U.S. patent application number 14/541525 was filed with the patent office on 2015-06-18 for layered pharmaceutical formulations.
The applicant listed for this patent is Orexigen Therapeutics, Inc.. Invention is credited to Anthony A. McKinney, Rick Soltero, Gary Tollefson, Eckard Weber.
Application Number | 20150164806 14/541525 |
Document ID | / |
Family ID | 39322569 |
Filed Date | 2015-06-18 |
United States Patent
Application |
20150164806 |
Kind Code |
A1 |
McKinney; Anthony A. ; et
al. |
June 18, 2015 |
LAYERED PHARMACEUTICAL FORMULATIONS
Abstract
In one embodiment a layered pharmaceutical formulation includes
two or more pharmaceutical layers and an intermediate layer
disposed between at least two of the two or more pharmaceutical
layers, the intermediate layer configured to dissolve in vivo to
thereby leave the two or more pharmaceutical layers substantially
intact. In one embodiment, an active pharmaceutical ingredient in
at least one of the pharmaceutical layers is selected from
bupropion, zonisamide, naltrexone, topiramate, phentermine,
metformin, olanzapine and fluoxetine.
Inventors: |
McKinney; Anthony A.; (San
Diego, CA) ; Tollefson; Gary; (Indianapolis, IN)
; Weber; Eckard; (San Diego, CA) ; Soltero;
Rick; (Holly Springs, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Orexigen Therapeutics, Inc. |
La Jolla |
CA |
US |
|
|
Family ID: |
39322569 |
Appl. No.: |
14/541525 |
Filed: |
November 14, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13680922 |
Nov 19, 2012 |
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14541525 |
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|
13330395 |
Dec 19, 2011 |
8318788 |
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13680922 |
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11937421 |
Nov 8, 2007 |
8088786 |
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13330395 |
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60865157 |
Nov 9, 2006 |
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Current U.S.
Class: |
424/472 ;
514/378 |
Current CPC
Class: |
A61K 31/138 20130101;
A61K 31/5513 20130101; A61P 3/10 20180101; A61K 9/2054 20130101;
A61K 31/485 20130101; A61P 25/24 20180101; A61K 31/155 20130101;
A61K 31/423 20130101; A61P 43/00 20180101; A61K 31/42 20130101;
A61P 25/08 20180101; A61P 25/04 20180101; A61K 9/2018 20130101;
A61P 3/06 20180101; A61K 9/0002 20130101; A61K 45/06 20130101; A61K
47/26 20130101; A61K 9/209 20130101; A61P 3/00 20180101; A61K
31/551 20130101; A61K 31/137 20130101; A61K 31/357 20130101; A61K
31/35 20130101; A61P 3/04 20180101; A61K 31/137 20130101; A61K
2300/00 20130101; A61K 31/138 20130101; A61K 2300/00 20130101; A61K
31/155 20130101; A61K 2300/00 20130101; A61K 31/35 20130101; A61K
2300/00 20130101; A61K 31/423 20130101; A61K 2300/00 20130101; A61K
31/485 20130101; A61K 2300/00 20130101; A61K 31/5513 20130101; A61K
2300/00 20130101 |
International
Class: |
A61K 9/24 20060101
A61K009/24; A61K 31/137 20060101 A61K031/137; A61K 47/26 20060101
A61K047/26; A61K 31/42 20060101 A61K031/42 |
Claims
1. A layered pharmaceutical formulation for the administration of
two or more active pharmaceutical ingredients comprising: a first
pharmaceutical layer comprising zonisamide; a second pharmaceutical
layer comprising bupropion; and an intermediate layer disposed
between the first and the second pharmaceutical layers.
2. The layered pharmaceutical formulation of claim 1, wherein the
intermediate layer comprises a monosaccharide sugar, a disaccharide
sugar or a starch.
3. The layered pharmaceutical formulation of claim 2, wherein the
intermediate layer comprises lactose.
4. The layered pharmaceutical formulation of claim 1, wherein the
intermediate layer is configured to rapidly dissolve in vivo, and
thereby leave the first and the second pharmaceutical layers
substantially intact but physically separated.
5. The layered pharmaceutical formulation of claim 4, wherein the
first and the second pharmaceutical layers separate in vivo in less
than 1 minute.
6. The layered pharmaceutical formulation of claim 1, wherein the
bupropion comprises a sustained-release bupropion
7. The layered pharmaceutical formulation of claim 6, wherein the
second pharmaceutical layer comprises between about 50 mg and about
200 mg of sustained-release bupropion.
8. The layered pharmaceutical formulation of claim 6, wherein the
second pharmaceutical layer comprises between about 75 mg and about
150 mg of the sustained-release bupropion.
9. The layered pharmaceutical formulation of claim 6, wherein the
second pharmaceutical layer comprises between about 85 mg and about
100 mg of the sustained-release bupropion.
10. The layered pharmaceutical formulation of claim 6, wherein the
zonisamide comprises a sustained-release zonisamide.
11. The layered pharmaceutical formulation of claim 10, wherein the
dissolution profile of sustained-release zonisamide in the
pharmaceutical formulation is substantially the same as a single
compressed tablet of naltrexone having the same size and shape as
the first pharmaceutical layer, and wherein the dissolution profile
of sustained-release bupropion in the layered pharmaceutical
formulation is substantially the same as a single compressed tablet
of the same pharmaceutical composition, size and shape as the
second pharmaceutical layer.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/680,922, filed Nov. 19, 2012, currently
pending, which is a continuation of U.S. patent application Ser.
No. 13/330,395, filed Dec. 19, 2011, now U.S. Pat. No. 8,318,788,
which issued on Nov. 27, 2012, which is a divisional of U.S. patent
application Ser. No. 11/937,421, filed Nov. 8, 2007, now U.S. Pat.
No. 8,088,786, which issued on Jan. 3, 2012, which claims priority
under 35 U.S.C. .sctn.119 to U.S. Provisional Application Ser. No.
60/865,157, filed Nov. 9, 2006, each of which is hereby
incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to pharmaceutical formulations having
two or more pharmaceutical layers interspersed with one or more
intermediate layers, wherein the pharmaceutical layers include, but
are not limited to, pharmaceutical compositions useful for
affecting weight loss, suppressing appetite and/or treating
obesity-related conditions in individuals.
[0004] 2. Description of the Related Art
[0005] Certain types of layered tablets are known in pharmaceutical
applications. Some pharmaceutical applications separate potentially
interacting layers from one another within a tablet. For example,
U.S. Pat. No. 6,576,256 discloses separating potentially
interacting compounds from each other using separate flat layers of
a tablet, concentric layers, coated beads or granules, and/or using
buffers. Thombre, A. G., L. E. Appel, et al. (2004), "Osmotic drug
delivery using swellable-core technology" J. Control Release 94(1):
75-89 discloses a core tablet containing a drug and a
water-swellable component, and one or more delivery ports in
different core configurations including a tablet-in-tablet (TNT)
bilayer and trilayer formation. U.S. Pat. No. 6,706,283 discloses
an osmotic delivery device fabricated in a bilayer geometry,
wherein the core comprises a sweller layer "sandwiched" between two
drug layers. The coating of a bilayer tablet may include a water
permeable membrane, but is substantially impermeable to the drug
and/or the excipients contained therein. U.S. Pat. No. 6,630,165
discloses dosage forms and methods for providing sustained release
reboxetine including a trilayered compressed core with a first
component drug layer, a second component push layer and a third
component barrier layer separating the drug layer from the push
layer. The barrier layer is inert with the respect to the
composition of the drug layer and substantially impermeable, such
that the drug and the components of the push layer are prevented
from mixing.
[0006] Among multiple layer tablet forms, one type includes a first
layer to provide immediate release of a drug and a second layer to
provide controlled-release of the drug. U.S. Pat. No. 6,514,531
discloses coated trilayer immediate/prolonged release tablets
comprising zolpidem hemitartrate. U.S. Pat. No. 6,087,386 discloses
a trilayer tablet with an enalapril layer, a losartan potassium
layer and a second enalapril maleate layer or an excipient layer.
U.S. Pat. No. 5,213,807 discloses an oral trilayer tablet with a
core comprising a nonsteroidal anti-inflammatory drug (NSAID),
ibuprofen and ibuprofen salts and an intermediate coating
comprising a substantially impervious/impermeable material to the
passage of ibuprofen. U.S. Pat. No. 6,926,907 discloses a trilayer
tablet that separates famotidine contained in a film coat from a
core comprising controlled-release naproxen formulated using
excipients which control the drug release. The film coat is an
enteric coating configured to delay the release of naproxen until
the dosage form reaches an environment where the pH is above
four.
SUMMARY
[0007] An embodiment provides a layered pharmaceutical formulation
comprising two or more pharmaceutical layers and an intermediate
layer disposed between at least two of the two or more
pharmaceutical layers. In some embodiments the intermediate layer
is configured to dissolve in vivo to thereby leave the two or more
pharmaceutical layers substantially intact, but physically
separated, essentially forming two distinct pills. In some
embodiments the dissolution rate of one of the separated two or
more pharmaceutical layers is substantially similar to that of a
singly compressed tablet comprising the same pharmaceutical
composition as that of the pharmaceutical layer.
[0008] Use of a first compound and a second compound in the
preparation of a medicament for affecting weight loss, suppressing
appetite and/or treating an obesity-related condition, wherein the
medicament comprises layered pharmaceutical formulations of the
present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] Other aspects of the disclosure will be readily apparent
from the description below and the appended drawings, in which like
reference numerals refer to similar parts throughout, which are
meant to illustrate and not to limit the disclosure, and in
which:
[0010] FIG. 1A illustrates an embodiment of a layered
pharmaceutical formulation.
[0011] FIGS. 1B & 1C illustrate the layered pharmaceutical
formulation of FIG. 1A in progressive stages as an intermediate
layer dissolves.
[0012] FIG. 2A illustrates a second embodiment of a layered
pharmaceutical formulation.
[0013] FIG. 2B illustrates the second embodiment of FIG. 2A after
an intermediate layer dissolves.
[0014] FIG. 3 illustrates a third embodiment of a layered
pharmaceutical formulation.
[0015] FIG. 4 illustrates a fourth embodiment of a layered
pharmaceutical formulation.
[0016] FIG. 5 illustrates a fifth embodiment of a layered
pharmaceutical formulation with multiple intermediate layers.
[0017] FIG. 6 illustrates a sixth embodiment of a layered
pharmaceutical formulation with lenticular shaped layers.
[0018] FIG. 7 illustrates a seventh embodiment of a layered
pharmaceutical formulation.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0019] Embodiments of the present disclosure provide significant
improvements to multilayer tablet technology. In an embodiment, a
layered pharmaceutical formulation comprises two or more
pharmaceutical layers and at least one intermediate layer disposed
between at least two of the two or more pharmaceutical layers. The
at least one intermediate layer is configured to dissolve in vivo
to thereby leave the two or more pharmaceutical layers
substantially intact. In some embodiments the dissolution rate of
one or more of a separated pharmaceutical layer is substantially
similar to that of a singly compressed tablet comprising the same
pharmaceutical composition as that of the pharmaceutical layer. The
separated pharmaceutical layer thus has an independent and
predictable dissolution profile.
[0020] A dissolution profile for a drug comprises the known
dissolution rate and particular dissolution characteristics of the
drug. A predictable dissolution profile for a specific drug allows
for more accurate treatment of a given symptom. Predictable
dissolution profiles for different drugs within a multilayer tablet
allow for coordinated treatment of multiple symptoms with a single
pharmaceutical formulation.
[0021] In general, multilayer pharmaceutical formulations present
challenges in maintaining predictable dissolution profiles. For
example, in vivo conditions often disrupt an otherwise predictable
multilayer pharmaceutical formulation dissolution profile. A
multilayer tablet may be manufactured with drugs of known
dissolution profiles. Once the multilayer tablet is ingested by a
patient, however, there is no guarantee that each drug will
dissolve as predicted by its individual dissolution profile. Drug
configuration within a tablet, tablet shape, excipients or fillers
in the tablet, tablet coatings and in vivo conditions may all
affect the dissolution profiles. Additionally, interaction between
different drugs within a multilayer tablet may cause a change in
dissolution profile for one or more compositions within the
multilayer tablet.
[0022] Further, in one possible in vivo condition, if the
multilayer tablet becomes attached to the lining of the stomach,
only a portion of the tablet would be exposed to the stomach
fluids. The dissolution of the exposed portion of the tablet may
occur at a more predictable rate while the unexposed portion of the
multilayer tablet shielded from the stomach fluids would have a
longer dissolution profile than would otherwise be expected from a
singly compressed tablet of an identical composition. As mentioned
above, having a multilayer tablet is desirable for ease of
administration of multiple pharmaceutical compositions within a
single tablet. Thus, it is desirable to configure a multilayer
pharmaceutical formulation such that each pharmaceutical layer has
a predictable dissolution profile.
[0023] Herein disclosed is a pharmaceutical formulation comprising
two or more pharmaceutical layers and at least one intermediate
layer configured to dissolve in vivo to thereby leave the two or
more pharmaceutical layers substantially intact. In preferred
embodiments the dissolution rate of one or more of the separated
pharmaceutical layers is substantially similar to that of a singly
compressed tablet comprising the same pharmaceutical composition as
that of the pharmaceutical layer. In some embodiments, the
pharmaceutical layer comprises a single pharmaceutically active
compound or drug. In other embodiments the pharmaceutical layer
comprises a pharmaceutical composition. The term "pharmaceutical
composition" refers to a mixture of a chemical compound or
compounds (e.g., a drug or drugs) with additional pharmaceutical
components, such as diluents or carriers. Herein, the term "drug"
is synonymous with the term "pharmaceutically active ingredient."
The pharmaceutical composition facilitates administration of the
drug to an organism. Pharmaceutical compositions can also be
obtained in the form of pharmaceutically acceptable salts by
reacting drug compounds with inorganic or organic acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, methanesulfonic acid, ethanesulfonic acid,
p-toluenesulfonic acid, salicylic acid and the like.
[0024] In some embodiments the two or more pharmaceutical layers
comprise one or more immediate-release formulations. The term
"immediate-release" is used herein to specify that the immediate
release formulation is not configured to alter the dissolution
profile of the pharmaceutical layer. For example, an immediate
release pharmaceutical layer may be a pharmaceutical composition
that does not contain ingredients included for the purpose of
altering the dissolution profile. In some embodiments the two or
more pharmaceutical layers comprise one or more controlled-release
formulations. The term "controlled-release" is used herein in its
ordinary sense and thus includes pharmaceutical compositions
combined with ingredients to alter their dissolution profile. A
"sustained-release" formulation is a type of controlled-release
formulation, wherein ingredients have been added to a
pharmaceutical composition such that the dissolution profile is
extended over a longer period of time than that of an immediate
release formulation comprising a similar pharmaceutical
composition.
[0025] In some embodiments the at least one intermediate layer is a
flat layer separating at least two pharmaceutical layers. In some
embodiments the at least one intermediate layer has exposed edges.
Exposed edges allow for fluid to contact and dissolve the at least
one intermediate layer. In some embodiments the pharmaceutical
formulations comprises a coating covering the two or more
pharmaceutical layers and the at least one intermediate layer. The
coating is configured to dissolve in vivo more or less uniformly
over the two or more pharmaceutical layers and the at least one
intermediate layer such that the at least one intermediate layer is
left exposed to the fluids that will dissolve the at least one
intermediate layer in vivo.
[0026] In some embodiments the at least one intermediate layer is
or comprises an impermeable membrane. In some embodiments the at
least one intermediate layer has a substantially higher dissolution
rate than at least one of the pharmaceutical layers. In some
preferred embodiments the at least one intermediate layer dissolves
in a nearly immediate fashion with respect to the dissolution of at
least one of the pharmaceutical layers. In some embodiments the at
least one intermediate layer comprises at least one of a
monosaccharide or a disaccharide sugar, a starch (e.g., corn or
potato starches), or any other suitable tablet ingredients known in
the art. In some preferred embodiments the at least one
intermediate layer comprises lactose. In some preferred
embodiments, the intermediate layer dissolves in a nearly immediate
fashion as compared to the dissolution rates of the respective
pharmaceutical layers, e.g., such that upon dissolution of the
intermediate layer, substantially all of the surface area of each
of the two pharmaceutical layers is exposed. Thus, in one
embodiment, under a standard dissolution test the immediate release
layer is dissolved to the extent that at least two pharmaceutical
layers present in the pharmaceutical formulation are separated in
less than 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 15, 20, 25 or 30 minutes.
[0027] Pharmaceutical formulations of drugs can be configured in
various ways and in a variety of dosage forms to modify a
dissolution rate of the drug. For example, one type of
controlled-release pharmaceutical formulation is a
sustained-release pharmaceutical formulation. Sustained-release
pharmaceutical formulations can contain a variety of excipients,
such as retardant excipients (also referred to as release
modifiers) and/or fillers that are selected and incorporated into
the formulation in such a way as to slow the dissolution rate of
the formulation (and thereby slow the dissolution and/or release of
the zonisamide) under in vivo conditions as compared to an
otherwise comparable immediate-release formulation. Thus, a
"comparable" immediate-release formulation is one that is
substantially identical to the controlled-release formulation,
except that that it is configured to provide immediate-release
instead of controlled-release under substantially identical
conditions.
[0028] The term "immediate-release" is used herein to specify a
formulation that is not configured to alter the dissolution profile
of the active ingredient (e.g., zonisamide, bupropion, naltrexone,
olanzapine, phentermine, topiramate, metformin, fluoxetine). For
example, an immediate-release pharmaceutical formulation may be a
pharmaceutical formulation that does not contain ingredients that
have been included for the purpose of altering the dissolution
profile. An immediate-release formulation thus includes drug
formulations that take less than 30 minutes for substantially
complete dissolution of the drug in a standard dissolution test. A
"standard dissolution test," as that term is used herein, is a 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. The term "controlled-release" is used herein in
its ordinary sense and thus includes pharmaceutical formulations
that are combined with ingredients to alter their dissolution
profile. A "sustained-release" formulation is a type of
controlled-release formulation, wherein ingredients have been added
to a pharmaceutical formulation such that the dissolution profile
of the active ingredient is extended over a longer period of time
than that of an otherwise comparable immediate-release formulation.
A controlled-release formulation thus includes drug formulations
that take 30 minutes or longer for substantially complete
dissolution of the drug in a standard dissolution test, conditions
which are representative of the in vivo release profile.
[0029] A pharmaceutical layer may be configured in various ways.
For example, in some embodiments a layer comprises a flat portion
of a pharmaceutical formulation. In some embodiments a layer
comprises a rounded portion of a pharmaceutical formulation. In
some embodiments a layer comprises a conical section of a
pharmaceutical formulation. In some embodiments a layer comprises
an elliptical section of a pharmaceutical formulation. In some
embodiments a layer comprises a sideways section of a
pharmaceutical formulation. In some embodiments a layer comprises a
cubical section of a pharmaceutical formulation. In some
embodiments a layer comprises a wedge of a pharmaceutical
formulation. In some embodiments a layer comprises a substantial
portion of a pharmaceutical formulation. A substantial portion is
preferably at least about 25% of the pharmaceutical formulation and
more preferably at least about 50% of the pharmaceutical
formulation.
[0030] In some embodiments at least one pharmaceutical layer reacts
when brought into contact with another of the pharmaceutical layers
within the layered pharmaceutical formulation. In some embodiments
at least one pharmaceutical layer does not react when brought into
contact with another of the pharmaceutical layers.
[0031] In some embodiments an intermediate layer is configured to
dissolve in vivo. Dissolving is the act of solvation wherein a
solute is dissolved in a solvent to create a solution. Dissolving
in vivo means that the dissolving takes place within an organism or
within living tissue either taken from or part of an organism. An
organism is any living animal, plant, bacteria or fungus. In
preferred embodiments the organism is human.
[0032] In some embodiments a dissolving intermediate layer
separates at least two of the pharmaceutical layers. In some
embodiments the two pharmaceutical layers contain different
pharmaceutical compositions. In some embodiments after the
intermediate layer dissolves, the pharmaceutical layers are no
longer held together within the pharmaceutical formulation. In some
embodiments after the intermediate layer dissolves, the
pharmaceutical layers remain substantially intact. A pharmaceutical
layer remains substantially intact when it retains at least about
50% of its original mass in a single entity post-dissolution of the
one or more intermediate layers. In preferred embodiments the
pharmaceutical layer remains substantially intact when it retains
at least about 75% of its original mass post-dissolution of the one
or more intermediate layers. In more preferred embodiments the
pharmaceutical layer remains substantially intact when it retains
at least about 85% of its original mass post-dissolution of the one
or more intermediate layers. In some embodiments each
pharmaceutical layer has a different dissolution rate. A
dissolution rate is the solvation of a pharmaceutical layer volume
per unit time. In some embodiments one or more pharmaceutical
layers have similar dissolution rates. Preferably the one or more
intermediate layers have a higher dissolution rate than the two or
more pharmaceutical layers.
[0033] FIG. 1A illustrates a preferred embodiment of a
pharmaceutical formulation 100. The pharmaceutical formulation 100
comprises two pharmaceutical layers 102A and 102B. Pharmaceutical
layer 102A comprises a pharmaceutical composition. In some
embodiments of the pharmaceutical formulation 100, the
pharmaceutical layer 102B comprises the same pharmaceutical
composition as that of the pharmaceutical layer 102A. In the
illustrated embodiment of pharmaceutical formulation 100, the
pharmaceutical layer 102A comprises a different pharmaceutical
composition than that of the pharmaceutical layer 102B. The
pharmaceutical formulation 100 also comprises an intermediate layer
106. In the illustrated embodiment the intermediate layer 106 is
configured to dissolve in vivo.
[0034] Each of the pharmaceutical layers 102A and 102B comprises
one or more pharmaceutical compositions. As illustrated in the
pharmaceutical formulation 100, the dosage amount of each
pharmaceutical layer 102A and 102B is similar. The dosage strength
of each pharmaceutical layer may also be similar. In other
embodiments the dosage amount and/or strength of one pharmaceutical
layer is much greater than that of another layer. This difference
in dosage amount or strength allows for individualized treatment of
symptoms that are addressed by increasing or decreasing a dosage of
one or more pharmaceutical layers while maintaining a dosage of
other layers. The amount or strength of dosage of a drug contained
within a pharmaceutical formulation will, of course, be dependent
on the subject being treated, on the subject's weight, the severity
of the affliction, the manner of administration and the judgment of
the prescribing physician.
[0035] The illustrated pharmaceutical formulation 100 includes, but
is not limited to, drugs for affecting weight loss, suppressing
appetite and/or treating an obesity-related condition in a patient.
Specifically, the illustrated pharmaceutical layer 102A comprises
zonisamide and the pharmaceutical layer 102B comprises bupropion.
The intermediate layer 106 comprises lactose or a suitable
monosaccharide sugar, disaccharide sugar or a starch. In another
embodiment, one or more of the pharmaceutical layers comprises
naltrexone, one or more of the pharmaceutical layers comprises
bupropion, and at least one intermediate layer comprises a
monosaccharide sugar, a disaccharide sugar or a starch. In another
embodiment, one or more of the pharmaceutical layers comprises
naltrexone, one or more of the pharmaceutical layers comprises
zonisamide, and at least one intermediate layer comprises a
monosaccharide sugar, a disaccharide sugar or a starch. In another
embodiment, one or more of the pharmaceutical layers comprises
naltrexone, one or more of the pharmaceutical layers comprises
fluoxetine, and at least one intermediate layer comprises a
monosaccharide sugar, a disaccharide sugar or a starch. In another
embodiment, one or more of the pharmaceutical layers comprises
olanzapine, one or more of the pharmaceutical layers comprises
zonisamide, and at least one intermediate layer comprises a
monosaccharide sugar, a disaccharide sugar or a starch. In another
embodiment, one or more of the pharmaceutical layers comprises
metformin, one or more of the pharmaceutical layers comprises
zonisamide, and at least one intermediate layer comprises a
monosaccharide sugar, a disaccharide sugar or a starch. In another
embodiment, one or more of the pharmaceutical layers comprises
phentermine, one or more of the pharmaceutical layers comprises
topiramate, and at least one intermediate layer comprises a
monosaccharide sugar, a disaccharide sugar or a starch.
[0036] In some embodiments the presence of one drug in a
pharmaceutical formulation enhances the desired physiological
effects and/or reduces undesired physiological effects of one or
more other drugs in the pharmaceutical formulation. In some
embodiments the presence of one or more drugs in a pharmaceutical
formulation enhances the desired physiological effects of the drugs
over the additive physiological effects of the one or more drugs in
comparable, but separate pharmaceutical formulations when
administered alone.
[0037] FIG. 1B illustrates the pharmaceutical formulation 100 of
FIG. 1A as a fluid, as represented by the arrow 108, begins to
dissolve the intermediate layer 106. In the illustrated embodiment,
the fluid comprises at least one bodily fluid selected from saliva,
sweat, chyme, mucus and bile. As the intermediate layer 106
dissolves the pharmaceutical layers 102A and 102B begin to separate
as shown. As noted above, in some embodiments each pharmaceutical
layer comprises the same pharmaceutical composition. However, in
the illustrated embodiment, the pharmaceutical layers 102A and 102B
each comprise a different pharmaceutical composition. In some
embodiments, one or more of the pharmaceutical layers comprises a
controlled-release formulation. In some embodiments, one or more of
the controlled-release formulations comprises a sustained-release
formulation.
[0038] FIG. 1C illustrates the layered pharmaceutical formulation
100 of FIG. 1A after the intermediate layer 106 has completely
dissolved. The pharmaceutical layers 102A and 102B have separated
and remain substantially intact.
[0039] FIG. 2A illustrates an embodiment of a second layered
pharmaceutical formulation 200. The second pharmaceutical
formulation 200 comprises second pharmaceutical layers 202A, 202B
and 202C. In some embodiments two or more of the second
pharmaceutical layers 202A, 202B and 202C comprise the same
pharmaceutical composition. In the illustrated embodiment each of
the pharmaceutical layers 202A, 202B and 202C comprises a different
pharmaceutical composition. The second pharmaceutical formulation
200 also comprises an intermediate layer 106 configured to dissolve
in vivo.
[0040] FIG. 2B illustrates the second layered pharmaceutical
formulation 200 of FIG. 2A. The fluid, as represented by the arrow
108, has dissolved an intermediate layer 106 and the second
pharmaceutical layers 202A, 202B and 202C are separated and left
substantially intact.
[0041] FIG. 3 illustrates an embodiment of a third layered
pharmaceutical formulation 300. The third pharmaceutical
formulation 300 comprises third pharmaceutical layers 302A, 302B
and 302C separated by an intermediate layer 106. Each of the third
pharmaceutical layers 302A, 302B and 302C comprises one or more
pharmaceutical compositions. As illustrated in the third layered
pharmaceutical formulation 300, the third pharmaceutical layer 302A
comprises a similar dosage volume to the third pharmaceutical layer
302B. The third pharmaceutical layer 302C, however, comprises a
larger dosage volume than third pharmaceutical layers 302A or 302B.
As noted above with regard to FIG. 1, varying dosage amounts or
strengths of particular pharmaceutical layers within a
pharmaceutical formulation allows for individualized treatment of
particular symptoms.
[0042] FIG. 4 illustrates an embodiment of a fourth layered
pharmaceutical formulation 400. The fourth pharmaceutical
formulation 400 includes, but is not limited to fourth
pharmaceutical layers 402A and 402B and an intermediate layer 106.
The fourth pharmaceutical layer 402A comprises a first drug 404A
and a second drug 404B. The first drug 404A and the second drug
404B are positioned within the fourth pharmaceutical layer 402A so
as to be in physical contact with the other; no intermediate layer
106 separates the first drug 404A from the second drug 404B within
the layer 402A. Similarly, the fourth pharmaceutical layer 402B
comprises a third drug 404C and a fourth drug 404D; no intermediate
layer 106 separates the third drug 404C and the fourth drug
404D.
[0043] In the fourth pharmaceutical formulation 400 the
intermediate layer 106 is disposed between fourth pharmaceutical
layers 402C and 402B. In this embodiment, the edges of intermediate
layer 106 are not aligned with the fourth pharmaceutical layers
402C and 402B. A space 408 allows for fluids to interact with and
dissolve the intermediate layer 106. Thus, although the
intermediate layer 106 is not flush with the outside edge of the
fourth pharmaceutical formulation 400, the intermediate layer 106
is exposed for purposes of dissolution upon contact with bodily
fluids.
[0044] FIG. 5 illustrates an embodiment of a fifth layered
pharmaceutical formulation 500 depicted after separation has
occurred. The fifth pharmaceutical formulation 500 includes, but is
not limited to fifth pharmaceutical layers 502A and 502B. The fifth
pharmaceutical layers 502A and 502B each include, but are not
limited to one or more pharmaceutical compositions.
[0045] The fifth pharmaceutical formulation 500 further comprises a
first intermediate layer 506A and a second intermediate layer 506B.
In some embodiments the first intermediate layer 506A is configured
to physically and chemically separate the fifth pharmaceutical
layers 502A and 502B. In some embodiments the second intermediate
layer 506B is configured to physically and chemically separate the
fifth pharmaceutical layers 502A and 502B. The first intermediate
layer 506A and the second intermediate layer 506B each comprise one
or more formulations configured to dissolve in vivo.
[0046] FIG. 6 illustrates an embodiment of a sixth layered
pharmaceutical formulation 600. The sixth pharmaceutical
formulation 600 includes, but is not limited to sixth
pharmaceutical layers 602A and 602B and an intermediate layer 106.
The sixth pharmaceutical formulation 600 is configured in a
lenticular shape, wherein each pharmaceutical layer 602A and 602B
comprises a single convex shape.
[0047] Pharmaceutical layers may be configured in various shapes.
For example, pharmaceutical layers may be configured in elliptical
shapes, spherical shapes, oblong shapes, square shapes or flat
shapes. In some embodiments pharmaceutical formulations are
combined with fillers or excipients and placed in tablets, granules
or capsules for later administration. In some embodiments the
tablets are configured in spherical, elliptical, lenticular or
capsule shapes.
[0048] FIG. 7 illustrates another embodiment of a seventh layered
pharmaceutical formulation 700. The seventh pharmaceutical
formulation 700 includes, but is not limited to seventh
pharmaceutical layers 702A, 702B, 702C, 702D, 702E and 702F. Each
seventh pharmaceutical layer 702A, 702B, 702C, 702D, 702E and 702F
comprises one or more pharmaceutical compositions. Each seventh
pharmaceutical layer 702A, 702B, 702C, 702D, 702E and 702F is in a
wedge shape. The seventh pharmaceutical formulation 700
additionally comprises an intermediate layer 106 disposed between
seventh pharmaceutical layers 702B, 702C and 702D and also between
seventh pharmaceutical layers 702A, 702F and 702E. As described
above the intermediate layer 106 is configured to dissolve in vivo
upon contact with a certain type of bodily fluid. The seventh
pharmaceutical formulation 700 additionally comprises a special
intermediate layer 706 disposed between seventh pharmaceutical
layers 702A and 702B and between seventh pharmaceutical layers 702D
and 702E. The special intermediate layer 706 is configured to
dissolve under bodily conditions different than those conditions
that dissolve intermediate layer 106. Upon dissolution of the
special intermediate layer 706, the seventh pharmaceutical layers
702A and 702B and the seventh pharmaceutical layers 702D and 702E
are left substantially intact.
[0049] For example, if intermediate layer 106 were configured to
dissolve under the acidic conditions of the stomach in a human
patient, special intermediate layer 706 may be configured to
dissolve only after the pharmaceutical formulation 700 reaches the
duodenum. In some embodiments at least one of the pharmaceutical
layers comprises an enteric coating.
Manufacture of Pharmaceutical Formulations
[0050] As noted above, pharmaceutical formulations may be
configured in various shapes and sizes for ease of administration
to a patient. Manufacture of pharmaceutical formulations configured
in tablets comprises steps known in the art. For example, tablets
may be prepared through wet-granulation, dry-granulation or direct
compression. Layered pharmaceutical formulations may be configured
in tablet form in a similar manner. To manufacture each
pharmaceutical layer, one or more drugs are obtained in, for
example, a crystalline, amorphous or powdered form, and mixed with
or without diluents and/or excipients into a solid with pressure.
The solid pharmaceutical layer is added with other pharmaceutical
layers and/or intermediate layers and configured in a desired
tablet geometry with pressure.
[0051] In some embodiments pharmaceutical formulations include, but
are not limited to, one or more of polyvinylpyrrolidine
(polyvinylpyrrolidone), hydroxypropyl cellulose (HPC),
hydroxypropylmethyl cellulose (HPMC), methyl cellulose (MC), vinyl
acetate/crotonic acid copolymers, methacrylic acid copolymers
(Eudragit), maleic anhydride/methyl vinyl ether copolymers.
[0052] In some embodiments pharmaceutical formulations include, but
are not limited to controlled-release formulations. In some
embodiments the controlled-release formulations include, but are
not limited to sustained-release formulations.
Pharmaceutical Formulations to Treat Obesity
[0053] In some embodiments the layered pharmaceutical formulation
may be used to treat obesity. Obesity is a disorder characterized
by the accumulation of excess fat in the body. Obesity has been
recognized as one of the leading causes of disease and is emerging
as a global problem. Increased instances of complications from
obesity, such as hypertension, non-insulin-dependent diabetes
mellitus, arteriosclerosis, dyslipidemia, certain forms of cancer,
sleep apnea and osteoarthritis, have been related to increased
instances of obesity in the general population.
[0054] Prior to 1994, obesity was generally considered a
psychological problem. The discovery of the adipostatic hormone
leptin in 1994 brought forth the realization that in certain cases,
obesity may have a biochemical basis. The corollary to this
realization was the idea that treatment of obesity may be achieved
by chemical approaches. Since then, a number of such chemical
treatments have entered the market.
[0055] Various methods of affecting weight loss, suppressing
appetite and/or treating an obesity-related condition in a patient
involve administering certain drugs or combinations thereof. For
example, a number of references disclose the administration of
certain weight loss formulations that include an anticonvulsant, an
opioid antagonist and/or a norepinephrine reuptake inhibitor (NRI)
to a patient in need thereof to affect weight loss. See, for
example, U.S. Patent Application Publication Nos. 2004/0033965;
2004/0198668; 2004/0254208; 2005/0137144; 2005/0143322;
2005/0181070; 2005/0215552; 2005/0277579; 2006/0009514;
2006/0142290; 2006/0160750 and 2006/0079501, all of which are
hereby incorporated by reference in their entireties. Weight gain
has been a major concern with certain of the newer antidepressants,
particularly, with paroxetine (PAXIL.RTM. PAXIL CR.RTM.) and
mirtazapine (Fava, J. Clin. Psych. 61 (suppl. 11):37-41 (2000);
Carpenter et al, J. Clin. Psych. 60:45-49 (1999); Aronne et al, J.
Clin. Psych. 64 (suppl. 8):22-29 (2003), both of which are
incorporated by reference herein in their entirety).
[0056] Other descriptions of bupropion, zonisamide,
controlled-release zonisamide and combinations thereof are
disclosed in U.S Provisional Patent Application Nos. 60/740,034,
filed on Nov. 28, 2005; 60/832,110, filed on Jul. 19, 2006;
60/835,564, filed on Aug. 4, 2006; and U.S. patent application Ser.
No. 11/194,201 entitled COMBINATION OF BUPROPION AND A SECOND
COMPOUND FOR AFFECTING WEIGHT LOSS, filed on Aug. 1, 2005; all of
which are hereby incorporated by reference in their entireties.
[0057] For methods of administering pharmaceutical compositions
useful for affecting weight loss, suppressing appetite and/or
treating obesity-related conditions in individuals
controlled-release formulations help to suppress some if not all of
the negative side effects that may arise from administration of
such medication. Even in controlled-release formulations, however,
the administration of certain anticonvulsants or opioid receptor
antagonists at a full dosage may initially incur severe adverse
side effects. Thus, at least initially, patients may be unable to
tolerate a full dosage of the prescribed drug, which may include,
but is not limited to an anticonvulsant or an opioid receptor
antagonist. This intolerance may lead to more severe side effects
and/or premature abandonment of the medication and/or the treatment
program.
[0058] Administering combinations of drugs, for example, a
combination including, but not limited to an anticonvulsant or an
opioid receptor antagonist in combination with an antidepressant
may enhance the ability of the anticonvulsant to affect weight
loss, but does not necessarily eliminate the initial adverse side
effects that may accompany the administration of the anticonvulsant
or the opioid receptor antagonist. In some embodiments a system
comprises a layered pharmaceutical for minimizing side effects
during treatment of obesity. In some embodiments a method comprises
administering a layered pharmaceutical formulation comprising an
anticonvulsant or the opioid receptor antagonist to affect weight
loss while minimizing or eliminating the initial adverse side
effects on the patient.
[0059] Thus, some preferred embodiments, the layered pharmaceutical
formulation is useful for the treatment of obesity and/or for
affecting weight loss. Some preferred embodiments comprise at least
one of an antidepressant and an anticonvulsant. Other preferred
embodiments comprise at least one of an antidepressant and an
opioid receptor antagonist. Other preferred embodiments comprise at
least one of an anticonvulsant and an opioid receptor antagonist.
Other preferred embodiments comprise at least one of an
anticonvulsant and an antidiabetic.
Antidepressants and Psychotherapeutics
[0060] In some embodiments an antidepressant comprises a dopamine
reuptake inhibitor or receptor antagonist. Examples of dopamine
reuptake inhibitors include, but are not limited to phentermine and
pharmaceutically acceptable salts or prodrugs thereof. Examples of
dopamine receptor antagonists include, but are not limited to
haloperidol, ocaperidone, risperidone, olanzapine, quetiapine,
amisulpride, and pimozide and pharmaceutically acceptable salts or
prodrugs thereof. In some embodiments the antidepressant comprises
a norepinephrine reuptake inhibitor. Examples of norepinephrine
reuptake inhibitors include, but are not limited to bupropion,
thionisoxetine, atomoxetine and reboxetine and pharmaceutically
acceptable salts or prodrugs thereof. Other embodiments include,
but are not limited to those in which the antidepressant is a
dopamine agonist. Dopamine agonists available on the market include
cabergoline, amantadine, lisuride, pergolide, ropinirole,
pramipexole, and bromocriptine. In some embodiments the
antidepressant comprises a serotonin reuptake inhibitor. Examples
of serotonin reuptake inhibitors include, but are not limited to
fluoxetine and pharmaceutically acceptable salts or prodrugs
thereof.
[0061] Throughout the disclosure of the present specification 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 can be obtained by reacting a compound of the disclosure with
inorganic acids such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid,
ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the
like. Pharmaceutical salts can also be obtained by reacting a
compound of the disclosure with a base to form a salt such as
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.
[0062] The term "prodrug" refers to an agent that is converted into
the parent drug in vivo. Prodrugs are often useful because, in some
situations, they are easier to administer than the parent drug.
They can, for instance, be bioavailable by oral administration
whereas the parent is not. The prodrug can also have improved
solubility in pharmaceutical compositions over the parent drug or
can demonstrate increased palpability or be easier to
formulate.
[0063] An example, without limitation, of a prodrug would be a
compound of the present disclosure which is administered as an
ester (the "prodrug") to facilitate transmittal across a cell
membrane where water solubility is detrimental to mobility but
which then is metabolically hydrolyzed to the carboxylic acid, the
active entity, once inside the cell where water-solubility is
beneficial. A further example of a prodrug might be a short peptide
(polyaminoacid) bonded to an acid group where the peptide is
metabolized to provide the active moiety.
[0064] Bupropion, whose chemical name is
(.+-.)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone,
is the active ingredient in the drugs marketed as ZYBAN.RTM. and
WELLBUTRIN.RTM., and is usually administered as a hydrochloride
salt. Throughout the present disclosure, whenever the term
"bupropion" is used, it is understood that the term encompasses
bupropion as a free base, or as a physiologically acceptable salt
thereof, or as a bupropion metabolite or salt thereof.
[0065] The metabolites of bupropion suitable for inclusion in the
methods and compositions described herein include the erythro- and
threo-amino alcohols of bupropion, the erythro-amino diol of
bupropion, and morpholinol metabolites of bupropion. In some
embodiments, the metabolite of bupropion is
(.+-.)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol.
In some embodiments the metabolite is
(-)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol,
while in other embodiments, the metabolite is
(+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol.
Preferably, the metabolite of bupropion is
(+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol, which
is known by its common name of radafaxine. The scope of the present
disclosure includes the above-mentioned metabolites of bupropion as
a free base or as a physiologically acceptable salt thereof.
Controlled-release bupropion formulations of bupropion are known in
the art. For example, U.S. Pat. No. 6,905,708 discloses a
once-daily dosage configured to deliver bupropion in vivo over a 6
to 12 hour period.
[0066] Olanzapine, whose chemical name is
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine,
is used as a psychotherapeutic agent primarily for the treatment of
schizophrenia, acute manic episodes in bipolar disorder acute,
maintenance treatment in bipolar disorder and agitation associated
with both these disorders. Throughout the present disclosure,
whenever the term "olanzapine" is used, it is understood that the
term encompasses olanzapine as a free base, or as a physiologically
acceptable salt thereof, or as a olanzapine metabolite or salt
thereof.
[0067] Olanzapine displays linear kinetics. Its elimination
half-life ranges from 21 to 54 hours. Steady state plasma
concentrations are achieved in about a week. Olanzapine undergoes
extensive first pass metabolism and bioavailability is not affected
by food.
[0068] The psychotherapeutic agent may be selected from the group
consisting of mirtazapine, setiptiline, paroxetine, venlafaxine,
olanzapine, bupropion, risperidone, lamotrogine, risperidone, a
lithium salt, valproic acid, and pharmaceutically acceptable salts
or prodrugs thereof. In some embodiments the psychotherapeutic
agent is an antidepressant, an antimigrane, an antibipolar, an
antimania drug, a mood stabilizer, or an antiepileptic. Examples of
antidepressants include paroxetine, mirtazapine, and bupropion.
Examples of antibipolar drugs include lithium, valproate,
carbamezepine, oxycarbamezepine, lamotrogine, tiagabine,
olanzapine, clozapine, risperidone, quetiapine, aripiprazole,
ziprasidone, and benzodiazepines. Also included are
pharmaceutically acceptable salts or prodrugs of these drugs,
extended release or controlled release formulations of the above
drugs, as well as combinations of the above drugs.
[0069] Fluoxetine is a selective serotonin reuptake inhibitor (S
SRI), whose chemical name is
N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]-propan-1-amine, is
used primarily for the treatment of depression (including pediatric
depression), obsessive-compulsive disorder (in both adult and
pediatric populations), bulimia nervosa, panic disorder,
premenstrual dysphoric disorder, hypochondriasis and body
dysmorphic disorder. Throughout the present disclosure, whenever
the term "fluoxetine" is used, it is understood that the term
encompasses fluoxetine as a free base, or as a physiologically
acceptable salt thereof, or as a fluoxetine metabolite or salt
thereof.
[0070] Fluoxetine has a bioavailability of approximately 72%, and
peak plasma concentrations are reached in 6 to 8 hours. It is
highly bound to plasma proteins, mostly albumin. Its elimination
half-life ranges from 1 to 3 days--after a single dose--to 4 to 6
days (after long-term use) in healthy adults, and is prolonged in
those with liver disease. The half-life of norfluoxetine is longer
(16 days after long-term use). Complete excretion of the drug may
take several weeks.
[0071] The SSRI can be selected from fluoxetine, fluvoxamine,
sertraline, paroxetine, citalopram, escitalopram, sibutramine,
duloxetine, and venlafaxine, and pharmaceutically acceptable salts
or prodrugs thereof. In some embodiments, the SSRI is fluoxetine or
a pharmaceutically acceptable salt or prodrug thereof.
[0072] Fluoxetine has a physiological half life of about 24 hours,
whereas that of naltrexone is about 1.5 hours. However their
metabolites may demonstrate half-lives in excess of 24 hours. Thus,
in some cases, it may be beneficial to administer one dose of
fluoxetine per day in conjunction with two or three or more doses
of naltrexone throughout the day. Naltrexone may also be in a
time-release formulation where the dose is administered once a day,
but naltrexone gradually enters the blood stream throughout the
day, or in the course of a 12 hour period.
[0073] Symptoms of the obsessive compulsive disorders are inhibited
in individuals being administered fluoxetine and naltrexone.
Adverse events associated with the obsessive compulsive disorders
are reduced in individuals being administered fluoxetine and
naltrexone. The effects of administration of both fluoxetine and
naltrexone on obsessive compulsive disorder are synergistic
compared to effects of those expected by administration of
fluoxetine and naltrexone alone.
[0074] Newer generation antidepressants include selective serotonin
reuptake inhibitors (e.g., fluoxetine, fluvoxamine, sertraline,
paroxetine, citalopram, and escitalopram), venlafaxine, duloxetine,
nefazodone, mianserin setiptiline, viqualine trazodone,
cianopramine, and mirtazapine.
[0075] Phentermine is an example of a dopamine reuptake inhibitor
with a chemical name 2-methyl-1-phenylpropan-2-amine and
2-methyl-amphetamine. Throughout the present disclosure, whenever
the term "phentermine" is used, it is understood that the term
encompasses phentermine as a free base, or as a physiologically
acceptable salt thereof, or as a phentermine metabolite or salt
thereof.
Antidiabetic
[0076] In some embodiments an antidiabetic includes, but is not
limited to a biguanide, glucosidase inhibitor, insulin,
meglitinide, sulfonylurea or a thiazolidinedione. In some
embodiments a biguanide comprises metformin hydrochloride. In some
embodiments a glucosidase inhibitor includes, but is not limited to
acarbose and miglitol. Examples of insulin include, but are not
limited to human insulin, pork insulin, beef insulin, beef-pork
insulin, insulin from different sources such as recombinant DNA and
animal sources, as well as regular, NPH, and LENTE.RTM. types of
insulin. Other examples of insulin include, but are not limited to
mixtures of the various forms of insulin (e.g. NPH and regular
human and pork insulin). Other examples of insulin include mixtures
of Insulin Lispro Protamine and Insulin Injection (rDNA origin), a
50/50 (or a 70/30) mixture of Human Insulin Isophane Suspension and
Human Insulin Injection, a 70/30 mixture of NPH Human Insulin
Isophane Suspension and Human Insulin Injection (rDNA), insulin
glargine, insulin lispro, insulin aspart, as well as insulin mixed
with other ingredients such as zinc crystals or in a phosphate
buffer. Insulin may be from Saccharomyces cerevisiae or other
sources. Examples of meglitinides include, but are not limited to
nateglinide and repaglinide. Examples of sulfonylureas include, but
are not limited to glimepiride, glyburide, glibenclamide,
gliquidone, gliclazide, chlorpropamide, tolbutamide, tolazamide and
glipizide. Examples of thiazolidinediones include, but are not
limited to rosiglitazone and pioglitazone. Also included are
extended release formulations of the above drugs, as well as
combinations of the above drugs and pharmaceutically acceptable
salts or prodrugs thereof.
[0077] As mentioned above, in certain embodiments, the antidiabetic
is metformin. Metformin, whose chemical name is
1-(diaminomethylidene)-3,3-dimethyl-guanidine, is often used in the
treatment of diabetes mellitus type 2, especially when accompanied
obesity and insulin resistance. Metformin has also been proven to
reduce the cardiovascular complications of diabetes.
Anticonvulsants
[0078] In some embodiments, the anticonvulsant is selected from the
group including, but not limited to zonisamide, topiramate,
nembutal, lorazepam, clonazepam, clorazepate, tiagabine,
gabapentin, fosphenytoin, phenytoin, carbamazepine, balproate,
felbamate, lebetiracetam, oxcarbazepine, lamotrigine, methsuximide
and ethosuxmide.
[0079] Zonisamide is a marketed anticonvulsant indicated as
adjunctive therapy for adults with partial onset seizures. Without
being bound by any particular theory, it is believed that the
mechanism of antiepileptic activity appears to be: (1)
sodium-channel blocking; and (2) reduction of inward T-type calcium
occurrence. In addition, zonisamide binds to the
GABA/benzodiazepine receptor complex without producing change in
chloride flux. Further, zonisamide facilitates serotonergic and
dopaminergic neurotransmission and possesses a weak inhibitory
effect on carbonic anhydrase.
[0080] Zonisamide has been shown to cause significant weight loss
(comparable to marketed weight loss medications) in patients
presenting primary obesity. It has been postulated that the affect
of zonisamide on the CNS concentration of serotonin, dopamine and
carbonic anhydrase is responsible for this effect. There is
evidence that zonisamide increases serotonin and dopamine synthesis
rates herein. There is further evidence suggesting that zonisamide
stimulates dopamine D.sub.2 receptors.
[0081] Zonisamide can be formulated in a controlled- or
sustained-release tablet or gel form. This allows a patient newly
prescribed zonisamide to ramp up the dosage level over a period of
several days. This increase in dosage form allows the patient to
avoid some of the negative side effects that have been exhibited
during the initial administration of zonisamide to a patient. Some
of these initial side effects include a shock to the body. Although
patients who start with a full dose of zonisamide will become
acclimated to the dosage over a period of time, the negative side
effects accompanying the initial shock to the body can be avoided
with a method wherein dosages are increased over a period of
several days.
[0082] In a pharmaceutical composition with a drug such as
bupropion, a method of administering sustained-release zonisamide
in a layered tablet can reduce shock to the body while maximizing
bioavailability, and thus have a maximum effect for prevention of
weight gain and/or treatment of obesity.
[0083] Although the exact dosages will be determined on a
drug-by-drug basis, in most cases some generalizations regarding
the dosage can be made. Some descriptions of appropriate unit
dosages of drugs including, but not limited to bupropion,
zonisamide, controlled-release zonisamide and combinations thereof
are disclosed in U.S. Provisional Patent Application No. 60/740,034
entitled CONTROLLED RELEASE FORMULATION OF ZONISIMIDE, filed on
Nov. 28, 2005; and U.S. patent application Ser. No. 11/194,202
entitled COMBINATION OF BUPROPION AND A SECOND COMPOUND FOR
AFFECTING WEIGHT LOSS, filed on Aug. 1, 2005; which are hereby
incorporated by reference in their entireties, and U.S. Patent
Publication Nos. 2005/0215552 and 2006/0079501 mentioned
previously.
[0084] In some embodiments the anticonvulsant is a .gamma.-amino
butyric acid (GABA) inhibitor, a GABA receptor antagonist or a GABA
channel modulator. By "GABA inhibitor" it is meant a compound that
reduces the production of GABA in the cells, reduces the release of
GABA from the cells, or reduces the activity of GABA on its
receptors, either by preventing the binding of GABA to GABA
receptors or by minimizing the effect of such binding. The GABA
inhibitor may be a 5-HT1b agonist or another agent that inhibits
the activity of NPY/AgRP/GABA neurons. In addition, the GABA
inhibitor may suppress the expression of the AgRP gene, or the GABA
inhibitor may suppress the production or release of AgRP. It is,
however, understood that a 5-HT1b agonist may inhibit the
NPY/AgRP/GABA neuron (and therefore activate pro-opiomelanocortin
(POMC) neurons) without acting as an inhibitor of the GABA
pathway.
[0085] In certain other embodiments the GABA inhibitor increases
the expression of the POMC gene. In some of these embodiments, the
GABA inhibitor increases the production or release of POMC protein.
In certain other of these embodiments, the GABA inhibitor increases
the activity on POMC expressing neurons.
[0086] In some embodiments, the GABA inhibitor is topiramate.
Topiramate, whose chemical name is
2,3:4,5-Bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate,
is often used to treat epilepsy, Lennox-Gastaut syndrome (a
disorder causing seizures and developmental delays), neuropathic
pain, bipolar disorder, obesity including reduction of binge
eating, alcoholism, Post Traumatic Stress Disorder, infantile
spasm, bulimia nervosa, or obsessive-compulsive disorder or to
assist smoking cessation or prevent migraines. Generally, initial
doses of topiramate are low and increased in slow steps. The usual
initial dose is 25 to 50 mg daily in 2 single doses. Recommended
increments vary, but are usually between 25 mg and 50 mg every 1 or
2 weeks. Common doses for maintenance treatment include, but are
not limited to doses of approximately 100 to 200 mg daily.
Opioid Receptor Antagonists
[0087] In certain embodiments the opioid antagonist antagonizes a
.mu.-opioid receptor (MOP-R) in a mammal. The mammal may be
selected from the group including, but not limited to mice, rats,
rabbits, guinea pigs, dogs, cats, sheep, goats, cows, primates,
such as monkeys, chimpanzees, and apes, and humans.
[0088] In some embodiments the opioid antagonist is selected from
the group including, but not limited to alvimopan,
norbinaltorphimine, nalmefene, naloxone, naltrexone,
methylnaltrexone, and nalorphine, and pharmaceutically acceptable
salts or prodrugs thereof.
[0089] In other embodiments, the opioid antagonist is a partial
opioid agonist. Compounds of this class have some agonist activity
at opioid receptors. However, because they are weak agonists, they
function as de-facto antagonists. Examples of partial opioid
agonists include, but are not limited to pentacozine,
buprenorphine, nalorphine, propiram, and lofexidine.
[0090] Naltrexone
(17-(cyclopropylmethly)-4,5.alpha.-epoxy-3,14-dihydroxymorphinan-6-one),
shown below, is an opioid receptor antagonist used primarily in the
management of alcohol dependence and opioid dependence.
.mu.-subtype selective opioid antagonists such as naltrexone are
also of considerable current interest as agents for the treatment
of obesity (Glass, M. J.; Billington, C. J.; Levine, A. S.
Neuropeptides 1999, 33, 350) and CNS disorders (Reneric, J. P.;
Bouvard, M. P. CNS Drugs 1998, 10, 365).
[0091] It is marketed as its hydrochloride salt, naltrexone
hydrochloride, under the trade name REVIA.TM.. REVIA.TM. is an
immediate release formulation of naltrexone, with 100 mg strength.
The maximum serum concentration of immediate release naltrexone is
reached very rapidly, typically a T.sub.max of approximately 1
hour. Immediate release naltrexone can induce side effects such as
nausea, which is attributable to the maximum blood plasma
concentration levels (C.sub.max).
[0092] An oral dosage form of naltrexone that is able to effect
naltrexone release at a rate sufficiently slow to ameliorate side
effects, yet sufficiently fast to achieve good bioavailability
would provide a significant improvement in dosing compliance and
convenience. Likewise, an improved dosage form which lowered the
incidence of gastrointestinal side-effects would also be of
significant value.
[0093] In some embodiments, oral dosage forms of naltrexone are
effective to provide an AUC between about 75% to about 125% of 50
mg immediate release naltrexone tablets. In some embodiments oral
dosage forms of naltrexone provide an amount of a retardant
excipient that is effective to provide a C.sub.max that is less
than or equal to about 80% of the C.sub.max of 50 mg immediate
release naltrexone tablets.
[0094] Formulations of controlled- or sustained-release naltrexone
have been disclosed in U.S. Provisional Patent Application Ser. No.
60/811,251, filed Jun. 5, 2006, which is hereby incorporated by
reference in its entirety. In some embodiments, oral dosage forms
of naltrexone are effective to provide an AUC between about 75% to
about 125% of 50 mg immediate release naltrexone tablets. In some
embodiments oral dosage forms of naltrexone comprise an amount of a
retardant excipient that is effective to provide a C.sub.max that
is less than or equal to about 80% of the C.sub.max of 50 mg
immediate release naltrexone tablets.
[0095] Those skilled in the art informed by the guidance provided
herein can formulate oral dosage forms described herein. For
example, one skilled in the art could formulate an oral dosage form
that includes, but is not limited to an amount of naltrexone
effective to provide an AUC between about 75% to about 125% of 50
mg immediate release naltrexone tablets, and an amount of an
appropriate retardant excipient effective to provide a C.sub.max
that is less than or equal to about 80% of the C.sub.max of 50 mg
immediate release naltrexone tablets. Further, given the guidance
provided herein, the skilled artisan could formulate an oral dosage
form having a pharmacodynamic profile characterized by coverage of
greater than or equal to 80% of the opioid receptors in the
hypothalamus.
EXAMPLES
[0096] Below are found specific examples of pharmaceutical
compositions that may be formed into layered pharmaceutical
formulations of the present disclosure.
TABLE-US-00001 TABLE 1 Formulations for Sustained-Release (SR)
Tablets Containing Bupropion 70 mg 90 mg Bupropion SR Bupropion SR
Amount per Amount per Ingredient Tablet Tablet Bupropion HCL, USP
70.0 mg 90.0 mg Microcrystalline Cellulose, 173.3 mg 153.3 mg NF
(Avicel PH 101) Hydroxypropyl Cellulose, 56.7 mg 56.7 mg NF (Klucel
HXF) Cysteine HCL, NF 12.5 mg 12.5 mg Magnesium Stearate, NF 2.5 mg
2.5 mg Tablet Weight 315.0 mg 315.0 mg
TABLE-US-00002 TABLE 2 Formulations for Sustained-Release (SR)
Tablets Containing Zonisamide 30 mg 60 mg 90 mg Zonisamide
Zonisamide Zonisamide SR SR SR Amount per Amount per Amount per
Ingredient Tablet Tablet Tablet Zonisamide 30 mg 60 mg 90 mg Klucel
110 mg 35 mg 35 mg Lactose 55 mg 70 mg 60 mg Colloidal Silicon 2 mg
2 mg 2 mg Dioxide, NF Cross Povidone 20 mg 14 mg 14 mg Magnesium
Stearate, NF 6 mg 6 mg 6 mg Microcrystalline 127 mg 163 mg 143 mg
Cellulose, NF
TABLE-US-00003 TABLE 3 Formulations for Sustained -Release (SR)
Tablets Containing Naltrexone Percent per Percent per Percent per
Tablet Tablet Tablet "12.5% "30% "44% HPMC" HPMC" HPMC" Ingredient
SR-Fast SR-Medium SR-Slow Naltrexone 6.667 6.667 6.667 (5 mg)
Hydroxypropylmethyl 10.000 30.000 44.333 Cellulose (Methocel K15
Premium) Common QBQ01 Placebo 81.733 61.833 47.500 Granulation
Colloidal Silicon Dioxide, NF 1.000 0.500 1.000 (Cab-O-Sil M5P)
Sodium Edetate 0.1 -- -- Magnesium Stearate, NF, 0.500 6.667 0.500
Ph. Eur. (Vegetable Source) (Grade 905-G) 100.000 100.000
100.000
[0097] Thus, as illustrated in Tables 1-3 above, embodiments of
pharmaceutical formulations may comprise controlled-release (e.g.,
sustained release in the illustrated embodiments) formulations of
bupropion, zonisamide and/or naltrexone. In one embodiment, a
layered pharmaceutical formulation is a tablet comprising a first
layer comprising a controlled-release zonisamide and a second layer
comprising a bupropion. In another embodiment a layered
pharmaceutical formulation is a tablet comprising a first layer
comprising a controlled-release naltrexone and a second layer
comprising a controlled-release bupropion. In some embodiments the
first layer and the second layer are separated by an intermediate
layer comprising lactose or other suitable fast-dissolving
ingredient.
[0098] The oral dosage forms of pharmaceutical formulations can, if
desired, be presented in a unit dosage package which may contain
one or more unit dosage forms containing the active ingredient. The
unit dosage package may for example comprise metal or plastic foil,
such as a blister pack. The unit dosage package may be accompanied
by instructions for administration. The unit dosage package may
also be accompanied with a notice associated with the container in
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 notice, for example, may
be the labeling approved by the U.S. Food and Drug Administration
for prescription drugs, or the approved product insert.
Compositions comprising a compound of the disclosure formulated in
a compatible pharmaceutical carrier may also be prepared, placed in
an appropriate container, and labeled for treatment of an indicated
condition.
[0099] Novel methods and systems for administering weight loss
medications are described in co-pending application entitled
METHODS FOR ADMINISTERING WEIGHT LOSS MEDICATIONS filed on the same
day as the present application, which is hereby incorporated by
reference in its entirety.
[0100] In some embodiments, the weight loss medications are
provided at least once, twice or three times a day for a set
period, which can be at least, at least about, less than, less than
about, equal to or between any range within 1, 2, 3, 4, 5, 6, 7, 8,
9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,
26, 27, 28, 29, or 30 consecutive days or at least, at least about,
less than, less than about, equal to or between any range within of
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,
20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 consecutive weeks or
at least, at least about, less than, less than about, equal to or
between any range within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or
30 consecutive months. The amount of drug in any pharmaceutical
formulation described herein includes, but is not limited to
amounts of at least, at least about, less than, less than about,
equal to or between any range within 0.01, 0.02, 0.03, 0.04, 0.05,
0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8,
0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50,
55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 250,
300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900,
950, 1000, 1500, 2000, 3000, 4000 or 5000 mg.
[0101] In one embodiment a layered pharmaceutical formulation for
the administration of two or more active pharmaceutical ingredients
comprises a first pharmaceutical layer comprising a first active
pharmaceutical ingredient, a second pharmaceutical layer comprising
a second active pharmaceutical ingredient and at least one
intermediate layer disposed between the first and the second
pharmaceutical layers, wherein the at least one intermediate layer
is configured to dissolve in vivo to thereby leave the first and
the second pharmaceutical layers substantially intact.
[0102] In some embodiments each of the first and the second
pharmaceutical layers comprises a dissolution profile substantially
similar to a singularly compressed tablet of a similar composition.
In some embodiments each of the first and the second pharmaceutical
layers comprises a different pharmaceutical composition. In some
embodiments at least one of the first and the second pharmaceutical
layers comprises a controlled-release pharmaceutical composition.
In some embodiments the controlled-release pharmaceutical
composition comprises a sustained release pharmaceutical
composition.
[0103] In some embodiments at least one of the first and the second
pharmaceutical layers comprises zonisamide. In some embodiments the
zonisamide comprises a controlled-release zonisamide. In some
embodiments the controlled-release zonisamide comprises a
sustained-release zonisamide. In some embodiments at least one of
the first and the second pharmaceutical layers comprises bupropion.
In some embodiments the bupropion comprises a controlled-release
bupropion. In some embodiments the controlled-release bupropion
comprises a sustained-release bupropion. In some embodiments at
least one of the first and the second pharmaceutical layers
comprises naltrexone. In some embodiments at least one of the first
and the second pharmaceutical layers comprises fluoxetine.
[0104] In some embodiments at least one of the first and the second
pharmaceutical layers comprises olanzapine. In some embodiments at
least one of the first and the second pharmaceutical layers
comprises an antidiabetic. In some embodiments the antidiabetic
comprises metformin. In some embodiments at least one of the first
and the second pharmaceutical layers comprises topiramate. In some
embodiments at least one of the first and the second pharmaceutical
layers comprises phentermine. In some embodiments the at least one
intermediate layer comprises at least one of a monosaccharide
sugar, a disaccharide sugar, or a starch. In some embodiments the
at least one intermediate layer comprises lactose.
[0105] In one embodiment a method for affecting weight loss,
suppressing appetite and/or treating an obesity-related condition
in a patient comprises providing a first dosage of the layered
pharmaceutical formulation to a patient in need thereof on a first
day and providing a second dosage of the layered pharmaceutical
formulation to the patient on a second day. In some embodiments the
first dosage is greater than the second dosage. In some embodiments
the second dosage is greater than the first dosage.
[0106] In one embodiment a method for treating an obesity related
condition in a patient comprises identifying a patient with an
obesity related condition or at risk of an obesity related
condition comprises providing a first dosage of the layered
pharmaceutical formulation of claim 1 to the patient on a first day
and providing a second dosage of the layered pharmaceutical
formulation to the patient on a second day. In some embodiments the
first dosage is different than the second dosage. In some
embodiments the second dosage is greater than the first dosage.
[0107] In one embodiment use of a first compound and a second
compound in the formulation of a medicament for affecting weight
loss, suppressing appetite or treating an obesity-related
condition, wherein the medicament comprises a layered
pharmaceutical formulation of the present invention.
[0108] It will be appreciated by those skilled in the art that
various modifications and changes can be made without departing
from the scope of the disclosure. Such modifications and changes
are intended to fall within the scope of the disclosure, as defined
by the appended claims.
* * * * *