ABUSE RESISTANT DRUG FORMS

• US 20140127300A1
• Filed: 07/02/2012
• Published: 05/08/2014
• Est. Priority Date: 06/30/2011
• Status: Abandoned Application

• Current Assignee: NEOS Therapeutics Incorporated
• Original Assignee: NEOS Therapeutics Incorporated
• Inventors: Tengler, Mark, McMahen, Russell
• Application Number:
  US14/128,750
• Publication Number:
  US 20140127300A1
• Time in Patent Office: Days
• US Class Current: 424/487
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• 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: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/36 Opioid-abuse

Abstract

The invention is directed to oral drug dosage forms designed to reduce the abuse potential of an oral dosage form of an opioid analgesic. The oral drug dosage form comprises a first population of drug-resin complex particles comprising an analgesically effective amount of an opioid drug, said first population of particles coated with a water-permeable diffusion barrier coating. The oral drug dosage form further comprises a second population of ion exchange-resin complex particles comprising an aversive agent, said second population of particles coated with a polymer coating sufficient to substantially prevent release of the aversive agent under normal use conditions. The aversive agent is present in an amount effective to partially or substantially deny the drug abuser the euphoric effect and/or cause an aversive effect in the user.

Claims

1. A sustained-release, abuse-resistant oral drug dosage form comprising at least two populations of drug-resin complex particles, wherein the first population of drug-resin complex particles is a sustained-release form comprising an analgesically effective amount of an opioid drug bound to a water-insoluble, pharmacologically inert matrix, said first population of drug-resin complex particles further comprising a water-permeable coating, and wherein the second population of drug-resin complex particles comprises an aversive agent in an amount sufficient to deter abuse if tampered with and a polymeric coating sufficient to substantially prevent release of the aversive agent under normal use conditions.

2. The drug dosage form of claim 1, wherein the opioid drug is selected from the group consisting of:

alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diamorphone, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, etorphine, dihydroetorphine, ethotheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metop on, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, prop eridine, propiram, propoxyphene, sufentanil, tramadol, tilidine, and mixtures of one or more of any of the foregoing.

3. The drug dosage form of claim 2, wherein the opioid drug is oxycodone, morphine (sulfate), oxycodone/acetaminophen, hydromorphone, tramadol hydrochloride, hydrocodone/acetaminophen, or codeine.

4. The drug dosage form of claim 2, wherein the opioid drug is in a salt form.

5. The drug dosage form of claim 1, wherein said aversive agent is an opioid antagonist selected from the group consisting of:

naltrexone, nalmefene, cyclazacine, levallorphan, dextromethorphan ((+)-3-hydroxy-N-methylmorphinan), its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), amantadine (1-amino adamantine), memantine (3,5 dimethylaminoadamantone), d-methadone (d-form of 6-dimethylamino-4, 4-diphenyl-3-heptanone hydrochloride), naloxone, etorphine, dihydroetorphine, and mixtures of one or more of any of the foregoing.

6. The drug dosage form of claim 1, wherein the opioid drug is prepared to include both a sustained release formulation and an immediate release formulation.

7. The drug dosage form of claim 1, wherein the drug-resin complex particles comprise a synthetic resin.

8. The drug dosage form of claim 1, wherein the drug-resin complex particles comprise a semi-synthetic resin.

9. The drug dosage form of claim 1, wherein the drug-resin complex particles are 30 to 500 microns in size.

10. The drug dosage form of claim 9, wherein the drug-resin complex particles are 40 to 150 microns in size.

11. The drug dosage form of claim 1, wherein the drug-resin complex particles are regularly shaped.

12. The drug dosage form of claim 1, wherein the first and second populations of drug-resin complex particles are substantially similar in one or more of size, color, appearance, and texture.

13. The drug dosage form of claim 1, wherein the first population of drug-resin complex particles comprises an enteric coating.

14. The drug dosage form of claim 1, wherein one or both of the populations of drug-resin complex particles further comprise a humectant.

15. The drug dosage form of claim 14, wherein the humectant is selected from the group consisting of:

polyethylene glycol, propylene glycol, lactose, methylcellulose, hydroxypropylmethylcellulose, sorbitol, mannitol, polyvinylpyrrolidone, carboxypolymethylene, xanthan gum, propylene glycol, alginate, and mixtures of one or more of any of the foregoing.

16. The drug dosage form of claim 1, wherein the first population of drug-resin complex particles further comprises unbound opioid drug.

17. The drug dosage form of claim 1, wherein the first population of drug-resin complex particles comprises opioid drug at a concentration to provide about 1 mg to about 800 mg of opioid drug per 70 kg patient in a single dose.

18. The drug dosage form of claim 17, wherein the first population of drug-resin complex particles comprises opioid drug to provide about 10 mg to about 500 mg of opioid drug per 70 kg patient in a single dose.

19. The drug dosage form of claim 1, wherein the opioid drug is loaded onto the first population of drug-resin complex particles at a concentration of about 30% to about 60% by weight.

20. The drug dosage form of claim 1, wherein the water-permeable polymer coating is selected from the group consisting of:

ethylcellulose, methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxyethlycellulose (HEC), acrylic acid ester, cellulose acetate phthalate, HEC phthalate, HPMC phthalate, and mixtures thereof.

21. The drug dosage form of claim 1, wherein the second population of particles further comprises one or more chelating agents.

22. The drug dosage form of claim 21, wherein the one or more chelating agents are administered between two coating layers covering the aversive agent.

23. The drug dosage form of claim 22, wherein the two coating layers covering the aversive agent comprise the same polymer coating.

24. The drug dosage form of claim 22, wherein the two coating layers covering the aversive agent comprise different polymer coatings.

25. The drug dosage form of claim 22, wherein the one or more chelating agents are selected from the group consisting of:

EDTA, edetate calcium disodium, edetate trisodium, edetate disodium, edetate sodium, desferrioxamine B, deferoxamine, dithiocarb sodium, penicillamine, pentetate calcium, sodium salts of pentetic acid, succimer, trientine, nitrilotriacetic acid, trans-diaminocyclohexanetetraacetic acid (DCTA), diethylenetriaminepentaacetic acid, bis(aminoethyl)glycolether-N,N,N′

,N′

-tetraacetic acid, iminodiacetic acid, citric acid, tartaric acid, fumaric acid, salts thereof, and mixtures or combinations thereof.

26. The drug dosage form of claim 1, wherein the form is prepared as a liquid form.

27. The drug dosage form of claim 1, wherein the form is prepared as a tablet form, a capsule form, an orally disintegrating tablet (ODT) form, or a sprinkle form.

28. The drug dosage form of claim 1, wherein the drug dosage form is finally formulated.

29. A method of treating pain in an individual comprising administering the drug dosage form according to claim 1 to a subject in need thereof.

30. A method of preventing drug abuse, comprising administering the drug dosage form according to claim 1 to a subject in need thereof.