Note: Descriptions are shown in the official language in which they were submitted.
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Novel Formulations Comprising
Lipid-Regulating Agents
Field of the Invention
The present invention relates to novel formulations for oral administration
comprising lipid-regulating agents.
Background of the Invention
2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethylester,
also
known as fenofibrate, is representative of a broad class of compounds having
pharmaceutical utility as lipid regulating agents. More specifically, this
compound is part of
a lipid-regulating agent class of compounds commonly known as fibrates, and is
disclosed
in U.S. Patent No. 4,058,552.
Fenofibrate has been prepared in several different formulations, c.f., U.S.
Patent No.
4,800,079 and U.S. Patent No. 4,895,726. U.S. Patent No. 4,895,726 discloses a
co-
micronized formulation of fenofibrate and a solid surfactant.
U.S. Patent No. 4,961,890 discloses a process for preparing a controlled
release
formulation containing fenofibrate in an intermediate layer in the form of
crystalline
microparticles included within pores of an inert matrix. The formulation is
prepared by a
process involving the sequential steps of dampening said inert core with a
solution based on
said binder, then projecting said fenofibrate microparticles in a single layer
onto said
dampened core, and thereafter drying, before said solution based on said
binder dissolves
said fenofibrate microparticles, and repeating said three steps in sequence
until said
intermediate layer is formed.
European Patent Application No. EP0793958A2 discloses a process for producing
a
fenofibrate solid dosage form utilizing fenofibrate, a surface active agent
and polyvinyl
pyrrolidone in which the fenofibrate particles are mixed with a polyvinyl
pyrrolidone
solution. The thus obtained mixture is granulated with an aqueous solution of
one or more
surface active agents, and the granulate thus produced is dried.
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PCT Publication No. WO 82/01649 discloses a fenofibrate formulation having
granules that are comprised of a neutral core that is a mixture of saccharose
and starch. The
neutral core is covered with a first layer of fenof brate, admixed with an
excipient and with
a second microporous outer layer of an edible polymer.
U.S. Patent No. 5,645,856 describes the use of a carrier for hydrophobic
drugs,
including fenofibrate, and pharmaceutical compositions based thereon. The
carrier
comprises a digestible oil and a pharmaceutically-acceptable surfactant
component for
dispersing the oil in vivo upon administration of the carrier, which comprises
a hydrophilic
surfactant, said surfactant component being such as not to substantially
inhibit the in vivo
lipolysis of the digestible oil.
Gemfibrozil is another member of the fibrate class of lipid-regulating agents.
U.S.
Patent No. 4,927,639 discloses a disintegratable formulation of gemfibrozil
providing both
immediate and sustained release, comprising a tablet compressed from a mixture
of a first
and second granulation, and a disintegration excipient operable to effect
partial or complete
disintegration in the stomach. The first granulation comprises finely divided
particles of
pure gemfibrozil granulated with at least one cellulose derivative, and the
second
granulation comprises finely divided particles of pure gemfibrozil granulated
with a
pharmaceuitcally-acceptable water soluble or insoluble polymer which are then
uniformly
coated with a pharmaceuitcally-acceptable (meth)acylate copolymer prior to
admixture with
the first granulation. The first and second granulations are present in the
final composition
in a ratio of from about 10:1 to about 1:10.
U.S. Patent 4,925,676 discloses a disintegratable gemfibrozil tablet providing
both
immediate and enteric release, which is compressed from a mixture of a first
granulation of
gemfibrozil with at least one acid-disintegratable binder, and a second
granulation formed
from the first granulation, but regranulated or coated with an alkali-
disintegratable
formulation of at least one substantially alkali-soluble and substantially
acid-insoluble
polymer.
Another class of lipid-regulating agents are commonly known as statins, of
which
pravastatin and atorvastatin are members. U.S. Patents 5,030,447 and 5,180,589
describe
stable pharmaceutical compositions, which when dispersed in water have a pH of
at least 9,
and include a medicament which is sensitive to a low pH environment, such as
prevastatin,
one or more fillers such as lactose and/or microcrystalline cellulose, one or
more binders,
such as microcrystalline cellulose (dry binder) or polyvinylpyrrolidone (wet
binder), one or
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more disintegrating agents such as croscarmellose sodium, one or more
lubricants such as
magnesium stearate and one or more basifying agents such as magnesium oxide.
It is an object of the present invention to provide formulations for oral
administration comprising lipid-regulating agents having enhanced
bioavailability when
compared to commercially available formulations.
Summary of the Invention
The present invention is directed to formulations for oral administration
comprising
a lipid-regulating agent, further comprising at least one propylene glycol
fatty acid ester as
the primary solvent medium for the lipid-regulating agent. One or more
emulsifiers may
optionally be added to the formulation.
The formulation may be administered directly, diluted into an appropriate
vehicle
for administration, encapsulated into soft or hard gelatin shells or capsules
for
administration, or administered by other means obvious to those skilled in the
art.
Brief Description of the Drawings
Figure 1 is a graph showing the plasma concentration in fasted dogs of the
formulation of Example 1 and a reference composition.
Figure 2 is a graph showing the plasma concentration in fasted dogs of the
formulation of Example 2 and a reference composition.
Figure 3 is a graph showing the plasma concentration in fasted and non-fasted
dogs
of the formulation of Example l and a reference composition.
Detailed Description of the Invention
The bulk lipid-regulating agent can be prepared by any available method, as
for
example the compound fenofibrate may be prepared by the procedure disclosed in
U.S.
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Patent No. 4,058,552 or the procedure disclosed in U.S. Patent No. 4,739,101,
both herein
incorporated by reference.
Representative propylene glycol fatty acid esters include, but are not limited
to,
propylene glycol dicaprylate/dicaprate, propylene glycol dicaprate, propylene
glycol laurate,
and propylene glycol mono- and dicaprylate.
Preferred propylene glycol fatty acid esters include Miglyol 840TM, a
propylene
glycol dicaprylate/dicaprate available from Creanova; Captex I00TM, a
propylene glycol
dicaprate available from Abitec; LauroglycolTM, a propylene glycol laurate
available from
Gattefosse; and Capmul PGBTM, a propylene glycol mono- and dicaprylate
available from
Abitec.
Suitable emulsifiers include pharmaceutically-acceptable emulsifiers such as,
for
example, TPGS (d-alpha tocopheryl polyethylene glycol 1000 succinate),
phospholipids,
polyoxyethylene sorbitan fatty acid derivatives, castor oil or hydrogenated
castor oil
ethoxylates, polyglycerol esters of fatty acids, fatty acid ethoxylates,
alcohol ethoxylates,
and polyoxyethylene-polyoxypropylene co-polymers and block co-polymers.
Preferred
emulsifiers include castor oil or hydrogenated castor oil ethoxylates. A more
preferred
emulsifier is Cremophor ELTM, a polyoxyl 35 castor oil, available from BASF.
Other optional ingredients which may be included in the compositions of the
present
invention are those which are conventionally used in oil-based drug delivery
systems, e.g.
antioxidants such as, for example, tocopherol, ascorbyl palmitate, ascorbic
acid, butylated
hydroxytoluene, butylated hydroxyanisole, propyl gallate, etc.; pH stabilizers
such as, for
example, citric acid, tartaric acid, fumaric acid, acetic acid, glycine,
arginine, lysine,
potassium hydrogen phosphate, etc.; thickeners/suspending agents such as, for
example,
hydrogenated vegetable oils, beeswax, colloidal silicon dioxide, gums,
celluloses, silicates,
bentonite, etc.; flavoring agents such as, for example, cherry, lemon, aniseed
flavors, etc.;
sweeteners such as, for example, aspartame, saccharin, cyclamates, etc.; and
co-solvents,
such as, for example, ethanol, propylene glycol, dimethyl isosorbide, etc.
The solution comprising the lipid-regulating agent is prepared by dissolving
said
agent in the propylene glycol fatty acid ester with adequate mixing at or
about room
temperature. If an emulsifier is used, it is added to the propylene glycol
fatty acid ester with
mixing prior to addition of said agent.
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The resulting premix liquid comprising said agent may be dosed directly for
oral
administration, diluted into an appropriate vehicle for oral administration,
filled into soft or
hard gelatin capsules for oral administration, or delivered by some other
means obvious to
those skilled in the art. The said premix liquid can be used to improve the
oral
5 bioavailability, and/or increase the solubility of said agent.
The invention will be understood more clearly from the following non-limiting
representative examples.
Example 1
Capmul PG8 (Abitec) (8.3 gm) was added to a scintillation vial. Cremophor EL
(BASF) (1.0 gm) was added to the vial and mixed until uniform. Fenofibrate
(Sigma) (0.7
gm) was then added to the vial and mixed until it was completely dissolved.
957 mg. of the
premix (containing 67 mg. fenofibrate) was added to each of six soft gelatin
capsules using
a syringe. The capsules were heat-sealed and stored.
Example 2
Captex 200 (propylene glycol dicaprylate/dicaprate) (Abitec)(9.3 gm) was added
to
a scintillation vial. Fenofibrate (Sigma) (0.7 gm) was added to the Captex 200
and mixed
until completely dissolved. 957 mg. of the premix (containing 67 mg.
fenofibrate) was
added to each of six soft gelatin capsules using a syringe. The capsules were
heat-sealed
and stored.
Example 3
Capsules prepared by the process described in Example Land 2, and from a
commercial fenofibrate composition, Lipanthyl 67M (troupe Fournier)
(reference), were
administered to a group of dogs at a dose of 67 mg/dog (one capsule per dog).
The plasma
concentrations of fenofibric acid were determined by HPLC. Concentrations were
normalized to a 6.7 mg/kg dose in each dog. Figures 1-3 present the resulting
data in graph
form.
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F,~ure 1
Mean (~SEM, n=6) Plasma Concentrations of Fenofibric Acid after a 67 mg
Capsule Dose
of Fenofibrate in Fasted Dogs
I,
lu
..
a
a
E
c
1U
C
U
a
c
0
CJ
4
0
° .1 8 13 16 20 ?d
Hours After Dosing
Note: 67 mg dose administered to n=6 dogs; concentrations normalized to a 6.7
mg/kg
dose.
The results, provided as mean t SD, n = 6 were as follows:
Lipanthyl 67M (Reference):
Cmax = 1.88 t 0.97 mcg/ml
Tmax =1.6 t 0.9 hr
tin = 4.5 hr
AUC (0-24) = 11.08 ~ 9.42 mcg~hr/ml
F(%) = 21.1 t 11.8
Capsules of Example 1:
Cmax = 9.21 ~ 2.61 mcg/ml
Tmax = 0.9 t 0.2 hr
tl,~ = 4.5 hr
AUC (0-24) = 33.22 t 5.81 mcg~hr/ml
F(%) = 70.4 t 13.2
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Fi ure 2
Mean (~SEM, n=6) Plasma Concentrations of Fenofibric Acid after a 67 mg
Capsule Dose
of Fenofibrate in Fasted Dogs
~.o
2.5
2.0
a
C
v
C
0
1.3
U L0
m
a.
0.3
1 Jr 0.0
0 4 b 13 I6 20 2J
Hours After Dosing
Note: 67 mg dose administered to n=6 dogs; concentrations normalized to a 6.7
mg/kg
dose.
The results, provided as mean t SD, n = 6 were as follows:
Lipanthyl 67M (Reference):
Cmax = 1.88 ~ 0.97 mcg/ml
Tmax = I .6 ~ 0.9 hr
t"~ = 4.5 hr
AUC (0-24) = 11.08 t 9.42 mcg~hr/ml
F(%) = 21.1 ~ 11.8
Capsules of Example 2:
Cmax = 2.67 ~ 1.67 mcg/ml
Tmax = 1.3 t 0.5 hr
t"~ = 8.1 hr
AUC (0-24) = 16.14 t 8.99 mcg~hr/ml
F(%) = 32.8 ~ I5.0
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Figure 3,
Effect of Food on the Mean (~SEM, n=6) Plasma Concentrations
of Fenofibric Acid after a 67 mg Capsule Dose
of Fenofibrate in Dogs
a
-:-- Capsules of Example l(+food)
--t- Reference capsules (+food)
"'~ Capsules of Example I (fasted)
_~ 6 1 ""d"- Reference capsules (fasted)
c
_o
_:J s(
3
i 2
20
o -
o ~ .~ s s io i=
Hours After Dosing
Note: 67 mg dose administered to n=6 dogs; concentrations normalized to a 6.7
mg/kg
dose.
The results, provided as mean ~ SD, n = 6 were as follows:
Lipanthyl 67M (Reference) (Fasted):
Cmax = 1.88 t 0.97 mcg/ml
Tmax = I .6 ~ 0.9 hr
AUC (0-24) = 11.08 t 9.42 mcg~hz:/ml
F(%) = 21.1 ~ 11.8
Lipanthyl 67M (Reference) (Non-fasted):
Cmax = 4.47 t I.37 mcg/ml
Tmax = 1.3 f 0.5 hr
AUC (0-24) = 25.44 f 4.28 mcg~hr/ml
F(%) = 54.8 ~
Capsules of Example 1 (Fasted):
Cmax = 9.21 t 2.61 mcg/ml
Tmax = 0.9 ~ 0.2 hr
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AUC (0-24) = 33.22 ~ 5.81 mcg~hr/ml
F(%) = 70.4 t 13.2
Capsules of Example 1 (Non-fasted):
Cmax = 6.79 t 2.59 mcg/ml
Tmax = 0.8 ~ 0.3 hr
AUC (0-24) = 31.88 ~ 8.25 mcg~hr/ml
F(%) = 68.3 t
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Example 4
Capmul PG8 (Abitec) (8.0 gm) is added to a scintillation vial. Cremophor EL
(BASF) (1.0 gm) is added to the vial and mixed until uniform. Pravastatin
(PravacholTM,
Bristol Myers Squibb) ( 1:0 gm) is then added to the vial and mixed until
uniformly
5 dispersed. The premix may be added to soft gelatin capsules in an amount
sufficient to
deliver the desired dose.
Example 5
Capmul PG8 (Abitec) (8.0 gm) is added to a scintillation vial. Cremophor EL
10 (BASF) (1.0 gm} is added to the vial and mixed until uniform. Atorvastatin
(LipitorTM,
Parke-Davis/Pfizer) ( 1.0 gm) is then added to the vial and mixed until
uniformly dispersed.
The premix may be added to soft gelatin capsules in an amount sufficient to
deliver the
desired dose.
