U.S. patent application number 10/665520 was filed with the patent office on 2004-03-25 for processes for producing fenofibrate compositions.
Invention is credited to Seth, Pawan, Stamm, Andre.
Application Number | 20040058005 10/665520 |
Document ID | / |
Family ID | 9502710 |
Filed Date | 2004-03-25 |
United States Patent
Application |
20040058005 |
Kind Code |
A1 |
Stamm, Andre ; et
al. |
March 25, 2004 |
Processes for producing fenofibrate compositions
Abstract
The invention provides processes for producing fenofibrate
compositions.
Inventors: |
Stamm, Andre; (Griesheim,
FR) ; Seth, Pawan; (Irvine, CA) |
Correspondence
Address: |
Edward D. Grieff, Esq.
HALE AND DORR LLP
1455 Pennsylvania Avenue, NW
Washington
DC
20004
US
|
Family ID: |
9502710 |
Appl. No.: |
10/665520 |
Filed: |
September 22, 2003 |
Related U.S. Patent Documents
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Application
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Filing Date |
Patent Number |
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10665520 |
Sep 22, 2003 |
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10288425 |
Nov 6, 2002 |
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6652881 |
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10288425 |
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10126875 |
Apr 22, 2002 |
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6589552 |
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10126875 |
Apr 22, 2002 |
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10078500 |
Feb 21, 2002 |
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6596317 |
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10078500 |
Feb 21, 2002 |
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09899026 |
Jul 6, 2001 |
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09899026 |
Jul 6, 2001 |
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09572330 |
May 18, 2000 |
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6277405 |
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09572330 |
May 18, 2000 |
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09005128 |
Jan 9, 1998 |
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6074670 |
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10665520 |
Sep 22, 2003 |
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10290333 |
Nov 8, 2002 |
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Current U.S.
Class: |
424/489 ;
514/571 |
Current CPC
Class: |
A61K 9/1676 20130101;
A61K 9/1617 20130101; A61K 9/2054 20130101; A61P 1/18 20180101;
A61P 3/04 20180101; A61K 9/16 20130101; A61K 9/1623 20130101; A61K
31/216 20130101; A61K 9/2027 20130101; A61K 31/215 20130101; A61P
3/06 20180101; A61K 31/12 20130101; A61K 9/14 20130101; A61K 9/1635
20130101; A61K 9/2077 20130101; A61K 9/2081 20130101 |
Class at
Publication: |
424/489 ;
514/571 |
International
Class: |
A61K 009/14; A61K
031/19 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 17, 1997 |
FR |
97 00 479 |
Claims
What is claimed is:
1. A process for producing a fenofibrate composition comprising:
(i) preparing a suspension comprising at least one hydrophilic
polymer, and micronized fenofibrate; (ii) spraying the suspension
onto inert carriers.
2. The process of claim 1, wherein step (i) of preparing the
suspension comprises (a) preparing a solution comprising at least
one hydrophilic polymer and (b) adding the micronized fenofibrate
to said solution to produce the suspension.
3. The process of claim 1, wherein step (i) of preparing the
suspension comprises (a) preparing a solution comprising at least
one hydrophilic polymer by dissolving said hydrophilic polymer and
(b) adding the micronized fenofibrate to said solution to produce
the suspension.
4. The process of claim 1, wherein step (i) of preparing the
suspension comprises (a) adding the micronized fenofibrate to a
solution to form the suspension, and (b) dissolving at least one
hydrophilic polymer in the suspension.
5. The process of claim 1, wherein the suspension is an aqueous
suspension.
6. The process of claim 1, wherein the suspension further comprises
at least one surfactant.
7. The process of claim 1, wherein said suspension comprises
fenofibrate and hydrophilic polymer in a weight ratio of
fenofibrate/hydrophilic polymer between 1/10 and 4/1.
8. The process of claim 1, wherein said suspension comprises
fenofibrate and hydrophilic polymer in a weight ratio of
fenofibrate/hydrophilic polymer between 1/2 and 2/1.
9. The process of claim 1, wherein the fenofibrate has a particle
size less than 20 .mu.m.
10. The process of claim 1, wherein the fenofibrate has a particle
size less than 10 .mu.m.
11. The process of claim 1, wherein said suspension comprises
fenofibrate in an amount from 1 to 40% by weight.
12. The process of claim 1, wherein said suspension comprises
fenofibrate in an amount from 10 to 25% by weight.
13. The process of claim 1, wherein said suspension comprises the
hydrophilic polymer in an amount from 5 to 40% by weight.
14. The process of claim 1, wherein said suspension comprises the
hydrophilic polymer in an amount from 10 to 25% by weight.
15. The process of claim 1, wherein the hydrophilic polymer is a
polyvinylpyrrolidone, a poly(vinyl alcohol), a
hydroxypropylcellulose, a hydroxymethylcellulose, a
hydroxypropylmethylcellulose, a gelatin, or a mixture of two or
more thereof.
16. The process of claim 1, wherein the hydrophilic polymer is a
polyvinylpyrrolidone.
17. The process of claim 6, wherein said suspension comprises the
surfactant in an amount of up to 10% by weight.
18. The process of claim 6, wherein said suspension comprises the
surfactant in an amount of up to 5% by weight.
19. The process of claim 6, wherein said suspension comprises
surfactant and hydrophilic polymer in a weight ratio of
surfactant/hydrophilic polymer between 1/500 and 1/10.
20. The process of claim 6, wherein said suspension comprises
surfactant and hydrophilic polymer in a weight ratio of
surfactant/hydrophilic polymer between 1/100 and 5/100.
21. The process of claim 6, wherein the surfactant is sodium lauryl
sulfate, monooleate, monolaurate, monopaimitate, monostearate or
another ester of polyoxyethylene sorbitane, sodium
dioctylsulfosuccinate, lecithin, stearylic alcohol, cetostearylic
alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene
fatty acid glycerides, poloxamer, or a mixture of two or more
thereof.
22. The process of claim 6, wherein the surfactant is sodium lauryl
sulfate.
23. The process of claim 1, wherein the inert carriers are inert
hydrosoluble carriers.
24. The process of claim 1, wherein step (ii) comprises spraying
the suspension onto inert carriers to form granulates.
25. The process of claim 24, further comprising step (iii)
comprising compressing the granulates to form the fenofibrate
tablet.
26. The process of claim 25, which further comprises, between steps
(ii) and (iii), mixing the granulates with at least one
pharmaceutical excipient.
27. The process of claim 26, wherein said pharmaceutical excipient
is selected from the group consisting of at least one binder, at
least one filler, at least one pigment, at least one disintegrating
agent, at least one lubricant, at least one wetting agent, at least
one buffer, and a mixture of two or more thereof.
28. The process of claim 26, wherein said pharmaceutical excipient
is selected from the group consisting of microcrystalline
cellulose, lactose, starch, colloidal silica, talc, glycerol
esters, sodium stearyl fumarate, titanium dioxide, magnesium
stearate, stearic acid, cross-linked polyvinyl pyrrolidone,
carboxymethyl starch, hydroxypropylcellulose,
hydroxymethylcellulose, hydroxypropylmethylcellul- ose, gelatin,
and a mixture of two or more thereof.
29. A process for producing a fenofibrate tablet comprising: (i)
preparing a suspension comprising at least one hydrophilic polymer,
and micronized fenofibrate; (ii) spraying the suspension onto inert
carriers to form granulates; and (iii) compressing the granulates
to form the fenofibrate tablet.
30. The process of claim 29, wherein step (i) of preparing the
suspension comprises (a) preparing a solution comprising at least
one hydrophilic polymer and (b) adding the micronized fenofibrate
to said solution to produce the suspension.
31. The process of claim 29, wherein step (i) of preparing the
suspension comprises (a) preparing a solution comprising at least
one hydrophilic polymer by dissolving said hydrophilic polymer and
(b) adding the micronized fenofibrate to said solution to produce
the suspension.
32. The process of claim 29, wherein step (i) of preparing the
suspension comprises (a) adding the micronized fenofibrate to a
solution to form the suspension, and (b) dissolving at least one
hydrophilic polymer in the suspension.
33. The process of claim 29, wherein the suspension is an aqueous
suspension.
34. The process of claim 29, wherein the suspension further
comprises at least one surfactant.
35. The process of claim 29, wherein said suspension comprises
fenofibrate and hydrophilic polymer in a weight ratio of
fenofibrate/hydrophilic polymer between 1/10 and 4/1.
36. The process of claim 29, wherein said suspension comprises
fenofibrate and hydrophilic polymer in a weight ratio of
fenofibrate/hydrophilic polymer between 1/2 and 2/1.
37. The process of claim 29, wherein the fenofibrate has a particle
size less than 20 .mu.m.
38. The process of claim 29, wherein the fenofibrate has a particle
size less than 10 .mu.m.
39. The process of claim 29, wherein said suspension comprises
fenofibrate in an amount from 1 to 40% by weight.
40. The process of claim 29, wherein said suspension comprises
fenofibrate in an amount from 10 to 25% by weight.
41. The process of claim 29, wherein said suspension comprises the
hydrophilic polymer in an amount from 5 to 40% by weight.
42. The process of claim 29, wherein said suspension comprises the
hydrophilic polymer in an amount from 10 to 25% by weight.
43. The process of claim 29, wherein the hydrophilic polymer is a
polyvinylpyrrolidone, a poly(vinyl alcohol), a
hydroxypropylcellulose, a hydroxymethylcellulose, a
hydroxypropylmethylcellulose, a gelatin, or a mixture of two or
more thereof.
44. The process of claim 29, wherein the hydrophilic polymer is a
polyvinylpyrrolidone.
45. The process of claim 34, wherein said suspension comprises the
surfactant in an amount of up to 10% by weight.
46. The process of claim 34, wherein said suspension comprises the
surfactant in an amount of up to 5% by weight.
47. The process of claim 34, wherein said suspension comprises
surfactant and hydrophilic polymer in a weight ratio of
surfactant/hydrophilic polymer between 1/500 and 1/10.
48. The process of claim 34, wherein said suspension comprises
surfactant and hydrophilic polymer in a weight ratio of
surfactant/hydrophilic polymer between 1/100 and 5/100.
49. The process of claim 34, wherein the surfactant is sodium
lauryl sulfate, monooleate, monolaurate, monopalmitate,
monostearate or another ester of polyoxyethylene sorbitane, sodium
dioctylsulfosuccinate, lecithin, stearylic alcohol, cetostearylic
alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene
fatty acid glycerides, poloxamer, or a mixture of two or more
thereof.
50. The process of claim 34, wherein the surfactant is sodium
lauryl sulfate.
51. The process of claim 29, wherein the inert carriers are inert
hydrosoluble carriers.
52. The process of claim 29, which further comprises, between steps
(ii) and (iii), mixing the granulates with at least one
pharmaceutical excipient.
53. The process of claim 52, wherein said pharmaceutical excipient
is selected from the group consisting of at least one binder, at
least one filler, at least one pigment, at least one disintegrating
agent, at least one lubricant, at least one wetting agent, at least
one buffer, and a mixture of two or more thereof.
54. The process of claim 52, wherein said pharmaceutical excipient
is selected from the group consisting of microcrystalline
cellulose, lactose, starch, colloidal silica, talc, glycerol
esters, sodium stearyl fumarate, titanium dioxide, magnesium
stearate, stearic acid, cross-linked polyvinyl pyrrolidone,
carboxymethyl starch, hydroxypropylcellulose,
hydroxymethylcellulose, hydroxypropylmethylcellul- ose, gelatin,
and a mixture of two or more thereof.
55. A process for producing a fenofibrate composition comprising:
(i) preparing an aqueous suspension comprising at least one
hydrophilic polymer, at least one surfactant, and micronized
fenofibrate; (ii) spraying the aqueous suspension onto inert
carriers.
56. The process of claim 55, wherein step (i) of preparing the
aqueous suspension comprises (a) preparing an aqueous solution
comprising at least one surfactant and at least one hydrophilic
polymer and (b) adding the micronized fenofibrate to said aqueous
solution to produce the aqueous suspension.
57. The process of claim 55, wherein step (i) of preparing the
aqueous suspension comprises (a) preparing an aqueous solution
comprising at least one surfactant and at least one hydrophilic
polymer by dissolving said surfactant and hydrophilic polymer and
(b) adding the micronized fenofibrate to said aqueous solution to
produce the aqueous suspension.
58. The process of claim 55, wherein step (i) of preparing the
aqueous suspension comprises (a) dissolving at least one surfactant
in an aqueous solution, (b) dissolving at least one hydrophilic
polymer in the aqueous solution, and (c) adding the micronized
fenofibrate to said aqueous solution to produce the aqueous
suspension.
59. The process of claim 55, wherein step (i) of preparing the
aqueous suspension comprises (a) dissolving at least one
hydrophilic polymer in an aqueous solution, (b) dissolving at least
one surfactant in the aqueous solution, and (c) adding the
micronized fenofibrate to said aqueous solution to form the aqueous
suspension.
60. The process of claim 55, wherein step (i) of preparing the
aqueous suspension comprises (a) dissolving at least one surfactant
in an aqueous solution, (b) adding the micronized fenofibrate to
said aqueous solution to form the aqueous suspension, and (c)
dissolving at least one hydrophilic polymer in the aqueous
suspension.
61. The process of claim 55, wherein step (i) of preparing the
aqueous suspension comprises (a) dissolving at least one
hydrophilic polymer in an aqueous solution, (b) adding the
micronized fenofibrate to said aqueous solution to form the aqueous
suspension, and (c) dissolving at least one surfactant in the
aqueous suspension.
62. The process of claim 55, wherein step (i) of preparing the
aqueous suspension comprises (a) adding the micronized fenofibrate
to an aqueous solution to form the aqueous suspension, (b)
dissolving at least one surfactant in the aqueous suspension, and
(c) dissolving at least one hydrophilic polymer in the aqueous
suspension.
63. The process of claim 55, wherein step (i) of preparing the
aqueous suspension comprises (a) adding the micronized fenofibrate
to an aqueous solution to form the aqueous suspension, (b)
dissolving at least one hydrophilic polymer in the aqueous
suspension, and (c) dissolving at least one surfactant in the
aqueous suspension.
64. The process of claim 55, wherein said suspension comprises
fenofibrate and hydrophilic polymer in a weight ratio of
fenofibrate/hydrophilic polymer between 1/10 and 4/1.
65. The process of claim 55, wherein said suspension comprises
fenofibrate and hydrophilic polymer in a weight ratio of
fenofibrate/hydrophilic polymer between 1/2 and 2/1.
66. The process of claim 55, wherein the fenofibrate has a particle
size less than 20 .mu.m.
67. The process of claim 55, wherein the fenofibrate has a particle
size less than 10 .mu.m.
68. The process of claim 55, wherein said suspension comprises
fenofibrate in an amount from 1 to 40% by weight.
69. The process of claim 55, wherein said suspension comprises
fenofibrate in an amount from 10 to 25% by weight.
70. The process of claim 55, wherein said suspension comprises the
hydrophilic polymer in an amount from 5 to 40% by weight.
71. The process of claim 55, wherein said suspension comprises the
hydrophilic polymer in an amount from 10 to 25% by weight.
72. The process of claim 55, wherein the hydrophilic polymer is a
polyvinylpyrrolidone, a poly(vinyl alcohol), a
hydroxypropylcellulose, a hydroxymethylcellulose, a
hydroxypropylmethylcellulose, a gelatin, or a mixture of two or
more thereof.
73. The process of claim 55, wherein the hydrophilic polymer is a
polyvinylpyrrolidone.
74. The process of claim 55 wherein said suspension comprises the
surfactant in an amount of up to 10% by weight.
75. The process of claim 55, wherein said suspension comprises the
surfactant in an amount of up to 5% by weight.
76. The process of claim 55, wherein said suspension comprises
surfactant and hydrophilic polymer in a weight ratio of
surfactant/hydrophilic polymer between 1/500 and 1/10.
77. The process of claim 55, wherein said suspension comprises
surfactant and hydrophilic polymer in a weight ratio of
surfactant/hydrophilic polymer between 1/100 and 5/100.
78. The process of claim 55, wherein the surfactant is sodium
lauryl sulfate, monooleate, monolaurate, monopalmitate,
monostearate or another ester of polyoxyethylene sorbitane, sodium
dioctylsulfosuccinate, lecithin, stearylic alcohol, cetostearylic
alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene
fatty acid glycerides, poloxamer, or a mixture of two or more
thereof.
79. The process of claim 55, wherein the surfactant is sodium
lauryl sulfate.
80. The process of claim 55, wherein the inert carriers are inert
hydrosoluble carriers.
81. The process of claim 55, wherein step (ii) comprises spraying
the suspension onto inert carriers to form granulates.
82. The process of claim 55, further comprising step (iii)
comprising compressing the granulates to form the fenofibrate
tablet.
83. The process of claim 82, which further comprises, between steps
(ii) and (iii), mixing the granulates with at least one
pharmaceutical excipient.
84. The process of claim 83, wherein said pharmaceutical excipient
is selected from the group consisting of at least one binder, at
least one filler, at least one pigment, at least one disintegrating
agent, at least one lubricant, at least one wetting agent, at least
one buffer, and a mixture of two or more thereof.
85. The process of claim 83, wherein said pharmaceutical excipient
is selected from the group consisting of microcrystalline
cellulose, lactose, starch, colloidal silica, talc, glycerol
esters, sodium stearyl fumarate, titanium dioxide, magnesium
stearate, stearic acid, cross-linked polyvinyl pyrrolidone,
carboxymethyl starch, hydroxypropylcellulose,
hydroxymethylcellulose, hydroxypropylmethylcellul- ose, gelatin,
and a mixture of two or more thereof.
86. A process for producing a fenofibrate tablet comprising: (i)
preparing an aqueous suspension comprising at least one surfactant,
at least one hydrophilic polymer, and micronized fenofibrate; (ii)
spraying the aqueous suspension onto inert carriers to form
granulates; and (iii) compressing the granulates to form the
fenofibrate tablet.
87. The process of claim 86, wherein step (i) of preparing the
aqueous suspension comprises (a) preparing an aqueous solution
comprising at least one surfactant and at least one hydrophilic
polymer and (b) adding the micronized fenofibrate to said aqueous
solution to produce the aqueous suspension.
88. The process of claim 86, wherein step (i) of preparing the
aqueous suspension comprises (a) preparing an aqueous solution
comprising at least one surfactant and at least one hydrophilic
polymer by dissolving said surfactant and hydrophilic polymer and
(b) adding the micronized fenofibrate to said aqueous solution to
produce the aqueous suspension.
89. The process of claim 86, wherein step (i) of preparing the
aqueous suspension comprises (a) dissolving at least one surfactant
in an aqueous solution, (b) dissolving at least one hydrophilic
polymer in the aqueous solution, and (c) adding the micronized
fenofibrate to said aqueous solution to produce the aqueous
suspension.
90. The process of claim 86, wherein step (i) of preparing the
aqueous suspension comprises (a) dissolving at least one
hydrophilic polymer in an aqueous solution, (b) dissolving at least
one surfactant in the aqueous solution, and (c) adding the
micronized fenofibrate to said aqueous solution to form the aqueous
suspension.
91. The process of claim 86, wherein step (i) of preparing the
aqueous suspension comprises (a) dissolving at least one surfactant
in an aqueous solution, (b) adding the micronized fenofibrate to
said aqueous solution to form the aqueous suspension, and (c)
dissolving at least one hydrophilic polymer in the aqueous
suspension.
92. The process of claim 86, wherein step (i) of preparing the
aqueous suspension comprises (a) dissolving at least one
hydrophilic polymer in an aqueous solution, (b) adding the
micronized fenofibrate to said aqueous solution to form the aqueous
suspension, and (c) dissolving at least one surfactant in the
aqueous suspension.
93. The process of claim 86, wherein said suspension comprises
fenofibrate and hydrophilic polymer in a weight ratio of
fenofibrate/hydrophilic polymer between 1/10 and 4/1.
94. The process of claim 86, wherein said suspension comprises
fenofibrate and hydrophilic polymer in a weight ratio of
fenofibrate/hydrophilic polymer between 1/2 and 2/1.
95. The process of claim 86, wherein the fenofibrate has a particle
size less than 20 .mu.m.
96. The process of claim 86, wherein the fenofibrate has a particle
size less than 10 .mu.m.
97. The process of claim 86, wherein said suspension comprises
fenofibrate in an amount from 1 to 40% by weight.
98. The process of claim 86, wherein said suspension comprises
fenofibrate in an amount from 10 to 25% by weight.
99. The process of claim 86, wherein said suspension comprises the
hydrophilic polymer in an amount from 5 to 40% by weight.
100. The process of claim 86, wherein said suspension comprises the
hydrophilic polymer in an amount from 10 to 25% by weight.
101. The process of claim 86, wherein the hydrophilic polymer is a
polyvinylpyrrolidone, a poly(vinyl alcohol), a
hydroxypropylcellulose, a hydroxymethylcellulose, a
hydroxypropylmethylcellulose, a gelatin, or a mixture of two or
more thereof.
102. The process of claim 86, wherein the hydrophilic polymer is a
polyvinylpyrrolidone.
103. The process of claim 86, wherein said suspension comprises the
surfactant in an amount of up to 10% by weight.
104. The process of claim 86, wherein said suspension comprises the
surfactant in an amount of up to 5% by weight.
105. The process of claim 86, wherein said suspension comprises
surfactant and hydrophilic polymer in a weight ratio of
surfactant/hydrophilic polymer between 1/500 and 1/10.
106. The process of claim 86, wherein said suspension comprises
surfactant and hydrophilic polymer in a weight ratio of
surfactant/hydrophilic polymer between 1/100 and 5/100.
107. The process of claim 86, wherein the surfactant is sodium
lauryl sulfate, monooleate, monolaurate, monopalmitate,
monostearate or another ester of polyoxyethylene sorbitane, sodium
dioctylsulfosuccinate, lecithin, stearylic alcohol, cetostearylic
alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene
fatty acid glycerides, poloxamer, or a mixture of two or more
thereof.
108. The process of claim 86, wherein the surfactant is sodium
lauryl sulfate.
109. The process of claim 86, wherein the inert carriers are inert
hydrosoluble carriers.
110. The process of claim 86, which further comprises, between
steps (ii) and (iii), mixing the granulates with at least one
pharmaceutical excipient.
111. The process of claim 110, wherein said pharmaceutical
excipient is selected from the group consisting of at least one
binder, at least one filler, at least one pigment, at least one
disintegrating agent, at least one lubricant, at least one wetting
agent, at least one buffer, and a mixture of two or more
thereof.
112. The process of claim 110, wherein said pharmaceutical
excipient is selected from the group consisting of microcrystalline
cellulose, lactose, starch, colloidal silica, talc, glycerol
esters, sodium stearyl fumarate, titanium dioxide, magnesium
stearate, stearic acid, cross-linked polyvinyl pyrrolidone,
carboxymethyl starch, hydroxypropylcellulose,
hydroxymethylcellulose, hydroxypropylmethylcellul- ose, gelatin,
and a mixture of two or more thereof.
113. A process for producing a fenofibrate composition comprising:
(i) preparing an aqueous suspension comprising
polyvinylpyrrolidone, sodium lauryl sulfate, and micronized
fenofibrate; (ii) spraying the aqueous suspension onto inert
carriers.
114. The process of claim 113, wherein step (i) of preparing the
aqueous suspension comprises (a) preparing an aqueous solution
comprising polyvinylpyrrolidone and sodium lauryl sulfate and (b)
adding the micronized fenofibrate to said aqueous solution to
produce the aqueous suspension.
115. The process of claim 113, wherein step (i) of preparing the
aqueous suspension comprises (a) preparing an aqueous solution
comprising polyvinylpyrrolidone and sodium lauryl sulfate by
dissolving said polyvinylpyrrolidone and sodium lauryl sulfate and
(b) adding the micronized fenofibrate to said aqueous solution to
produce the aqueous suspension.
116. The process of claim 113, wherein said suspension comprises
fenofibrate and polyvinylpyrrolidone in a weight ratio of
fenofibrate/polyvinylpyrrolidone between 1/10 and 4/1.
117. The process of claim 113, wherein said suspension comprises
fenofibrate and polyvinylpyrrolidone in a weight ratio of
fenofibrate/polyvinylpyrrolidone between 1/2 and 2/1.
118. The process of claim 113, wherein the fenofibrate has a
particle size less than 20 .mu.m.
119. The process of claim 113, wherein the fenofibrate has a
particle size less than 10 .mu.m.
120. The process of claim 113, wherein said suspension comprises
fenofibrate in an amount from 1 to 40% by weight.
121. The process of claim 113, wherein said suspension comprises
fenofibrate in an amount from 10 to 25% by weight.
122. The process of claim 113, wherein said suspension comprises
polyvinylpyrrolidone in an amount from 5 to 40% by weight.
123. The process of claim 113, wherein said suspension comprises
polyvinylpyrrolidone in an amount from 10 to 25% by weight.
124. The process of claim 113 wherein said suspension comprises
sodium lauryl sulfate in an amount of up to 10% by weight.
125. The process of claim 113, wherein said suspension comprises
sodium lauryl sulfate in an amount of up to 5% by weight.
126. The process of claim 113, wherein said suspension comprises
sodium lauryl sulfate and polyvinylpyrrolidone in a weight ratio of
sodium lauryl sulfate to polyvinylpyrrolidone between 1/500 and
1/10.
127. The process of claim 113, wherein said suspension comprises
sodium lauryl sulfate and polyvinylpyrrolidone in a weight ratio of
sodium lauryl sulfate to polyvinylpyrrolidone between 1/100 and
5/100.
128. The process of claim 113, wherein the inert carriers are inert
hydrosoluble carriers.
129. The process of claim 113, wherein step (ii) comprises spraying
the suspension onto inert carriers to form granulates.
130. A process for producing a fenofibrate tablet comprising: (i)
preparing an aqueous suspension comprising at least one surfactant,
at least one hydrophilic polymer, and micronized fenofibrate; by
(a) preparing an aqueous solution comprising at least one
surfactant and at least one hydrophilic polymer by dissolving said
surfactant and hydrophilic polymer and (b) adding the micronized
fenofibrate to said solution to produce the aqueous suspension;
(ii) spraying the aqueous suspension onto inert carriers to form
granulates; and (iii) compressing the granulates to form the
fenofibrate tablet.
131. The process of claim 130, wherein said suspension comprises
fenofibrate and hydrophilic polymer in a weight ratio of
fenofibrate/hydrophilic polymer between 1/10 and 4/1.
132. The process of claim 130, wherein said suspension comprises
fenofibrate and hydrophilic polymer in a weight ratio of
fenofibrate/hydrophilic polymer between 1/2 and 2/1.
133. The process of claim 130, wherein the fenofibrate has a
particle size less than 20 .mu.m.
134. The process of claim 130, wherein the fenofibrate has a
particle size less than 10 .mu.m.
135. The process of claim 130, wherein said suspension comprises
fenofibrate in an amount from 1 to 40% by weight.
136. The process of claim 130, wherein said suspension comprises
fenofibrate in an amount from 10 to 25% by weight.
137. The process of claim 130, wherein said suspension comprises
the hydrophilic polymer in an amount from 5 to 40% by weight.
138. The process of claim 130, wherein said suspension comprises
the hydrophilic polymer in an amount from 10 to 25% by weight.
139. The process of claim 130, wherein the hydrophilic polymer is a
polyvinylpyrrolidone, a poly(vinyl alcohol), a
hydroxypropylcellulose, a hydroxymethylcellulose, a
hydroxypropylmethylcellulose, a gelatin, or a mixture of two or
more thereof.
140. The process of claim 130, wherein the hydrophilic polymer is a
polyvinylpyrrolidone.
141. The process of claim 130, wherein said suspension comprises
the surfactant in an amount of up to 10% by weight.
142. The process of claim 130, wherein said suspension comprises
the surfactant in an amount of up to 5% by weight.
143. The process of claim 130, wherein said suspension comprises
surfactant and hydrophilic polymer in a weight ratio of
surfactant/hydrophilic polymer between 1/500 and 1/10.
144. The process of claim 130, wherein said suspension comprises
surfactant and hydrophilic polymer in a weight ratio of
surfactant/hydrophilic polymer between 1/100 and 5/100.
145. The process of claim 130, wherein the surfactant is sodium
lauryl sulfate, monooleate, monolaurate, monopalmitate,
monostearate or another ester of polyoxyethylene sorbitane, sodium
dioctylsulfosuccinate, lecithin, stearylic alcohol, cetostearylic
alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene
fatty acid glycerides, poloxamer, or a mixture of two or more
thereof.
146. The process of claim 130, wherein the surfactant is sodium
lauryl sulfate.
147. The process of claim 130, wherein the inert carriers are inert
hydrosoluble carriers.
148. The process of claim 130, which further comprises, between
steps (ii) and (iii), mixing the granulates with at least one
pharmaceutical excipient.
149. The process of claim 148, wherein said pharmaceutical
excipient is selected from the group consisting of at least one
binder, at least one filler, at least one pigment, at least one
disintegrating agent, at least one lubricant, at least one wetting
agent, at least one buffer, and a mixture of two or more
thereof.
150. The process of claim 148, wherein said pharmaceutical
excipient is selected from the group consisting of microcrystalline
cellulose, lactose, starch, colloidal silica, talc, glycerol
esters, sodium stearyl fumarate, titanium dioxide, magnesium
stearate, stearic acid, cross-linked polyvinyl pyrrolidone,
carboxymethyl starch, hydroxypropylcellulose,
hydroxymethylcellulose, hydroxypropylmethylcellul- ose, gelatin,
and a mixture of two or more thereof.
151. A process for producing a fenofibrate tablet comprising: (i)
preparing an aqueous suspension comprising sodium lauryl sulfate,
polyvinylpyrrolidone, and micronized fenofibrate; and wherein the
weight ratio of fenofibrate/polyvinylpyrrolidone is between 1/10
and 4/1 and the weight ratio of sodium lauryl
sulfate/polyvinylpyrrolidone being between 1/500 and 1/10; (ii)
spraying the aqueous suspension onto inert carriers to form
granulates; and (iii) compressing the granulates to form the
fenofibrate tablet.
152. The process of claim 151, wherein step (i) of preparing the
aqueous suspension comprises (a) preparing an aqueous solution
comprising sodium lauryl sulfate, polyvinylpyrrolidone and (b)
adding the micronized fenofibrate to said aqueous solution to
produce the aqueous suspension.
153. The process of claim 151, wherein step (i) of preparing the
aqueous suspension comprises (a) preparing an aqueous solution
comprising sodium lauryl sulfate, polyvinylpyrrolidone by
dissolving sodium lauryl sulfate, polyvinylpyrrolidone and (b)
adding the micronized fenofibrate to said aqueous solution to
produce the aqueous suspension.
154. The process of claim 151, wherein said suspension comprises
fenofibrate and polyvinylpyrrolidone in a weight ratio of
fenofibrate/polyvinylpyrrolidone between 1/2 and 2/1.
155. The process of claim 151, wherein the fenofibrate has a
particle size less than 20 .mu.m.
156. The process of claim 151, wherein the fenofibrate has a
particle size less than 10 .mu.m.
157. The process of claim 151, wherein said suspension comprises
fenofibrate in an amount from 1 to 40% by weight.
158. The process of claim 151, wherein said suspension comprises
fenofibrate in an amount from 10 to 25% by weight.
159. The process of claim 151, wherein said suspension comprises
polyvinylpyrrolidone in an amount from 5 to 40% by weight.
160. The process of claim 151, wherein said suspension comprises
polyvinylpyrrolidone in an amount from 10 to 25% by weight.
161. The process of claim 151, wherein said suspension comprises
sodium lauryl sulfate in an amount of up to 10% by weight.
162. The process of claim 151, wherein said suspension comprises
sodium lauryl sulfate in an amount of up to 5% by weight.
163. The process of claim 151, wherein said suspension comprises
sodium lauryl sulfate and polyvinylpyrrolidone in a weight ratio of
sodium lauryl sulfate to polyvinylpyrrolidone between 1/100 and
5/100.
164. The process of claim 151, wherein the inert carriers are inert
hydrosoluble carriers.
165. The process of claim 151, which further comprises, between
steps (ii) and (iii), mixing the granulates with at least one
pharmaceutical excipient.
166. The process of claim 165, wherein said pharmaceutical
excipient is selected from the group consisting of at least one
binder, at least one filler, at least one pigment, at least one
disintegrating agent, at least one lubricant, at least one wetting
agent, at least one buffer, and a mixture of two or more
thereof.
167. The process of claim 165, wherein said pharmaceutical
excipient is selected from the group consisting of microcrystalline
cellulose, lactose, starch, colloidal silica, talc, glycerol
esters, sodium stearyl fumarate, titanium dioxide, magnesium
stearate, stearic acid, cross-linked polyvinyl pyrrolidone,
carboxymethyl starch, hydroxypropylcellulose,
hydroxymethylcellulose, hydroxypropylmethylcellul- ose, gelatin,
and a mixture of two or more thereof.
168. A process for producing a fenofibrate tablet comprising: (i)
preparing an aqueous suspension comprising sodium lauryl sulfate,
polyvinylpyrrolidone, and micronized fenofibrate; and wherein the
weight ratio of fenofibrate/polyvinylpyrrolidone is between 1/10
and 4/1 and the weight ratio of sodium lauryl
sulfate/polyvinylpyrrolidone being between 1/500 and 1/10, by (a)
preparing an aqueous solution comprising sodium lauryl sulfate and
polyvinylpyrrolidone by dissolving said sodium lauryl sulfate and
polyvinylpyrrolidone and (b) adding the micronized fenofibrate to
said solution to produce the aqueous suspension; (ii) spraying the
aqueous suspension onto inert carriers to form granulates; and
(iii) compressing the granulates to form the fenofibrate
tablet.
169. The process of claim 168, wherein said suspension comprises
fenofibrate and polyvinylpyrrolidone in a weight ratio of
fenofibrate/polyvinylpyrrolidone between 1/2 and 2/1.
170. The process of claim 168, wherein the fenofibrate has a
particle size less than 20 .mu.m.
171. The process of claim 168, wherein the fenofibrate has a
particle size less than 10 .mu.m.
172. The process of claim 168, wherein said suspension comprises
fenofibrate in an amount from 1 to 40% by weight.
173. The process of claim 168, wherein said suspension comprises
fenofibrate in an amount from 10 to 25% by weight.
174. The process of claim 168, wherein said suspension comprises
polyvinylpyrrolidone in an amount from 5 to 40% by weight.
175. The process of claim 168, wherein said suspension comprises
polyvinylpyrrolidone in an amount from 10 to 25% by weight.
176. The process of claim 168, wherein said suspension comprises
sodium lauryl sulfate in an amount of up to 10% by weight.
177. The process of claim 168, wherein said suspension comprises
sodium lauryl sulfate in an amount of up to 5% by weight.
178. The process of claim 168, wherein said suspension comprises
sodium lauryl sulfate and polyvinylpyrrolidone in a weight ratio of
sodium lauryl sulfate to polyvinylpyrrolidone between 1/100 and
5/100.
179. The process of claim 168, wherein the inert carriers are inert
hydrosoluble carriers.
180. The process of claim 168, which further comprises, between
steps (ii) and (iii), mixing the granulates with at least one
pharmaceutical excipient.
181. The process of claim 180, wherein said pharmaceutical
excipient is selected from the group consisting of at least one
binder, at least one filler, at least one pigment, at least one
disintegrating agent, at least one lubricant, at least one wetting
agent, at least one buffer, and a mixture of two or more
thereof.
182. The process of claim 180, wherein said pharmaceutical
excipient is selected from the group consisting of microcrystalline
cellulose, lactose, starch, colloidal silica, talc, glycerol
esters, sodium stearyl fumarate, titanium dioxide, magnesium
stearate, stearic acid, cross-linked polyvinyl pyrrolidone,
carboxymethyl starch, hydroxypropylcellulose,
hydroxymethylcellulose, hydroxypropylmethylcellul- ose, gelatin,
and a mixture of two or more thereof.
183. The process of claim 1, wherein the composition comprises from
5 to 50% by weight of fenofibrate, from 10 to 75% by weight of
carrier, and from 20 to 60% by weight of hydrophilic polymer.
184. The process of claim 1, wherein the composition comprises from
20 to 45% by weight of fenofibrate, from 20 to 50% by weight of
carrier, and from 25 to 45% by weight of hydrophilic polymer.
185. The process of claim 183, wherein the composition further
comprises up to 10% by weight of surfactant.
186. The process of claim 184, wherein the composition further
comprises from 0.1 to 3% by weight of surfactant.
187. The process of claim 29, wherein the tablet comprises from 5
to 50% by weight of fenofibrate, from 10 to 75% by weight of
carrier, and from 20 to 60% by weight of hydrophilic polymer.
188. The process of claim 29, wherein the tablet comprises from 20
to 45% by weight of fenofibrate, from 20 to 50% by weight of
carrier, and from 25 to 45% by weight of hydrophilic polymer.
189. The process of claim 187, wherein the tablet further comprises
up to 10% by weight of surfactant.
190. The process of claim 188, wherein the tablet further comprises
from 0.1 to 3% by weight of surfactant.
191. The process of claim 55, wherein the composition comprises
from 5 to 50% by weight of fenofibrate, from 10 to 75% by weight of
carrier, from 20 to 60% by weight of hydrophilic polymer, and up to
10% by weight of surfactant.
192. The process of claim 55, wherein the composition comprises
from 20 to 45% by weight of fenofibrate, from 20 to 50% by weight
of carrier, from 25 to 45% by weight of hydrophilic polymer, and
from 0.1 to 3% by weight of surfactant.
193. The process of claim 86, wherein the tablet comprises from 5
to 50% by weight of fenofibrate, from 10 to 75% by weight of
carrier, from 20 to 60% by weight of hydrophilic polymer, and up to
10% by weight of surfactant.
194. The process of claim 86, wherein the tablet comprises from 20
to 45% by weight of fenofibrate, from 20 to 50% by weight of
carrier, from 25 to 45% by weight of hydrophilic polymer, and from
0.1 to 3% by weight of surfactant.
195. The process of claim 113, wherein the composition comprises
from 5 to 50% by weight of fenofibrate, from 10 to 75% by weight of
carrier, from 20 to 60% by weight of polyvinylpyrrolidone, and up
to 10% by weight of sodium lauryl sulfate.
196. The process of claim 113, wherein the composition comprises
from 20 to 45% by weight of fenofibrate, from 20 to 50% by weight
of carrier, from 25 to 45% by weight of polyvinylpyrrolidone, and
from 0.1 to 3% by weight of sodium lauryl sulfate.
197. The process of claim 130, wherein the tablet comprises from 5
to 50% by weight of fenofibrate, from 10 to 75% by weight of
carrier, from 20 to 60% by weight of hydrophilic polymer, and up to
10% by weight of surfactant.
198. The process of claim 130, wherein the tablet comprises from 20
to 45% by weight of fenofibrate, from 20 to 50% by weight of
carrier, from 25 to 45% by weight of hydrophilic polymer, and from
0.1 to 3% by weight of surfactant.
199. The process of claim 151, wherein the tablet comprises from 5
to 50% by weight of fenofibrate, from 10 to 75% by weight of
carrier, from 20 to 60% by weight of polyvinylpyrrolidone, and up
to 10% by weight of sodium lauryl sulfate.
200. The process of claim 151, wherein the tablet comprises from 20
to 45% by weight of fenofibrate, from 20 to 50% by weight of
carrier, from 25 to 45% by weight of polyvinylpyrrolidone, and from
0.1 to 3% by weight of sodium lauryl sulfate.
201. The process of claim 168, wherein the tablet comprises from 5
to 50% by weight of fenofibrate, from 10 to 75% by weight of
carrier, from 20 to 60% by weight of polyvinylpyrrolidone, and up
to 10% by weight of sodium lauryl sulfate.
202. The process of claim 168, wherein the tablet comprises from 20
to 45% by weight of fenofibrate, from 20 to 50% by weight of
carrier, from 25 to 45% by weight of polyvinylpyrrolidone, and from
0.1 to 3% by weight of sodium lauryl sulfate.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 10/288,425 filed Nov. 6, 2002; which is a continuation of U.S.
application Ser. No. 10/126,875 filed Apr. 22, 2002, issued as U.S.
Pat. No. 6,589,552; which is a continuation of U.S. application
Ser. No. 10/078,500 filed Feb. 21, 2002, issued as U.S. Pat. No.
6,596,317; which is a continuation of U.S. application Ser. No.
09/899,026 filed Jul. 6, 2001; which is a continuation of U.S.
application Ser. No. 09/572,330 filed May 18, 2000, issued as U.S.
Pat. No. 6,277,405; which is a continuation of U.S. application
Ser. No. 09/005,128 filed Jan. 9, 1998, issued as U.S. Pat. No.
6,074,670; which claims priority to French Application No. 97 00
479 filed Jan. 17, 1997. This application is also a continuation of
U.S. application Ser. No. 10/290,333 filed Nov. 8, 2002.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to a novel pharmaceutical
composition having high bioavailability through improved
dissolution, and a method for preparing it. The invention more
particularly relates to a pharmaceutical composition for
administration by oral route, containing an active ingredient of
poor aqueous solubility.
[0003] Numerous active ingredients suffer from the disadvantage of
being poorly soluble in an aqueous medium, thus having an
insufficient dissolution profile and, consequently, poor
bioavailability within the organism, following oral administration.
The therapeutic dose required to be administered must thus be
increased in order to obviate this disadvantage. This particularly
applies to numerous hypolipemiant active ingredients, such as those
belonging to the fibrate family.
[0004] Fenofibrate is a well-known hypolipemiant from the family of
fibrates, which is commercially available in various doses (100 and
300 mg for example Secalip.RTM.) but in a form leading to poor
bioavailability of the active ingredient. Indeed, due to it poor
hydrosolubility, fenofibrate is poorly absorbed in the digestive
tract and consequently its bioavailability is incomplete, irregular
and often varies from one person to another.
[0005] To improve the dissolution profile of fenofibrate and its
bioavailability, thereby reducing the dose requiring to be
administered, it would be useful to increase its dissolution so
that it could attain a level close to 100%.
[0006] Moreover, for patient comfort, it is advantageous to seek a
dosage form that only requires the medicament to be taken once
daily while giving the same effect as one administered several
times daily.
[0007] EP-A-0330532 discloses a method for improving
bioavailability of fenofibrate. This patent describes the effect of
co-micronizing fenofibrate with a surfactant, for example sodium
laurylsulfate in order to improve fenofibrate solubility and
thereby increase its bioavailability. This patent teaches that
co-micronizing fenofibrate with a solid surfactant improves
fenofibrate bioavailability to a much greater extent than the
improvement that would be obtained either by adding a surfactant,
or through solely micronizing the fenofibrate, or, yet again,
through intimately mixing the fenofibrate and surfactant,
micronized separately. The dissolution method employed is the
conventional rotating blade technique (European Pharmacopoeia):
product dissolution kinetics are measured in a fixed volume of the
dissolution medium, agitated by means of a standardized device; a
test was also carried out with an alternative technique to the
European Pharmacopoeia, using the continuous-flow cell method.
[0008] The process of EP-A-0330532 leads to a new dosage form in
which the active ingredient, co-micronized with a solid surfactant,
has improved fenofibrate dissolution, and thus increased
bioavailability, which makes it possible, for a given level of
effectiveness, to decrease the daily dose of the medicament:
respective 67 mg and 200 mg instead of 100 mg and 300 mg.
[0009] However, the preparation method in that patent is not
completely satisfactory inasmuch as it does not lead to complete
bioavailability of the active ingredient, and suffers from several
disadvantages. The technique of co-micronizing fenofibrate with a
solid surfactant does, it is true, improve dissolution of the
active ingredient, but this dissolution remains, however,
incomplete.
[0010] There is thus a need to improve fenofibrate bioavailability
in order to attain, over very short periods of time, a level close
to 100% (or, in any case, better than the following limits: 10% in
5 minutes, 20% in 10 minutes, 50% in 20 minutes and 75% in 30
minutes in a medium consisting of 1200 ml water to which 2%
Polysorbate 80 is added, or of 1000 ml of water to which 0.025M
sodium lauryl sulfate sodium is added, with a blade rotation speed
of 75 rpm), and this even when dissolution media having a low
surfactant content are used.
[0011] Applicant has found that, surprisingly, it is possible to
resolve this problem by a new method for preparing a pharmaceutical
composition by spraying a suspension of the active ingredient onto
an inert hydrosoluble carrier. The present invention also relates
to pharmaceutical compositions thus prepared.
[0012] The use is already known of a polymer, such as
polyvinylpyrrolidone for producing tablets, in concentrations of
the order of 0.5 to 5% by weight, at a maximum 10% by weight. In
this case, the polyvinylpyrrolidone is used as a binder. Similarly,
the use of a polymer such as hydroxymethylpropylmethyl cellulose as
a granulation binder is known. Thus, European patent application
0,519,144 discloses pellets of a poorly soluble substance,
omeprazole, obtained by spraying a dispersion or suspension of the
active ingredient in a solution containing said polymer onto inert
pellets in a fluidized-bed granulator. However, here again, the
polymer (HPMC and HPC) is only used as a granulation binder, in an
amount of about 50% by weight, based on the weight of the active
ingredient, which, bearing in mind the presence of the inert
pellets of a large size (about 700 .mu.m) and the overall final
weight leads to final active ingredient and polymer contents which
are very low, of the order of barely a few percent based on the
weight of the final covered pellet. Finally, it will be noted that
the size of the inert pellets in this documents is fairly large,
which, in the case of fenofibrate, would lead to a final
formulation having a volume which is much too large for ready oral
administration.
[0013] The use of polymer, such as polyvinylpyrrolidone for
manufacturing "solid dispersions" is also known, obtained in
general by co-precipitation, co-fusion or liquid-phase mixing
followed by drying. What we have here is fixation of the active
ingredient in isolated microparticles on the polyvinylpyrrolidone,
which avoids problems of poor wetting of the solid and
re-agglomeration of the particles. The article "Stable Solid
Dispersion System Against Humidity" by Kuchiki et al., Yakuzaigaku,
44 No. 1, 31-37 (1984) describes such a technique for preparing
solid dispersions using polyvinylpyrrolidone. The amounts of PVP
here are very high, and the ratio between the active ingredient and
PVP are comprised between 1/1 and 1/20. In the case however there
is no inert carrier.
[0014] WO-A-96 01621 further discloses a sustained release
composition, comprising an inert core (silica in all examples)
coated with a layer which contains the active ingredient in
admixture with a hydrophilic polymer, the weight ratio active
ingredient/polymer being comprised between 10/1 and 1/2 and the
weight ratio active ingredient/inert core being comprised between
5/1 and 1/2, with an outer layer to impart the sustained release
property. These compositions can be compressed. The hydrophilic
polymer can be polyvinylpyrrolidone. This document also discloses a
process for preparing said composition; for example in a
fluidized-bed granulator one will spray a dispersion of active
ingredient in a polymer solution onto the inert cores. This
document solely relates to sustained release compositions, the
technical problem to be solved being the compression, without
damages, of the outer layer imparting the sustained release
property.
[0015] Nevertheless, nothing in the state of the art teaches nor
suggest the present invention.
SUMMARY OF THE INVENTION
[0016] Thus, the present invention provides an immediate-release
fenofibrate composition comprising:
[0017] (a) an inert hydrosoluble carrier covered with at least one
layer containing a fenofibrate active ingredient in a micronized
form having a size less than 20 .mu.m, a hydrophilic polymer and,
optionally, a surfactant; said hydrophilic polymer making up at
least 20% by weight of (a); and
[0018] (b) optionally one or several outer phase(s) or
layer(s).
[0019] In one embodiment, a surfactant is present with the active
ingredient and the hydrophilic polymer.
[0020] The invention also provides a composition comprising
fenofibrate having a dissolution of at least 10% in 5 minutes, 20%
in 10 minutes, 50% in 20 minutes and 75% in 30 minutes, as measured
using the rotating blade method at 75 rpm according to the European
Pharmacopoeia, in a dissolution medium constituted by water with 2%
by weight polysorbate 80 or in a dissolution medium constituted by
water with 0.025M sodium lauryl sulfate.
[0021] A method for preparing a pharmaceutical composition is also
provided, comprising the steps of:
[0022] (a) preparing a fenofibrate suspension in micronized form
with a particle size below 20 .mu.m, in a solution of hydrophilic
polymer and, optionally surfactant;
[0023] (b) applying the suspension from step (a) to an inert
hydrosoluble carrier;
[0024] (c) optionally, coating granules thus obtained with one or
several phase(s) or layer(s).
[0025] Step (b) is preferably carried out in a fluidized-bed
granulator.
[0026] The method can comprise a step in which products obtained
from step (b) or (c) are compressed, with or without additional
excipients.
[0027] The invention also provides a suspension of fenofibrate in
micronized form having a size less than 10 .mu.m, in a solution of
hydrophilic polymer and, optionally, surfactant.
[0028] The invention will be described in more detail in the
description which follows, with reference to the attached
drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0029] FIG. 1 is a graph of a comparative study of the dissolution
profile of a composition according to the invention, compared to
that of Lipanthyl.RTM. 200M;
[0030] FIG. 2 is a graph illustrating a comparative study of the
dissolution profile of a composition according to the invention and
that of pharmaceutical products commercially available on the
German market.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0031] The expression "in micronized form" in this invention means
a substance in a particulate form, the dimensions of the particles
being less than or equal to about 20 .mu.m.
[0032] Advantageously, this dimension is less than or equal to 10
.mu.m.
[0033] In the framework of this invention, the expression "inert
hydrosoluble carrier" means any excipient, generally hydrophilic,
pharmaceutically inert, crystalline or amorphous, in a particulate
form, not leading to a chemical reaction under the operating
conditions employed, and which is soluble in an aqueous medium,
notably in a gastric acid medium. Examples of such excipients are
derivatives of sugars, such as lactose, saccharose, hydrolyzed
starch (malto-dextrine), etc. Mixture are also suitable. The
individual particle size of the inert hydrosoluble carrier can be,
for example, between 50 and 500 micron.
[0034] The expression "hydrophilic polymer" in the invention should
be taken to mean any high molecular weight substance (greater, for
example, than 300) having sufficient affinity towards water to
dissolve therein and form a gel. Examples of such polymers are
polyvinylpyrrolidone, poly(vinyl alcohol), hydroxypropylcellulose,
hydroxymethylcellulose, hydroxypropylmethylcellulose, gelatin, etc.
Polymer blends are also suitable.
[0035] The preferred hydrophilic polymer is polyvinylpyrrolidone
(PVP). The PVP used in this invention has, for example, a molecular
weight comprised between 10,000 and 100,000, preferably for example
between 20,000 and 55,000.
[0036] The term "surfactant" is used in its conventional sense in
this invention. Any surfactant is suitable, whether it be
amphoteric, non-ionic, cationic or anionic. Examples of such
surfactants are: sodium lauryl sulfate, monooleate, monolaurate,
monopalmitate, monostearate or another ester of polyoxyethylene
sorbitane, sodium dioctylsulfosuccinate (DOSS), lecithin, stearylic
alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene ricin
oil, polyoxyethylene fatty acid glycerides, poloxamer.RTM., etc.
Mixtures of surfactants are also suitable.
[0037] The preferred surfactant is sodium laurylsulfate, which can
be co-micronized with fenofibrate.
[0038] The compositions according to the invention can additionally
contain any excipient conventionally used in the pharmaceutical and
chemical fields which is compatible with the active ingredient,
such as binders, fillers, pigments, disintegrating agents,
lubricants, wetting agents, buffers, etc. As examples, excipients
able to be used in this invention we can cite: microcrystalline
cellulose, lactose, starch, colloidal silica, talc, glycerol
esters, sodium stearyl fumarate, titanium dioxide, magnesium
stearate, stearic acid, cross-linked polyvinyl pyrrolidone (AC DI
SOL.RTM.), carboxymethyl starch (Explotab.RTM., Primojel.RTM.),
hydroxypropylcellulose, hydroxymethylcellulose,
hydroxypropylmethylcellulose, gelatin, etc.
[0039] Here, the expression "outer phase or layer" should be taken
to mean any coating on the element (a) with the active ingredient
(forming a "core"). Indeed, it can be useful to have available one
or several phase(s) or layer(s) on top of the coated core. The
invention thus covers a single core with one layer, but also
several cores in a phase, as is the case of tablets which are
formed from "cores" mixed with a phase.
[0040] This outer layer comprises conventional excipients.
[0041] It is also possible to provide a layer comprising additives,
for the manufacture of tablets. In this embodiment, the outer layer
comprises a disintegration agent and, for example, a lubricant; the
thus covered and mixed granules can then be readily compressed and
easily disintegrate in water.
[0042] The compositions according to the invention comprise, in
general, based on the total composition weight excluding the outer
phase or layer, an inert hydrosoluble carrier making up from 10 to
80% by weight, preferably 20 to 50% by weight, the fenofibrate
representing from 5 to 50% by weight, preferably from 20 to 45% by
weight, the hydrophilic polymer representing from 20 to 60% by
weight, preferably 25 to 45% by weight, the surfactant making up
from 0 to 10% by weight, preferably 0.1 to 3% by weight.
[0043] The outer layer or phase if present, can make up to 80% by
weight of the total weight, preferably up to 50% by weight.
[0044] The hydrophilic polymer represents preferably more than 25%
by weight, based on the weight of (a).
[0045] The weight ratio of fenofibrate/hydrophilic polymer can for
example be comprised between 1/10 and 4/1, preferably, for example,
between 1/2 and 2/1.
[0046] When a surfactant is employed, the weight ratio
surfactant/hydrophilic polymer can be comprised for example between
1/500 and 1/10, preferably, for example, between 1/100 and
5/100.
[0047] In one embodiment, the composition according to the
invention takes the form of tablets.
[0048] This tablet preferably results from the compression of
elements (a) (under the form of granules) together with an outer
phase.
[0049] In another embodiment, the composition of the invention
takes the form of granules enclosed inside a capsule, for example
in gelatin, or inside a bag.
[0050] The compositions of the invention are particularly suitable
for administering active ingredients by oral route.
[0051] The composition according to the invention is prepared by a
novel process comprising spraying a suspension of the active
ingredient in a micronized form in a solution of a hydrophilic
polymer and, optionally, a surfactant, onto the inert core.
[0052] When a surfactant is present, the active ingredient can be
co-micronized with the surfactant. One will then use with advantage
the teachings of EP-A-0330532.
[0053] The method according to the invention consists in using the
fluidized bed granulation principle, but with specific starting
materials, in order to arrive at an improved dissolution profile
and thus, at elevated bioavailability. In particular, the invention
employs a suspension of the micronized active ingredient in a
solution of a hydrophilic polymer and, optionally, a
surfactant.
[0054] The fluidized-bed granulation technique is widely used in
the pharmaceutical industry for preparing capsules or tablets.
Conventionally, according to the prior art, a powder or a mixture
of powders (active ingredient+excipients) is put into suspension in
the fluidized bed in a granulator, and a solution containing a
binder and, optionally, a surfactant, is sprayed onto this bed to
form granules. The fluidized-bed granulation technique is well
known to those skilled in the art and reference should be made to
standard works such as for example "Die Tablette", by Ritschel, Ed.
Cantor Aulendorf, pages 211-212.
[0055] The invention, as has been indicated, comprises spraying a
suspension of an active ingredient micronized with a hydrophilic
polymer onto an inert carrier. Following granulation, the granulate
formed consists of crystals of, for example, lactose, which are
isolated (or possibly agglomerated together by the spray solution)
and particles of active ingredient and PVP adhering to the crystal
surface. The granule could similarly be constituted of coated
crystals which are agglomerated, or even of such an agglomerate
having received a coating.
[0056] The compositions according to the invention can also be
prepared by other methods, for example by spraying a solution of
the micronized active ingredient onto the hydrosoluble inert
carrier.
[0057] The granulates thus obtained can, if desired, be provided
with an outer coating or compressed into tablets, or form
agglomerates.
[0058] The outer layer or layer is/are applied using conventional
coating techniques such as coating in a pan or fluidized bed
coater.
[0059] When the granulate obtained (whether subsequently coated or
not) is compressed to form tablets, this step can be implemented
using any conventional technique which is suitable, for example
using an alternating or rotating compressing equipment.
[0060] The significant starting product is the suspension of the
active ingredient. This suspension is prepared by putting the
micronized active ingredient into suspension in a solution
comprising the hydrophilic polymer and, optionally, a surfactant,
in solution in a solvent. If a surfactant is employed, it is put
into solution in the solvent (beaker+magnetic or vane stirrer).
Next, the hydrophilic polymer (PVP) is dispersed, while stirring,
in the solution previously obtained. Depending on polymer
solubility, this either dissolves in the solution or forms a gel or
a suspension having varying degrees of thickness. While still
stirring, the micronized active ingredient is dispersed in the form
of a fine shower into the above solution or suspension, to form a
homogeneous suspension. The order of these steps can be reversed.
The solvent employed can be aqueous or organic (for example
ethanol). For example demineralized water can be used.
[0061] The active ingredient concentration in the suspension is
from 1 to 40% by weight, preferably from 10 to 25%.
[0062] The hydrophilic polymer concentration in the suspension is
from 5 to 40% by weight, preferably 10 to 25%.
[0063] The surfactant concentration in the suspension is from 0 to
10% by weight, preferably below 5%.
[0064] The invention also covers this novel suspension.
[0065] Without wishing to be tied down to a specific theory,
applicant believes that this novel method, through the use of a
micronized active ingredient suspension in a hydrophilic polymer
solution, enabled a novel composition to be obtained in which the
active ingredient is in a non-re-agglomerated form.
[0066] The following examples illustrate the invention without
limiting it.
EXAMPLE 1
[0067] Preparation of a pharmaceutical composition of fenofibrate
according to the invention.
[0068] A composition containing, as the element a), micronized
fenofibrate, Plasdone.RTM., Capsulac.RTM. and sodium lauryl sulfate
was prepared.
[0069] The micronized fenofibrate had a particle size of about 5
.mu.m, as measured using a Coulter counter.
[0070] The Plasdone K25.RTM. corresponds to a polyvinylpyrrolidone
PVP ISP and the Capsulac 60.RTM. corresponds to a coarse crystal
lactose monohydrate (Meggle) (particle size between 100 and 400
.mu.m).
[0071] The sodium laurylsulfate (7 g) is dissolved in water
(demineralized water, 1750 g) and the micronized fenofibrate (350
g) is put into suspension in the mixture obtained (for example
using a helix stirrer at 300 rpm for 10 minutes, then using an
Ultra Turrax agitator at 10,000 rpm, for 10 minutes). Following
this, the PVP (350 g) is added while still agitating, stirring
(helix stirrer) being continued until the latter had dissolved (30
minutes). It is all passed through a sieve (350 .mu.m) to eliminate
possible agglomerates.
[0072] Separately, the lactose (400 g) is put into suspension in a
fluidized air bed granulator (of the Glatt.RTM. GPCG1--Top Spray
type or equivalent) and heated to a temperature of 40.degree.
C.
[0073] The fenofibrate suspension is sprayed onto the lactose. This
step is carried out under the following conditions: spraying
pressure: 2.1 bar, air throughput 70 m.sup.3/h, air inlet
temperature: 45.degree. C.; air outlet temperature: 33.degree. C.;
product temperature 34.degree. C.; duration of spraying: 3 h.
[0074] The granulate thus obtained can be put inside capsules or
transformed into tablets. Any suitable conventional technique for
preparing such dosage forms can be used.
[0075] For transformation to tablet form, one will mix 191 g of the
granulate obtained (using for example a mixer-grinder type mixing
apparatus, a planetary mixer or turn-over mixer), with the outer
phase having the following composition:
[0076] 56 g Polyplasdone XL.RTM. (cross-linked polyvinylpyrrolidone
ISP, as described in the USA Pharmacopoeia "USP-NF" under the name
of crospovidone, mean molecular weight>1,000,000);
[0077] 88 g Avicel.RTM. PH200 (microcrystalline cellulose);
[0078] 3.5 g sodium stearyl fumarate (Mendell, U. S. A.); and
[0079] 2 g Aerosil.RTM. 200 (colloidal silica).
[0080] The cross-linked polyvinylpyrrolidone, the microcrystalline
cellulose, the sodium stearyl fumarate and the colloidal silica are
respectively, disintegration agents, binders, lubricating and flow
enhancing agents.
[0081] The tablet can be obtained on an alternating compression
machine (for example Korsch EKO) or a rotary machine (for example
Fette Perfecta 2).
1 element (a): micronized fenofibrate 100.0 PVP 100.0 Lactose 114.3
sodium laurylsulfate 2.0 outer phase (or layer): cross-linked PVP
92.7 microcrystalline cellulose 145.7 sodium stearyl fumarate 5.8
colloidal silica 3.3
EXAMPLE 2
[0082] Dissolution of a composition according to the invention and
a composition according to the prior art.
[0083] a) Dissolution Medium and Procedure for Measuring
Dissolution.
[0084] A dissolution medium which is discriminating, in other words
one in which two products having very different dissolution
profiles in gastric juices will have very different dissolution
curves is looked for.
[0085] For this, an aqueous medium containing a surfactant, this
being Polysorbate 80 (polyoxyethylene sorbitane mono-oleate) is
used. This surfactant is readily available from various suppliers,
is the object of a monograph in the Pharmacopoeias, and is thus
easy to implement (being also a water-soluble liquid product).
Other surfactants can also be used.
[0086] The rotating blade method (European Pharmacopoeia) is used
under the following conditions: volume of medium: 1200 ml; medium
temperature: 37.degree. C.; blade rotation speed: 75 rpm; samples
taken: every 2.5 minutes. Determination of the amount dissolved is
carried out by spectrophotometry. Test are repeated 6 times
over.
[0087] b) Results
[0088] The composition according to the invention consisted of two
tablets containing about 100 mg fenofibrate prepared according to
Example 1.
[0089] The prior art composition was Lipanthyl.RTM. 200M from
Laboratoires Fournier, containing 200 mg fenofibrate (corresponding
to capsules of 200 mg fenofibrate, co-micronized with sodium
laurylsulfate, and containing lactose, pre-gelatinized starch,
cross-linked polyvinylpyrrolidone and magnesium stearate, in line
with the teachings of EP-A-0330532).
[0090] The results obtained are shown graphically in FIG. 1, on
which the percentage of dissolution is shown, the observed standard
deviation being indicated between brackets.
[0091] These results clearly show that the compositions according
to the invention have a dissolution profile which is distinctly
better than that of the prior art compositions.
[0092] These results also clearly show that with the compositions
of the invention, the standard deviation observed is distinctly
lower than is the case with prior art compositions.
EXAMPLE 3
[0093] Study of bioavailability of compositions according to the
invention and prior art compositions.
[0094] A test of bioavailability on healthy volunteers was carried
out.
[0095] The following compositions were tested:
[0096] composition according to the invention: capsules containing
granules prepared according to example 1, containing 200 mg
fenofibrate.
[0097] first composition according to the prior art: Lipanthyl.RTM.
200M from Laboratoires Fournier, containing 200 mg fenofibrate,
identical to that in the previous example.
[0098] second prior art composition: Secalip.RTM. in capsule form
(300 mg fenofibrate in the form of three 100 mg capsules).
[0099] The study was carried out on 6 healthy volunteers receiving
a single dose of fenofibrate, with a minimum 6-day rest period
between administrations. The samples for pharmaco-kinetic analysis
were collected after each administration at the following times:
0.5 h; 1 h; 2 h; 3 h; 4 h; 5 h; 6 h; 8 h; 10 h; 12 h; 24 h; 36 h;
48 h; 72 h; and 96 hours following administration of the
medicament. Fenofibric acid content in plasma was measured for each
sample.
[0100] The results obtained are given in table 1 below.
2TABLE 1 dose Cmax tmax AUC 0-t AUC 0-.infin. Product (mg)
(.mu.g/ml) (h) t1/2 (h) (.mu.g .multidot. h/ml) (.mu.g .multidot.
h/ml) Invention 200 5.4 6 23 148 162 Secalip .RTM. 3 .times. 100
1.1 25 39 53 56 100 Lipanthyl .RTM. 200 1.6 8.3 41 71 92 200 M
Cmax: maximum plasma concentration tmax: time to reach Cmax t1/2:
plasma halflife AUC 0-t: area under the curve from 0 to t AUC
0-.infin.: area under the curve from 0 to .infin..
[0101] The results clearly show that the compositions of the
present invention have a dissolution profile that is an improvement
over compositions of the prior art, leading to a considerably
enhanced bioavailability of the active ingredient compared to that
obtained with compositions of the prior art.
EXAMPLE 4
[0102] Comparison of the dissolution profile of compositions
according to the invention and that of products currently on the
German market.
[0103] On the German market, immediate or sustained-release
fenofibrate formulations exist. Like in France, the 100 mg and 300
mg (conventional) forms coexist with 67 and 200 mg forms (having
enhanced bioavailability, according to the teaching of
EP-A-0330532). These products are as follows:
[0104] Fenofibrate--ratiopharm; Ratiopharm--Ulm;
[0105] Capsules;
[0106] Composition: 100 mg fenofibrate;
[0107] Excipients: lactose, corn starch, magnesium stearate, E 171
colorant, gelatine.
[0108] Durafenat; Durachemie--Wolfratshausen Capsules;
[0109] Composition: 100 mg fenofibrate;
[0110] Excipients: lactose, corn starch, magnesium stearate, E 171
colorant, gelatine.
[0111] Normalip pro; Knoll--Ludwigshafen;
[0112] Capsules;
[0113] Composition: 200 mg Fenofibrate;
[0114] Excipients: Crospovidone, gelatine, monohydrate lactose,
magnesium stearate, corn starch, sodium laurylsulfate, E 132 and E
171 colorants.
[0115] A comparison was made between:
[0116] the tablet of the invention as prepared using example 1
(2.times.100 mg)
[0117] Normalip pro.RTM. (200 mg);
[0118] Lipanthyl.RTM. 200M (200 mg) (according to the preceding
example);
[0119] Fenofibrate by Ratiopharm.RTM. (2.times.100 mg);
[0120] Durafenat.RTM. (2.times.100 mg)
[0121] The tests were implemented under the same conditions as in
the previous examples. FIG. 2 summarizes the results.
[0122] These results clearly show that the compositions of the
invention have a distinctly improved dissolution compared to prior
art compositions.
[0123] Obviously, the present invention is not limited to the
embodiments described but may be subject to numerous variations
readily accessible to those skilled in the art.
* * * * *