Note: Descriptions are shown in the official language in which they were submitted.
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COMPOSITIONS WITH CONTROLLED PHARMACOKINETICS
CROSS REFERENCE TO RELATED APPLICATION
[1] This application claims the benefit of U.S. Provisional Patent Application
filed
July 6, 2006, entitled "Compositions with Controlled Pharmacokinetics," Serial
No.
60/819,041, which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[2] The invention encompasses compositions which reduce the effect of food on
the bioavailability of the active drug ingredient, methods for making such
compositions, and
methods for reducing the food effect using such compositions.
BACKGROUND OF THE INVENTION
[3] In general, it is known that the absorption and bioavailability of any
particular
therapeutic agent can be affected by numerous factors when dosed orally. One
such factor is
the presence of food in the gastrointestinal (GI) tract. Many pharmaceutical
compounds
reportedly exhibit a food effect. A food effect can be defined as the
difference between
absorption rates under fast and fed conditions. The food effect may result
from interaction
between formulation and gastrointestinal environment, drug metabolism or both.
For some
drugs the food effect does not affect the pharmacodynamics of the drug. In
such cases the
drug can be administered under both fed and fast conditions. For other drugs
where food
effect is critical in the drug's pharmacodynamics, the effect of a drug is
greatly affected by
whether it is taken with or without food. Therefore, there is a need in the
art for the
development of a general method to control or reduce the food effect in a drug
composition.
[4] Atorvastatin is a member of the class of drugs called statins and can be
used as
a drug model to illustrate the general concept of the present invention.
[5] Statins are used alone or in combination (for example, with lipid
regulating
agents of a different mechanism of action (e.g., fenofibrate, ezetimibe,
torcetrapib), with
calcium ion antagonists or slow-channel blockers (e.g., amlodipine), with ACE
inhibitors
(e.g., benazepril), or with salicilates such as aspirin, clopidogrel,
pioglitazone, rosiglitazone,
or fosinopril. Statin drugs have been used to reduce low density lipoprotein
(LDL) particle
concentration in the blood stream of subjects.
[6] Atorvastatin is reportedly disclosed in U.S. Patent No. 4,681,893.
Atorvastatin is sold by Pfizer, Inc. in tablet form under the commercial name
Lipitor as an
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HMG-CoA reductase inhibitor and for the treatment of hypercholesterolemia and
hyperlipidemia. It has been reported that a food effect is observed in
Lipitor, which indicates
that the pharmacokinetics of atorvastatin may be affected by food intake. The
influence of
food on the administration of a single dose of atorvastatin (10 mg or 80 mg)
after breakfast or
an evening meal reportedly results in a lower Cm... and longer Tm,,,x with
little change in extent
of absorption compared to fasted volunteers (Radulovie L.L. et al., J. CLIN.
PHARM., 35: 990-
4 (1995); Whitfield, L.R. et al., EUR. J. DRUG METAB. PARMACOKINET., 25: 97-
101(2000)). It
is further reported that the bioavailability of atorvastatin is significantly
reduced when taken
with meals (9 % decrease in AUC and 25% decrease in Cmzx ) (Physician's Desk
Reference,
Jul. 2004). In the development of a bioequivalent formulation to Lipitor, a
similar and even
higher food effect as expressed by higher CmeX values and ratios (relative to
Lipitor) in fast
(Cmax ratio f.t = Cmax test(f.t) / Cmax reference f.t ) conditions when
compared to fed
conditions (Cmax ratio fed = Cmax test fed / Cmax referencefed) has been
observed. It has been
suggested that the food effect of atorvastatin is controlled in Lipitor by use
of a specific
ingredient, namely calcium carbonate, although the mechanism by which this
might occur is
not immediately apparent and thus not controllable by a formulator wishing to
develop a
similar composition.
[7] Various means of affecting bioavailability, including increasing and
decreasing bioavailability, have been disclosed in the literature. However,
these methods
affect (increase or decrease) bioavailability for both fed and fast
conditions. As a result, the
food effect remains substantially of the same magnitude.
[8] Therefore, one of the main challenges in the development of formulations
containing drugs such as atorvastatin is the effect of food on the
bioavailability of the drug.
Accordingly, there is a need for formulations and methods of their preparation
that effectively
reduce the food effect encountered by the administration of such drugs without
the use of
calcium carbonate.
SUMMARY OF THE INVENTION
[9] The present invention encompasses methods and compositions which decrease
the food effect associated with administration of drugs which exhibit such
food effect. In one'
embodiment, in addition to having a reduced food effect, the bioavailability
of the API in a
formulation is equivalent to an. FDA-approved formulation for that API.
[10] The invention also encompasses methods and compositions which effectively
control the bioavailability of a drug in fed and fast conditions. In certain
embodiments,
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bioavailability is controlled in fed conditions with minimal effect on fast
conditions or the
bioavailability is controlled in fast conditions with minimal effect on fed
conditions. For
example, in one embodiment, the bioavailability is decreased in fasted (or
fast) conditions
with minimal effect on fed conditions and/or is increased in fed conditions
with minimal
effect on fast conditions.
[11] In one embodiment, the invention encompasses a method for preparing a
formulation having a target food effect comprising (a) determining a target
food effect; and
(b) combining an API which exhibits food effect and a sufficient amount of (i)
at least one
biodegradable binder, (ii) at least one lipophilic binder, or (iii)
combinations thereof, to
produce a formulation having the target food effect.
[12] In a preferred embodiment, the method for preparing a formulation having
a
target food effect comprises (a) providing a formulation comprising an API
that exhibits an
initial food effect and (i) at least one biodegradable binder and/or (ii) at
least one lipophilic
binder; (b) determining a target food effect; and (c) adjusting the amount of
the biodegradable
binder or the lipophilic binder in the formulation to a sufficient amount to
produce an
adjusted formulation having the target food effect.
[131 In another preferred embodiment, the method for preparing a formulation
having a target food effect comprises (a) determining an initial food effect
of a test
formulation comprising an API which exhibits food effect and (i) at least one
biodegradable
binder and/or (ii) at least one lipophilic binder; (b) determining a reference
food effect of a
reference formulation comprising an API which exhibits food effect; and (c)
adjusting the
amount of the biodegradable binder and/or the lipophilic binder in the test
formulation to a
sufficient amount to produce an adjusted formulation having a relative food
effect that is
bioequivalent to the reference food effect.
[14] In certain embodiments, the formulation has a relative food effect of
about 0.8
to about 1.25, preferably about 0.8 to about 1, and more preferably about 1.
[15] In a preferred embodiment, the formulation includes a biodegradable
binder,
e.g., a biodegradable binder that includes binders degradable by at least one
of a
gastrointestinal enzyme, protease, lipase or amylase. Preferably, the
biodegradable binder
includes a binder degradable by a gastrointestinal enzyme. Preferably, the
biodegradable
binder includes a binder that is degradable at a pH of about 1 to about 7.5,
and more
preferably at a pH of about 1.3 to about 6.5 or about 1.2 to about 6.5.
[16) Preferably, the biodegradable binder includes at least one protein,
lipid, or
polysaccharide. Preferably, the biodegradable binder includes at least one of
gelatin, ZEIN,
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ZEIN derivatives, hydrogenated vegetable oil, hydrogenated castor oil,
glycerol
palmitostearate, glycerol behenate, PEG ester, or starch.
[17] In a preferred embodiment, the formulation includes a lipophilic binder,
e.g., a
lipaphilic binder that dissolves in lipophilic media, disintegrates in
lipophilic media, or both.
Preferably, the lipophilic binder degrades at a pH of about 2 to about 7, and
more preferably
at a pH of about 1.3 to about 6.5.
[18] Preferably, the lipophilic binder includes at least one of ethylcellulose
or a
mixture of ethylcellulose with polyethylene glycol, or poloxamer.
[19] In a preferred embodiment, the formulation comprises a total weight of
about
0.5% to about 60% by weight, preferably about 0.5% to about 40%, and more
preferably
about 1% to about 25% of the biodegradable binder and lipophilic binder. Also
preferably,
the formulation comprises a total weight of about 5% to about 15% or about 10%
to about
25% by weight of the biodegradable binder and lipophilic binder, depending on
the type of
binder used. .
[20] In one preferred embodiment, the formulation comprises granules and an
extra-granular component. Preferably, the biodegradable binder or lipophilic
binder is
present in the granules and the extra-granular component. Also preferably, the
formulation
further comprises at least one non-biodegradable binder or non-lipophilic
binder. Preferably,
the formulation further comprises at least one disintegrant.
[21] In another preferred embodiment, the formulation further comprises at
least
one of lactose, mannitol, croscarmellose sodium, crospovidone, polaccrillin
potasium,
microcrystalline cellulose, hydroxypropyl cellulose, povidone, magnesium
carbonate, vitamin
E TPGS, butylmethacrylat-(2-dimethylaminoethyl)methacrylate-methylmethacrylate
copolymer (1:2:1), magnesium aluminum silicate, or sodium stearyl fumarate.
[22] In another preferred embodiment, the formulation comprises lactose,
mannitol,
croscanmellose sodium, crospovidone, polacerillin potasium, microcrystalline
cellulose,
hydroxypropyl cellulose, povidone, magnesium carbonate, vitamin E TPGS,
butylmethacrylat-(2-dimethylaminoethyl)methacrylate-methylmethacrylate
copolymer
(1:2:1), magnesium aluminum silicate, and sodium stearyl fumarate.
[23] In one embodiment, the API which exhibits food effect includes at least
one
3,5 dihydroxy-acid, e.g., atorvastatin, fluvastatin, rosuvastatin,
pravastatin, simvastatin, or
lovastatin.
[24] Some embodiments also encompass a pharmaceutical composition comprising
at least one 3,5 dihydroxy-acid, preferably one that exhibits a food effect,
and at least one of a
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biodegradable binder or lipophilic binder. Preferred 3,5 dihydroxy-acids
include atorvastatin,
fluvastatin, rosuvastatin, pravastatin, simvastatin, or lovastatin.
[25] In one embodiment, the pharmaceutical composition comprises at least one
3,5
dihydroxy-acid and at least one of a biodegradable binder or lipophilic
binder, wherein the
food effect exhibited by the 3,5 dihydroxy-acid is reduced, e.g., by at least
about 10 percent,
at least about 20 percent, at least about 50 percent, or at least about 100
peroent compared to
an otherwise identical pharmaceutical composition comprising the 3,5 dihydroxy-
acid in the
absence of a biodegradable binder or a lipophilic binder.
1261 In another embodiment, the pharmaceutical composition comprises at least
one 3,5 dihydroxy-acid and about 0.5% to about 60% by weight total of at least
one of a
biodegradable binder or lipophilic binder.
[27] In one embodiment, the pharmaceutical composition has a relative food
effect
of about 0.8 to about 1.25, about 0.8 to about 1, or about 1. Preferably, the
food effect
exhibited by the API is reduced compared to an otherwise identical
pharmaceutical
composition comprising the API in the absence of a biodegradable binder or a
lipophilic
binder.
[28] Preferably, the formulation includes a biodegradable binder, e.g., a
biodegradable binder including a binder degradable by at least one of a
gastrointestinal
enzyme, protease, lipase or amylase. More preferably, the biodegradable binder
includes a
binder degradable by a gastrointestinal enzyme. Preferably, the biodegradable
binder
includes a binder that is degradable at a pH of about 1 to about 7.5, and more
preferably
about 1.3 to about 6.5.
[29] In one preferred embodiment, the biodegradable binder includes at least
one
protein, lipid, or polysaccharide. Preferably, the biodegradable binder
includes at least one of
gelatin, ZEIN, ZEIN derivatives, hydrogenated vegetable oil, hydrogenated
castor oil,
glycerol palmitostearate; glycerol behenate, stearoyl macrogolglycerides, or
starch.
[30] In another embodiment, the formulation includes a lipophilic binder,
e.g., a
lipophilic binder that dissolves in lipophilic media, disintegrates in
lipophilic media, or both.
Preferably, the lipophilic binder degrades at a pH of about 2 to about 7, and
more preferably
about 1.3 to about 6.5.
[31] In one preferred embodiment, the lipophilic binder includes at least one
of
ethylcellulose, a mixture of ethylcellulose and polyethylene glycol, or
poloxamer.
[32] In a preferred embodiment, the pharmaceutical composition comprises a
total
weight of about 0.5% to about 60% by weight, preferably about 0.5% to about
40%, and
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more preferably about 1% to about 25% of the biodegradable binder and
lipophilic binder.
Also preferably, the formulation comprises a total weight of about 5% to about
15% or about
10% to about 25% by weight of the biodegradable binder and lipophilic binder,
depending on
the type of binder used.
[33] In another preferred embodiment, the pharmaceutical composition comprises
granules and an extra-granular component. In another preferred embodiment, the
biodegradable binder or lipophilic binder is present in the granules and the
extra-granular
component.
[34] In one preferred embodiment, the pharmaceutical composition further
comprises at least one non-biodegradable binder or non-lipophilic binder. In
another
preferred embodiment, the pharmaceutical composition further comprises at
least one
disintegrant.
[35] In one embodiment, the pharmaceutical composition comprises at least one
of
lactose, mannitol, croscarmellose sodium, crospovidone, polaccrillin potasium,
microcrystalline cellulose, hydroxypropyl cellulose, povidone, magnesium
carbonate, vitamin
E TPGS, butylmethacrylat-(2-dimethylaminoethyl)methacrylate-methylmethacrylate
copolymer (1:2:1), magnesium aluminum silicate, or sodium stearyl fumarate.
Preferably,
the pharmaceutical composition comprises lactose, mannitol, croscarmellose
sodium,
crospovidone, polaccrillin potasium, microcrystalline cellulose, hydroxypropyl
cellulose,
povidone, magnesium carbonate, vitamin E TPGS, butylmethacrylat-(2-
dimethylaminoethyl)methacrylate-methylmethacrylate copolymer (1:2:1),
magnesium
aluminum silicate, and sodium stearyl fumarate.
[36] The invention also encompasses pharmaceutical compositions and
formulations of the invention having a relative food effect that is reduced by
at least about 10
percent, at least about 20 percent, at least about 50 percent, or at least
about 100 percent
compared to an otherwise identical pharmaceutical composition comprising the
API in the
absence of a biodegradable binder or a lipophilic binder.
[37] The present invention encompasses formulations prepared by the methods of
the invention, and methods for treating a medical disease by administering
these
formulations to a manunal in need thereof.
DESCRIPTION OF THE FIGURES
[38] Figure 1. In vitro dissolution rates of Example 1 in simulated fast (Fast
Model
1) vs. fed condition (Fed Model 1).
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[39] Figure 2: In vitro dissolution rates of Examples 1 and 2 with and without
pepsin in simulated fed condition (Fed Model 2).
[40] Figure 3. In vitro dissolution rates of Example 3 in simulated fast (Fast
Model
1) vs. fed condition (Fed Model 1).
DETAILED DESCRIPTION OF THE INVENTION
1411 The present invention encompasses methods and formulations for
effectively
reducing the food effect associated with administration of drugs which exhibit
such food
effect, preferably without need for the use of calcium carbonate as an agent
for reducing food
effect. Specifically, the present invention is directed to drugs which exhibit
a food effect,
particularly ones where bioavailability in fed conditions are lower when
compared with
bioavailability in fast conditions. The present invention also encompasses
drug combination
products exemplified by the above-mentioned drugs, where the second drug in
the
combination may or may not exhibit a similar or any food effect.
[42] As used herein, a "food effect" refers to the difference between the
absorption
rate under fast condition and the absorption rate under fed condition and is
defined herein as
Cmaxfed / Cmaxr,,,t. Thus, a food effect is exhibited where Cmaxfed / Cmaxfast
is less than or
greater than 1.
[43] The term "relative food effect" is defined as Cmax ratiored / Cmax
ratiof.t.
[44] The term "Cmax ratiored" means the Cmaxfed of the test formulation
divided by
the Cmaxrea of the reference formulation. Likewise, the term "Cmax ratior"'t"
means the
Cmaxrast of the test formulation divided by the Cmaxf.t of the reference
formulation.
[45] For example, a formulation that is bioequivalent to a reference
formulation
(e.g. Lipitor(b) would have a relative food effect that is about 0.8 to about
1.25, preferably
about 0.8 to about 1, and more preferably about 1. If the relative food effect
is less than 1,
the formulation will have a lower food effect than the reference formulation.
A formulation
with a relative food effect greater than 1 will exhibit a higher food effect
than the reference
product (e.g. Lipitor ).
[46] As used herein, the phrase "percent change in food effect" is based on
the
difference betweeri the initial food effect and 1. For example, a food effect
of 1.2 is said to
be reduced by 10 percent if the adjusted food effect is 1.18, which is
calculated as follows:
1.2-[(1.2- 1) x 10 fo)]= 1.2-0.02= 1.18.
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[47] As used herein in connection with a measured quantity, the term "about"
refers to that variation in the measured quantity as would be expected by the
skilled artisan
performing or interpreting the measurement and exercising a level of care
commensurate with
the objective of the measurement and the precision of the measuring equipment
being used.
[48] The bioavailability of a drug depends on its absorption rate. Absorption
rate
can be affected, for example, by the type of drug being administered, the
contents in the
stomach (including the type and amount of food present), and the dissolution
rate of the
formulation. It has now been discovered that the use of a biodegradable and/or
lipophilic
binder markedly decreases the in-vitro dissolution rate of the formulation in
dissolution
media simulating fast conditions, while only exhibiting a minimal effect on
the dissolution
rate in dissolution media stimulating fed conditions and containing
degradation enzymes.
Therefore, the difference between the absorption rates at fast and fed
conditions can be
reduced by the addition of a biodegradable and/or lipophilic binder.
[49] In preferred formulations encompassed by the present invention, typically
the
bioavailability, as evidenced by in-vitro dissolution rate, in simulated
fasted conditions is
affected more than that in fed conditions. With this new finding, one can
therefore control
substantially independently the bioavailability in fed and fast conditions. As
a result, the
invention allows for a decrease in food effect for drugs that exhibit such
food effect. The
invention further allows for the control of the bioavailabilities in fed and
fast conditions for
bioequivalent formulations of known preparations.
[50] Accordingly, the present invention encompasses methods and formulations
for
effectively controlling, e.g., reducing, the food effect associated with
administration of drugs
which exhibit such food effect. In one embodiment, the invention encompasses a
method for
reducing food effect in a drug which exhibits such food effect by preparing a
formulation
comprising a drug which exhibits food effect and at least one biodegradable
binder or
lipophilic binder, wherein the food effect of the API is reduced.
[51] In one embodiment, the invention encompasses a method for preparing a
formulation having a target food effect comprising (a) determining a target
food effect; and
(b) combining an API which exhibits food effect and a sufficient amount of (i)
at least one
biodegradable binder, (ii) at least one lipophilic binder, or (iii)
combinations thereof, to
produce a formulation having the target food effect.
[52] As used herein the term "sufficient amount" refers to an amount
sufficient to
accomplish the desired purpose, e.g., making a formulation having a target
food effect.
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[53] In a preferred embodiment, the method for preparing a formulation having
a
target food effect comprises (a) providing a formulation comprising an API
that exhibits an
initial food effect and (i) at least one biodegradable binder and/or (ii) at
least one lipophilic
binder; (b) determining a target food effect; and (c) adjusting the amount of
the biodegradable
binder or the lipophilic binder in the formulation to a sufficient amount to
produce an
adjusted formulation having the target food effect..
[54] In another preferred embodiment, the method for preparing a formulation
having a target food effect comprises (a) determining an initial food effect
of a test
formulation comprising an API which exhibits food effect and (i) at least one
biodegradable
binder and/or (ii) at least one lipophilic binder; (b) determining a reference
food effect of a
reference formulation comprising an API which exhibits food effect; and (c)
adjusting the
amount of the biodegradable binder and/or the lipophilic binder in the test
formulation to a
sufficient amount to produce an adjusted formulation having a relative food
effect that is
bioequivalent to the reference food effect.
[55] In one embodiment, the adjusted formulation has a relative food effect of
about 0.8 to about 1.25, about 0.8 to about 1, or about 1.
1561 Generally, preferred binders for use in this invention are those that
break down
preferentially in the "fed mode" as compared to the "fast mode." Thus, it
should be possible
to analyze a composition comprising a binder candidate by conducting an in
vitro
disintegration test of a tablet of the composition in the medium used below to
simulate the fed
mode and a disintegration test of the tablet of the composition in the medium
used below to
simulate the fasted mode. A significantly faster disintegration time in the
fed mode medium
as compared with the fast mode medium would indicate that such a binder is a
suitable
candidate for use in the preferred embodiments of the invention.
[57] Preferably, the biodegradable binder includes binders degradable by at
least
one of a gastrointestinal enzyme, protease, lipase or amylase. More
preferably, the
biodegradable binder includes a binder degradable by a gastrointestinal
enzyme. Also
preferably, the biodegradable binder includes a binder that is degradable at a
pH of about 1 to
about 7.5, and preferably about 1.3 to about 6.5 or about 1.2 to about 6.5.
[58] Binders are commonly used in pharmaceutical formulations. Their primary
role is to provide adhesion and tablet hardness (mechanical strength).
Different binders have
different binding properties and are typically characterized by their packing
rate,
consolidation and compressibility behavior, which lead to differences in a
drug's dissolution
rate. The binding capacity is determined by the amount of the binder used, the
nature of the
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binder, i.e., by binding per unit weight of the binder and by the binder
addition technique,
e.g., wet and dry granulation, spray drying, or mixing.
[591 The methods and formulations of the present invention comprise the use of
at
least one biodegradable binder, particularly binders degraded by gastric
enzymes, or
lipophilic/hydrophobic binders. Preferably, the biodegradable binder is a
polymeric binder.
Also preferably, the biodegradable binder is degradable by enzymes capable of
decreasing
their molecular weight by cleavage. Examples for such enzymes include pepsin,
lipase,
trypsin, chymotrypsin, elastase, carboxypeptidase, and amylase. Particularly
preferred
binders are those degradable by the enzymes pepsin and/or lipase. Particularly
preferred
binders are those degradable at a pH of about 1 to about 7.5, which can be
encountered in the
stomach or just distal thereto. Lipophilic binders, on the other hand, have
the capability of
faster drug release in lipophilic media at a pH of about 2 to about 7, e.g.,
about 1.3 to about
6.5.
[60] Examples of suitable biodegradable binders include proteins, such as
gelatin
and ZE1N, ZE1N derivatives (such as COZEEN, VPP), lipids, e.g., hydrogenated
vegetable
oil, hydrogenated castor oil, glycerol palmitostearate (Precirol ATO5),
glycerol behenate
(Compritol 888 ATO) and stearoyl macrogolglycerides (e.g., Gelucire 50/13)).
Also
preferably, the biodegradable binder includes polysaccharides such as starch
and its
derivatives (e.g. Contramid) such as chitosan.
[61] Preferably, the lipophilic binder is dissolved in lipophilic media,
disintegrated
in lipophilic media, or both. Preferably, the lipophilic binder includes at
least one of
ethylcellulose or a mixture of ethylcellulose with polyethylene glycol, or
poloxamer.
Preferably, the lipophilic binder includes at least one of ethylcellulose
alone or with polymers
such as polyethylene glycol, HPMC, or poloxamer (e.g., 124), proteins such as
ZEIN and
COZEEN, lipids, e.g., hydrogenated vegetable oil, hydrogenated castor oil,
glycerol
palmitostearate (Precirol ATO5), glycerol behenate (Compritol 888 ATO), or
stearoyl
macrogolglycerides (e.g., Gelucire 50/13). More preferably, the lipophilic
binder includes
ethylcellulose alone or with polymers for example as a mixture with
polyethylene glycol,
HPMC, or poloxamer (e.g., 124), proteins such as ZEIN and COZEEN, lipids,
e.g.,
hydrogenated vegetable oil, hydrogenated castor oil, glycerol palmitostearate
(Precirol
ATO5), glycerol behenate (Comprito1888 ATO), and stearoyl macrogolglycerides
(e.g.,
Gelucire 50/13). In addition to their use as binders, the biodegradable and/or
lipophilic
excipients of the invention can also be used as coating agents, lipophilic
matrix formers
(AAPS, PharmSciTech, 2003;4(3) and AAPS, PharmSciTech, 2001;2(2)), emulsifying
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agents, lubricants, disintegrants, diluents, solubilizing agents (U.S. Pat.
No. 6,923,988), or
stabilizing agents. The funetionality of these excipients is dependent on
their concentrations
and the manufacturing process involved. In addition, under certain conditions
these
excipients can also be used as sustained release binders and matrix formers.
[62] The formulations of the invention preferably comprise about 0.5% to about
60% by weight of the biodegradable binder or lipophilic binder. More
preferably, the
formulation comprises a total weight about 0.5% to about 40% by weight, and
more
preferably 1% to about 25% by weight of the biodegradable binder and
lipophilic binder.
Preferably, the formulation comprises a total weight about 5% to about 15% or
about 10% to
about 25% by weight of the biodegradable binder and lipophilic binder,
depending on the
type of binder used.
[63] In a preferred embodiment, the nature and amount of the binder are such
that
the degradation of the binder takes place primarily in the stomach at fed
conditions. Fed
conditions in the stomach are characterized by a highly lipophilic environment
with increased
pepsin and lipase activity. A suitable binder for use in the invention can be
determined by
conducting an in vitro disintegration test of a tablet composition containing
a particular
binder in the medium used herein to simulate the fed mode, and a
disintegration test of a
tablet composition in the medium used below to simulate the fast mode. A
significantly
shorter disintegration time in the fed mode medium compared with the fast mode
medium
indicates that the binder in question will be suitable for use in this
invention.
[64] Preferably, the formulation further comprises at least one non-
biodegradable
binder or non-lipophilic binder. In order to adjust the bioavailability as
desired, additional
excipients such as non-biodegradable binders and disintegrants may also be
added. Hence,
while the food effect is decreased by the use of a biodegradable and/or
lipophilic binder, the
addition of an appropriate amount a suitable disintegrant can increase the
bioavailability in
both fast and fed conditions. Similarly, the bioavailability can be reduced
for both fed and
fast conditions by adding or increasing the content of a non-biodegradable and
non-lipophilic
binder.
[65] Accordingly, one can control the bioavailability in fed conditions with
minimal effect on fast conditions, and/or control the bioavailability in
fast'conditions with
minimal effect on fed conditions. For example, one can decrease the
bioavailability in fast
conditions with minimal effect on fed conditions, or increase the
bioavailability in fed
conditions with minimal effect on fast conditions.
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[66] . While the invention is suitable for any formulation where control of
bioavailability is desired or needed, it is particularly suitable for drugs
exhibiting undesired
food effect. The present invention is suitable for drugs showing a food
effect, preferably
drugs where bioavailability in fed conditions are lower compared with that in
fast conditions.
Preferably, the drug which exhibits food effect includes at least one 3,5
dihydroxy-acid.
Preferably, the drug includes at least one of atorvastatin, fluvastatin,
rosuvastatin, pravastatin,
simvastatin, or lovastatin.
[67] In a preferred embodiment, the formulation comprises granules and an
extra-
granular component. The binder used can be present both intra-granularly and
extra-
granularly. More preferably, the biodegradable binder or lipophilic binder is
present in the
granules and/or as an extra-granular component. The formulations of the
invention can be
prepared, for example, by dry mixing, wet granulation, spray granulation, or a
combination
thereof.
[68] The formulations of the invention may also include other excipients which
are
not particularly biodegradable or lipophilic, such as acacia, alginic acid,
carbomer (e.g.
carbopol), carboxymethylcellulose sodium, dextrin, ethylcellulose, gelatin,
guar gum,
hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel ) hydroxypropyl
methyl
cellulose (e.g. Methocel ), liquid glucose, maltodextrin, methylcellulose,
polymethacrylates,
povidone (e.g. Povidone PVP K-30, Kollidon , Plasdone ), pregelatinized
starch, and
sodium alginate, croscarmellose sodium (e.g. Ac Di Sole, Primellose ),
crospovidone (e.g.
Kollidon , Polyplasdone ), microcrystalline cellulose, polacrilin potassium,
powdered
cellulose, sodium starch glycolate (e.g. Explotabg, Primoljelg) colloidal
silicon dioxide,
magnesium trisilicate, powdered cellulose, talc, magnesium stearate, calcium
stearate,
glyceryl monostearate, glyceryl palmitostearate, mineral oil, polyethylene
glycol, sodium
lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
[69] In a preferred embodiment, the formulation further comprises at least one
of
lactose, mannitol, croscarmellose sodium, crospovidone, polaccrillin potasium,
microcrystalline cellulose (e.g. Avicel), hydroxypropyl cellulose (Klucel),
povidone (e.g.
PVP K-30), magnesium carbonate, vitamin E TPGS, butylmethacrylat-(2-
dimethylaminoetliyl)methacrylate-rnethylrriethacrylate copolymer (1':2:1) (
Eudragit E),
magnesium aluminum silicate, or sodium stearyl fumarate. In another preferred
embodiment,
the adjusted formulation comprises lactose, mannitol, croscarmellose sodium,
crospovidone,
polaccrillin potasium, microcrystalline cellulose, hydroxypropyl cellulose,
povidone,
magnesium carbonate, vitamin E TPGS, butylmethacrylat-(2-
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dimethylaminoethyl)methacrylate-methylmethacrylate copolymer (1:2:1),
magnesium
aluminum silicate, and sodium stearyl fumarate.
[701 Some embodiments also encompass a pharmaceutical composition comprising
at least one 3,5 dihydroxy-acid, preferably one that exhibits a food effect,
and at least one of a
biodegradable binder or lipophilic binder. Preferred 3,5 dihydroxy-acids
include atorvastatin,
fluvastatin, rosuvastatin, pravastatin, simvastatin, or lovastatin.
[71] In one embodiment, the pharmaceutical composition comprises at least one
3,5
dihydroxy-acid and at least one of a biodegradable binder or lipophilic
binder, wherein the
food effect exhibited by the 3,5 dihydroxy-acid is reduced, e.g., by at least
about 10 percent,
at least about 20 percent, at least about 50 percent, or at least about 100
percent, compared to
an otherwise identical pharmaceutical composition comprising the 3,5 dihydroxy-
acid in the
absence of a biodegradable binder or a lipophilic binder.
[721 In a preferred embodiment, the pharmaceutical composition has a relative
food
effect of about 0.8 to about 1.25, about 0.8 to about 1, or preferably about
1. Preferably, the
relative food effect exhibited by the API is reduced compared to an otherwise
identical
pharmaceutical composition comprising the API in the absence of a
biodegradable binder or a
lipophilic binder. For example, the relative food effect can be reduced by at
least about 10
percent, at least about 20 percent, at least about 50 percent, or at least
about 100 percent
compared to an otherwise identical pharmaceutical composition comprising the
API in the
absence of a biodegradable binder or a lipophilic binder.
[73] In another embodiment, the pharmaceutical composition comprises at least
one 3,5 dihydroxy-acid and about 0.5% to about 60% by weight total of at least
one of a
biodegradable binder or lipophilic binder.
[74) Preferably, the biodegradable binder includes binders degradable by at
least
one of a gastrointestinal enzyme, protease, lipase or amylase. More
preferably, the
biodegradable binder includes a binder degradable by a gastrointestinal
enzyme. Preferably,
the biodegradable binder includes a binder that is degradable at a pH of about
1 to about 7.5,
and more preferably about 1.3 to about 6.5 or about 1.2 to about 6.5.
[75) In one preferred embodiment, the biodegradable binder includes at least
one
protein, lipid, or polysaccharide. Preferably, the biodegradable* binder
includes at least one of
gelatin, ZEIN, ZEIN derivatives, hydrogenated vegetable oil, hydrogenated
castor oil,
glycerol palmitostearate, glycerol behenate, stearoyl macrogoiglycerides, or
starch.
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[761 In another embodiment, the lipophilic binder dissolves in lipophilic
media,
disintegrates in lipophilic media, or both. Preferably, the lipophilic binder
degrades at a pH
of about 2 to about 7, and more preferably about 1.3 to about 6.5.
[77] In one preferred embodiment, the lipophilic binder includes at least one
of
ethylcellulose, a mixture of ethylcellulose and polyethylene glycol, or
poloxamer.
[78] In a preferred embodiment, the pharmaceutical composition comprises about
0.5% to about 60% by weight, preferably about 0.5% to about 40%, and more
preferably
about 1% to about 25% of the biodegradable binder or lipophilic binder. Also
preferably, the
formulation comprises about 5% to about 15% or about 10% to about 25% by
weight of the
biodegradable binder or lipophilic binder, depending on the type of binder
used.
[79] In another preferred embodiment, the pharmaceutical composition comprises
granules and an extra-granular component. In another preferred embodiment, the
biodegradable binder or lipophilic binder is present in the granules and the
extra-granular
component.
[801 - In one preferred embodiment, the pharmaceutical composition further
comprises at least one non-biodegradable binder or non-lipophilic binder. In
another
preferred embodiment, the pharmaceutical composition further comprises at
least one
disintegrant.
[81] In one embodiment, the pharmaceutical composition comprises at least one
of
lactose, mannitol, croscarmellose sodium, crospovidone, polaccrillin potasium,
microcrystalline cellulose, hydroxypropyl cellulose, povidone, magnesium
carbonate, vitamin
E TPGS, butylmethacrylat-(2-dimethylaminoethyl)methacrylate-methylmethacrylate
copolymer (1:2:1), magnesium aluminum silicate, or sodium stearyl fumarate.
Preferably,
the pharmaceutical composition comprises lactose, mannitol, croscarmellose
sodium,
crospovidone, polaccrillin potasium, microcrystalline cellulose, hydroxypropyl
cellulose,
povidone, magnesium carbonate, vitamin E TPGS, butylmethacrylat-(2-
dimethylaminoethyl)methacrylate-methylmethacrylate copolymer (1:2:1),
magnesium
aluminum silicate, and sodium stearyl fumarate.
[82] The present invention encompasses formulations prepared by the methods of
the invention, and methods for treating a medical disease by administering
these formulations
to a mammal in need thereof.
[83] The formulations of the invention are preferably in solid dosage form,
and
more preferably in the form of a tablet. Solid pharmaceutical compositions
that are
compacted into a dosage form, such as a tablet, may include excipients whose
functions
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include helping to bind the active ingredient and other excipients together
after compression.
Binders for solid pharmaceutical compositions include acacia, alginic acid,
carbomer (e.g.
carbopol), carboxymethylcellulose sodium, dextrin, ethylcellulose, , guar gum,
hydroxyethyl
cellulose, hydroxypropyl cellulose (e.g. Klucel ), hydroxypropyl methyl
cellulose (e.g.
Methocel ), liquid glucose, maltodextrin, methylcellulose, polymethacrylates,
povidone (e.g.
Povidone PVP K-30, Kollidon , PlasdoneS), pregelatinized starch, sodium
alginate and
starch.
[84] A compacted solid pharmaceutical composition may also include the
addition
of a disintegrant to the composition. Disintegrants include croscarmellose
sodium (e.g. Ac-
Di-Sol , Primellose ), crospovidone (e.g. Kollidon , Polyplasdone ),
microcrystalline
cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch,
sodium starch
glycolate (e.g. Explotab , Primoljel ) and starch.
[851 Glidants can be added to improve the flowability of pre-compacted or un-
compacted solid compositions and to improve the accuracy of dosing during
compaction and
capsule filling. Suitable glidants include colloidal silicon dioxide,
magnesium trisilicate,
powdered cellulose, and talc.
[86] A lubricant can also be added to reduce adhesion and/or ease the release
of the
product from, for example, dyes and punches. Suitable lubricants include
magnesium
stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate,
hydrogenated
castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol,
sodium lauryl sulfate,
sodium stearyl fumarate, stearic acid, talc and zinc stearate.
[87] Other excipients which may be incorporated into the formulation include
preservatives and/or antioxidants. One of ordinary skill in the art will
appreciate that any
other excipient commonly used in the pharmaceutical industry may be used.
[88] Having described the invention with reference to certain preferred
embodiments, other embodiments will become apparent to one skilled in the art
from
consideration of the specification. The invention is further defined by
reference to the
following examples describing in detail the analysis and processes for making
the invention.
It will be apparent to those skilled in the art that many modifications, both
to materials and
methods, may be practiced without departing from the scope of the invention.
EXAMPLES
[89] The following examples illustrate of concept of the invention using
atorvastatin compositions containing gelatin as the biodegradable binder and
hydrogenated
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castor oil as the biodegradable/lipophilic binder. The compositions were
tested with in-vitro
dissolution models simulating fast and fed conditions at 37 C using USP Paddle
Method. The
models are distinguished by lipophilicity and by enzyme content as follows:
= Fast Model 1: Hydrophilic medium (buffer phosphate pH 7.5, 700 ml, 80 rpm)
with
pancreatin. This model is intended as a simulation of intestinal environment
under fast
condition.
= Fed Model 1: Hydrophobic-lipophilic medium (oil in water emulsion, pH 6.0,
700 ml,
80 rpm) with pancreatin. This model is intended as a simulation of intestinal
environment
under fed condition.
= Fed Model 2: Hydrophobic medium (milk, eggs, HCI, sesame oil, pH 2.3, 780
ml)
with pepsin. This model is intended as a simulation of gastric environment
under fed
condition.
[90] When a formulation with only 4% gelatin used as a biodegradable binder
was
tested in dissolution media simulating fast and fed conditions, no effect with
gelatin on food
effect was observed (Figure 1). However, testing this formulation using the
fed model
including pepsin (Fed Model 2) showed that gelatin in the formulation could
fiuiction as a
biodegradable binder (Figure 2). A significant effect on the dissolution rate
was observed in
the presence of pepsin in fed conditions. Thus, increasing the content of
gelatin increases the
dissolution rate of fed condition more than the fast condition. As exemplified
below,
compositions with hydrogenated castor oil resulted in significantly reduced
dissolution in fast
condition, whereas higher dissolution was observed with lipophilic media
simulating fed
conditions. It is expected that the behavior observed in in vitro testing will
be reflected when
tested under in vivo conditions.
Example 1
Prenaration of a Gelatin Formulation
Ingredient Amount (mg/dose) %
Part I
Mannitol SD 200 709.5 74.8
Atorvastatin 82.9 8.7
Crospovidone XL-10 20.0 2.1
PVP k-30 32.0 3.4
Magnesium carbonate 12.0 1.3
Granulation solution 1
Alcohol 95%
Vitamin E TPGS 24.0 2.5
Granulation solution 2
Gelatin 38.0 4
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water
Part II
Crospovidone XL-10 20.0 2.1
Part III
Sodium Stearyl fumarate = 9.6 1.0
Theoretical end weight 948.0
Step 1: The ingredients in Part I were thoroughly blended in a high shear
mixer.
Step 2: The blend of Part I was granulated by adding granulation solution
1(alcohol
95% containing melted vitamin E (TPGS)). The resulting granules were dried in
a fluidized
bed drier (Mini Glatt) and sized through a 0.8 mm aperture screen (Frewitt
oscillating
granulator).
Step 3: The granules from Step 2 were granulated with granulation solution 2
(33%
gelatin solution in water (w/w) prepared by dissolving gelatin in water at 50-
60 C and mixing
with a magnetic stirrer). The gelatin solution (50 C) was added to the dry
granulates from
Step 2 in a high shear mixer with continuous mixing. The resulting granules
were dried in a
fluidized bed drier and sized through a 1.5-mm aperture screen.
Step 4: The ingredients in Part II were blended with the granules from Step 3.
Step 5: The ingredients in Part III were blended with the blend of Step 4. The
final
blend was compressed to tablets. The composition was tested under dissolution
media
simulating the GI conditions in fast and fed states. Although a combination of
high shear
mixer and fluidized bed drier were used, it is equally possible for all
granulation and drying
to be in a fluidized bed drier or for that matter a high shear mixer that has
an integral drying
mechanism.
[91] The results, illustrated in Figure 1, show that the amount of gelatin in
Example
1 seems to have no significant effect on the dissolution in fast (Fast Model
1) or fed
conditions (Fed Model 1). When tested in dissolution media simulating the
gastric condition
in fed mode, i.e., including pancreatin (Fed Model. 1, Figure 1), the
dissolution of Example I
was as high as in the fast mode. Thus, no significant difference was observed
between fast
and fed conditions in a formula containing only 4% gelatin.
[92] When tested in dissolution media simulating the gastric condition in fed
mode, '
i.e., including pepsin (Fed Model 2, Figure 2), the dissolution of Example 1
exhibits high
dissolution similar to the comparative conventional formula without gelatin
(control Example
2, having a Cm... of 113% in fed as compared to Lipitor). Therefore, gelatin
is "transparent"
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to fed conditions, meaning that the addition of gelatin does not effect the
rate of dissolution in
the fed mode. In addition, it can be seen that the drug release of Example 1
was enzyme
mediated, as lower dissolution was observed in the absence of pepsin from the
media (Figure
2). Because gastric conditions in the fast state include a significantly lower
pepsin
concentration, it is reasonable to assume that a higher percentage content of
gelatin in the
composition, above 6 percent for example, should have a slower dissolution in
the fasted state
while remaining constant in the fed state which includes higher pepsin levels.
[93] Therefore, in order to see an in vivo advantage of fed over fast
conditions a
tune up of the biodegradable binder content (gelatin) should be performed. For
example, one
can increase the gelatin content in a composition to a concentration threshold
over which the
dissolution/ in vivo bioavailability in fast conditions will be decreased,
without affecting the
dissolution/ in vivo bioavailability in fed conditions. This is illustrated by
the effect of pepsin
on the dissolution rate for gelatin-containing tablets. See Fig. 2.
Example 2 (Control)
Preparation of Formulation Without Gelatin
Ingredient Amount (mg/dose) %
Part I
Mannitol SD 200 709.5 73.9
Atorvastatin 82.9 8.6
Crospovidone XL-10 20.0 2.1
PVP k-30 32.0 3.3
Dibasic Ca Phosphate 50.0 5.2
Granulation solution 1
Alcoho195%
Vitamin E TPGS 24.0 2.5
Tris in water 12.0 1.3
Part .II
Crospovidone XL-10 20.0 2.1
Part III
Sodium Stearyl fumarate 9.6 1.0
Theoretical end weight 960.0
Step 1: The ingredients in Part I were thoroughly blended.
Step 2: The blend of Part I was granulated by adding granulation solution 1(a
mixture
of 95% alcohol containing melted vitamin E(TPGS) and Tris in water). The
resulting
granules were dried in a fluidized bed drier (Mini Glatt) and fitted with a
1.0 mm aperture
screen (Frewitt oscillating granulator).
Step 3: The ingredients in Part II were blended with the granules of Step 2.
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Step 4: The ingredients in Part III were blended with the blend of Step 3. The
final
blend was compressed to tablets. The composition was tested under dissolution
media
simulating the GI conditions in fed states (Fed Model 2) including pepsin
(Figure 2).
Example 3
Preparation of a Hydrogenated Castor Oil Formulation
[94] This example illustrates how the rate of dissolution in the fast mode can
be
reduced without influencing the dissolution rate in the fed mode by using an
ingredient such
as hydrogenated castor oil.
Ingredient Amount m dose %
Part I
Mannitol SD 200 709.5 60_4
Atorvastatin 82.9 7.1
Crospovidone XL-10 20.0 1.7
PVP k-30 16.0 1.4
Dibasic Calcium phosphate 50.0 4.3
Granulation solution #1
Tris-base in water 12.0 1.0
Vitamin E TPGS in alcohol 24.0 2.0
95%
Part II
Hydrogenated castor oil 230 20
Part III
Crospovidone XL-10 20.0 1.7
Part IV
Sodium Stearyl fumarate 9.6 0.8
Theoretical end weight 1174.0
Step 1: The ingredients in Part I were thoroughly blended.
Step 2: The blend of Part I was granulated by adding granulation solution 1(a
mixture
of 95% alcohol containing melted vitamin E (TPGS) and Tris in water). The
resulting
granules were dried in a fluidized bed drier (Mini Glatt) and sized through a
1 mm aperture
screen (Frewitt oscillating granulator).
Step 3: The ingredients in Part II were blended with the dry granules from
Step 2.
Step 4: The ingredients in Part III were blended with the blend from Step 3.
Step 5: The ingredients in Part IV were blended with the blend from Step 4.
The
mixture was then compressed into tablets (the mixture alternatively could be
filled into
capsules).
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[95] The composition of Example 3 containing 20% hydrogenated castor oil by
weight of the total tablet was tested in a dissolution media simulating GI
conditions in fast
(Fast Model 1) and fed states (Fed Model 1), as shown in Figure 3.
[96] Figure 3 shows that the presence of hydrogenated castor oil markedly
decreases the dissolution in the fast condition. The reduction in the
dissolution rate for the
fast mode in Example 3 was greater than is probably required to achieve a lack
of food effect,
but this example shows how the rate of dissolution in the fast mode can be
manipulated
without a significant affect on the fed mode rate of dissolution. However,
when tested in
dissolution media simulating the fed condition of lipophilic media containing
pancreatin (Fed
Model 1), a higher dissolution was observed. Thus, the use of hydrogenated
castor oil as a
binder has a significant effect on the dissolution rate of the fast condition
compared to the fed
conditions and therefore reduction in food effect was observed to the extent
that the food effect has been reversed.
Example 4
Preparation of a Hydrogenated Castor Oil Formulation of Atorvastatin with
Amlodipine
Ingredient Amount (mg/dose) %
Part I
Mannitol SD 200 709.5 61.9
Atorvastatin 82.9 7.2
Crospovidone XL-10 20.0 1.7
PVP k-30 16.0 1.4
Magnesium carbonate 12.0 1.0
Granulation solution 1
Vitamin E TPGS in alcohol 24.0 2.0
95%
Part II
Crospovidone XL-10 20.0 1.7
Part III
Amlodipine Besylate 13.9 1.2
Microcrystalline cellulose 60.0 5.2
Croscarmellose sodium 60.0 5.2
Hydrogenated castor oil 116 10.1
Colloidal Si02 1.0 0.087
Part IV
Sodium Stearyl fumarate 10.0 0.8
Theoretical end weight 1144.9
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Step 1: The ingredients in Part I are thoroughly blended.
Step 2: The blend of Part I is granulated by adding granulation solution 1(a
mixture
of 95% alcohol containing melted vitamin E-TPGS). The resulting granules are
dried in a
Mini Glatt and milled with Frewit (1 mm).
Step 3: The ingredients in Part II are blended with the dry granules from Step
2.
Step 4: The ingredients in Part III are blended with the blend from Step 3.
Step 5: The ingredients in Part IV are blended with the blend from Step 4 to
form a
final composition, and the mixture is compressed into tablets.
21
