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Liversidge et al.
(54)
NANOPARTICULATE CLOPIDOGREL
FORMULATIONS
Jan. 4, 2007
(60)
(Us)
(51)
Int. Cl.
A61K 9/14
(52)
Correspondence Address:
ELAN DRUG DELIVERY, INC.
C/O FOLEY & LARDNER LLP
(57)
(2006.01)
ABSTRACT
(73)
tive average particle siZe of less than about 2000 nm and are
11/430,180
(22) Filed:
May 9, 2006
Jan. 4, 2007
US 2007/0003628 A1
NANOPARTICULATE CLOPIDOGREL
FORMULATIONS
[0002]
methyl (+)-(S)-0t-(2-chorophenyl)-6,7-dihydrothieno[3,2-c]
pyridine-5(4H)-acetate sulfate (1:1). The empirical formula
of clopidogrel bisulfate is Cl6Hl6Cl NO2S.H2SO4 and its
molecular Weight is 419.9. The structural formula is as
folloWs:
clopidogrel compositions.
BACKGROUND
refractory ischemia.
platelets.
[0006] Another anti-platelet drug, clopidogrel, inhibits
ADP-induced platelet aggregation by direct inhibition of
adenosine diphosphate (ADP) binding to its receptor and of
pounds.
[0012] Clopidogrel has high therapeutic value in the pre
vention and treatment of pathologies induced by platelet
US 2007/0003628 A1
Jan. 4, 2007
[0013]
drug release.
B. Background Regarding Nanoparticulate Active Agent
Compositions
[0014] Nanoparticulate active agent compositions, ?rst
described in US. Pat. No. 5,145,684 (the 684 patent), are
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US 2007/0003628 A1
particulate
Compositions
Comprising
Amorphous
SUMMARY
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[0026]
thereof.
[0027]
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form can be, for example, a fast melt dosage form, con
gender.
application.
[0036]
meaning as comprising.
[0039]
[0040]
2000 nm.
(3) that the particles are chemically stable; and/or (4) Where
the clopiodogrel derivative has not been subject to a heating
step at or above the melting point of clopidogrel in the
[0041]
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US 2007/0003628 A1
interchangeably.
B. Preferred Characteristics of the Nanoparticulate Clopi
dogrel Compositions of the Invention
[0047]
1. Increased Bioavailability
[0052]
70%, not
50%, not
25%, not
15%, not
5% of the
formulation.
Jan. 4, 2007
US 2007/0003628 A1
[0056]
[0058]
[0060]
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US 2007/0003628 A1
desired ionic strength and pH, Which form the basis for the
biorelevance of the media. The desired pH and ionic strength
are those that are representative of physiological conditions
found in the human body. Such biorelevant aqueous media
can be, for example, aqueous electrolyte solutions or aque
ous solutions of any salt, acid, or base, or a combination
(1997).
[0072]
[0077]
templated.
[0082] 1. Clopidogrel Particles
[0083] The clopidogrel particles can comprise clopidogrel
or a salt or derivative thereof, such as clopidogrel bisulfate.
Jan. 4, 2007
US 2007/0003628 A1
[0084]
2. Surface Stabilizers
pounds.
[0086] Representative examples of surface stabiliZers
include hydroxypropyl methylcellulose (noW knoWn as
sorbitan
fatty
acid
esters
(e.g.,
the
(Croda,
Inc.);
CI8H37CHZ(CON(CH3)iCH2(CHOH)4(CH20H)2 (Eastman
ethylalkylamines,
MIRAPOLTM
and
ALKAQUATTM
[0089]
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US 2007/0003628 A1
[0098]
heteroatom;
[0099] (ix) tWo of Rl-R4 are CH3, one of Rl-R4 is
C6H5CH2, and one of Rl-R4 comprises at least one
halogen;
[0100]
cyclic fragment;
[0101]
phenyl ring; or
[0102]
SMCCTM).
[0108] Suitable lubricants, including agents that act on the
?oWability of the poWder to be compressed, are colloidal
silicon dioxide, such as Aerosil 200, talc, stearic acid,
magnesium stearate, calcium stearate, and silica gel.
[0109]
[0113]
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US 2007/0003628 A1
[0121]
biliZers
[0122]
[0116]
Exemplary Nanoparticulate
Clopidogrel Bisulfate Tablet Formulation #1
Component
g/Kg
Clopidogrel Bisulfate
Hypromellose, USP
about
about
about
about
about
about
about
about
about
Crospovidone, NF
Magnesium Stearate, NF
50 to about 500
10 to about 70
1 to about 10
100 to about 500
1 to about 40
50 to about 400
50 to about 300
20 to about 300
0.5 to about 5
[0127]
[0120]
TABLE #2
Exemplary Nanoparticulate
Clopidogrel Bisulfate Tablet Formulation #2
Component
g/Kg
Clopidogrel Bisulfate
Hypromellose, USP
about
about
about
about
about
about
about
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US 2007/0003628 A1
Exemplary Nanoparticulate
Clopidogrel Bisulfate Tablet Formulation #2
Component
g/Kg
Crospovidone, NF
Magnesium Stearate, NF
[0128]
Exemplary Nanoparticulate
Clopidogrel Bisulfate Tablet Formulation #3
g/Kg
Clopidogrel Bisulfate
Hypromellose, USP
about
about
about
about
about
about
about
about
about
Crospovidone, NF
Magnesium Stearate, NF
TABLE #3
Component
glycol.
[0133] Using a particle size reduction method, the particle
size of the clopidogrel is reduced to an e?cective average
particle size of less than about 2000 nm. E?ective methods
[0129]
TABLE #4
Exemplary Nanoparticulate
Clopidogrel Bisulfate Tablet Formulation #4
Component
g/Kg
Clopidogrel Bisulfate
Hypromellose, USP
about
about
about
about
about
about
about
about
about
Crospovidone, NF
Magnesium Stearate, NF
[0135]
[0136]
positions
[0130]
Dispersions
Milling a clopidogrel, or a salt or derivative
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3.0 g/cm3.
[0146] In general, suitable polymeric resins are chemically
and physically inert, substantially free of metals, solvent,
and monomers, and of suf?cient hardness and friability to
enable them to avoid being chipped or crushed during
Grinding Media
[0144] The grinding media for the particle siZe reduction
be employed.
Jan. 4, 2007
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dogrel Compositions
surface area.
ventional means.
pidogrel Compositions
[0153]
processing conditions.
the product.
Jan. 4, 2007
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[0167]
the speci?c dose level for any particular patient Will depend
upon a variety of factors: the type and degree of the cellular
or physiological response to be achieved; activity of the
EXAMPLE 1
[0174]
pared.
[0175] An aqueous dispersion of clopidogrel bisulfate can
be combined With one or more surface stabiliZers, folloWed
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US 2007/0003628 A1
[0176]
[0179]
prising:
(a) particles of clopidogrel or a derivative or a salt thereof
thereof.
benZalkonium
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US 2007/0003628 A1
state.
comprising:
(a) particles of clopidogrel or a derivative or a salt thereof
salt,
an
dosage;
(b) an AUC for clopidogrel When assayed in the plasma of
a mammalian subject folloWing administration that is
greater than the AUC for a non-nanoparticulate formu
dosage;
cationic guar.
comprising:
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US 2007/0003628 A1
prophylactic.