Orally administrable opioid formulations having extended duration of effect

Abstract

Sustained release oral solid dosage forms of opioid analgesics are provided as multiparticulate systems which are bioavailable and which provide effective blood levels of the opioid analgesic for at least about 24 hours. A unit dose of the opioid analgesic contains a plurality of substrates including the opioid analgesic in sustained release form. The substrates have a diameter from about 0.1 mm to about 3 mm.

1 . A sustained-release oral analgesic dosage form for once-a-day administration, comprising: 
 a unit dose of a plurality of inert pharmaceutically acceptable substrates comprising an analgesically effective amount of an opioid analgesic or a salt thereof in sustained release form, each of said substrates having a diameter from about 0.1 mm to about 3 mm, said unit dose being bioavailable and providing effective blood levels of said opioid analgesic for at least about 24 hours.    
   
   
       2 . The dosage form of  claim 1 , wherein said substrates are selected from the group consisting of spheroids, beads, microspheres, seeds, pellets, ion-exchange resin beads, granules, and mixtures thereof.  
   
   
       3 . (canceled)  
   
   
       4 . The dosage form of  claim 2 , wherein said substrates comprise matrices of a substantially uniform mixture of said opioid analgesic and a hydrophobic material.  
   
   
       5 . The dosage form of  claim 1 , wherein said opioid analgesic is selected from the group consisting of morphine, codeine, hydromorphone, hydrocodone, oxycodone, oxymorphone, dihydrocodeine, dihydromorphine, and mixtures thereof.  
   
   
       6 . The dosage form of  claim 1 , wherein said opioid analgesic is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, 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, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpinanone, opium, oxycodone, oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sulfentanil, tramadol, tilidine, salts thereof and mixtures thereof.  
   
   
       7 - 11 . (canceled)  
   
   
       12 . The dosage form of  claim 2 , wherein said hydrophobic material is selected from the group consisting of an acrylic polymer, an alkylcellulose, shellac, zein, hydrogenated vegetable oil, hydrogenated castor oil, and mixtures of any of the foregoing.  
   
   
       13 - 17 . (canceled)  
   
   
       18 . A dosage form of  claim 1 , further comprising a nonopioid drug.  
   
   
       19 . (canceled)  
   
   
       20 . The dosage form of  claim 18 , wherein said nonopioid drug is selected from the group consisting of ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam or isoxicam, and mixtures of any of the foregoing.  
   
   
       21 . A bioavailable sustained-release opioid analgesic dosage form for once-a-day oral administration, comprising 
 inert pharmaceutically acceptable beads having a diameter from about 0.1 mm to about 3 mm coated with an analgesically effective amount of an opioid analgesic or a salt thereof, said beads further comprising an sustained-release overcoat comprising an effective amount of a hydrophobic material selected from the group consisting of an acrylic polymer, an alkylcellulose shellac, zein, hydrogenated vegetable oil, hydrogenated castor oil, and mixtures of any of the foregoing to provide a sustained release of said opioid analgesic in aqueous solutions for at least about 24 hours.    
   
   
       22 - 28 . (canceled)  
   
   
       29 . The dosage form of  claim 21 , wherein said opioid analgesic is selected form the group consisting of morphine, codeine, hydromorphone, hydrocodone, oxycodone, oxymorphone, dihydrocodeine, dihydromorphine, and mixtures thereof.  
   
   
       30 . A dosage form of  claim 29 , further comprising a nonopioid drug.  
   
   
       31 . (canceled)  
   
   
       32 . The dosage form of  claim 30 , wherein said nonopioid drug is selected from the group consisting of ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam or isoxicam, and mixtures of any of the foregoing.  
   
   
       33 . A method for obtaining a bioavailable sustained release opioid analgesic dosage form for once-a-day oral administration, comprising preparing a plurality of substrates comprising a unit dose of an oral analgesic in a sustained release form, each of said substrates having a diameter from about 0.1 mm to about 3 mm, said substrates being manufactured to provide an in-vitro dissolution indicative of a once-a-day product.  
   
   
       34 . The method of  claim 33 , wherein said substrates are selected from the group consisting of spheroids, beads, microspheres, seeds, pellets, ion-exchange resin beads, granules, and mixtures thereof.  
   
   
       35 . The method of  claim 33 , further comprising preparing said substrates by coating inert beads with said opioid analgesic, and thereafter overcoating with a hydrophobic material is selected from the group consisting of an acrylic polymer, an alkylcellulose, shellac, zein, hydrogenated vegetable oil, hydrogenated castor oil, and mixtures of any of the foregoing.  
   
   
       36 . The method of  claim 33 , further comprising preparing said substrates as matrices of a substantially uniform mixture of said opioid analgesic and a hydrophobic material.  
   
   
       37 - 38 . (canceled)  
   
   
       39 . The method of  claim 33 , further comprising incorporating a therapeutically effective amount of a non-opioid drug into said unit dose.  
   
   
       40 . (canceled)  
   
   
       41 . A method of treating a patient for moderate to severe pain with a bioavailable sustained-release opioid analgesic dosage form for once-a-day oral administration, comprising preparing a plurality of substrates comprising a unit dose of an opioid analgesic, each of said substrates having a diameter from about 0.1 mm to about 3 mm, said substrates being manufactured in a sustained release form to provide therapeutically effective blood levels of said opioid analgesic for about 24 hours or more, and administering said unit dose to a patient to alleviate moderate to severe pain for about 24 hours or more.  
   
   
       42 . The method of  claim 41 , further comprising preparing said substrates in a form selected from the group consisting of spheroids, beads, microspheres, seeds, pellets, ion-exchange resin beads, granules, and mixtures thereof.  
   
   
       43 . The method of  claim 41 , further comprising preparing said substrates by coating inert beads with said opioid analgesic, and thereafter overcoating with a hydrophobic material is selected from the group consisting of an acrylic polymer, an alkylcellulose, shellac, zein, hydrogenated vegetable oil, hydrogenated castor oil, and mixtures of any of the foregoing.  
   
   
       44 . The method of  claim 41 , further comprising preparing said substrates as matrices of a substantially uniform mixture of said opioid analgesic and a hydrophobic material.  
   
   
       45 . The method of  claim 41 , further comprising incorporating a therapeutically effective amount of a nonsteroidal anti-inflammatory agent into said unit dose.  
   
   
       46 - 48 . (canceled)  
   
   
       49 . The dosage form of  claim 18 , wherein said non-opioid drug is selected from the group consisting of acetaminophen and aspirin.  
   
   
       50 . The dosage form of  claim 30 , wherein said non-opioid drug is selected from the group consisting of acetaminophen and aspirin.  
   
   
       51 . The method of  claim 39 , wherein said non-opioid drug is selected from the group consisting of acetaminophen and aspirin.  
   
   
       52 . (canceled)