Pharmaceutical formulation containing opioid agonist, opioid antagonist and gelling agent

• US 7,842,307 B2
• Filed: 08/06/2002
• Issued: 11/30/2010
• Est. Priority Date: 08/06/2001
• Status: Expired due to Term

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Purdue Pharma L.P.
• Inventors: Wright, Curtis, Oshlack, Benjamin, Breder, Christopher
• Primary Examiner(s): Kishore; Gollamudi S
• Assistant Examiner(s): Maewall; Snigdha
• Application Number:
  US10/214,413
• Publication Number:
  US 20030068371A1
• Time in Patent Office: 3,038 Days
• Field of Search: 424/434, 424/450, 424/464, 424/468
• US Class Current: 424/450
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/1635 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 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/205 Polysaccharides, e.g. alginate, gums; Cyclodextrin
• CPC Class Codes: A61K 9/2081 with microcapsules or coated microparticles according to A61K9/50
• CPC Class Codes: A61K 9/5078 with drug-free core
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/36 Opioid-abuse

Abstract

Disclosed in certain embodiments is an oral dosage form comprising a therapeutically effective amount of an opioid analgesic, an opioid antagonist and one or more pharmaceutically acceptable excipients; the dosage form further including a gelling agent in an effective amount to impart a viscosity unsuitable for administration selected from the group consisting of parenteral and nasal administration to a solubilized mixture formed when the dosage form is crushed and mixed with from about 0.5 to about 10 ml of an aqueous liquid.

Claims

1. An oral dosage form comprising:

(a) a therapeutically effective amount of an opioid analgesic selected from the group consisting of morphine, hydromorphone, hydrocodone, oxycodone, codeine, levorphanol, meperidine, dihydrocodeine, dihydromorphine, oxymorphone, pharmaceutically acceptable salts thereof and mixtures thereof;

(b) an agent selected from the group consisting of sugars, sugar derived alcohols, starch, starch derivatives, cellulose derivatives, attapulgites, bentonites, dextrins, alginates, carrageenan, gums, pectins, gelatin, kaolin, lecithin, magnesium aluminum silicate, carbomers carbopols, polyvinylpyrrolidone, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, silicon dioxide, curdlan, furcelleran, egg white powder, lacto albumin, soy protein, chitosan, surfactants emylsifiers and mixtures thereof,

wherein the ratio of the agent to the opioid analgesic is from about 1;

1 to about 30;

1 by weight,

the opioid analgesic and the agent are dispersed in the same controlled release matrix comprising a controlled release material,

the agent is in an effective amount to impart a viscosity to a mixture formed when the dosage form is crushed and mixed with from about 0.5 to about 10 ml of an aqueous liquid to render the mixture unsuitable for parenteral and nasal administration, and

the inclusion of the agent into the oral dosage form does not substantially change the dissolution rate of the opioid analgesic, as compared to said dosage form without the agent; and

(c) particles of a sequestered opioid antagonist, the particles consisting of the opioid antagonist, a hydrophobic material and one or more additional pharmaceutically acceptable excipients, wherein

the hydrophobic material is selected from the group consisting of a cellulose polymer, an acrylic polymer, a polylactic acid, polyglycolic acid and a copolymer of the polylactic and polyglycolic acid, and is in an effective amount to prevent the release of the antagonist from the dosage form which has been orally administered intact such that the antagonist is not released or substantially not released within 4, 8, 12 and 24 hours after the oral dosage form has been administered orally intact

but is released in an amount that will substantially block an analgesic effect of the opioid analgesic when the oral dosage form has been tampered with and administered orally, intranasally, parenterally or sublingually,

the dosage form providing pain relief for at least about 12 hours when orally administered intact to a human patient.

2. The oral dosage form of claim 1, wherein said opioid analgesic is selected from the group consisting of levorphanol, meperidine, dihydrocodeine, dihydromorphine, pharmaceutically acceptable salts thereof, and mixtures thereof.

3. The oral dosage form of claim 1, wherein said opioid analgesic is morphine or a pharmaceutically acceptable salt thereof.

4. The oral dosage form of claim 1, wherein said opioid analgesic is hydromorphone or a pharmaceutically acceptable salt thereof

5. The oral dosage form of claim 1, wherein said opioid analgesic is hydrocodone or a pharmaceutically acceptable salt thereof.

6. The oral dosage form of claim 1, wherein said opioid analgesic is oxycodone or a pharmaceutically acceptable salt thereof.

7. The oral dosage form of claim 1, wherein said opioid analgesic is codeine or a pharmaceutically acceptable salt thereof

8. The oral dosage form of claim 1, wherein said opioid analgesic is oxymorphone or a pharmaceutically acceptable salt thereof.

9. The oral dosage form of claim 1, wherein said ratio of said agent to said opioid analgesic is from about 2:

1 to about 10;

1.

10. The oral dosage form of claim 1, wherein said agent is selected from the group consisting of sugars, sugar derived alcohols, cellulose derivatives, gums, surfactants, emulsifying agents, and mixtures thereof.

11. The oral dosage form of claim 1, wherein said gums are selected from the group consisting of acacia, agar, tragacanth, guar gum, xanthan gum, locust bean gum, tara gum, karaya, gellan gum, welan gum, and rhamsan gum.

12. The oral dosage form of claim 1, wherein said agent is xanthan gum.

13. The oral dosage form of claim 1, wherein said unsuitable viscosity is attained when about 1 to about 3 ml of the aqueous liquid is mixed with the crushed dosage form.

18. The oral dosage form of claim 1, wherein said tampering is by means of crushing, shearing, grinding, chewing or dissolution in a solvent in combination with heating.

19. The oral dosage form of claim 1, wherein the amount of the opioid antagonist released from the oral dosage form which has been tampered with will reduce or eliminate a euphoric effect of the opioid analgesic.

20. The oral dosage form of claim 1, wherein oral administration of the intact dosage form does not pose a risk of precipitation of withdrawal in opioid tolerant or dependent patients.

27. The oral dosage form of claim 1, wherein the amount of the opioid antagonist released from the oral dosage form which has been tampered with will block an analgesic effect of the opioid analgesic when the tampered dosage form has been administered intranasally, parenterally or sublingually.

30. The dosage form of claim 1, wherein said cellulose derivatives are selected from the group consisting of microcrystalline cellulose, sodium carboxymethyl cellulose, ethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, ethylhydroxyethyl cellulose and ether derivatives of cellulose.

31. The dosage form of claim 1, wherein said agent is polyethylene oxide.

32. The dosage form of claim 1, wherein said hydrophobic material is an acrylic polymer.

33. The dosage form of claim 1, wherein said hydrophobic material is a cellulose polymer.

14. A method of minimizing abuse of an oral dosage form of an opioid analgesic comprising:

preparing the dosage form comprising

(a) an analgesically effective amount of an opioid analgesic selected from the group consisting of morphine, hydromorphone, hydrocodone, oxycodone, codeine, levorphanol, meperidine, dihydrocodeine, dihydromorphine, oxymorphone, pharmaceutically acceptable salts thereof and mixtures thereof;

(b) an agent selected from the group consisting of sugars, sugar derived alcohols, starch, starch derivatives, cellulose derivatives, attapulgites, bentonites, dextrins, alginates, carrageenan, gums, pectins, gelatin, kaolin, lecithin, magnesium aluminum silicate, carbomers, carbopols, polyvinylpyrrolidone, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, silicon dioxide, curdlan, furcelleran, egg white powder, lacto albumin, soy protein, chitosan, pullulan, polylaevulan, surfactants, emylsifiers and mixtures thereof,

wherein the ratio of the agent to the opioid analgesic is from about 1;

1 to about 30;

1 by weight,

the opioid analgesic and the gelling agent are dispersed in the same controlled release matrix comprising a controlled release material,

the agent is in an effective amount to impart a viscosity to a mixture formed when the dosage form is crushed and mixed with from about 0.5 to about 10 ml of an aqueous liquid to render the mixture unsuitable for parenteral and nasal administration,

and the inclusion of the agent into the oral dosage form does not substantially change the dissolution rate of the opioid analgesic, as compared to said dosage form without the agent; and

(c) particles of a sequestered opioid antagonist, the particles consisting of the opioid antagonist, a hydrophobic material and one or more additional pharmaceutically acceptable excipients

wherein the hydrophobic material is selected from the group consisting of a cellulose polymer, an acrylic polymer, a polylactic acid, polyglycolic acid and a copolymer of the polylactic and polyglycolic acid, and is in an effective amount to prevent the release of the antagonist from the dosage form which has been orally administered intact such that the antagonist is not released or substantially not released within 4, 8, 12 and 24 hours after the oral dosage form has been administered orally intact

but is released in an amount that will substantially block an analgesic effect of the opioid analgesic when the oral dosage form has been tampered with and administered orally, intranasally, parenterally or sublingually;

the dosage form providing pain relief for at least about 12 hours when orally administered intact to a human patient.

15. The method of claim 14, wherein the addition of from about 0.5 to about 10 ml of said aqueous liquid causes said solubilized mixture to have a viscosity of at least about 60 cP.

16. The method of claim 14, wherein said agent is selected from the group consisting of sugars or sugar derived alcohols, cellulose derivatives, gums, surfactants, emulsifying agents, and mixtures thereof.

21. The method of claim 14, wherein said tampering is by means of crushing, shearing, grinding, chewing or dissolution in a solvent in combination with heating.

22. The method of claim 14, wherein the amount of the opioid antagonist released from the oral dosage form which has been tampered with will reduce or eliminate a euphoric effect of the opioid analgesic.

23. The method of claim 14, wherein oral administration of the intact dosage form does not pose a risk of precipitation of withdrawal in opioid tolerant or dependent patients.

28. The method of claim 14, wherein the amount of the opioid antagonist released from the oral dosage form which has been tampered with will block an analgesic effect of the opioid analgesic when the tampered dosage form has been administered intranasally, parenterally or sublingually.

34. The method of claim 14, wherein said gums are selected from the group consisting of acacia, agar, tragacanth, guar gum, xanthan gum, locust bean gum, tara gum, karaya, gellan gum, welan gum, and rhamsan gum.

35. The method of claim 14, wherein said cellulose derivatives are selected from the group consisting of microcrystalline cellulose, sodium carboxymethyl cellulose, ethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, ethylhydroxyethyl cellulose and ether derivatives of cellulose.

36. The method of claim 14, wherein said agent is polyethylene oxide.

37. The method of claim 14, wherein said hydrophobic material is an acrylic polymer.

38. The method of claim 14, wherein said hydrophobic material is a cellulose polymer.

17. A method of treating pain comprising:

administering to a patient an oral dosage form comprising

(a) a therapeutically effective amount of an opioid analgesic selected from the group consisting of morphine, hydromorphone, hydrocodone, oxycodone, codeine, levorphanol, meperidine, dihydrocodeine, dihydromorphine, oxymorphone, pharmaceutically acceptable salts thereof and mixtures thereof;

(b) an agent selected from the group consisting of sugars, sugar derived alcohols, starch, starch derivatives, cellulose derivatives, attapulgites, bentonites, dextrins, alginates, carrageenan, gums, pectins, gelatin, kaolin, lecithin, magnesium aluminum silicate, carbomers, carbopols, polyvinylpyrrolidone, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, silicon dioxide, curdlan, furcelleran, egg white powder, lacto albumin, soy protein, chitosan, pullulan, polylaevulan, surfactants, emylsifiers and mixtures thereof,

wherein the ratio of the agent to the opioid analgesic is from about 1;

1 to about 30;

1 or is from about 2;

1 to about 10;

1 by weight,

the opioid analgesic and the agent are dispersed in the same controlled release matrix comprising a controlled release material,

the agent is in an effective amount to impart a viscosity to a mixture formed when the dosage form is crushed and mixed with from about 0.5 to about 10 ml of an aqueous liquid to render the mixture unsuitable for parenteral and nasal administration, and

the inclusion of the agent into the oral dosage form does not substantially change the dissolution rate of the opioid analgesic, as compared to said dosage form without the agent; and

(c) particles of a sequestered opioid antagonist, the particles consisting of the opioid antagonist, hydrophobic material and one or more additional pharmaceutically acceptable excipients

wherein the hydrophobic material is selected from the group consisting of a cellulose polymer, an acrylic polymer, a polylactic acid, polyglycolic acid and copolymer of the polylactic and polyglycolic acid, and is in an effective amount to prevent the release of the antagonist from the dosage form which has been orally administered intact such that the antagonist is not released or substantially not released within 4, 8, 12 and 24 hours after the oral dosage form has been administered orally intact

but is released in an amount that will substantially block an analgesic effect of the opioid analgesic when the oral dosage form has been tampered with and administered orally, intranasally, parenterally or sublingually;

the dosage form providing effective pain relief for at least about 12 hours when orally administered intact to a human patient.

24. The method of claim 17, wherein said tampering is by means of crushing, shearing, grinding, chewing or dissolution in a solvent in combination with heating.

25. The method of claim 17, wherein the amount of the opioid antagonist released from the oral dosage form which has been tampered with will reduce or eliminate a euphoric effect of the opioid analgesic.

26. The method of claim 17, wherein oral administration of the intact dosage form does not pose a risk of precipitation of withdrawal in opioid tolerant or dependent patients.

29. The method of claim 17, wherein the amount of the opioid antagonist released from the oral dosage form which has been tampered with will block an analgesic effect of the opioid analgesic when the tampered dosage form has been administered intranasally, parenterally or sublingually.

39. The method of claim 17, wherein said gums are selected from the group consisting of acacia, agar, tragacanth, guar gum, xanthan gum, locust bean gum, tara gum, karaya, gellan gum, welan gum, and rhamsan gum.

40. The method of claim 17, wherein said cellulose derivatives are selected from the group consisting of microcrystalline cellulose, sodium carboxymethyl cellulose, ethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, ethylhydroxyethyl cellulose and ether derivatives of cellulose.

41. The method of claim 17, wherein said agent is polyethylene oxide.

42. The method of claim 17, wherein said hydrophobic material is an acrylic polymer.

43. The method of claim 17, wherein said hydrophobic material is a cellulose polymer.