Tamper Resistant Dosage Form Comprising an Adsorbent and an Adverse Agent

Abstract

Pharmaceutical compositions and dosage forms comprising an adsorbent, and an adverse agent, such as an opioid antagonist. In one embodiment, at least a portion of the adverse agent is on the surface or within the micropore structure of an adsorbent material. The pharmaceutical compositions and dosage forms comprising the adsorbent and the adverse agent are useful for preventing or discouraging tampering, abuse, misuse or diversion of a dosage form containing an active pharmaceutical agent, such as an opioid. The present invention also relates to methods for treating a patient with such a dosage form, as well as kits containing such a dosage form with instructions for using the dosage form to treat a patient. The present invention further relates to process for preparing such pharmaceutical compositions and dosage forms.

1 - 71 . (canceled) 
     
     
         72 . A dosage form comprising an active agent, an adsorbent and an adverse agent, wherein at least a majority of the adverse agent is adsorbed onto the adsorbent, and wherein the adverse agent is an antagonist of the active agent or wherein the adverse agent causes vomiting, nausea, diarrhea, or bad taste, when absorbed into an animal's or patient's bloodstream, and wherein the active agent is selected from analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents, erectile-dysfunction-improvement agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, β-blockers, cardiac ionotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastrointestinal agents, histamine receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, cox-2-inhibitors, leukotriene inhibitors, macrolides, muscle relaxants, nutritional agents, opioid analgesics, protease inhibitors, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, anti-obesity agents, cognition enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostate hypertrophy agents, essential fatty acids, and non-essential fatty acids. 
     
     
         73 . The dosage form of  claim 72 , wherein at least about 80 wt % of the adverse agent is adsorbed onto the adsorbent. 
     
     
         74 . The dosage form of  claim 73 , wherein at least about 90 wt % of the adverse agent is adsorbed onto the adsorbent. 
     
     
         75 . The dosage form of  claim 72 , wherein the adsorbent comprises at least one material selected from the group consisting of activated charcoal, alumina, silicon dioxide bentonite, kaolin, and mixtures of any two or more of the foregoing. 
     
     
         76 . The dosage form of  claim 75 , wherein the adsorbent is activated charcoal. 
     
     
         77 . The dosage form of  claim 72 , further comprising at least one hydrophobic material disposed at least on a portion of the outer surface of the adsorbent. 
     
     
         78 . The oral dosage form of  claim 77 , wherein the at least one hydrophobic material is selected from the group consisting of acrylic and methacrylic acid polymers and copolymers, alkylcelluloses, natural and synthetic waxes, water insoluble waxes, fatty alcohols, fatty acids, hydrogenated fats, fatty acid esters, fatty acid glycerides, hydrocarbons, and hydrophobic and hydrophilic polymers having hydrocarbon backbones, and mixtures of any two or more of the foregoing. 
     
     
         79 . The dosage form of  claim 78 , wherein the at least one hydrophobic material is selected from the group consisting of glyceryl monosteareate; beeswax; cetyl alcohol; stearyl alcohol; hydrogenated castor oil; hydrogenated cottonseed oil; stearyl alcohol; stearic acid; and mixtures of any two or more of the foregoing. 
     
     
         80 . The dosage form of  claim 72 , wherein the dosage form is an oral dosage form. 
     
     
         81 . The dosage form of  claim 72 , wherein the dosage form releases about 0.5 mg or less of the adverse agent in vivo following intact administration. 
     
     
         82 . The dosage form of  claim 81 , wherein the dosage form releases 0.05 mg or less of the adverse agent in vivo following intact administration. 
     
     
         83 . A dosage form according to  claim 72  comprising: a plurality of first particles comprising an active agent; and a plurality of second particles comprising an adsorbent and an adverse agent; wherein at least a majority of the adverse agent is adsorbed onto the adsorbent. 
     
     
         84 . The dosage form of  claim 83 , wherein the adsorbent is selected from the group consisting of activated charcoal, alumina, bentonite, kaolin, and mixtures of any two or more of the foregoing. 
     
     
         85 . The dosage form of  claim 84 , wherein the adsorbent is activated charcoal. 
     
     
         86 . The dosage form of  claim 83 , wherein the plurality of second particles further comprise at least one hydrophobic material disposed on at least a portion of the outer surface of the adsorbent. 
     
     
         87 . The dosage form of  claim 86 , wherein the at least one hydrophobic material is selected from the group consisting of acrylic and methacrylic acid polymers and copolymers, alkylcelluloses, natural and synthetic waxes, water insoluble waxes, fatty alcohols, fatty acids, hydrogenated fats, fatty acid esters, fatty acid glycerides, hydrocarbons, and hydrophobic and hydrophilic polymers having hydrocarbon backbones, and mixtures of any two or more of the foregoing. 
     
     
         88 . The dosage form of  claim 87 , wherein the at least one hydrophobic material is selected from the group consisting of giyceryi monosteareate; beeswax; cetyl alcohol; stearyl alcohol; hydrogenated castor oil; hydrogenated cottonseed oil; stearyl alcohol; stearic acid; and mixtures of any two or more of the foregoing. 
     
     
         89 . The dosage form of  claim 72 , wherein the active agent is an opioid agonist and the adverse agent is an opioid antagonist. 
     
     
         90 . The dosage form of  claim 83 , wherein the active agent is an opioid agonist and the adverse agent is an opioid antagonist. 
     
     
         91 . The dosage form of  claim 89 , wherein the opioid agonist is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacyl morphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metophon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, proheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, pharmaceutically acceptable salts thereof, and mixtures of any two or more of the foregoing. 
     
     
         92 . The dosage form of  claim 91 , wherein the opioid agonist is selected from the group consisting of morphine, codeine, hydromorphone, hydrocodone, oxycodone, oxymorphone, dihydrocodeine, dihydromorphine, pharmaceutically acceptable salts thereof, and mixtures of any two or more of the foregoing. 
     
     
         93 . The dosage form of  claim 89 , wherein the opioid antagonist is selected from the group consisting of cyclazocine, naloxone, naltrexone, nalmefene, nalbuphine, nalorphine, cyclazacine, levallorphan, pharmaceutically acceptable salts thereof, and mixtures of any two or more of the foregoing. 
     
     
         94 . The dosage form of  claim 93 , wherein the opioid antagonist is selected from the group consisting of nalmefene, naloxone, naltrexone, pharmaceutically acceptable salts thereof, and mixtures of any two or more of the foregoing. 
     
     
         95 . The dosage form of  claim 83 , wherein the dosage form is an oral dosage form. 
     
     
         96 . The dosage form of  claim 95 , wherein the dosage form comprises a capsule containing the first particles and the second particles. 
     
     
         97 . The dosage form of  claim 83 , wherein the dosage form releases 0.5 mg or less of the adverse agent in vivo following intact administration. 
     
     
         98 . The dosage form of  claim 97 , wherein the dosage form releases 0.05 mg or less of the adverse agent in vivo following intact administration 
     
     
         99 . An oral dosage form according to  claim 83 , wherein the active agent is an opioid agonist, the adverse agent is an opioid antagonist, and wherein the first particles provide a controlled release of the opioid agonist upon oral administration to a patient. 
     
     
         100 . The oral dosage form of  claim 99 , wherein the first particles and the second particles each have a size of from about 0.1 mm to about 3.0 mm in any dimension. 
     
     
         101 . The oral dosage form of  claim 99 , wherein the second particles each comprise at least one hydrophobic material disposed on at least a portion of the outer surface of the adsorbent. 
     
     
         102 . The oral dosage form of  claim 101 , wherein the at least one hydrophobic material is selected from the group consisting of acrylic and methacrylic acid polymers and copolymers, alkylcelluloses, natural and synthetic waxes, water insoluble waxes, fatty alcohols, fatty acids, hydrogenated fats, fatty acid esters, fatty acid glycerides, hydrocarbons, and hydrophobic and hydrophilic polymers having hydrocarbon backbones, and mixtures of any two or more of the foregoing. 
     
     
         103 . The oral dosage form of  claim 102 , wherein the at least one hydrophobic material is selected from the group consisting of glyceryl monosteareate; beeswax; cetyl alcohol; stearyl alcohol; hydrogenated castor oil; hydrogenated cottonseed oil; stearyl alcohol; stearic acid; and mixtures of any two or more of the foregoing. 
     
     
         104 . The oral dosage form of  claim 99 , wherein the opioid agonist is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacyl morphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metophon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, proheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, pharmaceutically acceptable salts thereof, and mixtures of any two or more of the foregoing. 
     
     
         105 . The oral dosage form of  claim 104 , wherein the opioid agonist is selected from the group consisting of morphine, codeine, hydromorphone, hydrocodone, oxycodone, oxymorphone, dihydrocodeine, dihydromorphine, pharmaceutically acceptable salts thereof, and mixtures of any two or more of the foregoing. 
     
     
         106 . The oral dosage form of  claim 99 , wherein the opioid antagonist is selected from the group consisting of cyclazocine, naloxone, naltrexone, nalmefene, nalbuphine, nalorphine, cyclazacine, levallorphan, pharmaceutically acceptable salts thereof, and mixtures of any two or more of the foregoing. 
     
     
         107 . The oral dosage form of  claim 95 , wherein the opioid antagonist is selected from the group consisting of naloxone, naltrexone and nalmefene, pharmaceutically acceptable salts thereof, any mixtures of any two or more of the foregoing. 
     
     
         108 . The oral dosage form of  claim 99 , wherein the dosage form comprises a tablet comprising the first particles and the second particles or wherein the dosage form comprises a capsule containing the first particles and the second particles. 
     
     
         109 . The oral dosage form of  claim 99 , wherein the second particles release about 0.5 mg or less of the opioid antagonist in vivo following intact oral administration. 
     
     
         110 . The oral dosage form of  claim 97 , wherein the second particles release about 0.05 mg or less of the opioid antagonist in vivo following intact oral administration. 
     
     
         111 . The dosage form of  claim 80 , wherein the dosage form comprises a capsule containing a plurality of particles, or wherein the dosage form comprises a tablet. 
     
     
         112 . The dosage form of  claim 72 , wherein the dosage form further comprises: a core comprising the adsorbent and the adverse agent; and a shell comprising the active agent; wherein the shell surrounds a majority of the core. 
     
     
         113 . A method for preparing a dosage form as defined in any of  claims 72 , comprising the steps of: providing an adsorbent; providing a liquid comprising an adverse agent; contacting the adsorbent with the liquid comprising the adverse agent for sufficient time to allow at least a portion of the adverse agent to adsorb onto the adsorbent; separating the adsorbent from the liquid phase; and optionally, washing the adsorbent or comprising providing an adsorbent; providing a liquid comprising an adverse agent; adding the adsorbent to a fluidized bed; fluidizing the adsorbent; spraying the liquid onto the fluidized adsorbent; and optionally, drying the adsorbent. 
     
     
         114 . The method of  claim 113 , wherein the adsorbent comprises at least one material selected from the group consisting of activated charcoal, alumina, bentonite, kaolin, and mixtures of and two or more of the forgoing. 
     
     
         115 . The method of  claim 113 , further comprising applying at least one hydrophobic material to the outer surface of the adsorbent after removal of the adsorbent from the liquid phase. 
     
     
         116 . The method of  claim 115 , wherein the at least one hydrophobic material is selected from the group consisting of acrylic and methacrylic acid polymers and copolymers, alkylcelluloses, natural and synthetic waxes, water insoluble waxes, fatty alcohols, fatty acids, hydrogenated fats, fatty acid esters, fatty acid glycerides, hydrocarbons, and hydrophobic and hydrophilic polymers having hydrocarbon backbones, and mixtures of any two or more of the foregoing. 
     
     
         117 . The method of  claim 113 , wherein the adverse agent is an opioid antagonist. 
     
     
         118 . The method of  claim 117 , further comprising adding an opioid agonist to the dosage form. 
     
     
         119 . Use of a compound in the manufacture of a dosage form according to  claim 72  for the treatment of a medical condition or a symptom thereof. 
     
     
         120 . Use of a compound in the manufacture of a dosage form according to  claim 99  for the treatment of pain. 
     
     
         121 . A kit for treating a patient for pain comprising a dosage form according to  claim 98 , and instructions for directing the administration of the dosage form to the patient for the treatment of pain.