Encased tamper resistant controlled release dosage forms

0001The present invention is resistant to tampering, and preferably the active agent contained therein. With respect to a multi-layer pharmaceutical dosage form that provides a qualitatively zero-order release.

0002Pharmaceutical products are sometimes the subject of abuse. For example, a specific dose of opioid agonist may be May be more potent when given parenterally compared to the same dose given by mouth To. Some formulations use the opioid agonists contained therein for illegal use. It may be tampered with. Controlled release opioid agonist formulations are sometimes contained therein By substance abusers to provide immediate release of opioids by oral or parenteral administration Is crushed or subjected to extraction with a solvent (eg ethanol).

0003Controlled release opioids that can release some opioids upon exposure to ethanol Id-acting dosage form, if the patient ignores the instructions and uses alcohol at the same time as the dosage form The patient may also result in taking the dose faster than intended.

0004U.S. Patent Application Publication No. 2009/0081290, in certain embodiments, is a tablet or Pairs solid, oral, and extended release pharmaceutical forms containing extended release matrix formulations in the form of multiparticles. The elephant tamper-resistant dosage form is disclosed. Tablets or individual multiparticulates without destruction At least about 60 of the thickness of the tablet or individual polyparticles before flattening, which can be flattened It is characterized by the thickness of the flattened tablet or individual multiparticle agent corresponding to% or less, and even the flattened tablet. Or flattening polyparticles at 37 ° C in 900 mL of enzyme-free simulated gastric juice (SGF) 10 Non-flattened reference tablets or when measured in USP apparatus 1 (basket) at 0 rpm Deviates by about 20 percentage points or less from the corresponding in vitro elution rate of the non-flattening reference multiparticle In vitro elution rate with percent amount of active material released 0.5 hours after elution I will provide a.

0005Preferably, tampering provides a release profile of the active agent that is substantially zero order. The need for oral resistant pharmaceutical dosage forms continues to exist in the art.

0006All references and publications cited herein are for all purposes. All of them are incorporated herein by reference.

<p num="0007"> An object of an embodiment of the invention is an active agent (eg, opioid) that is resistant to tampering. To provide a solid controlled release dosage form containing analgesics).</p><p num="0008"> An object of an embodiment of the invention is an active agent (eg, opi) that is resistant to disruption. It is to provide a solid controlled release dosage form containing an oid analgesic).</p><p num="0009"> An object of an embodiment of the present invention is opioid sedative, which is less susceptible to parenteral abuse than other dosage forms. It is to provide a solid controlled release dosage form containing a pain drug.</p><p num="0010"> An object of an embodiment of the present invention is opioid sedation, which is less susceptible to intranasal abuse than other dosage forms. It is to provide a solid controlled release dosage form containing a pain drug.</p><p num="0011"> An object of an embodiment of the present invention is opioid analgesia, which is less likely to be abused orally than other dosage forms. It is to provide a solid controlled release dosage form containing a drug.</p><p num="0012"> A further object of one embodiment of the invention is an opioid, which is less likely to be diverted than other dosage forms. It is to provide a solid controlled release dosage form containing an analgesic.</p><p num="0013"> A further object of an embodiment of the invention is opioids while reducing the potential for abuse of dosage forms. To provide a method of treating pain in human patients with solid controlled release dosage forms containing analgesics. Is.</p><p num="0014"> A further object of an embodiment of the invention is the solid controlled release dosage form disclosed herein. Cures a disease or condition (eg, pain) by administering to a patient in need of it It is to treat.</p><p num="0015"> A further object of an embodiment of the invention is an active agent disclosed herein (eg, an active agent). , Opioid analgesics) to provide a method for producing oral dosage forms.</p><p num="0016"> A further object of an embodiment of the invention is to treat a disease state (eg, pain). To provide the use of pharmaceuticals (eg, opioid analgesics) in the manufacture of dosage forms.</p>

<p num="0017"> These and other purposes are, in certain embodiments, subdivided into a first matrix material. Cover the core containing the first part of the active drug being dissipated (eg, opioid analgesic) and the core Includes a shell containing a second portion of the active agent dispersed in a second matrix material Achieved by the present invention for solid controlled release dosage forms, the amount of active agent released from the dosage form USP at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C Elapsed from 8 to 24 hours as measured by in vitro elution in device 1 (basket) Proportional to time within 20%.</p><p num="0018"> In some other embodiments, the amount of active agent released from the dosage form is the enzyme at 37 ° C. In USP device 1 (basket) at 100 rpm in 900 mL of free simulated gastric juice (SGF) Measured by in vitro elution, (i) 4 to 24 hours, (ii) 8 to 24:00 Between (iii) 12 to 24 hours, (iv) 18 to 24 hours, (v) 4 8 hours, (vi) 4 to 12 hours, (vii) 4 to 18 hours, (vii) i) 8 to 12 hours, (ix) 8 to 18 hours, or (x) 12 to 18 hours At least one of up to is proportional to the elapsed time within 30%. In an alternative embodiment , The amount of active drug released from the dosage form is enzyme-free simulated gastric juice (SGF) 90 at 37 ° C. Measured by in vitro elution in USP apparatus 1 (basket) at 100 rpm in 0 mL Then (i) 8 to 24 hours, (ii) 8 to 12 hours, and (iii) 8 From to 18 hours all proportional to the elapsed time within 30%.</p><p num="0019"> In some other embodiments, the amount of active agent released from the dosage form is the enzyme at 37 ° C. In USP device 1 (basket) at 100 rpm in 900 mL of free simulated gastric juice (SGF) Measured by in vitro elution, (i) 4 to 24 hours, (ii) 8 to 24:00 Between (iii) 12 to 24 hours, (iv) 18 to 24 hours, (v) 4 8 hours, (vi) 4 to 12 hours, (vii) 4 to 18 hours, (vii) i) 8 to 12 hours, (ix) 8 to 18 hours, or (x) 12 to 18 hours At least one of the above is proportional to the elapsed time within 25%. In an alternative embodiment , The amount of active drug released from the dosage form is enzyme-free simulated gastric juice (SGF) 90 at 37 ° C. Measured by in vitro elution in USP apparatus 1 (basket) at 100 rpm in 0 mL Then (i) 8 to 24 hours, (ii) 8 to 12 hours, and (iii) 8 From to 18 hours all proportional to elapsed time within 25%.</p><p num="0020"> In some other embodiments, the amount of active agent released from the dosage form is the enzyme at 37 ° C. In USP device 1 (basket) at 100 rpm in 900 mL of free simulated gastric juice (SGF) Measured by in vitro elution, (i) 4 to 24 hours, (ii) 8 to 24:00 Between (iii) 12 to 24 hours, (iv) 18 to 24 hours, (v) 4 8 hours, (vi) 4 to 12 hours, (vii) 4 to 18 hours, (vii) i) 8 to 12 hours, (ix) 8 to 18 hours, or (x) 12 to 18 hours At least one of up to is proportional to the elapsed time within 20%. In an alternative embodiment , The amount of active drug released from the dosage form is enzyme-free simulated gastric juice (SGF) 90 at 37 ° C. Measured by in vitro elution in USP apparatus 1 (basket) at 100 rpm in 0 mL Then (i) 8 to 24 hours, (ii) 8 to 12 hours, and (iii) 8 From to 18 hours is proportional to the elapsed time within 20%.</p><p num="0021"> In some other embodiments, the amount of active agent released from the dosage form is the enzyme at 37 ° C. In USP device 1 (basket) at 100 rpm in 900 mL of free simulated gastric juice (SGF) Measured by in vitro elution, (i) 4 to 24 hours, (ii) 8 to 24:00 Between (iii) 12 to 24 hours, (iv) 18 to 24 hours, (v) 4 8 hours, (vi) 4 to 12 hours, (vii) 4 to 18 hours, (vii) i) 8 to 12 hours, (ix) 8 to 18 hours, or (x) 12 to 18 hours At least one of up to is proportional to the elapsed time within 10%. In an alternative embodiment , The amount of active drug released from the dosage form is enzyme-free simulated gastric juice (SGF) 90 at 37 ° C. Measured by in vitro elution in USP apparatus 1 (basket) at 100 rpm in 0 mL Then (i) 8 to 24 hours, (ii) 8 to 12 hours, and (iii) 8 From to 18 hours all proportional to elapsed time within 10%.</p><p num="0022"> In some other embodiments, the amount of active agent released from the dosage form is the enzyme at 37 ° C. In USP device 1 (basket) at 100 rpm in 900 mL of free simulated gastric juice (SGF) Measured by in vitro elution, (i) 4 to 24 hours, (ii) 8 to 24:00 Between (iii) 12 to 24 hours, (iv) 18 to 24 hours, (v) 4 8 hours, (vi) 4 to 12 hours, (vii) 4 to 18 hours, (vii) i) 8 to 12 hours, (ix) 8 to 18 hours, or (x) 12 to 18 hours At least one of up to is proportional to the elapsed time within 5%. In an alternative embodiment The amount of active drug released from the dosage form is enzyme-free simulated gastric juice (SGF) 900 at 37 ° C. Measured by in vitro elution in USP apparatus 1 (basket) at 100 rpm in mL Then, (i) 8 to 24 hours, (ii) 8 to 12 hours, and (iii) 8? All up to 18 hours are proportional to the elapsed time within 5%.</p><p num="0023"> In certain embodiments, the present invention is a first matrix material comprising polyethylene oxide. A core containing the first part of an active agent (eg, an opioid analgesic) dispersed in the drug, Activator that covers a and is dispersed in a second matrix material containing polyethylene oxide Target solid controlled release dosage forms, including shells containing a second portion of the agent. Alternative Embodiment Smell And only the first matrix material contains polyethylene oxide or the second matrix material Only the agent contains polyethylene oxide.</p><p num="0024"> In certain embodiments, the present invention is a first matrix material comprising polyethylene oxide. With a compressed core containing the first part of the active agent (eg, opioid analgesic) dispersed in the drug The activity that covers the core and is dispersed in a second matrix material containing polyethylene oxide. It is intended for solid controlled release dosage forms, including compression coatings containing a second portion of the sex agent.</p><p num="0025"> In certain embodiments, the present invention is an active agent dispersed in a first matrix material. A core containing the first part (eg, an opioid analgesic) and a second matrick covering the core Paired with a solid controlled release form containing a shell containing a second portion of the active agent dispersed in the material. As an elephant, U at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. Measured by in vitro elution in SP device 1 (basket), released from dosage form at 2 hours The amount of active drug released is less than about 25% and the active drug released from the dosage form at 4 hours. The amount of active agent is from about 10% to about 30%, and the amount of active agent released from the dosage form at 8 hours. Is from about 20% to about 60%, and the amount of active drug released from the dosage form at 12 hours , From about 40% to about 90%, and the amount of active agent released from the dosage form at 18 hours Over 70%.</p><p num="0026"> In certain embodiments, the present invention is an active agent dispersed in a first matrix material. A core containing the first part (eg, an opioid analgesic) and a second matrick covering the core Paired with a solid controlled release form containing a shell containing a second portion of the active agent dispersed in the material. As an elephant, U at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. Measured by in vitro elution in SP device 1 (basket), released from dosage form at 2 hours The amount of active drug released is less than about 20% and the active drug released from the dosage form at 4 hours. The amount of active agent is from about 10% to about 30%, and the amount of active agent released from the dosage form at 8 hours. Is from about 30% to about 60%, and the amount of active drug released from the dosage form at 12 hours , From about 50% to about 90%, and the amount of active agent released from the dosage form at 18 hours Over 80%.</p><p num="0027"> In certain embodiments, the present invention is an active agent dispersed in a first matrix material. A core containing the first part (eg, an opioid analgesic) and a second matrick covering the core Paired with a solid controlled release form containing a shell containing a second portion of the active agent dispersed in the material. As an elephant, U at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. Measured by in vitro elution in SP device 1 (basket), released from dosage form at 2 hours The amount of active drug released is less than about 15% and the active drug released from the dosage form at 4 hours. The amount of active drug released from the dosage form at 8 hours is from about 8% to about 20%. , From about 20% to about 50%, and the amount of active drug released from the dosage form at 12 hours From about 40% to about 70%, the amount of active agent released from the dosage form at 18 hours is about Over 70%, the amount of active agent released from the dosage form at 24 hours exceeds about 90%. Ah In certain embodiments, the present invention relates to therapeutically effective amounts of hydrocodone or pharmaceutically acceptable so. For solid controlled release dosage forms containing salts and controlled release excipients of The amount of peoid analgesic is 10 in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. Measured by in vitro elution in USP device 1 (basket) at 0 rpm, from 8 It is proportional to the elapsed time up to 24 hours within 20%, and the dosage form can be flattened without breaking. The thickness of the dosage form after flattening corresponds to about 20% or less of the thickness of the dosage form before flattening, and the flattening agent The amount of hydrocodone or salt thereof released 0.5 hours after form is the enzyme at 37 ° C. In USP device 1 (basket) at 100 rpm in 900 mL of free simulated gastric juice (SGF) Deviates by about 20 percentage points or less from the non-flattenant form as measured by in vitro elution at ..</p><p num="0028"> In certain embodiments, the present invention is a therapeutically effective amount of hydrocodone or pharmaceutically acceptable. Fermented at 37 ° C for solid controlled release dosage forms containing the salt and controlled release excipients USP device 1 (basket) at 100 rpm in 900 mL of plain-free simulated gastric juice (SGF) Hydrocodone released from the dosage form at 2 hours as measured by in vitro elution within The amount of salt is less than about 25% and hydrocodone released from the dosage form at 4 hours The amount of salt is from about 10% to about 30%, and the hide released from the dosage form at 8 hours. The amount of locodon or salt thereof is from about 20% to about 60%, from the dosage form at 12 hours The amount of hydrocodone or its salt released is from about 40% to about 90%, at 18:00 The amount of hydrocodone or salt thereof released from the dosage form in the interim is over about 70%, and the dosage form is It can be flattened without breaking, and the thickness of the dosage form after flattening is about the thickness of the dosage form before flattening. Hydrocodone or its equivalent, equivalent to 20% or less, released 0.5 hours after flattening form The amount of salt is 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. From non-flattenant form as measured by in vitro elution in USP apparatus 1 (basket) Deviate by about 20 percentage points or less.</p><p num="0029"> In certain embodiments, the present invention relates to a therapeutically effective amount of hide dispersed in a controlled release excipient. For solid controlled release dosage forms containing locones or their pharmaceutically acceptable salts, among the dosage forms Part 60% contains at least 80% hydrocodone or a salt thereof and is released from the dosage form The amount of hydrocodone or its salt is 900 m of enzyme-free simulated gastric juice (SGF) at 37 ° C. Measured by in vitro elution in USP device 1 (basket) at 100 rpm in L Then, it is proportional to the elapsed time from 8 to 24 hours within 20%.</p><p num="0030"> In certain embodiments, the present invention is an active agent dispersed in a first matrix material. Preparing a core containing the first part (eg, an opioid analgesic), and a second matte Includes covering the core with a shell containing a second portion of the active agent dispersed in the lix material Targeting methods for preparing solid controlled release dosage forms, the amount of active agent released from the dosage form is 37. USP device 1 at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at ° C 2 in elapsed time from 8 to 24 hours, measured by in vitro elution in basket) Proportional within 0%.</p><p num="0031"> In certain embodiments, the present invention is a first matrix material comprising polyethylene oxide. Prepare a core containing the first portion of an active agent (eg, an opioid analgesic) dispersed in the drug And dispersed in a second matrix material containing polyethylene oxide Those preparing solid controlled release dosage forms involving covering the core with a shell containing a second portion of the active agent Target the law. In alternative embodiments, the corresponding dosage form is only the first matrix material. Contains polyethylene oxide or only the second matrix material contains polyethylene oxide Prepared to include.</p><p num="0032"> In certain embodiments, the present invention is a first matrix material comprising polyethylene oxide. A compressed core containing the first part of an active agent (eg, an opioid analgesic) dispersed in the drug. To prepare and to a second matrix material containing polyethylene oxide throughout the core Covering the core by compression coating the second part of the dispersed active agent The subject is a method of preparing a solid controlled release dosage form containing. In the alternative embodiment, the corresponding pressure In the crimp-coated dosage form, only the first matrix material contains polyethylene oxide Only the second matrix material is prepared to contain polyethylene oxide.</p><p num="0033"> In certain embodiments, the present invention is an active agent dispersed in a first matrix material. Preparing a core containing the first part (eg, an opioid analgesic), and throughout the core Cover the core with a shell containing the second portion of the active agent dispersed in the second matrix material For methods of preparing solid controlled release dosage forms, including enzyme-free simulated stomach at 37 ° C. Inbit in USP device 1 (basket) at 100 rpm in 900 mL of liquid (SGF) (B) The amount of active agent released from the dosage form at 2 hours, measured by elution, is less than about 25%. The amount of active drug released from the dosage form at 4 hours is from about 10% to about 30%. Therefore, the amount of active drug released from the dosage form at 8 hours is from about 20% to about 60%. The amount of active agent released from the dosage form at 12 hours ranges from about 40% to about 90%, 1 The amount of active agent released from the dosage form at 8 hours exceeds about 70%.</p><p num="0034"> In certain embodiments, the present invention is a therapeutically effective amount of hydrocodone or pharmaceutically acceptable. Prepare a solid controlled release dosage form containing a combination of a salt thereof and a controlled release excipient. Targeting methods, 100 rp in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C Measured by in vitro elution in USP device 1 (basket) at m, agent at 2 hours The amount of hydrocodone or salt thereof released from the form is less than about 25% and the agent at 4 hours The amount of hydrocodone or salts thereof released from the form is from about 10% to about 30%, The amount of hydrocodone or salt thereof released from the dosage form at 8 hours is about 20% to about 60%. Up to, the amount of hydrocodone or salt thereof released from the dosage form at 12 hours is about 40 From% to about 90%, hydrocodone or salts thereof released from the dosage form at 18 hours The amount of the dosage form exceeds about 70%, the dosage form can be flattened without breaking, and the dosage form after flattening The thickness corresponds to about 20% or less of the thickness of the dosage form before flattening, 0.5 hours after the flattening agent form. The amount of hydrocodone or its salt released is enzyme-free simulated gastric juice (SGF) at 37 ° C. ) For in vitro elution in USP device 1 (basket) at 100 rpm in 900 mL More measured, it deviates by about 20 percentage points or less from the non-flatting agent form.</p><p num="0035"> In certain embodiments, the present invention is a therapeutically effective amount of hydrocodone or pharmaceutically acceptable. Prepare a solid controlled release dosage form containing a combination of a salt thereof and a controlled release excipient. Targeting the method, the amount of hydrocodone or salt thereof released from the dosage form is at 37 ° C. USP device 1 (basket) at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) ) At any two time points from 8 to 24 hours, measured by in vitro elution And proportional to the elapsed time within 20%, the dosage form can be flattened without breaking and flattening The thickness of the later dosage form corresponds to about 20% or less of the thickness of the dosage form before flattening, and is 0. The amount of hydrocodone or salt thereof released at 5 hours is an enzyme-free simulated stomach at 37 ° C. Invisibility in USP device 1 (basket) at 100 rpm in 900 mL of liquid (SGF) It deviates by about 20 percentage points or less from the non-flattenant form as measured by toro elution.</p><p num="0036"> In certain embodiments, the present invention presents a controlled release excipient with a therapeutically effective amount of hydrocodone or Paired with a method of preparing a solid controlled release dosage form comprising dispersing the pharmaceutically acceptable salt thereof. Elephant, 60% inside the dosage form contains at least 80% hydrocodone or a salt thereof, agent The amount of hydrocodone or its salt released from the form is enzyme-free simulated gastric juice at 37 ° C. In vitro in USP device 1 (basket) at 100 rpm in 900 mL of SGF) Measured by elution, it is proportional to the elapsed time from 8 to 24 hours within 20%.</p><p num="0037"> In certain embodiments, the present invention includes opioid analgesics disclosed herein. A method for treating pain in a patient or subject, including administration of a solid controlled release dosage form. Let's be an elephant.</p><p num="0038"> In a preferred embodiment, the invention is substantially zero-order after administration to a patient or subject. The dosage forms of the present invention that indicate the release rate are targeted.</p><p num="0039"> The term "zero-order release rate" is independent of the remaining active drug concentration in the dosage form. It refers to the rate of release of the active drug from the dosage form, which is relatively constant over a period of time. Sea urchin. Dosage forms that exhibit zero-order release rates are the active agent released percent vs. time. Will show a relatively straight line in the graph representation of. Smell of certain embodiments of the present invention And a substantial zero-order release in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. Measured by in vitro elution in USP device 1 (basket) at 100 rpm Emitted within 20% proportional to the elapsed time of 8 to 24 hours or 4 to 12 hours It is defined as a dosage form with an amount of active drug. For example, 20% of the drug in vitro at 8 hours The amount released from the shape, and the amount released at 60% (± 12) at 24 hours, is 8 to 2. It will literally meet the definition of being proportional to the elapsed time up to 4 hours within 20%. this thing The latter elapsed time (24 hours) and the latter release (60%) are the former time (8 hours) And the same multiple (3) of the former release (20%). 8 to 24 Meet the definition proportional to the elapsed time to time (or any other period) within 20% In order to do so, it is only necessary to consider the end point of the number, but the definition is the same at other time points within the end point. It does not exclude that it may be proportional to.</p><p num="0040"> In another embodiment of the invention, the substantial zero-order release is enzyme-free simulation at 37 ° C. In-USP device 1 (basket) at 100 rpm in 900 mL of gastric juice (SGF) Measured by vitro elution, the amount of active agent released from the dosage form at 2 hours is about 25% Less than, and the amount of active agent released from the dosage form at 4 hours is from about 10% to about 30% The amount of active drug released from the dosage form at 8 hours is from about 20% to about 60%. Therefore, the amount of active drug released from the dosage form at 12 hours is from about 40% to about 90%. , The amount of active drug released from the dosage form at 18 hours is defined as a dosage form exceeding about 70%. ..</p><p num="0041"> The term "polyethylene oxide" is used in the art for the purposes of the present invention. It has a molecular weight of at least 25,000, as measured conventionally, preferably less. Also defined as a composition of polyethylene oxide (PEO) with a molecular weight of 100,000 Is done. Lower molecular weight compositions are commonly referred to as polyethylene glycol.</p><p num="0042"> The term "high molecular weight polyethylene oxide (PEO)" is used for the purposes of the present invention. Determined to have an approximate molecular weight of at least 1,000,000 based on rheological measurements Be justified.</p><p num="0043"> The term "low molecular weight polyethylene oxide (PEO)" is used for the purposes of the present invention. Defined to have an approximate molecular weight of less than 1,000,000 based on rheological measurements To.</p><p num="0044"> The term "direct compression" is used for the purposes of the present invention, where the dosage form blends the ingredients. By a process involving the process of compressing the blend to form a dosage form, for example. Processes made by using diffusion blending and / or convection mixing processes Defined to point to (eg Guidance for Industry, SUPAC-IR / MR: Immediate Releas) e and Modified Release Solid Oral Dosage Forms, Manufacturing Equipment Addendum See).</p><p num="0045"> The term "flattening" as used in the context of flattening dosage forms according to the invention. And related terms are the minimum diameter (ie, thickness) of the dosage form if the dosage form is non-spherical. Mark from a direction substantially along the line, and from any direction if the dosage form shape is spherical. It means receiving the force applied.</p><p num="0046"> The term "resistant to crushing" is used for the purposes of certain embodiments of the present invention. Can at least be flattened on the bench press described herein without breaking Defined to refer to a dosage form.</p><p num="0047"> For the purposes of the present invention, the term "opioid analgesic" is used as a base opioid. Agonists, mixed opioid agonists-antagonists, partial opioid agonists, pharmaceutically acceptable Their salts, complexes, stereoisomers, ethers, esters, hydrates and solvates and their Means one or more compounds selected from their mixture.</p><p num="0048"> As used herein, the terms "simulated gastric juice" or "SGF" mimic gastric conditions. Point to the aqueous solution used in the dissolution test to replicate, eg, a solution of 0.1N HCl. Su.</p><p num="0049"> For example, "Is the amount of active agent released from the flattening form 0.5 hours after the non-flattening form? For "percentage points" in the context of "deviation of about 20 percentage points or less" The word is that the difference between% emission prior to flattening and% emission after flattening does not exceed 20 (ie 2). It means that it is 0 or less). For example, 60% release from flattening form is non-flattening form It is less than about 20 percentage points from the 40% release of.</p><p num="0050"> With the term "percentage" or "percentage (ie%) points" The use of irrelevant "%" is the usual meaning of percentage. For example, 48% release is 60 40% is literally within 20% of 60% emission, whereas it is within 20% of% emission Will not be.</p><p num="0051"> The term "patient" refers to the clinical practice of a particular symptomatology or symptomatology that suggests the need for treatment. Show signs and are preventatively or prophylactically due to the condition Means a subject (preferably a human) who has been or has been diagnosed with a condition to be treated. To.</p><p num="0052"> The term "subject" includes the definition of the term "patient" and is a "healthy subject" (ie, that is. For individuals (eg, humans) who are quite normal in all respects or with respect to a particular condition Including words.</p><p num="0053"> As used herein, the term "character isomer" refers to the orientation of those atoms in space. A general term for all isomers of individual molecules that differ only. It's Enantioma -And isomers of compounds with two or more chiral centers that are not mirror images of each other (diastereomers) Ma) is included.</p><p num="0054"> The term "chiral center" refers to a carbon atom to which four different groups are connected.</p><p num="0055"> The term "enantiomer" or "enantiomer" is superimposed on the mirror image. Refers to molecules that cannot and are therefore optically active, and enantiomers are biased in one direction. The light plane is rotated, and the mirror image rotates the polarizing plane in the opposite direction.</p><p num="0056"> The term "racemic" refers to a mixture of enantiomers.</p><p num="0057"> The term "split" refers to the separation or concentration of one of the two enantiomeric forms of the molecule. Refers to shrinkage or depletion.</p><p num="0058"> "Hydrocodone" is a hydrocodone free base, as well as pharmaceutical, for the purposes of the present invention. Tolerable salts, complexes, stereoisomers, ethers, esters, hydrates and solvates And defined to include mixtures thereof.</p><p num="0059"> The term "USP paddle or basket method" is used, for example, in the United States Pharmacopeia XII (19). The paddle and basket method described in 90).</p><p num="0060"> The term "pH-dependent" for the purposes of the present invention is a characteristic that changes with environmental pH. Defined to have (eg, elution).</p><p num="0061"> The term "pH-independent" for the purposes of the present invention is substantially influenced by pH. Defined to have no characteristics (eg, elution).</p><p num="0062"> The term "bioavailability" is used for the purposes of the present invention as a drug (eg, hydrocode). Is defined as the degree of association absorbed from the unit dosage form. Bioavailability is AUC That is, it is also called (the area under the plasma concentration / time curve).</p><p num="0063"> The terms "controlled release", "prolonged release" or "sustained release" are interchangeable and For the purposes of the present invention, blood (eg, plasma) concentrations are within therapeutic range, but at least Maintained below toxic concentration for a period of approximately 12 hours or more, or at least 24 hours or more It is defined as the release of a drug (eg, hydrocodone) at such a rate. Preferably , Controlled release dosage forms can provide once-daily or twice-daily dosing.</p><p num="0064"> "C_maxThe term "refers to the maximum plasma concentration obtained during the dosing interval.</p><p num="0065"> "C₂₄The term "" is used 24 hours after administration, as used herein. The plasma concentration of the drug.</p><p num="0066"> "T_maxThe term "maximum plasma concentration (C)"_max) Indicates the time.</p><p num="0067"> "C₂₄/ C_maxThe term "ratio" is used 24 hours after administration for the purposes of the present invention. It is defined as the ratio of the plasma concentration of a drug to the maximum plasma concentration of the drug reached within the dosing interval.</p><p num="0068"> "T_lagIndicates the point in time immediately prior to the first measurable plasma concentration.</p><p num="0069"> "T_1/2The term refers to the plasma half-life of the terminal phase. This is optional in the terminal phase It is the time it takes for the concentration of to decrease in half. For the concentration of opioids such as hydrocodone The term "minimum effective analgesic concentration" or "MEAC" is extremely difficult to quantify. It's difficult. However, in general, less than that does not provide pain relief plasma hydroco There is a minimum effective analgesic concentration of Don. For example, between plasma hydrocodon levels and pain loss Higher and prolonged plasma levels, albeit intimately related, are generally superior pain Is related to mitigation. With time of peak plasma hydrocodon level and time of peak drug effect There is a delay (or hysteresis) between. This is generally the case with opioid analgesics Applies to the treatment of pain.</p><p num="0070"> For the purposes of the present invention, the term "patient" or "subject" unless otherwise specified. The discussion (or claim) targets the pharmacokinetic parameters of an individual patient or subject. Means that.</p><p num="0071"> The terms "patient population" or "subject population" or "healthy subject population" are controversial ( Or claim), but at least 2 patients, subjects, or healthy subjects, at least 6 Patient, subject, or healthy subject, or at least 12 patients, subjects, or healthy pairs Meaning to target the average pharmacokinetic parameters of an elephant.</p><p num="0072"> For the purposes of the present invention, the controlled release formulations disclosed herein are preferably administered. It is proportional to the quantity. In a dose-proportional formulation, pharmacokinetic parameters (eg, AUC) And C_max) And / or in vitro release directly from one dose intensity to another It increases linearly. Therefore, specific doses of pharmacokinetic parameters and in vitro parameters Lameter can be inferred from the parameters of the same formulation at different doses.</p><p num="0073"> The term "first dose" refers to an individual subject, patient, or healthy subject or population, patient. It means a single dose of the present invention at the start of treatment for a population of individuals or a healthy subject population. To.</p><p num="0074"> The term "steady state" means that the amount of drug that reaches the system is the amount of drug that leaves the system. It means that they are the same. That is, in the "steady state", the patient's body is loaded with the drug. Eliminate the drug at approximately the same rate as it becomes available to the patient's system through absorption into the bloodstream To.</p>

0075<figref num="1">It is a graph which draws the elution of the composition of Examples 1 to 4.</figref><figref num="2">It is a graph which depicts the elution of the composition of Examples 5 and 6.</figref><figref num="3">It is a graph which draws the elution of the composition of Examples 7-12.</figref><figref num="4">It is a graph which draws the mean plasma concentration time curve of the repetition 1 of Example 13.</figref><figref num="5">It is a graph which draws the mean plasma concentration time curve of the repetition 2 of Example 13.</figref><figref num="6">It is a graph which draws the average plasma concentration time curve of the repetition 3 of Example 13.</figref><figref num="7">It is a graph which draws the plasma concentration of the composition of Examples 14-20.</figref>

0076The present invention, in certain embodiments, has a higher concentration in the inner region of the dosage form as compared to the outer region. The target is controlled release pharmaceutical products containing drugs. Preferably, the inner and outer regions are inside As a part core (eg, compressed tablet) and a shell covering the core (eg, compression coating) It is composed of. The active agent is contained only in the core or in both the core and shell You can. In a preferred embodiment, the release of the active agent from the dosage form is substantially zero order. And reduce dosing certainty and plasma variability compared to alternative therapies (eg, immediate release dosage forms) provide.

0077The dosage forms of the present invention are preferably tampered with because they are difficult to crush or grind. Resistant (eg, according to the flattening criteria disclosed herein). This feature is a book A large throw in which the dosage form of the invention is intended to be released from each dose unit over a period of time. Make it particularly suitable for controlled release opioid analgesic products with doses of opioid analgesics .. Substance abusers typically obtain controlled release products and note most or all of the dosage form. Products to be available for immediate absorption by firing, inhalation, and / or oral consumption May be crushed, sheared, crushed, chewed, melted, heated, extracted or otherwise damaged ..

0078The dosage form shells of the present invention are preferably difficult to physically separate from the core. This makes it difficult for abusers to access the larger drug payload in the core. Therefore, it is particularly useful in embodiments that have an increased amount of active agent in the core compared to the shell. Is.

0079In certain embodiments, the present invention is an opioid dispersed in a first matrix material. The core containing the first part of the analgesic and the core is covered and dispersed in a second matrix material It is intended for solid controlled release forms, including shells containing a second portion of opioid analgesics.

0080The dosage form core can be formed, for example, by direct compression, extrusion or molding. Prefer Alternatively, the inner core provides a controlled release excipient and is in the form of a compressed tablet.

0081Dosage form shells are, for example, compression coated, molded, with one or more layers on the core. Shaped by spraying, immersing one or more layers on the core, or a combination thereof Can be done. Preferably, the shell contains a controlled release excipient and is a compression coating. It is

0082In a preferred embodiment, the weight ratio of core to shell of the dosage form described herein is , About 1: 0.5 to about 1: 5, about 1: 0.5 to about 1: 2, about 1: 0.6 to about Up to 1: 1.5, or from about 1: 0.8 to about 1: 1.2.

0083In a preferred embodiment, the core and shell are visually indistinguishable (eg, by color). ), There is no clear boundary between each component. This, in certain embodiments, of the active agent Contributes to dosage form tamper resistance by interfering with efforts to access the core containing the majority I am giving. One measurement that can be used to evaluate the color of the shell and core , CIE L^*A^*B^*The value. Preferably, the core and shell CIE L^*A^*B^*Values are within 10% of each other. Another measurement for evaluating color is RYB or RGB With the use of color wheels, the core and shell are preferably of the same hue or adjacent It corresponds to the hue.

0084In certain embodiments, the first matrix material comprises PEO. In other embodiments And the second matrix material contains PEO. In yet another embodiment, the first The matrix material contains PEO and the second matrix material contains PEO. Prefer Or polyethylene oxide is contained in both constituents. In such an embodiment Therefore, the molecular weight of PEO in the first matrix material is the average in the second matrix material. Same or different molecular weight. In certain embodiments, PE contained in both components The molecular weight of O is within 20%, within 10% or within 5% of each other.

0085In a preferred embodiment of the invention, polyethylene oxide is the primary matrix. If present in both of the second matrix, in the first matrix (in the core) ) The molecular weight of the polyethylene oxide used is in the second matrix material (She Lower than the molecular weight of polyethylene oxide used. For example, the preferred fruit In the embodiment, the polyethylene oxide in the first matrix material is about 300,00. A second matrix material that may have a molecular weight from 0 to about 10,000,000 Polyethylene oxide in is from about 1,000,000 to about 10,000,000 It may have a molecular weight. In another preferred embodiment, in the first matrix material Polyethylene oxide has a molecular weight from about 300,000 to about 3,000,000 Polyethylene oxide in the second matrix material is about 4,000,0 It may have a molecular weight from 00 to about 10,000,000. Other preferred embodiments In, polyethylene oxide in the first matrix material is from about 500,000 It may have a molecular weight of up to about 1,000,000 and is poly in the second matrix material. Ethylene oxide has a molecular weight from about 6,000,000 to about 8,000,000 You can do it.

0086In certain embodiments, the active agent (in the core) in the first part (eg, opioid analgesia) The drug) is the same as the active drug (in the shell) in the second part. In other embodiments, The active agent in one part is different from the active agent in the second part.

0087In certain embodiments, the ratio of active agents (eg, opioid analgesics) in the core and the cheeks. The ratio of activators in the le is from about 1: 1 to about 10: 1, from about 2: 1 to about 8: 1, about 2: From 1 to about 5: 1 or about 4: 1.

0088In certain embodiments, the active agent in the first matrix material (eg, opioid antispasmodic) The weight ratio of the first part of (pain drug) to polyethylene oxide 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, about 1: 1 From about 1:10, from about 1:15 to about 1:20, from about 1: 1.5 to about 1: 4, It is about 1:18 or about 1: 2.

0089In an alternative embodiment, the active agent in the second matrix material (eg, opioid antispasmodic) The weight ratio of the second part of (pain drug) to polyethylene oxide is from about 1: 1 to about 1: 200, About 1: 1 to about 1: 125, about 1: 2 to about 1: 100, about 1: 5 to about 1: 5 Up to 0, from about 1:12 to about 1:25, about 1:98 or about 1:15.

0090In certain embodiments, of an active agent released from the dosage form (eg, an opioid analgesic) The amount is US at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. 8 to 24 hours as measured by in vitro elution in P device 1 (basket) It is proportional to the elapsed time within 20%, within 10%, or within 5%.

0091In certain embodiments, of an active agent released from the dosage form (eg, an opioid analgesic) The amount is US at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. 8 to 18 hours as measured by in vitro elution in P device 1 (basket) It is proportional to the elapsed time within 20%, within 10%, or within 5%.

0092In certain embodiments, of an active agent released from the dosage form (eg, an opioid analgesic) The amount is US at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. Up to 8-12 hours as measured by in vitro elution in P device 1 (basket) It is proportional to the elapsed time within 20%, within 10%, or within 5%.

0093In certain embodiments, of an active agent released from the dosage form (eg, an opioid analgesic) The amount is US at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. From 12 to 24 hours as measured by in vitro elution in P device 1 (basket) Is proportional to the elapsed time of 20%, 10%, or 5%.

0094In certain embodiments, of an active agent released from the dosage form (eg, an opioid analgesic) The amount is US at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. From 12 to 18 hours as measured by in vitro elution in P device 1 (basket) Is proportional to the elapsed time of 20%, 10%, or 5%.

0095In certain embodiments, of an active agent released from the dosage form (eg, an opioid analgesic) The amount is US at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. Up to 4 to 20 hours as measured by in vitro elution in P device 1 (basket) It is proportional to the elapsed time within 20%, within 10%, or within 5%.

0096In certain embodiments, of an active agent released from the dosage form (eg, an opioid analgesic) The amount is US at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. Up to 4 to 15 hours as measured by in vitro elution in P device 1 (basket) It is proportional to the elapsed time within 20%, within 10%, or within 5%.

0097In certain embodiments, of an active agent released from the dosage form (eg, an opioid analgesic) The amount is US at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. Up to 4 to 10 hours as measured by in vitro elution in P device 1 (basket) It is proportional to the elapsed time within 20%, within 10%, or within 5%.

0098In certain embodiments, of an active agent released from the dosage form (eg, an opioid analgesic) The amount is US at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. Up to 8 to 20 hours as measured by in vitro elution in P device 1 (basket) It is proportional to the elapsed time within 20%, within 10%, or within 5%.

0099In certain embodiments, of an active agent released from the dosage form (eg, an opioid analgesic) The amount is US at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. From 10 to 15 hours as measured by in vitro elution in P device 1 (basket) Is proportional to the elapsed time of 20%, 10%, or 5%.

0100In one embodiment, 1 in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. Measured by in vitro elution in USP device 1 (basket) at 00 rpm, 2 The amount of active drug (eg, opioid analgesic) released from the dosage form at the hour is about 25% less The amount of active drug that is full and released from the dosage form at 4 hours is from about 10% to about 30%. Yes, the amount of active drug released from the dosage form at 8 hours is from about 20% to about 60%. The amount of active drug released from the dosage form at 12 hours is from about 40% to about 90%, The amount of active agent released from the dosage form at 18 hours exceeds about 70%.

0101In one embodiment, 1 in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. Measured by in vitro elution in USP device 1 (basket) at 00 rpm, 2 The amount of active agent (eg, opioid analgesic) released from the dosage form at the hour is about 15% less The amount of active drug that is full and released from the dosage form at 4 hours is from about 10% to about 20%. Yes, the amount of active drug released from the dosage form at 8 hours is from about 30% to about 45%. The amount of active drug released from the dosage form at 12 hours is from about 50% to about 70%, The amount of active agent released from the dosage form at 18 hours exceeds about 90%.

0102In one embodiment, 1 in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. Measured by in vitro elution in USP device 1 (basket) at 00 rpm, 2 The amount of active agent (eg, opioid analgesic) released from the dosage form at the hour is about 10% less The amount of active drug that is full and released from the dosage form at 4 hours is from about 20% to about 30%. Yes, the amount of active drug released from the dosage form at 8 hours is from about 45% to about 60%. The amount of active drug released from the dosage form at 12 hours is from about 70% to about 90%, The amount of active agent released from the dosage form at 18 hours exceeds about 95%.

0103In certain embodiments, of an active agent released from the dosage form (eg, an opioid analgesic) The amount is US at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. Measured by in vitro elution in P device 1 (basket), 8 to 24 hours Proportional to overtime within 20% and at least one of the following is shown: (i) 2nd hour The amount of opioid analgesics released to is less than about 20% and (ii) released at 4 hours. The amount of opioid analgesics used ranges from about 10% to about 30%, (iii) at 8 hours. The amount of opioid analgesics released is from about 30% to about 60%, (iv) 12:00 The amount of opioid analgesics released in the interim is from about 50% to about 90%, or ( v) The amount of opioid analgesics released at 18 hours exceeds about 80%.

0104In certain embodiments, of an active agent released from the dosage form (eg, an opioid analgesic) The amount is US at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. Measured by in vitro elution in P device 1 (basket), 8 to 24 hours Proportional to overtime within 20% and at least one of the following is shown: (i) 2nd hour The amount of opioid analgesics released to is less than about 15% and (ii) released at 4 hours. The amount of opioid analgesics used ranges from about 10% to about 20%, (iii) at 8 hours. The amount of opioid analgesics released is from about 30% to about 45%, (iv) 12:00 The amount of opioid analgesics released in the interim is from about 50% to about 70%, or ( v) The amount of opioid analgesics released at 18 hours exceeds about 90%.

0105In certain embodiments, of an active agent released from the dosage form (eg, an opioid analgesic) The amount is US at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. Measured by in vitro elution in P device 1 (basket), 8 to 24 hours Proportional to overtime within 20% and at least one of the following is shown: (i) 2nd hour The amount of opioid analgesics released to is less than about 10% and (ii) released at 4 hours. The amount of opioid analgesics used ranges from about 20% to about 30%, (iii) at 8 hours. The amount of opioid analgesics released is from about 45% to about 60%, (iv) 12:00 The amount of opioid analgesics released in the interim is from about 70% to about 90%, or ( v) The amount of opioid analgesics released at 18 hours exceeds about 95%.

0106In certain embodiments, of an active agent released from the dosage form (eg, an opioid analgesic) The amount is US at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. Measured by in vitro elution in P device 1 (basket), 8 to 24 hours Proportional to overtime within 20% and at least one of the following is shown: (i) 2nd hour The amount of opioid analgesics released to is less than about 15% and (ii) released at 4 hours. The amount of opioid analgesics used ranges from about 8% to about 20%, and (iii) released at 8 hours. The amount of opioid analgesics given is from about 20% to about 50%, (iv) 12 hours The amount of opioid analgesics released into the eye ranges from about 40% to about 70%, (v) 18 The amount of opioid analgesics released at the hour exceeds about 70%, or (vi) 24 hours The amount of opioid analgesics released into the eye exceeds about 90%.

0107Dosage form In certain embodiments, the core is a controlled release material, an active agent, and optionally other To dry blend the excipients and then granulate the mixture until a suitable granulation is obtained. Can be prepared more. The process can be carried out by dry or wet granulation method it can. In wet granulation, wet granules are typically dried in a fluidized bed dryer and sized appropriately. Sift until crushed. When the lubricant is typically mixed with the granules, the final core formulation is can get.

0108Non-limiting of suitable controlled release materials that can be selected for inclusion in the formulations according to the invention. The list includes sustained release polymers, gums, acrylics, protein-derived materials, waxes, and shi. Hydrophilic and hydrophobic materials such as Elac, as well as hydrogenated castor oil and hydrogenated vegetable oils Including oils such as. More specifically, the controlled release material is, for example, ethyl cellulose or the like. Alkyl cellulose, acrylic acid and methacrylic acid polymers and copolymers, Hydroxyalkyl cellulose (eg, hydroxypropyl methylcellulose) And may be cellulose ethers such as carboxyalkyl cellulose. wax For example, natural and synthetic waxes, fatty acids, fatty alcohols, and blends thereof. Combinations (eg beeswax, carnauba wax, stearic acid and stearyl alcohol) Including. In one embodiment, two of the above controlled release materials in the core matrix Use the above mixture. However, it is possible to confer a controlled release of the active agent. A pharmaceutically acceptable hydrophobic or hydrophilic controlled release material of the choice is used in accordance with the present invention. be able to.

0109The core is an appropriate amount of additional excipients such as lubricants, binders, granulation aids, diluents, colorants, It may also contain flavoring agents (eg, bitterants) and flow enhancers, all of which It is customary in the field of pharmaceutical technology.

0110Of pharmaceutically acceptable diluents and excipients that can be used in formulating the core Specific examples are the Handbook of Pharmaceutical Excipie incorporated herein by reference. nts, described in the American Pharmaceutical Association (1986).

0111In a preferred embodiment, the matrix of dosage forms of the invention is polyethylene oxide ( Incorporate high molecular weight PEO and / or low molecular weight PEO).

0112Polyethylene oxide has a Brookfield viscosity at 10 rpm at 25 ° C. Is the total 2% (by weight) aqueous solution of PEO using RVF type, spindle No. 1 400? When showing the viscosity range of 800 mPa-s (cP), the approximate molecular weight of 1,000,000 is used. Considered to have.

0113Polyethylene oxide has a Brookfield viscosity at 10 rpm at 25 ° C. 2000 2% (by weight) aqueous solution of PEO using total RVF type, spindle No.3. 2,000,000 approximate molecules when showing a viscosity range from to 4000 mPa-s (cP) Considered to have a quantity.

0114Polyethylene oxide at 25 ° C, 2 rpm, Brookfield viscometer 1% (by weight) aqueous solution of polyethylene oxide using RVF type, spindle No.2. However, when showing a viscosity range of 1650 to 5500 mPa-s (cP), 4,000,00 It is considered to have an approximate molecular weight of 0.

0115Polyethylene oxide at 25 ° C, 2 rpm, Brookfield viscometer 1% (by weight) aqueous solution of polyethylene oxide using RVF type, spindle No.2. However, when showing a viscosity range of 5500 to 7500 mPa-s (cP), 5,000,00 It is considered to have an approximate molecular weight of 0.

0116Polyethylene oxide at 25 ° C, 2 rpm, Brookfield viscometer 1% (by weight) aqueous solution of polyethylene oxide using RVF type, spindle No.2. 7,000, when showing a viscosity range of 7500 to 10,000 mPa-s (cP) It is considered to have an approximate molecular weight of 000.

0117Polyethylene oxide at 25 ° C, 2 rpm, Brookfield viscometer 1% (by weight) aqueous solution of polyethylene oxide using RVF type, spindle No.2. Is 8,00 when showing a viscosity range of 10,000 to 15,000 mPa-s (cP) It is considered to have an approximate molecular weight of 0,000.

0118For low molecular weight polyethylene oxide, polyethylene oxide is at 25 ° C. At 50 rpm, the Brookfield viscometer RVT type, spindle No. 1 is used. A 5% (by weight) aqueous solution of ethylene oxide has a viscosity of 30-50 mPa-s (cP). It is considered to have an approximate molecular weight of 100,000 if it indicates a range.

0119Polyethylene oxide at 25 ° C, 2 rpm, Brookfield viscometer 5% (by weight) aqueous solution of polyethylene oxide using RVF type, spindle No. 2. However, when showing a viscosity range of 8800 to 17,600 mPa-s (cP), 900,00 It is considered to have an approximate molecular weight of 0.

0120Compression coated dosage form In embodiments that utilize a compression coating, it is pharmaceutically acceptable in the coating. All or part of the excipient (s) are sufficient to provide a pharmaceutically acceptable product. It is preferable that compressibility should be imparted. Compression coating on a preformed core The excipient is selected in terms of polymer solubility, fluidity, glass transition temperature, etc. And depends in part on the individual characteristics of the active agent.

0121The compression coated dosage form, for example, utilizes a pre-made core or coatin. It can be prepared by preparing the core prior to (eg, by compression). The inner core wet or dry granulates the active agent with pharmaceutically acceptable excipients, followed by Dried and milled as needed to obtain granules and optionally blended appropriately Add the selected extragranular excipient and / or active agent, and if necessary, add a lubricant, tablets It can be prepared by compressing the granules with an agent press. If the resulting compression core is By functional coating or film coating prior to compression coating Can be coated.

0122Blends for compression coatings use any of the controlled release materials disclosed above It can be prepared by the same process as the blend for the core used. Preferably, The compression coating includes polyethylene oxide. Blend on core by compression Can be coated on. Compression of the core and / or coating is, for example, Killion or Fette rotation with compressive force from about 1 to about 20 kilonewtons You can use the less.

0123In one embodiment, a Manesty Dry-Cota press (eg, Type 900). ) Can be used. This device is from two side-by-side interconnected tablet presses The core is made on one press and then goes to the next press for compression coating. Transferred mechanically. For each press, the core blend is loaded onto one machine and the coater It has an independent power supply mechanism so that the ing blend can be loaded on top of other machines. The mechanical transfer arm rotates between machines to remove the core from the core press and coat it. Transfer them to the press. Other formulations that can be used to prepare the dosage forms of the present invention Les is Elizabeth Hata HT-AP44-MSU-C; Killian Includes RLUD; and Fette PT 4090, each of which is a coatin It has a dual supply system for gblends and prefabricated cores. These presses When used, multiple compressions can be made by reusing tablets that are already compression coated. It is possible to achieve a coating layer. All of these presses are vertical and radial It has a mechanism to center the tablet in the coating blend in both directions.

0124In certain embodiments, the compression coating has the same thickness at all points around the inner core. Instead of being applied in, it is applied in different thicknesses around the inner core. It's a coating The thinner region produces a compressed dosage form region that releases the drug from the inner core faster than the other regions. Will. This means, for example, coating cores that have a compression coating applied. It can be easily carried out by not aligning with the center in the press at the time of pressing.

0125In certain embodiments, the compression coated dosage form is a hydrophobic or enteric coating. It can be further overcoated with a wing material. In other embodiments, pressure The crimp-coated dosage form is in addition to or those with hydrophobic or enteric coatings. Can be coated with a hydrophilic coating instead of.

0126In still further embodiments, an optional coat (eg, hydrophobic, hydrophilic or intestinal) Soluble) is applied alternative or additionally as an intermediate layer between the core and the compression coating Can be

0127Active drug Opioid analgesics useful in the present invention are alfentanyl, allylprodine, al. Faprodin, anileridine, benzylmorphine, veggie tramid, buprenorphine, buprenorphine Torfanol, Chronitazen, Codeine, Desomorphine, Dextromoramide, Dezoshi Diampromide, diamorphone, dihydrocodeine, dihydromol Hine, dimenoxador, dimepheptanol, dimethylthianbutene, dioxaf butyrate Etil, dipipanone, eptazosin, ethoheptazine, ethylmethylthianbutene, ethi Lumorphine, etnitazen, etorphine, dihydroetorphine, fentanyl and Derivatives, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemi Don, Levorphanol, Levophenacylmorphan, Lofentanil, Meperidine, Me Ptadinol, metazocin, methadone, metopon, morphine, mylofin, narcein, Nicomorphine, norle vorphanol, normetadon, nalorphine, nalbufen (na) lbuphene), normorphine, norpipanone, opium, oxycodone, oxymorphone, pa Paveletum, pentazocine, phenadoxone, phenomorphan, phenazocine, pheno Peridine, pyrimidine, pyritramide, propheptazine, promed Lu, properidine, propoxyphene, sufentanil, tilidine, tramadol, drugs Those doctrinal salts, complexes (eg with cyclodextrin), stereoisomers , Ethers, esters, hydrates, solvates, and mixtures, but limited to them. It is not something that can be done.

0128Preferably, the opioid analgesic is codeine, hydrocodone, hydromorphone, molch. Ne, oxycodone, oxymorphone, tramadol, their pharmaceutically acceptable salts, compound Is it a group consisting of coalescence, stereoisomers, ethers, esters, hydrates, solvates, and mixtures? Will be selected.

0129In certain embodiments, opioid analgesics are hydrocodone, which is pharmaceutically acceptable. Consists of salts, complexes, stereoisomers, ethers, esters, hydrates, solvates, and mixtures It is selected from the group. Preferably, the opioid analgesic is hydrocodone bitartrate.

0130Opioids used in accordance with the present invention may contain one or more asymmetric centers. Yes, may give rise to enantiomers, diastereomers, or other stereoisomeric forms .. The present invention presents all such possible forms as well as those racemic and divided. Means to include the use of forms and their compositions. Described herein E and Z if the compound contains an olefinic double bond or other center of geometric asymmetry It is intended to include both geometric isomers of. All tautomers are books as well It is intended to be included by the invention.

0131Pharmaceutically acceptable salts are inorganic salts such as hydrochlorides, hydrobromic acids, sulfates, phosphates; Organic acids such as formate, acetate, trifluoroacetic acid, maleate, tartrate; methane Sulfates such as sulfonates, benzene sulfonates, p-toluene sulfonates; Amino acid salts such as arginate, aspartate, glutamate; nato Metal salts such as lysium salt, potassium salt, cesium salt; calcium salt, magnesium salt, etc. Alkaline earth metals; and triethylamine salts, pyridine salts, picoline salts, ethanol salts Min salt, triethanolamine salt, dicyclohexylamine salt, N, N'-dibenzyle Includes, but is not limited to, organic amine salts such as thirienamine salts.

0132In addition, active agents other than opioid analgesics that are potentially abused are in accordance with the present invention. Can be used. Such agents are, among other things, tranquilizers, the central nervous system, among others. Inhibitors, central nervous system stimulants, sedatives, hypnotics, stimulants (phenylpropanolamine, etc.) Includes appetite suppressants), and cannabinoids. More specifically, active drugs The agents are phenobarbital, secobarbital, pentobarbital, butabarbital. , Tarbutal, Approbarbital, Mefobarbital, Butalbital, Pharmaceutically Barbiturates such as those salts that are acceptable; diazepam, chlordiazepoxide, a Luprazolam, triazolam, estazolam, clonazepam, flunitrazepam, pharmaceutical Tolerable salts such as benzodiazepines; gamma-hydroxybutyrate, dext Loamphetamine, Methylphenidate, Sibutramine, Methylenedioxymethanefeta Stimulants such as min, their pharmaceutically acceptable salts; marinol, meprobamate and Other drugs such as carisoprodol; as well as all pharmaceutically acceptable salts of them, compound Choose from coalescing, stereoisomers, ethers, esters, hydrates, solvates, and mixtures be able to.

0133In a further embodiment, other therapeutically active agents may be used alone or in combination with opioids. Together, they can be used in accordance with the present invention. Examples of such therapeutically active agents are anti Histamine drugs (eg dimenhydrinate, diphenhydramine, chlorpheniramine) And dexchlorpheniramine maleate), non-steroidal anti-inflammatory drugs (eg, nappe) Lokisen, diclofenac, indomethacin, ibuprofen, sulindac, Cox-2 Inhibitors), acetaminophen, antiemetics (eg, metoclopramide, methylnaltreki) Son), antiepileptic drugs (eg, phenyloin), meprobmate ) And nitrazepam), vasodilators (eg nifedipine, papaverine, zirchiaze) Mu and nicardipine), antitussives and expectorants, anti-asthmatic drugs (eg, theophylline), control Acid drugs, antispasmodics (eg atropine, scopolamine), anti-diabetic drugs (eg insulin) ), Diuretics (eg etacrynic acid, bendrofluthiazide), Antihypotensive drugs (eg propranolol, clonidine), antihypertensive drugs (eg clonidine) , Methyldopa), bronchodilators (eg, albuterol), steroids (eg, albuterol) Hydrocortisone, triamcinolone, prednisone), antibiotics (eg tetrasai) Clean), anti-hemorrhoids, psychotropic drugs, antidiarrheals, mucolytics, decongestants (eg, Psoidoe) Fedrin), laxatives, vitamins, and their pharmaceutically acceptable salts, complexes, standing Includes isomers, ethers, esters, hydrates, solvates, and mixtures.

0134Hydrocodone Embodiment The controlled release oral dosage form of the present invention is preferably hydrocodone from about 0.5 mg to about 1250. Includes up to mg or equivalent of the pharmaceutically acceptable salt. In other embodiments, the agent The form is hydrocodone from about 2 mg to about 200 mg or equivalent pharmaceutically acceptable. Salt, or hydrocodone from about 16 mg to about 120 mg or equivalent pharmaceutically acceptable Contains that salt that can be made. In certain preferred embodiments, the dosage form is choline bitartrate. About 20 mg, about 30 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg or Contains about 120 mg.

0135Suitable pharmaceutically acceptable salts of hydrocodone are hydrocodone bitartrate, choline bitartrate. Locodon hydrate, hydrocodone hydrochloride, hydrocodone p-toluenesulfonic acid, hydrophosphate Locodon, hydrocodone thiosemicarbazone, hydrocodone sulfate, trifluoroacetate hydride Locodone, Hydrocodone Hemi pentahydrate, Hydrocodone pentafluoropropionate, Hydone Locodone p-nitrophenyl hydrazone, hydrocodone o-methyloxime, hydrocodone Semicarbazone, hydrocodone hydrobromide, hydrocodone mucodone, hydrocodone oleate Don, dibasic hydrocodone phosphate, monobasic hydrocodone phosphate, hydrocodone inorganic salt , Hydrocodone Organic Salt, Hydrocodone Acetate Trihydrate, Bis (Heptafluorobutyric Acid) Hydro Codon, bis (methylcarbamic acid) hydrocodone, bis (pentafluoropropionic acid) ) Hydrocodone, bis (pyridinecarboxylic acid) Hydrocodone, bis (trifluoroacetic acid) Hydrocodone, hydrocodone chlorhydrate, and hydrocosulfate Includes don pentahydrate. Preferably, hydrocodone is present as a choline bitartrate.

0136The hydrocodone dosage form of the present invention acts synergistically with the hydrocodone contained therein. It may further include one or more additional drugs that may or may not be included. Such an additional Examples of drug additions are ibuprofen, diclofenac, naproxen, benoxaprofen, Flurbiprofen, fenoprofen, flubufen, ketoprofen, Indiaprofen, piroprofen, carprofen, oxaprozin, Pramoprofen, muroprofen, trioxaprof En (trioxaprofen), suprofen, aminoprofen, tiaprofenic acid, flupro Fen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepyrac, thiopi Naku, Jidomethasin, Acemetacin, Fentiazak, Kuridanak, Oxpinak (oxpi) nac), mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid Acid, diflurisal, flufenisal, piroxicam, sudoxicam, i Soxycams and their pharmaceutically acceptable salts, complexes, stereoisomers, ethers, d. Includes non-steroidal anti-inflammatory drugs, including stealths, hydrates, solvates and mixtures. Such non-steroidal anti-inflammatory drugs include celecoxib, meloxicam, nabumetone, nime. Slides and their pharmaceutically acceptable salts, complexes, stereoisomers, ethers, esthetics Includes cyclooxygenase inhibitors such as hydrates, hydrates, solvates and mixtures.

0137Other additional drugs that can be co-formulated with hydrocodone are dextrolphan, de Xystrometolphan, 3- (1-naphthalenyl) -5- (phosphonomethyl) -L-fe Nylalanine, 3- (1-naphthalenyl) -5- (phosphonomethyl) -DL-phenyla Lanin, 1- (3,5-dimethylphenyl) naphthalene, 2- (3,5-dimethylphenyl) Le) Naphthalene, 2SR, 4RS-4-(((1H-tetrazol-5-yl) methyl) Oxy) piperidine-2-carboxylic acid, 2SR, 4RS-4-((((1H-tetrazo)) Lu-5-yl) methyl) oxy) methyl) piperidine-2-carboxylic acid, E and Z 2 SR-4- (O- (1H-tetrazol-5-yl) methyl) ketoximino) piperidine -2-Carboxylic acid, 2SR, 4RS-4-((1H-tetrazol-5-yl) thio) Peridine-2-carboxylic acid, 2SR, 4RS-4-((1H-tetrazole-5-yl)) Thio) Piperidine-2-carboxylic acid, 2SR, 4RS-4- (5-mercapto-1H-te) Trazol-1-yl) piperidine-2-carboxylic acid, 2SR, 4RS-4- (5-mel) Capto-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-tetrazol-2-yl) piperidine -2-Carboxylic acid, 2SR, 4RS-4-(((1H-tetrazole-5-yl) thio) Methyl) piperidine-2-carboxylic acid, 2SR, 4RS-4-((5-Mercapto-1H) -Tetrazole-1-yl) methyl) piperidine-2-carboxylic acid, 2SR, 4RS-4 -((5-Mercapto-2H-tetrazol-2-yl) methyl) piperidine-2-cal Bonic acids, as well as their pharmaceutically acceptable salts, complexes, stereoisomers, ethers, es Includes NMDA receptor antagonists such as tells, hydrates, solvates and mixtures.

0138Other suitable drugs that may be included in the hydrocodone dosage forms of the invention are acetaminophen. And aspirin included.

0139In a preferred embodiment, the hydrocodone formulation of the present invention is suitable for once-daily administration. It provides a relatively flat plasma profile and plasma levels of hydrocodone are about after administration. 0.55 to about 1.0 C₂₄/ C_maxMeans to provide a ratio. In one embodiment Put, C₂₄/ C_maxThe ratio is from about 0.55 to about 0.85, about 0.55 after administration of the dosage form. From about 0.75 or from about 0.60 to about 0.70.

0140In a preferred embodiment, the hydrocodone preparation of the present invention is about 4 to about 20:00 after administration. Hydrocodone T up to_maxProvide (h). In certain embodiments, T_maxIs , About 6 to about 12 hours, about 8 to about 10 hours, about 4 to about 10 hours, about 8 after administration of the dosage form From about 14 hours, or from about 14 to about 20 hours.

0141In yet another embodiment, the solid controlled release dosage form of the present invention is contained in the dosage form. About 200-450 or about 200 mg each of locones or their pharmaceutically acceptable salts AUC (ng) after 250-400 doses^*h / mL) is provided.

0142In certain embodiments, it contains 20 mg of hydrocodone or a pharmaceutically acceptable salt thereof. Solid controlled release forms to be from about 200 to about 450, about 250 to about 400, from about 275 AUC (ng) after administration of about 350, about 300 to 330 or about 280 to about 320^*h / mL) is provided.

0143In certain embodiments, it comprises 120 mg of hydrocodone or a pharmaceutically acceptable salt thereof. The solid controlled release form has about 1000 to about 3000, about 1500 to about 2400, about 1700 to about 2200, about 1800 to 2100 or about 1900 to about 2100 throws AUC (ng) after giving^*h / mL) is provided.

0144In other embodiments, the solid controlled release dosage form of the invention is a hydrocode contained in the dosage form. C after administration of about 5 to about 40 and about 10 to 30 per 20 mg each_max(ng / mL) I will provide a.

0145In certain embodiments, it contains 20 mg of hydrocodone or a pharmaceutically acceptable salt thereof. Solid controlled release forms to be about 5 to about 40, about 10 to about 30, about 12 to about 25, about 1 C after administration of 4 to 18 or about 12 to about 17_maxProvide (ng / mL).

0146In certain embodiments, it comprises 120 mg of hydrocodone or a pharmaceutically acceptable salt thereof. The solid controlled release form has about 30 to about 120, about 60 to about 180, about 100 to about C after administration of 160, about 110 to 150 or about 100 to about 140_max(ng / m L) is provided.

0147In certain embodiments, the solid controlled release dosage forms of the present invention are about 7 to about 22, 10 to about 2 Hydrocode after administration of 0, about 12 to about 18, about 13 to about 17 or about 14 to about 16 T_maxProvide (h).

0148In other embodiments, the solid controlled release dosage forms of the invention are from about 5 to about 10, about 6 to about 9. Hydrocodone T after administration of about 7 or about 8_1/2Provide (h).

0149In other embodiments, the solid controlled release dosage forms of the invention are from about 0.01 to about 0.2, about 0. After administration of .1 to about 0.18, about 0.3 to about 0.17 or about 0.06 to about 0.15 Hydrocodone T_lagProvide (h).

0150In other embodiments, the solid controlled release dosage forms of the invention are from about 0.2 to about 0.8, about 0. C of hydrocodone from 3 to about 0.7, or about 0.4 to about 0.6₂₄/ C_maxPropose a ratio To serve.

0151In certain embodiments, any one or all of the above average in vivo parameters Achieved after administration in a fasted state.

0152In certain embodiments, the average AUC (ng) of hydrocodone after administration in a feeding state^*h / mL) is the AUC (ng) of hydrocodone after administration in the fasted state.^*20% less than h / mL) Fully high, less than 16% higher or less than 12% higher.

0153In certain embodiments, the average C of hydrocodone after administration in a feeding state_max(ng / m L) is the C of hydrocodone after administration in the fasted state._maxLess than 80% higher than (ng / mL) Less than 70% higher or less than 60% higher.

0154In certain embodiments, the average T of hydrocodone after administration in a feeding state_max(h) is Hydrocodone T after fasting administration_maxWithin 25%, within 20% or above 15% Is inside.

0155In certain embodiments, the average T of hydrocodone after administration in a feeding state_1/2(h) is T after administration in a fasted state_1/2Within 8%, within 5% or within 2%.

0156In certain embodiments, the average T of hydrocodone after administration in a feeding state_lagIs fasting T after administration in the state_1/2Less than 150% higher, less than 125% higher or less than 100% higher I.

0157In certain embodiments, any one or all of the above in vivo parameters will be Subject, patient, or healthy subject (individual data) or human subject, patient or healthy subject Achieved after the first dose of dosage form to the population (mean data).

0158In certain alternative embodiments, any one or all of the above in vivo parameters To a population of human subjects, patients, or healthy subjects or human subjects, patients or healthy subjects Achieved after steady-state administration of the dosage form.

0159Hardened product In certain embodiments, the process of the invention further steps to cure the final dosage form. Including.

0160For embodiments that include polyethylene oxide in the controlled release formulation, the curing step is: It may include melting the polyethylene oxide in the formulation at least partially. A certain fruit In the embodiment, at least about 20% or at least about 20% or at least of polyethylene oxide in the formulation. About 30% melts. Preferably, at least about 40% of the polyethylene oxide in the formulation. , Or at least about 50%, or at least about 60%, or at least about 75%, Or at least about 90% melts during the curing step. In a preferred embodiment About 100% of polyethylene oxide melts.

0161In another embodiment, the curing step is to expose the formulation to high temperature over a period of time. including. In such an embodiment, the curing temperature is the softening temperature of polyethylene oxide. At least the same height. According to one embodiment, 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, about 62 ° C From about 80 ° C, from about 65 ° C to about 90 ° C, from about 65 ° C to about 85 ° C, or about 6 It ranges from 5 ° 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, It ranges from about 72 ° C to about 85 ° C or from about 72 ° C to about 80 ° C. Curing temperature is At least about 60 ° C, at least about 62 ° C, less than about 90 ° C or less than about 80 ° C I. Preferably, it is from about 62 ° C to about 72 ° C or from about 68 ° C to about 72 ° C. The range. Preferably, the curing temperature is below and below the softening temperature range of polyethylene oxide. At least the same height, or at least about 62 ° C, or at least about 68 ° C. Than Preferably, the curing temperature is within or less than the softening temperature range of polyethylene oxide. Both are about 70 ° C. In a further embodiment, the curing temperature is that of polyethylene oxide. At least as high as the upper limit of the softening temperature range, or at least about 72 ° C. Sa In the above embodiments, the curing temperature is above the upper limit of the softening temperature range of polyethylene oxide. Also high, or at least about 75 ° C, or at least about 80 ° C.

0162Those embodiments in which the curing step exposes the formulations to high temperatures over a period of time. In, this period is hereinafter referred to as curing time. For measuring the curing time, cure The start and end points of the tep are defined. For the purposes of the present invention, the starting point of the curing step is It is defined as the time when the curing temperature is reached.

0163In certain embodiments, the temperature profile during the curing step is the starting and ending points of curing. Shows a plateau-like morphology between. In such an embodiment, the end point of the curing step is, for example, For example, by ending or reducing heating and / or initiating subsequent cooling steps. By, it is defined as the time when heating is stopped or at least reduced, and the temperature is Subsequently, above about 10 ° C and below the curing temperature and / or of polyethylene oxide. It drops below the lower limit of the softening temperature range, for example below about 62 ° C. Reached the curing temperature and If the curing step is started, a deviation from the curing temperature will occur during the process of the curing step. I may mess with it. Such deviations are such that they are about ± 10 ° C, preferably about ± 6 ° C. Preferably, it is acceptable as long as it does not exceed a value of about ± 3 ° C. For example, at least about 75 ° C If the curing temperature is to be maintained, the measured temperature is about 85 ° C, about 81 ° C, or about 78 ° C. The value may be temporarily increased to the value of about 65 ° C, about 69 ° C or about 72 ° C. May be temporarily lowered. If the temperature is significantly reduced and / or the temperature is Polje When the temperature drops below the lower limit of the softening temperature range of chillene oxide, for example, below about 62 ° C. The curing step is aborted, i.e. reaching the end point. Curing reaches curing temperature again It can be restarted by.

0164In other embodiments, the temperature profile during the curing step is the starting and ending points of curing. Shows a parabolic or triangular morphology between. This reaches the starting point, the curing temperature. After a point in time, it means that the temperature further increases to reach the maximum value and then decreases. In such an embodiment, the end point of the curing step is when the temperature drops below the curing temperature. Defined as a point.

0165Different temperatures within the curing device, depending on the device used for curing (ie, the curing device) The degree can be measured and the curing temperature can be characterized.

0166In certain embodiments, the curing step may occur in the oven. Such an embodiment In the state, the temperature inside the oven is measured. Based on that, the curing step is If it occurs in a bun, the curing temperature is defined as the target internal temperature of the oven and the curing temperature The starting point of the oven is defined as the time when the internal temperature of the oven reaches the curing temperature. Hard The end points of the conversion step are: (1) heating is stopped or at least reduced and inside the oven The temperature subsequently exceeds the cure temperature above about 10 ° C with a plateau-like temperature profile. And / or below the lower limit of the softening temperature range of high molecular weight polyethylene oxide, eg, about When the temperature drops below 62 ° C, or (2) the temperature inside the oven is parabolic or triangular. It is defined in the temperature profile as the point at which the temperature drops below the curing temperature. Preferably cured The step is that the temperature inside the oven is at least about 62 ° C, at least about 68 ° C, less When reaching a curing temperature of about 70 ° C, at least about 72 ° C or at least about 75 ° C To start. In a preferred embodiment, the temperature profile during the curing step is plat. It has a -like morphology, and the curing temperature, that is, the internal temperature of the oven, is at least about 68 ° C, about 70 ° C, about 72 ° C, about 73 ° C, or in the range of about 70 ° C to about 75 ° C and hardened The time is preferably from about 30 minutes to about 20 hours, from about 30 minutes to about 15 hours, about 3 It ranges from 0 minutes to about 4 hours, or from about 30 minutes to about 2 hours. In one embodiment The curing time is in the range of about 30 minutes to about 90 minutes.

0167In some other embodiments, the curing is heated by an air stream and the heated air supply (inlet) And in a curing device that includes exhaust, such as a coating pan or fluidized bed. Like that Such a curing device will be hereinafter referred to as a convection curing device. In such a curing device The temperature of the intake air, that is, the temperature of the heated air entering the convection curing device and / or the temperature of the exhaust air, That is, it is possible to measure the temperature of the air leaving the convection curing device. For example, infrared By using a temperature measuring device (such as an IR gun) or inside a curing device near the formulation Convection curing during the curing step by measuring the temperature using a placed temperature probe It is also possible to determine or at least estimate the temperature of the formulation inside the device. Based on that If the curing step occurs in a convection curing device, the curing temperature can be defined and hard The conversion time can be measured as follows.

0168In one embodiment (Method 1), the curing temperature is defined as the target intake temperature and is cured. The starting point of the tep is defined as the time when the intake air temperature reaches the curing temperature. Curing step At the end of (1) heating is stopped or at least reduced, the intake air temperature is followed by plastic Toe-like temperature profile, above about 10 ° C and below curing temperature and / or high It drops below the lower limit of the softening temperature range of polyethylene oxide, for example, less than about 62 ° C. Time point, or (2) Inspiratory temperature below curing temperature in parabolic or triangular temperature profile It is defined as the time of descent to. Preferably, the curing step has a lower intake temperature. With about 62 ° C, at least about 68 ° C, at least about 70 ° C, at least about 72 ° C or less If the curing temperature reaches at least about 75 ° C, start according to Method 1. Preferred implementation In morphology, the temperature profile during the curing step shows a plateau-like morphology and the curing temperature. That is, the target intake temperature is preferably at least about 72 ° C, for example about 75 ° C. The curing time measured according to Method 1 is preferably from about 15 minutes to about 2 hours, eg. For example, it ranges from about 30 minutes to about 1 hour.

0169In another embodiment (Method 2), the curing temperature is defined as the target exhaust temperature and curing The starting point of the step is defined as the time when the exhaust temperature reaches the curing temperature. Curing step The end point of the pump is (1) the heating is stopped or at least reduced, and the exhaust temperature is followed by the pump. Latero-like temperature profile, above about 10 ° C and below curing temperature and / or high It drops below the lower limit of the softening temperature range of molecular weight polyethylene oxide, for example, less than about 62 ° C. At some point, or (2) the exhaust temperature is not cured in a parabolic or triangular temperature profile. It is defined as the time of full descent. Preferably, the curing step has a low exhaust temperature. At least about 62 ° C, at least about 68 ° C, at least about 70 ° C, at least about 72 ° C or Start according to Method 2 when a curing temperature of at least about 75 ° C is reached. Preferred fruit In the embodiment, the temperature profile during the curing step shows a plateau-like morphology and the curing temperature. The degree, i.e., the target exhaust temperature, is preferably at least about 68 ° C, at least about 70 ° C. Or at least about 72 ° C, for example, the target exhaust temperature is about 68 ° C, about 70 ° C, about 7 The curing time is preferably 2 ° C, about 75 ° C or about 78 ° C and measured according to Method 2. Ranges from about 1 minute to about 2 hours or from about 5 minutes to about 90 minutes, eg, cures The time is about 5 minutes, about 10 minutes, about 15 minutes, about 30 minutes, about 60 minutes, about 70 minutes, about 75 minutes or It takes about 90 minutes. In a more preferred embodiment, the cure time measured according to Method 2 is It ranges from about 15 minutes to about 1 hour.

0170In a further embodiment (Method 3), the curing temperature is defined as the target temperature of the formulation. The starting point of the curing step is, for example, the temperature of the formulation, which can be measured by an IR gun. It is defined as the time when the curing temperature is reached. At the end of the curing step, (1) heating stops Stopped or at least reduced, the temperature of the formulation is followed by a plateau-like temperature profile. , Above about 10 ° C and below the curing temperature and / or high molecular weight polyethylene oxide Below the lower limit of the softening temperature range of, for example, when the temperature drops below about 62 ° C, or (2) of the formulation. When the temperature drops below the curing temperature in a parabolic or triangular temperature profile Defined. Preferably, the curing step results in a lower formulation temperature of at least about 62 ° C. Hard at about 68 ° C, at least about 70 ° C, at least about 72 ° C or at least about 75 ° C When the conversion temperature is reached, start according to Method 3.

0171In yet another embodiment (method 4), the curing temperature is within the curing apparatus near the formulation. The target temperature measured using a temperature probe such as a wire thermocouple placed in the section. The starting point of the curing step is the temperature measured using the temperature probe, which is defined as curing. It is defined as the time when the temperature is reached. At the end of the curing step, (1) heating is stopped. The temperature, which is at least reduced and measured using a temperature probe, is subsequently platted. -Like temperature profile, above about 10 ° C and below curing temperature and / or polye Below the lower limit of the softening temperature range of chillene oxide, for example, when it drops below about 62 ° C, and (2) The temperature measured using the temperature probe is a parabolic or triangular temperature profile. It is defined as the time when the temperature drops below the curing temperature in the ill. Preferably, the curing step is The temperature measured using the temperature probe is at least about 62 ° C, at least about 68 ° C, Temperature in the curing device at least about 70 ° C, at least about 72 ° C or at least about 75 ° C Start when recording. In a preferred embodiment, the temperature profile during the curing step Il shows a plateau-like morphology with a curing temperature of at least about 68 ° C, for example about 70 ° C. Yes, the curing time measured according to Method 4 is preferably from about 15 minutes to about 2 hours. Range or about 60 minutes or about 90 minutes.

0172If curing occurs in a convection curing device, the curing time is one of the methods described above. It can be measured by either.

0173In certain embodiments, the curing temperature is defined as the target temperature range, for example, the curing temperature is the eye. It is defined as the target intake temperature range or the target exhaust temperature range. In such an embodiment, hard The starting point of the conversion step is defined as the time when the lower limit of the target temperature range is reached, and the curing step is defined. At the end of the pump, heating is stopped or at least reduced, and the temperature subsequently exceeds about 10 ° C. Below the lower limit of the target temperature range and / or the softening temperature range of polyethylene oxide It is defined as the time when it falls below the lower limit of the enclosure, for example, below about 62 ° C.

0174For example, a cure time that can be measured according to the method described above, i.e. The time that the formulation is exposed to the curing temperature is at least about 1 minute or at least about 5 minutes. .. Curing time is from about 1 minute to about 24 hours, about 5 depending on the specific formulation and curing temperature. From minutes to about 20 hours, from about 10 minutes to about 15 hours, from about 15 minutes to about 10 hours, It can vary from about 30 minutes to about 5 hours. According to one embodiment, the curing time is It changes from about 15 minutes to about 30 minutes. 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 or varies from about 62 ° C to about 85 ° C or from about 65 ° C to about 85 ° C According to the embodiment, the curing time is preferably at least 15 minutes and 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. Curing temperature is, for example, at least about 62 ° C, at least about 68 ° C, low At least about 70 ° C, at least about 72 ° C or at least about 75 ° C, or from about 62 ° C Up 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 Hard in preferred embodiments ranging from 80 ° C or from about 72 ° C to about 80 ° C. The conversion time is preferably at least about 1 minute, at least about 5 minutes, at least about 10 minutes, and less. At least about 15 minutes or at least about 30 minutes. In certain such embodiments, Curing time is still achieving the desired result (eg, increased resistance to tampering) You can choose to be as short as possible. For example, the curing time is preferably about 5 o'clock. No time, no more than about 3 hours, no more than about 2 hours. Preferably, the curing time is About 1 minute to about 5 hours, about 5 minutes to about 3 hours, about 15 minutes to about 2 hours, or It ranges from about 15 minutes to about 1 hour. Of curing temperature and curing time as disclosed herein Any combination is within the scope of the present invention.

0175In certain embodiments, the composition is such that the polyethylene oxide present in the formulation is soft. To be exposed to curing temperature until it reaches the conversion temperature and / or at least partially melts Not too much. In certain such embodiments, the curing time may be less than about 5 minutes, eg For example, the curing time is from over 0 minutes to about 3 hours, from about 1 minute to about 2 hours, or from about 2 minutes. It may change up to about 1 hour. Instant curing has less high molecular weight polyethylene oxide Polyethylene oxy in the formulation at least up to its softening temperature so that it also partially melts This is possible by selecting a curing device that enables instantaneous heating of the dough. Such hardened equipment The device is, for example, a light irradiation device such as a microwave oven, an ultrasonic device, a UV-irradiation device, or a super High frequency (UHF) electromagnetic fields or any other device known to those of skill in the art.

0176The size of the formulation depends on the curing time required to achieve the desired tamper resistance. And may determine the curing temperature.

0177In certain embodiments, the curing step leads to a decrease in the density of the formulation, resulting in a dense formulation. The degree is lower than the density of the formulation prior to the curing step. Preferably, the density of the cured product is It is reduced by at least about 0.5% compared to the density of the uncured product. More preferably made of cured The density of the agent is at least about 0.7% and at least about 0.8% compared to the density of the uncured product. , At least about 1.0%, at least about 2.0% or at least about 2.5%.

0178In certain embodiments, the solid controlled release dosage form is at least 1 minute, at least 5 minutes or Hard at least at the temperature of the softening point of polyethylene oxide for at least 15 minutes Be transformed.

0179In other embodiments, the solid controlled release dosage form is from about 1 minute to about 48 hours, from about 5 minutes. Low polyethylene oxide for up to about 24 hours, from about 15 minutes to about 1 hour or about 30 minutes It cures at least at the softening point temperature.

0180The solid controlled release form is, for example, at least about 60 ° C, at least about 65 ° C, at least Curing at a temperature of about 70 ° C, at least about 75 ° C or at a temperature of about 72 ° C Can be done.

0181In an alternative embodiment, is the solid controlled release dosage form from about 60 ° C to about 90 ° C, about 62 ° C? From about 72 ° C, from about 65 ° C to about 85 ° C, from about 70 ° C to about 80 ° C, from about 75 ° C It can be cured at temperatures up to about 80 ° C or from about 70 ° C to about 75 ° C.

0182Flattening procedure In certain embodiments, the dosage forms of the invention substantially reduce the release of the active substance or the integrity of the dosage form. It can be flattened without damage. Flatness is the ratio to the thickness of the minimum diameter of the unflattened shape It is described in terms of the thickness of the minimum diameter of the flattened shape compared. This comparison is based on (i) initial shape. Is the minimum diameter thickness of the non-flattened shape when is non-spherical or (ii) the initial shape is spherical It is expressed in% thickness based on the thickness of the diameter in some cases. The thickness is a thickness gauge (for example, de It can be measured using a digital thickness gauge (or digital caliper). Flattening The force can be applied by any possible method. Purpose of testing the dosage form of the present invention For the purpose of carver style bench press (unless otherwise specified), target flat Can be used to achieve degree / thickness reduction. According to certain embodiments of the present invention Flattening does not result in disruption of the dosage form into separate fragments, but edge splits and Cracks may occur.

0183In certain embodiments of the invention, a hammer can be used to flatten the dosage form. Wear. In such a process, the hammer blow substantially hangs on the thickest dimension of the dosage form. It can be applied manually from a straight direction. Then the flatness is as disclosed above It is described in the same way.

0184In other embodiments, flattening uses a Schleuniger MFP. For use, Remington's Pharmaceutical Sciences, 18th Edition, 1990, Chapter 89, "Oral Solid Do In connection with fracture strength or hardness testing, as described in sage Forms, pp. 16331665 Can be measured. In such an embodiment, the dosage form has a force, the thickest dimension of the dosage form. Applied substantially perpendicular to the method, thereby arranging in parallel so as to flatten the dosage form Pressed between a pair of flat plates. Dosage form flattening is flattening before the fracture strength test. It can be described from the viewpoint of% flattening based on the thickness of the dimensions. destruction strength( Alternatively, hardness) is defined as the force at which the test dosage form breaks. Not broken, but applied Dosage forms that are deformed due to a force are considered to be fracture resistant at that particular force.

0185Further testing to quantify the strength of the dosage form is the TA-XT2 Texture Analyzer -(Texture Analyzer) (Texture Technologies Corp., 1 8 Fairview Road, Scarsdale, NY10583) This is a press-fit test using a camphor analyzer. In this method, the dosage form has a surface Placed on top of a slightly recessed stainless steel stand, TA-8A 1/8 A descent of a texture analyzer such as a stainless steel ball probe with a ninch diameter Invaded by a robe. Before starting the measurement, the dosage form is aligned directly under the probe and The force of the descent probe is such that it penetrates into the center, i.e., the center of the dosage form. The application is made to be applied substantially at right angles to the diameter and substantially along the thickness of the dosage form. First, the texture analyzer probe is directed towards the dosage form sample at pretest speed. It starts to move. When the probe comes into contact with the dosage form surface and reaches the set trigger force, the pro The move continues its movement at test speed and invades the dosage form. Depth or distance of each penetration of the probe For separation, the corresponding force is measured. When the probe reaches the desired maximum penetration depth If so, the probe changes direction and returns at post-test velocity, with further measurements. Crack The force is defined as the first maximum force reached in the corresponding force / distance diagram. For example, the texture analyzer software "Texture Expert E" Calculated using xceed, Version 2.64 English.

0186The term "crush resistant" refers to about 6 for the purposes of certain embodiments of the present invention. Thickness of 0% or less, preferably about 50% or less, more preferably about 40% or less Even more preferably, the thickness is about 30% or less, most preferably about 20% or less. Less on the bench press listed above, without breaking up to 10% or 5% thickness It is defined as referring to a dosage form that can at least flatten.

0187In certain embodiments, the active agent released from the flattening form at 0.5 hour (eg, eg) The amount of opioid analgesic) is in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. Non-measured by in vitro elution in USP apparatus 1 (basket) at 100 rpm Approximately 10 percentage points, 15 percentage points or more from the amount released 0.5 hours from the flattening form Deviations less than 20 percentage points.

0188In an alternative embodiment, the solid controlled release dosage form can be flattened without breaking and is flat. The thickness of the dosage form after flattening is about 60% or less of the thickness of the dosage form before flattening, and about the thickness of the dosage form before flattening. 50% or less, about 40% or less of the thickness of the dosage form before flattening, about 30% or more of the thickness of the dosage form before flattening Corresponds to about 20% or less of the thickness of the lower or unflattened dosage form.

0189The following examples are described to aid in the understanding of the present invention and are described herein and patented. It should not be construed as specifically limiting the invention described in the claims. Our business A book that includes all currently known or upcoming equivalent substitutions within the scope of the person. Such variants of the invention, and changes in the formulation or experimental design, are described in the book. It should be considered to be within the scope of the invention incorporated in the detail book.

<p num="0190"> The present invention will then be described more fully with reference to the accompanying examples. But what The following description is merely an example and should never be taken as a limitation of the present invention. Should be understood. (Example 1)</p><p num="0191"> 400 mg tablets (Tablet A) containing 20 mg of hydrocodone bitartrate are listed in Table 1 below. High molecular weight polyethylene oxide (PEO 303-MW 7,00) as listed Prepared using 0,000).</p><p num="0192"><tables num="1"><img id="000002" he="50" wi="159" file="JP6232025B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0193"> Single Station Manesty Type F 3 Tablets to Prepare Core I attached a 7.94mm, circular, standard concave plain tooling to the less. Core blend Powdered aliquots, as listed above in Table 1, by the target weight of 200 mg It was separated, placed in a mold, and compressed to form the core of Tablet A.</p><p num="0194"> Single Station Manesty Type F 3 Tablets to Prepare Shell The press was fitted with 10.32 mm, circular, standard concave plain tooling. 100m The g-shell blend was placed in the mold as shown in Table 1. As prepared above Manually center the tablet core in the mold (on the powder bed) and add an additional 100 mg The gel blend was placed on top of the tablet in the mold. Then rotate the material, compression wheel The tablets A were manually compressed to form a compression-coated tablet A.</p><p num="0195"> Place some compression-coated tablets A tablets prepared as above on a tray Enter the Hotpack 43 5304 oven with a target of 72 ° C for 30 minutes. And cured.</p><p num="0196"> The elution of the cured tablet A tablet is then performed at 37 ° C with enzyme-free simulated gastric juice (SGF) 900. Tested in USP apparatus 1 (basket) at 100 rpm in mL. The results are shown in Figure 1. It is shown for the results of the formulations of Examples 2-4. (Example 2)</p><p num="0197"> A 500 mg tablet (Tablet B) containing 20 mg of hydrocodone bitartrate is listed in Table 2 below. High molecular weight polyethylene oxide (PEO 303-MW 7,00) as listed Prepared using 0,000).</p><p num="0198"><tables num="2"><img id="000003" he="50" wi="159" file="JP6232025B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0199"> Single Station Manesty Type F 3 Tablets to Prepare Core 8.73mm, round, standard concave plain tooling was attached to the less. Core blend Powdered aliquots, as listed above in Table 2, by the target weight of 300 mg It was separated, placed in a mold, and compressed to form the core of Tablet B.</p><p num="0200"> Single Station Manesty Type F 3 Tablets to Prepare Shell The press was fitted with 11.11 mm, circular, standard concave plain tooling. 200m The first part of the g-shell blend was placed in a mold as described above in Table 2. Above Manually center the tablet core as prepared (on the powder bed) in the mold, 20 The rest of the 0 mg shell blend was placed on top of the tablet in the mold. Then the material, Manually compress by rotating the compression wheel to form a compression-coated tablet B It was done.</p><p num="0201"> Place some compression-coated tablets B tablets prepared as above on a tray Enter the Hotpack 43 5304 oven with a target of 72 ° C for 30 minutes. And cured.</p><p num="0202"> The elution of hardened tablets B tablets is then performed at 37 ° C with enzyme-free simulated gastric juice (SGF) 900. Tested in USP apparatus 1 (basket) at 100 rpm in mL. The results are shown in Figure 1. It is shown for the results of the formulations of Examples 1 and 3-4. (Example 3)</p><p num="0203"> 500 mg tablets (tablets C) containing 20 mg of hydrocodone bitartrate are listed in Table 3 below. High molecular weight polyethylene oxide (PEO 303-MW 7,00) as listed Prepared using 0,000).</p><p num="0204"><tables num="3"><img id="000004" he="50" wi="159" file="JP6232025B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0205"> Single Station Manesty Type F 3 Tablets to Prepare Core I attached a 9.53mm, circular, standard concave plain tooling to the less. Core blend Powdered aliquots, as listed above in Table 3, by the target weight of 300 mg It was separated, placed in a mold, and compressed to form the core of Tablet C.</p><p num="0206"> Single Station Manesty Type F 3 Tablets to Prepare Shell The press was fitted with 11.11 mm, circular, standard concave plain tooling. 200m The first part of the g-shell blend was placed in a mold as shown in Table 3. Prepared on Manually center the tablet core (on the powder bed) in the mold as it was, 200m The rest of the g-shell blend was placed on top of the tablet in the mold. Then the material is compressed Manually compress by rotating the wheel to form a compression coated tablet C It was.</p><p num="0207"> Place some compression-coated tablets C tablets prepared as above on a tray Enter the Hotpack 43 5304 oven with a target of 72 ° C for 30 minutes. And cured.</p><p num="0208"> The elution of the cured tablet C tablet is then performed at 37 ° C with enzyme-free simulated gastric juice (SGF) 900. Tested in USP apparatus 1 (basket) at 100 rpm in mL. The results are shown in Figure 1. It is shown for the results of the formulations of Examples 1-2 and 4. (Example 4)</p><p num="0209"> 475 mg tablets (Tablet D) containing 20 mg of hydrocodone bitartrate are listed in Table 4 below. High molecular weight polyethylene oxide (PEO 303-MW 7,00) as listed Prepared using 0,000).</p><p num="0210"><tables num="4"><img id="000005" he="50" wi="159" file="JP6232025B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0211"> Single Station Manesty Type F 3 Tablets to Prepare Core I attached a 7.94mm, circular, standard concave plain tooling to the less. Core blend Weigh the powdered aliquot of 175 mg by the target weight as shown in Table 4. It was placed in a mold and compressed to form the core of Tablet D.</p><p num="0212"> Single Station Manesty Type F 3 Tablets to Prepare Shell The press was fitted with 11.11 mm, circular, standard concave plain tooling. 300m The first part of the g-shell blend was placed in a mold as shown in Table 4. Prepared on Manually center the tablet core (on the powder bed) in the mold as it was, 300m The rest of the g-shell blend was placed on top of the tablet in the mold. Then the material is compressed Manually compress by rotating the wheel to form a compression coated tablet D It was.</p><p num="0213"> Compression coated tablets D tablets prepared as above some, then tray Place on top and aim for 72 ° C for 30 minutes Hotpack 43 5304 Orb It was put in a jar and cured.</p><p num="0214"> The elution of the cured tablet D tablet is then performed at 37 ° C with enzyme-free simulated gastric juice (SGF) 900. Tested in USP apparatus 1 (basket) at 100 rpm in mL. The results are shown in Figure 1. It is shown for the results of the formulations of Examples 1-3. (Example 5)</p><p num="0215"> 500 mg tablets (Tablet E) containing 120 mg of hydrocodone are listed in Table 5 below. As you can see, for the core low molecular weight polyethylene oxide (PEO 205-MW) High molecular weight polyethylene oxide (PEO 30) for 600,000) and shells Prepared using 3-MW 7,000,000).</p><p num="0216"><tables num="5"><img id="000006" he="49" wi="159" file="JP6232025B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0217"> Single Station Manesty Type F 3 Tablets to Prepare Core 8.73mm, round, standard concave plain tooling was attached to the less. Core blend Weigh the powdered aliquot of 300 mg by the target weight as shown in Table 5. It was placed in a mold and compressed to form the core of Tablet E.</p><p num="0218"> Single Station Manesty Type F 3 Tablets to Prepare Shell The press was fitted with 11.11 mm, circular, standard concave plain tooling. 200m The first part of the g-shell blend was placed in a mold as shown in Table 5. Prepared on Manually center the tablet core (on the powder bed) in the mold as it was, 200m The rest of the g-shell blend was placed on top of the tablet in the mold. Then the material is compressed Manually compress by rotating the wheel to form a compression coated tablet E It was.</p><p num="0219"> Compression coated tablets E tablets prepared as above some, then tray Place on top and aim for 72 ° C for 30 minutes Hotpack 43 5304 Orb It was put in a jar and cured.</p><p num="0220"> The elution of hardened tablets E tablets is then performed at 37 ° C with enzyme-free simulated gastric juice (SGF) 900. Tested in USP apparatus 1 (basket) at 100 rpm in mL. The result is shown in Fig. 2. It is shown for the results of the formulations of Examples 5 and 6. (Example 6)</p><p num="0221"> 500 mg tablets (Tablet F) containing 120 mg of hydrocodone are listed in Table 6 below. As you can see, high molecular weight polyethylene oxide (PEO 303-MW 7,000,0) Prepared using 00).</p><p num="0222"><tables num="6"><img id="000007" he="49" wi="159" file="JP6232025B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0223"> Single Station Manesty Type F 3 Tablets to Prepare Core 8.73mm, round, standard concave plain tooling was attached to the less. Core blend Weigh the powdered aliquot of 300 mg by the target weight as shown in Table 6. It was placed in a mold and compressed to form the core of Tablet F.</p><p num="0224"> Single Station Manesty Type F 3 Tablets to Prepare Shell The press was fitted with 11.11 mm, circular, standard concave plain tooling. 200m The first part of the g-shell blend was placed in a mold as shown in Table 6. Prepared on Manually center the tablet core (on the powder bed) in the mold as it was, 200m The rest of the g-shell blend was placed on top of the tablet in the mold. Material, compression wheel Was manually compressed to form compression-coated tablets F by rotating.</p><p num="0225"> Compression coated tablets F tablets prepared as above some, then tray Place on top and aim for 72 ° C for 30 minutes Hotpack 43 5304 Orb It was put in a jar and cured.</p><p num="0226"> The elution of Tablet F Tablets is then performed at 37 ° C with 900 mL of enzyme-free simulated gastric juice (SGF). Tested in USP device 1 (basket) at 100 rpm. The results are the implementation in Figure 2. It is shown for the results of the formulations of Examples 5 and 6. (Examples 7 to 12)</p><p num="0227"> In total hydrocodone bitartrate 20 mg (tablets G, H and I) or hydrocholine bitartrate 6 different compression coatings containing 120 mg codons (tablets J, K and L) Tablets (designated tablets G ~ L), Table 7 (20 mg) or Table 8 (120 mg) below Prepared according to.</p><p num="0228"><tables num="7"><img id="000008" he="127" wi="159" file="JP6232025B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0229"><tables num="8"><img id="000009" he="127" wi="159" file="JP6232025B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0230"> High shear granulator (Collette 75L), hydrocodone bitartrate, microcrystalline cell Loin and hydroxypropyl cellulose were charged. Water, propellers and choppers -Turned on and added to the mixture (eg 8-15%). Wet granulation, Quadro It was passed through a coarse screen of a Comil mill grinder. Wet granulated material passed through the screen , Vector VFC-3 Dryed in a fluidized bed dryer. Dry granulated product, Quadr o Passed through the fine screen of the Comil mill grinder.</p><p num="0231"> 16 Q "V" blender, PEO POLYOX WSR205 and mill crushed The granulated material was charged and blended for 5 minutes. Stearate mug through screen Nesium was added to the mixture and blended over 1 minute to prepare a core blend.</p><p num="0232"> 16 Q "V" blender, PEO POLYOX WSR303, D &amp; C red 30 Charged with No. aluminum lake and milled granules and blended for 5 minutes It was. Magnesium stearate that has been screened is added to the mixture for 1 minute. Blended to prepare a dry coat blend.</p><p num="0233"> Dry core blend and dry coat blend on DryCota Press Compressed into coated tablets. Core blend, side one hopper Loaded inside and adjusted core weight to target 300 mg. Then dry coat blend Was loaded into a side two hopper and the total tablet weight was adjusted to the target. After adjusting the weight, the compression operation was started, and the press was operated at, for example, 6 rpm.</p><p num="0234"> Weigh approximately 10 kg of compression coated tablets and perforate a 24-inch Compu -Opa dry coating up to a target increase of about 1.0% (by weight) in Lab Pancoater Spray coated with suspension. The spray coating was performed as follows. Tablet bed, 5 It was warmed by setting the intake air temperature to 5 ° C. As soon as the discharge temperature reaches 39 ° C, Wilm coating to a pan rate of 12 rpm and a spray rate of approximately 44 mL / min I started. Film coating continued until the target 1% increase was achieved (this is Because the final coating with a 4% increase in Tep xii becomes sticky during curing, It was a partial coating prior to curing in step x).</p><p num="0235"> The partially coated tablets were cured in a perforated pan coater. Inlet temperature, It was set to 85 ° C at a pan speed of approximately 10 rpm. Take the pill for about 30 minutes It was cured at a discharge temperature of 72 ° C.</p><p num="0236"> After curing, the tablets were cooled in a rotating pan by setting the inlet temperature to 22 ° C. .. Cooling was continued until the discharge temperature fell below 28 ° C.</p><p num="0237"> The cured tablets are then placed at a pan rate of 12 rpm and a spray rate of approximately 44 mL / min. Target final increase of 4.0% in perforated pan coater (by weight, including previous 1% coating) ) Was spray coated with an additional coating suspension.</p><p num="0238"> Film-coated tablets in a tare polyethylene-lined drum Moved to.</p><p num="0239"> Dissolution results for these compression coated 20 mg and 120 mg tablets ( % Time-releasing actives) are shown in Figure 3 and Tables 9 and 10 below.</p><p num="0240"><tables num="9"><img id="000010" he="67" wi="159" file="JP6232025B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0241"><tables num="10"><img id="000011" he="69" wi="158" file="JP6232025B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0242"> Affecting the elution of the active agent from the dosage form, as shown by the elution of the examples above. Factors are core: shell weight ratio and tablet weight. In addition, the elution de shown above The data indicates that the formulations of the present invention exhibit substantially zero-order releases disclosed herein. Prove. (Example 13)</p><p num="0243"> Randomized, open-label, crossover study in healthy adult males and females Was carried out with the hydrocodone preparation (HYD) of Examples 7 to 12. The study is repetitive (a set of fixed) The process of repeating the study design each time with a different group of subjects undergoing the procedure) To. The following iteration was performed: Repeat 1: N = 36 Randomized, single dose, 3 treatments, 3 period crossover. . HYD 20mg, slow release tablet, fasting state (tablet G) . HYD 20mg, intermediate release tablet, fasting state (tablet H) . HYD 20mg, fast release tablet, fasting state (tablet I) Repeat 2: N = 36 Randomized, single dose, 3 treatments, 3 period crossover. . HYD 120mg, slow release tablet, fasting state (tablet J) . HYD120mg, intermediate release tablet, fasting state (tablet K) . HYD120mg, fast release tablet, fasting state (tablet L) Repeat 3: N = 16 Randomized, single dose, 2 treatments, 2 period crossover. . HYD 120mg, slow release tablet, fasting state (tablet J) . HYD120mg, slow release tablet, feeding condition (tablet J)</p><p num="0244"> 8 ounces of water (2) of each formulation as a single dose in the fasted or fed state shown. It was administered orally together with 40 mL).</p><p num="0245"> Since this study will be conducted in healthy humans, the opioid antagonist naltrexone hydrochloride Administration minimized opioid-related adverse events. Screening procedure The following screening procedure was performed within 28 days prior to the first dose. Performed on all potential subjects at Ning's visit: -Informed consent. -Informed consent for optional pharmacological genomics sampling. -Informed consent for optional hair sampling. -Weight, height, body mass index (BMI), and demographic data. -Evaluation of inclusion / exclusion criteria. -Medical history and medication history including concomitant medications. -Vital signs after sitting for approximately 5 minutes (systolic / diastolic blood pressure, pulse rate) , Respiratory rate, mouth temperature) and SpO₂.. -Additional vital signs after standing up for approximately 2 minutes (systolic / diastolic blood pressure, And pulse rate). -HDYF? The question was asked at the same time as the vital signs were measured. -Routine physical examination. -Laboratory evaluation following at least 4 hours of fasting (including biochemistry, hematology, and urinalysis) To do). -12 lead ECG. QTcF that does not exceed 450 msec. -Hepatitis screening (hepatitis B surface antigen [HBsAg], hepatitis C antibody [anti-HC] Including V]). -Screening for alcohol, cotinine, and selected substance abuse. -Serum pregnancy test, for women only; Serum Follicle Stimulating Hormone (FSH) for postmenopausal women only. -Serum pregnancy test (female only). -Serum follicle-stimulating hormone (FSH) test (postmenopausal women only). Incorporation criteria Subjects who met the following criteria were included in the study. -Provide written informed consent. -18 to 50 years old men and women (including both ends). Weights ranging from -50 to 100 kg (110 to 220 lbs) and 18 to 34 (18 to 34 lbs) kg / m²BMI up to) (including both ends). -Healthy and heavy as judged by medical history, physical examination, vital signs, and ECG There are no necessary abnormal findings. -Women who can give birth have a sufficient and reliable method of contraception (ie, additional sperm foam) Or jelly, intrauterine device, hormonal contraceptive barrier) must be used. Menstruation Women who have closed menstruation for more than a year and do not have elevated serum FSH Must be. -Willing to eat the food supplied during the study. -Avoid strenuous exercise during all studies. The subject can start a new exercise program or any other Do not always participate in strenuous physical exercise. Exclusion criteria The following criteria excluded potential subjects from the study. -Pregnant (beta human chorionic gonadotropin test positive) or lactating women .. -History or history of substance or alcohol abuse (within 5 years). -History or any status quo that may interfere with drug absorption, distribution, metabolism or excretion. -Use of opioid-containing drugs in the last 30 days prior to the first dose in this study. -Shoes of known susceptibility to hydrocodone, naltrexone, or related compounds History. -Any history of frequent nausea or vomiting regardless of pathogenesis. -Any history of seizures or head injuries with sequelae. -Participation in clinical drug studies during the 30 days prior to the first dose in this study. -Any serious illness during the 30 days prior to the first dose in this study. -Thyroid hormone therapy (hormone contraception is allowed) for 7 days prior to the first dose, Use of any medicine, including vitamins, herbs and / or mineral supplements. -Abnormal heart condition including any of the following: . QTc interval of 450 msec or more during screening (Fridericia correction) Calculated using). QTc interval of 480 msec or longer during the procedure (using Fridericia correction) Is calculated). -10 hours prior to study drug administration and 4 hours following study drug administration And refusal to completely cut off caffeine or xanthine-containing beverages during each restraint. -Arco 48 hours prior to initial study drug administration (Day 1) and at any time during the study Refusal to stop consuming beverages. -Smoking history or use of nicotine products or urinary cotinine within 45 days of study drug administration Test positive. -Within 60 days prior to study drug administration, unless required by this protocol Or blood or blood provided at any time during the study and over 30 days after the end of the study Liquid product. -Within 14 days prior to study drug administration, unless required by this protocol Or plasma provided at any time during the study. -Positive results of urine drug screening or alcohol screening. -HBsAg, anti-HCV positive results. -Positive naloxone hydrochloride challenge test. -Gilbert's syndrome, or the presence of any known hepatobiliary tract abnormalities. -To provide sufficient samples for only the optional hair sampling portion of the study Insufficient amount of hair. -Investigators may have multiple reasons not specifically stated in the exclusion criteria I think it is inappropriate because of this.</p><p num="0246"> Random studies of subjects that meet all inclusion criteria and do not meet any of the exclusion criteria It was tampered with.</p><p num="0247"> Each subject was assigned a unique subject number for screening. Allocation of target numbers Was in ascending order, and there were no omitted numbers. The subject number was used in all study documents.</p><p num="0248"> Check-in procedure Only on the first day of period 1, subjects were allowed to enter the research unit and naloxonchi hydrochloride I took a challenge test. Test results must be negative for the subject to remain in the study There wasn't. Vital signs and SPO₂Measured prior to and subsequently naloxone hydrochloride I decided.</p><p num="0249"> The following steps were also performed for all subjects at check-in over each period .. -Incorporation including confirmation of voluntary compliance with caffeine and xanthine restriction criteria / Confirmation of exclusion criteria. -Vital signs (after sitting for approximately 5 minutes) and SpO2. -HDYF (How Do You Feel)? It was performed at the same time as the ital sign was measured. -Including biochemistry (fasting for at least 4 hours), hematology and urinalysis Floor inspection evaluation (1st day, period 1 only), vital signs and SpO₂After being measured collected. -Alcohol (via urine or blood alcohol or alcohol detector), cotinine, and Screening for abuse of selected drugs (via urinalysis). -Urine pregnancy test (for all women). -Monitoring and recording of concomitant medications. -AE monitoring and recording.</p><p num="0250"> Drug screening (alcohol and cochini) for subjects to continue participating in the study Results must be available and negative prior to dosing. Addition Therefore, on-going compliance with concomitant medications and other restrictions at check-in in appropriate sources And confirmed through research. Treatment period procedure The procedure to be studied was pre-determined for each iteration. Data is available within the iteration Treatment was removed between cohorts as it would be possible. The removed treatment is the rest of the treatment Replaced with a return. -Subjects were randomized to treatment sequences prior to the first dose in period 1. -Subjects were given Nartreki Hydrochloride with 240 mL of water at 12 hours prior to dosing the study drug. Son tablets (50 mg) were taken. -Subjects to biochemistry (at least 4 hours) prior to study drug administration (except period 1) Hematology and urinalysis tests were performed (just fasting). -Subjects received the study drug with 240 mL of water as follows: . About fasting: Following a 10-hour nighttime fast, subjects received the study drug with 240 mL of water. Fasting Subjects receiving treatment continued to fast from food for 4 hours following dosing. . About feeding treatment: Following a 10-hour nighttime fast, subjects were marked 30 minutes prior to administration of the study drug with 240 mL of water. I ate a semi-meal (FDA high-fat breakfast). Food is not allowed for at least 4 hours after administration It was. For all meals that should be consumed within a specified time frame And made it extremely clear. Subjects were standing or sitting upright while taking the study drug dose. Fasting was not required for non-medication study days. -Subjects were given water 24 at -12, 0, 12, 24, and 36 hours for each study drug dose. Naltrexone hydrochloride 50 mg tablets were taken with 0 mL. -For subjects taking hydrocodone doses of -60 mg or higher, SpO₂Continuously It was monitored and started prior to dosing and continued 24 hours after dosing. -Vital signs (after sitting for approximately 5 minutes) and SpO₂Before administration , And post-dose 1, 2, 4, 6, 8, 12, 24, 36, 48, and for each period Obtained at 72 hours. -HDYF (How are you feeling)? The question is real at the same time as measuring vital signs gave. -Subjects include biochemistry (fasting for at least 4 hours), hematology, and urinalysis tests The study was conducted 24 hours after administration. -In addition, for each subject, 12-lead ECG was given approximately 12, before and after administration. Performed at 24 and 48 hours. If QTcF exceeds 480msec, the target is It was discontinued due to adverse events. -For each subject, a blood sample to determine hydrocodone plasma concentration should be given before administration. 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6 after administration for each period , 8, 10, 12, 14, 18 24, 36, 48, and 72 hours. -Subjects will be available from check-in to the unit the day before dosing until the end of the 48-hour procedure. Isolated on the knit. Subject returned to the unit for a 72-hour procedure. -Recorded AEs and concomitant medications during the study.</p><p num="0251"> In addition, subjects should immediately report any / all episodes of vomiting to research staff. Is extremely important, and this information is essential for the proper conduct and outcome of clinical trials. I told you that. Subjects never be penalized for reporting cases of vomiting I told him not to be charged. Research staff should be careful about any / all cases of vomiting Instructed to document.</p><p num="0252"> Research completion procedure Follow the steps below at the end of the study (end of study), 7-10 days after taking the final dose of study drug All subjects were performed at the study site later or at the time of early discontinuation from the study. -Concomitant drug evaluation. -Vital signs (after sitting for approximately 5 minutes) and SpO₂.. -HDYF? The question was asked at the same time as the vital signs were measured. -Physical examination. -12 lead ECG. -Laboratory evaluation (biochemistry [fasting for at least 4 hours], hematology, and urinalysis). -AE rating. -Serum pregnancy test (for women only).</p><p num="0253"> Draft results are shown in Figures 4-6 and Table 13 below:</p><p num="0254"><tables num="11"><img id="000012" he="210" wi="159" file="JP6232025B2_D0001.tif" img-format="tif" img-content="drawing" /></tables>(Examples 14 to 20)</p><p num="0255"> Hydrocodone bitartrate 20, 30, 40, 60, 80, 100 or 1 in total, respectively 7 different compression coated tablets containing 20 mg (designated tablets M ~ S) ) Are prepared according to Tables 14 (tablets M, N, O, P) and 15 (tablets Q, R, S) below. It was.</p><p num="0256"><tables num="12"><img id="000013" he="188" wi="159" file="JP6232025B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0257"><tables num="13"><img id="000014" he="188" wi="159" file="JP6232025B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0258"> Hydrocodone bitartrate, microcrystalline cellulose and hydroxypropi in a high shear mixer Lucellulose was charged.</p><p num="0259"> Mix the dry mix mixture at low speed with the chopper off for 1 minute, then Then, the chopper was turned on and mixed at high speed. Add water until the desired amount of water is added Was added to the mixture to produce a wet granulated product.</p><p num="0260"> The wet granules are then passed through a screening mill to remove lumps and transferred to a fluidized bed dryer. It was dried.</p><p num="0261"> The dry mixture was then passed through a fine screen until the target particle size range was achieved (&lt;1). .0%).</p><p num="0262"> The granulated product that has been passed through a dry screen is then passed through a screening mill for active granulation. Items were collected in a stainless steel container. For V blender, polyethylene oxide (P Approximately half of OLYOX WSR-205); Appropriate amount of active granulation (for assay) Adjusted to); Aluminum Lake; and Remaining Polyethylene Oxide (POLYOX) WSR-205) was charged and the mixture was blended for 10 minutes.</p><p num="0263"> The V-blender was then charged with magnesium stearate and the mixture was spread over 2 minutes. It was blended and discharged into a stainless steel drum.</p><p num="0264"> Approximately polyethylene oxide (POLYOX WSR-303) for V blender Half; appropriate amount of active granulation (prepared for assay); and remaining polyethylene Charge with oxide (POLYOX WSR-303) and shake the mixture for 10 minutes. I did.</p><p num="0265"> The V-blender is then charged with magnesium stearate and blended for 2 minutes. And discharged into a stainless steel drum.</p><p num="0266"> Assemble the left side of the press with 8.75mm, circular, shallow concave tooling and press The right side was assembled with 12mm, circular, shallow concave surface, and edge tooling.</p><p num="0267"> The core blend (colored) is then charged into the left hopper (gravity supply system). Core compression was started.</p><p num="0268"> The core weight was adjusted to the target weight (300 mg, +/- 5%).</p><p num="0269"> Then apply the dry coat blend (white to grayish white) to the right hopper (gravity). It was charged into the supply system) and tablet compression was started.</p><p num="0270"> 700 mg (300 mg) of initial dry coat fill and subsequent dry coat fill A + 400 mg dry coat) was adjusted to the target total tablet weight after core placement.</p><p num="0271"> For opadry color dispersions (target 20% solids), place an appropriate amount of purified water in the mixing vessel. Was charged and the mixer speed was adjusted to form a vortex. Sprinkle opadry powder for 2-5 minutes Was added to the container and mixed until a uniform dispersion was produced (at least 1 hour).</p><p num="0272"> Appropriate for opadry clear dispersion (target 7.5% solids) in a separate mixing vessel A large amount of purified water was charged and the mixer speed was adjusted to form a vortex. Opadry clear powder To the container over 2-5 minutes (target 3 minutes) until a uniform dispersion is produced (minimum) 1 hour) mixed.</p><p num="0273"> The compression coated tablets are then transferred to a perforated coated pan and 0.7% ~ 1 Film coated with opadry color dispersion to a target increase of .5%.</p><p num="0274"> Raise the heating temperature and allow the tablets to cure to a target discharge temperature of 72 ° C for approximately 30 minutes. Then, it was cooled.</p><p num="0275"> Opa tablet coating up to a target increase of 3%, including an increase from the previous coating Continued with a dry color dispersion.</p><p num="0276"> The tablets are then film coated with an opadry clear dispersion up to a 5% final goal increase. Wing.</p><p num="0277"> These compression coated 20mg, 30mg, 40mg, 60mg, 80mg , 100 mg, and 120 mg tablets elution results (% release activity over time) are shown below. It is shown in Table 16 of.</p><p num="0278"><tables num="14"><img id="000015" he="109" wi="159" file="JP6232025B2_D0001.tif" img-format="tif" img-content="drawing" /></tables>(Example 21)</p><p num="0279"> Randomized, open-label, single dose, 5 treatments in healthy adult male and female subjects, 4-period crossover, incomplete block study, hydrocodone formulations of Examples 14-20 Conducted at (HYD). The study consists of up to 5 treatments over 4 periods.</p><p num="0280"> HYD Tablet Strength, or Dosage Studyed: . 1 × 20mg HYD tablets . 1 × 40mg HYD tablets . 1 × 60mg HYD tablets . 1 × 80mg HYD tablets . 1 × 120mg HYD tablets And said.</p><p num="0281"> Each treatment is orally administered with 8 ounces (240 mL) of water as a single dose in a fasted state. did.</p><p num="0282"> Since this study will be conducted in healthy humans, the opioid antagonist naltrexone hydrochloride Administration minimized opioid-related adverse events. Target selection Screening procedure The following screening procedure was performed within 28 days prior to the first dose. Performed on all potential subjects at Ning's visit: -Informed consent. -Informed consent for optional pharmacological genomics sampling. -Informed consent for optional hair sampling. -Weight, height, body mass index (BMI), and demographic data. -Evaluation of inclusion / exclusion criteria. -Medical history and medication history including concomitant medications. -Vital signs after sitting for approximately 5 minutes (systolic / diastolic blood pressure, pulse rate) , Respiratory rate, mouth temperature) and SpO₂.. -Additional vital signs after standing up for approximately 2 minutes (systolic / diastolic blood pressure, And pulse rate). -HDYF? The question was asked at the same time as the vital signs were measured. -Routine physical examination. -Laboratory evaluation following at least 4 hours of fasting (including biochemistry, hematology, and urinalysis) To do). -12 lead ECG. QTcF that does not exceed 450 msec. -Hepatitis screening (hepatitis B surface antigen [HBsAg], hepatitis C antibody [anti-HC] Including V]). -Screening for alcohol, cotinine, and selected substance abuse. -Serum pregnancy test, for women only; Serum Follicle Stimulating Hormone (FSH) for postmenopausal women only. -Serum pregnancy test (female only). -Serum follicle-stimulating hormone (FSH) test (postmenopausal women only). Incorporation criteria Subjects who met the following criteria were included in the study. -Provide written informed consent. -18 to 50 years old men and women (including both ends). -Willing to eat the food supplied during the study. Weights ranging from -50 to 100 kg (110 to 220 lbs) and 18 to 30 (18 to 30 lbs) BMI up to kg / m2) (including both ends). -I am willing to refrain from strenuous exercise until the end of the clinical trial visit. The target is a new exercise program Do not start sickness or participate in any abnormally intense physical exercise. -Healthy and judged by medical history, physical examination, laboratory test values, vital signs, and ECG There are no significant abnormal findings. -Women who can give birth have a sufficient and reliable method of contraception (ie, additional sperm foam) Or jelly, intrauterine device, hormonal contraceptive barrier) must be used. Menstruation Women who have closed menstruation for more than a year and do not have elevated serum FSH Must be. Exclusion criteria The following criteria excluded potential subjects from the study. -Pregnant (beta human chorionic gonadotropin test positive) or lactating women .. -History or history of substance or alcohol abuse (within 5 years). -History or any status quo that may interfere with drug absorption, distribution, metabolism or excretion. -Opioid-containing drugs in the last 30 days prior to the first dose of study drug in this study use. -Shoes of known susceptibility to hydrocodone, naltrexone, or related compounds History. -Any history of frequent nausea or vomiting regardless of pathogenesis. -Any history of seizures or head injuries with sequelae. -Participation in clinical drug studies during the 30 days prior to the first dose of study drug in this study .. -Any serious illness during the 30 days prior to the first dose of study drug in this study. -Thyroid hormone therapy (presence or absence of progestin) for 7 days prior to the first dose of study drug Hormone contraception and hormone replacement therapy in the form of estrogen is allowed regardless) Use of any medicine, including vitamins, herbs and / or mineral supplements .. -Any personal or family history of extended QT interval or impaired cardiac rhythm. -Abnormal heart condition including any of the following: . QTc interval of 450 msec or more during screening (Fridericia correction) Calculated using). QTc interval of 480 msec or longer during the procedure (using Fridericia correction) Is calculated). -10 hours prior to study drug administration and 4 hours following study drug administration And refusal to completely cut off caffeine or xanthine-containing beverages during each restraint. -48 hours prior to initial study drug administration (Day 1) and at any time until the end of the study visit Refusal to stop consuming alcoholic beverages at the point. -30 days prior to initial study drug administration, unless required by this protocol Blood or blood products provided within or at any time until the end of the trial visit. -Smoking history or nicotine product use or urinary sickness within 45 days of initial study drug administration Nin test positive. -Positive results of urine drug screening or alcohol screening. -HBsAg, anti-HCV positive results. -Positive naloxone hydrochloride challenge test. -Gilbert's syndrome, or the presence of any known hepatobiliary tract abnormalities. -Investigators may have multiple reasons not specifically stated in the exclusion criteria I think it is inappropriate because of this.</p><p num="0283"> Random studies of subjects that meet all inclusion criteria and do not meet any of the exclusion criteria It was tampered with.</p><p num="0284"> Each subject was assigned a unique subject number for screening. Allocation of target numbers Was in ascending order, and there were no omitted numbers. The subject number was used in all study documents.</p><p num="0285"> Check-in procedure Only on the first day of period 1, subjects were allowed to enter the research unit and naloxonchi hydrochloride I took a challenge test. Test results must be negative for the subject to remain in the study There wasn't. Vital signs and SPO₂Measured prior to and subsequently naloxone hydrochloride I decided.</p><p num="0286"> The following steps were also performed for all subjects at check-in over each period .. -Incorporation including confirmation of voluntary compliance with caffeine and xanthine restriction criteria / Confirmation of exclusion criteria. -Vital signs (after sitting for approximately 5 minutes) and SpO2. -HDYF (How are you feeling)? The question is real at the same time as measuring vital signs gave. -Including biochemistry (fasting for at least 4 hours), hematology and urinalysis Floor inspection evaluation (1st day, period 1 only), vital signs and SpO₂After being measured collected. -Alcohol (via urine or blood alcohol or alcohol detector), cotinine, and Screening for abuse of selected drugs (via urinalysis). -Urine pregnancy test (for all women). -Monitoring and recording of concomitant medications. -AE monitoring and recording.</p><p num="0287"> Drug screening (alcohol and cochini) for subjects to continue participating in the study Results must be available and negative prior to dosing. Addition Therefore, on-going compliance with concomitant medications and other restrictions at check-in in appropriate sources And confirmed through research. Treatment period procedure The procedure to be studied was pre-determined for each iteration. Data is available within the iteration Treatment was removed between cohorts as it would be possible. The removed treatment is the rest of the treatment Replaced with a return. -Subjects were randomized to treatment sequences prior to the first dose in period 1. -Subjects were given Nartreki Hydrochloride with 240 mL of water at 12 hours prior to dosing the study drug. Son tablets (50 mg) were taken. -Subjects received the study drug with 240 mL of water following a 10-hour night fast. The target is , Continued fasting from food for 4 hours following dosing. Subjects were standing or sitting upright while taking the study drug dose. Fasting was not required for non-medication study days. -Subjects were given water 24 at -12, 0, 12, 24, and 36 hours for each study drug dose. Naltrexone hydrochloride 50 mg tablets were taken with 0 mL. -For subjects taking hydrocodone doses of -60 mg or higher, SpO₂Continuously It was monitored and started prior to dosing and continued 24 hours after dosing. -Vital signs (after sitting for approximately 5 minutes) and SpO₂Before administration , And for each period 1, 2.5, 4, 6, 8, 12, 24, 36, 48, And obtained at 72 hours. -HDYF (How are you feeling)? The question is real at the same time as measuring vital signs gave. -For each subject, 12-lead ECG was given approximately 12, 24 before and after administration. It was carried out in 48 hours. -For each subject, a blood sample to determine hydrocodone plasma concentration should be given before administration. 0.5, 1, 2.5, 4, 6, 8, 10, 12, 14, 16 after administration for each period , 18, 24, 36, 48, and 72 hours. -Subjects will be available from check-in to the unit the day before dosing until the 72-hour procedure is completed. Isolated on the knit. -Recorded AEs and concomitant medications during the study.</p><p num="0288"> In addition, subjects should immediately report any / all episodes of vomiting to research staff. Is extremely important, and this information is essential for the proper conduct and outcome of clinical trials. I told you that. Subjects never be penalized for reporting cases of vomiting I told him not to be charged. Research staff should be careful about any / all cases of vomiting Instructed to document.</p><p num="0289"> Research completion procedure Follow the steps below at the end of the study (end of study), 7-10 days after taking the final dose of study drug All subjects were performed at the study site later or at the time of early discontinuation from the study. -Concomitant drug evaluation. -Vital signs (after sitting for approximately 5 minutes) and SpO₂.. -HDYF? The question was asked at the same time as the vital signs were measured. -Physical examination. -12 lead ECG. -Laboratory evaluation (biochemistry [fasting for at least 4 hours], hematology, and urinalysis). -AE rating. -Serum pregnancy test (for women only).</p><p num="0290"> Draft results are shown in Figure 7 and Table 17 below:</p><p num="0291"><tables num="15"><img id="000016" he="127" wi="159" file="JP6232025B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0292"> The present invention is disclosed in an example intended as an illustration of a few aspects of the invention. Any embodiment that should not be limited in scope by specific embodiments and is functionally equivalent The state is within the scope of the present invention. In fact, in addition to what is shown and described herein. Various modifications of the present invention have been made apparent to those skilled in the art and are within the scope of the appended claims. Is intended.</p><p num="0293"> This application claims priority from US Provisional Application No. 61 / 426,306 filed December 22, 2010, the disclosure of which is incorporated herein by reference.<u style="single">The present invention also includes the following aspects.</u><u style="single">&lt;1&gt;</u><u style="single"> With a core containing the first part of the opioid analgesic dispersed in the first matrix material,</u><u style="single"> With a shell covering the core and containing a second portion of opioid analgesic dispersed in a second matrix material</u><u style="single">Is a solid controlled release form containing</u><u style="single"> The amount of opioid analgesic released from the dosage form is measured by in vitro elution in USP device 1 (basket) at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C for 8 to 24 hours. Solid controlled release dosage form that is proportional to the elapsed time to within 20%.</u><u style="single">&lt;2&gt;</u><u style="single"> The solid controlled release dosage form according to 1 above, wherein the core is a compressed tablet.</u><u style="single">&lt;3&gt;</u><u style="single"> The solid controlled release dosage form according to 1 or 2 above, wherein the shell is a compression coating.</u><u style="single">&lt;4&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 1 to 3 above, wherein the first matrix material contains polyethylene oxide.</u><u style="single">&lt;5&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 1 to 4 above, wherein the second matrix material contains polyethylene oxide.</u><u style="single">&lt;6&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 1 to 3 above, wherein both the first matrix material and the second matrix material contain polyethylene oxide.</u><u style="single">&lt;7&gt;</u><u style="single"> The solid controlled release dosage form according to 6 above, wherein the polyethylene oxide in the second matrix material has a higher viscosity than the polyethylene oxide in the first matrix material.</u><u style="single">&lt;8&gt;</u><u style="single"> The solid controlled release dosage form according to 4 above, wherein the first matrix material comprises polyethylene oxide having an average molecular weight from about 300,000 to about 10,000,000.</u><u style="single">&lt;9&gt;</u><u style="single"> 8. The solid controlled release dosage form according to 8 above, wherein the first matrix material comprises polyethylene oxide having an average molecular weight from about 500,000 to about 1,000,000.</u><u style="single">&lt;10&gt;</u><u style="single"> 5. The solid controlled release dosage form of 5 above, wherein the second matrix material comprises polyethylene oxide having an average molecular weight from about 1,000,000 to about 10,000,000.</u><u style="single">&lt;11&gt;</u><u style="single"> 10. The solid controlled release dosage form of 10 above, wherein the second matrix material comprises polyethylene oxide having an average molecular weight from about 6,000,000 to about 8,000,000.</u><u style="single">&lt;12&gt;</u><u style="single"> The polyethylene oxide in the second matrix material has an average molecular weight of about 4,000,000 to about 10,000,000, and the polyethylene oxide in the first matrix material has an average molecular weight of about 300,000 to about 3,000,000. The solid controlled release dosage form according to 6.</u><u style="single">&lt;13&gt;</u><u style="single"> The polyethylene oxide in the second matrix material has an average molecular weight of about 6,000,000 to about 8,000,000, and the polyethylene oxide in the first matrix material has an average molecular weight of about 500,000 to about 1,000,000. The solid controlled release dosage form according to 6.</u><u style="single">&lt;14&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 1 to 13 above, wherein the weight ratio of the core to the shell is from about 1: 0.5 to about 1: 5.</u><u style="single">&lt;15&gt;</u><u style="single"> The solid controlled release dosage form according to 14 above, wherein the weight ratio of the core to the shell is from about 1: 0.6 to about 1: 1.5.</u><u style="single">&lt;16&gt;</u><u style="single"> 15. The solid controlled release dosage form according to 15 above, wherein the weight ratio of the core to the shell is from about 1: 0.8 to about 1: 1.2.</u><u style="single">&lt;17&gt;</u><u style="single"> The solid controlled release form according to 4 above, wherein the weight ratio of the first portion of the opioid analgesic to polyethylene oxide in the first matrix material is from about 1: 0.5 to about 1: 100.</u><u style="single">&lt;18&gt;</u><u style="single"> 17. The solid controlled release dosage form of 17 above, wherein the weight ratio of the first portion of the opioid analgesic to polyethylene oxide in the first matrix material is from about 1: 1 to about 1:10.</u><u style="single">&lt;19&gt;</u><u style="single"> The solid controlled release form according to 18 above, wherein the weight ratio of the first portion of the opioid analgesic to polyethylene oxide in the first matrix material is from about 1: 1.5 to about 1: 4.</u><u style="single">&lt;20&gt;</u><u style="single"> 5. The solid controlled release form according to 5 above, wherein the weight ratio of the second portion of the opioid analgesic to polyethylene oxide in the second matrix material is from about 1: 2 to about 1: 200.</u><u style="single">&lt;21&gt;</u><u style="single"> 20. The solid controlled release form according to 20 above, wherein the weight ratio of the second portion of the opioid analgesic to polyethylene oxide in the second matrix material is from about 1: 5 to about 1:50.</u><u style="single">&lt;22&gt;</u><u style="single"> 21. The solid controlled release form according to 21 above, wherein the weight ratio of the second portion of the opioid analgesic to polyethylene oxide in the second matrix material is from about 1:12 to about 1:25.</u><u style="single">&lt;23&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 1 to 22 above, wherein the opioid analgesic in the first portion is the same as the opioid analgesic in the second portion.</u><u style="single">&lt;24&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 1 to 22 above, wherein the opioid analgesic in the first portion is different from the opioid analgesic in the second portion.</u><u style="single">&lt;25&gt;</u><u style="single"> The solid controlled release according to any one of 1 to 24 above, wherein the ratio of opioid analgesics in the core to the ratio of opioid analgesics in the shell is from about 1: 1 to about 10: 1. Dosage form.</u><u style="single">&lt;26&gt;</u><u style="single"> 25. The solid controlled release form according to 25 above, wherein the ratio of opioid analgesics in the core to the ratio of opioid analgesics in the shell is from about 2: 1 to about 8: 1.</u><u style="single">&lt;27&gt;</u><u style="single"> 25. The solid controlled release form according to 25 above, wherein the ratio of opioid analgesics in the core to the ratio of opioid analgesics in the shell is from about 2: 1 to about 5: 1.</u><u style="single">&lt;28&gt;</u><u style="single"> The opioid analgesics include alfentanil, allylprozine, alphaprozine, anileridine, benzylmorphine, vegitramide, buprenorfin, butorphanol, chronitazen, codeine, desomorphine, dexstromoramide, dezosin, diampromide, diamorphone, dihydrocodein, dihydromorphine. Dimenoxador, dimefeptanol, dimethylthianbutene, dioxafetyl butyrate, dipipanone, eptazosin, etoheptazine, ethylmethylthianbutene, ethylmorphine, etnitazen, etolphin, dihydromorphine, fentanyl and derivatives, hydrocodon, hydromorphone, hydroxypethidine, isometadone, ketobemidone , Levorfanol, levofenacylmorphan, lofentanil, meperidine, meptazine, metazosin, metadon, metopon, morphine, mylofin, narcein, nicomorphine, norlevorfanol, normetadon, nalolfin, nalbuphene, normorphine, norpipanone, achen , Oxycodon, oxymorphone, papabeletam, pentazocin, phenadoxone, phenomolfane, phenazocin, phenoperidine, pimidine, pyritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilydin, tramadol, pharmaceutically acceptable them The solid controlled release agent form according to any one of 1 to 27 above, selected from the group consisting of salts thereof, their hydrates, their solvates, and mixtures thereof.</u><u style="single">&lt;29&gt;</u><u style="single"> The opioid analgesic is selected from the group consisting of codeine, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, tramadol, their pharmaceutically acceptable salts, their hydrates, their solvates, and mixtures thereof. 28. The solid controlled release dosage form according to 28 above.</u><u style="single">&lt;30&gt;</u><u style="single"> 29. The solid controlled release form according to 29 above, wherein the opioid analgesic is selected from the group consisting of hydrocodone, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and a mixture thereof.</u><u style="single">&lt;31&gt;</u><u style="single"> 30. The solid controlled release dosage form of 30 above, wherein the opioid analgesic is hydrocodone bitartrate.</u><u style="single">&lt;32&gt;</u><u style="single"> 31. The solid controlled release dosage form according to 31 above, wherein the total amount of hydrocodone choline bitartrate in the dosage form is from about 0.5 mg to about 1250 mg.</u><u style="single">&lt;33&gt;</u><u style="single"> 31. The solid controlled release dosage form according to 31 above, wherein the total amount of hydrocodone choline bitartrate in the dosage form is from about 2 mg to about 200 mg.</u><u style="single">&lt;34&gt;</u><u style="single"> 31. The solid controlled release dosage form according to 31 above, wherein the total amount of hydrocodone choline bitartrate in the dosage form is from about 16 mg to about 120 mg.</u><u style="single">&lt;35&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 1 to 34 above, wherein the amount of the opioid analgesic released is proportional to the elapsed time from 8 to 24 hours within 10%.</u><u style="single">&lt;36&gt;</u><u style="single"> 35. The solid controlled release dosage form of 35 above, wherein the amount of opioid analgesic released is proportional to the elapsed time from 8 to 24 hours within 5%.</u><u style="single">&lt;37&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 1 to 34 above, wherein the amount of the opioid analgesic released is proportional to the elapsed time from 8 to 18 hours within 20%.</u><u style="single">&lt;38&gt;</u><u style="single">The solid controlled release dosage form according to any one of 1 to 34 above, wherein the amount of the opioid analgesic released is proportional to the elapsed time from 8 to 12 hours within 20%.</u><u style="single">&lt;39&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 1 to 34 above, wherein the amount of the opioid analgesic released is proportional to the elapsed time from 12 to 24 hours within 20%.</u><u style="single">&lt;40&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 1 to 34 above, wherein the amount of the opioid analgesic released is proportional to the elapsed time from 12 to 18 hours within 20%.</u><u style="single">&lt;41&gt;</u><u style="single"> 37. The solid controlled release dosage form of 37 above, wherein the amount of opioid analgesic released is proportional to the elapsed time from 8 to 18 hours within 10%.</u><u style="single">&lt;42&gt;</u><u style="single"> 38. The solid controlled release dosage form of 38 above, wherein the amount of opioid analgesic released is proportional to the elapsed time from 8 to 12 hours within 10%.</u><u style="single">&lt;43&gt;</u><u style="single"> 39. The solid controlled release dosage form of 39 above, wherein the amount of opioid analgesic released is proportional to the elapsed time from 12 to 24 hours within 10%.</u><u style="single">&lt;44&gt;</u><u style="single"> 40. The solid controlled release dosage form of 40 above, wherein the amount of opioid analgesic released is proportional to the elapsed time from 12 to 18 hours within 10%.</u><u style="single">&lt;45&gt;</u><u style="single"> 37. The solid controlled release dosage form of 37 above, wherein the amount of opioid analgesic released is proportional to the elapsed time from 8 to 18 hours within 5%.</u><u style="single">&lt;46&gt;</u><u style="single"> 38. The solid controlled release dosage form of 38 above, wherein the amount of opioid analgesic released is proportional to the elapsed time from 8 to 12 hours within 5%.</u><u style="single">&lt;47&gt;</u><u style="single"> 39. The solid controlled release dosage form of 39 above, wherein the amount of opioid analgesic released is proportional to the elapsed time from 12 to 24 hours within 5%.</u><u style="single">&lt;48&gt;</u><u style="single"> 40. The solid controlled release dosage form of 40 above, wherein the amount of opioid analgesic released is proportional to the elapsed time from 12 to 18 hours within 5%.</u><u style="single">&lt;49&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 1 to 48 above, wherein the amount of opioid analgesic released at 2 hours is less than about 25%.</u><u style="single">&lt;50&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 1 to 49 above, wherein the amount of opioid analgesic released at 4 hours is from about 10% to about 30%.</u><u style="single">&lt;51&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 1 to 50 above, wherein the amount of opioid analgesic released at 8 hours is from about 20% to about 60%.</u><u style="single">&lt;52&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 1 to 51 above, wherein the amount of opioid analgesic released at 12 hours is from about 40% to about 90%.</u><u style="single">&lt;53&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 1 to 52 above, wherein the amount of opioid analgesic released at 18 hours exceeds about 70%.</u><u style="single">&lt;54&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 1 to 53 above, wherein the amount of opioid analgesic released at 2 hours is less than about 20%.</u><u style="single">&lt;55&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 1 to 54 above, wherein the amount of opioid analgesic released at 4 hours is from about 10% to about 20%.</u><u style="single">&lt;56&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 1 to 55 above, wherein the amount of opioid analgesic released at 8 hours is from about 20% to about 40%.</u><u style="single">&lt;57&gt;</u><u style="single"> The solid controlled release form according to any one of 1 to 56 above, wherein the amount of opioid analgesic released at 12 hours is from about 40% to about 65%.</u><u style="single">&lt;58&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 1 to 57 above, wherein the amount of opioid analgesic released at 18 hours exceeds about 80%.</u><u style="single">&lt;59&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 1 to 58 above, wherein the amount of opioid analgesic released at 2 hours is less than about 15%.</u><u style="single">&lt;60&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 1 to 59 above, wherein the amount of opioid analgesic released at 4 hours is from about 20% to about 30%.</u><u style="single">&lt;61&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 1 to 60 above, wherein the amount of opioid analgesic released at 8 hours is from about 45% to about 60%.</u><u style="single">&lt;62&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 1 to 61 above, wherein the amount of opioid analgesic released at 12 hours is from about 70% to about 90%.</u><u style="single">&lt;63&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 1 to 62 above, wherein the amount of opioid analgesic released at 18 hours exceeds about 90%.</u><u style="single">&lt;64&gt;</u><u style="single"> 6. The solid controlled release dosage form according to 6 above, wherein the dosage form is cured at a temperature of at least the softening point of the polyethylene oxide for at least 1 minute.</u><u style="single">&lt;65&gt;</u><u style="single"> 6. The solid controlled release dosage form according to 6 above, wherein the dosage form is cured at a temperature of at least the softening point of the polyethylene oxide for at least 5 minutes.</u><u style="single">&lt;66&gt;</u><u style="single"> 6. The solid controlled release dosage form according to 6 above, wherein the dosage form is cured at a temperature of at least the softening point of the polyethylene oxide for at least 15 minutes.</u><u style="single">&lt;67&gt;</u><u style="single"> The solid controlled release dosage form according to 6 above, wherein the 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.</u><u style="single">&lt;68&gt;</u><u style="single"> The solid controlled release dosage form according to 6 above, wherein the dosage form is cured at a temperature of at least the softening point of the polyethylene oxide from about 5 minutes to about 24 hours.</u><u style="single">&lt;69&gt;</u><u style="single"> The solid controlled release dosage form according to 6 above, wherein the dosage form is cured at a temperature of at least the softening point of the polyethylene oxide from about 15 minutes to about 1 hour.</u><u style="single">&lt;70&gt;</u><u style="single"> The solid controlled release dosage form according to any of 64 to 69 above, wherein the dosage form is cured at a temperature of at least about 60 ° C.</u><u style="single">&lt;71&gt;</u><u style="single"> The solid controlled release dosage form according to any of 64 to 69 above, wherein the dosage form is cured at a temperature of at least about 65 ° C.</u><u style="single">&lt;72&gt;</u><u style="single"> The solid controlled release dosage form according to any of 64 to 69 above, wherein the dosage form is cured at a temperature of at least about 70 ° C.</u><u style="single">&lt;73&gt;</u><u style="single"> The solid controlled release dosage form according to any of 64 to 69 above, wherein the dosage form is cured at a temperature of at least about 75 ° C.</u><u style="single">&lt;74&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 64 to 69 above, wherein the dosage form is cured at a temperature of about 72 ° C.</u><u style="single">&lt;75&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 64 to 69 above, wherein the dosage form is cured at a temperature from about 60 ° C to about 90 ° C.</u><u style="single">&lt;76&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 64 to 69 above, wherein the dosage form is cured at a temperature from about 65 ° C to about 85 ° C.</u><u style="single">&lt;77&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 64 to 69 above, wherein the dosage form is cured at a temperature from about 70 ° C to about 80 ° C.</u><u style="single">&lt;78&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 64 to 69 above, wherein the dosage form is cured at a temperature from about 75 ° C to about 80 ° C.</u><u style="single">&lt;79&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 64 to 69 above, wherein the dosage form is cured at a temperature from about 70 ° C to about 75 ° C.</u><u style="single">&lt;80&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 1 to 79 above, wherein the core and the shell are visually indistinguishable.</u><u style="single">&lt;81&gt;</u><u style="single"> CIE L where the core and the shell are within 10% of each other</u>^{<u style="single">*</u>}<u style="single">A</u>^{<u style="single">*</u>}<u style="single">B</u>^{<u style="single">*</u>}<u style="single">The solid controlled release dosage form according to any one of 1 to 79 above, which has a value.</u><u style="single">&lt;82&gt;</u><u style="single"> 1 to 81 above, wherein the dosage form can be flattened without breaking, and the thickness of the dosage form after flattening corresponds to about 60% or less of the thickness of the dosage form before flattening. The solid controlled release dosage form according to any one of the above.</u><u style="single">&lt;83&gt;</u><u style="single"> The above-mentioned 82, wherein the dosage form can be flattened without breaking, and the thickness of the dosage form after flattening corresponds to about 50% or less of the thickness of the dosage form before flattening. Solid controlled release dosage form.</u><u style="single">&lt;84&gt;</u><u style="single"> The above-mentioned 82, wherein the dosage form can be flattened without breaking, and the thickness of the dosage form after flattening corresponds to about 40% or less of the thickness of the dosage form before flattening. Solid controlled release dosage form.</u><u style="single">&lt;85&gt;</u><u style="single"> The above-mentioned 82, wherein the dosage form can be flattened without breaking, and the thickness of the dosage form after flattening corresponds to about 30% or less of the thickness of the dosage form before flattening. Solid controlled release dosage form.</u><u style="single">&lt;86&gt;</u><u style="single"> The above-mentioned 82, wherein the dosage form can be flattened without breaking, and the thickness of the dosage form after flattening corresponds to about 20% or less of the thickness of the dosage form before flattening. Solid controlled release dosage form.</u><u style="single">&lt;87&gt;</u><u style="single"> The amount of opioid analgesic released 0.5 hours from the flattening form was measured by in vitro elution in USP device 1 (basket) at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. The solid controlled release form according to any one of 82 to 86 above, which deviates from the non-flattenant form by about 20 percentage points or less.</u><u style="single">&lt;88&gt;</u><u style="single"> The amount of opioid analgesic released 0.5 hours from the flattening form was measured by in vitro elution in USP apparatus 1 (basket) at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. The solid controlled release form according to any one of 82 to 86 above, which deviates from the non-flattenant form by about 15 percentage points or less.</u><u style="single">&lt;89&gt;</u><u style="single"> The amount of opioid analgesic released 0.5 hours from the flattening form was measured by in vitro elution in USP device 1 (basket) at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. The solid controlled release form according to any one of 82 to 86 above, which deviates from the non-flattenant form by about 10 percentage points or less.</u><u style="single">&lt;90&gt;</u><u style="single"> About 0.55 to about 1.0 hydrocodone C after administration</u>_{<u style="single">24</u>}<u style="single">/ C</u>_{<u style="single">max</u>}<u style="single">The solid controlled release dosage form according to 30 above, which provides a ratio.</u><u style="single">&lt;91&gt;</u><u style="single"> C</u>_{<u style="single">24</u>}<u style="single">/ C</u>_{<u style="single">max</u>}<u style="single">The solid controlled release dosage form according to 90 above, wherein the ratio is from about 0.55 to about 0.85.</u><u style="single">&lt;92&gt;</u><u style="single"> C</u>_{<u style="single">24</u>}<u style="single">/ C</u>_{<u style="single">max</u>}<u style="single">The solid controlled release dosage form according to 90 above, wherein the ratio is from about 0.55 to about 0.75.</u><u style="single">&lt;93&gt;</u><u style="single"> C</u>_{<u style="single">24</u>}<u style="single">/ C</u>_{<u style="single">max</u>}<u style="single">The solid controlled release dosage form according to 90 above, wherein the ratio is from about 0.60 to about 0.70.</u><u style="single">&lt;94&gt;</u><u style="single"> Hydrocodone T from about 4 to about 20 hours after administration</u>_{<u style="single">max</u>}<u style="single">The solid controlled release dosage form according to 30 above, which provides (h).</u><u style="single">&lt;95&gt;</u><u style="single"> T</u>_{<u style="single">max</u>}<u style="single">The solid controlled release dosage form according to 94 above, wherein (h) is from about 6 to about 12 hours.</u><u style="single">&lt;96&gt;</u><u style="single"> T</u>_{<u style="single">max</u>}<u style="single">The solid controlled release dosage form according to 94 above, wherein (h) is from about 8 to about 10 hours.</u><u style="single">&lt;97&gt;</u><u style="single"> T</u>_{<u style="single">max</u>}<u style="single">The solid controlled release dosage form according to 94 above, wherein (h) is about 4 to about 10 hours.</u><u style="single">&lt;98&gt;</u><u style="single"> T</u>_{<u style="single">max</u>}<u style="single">The solid controlled release dosage form according to 94 above, wherein (h) is from about 8 to about 14 hours.</u><u style="single">&lt;99&gt;</u><u style="single"> T</u>_{<u style="single">max</u>}<u style="single">The solid controlled release dosage form according to 94 above, wherein (h) is about 14 to about 20 hours after administration of the dosage form.</u><u style="single">&lt;100&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 90 to 99 above, wherein the administration is the first administration to a healthy subject.</u><u style="single">&lt;101&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 90 to 99 above, wherein the administration is the first administration to a healthy subject population.</u><u style="single">&lt;102&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 90 to 99 above, wherein the administration is steady-state administration to a healthy subject.</u><u style="single">&lt;103&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 90 to 99 above, wherein the administration is steady-state administration to a healthy population.</u><u style="single">&lt;104&gt;</u><u style="single"> 30. The solid controlled release form according to 30 above, which comprises about 20 mg of hydrocodone or a pharmaceutically acceptable salt thereof.</u><u style="single">&lt;105&gt;</u><u style="single"> 30. The solid controlled release form according to 30 above, which contains about 120 mg of hydrocodone or a pharmaceutically acceptable salt thereof.</u><u style="single">&lt;106&gt;</u><u style="single"> Approximately 250 to 400 post-administration average AUC (ng) for each 20 mg of hydrocodone contained in the dosage form</u>^{<u style="single">*</u>}<u style="single">The solid controlled release dosage form according to 30 above, which provides h / mL).</u><u style="single">&lt;107&gt;</u><u style="single"> Mean AUC (ng) after administration of about 250 to about 400, about 275 to about 350, about 300 to 330 or about 280 to about 320</u>^{<u style="single">*</u>}<u style="single">h / mL), the solid controlled release form according to 104 above.</u><u style="single">&lt;108&gt;</u><u style="single"> Mean AUC (ng) after administration of about 1500 to about 2400, about 1700 to about 2200, about 1800 to about 2100 or about 1900 to about 2100</u>^{<u style="single">*</u>}<u style="single">h / mL), the solid controlled release form according to 105 above.</u><u style="single">&lt;109&gt;</u><u style="single"> Approximately 10 to approximately 30 post-administration average C for each 20 mg of hydrocodone contained in the dosage form</u>_{<u style="single">max</u>}<u style="single">30. The solid controlled release dosage form according to 30 above, which provides (ng / mL).</u><u style="single">&lt;110&gt;</u><u style="single"> Mean C after administration of about 10 to about 30, about 12 to about 25, about 14 to about 18 or about 12 to about 17</u>_{<u style="single">max</u>}<u style="single">The solid controlled release dosage form according to 104 above, which provides (ng / mL).</u><u style="single">&lt;111&gt;</u><u style="single"> Mean C after administration of about 60 to about 180, about 100 to about 160, about 110 to about 150 or about 100 to about 140</u>_{<u style="single">max</u>}<u style="single">The solid controlled release dosage form according to 105 above, which provides (ng / mL).</u><u style="single">&lt;112&gt;</u><u style="single"> Mean T after administration of about 10 to about 20, about 12 to about 18, about 13 to about 17 or about 14 to about 16</u>_{<u style="single">max</u>}<u style="single">The solid controlled release dosage form according to 30 above, which provides (h).</u><u style="single">&lt;113&gt;</u><u style="single"> Mean T after administration of about 5 to about 10, about 6 to about 9, about 7 or about 8</u>_{<u style="single">1/2</u>}<u style="single">The solid controlled release dosage form according to 30 above, which provides (h).</u><u style="single">&lt;114&gt;</u><u style="single"> Mean T after administration of about 0.01 to about 0.2, about 0.1 to about 0.18, about 0.3 to about 0.17 or about 0.06 to about 0.15</u>_{<u style="single">lag</u>}<u style="single">The solid controlled release dosage form according to 30 above, which provides (h).</u><u style="single">&lt;115&gt;</u><u style="single"> The average C</u>_{<u style="single">24</u>}<u style="single">/ C</u>_{<u style="single">max</u>}<u style="single">30. The solid controlled release dosage form according to 30 above, wherein the ratio 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.</u><u style="single">&lt;116&gt;</u><u style="single"> The solid controlled release dosage form according to any one of 106 to 115 above, wherein the administration is in a fasting state.</u><u style="single">&lt;117&gt;</u><u style="single"> Mean AUC (ng) after administration in a feeding state</u>^{<u style="single">*</u>}<u style="single">h / mL) is AUC (ng) after administration in the fasted state</u>^{<u style="single">*</u>}<u style="single">The solid controlled release dosage form according to 30 above, which is less than 20% higher, less than 16% higher or less than 12% higher than h / mL).</u><u style="single">&lt;118&gt;</u><u style="single"> Mean C after administration in a feeding state</u>_{<u style="single">max</u>}<u style="single">(ng / mL) is C after administration in the fasted state</u>_{<u style="single">max</u>}<u style="single">The solid controlled release dosage form according to 30 above, which is less than 80% higher, less than 70% higher or less than 60% higher.</u><u style="single">&lt;119&gt;</u><u style="single"> Mean T after administration in a feeding state</u>_{<u style="single">max</u>}<u style="single">(h) is T after administration in the fasted state</u>_{<u style="single">max</u>}<u style="single">The solid controlled release dosage form according to 30 above, which is within 25%, within 20% or within 15% of (h).</u><u style="single">&lt;120&gt;</u><u style="single"> Mean T after administration in a feeding state</u>_{<u style="single">1/2</u>}<u style="single">(h) is T after administration in the fasted state</u>_{<u style="single">1/2</u>}<u style="single">The solid controlled release dosage form according to 30 above, which is within 8%, within 5% or within 2% of.</u><u style="single">&lt;121&gt;</u><u style="single"> Mean T after administration in a feeding state</u>_{<u style="single">lag</u>}<u style="single">(h) is T after administration in the fasted state</u>_{<u style="single">1/2</u>}<u style="single">The solid controlled release dosage form according to 30 above, which is less than 150% higher, less than 125% higher or less than 100% higher.</u><u style="single">&lt;122&gt;</u><u style="single"> With a core containing the first part of the opioid analgesic dispersed in the first matrix material containing polyethylene oxide,</u><u style="single"> With a shell covering the core and containing a second portion of opioid analgesic dispersed in a second matrix material containing polyethylene oxide</u><u style="single">Solid controlled release dosage form containing.</u><u style="single">&lt;123&gt;</u><u style="single"> A compressed core containing the first portion of opioid analgesic dispersed in a first matrix material containing polyethylene oxide,</u><u style="single"> With a compression coating covering the core and containing a second portion of opioid analgesic dispersed in a second matrix material containing polyethylene oxide</u><u style="single">Solid controlled release dosage form containing.</u><u style="single">&lt;124&gt;</u><u style="single"> With a core containing the first part of the opioid analgesic dispersed in the first matrix material,</u><u style="single"> With a shell covering the core and containing a second portion of opioid analgesic dispersed in a second matrix material</u><u style="single">Is a solid controlled release form containing</u><u style="single"> Measured by in vitro elution in USP device 1 (basket) at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C.</u><u style="single"> The amount of opioid analgesic released from the dosage form at 2 hours was less than about 25%.</u><u style="single"> The amount of opioid analgesic released from the dosage form at 4 hours is from about 10% to about 30%.</u><u style="single"> The amount of opioid analgesic released from the dosage form at 8 hours is from about 20% to about 60%.</u><u style="single"> The amount of opioid analgesic released from the dosage form at 12 hours is from about 40% to about 90%.</u><u style="single"> A solid controlled release dosage form in which the amount of opioid analgesic released from the dosage form at 18 hours exceeds approximately 70%.</u><u style="single">&lt;125&gt;</u><u style="single"> A therapeutically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof, and a controlled release excipient.</u><u style="single">Is a solid controlled release form containing</u><u style="single"> The amount of hydrocodone or salt thereof released from the dosage form is 8 to 24 as measured by in vitro elution in USP apparatus 1 (basket) at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. Proportional to the elapsed time to time within 20%,</u><u style="single"> The dosage form can be flattened without breaking, and the thickness of the dosage form after flattening corresponds to about 20% or less of the thickness of the dosage form before flattening.</u><u style="single"> The amount of hydrocodone or salt thereof released from the flattening form 0.5 hours by in vitro elution in USP apparatus 1 (basket) at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. A solid controlled release form that deviates by about 20 percentage points or less from the non-flattenant form when measured.</u><u style="single">&lt;126&gt;</u><u style="single"> A therapeutically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof, and a controlled release excipient.</u><u style="single">Is a solid controlled release form containing</u><u style="single"> Measured by in vitro elution in USP device 1 (basket) at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C.</u><u style="single"> The amount of hydrocodone or salt thereof released from the dosage form at 2 hours is less than about 25%.</u><u style="single"> The amount of hydrocodone or salt thereof released from the dosage form at 4 hours is from about 10% to about 30%.</u><u style="single"> The amount of hydrocodone or salt thereof released from the dosage form at 8 hours is from about 20% to about 60%.</u><u style="single"> The amount of hydrocodone or salt thereof released from the dosage form at 12 hours is from about 40% to about 90%.</u><u style="single"> The amount of hydrocodone or salt thereof released from the dosage form at 18 hours exceeds about 70%,</u><u style="single"> The dosage form can be flattened without breaking, and the thickness of the dosage form after flattening corresponds to about 20% or less of the thickness of the dosage form before flattening.</u><u style="single"> The amount of hydrocodone or salt thereof released from the flattening form 0.5 hours by in vitro elution in USP apparatus 1 (basket) at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. A solid controlled release form that deviates by about 20 percentage points or less from the non-flattenant form when measured.</u><u style="single">&lt;127&gt;</u><u style="single"> A therapeutically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof dispersed in a controlled release excipient.</u><u style="single">A solid controlled release dosage form comprising, wherein the internal 60% of the dosage form contains at least 80% of the hydrocodone or a salt thereof.</u><u style="single"> The amount of hydrocodone or salt thereof released from the dosage form is from 8 as measured by in vitro elution in USP apparatus 1 (basket) at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. Solid controlled release dosage form proportional to elapsed time up to 24 hours within 20%.</u><u style="single">&lt;128&gt;</u><u style="single"> 12. The solid controlled release dosage form of 127 above, wherein the internal 50% of the dosage form contains at least 80% of the hydrocodone or a salt thereof.</u><u style="single">&lt;129&gt;</u><u style="single"> A method for treating pain in a subject in need thereof, comprising administering to the subject the solid controlled release dosage form according to any of 1 to 128 above.</u><u style="single">&lt;130&gt;</u><u style="single"> Preparing a core containing the first part of the opioid analgesic dispersed in the first matrix material, and</u><u style="single"> Covering the core with a shell containing a second portion of opioid analgesic dispersed in a second matrix material.</u><u style="single">A method of producing a solid controlled release dosage form, comprising:</u><u style="single"> The amount of opioid analgesic released from the dosage form was measured by in vitro elution in USP device 1 (basket) at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C for 8 to 24 hours. A method that is proportional to the elapsed time up to within 20%.</u><u style="single">&lt;131&gt;</u><u style="single"> Preparing a core containing the first portion of an opioid analgesic dispersed in a first matrix material containing polyethylene oxide, and</u><u style="single"> Covering the core with a shell containing a second portion of opioid analgesic dispersed in a second matrix material containing polyethylene oxide.</u><u style="single">A method of producing a solid controlled release dosage form, including.</u><u style="single">&lt;132&gt;</u><u style="single"> Preparing a compressed core containing the first portion of opioid analgesic dispersed in a first matrix material containing polyethylene oxide, and.</u><u style="single"> Covering the core by compressively coating a second portion of the opioid analgesic dispersed in a second matrix material containing polyethylene oxide over the core.</u><u style="single">A method of producing a solid controlled release dosage form, including.</u><u style="single">&lt;133&gt;</u><u style="single"> Preparing a core containing the first part of the opioid analgesic dispersed in the first matrix material, and</u><u style="single"> Covering the core with a shell containing a second portion of opioid analgesic dispersed in a second matrix material throughout the core.</u><u style="single">A method of producing a solid controlled release dosage form, comprising:</u><u style="single"> Measured by in vitro elution in USP device 1 (basket) at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C.</u><u style="single"> The amount of opioid analgesic released from the dosage form at 2 hours was less than about 25%.</u><u style="single"> The amount of opioid analgesic released from the dosage form at 4 hours is from about 10% to about 30%.</u><u style="single"> The amount of opioid analgesic released from the dosage form at 8 hours is from about 20% to about 60%.</u><u style="single"> The amount of opioid analgesic released from the dosage form at 12 hours is from about 40% to about 90%.</u><u style="single"> A method in which the amount of opioid analgesic released from the dosage form at 18 hours exceeds about 70%.</u><u style="single">&lt;134&gt;</u><u style="single"> Combining a therapeutically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof, and a controlled release excipient</u><u style="single">A method of producing a solid controlled release dosage form, comprising:</u><u style="single"> The amount of hydrocodone or salt thereof released from the dosage form is 8 to 24 as measured by in vitro elution in USP apparatus 1 (basket) at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. At any two time points up to time, proportional to the elapsed time within 20%,</u><u style="single"> The dosage form can be flattened without breaking, and the thickness of the dosage form after flattening corresponds to about 20% or less of the thickness of the dosage form before flattening.</u><u style="single"> The amount of hydrocodone or salt thereof released from the flattening form 0.5 hours by in vitro elution in USP apparatus 1 (basket) at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. A method that, when measured, deviates by about 20 percentage points or less from the non-flattenant form.</u><u style="single">&lt;135&gt;</u><u style="single"> Combining a therapeutically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof, and a controlled release excipient</u><u style="single">A method of producing a solid controlled release dosage form, comprising:</u><u style="single"> Measured by in vitro elution in USP device 1 (basket) at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C.</u><u style="single"> The amount of hydrocodone or salt thereof released from the dosage form at 2 hours is less than about 25%.</u><u style="single"> The amount of hydrocodone or salt thereof released from the dosage form at 4 hours is from about 10% to about 30%.</u><u style="single"> The amount of hydrocodone or salt thereof released from the dosage form at 8 hours is from about 20% to about 60%.</u><u style="single"> The amount of hydrocodone or salt thereof released from the dosage form at 12 hours is from about 40% to about 90%.</u><u style="single"> The amount of hydrocodone or salt thereof released from the dosage form at 18 hours exceeds about 70%,</u><u style="single"> The dosage form can be flattened without breaking, and the thickness of the dosage form after flattening corresponds to about 20% or less of the thickness of the dosage form before flattening.</u><u style="single"> The amount of hydrocodone or salt thereof released from the flattening form 0.5 hours by in vitro elution in USP apparatus 1 (basket) at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. A method that, when measured, deviates by about 20 percentage points or less from the non-flattenant form.</u><u style="single">&lt;136&gt;</u><u style="single"> Dispersing a therapeutically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof in a controlled release excipient.</u><u style="single">A method of producing a solid controlled release dosage form comprising, wherein the internal 60% of the dosage form contains at least 80% of the hydrocodone or a salt thereof.</u><u style="single"> The amount of hydrocodone or salt released from the dosage form is from 8 as measured by in vitro elution in USP apparatus 1 (basket) at 100 rpm in 900 mL of enzyme-free simulated gastric juice (SGF) at 37 ° C. A method that is proportional to the elapsed time up to 24 hours within 20%.</u></p>