U.S. patent application number 11/979065 was filed with the patent office on 2008-03-13 for fenofibrate compositions.
This patent application is currently assigned to Paul Royalty Fund Holdings II. Invention is credited to Pawan Seth, Andre Stamm.
Application Number | 20080063726 11/979065 |
Document ID | / |
Family ID | 9502710 |
Filed Date | 2008-03-13 |
United States Patent
Application |
20080063726 |
Kind Code |
A1 |
Stamm; Andre ; et
al. |
March 13, 2008 |
Fenofibrate compositions
Abstract
The invention provides fenofibrate compositions comprising
granulates, where the granulates comprise micronized
fenofibrate.
Inventors: |
Stamm; Andre; (Griesheim,
FR) ; Seth; Pawan; (Irvine, CA) |
Correspondence
Address: |
VENABLE LLP
P.O. BOX 34385
WASHINGTON
DC
20043-9998
US
|
Assignee: |
Paul Royalty Fund Holdings
II
New York
NY
|
Family ID: |
9502710 |
Appl. No.: |
11/979065 |
Filed: |
October 30, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10665519 |
Sep 22, 2003 |
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11979065 |
Oct 30, 2007 |
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10288425 |
Nov 6, 2002 |
6652881 |
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11979065 |
Oct 30, 2007 |
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10126875 |
Apr 22, 2002 |
6589552 |
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10288425 |
Nov 6, 2002 |
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10078500 |
Feb 21, 2002 |
6596317 |
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10126875 |
Apr 22, 2002 |
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09899026 |
Jul 6, 2001 |
7037529 |
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10078500 |
Feb 21, 2002 |
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09572330 |
May 18, 2000 |
6277405 |
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09899026 |
Jul 6, 2001 |
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09005128 |
Jan 9, 1998 |
6074670 |
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09572330 |
May 18, 2000 |
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10290333 |
Nov 8, 2002 |
7041319 |
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11979065 |
Oct 30, 2007 |
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Current U.S.
Class: |
424/499 ;
514/683 |
Current CPC
Class: |
A61K 31/12 20130101;
A61K 9/2077 20130101; A61K 9/14 20130101; A61K 9/2081 20130101;
A61K 9/2054 20130101; A61K 9/16 20130101; A61K 9/1635 20130101;
A61K 31/216 20130101; A61K 9/1617 20130101; A61P 1/18 20180101;
A61K 9/1676 20130101; A61K 9/2027 20130101; A61K 9/1623 20130101;
A61K 31/215 20130101; A61P 3/04 20180101; A61P 3/06 20180101 |
Class at
Publication: |
424/499 ;
514/683 |
International
Class: |
A61K 31/12 20060101
A61K031/12; A61K 9/50 20060101 A61K009/50; A61P 1/18 20060101
A61P001/18 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 17, 1997 |
FR |
97 00 479 |
Claims
1. A fenofibrate composition comprising granulates, wherein the
granulates comprise micronized fenofibrate, inert carrier
particles, at least one hydrophilic polymer and at least one
surfactant, wherein the weight ratio of micronized fenofibrate to
hydrophilic polymer is between 1:10 and 4:1.
2. The composition of claim 1, wherein the weight ratio of
fenofibrate/hydrophilic polymer is between 1/2 and 2/1.
3. The composition of claim 1, wherein the fenofibrate has a size
less than 20 .mu.m.
4. The composition of claim 1, wherein the fenofibrate has a size
less than 10 .mu.m.
5. The composition of claim 1, wherein the inert carrier particles
are inert hydrosoluble carrier particles.
6. The composition of claim 1, wherein the inert carrier particles
have a particle size between 50 and 500 microns.
7. The composition of claim 1, wherein the inert carrier particles
have a particle size between 100 and 400 microns.
8. The composition 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.
9. The composition of claim 1, wherein the hydrophilic polymer is a
polyvinylpyrrolidone.
10. The composition of claim 1, 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.
11. The composition of claim 1, wherein the surfactant is sodium
lauryl sulfate.
12. The composition of claim 1, wherein the weight ratio of
surfactant to hydrophilic polymer is from 1/500 to 1/10.
13. The composition of claim 1, wherein the weight ratio of
surfactant to hydrophilic polymer is from 1/100 to 5/100.
14. The composition of claim 1, wherein the granulates comprise,
based on the weight of the granules, 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.
15. The composition of claim 1, wherein the granulates comprise,
based on the weight of the granules, 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.
16. A fenofibrate composition comprising granulates, wherein the
granulates comprise micronized fenofibrate, inert carrier
particles, at least one hydrophilic polymer and at least one
disintegrant, wherein the weight ratio of micronized fenofibrate to
hydrophilic polymer is between 1:10 and 4:1.
17. The composition of claim 16, wherein the weight ratio of
fenofibrate/hydrophilic polymer is between 1/2 and 2/1.
18. The composition of claim 16, wherein the fenofibrate has a size
less than 20 .mu.m.
19. The composition of claim 16, wherein the fenofibrate has a size
less than 10 .mu.m.
20. The composition of claim 16, wherein the inert carrier
particles are inert hydrosoluble carrier particles.
21. The composition of claim 16, wherein the inert carrier
particles have a particle size between 50 and 500 microns.
22. The composition of claim 16, wherein the inert carrier
particles have a particle size between 100 and 400 microns.
23. The composition of claim 16, 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.
24. The composition of claim 16, wherein the hydrophilic polymer is
a polyvinylpyrrolidone.
25. The composition of claim 16, wherein the at least one
disintegrating agent is selected from the group consisting of
starch, colloidal silica, cross-linked polyvinyl pyrrolidone and
carboxymethyl starch, and a mixture of two or more thereof.
26. The composition of claim 16, wherein the granulates further
comprise at least one surfactant.
27. The composition of claim 26, 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.
28. The composition of claim 26, 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.
29. The composition of claim 26, wherein the surfactant is sodium
lauryl sulfate.
30. The composition of claim 26, wherein the weight ratio of
surfactant to hydrophilic polymer is from 1/500 to 1/10.
31. The composition of claim 26, wherein the weight ratio of
surfactant to hydrophilic polymer is from 1/100 to 5/100.
32. The composition of claim 16, wherein the granulates comprise,
based on the weight of the granules, 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.
33. The composition of claim 16, wherein the granulates comprise,
based on the weight of the granules, 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.
34. The composition of claim 32, wherein the granulates comprise,
based on the weight of the granules, up to 10% by weight of
surfactant.
35. The composition of claim 33, wherein the granulates comprise,
based on the weight of the granules, from 0.1 to 3% by weight of
surfactant.
36. A fenofibrate composition comprising granulates and at least
one disintegrant, wherein the granulates comprise micronized
fenofibrate, inert carrier particles and at least one hydrophilic
polymer, wherein the weight ratio of micronized fenofibrate to
hydrophilic polymer is between 1:10 and 4:1.
37. The composition of claim 36, wherein the weight ratio of
fenofibrate/hydrophilic polymer is between 1/2 and 2/1.
38. The composition of claim 36, wherein the fenofibrate has a size
less than 20 .mu.m.
39. The composition of claim 36, wherein the fenofibrate has a size
less than 10 .mu.m.
40. The composition of claim 36, wherein the inert carrier
particles are inert hydrosoluble carrier particles.
41. The composition of claim 36, wherein the inert carrier
particles have a particle size between 50 and 500 microns.
42. The composition of claim 36, wherein the inert carrier
particles have a particle size between 100 and 400 microns.
43. The composition of claim 36, 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 composition of claim 36, wherein the hydrophilic polymer is
a polyvinylpyrrolidone.
45. The composition of claim 36, wherein the at least one
disintegrating agent is selected from the group consisting of
starch, colloidal silica, cross-linked polyvinyl pyrrolidone and
carboxymethyl starch, and a mixture of two or more thereof.
46. The composition of claim 36, wherein the granulates further
comprise at least one surfactant.
47. The composition of claim 36, 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.
48. The composition of claim 46, 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.
49. The composition of claim 46, wherein the surfactant is sodium
lauryl sulfate.
50. The composition of claim 46, wherein the weight ratio of
surfactant to hydrophilic polymer is from 1/500 to 1/10.
51. The composition of claim 46, wherein the weight ratio of
surfactant to hydrophilic polymer is from 1/100 to 5/100.
52. The composition of claim 36, wherein the granulates comprise,
based on the weight of the granules, 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.
53. The composition of claim 36, wherein the granulates comprise,
based on the weight of the granules, 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.
54. The composition of claim 52, wherein the granulates comprise,
based on the weight of the granules, up to 10% by weight of
surfactant.
55. The composition of claim 53, wherein the granulates comprise,
based on the weight of the granules, from 0.1 to 3% by weight of
surfactant.
56. A fenofibrate composition comprising granulates, wherein the
granulates comprise micronized fenofibrate, inert carrier
particles, at least one hydrophilic polymer, at least one
surfactant, wherein the weight ratio of micronized fenofibrate to
hydrophilic polymer is between 1:10 and 4:1 and the weight ratio of
surfactant/hydrophilic polymer is between 1/500 and 1/10.
57. The composition of claim 56, wherein the weight ratio of
fenofibrate/hydrophilic polymer is between 1/2 and 2/1.
58. The composition of claim 56, wherein the fenofibrate has a size
less than 20 .mu.m.
59. The composition of claim 56, wherein the fenofibrate has a size
less than 10 .mu.m.
60. The composition of claim 56, wherein the inert carrier
particles are inert hydrosoluble carrier particles.
61. The composition of claim 56, wherein the inert carrier
particles have a particle size between 50 and 500 microns.
62. The composition of claim 56, wherein the inert carrier
particles have a particle size between 100 and 400 microns.
63. The composition of claim 56, 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.
64. The composition of claim 56, wherein the hydrophilic polymer is
a polyvinylpyrrolidone.
65. The composition of claim 56, 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.
66. The composition of claim 56, wherein the surfactant is sodium
lauryl sulfate.
67. The composition of claim 56, wherein the weight ratio of
surfactant to hydrophilic polymer is from 1/100 to 5/100.
68. The composition of claim 56, wherein the granulates comprise,
based on the weight of the granules, 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.
69. The composition of claim 56, wherein the granulates comprise,
based on the weight of the granules, 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.
70. A fenofibrate composition comprising granulates, wherein the
granulates comprise micronized fenofibrate, inert carrier
particles, polyvinylpyrrolidone, sodium lauryl sulfate, wherein the
weight ratio of micronized fenofibrate to polyvinylpyrrolidone is
between 1:10 and 4:1 and the weight ratio of sodium lauryl
sulfate/polyvinylpyrrolidone is between 1/500 and 1/10.
71. The composition of claim 70, wherein the weight ratio of
fenofibrate/polyvinylpyrrolidone is between 1/2 and 2/1.
72. The composition of claim 70, wherein the fenofibrate has a size
less than 20 .mu.m.
73. The composition of claim 70, wherein the fenofibrate has a size
less than 10 .mu.m.
74. The composition of claim 70, wherein the inert carrier
particles are inert hydrosoluble carrier particles.
75. The composition of claim 70, wherein the inert carrier
particles have a particle size between 50 and 500 microns.
76. The composition of claim 70, wherein the inert carrier
particles have a particle size between 100 and 400 microns.
77. The composition of claim 70, wherein the weight ratio of sodium
lauryl sulfate to polyvinylpyrrolidone is from 1/100 to 5/100.
78. The composition of claim 70, wherein the granulates comprise,
based on the weight of the granules, 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.
79. The composition of claim 70, wherein the granulates comprise,
based on the weight of the granules, from 20 to 45% by weight of
fenofibrate, from 20 to 50% by weight of carrier, from 25 to 45% by
weight of polyvinylpyrrolidone polymer, and from 0.1 to 3% by
weight of sodium lauryl sulfate.
80. The composition of claim 1, wherein the fenofibrate is in a
non-reagglomerated form.
81. The composition of claim 16, wherein the fenofibrate is in a
non-reagglomerated form.
82. The composition of claim 36, wherein the fenofibrate is in a
non-reagglomerated form.
83. The composition of claim 56, wherein the fenofibrate is in a
non-reagglomerated form.
84. The composition of claim 70, wherein the fenofibrate is in a
non-reagglomerated form.
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@), 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).
[0082] One thus obtains tablets having the following composition,
expressed in mg:
[0083] element (a): TABLE-US-00001 micronized fenofibrate 100.0 PVP
100.0 Lactose 114.3 sodium laurylsulfate 2.0
[0084] outer phase (or layer): TABLE-US-00002 cross-linked PVP 92.7
microcrystalline cellulose 145.7 sodium stearyl fumarate 5.8
colloidal silica 3.3
EXAMPLE 2
[0085] Dissolution of a composition according to the invention and
a composition according to the prior art.
[0086] a) Dissolution Medium and Procedure for Measuring
Dissolution.
[0087] 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.
[0088] 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.
[0089] 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.
[0090] b) Results
[0091] The composition according to the invention consisted of two
tablets containing about 100 mg fenofibrate prepared according to
Example 1.
[0092] 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).
[0093] 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.
[0094] 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.
[0095] 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
[0096] Study of bioavailability of compositions according to the
invention and prior art compositions.
[0097] A test of bioavailability on healthy volunteers was carried
out.
[0098] The following compositions were tested: [0099] composition
according to the invention: capsules containing granules prepared
according to example 1, containing 200 mg fenofibrate. [0100] first
composition according to the prior art: Lipanthyl.RTM. 200M from
Laboratoires Fournier, containing 200 mg fenofibrate, identical to
that in the previous example. [0101] second prior art composition:
Secalip.RTM. in capsule form (300 mg fenofibrate in the form of
three 100 mg capsules).
[0102] 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.
[0103] The results obtained are given in table 1 below.
TABLE-US-00003 TABLE 1 dose Cmax tmax t 1/2 AUC 0-t AUC 0-.infin.
Product (mg) (.mu.g/ml) (h) (h) (.mu.g h/ml) (.mu.g h/ml) Invention
200 5.4 6 23 148 162 Secalip .RTM. 100 3 .times. 100 1.1 25 39 53
56 Lipanthyl .RTM. 200 1.6 8.3 41 71 92 200M Cmax: maximum plasma
concentration tmax: time to reach Cmax t 1/2: plasma halflife AUC
0-t: area under the curve from 0 to t AUC 0-.infin.: area under the
curve from 0 to .infin..
[0104] 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
[0105] Comparison of the dissolution profile of compositions
according to the invention and that of products currently on the
German market.
[0106] 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: [0107]
Fenofibrate--ratiopharm; Ratiopharm--Ulm; [0108] Capsules; [0109]
Composition: 100 mg fenofibrate; [0110] Excipients: lactose, corn
starch, magnesium stearate, E 171 colorant, gelatine. [0111]
Durafenat; Durachemie--Wolfratshausen Capsules; [0112] Composition:
100 mg fenofibrate; [0113] Excipients: lactose, corn starch,
magnesium stearate, E 171 colorant, gelatine. [0114] Normalip pro;
Knoll--Ludwigshafen; [0115] Capsules; [0116] Composition: 200 mg
Fenofibrate; [0117] Excipients: Crospovidone, gelatine, monohydrate
lactose, magnesium stearate, corn starch, sodium laurylsulfate, E
132 and E 171 colorants. [0118] A comparison was made between:
[0119] the tablet of the invention as prepared using example 1
(2.times.100 mg) [0120] Normalip pro.RTM. (200 mg); [0121]
Lipanthyl.RTM. 200M (200 mg) (according to the preceding example);
[0122] Fenofibrate by Ratiopharm.RTM. (2.times.100 mg); [0123]
Durafenat.RTM. (2.times.100 mg)
[0124] The tests were implemented under the same conditions as in
the previous examples. FIG. 2 summarizes the results.
[0125] These results clearly show that the compositions of the
invention have a distinctly improved dissolution compared to prior
art compositions.
[0126] 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.
* * * * *