Tamper-resistant oral opioid agonist formulations

• US 6,696,088 B2
• Filed: 02/08/2001
• Issued: 02/24/2004
• Est. Priority Date: 02/08/2000
• Status: Expired due to Term

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Euroceltique SA
• Inventors: Wright, Curtis, Haddox, J. David, Oshlack, Benjamin
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Sheikh, Humera N.
• Application Number:
  US09/781,081
• Publication Number:
  US 20030143269A1
• Time in Patent Office: 1,111 Days
• Field of Search: 424/400, 424/451, 424/464, 424/488, 424/490, 424/491, 424/465, 424/489
• US Class Current: 424/465
• 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, such that the ratio of the amount of antagonist released from said dosage form after tampering to the amount of said antagonist released from said intact dosage form is about 4:1 or greater, based on the in-vitro dissolution at 1 hour of said dosage form in 900 ml of Simulated Gastric Fluid using a USP Type II (paddle) apparatus at 75 rpm at 37 degrees C. wherein said agonist and antagonist are interdispersed and are not isolated from each other in two distinct layers.

Claims

1. An oral dosage form comprising:

(a) an opioid agonist;

(b) an opioid antagonist; and

(c) means for sequestering the opioid antagonist in an intact dosage form,

wherein the intact dosage form releases 36% or less of the antagonist after 36 hours based on the in-vitro dissolution of the dosage form in 900 ml of Simulated Gastric Fluid using a USP Type II (paddle) apparatus at 75 rpm and 37 degrees C. with a switch to Simulated Intestinal Fluid at 1 hour.

5. The oral dosage form of any of claims 1-4, 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, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl 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, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts thereof, stereoisomers thereof, ethers thereof, esters thereof, and mixtures thereof.

6. The oral dosage form of any of claims 1-4, wherein the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmefene, cyclazacine, levallorphan pharmaceutically acceptable salts thereof, stereoisomers thereof, ethers thereof, esters thereof, and mixtures thereof.

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

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

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

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

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

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

13. The oral dosage form of claim 6, wherein the opioid antagonist is naltrexone or a pharmaceutically acceptable salt thereof.

14. The oral dosage form of claim 7, wherein the opioid antagonist is naltrexone or a pharmaceutically acceptable salt thereof.

15. The oral dosage form of claim 8, wherein the opioid antagonist is naltrexone or a pharmaceutically acceptable salt thereof.

16. The oral dosage form of claim 9, wherein the opioid antagonist is naltrexone or a pharmaceutically acceptable salt thereof.

17. The oral dosage form of claim 10, wherein the opioid antagonist is naltrexone or a pharmaceutically acceptable salt thereof.

18. The oral dosage form of claim 11, wherein the opioid antagonist is naltrexone or a pharmaceutically acceptable salt thereof.

19. The oral dosage form of claim 12, wherein the opioid antagonist is naltrexone or a pharmaceutically acceptable salt thereof.

20. The oral dosage form of claim 6, wherein the opioid antagonist is naloxone or a pharmaceutically acceptable salt thereof.

21. The oral dosage form of claim 7, wherein the opioid antagonist is naloxone or a pharmaceutically acceptable salt thereof.

22. The oral dosage form of claim 8, wherein the opioid antagonist is naloxone or a pharmaceutically acceptable salt thereof.

23. The oral dosage form of claim 9, wherein the opioid antagonist is naloxone or a pharmaceutically acceptable salt thereof.

24. The oral dosage form of claim 10, wherein the opioid antagonist is naloxone or a pharmaceutically acceptable salt thereof.

25. The oral dosage form of claim 11, wherein the opioid antagonist is naloxone or a pharmaceutically acceptable salt thereof.

26. The oral dosage form of claim 12, wherein the opioid antagonist is naloxone or a pharmaceutically acceptable salt thereof.

27. The oral dosage form of claim 6, wherein the opioid antagonist is nalmefene or a pharmaceutically acceptable salt thereof.

28. The oral dosage form of claim 7, wherein the opioid antagonist is nalmefene or a pharmaceutically acceptable salt thereof.

29. The oral dosage form of claim 8, wherein the opioid antagonist is nalmefene or a pharmaceutically acceptable salt thereof.

30. The oral dosage form of claim 9, wherein the opioid antagonist is nalmefene or a pharmaceutically acceptable salt thereof.

31. The oral dosage form of claim 10, wherein the opioid antagonist is nalmefene or a pharmaceutically acceptable salt thereof.

32. The oral dosage form of claim 11, wherein the opioid antagonist is nalmefene or a pharmaceutically acceptable salt thereof.

33. The oral dosage form of claim 12, wherein the opioid antagonist is nalmefene or a pharmaceutically acceptable salt thereof.

34. The oral dosage form of any of claims 1-4, wherein the ratio of the opioid agonist to the opioid antagonist is about 1:

1 to about 50;

1.

35. The oral dosage form of claim 5, wherein the ratio of the opioid agonist to the opioid antagonist is about 1:

1 to about 50;

1.

36. The oral dosage form of claim 6, wherein the ratio of the opioid agonist to the opioid antagonist is about 1:

1 to about 50;

1.

37. The oral dosage form of claim 34, wherein the ratio of the opioid agonist to the opioid antagonist is about 1:

1 to about 20;

1.

38. The oral dosage form of claim 34, wherein the ratio of the opioid agonist to the opioid antagonist is about 15:

1 to about 30;

1.

39. The oral dosage form of any of claims 1-4, wherein the means for sequestering comprises a layer comprising a hydrophobic material.

40. A method for treating pain, comprising administering to a human patient in need thereof an effective amount of the oral dosage form of any of claims 1-4.

2. An oral dosage form comprising:

(a) an opioid agonist;

(b) an opioid antagonist; and

(c) means for sequestering the opioid antagonist in an intact dosage form,

wherein the intact dosage form releases 24.6% or less of the antagonist after 36 hours based on the in-vitro dissolution of the dosage form in 900 ml of Simulated Gastric Fluid using a USP Type II (paddle) apparatus at 75 rpm and 37 degrees C. with a switch to Simulated Intestinal Fluid at 1 hour.

3. An oral dosage form comprising:

(a) an opioid agonist;

(b) an opioid antagonist; and

(c) means for sequestering the opioid antagonist in an intact dosage form,

wherein the intact dosage form releases 10% or less of the antagonist after 36 hours based on the in-vitro dissolution of the dosage form in 900 ml of Simulated Gastric Fluid using a USP Type II (paddle) apparatus at 75 rpm and 37 degrees C. with a switch to Simulated Intestinal Fluid at 1 hour.

4. An oral dosage form comprising:

(a) an opioid agonist;

(b) an opioid antagonist; and

(c) means for sequestering the opioid antagonist in an intact dosage form,

wherein the intact dosage form releases 6.2% or less of the antagonist after 36 hours based on the in-vitro dissolution of the dosage form in 900 ml of Simulated Gastric Fluid using a USP Type II (paddle) apparatus at 75 rpm and 37 degrees C. with a switch to Simulated Intestinal Fluid at 1 hour.