U.S. patent application number 16/524495 was filed with the patent office on 2020-02-20 for extended-release topiramate capsules.
The applicant listed for this patent is UPSHER-SMITH LABORATORIES, LLC. Invention is credited to Sarah Michelle Betterman, Laura Marie Patrick, Jaidev Srinivas Tantry.
Application Number | 20200054570 16/524495 |
Document ID | / |
Family ID | 50072106 |
Filed Date | 2020-02-20 |
United States Patent
Application |
20200054570 |
Kind Code |
A1 |
Betterman; Sarah Michelle ;
et al. |
February 20, 2020 |
EXTENDED-RELEASE TOPIRAMATE CAPSULES
Abstract
An extended-release topiramate capsule that includes a capsule
shell containing a single population of coated particles; wherein
each coated particle includes a core and a coating thereon; wherein
each particle core includes a homogeneous mixture comprising
topiramate throughout its core; and wherein the coating includes
one or more release controlling agent(s).
Inventors: |
Betterman; Sarah Michelle;
(Champlin, MN) ; Tantry; Jaidev Srinivas; (Maple
Grove, MN) ; Patrick; Laura Marie; (Eden Prairie,
MN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
UPSHER-SMITH LABORATORIES, LLC |
Maple Grove |
MN |
US |
|
|
Family ID: |
50072106 |
Appl. No.: |
16/524495 |
Filed: |
July 29, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15677286 |
Aug 15, 2017 |
10363224 |
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16524495 |
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14775105 |
Sep 11, 2015 |
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PCT/US14/10284 |
Jan 6, 2014 |
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15677286 |
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61788880 |
Mar 15, 2013 |
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61779576 |
Mar 13, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 493/14 20130101;
A61K 9/2866 20130101; A61K 31/357 20130101; C07D 493/12 20130101;
A61K 9/16 20130101; A61K 9/5047 20130101; A61K 9/50 20130101; A61K
9/4891 20130101; A61P 25/08 20180101; Y10S 514/963 20130101; A61K
9/28 20130101; A61K 31/7048 20130101; C07D 311/02 20130101; Y10S
514/964 20130101 |
International
Class: |
A61K 9/50 20060101
A61K009/50; A61K 31/7048 20060101 A61K031/7048; A61K 31/357
20060101 A61K031/357; A61K 9/48 20060101 A61K009/48; C07D 493/14
20060101 C07D493/14; A61K 9/16 20060101 A61K009/16 |
Claims
1.-30. (canceled)
31. A method of dosing a subject for the prophylactic treatment of
a migraine, the method comprising: administering an
extended-release topiramate capsule once daily to the subject,
wherein the extended-release topiramate capsule comprises: a
capsule shell comprising a single population of coated particles;
wherein each coated particle comprises a core and a coating
thereon; wherein each particle core comprises a homogeneous mixture
comprising topiramate throughout its core; and wherein the coating
comprises one or more release controlling agent(s); wherein the
extended-release topiramate capsule, when given as a single-dose to
a healthy human subject, achieves an AUC.sub.0-inf of 170 to 210
h.cndot..mu.g/mL within a 95% confidence interval, and a C.sub.max
of 2 to 4 .mu.g/mL within a 95% confidence interval.
32. The method of claim 31 wherein the extended-release topiramate
capsule, when dosed to a healthy human subject once daily, achieves
at steady-state, an AUC.sub.0-24h, C.sub.max, and C.sub.min in the
subject's plasma that are within the 80% to 125% bioequivalence
criteria compared to immediate-release topiramate dosed twice per
day.
33. The method of claim 31 wherein the extended-release topiramate
capsule, when dosed to a healthy human subject once daily in the
morning, achieves at steady-state, a reduction of fluctuation index
of at least 15% compared to immediate-release topiramate dosed
twice per day.
34. The method of claim 31 wherein the extended-release topiramate
capsule, when dosed to a healthy human subject once daily in the
morning, achieves at steady-state, a C.sub.min in the subject's
plasma that is higher than the C.sub.min compared to
immediate-release topiramate dosed twice per day.
35. The method of claim 31 wherein the administering occurs once
daily in the morning.
36. The method of claim 31 wherein the administering occurs once
daily in the evening.
37. The method of claim 31 wherein the extended-release topiramate
capsule is free of an immediate release component.
38. The method of claim 31 wherein: each particle core comprises a
homogeneous mixture comprising: topiramate; one or more filler(s);
and one or more binder(s); and the coating comprises: one or more
release controlling agent(s); one or more pore former(s); and one
or more plasticizer(s).
39. The method of claim 38 wherein the one or more filler(s) is
selected from the group of microcrystalline cellulose, dibasic
calcium phosphate, lactose, tribasic calcium phosphate, mannitol,
and combinations thereof.
40. The method of claim 38 wherein the one or more binder(s) is
selected from the group of hydroxypropyl methylcellulose,
methylcellulose, carboxymethylcellulose, sodium
carboxymethylcellulose, hydroxypropyl cellulose,
hydroxyethylcellulose, polyvinyl pyrrolidine, starch, natural gum,
and combinations thereof.
41. The method of claim 38 wherein the one or more release
controlling agent(s) is selected from the group of ethylcellulose,
polyvinyl acetate, polyacrylate and polymethacrylate, copolymers
thereof, and combinations thereof.
42. The method of claim 38 wherein the one or more pore former(s)
is selected from the group of hypromellose, hydroxypropyl
cellulose, methylcellulose, hydroxyethylcellulose,
carboxymethylcellulose, sodium carboxymethylcellulose, polyethylene
glycol, guar gum, xanthan gum, sodium alginate,
polyvinylpyrrolidone, crospovidone, sodium starch glycolate,
croscarmellose sodium, starch, mannitol, glucose, sucrose,
fructose, mannose, galactose, sorbitol, dextran, sodium chloride,
potassium chloride, calcium chloride, and combinations thereof.
43. The method of claim 38 wherein the one or more plasticizer(s)
is selected from the group of diethyl phthalate, triethyl citrate,
dibutyl sebacate, polyethylene glycol, triacetin, tributyl citrate,
glycerol, propylene glycol, and combinations thereof.
44. The method of claim 38 wherein each particle core further
comprises one or more stabilizer(s).
45. The method of claim 44 wherein the one or more stabilizer(s) is
selected from the group of calcium hydroxide, calcium carbonate,
sodium bicarbonate, magnesium carbonate, and combinations
thereof.
46. The method of claim 38 wherein the extended-release topiramate
capsule comprises 40 wt-% to 50 wt-% of topiramate, based on the
total weight of an uncoated particle core.
47. The method of claim 38 wherein the extended-release topiramate
capsule comprises 3 wt-% to 7 wt-% of one or more binder(s), based
on the total weight of an uncoated particle core.
48. The method of claim 38 wherein the extended-release topiramate
capsule comprises 55 wt-% to 65 wt-% of one or more release
controlling agent(s), based on the total weight of the coating.
49. The method of claim 38 wherein the extended-release topiramate
capsule comprises 20 wt-% to 25 wt-% of one or more pore former(s),
based on the total weight of the coating.
50. The method of claim 38 wherein the extended-release topiramate
capsule comprises 10 wt-% to 20 wt-% of one or more plasticizer(s),
based on the total weight of the coating.
Description
CONTINUING APPLICATION DATA
[0001] This application claims the benefit of U.S. Provisional
Application Ser. No. 61/779,576, filed Mar. 13, 2013, and also
claims the benefit of U.S. Provisional Application Ser. No.
61/788,880, filed Mar. 15, 2013, each of which is incorporated by
reference herein.
BACKGROUND
[0002] The pharmaceutical industry employs a variety of dosage
formulations for orally administering medicinal agents to patients.
Typical formulations for oral administration include liquid
solutions, emulsions, or suspensions, as well as solid forms such
as capsules or tablets (as used herein, the term "tablet" means any
shaped and compressed solid dosage form, including caplets).
[0003] Efficacy of a drug product often depends on patient
compliance with a dosing schedule. Therefore, one per day,
extended-release, dosages have better efficacy over the long term
than multidose regimens.
SUMMARY
[0004] The present disclosure provides solid dosage formulations of
topiramate [2,3:4,5-bis-O-(1-methylethylidene)
-.beta.-D-fructopyranose sulfamate], particularly capsules,
containers including such capsules, and methods of dosing.
[0005] In one embodiment, the present disclosure provides an
extended-release formulation that is dosed once-per-day, in the
form of a capsule.
[0006] In one embodiment, the present disclosure provides an
extended-release topiramate capsule that includes a capsule shell
and a single population of coated particles contained within the
capsule shell, wherein each coated particle includes a core and a
coating thereon. In certain embodiments, the particles, whether
coated or uncoated, are spherical.
[0007] Each particle core includes a homogeneous mixture including
topiramate throughout the core. In certain embodiments, each
particle core also includes a filler and/or a binder (preferably,
both a filler and a binder) in the homogeneous mixture.
[0008] The coating includes a release controlling agent. In certain
embodiments, the coating also includes a pore former and/or a
plasticizer.
[0009] In one embodiment, an extended-release topiramate capsule is
provided that includes: a capsule shell containing a single
population of coated particles; wherein each coated particle
includes a core and a coating thereon; wherein each particle core
includes a homogeneous mixture throughout its core, the mixture
including: 40 wt-% to 50 wt-% of topiramate, based on the total
weight of an uncoated particle core; 45 wt-% to 55 wt-% of one or
more filler(s), based on the total weight of an uncoated particle
core; and 3 wt-% to 7 wt-% of one or more binder(s), based on the
total weight of an uncoated particle core; wherein the coating
includes: 55 wt-% to 65 wt-% of one or more release control
agent(s), based on the total weight of the coating; 20 wt-% to 25
wt-% of one or more pore former(s), based on the total weight of
the coating; and 10 wt-% to 20 wt-% of one or more plasticizer(s),
based on the total weight of the coating; wherein the particles are
coated in an amount sufficient to provide a (coating)weight gain of
8% to 14%.
[0010] As used herein, the terms "topiramate active agent" and
"active agent of topiramate" and "topiramate" are synonymous and
are used interchangeably throughout the specification to refer to
the compound
2,3:4,5-bis-O-(1-methylethylidene)-.beta.-D-fructopyranose
sulfamate. Included within these terms are also pharmaceutically
acceptable salts thereof as well as polymorphs, solvates, hydrates,
dehydrates, co-crystals, anhydrous, and amorphous forms
thereof.
[0011] The term "extended-release" means release of an active agent
over a period of time, which is much longer than the release from
an immediate release formulation, which usually releases more than
80% of the active agent in 60 minutes or less.
[0012] The term "therapeutically effective amount" as used herein
means that amount of active compound that elicits the biological or
medicinal response in a tissue, system, animal or human that is
being sought by a researcher, veterinarian, medical doctor or other
clinician, which includes alleviation and/or prevention of the
symptoms of the condition being treated.
[0013] The terms "comprises" and variations thereof do not have a
limiting meaning where these terms appear in the description and
claims. Such terms will be understood to imply the inclusion of a
stated step or element or group of steps or elements but not the
exclusion of any other step or element or group of steps or
elements. By "consisting of" is meant including, and limited to,
whatever follows the phrase "consisting of." Thus, the phrase
"consisting of" indicates that the listed elements are required or
mandatory, and that no other elements may be present. By
"consisting essentially of" is meant including any elements listed
after the phrase, and limited to other elements that do not
interfere with or contribute to the activity or action specified in
the disclosure for the listed elements. Thus, the phrase
"consisting essentially of" indicates that the listed elements are
required or mandatory, but that other elements are optional and may
or may not be present depending upon whether or not they materially
affect the activity or action of the listed elements.
[0014] The words "preferred" and "preferably" refer to embodiments
of the disclosure that may afford certain benefits, under certain
circumstances. However, other embodiments may also be preferred,
under the same or other circumstances. Furthermore, the recitation
of one or more preferred embodiments does not imply that other
embodiments are not useful, and is not intended to exclude other
embodiments from the scope of the disclosure.
[0015] As used herein, "a," "an," "the," "at least one," and "one
or more" are used interchangeably. Thus, for example, a particle
core that comprises "a" binder can be interpreted to mean that the
particle core includes "one or more" binders. Similarly, a coating
comprising "a" pore former can be interpreted to mean that the
composition includes "one or more" pore formers.
[0016] As used herein, the term "or" is generally employed in its
usual sense including "and/or" unless the content clearly dictates
otherwise.
[0017] The term "and/or" means one or all of the listed elements or
a combination of any two or more of the listed elements (e.g.,
preventing and/or treating an affliction means preventing,
treating, or both preventing and treating an affliction).
[0018] Also herein, all numbers are assumed to be modified by the
term "about" and preferably by the term "exactly." As used herein
in connection with a measured quantity, the term "about" refers to
that variation in the measured quantity as would be expected by the
skilled artisan making the measurement and exercising a level of
care commensurate with the objective of the measurement and the
precision of the measuring equipment used.
[0019] Also herein, the recitations of numerical ranges by
endpoints include all numbers subsumed within that range as well as
the endpoints (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4,
5, etc.). Herein, "up to" a number (e.g., up to 50) includes the
number (e.g., 50).
[0020] The above summary of the present disclosure is not intended
to describe each disclosed embodiment or every implementation of
the present disclosure. The description that follows more
particularly exemplifies illustrative embodiments. In several
places throughout the application, guidance is provided through
lists of examples, which examples can be used in various
combinations. In each instance, the recited list serves only as a
representative group and should not be interpreted as an exclusive
list.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0021] The present disclosure provides solid dosage formulations of
topiramate [2,3:4,5-bis-O-(1-methylethylidene)
-.beta.-D-fructopyranose sulfamate]. Such solid dosage formulations
are extended-release once-per-day dosage capsules (i.e., designed
for administration once per day).
[0022] In one embodiment, the present disclosure provides an
extended-release topiramate capsule that includes a capsule shell
and a single population of coated particles contained within the
capsule shell. In this context, "a single population" means that
all the particles in one capsule are the same (within reasonable
manufacturing variability) with respect to composition. In this
context, "same" means the particles in one capsule are made in a
single batch process or in multiple batches using identical
processes.
[0023] The use of a single population of particles in any one
capsule provides significant advantages from a manufacturing (e.g.,
quality and cost) perspective. For example, different populations
of particles (e.g., beads), having different compositions, do not
need to be manufactured for one product.
[0024] Furthermore, in certain embodiments, the capsules of the
present disclosure do not include an immediate release component in
any significant amount. Typically, capsules of the present
invention are free of an immediate-release component.
[0025] Each coated particle includes a core and a coating thereon.
In certain embodiments, the particles, whether coated or uncoated,
are spherical, as defined in greater detail below.
[0026] Each particle core includes a homogeneous mixture including
topiramate throughout the core. In certain embodiments, each
particle core also includes a filler and/or a binder (preferably,
both a filler and a binder) in the homogeneous mixture.
[0027] The coating on each core includes a release controlling
agent. In certain embodiments, the coating also includes a pore
former and/or a plasticizer.
[0028] In one embodiment, the present disclosure provides a solid
dosage formulation that includes a capsule including core particles
with a coating thereon. The core particles include the active
agent. The core particles can also include a filler and/or a binder
(preferably, both a filler and a binder). The coating includes a
release-controlling agent. The coating can also include a pore
former and/or a plasticizer.
[0029] In certain embodiments, the particles, whether coated or
uncoated, are spherical. In this context, the term "spherical"
refers to particles that are generally rounded by visual
inspection. They may or may not be perfectly spherical. A
representative population of spherical particles (i.e., beads)
typically has an average sphericity of at least 0.7. In certain
embodiments, the average sphericity of a representative population
of particles is at least 0.75, and in certain embodiments at least
0.8. A preferred sphericity is 0.8. Sphericity can be determined by
use of a digital microscope and a two-dimensional image analysis
software (e.g., such as that by Soft Imaging System GmbH, version
5.0 Build 1054).
[0030] In certain embodiments, the particle size (which is
typically the diameter of a spherical particle) of the coated
particles is at least 500 .mu.m (microns). In certain embodiments,
the particle size of the coated particles is up to 1300 .mu.m. In
certain embodiments, the majority of the particles in a capsule are
typically in a range of 700 .mu.m to 1000 .mu.m.
[0031] The rate of particle dissolution is typically dependent on
the coating weight, which can be adjusted during manufacture. In
certain embodiments, the particles are coated in an amount
sufficient to provide a weight gain of at least 2%, or at least 4%,
or at least 6%, or at least 8%, or at least 9%, or at least 10%. In
certain embodiments, the particles are coated in an amount
sufficient to provide a weight gain of up to 30%, or up to 25%, or
up to 20%, or up to 15%, or up to 12%. Preferably, the particles
are coated in an amount sufficient to provide a weight gain of 10%
to 12%. In certain embodiments, the particles are coated in an
amount sufficient to provide a weight gain of 8% to 14%.
[0032] In this context, "weight gain" is defined as the theoretical
weight gain of a population of particles as a result of coating,
assuming 100% coating efficiency. Thus, "weight gain" refers to
coating weight gain. As an example, 100 grams of uncoated particles
(e.g., beads) coated to a theoretical weight gain of 8% means that
an amount of coating solution having 8 grams (g) of non-volatile
components, e.g., release controlling agent, pore former, and
plasticizer, was applied to the uncoated beads in a coating step,
but there may be some losses in the manufacturing process.
[0033] Suitable active agents within the particle core include
topiramate (2,3:4,5-bis-O-(1-methylethylidene)
-.beta.-D-fructopyranose sulfamate). "Topiramate" refers to
2,3:4,5-bis-O-(1-methylethylidene) -.beta.-D-fructopyranose
sulfamate as well as pharmaceutically acceptable salts of
topiramate, including without limitation, topiramate sodium,
topiramate lithium, topiramate potassium, as well as polymorphs,
solvates, hydrates, dehydrates, co-crystals, anhydrous, and
amorphous forms thereof. Topiramate can be purchased from
commercial sources. It is presently available for marketing as an
immediate-release tablet product (as TOPAMAX) for certain seizure
indications and migraine prophylaxis.
[0034] An amount of topiramate active agent is included within a
capsule in an amount sufficient to deliver the desired dose.
Alternatively stated, a therapeutically effective amount of
topiramate is included within a capsule. A capsule can include a
topiramate active agent in an amount of at least 10 weight percent
(wt-% or % w/w), or at least 25 wt-%, or at least 35 wt-%, or at
least 40 wt-%, or at least 44 wt-%, based on the total weight of an
uncoated particle core. A capsule can include a topiramate active
agent in an amount of up to 80 wt-%, or up to 50 wt-%, or up to 46
wt-%, based on the total weight of an uncoated particle core. In
certain embodiments, the particle cores of the capsules of the
present disclosure include 40 wt-% to 50 wt-% topiramate active
agent, based on the total weight of an uncoated particle core. In
certain embodiments, the particle cores of the capsules of the
present disclosure include 44 wt-% to 46 wt-% topiramate active
agent, based on the total weight of an uncoated particle core.
[0035] The active agent can be homogeneously mixed within a
particle core that includes one or more fillers and/or binders. One
or more stabilizers can also be included in the particle core.
Inclusion of a stabilizer may help maintain the potency of
topiramate over time.
[0036] Herein, for any component specified, if there are multiple
grades (e.g., molecular weights) of such component, recitation of
the component implies any or all of such variations.
[0037] Suitable fillers for use in the particle cores include, but
are not limited to, microcrystalline cellulose, dibasic calcium
phosphate, lactose, tribasic calcium phosphate, mannitol, other
suitable carbohydrates (e.g., other sugars or starches).
Combinations of fillers can be used if desired. Preferably,
microcrystalline cellulose is used as a filler (such as that
available from JRS Pharma under the trade designation EMCOCEL
90M).
[0038] One or more fillers can be used in an amount of at least 10
wt-%, or at least 25 wt-%, or at least 45 wt-%, or at least 48
wt-%, based on the total weight of the uncoated particle core. One
or more fillers can be used in an amount of up to 85 wt-%, or up to
75 wt-%, or up to 55 wt-%, or up to 52 wt-%, based on the total
weight of the uncoated particle core. In certain embodiments, the
particle cores of the capsules of the present disclosure include 45
wt-% to 55 wt-% filler(s), based on the total weight of an uncoated
particle core. In certain embodiments, the particle cores of the
capsules of the present disclosure include 48 wt-% to 52 wt-%
filler(s), based on the total weight of an uncoated particle
core.
[0039] Suitable binders for use in the particle core include, but
are not limited to, hydroxypropyl methylcellulose (i.e.,
hypromellose or "HPMC"), methylcellulose, carboxymethylcellulose,
sodium carboxymethylcellulose, hydroxypropyl cellulose,
hydroxyethylcellulose, polyvinyl pyrrolidine (i.e., povidone),
starch (e.g., pregelatinized starch), and natural gum (e.g., acacia
gum, sodium alginate, guar gum, xanthan gum). Combinations of
binders can be used if desired. Preferably, hydroxypropyl
methylcellulose (hypromellose 2910) is used as a binder (such as
that available from The Dow Chemical Company under the trade
designation METHOCEL E5 Premium).
[0040] One or more binders can be used in an amount of at least 1
wt-%, or at least 2 wt-%, or at least 3 wt-%, or at least 4 wt-%,
based on the total weight of the uncoated particle core. One or
more binders can be used in an amount of up to 10 wt-%, or up to 9
wt-%, or up to 8 wt-%, or up to 7 wt-%, or up to 6 wt-%, based on
the total weight of the uncoated particle core. In certain
embodiments, the particle cores of the capsules of the present
disclosure include 3 wt-% to 7 wt-% binder(s), based on the total
weight of an uncoated particle core. In certain embodiments, the
particle cores of the capsules of the present disclosure include 4
wt-% to 6 wt-% binder(s), based on the total weight of an uncoated
particle core.
[0041] Particles described herein can further include a stabilizer,
preferably in the core. Suitable stabilizers for use in the
particle core include, but are not limited to, calcium hydroxide,
calcium carbonate, sodium bicarbonate, magnesium carbonate, and
other alkali or alkaline earth metal hydroxides and carbonates.
Combinations of stabilizers can be used if desired. Preferably,
calcium carbonate is used as a stabilizer.
[0042] One or more stabilizers can be used in an amount of at least
1 wt-%, or at least 2 wt-%, based on the total weight of the
particle core. One or more stabilizers can be used in an amount of
up to 10 wt-%, or up to 5 wt-%, based on the total weight of the
particle core. In certain embodiments, the particle cores of the
capsules of the present disclosure include 2 wt-% to 10 wt-%
stabilizer(s), based on the total weight of an uncoated particle
core.
[0043] Suitable release controlling agents for use in the coating
on the particle core include, but are not limited to,
ethylcellulose, polyvinyl acetate, polyacrylate and
polymethacrylate (e.g., Ammonio Methacrylate Copolymer, Type A and
Type B; Ethyl Acrylate and Methyl Methacrylate Copolymer), and
copolymers thereof. Combinations of release controlling agents can
be used if desired. Preferably, ethylcellulose (such as that
available from The Dow Chemical Company under the trade designation
ETHOCEL Standard 10 Premium) is used as a release controlling
agent.
[0044] One or more release controlling agents can be used in an
amount of at least 45 wt-%, or at least 50 wt-%, or at least 55
wt-%, or at least 60 wt-%, based on the total weight of the
coating. One or more release controlling agents can be used in an
amount of up to 80 wt-%, or up to 70 wt-%, or up to 65 wt-%, or up
to 62 wt-%, based on the total weight of the coating. In certain
embodiments, the particle coatings include 55 wt-% to 65 wt-%
release control agent(s), based on the total weight of the coating.
In certain embodiments, the particle coatings include 60 wt-% to 62
wt-% release control agent(s), based on the total weight of the
coating.
[0045] Herein, "based on the total weight of the coating" means the
total weight of the non-volatile components of the coating (e.g.,
release controlling agent, pore former, and plasticizer).
[0046] Pore formers that are suitable for use in the coating
formulation include, but are not limited to, hypromellose,
hydroxypropyl cellulose, methylcellulose, hydroxyethylcellulose,
carboxymethylcellulose, sodium carboxymethylcellulose, polyethylene
glycol, guar gum, xanthan gum, sodium alginate, povidone (i.e.,
polyvinylpyrrolidone), crospovidone, sodium starch glycolate,
croscarmellose sodium, starch (e.g., pregelatinized starch),
carbohydrates (e.g., mannitol, glucose, sucrose, fructose, mannose,
galactose, sorbitol, and dextran), sodium chloride, potassium
chloride, and calcium chloride. Preferred pore formers for use in
the coating on the particle core include, but are not limited to,
hydroxypropyl methylcellulose ("HPMC" such as hypromellose 2910 USP
available under the trade name METHOCEL E5 Premium, METHOCEL E15
Premium), carboxymethylcellulose, methylcellulose, croscarmellose
sodium, povidone, sodium starch glycolate, starch (e.g.,
pregelatinized starch), alginic acid, guar gum, and polyethylene
glycol. Combinations of pore formers can be used if desired.
Preferably, hydroxypropyl methylcellulose (hypromellose 2910) is
used as a pore former (such as that available from The Dow Chemical
Company under the trade designation METHOCEL E5 Premium).
[0047] One or more pore formers can be used in an amount of at
least 5 wt-%, or at least 10 wt-%, or at least 15 wt-%, or at least
20 wt-%, or at least 22 wt-%, based on the total weight of the
coating. One or more pore formers can be used in an amount of up to
30 wt-%, or up to 26 wt-%, or up to 25 wt-%, or up to 24 wt-%,
based on the total weight of the coating. In certain embodiments,
the particle coatings include 20 wt-% to 25 wt-% pore former(s),
based on the total weight of the coating. In certain embodiments,
the particle coatings include 22 wt-% to 24 wt-% pore former(s),
based on the total weight of the coating.
[0048] Suitable plasticizers for use in the coating on the particle
core include, but are not limited to, diethyl phthalate, triethyl
citrate, dibutyl sebacate, polyethylene glycol, triacetin, tributyl
citrate, glycerol, and propylene glycol. Combinations of
plasticizers can be used if desired. Preferably, diethyl phthalate
is used as a plasticizer.
[0049] One or more plasticizers can be used in an amount of at
least 5 wt-%, or at least 10 wt-%, or at least 15 wt-%, based on
the total weight of the coating. One or more plasticizers can be
used in an amount of up to 30 wt-%, or up to 20 wt-%, or up to 18
wt-%, based on the total weight of the coating. In certain
embodiments, the particle coatings include 10 wt-% to 20 wt-%
plasticizer(s), based on the total weight of the coating. In
certain embodiments, the particle coatings include 15 wt-% to 18
wt-% plasticizer(s), based on the total weight of the coating.
[0050] The coating solution typically includes the "solids" or
non-volatile components (e.g., ethylcellulose, hypromellose 2910
and diethyl phthalate) along with solvents, such as a mixture of
alcohol and water, such that the concentration of the non-volatile
components in the coating solution is 5 wt-% to 10 wt-%. In an
exemplary solution, the solvents are dehydrated alcohol and
purified water in a weight ratio of 3.7:1.
[0051] Particles can be coated with a coating composition as
described herein using conventional techniques known to one of
skill in the art. Briefly, such coating techniques include
bottom-spray fluid-bed coating (e.g., Wurster), top-spray fluid-bed
coating, and tangential-spray fluid-bed coating. Typically, such
methods result in a coating that is substantially uniform on each
individual particle.
[0052] An amount of coated particles sufficient to deliver the
desired dose may be encapsulated into a capsule of any desirable
size, for example, a size 000, 00, 0el, 0, 1, 2, 3, 4, or 5.
[0053] Components of a suitable capsule shell include, but are not
limited to, hydroxypropyl methylcellulose and gelatin. Preferably,
a capsule shell is a hydroxypropyl methylcellulose (HPMC) shell
(e.g., at least 90 wt-% HPMC, based on the weight of the shell).
Typically, commercially available HPMC capsules include small
amounts of water, colorants (e.g., TiO.sub.2 and iron oxides), and
optionally gelling agents and gelling promoters. They have
relatively low moisture content, making them suitable for
moisture-sensitive materials. Such capsules resist breakage even at
low moisture levels. HPMC capsules typically exhibit low solubility
in ethanol, particularly in acidic media such as found in the
stomach. Encapsulation of the particles of the present disclosure
in such an HPMC capsule shell preferably reduces dose dumping (and
immediate release) of topiramate from the coated particles (see
"Alcohol Dose Dumping" experiment in the Examples Section).
[0054] The chemical stability of capsules of the present disclosure
typically depends on humidity and/or water activity. Thus, it can
be desirable to reduce exposure to excessive moisture during
storage. This can be done, for example, by storing the capsules of
the present disclosure in a container, particularly a sealed
container that includes a desiccant. If a desiccant is used, the
ratio of weight of desiccant to weight of filled capsules can be at
least 0.01, or at least 0.1, or at least 0.25, and can be up to
0.9.
[0055] Suitable containers include, for example, high density
polyethylene (HDPE). Such containers can be bottles with screw
caps, or the like. Preferably, such bottles are sealed,
particularly induction sealed, in addition to a boundary layer
provided by the screw cap.
[0056] Suitable desiccants include, for example, silica gel,
bentonite clay, and molecular sieve. Combinations of desiccants can
be used if desired.
[0057] Capsules of the present disclosure are preferably chemically
stable. That is, capsules of the present disclosure retain a
potency of at least 90% after a given time period of storage in a
sealed container at 25.degree. C. and 60% relative humidity (RH).
They also demonstrate little or no decomposition after a given time
period such that no more than 2000 parts per million (ppm) each of
sulfate or sulfamate decomposition products are produced (see
Examples Section). In this context, the given time period is
preferably at least 12 months (typically, without any packaging),
or at least 24 months (potentially, without any packaging, although
packaging, e.g., sealed container and desiccant as described herein
would be preferred to achieve chemical stability for this length of
time), or at least 36 months (typically, with packaging, e.g.,
sealed container and desiccant as described herein).
[0058] The present disclosure also provides methods of dosing a
subject in need thereof. Such dosing could be for the treatment of
convulsions (e.g., convulsions associated with epilepsy). Such
dosing could be for prophylactic treatment, for example, of a
migraine. Such dosing methods include administering a topiramate
capsule. In certain embodiments, once-per-day dosing of the capsule
of the present disclosure occurs in the morning. In certain
embodiments, once-per-day dosing of the capsule of the present
disclosure occurs in the evening.
[0059] In certain embodiments, the extended-release topiramate
capsules of the present disclosure, when dosed to a healthy human
subject once daily (e.g., in the morning or evening), achieves at
steady-state, an AUC.sub.0-24h, C.sub.max, and C.sub.min in the
subject's plasma that are within the 80% to 125% bioequivalence
criteria compared to immediate-release topiramate dosed twice per
day (where the once-daily dose contains 2.times. the topiramate
active agent as the individual immediate-release doses).
[0060] In this context, two treatments are bioequivalent at steady
state (i.e., they are not different from one another) if the 90%
confidence interval (CI) of the least squares geometric mean of one
formulation-to-another formulation (e.g., capsules of the present
disclosure to once-daily dose topiramate) ratio for each
pharmacokinetic (PK) parameter (e.g., AUC.sub.0-24h, C.sub.max, and
C.sub.min) is completely contained within the 80-125% interval.
[0061] In certain embodiments, the extended-release topiramate
capsules of the present disclosure, when dosed to a healthy human
subject once daily in the morning, achieves at steady-state, a
reduction of fluctuation index of at least 15% compared to
immediate-release topiramate dosed twice per day. In certain
embodiments, the reduction of fluctuation index is at least 20%
compared to immediate-release topiramate dosed twice per day. In
certain embodiments, the reduction of fluctuation index is at least
25% compared to immediate-release topiramate dosed twice per
day.
[0062] In certain embodiments, the extended-release topiramate
capsules of the present disclosure, when dosed to a healthy human
subject once daily in the morning, achieves at steady-state, a
C.sub.minin the subject's plasma that is higher than the C.sub.min
compared to immediate-release topiramate dosed twice per day.
[0063] In certain embodiments, the extended-release topiramate
capsules of the present disclosure, when given as a single-dose to
a healthy human subject, achieves an AUC.sub.0-inf of 170 to 210
h.cndot..mu.g/mL within a 95% confidence interval, and a C.sub.max
of 2 to 4 .mu.g/mL within a 95% confidence interval.
[0064] Capsules of the present disclosure demonstrate a reduced
level of side effects compared to other topiramate products. For
example, in certain embodiments, the extended-release topiramate
capsules of the present disclosure, when dosed once daily to a
population of human patients suffering from epilepsy, achieves a
reduction in incidence of at least one side effect compared to
immediate-release topiramate dosed at the same total daily dose
divided twice per day. This comparison is based on the
extended-release topiramate capsules of the present disclosure
compared to placebo, and the immediate-release topiramate (TOPAMAX)
compared to placebo. The term "incidence" refers to the percentage
of patients who experience a new side effect during the study. The
at least one side effect includes somnolence, dizziness, ataxia,
disturbance in attention, memory impairment, cognitive disorder,
and psychomotor slowing.
LIST OF EXEMPLARY EMBODIMENTS
[0065] 1. An extended-release topiramate capsule comprising:
[0066] a capsule shell comprising (or consisting essentially of, or
consisting of) a single population of coated particles; [0067]
wherein each coated particle comprises a core and a coating
thereon; [0068] wherein each particle core comprises a homogeneous
mixture comprising topiramate throughout its core; and [0069]
wherein the coating comprises one or more release controlling
agent(s). 2. The capsule of embodiment 1 wherein:
[0070] each particle core comprises a homogeneous mixture
comprising: [0071] topiramate; [0072] one or more filler(s); and
[0073] one or more binder(s); and [0074] the coating comprises:
[0075] one or more release controlling agent(s); [0076] one or more
pore former(s); and [0077] one or more plasticizer(s). 3. An
extended-release topiramate capsule comprising (or consisting
essentially of, or consisting of):
[0078] a capsule shell comprising (or consisting essentially of, or
consisting of) a single population of coated particles; [0079]
wherein each coated particle comprises (or consists essentially of,
or consists of) a core and a coating thereon; [0080] wherein each
particle core comprises (or consists essentially of, or consists
of) a homogeneous mixture throughout its core, the mixture
comprising (or consisting essentially of, or consisting of): [0081]
40 wt-% to 50 wt-% of topiramate, based on the total weight of an
uncoated particle core; [0082] 45 wt-% to 55 wt-% of one or more
filler(s), based on the total weight of an uncoated particle core;
and [0083] 3 wt-% to 7 wt-% of one or more binder(s), based on the
total weight of an uncoated particle core; [0084] wherein the
coating comprises (or consists essentially of, or consists of):
[0085] 55 wt-% to 65 wt-% of one or more release control agent(s),
based on the total weight of the coating; [0086] 20 wt-% to 25 wt-%
of one or more pore former(s), based on the total weight of the
coating; and [0087] 10 wt-% to 20 wt-% of one or more
plasticizer(s), based on the total weight of the coating;
[0088] wherein the particles are coated in an amount sufficient to
provide a weight gain of 8% to 14%.
4. The extended-release topiramate capsule of any of embodiments 1
through 3 wherein the particles are coated in an amount sufficient
to provide a weight gain of 10% to 12%. 5. The extended-release
topiramate capsule of any of embodiments 1 through 4 wherein the
one or more filler(s) is selected from the group of
microcrystalline cellulose, dibasic calcium phosphate, lactose,
tribasic calcium phosphate, mannitol, and combinations thereof. 6.
The extended-release topiramate capsule of embodiment 5 wherein the
filler is microcrystalline cellulose. 7. The extended-release
topiramate capsule of any of embodiments 1 through 6 wherein the
one or more binder(s) is selected from the group of hydroxypropyl
methylcellulose, methylcellulose, carboxymethylcellulose, sodium
carboxymethylcellulose, hydroxypropyl cellulose,
hydroxyethylcellulose, polyvinyl pyrrolidine, starch, natural gum,
and combinations thereof. 8. The extended-release topiramate
capsule of embodiment 7 wherein the binder is hydroxypropyl
methylcellulose. 9. The extended-release topiramate capsule of any
of embodiments 1 through 8 wherein the one or more release
controlling agent(s) is selected from the group of ethylcellulose,
polyvinyl acetate, polyacrylate and polymethacrylate, copolymers
thereof, and combinations thereof. 10. The extended-release
topiramate capsule of embodiment 9 wherein the release controlling
agent is ethylcellulose. 11. The extended-release topiramate
capsule of any of embodiments 1 through 10 wherein the one or more
pore former(s) is selected from the group of hypromellose,
hydroxypropyl cellulose, methylcellulose, hydroxyethylcellulose,
carboxymethylcellulose, sodium carboxymethylcellulose, polyethylene
glycol, guar gum, xanthan gum, sodium alginate,
polyvinylpyrrolidone, crospovidone, sodium starch glycolate,
croscarmellose sodium, starch, mannitol, glucose, sucrose,
fructose, mannose, galactose, sorbitol, dextran, sodium chloride,
potassium chloride, calcium chloride, and combinations thereof. 12.
The extended-release topiramate capsule of embodiment 11 wherein
the pore former is hydroxypropyl methylcellulose. 13. The
extended-release topiramate capsule of any of embodiments 1 through
12 wherein the one or more plasticizer(s) is selected from the
group of diethyl phthalate, triethyl citrate, dibutyl sebacate,
polyethylene glycol, triacetin, tributyl citrate, glycerol,
propylene glycol, and combinations thereof. 14. The
extended-release topiramate capsule of embodiment 13 wherein the
plasticizer is diethyl phthalate. 15. The extended-release
topiramate capsule of any of embodiments 1 through 14 wherein each
particle core further comprises one or more stabilizer(s). 16. The
extended-release topiramate capsule of embodiment 15 wherein the
one or more stabilizer(s) is selected from the group of calcium
hydroxide, calcium carbonate, sodium bicarbonate, magnesium
carbonate, and combinations thereof. 17. The extended-release
topiramate capsule of embodiment 15 or 16 wherein the one or more
stabilizer(s) is present in an amount of 2 wt-% to 10 wt-%, based
on the total weight of an uncoated particle core. 18. An
extended-release topiramate capsule comprising (or consisting
essentially of, or consisting of):
[0089] a capsule shell comprising (or consisting essentially of, or
consisting of) a single population of coated particles; [0090]
wherein each coated particle comprises (or consists essentially of,
or consists of) a core and a coating thereon; [0091] wherein each
particle core comprises (or consists essentially of, or consists
of) a homogeneous mixture throughout its core, the mixture
comprising (or consisting essentially of, or consisting of): [0092]
40 wt-% to 50 wt-% of topiramate, based on the total weight of an
uncoated particle core; [0093] 45 wt-% to 55 wt-% of one or more
filler(s), based on the total weight of an uncoated particle core;
wherein the one or more filler(s) is selected from the group of
microcrystalline cellulose, dibasic calcium phosphate, lactose,
tribasic calcium phosphate, mannitol, and combinations thereof; and
[0094] 3 wt-% to 7 wt-% of one or more binder(s), based on the
total weight of an uncoated particle core; wherein the one or more
binder(s) is selected from the group of hydroxypropyl
methylcellulose, methylcellulose, carboxymethylcellulose, sodium
carboxymethylcellulose, hydroxypropyl cellulose,
hydroxyethylcellulose, polyvinyl pyrrolidine, starch, natural gum,
and combinations thereof; [0095] wherein the coating comprises (or
consists essentially of, or consists of): [0096] 55 wt-% to 65 wt-%
of one or more release control agent(s), based on the total weight
of the coating; wherein the one or more release controlling
agent(s) is selected from the group of ethylcellulose, polyvinyl
acetate, polyacrylate and polymethacrylate, copolymers thereof, and
combinations thereof; [0097] 20 wt-% to 25 wt-% of one or more pore
former(s), based on the total weight of the coating; wherein the
one or more pore former(s) is selected from the group of
hypromellose, hydroxypropyl cellulose, methylcellulose,
hydroxyethylcellulose, carboxymethylcellulose, sodium
carboxymethylcellulose, polyethylene glycol, guar gum, xanthan gum,
sodium alginate, polyvinylpyrrolidone, crospovidone, sodium starch
glycolate, croscarmellose sodium, starch, mannitol, glucose,
sucrose, fructose, mannose, galactose, sorbitol, dextran, sodium
chloride, potassium chloride, calcium chloride, and combinations
thereof; and [0098] 10 wt-% to 20 wt-% of one or more
plasticizer(s), based on the total weight of the coating; wherein
the one or more plasticizer(s) is selected from the group of
diethyl phthalate, triethyl citrate, dibutyl sebacate, polyethylene
glycol, triacetin, tributyl citrate, glycerol, propylene glycol,
and combinations thereof;
[0099] wherein the particles are coated in an amount sufficient to
provide a weight gain of 8% to 14%.
19. An extended-release topiramate capsule comprising (or
consisting essentially of, or consisting of):
[0100] a capsule shell comprising (or consisting essentially of, or
consisting of) a single population of coated particles; [0101]
wherein each coated particle comprises (or consists essentially of,
or consists of) a core and a coating thereon; [0102] wherein each
particle core comprises (or consists essentially of, or consists
of) a homogeneous mixture throughout its core, the mixture
comprising (or consisting essentially of, or consisting of): [0103]
40-50 wt-% of topiramate, based on the total weight of an uncoated
particle core; [0104] 45-55 wt-% of microcrystalline cellulose,
based on the total weight of an uncoated particle core; and [0105]
3-7 wt-% of hydroxypropyl methylcellulose, based on the total
weight of an uncoated particle core; [0106] wherein the coating
comprises (or consists essentially of, or consists of): [0107]
55-65 wt-% of ethylcellulose, based on the total weight of the
coating; [0108] 20-25 wt-% of hydroxypropyl methylcellulose, based
on the total weight of the coating; and [0109] 10-20 wt-% of
diethyl phthalate, based on the total weight of the coating;
[0110] wherein the particles are coated in an amount sufficient to
provide a weight gain of 8% to 14%.
20. An extended-release topiramate capsule comprising (or
consisting essentially of, or consisting of):
[0111] a capsule shell comprising (or consisting essentially of, or
consisting of) a single population of coated particles; [0112]
wherein each coated particle comprises (or consists essentially of,
or consists of) a core and a coating thereon; [0113] wherein each
particle core comprises (or consists essentially of, or consists
of) a homogeneous mixture throughout its core, the mixture
comprising (or consisting essentially of, or consisting of): [0114]
44-46 wt-% of topiramate, based on the total weight of an uncoated
particle core; [0115] 48-52 wt-% of microcrystalline cellulose,
based on the total weight of an uncoated particle core; and [0116]
4-6 wt-% of hydroxypropyl methylcellulose, based on the total
weight of an uncoated particle core; [0117] wherein the coating
comprises (or consists essentially of, or consists of): [0118]
60-62 wt-% of ethylcellulose, based on the total weight of the
coating; [0119] 22-24 wt-% of hydroxypropyl methylcellulose, based
on the total weight of the coating; and [0120] 15-18 wt-% of
diethyl phthalate, based on the total weight of the coating; [0121]
wherein the particles are coated in an amount sufficient to provide
a weight gain of 10-12%. 21. The extended-release topiramate
capsule of any of embodiments 1 through 20 which, when dosed to a
healthy human subject once daily (e.g., in the morning or evening),
achieves at steady-state, an AUC.sub.0-24h, C.sub.max, and
C.sub.min in the subject's plasma that are within the 80% to 125%
bioequivalence criteria compared to immediate-release topiramate
dosed twice per day. 22. The extended-release topiramate capsule of
any of embodiments 1 through 21 which, when dosed to a healthy
human subject once daily in the morning, achieves at steady-state,
a reduction of fluctuation index of at least 15% compared to
immediate-release topiramate dosed twice per day. 23. The
extended-release topiramate capsule of embodiment 22 which, when
dosed to a healthy human subject once daily in the morning,
achieves at steady-state, a reduction of fluctuation index of at
least 20% compared to immediate-release topiramate dosed twice per
day. 24. The extended-release topiramate capsule of embodiment 23
which, when dosed to a healthy human subject once daily in the
morning, achieves at steady-state, a reduction of fluctuation index
of at least 25% compared to immediate-release topiramate dosed
twice per day. 25. The extended-release topiramate capsule of any
of embodiments 1 through 24 which, when dosed to a healthy human
subject once daily in the morning, achieves at steady-state, a
C.sub.min in the subject's plasma that is higher than the C.sub.min
compared to immediate-release topiramate dosed twice per day. 26.
The extended-release topiramate capsule of any of embodiments 1
through 25 which, when given as a single-dose to a healthy human
subject, achieves an AUC.sub.0-inf of 170 to 210 h.cndot..mu.g/mL
within a 95% confidence interval, and a C.sub.max of 2 to 4
.mu.g/mL within a 95% confidence interval. 27. The extended-release
topiramate capsule of any of embodiments 1 through 26 which, when
dosed once daily to a population of human patients suffering from
epilepsy, achieves a reduction in incidence of at least one side
effect compared to immediate-release topiramate dosed at the same
total daily dose divided twice per day. 28. The extended-release
topiramate capsule of any of embodiments 1 through 27 which is
chemically stable for at least 12 months. 29. The extended-release
topiramate capsule of embodiment 28 which is chemically stable for
at least 24 months. 30. The extended-release topiramate capsule of
embodiment 29 which is chemically stable for at least 24 months
when stored in a sealed container with desiccant. 31. The
extended-release topiramate capsule of embodiment 30 which is
chemically stable for at least 36 months when stored in a sealed
container with desiccant. 32. The extended-release topiramate
capsule of any of embodiments 1 through 31 which is free of an
immediate release component. 33. The extended-release topiramate
capsule of any of embodiments 1 through 32 wherein the coated
particles have a sphericity of at least 0.7. 34. The
extended-release topiramate capsule of any of embodiments 1 through
33 wherein the coated particles have a particle size of at least
500 .mu.m. 35. The extended-release topiramate capsule of any of
embodiments 1 through 34 wherein the coated particles have a
particle size of up to 1300 .mu.m. 36. The extended-release
topiramate capsule of any of embodiments 1 through 35 wherein the
capsule shell comprises hydroxypropyl methylcellulose or gelatin.
37. The extended-release topiramate capsule of embodiment 36
wherein the capsule shell is a hydroxypropyl methylcellulose
capsule. 38. A container comprising an extended-release topiramate
capsule of any of embodiments 1 through 37 and desiccant. 39. The
container of embodiment 38 wherein the ratio of weight of desiccant
to weight of filled capsules is at least 0.01. 40. The container of
embodiment 38 or 39 wherein the ratio of weight of desiccant to
weight of filled capsules is up to 0.9. 41. The container of any of
embodiments 38 through 40 wherein the desiccant is selected from
silica gel, bentonite clay, molecular sieve, and combinations
thereof. 42. A method of dosing a subject in need thereof, the
method comprising administering an extended-release topiramate
capsule of any of embodiments 1 through 37 once daily to the
subject. 43. The method of embodiment 42 wherein the administering
occurs once daily in the morning. 44. The method of embodiment 42
wherein the administering occurs once daily in the evening. 45. The
method of any of embodiments 42 through 44 wherein the dosing is
for the treatment of convulsions. 46. The method of any of
embodiments 42 through 44 wherein the dosing is for the
prophylactic treatment of a migraine.
EXAMPLES
Process and Formulations
[0122] 1. High Shear Granulation: The core bead components listed
in the table below are added to the high shear granulator and
blended. After the pre-mix step, Purified Water is added to the
high shear granulator and the mixture kneaded to create a wet
granulation. 2. Extrusion: The wet granulation is then fed at a
specified rate into a twin dome extruder equipped with dome dies
having 0.8 mm pores to form an extrudate. 3. Spheronization:
Portions of the extrudate from the extruder are weighed out and
processed, for a specified time sufficient to form spherical
particles (i.e., beads), in a spheronizer equipped with a 2.times.2
mm friction plate. 4. Drying: The wet spherical particles are dried
in a fluid bed processor to a moisture content of not more than
(NMT) 3.0% w/w, as determined by an in-process loss-on-drying
analysis. 5. Sizing: The dried particles are sized using a 14-mesh
and a 30-mesh sieve (Market Grade mesh screen). Material passing
through the 14-mesh sieve, but retained on the 30-mesh sieve is
taken into the subsequent coating step. 6. Coating: The dried,
sized, uncoated beads are coated in a Wurster fluidized bed
processor to a desired coating weight gain using the coating
composition listed in the table below. 7. Sizing: Following
coating, the beads are sized using a 14-mesh and a 30-mesh sieve
(Market Grade mesh screen). Material passing through the 14-mesh
sieve, but retained on the 30-mesh sieve is taken into the
subsequent encapsulation step. 8. Encapsulation: Using a suitable
encapsulator, appropriate amounts of coated beads are filled into
appropriate size capsules to yield the different strengths of the
product. The encapsulated product is also run through a capsule
polisher, metal detector, and weight checker.
TABLE-US-00001 Formulation designation A B Coating Weight Gain**
12% w/w 10% w/w Core particle components (% w/w, based on weight of
the core) Topiramate 45 45 Microcrystalline Cellulose 50 50
Hypromellose 2910 5 5 Coating components*** (% w/w, based on weight
of the coating) Ethylcellulose 60.86 60.86 Hypromellose 2910 22.56
22.56 Diethyl Phthalate 16.58 16.58 Dehydrated Alcohol* NA NA
Purified Water* NA NA *Removed during processing. **Weight gain is
defined as the theoretical weight gain after coating of a
population of uncoated particles, assuming 100% coating efficiency.
***The solids content (non-volatile components, i.e.,
ethylcellulose, hypromellose 2910 and diethyl phthalate) of the
coating solution was 7.5% w/w for B and 6% w/w for A. The ratio of
Dehydrated Alcohol to Purified Water is about 3.7:1 on a weight
basis.
PK Results
[0123] In clinical studies, the extended-release topiramate
capsules of Formulation A, when given as a single-dose to a healthy
human subject, achieved an AUC.sub.0-inf of 173.9 to 200.1
h.cndot..mu.g/mL within a 95% confidence interval, and a C.sub.max
of 2.64 to 3.16 .mu.g/mL within a 95% confidence interval.
[0124] In clinical studies, the extended-release topiramate
capsules of Formulation B, when given as a single-dose to a healthy
human subject, achieved an AUC.sub.0-inf of 179.7 to 204.3
h.cndot..mu.g/mL within a 95% confidence interval, and a C.sub.max
of 2.94 to 3.43 .mu.g/mL within a 95% confidence interval.
Adverse Event Evaluation
[0125] In clinical studies, the extended-release topiramate
capsules of the present disclosure, when dosed to patients with
epilepsy (more specifically, as adjunctive treatment in patients
with refractory partial onset seizure with or without
generalization) once daily, achieved a reduction in incidence of at
least one side effect compared to immediate-release topiramate
dosed at the same total daily dose divided twice per day.
[0126] This comparison is based on the extended-release topiramate
capsules of the present disclosure compared to placebo, and the
immediate-release topiramate (TOPAMAX) compared to placebo. Each
being compared to placebo (as opposed to each other), this
evaluation demonstrated that the extended-release topiramate
capsules of the present disclosure achieve a reduction in at least
one side effect (e.g., somnolence, dizziness, ataxia, disturbance
in attention, memory impairment, cognitive disorder, and
psychomotor slowing).
Alcohol Dose Dumping
[0127] Capsules of the present disclosure, which included an
ethanol-soluble particle coating, were evaluated in vitro for dose
dumping in ethanol using a USP apparatus 1 (baskets) operating at
100 revolutions per minute (rpm) with a pH 1.2 HCl buffer
containing 5 to 40% v/v (volume by volume) ethanol. There was no
evidence of immediate release or unacceptable acceleration of
release of the topiramate.
Sulfate/Sulfamate Method
[0128] Sulfate and Sulfamate degradation products were measured
utilizing an ion chromatography (IC) method with ion suppression
conductivity detection. The chromatographic system used an Alltech
Novosep A-2, 250.times.4.0 mm, 5-.mu.m particle size column
maintained at 43.degree. C. The flow rate of the 3.6 mM sodium
carbonate mobile phase was 1.0 mL/min. A 7 mg/mL solution of
topiramate in water containing 10% acetonitrile was prepared from
particles (removed from a capsule of the present disclosure) using
sonication and mixing to extract the sulfate and sulfamate
degradation products. Particles within the capsules of the present
disclosure demonstrated little or no decomposition after a given
time period, such that no more than 2000 parts per million (ppm)
each of sulfate or sulfamate degradation products were
produced.
[0129] The complete disclosures of the patents, patent documents,
and publications cited herein are incorporated by reference in
their entirety as if each were individually incorporated. Various
modifications and alterations to this disclosure will become
apparent to those skilled in the art without departing from the
scope and spirit of this disclosure. It should be understood that
this disclosure is not intended to be unduly limited by the
illustrative embodiments and examples set forth herein and that
such examples and embodiments are presented by way of example only
with the scope of the disclosure intended to be limited only by the
claims set forth herein as follows.
* * * * *