U.S. patent application number 15/279297 was filed with the patent office on 2017-01-19 for sustained release formulation of naltrexone.
The applicant listed for this patent is Orexigen Therapeutics, Inc.. Invention is credited to Thea Elise Dunzo, Anthony A. McKinney, Richard Soltero, Gary D. Tollefson.
Application Number | 20170014404 15/279297 |
Document ID | / |
Family ID | 38790533 |
Filed Date | 2017-01-19 |
United States Patent
Application |
20170014404 |
Kind Code |
A1 |
McKinney; Anthony A. ; et
al. |
January 19, 2017 |
SUSTAINED RELEASE FORMULATION OF NALTREXONE
Abstract
A sustained-release oral dosage form of naltrexone or a
pharmaceutically acceptable salt thereof is provided. The oral
dosage form may be administered with another compound.
Administration of the oral dosage form may reduce a side effect,
which may be a side effect at least partially attributable to a
weight-loss treatment. The oral dosage form may be administered to
treat a weight-loss condition.
Inventors: |
McKinney; Anthony A.; (San
Diego, CA) ; Tollefson; Gary D.; (Indianapolis,
IN) ; Soltero; Richard; (Holly Springs, NC) ;
Dunzo; Thea Elise; (Durham, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Orexigen Therapeutics, Inc. |
La Jolla |
CA |
US |
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Family ID: |
38790533 |
Appl. No.: |
15/279297 |
Filed: |
September 28, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15046373 |
Feb 17, 2016 |
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15279297 |
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14826086 |
Aug 13, 2015 |
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15046373 |
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14555475 |
Nov 26, 2014 |
9107837 |
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14826086 |
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11757773 |
Jun 4, 2007 |
8916195 |
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14555475 |
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60811251 |
Jun 5, 2006 |
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60841114 |
Aug 29, 2006 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/2031 20130101;
A61K 9/209 20130101; A61K 31/137 20130101; A61K 9/0053 20130101;
A61K 9/2018 20130101; A61K 9/2054 20130101; A61K 9/20 20130101;
A61K 31/485 20130101; A61K 31/12 20130101; A61K 9/2027 20130101;
A61K 9/2009 20130101; A61K 9/2013 20130101 |
International
Class: |
A61K 31/485 20060101
A61K031/485; A61K 31/137 20060101 A61K031/137; A61K 9/00 20060101
A61K009/00 |
Claims
1. An oral dosage form, comprising a sustained-release naltrexone
formulation that is formulated to provide a reduction in at least
one adverse effect, wherein the adverse effect is associated with
co-administration of an immediate-release naltrexone formulation
and a second compound.
2. The oral dosage form of claim 1, wherein the second compound
comprises a monoamine reuptake inhibitor.
3. The oral dosage form of claim 1, wherein the second compound
comprises bupropion or a pharmaceutically acceptable salt
thereof.
4. The oral dosage form of claim 1, wherein the second compound
comprises fluoxetine or a pharmaceutically acceptable salt
thereof.
5. The oral dosage form of claim 1, wherein the reduction in the at
least one adverse effect comprises a reduction in one or more of
the severity, the duration, or the probability of experiencing the
at least one adverse effect.
6. The oral dosage form of claim 1, wherein the at least one
adverse effect comprises nausea.
7. The oral dosage form of claim 1, wherein the sustained-release
naltrexone formulation is in a unit dosage form comprising an
amount of naltrexone in the range of from about 4 mg to about 50
mg.
8. The oral dosage form of claim 1, wherein the sustained-release
naltrexone formulation is in a unit dosage form comprising an
amount of naltrexone in the range of from about 10 mg to about 25
mg.
9. The oral dosage form of claim 1, wherein the sustained-release
naltrexone formulation is in a unit dosage form comprising about 4
mg, about 8 mg, about 12 mg, about 16 mg, about 32 mg or about 48
mg of naltrexone.
10. The oral dosage form of claim 1, wherein the sustained-release
naltrexone formulation is in a unit dosage form suitable for
administration one or more times per day.
11. The oral dosage form of claim 10, wherein the unit dosage form
is suitable for administration two or more times per day.
12. The oral dosage form of claim 1, wherein the oral dosage form
further comprises the second compound.
13. The oral dosage form of claim 12, wherein the second compound
comprises bupropion or a pharmaceutically acceptable salt
thereof.
14. The oral dosage form of claim 13, wherein the bupropion or a
pharmaceutically acceptable salt thereof is a sustained release
formulation.
15. The oral dosage form of claim 14, wherein the sustained-release
naltrexone formulation is in a unit dosage form; wherein the unit
dosage form comprises naltrexone in an amount of about 4 mg, about
8 mg or about 12 mg; and wherein the unit dosage form comprises
bupropion or a pharmaceutically acceptable salt thereof in an
amount of about 90 mg.
16. The oral dosage form of claim 12, wherein the second compound
comprises fluoxetine or a pharmaceutically acceptable salt
thereof.
17. The oral dosage form of claim 1, wherein the oral dosage form
comprises an amount of a sustained-release carrier composition that
is effective to provide, after administration, an in vivo plasma
concentration profile comprising at least one selected from: (a) a
naltrexone C.sub.max that is about 80% or less of the naltrexone
C.sub.max of REVIA.TM. immediate-release naltrexone hydrochloride,
and a naltrexone AUC.sub.last that is in the range of about 80% to
about 125% of the naltrexone AUC.sub.last of REVIA.TM.
immediate-release naltrexone hydrochloride; and (b) a 6-beta
naltrexol C.sub.max that is about 80% or less of the 6-beta
naltrexol C.sub.max of REVIA.TM. immediate-release naltrexone
hydrochloride, and a 6-beta naltrexol AUC.sub.last that is in the
range of about 80% to about 125% of the 6-beta naltrexol
AUC.sub.last of REVIA.TM. immediate-release naltrexone
hydrochloride.
18. The oral dosage form of claim 17, wherein said
sustained-release carrier composition comprises at least one of
hydroxypropylmethyl cellulose, polyoxyethylene, polyacrylate, a
copolymer of acrylate and methacrylate, a methacrylate polymer, a
copolymer of acrylate and methacrylate, a copolymer of acrylate and
methacrylate with ammonium group, a copolymer of maleic anhydride
and methyl vinyl ether, hydroxy propyl ethyl cellulose, hydroxy
propyl cellulose, hydroxy ethyl cellulose, methyl cellulose,
hydroxymethyl methacrylate, maltodextrin, natural gum and xanthan
gum.
19. The oral dosage form of claim 17, wherein said
sustained-release carrier composition comprises at least one of
hydroxypropylmethylcellulose and polyoxyethylene.
20. An oral unit dosage form, comprising a sustained-release
naltrexone formulation that is effective to provide, after
administration, an in vivo plasma concentration profile comprising
at least one selected from: (a) a naltrexone C.sub.max that is
about 80% or less of the naltrexone C.sub.max of REVIA.TM.
immediate-release naltrexone hydrochloride, and a naltrexone
AUC.sub.last that is in the range of about 80% to about 125% of the
naltrexone AUC.sub.last of REVIA.TM. immediate-release naltrexone
hydrochloride; and (b) a 6-beta naltrexol C.sub.max that is about
80% or less of the 6-beta naltrexol C.sub.max of REVIA.TM.
immediate-release naltrexone hydrochloride, and a 6-beta naltrexol
AUC.sub.last that is in the range of about 80% to about 125% of the
6-beta naltrexol AUC.sub.last of REVIA.TM. immediate-release
naltrexone hydrochloride.
21. The oral unit dosage form of claim 20, comprising an amount of
naltrexone in the range of from about 4 mg to about 50 mg.
22. The oral unit dosage form of claim 20, comprising an amount of
naltrexone in the range of from about 10 mg to about 25 mg.
23. The oral unit dosage form of claim 20, comprising about 4 mg,
about 8 mg, about 12 mg, about 16 mg, about 32 mg or about 48 mg of
naltrexone.
24. An oral dosage form, comprising naltrexone or a
pharmaceutically acceptable salt thereof and a sustained-release
carrier composition, wherein said oral dosage form provides an in
vitro release rate of the naltrexone or pharmaceutically acceptable
salt thereof of less than about 80% in about 1 hour.
25. The oral dosage form of claim 24, wherein said in vitro release
rate is less than about 70% in about 1 hour.
26. The oral dosage form of claim 24, wherein said
sustained-release carrier composition comprises at least one of
hydroxypropylmethyl cellulose, polyoxyethylene, polyacrylate, a
copolymer of acrylate and methacrylate, a methacrylate polymer, a
copolymer of acrylate and methacrylate, a copolymer of acrylate and
methacrylate with ammonium group, a copolymer of maleic anhydride
and methyl vinyl ether, hydroxy propyl ethyl cellulose, hydroxy
propyl cellulose, hydroxy ethyl cellulose, methyl cellulose,
hydroxymethyl methacrylate, maltodextrin, natural gum and xanthan
gum.
27. The oral dosage form of claim 24, wherein said
sustained-release carrier composition comprises at least one of
hydroxypropylmethylcellulose and polyoxyethylene.
28. The oral dosage form of claim 24, wherein the naltrexone salt
comprises naltrexone hydrochloride.
29. A method of administering naltrexone, comprising administering
the oral dosage form of claim 1 to a subject.
30. The method of claim 29, comprising administering the oral
dosage form to the subject in a manner that is effective to cause
weight loss and/or inhibit weight gain.
31. The method of claim 29, further comprising administering a
second compound to the subject.
32. The method of claim 31, wherein the second compound comprises
bupropion or a pharmaceutically acceptable salt thereof.
33. The method of claim 32, wherein the sustained-release
naltrexone formulation is in a unit dosage form; wherein the unit
dosage form comprises naltrexone in an amount of about 4 mg, about
8 mg or about 12 mg; and wherein the unit dosage form comprises
bupropion or a pharmaceutically acceptable salt thereof in an
amount of about 90 mg.
34. The method of claim 31, wherein the second compound comprises
fluoxetine or a pharmaceutically acceptable salt thereof.
35. A method of administering naltrexone, comprising administering
a sustained-release naltrexone formulation to a subject in an
amount that is effective to provide an in vivo plasma concentration
profile comprising at least one selected from: (a) a naltrexone
C.sub.max that is about 80% or less of the naltrexone C.sub.max of
REVIA.TM. immediate-release naltrexone hydrochloride, and a
naltrexone AUC.sub.last that is in the range of about 80% to about
125% of the naltrexone AUC.sub.last of REVIA.TM. immediate-release
naltrexone hydrochloride; and (b) a 6-beta naltrexol C.sub.max that
is about 80% or less of the 6-beta naltrexol C.sub.max of REVIA.TM.
immediate-release naltrexone hydrochloride, and a 6-beta naltrexol
AUC.sub.last that is in the range of about 80% to about 125% of the
6-beta naltrexol AUC.sub.last of REVIA.TM. immediate-release
naltrexone hydrochloride.
36. The method of claim 35, comprising administering the
sustained-release naltrexone formulation to the subject in a manner
that is effective to cause weight loss and/or inhibit weight
gain.
37. The method of claim 35, further comprising administering a
second compound to the subject.
38. The method of claim 37, wherein the second compound comprises a
monoamine reuptake inhibitor.
39. The method of claim 38, wherein administration of the monoamine
reuptake inhibitor in combination with an immediate-release form of
naltrexone results in at least one adverse effect that is reduced
by the administration of the sustained-release naltrexone
formulation.
40. The method of claim 38, wherein the monoamine reuptake
inhibitor comprises bupropion or a pharmaceutically acceptable salt
thereof.
41. The method of claim 40, wherein the sustained-release
naltrexone formulation is in a unit dosage form; wherein the unit
dosage form comprises naltrexone in an amount of about 4 mg, about
8 mg or about 12 mg; and wherein the unit dosage form comprises
bupropion or a pharmaceutically acceptable salt thereof in an
amount of about 90 mg.
42. The method of claim 38, wherein the monoamine reuptake
inhibitor comprises fluoxetine or a pharmaceutically acceptable
salt thereof.
Description
RELATED APPLICATION INFORMATION
[0001] The present application is a continuation of U.S.
application Ser. No. 15/046,373, filed Feb. 17, 2016, which is a
continuation of U.S. application Ser. No. 14/826,086, filed Aug.
13, 2015, now abandoned, which is a continuation of U.S.
application Ser. No. 14/555,475, filed Nov. 26, 2014, now U.S. Pat.
No. 9,107,837, which is a continuation of U.S. application Ser. No.
11/757,773, filed Jun. 4, 2007, now U.S. Pat. No. 8,916,195, which
claims the benefit of priority to U.S. Provisional Patent
Application Ser. No. 60/811,251, filed Jun. 5, 2006, and U.S.
Provisional Patent Application Ser. No. 60/841,114, filed Aug. 29,
2006, all of which are hereby incorporated by reference in their
entireties.
BACKGROUND OF THE INVENTION
[0002] Field of the Invention
[0003] The present invention relates to pharmaceutical compositions
comprising sustained-release opioid receptor antagonists and
methods of administration and use thereof.
[0004] Description of the Related Art
[0005] Obesity is a major health concern in Western societies. It
is estimated that about 97 million adults in the United States are
overweight or obese. Epidemiological studies have shown that
increasing degrees of overweight and obesity are important
predictors of decreased life expectancy. Obesity causes or
exacerbates many health problems, both independently and in
association with other diseases. The medical problems associated
with obesity, which can be serious and life-threatening, include
hypertension; type 2 diabetes mellitus; elevated plasma insulin
concentrations; insulin resistance; dyslipidemias; hyperlipidemia;
endometrial, breast, prostate and colon cancer; osteoarthritis;
respiratory complications, such as obstructive sleep apnea;
cholelithiasis; gallstones; arteriosclerosis; heart disease;
abnormal heart rhythms; and heart arrythmias (Kopelman, P. G.,
Nature 404, 635-643 (2000)). Obesity is further associated with
premature death and with a significant increase in mortality and
morbidity from stroke, myocardial infarction, congestive heart
failure, coronary heart disease, and sudden death.
[0006] Obesity is often treated by encouraging patients to lose
weight by reducing their food intake or by increasing their
exercise level and therefore increasing their energy output. A
sustained weight loss of 5% to 10% of body weight has been shown to
improve the co-morbidities associated with obesity, such as
diabetes and hypertension, and can lead to improvement of
obesity-related conditions such as osteoarthritis, sleep apnea and
pulmonary and cardiac dysfunction.
[0007] Naltrexone, having the chemical name
(17-(cyclopropylmethyl)-4,5.alpha.-epoxy-3,14-dihydroxymorphinan-6-one)
and the chemical structure shown below, is an opioid receptor
antagonist used primarily in the management of alcohol dependence
and opioid dependence.
##STR00001##
[0008] Naltrexone for oral administration has been commercially
available for a number of years from various sources as the
hydrochloride salt, naltrexone hydrochloride, e.g., under the trade
names REVIA.TM. (50 mg) and DEPADE.TM. (25 mg, 50 mg and 100 mg).
The currently approved forms of oral naltrexone are immediate
release formulations that are efficacious even when dosed as
infrequently as once every 72 hours. For example, the label of the
DEPADE.RTM. brand of naltrexone hydrochloride indicates that
naltrexone is a potent opioid antagonist with a prolonged
pharmacological effect (24 to 72 hours) and recommends a dose of 50
mg once daily. The DEPADE.RTM. label discloses that clinical
studies indicate that 50 mg of naltrexone hydrochloride will block
the pharmacologic effects of 25 mg of intravenously administered
heroin for periods as long as 24 hours. The DEPADE.RTM. label goes
on to indicate that other data suggest that doubling the dose of
naltrexone hydrochloride provides blockade for 48 hours, and
tripling the dose of naltrexone hydrochloride provides blockade for
about 72 hours. Thus, despite reaching a peak serum concentration
quickly (T.sub.max of approximately 1 hour) after oral
administration, the immediate release form of naltrexone has
relatively long lasting effects.
[0009] The long-lasting effects of the immediate release form of
oral naltrexone may be used to encourage patient compliance by
utilizing a dosing frequency that is less than once per day, e.g.
every other day or every three days. For example, the DEPADE.RTM.
label indicates that a flexible approach to a dosing regimen may be
employed to enhance compliance. Thus, the DEPADE.RTM. label
discloses, patients may receive 50 mg of naltrexone hydrochloride
every weekday with a 100 mg dose on Saturday or patients may
receive 100 mg every other day, or 150 mg every third day. The
DEPADE.RTM. label refers to clinical studies reported in the
literature that have employed the following dosing regimen: 100 mg
on Monday, 100 mg on Wednesday, and 150 mg on Friday. Thus, use of
the immediate release oral form allows a patient to take a
relatively large dose of naltrexone at a time when the temptation
to abuse alcohol or opioids may be less (e.g., during the week),
with the effects lasting to a time when temptation may be greater
(e.g., over the weekend).
[0010] The DEPADE.RTM. label indicates that naltrexone has not been
shown to cause significant increases in complaints in
placebo-controlled trials in patients known to be free of opioids
for more than 7 to 10 days. Although a subset of the patient
population reports nausea upon initial administration of 25 mg or
50 mg dosages of the immediate release oral form of naltrexone, the
nausea often subsides as those patients develop a tolerance. The
DEPADE.RTM. label indicates that, in an open label safety study
with approximately 570 individuals with alcoholism receiving
naltrexone, the following new-onset adverse reactions occurred in
2% or more of the patients: nausea (10%), headache (7%), dizziness
(4%), nervousness (4%), fatigue (4%), insomnia (3%), vomiting (3%),
anxiety (2%) and somnolence (2%). Moderate to severe nausea was
reported by 18 patients (15%) in a 10-week open label study of
naltrexone among alcohol dependent participants, involving a
initial 25 mg dose followed by a dose of 50 mg daily for 10 weeks
(O'Malley, S. S. J. Clin. Psychopharmacol. 2000 February;
20(1):69-76). Eight of the eighteen patients that experienced
moderate to severe nausea discontinued treatment, nausea resolved
within one week for five subjects and within two weeks for four,
and it continued off and on throughout the ten-week period for one
subject. The authors linked the moderate to severe nausea to poorer
medication compliance and heavier drinking by the patients during
treatment.
[0011] It appears that while some patients experience adverse
effects upon administration of 25 mg or 50 mg dosages of immediate
release oral naltrexone, the adverse effects often subside within a
relatively short period of time and many patients are able to
tolerate significantly higher oral dosages, e.g., 100 mg or 150 mg.
A once-monthly injectable form of naltrexone is commercially
available under the tradename VIVITROL.RTM. for the treatment of
alcoholism. The prescribing information for VIVITROL.RTM. indicates
that patients should be advised that they may experience nausea
following the initial injection of the VIVITROL.RTM. naltrexone;
that these episodes of nausea tend to be mild and subside within a
few days post-injection, and that patients are less likely to
experience nausea in subsequent injections.
[0012] U.S. Patent Publication No. 2004/0254208 A1 discloses the
use of naltrexone in combination with other compounds for affecting
weight loss, but does not disclose any particular adverse effects
associated with the combinations.
SUMMARY OF THE INVENTION
[0013] An unexpectedly high incidence of adverse effects associated
with co-administration of naltrexone with bupropion and/or
fluoxetine has now been identified as a problem. For example,
during a clinical trial described in greater detail below, the
incidence of adverse events of moderate severity associated with
co-administration of immediate-release naltrexone with bupropion
was 30.7%. This incidence of adverse effects was significantly
higher than would be expected based on the typical incidence of
adverse effects associated with administration of immediate-release
naltrexone alone or bupropion alone.
[0014] In an embodiment, sustained release naltrexone formulations
have now been developed that provide a solution to this
problem.
[0015] An embodiment provides an oral dosage form, comprising a
sustained-release naltrexone formulation that is formulated to
provide a reduction in at least one adverse effect, wherein the
adverse effect is associated with co-administration of an
immediate-release naltrexone formulation and a second compound. In
an embodiment, the second compound comprises a monoamine reuptake
inhibitor, such as bupropion or fluoxetine. Another embodiment
provides a method of administering naltrexone, comprising
administering a sustained-release naltrexone formulation to a
subject, e.g., in a manner that is effective to cause weight loss
and/or inhibit weight gain.
[0016] Another embodiment provides an oral unit dosage form,
comprising a sustained-release naltrexone formulation that is
effective to provide, after administration, an in vivo plasma
concentration profile comprising at least one selected from: [0017]
(a) a naltrexone C.sub.max that is about 80% or less of the
naltrexone C.sub.max of REVIA.TM. immediate-release naltrexone
hydrochloride, and a naltrexone AUC.sub.last that is in the range
of about 80% to about 125% of the naltrexone AUC.sub.last of
REVIA.TM. immediate-release naltrexone hydrochloride; and [0018]
(b) a 6-beta naltrexol C.sub.max that is about 80% or less of the
6-beta naltrexol C.sub.max of REVIA.TM. immediate-release
naltrexone hydrochloride, and a 6-beta naltrexol AUC.sub.last that
is in the range of about 80% to about 125% of the 6-beta naltrexol
AUC.sub.last of REVIA.TM. immediate-release naltrexone
hydrochloride.
[0019] Another embodiment provides an oral dosage form, comprising
naltrexone or a pharmaceutically acceptable salt thereof and a
sustained-release carrier composition, wherein the oral dosage form
provides an in vitro release rate of the naltrexone or
pharmaceutically acceptable salt thereof of less than about 90% in
about 4 hours.
[0020] Another embodiment provides a method of administering a
sustained-release naltrexone formulation as described herein. For
example, an embodiment provides a method of administering
naltrexone, comprising administering a sustained-release naltrexone
formulation to a subject in an amount that is effective to provide
an in vivo plasma concentration profile comprising at least one
selected from: [0021] (a) a naltrexone C.sub.max that is about 80%
or less of the naltrexone C.sub.max of REVIA.TM. immediate-release
naltrexone hydrochloride, and a naltrexone AUC.sub.last that is in
the range of about 80% to about 125% of the naltrexone AUC.sub.last
of REVIA.TM. immediate-release naltrexone hydrochloride; and [0022]
(b) a 6-beta naltrexol C.sub.max that is about 80% or less of the
6-beta naltrexol C.sub.max of REVIA.TM. immediate-release
naltrexone hydrochloride, and a 6-beta naltrexol AUC.sub.last that
is in the range of about 80% to about 125% of the 6-beta naltrexol
AUC.sub.last of REVIA.TM. immediate-release naltrexone
hydrochloride.
[0023] In an embodiment, a sustained-release naltrexone formulation
as described herein is administered to a subject in a manner that
is effective to treat a weight related condition, e.g., to cause
weight loss and/or inhibit weight gain.
[0024] These and other embodiments are described in greater detail
below.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] FIG. 1 shows the dissolution profile of sustained release 5
mg naltrexone tablets containing polyethylene oxide.
[0026] FIG. 2 shows the dissolution profile of sustained release 5
mg naltrexone tablets containing hydroxypropylmethyl cellulose.
[0027] FIG. 3 shows the dissolution profile of sustained release
naltrexone and bupropion tablets containing hydroxypropylmethyl
cellulose.
[0028] FIG. 4 shows the individual plasma concentration time curves
of naltrexone in subjects receiving Naltrexone IR
[0029] FIG. 5 shows the individual plasma concentration time curves
of naltrexone in subjects receiving Naltrexone SR.
[0030] FIG. 6 shows the individual plasma concentration time curves
of 6-beta naltrexol in subjects receiving Naltrexone IR.
[0031] FIG. 7 shows the individual plasma concentration time curves
of 6-beta naltrexol in subjects receiving Naltrexone SR.
[0032] FIGS. 8A and 8B show the average plasma concentration time
curves of naltrexone across subjects receiving Naltrexone SR
(circles) or Naltrexone IR (squares) across two time scales.
[0033] FIGS. 9A and 9B show the average plasma concentration time
curves of 6-beta naltrexol across subjects receiving Naltrexone SR
(circles) or Naltrexone IR (squares) across two time scales.
[0034] FIG. 10 is a schematic illustrating the population of
subjects reporting nausea and vomiting using the UKU Adverse Event
Rating Scale.
[0035] FIG. 11 shows the average plasma concentrations of
naltrexone in subjects receiving naltrexone IR in combination with
bupropion SR ( ) or naltrexone SR in combination with bupropion SR
(.box-solid.).
[0036] FIG. 12 shows the average plasma concentrations of 6-beta
naltrexol in subjects receiving naltrexone IR in combination with
bupropion SR ( ) or naltrexone SR in combination with bupropion SR
(.box-solid.).
[0037] FIG. 13 shows the average trough plasma concentrations of
naltrexone in subjects receiving naltrexone IR in combination with
bupropion SR ( ) or naltrexone SR in combination with bupropion SR
(.box-solid.).
[0038] FIG. 14 shows the average trough plasma concentrations of
6-beta naltrexol in subjects receiving naltrexone IR in combination
with bupropion SR ( ) or naltrexone SR in combination with
bupropion SR (.box-solid.).
[0039] FIG. 15 shows the average plasma concentrations of bupropion
in subjects receiving bupropion SR in combination with naltrexone
SR ( ) or in combination with naltrexone IR (.box-solid.).
[0040] FIG. 16 shows the average plasma concentrations of the
bupropion metabolite hydroxybupropion in subjects receiving
bupropion SR in combination with naltrexone SR ( ) or in
combination with naltrexone IR (.box-solid.).
[0041] FIG. 17 shows the average plasma concentrations of the
bupropion metabolite threohydroxybupropion in subjects receiving
bupropion SR in combination with naltrexone SR ( ) or in
combination with naltrexone IR (.box-solid.).
[0042] FIG. 18 shows the average plasma concentrations of the
bupropion metabolite erythrohydroxybupropion in subjects receiving
bupropion SR in combination with naltrexone SR ( ) or in
combination with naltrexone IR (.box-solid.).
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0043] Various embodiments provide an oral dosage form that
comprises a sustained-release naltrexone formulation.
Co-administration of a sustained-release naltrexone formulation
with a second compound may provide a reduction in at least one
adverse effect as compared to co-administration of an
immediate-release naltrexone formulation with the second compound.
The second compound may be an monoamine reuptake inhibitor, such as
bupropion or a pharmaceutically acceptable salt thereof or
fluoxetine or a pharmaceutically acceptable salt thereof. The at
least one adverse effect may include nausea.
[0044] A sustained-release naltrexone formulation may provide a
naltrexone C.sub.max and/or a 6-beta naltrexol C.sub.max that is
about 80% or less of the naltrexone C.sub.max and/or the 6-beta
naltrexol C.sub.max of REVIA.TM. immediate-release naltrexone
hydrochloride. A sustained-release naltrexone formulation may
provide a naltrexone AUC.sub.last and/or a 6-beta naltrexol
AUC.sub.last that is in the range of about 80% to about 125% of the
naltrexone AUC.sub.last and/or the 6-beta naltrexol AUC.sub.last of
REVIA.TM. immediate-release naltrexone hydrochloride.
DEFINITIONS
[0045] The term "naltrexone" may be used in a general way herein to
refer to a free base of naltrexone, a pharmaceutically acceptable
naltrexone salt (including hydrates and anhydrous forms, e.g.,
naltrexone hydrochloride dihydrate and anhydrous naltrexone
hydrochloride), a naltrexone metabolite, a naltrexone isomer, a
naltrexone prodrug or mixtures thereof. Reference herein to
"naltrexone" will be understood as encompassing all such forms,
unless the context clearly indicates otherwise.
[0046] The term "pharmaceutically acceptable salt" refers to a
formulation of a compound that does not cause significant
irritation to an organism to which it is administered and does not
abrogate the biological activity and properties of the compound.
Pharmaceutical salts of basic compounds can be obtained by reacting
the compound with an acid such as hydrochloric acid, hydrobromic
acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic
acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid
and the like. For example, naltrexone hydrochloride is a
pharmaceutically acceptable salt of naltrexone. Pharmaceutical
salts of acidic compounds can be obtained by reacting the compound
with a base to form a salt such as an ammonium salt, an alkali
metal salt, such as a sodium or a potassium salt, an alkaline earth
metal salt, such as a calcium or a magnesium salt, a salt of
organic bases such as dicyclohexylamine, N-methyl-D-glucamine,
tris(hydroxymethyl) methylamine, and salts thereof with amino acids
such as arginine, lysine, and the like.
[0047] The term "oral dosage form", as used herein, has its
ordinary meaning as understood by those skilled in the art and thus
includes, by way of non-limiting example, a formulation of a drug
or drugs in a form administrable to a human. The illustrative
embodiments of the invention have been described primarily as being
directed to oral dosage forms such as tablets, cores, capsules,
caplets and loose powder, but other suitable dosage forms such as
solutions and suspensions are also contemplated.
[0048] The term "sustained release", as used herein, has its
ordinary meaning as understood by those skilled in the art and thus
includes, by way of non-limiting example, the controlled release of
a drug from a dosage form over an extended period of time. For
example, in some embodiments, sustained-release dosage forms are
those that have a release rate that is substantially longer than
that of a comparable immediate release form, e.g., greater than
125% of the release rate of an immediate-release dosage form.
[0049] The term "immediate release", as used herein, has its
ordinary meaning as understood by those skilled in the art and thus
includes, by way of non-limiting example, release of a drug from a
dosage form in a relatively brief period of time after
administration. Examples of immediate-release dosage forms of
naltrexone hydrochloride include REVIA.TM. immediate-release
naltrexone hydrochloride and DEPADE.TM. immediate-release
naltrexone hydrochloride. In some embodiments, immediate-release
dosage forms are those that have a release rate that is up to and
including 125% of the release rate for one or more of REVIA.TM.
immediate-release naltrexone hydrochloride and DEPADE.TM.
immediate-release naltrexone hydrochloride. The REVIA.TM.
immediate-release naltrexone hydrochloride may be a 50 mg dosage
form. The DEPADE.TM. immediate-release naltrexone hydrochloride may
be a 25 mg, 50 mg or 100 mg dosage form. As used herein, an
immediate-release formulation may refer to REVIA.TM.
immediate-release naltrexone hydrochloride. In some embodiments,
the dosage of the immediate-release formulation is substantially
the same as a sustained-release dosage form described herein, while
in other embodiments it is not.
[0050] The term "release rate", as used herein, has its ordinary
meaning as understood by those skilled in the art and thus
includes, by way of non-limiting example, a characteristic related
to the amount of an active ingredient released per unit time as
defined by in vitro or in vivo testing. An in vitro release rate is
determined by a "standard dissolution test," conducted according to
United States Pharmacopeia 24th edition (2000) (USP 24), pp.
1941-1943, using Apparatus 2 described therein at a spindle
rotation speed of 100 rpm and a dissolution medium of water, at
37.degree. C., or other test conditions substantially equivalent
thereto.
[0051] The term "pharmacokinetic profile," as used herein, has its
ordinary meaning as understood by those skilled in the art and thus
includes, by way of non-limiting example, a characteristic of the
curve that results from plotting blood serum concentration of a
drug over time, following administration of the drug to a subject.
A pharmacokinetic profile thus includes a pharmacokinetic parameter
or set of parameters that can be used to characterize the
pharmacokinetics of a particular drug or dosage form when
administered to a suitable patient population. Various
pharmacokinetic parameters are known to those skilled in the art,
including area under the blood plasma concentration vs. time curve
(AUC) and maximum blood plasma concentration after administration
(C.sub.max). AUC.sub.last indicates the area under the blood plasma
concentration vs. time curve from the time of administration until
the time of the last measurable concentration. Pharmacokinetic
parameters may be measured in various ways known to those skilled
in the art, e.g., single dosage or steady-state. Differences in one
or more of the pharmacokinetic profiles (e.g., C.sub.max) may
indicate pharmacokinetic distinctness between two formulations.
[0052] Those skilled in the art will understand that
pharmacokinetic parameters may be determined by comparison to a
reference standard using clinical trial methods known and accepted
by those skilled in the art, e.g., as described in the examples set
forth herein. Since the pharmacokinetics of a drug can vary from
patient to patient, such clinical trials generally involve multiple
patients and appropriate statistical analyses of the resulting data
(typically ANOVA at 90% confidence). Comparisons of pharmacokinetic
parameters are on a dose-adjusted basis, as understood by those
skilled in the art.
[0053] In various embodiments related to the sustained-release
naltrexone formulations described herein, the reference standard is
an immediate-release naltrexone formulation. Those skilled in the
art will understand that an immediate-release naltrexone
formulation appropriate for use as the reference standard in the
determination of pharmacokinetic parameters is the legend
immediate-release naltrexone formulation, widely available
commercially as the REVIA.RTM. brand of naltrexone hydrochloride,
or an immediate-release naltrexone formulation that is formulated
to have a pharmacokinetic profile that is substantially similar to
the REVIA.RTM. brand of naltrexone hydrochloride. The U.S.
government regulates the manner in which prescription drugs can be
labeled and thus reference herein to the REVIA.RTM. brand of
naltrexone hydrochloride has a well-known, fixed and definite
meaning to those skilled in the art.
Co-Administration of Naltrexone and a Second Compound
[0054] In some embodiments, it is recognized that co-administration
of immediate-release naltrexone with a second compound may be
associated with at least one adverse effect. The at least one
adverse effect may be of greater severity, duration and/or
probability of occurrence than expected by separate administration
of the immediate-release naltrexone and of the second compound. In
some embodiments, it is thought that the second compound can
potentiate naltrexone-induced effects in the chemoreceptor trigger
zone (CTZ) and/or the vomiting center, thereby potentiating an
adverse effect associated with administration of naltrexone. While
the adverse effect may generally be characterized as tolerable when
immediate-release naltrexone is administered alone, the potentiated
adverse effect may be characterized as less tolerable.
[0055] Co-administration of sustained-release naltrexone with the
second compound may provide a reduction in at least one adverse
effect as compared to the co-administration of immediate-release
naltrexone with the second compound. The reduction may include a
decrease in the severity, duration and/or probability of occurrence
of the at least one adverse effect. In some cases, e.g., involving
individual patients, such reductions may be in comparison to the
adverse effects that would be expected by one of skill in the art
in view of the known side effects of a immediate release form, and
thus it is not necessary that the patient actually experience side
effects from the immediate release form in order to benefit from
such reductions in adverse effects. While not wishing to be bound
to any particular theory, the reduction in the at least one adverse
effect may be a result of a lower peak blood concentration of
naltrexone or a metabolite thereof associated with the
administration of sustained-release naltrexone as compared to that
associated with the administration of immediate-release naltrexone.
A sustained-release form of naltrexone with dissolution over a
longer period may provide reduced excitation, antagonism and/or
inhibition to the chemoreceptor trigger zone and vomiting center
(VC) in the area postrema of the brain. Further, sustained-release
oral dosage forms may result in a lower concentration available to
be taken up by stomach opioid receptors.
[0056] In some embodiments, the at least one adverse effect is
primarily associated with administration of the second compound.
Co-administration of sustained-release naltrexone can reduce the at
least one adverse effect. In other embodiments, the at least one
adverse effect is primarily associated with administration of the
immediate-release naltrexone. Sustained-release naltrexone can
provide a reduction in the at least one adverse effect as compared
to the immediate-release formulation, and the sustained-release
naltrexone may then be co-administered with the second compound. In
still other embodiments, the at least one adverse effect is
primarily associated with the combination of the second compound
and the immediate-release naltrexone. The type of adverse effect
associated with the combination may be one that is also associated
with the administration of naltrexone alone and/or by the
administration of the second compound alone. The severity, duration
and/or probability of occurrence of the adverse effect may be
greater when immediate-release naltrexone is co-administered with
the second compound than would be expected from the separate
administrations of immediate-release naltrexone and of the second
compound. Co-administration of sustained-release naltrexone and the
second compound can provide a reduction in the at least one adverse
effect as compared to the co-administration of immediate-release
naltrexone and the second compound.
[0057] The immediate-release naltrexone may comprise REVIA.TM.
immediate-release naltrexone hydrochloride. The dosage of
naltrexone in the immediate-release naltrexone may be substantially
similar to that in the sustained-release naltrexone. In an
embodiment, the immediate-release naltrexone is one that is
substantially free of a sustained-release carrier composition.
[0058] The second compound may include an antidepressant. The
second compound may include a monoamine reuptake inhibitor and/or a
monoamine modulator. The monoamine may include norepinephrine,
dopamine and/or serotonin. The second compound may include a
dopamine reuptake inhibitor and/or a dopamine modulator. Dopamine
modulation may be an effect of serotonin modulation. The second
compound may include a selective serotonin reuptake inhibitor
and/or a serotonin modulator. The second compound may include a
compound that acts on the chemoreceptor trigger zone (CTZ) and/or
the vomiting center in the lateral medullary reticular formation.
The second compound may include bupropion or a pharmaceutically
acceptable salt thereof and/or fluoxetine or a pharmaceutically
acceptable salt thereof. The pharmaceutically acceptable salt may
comprise a hydrochloride salt. The second compound may be a
sustained release formulation.
[0059] The sustained-release naltrexone may be provided in an oral
dosage form. In some embodiments, the oral dosage form also
includes the second compound, while in other embodiments, it does
not.
[0060] Co-administration of immediate-release naltrexone or
sustained-release naltrexone with the second compound may include
administering an oral dosage form comprising both the naltrexone
and the second compound. The co-administration may include
administering the naltrexone and the second compound separately but
at substantially the same time. The co-administration may include
administering the naltrexone and the second compound at different
times (e.g., at different dosing schedules), but such that blood
plasma simultaneously includes naltrexone or a naltrexone
metabolite concentrations above a first threshold and
concentrations for the second compound or for metabolites of the
second compound above a second threshold. These thresholds may be
the minimum detectable level (e.g., zero). This latter
co-administration may be appropriate, for example, if the in vivo
T.sub.max or the dissolution rate of the naltrexone formulation is
substantially different from that of the second compound.
[0061] The at least one adverse effect may include an effect
associated with the chemoreceptor trigger zone (CTZ) and/or the
vomiting center. In some embodiments, the at least one adverse
effect includes one or more of nausea, retching, dizziness, stomach
upset, vertigo and vomiting. The at least one adverse effect may
include one or more of anxiety, nervousness, headache, sleeping
trouble, sneezing, nasal stuffiness, muscle pain, decreased sexual
function or desire, blurred vision, thirst, ringing in the ears,
weakness, tiredness, skin rash, confusion, mood changes,
hallucinations, severe diarrhea, and breathing trouble.
[0062] The at least one adverse effect may be associated with a
weight-loss treatment. The weight-loss treatment may comprise, for
example, administration of one or more of an atypical
antipsychotic, an antidepressant, a monoamine reuptake inhibitor, a
monoamine modulator, a norepinephrine reuptake inhibitor, a
dopamine reuptake inhibitor, and/or a nicotinic antagonist. The
weight-loss treatment may comprise administration of bupropion or a
pharmaceutically acceptable salt thereof and/or fluoxetine or a
pharmaceutically acceptable salt thereof. The weight-loss treatment
may comprise administration of naltrexone. In some embodiments, a
sustained-release naltrexone dosage form results in the reduction
of one or more adverse effects attributed, partially or wholly, to
one or more non-naltrexone active ingredients of a weight-loss
treatment. In some embodiments, a sustained-release naltrexone
dosage form results in the reduction of one or more adverse effects
attributed, partially or wholly, to a naltrexone active ingredients
of a weight-loss treatment.
Pharmacokinetic Profile of Sustained-Release Naltrexone
Formulations
[0063] In some embodiments, a sustained-release naltrexone
formulation provides a pharmacokinetic profile that is
pharmacokinetically distinct from an immediate-release naltrexone
formulation (e.g., REVIA.TM. immediate-release naltrexone
hydrochloride). The pharmacokinetic distinction may be due to a
difference between the C.sub.max values associated with the
immediate-release and sustained-release formulations. The
sustained-release naltrexone formulation may provide a naltrexone
C.sub.max and/or a 6-beta naltrexol C.sub.max that is about 80% or
less of the naltrexone C.sub.max and/or the 6-beta naltrexol
C.sub.max of an immediate-release naltrexone formulation (e.g.,
REVIA.TM. immediate-release naltrexone hydrochloride).
[0064] In some embodiments, the sustained-release naltrexone
formulation provides a naltrexone AUC.sub.last and/or a 6-beta
naltrexol AUC.sub.last that substantially similar to (e.g., between
about 80% to about 125% of) a naltrexone AUC.sub.last and/or a
6-beta naltrexol AUC.sub.last of an immediate-release naltrexone
formulation (e.g., REVIA.TM. immediate-release naltrexone
hydrochloride).
[0065] In some embodiments, the naltrexone dosage of the
immediate-release naltrexone formulation is substantially the same
as the naltrexone dosage of the sustained-release naltrexone
formulation. In some embodiments in which a C.sub.max value differs
between the immediate-release and sustained release formulations,
the naltrexone dosage of the sustained-release naltrexone
formulation is identified as one that provides a naltrexone
AUC.sub.last and/or a 6-beta naltrexol AUC.sub.last that is
substantially similar to (e.g., between about 80% to about 125% of)
a naltrexone AUC.sub.last and/or a 6-beta naltrexol AUC.sub.last of
the sustained-release naltrexone formulation
[0066] The pharmacokinetic profile may be related to an
effectiveness and/or a reduced side effect produced by the dosage
form. For example, a sustained-release naltrexone formulation may
produce substantially similar or improved efficacy as compared to
an immediate-release naltrexone formulation due to a substantially
similar naltrexone and/or 6-beta naltrexol AUC.sub.last. As another
example, a sustained-release naltrexone formulation may provide a
reduction in an adverse effect as compared to that of an
immediate-release naltrexone formulation due to a lower naltrexone
and/or 6-beta naltrexol C.sub.max.
[0067] Pharmacokinetic profiles can be determined by analyzing the
plasma of a patient population that has received sustained-release
naltrexone oral dosage forms, and comparing them to a comparable
patient population that has received an immediate-release
formulation, using the appropriate clinical trial methodology and
statistical analyses.
[0068] In some embodiments, the pharmacokinetic properties are
after a single-drug dosage, while in others, they are at
steady-state. For the single-dosage measurements, patients may be
provided with a single dosage of a composition comprising the
sustained-release naltrexone, and plasma specimens may be collected
from the patient at different time periods relative to the
administration of the composition to determine pharmacokinetic
profiles. For the steady-state measurements, patients may be
provided with a dosing regimen across a plurality of days
comprising administering oral dosage forms comprising
sustained-release naltrexone. Plasma specimens may then be
collected from the patient at different time periods relative to a
particular dosage during steady state. In some embodiments, the
steady state can be determined by monitoring a plasma naltrexone
and/or active naltrexone metabolite (e.g., 6 beta-naltrexol)
concentration profiles at specific times of anticipated peak and
trough blood levels relative to the administration of a dosage
across hours and days and determining when the profile has reached
steady state. For example, the in vivo plasma naltrexone and/or
active naltrexone metabolite (e.g., 6 beta-naltrexol) concentration
may be measured one hour after dosing across days, until the
concentration no longer significantly varies from day to day. In
other embodiments, the steady state may be estimated as a specific
number of days after the dosing regimen began. For example, steady
state may be estimated as six days after the dosing regimen began.
In some embodiments, steady state is estimated after dosing over
about five times the half-life of the drug.
[0069] Plasma may be analyzed using any appropriate method. In some
embodiments, blood is collected from a patient. Any suitable amount
of blood may be collected. Blood samples may then be centrifuged
until separation of red cells from plasma occurs. In some
embodiments, naltrexone and/or naltrexone metabolite analysis is
performed according to the analytical method validation entitled
"Validation of a High Performance Liquid Chromatographic Method
Using Tandem Mass Spectrometry Lithium Heparinized Plasma," hereby
incorporated by reference in its entirety.
[0070] In order to measure the pharmacokinetic parameters mentioned
above, in vivo naltrexone and/or naltrexone metabolite (e.g., 6
beta-naltrexol) concentrations may be measured at various time
intervals with respect to a naltrexone dosage. In some embodiments,
these concentrations are measured at least 10 times within a 24
hour period.
[0071] In some embodiments, a patient population undergoes a dosing
regimen comprising the administration of a sustained-release
naltrexone oral dosage form as described herein, and the reported
pharmacokinetic parameters are the average of the pharmacokinetic
parameters across patients. The average may be obtained by
calculating the parameters for each patient and then averaging
across patients. In some embodiments, the averaging comprises a
least-squares arithmetic mean or a least-squares geometric mean. In
some embodiments, pharmacokinetic parameters are obtained from
crossover studies.
Methods of Treating
[0072] In some embodiments, a sustained-release naltrexone
formulation is provided and/or administered as an oral dosage form.
The oral dosage form may also include a second compound, which is
described above. In an embodiment, oral dosage forms described
herein are effective in the treatment of one or more of a
weight-related condition. The weight-related condition may comprise
a condition characterized by a body-mass index of greater than or
equal to about 25 kg/m.sup.2, greater than or equal to about 30
kg/m.sup.2 or less than or equal to about 18.5 kg/m.sup.2. The
weight-related condition may comprise obesity. The weight-related
condition may be caused or expected to be caused by administration
of a medication. Oral dosage forms described herein may be
effective in affecting (e.g., causing) weight loss, inhibiting
weight gain and/or at least partially reversing weight gain.
[0073] The oral dosage form may be distributed, provided to a
patent for self-administration or administered to a patient. The
patient may be overweight or obese. The patient may have a
body-mass index (BMI) of about 20 kg/m.sup.2 or greater, about 25
kg/m.sup.2 or greater, or about 30 kg/m.sup.2 or greater. The
patient may be obese. The patient may be suffering from
diabetes.
[0074] Administration of sustained-release oral dosage forms
described herein may provide substantially the same or better
efficacy than immediate-release formulations. The sustained-release
oral dosage forms may be associated with reduced adverse effects as
compared to immediate-release formulations. In some embodiments,
the administration of an oral dosage form described herein may
result in improved patient compliance with a treatment (e.g., a
weight-loss treatment and/or a naltrexone treatment).
[0075] In some embodiments, methods of the present invention
include identifying a patient suffering from at least one adverse
side effect and/or who is particularly susceptible to at least one
adverse side effect associated with a weight-loss treatment (e.g.,
a weight-loss treatment that comprises administration of bupropion)
and/or treatment with an immediate-release naltrexone formulation
(e.g., REVIA.TM. immediate-release naltrexone hydrochloride), and
providing or administering to the patient a sustained-release
naltrexone dosage form as described herein.
[0076] Methods of use can include the step of administering a
therapeutically-effective amount of the sustained-release dosage
form to a mammal in need thereof by any suitable route or method of
delivery, including those described herein. Actual dosage levels of
the compounds in the pharmaceutical dosage forms may be varied so
as to administer an amount of naltrexone that is effective to
achieve the desired therapeutic response for a particular
patient.
Dosages
[0077] It will be understood that the specific dose level of the
sustained-released dosage forms described herein for any particular
patient can depend upon any of a variety of factors including the
genetic makeup, body weight, general health, diet, time and route
of administration, combination with other drugs and the particular
condition being treated, and its severity. In some embodiments, the
naltrexone dosage of the sustained-release dosage forms is at least
partially determined based upon the frequency of which the oral
dosage form is administered. Sustained-release oral dosage forms
may be administered more frequently, less frequently, or at
substantially the same frequency as immediate-release formulations
(e.g., REVIA.TM. immediate-release naltrexone hydrochloride).
[0078] In some embodiments, a sustained-release oral dosage form
comprising naltrexone provides dosages in a naltrexone free base
equivalent amount in the range of from about 4 mg to about 50 mg or
in the range of about 10 mg to about 25 mg. The oral dosage form
may include about 4 mg, about 8 mg, about 12 mg, about 16 mg, about
32 mg, or about 48 mg of naltrexone. The selection of a particular
dosage may be based on the weight of the patient. The selection of
a particular dosage may be based on the identity, dosage and/or
dosing schedule of another compound being co-administered. Unit
dosage forms suitable for administration to a human may be
configured to provide a naltrexone free base equivalent dosage in
the range of about 0.75 mg/kg to about 10 mg/kg, e.g., about 2
mg/kg (basis is mg of drug per kilogram of body weight). Dosages
may be at least partially determined by a pharmacokinetic profile.
For example, an amount of a sustained-release naltrexone oral
dosage form may be administered that is sufficient to provide an
AUC.sub.last substantially similar to that of an immediate-release
naltrexone oral dosage form.
[0079] The sustained-release dosage forms described herein may be
administered one, two or more times per day, with or without a
loading dose. In some embodiments, the number of administrations
per day is constant (e.g., one time per day). In other embodiments,
it is variable. The number of administrations may change depending
on effectiveness of the dosage form, observed side effects,
external factors (e.g., a change in another medication), or the
length of time that the dosage form has been administered.
[0080] In an embodiment, a sustained-release naltrexone dosage form
further comprises a second compound, as described herein. The
second compound may be present in any appropriate dosage. In an
embodiment, the second compound comprises bupropion or a
pharmaceutically acceptable salt thereof. The bupropion or
pharmaceutically acceptable salt thereof may be a sustained release
(SR) formulation. In an embodiment, the dosage form comprises both
naltrexone and bupropion, e.g., in the form of a tri-layer tablet
as described in U.S. Provisional Patent Application Ser. No.
60/865,157, filed Nov. 9, 2006. Examples of suitable unit dosage
forms include those in which the tri-layer tablet includes, e.g.,
about 4 mg naltrexone SR and 90 mg of bupropion SR; about 8 mg
naltrexone SR and 90 mg of bupropion SR; or about 12 mg naltrexone
SR and 90 mg of bupropion SR. In an embodiment, the dosage form may
be administered as two tablets twice a day, e.g., for a daily
dosage of about 16 mg, about 32 mg, or about 48 mg naltrexone, and
about 360 mg bupropion or a pharmaceutically acceptable salt
thereof. In an embodiment, the second compound (e.g., bupropion or
a pharmaceutically acceptable salt thereof) and naltrexone are
co-administered separately, e.g., as separate dosage forms that are
co-administered within about an hour of each other. In an
embodiment, the separate dosage forms are administered at about the
same time.
Formulations
[0081] Oral dosage forms may comprise naltrexone and a
sustained-release carrier. A sustained release carrier includes, by
way of non-limiting example, an ingredient or ingredients that are
included in a pharmaceutical formulation in amounts that are
effective to extend the release rate of naltrexone from the
formulation as compared to an immediate-release formulation (e.g.,
REVIA.TM. immediate-release naltrexone hydrochloride). A sustained
release carrier may be referred to herein as a retardant excipient.
Examples of sustained release carriers include hydroxypropylmethyl
cellulose, polyethylene oxide, polyacrylate, copolymer of acrylate
and methacrylate, methacrylate polymer, copolymer of acrylate and
methacrylate, copolymer of acrylate and methacrylate with ammonium
group, copolymer of maleic anhydride and methyl vinyl ether,
hydroxy propyl ethyl cellulose, hydroxy propyl cellulose, hydroxy
ethyl cellulose, methyl cellulose, hydroxymethyl methacrylate,
maltodextrin, natural gum and xanthan gum. In some embodiments, the
sustained-release carrier composition comprises at least one of
hydroxypropylmethylcellulose and polyoxyethylene. A sustained
release carrier composition may contain one or more sustained
release carriers, along with other suitable ingredients.
[0082] In some embodiments, an oral dosage form comprising
naltrexone comprises an amount of a sustained-release carrier
composition that is effective to render the dosage form
pharmacokinetically distinct from an immediate-release formulation
(e.g., REVIA.TM. immediate-release naltrexone hydrochloride). For
example, relative to the immediate-release formulation, the amount
and type of sustained-release carrier composition may be selected
to reduce the naltrexone C.sub.max and/or the 6-beta naltrexol
C.sub.max (e.g., to about 80% or less than the naltrexone C.sub.max
of or 6-beta naltrexol C.sub.max of immediate-release
naltrexone).
[0083] The amount of the sustained-release carrier composition may
be effective to provide an in vitro release rate of the naltrexone
of less than about 90%, or less than about 80%, in about 2 hours.
The amount of the sustained-release carrier composition may be
effective to provide an in vitro release rate of the naltrexone of
less than about 98% in about 4 hours. The amount of the
sustained-release carrier composition may be effective to provide
an in vitro release rate of the naltrexone of less than about 80%
or than about 70% in about 1 hour. In vitro release rate is
determined by a standard dissolution test as described above.
[0084] A description of representative sustained release carrier
materials can be found in the Remington: The Science and Practice
of Pharmacy (20.sup.th ed, Lippincott Williams & Wilkens
Publishers (2003)), which is incorporated herein by reference in
its entirety. Those skilled in the art can formulate
sustained-release carrier compositions using routine
experimentation informed by the detailed guidance provided
herein.
[0085] Dosage forms described herein may be formulated to comprise
various excipients, binders, carriers, disintegrants, coatings,
etc. Pharmaceutical preparations can be obtained by mixing one or
more solid excipients with a pharmaceutical composition as
described herein, optionally grinding the resulting mixture, and
processing the mixture of granules, after adding suitable
auxiliaries, if desired, to obtain pharmaceutical compositions
suitable for use in various forms, e.g., as pills, tablets,
powders, granules, dragees, capsules, liquids, sprays, gels,
syrups, slurries, suspensions and the like, in bulk or unit dosage
forms, for oral ingestion by a patient to be treated. Various
examples of unit dosage forms are described herein; non-limiting
examples include a pill, a tablet, a capsule, a gel cap, and the
like. Examples of suitable excipients are listed below, some of
which are mentioned above as having particular dissolution
properties. Pharmaceutically acceptable carriers or diluents for
therapeutic use are well known in the pharmaceutical art, and are
described, for example, in Remington: The Science and Practice of
Pharmacy (2003), which is hereby incorporated by reference in its
entirety. The term "carrier" material or "excipient" herein can
mean any substance, not itself a therapeutic agent, used as a
carrier, diluent, adjuvant, binder, and/or vehicle for delivery of
a therapeutic agent to a subject or added to a pharmaceutical
composition to improve its handling or storage properties or to
permit or facilitate formation of a dose unit of the composition
into a discrete article such as a capsule or tablet suitable for
oral administration. Excipients can include, by way of illustration
and not limitation, diluents, disintegrants, binding agents,
adhesives, wetting agents, polymers, lubricants, glidants,
substances added to mask or counteract a disagreeable taste or
odor, flavors, dyes, fragrances, and substances added to improve
appearance of the composition. The glidants may be one or more of
colloidal silicon dioxide, talc, corn starch, DL-leucine, sodium
lauryl sulfate, and magnesium, calcium and sodium stearates. The
diluents may be one or more of lactose, starch, mannitol, sorbitol,
dextrose, microcrystalline cellulose, dibasic calcium phosphate,
sucrose-based diluents, confectioner's sugar, monobasic calcium
sulfate monohydrate, calcium sulfate dihydrate, calcium lactate
trihydrate, dextrates, inositol, hydrolyzed cereal solids, amylose,
powdered cellulose, calcium carbonate, glycine, or bentonite.
Acceptable excipients include lactose, sucrose, starch powder,
maize starch or derivatives thereof, cellulose esters of alkanoic
acids, cellulose alkyl esters, talc, stearic acid, magnesium
stearate, magnesium oxide, sodium and calcium salts of phosphoric
and sulfuric acids, gelatin, acacia gum, sodium alginate,
polyvinyl-pyrrolidone, and/or polyvinyl alcohol, saline, dextrose,
mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine
hydrochloride, and the like. Examples of suitable excipients for
soft gelatin capsules include vegetable oils, waxes, fats,
semisolid and liquid polyols. Suitable excipients for the
preparation of solutions and syrups include, without limitation,
water, polyols, sucrose, invert sugar and glucose. The
pharmaceutical compositions can additionally include preservatives,
solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,
colorants, flavorings, buffers, coating agents, or antioxidants.
Dissolution or suspension of the active ingredient in a vehicle
such as water or naturally occurring vegetable oil like sesame,
peanut, or cottonseed oil or a synthetic fatty vehicle like ethyl
oleate or the like may be desired. Buffers, preservatives,
antioxidants and the like can be incorporated according to accepted
pharmaceutical practice. The compound can also be made in
microencapsulated form. If desired, absorption enhancing
preparations (for example, liposomes), can be utilized. Those
skilled in the art can formulate sustained-release dosage forms
containing one or more of the foregoing ingredients by routine
experimentation informed by the detailed guidance provided
herein.
Kits
[0086] In some embodiments, the present invention relates to a kit.
The kit may include one or more unit dosage forms comprising
sustained-release naltrexone. The unit dosage forms may be of an
oral formulation. The unit dosage forms may comprise tablets. The
kit may include a plurality of unit dosage forms.
[0087] The kit may include information. The information may be in a
form prescribed by a governmental agency regulating the
manufacture, use, or sale of pharmaceuticals, which notice is
reflective of approval by the agency of the form of the drug for
human or veterinary administration. Such information, for example,
may be the labeling approved by the U.S. Food and Drug
Administration for prescription drugs, or the approved product
insert. Dosage forms comprising a sustained-release naltrexone
formulation of the invention formulated in a compatible
pharmaceutical carrier may also be prepared, placed in an
appropriate container, and labeled for treatment of an indicated
condition.
[0088] The information may comprise instructions to administer the
unit dosage form at a dosage of about 4 mg, about 8 mg, about 12
mg, about 16 mg, about 32 mg or about 48 mg. These instructions may
be provided in a variety of ways. The information may comprise
instructions about when to administer the unit dosage forms. For
example, the information may comprise instructions about when to
administer the unit dosage forms relative to the administration of
another medication or meal.
[0089] The information may be provided on a readable medium. The
readable medium may comprise a label. The kit may comprise a
therapeutic package suitable for commercial sale. The kit may
comprise a container. The container can be in any conventional
shape or form as known in the art which is made of a
pharmaceutically acceptable material, for example a paper or
cardboard box, a glass or plastic bottle or jar, a re-sealable bag
(for example, to hold a "refill" of tablets for placement into a
different container), or a blister pack with individual dosages for
pressing out of the pack according to a therapeutic schedule. The
container employed can depend on the exact dosage form involved,
for example a conventional cardboard box would not generally be
used to hold a liquid suspension. It is feasible that more than one
container can be used together in a single package to market a
single dosage form. For example, tablets may be contained in a
bottle which is in turn contained within a box.
[0090] The information can be associated with the container, for
example, by being: written on a label (e.g., the prescription label
or a separate label) adhesively affixed to a bottle containing a
dosage form described herein; included inside a container as a
written package insert, such as inside a box which contains unit
dose packets; applied directly to the container such as being
printed on the wall of a box; or attached as by being tied or
taped, for example as an instructional card affixed to the neck of
a bottle via a string, cord or other line, lanyard or tether type
device. The information may be printed directly on a unit dose pack
or blister pack or blister card.
EXAMPLES
[0091] The examples below are non-limiting and are merely
representative of various aspects of the invention.
Example 1
[0092] A series of sustained-release naltrexone (5 mg) formulations
were prepared. Each of the sustained-release formulations contained
a "common excipient". The formulation for the common excipient is
shown in Table 1. The formulation shown in Table 2 contained
hydroxypropylmethyl cellulose as a sustained release carrier or
retardant excipient. The formulation is shown in Table 3 contained
polyethylene oxide as a retardant excipient.
[0093] To make the common excipient, the ingredients listed in
Table 1 were placed into a Key KG-5 hi-shear granulator (Key
International, Englishtown, N.J.) and granulated with a 10%
hydroxypropyl cellulose (HPC) solution. The granulation was dried
at room temperature to a final LOD of 2.71% and then screened
through a 20-mesh sieve.
[0094] To manufacture the naltrexone formulations, the active
pharmaceutical ingredient (API) was mixed with a colloidal silicon
dioxide as a glidant, the extending release polymer (e.g., either
HPMC or PolyOx) and the common excipient using a TURBULA mixer.
Magnesium stearate was added as a lubricant to the final
formulation.
[0095] Tablets with a 5 Kp harness were compressed to determine the
disintegration properties of the tablet. Under the conditions used,
the 5 Kp tablet did not disintegrate within 30 minutes in USP
water. Accordingly, tablets with a higher hardness were compressed
to 9 Kp using 1/4'' round standard concave tooling on a Carver
press.
[0096] Tablets compressed at 9 Kp were produced, and the properties
of the tablets are listed in Table 4.
TABLE-US-00001 TABLE 1 Formulation for the Common excipient
Ingredient Amount (Percent) Hydroxypropyl cellulose (Klucel HXF)
3.000 Microcrystalline cellulose, NF (Avicel PH 77.000 102) Lactose
Fast Flo, (Type 316) NF 20.000 USP water NA Total 100.000
TABLE-US-00002 TABLE 2 Formulations for Sustained Release 5 mg
Strength Tablets Containing Hydroxypropylmethylcellulose (HPMC) 5%
HPMC 10% HPMC 15% HPMC 22% HPMC 44% HPMC 66% HPMC Ingredient % per
tablet % per tablet % per tablet % per tablet % per tablet % per
tablet Naltrexone (5 mg) 6.667 6.667 6.667 6.667 6.667 6.667
Hydroxypropyl- 5.000 10.000 15.000 22.000 44.333 66.000
methylcellulose (Methocel K15 Premium) Common QBQ01 Placebo 86.833
81.833 76.833 69.833 47.500 25.833 Granulation Colloidal Silicon
Dioxide, 1.000 1.000 1.000 1.000 1.000 1.000 NF (Cab-O-Sil M5P)
Magnesium Stearate, NF, 0.500 0.500 0.500 0.500 0.500 0.500 Ph.
Eur. (Vegetable Source) (Grade, 905-G)
TABLE-US-00003 TABLE 3 Formulations for Sustained Release 5 mg
Strength Tablets Containing Polyethylene Oxide (PolyOx) 5% PolyOx
10% PolyOx 20% PolyOx 30% PolyOx 59% PolyOx 75% PolyOx Ingredient %
per tablet % per tablet % per tablet % per tablet % per tablet %
per tablet Naltrexone (5 mg) 6.667 6.667 6.667 6.667 6.667 6.667
Polyethylene Oxide 5.000 10.000 20.000 30.000 59.333 75.000 Common
QBQ01 Placebo 86.833 81.833 71.833 61.833 32.500 16.833 Granulation
Colloidal Silicon Dioxide, 1.000 1.000 1.000 1.000 1.000 1.000 NF
(Cab-O-Sil M5P) Magnesium Stearate, NF, 0.500 0.500 0.500 0.500
0.500 0.500 Ph. Eur. (Vegetable Source) (Grade, 905-G)
TABLE-US-00004 TABLE 4 In-Process Tablet Data Thickness Compression
Weight (mg) (mm) Hardness (Kp) force Formulation (N = 3) (N = 3) (N
= 3) (psi) 5% HPMC 75.0 2.47 9.2 850 10% HPMC 75.8 2.5 8.7 800 15%
HPMC 75.5 2.52 8.7 800 22% HPMC 74.2 2.45 9.2 850 44% HPMC 75.1
2.64 8.7 750 66% HPMC 73.9 2.65 9.6 650 5% PolyOx 75.7 2.48 8.3 650
10% PolyOx 76.6 2.53 8.9 750 20% PolyOx 75.9 2.54 8.7 850 30%
PolyOx 74.5 2.53 8.9 650 59% PolyOx 75.1 2.64 9.3 300 75% PolyOx
75.9 2.84 9.4 250
[0097] The following example describes the dissolution profiles of
the sustained release naltrexone formulations described above.
Example 2
[0098] The dissolution measurements for the tablets were completed
using a 10-mesh baskets at 100 rpm. Samples were analyzed using a
UV-VIS at .lamda..sub.max of 280. The dissolution data of the
active pharmaceutical ingredient (API) for the HPMC formulations
and PolyOx formulations are presented in Tables 5 and 6,
respectively. Dissolution data for the HPMC formulations and PolyOx
formulations are also plotted in FIGS. 1 and 2, respectively.
TABLE-US-00005 TABLE 5 Dissolution Data for HPMC Formulations % API
% API % API % API % API % API Released Std. Dev. Released Std. Dev.
Released Std. Dev. Released Std. Dev. Released Std. Dev. Released
Std. Dev. Time 5% 5% 10% 10% 15% 15% 22% 22% 44% 44% 66% 66% (min)
HPMC HPMC HPMC HPMC HPMC HPMC HPMC HPMC HPMC HPMC HPMC HPMC 0 0 0 0
0 0 0 0 0 0 0 0 0 30 35 11 23 5 20 8 60 96 4 99 4 39 5 39 4 33 7 17
4 120 100 4 96 1 62 1 51 3 48 7 29 3 240 94 4 97 8 86 6 63 5 65 3
38 5 360 96 0 98 7 91 6 72 2 80 5 53 3 420 93 4 98 7 88 9
TABLE-US-00006 TABLE 6 Dissolution Data for Polyethylene Oxide
Formulations % API % API % API % API % API % API Released Std. Dev.
Released Std. Dev. Released Std. Dev. Released Std. Dev. Released
Std. Dev. Released Std. Dev. Time 5% 5% 10% 10% 20% 20% 30% 30%
59.3% 59.3% 75% 75% (min) PolyOx PolyOx PolyOx PolyOx PolyOx PolyOx
PolyOx PolyOx PolyOx PolyOx PolyOx PolyOx 0 0 0 0 0 0 0 0 0 0 0 0 0
30 37 13 29 1 22 12 60 75 7 51 5 31 7 47 6 40 3 34 24 120 74 6 62 4
46 6 57 3 54 1 42 15 240 77 4 69 5 54 6 68 5 75 4 63 17 360 79 6 68
3 59 4 73 10 85 10 78 13 420 80 4 70 5 58 4
Example 3
[0099] Sustained-release naltrexone-bupropion tri-layer tablets
were made using the ingredients listed in Table 7 through Table 9,
in accordance with the general methods for making tri-layer tablets
described in U.S. Provisional Patent Application Ser. No.
60/865,157, filed Nov. 9, 2006, which is hereby incorporated by
reference in its entirety. A sustained-release naltrexone
formulation was made by combining the following components:
TABLE-US-00007 TABLE 7 Naltrexone Blend Formulation Component
mg/tablet mass (g) Naltrexone Hydrochloride 13.22 1983.0 Edetate
Disodium, USP 0.23 34.5 Hydroxypropylmethylcellulose 22.50 3375.0
(Methocel K15 Premium CR) Hydroxypropylcellulose 11.00 1650.0
Lactose Monohydrate NF, Fast 45.50 6825.0 Flo 316 Microcrystalline
cellulose 128.95 19342.5 (Avicel PH102) Colloidal silicon dioxide,
NF 2.30 345.0 Magnesium Stearate, NF 1.30 195.0 Total 225.0
33750.0
[0100] Thus, the sustained-release naltrexone formulation includes
10% HPMC. A bupropion blend was made by combining the following
components:
TABLE-US-00008 TABLE 8 Bupropion Blend Formulation Component
mg/tablet mass (g) Bupropion Hydrochloride 315.00 47250.0
Granulation Magnesium Stearate 2.00 300.0 Total 317.00 47550.0
[0101] An inert layer blend was made by combining the following
components:
TABLE-US-00009 TABLE 9 Inert Blend Formulation Component mg/tablet
mass (g) Anhydrous Lactose 30.00 4500.0 Microcrystalline cellulose
84.70 12705.0 (Avicel PH101) Crospovidone 3.60 540.0 Magnesium
Stearate 1.20 180.0 FDC Blue #2 Aluminum Lake 0.50 75.0 Total 120.0
18000.0
[0102] The sustained-release naltrexone formulation, bupropion
blend and inert layer blends were used to form 150 tri-layer
tablets with the naltrexone and bupropion layers on opposite sides
of the inert layer, such that each tablet was 662.00 mg. The
tablets each contained 11.94 mg of naltrexone (13.22 mg naltrexone
hydrochloride).
[0103] The dissolution data of naltrexone for the tablets is
presented in Table 10. Dissolution data is also plotted in FIG.
3.
TABLE-US-00010 TABLE 10 Dissolution Data for Naltrexone-Bupropion
Tablets Time (Hours) Naltrexone Released (Wt %) 0 0 0.5 48 1 67 2
85 4 95 8 99
Example 4
[0104] A single center, double-blind, crossover study of immediate
release naltrexone and sustained release naltrexone was conducted
for 40 healthy obese volunteers.
[0105] Subjects were randomized to receive a naltrexone
sustained-release formulation or an immediate-release formulation
in a 1:1 ratio. Subjects were administered 40 mg of SR Naltrexone
and 36 mg of IR Naltrexone. Subjects were randomly assigned to
receive the sustained-release and immediate-release in one of two
sequences: half of the subjects received the sustained-release
formulation in period 1 followed by the immediate-release
formulation in period 2; the remaining subjects received the
treatments in the reverse order.
[0106] The administration of study drug in each period was
separated by a five-day washout period. Serial blood samples were
collected at predose and at 0.167, 0.33, 0.5, 0.67, 0.83, 1, 1.25,
1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 60 and 72 hours
post-dose. Samples were analyzed for the concentrations of
naltrexone and 6-beta naltrexol by validated LCMS/MS methods. In
addition to spontaneously collected adverse events, information on
side effects was collected using the subject rated UKU Side Effect
Rating Scale. The scale was administered predose, at 8, 24 and 72
hours post-dose.
[0107] The concentration-time data were imported directly into
WinNonlin (Version 5.0, Pharsight Corporation). Data were analyzed
by noncompartmental methods using WinNonlin using Model 200 for
extravascular input.
[0108] Concentration-time data that were BLLOQ were excluded from
calculations prior to data summarization and pharmacokinetic
analysis. Data were summarized by scheduled (nominal) sampling
times. Actual sampling times were used if the deviation from
nominal was considered significant.
[0109] The following pharmacokinetic parameters were estimated for
naltrexone and 6-beta naltrexol concentrations for each subject and
each treatment:
[0110] C.sub.max=measured maximal concentration
[0111] T.sub.max=time to reach maximum concentration
[0112] Ke=terminal rate constant, estimated by log-linear
regression
[0113] AUC(0-t)=area under the concentration-time curve calculated
by the linear trapezoidal rule from time 0 to the time of last
sample with a quantifiable concentration (C.sub.t)
[0114] AUC(0-.infin.)=area under the concentration time curve from
time 0 extrapolated to infinity, calculated as AUC
(0-t)+C.sub.t/K.sub.e
[0115] T.sub.1/2=terminal half-life, calculated as
Ln(2)/K.sub.e
[0116] The AUC is used to describe the extent of drug absorption.
The rate of absorption is characterized by C.sub.max and T.sub.max.
K.sub.e and T.sub.1/2 describe the kinetics in the terminal phase,
which, for many substances, is governed by elimination processes.
Pharmacokinetic parameters were estimated for all cases.
[0117] FIGS. 4 and 5 show individual plasma concentration time
curves of naltrexone in subjects receiving Naltrexone IR and in
subjects receiving Naltrexone SR, respectively. FIGS. 6 and 7 show
individual plasma concentration time curves of 6-beta naltrexol in
subjects receiving Naltrexone IR and in subjects receiving
Naltrexone SR, respectively.
[0118] FIG. 8A shows the average plasma concentration time curves
of naltrexone in subjects receiving Naltrexone SR (circle) or
Naltrexone IR (square). FIG. 8B shows the entire plasma
concentration time curve. The Naltrexone C.sub.max is higher for
patients receiving Naltrexone IR than for those receiving
Naltrexone SR though the area under the curve is comparable between
both conditions. These results are dose normalized and quantified
in Table 11.
TABLE-US-00011 TABLE 11 Summary of Pharmacokinetic Parameters in
Subjects Receiving Naltrexone SR or Naltrexone IR C.sub.max
T.sub.max AUC.sub.last Analyte Formulation (ng/mL) (hr) (ng *
hr/mL) T.sub.1/2 (hr) Naltrexone SR 5.10 1.25 27.48 4.01 Dose
Normalized 4.59 24.7 IR 6.11 1.50 24.91 3.27 6-beta SR 37.45 3.00
486.00 16.55 naltrexol Dose Normalized 33.7 437.4 IR 43.39 1.5
496.95 16.99
[0119] FIG. 9A shows the average plasma concentration time curves
of 6-beta naltrexol in subjects receiving Naltrexone SR (circle) or
Naltrexone IR (square). FIG. 9B shows the entire plasma
concentration time curve. The 6-beta naltrexol C.sub.max is higher
for patients receiving Naltrexone IR than for those receiving
Naltrexone SR though the area under the curve is comparable between
both conditions. These results are dose normalized and quantified
in Table 11.
[0120] Table 12 provides the adverse events reported by patients
receiving Naltrexone SR and by patients receiving Naltrexone IR.
The adverse events are analyzed across patients for each of the
treatment conditions. These results are summarized in Table 13.
Individuals receiving Naltrexone SR were less likely to report an
adverse event (45% versus 48%) and were also less likely to report
more than one adverse event (13% versus 23%) than individuals
receiving Naltrexone IR.
TABLE-US-00012 TABLE 12 Summary of Individual Adverse Events.
Subject Period Treatment AE YM Adverse Event(s) 1 1 SR Yes Nausea 4
1 SR Yes Headache Anemia 5 1 SR Yes Elevated platelet count 11 1 SR
Yes Hyperglycemia 16 1 SR Yes Cramps, menstrual 17 2 SR Yes Pyuria
19 1 SR Yes Nausea Elevated Pyuria Leukocyte Esterase 22 1 SR Yes
Stomach pain 27 2 SR Yes Hypophosphatemia 32 1 SR Yes Hypertension
34 1 SR Yes Headache Headache 35 1 SR Yes Hyperleukemia 36 1 SR Yes
Nausea Stomach Cramps 37 1 SR Yes Tingle in lips 39 1 SR Yes Nausea
Diarrhea Dizziness 40 2 SR Yes Hematuria Hypophosphatemia 29 2 SR
Yes Increased TSH 1 2 IR Yes Pyuria 2 2 IR Yes Intermittent Pyuria
Hematuria Diarrhea 4 2 IR Yes Anemia 5 2 IR Yes Elevated platelet
count 7 2 IR Yes Elevated blood pressure 11 2 IR Yes Nausea
Hypertension Proteinuria Hematuria Hyperglycemia 13 2 IR Yes
Hyperglycemia 15 2 IR Yes Hyperleukemia 16 2 IR Yes Blood in urine
18 2 IR Yes Elevated Leukocyte Pyuria Leucocytosis Esterase 19 2 IR
Yes Nausea 22 2 IR Yes Stomach pain Vomited Elevated Leukocyte
Esterase 23 1 IR Yes Hyperglycemia 25 2 IR Yes Triglyceride 27 1 IR
Yes Hypophosphatemia 31 2 IR Yes Hypertension 32 2 IR Yes
Hypertension Increased TSH 34 2 IR Yes Elevated ALT Increased TSH
35 2 IR Yes Hyperglycemia 36 2 IR Yes Numbness in lips
Hyperglycemia
TABLE-US-00013 TABLE 13 Summary of Adverse Events, Gastrointestinal
and Headache, in Subjects Receiving Naltrexone SR and Naltrexone
IR. Item Formulation % % Subjects Reporting AE SR 45% 18 40 IR 48%
19 40 % Subjects Reporting >1 AE SR 13% 5 40 IR 23% 9 40 %
Subjects Reporting AEs in 33% 13 39 Both Periods % Subjects GI
Reporting AE SR 13% 5 40 IR 10% 4 40 % Subjects Reporting >1 GI
AE SR 5% 2 40 IR 3% 1 40 % Subjects Reporting GI AEs in (19, 22,
36) 8% 3 40 Both Periods % Subjects GI Reporting Headache AE SR 5%
2 40 IR 0% 0 40 % Subjects Reporting Headache AEs in 0% 0 40 Both
Periods
[0121] FIG. 10 is a schematic illustrating the population of
subjects reporting nausea and vomiting using the UKU Adverse Event
Rating Scale. Individuals receiving Naltrexone SR were less likely
to report severe nausea (score of 2 or greater) than those
receiving Naltrexone IR.
[0122] Those skilled in the art recognize that the incidence of
adverse events reported using the UKU Adverse Event Rating Scale is
typically higher than self-reporting. Patients have been reported
to be more likely to report adverse events when prompted to report
adverse events (Sheftell F D, Feleppa M, Tepper S J, Rapoport A M,
Ciannella L, Bigal M E. Assessment of adverse events associated
with triptans-methods of assessment influence the results.
Headache: The Journal of Head and Face Pain 44 (10), 978-982).
Thus, the incidence of adverse events obtained by the methods used
in this example is not directly comparable to the incidence of
adverse events obtained by the methods described in Example 5.
Example 5
[0123] A randomized double-blind, parallel, multiple dose study
compared the pharmacokinetics of a naltrexone SR/bupropion SR
combination product with a naltrexone IR/bupropion SR combination
product.
[0124] Naltrexone SR/bupropion SR group: Each capsule contained two
and one-half 5 mg mini tablets (prepared in accordance with Example
1) of sustained release naltrexone plus one 90 mg bupropion HCl SR
tablet (total dose of naltrexone SR 12.5 mg/bupropion SR 90 mg per
capsule) which was titrated over 7 days to a total daily dose of
naltrexone SR 37.5 mg/bupropion SR 270 mg.
[0125] Naltrexone IR/bupropion SR group: Each capsule contained
capsules containing one 12 mg naltrexone HCl IR tablet plus one 90
mg bupropion HCl SR tablet (total dose of 12 mg naltrexone IR/90 mg
bupropion SR per capsule) which was titrated over 7 days to a final
daily dose of naltrexone IR 36 mg/bupropion SR 270 mg. The
naltrexone IR formulation is formulated to have a pharmacokinetic
profile that is substantially similar to the REVIA.RTM. brand of
naltrexone hydrochloride.
[0126] Healthy obese volunteers randomly received one of the two
drug administrations. A total of 60 subjects were expected to
enroll, 59 subjects completed the study.
[0127] Blood was drawn on Day 1 (0.5, 1, 2, 4, 6, 8, 10, and 12
hrs) with trough samples drawn on Days 8 and 15. Plasma samples
were drawn from each subject to determine naltrexone,
6-beta-naltrexol, bupropion, hydroxybupropion,
threohydroxybupropion, and erthyrohydroxybupropion concentrations.
Plasma samples were analyzed using the SFBCi/Anapharm validated
methods for naltrexone and 6-beta naltrexol. The concentration-time
data were imported directly into WinNonlin (Version 5.0, Pharsight
Corporation). Data were analyzed by noncompartmental methods using
WinNonlin using Model 200 for extravascular input.
[0128] Concentration-time data that were BLLOQ were excluded from
calculations prior to data summarization and pharmacokinetic
analysis. Data were summarized by scheduled (nominal) sampling
times. Actual sampling times were used if the deviation from
nominal was considered significant.
[0129] Pharmacokinetic parameters measured herein are known to
those skilled in the art. Blood plasmas were collected at specific
intervals relative to the administration of a combination product.
The plasma was analyzed to determine the concentration of a
compound (e.g., naltrexone). C.sub.max indicates the maximum blood
plasma concentration of the compound after administration.
T.sub.max indicates the time at which the maximum blood plasma
concentration of the compound (C.sub.max) was reached. AUC
indicates the area under the curve of the concentration as a
function of time following administration. AUC.sub.last indicates
the area under the plasma-concentration curve from the time of
administration until the time of the last measurable
concentration.
[0130] Table 14 and FIG. 11 compare average naltrexone plasma
concentrations in subjects receiving treatments of naltrexone IR
and bupropion SR (IR/SR; circles) to that in subjects receiving
treatments of naltrexone SR and bupropion SR (SR/SR; squares). The
single dose of naltrexone at the onset of the titration schedule of
12 (IR) or 12.5 (SR) produces plasma concentrations during the
first 24 hours that are primarily below the lower limit of
quantitation (BLLOQ).
TABLE-US-00014 TABLE 14 Mean plasma concentrations of naltrexone in
subjects receiving naltrexone IR in combination with bupropion SR
(IR/SR) or naltrexone SR in combination with bupropion SR (SR/SR).
Treatment Time (hr) N Mean (ng/mL) SD (ng/mL) CV % IR/SR 0 0 NC NC
NC 0.5 8 1.17 0.18 15.45 1 18 1.64 0.41 25.28 2 10 1.36 0.37 27.44
4 0 NC NC NC 6 0 NC NC NC 8 0 NC NC NC 10 0 NC NC NC 12 0 NC NC NC
168 0 NC NC NC 336 1 6.78 NC NC SR/SR 0 0 NC NC NC 0.5 0 NC NC NC 1
0 NC NC NC 2 11 1.44 0.34 23.59 4 3 1.17 0.12 10.45 6 0 NC NC NC 8
0 NC NC NC 10 0 NC NC NC 12 0 NC NC NC 168 1 1.18 NC NC 336 2 2.55
1.64 64.1
[0131] Table 15 and FIG. 12 compare average 6-beta naltrexol plasma
concentrations in subjects receiving treatments of naltrexone IR
and bupropion SR (squares) to that in subjects receiving treatments
of naltrexone SR and bupropion SR (circles). The plasma
concentrations associated with the SR/SR treatment are lower during
the first few hours following administration than those associated
with the IR/SR treatment. As reported in Table 16, the SR/SR
treatment is associated with a lower C.sub.max but a similar AUC as
compared to the IR/SR treatment.
TABLE-US-00015 TABLE 15 Mean plasma concentrations of 6-beta
naltrexol in subjects receiving naltrexone IR in combination with
bupropion SR (IR/SR) or naltrexone SR in combination with bupropion
SR (SR/SR). Treatment Time (hr) N Mean (ng/ml) SD (ng/ml) CV %
IR/SR 0 0 NC NC NC 0.5 27 12.14 8.3 68.33 1 30 15.05 5.44 36.15 2
30 12.74 3.55 27.87 4 30 8.45 2.3 27.21 6 30 6.11 1.8 29.43 8 30
4.86 1.45 29.81 10 30 4.09 1.17 28.59 12 30 3.56 1.05 29.54 168 27
10.59 4.13 39.03 336 27 15.66 6.71 42.88 SR/SR 0 0 NC NC NC 1 13
3.2 1.65 51.66 1 27 4.16 2.21 52.99 2 29 9.05 2.69 29.74 4 29 8.51
2.17 25.47 6 29 6.77 1.95 28.84 8 29 5.37 1.49 27.82 10 29 4.43
1.35 30.53 12 29 3.72 1.09 29.37 168 28 11.21 4.54 40.52 336 26
18.67 10.74 57.52
TABLE-US-00016 TABLE 16 Mean pharmacokinetic parameters for 6-beta
naltrexol on Day 1 in subjects receiving naltrexone IR in
combination with bupropion SR (IR/SR) or naltrexone SR in
combination with bupropion SR (SR/SR). IR/SR SR/SR Parameter N Mean
SD CV % N Mean SD CV % Tmax 30 1.117 0.536 48 29 2.621 0.942 35.9
Cmax 30 16.731 6.391 38.2 29 9.686 2.323 24 AUClast 30 86.658
23.457 27.1 29 71.623 16.711 23.3 AUCINF_obs 30 118.445 35.191 29.7
29 115.771 45.398 39.2 HL_Lambda_z 30 5.989 1.796 30 29 7.838 4.58
58.4
[0132] FIGS. 13 and 14 compare the trough plasma concentrations of
naltrexone and 6-beta naltrexol, respectively, in subjects
receiving treatments of naltrexone IR and bupropion SR (circles) to
that in subjects receiving treatments of naltrexone SR and
bupropion SR (squares). For naltrexone, the trough levels on Day 8
and Day 15 are primarily BLLOQ, with the exception of 1 subject in
the IR group, and 2 subjects in the SR group. For 6-beta naltrexol,
the trough levels of Day 8 and Day 15 are similar between treatment
groups.
[0133] Table 17 and FIG. 15 compare average bupropion plasma
concentrations in subjects receiving treatments of naltrexone IR
and bupropion SR (squares) to that in subjects receiving treatments
of naltrexone SR and bupropion SR (circles). The plasma
concentration profiles are similar across the treatment
conditions.
TABLE-US-00017 TABLE 17 Mean Bupropion Plasma Concentrations in
subjects receiving bupropion SR in combination with naltrexone IR
(IR/SR) or in combination with naltrexone SR (SR/SR). Treatment
Time (hr) N Mean (ng/ml) SD (ng/ml) CV % IR/SR 0 0 NC NC NC 0.5 6
1.83 0.99 54.07 1 23 17.62 13.86 78.66 2 23 54.23 21.64 39.9 4 23
44.83 16.83 37.53 6 23 37.1 16.32 43.99 8 23 25.29 11.28 44.59 10
23 20.1 7.89 39.27 12 23 16.03 6.44 40.19 SR/SR 0 0 NC NC NC 0.5 7
4.77 2.62 54.95 1 20 17.14 13.41 78.23 2 20 55.04 24.96 45.35 4 20
43.96 20.3 46.18 6 20 33.77 18.18 53.83 8 20 21.98 8.77 39.89 10 20
18.13 9.43 52.02 12 20 15.22 7.03 46.18
[0134] Tables 18-20 and FIGS. 16-18 compare average plasma
concentrations for the bupropion metabolites of hydroxybupropion,
threohydroxybupropion and erythrohydroxybupropion in subjects
receiving treatments of naltrexone IR and bupropion SR (squares) to
that in subjects receiving treatments of naltrexone SR and
bupropion SR (circles). The plasma concentration profiles are
similar across the treatment conditions.
TABLE-US-00018 TABLE 18 Mean plasma concentrations of the bupropion
metabolite hydroxybupropion in subjects receiving bupropion SR in
combination with naltrexone IR (IR/SR) or in combination with
naltrexone SR (SR/SR). Treatment Time (hr) N Mean (ng/ml) SD
(ng/ml) CV % IR/SR 0 0 NC NC NC 0.5 7 9.72 4.43 45.59 1 26 32.41
17.36 53.58 2 26 85.82 31.03 36.16 4 27 125.34 47.16 37.63 6 27
142.53 56.45 39.6 8 27 147.57 59.78 40.51 10 27 155.42 61.9 39.82
12 27 157.17 62.65 39.86 SR/SR 0 0 NC NC NC 0.5 6 14.48 10.64 73.45
1 24 25.07 21.07 84.02 2 24 74.36 39.09 52.56 4 25 112.29 50.81
45.24 6 25 127.44 58.1 45.59 8 25 150.85 114.97 76.22 10 25 139.93
50.44 36.05 12 25 137.81 49.48 35.9
TABLE-US-00019 TABLE 19 Mean plasma concentrations of the bupropion
metabolite threohydroxybupropion in subjects receiving bupropion SR
in combination with naltrexone IR (IR/SR) or in combination with
naltrexone SR (SR/SR). Treatment Time (hr) N Mean (ng/ml) SD
(ng/ml) CV % IR/SR 0 0 NC NC NC 0.5 0 NC NC NC 1 20 4.44 3.41 76.95
2 27 26.16 13.99 53.48 4 27 44.57 21.2 47.57 6 27 48.28 21.57 44.68
8 27 45.88 21.29 46.4 10 27 45.39 22.2 48.92 12 27 43.61 22.5 51.58
SR/SR 0 0 NC NC NC 0.5 0 NC NC NC 1 15 4.39 3.62 82.52 2 24 25.15
11.2 44.51 4 25 41.77 15.84 37.92 6 25 47.17 20.4 43.24 8 24 45.65
20.85 45.68 10 25 46.44 21.98 47.34 12 25 44.08 20.09 45.57
TABLE-US-00020 TABLE 20 Mean plasma concentrations of the bupropion
metabolite erythrohydroxybupropion in subjects receiving bupropion
SR in combination with naltrexone IR (IR/SR) or in combination with
naltrexone SR (SR/SR). Treatment Time (hr) N Mean (ng/ml) SD
(ng/ml) CV % IR/SR 0 0 NC NC NC 0.5 0 NC NC NC 1 4 1.24 0.15 12.42
2 26 3.5 1.3 37.26 4 27 6.47 2.07 32.03 6 27 7.7 2.42 31.38 8 27
7.77 2.56 32.94 10 27 8.04 2.71 33.67 12 27 8.05 2.4 29.8 SR/SR 0 0
NC NC NC 0.5 0 NC NC NC 1 2 1.64 0.43 26.22 2 24 3.26 1.5 46.01 4
25 5.87 1.65 28.14 6 25 7.07 2.17 30.75 8 24 7.18 2.06 28.63 10 25
7.58 2.04 26.89 12 25 7.51 1.92 25.51
[0135] Table 21 reports the bupropion and bupropion metabolite
AUC.sub.last and the C.sub.max values for the two treatment
conditions. These values are similar for both treatments.
TABLE-US-00021 TABLE 21 Mean pharmacokinetic parameters for
bupropion and metabolites on Day 1 in subjects receiving bupropion
SR in combination with naltrexone IR (IR/SR) or in combination with
naltrexone SR (SR/SR). IR/SR SR/SR Analyte N Mean SD CV % N Mean SD
CV % Bupropion AUClast 23 367.6 122.4 33.3 20 348.7 149.1 42.8 Cmax
23 58.0 19.6 33.8 20 57.5 23.7 41.2 Hydroxybupropion AUClast 27
1452.6 556.8 38.3 25 1334.0 584.5 43.8 Cmax 27 162.3 64.4 39.7 25
163.3 114.0 69.8 Erythrohydroxybupropion AUClast 27 74.8 22.5 30.1
25 69.6 18.5 26.7 Cmax 27 8.5 2.7 31.5 25 8.0 2.1 26.6
Threohydroxybupropion AUClast 27 456.5 209.2 45.8 25 452.0 185.0
40.9 Cmax 27 51.2 23.0 44.8 25 50.7 21.7 42.8
[0136] Adverse event listings as well as dosing logs were used for
this analysis. Data was entered into spreadsheets, QA'd, and then
summarized for frequency of event, % of subjects reporting various
events, time to onset from first dose and day in titration
schedule. The incidence of adverse effects obtained using the
unprompted method of this example is not directly comparable to the
incidence obtained using the methods of Example 4.
[0137] As shown in Table 22, the percent of subjects reporting any
adverse events was 26% and 30% for the SR and IR groups,
respectively. The percent of subjects reporting any GI related
adverse events was 10% and 16% for the SR and IR groups; similar
percentages were observed for subjects reporting any CNS related
adverse events. More subjects reported more than one adverse event
in the IR group (6/30, 20%), than in the SR group (2/30, 6.6%).
Lastly, more subjects reported adverse events that were moderate or
greater in severity in the IR group (30.7%) compared with the SR
group (16.7%).
TABLE-US-00022 TABLE 22 Adverse events associated with IR and SR
naltrexone with SR bupropion treatment Group 1 Group 2 % Subjects
Reporting Any AEs 26% 30% Number of Subjects 8/30 9/30 % Subjects
Reporting Any GI related AEs* 10% 16% Number of Subjects 3/30 5/30
% Subjects Reporting Any CNS related 10% 16% AEs** Number of
Subjects 3/30 5/30 % Subjects Reporting More Than 1 AE 6.6% 20%
Number of Subjects 2/30 6/30 Average Day in Titration Schedule of
Onset 2 4 of AEs % AEs Reported as Moderate Severity 16.7% 30.7%
Distribution of Events 10 events as mild 18 events as mild 2 events
as moderate 8 events as moderate 0 events as severe 0 events as
severe *GI related events defined as any report of: nausea, stomach
pain, stomach cramps, loss of appetite, diarrhea, emesis,
queasiness, dry heaves, increased bowel movements **CNS related
events defined as any report of: headache, dizziness, drowsiness,
lightheadedness, sleepiness, lethargy ***Subjects reporting >1
type of GI or CNS adverse event were included in each event
frequency
[0138] Thus, the group that received the sustained-release
naltrexone with bupropion was less likely to experience adverse
events than the group that received the immediate-release
naltrexone with bupropion. Additionally, the reported adverse
events from the group that received the sustained-release
naltrexone with bupropion were less severe than those reported from
the immediate-release naltrexone group.
[0139] 4 subjects withdrew consent from the study; none are listed
as having not completed the study due to an adverse event. These
subjects are not removed from the calculations presented. Three of
the 4 subjects reported an adverse event, but none dropped out on
the day the event was reported. Three of the subjects were
receiving IR, the fourth was receiving SR.
[0140] All events (n=12) in the SR group were reported as mild,
with the exception of one instance of euphoria and one instance of
stomach cramps (both moderate). Most of the events (n=26) were
reported as mild. There were five GI-related (emesis, stomach pain,
nausea) and 3 CNS-related events that were described as moderate
(headache, fatigue).
[0141] It will be understood by those of skill in the art that
numerous and various modifications can be made without departing
from the spirit of the present invention. Therefore, it should be
clearly understood that the forms of the present invention are
illustrative only and are not intended to limit the scope of the
present invention.
* * * * *