NZ616600B2 - Tamper-resistant controlled release pharmaceutical dosage forms - Google Patents

Abstract

Disclosed is a solid oral extended release pharmaceutical dosage form comprising a multi-layered extended release matrix formulation with sandwich-type or half sandwich-type structure, the extended release matrix formulation comprising (1) a first composition forming an active agent-containing first layer of the extended release matrix formulation comprising: (a) at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1000000; and (b) at least one active agent (preferably selected from the opioid analgesics hydromorphone hydrochloride or hydrocodone bitartrate); and (2) a second composition forming an active agent-free second layer of the extended release matrix formulation comprising at least one polyethylene oxide, and wherein the extended release matrix formulation preferably has a cracking force of at least about 120 N, and/or a “penetration depth to crack” distance of at least about 1.4 mm. Also disclosed is a process of preparing a solid oral extended release pharmaceutical dosage form as defined above, comprising at least the steps of: (a) combining (1) at least one active agent, and (2) at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000, to yield a first composition for an active agent-containing layer first layer; (b) providing a second composition comprising at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000 or of less than 1,000,000, to yield a second composition for an active agent-free layer second layer, (c) shaping the compositions form (a) and (b) to form at least a bilayer extended release matrix formulation; and (d) curing said extended release matrix formulation comprising at least a curing step at a temperature which is at least the softening temperature of said at least one polyethylene oxide. layer of the extended release matrix formulation comprising: (a) at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1000000; and (b) at least one active agent (preferably selected from the opioid analgesics hydromorphone hydrochloride or hydrocodone bitartrate); and (2) a second composition forming an active agent-free second layer of the extended release matrix formulation comprising at least one polyethylene oxide, and wherein the extended release matrix formulation preferably has a cracking force of at least about 120 N, and/or a “penetration depth to crack” distance of at least about 1.4 mm. Also disclosed is a process of preparing a solid oral extended release pharmaceutical dosage form as defined above, comprising at least the steps of: (a) combining (1) at least one active agent, and (2) at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000, to yield a first composition for an active agent-containing layer first layer; (b) providing a second composition comprising at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000 or of less than 1,000,000, to yield a second composition for an active agent-free layer second layer, (c) shaping the compositions form (a) and (b) to form at least a bilayer extended release matrix formulation; and (d) curing said extended release matrix formulation comprising at least a curing step at a temperature which is at least the softening temperature of said at least one polyethylene oxide.

Description

TAMPER-RESISTANT CONTROLLED RELEASE PHARMACEUTICAL DOSAGE FORMS TECHNICAL FIELD OF THE INVENTION The present invention relates to controlled release pharmaceutical dosage forms, for example to a tamper resistant controlled release dosage form including an opioid sic, essentially ing a zero order release rate. The present invention further relates to processes of manufacture of these dosage forms, uses thereof as well as methods of treatment.

BACKGROUND OF THE INVENTION Controlled release formulations aim at achieving a release of an active agent contained therein starting at a predetermined time-point and extending over a ary period of time in order to provide for a red concentration of the active agent in the plasma of ts and to achieve a therapeutic effect for an extended period of time. There are medical conditions requiring the release of the active agent at a constant rate to maintain plasma levels of said active agent in the therapeutic range, thereby ng plasma level fluctuations characteristic of conventionally administered dosage forms in a ose regimen. Therefore, a need exists in the art for pharmaceutical oral dosage forms ing active agents essentially according to a zero order mode. This is in particular true for certain dosage forms comprising an opioid analgesic as an active agent. rmore pharmaceutical products, in particular pharmaceutical products comprising an opioid analgesic, are sometimes the subject of abuse. For example, a particular dose of opioid agonist may be more potent when administered parenterally as compared to the same dose administered orally. Some formulations can be tampered with to provide the opioid agonist contained therein for illicit use.

Controlled release opioid agonist formulations are sometimes crushed, or subject to extraction with solvents (e.g., ethanol) by drug abusers to provide the opioid contained therein for immediate release upon oral or parenteral administration.

Controlled release opioid agonist dosage forms which can liberate a portion of the opioid upon exposure to ethanol, can also result in a patient receiving the dose more rapidly than intended if a patient ards instructions for use and concomitantly uses alcohol with the dosage form.

There continues to exist a need in the art for pharmaceutical oral dosage forms comprising an active agent, in particular an opioid analgesic, without significantly changed release properties when in contact with alcohol and/or with resistance to crushing and which provide essentially zero order release.

SUMMARY OF THE INVENTION In s embodiments the present invention relates to solid oral extended release pharmaceutical dosage forms comprising an active agent, wherein the active agent is released ially ing a zero order mode.

In further embodiments the present invention relates to solid oral extended release pharmaceutical dosage forms comprising an active agent such as an opioid analgesic which are tamper ant.

In other embodiments the present invention to relates to oral extended release pharmaceutical dosage forms comprising an active agent such as an opioid analgesic which are resistant to crushing.

In further embodiments the present ion relates to solid oral extended release pharmaceutical dosage forms comprising an active agent such as an opioid analgesic which are resistant to alcohol extraction and dose dumping when concomitantly used with or in contact with alcohol.

The present invention as in particular described by the following ments relates to dosage forms and the respective manufacturing ses as well as the uses thereof.

In one embodiment, the invention concerns a solid oral extended release pharmaceutical dosage form comprising a multi-layered extended release matrix ation with sandwich-type or half-sandwich-type ure, the extended release matrix formulation sing (1) a first composition forming a first active agent containing layer of the extended release matrix formulation comprising: (a) at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000; and (b) at least one active agent; and (2) a second composition forming an active agent-free second layer of the extended release matrix ation comprising at least one polyethylene oxide.

In one ular embodiment the second composition comprises at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000.

In one particular embodiment the second composition comprises at least one polyethylene oxide , based on rheological measurements, an approximate molecular weight of less than 1,000,000.

In one particular embodiment, the active agent in the solid oral ed release pharmaceutical dosage form is selected from opioid analgesics.

In one particular embodiment, the multi-layered extended release matrix formulation is a bilayer formulation.

In one particular embodiment, the multi-layered ed release matrix formulation is thermoformed or subjected to a curing step.

Throughout this specification, unless the context es otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of ts, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

Any discussion of documents, acts, materials, devices, articles or the like which has been included in the t specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common l knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this specification. ation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graphic illustration of layered structures. which Fig. 1A) to IE) show sandwich-type ed release matrix formulations, comprise at least three , and half—sandwich—type structures comprising two layers.

Fig. 1 F) and G) show structures not covered by the present invention.

Figure 2 is a flow chart of the treatment periods of Example 7.

Figure 3shows the mean plasma concentration versus time following administration of Examples 1A, 1B and 1C in the fasted state in e time following the Figure 4 shows the mean plasma concentration versus in Example 7. administration of Examples 2A, 2B and 2C in the fasted state _ time following the Figure 5 shows the mean plasma concentration versus administration of Example 1B in thelfasted and fed state in Example time following the Figure 6 shows the mean plasma concentration versus administration of Example 2B in the fasted and fed state in Example DETAILED DESCRIPTION detail. At the onset Herein below, the present invention will be described in more various terms used herein are explained.

[Annotation] mpjs None set by mpjs ation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs invention to refer The term “extended release” is defined for purposes of the present which are formulated to make the to ayer dosage forms containing active agent, active agent available over an extended period after ingestion, thereby allowing form (e.g. as a reduction in dosing frequency compared to a conventional dosage the active agent. on or an immediate release dosage form) containing of the present ion to The term “immediate release” is defined for the purposes ated to allow the refer to dosage forms containing active agent which are with no delay or prolongation active agent to be ed in the gastrointestinal tract of the dissolution or absorption of the active agent. of active agent release from a The term “zero-order release rate” refers to the rate of active agent remaining in the dosage form which is independent of the amount a period of time. A dosage dosage form, such that the rate is relatively constant over exhibit a relatively straight line in a form exhibiting zero order release rate would released versus time during that graphical representation of percent active agent ion, “a release rate essentially period of time. In accordance with the present rate of release of active agent according to zero order release mode” is defined as a within 50%, 40% or 30% to elapsed time from a dosage form whichIS proportional 1n a USP Apparatus 1 from 2 to 12 hours, as measured by an in—vitro dissolution fluid without enzymes (SGF) at 37° (basket) at 100 rpm in 900 ml simulated gastric within 20% to elapsed time C. In one embodiment, the release rate is proportional the release is proportional within 50%, from 2 to 12 hours. In another embodiment, In another embodiment, the release 40% or 30% to elapsed time from 2 to 18 hours. time from 2 to 18 hours. Proportional rate is proportional within 20% to d 2 to 12 hours) means that such within a certain'% (e.g. 20%) to elapsed time (e.g. release rate, to be calculated certain % (e.g. 20%) difference from the mean-hourly 2 to 12 , is acceptable. using the release rates during said elapsed time (e.g.

[Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs of the present The term “multilayer” means that the extended release formulations invention have sandwich—type structures. with at least three layers, or half-sandwich- _type structures with two layers. three- In the present context, the term “sandwich-type structure” designates any and B)). dimensional structure comprising more than two layers (see Figure l, A) wherein one of the layers However, “sandwich-type” structures do not relate to those other layer(s) (see, for is completely d, encased or surrounded by one or more shell is not within example, Figure 1G). Also, a ure with a core encased by a the meaning of a “sandwich-type structure”. of two layers (see, e.g., Figure 1 A “half ch-type structure” is an arrangement or surrounded by C to E), ed that one of the layers is not completely covered shell is the second layer (as in Figure 1 F). Also, a structure with a core encased by a structure.” not within the meaningof a “sandwich-type used in the context of the present It should be noted that the term ” when but includes any form or shape. ion not only refers to essentially planar forms, in relation to each other.

Figure 1 D depicts two layers in a non—planar orientation form” refers to the The term “solid oral extended release ceutical dosage dose of active agent in administrable form of a pharmaceutical comprising a unit matrix formulation” and extended release form such as an ded release ves conventional in optionally one or more other excipients, adjuvants and/or the like, and optionally any the art, such as a protective coating or a capsule and in the dosage form. other additional features or components that are useful defined for purposes of the The term “extended release matrix formulation” is first and a second composition present invention as a shaped solid form comprising a either one or both orming at least a first and a second layer, respectively, oxide. compositions comprising at least a high weight molecular weight polyethylene [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs ation] mpjs Unmarked set by mpjs that The “multi-layered extended release matrix formulation” comprises a first layer comprises at least one active agent nafter also referred to as an e agent- least containing layer” or “active layer”). The first layer is in direct contact with at not containing the at least one active one other layer, e.g., at least a second layer “active agent-free layer” or agent of the first layer (hereinafter also referred to as the at least one “blocking layer”). The “active agent-containing layer” comprises active agent. active agent; the “active-agent free layer” is free of said at least one retardants Both layers can optionally comprise one or more other active agents, and/or other materials, including but not limited to low molecular weight in the art. The polyethylene oxide and other adjuvants and additives tional active containing layer is exposed to the surrounding , except Where the surface of surface areas thereof covered by the active agent-free layer(s). the active the active-agent—containing layer is covered by an active agent-free layer, medium to the active agent—free layer(s) preVent(s) direct access of the surrounding layer agent-containing layer. The entire surface area of the active agent-containing the active agent- will be completely exposed to the surrounding medium only once dissolve from the surface free layer has completely dissolved. The active agent can medium and, once of the active agent-containing layer exposed to the surrounding also pass by diffusion the active agent-free layer hydrates, the active agent may said layer. through the active agent—free layer from the surface of in Daltons.

Unless otherwise indicated, all cal values of molecular weights are is defined for proposes of the The term "high molecular weight polyethylene oxide" molecular weight of at least 1,000,000. present invention as having an approximate is based on For the e of this invention, the approximate molecular weight rheological measurements. Polyethylene oxide is considered to have an approximate of said lar weight of 1,000,000 when a 2% (by wt) aqueous solution Model RVF, spindle No. 1, at 10 Dolyethylene oxide using a Brookfield viscometer of 400 to 800 mPa 5 (CF). hylene oxide is rpm, at 25°C shows a viscosity range [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs considered to have an approximate molecular weight of 2,000,000 when a 2% (by wt) aqueous solution of said polyethylene oxide using a Brookfield viscometer Model RVF, spindle No. 3, at 10, rpm, at 25°C shows a viscosity range of 2000 to molecular 4000 mPa 5 (CF). Polyethylene oxide is ered to have an approximate oxide weight of 4,000,000 when a 1% (by wt) aqueous on of said polyethylene °C shows a using a eld viscometer Model RVF, spindle No. 2, at 2 rpm, at have Viscosity range of 1650 to 5500 mPa 5 (CF). Polyethylene oxide is considered to when a 1% (by wt) aqueous solution an approximate molecular weight 'of 5,000,000 No. 2, of said polyethylene oxide using a Brookfield viscometer Model RVF, spindle mPa s (cP). at 2 rpm, at 25°C shows a Viscosity range of 5500 to 7500 Polyethylene of 7,000,000 when a oxide is considered to have an approximate lar weight Brookfield 1% (by wt) s solution of said polyethylene oxide using a viscometer Model RVF, spindle No. 2, at 2 rpm, at 25°C shows a Viscosity range 7500 to 10,000 mPa 3 (GP). Polyethylene oxide is- considered to have an approximate solution of said molecular weight of 8,000,000 when a 1% (by wt) aqueous No. 2, at 2 hylene oxide using a Brookfield viscometer Model RVF, spindle of 10,000 to 15,000 mPa 3 (CF). rpm, at 25°C shows a viscosity range oxide is Regarding the lower molecular weight polyethylene oxides, polyethylene when a 5% (by wt) considered to have an approximate molecular weight of 100,000 oxide using a Brookfield viscometer Model aqueous solution of said polyethylene 50 mPa 5 RVT, spindle No. 1, at 50 rpm, at 25°C shows a viscosity range of 30 to molecular weight of (CF). Polyethylene oxide is considered to have an approximate oxide using a 900,000 when a 5% (by wt).aqueous solution of said polyethylene shows a Brookfield ViSCometer Model RVF, spindle No. 2, at 2 rpm, at 25°C Viscosity range of 8800 to 17,600 mPa 5 (CF). for purposes of the The term "low lar weight hylene oxide" is defined ements outlined above, present invention as having, based on the gical an approximate molecular weight of less than 1,000,000.

[Annotation] mpjs None set by mpjs [Annotation] mpjs ionNone set by mpjs [Annotation] mpjs Unmarked set by mpjs of the present The term “curing” or “temperature ” is defined for the es is applied to invention as referring to a process step wherein an elevated temperature the shaped extended release matrix formulation at atmospheric pressure. of the present invention as The term “thermoforming” is defined for the purposes before and/or during ing to a s wherein elevated temperature is applied and heat are the shaping of the extended release matrix ation, e.g., pressure simultaneously applied during process steps such as extrusion, injection molding, tool. g during tablet pressing, e. g. by using a heated tabletting of the t invention as The term "direct compression" is defined for purposes other compressed dosage referring to a tabletting s wherein the tablet or any of dry ng the components of form is made by a process comprising the steps form the formulation, e.g. by using the formulation and compressing the dry blend to g. Guidance for Industry, a diffusion blend and/or convection mixing process (e.

Solid Oral Dosage SUPAC—IR/MR: Immediate Release and Modified Release Forms, Manufacturing Equipment Addendum). for the purposes of the present The term “bed of free flowing tablets” is defined in motion with respect to each invention as referring to a batch of tablets that are kept rotation speed or in a fluidized bed of other as, e. g., in a coating pan set at a suitable reduces or prevents the sticking of s. The bed of free flowing tablets preferably tablets to one another. in the context of the flattening of The term “flattening” and related terms as used the present invention means that a tablets or other dosage forms in accordance with a direction tablet or other dosage form is subjected to a force applied from form, e.g. by substantially perpendicular to the widest diameter of the dosage be applied with a carver applying re to the flat face of a tablet. The force may to the extent necessary to Datyle bench press (unless expressly mentioned otherwise) to certain embodiments of achieve the target flatness/reduced thickness. According [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs into pieces; the ion, the flattening does not result in ng the tablet in terms of however, edge spits and cracks may occur. The flatness may be described of the non-flattened the ess of the flattened tablet compared to the thickness of the non flattened tablet. tablet, as expressed in % thickness, based on the thickness of a solid oral dosage Apart from tablets, the flattening can be applied to any shape to the form, wherein the force is applied from a direction substantially perpendicular than spherical, and widest diameter of the dosage form when the shape is other The flatness may then be applied from any direction when the shape is spherical. to the thickness described in terms of the thickness of the flattened shape compared based on the thickness of the of the non—flattened shape expressed in % thickness, be measured using a thickness gauge (e. g., a non flattened shape. The thickness may l thickness gauge or digital caliper). from using a bench press, a hammer In certain embodiments of the invention, apart forms. In such a flattening process, hammer can be used for flattening tablets/dosage to the strikes may be manually d from a direction substantially perpendicular then be described in terms of the widest diameter of the tablet. The flatness may the thickness of the non-flattened shape thickness of the flattened shape compared to the non-flattened shape. The expressed in % thickness, based on the thickness .of thickness gauge or digital thickness is ed using a thickness gauge (e.g., digital tablet ss test as By contrast, when conducting the ng strength or 18th edition, 1990, Chapter 89. described in ton’s ceutical Sciences, which is incorporated herein by “Oral Solid Dosage Forms”, pages 1633—1665, form is put between a reference, using the Schleuniger Apparatus the tablet/dosage of the flat , such pair of flat plates arranged in parallel, and d by means the thickness and substantially that the force is applied substantially perpendicular to the diameter in that direction. in line with the diameter of the tablet, thereby reducing 30DThis reduced diameter is described in terms of% diameter, based on the diameter of test. The breaking strength 0r ' the tablet before conducting the breaking strength [Annotation] mpjs None set by mpjs ation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs form breaks. tablet hardness is defined as the force at which the tested tablet/dosage the force s/dosage forms that do not break, but which are deformed due to applied are considered to be break-resistant at that particular force. is the indentation test A further test to quantify the strength of tablets/dosage forms using a Texture Analyzer, such as the TA-XT2 Texture Analyzer re this method, the Technologies Corp., 18 Fairview Road, Scarsdale, NY 10583). In stand with slightly concave s/dosage forms are placed on top of a stainless steel of the Texture e, and subsequently penetrated by the descending probe steel ball probe. Before Analyzer, such as a TA—8A 1/8 inch diameter stainless under the probe, such that the starting the measurement, the tablet is aligned directly in the center of the tablet, descending probe will penetrate the tablet pivotally, i.e. and such that the force of the ding probe is applied ntially perpendicular with the thickness of the tablet. First, the to the diameter and substantially in line towards the tablet sample at a pre-test probe of the Texture Analyzer starts to move surface and the trigger force set is reached, speed. When the probe contacts the tablet and penetrates the tablet. For the probe continues its movement with the test speed hereinafter be referred to as each penetration depth of the probe, which will and the data are collected. When the “distance”, the corresponding force is measured, it changes direction and probe has reached the desired maximum penetration depth, While further data can be collected. The cracking moves back at the est speed, maximum that is reached in the force is defined to be the force of the first local for e, the corresponding force/distance diagram and1S calculated using, Version 2.64 English”. t Texture Analyzer software “Texture Expert Exceed, that at this point, some structural wishing to be bound by any theory, it is believed form of cracking. However, the damage to the tablet/dosage form occurs in the embodiments of the present cracked tablets/dosage forms according to n resistance to the invention remain cohesive, as ced by the continued first local maximum is descending probe. The corresponding distance at the to crack” distance.

Diereinafter referred to as the “penetration depth [Annotation] mpjs None set by mpjs [Annotation] mpjs ionNone set by mpjs ation] mpjs Unmarked set by mpjs For the purposes of certain embodiments of the present invention, the term “breaking strength” refers to the hardness of the tablets/dosage forms that may preferably be measured using the Schleuniger apparatus, whereas the term ing lforce” reflects in the the strength of the tablets/dosage forms that may preferably be measured ation test using a Texture Analyzer. that can be derived A further parameter of the extended e matrix formulations release matrix from the indentation test as described above is the work the extended The work value formulation is subjected to in an indentation test as described above. corresponds to the integral of the force over the distance. of certain embodiments The phrase “resistant to crushing” is defined for the purposes least be flattened of the present invention as referring to dosage forms that can at In certain embodiments, the with a bench press as bed above without breaking. than dosage form can be flattened to no more than about 60% thickness, no more than about 30% about 50% thickness, no more than about 40% thickness, no more than about 10% thickness, or ess, no more than about 20% thickness, no more no more than about 5% ess without breaking. forms of the For the purpose of certain embodiments of the present invention, dosage alcohol extraction” when the present invention are regarded as being “resistant to when measured in a respective dosage form provides an in—vitro dissolution rate, without USP Apparatus l (basket) at 100 rpm in 900 ml simulated gastric fluid 40% ethanol at 37° C, characterized by the percent enzymes (SGF) comprising 0.75 hours, or at 0.5, 0.75 and 1 25 amount of active released at 0.5 hours, or at 0.5 and hour, or at 0.5, 0.75, l and 1.5 hours or at 0.75, l, 1.5 and 2 hours of dissolution that deviates no more than about 30 % points, no more than about 20 % points or no more in-vitro than about 15 % points at each of said time points from the corresponding l (basket) dissolution rate of a reference dosage form measured in a USP tus at 37° C t at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) ethanol.

[Annotation] mpjs None set by mpjs ation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs The term “tamper-resistant” for the purposes of the present invention refers to dosage alcohol forms which at least provide ance to crushing or resistance to extraction, or both, as defined above and may have further tamper-resistant characteristics. " is defined as a For purposes of the present invention the term "active agen pharmaceutically active substance useful for a therapeutic purpose. In certain embodiments, the term “active agent” refers to an opioid analgeSic. includes single For purposes of the present invention, the term “opioid analgesic” of opioids and compounds and combinations of compounds ed from the group combination which e an analgesic effect such as one single opioid agonist or a combination of of opioid ts, one single mixed opioid agonist-antagonist or a mixed opioid agonist-antagonists, or one single partial opioid t or a mixed combination of partial opioid agonists and combinations of an opioid ts, opioid opioid agonist-antagonists and partial opioid agonists with one or, more and solvates thereof, antagonists, stereoisomers, ethers, , salts, hydrates compositions of any of the foregoing, and the like. the use of The present invention disclosed herein is specifically meant to encompass form or in the form of any the active agents, as e.g. opioid analgesics, in their base pharmaceutically acceptable salt thereof. acid salts ceutically acceptable salts include,-but are not limited to, inorganic the like; organic acid such as hydrochloride, hydrobromide, sulfate, phosphate and and the like; salts such as formate, acetate, trifluoroacetate, maleate, tartrate and the sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like, and metal like; amino acid salts such as arginate, asparginate, ate salt and the like; alkaline earth Dalts such as sodium salt, potassium salt, cesium amine salts such as metals such as calcium salt, magnesium salt and the like; organic [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs salt, triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt and the like. invention may Active agents, as e.g. opioid analgesics, used according to the present contain one or more asymmetric centers and may give rise to enantiomers, invention is meant to diastereomers, or other stereoisomeric forms. The present forms, as well as their racemic and ed encompass the use of all such possible contains olefinic double forms and compositions thereof. When the active agent include both E and Z bonds or other centers of geometric asymmetry, it is intended to the present geometric isomers. All tautomers are intended to be encompassed by invention as well. for all isomers of As used herein, the term oisomers" is a general term their atoms in space. It individual molecules that differ only in the orientation of with more than one chiral center includes omers and isomers of compounds that are not mirror images of one another (diastereomers). which four different groups are The term "chiral center" refers to a carbon atom to attached. molecule that is non- The term "enantiomer" or "enantiomeric" refers to a wherein the superimposeable on its mirror image and hence optically active direction and its mirror image omer rotates the plane of polarized light in one direction. rotates the plane of polarized light in the opposite of enantiomers and which is The term "racemic" refers to a mixture of equal parts lly inactive. of one of The term ution“ refers to the tion or concentration or depletion Dhe two omeric forms of a molecule.

[Annotation] mpjs None set by mpjs [Annotation] mpjs ionNone set by mpjs [Annotation] mpjs Unmarked set by mpjs Pharrnacokinetic parameters such as Cmax, Tmax, AUCt, AUCinf, etc. describing the first plasma drug concentration versus time curve can be obtained in clinical trials, number cf test by -dose administration of the active agent, 6.g. oxycodone, to a The pharmacokinetic parameter values of persons, such as healthy human subjects. and mean the individual test persons are then averaged, e.g. mean AUC, mean Cmax unless Tmax values are each obtained. In the context of the present invention, otherwise explicitly indicated, pharmacokinetic parameters such as AUC, Cmax invention, in vivo Tm,x refer to mean . Further, in the context of the present and analgesic efficacy refer to parameters such as values for AUC, Cmax, Tmax, state or of a single dose parameters or values obtained after stration at steady . to human subjects. tration of the active The Cmax value indicates the maximum observed plasma which the Cmax value is d. In agent. The Tmax value indicates the time point at concentration. other words, Tmax is the time point of the maximum observed plasma the area of the plasma drug The AUC (Area Under the Curve) value corresponds to to the amount of concentration versus time curve. The AUC value is proportional total and hence is a measure for active agent absorbed into the blood circulation in the bioavailability. concentration versus The AUCt value corresponds to the area under the plasma drug measurable plasma drug time curve fromthe time of administration to the last rule. concentration and is calculated by the linear up/log down trapezoidal time curve AUCinf is the area under the plasma drug concentration versus extrapolated to infinity and is calculated using the formula: AUCinf = AUCt +7 is the apparent where Ct is the last measurable plasma tration and k2 terminal phase rate constant.

[Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs of the k2 is the apparent terminal phase rate constant, where M is the magnitude slope of the linear regression of the log concentration versus time profile during terminal phase. ife and is ly determined as t1 /22 is the apparent plasma terminal phase tl/ZZ = (1n2)/ 1.2. the first The lag time tlag is estimated as the timepoint immediately prior to measurable plasma drug concentration value. concentration at The ax ratio corresponds to the ratio between the plasma drug hour 24 and Cmax. with average values as The term “healthy human subject” refers to a male or female blood pressure, etc. regards height, weight and physiological parameters, such as invention are selected y human subjects for the purposes of the t based on and in accordance according to inclusion and exclusion criteria which are for Harmonization of Clinical with recommendations of the International Conference Trials (ICH). between 18 to 50 years, Thus, inclusion criteria comprise males and females aged 220 lbs) and a Body inclusive, a body weight ranging from 50 to 100 kg (110 to and free of Mass Index (BMI) 218 and S34 (kg/m2), that subjects are healthy significant abnormal findings as determined by medical history, physical of child—bearing examination, vital signs, and electrocardiogram, that females such as a potential must be using an adequate and reliable method of contraception, hormonal barrier with additional spermicide foam or jelly, an uterine device, that s who contraception (hormonal contraceptives alone are not acceptable), Z 1 year and have elevated are postmenopausal must have been nopausal that subjects are willing to eat all the aerum le stimulating hormone (FSH), and food supplied during the study.

[Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs from strenuous exercise A further inclusion criterion may be that subjects will refrain exercise program nor during the entire study and that they will not begin a new participate in any unusually strenuous physical on. beta human Exclusion criteria comprise that females who are pregnant (positive current drug or alcohol nic gonadotropin test) or lactating, any history of or that might interfere with abuse for five years, a y of or any current conditions of an opioid-containing drug tion, bution, metabolism or ion, use medication in the past thirty. (30) days, a history of known sensitivity of frequent nausea or hydrocodone, naltrexone, or related compounds, any history head trauma with current emesis regardless of etiology, any history of seizures or the thirty (30) days preceding sequelae, participation in a clinical drug study during s during the thirty (30) days the initial dose in this study, any significant medication including thyroid preceding the initial dose in this study, use of any is allowed), Vitamins, herbal, hormone replacement therapy nal contraception the initial dose, abnormal and/or mineral ments, during the 7 days preceding for 10 hours preceding and 4 hours cardiac conditions, refusal to abstain from food administration of the study drugs following stration or for 4 hours following each confinement, and to abstain from ne or xanthine entirely during hours of initial study consumption of lic beverages within forty-eight (48) initial study drug administration, drug administration (Day 1) or anytime following within 45 days of study drug history of smoking or use of nicotine products blood products donated stration or a positive urine cotinine test, blood or during the study within 60 days prior to administration of the study drugs or anytime the clinical study and for 30 days after completion of the study, except as required by administration of the study drug or protocol, plasma donated within 14 days prior to results for urine anytime during the study, except as required by the study, positive and hepatitis B surface drug screen, l screen at check-in of each period, a positive Naloxone HCl antigen (HBsAg), hepatitis C antibody (anti-HCV), known hepatobiliary challenge test, presence of Gilbert’s Syndrome or any [Annotation] mpjs None set by mpjs [Annotation] mpjs ionNone set by mpjs [Annotation] mpjs Unmarked set by mpjs abnormalities and that the Investigator believes the subject to be able for reason(s) not specifically stated above.

Subjects meeting all the inclusion criteria and none of the exclusion criteria will randomized into the study.

The enrolled population is the group of subjects who sign informed t.

The randomized safety population is the group of ts who are randomized, receive study drug, and have at least one post—dose safety assessment. who are The full analysis tion for PK metrics will be the group of subjects randomized, receive study drug, and have at least one valid PK metric. ts experiencing emesis within 24 hours after dosing might be excluded based on visual inspection of the PK profiles prior to database lock. Subjects and profiles/metrics Plan. excluded from the analysis set will be documented in the Statistical Analysis For the Naloxone HCl challenge test, vital signs and pulse oximetry (SPOZ) HCl challenge may obtained prior to the Naloxone HCl challenge test. The Naloxone be administered intravenously or subcutaneouSly. For the intravenous route, 0.2 mg of needle or cannula should remain in the arm during administration.

The subject is Naloxone HCl (0.5 mL) are administered by intravenous injection.

Then 0.6 mg observed for 30 seconds for evidence of withdrawal signs or symptoms.

The subject is of Naloxone HCl (1.5 mL) are administered by intravenous injection. observed for 20 minutes for signs and symptoms of Withdrawal. For the and the aneous route, 0.8 mg ofNaloxone HCl (2.0 mL) are administered withdrawal. Following t is observed for 20 s for signs and symptoms of and SPOz the 20-minute observation, post- Naloxone HCl challenge test vital signs are obtained.

[Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs Vital signs include systolic blood pressure, diastolic blood pressure, pulse rate, atory rate, and oral temperature.

For the “How Do You Feel?” (HDYF?) Inquiry, subjects will be asked a non-leading health “How Do You Feel?” question such as “Have there been any changes in your measurement. status since screening/since you were last asked?” at each vital sign is to be Subject’s se will be assessed to ine whether an adverse event reported. Subjects will also be encouraged to voluntarily report adverse events occurring at any other time during the study. meal Each subject receiving a fed treatment will consume a standard high—fat t and Fed in accordance with the “Guidance for Industry: Food-Effect Bioavailability Food and Bioequivalence s” (US ment of Health and Human Services, December 2002).

Drug Administration, Center for Drug Evaluation and Research, will be eaten at a steady rate The meal will be provided 30 minutes before g and minutes before dosing. over a 25-minute period so that it is ted by Clinical laboratory evaluations performed in the course of clinical studies include biochemistry (fasted at least 10 hours), hematology, serology, urinalysis, screen drugs of abuse, and further tests. of albumin, Biochemistry evaluations (fasted at least 10 hours) include determination Alkaline Phosphatase, alanine aminotransfcrase (alanine transaminase, ALT), calcium, de, aspartate aminotransferase tate transaminase, AST), total creatinine, glucose, inorganic phosphate, potassium, sodium, total bilirubin, protein, urea, lactate dehydrogenase (LDH), direct bilirubin and C02.

Hematology evaluations include determination of hematocrit, hemoglobin, platelet white blood cell differential (% count, red blood cell count, white blood cell count, and neutrophils. and te): basophils, eosinophils, lymphocytes, monocytes [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs Serology evaluations include determination of hepatitis B surface antigen (HBSAg), hepatitis B surface antibody (HBsAb) and hepatitis C dy (anti-HCV).

Urinalysis evaluations include determination of color, ance, pH, e, ketones, urobilinogen, nitrite, occult blood, protein, leukocyte esterase, microscopic and copic evaluation, specific gravity. to opiates, amphetamines, Screen for drugs of abuse includes urin screen with respect cannabinoids, benzodiazepines, e, cotinine, barbiturates, clidine, blood alcohol and methadone and propoxyphene and alcohol tests, such as breathalyzer test. urine pregnancy test and - Further tests for females only e serum pregnancy test, self reported postmenopausal Serum follicle stimulating hormone (FSH) test (for females only). detail.

The invention will now be described in more solid oral extended release In one embodiment, the invention concerns a extended release matrix ceutical dosage form comprising a multi-layered formulation, the extended release matrix formulation comprising layer of the (1) a first composition forming a first active agent—containing ed release matrix formulation comprising: based on rheological (a) at least one polyethylene oxide having, of at least 1,000,000; and ements, an approximate molecular weight (b) at least one active agent; and second layer of the (2) a second composition formmg an active agent-free oxide. extended release matrix formulation comprising at least one polyethylene ation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs least one In one particular embodiment the second composition comprises at polyethylene oxide having, based on rheological ements, an approximate molecular weight of at least 1,000,000. at least one In one ular embodiment the second composition comprises polyethylene oxide , based on rheological measurements, an approximate molecular weight of less than 1,000,000.

THE ACTIVE AGENT solid oral extended release In one particular embodiment, the active agent in the The opioid analgesic pharmaceutical dosage form is selected from opioid analgesics. of one or more opioid agonists. may comprise or consist but are not limited to,- Opioid agonists useful in the t invention include, bezitramide, a‘lfentanil, allylprodine, alphaprodine, idine, morphine, dextromoramide, buprenorphine, butorphanol, clonitazene, codeine, rphine, dezocine, diampromide, diamorphone, ocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, ethylmorphine, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, and derivatives, hydrocodone, etonitazene, etorphine, dihydroetorphine, yl levorphanol, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, methadone, leVophenacylmorphan, lofentanil, meperidine, meptazinol, cine, norleVOrphanol, . metOpon, morphine, myrophine, narceine, nicomorphine, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, phenomorphan, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, and the pharmaceutically properidine, propoxyphene, sufentanil, tilidine, tramadol, of any of the foregoing, and acceptable salts, hydrates and solvates thereof, mixtures 'Dhe like.

[Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs above Opioid antagonists useful in ation with opioid ts as described include, e.g. naloxone, naltrexone and nalmephene, and the pharmaceutically acceptable salts, hydrates and solvates thereof, mixtures of any of the ing, the like.

In certain embodiments, the opioid analgesic is selected from hydrocodone, and solvates hydromorphone and the pharmaceutically acceptable salts, hydrates thereof, mixtures of any of the foregoing, and the like. or a In certain embodiments, the opioid analgesic is hydromorphone, hydrocodone, pharmaceutically able salt thereof such as e.g. the hydromorphone form comprises hloride salt or the hydrocodone bitartrate salt. The dosage from about 0.5 from about 1 mg to about 100 mg orphonehydrochloride, or bitartrate, or from about 2 mg to about 200 mg mg to about 1250 mg hydrocodone used, equimolar hydrocodone bitartrate. If other salts, derivatives or forms are salt or derivative or form amounts of any other pharmaceutically acceptable the free base may be used. The including but not limited to hydrates and solvates or mg, 15 mg, 20 mg, 30 mg, 40 mg, dosage form may comprise, e.g., 5 mg, 7.5 mg, 150 mg hydrocodone bitartrate, or an 45 mg, 60 mg, 80 mg, 90 mg, 100 mg, 120 or acceptable salt, equimolar amount of the free base or any other pharmaceutically and solvates derivative or form thereof (including but not limited to hydrates 7.5 mg, 10 mg, 15 mg, 20 mg, thereof). The dosage form ses, e. g. 2 mg, 5 mg, or an equimolar mg, 30 mg, 32 mg or 64 mg hydromorphone hydrochloride salt, derivative or amount of the free base or any other pharmaceutically acceptable and solvates f). form thereof (including but not limited to hydrates be selected for use in accordance In certain embodiments, other active agents may in combination with an with the present invention either as the sole active agent or e antihistamines (e.g., opioid analgesic. Examples of such other active agents and dexchlorpheniramine Dimenhydrinate, hydramine, chlorpheniramine diclofenac, maleate), non -steroidal anti-inflammatory agents (e.g., naproxen, [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs anti— indomethacin, ibuprofen, sulindac, Cox-2 inhibitors) and acetaminophen, emetics (e. g., metoclopramide, methylnaltrexone), anti-epileptics (e.g., phenytoin, diltiazem meprobmate and nitrazepam), vasodilators (e.g., nifedipine, papaverine, codeine phosphate), anti— and nicardipine), anti-tussive agents and expectorants (e.g. asthmatics (e. g. theophylline), antacids, anti-spasmodics (e.g. atropine, scopolamine), anti- antidiabetics (e.g., insulin), diuretics (e.g., ethacrynic acid, bendrofluthiazide), clonidine, hypotensives (e.g., propranolol, clonidine), antihypertensives (e.g., methyldopa), bronchodilatiors (e.g., albuterol), steroids (e.g., hydrocortisone, antihemorrhoidals, inolone, prednisone), antibiotics (e.g., tetracycline), decongestants (e.g. hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, pseudoephedrine ), laxatives, vitamins, ants (including te suppressants well as pharmaceutically such as phenylpropanolamine) and cannabinoids, as acceptable salts, hydrates, and solvates f. directed to the use of Cox—2 inhibitors as In certain embodiments, the invention is with opioid analgesics, such as, e.g., active , by themselves or in ation the use of Cox—2 inhibitors such as cam (4-hydroxymethyl-N—(5-methyl disclosed in US. thiazoly1)—2H-1 ,2-benzothiazine—3—carboxamide—1,l—dioxide), as by reference; Serial No. 10/056,347 and 11/825,938, which are hereby incorporated disclosed in US. Serial No. nabumetone (4-(6-methoxynaphthyl)—2-butanone), as celecoxib (4—[5-(4- ,348, which is hereby incorporated by reference; methylphenyl)-3—(trifluoromethyl)- 1 H-pyrazol— 1 —yl]benzenesulfonamide), by reference; sed in US. Serial No. 11/698,394, which is hereby incorporated as disclosed in US. lide (N-(4-Nitrophenoxyphenyl)methane sulfonamide), reference, and N—[3- Serial No. 10/057,630, which is hereby incorporated by (formylamino)oxophenoxy-4Hbenzopyran—7-yl] methanesulfonamide (T— which is hereby incorporated by 614), as disclosed in US. Serial No. 10/057,632, reference. active agents such as, he present ion is also directed to dosage forms utilizing or amphetamines. e. g., benzodiazepines, barbiturates [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs ed set by mpjs derivatives The term “benzodiazepines” refers to benzodiazepines and drugs that are of iazepine that are able-to depress the-central nervous system. .

Benzodiazepines include, but are not limited to, alprazolam, bromazepam, chlordiazepoxide, clorazepate, diazepam, estazolam, flurazepam, pam, ketazolam, lorazepam, nitrazepam, oxazepam, prazepam, quazepam, temazepam, triazolam, methylphenidate as well as pharmaceutically acceptable salts, es, that can be used in the solvates, and mixtures thereof. iazepine antagonists flumazenil as well as present invention include, but are not limited to, thereof. pharmaceutically acceptable salts, hydrates, solvates and mixtures barbituric acid (2, 4, Barbiturates refer to sedative-hypnotic drugs derived from 6,-trioxohexahydropyrimidine). Barbiturates e, but are not limited to, amobarbital, aprobarbotal, butabarbital, butalbital, methohexital, mephobarbital, metharbital, pentobarbital, arbital, secobarbital as well as pharmaceutically Barbiturate antagonists that acceptable salts, hydrates, solvates, and mixtures thereof. but are not limited to, amphetamines as can be used in the present invention include, solvates and mixtures thereof. well as pharmaceutically acceptable salts, hydrates, such as amphetamine, Stimulants include, but are not limited to, amphetamines, dextroamphetamine resin complex, dextroamphetamine, methamphetamine, and es methylphenidate, as Well as pharmaceutically acceptable salts, hydrates, be used in the present invention and es thereof. Stimulant antagonists that can include, but are not limited to, iazepines, as well as pharmaceutically able salts, hydrates, solvates and es thereof.

TYPE STRUCTURE THE HALF-SANDWICH TYPE OR SANDWICH the multi—layer extended e Except for the shapes shown in Figures 1F and 1G, a cubic shape, Datrix formulation of the invention may have any physical shape, e.g. at least two a globular shape, etc., provided that a rectangular shape, an oval shape, [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs dimensions (in distinct layers are present. The two layers may have the same volume Vol.-%) or may have different volume dimensions. Examples of physical shapes plated by the invention are depicted in s 1 A) to E). Figures 1F and 1G invention. depict al shapes that are not encompassed by the present and the In certain embodiments of the invention, the active agent—containing layer from each other, y active agent-free layer are ly indistinguishable that can be presenting an obstacle to abuse of the active agent. One measurement utilized in order to evaluate the visual indistinguishability of the active agent- the color of the two containing layer and the active agent-free layer is determining layers by the CIE L*A*B* value. Preferably, the CIE L*A*B* values of the two to evaluate color is the layers are within 10% of each other. Another measurement where the two layers preferably correspond to use of a RYB or RGB color wheel, same hue or adjacent hues.

The weight ratio of the active agent-containing layer : active agent free layer or ng layer may range from about 1 to about 5 or from about 1.5 to about 3, or about 2 or is about 2.5.

THE COMPOSITIONS at least one The composition of the active agent-containing layer comprises an approximate polyethylene oxide having, based on gical measurements, molecular weight of at least 1,000,000, and at least one aCtive agent. does not comprise any active agent The composition of the active agent—free layer The composition of the active agent—free present in the active agent-containing layer. layer comprises at least one polyethylene oxide. In certain embodiments, the has an approximate polyethylene oxide, based on rheological measurements, In certain other embodiments, the Dnolecular weight of at least 1,000,000.

[Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs hylene oxide, based on rheological measurements, has an approximate molecular weight of less than 1,000,000. each of the active agent- In a further particular embodiment, the composition of than 25 % lactose. containing layer and the active agent free layer comprises less of each of the active agent- In a r particular embodiment, the composition lactose. containing layer and the active agent free layer ses essentially no of each of the active agent— In a further particular embodiment, the composition essentially no containing layer and the active agent free layer comprises hydrogenated castor oil. of each of the active agent- In a further particular embodiment, the composition the extended release matrix 'containing layer and the active agent free layer of formulation ses essentially no hydroxypropylmethylcellulose.

BHT (butylated hydroxytoluene), is In n embodiments, an antioxidant, e.g. added to the composition. first composition (of the active agent- In a further particular embodiment, the 70 % (by wt.), or 80 % containing layer) comprises at least about 60 % (by wt.), or oxide. (by wt.), or 90 % (by wt.) of polyethylene the active agent free In a further particular embodiment, the second composition (of layer) ses at least about 90 % (by wt.) of hylene. the composition forming the In certain embodiments of the above embodiment, % (by wt.), at least about 92 % (by active agent-free layer comprises at least about 91 least about 97 % (by wt.) or at least about 99 30am), at least about 95 % (by wt.), at (by wt.) of polyethylene oxide.

[Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs active agent-free According to certain embodiments, the ition forming the layer does not n any active agent. ing to other embodiments, the composition forming the active free layer does not contain any opioid antagonist, emetic or bitter substance. multi-/ or bilayer dosage forms According to certain embodiments, the layers of the a separation of the at are macroscopically indistinguishable, thereby preventing least two layers on the basis of their visual ance. form strongly In certain embodiments, the layers of the multi-/ or r dosage of the layers from each bond to each other, y preventing the easy separation other, and hindering abuse of opioid sic present in the active agent- containing layer'of the dosage form. at least about In certain embodiments of the invention, the compositions comprise layer, and at least 60% (by wt) polyethylene oxide in the active agent-containing in the active agent-free layer. about 90 % (by wt.) of polyethylene oxide molecular weight polyethylene oxide In fiirther particular embodiments, the high molecular weight of from has, based on rheological measurements, an approximate 2,000,000 to 8,000,000. molecular weight polyethylene oxide In further particular embodiments, the high molecular weight of has, based on rheological measurements, an approximate 2,000,000, 4,000,000, 7,000,000 or 8,000,000. extended release matrix In n embodiments of the invention, the layered with a polyethylene oxide formulation as described herein may be over—coated uncured formulation a powder layer of 30a powder layer by applying to the cured or curing the powder- polyethylene oxide surrounding the layered core and optionally [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs ation] mpjs Unmarked set by mpjs layered formulation as described herein. Such an outer polyethylene oxide layer release of the active agent starts and/or a slower may provide a lag time before the overall release rate. Such an outer layer may or may not comprise a certain amount of the active agent of the active agent-containing layer.

According to a r aspect of the invention, the density of the extended release matrix formulation in the solid oral extended e pharmaceutical dosage form, preferably in a dosage form containing hydromorphone HCl or hydrocodone bitartrate as active agent, is equal to or less than about 1.20 g/cm3. ably, the than about 1.18 density is equal to or less than about 1.19 g/cm3, equal to or less g/cm3, or equal to or less than about 1.17 g/cm3. For example, the density of the 1.10 g/cm3 to extended release matrix formulation may be in the range of from about from about 1.11 about 1.20 g/cm3, or from about 1.11 g/cm3 to about 1.20 g/cm3, or g/cm3 to about 1.19 g/cm3. Preferably, it is in the range of from about 1.12 g/cm3 to about 1.19 g/cm3 or from about 1.13 g/cm3 to about 1.19 g/cm3, more preferably from about 1.13 g/cm3 to about 1.18 g/cm3. determined by The density of the extended release matrix ation is preferably extended release Archimedes Principle using a liquid of known y (p0). The in a liquid and weighed. matrix formulation is first weighed in air and then- immersed matrix ation p can From these two weights, the density of the extended release be determined by the equation: p—__14——.po .A is the wherein p is the density of the extended release matrix formulation, of the weight of the extended release matrix formulation in air, B is the weight is the density extended e matrix formulation when immersed in a liquid and p0 is for of the liquid at a given temperature. A suitable liquid of known density p0 example hexane. measured using a Preferably, the density of an ed release matrix formulation is Serial # 1127430072 Top-loading Mettler Toledo balance Model # AB 135-S/FACT, [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs and a y determination kit 33360. Preferably, hexane is used as liquid of known density p0.

The density values throughout this document correspond to the density of the extended release matrix formulation at room temperature. release In those embodiments wherein the dosage form comprises the extended extended matrix ation coated with a cosmetic coating, the density of the the coating release matrix ation is preferably measured prior to performing extended release matrix ation step, or by removing the g from a coated release matrix and subsequently measuring the density of the uncoated extended formulation.

THE DISSOLUTION PROFILE matrix ation In a particular embodiment, the solid oral extended release 1 (basket) at provides a dissolution rate which, when measured in a USP Apparatus at 37° C, releases 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) mode. the active agent essentially according to a zero order release matrix In a further particular embodiment, the solid oral extended USP Apparatus 1 formulation provides a dissolution rate which, when ed in a without enzymes (SGF) at 37° t) at 100 rpm in 900 ml simulated gastric fluid released after-l hour and C, ranges from about 5% to about 15% (by wt.) active agent order mode. additionally may e the active agent essentially according to a zero release matrix In a r particular embodiment, the solid oral extended USP Apparatus l formulation provides a dissolution rate which, when measured in a at 37° (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) released after 2 hours D3, ranges from about 10% to about 30% (by wt.) active agent [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs order and additionally may release the active agent essentially according to a zero mode.

In a further particular embodiment, the solid oral extended release matrix formulation provides a dissolution rate which, when measured in a USP Apparatus (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) released after 4 37° C, ranges from about 20% to about 60% (by wt.) active agent to a zero hours and additionally may release the active agent essentially according order mode. release matrix In a further particular embodiment, the solid oral extended in a USP Apparatus l formulation provides a dissolution rate which, when measured (SGF) at 37° t) at 100 rpm in 900 ml simulated gastric fluid without enzymes active agent released after 8 hours C, ranges from about 40% to about 100% (by wt.) to a zero order and onally may release the active agent essentially according mode. extended release matrix In a further ular ment, the solid oral measured in a USP Apparatus 1 ation provides a dissolution rate which, when at 37° (basket) at 100 rpm in 900 m1 simulated c fluid without enzymes (SGF) active agent released per hour and C, ranges from about 5% to about 15% (by wt.) order mode. onally may release the active agent essentially according to a zero SPECIFIC HYDROCODONE AND HYDROMORPHONE COMPOSITIONS release pharmaceutical In a r particular embodiment, the solid oral extended bitartrate or dosage form comprises the opioid analgesic hydrocodone least about hydromorphone hydrochloride, and the first composition comprises at least about 2 % (by wt.) of 30a % (by wt.) of hydrocodone bitartrate or at hydromorphone hydrochloride.

[Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs least about In a further particular embodiment, the first composition comprises at 65 % (by wt.) polyethylene oxide , based on gical measurements, an approximate molecular weight of at least 000. release pharmaceutical In a further particular embodiment, the solid oral extended release matrix dosage form of the present invention comprises an extended formulation, the extended release matrix formulation sing: of said (1) a first composition forming an active agent-containing layer % (by wt.) of at least one extended release matrix formulation comprising at least 65 polyethylene oxide having, based on rheological measurements, an imate molecular weight of at least 1,000,000; and (2) about 5 mg hydrocodone bitartrate. extended release ceutical In a further particular embodiment, the solid oral extended release matrix dosage form of the present invention comprises an formulation, the extended release matrix formulation comprising: of said (1) an active agent—containing layer a first composition forming least 90 % (by wt.) of at least one extended release matrixforrnulation comprising at an approximate polyethylene oxide having, based on rheological measurements, molecular weight of at least 1,000,000; and (2) about 5 mg hydrocodone bitartrate. oral extended release pharmaceutical In a r particular embodiment, the solid ed release matrix dosage form of the present invention comprises an ation, the extended release matrix formulation comprising: (1) active agent-containing layer of said a first composition forming an 65 % (by wt.) of at least one extended release matrix formulation comprising at least approximate polyethylene oxide having, based on gical measurements, an 3ODnolecular weight of at least 1,000,000; and (2) about 10 mg hydrocodone bitartrate.

[Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs In a further particular embodiment, the solid oral extended release pharmaceutical matrix dosage form of the present invention comprises an extended release formulation, the extended e matrix ation comprising: of said (1) a first composition forming an active containing layer extended release matrix formulation comprising at least 65 % (by wt.) of at least one hylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000; and (2) about 15 mg or 20 mg hydrocodone rate. release ceutical In a further particular embodiment, the solid oral extended extended e matrix dosage form of the present invention ses an formulation, the extended release matrix formulation comprising: of said (1) a first composition forming an active agent-containing layer 65 % (by wt.) of at least'one extended release matrix formulation sing at least approximate polyethylene oxide having, based on rheological measurements, an molecular weight of at least 1,000,000; and (2) about 40 mg hydrocodone bitartrate. oral extended release pharmaceutical In a further particular embodiment, the solid extended release matrix dosage form of the present invention comprises an formulation, the extended release matrix formulation comprising: (1) active agent-containing layer of said a first composition forming an 65 % (by wt.) of at least one extended release matrix formulation comprising at least polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000; and , bitartrate. (2) about 60 mg, 80 mg, 100 mg or 120 mg hydrocodone extended release pharmaceutical In a further particular embodiment, the solid oral ed release matrix Dosage form of the present invention comprises an formulation, the extended-release matrix formulation comprising: [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs ed set by mpjs of said (1) a first ition forming an active agent-containing layer extended release matrix formulation comprising at least 90 % (by wt) of at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000; and (2) about 5 mg hydromorphone hydrochloride.

In a filrther particular embodiment, the solid oral extended release pharmaceutical matrix dosage form of the present invention comprises an extended release formulation, the extended release matrix formulation comprising: of said (l) a first composition forming an active agent-containing layer least one extended release matrix formulation comprising at least 90 % (by Wt) of at polyethylene oxide having, based on rheologicalmeasurements, an approximate molecular weight of at least 000; and (2) about 6 mg or 7 mg hydromorphone hydrochloride. release pharmaceutical In a further particular embodiment, the solid oral extended release matrix dosage form of the t invention comprises an extended ation, the extended release matrix formulation comprising: of said (1) a first composition g an active agent-containing layer of at least one ed release matrix formulation sing at least 90 % (by wt) polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000; and (2) about 8 mg or 10 mg hydromorphone hydrochloride. , In a further particular embodiment, the solid oral ed release pharmaceutical release matrix - dosage form of the present invention comprises an extended formulation, the ed release matrix formulation comprising: of said (1) a first composition forming an active agent-containing layer of at least one extended release matrix formulation comprising at least 90 % (by wt) Dolyethylene oxide , based on rheological measurements, an approximate molecular weight of at least 1,000,000; and [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs (2) about 12 mg orphone hydrochloride.

In a further particular embodiment, the solid oral extended release ceutical dosage form of the present invention comprises an extended release matrix formulation, the extended release matrix formulation comprising: of said (l) a first ition forming an active agent-containing layer least one extended release matrix formulation comprising at least 90 % (by wt) of at polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000; and (2) about 15 mg or 20 mg orphone hydrochloride. release pharmaceutical In a further particular embodiment, the solid oral extended release matrix dosage form of the present invention comprises an extended ation, the ed e matrix formulation comprising: of said (1) a first composition forming an active agent-containing layer of at least one extended release matrix formulation comprising at least 90 % (by wt) polyethylene oxide having, based on rheological measurements, an imate molecular weight of at leaSt 1,000,000; and (2) about 25 mg or 30 mg hydromorphone hloride. release pharmaceutical In a fiarther particular embodiment, the solid oral extended release matrix dosage form according to invention comprises an extended formulation, the extended release matrix formulation comprising: of said (1) a first composition forming an active agent-containing layer of at least one extended release matrix formulation comprising at least 90 % (by wt) polyethylene oxide having, based on rheological measurements, an approximate . molecular weight of at least 1,000,000; and (2) 32 mg hydromorphone hydrochloride.

[Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs ation] mpjs ed set by mpjs THERMOFORMING AND CURING release matrix This section describes thermoforming or curing of the extended formulation comprising the above compositions. release matrix formulation is In certain embodiments of the invention, the extended thermoformed or subject to a temperature curing step. matrix formulation is cured In a r particular embodiment, the extended release of at least one at a temperature which is at least the softening temperature polyethylene oxide included in the formulation. release matrix formulation is cured In a further particular embodiment, the extended for a time period of at least about 1 . at a temperature of at least about 60 °C release matrix formulation is cured In a further particular ment, the extended with respect to the process of in accordance with any ure as described preparation described herein.

PROCESS OF PREPARATION relates to a process of preparing a In a further embodiment, the present invention form sing an extended solid oral extended release pharmaceutical dosage release matrixformulation aCCording to any of the preceding embodiments, comprising at least the steps of: (a) combining at least (1) an active agent, and based on rheological (2) at least one polyethylene oxide having, measurements, an approximate molecular weight of at least 30D 1,000,000, [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs to yield a first composition forming an active agent-containing layer; (b) providing at least one further composition comprising at least one polyethylene oxide having, based on rheological measurements, an approximateVI molecular weight of at least 1,000,000 or less than 1,000,000, active agent-free layer, to yield a further composition forming at least one (c) shaping the compositions from (a) and (b) to form at least a r extended release formulation; and at least (d) curing said extended e matrix formulation comprising is at least the softening temperature of said at a curing step at a temperature which least one hylene oxide.

Said curing step may The curing step is generally ted at heric pressure. said at least one polyethylene oxide, be conducted at the softening temperature of about 2, about 3, time period, such as, e.g., for at least about 1, e.g. for an appropriate about 10, about 11, about 12, about 4, about 5, about 6, about 7, about 8, about 9, about 13, about 14, or about 15 minutes. is conducted for a time period of In a further particular embodiment, said curing step at least about 5 minutes. is conducted for a time period of In a further particular embodiment, said curing step at least about 15 minutes. of any one of the previous , In r particular embodiments of the processes of free flowing extended embodiments, the curing step ((1) takes place in a bed release matrix formulations. of any one of the previous In further ular embodiments of the processes allows an 30Gmbodiments, the curing step takes place in a coating pan. The coating pan before curing nt batch-wise curing step which allows conducting a coating step [Annotation] mpjs None set by mpjs ation] mpjs MigrationNone set by mpjs [Annotation] mpjs ed set by mpjs and a subsequent coating step without the need to transfer the dosage forms, e.g. tablets.

In a r particular embodiment of the processes referred to above, itions in step (c) are shaped in the form of a tablet.

In a further particular embodiment of the processes referred to above, steps (a) direct compression. to (c) provide the extended release matrix formulation by embodiments, the In further embodiments of the processes of any one of the previous matrix curing step (d) includes g and curing. The extended release first target weight formulations, e.g. in the form of tablets, are initially coated to a 90 °C for a time period gain, then cured at a temperature from about 60 °C to about 50 °C, and of at least about 1 minute, cooled down to a ature of below about ted in a coated to a second target weight gain. Curing step (d) is preferably is the weight gain coating pan. In particular embodiments, the first target weight gain be at least 0.5 %, obtained in a first coating step, e.g. the first target weight gain may In the second target weight at least 1.0 %, or at least 1.5 % of the final tablet weight. of at least 2.0 %, at least gaining step, the coating results in a final target weight gain least 4.5 %, or at least 5.0 % of 2.5 %, at least 3.0 %, at least 3.5 %, at least 4.0 %, at the tablet weight. the invention, step (d) is In further particular embodiments of the processes of 62 °C, preferably performed at a temperature of at least about 60 °C or at least about about 72 °C, or at least about 75 °C. at least about 68 °C, at least about 70 °C, at least the extended In further particular embodiments of the processes of the invention, of from release matrix formulation in step (d) is subjected to a curing temperature 90 °C, or from about 68 °C about 60 °C to about 90 °C, or from about 65 °C to about Us about 90 °C.

[Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs —38- extended In further particular embodiments of the processes of the invention, the least about release matrix formulation in step (d) is subjected to a temperature of at 62 °C or at least about 68 °C for a time period of from about 1 minute to about 5 hours, or from about 5 minutes to about 3 hours. the extended In further particular embodiments of the processes of the invention, of at least release matrix formulation in step (d) is subj ected to a curing ature about 15 s. about 62 °C or at least about 68 °C for a time period of at least the extended In r particular embodiments of the processes of the invention, of at least release matrix formulation in step (d) is subjected to a curing temperature least about 70 °C, about 60 °C, or at least about 62 °C, or at least about 68 °C, or at 75 °C, or from about 62 °C to about 85 °C, or at least about 72 °C, or at least about about 30 minutes, at least about for a time - of at least about 15 minutes, at least 60 minutes, or at least about 90 minutes. of any one of the previous In further particular embodiments of the processes is subjected to a ments, the extended release matrix formulation in step (d) 62 °C, but less than about curing temperature of at least about 60 °C or at least about 90 °C or less than about 80 °C. the invention, curing of the In particular embodiments of the above processes of extended release matrix formulation in step d) ses at least a curing step extended release matrix wherein the high molecular weight polyethylene oxide in the at least about formulation at least partially melts. For example, at least about 20%, or least about 60%, or at leaSt %, or at least about 40%, or at least about 50%, or at molecular weight about 75%, or at least about 90%, or about 100% of the high polyethylene oxide melts. release matrix formulation D1 other ments, the curing of the extended matrix formulation is comprises at least a curing step wherein the extended release [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs subjected to an elevated temperature for a certain period of time. In such embodiments, the curing temperature, is at least as high as the softening temperature bound by of the high molecular weight polyethylene oxide. Without wanting to be at a ature that is at least as high as the any theory, it is believed that curing softening temperature of the high lar weight polyethylene oxide causes each other or even to fuse together. polyethylene oxide particles to at least adhere to 60 °C, or at According to some embodiments, the curing temperature is at least about from about 62 °C to least about 62 °C, or ranges from about 62 °C to about 90 °C, or 65 °C to about 90 about 85 °C, or from about 62 °C to about 80 °C, or from about '10 °C to about 80 °C. The °C, or from about 65 °C to about 85 °C, or from about 65 90 °C, or from about curing temperature preferably ranges from about 68 °C to about from about 70 °C to 68 °C to about 85 °C, or from about 68 °C'to about 80 °C, or about 70 °C to about 80 about 90 °C, or from about 70 °C to about 85 °C, or from °C to about 85 °C, or from °C, or from about 72 °C to about 90 °C, or from about 72 be at least about 60 °C, or abOut 72 °C to about 80 °C. The curing ature may less than about 80 °C. Preferably, it . at least about 62 °C, but less than about 90 °C or fromabout 68 °C to is in the range of from about 62 °C to about 72 °C, in particular least as high as the lower limit about 72 °C. Preferably, the curing temperature is at oxide of the softening ature range of the high molecular weight polyethylene 68 °C. More preferably, the curing or at least about 62 °C or at least about of the high molecular weight temperature is within the softening temperature range the curing polyethylene oxide or at least about 70 °C. Even more preferably, of the softening temperature range of temperature is at least as high as the upper limit about 72 °C. In a further the high molecular weight polyethylene oxide or at least embodiment, the curing temperature is higher than the upper limit of the softening oxide, for example the temperature range of the high molecular weight polyethylene curing temperature is at least about 75 °C or at least about 80 release matrix ation In those embodiments where the curing of the extended release matrix formulation is Domprises at least a curing step n the ed this period of time subjected to an elevated temperature for a certain period of time, [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs of the curing is hereinafter referred to as the “curing time”. For the measurement defined. For the purposes time a starting point and an end point of the curing step is is defined to be the point of the. present ion, the ng point of the curing step in time when the curing temperature is reached. the curing step shows a In certain embodiments, the temperature profile during of the curing. In such plateau-like form between the starting point and the end point be the point in time when embodiments, the end point of the curing step is defined to the heating the heating is stopped or at least reduced, e.g. by terminating or reducing drops and/or by starting a uent cooling step, and the temperature subsequently °C and/ or below the lower limit below the curing temperature by more than about oxide, for of the softening temperature range of.high molecular weight polyethylene is reached and the curing example below about 62 °C. When the curing temperature the curing from the curing ature in the course of step is thus started, deviations tolerated as long as they do not exceed a value of step can occur. Such deviations are about i3 °C. For about :l:lO °C, preferably about 3:6 °C, and more preferably 75 °C is to be ined, the example, if a curing ature of at least about value of about 85 °C, preferably measured temperature may temporarily increase to a and the measured temperature may about 81 °C and more preferably-about 78 °C, about 65 °C, preferably about 69 °C and also temporarily drop down to a value of In the cases of a larger decrease of the temperature more preferably about 72 °C. below the lower limit of the softening and/or in the case that the temperature drops oxide, for example below temperature range of high molecular weight polyethylene end point is reached. Curing can about 62 °C, the curing step is discontinued, i.e., an be restarted by again reaching the curing temperature. the curing step shows a In other embodiments, the temperature profile during and the end point of the parabolic or ular form between the ng point in time when the curing curing. This means that after the starting point, i.e.,-the point perature is reached, the temperature further increases to reach a maximum, [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs is defined to be then decreases. In such embodiments, the end point of the curing step the point in time when the temperature drops below the curing temperature.

In this context, it has to be noted that depending on the apparatus used for the curing, kinds of temperatures which will hereinafter be called the curing device, different the curing temperature. within the curing device can be measured to characterize in an oven. In such In n embodiments, the curing step may take place Based thereon, when the embodiments, the temperature inside the oven is measured. is defined to be the target curing step takes place in an oven, the curing temperature of the curing step is defined to inside temperature of the oven and the starting point of the oven reaches the curing be the point in time when the inside temperature is defined to be (1) the point in time ature. The end point of the curing step and the temperature inside the oven when the heating is stopped or at least reduced than about 10 °C and/ or subsequently drops below the curing temperature by more of high molecular weight below the lower limit of the softening temperature range in a plateau-like temperature polyethylene oxide, for examplebelow abOut 62 °C, inside the oven drops below the profile,or (2) the point in time when the temperature profile. Preferably, the curing temperature in a parabolic or triangular ature the oven reaches a curing temperature curing step starts when the temperature inside least about 70 °C, more preferably of at least about 62 °C, at least about 68 °C or at °C. In preferred embodiments, the of at least about 72 °C or at least about 75 shows a u—like form, wherein the temperature profile during the curing step of the oven, is preferably at least about curing temperature, i.e. the inside temperature 73 °C, or lies within a range of from 68 °C, or about 70 °C or about 72°C or about is preferably in the range of from about 70 °C to about 75 °C, and the curing time from about 30 minutes to about about 30 minutes to about 20 hours, more ably 4 hours, or from about 30 minutes to hours, or from about 30 s to about is in the range of from about 30 about 2 hours. Most preferably, the curing time Dninutes to about 90 minutes.

[Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs devices that are heated In certain other embodiments, the curing takes place in curing like for by_ an air flow and se a heated air supply (inlet) and an exhaust, will hereinafter be example a coating pan or fluidized bed. Such curing devices is possible to measure the called convection curing devices. In such curing s, it of the heated air entering the temperature of the inlet air, i.e., the ature the temperature tion curing device and the ature of the exhaust air, i.e., also possible to determine, or at of the air leaving the convection curing device. It is inside the convection curing least estimate, the temperature of the formulations measurement device during the curing step, e.g., by using infrared temperature the temperature using a temperature instruments, such as an IR gun, or by measuring the extended release matrix probe that is placed inside the curing device near in a convection curing formulations. Based thereon, when the curing step takes place and the curing time can be measured as , the curing temperature can be defined the following. is measured according to method 1, the In one embodiment, wherein the curing time inlet air temperature and the starting curing temperature is defined to be the target in time when the inlet air point of the curing step is defined to be the point The end point of the curing step is temperature reaches the curing temperature. is stopped or at least reduced and defined to be (1) the point in time when the heating below the curing temperature by more the inlet air temperature subsequently drops the softening temperature range of high than about 10 0C or below the lower limit of below about 62 °C, in a plateau- - molecular weight polyethylene oxide, for example when the inlet air temperature drops like temperature profile, or (2) the point in time profile. below the curing ature in a parabolic or triangular temperature Preferably, the curing step starts according to method I, when the inlet air of at least about 62 °C, at least about 68 temperature reaches a curing temperature least about 75 °C. In a preferred °C, at least about 70 °C, at least about 72 °C, or at shows a plateau-like embodiment, the temperature profile during the curing step the target inlet air temperature, is Dorm, wherein the curing temperature, i.e., and the curing time which preferably at least about 72 °C, for example about 75 °C, [Annotation] mpjs None set by mpjs ation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs is measured according to method 1 is preferably in the range of from about 15 minutes to about 2 hours, for example about 30 minutes or about 1 hour. to the In another embodiment, wherein the curing time is measured with respect be the target t air target exhaust air, the curing temperature is defined to is defined to be the point in time temperature and the starting point of the curing step The end point of when the exhaust air temperature reaches the curing temperature. is stopped or at the curing step is defined to be (1) the point in time when the heating below the curing least reduced and the exhaust air temperature uently drops ow the lower limit of the softening temperature by more than about 10 °C and/ oxide, for example below temperature range of high molecular weight polyethylene in time when the about 62 °C, in a plateau-like ature profile or (2) the point in a parabolic or exhaust air temperature drops below the curing temperature to method triangular temperature profile. Preferably, the curing step starts according of at least about 2, when the exhaust air ature reaches a curing temperature about 72 °C, or at least about 62 °C, at least about 68 °C, at least about 70 °C, at least the curing step 75 °C. In preferred embodiments, the temperature profile during i.e. the target exhaust air shows a plateau-like form, wherein the curing temperature, °C, or at least about 72 °C. For temperature, is at least about 68 °C, at least about70 abOut 68 °C, about 70 °C, about 72 °C, example, the target exhaust air temperature is is measured according to about 75 °C or about 78 °C, and the curing time which method 2 is preferably in the range of from about 1 minute to about 2 hours, or frOm about 5 minutes to about 90 minutes. For e, the curing time is about 5 about 60 minutes, s, about 10 minutes, about 15 minutes, about 30 minutes, In a more preferred about 70 minutes, about 75 minutes or about 90 minutes. method 2, is in the embodiment, the curing time, which is measured accOrding to to about 1 hour. range of from about 15 minutes measured according to method 3, In a further embodiment, wherein the curing time is of the extended release D16 curing temperature is defined to be the target temperature is defined to be the point matrix ations and the starting pOint of the curing step [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs which can in time when the temperature of the extended release matrix formulations, be measured for example by an IR gun, reaches the curing temperature. The end when the heating is point of the curing step is defined to be (1) the point in time matrix stopped or at least reduced and the temperature of the extended release formulations subsequently drops below the curing temperature by more than about of high °C and/ or below the lower limit of the softening temperature range about 62 °C,1n a u- molecular weight polyethylene oxide, for example below I the temperature of the like temperature profile, or (2) the point in time when in a extended release matrix formulations drops below the curing temperature starts lic or triangular temperature profile. Preferably, the curing step extended e matrix according to method 3, when the ature of the about formulations reaches a curing temperature of at least about 62 °C, at least least about 75 °C. 68 °C, at least about 70 °C, at least about 72 °C, or at time is measured according to 1.5 In still another embodiment, wherein the curing method 4, the curing temperature is defined to be the target temperature measured that was placed inside the using a temperature probe, such as a wire couple, matrix formulations and the starting point of curing device near the ed release time when the temperature measured the curing step is defined to be the point in inside the curing device near the extended using a ature probe that was placed of the e matrix formulations reaches the curing temperature . The end point when the heating is stopped or at curing step is defined to be (1) the point in time the temperature probe least reduced and the temperature measured using than about 10 °C and/ or uently drops below the curing temperature by more of high molecular weight below the lower limit of the softening temperature range temperature polyethylene oxide, for example below about 62 °C, in a plateau-like measured using the temperature profile or (2) the point in time when the temperature triangular temperature probe drops below the curing temperature in a parabolic or method 4, when the profile. Preferably, the curing step starts according to that was placed inside the curing Demperature measured using a temperature probe s a curing temperature of device near the extended release matrix formulations [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs about 70 °C, at least about 72 °C, or at least about 62 °C, at least about 68 °C, at least the temperature profile during the at least about 75 °C. In a preferred embodiment, i.e. the target curing step shows a plateau-like form, n the curing temperature, that was placed inside the curing temperature measured using a temperature probe is preferably at least about device near the extended release matrix formulations, time which is measured 68 °C, for example it is about 70 °C, and the curing about 15 minutes to about 2 ing to method 4 is ably in the range of from minutes or about 90 minutes. hours, for example the curing time is about 60 the curing time can be measured If curing takes place in a convection curing device, embodiment, the curing time is by any one of s 1, 2, 3 or 4. In a preferred measured according to method 2. defined as a target temperature In certain ments, the curing temperatureis is defined as a target inlet air temperature range, for example the curing temperature the starting air temperature range. In such embodiments, range or a target t in time when the lower limit of the point of the curing step is defined to be the point and the end point of the curing step is defined target temperature range is reached, is stopped or at least reduced, and the be the point in" time when the heating the lower limit of the target temperature range ature subsequently drops below the lower limit of the softening temperature by more than about 10 °C and/or below oxide, for example below about 62 °C. range of high molecular weight polyethylene extended release matrix formulation is The curing time, i.e.‘ the time period the be measured according to subjected to the curing temperature, which can for example 1 minute or at least about 5 method 1, 2 3 or 4 as described above, is at least about 1 minute to about 24 hours, or from minutes. The curing time may vary from about about 10 minutes to about 15 hours, or about 5 minutes to about 20 hours, or from from about 30 minutes to about 5 hours, from about 15 minutes to about 10 hours, or 30Ddepending on the specific composition and on the formulation and the curing the curing time and the curing temperature. The parameters of the composition, [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs described herein. ature are chosen to achieve the tamper ance as minutes to According to certain embodiments, the curing time varies from about about 30 s. According to filrther embodiments wherein the curing temperature least about 70 °C, is at least about 60 °C, at least about 62 °C, at least about 68 °C, at from about 62 °C to about at least about 72 9C, or at least about 75 °C, or varies is preferably at least 85°C, or from about 65 °C to about 85 °C, the curing time 60 minutes, at least about about 15 minutes, at least about 30 minutes, at least about In preferred 75 minutes, at least about 90 minutes or about 120 minutes. least about 62°C, at embodiments, wherein the curing temperature is, for example, at 72 °C, or at least about 75 °C, least about 68 °C, at least about 70 °C, at least about 80 °C, from about 65 °C to about 80 °C, from or ranges from about 62 °C.to about about 80 °C or from about 72 °C to about 68 °C to about 80 °C, from about 70 °C to about 1 minute or at least about 5 about 80 °C, the curing time is ably at least least about 10 minutes, at least about minutes. More preferably, the curing time is at embodiments, the curing time can 15 minutes, or at least about 30 minutes. In n the d tamper be chosen to be as short as possible while still achieving does not exceed about 5 hours, or resistance. For example, the curing time preferably about 2 hours. Preferably, the does not exceed about 3 hours, or does not exceed curing time is in the range of from about 1 minute to about 5 hours, from about 5 _ about 2 hours, or from about 15 minutes to about 3 hours, from about 15 minutes to and curing time as minutes to about 1 hour. Any ation of curing temperature invention. sed herein lies within the scope of the present to the curing temperature In certain embodiments, the composition is only subjected in the extended release until the high molecular weight polyethylene oxide present and/or at least partially matrix formulation has reached its softening temperature be less than about 5 melts. In certain such embodiments, the curing time may from about 0 minutes to about 3 minutes, for example the curing time may vary to about 1 hours, or from about 1 minute to about 2 hours, or from about 2 minutes device which allows for instant 3O amour. Instant curing is possible by choosing a curing oxide in the extended release heating of the high molecular weight polyethylene [Annotation] mpjs None set by mpjs [Annotation] mpjs ionNone set by mpjs [Annotation] mpjs ed set by mpjs matrix formulation to at least its softening temperature, so that the high lar weight polyethylene oxide at least partially melts. Such curing deVices are, such as example, microwave ovens, ultrasound devices, light irradiation apparatus known UV—irradiation apparatus, ultra—high ncy (UHF) fields, or any method to the person skilled in the art. matrix formulation The skilled person is aware that the size of the extended release time and curing temperature to achieve the may determine the required curing it is believed desired tamper resistance. Without wishing to be bound by any theory, such as a large tablet, that in the case of a large extended release matrix formulation, to conduct the heat into the or of the a longer curing time will be necessary with r size. Higher formulation than in the case of a corresponding formulation and thereby decreases the temperature increases the thermal conductivity rate required curing time. be coated. An additional In certain embodiments, after curing, the dosage form-may and said additional curing step curing step can follow after coating the dosage form, In certain such embodiments, the curing can be performed as described above. is ably at least about 70 °C, at least temperature of the additional curing step time is preferably in the range of about 72 °C or at least about 75 °C, and the curing from about 15 minutes to about 1 hour, for example about 30 s. decrease in the density of the In certain embodiments, the curing step leads to a of the cured ed extended release matrix formulation such that the density the extended release matrix release matrix formulation is lower than the density of the cured extended formulation prior to the curing step. Preferably, the density of of the uncured extended release matrix formulation in comparison to the density 0.5%. More ably, the release matrix formulation decreases by at least about to the density density of the cured extended release matrix formulation in comparison decreases by at least about 0.7 %, Dfthe uncured extended e matrix formulation least about 2.0 % or at least about 2.5 %. at least about 0.8 %, at least about 1.0 %, at [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs extended release Without wanting to be bound by any theory, it is believed that the the curing step, matrix formulation, due to the absence of elevated pressure during expands, resulting in a density decrease. extended release According to a further aspect of the invention, the density of the matrix ation in the solid oral extended release ceutical dosage form, preferably in a dosage form containing hydromorphone HCl or hydrocodone 1.20 g/cm3. Preferably, it bitartrate as the active agent, is equal to or less than about than about 1.18 g/cm3, or is equal to or less than about 1.19 g/cm3, equal to or less of the extended equal to or less than about 1.17 g/cm3. For example, the density 1.10 g/cm3 to about release matrix formulation is in the range of from about from about 1.11 g/cm3 to 1.20 g/cm3, from about 1.11 g/cm3 to about 1.20 g/cm3, or about 1.12 g/cm3 to about about 1.19 g/cm3. Preferably it is in the range of from from 1.19 g/cm3 or from about 1.13 g/cm3 to about 1.19 g/cm3, more preferably about 1.13 g/cm3 to about 1.18 g/cm3. is preferably determined as The density of the extended release matrix formulation defined above. of the extended release matrix In certain embodiments of the invention, the g tablet press. However, any formulation is performed in a tablet-press, e.g., a bilayer in the art may be used. other process for manufacturing tablets as known directed to a process of preparing a In certain embodiments, the present invention is wherein step (a) above, may solid oral extended release pharmaceutical dosage form, other pharmaceutical comprise wet granulation of the active agent and optionally cellulose, additives or ents of the first ition, such as microcrystalline hydroxypropylcellulose, but not polyethylene oxide, in a granulator, e.g. a high—shear material granulator. After wet granulating these components, the wet granulation device. fter, the ed material Dnay be passed h a screen of a milling fluid bed dryer. The dried granulation product may may be dried, e.g., using a [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs optionally be further screened h a fine screen of a milling device.

Subsequently, the material is combined with the at least one polyethylene oxide Gemco 2 CU. the first composition using a conventional blender (e.g. a I‘V” blender, first layer FT.) to yield the first composition. Thereafter, further additives of the composition, e.g. magnesium stearate may be added to the blended mixture. to a process of In n embodiments, the present invention is further directed wherein a preparing a solid oral extended release pharmaceutical dosage form, for use in preparing further (in case of a bilayer dosage form, a ) composition of the multi— or bilayer pharmaceutical an “active agent-free” or “blocking layer” This step may dosage form of step (b) in the above s of the invention. other components comprise a blending process of polyethylene oxide and optionally conventional of the blocking layer, e.g., ium stearate, for example using a “V” blender (e. g. a “V” blender, Gemco 2 CU. FT.). of preparing a In certain embodiments, the present invention is directed to a process n the compositions solid oral extended release pharmaceutical dosage form, form a multi- or bilayer. obtained in steps (a) and (b), tively, are combined to tablet press (for example a The compositions may be compressed in a press, e.g. a the active layer Karnavati bilayer tablet press), wherein the compositions forming in the respective sites of the and the ng layer, respectively, may be charged hopper and the compression is then run. Subsequently, the ed tablets may be with Opadry® g coated to a first targeted weight gain, e.g. using spray coating tablets may be cured, sions. After coating to a first targeted weight gain, the After curing, the products are sufficiently cooled for spray- e.g., using a pan coater. obtain a second targeted coating with a coating suspension, e.g., in a pan coater to weight gain. of the invention, high In the above described embodiments of the processes based on rheological measurements, an Dnolecular weight polyethylene oxide having, from 2,000,000 to approximate molecular weight of from 2,000,000 to 15,000,000 or [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs 8,000,000 may be used. In particular, hylene oxides , based on rheological measurements, an approximate lar weight of 2,000,000, 4,000,000, 7,000,000 or 8,000,000 may be used. In particular, hylene oxides molecular weight of having, based on rheological measurements, an approximate 7,000,000 or 4,000,000, may be used. Moreover, also at least one low lar measurements, weight polyethylene oxide may be used having, based on rheological less than 1,000,000, such as polyethylene oxides an approximate molecular weight of molecular weight of having, based on rheological measurements, an approximate such low molecular weight from 100,000 to 900,000 may be used. The addition of release rate, such as polyethylene oxides may be used to specifically tailor the release rate too enhance the release rate of a formulation that otherwise provides a least one polyethylene oxide slow for the specific purpose. In such embodiments, at molecular weight of having, based on rheological measurements, an approximate of the 100,000 may be used. For example, in certain embodiments of the processes least one hylene invention, compositions may be prepared that comprise at molecular weight oxide having, based on rheological measurements, an approximate oxide having, based on rheological of at least 1,000,000 and at least one polyethylene of less than 1,000,000, wherein the measurements, an approximate molecular weight at least about 20 % (by Wt) of composition comprises at least about 10 % (by wt) or measurements, an imate the polyethylene oxide having, based on rheological such embodiments the curing molecular weight of less than 1,000,000. In certain less than about 77 °C temperature is less than about 80 °C or even oxide in the composition In certain embodiments the overall content of polyethylene in the processes of the invention of the first “active agent—containing” layer prepared be bound to any theory, it is is at least about 60 % (by wt). t g to for the tamper resistance as believed that high contents of polyethylene oxide provide resistance to alcohol described herein, such as high breaking strength and the active agent is either tion. According to n such embodiments, the . and the composition Drydrocodone rate or hydromorphone hydrochloride ation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs bitartrate or more than comprises more than about 5% (by wt) of the hydrocodone about 2 % (by wt.) of the hydromorphone hloride. in the processes of the In certain such embodiments in the composition prepared oxide in the “active agent- ion, the content of the at least one hylene containing”'layer having, based on rheological measurements, an approximate 60 % (by wt). In certain molecular weight of at least 1,000,000 is at least about least one hylene oxide embodiments, the content in the composition of the at molecular weight of at having, based on rheological ements, an imate 75 %, 80 %, 85% or at least about 90 % least 000 is at least about 65 %, 70 %, oxide having, based on rheological (by wt). In such embodiments, a polyethylene of at least 4,000,000 or at least measurements, an approximate molecular weight embodiments, the active agent is 7,000,000 may be employed. In n such although other active hydrocodone bitartrate or hydromorphone hydrochloride, this aspect of the invention, and the composition agents can also be used according to bitartrate or hydromorphone comprises more. than about 5% (by wt) hydrocodone hydrochloride. stearate is added during or after In certain embodiments of the invention, magnesium In certain such the curing step in order to avoid the tablets sticking together. added at the end of the curing process embodiments, the magnesium stearate is Other anti-tacking agents that could be before or during the cooling of the tablets. dal silica dioxide, m stearate, used would be talc, silica, fumed silica, such as stearic acid and stearyl carnauba wax, long chain fatty alcohols and Waxes, cellulose, glycerin, propylene glycol, alcohol, mineral oil, paraffin, micro crystalline the coating can be started at and polyethylene glycol. Additionally or alternatively, the high temperature to avoid sticking. is carried out in a coating pan, the In certain embodiments, wherein the curing step tablets can be separated) by increasing asticking of tablets can be avoided (or sticking in the latter case for example before or the pan speed during or after the curing step, ation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs during the cooling of the tablets. The pan speed may be increased up to a speed where all s are separated or no sticking occurs. of a film In certain embodiments of the invention, an initial film coating or a fraction above. This film coating is applied prior to performing the curing step d as bed formulations or coating provides an “Overcoat” for the extended release matrix the formulations or tablets to function as an anti-tacking agent, i.e. in order to avoid which is s sticking together. In certain such embodiments, the film coating the curing step d), a applied prior to the curing step is an Opadry film coating. After further film coating step can be performed. solid oral ed The present invention encompasses also any multi-/ or bilayer described release formulation obtainable by a process according to any s as above. the solid oral extended release In further particular embodiments of the invention, embodiments is pharmaceutical dosage form according to any one of the above said dosage form administered to a patient in need thereof for the ent of pain, comprising an opioid analgesic. methods of treatment In further particular ments, the invention relates to dosage forms using the above-disclosed solid oral extended release pharmaceutical in any of the above comprising the extended release matrix formulation described embodiments. matrix formulations of the In a further particular ment, the extended release ion are used in the manufacture of a medicament for the treatment ofpain, wherein the extended release matrix formulation comprises an opioid analgesic.

[Annotation] mpjs None set by mpjs ation] mpjs ionNone set by mpjs ation] mpjs Unmarked set by mpjs TAMPER RESISTANCE solid oral In certain particular embodiments, the present invention is directed to a release matrix extended release pharmaceutical dosage form comprising an extended wherein the formulation in the form of a multi-/ or bilayer tablet as described herein, thickness of the tablet can be at least flattened t breaking, terized by a about 60 % of the tablet after the flattening which corresponds to no more than flattened tablet provides an thickness of the tablet before flattening, and wherein said 1 (basket) at 100 rpm in in—vitro dissolution rate, when measured in a USP Apparatus 37° C, characterized by the 900 ml simulated gastric fluid without enzymes (SGF) at of dissolution that deviates no more percent amount of active released at 0.5 hours dissolution rate of a non— than about 30 % points from the corresponding in-Vitro flattened reference tablet. to a solid oral extended In certain embodiments, the present invention is directed ed release matrix e ceutical dosage form comprising an bed herein, wherein the formulation in the form of a multi-/ or bilayer tablet as characterized by a thickness of the tablet can at least be flattened without breaking, than about 60% of the tablet after the flattening whichcorresponds to no more the flattened or non flattened thickness ofthe tablet before flattening, and wherein in a USP Apparatus 1 tablet provide an in—vitro dissolution rate, when measured without enzymes (SGF) (basket) at 100 rpm in 900 ml simulated gastric fluid amount of active comprising 40% ethanol at 37° C, characterized by the percent than about 30 % points released at 0.5 hoUrs of ution that deviates no more in a USP Apparatus 1 from the corresponding in-vitro dissolution rate measured (SGF) at t) at 100 rpm in 900 ml simulated gastric fluid without enzymes reference tablets, 37° C without ethanol, using flattened and non flattened respectiVely. solid oral extended release an certain embodiments, the invention is ed to matrix formulation pharmaceutical dosage forms comprising an ed release [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs conipriSingfin active agent, said'dosage'forrns' being in the fo'rm'of a multi- or r characterized by tablet, wherein the tablet can at least be flattened without breaking, to no more than about a thickness of the tablet after the flattening which corresponds said flattened tablet 60 % of the thickness of the tablet before flattening, and wherein es an in-vitro dissolution rate, when measured in a USP Apparatus 1 (basket) at 37° C, at 100 rpm in 900 m1 ted gastric fluid without enzymes (SGF) hours of characterized by the percent amount of active released'at 1, 8 and 24 each of said time points dissolution that deviates no more than about 30 % points at non-flattened reference tablet. from the corresponding in-Vitro dissolution rate of a be flattened t breaking, In certain such embodiments, the tablet can at least which corresponds to no characterized by a thickness of the tablet after the flattening than about 40%, or no more than about 30%, or no more than about 50 %, or no more than about 16% of the thickness of the tablet more than about 20%, or no more in—vitro dissolution before flattening, and n said flattened tablet provides an» 1 (basket) at 100 rpm in 900 m1 simulated rate, when measured in a USP Apparatus characterized by the percent amount of gastric fluid without enzymes (SGF) at 37° C, that deviates no more than about active released at 1, 8 and 24 hours of dissolution than about 15 % points, % points, or no more than about 20 % points, or no more at each of said time points from the ponding or no more than about 10% points tablet. in-vitro dissolution rate of a non-flattened nce release matrix ation In a further embodiment, the solid oral extended when subjected to an according to any of the preceding embodiments has, indentation test, a cracking force of at least about 110 release matrix formulation has In certain ments of the invention the extended 110 N, or at least about 120 N, or at least about a cracking force of at least about 150 N, or at least about 160 N, or at 130 N, or at least about 140 N, or at least about 30neast about 170 N, or at least about 180 N, or at least about 190 N, or at least about 200 N.

[Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs matrix formulation, when In a further embodiment, the solid oral extended release distance” of at least subjected to an ation test, has a “penetration depth to crack about 1.0 mm. release matrix formulation has~ In certain embodiments of the invention, the extended of at least about 1.0 mm, or at least about a “penetration depth to crack” distance 1.5 mm, or at least about 1.6 mm, 1.2 mm, or at least about 1.4 mm, or at least about least about 1.9 mm, or at least about 2.0 mm, or at or at least about 1.8 mm, or at least about 2.6 mm. least about 2.2 mm, or at least about 2.4 mm, or at release matrix formulation has a In a further embodiment, the solid oral extended least about 130 N, or at least about 140 N cracking force of at least about 120 N, or at of at least about 1.2 mm, or at least and/or a “penetration depth to crack” distance least about 1.6 mm. . about 1.4 mm, or at least about. 1.5 mm, or at the extended release matrix In certain such embodiments of the ion, 110 N, or at least about 120 N, or at formulation has a cracking force of at least about least about 150 N, or at least about least about 130 N, or at least about 140 N, or at about 190 N, or at 160 N', or at least about 170 N, or at least about 180 N, or at least crack” distance of at least about 1.0 least about 200 N, and/or a ration depth to about 1.5 mm, or at 1.2 mmor at least about 1.4 mm, or at least mm, or at least about at least about 1.9 mm, or at least least about 1.6 mm, or at least about 1.8 mm, or least about 2.4mm, or at least about about 2.0 mm, or at least about 2.2 mm, or at values of cracking force and 2.6 mm. A combination of any of the aforementioned the scope of the present “penetration depth to crack” distance is included in invention. e matrix ations of the In a further embodiment, solid oral extended 30minvention resist work of at least about 0.06 J without cracking.

[Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs ation] mpjs Unmarked set by mpjs when subjected In certain such embodiments the extended release matrix formulation at least about 0.08 J, or to an indentation test resists work of at least about 0.06 J, or at least about 0.09 J, or at least about 0.11 J, or at least about 0.13 J, or at least about about 0.21 0.15 J, or at least about 0.17 J, or at least about 0.19 J, or at least J, or at least about 0.23 J, or at least about 0.25 J, without cracking. crack distance” and “work” The parameters “cracking force”, “penetration depth to indentation test as described above, using a Texture may be determined in an Technologies Corp., 18 Analyzer such as the TA-XT2 Texture er re and/or “penetration depth Fairview Road, Scarsdale, NY 10583). The cracking force uncoated or a coated extended release to crack” distance can be determined using an matrix formulation. matrix formulation is in the form of a In certain embodiments, the extended release and the tablet can at multi— or r tablet or multi- or bilayer multi particulates, thickness of the tablet after the least be flattened without breaking, characterized by a 60 % of the thickness of the flattening which corresponds to no more than about _ Preferably, the tablet can tablet or the individual articulates before ing. characterized by a thickness of the tablet after at least be flattened t ng, than about 50 %, or no more than about the flattening which corresponds to no more than about 20%, or no more than about 40 %, or no more than about 30%, or no more 16 % of the ess of the tablet before flattening. with a bench press, such as a Preferably, the flattening of the tablets is performed as described above. carver style bench press, or with a hammer, release matrix formulation is in the form In certain such embodiments the extended of a multi- or bilayer tablet and the tablet can at least be flattened without breaking, which corresponds to no characterized by a thickness of the tablet after the flattening the tablet before flattening, and wherein GHOI'E than about 60 % of the thickness of when measured in a USP said flattened tablet provides an in-vitro dissolution rate, [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes 0.5 hours or (SGF) at 37° C, characterized by the percent amount of active released at 1 hours, or at 0.5, 0.75, 1 and 1.5 hours, or at 0.5 and 0.75 hours, or at 0.5, 0.75 and % at 0.5, 0.75, 1, 1.5 and 2 hours of dissolution that deviates no more than about dissolution rate of a points at each of said time points from the corresponding in-vitro without non-flattened reference tablet. Preferably, the tablet can at least be flattened which breaking, characterized by a thickness of the tablet after the ing corresponds to no more than about 50 %, or no mere than about 40%, or no more than about 16% of the than about 30%, or no more than about 20%, or no more flattened tablet es an thickness of the tablet before flattening, and wherein said 1 (basket) at 100 rpm in in-vitro dissolution rate, when measured in a USP tus 37° C, characterized by the 900 m1 simulated gastric fluid without enzymes (SGF) at 0.5 and 0.75 hours, or at 0.5, percent amount of active released at 0.5 hours, or at 0.75 and 1 hours, or at 0.5, 0.75, 1 and 1.5 hours, or at 0.5, 0.75, 1, 1.5 and 2 hours of than about 20 % dissolution that deviates no more than about 30% points, or no more from the points, or no more than about 15 % points at each of said time points tablet. corresponding in-Vitro dissolution rate of a non-flattened reference of extended ably, the tablet hardness test to determine the breaking strength described release matrix formulations is performed in a niger Apparatus as 2E /106 above. For example, the ng th is determined using a Schleuniger about 196 N, or a Schleuniger Apparatus and applying a force of a maximum of about 439 N.

Model 6D Apparatus and applying a force of mum of formulations of the present It has been observed that the extended release matrix oxide can be flattened to invention sing a high molecular weight polyethylene about 18 % of the non—flattened thickness, and a thickness of between about 15 and its initial that the flattened bilayer tablet s in part or substantially s the swelling non-flattened shape or a portion thereof during dissolution, neglecting of the bilayer tablet Drat also takes place during dissolution, i.e. the thickness dissolution. Without increases and the diameter decreases considerably during [Annotation] mpjs None set by mpjs ation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs wishing to be bound to any theory, it is ed that the high molecular weight initial polyethylene oxide has a “form memory” providing the y to restore the in an environment form or a portion thereof after deformation, 6.g. after flattening, in dissolution that allows such restoration, such as an aqueous environment used in particular the tests. This ability is believed to contribute to the tamper resistance, alcohol resistance, of the dosage forms of the present invention.

CLINICAL STUDIES to the The solid oral extended release pharmaceutical dosage form according invention comprising hydrocodone or a pharmaceutically acceptable salt, hydrate the following insolvate thereof, or mixtures of any of the foregoing, may proVide vivo parameters. form may provide a C24/Cmax Such solid oral extended e pharr'naceutical dosage ratio of hydrocodone of about 0.40 to about 1.0 after administration of a single dose, The C24/Cmax ratio may be about 0.40 to about or after stration at steady state. about 0.70, or about 0.2 to about 0.85, or about 0.40 to about 0.75, or about 0.45 to 0.8, about 0.3 to about 0.7," or about 0.4 to about 0.6. form may provide a Tmax (h) Such solid oral extended release pharmaceutical dosage 6 to about 12 hours, or of hydrocodone from about 4 to about 20 hours, or about after administration about 4 to about 10 hours after administration of a single dose, or at steady state.

Such solid oral extended release pharmaceutical dosage form may provide a mean each 20 mg AUC (ng*h/mL) after stration of about 250 to 400 per Cmax hydrocodone included in the dosage form, and may also provide a mean mg hydrocodone (ng/rnL) after stration of about 10 to about 30 per each dcluded in the dosage form.

[Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs mg If such solid oral extended release pharmaceutical dosage form Contains about hydrocodone or a pharmaceutically acceptable salt thereof, it may provide a mean AUC mL) after administration of about 250 to about 400, or about 270 to about 350, and a mean Cmax (ng/mL) after stration of about 10 to about 30, about 12 to about 25, about 14 to about 18, or about 12 to about 17. about If such solid oral extended release pharmaceutical dosage form contains it may provide a 120 mg hydrocodone or a ceutically acceptable salt thereof, about 1500 to about 2400, about 1700 mean AUC (ng*h/mL) after administration of to about 2100, and a mean to about 2200, about 1800 to about 2100, or about 1900 about 80 to about 160.

Cmax ) after administration of about 60 to about 180, or also provides a Such solid oral extended release pharmaceutical dosage form may to about 10 h, about 6 to about 9 h, mean T1/2 (h) after administration of about of about 0.01 to about about 7 or about 8h, and a mean Tlag (h) after administration 0.2. form of the In general, the solid oral extended release pharmaceutical dosage The mean AUC invention is administered to a subject patient in the fasted state. less than 20% higher, or (ng*h/mL) after administration in the fed state is preferably AUC (ng*h/mL) after less than 16% , or less than 12% higher than the after administration in the fasted state. Likewise, the mean Cmax (ng/mL) than 70% administration in the fed state is preferably less than 80% higher, less in the fasted state. higher, or less than 60% higher than the Cmax after administration be within Additionally, the mean Tmax (h) after stration in the fed state may in the fasted state; the mean %, or within 30% of the Tm“ (h) after administration % of the T1 /2 after T1/2 (h) after administration in the fed state may be within in the fed administration in the fasted state; and the mean Tlag (h) after administration after administration in the fasted state may be less than 150% higher than the T1,; state.

[Annotation] mpjs None set by mpjs ation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs —60- multi- The invention also encompasses the method of treatment wherein a bilayer or condition of a t layer dosage form is administered for treatment of a disease or multi—/ or bilayer dosage that requires treatment in particular pain and the use of a ment for the form according to the invention for the manufacture of a that requires treatment in treatment of a e or certain condition of a patient ular pain. form of The invention also encompasses the use of a bilayer or multi—layer dosage treat a disease or condition of a the invention in the manufacture of a ment to patient requiring such treatment. In one embodiment, the condition is pain.

EXAMPLE 1 Hydrocodone bitartrate bilayer tablets. bitartrate were prepared, Three different bilayer tablets including 20 mg hydrocodone oxide blocking layer of each possessing a 400 mg active layer and a polyethylene 300 mg (Example 1C), respectively. 100 (Example 1A), 200 (Example 1B) and in Table l: The compositions of these tablets are shown [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs Table 1 _-—--- Ref. to Component mg/tablet mg/tablet mg/tablet Function ’ Standard .0 20.0 Active USP Hydrocodone bitartrate 20.0 Microcrystalline cellulose Hydroxypropylcellulose Polyethylene oxide (WSR—303) stearate , Magnesium Active Layer Subtotal Polyethylene oxide (WSR-303) and the 1 d water is used to e the hydrocodone bitartrate granulation coating suspension. It is not t in the final product. 2 HSE = in-house standard [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs Table 2A Components of the active layer in weight percent: ent % (by wt.) % (by wt.) Hydrocodone bitartrate Microcrystalline cellulose Hydroxypropylcellulose Polyethylene oxide 03) Magnesium stearate Table 2B Percentaged composition blocking layer: Ex. 1A Ex. 1B Polyethylene oxide (WSR-303) Magnesium stearate Table 2C Ratio active layer / blocking layer: Weight ratio active layer / blocking layer [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs Preparation of blocking layer blend: A “V” blender (Gemco “V” Blender ~— 2 CU. FT.) with intensifier bar was d with the polyethylene oxide WSR 303 and the magnesium stearate.

Step 1 materials were blended for one minute with the intensifier bar OFF.

Step 2 blend was charged into a clean, tared stainless steel or polyethylene lined container. ation of active layer blend: A high-shear granulator (Collette 75 L) was charged with the hydrocodone bitartrate, the microcrystalline cellulose and the hydroxypropylcellulose.

Water was added to the mixture with the propeller and chopper on.

The wet granulation from step 5 was passed through the coarse screen of a Quadro Comil g device.

The screened granulation'from step 6 was dried in a Vector VFC-3 fluid bed dryer.

The dried granulation from step 7 was passed through the fine screen of the Quadro Comil.

A “V” blender (Gemco 2 CU. FT.) with intensifier bar was charged with the polyethylene oxide WSR 303 and the milled granulation from step 8.

. Step 9 materials were blended for 7.5 minutes with the intensifier bar OFF. ll. Magnesium stearate was added to the mixture from step 10. 12. Step 11 als were blended for 1 minute with the intensifier bar OFF. 13. Step 12 blend was charged into a clean, tared ess steel or polyethylene lined container.

Pre aration of bila er tablets: D' The blends from step 3 and step 13 were concurrently compressed into r oval tablets on a Kamavati bilayer tablet'press (Kamavati UNIK-I) at [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs was loaded into the side one a rotation speed of 10 rpm. The active blend 400 mg. Then the hopper and the active layer weight was adjusted to target two hopper and the total tablet blocking layer blend was loaded into the side weight was adjusted to target. After weight adjustment, the compression run 10 rpm. was started and the press was run at . The aqueous Opadry® coating suspension was prepared by adding Opadry® in the purified water, white to the vortex. Once the Opadry® was orated the mixing was continued for about an hour prior to use. 16. Approximately 10 kg of the core tablets from step 14 were weighed out of about 1.0 '10 coated with the g suspension to a target weight gain % (by wt.) in a perforated 24 inch Compu-Lab pan coater (COMP-U-LAB inlet air temperature to 55 °C. 24). The tablet bed was warmed by setting the the film coating began at a pan Once the exhaust temperature d 39 °C, 45 mL/min. Film coating speed of 15 rpm and a spray rate of approximately was achieved. was continued until the target 1% weight gain cured in the ated pan 17. The partially coated tablets from step 16 were 85 °C at a pan speed- of approximately coater. The inlet temperature was set to of 72 °C for rpm. The tablets were cured at an exhaust temperature approximately 30 minutes. the inlet 18. After curing, the tablets were cooled in the rotating pan by g temperature to 22 °C. g was continued until the exhaust temperature was less than 28 °C. with the coating Suspension 19. The cured tablets from step 18 were spray—coated in the perforated pan coater at a to a target final weight gain of 4.0 % (by wt.) and spray rate of approximately 50 mL/min. pan speed of 15 rpm tared polyethylene lined drum.

. The film coated tablets were transferred into a [Annotation] mpjs None set by mpjs [Annotation] mpjs ionNone set by mpjs [Annotation] mpjs Unmarked set by mpjs EXAMPLE 2 Hydrocodone Bitartrate Film Coated Bilayer Tablets, 120 mg. 120 mg odone bitartrate In Example 2, three different bilayer tablets including 400 mg active layer and a polyethylene oxide were prepared, each possessing a and 300 mg blocking layer of 100 mg (Example 2A), 200 mg (Example 2B) (Example 2C), respectively. are shown in Table 3.

The compositions of Examples 2A, ZB and 2C, respectively are shown in Table 3.

The compositions of Examples 2A, 2B and 2C, respectively [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs Table 3 Ref. to Component mg/tablet mg/tablet mg/tablet Function Standard Hydrocodone bitartrate 120.0 120.0 -Ingredient -120.0 Active USP Microcrystalline 8.16 8.16 8.16 t NF bellulose - 00 ,_. Q Polyethylene oxide 261.68 261.68 261.68 Release- NF Controlling (WSR-303) Active Layer Subtotal 400.0 400.0 400.0 -- Blocking Layer Polyethylene oxide 99.5 199.0 298.5 Release- ‘ Controlling (WSR-303) 300.0 Blocking Layer 100.0 200.0 Subtotal ® White Y 18024-A 1 Purified Water is used to prepare the hydrocodone bitartrate granulation and the coating a suspension. It is not t in the final product. 2 HSE = in-house standard [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs -67— of the From the overall composition of Examples 2A, 2B and 2C, the amount in weight components of the active layer in weight percent and of the blocking layer / blocking layer, can be percent, as well as the percent ratio of the active layer calculated. This is shown in Tables 3A, 3B and 3C, respectively.

Table 3A OOB'UGBCD59m GIn, 95" (D h?0:3.<0 ET‘<(D'1 I—5 S(DI-(N5‘pp "U(D"I(3CD5H ent % (by wt.) % (by wt.) Hydrocodone bitartrate Microcrystalline cellulose Hydroxypropylcellulose Polyethylene oxide (WSR-303) Magnesium stearate Table 3B Components of the blocking layer in weight t ent Wm» Polyethylene oxide (WSR-303) Magnesium stearate [Annotation] mpjs None set by mpjs ation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs Table 3C Ratio active layer / blocking layer: ——-- Weight ratio active layer / blocking layer 4.00 2.00 1.33 The processing steps to cture the tablets in Examples 2A, 2B and 2C were as follows: Batch sizes 2A: 13 kg, 25,000 Tablets 2B: 15.6 kg, 25,000 Tablets 2C: 18.2 kg, 25,000 Tablets those The process conditions for the preparation of the above batches correspond to used in Example 1.

EXAMPLE 3 Hydromorphone hydrochloride film—coated s 12 mg.

In e 3, two different bilayer tablets including 12 mg hydromorphone hydrochloride were prepared, each possessing an active layer of 500 mg (Example oxide 3A) and 400 mg (Example 3B), respectively, and a 200 mg polyethylene bIOCking layer.

[Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs —69- The compositions of the compositions in Examples 3A and 3B, respectively are shown in Table 4.

Table 4 Ex. 3A Ref. to Component mg/tablet mg/tablet Function Standard Active layer Hydromorphone 12.0 12.0 hydrochloride Polyethylene oxide 485.5 386.0 400.0 Active Layer Subtotal Blocking Layer Polyethylene oxide 199.0 199.0 H O 1 Blocking Layer Subtotal 200.0 28.0 24.0 Opadry 11 Beige 33G97231 1 HSE 2 Not present in final product — In-house rd; of Examples 3A and 3B, the weight percent rom the overall composition and the ratio of composition of the active layer and the blocking layer, respectively, [Annotation] mpjs None set by mpjs [Annotation] mpjs ionNone set by mpjs [Annotation] mpjs Unmarked set by mpjs in Tables 5A, 5B and active layer / blocking layer may be calculated. This is shown 5C, respectively.

Table 5A Composition of active layer in weight percent: % (by wt.) Component Hydromorphone Hydrochloride Polyethylene Oxide (WSR—303) Magnesium Stearate 100.00 100.00 Composition of ng layer in weight percent: , % (by wt.) % (by wt.) Component Polyethylene Oxide (WSR—303) 99.50 99.50 Table 5C Ratio active layer / blocking layer: Ratio active layer / ng layer in Examples 3A and 3B, The processing steps to manufacture the tablets respectively, were as follows: [Annotation] mpjs None set by mpjs [Annotation] mpjs ionNone set by mpjs [Annotation] mpjs Unmarked set by mpjs Batch sizes: 3A: 14.560 kg, 20,000 Tablets 3B: 13.728 kg, 22,000 s Preparation of blocking layer blend: ‘ 1. A Gemco “V” Blender - 2 CU. FT. with intensifier bar was charged with the polyethylene oxide WSR 303 and the magnesium stearate. 2. Step 1 materials were blended for one minute with the intensifier bar OFF. 3. Step 2 blend was charged into a clean, tared stainless steel or polyethylene lined container.

Preparation of active layer blend: 4. A PK “V” Blender — l6 QT. with intensifier bar was d with the polyethylene oxide WSR 303 and the hydromorphone hydrochloride. 9°89?“ Step 4 materials were blended for 10 minutes with the intensifier bar ON.

Magnesium stearate was added to the mixture from step 5.

Step 6 als were blended for one minute with the intensifier bar OFF.

Step 7 blend was charged into clean, tared stainless steel or polyethylene lined container.

Preparation of r tablets: 9. The blends from step 3 and step 8 were concurrently compressed into bilayer oval tablets on a ti bilayer press (Kamavati UNIK-I) at a speed of 10 ' into the side one hopper and the active rpm. The active blend was loaded layer weight was adjusted to target weight. Then the blocking layer blend was adjusted was loaded into the side two hoppers and the total tablet weight to target weight. After weight adjustment, the compression run was started and the press was run at 10 rpm.

[Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs . The adueous Opadry® coating suspension was prepared by adding 'Opadry® Beige to the vortex. Once the Opadry®- was incorporated in the purified hour prior to use. water, the mixing was continued for about an 11. Approximately 10 kg of the core tablets from step 9 were weighed out and i 1.0 spray-coated with the coating suspension to a target weight gain of about % (by wt.) in a perforated 24 inch Compu-Lab pan coater (COMP-U—LAB to 55 °C. 24). The tablet bed was warmed by setting the inlet air temperature at a pan Once the exhaust ature reached 39 °C, the film coating began Film coating speed of 12 rpm and a spray rate of approximately 45 mL/min. was achieved. was continued until the target 1% weight gain in the perforated pan 12. The partially coated tablets from step 11 were cured at a pan speed of approximately coater. The inlet temperature was set to 85°C of 72 °C for 12 rpm. The tablets were cured at an exhaust temperature approximately 30 minutes. the inlet 13. After curing, the tablets were cooled in the ng pan by setting temperature to 22 °C. Cooling was continued until the exhaust temperature was 1eSs than 28 °C. with the g suspension 14. The cured tablets from step 13 were spray-coated in the ated pan coater at a to a target final weight gain of 4.0 % (by wt.) and spray rate of approximately 45 . pan speed of 12 rpm . The tablets were discharged.

EXAMPLE 4 32 mg.

Hydromorphone hloride Film Coated Bilayer Tablets, 32 mg hydromorphone In e 4, two different bilayer tablets including of 500 mg and 400 mg, hloride were prepared, each possessing an active layer respectively, and a 200 mg polyethylene oxide blocking layer.

[Annotation] mpjs None set by mpjs ation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs shown in The compositions of the tablets in Examples 4A and 4B, respectively, are Table 6.

Table 6 Ex. 4A mg/tablet Function Component mg/tablet Active layer 32 0 32,0 Active Ingredient orphone hloride Polyethylene oxide 465 .5 366,0 Release—Controlling NF (WSR—303) Polymer Magnesium stearate N O0 Active Layer Subtotal Blocking Layer Polyethylene oxide 199.0 199.0 (WSR-303) v—I O t“fi0"E.0WE.

- -Z’T} .._.i O Blocking Layer Subtotal 200.0 200.0 _- Opadry 11 Beige 33G97430 1 HSE 2 Not present in final product - In-house standard; of individual Based on the information presented in Table 6, the amounts 10Dcomponents of the active layer ition and the blocking layer composition of ratio active layer / blocking Examples 4A and 4B in weight percent as well as the [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs 7B and 7C, layer may be calculated. This information is shown in Tables 7A, tively.

Table 7A Magnesium stearate Table 7B Polyethylene oxide (WSR-303) 100.00 100.00 Table 7C Ratio active layer / blocking layer: Ratio active layer / blocking layer [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs The processing steps to manufacture the tablets are described herein below.

The batch sizes for Examples 4A and 4B were: 4A: 14.560 kg, 20,000 Tablets 4B: 13.728 kg, 22,000 Tablets similar to those The process conditions for Examples 4A and 4B were ially used in e 3.

EXAMPLE 5 bitartrate.

Dissolution of bilayertablets comprising-20 mg or 120 mg hydrocodone d out using USP The ution of hydrocodone bitartrate tablets was from Hanson Research equipped with USP apparatus I (e.g. Dissolution Apparatus I steel spring (e.g. a passivated mesh baskets) with 10 mesh baskets. A stainless ‘Lee Spring Co. (P/N stainless steel spring, 1-cm outside diameter and 2-cm length, tablet. The basket was LC 036G 04 S316) was inserted into each basket containing a fluid without enzymes (SGF) then rotated at 100 rpm in 900 m1 simulated gastric an automated with a temperature maintained at 37 °C. The samples (e.g. sampled by and in line dissolution sampling device equipped with in-residence sampling probes, reversed-phase MinisartCA, 28 mm, 1.2 pm filters (P/N 17593 Q) were analyzed by Waters AllianceTM high performance liquid chromatography (HPLC; e.g. using a detector or 996 photodiode 2690/2695 HPLC system with 2487 UV—Vis ance Waters SymmetryShield RP 18 (4.6 x 100 mm, 3.5 mm) array (PDA) detector) on a of 31 :69 acetonitrilesz column ined at 60 °C using a mobile phase consisting monobasic 2.1 of 10 mM sodium dodecyl sulfate and 20 mM sodium ate 230 nm. drate buffer, flow rate 1.0 mL/min, with UV detection at [Annotation] mpjs None set by mpjs [Annotation] mpjs ionNone set by mpjs ation] mpjs Unmarked set by mpjs The test procedure comprises the ing steps: 1. Assemble the dissolution apparatus. Adjust the height of all baskets 25 i 2 mm from the bottom of each dissolution vessel. 2. Tranfer 900 mL of dissolution medium in each vessel. Heat the water bath so that the temperature of dissolution medium in all vessels is within 37.0 0C i 0.5 °C. 3. Check the temperature of the dissolution medium in each vessel with a thermometer before beginning theetestr—T—he temperature of the dissolution medium in each vessel must be 37.0 i 0.5 °C. 4. Place one tablet into each USP 10 mesh basket and horizontally insert a stainless steel spring in the top of the basket.

. Attach baskets containing the tablets to the -adjusted shafts. 6. Rotate the shafts at 100 rpm, and lower the shafts to the predetermined height so that the bottom of the basket is 25 j; 2 mm from the vessel bottom. _ 7. At the times specified in the instructions or as required, withdraw and filter sufficient amount of sample aliquot from each vessel. Transfer about 1 mL of the samples to each HPLC vial. 8. Inject 10 ul for all ons. No more than 12 sample solutions should be injected between standard solution injection. 9. Calculate the % hydrocodone bitartrate dissolved for each tablet at Gch time point as follows: [Annotation] mpjs None set by mpjs [Annotation] mpjs ionNone set by mpjs [Annotation] mpjs Unmarked set by mpjs AU 900mL 199 %Hydr0c0dore rate Dissolved= x Csmx x ASTD 1 tablet LC where AU = Area of the odone peak in the sample chromatogram ASTD = Area of the Hydrocodone peak in the standard chromatogram LC ,= Label claim for the ular potency (20 or 120 mg) in the working CSTD = Concentration of Hydrocodone bitartrate corrected for purity standard solution, mg/mL, When using Hydrocodone Bitartrate WRS: Wstd 12 mL %PWRS CSTD 2 x x 100mL 100mL 100 When using the dried Hydrocodone bitartrate USP RS: Wstd 12 mL %PUSP CSTD = x x x1.1002 IOOmL IOOmL 100 Wstd= Weight of Hydrocodone bitartrate RS in mg %PWRs = Percent purity of Hydrocodone bitartrate - 2 1/2 H20 WRS (as is) RS (on dried %Pusp = Percent purity of Hydrocodone bitartrate anhydrous USP basis) bitartrate - 2 1.1002 = Conversion factor from Hydrocodone bitartrate to Hydrogene 1/2 H20 When a total of more than 10 mL aliquot is taken from each vessel during dissolution run, volume correction should be applied in the calculation.

B (for tablets he results of the dissolution tests are shown in Tables 8 A and 8 comprising 20 mg hydrocodone bitartrate) and Table 9 (for tablets comprising 120 mg odone bitartrate) below.

[Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs ed set by mpjs well as The time of the measurement and the percentage dissolution (mean as in Examples 1A- m or maximum values) are shown for the tablets produced lC as well as in Example 2A-2C.

Table 8 A) --Time (h) Example 1A 97 (94/103) 9999 Example 1B non cumulative non cumulative Mean (Min/Max) release release/h from hour 2 to 12 ———— ——__ 99999999 —— -——— Mean hourly release between (30%= i 1.7) 4.1 — 7.5 hour 2 and 12 and corresponding zero order ran 6 [Annotation] mpjs None set by mpjs ation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs Table 8 B) Example 1C non cumulative non cumulative Mean (Min/Max) release release/h from hour 2 to 12 Mean hourly release between 3.6—6.8 hour 2 and 12 corresponding zero order ran 6 [Annotation] mpjs None set by mpjs ation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs Table 9 Example 2A non cumulative non cumulative Mean (Min/Max) release release/h from hour 2 to 12 333333 — 3333333 _ 37 (36/39) 16 8 (hours 2 to 4) 64 (63/67) 27 6.75 (hours 4 to 8) 333333 3333333333 33333— 33373333 _ Mean hourly :l: 2.4) release between (40% = 3.7 — 8.5 hour 2 and 12 corresponding zero order ran _e Example 2B non tive non cumulative release/h from Mean (Min/Max) release hour 2 to 12 —1 33333 _ 333333 _ 333433 7333333333 59 (57/63) 5.75 (hours4to 8) WM _3333333333<> 333333 — Mean hourly - release between (30% =4: 1.7) 3.9 — 7.3 hour 2 and 12 corresponding zero order ran e ation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs ed set by mpjs Example 2C non cumulative non cumulative Mean (Min/Max) release release/h from hour 2 to 12 — luv/14> —— —21 (20/22) —34 (33/35) 75 (hours 2 to 4) “2 (512/13) 5.25 (hours 4 to 8) 71 (69/72) 4 (hours 8 to 12) 8634/83» —— 9493/92 Mean hourly release between (50% = :1: 2.5) hour 2 and 12 2.5 — 7.5 corresponding zero order ran EXAMPLE 6 Dissolution of bilayer tablets comprising 12 mg and 32 mg hydromorphone HCl The dissolution of hydromorphone hydrochloride tablets was carried out using a modified USP Apparatus I (e.g. Dissolution Apparatus I from Hanson Research equipped with USP 10 mesh baskets) with 10 mesh baskets. The modification to the USP Apparatus I consisted of inserting a stainless steel spring on top of USP 10 mesh baskets. The ess steel spring (e. g. a passivated stainless steel spring, 1-cm outside diameter and 2-cm , Lee Spring Co. (P/N LC 036G 04 S316) was inserted into each basket containing a tablet. The basket was then rotated at 75 rpm. in 900 ml ted gastric fluid t enzymes (SGF) with a temperature maintained at 37 °C. The samples (e.g. sampled by an automated dissolution ampling device equipped with in—residence sampling probes, and in-line 25mm Glass fiber 1.0-um filters s P/N WAT200818) or 10 canula filter (QLA P/N [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs ation] mpjs Unmarked set by mpjs FILOl 0—01) were analyzed by reversed-phase high performance liquid chromatography (HPLC; e.g. using a Waters AllianceTM 2690/2695 HPLC system with 2487 or 2489 UV-Vis absorbance detector or 996 photodiode array (PDA) °C using detector) on a Waters Novapak C18, 3.9 x 150 mm, 4 mm column kept at 30 sodium dodecyl sulfate, a mobile phase consisting of a mixture of acetonitrile, flow rate of monobasic sodium phosphate buffer and water with a final pH of 2.9 at a 1.5 , with UV detection at 220 nm.

The test procedure comprises the following steps: 1. Assemble the dissolution apparatus. Adjust the height of all baskets 25 j; 2 mm from the bottom of each dissolution vessel. r 900 mL of dissolution medium in each vessel. Heat the water vessels is within 37.0 °C i bath so that the temperature of dissolution medium in all 0.5 °C. vessel with a . 3. Check the temperature of the ution medium in each of the dissolution medium thermometer beforebeginning the test. The ature ineach vessel must be 37.0 i 0.5 °C. insert a 4. Place one tablet into each USP 10 mesh basket and horizontally stainless steel spring on top of the basket. shafts. 5. Attach s containing the tablets to the height-adjusted 6. Rotate the shafts at 100 rpm, and lower the shafts to the predetermined vessel bottom. height so that the bottom of the basket is 25 i 2 mm from the withdraw and D 7. At the times specified in the instructions or as required, Transfer about 1 mL of filter sufficient amount of sample aliquot from each vessel.

[Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs the samples to each HPLC vial. Cap vials before performing the HPLC analysis. of at least 3 When sampling, ensure that the ng apparatus has a pre-wash cycle mL before sample collection. should be 8. Inject 20 ul for all solutions. No more than 12 sample solutions injected between standard solution injection. each tablet 9. Calculate the % hydromorphone hydrochloride dissolved for at each time point as follows: time point was The % orphone HCl ved for each tablet at each calculated according to the following equation: AU 900mL 100 %Hydr0m0rphone HCl ved = x CSTDx x _— ASTD 1 tablet LC where: AU =Area ofthe hydromorphone peak in the sample chromatogram ' the standard chromatogram Aer = Area of the hydromorphone peak in 32 mg) LC =Label claim for the particular potency (12, 16, 24, or corrected for purity in the Cer = Concentration of Hydrocodone bitartrate working standard solution, mg/mL WtStd -15 mL %purily CSTD — x x lOOmL 200mL 100 volume When a total of more than 10 mL t is taken from each vessel, correction method should be applied for calculation. of the measurement and Ufhe results are shown in Tables 10 and 11 below. The time maximum values) are the percentage ution (mean as well as minimum or [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs shown for the tablets produced in Examples 3A and 3B, and for the tablets produced in Examples 4A and 4B, respectively: Table 10 Time (h) Example 3A non cumulative non tive Mean (Min/Max) release release/h from hour 2 to 12 ——_(7.94/8.80) ———(1353/1490) (2337/2506 (43 .03/44.24) (59.85/62.28) ——_(78..09/81.43) —_—(8860/9269) -—_(96.03/100.80 Mean hourly release between (20% = a. 0.9) 3.8 — 5.6 hour 2 and 12 corresponding zero order ran _e [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs Time (h) Example 3B non cumulative non cumulative to 12 1——(8.93/9.77) 2 _— 1549/1725 2556/2882) (45.03/49.28 6721) 18 _— » (80.50/84.70) 24 _—_ 9454) 36 ——- (95.12/99.78) Mean hourly release between 3.9—5.9 hour 2 and 12 corresponding zero order rane [Annotation] mpjs None set by mpjs [Annotation] mpjs ionNone set by mpjs [Annotation] mpjs Unmarked set by mpjs Table 11 Time (h) Example 4A non cumulative non cumulative Mean (Mm/Max) release release/h from hour . 2 to 12 —l 9-00(8-67/9.45 —— —2 1472/15-73)—— —4 2613(25.15/2666. . 56(hours2to4 __45 71 (44.73/4649) 4.9 hours4t08 6 . ——l—— 103.12 (101.99/104.69) Mean hourly release 4.8 between hour 2 and (20% =1: 1) 12 3.8- 5.8 and corresponding zero order ran e Example 4B non cumulative non cumulative Mean (Min/Max) release release/h from hour 2to 12 100000040_— _16.80(16.35/17.61) —28.07 (2738/2911) 11.3 5.7 (hour52t04) 65.80 (65 00/67 83) 4.4 8to 12) 3 101.09 (99.73/10329) Mean hourly release- between hour 2 and (20% = d: 1) 39—59 and corresponding zero order range [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs EXAMPLE 7 Pharmacokinetics of bilayer tablets sing 20 mg and 120 mg hydrocodone bitartrate In Example 7, a randomized, open—label, single-dose, four-treatment, four-period, was conducted to assess crossover study in y adult male and female subjects the pharmacokinetic characteristics of six hydrocodone formulations (20 mg 120 mg hydrocodone bitartrate, formulations of Examples 1A, 1B, and 1C as well as in the fasted of hydrocodone rate, formulations of Examples 2A, 2B and 2C) (all EXamples) and fed state (1B and 2B).

The formulations were each administered orally with 8 oz. (240 mL) water as a single dose in the fasted or fed state.

As this study was conducted in y human subjects, the opioid antagonist adverse naltrexone hydrochloride was administered to minimize opioid-related events .

Subject ion Screeningprocedures at a The following screening procedures were performed for all potential subjects screening visit conducted within 28 days prior to first dose administration: -Informed consent. med consent for optional pharrnacogenomic sampling. a —Informed consent for al hair sampling.

—Weight, height, body mass index (BMI), and demographic data.

[Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs —88— -Evaluation of inclusion/exclusion criteria.

-Medical and medication history, ing concomitant medication. oral -Vital signs (systolic/diastolic blood pressure, pulse rate, respiration rate, temperature) after being seated for approximately 5 minutes and SpOz -Additional vital signs (systolic/diastolic blood pressure, and pulse rate) after standing for approximately 2 minutes. measured.

-HDYF? Inquiry was performed at the same time vital signs are -Routine physical ation.

-Clinical laboratory evaluations following at least a 4 hour fast (including biochemistry, hematology, and ysis). lead ECG. QTCF not to exceed 450 msec.

-Screens for hepatitis (including hepatitis B surface antigen [HBsAg], hepatitis C dy [anti-HCV]). abuse.

-Screens for alcohol, cotinine, and selected drugs of —SerUm pregnancy test, female subjects only; Serum follicle stimulating hormone (PSI-I) postmenopausal females only;.

-Serum pregnancy test (female subj eCts only).

-Serum follicle stimulating hormone (FSH) test (postmenopausal females only) ion criteria in the study.

—Subjects who met the following criteria were ed ded written informed consent.

-Males and females aged 18 to 50, ive.

BMI 18 to 34 a -Body weight ranging from 50 to 100 kg (110 to 220 lbs) and a (kg/m2), inclusive.

[Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs -Hea1thy and free of significant abnormal findings as determined by medical history, physical examination, vital signs, and ECG.

-Females of child—bearing potential must be using an te and reliable method of contraception (i.e, barrier with additional spermicidal foam or jelly, intra-uterine device, al contraception). Females who are post- menopausal must have been postmenopausal Z 1 year and have elevated serum FSH.

-Willing to eat the food supplied during the study.

-Will refrain from strenuous exercise during the entire study. Subjects will strenuous not begin a new exercise program nor participate in any unusually physical exertion. ion criteria The following criteria excluded potential subjects from the study.

—Females who are pregnant ive beta human nic gonadotropin test) or lactating. abuse.

-Current or recent (within 5 years) y of drug or alcohol —History or any current ions that might interfere with drug tion, distribution, metabolism or excretion.

-Use of an opioid-containing medication in the past 30 days preceding initial dose in this study. related -History of known sensitivity to hydrocodone, naltrexone or compounds. of etiology.

-Any history of frequent nausea or emesis regardless a -Any history of seizures or head trauma with sequelae.

[Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs Participation in a al drug study during the 30 days preceding the initial dose in this study. dose in this -Any cant illness during the 30 days preceding the initial study.

—Use of any medication including thyroid hormonal therapy (hormonal contraception is allowed), vitamins, herbal and/or mineral supplements during the 7 days ing the initial dose.

-Abnormal cardiac conditions including any of the ing: o QTc interval 2 450 msec (calculated using Fridericia’s correction) ing. 0 QTc interval _>_ 480 msec lated using Fridericia’s correction) during Treatment .

-Refusal to abstain from food 10 hours preceding and 4 hours following study xanthine containing drug administration and to abstain from caffeine or beverages entirely during each confinement. 48 hours prior -Refusal to abstain from consumption of alcoholic beverages and anytime during study. to initial study drug administration (day l) 45 days of study drug -History of smoking or use of nicotine products within administration or a positive urine cotinine test.

-Blood or blood products donated within 60 days prior to study drug 7 administration or anytime during the study and for 30 days after completion of the study, except as required by this protocol.

-Plasma donated within 14 days prior to study drug administration or any time during the study, except as ed by this protocol.

-Positive results of urine drug screen or alcohol screen. ive results of HBsAg, anti-HCV. -_PositiVe naloxone HCl challenge test. abnormalities.

-Presence of Gilbert’s Syndrome, or any known hepatobiliary [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs -For the optional hair ng portion of the study only, an insufficient amount of scalp hair to provide an adequate sample.

-The igator es the subject to be unsuitable for reason(s) not specifically stated in the exclusion criteria.

Subjects meeting all the inclusion criteria and none of the exclusion criteria were randomized into the study.

Each subject was assigned a unique subject number at screening. Assignment of subject numbers was in ascending order and no numbers were omitted. Subject numbers were used on all study documentation.

Check-in Procedures On Day -1 of Period 1 only, subjects were admitted to the study unit and received a Naloxone HCl challenge test. The results of the test had to be negative for subjects to continue in the study. Vital signs and SP02 were measured prior to and ing the Naloxone HCl.

The ing procedures were also performed for all subjects at Check-in for each verification of . -Verification of inclusion/exclusion criteria, including willingness to comply with caffeine and xanthine restriction ia.

-Vital signs (after being seated for approximately 5 minutes) and Sp02.

-HDYF(How do you feel) ? Inquiry was performed at the same time vital signs are measured.

-Clinical laboratory evaluations (day —1, period 1 only) including a biochemistry ng for at least 4 hours), hematology and urinalysis; Appendix A) were collected after vital signs and Sp02 were measured.

[Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs -Screen for alcohol (via urine or blood alcohol or breathalyzer test), ne, and selected drugs of abuse (via urine testing). See ix A.

-Urine pregnancy test (for all female subjects; Appendix A). mitant medication monitoring and recording.

-AE monitoring and recording.

For subjects to continue their participation in the study, the results of the drug screen (including alcohol and cotinine) had to be available and negative prior to dosing. In addition, ued compliance with concomitant medication and other restrictions , source were verified at Check-in and throughout the study in the appropriate documentation.

Treatment Period Procedures Treatments to be d were predetermined for each Iteration. Within an Iteration, cohorts. Dropped as data became available, treatments were dropped between ents were ed with repeats of remaining treatments.

—Prior to the first dose in period 1, subjects were randomized to a treatment sequence.

-Subjects will received naltrexone HCl s (50 mg) with 240 mL of water at -12 h prior to study drug dosing.

-Prior to study drug administration (except period 1), subjects had chemistry (fasting for at least 4 hours), hematology and urinalysis tests performed.

-Subj ects were stered the study drug with 240 mL of water as follows: 0 For Fasted Treatment: Following a 10-hour overnight fast, subjects were administered study . drug with 240 mL of water. Subjects receiving‘fasted treatment continued fasting from food for 4 hours following dosing.

[Annotation] mpjs None set by mpjs [Annotation] mpjs ionNone set by mpjs [Annotation] mpjs Unmarked set by mpjs 0' For Fed Treatments: Following a 10-hour overnight fast, the subjectswere fed a standard meal (FDA high-fat breakfast, Appendix E) 30 minutes prior to administration of study drug with 240 mL of water. No food was allowed for at least 4 hours post-dose. It was made very clear to the subjects that all of the meal should be consumed within the designated time-frame. 0 Subjects were standing or in an upright sitting position while receiving their dose of study drug. 0 g was not required for nondosing study days. of water at -Subj ects will received naltrexone HCl 50-mg s with 240 mL -12, 0, 12, 24, and 36 hours relative to each study drug dosing.

—For ts receiving hydrocodone doses of 60 mg or more, SpOg was monitored continuously beginning prior to closing and continuing h hours ose. and SpOz, were -Vital signs (after being seated for approximately 5 minutes) ’ hour post obtained pre-dose and at hour 1, 2, 4, 6, 8, 12, 24, 36, 48, and 72 dose for each period. time vital -HDYF (How do you feel) ? Inquiry was med at the same signswere measured.

-Subj ects will had biochemistry (fasting for at least 4 hours), hematology, urinalysis tests performed 24 hours post-dese.

-In addition, 12-lead ECGs were performed for each subject pre-dose approximately 12, 24 and 48 hours post-dose. If QTcF exceeded 480 msec the subject was discontinued due to the reason of Adverse Event.

-Blood samples for determining oxycodone plasma concentrations were obtained for each t at pre—dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 14, 18 24, 36, 48, and 72 hours post-dose for each period.

[Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs ation] mpjs Unmarked set by mpjs —Subj ects were confined to the unit from check-in to the unit on the day before closing until the time that their 48 h procedures were completed. The subjects returned to the unit for the 72 h procedures.

-During the study, ABS and concomitant medications were recorded.

In addition, the subjects were ed that it is very important to report any/all episodes of emesis to the study staff immediately and that this information is informed that they to the proper t and outcome of the trial. The subjects were staff would not be penalized in any way due to reporting cases of emesis. The study of emesis. was instructed to carefully document any/all cases The treatment sequences for this study are presented below: Iteration 1 o HYD 20 mg, slow release tablet (Ex 1A), fasted state 0 HYD 20 mg, medium release (Ex 1B), fasted state 0 HYD 20 mg, fast release (Ex 1C), fasted state - HYD 20 mg, medium release tablet (Ex 1B), fed state Iteration 2 o HYD 120 mg, slow release tablet (Ex 2A), fasted state 0 HYD 120 mg, medium release tablet (EX 2B), fasted state. 0 HYD 120 mg, fast release tablet (Ex 2C), fasted state 0 HYD 120 mg, medium release tablet (Ex 2B), fed state Following a review of pharmacokinetic data from Cohort 1 subjects in Iterations 1 l of each and 2, it was determined that two of the four treatments studied in Cohort fed and Fast Iteration would not be further studied in Cohort 22 Medium release, release, fasted. These dropped treatments were replaced by repeats of the two Demaining treatments: Slow e, fasted and medium release, fasted. See Figure 2.

[Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs .

Study Completion Procedures The following procedures were performed at the study site for all subjects at end—of- study (study completiOn), 7 to 10 days after receiving their last dose of study drug or upon early discontinuation from the study.

-Concomitant medication evaluation.

-Vital signs (after being seated for approximately 5 minutes) and SpOz.

-HDYF? Inquiry was performed at the same time vital signs are measured. 1 0 -Physical examination.

Lead ECG.

—Clinical laboratory evaluations (including biochemistry [fasted at least 4 hours], logy, and ysis;).

-AE tions.

-Serum pregnancy test (for female subjects only;).

The pharmacokinetic s of this study. are shown in Table 12 as well as Figures 3 to 6.

[Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs [Annotation] mpjs Unmarked set by mpjs Table 12: Summary of Draft Plasma Hydrocodone Pharmacokinetic Parameters Iteration 1: 20 mg ion 2: 120 mg 20 mg 120 mg Slow Medium Fast Slow Medium Fast Medium Medium Fasted Fasted Fasted Fasted Fasted Fasted Fed Fed Parameter (Unit) Statistic (N=51 =49 (N=18 15 AUCt MEAN 270 274 279 1762 1898 1962 312 2073 (ng*h/mL) SD 82 86 65 547 502 464 75 454 MIN 73 66 183 705 781 1335 183 1398 MAX 449 452 421 2950 3095 2748 460 2872 AUCinf Mean 279 278 283 1773 1910 1971 316 2082 (ng*h/mL) SD 81 87 65 550 506 468 76 461 Min 76 70 186 711. 783 1337 185 1398 Max 451 462 423 2968 3106 2784 467 2905 Cmax Mean 12.2 12.8 14.9 82.6 90.0 95.8 18.8 120.2 (ng/mL) SD 3.7 3.9 4.1 22.1 22.9 24.8 4.6 26.0 Min 4.8 6.8 7.2 46.4 55.7 61.8 11.9 66.6 Max 22.3 23.4 23.4 158.0 168.0 162.0 26.9 150.0 Tmax Mean 7.4 7.8 7.5 6.3 8.0 8.2 10.1 10.7 (h) SD 3.6 3.4 2.8 2.0 3.1 3.1 1.8 3.5 Min 2 4 5 3 5 5 6 5 Median 6 6 7 6 8 8 10 10 Max 18 18 14 14 18 14 12 18 T1/2 Mean 9.7 7.7 7.6 8.4 8.1 8.1 8.8 8.9 (h) SD 6.3 2.5 2.3 3.3 2.8 3.4 4.5 3.5 Min 4.6 4.6 4.4 4.1 3.9 3.9 4.4 4.7 Max 46.1 15.5 10.9 19.9 15.5 15.9 17.2 14.6 Tlag Mean 0.04 0.04 0.19 0.00 0.03 0.00 0.20 0.07 (h) SD 0.13 0.13 0.40 0.00 0.11 0.00 0.25 0.17 Min 0 0 0 0 0 0 0 0 Max 0.5 0.5 1.5 o 0.5 0 0.5 0.5 C24/Cmax Mean 0.49 0.45 0.38 0.45 0.46 0.44 ND ND SD 0.20 0.21 0.17 0.20 0.19 0.14 ND ND D Min 005 0.05 0.12 0.06 0.04 0.12 ND ND Max 0.92 0.82 0.65 0.81 0.92 0.63 ND ND ND = Not done [Annotation] mpjs None set by mpjs [Annotation] mpjs MigrationNone set by mpjs ation] mpjs Unmarked set by mpjs The results in Table 12 show that the exemplified formulations provide the pharrnacokinetic characteristics as described and claimed .

The present invention is not to be limited in scope by the specific embodiments of the disclosed in the examples, which are intended as illustrations of a few s the scope invention, and any embodiments that are functionally equivalent are within addition to those of this invention. Indeed, various modifications of the invention in in the art and are shown and described herein will become apparent to those skilled intended to fall within the scope of the appended claims. ofwhich are A number of references have been cited, the entire disclosures orated herein by reference for all purposes.

Serial This application claims priority from U.S. Provisional Application which is hereby incorporated No. 61/467,824, filed March 25, 2011, the sure of by reference.

Claims (63)

Claims:

1. A solid oral extended release pharmaceutical dosage form comprising a multi-layered extended release matrix formulation with sandwich-type or halfsandwich-type structure, the extended release matrix formulation comprising (1) a first ition forming an active agent-containing first layer of the extended e matrix formulation comprising: (a) at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000; and (b) at least one active agent; and (2) a second composition forming an active free second layer of the extended release matrix formulation comprising at least one polyethylene oxide.

2. The solid oral extended e pharmaceutical dosage form according to claim 1, wherein the second composition comprises at least one polyethylene oxide having, based on gical measurements, an approximate molecular weight of at least 1,000,000.

3. The solid oral extended release ceutical dosage form according to claim 1, wherein the second composition comprises at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of less than 1,000,000.

4. The solid oral extended release pharmaceutical dosage form according to any one of claims 1 to 3, n the active agent is selected from opioid analgesics.

5. The solid oral extended release pharmaceutical dosage form according to any one of claims 1 to 4, n the multi-layered extended release matrix formulation is a bilayer extended release matrix formulation.

6. The solid oral extended e pharmaceutical dosage form according to claim 5, wherein the weight ratio of active agent-containing layer / active agent free layer ranges from about 1 to about 5, or from about 1.5 to about 3, or is about 2 or is about 2.5.

7. The solid oral extended release ceutical dosage form according to any one of claims 1 to 6, wherein the extended release matrix formulation is thermoformed or subjected to a curing step.

8. The solid oral extended release ceutical dosage form according to claim 7, wherein the extended release matrix formulation is subjected to a curing step at a temperature of at least about 60 °C for a time period of at least about 1 minute.

9. The solid oral extended release pharmaceutical dosage form according to any one of claims 1 to 8, wherein the active agent-containing layer and the active agent free layer comprise less than 25 % lactose.

10. The solid oral extended e pharmaceutical dosage form according to any one of claims 1 to 9, wherein the active agent-containing layer and the active agent free layer comprise essentially no lactose.

11. The solid oral extended release pharmaceutical dosage form according to any one of claims 1 to 10, wherein the active agent-containing layer and the active agent free layer comprise essentially no hydrogenated castor oil.

12. The solid extended release ceutical dosage form according to any one of claims 1 to 11, wherein the active agent-containing layer and the active agent free layer comprise essentially no hydroxypropylmethylcellulose.

13. The solid oral extended release pharmaceutical dosage form of any one of claims 1 to 12, wherein the dosage provides a dissolution rate, which when ed in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37º C releases the active agent essentially according to a zero order mode.

14. The solid oral extended release pharmaceutical dosage form of any one of claims 1 to 13, wherein the dosage provides a dissolution rate, which when measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37º C is from about 5% and about 15% (by wt.) active released per hour.

15. The solid oral extended release pharmaceutical dosage form of any one of claims 1 to 14, wherein the dosage provides a dissolution rate, which when ed in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37º C is from about 5% and about 15% (by wt.) active released after 1 hour.

16. The solid oral extended release ceutical dosage form of any one of claims 1 to 15, wherein the dosage provides a dissolution rate, which when measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37º C is from about 10% and about 30% (by wt.) active released after 2 hours.

17. The solid oral extended e ceutical dosage form of any one of claims 1 to 16, wherein the dosage provides a dissolution rate, which when measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37º C is from about 20% and about 60% (by wt.) active released after 4 hour.

18. The solid oral ed release pharmaceutical dosage form of any one of claims 1 to 16, wherein the dosage provides a ution rate, which when measured in a USP Apparatus 1 t) at 100 rpm in 900 ml ted gastric fluid t s (SGF) at 37º C is from about 40% and about 100% (by wt.) active released after 8 hour.

19. The solid oral ed release pharmaceutical dosage form of any one of claims 1 to 18, wherein the first composition comprises at least about 60 % (by wt.), at least about 70 % (by wt.), at least about 80 % (by wt.), at least about 90 % (by wt.) of said polyethylene oxide.

20. The solid oral extended release pharmaceutical dosage form according to any of claims 1 to 19, wherein the opioid analgesic is selected from the group of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl and derivatives, hydrocodone, hydromorphone, hydroxypethidine, hadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, yphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts, hydrates and es thereof, mixtures of any of the foregoing.

21. The solid oral extended release pharmaceutical dosage form according to any of claims 1 to 20, wherein the opioid analgesic is selected from the group of hydrocodone and orphone or pharmaceutically acceptable salts, hydrates and solvates thereof, mixtures of any of the foregoing.

22. The solid oral extended release pharmaceutical dosage form according to any of claims 1 to 21, wherein the opioid analgesic is hydrocodone bitartrate or hydromorphone hydrochloride.

23. The solid oral extended release pharmaceutical dosage form according to any of claims 1 to 22, wherein the dosage form comprises from about 5 mg to about 250 mg of hydrocodone rate or 1 mg to 100 mg of hydromorphone hloride.

24. The solid oral extended release pharmaceutical dosage form according to any of claims 1 to 23, n the dosage form comprises 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 45 mg, 60 mg, or 80 mg, 90 mg, 100 mg, 120 mg or 160 mg of hydrocodone bitartrate or 2 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 32 mg, or 64 mg of hydromorphone hydrochloride.

25. The solid oral extended release pharmaceutical dosage form of any one of claims 22 to 24, wherein the first composition comprises at least about 65 % (by wt.) polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000.

26. A solid oral extended e pharmaceutical dosage form according to claim 1 comprising an extended release matrix formulation, the extended release matrix formulation comprising: (1) a first composition forming an active agent-containing first layer of said ed e matrix formulation sing at least 65 % (by wt.) of one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000; (2) about 5 mg hydrocodone bitartrate.

27. A solid oral extended release pharmaceutical dosage form ing to claim 1 comprising an extended release matrix formulation, the extended release matrix ation comprising: (1) a first composition forming an active agent-containing first layer of said extended release matrix formulation comprising at least 90 % (by wt.) of one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000; (2) about 5 mg hydrocodone bitartrate.

28. A solid oral ed release pharmaceutical dosage form according to claim 1 comprising an extended release matrix formulation, the extended e matrix formulation sing: (1) a first composition forming an active agent-containing layer first layer of said extended e matrix formulation comprising at least 65 % (by wt.) of one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000; (2) about 10 mg hydrocodone bitartrate.

29. A solid oral extended release pharmaceutical dosage form according to claim 1 comprising an extended release matrix ation, the extended release matrix formulation comprising: (1) a first composition forming an active agent-containing layer first layer of said extended e matrix formulation comprising at least 65 % (by wt.) of one polyethylene oxide having, based on rheological ements, an approximate molecular weight of at least 000; (2) about 15 mg or 20 mg hydrocodone bitartrate.

30. A solid oral extended release pharmaceutical dosage form according to claim 1 comprising an extended release matrix formulation, the extended e matrix formulation comprising: (1) a first composition forming an active agent-containing layer first layer of said extended release matrix formulation comprising at least 65 % (by wt.) of one hylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000; (2) about 40 mg hydrocodone bitartrate.

31. A solid oral extended release pharmaceutical dosage form according to claim 1 comprising an extended release matrix formulation, the extended release matrix formulation comprising: (1) a first ition forming an active agent-containing layer first layer of said ed release matrix formulation comprising at least 65 % (by wt.) of one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000; (2) about 60 mg, 80 mg, 100 mg or 120 mg hydrocodone bitartrate.

32. A solid oral ed release ceutical dosage form according to claim 1 comprising an extended release matrix formulation, the extended release matrix formulation comprising: (1) a first composition forming an active agent-containing layer first layer of said extended release matrix formulation comprising at least 90 % (by wt) of one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000; (2) about 5 mg hydromorphone hydrochloride.

33. A solid oral extended release ceutical dosage form according to claim 1 comprising an extended release matrix formulation, the extended release matrix formulation comprising: (1) a first composition forming an active agent-containing layer first layer of said extended e matrix formulation comprising at least 90 % (by wt) of one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000; (2) about 6 mg or 7 mg orphone hydrochloride.

34. A solid oral extended release pharmaceutical dosage form according to claim 1 comprising an extended release matrix ation, the extended release matrix formulation comprising: (1) a first composition forming an active containing layer first layer of said extended release matrix formulation sing at least 90 % (by wt) of one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000; (2) 8 mg or 10 mg hydromorphone hydrochloride.

35. A solid oral extended release pharmaceutical dosage form according to claim 1 comprising an extended release matrix formulation, the extended release matrix formulation comprising: (1) a first ition forming an active agent-containing layer first layer of said extended release matrix formulation sing at least 90 % (by wt) of one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000; (2) 12 mg hydromorphone hydrochloride.

36. A solid oral extended release pharmaceutical dosage form according to claim 1 comprising an extended release matrix formulation, the extended release matrix ation comprising: (1) a first composition forming an active agent-containing layer first layer of said extended release matrix formulation comprising at least 90 % (by wt) of one polyethylene oxide having, based on rheological measurements, an approximate lar weight of at least 1,000,000; (2) about 15 mg or 20 mg hydromorphone hydrochloride.

37. A solid oral extended release pharmaceutical dosage form according to claim 1 comprising an extended e matrix formulation, the extended release matrix formulation comprising: (1) a first composition forming an active agent-containing layer first layer of said extended release matrix formulation sing at least 90 % (by wt) of one polyethylene oxide , based on rheological measurements, an imate molecular weight of at least 1,000,000; (2) about 25 mg or 30 mg hydromorphone hydrochloride.

38. A solid oral extended release pharmaceutical dosage form ing to claim 1 comprising an extended release matrix formulation, the extended release matrix formulation comprising: (1) a first composition forming an active agent-containing layer first layer of said extended release matrix formulation comprising at least 90 % (by wt) of one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 000; (2) 32 mg hydromorphone hydrochloride.

39. A solid oral extended release pharmaceutical dosage form according to any one of claims 1 to 38, comprising a second composition forming an active free layer second layer of the pharmaceutical dosage form comprising at least one polyethylene oxide having, based on rheological measurements, approximate molecular weight of at least 1,000,000, wherein said second ition comprises at least about 90 % (by wt.) of polyethylene oxide.

40. The solid oral extended release pharmaceutical dosage form according to any one of claims 1 to 39, wherein the extended release matrix formulation when subjected to an indentation test has a cracking force of at least about 110 N.

41. The solid oral extended release pharmaceutical dosage form according to any one of claims 1 to 40, wherein the ed release matrix formulation when subjected to an indentation test has a “penetration depth to crack distance“ of at least about 1.0 mm.

42. The solid oral extended release pharmaceutical dosage form according to claim 40, wherein the extended release matrix ation has a cracking force of at least about 120 N, at least about 130 N or at least about 140 N and/or a “penetration depth to crack” ce of at least about 1.2 mm.

43. The solid oral extended release pharmaceutical dosage form according to claim 42, wherein the extended e matrix formulation has a cracking force of at least about 120 N, at least about 130 N or at least about 140 N and/or a “penetration depth to crack” distance of at least about 1.4 mm, at least about 1.5 mm or at least about 1.6 mm.

44. The solid oral extended release pharmaceutical dosage form of any one of claims 1 to 43, wherein the extended release matrix formulation resists a work of at least about 0.06 J without cracking.

45. The solid controlled e dosage form ing to any one of preceding claims sing hydrocodone or a pharmaceutically acceptable salt, hydrate or solvate thereof, or mixtures of any of the foregoing.

46. The solid controlled e dosage form of clam 45, which provides a C24/Cmax ratio of hydrocodone of about 0.40 to about 1.0 after administration.

47. The solid controlled release dosage form of claim 45, wherein the C24/Cmax ratio is about 0.40 to about 0.85.

48. The solid controlled release dosage form of claim 45, wherein the C24/Cmax ratio is about 0.40 to about 0.75.

49. The solid controlled release dosage form of claim 45, wherein the C24/Cmax ratio is about 0.45 to about 0.70.

50. The solid controlled release dosage form of claim 45, which es a Tmax (h) of hydrocodone from about 4 to about 20 hours after administration.

51. The solid controlled release dosage form of claim 50, wherein the Tmax (h) is about 6 to about 12 hours.

52. The solid controlled release dosage form of claim 50, wherein the Tmax (h) is about 4 to about 10 hours.

53. The solid controlled release dosage form of any of claims 45 to 52, wherein the administration is a single dose stration.

54. The solid controlled release dosage form of any of claims 45 to 52, wherein the administration is a steady state administration.

55. The solid controlled release dosage form of claim 45, which contains about 20 mg hydrocodone or a pharmaceutically acceptable salt thereof.

56. The solid controlled release dosage form of claim 45, which contains about 120 mg hydrocodone or a pharmaceutically able salt thereof.

57. The solid controlled release dosage form of claim 45, which provides a mean AUC (ng*h/mL) after administration of about 250 to 400 per each 20 mg hydrocodone included in the dosage form.

58. The solid controlled e dosage form of claim 55, which provides a mean AUC (ng*h/mL) after stration of about 250 to about 400, or about 270 to about 350.

59. The solid controlled release dosage form of claim 56, which provides a mean AUC (ng*h/mL) after administration of about 1500 to about 2400, about 1700 to about 2200, about 1800 to about 2100 or about 1900 to about 2100.

60. The solid controlled release dosage form of claim 45, which provides a mean Cmax (ng/mL) after administration of about 10 to about 30 per each 20 mg hydrocodone included in the dosage form.

61. The solid controlled release dosage form of claim 55, which es a mean Cmax (ng/mL) after administration of about 10 to about 30, about 12 to about 25, about 14 to about 18 or about 12 to about 17.

62. The solid controlled release dosage form of claim 56, which provides a mean Cmax (ng/mL) after administration of about 60 to about 180, or about 80 to about 160.

63. The solid lled release dosage form of claim 45, which provides a mean T