Nanoparticulate fibrate formulations
First Claim
Patent Images
1. A stable fibrate composition comprising:
- (a) particles of a fibrate or a salt thereof, wherein the fibrate particles have an effective average particle size of less than about 2000 nm; and
(b) associated with the surface thereof at least one surface stabilizer, wherein the surface stabilizer is not PEG-derivatized vitamin E.
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Accused Products
Abstract
The present invention is directed to fibrate compositions having improved pharmacokinetic profiles and reduced fed/fasted variability. The fibrate particles of the composition have an effective average particle size of less than about 2000 nm.
140 Citations
135 Claims
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1. A stable fibrate composition comprising:
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(a) particles of a fibrate or a salt thereof, wherein the fibrate particles have an effective average particle size of less than about 2000 nm; and
(b) associated with the surface thereof at least one surface stabilizer, wherein the surface stabilizer is not PEG-derivatized vitamin E. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26)
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- 27. A composition comprising a fibrate or a salt thereof, wherein the pharmacokinetic profile of the fibrate or a salt thereof is not significantly affected by the fed or fasted state of a subject ingesting the composition, when administered to a human.
- 29. A composition comprising a fibrate or a salt thereof, wherein administration of the composition to a subject in a fasted state is bioequivalent to administration of the composition to a subject in a fed state, when administered to a human.
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31. A composition comprising about 145 mg of fenofibrate or a salt thereof and exhibiting minimal or no food effect when administered to a human.
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32. A composition comprising about 48 mg of fenofibrate or a salt thereof and exhibiting minimal or no food effect when administered to a human.
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33. A composition comprising fenofibrate or a salt thereof and having a Cmax under fasted conditions which is greater than the Cmax under high fat fed conditions when administered to a human.
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34. A composition comprising a fibrate or a salt thereof, wherein administration of the composition to a subject in a fasted state is bioequivalent to administration of the composition to a subject in a fed state, wherein “
- bioequivalency”
is established by a 90% Confidence Interval of between 0.80 and 1.25 for both Cmax and AUC, when administered to a human.
- bioequivalency”
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35. A composition comprising a fibrate or a salt thereof, wherein administration of the composition to a subject in a fasted state is bioequivalent to administration of the composition to a subject in a fed state, wherein “
- bioequivalency”
is established by a 90% Confidence Interval of between 0.80 and 1.25 for AUC and a 90% Confidence Interval of between 0.70 to 1.43 for Cmax, when administered to a human.
- bioequivalency”
- 36. A composition comprising a fibrate or a salt thereof, wherein the composition has a Tmax selected from the group consisting of less than about 6 hours, less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2 hours, less than about 1 hour, and less than about 30 minutes after administration to fasting subjects.
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38. A composition comprising fenofibrate or a salt thereof, wherein in comparative pharmacokinetic testing with a TRICOR®
- 160 mg tablet or 200 mg capsule, which are standard commercial formulations of microcrystalline fenofibrate, the fenofibrate composition exhibits a Tmax selected from the group consisting of less than about 90%, less than about 80%, less than about 70%, less than about 50%, less than about 30%, and less than about 25% of the Tmax exhibited by the standard commercial microcrystalline fenofibrate formulations.
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39. A fenofibrate composition comprising fenofibrate or a salt thereof, which when administered to a human as a dose of about 160 mg presents an AUC of about 139 μ
- g/mL.h.
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40. A stable fibrate composition comprising:
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(a) particles of a fibrate or a salt thereof, wherein the fibrate particles have a particle size in which the D99 is less than about 500 nm; and
(b) associated with the surface thereof at least one surface stabilizer.
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41. A stable fibrate composition comprising:
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(a) particles of a fibrate or a salt thereof, wherein the fibrate particles have a particle size in which the D50 is less than about 350 nm; and
(b) associated with the surface thereof at least one surface stabilizer.
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42. A stable fibrate composition comprising:
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(a) particles of a fibrate or a salt thereof, wherein the fibrate particles have a mean particle size of less than about 100 nm; and
(b) associated with the surface thereof at least one surface stabilizer.
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43. A fibrate composition comprising:
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(a) particles of a fibrate or a salt thereof, wherein the fibrate particles have an effective average particle size of less than about 2000 nm; and
(b) associated with the surface thereof at least one surface stabilizer, wherein said surface stabilizer is not a phospholipid.
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44. A stable fibrate composition comprising:
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(a) particles of a fibrate or a salt thereof, wherein the fibrate particles have an effective average particle size of less than about 2000 nm; and
(b) associated with the surface thereof at least one surface stabilizer, wherein said surface stabilizer is categorized by the U.S. Food and Drug Administration as GRAS.
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45. A fibrate composition comprising:
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(a) particles of a fibrate or a salt thereof, wherein the fibrate particles have an effective average particle size of less than about 2000 nm; and
(b) associated with the surface thereof at least one surface stabilizer selected from the group consisting of hypromellose, docusate sodium, Plasdone®
S630, HPC-SL, sodium lauryl sulfate, and combinations thereof,wherein the composition does not comprise PEG-derivatized vitamin E.
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46. A fibrate composition comprising:
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(a) particles of a fibrate or a salt thereof, wherein the fibrate particles have an effective average particle size of less than about 2000 nm; and
(b) associated with the surface thereof dioctyl sodium sulfosuccinate and hypromellose;
wherein the composition does not comprise PEG-derivatized vitamin E. - View Dependent Claims (47, 48, 49, 50)
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51. A fibrate composition comprising:
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(a) particles of a fibrate or a salt thereof, wherein the fibrate particles have an effective average particle size of less than about 2000 nm; and
(b) associated with the surface thereof at least one surface stabilizer;
wherein the composition is bioadhesive.
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- 52. A stable fibrate composition comprising a fibrate or a salt thereof, wherein within about 5 minutes at least about 20% of the composition is dissolved, wherein dissolution is measured in a media which is discriminating and wherein the rotating blade method (European Pharmacopoeia) is used to measure dissolution.
- 57. A stable fibrate composition comprising a fibrate or a salt thereof, wherein within about 10 minutes at least about 40% of the composition is dissolved, wherein dissolution is measured in a media which is discriminating and wherein the rotating blade method (European Pharmacopoeia) is used to measure dissolution.
- 61. A stable fibrate composition comprising a fibrate or a salt thereof, wherein within about 20 minutes at least about 70% of the composition is dissolved, wherein dissolution is measured in a media which is discriminating and wherein the rotating blade method (European Pharmacopoeia) is used to measure dissolution.
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65. A fibrate composition comprising:
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(a) particles of a fibrate or a salt thereof, wherein the fibrate particles have an effective average particle size of less than about 2000 nm; and
(b) associated with the surface thereof at least one surface stabilizer, wherein upon administration the composition redisperses such that the fibrate particles have an effective average particle size selected from the group consisting of less than about 2000 nm, less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm, and less than about 50 nm.
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66. A fibrate composition comprising
(a) particles of a fibrate or a salt thereof, wherein the fibrate particles have an effective average particle size of less than about 2000 nm; - and
(b) associated with the surface thereof at least one surface stabilizer, wherein the composition redisperses in a biorelevant media such that the fibrate particles have an effective average particle size selected from the group consisting of less than about 2 microns, less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 mm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm, and less than about 50 mm.
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67. A fenofibrate composition comprising a dosage of about 145 mg of particles of fenofibrate or a salt thereof, wherein:
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(a) said dosage is therapeutically effective; and
(b) the composition is bioequivalent to a TRICOR®
160 mg tablet or 200 mg capsule, wherein bioequivalency is established by a 90% Confidence Interval of between 0.80 and 1.25 for both Cmax and AUC or a 90% Confidence Interval of between 0.80 and 1.25 for AUC and a 90% Confidence Interval of between 0.70 to 1.43 for Cmax, when administered to a human. - View Dependent Claims (68, 69, 70)
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71. A fenofibrate composition comprising a dosage of 48 mg of particles of fenofibrate or a salt thereof, wherein:
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(a) said dosage is therapeutically effective; and
(b) the composition is bioequivalent to a TRICOR®
54 mg tablet, wherein bioequivalency is established by a 90% Confidence Interval of between 0.80 and 1.25 for both Cmax and AUC or a 90% Confidence Interval of between 0.80 and 1.25 for AUC and a 90% Confidence Interval of between 0.70 to 1.43 for Cmax, when administered to a human. - View Dependent Claims (72, 73, 74)
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75. A fenofibrate composition comprising the following:
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(a) about 50 to about 500 g/kg fenofibrate or a salt thereof;
(b) about 10 to about 70 g/kg hypromellose;
(c) about 1 to about 10 g/kg docusate sodium;
(d) about 100 to about 500 g/kg sucrose;
(e) about 1 to about 40 g/kg sodium lauryl sulfate;
(f) about 50 to about 400 g/kg lactose monohydrate;
(g) about 50 to about 300 g/kg silicified microcrystalline cellulose;
(h) about 20 to about 300 g/kg crospovidone; and
(i) about 0.5 to about 5 g/kg magnesium stearate. - View Dependent Claims (76)
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77. A fenofibrate composition comprising the following:
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(a) about 100 to about 300 g/kg fenofibrate or a salt thereof;
(b) about 30 to about 50 g/kg hypromellose;
(c) about 0.5 to about 10 g/kg docusate sodium;
(d) about 100 to about 300 g/kg sucrose;
(e) about 1 to about 30 g/kg sodium lauryl sulfate;
(f) about 100 to about 300 g/kg lactose monohydrate;
(g) about 50 to about 200 g/kg silicified microcrystalline cellulose;
(h) about 50 to about 200 g/kg crospovidone; and
(i) about 0.5 to about 5 g/kg magnesium stearate. - View Dependent Claims (78)
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79. A fenofibrate composition comprising the following:
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(a) about 200 to about 225 g/kg fenofibrate or a salt thereof;
(b) about 42 to about 46 g/kg hypromellose;
(c) about 2 to about 6 g/kg docusate sodium;
(d) about 200 to about 225 g/kg sucrose;
(e) about 12 to about 18 g/kg sodium lauryl sulfate;
(f) about 200 to about 205 g/kg lactose monohydrate;
(g) about 130 to about 135 g/kg silicified microcrystalline cellulose;
(h) about 112 to about 118 g/kg crospovidone; and
(i) about 0.5 to about 3 g/kg magnesium stearate. - View Dependent Claims (80)
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81. A fenofibrate composition comprising the following:
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(a) about 119 to about 224 g/kg fenofibrate or a salt thereof;
(b) about 42 to about 46 g/kg hypromellose;
(c) about 2 to about 6 g/kg docusate sodium;
(d) about 119 to about 224 g/kg sucrose;
(e) about 12 to about 18 g/kg sodium lauryl sulfate;
(f) about 119 to about 224 g/kg lactose monohydrate;
(g) about 129 to about 134 g/kg silicified microcrystalline cellulose;
(h) about 112 to about 118 g/kg crospovidone; and
(i) about 0.5 to about 3 g/kg magnesium stearate. - View Dependent Claims (82)
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- 83. A method of making a fibrate composition comprising contacting particles of a fibrate or a salt thereof with at least one surface stabilizer for a time and under conditions sufficient to provide a fibrate composition having an effective average particle size of less than about 2000 nm, wherein the surface stabilizer is not PEG-derivatized vitamin E,
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102. A method of making a fibrate composition comprising contacting particles of a fibrate or a salt thereof with at least one surface stabilizer for a time and under conditions sufficient to provide a fibrate composition having an effective average particle size of less than about 2000 nm, wherein if heat is utilized during the method the temperature is kept below the melting point, or depressed melting point, of the fibrate.
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103. A method of treating a subject in need comprising administering to the subject an effective amount of a composition comprising:
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(a) particles of a fibrate or a salt thereof, wherein the fibrate particles have an effective average particle size of less than about 2000 nm; and
(b) at least one surface stabilizer associated with the surface of the fibrate particles, wherein the surface stabilizer is not PEG-derivatized vitamin E. - View Dependent Claims (104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129)
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- 130. A therapeutic method comprising orally administering to a mammalian subject in need an effective amount of a composition comprising a fibrate or a salt thereof formulated in such a way as to provide a blood plasma concentration profile, after an initial dose of the composition, with a Tmax of the fibrate of less than about 6 hours.
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134. A method of treating a subject in need comprising administering to the subject an effective amount of a composition comprising:
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(a) particles of a fibrate or a salt thereof having an effective average particle size of less than about 2000 nm; and
(b) at least one surface stabilizer associated with the surface of the fibrate particles, wherein the surface stabilizer is categorized by the U.S. Food and Drug Administration as GRAS.
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135. A method of treating a subject in need comprising administering to the subject an effective amount of a composition comprising:
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(a) particles of a fibrate or a salt thereof having an effective average particle size of less than about 2000 nm; and
(b) at least one surface stabilizer associated with the surface of the fibrate particles, wherein the composition when administered in the fed state to a human is bioequivalent to the composition when administered in the fasted state to a human, as established by a 90% Confidence Interval of between 0.80 and 1.25 for both Cmax and AUC or a 90% Confidence Interval of between 0.80 and 1.25 for AUC and a 90% Confidence Interval of between 0.70 to 1.43 for Cmax.
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Specification