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
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.
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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.
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 fenofibrate, 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
pharmaceutically-acceptable water soluble or insoluble
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polymer which are then uniformly coated with a
pharmaceutically-acceptable (meth)acrylate 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 pravastatin,
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 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 of lipid-regulating agents having enhanced
bioavailability and longer half-life when compared to
commercially available formulations.
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Summary of the Invention
The present invention is directed to a formulation
comprising a lipid-regulating agent dissolved in an oil,
with subsequent emulsification using one or more
emulsifiers. This formulation forms fine and stable
emulsions. The emulsions result in an increase in drug
solubility, oral bioavailability and half-life.
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 Drawincts
Figure 1 is a graph showing the plasma concentration in
fasted dogs of the formulation of Example 1 and a reference
compound.
Detailed Description of the Invention
The bulk lipid-regulating agent may be prepared by any
available method, as for example the compound fenofibrate
may be prepared by the procedure disclosed in U.S. Patent
No. 4,058,552, or the procedure disclosed in U.S. Patent No.
4,739,101, both herein incorporated by reference.
The solution comprising the lipid-regulating agent is
prepared by dissolving said agent in the oil with adequate
mixing. An emulsifier or emulsifier blend is added to said
mixture and mixed until uniform. If desired, water can be
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then added to the resulting mixture with agitation to form a
uniform emulsion.
The delivery system of the present invention results in
5 increased solubility, half-life and bioavailability of the
lipid-regulating agent. It can be further diluted with
additional liquids or it may be thickened and/or stabilized
with various pharmaceutical excipients to vary its existing
properties.
Suitable oils include, but are not limited to, any
pharmaceutically acceptable oil, such as, for example,
soybean oil, coconut oil, canola oil, corn oil, palm kernel
oil, cottonseed oil, olive oil, peanut oil, safflower oil
and sesame oil.
Suitable emulsifiers include any pharmaceutically
acceptable hydrophilic or lipophilic emulsifier or
combinations thereof, such as, for example, phospholipids,
polyoxyethylene sorbitan fatty acid derivatives, sorbitan
fatty acid derivatives, polyoxyl-35-castor oil (Cremophor
EL, available from BASF), castor oil or hydrogenated castor
oil ethoxylates, polyglycerol esters of fatty acids, fatty
acid ethoxylates, alcohol ethoxylates, polyoxyethylene-
polyoxypropylene co-polymers and block co-polymers, and TPGS
(d-alpha tocopheryl polyethylene glycol 1000 succinate).
Preferred emulsifiers include polyoxyethylene sorbitan fatty
acid derivatives, sorbitan fatty acid derivatives and
polyoxyl-35-castor oil (Cremophor EL, 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
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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, polyethylene glycol, dimethyl isosorbide,
etc.
The resulting liquid comprising the lipid-regulating
agent may be dosed directly for oral administration, diluted
into an appropriate vehicle for oral administration, filled
into soft or hard shells or capsules for oral
administration, or delivered by some other means obvious to
those skilled in the art. The said liquid can be used to
improve the oral bioavailability, and increase the half-life
and solubility of said lipid-regulating agent.
The invention will be understood more clearly from the
following non-limiting representative examples:
Example 1
SR Soybean oil (24.33 g) was added to a beaker and
fenofibrate (0.67 g) was dissolved in it by stirring.
Sorbitan monooleate (2.5 g) was added to the beaker and
mixed until uniform. Polysorbate 80 (0.5 g) was then added
and mixed until uniform. Finally water (72 g) was added
slowly with constant mixing until a uniform emulsion
resulted.
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Example 2
SR Soybean oil (24 g) is added to a beaker and
pravastatin (1 g) is dispersed in it by stirring. Sorbitan
monooleate (2.5 g) is added to the beaker and mixed until
uniform. Polysorbate 80 (0.5 g) is then added and mixed
until uniform. Finally water (72 g) is added slowly with
constant mixing until a uniform emulsion resulted.
Example 3
SR Soybean oil (24 g) is added to a beaker and
atorvastatin (1 g) is dispersed in it by stirring. Sorbitan
monooleate (2.5 g) is added to the beaker and mixed until
uniform. Polysorbate 80 (0.5 g) is then added and mixed
until uniform. Finally water (72 g) is added slowly with
constant mixing until a uniform emulsion resulted.
Example 4
The emulsion prepared by the process described in
Example 1, and from a commercial fenofibrate composition,
Lipanthyl 67M (troupe Fournier) (Reference), were
administered to a group of dogs at a dose of 67 mg
fenofibrate/dog (10 mL emulsion or one capsule/dog). The
plasma concentrations of fenofibric acid were determined by
HPLC. Concentrations were normalized to a 6.7 mg/kg dose in
each dog. Figure 1 presents the resulting data in graph
form. The results provided as mean ~ SD, n=6, were as
follows
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Lipanthyl 67M (Reference):
Cmax = 1.88 ~ 0.97 mcg/ml
Tmax = 1.6 ~ 0.9 hr
t1~2 = 4.5 hr
AUC (0-24) - 11.08 ~ 9.42 mcg~hr/ml
Emulsion of Example 1:
Cmax = 4.97 ~ 3.13 mcg/ml
Tmax = 1.1 ~ 0.5 hr
t1~2 = 7.8 hr
AUC (0-24) - 24.21 ~ 11.69 mcg~hr/ml
AUC relative to Reference = 2.2
