Encased tamper resistant controlled release dosage forms

FIELD OF THE INVENTION

The present invention relates to multilayer pharmaceutical dosage forms which are tamper-proof and preferably release the active agent contained therein according to substantially zero order kinetics.

BACKGROUND OF THE INVENTION

Pharmaceutical products are sometimes abused. For example, a given dose of parenterally administered opioid agonist may be greater than the same dose administered orally. Some forms of the drug may be tampered with for the illicit use of the opioid agonist contained in them. Controlled-release opioid agonist pharmaceutical preparations are sometimes crushed or subjected to extraction with solvents (e.g. ethanol) by drug abusers in order to immediately release the opioid contained in them after oral or parenteral administration.

Dosage forms of controlled release opioid agonists, which can release some opioid due to the action of ethanol, may also result in the patient receiving the dose much faster than intended if the patient does not follow the instructions for use and abuses alcohol while taking dosage forms.

US Patent Application No. 2009/0081290 discloses tamper-proof dosage forms which, in some embodiments, are solid oral sustained release pharmaceutical dosage forms containing an extended release matrix formulation in the form of a tablet or a multiparticulate. The tablet or the individual multiparticulates may at least be flattened without disintegrating, wherein the thickness of the tablet or the individual multiparticulates after flattening is no more than about 60% of the thickness of the tablet or the individual multiparticulates prior to flattening, and wherein the flattened tablet or the flattened multiparticulates are pharmaceutically available in vitro in the USP Apparatus 1 (basket) with speed 100 rpm in 900 ml of artificial gastric juice without enzymes (SGF) at 37 ° C, wherein the percentage of active agent released after 0.5 h deviates from the dissolution by no more than about 20% points from the corresponding pharmaceutical availability measured in vitro of the non-flattened reference tablet or non-flattened reference multiparticulates.

A need still exists in the art for tamper-proof oral pharmaceutical dosage forms, said dosage forms preferably providing an active agent release profile at substantially zero order rates.

US 2009/0081290 A1 relates to pharmaceutical dosage forms, e.g., tamper-proof dosage forms containing an opioid analgesic, as well as a method of manufacture, use and methods of treatment using these.

US 2004/0241234 A1 relates to a pressed-coat formulation comprising a base composition comprising a water-soluble active agent and a wax material, and a coating composition comprising an active agent and a polymer, the coating composition being pressed over the base composition.

All sources and publications cited in this document are incorporated in its entirety by reference for all purposes.

SUBJECTS AND SUMMARY OF THE INVENTION

Some embodiments of the present invention provide controlled release solid dosage forms containing an active agent (e.g., an opioid analgesic) that are tamper-proof.

Some embodiments of the present invention provide controlled release solid dosage forms containing an active agent (e.g., opioid analgesic) that are resistant to crushing.

Some embodiments of the present invention provide controlled release solid dosage forms containing an opioid analgesic that are less likely to be abused parenterally than other dosage forms.

Some embodiments of the present invention provide controlled release solid dosage forms containing an opioid analgesic that are less likely to be abused in an intranasal fashion than other dosage forms.

Some embodiments of the present invention provide controlled release solid dosage forms containing an opioid analgesic that are less orally abused than other dosage forms.

Some embodiments of the present invention also provide controlled release solid dosage forms containing an opioid analgesic, which are less misused than other dosage forms.

Some embodiments of the present invention also provide a method of treating pain in humans using solid controlled release dosage forms containing an opioid analgesic while reducing the potential for abuse of these dosage forms.

It is also an object of some embodiments of the present invention to treat a disease or condition (e.g., pain) by administering a solid controlled release dosage form according to the present disclosure to a patient in need of such treatment.

Some embodiments of the present invention are also directed to a method of making an oral dosage form of an active agent (e.g., opioid analgesic), in accordance with the present disclosure.

Some embodiments of the present invention also relate to a method of using a pharmacological formulation (e.g., an opioid analgesic) in the manufacture of a dosage form for treating a disease state (e.g., pain).

These and other embodiments have been made within the framework of the present invention which relates to controlled release solid dosage forms and a method of their preparation in accordance with the appended claims. In particular, some embodiments of the present invention relate to controlled release solid dosage forms comprising a core comprising a first portion of hydrocodone bitartrate active agent dispersed in a first matrix material comprising polyethylene oxide having an average molecular weight from about 300,000 to about 3,000,000; and a sheath within which the core is enclosed and which comprises a second portion of hydrocodone bitartrate dispersed in the second matrix material, including polyethylene oxide having an average molecular weight of from about 4,000,000 to about 10,000,000; the core to sheath weight ratio is from about 1: 1.2 to about 1: 1.5; wherein the amount of active agent released from the dosage form is proportional to the duration of action from 8 to 24 hours as determined by the pharmaceutical availability measured in vitro in the USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free artificial gastric juice (SGF) at 37 ° C. In other words, the amount of opioid analgesic (hydrocodone bitartrate) released from the dosage form, determined on the basis of pharmaceutical availability measured in vitro on the USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free artificial gastric juice ( SGF) at 37 ° C, corresponds to equations (Ia) and (Ib):

amount released after 24 hours <(24/8 x amount released after 8 hours)^x 1.2 (1 a) amount released after 24 hours > (24/8 x quantity released after 8 hours)^x 0.5 (Ib).

In some other embodiments, the amount of active agent released from the dosage form is proportional to 30% of the duration of action over at least one of the following time intervals: (i) 4 to 24 hours, (ii) 8 to 24 hours. (iii) 12 to 24 hours, (iv) 18 to 24 hours, (v) 4 to 8 hours, (vi) 4 to 12 hours, (vii) 4 to 18 hours, (viii) 8 to 12 hours, (ix) 8 to 18 hours or (x) from 12 to 18 hours as determined from pharmaceutical availability measured in vitro on USP Apparatus 1 (basket) at 100 rpm in 900 ml of simulated gastric juice without enzymes (SGF) at 37 ° C. In alternative embodiments, the amount of active agent released from the dosage form is proportional to 30% of the duration of action over all of the following time intervals: (i) 8 to 24 hours, (ii) 8 to 12 hours. and (iii) from 8 to 18 hours as determined from pharmaceutical availability measured in vitro on the USP Apparatus 1 (basket) at 100 rpm in 900 ml of simulated gastric juice without enzymes (SGF) at 37 ° C.

In some other embodiments, the amount of active agent released from the dosage form is proportional to the duration of action within 25% of at least one of the following time intervals: (i) 4 to 24 hours, (ii) 8 to 24 hours. (iii) 12 to 24 hours, (iv) 18 to 24 hours, (v) 4 to 8 hours, (vi) 4 to 12 hours, (vii) 4 to 18 hours, (viii) 8 to 12 hours, (ix) 8 to 18 hours or (x) from 12 to 18 hours as determined from pharmaceutical availability measured in vitro on USP Apparatus 1 (basket) at 100 rpm in 900 ml of simulated gastric juice without enzymes (SGF) at 37 ° C. In alternative embodiments, the amount of active agent released from the dosage form is proportional to the duration of action within 25% of all the following time intervals: (i) 8 to 24 hours, (ii) 8 to 12 hours. and (iii) from 8 to 18 hours as determined from pharmaceutical availability measured in vitro on the USP Apparatus 1 (basket) at 100 rpm in 900 ml of simulated gastric juice without enzymes (SGF) at 37 ° C.

In some other embodiments, the amount of active agent released from the dosage form is proportional to the duration of action within 20% of at least one of the following time intervals: (i) 4 to 24 hours, (ii) 8 to 24 hours. (iii) 12 to 24 hours, (iv) 18 to 24 hours, (v) 4 to 8 hours, (vi) 4 to 12 hours, (vii) 4 to 18 hours, (viii) 8 to 12 hours, (ix) 8 to 18 hours or (x) from 12 to 18 hours as determined from pharmaceutical availability measured in vitro on USP Apparatus 1 (basket) at 100 rpm in 900 ml of simulated gastric juice without enzymes (SGF) at 37 ° C. In alternative embodiments, the amount of active agent released from the dosage form is proportional to 20% of the duration of action over all of the following time intervals: (i) 8 to 24 hours, (ii) 8 to 12 hours. and (iii) from 8 to 18 hours as determined from pharmaceutical availability measured in vitro on the USP Apparatus 1 (basket) at 100 rpm in 900 ml of simulated gastric juice without enzymes (SGF) at 37 ° C.

In some other embodiments, the amount of active agent released from the dosage form is proportional to the duration of action within 10% of at least one of the following time intervals: (i) 4 to 24 hours, (ii) 8 to 24 hours. (iii) 12 to 24 hours, (iv) 18 to 24 hours, (v) 4 to 8 hours, (vi) 4 to 12 hours, (vii) 4 to 18 hours, (viii) 8 to 12 hours, (ix) 8 to 18 hours or (x) from 12 to 18 hours as determined from pharmaceutical availability measured in vitro on USP Apparatus 1 (basket) at 100 rpm in 900 ml of simulated gastric juice without enzymes (SGF) at 37 ° C. In alternative embodiments, the amount of active agent released from the dosage form is proportional to 10% of the duration of action over all of the following time intervals: (i) 8 to 24 hours, (ii) 8 to 12 hours. and (iii) from 8 to 18 hours as determined from the pharmaceutical availability measured in vitro on the USP Apparatus 1 (basket) at 100 rpm in 900 ml enzyme-free artificial gastric juice (SGF) in temperature 37 ° C.

In some other embodiments, the amount of active agent released from the dosage form is proportional to the duration of action within 5% of at least one of the following time intervals: (i) 4 to 24 hours, (ii) 8 to 24 hours. (iii) 12 to 24 hours, (iv) 18 to 24 hours, (v) 4 to 8 hours, (vi) 4 to 12 hours, (vii) 4 to 18 hours, (viii) 8 to 12 hours, (ix) 8 to 18 hours or (x) from 12 to 18 hours as determined from pharmaceutical availability measured in vitro on USP Apparatus 1 (basket) at 100 rpm in 900 ml of simulated gastric juice without enzymes (SGF) at 37 ° C. In alternative embodiments, the amount of active agent released from the dosage form is proportional to the duration of action within 5% of all the following time intervals: (i) 8 to 24 hours, (ii) 8 to 12 hours. and (iii) from 8 to 18 hours as determined from pharmaceutical availability measured in vitro on the USP Apparatus 1 (basket) at 100 rpm in 900 ml of simulated gastric juice without enzymes (SGF) at 37 ° C.

In some embodiments, the core is a compressed core comprising a first portion of hydrocodone bitartrate dispersed in a first matrix material including polyethylene oxide with an average molecular weight from about 300,000 to about 3,000,000; and the sheath is a compression sheath surrounding the core and having a second hydrocodone bitartrate portion dispersed in the second matrix material including polyethylene oxide with an average molecular weight from about 4,000,000 to about 10,000,000; wherein the weight ratio of the core to the sheath is from about 1: 1.2 to about 1: 1.5.

In some embodiments, in the solid controlled release dosage form of the present invention, the amount of active agent released from the dosage form after 2 hours. is less than about 25%; amount of active agent released from the dosage form after 4 hours. ranges from about 10% to about 30%; amount of active agent released from the dosage form after 8 hours. it ranges from about 20% to about 60%; amount of active agent released from the dosage form after 12 hours. ranges from about 40% to about 90%; and the amount of active agent released from the dosage form after 18 hours. is greater than about 70%; as determined on the basis of pharmaceutical availability measured in vitro on USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free artificial gastric juice (SGF) at 37 ° C.

In some embodiments, in the solid controlled release dosage form of the present invention, the amount of active agent released from the dosage form after 2 hours. is less than about 20%; amount of active agent released from the dosage form after 4 hours. ranges from about 10% to about 30%; amount of active agent released from the dosage form after 8 hours. ranges from about 30% to about 60%; amount of active agent released from the dosage form after 12 hours. ranges from about 50% to about 90%; and the amount of active agent released from the dosage form after 18 hours. it is greater than about 80%; as determined on the basis of pharmaceutical availability measured in vitro on USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free artificial gastric juice (SGF) at 37 ° C.

In some embodiments, in the solid controlled release dosage form of the present invention, the amount of active agent released from the dosage form after 2 hours. is less than about 15%; amount of active agent released from the dosage form after 4 hours. ranges from about 8% to about 20%; amount of active agent released from the dosage form after 8 hours. ranges from about 20% to about 50%; amount of active agent released from the dosage form after 12 hours. it ranges from about 40% to about 70%; amount of active agent released from the dosage form after 18 hours. is greater than about 70%; and the amount of active agent released from the dosage form after 24 hours. is greater than about 90%; as determined on the basis of pharmaceutical availability measured in vitro on USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free artificial gastric juice (SGF) at 37 ° C. In some embodiments, the present invention relates to a solid controlled release dosage form comprising a therapeutically effective amount of hydrocodone bitartrate and a controlled release excipient as defined herein; wherein the amount of hydrocodone bitartrate released from the dosage form is proportional within 20% to the duration of action over a time interval of 8 to 24 hours, as determined from pharmaceutical availability measured in vitro on a USP Apparatus 1 (basket) at a rate of 100 rpm in 900 ml enzyme-free artificial gastric juice (SGF) at 37 ° C; in addition, the dispensing mold may be flattened without disintegrating, the thickness of the dispensing mold after flattening being no more than about 20% of the thickness of the dispensing mold prior to flattening; and the amount of hydrocodone bitartrate released after 0.5 h. from the flattened dosage form deviates by no more than 20% points from the non-flattened dosage form, which was determined on the basis of pharmaceutical availability measured in vitro in the USP Apparatus 1 device (basket) at a speed of 100 rpm in 900 ml of artificial gastric juice without enzymes (SGF) at 37 ° C.

In one embodiment of the present invention, a solid controlled release dosage form comprises a therapeutically effective amount of hydrocodone bitartrate and a controlled release excipient as defined herein; wherein the amount of hydrocodone bitartrate released from the dosage form after 2 hours. is less than about 25%; the amount of hydrocodone bitartrate released from the dosage form after 4 hours. ranges from about 10% to about 30%; the amount of hydrocodone bitartrate released from the dosage form after 8 hours. it ranges from about 20% to about 60%; the amount of hydrocodone bitartrate released from the dosage form after 12 hours. ranges from about 40% to about 90%; and the amount of hydrocodone bitartrate released from the dosage form after 18 h. is greater than about 70%; based on pharmaceutical availability measured in vitro on USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free artificial gastric juice (SGF) at 37 ° C; in addition, the dispensing mold may be flattened without disintegrating, the thickness of the dispensing mold after flattening being no more than about 20% of the thickness of the dispensing mold prior to flattening; and the amount of hydrocodone bitartrate released after 0.5 h. from the flattened dosage form deviates by no more than 20% points from the non-flattened dosage form, which was determined on the basis of pharmaceutical availability measured in vitro in the USP Apparatus 1 device (basket) at a speed of 100 rpm in 900 ml of artificial gastric juice without enzymes (SGF) at 37 ° C.

In some embodiments, the solid controlled release dosage form of the present invention comprises a therapeutically effective amount of hydrocodone bitartrate dispersed in a controlled release excipient as defined herein; wherein 60% inner portion of the dosage form comprises at least 80% hydrocodone bitartrate; wherein the amount of hydrocodone bitartrate released from the dosage form is proportional within 20% to the duration of action over a time interval of 8 to 24 hours, as determined from pharmaceutical availability measured in vitro on a USP Apparatus 1 (basket) at a rate of 100 rpm in 900 ml enzyme-free artificial gastric juice (SGF) at 37 ° C.

In some embodiments, the present invention relates to a method of preparing a solid controlled release dosage form by preparing a core comprising a first portion of hydrocodone bitartrate dispersed in a first matrix material including polyethylene oxide with an average molecular weight of about 300,000 to about 3,000,000; and on the closure of the core with a sheath having a second hydrocodone bitartrate portion dispersed in a second matrix material comprising polyethylene oxide with an average molecular weight from about 4,000,000 to about 10,000,000; wherein the weight ratio of the core to the sheath is from about 1: 1.2 to about 1: 1.5; wherein the amount of hydrocodone bitartrate released from the dosage form is proportional within 20% to the duration of action over a time interval of 8 to 24 hours, as determined from pharmaceutical availability measured in vitro on a USP Apparatus 1 (basket) at a rate of 100 rpm in 900 ml enzyme-free artificial gastric juice (SGF) at 37 ° C.

In some embodiments, the method of the present invention comprises preparing a compressed core comprising a first hydrocodone bitartrate portion dispersed in a first matrix material including polyethylene oxide, as defined herein; and enclosing the core in a sheath by compression coating the second portion of the hydrocodone bitartrate in a second matrix material, including polyethylene oxide as defined herein, on the core.

In some embodiments, the present invention relates to a method of preparing a solid controlled release dosage form by preparing a core containing a first portion of hydrocodone bitartrate active agent dispersed in a first matrix material containing polyethylene oxide with an average molecular weight of from about 300,000 to about 3,000,000; and on closing the core with a sheath containing a second portion of hydrocodone bitartrate active agent dispersed in the second matrix material, including polyethylene oxide with an average molecular weight of from about 4,000,000 to about 10,000,000; the core to sheath weight ratio is from about 1: 1.2 to about 1: 1.5; wherein the amount of active agent released from the dosage form after 2 hours. is less than about 25%; amount of active agent released from the dosage form after 4 hours. ranges from about 10% to about 30%; amount of active agent released from the dosage form after 8 hours. it ranges from about 20% to about 60%; amount of active agent released from the dosage form after 12 hours. ranges from about 40% to about 90%; and the amount of active agent released from the dosage form after 18 hours. is greater than about 70% as determined by in vitro pharmaceutical availability on the USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free simulated gastric juice (SGF) at 37 ° C.

In some embodiments, the present invention relates to a method of preparing a solid controlled release dosage form by combining a therapeutically effective amount of hydrocodone bitartrate and a controlled release excipient as defined herein; wherein the amount of hydrocodone bitartrate released from the dosage form after 2 hours. is less than about 25%; the amount of hydrocodone bitartrate released from the dosage form after 4 hours. ranges from about 10% to about 30%; the amount of hydrocodone bitartrate released from the dosage form after 8 hours. it ranges from about 20% to about 60%; the amount of hydrocodone bitartrate released from the dosage form after 12 hours. ranges from about 40% to about 90%; and the amount of hydrocodone bitartrate released from the dosage form after 18 h. is greater than about 70%; based on pharmaceutical availability measured in vitro on USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free artificial gastric juice (SGF) at 37 ° C; in addition, the dispensing mold may be flattened without disintegrating, the thickness of the dispensing mold after flattening being no more than about 20% of the thickness of the dispensing mold prior to flattening; and the amount of hydrocodone bitartrate released after 0.5 h. from the flattened dosage form deviates by no more than 20% points from the non-flattened dosage form, which was determined on the basis of pharmaceutical availability measured in vitro in the USP Apparatus 1 device (basket) at a speed of 100 rpm in 900 ml of artificial gastric juice without enzymes (SGF) at 37 ° C.

In one embodiment, the present invention relates to a method for making a solid controlled release dosage form by combining a therapeutically effective amount of hydrocodone bitartrate and a controlled release excipient as defined herein; wherein the amount of hydrocodone bitartrate released from the dosage form is proportional to the duration of action within 20% at any of two time points ranging from 8 to 24 hours as determined from pharmaceutical availability measured in vitro on a USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free artificial gastric juice (SGF) at 37 ° C; in addition, the dispensing mold may be flattened without disintegrating, the thickness of the dispensing mold after flattening being no more than about 20% of the thickness of the dispensing mold prior to flattening; and the amount of hydrocodone bitartrate released after 0.5 h. from the flattened dosage form deviates by no more than 20% points from the non-flattened dosage form, which was determined on the basis of pharmaceutical availability measured in vitro in the USP Apparatus 1 device (basket) at a speed of 100 rpm in 900 ml of artificial gastric juice without enzymes (SGF) at 37 ° C.

In some embodiments, the present invention relates to a method of making a solid controlled release dosage form by dispersing a therapeutically effective amount of hydrocodone bitartrate into a controlled release excipient as defined herein; wherein 60% inner portion of the dosage form comprises at least 80% hydrocodone bitartrate; wherein the amount of hydrocodone bitartrate released from the dosage form is proportional within 20% to the duration of action over a time interval of 8 to 24 hours, as determined from pharmaceutical availability measured in vitro on a USP Apparatus 1 (basket) at a rate of 100 rpm in 900 ml enzyme-free artificial gastric juice (SGF) at 37 ° C.

In some embodiments, the present invention relates to a method of treating pain in a patient or subject comprising the administration of a solid, controlled release dosage form comprising hydrocodone bitartrate in accordance with the present disclosure.

In preferred embodiments, the present invention relates to a dosage form according to the present invention which has a substantially zero-order release rate when administered to a patient or subject.

The term "zero order release rate" means a rate of release of active agent from a dosage form that is independent of the concentration of the remaining amount of active agent in the dosage form, such that the rate is relatively constant over a specified period of time. In a graph showing the percentage of active agent released over time, a dosage form showing a zero order release rate would appear as a substantially straight line. In some embodiments of the present invention, release at substantially zero order rate means that the amount of active agent released from the dosage form is proportional to within 20% of the operating time over a period of 8 to 24 hours. or 4 to 12 hours, determined on the basis of pharmaceutical availability measured in vitro on USP Apparatus 1 (basket) at 100 rpm in 900 ml of artificial gastric juice without enzymes (SGF) at 37 ° C . For example, the amount released from the in vitro dosage form after 8 h. of 20% and the amount released after 24 hours. of 60% (± 12) would literally be in line with the proportionality definition in the range of 20% for a runtime of 8 to 24 hours. This is shown by the data for the second action time (24 h) and the second release level (60%), which are multiples of (3) the first action time (8 h) and the first release (20%). For the definition of proportionality in the range of 20% for a runtime of 8 to 24 hours. (or any other period) only the endpoints of the numeric values ​​are required to be considered, although the definition does not exclude that proportionality may also occur at other time points within the endpoints.

In other embodiments of the present invention, substantially zero order release rate refers to a dosage form in which the amount of active agent is released after 2 hours. is less than about 25%; amount of active agent released from the dosage form after 4 hours. ranges from about 10% to about 30%; amount of active agent released from the dosage form after 8 hours. it ranges from about 20% to about 60%; amount of active agent released from the dosage form after 12 hours. ranges from about 40% to about 90%; and the amount of active agent released from the dosage form after 18 hours. is greater than about 70%; as determined on the basis of pharmaceutical availability measured in vitro on USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free artificial gastric juice (SGF) at 37 ° C.

The term "polyethylene oxide" for the purposes of the present invention means a polyethylene oxide (PEO) composition generally having a molecular weight of at least

000 as measured in a manner accepted in the art, and preferably having a molecular weight of at least 100,000. Lower molecular weight compositions are typically referred to as polyethylene glycols.

The term "high molecular weight polyethylene oxide (PEO)" for the purposes of the present invention means a compound with an approximate molecular weight of at least 1,000,000 as measured by theology.

The term "low molecular weight polyethylene oxide (PEO)" for the purposes of the present invention means a compound with an approximate molecular weight of less than 1,000,000 as measured by theology.

The term "direct compression" for the purposes of the present invention means a process for manufacturing a dosage form including the steps of mixing the ingredients and compressing the mixture to produce the dosage form, e.g. by using a diffusion mixture and / or a convective mixing process (e.g. Guidance for Industry, SUPAC-IR). MR: Immediate Release and Modified Release Solid Orał Dosage Forms, Manufacturing Installation Addendum).

The term "flattening" and related terms used in the context of flattening a dosage form in accordance with the present invention means that the dosage form is subjected to a force applied in a direction substantially conforming to the smallest diameter (i.e. thickness) of the dosage form when its shape is other than spherical. and in any direction when the shape of the dispensing mold is spherical.

The term "crush resistant" in the context of some embodiments of the present invention refers to dispensing forms that can at least be flattened with a bench press as described herein and not disintegrate.

For the purposes of the present invention, the term "opioid analgesic" generally means one or more compounds selected from basic opioid agonists, mixed opioid agonists-antagonists, partial opioid agonists, pharmaceutically acceptable salts, complexes, stereoisomers, ethers, esters, hydrates and solvates thereof. and mixtures thereof.

The term "artificial gastric juice" or "SGF" as used herein means an aqueous solution used in pharmaceutical availability studies to recreate the conditions of the stomach, eg 0.1 N HCl solution.

The term "percentage points" in the context of eg "amount of active agent released after 0.5 hr." from a flattened dosage form that does not differ by more than about 20% points from the amount released from the non-flattened dosage form "means that the difference in% in the level of release before flattening and in% in the level of release after flattening is no more than 20 ( i.e. 20 or less). For example, the difference between the 60% release from a flattened dosage form and the 40% release from a non-flattened dosage form does not exceed about 20% points.

The term "percentage" or the use of the "%" sign without reference to "percentage points (or%)" means a percentage. For example, the release of 48% is in the range of 20% of the release of 60%, while the release of 40% is literally not in the range of 20% of the release of 60%.

The term "patient" means an individual (preferably a human) who has a clinical symptom or symptoms indicative of the need for treatment, who is under prophylactic or prophylactic treatment for a particular condition, or who has been diagnosed with a condition requiring treatment.

The term "subject" includes a definition of the term "patient" as well as a definition of the term "healthy subject" (ie, an individual (eg, a human) whose health is normal in all respects or with respect to a particular disease state).

As used herein, the term "stereoisomers" is a general term used to refer to all isomers of the individual molecules that differ only in the orientation of the atoms in space. This term includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).

The term "chiral center" denotes a carbon atom to which four different groups are attached.

The term "enantiomer" or "enantiomeric" denotes a molecule that does not superimpose its mirror image and is therefore optically active, where the enantiomer turns the plane of light polarized in one direction and its mirror image turns the plane of polarized light in the opposite direction.

The term "racemic" refers to a mixture of enantiomers.

The term "differentiating" means to separate or concentrate or deplete one of the two enantiomeric forms of a molecule.

The term "hydrocodone" for the purposes of the present invention means the free form compound of hydrocodone as well as the pharmaceutically acceptable salts, complexes, stereoisomers, ethers, esters, hydrates and solvates thereof, and mixtures thereof. In the present invention, hydrocodone bitartrate is used specifically.

The term "USP paddle or basket method" means the paddle or basket method as described, for example, in the US Pharmacopoeia XII (1990).

The term "pH-dependent" for the purposes of the present invention means one whose properties (eg, pharmaceutical availability) vary with the surrounding pH.

The term "pH independent" for the purposes of the present invention means one whose properties (eg pharmaceutical availability) are essentially unaffected by the pH.

The term "bioavailability" in the context of the present invention means the substantial degree to which drug (eg, hydrocodone) is absorbed from unit dosage forms.

Bioavailability is also defined as the AUC area (ie the area under the plasma concentration / time curve).

The terms "controlled release", "sustained release" or "sustained release" are used interchangeably and for the purposes of the present invention mean the release of a drug (e.g., hydrocodone) at a rate sufficient to maintain blood (e.g. plasma) concentrations within the therapeutic range but below. a toxic concentration level for at least about 12 hours. or longer, or at least 24 hours. or longer. Advantageously, the controlled release dosage form may allow one or two doses per day to be administered.

The term "C_hasks "is the maximum plasma concentration reached in the dose interval.

The term "C24" as used herein means the plasma concentration of the drug after 24 hours. from the application.

The term "T._hasks ”is the time to reach maximum plasma concentration (Cmax).

The term "C24 / C value ratio_hasFr. " for the purposes of the present invention is the ratio of the 24 hr plasma drug concentration values. from administration to the highest plasma concentration value achieved during the dosing period.

The term "Ti_ag"Represents the time point immediately before the point of the first measurable plasma concentration.

The term "T1 / 2" represents the terminal plasma half-life. This is the time required to cut any terminal concentration in half. It is very difficult to quantify the term "minimum effective analgesic concentration" or "MEAC" when used in reference to concentrations of an opioid such as hydrocodone.

In general, however, there is a minimum effective plasma concentration of an analgesic, such as hydrocodone, below which an analgesic effect is absent. Although there is a direct correlation between e.g. plasma hydrocodone level and analgesic effect, higher and longer sustained plasma levels are usually associated with stronger analgesic effect. There is a lag (or hysteresis) between the time it takes to peak plasma hydrocodone levels and the time it takes to peak drug effect. This phenomenon is generally associated with the management of pain with opioid analgesics.

For the purposes of the present invention, unless otherwise defined, the term "patient" or "subject" means that the explanation (or claim) refers to the pharmacokinetic parameters of a single patient or subject.

The term "patient population" or "subject population" or "healthy subject population" means that the explanation (or claim) refers to the mean pharmacokinetic parameters of at least two subjects, subjects or healthy subjects; at least six patients, subjects or healthy subjects; or at least twelve patients, subjects or healthy subjects.

For the purposes of the present invention, the controlled release formulations disclosed herein are preferably dose-proportional formulations. For dose-proportional formulations, the pharmacokinetic parameters (e.g. AUC and Cmax values) and / or the level of in vitro release increase linearly from one dose rate to another. Therefore, the pharmacokinetic and in vitro parameters of a specific dose can be derived from the parameters of another dose of the same preparation.

The term "first administration" means one dose of an agent of the present invention administered to a subject, patient or healthy subject, or population of subjects, patient population, or population of healthy subjects at the start of treatment.

The term "steady state" means that the amount of drug entering the system is approximately the same as the amount of drug leaving the system. Thus, at steady state, the patient's body eliminates the drug at approximately the same rate that the drug becomes available in the patient's body through absorption into the bloodstream.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of the pharmaceutical availability of the compositions of Examples 1-4.

FIG. 2 is a graph of the pharmaceutical availability of the compositions of Examples and 6.

FIG. 3 is a graph of the pharmaceutical availability of the compositions of Examples 7-12.

FIG. 4 is a plot of the mean plasma concentration versus time curve for Iteration 1 of Example 13.

FIG. 5 is a plot of the mean plasma concentration versus time curve for Iteration 2 of Example 13.

FIG. 6 is a plot of the mean plasma concentration versus time curve for Iteration 3 of Example 13.

FIG. 7 is a graph of the plasma concentration of the compositions of Examples 14-20.

DETAILED DESCRIPTION

The present invention relates to controlled release pharmaceutical formulations which, in some embodiments, contain a higher drug concentration in the inner portion of the dosage form as compared to the outer portion. The inner and outer parts respectively form an inner core (e.g. a compressed tablet) and a sheath in which the core is encapsulated (e.g. a compression coating). The active agent (hydrocodone bitartrate) is contained in both the core and the shell. In preferred embodiments, the active agent is released from the dosage form at a substantially zero-order rate which provides for dispensing certainty and less fluctuation in plasma concentration levels compared to alternative treatments (e.g., immediate release dosage forms).

The dosage forms of the present invention are preferably tamper-proof because they are difficult to crush or grind (e.g., according to the flattening criteria disclosed herein). This feature makes them particularly suitable for use with opioid analgesic products containing a high dose of opioid analgesic to be released over a given period of time from any dosage form. Drug abusers may crush, cut, grind, chew, dissolve, heat, extract or otherwise destroy the product so that much or all of the contents of the dosage form become available for immediate consumption by injection, inhalation, and / or ingestion.

The dispensing mold casing of the present invention is preferably difficult to detach from the core. This is particularly useful in embodiments with a higher active agent content in the core than in the sheath, as drug abusers will have difficulty accessing the drug mass contained in the core.

The present invention relates to controlled release solid dosage forms comprising: a core comprising a first opioid analgesic portion dispersed in a first matrix material comprising polyethylene oxide with an average molecular weight of from about 300,000 to about 3,000,000; a sheath surrounding the core and having a second opioid analgesic portion dispersed in the second matrix material, the polyethylene oxide having an average molecular weight of from about 4,000,000 to about 10,000,000; wherein the ratio of core weight to sheath weight is from about 1: 1.2 to about 1: 1.5 and wherein the opioid analgesic in the first and second portions is hydrocodone bitartrate.

The core of the dispensing mold can be formed, for example, by direct compression, extrusion or molding. The inner core contains a controlled release excipient and is preferably in the form of a compressed tablet.

The housing of the dispensing mold can be produced, for example, by compression coating, molding, spraying one or more layers onto a core, dipping the core into one or more layers, or a combination of these methods. The cover contains a controlled release excipient and is preferably applied by compression coating.

The weight ratio of the core to the sheath of the dispensing mold described herein is from about 1: 1.2 to about 1: 1.5.

In preferred embodiments, the core cannot be distinguished from the sheath visually (e.g. by color) and there is no clear demarcation between these elements. In this way, the dosage form is tamper-proof as it is more difficult to access the core, which in some embodiments contains most of the active agent. One of the measurements that can be used to assess the color of the sheath and core is the CIE L * A * B * value. Preferably, the CIE L * A * B * values ​​of the core and the sheath are within 10% of each other. Another way to judge the color is the RYB or RGB color palette - in which case the color of the core and the sheath are preferably the same shade or adjacent shades.

The first matrix material comprises PEO and the second matrix material also comprises PEO. The molecular weight of the PEO in the first matrix material is different from the average molecular weight in the second matrix material.

In the present invention, the molecular weight of the polyethylene oxide used in the first matrix (in the core) is lower than that of the polyethylene oxide used in the second matrix material (in the sheath). The polyethylene oxide in the first matrix material has a molecular weight from about 300,000 to about 3,000,000 and the polyethylene oxide in the second matrix material has a molecular weight from about 4,000,000 to about 10,000,000. In preferred embodiments, the polyethylene oxide in the first matrix material may have a molecular weight from about 500,000 to about 1,000,000, and the polyethylene oxide in the second matrix material may have a molecular weight from about 6,000,000 to about 8,000,000.

The active agent (opioid analgesic, specifically hydrocodone bitartrate) in the first part (the core) is the same as the active agent in the second part (the sheath).

In some embodiments, the ratio of the amount of active agent (hydrocodone bitartrate) in the core to the amount of active agent (hydrocodone bitartrate) in the shell is from about 1: 1 to about 10: 1; from about 2: 1 to about 8: 1; from about 2: 1 to about 5: 1 or about 4: 1.

In some embodiments, the weight ratio of the first active agent portion (hydrocodone bitartrate) to the polyethylene oxide in the first matrix material is from about 1: 0.25 to about 1:30; from about 1: 0.5 to about 1: 100; from about 1: 0.5 to about 1:20; from about 1: 1 to about 1:10; from about 1:15 to about 1:20; from about 1: 1.5 to about 1: 4; about 1:18 or about 1: 2.

In alternative embodiments, the weight ratio of the second active agent portion (hydrocodone bitartrate) to the polyethylene oxide in the second matrix material is from about 1: 1 to about 1: 200; from about 1: 1 to about 1: 125; from about 1: 2 to about 1: 100; from about 1: 5 to about 1:50; from about 1:12 to about 1:25; around 1:98 or around 1:15.

In some embodiments, the amount of active agent (hydrocodone bitartrate) released from the dosage form is proportional to within 20%, within 10%, or within 5% of the duration of action from 8 to 24 hours as determined by pharmaceutical availability as measured under conditions in vitro in the USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free simulated gastric juice (SGF) at 37 ° C. In other words, in some embodiments, the amount of hydrocodone bitartrate released from the dosage form as determined from pharmaceutical availability measured in vitro on a USP Apparatus 1 (basket) machine at 100 rpm in 900 ml of enzyme-free artificial gastric juice (SGF) ) at 37 ° C, corresponds to equations (Ia) and (Ib):

amount released after 24 hours <(24/8 x amount released after 8 hours) * 1.2 (Ia) amount released after 24 hours > (24/8 * amount released after 8 hours) * 0.8 (Ib).

Preferably the amount of hydrocodone bitartrate corresponds to equations (Ia ') and (Ib'):

amount released after 24 hours <(24/8 * amount released after 8 hours) * 1.1 (Ia) amount released after 24 hours > (24/8 * amount released after 8 hours) * 0.9 (Ib), and more preferably corresponds to equations (la ") and (Ib"):

amount released after 24 hours <(24/8 * amount released after 8 hours) * 1.05 (Ia ”) amount released after 24 hours > (24/8 * amount released after 8 hours) * 0.95 (Ib).

as determined on the basis of pharmaceutical availability measured in vitro on USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free artificial gastric juice (SGF) at 37 ° C.

In some embodiments, the amount of active agent (hydrocodone bitartrate) released from the dosage form is proportional to within 20%, within 10%, or within 5% of the duration of action from 8 to 18 hours as determined by pharmaceutical availability measured under conditions in vitro in the USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free simulated gastric juice (SGF) at 37 ° C. In other words, in some embodiments, the amount of hydrocodone bitartrate released corresponds to equations (2a) and (2b):

amount released after 18 hours <(18/8 * amount released after 8 hours) * 1.2 (2a) amount released after 18 hours > (18/8 * amount released after 8 hours) * 0.8 (2b), preferably the amount of hydrocodone bitartrate released corresponds to equations (2a ') and (2b'):

amount released after 18 hours <(18/8 * amount released after 8 hours) * 1.1 (2a) amount released after 18 hours > (18/8 * amount released after 8 hours) * 0.9 (2b) and more preferably corresponds to equations (2a ") and (2b"):

amount released after 18 hours <(18/8 * amount released after 8 hours) * 1.05 (2a ”) amount released after 18 hours > (18/8 * amount released after 8 hours) * 0.95 (2b ”) determined from pharmaceutical availability measured in vitro on USP Apparatus 1 (basket) at 100 rpm at 900 ml of enzyme-free artificial gastric juice (SGF) at 37 ° C.

In some embodiments, the amount of active agent (hydrocodone bitartrate) released from the dosage form is proportional to within 20%, within 10%, or within 5% of the duration of action from 8 to 12 hours as determined by pharmaceutical availability as measured under conditions in vitro in the USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free simulated gastric juice (SGF) at 37 ° C. In other words, in some embodiments, the amount of hydrocodone bitartrate released corresponds to equations (3a) and (3b):

amount released after 12 hours <(12/8 x amount released after 8 hours) * 1.2 (3a) amount released after 12 hours > (12/8 * amount released after 8 hours) * 0.8 (3b), preferably the amount of hydrocodone bitartrate released corresponds to equations (3a ') and (3b'):

amount released after 12 hours <(12/8 x amount released after 8 hours) x 1.1 (3a) amount released after 12 hours > (12/8 x amount released after 8 hours) x 0.9 (3b) and more preferably corresponds to equations (3a ") and (3b"):

amount released after 12 hours <(12/8 x amount released after 8 hours) x 1.05 (3a ”) amount released after 12 hours > (12/8 x amount released after 8 h) x 0.95 (3b ”) determined from pharmaceutical availability measured in vitro on USP Apparatus 1 (basket) at 100 rpm in 900 ml enzyme-free artificial gastric juice (SGF) at 37 ° C.

In some embodiments, the amount of active agent (hydrocodone bitartrate) released from the dosage form is proportional to within 20%, within 10%, or within 5% of the duration of action from 12 to 24 hours as determined by pharmaceutical availability as measured under conditions in vitro in the USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free simulated gastric juice (SGF) at 37 ° C. In other words, in some embodiments, the amount of hydrocodone bitartrate released corresponds to equations (4a) and (4b):

amount released after 24 hours <(24/12 x amount released after 12 hours) x 1.2 (4a) amount released after 24 hours > (24/12 x amount released after 12 hours) x 0.8 (4b), preferably the amount of hydrocodone bitartrate released corresponds to equations (4a ') and (4b'):

amount released after 24 hours <(24/12 x amount released after 12 hours) x 1.1 (4a) amount released after 24 hours > (24/12 x amount released after 12 hours) x 0.9 and more preferably corresponds to equations (4a ") and (4b"):

amount released after 24 hours <(24/12 x amount released after 12 hours) x 1.05 amount released after 24 hours > (24/12 x amount released after 12 h) x 0.95 (4b) (4a) (4b) determined from pharmaceutical availability measured in vitro on USP Apparatus 1 (basket) at 100 rpm ./min in 900 ml of artificial gastric juice without enzymes (SGF) at 37 ° C.

In some embodiments, the amount of active agent (hydrocodone bitartrate) released from the dosage form is proportional to within 20%, within 10%, or within 5% of the duration of action from 12 to 18 hours as determined by pharmaceutical availability as measured under the conditions in vitro in the USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free simulated gastric juice (SGF) at 37 ° C. In other words, in some embodiments, the amount of hydrocodone bitartrate released corresponds to equations (5a) and (5b):

amount released after 18 hours <(18/12 x amount released after 12 hours) * 1.2 (5a) amount released after 18 hours > (18/12 * amount released after 12 hours) * 0.8 (5b), preferably the amount of hydrocodone bitartrate released corresponds to equations (5a ') and (5b'):

amount released after 18 hours <(18/12 x amount released after 12 hours) x 1.1 (5a) amount released after 18 hours > (18/12 x amount released after 12 hours) x 0.9 (5b) and more preferably corresponds to equations (5a ") and (5b"):

amount released after 18 hours <(18/12 x amount released after 12 hours) x 1.05 (5a ”) amount released after 18 hours > (18/12 x amount released after 12 h) x 0.95 (5b ”) determined from pharmaceutical availability measured in vitro on USP Apparatus 1 (basket) at 100 rpm in 900 ml enzyme-free artificial gastric juice (SGF) at 37 ° C.

In some embodiments, the amount of active agent (hydrocodone bitartrate) released from the dosage form is proportional to within 20%, within 10%, or within 5% of the duration of action from 4 to 20 hours as determined by pharmaceutical availability as measured under the conditions in vitro in the USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free simulated gastric juice (SGF) at 37 ° C.

In some embodiments, the amount of active agent (hydrocodone bitartrate) released from the dosage form is proportional to within 20%, within 10%, or within 5% of the duration of action from 4 to 15 hours as determined by pharmaceutical availability as measured under the conditions in vitro in the USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free simulated gastric juice (SGF) at 37 ° C.

In some embodiments, the amount of active agent (hydrocodone bitartrate) released from the dosage form is proportional to within 20%, within 10%, or within 5% of the duration of action from 4 to 10 hours as determined by pharmaceutical availability measured under conditions in. vitro in the USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free simulated gastric juice (SGF) at 37 ° C.

In some embodiments, the amount of active agent (hydrocodone bitartrate) released from the dosage form is proportional to within 20%, within 10%, or within 5% of the duration of action from 8 to 20 hours as determined by pharmaceutical availability as measured under conditions in vitro in the USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free simulated gastric juice (SGF) at 37 ° C.

In some embodiments, the amount of active agent (hydrocodone bitartrate) released from the dosage form is proportional to within 20%, within 10%, or within 5% of the duration of action from 10 to 15 hours as determined by pharmaceutical availability as measured under the conditions in vitro in the USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free simulated gastric juice (SGF) at 37 ° C.

In some embodiments, the amount of active agent (hydrocodone bitartrate) released after 2 hours. is less than about 25%; amount of active agent (hydrocodone bitartrate) released from the dosage form after 4 hours. ranges from about 10% to about 30%; amount of active agent (hydrocodone bitartrate) released from the dosage form after 8 hours. it ranges from about 20% to about 60%; amount of active agent (hydrocodone bitartrate) released from the dosage form after 12 hours. ranges from about 40% to about 90%; and the amount of active agent (hydrocodone bitartrate) released from the dosage form after 18 h. is greater than about 70%; as determined on the basis of pharmaceutical availability measured in vitro on USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free artificial gastric juice (SGF) at 37 ° C.

In some embodiments, the amount of active agent (hydrocodone bitartrate) released after 2 hours. is less than about 15%; amount of active agent (hydrocodone bitartrate) released from the dosage form after 4 hours. ranges from about 10% to about 20%; amount of active agent (hydrocodone bitartrate) released from the dosage form after 8 hours. ranges from about 30% to about 45%; amount of active agent (hydrocodone bitartrate) released from the dosage form after 12 hours. ranges from about 50% to about 70%; and the amount of active agent (hydrocodone bitartrate) released from the dosage form after 18 h. is greater than about 90%; as determined on the basis of pharmaceutical availability measured in vitro on USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free artificial gastric juice (SGF) at 37 ° C.

In some embodiments, the amount of active agent (hydrocodone bitartrate) released after 2 hours. is less than about 10%; amount of active agent (hydrocodone bitartrate) released from the dosage form after 4 hours. ranges from about 20% to about 30%; amount of active agent (hydrocodone bitartrate) released from the dosage form after 8 hours. ranges from about 45% to about 60%; amount of active agent (hydrocodone bitartrate) released from the dosage form after 12 hours. ranges from about 70% to about 90%; and the amount of active agent (hydrocodone bitartrate) released from the dosage form after 18 h. it is greater than about 95%; as determined on the basis of pharmaceutical availability measured in vitro on USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free artificial gastric juice (SGF) at 37 ° C.

In some embodiments, the amount of active agent (hydrocodone bitartrate) released from the dosage form is proportional to 20% of the duration of action from 8 to 24 hours as determined by pharmaceutical availability measured in vitro on a USP Apparatus 1 device (basket) at speed of 100 rpm in 900 ml of enzyme-free simulated gastric juice (SGF) at 37 ° C, and at least one of the following applies: (i) the amount of hydrocodone bitartrate released after 2 hours. is less than about 20%, (ii) the amount of hydrocodone bitartrate released after 4 hours. is from about 10% to about 30%, (iii) the amount of hydrocodone bitartrate released after 8 hours. is from about 30% to about 60%, (iv) the amount of hydrocodone bitartrate released after 12 hours. is from about 50% to about 90% or (v) the amount of hydrocodone bitartrate released after 18 hours. is greater than about 80%.

In some embodiments, the amount of active agent (hydrocodone bitartrate) released from the dosage form is proportional to 20% of the duration of action from 8 to 24 hours as determined by pharmaceutical availability measured in vitro on a USP Apparatus 1 device (basket) at speed of 100 rpm in 900 ml of enzyme-free simulated gastric juice (SGF) at 37 ° C, and at least one of the following applies: (i) the amount of hydrocodone bitartrate released after 2 hours. is less than about 15%, (ii) the amount of hydrocodone bitartrate released after 4 hours. is from about 10% to about 20%, (iii) the amount of hydrocodone bitartrate released after 8 hours. is from about 30% to about 45%, (iv) the amount of hydrocodone bitartrate released after 12 hours. is from about 50% to about 70% or (v) the amount of hydrocodone bitartrate released after 18 hours. is greater than about 90%.

In some embodiments, the amount of active agent (hydrocodone bitartrate) released from the dosage form is proportional to 20% of the duration of action from 8 to 24 hours as determined by pharmaceutical availability measured in vitro on a USP Apparatus 1 device (basket) at speed of 100 rpm in 900 ml of enzyme-free simulated gastric juice (SGF) at 37 ° C, and at least one of the following applies: (i) the amount of hydrocodone bitartrate released after 2 hours. is less than about 10%, (ii) the amount of hydrocodone bitartrate released after 4 hours. is from about 20% to about 30%, (iii) the amount of hydrocodone bitartrate released after 8 hours. is from about 45% to about 60%, (iv) the amount of hydrocodone bitartrate released after 12 hours. is from about 70% to about 90% or (v) the amount of hydrocodone bitartrate released after 18 hours. is greater than about 95%.

In some embodiments, the amount of active agent (hydrocodone bitartrate) released from the dosage form is proportional to 20% of the duration of action from 8 to 24 hours as determined by pharmaceutical availability measured in vitro on a USP Apparatus 1 device (basket) at speed of 100 rpm in 900 ml of enzyme-free simulated gastric juice (SGF) at 37 ° C, and at least one of the following applies: (i) the amount of hydrocodone bitartrate released after 2 hours. is less than about 15%, (ii) the amount of hydrocodone bitartrate released after 4 hours. is from about 8% to about 20%, (iii) the amount of hydrocodone bitartrate released after 8 hours. is from about 20% to about 50%, (iv) the amount of hydrocodone bitartrate released after 12 hours. is from about 40% to about 70% or (v) the amount of hydrocodone bitartrate released after 18 hours. is greater than about 70%; or (vi) the amount of hydrocodone bitartrate released from the dosage form after 24 is greater than about 90%.

DOSING FORMS

In some embodiments, the core can be prepared by dry blending the controlled release material, the active agent, and optionally other excipients, and the mixture is granulated until the desired granule size is obtained. The process can be carried out using dry or wet granulation methods. Typically, with wet granulation, the wet granules are dried in a fluid bed dryer and then screened and milled to the appropriate size. Lubricants are usually added to the granules to obtain the final core formulation.

The controlled release solid dosage forms of the present invention contain polyethylene oxide in a matrix material as described herein. Examples of suitable additional controlled release materials that can be included in the formulations of the present invention include hydrophilic and hydrophobic materials such as polymers, gums, acrylic resins, protein-derived materials, waxes, shellacs, and oils such as hydrogenated castor oil and hydrogenated vegetable oil. More specifically, the controlled release materials can be e.g. alkyl celluloses such as ethyl cellulose, acrylic and methacrylic acid polymers and copolymers, and cellulose ethers such as hydroxyalkyl celluloses (e.g. hydroxypropyl methyl cellulose) and carboxyalkyl celluloses. The waxes include, for example, natural and synthetic waxes, fatty acids, fatty alcohols, and mixtures thereof (e.g., beeswax, camauba wax, stearic acid and stearyl alcohol). In some embodiments, mixtures of two or more of the above-mentioned controlled release materials are used in a core matrix. However, any pharmaceutically acceptable hydrophobic or hydrophilic controlled release material which allows for the controlled release of the active agent may be used in the present invention.

The cores may also contain appropriate amounts of additional excipients, e.g., lubricants, binders, granulating aids, diluents, dyes, flavors (e.g., bitter tasting agents), and glidants, all of which are conventionally used in the pharmaceutical industry.

Specific examples of pharmaceutically acceptable diluents and excipients that can be used in the preparation of the cores are described in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986), incorporated herein by reference.

The matrixes of the dispensing molds of the present invention contain polyethylene oxide (e.g., high and / or low molecular weight PEO).

The approximate molecular weight of polyethylene oxide is considered to be 1,000,000 when a 2% (w / w) aqueous PEO solution at 25 ° C shows a viscosity in the range of 400 to 800 mPas (cP) as measured with a Brookfield viscometer , RVF model, with # 1 spindle, at 10 RPM.

The approximate molecular weight of polyethylene oxide is considered to be 2,000,000 when a 2% (w / w) aqueous PEO solution at 25 ° C shows a viscosity in the range of 2,000 to 4,000 mPa · s (cP) when measured with a Brookfield viscometer. RVF model, with # 3 spindle, at 10 rpm.

The approximate molecular weight of polyethylene oxide is considered to be 4,000,000 when a 1% (w / w) aqueous solution of polyethylene oxide at 25 ° C has a viscosity in the range of 1,650 to 5,500 mPa-s (cP) when measured with a Brookfield viscometer , RVF model, with # 2 spindle, at 2 RPM.

The approximate molecular weight of polyethylene oxide is considered to be 5,000,000 when a 1% (w / w) aqueous solution of polyethylene oxide at 25 ° C has a viscosity in the range of 5,500 to 7,500 mPa · s (cP) when measured with a Brookfield viscometer , RVF model, with # 2 spindle, at 2 RPM.

The approximate molecular weight of polyethylene oxide is considered to be 7,000,000 when a 1% (w / w) aqueous solution of polyethylene oxide at 25 ° C has a viscosity in the range of 7,500 to 10,000 mPas (cP) when measured with a viscometer Brookfield, Model RVF, # 2 spindle, 2 rpm.

The approximate molecular weight of polyethylene oxide is considered to be 8,000,000 when a 1% (w / w) aqueous solution of polyethylene oxide at 25 ° C has a viscosity in the range of 10,000 to 15,000 mPa · s (cP) when measured by Brookfield viscometer, model RVF, with spindle # 2, speed 2 rpm.

For lower molecular weight polyethylene oxides the approximate molecular weight of polyethylene oxide is considered to be 100,000 when a 5% (w / w) aqueous polyethylene oxide solution at 25 ° C has a viscosity in the range of 30 to 50 mPa-s (cP) ) when measured with a Brookfield viscometer, model RVT, with spindle No. 1, at 50 rpm.

The approximate molecular weight of polyethylene oxide is considered to be 900,000 when a 5% (w / w) aqueous solution of polyethylene oxide at 25 ° C has a viscosity ranging from 8,800 to 17,600 cps when measured with a Brookfield viscometer , RVF model, with # 2 spindle, at 2 RPM.

COMPRESSION COATED DOSING FORMS

In embodiments where compression coating is used, it is preferable that all or a portion of the pharmaceutically acceptable excipients in the coating allow sufficient compression to form a pharmaceutically acceptable product. Compression coating on the pre-formed core depends in part on the individual characteristics of the selected excipients and the active agent, e.g. in terms of solubility, flowability and glass transition temperature of the polymer, etc.

Compression coated dosage forms may be prepared e.g. by using a preformed core or by preparing the core (e.g. by compression) prior to coating. The inner core can be prepared by wet or dry granulating the active agent together with pharmaceutically acceptable excipients; followed by drying and grinding as needed to obtain granules; adding optional excipients and / or active agent in addition to the granules with appropriate mixing; adding lubricant as needed; and compressing the granulate with a tablet press. The resulting compressed core may optionally be coated with a functional coating or a film coating prior to compression coating.

The compression coating mixture can be prepared using a similar process as for the core using any of the controlled release materials disclosed above. Preferably, the compression shell comprises polyethylene oxide. The core can be coated with the mixture by compression. A Killion or Fette rotary press set to a compaction force, e.g., from about 1 to about 20 kilonewtons, may be used to compress the core and / or the shell.

In some embodiments, a Manesty Dry-Cota press (e.g., Model 900) may be used. This apparatus consists of two adjacent and connected tablet presses, the core being produced on one press and then transferred to the next press for compression coating. Each press has an independent powder feed mechanism - the core mixture is loaded into one unit and the coating mixture is loaded into the other unit. The cores are lifted from the press to the cores by mechanical transfer arms which rotate between the devices and then transferred to the coater press. Other presses that may be used to prepare the dispensing forms of the present invention include the Elizabeth Hata HT-AP44-MSU-C presses; Killian RLUD and Fette PT 4090, each with a dual feed system for the coating mixture and pre-fabricated cores. By using these presses, multiple compression coating layers can be produced by reusing tablets that have already been compression coated. Each of these presses is equipped with a mechanism for centering the tablet in the coating mixture, both vertically and axially.

In some embodiments, the applied compression coating is not the same thickness at all points around the inner core, but is applied with a different thickness around the inner core. The thinner areas of the coating will be areas of the compressed dosage form through which the drug will be released from the inner core earlier than from other areas. For this purpose, for example, that the core to which the compression coating is applied is not centered in the press at the time of coating.

In some embodiments, the compression coated dosage forms may be additionally coated with a hydrophobic or gastric acid resistant material. In other embodiments, the compression coated dosage forms may be coated with a hydrophilic coating in addition to or in place of a hydrophobic or gastric acid resistant coating.

In still other embodiments, an optional coating (e.g., hydrophobic, hydrophilic, or gastric acid-resistant) may alternatively or additionally be used as an intermediate coating between the core and the compression coating.

ACTIVE MEASURES

The opioid analgesic used in the present invention is hydrocodone bitartrate. The present disclosure also relates to other opioid analgesics, including but not limited to alfentanil, allylprodin, alfaprodin, anileridine, benzylmorphine, besithramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, desocin, diampromide, diamorphone, dihydrocodeine, dihydromorphine, ethylamine, ethylamine, dimethythebuthene, dimethythebuthexadol, dimethethanhamphuthenium , ethylmorphine, etonitazene, etorphin, dihydroetorphin, fentanyl and derivatives, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levofenacylmorphan, lofentanil, meperidine, meptainol, metazocin, methadone, methopone, morphine, myrophin, narcein, nicomorphine, norleworphanol, normetadone, nalorphine, nalbufen, normorphine, norpipanone, opium, oxycinomorphine, phenoxavereimorphine, phenoxavereymorphine, phenoxavereimorphine phenoperidine, piminodine , pyritramide, propeptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts, complexes (e.g. with cyclodextrin), stereoisomers, ethers, esters, hydrates, solvates and mixtures thereof.

The disclosed opioids may contain one or more asymmetric centers and may form enantiomers, diastereomers, or other stereoisomeric forms. The present invention relates to the use of all such possible forms as well as their racemic and dissolved forms and their compositions. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, these include the E and Z geometric isomers. The present invention also relates to all tautomers.

The pharmaceutically acceptable salts of the disclosed opioids include, inter alia, inorganic acid salts such as hydrochloride, hydrogen bromide, sulfate, phosphate and the like;

organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate and the like; amino acid salts such as arginate, aspartate, glutamate and the like; metal salts such as sodium salt, potassium salt, cesium salt, etc. alkaline earth metals such as calcium salt, magnesium salt and the like; and organic amine salts such as triethylamine salt, pyrimidine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N'-dibenzylethylnediamine salt and the like.

Additionally, active agents other than opioid analgesics that are potentially abused are disclosed. Such agents include, for example, sedatives, central nervous system depressants, central nervous system stimulants, sedatives, hypnotics, stimulants (including appetite suppressants such as phenylpropanolamine) and cannabinoids. More specifically, the active agent can be selected from barbiturates such as phenobarbital, secobarbital, pentobarbital, butabarbital, talbutal, aprobarbital, mephobarbital, butalbital, pharmaceutically acceptable salts thereof and the like; benzodiazepines such as diazepam, chlordiazepoxide, alprazolam, triazolam, estazolam, clonazepam, flunitrazepam, pharmaceutically acceptable salts thereof etc .; stimulants such as gamma-hydroxybutyrate, dextroamphetamine, methylphenidate, sibutramine, methylenedioxymethamphetamine, pharmaceutically acceptable salts and the like; other agents such as marinol, meprobamate, and carisoprodol; and all pharmaceutically acceptable salts, complexes, stereoisomers, ethers, esters, hydrates, solvates, and mixtures thereof.

In other embodiments, other therapeutically active agents in accordance with the present invention may be used in combination with hydrocodone bitartrate. Examples of such therapeutically active agents include antihistamines (e.g., dimenhydrinate, diphenhydramine, chlorpheniramine, and dexchlorpheniramine maleate), non-steroidal anti-inflammatory agents (e.g., naproxen, diclofenac, indomethacin, ibuprofen, sulindac, Coxofen-2 inhibitors, acetaminophen-2 inhibitors), e.g. metoclopramide, methylnaltrexone), antiepileptics (e.g. phenylethin, meprobm and nitrazepam), vasodilators (e.g. nifedipine, papaverine, diltiazem and nicardipine), antitussives and expectorants, asthma medications (e.g. theophylline), antacids, antispasmodics drugs (e.g. atropine, scopolamine), anti-diabetic drugs (e.g. insulin), diuretics (e.g. ethacrynic acid, bendrofluthiazide), antihypotensive drugs (e.g. propranolol, clonidine), antihypertensive drugs (e.g. clonidine, methyldopa), bronchodilators (e.g. albuterol), steroids (e.g.

hydrocortisone, triamcinolone, prednisone), antibiotics (e.g. tetracycline), drugs for hemorrhoids, psychotropic drugs, antidiarrheal drugs, mucus-dissolving agents, decongestants (e.g. pseudoephedrine), laxatives, vitamins and their pharmaceutically acceptable salts, complexes, stereoisomers , ethers, esters, hydrates, solvates, and mixtures thereof.

EXAMPLES OF THE DESIGN CONTAINING HYDROCODONE

The controlled release oral dosage forms of the present invention preferably contain from about 0.5 mg to about 1250 mg of hydrocodone bitartrate. In other embodiments, the dosage forms contain from about 2 mg to about 200 mg hydrocodone bitartrate or from about 16 mg to about 120 mg hydrocodone bitartrate. In some preferred embodiments, the dosage form comprises about 20 mg, about 30 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, or about 120 mg of hydrocodone bitartrate.

The present document also discloses, without being included within the scope of the claims, other pharmaceutically acceptable salts of hydrocodone, including hydrocodone hydrochloride, hydrocodone p-toluenesulfonate, hydrocodone phosphate, hydrocodone thiosemicarbazone, hydrocodone sulfate, hydrocodone trifluoroacetate, hydrocodone hydroconepropion hydrazepentahydrate, pentylodone pentahydrase, p-toluenesulfonate. hydrocodone, hydrocodone o-methyloxime, hydrocodone semicarbazone, hydrocodone hydrogen bromide, hydrocodone mucate, hydrocodone oleate, hydrocodone dibasic phosphate, hydrocodone monobasic phosphate, hydrocodone inorganic salt, organic hydrocodone salt, hydrocodone acetate trihydrate, hydrocodone bis (heptafluorobutyrate), hydrocodone bis (methylcarbamate), hydrocodone bis (pentafluoropropionate) bis (pentafluoropropionate) ) hydrocodone, hydrocodone chlorhydrate and hydrocodone sulfate pentahydrate.

The hydrocodone bitartrate-containing dosage form of the present invention may further comprise one or more additional drugs that may or may not act synergistically with the hydrocodone bitartrate contained therein. Examples of such additional drugs include non-steroidal anti-inflammatory agents, including ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprosine, pramoprofen, muropaprofen, trilaprofen, trilaprofen, trilaprofen, trilaprofen, trileprofen, trileprofen, trilaprofen. fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, thiopinac, Żydometacin, acemetacin, fentiazac, clidanac, oxspinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflunisal, flufenisal, piroxicam, sudoxicam, isoxicam, and their pharmaceutically acceptable salts, complexes, stereoisomers, ethers, esters, hydrates, solvates, and mixtures thereof. Such non-steroidal anti-inflammatory agents also include cyclooxygenase inhibitors such as celecoxib, meloxicam, nabumetone, nimesulide and their pharmaceutically acceptable salts, complexes, stereoisomers, ethers, esters, hydrates, solvates, and mixtures thereof.

Other additional drugs that may be combined with hydrocodone bitartrate include NMDA receptor antagonists, e.g. dextrorphan, dextromethorphan, 3- (1-naphthalenyl) -5- (phosphonomethyl) -L-phenylalanine, 3- (1-naphthalenyl) -5- (phosphonomethyl) -DL-phenylalanine, 1- (3,5-dimethylphenyl) naphthalene , 2- (3,5-dimethylphenyl) naphthalene, 2SR acid, 4RS-4 - (((1H-tetrazol-5-yl) methyl) oxy) piperidine-2-carboxylic acid, 2SR, 4RS-4 - ((( (1H-tetrazol-5-yl) methyl) oxy) methyl) piperidine-2-carboxylic acid, E and Z 2SR-4- (O- (1H-tetrazol-5-yl) methyl) ketoxyimino) piperidine-2-carboxylic acid , 2 SR acid, 4RS -4 - ((1H-tetrazol -5-yl) thi ojpiperidine-2-carboxylic acid, 2 SR acid, 4RS -4 - ((1H-tetrazol -5-yl) thi o-piperidine-2-carboxylic acid, 2SR, 4RS-4- (5-mercapto-1H-tetrazol-1-yl) piperidine-2-carboxylic acid, 2SR, 4RS-4- (5-mercapto-2H-tetrazol-2 -yl) piperidine-2-carboxylic acid, 2SR, 4RS-4- (5-mercapto-1H-tetrazol-1-yl) piperidine-2-carboxylic acid, 2SR, 4RS-4- (5-mercapto-2H-tetrazole -2-yl) piperidine-2-carboxylic acid, 2SR, 4RS-4 - (((1H-tetrazol-5-yl) thio) methyl) piperidine-2-carboxylic acid, 2SR, 4RS-4 - ((5-mercapto-1H-tetrazol-1-yl) methyl ) piperidine-2-carboxylic acid, 2SR, 4RS-4 - ((5-mercapto-2H-tetrazol-2-yl) methyl) piperidine-2-carboxylic acid and their pharmaceutically acceptable salts, complexes, stereoisomers, ethers, esters, hydrates , solvates, and mixtures thereof.

Other suitable drugs that may be included in the hydrocodone bitartrate dosage forms of the present invention include acetaminophen and aspirin.

In preferred embodiments, the hydrocodone bitartrate formulations of the present invention are suitable for once daily administration and provide a relatively flat plasma concentration profile, meaning that the plasma hydrocodone level provides a C24 / C ratio._hasFr. ranging from about 0.55 to about 1.0 after administration. In some embodiments, the C24 / C value ratio_hasFr. is from about 0.55 to about 0.85, from about 0.55 to about 0.75, or from about 0.60 to about 0.70 after administration of the dosage form.

In preferred embodiments, the hydrocodone bitartrate formulations of the present invention provide a T value_hasFr. (h) of hydrocodone from about 4 to about 20 hours. after administration. In some embodiments, the value of T_hasks is from about 6 to about 12 hours, from about 8 to about 10 hours, from about 4 to about 10 hours, from about 8 to about 14 hours. or from about 14 to about 20 hours. after giving the dosage form.

In still other embodiments, the solid controlled release dosage forms of the present invention provide an AUC (ng * hr / ml) post-dose of from about 200 to 450 or from about 250 to 400 for every 20 mg of hydrocodone bitartrate contained in the dosage form.

In some embodiments, a solid controlled release dosage form that contains 20 mg of hydrocodone bitartrate provides an AUC (ng * hr / mL) after administration of from about 200 to about 450, from about 250 to about 400, from about 275 to about 350, from about 300 to 330, or from about 280 to about 320.

In some embodiments, a solid controlled release dosage form that contains 120 mg of hydrocodone bitartrate provides an AUC (ng * hr / mL) post-dose of from about 1000 to about 3000, from about 1500 to about 2400, from about 1700 to about 2,200, from about 1,800 to about 2,100, or from about 1,900 to about 2,100.

In other embodiments, the solid controlled release dosage form of the present invention provides a C value_hasks (ng / ml) after administration is from about 5 to about 40, from about 10 to about 30 for every 20 mg of hydrocodone bitartrate contained in the dosage form.

In some embodiments, a solid controlled release dosage form that comprises 20 mg hydrocodone bitartrate provides a C_hasks (ng / mL) after administration ranging from about 5 to about 40, from about 10 to about 30, from about 12 to about 25, from about 14 to about 18, or from about 12 to about 17.

In some embodiments, a solid controlled release dosage form that comprises 120 mg hydrocodone bitartrate provides a C_hasks (ng / ml) after administration is from about 30 to about 120, from about 60 to about 180, from about 100 to about 160, from about 110 to about 150, or from about 100 to about 140.

In some embodiments, the solid controlled release dosage form of the present invention provides a T value_hasThe ks (h) of hydrocodone after administration is from about 7 to about 22, from 10 to about 20, from about 12 to about 18, from about 13 to about 17, or from about 14 to about 16.

In other embodiments, the solid controlled release dosage form of the present invention provides a T 1/2 (hr) of hydrocodone following administration of from about 5 to about 10, from about 6 to about 9, about 7, or about 8.

In other embodiments, the solid controlled release dosage form of the present invention provides a Ti value_ag (h) of hydrocodone after administration ranging from about 0.01 to about 0.2, from about 0.1 to about 0.18, from about 0.3 to about 0.17, or from about 0.06 to about 0, 15.

In other embodiments, the solid controlled release dosage form of the present invention provides a C24 / C ratio_hasa hydrocodone x of from about 0.2 to about 0.8, from about 0.3 to about 0.7, or from about 0.4 to about 0.6.

In some embodiments, any or all of the above in vivo mean parameters are obtained when administered in the fasted state.

In some embodiments, the mean AUC (ng * hr / ml) of hydrocodone after administration after food is less than 20% greater, less than 16% greater, or less than 12% greater than the AUC (ng * hr / ml). ml) of hydrocodone in the fasted state.

In some embodiments, the average value of C_hasThe ks (ng / ml) of hydrocodone when administered after eating is less than 80% higher, less than 70% higher or less than 60% higher than the C_hasof hydrocodone when administered on an empty stomach.

In some embodiments, the average value of T_hasThe ks (h) of hydrocodone after drug administration is within 25%, within 20% or within 15% of the T value_hasof hydrocodone when administered on an empty stomach.

In some embodiments, the mean T1 / 2 (hr) of hydrocodone after administration of a vehicle is within 8%, within 5%, or within 2% of the T 1/2 value after administration in the fasted state.

In some embodiments, the average value of Ti_ag Hydrocodone when administered under fed conditions is less than 150% higher, less than 125% higher, or less than 100% higher than the T1 / 2 value of hydrocodone in the fasted state.

In some embodiments, any or all of the above parameters in vivo are obtained upon first administration of the dosage form to a human, patient, or healthy subject (individual data), or a population of humans, patients, or healthy subjects (averaged data).

In alternative embodiments, any or all of the above in vivo parameters are obtained after steady state administration of the dosage form to a human, patient, or healthy subject, or a human population, patient or healthy subject.

HARDENED PREPARATIONS

In some embodiments, the method of the present invention further comprises the step of curing the final dosage form.

The curing step may be at least in part fusing the polyethylene oxide in the formulation. In some embodiments, at least about 20% or at least about 30% of the polyethylene oxide in the formulation is melted. Preferably, at least about 40%, at least about 50%, at least about 60%, at least about 75% or at least about 90% of the polyethylene oxide in the formulation is melted during the curing step. In a preferred embodiment, about 100% of the polyethylene oxide is melted.

In other embodiments, the curing step comprises exposing the formulation to elevated temperature for a specified period of time. In such embodiments, the curing temperature is at least equal to the softening point of the polyethylene oxide. In some embodiments, the curing temperature is at least about 60 ° C, at least about 62 ° C, from about 62 ° C to about 90 ° C, from about 62 ° C to about 85 ° C, from about 62 ° C. ° C to about 80 ° C, from about 65 ° C to about 90 ° C, from about 65 ° C to about 85 ° C, or from about 65 ° C to about 80 ° C. The curing temperature is preferably from about 68 ° C to about 90 ° C, from about 68 ° C to about 85 ° C, from about 68 ° C to about 80 ° C, from about 70 ° C to about 90 ° C , from about 70 ° C to about 85 ° C, from about 70 ° C to about 80 ° C, from about 72 ° C to about 90 ° C, from about 72 ° C to about 85 ° C, or from about 72 ° C to about 80 ° C. The curing temperature may be at least about 60 ° C, at least about 62 ° C, less than about 90 ° C, or less than about 80 ° C. It is preferably from about 62 ° C to about 72 ° C, or from about 68 ° C to about 72 ° C. Preferably, the curing temperature is at least the lower limit of the softening temperature range of the polyethylene oxide, or is at least about 62 ° C or at least about 68 ° C. More preferably, the curing temperature is within the softening temperature range of the polyethylene oxide or is at least 70 ° C. In other embodiments, the cure temperature is at least equal to the upper limit of the softening temperature range of the polyethylene oxide, or is at least 72 ° C. In other embodiments, the curing temperature is greater than the upper end of the softening temperature range of the polyethylene oxide, or is at least about 75 ° C or at least about 80 ° C.

In embodiments where the curing step consists of exposing the formulation to an elevated temperature for a specified period of time, that specified time is hereinafter referred to as the curing time. For the measurement of the curing time, a starting point and an end point of the curing step are defined. For the purposes of the present invention, the starting point of the curing step is defined as the time point at which the curing temperature is reached.

In some embodiments, the temperature profile during the curing step is close to a plateau between the curing starting point and the curing end point. In such embodiments, the end point of the curing step is defined as the point in time at which heating is stopped or at least limited, e.g. by terminating or reducing the heating and / or by initiating a further cooling step, the temperature then drops below the curing temperature by more than about 10 ° C and / or below a lower limit of the softening point of the polyethylene oxide, e.g., less than about 62 ° C. After the curing temperature is reached and the curing step is started, deviations from the curing temperature may occur during the curing step. Such variations are tolerated as long as they do not exceed values ​​of about 10 ° C, preferably about 6 ° C, and more preferably about 3 ° C. For example, if the temperature is to be maintained at least about 75 ° C, the measured temperature may temporarily rise to about 85 ° C, about 81 ° C, or about 78 ° C, and the measured temperature may also drop temporarily to about 65 ° C. C, about 69 ° C, or about 72 ° C. When the temperature is reduced more and / or the temperature is below the lower limit of the softening point of the polyethylene oxides, for example below about 62 ° C, the curing step is interrupted, i.e. the end point is reached. Curing can be restarted by reaching the curing temperature.

In other embodiments, the temperature profile during the curing step is parabolic or triangular between the starting point and the curing end point. This means that after the starting point, i.e. the time point at which the curing temperature is reached, the temperature further increases to a maximum level and then decreases. In such embodiments, the end point of the curing step is defined as the time point where the temperature drops below the curing temperature.

Depending on the device used for curing (i.e., the curing unit), different temperatures may be measured in the curing unit to determine the curing temperature.

In some embodiments, the curing step may be performed in an oven. In such embodiments, the temperature inside the oven is measured. On this basis, when the curing step is performed in an oven, the curing temperature is defined as the target temperature inside the oven and the starting point of the curing step is defined as the time point at which the temperature inside the oven reaches the curing temperature. The end point of the curing step is defined as (1) as the time point at which heating is stopped or at least limited and the temperature inside the oven consequently drops below the curing temperature by more than about 10 ° C and / or below the lower limit of the softening temperature range high molecular weight polyethylene oxide, e.g. below about 62 ° C, in a near plateau temperature profile, or (2) as the time point where the temperature inside the furnace drops below the cure temperature in a parabolic or triangular temperature profile. Preferably, the curing step begins when the temperature inside the oven reaches a curing temperature of at least about 62 ° C, at least about 68 ° C, at least about 70 ° C, at least about 72 ° C, or at least about 75 ° C. In preferred embodiments, the temperature profile during the curing step is plateau-like wherein the curing temperature, i.e. the temperature within the oven, is at least about 68 ° C, about 70 ° C, about 72 ° C, about 73 ° C or is preferably from about 70 ° C to about 75 ° C and the curing time is preferably from about 30 minutes to about 20 hours, from about 30 minutes to about 15 hours, from about 30 minutes to about 4 hours. . or from about 30 minutes to about 2 hours. In some embodiments, the curing time ranges from about 30 minutes to about 90 minutes.

In some other embodiments, the curing is performed in curing devices that are heated by air flow and have a heated air supply (inlet) system and an outlet, e.g., a substrate pan or fluidized bed. Such curing devices will hereinafter be referred to as convection curing devices. In such curing devices, the temperature at the air inlet, i.e. the temperature of the heated air entering the convection curing unit and / or the temperature of the exhaust air, i.e. the temperature of the air exhausted from the convection curing unit. The temperature of the formulations inside the convection curing device during the curing step may also be determined or at least estimated, e.g. by means of infrared temperature measuring devices (such as an infrared gun) or by measuring the temperature with a temperature probe placed in the curing device near the specimens. On this basis, when the curing step is performed in a convection curing device, the curing temperature can be determined and the curing time can be measured as follows.

In one embodiment (method 1), the curing temperature is defined as the target air inlet temperature and the starting point of the curing step is defined as the time point at which the air inlet temperature reaches the curing temperature. The end point of the curing step is defined (1) as the time point at which heating is stopped or at least limited and the air inlet temperature consequently drops below the curing temperature by more than about 10 ° C and / or below the lower limit of the temperature range softening of high molecular weight polyethylene oxide, e.g. below about 62 ° C, in a plateau-like temperature profile, or (2) as the time point at which the air inlet temperature drops below the cure temperature in a parabolic or triangular temperature profile. Preferably, the curing step is started in method 1 when the temperature at the air inlet reaches a curing temperature of at least about 62 ° C, at least about 68 ° C, at least about 70 ° C, at least about 72 ° C, or at least about 75 ° C. In a preferred embodiment, the temperature profile during the curing step is plateau-like, the curing temperature, i.e. the temperature at the air inlet, preferably being at least about 72 ° C, for example about 75 ° C and the curing time as measured according to in method 1, preferably from about 15 minutes to about 2 hours, for example about 30 minutes or about 1 hour.

In another embodiment (method 2), the curing temperature is defined as the target air outlet temperature and the starting point of the curing step is defined as the time point at which the air outlet temperature reaches the curing temperature. The end point of the curing step is defined (1) as the time point at which heating is stopped or at least limited and the air outlet temperature consequently drops below the curing temperature by more than about 10 ° C and / or below the lower limit of the temperature range softening of high molecular weight polyethylene oxide, e.g. below about 62 ° C, in a plateau-like temperature profile, or (2) as the time point at which the air outlet temperature drops below the cure temperature in a parabolic or triangular temperature profile. Preferably, the curing step is started in method 2 when the temperature at the air outlet reaches a curing temperature of at least about 62 ° C, at least about 68 ° C, at least about 70 ° C, at least about 72 ° C, or at least about 75 ° C. In preferred embodiments, the temperature profile during the curing step is plateau-like, the curing temperature, i.e. the temperature of the air outlet is preferably at least about 68 ° C, at least about 70 ° C or at least about 72 ° C, for example the target temperature of the air outlet is about 68 ° C, about 70 ° C, about 72 ° C , about 75 ° C or about 78 ° C, and the cure time measured according to 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, e.g. curing time is about 5 minutes, about 10 minutes, about 15 minutes, about 30 minutes, about 60 minutes, about 70 minutes, about 75 minutes, or about 90 minutes. In a more preferred embodiment, the cure time, measured according to Method 2, ranges from about 15 minutes to about 1 hour.

In another embodiment (method 3), the curing temperature is defined as the target formulation temperature and the starting point of the curing step is defined as the time point at which the temperature of the formulations, which can be measured e.g. with an infrared gun, reaches the curing temperature. The curing step end point is defined as (1) as the time point at which heating is stopped or at least limited and the temperature of the formulations consequently drops below the curing temperature by more than about 10 ° C and / or below the lower limit of the polyethylene oxide softening temperature range. with high molecular weight, e.g. below about 62 ° C, in a plateau-like temperature profile, or (2) as the time point where the formulation temperature drops below the cure temperature in a parabolic or triangular temperature profile. Preferably, the curing step is started according to method 3 when the temperature of the formulations reaches a curing temperature of at least about 62 ° C, at least about 68 ° C, at least about 70 ° C, at least about 72 ° C, or at least about 75 ° C.

In yet another embodiment (method 4), the curing temperature is defined as the target temperature measured with a temperature probe, such as a wire thermocouple, placed inside the curing apparatus near the formulations, and the starting point of the curing step is defined as the time point at which the temperature measured with the temperature probe reaches the curing temperature. The end point of the curing step is defined (1) as the time point at which the heating is stopped or at least limited and the temperature measured with the temperature probe consequently drops below the curing temperature by more than about 10 ° C and / or below the lower limit. the softening temperature range of polyethylene oxide, e.g. below about 62 ° C, in a plateau-like temperature profile, or (2) as the time point at which the temperature measured with the temperature probe drops below the cure temperature in a parabolic or triangular temperature profile. Preferably, the curing step is started when the temperature measured with the temperature probe reaches a temperature in the curing apparatus of at least about 62 ° C, at least about 68 ° C, at least about 70 ° C, at least about 72 ° C, or at least about 72 ° C or at least about 62 ° C. around 75 ° C. In a preferred embodiment, the temperature profile during the curing step is plateau-like, the curing temperature being at least about 68 ° C, for example about 70 ° C, and the curing time, measured according to method 4, is preferably in the range of about 15 minutes to about 2 hours, about 60 minutes, or about 90 minutes.

If the curing is carried out in a convection curing device, the curing time can be measured by any of the methods described above.

In some embodiments, the curing temperature is defined as a target temperature range, e.g., the curing temperature is defined as a target air inlet temperature range or a target air outlet temperature range. In such embodiments, the starting point of the curing step is defined as the time point at which the lower limit of the target temperature range is reached, and the end point of the curing step is defined as the time point at which heating is stopped or at least limited. and the temperature then drops below the lower limit of the target temperature range by more than about 10 ° C and / or below the lower limit of the softening point of the polyethylene oxide range, e.g., less than about 62 ° C.

The curing time, i.e. the time the formulation is subjected to the curing temperature, which may e.g. be measured according to the methods described above, is at least about 1 minute or at least about 5 minutes. Curing time can be from about 1 minute to about 24 hours, from about 5 minutes to about 20 hours, from about 10 minutes to about 15 hours, from about 15 minutes to about 10 hours. or from about 30 minutes to about 5 hours. Depending on the preparation and the curing temperature. According to some embodiments, the curing time ranges from about 15 minutes to about 30 minutes. According to other embodiments wherein the curing temperature is at least about 60 ° C, at least about 62 ° C, at least about 68 ° C, at least about 70 ° C, at least about 72 ° C, or at least about 75 ° C. C or is from about 62 ° C to about 85 ° C, or from about 65 ° C to about 85 ° C, the curing time is preferably at least about 15 minutes, at least about 30 minutes, at least about 60 minutes, at least about 75 minutes at least about 90 minutes or at least about 120 minutes. In preferred embodiments where the curing temperature is e.g. at least about 62 ° C, at least about 68 ° C, at least about 70 ° C, at least about 72 ° C, or at least about 75 ° C, or ranging from about 62 ° C to about 80 ° C, from about 65 ° C to about 80 ° C, from about 68 ° C to about 80 ° C, from about 70 ° C to about 80 ° C, or from about 72 ° C to about 80 ° C, curing time is preferably at least about 1 minute, at least about 5 minutes, at least about 10 minutes, at least about 15 minutes, or at least about 30 minutes. In some such embodiments, the shortest possible curing time can be used and still achieve the desired result (e.g. increased tamper resistance). For example, curing time preferably does not exceed about 5 hours, not more than about 3 hours. or does not exceed about 2 hours. Preferably, the curing time is in the range of from about 1 minute to about 5 hours, from about 5 minutes to about 3 hours, from about 15 minutes to about 2 hours. or from about 15 minutes to about 1 hour. Any combination of the curing temperatures and curing times disclosed herein is within the scope of the present invention.

In some embodiments, the composition is only exposed to the curing temperature until the polyethylene oxide present in the formulation has reached its softening point and / or has at least partially melted. In some such embodiments, the cure time may be less than about 5 minutes, for example, the cure time may range from greater than 0 minutes to about 3 hours, from about 1 minute to about 2 hours. or from about 2 minutes to about 1 hour. An immediate cure can also be applied by selecting a curing device which allows the polyethylene oxide in the formulation to be immediately heated to at least its melting point so that the high molecular weight polyethylene oxide is at least partially melted. Such curing devices include, for example, microwave ovens, ultrasonic devices, light irradiation devices, e.g. devices for irradiating UV light, ultra high frequency (UHF) fields, or any other devices known to those skilled in the art.

The cure time and cure temperature required to achieve the desired handling resistance may depend on the size of the formulation.

In some embodiments, the curing step tends to reduce the formulation density, for example, such that the density of the cured formulation is lower than the density of the formulation prior to the curing step. Preferably, the density of the cured formulation compared to the density of the uncured formulation is reduced by at least about 0.5%.

More preferably, the density of the cured formulation compared to that of the uncured formulation is reduced by at least about 0.7%, at least about 0.8%, at least about 1.0%, at least about 2.0%, or at least about 2. 5%.

In some embodiments, the solid, controlled release dosage form is cured at a temperature of at least the softening point of the polyethylene oxide for at least 1 minute, at least 5 minutes, or at least 15 minutes.

In other embodiments, the solid controlled release dosage form is cured at a temperature of at least the softening point of the polyethylene oxide from about 1 minute to about 48 hours, from about 5 minutes to about 24 hours, from about 15 minutes to about 1 hour. or about 30 minutes.

The solid controlled release dosage form can be cured, for example, at a temperature of at least about 60 ° C, at least about 65 ° C, at least about 70 ° C, at least about 75 ° C, or at a temperature of about 72 ° C.

In alternative embodiments, the solid, controlled release dosage form may be cured at a temperature of from about 60 ° C to about 90 ° C, from about 62 ° C to about 72 ° C, from about 65 ° C to about 85 ° C, from about 70 ° C to about 80 ° C, from about 75 ° C to about 80 ° C, or from about 70 ° C to about 75 ° C.

FLATTING PROCEDURES

In some embodiments, the dosage forms of the present invention can be flattened without significantly adversely affecting the release of the active agent or the integrity of the dosage form. Flatness is understood as the thickness of the smallest diameter of the flattened form compared to the thickness of the smallest diameter of the non-flattened form. This comparison is expressed as a% thickness value, based on (i) the thickness of the smallest diameter of the non-flattened mold when the mold initially has a non-spherical shape or (ii) the thickness of the diameter when the mold is initially spherical. Thickness may be measured using a thickness measuring device (e.g. a digital thickness measuring device or digital caliper). The flattening force can be applied by any possible method. For testing the dispensing molds of the present invention, they can be used with a carver bench press (unless otherwise specified) to achieve a targeted flatness or reduced thickness. According to some embodiments of the present invention, the flattening does not break the dispensing mold into separate pieces; however, there may be cracks and gaps at the edges.

In some embodiments of the present invention, a hammer may be used to flatten the dispensing mold. In such a process, it is possible to tap the hammer by hand in a direction substantially perpendicular to the thickest dimension of the dispensing mold. The flatness is then understood in the same way as disclosed above.

In other embodiments, the level of flattening can be measured against a burst strength test or a hardness test as described in Remington's Pharmaceutical Sciences, 18th ed., 1990, chapter 89, "Plowed Solid Dosage Forms," ​​pp. 1633-1665. Schleuniger Apparatus devices. In such an embodiment, the dispensing mold is squeezed between a pair of flat plates arranged in parallel so that a force is exerted substantially perpendicular to the thickest dimension of the dispensing mold, resulting in a flattening of the dispensing mold. The level of flattening of the dispensing mold can be described as the% flattening value, based on the thickest flattened dimension prior to the breaking strength test. The breaking strength (or hardness) is the force with which the test dosage form disintegrates. Dosing forms which do not disintegrate but deform under the applied force are considered to resist bursting under that force.

Another attempt to quantify the dosage forms is an indentation hardness test performed using a texture analyzer such as a ΤΑ-2 Texture Analyzer (Texture Technologies Corp., 18 Fairview Road, Scarsdale, NY 10583). In this method, the dispensing mold is placed on the top surface of a stainless steel rack with a slightly recessed surface and penetrated by a drop-down texture analyzer probe such as a TA-8A 1/8 inch diameter stainless steel ball probe. Before starting the measurement, the dosage form is positioned directly under the probe so that the lowered probe penetrates the tablet axially, i.e. at the center of the dispensing mold and such that the force of the lowered probe is exerted substantially perpendicular to the diameter and substantially in line with the thickness of the dispensing mold. The texture analyzer probe first begins to advance towards the sample of the dispensing mold at a preliminary test speed. When the probe contacts the surface of the dispensing mold and the trigger force is reached, the probe will continue to move at the test speed and penetrate the dispensing mold. The force corresponding to each penetration depth or probe distance is measured. When the desired maximum penetration depth is reached, the probe will reverse direction and return to the home position with the final test speed, while additional measurements will be taken. The fracture force is defined as the first maximum local force that is achieved on the corresponding force / distance diagram and is calculated using e.g. texture analyzer software "Texture Expert Exceed, Version 2.64 English".

The term "crush resistant" in the context of some embodiments of this invention means dispensing forms that can at least be flattened using a bench press as described above and not disintegrate to no more than about 60% thickness, preferably no more than about 50% thickness, more preferably no more than about 40% thickness, even more preferably no more than about 30% thickness, and most preferably no more than about 20% thickness. 10% of thickness or 5% of thickness.

In some embodiments, the amount of active (opioid analgesic) released after 0.5 hours. from the flattened form of dispensing differs by no more than about 10% points, 15% points or 20% points from the amount released after 0.5 h. from a non-flattened dosage form as determined by pharmaceutical availability measured in vitro on a USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free simulated gastric juice (SGF) at 37 ° C.

In alternative embodiments, the solid controlled release dosage form may be flattened and not crumble, with the thickness of the dispensing mold after flattening being no more than about 60% of the thickness of the dispensing mold prior to flattening, no more than about 50% of the thickness of the dispensing mold prior to flattening. no more than about 40% of the thickness of the dispensing mold before flattening, no more than about 30% of the thickness of the dispensing mold prior to flattening, or no more than about 20% of the thickness of the dispensing mold prior to flattening.

The following examples are intended to aid the understanding of the present invention and should not be construed as limiting the scope of the invention described herein and in the claims. Such variations of the present invention, including the replacement of all equivalents that are known or to be developed in the future, which are within the skill of one skilled in the art, and changes in formulation composition or minor changes in experimental design are within the scope of the invention described herein.

EXAMPLES

The present invention is described in more detail below with reference to the accompanying examples. It should be noted, however, that the following description is provided for illustrative purposes only and in no way limits the scope of the invention.

In the following examples, tablets designated A to F, Η, I, K and L do not form part of the scope of the present invention as defined in the appended claims. These examples are therefore reference examples. Tablets marked with the letters G, J and M to S are in accordance with the present invention as defined in the claims.

EXAMPLE 1

A 400 mg tablet (Tablet A) containing 20 mg of hydrocodone bitartrate was prepared using high molecular weight polyethylene oxide (PEO 303 - MW 7,000,000) as described in Table 1 below.

<td rowspan="2"></td><td rowspan="2">Hydrocodone</td><td colspan="3">Table 1 (Tablet A)</td>

<td>(mg) Total weight</td><td>% hydrocodone</td><td>Instrument size (mm)</td>

<td>Core</td><td> 16</td><td> 200</td><td> 8</td><td> 7,94</td>

<td>Cover</td><td> 4</td><td> 200</td><td> 2</td><td> 10,32</td>

<td>Together</td><td> 20</td><td> 400</td><td> 10</td><td></td>

For the production of the core, the Manesty Type F 3 single station tablet press was equipped with a round, convex and smooth standard device with a diameter of 7.94 mm. An aliquot of the core mixture in powder form was measured as described above in Table 1 for a target amount of 200 mg, loaded into a die and compressed to form the core of Tablet A.

For the production of the cover, the Manesty Type F 3 single station tablet press was equipped with a round, concave and smooth device with a diameter of 10.32 mm as standard. 100 mg of the sheath mixture was placed in the matrix as described in Table 1. A tablet core prepared as described above was manually centered in the die (on top of the powder bed) and an additional 100 mg of the sheath mixture was applied to the top of the tablet in the die. The materials were then pressed by hand by turning the compression knob to produce a compression coated Tablet A.

Several compression-coated Tablets A, prepared as described above, were placed in a tray and placed in a Hotpack model 435304 oven set at 72 ° C for 30 minutes to cure.

The pharmaceutical availability of cured Tablet A was then measured on a USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free artificial gastric juice (SGF) at 37 ° C. The results are compared to the results of the formulations of Examples 2-4 in Figure 1.

EXAMPLE 2

A 500 mg tablet (Tablet B) containing 20 mg of hydrocodone bitartrate was prepared using high molecular weight polyethylene oxide (PEO 303 - molecular weight 7,000,000) as described in Table 2 below.

Table 2 (Tablet B)

<td></td><td>Hydrocodone (mg)</td><td>total weight</td><td>% hydrocodone</td><td>Instrument size (mm)</td>

<td>Core</td><td> 16</td><td> 300</td><td> 5,3</td><td> 8,73</td>

<td>Cover</td><td> 4</td><td> 200</td><td> 2</td><td> 11,11</td>

<td>Together</td><td> 20</td><td> 500</td><td> 4</td><td></td>

For the production of the core, the Manesty Type F 3 single station tablet press was equipped with a round, smooth device for making pits with a diameter of 8.73 mm. An aliquot of the core mixture in powder form was measured as described above in Table 2 with a target amount of 300 mg, loaded into a die and compressed to form the core of Tablet B.

For the production of the cover, the Manesty Type F 3 single-station tablet press was equipped with a round, convex and smooth device with a diameter of 11.11 mm as standard. The first 200 mg of sheath mixture was placed in the die as described in Table 2. The tablet core prepared as described above was manually centered in the die (on top of the powder bed) and the remainder of 200 mg of the sheath mixture was applied to the top of the tablet. in the matrix. The materials were then pressed by hand by turning a compression knob to produce a compression coated Tablet B.

Several compression-coated Tablets B, prepared as described above, were placed on a tray and placed in a Hotpack model 435304 oven set at 72 ° C for 30 minutes to cure.

The pharmaceutical availability of the cured Tablet B was then measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free artificial gastric juice (SGF) at 37 ° C. The results are compared to the results of the formulations of Examples 1 and 3-4 in Figure 1.

EXAMPLE 3

A 500 mg tablet (Tablet C) containing 20 mg of hydrocodone bitartrate was prepared using high molecular weight polyethylene oxide (PEO 303 - molecular weight 7,000,000) as described in Table 3 below.

Table 3 (Tablet C)

<td></td><td>Hydrocodone (mg)</td><td>total weight</td><td>% hydrocodone</td><td>Instrument size (mm)</td>

<td>Core</td><td> 16</td><td> 300</td><td> 5,3</td><td> 9,53</td>

<td>Cover</td><td> 4</td><td> 200</td><td> 2</td><td> 11,11</td>

<td>Together</td><td> 20</td><td> 500</td><td> 4</td><td></td>

For the production of the core, the Manesty Type F 3 single station tablet press was equipped with a round, smooth device for making indentations with a diameter of 9.53 mm. A powdered aliquot of the core mixture as described above in Table 3 was measured with a target amount of 300 mg, loaded into the die and compressed to form the core of Tablet C.

For the production of the cover, the Manesty Type F 3 single station tablet press was equipped with a round, concave and smooth device with a diameter of 11.11 mm as standard. The first 200 mg of sheath mixture was placed in the die as described in Table 3. The tablet core prepared as described above was manually centered in the die (on top of the powder bed) and the remainder of 200 mg of the sheath mixture was applied to the top of the tablet. in the matrix. The materials were then pressed by hand by turning the compression knob to produce a compression coated Tablet C.

Several compression coated Tablets C, prepared as described above, were placed in a tray and placed in a Hotpack model 435304 oven set at 72 ° C for 30 minutes to cure.

The pharmaceutical availability of the cured Tablet C was then measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free artificial gastric juice (SGF) at 37 ° C. The results are compared to the results of the formulations of Examples 1-2 and 4 in Figure 1.

EXAMPLE 4

A 475 mg tablet (Tablet D) containing 20 mg of hydrocodone bitartrate was prepared using high molecular weight polyethylene oxide (PEO 303 - MW 7,000,000) as described in Table 4 below.

Table 4 (Tablet D)

<td></td><td>Hydrocodone (mg)</td><td>total weight</td><td>% hydrocodone</td><td>Instrument size (mm)</td>

<td>Core</td><td> 14</td><td> 175</td><td> 8</td><td> 7,94</td>

<td>Cover</td><td> 6</td><td> 300</td><td> 2</td><td> 11,11</td>

<td>Together</td><td> 20</td><td> 475</td><td> 4,2</td><td></td>

For the production of the core, the Manesty Type F 3 single station tablet press was equipped with a round, smooth device for making recesses with a diameter of 7.94 mm. An aliquot of the core mixture in powder form as described in Table 4 was measured at a target amount of 175 mg, loaded into the die and compressed to form the core of Tablet D.

For the production of the cover, the Manesty Type F 3 single station tablet press was equipped with a round, concave and smooth device with a diameter of 11.11 mm as standard. The first part of 300 mg of the sheath mixture was placed in the die as described in Table 4. The tablet core prepared as described above was manually centered in the die (on the top surface of the powder bed) and the remainder of the 300 mg of the sheath mixture was applied to the top of the tablet. in the matrix. The materials were then pressed by hand by turning the compression knob to produce compression coated tablets D.

Several compression-coated Tablets D, prepared as described above, were then placed in a tray which was placed in a Hotpack model 435304 oven set at 72 ° C for 30 minutes to cure.

The pharmaceutical availability of the cured Tablet D was then measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free artificial gastric juice (SGF) at 37 ° C. The results are compared to the results of the formulations of Examples 1-3 in Figure 1.

EXAMPLE 5

A 500 mg tablet (Tablet E) containing 120 mg of hydrocodone was prepared using low molecular weight ethylene oxide (PEO 205 - molecular weight 600,000) for core preparation and using high molecular weight polyethylene oxide (PEO 303 - molecular weight 7,000,000) for the manufacture of a sheath as described in Table 5 below.

Table 5 (Tablet E)

<td></td><td>Hydrocodone (mg)</td><td>total weight</td><td>% hydrocodone</td><td>Instrument size (mm)</td>

<td>Core</td><td> 96</td><td> 300</td><td> 32</td><td> 8,73</td>

<td>Cover</td><td> 24</td><td> 200</td><td> 12</td><td> 11,11</td>

<td>Together</td><td> 120</td><td> 500</td><td> 24</td><td></td>

For the production of the core, the Manesty Type F 3 single station tablet press was equipped with a round, smooth device for making pits with a diameter of 8.73 mm. A powdered aliquot of the core mixture as described in Table 5 was measured at a target amount of 300 mg, loaded into a die and compressed to form the core of Tablet E.

For the production of the cover, the Manesty Type F 3 single station tablet press was equipped with a round, concave and smooth device with a diameter of 11.11 mm as standard. The first part of 200 mg of the sheath mixture was placed in the die as described in Table 5. The tablet core prepared as described above was manually centered in the die (on the top surface of the powder bed) and the remaining 200 mg of the sheath mixture was applied to the top of the tablet. in the matrix. The materials were pressed by hand by turning the press knob to produce compression coated Tablets E.

Several compression-coated Tablets E, prepared as described above, were then placed on a tray which was placed in a Hotpack model 435304 oven set at 72 ° C for 30 minutes to cure.

The pharmaceutical availability of the cured Tablet E was then measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free artificial gastric juice (SGF) at 37 ° C. The results are compared to the results of the formulations of Examples 5 and 6 in Figure 2.

EXAMPLE 6

A 500 mg tablet (Tablet F) containing 120 mg of hydrocodone was prepared using high molecular weight polyethylene oxide (PEO 303 - MW 7,000,000) as described in Table 6 below.

Table 6 (Tablet F)

<td></td><td>Hydrocodone (mg)</td><td>total weight</td><td>% hydrocodone</td><td>Instrument size (mm)</td>

<td>Core</td><td> 96</td><td> 300</td><td> 32</td><td> 8,73</td>

<td>Cover</td><td> 24</td><td> 200</td><td> 12</td><td> 11,11</td>

<td>Together</td><td> 120</td><td> 500</td><td> 24</td><td></td>

For the production of the core, the Manesty Type F 3 single station tablet press was equipped with a round, convex and smooth standard device with a diameter of 8.73 mm. A powdered aliquot of the core mixture as described in Table 6 was measured at a target amount of 300 mg, loaded into a die and compressed to form the core of Tablet F.

For the production of the cover, the Manesty Type F 3 single station tablet press was equipped with a round, concave and smooth device with a diameter of 11.11 mm as standard. The first 200 mg of sheath mixture was placed in the die as described in Table 6. The tablet core prepared as described above was manually centered in the die (on the top surface of the powder bed) and the remainder of 200 mg of the sheath mixture was applied to the top of the tablet. in the matrix. The materials were pressed by hand by turning the compression knob to produce compression coated Tablets F.

Several compression-coated Tablets F, prepared as described above, were then placed in a tray which was placed in a Hotpack model 435304 oven set at 72 ° C for 30 minutes to cure.

The pharmaceutical availability of the cured Tablet E was then measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free artificial gastric juice (SGF) at 37 ° C. The results are compared to the results of the formulations of Examples 5 and 6 in Figure 2.

EXAMPLES 7-12

Six different compression coated tablets (labeled as GL Tablets) were prepared containing a total of 20 mg hydrocodone bitartrate (Tablets G, H and I) or 120 mg hydrocodone bitartrate (Tablets J, K and L) according to the information provided in Table 7 (20 mg) or Table 8 (120 mg) below.

<td colspan="4">Table 7 (Tablets G, Η, I)</td>

<td>20 mg</td><td>Preparation G</td><td>Preparation H</td><td>Preparation I</td>

<td>Ingredient</td><td>mg / tablet</td><td>mg / tablet</td><td>mg / tablet</td>

<td>Core</td><td></td><td></td><td></td>

<td>Hydrocodone bitartrate</td><td> 16</td><td> 16</td><td> 16</td>

<td>Microcrystalline cellulose, Avicel PH 101</td><td> 1,09</td><td> 1,09</td><td> 1,09</td>

<td>Hydroxypropyl cellulose, Klucel EXF</td><td> 1,09</td><td> 1,09</td><td> 1,09</td>

<td>PEO (MW = 600,000)</td><td></td><td></td><td></td>

<td>POLYOX WSR 205</td><td> 280,32</td><td> 280,32</td><td> 280,32</td>

<td>Magnesium stearate</td><td> 1,5</td><td> 1,5</td><td> 1,5</td>

<td>Together</td><td> 300</td><td> 300</td><td> 300</td>

<td>Dry coating</td><td></td><td></td><td></td>

<td>Hydrocodone bitartrate</td><td> 4</td><td> 4</td><td> 4</td>

<td>Microcrystalline cellulose, Avicel PH 101</td><td> 0,27</td><td> 0,27</td><td> 0,27</td>

<td>Hydroxypropyl cellulose, Klucel EXF</td><td> 0,27</td><td> 0,27</td><td> 0,27</td>

<td>PEO (MW = 7,000,000)</td><td></td><td></td><td></td>

<td></td><td> 393,26</td><td> 293,81</td><td> 194,36</td>

<td>POLYOX WSR 303 FP</td><td></td><td></td><td></td>

<td>Magnesium stearate</td><td> 2</td><td> 1,5</td><td> 1</td>

<td colspan="2">D&amp;C Yellow No.10 Aluminum0.2</td><td> 0,15</td><td> 0,1</td>

<td>Lak</td><td></td><td></td><td></td>

<td>Together</td><td> 400</td><td> 300</td><td> 200</td>

<td>Cosmetic coating</td><td> 28</td><td> 24</td><td> 20</td>

<td>Opadry coating mass, white color,</td><td></td><td></td><td></td>

<td>Y-5-18024-A</td><td></td><td></td><td></td>

<td>Together</td><td> 728</td><td> 624</td><td> 520</td>

Table 8 (J, K, L tablets)

<td>120 mg</td><td>Preparation J</td><td>Preparation K</td><td>Preparation L.</td>

<td>Ingredient</td><td>mg / tablet</td><td>mg / tablet</td><td>mg / tablet</td>

<td>Core Hydrocodone bitartrate</td><td> 96</td><td> 96</td><td> 96</td>

<td>Microcrystalline cellulose, Avicel PH 101</td><td> 6,54</td><td> 6,54</td><td> 6,54</td>

<td>Hydroxypropyl cellulose, Klucel EXF</td><td> 6,54</td><td> 6,54</td><td> 6,54</td>

<td>PEO (MW = 600,000)</td><td></td><td></td><td></td>

<td>POLYOX WSR</td><td></td><td></td><td></td>

<td> 205</td><td> 189,42</td><td> 189,42</td><td> 189,42</td>

<td>Magnesium stearate</td><td> 1,5</td><td> 1,5</td><td> 1,5</td>

<td>Together</td><td> 300</td><td> 300</td><td> 300</td>

<td>Dry coating</td><td></td><td></td><td></td>

<td>Hydrocodone bitartrate</td><td> 24</td><td> 24</td><td> 24</td>

<td>Microcrystalline cellulose, Avicel PH 101</td><td> 1,64</td><td> 1,64</td><td> 1,64</td>

<td>Hydroxypropyl cellulose, Klucel EXF</td><td> 1,64</td><td> 1,64</td><td> 1,64</td>

<td>PEO (MW = 7,000,000)</td><td></td><td></td><td></td>

<td>POLYOX WSR 303 FP</td><td> 370,52</td><td> 271,07</td><td> 171,62</td>

<td>Magnesium stearate</td><td> 2</td><td> 1,5</td><td> 1</td>

<td>D&amp;C Red No. 30 dye</td><td></td><td> 0,15</td><td></td>

<td>Aluminum Lake</td><td> 0,2</td><td></td><td> 0,1</td>

<td>Together</td><td> 400</td><td> 300</td><td> 200</td>

<td>Cosmetic coating</td><td></td><td></td><td></td>

<td>Opadry coating mass, pink color,</td><td></td><td></td><td></td>

<td>YS-1-14518A</td><td> 28</td><td> 24</td><td> 20</td>

<td>Together</td><td> 728</td><td> 624</td><td> 520</td>

Hydrocodone bitartrate, microcrystalline cellulose and hydroxypropyl cellulose were loaded into a high shear granulator (Collette 75 L). Water (e.g. 8-15%) was added to the mixture with the propeller and chopper turned on. The wet granules were passed through a coarse screen of a Quadro Comil grinder. The screened wet granules were then dried in a Vector VFC-3 fluid bed dryer. The dry granules were passed through the fine sieve of a Quadro Comil grinder.

PEO POLYOX WSR 205 and milled pellets were charged to a 16 Q "V" homogenizer and then homogenized for 5 minutes. The sieved magnesium stearate was added to the mixture and it was homogenized for 1 minute to prepare the core mixture.

PEO POLYOX WSR 303, D&amp;C Red # 30 Aluminum Lak and milled granules were charged to a 16 Q "V" homogenizer, followed by homogenization for 5 minutes. The sieved magnesium stearate was added to the mixture and it was homogenized for 1 minute to prepare a dry coating mixture.

The core mixture and the dry coat mixture were pressed into dry coated tablets on a DryCota press. The core mixture was loaded into the hopper on one side and then the core weight was adjusted to a target level of 300 mg. The dry-coat mixture was then loaded into the hopper on the other side and the total weight of the tablet was adjusted to the target level. After adjusting the weight, the pressing cycle was started and the press was started e.g. with a speed of 6 rpm.

About 10 kg of compression coated tablets were weighed and spray coated with the Opadry coating suspension, whereby the weight was targeted by a target increase of 1.0% (w / w) in a Compu-Lab's 24 inch perforated coating pan. Spray coating was performed as described below. The tablet bed was heated by setting the inlet air temperature to 55 ° C. When the exhaust air temperature reached 39 ° C, film coating was started at a container speed of 12 rpm and a spraying rate of about 44 ml / min. The film coating was continued until the weight increased by 1% (this was the partial coating step before the curing step x because the final coating that increased the weight by 4% and applied in step xii would become too sticky during curing).

The partially coated tablets were cured in a perforated coating pan. The inlet temperature was set to 85 ° C and the container speed was set to approximately 10 RPM. The tablets were cured at an exhaust air temperature of 72 ° C for approximately 30 minutes.

After curing, the tablets were cooled in the rotary container by setting the air inlet temperature to 22 ° C. Cooling was continued until the air outlet temperature was less than 28 ° C.

The cured tablets were then spray coated with an additional coating suspension for a weight gain of 4.0% (w / w, including previous 1% weight gain) in a perforated coating pan at a container speed of 12 rpm and a spraying rate of 44 ml / min.

The film coated tablets were transferred to a polyethylene tartrate lined drum.

The results of measuring the pharmaceutical availability (% amount of active agent released over time) of these 20 mg and 120 mg compression coated tablets are shown in Figure 3 and in Tables 9 and 10 below.

Table 9

<td>Dissolution time (h)</td><td>20 mg low release rate (G) of% percent active agent</td><td>20 mg average release rate (H) of the amount of% active agent</td><td>20 mg high release rate (AND) % amount of active agent</td>

<td> 1</td><td> 5</td><td> 6</td><td> 8</td>

<td> 2</td><td> 8</td><td> 10</td><td> 14</td>

<td> 4</td><td> 14</td><td> 19</td><td> 28</td>

<td> 8</td><td> 33</td><td> 43</td><td> 55</td>

<td> 12</td><td> 56</td><td> 66</td><td> 81</td>

<td> 18</td><td> 81</td><td> 91</td><td> 106</td>

<td> 24</td><td> 99</td><td> 102</td><td> 107</td>

Table 10

<td>Dissolution time (h)</td><td>120 mg low release rate (J) amount% active agent percentage</td><td>120 mg average release rate (K) of the amount of% active agent</td><td>120 mg high release rate (L)% active agent percentage</td>

<td> 1</td><td> 5</td><td> 6</td><td> 8</td>

<td> 2</td><td> 8</td><td> 10</td><td> 15</td>

<td> 4</td><td> 14</td><td> 20</td><td> 29</td>

<td> 8</td><td> 35</td><td> 47</td><td> 57</td>

<td> 12</td><td> 59</td><td> 72</td><td> 82</td>

<td> 18</td><td> 86</td><td> 100</td><td> 98</td>

<td> 24</td><td> 102</td><td> 103</td><td> 100</td>

As shown by the pharmaceutical availability data in the examples above, the factors that affect the pharmaceutical availability of the active agent from the dosage form are the weight ratio of the core to the sheath weight and the weight of the tablet. In addition , the pharmaceutical availability data set forth above show that the formulations of the present invention exhibit substantially zero order release rates as disclosed herein.

EXAMPLE 13

A randomized, open-label, crossover study was conducted in adult male and female patients using the hydrocodone (HYD) formulations of Examples 7-12. The study was iterated (the process of repeating the design study each time on a different group of subjects undergoing predetermined treatment).

The following iterations were performed:

Iteration 1:

N = 36

Randomized, single dose, 3-period, crossover with 3 treatment cycles.

• HYD 20 mg, low release tablet, fasted (Tablet G) • HYD 20 mg, medium release tablet, fasted (Tablet H) • HYD 20 mg, high release tablet, fasted (Tablet I )

Iteration 2:

N = 36

Randomized, single dose, 3-period, crossover with 3 treatment cycles.

• HYD 120 mg, low release tablet, fasted (Tablet J) • HYD 120 mg, medium release tablet, fasted (Tablet K) • HYD 120 mg, high release tablet, fasted (Tablet L )

Iteration 3:

N = 16

Randomized, single dose, 2-period, crossover with 2 treatment cycles.

• HYD 120 mg, low release tablet, fasted (J Tablet) • HYD 120 mg, low release tablet, fasted (J Tablet)

Each formulation was administered orally with 8 oz. (240 ml) of water in a single dose on an empty stomach or with food, as indicated.

As this study was conducted in healthy humans, they were given the opioid antagonist naltrexone hydrochloride to reduce opioid-related adverse events.

Screening procedures

The following screening procedures were used for all potential subjects at the screening visit 28 days prior to the first dose:

- Informed consent.

- Informed consent to optional pharmacogenomic sampling.

- Informed consent for optional hair sampling.

- Body weight, height, body mass index (BMI), and demographics.

- Assessment of inclusion / exclusion criteria.

- Medical history and history of medications taken, including medications taken concomitantly.

- Vital signs (systolic / diastolic blood pressure, pulse rate, respiratory rate, temperature in the mouth) after spending about 5 minutes sitting and SpO₂

- Extra vital functions (systolic / diastolic arterial pressure, pulse rate) after spending about 2 minutes standing up.

- Well-being was checked by measuring vital functions.

- Routine physical examination.

- Clinical laboratory evaluations at least after 4 hours since the last meal (including biochemistry, hematology, and urinalysis).

- 12-lead ECG test. The QTcF value must not exceed 450 ms.

- Test for hepatitis B virus infection (including hepatitis B surface antigen [HBsAg], antibodies against hepatitis C virus [anti-HCV]).

- Research for abuse of alcohol, cotinine and certain medications.

- Serum pregnancy test (female patients only).

- Serum follicle stimulating hormone (FSH) test (only applies to postmenopausal women).

Inclusion criteria

- Patients who met the criteria listed below participated in the study.

- Patients who have given their informed consent in writing.

- Men and women aged 18 to 50.

- A body weight of 50 to 100 kg (110 to 220 lb) and a BMI of 18 to 34 (kg / m²).

- Healthy patients with no significant abnormalities based on medical history, physical examination, vital signs, and ECG.

- Women of childbearing potential must use an appropriate and reliable method of contraception (ie a barrier with spermicidal foam or gel, an IUD, hormonal contraceptives). Postmenopausal women must be in the postmenopausal period for more than 1 year and have elevated serum FSH levels.

- Patients consenting to eat the food provided during the study.

- Patients who will not be doing strenuous physical activity throughout the study period. Patients will not start a new exercise program or engage in any activity that requires very high physical effort.

Exclusion criteria

Potential patients were excluded from the study based on the following criteria.

- Pregnant women (positive for chorionic beta-gonadotropin) or during lactation.

- Drug or alcohol abuse at the time of the examination or in the recent past (within 5 years).

- Past or existing conditions that may interfere with the absorption, distribution, metabolism or excretion of drugs.

- Use of opioid medication within 30 days prior to the first study dose.

- Known hypersensitivity to hydrocodone, naltrexone or related compounds.

- Frequent nausea or vomiting, regardless of etiology.

- Previous seizures or head injuries with complications.

- Participation in a drug clinical trial within 30 days prior to the first dose in this study.

- History of significant illness within 30 days prior to the first dose in this study.

- Use of any medication, including thyroid hormone therapy (hormonal contraceptives are allowed), vitamins, herbal and / or mineral supplements, in the 7 days prior to the first dose.

- Cardiac abnormalities, including:

• QTc interval> 450 ms (calculated using the Fridericia correction) at screening.

• QTc interval> 480 msec (calculated using the Fridericia correction) over the treatment period.

- Refusal to eat food for 10 hours before and 4 hours after administration of study drug and complete refraining from consuming beverages containing caffeine or xanthine during each stay.

- Refusal to refrain from consuming alcoholic beverages for 48 hours prior to the first dose of study medication (day 1) and at any time during the study.

- Smoking or use of nicotine-containing products within 45 days prior to administration of study drug or a positive urine cotinine test.

- Donate blood or blood products within 60 days prior to study medication administration or at any time during the study period and 30 days after study completion, except as required by the protocol.

- Plasma donation within 14 days prior to study drug administration or at any time during the study period, except as required by this protocol.

- A positive urine screening test for drugs or alcohol.

- Positive results of tests for the presence of HBsAg, antibodies to HCV.

- Positive Naloxone HCl challenge.

- Gilbert's syndrome or any known problems with the liver and bile ducts.

- For the optional hair sample part of the test only - not enough hair on head to collect adequate sample.

- The investigator concluded that the patient was unsuitable for participation in the study for reasons not listed in the exclusion criteria.

Patients meeting all inclusion criteria and none of the exclusion criteria were randomly assigned to study groups.

Each patient was assigned a unique patient number at screening. Patient numbers were assigned in ascending order and no number was omitted. Patient numbers were used throughout the study records.

REGISTRATION PROCEDURES

On day -1 of period 1 only, patients were admitted to the study site and were subjected to the naloxone HCl challenge test. This test had to be negative for the patient to continue participating in the study. Vital signs and SPO2 were measured before and after the naloxone HCl challenge test.

The following procedures were also performed for each patient during registration for each period:

- Verification of the inclusion / exclusion criteria, including verification of readiness to comply with the caffeine and xanthine ban.

- Vital signs (after spending about 5 minutes sitting) and SpO2.

- Well-being was checked by measuring vital functions.

- Clinical laboratory assessments (day -1 only, period 1) including biochemistry (fasting for at least 4 h), hematology, and urinalysis) were performed after the vital functions and SpO? Measurements.

- Test for alcohol (urine or blood alcohol test or breathalyzer test), cotinine and selected abused drugs (urine test). - A urine pregnancy test (for all female patients).

- Monitoring and recording of concomitant medications.

- Monitoring and logging of adverse events.

For patients to continue in the study, screening for drugs (including alcohol and cotinine) had to be available and negative prior to dosing. In addition, during registration and during the study, compliance with the recommendations for concomitant medication and other restrictions in the relevant source documentation was checked.

PROCEDURES DURING TREATMENT

The pre-tested treatments were identified for each iteration. In each iteration, after obtaining data, some methods were discontinued between groups of patients. Discontinued treatments were replaced by repeats of other treatments.

- Prior to the first dose in period 1, patients were randomized to treatment sequence.

- Patients received naltrexone HCl tablets (50 mg) with 240 ml of water at the -12 hour time point. prior to dosing of study medication.

- Prior to study drug administration (except period 1), chemical parameters (fasting for at least 4 hours), hematology, and urinalysis were performed.

- Patients were administered study medication with 240 ml of water as follows:

• Treatment on an empty stomach:

Patients fasting for 10 hours overnight, they received study drug with 240 mL of water. Subjects under fasting treatment did not consume food for 4 hours. after dosing.

• Treatment after eating:

Patients fasting for 10 hours received a standard meal (FDA high fat breakfast) overnight 30 minutes prior to administration of study drug with 240 mL of water. Patients were not allowed to eat any food for at least 4 hours. after dosing. It was made very clear to the patients that the entire meal should be eaten within the prescribed time frame.

• Subjects stood or sat upright while receiving the study drug dose.

• Patients were not required to abstain from eating on the days when they were not taking study medication.

- Patients received 50 mg naltrexone HCl tablets with 240 ml water at time points -12, 0, 12, 24, and 36 h. relative to each dose of study drug.

- SpO was continuously monitored for patients receiving doses of hydrocodone 60 mg or more₂ from before dosing to 24 hours. after dosing.

- Vital signs (in patients who remained sitting for about 5 minutes) and SpO were measured₂ prior to dosing and at time points 1, 2, 4, 6, 8, 12, 24, 36, 48, and 72 hours after dosing in each period.

- Well-being was checked by measuring vital functions.

- Patients underwent biochemistry (fasting for at least 4 hours), hematology and urinalysis for 24 hours. after dosing.

- In addition, 12-lead ECGs were performed on each patient prior to dosing and at approximately 12, 24 and 48 hours. after dosing. If the QTcF value exceeded 480 msec, the patient was excluded from the study due to an adverse event. - Blood samples were collected from each patient to determine the pre-dose plasma hydrocodone concentrations and at the 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8 time points , 10, 12, 14, 18 24, 36, 48, and 72 hours after dosing in each period.

- Patients remained in the facility from the time of registration on the day preceding dose administration until the completion of the 48-hour procedures. Patients returned to the facility for 72-hour procedures.

- Adverse events and concomitant medications were recorded during the study.

In addition, patients were informed that it is very important to inform study personnel immediately in the event of vomiting and that this information is necessary to ensure the proper conduct and result of the study. Patients were informed that they would not be punished in any way if they reported vomiting. Study personnel were instructed to accurately record all instances of vomiting.

PROCEDURES AT THE END OF THE TEST

At the study site, the following procedures were performed for each subject at the end of the study (end of study), 7 to 10 days after the last dose of study medication was administered, or upon termination of the study.

- Assessment of concomitant medications.

- Vital signs (after spending about 5 minutes sitting) and SpO₂.

- Well-being was checked by measuring vital functions.

- Physical examination.

- 12-lead ECG test.

- Clinical laboratory evaluations (including biochemistry [fasting for at least 4 hours], hematology and urinalysis).

- Assessment of adverse events.

- Serum pregnancy test (female patients only).

The operating results are given in Figures 4-6 and in Table 13 below:

Table 13 Summary of working data on plasma hydrocodone pharmacokinetic parameters

<td></td><td></td><td>Iteration 1:</td><td></td><td></td><td>Iteration 2:</td><td></td><td></td><td>Iteration</td><td> 3:</td>

<td></td><td></td><td>HYD 20 mg</td><td></td><td></td><td>HYD 120</td><td>mg</td><td></td><td>HYD 120</td><td>mg</td>

<td></td><td></td><td>Short</td><td>Average</td><td>High</td><td>Short</td><td>Average</td><td>High</td><td>Short</td><td>Short</td>

<td></td><td></td><td>speed</td><td>speed</td><td>speed</td><td>speed</td><td>speed</td><td>speed</td><td>speed</td><td>speed</td>

<td></td><td></td><td>(θ)</td><td>(H)</td><td>(AND)</td><td>(J)</td><td>(K)</td><td>(L)</td><td>(J)</td><td>(J)</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>After</td>

<td>Parameter</td><td>Data</td><td>On an empty stomach</td><td>On an empty stomach</td><td>On an empty stomach</td><td>On an empty stomach</td><td>On an empty stomach</td><td>On an empty stomach</td><td>On an empty stomach</td><td>eating</td>

<td>(Unit)</td><td colspan="2">statistical (N = 36)</td><td>(N = 36)</td><td>(N = 36)</td><td>(N = 36)</td><td>(N = 36)</td><td>(N = 36)</td><td>(N = 14)</td><td>(N = 16)</td>

<td>AUCt</td><td>AVERAGE</td><td> 302</td><td> 323</td><td> 330</td><td> 2028</td><td> 2074</td><td> 2048</td><td> 1921</td><td> 2025</td>

<td>(ng * hr / ml)</td><td>SD</td><td> 138</td><td> 101</td><td> 90</td><td> 439</td><td> 440</td><td> 514</td><td> 369</td><td> 420</td>

<td></td><td>MIN</td><td> 43</td><td> 95</td><td> 78</td><td> 1315</td><td> 1043</td><td> 430</td><td> 1417</td><td> 1135</td>

<td></td><td>MAX.</td><td> 619</td><td> 557</td><td> 499</td><td> 2911</td><td> 2869</td><td> 2917</td><td> 2586</td><td> 2716</td>

<td>AUCinf</td><td>Average</td><td> 312</td><td> 326</td><td> 329</td><td> 2037</td><td> 2083</td><td> 2055</td><td> 1933</td><td> 2032</td>

<td>(ng * hr / ml)</td><td>SD</td><td> 142</td><td> 102</td><td> 90</td><td> 442</td><td> 443</td><td> 516</td><td> 374</td><td> 420</td>

<td></td><td>Min</td><td> 44</td><td> 97</td><td> 83</td><td> 1320</td><td> 1046</td><td> 430</td><td> 1427</td><td> 1136</td>

<td></td><td>Max.</td><td> 623</td><td> 564</td><td> 507</td><td> 2935</td><td> 2908</td><td> 2924</td><td> 2594</td><td> 2717</td>

<td>Cmax.</td><td>Average</td><td> 15,0</td><td> 17,4</td><td> 20,9</td><td> 119</td><td> 138</td><td> 142</td><td> 110</td><td> 166</td>

<td>(ng / ml)</td><td>SD</td><td> 6,4</td><td> 5,8</td><td> 7,2</td><td> 35,8</td><td> 35,3</td><td> 39,3</td><td> 30</td><td> 34,2</td>

<td></td><td>Min</td><td> 4,3</td><td> 7,5</td><td> 7,7</td><td> 55,2</td><td> 76,7</td><td> 35,6</td><td> 67</td><td> 96,2</td>

<td></td><td>Max.</td><td> 30,7</td><td> 31,3</td><td> 39,0</td><td> 227</td><td> 241</td><td> 239</td><td> 162</td><td> 240</td>

<td>Tmax. (h)</td><td>Average</td><td> 15,2</td><td> 13,7</td><td> 11,4</td><td> 15,4</td><td> 12,7</td><td> 10,7</td><td> 15</td><td> 12,0</td>

<td></td><td>SD</td><td> 4,7</td><td> 2,6</td><td> 3,5</td><td> 2,9</td><td> 1,7</td><td> 2,0</td><td> 3</td><td> 1,0</td>

<td></td><td>Min</td><td> 5</td><td> 8</td><td> 6</td><td> 10</td><td> 10</td><td> 6</td><td> 12</td><td> 10</td>

<td></td><td>Median</td><td> 14</td><td> 14</td><td> 12</td><td> 14</td><td> 12</td><td> 10</td><td> 14</td><td> 12</td>

<td></td><td>Max.</td><td> 24</td><td> 18</td><td> 24</td><td> 24</td><td> 18</td><td> 14</td><td> 24</td><td> 14</td>

<td>Tl / 2 (h)</td><td>Average</td><td> 8,3</td><td> 7,6</td><td> 9,0</td><td> 7,1</td><td> 7,6</td><td> 7,1</td><td> 7,7</td><td> 7,8</td>

<td></td><td>SD</td><td> 3,1</td><td> 2,9</td><td> 4,9</td><td> 2,4</td><td> 3,3</td><td> 2,5</td><td> 2,4</td><td> 4,6</td>

<td></td><td>Min</td><td> 4,1</td><td> 4,5</td><td> 4,4</td><td> 4,5</td><td> 4,2</td><td> 4,1</td><td> 4,0</td><td> 3,8</td>

<td></td><td>Max.</td><td> 15,3</td><td> 17,3</td><td> 25,2</td><td> 16,0</td><td> 17,9</td><td> 13,4</td><td> 12,4</td><td> 21,4</td>

<td>Tlag (h)</td><td>Average</td><td> 0,15</td><td> 0,11</td><td> 0,13</td><td> 0,06</td><td> 0,03</td><td> 0,01</td><td> 0,03</td><td> 0,06</td>

<td></td><td>SD</td><td> 0,23</td><td> 0,21</td><td> 0,22</td><td> 0,16</td><td> 0,12</td><td> 0,09</td><td> 0,13</td><td> 0,17</td>

<td></td><td>Min</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>

<td></td><td>Max.</td><td> 0,5</td><td> 0,5</td><td> 0,5</td><td> 0,5</td><td> 0,5</td><td> 0,5</td><td> 0,5</td><td> 0,5</td>

C24 / Cmax.

<td>Average</td><td> 0,57</td><td> 0,45</td><td> 0,30</td><td> 0,52</td><td> 0,32</td><td> 0,23</td><td>n / a</td><td>n / a</td>

<td>SD</td><td> 0,28</td><td> 0,20</td><td> 0,18</td><td> 0,21</td><td> 0,15</td><td> 0,10</td><td>n / a</td><td>n / a</td>

<td>Min</td><td> 0,03</td><td> 0,10</td><td> 0,06</td><td> 0,17</td><td> 0,11</td><td> 0,07</td><td>n / a</td><td>n / a</td>

<td>Max.</td><td> 1,00</td><td> 0,84</td><td> 1,00</td><td> 1,00</td><td> 0,74</td><td> 0,48</td><td>n / a</td><td>n / a</td>

EXAMPLES 14-20

Seven different compression-coated tablets (designated as MS Tablets) were prepared containing a total of 20, 30, 40, 60, 80, 100 or 120 mg of hydrocodone bitartrate respectively as shown in Tables 14 (Tablets Μ, N, O, P) and 15 (Q, R, S tablets) below.

Table 14 (Tablets Μ, N, O, P)

<td></td><td>Preparation M (20 mg)</td><td>Preparation N (30 mg)</td><td>Preparation O (40 mg)</td><td>Preparation P (60 mg)</td>

<td>Ingredient</td><td>mg / tablet</td><td>mg / tablet</td><td>mg / tablet</td><td>mg / tablet</td>

<td>Core</td><td></td><td></td><td></td><td></td>

<td>Hydrocodone bitartrate Cellulose</td><td> 16,000</td><td> 24,000</td><td> 32,000</td><td> 48,000</td>

<td>microcrystalline, Avicel PH 101</td><td> 1,091</td><td> 1,636</td><td> 2,182</td><td> 3,273</td>

<td>Hydroxypropyl cellulose, Klucel EXF</td><td> 1,091</td><td> 1,636</td><td> 2,182</td><td> 3,273</td>

<td>Purified water PEO (molecular weight =</td><td> 279,918</td><td> 270,827</td><td> 261,736</td><td> 243,555</td>

<td>600,000) POLYOX WSR 205 FP Magnesium Stearate Yellow FD&amp;C Yellow No. 6</td><td> 1,500</td><td> 1,500</td><td> 1,500</td><td> 1,500</td>

<td>Aluminum Lake</td><td> 0,400</td><td> 0,400</td><td> 0,400</td><td> 0,400</td>

<td>Together</td><td> 300</td><td> 300</td><td> 300</td><td> 300</td>

<td>Dry coating Hydrocodone bitartrate</td><td> 4,000</td><td> 6,000</td><td> 8,000</td><td> 12,000</td>

<td>Microcrystalline cellulose, Avicel PH 101</td><td> 0,273</td><td> 0,409</td><td> 0,545</td><td> 0,818</td>

<td>Hydroxypropyl cellulose, Klucel EXF</td><td> 0,273</td><td> 0,409</td><td> 0,545</td><td> 0,818</td>

<td>Purified Water PEO (MW = 7,000,000) POLYOX WSR 303 FP</td><td> 393,455</td><td> 391,182</td><td> 388,909</td><td> 384,364</td>

<td>Magnesium stearate</td><td> 2,000</td><td> 2,000</td><td> 2,000</td><td> 2,000</td>

<td>Together</td><td> 400</td><td> 400</td><td> 400</td><td> 400</td>

<td>Cosmetic coating Opadry coating mass,</td><td> 14</td><td> 14</td><td> 14</td><td> 14</td>

colorless, 85F19250 Opadry coating compound, green color

<td>85F110049 21 Opadiy Coating Compound, Yellow Color, 85F120034 Opadiy Coating Compound,</td><td colspan="3"> 21</td>

<td>color gray, 85F175009 Opadiy coating compound, beige color, 85F170015</td><td></td><td> 21</td><td> 21</td>

<td>Opadiy Coating Compound, Pink, 85F140044 Opadiy Coating Compound, Blue, 85F105039 Opadiy Coating Compound, White, 85F18422 A total of 735</td><td> 735</td><td> 735</td><td> 735</td>

Table 15 (Q, R, S tablets)

<td></td><td>Preparation Q (80 mg)</td><td>Preparation R (100 mg)</td><td>Preparation S (120 mg)</td>

<td>Ingredient</td><td>mg / tablet</td><td>mg / tablet</td><td>mg / tablet</td>

<td>Core Hydrocodone bitartrate</td><td> 64,000</td><td> 80,000</td><td> 96,000</td>

<td>Microcrystalline cellulose, Avicel PH 101</td><td> 4,364</td><td> 5,455</td><td> 6,545</td>

<td>Hydroxypropyl cellulose, Klucel EXF</td><td> 4,364</td><td> 5,455</td><td> 6,545</td>

<td>Purified water</td><td></td><td></td><td></td>

<td>PEO (MW = 600,000) POLYOX WSR 205 FP</td><td> 225,373</td><td> 207,191</td><td> 189,009</td>

<td>Magnesium stearate FD&amp;C Yellow No. 6</td><td> 1,500</td><td> 1,500</td><td> 1,500</td>

<td>Aluminum Lake</td><td> 0,400</td><td> 0,400</td><td> 0,400</td>

<td>Together</td><td> 300</td><td> 300</td><td> 300</td>

<td>Dry coating Hydrocodone bitartrate</td><td> 16,000</td><td> 20,000</td><td> 24,000</td>

<td>Microcrystalline cellulose, Avicel PH 101</td><td> 1,091</td><td> 1,364</td><td> 1,636</td>

<td>Hydroxypropyl cellulose, Klucel EXF</td><td> 1,091</td><td> 1,364</td><td> 1,636</td>

<td>Purified water</td><td></td><td></td><td></td>

<td>PEO (MW = 7,000,000) POLYOX WSR 303 FP</td><td> 379,818</td><td> 375,273</td><td> 370,727</td>

<td>Magnesium stearate</td><td> 2,000</td><td> 2,000</td><td> 2,000</td>

<td>Together</td><td> 400</td><td> 400</td><td> 400</td>

Cosmetic coating

<td>Opadry coating mass, colorless,</td><td> 14</td><td> 14</td><td> 14</td>

<td>85F19250 Opadry Coating Compound, Green, 85F110049 Opadry Coating Compound, Yellow, 85F120034 Opadry Coating Compound, Gray, 85F175009 Opadry coating compound, color beige, 85F170015 Opadry Coating Compound, Pink, 85F140044 Opadry coating compound, color blue, 85F105039 Opadry Coating Compound, White, 85F18422</td><td> 21</td><td> 21</td><td> 21</td>

<td>Together</td><td> 735</td><td> 735</td><td> 735</td>

Hydrocodone bitartrate, microcrystalline cellulose and hydroxypropyl cellulose were charged to the high shear mixer.

The dry mixture was mixed for (1) minute at low speed with the grinder off, and then mixed at high speed with the grinder on. The desired amount of water was added to the mixture to form wet granules.

The granules were then passed through a grinder with a screen to remove lumps, and then transferred to a fluid bed dryer to dry.

The dry mixture was then passed through a fine mesh screen until the target particle size (&lt;1.0%) was achieved.

The dried and sieved granules were then passed through a sieve grinder, and the active granules were collected in stainless steel containers. About half of the polyethylene oxide (POLYOX WSR-205) was charged to a V homogenizer; the appropriate amount of active granules (adapted to the needs of the test); Aluminum Laka dye; and the remainder of the polyethylene oxide (POLYOX WSR-205) and the mixture was homogenized for 10 minutes.

Magnesium stearate was then charged to a V homogenizer and the mixture was mixed for 2 minutes before discharging into stainless steel drums.

About half of the polyethylene oxide (POLYOX WSR-303) was charged to a V homogenizer; the appropriate amount of active granules (adapted to the needs of the test); and the remainder of the polyethylene oxide (POLYOX WSR-303) and the mixture was homogenized for 10 minutes.

Magnesium stearate was then charged to a V homogenizer and the mixture was mixed for 2 minutes before discharging into stainless steel drums.

A circular fixture with a shallow recess of 8.75 mm was set up on the left side of the press and a circular fixture with a shallow recess and 12 mm bevelled edges was set up on the right side of the press.

The core mixture (colored) was then loaded into the left hopper (rain feed system) to begin pressing the core.

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

The dry coating mixture (white or off-white) was then loaded into the right hopper (rainfall feed system) to begin tablet compression.

The initial dry coat volume and the subsequent dry coat volume after insertion of the core were adjusted to a target total tablet weight of 700 mg (300 mg core + 400 mg dry coat).

For coating the Opadry colored coating mass dispersion (target level - 20% solids) a mixing vessel was filled with the appropriate amount of purified water and the speed of the agitator was adjusted to create a vortex. The colored Opadry powder was added to the vessel over 2-5 minutes and mixed until a homogeneous dispersion was formed (at least 1 hour).

For coating with a dispersion of a colorless Opadry coating mass (target level - 7.5% solids), an appropriate amount of purified water was charged into a separate mixing vessel and the speed of the agitator was adjusted to create a vortex. Colorless Opadry powder was added to the vessel over 2-5 minutes (target 3 min) and mixed until a homogeneous dispersion was formed (at least 1 hr).

Thereafter, the compression-coated tablets were transferred to a perforated coating pan and film coated with Opadry dyed mass to target a weight gain of 0.7% -1.5%.

The heating temperature was increased and the tablets were cured with a target exhaust temperature of 72 ° C for approximately 30 minutes, followed by cooling.

The coating of the tablets with the colored Opadry dispersion was continued until a target weight gain of 3% took into account the weight gain following application of the previous coating.

The tablets were then film coated with a dispersion of a colorless Opadry coating until a target weight gain of 5% was achieved.

The results of the pharmaceutical availability measurement (% amount of active agent released over time) of these compression-coated tablets of 20 mg, 30 mg, 40 mg, 60 mg, 80 mg, 100 mg and 120 mg are shown in Table 16 below.

Table 16

Measurement results of the pharmaceutical availability of compression-coated tablets of 20, 40, 60, 80, 120 mg (SGF, n = 12)

<td>Dissolution time (h)</td><td>20 mg% of active agent released</td><td>40 mg% of active agent released</td><td>60 mg% of active agent released</td><td>80 mg% of active agent released</td><td>120 mg% of active agent released</td>

<td> 1</td><td> 4</td><td> 4</td><td> 4</td><td> 5</td><td> 4</td>

<td> 2</td><td> 7</td><td> 7</td><td> 7</td><td> 7</td><td> 7</td>

<td> 4</td><td> 13</td><td> 13</td><td> 13</td><td> 13</td><td> 14</td>

<td> 6</td><td> 21</td><td> 21</td><td> 21</td><td> 21</td><td> 22</td>

<td> 8</td><td> 31</td><td> 32</td><td> 32</td><td> 31</td><td> 32</td>

<td> 10</td><td> 42</td><td> 43</td><td> 44</td><td> 43</td><td> 45</td>

<td> 12</td><td> 53</td><td> 55</td><td> 55</td><td> 55</td><td> 57</td>

<td> 14</td><td> 62</td><td> 65</td><td> 66</td><td> 65</td><td> 68</td>

<td> 16</td><td> 71</td><td> 74</td><td> 75</td><td> 74</td><td> 77</td>

<td> 18</td><td> 79</td><td> 82</td><td> 83</td><td> 83</td><td> 86</td>

<td> 20</td><td> 87</td><td> 91</td><td> 92</td><td> 91</td><td> 93</td>

<td> 22</td><td> 95</td><td> 99</td><td> 98</td><td> 98</td><td> 99</td>

<td> 24</td><td> 99</td><td> 102</td><td> 102</td><td> 101</td><td> 101</td>

EXAMPLE 21

A randomized, single dose, 4-period, open-label, crossover, 5-cycle, and incomplete-block, study was conducted in healthy male and female subjects using the hydrocodone (HYD) preparations of Examples 14-20. The study used a maximum of 5 treatment cycles over 4 periods. Strength of HYD tablets or tested doses:

• 1 ^x 20 mg HYD tablet • 1 40 mg HYD tablet • 1 χ 60 mg HYD tablet • 1 χ 80 mg HYD tablet • 1 χ 120 mg HYD tablet

Each dose was administered orally with 8 ounces (240 ml) of water in one dose on an empty stomach as indicated.

As this study was conducted in healthy people, they were administered the opioid antagonist naltrexone hydrochloride to reduce opioid-related adverse events.

PATIENT SELECTION

Screening procedures

The following screening procedures were used for all potential subjects at the screening visit 28 days prior to the first dose:

- Informed consent.

- Informed consent to optional pharmacogenomic sampling.

- Informed consent for optional hair sampling.

- Body weight, height, body mass index (BMI), and demographics.

- Assessment of inclusion / exclusion criteria.

- Medical history and history of medications taken, including medications taken concomitantly.

- Vital signs (systolic / diastolic blood pressure, pulse rate, respiratory rate, temperature in the mouth) after spending about 5 minutes sitting and SpO₂

- Extra vital functions (systolic / diastolic arterial pressure, pulse rate) after spending about 2 minutes standing up.

- Well-being was checked by measuring vital functions.

- Routine physical examination.

- Clinical laboratory evaluations at least after 4 hours since the last meal (including biochemistry, hematology, and urinalysis).

- 12-lead ECG test. The QTcF value must not exceed 450 ms.

- Test for hepatitis B virus infection (including hepatitis B surface antigen [HBsAg], antibodies against hepatitis C virus [anti-HCV]).

- Research for abuse of alcohol, cotinine and certain medications.

- Serum pregnancy test (female patients only).

- Serum follicle stimulating hormone (FSH) test (only applies to postmenopausal women).

Inclusion criteria

Patients who met the criteria listed below participated in the study.

- Patients who have given their informed consent in writing.

- Men and women aged 18 to 50.

- Patients consenting to eat the food provided during the study.

- A body weight of 50 to 100 kg (110 to 220 lb) and a BMI of 18 to 30 (kg / m2).

- Patients who will not be undertaking high physical activity until the last study visit. Patients will not start a new exercise program or engage in any activity that requires very high physical exertion.

- Healthy patients with no significant abnormalities based on medical history, physical examination, clinical laboratory values, vital signs, and ECG.

- Women of childbearing potential must use an appropriate and reliable method of contraception (ie a barrier with spermicidal foam or gel, an IUD, hormonal contraceptives). Postmenopausal women must be> 1 year postmenopausal and have elevated serum FSH levels.

Exclusion criteria

Potential patients were excluded from the study based on the following criteria.

- Pregnant women (positive for chorionic beta-gonadotropin) or during lactation.

- Drug or alcohol abuse at the time of the examination or in the recent past (within 5 years).

- Past or existing conditions that may interfere with the absorption, distribution, metabolism or excretion of drugs.

- Use of opioid medication within 30 days prior to the first dose of study medication in a study.

- Known hypersensitivity to hydrocodone, naltrexone or related compounds.

- Frequent nausea or vomiting, regardless of etiology.

- Previous seizures or head injuries with complications.

- Participation in a clinical study drug within 30 days prior to the first dose of study drug administered in this study.

- History of significant illness within 30 days prior to the first dose of study medication in this study.

- Use of any medication, including thyroid hormone therapy (use of hormonal contraceptives and estrogen replacement therapy with or without progestogen is allowed), vitamins, herbal and / or mineral supplements, within 7 days prior to the first dose of study medication.

- You or a family member have been diagnosed with a QT prolongation or abnormal heart rhythm.

- Cardiac abnormalities, including:

• QTc interval> 450 ms (calculated using the Fridericia correction) at screening.

• QTc interval> 480 msec (calculated using the Fridericia correction) over the treatment period.

- Refusal to eat food for 10 hours before and 4 hours after administration of study medication and complete refraining from consuming caffeinated or xanthine-containing beverages during each stay.

- Refusal to refrain from consuming alcoholic beverages for 48 hours prior to the first dose of study medication (day 1) and at any time until the last study visit.

- Donate blood or blood products within 30 days prior to administration of the first dose of study medication or at any time until the last study visit, except as required by protocol.

- Smoking or use of nicotine containing products within 45 days prior to the first dose of study drug or a positive urine cotinine test.

- A positive urine screening test for drugs or alcohol.

- Positive results of tests for the presence of HBsAg, antibodies to HCV.

- Naloxone HCl challenge was positive.

- Gilbert's syndrome or any known problems with the liver and bile ducts.

- The investigator concluded that the patient was unsuitable for participation in the study for reasons not listed in the exclusion criteria.

Patients meeting all inclusion criteria and none of the exclusion criteria were randomly assigned to study groups.

Each patient was assigned a unique patient number at screening. Patient numbers were assigned in ascending order and no number was omitted. Patient numbers were used throughout the study records.

REGISTRATION PROCEDURES

On day -1 of period 1 only, patients were admitted to the study site and were subjected to the naloxone HCl challenge test. This test had to be negative for the patient to continue participating in the study. Vital signs and SPO2 were measured before and after the naloxone HCl challenge test.

The following procedures were also performed for each patient during registration for each period:

- Verification of the inclusion / exclusion criteria, including verification of readiness to comply with the caffeine and xanthine ban.

- Vital signs (after spending about 5 minutes sitting) and SpO2.

- Well-being was checked by measuring vital functions.

- Clinical laboratory evaluations (day -1 only, period 1) including biochemistry (fasting for at least 4 h), hematology, and urinalysis) were performed after vital functions and SpO2 measurements.

- Test for alcohol (urine or blood alcohol test or breathalyzer test), cotinine and selected abused drugs (urine test).

- A urine pregnancy test (for all female patients).

- Monitoring and recording of concomitant medications.

- Monitoring and logging of adverse events.

For patients to continue in the study, screening for drugs (including alcohol and cotinine) had to be available and negative prior to dosing. In addition, during registration and during the study, compliance with the recommendations for concomitant medication and other restrictions in the relevant source documentation was checked.

PROCEDURES DURING TREATMENT

The pre-tested treatments were identified for each iteration. In each iteration, after obtaining data, some methods were discontinued between groups of patients. Discontinued treatments were replaced by repeats of other treatments.

- Prior to the first dose in period 1, patients were randomized to treatment sequence.

- Patients received naltrexone HCl tablets (50 mg) with 240 ml of water at the -12 hour time point. prior to dosing of study medication.

- Patients fasting for 10 hours overnight, study drug was administered with 240 mL of water as follows. The patients did not eat food for 4 hours. after dosing.

• Subjects stood or sat upright while receiving the study drug dose.

• Patients did not need to refrain from eating during the days when they were not taking study medication.

- Patients received 50 mg naltrexone HCl tablets with 240 ml water at time points -12, 0, 12, 24, and 36 h. relative to each dose of study drug.

- SpO was continuously monitored for patients receiving doses of hydrocodone 60 mg or more₂ from before dosing to 24 hours. after dosing. - Vital signs (in patients who remained sitting for about 5 minutes) and SpO were measured₂ prior to dosing and at time points 1, 2.5, 4, 6, 8, 12, 24, 36, 48, and 72 hours after dosing in each period.

- Well-being was checked by measuring vital functions.

- 12 lead ECGs were performed on each patient before dosing and at approximately 12, 24 and 48 hours. after dosing.

- Blood samples were taken from each patient to determine the pre-dose plasma hydrocodone concentrations and at the time points 0.5, 1, 2.5, 4, 6, 8, 10, 12, 14, 16, 18, 24, 36 , 48 and 72 hours after dosing in each period.

- Patients remained in the facility from registration on the day preceding dose administration until procedures were completed within 72 hours.

- Adverse events and concomitant medications were recorded during the study.

In addition, patients were informed that it is very important to immediately inform the study staff in the event of vomiting and that this information is necessary to ensure the proper conduct and result of the study. Patients were informed that they would not be punished in any way if they reported vomiting. Study personnel were instructed to accurately record all instances of vomiting.

PROCEDURES AT THE END OF THE TEST

At the study site, the following procedures were performed for each subject at the end of the study (end of study), 7 to 10 days after the last dose of study medication was administered, or upon termination of the study.

- Assessment of concomitant medications.

- vital signs (after spending about 5 minutes sitting) and SpO ?.

- Well-being was checked by measuring vital functions.

- Physical examination.

- 12-lead ECG test.

- Clinical laboratory assessments (including biochemistry [fasting for at least 4 hours], hematology, and urinalysis).

- Assessment of adverse events.

- Serum pregnancy test (female patients only).

The operating results are given in Figure 7 and in Table 17 below:

Table 17 Summary of working data on plasma hydrocodone pharmacokinetic parameters

HYD 20 HYD 40 HYD 60 HYD 80 HYD 120

Parameter Data mg mg mg mg mg (Unit) Statistical (N = 29) (N = 30) (N = 28) (N = 30) (N = 29)

<td>AUCt</td><td>AVERAGE</td><td> 281</td><td> 618</td><td> 1004</td><td> 1298</td><td> 1759</td>

<td>(ng * hr / ml)</td><td>SD</td><td> 127</td><td> 255</td><td> 292</td><td> 373</td><td> 671</td>

<td></td><td>MIN</td><td> 30</td><td> 85</td><td> 580</td><td> 559</td><td> 303</td>

<td></td><td>MAX.</td><td> 591</td><td> 1200</td><td> 1724</td><td> 2501</td><td> 3324</td>

<td>AUCinf</td><td>Average</td><td> 284</td><td> 622</td><td> 1009</td><td> 1304</td><td> 1768</td>

<td>(ng * hr / ml)</td><td>SD</td><td> 128</td><td> 256</td><td> 294</td><td> 375</td><td> 674</td>

<td></td><td>Min</td><td> 31</td><td> 86</td><td> 583</td><td> 564</td><td> 305</td>

<td></td><td>Max.</td><td> 595</td><td> 1213</td><td> 1742</td><td> 2514</td><td> 3347</td>

<td>Cmax.</td><td>Average</td><td> 15</td><td> 34</td><td> 54</td><td> 69</td><td> 110</td>

<td>(ng / ml)</td><td>SD</td><td> 5,5</td><td> 12</td><td> 15</td><td> 17</td><td> 44</td>

<td></td><td>Min</td><td> 3,5</td><td> 7,6</td><td> 33</td><td> 40</td><td> 28</td>

<td></td><td>Max.</td><td> 26</td><td> 54</td><td> 83</td><td> 109</td><td> 199</td>

<td>Tmax. (h)</td><td>Average</td><td> 15</td><td> 16</td><td> 16</td><td> 15</td><td> 15</td>

<td></td><td>SD</td><td> 4,5</td><td> 4,5</td><td> 4,7</td><td> 2,6</td><td> 4,4</td>

<td></td><td>Min</td><td> 6</td><td> 6</td><td> 10</td><td> 10</td><td> 6</td>

<td></td><td>Median</td><td> 16</td><td> 16</td><td> 14</td><td> 16</td><td> 14</td>

<td></td><td>Max.</td><td> 24</td><td> 24</td><td> 30</td><td> 24</td><td> 30</td>

The disclosed embodiments are only intended to illustrate certain aspects of the present invention and are not intended to limit the scope thereof, and any embodiments that are functionally equivalent are within the scope of the present invention. One skilled in the art will appreciate that in addition to the modifications to the present invention shown and described herein, other modifications may also be made and fall within the scope of the appended claims.

This document also discloses, without limiting the scope of the claims, the following:

1. A controlled release solid dosage form containing:

a core comprising a first portion of the opioid analgesic dispersed throughout the first matrix material; and a sheath surrounding the core and having a second portion of the opioid analgesic dispersed throughout the second matrix material;

wherein the amount of opioid analgesic released from the dosage form is proportional to the 20% duration of action from 8 to 24 hours as determined from pharmaceutical availability measured in vitro on a USP Apparatus 1 (basket) machine at 100 rpm min. in 900 ml of artificial gastric juice without enzymes (SGF) at 37 ° C.

2. The controlled release solid dosage form according to item 1, wherein the core is a compressed tablet.

3. The controlled release solid dosage form according to item 1 or 2, wherein the casing is a compression coating.

4. The controlled release solid dosage form according to any one of items 1 to 3, wherein the first matrix material comprises polyethylene oxide.

5. The controlled release solid dosage form according to any one of items 1 to 4, wherein the second matrix material comprises polyethylene oxide.

6. The controlled release solid dosage form according to any one of items 1 to 3, wherein both the first matrix material and the second matrix material comprise polyethylene oxide.

7. The controlled release solid dosage form according to item 6, wherein the polyethylene oxide in the second matrix material has a higher viscosity than the polyethylene oxide in the first matrix material.

8. The controlled release solid dosage form in accordance with item 4, wherein the first matrix material comprises polyethylene oxide with an average molecular weight from about 300,000 to about 10,000,000.

9. The controlled release solid dosage form in accordance with item 8, wherein the first matrix material comprises polyethylene oxide having an average molecular weight of from about 500,000 to about 1,000,000.

10. The controlled release solid dosage form in accordance with item 5, wherein the second matrix material comprises polyethylene oxide having an average molecular weight of from about 1,000,000 to about 10,000,000.

11. The controlled release solid dosage form in accordance with item 10, wherein the second matrix material comprises polyethylene oxide having an average molecular weight of from about 6,000,000 to about 8,000,000.

12. The controlled release solid dosage form in accordance with item 6, wherein the polyethylene oxide in the second matrix material has an average molecular weight from about 4,000,000 to about 10,000,000 and the polyethylene oxide in the first matrix material has an average molecular weight from about 300,000 to about 3,000,000.

13. The controlled release solid dosage form in accordance with item 6, wherein the polyethylene oxide in the second matrix material has an average molecular weight from about

000 000 to about 8,000,000 and the polyethylene oxide in the first matrix material has an average molecular weight of from about 500,000 to about 1,000,000.

14. The controlled release solid dosage form according to any one of items 1 to 13, wherein the ratio of the weight of the core to the weight of the sheath is from about 1: 0.5 to about 1: 5.

15. The controlled release solid dosage form according to item 14, wherein the ratio of the weight of the core to the weight of the sheath is from about 1: 0.6 to about 1: 1.5.

16. The controlled release solid dosage form according to item 15, wherein the ratio of the weight of the core to the weight of the sheath is from about 1: 0.8 to about 1: 1.2.

17. The controlled release solid dosage form of item 4, wherein the weight ratio of the first opioid analgesic portion to the polyethylene oxide in the first matrix material is from about 1: 0.5 to about 1: 100.

18. The controlled release solid dosage form in accordance with item 17, wherein the weight ratio of the first opioid analgesic portion to the polyethylene oxide in the first matrix material is from about 1: 1 to about 1:10.

19. The controlled release solid dosage form according to item 18, wherein the weight ratio of the first opioid analgesic portion to the polyethylene oxide in the first matrix material is from about 1: 1.5 to about 1: 4.

20. The controlled release solid dosage form according to item 5, wherein the weight ratio of the second portion of the opioid analgesic to the polyethylene oxide in the second matrix material is from about 1: 2 to about 1: 200.

21. The controlled release solid dosage form in accordance with item 20, wherein the weight ratio of the second portion of the opioid analgesic to the polyethylene oxide in the second matrix material is from about 1: 5 to about 1:50.

22. The controlled release solid dosage form according to item 21, wherein the weight ratio of the second portion of the opioid analgesic to the polyethylene oxide in the second matrix material is from about 1:12 to about 1:25.

23. A controlled release solid dosage form according to any one of items 1 to 22, wherein the opioid analgesic in the first part is the same as the opioid analgesic in the second part.

24. A controlled release solid dosage form according to any one of items 1 to 22, wherein the opioid analgesic in the first part is different from the opioid analgesic in the second part.

25. The controlled release solid dosage form according to any one of items through 24, wherein the ratio of the opioid analgesic in the core to the opioid analgesic in the sheath is from about 1: 1 to about 10: 1.

26. The controlled release solid dosage form according to item 25, wherein the ratio of the opioid analgesic in the core to the opioid analgesic in the sheath is from about 2: 1 to about 8: 1.

27. The controlled release solid dosage form in accordance with item 25, wherein the ratio of the opioid analgesic in the core to the opioid analgesic in the sheath is from about 2: 1 to about 5: 1.

28. A solid dosage form according to any one of items 1 to 27, wherein the opioid analgesic is selected from the group consisting of alfentanil, allylprodin, alphaprodin, anileridine, benzylmorphine, besithramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextramidate, desocin, diampromide, diamorphone, dihydrocodeine, dihydromorphin, dimenoxadol, dimefeptanol, dimethylthiambutene, dioxafethylbutyrate, dipipanone, eptazocin, etoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphin, dihydroetorphine, fentanyl and derivatives, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levofenacylmorphan, lofentanil, meperidine, meptainol, metazocin, metadorphine, normadorphine, meptainol, metazocin, metadorphine, metadorphine, metophthone nalbufen, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, fenadoxone, phenomorphan, fenazocin, phenoperidine, piminodine, pyritramide, propeptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, their pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

29. The controlled release solid dosage form according to item 28, wherein the opioid analgesic is selected from the group consisting of codeine, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, tramadol, pharmaceutically acceptable salts, hydrates, solvates and mixtures thereof.

thirty. A controlled release solid dosage form according to item 29, wherein the opioid analgesic is selected from the group consisting of hydrocodone, pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

31. The controlled release solid dosage form according to item 30, wherein the opioid analgesic is hydrocodone bitartrate.

32. The controlled release solid dosage form according to item 31, wherein the total amount of hydrocodone bitartrate in the dosage form is from about 0.5 mg to about 1250 mg.

33. The controlled release solid dosage form according to item 31, wherein the total amount of hydrocodone bitartrate in the dosage form is from about 2 mg to about 200 mg.

34. The controlled release solid dosage form according to item 31, wherein the total amount of hydrocodone bitartrate in the dosage form is from about 16 mg to about 120 mg.

35. A controlled release solid dosage form according to any one of items 1 to 34, wherein the released amount of opioid analgesic is proportional within 10% to the duration of action from 8 to 24 hours.

36. A controlled release solid dosage form according to item 35, wherein the released amount of opioid analgesic is proportional to 5% for the duration of action of 8 to 24 hours.

37. A controlled release solid dosage form according to any one of items 1 to 34, wherein the released amount of opioid analgesic is proportional to within 20% of the duration of action from 8 to 18 hours.

38. A controlled release solid dosage form according to any one of items 1 to 34, wherein the amount of the opioid analgesic released is proportional within 20% to the duration of action from 8 to 12 hours.

39. A controlled release solid dosage form according to any one of items 1 to 34, wherein the released amount of opioid analgesic is proportional within 20% to the duration of action from 12 to 24 hours.

40. A controlled release solid dosage form according to any one of items 1 to 34, wherein the released amount of opioid analgesic is proportional to within 20% of the duration of action from 12 to 18 hours.

41. A controlled release solid dosage form according to item 37, wherein the released amount of opioid analgesic is proportional to within 10% of the duration of action from 8 to 18 hours.

42. A controlled release solid dosage form according to item 38, wherein the released amount of opioid analgesic is proportional to within 10% of the duration of action from 8 to 12 hours.

43. A controlled release solid dosage form according to item 39, wherein the released amount of opioid analgesic is proportional to within 10% of the duration of action from 12 to 24 hours.

44. A controlled release solid dosage form according to item 40, wherein the released amount of opioid analgesic is proportional to 10% for the duration of action from 12 to 18 hours.

45. A controlled release solid dosage form according to item 37, wherein the released amount of opioid analgesic is proportional to the 5% duration of action from 8 to 18 hours.

46. A controlled release solid dosage form according to item 38, wherein the released amount of opioid analgesic is proportional within 5% to the duration of action from 8 to 12 hours.

47. A controlled release solid dosage form according to item 39, wherein the released amount of opioid analgesic is proportional to 5% for the duration of action from 12 to 24 hours.

48. A controlled release solid dosage form according to item 40, wherein the released amount of opioid analgesic is proportional to 5% for the duration of action from 12 to 18 hours.

49. A controlled release solid dosage form according to any one of items 1 to 48, wherein the amount of opioid analgesic released after 2 hours. is less than about 25%.

50. A controlled release solid dosage form according to any one of items 1 to 49, wherein the amount of opioid analgesic released after 4 hours. it ranges from about 10% to about 30%.

51. A controlled release solid dosage form according to any one of items 1 to 50, wherein the amount of opioid analgesic released after 8 hours. it is from about 20% to about 60%.

52. A controlled release solid dosage form according to any one of items 1 to 51, wherein the amount of opioid analgesic released after 12 hours. it is from about 40% to about 90%.

53. A controlled release solid dosage form according to any one of items 1 to 52, wherein the amount of opioid analgesic released after 18 hours. is greater than about 70%.

54. A controlled release solid dosage form according to any one of items 1 to 53, wherein the amount of opioid analgesic is released after 2 hours. is less than about 20%.

55. A controlled release solid dosage form according to any one of items 1 to 54, wherein the amount of opioid analgesic released after 4 hours. it is from about 10% to about 20%.

56. A controlled release solid dosage form according to any one of items 1 to 55, wherein the amount of opioid analgesic released after 8 hours. it is from about 20% to about 40%.

57. A controlled release solid dosage form according to any one of items 1 to 56, wherein the amount of opioid analgesic released after 12 hours. it is from about 40% to about 65%.

58. A controlled release solid dosage form according to any one of items 1 to 57, wherein the amount of opioid analgesic released after 18 hours. is greater than about 80%.

59. A controlled release solid dosage form according to any one of items 1 to 58, wherein the amount of opioid analgesic released after 2 hours. is less than about 15%.

60. A controlled release solid dosage form according to any one of items 1 to 59, wherein the amount of opioid analgesic released after 4 hours. it is from about 20% to about 30%.

61. A controlled release solid dosage form according to any one of items 1 to 60, wherein the amount of opioid analgesic released after 8 hours. it is from about 45% to about 60%.

62. A controlled release solid dosage form according to any one of items 1 to 61, wherein the amount of opioid analgesic released after 12 hours. it is from about 70% to about 90%.

63. A controlled release solid dosage form according to any one of items 1 to 62, wherein the amount of the opioid analgesic released after 18 hours. is greater than about 90%.

64. The controlled release solid dosage form according to item 6, wherein the dosage form is cured at a temperature of at least the softening point of the polyethylene oxide for at least 1 minute.

65. The controlled release solid dosage form according to item 6, wherein the dosage form is cured at a temperature of at least the softening point of the polyethylene oxide for at least 5 minutes.

66. The controlled release solid dosage form according to item 6, wherein the dosage form is cured at a temperature of at least the softening point of the polyethylene oxide for at least 15 minutes.

67. The controlled release solid dosage form in accordance with item 6, wherein the dosage form is cured at a temperature at least at the softening point of the polyethylene oxide for from about 1 minute to about 48 hours.

68. The controlled release solid dosage form in accordance with item 6, wherein the dosage form is cured to a temperature at least at the softening point of the polyethylene oxide for from about 5 minutes to about 24 hours.

69. The controlled release solid dosage form according to item 6, wherein the dosage form is cured at a temperature at least at the softening point of the polyethylene oxide for from about 15 minutes to about 1 hour.

70. The controlled release solid dosage form according to any of items 64-69, wherein the dosage form is cured at a temperature of at least about 60 ° C.

71. A controlled release solid dosage form according to any one of the items

64-69, wherein the dosage mold is cured at a temperature of at least about 65 ° C.

72. The controlled release solid dosage form according to any of items 64-69, wherein the dosage form is cured at a temperature of at least about 70 ° C.

73. The controlled release solid dosage form according to any of items 64-69, wherein the dosage form is cured at a temperature of at least about 75 ° C.

74. The controlled release solid dosage form according to any of items 64-69, wherein the dosage form is cured at about 72 ° C.

75. The controlled release solid dosage form according to any of items 64-69, wherein the dosage form is cured at a temperature of from about 60 ° C to about 90 ° C.

76. The controlled release solid dosage form according to any of items 64-69, wherein the dosage form is cured at a temperature of about 65 ° C to about 85 ° C.

77. The controlled release solid dosage form according to any of items 64-69, wherein the dosage form is cured at a temperature of about 70 ° C to about 80 ° C.

78. The controlled release solid dosage form according to any of items 64-69, wherein the dosage form is cured at a temperature from about 75 ° C to about 80 ° C.

79. The controlled release solid dosage form according to any of items 64-69, wherein the dosage form is cured at a temperature of about 70 ° C to about 75 ° C.

80. The controlled release solid dosage form according to any one of items 1 to 79, wherein the core and the sheath are visually indistinguishable.

81. The controlled release solid dosage form according to any one of items 1 to 79, wherein the CIE L * A * B * values ​​of the core and sheath are within 10% of each other.

82. The solid dosage form according to any one of items 1 to 81, wherein the dosage form may be flattened and non-disintegrating, wherein the thickness of the dosage form after flattening corresponds to no more than about 60% of the thickness of the dosage form prior to flattening.

83. A solid dosage form as set forth in item 82, wherein the dosage form may be flattened and not disintegrate, wherein the thickness of the flattened dosage form corresponds to no more than about 50% of the thickness of the dosage form prior to flattening.

84. A solid dosage form as set forth in item 82, wherein the dosage form may be flattened and not disintegrate, wherein the thickness of the flattened dosage form corresponds to no more than about 40% of the thickness of the dosage form prior to flattening.

85. A solid dosage form as set forth in item 82, wherein the dosage form may be flattened and not disintegrate, wherein the thickness of the flattened dosage form corresponds to no more than about 30% of the thickness of the dosage form prior to flattening.

86. A solid dosage form as set forth in item 82, wherein the dosage form may be flattened and not disintegrate, wherein the thickness of the flattened dosage form corresponds to no more than about 20% of the thickness of the dosage form prior to flattening.

87. A controlled release solid dosage form according to any of items 82-86, wherein the amount of opioid analgesic released after 0.5 h. from the flattened dosage form deviates by no more than about 20% points from the non-flattened dosage form, which was determined on the basis of pharmaceutical availability measured in vitro in the USP Apparatus 1 device (basket) at a speed of 100 rpm in 900 ml of artificial gastric juice no enzymes (SGF) at 37 ° C.

88. A controlled release solid dosage form according to any of items 82-86, wherein the amount of opioid analgesic released after 0.5 h. from the flattened dosage form deviates by no more than about 15% points from the non-flattened dosage form, which was determined on the basis of pharmaceutical availability measured in vitro in the USP Apparatus 1 device (basket) at 100 rpm in 900 ml of artificial gastric juice no enzymes (SGF) at 37 ° C.

89. A controlled release solid dosage form according to any one of the items

82-86, with the amount of opioid analgesic released after 0.5 h. from the flattened dosage form deviates by no more than about 10% from the non-flattened dosage form, which was determined on the basis of pharmaceutical availability measured in vitro in the USP Apparatus 1 device (basket) at a speed of 100 rpm in 900 ml of artificial gastric juice no enzymes (SGF) at 37 ° C. 90. A controlled release solid dosage form according to item 30 that provides a C24 / C ratio_hasHydrocodone x of from about 0.55 to about 1.0 after administration.

91. A solid dosage form according to item 90, wherein the value ratio is C24 / C_hasks is from about 0.55 to about 0.85.

92. A solid dosage form according to item 90, wherein the value ratio is C24 / C_hasks is from about 0.55 to about 0.75.

93. A solid dosage form according to item 90, wherein the value ratio is C24 / C_hasks is from about 0.60 to about 0.70.

94. The controlled release solid dosage form according to item 30 which provides the value of T_hasks (h) of hydrocodone from about 4 to about 20 hours. after administration.

95. A solid dosage form according to item 94, wherein the value of T_hasks (h) is from about 6 to about 12 hours.

96. A solid dosage form according to item 94, wherein the value of T_hasks (h) is from about 8 to about 10 hours.

97. A solid dosage form according to item 94, wherein the value of T_hasks (h) is from about 4 to about 10 hours.

98. A solid dosage form according to item 94, wherein the value of T_hasks (h) is from about 8 to about 14 hours.

99. A solid dosage form according to item 94, wherein the value of T _hasks (h) is from about 14 to about 20 hours. after giving the dosage form.

100. A controlled release solid dosage form according to any one of items 90-99, wherein the administration is the administration of the first dose to a healthy individual.

101. The controlled release solid dosage form according to any of items 90-99, wherein the administration is the administration of the first dose of a population of healthy subjects. 102. A solid controlled release dosage form according to any one of items 90-99, wherein the administration is steady state administration of a dose to a healthy individual. 103. A controlled release solid dosage form according to any one of items 90-99, wherein the administration is a steady state dose administration of a population of healthy individuals.

104. The controlled release solid dosage form according to item 30, which comprises about 20 mg of hydrocodone or a pharmaceutically acceptable salt thereof.

105. The controlled release solid dosage form according to item 30, which comprises about 120 mg of hydrocodone or a pharmaceutically acceptable salt thereof.

106. The controlled release solid dosage form of item 30 which provides an average AUC (ng * hr / ml) after administration in the range of about 250 to 400 for each 20 mg of hydrocodone contained in the dosage form.

107. The controlled release solid dosage form according to item 104 which provides an average AUC (ng * hr / ml) after administration of from about 250 to about 400, from about 275 to about 350, from about 300 to 330, or from about 280 to about 320.

108. The controlled release solid dosage form of item 105 which provides a mean AUC (ng * hr / ml) after administration from about 1,500 to about 2,400, from about 1,700 to about 2,200, from about 1,800 to about 2,100, or from about 1,900 to about 2,400. around 2100.

109. The controlled release solid dosage form according to item 30 which provides an average value of C_hasks (ng / ml) when administered from about 10 to about 30 for every 20 mg of hydrocodone contained in the dosage form.

110. The controlled release solid dosage form according to item 104, which provides an average value of C_hasks (ng / ml) after administration from about 10 to about 30, from about 12 to about 25, from about 14 to about 18, or from about 12 to about 17.

111. The controlled release solid dosage form according to item 105, which provides an average value of C_hasks (ng / ml) after administration from about 60 to about 180, from about 100 to about 160, from about 110 to about 150, or from about 100 to about 140.

112. The controlled release solid dosage form according to item 30 which provides an average T value_hasks (h) after administration from about 10 to about 20, from about 12 to about 18, from about 13 to about 17, or from about 14 to about 16.

113. The controlled release solid dosage form according to item 30 which provides an average T 1/2 (hour) after administration of from about 5 to about 10, from about 6 to about 9, about 7, or about 8.

114. The controlled release solid dosage form according to item 30 that provides an average Ti value_ag(h) after administration from about 0.01 to about 0.2, from about 0.1 to about 0.18, from about 0.3 to about 0.17, or from about 0.061 to about 0.15.

115. Controlled release solid dosage form, average C24 / C ratio_hasks is from about 0.2 to about 0.8, from about 0.3 to about 0.7, or from about

0.4 to about 0.6.

116. The controlled release solid dosage form according to any of items 106-115, wherein the dose is administered in the fasting state.

117. The controlled release solid dosage form according to item 30, wherein the mean AUC (ng * hr / ml) after fed is less than 20% greater, less than 16% greater, or less than 12% greater than the AUC ( ng * h / ml) after administration in the fasted state.

118. The controlled release solid dosage form according to item 30, the average value of C_hasks (ng / ml) after administration in the fasted state is less than 80% higher, less than 70% higher or less than 60% higher than the Cmax value.

119. The controlled release solid dosage form according to item 30, the average value of T_hasks (h) after vehicle administration is within 25%, within 20% or within 15% of the T value_hasks (h) after administration on an empty stomach.

120. A controlled release solid dosage form according to item 30, wherein the mean T1 / 2 (hr) after food administration is within 8%, within 5% or within 2% of the T1 / 2 value after fasting.

121. The controlled release solid dosage form according to item 30, average Ti_ag(h) after administration in the fed state is less than 150% higher, less than 125% higher, or less than 100% higher than the T1 / 2 value in the fasted state.

122. A controlled release solid dosage form containing:

a core comprising a first portion of the opioid analgesic dispersed in a first matrix material comprising polyethylene oxide; and a sheath surrounding the core and having a second opioid analgesic portion dispersed in the second polyethylene oxide matrix material.

123. A controlled release solid dosage form containing:

a compressed core comprising a first opioid analgesic portion dispersed in a first matrix material comprising polyethylene oxide; and a compression sheath surrounding the core and having a second opioid analgesic portion dispersed in the second matrix material comprising polyethylene oxide. 124. A solid dosage form with controlled release containing:

a core comprising a first portion of the opioid analgesic dispersed throughout the first matrix material; and a sheath surrounding the core and having a second portion of the opioid analgesic dispersed throughout the second matrix material;

wherein the amount of opioid analgesic released from the dosage form after 2 hours. is less than about 25%;

amount of opioid analgesic released from the dosage form after 4 hours. ranges from about 10% to about 30%;

amount of opioid analgesic released from the dosage form after 8 hours. it ranges from about 20% to about 60%;

amount of opioid analgesic released from the dosage form after 12 hours. ranges from about 40% to about 90%; and the amount of opioid analgesic released from the dosage form after 18 hours. is greater than about 70%;

as determined on the basis of pharmaceutical availability measured in vitro on USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free artificial gastric juice (SGF) at 37 ° C.

125. A controlled release solid dosage form containing:

a therapeutically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof and a controlled release excipient;

wherein the amount of hydrocodone or salt thereof released from the dosage form is proportional to the 20% duration of action from 8 to 24 hours as determined by pharmaceutical availability measured in vitro on a USP Apparatus 1 (basket) machine at a speed of 100 rpm. / min in 900 ml of artificial gastric juice without enzymes (SGF) at 37 ° C; and the dosage form may be flattened and non-disintegrating, wherein the thickness of the flattened dosage form corresponds to no more than about 20% of the thickness of the dosage form prior to flattening; and the amount of hydrocodone or its salt released after 0.5 h. from the flattened dosage form deviates by no more than about 20% points from the non-flattened dosage form, which was determined on the basis of pharmaceutical availability measured in vitro in the USP Apparatus 1 device (basket) at a speed of 100 rpm in 900 ml of artificial gastric juice no enzymes (SGF) at 37 ° C.

126. A controlled release solid dosage form containing:

a therapeutically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof and a controlled release excipient;

wherein the amount of hydrocodone or its salt released from the dosage form after 2 hours. is less than about 25%;

the amount of hydrocodone or its salt released from the dosage form after 4 hours. ranges from about 10% to about 30%;

the amount of hydrocodone or its salt released from the dosage form after 8 hours. it ranges from about 20% to about 60%;

the amount of hydrocodone or its salt released from the dosage form after 12 hours. ranges from about 40% to about 90%; and the amount of hydrocodone or its salt released from the dosage form after 18 hours. is greater than about 70%;

based on pharmaceutical availability measured in vitro on USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free artificial gastric juice (SGF) at 37 ° C; and the dosage form may be flattened and non-disintegrating, wherein the thickness of the flattened dosage form corresponds to no more than about 20% of the thickness of the dosage form prior to flattening; and the amount of hydrocodone or its salt released after 0.5 h. from the flattened dosage form deviates by no more than about 20% points from the non-flattened dosage form, which was determined on the basis of pharmaceutical availability measured in vitro in the USP Apparatus 1 device (basket) at a speed of 100 rpm in 900 ml of artificial gastric juice no enzymes (SGF) at 37 ° C.

127. A controlled release solid dosage form containing:

a therapeutically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof dispersed in the controlled release excipient; wherein 60% inner portion of the dosage form comprises at least 80% hydrocodone or a salt thereof;

wherein the amount of hydrocodone or salt thereof released from the dosage form is proportional to the 20% duration of action from 8 to 24 hours as determined by pharmaceutical availability measured in vitro on a USP Apparatus 1 (basket) machine at a speed of 100 rpm. / min in 900 ml of artificial gastric juice without enzymes (SGF) at 37 ° C.

128. A solid controlled release dosage form according to item 127, wherein the inner 50% of the dosage form comprises at least 80% hydrocodone or a salt thereof.

129. A method of treating pain in a subject in need of such treatment, which comprises administering to the subject a solid controlled release dosage form according to any one of items 1-128.

130. A method for preparing a solid controlled release dosage form comprising: preparing a core containing a first portion of an opioid analgesic dispersed in a first matrix material; and enclosing the core in a sheath containing a second portion of the opioid analgesic dispersed throughout the second matrix material;

wherein the amount of opioid analgesic released from the dosage form is proportional to the 20% duration of action from 8 to 24 hours as determined from pharmaceutical availability measured in vitro on a USP Apparatus 1 (basket) machine at 100 rpm min. in 900 ml of artificial gastric juice without enzymes (SGF) at 37 ° C.

131. A method for preparing a solid controlled release dosage form comprising: preparing a core containing a first portion of an opioid analgesic dispersed in a first matrix material comprising polyethylene oxide; and enclosing the core in a sheath containing a second portion of the opioid analgesic dispersed in the second matrix material comprising polyethylene oxide. 132. A method for preparing a solid controlled release dosage form comprising: preparing a compressed core containing a first portion of an opioid analgesic dispersed in a first matrix material containing polyethylene oxide; and closing the core by compression coating it with the second portion of the opioid analgesic dispersed in the second matrix material comprising polyethylene oxide.

133. The method of preparing a solid form of controlled release dosage consisting of:

preparing a core containing the first portion of the opioid analgesic dispersed in the first matrix material; and enclosing the core in a sheath containing a second portion of the opioid analgesic dispersed in the second matrix material around the core;

wherein the amount of opioid analgesic released from the dosage form after 2 hours. is less than about 25%;

amount of opioid analgesic released from the dosage form after 4 hours. ranges from about 10% to about 30%;

amount of opioid analgesic released from the dosage form after 8 hours. it ranges from about 20% to about 60%;

amount of opioid analgesic released from the dosage form after 12 hours. ranges from about 40% to about 90%; and the amount of opioid analgesic released from the dosage form after 18 hours. is greater than about 70%.

as determined on the basis of pharmaceutical availability measured in vitro on USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free artificial gastric juice (SGF) at 37 ° C.

134. The method of preparing a solid form of controlled release dosage consisting of:

a combination of a therapeutically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof and a controlled release excipient;

wherein the amount of hydrocodone or its salt released from the dosage form is proportional to the duration of action within 20%, at any two time points from 8 to 24 hours, as determined by pharmaceutical availability measured in vitro on a USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free simulated gastric juice (SGF) at 37 ° C; and the dosage form may be flattened and non-disintegrating, wherein the thickness of the flattened dosage form corresponds to no more than about 20% of the thickness of the dosage form prior to flattening; and the amount of hydrocodone or its salt released after 0.5 h. from the flattened dosage form deviates by no more than about 20% points from the non-flattened dosage form, which was determined on the basis of pharmaceutical availability measured in vitro in the USP Apparatus 1 device (basket) at a speed of 100 rpm in 900 ml of artificial gastric juice no enzymes (SGF) at 37 ° C.

135. The method of preparing a solid form of controlled release dosage consisting of:

a combination of a therapeutically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof and a controlled release excipient;

wherein the amount of hydrocodone or its salt released from the dosage form after 2 hours. is less than about 25%;

the amount of hydrocodone or its salt released from the dosage form after 4 hours. ranges from about 10% to about 30%;

the amount of hydrocodone or its salt released from the dosage form after 8 hours. it ranges from about 20% to about 60%;

the amount of hydrocodone or its salt released from the dosage form after 12 hours. ranges from about 40% to about 90%; and the amount of hydrocodone or its salt released from the dosage form after 18 hours. is greater than about 70%;

based on pharmaceutical availability measured in vitro on USP Apparatus 1 (basket) at 100 rpm in 900 ml of enzyme-free artificial gastric juice (SGF) at 37 ° C; and the dosage form may be flattened and non-disintegrating, wherein the thickness of the flattened dosage form corresponds to no more than about 20% of the thickness of the dosage form prior to flattening; and the amount of hydrocodone or its salt released after 0.5 h. from the flattened dosage form deviates by no more than about 20% points from the non-flattened dosage form, which was determined on the basis of pharmaceutical availability measured in vitro in the USP Apparatus 1 device (basket) at a speed of 100 rpm in 900 ml of artificial gastric juice no enzymes (SGF) at 37 ° C.

136. The method of preparing a solid form of controlled release dosage consisting of:

dispersing a therapeutically effective amount of the hydrocodone or a pharmaceutically acceptable salt thereof in the controlled release excipient; wherein 60% inner portion of the dosage form comprises at least 80% hydrocodone or a salt thereof;

wherein the amount of hydrocodone or its salt released from the dosage form is proportional to the duration of action from 8 to 24 hours as determined by pharmaceutical availability measured in vitro on a USP Apparatus 1 (basket) at 100 rpm. min. in 900 ml of artificial gastric juice without enzymes (SGF) at 37 ° C.