U.S. patent application number 14/790446 was filed with the patent office on 2016-01-21 for controlled dose drug delivery system.
The applicant listed for this patent is Shire LLC. Invention is credited to Richard A. Couch, Paul Hodgkins, Stephanie Read, Amir SHOJAEI.
Application Number | 20160015642 14/790446 |
Document ID | / |
Family ID | 38685424 |
Filed Date | 2016-01-21 |
United States Patent
Application |
20160015642 |
Kind Code |
A1 |
SHOJAEI; Amir ; et
al. |
January 21, 2016 |
CONTROLLED DOSE DRUG DELIVERY SYSTEM
Abstract
A multiple pulsed dose drug delivery system for pharmaceutically
active amphetamine salts, comprising a pharmaceutically active
amphetamine salt covered with an immediate-release coating and a
pharmaceutically active amphetamine salt covered with an enteric
coating wherein the immediate release coating and the enteric
coating provide for multiple pulsed dose delivery of the
pharmaceutically active amphetamine salt. 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: |
SHOJAEI; Amir;
(Phoenixville, PA) ; Read; Stephanie;
(Philadelphia, PA) ; Couch; Richard A.; (Bethel
Park, PA) ; Hodgkins; Paul; (Exton, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Shire LLC |
Florence |
KY |
US |
|
|
Family ID: |
38685424 |
Appl. No.: |
14/790446 |
Filed: |
July 2, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14498130 |
Sep 26, 2014 |
9173857 |
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14790446 |
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11383066 |
May 12, 2006 |
8846100 |
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14498130 |
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Current U.S.
Class: |
424/495 ;
424/490; 424/494; 424/497; 514/554; 514/654 |
Current CPC
Class: |
A61K 9/16 20130101; A61K
9/1676 20130101; A61K 9/5078 20130101; A61K 9/209 20130101; A61K
9/5047 20130101; A61K 9/5026 20130101; A61K 31/137 20130101; A61K
9/4808 20130101; A61K 31/194 20130101; A61K 31/197 20130101 |
International
Class: |
A61K 9/24 20060101
A61K009/24; A61K 31/194 20060101 A61K031/194; A61K 31/197 20060101
A61K031/197; A61K 31/137 20060101 A61K031/137 |
Claims
1-58. (canceled)
59. A sustained release pharmaceutical composition comprising: (a)
at least one amphetamine salt, (b) a sustained release coating, and
(c) a delayed release coating, wherein the sustained release
coating is external to the delayed release coating and the at least
one amphetamine salt is released about 4 to about 6 hours after
oral administration of the composition to a patient.
60. The pharmaceutical composition of claim 59, wherein about 50%
of the at least one amphetamine salt is released after about six
hours dissolution at a pH of about 7.5.
61. The pharmaceutical composition of claim 59, comprising: (a) at
least one amphetamine salt layered onto a core, (b) a delayed
release coating layered onto the at least one amphetamine salt
layer; (c) a sustained release coating layered onto the delayed
release coating, and (d) a protective coating layered onto the
sustained release coating.
62. The pharmaceutical composition of claim 59, wherein the at
least one amphetamine salt comprises dextroamphetamine sulfate,
dextroamphetamine saccharate, amphetamine aspartate monohydrate,
amphetamine sulfate, and mixtures thereof.
63. The pharmaceutical composition of claim 59, wherein the delayed
release coating is selected from the group consisting of: cellulose
acetate phthalate; cellulose acetate trimellitate; hydroxypropyl
methylcellulose phthalate; polyvinyl acetate phthalate;
carboxymethylethylcellulose; co-polymerized methacrylic
acid/methacrylic acid methyl esters, co-polymerized methacrylic
acid/methyl methacrylate, and co-polymerized methylacrylate/methyl
methacrylate/methacrylic acid.
64. The pharmaceutical composition of claim 63, wherein the delayed
release coating is a co-polymer of methylacrylate/methyl
methacrylate/methacrylic acid.
65. The pharmaceutical composition of claim 59, wherein the
sustained release coating is selected from the group consisting of:
polyvinyl acetate, cellulose acetate, cellulose acetate butyrate,
cellulose acetate propionate, ethyl cellulose, fatty acids and
esters thereof, alkyl alcohols, waxes, zein (prolamine from corn),
co-polymerized ethyl acrylate/methyl methacrylate, co-polymerized
ethylacrylate/methyl methacrylate/methacrylic acid with quaternary
ammonium groups, ethyl acrylate/methyl methacrylate/methacrylic
acid ester with quaternary ammonium groups, polyvinyl acetate, and
cellulose acetate latex.
66. The pharmaceutical composition of claim 65, wherein the
sustained release coating is ethyl cellulose.
67. The pharmaceutical composition of claim 59, comprising 12.5 mg
of the at least one amphetamine salt.
68. The pharmaceutical composition of claim 67, wherein the
composition has a d-amphetamine AUC (O-inf) of about 367
nghr/mL.
69. The pharmaceutical composition of claim 67, wherein the
composition has an 1-amphetamine AUC (O-inf) of about 125
nghr/mL.
70. The pharmaceutical composition of claim 59, wherein the
composition comprises 18.75 mg, 25 mg, 31.25 mg, 37.5 mg, or 50 mg
of at least one amphetamine salt and has a d-amphetamine AUC
(0-inf) that is linearly proportional to the AUC (O-inf) for the
12.5 mg at least one amphetamine salt composition of claim 10.
71. The pharmaceutical composition of claim 59, wherein the
composition comprises 18.75 mg, 25 mg, 31.25 mg, 37.5 mg, or 50 mg
of at least one amphetamine salt and has a l-amphetamine AUC
(0-inf) that is linearly proportional to the AUC (O-inf) for the
12.5 mg at least one amphetamine salt composition of claim 11.
72. The pharmaceutical composition of claim 59, comprising 12.5 mg
of the at least one amphetamine salt; wherein the composition has a
d-amphetamine Cmax of about 18.67 ng/mL.
73. The pharmaceutical composition of claim 59, comprising 12.5 mg
of the at least one amphetamine salt; wherein the composition has a
1-amphetamine Cmax of about 5.64 ng/mL.
74. The pharmaceutical composition of claim 59, wherein the
composition comprises 18.75 mg, 25 mg, 37.5 mg, or 50 mg of at
least one amphetamine salt and has a d-amphetamine Cmax that is
linearly proportional to the Cmax for the 12.5 mg at least one
amphetamine salt composition of claim 14.
75. The pharmaceutical composition of claim 59, wherein the
composition comprises 18.75 mg, 25 mg, 37.5 mg, or 50 mg of at
least one amphetamine salt and has a l-amphetamine Cmax that is
linearly proportional to the Cmax for the 12.5 mg at least one
amphetamine salt composition of claim 15.
76. The pharmaceutical composition of claim 59, comprising 12.5 mg
of the at least one amphetamine salt; wherein the composition has a
d-amphetamine Tmax of about 8.83 hours.
77. The pharmaceutical composition of claim 59, comprising 12.5 mg
of the at least one amphetamine salt; wherein the composition has a
1-amphetamine Tmax of about 9.33 hours.
78. The pharmaceutical composition of claim 59, wherein the
composition comprises 18.75 mg, 25 mg, 37.5 mg, or 50 mg of at
least one amphetamine salt and has a Tmax that is linearly
proportional to the Tmax for the 12.5 mg at least one amphetamine
salt composition of claim 9.
79. A method of treating ADHD comprising administering the
pharmaceutical composition of claim 59 in combination with an
immediate release mixed amphetamine salt composition and/or an
extended release mixed amphetamine salt composition to a patient in
need of such treatment.
80. The method of claim 79, wherein the pharmaceutical composition
of claim 1 and the immediate release mixed amphetamine salt
composition and/or the extended release mixed amphetamine salt
composition are administered simultaneously.
81. The method of claim 79, wherein the sustained release
pharmaceutical composition comprises about 10% to about 150% of the
amphetamine dosage of the immediate release mixed amphetamine salt
composition and/or an extended release mixed amphetamine salt
composition.
82. The method of claim 79, wherein the immediate release mixed
amphetamine salt composition and the extended release mixed
amphetamine salt composition comprise one dosage unit.
83. The method of claim 80, wherein the pharmaceutical composition
of claim 1, the immediate release mixed amphetamine salt
composition and the extended release mixed amphetamine salt
composition comprise one dosage unit.
Description
BACKGROUND OF THE INVENTION
[0001] Traditionally, drug delivery systems have focused on
constant/sustained drug output with the objective of minimizing
peaks and valleys of drug concentrations in the body to optimize
drug efficacy and reduce adverse effects. Reduced dosing frequency
and improved patient compliance can also be expected for
constant/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:
[0002] 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.
[0003] 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.
[0004] Chronopharmacology and circadian rhythms: Circadian rhythms
in certain physiological functions are well established. It has
been recognized that a symptom or disease onset can occur during
specific time periods of the 24 hour day, e.g., asthma and angina
pectoris attacks are most frequently in the morning hours (Lemmer,
B, J Controlled Release. 1991; 16:63-74; Lemmer B, Pulsatile Drug
Delivery: Current Applications and Future Trends (R Gurney, H E
Junginger, N A Peppeas, eds.) 1993; 11-24).
[0005] 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.
[0006] 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.
[0007] 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.
[0008] 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 exhibit 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.
[0009] 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 (Xu X and Lee P, Pharm Res.
1993; 10(8): 1144-1152). 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.
[0010] A retarding, swellable hydrophilic coating has been used for
oral delayed release systems (Gazzaniga et al., Eur J Pharm
Biopharm. 1994; 40(4):246-250; Gazzaniga et al., S.T.P. Pharma
Sciences. 1996; 5(1):83-88). It was demonstrated that lag time was
linearly correlated with coating weight gain and drug release was
pH independent.
[0011] 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 (Conte et al., Biomaterials. 1993; 14(13):
1017-1023). 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.
[0012] Special grades of hydroxypropyl methylcellulose, e.g.,
METOLOSE.RTM. 60SH, 90SH (Shin-Etsu Ltd., Japan), and METHOCEL.RTM.
F4M (Dow Chemical Company, USA) have been used as a hydrophilic
matrix material to achieve bimodal drug release for several drugs,
i.e., aspirin, ibuprofen, and adinazolam (WO 87/00044). Bimodal
release is characterized by a rapid initial release, followed by a
period of constant release, and then by a second rapid drug
release.
[0013] 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. 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. (Walia et al., Pharm Dev Tech.
1998; 3(1): 103-113)
[0014] 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.
[0015] The OROS.RTM. push-pull system (Alza Company) has been
developed for pulsatile delivery of water-soluble and
water-insoluble drugs (Theeuwes, Drug Dev Ind Pharm. 1983; 9(7):
1331-1357; Theeuwes F, Novel Drug Delivery and Its Therapeutic
Application (LF Prescott and WS Nimmos eds.) 1989; 323-340), 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.
[0016] The PULSINCAP.RTM. dosage form releases its drug content at
either a predetermined time or at a specific site (e.g., colon) in
the gastrointestinal tract (WO 90/09168). 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.RTM. 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,
reproducible 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. (Wilding et al., Pharm Res. 1992;
9(5):654-657)
[0017] ADDERALL.RTM. is an immediate release composition, which
includes a mixture of four amphetamine salts: dextroamphetamine
sulfate, dextroamphetamine saccharate, amphetamine aspartate
monohydrate and amphetamine sulfate. This combination of
amphetamines is indicated for the treatment of Attention Deficit
Hyperactivity Disorder in children from 3-10 years of age.
[0018] One disadvantage of immediate release-only treatments for
children 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 requires a second
treatment, which is time-consuming, inconvenient and may be
problematic for those children having difficulties in swallowing
tablet formulations. ADDERALL XR.RTM. met the need for a dosage
form, which can be administered once, in place of the two oral
doses which are needed using the conventional drug delivery
formulations of the prior art. See U.S. Pat. Nos. 6,322,819 and
6,605,300; co-pending Reissue application Ser. Nos. 11/091,010 and
11/091,011.
[0019] There are currently two medications (ADDERALL XR.RTM. and
STRATTERA.TM.) approved by the U.S. Food and Drug Administration
(FDA) for the treatment of ADHD in adults. ADDERALL XR.RTM. is a
mixed amphetamine salts medication. STRATTERA.TM. is an atomoxetine
(a norepinephrine reuptake inhibitor) medication. Long acting
stimulant preparations, such as ADDERALL XR.RTM. and CONCERTA.RTM.
(methylphenidate), are designed to provide a duration of effect up
to 12 hours. However, clinicians have noted that a proportion of
patients treated with these formulations require additional
treatment with a short-acting stimulant to extend the daily
therapeutic effect. For patients taking long-acting stimulant
formulations who require duration of clinical benefit beyond 10-12
hours, clinicians have augmented the morning long-acting
formulation, typically at 8-10 hours post-dose, with a dose of the
same immediate-release (IR) medication. Typically, the dose of the
IR medication is smaller than the long-acting dose. This
augmentation strategy is most relevant to the "longer day demands"
of adult and adolescents, rather than school age, pediatric
patients.
[0020] Thus, a need exists for a once-daily, long-acting oral
composition that provides effective treatment of ADHD, without
supplementation, for patients with longer day demands (e.g., 14-16
awake hours).
SUMMARY OF THE INVENTION
[0021] The present invention provides a long-acting amphetamine
pharmaceutical composition, which includes an immediate release
component, a delayed pulsed release component and a sustained
release component, to meet the therapeutic needs for ADHD patients
with longer-day demands. The present invention fills the need for
once-daily longer-day treatment of ADHD by providing an amphetamine
pharmaceutical composition that is bioequivalent to an equal dosage
of ADDERALL XR.RTM. followed by an IR amphetamine composition 8
hours later.
[0022] The addition of a second delayed pulsed release formulation,
having a lag time of about 8 hours, to ADDERALL XR.RTM. cannot, as
one might expect, meet the recognized need for a once-daily
long-acting amphetamine composition that meets a patient's longer
day requirements (i.e., a once-daily amphetamine composition that
is bioequivalent to ADDERALL XR.RTM. plus an immediate release
amphetamine composition administered 8 hours later). A delayed
pulsed formulation having a lag time of about 8 hours would be
unsuitable because it would release the active agent in the distal
gastrointestinal tract (the colon), resulting in decreased
absorption of the active agent.
[0023] Unexpectedly, it has been discovered that a sustained
release formulation administered in combination with immediate
release and delayed pulsed release components similar to those
present in ADDERALL XR.RTM. can mimic the bioavailability of an
equivalent total amphetamine dosage provided by ADDERALL XR.RTM.
followed by an immediate release amphetamine composition 8 hours
later. However, the "usual" or "typical" construction for a
sustained release formulation is not suitable. Typically, a
sustained release formulation is constructed with a delayed release
coating overlaying a sustained release coating. Such a usual or
typical sustained release construction results in a Tmax that is
too early after administration to a patient to result in a
composition that meets the longer-day requirements for the
treatment of ADHD. For example, the dissolution profiles for a
typical sustained release formulation (PD0149-124) and a sustained
release formulation of the present invention (PD0149-120) are
illustrated in FIG. 1. PD0149-124 has a typical sustained release
formulation construction, wherein the immediate release bead of
Example 1 (see Examples 1 and 2, infra) is coated with a sustained
release coating (SURELEASE.RTM.), the sustained release coating is
coated with a delayed release coating (EUDRAGIT.RTM. FS30 D), and
the delayed release coating is coated with a protective layer
(OPADRY.RTM.). PD0149-120 is an embodiment of a sustained release
formulation of the present invention. PD0149-120 has a construction
wherein the immediate release bead of Example 1 is coated with a
delayed release coating (EUDRAGIT.RTM. FS30 D), the delayed release
coating is coated with a protective coating (OPADRY.RTM.), and the
protective coating is coated with a sustained release coating
(SURELEASE.RTM.). As illustrated in FIG. 1, PD0149-120 provides a
later Tmax relative to a typically-constructed sustained release
formulation, PD0149-124.
[0024] According to the present invention, an atypical,
counter-intuitive construction for a sustained release amphetamine
formulation, when administered in combination with an immediate
release formulation and a delayed pulsed release formulation, is
bioequivalent to ADDERALL XR.RTM. followed by an immediate release
amphetamine formulation administered 8 hours later. A sustained
release formulation of the present invention comprises at least one
amphetamine salt layered onto, or incorporated into, a core; a
delayed release coating layered onto the amphetamine core; a
sustained release coating layered onto the delayed release coating;
and, optionally, a protective coating. See FIG. 2. In a preferred
embodiment, the delayed release component is pH dependent.
[0025] A sustained release pharmaceutical formulation of the
present invention can comprise about 10% to about 150% of the
amphetamine dosage of the immediate release mixed amphetamine salt
composition and/or an extended release mixed amphetamine salt
composition. For example, the sustained release formulation can be
administered, in the same or different dosage forms, with the IR
and delayed pulsed release components of ADDERALL XR.RTM. in an
amphetamine dosage ratio of 1:1:1 (e.g., 10 mg immediate release
amphetamine, 10 mg delayed pulsed release amphetamine, 10 mg
sustained release amphetamine). Thus, in this example, the
sustained release composition comprises about 33% of the total
amphetamine dose. In another example, a patient with ADHD and
insomnia can be administered a reduced amount of the sustained
release composition, e.g., 10 mg immediate release amphetamine, 10
mg delayed pulsed release amphetamine, and 5 mg sustained release
amphetamine (the sustained release composition comprises 20% of the
total amphetamine dose). Thus, according to the present invention,
a clinician can adjust the sustained release formulation dosage to
meet the needs of an individual patient suffering from ADHD.
[0026] The pharmaceutical composition of the present invention,
comprising an immediate release amphetamine component, a delayed
pulsed release amphetamine component and a sustained release
amphetamine component, delivers, in a single dose, mixed
amphetamine salts to a patient with a pharmacokinetic profile
similar to a 2-dose treatment with a currently available commercial
extended release composition (i.e., ADDERALL XR.RTM.) plus an
immediate release composition administered about eight hours after
the ADDERALL XR.RTM.. See, for example, FIG. 9. This similarity in
bioequivalence is surprising because it would be expected that some
part of the drug delivered by the delayed release components of
compositions of the present invention (i.e., the delayed pulsed
release and/or the sustained release components) would be lost
(i.e., not absorbed) in the colon. The FDA package insert and
labeling for ADDERALL XR.RTM. (Shire US, Inc.) are hereby
incorporated by reference in their entirety.
[0027] Preferred amphetamine salts are those in ADDERALL XR.RTM.,
i.e., dextroamphetamine sulfate, dextroamphetamine saccharate,
amphetamine aspartate monohydrate and amphetamine sulfate. However,
the invention is not limited to these salts. Other amphetamines and
amphetamine salts can be used in the pharmaceutical compositions of
the present invention including, for example, amphetamine base,
chemical and chiral derivatives thereof; other amphetamine salts;
and mixtures of the foregoing.
[0028] The three components comprising the extended release
amphetamine composition of the invention release doses of the
active ingredients at varying, pre-determined times to provide for
full day treatment (i.e., about 14 hours to about 16 hours) of
conditions such as ADHD. A treatment for ADHD, which can be
delivered in a single dosage is especially beneficial to
adolescents and adults who typically have longer daily waking hours
compared to children.
[0029] The compositions of the present invention comprise an
immediate release component, a delayed pulsed release component,
and a sustained release component. In embodiments of the invention,
delayed pulsed release and/or sustained release can be provided by
an enteric coating.
[0030] In a particular embodiment, the immediate release component,
delayed pulsed release component and sustained release component
each contain equal amounts of active ingredient.
[0031] In one embodiment, the immediate release, delayed pulsed
release and sustained release components of the composition are
present on the same core. In another embodiment, the immediate
release and delayed pulsed release components are present on
different cores. In a further embodiment, the delayed pulsed
release and sustained release components are present on different
cores. In a preferred embodiment, the immediate release, delayed
pulsed release and sustained release components are present on
different cores. See FIG. 3.
[0032] In yet another embodiment, the amphetamine salt is coated
onto a core. In a further embodiment, the amphetamine salt is
incorporated into a core.
[0033] It is contemplated that compositions of the present
invention can include a combination of the hereinabove referred to
cores (one or more cores that include three components on the same
core, one or more cores that include two of the three components on
the core, and one or more cores that include one of the three
components on the core).
[0034] In an embodiment of the present invention, a pharmaceutical
composition is provided in which there is immediate release of
drug, a delayed pulsed release of drug, and a sustained release of
drug, and wherein the drug includes one or more amphetamine salts
and mixtures thereof. In a preferred embodiment, the delayed pulsed
release of drug begins about one hour after oral administration of
the composition to a patient in the fasted state and the sustained
release of drug begins about four hours to about six hours after
oral administration to a patient in the fasted state.
[0035] Surprisingly, amphetamine salt pharmaceutical compositions
of the present invention deliver about bioequivalent drug levels to
a patient in either a fasted state or fed state. Thus, an
amphetamine salt composition according to the present invention
does not exhibit a food effect. This is surprising because it would
be expected that some of the drug delivered by delayed release
would be released earlier in the presence of food (especially fatty
food) due to the increase in gastric pH that accompanies the
ingestion of food.
[0036] A pharmaceutical composition according to the present
invention includes: [0037] (a) an immediate release bead comprising
an amphetamine salt; [0038] (b) a first delayed release bead
comprising an amphetamine salt; and [0039] (c) a second delayed
release bead comprising an amphetamine salt; wherein the first
delayed release bead provides pulsed release of the mixed
amphetamine salt and the second delayed release bead provides
sustained release of the mixed amphetamine salt.
[0040] A pharmaceutical composition of the present invention
provides a patient with at least about 14 hours to about 16 hours
of effective therapy for Attention Deficit Hyperactivity Disorder
(ADHD).
[0041] In an embodiment of the invention, the d-amphetamine
C.sub.max after administration of a 37.5 mg amphetamine
pharmaceutical composition to a human patient is about 50
ng/ml.
[0042] In another embodiment, the d-amphetamine area under the
curve from time 0 to the last measured time (AUC.sub.0-last) after
administration of a 37.5 mg amphetamine pharmaceutical composition
to a human patient is about 1058 ng-hr/ml.
[0043] Further, according to an embodiment of the present
invention, the d-amphetamine area under the curve from time 0 to
time infinity (AUC.sub.0-inf) after administration of a 37.5 mg
amphetamine pharmaceutical composition to a human patient is about
1085 nghr/ml.
[0044] In an embodiment, the present invention provides a
pharmaceutical composition, wherein the d-amphetamine T.sub.max is
about 8.2 hours after administration of a 37.5 mg amphetamine
pharmaceutical composition to a human patient.
[0045] In a particular embodiment, the l-amphetamine C.sub.max
after administration of a 37.5 mg amphetamine pharmaceutical
composition to a human patient is about 15 ng/ml.
[0046] In a further embodiment, the l-amphetamine area under the
curve from time 0 to the last measured time (AUC.sub.0-last) after
administration of a 37.5 mg amphetamine pharmaceutical composition
to a human patient is about 354 nghr/ml.
[0047] In another embodiment, the l-amphetamine area under the
curve from time 0 to time infinity (AUC.sub.0-inf) after
administration of a 37.5 mg amphetamine pharmaceutical composition
to a human patient is about 373 nghr/ml.
[0048] Further, in an embodiment of the present invention, the
l-amphetamine T.sub.max is about 8.4 hours after administration of
a 37.5 mg amphetamine pharmaceutical composition to a human
patient.
[0049] In a further embodiment, a protective layer is provided over
at least one enteric coating. In another embodiment, a protective
layer is provided between the amphetamine salt and at least one
enteric coating. A protective layer can also be provided over the
sustained release coating according to the present invention.
[0050] In a particular embodiment, the amphetamine salt is selected
from the group consisting of dextroamphetamine sulfate,
dextroamphetamine saccharate, amphetamine aspartate monohydrate,
amphetamine sulfate, and mixtures thereof.
[0051] In a more particular embodiment, the amphetamine salt is a
mixture of dextroamphetamine sulfate, dextroamphetamine saccharate,
amphetamine aspartate monohydrate, and amphetamine sulfate.
[0052] In an aspect of the present invention, the pharmaceutical
composition does not exhibit a food effect.
[0053] The present invention encompasses methods for treating ADHD,
which comprise administering the amphetamine salt pharmaceutical
composition of the present invention to a patient suffering from
ADHD.
[0054] The delayed pulsed release and sustained release components
retard or delay the release of the pharmaceutically active
ingredient(s) for a specified time period ("lag time") until a
predetermined time. For example, a delayed pulsed release component
having an enteric coating layer retards or delays the release of
the pharmaceutical active or drug for a lag time, then releases the
drug rapidly and completely, i.e., a pulsed release. In one
embodiment of a delayed pulsed release, the entire dose is released
within about 30-60 minutes following a lag time after
administration of the composition. In another example, a sustained
release component having an enteric release coating retards or
delays the release of the pharmaceutical active or drug for a lag
time and then the release of the drug is sustained (i.e., release
of the entire dose takes greater than about 60 minutes).
[0055] 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 can alter the pH of the
GI tract.
[0056] According to the present invention, the lag time for the
delayed pulsed release component can be pH dependent or pH
independent. In an embodiment of the invention, the lag time for
the delayed pulsed release component is only time-dependent, i.e.,
pH independent. In a preferred embodiment, the lag time is pH
dependent.
[0057] According to the present invention, a lag time can be about
1 hour to about 14 hours. Multiple dose formulations can have more
than one lag time. In a preferred embodiment, the delayed pulsed
release component has a lag time of about 60 minutes and the
sustained release component has a lag time of about 4 to about 6
hours.
[0058] 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.
[0059] In attempting to provide for delayed pulsed release of an
amphetamine salt, applicants found that use of an enteric release
coating as generally practiced in the art did not provide the
desired release profile. Using the typical amount of enteric
coating (10 to 15 wt %) for the delayed pulsed release component
resulted in undesired premature leakage of the drug from the
delivery system into the upper gastrointestinal tract, and drug
delivery at the desired, more distal location in the
gastrointestinal tract was reduced. Thus, this coating did not meet
the requirements for a drug release profile, which provides full
beneficial therapeutic activity at the desired time.
[0060] Applicants found that using a thicker application of enteric
coating on the delayed pulsed release component allowed for the
delayed release 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.
[0061] This was surprising because an increase in enteric coating
thickness above a minimum thickness of about 5 to 10 wt % typically
does not have a significant effect on release of drug from within
such coatings. Typically, application of a thicker coating (greater
than 15 wt %) will only marginally increase the time i.e., for a
brief period of time (about 20 minutes) for complete release at the
appropriate environmental condition (e.g., the appropriate pH for a
pH dependent coating) or appropriate time after ingestion (e.g.,
when a pH independent coating is used). Using the typical coating,
applicants could not achieve the desired delayed pulsed
release--rather, the coating leaked before the predetermined time
in an inappropriate environment resulting in significant loss of
the therapeutic agent.
[0062] Accordingly, in one aspect, the pulsed enteric release of
the amphetamine salts is accomplished by employing a certain
minimum thickness of the enteric coating, i.e., a coating weight
percent of about 24 to about 30 wt %.
[0063] In one embodiment of the invention, the pulsed dose delivery
comprises a multi-layered composition which comprises (1) one or
more amphetamine salts; (2) an enteric coating over the one or more
amphetamine salts; (3) a sustained release coating over the enteric
coating; (4) a second application (e.g., a layer) of amphetamine
salts over the sustained release coating; (5) a second enteric
coating over the one or more pharmaceutically active amphetamine
salts; (6) a third application (e.g., layer) of one or more
amphetamine salts over the second enteric coating layer; and an
immediate release layer coating.
[0064] In one aspect, the one or more amphetamine salts can be
provided within or as a part of a core seed around which the
sustained release enteric coating is applied. Alternatively, a core
seed can be coated with one or more layers of one or more
amphetamine salts.
[0065] It has further been discovered that a delayed pulsed release
drug delivery can also be accomplished by coating the drug first
with a protective layer prior to applying the delayed pulsed
release enteric coating.
[0066] Thus, in another embodiment, the delayed pulsed enteric
release is accomplished by employing a protective layer between the
drug and the delayed pulsed release enteric coating. In another
embodiment, the pulsed enteric release is accomplished by employing
a protective layer between drug and the sustained release enteric
coating. When using a protective coating, the delayed pulsed
release enteric coating or the sustained release enteric coating
may be of an increased thickness or may be of lower thickness.
[0067] In one aspect of the invention, 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 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.
[0068] Thus, in this embodiment, the protective layer comprises a
semi-permeable polymer and an immediate release coating layer. In a
further 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.
[0069] 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.
[0070] 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 ingrdient thus may be delayed
and the dissolution rate may be increased in an alkaline
environment.
[0071] In a further embodiment, the protective coating may be used
both over the drug and over the enteric coating.
[0072] With respect to this embodiment of the invention, the one or
more 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 amphetamine
salts.
[0073] Compositions of the present invention encompass mixed
amphetamine salt dosages of about 10 mg to about 100 mg. In an
embodiment of the present invention, the pharmaceutical composition
comprises a mixed amphetamine salt dosage of about 12.5 mg. In
further embodiments of the present invention, the pharmaceutical
composition comprises a mixed amphetamine salt dosage of about
18.75 mg, about 25 mg, about 31.25 mg, about 37.5 mg, about 43.75
mg, about 50 mg, about 62.5 mg, and about 75 mg. Dissolution
profiles for 12.5 mg, 25 mg, 37.5 mg and 50 mg compositions of the
invention are provided in FIGS. 4-7, respectively.
[0074] 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. In a specific embodiment
of the present invention, the drug delivery system comprises three
beads or beadlets in a dosage form, either capsule, tablet, sachet
or other method of orally administering the beads. In a preferred
embodiment, the immediate release beads, the delayed pulsed release
beads, and the sustained release beads are present in the
composition in an about 1:1:1 ratio.
BRIEF DESCRIPTION OF THE DRAWINGS
[0075] FIG. 1, is a graph showing the dissolution profiles for a
typical sustained release formulation (PD0149-124) and a sustained
release formulation of the present invention (PD0149-120). HFS is
the formulation exemplified in Example 2, infra; HIR is the
formulation exemplified in Example 1, infra; and FS is
EUDRAGIT.RTM. FS30 D.
[0076] FIG. 2 illustrates the construction of the sustained release
bead.
[0077] FIG. 3 illustrates a 3-bead controlled dose drug delivery
system of the present invention, including an immediate release
component (IR bead), a delayed pulsed release component (DR1 bead)
and a sustained release component (DR2 bead).
[0078] FIG. 4 is a graph showing the dissolution profile of a 12.5
mg mixed amphetamine salt 3-bead composition according to the
invention.
[0079] FIG. 5 is a graph showing the dissolution profile of a 25 mg
mixed amphetamine salt 3-bead composition according to the
invention. The following pH conditions were used: at 0-2 hours, pH
1.1; at 2-3 hours, pH 6.0; at three hours and greater, pH 7.5.
[0080] FIG. 6 is a graph showing the dissolution profile of a 37.5
mg mixed amphetamine salt 3-bead composition according to the
invention. The following pH conditions were used: at 0-2 hours, pH
1.1; at 2-3 hours, pH 6.0; at three hours and greater, pH 7.5.
[0081] FIG. 7 is a graph showing the dissolution profile of a 50 mg
mixed amphetamine salt 3-bead composition according to the
invention. The following pH conditions were used: at 0-2 hours, pH
1.1; at 2-3 hours, pH 6.0; at three hours and greater, pH 7.5.
[0082] FIG. 8 is a graph showing the dissolution profile of a
SPD465 sustained release bead (HDR2). The following pH conditions
were used: at 0-2 hours, pH 1.1; at 2-3 hours, pH 6.0; at three
hours and greater, pH 7.5.
[0083] FIG. 9 graphically illustrates the mean d-amphetamine plasma
concentration of SPD465 37.5 mg compared to ADDERALL XR.RTM. 25 mg
followed by immediate release mixed amphetamine salts 12.5 mg 8
hours later.
[0084] FIG. 10 graphically illustrates the mean 1-amphetamine
plasma concentration of SPD465 37.5 mg compared to ADDERALL XR.RTM.
25 mg followed by immediate release mixed amphetamine salts 12.5 mg
8 hours later.
[0085] FIG. 11 graphically illustrates mean d-amphetamine plasma
concentrations over time following administration of a single dose
and seven once-daily doses of 12.5 mg SPD465 to healthy
subjects.
[0086] FIG. 12 graphically illustrates mean d-amphetamine plasma
concentrations over time following administration of seven
once-daily doses of SPD465 to healthy subjects.
[0087] FIG. 13 graphically illustrates the power model analysis of
mean and individual Day 7 Cmax values for d-amphetamine by
dose.
[0088] FIG. 14 graphically illustrates the power model analysis of
mean and individual Day 7 AUC.sub.0-24 values for d-amphetamine by
dose.
[0089] FIG. 15 graphically illustrates mean l-amphetamine plasma
concentrations over time following administration of a single dose
and seven once-daily doses of 12.5 mg SPD465 to healthy
subjects.
[0090] FIG. 16 graphically illustrates mean d-amphetamine plasma
concentrations over time following administration of seven
once-daily doses of SPD465 to healthy subjects.
[0091] FIG. 17 graphically illustrates the power model analysis of
mean and individual Day 7 Cmax values for 1-amphetamine by
dose.
[0092] FIG. 18 graphically illustrates the power model analysis of
mean and individual Day 7 AUC.sub.0-24 values for l-amphetamine by
dose.
DETAILED DESCRIPTION OF THE INVENTION
[0093] Various types of controlled drug release and release
profiles are contemplated by the present invention.
[0094] The terms "bead" and "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, bead and pellet
encompass any discrete component of a dosage form.
[0095] "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.
[0096] "Rapid" and "slow" release refer to the rate of release
after onset. Once delivery of the drug begins, it may be released
relatively quickly or relatively slowly. A rapid release indicates
that, after onset, a maximum or peak dose is reached in a
relatively short period of time. A slow release indicates that,
after onset, a maximum or peak dose is reached in a relatively long
period of time. Once reached, the maximum dose may fall off at any
pace (e.g. fast, slow, or constant).
[0097] "Sustained" or "continuous" refers to the period of on-going
release, and means that the delivery of drug goes on (it continues
or is sustained) for an extended period of time after initial
onset, typically more than one hour, whatever the shape of the dose
release profile. For example, the drug release is sustained between
a maximum and minimum value (more than zero) for some relatively
long period of time. This release may be at a constant dose, or at
a dose which diminishes over time.
[0098] "Constant" release refers to the dose that is being
released, and means that a drug is delivered at a relatively
constant dose over a moderate or extended period of time. This can
be represented by a dose release profile that is relatively flat or
only gently sloped after initial onset, i.e. without highly
distinct peaks and valleys. Thus, a constant release will typically
be sustained or continuous, but a sustained or continuous release
may not be constant.
[0099] "Pulsed" release means that a drug is delivered in one or
more doses that fluctuate between a maximum and minimum dose over a
period of time. 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. When two
or more pulsed releases occur, there may or may not be a period of
no release between pulses. Typically, pulsed release results in
release of essentially all of a drug within about 60 minutes or
less.
[0100] "Extended" release refers to a formulation which provides
either a release of drug within a targeted dose range for a
relatively long period, or a plasma level of drug within a targeted
dose range for a relatively long period, without regard for the
particular mechanism or character of release, e.g. as sustained,
pulsed, or constant.
[0101] "Effective therapy" or "effective treatment," as used
herein, means to prevent, alleviate, arrest, or inhibit at least
one symptom or sign of ADHD. Symptoms and signs of ADHD include,
for example, inattention, hyperactivity and impulsivity.
[0102] "Food effect," as used herein, means a significant
difference in the bioavailability of a drug in a patient when the
drug is administered in a fasted state compared to a fed state. "No
food effect" means that there is no significant difference in the
bioavailability of a drug in a patient when the drug is
administered in a fasted state compared to a fed state.
[0103] The term "about" or "approximately" means within an
acceptable error range for the particular value as determined by
one of ordinary skill in the art, which will depend in part on how
the value is measured or determined, i.e., the limitations of the
measurement system, i.e., the degree of precision required for a
particular purpose, such as a pharmaceutical formulation. For
example, "about" can mean within 1 or more than 1 standard
deviations, per the practice in the art. Alternatively, "about" can
mean a range of up to 20%, preferably up to 10%, more preferably up
to 5%, and more preferably still up to 1% of a given value.
Alternatively, particularly with respect to biological systems or
processes, the term can mean within an order of magnitude,
preferably within 5-fold, and more preferably within 2-fold, of a
value.
[0104] 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 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.
[0105] Drug release profiles are distinct from plasma profiles. A
plasma profile is a measure or representation of the dose or level
of active ingredient (drug) in the bloodstream of a mammal, e.g. a
patient receiving a drug formulation. Upon release of a drug from a
formulation, e.g. into the gut of a mammal, the amount of drug that
is present in the bloodstream over time can be determined.
[0106] A drug release profile may be designed to produce a desired
or targeted plasma profile. Often, but not necessarily, a plasma
profile will mimic a release profile. For example, it might be
expected that a sustained release of drug would more likely produce
a sustained dose in the plasma, or that a pulsed release would
produce a pulsed (peak and valley) plasma profile. This is not
necessarily so, however. For example, the half-life of the drug in
the blood stream (its rate of decay) may be such that a sustained
or continuous plasma profile could result from a pulsed delivery
profile. Other factors may also play a role, such as
bio-absorption, bioavailability, and first pass effect. The plasma
profile produced by a particular release profile may also vary from
patient to patient.
[0107] Measures of bioavailability well known in the art include
the area under the plasma concentration-time curve (AUC), the
concentration maximum (C.sub.max), and the time to C.sub.max
(T.sub.max).
[0108] AUC is a measurement of the area under the plasma
concentration-time curve, and is representative of the amount of
drug absorbed following administration of a single dose of a drug
(Remington: The Science and Practice of Pharmacy, (Alfonso R.
Gennaro ed. 2000), page 999).
[0109] C.sub.max is the maximum plasma concentration achieved after
oral drug administration (Remington, page 999). An oral drug
administration results in one C.sub.max, but may result in greater
than one "peak plasma concentration" or "plasma concentration peak"
(for example, following the administration of a pulsed dose
formulation).
[0110] T.sub.max is the amount of time necessary to achieve the
C.sub.max after oral drug administration, and is related to the
rate of absorption of a drug (Remington, page 999).
[0111] Bioequivalence is the absence of a significantly different
rate and extent of absorption in the availability of the active
ingredient when administered at the same dose under similar
conditions. Bioequivalence can be measured by pharmacokinetic
parameters such as, for example, AUC and Cmax.
[0112] 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 exemplary core is
a sugar core. Exemplary matrixes include hydrophilic matrixes.
Polymers useful for forming a hydrophilic matrix include
hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose
(HPC), poly(ethylene oxide), poly(vinyl alcohol), xanthan gum,
carbomer, carrageenan, and zooglan. Other similar hydrophilic
polymers may also be employed.
[0113] Coating layers can provide immediate release, delayed pulsed
release or sustained release. Immediate release of the drug from
the immediate-release layer can be achieved by any of various
methods known in the art. One example is the use of a very thin
layer or coating which by virtue of its thinness is quickly
penetrated by gastric fluid allowing rapid leaching of the drug.
Another example is by incorporating the drug in a mixture that
includes a supporting binder or other inert material that dissolves
readily in gastric fluid, releasing the drug as the material
dissolves. A third is the use of a supporting binder or other inert
material that rapidly disintegrates upon contact with gastric
fluid, with both the material and the drug quickly dispersing into
the fluid as small particles. Examples of materials that rapidly
disintegrate and disperse are lactose and microcrystalline
cellulose. An example of a suspending agent and binder is
hydroxypropyl methylcellulose.
[0114] Enteric coatings for the delayed pulsed release component
can be pH-dependent or pH-independent. Enteric coatings for the
sustained release component are pH dependent. A pH dependent
coating is activated to release drug within a known pH range, which
typically is matched to the local pH of the environment where
delayed release is desired. Exemplary pH dependent coatings 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.RTM. L12.5, L100, or
EUDRAGIT.RTM. 512.5, 5100 or similar compounds used to obtain
enteric coatings. Aqueous colloidal polymer dispersions or
re-dispersions can be also applied, e.g. EUDRAGIT.RTM. L 30D-55,
EUDRAGIT.RTM. L100-55, EUDRAGIT.RTM. 5100, EUDRAGIT.RTM.
preparation 4110D (Rohm Pharma); AQUATERIC.RTM., AQUACOAT.RTM. CPD
30 (FMC); KOLLICOAT MAE.RTM. 30D and, 30DP (BASF); EASTACRYL.RTM.
30D (Eastman Chemical).
[0115] A pH independent coating includes materials susceptible to
enzymatic activation by azo-reductases in intestinal bacteria
(i.e., azo-polymers) or materials susceptible to degradation by
polysaccaridases in the colon (natural polysaccarides).
Non-limiting examples of azo-polymers include co-polymers of
2-hydroxyethyl methacrylate (HEMA) and methyl methacrylate (MMA).
Non-limiting examples of natural polysaccharides include amylose,
chitosan, chrondoitin, dextran, and xylan.
[0116] The sustained release component can include sustained
release coatings, sustained release matrices, and sustained release
osmotic systems. Sustained release coatings can be prepared using a
water-insoluble polymer, a combination of water-insoluble polymers,
or a combination water-insoluble and water-soluble polymers.
Conventional sustained release polymers well known to those of
ordinary skill in the formulary arts can be used for the sustained
release matrix.
[0117] Exemplary sustained release coatings can include polyvinyl
acetate, cellulose acetate, cellulose acetate butyrate, cellulose
acetate propionate, ethyl cellulose, fatty acids and esters
thereof, alkyl alcohols, waxes, zein (prolamine from corn), and
aqueous polymeric dispersions such as EUDRAGIT.RTM. RS and RL30D,
EUDRAGIT.RTM. NE30D, AQUACOAT.RTM., SURELEASE.RTM., KOLLICOAT.RTM.
SR30D, and cellulose acetate latex.
[0118] Principles of sustained release formulation technology
applicable to this invention, include those disclosed 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.
[0119] The present invention comprises a core or starting seed,
either a prepared or commercially available product. The cores or
starting seeds can be sugar spheres, spheres made from
microcrystalline cellulose and any suitable drug crystals.
[0120] 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:
[0121] Binders such as cellulose derivatives such as
methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxypropyl methylcellulose, polyvinylpyrrolidone,
polyvinylpyrrolidone/vinyl acetate copolymer and the like.
[0122] Disintegration agents such as com starch, pregelatinized
starch, cross-linked carboxymethylcellulose (AC-DI-SOL.RTM.),
sodium starch glycolate (EXPLOTAB.RTM.), cross-linked
polyvinylpyrrolidone (PLASDONE XL.RTM.), and any disintegration
agents used in tablet preparations.
[0123] 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.
[0124] Surfactants such as sodium lauryl sulfate, sorbitan
monooleate, polyoxyethylene sorbitan monooleate, bile salts,
glyceryl monostearate, PLURONIC.RTM. line (BASF), and the like.
[0125] Solubilizers such as citric acid, succinic acid, fumaric
acid, malic acid, tartaric acid, maleic acid, glutaric acid sodium
bicarbonate and sodium carbonate and the like.
[0126] Stabilizers such as any antioxidation agents, buffers,
acids, and the like, can also be utilized.
[0127] Methods of manufacturing the core include
[0128] 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.
[0129] 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.
[0130] 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.
[0131] For purposes of the present invention, the core particles
have a diameter in the range of about 50-1500 microns; preferably
100-800 microns.
[0132] These particles can then be coated in a fluidized bed
apparatus with an alternating sequence of coating layers.
[0133] 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. Pharmaceutically active amphetamine salts
contemplated to be within the scope of the present invention
include amphetamine base and salts thereof. Preferred
pharmaceutically active amphetamine salts include dextroamphetamine
sulfate, dextroamphetamine saccharate, amphetamine aspartate
monohydrate and amphetamine sulfate.
[0134] 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 delayed
pulsed or sustained release layer is coated thereupon. Another
active layer may also be added to the enteric delayed pulsed or
sustained layer to deliver an initial dose.
[0135] 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.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).
[0136] The enteric delayed pulsed release or sustained release
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. Suitable
coaters are well known in the art. For example, any commercially
available pH-sensitive polymer can be used. With such a polymer,
the pharmaceutical active is not released in the acidic stomach
environment of approximately below pH 4.5, but is 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.
[0137] Suitable enteric polymers for the delayed pulsed release
component and sustained release component include, for example,
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.RTM. L12.5, L100, or
EUDRAGIT.RTM. 512.5, 5100 or similar compounds used to obtain
enteric coatings. Aqueous colloidal polymer dispersions or
re-dispersions can be also applied, e.g. EUDRAGIT.RTM. L 30D-55,
EUDRAGIT.RTM. L100-55, EUDRAGIT.RTM. 5100, EUDRAGIT.RTM.
preparation 4110D (Rohm Pharma); AQUATERIC.RTM., AQUACOAT.RTM. CPD
30 (FMC); KOLLICOAT MAE.RTM. 30D and, 30DP (BASF); EASTACRYL.RTM.
30D (Eastman Chemical).
[0138] The enteric delayed pulsed release and sustained release
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 EUDRAGIT.RTM. RS and
EUDRAGIT.RTM. RL; a neutral ester dispersion without any functional
groups, sold under the trade names EUDRAGIT.RTM. NE30D; and other
pH independent coating products.
[0139] The modifying component of the protective layer used over
the enteric delayed pulsed release or sustained release 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. Coatings
commonly known to one skilled in the art can be used for this
purpose and applied by conventional 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 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.
[0140] 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). Talc can also be used for this purpose, e.g., a 2% w/w talc
treatment can be applied.
[0141] 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.
[0142] 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.
[0143] The composition can 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 (AVICEL(.RTM.), soy polysaccharide
(EMCOSOY.RTM.), pre-gelatinized starches (STARCH.RTM. 1500,
NATIONAL.RTM. 1551), and polyethylene glycols (CARBOWAX.RTM.). The
materials should be present in the range of 5-75% (w/w), with a
preferred range of 25-50% (w/w).
[0144] 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.RTM.), sodium starch glycolate (EXPLOTAB.RTM.,
PRIMOJEL.RTM.), 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).
[0145] Lubricants can be added to assure proper tableting, and
these can include, but are not limited to: magnesium stearate,
calcium stearate, stearic acid, polyethylene glycol, leucine,
glyceryl behenate, 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).
[0146] 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 sufficient to fracture the
beads or coatings.
[0147] A tablet according to the present invention can be
constructed in three layers, wherein the immediate release
component is dry blended, and the delayed pulsed release and the
sustained release components are wet granulated. The tablet is then
formed in a one layer or a three layer compression. Upon
dissolution of the layers in the one layer or three layer tablet,
each component is released and acts in its own way (i.e., the
immediate release particles provide immediate release, the delayed
pulsed release particles provide delayed pulsed release, and the
sustained release particles provide sustained release after a lag
time).
[0148] 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 14 hours
to about 16 hours with a single oral administration.
[0149] This invention also encompasses the use of a longer-day
amphetamine composition to treat conditions other than ADHD. These
conditions 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 any compositions or formulations of guanfacine or
buproprion; 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 dysfunction; apathy; fatigue;
Pick's disease; sleep disorders, e.g., narcolepsy, cataplexy, sleep
paralysis and hypnagogic hallucinations; etc.
[0150] The invention also contemplates combinations of the
longer-day amphetamine compositions of this invention with other
therapeutic agents. The drugs can be formulated in the same dosage
form as the longer-day amphetamine composition dose of the
invention or can be formulated separately, 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.
[0151] The other therapeutic agents can include e.g., for
Alzheimer's: galanthamine, tacrine, donepezil, rivastigmine,
memantine, human growth hormone, selegiline hydrochoride, estrogen,
clioquinol, ibuprofen, and Gingko bilboa; for ADHD: methylphenidate
(e.g., RITALIN.RTM., CONCERTA.RTM.), amphetamine, pemoline,
clonidine, guanfacine, etc; for depression: fluoxetine
hydrochloride, sertraline HCL, paroxetine HCL, reboxetine,
bupropion HCL, olanzapine, fluoxetine hydrochloride, amitriptyline,
imipramine, nortriptyline, phenelzine, tranylcypromine sulfate,
trazodone, and venlafaxine; for mood disorder: thorazine,
haloperidol, thiothixene, thioridazine, risperadone, clozapine,
risperidone, and olanzapine; for fatigue: benzodiazepines,
naproxen, fluoxetine hydrochloride, sertraline HCL, paroxetine HCL,
venlafaxine, and trazodone; for fibromyalgia: phenytoin,
carbamazepine, valproate, divalproex, desipramine, nortriptyline,
amitryptiline, doxepin, and non-steroidal inflammatory drugs; for
oppositional defiant disorder (ODD): clonidine, risperidone, and
olanzepine; for apathy: amisulpride, olanzapine, visperidone,
quetiapine, clozapine, and zotepine; for Parkinson's disease:
levodopa, bromocriptine, pergolide, and pramipexole; for
schizophrenia: clozapine, olanzepine, quetiapine fumarate, and
risperidone; for Huntington's disorder: haloperidol and clonzepam;
for dementia: thioridazine, haloperidol, risperidone, tacrine,
donepezil, and rivastigmine; for narcolepsy: modafinil,
amphetamine, modafinil and RITALIN.RTM.; for cataplexy: sodium
oxybate; for hallucinations: clozapine, risperidone, olanzepine,
and quetiapine fumarate; for sleep paralysis: PEROCET.RTM.,
VICODIN.RTM., and LORCET.RTM.; for obsessive compulsive disorder:
clomipramine, fluoxetine hydrochloride, sertraline HCL, paroxetine
HCL, fluvoxamine; and for anxiety: amitryptiline, amoxepine,
bupropion HCL, carbamazepine, clomipramine, desipramine, doxepin,
imipramine, nortriptyline, VENTYL.RTM., trimipramine etc; selective
serotonin reuptake inhibitors (SSRIs) including fluoxetine
hydrochloride, fluvoxamine, nefazodone, paroxetine HCL, sertraline
HCL venlafaxine, etc., benzodiazepines, including alprazolam,
chlordiazepoxide, clonazepam, diazepam, flurazepam, lorazepam,
oxazepam, triazolam, etc., monamine oxidase inhibitors including
moclobemide, phenelzine, tranylcypromine sulfate, etc.
[0152] The present invention is not to be limited in scope by the
specific embodiments described herein. Indeed, various
modifications of the invention in addition to those described
herein will become apparent to those skilled in the art from the
foregoing description and the accompanying figures. Such
modifications are intended to fall within the scope of the appended
claims.
[0153] The following examples are presented for illustration and do
not limit the invention.
EXAMPLES
Example 1
Immediate Release Formulation (HIR)
[0154] Sugar sphere seeds (30/35 Mesh, NF) were put into a FLM-15
fluid bed processor with a 9-Wurster column and fluidized at
60.degree. C. A suspension of a mixture containing amphetamine
aspartate; amphetamine sulfate, USP; dextroamphetamine saccharate;
and dextroamphetamine sulfate, USP with Hypromellose 2910, USP/NF
as a binder was sprayed onto the seeds under suitable conditions.
After drying, an OPADRY.RTM. Beige, YS-1-17274-A seal coating was
applied. The ingredients are listed by weight percent in Table
1.
TABLE-US-00001 TABLE 1 Ingredient Weight % Amphetamine aspartate
4.75 Amphetamine sulfate, USP 4.75 Dextroamphetamine saccharate
4.75 Dextroamphetamine sulfate, USP/NF 4.75 Sugar sphere 30/35
mesh, USP/NF 78.00 OPADRY .RTM. Beige, YS-1-17274-A 2.00
Hypromellose 2910, USP/NF 1.00 Purified water, USP * Total 100.00 *
removed during processing
Example 2
Intermediate Formulation (HFS)
[0155] The following formulation was used to coat the immediate
release mixed amphetamine salt pellets from Example 1 with
EUDRAGIT.RTM. FS30D (also referred to herein as EUDRAGIT.RTM.
4110D) (Rohm Pharma, Germany) coating dispersion. The immediate
release pellets of Example 1 were loaded in a fluid bed processor
with a reduced Wurster column (GPGC-15, Glatt). The coating
dispersion was prepared by dispersing triethyl citrate, USP/NF;
talc, USP/NF and EUDRAGIT.RTM. FS30D into water and mixing for at
least 30 minutes. Under suitable fluidization conditions, the
coating dispersion was sprayed onto the fluidized mixed amphetamine
salt pellets. The spraying was continued until the targeted coating
level of 25-30 weight percent (wt %) was achieved. The coated
pellets were dried at 30-35.degree. C. for 5 minutes before
stopping the process. After drying, the pellets were coated with
OPADRY.RTM. Beige, YS-1-17274-A. The ingredients are listed by
weight percent in Table 2.
TABLE-US-00002 TABLE 2 Ingredients Weight (%) Immediate release
pellets (Example 1) 65.50 MAA/MA/MMA Copolymer Suspension 27.77
(EUDRAGIT .RTM. FS30 D)* Triethyl citrate, USP/NF 1.35 Talc, USP/NF
3.38 OPADRY .RTM. Beige, YS-1-17274-A 2.00 Water ** Total 100.00
*MAA/MA/MMA Copolymer Suspension is Methyl Acrylate,
MethylMethacrylate, and Methacrylic Acid Copolymer (EUDRAGIT .RTM.
FS30D) ** removed during processing
Example 3
Delayed Release Formulation (HDR)
[0156] The following formulation was used to coat the immediate
release mixed amphetamine salt pellets from Example 1 with
EUDRAGIT.RTM. L30 D-55 coating dispersion. The immediate release
pellets of Example 1 were loaded in a fluid bed processor with a
reduced Wurster column (GPGC-15, Glatt). The coating dispersion was
prepared by dispersing Triethyl citrate, USP/NF; Talc, USP/NF and
EUDRAGIT.RTM. L30D-55 into water and mixing for at least 30
minutes. Under suitable fluidization conditions, the coating
dispersion was sprayed onto the fluidized mixed amphetamine salt
pellets. The spraying was continued until the targeted coating
level of 27-32 weight percent was achieved. The coated pellets were
dried at 30-35.degree. C. for 5 minutes before stopping the
process. After drying, the pellets were coated with OPADRY.RTM.
Beige, YS-1-17274-A. The ingredients are listed by weight percent
in Table 3.
TABLE-US-00003 TABLE 3 Ingredients Weight (%) Immediate release
pellets (Example 1) 63.00 Methacrylic Acid Copolymer Dispersion,
29.03 USP/NF (EUDRAGIT .RTM. L30 D-55)* Triethyl citrate, USP/NF
2.94 Talc, USP/NF 3.04 OPADRY .RTM. Beige, YS-1-17274-A 2.00 Water
** Total 100.01 *Methacrylic Acid Copolymer Dispersion, USP/NF
(EUDRAGIT .RTM. L30 D-55) is supplied as a 30% aqueous dispersion.
** removed during processing
Example 4
Sustained Release Formulation (HDR2)
[0157] Intermediate formulation pellets from Example 2 were loaded
into a fluid bed processor with a reduced Wurster column (GPGC-15,
Glatt). The coating dispersion was prepared by mixing
SURELEASE.RTM., talc, USP/NF 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 of 7-9
weight percent of SURELEASE.RTM. solids was achieved. The coated
pellets were then dried at 35-40.degree. C. for 10 minutes before
discharging from the bed. The ingredients are listed by weight
percent in Table 4. The dissolution profile for the HDR2 sustained
release bead is shown in FIG. 8.
TABLE-US-00004 TABLE 4 Ingredients Weight (%) Intermediate
formulation (Example 2) 90.00 Talc, USP/NF 2.00 SURELEASE .RTM.
Clear E-7-19010* 8.00 Water ** Total 100.00 *SURELEASE .RTM. Clear
E-7-19010 is supplied as a 24.5% solids aqueous dispersion **
removed during processing
[0158] A 12.5 mg mixed amphetamine salt sustained release bead (lot
no. B02013) produced according to this Example was administered to
12 subjects aged 18-55 years old and compared to ADDERALL.RTM. 10
mg in a crossover study (Clinical Study 101). Two other prototype
beads were also tested. A parametric (normal theory) general linear
model was applied to the calculation of AUC, Cmax, Tmax and tm for
each of the formulations. AUC and Cmax were also analyzed on a log
scale to assess bioequivalence between test treatments. The results
for the sustained release bead and the reference ADDERALL.RTM. are
shown in Table 5.
TABLE-US-00005 TABLE 5 AUC (0-inf) AUC (0-t) Cmax Tmax (ng hr/mL)
(ng hr/mL) (ng/mL) (hr) d-amphetamine 12.5 mg mixed 367.19* 353.64*
18.67 8.83* amphetamine salt sustained release bead 10 mg 280.59
266.70 18.62 2.17 ADDERALL .RTM. (reference) ratio of test to 1.03
1.05 0.80 reference (90% (0.97-1.11)** (0.98-1.12)** (0.76-0.84)
CI) 1-amphetamine 12.5 mg mixed 125.23* 112.44* 5.64 9.33*
amphetamine salt sustained release bead 10 mg 100.64 87.93 5.53
2.50 ADDERALL .RTM. (reference) ratio of test to 0.99 1.02 0.81
reference (90% (0.91-1.08)** (0.93-1.11)** (0.76-0.87) CI) *p <
0.05 compared to 10 mg ADDERALL .RTM. **90% confidence interval
fell within recommended 0.80-1.25 limits of bioequivalence when
analyzed on logarithmic scale.
[0159] The results of this pharmacokinetic study showed that a
single dose of the sustained release formulation had a Tmax
significantly longer than a single dose of ADDERALL.RTM..
Additionally, the AUCs of the sustained release formulation were
equivalent to that of dose-adjusted ADDERALL.RTM. for both d- and
1-amphetamine.
Example 5
Controlled Release Capsules (SPD465 25 mg/Capsule)
[0160] A controlled release capsule was produced by combining the
immediate release pellets of Example 1, and delayed release pellets
of Example 3 and Example 4. The theoretical milligram/capsule of
components for controlled release capsules, 25 mg/capsule are
listed in Table 5. The theoretical potency of each pellet type was
derived based on the starting ingredients for manufacture. Based on
the actual manufacturing process, along with observation of process
losses, the target potency value was: 170 mg/gram for Example 1
immediate release pellets, 107.1 mg/gram for Example 3 delayed
release pellets, and 100.2 mg/gram for Example 4 delayed release
pellets. The components are listed by theoretical
milligrams/capsule in Table 6.
TABLE-US-00006 TABLE 6 Components Theoretical milligram/capsule
Immediate release pellets of Example 1* 43.86 Delayed release
pellets of Example 3** 69.62 Delayed release pellets of Example
4*** 74.40 Capsule shell 61.00 Total 248.88 *The theoretical fill
weight was calculated based on the theoretical potency of Example 1
immediate release pellets, 190 mg/gram. **The theoretical fill
weight was calculated based on the theoretical potency of Example 3
delayed release pellets, 119.7 mg/gram. ***The theoretical fill
weight was calculated based on the theoretical potency of Example 4
delayed release pellets, 112.0 mg/gram.
[0161] The dissolution profile for SPD465 25 mg (lot no. A03547A)
is shown in FIG. 5.
Example 6
[0162] Controlled Release Capsules (SPD465 37.5 mg/capsule) A
controlled release capsule was produced by combining the immediate
release pellets of Example 1, and the delayed release pellets of
Example 3 and Example 4. The theoretical milligram/capsule of
components for controlled release capsules, 37.5 mg/capsule are
listed in Table 7. The theoretical potency of each pellet type was
derived based on the starting ingredients for manufacture. Based on
the actual manufacturing process, along with observation of process
losses, the target potency value was: 170 mg/gram for Example 1
immediate release pellets, mg/gram for Example 3 delayed release
pellets, and 100.2 mg/gram for Example 4 delayed release pellets.
The components are listed by theoretical milligrams/capsule in
Table 7.
TABLE-US-00007 TABLE 7 Components Theoretical milligram/capsule
Immediate release pellets of Example 1* 65.79 Delayed release
pellets of Example 3** 104.43 Delayed release pellets of Example
4*** 111.6 Capsule shell 81.00 Total 362.82 *The theoretical fill
weight was calculated based on the theoretical potency of Example 1
immediate release pellets, 190 mg/gram. **The theoretical fill
weight was calculated based on the theoretical potency of Example 3
delayed release pellets, 119.7 mg/gram. ***The theoretical fill
weight was calculated based on the theoretical potency of Example 4
delayed release pellets, 112.0 mg/gram.
[0163] The dissolution profile for SPD465 37.5 mg (lot no. A03549B)
is shown in FIG. 6.
Example 7
Controlled Release Capsules (SPD465 50 mg/Capsule)
[0164] A controlled release capsule was produced by combining the
immediate release pellets of Example 1, and delayed release pellets
of Example 3 and Example 4. The theoretical milligram/capsule of
components for controlled release capsules, 50 mg/capsule are
listed in Table 8. The theoretical potency of each pellet type was
derived based on the starting ingredients for manufacture. Based on
the actual manufacturing process, along with observation of process
losses, the target potency value was: 170 mg/gram for Example 1
immediate release pellets, mg/gram for Example 3 delayed release
pellets, and 100.2 mg/gram for Example 4 delayed release pellets.
The components are listed by theoretical milligrams/capsule in
Table 8.
TABLE-US-00008 TABLE 8 Components Theoretical milligram/capsule
Immediate release pellets of Example 1* 87.72 Delayed release
pellets of Example 3** 139.24 Delayed release pellets of Example
4*** 148.80 Capsule shell 96.00 Total 471.76 *The theoretical fill
weight was calculated based on the theoretical potency of Example 1
immediate release pellets, 190 mg/gram. **The theoretical fill
weight was calculated based on the theoretical potency of Example 3
delayed release pellets, 119.7 mg/gram. ***The theoretical fill
weight was calculated based on the theoretical potency of Example 4
delayed release pellets, 112.0 mg/gram.
[0165] The dissolution profile for SPD465 50 mg (lot no. A03536B)
is shown in FIG. 7.
Example 8
A Phase I Pharmacokinetic Study in Healthy Adult Volunteers to
Evaluate the Pharmacokinetic Profile of the 37.5 mg Controlled
Release Composition of Example 6 Relative to 25 mg ADDERALL
XR.RTM.+12.5 mg Mixed Amphetamine Salts IR (Clinical Study 103)
[0166] The objective of this study was to assess the
pharmacokinetics (PK) of the 37.5 mg controlled release composition
of Example 6 compared to a reference treatment of ADDERALL XR.RTM.
25 mg followed by a 12.5 mg dose of the mixed amphetamine salts
immediate-release (IR) formulation disclosed in Example 1
administered 8 hours later.
[0167] This was an open-label, randomized, single-dose, 2-way
crossover, 2-period, phase I study with at least a 7-day washout
between each period. In period 1, subjects were randomized to
receive a single morning dose of one of the two study formulations.
Each subject was crossed over to receive the alternate treatment in
the subsequent period. In Treatment A, subjects received a single
37.5 mg dose of the controlled release composition of Example 6. In
Treatment subjects received a single 25 mg dose of ADDERALL XR.RTM.
followed by a 12.5 mg dose of the mixed amphetamine salts immediate
release formulation of Example 1 administered 8 hours later. See
Table 9.
TABLE-US-00009 TABLE 9 Route of Treatment Composition Dose
Administration A Composition of 1 .times. 37.5 mg Oral Example 6
(Batch no. A03383-002L) B ADDERALL 1 .times. 25 mg ADDERALL Oral XR
.RTM. and the XR .RTM. (Batch no. immediate release A02936B)
followed 8 bead of Example hours later by 1 1 .times. 12.5 mg bead
of Example 1 (Batch no. A03383-003L)
[0168] At screening, each subject provided a medical and medication
history. A 12-lead electrocardiogram (ECG), vital signs, height,
and weight were obtained. Blood and urine samples were collected
for routine clinical laboratory analysis, antibody screening for
Human Immunodeficiency Virus (HIV), Hepatitis B and C, and urine
alcohol and drug screen. A serum pregnancy test was conducted on
all women of child-bearing potential (WOCP) during screening.
[0169] For each treatment period, subjects reported to the clinic
the morning prior to dosing at which time continued eligibility was
confirmed by urine alcohol and drug screen, urine pregnancy test
for WOCP, weight, routine clinical laboratory analysis, 12-lead
ECGs, and vital signs. Subjects also underwent a physical
examination, and a brief medical and medication history was
completed.
[0170] Blood samples for the determination of plasma d- and
l-amphetamine concentrations were collected at specified times in
each treatment period. Vital sign measurements were obtained prior
to dosing and at 2, 4, 8, 12, 24, and 60 hours post-dose. Adverse
events (AEs) and concomitant medications were reported throughout
each treatment period. Twelve-lead ECG measurements were collected
prior to dosing and at 2, 4, 8, 12, 24, and 60 hours post-dose.
[0171] Exit assessments at the end of each treatment period
included a physical examination, 12-lead ECG, routine clinical
laboratory measurements, vital signs, and AE assessment. A serum
pregnancy test for WOCP was performed at study exit/withdrawal. A
follow-up telephone call to assess AEs was made to all subjects
30.+-.2 days after last exposure to study medication.
[0172] Duration of study: 11 days (two treatment periods, each with
four days of confinement and a 7-day washout period between study
medication dosing).
[0173] Pharmacokinetics: d- and l-amphetamine concentrations were
determined in plasma samples collected at the following times: 30
minutes prior to dosing (Time 0) on Day 1, and at 1, 3, 4, 5, 6, 7,
8, 9, 10, 12, 14, 16, 24, 36, 48, and 60 hours post-dose for each
treatment. Plasma d- and l-amphetamine concentrations were measured
with a validated liquid chromatography with tandem mass
spectrometry (LC/MS/MS) method.
Statistical Methods:
[0174] Pharmacokinetic parameters were compared between treatment
groups using an analysis of variance (ANOVA) with sequence, period,
and treatment as fixed effects, and subject nested within sequence
as a random effect. This analysis was performed for the natural log
transformations of maximum plasma concentration (C.sub.max), area
under the plasma concentration-time curve from time 0 to time
infinity (AUC.sub.(0-inf)), and area under the plasma
concentration-time curve from time 0 to last measured time
(AUC.sub.(0-last)) using SAS PROC MIXED.
[0175] For C.sub.max, AUC.sub.(0-inf), and AUC.sub.(0-last),
exponentiated least squares (LS) means for each treatment were
obtained by taking the antilog of the LS means on the log scale.
Ratios of the exponentiated LS means for the test treatment (SPD465
37.5 mg) relative to the reference treatment (25 mg ADDERALL
XR.RTM. followed by 12.5 mg mixed amphetamine salts IR 8 hours
later) and 90% confidence intervals (CIs) of the ratios were
provided. The 90% CIs were obtained by taking the antilog of the
90% CIs for the difference between the LS means on the log
scale.
[0176] C.sub.max, AUC.sub.(0-last), AUC.sub.(0-inf), terminal
half-life (t1/2), terminal phase rate constant (.lamda..sub.z), and
time of maximum plasma concentration (t.sub.max) were summarized
descriptively for each treatment.
[0177] Adverse events were coded using the Medical Dictionary for
Regulatory Activities (MedDRA) version 7.1 adverse event
dictionary. The frequency of treatment-emergent adverse events
(TEAE) was tabulated by body system and preferred term for each
treatment. AEs were further summarized by severity, relationship to
study drug, gender, and ethnicity. AEs leading to study withdrawal
were summarized separately by body system, preferred term, and
treatment group.
[0178] Clinical laboratory evaluations were summarized by treatment
and visit. Hematology and biochemistry were summarized using
descriptive statistics; discrete urinalysis measurements were
summarized using frequencies and percents and continuous urinalysis
measurements were summarized using descriptive statistics.
Laboratory data outside the normal range was flagged in the subject
data listings.
[0179] Vital signs, including pulse, systolic and diastolic BP, and
respiration rate, were summarized by treatment for each measured
time point using descriptive statistics. Change from baseline was
also calculated and summarized for each post baseline time
point.
Results:
[0180] Subject Demographics:
[0181] The overall gender distribution was 60% (12/20) females and
40% (8/20) males. The overall racial distribution was 90% (18/20)
White and 10% (2/20) Black/African-American. The age of the study
subjects ranged from 21-50 years with an overall mean age (SD) of
30.0 years (8.83). Subjects weighed between 61 kg and 97 kg with a
mean weight (SD) of 73.8 kg (10.15), and height ranged between 158
cm-188 cm with a mean height (SD) of 172.6 cm (8.05). Body Mass
Index ranged between 20.1 kg/m.sup.2-29.2 kg/m.sup.2 with a mean
BMI (SD) of 24.75 (2.267).
Pharmacokinetic Results:
[0182] FIG. 9 shows the d-amphetamine plasma concentration profile
of SPD465 37.5 mg compared to ADDERALL XR.RTM. (25 mg) followed by
immediate release mixed amphetamine salts (12.5 mg) eight hours
later. Exposure to d-amphetamine, as described by C.sub.max and AUC
values, was comparable following Treatment A and Treatment B. The
90% Cl of the test-to-reference ratios were within the
bioequivalence range of 80%-125%.
[0183] FIG. 10 shows the l-amphetamine plasma concentration profile
of SPD465 37.5 mg compared to ADDERALL XR.RTM. (25 mg) followed by
immediate release mixed amphetamine salts (12.5 mg) eight hours
later. C.sub.max and AUC values of l-amphetamine following a dose
of Treatment A were similar to those following Treatment B; 90% Cl
of the test-to-reference ratios were within the bioequivalence
range of 80%-125%.
[0184] The elimination half lives of d- and l-amphetamine were
similar for both treatments. See Table 10.
TABLE-US-00010 TABLE 10 Plasma Pharmacokinetic Parameters for d-
and l-Amphetamine After a Single Dose of 37.5 mg SPD465 (Treatment
A) or 25 mg ADDERALL XR .RTM. + 12.5 mg Mixed Amphetamine Salts
(Treatment B) Exponentiated Treatment A Treatment B LS Mean Mean LS
Mean LS Ratio % Parameters n (.+-.SD) Mean n (.+-.SD) Mean (A)/(B)
90% CI d-Amphetamine C.sub.max 20 50.3 49.7 19 49.3 49.2 101.0
(96.9, 105.3) (ng/mL) (7.5) (7.4) AUC.sub.(0-last) 20 1058.0 1042.4
19 997.9 1000.8 104.2 (100.2, 108.3) (ng hr/mL) (184.5) (172.9)
AUC.sub.(0-inf) 20 1084.9 1067.8 19 1019.5 1022.5 104.4 (100.3,
108.7) (ng hr/mL) (196.2) (181.3) T.sub.max (hr) 20 8.2 19 9.7
(2.0) (2.1) l-Amphetamine C.sub.max 20 14.7 14.6 19 16.0 16.0 90.9
(87.5, 94.4) (ng/mL) (2.2) (2.3) AUC.sub.(0-last) 20 353.5 347.6 19
364.1 364.6 95.3 (91.0, 99.8) (ng hr/mL) (66.0) (66.5)
AUC.sub.(0-inf) 20 372.8 365.9 19 382.3 383.9 95.3 (91.2, 99.6) (ng
hr/mL) (73.5) (69.0) T.sub.max (hr) 20 8.4 19 10.7 (2.1) (1.3) LS =
Least squares
Conclusions:
[0185] Treatment A and Treatment B were bioequivalent with respect
to C.sub.max and AUC of d- and l-amphetamine. All treatments were
well tolerated and all reported AEs were expected.
Example 9
A Phase I Study to Evaluate the Pharmacokinetic Profile of SPD 465
50 mg Under Fed, Fasted, and Sprinkled Conditions in Healthy Adult
Volunteers (Clinical Study 105)
[0186] This was an open-label, randomized, single-dose, 3-way
crossover, 3-period study with a minimum 7-day washout between each
study drug dosing. Sixteen healthy male and female subjects between
the ages of 18 and 55 participated in the study. This study was
designed to evaluate (1) the effect of a high fat meal on the PK of
SPD465 50 mg compared to a reference treatment and (2) the effect
of a SPD465 50 mg capsule sprinkled on applesauce compared to a
reference treatment. The reference treatment was a 50 mg dose of
SPD465 following an at least hour fast. See Table 11. The primary
objective of this study was to assess the effect of a high fat meal
on the bioavailability of SPD465 relative to the fasted state.
TABLE-US-00011 TABLE 11 Treatment Study Drug Dosage Treatment A
SPD465 1 .times. 50 mg capsule after (reference) (batch no.
A03445-001L) an at least 10 hour fast Treatment B SPD465 1 .times.
50 mg capsule (batch no. A03445-001L) following a high fat meal
Treatment C SPD465 1 .times. 50 mg capsule (batch no. A03445-001L)
sprinkled on 1 tablespoon of applesauce
[0187] The study included three single-dose treatment periods
separated by a minimum 7-day washout period between study drug
dosing. On study day 1 of each period, according to the
randomization schedule, the subjects were administered a single
dose of SPD465 50 mg following an at least 10-hour fast, SPD465 50
mg following a standard high fat meal or the contents of a SPD465
50 mg capsule sprinkled on applesauce.
[0188] Blood samples for the determination of plasma d- and
l-amphetamine concentrations were collected 30 minutes prior to
drug administration (0 hour) and at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
12, 14, 16, 24, 36, 48, and 60 hours after dosing in each treatment
period.
[0189] Results:
[0190] d-amphetamine d-Amphetamine plasma levels as described by
C.sub.max, AUC.sub.(0-last), and AUC.sub.(0-inf) were highest in
fasted subjects, slightly lower in subjects receiving SPD465
sprinkled on applesauce, and lowest in subjects pretreated with a
high-fat meal. See Tables 12 and 13. The 90% Cl of the
test-to-reference ratios, with fasted as the reference treatment,
were within the typically acceptable bioequivalence range of 80% to
125%, which indicates that the there were no significant
differences across the unfed/fed conditions. The CIs on the ratios
between subjects receiving the high-fat meal and fasted subjects
were less than 100%.
[0191] The median time to maximum d-amphetamine plasma
concentrations (T.sub.max) in fasted subjects and those who
received SPD465 sprinkled on applesauce was 7 and 7.5 hours,
respectively. The T.sub.max in subjects who received SPD465
following a high-fat meal was delayed approximately 4 to 5 hours
with a median value of 12 hours.
TABLE-US-00012 TABLE 12 d-Amphetamine Plasma Pharmacokinetic
Parameters Following a Single Dose Administration of 50 mg SPD465
Fasted (A) High Fat Meal (B) Sprinkled (C) Parameter n = 14 n = 16
n = 16 C.sub.max (ng/ml) 72.3 60.0 67.3 Mean (SD) (13.72) (7.09)
(7.69) T.sub.max (hr) 7.0 12.0 7.5 Median (Min, Max) (6.0, 10.0)
(8.0, 14.0) (5.0, 9.0) AUC.sub.(0-last) (hr * ng/ml) 1531.9 1382.6
1450.8 Mean (SD) (292.36) (289.85) (253.28) AUC.sub.(0-inf) (hr *
ng/ml) 1589.5 1433.8 1497.9 Mean (SD) (359.98) (339.50) (300.83)
.lamda.z (1/hr) 0.07 0.07 0.07 Mean (SD) (0.014) (0.011) (0.012)
t.sub.1/2 (hr) 10.9 10.5 10.6 Mean (SD) (2.60) (2.11) (2.22)
TABLE-US-00013 TABLE 13 Statistical Analysis Results of Plasma
d-Amphetamine Following a Single Dose Administration of 50 mg
SPD465 Exponentiated LS Means High- Fat Ratio Fasted Meal Sprinkled
of LS (A) (B) (C) Means 90% CI Parameter n = 14 n = 16 n = 16 B/A
C/A B/A C/A AUC.sub.(0-inf) 1528.3 1392.5 1463.7 91.1 95.8 86.7,
91.1, (hr * ng/mL) 95.8 100.6 AUC.sub.(0-last) 1484.2 1350.3 1424.5
91.0 96.0 86.7, 91.5, (hr * ng/mL) 95.5 100.7 C.sub.max 69.6 59.4
66.7 85.3 95.8 80.4, 90.3, 90.5 101.6 LS = Least squares
[0192] 1-amphetamine
[0193] Amphetamine plasma levels as described by C.sub.max,
AUC.sub.(0-last), and AUC.sub.(0-inf) were highest in fasted
subjects, slightly lower in subjects receiving SPD465 sprinkled on
apple sauce, and lowest in subjects pretreated with a high-fat
meal. See Tables 14 and 15. The 90% CI of the test-to-reference
ratios, with fasted as the reference treatment, were within the
typically acceptable bioequivalence range of 80% to 125%, which
indicates that the there were no significant differences across the
unfed/fed conditions. The CIs on the ratios between subjects
receiving the high-fat meal and fasted subjects were less than
100%.
[0194] The median time to maximum 1-amphetamine plasma
concentrations (T.sub.max) in fasted subjects and those who
received SPD465 sprinkled on applesauce was 7.5 and 8 hours,
respectively. The T.sub.max in subjects who received SPD465
following a high-fat meal was delayed approximately 4.5 hours with
a median value of 12 hours.
TABLE-US-00014 TABLE 14 1-Amphetamine Plasma Pharmacokinetic
Parameters Following a Single Dose Administration of 50 mg SPD465
Fasted (A) High Fat Meal (B) Sprinkled (C) Parameter n = 14 n = 16
n = 16 C.sub.max (ng/ml) 21.1 17.6 20.0 Mean (SD) (3.74) (2.21)
(2.50) T.sub.max (hr) 7.5 12.0 8.0 Median (Min, Max) (6.0, 12.0)
(8.0, 14.0) (5.0, 12.0) AUC.sub.(0-last) (hr * ng/ml) 506.9 448.3
479.2 Mean (SD) (107.92) (107.79) (100.83) AUC.sub.(0-inf) (hr *
ng/ml) 545.2 481.7 511.4 Mean (SD) (147.92) (138.43) (127.13)
.lamda.z (1/hr) 0.05 0.06 0.06 Mean (SD) (0.014) (0.013) (0.011)
t.sub.1/2 (hr) 13.6 12.8 13.0 Mean (SD) (3.70) (3.30) (3.22)
TABLE-US-00015 TABLE 15 Statistical Analysis Results of Plasma
1-Amphetamine Following a Single Dose Administration of 50 mg
SPD465 Exponentiated LS Means High- Fat Ratio Fasted Meal Sprinkled
of LS (A) (B) (C) Means 90% CI Parameter n = 14 n = 16 n = 16 B/A
C/A B/A C/A AUC.sub.(O-inf) 522.3 463.4 495.0 88.7 94.8 83.9, 89.6,
(hr * ng/mL) 93.9 100.3 AUC.sub.(O-last) 492.2 436.1 468.1 88.6
95.1 83.8, 90.0, (hr * ng/mL) 93.7 100.5 C.sub.max 20.4 17.4 19.8
85.2 96.9 80.2, 91.2, (ng/mL) 90.6 103.0 LS = Least squares
[0195] Conclusion
[0196] There were no statistically significant differences in
plasma d- or 1-amphetamine levels when SPD465 50 mg was
administered to subjects in a fasted state, following a high-fat
meal, or when the SPD465 was administered with applesauce. The
pharmacokinetic findings indicate that in the presence of a
high-fat meal, the rate of absorption of d- and 1-amphetamines is
decreased but the extent of absorption is unaffected. Thus, these
results show that SPD465 administered with food was bioequivalent
to SPD465 administered without food.
Example 10
[0197] An open-label, incomplete block randomization, three-period,
four treatment, dose escalating study of the pharmacokinetics of
SPD 465 administered at steady state in healthy adult volunteers
(Clinical Study 110)
[0198] The primary objective of this study was to determine the
pharmacokinetics of SPD465 following repeat dose administration
over a range of doses from 12.5 mg to 75 mg. All 18 subjects
received SPD465 at a dose of 12.5 mg once daily for 7 days in
Period 1. The dose was increased so that about half the subjects
received 25 mg and the others received 50 mg once daily for the
next 7 days (Period 2). In Period 3, all subjects were increased to
75 mg once daily for 7 days following Period 2.
[0199] Blood samples were collected from each subject on days 1, 5,
6 and 7 of each Period for the determination of d- and
1-amphetamine concentrations. Blood and urine samples were
collected on day 7 of Period 3 for metabolite identification.
[0200] Subjects were administered the SPD465 dosages described in
Table 16.
TABLE-US-00016 TABLE 16 Mode of Dose level administration Batch
Number 12.5 mg (Period 1) 1 .times. 12.5 mg capsule A08763A 25 mg
(Period 2) 1 .times. 25 mg capsule A08767A 50 mg (Period 2) 1
.times. 50 mg capsule A08762A 75 mg (Period 3) 2 .times. 37.5 mg
capsules A08761A
[0201] The calculated pharmacokinetic parameters included:
[0202] Cmax: maximum plasma concentration
[0203] Tmax: time of maximum plasma concentration
[0204] AUC.sub.0-24: area under the plasma concentration-time curve
from time 0 to time 24 hours
[0205] Cmin: minimum plasma concentration
[0206] CL/F: apparent oral clearance
[0207] CL/F/Wt: weight adjusted apparent oral clearance
[0208] R: accumulation ratio
[0209] AUC.sub.o-24/AUC.sub.o-24 12.5 mg: area under the plasma
concentration-time curve from time 0 to time 24 hours on Day 7 at
25 mg, 50 mg, and 75 mg relative to the AUC.sub.0-24 on Day 7 at
12.5 mg.
[0210] Pharmacokinetic parameters were calculated by
non-compartmental techniques using WinNonlin.RTM. Professional
version 4.1. All calculations were based on actual sampling
times.
[0211] The pharmacokinetic parameters were determined from plasma
concentration-time data measured using a validated liquid
chromatography with tandem mass spectrometry (LC/MS/MS) method.
[0212] The pharmacokinetic results are graphically illustrated in
FIGS. 11-12 and 15-16 shown in Table 17.
TABLE-US-00017 TABLE 17 Single dose Multiple dose (Day 1) (Day 7)
12.5 mg 12.5 mg 25 mg 50 mg 75 mg Parameter Statistic (N = 18)* (N
= 18)* (N = 9) (N = 8) (N = 17)* d-amphetamine Cmax Mean 17.0 22.4
48.5 94.2 153.5 (ng/mL) (SD) (2.9) (5.8) (4.6) (32.1) (24.6) Tmax
Median 8.0 6.0 8.0 6.0 8.0 (hr) (min., max.) (6.0, 9.0) (2.0, 10.1)
(6.0, 9.0) (4.0, 12.1) (6.0, 12.0) AUC.sub.o-24 Mean 248.5 351.3
742.0 1499.7 2526.2 (hr * ng/mL) (SD) (45.3) (87.5) (77.5) (504.9)
(495.1) Cmin Mean -- 7.6 17.2 38.2 66.8 (ng/mL) (SD) (2.9) (5.6)
(10.5) (23.8) CL/F Mean 39.0 29.5 25.5 29.5 22.9 (L/hr) (SD) (7.2)
(13.5) (2.8) (16.6) (3.7) CL/F/Wt Mean 0.51 0.40 0.35 0.40 0.31
(L/hr/kg) (SD) (0.09) (0.18) (0.05) (0.23) (0.06) R Mean -- -- 1.4
-- -- (SD) (0.30) AUC.sub.o-24/ Mean -- -- 2.2 4.2 8.0 AUC.sub.q-24
(SD) (0.4) (0.6) (4.0) 12.5 mg 1-amphetamine Cmax Mean 5.2 7.6 15.9
30.2 52.0 (ng/ml) (SD) (0.9) (1.8) (1.6) (8.7) (9.6) Tmax Median
8.0 8.0 8.0 9.0 8.0 (hr) (min., (6.0, 10.0) (2.0, 10.1) (4.0, 9.0)
(4.0, 12.1) (6.0, 12.0) max.) AUC.sub.o-24 Mean 81.3 126.4 261.5
514.7 899.3 (hr * ng/mL) (SD) (14.8) (29.9) (31.8) (148.5) (205.9)
Cmin Mean -- 3.0 6.6 14.8 26.8 (ng/mL) (SD) (1.0) (2.1) (4.3)
(10.1) CL/F Mean 39.7 26.8 24.2 26.6 21.6 (L/hr) (SD) (7.1) (10.2)
(3.1) (9.7) (3.9) CL/F/Wt Mean 0.52 0.36 0.34 0.36 0.30 (L/hr/kg)
(SD) (0.08) (0.14) (0.05) (0.14) (0.07) R Mean -- 1.6 -- -- -- (SD)
(0.3) AUC.sub.o-24/ Mean -- -- 2.2 4.1 7.8 AUC.sub.o-24 (SD) (0.4)
(0.8) (3.4) 12.5 mg *N indicates the number of subjects in the
safety population who took drug. Due to early termination or
missing data, some subjects may not be contributing to the results
at all time points.
[0213] The dose proportionality of the Cmax and AUC.sub.0-24 of
SPD465 d- and 1-amphetamine were analyzed using the power model and
graphically by plotting individual subject and mean Day 7 Cmax and
AUC.sub.0-24 against dose with the estimated power model regression
line. See FIGS. 13-14 and 17-18.
[0214] These results showed that repeated doses of SPD465 led to
the accumulation of d- and 1-amphetamine in plasma consistent with
the half-life and dosing of the compound. Further, the Cmax and
AUC.sub.0-24 increased linearly with increasing doses of SPD465.
Because SPD465 includes an immediate release bead, a delayed pulsed
release bead, and a sustained release bead in a 1:1:1 ratio, the
Cmax and AUC.sub.0-24 for the sustained release bead alone also
increases linearly with increasing doses of SPD465 (e.g., the Cmax
for 25 mg of the sustained release bead is twice the Cmax for 12.5
mg of the sustained release bead, and the Cmax for 37.5 mg of the
sustained release bead is 3.times. the Cmax for 12.5 mg of the
sustained release bead).
[0215] The disclosures of patents, patent applications,
publications, product descriptions, and protocols cited throughout
this application are incorporated by reference in their
entireties.
[0216] It is to be understood that the scope of the present
invention is not to be limited to the specific embodiments
described above. The invention may be practiced other than as
particularly described and still be within the scope of the
accompanying claims.
* * * * *