Extruded extended release abuse deterrent pill

• US 9,492,444 B2
• Filed: 12/17/2014
• Issued: 11/15/2016
• Est. Priority Date: 12/17/2013
• Status: Active Grant

• Current Assignee: Pharmaceutical Manufacturing Research Services, Inc.
• Original Assignee: Pharmaceutical Manufacturing Research Services, Inc.
• Inventors: Thompson, Edwin R., Thompson, Eric R., Myslinski, Nicholas R., Kemeny, Steven F.
• Primary Examiner(s): THOMAS, TIMOTHY P
• Application Number:
  US14/574,005
• Publication Number:
  US 20150165041A1
• Time in Patent Office: 699 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• 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 9/2031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00
• CPC Class Codes: B29C 2948/92514 Pressure
• CPC Class Codes: B29C 2948/92704 Temperature
• CPC Class Codes: B29C 48/0011 combined with compression moulding
• CPC Class Codes: B29C 48/0022 combined with cutting
• CPC Class Codes: B29C 48/022 characterised by the choice of material
• CPC Class Codes: B29C 48/04 Particle-shaped making granules B29B9/00
• CPC Class Codes: B29C 48/05 Filamentary, e.g. strands
• CPC Class Codes: B29C 48/30 Extrusion nozzles or dies extrusion characterised by the shape or cross-section of the extruded article B29C48/03
• CPC Class Codes: B29C 48/303 using dies or die parts movable in a closed circuit, e.g. mounted on movable endless support B29C48/35 takes precedence
• CPC Class Codes: B29C 48/40 using two or more parallel screws or at least two parallel non-intermeshing screws, e.g. twin screw extruders
• CPC Class Codes: B29C 48/405 Intermeshing co-rotating screws
• CPC Class Codes: B29C 48/875 for achieving a non-uniform temperature distribution, e.g. using barrels having both cooling and heating zones
• CPC Class Codes: B29K 2071/02 : Polyalkylene oxides, e.g. PEO, i.e. polyethylene oxide, or derivatives thereof
• CPC Class Codes: B29K 2105/0038 : Plasticisers

Abstract

The present disclosure relates to an oral, extended release, abuse deterrent pill containing at least one active pharmaceutical ingredient susceptible to abuse which is homogenously spread throughout a matrix used to deter abuse. The pill can be prepared using a hot melt extrusion process and a forming unit. The formed pill meets regulatory guidelines for extended release formulations and is abuse deterrent to parenteral administration due at least to particle size, viscosity, or purity limitations.

Claims

1. An oral, extended release, abuse deterrent pill comprising:

(i) 4 wt % to 35 wt % of an active substance susceptible to abuse, wherein the active substance is oxycodone, hydrocodone, hydromorphone, morphine, methadone, or pharmaceutical acceptable salts thereof;

(ii) 38 wt % to 42 wt % of polyethylene oxide as a matrix agent, wherein the matrix agent has an average molecular weight between 50K Daltons and 150K Daltons;

(iii) 15 wt % to 45 wt % of hydroxypropyl methylcellulose as a controlled release agent;

(iv) 0.2 wt % to 20 wt % polyethylene glycol as a plasticizer;

wherein the active substance susceptible to abuse has an extended release profile,

wherein the pill exhibits less than a 10% increase in the release of the active substance in a simulated alcoholic gastric fluid environment,

wherein the pill has at least 50 wt % of particles with a particle size greater than 0.5 mm following physical or mechanical manipulation of the pill, and

wherein the pill is a formed, uniform extrudate having a uniform blend of active, matrix agent, controlled release agent and plasticizer, and is directly formed from an extrusion process.

2. The oral, extended release, abuse deterrent pill of claim 1, wherein the active substance is present at 5 to 200 mg.

3. The oral, extended release, abuse deterrent pill of claim 1, wherein the plasticizer is polyethylene glycol having an average molecular weight of less than 10K Daltons.

4. The oral, extended release, abuse deterrent pill of claim 1, wherein the pill further comprises at least one preservative or antioxidant selected from the group consisting of silica, sodium laurel sulfate, citric acid, butylated hydroxytoluene (BHT), ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA), erythorbic acid, hypophosphorous acid, lactobionic acid, monothioglycerol, potassium metabisulfite, propyl gallate, racemethionine, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, sodium thiosulfate, stannous chloride, sulfur dioxide and tocopherols.

5. The oral, extended release, abuse deterrent pill of claim 1,

wherein between 20% and 40% of the active substance is released from the pill after 1 hour of exposure to simulated gastric fluid,

wherein between 35% and 55% of the active substance is released from the pill after 2 hours of exposure to simulated gastric fluid,

wherein between 55% and 75% of the active substance is released from the pill after 4 hours of exposure to simulated gastric fluid,

wherein between 70% and 90% of the active substance is released from the pill after 6 hours of exposure to simulated gastric fluid, and

wherein not less than 80% of the active substance is released from the pill after 8 hours of exposure to simulated gastric fluid.

6. The oral, extended release, abuse deterrent pill of claim 1, wherein the physical barrier is the pill has at least a 2×

increase in small volume extraction viscosity compared to similar pills.

7. The oral, extended release, abuse deterrent pill of claim 1, wherein the purity of the drug following alcohol extraction is <

40%.

8. The oral, extended release, abuse deterrent dosage formulation of claim 1 formed using a tablet press and cured using preceding, simultaneous, or subsequent heat.

9. The oral, extended release, abuse deterrent pill of claim 1 formed using a hot melt extrusion process and a forming unit.

10. The oral, extended release, abuse deterrent pill of claim 1, comprising:

(i) 4 wt % to 6 wt % of the active substance susceptible to abuse;

(iii) 36 wt % to 39 wt % of hydroxypropyl methylcellulose; and

(iv) 14 wt % to 17 wt % of polyethylene glycol.

11. The oral, extended release, abuse deterrent pill of claim 1, comprising:

(i) 32 wt % to 35 wt % of the active substance susceptible to abuse;

(iii) 18 wt % to 22 wt % of hydroxypropyl methylcellulose; and

(iv) 4 wt % to 6 wt % of polyethylene glycol.

12. The oral, extended release, abuse deterrent pill of claim 1, comprising:

(i) 6 wt % to 9 wt % of the active substance susceptible to abuse;

(iii) 31 wt % to 38 wt % of hydroxypropyl methylcellulose; and

(iv) 16 wt % to 19 wt % of polyethylene glycol.

13. The oral, extended release, abuse deterrent pill of claim 1, comprising:

(i) 8 wt % to 12 wt % of the active substance susceptible to abuse;

(iii) 29 wt % to 35 wt % of hydroxypropyl methylcellulose; and

(iv) 16 wt % to 19 wt % of polyethylene glycol.

14. The oral, extended release, abuse deterrent pill of claim 1, comprising:

(i) 13 wt % to 17 wt % of the active substance susceptible to abuse;

(iii) 27 wt % to 31 wt % of hydroxypropyl methylcellulose; and

(iv) 13 wt % to 16 wt % of polyethylene glycol.

15. The oral, extended release, abuse deterrent pill of claim 1, comprising:

(i) 18 wt % to 22 wt % of the active substance susceptible to abuse;

(iii) 27 wt % to 31 wt % of hydroxypropyl methylcellulose; and

(iv) 8 wt % to 11 wt % of polyethylene glycol.

16. The oral, extended release, abuse deterrent pill of claim 1, comprising:

(i) 28 wt % to 32 wt % of the active substance susceptible to abuse;

(iii) 26 wt % to 30 wt % of hydroxypropyl methylcellulose; and

(iv) 0.2 wt % to 5 wt % of polyethylene glycol.

17. The oral, extended release, abuse deterrent pill of claim 1, comprising:

(i) 28 wt % to 32 wt % of the active substance susceptible to abuse;

(iii) 26 wt % to 30 wt % of hydroxypropyl methylcellulose; and

(iv) 0.2 wt % to 0.3 wt % of polyethylene glycol.

18. The oral, extended release, abuse deterrent pill of claim 1, comprising:

(i) 6 wt % to 9 wt % of the active substance susceptible to abuse;

(iii) 31 wt % to 38 wt % of hydroxypropyl methylcellulose; and

(iv) 10 wt % to 20 wt % of polyethylene glycol.

19. The oral, extended release, abuse deterrent pill of claim 1, comprising:

(i) 8 wt % to 12 wt % of the active substance susceptible to abuse;

(iii) 29 wt % to 35 wt % of hydroxypropyl methylcellulose; and

(iv) 10 wt % to 20 wt % of polyethylene glycol.