PHARMACEUTICAL DOSAGE FORMS
20210205295 ยท 2021-07-08
Inventors
Cpc classification
A61K9/209
HUMAN NECESSITIES
A61K45/06
HUMAN NECESSITIES
A61K2300/00
HUMAN NECESSITIES
A61K2300/00
HUMAN NECESSITIES
A61K9/2031
HUMAN NECESSITIES
A61K9/2853
HUMAN NECESSITIES
International classification
Abstract
The invention relates to a solid dosage form comprising a core-shell structure comprising two or more different active agents, wherein the core-shell structure comprises (1) a core comprising a first matrix formulation, the first matrix formulation comprising at least one active agent selected from the group of an active agent (A) and an active agent (B); and (2) a shell encasing the core and comprising a second matrix formulation, wherein the weight ratio of the first matrix formulation to the second matrix formulation is from about 1:10 to about 4:1. In certain embodiments, the solid dosage forms of the invention are in oral solid extended release dosage forms, which provide an extended release of at least a portion of at least one active agent included therein.
Claims
1. A solid oral extended release dosage form comprising a core-shell structure comprising an active agent (A) and an active agent (B), wherein the core-shell structure comprises (1) a core comprising a first matrix formulation, the first matrix formulation comprising at least one active agent selected from active agent (A) and active agent (B); and (2) a shell encasing the core and consisting of a second matrix formulation, wherein the weight ratio of the first matrix formulation to the second matrix formulation is from about 1:10 to about 4:1.
2-4. (canceled)
5. The solid oral extended release dosage form of claim 1, wherein the dosage form comprises a total amount of active agent (A) and a total amount of active agent (B), wherein at least 90 weight-% of the total amount of active agent (A) and at least 90 weight-% of the total amount of active agent (B) are contained in said first matrix formulation and/or said second matrix formulation.
6. The solid oral extended release dosage form of claim 1, wherein the first matrix formulation comprises at least one material selected from the group consisting of polyethylene oxides, alkylcelluloses, cellulose ethers, waxes, shellacs, gums, acrylic resins, polyacrylates, polymethacrylates, and mixtures thereof.
7. The solid oral extended release dosage form of claim 1, wherein the first matrix formulation comprises at least one material selected from the group consisting of polyethylene oxides having, based on rheological measurements, an approximate molecular weight of from 100,000 to 900,000, polyethylene oxides having, based on rheological measurements, an approximate molecular weight of from 1,000,000 to 8,000,000, acrylic and methacrylic acid polymers and copolymers, ethylcellulose, hydroxyalkylcelluloses, hydroxypropylmethylcellulose, carboxyalkylcelluloses, carboxymethylcelluloses, waxes selected from natural and synthetic waxes, fatty acids, and fatty alcohols, hydrogenated castor oil, hydrogenated vegetable oil, and mixtures thereof.
8. The solid oral extended release dosage form of claim 6, wherein the first matrix formulation comprises from about 20 weight-% to about 99 weight-% of said at least one material, preferably from about 40 weight-% to about 99 weight-% of said at least one material, more preferably from about 50 weight-%) to about 99 weight-% of said at least one material, most preferably from about 60 weight-% to about 99 weight-% of said at least one material (based on the weight of the first matrix formulation).
9. (canceled)
10. The solid oral extended release dosage form of claim 1, wherein the second matrix formulation comprises at least one material selected from the group consisting of polyethylene oxides, alkylcelluloses, cellulose ethers, waxes, shellacs, gums, acrylic resins, polyacrylates, polymethacrylates, and mixtures thereof.
11. The solid oral extended release dosage form of claim 1, wherein the second matrix formulation comprises at least one material selected from the group consisting of polyethylene oxides having, based on rheological measurements, an approximate molecular weight of from 100,000 to 900,000, polyethylene oxides having, based on rheological measurements, an approximate molecular weight of from 1,000,000 to 8,000,000, acrylic and methacrylic acid polymers and copolymers, ethylcellulose, hydroxyalkylcelluloses, hydroxypropylmethylcellulose, carboxyalkylcelluloses, carboxymethylcelluloses, waxes selected from natural and synthetic waxes, fatty acids, and fatty alcohols, hydrogenated castor oil, hydrogenated vegetable oil, and mixtures thereof.
12. The solid oral extended release dosage form of claim 10, wherein the second matrix formulation comprises from about 20 weight-% to about 100 weight-% of said at least one material, preferably from about 40 weight-% to about 100 weight-%) of said at least one material, more preferably from about 50 weight-% to about 100 weight-% of said at least one material, most preferably from about 60 weight-% to about 100 weight-% of said at least one material or from about 80 weight-% to about 100 weight-% of said at least one material (based on the weight of the second matrix formulation).
13-21. (canceled)
22. The solid oral extended release dosage form of claim 1, wherein the first matrix formulation comprises at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of from 100,000 to 900,000, preferably of from 100,000 to 600,000, more preferably of from 100,000 to 300,000.
23. (canceled)
24. The solid oral extended release dosage form of claim 1, wherein the first matrix formulation comprises from about 20 weight-% to about 99 weight-% of said at least one polyethylene oxide, preferably from about 40 weight-%) to about 99 weight-% of said at least one polyethylene oxide, more preferably from about 50 weight-%>to about 99 weight-%) of said at least one polyethylene oxide, most preferably from about 60 weight-% to about 99 weight-%) of said at least one polyethylene oxide (based on the weight of the first matrix formulation).
25-33. (canceled)
34. The solid oral extended release dosage form of claim 1, wherein both the first matrix formulation and the second matrix formulation comprise at least one polyethylene oxide.
35. (canceled)
36. The solid oral extended release dosage form of claim 34, wherein the first matrix formulation comprises at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of from 1,000,000 to 8,000,000; and the second matrix formulation comprises at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of from 100,000 to 600,000.
37. (canceled)
38. The solid oral extended release dosage form of claim 34, wherein the first matrix formulation comprises from about 50 weight-% to about 95 weight-% of said at least one polyethylene oxide, preferably from about 60 weight-% to about 95 weight-% of said at least one polyethylene oxide (based on the weight of the first matrix formulation), and the second matrix formulation comprises from about 60 weight-% to about 99 weight-% of said at least one polyethylene oxide, preferably from about 80 weight-% to about 98 weight-%) of said at least one polyethylene oxide (based on the weight of the second matrix formulation).
39. The solid oral extended release dosage form of claim 34, wherein the first matrix formulation comprises from about 50 weight-% to about 95 weight-%, preferably from about 60 weight-% to about 95 weight-% (based on the weight of the first matrix formulation) of at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of from 2,000,000 to 8,000,000, and the second matrix formulation comprises from about 60 weight-% to about 99 weight-%, preferably from about 85 weight-% to about 98 weight-% (based on the weight of the second matrix formulation) of at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of from 100,000 to 300,000.
40-49. (canceled)
50. The solid oral extended release dosage form of claim 1, wherein the dosage form comprises a plurality of particles, each particle comprising said core-shell structure.
51-56. (canceled)
57. The solid oral extended release dosage form of claim 1, wherein the first matrix formulation and the second matrix formulation have a CIE L*A*B* value within 10% of each other.
58. (canceled)
59. The solid oral extended release dosage form of claim 1, wherein the active agent (A) is an opioid agonist, and the active agent (B) is selected from the group consisting of antihistamines, nonsteroidal anti-inflammatory agents, anti-emetics, anti-epileptics, vasodilators, anti-tussive agents and expectorants, anti-asthmatics, antacids, anti-spasmodics, antidiabetics, diuretics, anti-hypotensives, antihypertensives, bronchodilators, steroids, antibiotics, antihemorrhoidals, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, vitamins, stimulants, appetite suppressants, and cannabinoids.
60. The solid oral extended release dosage form of claim 1, wherein the active agent (A) is an opioid agonist, and the active agent (B) is a non-opioid analgesic.
61-127. (canceled)
128. A method of treating or preventing pain comprising administering to a patient identified in need thereof a solid oral extended release dosage form according to claim 1, wherein active agent (A) is an opioid analgesic.
129-133. (canceled)
134. A method of independently adjusting the in vitro release profiles of an active agent (A) and an active agent (B) from a solid oral extended release dosage form, comprising preparing a core-shell structure comprising an amount of the active agent (A) and an amount of the active agent (B), wherein the core-shell structure comprises (1) a core comprising a first matrix formulation, and (2) a shell encasing the core and consisting of a second matrix formulation, wherein the weight ratio of the first matrix formulation to the second matrix formulation is from about 1:10 to about 4:1, wherein the amount of active agent (A) is distributed between the first and the second matrix formulation, and the amount of active agent (B) is distributed between the first and the second matrix formulation, such that the first matrix formulation comprises at least one active agent selected from active agent (A) and active agent (B), and providing said dosage form with said core-shell structure.
135. (canceled)
Description
BRIEF DESCRIPTION OF THE DRAWINGS
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DETAILED DESCRIPTION
[0113] In certain embodiments, the invention is directed to a solid oral extended release dosage form comprising a core-shell structure comprising an active agent (A) and an active agent (B), wherein the core-shell structure comprises [0114] (1) a core comprising a first matrix formulation, [0115] the first matrix formulation comprising at least one active agent selected from active agent (A) and active agent (B); and [0116] (2) a shell encasing the core and consisting of a second matrix formulation,
wherein the weight ratio of the first matrix formulation to the second matrix formulation is from about 1:10 to about 4:1.
[0117] In certain embodiments, the weight ratio of the first matrix formulation to the second matrix formulation is from about 1:10 to about 3:1, or from about 1:8 to about 3:1. In certain embodiments, the weight ratio of the first matrix formulation to the second matrix formulation is from about 1:7 to about 3:1, from about 1:6 to about 3:1, or from about 1:5 to about 3:1. In certain embodiments, the weight ratio of the first matrix formulation to the second matrix formulation is from about 1:5 to about 2:1, from about 1:5 to about 1:1, from about 1:5 to about 9:10, from about 1:4 to about 9:10, or from about 1:4 to about 5:6.
[0118] In certain embodiments, the dosage form comprises a total amount of active agent (A) and a total amount of active agent (B), wherein at least 90 weight % of the total amount of active agent (A) and at least 90 weight % of the total amount of active agent (B) are contained in the first matrix formulation and/or the second matrix formulation of the core-shell structure. In certain embodiments, at least 95 weight % of the total amount of active agent (A) and at least 95 weight % of the total amount of active agent (B) are contained in the first matrix formulation and/or the second matrix formulation of the core-shell structure. In certain embodiments, the total amount of active agent (A) and the total amount of active agent (B) are contained in the first matrix formulation and/or the second matrix formulation of the core-shell structure. It is understood that the total amount of active agent (A) and the total amount of active agent (B) contained in the solid oral extended release dosage form each represent a therapeutically effective amount.
[0119] In certain embodiments, the core comprises from about 90 weight-% to about 100 weight-%, or from about 95 weight-% to about 100 weight-%, or from about 98 weight-% to about 100 weight-% of the first matrix formulation. The indicated weight percentage values are based on the weight of the core. In certain embodiments, the core consists of the first matrix formulation.
Matrix Formulations
[0120] In certain embodiments, the first matrix formulation comprises at least one material selected from the group consisting of polyethylene oxides, acrylic polymers, alkylcelluloses, cellulose ethers, waxes, shellacs, gums, acrylic resins, polyacrylates, polymethacrylates, copolymers, and mixtures thereof.
[0121] In certain embodiments, the first matrix formulation comprises at least one material selected from the group consisting of polyethylene oxides having, based on rheological measurements, an approximate molecular weight of from 100,000 to 900,000, polyethylene oxides having, based on rheological measurements, an approximate molecular weight of from 1,000,000 to 8,000,000, acrylic and methacrylic acid polymers and copolymers, ethylcellulose, hydroxyalkylcelluloses, hydroxypropylmethylcellulose, carboxyalkyl-celluloses, carboxymethylcelluloses, waxes selected from natural and synthetic waxes, fatty acids, and fatty alcohols, hydrogenated castor oil, hydrogenated vegetable oil, and mixtures thereof.
[0122] In certain embodiments, the first matrix formulation comprises from about 20 weight-% to about 99 weight-%, or from about 40 weight-% to about 99 weight-%, or from about 50 weight-% to about 99 weight-%, or from about 60 weight-% to about 99 weight-% of said at least one material. In certain embodiments, the first matrix formulation comprises from about 20 weight-% to about 98 weight-%, or from about 40 weight-% to about 98 weight-%, or from about 50 weight-% to about 95 weight-%, or from about 60 weight-% to about 95 weight-% of said at least one material. The indicated weight percentage values are based on the weight of the first matrix formulation.
[0123] In certain embodiments, the second matrix formulation comprises at least one material selected from the group consisting of polyethylene oxides, alkylcelluloses, cellulose ethers, waxes, shellacs, gums, acrylic resins, polyacrylates, polymethacrylates, and mixtures thereof. In certain embodiments, the second matrix formulation comprises at least one material selected from the group consisting of polyethylene oxides having, based on rheological measurements, an approximate molecular weight of from 100,000 to 900,000, polyethylene oxides having, based on rheological measurements, an approximate molecular weight of from 1,000,000 to 8,000,000, acrylic and methacrylic acid polymers and copolymers, ethylcellulose, hydroxyalkylcelluloses, hydroxypropylmethylcellulose, carboxyalkylcelluloses, carboxymethylcelluloses, waxes selected from natural and synthetic waxes, fatty acids, and fatty alcohols, hydrogenated castor oil, hydrogenated vegetable oil, and mixtures thereof.
[0124] In certain embodiments, the second matrix formulation comprises from about 20 weight-% to about 100 weight-%, or from about 40 weight-% to about 100 weight-%, or from about 50 weight-% to about 100 weight-%, or from about 60 weight-% to about 100 weight-%, or from about 80 weight-% to about 100 weight-% of said at least one material. In certain embodiments, the second matrix formulation comprises from about 20 weight-% to about 99 weight-%, or from about 40 weight-% to about 99 weight-%, or from about 50 weight-% to about 99 weight-%, or from about 60 weight-% to about 99 weight-%, or from about 80 weight-% to about 99 weight-% of said at least one material. In certain embodiments, the second matrix formulation comprises from about 40 weight-% to about 98 weight-%, or from about 50 weight-% to about 98 weight-%, or from about 60 weight-% to about 98 weight-%, or from about 80 weight-% to about 98 weight-%, or from about 80 weight-% to about 98 weight-% of said at least one material. The indicated weight percentage values are based on the weight of the second matrix formulation.
[0125] In certain embodiments, the first matrix formulation further comprises a lubricant. In certain embodiments, the first matrix formulation comprises from about 0.5 weight-% to about 5 weight-%, or from about 0.5 weight-% to about 2 weight-% of the lubricant. The indicated weight percentage values are based on the weight of the first matrix formulation.
[0126] In certain embodiments, the second matrix formulation further comprises a lubricant. In certain embodiments, the second matrix formulation comprises from about 0.5 weight-% to about 5 weight-%, or from about 0.5 weight-% to about 2 weight-% of the lubricant. The indicated weight percentage values are based on the weight of the second matrix formulation.
[0127] In certain embodiments, both the first matrix formulation and the second matrix formulation comprise a lubricant. In certain embodiments, both the first matrix formulation and the second matrix formulation comprise from about 0.5 weight-% to about 2 weight-% of the lubricant.
[0128] In certain embodiments, the lubricant included in the first matrix formulation and/or the second matrix formulation is selected from the group consisting of magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, magnesium lauryl sulfate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, and mixtures thereof. In certain embodiments, the lubricant included in the first matrix formulation and/or the second matrix formulation is magnesium stearate.
Matrix Formulations Comprising Polyethylene Oxide
[0129] In certain embodiments, the first matrix formulation comprises at least one polyethylene oxide.
[0130] In certain embodiments, the first matrix formulation comprises at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of from 100,000 to 900,000, or of from 100,000 to 600,000, or of from 100,000 to 300,000. In certain embodiments, the first matrix formulation comprises at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of 100,000, 200,000, 300,000, 600,000 or 900,000.
[0131] In certain embodiments, the first matrix formulation comprises at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of from 1,000,000 to 8,000,000, or of from 2,000,000 to 8,000,000, or of from 4,000,000 to 8,000,000. In certain embodiments, the first matrix formulation comprises at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of 4,000,000, 5,000,000, 7,000,000, or 8,000,000. In certain embodiments, the first matrix formulation comprises at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of 4,000,000, or 5,000,000. In certain embodiments, the first matrix formulation comprises at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of 4,000,000.
[0132] For example, the following polyethylene oxide grades are commercially available from Dow Chemical company under the tradename POLYOX Water-Soluble Resins NF, and can be used in embodiments of the invention:
TABLE-US-00001 Approximate molecular weight PEO grade (based on rheological measurements) POLYOX WSR N-10 NF 100,000 POLYOX WSR N-80 NF 200,000 POLYOX WSR N-750 NF 300,000 POLYOX WSR-205 NF 600,000 POLYOX WSR-1105 NF 900,000 POLYOX WSR N-12K NF 1,000,000 POLYOX WSR N-60K NF 2,000,000 POLYOX WSR-301 NF 4,000,000 POLYOX WSR Coagulant NF 5,000,000 POLYOX WSR-303 NF 7,000,000
[0133] In certain embodiments, the first matrix formulation comprises from about 20 weight-% to about 99 weight-%, or from about 40 weight-% to about 99 weight-%, or from about 50 weight-% to about 99 weight-%, or from about 60 weight-% to about 99 weight-% of said at least one polyethylene oxide. In certain embodiments, the first matrix formulation comprises from about 20 weight-% to about 98 weight-%, or from about 40 weight-% to about 98 weight-%, or from about 50 weight-% to about 95 weight-%, or from about 60 weight-% to about 95 weight-% of said at least one polyethylene oxide. The indicated weight percentage values are based on the weight of the first matrix formulation.
[0134] In certain embodiments, in the first matrix formulation, the at least one polyethylene oxide, the optional active agent (A), the optional active agent (B), and an optional lubricant together make up from about 95 weight-% to about 100 weight-% of the first matrix formulation, or from about 98 weight-% to about 100 weight-% of the first matrix formulation, or from about 99 weight-% to about 100 weight-% of the first matrix formulation. The indicated weight percentage values are based on the weight of the first matrix formulation.
[0135] In certain embodiments, the second matrix formulation comprises at least one polyethylene oxide.
[0136] In certain embodiments, the second matrix formulation comprises at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of from 100,000 to 900,000, or of from 100,000 to 600,000, or of from 100,000 to 300,000. In certain embodiments, the second matrix formulation comprises at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of 100,000, 200,000, 300,000, 600,000 or 900,000. In certain embodiments, the second matrix formulation comprises at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of 100,000, 200,000, or 300,000. In certain embodiments, the second matrix formulation comprises at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of 100,000.
[0137] In certain embodiments, the second matrix formulation comprises at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of from 1,000,000 to 8,000,000, or of from 2,000,000 to 8,000,000, or of from 4,000,000 to 8,000,000. In certain embodiments, the second matrix formulation comprises at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of 4,000,000, 5,000,000, 7,000,000, or 8,000,000.
[0138] In certain embodiments, the second matrix formulation comprises from about 20 weight-% to about 100 weight-%, or from about 40 weight-% to about 100 weight-%, or from about 50 weight-% to about 100 weight-%, or from about 60 weight-% to about 100 weight-%, or from about 80 weight-% to about 100 weight-% of said at least one polyethylene oxide. In certain embodiments, the second matrix formulation comprises from about 20 weight-% to about 99 weight-%, or from about 40 weight-% to about 99 weight-%, or from about 50 weight-% to about 99 weight-%, or from about 60 weight-% to about 99 weight-%, or from about 80 weight-% to about 99 weight-% of said at least one polyethylene oxide. In certain embodiments, the second matrix formulation comprises from about 40 weight-% to about 98 weight-%, or from about 50 weight-% to about 98 weight-%, or from about 60 weight-% to about 98 weight-%, or from about 80 weight-% to about 98 weight-%, or from about 85 weight-to about 98 weight-% of said at least one polyethylene oxide. The indicated weight percentage values are based on the weight of the second matrix formulation.
[0139] In certain embodiments, in the second matrix formulation, the at least one polyethylene oxide, the optional active agent (A), the optional active agent (B), and an optional lubricant together make up from about 95 weight-% to about 100 weight-% of the second matrix formulation, or from about 98 weight-% to about 100 weight-% of the second matrix formulation, or from about 99 weight-% to about 100 weight-% of the second matrix formulation.
[0140] In certain embodiments, both the first matrix formulation and the second matrix formulation comprise at least one polyethylene oxide.
[0141] In certain embodiments, the first matrix formulation comprises at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of from 100,000 to 600,000, and the second matrix formulation comprises at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of from 1,000,000 to 8,000,000.
[0142] In certain embodiments, the first matrix formulation comprises at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of from 1,000,000 to 8,000,000; and the second matrix formulation comprises at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of from 100,000 to 600,000.
[0143] In certain embodiments, the first matrix formulation comprises at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of from 1,000,000 to 8,000,000; and the second matrix formulation comprises at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of from 1,000,000 to 8,000,000.
[0144] In certain embodiments, the first matrix formulation comprises from about 50 weight-% to about 95 weight-%, or from about 60 weight-% to about 95 weight-% of said at least one polyethylene oxide (based on the weight of the first matrix formulation), and the second matrix formulation comprises from about 60 weight-% to about 99 weight-%, or from about 80 weight-% to about 98 weight-% of said at least one polyethylene oxide (based on the weight of the second matrix formulation).
[0145] In certain embodiments, the first matrix formulation comprises from about 50 weight-% to about 95 weight-%, or from about 60 weight-% to about 95 weight-% (based on the weight of the first matrix formulation) of at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of from 2,000,000 to 8,000,000, and the second matrix formulation comprises from about 60 weight-% to about 99 weight-%, or from about 85 weight-% to about 98 weight-% (based on the weight of the second matrix formulation) of at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of from 100,000 to 300,000.
[0146] In certain embodiments, the first matrix formulation and the second matrix formulation comprise different percentages (weight-%) of polyethylene oxide, different percentages (weight-%) of active agent (A), and/or different percentages (weight-%) of active agent (B).
[0147] In certain embodiments, wherein the first matrix formulation comprises at least one polyethylene oxide, the first matrix formulation may be cured by subjecting the first matrix formulation to a temperature of from about 60 C. to about 90 C., or from about 62 C. to about 90 C., for a time period of from about 1 minute to about 24 hours, or from about 5 minutes to about 12 hours, or from about 15 minutes to about 5 hours. In certain embodiments, the curing step is conducted at atmospheric pressure.
[0148] In certain embodiments, wherein the first matrix formulation and the second matrix formulation comprise at least one polyethylene oxide, the first matrix formulation and the second matrix formulation may be cured by subjecting the first matrix formulation and the second matrix formulation to a temperature of from about 60 C. to about 90 C., or from about 62 C. to about 90 C., for a time period of from about 1 minute to about 24 hours, or from about 5 minutes to about 12 hours, or from about 15 minutes to about 5 hours. In certain embodiments, the curing step is conducted at atmospheric pressure.
[0149] In certain embodiments, the solid oral extended release dosage form as described herein is obtainable by a process comprising the following steps: [0150] a) combining at least [0151] at least one polyethylene oxide, [0152] at least one active agent selected from active agent (A) and active agent (B), and optionally a lubricant, to form a first composition, [0153] b) combining at least [0154] at least one polyethylene oxide, [0155] optionally at least one active agent selected from active agent (A) and active agent (B), and [0156] optionally a lubricant to form a second composition, [0157] c) shaping the first composition of step (a) to form the first matrix formulation, [0158] d) optionally curing said first matrix formulation comprising subjecting said first matrix formulation to a temperature of from about 60 C. to about 90 C., or from about 62 C. to about 90 C., for a time period of from about 1 minute to about 24 hours, [0159] e) applying the second composition of step (b) around the first matrix formulation of step (c) or (d) to form the second matrix formulation encasing the first matrix formulation; [0160] f) optionally curing said first matrix formulation and said second matrix formulation comprising subjecting said first matrix formulation and said second matrix formulation to a temperature of from about 60 C. to about 90 C., or from about 62 C. to about 90 C., for a time period of from about 1 minute to about 24 hours.
[0161] In certain embodiments, the first composition is shaped in step (c) by direct compression of said first composition. In certain embodiments, the second composition is applied in step (e) by compression-coating said second composition. In certain embodiments, the optional curing step (d) and/or (f) is conducted at atmospheric pressure.
[0162] The curing process may provide the matrix formulation(s) with a certain hardness, which can impede the crushing or pulverization of the dosage form.
Solid Oral Extended Release Dosage Form
[0163] In certain embodiments, the solid oral extended release dosage form as described herein is in the form of a tablet or a capsule. In certain embodiments, the solid oral extended release dosage form as described herein is in the form of a tablet. In certain embodiments, the solid oral extended release dosage form as described herein is in the form of a capsule.
[0164] In other embodiments, the solid oral extended release dosage forms of the invention comprise other extended release formulations known in the art. For example, the core-shell structure of the invention may be present in the form of coated beads, coated pellets, coated tablets or ion exchange resins.
[0165] In certain embodiments, the solid oral extended release dosage form as described herein comprises a plurality of particles, wherein each particle comprises said core-shell structure.
[0166] In certain embodiments, the solid oral extended release dosage form as described herein comprises at least two minitablets, each minitablet comprising said core-shell structure. In certain embodiments, the core-shell structure contained in the dosage form is in the form of a single-unit dose tablet. In certain embodiments, the core is a compressed tablet and the shell is a compression coating.
[0167] In certain embodiments, the core and the shell are visually indistinguishable. In certain embodiments, the first matrix formulation (of the core) and the second matrix formulation (of the shell) have a CIE L*A*B* value within 10% of each other.
Active Agents
[0168] In certain embodiments, the molar ratio of the active agent (A) contained in the dosage form to the active agent (B) contained in the dosage form is from about 1:100 to about 100:1, or from about 1:50 to about 50:1, or from about 1:30 to about 30:1, or from about 1:1 to about 30:1, or from about 1:1 to about 20:1.
[0169] The active agent that can be used in accordance with the invention can be any pharmaceutically active substance, either in the free base form or the pharmaceutically acceptable salt form. In certain embodiments, the active agent (A) and the active agent (B) belong to the same class of compounds (e.g., opioid analgesics). In other embodiments, the active agent (A) and the active agent (B) belong to different classes of compounds; for example, one active agent is an anti-epileptic drug, and the other active agent is a non-opioid analgesic.
[0170] In certain embodiments, the active agent (A) is an opioid agonist, and the active agent (B) is selected from the group consisting of antihistamines, non-steroidal anti-inflammatory agents, anti-emetics, anti-cancer agents, antidepressant agents, anti-epileptics, vasodilators, anti-tussive agents and expectorants, anti-asthmatics, antacids, anti-spasmodics, antidiabetics, diuretics, anti-hypotensives, antihypertensives, bronchodilators, steroids, antibiotics, antihemorrhoidals, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, vitamins, stimulants, appetite suppressants, non-opioid analgesics, and cannabinoids.
[0171] In certain embodiments, the active agent (A) is an opioid agonist, and the active agent (B) is a non-opioid analgesic. In certain embodiments, the non-opioid analgesic is selected from the group consisting of non-steroidal anti-inflammatory agents. In certain embodiments, the non-opioid analgesic is acetaminophen.
[0172] In certain embodiments, the active agent (A) is an opioid agonist, and the active agent (B) is an opioid antagonist. In certain embodiments, the opioid antagonist is selected from the group consisting of naloxone, naltrexone, methylnaltrexone, and nalmephene.
[0173] In certain embodiments, the active agent (A) is an opioid agonist, and the active agent (B) is a different opioid agonist.
[0174] In certain embodiments, the opioid agonist is selected from the group consisting 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, 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, tapentadol, tilidine, and tramadol. In certain embodiments, the opioid agonist is selected from the group consisting of codeine, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tramadol.
[0175] In certain embodiments, the active agent (A) is selected from the group consisting of codeine, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tramadol, and the active agent (B) is buprenorphine. In certain embodiments, the active agent (A) is oxycodone, and the active agent (B) is buprenorphine.
[0176] In certain embodiments comprising buprenophine as the active agent (B), the dosage form can comprise a total amount of buprenorphine which is equimolar to from about 0.5 mg to about 20 mg, or from about 2 mg to about 20 mg, or from about 2 mg to about 16 mg, of buprenorphine base (Mw=467.64 g/mol). In certain embodiments, the active agent (B) is buprenorphine hydrochloride and the dosage form comprises a total amount of buprenorphine hydrochloride which is equimolar to from about 0.5 mg to about 20 mg, or from about 2 mg to about 20 mg, or from about 2 mg to about 16 mg, of buprenorphine base (Mw=467.64 g/mol).
[0177] In certain embodiments comprising oxycodone as the active agent (A), the dosage form can comprise a total amount of oxycodone which is equimolar to from about 5 mg to about 500 mg, or from about 5 mg to about 160 mg, or from about 5 mg to about 120 mg, or from about 10 mg to about 80 mg of oxycodone hydrochloride (Mw=351.82 g/mol). In certain embodiments, the active agent (A) is oxycodone hydrochloride and the dosage form comprises a total amount of oxycodone hydrochloride which is equimolar to from about 5 mg to about 500 mg, or from about 5 mg to about 160 mg, or from about 5 mg to about 120 mg, or from about 10 mg to about 80 mg, of oxycodone hydrochloride (Mw=351.82 g/mol). In certain embodiments, the dosage form comprises a total amount of oxycodone hydrochloride which is equimolar to about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 45 mg, about 60 mg, about 80 mg, about 90 mg, about 120 mg or about 160 mg of oxycodone hydrochloride (Mw=351.82 g/mol).
[0178] In certain embodiments, the active agent (A) is oxycodone, and the active agent (B) is buprenorphine, and the dosage form comprises a total amount of oxycodone which is equimolar to from about 10 mg to about 80 mg of oxycodone hydrochloride (Mw=351.82 g/mol), and a total amount of buprenorphine which is equimolar to from about 0.5 mg to about 20 mg of buprenorphine base (Mw=467.64 g/mol). In certain embodiments, oxycodone is oxycodone hydrochloride, and buprenorphine is buprenorphine hydrochloride.
[0179] In certain embodiments, the active agent (A) is oxycodone, and the active agent (B) is buprenorphine, and the dosage form comprises [0180] a total amount of oxycodone, and [0181] a total amount of buprenorphine,
wherein the weight ratio of the total amount of oxycodone in the dosage form to the total amount of buprenorphine in the dosage form is from about 3:1 to about 20:1, calculated with the total amount of oxycodone in the dosage form expressed as the equimolar amount of oxycodone hydrochloride (Mw=351.82 g/mol) in mg and the total amount of buprenorphine in the dosage form expressed as the equimolar amount of buprenorphine base (Mw=467.64 g/mol) in mg. In certain embodiments, the weight ratio of the total amount of oxycodone in the dosage form to the total amount of buprenorphine in the dosage form is from about 4:1 to about 20:1, or from about 4:1 to about 10:1, or from about 5:1 to about 10:1. In certain embodiments, oxycodone is oxycodone hydrochloride, and buprenorphine is buprenorphine hydrochloride.
Distribution of Active Agents (A) and (B) Between the First and the Second Matrix Formulations
[0182] In certain embodiments, the invention is directed to a solid oral extended release dosage form comprising a core-shell structure comprising an active agent (A) and an active agent (B), wherein the core-shell structure comprises [0183] (1) a core comprising a first matrix formulation, [0184] the first matrix formulation comprising at least one active agent selected from active agent (A) and active agent (B); and [0185] (2) a shell encasing the core and consisting of a second matrix formulation, [0186] the second matrix formulation comprising at least one active agent selected from active agent (A) and active agent (B),
wherein the weight ratio of the first matrix formulation to the second matrix formulation is from about 1:10 to about 4:1.
[0187] In certain embodiments, the first matrix formulation comprises both active agent (A) and active agent (B), and the second matrix formulation comprises at least one active agent selected from active agent (A) and active agent (B). In other embodiments, the first matrix formulation comprises at least one active agent selected from active agent (A) and active agent (B), and the second matrix formulation comprises both active agent (A) and active agent (B).
[0188] Thus, in certain embodiments, the core-shell structure comprises [0189] (1) a core comprising a first matrix formulation, the first matrix formulation comprising both active agent (A) and active agent (B); and [0190] (2) a shell encasing the core and consisting of a second matrix formulation, the second matrix formulation comprising at least one active agent selected from active agent (A) and active agent (B).
[0191] In other embodiments, the core-shell structure comprises [0192] (1) a core comprising a first matrix formulation, the first matrix formulation comprising at least one active agent selected from active agent (A) and active agent (B); and [0193] (2) a shell encasing the core and consisting of a second matrix formulation, the second matrix formulation comprising both active agent (A) and active agent (B).
[0194] In certain embodiments (referred to herein embodiment #1), the core-shell structure comprises [0195] (1) a core comprising a first matrix formulation, the first matrix formulation comprising both active agent (A) and active agent (B); and [0196] (2) a shell encasing the core and consisting of a second matrix formulation, the second matrix formulation comprising both active agent (A) and active agent (B).
[0197] In certain embodiments (referred to herein embodiment #2), the core-shell structure comprises [0198] (1) a core comprising a first matrix formulation, the first matrix formulation comprising both active agent (A) and active agent (B); and [0199] (2) a shell encasing the core and consisting of a second matrix formulation, the second matrix formulation comprising active agent (B) and no active agent (A).
[0200] In certain embodiments (referred to herein embodiment #3), the core-shell structure comprises [0201] (1) a core comprising a first matrix formulation, the first matrix formulation comprising both active agent (A) and active agent (B); and [0202] (2) a shell encasing the core and consisting of a second matrix formulation, the second matrix formulation comprising active agent (A) and no active agent (B).
[0203] In certain embodiments (referred to herein embodiment #4), the core-shell structure comprises [0204] (1) a core comprising a first matrix formulation, the first matrix formulation comprising active agent (A) and no active agent (B); and [0205] (2) a shell encasing the core and consisting of a second matrix formulation, the second matrix formulation comprising both active agent (A) and active agent (B).
[0206] In certain embodiments (referred to herein embodiment #5), the core-shell structure comprises [0207] (1) a core comprising a first matrix formulation, the first matrix formulation comprising active agent (B) and no active agent (A); and [0208] (2) a shell encasing the core and consisting of a second matrix formulation, the second matrix formulation comprising both active agent (A) and active agent (B).
[0209] In certain embodiments, wherein both the first matrix formulation and the second matrix formulation comprise the active agent (A), the weight ratio of the active agent (A) in the first matrix formulation to the active agent (A) in the second matrix formulation can be from about 1:50 to about 50:1, or from about 1:20 to about 20:1, or from about 1:10 to about 10:1, or from about 1:2 to about 50:1, or from about 1:2 to about 20:1, or from about 1:2 to about 10:1, or from about 1:1 to about 20:1, or from about 1:1 to about 10:1, or from about 1:1 to about 9:1, or from about 1:1 to about 5:1, or from about 2:1 to about 5:1.
[0210] In certain embodiments, wherein both the first matrix formulation and the second matrix formulation comprise the active agent (B), the weight ratio of the active agent (B) in the first matrix formulation to the active agent (B) in the second matrix formulation can be from about 1:50 to about 50:1, or from about 1:20 to about 20:1, or from about 1:10 to about 10:1, or from about 1:50 to about 2:1, or from about 1:20 to about 2:1, or from about 1:10 to about 2:1, or from about 1:20 to about 1:1, or from about 1:10 to about 1:1, or from about 1:9 to about 1:1, or from about 1:5 to about 1:1, or from about 1:5 to about 1:2.
[0211] In certain embodiments (referred to herein embodiment #6), the core-shell structure comprises [0212] (1) a core comprising a first matrix formulation, the first matrix formulation comprising active agent (A) and no active agent (B); and [0213] (2) a shell encasing the core and consisting of a second matrix formulation, the second matrix formulation comprising active agent (B) and no active agent (A).
[0214] In certain embodiments (referred to herein embodiment #7), the core-shell structure comprises [0215] (1) a core comprising a first matrix formulation, the first matrix formulation comprising active agent (B) and no active agent (A); and [0216] (2) a shell encasing the core and consisting of a second matrix formulation, the second matrix formulation comprising active agent (A) and no active agent (B).
[0217] In certain embodiments (referred to herein embodiment #8), the core-shell structure comprises [0218] (1) a core comprising a first matrix formulation, the first matrix formulation comprising both active agent (A) and active agent (B); and [0219] (2) a shell encasing the core and consisting of a second matrix formulation, the second matrix formulation comprising neither active agent (A), nor active agent (B).
[0220] In certain embodiments (referred to herein embodiment #1A), the core-shell structure comprises [0221] (1) a core comprising a first matrix formulation, the first matrix formulation comprising [0222] from about 60 weight-% to about 95 weight-% (based on the weight of the first matrix formulation) of at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of from 1,000,000 to 8,000,000, [0223] a first amount of active agent (A), and [0224] a first amount of active agent (B); and [0225] (2) a shell encasing the core and consisting of a second matrix formulation, the second matrix formulation comprising [0226] from about 80 weight-% to about 98 weight-% (based on the weight of the second matrix formulation) of at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of from 100,000 to 600,000, [0227] a second amount of active agent (A), and [0228] a second amount of active agent (B);
wherein the weight ratio of the first matrix formulation to the second matrix formulation is from about 1:5 to about 2:1. In certain embodiments, the weight ratio of the first matrix formulation to the second matrix formulation is from about 1:5 to about 1:1, or from about 1:5 to about 9:10, or from about 1:4 to about 9:10, or from about 1:3 to about 9:10, or from about 1:4 to about 5:6, or from about 1:3 to about 5:6, or from about 1:2 to about 5:6, or from about 1:2 to about 3:4.
[0229] In certain embodiments, the weight ratio of the first amount of active agent (A) to the second amount of active agent (A) is from about 1:2 to about 10:1, and the weight ratio of the first amount of active agent (B) to the second amount of active agent (B) is from about 1:10 to about 2:1.
[0230] In other embodiments, the weight ratio of the first amount of active agent (A) to the second amount of active agent (A) is from about 1:1 to about 10:1, and the weight ratio of the first amount of active agent (B) to the second amount of active agent (B) is from about 1:10 to about 1:1.
[0231] In separate embodiments, the weight ratio of the first amount of active agent (A) to the second amount of active agent (A) is from about 1:1 to about 9:1, and weight ratio of the first amount of active agent (B) to the second amount of active agent (B) is from about 1:9 to about 1:1.
[0232] In certain embodiments, the weight ratio of the first amount of active agent (A) to the second amount of active agent (A) is from about 1:1 to about 5:1, and the weight ratio of the first amount of active agent (B) to the second amount of active agent (B) is from about 1:5 to about 1:1.
[0233] In an example of embodiment #1A, the active agent (A) is an opioid analgesic selected from the group of oxycodone, hydromorphone, fentanyl, morphine, or pharmaceutically acceptable salts thereof; and the active agent (B) is buprenorphine free base or a pharmaceutically acceptable salt thereof (collectively, as buprenorphine). In one embodiment, the active agent (A) is oxycodone free base or a pharmaceutically acceptable salt thereof (collectively, as oxycodone). In certain embodiments, the weight ratio of the total amount of the opioid analgesic (e.g., oxycodone) in the dosage form to the total amount of buprenorphine in the dosage form is from about 4:1 to about 20:1, or from about 4:1 to about 10:1. In certain embodiments, the active agent (A) in the dosage form is oxycodone hydrochloride, and the active agent (B) in the dosage form is buprenorphine hydrochloride.
In Vitro Release
[0234] In certain embodiments, the active agent (A) is oxycodone, and the amount of oxycodone released from the dosage form, as measured by an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37.0 C., meets at least one of the following criteria (a) to (d): [0235] a) the amount of oxycodone released from the dosage form at 1 hour is from about 3 weight-% to about 45 weight-%; and/or [0236] b) the amount of oxycodone released from the dosage form at 2 hours is from about 10 weight-% to about 65 weight-%; and/or [0237] c) the amount of oxycodone released from the dosage form at 4 hours is from about 40 weight-% to about 80 weight-%; and/or [0238] d) the amount of oxycodone released from the dosage form at 8 hours is from about 70 weight-% to about 98 weight-%.
[0239] In certain embodiments, the active agent (A) is oxycodone, and the amount of oxycodone released from the dosage form, as measured by an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37.0 C., meets at least one of the following criteria (a) to (d): [0240] a) the amount of oxycodone released from the dosage form at 1 hour is from about 5 weight-% to about 35 weight-%; and/or [0241] b) the amount of oxycodone released from the dosage form at 2 hours is from about from 20 weight-% to about 55 weight-%; and/or [0242] c) the amount of oxycodone released from the dosage form at 4 hours is from about 45 weight-% to about 75 weight-%; and/or [0243] d) the amount of oxycodone released from the dosage form at 8 hours is from about 75 weight-% to about 95 weight-%.
[0244] In certain embodiments, the active agent (B) is buprenorphine, and the amount of buprenorphine released from the dosage form, as measured by an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37.0 C., meets at least one of the following criteria (a) to (d): [0245] a) the amount of buprenorphine released from the dosage form at 1 hour is from about 20 weight-% to about 75 weight-%; and/or [0246] b) the amount of buprenorphine released from the dosage form at 2 hours is from about 40 weight-% to about 100 weight-%; and/or [0247] c) the amount of buprenorphine released from the dosage form at 4 hours is from about 45 weight-% to about 100 weight-%; and/or [0248] d) the amount of buprenorphine released from the dosage form at 8 hours is from about 50 weight-% to about 100 weight-%.
[0249] In certain embodiments, the active agent (B) is buprenorphine, and the amount of buprenorphine released from the dosage form, as measured by an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37.0 C., meets at least one of the following criteria (a) to (d): [0250] a) the amount of buprenorphine released from the dosage form at 1 hour is from about 30 weight-% to about 70 weight-%; and/or [0251] b) the amount of buprenorphine released from the dosage form at 2 hours is from about 50 weight-% to about 90 weight-%; and/or [0252] c) the amount of buprenorphine released from the dosage form at 4 hours is from about 55 weight-% to about 95 weight-%; and/or [0253] d) the amount of buprenorphine released from the dosage form at 8 hours is from about 60 weight-% to about 98 weight-%.
[0254] In certain embodiments, the active agent (A) is oxycodone and the active agent (B) is buprenorphine, and the amount of buprenorphine (in weight-% based on 100% buprenorphine) released from the dosage form at 1 hour exceeds the amount of oxycodone (in weight-% based on 100% oxycodone) released from the dosage form at 1 hour by a factor of at least 1.1, as measured by an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37.0 C. In certain embodiments, said factor is at least 1.2, or at least 1.5.
[0255] In certain embodiments, the active agent (A) is oxycodone and the active agent (B) is buprenorphine and the amount of buprenorphine (in weight-% based on 100% buprenorphine) released from the dosage form at 2 hours exceeds the amount of oxycodone (in weight-% based on 100% oxycodone) released from the dosage form at 2 hours by a factor of at least 1.1, as measured by an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37.0 C. In certain embodiments, said factor is at least 1.2, or at least 1.5.
[0256] In certain embodiments, the active agent (A) is oxycodone and the active agent (B) is buprenorphine and the amount of buprenorphine (in weight-% based on 100% buprenorphine) released from the dosage form at 4 hours exceeds the amount of oxycodone (in weight-% based on 100% oxycodone) released from the dosage form at 4 hours by a factor of at least 1.1, as measured by an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37.0 C. In certain embodiments, said factor is at least 1.2, or at least 1.5.
Manufacture of the Solid Dosage Forms
[0257] In certain embodiments, the solid oral extended release dosage form as described herein is manufactured by a process comprising the steps of: [0258] (i) combining at least [0259] at least one material selected from the group consisting of polyethylene oxides, alkylcelluloses, cellulose ethers, waxes, shellacs, gums, acrylic resins, polyacrylates, polymethacrylates, and mixtures thereof, [0260] at least one active agent selected from active agent (A) and active agent (B), and optionally a lubricant, to form a first composition, [0261] (ii) combining at least [0262] at least one material selected from the group consisting of polyethylene oxides, alkylcelluloses, cellulose ethers, waxes, shellacs, gums, acrylic resins, polyacrylates, polymethacrylates, and mixtures thereof, [0263] optionally at least one active agent selected from active agent (A) and active agent (B), and [0264] optionally a lubricant to form a second composition, [0265] (iii) shaping the first composition of step (i) to form the first matrix formulation, (iv) applying the second composition of step (ii) around the first matrix formulation to form the second matrix formulation encasing the first matrix formulation.
[0266] In certain embodiments, the solid oral extended release dosage form as described herein is manufactured by a process comprising the steps of: [0267] (i) combining at least [0268] at least one material selected from the group consisting of polyethylene oxides having, based on rheological measurements, an approximate molecular weight of from 100,000 to 900,000, polyethylene oxides having, based on rheological measurements, an approximate molecular weight of from 1,000,000 to 8,000,000, acrylic and methacrylic acid polymers and copolymers, ethylcellulose, hydroxyalkylcelluloses, hydroxypropylmethylcellulose, carboxyalkylcelluloses, carboxymethylcelluloses, waxes selected from natural and synthetic waxes, fatty acids, and fatty alcohols, hydrogenated castor oil, hydrogenated vegetable oil, and mixtures thereof, [0269] at least one active agent selected from active agent (A) and active agent (B), and [0270] optionally a lubricant, to form a first composition, [0271] (ii) combining at least [0272] at least one material selected from the group consisting of polyethylene oxides having, based on rheological measurements, an approximate molecular weight of from 100,000 to 900,000, polyethylene oxides having, based on rheological measurements, an approximate molecular weight of from 1,000,000 to 8,000,000, acrylic and methacrylic acid polymers and copolymers, ethylcellulose, hydroxyalkylcelluloses, hydroxypropylmethylcellulose, carboxyalkylcelluloses, carboxymethylcelluloses, waxes selected from natural and synthetic waxes, fatty acids, and fatty alcohols, hydrogenated castor oil, hydrogenated vegetable oil, and mixtures thereof, [0273] optionally at least one active agent selected from active agent (A) and active agent (B), and [0274] optionally a lubricant to form a second composition, [0275] (iii) shaping the first composition of step (i) to form the first matrix formulation, [0276] (iv) applying the second composition of step (ii) around the first matrix formulation to form the second matrix formulation encasing the first matrix formulation.
[0277] The shaping step (iii) can be performed, e.g., by direct compression, extrusion or molding of the first composition to form the first matrix formulation. However, any other process known in the art for manufacturing tablets or tablet cores, may also be used, such as wet granulation and subsequent compression of the granules to form tablets.
[0278] In certain embodiments, the first composition is shaped in step (iii) by direct compression of said first composition. Direct compression is an efficient and simple process for shaping tablets by avoiding process steps like wet granulation. Direct compression can be used, e.g., to prepare core-shell structures in the form of tablets or minitablets, wherein the core is a compressed tablet and the shell is a compression coating.
[0279] Step (iv) can be performed, e.g. by compression coating, molding, or spraying of the second composition, or by dipping into the second composition. In certain embodiments, the second composition is applied in step (iv) by compression-coating said second composition.
[0280] In certain embodiments, the first composition is shaped in step (iii) by direct compression of said first composition, and the second composition is applied in step (iv) by compression-coating said second composition.
[0281] In certain embodiments, the processes as described above comprise a further step (v) of coating the core-shell structure (e.g., by coating the second matrix formulation). In certain embodiments, the coating is a film coating (e.g., a cosmetic film coating such as an Opadry coating).
[0282] In certain embodiments, the invention is also directed to a solid oral extended release dosage form as described herein obtainable by the described processes of manufacture.
[0283] In certain embodiments, the solid oral extended release dosage form as described herein is manufactured by a process comprising the steps of: [0284] a) combining at least [0285] at least one polyethylene oxide, [0286] at least one active agent selected from active agent (A) and active agent (B), and [0287] optionally a lubricant, to form a first composition, [0288] b) combining at least [0289] at least one polyethylene oxide, [0290] optionally at least one active agent selected from active agent (A) and active agent (B), and [0291] optionally a lubricant to form a second composition, [0292] c) shaping the first composition of step (a) to form the first matrix formulation, [0293] d) optionally curing said first matrix formulation comprising subjecting said first matrix formulation to a temperature of from about 60 C. to about 90 C., or from about 62 C. to about 90 C., for a time period of from about 1 minute to about 24 hours, [0294] e) applying the second composition of step (b) around the first matrix formulation of step (c) or (d) to form the second matrix formulation encasing the first matrix formulation; [0295] f) optionally curing said first matrix formulation and said second matrix formulation comprising subjecting said first matrix formulation and said second matrix formulation to a temperature of from about 60 C. to about 90 C., or from about 62 C. to about 90 C., for a time period of from about 1 minute to about 24 hours.
[0296] The shaping step (c) can be performed, e.g., by direct compression, extrusion or molding of the first composition to form the first matrix formulation (due to the elevated temperature applied during extrusion or molding, a subsequent curing step may be unnecessary). However, any other process known in the art for manufacturing tablets or tablet cores, may also be used, such as wet granulation and subsequent compression of the granules to form tablets.
[0297] In certain embodiments, the first composition is shaped in step (c) by direct compression of said first composition. Direct compression can be used, e.g., to prepare core-shell structures in the form of tablets or minitablets, wherein the core is a compressed tablet and the shell is a compression coating.
[0298] Step (e) of applying the second composition can be performed, e.g. by compression coating, molding, or spraying of the second composition, or by dipping into the second composition. In certain embodiments, the second composition is applied in step (e) by compression-coating said second composition.
[0299] In certain embodiments, the first composition is shaped in step (c) by direct compression of said first composition, and the second composition is applied in step (e) by compression-coating said second composition. In certain such embodiments, the core is a compressed tablet and the shell is a compression coating.
[0300] The process of manufacture, and in particular, the shaping step (c) and the optional curing steps (d) and/or (f) including curing temperatures, curing times with starting points and end points of the curing, and devices used for the curing step, can be conducted in analogy to the teaching of PCT publication WO 2008/023261, in particular paragraphs [0046], [00126] to [00146], [00159] to [00161] thereof; the contents of which are hereby incorporated by reference. The shaping step (c) and step (e) of applying the second composition, including techniques and respective devices, as well as the optional curing steps (d) and/or (f) including curing temperatures, curing times with starting points and end points of the curing, and devices used for the curing step, can also be conducted in analogy to the teaching of PCT publication WO 2012/085656, in particular paragraphs [00113] to [00116], [00126] to [00132] and [00165] to [00187] thereof, the contents of which are hereby incorporated by reference.
[0301] In certain embodiments, the curing of step (d) and/or (f) is conducted at atmospheric pressure.
[0302] In certain embodiments, the curing of step (d) and/or (f) is conducted by subjecting the extended release matrix formulation to a temperature of from about 60 C. to about 90 C. for a time period of from about 1 minute to about 24 hours.
[0303] In certain embodiments, the curing of step (d) and/or (f) is conducted by subjecting the extended release matrix formulation to a temperature of from about 62 C. to about 85 C. for a time period of from about 5 minutes to about 5 hours.
[0304] In certain embodiments, the curing of step (d) and/or (f) is conducted by subjecting the extended release matrix formulation to a temperature of from about 65 C. to about 85 C. for a time period of from about 15 minutes to about 2 hours.
[0305] In certain embodiments, the curing of step (d) and/or (f) is conducted such that at least about 20%, or at least about 40%, or at least about 75%, or about 100% of the polyethylene oxide melts.
[0306] In certain embodiments, the process of manufacture comprises a curing step (f), and no curing step (d).
[0307] In certain embodiments, the process as described above comprises a further step (g) of coating the optionally cured core-shell structure (e.g., by coating the second matrix formulation). In certain such embodiments, the coating is a film coating (e.g., a cosmetic film coating, such as an Opadry coating).
[0308] In certain embodiments, an initial film coating or a fraction of a film coating is applied prior to performing curing step (d) and/or (f). This film coating provides an overcoat for the matrix formulations to function as an anti-tacking agent, i.e. to avoid that the matrix formulations stick together. In certain such embodiments the film coating which is applied prior to the curing step is an Opadry film coating. After the curing step (f), a further film coating step can be performed.
[0309] The invention is also directed to a solid oral extended release pharmaceutical dosage form obtained by a process as described herein.
Adjustment of In Vitro Release Profiles
[0310] In certain embodiments, the invention is directed to the use of a core-shell structure comprising an amount of an active agent (A) and an amount of an active agent (B), wherein said core-shell structure comprises [0311] (1) a core comprising a first matrix formulation, [0312] the first matrix formulation comprising at least one active agent selected from active agent (A) and active agent (B), and [0313] (2) a shell encasing the core and consisting of a second matrix formulation, [0314] wherein the weight ratio of the first matrix formulation to the second matrix formulation is from about 1:10 to about 4:1,
in a solid oral extended release dosage form, for independently adjusting the in vitro release profiles of the active agent (A) and the active agent (B) from said dosage form.
[0315] The in vitro release profiles of the active agent (A) and the active agent (B) from said dosage form can be independently adjusted by distributing the amount of active agent (A) between the first and the second matrix formulation, and distributing the amount of active agent (B) between the first and the second matrix formulation (e.g., such that a core-shell structure belonging to one of the embodiments #1 to #8 is realized, and/or by realizing one of the above described weight ratios of the active agent (A) in the first matrix formulation to the active agent (A) in the second matrix formulation, and/or by realizing one of the above described weight ratios of the active agent (B) in the first matrix formulation to the active agent (B) in the second matrix formulation). For a dosage form with a given total amount of active agent (A) and active agent (B), the in vitro release profiles of the active agent (A) and the active agent (B) from said dosage form can additionally be adjusted, e.g., by modifying the weight ratio of the first matrix formulation to the second matrix formulation (e.g., by realizing one of the weight ratios as described above), by modifying the materials used for the first and the second matrix formulation and their respective weight-% amounts, etc.
[0316] In certain embodiments, the use of the core-shell structure is in a solid oral extended release dosage form with the features as described herein.
[0317] In certain embodiments, the invention is directed to a method of independently adjusting the in vitro release profiles of an active agent (A) and an active agent (B) from a solid oral extended release dosage form, comprising [0318] preparing a core-shell structure comprising an amount of the active agent (A) and an amount of the active agent (B), wherein the core-shell structure comprises [0319] (1) a core comprising a first matrix formulation, and [0320] (2) a shell encasing the core and consisting of a second matrix formulation, [0321] wherein the weight ratio of the first matrix formulation to the second matrix formulation is from about 1:10 to about 4:1, [0322] wherein the amount of active agent (A) is distributed between the first and the second matrix formulation, and the amount of active agent (B) is distributed between the first and the second matrix formulation, such that the first matrix formulation comprises at least one active agent selected from active agent (A) and active agent (B), and [0323] providing said dosage form with said core-shell structure.
[0324] In certain embodiments, the solid oral extended release dosage form is a solid oral extended release dosage form with the features as described herein.
Methods of Treatment
[0325] Depending upon the nature (and efficacy) of the active agents incorporated therein, the solid dosage forms of the invention can be used to treat or prevent various conditions or diseases. For example, when the solid dosage forms include one or more anticancer agents, the solid dosage forms are useful for treating or preventing a cancer (or, preventing or inhibiting the maturation and proliferation of a neoplasm), which the anticancer agent has been proven to be efficacious. Likewise, when the solid dosage forms include one or more CNS stimulants (e.g., amphetamine, and methylphenidate), the solid dosage forms are useful for boosting brain activities in a patient, thereby treating conditions including such as, attention deficit hyperactivity disorder (ADHD) and narcolepsy.
[0326] In certain embodiments, the solid dosage forms of the invention include at least an analgesic (e.g., opioid or non-opioid analgesics). Thus, certain aspects of the invention provide a method of treating or preventing pain comprising administering to a patient identified in need thereof a solid oral extended release dosage form as described herein, wherein at least one of the active agents an analgesic. In one embodiment, the active agent (A) is an opioid analgesic.
[0327] In certain embodiments, the invention is directed to a solid oral extended release dosage form as described herein for use in a method of treating or preventing pain.
[0328] In one embodiment, the invention is directed to the use of a solid oral extended release dosage form as described herein for the manufacture of a medicament for treating or preventing pain.
[0329] In separate embodiments, the solid dosage forms of this invention contain an opioid analgesic and buprenorphine as the active agents. In certain embodiments, these solid dosage forms are useful for treating or preventing pain in a patient with reduced opioid-induced adverse pharmacodynamic responses. In other embodiments, the dosage forms of this invention are useful for treating or preventing one or more reduced opioid-induced adverse pharmacodynamic responses in a patient.
[0330] The opioid-induced adverse pharmacodynamic response is selected from the group consisting of bowel dysfunction, nausea, vomiting, somnolence, dizziness, respiratory depression, headache, dry mouth, sedation, sweats, asthenia, hypotension, dysphoria, delirium, miosis, pruritus, urticaria, urinary retention, allodynia, physical dependence and tolerance. In certain embodiments, the buprenorphine is included in a therapeutically effective amount. In some embodiments, the buprenorphine included in the solid dosage form is in the sub-analgesic amount.
[0331] The disclosures on benefits and/or uses associated with certain solid dosage forms of the invention can be found in US Patent Publication No. 2016/0106735 A1 and PCT Publication No. WO2013156850 A1, both of which are incorporated herein by their entireties.
EXAMPLES
[0332] The invention will now be more fully described with reference to the accompanying examples. It should be understood, however, that the following description is illustrative only and should not be taken in any way as a restriction of the invention.
Materials and General Information
[0333] For the manufacture of tablets according to Examples 1-17 below, the following materials were used:
TABLE-US-00002 Manufacturer/ Material supplier Lot Number(s) Oxycodone hydrochloride.sup.1 Rhodes 29-12 XYK Technologies Buprenorphine hydrochloride Noramco/ 15JN140-4 (Noramco) Rhodes 4-15BUH (Rhodes) Polyethylene Oxide NF Dow Chemical D682F6HPB3 (POLYOX WSR-301, 2I1701DLB5 (FP grade) LEO) Polyethylene Oxide NF Dow Chemical ZL2955S5H3 (POLYOX WSR N-10) Magnesium Stearate.sup.2 Peter Greven C302873 .sup.1According to the certificate of analysis, the oxycodone HCl material used for Examples 1-17 below has a water content of 5.2% + residual solvent 0.08% + total impurities 0.2%, which sums up to 5.48 (weight-)% in total. Accordingly, an adjustment factor can be calculated as follows: 100% 5.48% = 94.52% = 0.9452; .sup.2non-bovine
[0334] In the tables given below, which specify the composition of the tablets according to Examples 1-17, the respective column Target mg/unit [0335] refers to the amount of pure oxycodone hydrochloride (Mw=351.82 g/mol); and [0336] expresses the amount of buprenorphine hydrochloride as the equivalent amount of buprenorphine base (1 mg of buprenorphine HCl corresponding to 0.93 mg of buprenorphine base).
By contrast, the respective column Formulation (mg/unit) indicates the actual formulation and [0337] refers to the amount of oxycodone hydrochloride material (mg/unit) to be actually used to reach the target mg/unit of pure oxycodone hydrochloride (Mw=351.82 g/mol), which is calculated by applying the above indicated adjustment factor of 0.9452; and [0338] indicates the amount of buprenorphine hydrochloride (mg/unit) to be actually used.
[0339] Whenever the below tables refer to the weight ratio oxycodone.sub.total/buprenorphine.sub.total, the weight ratio of the total amount of oxycodone in the tablet to the total amount of buprenorphine in the tablet is meant, calculated with the total amount of oxycodone in the tablet expressed as the equimolar amount of oxycodone hydrochloride (Mw=351.82 g/mol) in mg and the total amount of buprenorphine in the tablet expressed as the equimolar amount of buprenorphine base (Mw=467.64 g/mol) in mg.
[0340] The In vitro dissolution testing of the tablets according to Examples 1-17 below was performed as follows: Tablets (uncured, or cured for a time period as indicated) were tested in vitro using a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37.0+0.5 C. In order to reduce the propensity of the tablets, once hydrated in the dissolution medium, to stick to the solid underside of the top of the basket or the base of the shaft, a retaining spring (passivized stainless steel 316 spring, 1.5-cm outside diameter and 2-cm length) was placed in the upper part of the basket (above the tablet). Sampling time points included 0.5, 1.0, 2.0, 4.0, 8.0, 12.0 and 18.0 hours (or as indicated). The samples were analyzed by reversed-phase high performance liquid chromatography (HPLC) on Waters) (Bridge phenyl, 4.675 mm, 3.5 m column maintained at 60 C. using a gradient method with mobile phase consisting of acetonitrile and potassium phosphate monobasic and ammonium hexafluorophosphate buffer with UV detection at 285 nm and 212 nm.
Example 1
[0341] In Example 1, tablets comprising oxycodone hydrochloride in the core and buprenorphine hydrochloride in the shell and having the composition as shown in Tables 1.1 and 1.2 were prepared.
TABLE-US-00003 TABLE 1.1 Target Formulation Formulation mg/unit (mg/unit) (weight-%) Core Oxycodone HCl 10.00 10.58 7.05 Buprenorphine HCl 0.00 0.00 0.00 Polyethylene Oxide ad 150.00 137.92 91.95 POLYOX WSR-301 Magnesium Stearate 1.50 1.50 1.00 Total core 150.00 150.00 100.00 Shell Oxycodone HCl 0.00 0.00 0.00 Buprenorphine HCl 0.50.sup.1 0.54 0.27 Polyethylene Oxide ad 200.00 197.96 98.98 POLYOX WSR N-10 Magnesium Stearate 1.50 1.50 0.75 Total shell 200.00 200.00 100.00 .sup.1expressed as equivalent amount of buprenorphine base
TABLE-US-00004 TABLE 1.2 Target Core + Shell mg/unit Weight ratios Oxycodone HCl 10.00 Buprenorphine HCl 0.50.sup.1 Weight ratio 20 oxycodone.sub.total/ buprenorphine.sub.total Total weight core + shell 350.00 Weight ratio core/shell 0.75 .sup.1expressed as equivalent amount of buprenorphine base
[0342] The processing steps to manufacture tablets of Example 1 were as follows:
Preparation of Core Blend:
[0343] 1. Polyethylene oxide (POLYOX WSR-301) was weighed and transferred into a 20 mL disposable scintillation vial. An individual vial was used for each preparation. [0344] 2. The active(s) and magnesium stearate were weighed and transferred into the scintillation vial of step 1. [0345] 3. The materials in the scintillation vial were vortexed for 15 seconds to yield the core blend.
Preparation of Shell Blend:
[0346] 4. Polyethylene oxide (POLYOX WSR N-10) was weighed and transferred into a 20 mL disposable scintillation vial. An individual vial was used for each preparation. [0347] 5. The active(s) and magnesium stearate were weighed and transferred into the scintillation vial of step 4. [0348] 6. The materials in the scintillation vial were vortexed for 15 seconds to yield the shell blend.
Preparation of Core Tablet:
[0349] 7. The core blend was discharged onto a weighing paper (tapping the scintillation vial with a spatula to dispense as much of the core blend as possible). [0350] 8. A Carver Press was setup with 9/32 inch unmarked, round concave tooling. [0351] 9. The core blend was transferred into the die and compressed by applying a compression force of 1500-1700 lbs.sup.1 to yield the core tablet. .sup.1 lb.=1 pound=0.45359237 kg
Preparation of Core-Shell Tablet(s)
[0352] 10. The shell blend was discharged onto a weighing paper (tapping the scintillation vial with a spatula to dispense as much of the shell blend as possible). [0353] 11. A Carver Press was set up with inch, round concave tooling. [0354] 12. Approximately half of the amount of the shell blend was transferred into the die. [0355] 13. The core tablet of step 9 was placed into the center of the die containing half of the amount of the shell blend. [0356] 14. The remaining amount of the shell blend was transferred into the die to cover the sides and the top of the core tablet. [0357] 15. Subsequently the shell blend was compressed by applying a compression force of 1000-1200 lbs to yield the core-shell tablet. [0358] 16. Steps 1 to 15 were repeated to yield several core-shell tablets.
Curing
[0359] 17. For curing, core-shell tablets were placed on a mesh screen and cured in a preheated gravity-flow convection oven at a temperature of 70 C. for 30 minutes.
[0360] The results of the in vitro dissolution testing of tablets of Example 1 are shown in Table 1.3 and in
TABLE-US-00005 TABLE 1.3 In vitro dissolution results for Example 1 Dissolution time [hours] 0.5 1 2 4 8 12 18 % oxycodone HCl released 1 6 22 48 78 89 93 % buprenorphine HCl 28 54 71 69 68 71 79 released Thickness (mm) Diameter (mm) Core tablet 3.99 7.09 Core-Shell tablet before curing 5.32 9.41 Core-Shell tablet after curing 5.88 9.55
Example 2
[0361] In Example 2, tablets comprising oxycodone hydrochloride and buprenorphine hydrochloride both in the core and in the shell and having the composition as shown in Tables 2.1 and 2.2 were prepared.
TABLE-US-00006 TABLE 2.1 Target Formulation Formulation mg/unit (mg/unit) (weight-%) Core Oxycodone HCl 7.500 7.93 5.29 Buprenorphine HCl 0.1251 0.13 0.09 Polyethylene Oxide ad 150.000 140.44 93.63 POLYOX WSR-301 Magnesium Stearate 1.500 1.50 1.00 Total core 150.000 150.00 100.00 Shell Oxycodone HCl 2.500 2.64 1.32 Buprenorphine HCl 0.375 0.40 0.20 Polyethylene Oxide ad 200.000 195.46 97.73 POLYOX WSR N-10 Magnesium Stearate 1.500 1.50 0.75 Total shell 200.000 200.00 100.00 .sup.1 expressed as equivalent amount of buprenorphine base
TABLE-US-00007 TABLE 2.2 Target Core + Shell mg/unit Weight ratios Oxycodone HCl 10.00 Weight ratio 3 oxycodone HCl.sub.core/ oxycodone HCl.sub.shell Buprenorphine HCl 0.50.sup.1 Weight ratio 0.33 buprenorphine HCl.sub.core/ buprenorphine HCl.sub.shell Weight ratio 20 oxycodone.sub.total/ buprenorphine.sub.total Total weight core + shell 350.00 Weight ratio core/shell 0.75 .sup.1expressed as equivalent amount of buprenorphine base
[0362] The processing steps to manufacture tablets of Example 2 correspond to the process of manufacture (steps 1 to 17) as described for Example 1.
[0363] The results of the in vitro dissolution testing of tablets of Example 2 are shown in Table 2.3 and in
TABLE-US-00008 TABLE 2.3 In vitro dissolution results for Example 2 Dissolution time [hours] 0.5 1 2 4 8 12 18 % oxycodone HCl released 10 21 39 59 83 92 95 % buprenorphine HCl 22 41 57 58 62 68 75 released Thickness (mm) Diameter (mm) Core tablet 4.11 7.10 Core-Shell tablet before curing 5.30 9.40 Core-Shell tablet after curing 5.97 9.55
Example 3
[0364] In Example 3, tablets comprising oxycodone hydrochloride and buprenorphine hydrochloride both in the core and in the shell and having the composition as shown in Tables 3.1 and 3.2 were prepared.
TABLE-US-00009 TABLE 3.1 Target Formulation Formulation mg/unit (mg/unit) (weight-%) Core Oxycodone HCl 60.00 63.48 25.39 Buprenorphine HCl 4.00.sup.1 4.30 1.72 Polyethylene Oxide ad 250.00 179.72 71.89 POLYOX WSR-301 Magnesium Stearate 2.50 2.50 1.00 Total core 250.00 250.00 100.00 Shell Oxycodone HCl 20.00 21.16 7.05 Buprenorphine HCl 12.00 12.90 4.30 Polyethylene Oxide ad 300.00 263.44 87.81 POLYOX WSR N-10 Magnesium Stearate 2.50 2.50 0.83 Total shell 300.00 300.00 100.00 .sup.1expressed as equivalent amount of buprenorphine base
TABLE-US-00010 TABLE 3.2 Target Core + Shell mg/unit Weight ratios Oxycodone HCl 80.00 Weight ratio 3 oxycodone HCl.sub.core/ oxycodone HCl.sub.shell Buprenorphine HCl 16.00.sup.1 Weight ratio 0.33 buprenorphine HCl.sub.core/ buprenorphine HCl.sub.shell Weight ratio 5 oxycodone.sub.total/ buprenorphine.sub.total Total weight core + shell 550.00 Weight ratio core/shell 0.83 .sup.1expressed as equivalent amount of buprenorphine base
[0365] The processing steps to manufacture tablets of Example 3 correspond to the process of manufacture (steps 1 to 17) as described for Example 1, with the following particulars: [0366] In step 8, 11/32 inch, round concave tooling was used. [0367] In step 11, 15/32 inch, round concave tooling was used.
[0368] The results of the in vitro dissolution testing of tablets of Example 3 are shown in Table 3.3 and in
TABLE-US-00011 TABLE 3.3 In vitro dissolution results for Example 3 Dissolution time [hours] 0.5 1 2 4 8 12 18 % oxycodone HCl released 11 23 40 59 81 91 94 % buprenorphine HCl 25 50 70 76 82 87 89 released Thickness (mm) Diameter (mm). Core tablet 4.26 8.75 Core-Shell tablet before curing 5.96 11.88 Core-Shell tablet after curing 6.40 11.38
Example 4
[0369] In Example 4, tablets comprising oxycodone hydrochloride and buprenorphine hydrochloride both in the core and in the shell and having the composition as shown in Tables 4.1 and 4.2 were prepared.
TABLE-US-00012 TABLE 4.1 Target Formulation Formulation mg/unit (mg/unit) (weight-%) Core Oxycodone HCl 72.00 76.17 30.47 Buprenorphine HCl 1.60 1.72 0.69 Polyethylene Oxide ad 250.00 169.61 67.84 POLYOX WSR-301 Magnesium Stearate 2.50 2.50 1.00 Total core 250.00 250.00 100.00 Shell Oxycodone HCl 8.00 8.46 2.82 Buprenorphine HCl 14.40.sup.1 15.48 5.16 Polyethylene Oxide ad 300.00 273.56 91.19 POLYOX WSR N-10 Magnesium Stearate 2.50 2.50 0.83 Total shell 300.00 300.00 100.00 .sup.1expressed as equivalent amount of buprenorphine base
TABLE-US-00013 TABLE 4.2 Target Core + Shell mg/unit Weight ratios Oxycodone HCl 80.00 Weight ratio 9 oxycodone HCl.sub.core/ oxycodone HCl.sub.shell Buprenorphine HCl 16.00.sup.1 Weight ratio 0.11 buprenorphine HCl.sub.core/ buprenorphine HCl.sub.shell Weight ratio 5 oxycodone.sub.total/ buprenorphine.sub.total Total weight core + shell 550.00 Weight ratio core/shell 0.83 .sup.1expressed as equivalent amount of buprenorphine base
[0370] The processing steps to manufacture tablets of Example 4 correspond to the process of manufacture (steps 1 to 17) as described for Example 3.
[0371] The results of the in vitro dissolution testing of tablets of Example 4 are shown in Table 4.3 and in
TABLE-US-00014 TABLE 4.3 In vitro dissolution results for Example 4 Dissolution time [hours] 0.5 1 2 4 8 12 18 % oxycodone HCl released 4 12 31 54 80 91 95 % buprenorphine HCl 28 59 82 87 90 92 92 released Thickness (mm) Diameter (mm) Core tablet 4.38 8.80 Core-Shell tablet before curing 5.98 11.87 Core-Shell tablet after curing 6.44 11.35
Example 5
[0372] In Example 5, tablets comprising oxycodone hydrochloride and buprenorphine hydrochloride both in the core and in the shell and having the composition as shown in Tables 5.1 and 5.2 were prepared.
TABLE-US-00015 TABLE 5.1 Target Formulation Formulation mg/unit (mg/unit) (weight-%) Core Oxycodone HCl 30.00 31.74 21.16 Buprenorphine HCl 2.00.sup.1 2.15 1.43 Polyethylene Oxide ad 150.00 114.61 76.41 POLYOX WSR-301 Magnesium Stearate 1.50 1.50 1.00 Total core 150.00 150.00 100.00 Shell Oxycodone HCl 10.00 10.58 5.29 Buprenorphine HCl 6.00 6.45 3.23 Polyethylene Oxide ad 200.00 181.47 90.74 POLYOX WSR N-10 Magnesium Stearate 1.50 1.50 0.75 Total shell 200.00 200.00 100.00 .sup.1expressed as equivalent amount of buprenorphine base
TABLE-US-00016 TABLE 5.2 Target Core + Shell mg/unit Weight ratios Oxycodone HCl 40.00 Weight ratio 3 oxycodone HCl.sub.core/ oxycodone HCl.sub.shell Buprenorphine HCl 8.00.sup.1 Weight ratio 0.33 buprenorphine HCl.sub.core/ buprenorphine HCl.sub.shell Weight ratio 5 oxycodone.sub.total/ buprenorphine.sub.total Total weight core + shell 350.00 Weight ratio core/shell 0.75 .sup.1expressed as equivalent amount of buprenorphine base
[0373] The processing steps to manufacture tablets of Example 5 correspond to the process of manufacture (steps 1 to 17) as described for Example 1, with the following particulars: [0374] In step 9, a compression force of 1000-1200 lbs was applied. [0375] In step 15, a compression force of 1800-2000 lbs was applied.
[0376] The results of the in vitro dissolution testing of tablets of Example 5 are shown in Table 5.3 and in
TABLE-US-00017 TABLE 5.3 In vitro dissolution results for Example 5 Dissolution time [hours] 0.5 1 2 4 8 12 18 % oxycodone HCl released 12 25 44 65 86 92 94 % buprenorphine HCl 29 60 75 82 91 95 96 released Weight Thickness Diameter (mg) (mm) (mm) Core tablet 147.5 4.04 7.12 Core-Shell tablet before curing 341.4 5.18 9.46 Core-Shell tablet after curing 339.5 5.73 9.25
Example 6
[0377] In Example 6, tablets comprising oxycodone hydrochloride and buprenorphine hydrochloride both in the core and in the shell and having the composition as shown in Tables 6.1 and 6.2 were prepared.
TABLE-US-00018 TABLE 6.1 Target Formulation Formulation mg/unit (mg/unit) (weight-%) Core Oxycodone HCl 30.00 31.74 21.16 Buprenorphine HCl 2.00.sup.1 2.15 1.43 Polyethylene Oxide ad 150.00 114.61 76.41 POLYOX WSR-301 Magnesium Stearate 1.50 1.50 1.00 Total core 150.00 150.00 100.00 Shell Oxycodone HCl 10.00 10.58 4.23 Buprenorphine HCl 6.00 6.45 2.58 Polyethylene Oxide ad 250.00 231.47 92.59 POLYOX WSR N-10 Magnesium Stearate 1.50 1.50 0.60 Total shell 250.00 250.00 100.00 .sup.1expressed as equivalent amount of buprenorphine base
TABLE-US-00019 TABLE 6.2 Target Core + Shell mg/unit Weight ratios Oxycodone HCl 40.00 Weight ratio 3 oxycodone HCl.sub.core/ oxycodone HCl.sub.shell Buprenorphine HCl 8.00.sup.1 Weight ratio 0.33 buprenorphine HCl.sub.core/ buprenorphine HCl.sub.shell Weight ratio 5 oxycodone.sub.total/ buprenorphine.sub.total Total weight core + shell 400.00 Weight ratio core/shell 0.6 .sup.1expressed as equivalent amount of buprenorphine base
[0378] The processing steps to manufacture tablets of Example 6 correspond to the process of manufacture (steps 1 to 17) as described for Example 5.
[0379] The results of the in vitro dissolution testing of tablets of Example 6 are shown in Table 6.3 and in
TABLE-US-00020 TABLE 6.3 In vitro dissolution results for Example 6 Dissolution time [hours] 0.5 1 2 4 8 12 18 % oxycodone HCl released 10 22 41 62 85 92 94 % buprenorphine HCl 25 53 75 83 91 96 98 released Weight Thickness Diameter (mg) (mm) (mm) Core tablet 146.7 4.05 7.12 Core-Shell tablet before curing 394.2 5.82 9.48 Core-Shell tablet after curing 392.3 6.35 9.24
Example 7
[0380] In Example 7, tablets comprising oxycodone hydrochloride and buprenorphine hydrochloride both in the core and in the shell and having the composition as shown in Tables 7.1 and 7.2 were prepared.
TABLE-US-00021 TABLE 7.1 Target Formulation Formulation mg/unit (mg/unit) (weight-%) Core Oxycodone HCl 30.00 31.74 31.74 Buprenorphine HCl 2.00.sup.1 2.15 2.15 Polyethylene Oxide ad 100.00 64.61 64.61 POLYOX WSR-301 Magnesium Stearate 1.50 1.50 1.50 Total core 100.00 100.00 100.00 Shell Oxycodone HCl 10.00 10.58 3.53 Buprenorphine HCl 6.00 6.45 2.15 Polyethylene Oxide ad 300.00 281.47 93.82 POLYOX WSR N-10 Magnesium Stearate 1.50 1.50 0.50 Total shell 300.00 300.00 100.00 .sup.1expressed as equivalent amount of buprenorphine base
TABLE-US-00022 TABLE 7.2 Target Core + Shell mg/unit Weight ratios Oxycodone HCl 40.00 Weight ratio 3 oxycodone HCl.sub.core/ oxycodone HCl.sub.shell Buprenorphine HCl 8.00.sup.1 Weight ratio 0.33 buprenorphine HCl.sub.core/ buprenorphine HCl.sub.shell Weight ratio 5 oxycodone.sub.total/ buprenorphine.sub.total Total weight core + shell 400.00 Weight ratio core/shell 0.33 .sup.1expressed as equivalent amount of buprenorphine base
[0381] The processing steps to manufacture tablets of Example 7 correspond to the process of manufacture (steps 1 to 17) as described for Example 5.
[0382] The results of the in vitro dissolution testing of tablets of Example 7 are shown in Table 7.3 and in
TABLE-US-00023 TABLE 7.3 In vitro dissolution results for Example 7 Dissolution time [hours] 0.5 1 2 4 8 12 18 % oxycodone HCl released 9 19 44 76 92 94 95 % buprenorphine HCl 22 46 73 86 95 97 97 released Weight Thickness Diameter (mg) (mm) (mm) Core tablet 96.7 2.96 7.14 Core-Shell tablet before curing 393.6 5.74 9.49 Core-Shell tablet after curing 391.7 6.04 9.36
Example 8
[0383] In Example 8, tablets comprising oxycodone hydrochloride and buprenorphine hydrochloride both in the core and in the shell and having the composition as shown in Tables 8.1 and 8.2 were prepared.
TABLE-US-00024 TABLE 8.1 Target Formulation Formulation mg/unit (mg/unit) (weight-%) Core Oxycodone HCl 36.00 38.09 25.39 Buprenorphine HCl 0.80.sup.1 0.86 0.57 Polyethylene Oxide ad 150.00 109.55 73.03 POLYOX WSR-301 Magnesium Stearate 1.50 1.50 1.00 Total core 150.00 150.00 100.00 Shell Oxycodone HCl 4.00 4.23 1.69 Buprenorphine HCl 7.20.sup.1 7.74 3.10 Polyethylene Oxide ad 250.00 236.53 94.61 POLYOX WSR N-10 Magnesium Stearate 1.50 1.50 0.60 Total shell 250.00 250.00 100.00 .sup.1expressed as equivalent amount of buprenorphine base
TABLE-US-00025 TABLE 8.2 Target Core + Shell mg/unit Weight ratios Oxycodone HCl 40.00 Weight ratio 9 oxycodone HCl.sub.core/ oxycodone HCl.sub.shell Buprenorphine HCl 8.00.sup.1 Weight ratio 0.11 buprenorphine HCl.sub.core/ buprenorphine HCl.sub.shell Weight ratio 5 oxycodone.sub.total/ buprenorphine.sub.total Total weight core + shell 400.00 Weight ratio core/shell 0.6 .sup.1expressed as equivalent amount of buprenorphine base
[0384] The processing steps to manufacture tablets of Example 8 correspond to the process of manufacture (steps 1 to 17) as described for Example 5.
[0385] The results of the in vitro dissolution testing of tablets of Example 8 are shown in Table 8.3 and in
TABLE-US-00026 TABLE 8.3 In vitro dissolution results for Example 8 Dissolution time [hours] 0.5 1 2 4 8 12 18 % oxycodone HCl released 4 13 32 59 86 93 95 % buprenorphine HCl 29 60 85 91 95 96 97 released Weight Thickness Diameter (mg) (mm) (mm) Core tablet 146.9 4.03 7.12 Core-Shell tablet before curing 394.0 5.85 9.48 Core-Shell tablet after curing 391.9 6.38 9.24
Example 9
[0386] In Example 9, tablets comprising oxycodone hydrochloride and buprenorphine hydrochloride both in the core and in the shell and having the composition as shown in Tables 9.1 and 9.2 were prepared.
TABLE-US-00027 TABLE 9.1 Target Formulation Formulation mg/unit (mg/unit) (weight-%) Core Oxycodone HCl 30.00 31.74 21.16 Buprenorphine HCl 1.00.sup.1 1.08 0.72 Polyethylene Oxide ad 150.00 115.68 77.12 POLYOX WSR-301 Magnesium Stearate 1.50 1.50 1.00 Total core 150.00 150.00 100.00 Shell Oxycodone HCl 10.00 10.58 4.23 Buprenorphine HCl 3.00.sup.1 3.23 1.29 Polyethylene Oxide ad 250.00 234.69 93.88 POLYOX WSR N-10 Magnesium Stearate 1.50 1.50 0.60 Total shell 250.00 250.00 100.00 .sup.1expressed as equivalent amount of buprenorphine base
TABLE-US-00028 TABLE 9.2 Target Core + Shell mg/unit Weight ratios Oxycodone HCl 40.00 Weight ratio 3 oxycodone HCl.sub.core/ oxycodone HCl.sub.shell Buprenorphine HCl 4.00.sup.1 Weight ratio 0.33 buprenorphine HCl.sub.core/ buprenorphine HCl.sub.shell Weight ratio 10 oxycodone.sub.total/ buprenorphine.sub.total Total weight core + shell 400.00 Weight ratio core/shell 0.6 .sup.1expressed as equivalent amount of buprenorphine base
[0387] The processing steps to manufacture tablets of Example 9 correspond to the process of manufacture (steps 1 to 17) as described for Example 5.
[0388] The results of the in vitro dissolution testing of tablets of Example 9 are shown in Table 9.3 and in
TABLE-US-00029 TABLE 9.3 In vitro dissolution results for Example 9 Dissolution time [hours] 0.5 1 2 4 8 12 18 % oxycodone HCl released 10 21 43 65 87 93 95 % buprenorphine HCl 26 56 78 86 94 98 101 released Weight Thickness Diameter (mg) (mm) (mm) Core tablet 147.2 4.04 7.12 Core-Shell tablet before curing 393.4 5.82 9.47 Core-Shell tablet after curing 391.3 6.32 9.23
Example 10
[0389] In Example 10, tablets comprising oxycodone hydrochloride and buprenorphine hydrochloride both in the core and in the shell and having the composition as shown in Tables 10.1 and 10.2 were prepared.
TABLE-US-00030 TABLE 10.1 Target Formulation Formulation mg/unit (mg/unit) (weight-%) Core Oxycodone HCl 60.00 63.48 31.74 Buprenorphine HCl 5.001 5.38 2.69 Polyethylene Oxide ad 200.00 131.14 65.57 POLYOX WSR-301 Total core 200.00 200.00 100.00 Shell Oxycodone HCl 20.00 21.16 3.85 Buprenorphine HCl 15.00.sup.1 16.13 2.93 Polyethylene Oxide ad 550.00 512.71 93.22 POLYOX WSR N-10 Total shell 550.00 550.00 100.00 .sup.1expressed as equivalent amount of buprenorphine base
TABLE-US-00031 TABLE 10.2 Target Core + Shell mg/unit Weight ratios Oxycodone HCl 80.00 Weight ratio 3 oxycodone HCl.sub.core/ oxycodone HCl.sub.shell Buprenorphine HCl 20.00.sup.1 Weight ratio 0.33 buprenorphine HCl.sub.core/ buprenorphine HCl.sub.shell Weight ratio 4 oxycodone.sub.total/ buprenorphine.sub.total Total weight core + shell 750.00 Weight ratio core/shell 0.36 .sup.1expressed as equivalent amount of buprenorphine base
[0390] The processing steps to manufacture tablets of Example 10 were as follows:
Preparation of Core Blend:
[0391] 1. Polyethylene oxide (POLYOX WSR-301) was weighed and transferred into a 13 mm100 mm glass test tube. An individual tube was used for each preparation. [0392] 2. The actives were weighed and transferred into the tube of step 1. [0393] 3. The materials in the tube were vortexed at high speed for 10 seconds to yield the core blend.
Preparation of Shell Blend:
[0394] 4. Polyethylene oxide (POLYOX WSR N-10) was weighed and transferred into a 13 mm100 mm glass test tube. An individual tube was used for each preparation. [0395] 5. The actives were weighed and transferred into the tube of step 4. [0396] 6. The materials in the tube were vortexed at high speed for 10 seconds to yield the shell blend.
Preparation of Core Tablet:
[0397] 7. The core blend was discharged onto a weighing paper (tapping the tube with a spatula to dispense as much of the core blend as possible). [0398] 8. A Manesty Type F3 tablet press was setup with 5/16 inch round flat tooling. [0399] 9. The core blend was transferred into the die and compressed with upper punch penetration dial set at 24 to yield the core tablet.
Preparation of Core-Shell Tablet(s)
[0400] 10. A Manesty Type F3 tablet press was set up with 12 mm round, bevel edge, shallow concave tooling. [0401] 11. An amount of 250 mg5 mg of the shell blend was discharged onto a weighing paper and transferred into the die. [0402] 12. The core tablet of step 9 was placed into the center of the die containing the indicated amount of the shell blend. [0403] 13. The remaining amount of the shell blend was discharged onto the same weighing paper (tapping the tube with a spatula to dispense as much of the shell blend as possible) and transferred into the die to cover the sides and the top of the core tablet. [0404] 14. Subsequently the shell blend was compressed with upper punch penetration dial set at 301 to yield the core-shell tablet. [0405] 15. Steps 1 to 14 were repeated to yield several core-shell tablets.
Curing
[0406] 16. For curing, core-shell tablets were placed on a mesh screen and cured in a preheated gravity-flow convection oven at a temperature of 70 C. for 30 minutes.
[0407] The results of the in vitro dissolution testing of tablets of Example 10 are shown in Table 10.3 and in
TABLE-US-00032 TABLE 10.3 In vitro dissolution results for Example 10 Dissolution time [hours] 0.5 1 2 3 4 6 9 12 % oxycodone HCl released 6 13 31 48 59 76 90 95 % buprenorphine HCl released 12 33 66 76 79 83 89 92 Weight (mg) Thickness (mm) Core tablet 196.5 3.81 Core-Shell tablet before curing 741.7 6.15 Core-Shell tablet after curing NT 6.63
Example 11
[0408] In Example 11, tablets comprising oxycodone hydrochloride and buprenorphine hydrochloride both in the core and in the shell and having the composition as shown in Tables 11.1 and 11.2 were prepared.
TABLE-US-00033 TABLE 11.1 Target Formulation Formulation mg/unit (mg/unit) (weight-%) Core Oxycodone HCl 7.50 7.93 5.29 Buprenorphine HCl 1.00.sup.1 1.08 0.72 Polyethylene Oxide ad 150.00 140.99 93.99 POLYOX WSR-301 Total core 150.00 150.00 100.00 Shell Oxycodone HCl 2.50 2.64 0.48 Buprenorphine HCl 1.00.sup.1 1.08 0.20 Polyethylene Oxide ad 550.00 546.28 99.32 POLYOX WSR N-10 Total shell 550.00 550.00 100.00 .sup.1expressed as equivalent amount of buprenorphine base
TABLE-US-00034 TABLE 11.2 Target Core + Shell mg/unit Weight ratios Oxycodone HCl 10.00 Weight ratio 3 oxycodone HCl.sub.core/ oxycodone HCl.sub.shell Buprenorphine HCl 2.00.sup.1 Weight ratio 1 buprenorphine HCl.sub.core/ buprenorphine HCl.sub.shell Weight ratio 5 oxycodone.sub.total/ buprenorphine.sub.total Total weight core + shell 700.00 Weight ratio core/shell 0.27 .sup.1expressed as equivalent amount of buprenorphine base
[0409] The processing steps to manufacture tablets of Example 11 correspond to the process of manufacture (steps 1 to 16) as described for Example 10, with the following particulars:
[0410] In step 9, the upper punch penetration dial set at 26; and in step 14, the upper punch penetration dial set at 28/29.
[0411] The results of the in vitro dissolution testing of tablets of Example 11 are shown in Table 11.3 and in
TABLE-US-00035 TABLE 11.3 In vitro dissolution results for Example 11 Dissolution time [hours] 0.5 1 2 3 4 6 9 12 % oxycodone HCl released 6 13 26 41 53 72 88 95 % buprenorphine HCl released 9 22 42 50 52 58 68 74 Weight (mg) Thickness (mm) Core tablet 147.3 3.06 Core-Shell tablet before curing 692.8 5.94 Core-Shell tablet after curing NT 6.58 NT = Not Tested
Example 12
[0412] In Example 12, tablets comprising oxycodone hydrochloride and buprenorphine hydrochloride both in the core and in the shell and having the composition as shown in Tables 12.1 and 12.2 were prepared.
TABLE-US-00036 TABLE 12.1 Target Formulation Formulation mg/unit (mg/unit).sup.1 (weight-%) Core Oxycodone HCl 30.00 31.74 21.16 Buprenorphine HCl 1.50.sup.2 1.61 1.07 Polyethylene Oxide ad 150.00 116.65 77.77 POLYOX WSR-301 Total core 150.00 150.00 100.00 Shell Oxycodone HCl 10.00 10.58 4.23 Buprenorphine HCl 4.50.sup.2 4.84 1.94 Polyethylene Oxide ad 250.00 234.58 93.83 POLYOX WSR N-10 Total shell 250.00 250.00 100.00 .sup.1In order to compensate for loss of material during handling, an overage of +7% was used for manufacturing individual tablets. .sup.2expressed as equivalent amount of buprenorphine base
TABLE-US-00037 TABLE 12.2 Target Core + Shell mg/unit Weight ratios Oxycodone HCl 40.00 Weight ratio 3 oxycodone HCl.sub.core/ oxycodone HCl.sub.shell Buprenorphine HCl 6.00.sup.1 Weight ratio 0.33 buprenorphine HCl.sub.core/ buprenorphine HCl.sub.shell Weight ratio 6.67 oxycodone.sub.total/ buprenorphine.sub.total Total weight core + shell 400.00 Weight ratio core/shell 0.6 .sup.1expressed as equivalent amount of buprenorphine base
[0413] The processing steps to manufacture tablets of Example 12 were as follows:
Preparation of Core Blend:
[0414] 1. Polyethylene oxide (POLYOX WSR-301) was weighed and transferred into a 13 mm100 mm glass test tube. An individual tube was used for each preparation. [0415] 2. The active(s) were weighed and transferred into the tube of step 1. [0416] 3. The materials in the tube were vortexed at high speed for 10 seconds to yield the core blend.
Preparation of Shell Blend:
[0417] 4. Polyethylene Oxide (POLYOX WSR N-10) was Weighed and Transferred into a 13 mm100 mm glass test tube. An individual tube was used for each preparation. [0418] 5. The active(s) were weighed and transferred into the tube of step 4. [0419] 6. The materials in the tube were vortexed at high speed for 10 seconds to yield the shell blend.
Preparation of Core Tablet:
[0420] 7. The core blend was discharged onto a weighing paper (tapping the tube with a spatula to dispense as much of the core blend as possible). [0421] 8. A Carver tablet press was setup with 9/32, round concave tooling. [0422] 9. The core blend was transferred into the die and compressed by applying a compression force of 1000-1200 lbs to yield the core tablet.
Preparation of Core-Shell Tablet(s)
[0423] 10. A Carver tablet press was set up with , round concave tooling. [0424] 11. An amount of 115 mg5 mg of the shell blend was discharged onto a weighing paper and transferred into the die. [0425] 12. The core tablet of step 9 was placed into the center of the die containing the indicated amount of the shell blend. [0426] 13. The remaining amount of the shell blend was discharged onto the same weighing paper (tapping the tube with a spatula to dispense as much of the shell blend as possible) and transferred into the die to cover the sides and the top of the core tablet. [0427] 14. Subsequently the shell blend was compressed by applying a compression force of 1800-2000 lbs to yield the core-shell tablet. [0428] 15. Steps 1 to 14 were repeated to yield several core-shell tablets.
[0429] The results of the in vitro dissolution testing of tablets of Example 12 are shown in Table 12.3 and in
TABLE-US-00038 TABLE 12.3 In vitro dissolution results for Example 12 Dissolution time [hours] 0.5 1 2 4 8 12 18 % oxycodone HCl released 11 22 42 65 92 100 102 % buprenorphine HCl 20 54 80 86 95 100 103 released Weight (mg) Core tablet 147.1 Core-Shell tablet 394.1
Example 13
[0430] In Example 13, tablets comprising oxycodone hydrochloride in the core and buprenorphine hydrochloride in the shell and having the composition as shown in Tables 13.1 and 13.2 were prepared.
TABLE-US-00039 TABLE 13.1 Target Formulation Formulation mg/unit (mg/unit).sup.1 (weight-%) Core Oxycodone HCl 30.00 31.74 21.16 Buprenorphine HCl 0.00 0.00 0.00 Polyethylene Oxide ad 150.00 118.26 78.84 POLYOX WSR-301 Total core 150.00 150.00 100.00 Shell Oxycodone HCl 0.00 0.00 0.00 Buprenorphine HCl 7.50.sup.2 8.06 3.22 Polyethylene Oxide ad 250.00 241.94 96.78 POLYOX WSR N-10 Total shell 250.00 250.00 100.00 .sup.1In order to compensate for loss of material during handling, an overage of +7% was used for manufacturing individual tablets. .sup.2expressed as equivalent amount of buprenorphine base
TABLE-US-00040 TABLE 13.2 Target Core + Shell mg/unit Weight ratios Oxycodone HCl 30.00 Buprenorphine HCl 7.50.sup.1 Weight ratio 4 oxycodone.sub.total/ buprenorphine.sub.total Total weight core + shell 400.00 Weight ratio core/shell 0.6
[0431] The processing steps to manufacture tablets of Example 13 correspond to the process of manufacture (steps 1 to 15) as described for Example 12.
[0432] The results of the in vitro dissolution testing of tablets of Example 13 are shown in Table 13.3 and in
TABLE-US-00041 TABLE 13.3 In vitro dissolution results for Example 13 Dissolution time [hours] 0.5 1 2 4 8 12 18 % oxycodone HCl released 0 3 25 57 89 99 101 % buprenorphine HCl 24 71 104 106 106 106 105 released Weight (mg) Core tablet 146.6 Core-Shell tablet 393.1
Example 14
[0433] In Example 14, tablets comprising buprenorphine hydrochloride in the core and oxycodone hydrochloride both in the core and in the shell, and having the composition as shown in Tables 14.1 and 14.2 were prepared.
TABLE-US-00042 TABLE 14.1 Target Formulation Formulation mg/unit (mg/unit).sup.1 (weight-%) Core Oxycodone HCl 21.00 22.22 14.81 Buprenorphine HCl 10.00.sup.2 10.75 7.17 Polyethylene Oxide ad 150.00 117.03 78.02 POLYOX WSR-301 Total core 150.00 150.00 100.00 Shell Oxycodone HCl 19.00 20.10 8.04 Buprenorphine HCl 0.00 0.00 0.00 Polyethylene Oxide ad 250.00 229.90 91.96 POLYOX WSR N-10 Total shell 250.00 250.00 100.00 .sup.1In order to compensate for loss of material during handling, an overage of +7% was used for manufacturing individual tablets. .sup.2expressed as equivalent amount of buprenorphine base
TABLE-US-00043 TABLE 14.2 Target Core + Shell mg/unit Weight ratios Oxycodone HCl 40.00 Weight ratio 1.11 oxycodone HCl.sub.core/ oxycodone HCl.sub.shell Buprenorphine HCl 10.00.sup.1 Weight ratio 4 oxycodone.sub.total/ buprenorphine.sub.total Total weight core + shell 400.00 Weight ratio core/shell 0.6 .sup.1expressed as equivalent amount of buprenorphine base
[0434] The processing steps to manufacture tablets of Example 14 correspond to the process of manufacture (steps 1 to 15) as described for Example 12.
[0435] The results of the in vitro dissolution testing of tablets of Example 14 are shown in Table 14.3 and in
TABLE-US-00044 TABLE 14.3 In vitro dissolution results for Example 14 Dissolution time [hours] 0.5 1 2 4 8 12 18 % oxycodone HCl released 20 39 59 76 94 99 101 % buprenorphine HCl 0 1 6 21 50 73 95 released Weight (mg) Core tablet 146.0 Core-Shell tablet 393.0
Example 15
[0436] In Example 15, core tablets comprising buprenorphine hydrochloride and oxycodone hydrochloride were prepared and coated with an active-free polyethylene oxide shell. The resulting core-shell tablets have the composition as shown in Tables 15.1 and 15.2.
TABLE-US-00045 TABLE 15.1 Target Formulation Formulation mg/unit (mg/unit).sup.1 (weight-%) Core Oxycodone HCl 30.00 31.74 21.16 Buprenorphine HCl 10.00.sup.2 10.75 7.17 Polyethylene Oxide ad 150.00 107.51 71.67 POLYOX WSR-301 Total core 150.00 150.00 100.00 Shell Polyethylene Oxide 250.00 250.00 100.00 POLYOX WSR N-10 Total shell 250.00 250.00 100.00 .sup.1In order to compensate for loss of material during handling, an overage of +7% was used for manufacturing individual tablets. .sup.2expressed as equivalent amount of buprenorphine base
TABLE-US-00046 TABLE 15.2 Target Core + Shell mg/unit Weight ratios Oxycodone HCl 30.00 Buprenorphine HCl 10.00.sup.2 Weight ratio 3 oxycodone.sub.total/ buprenorphine.sub.total Total weight core + shell 400.00 Weight ratio core/shell 0.6 .sup.2expressed as equivalent amount of buprenorphine base
[0437] The processing steps to manufacture tablets of Example 15 correspond to the process of manufacture (steps 1 to 15) as described for Example 12, with the exception that step 5 was omitted (i.e., no active(s) were added to the polyethylene oxide).
[0438] The results of the in vitro dissolution testing of tablets of Example 15 are shown in Table 15.3 and in
TABLE-US-00047 TABLE 15.3 In vitro dissolution results for Example 15 Dissolution time [hours] 0.5 1 2 4 8 12 18 % oxycodone HCl released 0 3 26 57 90 98 100 % buprenorphine HCl 0 0 7 23 53 77 98 released Weight (mg) Core tablet 145.6 Core-Shell tablet 391.2
Examples 16-47
[0439] In Examples 16 and 17, core tablets comprising buprenorphine hydrochloride and oxycodone hydrochloride were prepared and coated with an active-free polyethylene oxide shell. The tablets have the composition as shown in Table 16.1 (for Example 16) and Table 17.1 (for Example 17).
TABLE-US-00048 TABLE 16.1 Formu- Formu- Formu- Target lation lation lation Core mg/unit (mg/unit) (weight-%) (mg/batch) Oxycodone HCl 10.00 10.58 7.05 359.7 Buprenorphine 0.50.sup.1 0.54 0.36 18.3 HCl Polyethylene ad 150.00 137.38 91.59 4671 Oxide POLYOX WSR-301 FP Magnesium 1.50 1.50 1.00 51 Stearate Total core 150.00 150.00 100.00 5100.0 Target Formulation Formulation Shell mg/unit (mg/unit) (weight-%) Polyethylene Oxide 250.00 250.00 100.00 POLYOX WSR N-10 Total shell 250.00 250.00 100.00 Total weight core + 400.00 400.00 shell .sup.1expressed as equivalent amount of buprenorphine base
TABLE-US-00049 TABLE 17.1 Formu- Formu- Formu- Target lation lation lation Core mg/unit (mg/unit) (weight-%) (mg/batch) Oxycodone HCl 10.00 10.58 7.05 359.7 Buprenorphine 0.50.sup.1 0.54 0.36 18.3 HCl Polyethylene ad 150.00 137.38 91.59 4671 Oxide POLYOX WSR-301 FP Magnesium Stearate 1.50 1.50 1.00 51 Total core 150.00 150.00 100.00 5100.0 Target Formulation Formulation Shell mg/unit (mg/unit) (weight-%) Polyethylene Oxide 550.00 550.00 100.00 POLYOX WSR N-10 Total shell 550.00 550.00 100.00 Total weight core + 700.00 700.00 shell .sup.1expressed as equivalent amount of buprenorphine base
[0440] The processing steps to manufacture the tablets of Examples 16 and 17 were as follows:
Preparation of Core Tablets
[0441] The core tablets of Example 16 and 17 were manufactured in a 5100 mg batch as follows: [0442] 1. Add approximately half of the PEO into the 16 qt V-blender. [0443] 2. Mix a portion of PEO into the container of oxycodone HCl and manually mix for approximately 1 minute. [0444] 3. Screen the material from Step 2 through a 30-mesh screen while loading into the blender. [0445] 4. Mix a portion of PEO into the container of buprenorphine HCl and manually mix for approximately 1 minute. [0446] 5. Screen the material from Step 4 through a 30-mesh screen while loading into the blender. [0447] 6. Add the remaining PEO and mix for 5 minutes with the I-bar ON. [0448] 7. Add the magnesium stearate (screened through 30-mesh screen) and mix for 1 minute (no I-bar). [0449] 8. Discharge the blend. [0450] 9. Setup the Kilian tablet press (16 stations) with 9/32 inch round, standard concave tooling. [0451] 10. Add some blend to the hopper and adjust tablet parameters. [0452] 11. Compress the blend to target and collect tablets.
Preparation of Core-Shell Tablet(s)
[0453] 1. A Carver Press was set up with round concave tooling (size inch round concave for Example 16 and size 12 mm round shallow concave with beveled edges for Example 17). [0454] 2. Polyethylene oxide (POLYOX WSR N-10) was weighed. [0455] 3. Approximately 46% of the amount of polyethylene oxide of step 2 was transferred into the die. [0456] 4. A core tablet was placed into the center of the die containing the indicated partial amount of polyethylene oxide. [0457] 5. The remaining amount of polyethylene oxide was transferred into the die to cover the sides and the top of the core tablet. [0458] 6. Subsequently the polyethylene oxide was compressed by applying a compression force of 2000 lbs to yield the core-shell tablet. [0459] 7. Steps 1 to 6 were repeated to yield several core-shell tablets.
[0460] The results of the in vitro dissolution testing of (1) core tablets, (2) tablets of Example 16 and (3) tablets of Example 17 are shown in Table 16.2, 16.3 and 17.2, respectively. The indicated values are an average of three measurements.
TABLE-US-00050 TABLE 16.2 In vitro dissolution results for core tablets of Example 16/17 Dissolution time [hours] 0.5 1 2 4 8 12 18 % oxycodone HCl released 17 27 44 66 92 100 102 % buprenorphine HCl 9 16 26 44 74 91 97 released
TABLE-US-00051 TABLE 16.3 In vitro dissolution results for Example 16 Dissolution time [hours] 0.5 1 2 4 8 12 18 % oxycodone HCl released 0 2 24 54 84 94 97 % buprenorphine HCl 0 1 14 33 61 79 89 released
TABLE-US-00052 TABLE 17.2 In vitro dissolution results for Example 17 Dissolution time [hours] 0.5 1 2 4 8 12 18 % oxycodone HCl released 0 0 10 46 81 93 97 % buprenorphine HCl 0 0 5 27 57 77 90 released
[0461] Having now fully described this disclosure, it will be understood by those of ordinary skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations and other parameters without affecting the scope of the disclosure or any embodiment thereof.
[0462] Other embodiments of the disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.
[0463] All patents and publications cited herein are fully incorporated by reference in their entirety.