US5283065A
Expired / Lapsed
US
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Controlled release pharmaceutical compositions from spherical granules in tabletted oral dosage unit form
Assignee: Wyeth Holdings LLC
•
Filing: 1992-03-23
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Granted: 1994-02-01
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Expires: 2012-03-23
Abstract
Abstract A controlled release pharmaceutical composition in oral dosage unit form comprising a tablet comprising a therapeutically effective number of active spherical granules comprising an effective amount of active medicament, a pharmaceutically acceptable normally solid diluent adapted to form a diffusable matrix for the active medicament and an optional pharmaceutically acceptable excipient; and a number of compressible spherical granules comprising a mono- or di-saccharide, an optional pharmaceutically acceptable normally solid diluent adapted to form a diffusable matrix, an optional active medicament and/or an optional pharmaceutically acceptable excipient wherein the average compressive yield of the compressible spherical granules is less than the average compressive yield of the active spherical granules is provided. A method for the preparation and for the administration of the above defined composition is provided as well.
Inventors
- 👤 Daniel J. Doyon
- 👤 Madurai G. Ganesan
- 👤 Wendy A. Preston
- 👤 Nitin V. Sheth
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-03 13:37
CPC Classifications
A; A61; A61K; A61K9/00; A61K9/14; A61K9/16; A61K9/20; A61K9/2072; A61K9/2077; A61K9/2081
Claims Analysis
Total Claims: 49
Claim 1
Independent Claim
277 words
A controlled release pharmaceutical composition in oral dosage unit form comprising a table comprising (A) a therapeutically effective number of active spherical granules comprising (i) about 10 to about 80 parts by weight of at least one active medicament; (ii) about 75 to about 10 parts by weight of microcrystalline cellulose for controlling the release rate of said at least one active medicament (A) (i); and, (iii) 10 to about 75 parts by weight of at least one pharmaceutically acceptable excipient for further controlling the release rate of said at least one active medicament (A) (i), based upon 100 parts by weight of said active spherical granules; and (B) a number of compressible spherical granules comprising (i) about 25 to about 90 parts by weight of at least one mono- or di-saccharide; optionally, (ii) 75 to about 10 parts by weight of microcrystalline cellulose for controlling the release rate of any active medicament in said compressible spherical granules; optionally, (iii) an effective amount of at least one active medicament which may be the same as or different than (A) Ii); optionally (iv) 0 to about 90 parts by weight of at least one pharmaceutically acceptable excipient other than a mono- or di-saccharide which may be the same or different than either (A) (ii), (A) (iii) or (B) (ii) for further controlling the release rate of any active medicament in said compressible spherical granules; or optionally (v) a combination of any of (B) (ii), (B) (iii) and (B) (iv), based upon 100 parts by weight of said compressible spherical granules; wherein the average compressive yield of component (B) is less than the average compressive yield of component (A).
Claim 2
Dependent Claim
277 words
A controlled release pharmaceutical composition in oral dosage unit form comprising a table comprising (A) a therapeutically effective number of active spherical granules comprising (i) about 10 to about 80 parts by weight of at least one active medicament; (ii) about 75 to about 10 parts by weight of microcrystalline cellulose for controlling the release rate of said at least one active medicament (A) (i); and, (iii) 10 to about 75 parts by weight of at least one pharmaceutically acceptable excipient for further controlling the release rate of said at least one active medicament (A) (i), based upon 100 parts by weight of said active spherical granules; and (B) a number of compressible spherical granules comprising (i) about 25 to about 90 parts by weight of at least one mono- or di-saccharide; optionally, (ii) 75 to about 10 parts by weight of microcrystalline cellulose for controlling the release rate of any active medicament in said compressible spherical granules; optionally, (iii) an effective amount of at least one active medicament which may be the same as or different than (A) Ii); optionally (iv) 0 to about 90 parts by weight of at least one pharmaceutically acceptable excipient other than a mono- or di-saccharide which may be the same or different than either (A) (ii), (A) (iii) or (B) (ii) for further controlling the release rate of any active medicament in said compressible spherical granules; or optionally (v) a combination of any of (B) (ii), (B) (iii) and (B) (iv), based upon 100 parts by weight of said compressible spherical granules; wherein the average compressive yield of component (B) is less than the average compressive yield of component (A).
Claim 3
Independent Claim
334 words
A method for the preparation of a controlled release pharmaceutical composition in oral dosage unit form comprising a tablet comprising the steps of: (a) blending (i) about 10 to about 80 parts by weight of at least one active medicament; (ii) about 75 to about 10 parts by weight of microcrystalline cellulose; and optionally, (iii) 10 to about 75 parts by weight of at least one pharmaceutically acceptable excipient based upon 100 parts by weight of (a) (i), (a) (ii) and (a) (iii) combined; (b) independently blending (i) about 25 to about 90 parts by weight of at least one mono- or di-saccharide; optionally, (ii) 75 to about 10 parts by weight of microcrystalline cellulose; (iii) an effective amount of at least one active medicament which may be the same as or different than (a) (i); optionally (iv) 0 to about 90 parts by weight of at least one pharmaceutically acceptable excipient other than a mono- or di saccharide which may be the same or different than either (a) (ii), (a) (iii) or (b) (ii) for further controlling the release rate of any active medicament in said compressible spherical granules; or optionally (v) a combination of any of (b) (ii), (b) (iii) and (b) (iv), based upon 100 parts by weight of (b) (i), (b) (ii), and (b) (iii) and (b) (iv) combined; (c) independently granulating the resultant blends of steps (a) and (b) in the presence of a granulating liquid; (d) independently extruding the resultant granulates of step (c); (e) independently spheronizing the resultant extrudates of step (d) to form active spherical granules (A) derived from step (a) and compressible spherical granules (B) derived from step (b) so that the average compressive yield of components (B) is less than the average compressive yield of components (A); (f) drying components (A) and (B); (g) optionally adding a lubricant; and (h) forming a tablet from a blend of a therapeutically effective number of active spherical granules (A) and a number of compressible spherical granules (B).
Claim 4
Independent Claim
334 words
A method for the preparation of a controlled release pharmaceutical composition in oral dosage unit form comprising a tablet comprising the steps of: (a) blending (i) about 10 to about 80 parts by weight of at least one active medicament; (ii) about 75 to about 10 parts by weight of microcrystalline cellulose; and optionally, (iii) 10 to about 75 parts by weight of at least one pharmaceutically acceptable excipient based upon 100 parts by weight of (a) (i), (a) (ii) and (a) (iii) combined; (b) independently blending (i) about 25 to about 90 parts by weight of at least one mono- or di-saccharide; optionally, (ii) 75 to about 10 parts by weight of microcrystalline cellulose; (iii) an effective amount of at least one active medicament which may be the same as or different than (a) (i); optionally (iv) 0 to about 90 parts by weight of at least one pharmaceutically acceptable excipient other than a mono- or di saccharide which may be the same or different than either (a) (ii), (a) (iii) or (b) (ii) for further controlling the release rate of any active medicament in said compressible spherical granules; or optionally (v) a combination of any of (b) (ii), (b) (iii) and (b) (iv), based upon 100 parts by weight of (b) (i), (b) (ii), and (b) (iii) and (b) (iv) combined; (c) independently granulating the resultant blends of steps (a) and (b) in the presence of a granulating liquid; (d) independently extruding the resultant granulates of step (c); (e) independently spheronizing the resultant extrudates of step (d) to form active spherical granules (A) derived from step (a) and compressible spherical granules (B) derived from step (b) so that the average compressive yield of components (B) is less than the average compressive yield of components (A); (f) drying components (A) and (B); (g) optionally adding a lubricant; and (h) forming a tablet from a blend of a therapeutically effective number of active spherical granules (A) and a number of compressible spherical granules (B).
Claim 5
Dependent Claim
152 words
A controlled release pharmaceutical composition in oral dosage unit form comprising a compressed tablet consisting essentially of (A) a therapeutically effective number of active spherical granules which consist essentially of (i) from about 10 to about 80 parts by weight of at least one active medicament; (ii) from about 75 to about 10 parts by weight of microcrystalline cellulose for controlling the release rate of said at least one active medicament (A) (i) based on 100 parts by weight of said active spherical granules; and (B) a number of compressible spherical granules which consists essentially of (i) about 25 to about 90 parts by weight lactose; and (ii) from about 75 to about 10 parts by weight of microcrystalline cellulose based on 100 parts by weight of said compressible spherical granules; wherein prior to tabletting the average compressive yield of component (B) is less than the average compressive yield of component (A).
Claim 6
Dependent Claim
152 words
A controlled release pharmaceutical composition in oral dosage unit form comprising a compressed tablet consisting essentially of (A) a therapeutically effective number of active spherical granules which consist essentially of (i) from about 10 to about 80 parts by weight of at least one active medicament; (ii) from about 75 to about 10 parts by weight of microcrystalline cellulose for controlling the release rate of said at least one active medicament (A) (i) based on 100 parts by weight of said active spherical granules; and (B) a number of compressible spherical granules which consists essentially of (i) about 25 to about 90 parts by weight lactose; and (ii) from about 75 to about 10 parts by weight of microcrystalline cellulose based on 100 parts by weight of said compressible spherical granules; wherein prior to tabletting the average compressive yield of component (B) is less than the average compressive yield of component (A).
Claim 7
Dependent Claim
57 words
An oral dosage unit as defined in claim 1 wherein said active medicament (A) (i) cellulose in (A) (ii) comprises from about 25 parts to about 65 parts by weight and said excipient (A) (iii) comprises from about 10 to about 50 parts by weight based upon 100 parts by weight of said active spherical granules (A).
Claim 8
Dependent Claim
51 words
An oral dosage unit as defined in claim 1 wherein said active medicament (A) (i) comprises from about 120 to about 75 parts by weight and said microcrystalline cellulose comprises from about 75 to about 10 parts by weight based upon 1200 parts by weight of said active spherical granules (A).
Claim 9
Dependent Claim
43 words
An oral dosage unit as defined in claim 5 wherein said active medicament (A) (i) comprises about 50 parts by weight and said microcrystalline cellulose comprises about 540 parts by weight based upon 100 parts by weight of said active spherical granules (A).
Claim 10
Dependent Claim
150 words
A controlled release pharmaceutical composition in oral dosage unit form comprising a compressed tablet consisting essentially of (A) a therapeutically effective number of active spherical granules which consist essentially of (i) about 10 to about 90 parts by weight of at least one active medicament; (ii) about 90 to about 10 parts by weight of microcrystalline cellulose for controlling the release rate of said at least one active medicament (A) (i), based upon 100 parts by weight of said active spherical granules; and (B) a number of compressible spherical granules which consist essentially of (i) about 10 to about 90 parts by weight of lactose; and (ii) about 90 to about 10 parts by weight of microcrystalline cellulose based upon 100 parts by weight of said compressible spherical granules; wherein prior to tabletting the average compressive yield of component (B) is less than the average compressive yield of component (A).
Claim 11
Dependent Claim
150 words
A controlled release pharmaceutical composition in oral dosage unit form comprising a compressed tablet consisting essentially of (A) a therapeutically effective number of active spherical granules which consist essentially of (i) about 10 to about 90 parts by weight of at least one active medicament; (ii) about 90 to about 10 parts by weight of microcrystalline cellulose for controlling the release rate of said at least one active medicament (A) (i), based upon 100 parts by weight of said active spherical granules; and (B) a number of compressible spherical granules which consist essentially of (i) about 10 to about 90 parts by weight of lactose; and (ii) about 90 to about 10 parts by weight of microcrystalline cellulose based upon 100 parts by weight of said compressible spherical granules; wherein prior to tabletting the average compressive yield of component (B) is less than the average compressive yield of component (A).
Claim 12
Dependent Claim
17 words
A controlled release pharmaceutical composition as defined in claim 1 wherein the pharmaceutically acceptable excipient is lactose.
Claim 13
Dependent Claim
51 words
An oral dosage unit as defined in claim 1 wherein said mono- or di-saccharide (B) (i) comprises from about 50 to about 90 parts by weight and said microcrystalline cellulose comprises from about 50 to about 10 parts by weight based upon 100 parts by weight of said compressible spherical granules.
Claim 14
Dependent Claim
44 words
An oral dosage unit as defined in claim 9 wherein said mono- or di-saccharide (B) (i) comprises about 75 parts by weight and said microcrystalline cellulose comprises about 25 parts by weight based upon 100 parts by weight of said compressible spherical granules (B).
Claim 15
Dependent Claim
52 words
An oral dosage unit as defined in claim 1 wherein said active spherical granules (A) comprise from about 10 to about 90 parts by weight and said compressible spherical granules (B) comprise from about 90 to about 10 parts by weight based upon 100 parts by weight of (A) and (B) combined.
Claim 16
Dependent Claim
44 words
An oral dosage unit as defined in claim 11 wherein said active spherical granules (A) comprise about 50 parts by weight and said compressible spherical granules (B) comprise about 50 parts by weight based upon 100 parts by weight of (A) and (B) combined.
Claim 17
Dependent Claim
30 words
An oral dosage unit form as defined in claim 7 wherein said active medicament (A) (i) is selected from the group consisting of methazolamide, ibuprofen, diopyramide, and a tetracycline compound.
Claim 18
Dependent Claim
17 words
An oral dosage unit form as defined in claim 13 wherein said tetracycline compound is minocycline hydrochloride.
Claim 19
Dependent Claim
59 words
A controlled release pharmaceutical composition as defined in claim 1 wherein the pharmaceutically acceptable excipient is selected from the group consisting of lactose, microcrystalline cellulose, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, microcrystalline cellulose and sodium carboxymethyl cellulose and mixtures of the foregoing; the mono- or di-saccharide is lactose and the pharmaceutically acceptable diluent other than a mono- or di-saccharide is microcrystalline cellulose.
Claim 20
Dependent Claim
16 words
An oral dosage unit as defined in claim 1 wherein said active medicament (A)(i) comprises methazolamide.
Claim 21
Dependent Claim
23 words
An oral dosage unit as defined in claim 16 wherein each tablet contains from about 25 mg to about 75 mg of methazolamide.
Claim 22
Dependent Claim
76 words
An oral dosage unit as defined in claim 16 wherein not more than about 50 percent of said methazolamide is released from said active spherical granules (A) in about one hour and not less than about 75 percent of said methazolamide is released from said active spherical granules in about 12 hours when suspended in pH 4.5 acetate buffer at about 37° C. at a methazolamide concentration of about 50 mg of methazolamide/90 ml of buffer.
Claim 23
Dependent Claim
16 words
An oral dosage unit as defined in claim 1 wherein said active medicament (A)(i) comprises ibuprofen.
Claim 24
Dependent Claim
23 words
An oral dosage unit as defined in claim 19 where each tablet contains from about 200 mg to about 800 mg of ibuprofen.
Claim 25
Dependent Claim
71 words
An oral dosage unit as defined in claim 19 wherein not more than about 60 percent of said ibuprofen is released from said active spherical granules (A) in about one hour and not less than about 90 percent of said ibuprofen is released in about 8 hours when suspended in pH 7.2 phosphate buffer at about 37° C. at an ibuprofen concentration of about 800 mg of ibuprofen/900 ml of buffer.
Claim 26
Dependent Claim
17 words
An oral dosage unit as defined in claim 1 wherein said active medicament (A)(i) comprises disopyramide phosphate.
Claim 27
Dependent Claim
24 words
An oral dosage unit as defined in claim 22 wherein each tablet contains from about 100 mg to about 300 mg of disopyramide phosphate.
Claim 28
Dependent Claim
122 words
An oral dosage unit as defined in claim 22 wherein 5 to 25 percent of said disopyramide phosphate is released from said active spherical granules (A) in about 1 hour, 17 to 43 percent of said disopyramide phosphate is released from said active spherical granules (A) in about 2 hours, 50 to 80 percent of said disopyramide phosphate is released from said active spherical granules (A) in about 5 hours and not less than 85 percent of said disopyramide phosphate is released from said active spherical granules (A) in about 12 hours when suspended in pH 2.5 phosphate buffer at about 37° C. at a disopyramide phosphate concentration of from about 100 mg to about 300 mg disopyramide phosphate/900 ml of buffer.
Claim 29
Dependent Claim
18 words
An oral dosage unit as defined in claim 1 wherein said active medicament (A)(i) comprises a tetracycline compound.
Claim 30
Dependent Claim
24 words
An oral dosage unit as defined in claim 25 wherein each tablet contains from about 25 mg to about 200 mg of tetracycline compound.
Claim 31
Dependent Claim
24 words
An oral dosage unit as defined in claim 25 wherein each tablet contains from about 50 mg to about 100 mg of tetracycline compound.
Claim 32
Dependent Claim
83 words
An oral dosage unit as defined in claim 25 wherein not more than about 80 percent of said tetracycline compound is released from said active spherical granules (A) in about 1 hour and not less than about 90 percent of said tetracycline compound is released from said active spherical granules (A) in about 12 hours when suspended in deionized water at about 37° C. at a tetracycline compound concentration of about 50 mg to about 100 mg of tetracycline compound/900 ml of water.
Claim 33
Dependent Claim
16 words
An oral dosage unit as defined in claim 25 wherein said tetracycline compound comprises minocycline hydrochloride.
Claim 34
Dependent Claim
24 words
An oral dosage unit as defined in claim 29 wherein each tablet contains from about 50 mg to about 100 mg of minocycline hydrochloride.
Claim 35
Dependent Claim
82 words
An oral dosage unit as defined in claim 29 wherein not more than about 80 percent of said minocycline hydrochloride is released from said active spherical granules (A) in about 1 hour and not less than about 90 percent of said minocycline hydrochloride is released from said active spherical granules (A) in about 12 hours when suspended in deionized water at 37° C. at a minocycline hydrochloride concentration of about 50 mg to about 200 mg of minocycline hydrochloride/900 ml of water.
Claim 36
Dependent Claim
39 words
A method of controlling the release of at least one active medicament in the blood stream of a warm-blooded mammal over a prolonged period of time comprising the ingestion of an oral dosage unit as defined in claim 1.
Claim 37
Dependent Claim
49 words
An oral dosage unit as defined in claim 1 wherein at least one of said pharmaceutically acceptable excipients (A)(iii) and (B)(iv) comprises microcrystalline cellulose, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, microcrystalline cellulose in combination with lactose, microcrystalline cellulose in combination with sodium carboxymethyl cellulose or a mixture of any of the foregoing.
Claim 38
Dependent Claim
16 words
An oral dosage unit as defined in claim 1 wherein said mono- or di-saccharide comprises lactose.
Claim 39
Dependent Claim
37 words
An oral dosage unit as defined in claim 1 wherein said active spherical granules (A) and said compressible spherical granules (B) independently have an average diameter in the range of from about 0.1 to about 2.5 millimeters.
Claim 40
Dependent Claim
37 words
An oral dosage unit as defined in claim 35 wherein said active spherical granules (A) and said compressible spherical granules (B) independently have an average diameter in the range of from about 0.8 to about 1.2 millimeters.
Claim 41
Dependent Claim
35 words
An oral dosage unit as defined in claim 1 wherein said active spherical granules (A), said compressible spherical granules (B), said table or any combination of the foregoing includes a layer of a polymer coating.
Claim 42
Dependent Claim
39 words
An oral dosage unit as defined in claim 37 wherein said polymer comprises from about 1 to less than about 25 parts by weight based upon 100 parts by weight of either (A), (B) or the tablet being coated.
Claim 43
Dependent Claim
37 words
An oral dosage unit as defined in claim 38 wherein said polymer comprises from about 1 to about 5 percent by weight based upon 100 parts by weight of either (A), (B) or the tablet being coated.
Claim 44
Dependent Claim
74 words
An oral dosage unit as defined in claim 38 wherein said polymer is selected from (a) methylcellulose; (b) ethylcellulose; (c) hydroxyethyl cellulose; (d) hydroxypropyl cellulose; (e) hydroxypropyl methylcellulose; (f) hydroxypropyl methylcellulose phthalate; (g) cellulose acetate phthalate; (h) hydroxypropyl methylcellulose succinate; (i) a polymer or copolymer of (meth)acrylic acid or an ester thereof; or (j) a mixture of any of the foregoing, alone, or in further combination with a plasticizer, a colorant or a pigment.
Claim 45
Dependent Claim
29 words
An oral dosage unit as defined in claim 1 which also includes a top coating layer of the same or a different polymer over an intermediate polymer coating layer.
Claim 46
Dependent Claim
20 words
An oral dosage unit as defined in claim 41 wherein said intermediate layer and said top layer comprise hydroxypropyl methylcellulose.
Claim 47
Dependent Claim
174 words
An oral dosage unit as defined in claim 1 wherein said therapeutically effective number of active spherical granules (A) comprise a mixture of (A-1) a therapeutically effective number of active spherical granules comprising (i) about 10 to about 80 parts by weight of at least one active medicament; (ii) about 75 to about 10 parts by weight of microcrystalline cellulose for controlling the release rate of said at least one active medicament (A-1)(i); and, (iii) 10 to about 50 parts by weight of at least one pharmaceutically acceptable excipient based upon 100 parts by weight of said active spherical granules (A-1); and (A-2) a therapeutically effective number of active spherical granules comprising: (i) about 10 to about 80 parts by weight of at least one active medicament which is different than (A-1) (i); (ii) about 75 to about 10 parts by weight of microcrystalline cellulose; and, optionally, (iii) 10 to about 50 parts by weight of at least one pharmaceutically acceptable excipient based upon 100 parts by weight of said active spherical granules (A-2).
Claim 48
Dependent Claim
12 words
An oral dosage unit as defined in claim 1 which is scored.
Claim 49
Dependent Claim
55 words
An oral dosage unit as defined in claim 1 which also includes (C) a lubricant; (D) a disintegrant; (E) a plasticizer; (F) a colorant; (G) a pigment; (H) a flavoring; (I) an active medicament which is the same as or different than either (A)(i) or (B)(iii); or (J) a combination of any of the foregoing.
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