U.S. patent application number 11/030174 was filed with the patent office on 2005-07-21 for sustained release delivery of amphetamine salts.
Invention is credited to Burnside, Beth, Chang, Rong-Kun, Couch, Richard A..
Application Number | 20050158384 11/030174 |
Document ID | / |
Family ID | 31996998 |
Filed Date | 2005-07-21 |
United States Patent
Application |
20050158384 |
Kind Code |
A1 |
Couch, Richard A. ; et
al. |
July 21, 2005 |
Sustained release delivery of amphetamine salts
Abstract
A pharmaceutical composition comprises a once-a-day sustained
release formulation of at least one amphetamine salt which provides
mean plasma concentration profile aspects in human ADHD patients
which are substantially the same as that provided by ADDERALL
XR.RTM. type pulsatile formulations.
Inventors: |
Couch, Richard A.; (Chevy
Chase, MD) ; Burnside, Beth; (Bethesda, MD) ;
Chang, Rong-Kun; (Rockville, MD) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD.
SUITE 1400
ARLINGTON
VA
22201
US
|
Family ID: |
31996998 |
Appl. No.: |
11/030174 |
Filed: |
January 7, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11030174 |
Jan 7, 2005 |
|
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10353073 |
Jan 29, 2003 |
|
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60412799 |
Sep 24, 2002 |
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Current U.S.
Class: |
424/468 ;
514/554; 514/649 |
Current CPC
Class: |
A61P 25/18 20180101;
A61K 31/137 20130101; A61K 9/5015 20130101; A61P 11/06 20180101;
A61P 25/02 20180101; A61K 9/5026 20130101; A61K 31/205 20130101;
A61K 9/5047 20130101; A61P 25/00 20180101 |
Class at
Publication: |
424/468 ;
514/554; 514/649 |
International
Class: |
A61K 009/22; A61K
031/205; A61K 031/137 |
Claims
We claim:
1. A pharmaceutical composition comprising a once-a-day sustained
release formulation of at least one amphetamine salt which provides
a mean plasma concentration profile in human ADHD patients which is
substantially the same as that provided by a formulation thereof
comprising an immediate release dose and a dose delayed therefrom
by about 2 to about 6 hours.
2. A pharmaceutical composition of claim 1 wherein the immediate
and delayed release doses are the same.
3. The pharmaceutical composition of claim 2, wherein the at least
one amphetamine or amphetamine salt is a mixture of two or more
amphetamine salts.
4. The pharmaceutical composition of claim 2, wherein at least one
amphetamine or amphetamine salt is a mixture of dextroamphetamine
sulfate, dextroamphetamine saccharate, amphetamine aspartate
monohydrate and amphetamine sulfate.
5. A pharmaceutical composition of claim 4, wherein said profile is
substantially the same as that of FIG. 1.
6. A pharmaceutical composition comprising a once-a-day sustained
release formulation of at least one amphetamine salt which provides
a mean plasma concentration profile in human ADHD patients which is
substantially the same as that of FIG. 1.
7. The composition of claim 6, wherein at least one amphetamine or
amphetamine salt is a mixture of dextroamphetamine sulfate,
dextroamphetamine saccharate, amphetamine aspartate monohydrate and
amphetamine sulfate.
8. The pharmaceutical composition of claim 7, wherein the
dextroamphetamine sulfate, dextroamphetamine saccharate,
amphetamine aspartate monohydrate and amphetamine sulfate salts are
administered in equal amounts by weight.
9. The pharmaceutical composition of claim 6, wherein the at least
one amphetamine or amphetamine salt is provided in a core which is
coated with a coating comprising a pharmaceutically acceptable
water-insoluble film former or other polymer providing sustained
release.
10. The pharmaceutical composition of claim 9, wherein the coating
further comprises a dissolution regulating agent.
11. A pharmaceutical composition of claim 1 comprising a
sustained-release formulation of said salt(s) and a dosage form for
immediate release of at least one amphetamine salt.
12. The pharmaceutical composition of claim 6, wherein the at least
one amphetamine or amphetamine salt is provided in a sustained
release matrix.
13. A method for treating attention deficit hyperactivity disorder
which comprises administering to a human patient in need thereof a
pharmaceutical composition of claim 1.
14. A method for treating attention deficit hyperactivity disorder
which comprises administering to a human patient in need thereof a
pharmaceutical composition of claim 5.
15. A method for treating attention deficit hyperactivity disorder
which comprises administering to a human patient in need thereof a
pharmaceutical composition of claim 6.
16. A pharmaceutical composition comprising a once-a-day sustained
release formulation of at least one amphetamine salt which provides
a mean plasma concentration profile in human ADHD patients which
has substantially the same initial slope as that of FIG. 1.
17. A pharmaceutical composition comprising a once-a-day sustained
release formulation of amphetamine salts which provides a mean
plasma concentration profile in human ADHD patients which has an
initial slope of about 3.7 to about 11.4 ng/(mL hr) for
dextroamphetamines and about 1.4 to about 3 ng/(mL hr) for
levoamphetamines, all at a total amphetamine dose of 20 mg, or an
initial slope directly proportional thereto for a total dose other
than 20 mg.
18. A pharmaceutical composition comprising a once-a-day sustained
release formulation of at least one amphetamine salt which provides
a mean plasma concentration profile in human ADHD patients which
has an initial slope of about 4 to about 8 ng/(mL hr) for
dextroamphetamines and about 1.5 to about 2.2 ng/(mL hr) for
levoamphetamines.
19. A method for treating attention deficit hyperactivity disorder
which comprises administering to a human patient in need thereof a
pharmaceutical composition of claim 16.
20. A method for treating attention deficit hyperactivity disorder
which comprises administering to a human patient in need thereof a
pharmaceutical composition of claim 17.
21. A pharmaceutical composition comprising a once-a-day sustained
release formulation of at least one amphetamine salt which provides
a mean plasma concentration profile in human ADHD patients which
has an AUC of 556.6 mg hr/mL.+-.20% and a C.sub.max of 28.0
ng/mL.+-.20% for d-amphetamine and an AUC of 205.1 ng hr/mL.+-.20%
and a C.sub.max of 8.7 ng/mL.+-.20% for l-amphetamine.
22. A method for treating attention deficit hyperactivity disorder
which comprises administering to a human patient in need thereof a
once-a-day sustained release formulation which provides a mean
plasma concentration profile in human ADHD patients which has an
AUC of 556.6 mg hr/mL.+-.20% and a C.sub.max of 28.0 ng/mL.+-.20%
for d-amphetamine and an AUC of 205.1 ng hr/mL.+-.20% and a
C.sub.max of 8.7 ng/mL.+-.20% for l-amphetamine.
Description
[0001] Described herein are compositions for providing an orally
administrable sustained release (SR) form of one or more
amphetamines and/or amphetamine salts. Also described are methods
for administering the sustained release form of one or more
amphetamine salts to a patient in need thereof. Preferably, the
methods are carried out for treatment of patients having ADHD
(attention deficit hyperactivity disorder), but other disease
states can also be treated. The sustained-release forms of one or
more amphetamines and/or amphetamine salts according to the
invention are preferably formulated to provide an in vivo plasma
concentration profile (i.e., measured by total concentration of the
amphetamines and/or amphetamine salts (often with separate tracking
of d- and l-isomers) in the patients' blood plasma) which is
substantially equivalent to the in vivo plasma concentration
profile achieved by pulsatile release formulations of the same
amphetamines and/or amphetamine salts when administered to a
patient, e.g., those achieved by ADDERALL XR.RTM., Shire US Inc.,
whose FDA package insert and labeling are entirely incorporated by
reference herein. Further preferably, this sustained release
profile (the plasma concentration profile being distinguished from
the release profile) typically exhibits first order or biphasic or
sigmoidal characteristics.
[0002] Particularly preferably, the SR formulations according to
the invention exhibit a single dose in vivo plasma concentration
profile substantially the same as that shown in FIG. 1. The latter
shows the substantially smooth mean (over about 20 patients) plasma
concentration curves achieved for both the dextroamphetamine and
levoamphetamine salts in ADDERALL XR.RTM.. (The overall mean plasma
concentration curve for total amphetamine level is simply the sum
of the two curves shown in FIG. 1). Because the formulations of
this invention achieve substantially the same mean plasma
concentration curves, they can be termed fast sustained release
formulations, with regard to the initial rising slopes
involved.
[0003] By substantially the same "profile" herein is meant that two
curves have substantially the same AUC (area under the curve) and
C.sub.max, e.g., these parameters for each curve are .+-.20% of
each other, or even closer, e.g., .+-.10%, .+-.5%, .+-.2%, etc.,
which parameters are entirely conventionally defined and
determined. See, e.g., Fundamentals of Clinical Pharmacokinetics,
J. G. Wagner, Drug Intelligence Publications, Inc., Hamilton, Ill.,
1975; Guidance for Industry, Bioavailability and Bioequivalence
Studies for Orally Administered Drug Products-General
Considerations, FDA, CDER, October 2000. For FIG. 1, AUC (time zero
to infinity) is 556.6 ng hr/mL and C.sub.max is 28.0 ng/mL for
d-amphetamine and 205.1 ng hr/mL and 8.7 ng/mL, respectively, for
l-amphetamine. Of course, plasma curves achieved by this invention
can follow even more closely the course of a target curve such as
that shown in FIG. 1, e.g., substantially (e.g, .+-.20%) matching
initial rising slope, post-peak curve shapes, T.sub.max values,
(7.1 hr for d-amphetamine and 7.4 hr for l-amphetamine for FIG. 1),
etc. Whereas FIG. 1 shows data for 20 mg tablets (i.e., two 10 mg
pulsatile doses), the plasma curves (and e.g., AUC and C.sub.max)
corresponding to other daily doses such as 10, 30, 40, 50, 60, 70,
80, 90 mg will be essentially linearly proportional to those shown
in FIG. 1, corresponding to the involved dosage.
[0004] In another independent embodiment, the fast SR formulations
of this invention, for the ADDERALL XR.RTM. 20 mg dose of FIG. 1,
exhibit plasma concentration curves having initial (e.g., from 2
hours after administration to 4 hours after administration) slopes
of about 3.7 to about 11.4 ng/(mL hr) for dextroamphetamines and
about 1.4 to about 3 ng/(mL hr) for levoamphetamines, preferably,
about 4 to about 8 ng/(mL hr) and about 1.5 to about 2.2 ng/(mL
hr), respectively. The precise slope for a given individual will
vary according to usual factors, including whether the patient has
eaten or not. For other doses, e.g., those mentioned above, the
slopes vary directly (linearly) proportionally to dose.
[0005] The formulations of WO 00/23055 (whose entire disclosure is
incorporated by reference herein), e.g., that for ADDERALL XR.RTM.,
achieve a two-fold release of active amphetamine salts, one an
immediate release dosage form and the other a delayed release
dosage form. Typically, the lag time between the immediate release
(release upon administration) and delayed release forms is 2-6
hours, preferably about 3 to about 5 hours, more preferably about 3
to about 4 hours, and typically about four hours. In one
embodiment, the fast sustained release formulations of this
invention are used to provide a mean plasma concentration profile
substantially the same as that of Example 5 (combination of
Examples 1 and 2) of WO 00/23055, despite the latter's disclosure
that conventional sustained release formulation technology was not
suitable for amphetamines. (Note that the plasma profile of Example
5 shown in FIG. 7 of WO 00/23055 is not a mean profile, as is that
of FIG. 1 of this application, but rather is one from a single
individual.)
[0006] The SR formulations of this invention will be effective to
treat, e.g., ADHD, in the same manner as ADDERALL.RTM. XR. For
example, they will be effective to treat ADHD in the unexpectedly
good manner established in the data reported in Example 10. They
will also be effective to treat ADHD with low incidence of side
effects, including substance abuse, addiction, tolerance,
tachyphylaxis, etc.
[0007] Preferred salts are those in the commercial product ADDERALL
XR.RTM., i.e., dextroamphetamine sulfate, dextroamphetamine
saccharate, amphetamine aspartate monohydrate and amphetamine
sulfate. However, the invention is not limited to these specific
amphetamine salts. Other amphetamines and amphetamine salts and
mixtures thereof can be used in a sustained-release delivery system
to achieve the plasma concentration profiles of the invention. For
example, amphetamine base, chemical and chiral derivatives thereof
and other amphetamine salts can be used.
[0008] Preferred in vivo plasma concentration profiles of the
amphetamine salts can be accomplished by providing a solid dosage
form of the amphetamine salts which is capable of providing a
sustained release of the one or more amphetamine salts over a time
period of, for example, from 8-12 hours, or longer, preferably,
10-12 hours. For example, the amphetamine salts can be provided in
a core which is coated with a coating which allows the release of
the amphetamine salts there through over time, such as a
pharmaceutically acceptable water-insoluble film former alone or
with a dissolution regulating agent. In addition, by combining the
immediate-release beads with the sustained-release beads, a
biphasic release profile can be achieved. Other methods for
providing sustained-release of a drug, including those further
discussed below, are known and can be used to provide a
sustained-release delivery which results in the above-discussed in
vivo plasma concentration profile.
[0009] Suitable sustained-release systems, include SR coatings,
e.g., on beads, SR matrices (i.e., no coatings needed), SR osmotic
systems, etc. whereby amphetamine salts achieve a first order,
biphasic, sigmoidal etc. release profile to achieve the plasma
profile equivalent of pulsatile release systems of the same drugs
as discussed above. Matching to the desired target plasma
concentration profile using SR is conventional.
[0010] Sustained-release beads can be prepared by coating
conventional drug-containing cores with a water-insoluble polymer,
or a combination of water-insoluble polymers, or a combination of
water-insoluble and water-soluble polymers. This is usually not a
combination of layers, but a combination of polymers in a single
coating. The resultant beads (or tiny tablets) can then be placed
in a capsule. Other than beads in a capsule shell, tablets in a
capsule shell (e.g., one immediate-release tablet and one delayed,
sustained release tablet in a capsule shell, to provide an overall
sustained release) also can be used to attain the desired plasma
profile.
[0011] Various polymeric materials can be used to achieve the type
of pattern of release needed to result in the desired plasma
concentration profile, for example, so as to increase the fast rate
of delivery over the first 4 to 8 hours of delivery. For example, a
multiple dosage form (e.g., as discussed below) of the present
invention can deliver rapid and complete dosages of
pharmaceutically active amphetamine salts to achieve the desired
plasma profile of the drug in a recipient over the course of about
8-12 hours with a single oral administration. In so doing, the
levels of drug in blood plasma of the pharmaceutically active
amphetamine salts will reach a peak fairly rapidly, for example,
over the course of about 8 hours or less as desired, which then
slowly decreases over the course of, for example, the next 12 or
more hours. The desired plasma concentration profile can thus be
achieved using a fast sustained-release once daily dosage of the
amphetamine salts.
[0012] Examples of useful bead constructions for sustained-release
include the following:
[0013] Sugar core, coated with amphetamine, coated with
polymer,
[0014] Sugar core, coated with amphetamine, coated with mix of
amphetamine and polymer, coated with polymer,
[0015] Sugar core, coated with amphetamine, coated with relatively
high concentration mix of amphetamine and polymer, coated with
weaker concentration mix of amphetamine and polymer, coated with
polymer,
[0016] Bead containing amphetamine, coated with polymer,
[0017] Bead containing amphetamine, coated with mix of amphetamine
and polymer, coated with polymer,
[0018] Bead containing amphetamine, coated with relatively high
concentration mix of amphetamine and polymer, coated with weaker
concentration mix of amphetamine and polymer, coated with polymer,
and
[0019] Tablet or capsule containing multiple types of beads as
described above having differing timing of release of amphetamine
and/or different rates of release of amphetamine.
[0020] As mentioned, SR matrix beads can also be used, i.e., not
having any needed layers to achieve sustained release. The
components used in such matrices are chosen from conventional SR
polymers. In another construct, there can be included in the
formulation, along with the layered beads or matrix beads,
immediate release formulations which provide one way to achieve a
desired initial fast release. Such immediate release formulations
are fully conventional. See e.g., WO 00/23055.
[0021] Details of using the foregoing constructs and others to
achieve a desired plasma profile as discussed above are fully
conventional and can be determined by those of skill in the art
with at most a few routine parametric experiments, and conventional
adjustments, e.g., involving identities of polymers and mixtures
thereof, relative amounts of components, coating thicknesses, bead
diameters, number of layers and compositions thereof, etc. Thus,
for example, for a given construct (e.g., one of those in the
examples herein), dissolution profiles can be determined and in
vivo plasma profiles measured. The latter can then conventionally
be compared to the target plasma profile (e.g., that of ADDERALL
XR.RTM. and differences compensated by fully conventional
formulation and dissolution profile adjustments such as but not
limited to those mentioned.
[0022] Suitable materials which can be used in the SR formulations
of this invention are well known and include but are not limited to
polyvinyl acetate, cellulose acetate, cellulose acetate butyrate,
cellulose acetate propionate, ethyl cellulose, fatty acids and
their esters, alkyl alcohols, waxes, zein (prolamine from corn),
and aqueous polymeric dispersions such as Eudragit RS and RL30D,
Eudragit NE30D, Aquacoat, Surelease, Kollicoat SR30D, and cellulose
acetate latex.
[0023] Methods of manufacturing cores include:
[0024] a. Extrusion-Spheronization--the drug(s) and other additives
are granulated with the 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.
[0025] 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 action of mixing and milling. The
resulting granules or pellets are dried and sieved for further
applications.
[0026] c. Solution or Suspension Layering--A drug(s) solution or
dispersion with or without a binder is sprayed onto starting seeds
with a certain particle size in a fluidized 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.
[0027] For purposes of the present invention, the core particles,
preferably, have a diameter in the range of about 500-1500 microns
(micrometers); more preferably 100-800 microns. These particles can
then be coated in a fluidized bed apparatus with an alternating
sequence of selected coating layers.
[0028] The composition, preferably in the bead forms described
above, 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, for example,
polyethylene glycol, leucine, glyceryl behenate, magnesium stearate
or calcium stearate.
[0029] 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 tablet 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 (AVICEL.RTM.), soy polysaccharide
(EMCOSOY.RTM.), pre-gelatinized starches (STARCH.RTM. 1500,
NATIONAL.RTM. 1551), and polyethylene glycols (CARBOWAX.RTM.). The
materials are preferably present in the range of 5-75% (w/w), with
a more preferred range of 25-50% (w/w).
[0030] In addition, disintegrants are optionally 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.RTM.), sodium starch glycolate
(EXPLOTAB.RTM., PRIMOJEL.RTM.), and cross-linked
polyvinylpolypyrrolidone (Plasone-XL). These materials are
preferably present in the rate of 3-15% (w/w), with a more
preferred range of 5-10% (w/w).
[0031] Lubricants are also optionally 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 are preferably present in amounts from 0.1-10% (w/w),
with a more preferred range of 0.3-3.0% (w/w).
[0032] Tablets are formed, for example, as follows. The particles
are introduced into a blender along with AVICEL.RTM., 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 enough to fracture the
beads or coatings.
[0033] Various enteric materials, e.g., cellulose acetate
phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl
acetate phthalate, and the EUDRAGIT.RTM. acrylic polymers, can be
used as gastroresistant, enterosoluble coatings for drug release in
the intestine when desired. The enteric materials, which are
soluble at higher pH values, are frequently used for colon-specific
delivery systems and are entirely conventionally employable in the
SR systems of this invention. The enteric polymers used in this
invention can also be modified conventionally 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 EUDRAGIT.RTM. and EUDRAGIT.RTM. RL;
a neutral ester dispersion without any functional groups, sold
under the trade names EUDRAGIT.RTM. NE30D and EUDRAGIT.RTM. NE30;
and other pH independent coating products.
[0034] A conventional protective coating layer may also be applied
immediately outside the core, either a drug-containing matrix 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.RTM., SURELEASE.RTM.), EUDRAGIT.RTM.
RL 30D, OPADRY.RTM. and the like. The suggested coating levels are
from 1 to 6%, preferably 2-4% (w/w).
[0035] 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).
[0036] 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.
[0037] Optional modifying components of a protective layer which
can be used over the enteric or other coatings include a water
penetration barrier layer (semi-permeable polymer) which can be
successively coated after the enteric or other 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.RTM.
RS and RL 30D, EUDRAGIT.RTM. NE 30D, AQUACOAT.RTM., SURELEASE.RTM.,
cellulose acetate latex. The combination of the above polymers and
hydrophilic polymers such as hydroxyethyl cellulose, hydroxypropyl
cellulose (KLUCEL.RTM., Hercules Corp.), hydroxypropyl
methylcellulose (METHOCEL.RTM., Dow Chemical Corp.),
polyvinylpyrrolidone can also be used.
[0038] Principles of sustained release formulation technology
applicable to this invention, including the exemplary modes
mentioned herein, are disclosed, e.g., in R. K. Chang and J. R.
Robinson, chapter 4: "Sustained Drug Release from Tablets and
Particles Through Coating," in Pharmaceutical Dosage Forms:
Tablets, volume 3, edited by H. A. Lieberman, L. Lachman, and J. B.
Schwartz, Marcel Dekker, Inc., 1991; R. J. Campbell and G. L.
Sackett, chapter 3: "Film coating," in Pharmaceutical Unit
Operations: Coating, edited by K. E. Avis, A. J. Shukla, and R. K.
Chang, Interpharm Press, Inc., 1999, whose disclosures are entirely
incorporated by reference herein.
[0039] This invention also relates to use of the SR formulations to
treat indications other than ADHD at dosages and in regimens
analogous to those described herein. These include but are not
limited to Alzheimer's disease and other memory disorders,
fibromyalgia, chronic fatigue, depression, obsessive compulsive
disorder, alone or in combination with a SSRI; oppositional defiant
disorder (ODD), with or without ADHD and with or without guanfacine
or welbutrin; anxiety, with or without ADHD and alone or in
combination with an anxiolytic or SSRI; resistant depression;
stroke rehabilitation; Parkinson's disease; mood disorder;
schizophrenia; Huntington's disorder; dementia, e.g. AIDS dementia
and frontal lobe dementia; movement disfunction; apathy; fatigue;
Pick's disease; sleep disorders, e.g., narcolepsy, cataplexy, sleep
paralysis and hypnagogic hallucinations; etc.
[0040] The invention also relates to combinations of the SR
formulations of this invention with other therapeutic agents,
including all those useful for a given indication. The involved
drugs can be formulated in the same dosage form as the SR dose of
this invention or can be formulated separately, e.g., as
conventionally used alone, in which case, the drugs can be
administered sequentially in any order or simultaneously.
Typically, dosages can be in the same ranges as for each drug used
separately or, where synergistic effects occur, one or more of the
combined-drugs can be used in lower dosages. Combinations encompass
any where the drugs are made bioavailable in a patient at the same
time, including combinations coming into being in a patient.
[0041] These other therapeutic agents include e.g., for
Alzheimer's: Reminyl, Cognex, Aricept, Exelon, Akatinol, Neotropin,
Eldepryl, Estrogen, Clioquinol, Ibuprofen, and Ginko Bilboa; for
ADHD: methylphenidate (e.g., Ritalin), Dexedrine, Adderall, Cylert,
clonidine, guanfacine, etc; for depression: Prozac, Zoloft, Paxil,
Reboxetine, Wellbutrin, Olanzapine, Fluoxetine, Elavil, Totranil,
Pamelor, Nardil, Parnate, Desyrel, and Effexor; for mood disorder:
Thorazine, Haldol, Navane, Mellaril, Clozaril, Risperdal, Zyprexa,
Clozapine, Risperidone, and Olanzapine; for fatigue:
benzodiazapines, Anaprox, Naprosen, Prozac, Zoloft, Paxil, Effexor,
and Desyrel; for fibromyalgia: Dilantin, Carbatrol, Epitol,
Tegretol, Depacon, Depakote, Norpramin, Aventyl, Pamelor, Elavil,
Enovil, Adapin, Sinequan, Zonalon, and non-steroidal inflammatory
drugs; for oppositional defiant disorder (ODD): clonidine,
Risperidone, and Zyprexa; for apathy: Amisulpride, Olanzapine,
Visperidone, Quetiapine, Clozapine, and Zotepine; for Parkinson's
disease: Levodopa, Parlodel, Permax, and MIRAPEX; for
schizophrenia: Clozapine, Zyprexa, Seroquel, and Risperdal; for
Huntington's disorder: haloperidal and clonzepam; for dementia:
thioridazine, haloperidal, Risperidone, Cognex, Aricept, and
Exelon; for narcolepsy: Provigil, Dexedrine, Modafinil and Ritalin;
for cataplexy: Xyrem; for hallucinations: Clozapine, Risperidone,
Zyprexa, and Seroquel; for sleep paralysis: Perocet, Vicodin, and
Lorcet; for obsessive compulsive disorder: Anafranil, Prozac,
Zoloft, Paxil, Luvox; and for anxiety: Elavil, Asendin, Wellbutrin,
Tegretol, Anafranil, Norpramine, Adapin, Sinequan, Tofranil,
Epitol, Janimire, Pamelor, Ventyl, Aventyl, Surmontil etc;
selective serotonin reuptake inhibitors (SSRIs) including Prozac,
Luvox, Serzone, Paxil, Zoloft, Effexor, etc., benzodiazepines,
including Xanax, Librium, Klonopin, Valium, Zetran, Valrelease,
Dalmane, Ativan, Alzapam, Serax, Halcion, etc., monamine oxidase
inhibitors including Aurorix, Manerix, Nardil, Parnate, etc.
[0042] The entire disclosures of all applications, patents and
publication, cited above, and below, are hereby incorporated by
reference.
EXAMPLES
[0043] In the foregoing and in the following examples, all
temperatures are set forth uncorrected in degrees Celsius; and,
unless otherwise indicated, all parts and percentages are by
weight.
[0044] SR Coated Beads
Example 1
[0045] Mixed amphetamine salts loaded beads (MASL) 500 gram
[0046] Ethyl cellulose (Ethocel N-10, Dow Chemical) 15.46 gram
[0047] Ethyl acetate 515 gram
[0048] Ethyl cellulose (15.46 gram) was dissolved in 515 gram of
ethyl acetate. Into a Wurster column was charged 500 grams of MASL
beads which were then coated with the coating mixture under
conditions of 40.degree. C., spray pressure 1 bar, and spray rate
of 10 grams/min. The line was rinsed with ethyl acetate and the
pellets were dried for approximately twenty minutes and recovered
to give a product of 97% by weight MASL beads and 3% by weight
ethyl cellulose coating.
Example 2
[0049]
1 Mixed amphetamine salts loaded beads 500 grams Ethyl cellulose
(Ethocel N-10, Dow Chemical) 37.78 grams Hydroxypropyl cellulose
(Klucel LF, Aqualon) 8.70 grams Methylene chloride 744 grams
Methanol 186 grams
[0050] Ethyl cellulose (37.78 grams) and hydroxypropyl cellulose
(8.70 grams) were dissolved in a mixture of methylene chloride and
methanol (4:1). Into a Wurster column was charged 500 grams of MASL
beads which were then coated with the coating mixture under
conditions of 40.degree. C., spray pressure 1 bar, and spray rate
10 grams/min. The line was rinsed with methanol and the pellets
were dried for approximately twenty minutes and recovered to give a
product of 92% by weight MASL beads and 8% by weight ethyl
cellulose/hydroxypropyl cellulose coating.
Example 3
[0051]
2 Mixed amphetamine salts loaded beads 500 gram Surelease (Ethyl
cellulose-based 173.92 grams dispersion, Colorcon) Water 43.48
grams
[0052] Surelease (173.92 grams) was diluted with 43.48 grams of
water. Into a Wurster column (Versa-Glatt, Glatt Air Techniques)
was charged 500 grams of MASL beads which were then coated with the
coating mixture under conditions of 60.degree. C. inlet
temperature, spray pressure 1 bar, and spray rate 6 grams/min. The
line was rinsed with water and the pellets were dried for
approximately twenty minutes and recovered to give a product of 92%
by weight MASL beads and 8% by weight ethyl cellulose coating.
Example 4
[0053]
3 Mixed amphetamine salts loaded beads 500 grams Eudragit RS30D
111.49 grams Triethyl citrate 10.03 grams Water 115.94 grams
[0054] Triethyl citrate was mixed into Eudragit RS30D for 30 min.
The plasticized Eudragit RS30D was diluted with water and filtered
through a 60-mesh screen. Into a Wurster column was charged 500
grams of MASL beads which were then coated with the coating mixture
under conditions of 40.degree. C. inlet temperature, spray pressure
1 bar, and spray rate 6 grams/min. The line was rinsed with ethyl
acetate and the pellets were dried for approximately twenty minutes
and recovered to give a product of 92% by weight MASL beads and 8%
by weight ethyl cellulose coating.
Example 5
[0055]
4 Mixed amphetamine salts loaded beads 500 grams Mixed amphetamine
salts 48.5 grams Glyceryl behenate (Compritol 888, Gattefosse)
436.5 grams
[0056] Mixed amphetamine salts was dispersed in the molten glyceryl
behenate. The drug-containing hot melt was sprayed onto the mixed
amphetamine salts loaded beads in a Wurster column under conditions
of 30.degree. C. inlet temperature, spray pressure 2 bar, and a
spray rate of 10 grams/min.
Example 6
[0057]
5 Mixed amphetamine salts loaded beads 500 grams Eudragit L100
25.25 grams Ethyl cellulose (Ethocel N-10, Dow Chemical) 25.25
grams Triethyl citrate 5.05 grams Acetone 833.4 grams Methanol
277.8 grams
[0058] Eudragit L100 and ethyl cellulose were dissolved in the
mixture of acetone and methanol. Subsequently, triethyl citrate was
added to the polymer solution. Into the Wurster column was charged
500 grams of MASL beads which were then coated with the coating
mixture under conditions of 40.degree. C., spray pressure 1 bar,
and spray rate 10 grams/min. The line was rinsed with methanol and
the pellets were dried for approximately twenty minutes and
recovered to give a product of 90% by weight MASL beads and 10% by
weight ethyl cellulose/hydroxypropyl cellulose coating.
[0059] SR Matrix Beads/Tablets
Example 7
[0060]
6 Amphetamine Aspartate 50 grams Amphetamine Sulfate 50 grams
Dextroamphetamine saccharate 50 grams Dextroamphetamine sulfate 50
grams Microcrystalline cellulose 400 grams Poly(ethylene oxide),
Polyox WSR 303 1380 grams Magnesium stearate 20 grams
[0061] All the amphetamine salts, microcrystalline cellulose, and
poly(ethylene oxide) were sieved through a 60 mesh screen and
loaded into a V-shaped blender with an intensifier bar. The powder
mixture was blended for 15 min. with the intensifier bar on for 3
min. at the middle of the blending process. The powder blend was
unloaded and screened through a 60 mesh sieve. The screened powder
blend was lubricated with magnesium stearate in the V-shaped
blender for 3 min. The lubricated powder blend was compacted in a
roller compactor to form granules.
Example 8
[0062]
7 Amphetamine Aspartate 50 grams Amphetamine Sulfate 50 grams
Dextroamphetamine saccharate 50 grams Dextroamphetamine sulfate 50
grams Microcrystalline cellulose 1780 grams Magnesium stearate 20
grams
[0063] All the amphetamine salts and microcrystalline cellulose
were sieved through a 60 mesh screen and loaded into a V-shaped
blender with an intensifier bar. The powder mixture was blended for
15 min. with the intensifier bar on for 3 min. at the middle of the
blending process. The powder blend was unloaded and screened
through a 60 mesh sieve. The screened powder blend was lubricated
with magnesium stearate in the V-shaped blender for 3 min. The
lubricated powder blend was compressed into tablets using {fraction
(3/32)}" tooling.
Example 9
[0064]
8 Mini-tablets 500 grams Surelase 127.7 grams water 85.1 grams
[0065] Surelease (127.7 grams) was diluted with 85.1 grams of
water. Into the Wurster column (Versa-Glatt, Glatt Air Techniques)
was charged 500 grams of the mini-tablets which were then coated
with the coating mixture under conditions of 60 C. inlet
temperature, spray pressure 1 bar, and spray rate 6 grams/min. The
line was rinsed with water and the pellets were dried for
approximately twenty minutes and recovered to give a product of 94%
by weight MASL minitablets and 6% by weight ethyl cellulose
coating.
Example 10
[0066]
9 Mixed amphetamine salts loaded beads 500 grams Surlease (Ethyl
cellulose-based 272.7 grams dispersion, Colorcon) Water 68.2
grams
[0067] Surelease (272.7 grams) was diluted with 68.2 grams of
water. Into a Wurster column (Versa-Glatt, Glatt Air Techniques)
was charged 500 grams of MASL beads which were then coated with the
coating mixture under conditions of 60 degree C. inlet temperature,
spray pressure 1 bar, and spray rate 6 grams/min. The line was
rinsed with water and the pellets were dried for approximately
twenty minutes and recovered to give a product of 88% by weight
MASL beads and 12% by weight ethyl cellulose coating.
[0068] The dissolution data for 8% and 12% coating levels are
summarized as follows:
10 1 hour 2 hours 4 hours 6 hours 8 hours 8% coating 45% 74% 93%
98% 100% 12% coating 25% 47% 70% 81% 87%
Example 11
Background
[0069] A 2-component extended release formulation of Adderall.RTM.
(mixed salts of d- and l-amphetamine) designed to produce
pulse-release of medication, yields a therapeutic effect for the
treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) that
lasts throughout the day with one morning dose. This Adderall
XR.TM. capsule formulation is composed of 2 types of Microtrol.TM.
beads of mixed salts of amphetamine in a 50:50 ratio within one
capsule. The immediate-release beads are designed to release drug
content in a time course similar to Adderall.RTM. tablets. The
delayed-release beads are designed to release drug content
approximately 4 hours after oral administration of the capsule. An
initial formulation study with Adderall XR.TM. 20 mg QD
demonstrated comparable bioavailability and pharmacokinetic
profiles to immediate-release Adderall.RTM. 10 mg BID with a 4-hour
interval and concluded that Adderall XR.TM. 20 mg QD is
bioequivalent to Adderall.RTM. 10 mg BID (Michaels et al.
Presented, NCDEU 2001).
OBJECTIVES
[0070] The efficacy and extended duration of action of Adderall
XR.TM. in the treatment of children with ADHD has been demonstrated
in 2 previous pivotal double-blind studies: one conducted in a
laboratory classroom setting (McCracken et al. Submitted), and the
other in a naturalistic home and school environment (Biederman et
al. Pediatrics 2002. In press). This large-scale, open-label trial
has been conducted primarily to evaluate the tolerability and
effectiveness of Adderall XR.TM. in the treatment of pediatric ADHD
in the community practice setting.
METHODS
[0071] Presented here are unaudited data of this prospective,
open-label, 7-week study conducted at 378 sites nationwide. An
8-week extension arm was optional after completion of this initial
phase (Diagram A).
[0072] Subjects: Children aged 6 to 12 years who had a DSM-IV
diagnosis of ADHD and were currently taking stable doses of
immediate-release Adderall.RTM. or any methylphenidate formulation
were enrolled.
[0073] Inclusion Criteria: Good physical health with normal blood
pressure, pulse, and electrocardiogram (ECG); Conners Global Index
Scale--Parent (CGIS-P) rating score of <.sub.--12 for boys and
<.sub.--10 for girls; known responder to psychostimulant
medication. Exclusion Criteria: Uncontrolled, symptomatic comorbid
psychiatric disorder; IQ<80; history of seizure disorder or
Tourette's; concomitant medications, such as clonidine, guanfacine,
anticonvulsants, or any medications that affect blood pressure or
the heart.
[0074] Measures:
[0075] Primary Efficacy: Validated CGIS-P
[0076] Baseline: 2 to 3 hours after morning dose of previous
psychostimulant medication to assess degree of control of symptoms
plus additional assessments at 8 and 12 hours after dose
[0077] Following initiation of treatment with Adderall XR.TM.:
prior to clinic visit at weeks 1, 3, and 7; administered by same
parent/caregiver at 8 hours and again at 12 hours after the morning
dose of Adderall XR.TM...cndot.Secondary Efficacy: Clinical Global
Impression Scales (CGI). Rated by the clinician. Gives a global
evaluation of clinical status over time.
[0078] Subjects rated for severity at baseline while on previous
psychostimulant medication. The CGI-S is a 7-point scale ranging
from 1 (normal/not ill at all) to 7 (extremely ill).
[0079] Subjects rated for improvement at weeks 1, 3, and 7 by the
CGI-I, a 7-point scale ranging from 1 (very much improved) to 7
(very much worse).
[0080] Primary Tolerability: Pediatric quality of life
(PedsQL.TM.)
[0081] Validated measure assessing age-specific quality-of-life
markers in healthy children and those with acute and chronic health
conditions.
[0082] Completed by parent/caregiver at baseline and end of initial
phase of study (week 7).
[0083] Secondary Tolerability: Medication Satisfaction and
Preference Instruments Scales allowing evaluation of the
acceptability of Adderall XR.TM. by both the parent/caregiver and
physician (separate scales for physician and parent). Satisfaction
Instrument given at baseline and week 7. Preference Instrument
given at week 7.
[0084] Primary Safety: Physical exam at screening (including height
and weight); ECG baseline and end of study; vital signs, including
pulse, blood pressure, and weight at each study visit;
spontaneously reported adverse events (AEs) were recorded at each
visit.
CONCLUSIONS
[0085] In children receiving stable doses of various stimulant
medications, 8- and 12-hour post-dose CGIS-P scores reveal
significant improvement in ADHD symptoms after conversion to
Adderall XR.TM..
[0086] After switching to Adderall XR.TM., significant improvement
was also apparent in CGI improvement scores and pediatric
quality-of-life measures.
[0087] In this real-world clinical experience trial, satisfaction
and preference survey results from both physicians and
parents/caregivers (although not fully depicted here) also suggest
significant benefit from treatment with Adderall XR.TM. as compared
to previous medication therapy.
[0088] These findings likely reflect (1) the established efficacy
and longer duration of action of Adderall XR.TM., (2) elimination
of the need for additional daily doses for patients in
multiple-daily-dose groups (at baseline), and (3) the lower daily
doses of stimulant medication treatment regimens and higher level
of ADHD symptomatology previously identified with ADHD treatment
regimens in the community practice setting.
[0089] The incidence of adverse events occurring during treatment
was low, and the majority of AEs were mild in nature; study
medication was well tolerated. Adderall XR.TM. is a safe and
effective medication for the community practice treatment of
children with ADHD, and, although patients may be showing
significant benefit on other stimulant treatment regimens,
additional significant benefit may be attained by switching
patients to this once-daily-dosed product.
11TABLE 1 Medication Conversion Paradigm Adderall XR .TM. Current
Total Daily Dose Multiplication Starting Dose Treatment (mg) Factor
(mg) Adderall .RTM. 30 .times.1 30 single or 20 .times.1 20 divided
dose 10 .times.1 10 Concerta .TM. 54 .times.0.55 30 36 .times.0.55
20 18 .times.0.55 10 Methylphenidate Current total daily
.times.0.50, then 10, 20, (immediate and dose of rounded to or 30
sustained release, methylphenidate next lowest other than 10-mg
increment Concerta .TM.) of Adderall XR .TM. Note: Patients who
required a 40-mg starting dose of Adderall XR .TM. received two
20-mg capsules QD.
RESULTS
[0090] Of the 2968 subjects who received study medication, 2911
(98%) had at least one post-baseline CGIS-P total score available
for efficacy analysis. These subjects make up the intent-to-treat
(ITT) population (Table 2).
12TABLE 2 Demographic and Baseline Information All Participants ITT
Subjects Subject Population (N = 2968) (n = 2911) Age (y), mean
.+-. SD 9.5 .+-. 1.8 9.5 .+-. 1.8 Gender 76% male 76% male Race
White 88.0% 88.0% Black 6.7% 6.7% Hispanic 3.5% 3.4% Other 1.8%
1.9% Diagnosis Combined 2072 (70.2%) 2034 (70.2%) Inattentive 682
(23.1%) 669 (23.1%) Hyperactive 197 (6.7%) 193 (6.7%) Comorbidity
Oppositional defiant 109 (3.7%) 103 (3.5%) Conduct disorder 16
(0.5%) 16 (0.5%) Anxiety 83 (2.8%) 83 (2.9%) Depression 93 (3.1%)
91 (3.1%) Obsessive-compulsive disorder 42 (1.4%) 41 (1.4%) Other
78 (2.6%) 76 (2.6%) .about.Mean CGIS-P baseline score at 2 to 3
hours after morning dose of previous medication = 5.9.
Example 12
[0091] Individual patients were treated with ADDERALL XR.RTM., 20
mg. Subjects received either one single dose administered with food
or one single dose administered following a 10-hour overnight fast
through continued fast 3.5 hours post dosing. A sampling of
individuals' curves is given in FIGS. 7-12. The mean plasma
concentration profile of FIG. 1 was obtained from averaging such
individuals' curves.
[0092] The preceding examples can be repeated with similar success
by substituting the generically or specifically described reactants
and/or operating conditions of this invention for those used in the
preceding examples.
[0093] From the foregoing description, one skilled in the art can
easily ascertain the essential characteristics of this invention
and, without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions.
* * * * *