Encased tamper resistant controlled release dosage forms

Tamper-resistant encapsulated dosage forms with controlled release

Encased Tamper Resistant Controlled Release Dosage Forms

Full description

Background of the invention

The present invention relates to multi-layered pharmaceutical dosage forms that are tamper-resistant and preferably provide substantially zero release of the active agent contained therein.

Pharmaceutical products are sometimes subject to misuse. For example, a given dose of an opioid agonist may be more effective when administered non-gastrointestinally than the same dose administered orally. Some formulas can be tampered with to obtain the opioid-like adjuvant contained in them for illicit use. Controlled-release opioid adjuvant formulations are sometimes broken down or subjected to extraction with solvents (e.g., ethanol) by analgesic users to provide their opioids for immediate release upon orally or non-parenteral administration.

Controlled-release opioid adjuvant dosage forms that can release a portion of the opioid upon exposure to ethanol could also result in the patient receiving the dose more quickly than intended if the patient ignores the instructions for use and consumes alcohol at the same time as the dosage form.

U.S. Patent Application Publication No. 2009/0081290 discloses tamper-resistant dosage forms which, in certain embodiments, are directed to an orally administered, extended-release solid pharmaceutical dosage form comprising an extended-release block formulation in the form of a tablet or substances Multiple minutes. The tablet or individual polyparticles may be at least flat without cracking, characterized by a thickness of the tablet or individual polyparticles after flattening corresponding to not more than about 60% of the thickness of the tablet or individual particulates before flattening, and wherein the flat tablet or Multiple flat individual particulate matter In vitro dissolution rate, as measured in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C, Containing a percent amount of the active agent released at 0.5 hour dissolution deviates by no more than about 20% points from the corresponding laboratory dissolution rate of the non-flat reference tablet or multi-particle reference material. There is still a need in the field for orally administered tamper-resistant pharmaceutical dosage forms, as these dosage forms preferably provide release properties of the active agent that are largely on the order of zero. All references and publications cited in the present application are hereby incorporated by reference in their entirety for all purposes.

General description of the invention

One object of certain embodiments of the present invention is to provide a controlled-release solid dosage form comprising an active agent (e.g., an opioid analgesic), which is tamper resistant.

One object of certain embodiments of the present invention is to provide a controlled-release solid dosage form comprising an active agent (e.g., an opioid analgesic), which is resistant to crushing.

One object of certain embodiments of the present invention is to provide a controlled-release solid dosage form comprising an opioid analgesic, which is subject to less abuse via the gastrointestinal tract than other dosage forms.

One object of certain embodiments of the present invention is to provide a controlled-release solid dosage form comprising an opioid analgesic, which is subject to less intranasal abuse than other dosage forms.

One object of certain embodiments of the present invention is to provide a controlled-release solid dosage form comprising an opioid analgesic, which is subject to less orally administered abuse than other dosage forms.

An additional objective of certain embodiments of the present invention is to provide a controlled-release solid dosage form comprising an opioid analgesic, which is subject to less conversion than other dosage forms.

An additional objective of certain embodiments of the present invention is to provide a method for treating pain in human patients using a controlled-release solid dosage form comprising an opioid analgesic solid dosage while minimizing potential misuse of the dosage form.

An additional objective of certain embodiments of the present invention is to treat a disease or condition (e.g., pain) by administering a controlled-release solid dosage form as disclosed in the present application to a patient in need.

An additional objective of certain embodiments of the present invention is to provide a method for manufacturing an orally administered dosage form of an active agent (e.g., an opioid analgesic solid dosage) as disclosed in the present application.

An additional purpose of certain embodiments of the present invention is to provide for the use of a drug (e.g., solid dosage opioid analgesic) in the manufacture of a dosage form for the treatment of a disease condition (e.g., pain).

These and other objectives of the present invention are achieved by, in certain embodiments, being directed into a controlled-release solid dosage form comprising a core comprising a first portion of an active agent (e.g., an opioid analgesic) solid dosage dispersed in a first matrix. a first matrix material ; an envelope surrounding the core and containing a second portion of the active agent dispersed in the second template material; Where the amount of active agent released from the dose form is proportional in the range of 20% to the 8- to 24-hour time, as measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid. fluid without enzymes at 37°C.

In certain embodiments, the amount of active agent released from the dosage form is proportional within 30% to the time elapsed in at least one of (1) 4 to 24 hours, (2) 8 to 24 hours, (3) 12 to 24 hours. Hour, (4) from 18 to 24 hours, (5) from 4 to 8

hours, (6) from 4 to 12 hours, (7) from 4 to 18 hours, (8) from 8 to 12 hours, (9) from 8 to 18 hours, or (10) from 12 to 18 hours, according to the measurement It is dissolved in vitro in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C. In alternative embodiments, the amount of active agent released from the dosage form is proportional within 30% to the time spent in all (1) 8 to 24 hours, (2) 8 to 12 hours, and (3) 8 to 18 hours, As measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C.

In certain embodiments, the amount of active agent released from the dosage form is proportional within 25% to the time elapsed in at least one of (1) 4 to 24 hours, (2) 8 to 24 hours, (3) 12 to 24 hours. 1 hour, (4) 18 to 24 hours, (5) 4 to 8 hours, (6) 4 to 12 hours, (7) 4 to 18 hours, (8) 8 to 12 hours, (9) From 8 to 18 hours, or (10) from 12 to 18 hours, As measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C. In alternative embodiments, the amount of active agent released from the dosage form is proportional within 25% to the time spent in all of the following (1) from 8 to 24 hours, (2) from 8 to 12 hours, and (3) from 8 to 18 hours. Hours, as measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C.

In certain embodiments, the amount of active agent released from the dosage form is proportional within 20% to the time elapsed in at least one of (1) 4 to 24 hours, (2) 8 to 24 hours, (3) 12 to 24 hours. 1 hour, (4) 18 to 24 hours, (5) 4 to 8 hours, (6) 4 to 12 hours, (7) 4 to 18 hours, (8) 8 to 12 hours, (9) 8 to 18 hours, or (10) 12 to 18 hours, as measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm in 900 mL of simulated gastric fluid without enzymes at 37°C. In alternative embodiments, the amount of active agent released from the dosage form is proportional within 20% to the time spent in all of the following (1) from 8 to 24 hours, (2) from 8 to 12 hours, and (3) from 8 to 18 hours. Hours, as measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C.

In certain embodiments, the amount of active agent released from the dosage form is proportional within 10% to the time elapsed in at least one of (1) 4 to 24 hours, (2) 8 to 24 hours, (3) 12 to 24 hours. 1 hour, (4) 18 to 24 hours, (5) 4 to 8 hours, (6) 4 to 12 hours, (7) 4 to 18 hours, (8) 8 to 12 hours, (9) 8 to 18 hours, or (10) 12 to 18 hours, as measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm in 900 mL of simulated gastric fluid without enzymes at 37°C.

In alternative embodiments, the amount of active agent released from the dosage form is proportional within 10% to the time spent in all of the following (1) from 8 to 24 hours, (2) from 8 to 12 hours, and (3) from 8 to 18 hours. Hours, as measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C.

In certain embodiments, the amount of active agent released from the dosage form is proportional within 5% to the time elapsed in at least one of (1) 4 to 24 hours, (2) 8 to 24 hours, (3) 12 to 24 hours. 1 hour, (4) 18 to 24 hours, (5) 4 to 8 hours, (6) 4 to 12 hours, (7) 4 to 18 hours, (8) 8 to 12 hours, (9) 8 to 18 hours, or (10) 12 to 18 hours, as measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm in 900 mL of simulated gastric fluid without enzymes at 37°C. In alternative embodiments, the amount of active agent released from the dosage form is proportional within 5% to the time spent in all of the following (1) from 8 to 24 hours, (2) from 8 to 12 hours, and (3) from 8 to 18 hours. Hours, as measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C.

In certain embodiments, the present invention is directed to a controlled-release solid dosage form comprising a core comprising a first portion of an active agent (e.g., an opioid analgesic) dispersed in a first matrix material comprising polyethylene oxide; A shell surrounding the core and containing a second portion of the active agent dispersed in a second matrix material comprising polyethylene oxide.

In alternative embodiments, the first mold material comprises only polyethylene oxide or only the second mold material comprises polyethylene oxide.

In certain embodiments, the present invention is directed to a controlled-release solid dosage form comprising a pressurized core comprising a first portion of an active agent (e.g., an opioid analgesic) dispersed in a first matrix comprising polyethylene oxide; A pressure coating envelops the core and includes a second portion of the active agent dispersed in a second mold material comprising polyethylene oxide.

In certain embodiments, the present invention is directed to a controlled-release solid dosage form comprising a core comprising a first portion of an active agent (e.g., an opioid agonist) dispersed in a first matrix material; an envelope surrounding the core and containing a second portion of the active agent dispersed in the second template material; Where the amount of active agent released from the dosage form at 2 hours is less than about 25%; The amount of active agent released from the dosage form at 4 hours ranges from about 10% to about 30%; The amount of active agent released from the dosage form at 8 hours ranges 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%; The amount of active agent released from the dosage form at 18 hours is greater than about 70%; As measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C.

In certain embodiments, the present invention is directed to a controlled-release solid dosage form comprising a core comprising a first portion of an active agent (e.g., an opioid agonist) dispersed in a first matrix material; an envelope surrounding the core and containing a second portion of the active agent dispersed in the second template material; Where the amount of active agent released from the dosage form at 2 hours is less than about 20%; The amount of active agent released from the dosage form at 4 hours is from about 10% to about 30%; The amount of active agent released from the dosage form at 8 hours ranges from about 30% to about 60%; The amount of active agent released from the dosage form at 12 hours ranges from about 50% to about 90%; The amount of active agent released from the dosage form at 18 hours is greater than about 80%; As measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C.

In certain embodiments, the present invention is directed to a controlled-release solid dosage form comprising a core comprising a first portion of an active agent (e.g., an opioid agonist) dispersed in a first matrix material; an envelope surrounding the core and containing a second portion of the active agent dispersed in the second template material; Where the amount of active agent released from the dosage form at 2 hours is less than about 15%; The amount of active agent released from the dosage form at 4 hours ranges from about 8% to about 20%; The amount of active agent released from the dosage form at 8 hours ranges from about 20% to about 50%; The amount of active agent released from the dosage form at 12 hours ranges from about 40% to about 70%; The amount of active agent released from the dosage form at 18 hours is greater than about 70%; The amount of active agent released from the dosage form at 24 hours is greater than about 90%; As measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C. In certain embodiments, the present invention is directed to a controlled-release solid dosage form comprising a therapeutically effective amount of an aqueous codon or a pharmaceutically acceptable salt thereof, and a controlled-release excipient; The amount of opioid agonist released from the dosage form is proportional in the range of 20% to 8 to 24 hours, as measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of gastric fluid. Simulated without enzymes at 37 °C; The surface of the dose image may be leveled without cracking, where the thickness of the dose image after leveling corresponds to no more than about 20% of the thickness of the dose image before leveling; The amount of aqueous codon or its salt released at 0.5 h from the planar dosage form does not deviate more than about 20% drops from the nonplatform dosage form as measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm at 900 ml of simulated gastric fluid without enzymes at 37°C.

In a particular embodiment, the present invention is directed to a controlled-release solid dosage form comprising a therapeutically effective amount of an aqueous codon or a pharmaceutically acceptable salt thereof, and a controlled-release excipient; The amount of hydrocodone or its salt released from the dosage form at 2 hours is less than about 25%; The amount of hydrocodone or its salt released from the dosage form at 4 hours ranges from about 10% to about 30%; The amount of hydrocodone or its salt released from the dosing form at 8 hours ranges from about 20% to about 60%; The amount of hydrocodone or its salt released from the dosage form at 12 hours is from about 40% to about 90%; The amount of hydrocodone or its salt released from the dosage form at 18 hours is greater than about 70%; As measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C; The surface of the dose image can be leveled without cracking, as the thickness of the dose image after leveling corresponds to no more than about 20% of the thickness of the dose image before leveling; The amount of hydrocodone or its salt released at 0.5 hours from a flat-surface dosage form will deviate by no more than about 20% drops from a non-flat-surface dosage form as measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C.

In certain embodiments, the present invention is directed to a controlled-release solid dosage form comprising a therapeutically effective amount of a hydrocodone or a pharmaceutically acceptable salt thereof dispersed in a controlled-release excipient; wherein the internal 60% of the dosage form contains at least 80% hydrocodone or a salt thereof; The amount of hydrocodone or its salt released from the dosage form is proportional to the range of 20% over time from 8 to 24 hours, as measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of gastric fluid. Simulated without enzymes at 37°C.

In certain embodiments, the present invention is directed to a method for preparing a controlled-release solid dosage form comprising a core preparation comprising a first portion of an active agent (e.g., an opioid analgesic) dispersed in a first matrix material; Encasing the core in a shell containing a second part of the active agent dispersed in the second matrix material; Where the amount of active agent released from the dose form is proportional in the range of 20% to the 8 to 24 hour time, as measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid. fluid without enzymes at 37°C.

In certain embodiments, the present invention is directed to a method for preparing a controlled-release solid dosage form comprising a core preparation comprising a first portion of an active agent (e.g., an opioid analgesic) dispersed in a first matrix comprising polyethylene oxide; The core is encased in a shell that includes a second part of the active agent dispersed in a second matrix material that includes polyethylene oxide. In alternative embodiments, corresponding dosage forms are prepared such that the first matrix comprises only polyethylene oxide or the second matrix comprises only polyethylene oxide.

In certain embodiments, the present invention is directed to a method for preparing a controlled-release solid dosage form comprising preparing a compressed core comprising a first portion of an active agent (e.g., an opioid analgesic) dispersed in a first matrix material comprising polyethylene oxide; Wrapping the core with a pressure coating material for a second portion of the active agent dispersed in the second matrix material includes polyethylene oxide above the core. In alternative embodiments, corresponding pressure-coated dosage forms are prepared such that the first matrix comprises only polyethylene oxide or the second matrix comprises only polyethylene oxide.

In certain embodiments, the present invention is directed to a method for preparing a controlled-release solid dosage form comprising a core preparation comprising a first portion of an active agent (e.g., an opioid agonist) dispersed in a first matrix material; encasing the core in a shell comprising a second portion of the active agent dispersed in a second matrix material above the core; Where the amount of active agent released from the dosage form at 2 hours is less than about 25%; The amount of active agent released from the dosage form at 4 hours ranges from about 10% to about 30%; The amount of active agent released from the dosage form at 8 hours ranges 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%; The amount of active agent released from the dosing form at 18 hours is greater than about 70%, as measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C.

In certain embodiments, the present invention is directed to a method of preparing a controlled-release solid dosage form comprising combining a therapeutically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof, and a controlled-release excipient; The amount of hydrocodone or its salt released from the dosage form at 2 hours is less than about 25%; The amount of hydrocodone or its salt released from the dosage form at 4 hours ranges from about 10% to about 30%; The amount of hydrocodone or its salt released from the dosage form at 8 hours is from about 20% to about 60%; The amount of hydrocodone or its salt released from the dosage form at 12 hours is from about 40% to about 90%; The amount of hydrocodone or its salt released from the dosage form at 18 hours is greater than about 70%; As measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C; The surface of the dose image can be leveled without cracking, as the thickness of the dose image after leveling corresponds to no more than about 20% of the thickness of the dose image before leveling; The amount of hydrocodone or its salt released at 0.5 hours from a flat-surface dosage form will deviate by no more than about 20% drops from a non-flat-surface dosage form as measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C.

In a particular embodiment, the present invention is directed to a method of preparing a controlled-release solid dosage form comprising combining a therapeutically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof, and a controlled-release excipient; Wherein the amount of hydrocodone or a salt thereof released from the dosage form is proportional within 20% to the time elapsed, at any two time points from 8 to 24 hours, as measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm at 900 ml of simulated gastric fluid without enzymes at 37°C; The surface of the dose image can be leveled without cracking, as the thickness of the dose image after leveling corresponds to no more than about 20% of the thickness of the dose image before leveling; The amount of hydrocodone or its salt released at 0.5 hours from a flat-surface dosage form will deviate by no more than about 20% drops from a non-flat-surface dosage form as measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C.

In certain embodiments, the present invention directs to a method of preparing a controlled-release solid dosage form comprising dispersing a therapeutically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof into a controlled-release excipient; Wherein the internal 60% of the dosage form contains at least 80% hydrocodone or a salt thereof; Where the amount of hydrocodone or its salt released from the dosage form is proportional to the range of 20% over time from 8 to 24 hours, as measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of gastric fluid. Simulated without enzymes at 37°C.

In certain embodiments, the present invention is directed to a method for treating pain in a patient or subject comprising administering a controlled-release solid dosage form comprising an opioid analgesic as disclosed in the present application.

In preferred embodiments, the present invention is directed to a dosage form of the present invention that exhibits a rate of release of substantially zero after administration to a patient or subject.

The expression “zero release rate” refers to the rate of release of an active agent from a dosage form that is independent of the concentration of the active agent remaining in the dosage form, such that the rate is relatively constant over a period of time. A dose profile showing a release rate starting at zero would show a relatively straight line in a graph of the percentage of active agent released versus time. In certain embodiments of the present invention, zero baseline release is defined as a dose profile containing an amount of released active agent that is within 20% proportional to the time to 8 to 24 hours or 4 to 12 hours, as measured Dissolve in vitro in USP Apparatus 1 (Basket) at 100 rpm in 900 mL of simulated gastric fluid without enzymes at 37°C. For example, an absolute amount of the in vitro dosage form at 8 hours of 20% and an absolute amount at 24 hours of 60% (12) could effectively meet the definition of a proportional expression in the range of 20% with the time taken from 8 to 24 hours. This is evident from the last time spent (24 hours), so that the last launch (60%) is the same multiple (3) of the previous time (8 hours) and the previous launch (20%). To achieve the definition of a proportional expression in the range of 20% with the time taken from 8 to 24 hours (or any other time period) it is only necessary to take the end points of the numerical values into account, although the definition does not exclude other time points from being in the range The time frame is also proportional.

In other embodiments of the present invention, a zero-start release is defined as a dose profile in which the amount of active agent released at 2 hours is less than about 25%; The amount of active agent released from the dosage form at 4 hours ranges from about 10% to about 30%; or The amount of active agent released from the dosage form at 8 hours ranges from about 20% to about 60%; or The amount of active agent released from the dosage form at 12 hours ranges from about 40% to about 90%; or the amount of active agent released from the dosage form at 18 hours is greater than about 70%; As measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C.

The term “polyethylene oxide” is defined for the purpose of the invention as a composition of polyethylene oxide having a molecular weight of at least 25,000, as conventionally measured in the art, and preferably a molecular weight of at least 100,000. Compositions with a lower molecular weight are usually referred to as compounds polyethylene glycols. The term “high molecular weight polyethylene oxide” is defined for the purposes of the present invention as having an approximate molecular weight of at least 1,000,000, based on rheological measurements.

The term “low molecular weight polyethylene oxide” is defined for the purposes of the present invention as having an approximate molecular weight of less than 1,000,000, based on rheological measurements.

The term “direct compression” for the purposes of the present invention is defined to refer to a tableting process, whereby the tablet or other dosage form is made by a process comprising the steps of cold blending the compounds and compressing the dry mixture to form the dosage form, such as using a diffusion blending process and/or Convective mixing (eg Guidance for Industry, SUPAC-IR/MR: Immediate Release and Modified Release Solid Oral Dosage Forms, Manufacturing Equipment Addendum).

The expression “surface leveling” and related expressions as used in the context of leveling the surface of a dose form according to the present invention means that the dose form is subjected to an applied force from a direction closely compatible with the smallest diameter (i.e., thickness) of the dose form when it is of a shape other than Spherical shape, and from any direction when the dose image is spherical.

The expression “crush-resistant” for purposes of certain embodiments of the present invention is defined to refer to dosage forms that can be at least flattened by a bench press as described in the present application without crushing.

For the purposes of the present invention, the term “opiate analgesic” means one or more compounds selected from base opioid agonists, mixed opioid agonists-antagonists, partial opioid agonists, or pharmaceutically acceptable salts, Or complexes, or stereoisomers, or ethers or esters, or hydrates and their solutes and mixtures thereof.

The term "simulated gastric fluid" refers to an aqueous solution used in a dissolution test to simulate stomach conditions, for example, a solution of 0.1 p HCI.

The expression “percentage points” in the context of, for example, “the amount of active agent released at 0.5 hours from the planar dose profile deviates by no more than about 20% points from the nonplanar dose profile” means that the difference in % release before Surface leveling and % release after surface leveling is not more than 20 (i.e., 20 or less). For example, a 60% dose image release rate is planar surface by no more than about 20% points from a 40% dose profile release rate that is non-planar surface area.

The expression "percentage" or the use of "%" without the cross-reference to "percentage (or %) points" represents the ordinary meaning of percentage. For example, 48% is in the 20% range of 60% release, while 40% may not actually be in the 20% range of 60% release.

The term “patient” means a subject (preferably a human) who presents with a clinical condition with a particular symptom or symptom that suggests a need for treatment, who has been treated prophylactically or prophylactically for a condition, or who has been diagnosed as suffering from a condition for which treatment is required.

The expression “subject” is both restrictive to the definition of “sick” and inclusive of “healthy” (i.e., an individual (for example, a human being) who is completely normal in all respects or with respect to a particular condition).

As used herein, the term “stereoisomers” is a general term for all isomers that have individual molecules that differ only in the orientation of their atoms in space.

It includes enantiomers and isomers of compounds with more than one chiral center, which are not identical images of each other (diastereomers).

The term "chiral center" refers to a carbon atom to which four different groups are bonded.

The term "enantiomer" refers to a molecule that cannot be placed on top of its mirror image and is therefore photoactive, where the enantiomer causes the plane of polarized light to rotate in one direction and its mirror image causes the plane of polarized light to rotate in the opposite direction.

The term "racemic" refers to a mixture of equal parts enantiomers that is optically inactive.

The term "dissociation" refers to the separation, concentration, or depletion of one of the two isoforms of a molecule.

“hydrocodone” is defined for purposes of the invention to include a free hydrocodone base, as well as pharmaceutically acceptable salts, complexes, stereoisomers, ethers or esters, hydrates and solubilities thereof and mixtures thereof.

The expression “USP Paddle or Basket Method” represents the Paddle and Basket Method described, for example, in US Pharmacopoeia XII (1990).

The expression “pH dependent” for the purposes of the present invention is defined as having distinct properties (e.g., solubility) that vary according to the pH of the medium.

The expression “pH-independent” for purposes of the present invention is defined as having distinct properties (e.g., solubility) that are largely unaffected by pH.

The expression “bioavailability” is defined for the purposes of the present invention as the relevant extent to which the drug (eg, hydrocodone) is absorbed from unit dosage forms. Bioavailability is also indicated as AUC (ie, area under the plasma concentration/time curve).

The expressions “controlled release,” “sustained release” or “sustained release” are used interchangeably and are defined for purposes of the present invention as the release of the drug (eg, hydrocodone) at a certain rate such that concentrations (eg, plasma) are maintained Within the therapeutic range but below toxic concentrations over a time period of at least about 12 hours or longer, or at least 24 hours or longer. Preferably, a controlled-release dosage form provides once-daily or twice-daily dosing.

The expression “Cmax” refers to the maximum plasma concentration obtained during the dosing interval.

The expression “C24” as used in the present application represents the plasma drug concentration at 24 hours after administration.

The expression "Tmax" refers over time to the maximum plasma concentration (Cmax).

The expression “C24/Cmax ratio” for purposes of the present invention is defined as the ratio of the plasma drug concentration at 24 hours after administration to the highest plasma drug concentration achieved during the dosing interval.

The expression “Tlag” refers to the time point immediately before the first measurable concentration.

The expression “T1/2” refers to the plasma half-life of telophase. It is the time it takes for any concentration in the final phase to drop by half. The expression "minimum effective analgesic concentration" or "MEAC" is very difficult to quantify for concentrations of opioid agonists such as hydrocodone. However, there is a generally effective minimum analgesic concentration of hydrocodone in plasma below which no analgesia is provided. Although there is an indirect relationship between, for example, plasma hydrocodone levels and analgesia, higher and prolonged plasma levels are generally associated with greater pain relief. There is a delay (or slowdown) between the time of maximum hydrocodone levels in plasma and the time of maximum drug effects. This is true for treating pain with opioid analgesics in general.

For purposes of the present invention, unless otherwise specified, the expression “patient” or “subject” means that the discussion (or safeguard) is directed to the pharmacokinetic variables of a patient or subject.

The expression “patient groups,” “subject groups,” or “healthy subject groups” means that the discussion (or safeguard) is directed to the average pharmacokinetic variables of at least two patients, subjects, or healthy subjects, or at least six of the subjects. Sick, submissive, or healthy subjects; Or at least a dozen sick, submissive, or healthy submissives.

For purposes of the present invention, the controlled release formulations disclosed herein are preferably dose proportional. In dose-proportional formulations, the pharmacokinetic variables (e.g., AUC and Cmax) and/or in vitro release increase straight from one dosing strength to the next. Accordingly, the pharmacokinetic and in vitro variants of a given dose can be inferred from different dosage variants of the same formulation.

The expression “first administration” means a single dose of the present invention at the initiation of treatment to a subject, patients, healthy subjects or groups of subjects, groups of patients, or groups of healthy subjects.

The expression “steady state” means that the amount of drug entering the system is approximately the same as the amount of drug leaving the system. Thus, at “steady state,” the patient's body reduces the drug at approximately the same rate at which the drug becomes available to the patient's system through absorption into the bloodstream.

Brief explanation of the drawings

Figure 1 is a graph depicting the melting of the compositions from Examples 1-4.

Figure 2 is a graph depicting the melting of the compositions from Examples 5 and 6.

Figure 3 is a graph depicting the melting of the compositions from Examples 7-12.

Figure 4 is a graph depicting the time-recurrence curve of the average plasma concentration 1 from Example 13.

Figure 5 is a graph depicting the time-frequency curve of the average plasma concentration 2 from Example 13.

Figure 6 is a graph depicting the time-frequency curve of the average plasma concentration 3 from Example 13.

Figure 7 is a graph depicting the plasma concentrations in the compositions of Examples 14-20.

Detailed description

The present invention is directed to controlled release pharmaceutical formulations which in certain embodiments comprise a higher concentration of the drug in an internal region of the dosage form than in an external region. The inner and outer regions are preferably configured as an inner core (eg, compressed tablet) and a shell encasing the core (eg, compression encapsulation). The active agent can be contained only in the core or contained in both the core and the shell. In preferred embodiments, release of the active agent from the dosage form begins substantially at zero, providing dosing certainty and low plasma fluctuations compared to alternative therapies (e.g., immediate release dosage forms).

The dosage forms of the present invention are preferably tamper-resistant since they are difficult to crush or grind (e.g., according to the surface leveling standards disclosed in the present application). These parameters make them particularly suitable for the controlled release of opioid products containing a large dose of an opioid analgesic intended to be released over a period of time from each dosage unit.

Drug users typically take a controlled-release product and crush, cut, grind, chew, dissolve, heat, extract or otherwise destroy the product such that a significant portion or the entire contents of the dosage form becomes available for immediate absorption through injection injection, inhalation, and/or orally administered use.

It is preferable that the dose profile shell of the present invention is difficult to physically separate from the core. This is particularly useful in models that have an increased amount of active agent in the core compared to the envelope, since users will have difficulty accessing a larger drug load from the core.

In certain embodiments, the present invention is directed to a controlled-release solid dosage form comprising: a core comprising a first portion of an opioid-like analgesic dispersed in a first matrix material; A shell encasing the core and containing a second part of an opioid analgesic dispersed in a second matrix.

The core of the dosage form can be formed, for example, by direct pressing, extrusion or molding. Preferably, the inner core provides a controlled-release excipient in the form of a compressed tablet.

The dosage form shell may be formed, for example, by compression encapsulation, molding, sprinkling one or more layers on the core, or by dipping one or more layers on the core or a combination thereof. Preferably, the coating contains a controlled release excipient and is pressurized.

In preferred embodiments, the weight ratio of the core to shell of the dosage forms described in the present application ranges from about 1:0.5 to about 1:5; From about 1:0.5 to about 1:2; From about 1:0.6 to about 1:1.5; Or from about 1:0.8 to about 1:1.2.

In preferred embodiments, the core and shell are visually indistinguishable (for example, by color) and there is no clear distinction between each component. This helps prevent tampering with the dose profile by hindering efforts to reach the heart, which in certain embodiments contains the bulk of the active agent. One metric that can be used to evaluate shell and core color is the CIE L*A*B* value. Preferably, the CIE L*A*B* value of the core and shell should be within 10% of each other. Another measure for evaluating color is to use the RYB or RYB color wheel, where the core and envelope correspond to the same hue or adjacent tones.

In certain embodiments, the first mold material includes PEO. In other embodiments, the second mold material comprises PEO. In further embodiments, the first mold material comprises PEO and the second mold material comprises PEO. Preferably, polyethylene oxide should be contained in both components. In such embodiments, the molecular weight of PEO in the first template material is the same or different from the average molecular weight in the second template material. In certain embodiments, the molecular weight of the PEO contained in each of the two components is within 20%, within 10% or within 5% of each other.

In preferred embodiments of the present invention, when polyethylene oxide is present in both the first and second matrix, the molecular weight of the polyethylene oxide used in the first matrix (in the core) is less than the molecular weight of the polyethylene oxide used in the second matrix (in the shell). For example, in preferred embodiments, the polyethylene oxide in the first template material can have a molecular weight from about 300,000 to about 10,000,000 and the polyethylene oxide in the second template material can have a molecular weight from about 1,000,000 to about 10,000,000. In other preferred embodiments, the polyethylene oxide in the first mold material can have a molecular weight from about 300,000 to about 3,000,000 and the polyethylene oxide in the second mold material can have a molecular weight from about 4,000,000 to about 10,000,000. In other preferred embodiments, the polyethylene oxide in the first mold material can have a molecular weight from about 500,000 to about 1,000,000 and the polyethylene oxide in the second mold material can have a molecular weight from about 6,000,000 to about 8,000,000.

In certain embodiments, the active agent (eg, an opioid analgesic) in the first part (in the core) is identical to the active agent in the second part (in the shell). In other embodiments, the effective factor in the first part is different from the effective factor in the second part.

In certain embodiments, the ratio of the active agent (e.g., an opioid analgesic) in the core to the ratio of the active agent in the shell ranges from about 1:1 to about 10:1; From about 2:1 to about 8:1; From about 2:1 to about 5:1 or about 4:1.

In certain embodiments, the weight ratio of the first portion of the active agent (e.g., an opioid analgesic) to the polyethylene oxide in the first matrix material ranges from about 1:0.25 to about 1:30; From about 1:0.5 to about 1:100; From about 1:0.5 to about 1:20; From about 1:1 to about 1:10; From about 1:15 to about 1:20; From about 1:1.5 to about 1:4; About 1:18 or about 1:2.

In alternative embodiments, the weight ratio of the second portion of the active agent (e.g., an opioid analgesic) to the polyethylene oxide in the second matrix material ranges from about 1:1 to about 1:200; From about 1:1 to about 1:125; From about 1:2 to about 1:100; From about 1:5 to about 1:50; From about 1:12 to about 1:25; About 1:98 or about 1:15. In certain embodiments, the amount of active agent (e.g., an opioid-like analgesic) released by the dosage form is proportional within 20%, within 10%, or within 5% over time from 8 to 24 hours, as measured Dissolve in vitro in USP Apparatus 1 (Basket) at 100 rpm in 900 mL of simulated gastric fluid without enzymes at 37°C.

In certain embodiments, the amount of active agent (e.g., an opioid-like analgesic) released by the dose profile is proportional in the 20% range, 10% range, or 5% range to the 8 to 18 hour time course, as measured by Dissolve in vitro in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C.

In certain embodiments, the amount of active agent (e.g., an opioid-like analgesic) released by the dose profile is proportional in the 20% range, 10% range, or 5% range to the 8 to 12 hour time, as measured by Dissolve in vitro in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C.

In certain embodiments, the amount of active agent (e.g., an opioid-like analgesic) released by the dose profile is proportional in the 20% range, 10% range, or 5% range to the 12 to 24 hour time, as measured by Dissolve in vitro in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C. In certain embodiments, the amount of active agent (e.g., an opioid-like analgesic) released by the dose profile is proportional in the 20% range, 10% range, or 5% range to the 12 to 18 hour time, as measured Dissolve in vitro in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C.

In certain embodiments, the amount of active agent (e.g., an opioid-like analgesic) released by the dosage form is proportional in the range of 20%, within the range of 10%, or within the range of 5% to the time elapsed from 4 to 20 hours, as measured Dissolve in vitro in USP Apparatus 1 (Basket) at 100 rpm in 900 mL of simulated gastric fluid without enzymes at 37°C.

In certain embodiments, the amount of active agent (e.g., an opioid-like analgesic) released by the dose profile is proportional in the 20% range, 10% range, or 5% range to the 4 to 15 hour time, as measured by Dissolve in vitro in USP Apparatus 1 (Basket) at 100 rpm in 900 mL of simulated gastric fluid without enzymes at 37°C.

In certain embodiments, the amount of active agent (e.g., an opioid-like analgesic) released by the dose profile is proportional within 20%, within 10%, or within 5% to the time taken from 4 to 10 hours, as measured by It is dissolved in vitro in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C. In certain embodiments, the amount of active agent (e.g., an opioid-like analgesic) released by the dose profile is proportional in the 20% range, 10% range, or 5% range to the 8 to 20 hour time, as measured It is dissolved in vitro in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C.

In certain embodiments, the amount of active agent (e.g., an opioid-like analgesic) released by the dose profile is proportional in the 20% range, 10% range, or 5% range to the 10 to 15 hour time, as measured It is dissolved in vitro in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C.

In certain embodiments, the amount of active agent (eg, opioid agonist) released at 2 hours is less than about 25%; The amount of active agent released from the dosage form at 4 hours is from about 10% to about 30%; The amount of active agent released from the dosage form at 8 hours is from about 20% to about 60%; The amount of active agent absolute from the dose profile at 12 hours ranges from about 40% to about 90%; The amount of active agent released from the dosage form at 18 hours is greater than about 70%; As measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C.

In certain embodiments, the amount of active agent (eg, opioid agonist) released at 2 hours is less than about 15%; The amount of active agent released from the dosage form at 4 hours is from about 10% to about 20%; The amount of active agent released from the dosage form at 8 hours is from about 30% to about 45%; The absolute amount of active agent from the dose profile at 12 hours ranges from about 50% to about 70%; The amount of active agent released from the dosage form at 18 hours is greater than about 90%; As measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C.

In certain embodiments, the amount of active agent (e.g., opioid analgesic) released at 2 hours is less than about 10%; The amount of active agent released from the dosage form at 4 hours is from about 20% to about 30%; The amount of active agent released from the dosage form at 8 hours is from about 45% to about 60%; The amount of active agent absolute from the dose profile at 12 hours ranges from about 70% to about 90%; The amount of active agent released from the dosage form at 18 hours is greater than about 95%; As measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C.

In certain embodiments, the amount of active agent (e.g., opioid analgesic) released by the dosage form is proportional to within 20% over time from 8 to 24 hours, as measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C and at least one of the following is shown: (1) The amount of opioid analgesic released at 2 hours is less than about 20%, (2) the amount of opioid analgesic released at 4 hours is from about 10% to about 30%, (3) the amount of opioid analgesic released at 8 hours is about 30% to about 60%, (4) the amount of opioid analgesic released at 12 hours is greater than about 50% to about 90%, or (5) the amount of opioid analgesic released at 18 hours is greater than about 80%.

In certain embodiments, the amount of active agent (e.g., opioid agonist) released by the dosage form is proportional within a range of 20% over time from 8 to 24 hours, as measured by in vitro dissolution in USP Apparatus 1 (Basket). At 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C at least one of the following is demonstrated: (1) The amount of opioid analgesic released at 2 hours is less than about 15%, (2) the amount of opioid analgesic released at 4 hours is about 10% to about 20%, (3) the amount of opioid analgesic released at 8 hours is about 30% to about 45%, (4) the amount of opioid analgesic released at 12 hours is greater than about 50% to about 70%, or (5) the amount of opioid analgesic released at 18 hours is greater than about 90%.

In certain embodiments, the amount of active agent (e.g., an opioid-like analgesic) released by the dosage form is proportional to within 20% over time from 8 to 24 hours, as measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C and at least one of the following is shown: (1) The amount of opioid analgesic released at 2 hours is less than about 10%, (2) the amount of opioid analgesic released at 4 hours is about 20% to about 30%, (3) the amount of opioid analgesic released at 8 hours is about 45% to about 60%, (4) the amount of opioid analgesic released at 12 hours is greater than about 70% to about 90%, or (5) the amount of opioid analgesic released at 18 hours is greater than about 95%.

In certain embodiments, the amount of active agent (e.g., opioid analgesic) released by the dosage form is proportional to within 20% over time from 8 to 24 hours, as measured by in vitro dissolution in USP Apparatus 1 (Basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C and at least one of the following is shown: (1) The amount of opioid analgesic released at 2 hours is less than about 15%, (2) the amount of opioid analgesic released at 4 hours is from about 8% to about 20%, (3) the amount of opioid analgesic released at 8 hours is about 20% to about 50%, (4) the amount of opioid analgesic released at 12 hours ranges from about 40% to about 70%, (5) the amount of opioid analgesic released at 18 hours is greater than about 70%, or (6) the amount of analgesic The opioid release profile at 24 hours is greater than about 90%.

Dosage pictures

In certain embodiments, the core may be prepared by dry mixing the controlled release material, active agent, and optionally other excipients, followed by granulating the mixture until the appropriate granulation is obtained. The process can be performed by dry or wet granulation methods. Typically, with wet granulation, the wet granules are dried in a fluid bed dryer, screened and ground to a suitable size. Typically, lubricating agents are mixed with granulation to obtain the final core formula.

The non-restrictive list of suitable controlled-release substances that can be selected for inclusion in a formula according to the present invention includes hydrophilic and non-hydrophilic substances such as sustained release polymers, gums, acrylic resins, protein-derived substances, waxes, shellacs, Oils such as hydrogenated castor oil and hydrogenated vegetable oil. More specifically, controlled-release materials can be, for example, alkylcelluloses such as ethylcellulose, acrylic acid polymers, methacrylic acid copolymers, cellulose ethers, such as hydroxyalkylcelluloses (eg, hydroxypropylmethylcellulose) and

carboxyalkylcelluloses. Waxes include, for example, natural and synthetic waxes, fatty acids, fatty alcohols, and mixtures thereof (for example, beeswax, carnauba wax, stearic acid and stearyl alcohol). Certain embodiments include mixtures of two or more of the foregoing substances with controlled release in a core matrix. However, any pharmaceutically acceptable hydrophilic or hydrophilic controlled release substance capable of imparting a controlled release of the active agent may be used according to the present invention.

The cores may also contain appropriate amounts of additional excipients, for example, lubricants, binders, granulating aids, diluents, colorants, or flavorants (e.g. Bittering agents and lubricants, all of which are traditional in the pharmaceutical field.

Specific examples of pharmaceutically acceptable diluents and excipients that can be used in the formulation of cores are described in:

Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986), which is incorporated by reference into the present application.

In preferred embodiments, the dosage forms of the present invention comprise polyethylene oxide (e.g., PEO of high or/and low molecular weight).

Polyethylene oxide is considered to have an approximate molecular weight of 1,000,000 when a 2% (by weight) aqueous solution of PEO is demonstrated using a Brookfield model RVF viscometer, mandrel #1, at 10 rpm, at 25°C viscosity range of 400 to 800 MPa - Seconds (centipoise).

Polyethylene oxide is considered to have an approximate molecular weight of 2,000,000 when a 2% (by weight) aqueous solution of PEO using a Brookfield viscometer model RVF, No. 3 shaft, at 10 rpm, at 25°C shows a viscosity range of 2000 to 4000 M Pascal - second (centipoise).

Polyethylene oxide is considered to have an approximate molecular weight of 4,000,000 when a 1% (by weight) aqueous solution of polyethylene oxide using a Brookfield viscometer model RVF, No. 2 spindle, at 2 rpm, at 25°C, shows a viscosity range of 1650 to 5500 M Pascal - second (centipoise). Polyethylene oxide is considered to have an approximate molecular weight of 5,000,000 when a 1% (by weight) aqueous solution of polyethylene oxide using a Brookfield viscometer, model RVF, No. 2 spindle, at 2 rpm, at 25°C, shows a viscosity range of 5,500 to 7,500 M Pascal - second (centipoise).

Polyethylene oxide is considered to have an approximate molecular weight of 7,000,000 when a 1% (by weight) aqueous solution of polyethylene oxide using a Brookfield viscometer model RVF, No. 2 spindle, at 2 rpm, at 25°C shows a viscosity range of 7,500 to 10,000 M Pascal - second (centipoise).

Polyethylene oxide is considered to have an approximate molecular weight of 8,000,000 when a 1% (by weight) aqueous solution of polyethylene oxide using a Brookfield viscometer model RVF, No. 2 spindle, at 2 rpm, at 25°C, shows a viscosity range of 10,000 to 15,000 M Pascal - second (centipoise).

Considering low molecular weight polyethylene oxides, polyethylene oxide is considered to have an approximate molecular weight of 100,000 when a 5% (by weight) aqueous solution of polyethylene oxide appears using a Brookfield viscometer model RVT, spindle #1, at 50 rpm, at 25°C Viscosity range is 30 to 50 MPa s (centipoise).

Polyethylene oxide is considered to have an approximate molecular weight of 900,000 when a 5% (by weight) aqueous solution of polyethylene oxide using a Brookfield viscometer, model RVF, No. 2 spindle, at 2 rpm, at 25°C, shows a viscosity range of 8,800 to 17,600 M Pascal - second (centipoise).

Pictures of pressure coated doses

In embodiments using compression packaging, all or part of the pharmaceutically acceptable excipient(s) in the packaging preferably imparts sufficient compressibility to provide a pharmaceutically acceptable product. Pressure encapsulation of the preformed core is partly dependent on the individual characteristics of the excipients and active agent selected, for example, in terms of polymer solubility, flowability, glass transition temperature, etc.

Press-coated dosage forms may be prepared by, for example, using a pre-manufactured core or by preparing the core (e.g., by pressing) prior to packaging. The inner core may be prepared by wet or dry granulation of the active agent together with pharmaceutically acceptable excipients; Followed by drying and grinding as necessary to obtain a granule; By adding excipients or/and optional ultra-granulated active agent with appropriate mixing; adding lubricant as necessary; The granule was compressed with a tablet press. The resulting compressed core can optionally be coated with functional coating or film coating prior to compression coating.

The compression coating mixture may be prepared by a similar process wherein the mixture is used to stir any of the controlled release materials disclosed above. Preferably, the pressure packaging should include polyethylene oxide. The mixture can be coated on the heart with pressure. Core compression or/and casing may use a Killion piston or a Fette rotary piston at a compression force that, for example, ranges from about 1 to about 20 kN.

On certain models, a Manesty Dry-Cota press may be used (e.g., Model 900). This machine consists of two tablet presses interconnected side by side where the core is made on one press and then can be mechanically transferred to the next press for compression packaging. Each press contains an independent powder feeding mechanism, so that the core mixture is loaded into one of the two machines, and the packaging mixture is loaded into the other machine. Two mechanical transfer arms rotate between the two machines to remove the cores from the core press and transfer them to the packing press. Other presses that can be used to prepare dosage forms of the present invention include the Elizabeth Hata HT-AP44-MSU-C; Killian RLUD; and Fette PT 4090, each of which has a dual mix feeding system and pre-made cores. The use of these presses allows multiple layers of compression packaging to be achieved - by recycling tablets that have already been compression-coated. All of these presses contain mechanisms to center the disc within the scope of the packing mixture both vertically and radially.

In certain embodiments, the pressure coating is not applied at the same thickness at all points around the inner core, but is instead applied at different thickness values around the inner core. The thinner areas of the packaging create areas of the compressed dose profile that release the drug from the inner core faster than other areas. This can be achieved simply, for example, by not having the core on which the packaging is pressed into the middle of the press at the time of packaging.

In certain embodiments, the pressure-coated dosage form may be additionally overcoated with a non-hydrophilic or enteric coating material. In other embodiments, the pressure-coated dosage forms may be coated with a hydrophilic coating in addition to or in place of the non-hydrophobic or enteric coating.

In further embodiments, a coating layer (e.g., hydrophobic, hydrophilic or enteric) may be alternatively or additionally applied as an intermediate layer between the core and the pressure coating.

Active agents

The opioid aids used in the present invention include, but are not limited to:

Alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, , eptazocine, ethoheptazine, ethylmethylthiambutene , ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl

And derivatives of the above:

Hydrocodone, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene, norpipanone, ,opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, Propoxyphene, sufentanil, tilidine, tramadol

and pharmaceutically acceptable salts and complexes (for example, with cyclodextrin), stereoisomers, ethers or esters, or hydrates, melts thereof and mixtures thereof.

Preferably, the opioid analgesics should be selected from the group consisting of codeine, hydrocodone, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, tramadol, pharmaceutically acceptable salts, complexes, stereoisomers, ethers, esters, hydrates, solutes, and mixtures. Of which.

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

The opioids used according to the present invention may contain one or more asymmetric centers and may give rise to enantiomers, dimers, or other enantiomers. It is also intended that the present invention includes the use of all possible forms, as well as racemic and resolvable forms and combinations thereof. When compounds described herein contain olefinic double bonds or other geometrically dissimilar centers, they are intended to include both geometric E and Z isomers. It is also intended that the present invention includes all tautomers as well.

Pharmaceutical acceptable salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate and the like; sulfonates such as:

methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like; Amino acid salts such as arginate, asparaginate, glutamate and the like, and metal salts such as sodium salt, potassium salt, cesium salt and the like; Alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N'-dibenzylethylenediamine salt and the like.

Additionally, active agents other than opioid analgesics that are potentially subject to abuse may be used according to the present invention. Such agents include, for example, tranquilizers, CNS depressants, CNS stimulants, sedatives, hypnotics, stimulants (including appetite suppressants such as phenylpropanolamine), cannabinoids, and others.

More specifically, the active agent can be selected from barbiturates such as:

phenobarbital, secobarbital, pentobarbital, butabarbital, talbutal, aprobarbital, mephobarbital, butalbital, pharmaceutically acceptable salts thereof, and the like; benzodiazepines such as diazepam, chlordiazepoxide, alprazolam, triazolam, estazolam, clonazepam, flunitrazepam, and pharmaceutically acceptable salts thereof, and the like; Steroids such as:

gamma-hydroxybutyrate, dextroamphetamine, methylphenidate, sibutramine, methylenedioxyrnethamphetamine, pharmaceutically acceptable salts thereof, and the like; and other agents such as marinol, meprobamate and carisoprodol; And all pharmaceutically acceptable salts, complexes, stereoisomers, ethers, esters, hydrates, melts thereof, or mixtures thereof.

In additional embodiments, other therapeutically active agents may be used according to the present invention, either alone or in combination with opioid agonists. Examples of such therapeutically effective agents include antihistamines (eg:

dimenhydrinate, diphenhydramine, chlorpheniramine and dexchlorpheniramine maleate), non-steroidal anti-inflammatory agents (eg, naproxen, diclofenac, indomethacin, ibuprofen, sulindac, Cox-2 inhibitors) and acetaminophen, anti-emetics ( For example, metoclopramide, methylnaltrexone), anti-epileptics (eg, phenyloin, meprobmate and nitrazepam), vasodilators (eg, nifedipine, papaverine, diltiazem and nicardipine), anti-tussive agents and expectorants, anti-asthmatics (eg, theophylline), antacids, anti-spasmodics (eg, atropine, scopolamine), antihistamines. For diabetes, antidiabetics (eg, insulin), diuretics (eg, ethacrynic acid, bendrofluthiazide), anti-hypotensives (eg, propranolol, clonidine), antihypertensives (eg, clonidine, methyldopa), bronchodilators (eg, albuterol), steroids (eg, hydrocortisone, triamcinolone, prednisone), antibiotics (eg, tetracycline), anti-hemorrhoidals, psychotropics, psychiatric medications, anti-diarrheals, mucolytics, decongestants (eg, pseudoephedrine), laxatives laxatives, vitamins, pharmaceutically acceptable salts, complexes, stereoisomers, ethers, esters, hydrates, solubles thereof and mixtures thereof.

Hydrocodone models

The controlled-release dosage forms of the present invention preferably comprise from about 0.5 mg to about 1250 mg hydrocodone or an equivalent amount of a pharmaceutically acceptable salt thereof. In other embodiments, the dosage forms contain from about 2 mg to about 200 mg hydrocodone or an equivalent amount of a pharmaceutically acceptable salt thereof, or from about 16 mg to about 120 mg hydrocodone or an equivalent amount of a pharmaceutically acceptable salt thereof. In certain preferred embodiments, the dosage forms contain about 20 mg, about 30 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg or about 120 mg hydrocodone bitartrate.

Suitable pharmaceutically acceptable salts include:

Hydrocodone includes hydrocodone bitartrate, hydrocodone bitartrate hydrate, hydrocodone hydrochloride, hydrocodone p-toluenesulfonate, hydrocodone phosphate, hydrocodone thiosemicarbazone, hydrocodone sulfate, hydrocodone trifluoroacetate, hydrocodone hemipentahydrate, hydrocodone pentafluoropropionate, hydrocodone p-nitrophenylhydrazone, hydrocodone One o-methyloxime, hydrocodone semicarbazone, hydrocodone hydrobromide , hydrocodone mucate, hydrocodone oleate, hydrocodone phosphate dibasic, hydrocodone phosphate monobasic, hydrocodone inorganic salt, hydrocodone organic salt, hydrocodone acetate trihydrate, hydrocodone bis(heptafuorobutyrate), hydrocodone bis(methylcarbamate), hydrocodone bis(pentafluoropropionate), hydrocodone bis(pyridine carboxylate), hydrocodone bis(trifluoroacetate), hydrocodone chlorhydrate, and hydrocodone sulfate pentahydrate. Preferably, the hydrocodone is present as the bitartrate salt

The hydrocodone dosage form of the present invention may also include one or more additional drugs, which can act or act synergistically with the hydrocodone contained therein. Examples of such additional drugs include non-steroidal anti-inflammatory agents, including:

ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmet in, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam and the pharmaceutically acceptable salts, complexes, stereoisomers, ethers, esters, hydrates, solvates, and mixtures thereof. Such non-steroidal anti-inflammatory agents also include cyclo-oxygenase inhibitors such as celecoxib, meloxicam, nabumetone, nimesulide and the pharmaceutically acceptable salts, complexes, stereoisomers, ethers, esters, hydrates, solvates, and mixtures thereof.

Other additional drugs that may be formulated in combination with:

Hydrocodone include NMDA receptor antagonists such as dextrorphan, dextromethorphan, 3-(1-naphthalennyl)-5-(phosphonomethyl)-L-phenylalanine, 3-(1-naphthalenyl)-5-(phosphonomethyl)-DL-phenylalanine, 1-( 3,5-dimethylphenyl)naphthalene, 2-(3,5-dimethylphenyl)naphthalene, 2SR,4RS-4-(((1H-Tetrazol-5-yl)methyl)oxy)piperidine-2-carboxylic acid, 2SR,4RS -4-((((1H-Tetrazol-5-yl)methyl)oxy)methyl)piperidine-2-carboxylic acid, E and Z 2SR-4-(O-(1H-Tetrazol-5-yl)methyl)ketoximino)piperidine-2-carboxylic acid, 2SR,4RS-4-((1H-Tetrazol-5-yl)thio)piperidine- 2-carboxylic acid, 2SR,4RS-4-((1H-Tetrazol-5-yl)thio)piperidine-2-carboxylic acid, 2SR,4RS-4-(5-mercapto-1H-Tetrazol-1-yl)piperidine -2-carboxylic acid, 2SR,4RS-4-(5-mercapto-2H-Tetrazol-2-yl)piperidine-2-carboxylic acid, 2SR,4RS-4-(5-mercapto-1H-Tetrazol-1-yl) ) piperidine-2-carboxylic acid, 2SR,4RS-4-(5-mercapto-2H-Tetrazol-2-yl) piperidine-2-carboxylic acid, 2SR,4RS-4-(((1H-Tetrazol-5-yl)thio)methyl)piperidine-2-carboxylic acid, 2SR,4RS-4-((5-mercapto-1H-Tetrazol-1-yl)methyl) piperidine-2-carboxylic acid, 2SR,4RS-4-((5-mercapto-2H-Tetrazol-2-yl)methyl)piperidine-2-carboxylic acid, and the pharmaceutically acceptable salts, complexes, stereoisomers, ethers, esters, hydrates, solvates

And mixtures thereof.

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

In preferred embodiments, hydrocodone formulations of the present invention are suitable for once-daily administration and provide relatively stable plasma properties, meaning that the plasma hydrocodone level provides a C24/Cmax ratio of about 0.55 to about 1.0 after administration. In certain embodiments, the C24/Cmax ratio ranges from about 0.55 to about 0.85, from about 0.55 to about 0.75, or from about 0.60 to about 0.70 after the dosage form is administered.

In preferred embodiments, hydrocodone formulations of the present invention provide a Tmax (Q) of hydrocodone ranging from about 4 to about 20 hours after administration.

In certain embodiments, the Tmax value ranges from about 6 to about 12 hours, about 8 to about 10 hours, from about 4 to about 10 hours, from about 8 to about 14 hours, or from about 14 to about 20 hours after the form is administered.

In still other embodiments, the controlled-release solid dosage form of the present invention provides a post-administration AUC value of about 200 to 450 or about 250 to 400 per 20 mg hydrocodone or pharmaceutically acceptable salt thereof included in the dosage form. .

In certain embodiments, a controlled-release solid dosage form containing 20 mg hydrocodone or a pharmaceutically acceptable salt thereof provides a post-administration AUC value of about 200 to about 450, from about 250 to about 400. , about 275 to about 350, about 300 to 330 or about 280 to about 320.

In certain embodiments, a controlled-release solid dosage form containing 120 mg hydrocodone or a pharmaceutically acceptable salt thereof provides a post-administration AUC value of about 1000 to about 3000, about 1500 to about 2400, About 1700 to about 2200, about 1800 to about 2100 or about 1900 to about 2100.

In other embodiments, a controlled-release solid dosage form of the present invention provides a post-administration Cmax value (ng/ml) of about 5 to about 40, about 10 to about 30 for every 20 mg hydrocodone included in the dosage form.

In certain embodiments, a controlled-release solid dosage form containing 20 mg hydrocodone or a pharmaceutically acceptable salt thereof provides a post-administration Cmax value (ng/ml) of about 5 to about 40, about 10 to about 30, about 12 to about 25, about 14 to about 18 or about 12 to about 17.

In certain embodiments, a controlled-release solid dosage form containing 120 mg hydrocodone or a pharmaceutically acceptable salt thereof provides a post-administration Cmax value (ng/ml) of about 30 to about 120, about 60 to about 180, about 100 to about 160, about 110 to about 150 or about 100 to about 140.

In certain embodiments, the controlled-release solid dosage form of the present invention provides a Tmax value (x) of hydrocodone after administration of about 7 to about 22, 10 to about 20, about 12 to about 18, about 13 to about 17 or about 14 to About 16.

In other embodiments, the controlled-release solid dosage form of the present invention provides a T1/2(h) value of hydrocodone after administration of about 5 to about 10, about 6 to about 9, about 7 or about 8.

In other embodiments, a controlled-release solid dosage form of the present invention provides a Tlag(s) value of hydrocodone 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.

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

In certain embodiments, any one or all of the above in vivo averaging variables are achieved after administration in a fasted state.

In certain embodiments, the average AUC value (ng*h/ml) of hydrocodone after administration in the fed state is less than 20% higher, less than 16% higher, or less than 12% higher than the AUC value (ng*h/ml). ml) of hydrocodone after administration in the fasting state.

In certain embodiments, the average Cmax value (ng/ml) of hydrocodone after administration in the fed state is less than 80% higher, or less than 70% higher, or less than 60% higher than the Cmax of hydrocodone after administration in the fasted state.

In certain embodiments, the average Tmax value of hydrocodone after administration in the fed state is within 25%, within 20% or within 15% of the Tmax value of hydrocodone after administration in the fasted state.

In certain embodiments, the average T1/2(h) value of hydrocodone after administration in the fed state is within 8%, within 5% or within 2% of the T1/2 value after administration in the fasted state.

In certain embodiments, the average Tlag value of hydrocodone after administration in the fed state is less than 150% above, or less than 125% above or less than 100% above T1/2 after administration in the fasted state.

In certain embodiments, any one or all of the foregoing in vivo variables are achieved after the first administration of the dosage form to a human subject, a patient, or a healthy subject (individual data) or a group of human subjects, patients, or healthy subjects (average data).

In certain alternative embodiments, any one or all of the foregoing variables are achieved in vivo after the steady-state dosage form is administered to a human subject, a patient, a healthy subject, or a group of human subjects, patients, or healthy subjects .

Mature formulas

In certain embodiments, a process of the present invention also includes a final dosage form ripening step.

For embodiments comprising polyethylene oxide in a controlled release formulation, the ripening step may include melting the polyethylene oxide into the formulation at least partially. In certain embodiments, at least about 20% or at least about 30% of the polyethylene oxide is fused in the formula. Preferably, at least about 40%, or at least about 50%, or at least about 60%, or at least about 75%, or at least about 90% of the polyethylene oxide in the formula is melted during the ripening step. In a preferred embodiment, about 100% of the polyethylene oxide melts.

In other embodiments, the ripening step comprises exposing the formulation to an elevated temperature for a specified period of time. In such embodiments, the ripening temperature is at least as high as the polyethylene oxide thinning temperature. According to certain embodiments, the ripening temperature is at least about 60°C, at least about 62°C, and ranges from about 62°C to about 90°C, from about 62°C to about 85°C, and from about 62°C to about 80°C, from about 65°C to about 90°C, from about 65°C to about 85°C, or from about 65°C to about 80°C. It is preferable that the ripening temperature range from about 68 degrees Celsius to about 90 degrees Celsius, or from about 68 degrees Celsius to about 85 degrees Celsius, or from about 68 degrees Celsius to about 80 degrees Celsius, or from about 70 degrees Celsius to about 90 degrees Celsius. °C, or from about 70°C to about 85°C, or from about 70°C to about 80°C, or from about 72°C to about 90°C, or from about 72°C to about 85°C Or from about 72°C to about 80°C. The ripening temperature can be at least about 60°C, or at least about 62°C, or less than about 90°C, or less than about 80°C. Preferably, this should be in a range from about 62°C to about 72°C or from about 68°C to about 72°C. Preferably, the ripening temperature shall be at least at the maximum height of the lower limit of the polyethylene oxide thinning temperature range, or at least about 62°C, or at least about 68°C. More preferably, the ripening temperature should be within the polyethylene oxide thinning temperature range, or at least about 70°C. In additional embodiments, the ripening temperature is at least as high as the upper limit of the polyethylene oxide thinning temperature range, or at least about 72°C. In additional embodiments, the ripening temperature is above the upper limit of the polyethylene oxide thinning temperature range, or at least about 75 degrees Celsius, or at least about 80 degrees Celsius.

In those embodiments where the ripening step involves exposing the formula to an elevated temperature for a specified period of time, this period of time is hereafter referred to as the ripening time. To measure the ripening time, a starting point and a final point are determined for a ripening step. For purposes of the present invention, the starting point of the ripening step is defined as the point in time at which the ripening temperature is reached.

In certain embodiments, the temperature characteristics during the ripening step show a nearly planar appearance between the starting point and the final point of ripening. In such embodiments, the end point of the ripening step is defined as the point in time at which heating is stopped or at least reduced, e.g., by terminating or reducing heating or/and by beginning a next cooling step, and the temperature is accordingly reduced to below Ripening by more than about 10°C or/and below the lower limit of the polyethylene oxide thinning temperature range, for example, below about 62°C. When the ripening temperature is reached and the ripening step is thus initiated, deviations from the ripening temperature can occur in the course of the ripening step. These deviations are tolerated as long as they do not exceed a value of about 10°C, preferably around 6°C, and more preferably around 3°C. For example, if the ripening temperature is to be maintained at least at about 75°C, the measured temperature can be temporarily increased to a value of about 85°C, about 81°C, or about 78°C, and can be decreased Temporarily measured temperature to a value of about 65°C, or about 69°C, or about 72°C. In cases of a larger temperature drop or/and if the temperature drops below the lower limit of the polyethylene oxide thinning temperature range, for example below about 62 °C, the ripening step is stopped, i.e. the final point is reached. Ripening can be restarted by once again reaching the ripening temperature.

In other embodiments, the temperature characteristics during the ripening step appear as a parabola or rectangle between the starting point and the final point of ripening. Which means that after the starting point, i.e., the point in time when the ripening temperature is reached, the temperature increases further to reach the maximum temperature, and then decreases. In such models, the end point of the ripening step is defined as the point in time at which the temperature drops below the ripening temperature.

Depending on the device used for ripening (i.e., the ripening medium), various temperatures can be measured within the ripening medium to determine the ripening temperature characteristics.

In certain embodiments, the curing step may occur in an oven. In such models, the temperature inside the oven is measured. Accordingly, when the curing step occurs in an oven, the specific curing temperature is ranged so that it is targeted within the temperature range inside the kiln and the starting point for the curing step is defined as the point in time when the temperature inside the kiln reaches the curing temperature. The end point of the curing step is defined as (1) the point in time at which heating is stopped or at least reduced and the temperature inside the kiln thus falls below the curing temperature by more than about 10°C or/and below the lower limit of the temperature range. Thinning of high molecular weight polyethylene oxide, for example below about 62°C, In temperature characteristics similar to the rise or (2) point in time when the temperature inside the kiln falls below the curing temperature in the form of a parabolic or rectangular temperature. Preferably, the curing step should begin when the temperature inside the oven reaches a curing temperature of at least about 62°C, at least about 68°C, at least about 70°C, or at least about 72°C or at least about 75 Celsius. In preferred embodiments, the temperature characteristics during the curing step exhibit a crescendo-like appearance, wherein the curing temperature, i.e., the internal temperature of the kiln, is at least about 68°C, or about 70°C, or about 72°C, or about 73°C, or in a range from about 70°C to about 75°C, It is preferable that the ripening time range from about 30 minutes to about 20 hours, or from about 30 minutes to about 15 hours, or from about 30 minutes to about 4 hours, or from about 30 minutes to about two hours. In certain embodiments, the ripening time is in the range from about 30 minutes to about 90 minutes.

In certain embodiments, ripening may occur in a ripening medium heated by an air flow and comprising a supply of heated air (inlet) and exhaust, e.g., a packing vessel or fluidized bed. We will call the ripening methods mentioned hereafter “convection ripening methods.” In the mentioned ripening means, it is possible to measure the inlet air temperature, i.e., the temperature of the heated air entering the convection ripening medium and/or the exhaust air temperature, i.e., the temperature of the air leaving the convection ripening medium. It is also possible to determine or at least estimate the temperature of the formulations inside the curing medium by convection during the curing step, for example, by using infrared temperature measuring instruments (such as an IR gun) or by measuring the temperature using a temperature probe placed inside the curing medium close to Of formulas. Accordingly, when the ripening step occurs in the convection ripening medium, the ripening temperature can be defined and the ripening time can be measured as follows.

In one embodiment (Method 1), the ripening temperature is defined as the target inlet air temperature and the start point of the ripening step is defined as the time point at which the inlet air temperature reaches the ripening temperature. The end point of the curing step is defined as (1) the time point at which heating is stopped or at least reduced and the inlet temperature thus drops below the curing temperature by more than about 10 °C and/or below the minimum duration of laminating temperature for polyethylene High molecular weight oxide, for example below about 62°C, has temperature properties similar to that of quenching, or (2) the point in time at which the inlet air temperature drops below the ripening temperature in the form of a parabolic or rectangular temperature. Preferably, the curing step in accordance with Method 1 should begin when the inlet air temperature reaches a curing temperature of at least about 62°C, at least about 68°C, at least about 70°C, at least about 72°C or The lowest is about 75 degrees Celsius. In a preferred embodiment, the temperature properties during the ripening step exhibit an equator-like appearance, where the ripening temperature, i.e., the target inlet air temperature is preferably at least about 72°C, e.g., about 75°C, preferably The ripening time measured according to Method 1 ranges from about 15 minutes to about 2 hours, for example, about 30 minutes or about an hour.

In another embodiment (Method 2), the ripening temperature is defined as the target exhaust air temperature, and the start point of the ripening step is defined as the time point at which the exhaust air temperature reaches the ripening temperature. The end point of the curing step is defined as (1) the time point at which heating is stopped or at least reduced and thus the exhaust air temperature drops below the curing temperature by more than about 10°C and/or below the minimum polyethylene oxide delamination temperature High molecular weight, for example below about 62 °C, with temperature properties similar to the quenching state, or (2) the point in time at which the exhaust air temperature drops below the ripening temperature in a parabolic or rectangular temperature profile. Preferably, to begin the curing step in accordance with Method 2, the exhaust air temperature reaches a curing temperature of at least about 62°C, or at least about 68°C, or at least about 70°C, or at least about 72°C Or at least around 75 degrees Celsius. In preferred embodiments, the temperature characteristics during the curing step exhibit an equilibrium-like appearance, wherein the curing temperature, i.e., the target exhaust air temperature, is preferably at least about 68°C, at least about 70°C, or at least about 72°C. °C, for example the target exhaust air temperature is about 68°C, about 70°C, about 72°C, about 75°C or about 78°C, It is preferable that the ripening time measured according to Method 2 be in a range ranging from about 1 minute to about 2 hours, or from about 5 minutes to about 90 minutes. For example, the ripening time is about 5 minutes, about 10 minutes, about 15 minutes, about 30 minutes, about 60 minutes, about 70 minutes, about 75 minutes or about 90 minutes. In a more preferable embodiment, the ripening time measured according to Method 2 is in the range from about 15 minutes to about 1 hour.

In another embodiment (Method 3), the ripening temperature is defined as the target temperature of the formulas and the starting point of the ripening step is defined as the time point at which the temperature of the formulas, which can be measured for example by an IR gun, reaches the ripening temperature. The final point of the curing step is defined as (1) the point in time at which heating is stopped or at least reduced and the temperature of the formulations thus drops below the curing temperature by more than about 10°C and/or below the minimum delamination temperature for polyethylene oxide with High molecular weight, for example below about 62°C, In temperature properties similar to the state of equilibrium or (2) the point in time at which the temperature of the formulations drops below the ripening temperature in the form of a temperature in the form of a parabola or rectangle. Preferably, the ripening step according to Method 3 should begin when the temperature of the formulations reaches a ripening temperature of at least about 62°C, or at least about 68°C, or at least about 70°C, or at least about 72°C. Or at least around 75 degrees Celsius.

In yet another embodiment (Method 4), the ripening temperature is defined as the target temperature measured using a temperature probe, such as a wire thermocouple, placed inside the ripening medium near the formulas, and the starting point of the ripening step is defined as the time point at which The temperature measured using a temperature probe is the ripening temperature. The end point of the ripening step is defined as (1) the point in time at which heating is stopped or at least reduced and the temperature measured using the temperature probe thus drops below the ripening temperature by more than about 10°C and/or below the minimum temperature Thinning of polyethylene oxide, for example below about 62°C, has temperature properties similar to the quenching state, or (2) the point in time at which the temperature measured with the temperature probe falls below the ripening temperature in a parabolic or rectangular temperature profile. The ripening step should preferably begin when the temperature measured using a temperature probe in the ripening device registers at least about 62°C, or at least about 68°C, or at least about 70°C, or at least about 72°C. Or at least around 75 degrees Celsius.

In a preferred embodiment, the temperature properties during the ripening step appear to resemble a quenching state, where the ripening temperature is at least about 68°C, for example, about 70°C, and the ripening time measured according to Method 4 is preferably in the range It ranges from about 15 minutes to about 2 hours, about 60 minutes, or about 90 minutes.

If ripening occurs in a convection ripening device, the ripening time can be measured by any of the methods described above.

In certain embodiments, the ripening temperature is defined as a target temperature range, for example, the ripening temperature is defined as a target inlet air temperature range or a target exhaust air temperature range. In such embodiments, the start point of the ripening step is defined as the time point at which the lower limit of the target temperature range is reached, and the end point of the ripening step is defined as the time point at which heating is stopped or at least reduced, and the temperature is thus reduced. More than about 10°C below the minimum target temperature range and/or below the minimum laminating temperature for polyethylene oxide, for example, below about 62°C.

The ripening time, i.e., the period of time during which the formula is exposed to the ripening temperature, which can be measured, for example, according to the methods described above, is at least about 1 minute or at least about 5 minutes. The ripening time can vary from about one minute to about 24 hours, or from about 5 minutes to about 20 hours, or from about 10 minutes to about 15 hours, or from about 15 minutes to about 10 hours, or from about 30 minutes to about 5 hours depending on the specific formula and ripening temperature. According to certain embodiments, the ripening time varies from about 15 minutes to about 30 minutes. According to other embodiments, wherein the ripening temperature is at least about 60°C, or at least about 62°C, or at least about 68°C, or at least about 70°C, or at least about 72°C, or at least About 75 degrees Celsius, or varies from about 62 degrees Celsius to about 85 degrees Celsius, or from about 65 degrees Celsius to about 85 degrees Celsius, then it is preferable that the ripening time be at least about 15 minutes, or at least about 30 minutes, or at least At least about 60 minutes, or at least about 75 minutes, Or at least about 90 minutes or at least about 120 minutes. In preferred embodiments, wherein the ripening temperature is, for example, at least about 62°C, or at least about 68°C, or at least about 70°C, or at least about 72°C or at least about 75° Celsius, or from about 62°C to about 80°C, or from about 65°C to about 80°C, or from about 68°C to about 80°C, or from about 70°C to about 80°C Or from about 72°C to about 80°C, Then it is preferable that the ripening time be at least about a minute, or at least about 5 minutes, or at least about 10 minutes, or at least about 15 minutes, or at least about 30 minutes. In such particular embodiments, the ripening time may be chosen so as to be as short as possible and still achieve the desired result (e.g., increased tamper resistance). For example, it is preferable that the ripening time does not exceed about 5 hours, or does not exceed about 3 hours, or does not exceed about 2 hours.

Preferably, the ripening time should be in a range ranging from about 1 minute to about 5 hours, or from about 5 minutes to about 3 hours, or from about 15 minutes to about 2 hours, or from about 15 minutes to about 1 hour.

Any combination of ripening temperatures and ripening times as disclosed in the present application is within the scope of the present invention.

In certain embodiments, the composition is not subjected to a curing temperature until the polyethylene oxide contained in the formulation has reached its thinning temperature and/or is at least partially melted. In such specific embodiments, the ripening time can be less than about 5 minutes, for example the ripening time can vary from greater than 0 minutes to about 3 hours, or from about 1 minute to about 2 hours, or from about 2 minutes to about 1 hour. It is possible to obtain instantaneous ripening by selecting a ripening method that allows the instantaneous ripening of the polyethylene oxide in the formulation to at least reach its thinning temperature, such that the high molecular weight polyethylene oxide melts at least partially. The curing methods mentioned are, for example, microwave ovens, ultrasonic devices, a light emitting device such as an ultraviolet light radiator, ultra-high frequency (UHF) fields, or any other device known to the person. Experienced in the field.

The volume of the formula can determine the required ripening time and ripening temperature to achieve the desired tamper resistance.

In certain embodiments, the ripening step results in a decrease in the density of the formula, such that the density of the matured formula is less than the density of the formula before the ripening step. Preferably, the density of the mature formula should be reduced compared to the density of the immature formula by at least about 0.5%. More preferably, the density of the mature formulation should be reduced in comparison to the density of the immature formulation by at least about 0.7%, or at least about 0.8%, or at least about 1.0%, or at least about 2.0%, or at least about 2.5%.

In certain embodiments, the controlled release solid dosage form is matured at a temperature at least as high as the polyethylene oxide thinning point for at least 1 minute, at least 5 minutes, or at least 15 minutes.

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

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

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

Surface leveling procedures

In certain embodiments, the surface of dosage forms of the present invention may be flattened without significantly adversely affecting the release of the active agent or the integrity of the dosage form. Surface flatness is described in terms of the thickness of the smallest diameter of a flat-surfaced shape compared to the thickness of the smallest diameter of a non-planar shape. This comparison is expressed in percentage thickness, based on either (1) the thickness of the smallest diameter of the non-planar surface when the initial shape is aspheric (2) or the diameter of the thickness when the initial shape is spherical. Thickness can be measured using a thickness gauge (for example, a digital thickness gauge or digital caliper). The surface leveling force can be applied by any possible method. For purposes of testing the dosing images of the present invention, a sculptor-type bench press may be used (unless otherwise specified) such that the target surface flatness or reduced thickness is achieved.

According to certain embodiments of the invention, leveling the surface does not result in breaking the dose profile into discrete pieces; However, edge splitting or cracking can occur.

In certain embodiments of the invention, a hammer may be used to flatten the surface of the dose image. In such a process, hammer blows can be delivered manually from a very normal direction to a thicker dimension in the dose profile. The flatness of the surface is then described in the same way as previously disclosed.

In other embodiments, surface settlement may be measured for fracture strength or hardness tests, as described in:

Remington's Pharmaceutical Sciences, 18th edition, 1990, Chapter 89 "Oral Solid Dosage Forms", pages 1633-1665, using a Schleuniger device. In the aforementioned embodiment, the dose image is compressed between a pair of flat plates arranged in parallel such that the force is applied primarily and naturally to the thickest dimension of the dose image, thus flattening the surface of the dose image. Surface leveling dosage form can be described in terms of % surface leveling, based on the thickness of the dimension subject to surface leveling prior to performing the fracture strength test. Breaking strength (or hardness) is defined as the force at which the form of the dose under test breaks. Pictures of potions that do not break, but even deform because the applied force is resistant to breakage at that applied force.

An additional test to quantify the strength of dose images is the notch test using a Texture Analyzer, such as the TA-XT2 Texture Analyzer (Texture Technologies Corp., 18 Fairview Road, Scarsdale, NY 10583). In this method, the dose image is placed on top of a stainless steel holder with a slightly concave surface and interspersed with a descending Texture Analyzer probe, such as a TA-8A 1/8-inch diameter stainless steel ball probe. Before the measurement begins, the dose image is aligned directly below the probe, such that the falling probe penetrates the disk axially, i.e., at the center of the dose image, and so that the force of the falling probe can be applied essentially perpendicular to the diameter and essentially parallel to the thickness of the dose image. First, the Texture Analyzer probe begins moving toward the dose image sample at the pre-test speed. When the probe touches the surface of the dose image and the specified release force is reached, the probe continues to move at the test speed and penetrates the dose image. For each penetration depth or probe distance, the corresponding force is measured. When the probe reaches the desired maximum penetration depth, it changes direction and returns to the pre-test speed, while additional measurements are acquired. The crushing force is defined as the first local maximum force reached in the corresponding force/distance chart and is calculated using, for example, Texture Analyzer software “Texture Expert Exceed, Version 2.64 English”.

The term “crush-resistant” for purposes of specific embodiments of the present invention is defined to refer to dosage forms that can be at least flattened using a bench press as previously described without breaking to no more than about 60% thickness, preferably not to exceed about 50% thickness. , preferably no more than about 40% thickness, most preferably no more than about 30% thickness and best no more than about 20% thickness, 10% thickness or 5% thickness.

In certain embodiments, the amount of active agent (e.g., an opioid-like analgesic) released at 0.5 hours from a flat dosage form deviates by no more than about 10% drops, 15% drops, or 20% drops from the amount released at 0.5 hours from Non-flat dosage form as measured by in vitro dissolution in USP Apparatus 1 (basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C.

In alternative embodiments, the controlled-release solid dosage form may be surface leveled without cracking, wherein the thickness of the dosage form after surface leveling does not exceed about 60% of the thickness of the dosage form before surface leveling, but not more than about 50% of the thickness of the form Dose before surface leveling, not to exceed about 40% of the thickness of the dose image before surface leveling, not to exceed about 30% of the thickness of the dose image before surface leveling or not to exceed about 20% of the thickness of the dose image before surface leveling.

The following examples are provided to enhance understanding of the invention and should not be limited specifically to the invention described and mentioned in the patent claims. Said variations of the invention, including the substitution of all unknown or later developed equivalents, which shall be within the purview of those skilled in the art, and changes in formulation or minor changes in experimental design, which are within the scope of the invention and that of the present application.

Examples

The present invention will be described more fully by reference to the accompanying examples. It should be understood, however, that the following description is for illustrative purposes only and is not in any way limited to the invention.

Example 1

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

Table 1 (Disc A)

hydrocodone (mg)

Total weight

% of hydrocodone

Tooling size(mm)

heart

16

200

8

7.94

casing

4

200

2

10.32

Total

20

400

10

For core preparation, a Manesty Type F 3 single-station plate press is supplied with a 7.94 mm, standard plano concave, and round tool set. The weight of a powdered aliquot of core mixture, as previously reported in Table 1, was matched to the target weight of 200 mg, charged into the die, which was compressed to form the core of tablet A.

To prepare the casing, a Manesty Type F 3 single-station plate press is supplied with a 10.32 mm, standard concave and round flat tool set. 100 mg of the coating mixture, as mentioned in Table 1, was placed in the mold. The tablet core was placed as previously prepared by hand in the center of the die (on top of the powder layer surface), and an additional 100 mg of coating mixture was placed on top of the tablet surface in the die. The materials were then manually compressed by rotating the compression wheel to form a compression-coated disc.

Several tablets were prepared from compression-coated tablet A as previously, placed in a tray, and placed in a Hotpack oven model 435304 at 72°C for 30 minutes to cook.

Dissolution Mature Tablet A tablets were then tested in USP Apparatus 1 (basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C. The results are shown against the results of the formulas in Examples 2-4 in Figure 1.

Example 2

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

Table 2 (Disc B)

hydrocodone (mg)

Total weight

% of hydrocodone

Tooling size(mm)

heart

16

300

5.3

8.73

casing

4

200

2

11.11

Total

20

500

4

For core preparation, a Manesty Type F 3 single-station plate press is supplied with an 8.73 mm, standard plano concave, and round tool set. The weight of a powdered aliquot of the core mixture, as previously reported in Table 2, was matched to the target weight of 300 mg, charged into the die and compressed to form the core of tablet B.

To prepare the casing, a Manesty Type F 3 single-station plate press is supplied with an 11.11 mm, standard concave and round flat tool set. The first portion of 200 mg coating mixture, as mentioned in Table 2, was placed in the mold. The tablet core was placed as previously prepared by hand in the center of the die (on top of the powder layer surface), and the remaining portion of the 200 mg coating mixture was placed on top of the tablet surface in the die. The materials were then manually compressed by rotating the compression wheel to form a compression-coated disc B.

Several compression-coated tablets were prepared as above and placed in a tray, which was placed in a Hotpack model 435304 oven at 72°C for 30 minutes to cook.

Mature Tablet B was then tested for dissolution in USP Apparatus 1 (basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C. The results are shown against the results of the formulas from Examples 1 and 3-4 in Figure 1.

Example 3

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

Table 3 (Disc C)

hydrocodone (mg)

Total weight

% of hydrocodone

Tooling size(mm)

heart

16

300

5.3

9.53

casing

4

200

2

11.11

Total

20

500

4

For core preparation, a Manesty Type F 3 single-station plate press is supplied with a 9.53 mm, standard plano concave, and round tool set. The weight of a powdered aliquot of the core mixture, as previously reported in Table 3, was matched to the target weight of 300 mg, charged into the die and compressed to form the tablet core C.

To prepare the casing, a Manesty Type F 3 single-station plate press is supplied with an 11.11 mm, standard concave and round flat tool set. A first portion of 200 mg coating mixture, as mentioned in Table 3, was placed in the mold. The tablet core was placed as previously prepared by hand in the center of the die (on top of the powder layer surface), and the remaining portion of the 200 mg coating mixture was placed on top of the tablet surface in the die. The materials were then manually compressed by rotating the compression wheel to form a compression-coated disc C.

Several compression-coated tablets C were prepared as above and were placed in a tray, which was placed in a Hotpack model 435304 oven at 72°C for 30 minutes to cook.

The dissolution of mature Tablet C was then tested in USP Apparatus 1 (basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C. The results are shown against the results of the formulas from Examples 1-2 and 4 in Figure 1.

Example 4

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

Table 4 (Disc D)

hydrocodone (mg)

Total weight

% of hydrocodone

Tooling size(mm)

heart

14

175

8

7.94

casing

6

300

2

11.11

Total

20

475

4.2

For core preparation, a Manesty Type F 3 single-station plate press is supplied with a 7.94 mm, standard plano concave, and round tool set. The weight of a powdered aliquot of the core mixture, as reported in Table 4, was matched to the target weight of 175 mg, charged into the die and compressed to form the tablet core D.

To prepare the casing, a Manesty Type F 3 single-station plate press is supplied with an 11.11 mm, standard concave and round flat tool set.

A first portion of 300 mg coating mixture, as mentioned in Table 4, was placed in the mold. The tablet core was placed as previously prepared by hand in the center of the die (on top of the powder layer surface), and the remaining portion of the 300 mg coating mixture was placed on top of the tablet surface in the die. The materials were then manually compressed by rotating the compression wheel to form a compression-coated disc d.

Several compression-coated tablets were prepared as above and were then placed in a tray, which was placed in a Hotpack model 435304 oven at 72°C for 30 minutes to cook.

The dissolution of mature tablets was then tested in USP Apparatus 1 (basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C. The results are shown against the results of the formulas from Examples 1-3 in Figure 1.

Example 5

A 500 mg tablet (Tablet E), including 120 mg of hydrocodone, was prepared using low molecular weight polyethylene oxide (PEO 205 MW 600,000) for the core and using high molecular weight polyethylene oxide (PEO 303 MW 7,000,000) for the shell, as shown in Table 5 below. .

Table 5 (Disc E)

hydrocodone (mg)

Total weight

% of hydrocodone

Tooling size(mm)

heart

300

32

8.73

casing

24

200

12

11.11

Total

120

500

24

For core preparation, a Manesty Type F 3 single-station plate press is supplied with an 8.73 mm, standard plano concave, and round tool set. The weight of a powdered aliquot of the core mix, as reported in Table 5, was matched to the target weight of 300 mg, charged into the die and compressed to form the tablet core.

To prepare the casing, a Manesty Type F 3 single-station plate press is supplied with an 11.11 mm, standard concave and round flat tool set. A first portion of 200 mg coating mixture, as mentioned in Table 5, was placed in the mold.

The tablet core was placed as previously prepared by hand in the center of the die (on top of the powder layer surface), and the remaining portion of the 200 mg coating mixture was placed on top of the tablet surface in the die. These materials were manually compressed by rotating the compression wheel to form a compression-coated disc e.

Several compression-coated tablets were prepared as above and were then placed in a tray, which was placed in a Hotpack model 435304 oven at 72°C for 30 minutes to cook.

The dissolution of mature tablets was then tested in USP Apparatus 1 (basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C. The results are shown against the results of the formulas from Examples 2 and 6 in Figure 2.

Example 6

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

Table 6 (tablet F)

hydrocodone (mg)

Total weight

% of hydrocodone

Tooling size(mm)

heart

96

300

32

8.73

casing

24

200

12

11.11

Total

120

500

24

For core preparation, a Manesty Type F 3 single-station plate press is supplied with an 8.73 mm, standard plano concave, and round tool set. The weight of a powdered aliquot of the core mixture, as reported in Table 6, was matched to the target weight of 300 mg, charged into the die and compressed to form the core in the tablet.

To prepare the casing, a Manesty Type F 3 single-station plate press is supplied with an 11.11 mm, standard concave and round flat tool set. A first portion of 200 mg coating mixture, as mentioned in Table 6, was placed in the mold. The tablet core was placed as previously prepared by hand in the center of the die (on top of the powder layer surface), and the remaining portion of the 200 mg coating mixture was placed on top of the tablet surface in the die. These materials were manually compressed by rotating the compression wheel to form a compression-coated disc.

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

The tablet was then tested for dissolution and in USP Apparatus 1 (basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes at 37°C. The results are shown against the results of the formulas from Examples 2 and 5 in Figure 2.

Examples 7-12

Six different compression-coated tablets (named Tablets G-L) were prepared containing a total of either 20 mg hydrocodone bitartrate (Tablets G, H and I) or 120 mg hydrocodone bitartrate (Tablets J, K and L) according to Table 7 (20 mg). ) or Table 8 (120 mg) following.

Table 7 (discs g, h, i)

20 mg

Formula g

H formula

formula i

component

mg/tablet

mg/tablet

mg/tablet

heart

Hydrocodone Bitartrate

16

16

16

Microcrystalline Cellulose, Avicel PH 101

1.09

1.09

1.09

Hydroxypropyl Cellulose, Klucel EXF

1.09

1.09

1.09

PEO (Mw=600,000) POLYOX WSR 205

280.32

280.32

280.32

Magnesium Stearate

1.5

1.5

1.5

Partial total

300

300

300

Dry packaging

Hydrocodone Bitartrate

4

4

4

Microcrystalline Cellulose, Avicel PH 101

0.27

0.27

0.27

Hydroxypropyl Cellulose, Klucel EXF

0.27

0.27

0.27

PEO (Mw=7,000,000) POLYOX WSR 303 FP

393.26

293.81

194.36

Magnesium Stearate

2

1.5

D&C Yellow No. 10 Aluminum Lake

0.2

0.15

0.1

Partial total

400

300

200

Cosmetic packaging

Opadry White Y-5-18024-A

28

24

Total

728

624

520

Table 8 (Discs J, K, L)

120 mg

J formula

K formula

formula for

component

mg/tablet

mg/tablet

mg/tablet

heart

Hydrocodone Bitartrate

96

96

96

Microcrystalline Cellulose, Avicel PH 101

6.54

6.54

6.54

Hydroxypropyl Cellulose, Klucel EXF

6.54

6.54

6.54

PEO (Mw=600,000) POLYOX WSR 205

189.42

189.42

189.42

Magnesium Stearate

1.5

1.5

1.5

Partial total

300

300

300

Dry packaging

Hydrocodone Bitartrate

24

24

24

Microcrystalline Cellulose, Avicel PH 101

1.64

1.64

1.64

Hydroxypropyl Cellulose, Klucel EXF

1.64

1.64

1.64

PEO (Mw=7,000,000) POLYOX WSR 303 FP

370.52

271.07

171.62

Magnesium Stearate

2

1.5

D&C Red No. 30 Aluminum lake

0.2

0.15

0.1

Partial total

400

300

200

Cosmetic packaging

Opadry Pink YS-1-14518A

28

24

20

Total

728

624

520

A high shear granulation media (Collette 75 L) was charged with Hydrocodone Bitartate, microcrystalline cellulose and hydroxypropylcellulose. Water is added to the mixture (e.g., 8-15%) with the fan and strip running. The wet granulation was passed through the coarse screen of a Quadro Comil grinder. The filtered wet granulation was dried in a Vector VFC-3 fluid bed drying medium. The dried granulation was passed through the fine screen of a Quadro Comil grinding device.

The 16 Q V-shape mixer was charged with PEO POLYOX WSR 205, milled granulation, and blended for 5 minutes. Filtered magnesium stearate was added to the mixture and mixed for 1 minute to prepare a stirred mixture.

The 16 Q V-shaped mixer was charged with PEO POLYOX WSR 303, D&C Red No. 30 aluminum lake, milled granulation, and blending for 5 minutes. Filtered magnesium stearate was added to the mixture and mixed for 1 minute to prepare dry coat blend.

The inverting and coating mixture was dry pressed into the dry coated tablets on a DryCota Press. A core mixture was loaded into a first side section and the core weight was adjusted to 300 mg. Then a dry coat blend was loaded into the second side section and the total weight of the disc was adjusted to the target. After the weight is adjusted, compression is initiated and the piston is operated at, for example, 6 rpm.

Approximately 10 kg of compression coated tablets spray-coated using Opadry coating suspension were weight-matched to a target weight gain of approximately 1.0% (by weight) in a Compu-Lab 60.960 cm perforated container packaging medium. Spray coating was performed as follows. The disc layer was heated by setting the inlet air temperature to 55 °C. Once the exhaust temperature reached 39 °C, film coating began at a general speed of 12 rpm and a spray rate of approximately 44 ml/min. Film wrapping continued until a target weight gain of approximately 1% was reached (this is partial wrapping before ripening in step x, because the final wrapping with a weight gain of 4% in step xii is sticky during ripening).

The partially coated tablets were matured in a perforated container packaging medium. The inlet temperature was set to 85°C at a general speed of approximately 10 rpm. The tablets were ripened at an exhaust temperature of 72°C for approximately 30 minutes.

After ripening, the tablets were cooled in the rotating pan by setting the inlet temperature to 22°C. Cooling continued until the exhaust temperature reached below 28°C.

The mature tablets were then spray-coated with coating using additional coating suspension to achieve a target final weight gain of 4.0% (by weight, including 1% pre-coating) in a perforated bowl coating medium at a general speed of 12 rpm and spray rate. Approximately 44 ml/min.

The film-coated tablets were transferred into an empty cylinder lined with tarred polyethylene.

Dissolution results (% active ingredient released over time) for the 20 mg and 120 mg compression-coated tablets are shown in Figure 3 and Tables 9 and 10 that follow.

Melting time (h)

20 Slow mg(g)

20 Average mg (h)

20 fast mg(i)

5

6

8

2

8

10

14

4

14

19

28

8

33

43

55

12

56

66

81

18

81

91

106

24

99

102

107

Melting time (h)

120 slow mg(j)

120 Average mg (K)

120 Rapid mg (L)

5

6

8

2

8

10

15

4

14

20

29

8

35

47

57

12

59

72

82

18

86

100

98

24

102

103

100

As shown by the solubility in the previous examples, the factors that affect the solubility of the active agent from the dosage forms are the weight ratio of the core:coat and the weight of the tablet. Furthermore, the dissolution data presented previously demonstrate that the formulations of the present invention show essentially zero-order release as disclosed herein.

Example 13

A randomized, mutually exclusive, cross-over study of healthy adult males and females using hydrocodone formulations of Examples 7-12. The study consisted of replications (the process of repeating the study design each time using a unique set of cases subject to a set of predefined treatments). The following iterations were performed:

Repeat 1:

P=36

Random, single dose, 3 treatments, over 3 time periods.

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

HYD 20 mg, medium release tablet, fasting state (tablet H)

HYD 20 mg, fast release tablet, fasting state (tablet I)

Repeat 2:

P=36

Random, single dose, 3 treatments, over 3 time periods.

HYD 120 mg, slow release tablet, fasting state (tablet D)

HYD 120 mg, medium release tablet, fasting state (tablet K)

HYD 120 mg, fast release tablet, fasting state (tablet L)

Repeat 3:

P=16

Randomized, 1 dose, 2 treatments, over 2 time periods.

HYD 120 mg, slow release tablet, fasting state (tablet D)

HYD 120 mg, slow release tablet, fed status (tablet J)

Both formulations were administered orally with 8 oz (240 mL) of water as a single dose in a fasted or fed state as indicated.

While this study was conducted in healthy human subjects, the opioid antagonist naltrexone hydrochloride was administered to reduce opioid-related adverse events.

Choose status

Examination procedures

The following screening procedures were performed for all possible cases at a screening visit conducted within 28 days before the first dose was administered:

- Informed consent.

- Informed consent for voluntary access to a genetic drug sample.

- Informed consent to voluntarily obtain a hair sample.

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

- Evaluation of inclusion/exclusion criteria.

- Medical and medication history, including concomitant medication.

- Vital signs (diastolic blood pressure/systolic blood pressure, pulse rate, respiration rate, orally administered temperature) after sitting for approximately 5 minutes and SpO2

- Additional vital signs (diastolic blood pressure/systolic blood pressure, pulse rate) after standing for approximately 2 minutes.

- HDYF question was made? At the same time as measuring vital signs.

- Routine physical examination.

- Clinical laboratory evaluation after at least 4 hours of fasting (including biochemistry, hematology, and urinalysis).

- 12-lead ECG. QTcF does not exceed 450 milliseconds.

Screens for hepatitis (including hepatitis B surface antigen [HBsAg], hepatitis C antibody [HCV]).

Screens for alcohol, cotinine, and selected drugs for misuse.

- Serum pregnancy test, female cases only; Serum follicle stimulating hormone (FSH) after menopause in females only.

- Serum pregnancy test (female cases only).

- Serum follicle-stimulating hormone (FSH) test (post-menopausal females only).

Inclusion criteria

Cases meeting the following criteria were included in the study.

- Prior written informed consent.

- Male and female ages from 18 to 50, inclusive.

- Body weight ranges from 50 to 100 kg (110 to 220 lbs) and BMI from 18 to 30 (kg/m2), inclusive.

- Healthy and free of any notable abnormal findings as determined by medical history, physical examination, clinical laboratory values, vital signs, and ECG.

- Females of childbearing potential should use an appropriate and reliable method of contraception (i.e., diaphragm with additional spermicidal foam or gel, intrauterine method, hormonal method of contraception). Females must be >1 year postmenopausal and have an elevated serum FSH level.

- Desire for the nutrition provided during the study.

- The desire to refrain from strenuous physical exertion until the end of the study. Cases will not start a new training program and will not engage in any unusually strenuous physical exertion.

Exclusion criteria

The following criteria excluded potential cases from the study.

- Pregnant females (positive human chronic gonadotropin beta test) or breastfeeding.

- History of current or recent drug (within 5 years) or alcohol misuse.

- History or any existing conditions that may interfere with drug absorption, distribution, metabolism or excretion.

- Use of an opioid-containing medication in the last 30 days before the first dose of the study drug in this study.

- History of known allergy to hydrocodone, naltrexone, or related compounds.

- Any history of recurrent nausea or vomiting, regardless of the etiology.

- Any history of seizures or head trauma with herpes.

- Participation in a clinical drug study during the 30 days prior to the initial dose of the study drug in this study.

- Any significant illness during the 30 days before the initial dose of the study drug in this study.

- Use of any medication including thyroid hormone therapy (hormonal contraception and hormone replacement therapy), vitamins, herbal and/or mineral supplements during the 7 days before the initial dose of the study drug.

- Heart anomalies including any of the following:

QTc interval >450 ms (calculated using Fridericia correction) on screening

QTc interval > 480 ms (calculated using Fridericia correction) during treatment.

- Refuse to abstain from food for 10 hours before and 4 hours after administration of the study drug and abstain from caffeine or alcoholic beverages containing xanthine completely during each detention.

- Refusal to abstain from consuming alcoholic beverages for 48 hours before the initial administration of the study drug (day 1) and any period of time until the end of the study visit.

- History of smoking or use of nicotine products within 45 days of initial administration of study drug or positive urine cotinine test.

- Blood or blood products donated within 30 days prior to the initial administration of study drug or at any time until the end of the study visit, except as provided in this protocol.

- Plasma donated within 14 days before administration of the study drug or at any time during the study, except as stipulated in this protocol.

- Positive results of a drug test in urine or screens for alcohol.

- Positive results for HBsAg, anti-HCV.

Positive Naloxone HCl challenge test.

- The presence of Gilbert syndrome, or any known anomalies of the hepatobiliary duct.

- The researcher believes that the case is inappropriate for a reason(s) not specifically mentioned in the exclusion criteria.

Cases meeting all inclusion criteria and meeting any exclusion criteria were randomly selected into the study.

Each case was assigned a unique case number upon screening. Case number assignment was in ascending order and no numbers were omitted. Case numbers were used in all study documents.

Examination procedures

On day 1 of time period 1 only, cases were admitted to the study unit and received a Naloxone HCl challenge test. It is necessary for cases to have negative test results for the study to continue. Biomarkers and SpO2 were measured before and after Naloxone HCl.

The following procedure was also performed for all cases upon examination for each time period:

- Verification of inclusion/exclusion criteria, including verification of willingness to adhere to caffeine and xanthine restriction criteria.

- Vital signs (after sitting for approximately 5 minutes) and SpO2.

- HDYF question (How do you feel) was conducted? At the same time as measuring vital signs.

- Clinical laboratory evaluations (day 1, time period 1 only) including biochemistry (fasting for at least 4 hours), blood work and urinalysis were collected) after measuring vital signs and SPO2.

- Screens for alcohol (via urine or blood alcohol or breathalyzer test or breath test), cotinine, and selected drugs for misuse (urine test).

- Urine pregnancy test (for all female cases).

- Compare and register the accompanying property.

- Compare and record AE.

For cases that continue to participate in the study, drug test results (including alcohol and cotinine) must be available and negative before the dose is given. In addition, continued adherence to concomitant medication and other restrictions at screening and throughout the study was verified in the appropriate source document.

Duration of treatment procedures

The treatments to be studied were predetermined for each replication. Within replication, and as data become available, treatments are dropped between statistical groups. Dropped treatments were replaced with duplicates of the remaining treatments.

- Before the first dose in time period 1, cases were randomly selected into a treatment sequence.

- Cases received naltrexone HCl tablets (50 mg) with 240 ml of water at - 12 hours before the study drug dose was given.

- Before administering the study drug (except for time period 1), the cases underwent chemistry tests (fasting for at least 4 hours), hematology, and urinalysis.

The cases were given the study drug in 240 ml of water as follows:

Regarding treatment while fasting:

After 10 hours of overnight fasting, the subjects were given the study drug using 240 ml/liter of water.

Cases receiving treatment in a fasting state continued to abstain from food for 4 hours after the dose was given.

For treatments in the case of nutrition:

Following 10 hours of overnight fasting, subjects were fed a standard meal (FDA high-fat breakfast) 30 minutes before administration of the study drug using 240 mL of water. No food was allowed for at least 4 hours following the dose. All cases were advised that the meal should be completed within the allotted time frame.

Cases were standing or sitting upright while receiving the study drug dose.

Fasting was not necessary on study days when a dose was not received.

Cases received 50 mg naltrexone HCl tablets with 240 mL of water at 12, 0, 12, 24, and 36 hours for each dose of the study drug.

-For subjects receiving hydrocodone doses of 60 mg or greater, SpO2 was monitored continuously from before the dose was given until 24 hours after the dose.

-Vital signs (after sitting for approximately 5 minutes) and SpO2 were obtained before dose and at 1, 2, 4, 6, 8, 12, 24, 36, 48, and 72 hours after dose for each time period.

- HDYF question was conducted (How do you feel)? At the same time as measuring vital signs.

The cases underwent biochemistry tests (fasting for at least 4 hours), blood tests, and urinalysis 24 hours after taking the dose.

In addition, 12-lead ECGs were performed for each case before the dose and approximately 12, 24 and 48 hours after the dose. If QTcF exceeds 480 ms the condition stops due to the adverse event.

- Blood samples were obtained to determine plasma concentrations of hydrocodone for each case before the dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 14, 18, 24, 36. , 48, and 7 hours after the dose for each time period.

The cases were held in the unit from the examination to the unit on the day before the dose was given until the 48-hour procedure time was over. Cases are returned to the unit for resumption of procedures, which take 72 hours.

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

In addition, subjects were informed that it was necessary to notify study personnel of any/all sightings of vomiting immediately and that this information was essential to the proper conduct and results of the trial. Cases were informed that they would not be penalized in any way for notifying cases of vomiting. Study personnel were instructed to carefully document any/all instances of vomiting.

Study completion procedures

The following procedure was performed at the study site for all cases at the end of the study (study completion), 7 to 10 days after receiving the last dose of study drug or upon early withdrawal from the study.

- Evaluation of concomitant medication.

- Vital signs (after sitting for approximately 5 minutes) and SpO2.

- HDYF question was made? At the same time as measuring vital signs.

- Physical examination.

- 12- Lead ECG.

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

- AE ratings.

- Serum pregnancy test (for female cases only).

The results of the draft are reported in Figures 4-6 and the following Table 13:

Table 13 Summary of draft pharmacokinetic variables for hydrocodone in plasma

Repeat 1:

HYD 20 mg

Repeat 2:

HYD 120 mg

Repeat 3: HYD 120 mg

slow

(g)

Average (h)

fast

(i)

slow

(j)

average (k)

fast (l)

slow

(j)

slow (j)

a variable

Fasting

Fasting

Fasting

Fasting

Fasting

Fasting

Fasting

feed

lonliness

Counting

(p=36)

(p=36)

(p=36)

(p=36)

(p=36)

(p=36)

(p=14)

(n=16)

AUCt

middle

302

323

330

2028

2074

2048

1921

2025

nanogram*s/ml

SD

138

101

90

439

440

514

369

420

minimum

43

95

78

1315

1043

430

1417

1135

Maximum

619

557

499

2911

2869

2917

2586

2716

AUCinf

middle

312

326

329

2037

2083

2055

1933

2032

nanogram*s/ml

SD

142

102

90

442

443

516

374

420

minimum

44

97

83

1320

1046

430

1427

1136

Maximum

623

564

507

2935

2908

2924

2594

2717

Cmax

middle

15

17.4

20.9

119

138

142

110

166

ng/ml

SD

6.4

5.8

7.2

35.8

35.3

39.3

30

34.2

minimum

4.3

7.5

7.7

55.2

76.7

35.6

67

96.2

Maximum

30.7

31.3

39

227

241

239

162

240

Tmax(h)

middle

15.2

13.7

11.4

15.4

12.7

10.7

15

12

SD

4.7

2.6

3.5

2.9

1.7

2

3

minimum

5

8

6

10

10

6

12

10

middle

14

14

12

14

12

10

14

12

Maximum

24

18

24

24

18

14

24

14

T1/2(h)

middle

8.3

7.6

9

7.1

7.6

7.1

7.7

7.8

SD

3.1

2.9

4.9

2.4

3.3

2.5

2.4

4.6

minimum

4.1

4.5

4.4

4.5

4.2

4.1

4

3.8

Maximum

15.3

17.3

25.2

16

17.9

13.4

12.4

21.4

Tag (h)

middle

0.15

0.11

0.13

0.06

0.03

0.01

0.03

0.06

SD

0.23

0.21

0.22

0.16

0.12

0.09

0.13

0.17

minimum

0

0

0

0

0

0

0

0

Maximum

0.5

0.5

0.5

0.5

0.5

0.5

0.5

0.5

C24/Cmax

middle

0.57

0.45

0.3

0.52

0.32

0.23

N/A

N/A

SD

0.28

0.2

0.18

0.21

0.15

0.1

N/A

N/A

minimum

0.03

0.1

0.06

0.17

0.11

0.07

N/A

N/A

Maximum

0.84

0.74

0.48

N/A

N/A

Examples 14-20

Seven different compression-coated tablets (named as Tablets M-S) were prepared containing a total of 20, 30, 40, 60, 80, 100 or 120 mg of hydrocodone bitartrate, respectively, according to Tables 14 (Tablets M, N, and S). ,p) and 15 (discs q, r, s) next.

Table 14 (disks M, N, S, Z)

M formula

(20 mg)

n formula

(30 mg)

S formula

(40 mg)

p formula

(60 mg)

component

mg/tablet

mg/tablet

mg/tablet

mg/tablet

heart

With hydrocodone bitartrate

16

24

32

48

Microcrystalline cellulose, Avicel PH 101

1.091

1.636

2.182

3.273

hydroxypropylcellulose, Klucel EXF

1.091

1.636

2.182

3.273

Purified water

PEO (Mw=600,000) POLYOX WSR 205 FP

279.918

270.827

261.736

243.555

magnesium stearate

1.5

1.5

1.5

1.5

FD&C Yellow No. 6 Aluminum Lake

0.4

0.4

0.4

0.4

Partial total

300

300

300

300

Dry packaging

With hydrocodone bitartrate

4

6

8

12

Microcrystalline cellulose, Avicel PH 101

0.273

0.409

0.545

0.818

hydroxypropylcellulose, Klucel EXF

0.273

0.409

0.545

0.818

Purified water

PEO (Mw=7,000,000) POLYOX WSR 303 FP

393.455

391.182

388.909

384.364

magnesium stearate

2

2

2

2

Partial total

400

400

400

400

Cosmetic packaging

Opadry Clear 85F19250

14

14

14

14

Opadry Green 85F110049

21

Opadry Yellow 85F120034

21

Opadry Gray 85F175009

21

Opadry Beige 85F170015

21

Opadry Pink 85F140044

Opadry Blue 85F105039

Opadry White 85F18422

Total

735

735

735

735

Table 15 (Disks F, R, S)

F formula

(80 mg)

p.formula

(100 mg)

s formula

(120 mg)

component

mg/tablet

mg/tablet

mg/tablet

heart

With hydrocodone bitartrate

64

80

96

Microcrystalline cellulose, Avicel PH 101

4.364

5.455

6.545

hydroxypropylcellulose, Klucel EXF

4.364

5.455

6.545

Purified water

PEO (Mw=600,000) POLYOX WSR 205 FP

225.373

207.191

189.009

magnesium stearate

1.5

1.5

1.5

FD&C Yellow No. 6 Aluminum Lake

0.4

0.4

0.4

Partial total

300

300

300

Dry packaging

With hydrocodone bitartrate

16

20

24

Microcrystalline cellulose, Avicel PH 101

1.091

1.364

1.636

hydroxypropylcellulose, Klucel EXF

1.091

1.364

1.636

Purified water

PEO (Mw=7,000,000) POLYOX WSR 303 FP

379.818

375.273

370.727

magnesium stearate

2

2

2

Partial total

400

400

400

Cosmetic packaging

Opadry Clear 85F19250

14

14

14

Opadry Green 85F110049

Opadry Yellow 85F120034

Opadry Gray 85F175009

Opadry Beige 85F170015

Opadry Pink 85F140044

21

Opadry Blue 85F105039

21

Opadry White 85F18422

21

Total

735

735

735

High shear mixer shipped hydrocodone bitartrate, microcrystalline cellulose, and hydroxypropyl cellulose.

The dry mix mixture was mixed for one (1) minute at low speed with the sector turned off, and then mixed at high speed with the sector turned on. Water was added to the mixture until the desired amount of water was added, producing wet granulation.

The wet granulation was then passed through a screening mill to eliminate agglomeration, and transferred to a fluid bed dryer to dry.

The dry mixture was then passed through a fine mesh strainer until the target particle size range (<1.0%) was achieved.

The dry filtered granulation was then passed through a filter mill and the active granulation was collected in stainless steel containers. The V mixer was shipped with approximately half of the polyethylene oxide (POLYOX WSR-205); The right amount of effective granulation (adjusted for trial); Aluminum lake; And the remaining polyethylene oxide (POLYOX WSR-205), and the mixture was mixed for 10 minutes.

The V-type mixer was then charged with magnesium stearate and the mixture was blended for 2 minutes and discharged into stainless steel cylinders.

The V-shaped mixer is approximately half charged with polyethylene oxide (POLYOX WSR-303); The right amount of effective granulation (adjusted for the experiment); And the remaining polyethylene oxide (POLYOX WSR-303), and the mixture was mixed for 10 minutes.

The V mixer was then charged with magnesium stearate; Mixing for 2 minutes and discharging into stainless steel cylinders.

The left side of the piston was set up using an 8.75 mm, round, shallow concave tool set, and the right side of the piston was set up using a 12 mm, round, shallow cone, cone set.

A core mixture was then colored (coloured) and charged into the left side sector (gravity feed system) to initiate core compression.

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

A dry coat blend (white to off-white) was then charged into the right side section (gravity feed system) to initiate tablet compression.

The initial dry packaging and subsequent dry packaging were adjusted after the core was placed at a total target tablet weight of 700 mg (300 mg core + 400 mg dry coating).

For Opadry color dispersion (target solids 20%), a mixing bowl was charged with an appropriate amount of purified water and the mixer speed was adjusted to create a vortex. Add Opadry color powder to the bowl over a period of 2 to 5 minutes, mixing until a homogeneous dispersion is formed (minimum 1 hour).

For Opadry transparent dispersion (target solids 7.5%) a separate mixing vessel was charged with an appropriate amount of purified water and the mixer speed was adjusted to create a vortex. Transparent Opadry powder was added to the bowl over a period of 2 to 5 minutes (target 3 minutes), mixing until a homogeneous dispersion was formed.

(minimum 1 hour).

The compression-coated tablets were then transferred to a perforated packaging vessel and film coated using Opadry color dispersion to a target weight gain of 0.7%-1.5%.

The heating temperature was increased and the tablets were matured to a target exhaust temperature of 72°C for approximately 30 minutes, and then cooled.

The tablet was continued to be coated with Opadry color dispersion to a target weight gain of 3% including the weight gain from the previous packaging.

The tablets were then film coated using Opadry transparent dispersion to a final target weight gain of 5%.

The dissolution results (% active ingredient released over time) for these 20 mg, 30 mg, 40 mg, 60 mg, 80 mg, 100 mg, and 120 mg compression-coated tablets are shown in Table 16 below.

Table 16

Dissolution results of compression-coated tablets 20, 40, 60, 80, 120 mg (SGF, p=12)

Thawing time (h)

20 mg% active ingredient released

40 mg% active ingredient released

60 mg% active ingredient released

80 mg% active ingredient released

120 mg% active ingredient released

102

102

101

101

Example 21

A randomized, mutually exclusive, block study with 1 dose, 5 treatments, across 4 time periods, was conducted in non-complementary subjects in healthy adult males and females using hydrocodone (HYD) formulations of Examples 14-20. The study consisted of a maximum of 5 treatments, across 4 time periods.

The strength of the HYD tablet, or the doses studied, were:

1 20 mg HYD tablet

1 40 mg HYD tablet

1 60 mg HYD tablet

1 80 mg HYD tablet

1 120 mg HYD tablet

Both treatments were administered orally with 8 oz (240 mL) of water as a single dose in a fasted state.

With this study conducted in healthy humans, the opioid antagonist naltrexone hydrochloride was administered to minimize opioid-related adverse events.

Choose status

Examination procedures

The following screening procedures were performed for all possible cases at a screening visit conducted within 28 days before the first dose was administered:

- Informed consent.

- Informed consent for voluntary access to a genetic drug sample.

- Informed consent to voluntarily obtain a hair sample.

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

- Evaluation of inclusion/exclusion criteria.

- Medical and medication history, including concomitant medication.

- Vital signs (diastolic blood pressure/systolic blood pressure, pulse rate, respiration rate, orally administered temperature) after sitting for approximately 5 minutes and SpO2

- Additional vital signs (diastolic blood pressure/systolic blood pressure, pulse rate) after standing for approximately 2 minutes.

- HDYF question was made? At the same time as measuring vital signs.

- Routine physical examination.

- Clinical laboratory evaluation after at least 4 hours of fasting (including biochemistry, hematology, and urinalysis).

- 12-lead ECG. QTcF does not exceed 450 milliseconds.

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

Screens for alcohol, cotinine, and selected drugs for misuse.

- Serum pregnancy test, female cases only; Serum follicle stimulating hormone (FSH) after menopause in females only.

- Serum pregnancy test (female cases only).

- Serum follicle stimulating hormone (FSH) test (after menopausal females only).

Inclusion criteria

Cases meeting the following criteria were included in the study.

- Prior written informed consent.

- Male and female ages from 18 to 50, inclusive.

- Desire for the nutrition provided during the study.

- Body weight ranges from 50 to 100 kg (110 to 220 lbs) and BMI from 18 to 30 (kg/m2), inclusive.

- The desire to refrain from strenuous physical exertion until the end of the study. Cases will not start a new training program and will not engage in any unusually strenuous physical exertion.

- Healthy and free of any notable abnormal findings as determined by medical history, physical examination, clinical laboratory values, vital signs, and ECG.

- Females of childbearing potential should use an appropriate and reliable method of contraception (i.e., diaphragm with additional spermicidal foam or gel, intrauterine method, hormonal method of contraception). Females must be ≥ 1 year postmenopausal and have an elevated serum follicle stimulating hormone (FSH) level.

Exclusion criteria

The following criteria excluded potential cases from the study.

- Pregnant females (positive chronic human beta gonadotropin test) or breastfeeding.

- History of current or recent drug (within 5 years) or alcohol misuse.

- History or any existing conditions that may interfere with drug absorption, distribution, metabolism or excretion.

- Use of an opioid-containing medication in the last 30 days before the first dose of the study drug in this study.

- History of known allergy to hydrocodone, naltrexone, or related compounds.

- Any history of recurrent nausea or vomiting, regardless of the etiology.

- Any history of seizures or head trauma with herpes.

- Participation in a clinical drug study during the 30 days prior to the initial dose of the study drug in this study.

- Any significant illness during the 30 days before the initial dose of the study drug in this study.

- Use of any medication including thyroid hormone therapy (a method with a hormonal load and hormone replacement therapy in the form of estrogen with or without the use of progestin), vitamins, herbal and/or mineral supplements during the 7 days before the initial dose of the study drug.

- Any personal or family history of a prolonged QT interval or heart rhythm disturbances.

- Heart anomalies including any of the following:

QTc interval ≥ 450 ms (calculated using Fridericia correction) at screening

QTc interval ≥ 480 ms (calculated using Fridericia correction) during treatment.

- Refuse to abstain from food for 10 hours before and 4 hours after administration of the study drug and abstain from caffeine or alcoholic beverages containing xanthine completely during each detention.

- Refusal to abstain from consuming alcoholic beverages for 48 hours before the initial administration of the study drug (day 1) and any period of time until the end of the study visit.

- Blood or blood products donated within 30 days prior to the initial administration of study drug or at any time until the end of the study visit, except as provided in this protocol.

- History of smoking or use of nicotine products within 45 days of initial administration of study drug or positive urine cotinine test.

- Positive results of a drug test in urine or screens for alcohol.

- Positive results for HBsAg, anti-HCV.

Positive Naloxone HCl challenge test.

- The presence of Gilbert syndrome, or any known anomalies of the hepatobiliary duct.

- The researcher believes that the case is inappropriate for a reason(s) not specifically mentioned in the exclusion criteria.

Cases that met all inclusion criteria and none of the exclusion criteria were randomized into the study.

Each case was assigned a unique case number upon screening. Case number assignment was in ascending order and no numbers were omitted. Case numbers were used in all study documents.

Examination procedures

On day 1 of time period 1 only, cases were admitted to the study unit and received a Naloxone HCl challenge test. It is necessary for cases to have negative test results for the study to continue. Biomarkers and SpO2 were measured before and after Naloxone HCl.

The following procedure was also performed for all cases upon examination for each time period:

- Verification of inclusion/exclusion criteria, including verification of willingness to adhere to caffeine and xanthine restriction criteria.

- Vital signs (after sitting for approximately 5 minutes) and SpO2.

- HDYF question (How do you feel) was conducted? At the same time as measuring vital signs.

- Clinical laboratory evaluations (day 1, time period 1 only) including biochemistry (fasting for at least 4 hours), blood work and urinalysis were collected) after measuring vital signs and SPO2.

- Screens for alcohol (via urine or blood alcohol or breathalyzer test or breath test), cotinine, and selected drugs for misuse (urine test).

- Urine pregnancy test (for all female cases).

- Compare and register the accompanying property.

- Compare and record AE.

For cases that continue to participate in the study, drug test results (including alcohol and cotinine) must be available and negative before the dose is given. In addition, continued adherence to concomitant medication and other restrictions at screening and throughout the study was verified in the appropriate source document.

Duration of treatment procedures

The treatments to be studied were predetermined for each replication. Within replication, and as data become available, treatments are dropped between statistical groups. Dropped treatments were replaced with duplicates of the remaining treatments.

- Before the first dose in time period 1, cases were randomly selected into a treatment sequence.

- Cases received naltrexone HCl tablets (50 mg) with 240 ml of water at - 12 hours before the study drug dose was given.

The cases were given the study drug in 240 ml of water after 10 hours of fasting overnight. The cases continued to abstain from food for 4 hours after the dose was given.

Cases were standing or sitting upright while receiving the study drug dose.

Fasting was not necessary on study days when a dose was not received.

Cases received 50 mg naltrexone HCl tablets with 240 mL of water at 12, 0, 12, 24, and 36 hours for each dose of the study drug.

-For subjects receiving hydrocodone doses of 60 mg or greater, SpO2 was monitored continuously from before the dose was given until 24 hours after the dose.

-Vital signs (after sitting for approximately 5 minutes) and SpO2 were obtained before dose and at 1, 2, 4, 6, 8, 12, 24, 36, 48, and 72 hours after dose for each time period.

- HDYF question was conducted (How do you feel)? At the same time as measuring vital signs.

- 12-lead ECGs were performed for each case before the dose and approximately 12, 24 and 48 hours after the dose. - Blood samples were obtained to determine hydrocodone plasma concentrations for each case before the dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 14, 18, 24, 36, 48, And 7 hours after the dose for each time period.

The cases were held in the unit from the examination to the unit on the day before the dose was given until the 48-hour procedure time was over. Cases are returned to the unit for resumption of procedures, which take 72 hours.

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

In addition, subjects were informed that it was necessary to notify study personnel of any/all sightings of vomiting immediately and that this information was essential to the proper conduct and results of the trial. Cases were informed that they would not be penalized in any way for notifying cases of vomiting. Study personnel were instructed to carefully document any/all instances of vomiting.

Study completion procedures

The following procedure was performed at the study site for all cases at the end of the study (study completion), 7 to 10 days after receiving the last dose of study drug or upon early withdrawal from the study.

- Evaluation of concomitant medication.

- Vital signs (after sitting for approximately 5 minutes) and SpO2.

- HDYF question was made? At the same time as measuring vital signs.

- Physical examination.

-12-Lead ECG.

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

-AE ratings.

-Pregnancy serum test (female cases only).

The results of the draft are shown in Figure 7 and Table 17 below:

Table 17 Summary of draft pharmacokinetic variables for hydrocodone in plasma

a variable

HYD 20 mg

HYD 40 mg

HYD 60 mg

HYD 80 mg

HYD 120 mg

(lonliness)

Counting

(p=29)

(p=30)

(p=28)

(p=30)

(p=29)

AUCt

middle

281

618

1004

1298

1759

(ng*h/mL)

SD

127

255

292

373

671

MIN

85

580

559

303

MAX

591

1200

1724

2501

3324

AUCinf

middle

284

622

1009

1304

1768

(ng*h/mL)

SD

128

256

294

375

674

Min

31

86

583

564

305

Max

595

1213

1742

2514

3347

Cmax

middle

15

34

54

69

110

(ng/ml)

SD

5.5

12

15

17

44

Min

3.5

7.6

33

40

28

Max

26

54

83

109

199

Tmax(h)

middle

15

16

16

15

15

SD

4.5

4.5

4.7

2.6

4.4

Min

6

6

10

10

6

middle

16

16

14

16

14

Max

24

24

30

24

30

The present invention is not limited in its scope to the specific embodiments disclosed in the examples that are for the purpose of illustrating a few aspects of the invention, and any functionally equivalent embodiments are within the scope of this invention. Indeed, the various modifications of the invention will furthermore explain those shown and described in the present application to those skilled in the art and falling within the scope of the attached claims.