Pharmaceutical resinate compositions and methods of making and using same

Abstract

Disclosed herein are pharmaceutical compositions having a mixture of at least one active agent, an ion exchange resin, a binder, and a matrix material such that when administered to a patient in need thereof, the composition provides a therapeutic effect to the patient for at least about 8 hours, and related methods. Also provided herein are pharmaceutical compositions having a mixture of a susceptible abuse drug, a non-opioid analgesic, and an ion exchange resin, the compositions further comprising at least one gelling agent, and related methods.

Description

[0001] This application is a divisional application based on a patent application with an application date of October 8, 2018, application number 201880078034.9 (PCT / US2018 / 054830), and invention name: "Drug resin composition and preparation and use method thereof". Technical Field

[0002] The present invention relates to pharmaceutical compositions that are resistant to tampering and abuse. Background Art

[0003] Drug products may be abused. An individual seeking to abuse a drug product may tamper with it to extract the active agent contained therein and administer the active agent in a more potent form for abuse. For example, an opioid agonist may be more potent when administered parenterally than when administered orally at the same dose. As non-limiting examples, methods of tampering with a drug product containing an opioid agonist intended for oral administration may include crushing the drug product or immersing it in a solvent (e.g., as a non-limiting example, ethanol) to extract the opioid agonist and administer it in a more potent form (e.g., as a non-limiting example, a nasal or parenteral form).

[0004] There have been previous attempts to reduce the abuse potential associated with pharmaceutical products containing opioid analgesics. For example, Sanofi-Winthrop in the United States markets its The commercially available tablets sold by NX contain a combination of pentazocine hydrochloride equivalent to 50 mg and naloxone hydrochloride equivalent to 0.5 mg of base. When taken orally, the amount of naloxone present in this combination has low activity and interferes little with the pharmacological action of pentazocine. However, when administered parenterally, this amount of naloxone has an antagonistic effect on narcotic analgesics such as pentazocine. Therefore, the addition of naloxone can prevent the form of abuse of pentazocine, which may occur when the oral dosage form is dissolved and injected (i.e., parenteral gastric abuse). As another example of a similar approach, there is a fixed combination therapy in Germany comprising tilidine hydrochloride hemihydrate and naloxone hydrochloride dihydrate (marketed under the trade name tilidine hydrochloride dihydrate). N, Goedecke), and in New Zealand there is a fixed combination of buprenorphine and naloxone (trade name NX, Reckitt &

[0005] Colman).

[0006] However, there is still a need in the art for pharmaceutical compositions containing drugs susceptible to abuse that are resistant to parenteral and nasal abuse. In addition, in the case of opioid analgesics, there is still a need for tamper-resistant formulations that do not rely entirely on the inclusion of antagonists to prevent parenteral and nasal abuse. Summary of the invention

[0007] In at least one embodiment, the present invention provides tamper-resistant pharmaceutical compositions comprising at least one active agent.

[0008] In at least one embodiment, the present invention provides pharmaceutical compositions comprising at least one active agent that are less susceptible to parenteral abuse than other pharmaceutical compositions.

[0009] In at least one embodiment, the present invention provides pharmaceutical compositions comprising at least one active agent that are less susceptible to intranasal abuse than other pharmaceutical compositions.

[0010] In at least one embodiment, the present invention provides a pharmaceutical composition comprising at least one active agent that is less susceptible to diversion than other pharmaceutical compositions.

[0011] In at least one embodiment, the present invention provides a method of treating a disease or condition in a human patient by administering to a patient in need thereof a pharmaceutical composition disclosed herein.

[0012] In at least one embodiment, the present invention provides a method of treating pain in a human patient by administering to a human patient in need thereof a pharmaceutical composition comprising at least one opioid analgesic while reducing its potential for abuse.

[0013] In at least one embodiment, the present invention provides a method of preparing a pharmaceutical composition comprising at least one active agent as disclosed herein.

[0014] In at least one embodiment, the present invention provides for the use of a drug (eg, an opioid analgesic) in the preparation of a tamper-resistant pharmaceutical composition as disclosed herein for the treatment of a disease state (eg, pain).

[0015] In at least one embodiment, the present invention provides a pharmaceutical composition comprising a mixture of a complex comprising at least one active agent and an ion exchange resin, a binder, and a matrix material, wherein the composition, when administered to a patient in need thereof, provides a therapeutic effect to the patient for at least about 8 hours, or at least about 12 hours, or at least about 24 hours.

[0016] In at least one embodiment, the present invention provides a pharmaceutical composition comprising a mixture of (i) at least one active agent and an ion exchange resin, (ii) a binder, and (iii) a matrix material, wherein the composition, when administered to a patient in need thereof, provides a therapeutic effect to the patient for at least about 8 hours, or at least about 12 hours, or at least about 24 hours.

[0017] In at least one embodiment, the invention is directed to a method of treating a disease or condition, such as, as a non-limiting example, pain or attention deficit hyperactivity disorder (ADHD), comprising administering to a patient in need thereof a pharmaceutical composition comprising a mixture of a complex of at least one active agent and an ion exchange resin, a binder, and a matrix material, wherein the composition, when administered to a patient in need thereof, provides a therapeutic effect to the patient for at least about 8 hours, or at least about 12 hours, or at least about 24 hours.

[0018] In at least one embodiment, the present invention provides a method of treating a disease or condition, such as, as non-limiting examples, pain or attention deficit hyperactivity disorder (ADHD), comprising administering to a patient in need thereof a pharmaceutical composition comprising a mixture comprising (i) at least one active agent and an ion exchange resin, (ii) a binder, and (iii) a matrix material, wherein the composition, when administered to a patient in need thereof, provides a therapeutic effect to the patient for at least about 8 hours, or at least about 12 hours, or at least about 24 hours.

[0019] In at least one embodiment, the invention is directed to a method of discouraging abuse of an abuse-prone drug comprising administering to a patient in need thereof a pharmaceutical composition comprising a mixture of a complex comprising at least one active agent and an ion exchange resin, a binder, and a matrix material, wherein the composition, when administered to a patient in need thereof, provides a therapeutic effect to the patient for at least about 8 hours, or at least about 12 hours, or at least about 24 hours.

[0020] In at least one embodiment, the invention is directed to a method of discouraging abuse of an abuse-prone drug comprising administering to a patient in need thereof a pharmaceutical composition comprising a mixture comprising (i) at least one active agent and an ion exchange resin, (ii) a binder, and (iii) a matrix material, wherein the composition, when administered to a patient in need thereof, provides a therapeutic effect to the patient for at least about 8 hours, or at least about 12 hours, or at least about 24 hours.

[0021] In at least one embodiment, the invention relates to a method of preparing a pharmaceutical composition comprising forming a complex of at least one active agent and an ion exchange resin, combining the complex with a binder and forming a matrix comprising the complex, the binder and a matrix material, and incorporating the complex into a pharmaceutical composition, wherein the composition, when administered to a patient in need thereof, provides a therapeutic effect to the patient for at least about 8 hours, or at least about 12 hours, or at least about 24 hours.

[0022] In at least one embodiment, the invention relates to a method of preparing a pharmaceutical composition comprising forming a mixture comprising (i) at least one active agent and an ion exchange resin, (ii) a binder, and (iii) a matrix material and incorporating the complex into a pharmaceutical composition, wherein the composition, when administered to a patient in need thereof, provides a therapeutic effect to the patient for at least about 8 hours, or at least about 12 hours, or at least about 24 hours.

[0023] definition

[0024] In describing the present disclosure, the following terminology will be used as indicated below. As used herein, the singular forms "a", "an", and "the" include plural references unless the context clearly indicates otherwise. Thus, for example, reference to "an active agent" includes a single active agent as well as mixtures of two or more different active agents, and reference to "a resin" includes a single resin as well as mixtures of two or more different resins, etc.

[0025] As used herein, the term "about" is related to the measured quantity and refers to the normal variation of the measured quantity, as expected by a person skilled in the art when making the measurement and measuring with a degree of care commensurate with the precision of the measurement target and the measurement equipment. In certain embodiments, the term "about" includes the stated value ± 10%, such as "about 10" includes 9 to 11.

[0026] The term "at least about" in relation to a measured amount refers to the normal variation of the measured amount, as would be expected by one skilled in the art when making the measurement and measuring with a degree of care commensurate with the precision of the measurement target and the measuring equipment, as well as any amount above this value. In certain embodiments, the term "at least about" includes the stated number minus 10% and any amount above that number, such that "at least about 10" will include 9 and any amount above 9. The term may also be expressed as "about 10 or more". Similarly, the term "less than about" generally includes the stated number plus 10% and any lower amount, such as "less than about 10" will include 11 and any amount less than 11. The term may also be expressed as "about 10 or less".

[0027] As used herein, the terms "active agent," "active ingredient," "pharmaceutical agent," and "drug" refer to any material intended to produce a therapeutic, prophylactic, or other desired effect in a patient in need thereof, whether or not approved by a governmental agency for such purpose. These terms, as they relate to a particular agent, include all pharmaceutically active forms of that agent, including the free base form of that agent, as well as all pharmaceutically acceptable salts, complexes, stereoisomers, crystalline forms, co-crystals, ethers, esters, hydrates, solvates, and mixtures thereof, wherein such forms are pharmaceutically active.

[0028] The term "mixed agent" with respect to at least one active agent and an ion exchange material means that the two materials are at least partially dispersed within each other in the form of a physical mixture without chemical interaction.

[0029] The term "complex" with respect to at least one active agent and an ion exchange material refers to a material or mixture in which the at least one active agent and the ion exchange material chemically interact, such as by covalent bonding, ionic bonding, van der Waals forces to form a chemical bond between the two materials, as non-limiting examples. In certain embodiments, 25% or more, 50% or more, 75% or more, 85% or more, or 95% or more of the mixture comprises a complex of at least one active agent and an ion exchange resin.

[0030] As used herein, the term "therapeutically effective" refers to the amount of a drug or the rate of administration of a drug required to produce the desired therapeutic result in a patient.

[0031] As used herein, the term "prophylactically effective" refers to the amount of a drug or the rate of drug administration required to produce the desired prophylactic result.

[0032] As used herein, the term "stereoisomer" is a general term for all isomers of a single molecule that differ only in the orientation of their atoms in space. It includes enantiomers and isomers (diastereomers) of compounds with one or more chiral centers that are not mirror images of each other.

[0033] The term "enantiomer" or "enantiomerically" refers to a molecule that is non-superimposable on its mirror image and is therefore optically active wherein the enantiomer rotates the plane of polarized light to a certain degree in one direction and its mirror image rotates the plane of polarized light to the same degree but in the opposite direction.

[0034] The term "chiral center" refers to a carbon atom to which four different groups are attached.

[0035] The term "racemic" refers to a mixture of enantiomers.

[0036] The term "resolution" refers to the separation, concentration or reduction of one of the two enantiomeric forms of a molecule.

[0037] The term "patient" refers to a subject, especially a human, who exhibits clinical manifestations of a particular symptom or symptoms requiring treatment, who is being treated prophylactically or preventively for the disease, or who has been diagnosed as having the disease to be treated. The term "subject" includes the definition of the term "patient" and does not exclude individuals who are completely normal in all respects or with respect to a particular condition.

[0038] For the purposes of this disclosure, "pharmaceutically acceptable salts" include, but are not limited to, inorganic acid salts, such as hydrochlorides, hydrobromides, sulfates, phosphates, and the like; organic acid salts, such as formates, acetates, trifluoroacetates, maleates, tartrates, and the like; sulfonates, such as methanesulfonates, benzenesulfonates, p-toluenesulfonates, and the like; amino acid salts, such as arginine salts, asparagine salts, glutamate salts, and the like; metal salts, such as sodium salts, potassium salts, cesium salts, and the like; alkaline earth metals, such as calcium salts, magnesium salts, and the like; and organic amine salts, such as triethylamine salts, pyridinium salts, methylpyridine salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, and the like.

[0039] As used herein, the term "ppm" means "parts per million."

[0040] The term "laminated" means fully or partially coated on a substrate.

[0041] The term "bioavailability" refers to the relative extent to which a drug (eg, oxycodone) is absorbed from a unit dosage form / drug composition. Bioavailability is also referred to as AUC (ie, the area under the plasma concentration / time curve).

[0042] The term "C rnax ” indicates the maximum plasma concentration achieved during the dosing interval.

[0043] The term "T max ” indicates the maximum plasma concentration (C max ) time.

[0044] The terms "patient population," "subject population," and "healthy subject population" refer to the average pharmacokinetic parameters of at least two patients, subjects, or healthy subjects; at least six patients, subjects, or healthy subjects; or at least twelve patients, subjects, or healthy subjects.

[0045] The term "substrate" refers to a substance or layer of material. In at least one embodiment, the term "substrate" refers to an inert core. In at least one embodiment, the term "substrate" refers to a particle or particle, including but not limited to particles or particles comprising an active agent that is different or the same as the at least one active agent.

[0046] For the purposes of this disclosure, the formulations disclosed herein can be dose proportional. In dose proportional formulations, pharmacokinetic parameters (e.g., AUC and C max ) and / or in vitro release increases linearly from one dosage strength to another. Therefore, the pharmacokinetics and in vitro parameters of a specific dose can be inferred from the parameters of the same formulation at different doses.

[0047] As used herein, the term "high molecular weight" refers to an approximate molecular weight of at least 1,000,000 Da. The approximate molecular weight is based on a rheological method of obtaining the rheological properties of a compound. For example, when a 2% (by weight) aqueous solution of polyethylene oxide (measured by a Brookfield viscometer model RVF, spindle No. 1, at 10 rpm, at 25°C) shows a viscosity range of 400 to 800 mPa s (cP), the polyethylene oxide has an approximate molecular weight of 1,000,000 Da. When a 2% (by weight) aqueous solution of polyethylene oxide (measured by a Brookfield viscometer model RVF, spindle No. 3, at 10 rpm, at 25°C) shows a viscosity range of 2000 to 4000 mPa s (cP), the polyethylene oxide has an approximate molecular weight of 2,000,000 Da. When a 1% (by weight) aqueous solution of polyethylene oxide (measured by a Brookfield viscometer model RVF, spindle No. 2, at 2 rpm, at 25° C.) shows a viscosity range of 1650 to 5500 mPa s (cP), polyethylene oxide has an approximate molecular weight of 4,000,000 Da. When a 1% (by weight) aqueous solution of polyethylene oxide (measured by a Brookfield viscometer model RVF, spindle No. 2, at 2 rpm, at 25° C.) shows a viscosity range of 5500 to 7500 mPa s (cP), polyethylene oxide has an approximate molecular weight of 5,000,000 Da. When a 1% (by weight) aqueous solution of polyethylene oxide (measured by a Brookfield viscometer model RVF, spindle No. 2, at 2 rpm, at 25° C.) shows a viscosity range of 7500 to 10,000 mPa s (cP), polyethylene oxide has an approximate molecular weight of 7,000,000 Da. When a 1 wt% aqueous solution of polyethylene oxide (measured by a Brookfield viscometer model RVF, spindle No. 2, at 2 rpm, at 25°C) shows a viscosity range of 10,000 to 15,000 mPa s (cP), the polyethylene oxide has an approximate molecular weight of 8,000,000 Da. The same rheological method described above or other rheological methods known to those skilled in the art can be used to determine the molecular weight of other compounds, including, but not limited to, high molecular weight hydroxypropyl methylcellulose, high molecular weight hydroxypropyl cellulose, and high molecular weight ethyl cellulose.

[0048] The term "low molecular weight" means having an approximate molecular weight of less than 1,000,000 Da based on the above rheological method. For example, when a 5 wt % aqueous solution of polyethylene oxide (measured by a Brookfield viscometer model RVT, spindle No. 1, at 50 rpm, at 25° C.) shows a viscosity range of 30 to 50 mPa s (cP), the polyethylene oxide has an approximate molecular weight of 100,000 Da. When a 5 wt % aqueous solution of polyethylene oxide (measured by a Brookfield viscometer model RVF, spindle No. 2, at 2 rpm, at 25° C.) shows a viscosity range of 8800 to 17,600 mPa s (cP), the polyethylene oxide has an approximate molecular weight of 900,000 Da. The same rheological method described above or other rheological methods known to those skilled in the art can be used to determine the molecular weight of other compounds, including, but not limited to, low molecular weight hydroxypropyl methylcellulose, low molecular weight hydroxypropyl cellulose, and low molecular weight ethyl cellulose. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 is a diagram of an exemplary pharmaceutical composition according to an exemplary embodiment of the present disclosure comprising a mixture of at least one active agent and an ion exchange material formed in the absence of an aqueous medium.

[0051] Figure 2 is a schematic representation of a pharmaceutical composition according to an exemplary embodiment of the present disclosure, comprising a complex of at least one active agent and an ion exchange material formed in the presence of an aqueous medium.

[0052] Figure 3 is a flow chart of an exemplary method for preparing a pharmaceutical composition comprising a complex of at least one active agent and an ion exchange material according to an exemplary embodiment of the present disclosure.

[0053] Figure 4 is a flow chart of an exemplary method for preparing a pharmaceutical composition comprising a complex of at least one active agent and an ion exchange material according to an exemplary embodiment of the present disclosure.

[0054] Figure 5 is a graph showing the dissolution profile of an exemplary pharmaceutical composition comprising a complex of at least one active agent and an ion exchange material according to an exemplary embodiment of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0056] Pharmaceutical preparations may be objects of abuse. As an example of a method for abusing a pharmaceutical preparation, a pharmaceutical composition in solid dosage form is crushed to release the activating agent contained therein and administered, for example, in a more effective form by parenteral administration or nasal administration (absorption through mucosal surfaces). As another example, a pharmaceutical composition is dissolved (e.g., dissolved in an aqueous or non-aqueous solvent) to prepare an activating agent solution that can be easily drawn into a syringe for parenteral administration.

[0057] Controlled release dosage forms play a role in the treatment of both acute and chronic conditions (e.g., pain management with opioid analgesics). Thus, tamper-resistant pharmaceutical compositions of drugs susceptible to abuse can maintain controlled release properties when administered orally as prescribed.

[0058] In at least one embodiment, the present invention provides a pharmaceutical composition comprising at least one active agent, an ion exchange material, a binder and a matrix material, which provides controlled release of at least one active agent when administered orally as prescribed, but exhibits reduced dissolution of at least one active agent when placed in a medium that does not simulate gastric fluid, e.g., an aqueous medium (e.g., water) or an alcohol, a mixed alcohol, or a mixed alcohol / water medium. In at least one embodiment, the at least one active agent and the ion exchange material form a complex such that the complex releases at least one active agent at different rates after exposure to different media. In another such at least one embodiment, the pharmaceutical composition includes a mixture of at least one active agent and an ion exchange material such that at least one active agent and the ion exchange material form the complex when the pharmaceutical composition is placed in a medium that does not simulate gastric fluid. In a specific embodiment, the composition of the present invention exhibits reduced dissolution of at least one active agent at a pH above about 4.5, above about 5.5 or above about 6.5.

[0059] The present invention therefore provides a pharmaceutical composition comprising a complex or mixture of at least one active agent and an ion exchange material, wherein the composition, when administered to a patient in need thereof, provides a therapeutic effect to the patient for at least about 8 hours, or at least about 12 hours, or at least about 24 hours. In certain embodiments, the composition releases about 10% to about 45% of the active agent after 1 hour, about 12.5% ​​to about 55% (by weight) of the active agent after 2 hours, about 25% to about 65% (by weight) of the active agent after 4 hours, about 45% to about 85% (by weight) of the active agent after 6 hours, and about 55% to about 95% (by weight) of the active agent after 8 hours, and optionally about 75% to 100% (by weight) of the active agent after 12 hours, as measured by in vitro dissolution in about 900 ml of simulated gastric fluid at about 37°C in a USP apparatus 2 (paddle) at about 50 rpm.

[0060] In other embodiments, the pharmaceutical composition exhibits one or more of the following: (i) less than 10% release of the active agent in 1 hour, (ii) less than 20% release of the active agent in 2 hours, (iii) less than 25% release of the active agent in 4 hours, (iv) less than 30% release of the active agent in 6 hours, (v) less than 40% release of the active agent in 8 hours and (vi) less than 50% release of the active agent in 12 hours as measured by in vitro dissolution in about 900 ml of simulated gastric fluid at about 37°C in a USP Apparatus 2 (paddle) at about 50 rpm.

[0061] When placed in an aqueous medium, however, the pharmaceutical compositions disclosed herein may show reduced dissolution of at least one active agent. For example, according to at least one embodiment, the pharmaceutical compositions disclosed herein may release about 20% or less, or about 15% or less, or about 10% or less, or about 5% or less of at least one active agent in about 20 minutes, as measured by in vitro dissolution at about 50 rpm in about 900 ml of water at about 37°C in USP apparatus 2 (paddle). In at least one embodiment, the composition may release about 30% or less, or about 20% or less, or about 15% or less of at least one active agent in about 45 minutes, as measured by in vitro dissolution at about 50 rpm in about 900 ml of water at about 37°C in USP apparatus 2 (paddle). In at least one embodiment, the composition releases about 20% or less, or about 15% or less, or about 10% or less, or about 5% or less of at least one active agent in about 20 minutes as measured by in vitro dissolution in about 900 ml of 40% ethanol in water v / v at about 37° C. in a USP Apparatus 2 (paddle) at about 50 rpm. In at least one embodiment, the composition releases about 30% or less, or about 20% or less, or about 15% or less, or about 10% or less of at least one active agent in about 45 minutes as measured by in vitro dissolution in about 900 ml of 40% ethanol in water v / v at about 37° C. in a USP Apparatus 2 (paddle) at about 50 rpm.

[0062] Similarly, when placed in alcohol or mixed aqueous / alcohol medium, the pharmaceutical composition disclosed herein can show the dissolution of the reduction of at least one active agent. For example, the pharmaceutical composition disclosed herein can release about 20% or less, about 10% or less, or about 5% or less of at least one active agent in about 20 minutes, which is measured by in vitro dissolution at about 50rpm in about 900ml of an aqueous solution (v / v) of about 40% alcohol at about 37°C in USP device 2 (paddle). In certain embodiments, the composition can release about 30% or less, about 20% or less, or about 10% or less of the active agent in about 45 minutes, which is measured by in vitro dissolution at about 50rpm in about 900ml of an aqueous solution (v / v) of about 40% alcohol at about 37°C in USP device 2 (paddle). The non-limiting example of alcohol is ethanol.

[0063] When placed in an aqueous medium, the reduced dissolution of at least one active agent in the pharmaceutical composition disclosed herein can be measured by "injectability". For the purpose of this disclosure, "injectability" refers to the amount of at least one active agent that can be extracted from a mixture of a pharmaceutical composition and a solvent into a syringe of a specific specification (e.g., 21G, 23G, 25G, 27G, 28G, 29G, 30G, 31G, etc.) by a cotton ball or other filter material, relative to the total amount of at least one active agent initially present in the pharmaceutical composition. Non-limiting examples of aqueous media that can be used as solvents to test injectability include, for example, 40% ethanol aqueous solution, saline, tap water, and vinegar, for example. For example, the pharmaceutical composition can be complete, crushed or ground and dissolved in a small amount of solvent (e.g., 1ml, 5ml or 10ml). Dissolution can be carried out in a specific time period (e.g., 1 minute, 5 minutes or 10 minutes) with or without stirring (e.g., vigorous shaking, ultrasound, etc.). The solvent can be room temperature or boiling, for example. In at least one embodiment, the percentage of at least one active agent extracted from the mixture of a pharmaceutical composition disclosed herein and an aqueous solvent into a syringe can be about 30% or less relative to the total amount of the at least one active agent in the pharmaceutical composition. In at least one embodiment, for example, the percentage extracted can be about 29% or less, about 28% or less, about 27% or less, about 26% or less, about 25% or less, about 24% or less, about 23% or less, about 22% or less, about 21% or less, about 20% or less, about 19% or less, about 18% or less, about 17% or less, about 16% or less, about 15% or less, about 14% or less, about 13% or less, about 12% or less, about 11% or less, about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, or about 1% or less.

[0064] Ion exchange materials

[0065] Ion exchange materials suitable for use in the pharmaceutical compositions disclosed herein are selected from pharmaceutically acceptable ion exchange materials that are capable of associating or chemically interacting with at least one active agent in solution or in situ to form a complex, such as a resinate, and releasing at least one active agent when the complex is exposed to a release medium. Pharmaceutically acceptable ion exchange materials include any of the following ion exchange materials that are non-toxic to animals such as humans, do not substantially interfere with the pharmaceutical action of the active agent associated with the ion exchange material, contain a pharmacologically inert matrix (the inert matrix contains ionic or ionizable functional groups under certain pH conditions), have a moisture content between 0% and the water retention capacity of the ion exchange material, and are slightly soluble in water or insoluble in water. In at least one embodiment, the ion exchange material, such as a resin, can be a macroporous or gel-type resin. In general, ion exchange materials suitable for use in ion exchange chromatography or for use in applications such as deionized water, such as resins, are suitable ion exchange materials in the pharmaceutical compositions disclosed herein. Examples of ion exchange materials (including resins) are described in "Principles of Ion Exchange" (pp. 312-343) and "Techniques and Applications of ion-Exchange Chromatography" (pp. 344-361) in Chromatography. (E. Heftmann, ed.), Van Nostrand Reinhold Company, New York (1975); Kitagawa, US Pat. No.

[0066] 6,218,440; Barby, US Pat. No. 4,522,953; Dowex: Ion Exchange Resins. Fundamentals of Ion Exchange (2000); and Hughes, Ion Exchange Resins; Unique Solutions to Formulation Problems, Pharmaceutical Technology: Excipients and Solid Dosage Forms, pp. 20-25 (June 2004). Examples of ion exchange materials other than resins are described in Hollenbeck, U.S. Patent Publication No. 2005 / 0013792. Other ion exchange materials may also be used, such as crosslinked sodium carboxymethylcellulose and carbomers, such as those sold under the trade name CARBOXYL. (Noveon Inc., Cleveland, Ohio). Other examples of ion exchange materials other than resins are disclosed in Hollenbeck, US Patent Publication No. 2005 / 0013792.

[0067] The ion exchange material or resin may be in ionic form, salt form, or partial salt form, and may be cationic or anionic. Typically, cationic ion exchange materials are used with positively charged active agents, and anionic ion exchange materials are used with negatively charged active agents. Non-limiting examples of anion exchange resins include, but are not limited to, styrene-type strong base anion exchange resins with quaternary amine functional groups; styrene-type weak base anion exchange resins with primary, secondary, or tertiary amine functional groups; acrylic or methacrylic acid strong base anion exchange resins with quaternary amine functional groups; acrylic or methacrylic acid weak base anion exchange resins with primary, secondary, or tertiary amine functional groups; and at least one of acrylic acid and ethylene-type weak base anion exchange resins with primary, secondary, or tertiary amine functional groups.

[0068] Examples of cation exchange resins include, but are not limited to, at least one of styrene-type strong acid cation exchange resins having sulfonic acid or phosphonic acid functional groups; styrene-type weak acid cation exchange resins having carboxylic acid or phenolic acid functional groups; and acrylic acid or methacrylic acid weak acid cation exchange resins having carboxylic acid or phenolic acid functional groups.

[0069] According to at least one embodiment, the ion exchange resin may include a sulfonated copolymer of styrene and divinylbenzene. In certain embodiments, a suitable ion exchange resin may be a resin sold by Dow under the trade name AMBERLITE TM Pharmaceutical grade cation exchange resins sold by IRP69. Other non-limiting examples of pharmaceutically acceptable ion exchange materials suitable for the pharmaceutical compositions disclosed herein include those sold by Dow under the trade name AMBERLITE TM IRP476、AMBERLITE TM IRP64 and AMBERLITE TM Those sold by IRP88.

[0070] In at least one embodiment, the ion exchange material may include a partial potassium salt of a copolymer of methacrylic acid and divinylbenzene, such as, for example, polyclinic potassium. Non-limiting examples of polyclinic potassium include products sold by Purolite under the trade name C115KMR. Other non-limiting examples of pharmaceutically acceptable ion exchange materials suitable for the pharmaceutical compositions disclosed herein include those sold by Purolite under the trade names A430MR, C100CaMR, C100MRNS, C108DR, and C115HMR.

[0071] In at least one embodiment disclosed herein, the ion exchange material is selected from the group consisting of polacrilex resins, polycrylin salts, sodium polystyrene sulfonate, cholestyramine resins, and mixtures thereof.

[0072] In at least one embodiment disclosed herein, the ion exchange material is selected from (i) sulfonated copolymers of styrene and divinylbenzene, (ii) methacrylic acid-divinylbenzene copolymers, and (iii) polystyrene resins having amine and / or ammonium side groups.

[0073] At least one active agent

[0074] At least one active agent in the pharmaceutical composition disclosed herein can be selected from, but is not limited to, angiotensin-converting enzyme (ACE) inhibitors, adenohypophoseal hormones, adrenergic neuron blockers, adrenocortical steroids, adrenocortical steroid biosynthesis inhibitors, alpha-adrenergic agonists, alpha-adrenergic antagonists, selective alpha-2-adrenergic agonists, analgesics, antipyretics and anti-inflammatory agents, androgens, local and general anesthetics, anti-addiction agents, antiandrogens, antiarrhythmic agents, antiasthmatics, anticholinergics, anticholinesterase agents, anticoagulants, antidiabetics, antidiarrheals, antiuretics, antiemetics, prokinetic agents, antiepileptics, antiestrogens, antifungals, antihypertensives, antibacterials, antimigraines , antimuscarinics, antineoplastics, antiparasitics, antiparkinsonian agents, antiplatelet agents, antiprogestins, antischizophrenia agents, antithyroid agents, antitussives, antivirals, atypical antidepressants, azaspirodecanediones, barbiturates, benzodiazepines, benzothiadiazides, beta-adrenergic stimulants, beta-adrenergic antagonists, selective beta-1-adrenergic antagonists, selective beta-2-adrenergic stimulants, bile salts, Liquid volume and composition of substances, butyrophenones, drugs that affect calcification, calcium channel blockers, cardiovascular drugs, catecholamines and sympathomimetics, cholinergic stimulants, cholinesterase reactivators, central nervous system (CNS) depressants, stimulants such as CNS stimulants, contraceptives, dermatological drugs, diphenylbutyl piperidine, diuretics, ergot alkaloids, estrogens, ganglion blockers, ganglion stimulants, hydantoins, drugs used to control gastric acid and treat peptic ulcers, hematinics, histamine, antihistamines, hormones, serotonin antagonists, drugs for the treatment of hyperlipoproteinemia, hypnotics, sedatives, immunosuppressants, laxatives, methylxanthines, monoamine oxidase inhibitors, neuromuscular blockers, organic nitrates, opioid agonists, opioid antagonists, pancreatic enzymes, phenothiazines, progestogens, prostaglandins, drugs for the treatment of mental disorders, psychotropics, retinoids, sedative-hypnotics, sodium channel blockers, drugs for the treatment of spasms and acute muscle cramps, succinimide, testosterone, thioxanthines, thrombolytics, thyroid agents, tricyclic antidepressants, inhibitors of tubular transport of organic compounds, tranquilizers, drugs affecting uterine motility, vasodilators, vitamins and mixtures thereof.

[0075] In at least one embodiment, the at least one active agent is a drug that is susceptible to abuse, such as, for example, an opioid analgesic such as an opioid agonist. Non-limiting examples of opioid agonists include alfentanil, allylprodine, alfaprodine, anileridine, benzylmorphine, bezitamide, buprenorphine, butorphanol, clonitrazine, codeine, dihydrodeoxymorphine, dextromoramide, dezocine, diampramide, diamorphone, dihydrocodeine, dihydromorphine, dimesadol, dimepanol, dimethylthiambutene, morphine butyl ester, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonizine, fentanyl, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol ... levophenacylmorphan, lofentanil, pethidine, meptazinol, metazocine, methadone, methoprene, myrophine, nalbuphine, nalceine, nicomorphine, norlevorphanol, normethadone, nalorfen, normorphine, norpipanone, oxycodone, oxymorphone, opium base, pentazocine, phenoxetine, phenorphan, phenazocine, phenoperidine, piminodine, piritramide, proheptazine, dimethopethidine, properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts thereof and mixtures thereof.

[0076] In certain embodiments, the opioid agonist may be selected from codeine, fentanyl, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, tramadol, oxymorphone, pharmaceutically acceptable salts thereof, and mixtures thereof.

[0077] In various embodiments, the opioid agonist may be selected from at least one of oxycodone, oxymorphone, hydrocodone, hydromorphone, codeine, tramadol, tapentadol, fentanyl, a pharmaceutically acceptable salt, a hydrate and a solvate thereof, or a mixture thereof. As a non-limiting example, a pharmaceutically acceptable salt of an opioid agonist includes oxycodone hydrochloride, hydrocodone bitartrate and hydromorphone hydrochloride.

[0078] In at least one embodiment, the at least one active agent comprises an opioid agonist such as oxycodone or a pharmaceutically acceptable salt thereof, present in an amount of, for example, about 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg. In at least one embodiment, the at least one active agent comprises hydrocodone bitartrate, present in an amount of, for example, 2.5 mg, 5 mg, 7.5 mg, 10 mg, and 15 mg.

[0079] In at least one embodiment, the at least one active agent is codone hydrochloride, and the oxycodone hydrochloride has a 14-hydroxycodeinone level of less than about 25 ppm, less than about 15 ppm, less than about 5 to about 10 ppm, less than about 5 ppm, less than about 2 ppm, less than about 1 ppm, less than about 0.5 ppm, or less than about 0.25 ppm. WO 2005 / 097801 A1, U.S. Pat. No. 7,129,248 B2, and US 2006 / 0173029 A1, all of which are incorporated herein by reference, describe a process for preparing oxycodone hydrochloride having a low level of 14-hydroxycodeinone.

[0080] In at least one embodiment, the drug that is prone to abuse can be selected from at least one central nervous system (CNS) stimulant. Non-limiting examples of CNS stimulants include phenidates, CNS depressants, tranquilizers, sedatives, hypnotics, benzodiazepines, barbiturates, pharmaceutically acceptable salts thereof, and combinations thereof. In at least one embodiment, the at least one active agent may include a CNS stimulant or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a mixture thereof. In at least one embodiment, the CNS stimulant includes, for example, gamma-hydroxybutyrate, methamphetamine, methylphenidate, and pharmaceutically acceptable salts, hydrates and solvates thereof and mixtures thereof.

[0081] In at least one embodiment, the CNS stimulant comprises a phenidate, such as, for example, methylphenidate or dexmethylphenidate, and pharmaceutically acceptable salts, hydrates and solvates and mixtures thereof.

[0082] Non-limiting examples of benzodiazepines useful as active agents of the pharmaceutical compositions disclosed herein include alprazolam, bromazepam, chlordiazepoxide, clorazepate potassium, diazepam, estazolam, flurazepam, halazepam, ketazola, lorazepam, nitrazepam, oxazepam, prazepam, quazepam, temazepam, triazolam, and pharmaceutically acceptable salts, hydrates and solvates thereof, and mixtures thereof.

[0083] Non-limiting examples of barbiturates useful as active agents in the pharmaceutical compositions disclosed herein include amobarbital, aprobarbital, butalbital, butalbital, methohexital, methylphenobarbital, metharbital, pentobarbital, phenobarbital, secobarbital, and pharmaceutically acceptable salts, hydrates and solvates thereof, and mixtures thereof.

[0084] In at least one embodiment, the pharmaceutical compositions disclosed herein include a second active agent, such as a non-opioid analgesic. Non-limiting examples of non-opioid analgesics include acetaminophen and non-steroidal anti-inflammatory agents include, but are not limited to, aspirin, celecoxib, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, moraprofen, trioxaprofen, suprofen, aminoprofen, oxadiazine ... ofen), tiaprofenic acid, fluprofen, buclofen, indomethacin, sulindac, tolmetin, zomepirac, tiopinic acid, zidometacin, acemetacin, fentiazolic acid, clorinac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflunisal, flufenal, piroxicam, sudoxicam, esoxicam, pharmaceutically acceptable salts, hydrates and solvates thereof, and mixtures thereof. In at least one embodiment, the second active agent comprises acetaminophen in granular form. Non-limiting examples of acetaminophen granules suitable for use in the pharmaceutical compositions disclosed herein are those sold by Granules India under the trade name COMPRESSO PAP90CPF absorption.

[0085] Alternatively, the second active agent may be an antagonist of the active agent, such as, for example, naltrexone, naloxone, nalmefene, cyclazacine, levallorphan, buprenorphine, pharmaceutically acceptable salts, hydrates and solvates thereof, and mixtures thereof. In at least one embodiment, the antagonist may be an opioid antagonist, non-limiting examples of which include amibenazole, naltrexone, methylnaltrexone, naloxone, nalbuphine, nalorphine, nalorphinedinicotinate, nalmefene, coenzyme, levallorphan, cyclazocine, pharmaceutically acceptable salts, hydrates and solvates thereof, and mixtures thereof (e.g., naltrexone hydrochloride, naloxone hydrochloride, etc.). In at least one embodiment, the antagonist may be combined with at least one active agent and an ion exchange material such that, in addition to a complex of at least one active agent and the ion exchange material, the antagonist forms a complex with the ion exchange material. .

[0086] In a pharmaceutical composition having (1) at least one active agent admixed or complexed with an ion exchange material and (2) a second active agent (e.g., a pharmaceutical composition in which a mixture or complex comprising at least one active agent is admixed with or coated on a substrate comprising a second active agent), the first active agent can be an opioid agonist and the second active agent can be a non-opioid analgesic. In at least one such embodiment, the non-opioid analgesic is selected from, for example, acetaminophen and a nonsteroidal anti-inflammatory agent (e.g., acetaminophen, ibuprofen, aspirin, or diclofenac as described herein) and the opioid agonist is selected from, for example, oxycodone, hydrocodone, or a pharmaceutically acceptable salt, hydrate, or solvate thereof (e.g., oxycodone hydrochloride or hydrocodone bitartrate).

[0087] Adhesives

[0088] At least one adhesive in the pharmaceutical composition disclosed herein can be selected from, but not limited to, cellulose polymers such as hydroxypropyl methylcellulose, hydroxypropyl cellulose or hydroxyethyl cellulose. The adhesive can be, for example, low molecular weight hydroxypropyl methylcellulose, low molecular weight hydroxypropyl cellulose, or low molecular weight hydroxyethyl cellulose. Other adhesives include, but are not limited to, polyethylene glycol, acrylic acid polymers, acrylic acid copolymers, graft copolymers of polyvinyl alcohol and polyethylene glycol, polyvinyl alcohol, alginic acid, sodium alginate, starch, pregelatinized starch, sucrose, guar gum, its salt, its derivatives and combinations thereof. In certain embodiments, the pharmaceutical composition includes a complex including at least one active agent and an ion exchange resin, an adhesive (e.g., low molecular weight hydroxypropyl methylcellulose) and at least one pharmaceutically acceptable excipient (e.g., a mixture of lactose monohydrate and microcrystalline cellulose) The particles, wherein the particles are dispersed in a matrix material (e.g., high molecular weight hydroxypropyl methylcellulose). According to various embodiments, the binder (e.g., hydroxypropyl methylcellulose) may have a molecular weight of about 100 Da to less than 1,000,000 Da, or about 1,000 Da to about 750,000 Da, or about 5,000 Da to about 500,000 Da, or about 10,000 Da to about 100,000 Da, or about 12,000 Da to about 50,0000, or about 16,000 Da to about 20,000 Da, or about 12,000 Da, or about 14,000 Da, or about 16,000 Da, or about 20,000 Da, or about 25,000 Da.

[0089] Other binder materials include, but are not limited to, natural or synthetic waxes, fatty alcohols (e.g., lauryl, myristyl, stearyl, cetyl or cetearyl alcohol), fatty acids (including, but not limited to, fatty acid esters and fatty acid glycerides, e.g., mono-, di- and tri-glycerides), hydrogenated fats, hydrocarbons, stearic acid, hydrophobic and hydrophilic materials having a hydrocarbon backbone, gum arabic, tragacanth, sucrose, gelatin, glucose, cellulosic materials (e.g., low molecular weight hydroxypropyl methylcellulose, methylcellulose and sodium carboxymethylcellulose (e.g., Tylose TM )), magnesium aluminum silicate, polysaccharide acid, bentonite, polyvinyl pyrrolidone (PVP), polymethacrylate and pregelatinized starch (such as National TM 1511 and starch 1500) and combinations thereof. Suitable waxes include, for example, beeswax, glycowax, castor wax, carnauba wax and other waxy substances. "Waxy" substances are defined as any material that is generally solid at room temperature and has a melting point of about 30°C to about 100°C. Pharmaceutical compositions according to the present disclosure may include one or more adhesives and / or tackifiers, and range from about 0.5% to about 25% of the total formulation weight, or from about 0.75% to about 15%, or from about 1% to about 10%. In certain embodiments of the pharmaceutical composition, low molecular weight hydroxypropyl methylcellulose is used as an adhesive. The presence range of an adhesive (e.g., low molecular weight hydroxypropyl methylcellulose) may be from about 0.5% to about 10% of the total formulation weight, or from about 1% to about 8%, or from about 2% to about 4%.

[0090] Other examples of binders that may be used include, but are not limited to, digestible, long chain (C8-C 50 , especially C 12 -C 40 ), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, fatty acid glycerides, mineral and vegetable oils, natural and synthetic waxes and polyalkylene glycols. In certain embodiments, hydrocarbons having a melting point ranging from about 25° C. to about 90° C. may be included. In long-chain hydrocarbon binder materials, according to certain embodiments, fatty (aliphatic) alcohols may be incorporated into the mixture. In other embodiments, the mixture or pharmaceutical composition may contain up to 80% (by weight) of at least one digestible long-chain hydrocarbon.

[0091] Pharmaceutically acceptable excipients

[0092] According to the pharmaceutical composition of the present disclosure, one or more pharmaceutically acceptable excipients may be further included. Examples of possible pharmaceutically acceptable excipients are described in Pharmaceutical Excipients, American Pharmaceutical Association, 8th, Ed. (2017), which are incorporated herein by reference. Suitable excipients include, but are not limited to, plasticizers, colorants, lubricants, thermal lubricants, antioxidants, buffers, disintegrants or granulating agents, adhesives, diluents, glidants, antiadhesives, sweeteners, chelating agents, granulating agents, extenders, spices, surfactants, solubilizers, stabilizers, hydrophilic polymers, hydrophobic polymers, waxes, lipophilic materials, absorption enhancers, preservatives, absorbents, cross-linking agents, bioadhesive polymers, pore-forming agents, permeants, polycarboxylic acids or combinations thereof.

[0093] Examples of suitable disintegrants include, but are not limited to, sodium starch glycolate, clays (such as magnesium aluminum silicate, TM HV), cellulose (e.g., purified cellulose, methylcellulose, sodium carboxymethylcellulose, and carboxymethylcellulose), cross-linked sodium carboxymethylcellulose, starch, cross-linked polyvinyl pyrrolidone (e.g., polyvinyl polypyrrolidone), alginates, corn starch, pregelatinized corn starch (e.g., National TM 1551 and National TM 1550), gums (such as agar, guar gum, locust bean gum, pectin and tragacanth) and mixtures thereof. Disintegrants may be added at any appropriate step during the preparation of the pharmaceutical composition, such as before granulation or during a lubrication step before compression or encapsulation. The pharmaceutical compositions described herein may include one or more disintegrants in an amount ranging from about 0.5% to about 30%, or from about 1% to about 10%, or from about 2% to about 6% of the total weight of the formulation.

[0094] Suitable bulking agents include, but are not limited to, starch (e.g., corn starch), microcrystalline cellulose, lactose (e.g., lactose monohydrate), sucrose, dextrose, mannitol, calcium phosphate, and dicalcium phosphate.

[0095] According to certain embodiments, the pharmaceutical composition may include a plasticizer. A plasticizer may interact with a hydrophobic material, thereby causing the mixture to have a lower viscosity when measured under the same conditions compared to a mixture without a plasticizer. Some plasticizers may reduce the glass transition temperature (Tg) of a hydrophobic material. Suitable plasticizers include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols with aliphatic hydroxyl groups, ester type plasticizers, glycol ethers, poly (propylene glycol), multi-block polymers, single block polymers, low molecular weight poly (ethylene glycol), citrate ester type plasticizers, triacetin, propylene glycol and glycerol. The plasticizer may include ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol and other poly(ethylene glycol) compounds, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitan lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, acetyl triethyl citrate, tributyl citrate and allyl glycolate. In certain embodiments, the amount of the plasticizer may be about 5% or less, or about 4% or less, or about 2% or less, or 0% (i.e., no plasticizer), relative to the gross weight of the composition.

[0096] In at least one embodiment, the pharmaceutical composition comprises a glidant. A glidant is an excipient that improves the flow characteristics of a compressible powder such as a tablet component or granules. Suitable glidants include, but are not limited to, silicon dioxide, colloidal silicon dioxide, and the like.

[0097] Suitable diluents for use in the pharmaceutical compositions described herein include, but are not limited to, lactose (e.g., lactose (anhydrous), lactose (spray dried), lactose monohydrate), starch (e.g., direct compressible starch), mannitol, sorbitol, dextrose monohydrate, microcrystalline cellulose, dibasic calcium phosphate dihydrate, sucrose-based diluents, confectioners' sugar, dibasic calcium sulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate granules, dextrose binders (e.g., Emdex TM ), dextrose (e.g., Cerelose TM ), inositol, hydrolyzed cereal solids such as Maltrons TM and Mor-Rex TM , amylose, powdered cellulose (e.g., Elcema TM), calcium carbonate, glycine, bentonite, polyvinyl pyrrolidone, etc. In certain embodiments, the pharmaceutical composition described herein may include a diluent in an amount of about 5% to about 99%, or about 25% to about 90%, or about 40% to about 80% of the total weight of the formulation. Lactose has a melting point of about 202°C. Microcrystalline cellulose has a burning point greater than 200°C before it reaches its melting point, and is therefore also suitable because it does not have a low melting point.

[0098] Suitable lubricants include, but are not limited to, glyceryl behenate (Compritol TM 888), metallic stearates (e.g., magnesium stearate, calcium stearate, and sodium stearate), stearic acid, hydrogenated vegetable oils (e.g., Sterotex TM ), talc, waxes such as beeswax and carnauba wax, silicon dioxide, fumed silica, colloidal silicon dioxide, calcium stearate, long chain fatty alcohols, boric acid, sodium benzoate and acetate, sodium chloride, DL-leucine, polyethylene glycols (e.g., Carbowax TM 4000 and Carbowax TM 6000), sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, sodium stearyl fumarate (Pruv TM ), magnesium lauryl sulfate, stearic acid, stearyl alcohol, mineral oil, paraffin, microcrystalline cellulose, glycerol, propylene glycol and combinations thereof. In certain embodiments, the pharmaceutical composition may include one or more lubricants in an amount of about 0.1% to about 10%, or about 0.2% to about 8%, or about 0.25% to about 5% of the total weight of the formulation. Magnesium stearate is a lubricant suitable for use in certain embodiments of the pharmaceutical composition. Magnesium stearate has a melting point of about 90°C. Although magnesium stearate has a low melting point, it can be used as a lubricant in a small amount (e.g., about 0.5%) without significantly affecting the stability of the peripheral opioid formulation of the present invention.

[0099] Suitable anti-sticking agents include, but are not limited to, talc, corn starch, colloidal silicon dioxide (Cab-O-Sil TM ), DL-leucine, sodium lauryl sulfate, and metal stearates. In certain embodiments, the pharmaceutical composition may include an antiadhesive agent in an amount of about 0.1% to about 15%, or about 0.25% to about 10%, or about 0.5% to about 5%, of the total weight of the formulation. Colloidal silicon dioxide is an antiadhesive agent suitable for use in certain embodiments of the pharmaceutical composition in an amount of about 0.1% to about 10%, or about 0.25% to about 5%, or about 0.5% to about 2%, of the total weight of the formulation. Colloidal silicon dioxide has a melting point of about 1700°C.

[0100] Other excipients such as colorants, flavors, and sweeteners may be used in embodiments of the pharmaceutical compositions in which they have little or no deleterious effect on the stability of the pharmaceutical composition.

[0101] In certain embodiments, the pharmaceutical composition may include a film coating. The film coating may include, but is not limited to, hydroxypropyl methylcellulose, polyethylene glycol, polyvinyl alcohol, or any mixture of two or more thereof. According to certain embodiments, the film coating may provide a tablet weight gain of about 5% or less, or about 4% or less, or about 2% or less.

[0102] In certain embodiments, the pharmaceutical composition may further include other materials for preventing abuse, such as gelling agents, bittering agents and / or irritants. As non-limiting examples, gelling agents may be selected from sugar, sugar-derived alcohol, starch, starch derivatives such as pregelatinized starch, cellulose derivatives, attapulgite, bentonite, dextrin, alginate, carrageenan, glue, pectin, gelatin, kaolin, lecithin, magnesium aluminum silicate, carbomer, carbopol, polyvinyl pyrrolidone, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, silicon dioxide, curd, furcellaran, protein powder, whey protein, soy protein, chitosan, surfactants such as but not limited to sodium lauryl sulfate, emulsifiers, and pharmaceutically acceptable salts thereof and mixtures thereof. Non-limiting examples of pregelatinized starch suitable for use in pharmaceutical compositions disclosed herein are products sold by Asahi Kasei under the trade name SWELSTAR MX-1. A non-limiting example of a gum suitable for use in the pharmaceutical compositions disclosed herein is xanthan gum, such as, for example, the product sold by CPKelco under the trade name XANTURAL 180. As a non-limiting example, the bittering agent can be selected from flavoring oils, flavoring spices, oleoresins, plant extracts, leaf extracts, flower extracts, fruit extracts, sucrose derivatives, chlorosucrose derivatives, quinine sulfate, denatonium benzoate, and mixtures thereof. As a non-limiting example, the irritant can be selected from surfactants, capsaicin, capsaicin analogs, and mixtures thereof.

[0103] Matrix material

[0104] In different embodiments, at least one host material may be included according to the pharmaceutical composition of the present disclosure. Suitable host materials may include, but are not limited to, hydrophilic or hydrophobic polymers, such as, for example, glue, cellulose ether, cellulose ester, acrylic resin, protein-based materials, nylon, polyvinyl chloride, starch and / or polyvinyl pyrrolidone. Suitable water-soluble polymers include, but are not limited to, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, poly (vinyl alcohol), alginate, polydextrose, carboxymethylene, hydrogenated hydroxyalkyl cellulose and / or hydroxypropyl methyl cellulose ether. Suitable water-insoluble or partially water-insoluble polymers include, but are not limited to, polyvinyl chloride, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, cellulose acetate, cellulose acetate phthalate, ethylene vinyl alcohol, alginic acid and / or its derivatives, acrylic acid and / or methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylate copolymers, cyanoethyl methacrylate, cyanoaminoalkyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymers, poly(methyl methacrylate), poly(methacrylic anhydride), methyl methacrylate, polymethacrylate, poly(methyl methacrylate) copolymers, polyacrylamide, aminoalkyl methacrylate copolymers and / or glycidyl methacrylate copolymers.

[0105] Other suitable matrix materials include, but are not limited to, digestible, substituted or unsubstituted long chain (C8-C 50 , especially C 12 -C 40 ) hydrocarbons, for example, fatty acids, fatty alcohols (lauryl alcohol, myristyl alcohol, stearyl alcohol, cetearyl alcohol, ceryl alcohol or cetyl alcohol), fatty acid glycerides (Witepsol, glyceryl monostearate), mineral oils and vegetable oils (hydrogenated castor oil) and / or waxes (paraffin, silicone wax, beeswax, castor wax, carnauba wax and / or Glyco wax).

[0106] According to certain embodiments, the pharmaceutical compositions described herein may include high molecular weight hydroxypropyl methylcellulose, high molecular weight polyethylene oxide, high molecular weight hydroxyethyl cellulose, high molecular weight hydroxypropyl cellulose, high molecular weight methyl cellulose, alginate, carbopol (polyacrylic acid), polymethacrylate, wax, carnauba wax, beeswax, glyceryl alginate Polyethylene glycol glycerides and combinations thereof. According to various embodiments of the pharmaceutical compositions described herein, the high molecular weight component may have a molecular weight of at least 1,000,000 Da, or at least 2,000,000 Da, or at least 5,000,000 Da, or at least 7,500,000 Da, or at least 10,000,000 Da, or about 1,000,000 Da to about 10,000,000 Da, or about 2,000,000 Da to about 7,500,000 Da, or about 3,000,000 Da to about 5,000,000 Da. The pharmaceutical compositions described herein may comprise about 1% to about 90% (by weight) of one or more hydrophilic or hydrophobic polymers as a matrix material.

[0107] Dosage form

[0108] The pharmaceutical compositions disclosed herein may be solid oral dosage forms, such as pharmaceutically acceptable tablets or capsules. Typically, a mixture or blend of dry particles or particles, such as (1) a mixture or complex of at least one active agent and an ion exchange material, (2) a binder, (3) a matrix material, and (4) optionally an excipient, is compressed into a tablet or encapsulated in a pharmaceutically acceptable capsule. Alternatively, the mixture or blend of dry particles or particles may include (1) a coating of the mixture or complex and a binder, which is on (2) a substrate, which may or may not contain the same or different active agents as the mixture or complex, (3) a matrix material, wherein the substrate is dispersed in the matrix material, and (4) optionally, an excipient, and the mixture or blend is then compressed into a tablet or encapsulated in a pharmaceutically acceptable capsule.

[0109] The pharmaceutical compositions disclosed herein may include controlled release dosage forms prepared using any suitable method known in the art.

[0110] Preparation method

[0111] The present invention also provides a method for preparing a pharmaceutical composition disclosed herein, comprising (i) combining at least one active agent and an ion exchange material to form a mixture or complex of at least one active agent and an ion exchange material, (ii) combining the mixture or complex with a binder, (iii) optionally forming particles from the mixture or complex and the binder, (iv) dispersing the mixture or complex and the binder (e.g., as particles) in a matrix material and (iv) incorporating the resulting matrix into a pharmaceutical composition, wherein the composition, when administered to a patient in need thereof, provides a therapeutic effect to the patient for at least about 8 hours, or at least about 12 hours, or at least about 24 hours.

[0112] refer to Figure 1 and 2According to various embodiments, the present invention provides pharmaceutical compositions, such as tablets and capsules, wherein (a) a mixture 100 of at least one active agent 105 and an ion exchange resin 110 is formed in the absence of an aqueous medium or (b) a complex 200 of at least one active agent 205 and an ion exchange resin 215 is formed in the presence of an aqueous medium 210.

[0113] Thus, in at least one embodiment, the method for preparing a pharmaceutical composition disclosed herein comprises (i) preparing an aqueous mixture by mixing at least one active agent, an ion exchange material, a binder, and an aqueous medium; and (ii) drying the aqueous mixture. The at least one active agent, the ion exchange material, the binder, and the aqueous medium can be mixed in any order. In certain embodiments, however, preparing the aqueous mixture comprises (i) preparing a solution of the active agent in an aqueous medium, (ii) adding the ion exchange material to the solution, and (iii) adding the binder to the solution.

[0114] In at least one embodiment, the at least one active agent is added to the aqueous medium in an amount such that they form a solution having a concentration of the at least one active agent in the aqueous medium in the range of, as non-limiting examples, from about 10 mg / mL to about 100 mg / mL, from about 20 mg / mL to about 90 mg / mL, from about 30 mg / mL to about 80 mg / mL, from about 40 mg / mL to about 70 mg / mL, or from about 50 mg / mL to about 60 mg / mL (step 305). In at least one embodiment, the concentration of the at least one active agent in the aqueous medium is about 50 mg / mL.

[0115] In at least one embodiment, the ion exchange material is added to the at least one active agent in an amount such that the weight ratio of the ion exchange material to the at least one active agent in the mixture (with or without an aqueous medium) ranges from, as non-limiting examples, about 1:1 to about 20:1 or about 1:1 to about 10:1, such as about 4:1 to about 6:1, or such as about 3:1 to about 5:1. In at least one embodiment, the ion exchange material and the at least one active agent are mixed in a weight ratio selected from about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 11:1, about 12:1, about 13:1, about 14:1, about 15:1, about 16:1, about 17:1, about 18:1, about 19:1, and about 20:1. In at least one embodiment, when the ion exchange material and the at least one active agent are mixed, the weight ratio of the ion exchange material to the at least one active agent is about 5:1.

[0116] In at least one embodiment, the method comprises leaving an aqueous mixture of at least one activating agent, ion exchange material and aqueous medium to stand for a period of about 24 hours or less, about 12 hours or less, about 8 hours or less, about 4 hours or less, about 2 hours or less, about 1.5 hours or less, about 1 hour or less, about 50 minutes or less, about 45 minutes or less, about 40 minutes or less, about 30 minutes or less. In at least one embodiment, the standing aqueous mixture is stirred, for example, by stirring or shaking, at least part of the time, and in at least some embodiments, is stirred or shaken all the time, and then dried. Therefore, in at least one embodiment, the aqueous mixture is left to stand while mixing for about 2 hours. In at least one embodiment, however, the aqueous mixture need not be left to stand before drying.

[0117] In at least one embodiment, after mixing at least one active agent, ion exchange material and aqueous medium, the resulting aqueous mixture is dried, as non-limiting examples, by spray drying, top drying, or forced air drying such as in a fluid bed dryer or oven, or any other suitable drying method known in the art, for a period of time, for example, from about 15 minutes to about 12 hours, from about 1 hour to about 4 hours, or from about 1 hour to about 2 hours. In at least one embodiment, the resulting aqueous mixture is dried in a fluid bed dryer for about 1 hour.

[0118] In at least one embodiment, after mixing at least one active agent, ion exchange material, binder and aqueous medium, the resulting aqueous mixture is dried, as non-limiting examples, by spray granulation, spray drying, top drying, or forced air drying such as in a fluidized bed dryer or oven, or any other suitable drying method known in the art. The aqueous mixture can be dried for a period of time, for example, from about 15 minutes to about 12 hours, from about 1 hour to about 4 hours, or from about 1 hour to about 2 hours. In at least one embodiment, the resulting aqueous mixture is dried in a fluidized bed dryer for about 1 hour.

[0119] One or more substrates may be incorporated. In at least one non-limiting example, the substrate comprises spheres or particles of sugar, and a mixture of a complex of at least one active agent with an ion exchange material and a binder is mixed with the spheres or particles of sugar to form a complex-substrate particle or a complex-substrate composition. In at least another embodiment, the substrate may comprise a second active agent, such as acetaminophen in particle form, such that the mixing results in a complex-substrate particle or a complex-substrate composition comprising at least two active agents.

[0120] In at least one embodiment, the composite-substrate particle or composite-substrate composition is incorporated into a pharmaceutical composition without washing or rinsing. However, washing and rinsing are not excluded from the scope of the present disclosure.

[0121] Figure 3 is a flow chart of an exemplary method 300 for preparing a pharmaceutical composition comprising a complex of an active agent and an ion exchange material according to an exemplary embodiment of the present disclosure. Figure 3 As shown, method 300 may include mixing at least one active agent (e.g., oxycodone hydrochloride) and an aqueous medium (e.g., water) to form a mixture (step 305), the mixture having, for example, a concentration of at least one active agent in the aqueous medium of about 10 mg / mL to about 200 mg / mL, or about 50 mg / mL to about 150 mg / mL, about 75 mg / mL to about 110 mg / mL, or about 110 mg / mL. Method 300 may also include adding an ion exchange material (e.g.,

[0122] IRP69) to form a slurry or suspension (step 310). Method 300 may further include adding a binder to the slurry or suspension (step 315). Method 300 may further include, for example, in a spray granulation process, or in a fluidized bed dryer, drying the slurry or suspension for a period of about 15 minutes to about 12 hours, for example, about 2 hours (step 320). Optionally, method 300 may include, for example, mixing the slurry or suspension with the binder with at least one excipient during spray granulation (step 325) to form particles. Method 300 may further include dispersing the slurry or suspension comprising the binder and optionally at least one excipient (e.g., as particles) in a matrix material (step 330). Method 300 may include compressing the resulting dry mixture into tablets or encapsulating the resulting dry mixture in capsules (step 335).

[0123] Figure 4 is a flow chart of an exemplary method 400 for preparing a pharmaceutical composition comprising a complex of at least one active agent and an ion exchange material according to an exemplary embodiment of the present disclosure. Figure 4 As shown, method 400 may include mixing at least one active agent (e.g., oxycodone hydrochloride) and an aqueous medium (e.g., water) to form a mixture (step 405) having, for example, a concentration of at least one active agent in the aqueous medium of about 10 mg / mL to about 100 mg / mL, or about 50 mg / mL. Method 400 may also include adding an ion exchange material (e.g., IRP69) to form a slurry or suspension (step 410). Method 400 may further include adding a binder to the slurry (step 415). Method 400 may further include mixing the slurry or suspension with the binder with a substrate (e.g., particles or granules of a second active agent, sugar spheres, or any other suitable substrate known in the art) and drying (step 420). In at least one embodiment, step 420 may include mixing the slurry or suspension with the substrate for a period of time suitable for forming a dry composite-substrate particle or composite-substrate composition by spray granulation, spray drying, or top spraying the slurry or suspension onto the substrate using a fluidized bed dryer, wherein the suitable amount of time may be, for example, about 15 minutes to about 12 hours, about 1 hour to about 4 hours, or about 1 hour to about 2 hours. In at least one embodiment of step 420, the slurry or suspension is mixed with the substrate and dried in a fluidized bed dryer for about 1 hour to form a composite-substrate composition. The method 400 may optionally include adding at least one excipient to the composite-substrate composition (step 425), and compressing the resulting mixture into a tablet or encapsulating the resulting mixture in a capsule (step 430).

[0124] In at least one embodiment, the method for preparing the pharmaceutical composition disclosed herein comprises mixing at least one active agent and an ion exchange material to form a mixture. In at least one such embodiment, the method comprises mixing at least one active agent, an ion exchange material, a binder, and a matrix material in the absence of an aqueous medium, and as a non-limiting example, forming a pharmaceutical composition by granulating the resulting dry mixture to form granules and pressing the granules into tablets or filling capsules with the granules using any suitable technique known in the art. In at least one optional embodiment, the mixture of the at least one active agent and the ion exchange material can be mixed with (1) a substrate comprising an active agent that is the same or different from the at least one active agent and (2) an optional excipient disclosed herein to form a dry mixture, which can be granulated and then compressed into tablets or encapsulated in capsules using any suitable technique known in the art.

[0125] How to use

[0126] The present invention relates to a method for treating pain comprising administering to a patient in need thereof a pharmaceutical composition disclosed herein, for example, a pharmaceutical composition comprising an opioid analgesic, or an opioid analgesic in combination with acetaminophen or other nonsteroidal anti-inflammatory agents, wherein the opioid analgesic forms a mixture or complex with an ion exchange material as described herein.

[0127] The present invention also relates to a method of treating attention deficit disorder (ADHD) comprising administering to a patient in need thereof a pharmaceutical composition disclosed herein, for example, a pharmaceutical composition comprising a mixture or complex of a central nervous system stimulant described herein and an ion exchange material.

[0128] The present invention further relates to methods of deterring abuse of abuse-prone drugs (eg, opioid agonists) comprising preparing a pharmaceutical composition disclosed herein, eg, a mixture or complex comprising an opioid agonist described herein and an ion exchange material.

[0129] The following examples illustrate various embodiments of the present disclosure. They are not intended to limit the claims in any way. Example

[0130] Example 1

[0131] Exemplary Process for Preparing Oxycodone HCl Resinate Tablets

[0132] Tablet compositions comprising the formulations listed in Table 1 were prepared according to the general procedure outlined below.

[0133] Table 1

[0134]

[0135] 1. Dissolve oxycodone hydrochloride in water (eg, purified water) to form, for example, a 60 mg / mL oxycodone hydrochloride / water solution.

[0136] 2. By stirring IRP69 resin is added to the oxycodone hydrochloride / water solution to form a slurry in an amount such that the weight ratio of ion exchange resin to active agent in the resulting slurry is about 3: 1. The slurry is stirred for at least about 2 hours.

[0137] 3. Mix the slurry with a binder (eg, low molecular weight HPMC).

[0138] 4. Granulate by top spraying (i.e., spray granulation) the slurry onto a mixture of lactose monohydrate and microcrystalline cellulose using a fluidized bed dryer to form dry complex-base granules or complex-base compositions comprising particles of oxycodone HCl / resin complex, low molecular weight HPMC, lactose monohydrate, and microcrystalline cellulose.

[0139] 5. The granules from step 4 were blended with high molecular weight HPMC and then blended with magnesium stearate using a lab scale twin shell blender.

[0140] 6. The resulting mixture was compressed into oval tablets using a rotary tablet press to form oval shaped tablets that were 0.3040 inches x 0.7380 inches, each having a total weight of 750 mg, 60 mg of oxycodone HCl, and a hardness of about 7 kP to about 12 kP.

[0141] Example 2

[0142] Injectability of oxycodone hydrochloride from oxycodone HCl 60 mg resinate tablets in aqueous solvents

[0143] At room temperature (i.e., about 20°C-25°C, or about 21°C) and elevated temperature (i.e., 95°C), the injectability of the resin tablet containing 60mg oxycodone hydrochloride according to the pharmaceutical composition and method described herein in tap water and saline was tested. In order to test the injectability of oxycodone HCl in tap water, the tablet was crushed using a mortar and pestle and then placed in a container. 10mL of tap water was added to a 20mL scintillation bottle at room temperature and the contents were mixed by vigorous shaking for about 2 minutes. A syringe with a 21-gauge needle was then inserted into the resulting mixture, a cotton ball was used as a filter, and the plunger was withdrawn by hand for a time of no more than 5 minutes. High performance liquid chromatography (HPLC) was then used to measure and analyze the contents inside the syringe.

[0144] The process was repeated using saline as the solvent instead of tap water. Additionally, for each solvent, the process was repeated with the additional step of increasing the temperature of the contents of the 10 mL container from room temperature to boiling (eg, 95° C.) before inserting the syringe.

[0145] The results of the syringeability study are listed in Table 2. The column "Amount Aspirated" lists the total volume of the mixture aspirated or withdrawn into the syringe. The column "% Oxycodone HCl Extracted" indicates the amount of oxycodone HCl present in the syringe relative to the original oxycodone HCl in the tablet (e.g., as measured by HPLC).

[0146] Table 2

[0147]

[0148] Example 3

[0149] Large Volume Solvent Extraction of Oxycodone Hydrochloride from Aqueous Solutions of Oxycodone HCl 60 mg Resinate Tablets

[0150] Solvent extraction of resin tablets containing 60 mg of oxycodone hydrochloride according to the pharmaceutical compositions and methods described herein was tested. In this solvent extraction study, the resin tablets were ground and placed in a container. One hundred milliliters of tap water was added to the container at room temperature or 95°C. The contents of the container were mixed at medium speed using a shaker for 5 minutes, 10 minutes, 20 minutes, 60 minutes, and 360 minutes. The contents inside the container were then measured and analyzed using HPLC.

[0151] The results of the bulk solvent extraction studies are listed in Table 3. The "% Amount" column lists the percentage of oxycodone HCl that could be recovered from a tablet containing 60 mg oxycodone HCl.

[0152] Table 3

[0153]

[0154] Example 4

[0155] Dissolution profile of 60 mg oxycodone HCl resinate tablets

[0156] Dissolution testing of extended release 60 mg oxycodone HCl resinate tablets prepared as described in Example 1 was performed using USP Apparatus 1 equipped with horizontal springs on top of each basket to prevent tablet sticking, operating at 100 RPM, wherein the tablets were dissolved in 900 ml of enzyme-free simulated gastric fluid (0.1 N HCl). The dissolution data for the tablets are shown in Table 4 and the dissolution profiles are shown in Figure 5 .

[0157] Table 4

[0158]

[0159] Example 5 (Prophetic)

[0160] Dissolution profile of oxycodone HCl resinate tablets

[0161] Extended release 60 mg oxycodone HCl resinate tablets are prepared essentially as described in Example 1, except that less Methocel K4M is used, or the matrix material has a lower molecular weight than Methocel K4M, and / or sodium carboxymethylcellulose is used as the matrix material. Dissolution testing can be performed using USP apparatus 1, which is equipped with a horizontal spring on the top of each basket to prevent tablet sticking, operating at 100 RPM, where the tablets are dissolved in 900 ml of enzyme-free simulated gastric fluid (0.1N HCl). The above parameters can be optimized to release about 10% to about 45% of the active agent after 1 hour, about 12.5% ​​to about 55% (weight) of the active agent after 2 hours, about 25% to about 65% (weight) of the active agent after 4 hours, about 45% to about 85% (weight) of the active agent after 6 hours and about 55% to about 95% (weight) of the active agent after 8 hours, and optionally about 75% to 100% (weight) of the active agent after 12 hours, as measured by in vitro dissolution in about 900 ml of simulated gastric fluid at about 37°C in a USP Apparatus 2 (paddle) at about 50 rpm.

Claims

1. A pharmaceutical composition comprising: Contains a mixture of: at least one active agent; Ion exchange resins; Adhesives; and Matrix material, Wherein the composition, when administered to a patient in need thereof, provides a therapeutic effect to the patient for at least about 8 hours.

2. The pharmaceutical composition of claim 1, wherein the composition releases about 10% to about 45% of the active agent after 1 hour, about 12.5% ​​to about 55% (by weight) of the active agent after 2 hours, about 25% to about 65% (by weight) of the active agent after 4 hours, about 45% to about 85% (by weight) of the active agent after 6 hours, and about 55% to about 95% (by weight) of the active agent after 8 hours, and optionally about 75% to 100% (by weight) of the active agent after 12 hours, as measured by in vitro dissolution in about 900 ml of simulated gastric fluid at about 37°C in a USP Apparatus 2 (paddle) at about 50 rpm.

3. The pharmaceutical composition of claim 1 or 2, wherein the composition releases about 10% or less of at least one active agent in about 20 minutes as measured by in vitro dissolution in a USP Apparatus 2 (paddle) at about 50 rpm in about 900 ml of water at about 37°C.

4. The pharmaceutical composition of claim 1 or 2, wherein the composition releases about 20% or less of at least one active agent in about 45 minutes as measured by in vitro dissolution in a USP Apparatus 2 (paddle) at about 50 rpm in about 900 ml of water at about 37°C.

5. The pharmaceutical composition of claim 1 or 2, wherein the composition releases about 10% or less of at least one active agent in about 20 minutes as measured by in vitro dissolution in about 900 ml of 40% ethanol in water v / v at about 37°C in a USP Apparatus 2 (paddle) at about 50 rpm.

6. The pharmaceutical composition of claim 1 or 2, wherein the composition releases about 20% or less of at least one active agent in about 45 minutes as measured by in vitro dissolution in about 900 ml of 40% ethanol in water v / v at about 37°C in a USP Apparatus 2 (paddle) at about 50 rpm.

7. A pharmaceutical composition according to any one of the preceding claims, wherein the at least one active agent comprises a drug susceptible to abuse.

8. The pharmaceutical composition of claim 7, wherein the drug susceptible to abuse comprises an opioid agonist.

9. The pharmaceutical composition of claim 8, wherein the opioid agonist is selected from the group consisting of oxycodone, oxymorphone, hydrocodone, hydromorphone, codeine, tramadol, tapentadol, fentanyl, and pharmaceutically acceptable salts, hydrates and solvates thereof, and mixtures thereof.

10. The pharmaceutical composition of claim 8, wherein the opioid agonist is selected from the group consisting of oxycodone hydrochloride, hydrocodone bitartrate, and hydromorphone hydrochloride.

11. The pharmaceutical composition of claim 8, further comprising at least one second active agent.

12. The pharmaceutical composition of claim 11, wherein the at least one second active agent comprises a non-opioid analgesic.

13. The pharmaceutical composition of claim 12, wherein the non-opioid analgesic is selected from the group consisting of nonsteroidal anti-inflammatory agents and acetaminophen.

14. The pharmaceutical composition of claim 11, wherein the at least one second active agent comprises an antagonist of the active agent.

15. The pharmaceutical composition of claim 14, wherein the antagonist is selected from the group consisting of naltrexone, naloxone, nalmefene, cyclazocine, levallorphan, buprenorphine, pharmaceutically acceptable salts, hydrates and solvates thereof, and mixtures thereof.

16. The pharmaceutical composition of claim 15, wherein the antagonist is selected from the group consisting of naltrexone, naloxone, pharmaceutically acceptable salts, hydrates and solvates thereof, and mixtures thereof.

17. The pharmaceutical composition of claim 15, wherein the antagonist is naltrexone hydrochloride or naloxone hydrochloride.

18. The pharmaceutical composition of claim 7, wherein the drug susceptible to abuse is selected from the group consisting of central nervous system (CNS) stimulants, CNS depressants, tranquilizers, sedatives, hypnotics, and combinations thereof.

19. The pharmaceutical composition of claim 18, wherein the drug susceptible to abuse comprises a CNS stimulant.

20. The pharmaceutical composition of claim 19, wherein the CNS stimulant is selected from the group consisting of gamma-hydroxybutyrate, methamphetamine, and pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

21. The pharmaceutical composition of claim 19, wherein the CNS stimulant comprises a phenidate or a pharmaceutically acceptable salt, hydrate, solvate or mixture thereof.

22. The pharmaceutical composition of claim 21, wherein the phenidate is selected from methylphenidate, dexmethylphenidate, and pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

23. A pharmaceutical composition according to any one of the preceding claims, wherein the ion exchange resin comprises at least one material selected from the group consisting of: (i) sulfonated copolymers of styrene and divinylbenzene, (ii) methacrylic acid-divinylbenzene copolymers, and (iii) polystyrene resins having amine and / or ammonium side groups.

24. The pharmaceutical composition according to any one of the preceding claims, wherein the weight ratio of ion exchange resin to at least one active agent is from about 1:1 to about 10:

1.

25. The pharmaceutical composition of claim 24, wherein the weight ratio of ion exchange resin to at least one active agent is from about 4:1 to about 6:

1.

26. The pharmaceutical composition of claim 25, wherein the weight ratio of the ion exchange resin to the at least one active agent is from about 3:1 to about 5:

1.

27. A pharmaceutical composition according to any one of the preceding claims, wherein the binder is selected from the group consisting of low molecular weight hydroxypropyl methylcellulose, low molecular weight hydroxypropyl cellulose, low molecular weight hydroxyethyl cellulose, polyethylene glycol, acrylic acid polymers, acrylic acid copolymers, graft copolymers of polyvinyl alcohol and polyethylene glycol, polyvinyl alcohol, alginic acid, sodium alginate, starch, pregelatinized starch, sucrose, guar gum, derivatives thereof, and combinations thereof.

28. A pharmaceutical composition according to any one of claims 1 to 26, wherein the binder comprises a cellulose polymer having a molecular weight of about 100 Da to less than 1,000,000 Da.

29. A pharmaceutical composition according to any one of the preceding claims, wherein the binder comprises hydroxypropyl methylcellulose having a molecular weight of about 100 Da to less than 1,000,000 Da.

30. A pharmaceutical composition according to any one of the preceding claims, wherein the mixture comprises particles, each particle comprising the active agent, an ion exchange resin and a binder.

31. The pharmaceutical composition of claim 30, wherein the particles are dispersed in a matrix material.

32. The pharmaceutical composition of claim 30 or 31, wherein the particles further comprise at least one pharmaceutical excipient.

33. A pharmaceutical composition according to any one of the preceding claims, wherein the active agent and the ion exchange resin are in the form of a complex.

34. The pharmaceutical composition according to claim 33, wherein the complex is formed by dissolving at least one active agent in an aqueous liquid and adding an ion exchange resin to the aqueous liquid.

35. The pharmaceutical composition of claim 34, wherein the binder is added to an aqueous liquid to form a composite-binder mixture.

36. The pharmaceutical composition of claim 35, wherein the complex-binder mixture is dried by spray granulation.

37. The pharmaceutical composition of claim 36, wherein the composite-adhesive mixture is sprayed onto at least one substrate to form a mixture-substrate composition.

38. The pharmaceutical composition of claim 35, wherein the mixture is dried in a forced air dryer, comprising drying the mixture with at least one substrate in a fluidized bed dryer or an oven to form a mixture-substrate composition.

39. The pharmaceutical composition of claim 37 or 38, wherein the at least one substrate comprises at least one pharmaceutically acceptable excipient.

40. The pharmaceutical composition of claim 37 or 38, wherein the mixture-substrate composition is dispersed in a matrix material.

41. The pharmaceutical composition of claim 39, wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of plasticizers, colorants, lubricants, thermolubricants, antioxidants, buffers, disintegrants, binders, diluents, glidants, antiadherents, sweeteners, chelating agents, flavors, surfactants, solubilizers, stabilizers, hydrophilic polymers, hydrophobic polymers, waxes, lipophilic materials, absorption enhancers, preservatives, absorbents, cross-linking agents, bioadhesive polymers, pore formers, osmotic agents, polycarboxylic acids, and combinations thereof.

42. The pharmaceutical composition of claim 39, wherein the pharmaceutically acceptable excipient comprises a mixture of lactose monohydrate and microcrystalline cellulose.

43. A pharmaceutical composition according to any one of the above claims, wherein the matrix material is selected from the group consisting of high molecular weight hydroxypropyl methylcellulose, high molecular weight polyethylene oxide, high molecular weight hydroxyethyl cellulose, high molecular weight hydroxypropyl cellulose, high molecular weight methylcellulose, alginates, carbopol, polymethacrylates, waxes, carnauba wax, beeswax, glyceryl alginate, polyglycolyzed glycerides, and combinations thereof.

44. A pharmaceutical composition according to any one of claims 1 to 31, further comprising at least one pharmaceutically acceptable excipient.

45. The pharmaceutical composition of claim 44, wherein the pharmaceutically acceptable excipient is selected from the group consisting of plasticizers, colorants, lubricants, thermolubricants, antioxidants, buffers, disintegrants, binders, diluents, glidants, antiadherents, sweeteners, chelating agents, flavors, surfactants, solubilizers, stabilizers, hydrophilic polymers, hydrophobic polymers, waxes, lipophilic materials, absorption enhancers, preservatives, absorbents, cross-linking agents, bioadhesive polymers, pore formers, osmotic agents, polycarboxylic acids, and combinations thereof.

46. ​​The pharmaceutical composition of claim 44, wherein the at least one pharmaceutically acceptable excipient comprises at least one diluent.

47. The pharmaceutical composition of claim 46, wherein the at least one diluent is selected from the group consisting of lactose, starch, mannitol, sorbitol, dextrose monohydrate, microcrystalline cellulose, dibasic calcium phosphate dihydrate, sucrose based diluents, confectioners' sugar, dibasic calcium sulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate granules, glucose binder, dextrose, inositol, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, glycine, bentonite, and polyvinylpyrrolidone.

48. The pharmaceutical composition of claim 44, wherein the pharmaceutically acceptable excipients comprise lactose monohydrate and microcrystalline cellulose.

49. The pharmaceutical composition according to any of the preceding claims, further comprising at least one abuse deterrent selected from at least one gelling agent, at least one bittering agent and at least one stimulant.

50. The pharmaceutical composition of claim 49, wherein the at least one gelling agent is selected from the group consisting of sugars, sugar-derived alcohols, starches, starch derivatives, cellulose derivatives, attapulgite, bentonite, dextrin, alginate, carrageenan, gum, pectin, gelatin, kaolin, lecithin, magnesium aluminum silicate, carbomer, carbopol, polyvinyl pyrrolidone, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, silicon dioxide, curdlan, furcellaran, protein powder, whey protein, soy protein, chitosan, surfactants, emulsifiers, and pharmaceutically acceptable salts thereof, and mixtures thereof.

51. The pharmaceutical composition of claim 49, wherein the at least one bittering agent is selected from the group consisting of flavoring oils, flavoring spices, oleoresins, plant extracts, leaf extracts, flower extracts, fruit extracts, sucrose derivatives, chlorosucrose derivatives, quinine sulfate, denatonium benzoate, and pharmaceutically acceptable salts thereof, and mixtures thereof.

52. The pharmaceutical composition of claim 49, wherein the at least one irritant is selected from the group consisting of surfactants, capsaicin, capsaicin analogs, and mixtures thereof.

53. A pharmaceutical composition according to any of the above claims, wherein the recovery of at least one active agent is less than about 20%, or less than about 10%, or less than about 5%, or less than about 2%, based on a syringeability test in which the composition is dissolved in 10 ml of water with stirring at room temperature for about 2 minutes and the resulting solution is aspirated with a 21 gauge needle.

54. A pharmaceutical composition according to any of the above claims, wherein the recovery of at least one active agent is less than about 20%, or less than about 10%, or less than about 5%, or less than about 2%, based on a syringeability test wherein the composition is dissolved in 10 ml of water with stirring at 95° C. for about 2 minutes and the resulting solution is aspirated using a 21 gauge needle.

55. A pharmaceutical composition according to any of the above claims, wherein the recovery of at least one active agent is less than about 20%, or less than about 10%, or less than about 5%, or less than about 2%, based on a syringeability test wherein the composition is dissolved in 10 ml of saline with stirring at room temperature for about 2 minutes and the resulting solution is aspirated with a 21 gauge needle.

56. A pharmaceutical composition according to any of the above claims, wherein the recovery of at least one active agent is less than about 20%, or less than about 10%, or less than about 5%, or less than about 2%, based on a syringeability test wherein the composition is dissolved in 10 ml of saline with stirring at 95° C. for about 2 minutes and the resulting solution is aspirated with a 21 gauge needle.

57. A pharmaceutical composition according to any of the above claims, wherein the recovery of at least one active agent is less than about 20%, or less than about 15%, or less than about 12%, based on the following solvent extraction test, wherein the composition is ground and dissolved in 100 ml of water with stirring at room temperature for 5 minutes.

58. A pharmaceutical composition according to any of the above claims, wherein the recovery of at least one active agent is less than about 25%, or less than about 20%, or less than about 17%, based on the following solvent extraction test, wherein the composition is ground and dissolved in 100 ml of water with stirring at room temperature for 10 minutes.

59. A pharmaceutical composition according to any of the above claims, wherein the recovery of at least one active agent is less than about 30%, or less than about 25%, or less than about 21%, based on the following solvent extraction test, wherein the composition is ground and dissolved in 100 ml of water with stirring at room temperature for 20 minutes.

60. A pharmaceutical composition according to any of the above claims, wherein the recovery of at least one active agent is less than about 20%, or less than about 15%, or less than about 12%, based on a solvent extraction test wherein the composition is ground and dissolved in 100 ml of water with stirring at 95°C for 5 minutes.

61. A pharmaceutical composition according to any of the above claims, wherein the recovery of at least one active agent is less than about 20%, or less than about 15%, or less than about 12%, based on the following solvent extraction test, wherein the composition is ground and dissolved in 100 ml of water with stirring at 95°C for 20 minutes.

62. A pharmaceutical composition according to any of the above claims, wherein the recovery of at least one active agent is less than about 25%, or less than about 20%, or less than about 15%, based on the following solvent extraction test, wherein the composition is ground and dissolved in 100 ml of water with stirring at 95° C. for 60 minutes.

63. A pharmaceutical composition according to any one of the preceding claims, wherein the composition comprises a compressed tablet.

64. A pharmaceutical composition according to any one of the preceding claims, wherein the composition is contained in a pharmaceutically acceptable capsule.

65. A method of treating pain comprising administering a pharmaceutical composition according to any one of claims 8, 9 or 10 to a patient in need thereof.

66. A method of treating attention deficit hyperactivity disorder (ADHD) comprising administering to a patient in need thereof a pharmaceutical composition according to any one of claims 18 to 22.

67. A method of deterring the abuse of an abuse-prone drug comprising preparing a pharmaceutical composition according to any one of claims 1-64.

68. A method for preparing a pharmaceutical composition, comprising: A mixture is formed comprising: at least one active agent, Ion exchange resins; and Adhesives, forming a matrix comprising the mixture and a matrix material, Wherein the composition, when administered to a patient in need thereof, provides a therapeutic effect to the patient for at least about 8 hours.

69. The method of claim 68, wherein forming the mixture comprises forming a complex of at least one active agent and an ion exchange resin.

70. The method of claim 69, wherein forming the complex comprises dissolving at least one active agent in an aqueous liquid.

71. The method of claim 70, wherein dissolving the at least one active agent in the aqueous liquid comprises mixing the at least one active agent in the aqueous liquid for about 0.5 hour to about 4 hours.

72. The method of claim 70, wherein dissolving the at least one active agent in the aqueous liquid comprises mixing the at least one active agent in the aqueous liquid for at least about 2 hours.

73. The method of any one of claims 70-72, further comprising adding an ion exchange resin to the aqueous liquid to form a slurry.

74. The method of claim 73, further comprising allowing the slurry to stand for about 12 hours or less, about 8 hours or less, about 4 hours or less, about 2 hours or less, about 1 hour or less, or about 30 minutes or less before drying.

75. The method of any one of claims 68-74, wherein the weight ratio of ion exchange resin to at least one active agent is from about 1:1 to about 10:

1.

76. The method of any one of claims 68-74, wherein the weight ratio of ion exchange resin to at least one active agent is from about 4:1 to about 6:

1.

77. The method of any one of claims 68-74, wherein the weight ratio of ion exchange resin to at least one active agent is from about 3:1 to about 5:

1.

78. The method of any one of claims 68-77, wherein forming the matrix comprises mixing a composite with a binder in an aqueous liquid to form a mixture.

79. The method of claims 68-78, wherein forming the matrix further comprises drying the mixture by spray granulation or in a forced air dryer.

80. The method of claim 79, wherein the spray granulating comprises spraying the mixture onto at least one substrate to form a mixture-substrate composition.

81. The method of claim 79, wherein drying in a forced air dryer comprises contacting the mixture with at least one substrate in a fluidized bed dryer or an oven to form the mixture-substrate composition.

82. The method of claim 80 or 81, wherein the at least one substrate comprises a second active agent.

83. The method of claim 80 or 81, wherein the at least one substrate comprises a pharmaceutically acceptable excipient.

84. The method of claim 83, wherein the pharmaceutically acceptable excipient is selected from the group consisting of plasticizers, colorants, lubricants, thermolubricants, antioxidants, buffers, disintegrants, binders, diluents, glidants, antiadherents, sweeteners, chelating agents, flavors, surfactants, solubilizers, stabilizers, hydrophilic polymers, hydrophobic polymers, waxes, lipophilic materials, absorption enhancers, preservatives, absorbents, cross-linking agents, bioadhesive polymers, pore formers, osmotic agents, polycarboxylic acids, and combinations thereof.

85. The pharmaceutical composition of claim 83, wherein the at least one pharmaceutically acceptable excipient comprises at least one diluent.

86. The pharmaceutical composition of claim 85, wherein the at least one diluent is selected from the group consisting of lactose, starch, mannitol, sorbitol, dextrose monohydrate, microcrystalline cellulose, dibasic calcium phosphate dihydrate, sucrose based diluents, confectioners' sugar, dibasic calcium sulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate granules, glucose binder, dextrose, inositol, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, glycine, bentonite, and polyvinylpyrrolidone.

87. The pharmaceutical composition of claim 83, wherein the pharmaceutically acceptable excipients comprise lactose monohydrate and microcrystalline cellulose.

88. The method of claim 83, wherein the pharmaceutically acceptable excipient comprises a mixture of lactose monohydrate and microcrystalline cellulose.

89. The method of any one of claims 80-88, wherein the mixture-substrate composition is in the form of particles.

90. A method according to any one of claims 80 to 89 comprising dispersing the mixture-substrate composition in a matrix material.

91. The method of claim 68, wherein the composition releases about 10% to about 45% of the active agent after 1 hour, about 12.5% ​​to about 55% (by weight) of the active agent after 2 hours, about 25% to about 65% (by weight) of the active agent after 4 hours, about 45% to about 85% (by weight) of the active agent after 6 hours, and about 55% to about 95% (by weight) of the active agent after 8 hours, and optionally about 75% to 100% (by weight) of the active agent after 12 hours as measured by in vitro dissolution in about 900 ml of simulated gastric fluid at about 37°C in a USP Apparatus 2 (paddle) at about 50 rpm.

92. The method of claim 68, wherein the composition releases about 10% or less of at least one active agent in about 20 minutes as measured by in vitro dissolution in a USP Apparatus 2 (paddle) at about 50 rpm in about 900 ml of water at about 37°C.

93. The method of claim 68, wherein the composition releases about 20% or less of at least one active agent in about 45 minutes as measured by in vitro dissolution in a USP Apparatus 2 (paddle) at about 50 rpm in about 900 ml of water at about 37°C.

94. The method of claim 68, wherein the composition releases about 10% or less of at least one active agent in about 20 minutes as measured by in vitro dissolution in about 900 ml of 40% ethanol in water v / v at about 37°C in a USP Apparatus 2 (paddle) at about 50 rpm.

95. The method of claim 68, wherein the composition releases about 20% or less of at least one active agent in about 45 minutes as measured by in vitro dissolution in about 900 ml of 40% ethanol in water v / v at about 37°C in a USP Apparatus 2 (paddle) at about 50 rpm.

96. The method of any one of claims 68-95, wherein the at least one active agent is a drug susceptible to abuse.

97. The method of claim 96, wherein the abuse-prone drug comprises an opioid agonist.

98. The method of claim 97, wherein the opioid agonist is selected from the group consisting of oxycodone, oxymorphone, hydrocodone, hydromorphone, codeine, tramadol, tapentadol, fentanyl, and pharmaceutically acceptable salts, hydrates, solvates thereof, and mixtures thereof.

99. The method of claim 97, wherein the opioid agonist is oxycodone hydrochloride, hydrocodone bitartrate, or hydromorphone hydrochloride.

100. The method of claim 97, wherein the composition further comprises a second active agent.

101. The method of claim 100, wherein the second active agent is a non-opioid analgesic.

102. The method of claim 100, wherein the non-opioid analgesic is selected from the group consisting of nonsteroidal anti-inflammatory agents and acetaminophen.

103. The method of claim 100, wherein the second active agent is an antagonist of at least one active agent.

104. The method of claim 103, wherein the antagonist is selected from the group consisting of naltrexone, naloxone, nalmefene, cyclazocine, levallorphan, buprenorphine, pharmaceutically acceptable salts, hydrates and solvates thereof, and mixtures thereof.

105. The method of claim 96, wherein the abuse-prone drug is selected from the group consisting of a central nervous system (CNS) stimulant, a CNS depressant, a tranquilizer, a sedative-hypnotic, and combinations thereof.

106. The method of claim 105, wherein the drug susceptible to abuse comprises a CNS stimulant.

107. The method of claim 106, wherein the CNS stimulant is selected from the group consisting of gamma-hydroxybutyrate, methamphetamine, and pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

108. The method of claim 106, wherein the CNS stimulant comprises piperate or a pharmaceutically acceptable salt, hydrate, solvate, or mixture thereof.

109. The method of claim 108, wherein the phenidate is selected from the group consisting of methylphenidate, dexmethylphenidate, and pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

110. The method of any one of claims 68-109, wherein the ion exchange resin comprises at least one material selected from the group consisting of: (i) sulfonated copolymers of styrene and divinylbenzene, (ii) methacrylic acid-divinylbenzene copolymers, and (iii) polystyrene resins having amine and / or ammonium side groups.

111. The method according to any one of claims 68-110, wherein the binder is selected from low molecular weight hydroxypropyl methylcellulose, low molecular weight hydroxypropyl cellulose, low molecular weight hydroxyethyl cellulose, polyethylene glycol, acrylic acid polymers, acrylic acid copolymers, graft copolymers of polyvinyl alcohol and polyethylene glycol, polyvinyl alcohol, alginic acid, sodium alginate, starch, pregelatinized starch, sucrose, guar gum, derivatives thereof, and combinations thereof.

112. The method of any one of claims 68-111, wherein the binder comprises a cellulosic polymer having a molecular weight of about 100 Da to less than 1,000,000 Da.

113. A pharmaceutical composition according to any one of claims 68-112, wherein the binder comprises hydroxypropyl methylcellulose having a molecular weight of about 100 Da to less than 1,000,000 Da.

114. The method of any one of claims 68-113, wherein the matrix material is selected from high molecular weight hydroxypropyl methylcellulose, high molecular weight polyethylene oxide, high molecular weight hydroxyethyl cellulose, high molecular weight hydroxypropyl cellulose, high molecular weight methylcellulose, alginate, carbopol, polymethacrylate, wax, carnauba wax, beeswax, glyceryl alginate, polyglycolyzed glyceride, and combinations thereof.

115. The method of any one of claims 68-82 or 89-114, further comprising incorporating at least one pharmaceutically acceptable excipient into the pharmaceutical composition.

116. The method of any one of claims 68-115, further comprising incorporating into the pharmaceutical composition at least one abuse deterrent selected from at least one gelling agent, at least one bittering agent, and at least one stimulant.

117. The method of claim 116, wherein the at least one gelling agent is selected from the group consisting of sugars, sugar-derived alcohols, starches, starch derivatives, cellulose derivatives, attapulgite, bentonite, dextrin, alginate, carrageenan, gum, pectin, gelatin, kaolin, lecithin, magnesium aluminum silicate, carbomer, carbopol, polyvinyl pyrrolidone, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, silicon dioxide, curdlan, furcellaran, protein powder, whey protein, soy protein, chitosan, surfactants, emulsifiers, and pharmaceutically acceptable salts thereof, and mixtures thereof.

118. The method of claim 116, wherein the at least one gelling agent is selected from the group consisting of polyethylene oxide, starch, xanthan gum, and mixtures thereof.

119. The method of claim 116, wherein the at least one bittering agent is selected from the group consisting of flavoring oils, flavoring spices, oleoresins, plant extracts, leaf extracts, flower extracts, fruit extracts, sucrose derivatives, chlorosucrose derivatives, quinine sulfate, denatonium benzoate, and mixtures thereof.

120. The method of claim 116, wherein the at least one irritant is selected from the group consisting of surfactants, capsaicin, capsaicin analogs, and mixtures thereof.

121. The method of any one of claims 68-120, wherein the recovery of at least one active agent is less than about 20%, or less than about 10%, or less than about 5%, or less than about 2%, based on a syringeability test wherein the composition is dissolved in 10 ml of water with stirring at room temperature for about 2 minutes and the resulting solution is aspirated with a 21 gauge needle.

122. The method of any one of claims 68-121, wherein the recovery of at least one active agent is less than about 20%, or less than about 10%, or less than about 5%, or less than about 2%, based on a syringeability test wherein the composition is dissolved in 10 ml of water with stirring at 95°C for about 2 minutes and the resulting solution is aspirated using a 21 gauge needle.

123. The method of any one of claims 68-122, wherein the recovery of at least one active agent is less than about 20%, or less than about 10%, or less than about 5%, or less than about 2%, based on a syringeability test wherein the composition is dissolved in 10 ml of saline with stirring at room temperature for about 2 minutes and the resulting solution is aspirated with a 21 gauge needle.

124. The method of any one of claims 68-123, wherein the recovery of at least one active agent is less than about 20%, or less than about 10%, or less than about 5%, or less than about 2%, based on a syringeability test wherein the composition is dissolved in 10 ml of saline with stirring at 95°C for about 2 minutes and the resulting solution is aspirated with a 21 gauge needle.

125. The method of any one of claims 68-124, wherein recovery of at least one active agent is less than about 20%, or less than about 15%, or less than about 12%, based on a solvent extraction test wherein the composition is ground and dissolved in 100 ml of water with stirring at room temperature for 5 minutes.

126. The method of any one of claims 68-125, wherein recovery of at least one active agent is less than about 25%, or less than about 20%, or less than about 17%, based on a solvent extraction test wherein the composition is ground and dissolved in 100 ml of water with stirring at room temperature for 10 minutes.

127. The method of any one of claims 68-126, wherein recovery of at least one active agent is less than about 30%, or less than about 25%, or less than about 21%, based on a solvent extraction test wherein the composition is ground and dissolved in 100 ml of water with stirring at room temperature for 20 minutes.

128. The method of any one of claims 68-127, wherein recovery of at least one active agent is less than about 20%, or less than about 15%, or less than about 12%, based on a solvent extraction test wherein the composition is ground and dissolved in 100 ml of water with stirring at 95°C for 5 minutes.

129. The method of any one of claims 68-128, wherein recovery of at least one active agent is less than about 20%, or less than about 15%, or less than about 12%, based on a solvent extraction test wherein the composition is ground and dissolved in 100 ml of water with stirring at 95°C for 20 minutes.

130. The method of any one of claims 68-129, wherein recovery of at least one active agent is less than about 25%, or less than about 20%, or less than about 15%, based on a solvent extraction test wherein the composition is ground and dissolved in 100 ml of water with stirring at 95°C for 60 minutes.

131. The method of any one of claims 68-130, wherein the composition comprises a compressed tablet.

132. The method of any one of claims 68-131, wherein the composition is contained in a pharmaceutically acceptable capsule.

133. A pharmaceutical composition comprising: A matrix comprising: A complex containing a drug susceptible to abuse and an ion exchange resin; a binder comprising a low molecular weight polymer; and Including polymer matrix materials.

134. A pharmaceutical composition comprising: A matrix comprising: (a) a particle comprising: Complexes of drugs of abuse with ion exchange resins; and a binder comprising a low molecular weight polymer; and (b) Matrix material, Wherein the composition, when administered to a patient in need thereof, provides a therapeutic effect to the patient for at least about 8 hours.

135. A pharmaceutical composition comprising: A matrix comprising: (i) A particle comprising: (a) a complex of a drug susceptible to abuse selected from the group consisting of oxycodone, oxymorphone, hydrocodone, hydromorphone, codeine, tramadol, tapentadol, fentanyl, and pharmaceutically acceptable salts, hydrates and solvates thereof, and mixtures thereof, and an ion exchange resin selected from the group consisting of a sulfonated copolymer of styrene and divinylbenzene, a methacrylic acid-divinylbenzene copolymer, and a polystyrene resin having amine and / or ammonium side groups; and (b) a binder selected from the group consisting of low molecular weight hydroxypropyl methylcellulose, low molecular weight hydroxypropyl cellulose, low molecular weight hydroxyethyl cellulose, polyethylene glycol, acrylic acid polymers, acrylic acid copolymers, graft copolymers of polyvinyl alcohol and polyethylene glycol, polyvinyl alcohol, alginic acid, sodium alginate, starch, pregelatinized starch, sucrose, guar gum, derivatives thereof, and combinations thereof; and (ii) a matrix material selected from the group consisting of high molecular weight hydroxypropyl methylcellulose, high molecular weight polyethylene oxide, high molecular weight hydroxyethyl cellulose, high molecular weight hydroxypropyl cellulose, high molecular weight methyl cellulose, alginates, carbopol, polymethacrylates, waxes, carnauba wax, beeswax, glyceryl alginate and polyglycolized glycerides, and combinations thereof, Wherein the composition, when administered to a patient in need thereof, provides a therapeutic effect to the patient for at least about 8 hours.

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