U.S. patent application number 09/176542 was filed with the patent office on 2001-12-27 for oral pulsed dose drug delivery system.
Invention is credited to BURNSIDE, BETH A., CHANG, RONG-KUN, COUCH, RICHARD A., FISKE, KIMBERLY, GUO, XIAODI, MCGUINNESS, CHARLOTTE M., RUDNIC, EDWARD M., TREACY, DONALD J..
Application Number | 20010055613 09/176542 |
Document ID | / |
Family ID | 22644775 |
Filed Date | 2001-12-27 |
United States Patent
Application |
20010055613 |
Kind Code |
A1 |
BURNSIDE, BETH A. ; et
al. |
December 27, 2001 |
ORAL PULSED DOSE DRUG DELIVERY SYSTEM
Abstract
A multiple pulsed dose drug delivery system for pharmaceutically
active amphetamine salts, comprising an immediate-release component
and an enteric delayed-release component wherein (1) the enteric
release coating has a defined minimum thickness and/or (2) there is
a protective layer between the pharmaceutically active amphetamine
salt and the enteric release coating and/or (3) there is a
protective layer over the enteric release coating. The product can
be composed of either one or a number of beads in a dosage form,
including either capsule, tablet, or sachet method for
administering the beads.
Inventors: |
BURNSIDE, BETH A.; (SILVER
SPRING, MD) ; GUO, XIAODI; (DERWOOD, MD) ;
FISKE, KIMBERLY; (COLUMBIA, MD) ; COUCH, RICHARD
A.; (BETHESDA, MD) ; CHANG, RONG-KUN;
(HOCKESSIN, DE) ; TREACY, DONALD J.; (ARNOLD,
MD) ; MCGUINNESS, CHARLOTTE M.; (BETHESDA, MD)
; RUDNIC, EDWARD M.; (POTOMOC, MD) |
Correspondence
Address: |
RAINA SEMIONOW
CARELLA BYRNE BAIN GILFILLAN CECCHI
STEWART & OLSTEIN
6 BECKER FARM ROAD
ROSELAND
NJ
07068
|
Family ID: |
22644775 |
Appl. No.: |
09/176542 |
Filed: |
October 21, 1998 |
Current U.S.
Class: |
424/468 ;
424/457; 424/458; 424/459; 424/460; 424/461; 424/462; 424/470;
424/472; 424/474; 424/480; 424/482; 424/494; 424/497 |
Current CPC
Class: |
A61K 9/5078 20130101;
A61P 25/00 20180101; A61K 9/5026 20130101; A61K 9/5047 20130101;
A61K 31/137 20130101; A61P 25/28 20180101 |
Class at
Publication: |
424/468 ;
424/472; 424/474; 424/497; 424/494; 424/482; 424/480; 424/458;
424/459; 424/460; 424/461; 424/462; 424/470; 424/457 |
International
Class: |
A61K 009/22; A61K
009/16; A61K 009/50; A61K 009/24; A61K 009/28; A61K 009/52; A61K
009/54; A61K 009/58; A61K 009/32; A61K 009/26 |
Claims
1. A pharmaceutical composition for enteric delivery of one or more
pharmaceutically active amphetamine salts comprising: (a) one or
more pharmaceutically active amphetamine salts covered with an
immediate release coating; and (b) one or more pharmaceutically
active amphetamine salts that are covered with an enteric release
coating wherein the enteric release coating has a thickness of at
least 25.mu..
2. The pharmaceutical composition of claim 1 wherein the one or
more pharmaceutically active amphetamine salts are coated onto a
core.
3. The pharmaceutical composition of claim 1 wherein the one or
more pharmaceutically active amphetamine salts are incorporated
into a core.
4. The pharmaceutical composition of claim 1, wherein the immediate
release and enteric release portions of the composition are present
on a single core.
5. The pharmaceutical composition of claim 1, wherein the immediate
release and enteric release components are present on different
cores.
6. A pharmaceutical composition for enteric delivery of one or more
pharmaceutically active amphetamine salts comprising: (a) one or
more pharmaceutically active amphetamine salts covered with an
immediate release coating; (b) one or more pharmaceutically active
amphetamine salts that are covered with an enteric release coating;
and (c) a protective layer between the at least one
pharmaceutically active amphetamine salt and the enteric release
coating.
7. The pharmaceutical composition of claim 6 wherein the one or
more pharmaceutically active amphetamine salts are coated onto a
core.
8. The pharmaceutical composition of claim 6 wherein the one or
more pharmaceutically active amphetamine salts are incorporated
into a core.
9. The pharmaceutical composition of claim 6 wherein the enteric
release coating has a minimum thickness of 25.mu..
10. A pharmaceutical composition for delivering one or more
pharmaceutically active amphetamine salts comprising: (a) one or
more pharmaceutically active amphetamine salts covered with an
immediate release coating; (b) one or more pharmaceutically active
amphetamine salts that are covered with an enteric release coating;
and (c) a protective layer over the enteric release coating.
11. The pharmaceutical composition of claim 10 wherein the one or
more pharmaceutically active amphetamine salts are coated onto a
core.
12. The pharmaceutical composition of claim 10 wherein the one or
more pharmaceutically active amphetamine salts are incorporated
into a core.
13. The composition of claim 1 wherein the pharmaceutically active
amphetamine salt is selected from amphetamine base, salts, chemical
and chiral derivatives thereof; methylphenidate derivatives and
salts thereof; and phenylpropanolamine hydrochloride chemical and
chiral derivatives and salts thereof.
Description
[0001] This invention pertains to a multiple dosage form delivery
system comprising one or more amphetamine salts for administering
the amphetamine salts to a recipient.
BACKGROUND OF THE INVENTION
[0002] Traditionally, drug delivery systems have focused on
constant/sustained drug ouput with the objective of minimizing
peaks and valleys of drug concentrations in the body to optimize
drug efficacy and to reduce adverse effects. A reduced dosing
frequency and improved patient compliance can also be expected for
the controlled/sustained release drug delivery systems, compared to
immediate release preparations. However, for certain drugs,
sustained release delivery is not suitable and is affected by the
following factors:
[0003] First pass metabolism: Some drugs, such as .beta. blockers,
.beta.-estradiol, and salicylamide, undergo extensive first pass
metabolism and require fast drug input to saturate metabolizing
enzymes in order to minimize pre-systemic metabolism. Thus, a
constant/sustained oral method of delivery would result in reduced
oral bioavailability.
[0004] Biological tolerance: Continuous release drug plasma
profiles are often accompanied by a decline in the
pharmacotherapeutic effect of the drug, e.g., biological tolerance
of transdermal nitroglycerin.
[0005] Chronopharmacology and circadian rhythms: Circadian rhythms
in certain physiological functions are well established. It has
been recognized that many symptoms and onset of disease occur
during specific time periods of the 24 hour day, e.g., asthma and
angina pectoris attacks are most frequently in the morning hours
(1,2).
[0006] Local therapeutic need: For the treatment of local disorders
such as inflammatory bowel disease, the delivery of compounds to
the site of inflammation with no loss due to absorption in the
small intestine is highly desirable to achieve the therapeutic
effect and to minimize side effects.
[0007] Gastric irritation or drug instability in gastric fluid: For
compounds with gastric irritation or chemical instability in
gastric fluid, the use of a sustained release preparation may
exacerbate gastric irritation and chemical instability in gastric
fluid.
[0008] Drug absorption differences in various gastrointestinal
segments: In general, drug absorption is moderately slow in the
stomach, rapid in the small intestine, and sharply declining in the
large intestine. Compensation for changing absorption
characteristics in the gastrointestinal tract may be important for
some drugs. For example, it is rational for a delivery system to
pump out the drug much faster when the system reaches the distal
segment of the intestine, to avoid the entombment of the drug in
the feces.
[0009] Pulsed dose delivery systems, prepared as either single unit
or multiple unit formulations, and which are capable of releasing
the drug after a predetermined time, have been studied to address
the aforementioned problematic areas for sustained release
preparations. These same factors are also problematic in pulsed
dose formulation development. For example, gastrointestinal transit
times vary not only from patient to patient but also within
patients as a result of food intake, stress, and illness; thus a
single-unit pulsed-release system may give higher variability
compared to a multiple unit system. Additionally, drug layering or
core making for multiple unit systems is a time-consuming and
hard-to-optimize process. Particularly challenging for formulation
scientists has been overcoming two conflicting hurdles for
pulsatile formulation development, i.e., lag time and rapid
release.
[0010] Various enteric materials, e.g., cellulose acetate
phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl
acetate phthalate, and the Eudragit.RTM. acrylic polymers, have
been used as gastroresistant, enterosoluble coatings for single
drug pulse release in the intestine (3). The enteric materials,
which are soluble at higher pH values, are frequently used for
colon-specific delivery systems. Due to their pH-dependent
attributes and the uncertainty of gastric retention time, in-vivo
performance as well as inter- and intra-subject variability are
major issues for using enteric coated systems as a time-controlled
release of drugs.
[0011] A retarding swellable hydrophilic coating has been used for
oral delayed release systems (4,5). It was demonstrated that lag
time was linearly correlated with coating weight gain and drug
release was pH independent.
[0012] Hydroxypropyl methylcellulose barriers with erodible and/or
gellable characteristics formed using press coating technology for
tablet dosage forms have been described to achieve time-programmed
release of drugs (6). Barrier formulation variables, such as grade
of hydroxypropyl methylcellulose, water-soluble and water-insoluble
excipients, significantly altered the lag time and the release rate
from the center cores.
[0013] Special grades of hydroxypropyl methylcellulose, e.g.,
Metolose.RTM. 60SH, 90SH (Shin-Etsu Ltd., Japan), and Methocel.RTM.
F4M (Dow Chemical Company, USA), as a hydrophilic matrix material
have been used to achieve bimodal drug release for several drugs,
i.e., aspirin, ibuprofen, and adinazolam (7). Bimodal release is
characterized by a rapid initial release, followed by a period of
constant release, and finalized by a second rapid drug release.
[0014] Tablets or capsules coated with a hydrophobic wax-surfactant
layer, made from an aqueous dispersion of carnauba wax, beeswax,
polyoxyethylene sorbitan monooleate, and hydroxypropyl
methylcellulose have been used for rapid drug release after a
predetermined lag time. For example,. However, even though a
two-hour lag time was achieved for the model drug theophylline at a
higher coating level (60%), three hours were required for a
complete release of theophylline after the lag time. (8)
[0015] A sustained-release drug delivery system is described in
U.S. Pat. No. 4,871,549. When this system is placed into
dissolution medium or the gastrointestinal tract, water influx and
the volume expansion of the swelling agent cause the explosion of
the water permeable membrane. The drug thus releases after a
predetermined time period.
[0016] The OROS.RTM. push-pull system (Alza Company) has been
developed for pulsatile delivery of water-soluble and
water-insoluble drugs (9, 10), e.g. the OROS-CT.RTM. system and is
based on the swelling properties of an osmotic core compartment
which provides a pH-independent, time-controlled drug release.
[0017] The Pulsincap.TM. dosage form releases its drug content at
either a predetermined time or at a specific site (e.g., colon) in
the gastrointestinal tract (11). The drug formulation is contained
within a water-insoluble capsule body and is sealed with a hydrogel
plug. Upon oral administration, the capsule cap dissolves in the
gastric juice and the hydrogel plug swells. At a controlled and
predetermined time point, the swollen plug is ejected from the
Pulsincap.TM. dosage form and the encapsulated drug is released. A
pulsatile capsule system containing captopril with release after a
nominal 5-hr period was found to perform reproducibly in
dissolution and gamma scintigraphy studies. However, in the
majority of subjects, no measurable amounts of the drug were
observed in the blood, possibly due to instability of the drug in
the distal intestine. (12)
[0018] Adderal.RTM. comprises a mixture of four amphetamine sulfate
salts which, in combination, is indicated for treatment of
Attention Deficit Hyperactivity Disorder in children from 3-10
years of age. One disadvantage of current treatment is that a
tablet form is commonly used which many young children have
difficulty in swallowing. Another disadvantage of current treatment
is that two separate doses are administered, one in the morning and
one approximately 4-6 hours later, commonly away from home under
other than parental supervision. This current form of treatment,
therefore, requires a second treatment which is time-consuming,
inconvenient and may be problematic for those children having
difficulties in swallowing tablet formulations.
SUMMARY OF THE INVENTION
[0019] Accordingly, in view of a need for successfully
administering a multiple pulsed dose of amphetamine salts and
mixtures thereof, the present invention provides an oral multiple
pulsed dose delivery system for amphetamine salts and mixtures
thereof. FIG. 1 illustrates the desired target plasma level profile
of the pharmaceutical active contained within the delivery
system.
[0020] In accordance with a preferred embodiment of the present
invention, there is provided a pharmaceutical composition for
delivering one or more pharmaceutically active amphetamine salts
that includes:
[0021] (a) one or more pharmaceutically active amphetamine salts
that are covered with an immediate release coating, and
[0022] (b) one or more pharmaceutically active amphetamine salts
that are covered with an enteric release coating wherein (1) the
enteric release coating has a defined minimum thickness and/or (2)
there is a protective layer between the at least one
pharmaceutically active amphetamine salt and the enteric release
coating and/or (3) there is a protective layer over the enteric
release coating.
[0023] In one embodiment, the immediate release and enteric release
portions of the composition are present on the same core.
[0024] In another embodiment, the immediate release and enteric
release components are present on different cores.
[0025] It is also contemplated that the composition may include a
combination of the hereinabove referred to cores (one or more cores
that include both components on the same core and one or more cores
that include only one of the two components on the core).
[0026] The present invention provides a composition in which there
is immediate release of drug and enteric release of drug wherein
the enteric release is a pulsed release and wherein the drug
includes one or more amphetamine salts and mixtures thereof.
[0027] The immediate release component releases the pharmaceutical
agent in a pulsed dose upon oral administration of the delivery
system.
[0028] The enteric release coating layer retards or delays the
release of the pharmaceutical active or drug for a specified time
period ("lag time") until a predetermined time, at which time the
release of the drug is rapid and complete, i.e., the entire dose is
released within about 30-60 minutes under predetermined
environmental conditions, i.e. a particular location within the
gastrointestinal tract.
[0029] The delay or lag time will take into consideration factors
such as transit times, food effects, inflammatory bowel disease,
use of antacids or other medicaments which alter the pH of the GI
tract.
[0030] In a preferred embodiment, the lag time period is only
time-dependent, i.e., pH independent. The lag time is preferably
within 4 to 6 hours after oral administration of the delivery
system.
[0031] In one aspect, the present invention is directed to a
composition that provides for enteric release of at least one
pharmaceutically active amphetamine salt, including at least one
pharmaceutically active amphetamine salt that is coated with an
enteric coating wherein (1) the enteric release coating has a
defined minimum thickness and/or (2) there is a protective layer
between the at least one pharmaceutically active amphetamine salt
and the enteric release coating and/or (3) there is a protective
layer over the enteric release coating.
[0032] In attempting to provide for enteric release of an
amphetamine salt, applicants found that use of an enteric release
coating as generally practiced in the art did not provide effective
enteric release.
[0033] Typical enteric coating levels did not meet the above
requirements for the desired dosage profile of amphetamine salts.
Using the typical amount of enteric coating (10-20.mu.) resulted in
undesired premature leakage of the drug from the delivery system
into the upper gastrointestinal tract and thus no drug delivery at
the desired location in the gastrointestinal tract after the
appropriate lag time. Thus this coating did not meet the
requirements for the drug release profile to provide full
beneficial therapeutic activity at the desired time.
[0034] Surprisingly, applicants found that using a thicker
application of enteric coating on the formulation allowed for the
second pulsed dose to be released only and completely at the
appropriate time in the desired predetermined area of the
gastrointestinal tract, i.e., in the intestine.
[0035] This was surprising because an increase in thickness of
about 5-101.mu. of enteric coatings above a minimum thickness of
about 10-20.mu. typically does not have a significant effect on
release of drug from within such coatings. Enteric coatings
typically are pH dependent and will only dissolve/disperse when
exposed to the appropriate environment. Typically, application of a
thicker coating (greater than 20.mu.) will only marginally increase
the time for complete release at the appropriate environmental
condition i.e., for a brief period of time (20 minutes). Using the
typical coating, applicants could not achieve the desired
result--rather, the coating leaked before the predetermined time in
an inappropriate environment resulting in significant loss of the
therapeutic agent.
[0036] Accordingly, in one aspect, the pulsed enteric release of
the amphetamine salts is accomplished by employing a certain
minimum thickness of the enteric coating.
[0037] In one embodiment of the invention, the pulsed dose delivery
comprises a composition which comprises one or more
pharmaceutically active amphetamine salts; an enteric coating over
the one or more pharmaceutically active amphetamine salts, wherein
the thickness of the enteric coating layer is at least 25.mu.; a
further layer of one or more pharmaceutically active amphetamine
salts over the enteric coating layer; and an immediate release
layer coating. The thicker enteric coating surprisingly provides
the required delayed immediate release of the pharmaceutically
active amphetamine salt at the desired time in the desired area of
the gastrointestinal tract. FIG. 2 illustrates a model of this
delivery system.
[0038] In this aspect, the one or more pharmaceutically active
amphetamine salts can be provided within or as a part of a core
seed around which the enteric coating is applied. Alternatively, a
core seed can be coated with one or more layers of one or more
pharmaceutically active amphetamine salts.
[0039] It has further been discovered that a delayed immediate
release drug delivery can also be accomplished by coating the drug
first with a protective layer prior to applying the enteric
coating.
[0040] Thus, in another embodiment, the pulsed enteric release is
accomplished by employing a protective layer between the drug and
the enteric coating. When using a protective coating, the enteric
coating may be of an increased thickness or may be of lower
thickness.
[0041] Thus, in another aspect, the object of the invention is met
by providing a composition comprising one or more pharmaceutically
active amphetamine salts; a protective layer coating over the one
or more pharmaceutically active amphetamine salt layer(s), and an
enteric coating layer over the protective coating layer; a further
pharmaceutically active amphetamine salt layer and an immediate
release layer coating. In a preferred embodiment of this aspect,
the thickness of the enteric coating is at least 25.mu., and the
protective layer comprises an immediate release coating.
[0042] With respect to this embodiment of the invention, the one or
more pharmaceutically active amphetamine salts can be provided
within or as a part of a core seed, during the core seed
manufacturing process, around which the protective coating is
applied. Alternatively, a core seed can be coated with one or more
layers of one or more pharmaceutically active amphetamine
salts.
[0043] In another embodiment, the pulsed enteric release is
accomplished by employing a protective layer over the enteric
coating.
[0044] Accordingly, in this embodiment of the present invention,
there is provided a pulsed dose release drug delivery system
comprising one or more pharmaceutically active amphetamine salts;
an enteric coating layer over the pharmaceutically active
amphetamine salt layer(s); and a protective layer over the enteric
coating; a second pharmaceutically active amphetamine salt layer;
and an immediate release layer coating.
[0045] In one aspect of this embodiment, the protective layer is
comprised of one or more components, which includes an immediate
release layer and a modifying layer. The modifying layer is
preferably comprised of a semi water-permeable polymer. Applicants
have surprisingly found that a semi-permeable polymer coating used
in combination with an immediate release layer coating provided a
delayed pulsed release drug delivery profile when layered over the
enteric coating.
[0046] Thus, in this embodiment, the protective layer comprises a
semi-permeable polymer and an immediate release coating layer. In a
preferred embodiment, the modifying layer comprises a first layer
of a semi-permeable polymer which is adjacent to the enteric
coating layer and a second coating layer over the semi-permeable
polymer coating layer comprising an immediate release polymer
coating layer.
[0047] In one aspect of this embodiment, a semi-permeable polymer,
which may comprise a low water-permeable pH-insensitive polymer, is
layered onto the outer surface of the enteric layer, in order to
obtain prolonged delayed release time. This semi-permeable polymer
coating controls the erosion of the pH-sensitive enteric polymer in
an alkaline pH environment in which a pH-sensitive polymer will
dissolve rapidly. Another pH-sensitive layer may be applied onto
the surface of a low water-permeability layer to further delay the
release time.
[0048] In a still further aspect of the invention, in addition to a
protective layer, the composition comprises an acid which is
incorporated into the pharmaceutical active layer or coated onto
the surface of the active layer to reduce the pH value of the
environment around the enteric polymer layer. The acid layer may
also be applied on the outer layer of the pH-sensitive enteric
polymer layer, followed by a layer of low water-permeability
polymer. The release of the active thus may be delayed and the
dissolution rate may be increased in an alkaline environment.
[0049] In a further embodiment, the protective coating may be used
both over the drug and over the enteric coating.
[0050] With respect to this embodiment of the invention, the one or
more pharmaceutically active amphetamine salts can be provided
within or as a part of a core seed, during the core seed
manufacturing process, around which the enteric coating is applied.
Alternatively, a core seed can be coated with one or more layers of
one or more pharmaceutically active amphetamine salts.
[0051] The drug delivery system of the present invention as
described herein preferably comprises one or a number of beads or
beadlets in a dosage form, either capsule, tablet, sachet or other
method of orally administering the beads.
BRIEF DESCRIPTION OF THE DRAWINGS
[0052] FIG. 1 illustrates a multiple pulse drug delivery system
target plasma profile of the drug delivery system of the present
invention. The profile reflects an immediate-release component
followed by a delayed-release component.
[0053] FIG. 2 schematically illustrates the delayed-release system
of the present invention.
[0054] FIG. 2a graphically illustrates a pulsed dose delivery
system.
[0055] FIGS. 2b and c graphically illustrate the drug release
mechanism from the proposed delivery system.
[0056] FIG. 3 is a plot of the percent drug released versus time
from the drug-loaded pellets described in Example 1 which
exemplifies the immediate release component of the present
invention.
[0057] FIG. 4 is a plot of the percent drug released versus time
from the coated pellets described in Example 2 which exemplifies
the immediate release component and the delayed release components
of the present invention.
[0058] FIG. 5 is a plot of the percent drug released versus time
from the coated pellets of Example 3 which exemplifies the
immediate release component and the delayed release components of
the present invention.
[0059] FIG. 6 illustrates the drug release profile of coated
pellets described in Example 4 which exemplifies the immediate
release component and the delayed release components of the present
invention.
DETAILED DESCRIPTION OF THE INVENTION
[0060] The present invention comprises a core or starting seed,
either prepared or commercially available product. The cores or
starting seeds can be sugar spheres; spheres made from
microcrystalline cellulose and any suitable drug crystals.
[0061] The materials that can be employed in making drug-containing
pellets are any of those commonly used in pharmaceutics and should
be selected on the basis of compatibility with the active drug and
the physicochemical properties of the pellets. The additives except
active drugs are chosen below as examples:
[0062] Binders such as cellulose derivatives such as
methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxypropyl methylcellulose, polyvinylpyrrolidone,
polyvinylpyrrolidone/vinyl acetate copolymer and the like.
[0063] Disintegration agents such as corn starch, pregelatinized
starch, cross-linked carboxymethylcellulose (Ac-Di-Sol), sodium
starch glycolate (Explotab), cross-linked polyvinylpyrrolidone
(Plasdone XL), and any disintegration agents used in tablet
preparations.
[0064] Filling agents such as lactose, calcium carbonate, calcium
phosphate, calcium sulfate, microcrystalline cellulose, dextran,
starches, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium
chloride, polyethylene glycol, and the like.
[0065] Surfactants such as sodium lauryl sulfate, sorbitan
monooleate, polyoxyethylene sorbitan monooleate, bile salts,
glyceryl monostearate, Pluronic.RTM. line (BASF), and the like.
[0066] Solubilizer such as citric acid, succinic acid, fumaric
acid, malic acid, tartaric acid, maleic acid, glutaric acid sodium
bicarbonate and sodium carbonate and the like.
[0067] Stabilizers such as any antioxidation agents, buffers,
acids, and the like, can also be utilized.
[0068] Methods of Manufacturing the Core Include
[0069] a. Extrusion-Spheronization--Drug(s) and other additives are
granulated by addition of a binder solution. The wet mass is passed
through an extruder equipped with a certain size screen. The
extrudates are spheronized in a marumerizer. The resulting pellets
are dried and sieved for further applications.
[0070] b. High-Shear Granulation--Drug(s) and other additives are
dry-mixed and then the mixture is wetted by addition of a binder
solution in a high shear-granulator/mixer. The granules are kneaded
after wetting by the combined actions of mixing and milling. The
resulting granules or pellets are dried and sieved for further
applications.
[0071] c. Solution or Suspension Layering--A drug solution or
dispersion with or without a binder is sprayed onto starting seeds
with a certain particle size in a fluid bed processor or other
suitable equipment. The drug thus is coated on the surface of the
starting seeds. The drug-loaded pellets are dried for further
applications.
[0072] For purposes of the present invention, the core particles
have a diameter in the range of about 500-1500 microns; preferably
100-800 microns.
[0073] These particles can then be coated in a fluidized bed
apparatus with an alternating sequence of coating layers.
[0074] The core may be coated directly with a layer or layers of at
least one pharmaceutically active amphetamine salts and/or the
pharmaceutically active amphetamine salt may be incorporated into
the core material. Pharmaceutical active amphetamine salts
contemplated to be within the scope of the present invention
include amphetamine base, all chemical and chiral derivatives and
salts thereof; methylphenidate, all chemical and chiral derivatives
and salts thereof; phenylpropanolamine and its salts; and all other
compounds indicated for the treatment of attention deficit
hyperactivity disorder (ADHD).
[0075] A protective layer may be added on top of the pharmaceutical
active containing layer and also may be provided between active
layers. A separation or protective layer may be added onto the
surface of the active-loaded core, and then the enteric layer is
coated thereupon. Another active layer may also be added to the
enteric layer to deliver an initial dose.
[0076] A protective coating layer may be applied immediately
outside the core, either a drug-containing core or a drug-layered
core, by conventional 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. Suitable
materials for the protective layer include cellulose derivatives
such as hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxypropyl methylcellulose, polyvinylpyrrolidone,
polyvinylpyrrolidone/vinyl acetate copolymer, ethyl cellulose
aqueous dispersions (Aquacoat, Surelease), Eudragit RL 30D,
Opadry.RTM. and the like. The suggested coating levels are from 1
to 6%, preferably 2-4% (w/w).
[0077] The enteric coating layer is applied onto the cores with or
without seal coating by conventional 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. All commercially available pH-sensitive polymers are
included. The pharmaceutical active is not released in the acidic
stomach environment of approximately below pH 4.5, but not limited
to this value. The pharmaceutical active should become available
when the pH-sensitive layer dissolves at the greater pH; after a
certain delayed time; or after the unit passes through the stomach.
The preferred delay time is in the range of two to six hours.
[0078] Enteric polymers include cellulose acetate phthalate,
Cellulose acetate trimellitate, hydroxypropyl methylcellulose
phthalate, polyvinyl acetate phthalate,
carboxymethylethylcellulose, co-polymerized methacrylic
acid/methacrylic acid methyl esters such as, for instance,
materials known under the trade name Eudragit L12.5, L100, or
Eudragit S12.5, S100 or similar compounds used to obtain enteric
coatings. Aqueous colloidal polymer dispersions or re-dispersions
can be also applied, e.g. Eudragit L 30D-55, Eudragit L100-55,
Eudragit S100, Eudragit preparation 4110D (Rohm Pharma); Aquateric,
Aquacoat CPD 30 (FMC); Kollicoat MAE 30D and 30DP (BASF); Eastacryl
30D (Eastman Chemical).
[0079] The enteric polymers used in this invention can be modified
by mixing with other known coating products that are not pH
sensitive. Examples of such coating products include the neutral
methacrylic acid esters with a small portion of
trimethylammonioethyl methacrylate chloride, sold currently under
the trade names EudragitRS and Eudragit RL; a neutral ester
dispersion without any functional groups, sold under the trade
names Eudragit NE30D and Eudragit NE30; and other pH independent
coating products.
[0080] The modifying component of the protective layer used over
the enteric coating can include a water penetration barrier layer
(semipermeable polymer) which can be successively coated after the
enteric coating to reduce the water penetration rate through the
enteric coating layer and thus increase the lag time of the drug
release. Sustained-release coatings commonly known to one skilled
in the art can be used for this purpose by conventional 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. For example, the following materials
can be used, but not limited to: Cellulose acetate, Cellulose
acetate butyrate, Cellulose acetate propionate, Ethyl cellulose,
Fatty acids and their esters, Waxes, zein, and aqueous polymer
dispersions such as Eudragit RS and RL 30D, Eudragit NE 30D,
Aquacoat, Surelease, cellulose acetate latex. The combination of
above polymers and hydrophilic polymers such as Hydroxyethyl
cellulose, Hydroxypropyl cellulose (Klucel, Hercules Corp.),
Hydroxypropyl methylcellulose (Methocel, Dow Chemical Corp.),
Polyvinylpyrrolidone can also be used.
[0081] An overcoating layer can further optionally be applied to
the composition of the present invention. Opadry.RTM., Opadry
II.RTM. (Colorcon) and corresponding color and colorless grades
from Colorcon can be used to protect the pellets from being tacky
and provide colors to the product. The suggested levels of
protective or color coating are from 1 to 6%, preferably 2-3%
(w/w).
[0082] Many ingredients can be incorporated into the overcoating
formula, for example to provide a quicker immediate release, such
as plasticizers: acetyltriethyl citrate, triethyl citrate,
acetyltributyl citrate, dibutylsebacate, triacetin, polyethylene
glycols, propylene glycol and the others; lubricants: talc,
colloidal silica dioxide, magnesium stearate, calcium stearate,
titanium dioxide, magnesium silicate, and the like.
[0083] The composition, preferably in beadlet form, can be
incorporated into hard gelatin capsules, either with additional
excipients, or alone. Typical excipients to be added to a capsule
formulation include, but are not limited to: fillers such as
microcrystalline cellulose, soy polysaccharides, calcium phosphate
dihydrate, calcium sulfate, lactose, sucrose, sorbitol, or any
other inert filler. In addition, there can be flow aids such as
fumed silicon dioxide, silica gel, magnesium stearate, calcium
stearate or any other material imparting flow to powders. A
lubricant can further be added if necessary by using polyethylene
glycol, leucine, glyceryl behenate, magnesium stearate or calcium
stearate.
[0084] The composition may also be incorporated into a tablet, in
particular by incorporation into a tablet matrix, which rapidly
disperses the particles after ingestion. In order to incorporate
these particles into such a tablet, a filler/binder must be added
to a table that can accept the particles, but will not allow their
destruction during the tableting process. Materials that are
suitable for this purpose include, but are not limited to,
microcrystalline cellulose (A vicel), soy polysaccharide (Emcosoy),
pre-gelatinized starches (STARCH 1500, National 1551), and
polyethylene glycols (Carbowax). The materials should be present in
the range of 5-75% (w/w), with a preferred range of 25-50%
(w/w).
[0085] In addition, disintegrants are added in order to disperse
the beads once the tablet is ingested. Suitable disintegrants
include, but are not limited to: cross-linked sodium carboxymethyl
cellulose (Ac-Di-Sol), sodium starch glycolate (Explotab,
Primojel), and cross-linked polyvinylpolypyrrolidone (Plasone-XL).
These materials should be present in the rate of 3-15% (w/w), with
a preferred range of 5-10% (w/w).
[0086] Lubricants are also added to assure proper tableting, and
these can include, but are not limited to: magnesium stearate,
calcium stearate, stearic acid, polyethylene glycol, leucine,
glyceryl behanate, and hydrogenated vegetable oil. These lubricants
should be present in amounts from 0.1-10% (w/w), with a preferred
range of 0.3-3.0% (w/w).
[0087] Tablets are formed, for example, as follows. The particles
are introduced into a blender along with Avicel, disintegrants and
lubricant, mixed for a set number of minutes to provide a
homogeneous blend which is then put in the hopper of a tablet press
with which tablets are compressed. The compression force used is
adequate to form a tablet; however, not sufficient to fracture the
beads or coatings.
[0088] It will be appreciated that the multiple dosage form of the
present invention can deliver rapid and complete dosages of
pharmaceutically active amphetamine salts to achieve the desired
levels of the drug in a recipient over the course of about 8 hours
with a single oral administration.
[0089] In so doing, the levels of drug in blood plasma of the
pharmaceutically active amphetamine salts will reach a peak fairly
rapidly after about 2 hours, and after about 4 hours a second pulse
dose is released, wherein a second fairly rapid additive increase
of plasma drug levels occurs which slowly decreases over the course
of the next 12 hours.
[0090] The following examples are presented to illustrate and do
not limit the invention.
EXAMPLES
Example 1
Immediate Release Formulation
[0091] The following formulation was used to layer the drug onto
sugar spheres. Nonpareil seeds (30/35 mesh, Paulaur Corp., N.J.),
6.8 kg were put into a FLM-15 fluid bed processor with a 9" Wurster
column and fluidized at 60.degree. C. The suspension of mixed
amphetamine salts (MAS) with 1% HPMC E5 Premium (Dow Chemical) as a
binder was sprayed onto the seed under suitable conditions. Almost
no agglomeration and no fines were observed with a yield of at
least 98%. The drug-loaded cores were used to test enteric coatings
and sustained release coatings.
1 TABLE 1 Ingredients Amount (%) Nonpareil seed 88.00 mixed
amphetamine salts 11.40 Methocel E5 Premium 0.60 Water * *removed
during processing The drug release profile of the drug-loaded
pellets of this example is shown in FIG. 3.
Example 2
[0092] The following formulation was used to coat the mixed
amphetamine salts loaded (MASL) pellets from Example 1 with the
Eudragit.RTM. L 30D-55 (Rohm Pharma, Germany) coating dispersion. 2
kg of MASL pellets were loaded into a fluid bed processor with a
reduced Wurster column equipped with a precision coater (MP 2/3,
Niro Inc.). The coating dispersion was prepared by dispersing
Triethyl citrate, Talc and Eudragit.RTM. L 30D-55 into water and
mixing for at least 30 minutes. Under suitable fluidization
conditions, the coating dispersion was sprayed onto the fluidized
MASL pellets. The spraying was continued until the targeted coating
level was achieved (20.mu.). The coated pellets were dried at
30-35.degree. C. for 5 minutes before stopping the process. The
enteric coated PPA pellets were tested at different pH buffers by a
USP paddle method. The drug content was analyzed using HPLC. The
results showed that the enteric coating delayed the drug release
from the coated pellets until after exposure to pH 6 or higher (see
Table 2 below). (Reference #AR98125-4)
2 TABLE 2 Ingredients Amount (%) MASL pellets 40.00 Eudragit .RTM.
L 30D-55 24.88 Triethyl citrate 2.52 Talc 2.60 Water * *removed
during processing The drug release profile of the coated pellets of
this example is shown in FIG. 4.
Example 3
[0093] The following formulation was used to coat the MASL pellets
from Example 1 with the Eudragit.RTM. 4110D (Rohm Pharma, Germany)
coating dispersion. MASL pellets (2 kg) were loaded in a fluid bed
processor with a reduced Wurster column (GPGC-15, Glatt). The
coating dispersion was prepared by dispersing Triethyl citrate,
Talc and Eudragit.RTM. 4110D into water and mixing for at least 30
minutes. Under suitable fluidization conditions, the coating
dispersion was sprayed onto the fluidized MASL pellets. The
spraying was continued until the targeted coating level was
achieved. The coated pellets were dried at 30-35.degree. C. for 5
minutes before stopping the process. The enteric coated MASL
pellets were tested using a USP paddle method at different pH
buffers. The drug content was analyzed using HPLC. The enteric
coating delayed the drug release for several hours from the coated
pellets until the pH value reached 6.8 or higher, as shown below in
Table 3. (Reference # AR98125-3)
3 TABLE 3 Ingredients Amount (%) MASL pellets 70.00 Eudragit .RTM.
4110D 26.24 Triethyl citrate 0.76 Talc 3.00 Water * *removed during
processing The drug release profile of coated pellets of this
example is shown in FIG. 5.
Example 4
[0094] The following formulation was selected to coat the enteric
coated MASL pellets. Coated MASL pellets from Example 2 or coated
MASL pellets from Example 3 (2 kg of either) were loaded into a
fluid bed processor with a reduced Wurster column (GPGC-15, Glatt).
The coating dispersion was prepared by mixing Surelease.RTM.
(Colorcon) and water for at least 15 minutes prior to spraying.
Under suitable fluidization conditions, the coating dispersion was
sprayed onto the fluidized pellets. The spraying was continued
until the targeted coating level was achieved. The coated pellets
were coated with a thin layer of Opadry.RTM. white (Colorcon) (2%)
to prevent the tackiness of the coated pellets during storage. The
coated pellets were then dried at 35-40.degree. C. for 10 minutes
before discharging from the bed. The drug dissolution from both
coated pellets was performed using a USP paddle method at different
pH buffers. The drug content was analyzed using HPLC. The results
are shown below in Table 4. The 8% Surelease coating slightly
sustained the drug release from Eudragit L 30D-55 coated pellets at
pH 7.5 buffer, while the Surelease coating delayed the drug release
up to 2 hours after the buffer switched from pH 1 to pH 7.5.
(Reference ## AR98I25-1)
4 TABLE 4 Ingredients Amount, kg Enteric coated MASL pellets 90.00
Surelease .RTM. 8.00 Opadry white 2.00 Water * *removed during
processing The drug release profile of the coated pellets from this
example is shown in FIG. 6.
Cited Literature
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Controlled Release, 16, 63-74 (1991)
[0096] 2. B. Lemmer, "Why are so many Biological Systems Periodic?"
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[0097] 3. X. Xu and P I Lee, "Programmable Drug Delivery from an
Erodible Association Polymer System", Pharm. Res. 10(8), 1144-1152
(1993)
[0098] 4. A. Gazzaniga, M E Sangalli, and F Giodano, "Oral
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[0099] 5. A Gazzaniga, C Busetti, L Moro, M E Sangalli and F
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Biomaterials, 14(13), 1017-1023 (1993)
[0101] 7. A C Shah International Patent Application WO87/00044
[0102] 8. P S Walia, P Jo Mayer Stout and R Turton, "Preliminary
Evaluation of an Aqueous Wax Emulsion for Controlled Release
Coating", Pharm Dev Tech, 3(1), 103-113 (1998)
[0103] 9. F Theeuwes, "Oros Osmotic System Development", Drug Dev
Ind Pharm 9(7), 1331-1357 (1983)
[0104] 10. F Theeuwes, "Triggered, Pulsed and Programmed Drug
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F Prescott and W S Nimmos. eds. (Wiley, N.Y., 1989) pp. 323-340
[0105] 11. M McNeil, A Rashid and H Stevens, "International Patent
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[0106] 12. I R Wilding, S S Davis, M Bakhshaee, H N E Stevens, R A
Sparrow and J Brennan, "Gastrointestinal Transit and Systemic
Absorption of Captopril from a Pulsed Release Formulation", Pharm
Res 9(5), 654-657 (1992)
* * * * *