U.S. patent application number 10/324953 was filed with the patent office on 2004-01-08 for formulations of fenofibrate and/or fenofibrate derivatives with improved oral bioavailability.
Invention is credited to Burnside, Beth A., Ibrahim, Scott A., Shojaei, Amir H..
Application Number | 20040005339 10/324953 |
Document ID | / |
Family ID | 30002832 |
Filed Date | 2004-01-08 |
United States Patent
Application |
20040005339 |
Kind Code |
A1 |
Shojaei, Amir H. ; et
al. |
January 8, 2004 |
Formulations of fenofibrate and/or fenofibrate derivatives with
improved oral bioavailability
Abstract
A fibrate oral formulation with improved bioavailability when
compared to commercially available formulations containing a
therapeutically effective dose of fenofibrate or a fenofibrate
derivative dissolved in N-alkyl derivative of 2-pyrrolidone,
ethylene glycol monoether, C.sub.8-12 fatty acid ester of
polyethylene glycol, fatty acids, or combinations thereof useful
for the treatment of hypercholesterolaemia or hypertriglyceridaemia
in mammals.
Inventors: |
Shojaei, Amir H.;
(Gaithersburg, MD) ; Ibrahim, Scott A.;
(Burtonville, MD) ; Burnside, Beth A.; (Bethesda,
MD) |
Correspondence
Address: |
Gregory P. LaPointe
BACHMAN & LaPOINTE, P.C.
Suite 1201
900 Chapel Street
New Haven
CT
06510-2802
US
|
Family ID: |
30002832 |
Appl. No.: |
10/324953 |
Filed: |
December 20, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60392806 |
Jun 28, 2002 |
|
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60392791 |
Jun 28, 2002 |
|
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Current U.S.
Class: |
424/400 ;
514/571 |
Current CPC
Class: |
A61K 31/216 20130101;
A61K 9/1075 20130101; A61K 9/4866 20130101; A61K 9/4858 20130101;
Y02A 50/393 20180101; Y02A 50/30 20180101 |
Class at
Publication: |
424/400 ;
514/571 |
International
Class: |
A61K 031/192; A61K
009/00 |
Claims
1--A pharmaceutical formulation of a fibrate with improved oral
bioavailability comprising a fibrate selected from fenofibrate ,
derivative of fenofibrate or mixtures thereof dissolved in a water
miscible fibrate solubilizer selected from N-alkyl derivative of
2-pyrrolidone, ethylene glycol monoether, C.sub.8-12 fatty acid
ester of polyethylene glycol, fatty acids and combinations thereof;
wherein the fibrate to solubilizer weight ratio is between about
1:1 and about 1:100.
2--A formulation according to claim 1 wherein the formulation
further includes at least one surfactant.
3--A formulation according to claim 1 wherein the formulation
further includes a gelling agent.
4--A formulation according to claim 2 wherein the formulation is a
self-emulsifying formulation wherein the water miscible fibrate
solubilizer is selected from N-C.sub.1-4 alkyl derivative of
2-pyrrolidone or C.sub.6-8 ethylene glycol monoether and mixtures
thereof, in combination with at least one C.sub.8-12 fatty acid
ester of polyethylene glycol and at least one non-ionic surfactant
with a HLB value lower than or equal to 10.
5--A formulation according to claim 2 wherein the solubilizer
comprises a non-oily component selected from N-C.sub.1-4 alkyl
derivative of 2-pyrrolidone, C.sub.6-8 ethylene glycol monoether
and combinations thereof; and an oily component selected from
C.sub.8-12 fatty acid ester of polyethylene glycol, fatty acids and
mixtures thereof.
6--A formulation according to claim 2 wherein the surfactant is
nonionic hydrophobic surfactant.
7--A formulation according to claims 1 or 5 wherein the solubilizer
is selected from mixtures of N-C.sub.1-4 alkyl derivative of
2-pyrrolidones, C.sub.6-8 ethylene glycol monoethers or
combinations thereof; with one or more polyethylene glycol mono-
and diester of C.sub.8-12 fatty acids or combinations of
polyethylene glycol mono- and diester of C.sub.8-12 fatty acids and
fatty acids.
8--A formulation according to claim 7 wherein the weight ratio of
the N-C.sub.1-4 alkyl derivative of 2-pyrrolidone or a C.sub.6-8
ethylene glycol monoethers or combinations thereof to one or more
polyethylene glycol mono- and diester of C.sub.8-12 fatty acids or
combinations of polyethylene glycol mono- and diester of C.sub.8-12
fatty acids and fatty acids is between about 100:1 to about
1:4.
9--A formulation according to claim 1 wherein the N-C.sub.1-4 alkyl
derivative of 2-pyrrolidone is selected from
N-Methyl-2-Pyrrolidone, N-Ethyl-2-pyrrolidone,
N-Propyl-2-pyrrolidone, N-Isopropyl-2-pyrrolidone,
N-Butyl-2-pyrrolidone, and N-(2-Hydroxyethyl)-2-pyrrolidone or
mixtures thereof.
10--A formulation according to claim 9 wherein the N-C.sub.1-4
alkyl derivative of 2-pyrrolidone is N-methyl-2-pyrrolidone.
11--A formulation according to claim 1 wherein the ethylene glycol
monoether is diethylene glycol monoethyl ether.
12--A formulation according to claim 6 wherein the surfactant has a
HBL value lower than or equal to 10.
13--A formulation according to claim 2 wherein the formulation
further includes at least one co-surfactant.
14--A formulation according to claim 13 wherein the
surfactant/co-surfactant combination has a HLB value lower than or
equal to 10.
15--A formulation according to claim 14 wherein the formulation
further includes a surfactant selected from non-ionic surfactants
with HLB values greater than 10 and at least one non-ionic
co-surfactant with low HLB values lower than or equal to 6.
16--A formulation according to claim 15 wherein the co-surfactant
is at least one non-ionic surfactants with HLB value between 10 and
18, one or more non-ionic co-surfactant with a HLB value between 2
and 6, provided that the HBL value of the combination is less than
or equal to 10.
17--A self-emulsifying oral pharmaceutical formulation with
improved bioavailability comprising: a therapeutically effective
amount of the fenofibrate or a fenofibrate derivative; at least one
non-ionic hydrophobic surfactant; and a water miscible fibrate
solubilizer selected from N-C.sub.1-4 alkyl derivative of
2-pyrrolidone, C.sub.3-8 ethylene glycol monoether, or combinations
thereof; mixed with at least one of C.sub.8-12 fatty acid ester of
polyethylene glycol, fatty acids or mixtures thereof.
18--A method of treating endogenous hyperlipidaemias,
hypercholesterolaemias and hypertriglyceridaemias in mammals
comprising the administration of a fibrate formulation of any of
claims 1 or 5.
19--A process for improving the bioavailability of fenofibrate or a
fenofibrate derivative comprising dissolving the fenofibrate or a
fenofibrate derivative in N-methyl-2-pyrrolidone.
20--A pharmaceutical dosage unit for oral administration comprising
of a fibrate formulation containing a therapeutically effective
dose of fenofibrate or a fenofibrate derivative dissolved in
N-alkyl derivative of 2-pyrrolidone, ethylene glycol monoether,
C.sub.8-12 fatty acid ester of polyethylene glycol, fatty acids, or
combinations thereof.
21--A pharmaceutical dosage unit for oral administration comprising
of a fibrate formulation containing a therapeutically effective
amount of the fenofibrate, a fenofibrate derivative or mixtures
thereof and one or more N-alkyl derivative of 2-pyrrolidone,
ethylene glycol monoether and mixtures thereof in combination with
at least one of C.sub.8-12 fatty acid ester of polyethylene glycol,
fatty acids and mixtures thereof, and at least one non-ionic
hydrophobic surfactant or surfactant combinations.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a non-aqueous
pharmaceutical formulation of fenofibrate or fenofibrate
derivatives having an improved oral bioavailability when compared
to a commercial available formulation.
BACKGROUND OF THE INVENTION
[0002] Fenofibrate is a fibrate used in the treatment of endogenous
hyperlipidaemias, hypercholesterolaemias and hypertriglyceridaemias
in adults. The preparation of fenofibrate is disclosed in U.S. Pat.
No. 4,058,552. Fenofibric acid, the active metabolite of
fenofibrate, produces reductions in total cholesterol, LDL
cholesterol, apolipoprotein B, total triglycerides and triglyceride
rich lipoprotein (VLDL) in treated patients. Also, treatment with
fenofibrate results in increases in high-density lipoprotein (HDL)
and apoproteins apoAI and apoAII. Prolonged treatment with
fenofibrate at the rate of 300 to 400 mg per day makes it possible
to obtain a reduction in total cholesterol of 20 to 25% and a
reduction in the levels of triglycerides of 40 to 50%. It thus
opposes the development of arteriosclerosis. The customary adult
fenofibrate dosage is three gelatin capsules per day, each
containing 100 mg of fenofibrate.
[0003] Fenofibrate is not soluble in water, which limits its
absorption in the gastrointestinal (GI) tract. To remedy this
problem, research groups have tried a multitude of strategies. In
U.S. Pat. Nos. 4,800,079 and 4,895,726 micronized fenofibrate
formulations of are disclosed. In U.S. Pat. No. 6,277,405 the
immediate release of micronized fenofibrate in a tablet or in the
form of granules inside a capsule is shown. In U.S. Pat. No.
6,074,670 the immediate release of micronized fenofibrate in a
solid state is shown. In U.S. Pat. No. 5,880,148 the combination of
fenofibrate and vitamin E is discussed, this formulation is claimed
to be useful as an antiatheromatous drug and exhibit a synergistic
effect in regards to protecting low-density lipoproteins (LDL) from
oxidation. In U.S. Pat. No. 5,827,536 the use of diethylene glycol
monoethyl ether (DGME) as solubilizer is discussed and an
enhancement in bioavailability claimed. In U.S. Pat. No. 5,545,628
the combination of fenofibrate with one or more polyglycolyzed
glycerides is disclosed.
[0004] In order to prepare the solid formulations of Fenofibrate,
the compound is normally dissolved in a proper solvent or
solubilizers. Fenofibrate is known to be soluble in many different
solubilizers, including anionic (e.g. SDS) and non-ionic (e.g.
Triton X-100) surfactants, complexing agents (N-methyl pyrrolidone)
(Temeljotov et al (1995) Farmacevtski Vestnik (Slovenia),
46/(Special Issue)).
[0005] The technology developed to increase the bioavailability of
fenofibrate includes elements and process steps that increase the
cost of production making them commercially unattractive. If a
formulation for the use fenofibrate and its method of preparation
of said formulation could be simplified while increasing the
bioavailability of fenofibrate, the resulting product would satisfy
an existing need in this field. The present invention provides such
a product, a liquid or semi-solid formulation with improved
bioavailability for oral administration of fenofibrate or
fenofibrate derivatives wherein the particle size of the active
agent is not critical to the bioavailability of the product.
SUMMARY OF THE INVENTION
[0006] The object of the present invention includes an oral
pharmaceutical formulation with improved bioavailability when
compared to a commercial available formulation comprising a
therapeutically effective amount of the a fibrate dissolved in
N-alkyl derivative of 2-pyrrolidone, ethylene glycol monoether,
C.sub.8-12 fatty acid ester of polyethylene glycol or combinations
thereof. The present invention additionally includes oral
pharmaceutical formulations with improved bioavailability
comprising a therapeutically effective amount of fenofibrate or a
fenofibrate derivative in a N-alkyl derivative of 2-pyrrolidone,
ethylene glycol monoether, C.sub.8-12 fatty acid ester of
polyethylene glycol or combinations thereof wherein the
bioavailability of the active ingredient is enhanced due to a
significant (P<0.05) change in the rate, C.sub.max, and/or
extent, AUC.sub.0-.infin., of absorption when compared to a
commercial available formulation such as Lipanthyl.RTM. (trade mark
of Groupe Fournier) or TriCor.RTM. (trade mark of Abbott
Laboratories).
[0007] In an alternate embodiment of the invention a fibrate
pharmaceutical formulation containing a therapeutically effective
amount of the fenofibrate or its derivatives dissolved in N-alkyl
derivative of 2-pyrrolidone, ethylene glycol monoether, C.sub.8-12
fatty acid ester of polyethylene glycol or combinations thereof and
at least one surfactant is disclosed.
[0008] According to a further aspect of the invention, there is
provided a method for treating a mammal with hypercholesterolaemia
or hypertriglyceridaemia comprising the oral administration of a
fibrate formulation containing a therapeutically effective dose of
fenofibrate or a fenofibrate derivative dissolved in N-alkyl
derivative of 2-pyrrolidone, ethylene glycol monoether, fatty
acids, fatty acids, C.sub.8-12 fatty acid ester of polyethylene
glycol or combinations thereof.
[0009] The present invention includes an self-emulsifying oral
pharmaceutical formulation with improved bioavailability comprising
a therapeutically effective amount of fenofibrate or a fenofibrate
derivative, at least one non-ionic hydrophobic surfactant (HLB
value lower than or equal to 10), and a water miscible fenofibrate
solubilizer selected from N-C.sub.1-4 alkyl derivative of
2-pyrrolidone, ethylene glycol monoether, or combinations thereof
mixed with at least one of fatty acids or C.sub.8-12 fatty acid
ester of polyethylene glycol.
[0010] The present invention also includes oral self-emulsifying
pharmaceutical formulations with improved bioavailability when
compared to a commercial available formulation comprising a
therapeutically effective amount of fenofibrate or a fenofibrate
derivative, one or more non-ionic surfactant with an HLB value
higher about 10, one or more non-ionic co-surfactant with a HLB
value lower or equal to about 6, provide that the
surfactant/co-surfactant combination has a HLB value lower than or
equal to about 10 and a water miscible fenofibrate solubilizer
selected from N-C.sub.1-4 alkyl derivative of 2-pyrrolidone,
ethylene glycol monoether, or combinations thereof mixed with at
least one of fatty acids or C.sub.8-12 fatty acid ester of
polyethylene glycol.
[0011] The present invention additionally includes an oral
self-emulsifying pharmaceutical formulation with improved
bioavailability comprising a therapeutically effective amount of
the fenofibrate or a fenofibrate derivative, one or more non-ionic
surfactant with an HLB value between 10 and 18, one or more
non-ionic co-surfactant with a HLB value between 2 and 6, and a
fenofibrate solubilizer selected from water miscible N-C.sub.1-4
alkyl derivative of 2-pyrrolidone, water miscible ethylene glycol
monoether, fatty acids, C.sub.8-12 fatty acid ester of polyethylene
glycol and combinations thereof wherein the bioavailability of the
active ingredient is significantly enhanced when compared to a
commercial available formulation due to a significantly (P<0.05)
enhanced rate (C.sub.max, reduction in the time to reach maximum
plasma levels, T.sub.max) and/or extent of absorption
(AUC.sub.0-.infin.) of the fibrate.
[0012] In an embodiment of the present invention fibrate
formulations described above wherein the improvement in C.sub.max
is at least 1.2 times than that for commercial formulation and/or
the AUC.sub.0-.infin.improvement is at least 1.5 times that of
commercial formulation are disclosed.
[0013] The scope of the invention includes a pharmaceutical dosage
unit for oral administration comprising of a fibrate formulation
containing a therapeutically effective dose of fenofibrate or a
fenofibrate derivative dissolved in N-alkyl derivative of
2-pyrrolidone, ethylene glycol monoether, fatty acids, C.sub.8-12
fatty acid ester of polyethylene glycol or combinations
thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0014] The present invention provides non-aqueous formulations with
enhanced systemic absorption of fenofibrate and/or derivatives of
fenofibrate when compared to a commercial available
formulation.
[0015] Due to the physicochemical properties of fibrates such as
fenofibrate, the systemic absorption of the drug is believed to be
dissolution rate limited. By providing an oral formulation wherein
the fenofibrate or fenofibrate derivative is dissolved in a water
miscible organic solvent such as the N-alkyl derivatives of
2-pyrrolidone, ethylene glycol monoether, C.sub.8-12 fatty acid
ester of polyethylene glycol or combinations thereof. The water
miscible solvent or solubilizer used in the present invention
additionally may act as an agent that prevents or minimizes the
crystallization of fibrate in the formulation upon contact with an
aqueous environment. The fibrate solubilizer may be a complexing
agent soluble in water. With the complete dissolution of the
fibrate, the fibrate solution allows for an increase in absorption
by the patient. The ease with which the fenofibrate or fenofibrate
derivative dissolves in a solvent is inversely proportional to the
particle size of the fibrate. Therefore, the present invention
includes an oral fibrate formulation comprising fenofibrate or a
fenofibrate derivative and a water miscible organic solubilizer
that allows the complete dissolution of the fenofibrate or a
fenofibrate derivative and prevents or minimizes the
crystallization of fibrate in the formulation upon contact with an
aqueous environment. The present invention includes fibrate
formulation wherein the fibrate to fibrate solubilizer weight ratio
is between about 1:1 and about 1:100.
[0016] As used in this application, the term "fatty acid"
represents a C.sub.1-30 unbranched or branched, saturated or
unsaturated hydrocarbon chain and a terminal carboxyl group.
[0017] The solubilizer comprises the combination of solvents,
surfactants, optional co-surfactants, and stabilizing agents used
in the formulation. In an embodiment of the present invention the
fibrate solubilizer may contain an oily component and a non-oily
component. The oily component of the solubilizer may consist of
alcohols, propylene glycol, polyethylene glycol, propylene glycol
esters, medium chain mono-, di-, or triglycerides, long chain fatty
acids, naturally occurring oils, and a mixture thereof. The oily
component of the solubilizer may contain non-surface active oils,
which have no hydrophile lipophile balance value. The non-oily
component of the solubilizer may contain molecules with highly
polar functionalities such as carbonyl groups as well as primary
amines with short chain (C.sub.1-C.sub.3) alkyl groups. The present
invention includes self-emulsifying fibrate formulation wherein the
fibrate to fibrate solubilizer weight ratio is between about 1:1
and about 1:100.
[0018] In a further embodiment of the present invention an oral
fenofibrate formulation comprising fenofibrate or a fenofibrate
derivative and a water miscible fibrate solubilizer is N-alkyl
derivative of 2-pyrrolidone, ethylene glycol monoether,
C.sub.8-12fatty acid ester of polyethylene glycol or combinations
thereof is provided. The formulations described may further contain
a gelling agent that alters the texture of the final formulation
through formation of a gel.
[0019] Gelling agents used in the present invention include but are
not limited to carrageenan, cellulose gel, colloidal silicon
dioxide, gelatin, propylene carbonate, carbonic acid, alginic acid,
agar, carboxyvinyl polymers or carbomers and polyacrylamides,
acacia, ester gum, guar gum, gum arabic, ghatti, gum karaya,
tragacanth, terra, pectin, tamarind seed, larch arabinogalactan,
alginates, locust bean, xanthan gum, starch, veegum, tragacanth,
polyvinyl alcohol, gellan gum, hydrocolloid blends, and
povidone.
[0020] The present invention further includes an oral
self-emulsifying fibrate formulation with improved oral
bioavailability comprising a therapeutically effective amount of
the fenofibrate or fenofibrate derivative dissolved in a water
miscible fibrate solubilizer selected from N-C.sub.1-4 alkyl
derivative of 2-pyrrolidone or ethylene glycol monoether and
mixtures thereof, in combination with at least one of fatty acids
and/or C.sub.8-12 fatty acid ester of polyethylene glycol and at
least one non-ionic surfactant with a high HLB value lower than or
equal to 10.
[0021] The present invention also provides an oral self-emulsifying
formulation wherein the fenofibrate is dissolved in one or more
non-ionic surfactant with an HLB value higher or equal to about 10,
one or more non-ionic co-surfactant with a HLB value lower or equal
to about 6, and a water miscible fenofibrate solubilizer selected
from N-C.sub.1-4 alkyl derivative of 2-pyrrolidone, ethylene glycol
monoether, C.sub.8-12 fatty acid ester of polyethylene glycol and
combinations thereof, wherein the resulting fenofibrate
self-emulsifying formulation allows for an improved systemic
absorption of the fenofibrate by the patient.
[0022] The term "HLB" value is defined as hydrophilic-lipophilic
balance and defines the relative hydrophilicity and hydrophobicity
of the surfactant. Surfactants with lower HLB values are more
hydrophobic, and have greater solubility in oils, while surfactants
with higher HLB values are more hydrophilic, and have greater
solubility in aqueous solutions. Surfactants having an HLB value
less than about 10 are considered to be hydrophobic surfactants.
Therefore hydrophilic surfactants have HLB values greater than
about 10. Combinations of hydrophilic surfactants and hydrophobic
surfactants thereof are within the scope of the present
invention.
[0023] The surfactants used in the present invention include those
having a HLB value of less than or equal to 10. These surfactants
may include propylene glycols, glyceryl fatty acids, glyceryl fatty
acid esters, polyethylene glycol esters, propylene glycol laureate,
glyceryl glycol esters, polyglycolyzed glycerides, propylene glycol
esters or partial esters and polyoxyethyl steryl ethers. Mixtures
of surfactants are also included in the scope of the invention.
These surfactants, mixtures, and other equivalent compositions
having an HLB less than or equal to 10 may be used for the
self-emulsifying formulation.
[0024] The use of surfactants with an HLB greater than 10 are
within the scope of the present invention. Surfactants that have a
HLB value greater than 10 may be used in combination with other
surfactant as co-surfactants. Suitable co-surfactants include
glyceryl glycol esters, polyethylene glycol esters, polyglycolyzed
glycerides, polyoxyethylene glycerol esters, oleate or laureate
ester of a polyalcohol copolymerized with ethylene oxide and a
mixture thereof. Examples of commercially available surfactants are
Labrasol, Gelucire 44/14 and Tween 80
[0025] The term "fenofibrate" is a fibrate and is defined as a
compound of formula (I),
2-[4-(4-Chlorobenzoyl)phenoxy]-2-methylpropanoic acid 1-methylethyl
ester: 1
[0026] The term "fenofibrate derivatives" is defined as a compound
of formula (II) 2
[0027] wherein
[0028] R.sub.1 represents a phenyl group or a phenyl group
substituted by one or more CH.sub.3, CF.sub.3 or by halogens;
[0029] R.sub.2 and R.sub.3 independently represent a hydrogen atom
or a halogen atom (preferably fluorine, chlorine, or bromine), an
C.sub.1-4 alkyl or an C.sub.1-5 alkoxy or one of the following
groups: CF.sub.3, SCH.sub.3, SOCH.sub.3, SO.sub.2CH.sub.3, or OH;
and
[0030] Y represents one of the following groups: OH; C.sub.1-5
alkoxy, preferably in C.sub.1-C.sub.4; --NR.sub.4R.sub.5 ;
--NHCH.sub.2CH.sub.2NR.sub.4R.sub.5; or --O--C.sub.1-6
alkylene-NR.sub.4R.sub.5, with the alkylene having, in particular,
two to six atoms of carbon, and with R.sub.4 and R.sub.5 being
identical or different and each representing a hydrogen atom or one
of the following groups: C.sub.1-5 alkyl, C.sub.3-C.sub.7
cycloalkyl, preferably C.sub.5-6 cycloalkyl; C.sub.6-10 aryl or
aryl substituted on the aromatic residue by one or more halogen,
methyl, or --CF.sub.3 groups; or else R.sub.4 and R.sub.5
constitute, together with the nitrogen atom to which they are
connected, one of the following groups: either an n-heterocyclic
group having 5 to 7 vertices capable of enclosing a second
heteroatom selected from N, O, and S, and capable of being
substituted; or else an amide residue derived from lysine or
cysteine; including the pharmaceutically acceptable salts, esters,
amides and prodrugs thereof
[0031] wherein said derivative has a solubility not less than 0.5
mg/ml in the water miscible solubilizer used in the fibrate
formulation object of the present invention.
[0032] The scope of the present invention includes formulations
summarized in Tables 1A and 1B:
1TABLE 1A Quantitative representation of fenofibrate formulations
in the form of non-emulsifiable systems, such as binary solutions
Amount Ingredient (% w/w) Fenofibrate 5-50 Solubilizer 5-50 Other
possible formulation additives* 0-70 *Excipients required for
stability enhancement of the final formulation these would include
antioxidants, thickening agents, suspending agents, etc.
[0033]
2TABLE 1B Quantitative representation of self-emulsifying
formulations providing for enhanced systemic absorption of
fenofibrate Amount Ingredient (% w/w) Fenofibrate 5-30 Total
oleaginous component 35-45 Solubilizer 5-30 Surfactant 10-15 Other
possible formulation additives* 5-15 *Excipients required for
stability enhancement of the final formulation, these would include
antioxidants, thickening agents, suspending agents, etc.
[0034] The present invention includes a fenofibrate formulation
wherein the water miscible fenofibrate solubilizer includes the use
of N-alkyl derivatives 2-pyrrolidones, wherein the alkyl group has
1 to 4 carbons, C.sub.6-8ethylene glycol monoethers, C.sub.8-12
fatty acid ester of polyethylene glycol, fatty acids or
combinations thereof is provided. The present invention includes
N-alkyl derivatives 2-pyrrolidone wherein the alkyl group has 1 to
3 carbons.
[0035] The amount of fibrates such as fenofibrate, fenofibrate
derivatives or mixtures thereof contained in the formulation of
this invention is not specifically restricted but may be any amount
convenient for pharmaceutical purposes. For filling a gel capsule,
a concentrated solution of up to the saturation point of the
fibrate solubilizer may be of interest. For example the solubility
of fenofibrate in N-methyl-2-pyrrolidone is about 591 mg/ml, so a
concentrated fenofibrate solutions of >500 mg/ml would be of
interest for use in the oral formulation object of the present
invention. The present invention would also include fenofibrate in
N-methyl-2-pyrrolidone solutions with concentrations below about
500 mg/ml.
[0036] In an alternate embodiment of the present invention, the
fenofibrate or fenofibrate derivative solubilizer is selected from
N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone,
N-propyl-2-pyrrolidone, N-isopropyl-2-pyrrolidone,
N-butyl-2-pyrrolidone, N-(2-hydroxyethyl)-2-py- rrolidone,
diethylene glycol monoethyl ether, polyethylene glycol mono- and
diester of C.sub.8-12 fatty acids and combinations thereof. The
invention includes the combination of the N-alkyl derivatives of
2-pyrrolidone with ethylene glycol monoether and/or C.sub.8-12
fatty acid ester of polyethylene glycol; or combinations of fatty
acids and C.sub.8-12 fatty acid ester of polyethylene glycol. The
formulation object of the present invention may use
N-methyl-2-pyrrolidone, diethylene glycol monoethyl ether,
polyethylene glycol mono- and diester of caproic acid, caprylic
acid, capric acid, lauric acid or mixtures of polyethylene glycol
mono- and diester of caproic acid, caprylic acid, capric acid,
lauric acid with one or more fatty acids selected from caproic
acid, caprylic acid, capric acid, lauric acid and mixtures thereof;
and combinations thereof as solubilizers of fenofibrate. The mono-
and diester of C.sub.8-12 fatty acids and combinations thereof also
include use of Captex.RTM. 100 , Captex.RTM. 200, Captex.RTM. 200
E-6, Capmul.RTM. MCM, Capmul.RTM. PG-8, Capmul.RTM. PG-10, (Abitec
Corp.) and Gelucire.RTM. 44/14, Gelucire.RTM. 50/13 (Gattefosse
Corp.). Combinations of N-Methyl-2-Pyrrolidone and diethylene
glycol monoethyl ether as fibrate solubilizers are within the scope
of the present invention. The invention includes combinations of
N-methyl-2-pyrrolidone and diethylene glycol monoethyl ether
wherein the weight rations of N-methyl-2-pyrrolidone to diethylene
glycol monoethyl ether is between about 1:0.01 and about 0.01:1.
The invention also includes combinations of N-methyl-2-pyrrolidone
and diethylene glycol monoethyl ether wherein the weight rations of
N-methyl-2-pyrrolidone to diethylene glycol monoethyl ether is
between about 1:0.1 and about 0.1:1.
[0037] In a further embodiment of the present invention, the water
miscible fibrate solubilizer is chosen from combinations of
N-C.sub.1-4 alkyl derivative of 2-pyrrolidone or a ethylene glycol
monoether or combinations thereof, with one or more polyethylene
glycol mono- or diester of C.sub.8-12 fatty acids or mixtures
polyethylene glycol mono- and diester of C.sub.8-12 fatty acids and
fatty acids. The weight ratio of the N-C.sub.1-4 alkyl derivative
of 2-pyrrolidone or a ethylene glycol monoether or combinations
thereof to one or more polyethylene glycol mono- and diester of
C.sub.8-12 fatty acids or mixtures polyethylene glycol mono- and
diester of C.sub.8-12 fatty acids and fatty acids is between about
100:1 to about 1:4. The present invention includes rations between
20:1 to about 1:4.
[0038] The amount of fibrate solubilizer used will depend on the
dose of fibrate; enough solubilizer should be used to maintain the
fibrate in solution. The weight ratio fibrate to the fibrate
solubilizer is chosen so as to obtain a complete dissolution of
fenofibrate or fenofibrate derivative. The fibrate: fibrate
solubilizer ratio is chosen to obtain a solution whose fibrate
concentration is below the saturation point. The weight ratio of
fibrate to fibrate solubilizer may be between about 1:1 to about
1:100. The weight ratios include about 1:1 to about 1:10. The
fibrate:fibrate solubilizer weight ratio may also be between about
3:4 to about 1:100. The fibrate:fibrate solubilizer weight ratio
between about 3:4 to about 1:10 is within the scope of the
invention.
[0039] The present invention includes an oral fibrate formulation
comprising fenofibrate or a fenofibrate derivative and a water
miscible organic solubilizer that allows the complete dissolution
of the fenofibrate or a fenofibrate derivative and prevents or
minimizes the crystallization of fibrate in the formulation upon
contact with an aqueous environment with an improved
bioavailability equal to or greater that about 10%. The invention
includes fibrate formulation comprising a therapeutically effective
amount of the fenofibrate, a fenofibrate derivative or combinations
thereof and a N-alkyl derivative of 2-pyrrolidone, or combinations
of N-alkyl derivative of 2-pyrrolidones, ethylene glycol monoether,
C.sub.8-12 fatty acid ester of polyethylene glycol or combinations
thereof. The bioavailability is enhanced due to a significantly
(P<0.05) enhanced rate (C.sub.max, reduction in the time to
reach maximum plasma levels, T.sub.max) and/or extent of absorption
(AUC.sub.0-.infin.). The % bioavailability enhancement value is
defined as the ratio obtained by formula (III):
{(AUC.sub.0-24 (fibrate formulation)/Dose.sub.fibrate
formulation)/(AUC.sub.0-24 (Commercial
formulation)/Dose.sub.Commercial formulation)}.times.100 (III)
[0040] The present invention includes the use of
N-methyl-2-pyrrolidone (NMP) in a formulation to solubilize
fenofibrate and/or its derivatives with similar solubility profile,
and enhance bioavailability after oral administration to a %
enhancement value equal to or greater than 50%.
N-methyl-2-pyrrolidone is an organic liquid excipient and is also
known as 1-methyl pyrrolidinone, N-methyl-2-pyrrolidinone,
1-methyl-5-pyrrolidinone, methylpyrrolidinone,
N-methylpyrrolidinone, methylpyrrolidinone, N-methylpyrrolidone,
M-pyrol, and NMP.
[0041] The present invention additionally includes an oral
pharmaceutical formulation with improved oral bioavailability
comprising a therapeutically effective amount of fenofibrate, a
fenofibrate derivative or mixtures thereof and one or more
solubilizers selected from N-alkyl derivative of 2-pyrrolidone,
ethylene glycol monoether, C.sub.8-12 fatty acid ester of
polyethylene glycol, mixtures of C.sub.8-12 fatty acid ester of
polyethylene glycol and fatty acids, or combinations thereof
wherein the bioavailability of said formulation is significantly
(P<0.05) enhanced in both the rate (C.sub.max) and the extent
(AUC.sub.0-.infin.) of absorption as compared to that of a
commercial formulation. The present invention includes said
formulations wherein the improvement in C.sub.max is at least about
1.2 times that of a commercial formulation such as Lipanthyl.RTM.
(trade mark of Groupe Fournier) or TriCor.RTM. (trade mark of
Abbott Laboratories) and/or the AUC.sub.0-.infin. improvement is at
least about 1.5 times that of a commercial formulation such as
Lipanthyl.RTM. (trade mark of Groupe Fournier) or TriCor.RTM.
(trade mark of Abbott Laboratories).
[0042] The present invention further includes oral self-emulsifying
fibrate formulation with improved oral bioavailability comprising a
therapeutically effective amount of the fenofibrate or fenofibrate
derivative dissolved in a water miscible fibrate solubilizer
selected from N-C.sub.1-4 alkyl derivative of 2-pyrrolidone or
ethylene glycol monoether and mixtures thereof, in combination with
at least one C.sub.8-12 fatty acid ester of polyethylene glycol and
at least one non-ionic surfactant with a high HLB value lower than
or equal to 10 wherein the oral bioavailability of said formulation
is significantly (P<0.05) enhanced in both the rate (C.sub.max)
and the extent (AUC.sub.0-.infin.) of absorption as compared to
that of a commercial formulation such as Lipanthyl .RTM. (trade
mark of Groupe Fournier) or TriCor.RTM. (trade mark of Abbott
Laboratories). The present invention includes said formulations
wherein the improvement in C.sub.max is at least 1.2 times that a
commercial formulation such as Lipanthyl.RTM. (trade mark of Groupe
Fournier) or TriCor.RTM. (trade mark of Abbott Laboratories) and/or
the AUC.sub.-.infin. improvement is at least 1.5 times that of a
commercial formulation such as Lipanthyl.RTM. (trade mark of Groupe
Fournier) or TriCor.RTM. (trade mark of Abbott Laboratories).
[0043] The present invention also provides an oral self-emulsifying
formulation wherein the fenofibrate is dissolved in one or more
non-ionic surfactant with an HLB value higher or equal to about 10,
one or more non-ionic co-surfactant with a HLB value lower or equal
to about 6, and a water miscible fenofibrate solubilizer selected
from N-C.sub.1-4 alkyl derivative of 2-pyrrolidone, ethylene glycol
monoether, C.sub.8-12 fatty acid ester of polyethylene glycol or
mixtures of C.sub.8-12 fatty acid ester of polyethylene glycol and
fatty acids, and combinations thereof, wherein the resulting
fenofibrate self-emulsifying formulation allows for an improved
systemic absorption of the fenofibrate by the patient and the oral
bioavailability of said formulation is significantly (P<0.05)
enhanced in both the rate (C.sub.max) and the extent
(AUC.sub.0-.infin.) of absorption as compared to that of a
commercial formulation such as Lipanthyl.RTM. (trade mark of Groupe
Fournier) or TriCor.RTM. (trade mark of Abbott Laboratories). The
present invention includes said formulations wherein the
improvement in C.sub.max is at least 1.2 times that a commercial
formulation such as Lipanthyl.RTM. (trade mark of Groupe Fournier)
or TriCor.RTM. (trade mark of Abbott Laboratories). and/or the
AUC.sub.0-.infin. improvement is at least 1.5 times that of a
commercial formulation such as Lipanthyl.RTM. (trade mark of Groupe
Fournier) or TriCor.RTM. (trade mark of Abbott Laboratories).
[0044] The present invention additionally includes an oral
self-emulsifying pharmaceutical formulation with improved
bioavailability comprising a therapeutically effective amount of
the fenofibrate or a fenofibrate derivative, one or more non-ionic
surfactant with an HLB value between 10 and 18, one or more
non-ionic co-surfactant with a HLB value between 2 and 6, and a
fenofibrate solubilizer selected from water miscible N-C.sub.1-4
alkyl derivative of 2-pyrrolidone, water miscible ethylene glycol
monoether, C.sub.8-12 fatty acid ester of polyethylene glycol or
mixtures of C.sub.8-12 fatty acid ester of polyethylene glycol and
fatty acids, and combinations thereof wherein the bioavailability
of the active ingredient is significantly enhanced, wherein the
fenofibrate may or may not be micronized. The bioavailability when
compared to a commercial available formulation is enhanced due to a
significantly (P<0.05) enhanced rate (reduction in the time to
reach maximum plasma levels, T.sub.max) and/or extent of absorption
(AUC.sub.0-.infin.).
[0045] The oral formulation object of the present invention may be
provided in the form of a solution, a self-emulsifying system, a
straight binary system, semi-solid system or any other
pharmaceutically acceptable form. The oral formulation may be
encapsulated in a hard or soft gelatin capsule, a starch capsule or
any other pharmaceutically acceptable capsule.
[0046] The present invention includes a pharmaceutical formulation
with improved oral bioavailability when compared to a commercially
available formulation comprising a therapeutically effective amount
of the fenofibrate, a fenofibrate derivative or mixtures thereof
dissolved in a solubilizer selected from N-alkyl derivative of
2-pyrrolidone, ethylene glycol monoether, C.sub.8-12 fatty acid
ester of polyethylene glycol or mixtures of C.sub.8-12 fatty acid
ester of polyethylene glycol and fatty acids, or mixtures thereof
and at least one non-ionic surfactant with an HLB value higher or
equal to about 10.
[0047] The present invention includes the use of surfactants
selected from sucrose esters, polysorbates, polyethylene
glycosylated glycerides, PEGylated glycerides and combinations
thereof. These non-ionic surfactant may include mixtures of
monoglycerides, diglycerides, and triglycerides and monoesters and
diesters of polyethylene glycol, polyethylene glycosylated almond
glycerides, polyethylene glycosylated corn glycerides, polyethylene
glycosylated caprylic/capric triglyceride, polysorbate 20,
polysorbate 60, polysorbate 80, Polyoxyl 20 Cetostearyl Ether,
Polyoxyl 10 Oleyl Ether and combinations thereof. Additionally
suitable non-ionic surfactants include PEG stearate, PEG
hydrogenated castor oil, PEG laurate, PEG apricot kernel oil
esters, PEG caprylate, PEG caprate, PEG myristate, PEG palmitate,
and PEG oleate and combinations thereof.
[0048] The present invention includes an oral self-emulsifying
pharmaceutical formulation with improved bioavailability comprising
a therapeutically effective amount of the fenofibrate, a
fenofibrate derivative or mixtures thereof and dissolved in one or
more N-alkyl derivative of 2-pyrrolidone or ethylene glycol
monoether or mixtures thereof, combined with at least one
C.sub.8-12 fatty acid ester of polyethylene glycol or mixtures of
C.sub.8-12 fatty acid ester of polyethylene glycol and fatty acids,
and at least one non-ionic hydrophobic surfactants. The formulation
includes the use of surfactants with an HLB value lower than or
equal to about 10. The present invention also includes the use of
non-ionic surfactants with an HLB value lower or equal to about 6.
The present invention also includes the use of surfactants selected
from mono-acyl glycerides, sorbitan fatty acid esters, sucrose
distearate, ethylene glycol monoether and combinations thereof.
[0049] Non-ionic surfactants used in the oral self-emulsifying
pharmaceutical formulation with improved bioavailability object of
the present invention may include sorbitan tristearate, sorbitan
sesquioleate, glyceryl monostearate, sorbitan monooleate, sorbitan
monostearate, sorbitan distearate, propylene glycol monostearate,
glyceryl monooleate, glyceryl stearate mono, propylene glycol
monolaurate, glyceryl monolaurate, diethylene glycol monoethyl
ether and combinations thereof.
[0050] The present invention includes an oral self-emulsifying
pharmaceutical formulation with improved bioavailability comprising
a therapeutically effective amount of the fenofibrate, a
fenofibrate derivative or mixtures thereof and one or more N-alkyl
derivative of 2-pyrrolidone, ethylene glycol monoether and mixtures
thereof in combination with at least one C.sub.8-12 fatty acid
ester of polyethylene glycol or mixtures of C.sub.8-12 fatty acid
ester of polyethylene glycol and fatty acids, at least one
non-ionic surfactant with an HLB value higher than about 10 and at
least one non-ionic co-surfactants with an HLB value lower than or
equal to about 6. The invention includes formulations wherein the
combinations of the high HLB and low HLB value surfactants have a
final HLB value equal to or lower han 10.
[0051] The present invention includes an oral self-emulsifying
pharmaceutical formulation comprising a fibrate dissolved in a
fibrate solubilizer composed of a non-oily component selected from
N-alkyl derivative of 2-pyrrolidone, ethylene glycol monoether and
mixtures thereof and an oily component comprising one or more
C.sub.8-12fafty acid esters of polyethylene glycol; and at least
one surfactant with an HLB value lower than or equal to about
10.
[0052] The present invention also includes an oral self-emulsifying
pharmaceutical formulation with improved bioavailability comprising
a therapeutically effective amount of the fenofibrate, a
fenofibrate derivative or mixtures thereof and combinations of one
or more N-alkyl derivative of 2-pyrrolidone with ethylene glycol
monoether, at least one C.sub.8-12 fatty acid ester of polyethylene
glycol or mixtures of C.sub.8-12 fatty acid ester of polyethylene
glycol and fatty acids, at least one non-ionic surfactant with an
HLB value higher than about 10 selected from sucrose esters,
polysorbates, polyethylene glycosylated glycerides, PEGylated
glycerides and combinations thereof; and at least one non-ionic
co-surfactant with an HLB value lower or equal to about 6 selected
from mono-acyl glycerides, sorbitan fatty acid esters, sucrose
distearate, ethylene glycol monoether and combinations thereof
wherein the combination of the high HLB and low HLB value
surfactants have a final HLB value equal to or lower than 10. The
invention includes those oral self-emulsifying pharmaceutical
formulation with improved bioavailability described above wherein
the improvement in C.sub.max is at least 1.2 times that of a
commercial formulation such as Lipanthyl.RTM. (trade mark of Groupe
Fournier) or TriCor.RTM. (trade mark of Abbott Laboratories) and/or
the AUC.sub.0-.infin. improvement is at least 1.5 times that of a
commercial formulation such as Lipanthyl ( (trade mark of Groupe
Fournier) or TriCor.RTM. (trade mark of Abbott Laboratories).
[0053] All the formulations object of the present invention may be
prepared using both micronized and non-micronized fibrate.
[0054] Other commonly used pharmaceutical excipients which may also
be added to the formulations object of the present invention, these
may include antioxidants, preservatives or stabilizing agents, such
as butylated hydroxytoluene, butylated hydroxyanisole sodium
bisulfide, sodium sulfite, citric acid, ascorbic acid, or EDTA,
coloring agents and flavoring agents (to improve patient
acceptance, especially for liquid dosage forms), and ingredients
used to stabilize gelatin capsules, such as glycerine, or
gelatin.
[0055] The fibrate formulations disclosed are useful in the
treatment of hypercholesterolaemias and hypertriglyceridaemias.
According to a further aspect of the invention, there is provided a
method for treating a patient with hypercholesterolaemia or
hypertriglyceridaemia comprising the oral administration of a
fibrate formulation containing a therapeutically effective dose of
fenofibrate, a fenofibrate derivative or mixtures thereof dissolved
in a water miscible solubilizer selected from N-C.sub.1-4 alkyl
derivative of 2-pyrrolidone, 2-C.sub.6-8 ethylene glycol
monoethers, C.sub.8-12 fatty acid ester of polyethylene glycol or
combinations thereof. The method of treatment may include the use
of fibrate formulation described above. As will be appreciated by
those skilled in the art, the formulations object of the present
invention can be used prophylaxis as well as the treatment of
established symptoms.
[0056] In an alternate embodiment of the present invention includes
the use of a therapeutically effective dose of fenofibrate, a
fenofibrate derivative or mixtures thereof dissolved in a water
miscible solubilizer selected from N-C.sub.1-4 alkyl derivative of
2-pyrrolidone, C.sub.6-8 ethylene glycol monoethers, C.sub.8-12
fatty acid ester of polyethylene glycol, fatty acids or
combinations thereof in the preparation of a medicament for the
treatment of hypercholesterolaemias and hypertriglyceridaemias.
[0057] The present invention includes a solubilization process of
fenofibrate, fenofibrate derivative or mixtures thereof wherein
fenofibrate, fenofibrate derivative or combinations thereof are
solubilized in N-alkyl derivative of 2-pyrrolidone or mixtures of
N-C.sub.1-4 alkyl derivative of 2-pyrrolidones or combinations of
N-C.sub.1-4 alkyl derivative of 2-pyrrolidone with C.sub.6-8
ethylene glycol monoethers. The NMP is included in the scope of the
invention.
[0058] A further aspect of the present invention includes a process
for improving the bioavailability of fenofibrate, a fenofibrate
derivative or mixtures thereof comprising dissolving the active
agent in water miscible solubilizer selected from N-alkyl
derivative of 2-pyrrolidone, ethylene glycol monoether, C.sub.8-12
fatty acid ester of polyethylene glycol, fatty acids or
combinations thereof. The present invention includes a process for
improving the bioavailability of fenofibrate or a fenofibrate
derivative comprising dissolving the fenofibrate or a fenofibrate
derivative in N-methyl-2-pyrrolidone.
[0059] The scope of the invention includes a pharmaceutical dosage
unit for oral administration comprising of a fibrate formulation
containing a therapeutically effective dose of fenofibrate or a
fenofibrate derivative dissolved in N-alkyl derivative of
2-pyrrolidone, ethylene glycol monoether, C.sub.8-12 fatty acid
ester of polyethylene glycol, fatty acids, or combinations
thereof.
[0060] The scope of the invention includes a pharmaceutical dosage
unit for oral administration comprising of a fibrate formulation
containing a therapeutically effective amount of the fenofibrate, a
fenofibrate derivative or mixtures thereof and one or more N-alkyl
derivative of 2-pyrrolidone, ethylene glycol monoether and mixtures
thereof in combination with at least one of C.sub.8-12 fatty acid
ester of polyethylene glycol, fatty acids an mixtures thereof, and
at least one non-ionic surfactant with an HLB value lower than
about 10.
[0061] The scope of the invention includes a pharmaceutical dosage
unit for oral administration comprising of a self emulsifying
fibrate formulation containing a therapeutically effective amount
of the fenofibrate, a fenofibrate derivative or mixtures thereof
and one or more N-alkyl derivative of 2-pyrrolidone, ethylene
glycol monoether and mixtures thereof in combination with at least
one of C.sub.8-12fatty acid ester of polyethylene glycol or
mixtures of C.sub.8-12 fatty acid ester of polyethylene glycol and
fatty acids, at least/one non-ionic surfactant with an HLB value
higher than about 10 and at least one non-ionic co-surfactants with
an HLB value lower than or equal to about 6. The invention includes
a pharmaceutical dosage unit for oral administration comprising of
a self-emulsifying fibrate formulation wherein the combinations of
the high HLB and low HLB value surfactants have a final HLB value
equal to or lower than 10.
[0062] In an alternate embodiment of the present invention a method
of preparation for a oral formulation of fenofibrate or fenofibrate
derivative with an improved bioavailability comprising:
[0063] dissolving the fenofibrate, fenofibrate derivative or
mixtures thereof in an appropriate volume of water miscible
solubilizer selected from N-alkyl derivative of 2-pyrrolidone,
ethylene glycol monoether, C.sub.8-12 fatty acid ester of
polyethylene glycol or combinations thereof to obtain a fenofibrate
solution; and
[0064] incorporating the fibrate solution into a capsule.
[0065] The present process may additionally include the banding of
the capsule to prevent leakage.
[0066] In an alternate embodiment of the present invention a method
of preparation for a oral formulation of fenofibrate or fenofibrate
derivative with an improved bioavailability comprising:
[0067] dissolving the fenofibrate, fenofibrate derivative or
mixtures thereof in an appropriate volume of water miscible
solubilizer selected from N-alkyl derivative of 2-pyrrolidone,
C.sub.6-8 ethylene glycol monoethers, C.sub.8-12 fatty acid ester
of polyethylene glycol, mixtures of C.sub.8-12 fatty acid ester of
polyethylene glycol and fatty acids, or combinations thereof;
and
[0068] incorporating the fenofibrate formulation into a
capsule.
[0069] In an alternate embodiment of the present invention a method
of preparation for a oral formulation of fenofibrate or fenofibrate
derivative with an improved bioavailability comprising:
[0070] dissolving the fenofibrate, fenofibrate derivative or
mixtures thereof in an appropriate volume of water miscible
solubilizer selected from combinations of one or more N-alkyl
derivative of 2-pyrrolidone, with ethylene glycol monoether or
C.sub.8-12 fatty acid ester of polyethylene glycol or fatty acids
or mixtures thereof; and a surfactant/co-surfactant mixture
comprising at least one non-ionic surfactants with an HLB value
higher or equal to about 10 and least one non-ionic co-surfactants
with an HLB value lower or equal to about 6; and
[0071] incorporating the fenofibrate formulation into a
capsule.
[0072] In an alternate embodiment of the present invention a method
of preparation for a oral formulation of fenofibrate or fenofibrate
derivative with an improved bioavailability comprising:
[0073] dissolving the fenofibrate, fenofibrate derivative or
mixtures thereof in an appropriate volume of a fibrate solubilizers
defined above to obtain a fenofibrate solution;
[0074] mixing the fenofibrate solution with an appropriate amount
of a molten gelling agent to obtain a hot fenofibrate gel; and
[0075] incorporating the fenofibrate gel into a capsule.
[0076] In an alternate embodiment of the present invention a method
of preparation for a oral formulation of fenofibrate or fenofibrate
derivative with an improved bioavailability comprising:
[0077] dissolving the fenofibrate, fenofibrate derivative or
mixtures thereof in an appropriate volume of a fibrate solubilizers
defined above to obtain a fenofibrate solution;
[0078] the liquid solution is mixed with appropriate amounts of an
adsorbing powder (suitable adsorbing powder include dibasic calcium
phosphate); to obtain a free flowing powder mixture; and
[0079] incorporation of said free flowing powder mixture into a
capsule.
[0080] The present invention also includes a commercial package
containing a fenofibrate formulation containing a therapeutically
effective dose of fenofibrate, a fenofibrate derivative or mixtures
thereof dissolved water miscible solubilizer selected from
N-C.sub.1-4 alkyl derivative of 2-pyrrolidone, C.sub.6-8 ethylene
glycol monoethers, C.sub.8-12 fatty acid ester of polyethylene
glycol, fatty acids or combinations thereof. The formulation may
further contain one or more non-ionic surfactants. The commercial
package further includes instructions for the use of the
pharmaceutical formulation in the treatment of
hypercholesterolaemias and hypertriglyceridaemias in mammals. If
required, the pharmaceutical formulation is admixed with a
pharmaceutically acceptable carrier, excipient or adjuvant. The
pharmaceutical agent may be incorporated into a drug delivery
device suitable for oral administration and enclosed in a
pharmaceutical acceptable container.
[0081] The following examples illustrate the present invention in a
manner of which it can be practiced but, as such, should not be
construed as limitations upon the overall scope of the processes of
this invention.
EXAMPLE 1
Liquid Formulation
[0082] Formulation PD0106-40B was prepared by first dissolving the
active (fenofibrate) in appropriate amounts of NMP. Upon complete
dissolution of the drug in NMP, the remaining excipients were added
and the final solution was encapsulated in size 0 hard gelatin
capsules. The filled capsules were then banded using a Quali-Seal
lab top banding machine to prevent leakage of the fill contents
from the capsules.
[0083] Formulation PD01 06-50 was prepared similarly in that the
drug was first dissolved in NMP and then an appropriate amount of a
molten agent such as polyglycolyzed glyceride (e.g. Gelucire 50/13)
was added to this solution. The hot melt was encapsulated into size
1 hard gelatin capsules. The solution in the capsules congealed
upon reaching room temperature and thus the final state of the fill
material was semi-solid, gel-like, matter. This formulation is
advantageous in that once processing step, namely leak proof
banding, is eliminated from the manufacturing scheme.
3TABLE 2 Composition of Typical Formulations of Fenofibrate
PD0106-40B PD0106-50 Ingredients A B A B Fenofibrate 67 15 67 20
NMP 89.4 20 67 20 Captex 200 179 40 -- -- Gelucire 44/14 89 20
Cremophor RH 11 2.5 -- -- 40 Span 80 11 2.5 -- -- Gelucire 50/13 --
-- 201 60 A = composition in mg per capsule B = composition in %
weight Note: Captex 200 is a trade name for Propylene Glycol
Dicaprylate/Dicaprate and marketed by Abitec Corp. Gelucire 44/14
and 50/13 are trade names for a mixture of mono-, di- and
triglycerides and mono- and di- fatty acid esters of polyethylene
glycol and marketed by Gattefosse Corp. Cremophor RH40 is a trade
name for PEG-n-Hydrogenated Castor Oil and marketed by BASF Corp.
Span 80 is a trade name for sorbitan monooleate and marketed by ICI
Chemical.
[0084] Content uniformity tests were conducted by determining the
amount of fenofibrate in each of 10 capsules (Samples A through J)
using a high pressure liquid chromatography (HPLC) methodology
specific for fenofibrate detection. The relative standard deviation
(RSD) of the average of 10 capsules is then taken as an indicator
of content uniformity with %RSD<5.0 as passing. The content
uniformity data is given in Table 2 below.
4TABLE 3 Content Uniformity Data for Fenofibrate Capsule
Formulation PD0106-32B Sample X Y A 66.46 99.2 B 67.85 101.3 C
66.73 99.6 D 65.06 97.1 E 69.47 103.7 F 67.27 100.4 G 66.20 98.8 H
66.98 100.0 I 67.84 101.3 J 67.20 100.3 Mean 67.11 100.2 % RSD 1.74
X = weight (mg) per capsule Y = percent label claim per capsule
EXAMPLE 2
Biologic Activity
[0085] Formulations tested were administered orally to dogs using
67 mg capsules of enofibrate. Two formulations containing NMP as a
solubilizer were tested in vivo as part of the dog study (n=5). The
formulations were prepared similar to that described in example 1.
Lipanthyl.RTM. (current marketed fenofibrate product) served as the
reference formulation, and the two test formulations were liquid
filled (PD0106-40B) and gel filled (PD0106-50) capsules.
5TABLE 4 Plasma Concentrations of Fenofibrate in Fasted Dogs after
a 67 mg Dose Formulation (Fenofibrate C.sub.max T.sub.max
AUC.sub.0-24 % Strength) (.mu.g/ml) (hr) (.mu.g.hr/ml) Enhancement
Lipanthyl .RTM. SD 1.88 1.6 11.08 -- 67 mg 0.97 0.9 9.42 PD0106-40B
SD 6.11 1.4 29.96 270 67 mg 2.49 0.5 11.87 PD0106-50 SD 3.60 0.9
18.11 164 67 mg 1.06 0.2 3.65 * Enhancement values were calculated
by (AUC.sub.0-24 (test)/AUC.sub.0-24 (Lipanthyl)) .times. 100
[0086] The data summarized in Table 3. The mean C.sub.max for
Lipanthyl.RTM., PD0106-40B, and PD0106-50 were 1.88, 6.11, and 3.60
.mu.g/ml, respectively. The mean AUC.sub.0-24 for Lipanthyl.RTM.,
PD0106-40B, and PD0106-50 were 11.08, 29.96, and 18.11 .mu.g.hr/ml,
respectively. Both test formulations were effective in
significantly increasing the C.sub.max and AUC.sub.0-24 compared to
Lipanthyl.RTM..
[0087] Note:
[0088] Lipanthyl is a registered trademark of Groupe Fournier and
is used as a reference formulation.
EXAMPLE 3
Semi-solid Fenofibrate Formulation
[0089] Formulations are prepared following the procedure outlined
in Example 1.
6TABLE 5 Examples of formulations of fenofibrate in hard gelatin
capsule: Ingredient Amount Fenofibrate 150 mg 54 mg 54 mg (20% W/W)
(20% W/W) (20% W/W) NMP 150 mg 54 mg 40.5 mg (20% W/W) (20% W/W)
(15% W/W) Gelucire 50/13 450 mg 162 mg 175.5 mg (60% W/W) (60% W/W)
(65% W/W) TOTAL 750 mg 270 mg 270 mg
EXAMPLE 4
Self-Emulsifying Formulations
[0090] A) Formulation PD0106-36 and PD0106-72
[0091] The formulations were prepared by first dispersing
non-micronized fenofibrate in appropriate amounts of DGME. Upon
complete wetting and dispersion of the drug in DGME, the remaining
excipients were added and the final formulation was in the form of
a solution. This solution was encapsulated in size 0 hard gelatin
capsules. The filled capsules were then banded using a Quali-Seal
lab top banding machine to prevent leakage of the fill contents
from the capsules.
7TABLE 6A Composition of A Self-Emulsifying Formulation of
Fenofibrate PD0106-72 PD0106-36 Ingredients A B A* B Fenofibrate 54
15 67 15 Transcutol .RTM. P 108 30 134 30 (DGME) Captex .RTM. 162
45 201 45 200 Labrasol .RTM. 18 5 22 5 Span .RTM. 80 18 5 22 5 *A =
composition in mg per capsule B = composition in % weight
[0092] Note:
[0093] Transcutol.RTM. P is a trade name for Diethylene Glycol
Monoethyl Ether, USP/NF, and is marketed by Gattefosse Corp.
[0094] Captex.RTM. 200 is a trade name for Propylene Glycol
Dicaprylate/Dicaprate and marketed by Abitec Corp.
[0095] Labrasol.RTM. is a trade name for Caprylocaproyl
Macrogolglycerides, EP, and is marketed by Gattefosse Corp.
[0096] Span.RTM. 80 is a trade name for sorbitan monooleate and
marketed by ICI Chemical.
[0097] Content uniformity tests were conducted by determining the
amount of fenofibrate in each of 10 capsules (Samples A through J)
using a high pressure liquid chromatography (HPLC) methodology
specific for fenofibrate detection. The relative standard deviation
(RSD) of the average of 10 capsules is then taken as an indicator
of content uniformity with %RSD<5.0 as passing. The content
uniformity data is given in Table 6C below.
[0098] B) Formulation PD0106-40B
[0099] Formulation PD0106-40B was prepared by first dissolving the
non-micronized fenofibrate in appropriate amounts of NMP. Upon
complete dissolution of the drug in NMP, the remaining excipients
were added and the final solution was encapsulated in size 0 hard
gelatin capsules. The filled capsules were then banded using a
Quali-Seal lab top banding machine to prevent leakage of the fill
contents from the capsules.
8TABLE 6B Composition of A Self-Emulsifying PD0106-40B Formulation
of Non-Micronized Fenofibrate PD0106-40B Ingredients A B
Fenofibrate 67 15 NMP 89.4 20 Captex .RTM. 200 179 40 Gelucire
.RTM. 44/14 89 20 Cremophor .RTM. 11 2.5 RH 40 Span .RTM. 80 11 2.5
* A = composition in mg per capsule B = composition in % weight
Note: Captex .RTM. 200 is a trade name for Propylene Glycol
Dicaprylate/Dicaprate and marketed by Abitec Corp. Gelucire .RTM.
44/14 and 50/13 are trade names for a mixture of mono-, di- and
triglycerides and mono- and di- fatty acid esters of polyethylene
glycol and marketed by Gattefosse Corp. Cremophor .RTM. RH40 is a
trade name for PEG-n-Hydrogenated Castor Oil and marketed by BASE
Corp. Span .RTM. 80 is a trade name for sorbitan monooleate and
marketed by ICI Chemical.
[0100]
9TABLE 6C Content Uniformity Data for Fenofibrate Capsule
Formulation PD0106-36 Sample mg % A 63.00 94.0 B 71.75 107.1 C
71.75 107.1 D 65.30 97.5 E 65.91 98.4 F 70.59 105.4 G 72.57 108.3 H
68.25 101.90 I 65.03 97.1 J 67.46 100.7 Mean 68.16 101.8 % RSD
4.92
[0101]
10TABLE 6D Self-emulsifying system with NMP/Captex 200 as the
solubilizer PD0106-77A* Ingredients A B(mg) Fenofibrate 15% 300 NMP
30% 600 Captex 200 45% 900 Labrasol 5% 100 Span 80 5% 100
*Formulation in both LiCaps (CAPSUGEL) and Conisnaps (CAPSUGEL)
Note: Transcutol .RTM. P is a trade name for Diethylene Glycol
Monoethyl Ether, USP/NF, and is marketed by Gattefosse Corp.
[0102]
11TABLE 6E Self-emulsifying system with NMP/Transcutol/Captex 200
mixture as the solubilizer PD0106-77C* Ingredients A B (mg)
Fenofibrate 15% 300 Transcutol 24% 480 NMP 6% 120 Captex 200 45%
900 Labrasol 5% 100 Span 80 5% 100 *Formulation in both LiCaps
(CAPSUGEL) and Conisnaps (CAPSUGEL)
[0103]
12TABLE 6F Self-emulsifying system with NMP/Transcutol/Captex 200
mixture as the solubilizer PD0106-77D* Ingredients A B (mg)
Fenofibrate 15% 300 Transcutol 15% 300 NMP 15% 300 Captex 200 45%
900 Labrasol 5% 100 Span 80 5% 100 *Formulation in both LiCaps
(CAPSUGEL) and Conisnaps (CAPSUGEL)
[0104]
13TABLE 6G Self-emulsifying system with NMP/Transcutol/Miglyol 812
mixture as the solubilizer PD0106-77F* Ingredients A B (mg)
Fenofibrate 15% 300 Transcutol 24% 480 NMP 6% 120 Miglyol 812 45%
900 Labrasol 5% 100 Span 80 5% 100 *Formulation in both LiCaps
(CAPSUGEL) and Conisnaps (CAPSUGEL)
[0105] Note:
[0106] Miglyol is a registered trade mark for of Caprylic-/Capric
acid Triglycerides composed of saturated C.sub.8 (50-65%) and
C.sub.10 (30-45%) triglycerides and owned by Dynamit Nobel
Aktiengesellschaft Corporation
14TABLE 6H Self-emulsifying system with NMP/Transcutol/fatty
acids/Captex 200 mixture as the solubilizer PD0106-77G* Ingredients
A B (mg) Fenofibrate 15% 300 Transcutol 14% 280 NMP 14% 280 Captex
200 45% 900 Labrasol 5% 100 Capric acid 1% 20 Caprylic acid 1% 20
Span 80 5% 100 *Formulation in both LiCaps (CAPSUGEL) and Conisnaps
(CAPSUGEL)
[0107]
15TABLE 6I Self-emulsifying system with NMP/Transcutol/fatty
acid/Miglyol 812 mixture as the solubilizer PD0106-77H* Ingredients
A B (mg) Fenofibrate 15% 300 Transcutol 14% 280 NMP 14% 280 Miglyol
812 45% 900 Labrasol 5% 100 Capric acid 1% 20 Caprylic acid 1% 20
Span 80 5% 100 *Formulation in both LiCaps (CAPSUGEL) and Conisnaps
(CAPSUGEL)
EXAMPLE 5
In Vivo Activity of Self-Emulsifying Formulation
[0108] Formulations tested were administered orally to dogs using
67 mg capsules of fenofibrate. The self-emulsifying formulation of
Example 1 (Table 1A) was tested in vivo as part of the dog study
(n=5). Lipanthyl.RTM. 67 mg (current marketed fenofibrate product)
served as the reference formulation, and the test formulation was
liquid filled hard gelatin capsule.
[0109] The data summarized in Table 7.
16TABLE 7 Plasma Concentrations of Fenofibrate in Fasted Dogs after
a 67 mg Dose C.sub.max T.sub.max AUC.sub.0-24 Formulation
(.mu.g/ml) (hr) (.mu.g.hr/ml) % Enhancement* Lipanthyl .RTM. 1.88
1.6 11.08 -- SD 0.97 0.9 9.42 PD0106-36 4.17 1.1 24.17 218 SD 1.83
0.5 7.96
[0110] The mean C.sub.max for Lipanthyl.RTM. and PD0106-36 were
1.88 and 4.17 .mu.g/ml, respectively. The mean AUC.sub.0-24 for
Lipanthyl.RTM. and PD0106-36 were 11.08 and 24.17 .mu.g.hr/ml,
respectively. The test formulation was effective in significantly
increasing the C.sub.max and AUC.sub.0-24 compared to
Lipanthyl.RTM..
[0111] Note:
[0112] Lipanthyl.RTM. is a marketed product of Groupe Fournier and
is used as a reference formulation.
EXAMPLE 6
Self-Emulsifying Properties
[0113] To evaluate the behavior of the self-emulsifying formulation
as it becomes exposed to aqueous media, five grams of various
fenofibrate solution formulations were prepared and known amounts
of water were added to the respective formulas. The compositions of
the formulations along with the outcome of the water addition are
shown in Table 8.
17TABLE 8 Effect of water addition on various liquid fenofibrate
formulations COMPOSITION FORMULATION* (% W/W) OBSERVATION
PD0106-61A Fenofibrate, 20% Upon addition of only 1 ml of water,
Transcutol P, 80% fenofibrate crashed out of solution and large
crystal precipitates appeared. PD1016-61B Fenofibrate, 15% Upon
addition of water the self- Transcutol P, 30% emulsifying
formulation turned into a Captex 200, 45% white emulsion with no
precipitates Labrasol, 5% forming even after addition of 11 ml of
Span 80, 5% water, which was more than twice the volume of the
starting formulation. PD0106-61C Fenofibrate, 6.25% Upon addition
of only 2 ml of water, Transcutol P, 93.75% fenofibrate crashed out
of solution and large crystal precipitates appeared. PD0106-65A
Fenofibrate, 15% Upon addition of only 1 ml of water, Transcutol P,
75% fenofibrate crashed out of solution and Labrasol, 5% large
crystal precipitates appeared. Span 80, 5% PD0106-65B Fenofibrate,
15% Upon addition of only 2 ml of water, Captex 200, 75%
fenofibrate crashed out of solution and Labrasol, 5% crystalline
precipitates appeared. Span 80, 5% PD0106-65C Fenofibrate, 15% Upon
addition of water the self- Captex 200, 45% emulsifying formulation
turned into a N-methyl-2-pyrrolidone white emulsion with no
precipitates (NMP), 30% forming even after addition of 5 ml of
Labrasol, 5% water. Span 80, 5% PD0106-65D Fenofibrate, 15% Upon
addition of only 2 ml of water, NMP, 75% fenofibrate crashed out of
solution and Labrasol, 5% crystalline precipitates appeared. Span
80, 5% PD0106-65E Fenofibrate, 15% Upon addition of only 2 ml of
water, Transcutol P, 45% fenofibrate crashed out of solution and
NMP, 30% crystalline precipitates appeared. Labrasol, 5% Span 80,
5% PD0106-66 Fenofibrate, 15% Upon addition of only 1 ml of water,
Transcutol, 80% fenofibrate crashed out of solution and Labrasol,
5% large crystal precipitates appeared. *All formulations were in
complete solution before water addition Note: Transcutol .RTM. P is
a trade name for Diethylene Glycol Monoethyl Ether, USP/NF, and is
marketed by Gattefosse Corp. Captex .RTM. 200 is a trade name for
Propylene Glycol Dicaprylate/Dicaprate and marketed by Abitec Corp.
Labrasol .RTM. is a trade name for Caprylocaproyl
Macrogolglycerides, EP, and is marketed by Gattefosse Corp. Span
.RTM. 80 is a trade name for sorbitan monooleate and marketed by
ICI Chemical.
[0114] The self-emulsifying formulations (PD0106-61B and
PD0106-65C) did not crash in presence of excessive amounts of
water, whereas all other formulations containing various solutions
of fenofibrate severely crashed out of solution by forming large
crystalline particulates upon addition of 1 or 2 ml of water. Our
self-emulsifying formulations are superior to solution formulations
containing the drug and a solubilizer.
* * * * *