Tamper-resistant oral opioid agonist formulations

• US 7,658,939 B2
• Filed: 11/04/2003
• Issued: 02/09/2010
• Est. Priority Date: 02/08/2000
• Status: Expired due to Term

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Purdue Pharma L.P.
• Inventors: Wright, Curtis, Oshlack, Benjamin, Haddox, J. David
• Primary Examiner(s): Richter; Johann R
• Assistant Examiner(s): ALSTRUM ACEVEDO, JAMES HENRY
• Application Number:
  US10/701,041
• Publication Number:
  US 20050095291A1
• Time in Patent Office: 2,289 Days
• Field of Search: None
• US Class Current: 424/420
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61K 9/02 Suppositories; Bougies; Bases therefor; Ovulesapparatus for making A61J3/08; devices for introducing into the body A61M31/00
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/1676 having a drug-free core with discrete complete coating layer containing drug adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/2081 with microcapsules or coated microparticles according to A61K9/50
• CPC Class Codes: A61K 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/50 Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals A61K9/2081 takes precedence; particles with a single coating comprising drug A61K9/167
• CPC Class Codes: A61K 9/501 Inorganic compounds
• CPC Class Codes: A61K 9/5015 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5078 : with drug-free core
• CPC Class Codes: A61K 9/5084 : Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077
• CPC Class Codes: A61K 9/51 : Nanocapsules; Nanoparticles; nanotubes A61K9/0092; polymeric micelles A61K9/1075; polymersomes A61K9/1273; pure drug nanoparticles A61K9/14; drug nanoparticles with adsorbed surface modifiers A61K9/141; conjugates, e.g. between drug and non-active nanoparticles, A61K47/50; preparations for in vivo diagnosis A61K49/00; with radioactive substances A61K51/00
• CPC Class Codes: A61K 9/7053 : obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
• CPC Class Codes: A61K 9/7061 : Polyacrylates
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 : Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/36 : Opioid-abuse
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 39/00 : General protective or antinoxious agents
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Disclosed is an oral dosage form comprising (i) an opioid agonist in releasable form and (ii) a sequestered opioid antagonist which is substantially not released when the dosage form is administered intact.

Claims

1. An opioid antagonist composition comprising an inert core, a first layer and a second layer, the first layer being between the core and the second layer, the first layer consisting of the opioid antagonist, and the second layer comprising a hydrophobic material,

wherein the hydrophobic material sequesters the opioid antagonist such that

an amount of the antagonist released from the composition which has been administered intact is bioequivalent to 0.125 mg naltrexone or less, based on the in-vitro dissolution at 1 hour of the composition in 900 ml of Simulated Gastric Fluid using a USP Type II (paddle) apparatus at 75 rpm at 37°

C., and

less than 15% by weight of the opioid antagonist is released within 36 hours from the intact composition, based on the in-vitro dissolution in a dissolution bath, and the composition is free from an opioid agonist.

3. The composition of claims 1 or 2, wherein the composition comprises from about 12% to about 15% hydrophobic material by weight of the composition.

4. An oral dosage form comprising an opioid agonist and the opioid antagonist composition of claim 1, wherein the hydrophobic material separates the opioid antagonist from the opioid agonist.

5. The oral dosage form of claim 4, wherein the opioid agonist is alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitraminde, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, noylevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, prophetazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts or mixtures thereof.

6. The oral dosage form of claim 5, wherein the opioid agonist is oxycodone or a pharmaceutically acceptable salt thereof.

7. The oral dosage form of claim 5, wherein the opioid agonist is hydrocodone or a pharmaceutically acceptable salt thereof.

8. An oral dosage form comprising an opioid agonist and the opioid antagonist composition of claim 1 comprising from about 14% to about 22% of the hydrophobic material by weight of the oral dosage form, wherein the hydrophobic material separates the opioid antagonist from the opioid agonist.

9. The oral dosage form of claim 8, wherein the opioid agonist is alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitraminde, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, novlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, prophetazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts or mixtures thereof.

10. The oral dosage form of claim 4 wherein the opioid antagonist is naltrexone, naloxone, nalmefene, cyclazacine, levallorphan, a pharmaceutically acceptable salt or a mixture thereof.

11. The oral dosage form of claim 8, wherein the opioid antagonist is naltrexone, naloxone, nalmefene, cyclazacine, levallorphan, a pharmaceutically acceptable salt or a mixture thereof.

12. A method for treating pain, comprising administering to a human patient in need thereof an oral dosage form comprising an effective amount of an opioid agonist and the opioid antagonist composition of claim 1.

13. A method for treating pain, comprising administering to a human patient in need thereof an oral dosage form comprising an effective amount of an opioid agonist and the opioid antagonist composition of claim 1 comprising from about 14% to about 22% of the hydrophobic material by weight of the oral dosage form.

14. The opioid antagonist composition of claim 1, wherein the hydrophobic material sequesters the opioid antagonist such that, upon inclusion into a solid oral dosage form containing an opioid agonist, an amount of the opioid antagonist released from the solid oral dosage form which has been orally administered intact is insufficient to produce an antagonistic effect of the opioid antagonist in a human patient.

15. The opioid antagonist composition of claim 14, wherein the hydrophobic material sequesters the opioid antagonist such that an amount of the opioid antagonist released from the solid oral dosage which has been tampered with and administered orally, intranasally, parenterally or sublingually will substantially block an effect of the opioid agonist.

18. The opioid antagonist composition of claim 1, wherein the hydrophobic material sequesters the opioid antagonist such that, upon inclusion into a solid oral dosage form, the ratio of the amount of antagonist released from the dosage form after tampering to the amount of the antagonist released from the intact dosage form is about 4:

1 or greater, based on the in-vitro dissolution at 1 hour of the composition in 900 ml of Simulated Gastric Fluid using a USP Type II (paddle) apparatus at 75 rpm at 37°

C.

19. The opioid antagonist composition of claim 18, wherein the tampering is by crushing, shearing, grinding, chewing, dissolving in a solvent, heating, or any combination thereof.

22. The opioid antagonist composition of any one of claims 1, 2, 3, 14, 15, 16, or 17, wherein the intact composition releases at least 0.025 mg of naltrexone or a bioequivalent dose of another antagonist at 1 hour, based on the in-vitro dissolution at 1 hour of the dosage form in 900 ml of Simulated Gastric Fluid using a USP Type II (paddle) apparatus at 75 rpm at 37°

C.

23. The opioid antagonist composition of any one of claims 1, 2, 3, 14, 15, 16, or 17, wherein an amount of the antagonist released at 1, 2, 4 and 12 hours from the intact composition, based on the in-vitro dissolution in a dissolution bath, is undetectable by High Performance Liquid Chromatography.

24. The opioid antagonist composition of claim 23, wherein the second layer further comprises talc.

2. An opioid antagonist composition comprising an inert core, a first layer and a second layer, the first layer being between the core and the second layer, the first layer comprising naltrexone, nalmefene, or pharmaceutically acceptable salts thereof, and the second layer comprising a hydrophobic material,

wherein the hydrophobic material sequesters naltrexone, nalmefene or pharmaceutically acceptable salts thereof such that

an amount of the antagonist released from the composition which has been administered intact is bioequivalent to 0.125 mg naltrexone or less, based on the in-vitro dissolution at 1 hour of the composition in 900 ml of Simulated Gastric Fluid using a USP Type II (paddle) apparatus at 75 rpm at 37°

C., and less than 15% by weight of the opioid antagonist is released within 36 hours from the intact composition, based on the in-vitro dissolution in a dissolution bath, and the composition is free from an opioid agonist.

16. The opioid antagonist composition of claim 2, wherein the hydrophobic material sequesters naltrexone, nalmefene, or pharmaceutically acceptable salts thereof such that, upon inclusion into a solid oral dosage form containing an opioid agonist, an amount of naltrexone, nalmefene, or pharmaceutically acceptable salts thereof released from the solid oral dosage form which has been orally administered intact is insufficient to produce an effect of the naltrexone, nalmefene, or pharmaceutically acceptable salts thereof in a human patient.

17. The opioid antagonist composition of claim 16, wherein the hydrophobic material sequesters naltrexone, nalmefene, or pharmaceutically acceptable salts thereof such that the amount of naltrexone, nalmefene, or pharmaceutically acceptable salts thereof released from the solid oral dosage form which has been tampered with and administered orally, intranasally, parenterally or sublingually will substantially block an effect of the opioid agonist.

20. The opioid antagonist composition of claim 2, wherein the hydrophobic material sequesters naltrexone, nalmefene, or pharmaceutically acceptable salts thereof such that, upon inclusion into a solid oral dosage form, the ratio of the amount of naltrexone, nalmefene, or pharmaceutically acceptable salts thereof released from the dosage form after tampering to the amount of naltrexone, nalmefene, or pharmaceutically acceptable salts thereof released from the intact dosage form is about 4:

1 or greater, based on the in-vitro dissolution at 1 hour of the composition in 900 ml of Simulated Gastric Fluid using a USP Type II (paddle) apparatus at 75 rpm at 37°

C.

21. The opioid antagonist composition of claim 20, wherein the tampering is by crushing, shearing, grinding, chewing, dissolving in a solvent, heating, or any combination thereof.