissolution of after 120 minutes, measuring: 17%

The medicine dissolution of after 240 minutes, measuring: 27%

Embodiment 5: the medicine dissolution of the tablet of film coated

(USP dissolver II (Paddle), USP XXV in officinal device according to US; 37 ℃, 0.01M HCl, 50rpm) mensuration is according to the medicine dissolution of the tablet of embodiment 2.Measure the content that is released into the active component the moisture HCl medium from tablet by HPLC at different intervals.

The tablet that in film coating, contains the film coated of 90mg acetaminophen

The medicine dissolution of after 30 minutes, measuring: 16%

The medicine dissolution of after 60 minutes, measuring: 20%

The medicine dissolution of after 120 minutes, measuring: 27%

The medicine dissolution of after 240 minutes, measuring: 36%

Owing to be present in the initial rapid release of active component in the film coating, improve about 10% in the medicine dissolution speed of each test interval.

Embodiment 6: the medicine dissolution of the tablet of film coated

(paddle method, USP XXV in officinal device according to US; 37 ℃, 0.01MHCl, 50rpm) mensuration is according to the medicine dissolution of the tablet of embodiment 3.Measure the content that is released into the active component the moisture HCl medium from tablet by HPLC at different intervals.

The tablet that does not have the applied film coating

The medicine dissolution of after 30 minutes, measuring: 7%

The medicine dissolution of after 60 minutes, measuring: 12%

The medicine dissolution of after 120 minutes, measuring: 19%

The medicine dissolution of after 240 minutes, measuring: 29%

The medicine dissolution of after 360 minutes, measuring: 37%

The medicine dissolution of after 480 minutes, measuring: 43%

The tablet that in film coating, contains the film coated of 120mg acetaminophen

The medicine dissolution of after 30 minutes, measuring: 28%

The medicine dissolution of after 60 minutes, measuring: 35%

The medicine dissolution of after 120 minutes, measuring: 43%

The medicine dissolution of after 240 minutes, measuring: 53%

The medicine dissolution of after 360 minutes, measuring: 62%

The medicine dissolution of after 480 minutes, measuring: 69%

Owing to be present in the initial rapid release of active component in the film coating, improve about 25% in the medicine dissolution speed of each test interval.

Embodiment 7:

Test according to embodiment 3, but substitute IR has used the solid triturate based on hydroxypropyl emthylcellulose, and it contains fraction ferrum oxide color pigment.Because aqueous suspension is higher viscosity obviously, and total solid concentration only is adjusted to 20% weight, consequently spray time increases, and other technological parameters remain unchanged simultaneously.The coating of observing on the tablet adheres to very good.Little red/smooth surface of brown film coated tablet and evenly.

Embodiment 8:

Test according to embodiment 3, but substitute

IR has used the solid triturate based on polyvinyl alcohol, and it contains fraction titanium dioxide pigment.Because the slightly high viscosity of aqueous suspension only is adjusted to 25% weight with total solid concentration, consequently spray time increases, and other technological parameters remain unchanged simultaneously.The coating of observing on the tablet adheres to very good.The smooth surface of pure white film coated tablet and evenly.

Embodiment 9:

To be stored in according to the thin film tablets of embodiment 3,7 and 8 manufacturings in the sealed glass jars under 40 ℃ and 60 ℃.After 1 month, observing does not have visible breaking on the tablet, not adhesion.Medicine dissolution by the measurement of the method described in the embodiment 4 shows and stores the value that writes down when beginning do not have variation.

Embodiment 10:

Tablet (90mg acetaminophen in the film coating) sampling of the film coated that will make according to embodiment 3, by microtome tablet laterally obtain thinly-sliced, and detect at microscopically.In image film coating easily and the tablet core make a distinction.Measuring film coating in image is about 300 microns.Wash coat suspension is obvious especially to the smoothing effect of coarse tablet surface, as also seeing from Fig. 1,3 and 4.

Embodiment 11: the dissolving in HCl and ethanol water

It below is the description of the illustrative methods of the rate of dissolution of research particular composition in HCl and 20% ethanol water.Similar methods can be used for studying the rate of dissolution at 40% ethanol water.

Following device and program are used for dissolving at 0.01N hydrochloric acid and 20/40% ethanol water:

(I) dissolving in 0.01N HCl

Device: USP dissolver II (Paddle)

Rotating speed: 50rpm

Medium: 0.01N HCl

Temperature: 37 ℃

Discharge the sample time of test for 30h: 30/60/120/180/240/360/420/480/600/720/840/1080/1320/1560/1800 minute

Sample volume: 10mL (no volume substitutes)

Sample is prepared: in statu quo use

Analyze and finish: UV detects, wavelength 280nm

(II) dissolving in 20% or 40% ethanol water

Device: USP dissolver II (Paddle)

Rotating speed: 50rpm

Medium: 20% or 40% ethanol water

Temperature: 37 ℃

Sample volume: 10mL (no volume substitutes)

Sample is prepared: in statu quo use

Analyze and finish: UV detects, wavelength 280nm

III. intact tablet test of the dissolving among the 0.01 N HCl under 37 ℃

A.) quick-release formulation (about acetaminophen) in 37 ℃ of following 0.01N HCl has been described in the Table X.Table I X has described the core of preparation 5 and the composition of external coating.

Table I X: preparation 5

Table X has been described the dissolution data of hydrocodone (X (a)) and acetaminophen (X (b))

Table X (a):

The hydrocodone drug release	In 0.01 N HCl
		Testing time point (min)	Average %

0 30 60 120 180 240 300 360 420 480 600 720 840 1080 1320 1560 1800

0 14 27 43 57 67 76 84 90 94 98 98 98 99 99 99 100

Table X (b)

The acetaminophen drug release	In 0.01 N HCl
		Testing time point (min)	Average %
0 30 60 120 180 240 300 360 420 480 600 720 840 1080 1320 1560 1800	0 33 39 46 56 64 71 78 85 90 98 100 101 100 100 100 100

B.) slow releasing preparation (about acetaminophen) in 37 ℃ of following 0.01N HCl has been described among the Table X II.Table X I has described the core of preparation 6 and the composition of external coating.

Table X I: preparation 6

The dissolution data of hydrocodone (XII (a)) and acetaminophen (XII (b))

Table X II (a)

The hydrocodone drug release	0.01 among the N HCl
		Testing time point (min)	Average %

0 30 60 120 180 240 300 360 420 480 600 720 840 1080 1320 1560 1800

0 17 31 46 57 67 75 82 88 91 96 97 98 99 99 99 100

Table X II (b)

The acetaminophen drug release	In 0.01 N HCl
		Testing time point (min)	Average %
0 30 60 120 180 240 300 360 420 480 600 720 840 1080 1320 1560 1800	0 34 41 47 51 56 60 65 68 71 76 80 84 89 100 100 100

IV. intact tablet test of the dissolving in 40% ethanol water under 37 ℃

A.) slow releasing preparation (about acetaminophen) in 40% ethanol water under 37 ℃ has been described among the Table X IV.Table X III has described the core of preparation 5 and the composition of external coating.

Table X III: preparation 5

Table X IV has described the dissolution data of hydrocodone (XIV (a)) and acetaminophen (XIV (b)).

Table X IV (a):

The hydrocodone drug release	In 40%EtOH
		Testing time point (min)	Average %

0 30 60 120 180 240 300 360 420 480 600 720 840 1080 1320 1560 1800

0 15 33 56 77 90 97 97 97 98 98 99 100 98 99 99 100

Table X IV (b)

The acetaminophen drug release	In 40%EtOH
		Testing time point (min)	Average %
0 30 60 120 180 240 300 360 420 480 600 720 840 1080 1320 1560 1800	0 31 51 67 82 93 98 99 101 101 101 101 101 101 101 101 102

B.) slow releasing preparation (about acetaminophen) in 40% ethanol water under 37 ℃ has been described among the Table X VI.Table X V has described the core of preparation 8 and the composition of external coating.

Table X V: preparation 8:

Table X VI has described the dissolution data of hydrocodone (XVI (a)) and acetaminophen (XVI (b))

Table X VI (a):

The hydrocodone drug release	In 40%EtOH
		Testing time point (min)	Average %
0 30 60 120 180 240 300 360 420 480 600 720 840 1080 1320 1560 1800	0 12 24 38 51 62 72 80 85 91 96 99 100 100 102 101 100

Table X VI (b)

The acetaminophen drug release	In 40%EtOH
		Testing time point (min)	Average %
0 30 60 120 180 240 300 360 420 480 600 720 840 1080 1320 1560 1800	0 23 38 47 57 65 73 80 84 90 94 98 100 100 101 101 102

V. ground tablet (coffee mill 60sec) descends in 40% ethanol waters at 37 ℃ The dissolving test

In the domestic coffee mill ,～20,000-50 extrudes tablet with 3 under the 000rpm and grinds 60sec.Collect powder, and the powder transfer that will equate content with a slice tablet is used for discharging test to the dissolving bottle.

For the granularmetric analysis of working sample, collect powder and sieve by screen cloth with 355 μ m orders footpath.To sieve once more by screen cloth by the material of screen cloth with 63 μ m orders footpath.Obtain following part:

Part 1: particle diameter＞355 μ m (～powder total amount 20%)

Part 2: particle diameter＞63 μ m and＜355 μ m (～powder total amount 66%)

Part 3: particle diameter＜63 μ m (～powder total amount 14%)

A.) quick-release formulation (about acetaminophen) in 40% ethanol water under 37 ℃ has been described among the Table X VII.Below described the dissolution data of hydrocodone (XVII (a)) and acetaminophen (XVII (b)).

Table X VII (a):

The hydrocodone drug release	In 40%EtOH
		Testing time point (min)	Average %

0 30 60 120 180 240 300 360 420 480

0 56 75 92 99 101 101 100 101 100

Table X VII (b):

The acetaminophen drug release	In 40%EtOH
		Testing time point (min)	Average %
0 30 60 120 180 240 300 360 420 480	0 51 69 87 94 97 97 97 97 97

B.) slow releasing preparation (about acetaminophen) in 40% ethanol water under 37 ℃ has been described among the Table X VIII.Below described the dissolution data of hydrocodone (XVIII (a)) and acetaminophen (XVIII (b)).

Table X VIII (a):

The hydrocodone drug release	In 40%EtOH
		Testing time point (min)	Average %

0 30 60 120 180 240 300 360 420 480

0 42 56 74 84 91 96 98 100 100

Table X VIII (b):

The acetaminophen drug release	In 40%EtOH
		Testing time point (min)	Average %
0 30 60 120 180 240 300 360 420 480	0 33 45 62 73 80 84 87 88 89

VI. the dissolving test of intact tablet in 4 ℃ of following 0.01N HCl

A.) quick-release formulation (about acetaminophen) among the 0.01 N HCl under 4 ℃ has been described among the Table X IX.Below described the dissolution data of hydrocodone (XIX (a)) and acetaminophen (XIX (b)).

Table X IX (a):

The hydrocodone drug release	In 0.01 N HCl
		Testing time point (min)	Average %

0 30 60 120 180 240 300 360 420 480

0 0 5 15 24 30 36 42 45 49

Table X IX (b):

The acetaminophen drug release	In 0.01N HCl
		Testing time point (min)	Average %
0 30 60 120 180 240 300 360 420 480	0 16 23 30 34 36 39 41 43 44

B.) slow releasing preparation (about acetaminophen) in 4 ℃ of following 0.01N HCl has been described among the Table X X.Below described the dissolution data of hydrocodone (XX (a)) and acetaminophen (XX (b)).

Table X X (a):

The hydrocodone drug release	In 0.01N HCl
		Testing time point (min)	Average %

0 30 60 120 180 240 300 360 420 480

0 2 8 17 23 28 32 37 41 44

Table X X (b):

The acetaminophen drug release	In 0.01N HCl
		Testing time point (min)	Average %
0 30 60 120 180 240 300 360 420 480	0 13 17 21 24 26 28 30 31 33

VIII. surface roughness

The coating of extruding tablet causes tablet surface obviously level and smooth, as appreciable in Fig. 1:

In order to measure the variation of surface roughness, along minor axis will be coated with and uncoated tablet in two.The surface of this cross section is ground, to obtain level and smooth surface.Use the light micrograph of cross section to measure average surface roughness.In order to analyze, as shown in Figure 2, used centrage meansigma methods method (CLA), wherein measured average height/the leave unit length of centrage.Centrage is placed microphotograph, make online and offline area about equally.

According to following equation, use the sample of even interval location to calculate CLA:

CLA = R_{a} = \frac{Σh}{n} = \frac{h_{1} + h_{2} + . . . + h_{n}}{l}

Length overall 1 is 4.69nm, and the distance between the increment is 68 μ m.For uncoated preparation, in the time of (N=69), CLA=0.56, as shown in Figure 3.And for the preparation that is coated with, in the time of (N=69), CLA=0.15, as shown in Figure 4.

IX. for the dissolving of intact tablet in 37 ℃ of following 0.01N HCl of different coating thickness Test

A.) among Table X XII and the XXIII slow releasing preparation (about acetaminophen) in 37 ℃ of following 0.01N HCl has been described for different preparation 9-12.Described the composition of preparation among the Table X XI.

Table X XI:
					Preparation	Preparation 9	Preparation 10	Preparation 11	Preparation 12
Form coating	60 % acetaminophen 12,6% Eudragit RL- PO 6,0%Hypromellose Ph.Eur.USP 2208 Type V 100 (Methocel K100) 6,0% Hypromellose Ph.Eur.2208 Type V, 20000 (Methocel K100M) 12,6% xylitol Ph. Eur./NF Typ Xylisorb, 90 1,8% hydrocodone 1%Aerosil 200Ph. Eur./NF	60 % acetaminophen 12,6%Eudragit RL- PO 6,0%Hypromellose Ph.Eur.USP 2208 Type V 100 (Methocel K100) 6,0% Hypromellose Ph.Eur.2208 Type V, 20000 (Methocel K100M) 12,6% xylitol Ph. Eur./NF Typ Xylisorb 90 1,8% hydrocodone, 1% Aerosil, 200 Ph. Eur./NF 50,0mg acetaminophen 16,0mg Kollicoat IR	60 % acetaminophen 12,6%Eudragit RL- PO 6,0%Hypromellose Ph.Eur.USP 2208 Type V 100 (Methocel K100) 6,0%Hypromellose Ph.Eur.2208 Type V 20000 (Methocel K100M) 12,6% xylitol Ph. Eur./NF Typ Xylisorb 90 1,8% hydrocodone, 1% Aerosil, 200 Ph. Eur./NF 85,0mg acetaminophen 27,2mg Kollicoat IR	60 % acetaminophen 12,6%Eudragit RL- PO 6,0%Hypromellose Ph.Eur.USP 2208 Type V 100 (Methocel K100) 6,0%Hypromellose Ph.Eur.2208 Type V 20000 (Methocel K100M) 12,6% xylitol Ph. Eur./NF Typ Xylisorb 90 1,8% hydrocodone, 1% Aerosil, 200 Ph. Eur./NF 120,0mg acetaminophen 38,39mg Kollicoat IR
					Gross weight	833mg	899mg	945,2mg	991,39mg

Table X XII:
					The hydrocodone drug release	Preparation 9	Preparation 10	Preparation 11	Preparation 12
Test point (min)	Average %	Average %	Average %	Average %
					?0?30?60?120?180?240?300?360?420?480	0 21 30 42 51 58 64 69 74 78	0 20 30 43 53 60 67 72 77 81	0 19 30 44 54 62 68 74 79 83	0 16 28 43 53 61 67 73 78 82
Table X XIII:
					The acetaminophen drug release	Preparation 9	Preparation 10	Preparation 11	Preparation 12
Test point (min)	Average %	Average %	Average %	Average %

0 30 60 120 180 240 300 360 420 480

0 7 11 17 22 26 30 33 36 39

0 15 19 25 29 33 36 39 42 45

0 19 23 29 33 37 40 42 45 48

0 22 26 32 36 40 43 45 48 51

X. there be not the dissolving test of intact tablet in 37 ℃ of following 0.01N HCl of coating

A.) quick-release formulation (about acetaminophen) in 37 ℃ of following 0.01N HCl has been described among the Table X XV.Table X XIV has described the composition of the core of preparation 13.

Table X XV: preparation 13

The dissolution data of hydrocodone (XXV (a)) and acetaminophen (XXV (b)) has below been described:

Table X XV (a):

The hydrocodone drug release	In 0.01N HCl
		Testing time point (min)	Average %
0 30 60 120 180 240 300 360 420 480 600 720 840 1080 1320 1560 1800	0 28 38 50 62 72 80 88 95 98 100 98 97 97 97 97 98

Table X XV (b):

The acetaminophen drug release	In 0.01N HCl
		Testing time point (min)	Average %
0 30 60 120 180 240 300 360 420 480 600 720 840 1080 1320 1560 1800	0 13 19 27 41 54 66 79 88 95 105 106 104 104 104 104 104

B.) slow releasing preparation (about acetaminophen) in 37 ℃ of following 0.01N HCl has been described among the Table X XVII.Table X XVI has described the composition of the core of preparation 13.

Table X XVI: preparation 14

The dissolving religion certificate of hydrocodone (XXVII (a)) and acetaminophen (XXVII (b)) has below been described:

Table X XVII (a):

The hydrocodone drug release	In 0.01N HCl
		Testing time point (min)	Average %
0 30 60 120 180 240 300 360 420 480 600 720 840 1080 1320 1560 1800	0 30 42 54 65 72 79 88 94 96 99 101 100 100 100 100 100

Table X XVII (a):

The acetaminophen drug release	In 0.01N HCl
		Testing time point (min)	Average %

0 30 60 120 180 240 300 360 420 480 600 720 840 1080 1320 1560 1800

0 11 17 25 31 36 42 48 53 56 63 69 74 91 99 104 103

Embodiment 12: the compare test preparation is with respect to the bioavailability of contrast

The purpose of research be two kinds of test formulation 15 of comparison and 16 with reference to the bioavailability that contrasts tablet.Research design comprise the single dose of 21 individualities, fast, open label, three stages, crossing research.Option A comprises a tablet preparation 15; Option b comprises a tablet preparation 16; Scheme C comprises a slice contrast 1.When research 0,0.25,0.5,0.75,1,2,3,4,6,8,10,12,16,24,36 and 48 hour after the administration in the 1st day, collect blood sample.Following table XXVIII has illustrated test formulation 15,16 and has contrasted 1 composition.Can also be referring to Fig. 5 and 6, this is preparation 15,16 and contrasts 1 average hydrocodone and acetaminophen concentration.Preparation 5,7 and 15 is mutually the same basically, yet, based on the different numberings of test, with they different numberings with experiment.Similarly, preparation 6,8 and 16 is mutually the same basically, yet, based on the different numberings of test, with they different numberings with experiment.Also similar is, contrast 1 and 2 is mutually the same basically, yet, based on the different numberings of test and experiment, with their different numberings.In one embodiment of the invention, preferred dosage form is a preparation 15, because preparation 15 provides than preparation 16 better mixing characteristics, is not always the case for the mixing of Hycodan five semihydrates and HPMC and the mixing of all the components.In addition, preparation 15 mixture provide than preparation 16 and have better flowed to characteristic in the extruder.In addition, preparation 15 provides than preparation 16 better straight forming characteristics, because preparation 15 does not have preparation 16 sticking.In addition, expection preparation 15 has than preparation 16 better abuse prevention property.

Table X XVIII:

Described preparation 15,16 and contrasted 1 preliminary pharmacokinetic parameter among the following Table X XIX:

Table X XIX:

Shown preparation 15 and 16 preliminary relative bioavailability among the following Table X XX with respect to contrast 1:

Table X XX:

^*The antilogarithm of least square is represented logarithm.

The antilogarithm of the difference of+least square (test deducts reference) is represented logarithm.

Based on preliminary data, for C _MaxAnd AUC _∞, two kinds of test formulation 15 and 16 and contrast 1 be bioequivalent.1 compare with contrast, the initial speed that test formulation 15 and 16 hydrocodone absorb is slightly slow.

Embodiment 13: the vitro drug release feature:

Studied the vitro drug release feature of the preparation 17 shown in the following table XXXI and 18, and with the comparing of this feature and uncoated core VM-1 and contrast 2, as Fig. 7 (a) with (b).

Table X XXI:

Embodiment 14: make tablet by melt extrusion, deburring and film coating:

For each example according to Table X XXII, preparation contains the uniform powder mixture of all the components.In the situation of example 14A to 16A, carry out the mixing of two steps, with the uniform distribution of API composition (Hycodan 2.5-hydrate) in final mixture of guaranteeing low dosage.Mixed method is described among the Table X XXIII.In the situation of example 14A-16A,, 5 powder samples of sum had been analyzed before extruding from each final mixture of powders for the content uniformity of Hycodan 2.5-hydrate.

Mixture of powders before Table X XXII has described to extrude and the final composition of extruding tablet (behind melt extrusion and the straight forming).According to the US pharmacopeia (USP, NF) and/or test shown in the European Pharmacopoeia (Ph.Eur) and discharge all the components.

Table X XXII:

Table X XXIII: the mixed method of embodiment 14-17

Will be quantitative in co-rotating twin screw extruder with constant feed rate from the final mixture of embodiment 14B-17B.Uniform, the white medicine fused mass that contains that leaves extruder nozzle is become elongated tablet by the calendering straight forming between the cylinder of two reverse rotations, and these two cylinders have the pit according to size shown in the Table X XXIV in its surface.The processing parameter setting of melt extrusion and calendering is listed among the Table X XXIV.

Table X XXIV has described melt extrusion and straight forming (calendering) process:

Processing parameter setting	Embodiment 14C	Embodiment 15C	Embodiment 16C	Embodiment 17C
					Extruder (screw diameter)	18mm	18mm	18mm	40mm
Tablet size (calendering cylinder pit size) (length/width/height)	19.0/6.9/ 3.0mm	20.0/5.9/ 2.5mm	17.5/7.97/ 7.6mm	19.0/6.9/ 3.0mm
					Extrusion temperature (melt temperature)	129℃	124℃	140℃	140℃
The calender temperature	11℃	20℃	11℃	11℃
					Extrude output	1.5kg/h	1.5kg/h	1.5kg/h	25kg/h
Batch size	12kg	12kg	3kg	50kg

To be transferred to according to the tablet of embodiment 14C, 15C and 17C in the Driam600 film coating machine.In a first step, the rotating speed of tablet with maximum overturn in coating machine, with tablet polishing and remove the seems around the tablet of being centered around that produces in the calendering formation process.Remove from coating drum and waste gas from this material that tablet is removed.After being somebody's turn to do " deburring " step, in identical coating machine, directly begin the film coating of tablet.In the situation of embodiment 16C, in case finished the removal of edge and seems, tablet is placed the closed stainless steel container, and rotated 10 minutes.Then tablet is taken off dirt and be transferred in the identical Driam film coating machine on screen cloth, this situation with other embodiment is identical.The processing parameter setting of the composition of film coating and deburring step and film coating is subsequently listed among the Table X XXV.

Table X XXV has described the deburring of calendering back tablet.

Table X XXV:

Processing parameter setting	Embodiment 14D	Embodiment 15D	Embodiment 16D	Embodiment 17D
					The deburring time in the Driam film coating machine	20min.	94min.	-	60min.
The deburring time in the stainless steel drum	-	-	10min.	-
					Bowl temperature	25℃	25℃	25℃	25℃
Tablet weight after the deburring (on average)	684.3mg	536.4mg	840.7	716mg
					Acetaminophen medicament contg/sheet (according to forming and average tablet re-computation)	382.5mg	350.8mg	500.4mg	442.5mg
Hycodan 2.5 hydrate content/sheets (according to forming and average tablet re-computation)	15.0mg	15.0mg	15.1mg	-
					Batch size	4.9kg	6.5kg	1kg	7.8kg

Usually prepare the manufacturing of the film coating suspension of embodiment 14E-16E by following steps: at first, in the whipping process at room temperature acetaminophen is scattered in the water.In this suspension, the adding polymer (

And continue to stir IR), until forming uniform suspension.This suspension is directly used in film coating.In whole film coating process, continue to stir.For embodiment 14E-17E, used the acetaminophen powder (Rhodia, acetaminophen " fine powder ") that can use.Do not carry out other sieving or micronization.The composition of film coating suspension is summarized among the Table X XXVI.

Table X XXVI has described the composition of film coating suspension

Table X XXVI:

In Driam 600 film coating machines, carry out the film coating of deburring tablet.Processing conditions, parameter setting and list among the Table X XXVII from the data of film coating tablet.In the situation of all embodiment 14F-17F, the different time points sampling in film coating Main Stage process.This is to be used for studying the coating layer thickness Abensanil of different content and the influence that two kinds of medicines of Hycodan discharge from the film coating tablet.The spray rate of film coating Main Stage be peristaltic pump metering acetaminophen/ The maximum rate of IR suspension.Higher spray rate should be fine.

Table X XXVII has described the film coating processing conditions

Table X XXVII:

Usually, the specific preferred embodiment of the present invention provides dosage form and the method that is used for delivering drugs (particularly Drug abuse), it is characterized in that anti-solvent extraction; Smash (tampering) to pieces, pulverize or grind, and initial fulminant drug release is provided, follow long controlled drug release.

In addition, as shown in following table XXXVIII, in a preferred embodiment, the invention provides pharmaceutical composition with core and non-core layer, it contains: (a) hydrocodone, acceptable salt or hydrate and (b) acetaminophen or ibuprofen on its materia medica.In this embodiment, at least 75% all hydrocodone, acceptable salt or hydrate are in core on its materia medica, and acetaminophen or ibuprofen are in non-core layer.In addition, said composition is applicable to be administered orally in the people 3,2 or 1 times every day.Preferably, surpass 90% hydrocodone, acceptable salt or hydrate are in core on its materia medica.More preferably, all basically hydrocodones, acceptable salt or hydrate are in core on its materia medica.In another embodiment, core also contains acetaminophen or ibuprofen.More preferably, core also contains acetaminophen.

In specific embodiment, during the patient of the single dose administration that will contain Hycodan five semihydrates of the 15mg that has an appointment and about 500mg acetaminophen in fasting, preferably present following pharmacokinetic characteristic.Preferably, when delivering medicine to people patient, the blood plasma feature that drug regimen deposits yields feature is following: behind the single dose, for hydrocodone, about 0.6ng/mL/mg is to the Cmax of about 1.4ng/mL/mg with for acetaminophen, the Cmax of about 2.8ng/mL/mg to 7.9ng/mL/mg.In another embodiment, the blood plasma feature that drug regimen deposits yields feature is following: behind the single dose, for hydrocodone, about 0.4ng/mL/mg is to the Cmax of about 1.9ng/mL/mg with for acetaminophen, the Cmax of about 2.0ng/mL/mg to 10.4ng/mL/mg.In another embodiment, the blood plasma feature that drug regimen deposits yields feature is following: for hydrocodone, about 0.6ng/mL/mg is to the Cmax of about 1.0ng/mL/mg with for acetaminophen, and about 3.0ng/mL/mg is to the Cmax of about 5.2ng/mL/mg.Other embodiments of dosage form comprise about 5-20mg Hycodan five semihydrates and about 400-600mg acetaminophen.Another embodiment of dosage form comprises 10-15mg Hycodan five semihydrates and about 500-600mg acetaminophen.

In specific embodiment, during the patient of the single dose administration that will contain Hycodan five semihydrates of the 15mg that has an appointment and about 500mg acetaminophen in fasting, preferably present following pharmacokinetic characteristic.When delivering medicine to people patient, for hydrocodone, dosage form produces the AUC of about 9.1ng*hr/mL/mg to about 19.9ng*hr/mL/mg, and for acetaminophen, dosage form produces the AUC of about 28.6ng*hr/mL/mg to about 59.1ng*hr/mL/mg.In another embodiment, for hydrocodone, dosage form produces the AUC of about 7.0ng*hr/mL/mg to about 26.2ng*hr/mL/mg, and for acetaminophen, dosage form produces the AUC of about 18.4ng*hr/mL/mg to about 79.9ng*hr/mL/mg.In another embodiment, for hydrocodone, dosage form produces the AUC of about 11.3ng*hr/mL/mg to about 18.7ng*hr/mL/mg, and for acetaminophen, dosage form produces the AUC of about 28.7ng*hr/mL/mg to about 53.5ng*hr/mL/mg.Preferably, in this embodiment, the in-vitro release rate of pharmaceutical composition has two stage release characteristics, and wherein for each stage of in-vitro release rate, for acetaminophen is zero level or one-level, and is zero level or one-level for Hycodan five semihydrates.

In other specific embodiments, during the patient of the single dose administration that will contain Hycodan five semihydrates of the 15mg that has an appointment and about 500mg acetaminophen in fasting, preferably present following pharmacokinetic characteristic.Preferably, when delivering medicine to people patient, for hydrocodone, pharmaceutical composition produced the plasma concentration (C1) of about 0.30ng/mL/mg to about 1.06ng/mL/mg in the time of 1 hour, and for acetaminophen, C1 is that about 2.75ng/mL/mg is to about 5.57ng/mL/mg.In preferred embodiments, for hydrocodone, dosage form produces the C1 of about 0.45ng/mL/mg to about 1.06ng/mL/mg, and for acetaminophen, about 2.75ng/mL/mg is to the C1 of about 4.43ng/mL/mg.

In preferred embodiments, the invention provides a kind of compositions, wherein core layer contain can control drug release excipient or excipient mixture, but not core layer contains the excipient that can discharge medicine immediately.In addition, in preferred embodiments, the fused mass straight forming that then will contain medicine by melt extrusion is made core layer, and non-core layer spraying is coated on the core layer.Most preferably, said composition contains Hycodan five semihydrates of have an appointment 500mg acetaminophen and about 15mg.In another embodiment, can prepare non-core layer by another kind of method, or the tablet coating.In the method, separately make film coating and extrudate is molded into thin slice by extruding.In the core manufacture process, this thin slice is introduced in the calender.This method is particularly suited for thick coating (saving the long spray-painting time) and is no-solvent process.This technology is also referred to as the Xellex technology.

Another embodiment of the invention provides the pharmaceutical composition with core layer and non-core layer.In said composition, core layer comprises the mixture of being made up of following material: (a) at least a opioid; (b) acceptable polymer, copolymer or its combination on the materia medica of at least a change speed.Non-core layer contains at least a non-opioid analgesic drugs.In addition, these compositionss are improved, made to can be used for to be administered orally in the people 3,2 or 1 times every day.Preferably, core layer also contains at least a non-opium sample analgesic.In preferred embodiments, compositions is characterised in that at least one following feature:

In specific embodiment, during the patient of the single dose administration that will contain Hycodan five semihydrates of the 15mg that has an appointment and about 500mg acetaminophen in fasting, preferably present following pharmacokinetic characteristic.When delivering medicine to people patient, for hydrocodone, dosage form produces the AUC of about 9.1ng*hr/mL/mg to about 19.9ng*hr/mL/mg, and for acetaminophen, dosage form produces the AUC of about 28.6ng*hr/mL/mg to about 59.1ng*hr/mL/mg.In another embodiment, for hydrocodone, dosage form produces the AUC of about 7.0ng*hr/mL/mg to about 26.2ng*hr/mL/mg, and for acetaminophen, dosage form produces the AUC of about 18.4ng*hr/mL/mg to about 79.9ng*hr/mL/mg.In another embodiment, for hydrocodone, dosage form produces the AUC of about 11.3ng*hr/mL/mg to about 18.7ng*hr/mL/mg, and for acetaminophen, dosage form produces the AUC of about 28.7ng*hr/mL/mg to about 53.5ng*hr/mL/mg.Preferably, in this embodiment, the in-vitro release rate of pharmaceutical composition has two stage release characteristics, and wherein for each stage of in-vitro release rate, is zero level or one-level for acetaminophen, and is zero level or one-level for hydrocodone.

In preferred embodiments, the invention provides a kind of compositions, wherein core layer contain can control drug release excipient or excipient mixture, but not core layer contains the excipient that can discharge medicine immediately.In addition, in preferred embodiments, the fused mass straight forming that then will contain medicine by melt extrusion is made core layer, and non-core layer spraying is coated on the core layer.Most preferably, said composition contains Hycodan five semihydrates of have an appointment 500mg acetaminophen and about 15mg.

In another embodiment, the invention provides pharmaceutical composition with core and non-core layer.In said composition, core layer comprises the mixture of being made up of following material: (a) at least a opioid and at least a first non-opioid analgesic drugs; (b) acceptable polymer, copolymer or its combination on the materia medica of at least a change speed.Non-core layer contains at least a second non-opioid analgesic drugs.In addition, these compositionss are applicable to be administered orally in the people 3,2 or 1 times every day.In this embodiment, preferred, opioid contains hydrocodone, and first kind and the second non-opium sample analgesic contain acetaminophen or ibuprofen.More preferably, opioid contains hydrocodone, and first kind and the second non-opioid analgesic drugs contain acetaminophen.In addition, in this embodiment, non-core layer contains: (a) acetaminophen; (b) acceptable polymer, copolymer or its combination on the materia medica of at least a change speed.Preferably, polymer or copolymer are selected from: hydroxypropyl cellulose, hydroxypropyl emthylcellulose, hydroxyethyl-cellulose; Polymethacrylates, polyvinyl alcohol, poly(ethylene oxide) and combination thereof.More preferably, polymer or copolymer are selected from: hydroxypropyl emthylcellulose and polyvinyl alcohol, or its combination.Again more preferably, polymer or copolymer are selected from: polyvinyl alcohol and poly(ethylene oxide) graft copolymer.In addition, in this embodiment, the ratio of acetaminophen and rate control polymer or copolymer or its combination is about 1: 1 to about 10: 1.More preferably, the ratio of acetaminophen and rate control polymer or copolymer or its combination is about 3: 1 to about 5: 1.As providing among the present invention, in a preferred embodiment, non-core layer has at least one following feature:

(b) be (not sticking) that does basically;

(c) provide the painted of white to preparation, and do not have other pigment.

In preferred embodiments, compositions is characterised in that at least one following feature:

I) be less than or equal in the amount of the external abuse related drugs that in 37 ℃ of next hours, comes out 1.5 times at the external hydrocodone content that in 37 ℃ of next hours, from compositions, extracts by the 0.01N hydrochloric acid extraction by 40% ethanol water,

Iii) in first hour of dissolution in vitro test process, compositions discharges at least 20% hydrocodone and is no more than 45% hydrocodone, and first hour of preferred test in vivo also be so in the process,

Iv) compositions discharges the acetaminophen of treatment effective dose in 1 to 2 hour behind single dose,

V) discharge the acetaminophen and/or the abuse related drugs of treatment effective dose when compositions behind single dose 1 hour and 12 hours,

Vi) in compositions, 20,000-50 in the time of 1 minute, compares the compositions grinding under the 000rpm with intact tablet by coffee mill, and 37 ℃ of next hours in 40% ethanol water, the release raising of the hydrocodone after the grinding is lower than 2 to 3 times,

Detailed before description and subsidiary embodiment illustratively do not think to limit the scope of the invention, and this scope only is subjected to the qualification of claims and equivalent thereof.To the various variations of disclosed embodiment and change is that those skilled in the art are conspicuous and be a part of the present invention.Can carry out such variation and change, include but not limited to those relevant, and do not break away from its spirit and scope with chemical constitution of the present invention, substituent group, derivant, intermediate product, synthetic, preparation and/or using method.

Claims

1. have the pharmaceutical composition of core and non-core layer, it contains:

(a) hydrocodone, on its materia medica acceptable salt or hydrate and

(b) acetaminophen or ibuprofen,

Wherein on all hydrocodones of at least 75%, its materia medica acceptable salt or hydrate in core,

Wherein acetaminophen or ibuprofen in non-core layer and

Wherein said compositions is applicable to be administered orally in the people 3,2 or 1 times every day.

2. the compositions of claim 1 wherein is higher than on 90% hydrocodone, its materia medica acceptable salt or hydrate in core.

3. the compositions of claim 1, acceptable salt or hydrate are in core on wherein all basically hydrocodones, its materia medica.

4. the compositions of claim 1, wherein core also contains acetaminophen.

5. the compositions of claim 1, wherein core also contains acetaminophen or ibuprofen.

6. each compositions of claim 1 to 5, when wherein delivering medicine to people patient, the blood plasma feature that drug regimen deposits yields feature is following: behind the single dose, for hydrocodone, about 0.6ng/mL/mg is to the Cmax of about 1.4ng/mL/mg, with for acetaminophen, the Cmax of about 2.8ng/mL/mg to 7.9ng/mL/mg.

7. each compositions of claim 1 to 5, when wherein delivering medicine to people patient, the blood plasma feature that drug regimen deposits yields feature is following: behind the single dose, for hydrocodone, about 0.4ng/mL/mg is to the Cmax of about 1.9ng/mL/mg, with for acetaminophen, about 2.0ng/mL/mg is to the Cmax of about 10.4ng/mL/mg.

8. each compositions of claim 1 to 5, when wherein delivering medicine to people patient, the blood plasma feature that drug regimen deposits yields feature is following: behind the single dose, for hydrocodone, about 0.6ng/mL/mg is to the Cmax of about 1.0ng/mL/mg, with for acetaminophen, about 3.0ng/mL/mg is to the Cmax of about 5.2ng/mL/mg.

9. each compositions of claim 1 to 5, when wherein delivering medicine to people patient, for hydrocodone, dosage form produces the AUC of about 9.1ng*hr/mL/mg to about 19.9ng*hr/mL/mg, for acetaminophen, dosage form produces the AUC of about 28.6ng*hr/mL/mg to about 59.1ng*hr/mL/mg.

10. each compositions of claim 1 to 5, when wherein delivering medicine to people patient, for hydrocodone, dosage form produces the AUC of about 7.0ng*hr/mL/mg to about 26.2ng*hr/mL/mg, for acetaminophen, dosage form produces the AUC of about 18.4ng*hr/mL/mg to about 79.9ng*hr/mL/mg.

11. each compositions of claim 1 to 5, when wherein delivering medicine to people patient, for hydrocodone, dosage form produces the AUC of about 11.3ng*hr/mL/mg to about 18.7ng*hr/mL/mg, for acetaminophen, dosage form produces the AUC of about 28.7ng*hr/mL/mg to about 53.5ng*hr/mL/mg.

12. each compositions of claim 1 to 5, wherein the in-vitro release rate of pharmaceutical composition has two stage release characteristics, and, be zero level or one-level wherein, and be zero level or one-level for hydrocodone for acetaminophen for each stage of in-vitro release rate.

13. each compositions of claim 1 to 5, wherein in 0.01N HCl, under 50rpm, 37 ℃, the hydrocodone of about 20-45% discharges from pharmaceutical composition external in about 1 hour, and the acetaminophen of about 20-45% discharges from pharmaceutical composition external in about 1 hour.

14. each compositions of claim 1 to 5, wherein in 0.01N HCl, under 50rpm, 37 ℃, the hydrocodone of about 25-35% discharges from pharmaceutical composition external in about 1 hour, and the acetaminophen of about 25-35% discharges from pharmaceutical composition external in about 1 hour.

15. each compositions of claim 1 to 5, wherein in about 8 hours to about 12 hours, at least 90% hydrocodone discharges from pharmaceutical composition and in about 6 hours to about 8.5 hours, at least 60% to about 99% acetaminophen discharges from pharmaceutical composition external.

16. each compositions of claim 1 to 5, wherein in about 18 hours to about 23 hours, at least 90% hydrocodone discharges from pharmaceutical composition and in about 18 hours to about 23 hours, at least 90% acetaminophen discharges from pharmaceutical composition external.

17. each compositions of claim 1 to 5, wherein in about 8 hours to about 11 hours, at least 90% hydrocodone discharges from pharmaceutical composition and in about 8 hours to about 11 hours, at least 90% acetaminophen discharges from pharmaceutical composition external.

18. each compositions of claim 1 to 5, wherein in about 9 hours to about 12 hours, at least 95% hydrocodone discharges from pharmaceutical composition and in about 9 hours to about 12 hours, at least 95% acetaminophen discharges from pharmaceutical composition external.

19. each compositions of claim 1 to 5, wherein in about 10 hours to about 12 hours, at least 95% hydrocodone discharges from pharmaceutical composition and in about 10 hours to about 12 hours, at least 95% acetaminophen discharges from pharmaceutical composition external.

20. each compositions of claim 1 to 5, wherein in about 20 hours to about 25 hours, at least 95% hydrocodone discharges from pharmaceutical composition and in about 20 hours to about 25 hours, at least 95% acetaminophen discharges from pharmaceutical composition external.

21. each compositions of claim 1 to 5, wherein in about 21 hours to about 22 hours, at least 95% hydrocodone discharges from pharmaceutical composition and in about 21 hours to about 22 hours, at least 95% acetaminophen discharges from pharmaceutical composition external.

22. each compositions of claim 1 to 5, wherein in about 11 hours to about 12 hours, at least 99% hydrocodone discharges from pharmaceutical composition and in about 11 hours to about 12 hours, at least 99% acetaminophen discharges from pharmaceutical composition external.

23. each compositions of claim 1 to 5 wherein is being less than in about 13 hours, at least 99% hydrocodone discharges from pharmaceutical composition and is being less than in about 13 hours, and at least 99% acetaminophen discharges from pharmaceutical composition external.

24. each compositions of claim 1 to 5, wherein in about 22 hours to about 26 hours, at least 99% hydrocodone discharges from pharmaceutical composition and in about 22 hours to about 26 hours, at least 99% acetaminophen discharges from pharmaceutical composition external.

25. each compositions of claim 1 to 5 wherein is being less than in about 27 hours, at least 99% hydrocodone discharges from pharmaceutical composition and is being less than in about 27 hours, and at least 99% acetaminophen discharges from pharmaceutical composition external.

26. claim 1 or 5 each compositionss, wherein core layer contain can control drug release excipient, and non-core layer contains the excipient that can discharge medicine immediately.

27. each compositions of claim 1 to 5 is wherein made core layer by the fused mass straight forming that melt extrusion then will contain medicine, and non-core layer spraying is coated on the core layer.

28. each compositions of claim 1 to 27, wherein compositions contains have an appointment 500mg acetaminophen and about 15mg Hycodan five semihydrates.

29. have the pharmaceutical composition of core and non-core layer, it contains:

(a) the abuse related drugs in the core layer, on its materia medica on acceptable salt or hydrate and non-abuse related drugs or its materia medica acceptable salt and

(b) the non-abuse related drugs in the non-core layer, acceptable salt or hydrate on its materia medica,

Wherein said compositions is applicable to be administered orally in the people 3 times, 2 times or 1 time every day; With

Wherein said composition is characterised in that at least one following feature:

30. the compositions of claim 29, wherein the amount of the abuse related drugs that extracts from preparation by 40% ethanol water in 37 ℃ of next hours is about 70% to about 90% of the amount of the medicine that comes out by the 0.01N hydrochloric acid extraction in 37 ℃ of next hours.

31. the compositions of claim 29, wherein the amount of the abuse related drugs that extracts from preparation by 40% ethanol water in 37 ℃ of next hours is about 70% to about 130% of the amount of the medicine that comes out by the 0.01N hydrochloric acid extraction in 37 ℃ of next hours.

32. the compositions of claim 29, wherein the amount of the abuse related drugs that extracts from preparation by 40% ethanol water in 37 ℃ of next hours is about 75% to about 90% of the amount of the medicine that comes out by the 0.01N hydrochloric acid extraction in 37 ℃ of next hours.

33. have the pharmaceutical composition of core layer and non-core layer,

(A) wherein core layer contains the mixture of following material:

(a) at least a opioid;

(b) acceptable polymer, copolymer or its combination on the materia medica of at least a change speed;

(B) wherein non-core layer contains at least a non-opioid analgesic drugs; With

(C) wherein said compositions is applicable to be administered orally in the people 3 times, 2 times or 1 time every day.

34. the compositions of claim 33, wherein core layer also contains at least a non-opioid analgesic drugs.

35. the compositions of claim 33, wherein said composition is characterised in that at least one following feature:

36. the composition of claim 33; Wherein opioid is selected from alfentanil; Allylprodine; Alphaprodine; Anileridine; Benzylmorphine; Bezitramide; Buprenorphine; Butorphanol; Clonitazene; Codeine; Cyclazocine; Dihydrodesoxymorphine; Dextromoramide; Dezocine; Diampromide; Paracodin; Paramorphane; Dimenoxadol; Dimepheptanol; Dimethylthiambutene; Amidalgon; Dipipanone; Eptazocine; Ethoheptazine; Ethylmethylthiambutene; Dionin; Etonitazene; Fentanyl; Heroin; Hydrocodone; Hydromorphone; Hydroxypethidine; Isomethadone; Ketobemidone; Levallorphan; Levophenacylmorphan; Levorphanol; Lofentanil; Dolantin; Meptazinol; Metazocine; Methadone; Metopon; Morphine; Myrophine; Nalbuphine; Narceine; Nicomorphine; Norpipanone; Opium; Oxycodone; Oxymorphone; Papvretum; Pentazocine; Phenadon-X; Phenazocine; Phenomorphan; Phenoperidine; Piminodine; Disopyramide; Dextropropoxyphene; Sufentanil; Tilidine and C16H25NO2; And salt; Hydrate and mixture; And non-opioid analgesic drugs is selected from acetaminophen; Aspirin; Fentaynl; Brufen; Indomethacin; Ketorolac; Naproxen; Phenaetin; Piroxicam; New fentanyl; Su Lin acid; Interferon-' alpha ', and salt; Hydrate and mixture.

37. the compositions of claim 33, wherein opioid is a hydrocodone, and non-opioid analgesic drugs is acetaminophen or ibuprofen.

38. the compositions of claim 33, wherein opioid is a hydrocodone, and non-opioid analgesic drugs is an acetaminophen.

39. each compositions of claim 33 to 38, when wherein delivering medicine to people patient, the blood plasma feature that drug regimen deposits yields feature is following: behind the single dose, for hydrocodone, about 0.6ng/mL/mg is to the Cmax of about 1.4ng/mL/mg, with for acetaminophen, the Cmax of about 2.8ng/mL/mg to 7.9ng/mL/mg.

40. each compositions of claim 33 to 38, when wherein delivering medicine to people patient, the blood plasma feature that drug regimen deposits yields feature is following: behind the single dose, for hydrocodone, about 0.4ng/mL/mg is to the Cmax of about 1.9ng/mL/mg, with for acetaminophen, the Cmax of about 2.0ng/mL/mg to 10.4ng/mL/mg.

41. each compositions of claim 33 to 38, when wherein delivering medicine to people patient, the blood plasma feature that drug regimen deposits yields feature is following: behind the single dose, for hydrocodone, about 0.6ng/mL/mg is to the Cmax of about 1.0ng/mL/mg, with for acetaminophen, about 3.0ng/mL/mg is to the Cmax of about 5.2ng/mL/mg.

42. each compositions of claim 33 to 38, when wherein delivering medicine to people patient, for hydrocodone, dosage form produces the AUC of about 9.1ng*hr/mL/mg to about 19.9ng*hr/mL/mg, for acetaminophen, dosage form produces the AUC of about 28.6ng*hr/mL/mg to about 59.1ng*hr/mL/mg.

43. each compositions of claim 33 to 38, when wherein delivering medicine to people patient, for hydrocodone, dosage form produces the AUC of about 7.0ng*hr/mL/mg to about 26.2ng*hr/mL/mg, for acetaminophen, dosage form produces the AUC of about 18.4ng*hr/mL/mg to about 79.9ng*hr/mL/mg.

44. each compositions of claim 33 to 38, when wherein delivering medicine to people patient, for hydrocodone, dosage form produces the AUC of about 11.3ng*hr/mL/mg to about 18.7ng*hr/mL/mg, for acetaminophen, dosage form produces the AUC of about 28.7ng*hr/mL/mg to about 53.5ng*hr/mL/mg.

45. each compositions of claim 33 to 38, wherein the in-vitro release rate of pharmaceutical composition has two stage release characteristics, and, be zero level or one-level wherein, and be zero level or one-level for hydrocodone for acetaminophen for each stage of in-vitro release rate.

46. each compositions of claim 33 to 38, wherein in 0.01N HCl, under 50rpm, 37 ℃, the hydrocodone of about 20-45% discharges from pharmaceutical composition external in about 1 hour, and the acetaminophen of about 20-45% discharges from pharmaceutical composition external in about 1 hour.

47. each compositions of claim 33 to 38, wherein in 0.01N HCl, under 50rpm, 37 ℃, the hydrocodone of about 25-35% discharges from pharmaceutical composition external in about 1 hour, and the acetaminophen of about 25-35% discharges from pharmaceutical composition external in about 1 hour.

48. each compositions of claim 33 to 38, wherein in about 8 hours to about 12 hours, about 90% hydrocodone discharges from pharmaceutical composition and in about 6 hours to about 8.5 hours, at least 60% to about 99% acetaminophen discharges from pharmaceutical composition external.

49. each compositions of claim 33 to 38, wherein in about 18 hours to about 23 hours, about 90% hydrocodone discharges from pharmaceutical composition and in about 18 hours to about 23 hours, about 90% acetaminophen discharges from pharmaceutical composition external.

50. each compositions of claim 33 to 38, wherein in about 8 hours to about 11 hours, about 90% hydrocodone discharges from pharmaceutical composition and in about 8 hours to about 11 hours, about 90% acetaminophen discharges from pharmaceutical composition external.

51. each compositions of claim 33 to 38, wherein in about 9 hours to about 12 hours, about 95% hydrocodone discharges from pharmaceutical composition and in about 9 hours to about 12 hours, about 95% acetaminophen discharges from pharmaceutical composition external.

52. each compositions of claim 33 to 38, wherein in about 10 hours to about 12 hours, about 95% hydrocodone discharges from pharmaceutical composition and in about 10 hours to about 12 hours, about 95% acetaminophen discharges from pharmaceutical composition external.

53. each compositions of claim 33 to 38, wherein in about 20 hours to about 25 hours, about 95% hydrocodone discharges from pharmaceutical composition and in about 20 hours to about 25 hours, about 95% acetaminophen discharges from pharmaceutical composition external.

54. each compositions of claim 33 to 38, wherein in about 21 hours to about 22 hours, about 95% hydrocodone discharges from pharmaceutical composition and in about 21 hours to about 22 hours, about 95% acetaminophen discharges from pharmaceutical composition external.

55. each compositions of claim 33 to 38, wherein in about 11 hours to about 12 hours, about 99% hydrocodone discharges from pharmaceutical composition and in about 11 hours to about 12 hours, about 99% acetaminophen discharges from pharmaceutical composition external.

56. each compositions of claim 33 to 38 wherein is being less than in about 13 hours, about 99% hydrocodone discharges from pharmaceutical composition and is less than in about 13 hours, and about 99% acetaminophen discharges from pharmaceutical composition external.

57. each compositions of claim 33 to 38, wherein in about 22 hours to about 26 hours, about 99% hydrocodone discharges from pharmaceutical composition and in about 22 hours to about 26 hours, about 99% acetaminophen discharges from pharmaceutical composition external.

58. each compositions of claim 33 to 38 wherein is being less than in about 27 hours, about 99% hydrocodone discharges from pharmaceutical composition and is less than in about 27 hours, and about 99% acetaminophen discharges from pharmaceutical composition external.

59. each compositions of claim 33 to 38, wherein core layer contain can control drug release excipient, and non-core layer contains the excipient that can discharge medicine immediately.

60. each compositions of claim 33 to 38 is wherein made core layer by the fused mass straight forming that melt extrusion then will contain medicine, and non-core layer spraying is coated on the core layer.

61. have the pharmaceutical composition of core layer and non-core layer,

(A) wherein core layer contains the mixture of following material:

(a) at least a opioid and at least a first non-opioid analgesic drugs;

(B) wherein non-core layer contains at least a second non-opioid analgesic drugs; With

62. according to the compositions of claim 61, wherein opioid contains hydrocodone, and the first and second non-opioid analgesic drugs contain acetaminophen or ibuprofen.

63. according to the compositions of claim 61, wherein opioid contains hydrocodone, and first kind and the second non-opioid analgesic drugs contain acetaminophen.

64. according to the compositions of claim 61, wherein non-core layer contains:

Acetaminophen; With

Acceptable polymer, copolymer or its combination on the materia medica of at least a change speed.

65. according to the compositions of claim 64, wherein polymer or copolymer are selected from: hydroxypropyl cellulose, hydroxypropyl emthylcellulose, hydroxyethyl-cellulose; Polymethacrylates, polyvinyl alcohol, poly(ethylene oxide) and combination thereof.

66. according to the compositions of claim 64, wherein polymer or copolymer are selected from: hydroxypropyl emthylcellulose and polyvinyl alcohol, or its combination.

67. according to the compositions of claim 64, wherein polymer or copolymer are selected from: polyvinyl alcohol and poly(ethylene oxide) graft copolymer.

68. according to the compositions of claim 64, wherein acetaminophen is about 1: 1 to about 10: 1 with the polymer of control speed or the ratio of copolymer or its combination.

69. according to the compositions of claim 64, wherein acetaminophen is about 3: 1 to about 5: 1 with the polymer of control speed or the ratio of copolymer or its combination.

70. according to each compositions of claim 61 to 69, wherein non-core layer has at least one following feature:

(b) be (not sticking) that does basically;

(c) provide the painted of white to preparation, and do not have other pigment.

71. each compositions of claim 61 to 70, when wherein delivering medicine to people patient, the blood plasma feature that drug regimen deposits yields feature is following: behind the single dose, for hydrocodone, about 0.6ng/mL/mg is to the Cmax of about 1.4ng/mL/mg, with for acetaminophen, the Cmax of about 2.8ng/mL/mg to 7.9ng/mL/mg.

72. each compositions of claim 61 to 70, when wherein delivering medicine to people patient, the blood plasma feature that drug regimen deposits yields feature is following: behind the single dose, for hydrocodone, about 0.4ng/mL/mg is to the Cmax of about 1.9ng/mL/mg, with for acetaminophen, the Cmax of about 2.0ng/mL/mg to 10.4ng/mL/mg.

73. each compositions of claim 61 to 70, when wherein delivering medicine to people patient, the blood plasma feature that drug regimen deposits yields feature is following: behind the single dose, for hydrocodone, about 0.6ng/mL/mg is to the Cmax of about 1.0ng/mL/mg, with for acetaminophen, about 3.0ng/mL/mg is to the Cmax of about 5.2ng/mL/mg.

74. each compositions of claim 61 to 70, when wherein delivering medicine to people patient, for hydrocodone, dosage form produces the AUC of about 9.1ng*hr/mL/mg to about 19.9ng*hr/mL/mg, for acetaminophen, dosage form produces the AUC of about 28.6ng*hr/mL/mg to about 59.1ng*hr/mL/mg.

75. each compositions of claim 61 to 70, when wherein delivering medicine to people patient, for hydrocodone, dosage form produces the AUC of about 7.0ng*hr/mL/mg to about 26.2ng*hr/mL/mg, for acetaminophen, dosage form produces the AUC of about 18.4ng*hr/mL/mg to about 79.9ng*hr/mL/mg.

76. each compositions of claim 61 to 70, when wherein delivering medicine to people patient, for hydrocodone, dosage form produces the AUC of about 11.3ng*hr/mL/mg to about 18.7ng*hr/mL/mg, for acetaminophen, dosage form produces the AUC of about 28.7ng*hr/mL/mg to about 53.5ng*hr/mL/mg.

77. each compositions of claim 61 to 70, wherein the in-vitro release rate of pharmaceutical composition has two stage release characteristics, and, be zero level or one-level wherein, and be zero level or one-level for hydrocodone for acetaminophen for each stage of in-vitro release rate.

78. each compositions of claim 61 to 70, wherein in 0.01N HCl, under 50rpm, 37 ℃, the hydrocodone of about 20-45% discharges from pharmaceutical composition external in about 1 hour, and the acetaminophen of about 20-45% discharges from pharmaceutical composition external in about 1 hour.

79. each compositions of claim 61 to 70, wherein in 0.01N HCl, under 50rpm, 37 ℃, the hydrocodone of about 25-35% discharges from pharmaceutical composition external in about 1 hour, and the acetaminophen of about 25-35% discharges from pharmaceutical composition external in about 1 hour.

80. each compositions of claim 61 to 70, wherein in about 8 hours to about 12 hours, about 90% hydrocodone discharges from pharmaceutical composition and in about 6 hours to about 8.5 hours, at least 60% to about 99% acetaminophen discharges from pharmaceutical composition external.

81. each compositions of claim 61 to 70, wherein in about 18 hours to about 23 hours, about 90% hydrocodone discharges from pharmaceutical composition and in about 18 hours to about 23 hours, about 90% acetaminophen discharges from pharmaceutical composition external.

82. each compositions of claim 61 to 70, wherein in about 8 hours to about 11 hours, about 90% hydrocodone discharges from pharmaceutical composition and in about 8 hours to about 11 hours, about 90% acetaminophen discharges from pharmaceutical composition external.

83. each compositions of claim 61 to 70, wherein in about 9 hours to about 12 hours, about 95% hydrocodone discharges from pharmaceutical composition and in about 9 hours to about 12 hours, about 95% acetaminophen discharges from pharmaceutical composition external.

84. each compositions of claim 61 to 70, wherein in about 10 hours to about 12 hours, about 95% hydrocodone discharges from pharmaceutical composition and in about 10 hours to about 12 hours, about 95% acetaminophen discharges from pharmaceutical composition external.

85. each compositions of claim 61 to 70, wherein in about 20 hours to about 25 hours, about 95% hydrocodone discharges from pharmaceutical composition and in about 20 hours to about 25 hours, about 95% acetaminophen discharges from pharmaceutical composition external.

86. each compositions of claim 61 to 70, wherein in about 21 hours to about 22 hours, about 95% hydrocodone discharges from pharmaceutical composition and in about 21 hours to about 22 hours, about 95% acetaminophen discharges from pharmaceutical composition external.

87. each compositions of claim 61 to 70, wherein in about 11 hours to about 12 hours, about 99% hydrocodone discharges from pharmaceutical composition and in about 11 hours to about 12 hours, about 99% acetaminophen discharges from pharmaceutical composition external.

88. each compositions of claim 61 to 70 wherein is being less than in about 13 hours, about 99% hydrocodone discharges from pharmaceutical composition and is being less than in about 13 hours, and about 99% acetaminophen discharges from pharmaceutical composition external.

89. each compositions of claim 61 to 70, wherein in about 22 hours to about 26 hours, about 99% hydrocodone discharges from pharmaceutical composition and in about 22 hours to about 26 hours, about 99% acetaminophen discharges from pharmaceutical composition external.

90. each compositions of claim 61 to 70 wherein is being less than in about 27 hours, about 99% hydrocodone discharges from pharmaceutical composition and is being less than in about 27 hours, and about 99% acetaminophen discharges from pharmaceutical composition external.

91. each compositions of claim 61 to 70, wherein said composition is characterised in that at least one following feature:

I) be less than or equal in the amount of the external hydrocodone that in 37 ℃ of next hours, comes out 1.5 times in the amount of the external hydrocodone that in 37 ℃ of next hours, from compositions, extracts by the 0.01N hydrochloric acid extraction by 40% ethanol water,

92. each compositions of claim 61 to 70 is wherein made core layer by the fused mass straight forming that melt extrusion then will contain medicine, and non-core layer spraying is coated on the core layer.