U.S. patent application number 09/330589 was filed with the patent office on 2001-07-12 for novel formulations comprising lipid-regulating agents.
Invention is credited to HANSRANI, PAWAN, LIU, RONG (RON), PAN, QINGHAI.
Application Number | 20010007670 09/330589 |
Document ID | / |
Family ID | 23290430 |
Filed Date | 2001-07-12 |
United States Patent
Application |
20010007670 |
Kind Code |
A1 |
LIU, RONG (RON) ; et
al. |
July 12, 2001 |
NOVEL FORMULATIONS COMPRISING LIPID-REGULATING AGENTS
Abstract
The present invention is directed to a semi-solid formulation
comprising a lipid-regulating agent. Said formulation is prepared
by solubilizing said lipid-regulating agent in one or more liquid
components to form a clear liquid solution, then solidifying said
solution by adding one or more solid or semi-solid components to
said solution to form a semi-solid formulation. Said formulation
can melt or dissolve upon mixing with a bulk aqueous medium. The
resulting formulation results in an increase in drug solubility and
oral bioavailability, and an improved dissolution rate.
Inventors: |
LIU, RONG (RON); (GURNEE,
IL) ; PAN, QINGHAI; (LAKE BLUFF, IL) ;
HANSRANI, PAWAN; (BUFFALO GROVE, IL) |
Correspondence
Address: |
ABBOTT LABORATORIES
DEPT. 377 - AP6D-2
100 ABBOTT PARK ROAD
ABBOTT PARK
IL
60064-6050
US
|
Family ID: |
23290430 |
Appl. No.: |
09/330589 |
Filed: |
June 11, 1999 |
Current U.S.
Class: |
424/400 |
Current CPC
Class: |
Y10S 514/96 20130101;
A61P 3/06 20180101; A61P 3/04 20180101; A61K 9/4858 20130101; Y10S
514/962 20130101 |
Class at
Publication: |
424/400 |
International
Class: |
A61K 009/00 |
Claims
1. A composition comprising a semi-solid formulation of a
lipid-regulating agent, one or more liquid components, and one or
more solid or semi-solid components.
2. A composition of claim 1 wherein said lipid-regulating agent is
a fibrate.
3. A composition of claim 2 wherein said fibrate is
fenofibrate.
4. A composition of claim 1 wherein said lipid-regulating agent is
a statin.
5. A composition of claim 4 wherein said statin is prevastatin.
6. A composition of claim 4 wherein said statin is
atorvastatin.
7. A composition of claim 1 wherein at least one or more of said
liquid components is an oily or non-aqueous solvent selected from
the group consisting of acetylated monoglycerides, propylene glycol
fatty acid esters, and unsaturated polyglycolysed glycerides.
8. A composition of claim 1 wherein one or more of said liquid
components is a non-ionic surfactant selected from the group
consisting of mono fatty acid esters of polyoxyethylene sorbitan,
anionic surfactants, polyoxyethylene castor oil derivatives, and
Vitamin E TPGS (d-alpha -tocopheryl succinate).
9. A composition of claim 1 wherein at least one or more of said
solid or semi-solid components is a semisolid pharmaceutical or
solid pharmaceutical excipient selected from the group consisting
of polypropylene glycol; polyethylene glycol, polyoxyethylene
castor oil derivatives, polyoxyethylene glycerol oxystearate,
saturated polyglycolized glycerides, polyethylene polypropylene
glycol and Vitamin E TPGS (d-alpha -tocopheryl polyethylene glycol
1000 succinate).
10. A delivery system comprising a composition of claim 1.
11. A delivery system of claim 10 wherein said delivery system is a
capsule.
12. A method of treating hyperlipidemia comprising the
administration of a composition of claim 1 to a patient.
13. A method of treating hyperlipidemia comprising the
administration of a composition of claim 3 to a patient.
15. A method of treating hyperlipidemia comprising the
administration of a composition of claim 11 to a patient.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to novel formulations
comprising lipid-regulating agents.
BACKGROUND OF THE INVENTION
[0002] 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. Pat. No. 4,058,552.
[0003] Fenofibrate has been prepared in several different
formulations, c.f., U.S. Pat. No. 4,800,079 and U.S. Pat. No.
4,895,726. U.S. Pat. No. 4,895,726 discloses a co-micronized
formulation of fenofibrate and a solid surfactant.
[0004] U.S. Pat. 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.
[0005] 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.
[0006] 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.
[0007] U.S. Pat. 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.
[0008] Gemfibrozil is another member of the fibrate class of
lipid-regulating agents. U.S. Pat. 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 polymer
which are then uniformly coated with a pharmaceutically-acceptabl-
e (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.
[0009] U.S. Pat. No. 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.
[0010] Another class of lipid-regulating agents are commonly known
as statins, of which pravastatin and atorvastatin are members. U.S.
Pat. Nos. 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 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.
[0011] It is an object of the present invention to provide
formulations of lipid-regulating agents having enhanced
bioavailability when compared to commercially available
formulations.
SUMMARY OF THE INVENTION
[0012] The present invention is directed to a semi-solid
formulation comprising a lipid-regulating agent, a liquid
component, and a solid or semi-solid component.
[0013] Said formulation is prepared by solubilizing said
lipid-regulating agent in one or more liquid components to form a
clear liquid solution, then solidifying said solution by adding one
or more solid or semi-solid components to said solution to form a
semi-solid formulation. Said formulation can melt or dissolve upon
mixing with a bulk aqueous medium. The resulting formulation
results in an increase in drug solubility and oral bioavailability,
and an improved dissolution rate.
[0014] The formulation may be administered directly, diluted into
an appropriate vehicle for administration, encapsulated into soft
or hard gelatin capsules for administration, or administered by
other means obvious to those skilled in the art.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIGS. 1 and 2 are graphs showing the plasma concentration in
fasted dogs of the formulation of Example 1 and 2, respectively,
and a commercial, reference compound
DETAILED DESCRIPTION OF THE INVENTION
[0016] 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. Pat. No. 4,058,552, or
the procedure disclosed in U.S. Pat. No. 4,739,101, both herein
incorporated by reference.
[0017] The composition comprising the lipid-regulating agent is
prepared by solubilizing said lipid-regulating agent in one or more
liquid components to form a clear liquid solution, then solidifying
said solution by adding one or more solid or semi-solid components
to said solution to form a semi-solid formulation. Said formulation
can melt or dissolve upon mixing with a bulk aqueous medium.
[0018] The delivery system of the present invention results in
increased solubility and bioavailability, and improved dissolution
rate of the lipid-regulating agent.
[0019] The selection of liquid components is based on the
component's ability to solubilize fenofibrate. Suitable liquid
components thus include, for example, any
pharmaceutically-acceptable liquid surfactants, solvents and oils.
Examples of such components includes
[0020] Pharmaceutically-acceptable solvents include oily or
non-aqueous solvents, for example, acetylated monoglycerides,
propylene glycol fatty acid esters, including but not limited to
propylene glycol dicaprylat/dicaprate, propylene glycol laurate,
propylene glycol dicaprylate, and propylene glycol mono and
dicaprylate; and unsaturated polyglycolysed glycerides, for
example, Labrafil M 2125CS Gattefosse). Preferred acetylated
monoglycerides include, for example, Myvacet 9-08, Myvacet 9-45 and
Myverol 18-92 (Eastman Chemicals); Lauroglycol, a propylene glycol
monolaurate (Gattefosse); and Capmul PG 8, a propylene glycol mono
and dicaprylate available (Abitec).
[0021] Other solvents include, for example,
pharmaceutically-acceptable alcohols such as, for example,
propylene glycol; ethanol; transcutol (Gattefosse); glycerol; and
polyethylene glycol 200, polyethylene glycol 300, and polyethylene
glycol 400 (Union Carbide).
[0022] Other solvents include, for example, pharmaceutically
acceptable oils such as, for example, mineral oil or a vegetable
oil including, safflower oil, olive oil, fractionated coconut oil,
for example, mixed triglycerides with caprylic acid and capric acid
(Miglyol 812, Huls).
[0023] Pharmaceutically-acceptable surfactants include non-ionic
surfactants such as mono fatty acid esters of polyoxyethylene
sorbitan, for example, polyoxyethylene (20) sorbitan monooleate
(Tween 80), polyoxyethylene (20) sorbitan monostearate (Tween 60),
polyoxyethylene (20) sorbitan monolaurate (Tween 20) (Sigma);
anionic surfactants such as, for example, sodium lauryl sulfate;
polyoxyethylene castor oil derivatives, for example
polyoxyethyleneglycerol triiricinoleate or polyoxyl 35 castor oil
(Cremophor EL, BASF); and Vitamin E TPGS (d-alpha -tocopheryl
succinate).
[0024] The solid or semi-solid component primarily functions as a
solidifying agent, however, depending upon the characteristics of
such component, such component may also assist as a solubilizer.
Examples of such components include polypropylene glycol;
polyethylene glycol (for example polyethylene glycol 1450,
polyethylene glycol 3350, polyethylene glycol 6000, and the like
(Union Carbide); polyoxyethylene castor oil derivatives, for
example polyoxyethylene glycerol tricinoleate or polyoxyl 35 castor
oil (Cremophor EL, BASF), polyoxyethylene glycerol oxystearate
(Cremophor RH 40 (polyethylene glycol 40 hydrogenated castor oil)
or Cremophor RH 60 (polyethyleneglycol 60 hydrogenated castor oil),
BASF); saturated polyglycolized glycerides, for example, Gelucire
35/10, Gelucire 44/14 or Gelucire 53/10 and the like Gattefosse);
polyethylene polypropylene glycol (Poloxamer 68 and Poloxamer 127
(BASF); Vitamin E TPGS (d-alpha -tocopheryl polyethylene glycol
1000 succinate, Eastman Chemical).
[0025] Other pharmaceutically-acceptable excipients may be added to
the formulation prior to forming the desired final product.
Suitable excipients include, for example, antioxidants (for
example, ascorbic acid, BHA (butylated hydroxyanisole), and vitamin
E.
[0026] The resulting composition 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 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.
[0027] The invention will be understood more clearly from the
following non-limiting representative examples:
EXAMPLE 1
[0028] Myvacet 9-08 (Eastman Chemical) (402 mg) was mixed with
propylene glycol laurate (Gattefosse) (67 mg). To this solution was
added fenofibrate (Sigma)(67 mg) and the resulting mixture was
mixed well until the fenofibrate dissolved. The resulting solution
was heated to about 45-50.degree. C. To the solution was added
Vitamin E TPGS (Eastman Chemical) (134 mg) and the resulting
mixture was stirred until a clear solution obtained. The resulting
solution (670 mg) was filled into hard gelatin capsules while the
solution was still warm and in a liquid state. Each capsule
contained 67 mg of fenofibrate.
EXAMPLE 2
[0029] Capmul PG-8 (Abitec) (6.75 g) was added to a scintillation
vial. Fenofibrate (Sigma) (1.0 g) was then added to the vial and
mixed until it was completely dissolved. To this solution was added
Cremophor RH 40 (BASF) (2.0 gm). The resulting solution was heated
to about 45-50.degree. C. and mixed until a clear solution was
obtained. To this solution was added polyethylene glycol 3350
(Union Carbide) (0.25 g) and the resulting mixture was stirred
until a clear solution was obtained. The resulting solution (0.67
g) was filled into hard gelatin capsules while the solution was
still warm and in a liquid state. Each capsule contained 67 mg of
fenofibrate.
EXAMPLE 3
[0030]
1 Pravastatin 1.0 g Myvacet 9-08 6.0 g Propylene glycol Laurate 1.0
g Vitamin E TPGS 2.0 g
[0031] Add Myvacet 9-08 in a scintillation vial. Add propylene
glycol laurate and mix until uniform. Add the pravastatin and mix
until uniformly dispersed. Heat the solution to approximately 45
-50C and add Vitamin E TPGS and mix until uniformly dispersed. Fill
an amount of the pre-mix into capsules, sufficient to deliver the
desired dose.
EXAMPLE 4
[0032] Capsules prepared by the process described in Examples 1 and
2 and from a commercial fenofibrate composition, Lipanthyl 67M
(Groupe Fournier) (Reference), were administered to a group of dogs
at a dose of 67 mg fenofibrate/dog (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.
FIGS. 1 and 2 presents the resulting data in graph form. The
results provided as mean .+-.SD, n=6, were as follows:
[0033] FIG. 1
[0034] Lipanthyl 67M (Reference):
[0035] Cmax=1.88.+-.0.97 mcg/ml
[0036] Tmax=1.6.+-.0.9 hr
[0037] t.sub.1/2=4.5 hr
[0038] AUC (0-24)=11.08.+-.9.42 mcg.multidot.hr/ml
[0039] Capsule of Example 1:
[0040] Cmax=6.60.+-.1.60 mcg/ml
[0041] Tmax=1.3.+-.0.5 hr
[0042] t.sub.1/2=4.4 hr
[0043] AUC (0-24)=27.68.+-.5.62 mcg.multidot.hr/ml
[0044] FIG. 2
[0045] Lipanthyl 67M (Reference):
[0046] Cmax=1.88.+-.0.97 mcg/ml
[0047] Tmax=1.6.+-.0.9 hr
[0048] t.sub.1/2=4. 5 hr
[0049] AUC (0-24)=11.08.+-.9.42 mcg.multidot.hr/ml
[0050] Capsule of Example 2:
[0051] Cmax=7.74.+-.2.27 mcg/ml
[0052] Tmax=0.7.+-.0.3 hr
[0053] t.sub.1/2=7. 5 hr
[0054] AUC (0-24)=26.27.+-.8.11 mcg.multidot.hr/ml
* * * * *