Abuse-resistant opioid solid dosage form
The present invention pertains to a solid dosage form comprising an analgesically effective amount of opioid analgesic and an opioid abuse-deterring amount of a nontoxic N-methyl-D-aspartate receptor antagonist contained in a carrier which isolates, or separates, the antagonist from the opioid analgesic. The nontoxic N-methyl-D-aspartate receptor antagonist is released and made available only when the dosage form is misused, as would be the case when the dosage form is crushed or dissolved and thereafter administered in a manner other than that indicated, e.g., by injection or intranasally.
1 . An abuse-resistant opioid-containing pharmaceutical solid dosage form which comprises:
a) an analgesically effective amount of opioid analgesic; and,
b) an isolated nontoxic N-methyl-D-aspartate receptor antagonist which is substantially not released when the dosage form is administered intact, but is released in an opioid euphoria-inhibiting amount when the dosage form is crushed or dissolved and then administered.
2 . The dosage form of claim 1 wherein the opioid analgesic is at least one member selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanyl, tilidine, tramadol and their pharmaceutically acceptable salts.
3 . The dosage form of claim 1 wherein the opioid analgesic is at least one member selected from the group consisting of codeine, dihydrocodeine, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene and their pharmaceutically acceptable salts.
4 . The dosage form of claim 1 wherein the nontoxic NMDA receptor antagonist is at least one member selected from the group consisting of dextromethorphan, dextrorphan, memantine, amantidine, d-methadone and their pharmaceutically acceptable salts.
5 . The dosage form of claim 3 wherein the nontoxic NMDA receptor antagonist is at least one member selected from the group consisting of dextromethorphan, dextrorphan, memantine, amantidine, d-methadone and their pharmaceutically acceptable salts.
6 . The dosage form of claim 1 wherein the opioid analgesic is in a controlled release carrier.
7 . The dosage form of claim 6 wherein the controlled release carrier comprises a base material selected from the group consisting of hydrophilic polymers, hydrophobic polymers, long chain hydrocarbons, polyalkylene glycols, higher aliphatic alcohols, acrylic resins, and mixtures thereof.
8 . The dosage form of claim 1 wherein the opioid analgesic is present in an amount of from about 1 mg to about 800 mg per 70 kg body weight per unit dose and the nontoxic NMDA receptor antagonist is present in an amount of from about 100 mg to about 500 mg per 70 kg body weight per unit dose.
9 . The dosage form of claim 1 wherein the opioid analgesic is present in an amount of from about 10 mg to about 500 mg per 70 kg body weight per unit dose and the nontoxic NMDA receptor antagonist is present in an amount of from about 200 mg to about 400 mg per 70 kg body weight per unit dose.
10 . The dosage form of claim 1 wherein the opioid analgesic is selected from the group consisting of fentanyl and sufentanyl and is present in an amount of from about 5 μg to about 250 μg per 70 kg body weight per unit dose and the nontoxic NMDA receptor antagonist is present in an amount of from about 100 mg to about 500 mg per 70 kg body weight per unit dose.
11 . The dosage form of claim 6 wherein the opioid analgesic is present in an amount of from about 1 mg to about 800 mg per 70 kg body weight per unit dose and the nontoxic NMDA receptor antagonist is present in an amount of from about 100 mg to about 500 mg per 70 kg body weight per unit dose.
12 . The dosage form of claim 6 wherein the opioid analgesic is present in an amount of from about 10 mg to about 500 mg per 70 kg body weight per unit dose and the nontoxic NMDA receptor antagonist is present in an amount of from about 200 mg to about 400 mg per 70 kg body weight per unit dose.
13 . The dosage form of claim 6 wherein the opioid analgesic is selected from the group consisting of fentanyl and sufentanyl and is present in an amount of from about 5 μg to about 250 μg per 70 kg body weight per unit dose and the nontoxic NMDA receptor antagonist is present in an amount of from about 100 mg to about 500 mg per 70 kg body weight per unit dose.
14 . The dosage form of claim 7 wherein the opioid analgesic is present in an amount of from about 1 mg to about 800 mg per 70 kg body weight per unit dose and the nontoxic NMDA receptor antagonist is present in an amount of from about 100 mg to about 500 mg per 70 kg body weight per unit dose.
15 . The dosage form of claim 7 wherein the opioid analgesic is present in an amount of from about 10 mg to about 500 mg per 70 kg body weight per unit dose and the nontoxic NMDA receptor antagonist is present in an amount of from about 200 mg to about 400 mg per 70 kg body weight per unit dose.
16 . The dosage form of claim 7 wherein the opioid analgesic is selected from the group consisting of fentanyl and sufentanyl and is present in an amount of from about 5 μg to about 250 μg per 70 kg body weight per unit dose and the nontoxic NMDA receptor antagonist is present in an amount of from about 100 mg to about 500 mg per 70 kg body weight per unit dose.
17 . The dosage form of claim 1 wherein the slow-release or non-release carrier is a barrier which is slowly permeable or impermeable to the nontoxic N-methyl-D-aspartate receptor antagonist.
18 . The dosage form of claim 17 wherein the barrier is, or contains, a material selected from the group consisting of polyethylene, polypropylene, ethylene/propylene copolymer, ethylene/ethylacrylate copolymer, ethylene/vinyl acetate copolymer, silicone elastomer, medical-grade polydimethylsiloxane, neoprene rubber, polyisobutylene, chlorinated polyethylene, polyvinyl chloride, vinyl chloride-vinyl acetate copolymer, polymethacrylate polymer, polyvinylidene chloride, polyethylene terephathalate, butyl rubber, epichlorohydrin rubber, ethylene-vinyl alcohol copolymer, ethylenevinyloxyethanol copolymer, silicone copolymer, cellulose polymer, polycarbonate, polytetrafluoroethylene, starch, gelatin, natural or synthetic gum and their mixtures.
19 . The dosage form of claim 1 further comprising an isolated opioid antagonist which is substantially not released when the dosage form is administered intact.
20 . The dosage form of claim 19 wherein the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmephene, cyclazocine, levallorphan, and mixtures thereof.
21 . An abuse-resistant opioid-containing pharmaceutical solid dosage form which comprises:
a) an analgesically effective amount of at least one opioid analgesic selected from the group consisting of codeine, dihydrocodeine, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymophone, propoxyphene and their pharmaceutically acceptable salts; and,
b) an isolated amount of dextromethorphan which is substantially not released when the dosage form is administered intact, said dextromethorphan being present in an opioid euphoria-inhibiting amount.
22 . The dosage form of claim 21 wherein the opioid analgesic is in a controlled release carrier.
23 . The dosage form of claim 22 wherein the controlled release carrier is selected from the group consisting of hydrophilic polymers, hydrophobic polymers, long chain hydrocarbons, polyalkylene glycols, higher aliphatic alcohols, acrylic resins, and mixtures thereof.
24 . The dosage form of claim 21 wherein the slow-release or non-release carrier is a barrier which is slowly permeable or impermeable to the dextromethorphan.
25 . The dosage form of claim 22 wherein the slow-release or non-release carrier is a barrier which is slowly permeable or impermeable to the dextromethorphan.
26 . The dosage form of claim 23 wherein the slow-release or non-release carrier is a barrier which is slowly permeable or impermeable to the dextromethorphan.
27 . The dosage form of claim 21 wherein the opioid analgesic is present in an amount of from about 1 mg to about 800 mg per 70 kg body weight per unit dose and the dextromethorphan is present in an amount of from about 100 mg to about 500 mg per 70 kg body weight per unit dose.
28 . The dosage form of claim 21 wherein the opioid analgesic is present in an amount of from about 10 mg to about 500 mg per 70 kg body weight per unit dose and the dextromethorphan is present in an amount of from about 200 mg to about 400 mg per 70 kg body weight per unit dose.
29 . The dosage form of claim 21 wherein the opioid analgesic is selected from the group consisting of fentanyl and sufentanyl and is present in an amount of from about 5 μg to about 250 μg per 70 kg body weight per unit dose and the nontoxic NMDA receptor antagonist is present in an amount of from about 100 mg to about 500 mg per 70 kg body weight per unit dose.
30 . The dosage form of claim 22 wherein the opioid analgesic is present in an amount of from about 1 mg to about 800 mg per 70 kg body weight per unit dose and the dextromethorphan is present in an amount of from about 100 mg to about 500 mg per 70 kg body weight per unit dose.
31 . The dosage form of claim 22 wherein the opioid analgesic is present in an amount of from about 10 mg to about 500 mg per 70 kg body weight per unit dose and the dextromethorphan is present in an amount of from about 200 mg to about 400 mg per 70 kg body weight per unit dose.
32 . The dosage form of claim 22 wherein the opioid analgesic is selected from the group consisting of fentanyl and sufentanyl and is present in an amount of from about 5 μg to about 250 μg per 70 kg body weight per unit dose and the nontoxic NMDA receptor antagonist is present in an amount of from about 100 mg to about 500 mg per 70 kg body weight per unit dose.
33 . The dosage form of claim 23 wherein the opioid analgesic is present in an amount of from about 1 mg to about 800 mg per 70 kg body weight per unit dose and the dextromethorphan is present in an amount of from about 100 mg to about 500 mg per 70 kg body weight per unit dose.
34 . The dosage form of claim 23 wherein the opioid analgesic is present in an amount of from about 10 mg to about 500 mg per 70 kg body weight per unit dose and the dextromethorphan is present in an amount of from about 200 mg to about 400 mg per 70 kg body weight per unit dose.
35 . The dosage form of claim 23 wherein the opioid analgesic is selected from the group consisting of fentanyl and sufentanyl and is present in an amount of from about 5 μg to about 250 μg per 70 kg body weight per unit dose and the nontoxic NMDA receptor antagonist is present in an amount of from about 100 mg to about 500 mg per 70 kg body weight per unit dose.
36 . The dosage form of claim 21 further comprising an isolated opioid antagonist which is substantially not released when the dosage form is administered intact.
37 . The dosage form of claim 36 wherein the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmephene, cyclazocine, levallorphan, and mixtures thereof.
38 . A solid opioid-containing pharmaceutical solid dosage form which is resistant to abuse by intranasal administration which comprises:
a) an analgesically effective amount of opioid analgesic; and,
b) an isolated nontoxic N-methyl-D-aspartate receptor antagonist which is substantially not released when the dosage form is administered intact but is released in a nasal mucosa-irritating amount when the dosage form is crushed or dissolved and then administered intranasally.
39 . The dosage form of claim 38 wherein the opioid analgesic is at least one member selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanyl, tilidine, tramadol and their pharmaceutically acceptable salts.
40 . The dosage form of claim 38 herein the opioid analgesic is at least one member selected from the group consisting of codeine, dihydrocodeine, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene and their pharmaceutically acceptable salts.
41 . The dosage form of claim 38 herein the nontoxic NMDA receptor antagonist is at least one member selected from the group consisting of dextromethorphan, dextrorphan, memantine, amantidine, d-methadone and their pharmaceutically acceptable salts.
42 . The dosage form of claim 40 wherein the nontoxic NMDA receptor antagonist is at least one member selected from the group consisting of dextromethorphan, dextrorphan, memantine, amantidine, d-methadone and their pharmaceutically acceptable salts.
43 . The dosage form of claim 38 wherein the opioid analgesic is present in an amount of from about 1 mg to about 800 mg per 70 kg body weight per unit dose and the nontoxic NMDA receptor antagonist is present in an amount of from about 100 mg to about 500 mg per 70 kg body weight per unit dose.
44 . The dosage form of claim 38 wherein the opioid analgesic is present in an amount of from about 10 mg to about 500 mg per 70 kg body weight per unit dose and the nontoxic NMDA receptor antagonist is present in an amount of from about 200 mg to about 400 mg per 70 kg body weight per unit dose.
45 . The dosage form of claim 38 wherein the opioid analgesic is selected from the group consisting of fentanyl and sufentanyl and is present in an amount of from about 5 μg to about 250 μg per 70 kg body weight per unit dose and the nontoxic NMDA receptor antagonist is present in an amount of from about 100 mg to about 500 mg per 70 kg body weight per unit dose.