Extruded immediate release abuse deterrent pill

• US 10,639,281 B2
• Filed: 12/05/2018
• Issued: 05/05/2020
• Est. Priority Date: 08/12/2013
• 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:
  US16/210,714
• Publication Number:
  US 20190209481A1
• Time in Patent Office: 517 Days
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• 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: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• 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: B29C 2043/463 corrugated, patterned or embossed surface
• CPC Class Codes: B29C 2043/483 cooperating with a second endless belt, i.e. double band presses
• CPC Class Codes: B29C 43/48 Endless belts
• CPC Class Codes: B29C 48/0011 combined with compression moulding
• 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 48/06 Rod-shaped
• 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: B29K 2071/02 : Polyalkylene oxides, e.g. PEO, i.e. polyethylene oxide, or derivatives thereof
• CPC Class Codes: B29K 2105/0035 : Medical or pharmaceutical agents
• CPC Class Codes: B29K 2105/0038 : Plasticisers
• CPC Class Codes: B30B 11/02 : using a ram exerting pressure on the material in a moulding space
• CPC Class Codes: B30B 11/027 : Particular press methods or systems
• CPC Class Codes: B30B 11/14 : co-operating with moulds on a movable carrier other than a turntable or a rotating drum
• CPC Class Codes: B30B 11/16 : using pocketed rollers, e.g. two co-operating pocketed rollers
• CPC Class Codes: B30B 15/308 : in a continuous manner, e.g. for roller presses, screw extrusion presses

Abstract

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

Claims

1. An oral, immediate release, abuse deterrent dosage form comprising:

(i) 0.1 wt. % to 30.0 wt. % of an active substance susceptible to abuse;

(ii) a matrix agent, wherein the matrix agent is 45 wt. % to 55 wt. % polyethylene oxide (PEO) having an average molecular weight between 50K and 150K Daltons;

(iii) 15 wt. % to 30 wt. % of a plasticizer, wherein the plasticizer has an average molecular weight between 1K Daltons and 15K Daltons, wherein the plasticizer is a polyalkylene glycol;

(iv) 0 wt. % to 40 wt. % of a filler,

(v) 0 wt. % to 2.0 wt. % of an antioxidant, and,

(vi) 0 wt. % to 20.0 wt. % of a dye,

wherein the active substance susceptible to abuse is selected from the group consisting of;

alfentanil, allylprodine, alphaprodine, amphetamine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextroamphetamine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levophenacylmorphan, levorphanol, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbulphine, narceine, nicomorphine, norpipanone, opium, oxycodone, papvretum, pentazocine, phenadoxone, phenazocine, phenomorphan, phenoperidine, piminodine, propiram, propoxyphene, sufentanil, tilidine, tramadol, and pharmaceutically acceptable salts and/or mixtures thereof;

wherein the active substance susceptible to abuse has an immediate release profile wherein greater than or equal to 75 wt. % of the active substance is released from the dosage form at 45 minutes following a dissolution test in deaerated water, wherein the dosage form includes a physical barrier to reduce abuse, wherein the physical barrier is having at least 50 wt. % of particles with a particle size greater than 0.5 mm following physical or mechanical manipulation of the dosage form, wherein said physical or mechanical manipulation comprises grinding in a MR. COFFEE®

model number IDS55 coffee grinder or equivalent at 20,000 rpm and for 30-60 seconds;

wherein the dosage form is a formed, uniform extrudate having a uniform blend of active, matrix agent and plasticizer, and is directly formed from an extrusion process, and wherein said dosage form excludes disintegrant that promotes disintegration of the dosage form and dissolution of the active substance.

2. The oral, immediate release, abuse deterrent pill of claim 1, wherein the active substance is Oxycodone or Hydrocodone.

3. The oral, immediate release, abuse deterrent pill of claim 1, wherein the physical barrier reduces abuse by pulverizing and swallowing, pulverizing and snorting, or pulverizing and injecting.

4. The oral, immediate release, abuse deterrent pill of claim 1, comprising 20 wt. % to 30 wt. % of said filler.

5. The oral, immediate release, abuse deterrent pill of claim 1, further comprising 0.1 wt. % to 2.0 wt. % of one or more preservatives.

6. The oral, immediate release, abuse deterrent pill of claim 1, further comprising a FD&

C dye.

7. The oral, immediate release, abuse deterrent pill of claim 1, wherein less than or equal to 60 wt. % of the active substance is released from the dosage form at 20 minutes following a dissolution test in deaerated water.

8. The oral, immediate release, abuse deterrent pill of claim 1, which is a 100 mg pill.

9. A method of treating pain comprising administering to an individual in need thereof a therapeutically effective amount of the oral, immediate release, abuse deterrent dosage form of claim 1.

10. A process for the production of an oral, immediate release, abuse deterrent dosage form containing at least one active substance susceptible to abuse, said process comprising:

(i) processing a uniform blend of at least one active substance susceptible to abuse, a matrix agent, a plasticizer, and optionally a filler, an antioxidant, and a dye, by hot melt extrusion using an extruder to make an extrudate; and

(ii) forming the extrudate using a forming unit into the dosage form,

wherein the dosage form excludes disintegrant that promotes disintegration of the dosage form and dissolution of the active substance, said dosage form comprises;

(a) 0.1 wt. % to 30.0 wt. % of the active substance susceptible to abuse;

(b) 45 wt. % to 55 wt. % of the matrix agent which is polyethylene oxide (PEO) having an average molecular weight between 50K Daltons and 150K Daltons;

(c) 15 wt. % to 30 wt. % of the plasticizer which is polyalkylene glycol having an average molecular weight between 1K Daltons and 15K Daltons;

(d) 0 wt. % to 40 wt. % of a filler;

(e) 0 wt. % to 2.0 wt. % of an antioxidant, and,

(f) 0 wt. % to 20.0 wt. % of a dye,

wherein the active substance susceptible to abuse is selected from the group consisting of;

alfentanil, allylprodine, alphaprodine, amphetamine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextroamphetamine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levophenacylmorphan, levorphanol, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbulphine, narceine, nicomorphine, norpipanone, opium, oxycodone, papvretum, pentazocine, phenadoxone, phenazocine, phenomorphan, phenoperidine, piminodine, propiram, propoxyphene, sufentanil, tilidine, tramadol, and pharmaceutically acceptable salts and/or mixtures thereof;

wherein greater than or equal to 75 wt. % of the active substance is released from the dosage form at 45 minutes following a dissolution test in deaerated water, wherein the dosage form includes a physical barrier to reduce abuse, wherein the physical barrier is having at least 50 wt. % of particles with a particle size greater than 0.5 mm following physical or mechanical manipulation of the dosage form, wherein said physical or mechanical manipulation comprises grinding in a MR. COFFEE®

model number IDS55 coffee grinder or equivalent at 20,000 rpm and for 30-60 seconds.

11. The process for the production of an oral, immediate release, abuse deterrent dosage form of claim 10, wherein the forming unit is a unit capable of forming the dosage form without prior cutting of the extrudate.

12. The process for the production of an oral, immediate release, abuse deterrent dosage form of claim 11, wherein the unit capable of forming the dosage form is a calendar, a rotary or a chain forming machine.

13. The process for the production of an oral, immediate release, abuse deterrent dosage form of claim 10, wherein the processing of the uniform blend is performed at a processing temperature and a processing pressure such that the matrix agent and plasticizer soften and the at least one active substance susceptible to abuse does not substantially degrade.

14. The process for the production of an oral, immediate release, abuse deterrent dosage form of claim 13, wherein at least one temperature zone of the extruder has a processing temperature equal to or below 75°

C.

15. The process for the production of an oral, immediate release, abuse deterrent dosage form of claim 13, wherein at least one pressure zone of the extruder has a processing pressure equal to or above 5 Bar.

16. The process for the production of an oral, immediate release, abuse deterrent dosage form of claim 10, further comprising transferring the extrudate to the forming unit using a transfer unit capable of controlling the temperature, pressure, environment, and/or shape of the extrudate.

17. The process for the production of an oral, immediate release, abuse deterrent dosage form of claim 10, further comprising monitoring a mixture of the at least one active substance susceptible to abuse, the matrix agent and the plasticizer during blending using a process analytical technique to determine when a uniform blend is achieved.

18. The process for the production of an oral, immediate release, abuse deterrent dosage form of claim 10, further comprising determining the quality, volume and weight of the dosage form using an optical inspection technique.

19. A process for the production of an oral, immediate release, abuse deterrent dosage form, said process comprising processing an analytically determined uniform blend of at least one active substance susceptible to abuse, a matrix agent and a plasticizer by hot melt extrusion using an extruder to make an extrudate and forming the dosage form, wherein said dosage form excludes disintegrant that promotes disintegration of the dosage form and dissolution of the active substance, said dosage form comprises:

(a) 0.1 wt. % to 30.0 wt. % of the active substance susceptible to abuse;

(b) 45 wt. % to 55 wt. % of the matrix agent which is polyethylene oxide (PEO) having an average molecular weight between 50K Daltons and 150K Daltons;

(c) 15 wt. % to 30 wt. % of the plasticizer which is polyalkylene glycol having an average molecular weight between 1K Daltons and 15K Daltons;

(d) 0 wt. % to 40 wt. % of a filler;

(e) 0 wt. % to 2.0 wt. % of an antioxidant, and,

(f) 0 wt. % to 20.0 wt. % of a dye

wherein the active substance susceptible to abuse is selected from the group consisting of;

alfentanil, allylprodine, alphaprodine, amphetamine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextroamphetamine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levophenacylmorphan, levorphanol, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbulphine, narceine, nicomorphine, norpipanone, opium, oxycodone, papvretum, pentazocine, phenadoxone, phenazocine, phenomorphan, phenoperidine, piminodine, propiram, propoxyphene, sufentanil, tilidine, tramadol, and pharmaceutically acceptable salts and/or mixtures thereof.

20. A process for the production of an oral, immediate release, abuse deterrent dosage form containing at least one active substance susceptible to abuse comprising:

(i) combining the at least one active substance susceptible to abuse, a matrix agent and a plasticizer in a hopper to form a mixture;

(ii) blending the mixture in the hopper until a uniform blend is achieved;

(iii) monitoring the mixture during blending using a process analytical technique to determine when a uniform blend is achieved;

(iv) feeding the uniform blend into an extruder;

(v) processing the uniform blend by hot melt extrusion in the extruder to make an extrudate;

(vi) transferring the extrudate to a forming unit using a transfer unit capable of controlling the temperature, pressure, environment or shape of the extrudate;

(vii) forming the extrudate using the forming unit into the dosage form; and

(viii) determining the quality, volume and weight of the dosage form using an optical inspection technique,

wherein said dosage form excludes disintegrant that promotes disintegration of the dosage form and dissolution of the active substance, said dosage form comprises;

(a) 0.1 wt. % to 30.0 wt. % of the active substance susceptible to abuse;

(b) 45 wt. % to 55 wt. % of the matrix agent which is polyethylene oxide (PEO) having an average molecular weight between 50K Daltons and 150K Daltons;

(c) 15 wt. % to 30 wt. % of the plasticizer which is polyalkylene glycol having an average molecular weight between 1K Daltons and 15K Daltons;

(d) 0 wt. % to 40 wt. % of a filler;

(e) 0 wt. % to 2.0 wt. % of an antioxidant, and,

(f) 0 wt. % to 20.0 wt. % of a dye

wherein the active substance susceptible to abuse is selected from the group consisting of;

alfentanil, allylprodine, alphaprodine, amphetamine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextroamphetamine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levophenacylmorphan, levorphanol, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbulphine, narceine, nicomorphine, norpipanone, opium, oxycodone, papvretum, pentazocine, phenadoxone, phenazocine, phenomorphan, phenoperidine, piminodine, propiram, propoxyphene, sufentanil, tilidine, tramadol, and pharmaceutically acceptable salts and/or mixtures thereof.