Note: Descriptions are shown in the official language in which they were submitted.
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SINGLE UNIT PHARMACEUTICAL COMPOSITION COMPRISING A MIXTURE OF A FIBRATE AND
AN
HOMOCYSTEINE REDUCING AGENT
The present invention relates to a single unit pharmaceutical composition
s comprising fenofibrate and at least a homocysteine lowering agent useful to
reduce the plasma levels of homocysteine in patients to whom fibrates are
administered. The homocysteine lowering agent is selected from the group
consisting of folic acid, vitamin B12, Vitamin B6 and Betaine. The
homocysteine lowering agent is formulated as a modified release
io composition i.e.delayed or extended release
The composition of the present invention may be administered to patients
once a day.
Compositions of the present invention are further characterised that the
single dosage unit contains amounts of fenofibrate comprised between
is 25mg and 300mg and therapeutic amounts of one or several modified
release homocysteine lowering agents
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BACKGROUND OF THE INVENTION
Number of studies have shown that the lipid lowering therapy including
administration of drugs from the fibrate family is associated with an
increase of the plasma concentration of total homocysteine. While more
s studies are needed that investigate the underlying mechanism responsible
for the homocysteine increase, it appears that such increases of
homocysteine are associated with increased cardiovascular risks and
increase incidence of cerebro-vascular diseases.
The increase of homocysteine in patients is known as
to hyperhomocysteinemia and can be divided into three classes: Severe
(homocysteine plasma concentration > 100Nmol/L), moderate (25 to
100pmol/L), or mild (16 to 24pmol/L).
Severe hyperhomocysteinemia is usually caused by a homozygous
deficiency of the enzyme cystathionine (i-synthase. Affected persons have
is severe mental retardation, ectopic lens, skeletal abnormalities, and severe
premature arterial and venous thrombotic disease.
Mild or moderate hyperhomocysteinemia is found in patients with either
hereditary or acquired defects in the homocysteine metabolic pathway.
Heterozygous deficiency in cystathionine ~3-synthase is quite common in the
2o general population, with a frequency of 0.3% to 1.4%. A defect in the
remethylation pathway is commonly caused by a thermolabile mutant of the
methylene-tetra-hydofolate reductase (MTHFR) enzyme that has
approximately 50% of the normal enzyme activity; the homozygous state
has a prevalence of 5% in the general population. Common causes of
2s acquired hyperhomocysteinemia are deficiency of dietary cobalamin, folate,
or pyridoxine (the essential cofactors for the homocysteine metabolic
pathway). A recent prospective study showed that mild
hyperhomocysteinemia is quite common in the elderly, despite normal
serum vitamin concentrations.
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Mild to moderate hyperhomocysteinemia is associated with cerebrovascular
disease, coronary artery disease, and peripheral vascular disease in
persons younger than 55 years and with carotid artery stenosis in the
elderly. It is found in 10% of patients with a first episode of DVT (Deep
s Vein Thrombosis). In a recent prospective study, a graded relationship was
found between elevated plasma homocysteine levels and mortality in
patients with coronary artery disease.
Homocysteine is a highly reactive amino acid containing a free sulfhydryl
group. It can promote oxidation of low-density lipo-protein (LDL)
io cholesterol and presumably is toxic to vascular endothelium. It may also
inhibit thrombomodulin expression and protein C activation and suppress
endothelial heparan sulfate expression, both of these effects lead to
hypercoagulability. Recently, homocysteine was shown to enhance the
binding of lipoprotein(a), and atherogenic lipoprotein to fibrin, which may
is provide a linle between hyperhomocysteinemia, thrombosis, and premature
atherosclerosis. The vascular damage caused by high homocysteine levels
leads to arterial and venous thrombosis and, perhaps, accelerated
atherosclerosis.
Fenofibrate pertain to the lipid lowering family drugs of fibrates.
2o The lipid-modifying effects of fenofibrate are mediated via the activation
of
the peroxisome proliferator-activated receptors (PPARs).
Fenofibrate reduce plasma total cholesterol (TC), low-density lipoprotein
cholesterol (LDL-C), triglyceride (TG) and very-low-density lipoprotein
(VLDL) cholesterol levels, and increase high-density lipoprotein cholesterol
2s (HDL-C) and apolipoprotein (Apo) AI and Apo All levels in patients with
dyslipidaemia. Fenofibrate also reduce plasma fibrinogen levels in both
normolipidemic individuals and those with dyslipidemia, and is significantly
more effective in that reduction than Simvastatin, Atorvastatin or
Pravastatin. This is of significance since increased levels of fibrinogen or
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plasminogen activator inhibitor (PAI-1 ) are associated with an increased
risk of atherosclerosis and coronary heart disease (CHD).
Fenofibrate has also demonstrated a very important activity in reducing the
levels of the inflammatory marker C reactive protein (CRP)., which has
s been recognized to have a negative effect on the evolution of the
pathogenesis of atherosclerosis and coronary heart diseases.
Fenofibrate or p-(4-chlorobenzoyl)-phenoxy isobutyrate isopropyl ester is
useful for the treatment of adult patients with very high elevations of serum
triglyceride levels and/or cholesterol levels. The usual daily dosage is 50 to
io 300mg which is administered in one or two doses. Fenofibrate absorbed as
fenofibric acid, resulting from the hydrolysis of fenofibrate, is extensively
bound to plasma albumin. Fenofibric acid has a Tmax (time to peak
plasma level) of 3-6 hours after oral administration of a conventional
marketed form such as Lipanthyl~ tablet or Fenogal~ capsule.
is The plasma half-life is about 20 hours. Fenofibric acid is excreted
predominantly in the urine, mainly as the glucuronide conjugate, but also as
a reduced form of fenofibric acid and its glucuronides.
While some study results seem to be contradictory. It is now, commonly
admitted by the medical community that, Fenofibrate administration (like
20 other fibrates) to patient increases the level of homocysteine in the
plasma
(Drug Safety 2003:26(2) 31-91).
The effect of Fenofibrate, compared with Placebo on total plasma
homocysteine levels in the fasted and the fed states has been examined.
Fenofibrate caused marked decrease in all triglyceride rich protein
2s parameters and was associated with an increase in fasting total
homocysteine, from 10.3Nmol/L to 14.4Nmol/L (+40%) and fed total
homocysteine levels 6 hours past prandil load from 11.6~rmol/L t0
17.1 pmol/L [Atherosclerosis.2001 Apr:155(2): 455-62).
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A homocysteine lowering agent is defined as a substance able to decrease
plasma levels of homocysteine in humans in such a need. Examples of
those homocysteine lowering agents are: Folic acid, vitamin B6, vitamin
B12 and Betaine.
s Also it has been shown that in patient not receiving lipid-lowering drugs,
vitamin supplementation with folic acid and vitamin B12 effectively reduces
the plasma homocysteine levels.
Also, while some studies have shown that folic acid or vitamin combination
to Fenofibrate could allow to decrease the homocysteine increase
io associated with the Fenofibrate administration. These studies were
performed alternately (one day fibrate and one day vitamin) or by
administration of folic acid, vitamin B6 and/or B12 upon completion of the
fibrate treatment or by a separate administration of fenofibrate and the lipid
lowering agent. Also the lipid lowering agent was always given as an
is immediate release oral form what is probably not the most efficient way of
administration.
What was never disclosed, nor suggested is an oral single unit
pharmaceutical composition consisting of the combination of a therapeutic
effective amount of fibrate derivative with at least an effective amount of
20 lowering homocysteine agent or a mixture of such lowering homocysteine
agents, the release of this homocysteine lowering agents) being controlled
in order to better suit to the release of fenofibrate.
By controlled release composition, we mean any composition which is not
2s an immediate release composition (also called convetional form). In other
words controlled release compositions are compositions containing an
agent being capable of modifying the release of the compound (when
compared to immediate release forms) either by delaying it or by prolonging
it. Examples of such formulations are coated tablets or matrix tablets,
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coated or matrix beads, osmotic pumps, bioadhesive forms, multilayer
tablets, fatty matrix, . ..
In the present invention the terms "beads", "pellets" and "microgranules" are
synonyms
s Indeed, as fenofibrate present a Tmax of 3-6 hours after oral administration
and has a long half life, it would be advantageous to release the
homocysteine lowering agents) in such a way that its tmax is close to the
one of fenofibrate. Pharmaceutical compositions containing folic acid,
vitamine B12 and vitamine B6 of mixtures thereof are available on the
to market as immediate release forms i.e. forms releasing the compound
immediately in the gastro-intestinal tract. Altough the value of Tmax of
those substances may vary depending on the compound considered, the
tmax is often of 0.5 to 2 hours after oral administration.
The object of the present invention is to dispose, in the same
Is pharmaceutical form, of a combination of fenofibrate and an homocysteine
lowering agent, said form releasing fenofibrate in a similar way as the
compositions of fenofibrate available on the market (Tmax of 3-6 hours)
and the homocysteine lowering agent in a modified release in order be as
close as possible to fenofibrate's release (Tmax at least greater than 1
2o hourn preferably greater than 2 hours).
A single unit form is a pharmaceutical form containing both the fibrate
derivative and the modified release homocysteine lowering agent in such a
way that the patient can swallow the said pharmaceutical form in a single
intake.
2s Also, all the previous art was directed towards reducing the levels of
homocysteine after they were first increased while an object of the present
invention is to provide for a pharmaceutical composition that avoids the
increase of homocysteine in the patient. In other words, the present
invention relates to a pharmaceutical composition containing a fibrate and
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able, to some extent, to prevent the increase of homocysteine plasma
levels caused by the fibrate.
It is an object of the present invention to provide an orally administered
pharmaceutical composition of a fibrate and a modified release
s homocysteine lowering agent that provides for a therapeutically effective
amount of the fibrate and that substantially reduces the increase of plasma
homocysteine otherwise encountered after administration of such amount
of fibrate to the patient.
It is another object of the present invention to provide an orally
io administered pharmaceutical composition of a fibrate and a modified
release homocysteine lowering agent which is contained into a single unit
formulation.
It is another object of the present invention to provide an orally
administered pharmaceutical composition of a fibrate and a modified
is release homocysteine lowering agent which is suitable for once a day
administration.
It is another object of the present invention to provide an orally
administered pharmaceutical composition of a fibrate and a modified
release homocysteine lowering agent, from which the release of the
2o homocysteine lowering agent is delayed, extended or any combination for
thereof.
It is another object of the present invention to provide an orally
administered pharmaceutical composition of a fibrate and a homocysteine
lowering agent which comprises a modified release homocysteine lowering
2s agent selected from the group comprising folic acid, vitamin B6, vitamin
B12, betaine alone or in mixtures thereof.
It is another object of the present invention to provide a method of
treatment of hypercholesterolemia and related diseases of dyslipidemia
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comprising the administration of the dosage forms of the composition of the
present invention to a patient in need of treatment.
Details and advantageous characteristics of compositions of the invention
are given in the attached claims.
s DETAILED DESCRIPTION OF' THE INVENTION
Different pharmaceutical formulations may be used to obtain the single unit
form of the present invention. For instance, a capsule containing a coated,
or uncoated or multilayer tablet of a modified release homocysteine
lowering agent with a semi-solid composition of fenofibrate is suitable.
io Other alternatives are capsules containing the modified release
homocysteine lowering agent under the form of pellets or tablets and
fenofibrate formulated as a paste, semi-solid tablet, granulated powder or
pellets, coated or uncoated tablets, but always combined in a single unit
form.
is The modified release form of homocysteine lowering agent release may be
a delayed form such as an enteric tablet or capsule, or a sustained release
form (tablet or granules) or a form combining an immediate release form of
the homocysteine lowering agent with a prolonged release form of the
same homocysteine lowering agent.
2o The homocysteine lowering agent may also be present in the final
composition as bilayer tablet where the homocysteine lowering agent is in
the core (central layer or inner layer) of the tablet and the sustained
release
properties are conferred by the outer layer of the tablets. This formulation
presents the advantage to avoid any physical contact between the
2s homocysteine lowering agent and fenofibrate, and hence to prevent any
kind of chemical interaction between the two compounds. Furthermore, this
composition canenhac ethe stability properties of the homocysteine
lowering agent within the final composition
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As fenofibrate present a relatively long elimination half-life, from 20 to 90
hours and some of vitamin B derivatives present a short half-life (folic acid
3 hours), it is particularly advantageous for the present invention to provide
s the patient with a composition where the fibrate is formulated as an
immediate release form and the vitamin B derivative at least partly as a
sustained or delayed release formulation (both derivatives being finally put
into a single unit form) in order to optimize the duration of action of the
vitamin B derivative and to increase as much as possible its therapeutic
to homocysteine lowering effect.
For instance, the single unit final form can be a capsule containing a semi-
solid formulation of fenofibrate, and a sustained release tablet (coated or
not) containing the vitamin B derivative.
Examples of such sustained release vitamin B formulations can be matrix
is tablets containing an hydrophilic or an hydrophobic polymer (or a mixture
thereof), bilayer or mulilayer tablets, sustained release coated granules,
matrix granules, etc,...
When formulating sustained release compositions of vitamins B derivatives,
the absorption window should be taken into account. For instance, folic
2o acid and vitamine B6 have their main absorption window in the proximal
jejunum. The sustained release of folic acid or vitamine B6 should
therefore not be too slow because it should be delivered completely within
the absorption window to keep an acceptable bioavailability. For instance,
such sustained release formulations of folic acid should present a Tmax in
2s vivo of between 1 and 10 hours, preferably between 2 and 8 hours, more
preferably between 2 and 6 hours. When tested in vitro, on a paddle
dissolution apparatus (EP 2003, 4t" edition, 2.9.3) at 100 round per minute
(rpm) in water, the dissolution rate is for instance of 0 to 50 % after 30
minutes, 5 to 75 % dissolved after 1 hour, 20 to 90 % dissolved after 2
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hours, 50-95 % dissolved after 4 hours and more than 80 % dissolved after
8 hours.
Alternatively the homocysteine lowering agent can be a combination of
s various homocysteine lowering agents such as, but not limited to, a
combination of folic acid and vitamin B12 or a combination of folic acid and
vitamin B6 or even a combination of folic acid with vitamin B12 and vitamin
B6. In this case, all of the homocysteine lowering agents are present as
modified release forms or alternatively some of the homocysteine lowering
to agents are present as modified release forms and other are immediate
release.
Also alternatively, the homocysteine lowering agent can be formulated
insuch a way that it presents a biphasic or multiphasic release what means
that it, for instance, can present both immediate and sustained release
is properties. For instance, a sustained release matrix tablet of folic acid
may
be further coated with an additional amount of folic acid (iwhich is release
rapidly). This coated tablet is then put into a capsule with a semi-solid
composition of fenofibrate to obtain the final composition of the present
invention.
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Examples
The invention is additionally illustrated in connection with the following
examples, which are considered to be illustrative of the present invention.
s It should be understood, however, that the invention is not limited to the
specific details of the Examples.
Example 1
example 1 a : Folic acid uncoated tablet
Ingredient Name Amount [g~
folic acid 1
Lactose monohydrate 100
Cellulose microcrystalline36
Povidone K30 2
Water for granulation 25
Magnesium stearate 2
Sodium starch glycolate 13
to
Folic acid, lactose monohydrate, cellulose microcrystalline and povidone
K30 were blended in a planetary mixer for about 5 to 10 minutes until an
homogeneous blend is obtained. While under agitation, a solution
containing the water for granulation is added to granulate the powders. The
is granules obtained are dried at about 40°C for about 5 hours.
Thereafter the
dried granules are screened through a 1.0 mm sieve, and further blended
into a planetary mixer for about 2 minutes after the addition of the
magnesium stearate and sodium starch glycolate.
The final mix is compressed into tablets using a rotary compressing
2o machine equipped with punches of the deep cup type with a diameter of
6.5mm. The mean weight of the tablets is of about 180 mg, corresponding
to tablets containing 1 mg of folic acid. The tablet hardness is comprised
between 4 and 6 kilopascals (Kp).
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Example 1 b : coating of folic acid tablets
Ingredient Name Amount [g]
Povidone K30 15
ethylcellulose 5
Talc 35
Triacetin 5
Absolute Alcohol 300
The coating solution of example1 b is applied to the tablets from Example
s 1 a using a pan coater. The amount of coating applied is about 15 mg of dry
coating (weight gain) per tablet. In this composition, ethylcellulose is the
agent responsible of the prolonged release of folic acid.
Example 1 c : semi-solid fenofibrate composition
Amount
Ingredient Name
Ig1
Fenofibrate powder 160
Lauroyl macrogolglyceride
240
(gelucire 44/14)
Polyethylene glycol 20,00048
Hydroxypropylcellulose 95.0
Sodium starch glycolate 20.0
Ascorbyl palmitate 1.0
to
Gelucire 44/14 and polyethylene glycol 20,000 are added to a mixer
equipped with a double wall bowl. The mixer is started and the bowl is
warmed at about 75°C. When the gelucire and the polyethylene glycols
are
molten, the other ingredients (Fenofibrate, hydroxypropyl cellulose, sodium
Is starch glycolate and ascorbyl palmitate) are added while maintaining the
temperature at about 70 - 75°C.
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Example 1 : Final composition
The combination product is obtained by filling, into size 0 elongated hard
s gelatin capsules, one tablet of Example 1 a coated with 1 b and 564mg of
the hot blend of Example 3. After filling, the capsules are cooled by placing
them on trays between 4 and 8°C.
The capsules obtained contained 1 mg of folic acid and 160mg of
fenofibrate. It should be noted that the matrix tablet obtained allow to
io deliver folic acid in a sustained release manner as demonstrated by the in
vitro dissolution curve given hereinbelow.
in vitro dissolution curve of folic acid and fenofibrate from the final
composition of example 1 in comparison with a marketed form of folic
is acid (folavit~, Wolfs)(Paddle apparatus, 100 rpm, phosphate buffer 7.5)
120
100
-o- Folavit 4 mg (wolfi~) ~
20 ~ 80
°n 60 --~--- ~iic acid from
example1
40 ~-fenofibrate from
20 example 1
0
25 ~ 0 50 100 150 200
time (minutes)
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Example 2
Example 2a : folic acid and vifiamine b12 matrix tablets
Ingredient Name Amount [g]
folic acid 2
vitamin B12 0.5
EUDRAGIT~ NE30D 10
Lactose monohydrate 100
Cellulose microcristalline40
Povidone IC30 2
Water for granulation 30
Magnesium stearate 2
Sodium starch glycolate 13
Folic acid, Vitamin B12, Lactose monohydrate, cellulose microcrystalline
and povidone 1030 are blended in a planetary mixer for about 5 to 10
minutes until an homogeneous blend is obtained. While under agitation, an
aqueous suspension of EUDRAGIT~ NE30D (polyacrylate dispersion 30
io which is the agent responsible for the controllled release) into the water
for
granulation is added to granulate the powders. The granules obtained are
dried at about 40°C for about 5 hours. After the dried granules are
screened through a 1.0 mm sieve, they are blended into a planetary mixer
for about 2 minutes after the addition of the magnesium stearate and
is sodium starch glycolate. The final mix is compressed into tablets using a
rotary compressing machine equipped with punches of the deep cup type
with a diameter of 6.5mm. The mean weight of the tablets is of about 200
mg. The tablets had hardness comprised between 4 and 6 kilopascals
(KP)~
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Example 2b : fenofibrates granules
Ingredient Amount [g]
Fenofibrate powder 160
Lactose 300
Povidone K30 15
Sodium Lauryl Sulfate 7
Crospovidone 15
Magnesium Stearate 3
Fenofibrate, lactose, povidone and sodium lauryl sulfate are blended in a
s planetary mixer and water is added to granulate. After oven drying for
about 5 hours at 50°C, the granules are screened through a 1 mm sieve.
After addition of crospovidone and the magnesium stearate the granules
that are blended for an additional 3 minutes in the planetary mixer.
to
Example 2 : Final composition
500 mg of lubricated granules of Example 2b and a tablet of Example 2a
are filled into 0 elongated hydroxypropylmethylcellulose capsules to
is produce a combination product containing 2 mg of folic acid, 0.5 mg of
vitamin B12 and 160mg of fenofibrate.
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Example 3
Example 3a : folic acid coated beads
Ingredient Name Amount [g~
Folic acid 5
sucroester (Crodesta°) 20
Microcrystalline cellulose 100
Povidone K30 20
145
Water is added to the blend of all the ingredients in a planetary mixer to
granulate the powder. The paste obtained is extruded and spheronized in
order to obtain beads with a diameter of about 1 mm. The beads are tray
dried in an oven at about 40°C for approximately 5 hours. The beads are
to thereafter screened between 0.7mm and 1.4mm sieves.
500 g of beads from Example 3a are coated with 200 g of coating solution)
of Example 1b using a fluid bed coater (Strea 1) equipped with a wurster
column.
is
Example 3 final composition
A combination formulation is produced by filling in a 00 hard gelatin
capsules with 500 mg of Fenofibrate lubricated granules of Example 2b and
145 mg of folic acid beads of Example 3a.
2o The resulting combination formulation contained 5 mg of folic acid and
160mg of fenofibrate.
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Example 4
bilayer tablets
example 4a : inner layer containing folic acid
Amount
Ingredient Name
[mg] / tablet
Folic acid 5
aerosil~ 0.2
Microcrystalline cellulose5
Mannitol 19.31
Magnesium stearate 0.48
Butylhydroxyanisole 0.01
s The diameter of the inner tablet is 4 mm and the hardness around 2 Kp
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example 4b : outer layer (sustained release layer)
Amount
Ingredient Name
[mgt / tablet
Lactose 62
Mannitol 33
Stearic acid 5
Povidone 5
Magnesium stearate 0.5
The diameter of the inner tablet is 6 mm and the hardness around 28-10 Kp
The bilayered tablet is obtaining by proceeding to the compression of the
s inner tablet and hence to proceed to the compression of the outlayer tablet
around the inner tablet while mainting the inner tablet centrally such as
after
compression of the outer tablet, the inner tablet is no more visible.
The final composition of example 4 is obtained by combining in a size 0
to elongated hard gelatin capsule, 564 mg of the semi-solid composition of
fenofibrate of example 1 c with the bilayer tablets cotnaining folic acid
described hereinabove
The dissolution curve hereinbelow shows the extended release profile of
is the bilayer folic acid tablets in comparison to the core only. The bilayer
tablets clealry possess extended release properties due to the presence of
stearic acid in the oute rlayer of the tablet.
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Comparative in vitro dissolution curve of the inner layer tablet (core)
containing folic acid alone and the final bilayer extended release
tablet (Paddle apparatus, 100 rpm, phosphate buffer 7.5)
s
120 -
100 -
'
a
d
80
N
~o -+- bilayer tablets
60
a -~-- inner tablets
(core)
40
~
o
0 20
0
0 30 60 90 120 150 180
time (minutes)
