CA2661573A1 - Tamper resistant oral pharmaceutical dosage forms comprising an opioid analgesic - Google Patents

Tamper resistant oral pharmaceutical dosage forms comprising an opioid analgesic Download PDF

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Publication number
CA2661573A1
CA2661573A1 CA002661573A CA2661573A CA2661573A1 CA 2661573 A1 CA2661573 A1 CA 2661573A1 CA 002661573 A CA002661573 A CA 002661573A CA 2661573 A CA2661573 A CA 2661573A CA 2661573 A1 CA2661573 A1 CA 2661573A1
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CA
Canada
Prior art keywords
extended release
dosage form
tablet
temperature
polyethylene oxide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CA002661573A
Other languages
French (fr)
Other versions
CA2661573C (en
Inventor
Richard Owen Mannion
Edward Patrick O'donnell
William Henry Mckenna
Haiyong Hugh Huang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Purdue Pharma LP
Original Assignee
Purdue Pharma L.P.
Richard Owen Mannion
Edward Patrick O'donnell
William Henry Mckenna
Haiyong Hugh Huang
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=38754532&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CA2661573(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Purdue Pharma L.P., Richard Owen Mannion, Edward Patrick O'donnell, William Henry Mckenna, Haiyong Hugh Huang filed Critical Purdue Pharma L.P.
Priority to CA2707204A priority Critical patent/CA2707204C/en
Publication of CA2661573A1 publication Critical patent/CA2661573A1/en
Application granted granted Critical
Publication of CA2661573C publication Critical patent/CA2661573C/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

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    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29K—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2071/00—Use of polyethers, e.g. PEEK, i.e. polyether-etherketone or PEK, i.e. polyetherketone or derivatives thereof, as moulding material
    • B29K2071/02—Polyalkylene oxides, e.g. PEO, i.e. polyethylene oxide, or derivatives thereof
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29K—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2105/00—Condition, form or state of moulded material or of the material to be shaped
    • B29K2105/0005—Condition, form or state of moulded material or of the material to be shaped containing compounding ingredients
    • B29K2105/0035—Medical or pharmaceutical agents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29K—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2105/00—Condition, form or state of moulded material or of the material to be shaped
    • B29K2105/25—Solid
    • B29K2105/251—Particles, powder or granules
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29K—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2995/00—Properties of moulding materials, reinforcements, fillers, preformed parts or moulds
    • B29K2995/0037—Other properties
    • B29K2995/0088—Molecular weight
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29L—INDEXING SCHEME ASSOCIATED WITH SUBCLASS B29C, RELATING TO PARTICULAR ARTICLES
    • B29L2031/00—Other particular articles
    • B29L2031/753—Medical equipment; Accessories therefor

Abstract

The present invention relates to pharmaceutical dosage forms, for example to a tamper resistant dosage form including an opioid analgesic, and proces ses of manufacture, uses, and methods of treatment thereof.

Claims (164)

1. A process of preparing a solid oral extended release pharmaceutical dosage form, comprising at least the steps of:
(a) combining at least (1) at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000, and (2) at least one active agent, to form a composition;
(b) shaping the composition to form an extended release matrix formulation; and (c) curing said extended release matrix formulation comprising at least a curing step of subjecting the extended release matrix formulation to a temperature which is at least the softening temperature of said polyethylene oxide for a time period of at least about 1 minute.
2. The process of claim 1, wherein in step c) the extended release matrix formulation is subjected to a temperature which is at least the softening temperature of said polyethylene oxide for a time period of at least about 5 minutes.
3. The process of claim 1, wherein in step c) the extended release matrix formulation is subjected to a temperature which is at least the softening temperature of said polyethylene oxide for a time period of at least about 15 minutes.
4. The process of claim 1, 2 or 3, wherein in step b) the composition is shaped to form an extended release matrix formulation in the form of tablet.
5. The process of claim 4, wherein in step b) the composition is shaped by direct compression of said composition.
6. The process of any one of claims 1 to 5, wherein in step c) the extended release matrix formulation is subjected to a temperature of at least about 60 °C or at least about 62 °C, preferably at least about 68 °C, at least about 70 °C, at least about 72 °C or at least about 75 °C.
7. The process of claim 6, wherein the extended release matrix formulation is subjected to a temperature of from about 62 °C to about 90 °C, from about 65 °C to about 90 °C or from about 68 °C to about 90 °C.
8. The process of claim 6, wherein the extended release matrix formulation is subjected to a temperature of at least about 62 °C or at least about 68 °C for a time period of from about 1 minute to about 5 hours or from about 5 minutes to about 3 hours.
9. The process of claim 6, wherein the extended release matrix formulation is subjected to a temperature of at least about 62 °C or at least about 68 °C for a time period of at least about 15 minutes.
10. The process of claim 6, wherein the dosage form is subjected to a temperature of at least about 60 °C or at least about 62 °C, preferably at least about 68 °C, at least about 70 °C, at least about 72 °C or at least about 75 °C
or from about 62 °C to about 85 °C for a time period of at least about 15 minutes, at least about 30 minutes, at least about 60 minutes or at least about 90 minutes.
11. The process of any one of claims 1 to 10, wherein the extended release matrix formulation in step c) is subjected to a temperature of at least about 60 °C or at least about 62 °C, but less than about 90 °C or less than about 80 °C.
12. The process of any one of claims 1 to 11, wherein the curing step c) takes place in an oven with an inside temperature.
13. The process of claim 12, wherein the temperature of step c) is the target inside temperature of the oven and wherein the curing step starts when the inside temperature of the oven reaches said temperature, and the curing step ends either when the heating is stopped or at least reduced and the inside temperature of the oven subsequently drops below said temperature by more than about 10 °C or below about 62 °C, in a plateau-like temperature profile or when the inside temperature of the oven drops below said temperature in a parabolic or triangular temperature profile.
14. The process of claim 13, wherein the temperature profile during the curing step shows a plateau-like form and wherein said temperature is preferably at least about 68 °C and the curing time is preferably in the range of from about 30 minutes to about 20 hours.
15. The process of any one of claims I to 11, wherein the curing step c) takes place in a convection curing device comprising an inlet air temperature, an exhaust air temperature and/or a temperature probe.
16. The process of claim 15, wherein the temperature of step c) is defined to be the target inlet air temperature and wherein the curing step starts when the inlet air temperature reaches said temperature and the curing step ends either when the heating is stopped or at least reduced and the inlet air temperature subsequently drops below said temperature by more than about 10 °C or below about 62 °C, in a plateau-like temperature profile or when the inlet air temperature drops below said temperature in a parabolic or triangular temperature profile.
17. The process of claim 16, wherein the temperature profile during the curing step shows a plateau-like form and wherein said temperature is preferably at least about 72 °C and the curing time is preferably in the range of from about 15 minutes to about 2 hours.
18. The process of claim 15, wherein the temperature of step c) is the target exhaust air temperature and wherein the curing step starts when the exhaust air temperature reaches said temperature and the curing step ends either when the heating is stopped or at least reduced and the exhaust air temperature subsequently drops below said temperature by more than about 10 °C or below about 62 °C, in a plateau-like temperature profile or when the exhaust air temperature drops below said temperature in a parabolic or triangular temperature profile.
19. The process of claim 18, wherein the temperature profile during the curing step shows a plateau-like form and wherein said temperature is preferably at least about 68 °C and the curing time is preferably in the range of from about 1 minute to about 2 hours.
20. The process of claim 15, wherein the temperature of step c) is the target temperature of the extended release matrix formulations and wherein the curing step starts when the temperature of the extended release matrix formulations reaches said temperature and the curing step ends either when the heating is stopped or at least reduced and the temperature of the extended release matrix formulations subsequently drops below said temperature by more than about 10 °C or below about 62 °C, in a plateau-like temperature profile or when the temperature of the extended release matrix formulations drops below said temperature in a parabolic or triangular temperature profile.
21. The process of claim 15, wherein the temperature of step c) is the target temperature measured using a temperature probe and wherein the curing step starts when the temperature measured using the temperature probe reaches said temperature and the curing step ends either when the heating is stopped or at least reduced and the temperature measured using the temperature probe subsequently drops below said temperature by more than about 10 °C or below about 62 °C, in a plateau-like temperature profile or when the temperature measured using the temperature probe drops below said temperature in a parabolic or triangular temperature profile.
22. The process of claim 21, wherein the temperature profile during the curing step shows a plateau-like form and wherein said temperature is preferably at least about 68°C and the curing time is preferably in the range of from about 15 minutes to about 2 hours.
23. The process of any one of claims 1 to 11 and 15 to 22, wherein the curing step c) takes place in a bed of free flowing extended release matrix formulations.
24. The process of claim 23, wherein the curing takes place in a coating pan.
25. The process of any one of claims 1 to 24, comprising a further step of coating the cured extended release matrix formulation.
26. The process of claim 25, comprising the steps of:
(a) combining at least (1) at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000, and (2) at least one active agent, to form a composition;
(b) shaping said composition to form the extended release matrix formulation in the form of a tablet by direct compression;

(c) curing said tablet by - subjecting a bed of free flowing tablets to a temperature from about 62°C to about 90°C for a time period of at least about 1 minute in a coating pan and - subsequently cooling the bed of free flowing tablets to a temperature of below about 50 °C;
and subsequently (d) coating the dosage form in said coating pan.
27. A process of preparing a solid oral extended release pharmaceutical dosage form, comprising at least the steps of:
(a) combining at least (1) at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000, and (2) at least one active agent, to form a composition;
(b) shaping the composition to form an extended release matrix formulation; and (c) curing said extended release matrix formulation comprising at least a curing step wherein said polyethylene oxide at least partially melts.
28. The process of claim 27, wherein in step b) the composition is shaped to form an extended release matrix formulation in the form of tablet.
29. The process of claim 28, wherein in step b) the composition is shaped by direct compression of said composition.
30. The process of claim 29, wherein at least about 20%, at least about 40% or at least about 75% of the high molecular weight polyethylene oxide melts.
31. The process of claim 30, wherein about 100% of the high molecular weight polyethylene oxide melts.
32. The process of any one of claims 27 to 31, wherein the curing step c) takes place in an oven.
33. The process of any one of claims 27 to 31, wherein the curing step c) takes place in a convection curing device.
34. The process of any one of claims 27 to 31, wherein the curing step c) takes place in a bed of free flowing extended release matrix formulations.
35. The process of claim 34, wherein the curing takes place in a coating pan.
36. The process of any one of claims 27 to 35, comprising a further step of coating the cured extended release matrix formulation.
37. The process of any one of claims 1 to 36, wherein the active agent is an opioid analgesic.
38. The process of claim 37 wherein the opioid analgesic is selected from the group of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl and derivatives, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts, hydrates and solvates thereof, mixtures of any of the foregoing.
39. The process of claim 37, wherein the opioid analgesic is selected from the group of codeine, morphine, oxycodone, hydrocodone, hydromorphone, or oxymorphone or pharmaceutically acceptable salts, hydrates and solvates thereof, mixtures of any of the foregoing.
40. The process of claim 39, wherein the opioid analgesic is oxycodone hydrochloride and the dosage form comprises from about 5 mg to about 500 mg of oxycodone hydrochloride.
41. The process of claim 40, wherein the dosage form comprises 5 mg, 7.5 mg, 10mg, 15 mg, 20 mg, 30 mg, 40 mg, 45 mg, 60 mg, or 80 mg, 90 mg, 120mgor 160 mg of oxycodone hydrochloride.
42. The process of any one of claims 39 to 41, wherein the active agent is oxycodone hydrochloride and the oxycodone hydrochloride has a 14-hydroxycodeinone level of less than about 25 ppm, preferably of less than about 15 ppm, less than about 10 ppm, or less than about 5 ppm.
43. The process of claim 37, wherein the opioid analgesic is oxymorphone hydrochloride and the dosage form comprises from about 1 mg to about 500 mg of oxymorphone hydrochloride.
44. The process of claim 43, wherein the dosage form comprises 5 mg, 7.5 mg, mg, 15 mg, 20 mg, 30, mg, 40 mg, 45 mg, 60 mg, or 80 mg, 90 mg, 120 mg or 160 mg of oxymorphone hydrochloride.
45. The process of claim 37, wherein the opioid analgesic is hydromorphone hydrochloride and the dosage form comprises from about 1 mg to about 100 mg of hydromorphone hydrochloride.
46. The process of claim 45, wherein the dosage form comprises 2 mg, 4 mg, 8 mg, 12 mg, 16 mg, 24 mg, 32 mg, 48 mg or 64 mg of hydromorphone hydrochloride.
47. The process of any one of claims 1 to 46, wherein the at least one polyethylene oxide has, based on rheological measurements, an approximate molecular weight of from 2,000,000 to 8,000,000.
48. The process of claim 47, wherein the at least one polyethylene oxide has, based on rheological measurements, an approximate molecular weight of 2,000,000, 4,000,000, 7,000,000 or 8,000,000.
49. The process of any one of claims 1 to 48, wherein the composition further comprises at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of less than 1,000,000.
50. The process of claim 49, wherein the composition further comprises at least one polyethylene oxide having, based on rheological measurements, an approximate - molecular weight of from 100,000 to 900,000.
51. The process of claim 50, wherein the composition further comprises at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of 100,000.
52. The process of any one of claims 1 to 51, wherein the overall content of polyethylene oxide in the composition is at least about 80 % (by wt).
53. The process of any one of claims 1 to 52, wherein the active agent is oxycodone hydrochloride and the overall content of oxycodone hydrochloridein the composition is more than about 5% (by wt)
54. The process of any one of claims 1 to 53, wherein the content in the composition of the at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000 is at least about 80 % (by wt).
55. The process of any one of claims 1 to 54, wherein the composition comprises at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000 and at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of less than 1,000,000, wherein the composition comprises at least about 10 %
(by wt) or at least about 20 % (by wt) of the polyethylene oxide having, based on rheological measurements, an approximate molecular weight of less than 1,000,000.
56. The process of claim 55, wherein the dosage form is subjected to a temperature of less than about 80 °C or less than about 77 °C.
57. The process of any one of claims 1 to 56, wherein the curing step c) leads to a decrease in the density of the extended release matrix formulation.
58. The process of claim 57, wherein the density of the cured extended release matrix formulation in comparison to the density of the uncured extended release matrix formulation decreases by at least about 0.5%, preferably at least about 0.7%.
59. A solid oral extended release pharmaceutical dosage form obtainable by a process according to any one of claims 1 to 58.
60. A solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation comprising an active agent in the form of a tablet or multi particulates, wherein the tablet or the individual multi particulates can at least be flattened without breaking, characterized by a thickness of the tablet or of the individual multi particulate after the flattening which corresponds to no more than about 60 %
of the thickness of the tablet or the individual multi particulate before flattening, and wherein said flattened tablet or the flattened multi particulates provide an in-vitro dissolution rate, when measured in a USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C, characterized by the percent amount of active agent released at 0.5 hours of dissolution that deviates no more than about 20 % points from the corresponding in-vitro dissolution rate of a non-flattened reference tablet or reference multi particulates.
61. The solid oral extended release pharmaceutical dosage form of claim 60, wherein the tablet or the multi particulates can at least be flattened without breaking, characterized by a thickness of the tablet or the individual multi particulate after the flattening which corresponds to no more than about 50 %, or no more than about 40%, or no more than about 30%, or no more than about 20%, or no more than about 16% of the thickness of the tablet or the individual multi particulate before flattening, and wherein said flattened tablet or the multi particulates provide an in-vitro dissolution rate, when measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C, characterized by the percent amount of active agent released at 0.5 hours of dissolution that deviates no more than about 20 % points or no more than about 15 % points from the corresponding in-vitro dissolution rate of a non-flattened reference tablet or reference multi particulates.
62. A solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation comprising an active agent in the form of a tablet or multi particulates, wherein the tablet or the individual multi particulates can at least be flattened without breaking, characterized by a thickness of the tablet or of the individual multi particulate after the flattening which corresponds to no more than about 60 %
of the thickness of the tablet or the individual multi particulate before flattening, and wherein said flattened tablet or the flattened multi particulates and the non-flattened reference tablet or reference multi particulates provide an in-vitro dissolution rate, which when measured in a USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C, is between 5 and 40% (by wt) active agent released after 0.5 hours.
63. The solid oral extended release pharmaceutical dosage form of claim 62, wherein the tablet or the multi particulates can at least be flattened without breaking, characterized by a thickness of the tablet or the individual multi particulate after the flattening which corresponds to no more than about 50 %, or no more than about 40%, or no more than about 30%, or no more than about 20%, or no more than about 16% of the thickness of the tablet or the individual multi particulate before flattening, and wherein said flattened tablet or the flattened multi particulates and the non-flattened reference tablet or reference multi particulates provide an in-vitro dissolution rate, which when measured in a USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C, is between 5 and 40% (by wt) active agent released after 0.5 hours or is between 5 and 30% (by wt) active agent released after 0.5 hours or is between 5 and 20% (by wt) active agent released after 0.5 hours or is between 10 and 18% (by wt) active agent released after 0.5 hours.
64. A solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation comprising an active agent in the form of a tablet or multi particulates, wherein the tablet or the individual multi particulates can at least be flattened without breaking, characterized by a thickness of the tablet or the individual multi particulate after the flattening which corresponds to no more than about 60% of the thickness of the tablet or the individual multi particulate before flattening, and wherein the flattened or non flattened tablet or the flattened or non flattened multi particulates provide an in-vitro dissolution rate, when measured in a USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) comprising 40%

ethanol at 37° C, characterized by the percent amount of active agent released at 0.5 hours of dissolution that deviates no more than about 20 % points from the corresponding in-vitro dissolution rate measured in a USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37°
C without ethanol, using a flattened and non flattened reference tablet or flattened and non flattened reference multi particulates, respectively.
65. The solid oral extended release pharmaceutical dosage form of claim 64, wherein the tablet or the multi particulates can at least be flattened without breaking, characterized by a thickness of the tablet or the individual multi particulate after the flattening which corresponds to no more than about 60%, or no more than about 50%, or no more than about 40%, or no more than about 30%, or no more than about 20%, or no more than about 16% of the thickness of the tablet or the individual multi particulate before flattening, and wherein the flattened or non flattened tablet or the individual multi particulates provide an in-vitro dissolution rate, when measured in a USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) comprising 40% ethanol at 37° C, characterized by the percent amount of active agent released at 0.5 hours of dissolution that deviates no more than about 20 % points or no more than about 15 % points from the corresponding in-vitro dissolution rate measured in a USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C without ethanol, using a flattened and a non flattened reference tablet or reference multi particulates, respectively.
66. A solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation comprising an active agent in the form of a tablet or multi particulates, wherein the tablet or the individual multi particulates can at least be flattened without breaking, characterized by a thickness of the tablet or the individual multi particulate after the flattening which corresponds to no more than about 60%
of the thickness of the tablet or the individual multi particulate before flattening, and wherein the flattened or non flattened tablet or the flattened or non flattened multi particulates provide an in-vitro dissolution rate, which when measured in a USP
Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) comprising 40% or 0% ethanol at 37° C, is between 5 and 40% (by wt) active agent released after 0.5 hours.
67. The solid oral extended release pharmaceutical dosage form of claim 66, wherein the tablet or the multi particulates can at least be flattened without breaking, characterized by a thickness of the tablet or the individual multi particulate after the flattening which corresponds to no more than about 50%, or no more than about 40%, or no more than about 30%, or no more than about 20%, or no more than about 16% of the thickness of the tablet or the individual multi particulate before flattening, and wherein the flattened or non flattened tablet or the individual multi particulates provide an in-vitro dissolution rate, which when measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) comprising 40% or 0% ethanol at 37° C, is between 5 and 40% (by wt) active agent released after 0.5 hours or is between 5 and 30% (by wt) active agent released after 0.5 hours or is between 5 and 20% (by wt) active agent released after 0.5 hours or is between 10 and 18% (by wt) active agent released after 0.5 hours.
68. A solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation, the extended release matrix formulation comprising a composition comprising at least:
(1) at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000;
and (2) at least one active agent selected from opioid analgesics; and wherein the composition comprises at least about 80 % (by wt) polyethylene oxide.
69. The solid oral extended release pharmaceutical dosage form of claim 68, wherein the opioid analgesic is oxycodone hydrochloride or hydromorphone hydrochloride and the composition comprises more than 5% (by wt) of the oxycodone hydrochloride or hydromorphone hydrochloride.
70. The solid oral extended release pharmaceutical dosage form of claim 68, wherein the composition comprises at least about 80 % (by wt) polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000.
71. A solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation, the extended release matrix formulation comprising a composition comprising at least:

(1) at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000;
and (2) 10 mg oxycodone hydrochloride; and wherein the composition comprises at least about 85 % (by wt) polyethylene oxide.
72. A solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation, the extended release matrix formulation comprising a composition comprising at least:
(1) at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000;
and (2) 15 mg or 20 mg oxycodone hydrochloride; and wherein the composition comprises at least about 80 % (by wt) polyethylene oxide.
73. A solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation, the extended release matrix formulation comprising a composition comprising at least:
(1) at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000;
and (2) 40 mg oxycodone hydrochloride; and wherein the composition comprises at least about 65 % (by wt) polyethylene oxide.
74. A solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation, the extended release matrix formulation comprising a composition comprising at least:
(1) at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000;
and (2) 60 mg or 80 mg oxycodone hydrochloride; and wherein the composition comprises at least about 60 % (by wt) polyethylene oxide.
75. A solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation, the extended release matrix formulation comprising a composition comprising at least:
(1) at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000;
and (2) 8 mg hydromorphone hydrochloride; and wherein the composition comprises at least about 94 % (by wt) polyethylene oxide.
76. A solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation, the extended release matrix formulation comprising a composition comprising at least:
(1) at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000;
and (2) 12 mg hydromorphone hydrochloride; and wherein the composition comprises at least about 92 % (by wt) polyethylene oxide.
77. A solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation, the extended release matrix formulation comprising a composition comprising at least:
(1) at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000;
and (2) 32 mg hydromorphone hydrochloride; and wherein the composition comprises at least about 90 % (by wt) polyethylene oxide.
78. A solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation, the extended release matrix formulation comprsing a composition comprising at least:
(1) at least one active agent selected from opioid analgesics;
(2) at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000;
and (3) at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of less than 1,000,000.
79. The solid oral extended release pharmaceutical dosage form of claim 78, wherein the composition comprises at least about 80 % (by wt) of polyethylene oxide.
80. The solid oral extended release pharmaceutical dosage form of claim 78, wherein the composition comprises at least:
1. 15 to 30 % (by wt) of polyethylene oxide having, based on rheological measurements, a molecular weight of at least 1,000,000; and 65 to 80 % (by wt) polyethylene oxide having, based on rheological measurements, a molecular weight of less than 1,000,000; or 2. at least about 20% (by wt) or at least about 30 % (by wt) or at least about 50 % (by wt) of polyethylene oxide having, based on rheological measurements, a molecular weight of at least 1,000,000.
81. A solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation, the extended release matrix formulation comprising a composition comprising at least:
(1) at least one polyethylene oxide having, based on rheological measurements, a molecular weight of at least 800,000; and (2) at least one active agent selected from opioid analgesics; and wherein the composition comprises at least about 80 % (by wt) polyethylene oxide.
82. The solid oral extended release pharmaceutical dosage form of claim 81, wherein the composition comprises at least one polyethylene oxide having, based on rheological measurements, a molecular weight of at least 900,000.
83. The solid oral extended release pharmaceutical dosage form of anyone of claims 59 to 82, wherein the density of the extended release matrix formulation is equal to or less than about 1.20 g/cm, preferably equal to or less than about 1.19 g/cm3.
84. A solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation, the extended release matrix formulation comprising a composition comprising at least:
(1) at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000;
and (2) at least one active agent; and wherein the extended release matrix formulation when subjected to an indentation test has a cracking force of at least about 110 N.
85. A solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation, the extended release matrix formulation comprising a composition comprising at least:
(1) at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000;
and (2) at least one active agent; and wherein the extended release matrix formulation when subjected to an indentation test has a "penetration depth to crack distance" of at least about 1.0 mm.
86. The solid oral extended release pharmaceutical dosage form of any one of claims 84 and 85, wherein the extended release matrix formulation has a cracking force of at least about 120 N, at least about 130 N or at least about 140 N and/or a "penetration depth to crack" distance of at least about 1.2 mm, preferably of at least about 1.4 mm, at least about 1.5 mm or at least about 1.6 mm.
87. The solid oral extended release pharmaceutical dosage form of any one of claims 84 and 85, wherein the extended release matrix formulation resists a work of at least about 0.06 J without cracking.
88. The solid oral extended release pharmaceutical dosage form of anyone of claims 60, 62, 64, 66, 68, 71-78, 81, 84 and 85, wherein the extended release matrix formulation after having been stored at 25 °C
and 60 % relative humidity (RH) for at least 1 month provides a dissolution rate, when measured in a USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C, characterized by the percent amount of active agent released at 1, 4 and 12 hours of dissolution that deviates no more than about 15 % points from the corresponding in-vitro dissolution rate of a reference formulation prior to storage.
89. The solid oral extended release pharmaceutical dosage form of claim 88, wherein the extended release matrix formulation has been stored at 40 °C and 75 % relative humidity (RH).
90. The solid oral extended release pharmaceutical dosage form of anyone of claims 60, 62, 64, 66, 68, 71-78, 81, 84 and 85, wherein the extended release matrix formulation after having been stored at 25 °C
and 60 % relative humidity (RH) for at least 1 month contains an amount of the at least one active agent in % (by wt) relative to the label claim of the active agent for the extended release matrix formulation that deviates no more than about 10 %
points from the corresponding amount of active agent in % (by wt) relative to the label claim of the active agent for the extended release matrix formulation of a reference formulation prior to storage.
91. The solid oral extended release pharmaceutical dosage form of claim 90, wherein the extended release matrix formulation has been stored at 40 °C and 75 %
relative humidity (RH).
92. The solid oral extended release pharmaceutical dosage form of anyone of claims 60, 62, 64, 66, 68, 71-78, 81, 84 and 85, wherein the dosage provides a dissolution rate, which when measured in a USP
Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C, is between 12.5 and 55% (by wt) active released after 1 hour, between 25 and 65% (by wt) active released after 2 hours, between 45 and 85%
(by wt) active released after 4 hours and between 55 and 95% (by wt) active released after 6 hours.
93. The solid oral extended release pharmaceutical dosage form of anyone of claims 60, 62, 64, 66, 68, 71-78, 81, 84 and 85, wherein the active agent is oxycodone hydrochloride and wherein the dosage form when tested in a comparative clinical study is bioequivalent to the commercial product OxyContin.TM..
94. The solid oral extended release pharmaceutical dosage form of anyone of claims 60, 62, 64, 66, 68, 71-78, 81, 84 and 85, wherein the active agent is oxycodone hydrochloride and wherein a dosage form comprising 10 mg of oxycodone hydrochloride when tested in a comparative clinical study is bioequivalent to a reference tablet containing 10 mg of oxycodone hydrochloride in a matrix formulation containing:
a) Oxycodone hydrochloride: 10.0 mg/tablet b) Lactose (spray-dried): 69.25 mg/tablet c) Povidone : 5.0 mg/tablet d) Eudragit® RS 30D (solids) : 10.0 mg/tablet e) Triacetin®: 2.0 mg/tablet f) Stearyl alcohol: 25.0 mg/tablet g) Talc: 2.5 mg/tablet h) Magnesium Stearate: 1.25 mg/tablet;
and wherein the reference tablet is prepared by the following steps:
1. Eudragit® RS 30D and Triacetin® are combined while passing through a 60 mesh screen, and mixed under low shear for approximately 5 minutes or until a uniform dispersion is observed.
2. Oxycodone HCl, lactose, and povidone are placed into a fluid bed granulator/dryer (FBD) bowl, and the suspension sprayed onto the powder in the fluid bed.
3. After spraying, the granulation is passed through a #12 screen if necessary to reduce lumps.
4. The dry granulation is placed in a mixer.
5. In the meantime, the required amount of stearyl alcohol is melted at a temperature of approximately 70 °C.
6. The melted stearyl alcohol is incorporated into the granulation while mixing.
7. The waxed granulation is transferred to a fluid bed granulator/dryer or trays and allowed to cool to room temperature or below.
8. The cooled granulation is then passed through a #12 screen.
9. The waxed granulation is placed in a mixer/blender and lubricated with the required amounts of talc and magnesium stearate for approximately 3 minutes.
10. The granulate is compressed into 125 mg tablets on a suitable tableting machine.
95. The extended release dosage form of claims 84 to 94, wherein the composition comprises at least about 80 % (by wt) of polyethylene oxide.
96. The extended release dosage form of claim 95, wherein the composition comprises at least about 80 % (by wt) polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000.
97. The extended release dosage form of any one of claims 60 to 96, wherein the active agent is an opioid analgesic.
98. The extended release dosage form of claim 97, wherein the opioid analgesic is selected from the group of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl and derivatives, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts, hydrates and solvates thereof, mixtures of any of the foregoing.
99. The extended release dosage form of claim 97, wherein the opioid analgesic is selected from the group of codeine, morphine, oxycodone, hydrocodone, hydromorphone, or oxymorphone or pharmaceutically acceptable salts, hydrates and solvates thereof, mixtures of any of the foregoing.
100. The extended release dosage form of claim 98, wherein the opioid analgesic is oxycodone hydrochloride and the dosage form comprises from about 5 mg to about 500 mg of oxycodone hydrochloride.
101. The extended release dosage form of claim 100, wherein the dosage form comprises 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30, mg, 40 mg, 45 mg, 60 mg, or mg, 90 mg, 120 mg or 160 mg of oxycodone hydrochloride.
102. The extended release dosage form of claim 97, wherein the opioid analgesic is oxycodone hydrochloride having a 14-hydroxycodeinone level of less than about 25 ppm, preferably of less than about 15 ppm, less than about 10 ppm, or less than about 5 ppm.
103. The extended release dosage form of claim 97, wherein the opioid analgesic is oxymorphone hydrochloride and the dosage form comprises from about 1 mg to about 500 mg of oxymorphone hydrochloride.
104. The extended release dosage form of claim 103, wherein the dosage form comprises 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 45 mg, 60 mg, or 80 mg, 90 mg, 120 mg or 160 mg of oxymorphone hydrochloride.
105. The extended release dosage form of claim 97, wherein the opioid analgesic is hydromorphone hydrochloride and the dosage form comprises from about 1 mg to about 100 mg of hydromorphone hydrochloride.
106. The extended release dosage form of claim 105, wherein the dosage form comprises 2 mg, 4 mg, 8 mg, 12 mg, 16 mg, 24 mg, 32 mg, 48 mg or 64 mg of hydromorphone hydrochloride.
107. The extended release dosage form of any one of claims 60 to 106, which is in the form of a tablet formed by direct compression of the composition and cured by at least subjecting said tablet to a temperature of at least about 60 °C or at least about 62 °C for a time period of at least about 1 minute, preferably at least about 5 minutes or at least about 15 minutes.
108. The extended release dosage form of any one of claims 60 to 107, which is in the form of a tablet and which is over coated with a polyethylene oxide powder layer to form a tablet that has a core tablet and a layer of polyethylene oxide surrounding the core tablet.
109. The extended release dosage form of any one of claims 60 to 107, which is in the form of a stacked bi or multi layered tablet, wherein one of the layers contains an extended release formulation and one of the other layers contains an immediate release formulation.
110. The extended release dosage form of claim 109, wherein the extended release formulation and the immediate release formulation contain the same or different active agents.
111. The extended release dosage form of claim 109, wherein the extended release formulation comprises an opioid analgesic and the immediate release formulation comprises a non opioid analgesic.
112. A method of treatment wherein a dosage form according to any one of claims 60 to 111 is administered for treatment of pain to a patient in need thereof, wherein the dosage form comprises an opioid analgesic.
113. Use of a dosage form according to any one of claims 60 to 111 for the manufacture of a medicament for the treatment of pain, wherein the dosage form comprises an opioid analgesic.
114. Use of high molecular weight polyethylene oxide that has, based on rheological measurements, a molecular weight of at least 1,000,000, as matrix forming material in the manufacture of a solid extended release oral dosage form comprising an active agent selected from opioids for imparting to the solid extended release oral dosage form resistance to alcohol extraction.
115. A process of preparing a solid oral extended release pharmaceutical dosage form, comprising at least the steps of:
(a) combining at least (1) at least one polyethylene oxide having, based on rheological measurements, a molecular weight of at least 1,000,000, and (2) at least one active agent, to form a composition;
(b) shaping the composition to form an extended release matrix formulation; and (c) curing said extended release matrix formulation comprising at least a curing step of subjecting the extended release matrix formulation to a temperature which is at least the softening temperature of said polyethylene oxide for a time period of at least 5 minutes.
116. The process of claim 115, wherein the composition is shaped to form an extended release matrix formulation in the form of tablet.
117. The process of claim 116, wherein the composition is shaped by direct compression of said composition.
118. The process of any one of claims 115 to 117, wherein in step c) the extended release matrix formulation is subjected to a temperature of at least 60 °C.
119. The process of claim 118 wherein the extended release matrix formulation is subjected to a temperature of from 65 °C to 90 °C.
120. The process of claim 118, wherein the extended release matrix formulation is subjected to a temperature at of least 60 °C or form 65 °C to 90 °C for a time period of at least 15 minutes or at least 30 minutes.
121. The process of claim 118, wherein the dosage form is subjected to a temperature of at least 60 °C or from 65 °C to 85 °C for a time period of at least 60 minutes, at least 75 minutes, at least 90 minutes or for 120 minutes.
122. The process of any one of claims 115 to 121, wherein the extended release matrix formulation in step c) is subjected to a temperature of at least 60 °C, but less than 90 °C or less than 80 °C.
123. The process of any one of claims 115 to 122, wherein the curing step c) takes place in an oven.
124. The process of any one of claims 115 to 122, wherein the curing step c) takes place in a bed of free flowing extended release matrix formulations.
125. The process of claim 124, wherein the curing takes place in a coating pan.
126. The process of any one of claims 115 to 125, comprising a further step of coating the cured extended release matrix formulation.
127. The process of claim 126, comprising the steps of:
(a) combining at least (1) at least one polyethylene oxide having, based on rheological measurements, a molecular weight of at least 1,000,000, and (2) at least one active agent, to form a composition;
(b) shaping said composition to form the extended release matrix formulation in the form of a tablet by direct compression;
(c) curing said tablet by - subjecting a bed of free following tablets to a temperature from 70°C

to 90°C for a time period of at least 30 minutes in a coating pan and - subsequently cooling the bed of free flowing tablets to a temperature of below 50 °C;
and subsequently (d) coating the dosage form in said coating pan.
128. The process of any one of claims 115 to 127, wherein the active agent is an opioid analgesic.
129. The process of claim 128 wherein the opioid analgesic is selected from the group of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl and derivatives, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts, hydrates and solvates thereof, mixtures of any of the foregoing.
130. The process of claim 128, wherein the opioid analgesic is selected from the group of codeine, morphine, oxycodone, hydrocodone, hydromorphone, or oxymorphone or pharmaceutically acceptable salts, hydrates and solvates thereof, mixtures of any of the foregoing.
131. The process of claim 128, wherein the opioid analgesic is oxycodone hydrochloride and the dosage form comprises from 5 mg to 500 mg of oxycodone hydrochloride.
132. The process of claim 131 wherein the dosage form comprises 5 mg, 10 mg, 15 mg, 20 mg, 30, mg, 40 mg, 45 mg, 60 mg, or 80 mg, 90 mg, 120 mg or 160 mg oxycodone hydrochloride.
133. The process of claim 128, wherein the opioid analgesic is oxymorphone hydrochloride and the dosage form comprises from 1 mg to 500 mg of oxymorphone hydrochloride.
134. The process of claim 133 wherein the dosage form comprises 5 mg, 10 mg, 15 mg, 20 mg, 30, mg, 40 mg, 45 mg, 60 mg, or 80 mg, 90 mg, 120 mg or 160 mg oxymorphone hydrochloride.
135. The process of claim 128, wherein the opioid analgesic is hydromorphone hydrochloride and the dosage form comprises from 1 mg to 100 mg of hydromorphone hydrochloride.
136. The process of claim 135, wherein the dosage form comprises 2 mg, 4 mg, 8 mg, 12 mg, 16 mg, 24 mg, 32 mg, 48 mg or 64 mg hydromorphone hydrochloride.
137. The process of any one of claims 115 to 136, wherein the at least one polyethylene oxide has, based on rheological measurements, an approximate molecular weight of from 2,000,000 to 8,000,000.
138. The process of claim 136, wherein the at least one polyethylene oxide has, based on rheological measurements, an approximate molecular weight of 2,000,000, 4,000,000, 7,000,000 or 8,000,000.
139. The process of any one of claims 115 to 138, wherein the composition further comprises at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of less than 1,000,000.
140. The process of claim 139, wherein the composition further comprises at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of from 100,000 to 900,000.
141. The process of claim 139, wherein the composition further comprises at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of 100,000.
142. The process of any one of claims 115 to 141, wherein the overall content of polyethylene oxide in the composition is at least 80 % (by wt).
143. The process of any one of claims 115 to 142, wherein the content in the composition of the at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000 is at least 80 % (by wt).
144. The process of any one of claims 115 to 143, wherein the composition comprises at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000 and at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of less than 1,000,000, wherein the composition comprises at least % (by wt) or at least 20 % (by wt) of the polyethylene oxide having, based on rheological measurements, an approximate molecular weight of less than 1,000,000.
145. The process of claim 144, wherein the dosage form is subjected to a temperature of less than 80 °C or less than 77 °C.
146. A solid oral extended release pharmaceutical dosage form obtainable by a process according to any one of claims 115 to 145.
147. A solid oral extended release pharmaceutical dosage form comprising a extended release matrix formulation in the form of a tablet or multi particulates, wherein the tablet or the individual multi particulates can at least be flattened without breaking, characterized by a thickness of the tablet or of the individual multi particulate after the flattening which corresponds to no more than 60 % of the thickness of the tablet or the individual multi particulate before flattening, and wherein said flattened tablet or the flattened multi particulates provide an in-vitro dissolution rate, when measured in a USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C, characterized by the percent amount of active released at 0.5 hours of dissolution that deviates no more than 20 %
points from the corresponding in-vitro dissolution rate of a non-flattened reference tablet or reference multi particulates.
148. The solid oral extended release pharmaceutical dosage form of claim 147, wherein the tablet or the multi particulates can at least be flattened without breaking, characterized by a thickness of the tablet or the individual multi particulate after the flattening which corresponds to no more than 50 %, or no more than 40%, or no more than 30%, or no more than 20%, or no more than 16% of the thickness of the tablet or the individual multi particulate before flattening, and wherein said flattened tablet or the multi particulates provide an in-vitro dissolution rate, when measured in a USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C, characterized by the percent amount of active released at 0.5 hours of dissolution that deviates no more than 20 % points or no more than 15 %
points from the corresponding in-vitro dissolution rate of a non-flattened reference tablet or reference multi particulates.
149. A solid oral extended release pharmaceutical dosage form comprising a extended release matrix formulation in the form of a tablet or multi particulates, wherein the tablet or the individual multi particulates can at least be flattened without breaking, characterized by a thickness of the tablet or the individual multi particulate after the flattening which corresponds to no more than 60% of the thickness of the tablet or the individual multi particulate before flattening, and wherein the flattened or non flattened tablet or the flattened or non flattened multi particulates provide an in-vitro dissolution rate, when measured in a USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) comprising 40% ethanol at 37° C, characterized by the percent amount of active released at 0.5 hours of dissolution that deviates no more than 20 % points from the corresponding in-vitro dissolution rate measured in a USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C without ethanol, using a flattened and non flattened reference tablet or flattened and non flattened reference multi particulates, respectively.
150. The solid oral extended release pharmaceutical dosage form of claim 149, wherein the tablet or the multi particulates can at least be flattened without breaking, characterized by a thickness of the tablet or the individual multi particulate after the flattening which corresponds to no more than 60%, or no more than 50%, or no more than 40%, or no more than 30%, or no more than 20%, or no more than 16% of the thickness of the tablet or the individual multi particulate before flattening, and wherein the flattened or non flattened tablet or the individual multi particulates provide an in-vitro dissolution rate, when measured in a USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) comprising 40%

ethanol at 37° C, characterized by the percent amount of active released at 0.5 hours of dissolution that deviates no more than 20 % points or no more than 15 %
points from the corresponding in-vitro dissolution rate measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37°
C without ethanol, using a flattened and a non flattened reference tablet or reference multi particulates, respectively.
151. A solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation, the extended release matrix formulation comprising a composition comprising at least:
(1) at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000;
and (2) at least one active agent; and wherein the composition comprises at least 80 % (by wt) polyethylene oxide.
152. The solid oral extended release pharmaceutical dosage form of claim 151, wherein the composition comprises at least 80 % (by wt) polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000.
153. A solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation, the extended release matrix formulation comprising a composition comprising at least:
(1) at least one active agent;
(2) at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000;
and (3) at least one polyethylene oxide having, based on rheological measurements, a molecular weight of less than 1,000,000.
154. The extended release dosage form of claim 153, wherein the composition comprises at least 80 % (by wt) of polyethylene oxide.
155. The extended release dosage form of any one of claims 151 to 154, which is in the form of a tablet formed by direct compression of the composition and cured by at least subjecting said tablet to a temperature of the least 60 °C for a time period of at least 15 minutes.
156. The extended release dosage form of any one of claims 146 to 155, which is in the form of a tablet and which is over coated with a polyethylene oxide powder layer to form a tablet that has a core tablet and a layer of polyethylene oxide surrounding the core tablet.
157. The extended release dosage form of any one of claims 146 to 155, which is in the form of a stacked bi or multi layered tablet, wherein one of the layers contains an extended release formulation and one of the other layers contains an immediate release formulation.
158. The extended release dosage form of claim 157, wherein the extended release formulation and the immediate release formulation contain the same or different active agents.
159. The extended release dosage form of claim 157, wherein the extended release formulation comprises an opioid analgesic and the immediate release formulation comprises a non opioid analgesic..
160. A method of treatment wherein a dosage form according to any one of claims 146 to 155 is administered for treatment of pain to a patient in need thereof, wherein the dosage form comprises an opioid analgesic.
161. Use of a dosage form according to any one of claims 146 to 155 for the manufacture of a medicament for the treatment of pain, wherein the dosage form comprises an opioid analgesic.
162. Use of high molecular weight polyethylene oxide that has, based on rheological measurements, a molecular weight of at least 1,000,000, as matrix forming material in the manufacture of a solid extended release oral dosage form comprising an active selected from opioids for imparting to the solid extended release oral dosage form resistance to alcohol extraction.
163. The process of any one of claims 1 to 58 and 115 to 145, wherein the curing is conducted at atmospheric pressure.
164. The process of any one of claims 23, 24, 124 and 125, wherein magnesium stearate is added during or after the curing step.
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