U.S. patent application number 13/295708 was filed with the patent office on 2012-03-15 for fibrate-statin combinations with reduced fed-fasted effects.
This patent application is currently assigned to Jagotec AG. Invention is credited to Pol-Henri Guivarc'h, Indu Parikh, Robert A. Snow.
Application Number | 20120064160 13/295708 |
Document ID | / |
Family ID | 23030144 |
Filed Date | 2012-03-15 |
United States Patent
Application |
20120064160 |
Kind Code |
A1 |
Guivarc'h; Pol-Henri ; et
al. |
March 15, 2012 |
Fibrate-statin Combinations with Reduced Fed-fasted Effects
Abstract
This invention discloses an orally administered pharmaceutical
composition for the treatment of elevated levels of cholesterol and
related conditions comprising a statin and fenofibrate in the form
of microparticles of solid fenofibrate that are stabilized by
phospholipid as a surface active substance, wherein a
therapeutically effective amount of the composition provides the
statin and a quantity of fenofibrate to a fasted human patient that
is greater than 80% of the quantity of fenofibrate provided by the
same amount of the composition when administered to the same
patient who has been fed a high fat meal.
Inventors: |
Guivarc'h; Pol-Henri;
(Paris, FR) ; Parikh; Indu; (Verdun, CA) ;
Snow; Robert A.; (West Chester, PA) |
Assignee: |
Jagotec AG
Muttenz
CH
|
Family ID: |
23030144 |
Appl. No.: |
13/295708 |
Filed: |
November 14, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10388597 |
Mar 17, 2003 |
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13295708 |
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09838583 |
Apr 20, 2001 |
6534088 |
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10388597 |
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60270157 |
Feb 22, 2001 |
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Current U.S.
Class: |
424/474 ;
424/400; 514/275; 514/277; 514/311; 514/419; 514/423; 514/460;
514/510 |
Current CPC
Class: |
A61K 45/06 20130101;
A61P 3/00 20180101; A61K 31/216 20130101; A61K 31/365 20130101;
A61K 31/44 20130101; A61K 31/405 20130101; Y10S 977/906 20130101;
A61K 31/40 20130101; A61K 31/66 20130101; Y10S 424/824 20130101;
A61K 31/22 20130101; A61K 31/505 20130101; A61P 3/06 20180101; A61K
9/1623 20130101; A61K 9/145 20130101; A61K 31/22 20130101; A61K
2300/00 20130101; A61K 31/365 20130101; A61K 2300/00 20130101; A61K
31/40 20130101; A61K 2300/00 20130101; A61K 31/405 20130101; A61K
2300/00 20130101; A61K 31/44 20130101; A61K 2300/00 20130101; A61K
31/505 20130101; A61K 2300/00 20130101; A61K 31/66 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
424/474 ;
514/460; 514/510; 514/423; 514/275; 514/419; 514/277; 514/311;
424/400 |
International
Class: |
A61K 9/28 20060101
A61K009/28; A61K 31/225 20060101 A61K031/225; A61K 31/40 20060101
A61K031/40; A61K 31/505 20060101 A61K031/505; A61P 3/00 20060101
A61P003/00; A61K 31/4418 20060101 A61K031/4418; A61K 31/47 20060101
A61K031/47; A61K 9/14 20060101 A61K009/14; A61P 3/06 20060101
A61P003/06; A61K 31/366 20060101 A61K031/366; A61K 31/405 20060101
A61K031/405 |
Claims
1. A dosage form of a pharmaceutical composition comprising a
combination of a statin and microparticles of fenofibrate that are
stabilized by a phospholipid surface active substance, wherein the
dosage form provides to a patient in need of treatment by the
statin and fenofibrate a therapeutically effective dose of the
statin and a therapeutically effective quantity of fenofibrate
active species to said patient when fasted that is at least 80% of
the quantity of fenofibrate active species provided by said amount
to said patient when fed a meal containing fat.
2. A dosage form of a pharmaceutical composition comprising a
combination of a statin and microparticles of fenofibrate that are
stabilized by a phospholipid surface active substance, wherein the
dosage form provides to a human patient in need of treatment by the
statin and fenofibrate a therapeutically effective dose of the
statin and a therapeutically effective quantity of fenofibrate
active species to said patient when fasted that is greater than 80%
of the quantity of fenofibrate active species provided by said
amount to said patient when fed at least 1000 calories 50% of which
are from fat.
3. An oral dosage form of a pharmaceutical composition comprising a
combination of a statin and microparticles of fenofibrate that are
stabilized by a phospholipid surface active substance, wherein the
dosage form provides to a human patient in need of treatment by the
statin and fenofibrate a therapeutically effective dose of the
statin and a therapeutically effective quantity of fenofibrate
active species into the blood of said patient when fasted that is
between 85% and 115% of the quantity of fenofibrate active species
provided by said amount into the blood of said patient when fed at
least 1000 calories 50% of which are from fat.
4. An oral dosage form of a pharmaceutical composition comprising a
combination of a statin and microparticles of fenofibrate that are
stabilized by a phospholipid surface active substance, wherein the
dosage form provides to a human patient in need of treatment by the
statin and fenofibrate therapeutically effective dose of the statin
and a therapeutically effective quantity of fenofibrate active
species to said patient when fasted that is at least 85% of the AUC
quantity of fenofibrate active species provided by said amount to
said patient when fed at least 1000 calories 50% of which are from
fat.
5. The dosage form of claim 1 wherein the microparticles have been
prepared in the presence of the phospholipid surface active
substance.
6. The dosage form of claim 1 where the statin is
water-soluble.
7. The dosage form of claim 1 where the statin is water insoluble
or poorly water-soluble.
8. The dosage form of claim 7 where the statin is in the form of a
microparticle or is a constituent of a microparticle.
9. The dosage form of any of claim 1 where the statin is in the
form of a microparticle that is stabilized by one or more surface
active substance or is a constituent of a microparticle that is
stabilized by one or more surface active substance.
10. The dosage form of claim 9 where the surface active substance
comprises a phospholipid.
11. The dosage form of any of claim 1 where the statin is selected
from the group consisting of lovastatin, pravastatin, simvastatin,
atorvastatin, rosuvastatin, fluvastatin, itavastatin, and
cerivastatin.
12. The dosage form of claim 1 where the statin is lovas Latin.
13. The dosage form of claim 12 where the lovastatin is present in
the range of 2 mg to 50 mg.
14. The dosage form of claim 1 where the statin is pravastatin.
15. The dosage form of claim 14 where the pravastatin is present in
the range of 2 mg to 50 mg.
16. The dosage form of claim 1 where the statin is simvastatin.
17. The dosage form of claim 16 where the simvastatin is present in
the range of 2 mg to 100 mg.
18. The dosage form of claim 1 where the statin is
atorvastatin.
19. The dosage form of claim 18 where the atorvastatin is present
in the range of 2 mg to 100 mg.
20. The dosage form of claim 1 where the statin is
rosuvastatin.
21. The dosage form of claim 20 where the rosuvastatin is present
in the range of 2 mg to 100 mg.
22. The dosage form of claim 1 where the statin is fluvastatin.
23. The dosage form of claim 22 where the fluvastatin is present in
the range of 2 mg to 50 mg.
24. The dosage form of claim 1 where the statin is itavastatin.
25. The dosage form of claim 24 where the itavastatin is present in
the range of 0.2 mg to 100 mg.
26. The dosage form of claim 1 where the statin is
cerivastatin.
27. The dosage form of claim 26 where the cerivastatin is present
in the range of 0.05 mg to 2 mg.
28. The dosage form of claim 1 where the fenofibrate is a
solid.
29. The dosage form of claim 1 where the fenofibrate is
crystalline.
30. The dosage form of claim 1 where the microparticles have a
volume weighted mean size smaller than 5 micrometers.
31. The dosage form of claim 1 where the microparticles have a
volume weighted mean size smaller than 4 micrometers.
32. The dosage form of claim 1 where the microparticles have a
volume weighted mean size smaller than 3 micrometers.
33. The dosage form of claim 1 where the microparticles have a
volume weighted mean size smaller than 2 micrometers.
34. The dosage form of claim 1 where the microparticles have a
volume weighted mean size smaller than 1 micrometers.
35. The dosage form of claim 1 where the microparticles have a
volume weighted mean size smaller than 0.5 micrometers.
36. The dosage form of claim 1 where the microparticles have been
prepared by a process selected from the group consisting of
homogenization, microfluidization, hot melt microfluidization, and
sonication.
37. The dosage form of claim 1 where the microparticles have been
prepared by a process selected from the group consisting of a
milling process, a precipitation process, an emulsification
process, a solvent evaporation spray process, a particle
preparation process that utilizes a liquefied gas, and a particle
preparation process that utilizes a supercritical fluid.
38. The dosage form of claim 1 that contains a weight of
fenofibrate in the range from 40 mg to 300 mg.
39. The dosage form of claim 1 that contains a weight of
fenofibrate selected from the group consisting of 40 mg, 50 mg, 51
mg, 52 mg, 53 mg, 54 mg, 67 mg, 100 mg, 102 mg, 103 mg, 104 mg, 134
mg, 150 mg, 153 mg, 156 mg, 159 mg, 160 mg, 200 mg, 213 mg, 250 mg,
and 300 mg of fenofibrate.
40. The dosage form of claim 1 further comprising one or more
pharmaceutically acceptable excipient.
41. The dosage form of claim 1 further comprising one or more
excipients selected from the group consisting of monosaccharides,
disaccharides, trisaccharides, sucrose, raffinose, lactose,
mannitol, sorbitol, trehalose, glycerol, dextrose, fructose,
pentoses, hexoses, xylitol, and mixtures thereof.
42. The dosage form of claim 1 wherein the phospholipid surface
active substance comprises a mixture of phospholipids.
43. The dosage form of claim 1 wherein the phospholipid surface
active substance is selected from the group consisting of saturated
phospholipids, unsaturated phospholipids, naturally derived
phospholipids, synthetic phospholipids, and semisynthetic
phospholipids.
44. The dosage form of claim 1 wherein the phospholipid surface
active substance is selected from the group consisting of Lipoid
E80, Lipoid EPC, Lipoid SPC, DMPG, Phospholipon 100H, a
hydrogenated soybean phosphatidylcholine, Phospholipon 90H, Lipoid
SPC-3, egg phospholipid, purified egg phopholipid, and mixtures
thereof.
45. The dosage form of claim 1 that comprises a capsule.
46. The dosage form of claim 1 that comprises a tablet.
47. The dosage form of claim 1 that comprises a powder dispersible
in water or a beverage.
48. The dosage form of claim 1 further comprising a bulking
agent.
49. A process for preparing a dosage form of claim 1 comprising the
steps of: (a) mixing at high shear an admixture of fenofibrate and
a phospholipid substance in an aqueous carrier in the absence of an
organic solvent within a first temperature range at or above the
melting point of fenofibrate to form a heated suspension wherein
fenofibrate is molten; (b) homogenizing said heated suspension in a
first pressure range and within said first temperature range to
form a heated homogenate containing fenofibrate; (c) cooling said
heated homogenate to a second temperature range below the melting
temperature of fenofibrate to form a transiently stable cooled
homogenate containing fenofibrate; (d) applying a particle
stabilizing energetic process to said cooled homogenate within a
second temperature range below the melting temperature of
fenofibrate and in a second pressure range to form a cooled
dispersion of small particles containing fenofibrate, and (e)
drying said cooled dispersion to form dried small particles
containing fenofibrate.
50. The process of claim 49 further comprising the step of adding a
statin in any of steps (a) through (d).
51. The process of claim 50 where the statin is water-soluble.
52. The process of claim 50 where the statin is water insoluble or
poorly water-soluble.
53. The process of claim 50 further comprising the addition of one
or more bulking agents in any of steps (a) through (d).
54. The process of claim 53 where the bulking agent is selected
from the group consisting of a monosaccharide, a disaccharide, a
trisaccharide, sucrose, raffinose, lactose, mannitol, sorbitol,
trehalose, glycerol, dextrose, fructose, a sugar, a pentose, a
hexose, xylitol, and mixtures thereof.
55. The process of claim 53 wherein the bulking agent is selected
from the group consisting of trehalose, sucrose, raffinose,
sorbitol and mixtures thereof.
56. The dosage form of claim 1 prepared by a process comprising
blending dried small particles containing fenofibrate stabilized by
a phospholipid surface active substance with a statin.
57. The dosage form of claim 1 further comprising one or more
pharmaceutically acceptable excipients.
58. The process of claim 49 where the phospholipid substance is
selected from the group consisting of Lipoid E80, Lipoid EPC,
Lipoid SPC, DMPG, Phospholipon 100H, Lipoid SPC-3, egg
phospholipid, purified egg phospholipid, and mixtures thereof.
59. The process of claim 49 where the phospholipid substance is
Lipoid E80.
60. The process of claim 49 wherein the first temperature range is
from the melting point of fenofibrate to 20.degree. C. above the
melting point of fenofibrate.
61. The process of claim 49 wherein the second temperature range is
from 4.degree. C. to 40.degree. C. and fenofibrate is not
molten.
62. The process of claim 49 wherein the aqueous carrier is selected
from the group consisting of water, sterile water, water for
injection, and phosphate buffered water having a pH from 4 to
10.
63. The process of claim 49 wherein the aqueous carrier is
phosphate buffered water having a pH from 7 to 9.
64. The process of claim 49 wherein the first pressure range is
from 2,000 to 30,000 psi.
65. The process of claim 49 wherein the second pressure range is
18,000 to 5,000 psi.
66. The process of claims 49 wherein the small particles have size
in the range from 0.05 to 2 micrometers.
67. A method of treatment of dyslipidemia and dyslipoproteinemia in
a patient comprising the administration to said patient of a dosage
form of a pharmaceutical composition comprising a combination of a
statin and microparticles of fenofibrate that are stabilized by a
phospholipid surface active substance, wherein the dosage form
provides to a patient in need of treatment by the statin and
fenofibrate a therapeutically effective dose of the statin and a
therapeutically effective quantity of fenofibrate active species to
said patient when fasted that is at least 80% of the quantity of
fenofibrate active species provided by said amount to said patient
when fed a meal containing fat.
68. A method of treatment of dyslipidemia and dyslipoproteinemia in
a patient comprising the administration to said patient of a dosage
form of a pharmaceutical composition comprising a combination of a
statin and microparticles of fenofibrate that are stabilized by a
phospholipid surface active substance, wherein the dosage form
provides to a human patient in need of treatment by the statin and
fenofibrate a therapeutically effective dose of the statin and a
therapeutically effective quantity of fenofibrate active species to
said patient when fasted that is greater than 80% of the quantity
of fenofibrate active species provided by said amount to said
patient when fed at least 1000 calories 50% of which are from
fat.
69. A method of treatment of dyslipidemia and dyslipoproteinemia in
a patient comprising the administration to said patient of an oral
dosage form of a pharmaceutical composition comprising a
combination of a statin and microparticles of fenofibrate that are
stabilized by a phospholipid surface active substance, wherein the
dosage form provides to a human patient in need of treatment by the
statin and fenofibrate a therapeutically effective dose of the
statin and a therapeutically effective quantity of fenofibrate
active species into the blood of said patient when fasted that is
between 85% and 115% of the quantity of fenofibrate active species
provided by said amount into the blood of said patient when fed at
least 1000 calories 50% of which are from fat.
70. A method of treatment of dyslipidemia and dyslipoproteinemia in
a patient comprising the administration to said patient of an oral
dosage form of a pharmaceutical composition comprising a
combination of a statin and microparticles of fenofibrate that are
stabilized by a phospholipid surface active substance, wherein the
dosage form provides to a human patient in need of treatment by the
statin and fenofibrate a therapeutically effective dose of the
statin and a therapeutically effective quantity of fenofibrate
active species to said patient when fasted that is at least 85% of
the AUC quantity of fenofibrate active species provided by said
amount to said patient when fed at least 1000 calories 50% of which
are from fat.
71. The method of treatment of claim 67 where the administration is
one a day.
72. The method of treatment of claim 67 where the administration is
twice a day.
73. The method of treatment of claim 67 where the administration is
three to five times a day.
74. The method of treatment of claim 67 where the dyslipidemia
comprises hypercholesterolemia, hyperlipidemia,
hypertrigylceridaemia or combinations thereof.
75. The tablet of claim 46 selected from the group consisting of a
film-coated tablet, a moisture resistant tablet, and a tablet
coated with a pharmaceutically acceptable polymer.
76. A capsule or tablet dosage form for oral administration
comprising a pharmaceutically effective amount of a composition
containing a statin and small particles of a fibrate stabilized by
a phospholipid stabilizing agent, a sugar, and optionally a
carbohydrate-derived alcohol wherein said amount of said dosage
form provides a therapeutically effective dose of the statin and a
therapeutically effective level of fibrate active species into the
blood of a patient in a fasted state that differs by less than 20%
of the level of said fibrate active species that said patient
receives in a fed state.
77. A dosage form of a pharmaceutical composition comprising a
combination of a statin, a carbohydrate bulking agent, and
microparticles of fenofibrate that are stabilized by a phospholipid
surface active substance, wherein the dosage form provides to a
patient in need of treatment by the statin and fenofibrate a
therapeutically effective dose of the statin and a therapeutically
effective quantity of fenofibrate active species to said patient
when fasted that is at least 80% of the quantity of fenofibrate
active species provided by said amount to said patient when fed a
meal containing fat.
78. A dosage form of a pharmaceutical composition comprising a
combination of a statin, a carbohydrate bulking agent, and
microparticles of fenofibrate that are stabilized by a phospholipid
surface active substance, wherein the dosage form provides to a
human patient in need of treatment by the statin and fenofibrate a
therapeutically effective dose of the statin and a therapeutically
effective quantity of fenofibrate active species to said patient
when fasted that is greater than 80% of the quantity of fenofibrate
active species provided by said amount to said patient when fed at
least 1000 calories 50% of which are from fat.
79. An oral dosage form of a pharmaceutical composition comprising
a combination of a statin, a carbohydrate bulking agent, and
microparticles of fenofibrate that are stabilized by a phospholipid
surface active substance, wherein the dosage form provides to a
human patient in need of treatment by the statin and fenofibrate a
therapeutically effective dose of the statin and a therapeutically
effective quantity of fenofibrate active species into the blood of
said patient when fasted that is between 85% and 115% of the
quantity of fenofibrate active species provided by said amount into
the blood of said patient when fed at least 1000 calories 50% of
which are from fat.
80. An oral dosage form of a pharmaceutical composition comprising
a combination of a statin, a carbohydrate bulking agent, and
microparticles of fenofibrate that are stabilized by a phospholipid
surface active substance, wherein the dosage form provides to a
human patient in need of treatment by the statin and fenofibrate a
therapeutically effective dose of the statin and a therapeutically
effective quantity of fenofibrate active species to said patient
when fasted that is at least 85% of the AUC quantity of fenofibrate
active species provided by said amount to said patient when fed at
least 1000 calories 50% of which are from fat.
81. The dosage form of claim 77 wherein the microparticles have
been prepared in the presence of the phospholipid surface active
substance.
82. The dosage form of claim 77 where the statin is
water-soluble.
83. The dosage form of claim 77 where the statin is water insoluble
or poorly water-soluble.
84. The dosage form of claim 83 where the statin is in the form of
a microparticle or is a constituent of a microparticle.
85. The dosage form of claim 77 where the statin is in the form of
a microparticle that is stabilized by one or more surface active
substance or is a constituent of a microparticle that is stabilized
by one or more surface active substance.
86. The dosage form of claim 85 where the surface active substance
comprises a phospholipid.
87. The dosage form of claim 77 where the statin is selected from
the group consisting of lovastatin, pravastatin, simvastatin,
atorvastatin, rosuvastatin, fluvastatin, itavastatin, and
cerivastatin.
88. The dosage form of claim 77 where the statin is lovastatin.
89. The dosage form of claim 88 where the lovastatin is present in
the range of 2 mg to 50 mg.
90. The dosage form of claim 77 where the statin is
pravastatin.
91. The dosage form of claim 90 where the pravastatin is present in
the range of 2 mg to 50 mg.
92. The dosage form of claim 77 where the statin is
simvastatin.
93. The dosage form of claim 92 where the simvastatin is present in
the range of 2 mg to 100 mg.
94. The dosage form of claim 77 where the statin is
atorvastatin.
95. The dosage form of claim 94 where the atorvastatin is present
in the range of 2 mg to 100 mg.
96. The dosage form of claim 77 where the statin is
rosuvastatin.
97. The dosage form of claim 96 where the rosuvastatin is present
in the range of 2 mg to 100 mg.
98. The dosage form of claim 77 where the statin is
fluvastatin.
99. The dosage form of claim 98 where the fluvastatin is present in
the range of 2 mg to 50 mg.
100. The dosage form of claim 77 where the statin is
itavastatin.
101. The dosage form of claim 100 where the itavastatin is present
in the range of 0.2 mg to 100 mg.
102. The dosage form of claim 77 where the statin is
cerivastatin.
103. The dosage form of claim 102 where the cerivastatin is present
in the range of 0.05 mg to 2 mg.
104. The dosage form of claim 77 where the fenofibrate is a
solid.
105. The dosage form of claim 77 where the fenofibrate is
crystalline.
106. The dosage form of claim 77 where the microparticles have a
volume weighted mean size smaller than 5 micrometers.
107. The dosage form of claim 77 where the microparticles have a
volume weighted mean size smaller than 4 micrometers.
108. The dosage form of claim 77 where the microparticles have a
volume weighted mean size smaller than 3 micrometers.
109. The dosage form of claim 77 where the microparticles have a
volume weighted mean size smaller than 2 micrometers.
110. The dosage form of claim 77 where the microparticles have a
volume weighted mean size smaller than 1 micrometers.
111. The dosage form of claim 77 where the microparticles have a
volume weighted mean size smaller than 0.5 micrometers.
112. The dosage form of claim 77 where the microparticles have been
prepared by a process selected from the group consisting of
homogenization, microfluidization, hot melt microfluidization, and
sonication.
113. The dosage form of claim 77 where the microparticles have been
prepared by a process selected from the group consisting of a
milling process, a precipitation process, an emulsification
process, a solvent evaporation spray process, a particle
preparation process that utilizes a liquefied gas, and a particle
preparation process that utilizes a supercritical fluid.
114. The dosage form of claim 77 that contains a weight of
fenofibrate in the range from 40 mg to 300 mg.
115. The dosage form of claim 77 that contains a weight of
fenofibrate selected from the group consisting of 40 mg, 50 mg, 51
mg, 52 mg, 53 mg, 54 mg, 67 mg, 100 mg, 102 mg, 103 mg, 104 mg, 134
mg, 150 mg, 153 mg, 156 mg, 159 mg, 160 mg, 200 mg, 213 mg, 250 mg,
and 300 mg of fenofibrate.
116. The dosage form of claim 77 further comprising one or more
pharmaceutically acceptable excipient.
117. The dosage form of claim 77 where the carbohydrate is a
sugar.
118. The dosage form of claim 77 where the carbohydrate is selected
from the group consisting of monosaccharides, disaccharides,
trisaccharides, sucrose, raffinose, lactose, mannitol, sorbitol,
trehalose, glycerol, dextrose, fructose, pentoses, hexoses,
xylitol, and mixtures thereof.
119. The dosage form of claim 77 wherein the phospholipid surface
active substance comprises a mixture of phospholipids.
120. The dosage form of claim 77 wherein the phospholipid surface
active substance is selected from the group consisting of saturated
phospholipids, unsaturated phospholipids, naturally derived
phospholipids, synthetic phospholipids, and semisynthetic
phospholipids.
121. The dosage form of claim 77 wherein the phospholipid surface
active substance is selected from the group consisting of Lipoid
E80, Lipoid EPC, Lipoid SPC, DMPG, Phospholipon 100H, a
hydrogenated soybean phosphatidylcholine, Phospholipon 90H, Lipoid
SPC-3, egg phospholipid, purified egg phopholipid, and mixtures
thereof.
122. The dosage form of claim 77 that comprises a capsule.
123. The dosage form of claim 77 that comprises a tablet.
124. The dosage form of claim 77 that comprises a powder
dispersible in water or a beverage.
125. A process for preparing a dosage form of claim 77 comprising
the steps of: (a) mixing at high shear an admixture of fenofibrate
and a phospholipid substance in an aqueous carrier in the absence
of an organic solvent within a first temperature range at or above
the melting point of fenofibrate to form a heated suspension
wherein fenofibrate is molten; (b) homogenizing said heated
suspension in a first pressure range and within said first
temperature range to form a heated homogenate containing
fenofibrate; (c) cooling said heated homogenate to a second
temperature range below the melting temperature of fenofibrate to
form a transiently stable cooled homogenate containing fenofibrate;
(d) applying a particle stabilizing energetic process to said
cooled homogenate within a second temperature range below the
melting temperature of fenofibrate and in a second pressure range
to form a cooled dispersion of small particles containing
fenofibrate, and (e) drying said cooled dispersion to form dried
small particles containing fenofibrate, wherein the process further
comprises the addition of a carbohydrate bulking agent at any of
the steps (a) through (e) and wherein the process further comprises
the addition of a statin in any of steps (a) through (e).
126. The process of claim 125 where the statin is
water-soluble.
127. The process of claim 125 where the statin is water insoluble
or poorly water-soluble.
128. The process of claim 125 further comprising the addition of
another bulking agent in any of steps (a) through (e).
129. The process of claim 125 where the carbohydrate is a
sugar.
130. The process of claim 125 where the carbohydrate is selected
from the group consisting of a monosaccharide, a disaccharide, a
trisaccharide, sucrose, raffinose, lactose, mannitol, sorbitol,
trehalose, glycerol, dextrose, fructose, a sugar, a pentose, a
hexose, xylitol, and mixtures thereof.
131. The process of claim 125 wherein the bulking agent is selected
from the group consisting of trehalose, sucrose, raffinose,
sorbitol and mixtures thereof.
132. The dosage form of claim 77 prepared by a process comprising
blending dried small particles containing fenofibrate stabilized by
a phospholipid surface active substance with a statin.
133. The dosage form of claim 77 further comprising one or more
pharmaceutically acceptable excipients.
134. The process of claim 125 where the phospholipid substance is
selected from the group consisting of Lipoid E80, Lipoid EPC,
Lipoid SPC, DMPG, Phospholipon 100H, Lipoid SPC-3, egg
phospholipid, purified egg phospholipid, and mixtures thereof.
135. The process of claim 125 where the phospholipid substance is
Lipoid E80.
136. The process of claim 125 wherein the first temperature range
is from the melting point of fenofibrate to 20.degree. C. above the
melting point of fenofibrate.
137. The process of claim 125 wherein the second temperature range
is from 4.degree. C. to 40.degree. C. and fenofibrate is not
molten.
138. The process of claim 125 wherein the aqueous carrier is
selected from the group consisting of water, sterile water, water
for injection, and phosphate buffered water having a pH from 4 to
10.
139. The process of claim 125 wherein the aqueous carrier is
phosphate buffered water having a pH from 7 to 9.
140. The process of claim 125 wherein the first pressure range is
from 2,000 to 30,000 psi.
141. The process of claim 125 wherein the second pressure range is
18,000 to 5,000 psi.
142. The process of claims 125 wherein the small particles have
size in the range from 0.05 to 2 micrometers.
143. A method of treatment of dyslipidemia and dyslipoproteinemia
in a patient comprising the administration to said patient of a
dosage form of a pharmaceutical composition comprising a
combination of a statin, a carbohydrate bulking agent, and
microparticles of fenofibrate that are stabilized by a phospholipid
surface active substance, wherein the dosage form provides to a
patient in need of treatment by the statin and fenofibrate a
therapeutically effective dose of the statin and a therapeutically
effective quantity of fenofibrate active species to said patient
when fasted that is at least 80% of the quantity of fenofibrate
active species provided by said amount to said patient when fed a
meal containing fat.
144. A method of treatment of dyslipidemia and dyslipoproteinemia
in a patient comprising the administration to said patient of a
dosage form of a pharmaceutical composition comprising a
combination of a statin, a carbohydrate bulking agent, and
microparticles of fenofibrate that are stabilized by a phospholipid
surface active substance, wherein the dosage form provides to a
human patient in need of treatment by the statin and fenofibrate a
therapeutically effective dose of the statin and a therapeutically
effective quantity of fenofibrate active species to said patient
when fasted that is greater than 80% of the quantity of fenofibrate
active species provided by said amount to said patient when fed at
least 1000 calories 50% of which are from fat.
145. A method of treatment of dyslipidemia and dyslipoproteinemia
in a patient comprising the administration to said patient of an
oral dosage form of a pharmaceutical composition comprising a
combination of a statin, a carbohydrate bulking agent, and
microparticles of fenofibrate that are stabilized by a phospholipid
surface active substance, wherein the dosage form provides to a
human patient in need of treatment by the statin and fenofibrate a
therapeutically effective dose of the statin and a therapeutically
effective quantity of fenofibrate active species into the blood of
said patient when fasted that is between 85% and 115% of the
quantity of fenofibrate active species provided by said amount into
the blood of said patient when fed at least 1000 calories 50% of
which are from fat.
146. A method of treatment of dyslipidemia and dyslipoproteinemia
in a patient comprising the administration to said patient of an
oral dosage form of a pharmaceutical composition comprising a
combination of a statin, a carbohydrate bulking agent, and
microparticles of fenofibrate that are stabilized by a phospholipid
surface active substance, wherein the dosage form provides to a
human patient in need of treatment by the statin and fenofibrate a
therapeutically effective dose of the statin and a therapeutically
effective quantity of fenofibrate active species to said patient
when fasted that is at least 85% of the AUC quantity of fenofibrate
active species provided by said amount to said patient when fed at
least 1000 calories 50% of which are from fat.
147. The method of treatment of claim 143 where the administration
is one a day.
148. The method of treatment of claim 143 where the administration
is twice a day.
149. The method of treatment of claim 143 where the administration
is three to five times a day.
150. The method of treatment of claim 143 where the dyslipidemia
comprises hypercholesterolemia, hyperlipidemia,
hypertrigylceridaemia or combinations thereof.
151. The tablet of claim 123 selected from the group consisting of
a film-coated tablet, a moisture resistant tablet, and a tablet
coated with a pharmaceutically acceptable polymer.
152. The process of claim 49 where the cooled dispersion is dried
by spray drying or by lyophilization.
Description
[0001] This invention relates to therapeutically effective
compositions and methods for treatment of patients with
dyslipidemia, hyperlipidemia, hypercholesterolemia and related
conditions comprising a combination in one dosage form of a
hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor or
statin and a fibrate formulated together to provide simultaneously
a therapeutically effective amount of the hydroxymethylglutaryl
coenzyme A reductase inhibitor and a therapeutically effective
amount of the fibrate taken into the blood of a patient in need of
treatment where the amount of the fibrate taken into the blood is
not substantially affected by the presence or absence of food or
levels of fat in food taken by the patient proximal to the
administration of the dosage form. The compositions of this
invention are also useful for the prevention of type III
hyperlipoproteinemia in patients prone to that condition.
[0002] In particular, this invention relates to an oral dosage form
of a pharmaceutical composition comprising a combination of a
statin, a carbohydrate bulking agent, and microparticles of
fenofibrate that are stabilized by a phospholipid surface active
substance, wherein the dosage form provides to a patient in need of
treatment by the statin and fenofibrate a therapeutically effective
dose of the statin and a therapeutically effective quantity of
fenofibrate active species to said patient when fasted that is at
least 80% and especially at least 85% of the quantity of
fenofibrate active species, particularly the AUC quantity of
fenofibrate active species, provided by said amount to said patient
when fed a meal containing fat, especially when fed at least 1000
calories 50% of which are from fat.
BACKGROUND
[0003] In humans, cholesterol and triglycerides (TG) are part of
lipoprotein complexes in the bloodstream, and can be separated via
ultracentrifugation into high-density lipoprotein (HDL),
intermediate-density lipoprotein (IDL), low-density lipoprotein
(LDL) and very-low-density lipoprotein (VLDL) fractions.
Cholesterol and triglycerides are synthesized in the liver,
incorporated into VLDL, and released into the plasma. High levels
of total cholesterol (total-C), LDL-C, and apolipoprotein B (apo-B,
a membrane complex for LDL-C) promote human atherosclerosis, and
decreased levels of HDL-C and its transport complex, apolipoprotein
A, are associated with the development of atherosclerosis.
Cardiovascular morbidity and mortality in humans can vary directly
with the level of total-C and LDL-C and inversely with the level of
HDL-C.
[0004] Orally administered statins are hydroxymethylglutaryl
coenzyme A (HMG-CoA) reductase inhibitors that are used in patients
to lower low density lipoprotein (LDL) cholesterol. Complimentary
to this are orally administered fibrates which are used in patients
to decrease lipoproteins rich in triglycerides, to increase high
density lipoprotein (HDL), and to decrease atherogenic-dense LDL.
Patients who take statins or fibrates are frequently on diets with
low and variable fat content.
[0005] Uptake of a fibrate such as fenofibrate by a patient is
sensitive to a positive food effect, hereinafter referred to simply
as a food effect. A positive food effect (or food effect) exits
when the amount of an active drug taken into the blood from a given
oral dosage form by a fasting patient is less than the amount of
the active drug taken into the blood from the same dosage form by
the same patient who has eaten a fat-containing meal proximal to
the time of administration of the dosage form. A negative food
effect exits when the amount of an active drug taken into the blood
from a given oral dosage form by a fasting patient is more than the
amount of the active drug taken into the blood from the same dosage
form by the same patient who has eaten a fat-containing meal
proximal to the time of administration of the dosage form. The
compositions of this invention generally exhibit a positive food
effect.
[0006] Patients with severe primary hypercholesterolemia often
present with blood levels of low density lipoprotein (LDL)
cholesterol greater than 190 mg/dl (4.9 mmol/L) and triglyceride
levels up to 350 mg/dl (3.9 mmol/L). The use of diet and
single-drug therapy does not always decrease LDL cholesterol and
triglycerides adequately enough to reach targeted values in
patients with primary severe hypercholesterolemia with or without a
concomitant increase in triglycerides. In these patients a
combination of complementary fibrate therapy and statin therapy can
be desirable.
[0007] HMG-CoA reductase (3-hydroxy-3-methylglutaryl-coenzyme A) is
the microsomal enzyme that catalyzes the rate limiting reaction in
cholesterol biosynthesis (Mevalonate). A statin compound is an
HMG-CoA reductase inhibitor that inhibits HMG-CoA reductase, and
therefore inhibits or interferes with the synthesis of cholesterol.
Inhibition of cholesterol synthesis can lead to a reduction in
blood cholesterol levels.
[0008] A large number of naturally or synthetically obtained or
synthetically modified compounds have been found to inhibit HMG-CoA
reductase. These compounds form a category of agents useful for
practicing the present invention. Traditionally these agents have
been used to treat individuals with hypercholesterolemia. Examples
include statins, which are commercially available, such as
lovastatin and mevinolin disclosed in U.S. Pat. No. 4,231,938,
pravastatin and pravastatin sodium disclosed in U.S. Pat. No.
4,346,227, fluvastatin and fluvastatin sodium and XU 62-320
disclosed in EP 0 114 027 and U.S. Pat. No. 4,739,073, atorvastatin
disclosed in U.S. Pat. No. 5,273,995, itavastatin also known as
NK-104 disclosed in EP304063, mevastatin disclosed in U.S. Pat. No.
3,983,140, rosuvastatin, velostatin and synvinolin and simvastatin
disclosed in U.S. Pat. No. 4,448,784 and U.S. Pat. No. 4,450,171,
cerivastatin and numerous others described in U.S. Pat. No.
5,622,985, U.S. Pat. No. 5,135,935, U.S. Pat. No. 5,356,896, U.S.
Pat. No. 4,920,109, U.S. Pat. No. 5,286,895, U.S. Pat. No.
5,262,435, U.S. Pat. No. 5,260,332, U.S. Pat. No. 5,317,031, U.S.
Pat. No. 5,283,256, U.S. Pat. No. 5,256,689, U.S. Pat. No.
5,182,298, U.S. Pat. No. 5,369,125, U.S. Pat. No. 5,302,604, U.S.
Pat. No. 5,166,171, U.S. Pat. No. 5,202,327, U.S. Pat. No.
5,276,021, U.S. Pat. No. 5,196,440, U.S. Pat. No. 5,091,386, U.S.
Pat. No. 5,091,378, U.S. Pat. No. 4,904,646, U.S. Pat. No.
5,385,932, U.S. Pat. No. 5,250,435, U.S. Pat. No. 5,132,312, U.S.
Pat. No. 5,130,306, U.S. Pat. No. 5,116,870, U.S. Pat. No.
5,112,857, U.S. Pat. No. 5,102,911, U.S. Pat. No. 5,098,931, U.S.
Pat. No. 5,081,136, U.S. Pat. No. 5,025,000, U.S. Pat. No.
5,021,453, U.S. Pat. No. 5,017,716, U.S. Pat. No. 5,001,144, U.S.
Pat. No. 5,001,128, U.S. Pat. No. 4,997,837, U.S. Pat. No.
4,996,234, U.S. Pat. No. 4,994,494, U.S. Pat. No. 4,992,429, U.S.
Pat. No. 4,970,231, U.S. Pat. No. 4,968,693, U.S. Pat. No.
4,963,538, U.S. Pat. No. 4,957,940, U.S. Pat. No. 4,950,675, U.S.
Pat. No. 4,946,864, U.S. Pat. No. 4,946,860, U.S. Pat. No.
4,940,800, U.S. Pat. No. 4,940,727, U.S. Pat. No. 4,939,143, U.S.
Pat. No. 4,929,620, U.S. Pat. No. 4,923,861, U.S. Pat. No.
4,906,657, U.S. Pat. No. 4,906,624, RE36,520, and U.S. Pat. No.
4,897,402, the disclosures of which patents are incorporated herein
by reference.
[0009] Lovastatin, an inactive lactone, is a white, nonhygroscopic
crystalline powder isolated from a strain of Aspergillus terreus
that is insoluble in water and sparingly soluble in ethanol,
methanol, and acetonitrile. Lovastatin is hydrolyzed after oral
ingestion to the corresponding (beta)-hydroxyacid. This is
metabolite is, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme
A (HMG-CoA) reductase. When formulated for oral administration as
Mevacor, tablets can contain 10 to 40 mg of lovastatin together
with pharmaceutically acceptable excipients such as cellulose,
lactose, magnesium stearate, starch, and butylated hydroxyanisole
as a preservative. When taken separately, lovastatin can treat
related hyperlipidemia such as reduce plasma total-C, LDL-C,
total-C/HDL-C ratio and LDL-C/HDL-C ratio as well as increase
HDL-C, and modestly decrease VLDL-C and plasma triglycerides TG.
Mevacor can lower total-C and LDL-C to target levels, and reduce
elevated total-C and LDL-C levels in patients with primary
hypercholesterolemia (Types IIa and IIb). Single daily doses given
in the evening can be more effective than the same dose given in
the morning, perhaps because cholesterol is synthesized mainly at
night. A recommended starting dose of Mevacor is preferably given
with a meal. 20 mg once a day can be given with the evening meal.
Storage between 5-30.degree. C. (41-86.degree. F.) is
preferred.
[0010] Fluvastatin (also known as fluvastatin sodium), a synthetic
HMG-CoA reductase inhibitor, is a white to pale yellow, hygroscopic
powder soluble in water, ethanol and methanol. When formulated for
oral administration as Lescol.RTM., capsules can contain 20 to 40
mg of fluvastatin together with pharmaceutically acceptable
excipients such as gelatin, magnesium stearate, microcrystalline
cellulose, pregelatinized starch, red iron oxide, sodium lauryl
sulfate, talc, titanium dioxide, yellow iron oxide, and other
ingredients. Fluvastatin sodium reduces Total-C, LDL-C, and
apolipoprotein B, and moderately reduces triglycerides (TG) while
producing an increase in HDL-C of variable magnitude. Following
oral administration, fluvastatin is absorbed rapidly and completely
with peak concentrations reached in less than 1 hour.
Administration with food reduces the rate but not the extent of
absorption. Fluvastatin sodium is indicated as an adjunct to diet
in the treatment of elevated total cholesterol (Total-C), LDL-C, TG
and Apo B levels in patients with primary hypercholesterolemia and
mixed dyslipidemia (Frederickson Type IIa and IIb). It is also
indicated to slow the progression of coronary atherosclerosis in
patients with coronary heart disease as part of a treatment
strategy to lower total and LDL cholesterol to target levels.
[0011] Atorvastatin (or Atorvastatin calcium 2:1) is a white to
off-white crystalline trihydrate powder that is insoluble in
aqueous solutions of pH 4 and below, and is very slightly soluble
in distilled water, pH 7.4 phosphate buffer, and acetonitrile,
slightly soluble in ethanol, and freely soluble in methanol. When
formulated in Lipitor.RTM. tablets for oral administration, tablets
can contain 10 to 80 mg of atorvastatin as well as pharmaceutically
acceptable excipients such as calcium carbonate, USP; candelilla
wax, FCC; croscarmellose sodium, NF; hydroxypropyl cellulose, NF;
lactose monohydrate, NF; magnesium stearate, NF; microcrystalline
cellulose, NF; Opadry White YS-1-7040
(hydroxypropylmethylcellulose, polyethylene glycol, talc, titanium
dioxide): polysorbate 80, NF; and simethicone emulsion.
Atorvastatin can reduce total-C, LDL-C, and apo B in patients with
homozygous and heterozygous familial hypercholesterolemia,
nonfamilial forms of hypercholesterolemia, and mixed dyslipidemia.
Atorvastatin can also reduce VLDL-C and TG and produces variable
increases in HDL-C and apolipoprotein A-1. Atorvastatin can reduce
total-C, LDL-C, VLDL-C, apo B, TG, and non-HDL-C, and can increase
HDL-C in patients with isolated hypertriglyceridemia. Atorvastatin
can reduce intermediate density lipoprotein cholesterol (IDL-C) in
patients with dvsbetalipoproteinemia. Food decreases the rate and
extent of drug absorption as assessed by Cmax and AUC, but LDL-C
reduction is similar whether atorvastatin is given with or without
food. Atorvastatin can be administered as a single dose at any time
of the day, with or without food. Atorvastatin can reduce total-C,
LDL-C, VLDL-C, apo B, and TG, and can increase HDL-C in patients
with hypercholesterolemia and mixed dyslipidemia.
[0012] Simvastatin is a white to off-white, nonhygroscopic,
crystalline powder that is practically insoluble in water, and
freely soluble in chloroform, methanol and ethanol. Simvastatin is
derived synthetically from a fermentation product of Aspergillus
terreus. After oral ingestion, simvastatin, which is an inactive
lactone, is hydrolyzed to the corresponding (beta)-hydroxyacid form
which is an inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A
(HMG-CoA) reductase. When formulated as Zocor for oral
administration; tablets can contain 5 mg to 80 mg of simvastatin as
well as pharmaceutically acceptable excipients cellulose,
hydroxypropyl cellulose, hydroxypropyl methylcellulose, iron
oxides, lactose, magnesium stearate, starch, talc, titanium dioxide
as well as other ingredients including butylated hydroxyanisole
which can be added as a preservative. Simvastatin shows no
fed-fasted effect when administered immediately before a low-fat
meal. Simvastatin can reduce total-C, LDL-C, total-C/HDL-C ratio,
and LDL-C/HDL-C ratio as well as decrease TG and increase
HDL-C.
[0013] Cerivastatin (or Cerivastatin sodium) is a white to
off-white hygroscopic amorphous powder that is soluble in water,
methanol, and ethanol, and very slightly soluble in acetone.
Cerivastatin sodium is a synthetic, enantiomerically pure
competitive inhibitor of the enzyme
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase that
catalyzes the conversion of HMG-CoA to mevalonate in an early and
rate-limiting step in the biosynthesis of cholesterol. The
inhibition of cholesterol biosynthesis reduces the level of
cholesterol in hepatic cells which stimulates the synthesis of LDL
receptors and increases the uptake of cellular LDL particles. This
can lead to a reduction in plasma cholesterol concentration. When
formulated as Baycol.RTM., cerivastatin sodium tablets can contain
0.2 to 0.8 mg of cerivastatin sodium for oral administration and
can be taken with or without food. Other tablet ingredients can
include pharmaceutically acceptable excipients such as mannitol,
magnesium stearate, sodium hydroxide, crospovidone, povidone, iron
oxide yellow, methylhydroxypropylcellulose, polyethylene glycol,
and titanium dioxide. In patients with hypercholesterolemia,
cerivastatin sodium can produce reduced levels of plasma total
cholesterol, LDL-C, and apolipoprotein B, VLDL-C and plasma
triglycerides and increases plasma HDL-C and apolipoprotein A-1.
Cerivastatin systemic exposure (area under the curve, AUC) and
C.sub.max are not sensitive to a food effect, but once daily doses
of 0.2 mg can be more efficacious than twice daily doses of 0.1 mg.
Cerivastatin sodium can be effective as an adjunct to diet to
reduce elevated Total-C, LDL-C, apo B, and TG and to increase HDL-C
levels in patients with primary hypercholesterolemia and mixed
dyslipidemia (Fredrickson Types IIa and IIb) when the response to
dietary restriction of saturated fat and cholesterol and other
non-pharmacological measures alone is inadequate.
[0014] Pravastatin (or pravastatin sodium) is a white to off-white,
fine or crystalline powder. It is a relatively polar hydrophilic
compound with a partition coefficient (octanol/water) of 0.59 at a
pH of 7.0. It is soluble in methanol and water (>300 mg/mL),
slightly soluble in isopropanol, and practically insoluble in
acetone, acetonitrile, chloroform, and ether. When formulated as
Pravachol for oral administration, tablets can contain 10 to 40 mg
of pravastatin. Inactive ingredients can include pharmaceutically
acceptable excipients such as croscarmellose sodium, lactose,
magnesium oxide, magnesium stearate, microcrystalline cellulose,
and povidone. A 10 mg tablet can also contain Red Ferric Oxide, a
20 mg tablet can also contain Yellow Ferric Oxide, and a 40 mg
tablet can also contain Green Lake Blend (mixture of D&C Yellow
No. 10-Aluminum Lake and FD&C Blue No. 1-Aluminum Lake).
[0015] Itavastatin is an inhibitor of HMG-CoA reductase and can be
dosed in tablets containing from about 1 mg to about 20 mg,
preferably from about 2 mg to about 10 mg. Rosuvastatin is an
inhibitor of HMG-CoA reductase and can be dosed in tablets
containing from about 4 or 5 mg to about 10 or 20 mg, with reported
doses of up to about 80 mg per day when formulated as Crestor.
[0016] Preferred statins in this invention are those useful for
oral administration. Most preferred statins in this invention
include lovastatin, pravastatin, simvastatin, atorvastatin,
rosuvastatin, fluvastatin, itavastatin and cerivastatin.
[0017] While blood levels of active drug or active species from an
oral dose of a fibrate such as fenofibrate in a patient are
susceptible to a food effect (i.e., variable uptake between fed and
fasted states) leading to variation in the amount of active drug
species received from a given dose of a fibrate, the efficacy of
most statins is not substantially compromised by the presence or
absence of food. In a combination dosage form of a statin and a
fibrate such as fenofibrate, intake or absence of intake of food
can lead to unexpectedly high or low levels of the active fibrate
in the presence of a given dosage level of a statin. This lack of
control of fibrate level in the blood can potentially lead to
undesired side effects such as myopathy and rhabdomyolysis that
have sometimes been seen previously with statins alone and with
fibrates and statins when administered concurrently to a patient,
particularly as a result of concurrent administration of
gemfibrozil and lovastatin. Administration of separate dosage forms
of a statin and of a fibrate can also pose the potential for
variable uptake of either drug, for example when a patient
overdoses or underdoses one or the other individual dosage form by
taking more or fewer doses of either separate drug than the
patient's condition would require for treatment. This can happen
when a patient forgets to take one or the other drug dosage form,
or when the patient forgets that he or she has taken one or the
other drug dosage form and subsequently takes a second or even a
third or more dosage form of one or both of the drugs. This can be
especially prevalent in an older patient and in a patient with a
failing memory.
[0018] Thus there is a need for a single therapeutically effective
oral dosage form comprising a combination of a
hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (or
a statin) and a fibrate that provides adequate delivery of both a
therapeutically effective amount the HMG-CoA reductase inhibitor
(statin) and a therapeutically effective amount of the fibrate
active species without substantial variability in the amounts of
either of the drugs received in a patient between a fasted and fed
states. It is an object of this invention to provide such a dosage
form.
In this regard, this invention provides a novel pharmaceutical
composition comprising a combination of a hydroxymethylglutaryl
coenzyme A reductase inhibitor and a fibrate, particularly
fenofibrate, in the form of microparticles of solid fibrate that
are stabilized by phospholipid as a surface active substance and
that provide reduced in vivo variability in the therapeutically
effective amounts of either of the drugs in a patient between a fed
and fasted states when administered orally. The present invention
further provides novel pharmaceutical compositions comprising a
combination of a statin and a fibrate, particularly fenofibrate, in
the form of microparticles of solid fibrate that are stabilized by
phospholipid as a surface active substance and that provide reduced
in vivo variability in the bioavailability of the drug among fed
and fasted patients when administered orally.
[0019] In particular, the present invention provides a dosage form
such as an orally administered dosage form of a pharmaceutical
composition comprising a combination of a statin and microparticles
of fenofibrate that are stabilized by a phospholipid surface active
substance, wherein the dosage form provides to a patient in need of
treatment by the statin and fenofibrate a therapeutically effective
dose of the statin and a therapeutically effective quantity of
fenofibrate active species to said patient when fasted that is at
least 80% of the quantity of fenofibrate active species provided by
said amount to said patient when fed a meal containing fat.
[0020] It has long been known that the bioavailability of many
hydrophobic drugs can be improved if the drugs are administered
with food, i.e., the drugs exhibit a food effect. A patient is
often instructed to take the drug at meal times. Various
explanations of the food effect have been advanced including:
delayed gastric emptying to allow more drug to dissolve before
reaching the small intestine thereby producing longer residence
times at specific absorption sites in the small intestine; direct
interaction and solubilization of drug by food, especially by
hydrophobic food components such as fats and lipids; food-related
increases in hepatic blood flow to cause a decrease in first-pass
metabolism; and increased gastrointestinal secretions that can
improve drug solubility.
[0021] Dosage forms or quantities of compositions containing a
fibrate such as fenofibrate have been marketed and prescribed for
the treatment of hypercholesterolemia, hyperlipidemia,
hypertrigylceridaemia and related disorders. There have been a
number of improvements in dosage forms of fenofibrate in an effort
to increase bioavailability of the drug and hence its efficacy.
However, there is still a need for a dosage formulation that can
substantially reduce or overcome the differential between the
bioavailability of the drug in patients who are fasted versus the
bioavailability of the drug in patients who are fed.
[0022] Fenofibrate or
2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid
1-methylethyl ester is an example of a poorly water-soluble
compound. It is a benzophenone containing a para-chlorophenyl group
and a para-isopropyloxycarbonylisopropoxyphenyl group, both of
which are substantially hydrophobic groups. Fenofibrate exhibits a
melting point reported to be in the range of 79 to 82.degree. C.
(Physician's Desk Reference, 1999 Edition, page 477), which is
above that of the symmetrically unsubstituted benzophenone with a
reported melting point range of 48 to 51.degree. C. but below that
of the symmetrically substituted 4,4'-dichlorobenzophenone with a
reported range of 144 to 146.degree. C. (Aldrich Chemical Co.
catalog) 1999).
[0023] Fenofibrate acts as a potent lipid modulator agent offering
unique and significant clinical advantages over existing products
in the fibrate class of drugs. Fenofibrate produces substantial
reductions in plasma triglyceride levels in hypertriglyceridemic
patients and in plasma cholesterol and LDL-cholesterol in
hypercholesterolemic and mixed dyslipidemic patients.
[0024] Fenofibrate is practically insoluble in water. It is
normally poorly and variably absorbed, and has to be taken with
food. Fenofibrate is a prodrug that is absorbed and then hydrolyzed
by tissue and plasma esterases to fenofibric acid, its active
metabolite. The major metabolite of fenofibrate found in blood or
plasma, fenofibric acid, has an elimination half-life of
approximately twenty hours. Fenofibric acid is a fenofibrate active
species responsible for the pharmacological activity of
fenofibrate.
[0025] Fenofibrate was first available in a pharmaceutical dosage
form (Lipidil.RTM.) consisting of a hard gelatin capsule containing
fenofibrate and pharmaceutically acceptable excipients such as
lactose, pregelatinized starch and magnesium stearate. After oral
administration, during a meal, about 60% of the dose of this
conventional form is absorbed and found in the blood as fenofibric
acid (Weil et al., The metabolism and disposition of
14C-fenofibrate in human volunteers, Drug. Metabol. Dispos. Biol.
Fate. Chem., 18 (1990) 115-120).
[0026] Historically, in order to improve the intestinal absorption,
another pharmaceutical dosage form was introduced (Lipidil
Micro.RTM.). European Patent Application 330,532 and U.S. Pat. No.
4,895,726 disclose a fenofibrate composition in which the
fenofibrate powder is co-micronized with a solid wetting agent.
Sodium lauryl sulfate is described as the wetting agent of choice.
The co-micronized powder so obtained is mixed with capsule filling
pharmaceutically acceptable excipients such as lactose, starch,
cross-linked polyvinyl pyrrolidone (PVP), and magnesium stearate. A
study comparing Lipidil Micro.RTM. formulation to the conventional
form (Lipidil.RTM.) had showed statistically significant increase
in bioavailability with the former but without elimination of food
effect. A formulation of fenofibrate that refers to this patent is
currently available in the United States under the name Tricor
Micronized.RTM..
[0027] European Patent Application 724,877 describes fenofibrate
powder co-micronized with a wetting agent in association with a
vitamin E component (tocopherol and/or its organic acid ester) for
treating or preventing disorders associated with lipoprotein
oxidation.
[0028] U.S. Pat. No. 4,800,079 describes a medicinal composition in
the form of granules with controlled release of fenofibrate. Each
granule includes an inert core, a layer based on fenofibrate and a
protective layer. Fenofibrate is present in the form of crystalline
microparticles of dimensions not greater than 30 .mu.m.
[0029] U.S. Pat. No. 4,961,890 describes a process for preparing a
controlled release formulation containing fenofibrate in an
intermediate layer in the form of crystalline microparticles (less
than 30 .mu.m in diameter) within a multilayer inert matrix.
[0030] European Patent Application 757,911 describes a fenofibrate
pharmaceutical dosage form in which fenofibrate is in solution in
diethylene glycol monoethyl ether (EMDG) which is a non-ionic
surfactant.
[0031] European Patent Application 904,781 describes a process for
making granules of a solid dispersion of a disintegrant in molten
fenofibrate by blending a solid dispersing agent into molten
fenofibrate, cooling and solidifying the bulk mixture in a tray,
and then milling the solid through a screen to produce granules.
Disintegrants include polymers such as starch, croscarmellose
sodium, sodium starch glycolate, and crospovidone which are
pharmaceutically acceptable excipients. Such disintegrants are slow
to swell and dissolve in aqueous media. Furthermore, when
crosslinked as in the case of crospovidone, a polymeric
disintegrant will not be uniformly dissolved in molten drug but
rather at best will form micro-domains in molten fenofibrate. In
addition, polymeric materials can exhibit phase separation
phenomena when distributed in a substance with which there is not
complete compatibility. This was shown, in part, by Sheu, M. T. et
al., "Characterization and dissolution of fenofibrate solid
dispersion systems", Int. J. Pharm. (1994), 103(2), 137-46 using
differential scanning calorimetry measurements that found
fenofibrate to be incompatible with poly(vinyl pyrrolidone). Thus,
preparation of a bulk mixture in the melt followed by
solidification and grinding can lead to non-uniform distributions
and compositions in granules. This can adversely effect the
bioavailability of the active component.
[0032] U.S. Pat. No. 5,700,471 discloses a process for the
micronization of compounds having low solubility in water by
exposing such compounds briefly to a temperature above their
respective melting points, dispersing them with turbulence in an
aqueous or organic phase, and subsequently cooling the phase to
form a fine particle dispersion. However, it is specified (column
2, lines 1-9) that certain substances and specifically fenofibrate
are not amenable to processing entirely without organic solvents
because their aqueous dispersions agglomerate and cannot be
metered. Thus, in example 2 of U.S. Pat. No. 5,700,471, fenofibrate
is not directly dispersed in water but rather is first dissolved in
a four-fold excess of a water-miscible organic solvent
(isopropanol) which must be removed in a subsequent step. Organic
solvents can pose flammability risks, exposure dangers to process
operators, potential environmental problems, and added expense
related to their storage, ultimate removal from a formulation, and
disposal. Thus it is desirable to overcome the use of organic
solvents where possible.
[0033] U.S. Pat. No. 4,880,634 describes a method of production of
an excipient system containing a pharmacologically active substance
for peroral administration of lipid nano-pellets in an aqueous,
colloidal suspension. The method consists of forming a melt of a
mixture of at least one surfactant, a pharmacologically active
substance, and at least one lipid, dispersing the molten mixture
within an aqueous solution at a temperature above the melting point
of the lipid to form lipid nano-pellets, and cooling the suspension
below the melting point of the lipid. Animal and plant
phospholipids such as lecithin and their hydrogenated forms may be
employed in the process although the use of chloroform is taught in
examples citing phospholipon 100H. The pharmacologically effective
substance can be added to the melted lipid in molten form or
dissolved or dispersed in the molten lipid.
[0034] U.S. Pat. No. 4,895,726 discloses a gelatin capsule dosage
form of fenofibrate containing a co-micronized mixture of particles
of fenofibrate and a solid surfactant. The dosage form exhibits
improved dissolution rate and bioavailability of fenofibrate over
that of micronized fenofibrate alone or that of micronized
fenofibrate subsequently mixed with solid surfactant. However, the
surfactant must be a solid so it can be micronized, and the
micronized surfactant in the form of particles is not uniformly
juxtaposed or coated on the surface of the fenofibrate
particles.
[0035] U.S. Pat. No. 5,545,628 discloses a melted and cooled
pharmaceutical composition in a hard gelatin capsule for treating
hyperlipidemia and/or hypercholesterolemia. The composition
contains fenofibrate, one or more polyglycolyzed glycerides, and
optionally other polyalkylene glycol polymers that are added to
adjust HLB value, melting point, and stability. The composition
provides an increased bioavailability of fenofibrate with respect
to previously marketed forms of fenofibrate (i.e., non
co-micronized Lypantyl 200.TM. and co-micronized Lypantyl 200
M.TM.).
[0036] U.S. Pat. Nos. 5,645,856 and 6,096,338 disclose a
composition and method of improving the in vivo bioavailability of
a hydrophobic drug from a pharmaceutical composition comprising the
drug dispersed or dissolved in a digestible oil containing a
hydrophilic surfactant which substantially inhibits the in vivo
lipolysis of the digestible oil, wherein there is added to the
composition a lipophilic surfactant capable of reducing the
inhibitory effect of the hydrophilic surfactant.
[0037] U.S. Pat. Nos. 5,776,495 and 6,027,747 disclose a solid
dispersion with enhanced bioavailability of a surface active agent
and at least one therapeutic agent in a hydrophilic carrier having
enhanced solubility in an aqueous medium. The dispersion is
prepared by dissolving the therapeutic agent in a volatile organic
solvent containing a very hydrophilic polymer and without strong
heat or vacuum evaporating the solvent to dryness to form a
co-precipitate of therapeutic agent and hydrophilic polymer.
[0038] U.S. Pat. No. 5,827,536 discloses soluble fenofibrate
pharmaceutical dosage formulations exhibiting improved
bioavailability after oral administration. However, the
formulations contain fenofibrate as a solution in a solubilizing
agent consisting of diethylene glycol monoethyl ether.
[0039] U.S. Pat. No. 6,042,847 discloses a three-phase
pharmaceutical form exhibiting constant and controlled release of
an amorphous active ingredient stabilized with polymers for a
single daily peroral application. The first phase consists of a
core containing an amorphous active ingredient,
polyvinylpyrrolidone and a cellulose ether as carriers and as
inhibitors of its crystallization, and a surfactant that improves
the solubility of the active ingredient and promotes the absorption
of the amorphous active ingredient from the gastrointestinal tract.
The second phase contains a cellulose ether and a mixture of mono-,
di- and triglycerides as sustained release agents. The third phase
is a poorly soluble or gastro-resistant polymeric film coating.
[0040] U.S. Pat. No. 6,068,854 discloses a constant release tablet
consisting of a matrix of gelatin in which is dispersed as an
emulsion, dispersion or colloid a lipophilic and/or poorly
water-soluble pharmaceutical substance with a particle size below
200 micrometers.
[0041] U.S. Pat. No. 6,074,670 discloses an immediate-release
fenofibrate composition comprising an inert hydrosoluble carrier
covered with a layer containing fenofibrate in a micronized form
having a size less than 20 micrometers, a hydrophilic polymer and,
optionally, a surfactant. In an example cited, a suspension of
micronized fenofibrate and sodium lauryl sulfate is suspended in a
solution of sodium lauryl sulfate and polyvinylpyrrolidone, sprayed
onto 100 to 400 micrometers size lactose particles suspended in a
fluidized air bed granulator, and the granulate is placed in
capsules or transformed into tablets by mixing with cross-linked
PVP, microcrystalline cellulose, colloidal silica, and sodium
stearyl fumarate. The composition showed enhanced bioavailability
of fenofibrate. However, increased dissolution rates of a
formulation of fenofibrate do not translate directly or linearly to
increase uptake of the drug, and show that an in vitro experimental
result can not necessarily predict the results of an in vivo
experiment.
[0042] It is generally accepted that water insoluble or poorly
water-soluble drugs can be made more bioavailable when presented in
the form of small particles. In many cases, it is known that small
particles must be stabilized against particle size growth and
agglomeration by the addition of one or more surface active agents
at some point in the preparation of the particles, especially in a
size reduction process that employs the input of mechanical energy.
Because they are biocompatible and well tolerated in vivo,
preferred surface active agents or particle stabilizers are
phospholipids, and preferred small particles of fenofibrate are
stabilized by phospholipid particle stabilizers.
[0043] Microparticles of water insoluble or poorly soluble
substances are small particles having diameters of from nanometers
to micrometers and refer to solid particles of irregular,
non-spherical or spherical shapes. When the insoluble and poorly
soluble substances are therapeutically and diagnostically useful
substances, formulations containing them as microparticles or small
particles provide some specific advantages over unformulated
non-micronized drug particles. These advantages include improved
oral bioavailability of drugs that are poorly absorbed from the GI
tract, development of injectable formulations that are currently
available only in oral dosage form, preparation of inhaled drugs
that otherwise could not be formulated for nasal or aerosol
delivery as well as other advantages.
[0044] Current technology for delivering insoluble drugs as
described in U.S. Pat. Nos. 5,091,188; 5,091,187 and 4,725,442
focuses on (a) either coating small drug particles with surface
active substances that are natural or synthetic phospholipids or
(b) dissolving the drug in a suitable lipophilic carrier and
forming an emulsion stabilized with surface active substances that
are natural or semisynthetic phospholipids.
[0045] U.S. Pat. No. 5,145,684 discloses methods for preparation
and dispersions of particles consisting of crystalline drug
substance having a surface modifier or surface active substance
adsorbed to maintain an effective average particle size of less
than about 400 nm. However, the method requires a milling step that
can result in impurities being added to the formulation from
fractured milling media.
[0046] U.S. Pat. Nos. 5,470,583 and 5,336,507 disclose methods for
preparation of nanoparticles using a charged phospholipid as a
cloud point modifier.
[0047] U.S. Pat. No. 5,302,401 discloses compositions and methods
for forming nanoparticles with a surface modifier and a
cryoprotectant adsorbed thereon.
[0048] International Patent Application WO 99/39700 describes the
preparation of submicron nanoparticles from a pharmacologically
active principle and a composite material consisting of at least
one lipidic substance and at least one amphiphilic substance using
high pressure homogenization to form a microemulsion of the
composite material at a temperature higher than the melting
temperature of at least one of the materials forming the composite
and in the presence of one or more aqueous surfactants as surface
active substances and then cooling the microemulsion to form a
dispersion of solid particles.
[0049] U.S. Pat. No. 5,785,976 discloses a heated aqueous
emulsification and cooling process for the preparation of solid
lipid particles. In that process a solid lipid or bioactive agent
or a mixture of solid lipids or bioactive agents is melted and
stabilizers, i.e., surface active substances, are added either to
the lipid or bioactive agent and to the aqueous phase or to the
aqueous phase only. The aqueous phase is heated to the temperature
of the melt before mixing and may contain stabilizers, isotonicity
agents, buffering substances, cryoprotectants and/or preservatives.
The molten lipid compounds and the bioactive agents can be
emulsified in the aqueous phase by high-pressure homogenization.
The homogenized dispersion is then allowed to cool until solid
particles are formed by recrystallization of the dispersed agents.
Drugs or other bioactive substances to be incorporated into the
particles may be melted together with the lipids or may be
dissolved, solubilized or dispersed in the lipid melt before an
emulsification by homogenization step.
[0050] U.S. Pat. No. 5,922,355 discloses a method for preparing
submicron size microparticles by particle size reduction methods in
which a solid material is reduced in size over a period of time
while continuously below the melting point of the material or by
precipitation while the particles are stabilized with phospholipids
as surface active substances in combination with other surface
modifiers to control growth of particle size and enhance storage
stability. The use of one or more surface modifiers in addition to
a phospholipid provides volume weighted mean particle size values
that are much smaller than what can be achieved using phospholipid
alone without the use of an additional surface active substance
(surfactant) with the same energy input while providing
compositions resistant to particle size growth on storage. The
phospholipid and the surfactant are both present at the time of
particle size reduction.
[0051] WO 00/30616 discloses a rapidly dispersing solid dry dosage
form comprised of a water insoluble compound existing as a
nanometer or micrometer particulate solid which is surface
stabilized by the presence of at least one phospholipid, the
particulate solid being dispersed throughout a bulking matrix. When
the dosage form is introduced into an aqueous environment, the
bulking matrix is substantially completely dissolved within less
than 2 minutes thereby releasing the water insoluble particulate
solid in an unaggregated and/or unagglomerated state. The matrix is
composed of a water insoluble substance or therapeutically useful
water insoluble or poorly water-soluble compound, a phospholipid
and optionally also at least one non-ionic, anionic, cationic, or
amphiphatic surfactant, together with a matrix or bulking agent and
if needed a release agent. The volume weighted mean particle size
of the water insoluble particle is 5 micrometers or less.
[0052] While these disclosures provide compositions and methods to
enhance the bioavailability of fenofibrate from various dosage
forms, none address the need to substantially reduce or eliminate
the food effect observed with fenofibrate, i.e., the difference
between the amount of the drug taken up in a patient who is fasting
versus the oterwise enhanced uptake of the drug in the patient who
is fed (food effect).
Besides the fibric acid derivatives such as fenofibrate,
clofibrate, gemfibrozil, bezafibrate, ciprofibrate, clinofibrate,
simfibrate, theofibrate, pirifibrate, plafibride, and binifibrate,
there are a number of other classes of drugs which, when
administered to patients, reduce cholesterol and/or lipids. These
include bile acid sequesters such as cholestyramine, and meglutol,
melinamide, sitosterol, tiadenol, probucol, and nicotinic acid. In
addition to these there is a relatively new class of drugs referred
to as statins. The latter class of drugs include atorvastin,
cerivastatin, epastatin, fluvastatin, itavastatin, lovastatin,
mevastatin, pravastatin, rosuvastatin, and simvastatin.
[0053] Combination of a statin with a fibrate has been shown to
produce beneficial effect in the treatment of hyperlipidemia and
hyperlipoproteinemia. However, the fibrates used previously have a
limitation related to the presence of a food effect and require
patient restrictions and relatively higher dosage amounts of each
drug. Surprisingly, the compositions of this invention comprising a
fibrate, more specifically fenofibrate, together with a statin are
substantially devoid of food effect, particularly with respect to
the uptake of the fibrate.
[0054] Raza, et al. in WO 0045817 disclosed safe non-interacting
drug combinations of a 3-hydroxy-3-methylglutaryl CoA (HMG-CoA)
reductase inhibitor and a drug that is either an inducer,
inhibitor, or substrate of cytochrome P 450. Particular
combinations are useful in treating hyperlipidemia in humans who
are receiving immunosuppressive chemotherapy. A preferred
combination is the agent and a fibrate drug, the use of such a
combination in treating hyperlipidemia in mammals, and medicaments
containing such a combination for use in such treatments.
Lipantil.TM., a brand of fenofibrate used is known to have food
effects
[0055] Pan et al. in J. Clin. Pharmacol. (2000), 40(3), 316-323
reported that concomitant administration of fenofibrate and
pravastatin did not affect the pharmacokinetics of either
fenofibric acid or pravastatin in healthy adult volunteers who
received single doses of 201 mg fenofibrate alone, 201 mg
fenofibrate+40 mg pravastatin, and 40 mg pravastatin alone.
However, the combination of fenofibrate and pravastatin was
administered as separate dosage forms, and uptake of fenofibrate is
subject to a food effect.
[0056] Farnier, M. and Dejager, S. in Am. J. Cardiol. (2000),
85(1), 53-57 reported that the addition of fluvastatin to
micronized fenofibrate results in substantial improvement in
atherogenic plasma lipids levels in severe primary
hypercholesterolemia and is well tolerated. Patients received
micronized fenofibrate 200 mg, fluvastatin 20 mg plus micronized
fenofibrate 200 mg, or fluvastatin 40 mg plus micronized
fenofibrate 200 mg. However, the fenofibrate and the statin were
administered in separate dosage forms, and uptake of micronized
fenofibrate demonstrates a food effect.
[0057] Kayikcioglu et al. in Am. J. Cardiol. (1999), 83(7),
1135-1137 reported that simvastatin 10 mg administered on alternate
days with fenofibrate 250 mg is as effective as a daily dose of
simvastatin 10 mg and fenofibrate 250 mg in lowering plasma
cholesterol, triglycerides, and LDL cholesterol, and increasing HDL
cholesterol levels in patients with mixed hyperlipidemia. The
fenofibrate and simvastatin were administered in separate dosage
forms and uptake of fenofibrate is subject to a food effect.
[0058] EP 0 475 148 A1 discloses that tablets containing
pravastatin in combination with tablets of a fibric acid derivative
were useful for prevention or treatment of type III
hyperlipoproteinemia.
[0059] EP 0 455 042A1 discloses a combination of pravastatin and
fenofibrate in a single capsule for the treatment of dyslipidemia.
However, the combination is prepared by grinding a tablet of
pravastatin and a tablet of fenofibrate to a powder for use in a
single capsule, and this form of fenofibrate exhibits a food
effect.
[0060] Ippen et al in WO 0037078 describe a combination of the
3-hydroxy-3-methylglutaryl-coenzyme A inhibitor, cerivastatin with
fenofibrate and to its use in the prophylaxis and treatment of
disorders and diseases of lipid metabolism. The tablets containing
the two actives are prepared by standard wet granulation. Such
forms of fenofibrate exhibit a food effect.
[0061] Canadian patent 2,048,395 provides a method for preventing
or treating type III hyperlipoproteinemia by administering
pravastatin alone or in combination with a fibric acid derivative
such as fenofibrate. Tablets containing pravastatin and fenofibrate
alone or in combined were prepared by standard dry granulation
method using fenofibrate that is subject to food effect.
[0062] It is an object of this invention to provide an orally
administered pharmaceutical composition of a statin and a fibrate
that provides a therapeutically effective amount of the statin and
the fibrate that substantially increases the bioavailability of the
fibrate and substantially reduces the difference between the amount
of the active species of the drug taken up in a patient who is
fasting versus the amount of the active species of the drug in the
patient who is fed (i.e., substantially reducing the food
effect).
[0063] It is another object of this invention to provide an orally
administered pharmaceutical composition of a statin and fenofibrate
that provides a therapeutically effective amount of the statin and
fenofibrate that substantially increases the bioavailability of the
fenofibrate and substantially reduces the difference between the
amount of the active species of the drug taken up in a patient who
is fasting versus the amount of the active species of the drug in
the patient who is fed (i.e., substantially reducing the food
effect known to be associated with administration of
fenofibrate).
[0064] It is well accepted in practice that an improved
bioavailability of a drug allows for an appropriate reduction in
daily dosage amount.
[0065] It is another object of this invention to provide an orally
administered pharmaceutical composition of a water-soluble statin
and fenofibrate that provides a therapeutically effective amount of
the statin and fenofibrate that substantially increases the
bioavailability of the fenofibrate and substantially reduces the
difference between the amount of the active species of the drug
taken up in a patient who is fasting versus the amount of the
active species of the drug in the patient who is fed (i.e.,
substantially reducing the food effect known to be associated with
administration of fenofibrate).
[0066] It is another object of this invention to provide an orally
administered pharmaceutical composition of a water insoluble or
poorly water-soluble statin and fenofibrate that provides a
therapeutically effective amount of the statin and fenofibrate that
substantially increases the bioavailability of the fenofibrate and
substantially reduces the difference between the amount of the
active species of the drug taken up in a patient who is fasting
versus the amount of the active species of the drug in the patient
who is fed (i.e., substantially reducing the food effect known to
be associated with administration of fenofibrate).
[0067] It is another object of this invention to provide a combined
pharmaceutical dosage form of fenofibrate and a statin that can be
administered in a capsule, a tablet, a powder that can be dispersed
in a beverage, or other convenient dosage form such as oral liquid
in a capsule as known in the art.
[0068] It is another object of this invention to provide a
once-a-day pharmaceutically effective single dosage form of
fenofibrate and a statin that can be administered to a patient in
need of treatment while substantially reducing the food effect
known to be associated with administration of fenofibrate.
[0069] It is another object of this invention to provide a method
of treatment of hypercholesterolemia and related diseases of
dyslipidemia and dyslipoproteinemia comprising the administration
of dosage forms of the compositions of this invention to a patient
in need of treatment.
BRIEF SUMMARY OF THE INVENTION
[0070] The present invention provides a dosage form of a
pharmaceutical composition comprising a combination of a statin and
microparticles of fenofibrate that are stabilized by a phospholipid
surface active substance, wherein the dosage form provides to a
patient in need of treatment by the statin and fenofibrate a
therapeutically effective dose of the statin and a therapeutically
effective quantity of fenofibrate active species to said patient
when fasted that is at least 80% of the quantity of fenofibrate
active species provided by said amount to said patient when fed a
meal containing fat.
[0071] The present invention also provides a dosage form of a
pharmaceutical composition comprising a combination of a statin and
microparticles of fenofibrate that are stabilized by a phospholipid
surface active substance, wherein the dosage form provides to a
human patient in need of treatment by the statin and fenofibrate a
therapeutically effective dose of the statin and a therapeutically
effective quantity of fenofibrate active species to said patient
when fasted that is greater than 80% of the quantity of fenofibrate
active species provided by said amount to said patient when fed at
least 1000 calories 50% of which are from fat.
[0072] The present invention also provides an oral dosage form of a
pharmaceutical composition comprising a combination of a statin and
microparticles of fenofibrate that are stabilized by a phospholipid
surface active substance, wherein the dosage form provides to a
human patient in need of treatment by the statin and fenofibrate a
therapeutically effective dose of the statin and a therapeutically
effective quantity of fenofibrate active species into the blood of
said patient when fasted that is between 85% and 115% of the
quantity of fenofibrate active species provided by said amount into
the blood of said patient when fed at least 1000 calories 50% of
which are from fat.
[0073] The present invention also provides an oral dosage form of a
pharmaceutical composition comprising a combination of a statin and
microparticles of fenofibrate that are stabilized by a phospholipid
surface active substance, wherein the dosage form provides to a
human patient in need of treatment by the statin and fenofibrate a
therapeutically effective dose of the statin and a therapeutically
effective quantity of fenofibrate active species to said patient
when fasted that is at least 85% of the AUC quantity of fenofibrate
active species provided by said amount to said patient when fed at
least 1000 calories 50% of which are from fat.
[0074] The present invention also provides a dosage form of a
pharmaceutical composition comprising a combination of a statin and
microparticles of fenofibrate that are stabilized by a phospholipid
surface active substance, wherein the microparticles of fenofibrate
are prepared by a process comprising the steps of:
[0075] (a) mixing at high shear an admixture of fenofibrate and a
phospholipid substance in an aqueous carrier in the absence of an
organic solvent within a first temperature range at or above the
melting point of fenofibrate to form a heated suspension wherein
fenofibrate is molten;
[0076] (b) homogenizing said heated suspension in a first pressure
range and within said first temperature range to form a heated
homogenate containing fenofibrate;
[0077] (c) cooling said heated homogenate to a second temperature
range below the melting temperature of fenofibrate to form a
transiently stable cooled homogenate containing fenofibrate;
[0078] (d) applying a particle stabilizing energetic process to
said cooled homogenate within a second temperature range below the
melting temperature of fenofibrate and in a second pressure range
to form a cooled dispersion of small particles containing
fenofibrate, and
[0079] (e) drying said cooled dispersion to form dried small
particles containing fenofibrate.
[0080] In another aspect, this invention also provides a method of
treatment of dyslipidemia and dislipoproteinemia and related
diseases in a patient comprising the administration to said patient
of a dosage form of the aforementioned pharmaceutical compositions
comprising a combination of a statin and microparticles of
fenofibrate.
[0081] In another aspect, this invention provides a
pharmaceutically effective composition comprising small particles
of fenofibrate stabilized by a phospholipid stabilizing agent which
when dried in the presence of a sugar and optionally also in the
presence of a carbohydrate-derived alcohol can be formulated as a
capsule or tablet dosage form for oral administration to patients
in need of treatment by fenofibrate. The dosage form provides
dosage levels of active agent (e.g., fenofibrate active species)
into the blood of a fasting patient and into the blood of a fed
patient where the amount of drug or active ingredient that the
patient receives in the fasted state differs by less than 25%,
preferably by less than 20%, more preferably by less than 15%, even
more preferably by less than 10%, and most preferably by less than
5% from the amount of drug or active ingredient that the patient
receives in the fed state.
[0082] In a clinical study using capsule dosage forms and
monitoring the pharmacokinetic comparison of a single dose of a
phospholipid-stabilized fenofibrate formulation of this invention
versus a comicronized fenofibrate (Lipanthyl 67M) dose in healthy
volunteers under fed and fasted conditions, distinct advantages are
seen. For example, under fasted conditions, the formulation of this
invention provides a statistically significant increase in relative
bioavailability of fenofibrate over that of a comicronized
formulation as evidenced by a higher mean maximum concentration
(C.sub.max) of the drug and a higher mean AUC (area under the
curve). This difference between the two formulations substantially
disappears under fed conditions.
[0083] When the bioavailability of a comicronized (Lipanthyl 67M)
formulation under fed conditions is compared to that under fasted
conditions, the C.sub.max significantly increases and the mean
AUC's significantly increases in fed state. In addition, the mean
terminal half-life appears to be shortened.
[0084] In contrast and unexpectedly, when the bioavailability of
fenofibrate formulations of this invention are compared under fed
versus fasted conditions, the relative increase in C.sub.max is
substantially less than the relative increase seen in the Lipanthyl
67M case in fed state, and the relative increase in mean AUC is
substantially less than the relative increase seen in the Lipanthyl
67M case in fed state. The relative bioavailability is
approximately substantially close to unity (within 20%) when
comparing fasted versus fed conditions using the formulation of
this invention. No significant variation in mean terminal half-life
is observed.
[0085] The phospholipid-stabilized fenofibrate particle formulation
of this invention provides a pharmacokinetic profile in which the
effect of ingestion of food on the uptake of the fenofibrate active
species is substantially reduced over that observed with the
commercially available comicronized formulation.
[0086] Statins are subject to substantial first pass metabolism in
the liver where they inhibit HMG-CoA reductase to reduce production
of cholesterol. Efficacies of statins are not substantially reduced
by the presence or absence of food.
[0087] Small particles or microparticles of fenofibrate of this
invention can be conveniently prepared by a microfluidization
process in the form of an aqueous suspension. The microfluidization
process is a one- or two-stage size reduction process that can be
done in the presence of a liquefied or vesiclar surface active
agent (e.g., a phospholipid such as Lipoid E80), and optionally in
the presence of additives and/or pharmaceutically acceptable
excipients such as sucrose and/or sorbitol, and preferably in an
aqueous buffer such as a sodium phosphate buffer. Preferably, when
the microfluidization is done in two stages or processing steps
wherein the first stage is run at a first temperature above the
melting point of the drug and the second stage is run at a second
temperature below the melting point of the drug, we refer to such a
process as a hot melt microfluidization process. A desired amount
of a statin can be conveniently added during any step of the
process, and is preferably added in the second stage of
microfluidization. Water is then subsequently removed from the
suspension by a lyophilization (i.e., a freeze-drying step) or
spray drying to form a substantially dry powder comprising a solid
matrix containing fine particles of fenofibrate and a statin. The
water can also be removed by other means such as by
evaporation.
[0088] In one embodiment of this invention comprising a hot melt
process, when the statin is soluble in water or other aqueous media
such as aqueous buffer solutions and/or aqueous solutions
containing one or more pharmaceutically acceptable excipients or
bulking agents such as carbohydrates including sugars, it can be
convenient to add the statin to the fenofibrate-containing aqueous
medium as either a solid that readily dissolves in the aqueous
medium or as an aqueous solution of the statin. A water-soluble
statin can be added to the fenofibrate-containing suspensions or
dispersions before or after the microfluidization steps, and
preferably before or after the second microfluidization step.
[0089] In another embodiment of this invention, when the statin is
insoluble or poorly soluble in water, it can be micronized in the
presence of a surface active substance, preferably a phospholipid,
and more preferably with a phospholipid used to stabilize the
particles containing fenofibrate, and then mixed with the
suspension of fenofibrate before or after any microfluidization
steps, and preferably before or after a microfluidization step done
below the melting point of fenofibrate.
[0090] Optionally, in another embodiment of this invention, the
statin and the fenofibrate can be co-suspended and co-micronized in
the presence of a phospholipid stabilizing substance to form
microparticles comprising the statin and fenofibrate.
[0091] In one aspect, small particles of fenofibrate of this
invention stabilized by phospholipid can be prepared as a
suspension by a process comprising the steps of (a) mixing at high
shear an admixture of a fibrate drug and one or more than one
surface active substance in an aqueous carrier in the absence of an
organic solvent within a first temperature range at or above the
melting point of the poorly water-soluble drug to form a heated
suspension containing the drug, then (b) homogenizing said heated
suspension in a first pressure range and within said first
temperature range to form a heated homogenate containing the drug,
then (c) cooling said heated homogenate to a second temperature
range below the melting temperature of the poorly water-soluble
drug to form a transiently stable cooled homogenate containing the
drug, then (d) applying a particle stabilizing energetic process to
said cooled homogenate within a second temperature range below the
melting point of the drug and in a second pressure range to form a
cooled dispersion of stabilized small particles of the drug, and
then (e) optionally drying the cooled dispersion to form dried
matrix of small particles containing the fibrate wherein a statin
can be added at any of the previous steps, preferably after the
first homogenization step.
[0092] In a typical procedure, a premix of fenofibrate,
phospholipid Lipoid E80 (dispensed frozen but liquefied or
vesiclized at processing temperatures), and optionally sorbitol and
sucrose in 10 millimolar aqueous phosphate buffer at pH 8 is
microfluidized above the melting temperature of fenofibrate for
about 3 to 10 volume passes, cooled, and further microfluidized
after addition of a statin for another 10 volume passes to form a
suspension of microparticles stabilized by phospholipid.
[0093] Particularly important to this aspect of the preparation of
the composition of this invention is the use of two homogenization
steps separated by a cooling step. The first homogenization step is
done on a heated suspension having the poorly water-soluble drug in
a molten phase in the presence of one or more than one surface
active substance and optionally in the presence of a statin to
provide a heated homogenate containing the drug. The heated
homogenate is usually in the form of a microemulsion comprising
small molten particles or droplets of drug stabilized by one or
more than one surface active substance such as a phospholipid
substance. The heated homogenate containing the drug is then cooled
to provide a transiently stable cooled homogenate containing the
drug. The transiently stable cooled homogenate comprises small
particles of drug in which the drug is in a solid phase that may be
amorphous, crystalline, or a combination of both. The small
particles of the cooled homogenate are stabilized by the surface
active substance or substances but the particles are transiently
stable with respect to particle size growth and eventual
precipitation of solid drug from the aqueous carrier unless further
processed by an stabilizing energetic step.
[0094] The second homogenization step of this aspect of the
invention is done on the cooled homogenate after a cooling step to
produce a cooled dispersion of small particles containing the drug
and having greater stability to particle growth and precipitation
than the cooled homogenate. The second homogenization step is a
stabilizing energetic process. It provides small particles that are
more stable than the transiently stable particles of the cooled
homogenate prepared in the first homogenization step and prevents
relatively large crystals and/or agglomerates of the poorly
water-soluble drug from forming. The second homogenization step
facilitates the formation of stabilized small particles of the
poorly water-soluble drug. It also provides overall rapid formation
of desired small particles containing the poorly water-soluble
drug. Optionally, the small particles can be isolated by a drying
process, for example by lyophilization or by spray drying. Thus,
the process can provide dried small particles containing poorly
water-soluble drug. In the absence of the second homogenization
step, very large amounts of the poorly water-soluble drug can
precipitate from the transiently stable aqueous cooled homogenate
or very large amounts of the poorly water-soluble drug can form a
sediment by precipitation from the aqueous carrier.
[0095] In one aspect of this invention, we have unexpectedly found
that small particles containing the poorly water-soluble drug
fenofibrate can be prepared by a process comprising the steps
of
[0096] (a) mixing at high shear an admixture of fenofibrate and a
phospholipid substance in an aqueous carrier in the absence of an
organic solvent within a first temperature range at or above the
melting point of fenofibrate to form a heated suspension wherein
fenofibrate is molten;
[0097] (b) homogenizing said heated suspension in a first pressure
range and within said first temperature range to form a heated
homogenate containing fenofibrate;
[0098] (c) cooling said heated homogenate to a second temperature
range below the melting temperature of fenofibrate to form a
transiently stable cooled homogenate containing fenofibrate;
[0099] (d) applying a particle stabilizing energetic process to
said cooled homogenate within a second temperature range below the
melting temperature of fenofibrate and in a second pressure range
to form a cooled dispersion of small particles containing
fenofibrate, and
[0100] (e) drying said cooled dispersion to form dried small
particles containing fenofibrate.
[0101] In this process, a statin can be added to the admixture, to
the heated suspension, to the heated homogenate, to the cooled
homogenate, to the cooled dispersion, and optionally to the dried
small particles such as in a blending step. At which step in the
process the statin can be added to provide the best formulation
result in terms of particle size, bioavailability, or any other
desired property of the formulation can be determined by simple
experimentation and process optimization by varying concentrations
of the ingredients, temperature, processing time, and the like.
Addition of the statin at some time after the cooling of the heated
homogenate is currently preferred.
[0102] Particularly important to this aspect of the invention is
the use of two homogenization steps separated by a cooling step and
the use of a phospholipid as a surface active substance. The first
homogenization Step is done on a heated suspension in the presence
of a phospholipid as a surface active substance, in the absence of
an organic solvent, and wherein fenofibrate is molten to provide a
homogenized microemulsion containing fenofibrate. The second
homogenization step is done on a transiently stable cooled
homogenate in the presence of the phospholipid and wherein the
fenofibrate is a solid to provide a homogenized dispersion of small
particles containing fenofibrate. In the absence of the second
homogenization step, relatively large crystals of fenofibrate
otherwise readily form from the transiently stable cooled
homogenate. In the absence of a heated first homogenization step on
the molten drug, homogenization of solid fenofibrate to provide a
suspension of small particles of fenofibrate takes a prolonged or
much longer time in the same homogenization apparatus under
substantially the same homogenization conditions of pressure and
temperature relative to the time taken in the second homogenization
step of this invention, and the properties of the dispersions
produced by both routes are not identical.
[0103] In a preferred aspect of this invention, a stable
combination formulation containing fenofibrate and a statin can be
prepared if a desired amount of a statin is added to the cooled
homogenate just prior to the energetic process of second
homogenization in the above described procedure. The resulting
dispersion can be dried such as by freeze-drying or spray drying or
other suitable drying method, optionally in the presence of one or
more sugars, for example sucrose and/or sorbitol, to provide a
matrix of the two drugs in the dried sugar. The fenofibrate
comprises dried small particles stabilized by the surface active
substance. The sugar can be amorphous or crystalline.
[0104] It is an advantage of this invention that small particles
containing a poorly water-soluble fibrate drug stabilized with one
or more than one surface active substances can be prepared in
combination with a statin as a dispersion in an aqueous carrier or
as dried small particles.
[0105] It is another advantage of this invention that a combination
of small particles containing a poorly water-soluble fibrate drug
and a statin can be prepared in the absence of an organic
solvent.
[0106] It is another advantage of this invention that a combination
of small particles containing a poorly water-soluble fibrate drug
stabilized by a phospholipid surface active substance and a statin
can be prepared in the absence of an organic solvent.
[0107] It is another advantage of this invention that a dosage form
comprising a combination of small particles containing a poorly
water-soluble fibrate drug and a statin can be prepared using
pharmaceutically acceptable excipients such as phospholipids,
sugars and polyols.
[0108] It is a further advantage of this invention that a
suspension of a combination of small particles containing a poorly
water-soluble fibrate drug and a statin can be prepared which
suspension is relatively stable to mechanical agitation and to
growth of larger crystals of drug over a period of time.
[0109] It is another advantage of this invention that a matrix of
small particles containing fenofibrate and a statin can be prepared
without the use of an organic solvent.
[0110] It is a further advantage of this invention that a
suspension of small particles containing fenofibrate and a statin
can be prepared which suspension is relatively stable to mechanical
agitation and to growth of larger crystals of drug over a period of
time.
[0111] It is a further advantage of this invention that a
composition of a combined pharmaceutical dosage form of particles
of fenofibrate stabilized by a phospholipid surface active agent
and a statin is provided that substantially reduces the difference
between the amount of fenofibrate taken up in a patient who is
fasting versus the amount of fenofibrate taken up in the same
patient who is fed.
[0112] It is yet another advantage of this invention that a
combination pharmaceutical dosage form of fenofibrate and a statin
is provided that can be administered orally such as in a capsule,
in a tablet, in a powdered form dispersible in a beverage, or
suspended or dissolved in a liquid oil form.
[0113] It is still another advantage of this invention that a
once-a-day pharmaceutically effective combination dosage form of
fenofibrate and a statin is provided that can be administered
orally to a patient in need of treatment by the drugs without
regard to the amount of food a patient has ingested prior to or
following administration of the dosage form.
[0114] These and other advantages will be readily apparent from the
description of the invention.
BRIEF DESCRIPTION OF DRAWINGS
[0115] FIG. 1 is an optical microscopic comparison of
microfluidized fenofibrate with micronized fenofibrate and
fenofibrate compositions prepared in the presence of starch.
[0116] FIG. 2 is a comparison of the oral bioavailability of
microparticles of fenofibrate prepared by microfluidization in the
presence of a phospholipid stabilizing agent versus the oral
bioavailability of micronized fenofibrate under fasting, low fat
fed, and high fat fed conditions.
DETAILED DESCRIPTION OF THE INVENTION
[0117] The present invention provides an orally administered
combination pharmaceutical composition comprising microparticles of
solid fenofibrate that are stabilized by a phospholipid surface
active substance and a statin, wherein said microparticles are
preferably prepared in the presence of said phospholipid surface
active substance, and wherein a therapeutically effective amount of
said composition provides a quantity of fenofibrate to a fasted
human patient in need of treatment by fenofibrate that is greater
than 80% of the quantity of fenofibrate provided by said amount to
said patient when fed a high fat meal comprising at least 1000
calories 50% of which are from fat.
[0118] The present invention also provides a dosage form of a
pharmaceutical composition comprising a combination of a statin and
microparticles of fenofibrate that are stabilized by a phospholipid
surface active substance, wherein the dosage form provides to a
patient in need of treatment by the statin and fenofibrate a
therapeutically effective dose of the statin and a therapeutically
effective quantity of fenofibrate active species to said patient
when fasted that is at least 80% of the quantity of fenofibrate
active species provided by said amount to said patient when fed a
meal containing fat. The microparticles are preferably prepared in
the presence of said phospholipid surface active substance.
[0119] The present invention also provides a dosage form of a
pharmaceutical composition comprising a combination of a statin and
microparticles of fenofibrate that are stabilized by a phospholipid
surface active substance, wherein the dosage form provides to a
human patient in need of treatment by the statin and fenofibrate a
therapeutically effective dose of the statin and a therapeutically
effective quantity of fenofibrate active species to said patient
when fasted that is greater than 80% of the quantity of fenofibrate
active species provided by said amount to said patient when fed at
least 1000 calories 50% of which are from fat. The microparticles
are preferably prepared in the presence of said phospholipid
surface active substance.
[0120] The present invention also provides an oral dosage form of a
pharmaceutical composition comprising a combination of a statin and
microparticles of fenofibrate that are stabilized by a phospholipid
surface active substance, wherein the dosage form provides to a
human patient in need of treatment by the statin and fenofibrate a
therapeutically effective dose of the statin and a therapeutically
effective quantity of fenofibrate active species into the blood of
said patient when fasted that is between 85% and 115% of the
quantity of fenofibrate active species provided by said amount into
the blood of said patient when fed at least 1000 calories 50% of
which are from fat. The microparticles are preferably prepared in
the presence of said phospholipid surface active substance.
[0121] The present invention also provides an oral dosage form of a
pharmaceutical composition comprising a combination of a statin and
microparticles of fenofibrate that are stabilized by a phospholipid
surface active substance, wherein the dosage form provides to a
human patient in need of treatment by the statin and fenofibrate a
therapeutically effective dose of the statin and a therapeutically
effective quantity of fenofibrate active species to said patient
when fasted that is at least 85% of the AUC quantity of fenofibrate
active species provided by said amount to said patient when fed at
least 1000 calories 50% of which are from fat. The microparticles
are preferably prepared in the presence of said phospholipid
surface active substance.
[0122] The present invention also provides a dosage form of a
pharmaceutical composition comprising a combination of a statin and
microparticles of fenofibrate that are stabilized by a phospholipid
surface active substance, wherein the microparticles of fenofibrate
are prepared by a process comprising the steps of:
[0123] (a) mixing at high shear an admixture of fenofibrate and a
phospholipid substance in an aqueous carrier in the absence of an
organic solvent within a first temperature range at or above the
melting point of fenofibrate to form a heated suspension wherein
fenofibrate is molten;
[0124] (b) homogenizing said heated suspension in a first pressure
range and within said first temperature range to form a heated
homogenate containing fenofibrate;
[0125] (c) cooling said heated homogenate to a second temperature
range below the melting temperature of fenofibrate to form a
transiently stable cooled homogenate containing fenofibrate;
[0126] (d) applying a particle stabilizing energetic process to
said cooled homogenate within a second temperature range below the
melting temperature of fenofibrate and in a second pressure range
to form a cooled dispersion of small particles containing
fenofibrate, and
[0127] (e) drying said cooled dispersion to form dried small
particles containing fenofibrate.
[0128] In another aspect, this invention also provides a method of
treatment of dyslipidemia and dyslipoproteinemia and related
diseases in a patient comprising the administration to said patient
of a dosage form of the aforementioned pharmaceutical compositions
comprising a combination of a statin and microparticles of
fenofibrate.
[0129] This invention also describes an orally administered
combination pharmaceutical composition comprising microparticles of
solid fenofibrate that are stabilized by a phospholipid surface
active substance and a statin, wherein said microparticles are
prepared in the presence of said phospholipid surface active
substance and one or more excipients, and wherein a therapeutically
effective amount of said composition provides a quantity of
fenofibrate to a fasted human patient in need of treatment by
fenofibrate that is greater than 80% of the quantity of fenofibrate
provided by said amount to said patient when fed a high fat meal
comprising at least 1000 calories 50% of which are from fat.
[0130] As used herein, a fasted patient is defined as a patient who
has not eaten any food, i.e., who has fasted for at least 10 hours
before the administration of a dosage form of this invention
comprising a combination of a statin and microparticles of
fenofibrate stabilized by a phospholipid surface active substance
and who does not eat any food and continues to fast for at least 4
hours after the administration of the dosage form. The dosage form
is preferably administered with 180 ml of water during the fasting
period, and water can be allowed ad libitum after 2 hours.
[0131] As used herein, a fed patient is defined as a patient who
has fasted for at least 10 hours overnight and then has consumed an
entire test meal within 30 minutes of first ingestion. The dosage
form of this invention is administered with 180 ml of water within
5 minutes after completion of the meal. No food is then allowed for
at least 4 hours post-dose. Water can be allowed ad libitum after 2
hours. A high fat test meal provides approximately 1000 calories to
the patient of which approximately 50% of the caloric content is
derived from fat content of the meal. A representative high fat
high calorie test meal comprises 2 eggs fried in butter, 2 strips
of bacon, 2 slices of toast with butter, 4 ounces of hash brown
potatoes, and 8 ounces of whole milk to provide 150 protein
calories, 250 carbohydrate calories, and 500 to 600 fat calories.
High fat meals can be used in clinical bioequivalence and
bioavailability studies of fenofibrate. High fat meals can promote
increased absorption and uptake of fenofibrate.
[0132] The compositions and methods of this invention will find
utility in treatment of patients suffering from
hypercholesterolemia and related lipid disorders described herein.
It should be recognized that the definitions of fasted and fed
states are primarily for the purposes of clinical comparison with
respect to this invention to other dosage forms known in the art.
Patients will benefit from the compositions and methods of this
invention if they are in the fasted state as defined above, in the
fed state as defined above, and also in other fed states where the
food consumed contains more or less that 1000 calories and/or more
or less than 50% of caloric content derived from fat. Patients who
will benefit from the compositions and methods of this invention
will often be on a fat restricted diet, a calorie restricted diet,
or both, and will naturally consume variable amounts of food from
numerous sources at numerous different times of the day, from day
to day. The definitions of fasted and fed above are not meant to
limit the utility of this invention or to exclude patients in need
of treatment by the compositions and methods of this invention.
[0133] In a clinical setting, the absence or substantial
elimination of a food effect for fenofibrate can be concluded when
the 90% confidence intervals for the ratio of the geometric means
based on log-transformed data in clinical studies of fed and fasted
treatments fall within 80% to 125% for AUC (area under the
concentration time curve) and 70% to 143% for C.sub.max (peak
concentration). The presence of a food effect can be concluded when
the 90% confidence intervals for the ratio of the geometric means
based on log-transformed data in clinical studies of fed and fasted
treatments fall outside 80% to 125% for AUC and outside 70% to 143%
for C.sub.max.
[0134] As used herein, "small particle" refers to a particle or a
distribution of particles having a diameter or an average diameter,
respectively, of from nanometers to micrometers, preferably below
10 micrometers. Small particles are microparticles, as used herein,
and also refer to solid particles of irregular, non-spherical or
spherical shapes. Preferably the microparticles of this invention
have a volume weighted mean particle size smaller than 10
micrometers, more preferably smaller than 0.5 micrometers, even
more preferably smaller than 4 micrometers, even more preferably
smaller than 3 micrometers, yet even more preferably smaller than 2
micrometers, yet even more preferably smaller than 1 micrometers,
and in some aspects of this invention smaller than 0.5
micrometers.
[0135] By "dried" we mean having a water or moisture content
greater than zero percent and below 5% by weight, preferably below
4% by weight, more preferably below 3% by weight, and even more
preferably below 2% by weight, and most preferably below 1% by
weight. In preferred embodiments, the amount of water is between
0.1% and 3%, more preferably between 0.1% and 2%, and most
preferably between 0.1% and 1% by weight. By "anhydrous" we mean
have zero water content.
[0136] By "transiently stable" we mean that the small particles of
the cooled homogenate remain as small particles in a dispersion of
the aqueous carrier at substantially the size finally produced in
the first homogenization step but for a relatively short period of
time and not indefinitely. The period of time that a cooled
homogenate remains transiently stable can vary from up to about one
second to up to about 48 hours, and preferably from up to about 15
minutes to up to about 24 hours, and most preferably from up to
about 6 hours to up to about 24 hours although the period of time
can vary with many factors. Unless subsequently treated by a
stabilizing energetic step, the transiently stable material can
change. For example, as commonly seen in recrystallization of a
crystalline substance from an organic solvent, the growth and
precipitation of crystals can be induced or enhanced by the
presence of seed crystals, by stirring of a cooled supersaturated
solution of drug, and by scratching the internal surface of a
vessel containing supersaturated dissolved drug below the level of
the liquid thereby creating nucleation sites for crystallization.
Such factors can affect the time of transient stability in the
cooled homogenate of this invention, and such crystal growth is not
desirable in the present invention. The transiently stable
particles of the cooled homogenate can grow slightly in size (i.e.,
in average diameter) over the relatively short period of time by as
much as 1000% of their original size or more from that size
produced in the heated homogenization step, but preferably will
remain at the size at which they were produced in the first
homogenization step up to a size about 100% larger in diameter, and
more preferably up to a size about 50% larger in diameter. After
the relatively short period of time, the particles will undesirably
continue to become larger such as by Ostwald ripening and
crystallization. After the relatively short period of time, drug
may also undesirably crystallize in the form of large particles
from the suspension. The particles of the heated homogenate may
also undesirably and irreversibly agglomerate after the relatively
short period of time. Additionally, after the relatively short
period of time, the components of the formulation may undesirably
phase separate from the aqueous carrier and precipitate and
undesirably separate into components that contain largely drug and
largely surface active substance unless a stabilizing energetic
process is applied to the cooed homogenate.
[0137] Examples of some suitable surface active substances that are
useful in the hot melt microfluidization process described herein
include: (a) natural surfactants such as casein, gelatin,
tragacanth, waxes, enteric resins, paraffin, acacia, gelatin,
cholesterol esters, phospholipids, and triglycerides, (b) nonionic
surfactants such as polyoxyethylene fatty alcohol ethers, sorbitan
fatty acid esters, polyoxyethylene fatty acid esters, sorbitan
esters, glycerol monostearate, polyethylene glycols, cetyl alcohol,
cetostearyl alcohol, stearyl alcohol, poloxamers, polaxamines,
methylcellulose, hydroxycellulose, hydroxy propylcellulose, hydroxy
propylmethylcellulose, noncrystalline cellulose, polyvinyl alcohol,
polyvinylpyrrolidone, and synthetic phospholipids, natural gums (c)
anionic surfactants such as potassium laurate, triethanolamine
stearate, sodium lauryl sulfate, alkyl polyoxyethylene sulfates,
sodium alginate, dioctyl sodium sulfosuccinate, negatively charged
phospholipids (phosphatidyl glycerol, phosphatidyl inosite,
phosphatidylserine, phosphatidic acid and their salts), and
negatively charged glyceryl esters, sodium carboxymethylcellulose,
and calcium carboxymethylcellulose, (d) cationic surfactants such
as quaternary ammonium compounds, benzalkonium chloride,
cetyltrimethylammonium bromide, chitosans and
lauryldimethylbenzylammonium chloride, (e) colloidal clays such as
bentonite and veegum. A detailed description of these surfactants
may be found in Remington's Pharmaceutical Sciences, and Theory and
Practice of Industrial Pharmacy, Lachman et al, 1986.
[0138] More specifically, examples of suitable surface active
substances include one or combination of the following: poloxamers,
such as Pluronic.TM. F68, F108 and F127, which are block copolymers
of ethylene oxide and propylene oxide available from BASF, and
poloxamines, such as Tetronic.TM.908 (T908), which is a
tetrafunctional block copolymer derived from sequential addition of
ethylene oxide and propylene oxide to ethylene-diamine available
from BASF. Triton.TM. X-200, which is an alkyl aryl polyether
sulfonate, available from Rohm and Haas. Tween 20, 40, 60 and 80,
which are polyoxyethylene sorbitan fatty acid esters, available
from ICI Speciality Chemicals, Carbowax.TM. 3550 and 934, which are
polyethylene glycols available from Union Carbide,
hydroxypropylmethylcellulose, dimyristoyl phosphatidylglycerol
sodium salt, sodium dodecylsulfate, sodium deoxycholate, and
cetyltrimethylammonium bromide.
[0139] Preferred surface active substances are phospholipid surface
active substances. By phospholipid surface active substances or
phospholipid surface active agents is meant a single phospholipid
of a mixture of two or more phospholipids, for example a mixture of
two or a mixture of three or a mixture of four or a mixture of five
or a mixture of from six to about ten phospholipids. Suitable
phospholipids include saturated phospholipids; unsaturated
phospholipids; naturally derived phospholipids; synthetic
irreversibly agglomerate after the relatively short period of time.
Additionally, after the relatively short period of time, the
components of the formulation may undesirably phase separate from
the aqueous carrier and precipitate and undesirably separate into
components that contain largely drug and largely surface active
substance unless a stabilizing energetic process is applied to the
cooed homogenate.
[0140] Examples of some suitable surface active substances that are
useful in the hot melt microfluidization process described herein
include: (a) natural surfactants such as casein, gelatin,
tragacanth, waxes, enteric resins, paraffin, acacia, gelatin,
cholesterol esters, phospholipids, and triglycerides, (b) nonionic
surfactants such as polyoxyethylene fatty alcohol ethers, sorbitan
fatty acid esters, polyoxyethylene fatty acid esters, sorbitan
esters, glycerol monostearate, polyethylene glycols, cetyl alcohol,
cetostearyl alcohol, stearyl alcohol, poloxamers, polaxamines,
methylcellulose, hydroxycellulose, hydroxy propylcellulose, hydroxy
propylmethylcellulose, noncrystalline cellulose, polyvinyl alcohol,
polyvinylpyrrolidone, and synthetic phospholipids, natural gums (c)
anionic surfactants such as potassium laurate, triethanolamine
stearate, sodium lauryl sulfate, alkyl polyoxyethylene sulfates,
sodium alginate, dioctyl sodium sulfosuccinate, negatively charged
phospholipids (phosphatidyl glycerol, phosphatidyl inosite,
phosphatidylserine, phosphatidic acid and their salts), and
negatively charged glyceryl esters, sodium carboxymethylcellulose,
and calcium carboxymethylcellulose, (d) cationic surfactants such
as quaternary ammonium compounds, benzalkonium chloride,
cetyltrimethylammonium bromide, chitosans and
lauryldimethylbenzylammonium chloride, (e) colloidal clays such as
bentonite and veegum. A detailed description of these surfactants
may be found in Remington's Pharmaceutical Sciences, and Theory and
Practice of Industrial Pharmacy, Lachman et al, 1986.
[0141] More specifically, examples of suitable surface active
substances include one or combination of the following: poloxamers,
such as Pluronic.TM. F68, F108 and F127, which are block copolymers
of ethylene oxide and propylene oxide available from BASF, and
poloxamines, such as Tetronic.TM. 908 (T908), which is a
tetrafunctional block copolymer derived from sequential addition of
ethylene oxide and propylene oxide to ethylene-diamine available
from BASF, Triton.TM. X-200, which is an alkyl acyl polyether
sulfonate, available from Rohm and Haas. Tween 20, 40, 60 and 80,
which are polyoxyethylene sorbitan fatty acid esters, available
from ICI Speciality Chemicals, Carbowax.TM. 3550 and 934, which are
polyethylene glycols available from Union Carbide,
hydroxypropylmethylcellulose, dimyristoyl phosphatidylglycerol
sodium salt, sodium dodecylsulfate, sodium deoxycholate, and
cetyltrimethylammonium bromide.
[0142] Preferred surface active substances are phospholipid surface
active substances. By phospholipid surface active substances or
phospholipid surface active agents is meant a single phospholipid
or a mixture of two or more phospholipids, for example a mixture of
two or a mixture of three or a mixture of four or a mixture of five
or a mixture of from six to about ten phospholipids. Suitable
phospholipids include saturated phospholipids; unsaturated
phospholipids; naturally derived phospholipids; synthetic
phospholipids and semisynthetic phospholipids; animal and plant
phospholipids; egg phospholipids; soya bean phospholipids; corn
phospholipids; wheat germ, flax, cotton, and sunflower seed
phospholipids; milk fat phospholipids; purified phospholipids from
these and other natural sources; glycerophospholipids;
sphingophospholipids; phosphatides; phospholipids containing fatty
acid esters including palmitate, stearate, oleate, linoleate, and
arachidonate which esters can be mixtures and mixtures of isomers
in the phospholipids; phospholipids composed of fatty acids
containing one or more than one double bonds such as dioleoyl
phosphatidylcholine and egg phosphatidylcholine that are not stable
as powders but are hygroscopic and can absorb moisture and become
gummy; phospholipids composed of saturated fatty acids that are
stable as powders and are relatively less amenable to absorption of
moisture; phosphatidylserines; phosphatidylcholines;
phosphatidylethanolamines; phosphatidylinositols;
phosphatidylglycerols such as dimyristoyl phosphatidylglycerol,
L-alpha-dimyristoyl phosphatidylglycerol also known as
1,2-dimyristoyl-sn-glycero-3-phospho(rac-1-glycerol) and also known
as DMPG; phosphatidic acid; hydrogenated natural phospholipids; and
commercially available saturated and unsaturated phospholipids such
as those available from Avanti Polar Lipids, Inc. of Alabaster,
Ala., USA. In the absence of an internal counterion in the
phospholipid, a preferred counterion is a monovalent cation such as
sodium ion. The phospholipid may be salted or desalted,
hydrogenated, or partially hydrogenated. The phospholipid surface
active substance can be a mixture of these phospholipids.
[0143] Preferred phospholipids include Lipoid E80, Lipoid EPC,
Lipoid SPC, DMPG, Phospholipon 100H, a hydrogenated soybean
phosphatidylcholine, Phospholipon 90H, Lipoid SPC-3, egg
phospholipid, purified egg phospholipid, and mixtures thereof. A
currently most preferred phospholipid is Lipoid E80.
[0144] The concentration of surface active substance added to the
formulations prepared according to this invention can be present in
the range of 0.1 to 50%, preferably 0.2 to 20%, and more preferably
0.4 to 15%. A currently preferred level of Lipoid E80 is from about
0.4% to 15%, more preferably from about 0.5% to about 10%, and most
preferably from 2 to 5%.
[0145] In a preferred aspect, a process is provided for the
preparation of small particles containing fenofibrate and a
phospholipid surface stabilizing substance which comprises the
steps of (a) mixing at high shear an admixture of the poorly
water-soluble drug and a phospholipid substance in an aqueous
carrier in the absence of an organic solvent and optionally in the
presence of one or more than one surface active substances within a
first temperature range at or above the melting point of the drug
to form a heated suspension containing the drug, then (b)
homogenizing said heated suspension in a first pressure range and
within said first temperature range to form a heated homogenate
containing the drug, then (c) cooling said heated homogenate to a
second temperature range below the melting temperature of the drug
to form a transiently stable cooled homogenate containing the drug,
then (d) applying a particle stabilizing energetic process to said
cooled homogenate within a second temperature range and in a second
pressure range to form a cooled dispersion of stabilized small
particles containing the drug, and then (e) optionally drying the
cooled dispersion to form dried small particles containing the
drug. A statin can be added at any of the above steps, but is
preferably added at some point after cooling of the heated
homogenate.
[0146] In a specific aspect, the present invention is directed to a
composition and a process for the preparation of microparticles of
fenofibrate, which small particles are used to prepare an orally
administered pharmaceutical composition comprising said
microparticles of solid fenofibrate and a statin that are
stabilized by a phospholipid surface active substance, wherein said
microparticles are prepared in the presence of said phospholipid
surface active substance, and wherein a therapeutically effective
amount of said composition provides a quantity of fenofibrate to a
fasted human patient in need of treatment that is greater than 80%
of the quantity of fenofibrate provided by said amount to said
patient when fed at least 1000 calories 50% of which are from
fat.
[0147] The process comprises the steps of (a) mixing at high shear
an admixture of the poorly water-soluble drug fenofibrate and a
phospholipid substance in an aqueous carrier in the absence of an
organic solvent and optionally in the presence of one or more than
one surface active substances within a first temperature range at
or above the melting point of the drug to form a heated suspension
containing the drug, then (b) homogenizing said heated suspension
in a first pressure range and within said first temperature range
to form a heated homogenate containing the drug, then (c) cooling
said heated homogenate to a second temperature range below the
melting temperature of the drug to form a transiently stable cooled
homogenate containing the drug, then (d) adding a desired amount of
a statin to the cooled homogenate, then (e) applying a particle
stabilizing energetic process to said cooled homogenate within a
second temperature range and in a second pressure range to form a
cooled dispersion of stabilized small particles containing both
drugs, and then (t) optionally drying the cooled dispersion to form
dried matrix containing both drugs.
[0148] An admixture of a poorly water-soluble fibrate and a surface
active substance such as a phospholipid substance can be prepared
by adding a surface active substance and the poorly water-soluble
fibrate to an aqueous carrier and then mixing at high shear, for
example for up to 30 minutes at a shear rate of up to 10,000 rpm.
As an example, an admixture of fenofibrate and a phospholipid
substance can be prepared by adding a phospholipid substance and
fenofibrate to an aqueous carrier and then mixing the admixture at
high shear for up to 30 minutes at a shear rate of up to 10,000
rpm.
[0149] Preferably the fenofibrate used to form the admixture is in
the form of a powder or small crystals or small pieces that are
less than about 5 mm in diameter to facilitate mixing. Larger sized
crystals or masses of drug can be milled to about 5 mm or smaller
before forming the admixture used in this invention to facilitate
mixing.
[0150] Suitable aqueous carriers include water, sterile water,
water for injection, and buffered water such as phosphate buffered
water. The pH of the buffer can be in the range of from 4 to 10,
preferably from 7 to 9, and most preferably from 7.5 to 8.5. A
preferred aqueous carrier is 0.01 to 10 mM sodium phosphate buffer.
The pH of the carrier is preferably established at room temperature
before mixing with the phospholipid substance and the poorly
water-soluble drug and before heating to a first temperature. The
pH may be adjusted by addition of an acid or base such as HCl or
NaOH to a solution of a phosphate salt. Preferably the aqueous
carrier contains no dissolved oxygen. A currently most preferred
aqueous carrier is 10 mM phosphate buffer. Optionally, one or more
carbohydrates or bulking agents can be added to the aqueous
carrier. Preferred carbohydrates and bulking agents include
monosaccharides, disaccharides, trisaccharides, and sugars such as
sucrose, raffinose, lactose, mannitol, sorbitol, trehalose,
glycerol, dextrose, fructose, a pentose, a hexose, xylitol, and
mixtures thereof. Most preferred carbohydrates and bulking agents
include sucrose, raffinose, sorbitol, trehalose, and mixtures
thereof. Concentrations of the carbohydrates can range from about
5% to about 40%, preferably about 10% to about 30%.
[0151] When raffinose is used in the compositions of this
invention, it is preferably used together with sucrose with the
ratio of sucrose to raffinose in the range of about 1:1 to about
500:1, more preferably in the range from 10:1 to 100:1.
[0152] In one aspect, the aqueous carrier can initially be at a
temperature between about 4.degree. C. to about 100.degree. C.,
preferably between 20.degree. C. and 90.degree. C., and more
preferably between 20.degree. C. and 50.degree. C. This is
particularly useful for fenofibrate. The aqueous carrier can be
heated to the desired first temperature range before or after the
addition of the admixture.
[0153] In another aspect, the aqueous carrier can be heated to a
temperature higher than 100.degree. C., for example superheated up
to 275.degree. C. In this case, the aqueous carrier can be
contained in a closed vessel or apparatus at a pressure higher than
ambient pressure. The superheated aqueous carrier and the admixture
can be contained in a pressurized closed system such as a stainless
steel vessel in which high speed shear can be applied. The vessel
is preferably connected through suitable piping and valves to a
heated homogenization apparatus which further comprises a reservoir
and optionally a return pipe that can carry homogenate from the
homogenizer back to the vessel if used in a continuous or
batch-wise mode. The vapor pressure of water at 100.degree. C. is
approximately 14.7 psi and it rises as the temperature is
increased. For example, at 120.degree. C. the vapor pressure of
water is approximately 28.8 psi; at 140.degree. C. it is
approximately 52.4 psi; at 160.degree. C. it is approximately 89.6
psi; at 180.degree. C. it is approximately 145.4 psi; at
200.degree. C. it is approximately 225.5 psi; at 220.degree. C. it
is approximately 337 psi; at 240.degree. C. it is approximately 486
psi; at 260.degree. C. it is approximately 680 psi; and at
275.degree. C. it is approximately 863 psi. A closed system useful
in this invention can safely contain the heated components of this
invention at least at these and higher pressures and temperatures
and used to provide small particles of poorly water-soluble drug
according to this invention.
[0154] After the poorly water-soluble drug and surface active
substance such as fenofibrate and a phospholipid substance are
added to the aqueous carrier, the admixture can then be heated if
not already so, preferably in the absence of oxygen such as under a
nitrogen or argon atmosphere, until the temperature rises to a
first temperature range that is at or above the melting point of
the drug. In the case of fenofibrate the admixture in the aqueous
carrier can be heated to between 79.degree. C. (the reported lowest
melting point of fenofibrate) and 99.degree. C., preferably between
79.degree. C. and 95.degree. C. and most preferably between
80.degree. C. and 90.degree. C. In general it is preferred that the
temperature is at or up to about 20.degree. C. above the melting
point of the drug. Thus, the preferred first temperature range is
in general from the melting point of the drug to about 20.degree.
C. above the melting point of the drug. The aqueous carrier can be
heated to the first temperature range before or after the addition
of the drug and the surface active substance. The admixture is
maintained at the first temperature range while high shear mixing
is applied. The admixture when thus prepared comprises a crude
emulsion of melted drug and surface active substance in the heated
aqueous carrier.
[0155] During the heating of the admixture, high shear mixing is
applied. Suitable shear is derived for example from
propeller-containing mixers, homogenizers, blenders, sonicators or
other devices capable of producing a heated suspension. Suitable
shear rates can range between 500 to 10,000 rpm, preferably 2,000
to 5,000 rpm. High shear mixing can be continued for up to 30
minutes or even longer if needed to form a heated suspension
containing the drug. High shear mixing of the admixture when the
temperature is below the melting point of the drug provides a
suspension of the admixture in the aqueous carrier, and such
suspension is useful as an antecedent to the heated suspension that
is produced when the temperature is increased to or above the
melting point of the drug. Continued application of high shear
mixing or application of more vigorous or ultra-high shear mixing
when the temperature is above the melting point of the drug can
produce a heated homogenate of the admixture in the aqueous
carrier. When the temperature is above the melting point of the
drug, the heated suspension is a suspension of melted drug and
surface active substance in the aqueous carrier. In one aspect, the
heated suspension is an emulsion of melted drug and surface active
substance in the aqueous carrier. High shear mixing and ultra-high
shear mixing can be produced by the input of mechanical energy for
example using a mechanical mixer or stirrer or mill configured with
a mixing blade or propeller that can induce efficient mixing and
particle size reduction through high shear turbulence, turbulent
eddies, transfer of high fluid kinetic energy, high energy
dissipation, pressure induced cavitation, and similar known
mechanisms of homogenization.
[0156] In one aspect, devices useful in the preparation of a heated
suspension of this invention can be employed in the preparation of
the heated homogenate of this invention if sufficient energy is
transferred to the particles of the heated suspension to produce a
heated homogenate. In this case, heating of the admixture to form a
heated suspension and then homogenization of the heated suspension
to form a heated homogenate can be done as a continuous step
combining step (a) and step (b) into a single step wherein a heated
suspension is formed and then converted into a heated homogenate
without substantial change in apparatus or without substantial
increase in energy applied to the heated admixture formulation.
[0157] As used herein, homogenization refers to the creation of a
homogenate or uniform distribution of small particles containing
drug in an aqueous carrier as a result of an energetic process
being applied to an antecedent composition such as a mixture,
admixture, blend, emulsion, suspension, dispersion or other
composition of solids or solid particles or liquids or liquid
particles or droplets comprising drug and one or more than one
surface active substance in an aqueous carrier wherein the
homogenate and the small particles produced are at least
transiently stable toward phase separation into larger particles or
droplets or non-uniform solid or liquid domains. Homogenization,
particularly with respect to the formation of a heated suspension
and a heated homogenate, can be achieved by input of mechanical
energy such as by high shear mixing, ultra high shear mixing, high
speed blending, microfluidization, and milling such as by
dispersion milling, ball milling, attrition milling, vibrator
milling, and media milling, or by application of sonic energy in
the form of sonication. Preferably in the case of a mill being used
in this process wherein the mill contains media or grinding media,
such media is removed in a filtration or other suitable separation
process to provide homogenized compositions of this invention.
Homogenization is preferably achieved by passing an antecedent
composition under high pressure, for example under more than 1000
psi, through a tiny orifice which can result in a decrease in the
average diameter and an increase in the number and surface area of
particles or droplets in the antecedent composition and produce
small particles. A preferred homogenization method comprises
passing an antecedent composition under high pressure through a
tiny orifice and includes microfluidization, particularly with
respect to homogenization to prepare a cooled dispersion of this
invention.
[0158] The drug can be added to the aqueous carrier as a solid.
Preferably for example the drug such as fenofibrate can be added in
the form of particles ranging in size up to about 10 mm such as
milled or micronized particles or powders. Milled particles can be
obtained for example by air jet milling of bulk powdered or
crystalline fenofibrate. The drug can also be added to the aqueous
carrier as a molten material, i.e., heated at or above its melting
point, preferably at the melting point of the drug to about
20.degree. C. above the melting point of the drug but at a
temperature less than its decomposition point. For fenofibrate the
preferred temperature can be from about 80.degree. C., the melting
point of the drug, to about 100.degree. C. although temperatures up
to the decomposition point of the drug are also suitable.
[0159] The concentration of the surface active substance in the
aqueous carrier can vary between 0.1% w/w and 90% w/w, preferably
between 0.1% w/w and 50% w/w, and more preferably between 0.2% and
20%, and most preferably between 0.5% to 10% w/w. The concentration
of the drug such as fenofibrate in the aqueous carrier can vary
between 0.1% w/w and 90% w/w, preferably between 0.5% w/w and 50%
w/w, and more preferably between 1% and 20% w/w. For example, in
one aspect a currently preferred composition comprises 3% to 10% of
a phospholipid substance as a surface active substance and 14% of
the poorly water-soluble drug fenofibrate in 10 mM phosphate buffer
at pH 8 as receiving vessel back into the heated reservoir such as
by means of a pump or by pouring, and the heated homogenization
step is repeated. In another aspect, the processed heated
suspension is fed directly back into the heated reservoir in a
continuous process. If the aqueous carrier is heated above
100.degree. C., the system is contained as a closed system under
pressure during the feeding of the admixture to the homogenization
apparatus and during the return of the homogenized or partially or
not-completely homogenized heated suspension to the heated
reservoir. If the initial volume of the heated suspension before
homogenization is defined as a volume pass, then the number of
volume passes made through the homogenizer in this manner can range
from one to about 20, preferably from one to ten, more preferably
from 2 to 8, and most preferably from 4 to 7 to produce a heated
homogenate that is initially at the first temperature range at or
above the melting point of the drug. A preferred drug in this
process is fenofibrate which has a preferred first temperature
range of from 80.degree. C. to about 100.degree. C. and more
preferred from 80.degree. C. to about 90.degree. C.
[0160] While it is not known with certainty, it is appreciated that
forcing a drug and a surface active substance such as a
phospholipid under conditions of elevated pressure and temperature
through a microfluidizing chamber can cause transient gradients in
temperature, the microfluidization process being exothermic and
causing a rise in the temperature of the processed suspension of
particles or emulsions during particle size reduction. While the
transient rise in temperature is usually controlled by a
temperature regulating device such as a heat exchanger, it is
possible that transient concentration gradients of poorly
water-soluble drug and stabilizer are established or continue to
exist in the rapidly moving non-equilibrium state of the
microfluidizer. Water insoluble or poorly soluble components of the
formulation (e.g., fenofibrate and phospholipid) may be forced into
solution temporarily, perhaps at a molecular level thereby creating
a supersaturated or molecularly distorted environment which if left
undisturbed will subsequently achieve equilibrium again. It is
postulated that transient concentration gradients may be
established in the microfluidization process wherein molecules of
drug and stabilizer are forced into an aqueous environment to give
a transiently stable but novel composition and non-equilibrium
condition. It is expected that this novel composition will not be
achieved if the microfluidization is carried out on solid
fenofibrate at a lower temperature, and a different composition
will obtain in that case.
[0161] We have found that this heated homogenate can be cooled to a
transiently stable or metastable cooled homogenate. By metastable
stable we mean that upon agitation or long-term standing the
transiently stable particles of the cooled homogenate will convert
to larger particles of crystallized or precipitated drug and can
demonstrate phase separation of components of the homogenate from
the aqueous carrier. For example, under these conditions
fenofibrate forms a transiently stable or metastable cooled
homogenate that on standing or application of manual agitation such
as shaking or stirring produces larger crystals. However, we have
surprisingly found that the lifetime of the transiently stable
particles of the cooled homogenate can be moderately extended by
control of cooling conditions. Additional prolonged stability of
the small particles can be obtained by subsequent homogenization at
a second temperature range that is below the melting point of the
drug. We have also found that the total number of homogenization
volume passes used in the heated and cooled homogenization
processes of this invention is substantially fewer than the number
of volume passes needed to produce an approximately comparable drug
suspension starting from the powdered or micronized drug that was
used to prepared the admixture in this invention but homogenized
while the drug was maintained entirely in the solid state according
to prior art methods.
In one aspect the average particle size of the heated homogenate
can be measured using a laser light diffraction based instrument
such as a Malvern Mastersizer Microplus and shown to be less than
one micrometer. However, if an attempt is made to collect and keep
the heated homogenate in a receiving vessel that is not preheated
to the first temperature, a poorly ater-soluble drug such as
fenofibrate immediately precipitates from the heated homogenate as
a solid, and in the case of fenofibrate as crystals. This is very
likely related to agitation of the transiently stable
dispersion.
[0162] In the case of fenofibrate, microscopic examination of a
heated homogenate shows it to be comprised of small and
non-crystalline particles in suspension, but there is a tendency
for fenofibrate to crystallize out on the microscope slide. This
rapid crystallization is also seen if the heated homogenate is
collected in a receiver at ambient temperature.
[0163] A transiently stable or metastable cooled homogenate can be
obtained from a heated homogenate derived from an admixture of drug
and a surface active substance such as a phospholipid substance in
an aqueous carrier by rapidly cooling the heated homogenate under
non-agitating conditions from a first temperature range at or above
the melting temperature of the drug to a second temperature range
below the melting point of the drug, preferably to the range of
1.degree. C. to about 20.degree. C. In some cases, depending on how
readily the drug crystallizes, under non-stirred conditions the
cooled homogenate can retain small non-crystalline particles very
similar to those detected initially in the heated homogenate.
Optionally, the heated homogenate can be held at the first
temperature range that is above the melting point of the drug, for
a holding time before the onset of cooling to the second
temperature range. Agitation during the holding period above the
melting point of the drug does not effect crystallization of the
drug. However, agitation such as by stirring of the cooled
homogenate can induce growth in particle size and crystallization
and precipitation of drug.
[0164] In particular, in the case of fenofibrate we have found that
a transiently stable or metastable cooled homogenate can be
obtained from a heated homogenate derived from an admixture of
fenofibrate and a phospholipid substance in an aqueous carrier by
rapidly cooling the heated homogenate under non-agitating
conditions from a first temperature range at or above the melting
temperature of fenofibrate to a second temperature range below the
melting point of fenofibrate, preferably to the range of 1.degree.
C. to about 40.degree. C., more preferably from about 4.degree. C.
to about 40.degree. C. and fenofibrate is not molten. Under
non-stirred conditions the cooled homogenate retains small
non-crystalline particles very similar to those detected initially
in the heated homogenate. Optionally, the heated homogenate can be
held at the first temperature range, for example at 80.degree. C.
to 90.degree. C., for a holding time before the onset of cooling to
the second temperature range. Agitation during the holding period
does not effect crystallization of the fenofibrate.
[0165] To determine a minimum holding time at 80 to 90.degree. C.
before the induction of cooling for a fenofibrate-containing heated
homogenate, the holding time was varied at 15 minute intervals from
0 to 60 minutes and a cooling period in a bath held at 5.degree. C.
was kept constant at 30 minutes after the onset of cooling. In
these experiments we find that particle mean diameters of the
cooled homogenate are similar under all conditions studied. Thus,
samples of freshly prepared heated homogenate can be held at a
first temperature range for a holding period or they can be
immediately cooled to a second temperature range after completion
of the first homogenization step.
[0166] A number of cooling methods can be applied to the heated
homogenate containing a poorly water-soluble drug to cool it from
the first temperature ranee at or above the melting point of the
drug to a temperature below the melting point of the drug to form a
cooled homogenate. Examples of several methods are listed and
illustrated with respect to fenofibrate as follows.
[0167] Method 1: slow cooling in ambient air optionally in a closed
vessel that excludes oxygen and air by allowing the heated
homogenate to stand unagitated and to cool from above the melting
point of the drug to ambient room temperature;
[0168] Method 2: slow unagitated cooling from above the melting
point of the drug which for fenofibrate is about 85.degree. C. in a
water bath at ambient temperature which is approximately 15.degree.
C. to 20.degree. C.;
[0169] Method 3: slow stepwise cooling at 1 degree Centigrade per
minute in a stirred oil bath from above the melting point of the
drug to ambient temperature;
[0170] Method 4: slow stepwise cooling from above the melting point
of the drug to about 20.degree. C. below the melting point of the
drug which for fenofibrate is from about 85.degree. C. down to
65.degree. C., followed by cooling to 4.degree. C. in an
isothermally cooled 4.degree. C. water bath;
[0171] Method 5: fast cooling in an isothermally cooled 4.degree.
C. water bath;
[0172] Method 6: slow stepwise cooling from above the melting point
of the drug to about 40.degree. C. below the melting point of the
drug which for fenofibrate is from about 85.degree. C. to about
40.degree. C. at the rate of 1 Centigrade degree per minute.
[0173] For cooling from temperatures initially above 100.degree. C.
the heated homogenate is maintained in a pressurized vessel. After
cooling, the pressure can then be optionally adjusted to ambient
without agitation of the contents of the vessel typically by means
of a valve that permits pressure equalization to ambient pressure
conditions. Preferably an inert atmosphere such as a nitrogen or
argon atmosphere is maintained in contact with the formulations of
this invention.
[0174] The effect of stirring during the cooling phase was examined
for fenofibrate as an example. In some studies, samples were left
unagitated while others were stirred magnetically at 250 rpm using
Teflon-coated magnetic stirring bars during cooling methods.
Additionally, in some experiments, heated homogenate was diluted
ten fold with additional aqueous carrier that had been heated to
the first temperature, the diluted heated homogenate was then
swirled to evenly distribute the added aqueous carrier, and then
the diluted heated homogenate was cooled.
[0175] Particle size determinations were carried out using a
Malvern Microplus Mastersizer. Samples were examined at two to
three hours after the initiation of cooling. Results are reported
as volume weighted averages or D(4,3). Samples were also examined
microscopically under bright polarized light using both in-phase
and out-of-phase modes. In-phase light allowed determination of the
primary particle size and the detection of aggregates. Out-of-phase
examination gave an indication of the amount of crystals formed in
the composition. Morphologically small crystalline particles of
fenofibrate were easily distinguished from large fenofibrate
crystals.
[0176] When 3% Lipoid E80 (also sometimes referred to as E80 herein
below) was used as a phospholipid substance in a single pass
homogenization preparation of a heated homogenate containing 10%
fenofibrate, little difference was observed in the particle
characteristics when cooled by either method 1 or 2 (average
particle size at 3 hours was 2.42 and 2.96 micrometers,
respectively). The particles were initially non-crystalline,
spherical and submicron but crystals appeared within 3 hours. In
contrast, when 3% Lipoid E80 was used as a phospholipid substance
in a two pass homogenization preparation of a heated homogenate
containing 10% fenofibrate, a smaller particle size was
unexpectedly observed when a sample was cooled by method 1 versus
when a sample was cooled by method 2 (0.56 and 1.64 micrometers,
respectively after 3 hours of cooling). This difference was
different from that seen in heated homogenates prepared with
saturated lipids such as phospholipon 100H (also sometimes referred
to as 100H herein below) and phospholipon 90H (also sometimes
referred to as 90H herein below) when processed for two passes. In
these formulations, the particle size at 2 to 3 hours after
initiation of cooling was significantly higher than that seen using
Lipoid E80. For heated homogenates prepared using 3% phospholipon
100H in two passes and cooled for 3 hours according to methods 1
and 2, the average particle sizes were 14.72 and 10.31 micrometers,
respectively. For heated homogenates prepared using 3% phospholipon
90H in two passes and cooled for 2 hours according to methods 1 and
2, the average particle sizes were 6.07 and 5.23 micrometers,
respectively. Microscopically the cooled homogenates containing
phospholipon 100H and phospholipon 90H consisted of particle
aggregates with crystals appearing over time. Aggregates were not
typically seen in Lipoid E80 formulations but crystal growth
occurred over time.
[0177] It was unexpectedly found that increasing the cooling rate
in the absence of agitation produced cooled homogenates that
maintained small particles containing the poorly water-soluble drug
fenofibrate to a greater degree than those produced by slow cooling
methods. This was especially true when Lipoid E80 was used as the
phospholipid substance. For example, when a sample of heated
homogenate prepared from 3% Lipoid E80 as the surface active
substance and 10% fenofibrate in two homogenization passes was
cooled by method 5 (fast cooling) and compared to a cooled sample
of heated homogenate of the same composition cooled according to
methods 1 or 2 (slow cooling), the particle size at 3 hours for
fast cooling was 0.63 micrometers versus 0.76 micrometers for slow
cooling.
[0178] For non-stirred samples; minimal particle size increases can
be observed in all cooling methods while under stirred conditions
substantial crystallization or precipitation or agglomeration of
poorly water-soluble drug can be observed. For example, for
non-stirred samples containing fenofibrate, minimal particle size
increases were observed in all cooling methods. In contrast, under
stirred conditions substantial crystallization of fenofibrate was
observed for all cooling methods. For sample cooled in a slow step
process, crystal growth occurred at temperatures lower than about
20.degree. C. below the melting point of the drug, i.e., for
fenofibrate below about 60.degree. C.
[0179] It can be seen that energy imparted to the cooled homogenate
by mechanical stirring for example using a stirring bar or spatula
is not sufficient to impart stability to the particles of the
cooled homogenate. To be effective, a particle stabilizing
energetic process must impart sufficient energy to the particles of
the cooled homogenate to convert them from a transiently stable
homogenate into a longer lived dispersion of particles. Otherwise,
undesirably large particles will be produced from the transiently
stable cooled homogenate. Preferred particle stabilizing energetic
processes include sonication, homogenization and microfluidization.
A most preferred particle stabilizing energetic process is
homogenization. It is believed that enough energy must be applied
to the particles to modify some aspect of the particle composition
which, while currently unknown, may be related to further reduction
in particle size in the presence of a surface active substance or
reorganization of drug and/or surface active substance molecules at
or on the surface of the particle, or other phenomena.
[0180] Oral formulations of fenofibrate microparticles stabilized
by phospholipid surface active substance and prepared by
homogenization or microfluidization or hot melt homogenization or
sonication provide unexpected reduction in food effect on the
uptake of fenofibrate between fasted and fed conditions.
Diluting the heated homogenate ten fold with additional heated
aqueous carrier was found unexpectedly to have a beneficial effect
on the size of particles when cooled. Results for fenofibrate as an
example are displayed in Table 1. Attention is drawn to the bottom
two rows of Table 1 which show that the particle size of diluted
suspension of fenofibrate is smaller than that of undiluted
suspension
TABLE-US-00001 TABLE 1 Effect of dilution with aqueous carrier on
cooled particle sizes in micrometers of heated homogenate
containing 10% fenofibrate and 3% phospholipid Phospholipid (one
pass) E80 E80 100H 100H 90H 90H Cooling method 1 2 1 2 1 2 (time of
cooling) (3 h) (3 h) (3 h) (3 h) (2 h) (2 h) Undiluted average 2.42
2.96 11.46 9.71 4.83 4.12 particle size Diluted average 1.84 1.69
3.29 3.77 2.17 2.73 particle size
[0181] Cooled homogenate having average particle size of less than
1 micrometer can usually be achieved by subjecting the heated
homogenate containing melted drug to multiple homogenization passes
prior to rapid cooling. The effect of multiple homogenization is to
produce smaller particles, but the size reducing effect is
non-linear and shows decreasing rates of return, i.e., the average
particle size decreases non-linearly with an increasing number of
passes.
In the case of fenofibrate, it was also found that increasing the
number of heated homogenization passes from one to two followed by
cooling produced a cooled homogenate with smaller particle size
with Lipoid E80 but not with Phospholipon 100H or Phospholipon 90H.
For example, at 3 hours after cooling, a cooled homogenate sample
containing fenofibrate prepared according to method 1 had a
particle size of 0.56 micrometers when the antecedent heated
homogenate had been subjected to two passes of homogenization
compared to a particle size of 2.42 micrometers when the antecedent
heated homogenate had been subjected to one homogenization pass.
When a heated homogenate had been subjected to 10 homogenization
passes, the cooled homogenate had a particle size of 0.29
micrometers. It was generally found that cooled homogenate having
particle size of about 0.3 micrometers could be achieved from
heated homogenate that had been subjected to at least 5
homogenization passes. Additional homogenization produced smaller
particles, but at decreasing rates per volume pass. For examples,
particles as small as 0.1 micrometers can be achieved under
homogenization conditions. Results for one and two homogenization
volume passes as a function of phospholipid are displayed in Table
2.
TABLE-US-00002 TABLE 2 Difference between one and two heated
homogenization passes on cooled particle sizes in micrometers of
heated homogenates containing 10% fenofibrate and 3% phospholipid
Phospholipid E80 E80 100H 100H 90H 90H Cooling method 1 2 1 2 1 2
(time of cooling) (3 h) (3 h) (3 h) (3 h) (2 h) (2 h) One pass
average 2.42 2.96 11.46 9.71 4.83 4.12 particle size Two pass
average 0.56 1.64 14.72 10.31 6.07 5.23 particle size
[0182] We have also found that the pass dependent particle size of
the cooled homogenate can be a function of the ratio of the
concentration of surface active substance to drug. For example, a
heated homogenate prepared using 3% Lipoid E80 as the surface
active substance and 10% fenofibrate as the drug and subjected to
10 homogenization passes produced a cooled homogenate by method 6
that had a particle size of 0.35 micrometers while a heated
homogenate prepared using 10% Lipoid E80 as the surface active
substance and 10% fenofibrate as the drug and subjected to 10
homogenization passes produced a cooled homogenate by method 6 that
had a particle size of 1.3 micrometers.
[0183] Furthermore, when a heated homogenate was prepared using 3%
Phospholipon 100H as the surface active substance and 10%
fenofibrate as the drug, subjected to 10 homogenization passes and
cooled, a cooled homogenate was produced by method 5 that had a
particle size of 1.45 micrometers. In comparison, when a heated
homogenate was prepared using 3% Lipoid E80 as the surface active
substance and 10% fenofibrate as the drug, subjected to 10
homogenization passes and cooled, a cooled homogenate was produced
that had a particle size of 1.3 micrometers.
[0184] Fast cooling of heated homogenates in a 4.degree. C. bath
under non-stirred conditions produces cooled homogenates with
minimum change in morphology and particle size from that observed
in the heated homogenates prior to cooling. For example, we have
discovered that fast cooling of heated homogenates containing a
phospholipid as the surface active substance and fenofibrate as the
drug in a 4.degree. C. bath under non-stirred conditions produced
non-crystalline cooled homogenates with minimum change in
morphology and particle size from that observed in the heated
homogenates prior to cooling. When samples of heated homogenate
were held at 80.degree. C. for up to one hour and then cooled to
form cooled homogenates that were held for 30 minutes at 5.degree.
C., no differences in particle size could be detected as a function
of the time the heated homogenate was held at 80.degree. C. before
cooling. For optimum processing speed, freshly prepared samples of
heated homogenate can be cooled from the first temperature range to
a second temperature range immediately after an adequate number of
homogenization passes such as five passes of heated homogenization
to provide cooled homogenates. However, cooled homogenates thus
prepared appear to be transiently stable or metastable toward
formation of crystals of drug that can grow larger and precipitate
from the suspension of the cooled homogenate if allowed to stand.
The formation of larger particles and crystals is enhanced if the
cooled homogenate is disturbed such as by stirring or shaking.
[0185] Preferably, the average particle size of the microparticles
of fenofibrate stabilized with phospholipid is less than 10
microns, more preferably less than 5 microns, even more preferably
less than 4 microns, yet even more preferably less than 3 microns,
yet even more preferably less than 2 microns, and most preferably
less than 1 micron. Microparticles that are less than about 0.5
microns are especially preferred.
[0186] In another aspect of this invention, bulking agents or
bulking agent, excipients (i.e., pharmaceutically acceptable
excipients including those used in currently available formulations
of fibrates alone and of statins alone) can be added as solids or
in solutions of aqueous carrier at steps in the current procedure.
Preferably soluble sugars can be added to the admixture of drug and
a surface active substance in an aqueous carrier in the process of
this invention.
[0187] A bulking agent is herein defined as a compound, usually a
pharmaceutically acceptable excipient, useful in assisting
redispersion of dried small particles back into a suspension such
as an aqueous suspension. Suitable bulking agents include
hydroxyl-containing, hydrophilic, relatively low molecular weight
(less than 50,000) compounds such as sugars, including
monosaccharides, disaccharides, trisaccharides, sucrose, raffinose,
lactose, mannitol, sorbitol, trehalose, glycerol, dextrose,
fructose, pentoses, hexoses, xylitol, and mixtures thereof. Bulking
agents are useful as protectants in a drying process such as
cryoprotectants in a lyophilization process or as additives in a
spray drying process or an evaporation process, preventing or
substantially reducing particle fusion, combination, suspension
degradation and agglomeration during drying, and assisting in the
resuspension of particles from a dried state to form a suspension
of the particles. Dry small particles containing a poorly
water-soluble drug can be produced for example as a lyophilizate
which is a solid produced from a cooled dispersion of particles by
the process of freezing the aqueous carrier to a solid comprising a
dispersion in ice and then removing the water by subliming the ice
under reduced pressure. Bulking agents can also reduce or depress
the freezing point of aqueous compositions in which they are
dissolved or partially dissolved.
[0188] Bulking agents can be added in amounts from 0.1% to about
60% w/w or more depending on the intended use. Additional amounts
of bulking agents can be added to the phospholipid-stabilized
microparticles after they have been prepared as a suspension, for
example prior to a drying step such as a spray drying step or a
lyophilization step, or after they have been dried or substantially
dried. Mixing of bulking agents with dried or substantially dried
microparticles can be done by mixing the ingredients or by adding
one or more bulking agents to the microparticles or vice versa and
subsequently blending the ingredients. Alternatively, the
microparticles can be resuspended in a liquid or fluid such as an
aqueous fluid and admixed with bulking agents as solutions,
suspensions, or as dried substances, and the liquid or fluid can be
subsequently removed. Depending on the intended use and ultimate
formulation and dosage form, bulking agents such as
monosaccharides, disaccharides, trisaccharides, sucrose, raffinose,
lactose, mannitol, sorbitol, trehalose, glycerol, dextrose,
fructose, pentoses, hexoses, xylitol, and mixtures thereof can be
added in amounts varying from about 0.1% up to their solubility
limits in solution. Additional quantities can be added by blending
of dried microparticles plus bulking agents with additional bulking
agents. A preferred range of these ingredients is such to provide
from about 1% to about 90% of a tablet or capsule dosage form.
[0189] In yet another aspect of this invention, the
phospholipid-stabilized microparticles can be sprayed onto the
surface of a bulking agent. For example, if the bulking agent is in
the form of a particle or bead, preferably in the range of about 5
micrometers to about 0.5 millimeters or even up to about 2 mm in
some cases, of a pharmaceutically acceptable material or excipient,
a suspension of phospholipid-stabilized microparticles optionally
containing additional dissolved or suspended bulking agent (which
can be the same composition as the particle or bead or a different
composition from the material in the particle or bead) can be spray
coated onto the surface of the bulking agent particle or bead to
create a layer and optionally a multilayer derived from repetitive
spray coating. For example, a combination of a statin and
fenofibrate microparticles stabilized by a phospholipid in an
aqueous suspension of a sugar such as sucrose can be sprayed onto
the surface of a sugar bead or particle such as a sucrose bead or a
lactose bead or a starch bead or a polyvinylpyrrolidone or PVP bead
in a single layer or in multiple layers, and the coated beads so
produced can be optionally mixed with pharmaceutically acceptable
excipients and placed in capsules or compressed into tablets or
maintained as powders to provide dosage forms of this
invention.
[0190] Currently preferred bulking agents include trehalose,
sucrose, raffinose, sorbitol, and mixtures thereof. Preferred
levels of these bulking agents in the admixture range from about 1%
to about 40% w/w, and more preferably from about 2% to about 30%
w/w.
[0191] The combination of statin and phospholipid-stabilized
microparticles that exhibit a substantial reduction in food effect
as described in this invention can be employed in a number of
dosage forms including tablets, capsules, and powders, which
powders can be dispersed in a beverage such as a citrus beverage
(e.g., orange juice and the like) or a food beverage such as a
vegetable juice, or a flavored beverage sometimes used by a patient
on a restricted calorie diet or a restricted fat diet such as
Slim-Fast.TM. and similar beverages. Particularly useful also are
the dosage forms disclosed in WO 00/30616, the contents of which is
hereby incorporated by reference.
[0192] Bulking agents can be added to the admixture, to the heated
suspension, to the heated homogenate, to the cooled homogenate to
the cooled dispersion, and to the dried particles. They can be
added as solids, as liquids, as solutions in aqueous carrier when
soluble therein, or in combinations thereof. In one embodiment,
bulking agents added to a composition such as a cooled homogenate
and the like as part of this invention are preferably soluble in
the aqueous suspension rather than only swellable therein when the
composition plus bulking agent is to undergo an additional
homogenization step with a microfluidizer.
[0193] The stability of cooled homogenate formulations with respect
to the effect of addition of a bulking agent (or a pharmaceutically
acceptable excipient) or a combination of excipients was examined.
When bulking agents were added as solids or liquids to heated
admixtures of fenofibrate and a phospholipid substance as a surface
active substance in an aqueous carrier, then processed for example
using 10 heated homogenization passes at 80.degree. C. and
subsequently cooled in a 4.degree. C. water bath, particle size
estimates suggested that with the exception of the bulking agent
sucrose (10%), there was little increase in particle mean diameter
measurements over a 2 h period. However microscopic observations
revealed the presence of a significant number of large crystals
after the cooling step. Addition of 2-fold hot buffer solution
containing either nothing or bulking agents to the processed
formulations caused a large increase in the mean particle diameter.
This was attributed by microscopic examination to be due to
particle aggregation together with large crystals also present.
[0194] When trehalose was added to an admixture of fenofibrate and
a phospholipid substance in an aqueous carrier, on stirring
crystals were detected indicating that trehalose did not stabilize
these metastable formulations with respect to crystal formation and
precipitation. PVP 17 and glycerol were added to heated
homogenates, and in both cases crystal growth was observed
microscopically under stirred conditions. When glycerol alone or
glycerol and trehalose were added to the admixture and then
homogenized, results from stirring experiments again showed that
these formulations were unstable with extensive crystallization
observed over time. Thus, adding bulking agents or PVP to either
the admixture or to the heated homogenate does not result in
stabilization of the metastable formulation under stirring
conditions.
[0195] Whereas a cooled homogenate can be unstable with respect to
agitation such as stirring or manual shaking, we have surprisingly
found that a cooled homogenate can be transformed into a more
stable cooled dispersion by application of a particle stabilizing
energetic process applied at the second temperature range and in a
second pressure range.
[0196] For example, although the aforementioned cooled homogenates
of fenofibrate were found to be unstable with respect to agitation
such as stirring or manual shaking that lead to the formation of
crystals of fenofibrate, we have found that the cooled homogenate
can be transformed into a more stable cooled dispersion by
application of a particle stabilizing energetic process applied at
the second temperature range and in a second pressure range.
[0197] Examples of suitable particle stabilizing energetic
processes include homogenization, microfluidization, and
sonication. Microfluidization is generally considered to be a
method of homogenization. Microfluidization of fenofibrate in the
presence of a phospholipid stabilizing agent produces a novel
composition that when formulated into a suitable dosage form such
as a tablet or capsule as a dried solid optionally in the presence
of one or more excipients such as sucrose, raffinose, sorbitol,
trehalose, Tween 80, mannitol, other sugars and starch, and the
like provides a novel oral dosage form of the drug. The dosage
form, when administered to a fasted patient, provides at least 80%
of the amount of active drug species received by the patient by the
dosage form when the patient is fed a high fat meal. The unexpected
and sizable reduction in food effect on the uptake of drug by a
fasted or fed patient is useful in the prescription of the drug to
a patient undergoing treatment because the patient will receive
comparable and therapeutically useful levels of the drug regardless
of whether the patient is fed or fasted or on a reduced calorie or
reduced fat diet.
[0198] In one aspect, particles of a heated homogenate containing a
poorly soluble drug can be non-crystalline while the cooled
dispersion particles produced as a result of application of a
particle stabilizing energetic process can be crystalline. While
stirring can induce significant particle growth in a cooled
homogenate, stirring does not induce significant particle growth in
a cooled dispersion formed from the cooled homogenate by an
energetic process. The cooled dispersion thus produced is more
robust toward particle growth than the cooled homogenate. The
particles of the cooled dispersion are preferably in the micron and
submicron range. Depending on the number of stabilizing processing
steps, i.e., volume passes, employed in the preparation of the
cooled dispersion, the cooled dispersion can also comprise weakly
associated aggregates of particles that can be readily broken up or
dispersed or de-aggregated by stirring the dispersion. Preferably,
an increase in the number of processing steps from 1 to a range of
from 5 to 20, preferably from 10 to 20, can produce fewer and more
easily dispersed aggregates. Formulation instability toward
stirring can be decreased as a result of the particle stabilizing
energizing process.
[0199] Microscopically, in the case of fenofibrate as an example of
a poorly soluble drug, heated homogenate particles are
non-crystalline while cooled dispersion particles produced as a
result of application of a particle stabilizing energetic process
are solid and crystalline. Importantly, while stirring can induce
significant particle growth in a cooled homogenate, stirring does
not induce significant particle growth in a cooled dispersion
formed from the cooled homogenate. The cooled dispersion thus
produced is more robust toward particle size growth than the cooled
homogenate. One possible explanation is that the number of
nucleation sites for formation of crystals of the poorly soluble
drug is substantially increased by application of a particle
stabilizing energetic process such as microfluidization in the
presence of a surface active substance giving rise to stable small
crystalline particles in the micron and submicron range.
[0200] In one embodiment of the combination of a statin and
microparticles of fenofibrate stabilized by a phospholipid surface
active substance of this invention, sometimes hereinafter referred
to as Fenostatin and disclosed herein, a desired amount of a statin
can be added at any step of the preferred process, but preferably
can be added to the cooled homogenate containing fenofibrate just
prior to the second stage energetic microfluidization process. This
is particularly preferred when the statin is thermally or
hydrolytically labile. A desired amount of statin to be present in
a dosage form of this invention can be determined in one aspect
based on the clinically practiced daily dose amount of the statin.
Thus for example, for simvastatin the amount to be added to the
cooled homogenate will be between 5% to 30% relative to the amount
of fenofibrate, and preferably between 7% to 15%. The statin can be
added to the cooled homogenate of fenofibrate as powder or as a
solution depending on its solubility in an aqueous carrier used
such as 10 mM phosphate buffer at pH 8. In the case of lovastatin,
simvastatin, itavastatin and certain others, the lactone ring may
open to the corresponding hydroxyacid form or a salt thereof under
certain aqueous buffer conditions. In this embodiment, after
addition of a desired amount of a statin to the cooled homogenate
containing fenofibrate, the cooled homogenate plus the added statin
are subjected to the energetic microfluidization process, an
example of which is described below.
[0201] In the dosage forms of the current invention, the statin can
be water soluble, water insoluble, or poorly water soluble.
[0202] In the dosage forms of the current invention, particularly
when the statin is water insoluble or poorly water soluble, the
statin can be in the form of a microparticle or can be a
constituent of a microparticle, preferably in the form of a
microparticle that is stabilized by one or more surface active
substance or is a constituent of a microparticle that is stabilized
by one or more surface active substance. In this aspect, a
preferred surface active substance comprises a phospholipid.
In the dosage forms of the current invention, the statin is
selected from the group consisting of lovastatin, pravastatin,
simvastatin, atorvastatin, rosuvastatin, fluvastatin, itavastatin,
and cerivastatin. In preferred embodiments of the dosage forms of
this invention, the statin can be lovastatin where the lovastatin
is present in the range of 2 mg to 50 mg; the statin can be
pravastatin present in the range of 2 mg to 50 mg; the statin can
be simvastatin where the simvastatin is present in the range of 2
mg to 100 mg; the statin can be atorvastatin where the atorvastatin
is present in the range of 2 mg to 100 mg; the statin can be
rosuvastatin where the rosuvastatin is present in the range of 2 mg
to 100 mg; the statin can be fluvastatin where the fluvastatin is
present in the range of 2 mg to 50 mg; the statin is itavastatin
where the itavastatin is present in the range of 0.2 mg to 100 mg;
the statin is cerivastatin where the cerivastatin is present in the
range of 0.05 mg to 2 mg.
[0203] A preferred particle stabilizing energetic process is
microfluidization for example using a Microfluidix M110EH
apparatus. Microfluidization can be accomplished using from 1 to 20
volume passes, preferably from 2 to 20 volume passes, more
preferably from 5 to 20 volume passes, and most preferably from 10
to 20 volume passes. Microfluidization can be done in continuous
mode or in batch mode. A preferred second temperature range is the
second temperature range used for the preparation of the cooled
homogenate and is preferably from 1.degree. C. to 40.degree. C.,
more preferably from 4.degree. C. to 40.degree. C., even more
preferably form 4.degree. C. to 20.degree. C. and most preferably
from 4.degree. C. to 15.degree. C. A useful pressure range for the
preparation of the cooled dispersion is a second pressure range,
that is, from 2,000 to about 30,000 psi, preferably from 5,000 to
about 20,000 psi, and most preferably from 5,000 to 18,000 psi.
[0204] The above described microfluidization process is preferably
carried out in absence of air by replacing air with an inert gas
such as nitrogen or argon.
[0205] Microscopically, in one embodiment of a dosage form of this
invention comprising microparticles of fenofibrate and a statin,
the cooled dispersion comprises a suspension of crystalline
fenofibrate microparticles and statin microparticles. Depending
directly on the number of stabilizing processing steps or volume
passes employed in the preparation of the cooled dispersion, the
cooled dispersion can also comprise weakly associated aggregates of
crystalline fenofibrate microparticles and statin microparticles
that can be broken up or dispersed or de-aggregated by stirring the
suspension or manually shaking the suspension.
[0206] FIG. 1 is an optical microscopic comparison of
microfluidized fenofibrate with micronized fenofibrate and
fenofibrate compositions prepared in the presence of starch. In
FIG. 1(A), crystals of fenofibrate 20 and domains of starch 10 are
large with respect to the 100 micrometer scale. In FIG. 1(B),
encircled micronized fenofibrate 40 is seen to be non-uniformly
sized and dispersed and particles are entrained in starch domain
30. In FIG. 1(C), encircled microfluidized fenofibrate particles 40
that are stabilized with phospholipid are uniformly distributed in
an average size smaller than micronized fenofibrate of FIG.
1(B).
[0207] A reduction in the cooled dispersion particle mean diameter
can be achieved by increasing the number of volume passes during
the cold homogenization step. For example, as shown in Table 3 for
a formulation derived from an admixture of 3% Lipoid E80 as the
surface active substance and 10% fenofibrate as a poorly
water-soluble drug processed first for 10 volume passes to form a
heated homogenate containing the drug, cooled according to method 5
to form a transiently stable cooled homogenate containing the drug,
and then microfluidized for 2 volume to 10 volume passes to form a
cooled dispersion of small particles containing the drug, the
observed mean diameter was 0.26 to 0.54 micrometers as a cooled
homogenate prior to undergoing a particle stabilizing energizing
process, 1.45 micrometers as a cooled dispersion when processed for
2 volume passes, and 0.9 micrometers when processed for 10 volume
passes. Surprisingly, formulation stability toward stirring was
dramatically increased as a result of the particle stabilizing
energizing process. Without the additional particle stabilizing
energizing process, the average particle size of the cooled
homogenate increased by two orders of magnitude with stirring
within 30 minutes. However, after application of the particle
stabilizing energizing process, the average particle size did not
increase substantially with stirring up to 24 hours. In addition,
the average particle size of the cooled dispersion was smaller and
remained smaller up to 5 days when the formulation was processed
for 10 volume passes.
TABLE-US-00003 TABLE 3 Particle size changes of cooled homogenate
and cooled dispersion From an admixture of 10% Fenofibrate, 3%
Lipoid E80 as the surface active substance in 10 mM phosphate
buffer at pH 8. at 4.degree. C. Average size Average size Time not
stirred stirred (minutes) (micrometers) (micrometers) Cooled
homogenate 0 0.26 0.26 (10 volume Passes) 30 0.26 14.22 60 0.54
9.44 Cooled dispersion 0 1.45 1.45 (2 volume Passes) 30 1.45 1.29
60 1.37 1.37 1440 Not measured 1.12 Cooled dispersion 0 0.87 Not
measured (10 volume passes) 1140 0.93 Not measured 5700 0.97 Not
measured
When egg lecithin Lipoid E80 was replaced with phospholipon H100,
the cooled homogenate particle size was higher after 10 passes than
with Lipoid E80 equivalent (2.3 micrometers versus 0.3 micrometers,
respectively). In addition after processing to form a cooled
dispersion of small particles containing the drug, a further
relative increase in particle size of cooled dispersion was
detected. This can be attributed to aggregation of the primary
particles. For both the Lipoid E80 formulation and the phospholipon
H100 formulation, aggregate sizes could be decreased over time with
stirring.
[0208] Scanning electron microscopic (SEM) analysis of examples of
cooled dispersions prepared originally from fenofibrate and a
phospholipid as a surface active substance in the admixture and by
10 volume passes revealed them to exist as single crystalline
particles each about 1 micron in mean diameter. Cooled dispersions
are approximately comparable to microfluidized formulations of
phospholipid and fenofibrate that can be prepared by
microfluidization below the melting point of fenofibrate such as
according to IDD-P.TM. technology developed by RTP Pharma Inc. as
described in U.S. Pat. No. 5,091,187 which is hereby incorporated
by reference in that microparticles of phospholipid stabilized
fenofibrate can be prepared. However, to achieve such particle size
reduction without first melting the drug can require substantially
more volume passes of microfluidization, for example as many as 200
passes at about 18,000 psi.
[0209] In another aspect of this invention, more than one surface
active substance can be used to prepare formulations according to
this invention. At least one surface active substance is needed to
prepare the initial admixture of this invention, and in one aspect
can suffice in the preparation of subsequent heated suspensions,
heated homogenates, cooled homogenates, cooled dispersions and
dried particles (e.g., spray dried and lyophilized) prepared
according to this invention. In another aspect, addition of more
than one surface active substance can be made to the admixture, the
heated suspension, the heated homogenate, the cooled homogenate,
and the cooled dispersion of this invention. Such additions can be
made at one individual step in the rocess or at more than one step
in the process. For example, a second surface active agent can be
added to the admixture or to the heated suspension, and additional
amounts of the second surface active agent or a third surface
active agent can be added to the cooled homogenate or to the cooled
suspension or even to the dried small particles prepared according
to this invention.
[0210] Preferred compositions of this invention that provide
substantial elimination of the food effect observed with
fenofibrate alone that has been micronized in the presence of a
surfactant such as sodium lauryl sulfate (for example in a jet
milling process) and then mixed with a statin or of such
fenofibrate that is dosed separately from a statin comprise a
combination of phospholipid stabilized microparticles of
fenofibrate and a statin in the presence of a sugar such as
sucrose, raffinose, sorbitol, trehalose, and the like.
[0211] In one embodiment, the total concentration of one or of more
than one surface active substance added to the formulations
prepared according to this invention can be in the range of 0.1 to
50%, preferably 0.2 to 20%, and more preferably 0.5 to 10%.
[0212] In another embodiment, the total concentration of one or of
more than one surface active substance added to the formulations
prepared according to this invention that comprise phospholipid
stabilized microparticles can be in the range of 0.1 to 50%,
preferably 0.2 to 20%, and more preferably 0.5 to 10%.
[0213] In another aspect of this invention, bulking agents can be
added to the admixture, to the heated homogenate, to the cooled
homogenate, and to the cooled dispersion. Bulking agents can be
added as solids, as mixtures, as solutions in aqueous carrier, and
in combinations of solids and solutions. Bulking agents can be
added at the beginning or end of the steps leading to the formation
of a heated homogenate, cooled homogenate, and cooled dispersion,
and they can be added at more than one stage during the process.
The amount of total bulking agents that can be added ranges from
about 0.1% to about 50%, preferably from 1% to about 30%, and more
preferably from about 2% to about 30%. Bulking agents can be added
as individual agents at these levels or in combination such that
the total amount of bulking agent resides within these levels.
[0214] With respect to the compositions and methods of this
invention, bulking agents are preferably pharmaceutically
acceptable excipients.
[0215] Addition of a variety of bulking agents at different steps
in the process of this invention does not produce a substantial
increase the mean particle diameter of a cooled dispersion over a
period of time such as over 24 hours. For example, when bulking
agents sorbitol (5%) and sucrose (10%) were added to a 3% Lipoid
E80 and 10% fenofibrate admixture and the formulation was processed
for 10 passes to form a cooled homogenate and for 10 passes to form
a cooled dispersion of small particles containing the drug, the
particle size of the cooled dispersion (0.97 micrometers) was very
similar in size to that of an analogous formulation composition
(i.e., 0.91 micron) where the same bulking agents were added after
the formation of the cooled dispersion.
[0216] In one embodiment, subsequent to the formation of the cooled
dispersion, a statin can be added. The statin can be in the form of
a water soluble solid, a water soluble solid that is pre-dissolved
in an aqueous medium, or a water insoluble or poorly water soluble
solid that is preferably dispersed in an aqueous medium or
dispersible in the cooled dispersion or subsequent compositions,
more preferably dispersed as microparticles of the statin
stabilized by a phospholipid surface active substance that is most
preferably compatible with the phospholipid substance used in the
stabilization of the microparticles of fenofibrate of this
invention.
[0217] Dried compositions containing microparticles of fenofibrate
stabilized by a phospholipid such as those that can be prepared by
drying an aqueous suspension containing microparticles of
fenofibrate stabilized by a phospholipid plus a bulking agent such
as a sugar (e.g., sucrose, raffinose, trehalose, and individual
sugars such as those that can give crystalline sugar states on
drying such as by spray drying as well as mixtures of sugars such
as sucrose and raffinose and similar mixtures that can give glassy
or amorphous or crystalline sugar states on drying such as by
lyophilization) can be further blended with a statin and optionally
with additional bulking agents and other known pharmaceutically
acceptable excipients useful in the preparation of a dosage form or
this invention.
[0218] Homogenization of the cooled homogenate containing the drug
(fenofibrate and optionally a statin added prior to or at this
step) can be carried out in equipment suitable for that process.
Useful equipment includes but is not limited to commercially
available high pressure homogenization equipment such as APV Gaulin
M15. Avestin Emulsiflex C5 or C50, MFIC Microfluidizer M110EH, and
other microfluidizers and homogenizers. Homogenization can also be
carried out using high shear and ultra high shear mechanical mixers
and mills and propeller-containing mixers than can impart
sufficient turbulence or energy transfer to the particles to form
stable small particles of this invention. The apparatus is cooled
to maintain the cooled homogenate and cooled dispersion at the
second temperature range. Cooling can be done by use of a cooled
air bath, a cooled fluid bath such as a water or ice/water bath, or
a suitable heat exchanger that is cooled and maintained at or below
the second temperature range that is below the melting point of the
drug.
[0219] In this aspect of the invention, in an ensuing step of this
process to prepare microparticulate fenofibrate or a Fenostatin
combination comprising microparticles of fenofibrate and a statin,
the cooled dispersion comprising a bulking agent (e.g. sucrose,
sorbitol, trehalose, raffinose, or other sugars or combinations
thereof) and fenofibrate microparticles optionally in combination
with a statin as appropriate can be dried to provide a matrix of
small particles containing fenofibrate alone or a combination of
fenofibrate and a statin. The microparticles of fenofibrate can
comprise a number of possible compositions in this invention. For
example, the microparticles of fenofibrate can comprise a
substantially solid core of fenofibrate, phospholipid plus
fenofibrate in the particle, a mixture of fenofibrate and statin in
the same particle, a mixture of fenofibrate and statin in different
particles, a mixture of fenofibrate and statin in rad lent amounts
of fenofibrate and statin in the same distribution of particles,
regions of fenofibrate and statin phase separated in the same
particle, domains fenofibrate and statin phase separated in the
same particle, or other distributions of fenofibrate and statin and
phospholipid. Drying can be done using a number of commonly known
methods, for example by spray drying, lyophilization, and
evaporation. Preferably at least one or more than one bulking agent
is present in the formulation undergoing drying.
[0220] When drying is done by spray drying, the cooled dispersion
of microparticles of fenofibrate stabilized by a surface active
substance (preferably a phospholipid) and optionally a statin in
suitable form (e.g., in solution, as a dispersion of
microparticles, etc.) is fed into the spray dryer as a liquid,
preferably at a temperature in the second temperature range and
preferably as a dispersion comprising one or more than one bulking
agent in an aqueous medium such as a solution of a sugar in an
aqueous medium.
[0221] In one embodiment of this invention, organic solvents such
as water miscible organic solvents can be employed, particularly
with the statin or at the drying stage. For example, a
water-insoluble or poorly water-soluble statin can be dissolved in
a water compatible organic solvent such as methanol, ethanol,
isopropanol, acetone, tetrahydrofuran, acetonitrile, or other
appropriate solvent including one or more of those previously
mentioned herein, optionally together with one or more surface
active substance such as a phospholipid or a mixture of
phospholipid and a polyoxyethylene-containing surfactant, and the
solution can be added to water or other aqueous medium to provide a
dispersion of the statin stabilized by the surface active
substance(s). The organic solvent can then be removed in the drying
process together with the water or distilled from the water prior
to drying. Organic solvents such as ethanol and acetone and others
can form azeotropic mixtures with water (e.g. binary azeotropes,
tertiary azeotropes, etc.). In one aspect, amounts of one or more
azeotrope forming organic solvents can be used sufficient to form
an azeotropic mixture with the water of the aqueous medium. The
organic solvent(s) and the water can be removed in a drying step
such as by spray drying or evaporation. Formation of an azeotrope
can have the advantage of lowering the temperature required to
evaporate the water from the aqueous mixture. Further, if less than
an azeotrope forming quantity of organic solvent is used in this
aspect of the invention, the azeotropic composition will be removed
at a temperature below that required to remove water, and thus the
organic solvent will be more completely removed by an evaporation
process.
[0222] When drying is done by evaporation, the aqueous carrier of
the cooled dispersion can be maintained as a liquid and water (and
optionally added organic solvent and/or azeotrope) is removed under
reduced pressure and with application of enough heat to keep at
least some and preferably all of the aqueous carrier in the cooled
dispersion that is drying in the liquid state until it is
dried.
[0223] In currently preferred embodiments of this invention, an
organic solvent is not employed or is not present in the drying
step.
[0224] When drying is done by lyophilization, the aqueous carrier
of the cooled dispersion is frozen and the composition is
lyophilized under reduced pressure and application of heat to the
frozen suspension to provide a lyophilizate comprising a matrix of
small particles containing fenofibrate or a lyophilizate comprising
a combination a matrix of small particles containing fenofibrate
and a statin. Freezing and lyophilization are preferably done in a
conventional freeze dryer, for example, in a Virtis Corporation
Unitop freeze dryer using conventional techniques. Freezing can be
done using the freezing apparatus in the freeze dryer or by other
means such as by freezing using liquefied gas such as liquid
nitrogen or by freezing methods employing solid carbon dioxide as a
cooling agent. Lyophilization can be done on frozen dispersions in
bulk such as on dispersions added to trays and then frozen or on
dispersions that have been added to vials, for example in 2 mL or
10 mL vials, and then frozen. Bulking agents can be added to the
formulation to facilitate reconstitution of the lyophilizate.
[0225] In compositions of this invention that comprise in an
aqueous carrier cooled dispersions containing a combination of
fenofibrate and a statin, in a final step of the process the cooled
dispersion can be dried by freezing the aqueous carrier in the
dispersion and lyophilizing the frozen dispersion under reduced
pressure and by application of heat to provide a lyophilizate
comprising a matrix of small particles containing fenofibrate and a
statin. Optionally, the cooled suspension can be spray dried to
provide a dried powder of particles containing fenofibrate and a
statin. Alternatively, the water in the aqueous carrier of the
cooled dispersion can be evaporated, for example under reduced
pressure to provide dried small particles containing fenofibrate
and a statin.
[0226] By small particles containing a poorly water-soluble drug is
meant particles in the range of 0.1 micron to 20 micrometers in
average diameter containing a poorly water-soluble drug, preferably
in the range of 0.1 to 5 micrometers containing a poorly
water-soluble drug, and most preferably in the range of 0.1 to 2
micron containing a poorly water-soluble drug.
[0227] By small particles containing fenofibrate is meant particles
in the range of 0.1 micron to 20 micrometers in average diameter
containing fenofibrate, preferably in the range of 0.1 to 5
micrometers containing fenofibrate, and most preferably in the
range of 0.1 to 2 micron containing, fenofibrate.
[0228] Addition of bulking agents such as sucrose and sorbitol for
example to the admixture before processing or to the cooled
dispersion just prior to drying provides suspensions of particles
which on reconstitution with water or aqueous media are similar in
particle size to those of the antecedent cooled dispersion. Drying
can be done preferably by lyophilization or spray drying.
[0229] Addition of bulking agent such as trehalose either to the
admixture before processing, to the heated homogenate, to the
cooled homogenate, or to the cooled dispersion just prior to drying
provides particle size suspensions that on drying and subsequent
reconstitution provide dispersions or particles similar in size to
those of the antecedent cooled dispersion.
[0230] Samples of cooled dispersion can be dried for example by
lyophilization with bulking agents and reconstituted in modified
simulated gastric fluid (SGF) with gentle inversion immediately
after lyophilization. The particle sizes of the dispersions on
reconstitution can be similar to, i.e., the same or slightly larger
than, those of the antecedent cooled dispersion. Microscopically in
one aspect, the reconstituted suspensions can exist primarily as
single crystalline particles together with occasional aggregates.
For example, a cooled dispersion prepared from an admixture of 3%
Lipoid E80 as the surface active substance, 10% fenofibrate, 10%
sucrose, and 5% sorbitol as an antecedent cooled dispersion has an
average particle size of 0.96 micrometers. On reconstitution of the
corresponding lyophilizate, the average particle size of the
reconstituted suspension is 1.57 micrometers. For the
compositionally equivalent formulation where the bulking agents are
added to the cooled dispersion, mean particle diameters before and
after lyophilization are 0.91 and 1.38 micrometers, respectively. A
statin can be added to these dried fenofibrate compositions by
blending as a solid statin or in the form of dried microparticles
of statin or dried micronized particles of statin with the dried
fenofibrate composition and optionally with additional
excipients.
[0231] Other bulking agents, for example glycerol at 2%, sucrose at
5%, also yield dried particles that reconstitute easily and provide
suspensions of single crystalline particles.
[0232] The period of stability of the particles of the cooled
dispersion of stabilized small particles containing the drug can
extend from the stability period of the transiently stable
particles of the cooled homogenate up to several months. Stability
of more than a year is also contemplated.
[0233] Formulations prepared by this invention may be dried into
powders with the addition or blending of binders and other blended
excipients known in the art. The resulting blended dried powders
can be resuspended e.g. in a beverage suitable for administering a
dose of the composition of this invention.
[0234] Formulations prepared by this invention may be dried into
powders, optionally blended with excipients or bulking agents, and
then can be filled into capsules or converted into granules or
tablets with the addition of binders and other excipients known in
the art of tablet making such as, for example, silica as a flow aid
and magnesium stearate.
[0235] In one aspect of this invention, the dosage form can be a
tablet, preferably a coated tablet such as a film-coated tablet, a
tablet coated with a moisture resistant or moisture retardant layer
such as a hydrophobically substituted polymer that does not readily
swell in moist air, a tablet coated with a pharmaceutically
acceptable polymer such as a cellulose or chemically modified
cellulose derivative, a tablet with a coating containing gelatin,
an tablet coated with an enteric coating, a tablet with a coating
containing a pharmaceutically acceptable sugar that can be
amorphous, a tablet with a coating that can be applied from a
liquid, a tablet with a coating that can be sprayed onto the
surface of the tablet, a tablet that is encapsulated in a coating,
a tablet with a coating that can be applied by a dry coating
process, a tablet with a coating that can be applied as a heated or
thermally softened or molten substance that is cooled to form a
hardened or solid coating, a tablet with a coating that can be
applied using electrostatic attraction forces between the tablet
and constituents that form the coating, tablet with a other
pharmaceutically acceptable coating materials and coating
processes.
[0236] Another currently preferred dosage form of this invention is
a capsule dosage form. A currently preferred formulation
composition for oral administration in a capsule dosage form
comprises a combination of microparticles of phospholipid
stabilized fenofibrate and a statin together with a bulking agent.
For example, a preferred composition comprises fenofibrate at 10%
w/w in the form of phospholipid stabilized microparticles prepared
by microfluidization in 10 mM phosphate buffer with phospholipid
Lipoid E80 at 3% w/w, a statin present at 1%, a bulking agent
sucrose present at 10% w/w, and an additional bulking agent
sorbitol present at 5% w/w. The suspension of microparticles
prepared by microfluidization of these ingredients is dried by
lyophilization to remove water and form a solid which is blended
with colloidal silicon dioxide (up to 1% w/w) and magnesium
stearate (up to 5% w/w). This blend is then filled into capsules
for oral delivery to a patient.
[0237] Alternatively, the above blend can be compressed into
tablets that can be optionally coated as described above to form
tablets suitable for oral delivery to a patient.
[0238] The amount of fenofibrate per capsule or tablet can range
from about 20 mg to about 300 mg, and preferably from about 40 mg
to about 300 mg, and is most preferably 40 mg, 50 mg, 51 mg, 52 mg,
53 mg, 54 mg, 67 mg, 100 mg, 102 mg, 103 mg, 104 mg, 134 mg, 150
mg, 153 mg, 156 mg, 159 mg, 160 ng, 200 mg, 213 mg, 250 mg, and 300
mg of fenofibrate per capsule or per tablet. Currently most
preferred dosage levels contain 50 mg, 67 mg, 100 mg, 134 mg, 150
mg, 160 mg, 200 mg and 213 mg of fenofibrate as microparticles
stabilized with phospholipid.
[0239] In the compositions of this invention, the statin can be
water-soluble or water insoluble or poorly water-soluble. In one
aspect of this invention, the dosage forms of this invention can
contain water insoluble or poorly water-soluble statins in the form
of microparticles such as a phospholipid stabilized microparticles
of a solid statin core, or as a constituent of a microparticle such
as may occur if the statin is present in a microparticle core
comprising fenofibrate. Preferred statins are lovastatin,
pravastatin, simvastatin, atorvastatin, rosuvastatin, fluvastatin,
itavastatin, and cerivastatin.
[0240] The amount of a statin in a dosage form of this invention
will depend on which statin is used for the combination
formulation. For example, for a combination comprising fenofibrate
and simvastatin, the amount of simvastatin per capsule or tablet
can range from about 1 mg to about 20 mg and in some cases up to
100 mg, although preferably it will be from 5 mg to about 10
mg.
[0241] For a combination comprising fenofibrate and lovastatin, the
amount of lovastatin in a dosage form of this invention is in the
range of 2 mg to 50 mg although preferably it will be from 10 to 40
mg.
[0242] For a combination comprising fenofibrate and pravastatin,
the amount of pravastatin in a dosage form of this invention is in
the range of 2 mg to 50 mg although preferably it will be from 10
to 40 mg.
[0243] For a combination comprising fenofibrate and atorvastatin,
the amount of atorvastatin in a dosage form of this invention is in
the range of 2 mg to 100 mg although preferably it will be from 5
to 80 mg, and more preferably from 5 to 20 mg.
[0244] For a combination comprising fenofibrate and rosuvastatin,
the amount of rosuvastatin in a dosage form of this invention is in
the range of 2 mg to about 80 mg although preferably it will be
from 5 to 20 mg.
[0245] For a combination comprising fenofibrate and fluvastatin,
the amount of fluvastatin in a dosage form of this invention is in
the range of 2 mg to 50 mg although preferably it will be from 20
to 40 mg.
[0246] For a combination comprising fenofibrate and itavastatin,
the amount of itavastatin in a dosage form of this invention is in
the range of 0.1 to about 20 mg although preferably it will be from
2 to 10 mg.
[0247] For a combination comprising fenofibrate and cerivastatin,
the amount of cerivastatin in a dosage form of this invention is in
the range of 0.02 mg to 1.2 mg although preferably it will be from
0.2 to 0.8 mg.
[0248] Capsules and tablets for oral administration provide
fenofibrate to a human patient in need of treatment that is
substantially independent of food effect. Thus, a patient in a
fasted state will receive at least 80% of the dose of the drug that
the patient in a fed state will receive by taking the same capsule
or tablet dosage form. More preferably, a patient in a fasted state
will receive at least 85% of the dose of the drug that the patient
in a fed state will receive by taking the same capsule or tablet
dosage form. Even more preferably, a patient in a fasted state will
receive at least 87% of the dose of the drug that the patient in a
fed state will receive by taking the same capsule or tablet dosage
form. Even more preferably, a patient in a fasted state will
receive at least 90% of the dose of the drug that the patient in a
fed state will receive by taking the same capsule or tablet dosage
form. Yet even more preferably, a patient in a fasted state will
receive at least 95% of the dose of the drug that the patient in a
fed state will receive by taking the same capsule or tablet dosage
form.
[0249] Particles of drug provided according to this invention have
bioavailability comparable to or better than similar sized
particles prepared by alternate methods. This is illustrated
graphically in FIG. 2 which compares the oral bioavailability of
microparticles of fenofibrate prepared by microfluidization in the
presence of a phospholipid stabilizing agent versus the oral
bioavailability of micronized fenofibrate under fasting, low fat
fed, and high fat fed conditions. In FIG. 2A, the fenofibrate in
microfluidized phospholipid-stabilized microparticles (bar 2) is
nearly twice as bioavailable as that in a micronized formulation
(bar 1) in the fasted state. In FIG. 2B, the fenofibrate in
microfluidized phospholipid-stabilized microparticles (bar 4) is
more bioavailable than that in a micronized formulation (bar 3) in
a low fat fed state. In FIG. 2C, there is no significant difference
in bioavailability between the fenofibrate in microfluidized
phospholipid-stabilized microparticles (bar 6) and in a micronized
formulation (bar 5). Bioavailability of fenofibrate increases by
more than a factor of two when comparing bars 1, 3, and 5 that
refer to a micronized formulation of fenofibrate. However,
bioavailability of fenofibrate is approximately constant when
comparing bars 2, 4, and 6 that refer to fenofibrate in a
microfluidized phospholipid-stabilized microparticle formulation.
The bioavailability of fenofibrate in formulations of
microfluidized phospholipid-stabilized microparticles is seen to
increase by less than 25% when comparing fasting and high fat fed
conditions (bars 2 and 6), preferably increasing by less than 20%,
and more preferably by less than 15% (bars 2 and 6). The clinical
data used to produce bars 2 and 6 indicate an increase of 14% in
the bioavailability of fenofibrate between fasted and high fat fed
conditions, i.e., a factor of 1.14 between bioavailabilities
represented by bar 2 (fasted) versus bar 6 (high fat fed). Blood
levels of fenofibric acid, the fenofibrate active species, were
measured to obtain the data from which FIG. 2 was generated.
[0250] This invention provides a dosage form of a pharmaceutical
composition comprising a combination of a statin and microparticles
of fenofibrate that are stabilized by a phospholipid surface active
substance, wherein the dosage form provides to a patient in need of
treatment by the statin and fenofibrate a therapeutically effective
dose of the statin and a therapeutically effective quantity of
fenofibrate active species to said patient when fasted that is at
least 80% of the quantity of fenofibrate active species provided by
said amount to said patient when fed a meal containing fat.
[0251] This invention also provides a dosage form of a
pharmaceutical composition comprising a combination of a statin and
microparticles of fenofibrate that are stabilized by a phospholipid
surface active substance, wherein the dosage form provides to a
human patient in need of treatment by the statin and fenofibrate a
therapeutically effective dose of the statin and a therapeutically
effective qualitity of fenofibrate active species to said patient
when fasted that is greater than 80% of the quantity of fenofibrate
active species provided by said amount to said patient when fed at
least 1000 calories 50% of which are from fat.
[0252] The invention also provides an oral dosage form of a
pharmaceutical composition comprising a combination of a statin and
microparticles of fenofibrate that are stabilized by a phospholipid
surface active substance, wherein the dosage form provides to a
human patient in need of treatment by the statin and fenofibrate a
therapeutically effective dose of the statin and a therapeutically
effective quantity of fenofibrate active species into the blood of
said patient when fasted that is between 85% and 115% of the
quantity of fenofibrate active species provided by said amount into
the blood of said patient when fed at least 1000 calories 50% of
which are from fat.
[0253] This invention also provides an oral dosage form of a
pharmaceutical composition comprising a combination of a statin and
microparticles of fenofibrate that are stabilized by a phospholipid
surface active substance, wherein the dosage form provides to a
human patient in need of treatment by the statin and fenofibrate a
therapeutically effective dose of the statin and a therapeutically
effective quantity of fenofibrate active species to said patient
when fasted that is at least 85% of the AUC quantity of fenofibrate
active species provided by said amount to said patient when fed at
least 1000 calories 50% of which are from fat.
[0254] The amount of a given statin in a dosage form of this
invention can be the same as the amount of that statin in currently
available dosage forms of that statin alone such as those listed
previously, or it can be an amount that is lower than the amount of
that statin in currently available dosage forms of that statin
alone. The presence of the statin augments or supplements the
effect of the fenofibrate of this invention, and the presence of
the fenofibrate augments or supplements the effect of the statin.
Thus, a therapeutically effective dosage form of this invention
containing a statin and fenofibrate can have relatively lower
amounts of the statin, relatively lower amounts of fenofibrate, or
relatively lower amounts of both than the amount of the statin when
in a dosage form without fenofibrate or than the amount of
fenofibrate when in a dosage form without the statin, or both.
[0255] The dosage forms of this invention can be prepared by a
process comprising blending dried small particles containing
fenofibrate stabilized by a phospholipid surface active substance
with a statin and optionally with one or more pharmaceutically
acceptable excipients such a one or more sugars (e.g., sucrose,
raffinose, sorbitol, and trehalose).
[0256] The dosage forms of this invention can be prepared by a
process comprising blending dried small particles containing
fenofibrate stabilized by a phospholipid surface active substance
with a statin and with a bulking agent comprising a sugar and
optionally with one or more pharmaceutically 10, acceptable
excipients such a one or more additional sugars (e.g., sucrose,
raffinose, sorbitol, and trehalose).
[0257] Dosage forms of this invention can be administered to a
patient in need of treatment by a combination of a statin and
fenofibrate can be administered several times a day such as three
or four times a day, but more preferably twice a day, and most
preferably once a day. Preferably, the more frequent the
administration of the drug, the smaller the quantity of the drug
contained in a given dosage form.
[0258] This invention further comprises a method of treatment of
dyslipidemia. This invention further comprises a method of
treatment of dyslipidemia where the dyslipidemia comprises
hypercholesterolemia, hyperlipidemia, hypertrigylceridaemia or
combinations thereof.
[0259] This invention further comprises a method of treatment of
dyslipidemia and dyslipoproteinemia in a patient comprising the
administration to said patient of a dosage form of a pharmaceutical
composition comprising a combination of a statin and microparticles
of fenofibrate that are stabilized by a phospholipid surface active
substance, wherein the dosage form provides to a patient in need of
treatment by the statin and fenofibrate a therapeutically effective
dose of the statin and a therapeutically effective quantity of
fenofibrate active species to said patient when fasted that is at
least 80% of the quantity of fenofibrate active species provided by
said amount to said patient when fed a meal containing fat.
[0260] This invention further comprises a method of treatment of
dyslipidemia and dyslipoproteinemia in a patient comprising the
administration to said patient of a dosage form of a pharmaceutical
composition comprising a combination of a statin and microparticles
of fenofibrate that are stabilized by a phospholipid surface active
substance, wherein the dosage form provides to a human patient in
need of treatment by the statin and fenofibrate a therapeutically
effective dose of the statin and a therapeutically effective
quantity of fenofibrate active species to said patient when fasted
that is greater than 80% of the quantity of fenofibrate active
species provided by said amount to said patient when fed at least
1000 calories 50% of which are from fat.
[0261] This invention further comprises a method of treatment of
dyslipidemia and dyslipoproteinemia in a patient comprising the
administration to said patient of an oral dosage form of a
pharmaceutical composition comprising a combination of a statin and
microparticles of fenofibrate that are stabilized by a phospholipid
surface active substance, wherein the dosage form provides to a
human patient in need of treatment by the statin and fenofibrate a
therapeutically effective dose of the statin and a therapeutically
effective quantity of fenofibrate active species into the blood of
said patient when fasted that is between 85% and 115% of the
quantity of fenofibrate active species provided by said amount into
the blood of said patient when fed at least 1000 calories 50% of
which are from fat.
[0262] This invention further comprises a method of treatment of
dyslipidemia and dyslipoproteinemia in a patient comprising the
administration to said patient of an oral dosage form of a
pharmaceutical composition comprising a combination of a statin and
microparticles of fenofibrate that are stabilized by a phospholipid
surface active substance, wherein the dosage form provides to a
human patient in need of treatment by the statin and fenofibrate a
therapeutically effective dose of the statin and a therapeutically
effective quantity of fenofibrate active species to said patient
when fasted that is at least 85% of the AUC quantity of fenofibrate
active species provided by said amount to said patient when fed at
least 1000 calories 50% of which are from fat.
[0263] While a preferred method of preparation of microparticles of
fenofibrate stabilized with phospholipid comprises a
microfluidization process, other methods of preparation of
microparticles of fenofibrate can find utility in this invention.
For example, it is possible to prepare microparticles of
fenofibrate stabilized with phospholipid using a sonication
process; using a milling process such as media milling, jet
milling, ball milling, attrition milling and the like; using a
precipitation process such as precipitation of drug from a solvent
miscible with water in the presence of a phospholipid to form a
suspension of microparticles; using an emulsification process;
using a solvent evaporation process such as a solvent spray
process; using a particle preparation process that utilizes a
liquefied gas; and using a particle preparation process that
utilizes a supercritical fluid. Microparticles of fenofibrate
prepared according to these known methods and stabilized with a
phospholipid can be formulated with a statin in the presence of the
bulking agents and prepared into dosage forms for use in patients
as described herein.
[0264] The invention is additionally illustrated in connection with
the following examples, which are considered to be illustrative of
the present invention. It should be understood, however, that the
invention is not limited to the specific details of the
Examples.
Example 1
[0265] A mixture of 60 parts of Lipoid E80 as the surface active
substance and 200 parts of a poorly water-soluble drug,
fenofibrate, is homogeneously dispersed in 1440 parts of 10 mM pH
8.0+/-0.2 aqueous phosphate buffer using a ProScientific 400 high
shear mixer at 2,000 to 3,600 rpm at ambient temperature for 30
minutes, and then heated to 95.degree. C., 15.degree. C. above the
melting point of the drug, during continuous high shear mixing at
2,500 to 4,000 rpm. The heated suspension is then recirculatively
homogenized for 10 batch volume cycles or passes using a
Microfluidizer M110Y operated at 3,400 to 3,600 psig while
maintained at 85.degree. C. to 99.degree. C. to form a heated
homogenate containing the drug. After 10 passes, the heated
homogenate is cooled by passage through a heat exchanger cooled by
chilled water at 5.degree. C. to 10.degree. C. to provide a
transiently stable cooled homogenate. To the cooled homogenate is
added 10-30 parts of simvastatin and the cooled homogenate plus
statin is further homogenized for 10 to 20 batch volume cycles or
passes using a Microfluidics M110 EH homogenizer operated at 18,000
psig (peak) while maintained at 4.degree. C. to 13.degree. C. The
resulting cooled dispersion comprising the statin and small
particles containing fenofibrate of size less than 1.0 micron in
diameter is then dried by freezing to about -40.degree. C. and
lyophilized under vacuum to produce a matrix of dried small
particles containing fenofibrate and the simvastatin.
Example 2
[0266] A mixture of 60 parts of Lipoid E80 as the surface active
substance and 200 parts of a poorly water-soluble drug,
fenofibrate, is homogeneously dispersed in 1440 parts of 10 mM pH
8.0+/-0.2 aqueous phosphate buffer using a ProScientific 400 high
shear mixer at 2,000 to 3,600 rpm at ambient temperature for 30
minutes, and then heated to 95.degree. C., 15.degree. C. above the
melting point of the drug, during continuous high shear mixing at
2,500 to 4,000 rpm. The heated suspension is then recirculatively
homogenized for 10 batch volume cycles or passes using a
Microfluidizer M110Y operated at 3,400 to 3,600 psig while
maintained at 85.degree. C. to 99.degree. C. to form a heated
homogenate containing the drug. After 10 passes, the heated
homogenate is cooled by passage through a heat exchanger cooled by
chilled water at 5.degree. C. to 10.degree. C. and the transiently
stable cooled homogenate is further homogenized for 10 to 20 batch
volume cycles or passes using a Microfluidics M110 EH homogenizer
operated at 18,000 psig (peak) while maintained at 4.degree. C. to
13.degree. C. Alternatively appropriate amounts of bulking agents
are added to the cooled homogenate before the microfluidization
with M110 EH. The resulting cooled dispersion comprising small
particles containing fenofibrate of size less than 1.0 micron in
diameter is then dried by freezing to about -40.degree. C. and
lyophilized under vacuum to produce a matrix of dried small
particles containing fenofibrate.
Example 3
[0267] A mixture of 60 parts of Lipoid E80 as the surface active
substance and 200 parts of a poorly water-soluble drug,
fenofibrate, is homogeneously dispersed in 1440 parts of 10 mM pH
8.0+/-0.2 aqueous phosphate buffer using a ProScientific 400 high
shear mixer at 2,000 to 3,600 rpm at ambient temperature for 30
minutes, and then heated to 95.degree. C., 15.degree. C. above the
melting point of the drug, during continuous high shear mixing at
2,500 to 4,000 rpm. The heated suspension is then recirculatively
homogenized for 10 batch volume cycles or passes using a
Microfluidizer M110Y operated at 3,400 to 3,600 psig while
maintained at 85.degree. C. to 99.degree. C. to form a heated
homogenate containing the drug. After 10 passes, the heated
homogenate is cooled by passage through a heat exchanger cooled by
chilled water at 5.degree. C. to 10.degree. C. and the transiently
stable cooled homogenate is further homogenized for 10 to 20 batch
volume cycles or passes using a Microfluidics M110 EH homogenizer
operated at 18,000 psig (peak) while maintained at 4.degree. C. to
13.degree. C. Between 1-2 parts of cerivastatin dissolved in 10
parts of 10 mM aqueous phosphate buffer, pH 8.0 is added to the
resulting cooled dispersion. The suspension is further mixed with a
ProScientific 400 high shear mixer at 2000 to 3000 rpm at 5.degree.
C. to 15.degree. C. for 15 minutes. The resulting suspension
comprising small particles of fenofibrate of size less than 1.0
micron in diameter and dissolved cerivastatin is then dried by
freezing to about -40.degree. C. and lyophilization under vacuum to
produce a matrix of dried small particles containing fenofibrate
and cerivastatin.
Example 4
[0268] A mixture of 60 parts of Lipoid E80 as the surface active
substance and 200 parts of a poorly water-soluble drug,
fenofibrate, is homogeneously dispersed in 1440 parts of 10 mM pH
8.0+/-0.2 aqueous phosphate buffer using a ProScientific 400 high
shear mixer at 2,000 to 3,600 rpm at ambient temperature for 30
minutes, and then heated to 95.degree. C., 15.degree. C. above the
melting point of the drug, during continuous high shear mixing at
2,500 to 4,000 rpm. The heated suspension is then recirculatively
homogenized for 10 batch volume cycles or passes using a
Microfluidizer M110Y homogenizer operated at 3,400 to 3,600 psig
while maintained at 85.degree. C. to form a heated homogenate
containing drug. After 10 passes, the heated homogenate is cooled
by passage through a heat exchanger chilled with ice water, and to
the transiently stable cooled homogenate is added 10 to 30 parts of
simvastatin followed by further homogenization for 10 to 20 batch
volume cycles or passes using a Microfluidics M110 EH homogenizer
operated at 18,000 psig (peak) while maintained between 4.degree.
C. and 15.degree. C. The resulting cooled dispersion comprising
small particles containing the drug of size less than 1.0 micron in
diameter is treated with a solution of 200 parts of sucrose plus
100 parts of sorbitol as bulking agents in additional aqueous
carrier and is then dried by freezing in liquid nitrogen and
lyophilization under vacuum to produce a matrix of dried small
particles containing fenofibrate and simvastatin.
Example 5
[0269] A mixture of 60 parts of Lipoid E80 as the surface active
substance and 200 parts of a poorly water-soluble drug,
fenofibrate, is homogeneously dispersed in 1440 parts of 10 mM pH
8.0+/-0.2 aqueous phosphate buffer using a ProScientific 400 high
shear mixer at 2,000 to 3,600 rpm at ambient temperature for 30
minutes, and then heated to 95.degree. C., 15.degree. C. above the
melting point of the drug, during continuous high shear mixing at
2,500 to 4,000 rpm. The heated suspension is then recirculatively
homogenized for 10 batch volume cycles or passes using a
Microfluidizer M110Y homogenizer operated at 3,400 to 3,600 psig
while maintained at 85.degree. C. to form a heated homogenate
containing drug. After 10 passes, the heated homogenate is cooled
by passage through a heat exchanger chilled with ice water, kept at
4.degree. C. for 30 min, and the transiently stable cooled
homogenate is further homogenized for 10 to 20 batch volume cycles
or passes using a Microfluidics M110 EH homogenizer operated at
18,000 psig (peak) while maintained between 4.degree. C. and
15.degree. C. Between 1 to 2 parts of cerivastatin dissolved in 10
parts of 10 mM aqueous phosphate buffer, pH 8.0 is added to the
resulting cooled dispersion. The suspension is further mixed with a
ProScientific 44 high shear mixer at 2000 to 3000 rpm at 5.degree.
C. to 15.degree. C. for 15 minutes. The resulting suspension
comprising small particles of fenofibrate of size less than 1.0
micron in diameter and dissolved cerivastatin is treated with a
solution of 200 parts of sucrose plus 100 parts of sorbitol as
bulking agents in additional aqueous carrier and is then dried by
freezing in liquid nitrogen and lyophilization under vacuum to
produce a matrix of dried small particles containing fenofibrate
and cerivastatin.
* * * * *