U.S. patent application number 17/081383 was filed with the patent office on 2021-10-07 for modified release preparations containing oxcarbazepine and derivatives thereof.
This patent application is currently assigned to Supernus Pharmaceuticals, Inc.. The applicant listed for this patent is Supernus Pharmaceuticals, Inc.. Invention is credited to Padmanabh P. BHATT, Kevin EDWARDS, Argaw KIDANE.
Application Number | 20210308142 17/081383 |
Document ID | / |
Family ID | 1000005851568 |
Filed Date | 2021-10-07 |
United States Patent
Application |
20210308142 |
Kind Code |
A9 |
BHATT; Padmanabh P. ; et
al. |
October 7, 2021 |
MODIFIED RELEASE PREPARATIONS CONTAINING OXCARBAZEPINE AND
DERIVATIVES THEREOF
Abstract
Controlled-release preparations of oxcarbazepine and derivatives
thereof for once-a-day administration are disclosed. The inventive
compositions comprise solubility- and/or release enhancing agents
to provide tailored drug release profiles, preferably sigmoidal
release profiles. Methods of treatment comprising the inventive
compositions are also disclosed.
Inventors: |
BHATT; Padmanabh P.;
(Rockville, MD) ; KIDANE; Argaw; (Montgomery
Village, MD) ; EDWARDS; Kevin; (Lovettsville,
VA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Supernus Pharmaceuticals, Inc. |
Rockville |
MD |
US |
|
|
Assignee: |
Supernus Pharmaceuticals,
Inc.
Rockville
MD
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20210038613 A1 |
February 11, 2021 |
|
|
Family ID: |
1000005851568 |
Appl. No.: |
17/081383 |
Filed: |
October 27, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16252106 |
Jan 18, 2019 |
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17081383 |
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15834401 |
Dec 7, 2017 |
10220042 |
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16252106 |
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15166816 |
May 27, 2016 |
9855278 |
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15834401 |
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14836179 |
Aug 26, 2015 |
9351975 |
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15166816 |
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14445233 |
Jul 29, 2014 |
9119791 |
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14836179 |
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14103103 |
Dec 11, 2013 |
8821930 |
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14445233 |
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13476337 |
May 21, 2012 |
8617600 |
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14103103 |
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13137382 |
Aug 10, 2011 |
8211464 |
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13476337 |
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12230275 |
Aug 27, 2008 |
8017149 |
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13137382 |
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11734874 |
Apr 13, 2007 |
7722898 |
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12230275 |
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60794837 |
Apr 26, 2006 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 2800/56 20130101;
A61K 9/2027 20130101; A61K 9/2013 20130101; A61K 9/205 20130101;
A61K 9/0073 20130101; A61K 9/2054 20130101; A61K 9/2031 20130101;
A61K 31/55 20130101 |
International
Class: |
A61K 31/55 20060101
A61K031/55; A61K 9/00 20060101 A61K009/00; A61K 9/20 20060101
A61K009/20 |
Claims
1. A method of treating seizures, comprising administering to a
subject in need thereof a controlled-release formulation comprising
oxcarbazepine, wherein the amount of oxcarbazepine is effective to
produce a steady state blood level of monohydroxy derivative of
oxcarbazepine in the range of about 2 .mu.g/ml to about 10
.mu.g/ml, and wherein the treatment exhibits reduced
side-effects.
2. The method of claim 1, wherein the formulation is effective in
minimizing fluctuations between C.sub.min and C.sub.max of
monohydroxy derivative of oxcarbazepine.
3. The method of claim 2, wherein C.sub.max levels of monohydroxy
derivative of oxcarbazepine are in the range of about 6 .mu.g/ml to
about 10 .mu.g/ml and C.sub.min levels of monohydroxy derivative of
oxcarbazepine are in the range of about 2 .mu.g/ml to about 5
.mu.g/ml.
4. The method of claim 1, wherein the controlled-release
formulation is administered to the subject once-a-day.
5. The method of claim 1, wherein the amount of oxcarbazepine is
600 mg.
6. The method of claim 1, wherein the seizure is an epileptic
seizure.
7. The method of claim 6, wherein the epileptic seizure is a
partial seizure or a generalized tonic-clonic seizure.
8. The method of claim 6, wherein the epileptic seizure is a
generalized tonic-clonic seizure.
9. The method of claim 1, wherein the subject is an adult or child.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Continuation of U.S. application Ser.
No. 16/252,106, filed Jan. 18, 2019, which is a Continuation of
U.S. application Ser. No. 15/834,401, filed Dec. 7, 2017, now U.S.
Pat. No. 10,221,042, which is a Continuation of U.S. application
Ser. No. 15/166,816, filed May 27, 2016, now U.S. Pat. No.
9,855,278, which is a Continuation of U.S. application Ser. No.
14/836,179, filed Aug. 26, 2015, now U.S. Pat. No. 9,351,975, which
is a Continuation of U.S. application Ser. No. 14/445,233, filed
Jul. 29, 2014, now U.S. Pat. No. 9,119,791, which is a Continuation
of U.S. application Ser. No. 14/103,103, filed Dec. 11, 2013, now
U.S. Pat. No. 8,821,930, which is a Continuation of U.S.
application Ser. No. 13/476,337, filed May 21, 2012, now U.S. Pat.
No. 8,617,600, which is a Continuation of U.S. application Ser. No.
13/137,382, filed Aug. 10, 2011, now U.S. Pat. No. 8,211,464, which
is a Divisional of U.S. application Ser. No. 12/230,275, filed Aug.
27, 2008, now U.S. Pat. No. 8,017,149, which is a Continuation of
U.S. application Ser. No. 11/734,874, filed Apr. 13, 2007, now U.S.
Pat. No. 7,722,898, which claims priority to U.S. Provisional
Application No. 60/794,837, filed Apr. 26, 2006.
FIELD OF THE INVENTION
[0002] The present invention is directed to controlled-release
preparations of oxcarbazepine and derivatives thereof for
once-a-day administration.
BACKGROUND OF THE INVENTION
[0003] Oxcarbazepine belongs to the benzodiazepine class of drugs
and is registered worldwide as an antiepileptic drug. Oxcarbazepine
is approved as an adjunct or monotherapy for the treatment of
partial seizures and generalized tonic-clonic seizures in adults
and children. An immediate-release (IR) formulation of
oxcarbazepine is currently on the market under the trade name
Trileptal.RTM. and is administered twice a day to control epileptic
seizures. Such immediate release compositions provide the drug to
the patient in a manner that result in a rapid rise of the plasma
drug concentration followed by a rapid decline. This sharp rise in
drug concentration can result in side effects, and make multiple
daily administration of the drug necessary in order to maintain a
therapeutic level of the drug in the body. The need for a
controlled-release dosage form for drugs taken chronically such as
oxcarbazepine and derivatives is self-evident. Patient compliance
is greatly improved with controlled-release (CR) dosage forms that
are taken, for example, once-a-day. Also, there are significant
clinical advantages such as better therapeutic efficacy as well as
reduced side effects with controlled-release dosage forms.
[0004] Oxcarbazepine and its derivatives contemplated in this
invention are poorly soluble in water. Due to their poor
solubility, their release from a sustained release dosage form is
rather incomplete. Whereas the in vitro release of oxcarbazepine is
dependent on the dissolution method, including the dissolution
media used, it has been found through in silico modeling that the
release of oxcarbazepine in vivo from a traditional
sustained-release dosage form is relatively low. This results in
reduced bioavailability of the drug making the dosage form
ineffective in providing a therapeutically effective concentration
in the body. This poses a serious challenge to the successful
development of sustained-release dosage forms for oxcarbazepine and
its derivatives.
[0005] The rate of drug release from a dosage form has a
significant impact on the therapeutic usefulness of the drug and
its side effects. Hence, drug release profiles must be customized
to meet the therapeutic needs of the patient. An example of a
customized release profile is one that exhibits a sigmoidal release
pattern, characterized by an initial slow release followed by fast
release which is then followed by slow release until all of the
drug has been released from the dosage form.
[0006] Sustained-release dosage forms for oxcarbazepine and
derivatives have been described in the art. For example,
Katzhendler et al. (U.S. Pat. No. 6,296,873) describes
sustained-release delivery systems for carbamazepine and its
derivatives. Katzhendler et al. teaches that a zero-order release
profile is achieved for carbamazepine and derivatives through the
use of hydrophilic and hydrophobic polymers. Zero-order (constant)
release was achieved using high molecular weight hydroxypropyl
methyl cellulose (HPMC) along with some optional hydrophobic
excipients. A similar approach is taught by Shah et al. (US Patent
Application 20020169145). Franke et al. (US Patent Application
20040142033) discloses sustained-release formulations of
oxcarbazepine that are characterized by the release of 55%-85% of
the drug in 15 minutes, and up to 95% in 30 minutes. According to
the authors, such release profiles provide adequate
sustained-release to achieve once-a-day administration of
oxcarbazepine. However, the solubility and bioavailability of the
drug from these enhanced preparations suitable for once-a-day
administration. The prior art does not teach how to make
preparations of oxcarbazepine and derivatives characterized by
sigmoidal release profiles.
SUMMARY OF THE INVENTION
[0007] It is an object of this invention to provide
controlled-release formulations of oxcarbazepine for once-a-day
administration. The composition of this invention is administered
once-a-day and yet meets the therapeutic need of the patient. It is
another object of this invention to improve the bioavailability of
oxcarbazepine and derivatives thereof. It is yet another object of
this invention to meet the therapeutic need of the patient without
causing "spikes" in blood drug concentration that may lead to
toxicity. It is yet another object of this invention to keep the
blood concentration of the drug within the therapeutic window. It
is yet another object of this invention to minimize the fluctuation
between the C.sub.max and C.sub.min that is typical of many
immediate-release and sustained-release preparations.
[0008] Many, if not all, of these objectives may be achieved in
this invention through formulations that comprise both
solubility-enhancing agents and release-promoting agents, and are
characterized by release profiles that meet the requirement for
once-a-day administration. The objectives may also be achieved
through the combination of a multiplicity of units with different
release profiles in one dosage unit. Minipellets/granules/tablets,
which can be mixed in a certain ratio, provide a dosage form that
meets the above stated therapeutic objectives.
[0009] This invention also pertains to multi-layer tablets.
Multi-layer tablets can be prepared with each layer releasing the
drug at a rate that is different from the rate of release from
another layer. In multi-layer tablets, each layer may or may not be
coated.
[0010] All of the advantages that stem from once-daily
administration of a drug apply to the compositions of this
invention. Some of the specific advantages of this invention may
be: reduced fluctuation between C.sub.max and C.sub.min during the
course of treatment and hence better therapeutic profile, reduced
side-effects, improved patient compliance, and improved
bioavailability of the drug.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1 shows the dissolution profiles for the three
exemplary (CR-F, CR-M, and CR-S) oxcarbazepine formulations
containing no solubility/release enhancer. The profiles show a
non-zero order release with a lag. The T.sub.80s (time for 80% of
the dose to be released in vitro) for the CR-F, CR-M, and CR-S
formulations were 2 Hrs, 5 Hrs and 11 Hrs, respectively. USP
Apparatus II at 60 RPM was used. Dissolution medium was 1% SLS in
water.
[0012] FIG. 2 shows the human pharmacokinetic (PK) profiles with
respect to oxcarbazepine for the three exemplary controlled-release
formulations of example 1 versus an immediate-release reference
product (Trileptal.RTM. 600 mg). The strength of each formulation
is 600 mg oxcarbazepine per tablet.
[0013] FIG. 3 shows the PK profiles with respect to the metabolite
of oxcarbazepine (MHD) for the three exemplary controlled-release
formulations of example 1 versus an immediate-release reference
product (Trileptal.RTM. 600 mg). The strength of each formulation
is 600 mg oxcarbazepine per tablet.
[0014] FIG. 4 shows the solubility results of oxcarbazepine with
selected excipients.
[0015] FIG. 5 shows the dissolution profiles of oxcarbazepine CR
formulations with solubility enhancer (CRe), without solubility
enhancer (CR) and a "fast formulation" (CR-F) developed in Example
1. The time to dissolve 80% of the drug (T.sub.80) for CRe, CR, and
CR-F are 5-6 Hrs, 8 Hrs, and 1.5 Hrs, respectively.
[0016] FIG. 6 shows the dissolution profiles for the fast (CRe-F),
medium (CRe-M), and slow (CRe-S) oxcarbazepine formulations
containing solubility/release enhancers. The T.sub.80s for the
CRe-F, CRe-M, and CRe-S are 1.5 Hrs, 5 Hrs, and 8 Hrs,
respectively. USP Apparatus II at 60 RPM was used. Dissolution
medium was 1% SLS in water.
[0017] FIG. 7 shows the canine pharmacokinetic profiles with
respect to oxcarbazepine, comparing the enhanced formulation (CRe)
with non-enhanced formulations containing oxcarbazepine (CR and
CR-F).
[0018] FIG. 8 shows the canine pharmacokinetic profiles with
respect to MHD, comparing the enhanced formulation (CRe) with
non-enhanced formulations containing oxcarbazepine (CR and
CR-F).
[0019] FIG. 9 shows the PK profiles shown in FIG. 8 with in silico
predicted PK profile for a twice-a-day 300 mg IR.
[0020] FIG. 10 shows in silico predicted PK profiles for various in
vitro release profiles.
[0021] FIG. 11 shows the in silico predicted in vivo release
profiles for the systems in FIG. 10.
[0022] FIG. 12 shows human plasma concentration vs. time profiles
with respect to MHD of the three Oxcarbazepine CR formulations in
Example 4 (CRe-F, CRe-M, CRe-S) and Trileptal.RTM. as an IR
control, dosed BID.
[0023] FIG. 13 shows human plasma concentration vs. time profiles
with respect to the oxcarbazepine of the three Oxcarbazepine CR
formulations in Example 4 (CRe-F, CRe-M, CRe-S) and Trileptal.RTM.
as an IR control, dosed BID.
[0024] FIG. 14 shows the in silico predicted steady-state plasma
profiles for the three exemplary formulations (CRe-F, CRe-M, and
CRe-S) described in Example 4.
DETAILED DESCRIPTION OF THE INVENTION
[0025] It is the object of this invention to provide
controlled-release oxcarbazepine formulations suitable for
once-a-day administration. It is an additional object of the
invention to incorporate a combination of solubility-enhancing
excipients and/or release-promoting agents into the formulations to
enhance the bioavailability of oxcarbazepine and its derivatives.
Such compositions are referred to as enhanced formulations.
[0026] Oxcarbazepine was formulated to provide release profiles
characterized by slow release initially, followed by rapid release
and then followed by another period of slow release. Such a release
profile is known to those skilled in the art as sigmoidal.
Oxcarbazepine formulations with sigmoidal release profiles were
tested in human pharmacokinetic (PK) studies. Based on the human
data, improvements were made to the formulations by incorporating
solubility enhancers and/or release-promoting excipients (such
formulation are referred to as enhanced formulations). The enhanced
formulations were tested in canine models and were surprisingly
found to provide significant increase in bioavailability of
oxcarbazepine compared to formulations containing no
solubility/release enhancing excipients.
[0027] The incorporation of solubility enhancing agents in
formulations containing poorly soluble drugs such as oxcarbazepine
has a profound effect on the in vivo solubility and hence
bioavailability of the drugs. Enhancing the solubility of
oxcarbazepine results in an increase in its bioavailability and
hence in better therapeutic performance of the drug. A combination
of solubility and release promoters is contemplated in this
invention. Preferable release promoting agents are pH dependent
polymers, also known as enteric polymers. These materials are well
known to those skilled in the art and exhibit pH dependent
solubility such that they dissolve at pH values higher than about
4.0, while remaining insoluble at pH values lower than 4.0.
Solubilizers function by increasing the aqueous solubility of a
poorly soluble drug. When a formulation containing both the enteric
polymer and solubilizer is exposed to an aqueous media of pH higher
than 4.0, the enteric polymer dissolves rapidly leaving a porous
structure, resulting in increased contact surface between the
aqueous medium and the poorly soluble drug. This increased surface
area enhances the efficiency of the solubilizer(s), and hence, the
overall solubility and release rate of the drug is enhanced to a
point where it impacts the availability of the drug for systemic
absorption in patients.
[0028] Excipients that function as solubility enhancers can be
ionic and non-ionic surfactants, complexing agents, hydrophilic
polymers, pH modifiers, such as acidifying agents and alkalinizing
agents, as well as molecules that increase the solubility of poorly
soluble drug through molecular entrapment. Several solubility
enhancers can be utilized simultaneously. All enteric polymers that
remain intact at pH value lower than about 4.0 and dissolve at pH
values higher than 4.0, preferably higher than 5.0, most preferably
about 6.0, are considered useful as release-promoting agents for
this invention.
[0029] Suitable pH-sensitive enteric polymers include cellulose
acetate phthalate, cellulose acetate succinate, methylcellulose
phthalate, ethylhydroxycellulose phthalate, polyvinylacetate
phthalate, polyvinylbutyrate acetate, vinyl acetate-maleic
anhydride copolymer, styrene-maleic monoester copolymer, methyl
acrylate-methacrylic acid copolymer, methacrylate-methacrylic
acid-octyl acrylate copolymer, etc. These may be used either alone
or in combination, or together with the polymers other than those
mentioned above. Preferred enteric polymers are the
pharmaceutically acceptable methacrylic acid copolymers. These
copolymers are anionic polymers based on methacrylic acid and
methyl methacrylate and, preferably, have a mean molecular weight
of about 135000. A ratio of free carboxyl groups to
methyl-esterified carboxyl groups in these copolymers may range,
for example, from 1:1 to 1:3, e.g. around 1:1 or 1:2. Such polymers
are sold under the trade name Eudragit.TM. such as the Eudragit L
series e.g. Eudragit L 12.5.TM., Eudragit L 12.5P.TM., Eudragit
L100.TM., Eudragit L 100-55.TM., Eudragit L-30D.TM., Eudragit L-30
D-55.TM., the Eudragit S.TM. series e.g. Eudragit S 12.5.TM.,
Eudragit S 12.5P.TM., Eudragit S100.TM.. The release promoters are
not limited to pH dependent polymers. Other hydrophilic molecules
that dissolve rapidly and leach out of the dosage form quickly
leaving a porous structure can be also be used for the same
purpose.
[0030] The release-promoting agent can be incorporated in an amount
from 10% to 90%, preferably from 20% to 80% and most preferably
from 30% to 70% by weight of the dosage unit. The agent can be
incorporated into the formulation either prior to or after
granulation. The release-promoting agent can be added into the
formulation either as a dry material, or it can be dispersed or
dissolved in an appropriate solvent, and dispersed during
granulation.
[0031] Solubilizers preferred in this invention include surface
active agents such as sodium docusate, sodium lauryl sulfate,
sodium stearyl fumarate, Tweens.RTM. and Spans (PEO modified
sorbitan monoesters and fatty acid sorbitan esters), poly(ethylene
oxide)-polypropylene oxide-poly(ethylene oxide) block copolymers
(aka Pluronics.TM.); complexing agents such as low molecular weight
polyvinyl pyrrolidone and low molecular weight hydroxypropyl methyl
cellulose; molecules that aid solubility by molecular entrapment
such as cyclodextrins, and pH modifying agents, including
acidifying agents such as citric acid, fumaric acid, tartaric acid,
and hydrochloric acid; and alkalizing agents such as meglumine and
sodium hydroxide.
[0032] Solubilizing agents typically constitute from 1% to 80% by
weight, preferably from 1% to 60%, more preferably from 1% to 50%,
of the dosage form and can be incorporated in a variety of ways.
They can be incorporated in the formulation prior to granulation in
dry or wet form. They can also be added to the formulation after
the rest of the materials are granulated or otherwise processed.
During granulation, solubilizers can be sprayed as solutions with
or without a binder.
[0033] This invention also contemplates controlled-release
formulations comprising oxcarbazepine that release the drug at
variable rates in the GI tract. It is also an object of this
invention to design a drug delivery system to deliver drug at a
very low rate early, followed by a relatively increased rate. It is
another object of this invention to provide a drug release profile
that is characterized by an immediate-release followed by a
modified-release, such as extended-release (XR) or delayed-release
(DR). These types of release profiles ensure that the C.sub.max
(maximum concentration of the drug in blood/plasma) is kept within
the therapeutic window while extending the maintenance of an
effective drug level in the body. The goal of this invention is to
develop a controlled-release pharmaceutical composition of
oxcarbazepine that provides steady-state blood levels of MHD, an
active metabolite of oxcarbazepine, at a concentration of about 2
.mu.g/ml to about 10 .mu.g/ml. In the preferred embodiment,
steady-state blood C.sub.max levels of MHD fall in the range of
about 6 .mu.g/ml to about 10 .mu.g/ml, and C.sub.min levels of MHD
fall in the range of about 2 .mu.g/ml to about 5 .mu.g/ml. Reduced
fluctuation between C.sub.max and C.sub.min during the course of
treatment results in a better therapeutic profile, reduced
side-effects, improved patient compliance, and improved
bioavailability of the drug.
[0034] The desired drug release pattern contemplated by this
invention is achieved by using "matrix" polymers that hydrate and
swell in aqueous media, such as biological fluids. As these
polymers swell, they form a homogenous matrix structure that
maintains its shape during drug release and serves as a carrier for
the drug, solubility enhancers and/or release promoters. The
initial matrix polymer hydration phase results in slow-release of
the drug (lag phase). Once the polymer is fully hydrated and
swollen, the porosity of the matrix increases due to the leaching
out of the pH-dependent release promoters, and drug is released at
a faster rate. The rate of the drug release then becomes constant,
and is a function of drug diffusion through the hydrated polymer
gel.
[0035] Thus, the release vs. time curve is characterized by at
least two slopes: one slope for the lag phase where drug release
rate is low and a second slope where drug release is faster. The
slope of the rising part of the release vs. time curve can be
customized as to match the rate at which the drug is eliminated
from the body. A desired release profile can be achieved by using
swellable polymers alone or in combination with binders, such as
gelling and/or network forming polymers.
[0036] The water-swellable, matrix forming polymers useful in the
present invention are selected from a group comprising cellulosic
polymers, such as hydroxypropylmethylcellulose (HPMC),
hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC),
methylcellulose (MC), powdered cellulose such as microcrystalline
cellulose, cellulose acetate, sodium carboxymethylcellulose,
calcium salt of carboxymethylcellulose, and ethylcellulose;
alginates, gums such as guar and xanthan gums; cross-linked
polyacrylic acid derivatives such as Carbomers (aka Carbopol.TM.)
available in various molecular weight grades from Noveon Inc.
(Cinncinatti, Ohio); carageenan; polyvinyl pyrrolidone and its
derivatives such as crospovidone; polyethylene oxides; and
polyvinyl alcohol. Preferred swellable polymers are the cellulosic
compounds, HPMC being the most preferred.
[0037] The swellable polymer can be incorporated in the formulation
in proportion from 1% to 50% by weight, preferably from 5% to 40%
by weight, most preferably from 5% to 20% by weight. The swellable
polymers and binders may be incorporated in the formulation either
prior to or after granulation. The polymers can also be dispersed
in organic solvents or hydro-alcohols and sprayed during
granulation.
[0038] It is yet another aspect of this invention to prepare
formulations of oxcarbazepine that combine multiple
modified-release "units," each "unit" prepared according to any one
or more of the above-disclosed dosage forms, to provide for a
customized release profile.
[0039] The modified-release units comprise
minipellets/granules/tablets etc., each with unique release
profiles, that can be mixed in a certain ratio to provide a dosage
form that meets the above-stated therapeutic objectives.
Alternatively, multiple modified release units may be formed into
of multi-layer tablets. Multi-layer tablets can be prepared with
each layer releasing the active compound at a rate that is
different from the rate of release of the active ingredient from
another layer. In multi-layer tablets, each layer may optionally be
coated with controlled-release polymer(s). The combination dosage
forms can exhibit release profiles that comprise any/all possible
combinations of immediate release (IR), delayed release (DR), and
extended release (XR) formulations. Pellets/granules/tablets or
each layer of a single tablet may optionally be coated.
[0040] Various hydrophobic excipients can be used to modify the
hydration rate of the dosage unit when exposed to water or aqueous
media. These excipients retard the wetting of the dosage unit and
hence modify the release of the active agent. Hydrophobic
excipients suitable for this invention are represented by, but not
limited to, glyceryl monstearate, mixtures of glyceryl monostearate
and glyceryl monopalmitate (Myvaplex, Eastman Fine Chemical
Company), glycerylmonooleate, a mixture of mono, di and
tri-glycerides (ATMUL 84S), glycerylmonolaurate, glyceryl behenate,
paraffin, white wax, long chain carboxylic acids, long chain
carboxylic acid esters and long chain carboxylic acid alcohols.
[0041] Examples of saturated straight chain acids, useful with the
invention, are n-dodecanoic acid, n-tetradecanoic acid,
n-hexadecanoic acid, caproic acid, caprylic acid, capric acid,
lauric acid, myristic acid, palmitic acid, stearic acid, arachidic
acid, behenic acid, montanic acid and melissic acid. Also useful
are unsaturated monoolefinic straight chain monocarboxylic acids.
Examples of these are oleic acid, gadoleic acid and erucic acid.
Also useful are unsaturated (polyolefinic) straight chain
monocarboxylic acids such as linoleic acid, linolenic acid,
arachidonic acid and behenolic acid. Useful branched acids include,
for example, diacetyl tartaric acid.
[0042] Examples of long chain carboxylic acid esters include, but
are not limited to: glyceryl monostearates; glyceryl
monopalmitates; mixtures of glyceryl monostearate and glyceryl
monopalmitate (Myvaplex 600, Eastman Fine Chemical Company);
glyceryl monolinoleate; glyceryl monooleate; mixtures of glyceryl
monopalmitate, glyceryl monostearate, glyceryl monooleate and
glyceryl monolinoleate (Myverol 18-92, Eastman Fine Chemical
Company); glyceryl monolinoleate; glyceryl monogadoleate; mixtures
of glyceryl monopalmitate, glyceryl monostearate, glyceryl
monooleate, glyceryl monolinoleate, glyceryl monolinoleate and
glyceryl monogadoleate (Myverol 18-99, Eastman Fine Chemical
Company); acetylated glycerides such as distilled acetylated
monoglycerides (Myvacet 5-07, 7-07 and 9-45, Eastman Fine Chemical
Company); mixtures of propylene glycol monoesters, distilled
monoglycerides, sodium stearoyl lactylate and silicon dioxide
(Myvatex TL, Eastman Fine Chemical Company); mixtures of propylene
glycol monoesters, distilled monoglycerides, sodium stearoyl
lactylate and silicon dioxide (Myvatex TL, Eastman Fine Chemical
Company), d-alpha tocopherol polyethylene glycol 1000 succinate
(Vitamin E TPGS, Eastman Chemical Company); mixtures of mono- and
diglyceride esters such as Atmul (Humko Chemical Division of Witco
Chemical); calcium stearoyl lactylate; ethoxylated mono- and
di-glycerides; lactated mono- and di-glycerides; lactylate
carboxylic acid ester of glycerol and propylene glycol; lactylic
esters of long chain carboxylic acids; polyglycerol esters of long
chain carboxylic acids, propylene glycol mono- and di-esters of
long chain carboxylic acids; sodium stearoyl lactylate; sorbitan
monostearate; sorbitan monooleate; other sorbitan esters of long
chain carboxylic acids; succinylated monoglycerides; stearyl
monoglyceryl citrate; stearyl heptanoate; cetyl esters of waxes;
cetearyl octanoate; C.sub.10-C.sub..30 cholesterol/lavosterol
esters; and sucrose long chain carboxylic acid esters. In addition,
waxes can be useful alone or preferably in combination with the
materials listed above. Examples of these are white wax, paraffin
and carnauba wax.
[0043] Drug, polymers, and other excipients are typically combined
and wet granulated using a granulating fluid. However, other
methods of forming granules such as slugging, and roller compaction
can also be used to manufacture matrix granules. Matrix tablets can
also be made by direct compression. In wet granulation, typical
granulating fluids are: water, a mixture of water and alcohol,
anhydrous alcohol. Wet granules can be made in any granulating
device such as mixers, high shear granulators, and fluid bed
granulators. Granules can be dried in appropriate drying equipment
such as fluid bed dryers, ovens, microwave dryers etc. Granules can
also be air-dried. Dried granules can be milled using appropriate
milling device to achieve a particular particle size distribution.
Granules can be filled in to capsules, or blended with other
excipients and tableted on a tablet press. Granules can also be
packaged into sachets for sprinkle application. Other excipients
used to aid tableting are well known to those skilled in the art
and include magnesium stearate, talc, cabosil etc. Granules and
tablets can, optionally, be coated to further modify release rates.
Furthermore, formulations can also optionally contain dyes.
[0044] Optionally, but preferably, the tablet composition can
contain one or more lubricants, which may be added to assure proper
tableting. Non-limiting examples of lubricants include magnesium
stearate, calcium stearate, zinc stearate, stearic acid,
polyethylene glycol, leucine, glyceryl behenate, sodium stearyl
fumarate, hydrogenated vegetable oils, and other waxes, including
but not limited to, beeswax, carnuba wax, cetyl alcohol, glyceryl
stearate, glyceryl palmitate, and stearyl alcohol. The lubricant,
when present, is typically included in an amount of from about 0.1
wt. % to about 20 wt. % of the composition, preferably from about 1
to about 10 wt. %, and more preferably about 0.3 to about 3.0 wt.
%.
[0045] The oxcarbazepine dosage can be formulated into tablets,
granules, and pellets. The steps involved in the manufacturing of
these dosage forms are well known to those skilled in the art.
Briefly, tablets can be compressed from directly compressible blend
containing the active or pre-formed granules. The tablets can be
coated or not coated. The coating may optionally impart
modification of release. Granules can be made by high shear
granulation or fluid bed processing. The granules may or may not be
coated. Pellets can be manufactured by drug layering on inert
carriers such as sugar spheres. Pellets can also be manufactured by
extrusion/spheronization process. The pellets may or may not be
coated. Coated pellets and granules can be filled into
capsules.
[0046] Formulations of this invention can also be made in
pelletized forms, which can be filled into capsules or dispensed in
sachets for sprinkle application. Each pellet is composed of the
drug, swellable polymer(s) and other excipients that aid the
processing. Pellets can be prepared in one of the many ways that
are known by those skilled in the art. These include, for example,
extrusion/spheronization and roller compaction (slugging). In the
extrusion/spheronization technique, drug is mixed with swellable
polymer(s), such as cellulosic polymers and other excipients. The
blend is then granulated in a high shear granulator. The wet mass
is then passed through an extruder and spheronized using a
spheronizer. The pellets are then dried in an oven or fluid bed
processor. The dried pellets are either processed further or
encapsulated without further processing.
[0047] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. All
publications, patent applications, patents, and other references
mentioned herein are incorporated by reference in their entirety.
In case of conflict, the present specification, including
definitions, will control. In addition, the materials, methods, and
examples are illustrative only and not intended to be limiting.
[0048] The invention now will be described in particularity with
the following illustrative examples; however, the scope of the
present invention is not intended to be, and shall not be, limited
to the exemplified embodiments below.
EXAMPLES
Example 1. Oxcarbazepine Formulations with Sigmoidal Release
Profiles
[0049] Table 1 provides the formula composition of oxcarbazepine
controlled-release preparations with sigmoidal release profiles.
Granules were prepared by high shear granulation using anhydrous
ethanol as the granulating liquid. All ingredients, except for
magnesium stearate, were charged in to VG-65/10M high shear
granulator. The dry powders are blended by running the blade for 3
minutes, after which time the anhydrous ethanol was sprayed onto
the mixing blend at a spray rate of approximately 40-60 gm/min.
After about a minute of spray, the chopper on the VG-65/10M was
started and run throughout the spray. Once the granulation was
completed, the granulation was discharged from the VG high shear
granulator, spread on an appropriate tray and placed in an oven to
dry at 40.degree. C. for 24 Hrs. Alternatively, granules can be
dried using a fluid bed processor. Dry granules were screened
through an 18-mesh screen. Screened granules were blended with
magnesium stearate in a proportion of 99.5% granules and 0.5%
magnesium stearate. The blend was then tableted on a rotary tablet
press.
TABLE-US-00001 TABLE 1 Formula composition of Oxcarbazepine CR
formulations with changing slope SLI 530 CR-F SLI530 CR-M SLI530
CR-S Ingredients (Fast) (Medium) (Slow) Oxcarbazepine 60 60 60
Compritol 888ATO 9.5 7 -- Prosolv HD90 9.8 20.3 15 Kollidon 25 10
-- -- Kollidon 90 -- 3 -- Methocel E5 Prem. LV -- -- 10 Methocel
K4M Premium CR -- -- 5 Carbopol 971P 10 9 9 Mg Stearate 0.5 0.5 0.5
FD&C Red #40 -- -- 0.5 FD&C Blue #1 0.2 -- -- FD&C
Yellow #6 -- 0.2 -- Anhydrous Ethanol * * * Total 100 100 100 *
Removed during processing
[0050] FIG. 1 shows the dissolution profiles of three exemplary
oxcarbazepine CR formulations (CR-F, CR-M, and CR-S). The profiles
exhibited non-zero order release.
Example 2. Human Pharmacokinetic Evaluation of Oxcarbazepine CR
Formulations from Example 1
[0051] The three formulations from the Example 1 were evaluated in
humans to obtain pharmacokinetic information. An immediate release
tablet (Trileptal.RTM. 600 mg) was used as a control reference. The
formulations were examined in a randomized, single dose, crossover
study in healthy human volunteers. Blood samples were analyzed for
both the parent molecule oxcarbazepine and its metabolite (the
monohydroxy derivative, MHD).
[0052] Table 2 provides the mean PK parameters for MHD. The PK
profiles are shown in FIGS. 2 and 3.
TABLE-US-00002 TABLE 2 Pharmacokinetic parameters of the three
exemplary formulations in example 1 and immediate release reference
product. CR-F CR-M CR-S Trileptal .TM. PK Parameters Fast Med Slow
IR T.sub.max (Hr) 6.5 8.4 9.1 1.4 C.sub.max (ug/mL) 0.248 0.146
0.103 1.412 AUC.sub.last 3.0 2.5 1.7 5.7 (Hr * ug/mL) Rel BA 53%
44% 30% 100%
Example 3. Solubility Enhancers Screening
[0053] The solubility of oxcarbazepine in the presence of
excipients was evaluated as follows:
[0054] Excipients were dissolved in phosphate buffer to make
solutions with concentrations shown in Table 3. One gram of
oxcarbazepine was then mixed with 19 gm of the excipient solution.
The mixture was rocked overnight at room temperature and then
filtered using 0.22 .mu.m filter. The filtrates were analyzed by
HPLC. The solubility results are given in Table 3 and FIG. 4.
TABLE-US-00003 TABLE 3 Solubility of Oxcarbazepine in the presence
of excipients Excipient conc. Solubility Excipients (% w/w) (mg/mL)
Phosphate Buffer Control NA 0.4009 Hydroxypropyl 5 1.0218
betacyclodextrin (HBCD) Sodium Lauryl Sulfate (SLS) 5 4.1113
Kollidon 17 1 0.1717 SLS/HBCD 1, 1 0.3489 Cremophor RH40 1 0.3140
Docusate Sodium 5 6.5524 SLS/Polyethylene Glycol 400 5, 1 3.0516
(PEG400) SLS/Stearic Acid/PEG400 5, 1, 1 3.2821 De-ionized Water NA
0.2733
Example 4. Formulation of Enhanced Dosage Forms
[0055] Tables 4 and 5 provide the composition of the formulation
containing solubility- and release-enhancing agents. Granules were
manufactured by high shear granulation using water as the
granulating liquid. All ingredients, except for magnesium stearate,
were charged into a VG-65/10M high shear granulator. The dry
powders were blended by running the blade for 3 minutes, upon which
time water was sprayed onto the mixing blend at a spray rate of
approximately 40-60 gm/min. After about a minute of spray, the
chopper on the VG-65/10M was started and run throughout the spray.
Once the granulation was completed, the granulation was discharged
from the VG high shear granulator, spread on an appropriate tray
and placed in an oven to dry at 40.degree. C. for 24 Hrs.
Alternatively, granules can be dried using a fluid bed processor.
Dry granules are screened through an 18-mesh screen. Screened
granules were blended with magnesium stearate in a proportion of
99.5% granules and 0.5% magnesium stearate. The resulting blend was
then tableted on a rotary tablet press. Dissolution profiles for
these formulations are shown in FIGS. 5 and 6.
TABLE-US-00004 TABLE 4 Percent Composition of Enhanced (CRe-M) and
non-Enhanced (CR) Prototypes % PD0294-005 % PD0294-008 Formulation
Enhanced Non-Enhanced Oxcarbazepine 60 60 Prosolv SMCC50 10 25 PVP
K25 5 5 HPMC K4M 10 10 premium SLS 5 0 Eudragit L100-55 10 0
Magnesium 0.5 0.5 Stearate
TABLE-US-00005 TABLE 5 Percent Composition for the three exemplary
enhanced formulations: CRe-F, CRe-M, and CRe-S. % % % PD0294-046
PD0294-051 PD0294-054 Formulation CRe-F CRe-M CRe-S Oxcarbazepine
60 60 60 Prosolv SMCC50 15 10 5 PVP K25 5 5 5 HPMC K4M 5 10 15
premium SLS 5 5 5 Eudragit L100-55 10 10 10 Magnesium Stearate 0.5
0.5 0.5
Example 5. Canine PK Studies on Formulations from Example 4, Table
4 and Example 1. (SLI530CR-F)
[0056] Six male beagle dogs were dosed orally with the formulations
in the order given in Table 6. Blood was drawn over a 24 Hr period
and blood samples were analyzed by HPLC. A noncompartmental
analysis of the data was used to generate T.sub.max, C.sub.max,
AUC.sub.last, and AUC.sub.inf. Relative Bioavailability was
calculated in Excel using the AUC.sub.last and AUC.sub.inf for the
CRf formulation as the control. The PK profiles for oxcarbazepine
and 10-hydroxycarbazepine are given in FIGS. 7 and 8.
TABLE-US-00006 TABLE 6 Prototypes tested in dogs Dose Phase Test
Article SLI Lot # (mg) 1 Oxcarbazepine CR PD0294-024A 600 2
Oxcarbazepine PD0294-024B 600 CRe 3 Oxcarbazepine B04032 600
CR-F
TABLE-US-00007 TABLE 7 Canine pharmacokinetic profiles for
enhanced, non-enhanced and control formulations of oxcarbazepine
Non-Enhanced Enhanced CR Fast CR CR (CR) (CRe-M) (CR-F) Prototypes
PD0294-024A PD0294-024B B04032 T.sub.max 1.5 1.8 1.7 C.sub.max 1.20
1.72 0.7 AUC.sub.last 3.44 7.98 3.41 AUC.sub.inf 3.74 11.09 4.01
Rel BA.sub.last 101% 234% 100% Rel BA.sub.inf 93% 276% 100%
Example 6 in Silico Modeling of Various Release Profiles of
Oxcarbazepine XR
[0057] In silico modeling was carried out for various hypothetical
systems. Results are shown in FIGS. 9-11.
Example 7. Human Pharmacokinetic Evaluation of Solubility Enhanced
Oxcarbazepine CR formulations from Example 4
[0058] The three solubility enhanced prototypes from the Example 4
were evaluated in humans to obtain pharmacokinetic information. An
immediate release tablet (Trileptal.RTM. 300 mg) given BID was used
as a reference. The formulations were examined in a randomized,
single dose, crossover study in healthy human volunteers. Blood
samples were analyzed for both the parent molecule oxcarbazepine
and its metabolite (the monohydroxy derivative, MHD).
[0059] Table 8 provides the mean PK parameters for MHD. The PK
profiles are shown in FIGS. 12 and 13.
TABLE-US-00008 TABLE 8 Pharmacokinetic parameters of the three
exemplary solubility enhanced formulations in Example 4 and
Trileptal .TM. CRe-F CRe-M CRe-S Trileptal .TM. PK Parameters Fast
Med Slow BID T.sub.max (Hr) 9 11 14 16 C.sub.max (ug/mL) 5.32 5.14
4.40 6.23 AUC.sub.last 160.3 161.3 148.9 167.1 (Hr * ug/mL) Rel BA
96% 97% 89% 100%
* * * * *