U.S. patent application number 13/947861 was filed with the patent office on 2014-03-13 for dosage forms for oral administration and methods of treatment using the same.
This patent application is currently assigned to NEOS THERAPEUTICS, LP. The applicant listed for this patent is NEOS THERAPEUTICS, LP. Invention is credited to Russell MCMAHEN, Mark TENGLER.
Application Number | 20140072645 13/947861 |
Document ID | / |
Family ID | 47424553 |
Filed Date | 2014-03-13 |
United States Patent
Application |
20140072645 |
Kind Code |
A1 |
TENGLER; Mark ; et
al. |
March 13, 2014 |
DOSAGE FORMS FOR ORAL ADMINISTRATION AND METHODS OF TREATMENT USING
THE SAME
Abstract
The invention relates to dosage forms that provide prolonged
therapy. In particular, the invention relates to dosage forms
including various pluralities of drug-containing resin particles.
The invention also relates to methods of making these dosage forms
and methods of treating using these dosage forms.
Inventors: |
TENGLER; Mark; (Colleyville,
TX) ; MCMAHEN; Russell; (Flower Mound, TX) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NEOS THERAPEUTICS, LP |
Grand Prairie |
TX |
US |
|
|
Assignee: |
NEOS THERAPEUTICS, LP
Grand Prairie
TX
|
Family ID: |
47424553 |
Appl. No.: |
13/947861 |
Filed: |
July 22, 2013 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
13844510 |
Mar 15, 2013 |
|
|
|
13947861 |
|
|
|
|
PCT/US2012/044698 |
Jun 28, 2012 |
|
|
|
13844510 |
|
|
|
|
61502189 |
Jun 28, 2011 |
|
|
|
61528554 |
Aug 29, 2011 |
|
|
|
Current U.S.
Class: |
424/495 ;
424/490; 424/494; 424/497; 424/78.1 |
Current CPC
Class: |
A61K 9/5084 20130101;
A61K 31/137 20130101; A61K 31/4458 20130101; A61P 3/04 20180101;
A61K 9/146 20130101; A61K 9/5026 20130101; A61K 9/0056 20130101;
A61K 47/585 20170801; A61K 9/5042 20130101; A61K 9/5047 20130101;
A61K 9/50 20130101; A61K 47/58 20170801; A61P 25/00 20180101; A61K
9/14 20130101; C12N 9/2402 20130101 |
Class at
Publication: |
424/495 ;
424/78.1; 424/490; 424/497; 424/494 |
International
Class: |
A61K 47/48 20060101
A61K047/48; A61K 31/4458 20060101 A61K031/4458 |
Claims
1. A method for treating Attention-Deficit Disorder or
Attention-Deficit Hyperactivity Disorder comprising administering
to a subject in need thereof an effective amount of a
pharmaceutical composition comprising an ADHD effective agent
complexed with ion-exchange resin particles to form drug-resin
particles, wherein said ADHD effective agent is methylphenidate,
and wherein said composition comprises a first plurality of
drug-resin particles that provide for an immediate release of
methylphenidate and a second plurality of drug-resin particles that
provide for a delayed release of methylphenidate.
2. The method of claim 1, wherein the second plurality of
drug-resin particles comprises a triggered-release coating
triggered by a pH change.
3. The method of claim 2, wherein the triggered-release coating is
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/acrylic acid ethyl esters, or mixtures thereof.
4. The method of claim 2, wherein said drug-resin particles coated
with a triggered-release coating further comprise a diffusion
barrier coating.
5. The method of claim 4, wherein the diffusion barrier coating is
a water insoluble, water permeable membrane.
6. The method of claim 5, wherein the diffusion barrier coating
contains polyvinylpyrrolidone, polyvinylacetate, polyvinylalcohol
or mixtures thereof.
7. The method of claim 5, wherein the water insoluble, water
permeable membrane is ethylcellulose.
8. The method of claim 4, wherein the triggered-release coating
covers the diffusion barrier coating.
9. The method of claim 7, wherein the diffusion barrier coating is
ethylcellulose.
10. The method of claim 1, wherein the resin particles are strong
acidic cation exchange resins, selected from the group consisting
of polistirex, polacrilex, cholestyramine, polacrilin or mixtures
thereof.
11. The method of claim 1, wherein the composition comprises
20%-30% of the first plurality of drug-resin particles and 70-80%
of the second plurality of drug-resin particles.
12. The method of claim 10, wherein the composition comprises about
25% of the first plurality of drug-resin particles and about 75% of
the second plurality of drug-resin particles.
13. The method of claim 1, wherein the composition is a liquid
suspension, chewable composition, or an orally disintegrating
tablet composition.
14. The method of claim 1, wherein the amount of drug delivered to
said subject is between about 2 mg/24 hours to about 60 mg/24
hours.
15. The method of claim 1, wherein the effective amount is 0.5
mg/kg/day to 1.5 mg/kg/day.
16. The method of claim 1, wherein said pharmaceutical composition
is sufficient to maintain an effective level of ADHD effective
agent in the patient over the course of at least 8 hours without
further administration of ADHD effective agent.
17. The method of claim 1, wherein 30-33% of the ADHD effective
agent is released within the first 30 minutes after the drug-resin
particles are introduced into an in vitro dissolution assay, 34-42%
of the agent is released within 2 hours, 40-80% of the agent is
released within 4 hours, and 80-100% of the agent is released
within 24 hours, wherein the conditions of the dissolution assay
are an initial dissolution medium of 0.1 N HCL, and after 2 hours,
the medium is adjusted to a pH of about 6.8; and the dissolution
assay is performed using a USP Apparatus 2.
18. The method of claim 1, wherein the composition has an in vivo
serum profile that is statistically similar to at least one profile
selected from FIGS. 27-28.
19. The method of claim 1, wherein the in vivo serum profile of the
composition is statistically similar to the in vivo serum profile
of a composition with the profiles of FIG. 24.
20. (canceled)
21. The method of claim 1, wherein the amount of ADHD effective
agent is equivalent to a 10 mg, 20 mg, 30 mg, 40 mg, 50 mg or 60 mg
reference composition without resin particles, said reference
composition having the profiles of FIG. 24.
22. The method of claim 1, wherein administration of the
composition to a human produces a mean plasma concentration profile
in human patients which has one or more parameters selected from
the group consisting of AUC.sub.0-3, AUC.sub.0-5, AUC.sub.0-Tmax,
AUC.sub.5-12, AUC.sub.5-24, AUC.sub.Tmax-24, AUC.sub.Tmas-12,
AUC.sub.5-t, AUC.sub.Tmax-t, AUC.sub.0-24, and AUC.sub.0-.infin. of
methylphenidate, which is substantially similar to those parameters
of a composition with the profiles of FIG. 24.
23. The method of claim 1, wherein said composition is an orally
disintegrating tablet and is effective to provide a mean plasma
concentration profile in human ADHD patients which has an
AUC.sub.0-3 of 20.53 ng hr/mL -20%/+25% and a C.sub.max of 20.17
ng/mL -20%/+25% for d-methylphenidate, an AUC.sub.0-3 of 0.62 ng
hr/mL -20%/+25% and a C.sub.max of 0.44 ng/mL -20%/+25% for
l-methylphenidate, and/or an AUC.sub.-3 of 21.29 ng hr/mL -20%/+25%
and a C.sub.max of 20.60 ng/mL -20%/+25% for total methylphenidate,
for a 60 mg total dose, or respective AUC and C.sub.max values
directly proportional thereto for a total dose other than 60
mg.
24. The method of claim 1, wherein said composition is an orally
disintegrating product and is effective to provide a mean plasma
concentration profile in human ADHD patients which has an
AUC.sub.0-5 of 50.16 ng hr/mL -20%/+25% and a C.sub.max of 20.17
ng/mL -20%/+25% for d-methylphenidate, an AUC.sub.0-5 of 1.07 ng
hr/mL -20%/+25% and a C.sub.max of 0.44 ng/mL -20%/+25% for
l-methylphenidate, and/or an AUC.sub.0-5 of 51.43 ng hr/mL
-20%/+25% and a C.sub.max of 20.60 ng/mL -20%/+25% for total
methylphenidate, for a 60 mg total dose, or respective AUC and
C.sub.max values directly proportional thereto for a total dose
other than 60 mg.
25. The method of claim 1, wherein said composition is an orally
disintegrating product and is effective to provide a mean plasma
concentration profile in human ADHD patients which has an
AUC.sub.5-24 of 103.84 ng hr/mL -20%/+25% and a C.sub.max of 20.17
ng/mL -20%/+25% for d-methylphenidate, an AUC.sub.5-24 of 0.96 ng
hr/mL -20%/+25% and a C.sub.max of 0.44 ng/mL -20%/+25% for
l-methylphenidate, and/or an AUC.sub.5-24 of 105.07 ng hr/mL
-20%/+25% and a C.sub.max of 20.60 ng/mL -20%/+25% for total
methylphenidate, for a 60 mg total dose, or respective AUC and
C.sub.max values directly proportional thereto for a total dose
other than 60 mg.
26. The method of claim 1, wherein said composition is an orally
disintegrating product and is effective to provide a mean plasma
concentration profile in human ADHD patients which has an
AUC.sub.0-24 of 156.72 ng hr/mL -20%/+25% and a C.sub.max of 20.17
ng/mL -20%/+25% for d-methylphenidate, an AUC.sub.0-24 of 2.19 ng
hr/mL -20%/+25% and a C.sub.max of 0.44 ng/mL -20%/+25% for
l-methylphenidate, and/or an AUC.sub.0-24 of 159.25 ng hr/mL
-20%/+25% and a C.sub.max of 20.60 ng/mL -20%/+25% for total
methylphenidate, for a 60 mg total dose, or respective AUC and
C.sub.max values directly proportional thereto for a total dose
other than 60 mg.
27. The method of claim 1, wherein said composition, when
containing about a total dose of 60 mg, will produce in a human, a
mean plasma concentration versus time curve (ng/ml versus hours)
having an area under the curve (AUC.sub.0-.infin.) of about 160 to
about 180 for total methylphenidate.
28. The method of claim 1, wherein one or more in vivo
pharmacokinetic parameters of the composition selected from the
group consisting of C.sub.max, AUC.sub.0-3, AUC.sub.0-5,
AUC.sub.0-Tmax, AUC.sub.5-12, AUC.sub.5-24, AUC.sub.Tmax-24,
AUC.sub.Tmax-12, AUC.sub.5-t, AUC.sub.Tmax-t, AUC.sub.0-24, and
AUC.sub.0-.infin. have a 90% confidence interval with upper and
lower bounds within a range from 90%-115% of the value of the same
parameter(s) for a bioequivalent reference composition.
29. A method according to claim 1 wherein said pharmaceutical
composition is administered to a subject substantially
contemporaneously with ethanol and wherein the subject is exposed
to a reduced amount of methylphenidate compared to when a reference
composition without resin particles, said reference composition
having the profiles of FIG. 24, is administered to a subject
substantially contemporaneously with ethanol.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of Ser. No. 13/844,510
filed Mar. 15, 2013, which is a continuation-in-part of
International Application No. PCT/US2012/044698, filed Jun. 28,
2012, which claims priority to U.S. Provisional Application No.
61/502,189, filed Jun. 28, 2011, and U.S. Provisional Application
No. 61/528,554, filed Aug. 29, 2011, the disclosures of each of
which are hereby incorporated by reference in their entireties.
BACKGROUND OF THE INVENTION
[0002] (a) Field of the Invention
[0003] The invention relates to Attention Deficit Hyperactivity
Disorder (ADHD) effective agent dosage forms that both facilitate
oral ingestion and provide an effective treatment over a prolonged
period of time. In particular, the invention provides for
pharmaceutical compositions having a first and second plurality of
drug-resin particles, where the first plurality of drug-resin
particles does not have a delayed release coating and the second
plurality of drug-resin particles does have a delayed release
coating, where the drug is an ADHD effective agent and the
composition achieves an escalating in vivo plasma concentration of
the ADHD effective agent.
[0004] (b) Description of the Related Art
[0005] Many drug therapies use immediate-release oral dosage forms
administered at spaced intervals to provide and maintain a desired
therapeutic effect over a prolonged therapy period. For example,
drugs used in treating Attention Deficit Disorder (ADD) and ADHD
such as ADDERALL.RTM. and RITALIN.RTM. are administered two or
three times a day.
[0006] For various reasons, subjects often experience difficulty
complying with this administration schedule. In particular, because
ADD and ADHD are commonly diagnosed in children, the dosage regimen
generally requires that at least one dose is administered during
the school day. Children are typically not permitted to
self-administer the drug at school. As such, authorized school
personnel generally take on the responsibility for administering
the drug to children during the school day. However, this approach
raises issues of medical privacy and potential stigmatizing of the
child by peers. In addition, the compliance issue becomes further
complicated as transportation, storage and supply of the drug
typically must be documented and/or monitored, and the schedules of
the different parties involved, i.e., the child, the educators and
the authorized school personnel, must be coordinated and
accommodated. The unfortunate result is that doses may be given
late or missed altogether resulting in decreased efficacy of the
therapy.
[0007] To avoid administering multiple doses during the day,
once-a-day sustained and extended release medications have been
developed. For example, ADDERALL XR.RTM., a mixed amphetamine salts
medication, is administered once-a-day for the treatment of ADD and
ADHD. To achieve extended release, ADDERALL XR requires a mixture
of four amphetamine salts: dextroamphetamine sulfate,
dextroamphetamine saccharate, amphetamine aspartate, and
amphetamine sulfate. U.S. Pat. Nos. 6,322,819 and 6,605,300, which
disclose ADDERALL XR, are hereby incorporated by reference in their
entirety. U.S. Pat. No. 6,913,768, which is hereby incorporated by
reference, also discloses a four amphetamine salt composition.
[0008] METADATE CD.RTM. is another once-a-day ADHD treatment. This
formulation comprises methylphenidate hydrochloride and achieves an
extended-release profile through its make up of 30% immediate
release beads and 70% extended release beads.
[0009] Prior art ADHD compositions such as ADDERALL XR and METADATE
CD are only available in solid dosage forms. Many people,
especially children, have difficulty swallowing standard solid
dosage forms. Accordingly, there is a need in the art to develop
easily ingested, once-daily oral compositions that provide
effective, prolonged treatment.
[0010] U.S. Pat. No. 2,990,332 to Keating discloses adsorbing
amphetamines onto a sulphonic acid cation exchange resin from which
the drug is slowly and uniformly released by gastric and intestinal
juices. In particular, this patent discloses a homogeneous
pharmaceutical drug compound which will immediately release its
drug continuously over a long period of time without the necessity
of complicated and expensive enteric coating procedures. The
amphetamine-resin complex of this patent is such that not more than
approximately 50% of the amphetamine is released in one hour by
elution with simulated gastric juice and at least approximately 10%
in three hours by such elution.
[0011] Hinsvark, et al. (Journal of Phamacokinetics and
Biophaaceutics, 1(4):319-328, 1973) reports the comparison of oral
bioavailability and pharmacokinetics of between a resin-bound form
of amphetamine and the soluble hydrochloride salt. The efficiency
of absorption was the same for resinate as for soluble salt, but
the speed of absorption was about three times slower for the
resinate and blood levels after the resinate reached a lower, later
and flatter peak. Without any coating, the resin-bound amphetamine
produced more sustained blood levels.
[0012] Although, as described by Keating and Hinsvark, amphetamine
adsorbed on ion exchange resin was released more slowly into
gastric and/or intestinal juices than soluble salts, the
pharmacokinetic profile is not comparable to ADDERALL XR or
METADATE CD. As such, there is still a need for a once-a-day
formulation that is easily ingested.
SUMMARY OF VARIOUS EMBODIMENTS OF THE INVENTION
[0013] The invention provides pharmaceutical compositions
comprising drug-resin particles comprising at least one ADHD
effective agent (e.g., amphetamine, methylphenidate), methods of
making such compositions, and methods of treatment using these
compositions. In particular, the invention provides for easily
ingested, once-daily oral compositions that provide effective,
prolonged treatment.
[0014] The invention provides various advantage over prior art
compositions and methods. For example, the invention provides for
liquid drug suspensions, chewable compositions, and orally
disintegrating compositions--compositions favored by individuals
who have difficulty swallowing conventional solid dosage forms
(e.g., children or dysphagic individuals). Moreover, the
compositions comprise ion-exchange resins and thus have enhanced
taste masking properties as compared to traditional drug
formulations. The use of multiple coated resin beads for the
controlled release portions of the compositions reduces the risk of
dose dumping when the composition is chewed or crushed, because
there is no single point where failure of the controlled release
mechanism can occur.
[0015] In some embodiments, the compositions of the invention are
advantageous as compared to currently available amphetamine
compositions. For example, the compositions minimize the amount of
sulfates, which reduces the likelihood of formation alkyl
sulfonates--toxic compounds that the FDA recommends limiting or
excluding from drug formulations. Moreover, unlike ADDERALL XR,
various compositions of the invention do not require four
amphetamine salts. As such, the compositions streamline the supply
chain by reducing the number of distinct components required, i.e.,
simplifies processing and handling.
[0016] Also, in the presence of ethanol, the compositions have an
improved exposure level of amphetamines and methylphenidate
compared to ADDERALL XR and METADATE CD, respectively, i.e., the
invention reduces dose dumping when the composition and ethanol are
ingested by a subject. For example, the inventors have shown that
in the presence of varying concentrations of alcohol (e.g., 4%,
20%, and 40% ethanol) did not significantly alter the rate and
extent of absorption of a controlled-release ODT amphetamine
composition described herein.
[0017] Also in the presence of food, the liquid suspension
amphetamine compositions have an increased exposure of amphetamines
compared to fed ADDERALL XR during the first four hours or up to
the T.sub.max, i.e., these compositions have less food effect than
ADDERALL XR.
[0018] In particular, the invention relates to pharmaceutical
compositions comprising a plurality of drug-resin particles,
wherein the drug in said drug-resin particles comprises at least
one ADHD effective agent. For example, in one embodiment, the
pharmaceutical composition comprises (a) at least one
pharmaceutically active ADHD effective agent drug-resin complex
providing for immediate release; and (b) at least one
pharmaceutically active ADHD effective agent drug-resin complex
covered with a delayed release coating, wherein said component (a)
provides for an immediate release of ADHD effective agent from the
drug resin complex to provide a first blood level of ADHD effective
agent and component (b) provides a delayed release of ADHD
effective agent from the drug-resin complex that increases the
blood level of ADHD effective agent to a second level.
[0019] In one embodiment, the ADHD effective agent is at least one
amphetamine such as a mixture of amphetamine and dextroamphetamine
(e.g., a mixture of 75% dextroamphetamine and 25% levoamphetamine).
In one embodiment, the compositions are substantially free of
dextroamphetamine saccharate and/or amphetamine asparate.
Alternatively, where the compositions consist essentially of
amphetamine salts, anions of those salts are polymeric. In another
alternative, the compositions or the drug-resin particles are
substantially free of soluble anions. In another embodiment, the
ADHD effective agent is methylphenidate.
[0020] In preferred embodiments, the compositions comprise a first
plurality of drug-resin particles that are not coated with a
delayed release coating, and a second plurality of drug-resin
particles that are coated with a delayed release coating. The
delayed release may comprise a triggered-release coating (e.g.,
where a pH change triggers the triggered-release coating such as
EUDRAGIT.RTM. L100). The particles covered by a triggered-release
coating may further comprise an extended release coating such as a
diffusion barrier coating (e.g., a water insoluble, water permeable
membrane such as ethylcellulose).
[0021] The compositions may comprise various amounts of the first
and second plurality of drug-resin particles. For example, in one
embodiment, the compositions comprise 20%-50% of the first
plurality of drug-resin particles and 50-80% of the second
plurality of drug-resin particles. In particular, the compositions
may comprise 40%-50%, or about 45%, of the first plurality of
drug-resin particles and 50%-60% or about 55% of the second
plurality of drug-resin particles. In other particular embodiments,
the compositions may comprise 20%-30%, or about 25%, of the first
plurality of drug-resin particles and 70%-80% or about 75% of the
second plurality of drug-resin particles.
[0022] In some embodiments, the resin particles are strong acidic
cation exchange resins such as polistirex, polacrilex, or
polacrilin. In other embodiments, the resin particles are
AMBERLITE.RTM. IRP64, IRP69, or IRP88 resins, or DUOLITE.TM. AP143
resins. The compositions may be liquid suspensions, chewable
compositions, or an orally disintegrating tablet compositions.
[0023] The invention provides for compositions having unique in
vitro dissolution profiles. In particular, the rate of appearance
of the drug in a dissolution medium increases after a period of
decrease in the rate of appearance of the drug in the dissolution
medium. The period of decrease in the rate of appearance of the
drug may occur within 0.5, 1, 1.5, 2, or 2.25 hours after the
composition is introduced into the dissolution medium. In some
embodiments, 30-60% of the drug may be released before the rate of
appearance of the drug in a dissolution medium increases.
Typically, release of 80% or more of the drug is achieved only
after the rate of appearance of the drug in the dissolution medium
has decreased and then increased. In particular, 80% or more of the
drug is released during the dissolution assay within the first half
(i.e., within 12 hours) of the dosing interval (i.e., 24 hour
dosing interval).
[0024] In other embodiments, 40-45% of the drug is released within
the first 45 minutes after the drug-resin particles are introduced
into a dissolution assay, followed by a period of substantially no
drug release from 45 minutes to 2 hours, and concluding with period
of from 2 to 8 hours during which substantially all of the
remaining drug is released. In another embodiment, 40-45% of the
drug is released within the first 45 minutes after the drug-resin
particles are introduced into a dissolution assay, 45-50% of the
drug is released within 2 hours, and 50-100% of the drug is
released by 8 hours. In another embodiment, 30-33% of the drug is
released the first 30 minutes after the drug-resin particles are
introduced into a dissolution assay, 34-42% of the drug is released
within 2 hours, 40-80% of the drug is released within 4 hours and
80-100% of the drug is released within 24 hours. In any of these
embodiments, the conditions of the dissolution assay are an initial
dissolution medium of 0.1 N HCL, and after 2 hours, the medium is
adjusted to a pH of .about.6.8; and dissolution testing is
performed using a USP Apparatus 2.
[0025] The invention also provides for compositions having unique
in vivo serum profiles. In some embodiments, the composition has an
in vivo serum profile with a first and second peak (e.g., where the
second peak is the C.sub.max). For example, the composition may
have an in vivo serum profile with a first peak between 1 and 3
hours after ingestion of the composition, and with a second peak
between 4 and 7 hours after ingestion of the composition. In a
particular mode, the composition may have an in vivo serum profile
with a first peak between 1 and 2.5 hours after ingestion of the
composition, and with a second peak between 4 and 6 hours after
ingestion of the composition. Alternatively, the composition may
have an in vivo serum profile that reaches a therapeutically
effective level fairly rapidly (1-3 hours) and them continues to
increase more slowly up to a maximum serum level between 4 hours
and 7 hours after ingestion.
[0026] In one aspect, the compositions have in vivo serum profiles
bioequivalent to the profiles of compositions described in the
Examples and shown in the Figures. In particular aspect, the in
vivo serum profile of the composition is bioequivalent to the in
vivo serum profile of ADDERALL XR (e.g., under fasted conditions).
In other embodiments, the compositions have one or more partial
AUCs (e.g., AUC.sub.0-5, AUC.sub.0-5, AUC.sub.4-12, AUC.sub.5-12,
AUC.sub.5-t (AUC.sub.5-last).sup.1, AUC.sub.0-24, and/or
AUC.sub.0-.infin.) which meet the bioequivalence conditions of the
compositions described in the Examples (e.g., ADDERALL XR) and
shown in the Figures. In another embodiment, the composition, in
the presence of ethanol, provides that the recipient of the
composition is exposed to a reduced amount of amphetamines compared
to ADDERALL XR. .sup.1(AUC.sub.5-last)=AUC.sub.5-t=the area under
the plasma concentrate time curve for the time between 5 hours
after ingestion to the last data point collected.
[0027] The invention also provides for methods of treating various
conditions such as Attention-Deficit Disorder or ADHD, fatigue,
obesity or imparting alertness, by administering an effective
amount of the compositions described herein. In one embodiment, the
amount of drug delivered to the subject is between about 2 mg/24
hours to about 60 mg/24 hours. In another embodiment, the amount of
drug delivered to the subject is about 5 mg/24 hours to about 30
mg/24 hours. In particular embodiments, the effective amount is 0.5
mg/kg/day to 1.5 mg/kg/day, 0.25 mg/kg/day to 0.5 mg/kg/day, or
0.28/kg/day to 0.4 mg/kg/day. The composition may be administered
once-a-day as a single or multiple unit dose. This invention is
preferred for a subject suffering from dysphagia.
[0028] The invention also relates to methods of reducing the
effects of an elevated exposure of a subject to ADHD effective
agents (e.g., amphetamines). For example, when the compositions are
administered substantially contemporaneously with ethanol, such
that the subject is exposed to a reduced amount of amphetamines
compared to administering ADDERALL XR to a subject substantially
contemporaneously with ethanol.
[0029] The invention also provides for various methods of making
the compositions. In one embodiment, the method involves (a)
loading a plurality of resin particles with at least one ADHD
effective agent (e.g., at least one amphetamine, methylphenidate)
to form drug-resin particles; (b) coating a subset of the
drug-resin particles with a triggered-release coating to form
coated drug-resin particles; and (c) combining uncoated drug-resin
particles with the subset of coated drug-resin particles in a
pharmaceutical composition. In another embodiment, the method
involves (a) loading a plurality of resin particles with an ADHD
effective agent (e.g., methylphenidate) to form drug-resin
particles; (b) coating drug-resin particles with an extended
release coating (e.g., ethyl cellulose) to form extended release
coated drug-resin particles; (c) further coating the extended
release coated drug-resin particles with a delayed release coating
(e.g., triggered-release coating) to form extended release/delayed
release coated drug-resin particles; and (d) combining loaded, but
uncoated drug-resin particles with the extended release/delayed
release coated drug-resin particles in a pharmaceutical
composition.
[0030] In another embodiment, the composition, wherein, for in vivo
pharmacokinetic parameters of the composition, one or more in vivo
pharmacokinetic parameters selected from the group consisting of
C.sub.max, AUC.sub.0-5, AUC.sub.5-12, AUC.sub.5-24, AUC.sub.5-t
(AUC.sub.5-last), AUC.sub.0-12, AUC.sub.0-24, AUC.sub.0-t, and
AUC.sub.0-.infin. have a 90% confidence interval with upper and
lower bounds within a range from 90%-115% of the value of the same
parameter(s) for a bioequivalent reference composition (e.g.,
ADDERALL XR).
BRIEF DESCRIPTION OF THE DRAWINGS
[0031] FIG. 1 depicts an exemplary process for loading amphetamines
onto resin particles.
[0032] FIG. 2 shows the dissolution profile of the composition
described in Example 4.
[0033] FIG. 3 shows the dissolution profile of the composition
described in Example 5.
[0034] FIG. 4 shows the dissolution profile of the composition
described in Example 6.
[0035] FIG. 5 shows the dissolution profile of the composition
described in Example 7.
[0036] FIG. 6 shows the dissolution profile of the composition
described in Example 8.
[0037] FIG. 7 shows the dissolution profile of the composition
described in Example 9.
[0038] FIG. 8 shows the results of a pH study on different coated
resins described in Example 10.
[0039] FIG. 9 shows the plasma concentrations of amphetamine
released from two different amphetamine formulations compared to
ADDERALL XR (i.e., the reference formulation) in the pig study
described in Example 12.
[0040] FIGS. 10A and 10B shows the plasma concentrations of
exemplary amphetamine formulations compared to ADDERALL XR (i.e.,
the reference formulation) with alcohol and without alcohol as
described in Example 13A. FIG. 10A shows the results of
d-amphetamine. FIG. 10B shows the results of l-amphetamine.
[0041] FIG. 11 shows in vitro release profiles of ADDERALL XR
(i.e., the reference formulation) with the addition of 0%, 20%, and
40% alcohol as described in Example 13B.
[0042] FIG. 12 shows the in vitro release profiles of the drug
sample similar to that in Example 6 with the addition of 0%, 20%,
and 40% alcohol as described in Example 13B.
[0043] FIG. 13 shows the amount of drug released over a range of
pHs for three different lots of the delayed release product
described in Example 6.
[0044] FIGS. 14A and 14B show the mean d-amphetamine
concentration-time profiles after administration of Test
Formulation #1 (Treatment A), Test Formulation #2 (Treatment B),
and Reference Product (Treatment C), as described in Example
15.
[0045] FIGS. 15A and 15B show the mean l-amphetamine
concentration-time profiles after administration of test
formulation #1 (Treatment A), test formulation #2 (Treatment B),
and reference product (Treatment C), as described in Example
15.
[0046] FIG. 16 shows the mean d-amphetamine concentration-time
profiles after administration of the ODT formulation and Reference
Product (ADDERALL XR), as described in Example 16.
[0047] FIG. 17 shows the mean l-amphetamine concentration-time
profiles after administration of the ODT formulation and Reference
Product (ADDERALL XR), as described in Example 16.
[0048] FIG. 18 shows the mean d-amphetamine concentration-time
profiles after administration of the suspension formulation and
Reference Product (ADDERALL XR), as described in Example 16.
[0049] FIG. 19 shows the mean l-amphetamine concentration-time
profiles after administration of the suspension formulation and
Reference Product (ADDERALL XR), as described in Example 16.
[0050] FIGS. 20A and 20B show the mean d-methylphenidate
concentration-time profiles after administration of Test
Formulation #1 (Treatment A), Test Formulation #2 (Treatment B),
and Reference Product (Treatment C), as described in Example
18.
[0051] FIGS. 21A and 21B show the mean l-methylphenidate
concentration-time profiles after administration of Test
Formulation #1 (Treatment A), Test Formulation #2 (Treatment B),
and Reference Product (Treatment C), as described in Example
18.
[0052] FIGS. 22A and 22B show the mean total methylphenidate (d+l)
concentration-time profiles after administration of Test
Formulation #1 (Treatment A), Test Formulation #2 (Treatment B),
and Reference Product (Treatment C), as described in Example
18.
[0053] FIG. 23 shows the mean d-amphetamine and l-amphetamine
plasma concentrations following administration of ADDERALL XR 20 mg
(8 am) and ADDERALL (immediate-release) 10 mg twice daily (8 am and
noon) in the fed state as reported in the prior art.
[0054] FIG. 24 shows the mean plasma concentrations following
administration of immediate release methylphenidate and METADATE CD
formulations as reported in the prior art.
[0055] FIGS. 25A-25C show in vitro release profiles of METADATE CD
(i.e., the reference drug) with the addition of 0%, 5%, 10%, 20%,
and 40% alcohol (FIG. 25A), the in vitro release profiles of a
formulation similar to those formulations described in Example 17
with the addition of 0%, 5%, 10%, 20%, and 40% alcohol (FIG. 25B),
and the in vitro release profiles of METADATE CD and a formulation
similar to those described in Example 17 with the addition of 0%,
5%, 10%, 20%, and 40% alcohol (FIG. 25C).
[0056] FIG. 26 shows the dissolution profile of compositions A and
B described in Example 17.
[0057] FIGS. 27A and 27B show the mean methylphenidate (d+l)
concentration-time profiles after administration of Formulation
#102-Fasted (Treatment A) and Formulation #102-Fed (Treatment B),
as described in Example 20.
[0058] FIGS. 28A and 28B show the mean d-methylphenidate
concentration-time profiles after administration of Formulation
#102-Fasted (Treatment A) and Formulation #102-Fed (Treatment B),
as described in Example 20.
[0059] FIGS. 29A and 29B show the mean l-methylphenidate
concentration-time profiles after administration of Formulation
#102-Fasted (Treatment A) and Formulation #102-Fed (Treatment B),
as described in Example 20.
[0060] FIGS. 30A and 30B show the mean d-amphetamine
concentration-time profiles after administration of test
formulation-fed (Treatment A) and test formulation-fasted
(Treatment B), as described in Example 21.
[0061] FIGS. 31A and 31B show the mean l-amphetamine
concentration-time profiles after administration of test
formulation-fed (Treatment A) and test formulation-fasted
(Treatment B), as described in Example 21.
[0062] FIGS. 32A and 32B show the mean d-amphetamine
concentration-time profiles after administration of controlled
release ODT with Deionized Water (0% Ethanol Solution) (Treatment
A), 4% ethanol (Treatment B), 20% ethanol (Treatment C) and 40%
ethanol (Treatment D) on linear (upper panel) and semi-logarithmic
(lower panel) scales, as described in Example 22.
[0063] FIGS. 33A and 33B shows the mean l-amphetamine
concentration-time profiles after administration of controlled
release ODT with Deionized Water (0% Ethanol Solution) (Treatment
A), 4% ethanol (Treatment B), 20% ethanol (Treatment C) and 40%
ethanol (Treatment D) on linear (upper panel) and semi-logarithmic
(lower panel) scales, as described in Example 22.
[0064] FIGS. 34A and 34B mean d-amphetamine concentration-time
profiles after administration of amphetamine-containing ODT for
Group 1 (Ages 6-7), Group 2 (Ages 8-9), and Group 3 (Ages 10-12),
as described in Example 23.
[0065] FIGS. 35A and 35B mean d-amphetamine concentration-time
profiles after administration of amphetamine-containing ODT for
Group 1 (Ages 6-7), Group 2 (Ages 8-9), and Group 3 (Ages 10-12),
as described in Example 23.
[0066] FIGS. 36A and 36B show the mean d-amphetamine
concentration-time profiles after administration of Test
Formulation #1 (Treatment A), Test Formulation #2 (Treatment B),
Test Formulation #3 (Treatment C), and the Reference Product
(Treatment D), as described in Example 24.
[0067] FIGS. 37A and 37B show the mean l-amphetamine
concentration-time profiles after administration of Test
Formulation #1 (Treatment A), Test Formulation #2 (Treatment B),
Test Formulation #3 (Treatment C), and the Reference Product
(Treatment D), as described in Example 24.
[0068] FIG. 38: Mean d-Amphetamine Concentration-Time Profiles
after Administration of Suspension under Fasted Conditions
(Treatment A), Suspension under Fed Conditions (Treatment B), and
the Reference Product under Fed Conditions (Treatment C).
[0069] FIG. 39: Mean l-Amphetamine Concentration-Time Profiles
after Administration of Suspension under Fasted Conditions
(Treatment A), Suspension under Fed Conditions (Treatment B), and
the Reference Product under Fed Conditions (Treatment C)
DETAILED DESCRIPTION OF THE INVENTION
[0070] The invention provides for various dosage forms comprising
drug-resin particles that provide an effective treatment over a
prolonged period of time. The invention provides pharmaceutical
compositions such as liquid drug suspensions, chewable
compositions, or orally disintegrating compositions comprising at
least one plurality of drug-resin particles comprising a
delayed-release coating. The invention also provides for methods of
making pharmaceutical compositions and methods of treatment using
these pharmaceutical compositions.
[0071] For example, the invention provides for such pharmaceutical
compositions in which (i) the rate of appearance of the drug (e.g.,
at least one amphetamine) in a dissolution medium is increasing
during a time period from a first time point through to a second
time point, wherein the first time point is at least one hour after
the composition is introduced into the dissolution medium; and/or
(ii) the composition achieves an ascending plasma concentration of
the drug (e.g., at least one amphetamine) after a therapeutically
effective level is reached (e.g., one, two, three hours after
ingestion of the composition).
[0072] The inventors have also observed that, when monitoring the
release of the compositions of the invention and a reference listed
ADHD effective agent (e.g., amphetamine, methylphenidate) in vivo,
contemporaneous consumption of alcohol and drug affected both the
rate and amount of ADHD effective agent appearing in the subject's
circulation. Consequently, alcohol consumption by a patient being
treated for ADHD can substantially increase the patient's level of
exposure to ADHD effective agent (e.g., amphetamine,
methylphenidate). The compositions of this invention help control
the exposure, by reducing dose dumping.
DEFINITIONS
[0073] As used herein, a "drug-resin particle" is a drug-containing
ion-exchange resin particle in which there is an ionic bond between
the drug and the ion-exchange resin particle.
[0074] As used herein, an "ADHD effective agent" is any agent
effective to treat ADHD or ADD in any patient population (e.g.,
children, adolescents, adults), wherein the agent includes
stimulants such as amphetamine, lisdexamphetamine, methylphenidate,
and their optical isomers; non-stimulants such as atomoxetine,
guanfacine, and clonidine; antidepressants such as bupropion;
anti-hypertussives such as gaunfacine and clonidine, derivatives
thereof, or any combination that comprises at least one of these
agents. As discussed herein, ADHD effective agents may also be used
in the effective treatment of other conditions such as fatigue,
obesity and for imparting alertness.
[0075] As used herein, "controlled release" means the time course
of drug appearance in medium surrounding the composition is
modified compared to an immediate release composition. Controlled
release encompasses "delayed release" and "extended release"
formulations.
[0076] As used herein, "delayed release" means that appearance of
drug in the medium surrounding the composition occurs after a time
lapse. An example of a delayed release coating is a
triggered-release coating.
[0077] As used herein, a "triggered-release coating" is a coating
that degrades as a result of a triggering event, where the
triggering event is a change in the physiological environment of
surrounding the triggered-release coating. Triggering events
include, but are not limited to, a pH change which occurs upon
transit from one stage to another stage in a subject's GI tract, an
enzyme secreted in a particular region in a subject's GI tract, or
enzymatic presence in digestion.
[0078] As used herein, "extended release" means that the rate of
release is slower than the rate for an immediate release or delayed
release composition from the initial point of release.
[0079] As used herein, "immediate release" means the initial period
during which drug is released from the composition that does not
involve delayed or extended release but may include
taste-masking.
[0080] As used herein, a "subject" means any animal, but is
preferably a mammal, such as, for example, a human.
[0081] As used herein, "dose dumping" means the premature and/or
accelerated release of a drug. Dose dumping could produce adverse
effects or toxicity due to exposure of the patient to higher levels
of the drug.
[0082] As used herein, "substantially free of dextroamphetamine
saccharate and/or amphetamine asparate" means little to no
dextroamphetamine saccharate and/or amphetamine asparate is
present. Thus, while trace amounts of dextroamphetamine saccharate
and/or amphetamine asparate may be included, therapeutically
effective levels of dextroamphetamine saccharate and/or amphetamine
asparate are excluded.
[0083] As used herein, "substantially free of soluble anions" means
little to no soluble anions may be included. Thus, while trace
amounts of soluble anions may be included, these trace amounts will
affect the release of the drug by no more than 5%, preferably no
more than 2%. Particularly, the trace amounts will affect the
release of the drug by no more than 5%, preferably no more than 2%,
during the first half hour after ingestion of the drug or after
introduction of the drug to a dissolution assay.
[0084] As used herein, "substantially contemporaneously with
ethanol" means ingesting (or introducing) a substance containing
ethanol (e.g., beer, wine, hard liquor) within 5, 10, 15, 30, 45,
60, 75, 90, or 120 minutes before or after ingesting (or
introducing) a composition of the invention.
[0085] As used herein, "substantially all," in the context of drug
release, means 90% or more.
[0086] As used herein, "substantially similar" parameters have
values within -20%/+25% of each other.
Bioavailability
[0087] 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).
[0088] 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
(see Remington: The Science and Practice of Pharmacy, (Alfonso R.
Gennaro ed. 2000), page 999).
[0089] C.sub.max is the maximum plasma concentration achieved after
oral drug administration (see Remington, page 999). An oral drug
administration results in at least one C.sub.max but may result in
more than one "peak plasma concentration" or "plasma concentration
peak" (for example, following the administration of a pulsed dose
formulation).
[0090] 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 (see Remington, page 999).
[0091] 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 C.sub.max. According to
the FDA, two products are bioequivalent if the 90% confidence
intervals of the relative mean AUC, C.sub.max, and T.sub.max of the
test formulation are within 80% to 125% (-20%/+25%) of the
reference formulation drug when administered in the fasting state.
In a particular embodiment, bioequivalence may be established by
comparing a test drug to a reference drug by comparing partial AUCs
(e.g., over statistically or clinically relevant time intervals).
This bioequivalence measure based partial AUCs may be used alone or
in combination with the bioequivalence measure discussed above.
[0092] As used herein, a dissolution profile is "statistically
similar" to another profile if the f2 similarity factor calculated
for the two profiles is greater than or equal to 50. (See Moore and
Flanner, Pharm. Tech. 20: 64-74, 1996).
Drug-Containing Resin Particles
[0093] The invention provides for various dosage forms comprising
drug-containing ion-exchange resin particles. These particles
generally comprise at least one ADHD effective agent (e.g., at
least one amphetamine, methylphenidate) bound to particles of an
ion-exchange resin to provide a drug-resin complex. This complex
may be coated with (i) a delayed release coating (e.g.,
triggered-release coating); (ii) an extended release coating (e.g.,
a water-permeable diffusion barrier coating that is insoluble in
gastrointestinal fluids (and water) thereby providing a
controllable extended release of drug under conditions encountered
in the gastrointestinal tract); or (iii) both (i) and (ii). The
drug-resins may also include a slow-dissolve polymer coating.
Alternatively, the drug-resin particles are uncoated, i.e., omit a
delayed release coating (e.g., triggered-release coating) and/or
other coating (e.g., water-permeable diffusion barrier
coating).
[0094] Resins
[0095] Ion-exchange resins suitable for use in the preparations and
methods described herein are water-insoluble and comprise an
indigestible organic and/or inorganic matrix containing covalently
bound functional groups that are ionic or capable of being ionized
under the appropriate conditions of pH. The organic matrix may be
synthetic (e.g., polymers or copolymers of acrylic acid,
methacrylic acid, sulfonated styrene, sulfonated divinylbenzene),
or partially synthetic (e.g., modified cellulose and dextrans). The
inorganic matrix preferably comprises silica gel modified by the
addition of ionic groups. Covalently bound ionic groups may be
strongly acidic (e.g., sulfonic acid, phosphoric acid), weakly
acidic (e.g., carboxylic acid), strongly basic (e.g., primary
amine), weakly basic (e.g. quaternary ammonium), or a combination
of acidic and basic groups. In general, the types of ion-exchangers
suitable for use in ion-exchange chromatography and for such
applications as deionization of water are suitable for use in the
controlled release of drug preparations. Suitable ion exchange
resins are also sold under the trade names AMBERLITE and Dowex.
Such ion-exchangers are described by H. F. Walton in "Principles of
Ion Exchange" (pp. 312-343) and "Techniques and Applications of
Ion-Exchange Chromatography" (pp. 344-361) in Chromatography. (E.
Heftmann, editor), Van Nostrand Reinhold Company, New York (1975),
incorporated herein by reference. Exemplary ion-exchange resins
that can be used in the present invention have exchange capacities
below about 6 milliequivalents (meq)/gram and preferably below
about 5.5 meq/gram.
[0096] Typically, the size of the ion-exchange particles is from
about 30 microns to about 500 microns, preferably the particle size
is within the range of about 40 micron to about 150 micron for
liquid dosage forms, although particles up to about 1,000 micron
can be used for solid dosage forms, e.g., tablets and capsules.
Particle sizes substantially below the lower limit are difficult to
handle in all steps of the processing. Commercially-available
ion-exchange resins having an irregular shape and larger diameters
up to about 200 micron are gritty in liquid dosage forms. Moreover,
it is believed that the increased distance that a displacing ion
must travel in its diffusion into these large particles, and the
increased distance the displaced drug must travel in its diffusion
out of these large particles, cause a measurable but not readily
controlled prolongation of release, even when the drug-resin
complexes are uncoated. Release of drug from uncoated drug-resin
complexes with particle sizes in the approximate range of 40 micron
to 150 micron is relatively rapid in the appropriate environment.
Satisfactory control of the release from such complexes is achieved
almost exclusively by applying a diffusion barrier coating.
[0097] Both regularly and irregularly shaped particles may be used
as resins. Regularly shaped particles are those particles that
substantially conform to geometric shapes, such as spherical,
elliptical, cylindrical and the like, which are exemplified by Dow
XYS-40010.00 and Dow XYS-40013.00 (The Dow Chemical Company).
Irregularly shaped particles are all particles not considered to be
regularly shaped, such as particles with amorphous shapes and
particles with increased surface areas due to surface channels or
distortions. Irregularly shaped ion-exchange resins of this type
are exemplified by AMBERLITE IRP-69 (Rohm and Haas). Two of the
preferred resins of this invention are AMBERLITE IRP-69 and Dow
XYS-40010.00. Both are sulfonated polymers composed of polystyrene
cross-linked with 8% of divinylbenzene, with an ion-exchange
capacity of about 4.5 to 5.5 meq/g of dry resin (Na.sup.+-form).
Their essential difference is in physical form. AMBERLITE IRP-69
consists of irregularly-shaped particles with a size range of 47
micron to 149 micron produced by milling the parent large-sized
spheres of AMBERLITE.RTM. IRP-120. The Dow XYS-40010.00 product
consists of spherical particles with a size range of 45 micron to
150 micron. Another useful exchange resin, Dow XYS-40013.00, is a
polymer composed of polystyrene cross-linked with 8% of
divinylbenzene and functionalized with a quaternary ammonium group;
its exchange capacity is normally within the range of approximately
3 to 4 meq/g of dry resin.
[0098] The following U.S. patents and Publications describe resins
suitable for use in the preparations and methods described herein:
U.S. Pat. Nos. 4,221,778; 4,996,047; and 5,980,882; U.S.
Publication Nos. 2003/0099711; 2006/0193877; 2007/0059270;
2007/01400983; 2007/0148239; and 2009/0011027. The disclosure of
each of these patents and publications is incorporated by reference
herein in their entireties.
[0099] Drugs
[0100] Drugs that are suitable for the invention may be acidic,
basic or amphoteric. Basic drugs that can be used in the present
invention include amphetamine and methylphenidate. Drugs which may
be used in the invention include ADHD effective agents such as
amphetamine, dextroamphetamine, levoamphetamine, lisdexamphetamine,
methylphenidate, dexmethylphenidate, atomoxetine, guanfacine,
clonidine, and bupropion. In preferred embodiments, the drug is a
stimulant such as amphetamine and methylphenidate.
[0101] Drug-Resin Complexes
[0102] Binding of drug to resin can be accomplished using methods
known in the art. Indeed, one of ordinary skill in the art can
easily determine the appropriate method depending upon the drug.
Typically four general reactions are used for a basic drug, these
are: (a) resin (Na.sup.+-form) plus drug (salt form); (b) resin
(Na.sup.+-form) plus drug (as free base); (c) resin (H.sup.+-form)
plus drug (salt form); and (d) resin (H.sup.+-form) plus drug (as
free base). All of these reactions except (d) have cationic
by-products and these by-products, by competing with the cationic
drug for binding sites on the resin, reduce the amount of drug
bound at equilibrium. For basic drugs, stoichiometric binding of
drug to resin is accomplished only through reaction (d).
[0103] Typically, the ion-exchange resin, in the form indicated by
the chosen reaction, is placed in an aqueous solution of the chosen
form of drug and agitated. The drug-resin complex thus formed is
collected and washed with deionized or purified water to ensure
removal of any unbound drug. The complexes are then dried.
[0104] Uncoated drug-resin complexes rapidly release the drug in
the subject, such as, for example, in the gastrointestinal tract.
To delay the release of drug from the drug-resin complex, the
complex may be coated as described below.
[0105] The amount of drug that can be loaded onto a resin will
typically range from about 1% to about 80%, preferably about 15% to
about 60%, by weight of the loaded drug-resin particles. A skilled
artisan with little or no experimentation can readily determine the
optimum loading for any drug resin complex. In a preferred
embodiment, loadings of about 30% to about 60% by weight of the
drug-resin particles can be employed.
[0106] Those of skill in the art will appreciate that certain drugs
will have an affinity for particular types of resins. The inventors
have determined that the loading levels of amphetamine are suitable
on strongly acidic cation exchange resins such as AMBERLITE IRP-64
and AMBERLITE IRP-69 resins. Resins useful in the invention with
modification of the API are strong base anion exchange resins
(e.g., DUOLITE.TM. AP143) and weak acid cation exchange resins
(e.g., AMBERLITE IRP-88).
[0107] Amphetamine resin complexes can be formed using any
amphetamine salt, since the salt counter-ion is replaced by the ion
exchange resin, and release of the drug is controlled by coating
and ionic bonding, rather than differential solubility of the
salts. In a preferred mode, resin particles are loaded using a
single salt of racemic amphetamine and a single salt of
dextroamphetamine.
[0108] The following U.S. patents and Publications describe
preparations and methods suitable for drug-resin complexes
described herein: U.S. Pat. Nos. 4,221,778; 4,996,047; and
5,980,882; U.S. Publication Nos. 2003/0099711; 2006/0193877;
2007/0059270; 2007/01400983; 2007/0148239; and 2009/0011027. The
disclosure of each of these patents and publications is
incorporated by reference herein in their entireties.
[0109] Impregnation
[0110] Drug-resin particles can be impregnated with a humectant
substantially as described in U.S. Pat. No. 4,221,778. The
humectant can be added as an ingredient in the resin drug
complexation step or, preferably, the particles can be treated with
the humectant after complexing. This treatment helps particles
retain their geometry, and enables the effective application of
diffusion barrier coatings to such particles. One preferred
humectant is polyethylene glycol, a hydrophilic agent. Other
effective humectant agents include, for example, propylene glycol,
lactose, methylcellulose, hydroxypropylmethylcellulose, sugar
alcohols such as sorbitol, mannitol, polyvinylpyrrolidone,
carboxypolymethylene, xanthan gum, propylene glycol, alginate and
combinations of these agents. The humectant may be added in an
amount of up to about 50 parts per 100 parts by weight of the resin
or 50 to 150 parts per 100 parts of the resin; such humectant
levels have been found to be effective. Preferably, the humectant
(solvating agent) is added in an amount of about 75 to about 100
parts per 100 parts of resin.
[0111] Coatings
[0112] Coating layers can provide immediate release, delayed
release, pulsed release, or extended release of drug from the
drug-resin particle. 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.
[0113] The following U.S. patents and Publications describe coating
materials suitable for use in the preparations and methods
described herein: U.S. Pat. Nos. 4,221,778; 4,996,047; and
5,980,882; U.S. Publication Nos. 2003/0099711; 2006/0193877;
2007/0059270; 2007/01400983; 2007/0148239; US 2007/0264323; and
2009/0011027. The disclosure of each of these patents and
publications is incorporated by reference herein in their
entireties.
[0114] Diffusion Barrier Coating
[0115] Loaded particles may be coated with a diffusion barrier
comprising a water-permeable, film-forming polymer. Any coating
procedure which provides a contiguous coating on each particle of
drug-resin complex without significant agglomeration of particles
may be used. Coatings may be applied with a fluid-bed coating
apparatus having the Wurster configuration. Measurements of
particle size distribution can be done before and after coating to
show that agglomeration of particles is acceptable.
[0116] The polymer may be any of a large number of natural or
synthetic film-formers used singly, or in admixture with each
other, and optionally in admixture with plasticizers, pigments and
other substances to alter the characteristics of the coating. In
general, the diffusion barrier coating should be insoluble or
slowly soluble in water and permeable to water. Additional examples
of coating polymers are described by R. C. Rowe in Materials Used
in Pharmaceutical Formulation (A. T. Florence, editor), Blackwell
Scientific Publications, Oxford, 1-36 (1984), incorporated by
reference herein.
[0117] Preferably, the diffusion barrier is ethyl cellulose, for
example, an ethyl cellulose having the content of ethoxyl group
from 44 to 47.5%, preferably from 45 to 46.5%. In embodiments of
the present invention, the inclusion of an effective amount of a
plasticizer in the aqueous dispersion of hydrophobic polymer will
further improve the physical properties of the film. For example,
because ethylcellulose has a relatively high glass transition
temperature and does not form flexible films under normal coating
conditions, it may be necessary to add plasticizer to the
ethylcellulose before using the same as a coating material.
Generally, the amount of plasticizer included in a coating solution
is based on the concentration of the film-former, e.g., most often
from about 1 to about 50 percent by weight of the film-former.
Concentration of the plasticizer, however, can only be properly
determined after routine experimentation with the particular
coating solution and method of application.
[0118] Examples of suitable plasticizers for ethylcellulose include
water insoluble plasticizers such a dibutyl sebacate, diethyl
phthalate, triethyl citrate, tributyl citrate and triacetin,
although it is possible that other water-insoluble plasticizers
(such as acetylated monoglycerides, phthalate esters, castor oil,
etc.) may be used. A plasticizer such as Durkex 500 vegetable oil
may also be incorporated to improve the film forming property. In
one alternative, it is desirable to incorporate a water-soluble
substance, such as methyl cellulose, to alter the permeability of
the coating.
[0119] The diffusion barrier coating materials can be applied as an
aqueous suspension. One commercially available aqueous dispersion
of ethylcellulose is Aquacoat.RTM. (FMC Corp., Philadelphia, Pa.,
U.S.A.). Aquacoat.RTM. is typically prepared by dissolving the
ethylcellulose in a water-immiscible organic solvent and then
emulsifying the same in water in the presence of a surfactant and a
stabilizer. After homogenization to generate submicron droplets,
the organic solvent is evaporated under vacuum to form a
pseudolatex. The plasticizer is not incorporated in the pseudolatex
during the manufacturing phase. Thus, prior to using the same as a
coating, it is preferable to intimately mix the Aquacoat.RTM. with
a suitable plasticizer prior to use.
[0120] Another aqueous dispersion of ethylcellulose is commercially
available as Surelease.RTM. (Colorcon, Inc., West Point, Pa.,
U.S.A.). This product is typically prepared by incorporating
plasticizer into the dispersion during the manufacturing process. A
hot melt of a polymer, plasticizer (e.g., dibutyl sebacate), and
stabilizer (e.g., oleic acid) may be prepared as a homogeneous
mixture, which is then diluted with an alkaline solution to obtain
an aqueous dispersion which can be applied directly onto
substrates.
[0121] Another alternative coating material is a mixture of an
insoluble, film-forming polymer and a water soluble pore former or
polymer, i.e., refers to a two-component system. One preferred
water soluble polymer is methyl cellulose, which may be used in a
two-component system with ethylcellulose.
[0122] Another alternative coating material is a mixture of two
insoluble, film-forming polymers; for example polyvinyl acetate
phthalate (PVAP) and ethylcellulose. Another alternative coating
material is polyvinylpyrrolidone (PVP), polyvinylalcohol,
polyvinylacetate and mixtures thereof.
[0123] Typically, the water-permeable, film-forming polymer
comprises from about 1% to about 60% by weight of the drug-resin
complex, and preferably from about 20% to about 50% by weight of
the dry resin. In terms of coat thickness, preferably, the
diffusion barrier coat thickness is at least 5 microns and more
preferably, the diffusion barrier coat thickness is from about 10
microns to about 50 microns. Optimum coat weight and coat thickness
may be determined for each drug-resin complex and generally depend
on the drug release characteristics of the resin for a particular
drug. For example, to achieve drug release times within about 1
hour to about 4 hours, the drug-resin complex may be coated with a
light coat weight. A light coat weight is a coat weight present in
the amount of about 10% to about 20% by weight of the dry resin. To
achieve drug release times from about 6 hours to 10 hours, a medium
coat weight may be used, i.e. a coat weight present in the amount
of 30% to about 35% by weight. To achieve drug release times for
about 12 hours, a heavy coat weight may be used, i.e. a coat weight
of about 40% to 50% by weight of the dry resin.
[0124] Triggered-Release Coatings
[0125] A water-soluble barrier comprises a pharmaceutically
acceptable polymer such as, for example, methylcellulose (dissolves
in cold water), hydroxypropylmethylcellulose (HPMC),
hydroxyethlycellulose (HEC), acrylic acid ester, cellulose acetate
phthalate, HEC phthalate, HPMC phthalate, hydroxypropyl cellulose
(HPC), polyethylene glycol, polyvinyl alcohol, xanthan gum,
carbomer, carrageenan, zooglan or other cellulosic polymers, or
mixtures of polymers. Drugs mixed with one or more of these
polymers, or covered by a layer of the polymer, will not be
released until the polymer dissolves or degrades.
[0126] Triggered-release coatings are degraded as a result of a
triggering event. Triggering events may be pH dependent or pH
independent. 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 (PVAP), carboxymethylethylcellulose,
co-polymerized methacrylic acid/acrylic acid ethyl esters,
co-polymerized methacrylic acid/methacrylic acid methyl esters such
as, for instance, materials known under the trade name EUDRAGIT
L12.5, L100, or EUDRAGIT S12.5, S100 or similar compounds. Aqueous
colloidal polymer dispersions or re-dispersions can be also
applied, e.g., EUDRAGIT L 30D-55, EUDRAGIT L100-55, EUDRAGIT S100,
EUDRAGIT preparation 4110D (Rohm Pharma); AQUATERIC, AQUACOAT CPD
30 (FMC); KOLLICOAT MAE 30D and. 30DP (BASF); or EASTACRYL 30D
(Eastman Chemical). Aqueous colloidal polymer dispersions or
re-dispersions can be also applied, e.g. EUDRAGIT.RTM. L 30D-55,
EUDRAGIT L100-55, EUDRAGIT S100, EUDRAGIT preparation 4110D (Rohm
Pharma); AQUATERIC.RTM., AQUACOAT CPD 30 (FMC); KOLLICOAT MAE.RTM.
30D and 30DP (BASF); EASTACRYL.RTM. 30D (Eastman Chemical).
[0127] A pH independent coating includes materials susceptible to
enzymatic activation. Exemplary triggered-release coatings include
cross-linked gelatin, polylactic acid, cellophane, plastarch
material, polycaprolactone, polyglycolide, poly-3-hydroxybutyrate,
zein, materials susceptible to enzymatic activation by
azo-reductases in intestinal bacteria, and materials susceptible to
degradation in the colon.
[0128] The invention provides for combinations of triggered-release
coatings and diffusion barrier coatings. For example, the invention
provides for drug-resin particles that include a diffusion barrier
coating such as ethylcellulose which is overcoated with a
triggered-release coating (or vice versa, i.e., the
triggered-release coating is overcoated with a diffusion barrier
coating). This multicoated particle provides for a delayed release
(via the triggered-release coating) followed by an immediate or
extended release (via the diffusion barrier coating).
Dosage Forms
[0129] The invention provides for pharmaceutical compositions
comprising various pluralities of drug-resin particles in which the
pharmaceutical composition is, for example, a liquid, a chewable
composition, or an orally disintegrating solid. Alternatively,
pharmaceutical compositions according to this invention may be
prepared in capsules or by standard tableting methods. For example,
the invention provides for such pharmaceutical compositions in
which (i) the rate of appearance of the drug (e.g., at least one
amphetamine) in a dissolution medium is increasing during a time
period from a first time point through to a second time point,
wherein the first time point is at least one hour after the
composition is introduced into the dissolution medium; and/or (ii)
the composition achieves an ascending plasma concentration of the
drug (e.g., at least one amphetamine) after a therapeutic effective
level is reached (e.g., one, two, three hours after ingestion of
the composition).
[0130] In any of the dosage forms described herein, the drug may be
at least one of an amphetamine or dextroamphetamine, or
methylphenidate. In some preferred modes, both amphetamine or
dextroamphetamine are present.
[0131] Liquid Drug Suspensions
[0132] The invention provides for liquid oral dosage forms. These
dosage forms have distinct advantages over prior art solid dosage
forms including dosage flexibility and ease of swallowing. Liquid
dosage forms are especially preferred for pediatric use.
[0133] Liquid oral dosage forms include aqueous and nonaqueous
solutions, emulsions, suspensions, and solutions and/or suspensions
reconstituted from non-effervescent granules, containing suitable
solvents, preservatives, emulsifying agents, suspending agents,
diluents, sweeteners, coloring agents, and flavoring agents. Liquid
forms, such as syrups and suspensions, preferably contain from
about 1% to about 50%, and more preferably from about 1% to about
25%, and most preferably from about 3% to about 10%, of the
drug-resin complex. Other optional ingredients well known to the
pharmacist's art may also be included in amounts generally known
for these ingredients, for example, natural or artificial
sweeteners, flavoring agents, colorants and the like to provide a
palatable and pleasant looking final product; acidulants, for
example, citric acid, ascorbic acid, or malic acid and the like to
adjust pH; antioxidants, for example, butylated hydroxy anisole or
butylated hydroxy toluene; and preservatives, for example, methyl
or propyl paraben or sodium benzoate, to prolong and enhance shelf
life.
[0134] In preparing the liquid oral dosage forms, the coated
drug-resin complexes are incorporated into an aqueous-based orally
acceptable pharmaceutical carrier consistent with conventional
pharmaceutical practices. An "aqueous-based orally acceptable
pharmaceutical carrier" is one wherein the entire or predominant
solvent content is water. Typical carriers include simple aqueous
solutions, syrups, dispersions and suspensions, and aqueous based
emulsions such as the oil-in-water type. Preferably, the carrier is
a suspension of the pharmaceutical composition in an aqueous
vehicle containing a suitable suspending agent. Suitable suspending
agents include Avicel RC-591 (a microcrystalline cellulose/sodium
carboxymethyl cellulose mixture available from FMC), guar gum and
the like. Such suspending agents are well known to those skilled in
the art. While the amount of water in the compositions of this
invention can vary over quite a wide range depending upon the total
weight and volume of the drug-resin complex and other optional
non-active ingredients, the total water content, based on the
weight of the final composition, will generally range from about 20
to about 75%, and, preferably, from about 20 to about 40%, by
weight/volume.
[0135] Although water itself may make up the entire carrier,
typical liquid formulations may contain a co-solvent, for example,
propylene glycol, glycerin, sorbitol solution and the like, to
assist solubilization and incorporation of water-insoluble
ingredients, such as flavoring oils and the like, into the
composition. In general, therefore, the compositions of this
embodiment preferably contain from about 5 to about 25
volume/volume percent and, most preferably, from about 10 to about
20 volume/volume percent, of the co-solvent.
[0136] Orally Disintegrating and Chewable Dosage Forms
[0137] The invention also provides for compositions and methods of
making orally disintegrating or chewable, controlled-release
formulations. In particular, the invention provides for orally
disintegrating and chewable dosage forms comprising the various
pluralities of drug-resin particles described herein Like liquid
dosage forms, orally disintegrating and chewable dosage forms have
distinct advantages over prior art solid dosage forms including
ease of ingestion. Methods of preparing orally disintegrating and
chewable dosage forms with drug-resins are known in the art. See
U.S. Publication No. 2007/0092553, which is hereby incorporated by
reference in its entirety.
Drug Release Profiles
[0138] The invention provides for compositions having various drug
(e.g., ADHD effective agent) release profiles. In particular, the
compositions may be administered in the morning and have
therapeutically effective activity throughout the course of the
day. For example, in one embodiment, the composition is
administered to a child during breakfast (i.e., before school
starts) and, by the time school starts, the ADHD effective agent
(e.g., amphetamine, methylphenidate) will begin having a
therapeutic effect on the child. The composition will continue to
be therapeutically effective throughout the day including the
mid-afternoon, when children tend to be fatigued. As such, the
compositions described herein have an escalating in vivo serum
profile.
[0139] In some embodiments, the invention provides for compositions
in which the rate of appearance of the ADHD effective agent (e.g.,
at least one amphetamine) in a dissolution medium increases after a
period of decrease in the rate of appearance of the drug in the
dissolution medium. The compositions typically contain an immediate
release and delayed release portion. The immediate release portion,
in an in vitro dissolution assay, contributes to an initial release
of ADHD effective agent (e.g., 30-60%) within an initial time
period (e.g., 0.5, 1, 1.5, 2, or 2.25 hours from when the
composition is introduced into the dissolution medium). After the
initial increase amount of ADHD effective agent in the dissolution,
due to the immediate release portion, the release rate of ADHD
effective agent will decrease or level off. After this decrease or
leveling off, typically the delayed release portion will release
and the amount of ADHD effective agent released increases until,
e.g., 80% or more of the ADHD effective agent is released. It will
be appreciated that the first and second time points will vary
depending on the ADHD effective agent, coatings used, and ratio of
immediate and delayed release drug-resin particles.
[0140] In a particular embodiment, 40-45% of the drug (e.g., ADHD
effective agent such as at least one amphetamine) is released
within the first 45 minutes after the drug-resin particles are
introduced into a dissolution assay, followed by a period of
substantially no drug release from 45 minutes to 2 hours, and
concluding with period of from 2 to 8 hours in which substantially
all of the remaining ADHD effective agent is released from 2 to 8
hours. In another embodiment, 40-45% of the drug (e.g., ADHD
effective agent such as at least one amphetamine) is released
within the first 45 minutes after the drug-resin particles are
introduced into a dissolution assay, 45-50% of the drug is released
within 45 minutes to 2 hours, and 50-100% of the drug is released
within 2 to 8 hours. In another embodiment, the delayed release
coating releases substantially all of the one or more
pharmaceutically active ADHD effective agents (e.g., amphetamines)
coated with the delayed release coating within about 60 minutes
after initiation of the delayed release. In yet another embodiment,
30-33% of the drug (e.g., ADHD effective agent such as
methylphenidate) is released the first 30 minutes after the
drug-resin particles are introduced into a dissolution assay,
34-42% of the drug is released within 30 minutes to 2 hours, 40-80%
of the drug is released within 2 to 4 hours and 80-100% of the drug
is released within 4 to 24 hours. For any of these embodiments, the
conditions of the dissolution assay may be an initial dissolution
medium of 0.1 N HCL, and after 2 hours, the medium is adjusted to a
pH which triggers the triggered release coating, e.g., pH of
.about.6.8; and dissolution testing is performed using a USP
Apparatus 2. In other embodiments, the pH is adjusted to e.g., pH
6.8, 7, etc.
[0141] The invention also provides for compositions in which the
composition achieves an ascending plasma concentration of the drug
(e.g., at least one amphetamine during a time period) after a
therapeutically effective level is reached. Typically, a
therapeutically effective level is reached within one, two, three,
four, or five hours after ingestion of the composition. Sometime
after the therapeutically effective level is reached, the plasma
concentration of drug increases due to additional release of drug
from the drug-resin complex in the composition to a peak drug
concentration level. In some individuals, clearance of drug will
result in a decrease in plasma level between these two releases,
resulting in two successive peak drug levels. In others, the timing
of the two releases is close enough that no decrease is observed.
As a result, the in vivo plasma concentration profile is preferably
bimodal with two peaks. For example, the first peak may be
achieved, between 1 to 3, 1 to 2.5, or 1 to 2 hours after ingestion
of the composition. The second peak may be achieved 4 to 7, 4 to 6,
or 4 to 5 hours after ingestion of the composition. The first or
second peak may be the C.sub.max. Alternatively, the composition
may have an in vivo serum profile that reaches a therapeutically
effective level fairly rapidly (1-3 hours) and them continues to
increase more slowly up to a maximum serum level between 4 hours
and 7 hours after ingestion. It will be appreciated that the
therapeutic and peak drug concentration level will vary depending
on the subject, drug, coatings used, and ratio of immediate and
delayed release drug-resin particles.
[0142] The compositions of the invention may include at least one
plurality of drug-resin particles coated with a triggered-release
coating. In a particular embodiment, the invention provides for a
first plurality of uncoated drug-resin particles and a second
plurality of drug-resin particles being coated with a
triggered-release coating. In another embodiment, the invention
provides for a first plurality of uncoated drug-resin particles, a
second plurality of drug-resin particles being coated with a
triggered-release coating, and a third plurality of drug-resin
particles being coated with a diffusion barrier coating. In another
embodiment, the composition is a liquid dosage form and includes at
least one plurality of drug-resin particles being coated with a
triggered-release coating accompanied by unbound drug in
solution.
[0143] Any of the diffusion barrier coatings or triggered-release
coatings described herein may be used in any of the dosage forms
described herein. For example, the some embodiments, the
triggered-release coating is EUDRAGIT L100 or EUDRAGIT L100-55. In
some embodiments, the triggered-release coating may have an
overcoat (e.g., HPMC).
[0144] In other embodiments, the drug-resin particles may comprise
both a triggered-release and a diffusion barrier coating. For
example, the triggered-release coating may cover (i.e., overcoat)
the diffusion barrier coating. In one embodiment, the diffusion
barrier coating is ethylcellulose and the triggered-release coating
is polyvinyl acetate phthalate (PVAP).
[0145] The invention provides pharmaceutical compositions
comprising various mixtures of immediate release drug-resin
particles (e.g., uncoated drug-resin particles) and delayed release
drug-resin particles (e.g., triggered-release coated drug-resin
particles). In one embodiment, the pharmaceutical composition
comprises 20%-50% of immediate release drug-resin particles and
50-80% of delayed release drug-resin particles. In a particular
embodiment, the composition comprises 40%-50% of immediate release
drug-resin particles and 50%-60% of delayed release drug-resin
particles. In a specific embodiment, the pharmaceutical composition
comprises 45% of immediate release drug-resin particles and 55% of
delayed release drug-resin particles. In another embodiment, the
composition comprises 20%-30% of immediate release drug-resin
particles and 70%-80% of delayed release drug-resin particles. In a
specific embodiment, the pharmaceutical composition comprises 25%
of immediate release drug-resin particles and 75% of delayed
release drug-resin particles. As shown in the Examples, the
percentage of uncoated and coated particles, as well as the types
and percentages of coatings, effects the release profiles of the
drug (e.g., at least one amphetamine).
[0146] The Examples provide in vitro dissolution and in vivo serum
profiles for exemplary compositions of the inventions. These
compositions (and their profiles) are encompassed within the
invention. It will be understood that complete and partial profiles
(e.g., partial AUCs) of the compositions set forth and described in
the Examples are encompassed within the invention.
[0147] In one embodiment, the invention provides for administering
an effective amount of a ADHD effective agent (e.g., at least one
amphetamine such as a mixture of levo-amphetamine and
dextroamphetamine). The effective dosage may range from 3.13 mg of
amphetamine calculated as free base (equivalent to 5 mg of mixed
amphetamine salts found in ADDERALL XR) to 18.8 mg of amphetamine
calculated as free base (equivalent to 30 mg of mixed amphetamine
salts found in ADDERALL XR). The amphetamine provided is preferably
a mixture of 75% dextroamphetamine and 25% levoamphetamine. A
delivery of about 2 mg/24 hours to about 60 mg/24 hours of the
compositions of the invention, and more preferably from about 5
mg/24 hours to about 30 mg/24 hours, is typically needed to achieve
a therapeutically effective dose in a patient (based on mixed
amphetamine salts in ADDERALL XR). In particular embodiments,
children 6-12 years old may take 10-30 mg/day (e.g., 0.5 mg/kg/day
to 1.5 mg/kg/day), adolescents 13-17 years old may take 10-20
mg/day (0.25 mg/kg/day to 0.5 mg/kg/day), and adults may take 20
mg/day (0.28/kg/day to 0.4 mg/kg/day) (based on a mixed amphetamine
salt in ADDERALL XR).
[0148] In another embodiment, the invention provides for
administering an effective amount of methylphenidate. In one
embodiment, the effective dosage ranges from 8.7 mg of
methylphenidate base (equivalent to 10 mg of methylphenidate HCl)
to 52.2 mg of methylphenidate base (equivalent to 60 mg of
methylphenidate HCl). In another embodiment, the effective dosage
is 26.1 mg of methylphenidate base (equivalent to 30 mg of
methylphenidate HCl). A delivery of about 10 mg/24 hours to about
60 mg/24 hours of the compositions of the invention, and more
preferably from about 20 mg/24 hours to about 40 mg/24 hours, is
typically needed to achieve a therapeutically effective dose in a
patient (based on methylphenidate HCl).
[0149] The compositions may be administered once-a-day (e.g., in a
single unit or multiple unit compositions) in an amount that
provides a therapeutic benefit equivalent to multiple doses of
immediate release dosages.
[0150] The invention also provides for unit doses and packaging
comprising unit dosages. For example, the invention provides for
individually packaged liquid drug suspensions (e.g., 5, 10, 15, 30,
or 60 ml), or the equivalent amount of drug as a chewable
compositions or orally disintegrating dosage forms described
herein. Methods of preparing unit dosage forms are known in the
art.
[0151] It will be understood that the various aspects described
herein may be combined. For example, the invention provides for a
pharmaceutical composition comprising a first plurality of
drug-resin particles being uncoated and a second plurality of
drug-resin particles being coated with a triggered-release coating,
wherein the drug is an ADHD effective agent (e.g., at least one
amphetamine, methylphenidate) and the resin is IRP-64, IRP-69,
IRP-88, or AP143.
Methods of Making Dosage Forms
[0152] The invention provides for methods of making the
pharmaceutical compositions described herein. In one embodiment,
the method comprises (a) loading a plurality of resin particles
with at least one ADHD effective agent (e.g., at least one
amphetamine, methylphenidate) to form drug-resin particles; (b)
coating a subset of the loaded drug-resin particles with a delayed
release coating (e.g., triggered-release coating) to form coated
drug-resin particles; and (c) combining a subset of loaded,
uncoated drug-resin particles with coated drug-resin particles in a
pharmaceutical composition. In another embodiment, the method
comprises (a) loading a plurality of resin particles with at least
one ADHD effective agent (e.g., at least one amphetamine,
methylphenidate) to form drug-resin particles; (b) coating
drug-resin particles with a delayed release coating (e.g.,
triggered-release coating) to form coated drug-resin particles; and
(c) combining said drug-resin particles with said coated drug-resin
particles in a pharmaceutical composition.
[0153] In another embodiment, the method involves (a) loading a
plurality of resin particles with an ADHD effective agent (e.g.,
methylphenidate) to form drug-resin particles; (b) coating
drug-resin particles with an extended release coating (e.g., ethyl
cellulose) to form extended release coated drug-resin particles;
(c) further coating the extended release coated drug-resin
particles with a delayed release coating (e.g., triggered-release
coating) to form extended release/delayed release coated drug-resin
particles; and (d) combining loaded, but uncoated drug-resin
particles with the extended release/delayed release coated
drug-resin particles in a pharmaceutical composition. In an
alternative embodiment, a delayed release coating is applied to the
loaded drug-resin particles to form delayed release coated
drug-resin particles, and the extended release coating is then
applied to the delayed release coated drug-resin particles.
[0154] The compositions made by the methods described herein may
comprise various pluralities of drug-resin particles with the
profiles described herein. For example, the composition may
comprise pluralities of drug-resin particles such that (i) the rate
of appearance of the drug (e.g., at least one amphetamine) in a
dissolution medium is increasing during a time period from a first
time point through to a second time point, wherein the first time
point is at least one hour after the composition is introduced into
the dissolution medium; and/or (ii) the composition achieves an
ascending plasma concentration of the drug (e.g., at least one
amphetamine) after a therapeutic effective level is reached (e.g.,
one, two, three hours after ingestion of the composition).
[0155] Methods of loading drugs onto resin particles are generally
known in the art. The invention provides for methods of loading
ADHD effective agents (e.g., at least one amphetamine,
methylphenidate) onto resin particles (e.g., IRP-69, IRP-64,
IRP-88, AP143). An exemplary method of loading is depicted in FIG.
1 and described in Example 1. In another embodiment, the
composition comprises drug-resin particles comprise a mixture of l-
and d-amphetamine (e.g., 25% l-amphetamine and 75% d-amphetamine),
wherein each enantiomer is loaded onto a separate resin and the
separately loaded resins are combined to form drug-resin particles.
Alternatively, l- and d-amphetamine are mixed together in the
desired ratio (e.g., 25% l-amphetamine and 75% d-amphetamine) and
the mixed amphetamines are then loaded onto resins to form
drug-resin particles.
[0156] Methods of coating drug-resin particles are also generally
known in the art. The invention provides for various coating
solutions and combinations of coatings (e.g., triggered-release
coating such as EUDRAGIT L100, and a combination of EUDRAGIT 100
with HPMC). Example 2 provides an exemplary coating process and
Examples 4-9 provide exemplary compositions with different
coatings. Coatings may be applied using methods known in the art,
such as with a fluid-bed coating apparatus having the Wurster
configuration.
[0157] In alternative embodiments, the invention provides for
methods of making orally disintegrating and chewable dosage forms
comprising the various pluralities described herein. Methods of
preparing orally disintegrating and chewable dosage forms with
drug-resins are known in the art. See U.S. Publication No.
2007/0092553, which is hereby incorporated by reference in its
entirety.
[0158] It will be understood that the various aspects described
herein may be combined. For example, the invention provides for a
pharmaceutical composition comprising a first plurality of
drug-resin particles being uncoated and a second plurality of
drug-resin particles being coated with a triggered-release coating,
wherein the drug is at least one amphetamine or methylphenidate and
the resin is IRP-64, IRP-69, IRP-88, AP143.
Methods of Treatment
[0159] The invention provides for various methods of treatment
using the dosage forms described herein. In a particular
embodiment, the invention provides for methods of treating ADD or
ADHD, fatigue, obesity, or for imparting alertness, comprising
administering an effective amount of any of the compositions
described herein (e.g., a composition comprising at least one
plurality of drug-resin particles being uncoated and at least one
plurality of drug-resin particles coated with a delayed release
coating such as a triggered-release coating, where the drug is at
least one ADHD effective agent and the composition is, for example,
a liquid, a chewable composition, or an orally disintegrating
solid). In a preferred method, the individual being treated suffers
from dysphagia.
[0160] It will be understood that the various aspects described
herein may be combined. For example, the invention provides for
methods of treating ADD or ADHD comprising administering an
effective amount of a pharmaceutical composition comprising a first
plurality of drug-resin particles being uncoated and a second
plurality of drug-resin particles being coated with a
triggered-release coating, wherein the drug is at least one
amphetamine or methylphenidate and the resin is IRP-64, IRP-69,
IRP-88, AP143.
Methods of Reducing Exposure of Amphetamines
[0161] The inventors have observed that, when the compositions
described herein are administered to a subject substantially
contemporaneously with ethanol, the subject has a reduced exposure
level of an ADHD effective agent (e.g., amphetamines) compared to
administering a reference listed drug (e.g., ADDERALL XR) to a
subject substantially contemporaneously with ethanol. In particular
embodiments, the exposure of amphetamines are reduced within 1.0,
1.5, 2.0, 2.5, and/or 3.0 hours after ingestion of the composition
and ethanol. As such, the invention relates to methods of reducing
exposure of amphetamines and, in particular, reduced exposure
levels as compared to ADDERALL XR. The reduction in exposure is
detectable; and assays for detecting exposure levels and comparing
exposure levels are known in the art.
[0162] The inventors also observed that, when the compositions
described herein are introduced into a dissolution medium
substantially contemporaneously with ethanol, dose dumping of an
ADHD effective agent (e.g., amphetamines) is reduced compared to
introducing a reference listed drug (e.g., ADDERALL XR) into the
same dissolution medium substantially contemporaneously with
ethanol. As such, the invention relates to methods of reducing dose
dumping of amphetamines in vitro and, in particular, reduced dose
dumping as compared to ADDERALL XR. The reduction in dose dumping
is detectable; and assays for detecting dose dumping levels and
comparing such levels are known in the art. For example, cumulative
release in vitro may be measured for the initial portion of the
release curve, e.g., the first 0.5, 1, 1.5, 2, or 3 hours. Dose
dumping may be evaluated from a partial area under the curve
measurement to a relevant time point.
Dosage Forms Bioequivalent to a Target Product
[0163] The invention provides for dosage forms, methods of making
dosage forms, and methods of administering dosage forms (e.g., for
the conditions described herein such as ADHD) that are
bioequivalent to a target product. In various embodiments, the
invention provides for dosage forms (e.g., a liquid drug
suspension, orally disintegrating tablet) that are bioequivalent to
the in vivo serum profile of ADDERALL XR, or METADATE CD methods of
making such dosage forms, and methods of treatment (as described
herein) using such dosage forms. In particular embodiments, the
compositions have complete and/or partial profiles (e.g., partial
AUCs) that are bioequivalent to the profiles of ADDERALL XR or
METADATE CD. Examples 16 and 17 describe such compositions. For
example, the invention encompasses compositions that, when
administered to a human, produce a mean plasma concentration
profile which has any one of AUC.sub.0-3, AUC.sub.0-4, AUC.sub.0-5,
AUC.sub.0-tmax, AUC.sub.4-12, AUC.sub.5-12, AUC.sub.tmax-12,
AUC.sub.5-24, AUC.sub.tmax-24, AUC.sub.5-t, AUC.sub.tmax-t
AUC.sub.0-24 and/or AUC.sub.0-.infin. (e.g., at least 2, 3, 4, 5,
6, 7, 8, 9, 10, 11, 12 and/or 13 AUC values) that is/are
bioequivalent to the corresponding profiles of ADDERALL XR or
METADATE CD.
[0164] U.S. Pat. Nos. 6,322,819 and 6,605,300, which are hereby
incorporated by reference in their entirety, provide release
profiles and plasma concentrations of ADDERALL XR. See also FIG.
23.
[0165] In another embodiment, the invention provides for dosage
forms (e.g., orally disintegrating tablet) that are statistically
similar and/or have partial AUCs with 90% confidence intervals that
are within 80-125% of METADATE CD. For example, Example 18
describes compositions in which d-methylphenidate and total
methylphenidate (d+l) are statistically similar and/or have
AUC.sub.last and AUC.sub.inf with 90% confidence intervals that are
within 80-125% of METADATE CD; but which does not have T.sub.max
that is substantially similar.
EXAMPLES
[0166] The following examples describe various compositions
encompassed within the invention and their corresponding
dissolution and in vivo serum profiles. These examples are not
intended to limit the invention in any way.
Example 1
Loading the Resin Particles with Drug
[0167] The invention relates pharmaceutical compositions comprising
drug-resin particles and the methods of making these compositions.
This example provides an exemplary method of loading amphetamines
onto resin particles. FIG. 1 depicts this loading method.
[0168] In a kettle, amphetamine sulfate and dextroamphetamine
sulfate are mixed in purified water until fully dissolved.
AMBERLITE IRP 69 resins are added to the kettle and mixed. The
solution is filtered through a 20 .mu.m filter (Grade 54), then
again through a 8 .mu.m filter (Grade 540). The loaded resinate is
collected on the filter paper during each filtration.
[0169] In a kettle, polyethylene glycol is mixed in purified water
until fully dissolved. After it is completely dissolved, the loaded
resinate is added, and the solution is mixed until uniform. The
solution is filtered through a 20 .mu.m filter (Grade 54), then
again through a 8 .mu.m filter (Grade 540). The loaded resinate/PEG
is collected on the filter paper during each filtration.
[0170] The loaded resinate/PEG is dried in an oven until Loss on
Drying is between 3% and 7%. The dried material is screened through
a 100-mesh and 325-mesh screen.
[0171] The material that passed through the 100-mesh screen, but
did not pass through the 325-mesh screen, is collected. This
material is used as the uncoated delayed release resinate.
Alternatively, this material could be used as a substitute
immediate release resinate.
[0172] The material that did not pass through the 100-mesh screen
is milled using a Fitzmill (with knives forward and a 50-mesh
screen). This material is added together with the material that
passed through the 325-mesh screen to become the immediate release
resinate. These two materials are blended together.
Example 2
Coating Drug-Resin Particles
[0173] The pharmaceutical compositions of the invention may
comprise a coated and uncoated plurality of drug-resin particles.
The coated drug-resin particles provide the delayed or
triggered-release portion of the composition. This example provides
an exemplary method of preparing a polymer coating for the coated
drug-resin particles.
[0174] A clean, stainless steel container is pre-weighed. Acetone
and ethanol are added to the container. Plasticizer is then added
to the container and mixed until dispersed. A coating polymer such
as HPMC, is slowly added to the container while mixing. The polymer
solution is continuously stirred for at least an hour and until all
of the solids are dissolved. This coating solution is continuously
stirred during the coating process. The loaded resinate of Example
1 may be coated (e.g., in a wurster coater) with this coating
solution to prepare coated drug-resin complexes.
Example 3
Loading Resin Particles with Drug and Coating the Drug-Resin
Particles
[0175] The methods of Examples 1 and 2 may be combined to prepare
the pharmaceutical compositions of the invention. In particular,
drug-resin particles may be prepared using the method of Example 1,
and those drug-resin particles to be used as the delayed release
portion of the composition may be coated with a polymer coating
prepared by the method of Example 2. The particles may be dried and
mixed in a V-blender. The specific ratio of immediate release and
delayed release particles may vary as described below.
[0176] Once the resin particles are loaded, coated, and mixed, the
resulting drug-resin particles may be used in any suitable dosage
form (e.g., suspension, chewable composition, orally disintegrating
composition, capsule, tablet, etc.).
Example 4
Orally Disintegrating Tablet with 45% IR and 55% DR (Formula A)
[0177] An orally disintegrating tablet was formulated with 45% of
the amphetamine from immediate release resin complex and 55% of the
amphetamine from a delayed release resin complex. A hydroxypropyl
methylcellulose (HPMC) coating overlays the delayed released resin
complex. The formula is presented below in Table 1.
TABLE-US-00001 TABLE 1 ODT amphetamine formulation with 45% IR and
55% DR with HPMC Overcoat IR - 34.17% base assay & DR - 6.26%
base assay: These values will be variable. Formula A (HPMC
overcoat) (45% active from IR Resin & 55% active from DR Resin)
mg/dose Notes % Uncoated (IR) AMP Resin 24.76 The 24.76 mg/dose
quantity is 3.75 Amphetamine (base) 4.23 the actual amount of IR
resin (at Dextroamphetamine (base) 4.23 a 34.17% assay value)
AMBERLITE IRP069 Resin 13.82 that went into each tablet. Humectant
1.24 The values in the gray area are Purified Water 1.24 the
quantities of each material that compromise the IR material. Coated
(DR) AMP Resin 165.08 The 165.08 mg/dose quantity is 25.01
Amphetamine (base) 5.17 the actual amount of DR resin (at
Dextroamphetamine (base) 5.17 a 6.26% assay value) AMBERLITE IRP069
Resin 16.89 that went into each tablet. Polyethylene Glycol 1.51
The IR resin material was used to Purified Water 1.51 make the
165.08 mg/dose DR HPMC Overcoat 43.92 material. EUDRAGIT L100 77.27
The values in the gray area are Plasticizer 13.64 the quantities of
each material that compromise the DR material. Excipients 470.16
71.24 Total 660.00 mg 100%
Dissolution Method
[0178] Dissolution Parameters:
[0179] Dissolution testing is carried out using a USP Apparatus 2
with cannulas and cannula filters (Quality Lab Accessories, Porus
Micron full flow filters 20 micron); paddle speed--100 rpm; kettle
size--1000 mL; temperature--37.0.+-.0.5.degree. C.; filter--25 mm
0.45 um PVDF w/GMF; syringe--B-D10 mL Luer-Lok.
[0180] Dissolution Media:
[0181] The medium for the dissolution assay is 900 mL of 0.1N HCl
for the first hour; after 2 hour time point .about.100 mL of
potassium phosphate/sodium hydroxide solution is added to bring to
pH .about.6.8.
[0182] The sample is weighed and is placed into the corresponding
kettle, and the dissolution timing started.
[0183] Sampling pull times are 30 minutes, 1 hour, 2 hours, 3
hours, and 4 hours. For each sample pull time and each kettle, 10
mL of sample are pulled into a B-D 10 mL Luer-Lok syringe and
returned to the kettles before the sample pull to flush out the
cannula from the prior pulls. 2 ml are then pulled for filtration
and placed into an HPLC vial. Non-media replacement and volume
changes from the two media changes are calculated.
[0184] Dissolution Profile:
[0185] The amount of drug in the filtrate at each time point is
determined by HPLC, and the percentage released from the drug-resin
is plotted in FIG. 2.
[0186] The same profile was obtained without the use of the HPMC
overcoat.
Example 5
Orally Disintegrating Tablet with 30% IR and 70% DR (Formula B)
[0187] An orally disintegrating tablet was formulated with 30% of
the amphetamine from immediate release resin complex and 70% of the
amphetamine from a delayed release resin complex. An HPMC coating
overlays the delayed released resin complex. The formula is
presented in Table 2.
TABLE-US-00002 TABLE 2 ODT amphetamine formulation with 30% IR and
70% DR with HPMC Overcoat IR - 34.17% base assay & DR- 6.26%
base assay: These values will be variable. Formula B (HPMC
overcoat) (30% active from IR Resin & 70% active from DR Resin)
mg/dose Notes % Uncoated (IR) AMP Resin 16.50 The 16.50 mg/dose
quantity is 2.50 Amphetamine (base) 2.82 the actual amount of IR
resin (at Dextroamphetamine (base) 2.82 a 34.17% assay value)
AMBERLITE IRP069 Resin 13.82 that went into each tablet. Humectant
1.24 The values in the gray area are Purified Water 1.24 the
quantities of each material that compromise the IR material. Coated
(DR) AMP Resin 210.12 The 210.12 mg/dose quantity is 31.84
Amphetamine (base) 6.58 the actual amount of DR resin (at
Dextroamphetamine (base) 6.58 a 6.26% assay value) AMBERLITE IRP069
Resin 21.50 that went into each tablet. Humectant 1.92 The IR resin
material was used to Purified Water 1.92 make the 210.12 mg/dose DR
HPMC Overcoat 55.91 material. EUDRAGIT L100 98.35 The values in the
gray area are Triethyl Citrate 17.36 the quantities of each
material that compromise the DR material. Excipients 433.38 65.66
Total 660.00 mg 100%
[0188] The dissolution method is performed as described in the
previous Example, except that sample pull times are 0.5, 1.0, 1.5,
2.0, 3.0, 4.0, 5.0, and 6.0 hours.
[0189] Dissolution Profile:
[0190] The amount of drug in the filtrate at each time point is
determined by HPLC, and the percentage released from the drug-resin
is plotted in FIG. 3.
[0191] The same profile was obtained without the use of the HPMC
overcoat.
Example 6
Orally Disintegrating Tablet with 45% IR and 55% DR (Formula C)
[0192] An orally disintegrating tablet was formulated with 45% of
the amphetamine from immediate release resin complex and 55% of the
amphetamine from a delayed release resin complex. This formulation
did not include an HPMC overcoat. The formula is presented in Table
3.
TABLE-US-00003 TABLE 3 ODT amphetamine formulation with 45% IR and
55% DR IR - 34.17% base assay & DR - 8.53% base assay: (These
values will be variable.) Formula C (no HPMC overcoat) (45% active
from IR Resin & 55% active from DR Resin) mg/dose Notes %
Uncoated (IR) AMP Resin 24.76 The 24.76 mg/dose quantity is 3.75
Amphetamine (base) 4.23 the actual amount of IR resin (at
Dextroamphetamine (base) 4.23 a 34.17% assay value) AMBERLITE
IRP069 Resin 13.82 that went into each tablet. Humectant 1.24 The
values in the gray area are Purified Water 1.24 the quantities of
each material that compromise the IR material. Coated (DR) AMP
Resin 121.16 The 121.16 mg/dose quantity is 18.36 Amphetamine
(base) 5.17 the actual amount of DR resin (at Dextroamphetamine
(base) 5.17 an 8.53% assay value) AMBERLITE IRP069 Resin 16.89 that
went into each tablet. Humectant 1.51 The IR resin material was
used to Purified Water 1.51 make the 121.16 mg/dose DR HPMC 20%
overcoat -- material. EUDRAGIT L100 77.27 The values in the gray
area are Plasticizer 13.64 the quantities of each material that
compromise the DR material. Excipients 514.08 77.89 Total 660.00 mg
100%
[0193] The dissolution method is performed as described in Example
4, except that sample pull times are 0.5, 1.0, 1.5, 2.0, 3.0, 4.0,
5.0, 6.0, 7.0, and 8.0 hours.
[0194] Dissolution Profile:
[0195] The amount of drug in the filtrate at each time point is
determined by HPLC, and the percentage released from the drug-resin
is plotted in FIG. 4.
Example 7
Suspension with 50% IR and 50% DR (Formula A1)
[0196] A suspension was formulated with 50% of the amphetamine from
immediate release resin complex and 50% of the amphetamine from a
delayed release resin complex. The resin was IRP-69. The delayed
release resin complexes coated with 15% TEC, and 70% EUDRAGIT L100.
The formulation is presented in Table 4.
TABLE-US-00004 TABLE 4 Suspension amphetamine formulation with 50%
IR and 50% DR Amount per Ingredient Application 15 ml Purified
Water Diluent 7.9 g Ascorbic Acid pH 6.00 mg Propylene Glycol
Solvent 525.00 mg Methylparaben Preservative 12.00 mg Propylparaben
Preservative 1.50 mg Polysorbate 80 Surfactant 15.00 mg Xanthan Gum
Suspending Agent 90.00 mg Vegetable (Corn) Oil Viscosity Agent
30.00 mg Amphetamine Active Resin 27.57 mg Uncoated Resin
Amphetamine Active Resin 76.19 mg Coated Resin Sucrose Sweetener
2250.00 mg High Fructose Com Syrup Sweetener 6750.00 mg
[0197] The dissolution method was performed as described in Example
4, except that the samples were pulled at different time points:
0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, and 6.0 hours.
[0198] Dissolution Profile:
[0199] The amount of drug in the filtrate at each time point was
determined by HPLC, and the percentage released from the drug-resin
is plotted in FIG. 5 and reflected below.
TABLE-US-00005 Leakage 2 W 2 W Initial AMB.sup.1 ASL.sup.2 30 Mins
(% Release): @ 2 Hours 47.9 56.8 60.3 (% Release): Profile (%
Release) Hours 51.5 67.2 72.4 0.5 47.9 56.8 60.3 1 51.5 66.7 70.5
1.5 52.2 66.1 72.5 2 52.8 67.2 72.4 2.5 93.4 100.2 97.8 3 94.9 99.9
97.8 4 95.6 100.1 98.1 6 102.5 98.2 .sup.1Two weeks under ambient
conditions. .sup.2Two weeks under accelerated shelf life
conditions.
Example 8
ODT with 50% IR and 50% DR (Formula D)
[0200] An orally disintegrating tablet was formulated with 50% of
the amphetamine from immediate release resin complex and 50% of the
amphetamine from a delayed release resin complex. This formulation
was similar to Examples 4-6 and is reflected in Table 5. The resin
was IRP-69. The delayed release coated resin comprised 15% TEC, and
70% EUDRAGIT L100.
TABLE-US-00006 TABLE 5 ODT amphetamine formulation with 50% IR and
50% DR. Amount per Ingredient Application tablet Amphetamine Resin
IR Active Resin I 38.10 mg (Assay -16.9%) Amphetamine Resin DR
Active Resin II 13.79 mg (Assay -46.7%) Ludiflash Compressing
371.11 mg Agent Croscarmellose Sodium Disintegrant 22.50 mg
Magnesium Stearate Lubricant 4.50 mg
[0201] The dissolution method was performed as described in Example
4, except that the samples were pulled at different time
points.
[0202] Dissolution Profile:
[0203] The amount of drug in the filtrate at each time point was
determined by HPLC, and the percentage released from the drug-resin
is plotted in FIG. 6 and reflected below.
TABLE-US-00007 Profile (% Release) Hours 0.5 50.5 1 51.0 1.5 51.5 2
52.4 2.5 85.3 3 96.0 4 96.9
Example 9
ODT with 35% IR and 65% DR (Formula E)
[0204] An orally disintegrating tablet was formulated with 35% of
the amphetamine from immediate release resin complex and 65% of the
amphetamine from a delayed release resin complex. This formulation
was similar to Examples 4-6 and is reflected in Table 6. Unlike
these examples, however, the resin was an IRP-64 resin. The delayed
release coated resin comprised 15% HPMC, 15% TEC, and 110% EUDRAGIT
L100.
TABLE-US-00008 TABLE 6 ODT amphetamine formulation with 35% IR and
65% DR with HPMC Overcoat Amount per Ingredient Application tablet
Amphetamine Resin DR Active Resin I 128.8 mg.sup.1 (Assay -6.5%)
Amphetamine Resin IR Active Resin II 7.07 mg.sup.2 (Assay -63.73%)
Ludiflash Compressing 287.13 mg Agent Croscarmellose Sodium
Disintegrant 22.50 mg Magnesium Stearate Lubricant 4.50 mg
[0205] The dissolution method was performed as described in Example
4, except that the samples were pulled at different time
points.
[0206] Dissolution Profile
[0207] The amount of drug in the filtrate at each time point was
determined by HPLC, and the percentage released from the drug-resin
is plotted in FIG. 7 and reflected below.
TABLE-US-00009 Profile Hours (% Release) 0.5 47.6 1 52.4 1.5 56 2
58.2 2.5 81.8 3 88.9 4 93.4 24 108.3
Example 10
pH Study
[0208] A pH study was also conducted to compare a control and four
different coated drug-resin particles prepared according to the
methods described in Examples 1 and 2 for the following coatings
and resins: (1) 70% EUDRAGIT L100/IRP69; (2) 110% EUDRAGIT L100/IRP
64; (3) 40% EUDRAGIT L100-55/IRP 69; (4) 70% EUDRAGIT L100-55/IRP
64.
[0209] pH Study Protocol:
[0210] The medium for the dissolution assay is 0.1N HCl. pH change
buffer described in the previous examples is added, drop wise,
until a pH of 2.0, 3.0, 4.0, 5.0, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7,
5.8, 5.9, 6.0, 6.1, 6.2, and 6.5 is reached. At each pH point, 2 mL
of sample was removed and then pH change buffer solution is added
to adjust pH to next pH target. The next sample is taken 10 minutes
after adjusted pH.
[0211] Varying the coating and the resin composition shifted the
release curve as shown in FIG. 8. EUDRAGIT L100 and IRP69 gave
results closest to the pH for release observed with ADDERALL
XR.
Example 11
Pig Study Using Pharmaceutical Compositions
[0212] This study is an open-label, random order, crossover
comparison study of three test formulations (two tablets and one
liquid suspension) and the currently marketed reference drug
(ADDERALL XR). In vivo studies are performed using pigs. A total of
12 animals are initially assigned to study (3 males per
group.times.4 groups). All animals are fasted overnight prior to
dosing and through the first 4 hours of blood sample collection
(total fasting time not to exceed 24 hours). Water is available ad
libitum. Animals are dosed on days 1, 4, 8, and 15).
[0213] Phase 1:
[0214] Each animal in Groups 1 and 2 receives a 2 tablet dose of
the appropriate test article formulation as outlined in the study
design in Table 7 below. Each animal in Group 4 receives a 1
capsule dose of the reference formulation as outlined in Table 7. A
balling gun may be used, if appropriate, to facilitate dosing.
Whether animals are hand-dosed or a balling gun is used for dosing,
a subsequent 10 mL tap water rinse is administered orally following
dosing. Each animal in Group 3 receives a single oral gavage (PO)
dose of the appropriate test article formulation as outlined in the
study design table below. The dosing syringes are weighed when
loaded with the test formulation and then again following dose
administration for each animal (i.e. loaded and delivered syringe
weights). Oral gavage dosing formulations will be continuously
stirred throughout dosing. The gavage tube should be rinsed with
approximately 10 mL of tap water following dosing (prior to removal
of the gavage tube).
[0215] Phase 2:
[0216] Following a washout at least 3 days, each animal in Groups 2
and 3 receives a 2 tablet dose of the appropriate test article
formulation as outlined in Table 7. Each animal in Group 1 receives
a 1 capsule dose of the reference formulation as outlined in Table
7. A balling gun may be used, if appropriate, to facilitate dosing.
Whether animals are hand-dosed or a balling gun is used for dosing,
a subsequent 10 mL tap water rinse is administered orally following
dosing. Each animal in Group 4 receives a single oral gavage (PO)
dose of the appropriate test article formulation as outlined in the
study design table below. The dosing syringes should be weighed
when loaded and then again following dose administration for each
animal (i.e. loaded and delivered syringe weights). Oral gavage
dosing formulations should be continuously stirred throughout
dosing. The gavage tube should be rinsed with approximately 10 mL
of tap water following dosing (prior to removal of the gavage
tube).
[0217] Phase 3:
[0218] Following a washout of at least 3 days, each animal in
Groups 3 and 4 receives a 2 tablet dose of the appropriate test
article formulation as outlined in Table 7. Each animal in Group 2
receives a 1 capsule dose of the reference formulation as outlined
in Table 7. A balling gun may be used, if appropriate, to
facilitate dosing. Whether animals are hand-dosed or a balling gun
is used for dosing, a subsequent 10 mL tap water rinse is
administered orally following dosing. Each animal in Group 1
receives a single oral gavage (PO) dose of the appropriate test
article formulation as outlined in the study design table below.
The dosing syringes are weighed when loaded and then again
following dose administration for each animal (i.e. loaded and
delivered syringe weights). Oral gavage dosing formulations are
continuously stirred throughout dosing. The gavage tube is rinsed
with approximately 10 mL of tap water following dosing (prior to
removal of the gavage tube).
[0219] Phase 4:
[0220] Following a washout of at least 3 days, each animal in
Groups 1 and 4 receives a 2 tablet dose of the appropriate test
article formulation as outlined in Table 7. Each animal in Group 3
receives a 1 capsule dose of the reference formulation as outlined
in Table 7. A balling gun may be used, if appropriate, to
facilitate dosing. Whether animals are hand-dosed or a balling gun
is used for dosing, a subsequent 10 mL tap water rinse is
administered orally following dosing. Each animal in Group 2
receives a single oral gavage (PO) dose of the appropriate test
article formulation as outlined in the study design table below.
The dosing syringes are weighed when and then again following dose
administration for each animal (i.e. loaded and delivered syringe
weights). Oral gavage dosing formulations are continuously stirred
throughout dosing. The gavage tube is rinsed with approximately 10
mL of tap water following dosing (prior to removal of the gavage
tube).
TABLE-US-00010 TABLE 7 Pig study design. Number of Dose Dose Level
Dose Volume/ Matrix Group Test Article Males* Route (mg) Amount
Collected PHASE 1 1 Neos 2 Formulation #1 3 Oral, tablet 30 2
tablets Blood.sup.E (15 mg/tablet) 2 Neos 2 Formulation #2 3 Oral,
tablet 30 2 tablets Blood.sup.E (15 mg/tablet) 3 Neos 2 Formulation
#3 3 PO, Liquid 30 15 mL Blood.sup.E suspension 4 Reference Drug 3
Oral, 30 1 capsule Blood.sup.E (ADDERALL XR) capsule (30
mg/capsule) Formulation PHASE 2 1 Reference Drug 3 Oral, 30 1
capsule Blood.sup.E (ADDERALL XR) capsule (30 mg/capsule)
Formulation 2 Neos 2 Formulation #1 3 Oral, tablet 30 2 tablets
Blood.sup.E (15 mg/tablet) 3 Neos 2 Formulation #2 3 Oral, tablet
30 2 tablets Blood.sup.E (15 mg/tablet) 4 Neos 2 Formulation #3 3
PO, Liquid 30 15 mL Blood.sup.E suspension PHASE 3 1 Neos 2
Formulation #3 3 PO, Liquid 30 15 mL Blood.sup.E suspension 2
Reference Drug 3 Oral, 30 1 capsule Blood.sup.E (ADDERALL XR)
capsule (30 mg/capsule) Formulation 3 Neos 2 Formulation #1 3 Oral,
tablet 30 2 tablets Blood.sup.E (15 mg/tablet) 4 Neos 2 Formulation
#2 3 Oral, tablet 30 2 tablets Blood.sup.E (15 mg/tablet) PHASE 4 1
Neos 2 Formulation #2 3 Oral, tablet 30 2 tablets Blood.sup.E (15
mg/tablet) 2 Neos 2 Formulation #3 3 PO, Liquid 30 15 mL
Blood.sup.E suspension 3 Reference 3 Oral, 30 1 capsule Blood.sup.E
(ADDERALL XR) capsule (30 mg/capsule) Formulation 4 Neos 2
Formulation #1 3 Oral, tablet 30 2 tablets Blood.sup.E (15
mg/tablet) .sup.D Reference Formulation is a Marketed Product. All
capsules and tablets will be used as received. .sup.EBlood samples
will be collected predose and at approximately 1, 2, 3, 4, 5, 6, 7,
8, 9, 12, 16, and 24 hours postdose. *The same animals will be used
for each phase following a washout of at least 3 days.
[0221] For each phase, blood samples (approximately 2 mL/sample)
are collected from the thoracic inlet (jugular vein, or other
suitable vein) predose and at approximately 1, 2, 3, 4, 5, 6, 7, 8,
9, 12, 16, and 24 hours postdose and placed into tubes containing
K.sub.2EDTA. All blood samples are placed on an ice block (or wet
ice) following collection. The samples are centrifuged and the
resulting plasma is separated and stored frozen at approximately
-70.degree. C. until analyzed (following separation; the plasma may
be initially placed on dry ice prior to being stored in the
-70.degree. C. freezer). Any clotted samples should be noted.
[0222] Plasma samples are analyzed for amphetamine over the range
of 0.1 ng/mL to 200 ng/mL. Control plasma procured from a
commercial source is used for all analyses. Each analysis batch
includes duplicate calibration samples (one set run at beginning of
batch and one at the end of batch) with a minimum of 6 non-zero
levels, and duplicate QC samples prepared at 4 concentration
levels. The calibration and QC samples are prepared from separate
stocks. Acceptance criteria for each batch is that at least 75% of
individual calibration points and 62.5% of the QC samples must be
within +/-30% of the target concentration.
Example 12
In Vivo Study
[0223] Drug samples from Examples 4 and 5 were administered to pigs
as described in Example 11. Capsules of ADDERALL XR were
administered as controls under the same conditions.
[0224] Results of the pig study are depicted in FIG. 9. Outliers
were excluded. FIG. 9 shows the plasma concentrations of drug
released from the formulas in Examples 4 and 5 compared to ADDERALL
XR (i.e., the reference formulation). The relative amounts of
coated and uncoated particles differed between Examples 4 and 5;
both compositions showed two peaks in the in vivo release profile,
but with the composition having relatively more coated particles,
the T.sub.max for both peaks is later, and the C.sub.max for the
second peak is higher. Thus, the skilled person can adjust the
relative C.sub.max and AUC for each of the two peaks by adjusting
the relative amounts of coated and uncoated drug-resin particles in
the composition.
Example 13
Ethanol Study
[0225] A. In Vivo Study
[0226] The effects of ethanol were also tested. In vivo studies
were carried out using drug samples similar to that from Example 6
administered to pigs as described in Example 11. The drug
formulations were administered to pigs as described in Example 11,
except that alcohol (240 ml of 20% ethanol) was also administered
to the pigs contemporaneously. Capsules of ADDERALL XR were
administered under the same conditions as controls.
[0227] Results of the pig study are depicted in FIGS. 10A and 10B.
Outliers were excluded. FIGS. 3A and 3B show the plasma
concentrations of drug released from the resin formulas similar to
that in Example 6 compared to ADDERALL XR (i.e., the reference
formulation) and IR mixed amphetamines in the presence and absence
of alcohol. The figures show (1) an increased exposure of
amphetamines in the presence of alcohol; and (2) in the present of
ethanol, formulations of the invention have a significantly reduced
exposure level of amphetamines as compared to ADDERALL XR as
demonstrated by comparison between the curves shown.
[0228] Often drugs products exhibit dose dumping in the presence of
ethanol. This is one of the reason that the FDA asks for ethanol
interaction studies on controlled release formulations. If a drug
product showed dose dumping, all of the drug that is to be
administered over time would become immediately available and
adverse events could be seen. In contrast, the graph clearly shows
that the integrity of the controlled release mechanism remains
intact and two peaks can be distinguished. The first peak being the
immediate release portion and the second peak being the still
intact delayed release portion. The increased exposure,
approximately 3 times the area under the curve (AUC), for both
peaks is due to another physiological effect in the presence of
ethanol such as impairment of the liver metabolism by the ethanol
and thus lower first pass metabolism of the drug in the liver or
other mechanism resulting in greater than expected blood levels for
a given dose.
[0229] B. In Vitro Study
[0230] In vitro dissolution studies using amphetamine compositions
in the presence or absence of ethanol were also carried out. Drug
compositions to be tested were introduced into USP dissolution
Apparatus 2 as described above, except that the media started with
alcoholic 0.1N HCl and samples were taken at different time points.
FIG. 11 shows the release profiles of the ADDERALL XR reference
formulation with 0%, 20%, and 40% ethanol. These results
demonstrate that the addition of 20% or 40% ethanol substantially
increases the amount of drug released in the reference formulation,
i.e., there is a substantial increase in drug released through dose
dumping in the presence of ethanol. This dose dumping may
exacerbate the exposure of the subject to amphetamines which
increases in vivo approximately 3 times in the presence of
ethanol.
[0231] FIG. 12 shows the release profiles of the drug sample
similar to that from Example 6 with 0%, 20%, and 40% ethanol. These
results demonstrate that the addition 20% ethanol does not
substantially increase the amount of drug released. Moreover, the
addition of 40% ethanol increases the amount of drug released but
to a lesser extent than in the reference formulation. As such, the
ethanol study's results show that, in the presence of ethanol, the
formulations of the invention have a reduced exposure level of
amphetamines as compared to the reference formulation. This
prevents or substantially reduces the likelihood of dose dumping
when the formulations of the invention and ethanol are ingested by
a subject.
Example 14
pH Study
[0232] A pH study was also conducted on the compositions
administered to the pigs in Example 13. The dissolution and pH
protocols are the same as described in Example 10. The results of
the pH study on three different lots of the delayed release
particles from Example 6 are depicted in FIG. 13.
Example 15
Human Pharmacokinetic Study Using ODT Pharmaceutical
Compositions
[0233] This example describes a single-dose, open-label,
randomized, three-period, three-treatment crossover study comparing
the rate of absorption and oral bioavailability of two controlled
release ODT preparations of mixed amphetamine polistirex
(equivalent to 30 mg mixed amphetamines) to an equivalent 30 mg
oral dose of the commercially available reference product, ADDERALL
XR, (Shire US Inc.) following an overnight fast of at least 10
hours. Subjects were randomly assigned to a treatment sequence and
received three, separate single-dose administrations of study
medication, one treatment per period, according to the
randomization schedule. Dosing days were separated by a washout
period of at least 7 days.
[0234] Subjects received each of the treatments listed below during
the three treatment periods:
[0235] Treatment A: Test Formulation #1 (mixed amphetamine resins)
controlled-release ODT. Test Formulation #1 is substantially
similar to Formula C in Example 6. Dose=1.times.mixed amphetamine
polistirex ODT equivalent to 30 mg mixed amphetamine salts.
[0236] Treatment B: Test Formulation #2 (mixed amphetamine resins)
controlled-release ODT. Test Formulation #2 is substantially
similar to Formula C in Example 6. Dose=1.times.mixed amphetamine
polistirex ODT equivalent to 30 mg mixed amphetamine salts
[0237] Treatment C: Reference Product ADDERALL XR Shire US, Inc.
Dose=1.times.30 mg capsule
Clinical Procedures Summary
[0238] During each study period, 4 mL blood samples were obtained
prior to each dosing and following each dose at selected times
through 60 hours post-dose. A total of 60 pharmacokinetic blood
samples were collected from each subject, 20 samples in each study
period. In addition, blood was drawn and urine was collected for
clinical laboratory testing at screening and study exit.
[0239] In each study period, subjects were admitted to the study
unit in the evening prior to the scheduled dose. Subjects were
confined to the research center during each study period until
completion of the 36-hour blood collection and other study
procedures. Subjects returned to the study unit for outpatient
pharmacokinetic blood samples at 48 and 60 hours. Thirty-three (33)
of the 36 subjects enrolled completed the study.
Procedures for Collecting Samples for Pharmacokinetic Analysis
[0240] Blood samples (1.times.4 mL) were collected in vacutainer
tubes containing K.sub.2-EDTA as a preservative at pre-dose (0) and
at 1.0, 2.0, 3.0, 4.0, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 9.0,
10.0, 12.0, 16.0, 24.0, 36.0, 48.0, and 60.0 hours after
dosing.
Bioanalytical Summary
[0241] Plasma samples were analyzed for d-amphetamine and
l-amphetamine by a third party laboratory using a validated LC MS
MS procedure. The method was validated for a range of 0.500 to 80.0
ng/mL for d-amphetamine and 0.200 to 32.0 ng/mL for l-amphetamine,
based on the analysis of 0.150 mL of human EDTA plasma.
Pharmacokinetic Analysis
[0242] Concentration time data were analyzed by noncompartmental
methods in WinNonlin. Concentration time data that were below the
limit of quantification (BLQ) were treated as zero in the data
summarization and descriptive statistics. In the pharmacokinetic
analysis, BLQ concentrations were treated as zero from time-zero up
to the time at which the first quantifiable concentration was
observed; embedded and/or terminal BLQ concentrations were treated
as "missing". Full precision concentration data (not rounded to
three significant figures) and actual sample times were used for
all pharmacokinetic and statistical analyses.
[0243] The following pharmacokinetic parameters were calculated:
peak concentration in plasma (C.sub.max), time to peak
concentration (T.sub.max), elimination rate constant (.lamda.z),
terminal half-life (T1/2), area under the concentration-time curve
from time-zero to the time of the last quantifiable concentration
(AUC.sub.last), and area under the plasma concentration time curve
from time-zero extrapolated to infinity (AUC.sub.inf). Secondary
pharmacokinetic endpoints included partial AUCs. The following
partial AUCs were calculated using the linear trapezoidal method:
AUC.sub.0-4, AUC.sub.4-12, and AUC.sub.0-24.
[0244] Analysis of variance (ANOVA) and the Schuirmann's two one
sided t test procedures at the 5% significance level were applied
to the log-transformed pharmacokinetic exposure parameters,
C.sub.max, AUC.sub.last, and AUC.sub.inf. The 90% confidence
interval for the ratio of the geometric means (Test/Reference) was
calculated. Bioequivalence was declared if the lower and upper
confidence intervals of the log-transformed parameters were within
80% to 125%. Comparisons of partial AUC.sub.0-4, AUC.sub.4-12, and
AUC.sub.0-24 across treatments were performed as supportive
evidence of equivalence.
Results
[0245] Data from 33 subjects who completed the study were included
in the pharmacokinetic and statistical analyses. Mean
concentration-time data are shown in FIGS. 14 and 15. Results of
the pharmacokinetic and statistical analyses are shown below in
Tables 8 through 11.
[0246] The results show that the d- and l-amphetamine enantiomers
of Test Formulations #1 and #2 were bioequivalent to the Reference
Product. In particular, nearly all of the partial AUCs
(AUC.sub.4-12 and AUC.sub.0-24) of the d- and l-amphetamine
enantiomers of Test Formulations #1 and #2 were bioequivalent to
the Reference Product.
[0247] FIGS. 14A and 14B show the mean d-amphetamine
concentration-time profiles after administration of Test
Formulation #1 (Treatment A), Test Formulation #2 (Treatment B),
and Reference Product (Treatment C).
[0248] FIGS. 15A and 15B show the mean l-amphetamine
concentration-time profiles after administration of test
formulation #1 (Treatment A), test formulation #2 (Treatment B),
and reference product (Treatment C).
TABLE-US-00011 TABLE 8 Statistical analysis of the log-transformed
systemic exposure parameters of d-amphetamine comparing Test
Formulation #1 (Treatment A) to the Reference Product (Treatment
C). Dependent Geometric Mean.sup.a Ratio (%).sup.b 90% CI.sup.c
ANOVA Variable Test Ref (Test/Ref) Lower Upper Power CV %
ln(C.sub.max) 44.5370 45.9975 96.82 94.62 99.08 1.0000 5.61
ln(AUC.sub.0-4) 85.9326 100.9418 85.13 78.30 92.56 0.9965 20.54
ln(AUC.sub.4-12) 290.8805 294.3597 98.82 96.85 100.82 1.0000 4.89
ln(AUC.sub.0-24) 613.2608 631.8461 97.06 94.84 99.32 1.0000 5.61
ln(AUC.sub.last) 825.7531 843.4700 97.90 94.99 100.90 1.0000 7.34
ln(AUC.sub.inf) 848.3149 866.4947 97.90 94.73 101.18 1.0000 7.88
.sup.aGeometric Mean for the Test Formulation #1 (Test) and
Reference Product (Ref) based on Least Squares Mean of
log-transformed parameter values .sup.bRatio (%) = Geometric Mean
(Test)/Geometric Mean (Ref) .sup.c90% Confidence Interval Note:
T.sub.1/2 and parameters based on extrapolation could not be
calculated for all subjects; statistical analysis is based on n =
33 for C.sub.max, AUC.sub.0-4, AUC.sub.4-12, AUC.sub.0-24,
AUC.sub.last, and n = 32 for AUC.sub.inf
TABLE-US-00012 TABLE 9 Statistical analysis of the log-transformed
systemic exposure parameters of d-amphetamine comparing Test
Formulation #2 (Treatment B) to the Reference Product (Treatment
C). Dependent Geometric Mean.sup.a Ratio (%).sup.b 90% CI.sup.c
ANOVA Variable Test Ref (Test/Ref) Lower Upper Power CV %
ln(C.sub.max) 45.2664 45.9975 98.41 96.17 100.70 1.0000 5.61
ln(AUC.sub.0-4) 80.8609 100.9418 80.11 73.68 87.09 0.9965 20.54
ln(AUC.sub.4-12) 295.5819 294.3597 100.42 98.42 102.45 1.0000 4.89
ln(AUC.sub.0-24) 616.5054 631.8461 97.57 95.35 99.85 1.0000 5.61
ln(AUC.sub.last) 830.7075 843.4700 98.49 95.56 101.50 1.0000 7.34
ln(AUC.sub.inf) 851.1774 866.4947 98.23 95.05 101.52 1.0000 7.88
.sup.aGeometric Mean for the Test Formulation #2 (Test) and
Reference Product (Ref) based on Least Squares Mean of
log-transformed parameter values .sup.bRatio (%) = Geometric Mean
(Test)/Geometric Mean (Ref) .sup.c90% Confidence Interval Note:
T.sub.1/2 and parameters based on extrapolation could not be
calculated for all subjects; statistical analysis is based on n =
33 for C.sub.max, AUC.sub.0-4, AUC.sub.4-12, AUC.sub.0-24,
AUC.sub.last, and n = 32 for AUC.sub.inf
TABLE-US-00013 TABLE 10 Statistical analysis of the log-transformed
systemic exposure parameters of l-amphetamine comparing Test
Formulation #1 (Treatment A) to the Reference Product (Treatment
C). Dependent Geometric Mean.sup.a Ratio (%).sup.b 90% CI.sup.c
ANOVA Variable Test Ref (Test/Ref) Lower Upper Power CV %
ln(C.sub.max) 14.2494 14.1857 100.45 98.07 102.89 1.0000 5.85
ln(AUC.sub.0-4) 26.3537 30.0286 87.76 80.53 95.64 0.9951 21.14
ln(AUC.sub.4-12) 95.1124 93.0132 102.26 100.09 104.47 1.0000 5.20
ln(AUC.sub.0-24) 204.9113 203.7331 100.58 98.07 103.15 1.0000 6.14
ln(AUC.sub.last) 295.5590 290.6272 101.70 98.33 105.18 1.0000 8.21
ln(AUC.sub.inf) 312.0976 307.0441 101.65 97.80 105.64 1.0000 9.24
.sup.aGeometric Mean for the Test Formulation #1 (Test) and
Reference Product (Ref) based on Least Squares Mean of
log-transformed parameter values .sup.bRatio (%) = Geometric Mean
(Test)/Geometric Mean (Ref) .sup.c90% Confidence Interval Note:
T.sub.1/2 and parameters based on extrapolation could not be
calculated for all subjects; statistical analysis is based on n =
33 for C.sub.max, AUC.sub.0-4, AUC.sub.4-12, AUC.sub.0-24,
AUC.sub.last, and n = 32 for AUC.sub.inf
TABLE-US-00014 TABLE 11 Statistical analysis of the log-transformed
systemic exposure parameters of l-amphetamine comparing Test
Formulation #2 (Treatment B) to the Reference Product (Treatment
C). Dependent Geometric Mean.sup.a Ratio (%).sup.b 90% CI.sup.c
ANOVA Variable Test Ref (Test/Ref) Lower Upper Power CV %
ln(C.sub.max) 14.6051 14.1857 102.96 100.51 105.46 1.0000 5.85
ln(AUC.sub.0-4) 24.9270 30.0286 83.01 76.17 90.46 0.9951 21.14
ln(AUC.sub.4-12) 96.8135 93.0132 104.09 101.88 106.34 1.0000 5.20
ln(AUC.sub.0-24) 206.6684 203.7331 101.44 98.91 104.03 1.0000 6.14
ln(AUC.sub.last) 297.5544 290.6272 102.38 98.99 105.89 1.0000 8.21
ln(AUC.sub.inf) 313.3883 307.0441 102.07 98.21 106.07 1.0000 9.24
.sup.aGeometric Mean for the Test Formulation #2 (Test) and
Reference Product (Ref) based on Least Squares Mean of
log-transformed parameter values .sup.bRatio(%) = Geometric Mean
(Test)/Geometric Mean (Ref) .sup.c90% Confidence Interval Note:
T.sub.1/2 and parameters based on extrapolation could not be
calculated for all subjects; statistical analysis is based on n =
33 for C.sub.max, AUC.sub.0-4, AUC.sub.4-12, AUC.sub.0-24,
AUC.sub.last, and n = 32 for AUC.sub.inf
Example 16
Human Pharmacokinetic Study Comparing ODT to Suspension
Formulations
[0249] This example compared the rate of absorption and oral
bioavailability of a controlled release ODT preparation of mixed
amphetamine polistirex (equivalent to 30 mg mixed amphetamine
salts) and a controlled release liquid suspension of mixed
amphetamine polistirex (equivalent to 30 mg mixed amphetamine
salts) to an equivalent 30 mg oral dose of the commercially
available reference product, ADDERALL XR (Shire US Inc.) following
an overnight fast of at least 10 hours. Subjects were randomly
assigned to a treatment sequence and received three separate
single-dose administrations of study medication, one treatment per
period, according to the randomization schedule as described in the
previous Example. Dosing days were separated by a washout period of
at least 7 days.
[0250] Subjects received each of the treatments listed below during
the three treatment periods:
[0251] Treatment A: Test Formulation #3 (mixed amphetamine resins)
controlled-release ODT. Dose=1.times.mixed amphetamine polistirex
ODT equivalent to 30 mg mixed amphetamine salts.
[0252] Treatment B: Test Formulation #4 (mixed amphetamine resins)
controlled-release suspension. Dose=1.times.mixed amphetamine
polistirex suspension equivalent to 30 mg mixed amphetamine
salts.
[0253] Treatment C: Reference Product ADDERALL XR, Shire US, Inc.
Dose=1.times.30 mg capsule.
TABLE-US-00015 TABLE 12 Test Formulation #3 (ODT amphetamine with
45% IR and 55% DR) IR Resin - 34.08% base assay & DR Resin -
7.28% base assay: These values will be variable Formula #3 (45%
active from IR Resin & 55% active from DR Resin) mg/dose Notes
% Uncoated (IR) AMP Resin 24.82 3.76 Amphetamine (base) 4.23
Dextroamphetamine (base) 4.23 AMBERLITE IRP069 Resin 13.88
Polyethylene Glycol 1.24 Purified Water 1.24 Coated (DR) AMP Resin
142.03 21.52 Amphetamine (base) 5.17 Dextroamphetamine (base) 5.17
AMBERLITE IRP069 Resin 16.96 Polyethylene Glycol 1.52 Purified
Water 1.52 EUDRAGIT L100 97.21 Triethyl Citrate 14.48 Prosolv ODT
323.20 48.97 Crospovidone 105.60 16.00 Flavorings 65.35 9.75 Total
660.00 mg 100%
TABLE-US-00016 TABLE 13 Test Formulation #4 (Suspension amphetamine
with 45% IR and 55% DR) IR Resin - 34.08% base assay & DR Resin
- 7.28% base assay: Formula #4 (45% active from IR Resin & 55%
active from DR Resin) mg per 15 mL dose Notes % Uncoated (IR) AMP
Resin 24.82 0.14 Amphetamine (base) 4.23 Dextroamphetamine (base)
4.23 AMBERLITE IRP069 Resin 13.88 Polyethylene Glycol 1.24 Purified
Water 1.24 Coated (DR) AMP Resin 142.03 0.79 Amphetamine (base)
5.17 Dextroamphetamine (base) 5.17 AMBERLITE IRP069 Resin 16.96
Polyethylene Glycol 1.52 Purified Water 1.52 EUDRAGIT L100 97.21
Triethyl Citrate 14.48 Purified Water 8123.2 Each 15 mL dose of
suspension is 45.13 Ascorbic Acid 6.00 equivalent to 18 grams at
the 0.03 Propylene Glycol 525.00 theoretical suspension specific
2.92 Preservative 3.75 gravity of 1.2. 0.03 Polysorbate 80 15.00
0.08 Xanthan Gum 90.00 0.50 Vegetable Oil 30.00 0.17 Color &
Flavor 40.20 <0.23 Sucrose 2250.00 12.50 High Fructose Corn
Syrup 6750.00 37.50 Total 18,000.00 mg 100%
[0254] Administration, data collection and analysis were carried
out as described in the previous Example. Data from subjects who
completed the study were included in the pharmacokinetic and
statistical analyses. Mean concentration-time data are shown in
FIGS. 16-19. Results of the pharmacokinetic and statistical
analyses are shown below in Tables 14 through 17.
TABLE-US-00017 TABLE 14 Statistical Analysis of Human
Bioequivalence Studies: ODT Data (D-Isomer) Mean Ratio (%) 90% CI
Dependent Variable Test Ref (Test/Ref) Lower Upper ln(C.sub.max)
44.5 46.0 96.7 94.6 99.1 ln(AUC.sub.0-4) 85.9 100.9 85.1 78.3 92.6
ln(AUC.sub.0-5) 126.3 46.0 87.7 82.1 93.7 (?) ln(AUC.sub.4-12)
290.9 294.4 98.8 96.9 100.8 ln(AUC.sub.5-12) 250.5 251.6 99.5 97.3
101.8 ln(AUC.sub.0-24) 613.3 631.8 97.1 94.8 99.3 ln(AUC.sub.last)
825.8 843.5 97.9 95.0 100.9 ln(AUC.sub.inf) 848.3 866.5 97.9 94.7
101.2 T.sub.max 5.26 4.53
TABLE-US-00018 TABLE 15 Statistical Analysis of Human
Bioequivalence Studies: ODT Data (L-Isomer) Mean Ratio (%) 90% CI
Dependent Variable Test Ref (Test/Ref) Lower Upper ln(C.sub.max)
14.2 14.2 100.5 98.1 102.9 ln(AUC.sub.0-4) 26.4 30.0 87.8 80.5 95.6
ln(AUC.sub.0-5) 39.2 43.2 90.7 84.6 97.1 ln(AUC.sub.4-12) 95.1 93.0
102.3 100.1 104.5 ln(AUC.sub.5-12) 82.3 79.9 103.0 100.5 105.5
ln(AUC.sub.0-24) 204.9 203.7 100.6 98.1 103.2 ln(AUC.sub.last)
295.6 290.6 101.7 98.3 105.2 ln(AUC.sub.inf) 312.1 307.0 101.7 97.8
105.6 T.sub.max 5.70 4.59
TABLE-US-00019 TABLE 16 Statistical Analysis of Human
Bioequivalence Studies: Suspension Data (D-Isomer) Dependent Mean
Ratio (%) 90% CI Variable Test Ref (Test/Ref) Lower Upper
In(C.sub.max) 46.3 49.1 94.2 91.4 97.0 In(AUC.sub.0-4) 104.7 107.4
97.5 88.7 107.0 In(AUC.sub.0-5) 148.6 152.4 97.5 90.7 104.9
In(AUC.sub.4-12) 300.4 313.8 95.7 92.7 98.9 In(AUC.sub.5-12) 256.9
269.1 95.5 92.1 98.9 In(AUC.sub.0-24) 651.8 680.2 95.8 92.6 99.2
In(AUC.sub.last) 861.2 904.5 95.2 91.0 99.6 In(AUC.sub.inf) 892.8
935.4 95.4 91.0 100.1 T.sub.max 4.61 4.96
TABLE-US-00020 TABLE 17 Statistical Analysis of Human
Bioequivalence Studies: Suspension Data (L-Isomer) Mean Ratio (%)
90% CI Dependent Variable Test Ref (Test/Ref) Lower Upper
ln(C.sub.max) 14.6 14.8 98.9 96.3 101.6 ln(AUC.sub.0-4) 31.8 31.6
100.8 91.6 110.8 ln(AUC.sub.0-5) 45.7 45.2 101.1 93.8 108.9
ln(AUC.sub.4-12) 96.8 97.1 99.7 96.4 103.2 ln(AUC.sub.5-12) 83.2
83.6 99.5 95.9 103.2 ln(AUC.sub.0-24) 215.2 215.5 99.9 96.3 103.6
ln(AUC.sub.last) 304.8 306.8 99.3 94.6 104.4 ln(AUC.sub.inf) 325.3
327.0 99.5 94.0 105.2 T.sub.max 5.09 5.27
Example 17
Orally Disintegrating Tablet with 25% IR and 75% ER/DR
[0255] An orally disintegrating tablet was formulated with 25% of
methylphenidate from immediate release resin complex and 75% of the
methylphenidate from an extended release (ER)/delayed release (DR)
resin complex. In the ER/DR coating, ethylcellulose overlays
EUDRAGIT. The formula is presented below.
TABLE-US-00021 TABLE 18 ODT methylphenidate Formulation A with 25%
IR and 75% ER/DR. IR Resin - 36.98% base assay & ER/DR Resin -
13.11% base assay: These values are variable Formula A (25% active
from IR Resin & 75% active from ER/DR Resin) mg/dose Notes %
Uncoated (IR) MPH Resin 17.65 The 17.65 mg/dose quantity is the
2.67 Methylphenidate (base) 6.525 actual amount of IR resin (at a
AMBERLITE IRP069 Resin 10.24 36.98% assay value) that Polyethylene
Glycol 0.441 goes into each tablet. Purified Water 0.441 The values
in the gray area are the quantities of each material that
compromise the IR material. Coated (ER/DR) MPH Resin 149.37 The
149.37 mg/dose quantity is 22.63 Methylphenidate (base) 19.575 the
actual amount of ER/DR resin AMBERLITE IRP069 Resin 30.72 (at a
13.11% assay value) Polyethylene Glycol 1.32 that goes into each
tablet. Purified Water 1.32 The IR resin material was used to
Ethylcellulose N-10 11.505 make the 149.37 mg/dose ER/DR EUDRAGIT
L100 73.37 material. Triethyl Citrate 11.56 The values in the gray
area are the quantities of each material that compromise the ER/DR
material. Prosolv ODT 369.83 The Prosolv ODT quantity will 56.03
Crospovidone 66.00 be variable to account for the variable 10.00
Sucralose Powder 23.00 assay value of the IR and DR resin 3.48
Citric Acid 10.00 1.52 Flavor & Color 17.55 2.66 Magnesium
Stearate 6.60 1.00 Total 660.00 mg 100%
TABLE-US-00022 TABLE 19 ODT methylphenidate Formulation B with 25%
IR and 75% ER/DR. IR Resin - 36.98% base assay & ER/DR Resin -
12.77% base assay: These values are variable. Formula B (25% active
from IR Resin & 75% active from ER/DR Resin) mg/dose Notes %
Uncoated (IR) MPH Resin 17.65 The 17.65 mg/dose quantity is the
2.67 Methylphenidate (base) 6.525 actual amount of IR resin (at a
AMBERLITE IRP069 Resin 10.24 36.98% assay value) that Polyethylene
Glycol 0.441 goes into each tablet. Purified Water 0.441 The values
in the gray area are the quantities of each material that
compromise the IR material. Coated (ER/DR) MPH Resin 153.32 The
153.32 mg/dose quantity is 23.23 Methylphenidate (base) 19.575 the
actual amount of ER/DR resin AMBERLITE IRP069 Resin 30.72 (at a
12.77% assay value) Polyethylene Glycol 1.32 that goes into each
tablet. Purified Water 1.32 The IR resin material was used to
Ethylcellulose N-10 13.13 make the 153.32 mg/dose ER/DR EUDRAGIT
L100 75.31 material. Triethyl Citrate 11.945 The values in the gray
area are the quantities of each material that compromise the ER/DR
material. Prosolv ODT 365.88 The Prosolv ODT quantity will 55.44
Crospovidone 66.00 be variable to account for the variable 10.00
Sucralose Powder 23.00 assay value of the IR and DR resin. 3.48
Citric Acid 10.00 1.52 Flavor & Color 17.55 2.66 Magnesium
Stearate 6.60 1.00 Total 660.00 mg 100%
[0256] These formulas are exactly the same except for the level of
actual ethylcellulose coating (as determined by assay). Formula "A"
has 18.6% ethylcellulose coating and "B" has 20.7%. These are the
calculated coating levels of ethylcellulose prior to the EUDRAGIT
coating.
[0257] Dissolution Method
[0258] Dissolution testing is carried out using an Apparatus 2 with
cannulas and cannula filters (Quality Lab Accessories, Porus Micron
full flow filters 20 micron); paddle speed--100 rpm; kettle
size--1000 mL; temperature--37.0.+-.0.5.degree. C.; filter--25 mm
0.45 um PTFE; syringe--B-D10 mL Luer-Lok.
[0259] Dissolution Media:
[0260] The medium for the dissolution assay is 900 mL of 0.1N HCl
for the first hour; after 2 hour time point .about.100 mL of
potassium phosphate/sodium hydroxide solution is added to bring to
pH .about.6.8.
[0261] The sample is weighed and is placed into the corresponding
kettle, and the dissolution timing started.
[0262] Sampling pull times are 30 minutes, 2 hours, 4 hours and 8
hours. For each sample pull time and each kettle, 10 mL of sample
are pulled into a B-D 10 mL Luer-Lok syringe and returned to the
kettles before the sample pull to flush out the cannula from the
prior pulls. 4 ml are then pulled for filtration, discarding the
first 2 ml to waste and the remaining sample into an HPLC vial.
Non-media replacement and volume changes from the two media changes
are calculated.
[0263] Dissolution Profile:
[0264] The amount of drug in the filtrate at each time point is
determined by HPLC, and the percentage released from Formulae A and
B, respectively, are shown below and in FIG. 26.
[0265] Formula A Profile
TABLE-US-00023 Profile Hours (% Release) 0.5 31% 2 39% 4 79% 8 87%
24 87%
[0266] Formula B Profile
TABLE-US-00024 Profile Hours (% Release) 0.5 32% 2 41% 4 80% 8 90%
24 90%
Example 18
Human Pharmacokinetic Study Using ODT Pharmaceutical
Compositions
[0267] This example describes a single-dose, open-label,
randomized, three-period, three-treatment crossover study comparing
the rate of absorption and oral bioavailability of two controlled
release ODT preparations of methylphenidate polistirex (equivalent
to 60 mg methylphenidate) to an equivalent 60 mg oral dose of the
commercially available reference product, METADATE CD, (UCB, Inc.)
following an overnight fast of at least 10 hours. Subjects were
randomly assigned to a treatment sequence and received three,
separate single-dose administrations of study medication, one
treatment per period, according to the randomization schedule.
Dosing days were separated by a washout period of at least 7
days.
[0268] Subjects received each of the treatments listed below during
the three treatment periods:
[0269] Treatment A: Test Formulation #1 (methylphenidate resins)
controlled-release ODT. Test Formulation #1 is substantially
similar to the formulation A described in Example 17.
Dose=2.times.methylphenidate polistirex ODT containing 26.1 mg
methylphenidate base, equivalent to 60 mg methylphenidate HCl.
[0270] Treatment B: Test Formulation #2 (methylphenidate resins)
controlled-release ODT. Test Formulation #2 is substantially
similar to the formulation B described in Example 17.
Dose=2.times.methylphenidate polistirex ODT containing 26.1 mg
methylphenidate base, equivalent to 60 mg methylphenidate HCl.
[0271] Treatment C: Reference Product METADATE CD UCB, Inc.
Dose=1.times.60 mg capsule
Clinical Procedures Summary
[0272] During each study period, 6 mL blood samples were obtained
prior to each dosing and following each dose at selected times
through 36 hours post-dose. A total of 63 pharmacokinetic blood
samples were collected from each subject, 21 samples in each study
period. In addition, blood was drawn and urine was collected for
clinical laboratory testing at screening and study exit.
[0273] In each study period, subjects were admitted to the study
unit in the evening prior to the scheduled dose. Subjects were
confined to the research center during each study period until
completion of the 24-hour blood collection and other study
procedures. Subjects returned to the study unit for outpatient
pharmacokinetic blood samples at 36 hours. Thirty-eight (38) of the
42 subjects enrolled completed the study.
Procedures for Collecting Samples for Pharmacokinetic Analysis
[0274] Blood samples (1.times.6 mL) were collected in vacutainer
tubes containing K.sub.2-EDTA as a preservative at pre-dose (0) and
at 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5,
7.0, 8.0, 10.0, 12.0, 18.0, 24.0, and 36.0 hours after dosing.
Bioanalytical Summary
[0275] Plasma samples were analyzed for d-methylphenidate and
l-methylphenidate by a third party laboratory using a validated
LC-MS-MS procedure. The method was validated for a range of 0.250
to 50.0 ng/mL for d-methylphenidate and 0.0100 to 2.00 ng/mL for
l-methylphenidate, based on the analysis of 0.100 mL of human EDTA
plasma.
Pharmacokinetic Analysis
[0276] Concentration time data were analyzed by noncompartmental
methods in WinNonlin. Concentration time data that were below the
limit of quantification (BLQ) were treated as zero in the data
summarization and descriptive statistics. In the pharmacokinetic
analysis, BLQ concentrations were treated as zero from time-zero up
to the time at which the first quantifiable concentration was
observed; embedded and/or terminal BLQ concentrations were treated
as "missing". Full precision concentration data (not rounded to
three significant figures) and actual sample times were used for
all pharmacokinetic and statistical analyses.
[0277] The following pharmacokinetic parameters were calculated for
d-methylphenidate, 1-methylphenidate, and total methylphenidate
(d+l): peak concentration in plasma (C.sub.max), time to peak
concentration (T.sub.max), elimination rate constant (.lamda.z),
terminal half-life (T1/2), area under the concentration-time curve
from time-zero to the time of the last quantifiable concentration
(AUC.sub.last), and area under the plasma concentration time curve
from time-zero extrapolated to infinity (AUC.sub.inf). Secondary
pharmacokinetic endpoints included partial AUCs. The following
partial AUCs were calculated using the linear trapezoidal method:
AUC.sub.0-3, AUC0-.sub.tmax (AUC.sub.0-5), AUC.sub.tmax-24
(AUC.sub.5-24), AUC.sub.0-24, and AUC.sub.tmax-tlast.
[0278] Test Formulations #1 and #2 were compared to the reference
product. Analysis of variance (ANOVA) and the Schuirmann's two one
sided t test procedures at the 5% significance level were applied
to the log-transformed pharmacokinetic exposure parameters,
C.sub.max, AUC.sub.last, and AUC.sub.inf d-methylphenidate,
l-methylphenidate, and total methylphenidate (d+l). The 90%
confidence interval for the ratio of the geometric means
(Test/Reference) was calculated. Bioequivalence was declared if the
lower and upper confidence intervals of the log-transformed
parameters were within 80% to 125%. mComparisons of partial AUCs,
AUC.sub.0-3, AUC0.sub.-tmax (AUC.sub.0-5), AUC.sub.tmax-24
(AUC.sub.5-24), AUC.sub.0-24, and AUC.sub.tmax-tlast across
treatments were performed as supportive evidence of
equivalence.
Results
[0279] Data from 38 subjects who completed the study were included
in the pharmacokinetic and statistical analyses.
[0280] FIGS. 20A and 20B show the mean linear and log
d-methylphenidate concentration-time profiles after administration
of Test Formulation #1 (Treatment A), Test Formulation #2
(Treatment B), and Reference Product (Treatment C).
[0281] FIGS. 21A and 21B show the mean linear and log
l-methylphenidate concentration-time profiles after administration
of Test Formulation #1 (Treatment A), Test Formulation #2
(Treatment B), and Reference Product (Treatment C).
[0282] FIGS. 22A and 22B show the mean linear and log total
methylphenidate (d+l) concentration-time profiles after
administration of Test Formulation #1 (Treatment A), Test
Formulation #2 (Treatment B), and Reference Product (Treatment
C).
TABLE-US-00025 TABLE 20 Statistical Analysis of the Log-Transformed
Systemic Exposure Parameters of d-Methylphenidate Comparing Test
Formulation 1 (Treatment A) to the Reference Product (Treatment C)
Dependent Geometric Mean.sup.a Ratio (%).sup.b 90% CI.sup.c ANOVA
Variable Test Ref (Test/Ref) Lower Upper Power CV % ln(C.sub.max)
20.1714 16.3095 123.68 117.21 130.50 1.0000 14.10 ln(AUC.sub.0-3)
20.5344 23.7682 86.39 79.10 94.36 0.9935 23.36
ln(AUC.sub.0-tmax).sup.d 50.1624 50.0850 100.15 93.53 107.25 0.9998
18.03 ln(AUC.sub.tmax-24).sup.d 103.8409 95.3024 108.96 104.11
114.04 1.0000 11.94 ln(AUC.sub.0-24) 156.7217 146.3987 107.05
103.73 110.48 1.0000 8.25 ln(AUC.sub.tmax-tlast).sup.d 104.3909
100.4459 103.93 98.76 109.37 1.0000 13.39 ln(AUC.sub.last) 157.4500
151.7064 103.79 100.26 107.44 1.0000 9.05 ln(AUC.sub.inf) 161.1557
157.9722 102.02 98.78 105.35 1.0000 8.43 .sup.aGeometric Mean for
the Test Formulation 1 (Test) and Reference Product (Ref) based on
Least Squares Mean of log-transformed parameter values
.sup.bRatio(%) = Geometric Mean (Test)/Geometric Mean (Ref)
.sup.c90% Confidence Interval .sup.dThe median T.sub.max of the
Reference Product (5.00 hr) was used
TABLE-US-00026 TABLE 21 Statistical Analysis of the Log-Transformed
Systemic Exposure Parameters of d-Methylphenidate Comparing Test
Formulation 2 (Treatment B) to the Reference Product (Treatment C).
Dependent Geometric Mean.sup.a Ratio (%).sup.b 90% CI.sup.c ANOVA
Variable Test Ref (Test/Ref) Lower Upper Power CV % ln(C.sub.max)
20.4113 16.3095 125.15 118.62 132.04 1.0000 14.10 ln(AUC.sub.0-3)
21.7843 23.7682 91.65 83.92 100.10 0.9936 23.36
ln(AUC.sub.0-tmax).sup.d 51.9061 50.0850 103.64 96.79 110.97 0.9998
18.03 ln(AUC.sub.tmax-24).sup.d 105.8856 95.3024 111.10 106.16
116.27 1.0000 11.94 ln(AUC.sub.0-24) 160.7525 146.3987 109.80
106.40 113.31 1.0000 8.25 ln(AUC.sub.tmax-tlast).sup.d 106.3546
100.4459 105.88 100.62 111.42 1.0000 13.39 ln(AUC.sub.last)
161.3617 151.7064 106.36 102.75 110.10 1.0000 9.05 ln(AUC.sub.inf)
165.4229 157.9722 104.72 101.40 108.14 1.0000 8.43 .sup.aGeometric
Mean for the Test Formulation 2 (Test) and Reference Product (Ref)
based on Least Squares Mean of log-transformed parameter values
.sup.bRatio(%) = Geometric Mean (Test)/Geometric Mean (Ref)
.sup.c90% Confidence Interval .sup.dThe median T.sub.max of the
Reference Product (5.00 hr) was used
TABLE-US-00027 TABLE 22 Statistical Analysis of the Log-Transformed
Systemic Exposure Parameters of l-Methylphenidate Comparing Test
Formulation 1 (Treatment A) to the Reference Product (Treatment C).
Dependent Geometric Mean.sup.a Ratio (%).sup.b 90% CI.sup.c ANOVA
Variable Test Ref (Test/Ref) Lower Upper Power CV % ln(C.sub.max)
0.4471 0.2224 201.01 167.90 240.64 0.6550 49.75 ln(AUC.sub.0-3)
0.6292 0.2691 233.82 198.86 274.92 0.7346 44.29
ln(AUC.sub.0-tmax).sup.d 1.0739 0.5281 203.35 175.47 235.66 0.8024
40.01 ln(AUC.sub.tmax-24).sup.d 0.9649 0.7668 125.84 108.56 145.87
0.8013 40.08 ln(AUC.sub.0-24) 2.1909 1.3404 163.45 143.93 185.62
0.8936 34.18 ln(AUC.sub.tmax-tlast).sup.d 0.8821 0.7435 118.64
101.75 138.33 0.7736 41.81 ln(AUC.sub.last) 2.1125 1.3231 159.66
140.14 181.90 0.8801 35.09 ln(AUC.sub.inf) 2.2098 1.5598 141.68
122.06 164.44 0.7952 40.46 .sup.aGeometric Mean for the Test
Formulation 1 (Test) and Reference Product (Ref) based on Least
Squares Mean of log-transformed parameter values .sup.bRatio(%) =
Geometric Mean (Test)/Geometric Mean (Ref) .sup.c90% Confidence
Interval .sup.dThe median T.sub.max of the Reference Product (5.00
hr) was used
TABLE-US-00028 TABLE 23 Statistical Analysis of the Log-Transformed
Systemic Exposure Parameters of l-Methyphenidate Comparing Test
Formulation 2 (Treatment B) to the Reference Product (Treatment C)
Dependent Geometric Mean.sup.a Ratio (%).sup.b 90% CI.sup.c ANOVA
Variable Test Ref (Test/Ref) Lower Upper Power CV % ln(C.sub.max)
0.5092 0.2224 228.93 191.26 274.02 0.6557 49.75 ln(AUC.sub.0-3)
0.6798 0.2691 252.63 214.89 296.99 0.7354 44.29
ln(AUC.sub.0-tmax).sup.d 1.1261 0.5281 213.23 184.02 247.07 0.8031
40.01 ln(AUC.sub.tmax-24).sup.d 1.1095 0.7668 144.70 124.85 167.70
0.8021 40.08 ln(AUC.sub.0-24) 2.4426 1.3404 182.23 160.49 206.92
0.8942 34.18 ln(AUC.sub.tmax-tlast).sup.d 1.0239 0.7435 137.71
118.13 160.55 0.7744 41.81 ln(AUC.sub.last) 2.3641 1.3231 178.68
156.86 203.54 0.8807 35.09 ln(AUC.sub.inf) 2.4774 1.5598 158.83
136.87 184.32 0.7959 40.46 .sup.aGeometric Mean for the Test
Formulation 2 (Test) and Reference Product (Ref) based on Least
Squares Mean of log-transformed parameter values .sup.bRatio(%) =
Geometric Mean (Test)/Geometric Mean (Ref) .sup.c90% Confidence
Interval .sup.dThe median T.sub.max of the Reference Product (5.00
hr) was used
TABLE-US-00029 TABLE 24 Statistical Analysis of the Log-Transformed
Systemic Exposure Parameters of Total Methylphenidate (d + l)
Comparing Test Formulation 1 (Treatment A) to the Reference Product
(Treatment C) Dependent Geometric Mean.sup.a Ratio (%).sup.b 90%
CI.sup.c ANOVA Variable Test Ref (Test/Ref) Lower Upper Power CV %
ln(C.sub.max) 20.6080 16.5477 124.54 117.98 131.46 1.0000 14.21
ln(AUC.sub.0-3) 21.2961 24.1188 88.30 80.92 96.35 0.9943 23.10
ln(AUC.sub.0-tmax).sup.d 51.4307 50.7312 101.38 94.67 108.56 0.9998
18.02 ln(AUC.sub.tmax-24).sup.d 105.0763 96.2603 109.16 104.30
114.24 1.0000 11.94 ln(AUC.sub.0-24) 159.2597 148.0008 107.61
104.29 111.03 1.0000 8.20 ln(AUC.sub.tmax-tlast).sup.d 105.6235
102.0912 103.46 98.33 108.86 1.0000 13.35 ln(AUC.sub.last) 159.9855
153.9687 103.91 100.39 107.55 1.0000 9.03 ln(AUC.sub.inf) 163.6833
159.5401 102.60 99.37 105.93 1.0000 8.36 .sup.aGeometric Mean for
the Test Formulation 1 (Test) and Reference Product (Ref) based on
Least Squares Mean of log-transformed parameter values
.sup.bRatio(%) = Geometric Mean (Test)/Geometric Mean (Ref)
.sup.c90% Confidence Interval .sup.dThe median T.sub.max of the
Reference Product (5.00 hr) was used
TABLE-US-00030 TABLE 25 Statistical Analysis of the Log-Transformed
Systemic Exposure Parameters of Total Methylphenidate (d + l)
Comparing Test Formulation 2 (Treatment B) to the Reference Product
(Treatment C). Dependent Geometric Mean.sup.a Ratio (%).sup.b 90%
CI.sup.c ANOVA Variable Test Ref (Test/Ref) Lower Upper Power CV %
ln(C.sub.max) 20.8467 16.5477 125.98 119.35 132.97 1.0000 14.21
ln(AUC.sub.0-3) 22.5591 24.1188 93.53 85.73 102.05 0.9944 23.10
ln(AUC.sub.0-tmax).sup.d 53.1774 50.7312 104.82 97.90 112.24 0.9998
18.02 ln(AUC.sub.tmax-24).sup.d 107.4905 96.2603 111.67 106.70
116.86 1.0000 11.94 ln(AUC.sub.0-24) 163.6952 148.0008 110.60
107.20 114.12 1.0000 8.20 ln(AUC.sub.tmax-tlast).sup.d 108.1238
102.0912 105.91 100.66 111.43 1.0000 13.35 ln(AUC.sub.last)
164.4747 153.9687 106.82 103.21 110.57 1.0000 9.03 ln(AUC.sub.inf)
168.3659 159.5401 105.53 102.22 108.95 1.0000 8.36 .sup.aGeometric
Mean for the Test Formulation 2 (Test) and Reference Product (Ref)
based on Least Squares Mean of log-transformed parameter values
.sup.bRatio(%) = Geometric Mean (Test)/Geometric Mean (Ref)
.sup.c90% Confidence Interval .sup.dThe median T.sub.max of the
Reference Product (5.00 hr) was used
Conclusions
[0283] Based on C.sub.max, the peak exposure to d-methylphenidate
is higher after administration of Test Formulations 1 and 2
relative to that after METADATE CD and the 90% confidence intervals
about the ratios for C.sub.max (Test Formulation 1/Reference and
Test Formulation 2/Reference) are not within the 80% to 125% range
necessary to establish traditional bioequivalence. However, based
on AUC.sub.last and AUC.sub.inf, the overall systemic exposure to
d-methylphenidate after administration of Test Formulations 1 and 2
is comparable to that after METADATE CD and the 90% confidence
intervals about the ratios for AUC.sub.last and AUC.sub.inf are
within the 80% to 125% range, indicating no significant difference
in bioavailability. Except for AUC.sub.0-3 after Test Formulation 1
(ratio: 86.39%; 90% confidence interval: 79.10%-94.36%), the 90%
confidence intervals about the Test/Reference ratios for all
partial AUCs are within the 80% to 125% range, indicating
comparable early systemic exposure through T.sub.max (5.00 hr) and
24 hours after Test Formulations 1 and 2 relative to METADATE
CD.
[0284] Based on C.sub.max, AUC.sub.last, and AUC.sub.inf, peak and
overall systemic exposure to l-methylphenidate is higher after
administration of Test Formulations 1 and 2 relative to that after
METADATE CD and the 90% confidence intervals about the
Test/Reference ratios (Test Formulation 1/Reference and Test
Formulation 2/Reference) are not within the 80% to 125% range
necessary to establish traditional bioequivalence. Similarly, based
on partial AUCs, early systemic exposure to l-methylphenidate is
higher after administration of Test Formulations 1 and 2 relative
to that after METADATE CD and the 90% confidence intervals about
the Test/Reference ratios for all partial AUCs are not within the
80% to 125% range.
[0285] Based on AUC.sub.last and AUC.sub.inf, the overall systemic
exposure to total methylphenidate (d+l) after administration of
Test Formulations 1 and 2 is comparable to that after METADATE CD
and the 90% confidence intervals about the ratios for AUC.sub.last
and AUC.sub.inf are within the 80% to 125% range, indicating no
significant difference in bioavailability. In addition, the 90%
confidence intervals about the Test/Reference ratios for all
partial AUCs are within the 80% to 125% range, indicating
comparable early systemic exposure through 3 hours, T.sub.max (5.00
hr), and 24 hours after Test Formulations 1 and 2 relative to
METADATE CD.
Example 19
Ethanol Study
[0286] In vitro dissolution studies using methylphenidate
compositions in the presence or absence of ethanol were also
carried out. One 60 mg capsule of METADATE CD, and separately, two
(30 mg) tablets of a formulation similar to Example 17, were
introduced into USP dissolution Apparatus 2. The dissolution media
started with alcoholic 0.1N HCl with various amounts of ethanol
(0%, 5%, 10%, 20%, and 40%). Appropriate amounts of pH change
buffer were added to the media at 2 hours (after the sample was
introduced) to make the pH of the media to 6.8. Samples were taken
at different time points. The results are shown in FIGS. 25A
(METADATE CD), 25B (test formulation) and 25C (METADATE CD and test
formulation).
[0287] FIG. 25A shows that the addition of 40% ethanol
substantially increases the amount of drug released in the
reference formulation, i.e., there is a substantial increase in
drug released through dose dumping in the presence of ethanol.
[0288] FIG. 25B shows that the addition 40% ethanol increases the
amount of drug released but to a lesser extent than in the
reference formulation. As such, the ethanol study's results show
that, in the presence of ethanol, the formulations of the invention
have a reduced exposure level of methylphenidate as compared to the
reference formulation. This prevents or substantially reduces the
likelihood of dose dumping when the formulations of the invention
and ethanol are ingested by a subject.
Example 20
Food-Effect Study of an Extended Release Methylphenidate ODT
Formulation in Healthy Subjects
[0289] This example describes a single-dose, open-label,
randomized, two-period crossover study that assessed the effect of
food on the rate of absorption and oral bioavailability of a single
dose (two ODTs) of a methylphenidate extended release ODT
(equivalent to 60 mg methylphenidate HCl), under fed and fasted
conditions.
[0290] Subjects in both treatment conditions fasted overnight for
at least 10 hours. Subjects in the fed condition were dosed 5
minutes after completing consumption of a Food and Drug
Administration (FDA) standard high-calorie, high-fat breakfast
meal. Consumption of the FDA standard high-calorie, high-fat
breakfast began 30 minutes prior to dosing. Subjects in the fasted
condition continued to fast up until the time that they were dosed.
Each drug administration was separated by a washout period of 7
days.
[0291] Subjects were administered a single 2 ODT dose of each of
the treatments in a randomized, sequenced fashion. Immediately
prior to dose, each subject was given 60 mL of room temperature
water in a cup and instructed to swish the water around in the
mouth and to spit it out in order to wet the mouth.
[0292] Treatment A (Fasted): Test Formulation #102 (shown below)
was orally administered following a 10-hour overnight fast.
Dose=2.times.methylphenidate polistirex ODT containing 26.1 mg
methylphenidate base Formulation #102, equivalent to 60 mg of
methylphenidate HCl.
[0293] Treatment B (Fed): Test Formulation #102 (shown below) was
orally administered following a 10-hour overnight fast and
consumption of an FDA standard high-fat, high-calorie breakfast
beginning 30 minutes prior to dose. Dose=2.times.methylphenidate
polistirex ODT, each containing 26.1 mg methylphenidate base
Formulation #102; this dose is equivalent to 60 mg of
methylphenidate HCl.
[0294] The subjects fasted for 4 hours thereafter. Standard meals
were provided at approximately 4 and 10 hours after drug
administration and at appropriate times thereafter.
[0295] Except for the 60 mL mouth rinse given immediately prior to
each dose (and which the subjects spit out), no water was allowed
for 1 hour prior through 1 hour after dose. Each subject was
required to drink approximately 360 mL of fluid with each snack or
meal administered during confinement after dosing on Day 1. Each
subject was required to drink 120 mL of water at approximately 1,
2, and 3 hours after dose administration. Subjects were provided
approximately 700 mL of water that was required to be consumed
between lunch and snack administrations during confinement on Day
1. After snack administration on Day 1, water was allowed ad
lib.
TABLE-US-00031 TABLE 26 ODT methylphenidate Formulation #102 with
25% IR and 75% ER/DR IR Resin - 36.97% base assay & ER/DR Resin
- 12.88% base assay Formulation #102 (25% active from IR Resin
& 75% active from ER/DR Resin) mg/dose Notes % Uncoated (IR)
MPH Resin 17.65 The 17.65 mg/dose quantity is the 2.67
Methylphenidate (base) 6.525 actual amount of IR resin (at a
AMBERLITE IRP069 Resin + Water 11.08 36.97% assay value) that
Polyethylene Glycol 0.045 goes into each tablet. The values in the
gray area are the quantities of each material that compromise the
IR material. Coated (ER/DR) MPH Resin 151.98 The 151.98 mg/dose
quantity is the 23.03 Methylphenidate (base) 19.575 actual amount
of ER/DR resin (at a AMBERLITE IRP069 Resin + Water 32.04 12.88%
assay value) that Polyethylene Glycol 0.38 goes into each tablet.
Ethylcellulose N-10 12.00 The IR resin material was used to
EUDRAGIT L100 75.94 make the 151.98 mg/dose ER/DR Triethyl Citrate
12.045 material. The values in the gray area are the quantities of
each material that compromise the ER/DR material. Prosolv ODT
367.22 The Prosolv ODT quantity will 55.64 Crospovidone 66.00 be
variable to account for the variable 10.00 Sucralose Powder 23.00
assay value of the IR and DR resin. 3.48 Citric Acid 10.00 1.52
Flavor & Color 17.55 2.66 Magnesium Stearate 6.60 1.00 Total
660.00 mg 100%
[0296] Data collection and analysis were carried out as similarly
as described above. Twenty-three (23) of the 24 subjects enrolled
completed the study. Data from 23 subjects were included in the
pharmacokinetic and statistical analyses Mean concentration-time
data are shown in FIGS. 27-29. Results of the pharmacokinetic and
statistical analysis are shown below in Tables 27 through 29.
Results:
[0297] FIGS. 27A and 27B show the mean methylphenidate (d+l)
concentration-time profiles after administration of Formulation
#102-Fasted (Treatment A) and Formulation #102-Fed (Treatment
B).
[0298] FIGS. 28A and 28B mean d-methylphenidate concentration-time
profiles after administration of Formulation #102-Fasted (Treatment
A) and Formulation #102-Fed (Treatment B).
[0299] FIGS. 29A and 29B mean l-methylphenidate concentration-time
profiles after administration of Formulation #102-Fasted (Treatment
A) and Formulation #102-Fed (Treatment B).
TABLE-US-00032 TABLE 27 Statistical Analysis of the Log-Transformed
Systemic Exposure Parameters of Methylphenidate (d + l) Dependent
Geometric Mean.sup.a Ratio (%).sup.b 90% CI.sup.c ANOVA Variable
Test Ref (Test/Ref) Lower Upper Power CV % ln(C.sub.max) 22.4817
25.9799 86.53 80.52 93.00 0.9992 14.25 ln(AUC.sub.last) 229.2966
205.8759 111.38 106.74 116.21 1.0000 8.38 ln(AUC.sub.inf) 237.5598
211.0504 112.56 108.18 117.11 1.0000 7.82 .sup.aGeometric Mean for
Formulation #102-Fed (Test) and Formulation #102-Fasted (Ref) based
on Least Squares Mean of log-transformed parameter values
.sup.bRatio(%) = Geometric Mean (Test)/Geometric Mean (Ref)
.sup.c90% Confidence Interval
TABLE-US-00033 TABLE 28 Statistical Analysis of the Log-Transformed
Systemic Exposure Parameters of d-Methylphenidate Dependent
Geometric Mean.sup.a Ratio (%).sup.b 90% CI.sup.c ANOVA Variable
Test Ref (Test/Ref) Lower Upper Power CV % ln(C.sub.max) 22.1811
25.5705 86.74 80.74 93.20 0.9992 14.20 ln(AUC.sub.last) 226.7299
203.5182 111.41 106.79 116.22 1.0000 8.34 ln(AUC.sub.inf) 234.9939
208.7056 112.60 108.24 117.13 1.0000 7.78 .sup.aGeometric Mean for
Formulation #102 -Fed (Test) and Formulation #102 -Fasted (Ref)
based on Least Squares Mean of log-transformed parameter values
.sup.bRatio(%) = Geometric Mean (Test)/Geometric Mean (Ref)
.sup.c90% Confidence Interval
TABLE-US-00034 TABLE 29 Statistical Analysis of the Log-Transformed
Systemic Exposure Parameters of l-Methylphenidate Dependent
Geometric Mean.sup.a Ratio (%).sup.b 90% CI.sup.c ANOVA Variable
Test Ref (Test/Ref) Lower Upper Power CV % ln(C.sub.max) 0.3806
0.4171 91.25 74.52 111.73 0.5695 41.51 ln(AUC.sub.last) 2.1957
1.9338 113.54 99.76 129.23 0.8869 25.90 ln(AUC.sub.inf) 2.3594
2.0529 114.93 100.74 131.12 0.8768 26.40 .sup.aGeometric Mean for
Formulation #102 -Fed (Test) and Formulation #102 -Fasted (Ref)
based on Least Squares Mean of log-transformed parameter values
.sup.bRatio(%) = Geometric Mean (Test)/Geometric Mean (Ref)
.sup.c90% Confidence Interval
Conclusions
[0300] There were no unusual or unexpected adverse events (AEs)
related to the study medication. In general, the AE profile was
consistent with the mechanism of action for this drug.
[0301] The 90% confidence intervals for comparing the
log-transformed exposure parameters ln(C.sub.max),
ln(AUC.sub.last), and ln(AUC.sub.inf) were within the accepted 80%
to 125% limits for the a priori designated endpoint,
methylphenidate (d+l).
[0302] Therefore, the presence of food did not significantly alter
methylphenidate (d+l) exposure following the administration of
methlyphenidate-polistirex formulated as ODT (equivalent to 60 mg
methylphenidate HCl) under fasting and fed conditions.
Example 21
The Effect of Food on the Pharmacokinetics of a Controlled Release
Amphetamine ODT in Healthy Subjects
[0303] This example describes a single-dose, open-label,
randomized, two-period, two-treatment crossover study that assessed
the effect of food on the rate of absorption and oral
bioavailability of a controlled release ODT preparations of mixed
amphetamine polistirex (equivalent to 30 mg mixed amphetamines),
under fed and fasted conditions.
[0304] The protocol was the same as described in Example 20, except
subjects received treatment listed below during the two treatment
periods:
[0305] Treatment A (Fed Conditions): Test Formulation #1002A (mixed
amphetamine resins) controlled-release ODT (shown below).
Dose=1.times.mixed amphetamine polistirex ODT equivalent to 30 mg
mixed amphetamine salts.
[0306] Treatment B (Fasted Conditions): Test Formulation #1002A
(mixed amphetamine resins) controlled-release ODT (shown below).
Dose=1.times.mixed amphetamine polistirex ODT equivalent to 30 mg
mixed amphetamine salts.
TABLE-US-00035 TABLE 30 ODT amphetamine formulation with 45% IR and
55% DR IR Resin - 34.08% base assay & DR Resin - 7.28% base
assay Formula #1002A (45% active from IR Resin & 55% active
from DR Resin) mg/dose Notes % Uncoated (IR) AMP Resin 24.8 The
24.8 mg/dose quantity is the 3.76 Amphetamine (base) 4.23 actual
amount of IR resin (at a 34.08% Dextroamphetamine (base) 4.23 assay
value) that goes into each tablet. AMBERLITE IRP069 Resin + Water
16.34 The values in the gray area are the quantities of each
material that compromise the IR material. Coated (DR) AMP Resin
142.0 The 142.0 mg/dose quantity is the 21.52 Amphetamine (base)
5.17 actual amount of DR resin (at an 7.28% Dextroamphetamine
(base) 5.17 assay value) that goes into each tablet. AMBERLITE
IRP069 Resin + Water 23.75 The IR resin material was used to make
Humectant 0.32 the 142.0 mg/dose DR material. EUDRAGIT L100 93.72
The values in the gray area are the Plasticizer 13.87 quantities of
each material that compromise the DR material. Prosolv ODT 323.3
The Prosolv ODT quantity will 48.98 Crospovidone 105.6 be variable
to account for the variable 16.00 Sucralose Powder 20.3 assay value
of the IR and DR resin. 3.08 Citric Acid 22.5 3.41 Color and Flavor
14.9 2.26 Magnesium Stearate 6.6 1.00 Total 660.00 mg 100%
[0307] Data collection and analysis were carried out similarly as
described above. All 16 subjects enrolled completed the study. Data
from the 16 subjects were included in the pharmacokinetic and
statistical analyses. Mean concentration-time data are shown in
FIGS. 30 and 31. Results of the pharmacokinetic and statistical
analysis are shown below in Tables 31 and 32.
Results
TABLE-US-00036 [0308] TABLE 31 Statistical Analysis of the
Log-Transformed Systemic Exposure Parameters of d-amphetamine
Comparing Test Formulation-Fed (Treatment A) to Test
Formulation-Fasted (Treatment B) Dependent Geometric Mean.sup.a
Ratio (%).sup.b 90% CI.sup.c ANOVA Variable Fed Fasted (Fed/Fasted)
Lower Upper Power CV % ln(C.sub.max) 40.8357 47.6112 85.77 81.34
90.44 1.0000 8.54 ln(AUC.sub.last) 886.6801 962.1617 92.16 88.40
96.07 1.0000 6.68 ln(AUC.sub.inf) 941.2440 1018.5933 92.41 88.11
96.91 1.0000 7.35 .sup.aGeometric Mean for the Test Formulation-Fed
and Test Formulation-Fasted based on Least Squares Mean of
log-transformed parameter values .sup.bRatio(%) = Geometric Mean
(Fed)/Geometric Mean (Fasted) .sup.c90% Confidence Interval Note:
T.sub.1/2 and parameters based on extrapolation could not be
calculated for all subjects; statistical analysis is based on n =
16 for C.sub.max, AUC.sub.last and n = 15 for AUC.sub.inf
TABLE-US-00037 TABLE 32 Statistical Analysis of the Log-Transformed
Systemic Exposure Parameters of l-amphetamine Comparing Test
Formulation-Fed (Treatment A) to Test Formulation-Fasted (Treatment
B) Dependent Geometric Mean.sup.a Ratio (%).sup.b 90% CI.sup.c
ANOVA Variable Fed Fasted (Fed/Fasted) Lower Upper Power CV %
ln(C.sub.max) 12.8378 14.8236 86.60 82.37 91.06 1.0000 8.07
ln(AUC.sub.last) 312.5311 342.9993 91.12 86.84 95.61 1.0000 7.74
ln(AUC.sub.inf) 346.2042 378.5080 91.47 86.33 96.91 0.9999 8.94
.sup.aGeometric Mean for the Test Formulation-Fed and Test
Formulation-Fasted based on Least Squares Mean of log-transformed
parameter values .sup.bRatio(%) = Geometric Mean (Fed)/Geometric
Mean (Fasted) .sup.c90% Confidence Interval Note: T.sub.1/2 and
parameters based on extrapolation could not be calculated for all
subjects; statistical analysis is based on n = 16 for C.sub.max,
AUC.sub.last and n = 15 for AUC.sub.inf
Conclusions
[0309] There were no unusual or unexpected adverse events related
to the study medication. Study exit clinical laboratory, ECG, and
physical examination evaluations were completed with no clinically
significant findings. The 90% confidence intervals for comparing
the maximum exposure, based on ln(C.sub.max), are within 80% to
125% for both d- and l-amphetamine. The 90% confidence intervals
for comparing total systemic exposure, based on ln(AUC.sub.last)
and ln(AUC.sub.inf), are within 80% to 125% for both d- and
l-amphetamine. On the other hand, T.sub.max values were
statistically different for the two treatments.
[0310] These data confirm that the extended-release characteristics
of ODT containing amphetamine polistirex were maintained in the
presence of a high-fat meal, and that a high-fat meal does not have
a significant effect on the rate of absorption or oral
bioavailability of mixed amphetamine resins in controlled-release
ODT.
Example 22
The Effect of Alcohol on the Pharmacokinetics of a Controlled
Release Amphetamine ODT in Healthy Subjects
[0311] This example describes a single-dose, open-label,
randomized, four-period, four-treatment, four-sequence crossover
study that assessed the effect of varying concentrations of alcohol
on the rate of absorption and oral bioavailability of a controlled
release ODT preparation of mixed amphetamine polistirex (equivalent
to 30 mg mixed amphetamines), in healthy adults.
[0312] Subjects fasted overnight for at least 10 hours, but were
administered intravenous (IV) fluids continuously from
approximately 10 hours predose to approximately 2 hours predose.
The subjects received dose administrations of a controlled-release
ODT preparation of amphetamines followed by varying concentrations
of alcohol. Subjects were assigned to one of two cohorts (Group 1
or Group 2), randomly assigned to a treatment sequence, and
received four, separate single-dose administrations of study
medication, one treatment per period, according to the
randomization schedule. Dosing days were separated by a washout
period of at least 14 days. Subjects were divided into two groups
of 16.
[0313] Subjects received the treatments listed below during the
four treatment periods:
[0314] Treatment A: Test Formulation #1002A (described in Example
21) controlled-release ODT followed by 240 mL of deionized water
(0% ethanol).
[0315] Treatment B: Test Formulation #1002A (described in Example
21) controlled-release ODT followed by 240 mL of 4% ethanol
solution.
[0316] Treatment C: Test Formulation #1002A (described in Example
21) controlled-release ODT followed by 240 mL of 20% ethanol
solution
[0317] Treatment D: Test Formulation #1002A (described in Example
21) controlled-release ODT followed by 240 mL of 40% ethanol
solution.
[0318] Subjects were given a single oral dose of the formulation
followed by varying amounts of alcohol at a pre-specified time in
each period, after a 10 hour overnight fast that was preceded by a
standard meal. The subjects fasted for 4 hours thereafter. Water
was allowed ad lib during the study except for 1 hour prior through
1 hour post-dose. Standard meals were provided at approximately 4
and 10 hours after drug administration and at appropriate times
thereafter.
[0319] The water and/or alcohol solution was administered following
confirmation that the ODT formulation had completely disintegrated.
The deionized water and/or alcohol solution was consumed within 30
minutes.
[0320] Data collection and analysis were carried out as similarly
as described above. Twenty seven (27) of the 32 subjects enrolled
completed the study. Data from 32 subjects who completed at least
one study period were included in the pharmacokinetic and
statistical analyses. Mean concentration-time data are showing in
FIGS. 32 and 33. Results of the pharmacokinetic and statistical
analysis are shown below in Tables 33 through 38.
Results
[0321] FIGS. 32A and 32B show mean d-amphetamine concentration-time
profiles after administration of controlled Release ODT with
Deionized Water (0% Ethanol Solution) (Treatment A), 4% ethanol
(Treatment B), 20% ethanol (Treatment C) and 40% ethanol (Treatment
D) on linear (upper panel) and semi-logarithmic (lower panel)
scales.
[0322] FIGS. 33A and 33B show mean l-amphetamine concentration-time
profiles after administration of controlled Release ODT with
Deionized Water (0% Ethanol Solution) (Treatment A), 4% ethanol
(Treatment B), 20% ethanol (Treatment C) and 40% ethanol (Treatment
D) on linear (upper panel) and semi-logarithmic (lower panel)
scales.
TABLE-US-00038 TABLE 33 Statistical Analysis of the Log-Transformed
Systemic Exposure Parameters of d-amphetamine Comparing Formula
#1002A + 4% Ethanol (Treatment B) to Formula #1002A + Deionized
Water (0% Ethanol Solution) (Treatment A) Dependent Geometric
Mean.sup.a Ratio (%).sup.b 90% CI.sup.c ANOVA Variable Test Ref
(Test/Ref) Lower Upper Power CV % ln(C.sub.max) 42.6047 41.6151
102.38 98.11 106.83 1.0000 9.88 ln(AUC.sub.last) 880.9005 854.9740
103.03 97.48 108.90 1.0000 12.88 ln(AUC.sub.inf) .sup.GRP1
1000.2608 931.5954 107.37 102.69 112.27 1.0000 6.96 ln(AUC.sub.inf)
.sup.GRP2 909.5489 865.2939 105.11 100.49 109.95 1.0000 7.39
.sup.aGeometric Mean for Formula #1002A + 4% Ethanol (Test) Formula
#1002A + Deionized Water (0% Ethanol Solution) (Ref) based on Least
Squares Mean of log-transformed parameter values .sup.bRatio(%) =
Geometric Mean (Test)/Geometric Mean (Ref) .sup.c90% Confidence
Interval .sup.GRP1/GRP2 = Group 1/Group 2
TABLE-US-00039 TABLE 34 Statistical Analysis of the Log-Transformed
Systemic Exposure Parameters of d-amphetamine Comparing Formula
#1002A + 20% Ethanol (Treatment C) to Formula #1002A + Deionized
Water (0% Ethanol Solution) (Treatment A) Dependent Geometric
Mean.sup.a Ratio (%).sup.b 90% CI.sup.c ANOVA Variable Test Ref
(Test/Ref) Lower Upper Power CV % ln(C.sub.max) 40.0621 41.6151
96.27 92.21 100.51 1.0000 9.88 ln(AUC.sub.last) 841.7095 854.9740
98.45 93.08 104.13 1.0000 12.88 ln(AUC.sub.inf) .sup.GRP1 895.8201
931.5954 96.16 91.85 100.67 1.0000 6.96 ln(AUC.sub.inf) .sup.GRP2
916.3051 865.2939 105.90 101.24 110.77 1.0000 7.39 .sup.aGeometric
Mean for Formula #1002A + 20% Ethanol (Test) and Formula #1002A +
Deionized Water (0% Ethanol Solution) (Ref) based on Least Squares
Mean of log-transformed parameter values .sup.bRatio(%) = Geometric
Mean (Test)/Geometric Mean (Ref) .sup.c90% Confidence Interval
.sup.GRP1/GRP2 = Group 1/Group 2
TABLE-US-00040 TABLE 35 Statistical Analysis of the Log-Transformed
Systemic Exposure Parameters of d-amphetamine Comparing Formula
#1002A + 40% Ethanol (Treatment D) to Formula #1002A + Deionized
Water (0% Ethanol Solution) (Treatment A) Dependent Geometric
Mean.sup.a Ratio (%).sup.b 90% CI.sup.c ANOVA Variable Test Ref
(Test/Ref) Lower Upper Power CV % ln(C.sub.max) 39.5057 41.6151
94.93 90.88 99.17 1.0000 9.88 ln(AUC.sub.last) 848.9149 854.9740
99.29 93.81 105.10 1.0000 12.88 ln(AUC.sub.inf) .sup.GRP1 908.1250
931.5954 97.48 93.18 101.98 1.0000 6.96 ln(AUC.sub.inf) .sup.GRP2
868.8805 865.2939 100.41 95.91 105.13 1.0000 7.39 .sup.aGeometric
Mean for Formula #1002A + 40% Ethanol (Test) and Formula #1002A +
Deionized Water (0% Ethanol Solution) (Ref) based on Least Squares
Mean of log-transformed parameter values .sup.bRatio(%) = Geometric
Mean (Test)/Geometric Mean (Ref) .sup.c90% Confidence Interval
.sup.GRP1/GRP2 = Group 1/Group 2
TABLE-US-00041 TABLE 36 Statistical Analysis of the Log-Transformed
Systemic Exposure Parameters of l-amphetamine Comparing Formula
#1002A + 4% Ethanol (Treatment B) to Formula #1002A + Deionized
Water (0% Ethanol Solution) (Treatment A) Dependent Geometric
Mean.sup.a Ratio (%).sup.b 90% CI.sup.c ANOVA Variable Test Ref
(Test/Ref) Lower Upper Power CV % ln(C.sub.max) 13.6773 13.3098
102.76 98.64 107.05 1.0000 9.50 ln(AUC.sub.last) 316.6826 307.3284
103.04 96.77 109.73 1.0000 14.63 ln(AUC.sub.inf) .sup.GRP1 379.7166
345.8712 109.79 103.92 115.98 1.0000 8.56 ln(AUC.sub.inf) .sup.GRP2
342.6777 325.5756 105.25 100.16 110.60 1.000 8.15 .sup.aGeometric
Mean for Formula #1002A + 4% Ethanol (Test) and Formula #1002A +
Deionized Water (0% Ethanol Solution) (Ref) based on Least Squares
Mean of log-transformed parameter values .sup.bRatio(%) = Geometric
Mean (Test)/Geometric Mean (Ref) .sup.c90% Confidence Interval
.sup.GRP1/GRP2 = Group 1/Group 2
TABLE-US-00042 TABLE 37 Statistical Analysis of the Log-Transformed
Systemic Exposure Parameters of l-amphetamine Comparing Formula
#1002A + 20% Ethanol (Treatment C) to Formula #1002A + Deionized
Water (0% Ethanol Solution) (Treatment A) Dependent Geometric
Mean.sup.a Ratio (%).sup.b 90% CI.sup.c ANOVA Variable Test Ref
(Test/Ref) Lower Upper Power CV % ln(C.sub.max) 12.9647 13.3098
97.41 93.45 101.53 1.0000 9.50 ln(AUC.sub.last) 301.3609 307.3284
98.06 92.01 104.50 1.0000 14.63 ln(AUC.sub.inf) .sup.GRP1 333.1404
345.8712 96.32 91.03 101.91 1.000 8.56 ln(AUC.sub.inf) .sup.GRP2
346.3956 325.5756 106.39 101.25 111.80 1.0000 8.15 .sup.aGeometric
Mean for Formula #1002A + 20% Ethanol (Test) and Formula #1002A +
Deionized Water (0% Ethanol Solution) (Ref) based on Least Squares
Mean of log-transformed parameter values .sup.bRatio(%) = Geometric
Mean (Test)/Geometric Mean (Ref) .sup.c90% Confidence Interval
.sup.GRP1/GRP2 = Group 1/Group 2
TABLE-US-00043 TABLE 38 Statistical Analysis of the Log-Transformed
Systemic Exposure Parameters of l-amphetamine Comparing Formula
#1002A + 40% Ethanol (Treatment D) to Formula #1002A + Deionized
Water (0% Ethanol Solution) (Treatment A) Dependent Geometric
Mean.sup.a Ratio (%).sup.b 90% CI.sup.c ANOVA Variable Test Ref
(Test/Ref) Lower Upper Power CV % ln(C.sub.max) 12.6112 13.3098
94.75 90.86 98.81 1.0000 9.50 ln(AUC.sub.last) 306.0284 307.3284
99.58 93.36 106.21 1.0000 14.63 ln(AUC.sub.inf) .sup.GRP1 337.9262
345.8712 97.70 92.43 103.27 1.0000 8.56 ln(AUC.sub.inf) .sup.GRP2
328.1746 325.5756 100.80 95.83 106.03 1.0000 8.15 .sup.aGeometric
Mean for Formula #1002A + 40% Ethanol (Test) and Formula #1002A +
Deionized Water (0% Ethanol Solution) (Ref) based on Least Squares
Mean of log-transformed parameter values .sup.bRatio(%) = Geometric
Mean (Test)/Geometric Mean (Ref) .sup.c90% Confidence Interval
.sup.GRP1/GRP2 = Group 1/Group 2
Conclusions
[0323] The 90% confidence intervals for comparing the maximum
exposure to d-amphetamine and l-amphetamine, based on
ln(C.sub.max), are within the accepted 80% to 125% limits across
all comparisons
[0324] The 90% confidence intervals for comparing total systemic
exposure to d-amphetamine and l-amphetamine, based on
ln(AUC.sub.last) and ln(AUC.sub.inf), are within the accepted 80%
to 125% limits across all comparisons.
[0325] Therefore, varying concentrations of alcohol (4%-40% ethanol
solution) did not significantly alter the rate and extent of
absorption of Formula #1002A amphetamine polistirex (equivalent to
30 mg mixed amphetamine salts), in healthy subjects. The results of
this study indicate that the controlled-release properties of
formulations according to this invention are maintained in the
presence of alcohol.
Example 23
Human Pharmacokinetic Study of a Controlled Release Amphetamine ODT
Under Fasted Conditions in Children with ADHD
[0326] This example describes a single-dose, open-label,
single-period, one-treatment study to determine the pharmacokinetic
profile of a controlled release ODT preparation of mixed
amphetamine polistirex (equivalent to 30 mg mixed amphetamines), in
children (6-12 years old). Subjects were children diagnosed with
ADHD, and 28 enrolled children were divided into three cohorts (6
of 6-7 years, 11 of 8-9 years, and 11 of 10-12 years).
[0327] Following a 10-hour overnight fast, subjects received 1 dose
of Test Formulation #1002A (described in Example 21). This dose was
administered without water (other than a small mouth rinse (which
was not ingested) prior to drug administration) and allowed to
disintegrate on the tongue. After dosing, no food was allowed until
4 hours post-dose. No water was to be consumed for 1 hour prior
through 1 hour post-dose.
[0328] Subjects remained in the research center until completion of
the 12-hour blood sampling for the study period and returned for
outpatient visits at approximately 24 (Visit 3), 36 (Visit 4), and
48 hours (Visit 5) post-dose in the study period. After the final
plasma sample was collected, subjects were permitted to resume
taking their usual dose of amphetamines. The final safety visit
took place 2 days after dosing as part of Visit 5 (Day 7).
[0329] During the study period, 3 mL blood samples were obtained
prior to dosing and following the dose at selected times through 48
hours post-dose. Data collection and analysis were carried out as
described above. The following PK parameters were determined:
[0330] .lamda.Z: The elimination rate constant (.lamda.Z) was
calculated as the negative of the slope of the terminal log-linear
segment of the plasma concentration-time curve; the range of data
to be used was determined by visual inspection of a
semi-logarithmic plot of concentration versus time. [0331] CL/F:
Oral clearance (CL/F) was calculated as:
[0331] CL/F=D/AUC.sub.inf, [0332] where D was the administered
dose. [0333] Vz/F: Volume of distribution in the terminal phase
after oral administration (Vz/F) was calculated as:
[0333] Vz/F=(CL/F)/.lamda.Z.
Results
[0334] Data from 28 enrolled subjects who completed the study were
included in the pharmacokinetic and statistical analyses. Mean
concentration-time data are showing in FIGS. 34 and 35. Results of
the pharmacokinetic and statistical analysis are shown below in
Tables 39 and 40.
[0335] FIGS. 34A and 34B mean d-amphetamine Concentration-Time
Profiles after Administration of Formula #1002A ODT for Group 1
(Ages 6-7), Group 2 (Ages 8-9), and Group 3 (Ages 10-12).
[0336] FIGS. 35A and 35B show mean l-amphetamine Concentration-Time
Profiles after Administration of Formula #1002A ODT for Group 1
(Ages 6-7), Group 2 (Ages 8-9), and Group 3 (Ages 10-12).
TABLE-US-00044 TABLE 39 Statistical Analysis of Weight-Normalized
Clearance and Volume of Distribution of d-amphetamine. Supplied as
Formula #1002A Age Group 1 (6-7 yrs): Target Confidence 95%
Confidence Interval Range 60%- Interval 140% Geometric Lower Upper
Lower Upper Parameter n Mean Bound Bound Bound Bound Vz/F (L/kg) 6
10.08 8.448 11.95 6.048 14.11 CL/F (L/h/kg) 6 0.7619 0.6682 0.8648
0.4571 1.067 Age Group 2 (8-9 yrs): Target Confidence 95%
Confidence Interval Range 60%- Interval 140% Geometric Lower Upper
Lower Upper Parameter n Mean Bound Bound Bound Bound Vz/F (L/kg) 11
9.177 8.284 10.28 5.506 12.85 CL/F (L/h/kg) 11 0.7117 0.6371 0.8057
0.4270 0.9964 Age Group 3 (10-12 yrs): Target Confidence 95%
Confidence Interval Range 60%- Interval 140% Geometric Lower Upper
Lower Upper Parameter n Mean Bound Bound Bound Bound Vz/F (L/kg) 11
8.678 8.064 9.396 5.207 12.15 CL/F (L/h/kg) 11 0.6094 0.5349 0.7106
0.3656 0.8532 Note: Target confidence interval range was calculated
by multiplying the geometric mean by 0.6 for the 60% lower bound
and 1.4 for the 140% upper bound. Abbreviations: CL/F = oral
clearance; CR = controlled release; h = hour; MAR = mixed
amphetamine resin; ODT = oral disintegrating tablet; Vz/F = volume
of distribution in the terminal phase after oral administration;
yrs = years.
TABLE-US-00045 TABLE 40 Statistical Analysis of Weight-Normalized
Clearance and Volume of Distribution of l-amphetamine Supplied as
Formula #1002A Age Group 1 (6-7 yrs): Target Confidence 95%
Confidence Interval Range 60%- Interval 140% Geometric Lower Upper
Lower Upper Parameter n Mean Bound Bound Bound Bound Vz/F (L/kg) 6
32.68 26.72 39.63 19.61 45.75 CL/F (L/h/kg) 6 2.137 1.840 2.466
1.282 2.992 Age Group 2 (8-9 yrs): Target Confidence 95% Confidence
Interval Range 60%- Interval 140% Geometric Lower Upper Lower Upper
Parameter n Mean Bound Bound Bound Bound Vz/F (L/kg) 11 29.63 26.46
33.65 17.78 41.48 CL/F (L/h/kg) 11 2.019 1.778 2.335 1.211 2.827
Age Group 3 (10-12 yrs): Target Confidence 95% Confidence Interval
Range 60%- Interval 140% Geometric Lower Upper Lower Upper
Parameter n Mean Bound Bound Bound Bound Vz/F (L/kg) 11 28.35 26.23
30.84 17.01 39.69 CL/F (L/h/kg) 11 1.712 1.497 2.001 1.027 2.397
Note: Target confidence interval range was calculated by
multiplying the geometric mean by 0.6 for the 60% lower bound and
1.4 for the 140% upper bound. Abbreviations: CL/F = oral clearance;
CR = controlled release; h = hour; MAR = mixed amphetamine resin;
ODT = oral disintegrating tablet; Vz/F = volume of distribution in
the terminal phase after oral administration; yrs = years.
Conclusions
[0337] There were no unusual or unexpected adverse effects (AEs)
related to the study medication. There were no deaths, SAEs, or
discontinuations. In general, the nature of the TEAEs reported was
consistent with the mechanism of action for these study
medications.
[0338] An age-related trend in mean maximum and total d-amphetamine
and l-amphetamine exposure was observed; as age increased, mean
amphetamine exposure decreased. Weight did not appear to be a
prominent factor in the observed downward age-related trend in
amphetamine exposure.
[0339] Mean weight-normalized CL/F and Vz/F values for
d-amphetamine and l-amphetamine decreased slightly with an increase
in age. Mean T.sub.1/2 was similar across age groups. Additionally,
the geometric means and 95% CIs calculated for d-amphetamine and
l-amphetamine CL/F and Vz/F were within the target range of 60% to
140% for each age group.
Example 24
Human Pharmacokinetic Study Using Amphetamine Liquid Formulations
And ADDERALL XR Under Fasted Conditions
[0340] This was a single-dose, open-label, randomized, four-period,
four-treatment crossover study that compared the rate of absorption
and oral bioavailability of three different amphetamine
controlled-release liquid suspensions (equivalent to 30 mg mixed
amphetamine salts/15 mL) to an equivalent 30 mg dose of ADDERALL XR
capsule, in healthy subjects.
[0341] All doses were administered after an overnight fast of at
least 10 hours. Each dose administration was separated by a washout
period of at least 7 days.
[0342] Subjects received the treatments listed below during the
four treatment periods:
[0343] Treatment A: Test Formulation #1005A controlled-release
liquid (shown below). Dose=1.times.15 mL of suspension. This dose
was administered orally without water.
[0344] Treatment B: Test Formulation #1005B controlled-release
liquid (shown below). Dose=1.times.15 mL of suspension. This dose
was administered orally without water.
[0345] Treatment C: Test Formulation #1005C controlled-release
liquid (shown below). Dose=1.times.15 mL of suspension. This dose
was administered orally without water.
[0346] Treatment D (Reference Product): ADDERALL XR Shire US, Inc.
Dose=1.times.30 mg capsule. This dose was administered orally with
60 mL (2 fl. oz.) of water.
TABLE-US-00046 TABLE 41 Test Formulation #1005A (suspension
amphetamine with 45% IR and 55% DR) IR Resin - 36.05% base assay
& DR Resin - 7.82% base assay Formula 1005A (45% active from IR
Resin & 55% active from DR Resin) mg per 15 mL dose Notes %
Uncoated (IR) AMP Resin 23.5 The 23.5 mg/dose quantity is the 0.145
Amphetamine (base) 4.23 actual amount of IR resin (at a 36.05%
Dextroamphetamine (base) 4.23 assay value) that goes into each 15
mL AMBERLITE IRP069 Resin + Water 15.04 dose. The values in the
gray area are the quantities of each material that compromise the
IR material. Coated (DR) AMP Resin 132.2 The 132.2 mg/dose quantity
is the 0.816 Amphetamine (base) 5.17 actual amount of DR resin (at
an 7.82% Dextroamphetamine (base) 5.17 assay value) that goes into
each 15 mL AMBERLITE IRP069 Resin + Water 21.98 dose. Humectant
0.34 The IR resin material was used to make EUDRAGIT L100 86.74 the
132.2 mg/dose DR material. Plasticizer 12.84 The values in the gray
area are the quantities of each material that compromise the DR
material. Purified Water 9839.55 Each 15 mL dose of liquid
suspension 60.74 Citric Acid 5.10 is equivalent to 16.2 grams at
the 0.03 Propylene Glycol 577.50 theoretical specific gravity of
1.08. 3.56 Preservative 8.55 0.05 Xanthan Gum 116.25 0.72 Vegetable
Oil 33.00 0.20 Maltitol Syrup 5400.00 33.33 Flavor and Color 4.35
<0.39 Total 16,200.0 mg 100%
TABLE-US-00047 TABLE 42 Test Formulation #1005B (suspension
amphetamine with 45% IR and 55% DR) IR Resin - 36.05% base assay
& DR Resin - 7.82% base assay Formula #1005B (45% active from
IR Resin & 55% active from DR Resin) mg per 15 mL dose Notes %
Uncoated (IR) AMP Resin 23.5 The 23.5 mg/dose quantity is the 0.145
Amphetamine (base) 4.23 actual amount of IR resin (at a 36.05%
Dextroamphetamine (base) 4.23 assay value) that goes into each 15
mL AMBERLITE IRP069 Resin + Water 15.04 dose. The values in the
gray area are the quantities of each material that compromise the
IR material. Coated (DR) AMP Resin 132.2 The 132.2 mg/dose quantity
is the 0.816 Amphetamine (base) 5.17 actual amount of DR resin (at
an 7.82% Dextroamphetamine (base) 5.17 assay value) that goes into
each 15 mL AMBERLITE IRP069 Resin + Water 21.98 dose. Humectant
0.34 The IR resin material was used to make EUDRAGIT L100 86.74 the
132.2 mg/dose DR material. Plasticizer 12.84 The values in the gray
area are the quantities of each material that compromise the DR
material. Purified Water 11,227.05 Each 15 mL dose of liquid
suspension 69.30 Citric Acid 5.10 is equivalent to 16.2 grams at
the 0.03 Propylene Glycol 577.50 theoretical specific gravity of
1.08. 3.56 Preservative 8.55 0.05 Xanthan Gum 116.25 0.72 Vegetable
Oil 33.00 0.20 70% Sorbitol Solution 4012.5 24.77 Flavor and Color
64.35 <0.39 Total 16,200.0 mg 100%
TABLE-US-00048 TABLE 43 Test Formulation #1005C (suspension
amphetamine with 45% IR and 55% DR) IR Resin - 36.05% base assay
& DR Resin - 7.82% base assay Formula #1005C (45% active from
IR Resin & 55% active from DR Resin) mg per 15 mL dose Notes %
Uncoated (IR) AMP Resin 23.5 The 23.5 mg/dose quantity is the 0.145
Amphetamine (base) 4.23 actual amount of IR resin (at a 36.05%
Dextroamphetamine (base) 4.23 assay value) that goes into each 15
mL AMBERLITE IRP069 Resin + Water 15.04 dose. The values in the
gray area are the quantities of each material that compromise the
IR material. Coated (DR) AMP Resin 132.2 The 132.2 mg/dose quantity
is the 0.816 Amphetamine (base) 5.17 actual amount of DR resin (at
an 7.82% Dextroamphetamine (base) 5.17 assay value) that goes into
each 15 mL AMBERLITE IRP069 Resin + Water 21.98 dose. Humectant
0.34 The IR resin material was used to make EUDRAGIT L100 86.74 the
132.2 mg/dose DR material. Plasticizer 12.84 The values in the gray
area are the quantities of each material that compromise the DR
material. Purified Water 11,201.55 Each 15 mL dose of liquid
suspension 69.15 Citric Acid 5.10 is equivalent to 16.2 grams at
the 0.03 Propylene Glycol 577.50 theoretical specific gravity of
1.08. 3.56 Preservative 8.55 0.05 Xanthan Gum 116.25 0.72 Vegetable
Oil 33.00 0.20 Sodium Polystyrene Sulfonate 25.5 0.16 Maltitol
Syrup 4012.5 24.77 Flavor and Color 64.35 <0.39 Total 16,200.0
mg 100%
[0347] Data collection and analysis were carried out as similarly
described above. 44 subjects participated in the study with 39
subjects completing all four study periods, and 42 subjects
completing at least one test period and the reference period of the
study. Data for the 42 subjects were included in the
pharmacokinetic and statistical analyses. Mean concentration-time
data are showing in FIGS. 36 and 37. Results of the pharmacokinetic
and statistical analysis are shown below in Tables 44 through
49.
[0348] FIGS. 36A and 36B show mean d-amphetamine Concentration-Time
Profiles after Administration of Test Formulation #1 (Treatment A),
Test Formulation #2 (Treatment B), Test Formulation #3 (Treatment
C), and the Reference Product (Treatment D).
[0349] FIGS. 37A and 37B show mean l-amphetamine Concentration-Time
Profiles after Administration of Test Formulation #1 (Treatment A),
Test Formulation #2 (Treatment B), Test Formulation #3 (Treatment
C), and the Reference Product (Treatment D).
TABLE-US-00049 TABLE 44 Statistical Analysis of the Log-Transformed
Systemic Exposure Parameters of d-amphetamine Comparing Test
Formulation #1 (Treatment A) to the Reference Product (Treatment D)
Dependent Geometric Mean.sup.a Ratio (%).sup.b 90% CI.sup.c ANOVA
Variable Test Ref (Test/Ref) Lower Upper Power CV % ln(C.sub.max)
50.1580 49.5786 101.17 99.16 103.22 1.0000 5.43 ln(AUC.sub.0-5)
130.5315 153.2270 85.19 79.53 91.25 0.9997 18.76 ln(AUC.sub.5-12)
287.7548 272.5554 105.58 103.05 108.16 1.0000 6.56
ln(AUC.sub.5-last) 823.1422 791.92221 103.94 100.64 107.35 1.0000
8.75 ln(AUC.sub.0-24) 696.5164 696.4442 100.01 98.18 101.88 1.0000
5.01 ln(AUC.sub.last) 958.9738 951.6525 100.77 98.40 103.19 1.0000
6.45 ln(AUC.sub.inf) 1001.0534 995.6153 100.55 97.95 103.21 1.0000
7.10 .sup.aGeometric Mean for Test Formulation #1 (Test) and
Reference Product (Ref) based on Least Squares Mean of
log-transformed parameter values .sup.bRatio(%) = Geometric Mean
(Test)/Geometric Mean (Ref) .sup.c90% Confidence Interval
TABLE-US-00050 TABLE 45 Statistical Analysis of the Log-Transformed
Systemic Exposure Parameters of d-amphetamine Comparing Test
Formulation #2 (Treatment B) to the Reference Product (Treatment D)
Dependent Geometric Mean.sup.a Ratio (%).sup.b 90% CI.sup.c ANOVA
Variable Test Ref (Test/Ref) Lower Upper Power CV % ln(C.sub.max)
50.0963 49.3574 101.50 99.82 103.20 1.0000 4.42 ln(AUC.sub.0-5)
135.9603 152.6483 89.07 84.05 94.38 1.0000 15.45 ln(AUC.sub.5-12)
286.6888 271.5835 105.56 103.52 107.64 1.0000 5.18
ln(AUC.sub.5-last) 821.7640 789.8344 104.04 100.69 107.51 1.0000
8.71 ln(AUC.sub.0-24) 699.0396 694.7072 100.62 98.59 102.70 1.0000
5.41 ln(AUC.sub.last) 960.8482 949.2052 101.23 98.63 103.90 1.0000
6.91 ln(AUC.sub.inf) 1003.0198 993.2407 100.98 98.07 103.99 1.0000
7.79 .sup.aGeometric Mean for Test Formulation #2 (Test) and
Reference Product (Ref) based on Least Squares Mean of
log-transformed parameter values .sup.bRatio(%) = Geometric Mean
(Test)/Geometric Mean (Ref) .sup.c90% Confidence Interval
TABLE-US-00051 TABLE 46 Statistical Analysis of the Log-Transformed
Systemic Exposure Parameters of d-amphetamine Comparing Test
Formulation #3 (Treatment C) to the Reference Product (Treatment D)
Dependent Geometric Mean.sup.a Ratio (%).sup.b 90% CI.sup.c ANOVA
Variable Test Ref (Test/Ref) Lower Upper Power CV % ln(C.sub.max)
50.7295 49.3066 102.89 100.35 105.49 1.0000 6.51 ln(AUC.sub.0-5)
136.5321 152.7544 89.38 84.81 94.20 1.0000 13.75 ln(AUC.sub.5-12)
289.7260 271.3370 106.78 105.26 108.31 1.0000 3.72
ln(AUC.sub.5-last) 829.3721 787.7095 105.29 102.81 107.83 1.0000
6.22 ln(AUC.sub.0-24) 705.8156 693.9269 101.71 99.85 103.61 1.0000
4.82 ln(AUC.sub.last) 970.1670 947.3535 102.41 100.17 104.69 1.0000
5.76 ln(AUC.sub.inf) 1015.0619 991.6597 102.36 99.66 105.13 1.0000
6.96 .sup.aGeometric Mean for Test Formulation #3 (Test) and
Reference Product (Ref) based on Least Squares Mean of
log-transformed parameter values .sup.bRatio(%) = Geometric Mean
(Test)/Geometric Mean (Ref) .sup.c90% Confidence Interval
TABLE-US-00052 TABLE 47 Statistical Analysis of the Log-Transformed
Systemic Exposure Parameters of l-amphetamine Comparing Test
Formulation #1 (Treatment A) to the Reference Product (Treatment D)
Dependent Geometric Mean.sup.a Ratio (%).sup.b 90% CI.sup.c ANOVA
Variable Test Ref (Test/Ref) Lower Upper Power CV % ln(C.sub.max)
15.6903 14.9321 105.08 102.81 107.40 1.0000 5.92 ln(AUC.sub.0-5)
39.6019 45.0296 87.95 81.98 94.35 0.9996 19.20 ln(AUC.sub.5-12)
92.7020 85.1083 108.92 106.39 111.52 1.0000 6.39 ln(AUC.sub.5-last)
302.9169 283.7188 106.77 103.27 110.38 1.0000 9.03 ln(AUC.sub.0-24)
230.3610 222.7249 103.43 101.39 105.51 1.0000 5.40 ln(AUC.sub.last)
344.2092 330.7995 104.05 101.35 106.83 1.0000 7.14 ln(AUC.sub.inf)
373.9861 360.6700 103.69 100.39 107.10 1.0000 8.78 .sup.aGeometric
Mean for Test Formulation #1 (Test) and Reference Product (Ref)
based on Least Squares Mean of log-transformed parameter values
.sup.bRatio(%) = Geometric Mean (Test)/Geometric Mean (Ref)
.sup.c90% Confidence Interval
TABLE-US-00053 TABLE 48 Statistical Analysis of the Log-Transformed
Systemic Exposure Parameters of l-amphetamine Comparing Test
Formulation #2 (Treatment B) to the Reference Product (Treatment D)
Dependent Geometric Mean.sup.a Ratio (%).sup.b 90% CI.sup.c ANOVA
Variable Test Ref (Test/Ref) Lower Upper Power CV % ln(C.sub.max)
15.6747 14.8460 105.58 103.86 107.33 1.0000 4.36 ln(AUC.sub.0-5)
41.2088 44.8276 91.93 86.65 97.52 1.0000 15.75 ln(AUC.sub.5-12)
92.3827 84.8244 108.91 106.73 111.14 1.0000 5.37 ln(AUC.sub.5-last)
303.6696 283.1073 107.26 103.43 111.24 1.0000 9.66 ln(AUC.sub.0-24)
231.4482 222.2016 104.16 101.78 106.59 1.0000 6.12 ln(AUC.sub.last)
345.8479 330.0470 104.79 101.67 108.00 1.0000 8.02 ln(AUC.sub.inf)
375.9631 360.0332 104.42 100.75 108.23 1.0000 9.51 .sup.aGeometric
Mean for Test Formulation #2 (Test) and Reference Product (Ref)
based on Least Squares Mean of log-transformed parameter values
.sup.bRatio(%) = Geometric Mean (Test)/Geometric Mean (Ref)
.sup.c90% Confidence Interval
TABLE-US-00054 TABLE 49 Statistical Analysis of the Log-Transformed
Systemic Exposure Parameters of l-amphetamine Comparing Test
Formulation #3 (Treatment C) to the Reference Product (Treatment D)
Dependent Geometric Mean.sup.a Ratio (%).sup.b 90% CI.sup.c ANOVA
Variable Test Ref (Test/Ref) Lower Upper Power CV % ln(C.sub.max)
16.0082 14.8077 108.11 105.08 111.23 1.0000 7.42 ln(AUC.sub.0-5)
41.4033 44.8626 92.29 87.52 97.32 1.0000 13.89 ln(AUC.sub.5-12)
93.3817 84.7844 110.14 108.48 111.83 1.0000 3.97 ln(AUC.sub.5-last)
305.8158 282.5814 108.22 105.23 111.30 1.0000 7.32 ln(AUC.sub.0-24)
233.5886 222.0427 105.20 103.03 107.41 1.0000 5.42 ln(AUC.sub.last)
348.6608 329.6149 105.78 103.04 108.59 1.0000 6.85 ln(AUC.sub.inf)
380.0816 359.7935 105.64 101.93 109.48 1.0000 9.32 .sup.aGeometric
Mean for Test Formulation #3 (Test) and Reference Product (Ref)
based on Least Squares Mean of log-transformed parameter values
.sup.bRatio(%) = Geometric Mean (Test)/Geometric Mean (Ref)
.sup.c90% Confidence Interval
Conclusions
[0350] There were no unusual or unexpected adverse events related
to the study medication. The 90% confidence interval for comparing
the maximum exposure, based on ln(C.sub.max), is within the
accepted 80% to 125% limits for all comparisons and analytes.
[0351] The 90% confidence intervals for comparing total systemic
exposure, based on ln(AUC.sub.last) and ln(AUC.sub.inf), are within
the accepted 80% to 125% limits for all comparisons and
analytes.
[0352] With the exception of the log-transformed AUC.sub.O-5 Test
Formulation #1005A vs. reference comparison for d-amphetamine, all
log-transformed partial AUC parameters were within the accepted 80%
to 125% range across all treatment comparisons and analytes. The
lower bound of the 90% confidence interval for the log-transformed
AUC.sub.O-5 Test Formulation #1005A vs. reference comparison was
79.53%, slightly below 80% for d-amphetamine.
[0353] Therefore, Test Formulations #1005B and #1005C (equivalent
to 30 mg mixed amphetamine salts/15 mL) are bioequivalent to
ADDERALL XR under fasted conditions.
[0354] Test Formulation #1005A (equivalent to 30 mg mixed
amphetamine salts/15 mL) is bioequivalent to ADDERALL XR under
fasted conditions based on standard bioequilvance metrics
(C.sub.max, AUC.sub.last, AUC.sub.inf) and additional metrics such
as AUC.sub.5-12, AUC.sub.5-last, and AUC.sub.O-24; bioequilvance
criteria were not met for AUC.sub.0-5 for d-amphetamine.
Example 25
Rate of Absorption and Oral Bioavailability of Mixed Amphetaminers
in Oral Liquid Suspension Compared to the Commercially Available
Reference Product, Adderall XR
[0355] This was an open-label, single-dose, 3-treatment, 3-period,
randomized, crossover study to assess the effect of food on the
rate of absorption and oral bioavailability of mixed amphetamines
on ion exchange resin in oral liquid suspension. The oral liquid
suspension is similar to the suspension described in Example 24.
Subjects were randomly assigned to a treatment sequence and
received three separate single-dose administrations of study
medication, one treatment per period, according to the
randomization schedule. Dosing days were separated by a washout
period of at least 7 days. Subjects received each of the treatments
listed below during the three treatment periods:
[0356] Treatment A: Test Formulation 25A, an Oral Liquid suspension
(equivalent to 30 mg mixed amphetamine salts/15 mL) was
administered under fasted conditions; Dose=1.times.15 mL liquid
oral suspension.
[0357] Treatment B: Test Formulation 25B, an Oral Liquid Suspension
(equivalent to 30 mg mixed amphetamine salts/15 mL) was
administered under fed conditions; Dose=1.times.15 mL liquid oral
suspension.
[0358] Treatment C: Reference Product 25C, an Adderall XR.RTM.
administered under fed conditions; Dose=1.times.30 mg capsule.
[0359] In each study period, subjects were admitted to the study
unit in the evening prior to the scheduled dose. Subjects were
confined to the research center during each study period until
completion of the 36-hour blood collection and other study
procedures. Subjects returned to the study unit for outpatient
pharmacokinetic blood samples at 48 and 60 hours.
Procedures for Collecting Samples for Pharmacokinetic Analysis
[0360] Blood samples (1.times.4 mL) were collected and analyzed for
d- and l-amphetamine. Samples were analyzed as described above. The
following pharmacokinetic parameters were calculated: peak
concentration in plasma (C.sub.max), time to peak concentration
(T.sub.max), elimination rate constant (.lamda..sub.z), terminal
half-life (T.sub.1/2), area under the concentration-time curve from
time-zero to 5.00 hours (AUC.sub.O-5), area under the
concentration-time curve from 5.00 hours to the time of the last
quantifiable concentration (AUC.sub.5-last), area under the
concentration-time curve from time-zero to the time of the last
quantifiable concentration (AUC.sub.last), and area under the
plasma concentration time curve from time-zero extrapolated to
infinity (AUC.sub.inf).
[0361] To assess the bioequivalence for Treatment B (fed) vs.
Adderall XR (Treatment C, fed), an analysis of variance (ANOVA)
model and the two one-sided t-tests procedure was performed on the
log-transformed pharmacokinetic parameters C.sub.max, AUC.sub.0-5,
AUC.sub.5-last, and AUC.sub.inf for d- and l-amphetamine across
treatments. Bioequivalence was demonstrated if the 90% confidence
intervals were within the accepted limits of 80.00 to 125.00%.
[0362] To assess the effect of food on the rate and extent of
absorption of Treatment B (fed) vs. Treatment A (fast), an analysis
of variance (ANOVA) model and the two one-sided t-tests procedure
was performed on the log-transformed pharmacokinetic parameters
C.sub.max, AUC.sub.last, and AUC.sub.inf for d- and l-amphetamine
across treatments. No significant food effect was demonstrated if
the 90% confidence intervals were within the accepted limits of
80.00 to 125.00%.
Results
[0363] Data from 29 subjects were included in the pharmacokinetic
and statistical analyses. Mean concentration-time data are shown in
FIGS. 38 and 39. Results of the pharmacokinetic and statistical
analyses are shown below in Tables 50 through 53.
Conclusions
[0364] Bioequivalence Assessment (Treatment B, (Fed) Vs. Adderall
XR (Treatment C, (Fed))
[0365] The 90% confidence interval for comparing the maximum
exposure, based on ln(C.sub.max), is within the accepted 80% to
125% limits for d- and l-amphetamine. The 90% confidence intervals
for comparing late and total systemic exposure, based on
ln(AUC.sub.5-last) and ln(AUC.sub.inf), are within the accepted 80%
to 125% limits for d- and l-amphetamine. The 90% confidence
intervals for comparing early systemic exposure, based on
ln(AUC.sub.0-5) are not within the accepted 80% to 125% limits for
either d- and l-amphetamine. Therefore, a formulation of mixed
amphetamine resin Oral Liquid Suspension (equivalent to 30 mg mixed
amphetamine salts/15 mL) is not bioequivalent to the reference
listed drug product (RLD) Adderall XR under fed conditions. Rather,
formulating amphetamines in a suspension of drug-resin particles
maintains an early onset of amphetamine effect, even when taken
with meals.
Food Effect Assessment (Treatment B, Fed) Vs. (Treatment A,
Fast))
[0366] The 90% confidence interval for comparing the maximum
exposure, based on ln(C.sub.max), is within the accepted 80% to
125% limits for d- and l-amphetamine. The 90% confidence intervals
for comparing total systemic exposure, based on ln(AUC.sub.last)
and ln(AUC.sub.inf), are within the accepted 80% to 125% limits for
d- and l-amphetamine. Therefore, no significant food effect was
demonstrated for the formulations of Oral Liquid Suspension
containing mixed amphetamines on resin particles (equivalent to 30
mg mixed amphetamine salts/15 mL). Such suspensions provide
amphetamine exposure levels that more closely resemble the fasted
state, even when taken with meals.
TABLE-US-00055 TABLE 50 Statistical Analysis of the Log-Transformed
Systemic Exposure Parameters of d-Amphetamine Comparing Fed
Conditions (Treatment B) to the Reference Product under Fed
Conditions (Treatment C) Dependent Geometric Mean.sup.a Ratio
(%).sup.b 90% CI.sup.c ANOVA Variable Test Ref (Test/Ref) Lower
Upper Power CV % ln(C.sub.max) 45.2535 41.6470 108.66 103.14 114.47
1.0000 11.66 ln(AUC.sub.0-5) 125.0648 72.1095 173.44 145.51 206.73
0.6764 40.70 ln(AUC.sub.5-last) 773.0222 757.8067 102.01 97.59
106.63 1.0000 9.90 ln(AUC.sub.inf) 945.7804 866.6134 109.14 104.84
113.61 1.0000 8.97 .sup.aGeometric Mean for Treatment B, Fed (Test)
and Reference Product-Fed (Ref) based on Least Squares Mean of
log-transformed parameter values .sup.bRatio(%) = Geometric Mean
(Test)/Geometric Mean (Ref) .sup.c90% Confidence Interval
TABLE-US-00056 TABLE 51 Statistical Analysis of the Log-Transformed
Systemic Exposure Parameters of d-Amphetamine Comparing Fed
Conditions (Treatment B) to Fasted Conditions (Treatment A)
Dependent Geometric Mean.sup.a Ratio (%).sup.b 90% CI.sup.c ANOVA
Variable Test Ref (Test/Ref) Lower Upper Power CV % ln(C.sub.max)
45.3087 51.0913 88.68 85.41 92.08 1.0000 8.40 ln(AUC.sub.last)
909.6180 942.7716 96.48 93.20 99.89 1.0000 7.74 ln(AUC.sub.inf)
945.6631 977.1454 96.78 93.30 100.39 1.0000 8.19 .sup.aGeometric
Mean for Treatment B, Fed (Test) and Treatment A Fasted (Ref) based
on Least Squares Mean of log-transformed parameter values
.sup.bRatio(%) = Geometric Mean (Test)/Geometric Mean (Ref)
.sup.c90% Confidence Interval
TABLE-US-00057 TABLE 52 Statistical Analysis of the Log-Transformed
Systemic Exposure Parameters of l-Amphetamine Comparing Fed
Conditions (Treatment B) to the Reference Product under Fed
Conditions (Treatment C) Dependent Geometric Mean.sup.a Ratio
(%).sup.b 90% CI.sup.c ANOVA Variable Test Ref (Test/Ref) Lower
Upper Power CV % ln(C.sub.max) 14.3840 12.5275 114.82 109.16 120.78
1.0000 11.32 ln(AUC.sub.0-5) 38.7444 20.9999 184.50 154.35 220.53
0.6642 41.41 ln(AUC.sub.5-last) 281.9542 258.7635 108.96 103.88
114.29 1.0000 10.68 ln(AUC.sub.inf) 349.4520 301.4583 115.92 110.57
121.53 1.0000 10.56 .sup.aGeometric Mean for Treatment B, Fed
(Test) and Reference Product-Fed (Ref) based on Least Squares Mean
of log-transformed parameter values .sup.bRatio(%) = Geometric Mean
(Test)/Geometric Mean (Ref) .sup.c90% Confidence Interval
TABLE-US-00058 TABLE 53 Statistical Analysis of the Log-Transformed
Systemic Exposure Parameters of l-Amphetamine Comparing Fed
Conditions (Treatment B) to Fasted Conditions (Treatment A)
Dependent Geometric Mean.sup.a Ratio (%).sup.b 90% CI.sup.c ANOVA
Variable Test Ref (Test/Ref) Lower Upper Power CV % ln(C.sub.max)
14.3990 16.0658 89.63 86.43 92.94 1.0000 8.11 ln(AUC.sub.last)
324.6557 338.2024 95.99 92.54 99.58 1.0000 8.19 ln(AUC.sub.inf)
349.3468 361.6533 96.60 92.75 100.61 1.0000 9.09 .sup.aGeometric
Mean for Treatment B, Fed (Test) and Treatment A, Fasted (Ref)
based on Least Squares Mean of log-transformed parameter values
.sup.bRatio(%) = Geometric Mean (Test)/Geometric Mean (Ref)
.sup.c90% Confidence Interval
[0367] All documents (e.g., patents and published patent
applications) mentioned in this specification are hereby
incorporated by reference in their entirety.
* * * * *