Note: Descriptions are shown in the official language in which they were submitted.
CA 02758556 2011-11-17
,
PHARMACEUTICAL COMPOSITION OF AMPHETAMINE
MIXED SALTS
FIELD OF THE INVENTION
The present invention relates to an orally administrable modified release
pharmaceutical
composition comprising pellets containing one or more active ingredients, more
specifically the present invention is directed to dosage form comprising one
or more
amphetamine salts.
BACKGROUND OF THE INVENTION
Continued development and improvement of modified release pharmaceutical
compositions has long been a focus in the field of pharmaceutical
formulations.
Advantages of a modified release composition include increased convenience of
administration, and a more consistent therapeutic effect throughout a desired
period of
time.
Amphetamine is a psychostimulant drug of the phenethylamine class which
produces
increased wakefulness and focus in association with decreased fatigue and
appetite.
Amphetamines are non-catecholamine, sympathominetic amines with central
nervous
system stimulant activity, which have been widely utilized in treating
narcolepsy and
Attention Deficit Hyperactivity Disorder (ADHD). The amphetamine salts
generally
include the neutral sulfate salts of dextroamphetamine and amphetamine, the
dextro
isomer of amphetamine saccharate and d,l-amphetamine aspartate.
Brand names of medications that contain, or metabolize into, amphetamine
include
Adderall, Dexedrine, Dextrostat, Desoxyn, ProCentra, and Vyvanse, as well as
Benzedrine.
Currently marketed oral amphetamine products to treat narcolepsy and/or ADHD
include
both immediate-release and modified-release forms. The Dexedrine product is
marketed as a sustained-release formulation with dextroamphetamine sulfate as
the only
active ingredient.
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Adderall is an immediate release composition and Adderall XR , a once daily
sustained-release, are single-entity dosage forms containing a mixture of four
amphetamine salts: dextroamphetamine sulfate, dextroamphetamine saccharate,
amphetamine aspartate monohydrate and amphetamine sulfate, which is indicated
for
treatment of ADHD in children from 3-10 years of age.
Adderall is also known like an immediate release composition, which includes
a mixture
of four amphetamine salts.
Drug absorption is different in various segments of the gastrointestinal
system. For
example, it drug absorption is moderately slow in the stomach, rapid in the
small
intestine, and sharply declines in the large intestine. Compensation for
changing
absorption characteristics in the gastrointestinal tract may be important for
some drugs.
The mixture of amphetamine salts is well known. For example, see the following
references: CA2605185, CA2651890, W020050044238, W02007133203,
US2006204575, CA2348090 (US 6322819), CA2432178 (US 6287599)
CA2348090 (US6322819) discloses a multiple pulsed dose drug delivery system
for
pharmaceutically active amphetamine salts, comprising immediate-release
pellets for
releasing in the stomach and an enteric delayed-release pellets releasing in
the small
intestine, and a person skilled in the art would recognize an inherent food
effect.
CA2432178 (US6287599) discloses pharmaceutical composition comprising at least
one pharmaceutically active agent that is pH dependent, at least one non-pH
dependent
sustained release agent, and at least one pH dependent agent that increases
the
dissolution rate of the at least one pharmaceutically active agent at pH in
excess of 5.5.
US6384020 (SHIRE LAB INC.) discloses an immediate-release oral dosage form in
delivering amphetamines and their salts. This dosage form solves particular
process
problems and has an adequate stability profile. However, this reference does
not teach
how to make a sustained-release formulation.
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There are other references which disclose different amphetamine dosage forms
with a
plurality of modified release units, particularly extended release dosage
forms, mixed
salts of amphetamine extended release capsules, where it is formulated by
mixing two
types of pellets, immediate release pellets and delayed release pellets in 1:
1 ratio to
have a dual type of release. The immediate release pellets releases the
amphetamine
salts immediately after ingestion and the delayed release pellets release the
amphetamine salts once the pellets reache the intestine.
A number of factors may influence the efficacy of pulse drug release and thus,
represent
a source of variability. Such factors include the complexity of the process
for drug
formulation, reproducibility of the manufacturing process, and uniformity of
the product
produced by the manufacturing process. One of the disadvantages of the
manufacturing
process used to prepare such pulse drug release formulations is the filling of
two or
more pellets requires specialized filling machines and change parts and could
bring
variability in dissolution if the correct amount of each type of pellets is
not filled.
In addition, gastrointestinal transit times vary not only from patient-to-
patient but also
within patients as a result of food intake (i.e. fed or fasted states),
stress, and illness.
Thus, while a variety of formulations have been proposed in consideration of
one or
more of these factors, improved formulations are still desirable.
Therefore, accordingly to a need exist to overcome the existing drawbacks by
modified
release formulation of amphetamine mixed salts.
SUMMARY OF THE INVENTION
An aspect of the present invention is directed to a modified release
pharmaceutical
composition comprising pellets containing one or more active ingredients, said
pellets
comprising:
(a) an inert core;
(b) a first layer disposed over the inert core, said layer comprises at least
one
pharmaceutically active ingredient and at least one hydrophilic binder; and
(c) a modified enteric coating disposed over the first layer, said modified
enteric
coating comprises an enteric polymer and a channeling agent,
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CA 02758556 2011-11-17
wherein said composition provides: a continuous release of the
pharmaceutically active
ingredient once the dosage form is exposed to a media of pH less than 5.5; and
a
pulsatile release of the pharmaceutically active ingredient at pH 6.0 or more.
Preferably, the pharmaceutically active ingredient is selected from the group
consisting
of amphetamine salts, and more preferably, amphetamine base salts.
More preferably, the amphetamine salts are selected from the group consisting
of:
amphetamine sulphate, dextroamphetamine sulphate, dextroamphetamine
saccharate,
amphetamine aspartate and mixtures thereof.
Another aspect of the present invention is directed to a modified release
pharmaceutical
composition which provides a dual type of release:
- a continuous release of the pharmaceutically active ingredient at a pH less
than
5.5, and
- a pulsatile release of the pharmaceutically active ingredient at pH 6.0 or
more.
Preferably, the dual type of release of said modified release pharmaceutical
composition
is provided from a single type of pellets containing one or more active
ingredients.
Yet another aspect of the present invention is directed to a modified release
pharmaceutical composition comprising pellets containing one or more active
ingredients
which comprising: an inert core; a first layer disposed over the inert core
and a modified
enteric coating disposed over the drug layered pellet, wherein said
composition
provides: a continuous release of the pharmaceutically active ingredient at pH
less than
5.5, and a pulsatile release of the pharmaceutically active ingredient at pH
6.0 or more,
and has an in vitro dissolution profile of at least 95% of the active
ingredient dissolved
within 4 hours of administration as measured by USP Type II Apparatus
(sinkers), with
750 ml of 0,08 N HCI for 2hrs, and then 200m1 of buffer concentrate added to
make pH
6.0 for the next two hours, at 37 deg. C., at a paddle speed of 50 rpm.
Preferably, the inert core comprises at least one pharmaceutically acceptable
excipient
selected from the group consisting of: inert water soluble, inert water
insoluble, swellable
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material and mixtures thereof. More preferably, the pellet further comprises a
seal coat
disposed between the inert core and the first layer.
Also, preferably the first layer disposed over the inert core comprises at
least one
pharmaceutically active ingredient and at least one hydrophilic binder, which
is selected
from the group consisting of: hydroxypropyl cellulose, hydroxypropylmethyl
cellulose,
carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose,
carboxyethyl cellulose,
carboxymethylhydroxyethyl cellulose, polyvinyl pyrrolidone, polyethylene
glycol, polyvinyl
alcohol, hypromellose, and combinations thereof. More preferably, the
hydrophilic binder
is hypromellose.
Another aspect of the present invention is directed to a modified release
pharmaceutical
composition with a dual type of release from a single type of pellets
containing one ore
more active ingredients comprising: an inert core; a first layer disposed over
the inert
core, and a modified enteric coating disposed over the drug layered pellet,
wherein said
modified enteric coating comprises an enteric polymer, a channeling agent and
at least
one pharmaceutically acceptable excipient.
Preferably, the modified enteric coating comprises an enteric polymer selected
from the
group consisting of: ammonialkyl methacrylate copolymers, methacrylate
copolymers,
and a combination thereof. More preferably, the enteric polymer is Eudragit
L3OD 558.
Also, preferably the channeling agent of the modified enteric coating is
selected from the
group consisting of: hydrophilic excipients or hydrophilic polymers,
comprising one or
more of glucose, mannitol, lactose, xylitol, dextrose, sucrose and
combinations thereof.
More preferably, the channeling agent is mannitol.
Preferably, one or more pharmaceutically acceptable excipients are selected
from the
group consisting of: binders, plasticizers, lubricants, disintegrants,
diluents, glidants, anti
adherents and acidifying agents. More preferably, the plasticizer is triethyl
citrate.
More preferable, the modified release pharmaceutical composition comprising
pellets
containing one or more active ingredients, which comprises: about 50 %w/w to
about 90
%w/w of an inert core, about 2 %w/w to about 15 % w/w of a pharmaceutically
active
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ingredient, about 1.0 %w/w to about 12.0 %w/w of an enteric polymer, about 0.1
%w/w
to about 3.0 % w/w of a channeling agent, about 0.1 %w/w to about 3 %w/w of a
hydrophilic binder, about 0.1 %w/w to about 3.0 % w/w of Plasacryle, and about
0.1
%w/w to about 2.0 % w/w of a plasticizer, all based on the total weight of the
modified
release pharmaceutical composition.
Yet, another aspect of the present invention is directed to a modified release
pharmaceutical composition comprising pellets containing one or more active
ingredients, the composition comprising: an inert core; a first layer disposed
over the
inert core, said layer comprises at least one pharmaceutically active
ingredient and at
least one hydrophilic binder; a protective coating disposed over the first
(drug) layered
core, said coating comprises a hydrophilic polymer and at least one
pharmaceutically
acceptable excipient; and a modified enteric coating disposed over the
protective
coating, said modified enteric coating comprises an enteric polymer, a
channeling agent,
and at least one pharmaceutically acceptable excipient, wherein said
composition
provides continuous release of the active ingredient at pH less than 5.5, and
pulsatile
release of the pharmaceutically active ingredient at pH 6.0 or more.
Preferably, pellet further comprises a protective coating disposed over the
first layer, in
between the first layer and the modified enteric coating.
Also, preferably the hydrophilic polymer is selected from the group consisting
of:
hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl
cellulose, methyl
cellulose, hydroxyethyl cellulose, carboxyethyl cellulose,
carboxymethylhydroxyethyl
cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol,
hypromellose, and
combinations thereof. More preferably, the hydrophilic polymer of the
protective coating
is hypromellose and one of pharmaceutically acceptable excipients is colloidal
silicon
dioxide.
Further aspect of the present invention is directed to modified release
pharmaceutical
composition comprising pellets containing one or more active ingredients and
at least
one pharmaceutically acceptable excipient, wherein said composition has an in
vitro
dissolution profile of at least 95% of the active ingredient dissolved within
4 hours of
administration as measured by USP Type II Apparatus (sinkers), with 750 ml of
0,08 N
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CA 02758556 2011-11-17
HCI for 2hrs and then 200m1 of buffer concentrate added to make pH 6.0 for the
next two
hours, at 37 deg. C, at a paddle speed of 50 rpm.
Preferably, the modified release pharmaceutical composition comprising pellets
containing one or more active ingredients, which comprises: about 50 %w/w to
about 90
%w/w of an inert core, about 2 %w/w to about 15 % w/w of a pharmaceutically
active
ingredient, about 1.0 %w/w to about 12.0 %w/w of an enteric polymer, about 0.1
%w/w
to about 3.0 % w/w of a channeling agent, about 0.1 %w/w to about 3 %w/w of a
hydrophilic binder, about 1.0 %w/w to about 8.0 % w/w of a hydrophilic
polymer, about
0.1 %w/w to about 2.0 % w/w of an anti-adherent, about 0.1 %w/w to about 3.0
A w/w of
Plasacryle, and about 0.1 %w/w to about 2.0 % w/w of a plasticizer, all based
on the
total weight of the modified release pharmaceutical composition.
Preferably, said pharmaceutical composition has an in vitro dissolution
profile:
- about 10% to about 40% of the pharmaceutically active ingredient is released
after 60 min;
- about 40% to about 50% of the pharmaceutically active ingredient is
released
after 120 min;
- about 80% to about 100% of the pharmaceutically active ingredient is
released
after 180 min; and
- about 100% of the pharmaceutically active ingredient is released after 240
min,
as measured by Apparatus USP Type II (sinkers), with 750 ml of 0.08 N HCI for
2hrs and then 200m1 of buffer concentrate added to make pH 6.0 for the next
two
hours, at a paddle speed of 50rpm.
Another aspect of the present invention is directed to a modified release
pharmaceutical
composition comprising pellets containing one or more active ingredients and
at least
one pharmaceutically acceptable excipient, wherein the in vitro dissolution
profile of said
composition provides at least 95% of the active ingredient dissolved within 4
hours,
which is substantially the same as provided by an equivalent dose of Adderal
XR, as
measured by USP Type II Apparatus(sinkers), with 750 ml of 0,08 N HCI for 2hrs
and
then 200m1 of buffer concentrate added to make pH 6.0 for the next two hours,
at 37
deg. C., at a paddle speed of 50 rpm.
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Further aspect of the present invention is directed to a modified release
pharmaceutical
composition comprising pellets containing one or more active ingredients and
at least
one pharmaceutically acceptable excipient, wherein the modified enteric
coating allows
to release the active ingredient in such a way that less than 50% of the
active ingredient
is released in the stomach and substantially the same amount of the remaining
active
ingredient is released in the intestine.
Preferable, the pulsatile release provides a release of amphetamine salts from
about 2
hours to about 4 hours after administration.
Yet, another aspect of the present invention is directed to a method of
manufacturing a
modified release pharmaceutical composition, wherein the method comprises the
following steps:
1) Drug layering:
a) loading a sugar spheres or optionally seal coated pellets in a coating
equipment;
b) dissolving the active ingredient;
c) mixing the active ingredient with a hydrophilic binder and at least one
pharmaceutically acceptable excipient;
d) spraying solution comprising the active ingredient, a binder and at least
one
pharmaceutically acceptable excipient onto the sugar spheres or seal coated
pellets to
obtain a drug layered pellet;
2) Protective coating:
e) dissolving a hydrophilic polymer and at least one pharmaceutically
acceptable
excipient;
f) loading the drug layered pellets in a fluid bed processor;
g) coating drug layered pellets with solution of step (e) to obtain sub-coated
pellets;
3) Modified enteric coating:
h) dissolving a channeling agent;
i) preparing a dispersion solution; adding enteric polymer to solution of step
(h);
j) adding an enteric polymer and at least one pharmaceutically acceptable
excipient to solution of step (i);
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k) loading sub-coated pellets in a fluid bed processor;
I) applying a solution of step (j) onto the sub-coated pellets of step (2) to
obtain
modified enteric coated pellets.
Preferably, the layers are applied as a solution/ dispersion of coating
ingredients. The
modified release pharmaceutical composition preferably is in the form of a
capsule.
The present invention is further related to use of said pharmaceutical
composition for the
treatment or prevention of narcolepsy and Attention-Deficit/Hyperactivity
Disorder
(ADHD).
These and other aspects, advantages and features of the present invention
become
clear when detailed description and examples are provided.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows dissolution profiles for modified release composition versus time
for an
example compared to Adderall XR .
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an orally administrable modified release
pharmaceutical
composition comprising pellets containing one or more active ingredients which
comprising: an inert core; a first layer disposed over the inert core, and a
modified
enteric coating disposed over the first layer, wherein said composition
provides:
- continuous release of the pharmaceutically active ingredient at an pH less
than
5.5, and
- pulsatile release of the pharmaceutically active ingredient at pH 6.0 or
more.
A controlled release pharmaceutical composition means a pharmaceutical
composition
including at least one active pharmaceutical ingredient which is formulated
with at least
one pharmaceutically acceptable film forming polymer and optionally with at
least one
pharmaceutically acceptable excipient, where the pharmaceutical composition
shows a
pH-dependent or a pH-independent reproducible release profile.
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The term "controlled release pharmaceutical composition", as referred to
herein, is
defined to mean oral pharmaceutical compositions which when administered
releases
the active ingredient at a relatively constant rate and provide plasma
concentrations of
the active ingredient that remain substantially invariant with time within the
therapeutic
range of the active ingredient over a 24-hour period and encompasses
"prolonged
release", "extended release", "modified release", "delayed release" and
"sustained
release" compositions.
The term "modified release" as referred to herein, means that the escape of
the drug
from the tablet has been modified in some way. Usually this is to slow the
release of the
drug so that the medicine doesn't have to be taken too often and therefore
improves
compliance. The other benefit from modifying release is that the drug release
is
controlled and there are smaller peaks and troughs in blood levels therefore
reducing the
chance of peak effects and increasing the likelihood of therapeutic
effectiveness for
longer periods of time.
The term "continuous release", means that a term applied to a drug that is
designed to
deliver a dose of a medication over an extended period. The most common device
for
this purpose is a soft, soluble capsule containing minute pellets of the drug
for release at
different rates in the GI tract, depending on the thickness and nature of the
oil, fat, wax,
or resin coating on the pellets. Another system consists of a porous plastic
carrier
impregnated with the drug and a surfactant to facilitate the entry of GI
fluids that slowly
leach out of the drug. Ion exchange resins that bind to drugs and liquids
containing
suspensions of slow-release drug granules are also used to provide medication
over an
extended period.
The term "pulsatile release" means that a drug is delivered in one or more
doses that
fluctuate between a maximum and minimum dose over a predetermined time
intervals.
This can be represented by a dose release profile having one or more distinct
peaks or
valleys. However, two or more pulsed releases may produce an overlapping,
overall, or
composite release profile that appears or effectively is constant. The need
for pulsatile
release may include the desire to avoid drug degradation in the stomach or
first pass
metabolism. Pulsatile release can be achieved via coating of multiparticulates
with pH
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dependent and/or barrier membrane coating systems, followed by blending of the
multiparticulates to achieve desired release profiles.
"Immediate" and "delayed" release" refer to the onset of release in
relationship to
administration of the drug. "Immediate" means that the release of drug begins
very soon,
within a relatively short time after administration, e.g. a few minutes or
less. "Delayed"
means that the release of drug is postponed, and begins or is triggered some
period of
time after administration (e.g., the lag time), typically a relatively long
period of time, e.g.
more than one hour.
The terms "pellet" refer to a discrete component of a dosage form. For
example, a
capsule shell is filled with a plurality of beads or pellets. As used herein,
pellet means
any discrete component of a dosage form.
A drug delivery system of the invention typically may comprise a core seed or
matrix,
which may or may not be loaded with drug, and one or more coating layers
comprising
drug, and/or comprising a layer have release characteristics which control the
onset and
release characteristics of the drug.
An inert core comprises at least one pharmaceutically acceptable excipient
selected
from the group consisting of: inert water soluble, inert water insoluble,
swellable material
and mixtures thereof. Preferably, the inert core is made of sugar spheres and
more
preferably the pellet further comprises a seal coat disposed between the inert
core and
the first layer.
The term "active ingredient" refers to an Active Pharmaceutical Ingredients
(API) which
are active chemicals used in the manufacturing of drugs. The active agent can
be a
therapeutic, a prophylactic, or a diagnostic agent.
According to the present invention the pharmaceutically active ingredient is
selected
from the group consisting of Amphetamine base salts, wherein the amphetamine
salts
are selected from the group consisting of: amphetamine sulphate,
dextroamphetamine
sulphate, dextroamphetamine saccharate, amphetamine aspartate and mixtures
thereof.
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In addition to the pharmaceutically active ingredient(s), the pharmaceutical
composition
according to the present invention contains at least one enteric polymer, at
least one
channeling agent, at least one hydrophilic polymer and at least one
pharmaceutically
acceptable excipient.
An enteric polymers that may be used in the oral modified release
pharmaceutical
composition is selected from the group, but are not limited to: ammonialkyl
methacrylate
copolymers, methacrylate copolymers, hydroxypropyl methylcellulose acetate
succinate
(HPMCAS), hydroxypropyl nnethylcellulose phthalate (HPMCP), polyvinyl acetate
phthalate, cellulose acetate phthalate, cellulose acetate trimellitate,
shellac, zein,
polymethacrylates containing carboxyl groups, amylose acetate phthalate,
styrene
maleic acid copolymer, and cellulose acetate succinate and a combination
thereof.
Examples of commercially available enteric material are available under the
trade names
EUDRAGIT . Preferably, the enteric polymer is EUDRAGITO L 30D-55 (methacrylic
acid/ethyl acrylate copolymer), but similar enteric polymer may also be
employed.
The present invention includes pharmaceutical composition producing a modified
release having channels. The channels act as controlled transmission passages
through
the polymer.
The channeling agent is selected from the group consisting, but not limited
to:
hydrophilic excipients or hydrophilic polymers, comprising one or more of
glucose,
mannitol, lactose, xylitol, dextrose, sucrose and combinations thereof.
Preferably, the
channeling agent is mannitol, but similar channeling agent may also be
employed.
Hydrophilic polymers that may be used in the oral modified release
pharmaceutical
composition is selected from the group, but are not limited to: hydroxypropyl
cellulose,
hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl cellulose,
hydroxyethyl
cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose,
polyvinyl
pyrrolidone, polyethylene glycol, polyvinyl alcohol, hypromellose, and
combinations
thereof.
In addition to the active ingredients and listed polymers the pharmaceutical
composition
of the present invention contains the pharmaceutically acceptable excipients
added to
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CA 02758556 2011-11-17
the composition for a variety of purposes. One or more pharmaceutically
acceptable
excipients may be present in the composition of the present invention, but not
limited to:
diluents, binders, lubricants, disintegrants, glidants, and acidifying agents.
As
understood by a person skilled in the art, these excipients are conventional
excipients
which are well known in the pharmaceutical art.
The hydrophilic binder is selected from the group consisting of: hydroxypropyl
cellulose,
hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl cellulose,
hydroxyethyl
cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose,
polyvinyl
pyrrolidone, polyethylene glycol, polyvinyl alcohol, hypromellose, and a
combination
thereof. Preferably, the hydrophilic binder is hypromellose, but similar
hydrophilic binders
may also be employed.
According to the present invention the plasticizer of the modified enteric
coating is
selected from the group consisting of: diethylphthalate, dibutylphthalate,
dibutylsebacate,
tributyl citrate, triethyl citrate, acetyltributyl citrate, propylene glycols,
glyceryl
monostearate, and a combination thereof. Preferably the plasticizer is
triethyl citrate, but
similar plasticizer may also be employed.
Oral dosage forms which may be employed with the present invention include
pellets in
a capsule or in any other suitable solid form.
During drug development, in vitro dissolution testing is an important tool in
the evaluation
of the 'best' formulation. Dissolution testing is also utilized to define the
biopharmaceutical characteristics and to identify possible risks such as
potential food
effects on bioavailability or interaction with other drugs. The simulation of
specific
gastrointestinal conditions which may lead to potential therapeutic failure or
adverse
events seems to be another point of interest during drug development. At this
stage
various models and test conditions for in vitro dissolution studies are
applied to learn
about the biopharmaceutical characteristics of early formulations and about
the
discriminating power of the test system.
Drug release and drug release profiles are measures or representations of the
manner
and timing by which a formulation releases or delivers active ingredients
(drug) to a
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CA 02758556 2011-11-17
receiving environment (e.g. the stomach, intestines, etc.) upon
administration. Various
methods are known for evaluating drug release and producing release profiles,
including
in vitro tests which model the in vivo behavior of a formulation. These
include USP
dissolution testing for immediate release and controlled release solid dosage
forms.
According to an aspect of the present invention, the method of manufacturing a
modified
release pharmaceutical composition comprising a single type of pellets
containing one or
more active ingredients which comprising: an inert core; a first layer; and a
modified
enteric coating, wherein said method comprises the following steps:
1) Drug layering:
a) loading a sugar spheres or seal coated pellets in a coating equipment;
b) dissolving the active ingredient;
c) mixing the active ingredient with a hydrophilic binder and at least one
pharmaceutically acceptable excipient;
d) spraying solution comprising the active ingredient, a binder and at least
one
pharmaceutically acceptable excipient onto the sugar spheres or seal coated
pellets to obtain a drug layered pellet;
2) Protective coating:
e) dissolving a hydrophilic polymer and at least one pharmaceutically
acceptable
excipient;
f) loading the drug layered pellets in a fluid bed processor;
g) coating drug layered pellets with solution of step (e) to obtain sub-coated
pellets;
3) Modified enteric coating:
h) dissolving a channeling agent;
i) preparing a dispersion solution; adding enteric polymer to solution of step
(h);
j) adding an enteric polymer and at least one pharmaceutically acceptable
excipient to solution of step (i);
k) loading sub-coated pellets in a fluid bed processor;
I) applying a solution of step (j) onto the sub-coated pellets of step (2) to
obtain
modified enteric coated pellets; and optionally
m) filing obtained pellets into a suitable sized capsule.
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The following Example 1 illustrates the preferred embodiment but not limiting
the present
invention.
Example 1,
Modified Release Pharmaceutical Composition of Amphetamine Mixed Salts
The required quantities of amphetamine salts: Amphetamine sulphate,
Dextroamphetamine sulfate, Dextroamphetamine saccharate and Amphetamine
aspartate are dissolved in purified water to make 15.7% w/w solution
(amphetamine
salts mixture). The mixture of amphetamine salts may be in a 1:1:1:1 ratio.
The modified
release composition comprises about 2.0 %w/w to about 15 % w/w of the
pharmaceutically active amphetamine salts. Preferably, the modified release
composition comprises about 2.0 %w/w to about 4.0 % w/w of each amphetamine
salt,
more preferably about 2.96 %w/w.
A suitable binder adhere particles of the selected composition to a core.
Suitable binders
include, for example, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose,
carboxyethyl cellulose,
carboxymethylhydroxyethyl cellulose, polyvinyl pyrrolidone, polyethylene
glycol, polyvinyl
alcohol, hypromellose, and a combination thereof. In present embodiment, the
binder is
hypromellose. The modified release composition comprises about 0.1 %w/w to
about 3.0
% w/w of the binder, preferably about 2.36 %w/w.
A protective coating layer may be disposed on the inert core before and/or
after coating
of the active agent. The inert core may be coated with a protective layer
comprising a
second binder (sub-coat) and/or an active agent-coated core may be coated with
a
protective layer comprising a third binder (outer-coat), by coating techniques
such as
pan coating or fluid bed coating using solutions of polymers in water or
suitable organic
solvents or by using aqueous polymer dispersions.
The pellet further comprises a seal coat disposed between the inert core and
the first
layer.
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CA 02758556 2011-11-17
The sugar spheres or seal coated pellets is loaded in a bottom spray fluid bed
processor.
A mixture comprising said pharmaceutically active amphetamine salts and a
binder is
sprayed over the sugar spheres or seal coated inert core in an amount
sufficient to
provide an Amphetamine drug layered pellets.
The required quantity of hypromellose is dissolved in purified water and to
this solution
colloidal silicon dioxide is dispersed to make 6.8% w/w protective coating
solution. The
modified release composition comprises about 1 %w/w to about 8 % w/w of the
hypromellose, preferably about 7.9 %w/w and about 0.1 %w/w to about 2.0 % w/w
of the
colloidal silicon dioxide, preferably 1.2%w/w.
Amphetamine drug layered pellets are loaded in a bottom spray fluid bed
processor. The
protective coating solution is sprayed on the drug layered pellets to obtain
Amphetamine
sub coated pellets.
The required quantity of mannitol is dissolved in purified water. The modified
release
composition comprises about 0.1 %w/w to about 3.0 % w/w of mannitol,
preferably about
2.20 %w/w. To this solution the Plasacryle is dispersed and stirred for 45
minutes. The
modified release composition comprise about 0.1 %w/w to about 3.0 % w/w of
Plasacryle, preferably about 2.20 %w/w. Further to said dispersion the
Eudragit L3OD
55 is added. The modified release composition comprises about 1.0%w/w to
about
12.0% w/w of Eudragit L3OD 550, preferably about 11.1%w/w.
Further the triethyl citrate is added to make 15% w/w dispersion for the
modified enteric
coating. The modified release composition comprises about 0.1%w/w to about 2.0
A)
w/w of triethyl citrate, preferably about 1.1 %w/w. The modified enteric
coating
dispersion is stirred for 30 minutes before using. Amphetamine sub-coated
pellets are
loaded in a bottom spray fluid bed processor. The modified enteric coating
dispersion is
sprayed over the Amphetamine drug layered pellets to obtain modified enteric
coated
pellets.
16
CA 02758556 2011-11-17
A modified release pharmaceutical composition comprising pellets containing
one ore
more active ingredients which comprises: from about 50 %w/w to about 90 %w/w
of an
inert core, about 2 %w/w to about 15 % w/w of a pharmaceutically active
ingredient,
about 1 %w/w to about 12 % w/w of an enteric polymer, about 0.1 %w/w to about
3.0 %
w/w of a channeling agent, about 0.1 %w/w to about 3 %w/w of a hydrophilic
binder,
about 0.1 %w/w to about 3.0 % w/w of Plasacryle, and about 0.1 %w/w to about
2.0 %
w/w of a plasticizer, all based on the total weight of the modified release
pharmaceutical
composition.
The modified enteric coated pellets further are incorporated into a capsule.
The formulation and manufacturing steps of Example 1 is set out in Table 1.
Table 1
FORMULATION AND MANUFACTORING OF AMPHETAMINE MIXED SALTS
I. Drug layering
No. Ingredients % w/w Function
1. Inert core (seal coated spheres) 85.8 Substrate for coating
2. Amphetamine sulphate 2.96 Active ingredient
3. Dextroamphetamine sulfate 2.96 Active ingredient
4. Amphetamine aspartate monohydrate 2.96 Active ingredient
5. Dextramphetamine Saccharate 2.96 Active ingredient
Hypromellose 2.36 Binder
Purified water Quantity sufficient Dispersing agent
to make 15.7%
6. w/w
TOTAL 100.0
II. Sub Coating/ Protective Coating
17
CA 02758556 2011-11-17
=
No. Ingredients % wlw Function
1. Drug layered pellets 90.9 Substrate for coating
Hypromellose 7.90 Protective coating
2.
polymer
3. Colloidal silicon dioxide 1.20 Anti adherent
Purified water Quantity sufficient Dispersing agent
4 . to make 6.8%
w/w
TOTAL 100.0
III. Modified enteric coating
No. Ingredients % Wm/ Function
1. Sub coated pellets 83.3 Substrate
2. Eudragit L-30D 55 11.1 Ph dependant polymer
3. Mannitol 2.20 Channeling agent
4. Plasacryl 2.20 Anti adherent
5. Triethyl citrate 1.10 Plasticizer
Purified water Quantity sufficient Dispersing agent
6. to make15% w/w
TOTAL 100.0
The pharmaceutical composition obtained from Example 1 was subsequently tested
for
in vitro dissolution rate, measured by Apparatus (USP Type II with sinkers),
using the
following parameters:
Media: 750 ml of 0.08N HCI for 2hrs and
200 ml of buffer concentrate added to make pH 6.0 for the next two hours;
Speed: 50 RPM
A modified release pharmaceutical composition, wherein the in vitro
dissolution profile of
said composition provides at least 95% of the active ingredient dissolved
within 4 hours,
which is substantially the same as provided by an equivalent dose of Adderal
XR, as
measured by USP Type II Apparatus(sinkers), with 750 ml of 0,08 N HCI for 2hrs
and
then 200m1 of buffer concentrate added to make pH 6.0 for the next two hours,
at 37
deg. C., at a paddle speed of 50 rpm as illustrated in FIG. 1 and described
below.
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CA 02758556 2011-11-17
In present embodiment a modified release pharmaceutical composition exhibits
the
following dissolution profile:
- about 10% to about 40% of the mixed amphetamine salts is released after 60
min;
- about 40% to about 50% of the mixed amphetamine salts is released after 120
min;
- about 80% to about 100% of the mixed amphetamine salts is released after 180
min;
- about 100% of the mixed amphetamine salts is released after 240 min, as
measured by
USP Type II Apparatus(sinkers), with 750 ml of 0,08 N HCI for 2hrs and then
200m1 of
buffer concentrate added to make pH 6.0, at a paddle speed of 50 rpm.
The dissolution results are set out in Table 2.
Table 2
Dissolution rate of Amphetamine mixed salts pharmaceutical composition of
Example 1.
Time Adderal XR 30 mg
(mm) A60144B Example 1
30 50 11
60 51 32
120 52 48
180 91 101
240 98 100
Table 2 shows a comparison of the dissolution parameters for the
pharmaceutical
composition of the present invention compared to Adderall XR .
19
