Abuse deterrent pharmaceutical compositions for controlled release

• US 9,549,899 B2
• Filed: 07/01/2013
• Issued: 01/24/2017
• Est. Priority Date: 07/06/2012
• Status: Expired due to Fees

• Current Assignee: Egalet, Ltd. (Assertio Holdings, Inc.)
• Original Assignee: Egalet, Ltd. (Assertio Holdings, Inc.)
• Inventors: Tygesen, Peter Holm, Lindhardt, Karsten, Olsen, Martin Rex, Fischer, Gina Engslev, Overgard, Jan Martin, Boye, Georg, Skak, Nikolaj, Elhauge, Torben
• Primary Examiner(s): Song, Jianfeng
• Application Number:
  US13/933,053
• Publication Number:
  US 20140010873A1
• Time in Patent Office: 1,303 Days
• Field of Search: None
• US Class Current: 1/1
• 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 31/46 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• 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 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/2031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• CPC Class Codes: A61K 9/28 Dragees; Coated pills or tablets , e.g. with film or compression coating A61K9/2072 takes precedence, e.g. partially coated tablets A61K9/2072, coated multilayer tablets A61K9/2086, tablets with drug-coated core A61K9/209
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/26 Psychostimulants, e.g. nicotine, cocaine

Abstract

The present disclosure relates to pharmaceutical compositions that are abuse resistant and may also provide controlled release. The present disclosure also relates to the use of pharmaceutical compositions in the treatment of pain.

Claims

1. An abuse-deterrent tablet formulated for oral administration of an opioid, the tablet consisting of a tablet composition and, optionally, a cosmetic coat, wherein:

the tablet composition consists of;

(a) about 1-70% w/w of the opioid; and

(b) about 30-98% w/w of a polyethylene oxide (PEO) selected from the group consisting of (i) a single PEO having an average molecular weight of from about 400,000 daltons to about 900,000 daltons and (ii) two or more PEOs having a combined average molecular weight of from about 400,000 daltons to about 900,000 daltons and, optionally,

(c) a stabilizer selected from one or more of tripropylene glycol (TPG), tocopherol polyethylene glycol succinate (TPGS), butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), t-butyl hydroquinone, calcium ascorbate, gallic acid, hydroquinone, maltol, octyl gallate, sodium bisulfite, sodium metabisulfite, tocopherol, citric acid, tartaric acid, ascorbic acid, phosphite, erythorbic acid, etidronic acid, hypophosphorous acid, nordihydroguaiaretic acid, propionic acid, dodecyl gallate, octyl gallate, 1,3,5-trihydroxybenzene, calcium ascorbate, sodium ascorbate, sodium bisulphite, sodium metabisulfite, sodium sulfite, potassium bisulphite, potassium metabisulphite), dilauryl thiodipropionate, dimyristyl thiodipropionate, distearyl thiodipropionate, tocopherol, D-α

-tocopherol, d,l-α

-tocopherol, tocopheryl acetate, d-α

-tocopheryl acetate, d,l-α

-tocopheryl acetate, sorbitol glyceryl tricitrate, and sucrose octaacetate, the cosmetic coat, when present, covers at least a portion of the tablet composition, and dissolves within 30 minutes after contact with aqueous media,

wherein the tablet composition does not provide immediate release of the opioid even after being subjected to physical tampering selected from crushing, grinding, grating, cutting, or crisping, and

wherein the tablet composition exhibits a viscosity of at least 170 mPa·

s when measured by Viscosity Test #2, or a viscosity of at least 46 Pa·

s when measured by Viscosity Test #1.

2. The abuse deterrent tablet of claim 1, wherein the tablet composition is resistant to physical tampering such that after being subjected to grating using a grater with a stainless steel blade for 1 ½

minutes the grated composition does not exhibit immediate release of the opioid by releasing at least 80% w/w of the opioid within 30 minutes, when subjected to dissolution testing according to USP 35, NF 30, (711), Apparatus 2, in 900mL of dilute hydrochloric acid dissolution medium and a paddle rotation speed of 75 rpm.

3. The abuse deterrent tablet of claim 1, wherein the tablet composition is resistant to physical tampering such that after being subjected to grinding in a coffee grinder with stainless steel blades at 30,000-50,000 rpm for 15 seconds at least 90 wt % of the composition exhibits a particle size of larger than about 1,050 μ

m.

4. The abuse deterrent tablet of claim 1, wherein the tablet composition is resistant to physical tampering such that after being subjected to grinding in a coffee grinder with stainless steel blades at 30,000-50,000 rpm for 15 seconds the grinded composition does not exhibit immediate release of the opioid by releasing at least 80% w/w of the opioid within 30 minutes, when subjected to dissolution testing according to USP 35, NF 30, (711), Apparatus 2, in 900 mL of dilute hydrochloric acid dissolution medium and a paddle rotation speed of 75 rpm.

5. The abuse deterrent tablet of claim 1, wherein the opioid is selected from the group consisting of buprenorphine, codeine, dextromoramide, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, morphine, pentazocine, oxycodeine, oxycodone, oxymorphone, norhydrocodone, noroxycodone, morphine-6-glucuronode, tramadol, tapentadol, dihydromorphine, and pharmaceutically acceptable salts thereof.

6. The abuse deterrent tablet of claim 1, wherein the opioid is selected from the group consisting of morphine and pharmaceutically acceptable salts thereof.

7. The abuse deterrent tablet of claim 1, wherein the tablet composition exhibits a release rate of opioid in phosphate buffered saline with 40% v/v ethanol that is equal to or lower than the release rate of opioid in phosphate buffered saline.

8. The abuse deterrent tablet of claim 1, wherein the tablet yields a non-snortable composition when subjected to physical tampering selected from crushing, hammering, grinding, grating, and cutting.

9. The abuse deterrent tablet of claim 1, wherein the average molecular weight of the PEO included in the tablet composition is from about 400,000 to about 600,000 daltons.

10. The abuse deterrent tablet of claim 1, wherein the average molecular weight of the PEO included in the tablet composition is about 400,000 daltons.

11. The abuse deterrent tablet of claim 1, wherein the tablet composition comprises two or more active drug substances.

12. A method for treating an individual suffering from moderate to severe pain, the method comprising administering to the individual an abuse-deterrent tablet according to claim 1.

13. An abuse-deterrent tablet formulated for oral administration of an opioid, the tablet consisting of a tablet composition and, optionally, a cosmetic coat, wherein:

the tablet composition consists of;

(a) about 1-70% w/w of the opioid; and

(b) about 30-98% w/w of a polyethylene oxide (PEO) selected from the group consisting of (i) a single PEO having an average molecular weight of from about 400,000 daltons to about 900,000 daltons and (ii) two or more PEOs having a combined average molecular weight of from about 400,000 daltons to about 900,000 daltons and, optionally,

(c) a stabilizer selected from one or more of tripropylene glycol (TPG), tocopherol polyethylene glycol succinate (TPGS), butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), t-butyl hydroquinone, calcium ascorbate, gallic acid, hydroquinone, maltol, octyl gallate, sodium bisulfite, sodium metabisulfite, tocopherol, citric acid, tartaric acid, ascorbic acid, phosphite, erythorbic acid, etidronic acid, hypophosphorous acid, nordihydroguaiaretic acid, propionic acid, dodecyl gallate, octyl gallate, 1,3,5-trihydroxybenzene, calcium ascorbate, sodium ascorbate, sodium bisulphite, sodium metabisulfite, sodium sulfite, potassium bisulphite, potassium metabisulphite), dilauryl thiodipropionate, dimyristyl thiodipropionate, distearyl thiodipropionate, tocopherol, D-α

-tocopherol, d,l-α

-tocopherol, tocopheryl acetate, d-α

-tocopheryl acetate, d,l-α

-tocopheryl acetate, sorbitol glyceryl tricitrate, and sucrose octaacetate, the cosmetic coat, when present, covers at least a portion of the tablet composition, and dissolves within 30 minutes after contact with aqueous media,

wherein the tablet composition is resistant to physical tampering such that after being subjected to grating using a grater with a stainless steel blade for 1 ½

minutes the grated composition does not exhibit immediate release of the opioid by releasing at least 80% w/w of the opioid within 30 minutes, when subjected to dissolution testing according to USP 35, NF 30, (711), Apparatus 2, in 900 mL of dilute hydrochloric acid dissolution medium and a paddle rotation speed of 75 rpm.

14. The abuse deterrent tablet of claim 13, wherein the opioid is selected from the group consisting of buprenorphine, codeine, dextromoramide, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, morphine, pentazocine, oxycodeine, oxycodone, oxymorphone, norhydrocodone, noroxycodone, morphine-6-glucuronode, tramadol, tapentadol, dihydromorphine, and pharmaceutically acceptable salts thereof.

15. The abuse deterrent tablet of claim 13, wherein the opioid is selected from the group consisting of morphine and pharmaceutically acceptable salts thereof.

16. The abuse deterrent tablet of claim 13, wherein the tablet composition exhibits a release rate of opioid in phosphate buffered saline with 40% v/v ethanol that is equal to or lower than the release rate of opioid in phosphate buffered saline.

17. The abuse deterrent tablet of claim 13, wherein the tablet yields a non-snortable composition when subjected to physical tampering selected from crushing, hammering, grinding, grating, and cutting.

18. The abuse deterrent tablet of claim 13, wherein the average molecular weight of the PEO included in the tablet composition is from about 400,000 to about 600,000 daltons.

19. The abuse deterrent tablet of claim 13, wherein the average molecular weight of the PEO included in the tablet composition is about 400,000 daltons.

20. A method for treating an individual suffering from moderate to severe pain, the method comprising administering to the individual an abuse-deterrent tablet according to claim 13.

21. An abuse-deterrent tablet formulated for oral administration of an opioid, the tablet consisting of a tablet composition and, optionally, a cosmetic coat, wherein:

the tablet composition consists of;

(a) about 1-70% w/w of the opioid; and

(b) about 30-98% w/w of a polyethylene oxide (PEO) selected from the group consisting of (i) a single PEO having an average molecular weight of from about 400,000 daltons to about 900,000 daltons and (ii) two or more PEOs having a combined average molecular weight of from about 400,000 daltons to about 900,000 daltons and, optionally,

(c) a stabilizer selected from one or more of tripropylene glycol (TPG), tocopherol polyethylene glycol succinate (TPGS), butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), t-butyl hydroquinone, calcium ascorbate, gallic acid, hydroquinone, maltol, octyl gallate, sodium bisulfite, sodium metabisulfite, tocopherol, citric acid, tartaric acid, ascorbic acid, phosphite, erythorbic acid, etidronic acid, hypophosphorous acid, nordihydroguaiaretic acid, propionic acid, dodecyl gallate, octyl gallate, 1,3,5-trihydroxybenzene, calcium ascorbate, sodium ascorbate, sodium bisulphite, sodium metabisulfite, sodium sulfite, potassium bisulphite, potassium metabisulphite), dilauryl thiodipropionate, dimyristyl thiodipropionate, distearyl thiodipropionate, tocopherol, D-α

-tocopherol, d,l-α

-tocopherol, tocopheryl acetate, d-α

-tocopheryl acetate, d,l-α

-tocopheryl acetate, sorbitol glyceryl tricitrate, and sucrose octaacetate, the cosmetic coat, when present, covers at least a portion of the tablet composition, and dissolves within 30 minutes after contact with aqueous media,

wherein the tablet composition is resistant to physical tampering such that after being subjected grinding in a coffee grinder with stainless steel blades at 30,000-50,000 rpm for 15 seconds the grinded composition does not exhibit immediate release of the opioid by releasing at least 80% w/w of the opioid within 30 minutes, when subjected to dissolution testing according to USP 35, NF 30, (711), Apparatus 2, in 900 mL of dilute hydrochloric acid dissolution medium and a paddle rotation speed of 75 rpm.

22. The abuse deterrent tablet of claim 21, wherein the tablet composition is resistant to physical tampering such that after being subjected to grinding in a coffee grinder with stainless steel blades at 30,000-50,000 rpm for 15 seconds at least 90 wt % of the composition exhibits a particle size of larger than about 1,050 μ

m.

23. The abuse deterrent tablet of claim 21, wherein the opioid is selected from the group consisting of buprenorphine, codeine, dextromoramide, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, morphine, pentazocine, oxycodeine, oxycodone, oxymorphone, norhydrocodone, noroxycodone, morphine-6-glucuronode, tramadol, tapentadol, dihydromorphine, and pharmaceutically acceptable salts thereof.

24. The abuse deterrent tablet of claim 21, wherein the opioid is selected from the group consisting of morphine and pharmaceutically acceptable salts thereof.

25. The abuse deterrent tablet of claim 21, wherein the tablet composition exhibits a release rate of opioid in phosphate buffered saline with 40% v/v ethanol that is equal to or lower than the release rate of opioid in phosphate buffered saline.

26. The abuse deterrent tablet of claim 21, wherein the tablet yields a non-snortable composition when subjected to physical tampering selected from crushing, hammering, grinding, grating, and cutting.

27. The abuse deterrent tablet of claim 21, wherein the average molecular weight of the PEO included in the tablet composition is from about 400,000 to about 600,000 daltons.

28. The abuse deterrent tablet of claim 21, wherein the average molecular weight of the PEO included in the tablet composition is about 400,000 daltons.

29. A method for treating an individual suffering from moderate to severe pain, the method comprising administering to the individual an abuse-deterrent tablet according to claim 21.