U.S. patent application number 10/770290 was filed with the patent office on 2004-08-12 for controlled release formulation of divalproex sodium.
Invention is credited to Bollinger, J. Daniel, Cheskin, Howard S., Dutta, Sandeep, Engh, Kevin R., Poska, Richard P., Qiu, Yihong.
Application Number | 20040156897 10/770290 |
Document ID | / |
Family ID | 22807934 |
Filed Date | 2004-08-12 |
United States Patent
Application |
20040156897 |
Kind Code |
A1 |
Qiu, Yihong ; et
al. |
August 12, 2004 |
Controlled release formulation of divalproex sodium
Abstract
A new oral polymeric controlled release formulation suitable for
the once-a-day administration of valproate compounds, such as
divalproex sodium, has been discovered. This formulation exhibits
significant advantages over the sustained release valproate
formulations of the prior arts. This formulation minimnizes the
variation between peak and trough plasma levels of valproate over a
24 hour dosing period. This formulation follows a zero-order
release pattern thus producing essentially flat plasma levels of
valproate, once steady-state levels have been achieved. This
results in a significantly lower incidence of side effects for
patients consuming such a formulation.
Inventors: |
Qiu, Yihong; (Gumee, IL)
; Bollinger, J. Daniel; (Libertyville, IL) ;
Cheskin, Howard S.; (Glencoe, IL) ; Dutta,
Sandeep; (Waukegan, IL) ; Engh, Kevin R.;
(Kenosha, WI) ; Poska, Richard P.; (Mundelein,
IL) |
Correspondence
Address: |
STEVEN F. WEINSTOCK
ABBOTT LABORATORIES
100 ABBOTT PARK ROAD
DEPT. 377/AP6A
ABBOTT PARK
IL
60064-6008
US
|
Family ID: |
22807934 |
Appl. No.: |
10/770290 |
Filed: |
February 2, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10770290 |
Feb 2, 2004 |
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10215142 |
Aug 8, 2002 |
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6713086 |
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10770290 |
Feb 2, 2004 |
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09216650 |
Dec 18, 1998 |
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6419953 |
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Current U.S.
Class: |
424/468 ;
514/557 |
Current CPC
Class: |
A61K 31/19 20130101;
A61K 9/2009 20130101; A61K 9/2054 20130101; A61K 9/2018
20130101 |
Class at
Publication: |
424/468 ;
514/557 |
International
Class: |
A61K 009/22; A61K
031/19 |
Claims
We claim:
1. A oral polymeric controlled release formulation suitable for
once-a-day administration comprising: a) divalproex sodium; b) said
divalproex sodium is in association with a sufficient quantity of a
pharmaceutically acceptable polymer, and; c) when said formulation
is ingested orally, said formulation produces a C.sub.max that is
statistically significantly lower than the C.sub.max produced by a
delayed release divalproex sodium tablet, when each is determined
at steady state in a healthy fasting population.
2. The formulation according to claim 1 which produces a C.sub.min
that is not statistically significantly different from the
C.sub.min produced by said delayed release divalproex sodium
tablet, when each is determined at steady state in a healthy
fasting population.
3. The formulation according to claim 1 in which said formulation
produces an AUC value that is equivalent to the AUC value generated
by said divalproex sodium delayed release tablet, when each is
determined at steady state in a healthy fasting population.
4. The formulation according to claim 1 which: a) produces a
C.sub.min that is not statistically significantly different from
the C.sub.min produced by said delayed release divalproex sodium
tablet, when each is determined at steady state in a healthy
fasting population, and; b) said formulation produces an AUC value
that is equivalent to the AUC value generated by said divalproex
sodium delayed release tablet, when each is determined at steady
state in a healthy fasting population.
5. The formulation according to claim 4 which produces a DFL that
is lower than the DFL produced said delayed release divalproex
sodium tablet, when each is determined at steady state in a healthy
fasting population.
6. The formulation according to claim 1 in which said formulation
is a matrix system, an osmotic pump system or a reservoir polymeric
system.
7. A oral polymeric controlled release formulation suitable for
once-a-day administration comprising: a) divalproex sodium; b) said
divalproex sodium is in association with a pharmaceutically
acceptable polymer, and; c) when said formulation is ingested
orally said formulation produces: i. a C.sub.max that is
statistically significantly lower than the C.sub.max produced by a
delayed release divalproex sodium tablet, when each C.sub.max is
determined at steady state in a healthy fasting population, ii. a
C.sub.min that is not statistically significantly different from
the C.sub.min produced by said delayed release divalproex sodium
tablet, when each C.sub.min is determined at steady state in a
healthy fasting population, and; iii. said formulation produces an
AUC value that is equivalent to the AUC value generated by said
divalproex sodium delayed release tablet, when each AUC is
determined at steady state in a healthy fasting population.
8. The formulation according to claim 7 in which said formulation
produces steady state peak plasma valproate levels that are about
10 to about 20% lower than that produced by a said delayed release
divalproex sodium tablet.
9. A method for the treatment of migraine comprising the
administration of a formulation according to claim 1 to a patient
in need thereof.
10. A method for the treatment of epilepsy comprising the
administration of a formulation according to claim 1 to a patient
in need thereof.
11. A method for the treatment of mania associated with a bipolar
disorder comprising the administration of a formulation according
to claim 1 to a patient in need thereof.
12. A method for the reduction of side effects associated with
divalproex sodium therapy comprising the administration of a
formulation according to claim 1.
13. A oral polymeric controlled release formulation suitable for
once-a-day administration comprising: a) a valproate compound; b)
said valproate compound is in association with a sufficient
quantity of a pharmaceutically acceptable polymer, and; c) when
said formulation is ingested orally, said formulation produces a
C.sub.max that is statistically significantly lower than the
C.sub.max produced by a bid dosage form of said valproate compound,
when each is determined at steady state in a healthy fasting
population.
14. The formulation according to claim 13 which produces a
C.sub.min that is not statistically significantly different from
the C.sub.min produced by said bid dosage form when each is
determined at steady state in a healthy fasting population.
15. The formulation according to claim 13 in which said formulation
produces an AUC value that is equivalent to the AUC value generated
by said bid valproate dosage form, when each is determined at
steady state in a healthy fasting population.
16. The formulation according to claim 13 which: a) produces a
C.sub.min that is not statistically significantly different from
the C.sub.min produced by said bid valproate dosage form, when each
is determined at steady state in a healthy fasting population, and;
b) said formulation produces an AUC value that is equivalent to the
AUC value generated by said bid valproate dosage form, when each is
determined at steady state in a healthy fasting population.
17. The formulation according to claim 13 which produces a DFL that
is not statistically significantly different than the DFL by
produced said bid valproate dosage form, when each is determined at
steady state in a healthy fasting population.
18. The formulation according to claim 13 in which said formulation
is a matrix system, an osmotic pump system or a reservoir polymeric
system.
19. An oral matrix formulation suitable for once-a-day
administration comprising: a) from about 40 to about 80 w/w% of
divalproex sodium; b) a sufficient quantity of a pharmaceutically
acceptable polymer, and; c) when said formulation is ingested
orally: i. said formulation produces a C.sub.max that is
statistically significantly lower than the C.sub.max produced by a
delayed release divalproex sodium tablet, when each is determined
at steady state in a healthy fasting population, ii. a C.sub.min
that is not statistically significantly different from the
C.sub.min produced by said delayed release divalproex sodium
tablet, when each C.sub.min is determined at steady state in a
healthy fasting population, and; iii. said formulation produces an
AUC value that is equivalent to the AUC value generated by said
divalproex sodium delayed release tablet, when each AUC is
determined at steady state in a healthy fasting population.
20. A oral osmotic pump formulation suitable for once-a-day
administration comprising: a) divalproex sodium; b) said divalproex
sodium is in association with a sufficient quantity of a
pharmaceutically acceptable semipermeable polymer, and; c) when
said formulation is ingested orally: i. said formulation produces a
C.sub.max that is statistically significantly lower than the
C.sub.max produced by a delayed release divalproex sodium tablet,
when each is determined at steady state in a healthy fasting
population, ii. a C.sub.min that is not statistically significantly
different from the C.sub.min produced by said delayed release
divalproex sodium tablet, when each C.sub.min is determined at
steady state in a healthy fasting population, and; iii. said
formulation produces an AUC value that is equivalent to the AUC
value generated by said divalproex sodium delayed release tablet,
when each AUC is determined at steady state in a healthy fasting
population.
21. A reservoir polymeric formulation suitable for once-a-day
administration comprising: a) divalproex sodium; b) said divalproex
sodium is in association with a sufficient quantity of a
pharmaceutically acceptable polymer, and; c) when said formulation
is ingested orally: i. said formulation produces a C.sub.max that
is statistically significantly lower than the C.sub.max produced by
a delayed release divalproex sodium tablet, when each is determined
at steady state in a healthy fasting population, ii. a C.sub.min
that is not statistically significantly different from the
C.sub.min produced by said delayed release divalproex sodium
tablet, when each C.sub.min is determined at steady state in a
healthy fasting population, and; iii. said formulation produces an
AUC value that is equivalent to the AUC value generated by said
divalproex sodium delayed release tablet, when each AUC is
determined at steady state in a fasting population.
Description
CROSS REFERENCE
[0001] This application is a continuation-in-part of U.S. patent
application Ser. No. 09/216,650, filed Dec. 18, 1998, the contents
of which are hereby incorporated by reference.
TECHNICAL FIELD
[0002] The present invention relates to pharmaceutical
formulations. More particularly, the present invention concerns a
formulation comprising valproic acid, a pharmaceutically acceptable
salt, ester, or amide thereof, or divalproex sodium, in a
controlled release formulation. These controlled release dosage
forms have an improved pharmacokinetic profile. These dosage forms
minimize the variance between peak and trough plasma levels of
valproate, resulting in a reduction in the incidence of side
effects.
BACKGROUND
[0003] 2-Propylpentanoic acid, more commonly known as valproic acid
("VPA") is effective as an antiepileptic agent. After ingestion,
the free acid dissociates to the valproate ion within the
gastrointestinal tract. The valproate ion is absorbed and produces
the therapeutic effect described above. Physicians Desk Reference
("PDR"), 52.sup.nd Edition, page 426 (2000).
[0004] Divalproex sodium is effective in the treatment of epilepsy,
migraine, and bipolar disorders. It also dissociates to the
valproate ion within the gastrointestinal tract This substance is
described in more detail in U.S. Pat. No. 4,988,731, and U.S. Pat.
No. 5,212,326, the contents of both, which are hereby incorporated
by reference.
[0005] The acid moiety of valproic acid has been functionalized in
order to produce prodrugs capable of generating a valproate ion
in-vivo. For example, the amide of valproic acid, valpromide
("VPO"), has been produced, as well certain salts and esters of the
acid.
[0006] Despite the efficacy of these drugs in the treatment of
conditions such as epilepsy, they all suffer from a common
disadvantage. These valproate compounds have a relatively short
half life. For example, the half life of valproic acid is reported
to be between six and seventeen hours in adults and between four
and fourteen hours in children. This leads to substantial
fluctuations in the plasma concentration of the drug, especially in
chronic administration. To maintain reasonably stable plasma
concentrations, it is necessary to resort to frequent dosing, and
the resulting inconvenience to the patient often results in lowered
compliance with the prescribed dosing regimen. Moreover, widely
fluctuating plasma concentrations of the drug may result in
administration of less than therapeutic amounts of the drug in a
conservative dosing regimen, or amounts too large for the
particular patient in an aggressive dosing regimen. The logical
solution to this problem would be to develop sustained release
dosage forms that decrease the dosing frequency of the
compounds.
[0007] However, the pharinacokinetics of valproic acid, and other
valproate compounds, has complicated such development efforts. The
relationship between plasma concentration and clinical response is
not well documented for valproate. One contributing factor is the
nonlinear, concentration dependent protein binding of valproate,
which affects the clearance of the drug. As the dose of valproate
increases, serum levels rise faster than might be expected since
proportionately less of the dose is bound to plasma proteins. For
example, because the plasma protein binding of valproate is
concentration dependant, the free fraction increases from
approximately 10% at 40.mu.g/ml to 18.5% at 130.mu.g/ml.
[0008] These nonlinear kinetics significantly increase the
difficulty of designing sustained release dosage forms. Identical
doses of the valproate compound can produce vastly different blood
levels depending upon the rate at which the valproate compound is
released from the dosage form.
[0009] Further complicating development efforts is the fact that a
correlation between valproate levels and efficacy is unknown for
disease states other than epilepsy. For example, therapeutic
concentrations required to treat migraine headaches and bipolar
disorders have not been established.
[0010] What impact valproate levels play in a number of side
effects is also unknown at the present time. GI irritation is very
common in patients consuming valproate, affecting up to one third
of patients. The incidence increases at elevated doses. It is
unknown if this side effect is caused by local irritation within
the GI tract or is mediated via the stimulation of a receptor
within the central nervous system (and thus is dependant upon
plasma valproate levels). Other side effects such as asthenia,
dizziness, somnolence, alopecia, and weight gain are quite common.
It is also unknown if these side effects can be correlated with
plasma levels of valproate. A more detailed discussion of valproate
side effects may be found in PDR supra, page 421-437.
[0011] In spite of the nonlinear kinetics of the compounds, a
concerted effort has been devoted to the discovery of valproate
formulations that will maintain more constant plasma levels of the
drug following administration. The ultimate goal of these studies
has been the discovery of a formulation which affords stable plasma
levels in a once-a-day dosing regimen. These efforts fall generally
into one of two categories: (a) finding a form of the active
ingredient which is more slowly released to the body metabolically,
and (b) finding a formulation which delivers the drug by either a
timed-or controlled-release mechanism.
[0012] U.S. Pat. No. 4,369,172 to Schor, et al. describes, for
example, a prolonged release therapeutic composition based on
mixtures of hydroxypropyl methylcellulose, ethyl cellulose and/or
sodium carboxymethyl cellulose. The patentees provide a long list
of therapeutic agents which they suggest can be incorporated into
the formulation including sodium valproate.
[0013] U.S. Pat. No. 4,913,906 to Friedman, et al. discloses a
controlled release dosage form of valproic acid, its amide, or one
of its salts or esters in combination with a natural or synthetic
polymer, pressed into a tablet under high pressure.
[0014] U.S. Pat. No. 5,009,897 to Brinker, et al. discloses
granules, suitable for pressing into tablets, the granules
comprising a core of divalproex sodium and a coating of a mixture
of a polymer and microcrystaline cellulose.
[0015] U.S. Pat. No. 5,019,398 to Daste discloses a
sustained-release tablet of divalproex sodium in a matrix of
hydroxypropyl methylcellulose and hydrated silica. U.S. Pat. No.
5,055,306 to Barry, et al. discloses an effervescent or
water-dispersible granular sustained release formulation suitable
for use with a variety of therapeutic agents. The granules comprise
a core comprising the active ingredient and at least one excipient,
and a water insoluble, water-swellable coating comprising a
copolymer of ethyl acrylate and methyl methacrylate and a water
soluble hydroxylated cellulose derivative. The patentees suggest a
list of therapeutic agents which may be used in the formulation of
the invention, including sodium valproate.
[0016] U.S. Pat. No. 5,169,642 to Brinkler, et al. discloses a
sustained release dosage form comprising granules of divalproex
sodium or amides or esters of valproic acid coated with a sustained
release composition comprising ethyl cellulose or a methacrylic
methyl ester, a plasticizer, a detackifying agent, and a
slow-release polymeric viscosity agent.
[0017] U.S. Pat. No. 5,185,159 to Aubert, et al. discloses a
formulation of valproic acid and sodium valproate which is prepared
without the use of either a binder or a granulating solvent. The
formulation optionally contains precipitated silica as an
anti-sticking or detackifying agent. U.S. Pat. No. 5,589,191 to
Exigua, et al. discloses a slow release sodium valproate tablet
formulation in which the tablets are coated with ethyl cellulose
containing silicic acid anhydride.
[0018] Published PCT application WO 94/27587to Ayer, et al.
discloses a method for control of epilepsy by delivering a
therapeutic composition of divalproex sodium in combination with a
poly (alkylene oxide).
[0019] Bialer, et al., "Metabolism of Antiepileptic Drugs," pp.
143-151, R H. Levy, Ed., Raven Press, New York, 1984;Int. J.
Pharmaceutics, 20: 53-63 (1984); and Biopharmaceutics and Drug
Disposition, 6: 401-411 (1985); and Israel J. Med. Sci., 20: 4649
(1995) report the pharmacokinetic evaluation of several sustained
release formulations of valproic acid.
[0020] Despite all of these efforts, there remains the need for a
sustained release formulation of divaproex sodium, and other
valproate compounds, that will permit once-a-day dosing. Further,
there remains the need for a formulation which will effectively
maintain plasma concentrations of the drug at more constant levels
over a 24 hour dosing period (i.e. minimize the variation between
peak and trough plasma levels). Further, sustained release
formulations are needed that will decrease the incidence of side
effects associated with valproate therapy. More specifically, there
remains the need to reduce the incidence of nausea, vomiting,
asthenia, somnolence, alopecia, weight gain, etc. in patients
undergoing vaiproate therapy.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] In the drawings, which form a part of this
specification:
[0022] FIG. 1 is a graphical representation of the release of drug
from several tests controlled release tablet formulations under in
vitro conditions.
[0023] FIG. 2 is a graphical representation of in vitro release of
drug from two preferred controlled release tablet formulations of
the invention.
[0024] FIG. 3 is a graphical representation of plasma valproate
levels of two qd (once-a-day) and one bid (twice-a-day) dosage
form.
[0025] FIG. 4 is a graphical representation of plasma valproate
levels of a qd (once-a-day) and bid (twice-a-day) dosage form.
SUMMARY OF THE INVENTION
[0026] In accordance with the present invention, a new oral
polymeric controlled release formulation suitable for the
once-a-day administration of valproate compounds, such as
divalproex sodium, has been discovered. This formulation exhibits
significant advantages over the sustained release valproate
formulations of the prior art This formulation minimizes the
variation between peak and trough plasma levels of valproate over a
24 hour dosing period. This formulation follows a zero-order
release pattern thus producing essentially flat plasma levels of
valproate, once steady-state levels have been achieved. This
results in a significantly lower incidence of side effects for
patients consuming such a formulation.
[0027] Peak concentrations of valproate, C.sub.max, are
statistically significantly (p<0.05) below those produced by
valproate dosage forms suitable for twice a day administration when
measured over a 24 hour period. Trough levels of valproate,
C.sub.min, are not statistically significantly different from those
obtained with a twice-a-day dosage form (over 24 hours). The extent
of absorption, as defined by area under the curve ("AUC"), is
equivalent to those produced by the twice-a-day valproate dosage
forms, (over 24 hours). Such a combination of properties has
unexpected benefits. It allows therapeutic levels of valproate to
be maintained over a 24 hour dosing period. Further, it has been
discovered that a significantly lower incidence of side effects has
been achieved by this reduction in peak plasma concentration.
Gastrointestinal side effects, alopecia, and certain CNS side
effects have been reduced.
[0028] The once-a-day formulation ("qd") comprises a valproate
compound that is in association with at least one pharmaceutically
acceptable polymer. A sufficient quantity of the polymer is
utilized, so that upon ingestion, steady state plasma valproate
levels are obtained having a degree of fluctuation that is lower
than that produced by a corresponding twice-a-day valproate dosage
form. The qd formulation also typically provides for total
absorption (AUC) of the valproate compound that is at least 80% of
that achieved by a daily dose of the corresponding twice-a-day
formulation.
[0029] It is important to emphasize that the formulations of this
invention are not limited to any one particular mechanism of drug
release. Given the guidance of this patent application, one skilled
in the art could achieve the enhanced pharmacokinetic and side
effect profile using any oral controlled release polymeric dosage
form known in the art. This includes osmotic pump systems, matrix
systems, or reservoir systems.
[0030] A more specific embodiment of this invention is directed to
a once-a-day divalproex sodium dosage form. This formulation has a
degree of fluctuation that is less than that achieved by a
divalproex sodium delayed release tablet. This qd dosage form also
produces total valproate absorption that is at least 80% of that
achieved by the divalproex sodium delayed release tablets. Peak
steady state serum valproate levels obtained with the qd dosage
form are 10-20% lower than that produced by the divalproex sodium
delayed release tablets. Trough levels, which are important in
maintaining control of epileptic seizures, are not statistically
significantly different from those obtained with the divalproex
sodium delayed release tablets.
DETAILED DESCRIPTION
[0031] I. Definitions
[0032] As noted above, the invention relates to new and improved
dosage forms of valproic acid and other valproate compounds which
disassociate in-vivo to produce a valproate ion. Several valproate
compounds are currently available commercially in the United States
or have been described in the literature.
[0033] One such compound is valproic acid. Valproic acid may be
represented by the following structure: 1
[0034] Valproic acid is available commercially from Abbott
Laboratories of Abbott Park, Ill. Methods for its synthesis are
described in Oberreit, Ber. 29, 1998. (1896) and Keil, Z. Physiol.
Chem. 282, 137 (1947). It's activity as an antiepileptic compound
is described in the PDR, 52nd Edition, page 421, 1998. Upon oral
ingestion within the gastrointestinal tract, the acid moiety
disassociates to form a carboxylate moiety (i.e. a valproate
ion).
[0035] The sodium salt of valproic acid is also known in the art as
an anti-epileptic agent. It is also known as sodium valproate and
is described in detail in The Merck Index, 12 Edition, page 1691
(1996). Further descriptions may be found in the PDR, 52nd Edition,
page 417, (1998).
[0036] Divalproex sodium is effective as an antiepileptic agent and
is also used for migraine and bipolar disorders. Methods for its
preparation may be found in U.S. Pat. Nos. 4,988,731 and 5,212,326,
the contents of both which are hereby incorporated by reference.
Like valproic acid, it also disassociates within the
gastrointestinal tract to form a valproate ion.
[0037] In addition to these specific compounds, one of ordinary
skill in the art would readily recognize that the carboxylic moiety
of the valproate compound may be functionalized in a variety of
ways. This includes forming compounds which readily metabolize
in-vivo to produce valproate, such as valproate amide (valpromide),
as well as other pharmaceutically acceptable amides and esters of
the acid (i.e. prodrugs). This also includes forming a variety of
pharmaceutically acceptable salts.
[0038] Suitable pharmaceutically acceptable basic addition salts
include, but are not limited to cations based on alkali metals or
akline earth metals such as lithium, sodium, potassium, calcium,
magnesium and aluminum salts and the like and nontoxic quaternary
ammonia and amine cations including ammonium, tetramethylammonium,
tetraethylammonium, methylamine, dimethylamine, trimethylamine,
triethylamine, diethylamine, ethylamine and the like. Other
representative organic amines useful for the formation of base
addition salts include ethylenediamine; ethanolamine,
diethanolamine, piperidine, piperazine and the like.
[0039] Other possible compounds include pharmaceutically acceptable
amides and esters. "Pharmaceutically acceptable ester" refers to
those esters which retain, upon hydrolysis of the ester bond, the
biological effectiveness and properties of the carboxylic acid and
are not biologically or otherwise undesirable. For a description of
pharmaceutically acceptable esters as prodrugs, see Bundgaard, E.,
ed., (1985) Design of Prodrugs, Elsevier Science Publishers,
Amsterdam, which is hereby incorporated by reference. These esters
are typically formed from the corresponding carboxylic acid and an
alcohol. Generally, ester formation can be accomplished via
conventional synthetic techniques. (See, e.g., March Advanced
Organic Chemistry, 3rd Ed., John Wiley & Sons, New York (1985)
p. 1157 and references cited therein, and Mark et al. Encyclopedia
of Chemical Technology, John Wiley & Sons, New York (1980)),
both of which are hereby incorporated by reference. The alcohol
component of the ester will generally comprise (i) a C.sub.2-C
.sub.12 aliphatic alcohol that can or can not contain one or more
double bonds and can or can not contain branched carbons or (ii) a
C.sub.7-Ci.sub.2 aromatic or heteroaromatic alcohols. This
invention also contemplates the use of those compositions, which
are both esters as described herein, and at the same time are the
pharmaceutically acceptable salts thereof. "Pharmaceutically
acceptable amide" refers to those amides which retain, upon
hydrolysis of the amide bond, the biological effectiveness and
properties of the carboxylic acid and are not biologically or
otherwise undesirable. For a description of pharmaceutically
acceptable amides as prodrugs, see Bundgaard, H., Ed., (1985)
Design of Prodrugs, Elsevier Science Publishers, Amsterdam. These
amides are typically formed from the corresponding carboxylic acid
and an amine. Generally, amide formation can be accomplished via
conventional synthetic techniques. (See, e.g., March Advanced
Organic Chemistry, 3rd Ed., John Wiley & Sons, New York (1985)
p. 1152 and Mark et al. Encyclopedia of Chemical Technology, John
Wiley & Sons, New York (1980)), both of which are hereby
incorporated by reference. This invention also contemplates the use
of those compositions, which are both amides as described herein,
and at the same time are the pharmaceutically acceptable salts
thereof.
[0040] As used in -this application:
[0041] a) any reference to "valproate" or "valproate compounds"
should be construed as including a compound which disassociates
within the gastrointestinal tract to produce a valproate ion
including, but not limited to, valproic acid, the sodium salt of
valproate, divalproex sodium, any of the various salts of valproic
acid described above, and any of the prodrugs of valproic acid
described above. Divalproex sodium is the most preferred valproate
compound of the present invention.
[0042] b) "C.sub.max" to means maximum plasma concentration of the
valproate ion, produced by the ingestion of the composition of the
invention or the twice-a-day comparator (BID).
[0043] c) "C.sub.min" means minimum plasma concentration of the
valproate ion, produced by the ingestion of the composition of the
invention or the BID comparator.
[0044] d) "C.sub.avg" means the average concentration of valproate
ion within the 24-hour interval produced by the ingestion of the
composition of the invention or the BID comparator. C.sub.avg is
calculated as AUC over a 24 hour interval divided by 24.
[0045] e) "T.sub.max" means time to the maximum observed plasma
concentration produced by the ingestion of the composition of the
invention or the BID comparator.
[0046] f) "AUC" as used herein, means area under the plasma
concentration-time curve, as calculated by the trapezoidal rule
over the complete 24-hour interval for all the formulations.
[0047] g) "Degree of Fluctuation (DFL)" as used herein, is
expressed as: DFL=(C.sub.max-C.sub.min)/C.sub.avgproduced by the
ingestion of the composition of the invention or the BID
comparator.
[0048] h) "Pharmaceutically acceptable" as used herein, means those
salts/polymers/excipients which are, within the scope of sound
medical judgment, suitable for use in contact with the tissues of
humans and lower animals without undue toxicity, irritation,
allergic response, and the like, in keeping with a reasonable
benefit/risk ratio, and effective for their intended use in the
treatment and prophylaxis of migraine, epilepsy, bipolar disorders,
etc.
[0049] i) "Side effects" as used herein, means those physiological
effects to various systems in the body such as cardiovascular
systems, nervous system, digestive system, and body as a whole,
which cause pain and discomfort to the individual subject, and
which are the direct result of the ingestion of the valproate
compound.
[0050] j) "decreased incidence of side effects" refers to a reduced
incidence of side effects in a patient population, and not to a
total absence of side effects, when measured in a comparable
population consuming a valproate dosage form suitable for twice
daily administration. As is well known to those skilled in the art,
even placebo dosage forms made of sugar produce some measurable
incidence of side effects. Thus an improved side effect profile
must be interpreted in light of the relevant art.
[0051] k) "delayed release divalproex sodium tablets" refers to an
enteric coated dosage form containing divalproex sodium intended to
delay the release of the medication until the dosage form has
passed through the stomach.
[0052] l) "bid" refers to the administration of a formulation twice
during a 24 hour period.
[0053] m) "qd" refers to a dosage form that may be administered
once during a 24 hour period.
[0054] n) A statistical test is said to be statistically
significant where the resulting p-value is less than or equal to
0.05, unless otherwise noted. Equivalence and statistical
significance are not synonymous.
[0055] As used in this application, the terms "C.sub.min" and
"trough levels", should be considered synonyms. Likewise, the terms
"C.sub.max" and "peak levels" should also be considered synonyms.
Any reference to a plasma concentration of valproate ion, and more
specifically to any quantification thereof, such as, for example,
C.sub.min, C.sub.max, AUC, DFL, etc., should be considered to have
been determined at steady state in a fasting population, unless
expressly stated otherwise.
[0056] II. Pharmacokinetic Profile
[0057] As noted above, the invention resides in the discovery that
a formulation having an improved pharmacokinetic profile will
simultaneously accomplish two results. First, it will provide a
dosage form of valproate that will maintain therapeutic levels of
the valproate ion over a 24 hour dosing period, thus providing once
daily dosing. Secondly, it will reduce the incidence of side
effects associated with valproate therapy.
[0058] In order to obtain these benefits, it is necessary for the
once-a-day valproate dosage form to achieve certain pharmacokinetic
parameters, when compared to a bid valproate dosage form. The qd
dosage form must reduce peak plasma levels of valproate (C.sub.max)
without significantly impacting either trough levels (C.sub.min) or
the extent of valproate absorption (AUC). Further, the qd dosage
form will exhibit a DFL that is lower than that exhibited by a
corresponding bid valproate dosage form.
[0059] C.sub.max for the qd dosage form should be statistically
significantly lower than the C.sub.max for a bid dosage form of the
same valproate compound, when each is measured at steady state in a
fasting population. For example, a once-a-day divalproex sodium
dosage form will exhibit a C.sub.max that is statistically
significantly lower than that produced by a divalproex sodium
delayed release tablet, when each is measured at steady state in a
fasting population. Typically, peak plasma levels of valproate are
reduced at least 10%. More typically, these peak plasma levels are
reduced up to about 20%. This reduction must be accomplished with
out any significant reduction in trough levels or total absorption
of valproate.
[0060] C.sub.min for the qd dosage form should not be statistically
significantly different from that obtained with a bid dosage form
of the same valproate compound, when each is determined at steady
state in a fasting population. More specifically, C.sub.min for a
once-day divalproex sodium dosage form should not be statistically
significantly different from that obtained with a delayed release
divalproex sodium tablet when each is measured at steady state in a
fasting population. Maintaining comparable trough levels to those
obtained with the prior art bid dosage forms is necessary to
maintain the therapeutic efficacy of the valproate compound.
Inadequate trough levels are associated with seizures in epileptic
patients.
[0061] In addition to reducing peak valproate levels as described
above, it is also important that the total amount of valproate
absorbed from the qd dosage form not be decreased significantly,
when compared to a bid dosage form of the same valproate compound
when dosed over a 24 hour dosing interval. Total drug absorption is
also referred to as AUC (area under the curve). Methods for
quantifying drug absorption are well known to those skilled in the
art and have been standardized by the United States Food and Drug
Administration at www.fda.gov/cder/guidance/stat-two- .pdf, the
contents of which are hereby incorporated by reference.
[0062] AUC for the qd dosage form will be equivalent to the AUC of
the bid dosage form of the same valproate compound when each is
measured at steady state in a fasting population over a 24 hour
period. Equivalence of a pharmacokinetic parameter refers to the
90% confidence interval of the ratio of the central values of the
pharmacokinetic parameter of the test formulation to the reference
formulation being contained within 0.80 to 1.25. More specifically,
the AUC of qd divalproex sodium tablet form will be equivalent to
that obtained with a delayed release divalproex sodium dosage form
when each is determined at steady state in a fasting population
over a 24 hour dosing period.
[0063] An AUC of at least 80% should be achieved with the
formulations of this invention, when compared to a bid dosage form
over a 24 hour interval. Values below 80% tend to negatively impact
trough levels leading to sub-therapeutic concentrations of
valproate and loss of epileptic control, etc. AUC's in excess of
125% should also be avoided. Thus with respect to the extent of
absorption, the formulations of this invention should be considered
equivalent to the corresponding bid valproate dosage form.
[0064] Degree of Fluctuation ("DEL") is a measurement of how much
plasma levels of a drug vary over the course of a dosing interval.
The closer the DFL is to zero (0), the less variance there is over
the course of a dosing period. Thus a reduced DFL signifies that
the difference in peak and trough plasma levels has been reduced.
The DFL for a qd dosage form of this invention will be lower than
that of the corresponding bid dosage form, for the same valproate
compound, when each is evaluated at steady state in a fasting
population. In a more specific embodiment, a qd divalproex sodium
dosage form will have a DFL that is lower than that achieved with a
bid delayed release divalproex sodium tablet when each is evaluated
at steady state in a fasting population.
[0065] Despite the numerous therapeutic advantages of valproate
therapy, certain patients consuming these medications experience
side effects. For example, with divalproex sodium delayed release
tablets, approximately 7% of patients report alopecia (hair loss)
PDR supra, page 435-436. Up to 8% of patients report significant
weight gain PDR supra, page 435-436. Such side effects can have
disastrous consequences for the self image of patients, especially
for females, or younger patients. It is unknown whether this hair
loss or weight gain is associated with obtaining or maintaining
certain plasma levels of valproate likewise, up to one-third of
patients consuming divalproex sodium delayed release tablets report
suffering from nausea. While such an event is certainly not life
threatening, it is unpleasant for the patient. The nausea can lead
to non-compliance and subsequent worsening of the patient's
disease. Dizziness, tremor, asthenia, somnolence are also common
with valproate therapy. The impact of plasma levels on these side
effects is also unknown. For a more complete discussion of
valproate side effects, please refer to PDR supra, page
421-437.
[0066] The incidence of these side effects can be reduced
significantly by reducing peak plasma levels of valproate by
approximately 10-20%. Further, therapeutic control can be
maintained by meeting the DFL, C.sub.min, and AUC guidelines
discussed above. Such a finding was totally unexpected. The
literature clearly documents that the correlation between side
effects and plasma valproate levels is unknown.
[0067] III. Dosage Forms
[0068] As noted above, the benefits of this invention are not
limited to a single type of dosage form having a particular
mechanism of drug release. This enhanced pharmacokinetic profile
can be obtained with any of the oral sustained release dosage forms
in use today, following the teachings above.
[0069] As of the filing date of this application, there are three
types of commonly used oral polymeric controlled release dosage
forms. This includes matrix systems, osmotic pumps, and membrane
controlled technology (also referred to as reservoir systems). Each
of these systems is described in greater detail below. A detailed
discussion of such dosage forms may also be found in: (i) Handbook
of pharmaceutical controlled release technology, ed. D.L. Wise,
Marcel Dekker, Inc. New York, N.Y. (2000), and (ii). Treatise on
controlled drug delivery, fundamentals, optimization, and
applications, ed. A. Kydonieus, Marcel Dekker, Inc. New York, N.Y.
(1992), the contents of each which is hereby incorporated by
reference.
[0070] A) Matrix Systems
[0071] Matrix systems are well known in the art. In a matrix
system, the drug is homogeneously dispersed in a polymer in
association with conventional excipients. This admixture is
typically compressed under pressure to produce a tablet. Drug is
released from this tablet by diffusion and erosion. Matrix systems
are described in detail by Wise and Kydonieus, supra.
[0072] The matrix formulations of this invention comprise a
valproate compound and a pharmaceutically acceptable polymer.
Preferably, the valproate compound is divalproex sodium. The amount
of the valproate compound varies from about 40% to about 80% by
weight of the dosage form. Preferably, the dosage form comprises
about 45% to about 65% by weight of the valproate compound.
[0073] The pharmaceutically acceptable polymer is a water-soluble
hydrophilic polymer, or a water insoluble hydrophobic polymer
(including waxes). Examples of suitable water soluble polymers
include polyvinylpyrrolidine, hydroxypropylcellulose,
hydroxypropylmethyl cellulose, methyl cellulose, vinyl acetate
copolymers, polysaccharides (such as alignate, xanthium gum, etc.),
polyethylene oxide, methacrylic acid copolymers, maleic
anhydride/methyl vinyl ether copolymers and derivatives and
mixtures thereof. Examples of suitable water insoluble polymers
include acrylates, cellulose derivatives such ethylcellulose or
cellulose acetate, polyethylene, methacrylates, acrylic acid
copolymers and high molecular weight polyvinylalcohols. Examples of
suitable waxes include fatty acids and glycerides.
[0074] Preferably, the polymer is selected from hydroxypropyl
cellulose, hydroxypropylmethyl cellulose, and methyl cellulose.
More preferably, the polymer is hydroxypropylmethyl cellulose. Most
preferably, the polymer is a high viscosity hydroxypropyl-methyl
cellulose with viscosity ranging from about 4,000 cps to about
100,000 cps. The most preferred high viscosity polymer is a
hydroxypropylmethyl cellulose with a viscosity of about 15,000 cps,
commercially available under the Tradename, Methocel, from The Dow
Chemical Company.
[0075] The amount of the polymer in the dosage form generally
varies from about 20% to about 50% by weight of the composition.
Preferably, the amount of polymers varies from about 25% to about
45% by weight of the dosage form. Most preferably, the amount of
polymer varies from about 30% to about 40% by weight of the dosage
form.
[0076] The composition of the invention also typically includes
pharmaceutically acceptable excipients. As is well known to those
skilled in the art, pharmaceutical excipients are routinely
incorporated into solid dosage forms. This is done to ease the
manufacturing process as well as to improve the performance of the
dosage form. Common excipients include diluents or bulking agents,
lubricants, binders, etc. Such excipients are routinely used in the
dosage forms of this invention.
[0077] Diluents, or fillers, are added in order to increase the
mass of an individual dose to a size suitable for tablet
compression. Suitable diluents include powdered sugar, calcium
phosphate, calcium sulfate, microcrystalline cellulose, lactose,
mannitol, kaolin, sodium chloride, dry starch sorbitol, etc.
[0078] Lubricants are incorporated into a formulation for a variety
of reasons. They reduce friction between the granulation and die
wall during compression and ejection. This prevents the granulate
from sticking to the tablet punches, facilitates its ejection from
the tablet punches, etc. Examples of suitable lubricants include
talc, stearic acid, vegetable oil, calcium stearate, zinc stearate,
magnesium stearate, etc.
[0079] Glidant's are also typically incorporated into the
formulation. A glidant improves the flow characteristics of the
granulation. Examples of suitable glidant's include talc, silicon
dioxide, and cornstarch.
[0080] Binders may be incorporated into the formulation. Binders
are typically utilized if the manufacture of the dosage form uses a
granulation step. Examples of suitable binders include povidone,
polyvinylpyrrolidone, xanthan gum, cellulose gums such as
carboxymethylcellulose, methyl cellulose,
hydroxypropylmethycellulose, hydroxycellulose, gelatin, starch, and
pregelatinized starch.
[0081] Other excipients that may be incorporated into the
formulation include preservatives, antioxidants, or any other
excipient commonly used in the pharmaceutical industry, etc. The
amount of excipients used in the formulation will correspond to
that typically used in a matrix system. The total amount of
excipients, fillers and extenders, etc. varies from about 10% to
about 40% by weight of the dosage form.
[0082] The matrix formulations are generally prepared using
standard techniques well known in the art Typically, they are
prepared by dry blending the polymer, filler, valproate compound,
and other excipients followed by granulating the mixture using an
alcohol until proper granulation is obtained. The granulation is
done by methods known in the art. The wet granules are dried in a
fluid bed dryer, sifted and ground to appropriate size. Lubricating
agents are mixed with the dried granulation to obtain the final
formulation.
[0083] The compositions of the invention can be administered orally
in the form of tablets, pills, or the granulate may be loose filled
into capsules. The tablets can be prepared by techniques known in
the art and contain a therapeutically useful amount of the
valproate compound and such excipients as are necessary to form the
tablet by such techniques. Tablets and pills can additionally be
prepared with enteric coatings and other release-controlling
coatings for the purpose of acid protection, easing swallow
ability, etc. The coating may be colored with a pharmaceutically
accepted dye. The amount of dye and other excipients in the coating
liquid may vary and will not impact the performance of the extended
release tablets. The coating liquid generally comprises film
forming polymers such as hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, cellulose esters or ethers (such as
cellulose acetate or ethylcellulose), an acrylic polymer or a
mixture of polymers. The coating solution is generally an aqueous
solution or an organic solvent further comprising propylene glycol,
sorbitan monoleate, sorbic acid, fillers such as titanium dioxide,
a pharmaceutically acceptable dye.
[0084] A particularly preferred matrix system for the extended
release of the valproate compound there from comprises: from about
50 weight percent to about 55 weight percent of a valproate
compound; from about 20 weight percent to about 40 weight percent
of hydroxypropyl methylcellulose; from about 5 weight percent to
about 15 weight percent of lactose, from about 4 weight percent to
about 6 weight percent of microcrystalline cellulose, and from
about 1 weight percent to about 5 weight percent of silicon
dioxide, in which said silicon dioxide has an average particle size
ranging between about 1 micron and about 10 microns; and all weight
percentages based upon the total weight of the dosage form.
[0085] This preferred embodiment of the invention also extends a
dry granular composition suitable for compressing into a tablet
dosage form, the granular composition comprising particles of a
size smaller than about 1 mm and comprising from about 50 weight
percent to about 55 weight percent of an active ingredient selected
from the group consisting of valproic acid, a pharmaceutically
acceptable salt or ester of valproic acids divalproex sodium, and
valpromide; from about 20 weight percent to about 40 weight percent
of hydroxypropyl methylcellulose; from about 5 weight percent to
about 15 weight percent of lactose, from about 4 weight percent to
about 6 weight percent of microcrystaline cellulose, and from about
1 weight percent to about 5 weight percent of silicon dioxide, in
which said silicon dioxide has an average particle size ranging
between about 1 micron and about 10 microns; and all weight
percentages based upon the total weight of the granular
composition.
[0086] More specifically, a divalproex matrix may be prepared by a)
dry blending a mixture of from about 50 weight percent to about 55
weight percent divalproex sodium, from about 20 weight percent to
about 35 weight percent hydroxypropylmethyl cellulose, from about 5
weight percent to about 15 weight percent lactose to form a uniform
mixture of the dry ingredients; b) wet granulating the dry uniform
mixture from step a); c) drying and sizing the wet granules from
step b) to select granules having an average size below 1 mm; d)
dry blending the granules with from about 4 weight percent to about
6 weight percent microcrystalline cellulose, and from about 1
weight percent to about 5 weight percent silicon dioxide having an
average particle size ranging between about 1 micron and about 10
microns; and e) compressing the blended granules of step h) under a
force ranging between about 2000 lbf (about 8.9 .times.10.sup.3
Newtons) and 10,000 lbf (about 4.45 .times.10.sup.4 Newtons). In a
similar manner, the microcrystalline cellulose can be dry blended
in step (a) with the divalproex sodium, hydroxypropyl
methylcellulose and lactose.
[0087] B) Osmotic Pumps
[0088] In an osmotic pump system, a tablet core is encased by a
semipermeable membrane having at least one orifice. The
semipermeable membrane is permeable to water, but impermeable to
the drug. When the system is exposed to body fluids, water will
penetrate through the semipermeable membrane into the tablet core
containing osmotic excipients and the active drug. Osmotic pressure
increases within the dosage form and drug is released through the
orifice in an attempt to equalize pressure.
[0089] In more complex pumps, the tablet core contains two internal
compartments. The first compartment contains the drug. The second
compartment contains a polymer which swells on contact with fluid.
After ingestion, this polymer swells into the drug containing
compartment at a predetermined rate and forces drug from the dosage
form at that rate. Such dosage forms are often used when are zero
order release profile is desired, such as in the instant
invention.
[0090] Osmotic pumps are well known in the art and have been
described in the literature. U.S. Pat. Nos. 4,088,864; 4,200,098;
and 5,573,776; all of which are hereby incorporated by reference,
describe osmotic pumps and methods for their manufacture. Osmotic
pumps containing valproate compounds, such as divalproex sodium,
have been described by Ayer et al in U.S. Pat. No. 5,980,943, the
contents of which are hereby incorporated by reference. One skilled
in the art, taking into account this applications teachings and
those of the '864,'098,'776 and '943 patents could produce an
osmotic pump matching the pharmacokinetic profile described
above.
[0091] As a general guideline, the osmotic pumps of this invention
are typically formed by compressing a tablet of an osmotically
active drug (or an osmotically inactive drug in combination with an
osmotically active agent or osmagent) and then coating the tablet
with a semipermeable membrane which is permeable to an exterior
aqueous-based fluid but impermeable to the passage of drug and/or
osmagent. One or more delivery orifices may be drilled through the
semipermeable membrane wall. Alternatively, orifice(s) through the
wall may be formed in situ by incorporating leachable pore forming
materials in the wall. In operation, the exterior aqueous based
fluid is imbibed through the semipermeable membrane wall and
contacts the drug and/or salt to form a solution or suspension of
the drug. The drug solution or suspension is then pumped out
through the orifice as fresh fluid is imbibed through the
semipermeable membrane.
[0092] In a further preferred embodiment, the tablet contains two
distinct compartments. The first compartment contains the drug as
described-above. The second compartment contains an expandable
driving member consisting of a layer of a swellable hydrophilic
polymer, which operates to diminish the volume occupied by the
drug, thereby delivering the drug from the device at a controlled
rate over an extended period of time.
[0093] Typical materials for the semipermeable membrane include
semipermeable polymers known to the art as osmosis and reverse
osmosis membranes, such as cellulose acylate, cellulose diacylate,
cellulose triacylate, cellulose acetate, cellulose diacetate,
cellulose. triacetate, agar acetate, amylose triacetate, beta
glucan acetate, acetaldehyde dimethyl acetate, cellulose acetate
ethyl carbamate, polyamides, polyurethanes, sulfonated
polystyrenes, cellulose acetate phthalate, cellulose acetate methyl
carbamate, cellulose acetate succinate, cellulose acetate dimethyl
aminoacetate, cellulose acetate ethyl carbamate, cellulose acetate
chloracetate, cellulose dipalmitate, cellulose dioctanoate,
cellulose dicaprylate, cellulose dipentanlate, cellulose acetate
valerate, cellulose acetate succinate, cellulose propionate
succinate, methyl cellulose, cellulose acetate p-toluene sulfonate,
cellulose acetate butyrate, cross-linked selectively semipermeable
polymers formed by the coprecipitation of a polyanion and a
polycation as disclosed in U.S. Pat. Nos. 3,173,876; 3,276,586;
3,541,005; 3,541,006; and 3,546,142, semipermeable polymers as
disclosed by Loeb and Sourirajan in U.S. Pat. No. 3,133,132,
lightly cross-linked polystyrene derivatives, cross-linked
poly(sodium styrene sulfonate), poly(vinylbenzyltrimethyl ammonium
chloride), cellulose acetate having a degree of substitution up to
1 and an acetyl content up to 50%, cellulose diacetate having a
degree of substitution of 1 to 2 and an acetyl content of 21 to
35%, cellulose triacetate having a degree of substitution of 2 to 3
and an acetyl content of 35 to 44.8%, as disclosed in U.S. Pat. No.
4,160,020.
[0094] The osmotic agent present in the pump, which may be used
when the drug itself is not osmotically active, are osmotically
effective compounds soluble in the fluid that enters the device,
and exhibits an osmotic pressure gradient across the semipermeable
wall against the exterior fluid. Osmotically effective osmagents
useful for the present purpose include magnesium sulfate, calcium
sulfate, magnesium chloride, sodium chloride, lithium chloride,
potassium sulfate, sodium carbonate, sodium sulfite, lithium
sulfate, potassium chloride, sodium sulfate, d-mannitol, urea,
sorbitol, inositol, raffinose, sucrose, glucose, hydrophilic
polymers such as cellulose polymers, mixtures thereof, and the
like. The osmagent is usually present in an excess amount, and it
can be in any physical form, such as particle, powder, granule, and
the like. The osmotic pressure in atmospheres of the osmagents
suitable for the invention will be greater than zero and generally
up to about 500 atm, or higher.
[0095] The expandable driving member is typically a swellable,
hydrophilic polymer which interacts with water and aqueous
biological fluids and swells or expands to an equilibrium state.
The polymers exhibit the ability to swell in water and retain a
significant portion of the imbibed water within the polymer
structure. The polymers swell or expand to a very high degree,
usually exhibiting a 2 to 50 fold volume increase. The polymers can
be noncross-linked or cross-linked. The swellable, hydrophilic
polymers are in one presently preferred embodiment lightly
cross-linked, such cross-links being formed by covalent ionic bonds
or hydrogen bonds. The polymers can be of plant, animal or
synthetic origin. Hydrophilic polymers suitable for the present
purpose include poly(hydroxy alkyl methacrylate) having a molecular
weight of from 30,000 to 5,000,000; kappa carrageenan,
polyvinylpyrrolidone having molecular weight of from 10,000 to
360,000; anionic and cationic hydrogels; polyelectrolyte complexes;
poly(vinyl alcohol) having a low acetate residual, cross-linked
with glyoxal, formaldehyde, or glutaraldehyde and having a degree
of polymerization from 200 to 30,000; a mixture of methyl
cellulose; cross-linked agar and carboxymethyl cellulose; a water
insoluble, water swellable copolymer produced by forming a
dispersion of finely divided copolymer of maleic anhydride with
styrene, ethylene,; propylene, butylene or isobutylene cross-linked
with from 0.001 to about 0.5 moles of saturated crosslinkng agent
per mole of maleic anhydride in copolymer, water swellable polymers
of N-vinyl lactams, and the like.
[0096] The expression "orifice" as used herein comprises means and
methods suitable for releasing the drug from the system. The
expression includes one or more apertures or orifices which have
been bored through the semipermeable membrane by mechanical
procedures. Alternatively it may be formed by incorporating an
erodible element, such as a gelatin plug, in the semipermeable
membrane. In cases where the semipermeable membrane is sufficiently
permeable to the passage of drug, the pores in the membrane may be
sufficient to release the agent/drug in therapeutically effective
amounts. In such cases, the expression "passageway" refers to the
pores within the membrane wall even though no bore or other orifice
has been drilled there through. A detailed description of osmotic
passageways and the maximum and minimum dimensions for a passageway
are disclosed in U.S. Pat. Nos. 3,845,770 and 3,916,899, the
disclosures of which are incorporated herein by reference.
[0097] The osmotic pumps of this invention are manufactured by
standard techniques. For example, in one embodiment, the drug and
other ingredients that may be housed in one area of the compartment
adjacent to the passageway, are pressed into a solid possessing
dimension that corresponds to the internal dimensions of the area
of the compartment the agent will occupy, or the agent and other
ingredients and a solvent are mixed into a solid or semisolid form
by conventional methods such as ballmilling, calendaring, stirring
or rolimilling, and then pressed into a preselected shape. Next, a
layer of a hydrophilic polymer is placed in contact with the layer
of agent in a like manner, and the two layers surrounded with a
semipermeable wall. The layering of agent formulation and
hydrophilic polymer can be fabricated by conventional two-layer
press techniques. The wall can be applied by molding, spraying or
dipping the pressed shapes into a wall forming material. Another
and presently preferred technique that can be use for applying the
wall is the air suspension procedure. This procedure consists of
suspending and tumbling the pressed agent and dry hydrophilic
polymer in a current of air and a wall forming composition until
the wall is applied to the agent-hydrophilic polymer composite. The
air suspension procedure is described in U.S. Pat. No. 2,799,241;J.
Am. Pharm. Assoc., Vol. standard manufacturing procedures are
described in Modern Plastics Encyclopedia, Vol. 46, pp. 62-70
(1969); and in Pharmaceutical Sciences, by Remington, Fourteenth
Edition, pp. 1626-1678 (1970), published by Mack Publishing
Company, Easton, Pa.
[0098] C) Reservoir Polymeric Systems
[0099] Reservoir systems are well known in the art This technology
is also commonly referred to as microencapsulation, bead
technology, or coated tablets. Small particles of the drug are
encapsulated with pharmaceutically acceptable polymer. This
polymer, and its relative quantity, offers a predetermined
resistance to drug diffusion from the reservoir to the
gastrointestinal tract. Thus drug is gradually released from the
beads into the gastrointestinal tract and provides the desired
sustained release of valproate compound.
[0100] These dosage forms are well known in the art U.S. Pat. No's.
5,286,497 and 5,737,320, both of which are hereby incorporated by
reference, describe such formulations and their methods of
production. U.S. Pat. No's. 5,354,556; 4,952,402; and 4,940,588;
all of which are hereby incorporated by reference, specifically
discuss using such technology to produce sustained release dosage
forms of valproate compounds such as sodium valproate. One skilled
in the art, tag into account this applications teachings and those
of the '556, '402, '588, '320, and the 497 patents could produce a
bead or pellet based dosage form matching the pharmacokinetic
profile described above.
[0101] As a general guideline however, a pellet is formed with a
core of a valproate compound, optionally in association with
conventional excipients. This core is then coated with one, or
more, pharmaceutically acceptable polymers. Often, the coating
polymer is an admixture of a major proportion of a pharmaceutically
acceptable water insoluble polymer and a minor proportion of a
pharmaceutically acceptable water soluble polymer. The central core
may be prepared by a number of techniques known in the art,
Typically the valproate compound is bound to an inert carrier with
a conventional binding agent. The inert carrier is typically a
starch or sugar sphere. Before the valproate is bound to the inert
carrier, it is typically blended with conventional excipients to
expedite its handling and to improve the properties of the final
dosage form. These excipients are identical to those described
above for the matrix systems. The quantity of these excipients can
vary widely, but will be used in conventional amounts. The central
core is then produced by utilizing a binding agent to attach the
powdered valproate blend to the solid carrier. This can be
accomplished by means known in the art for producing pharmaceutical
beads. Suitable means include utilization of a conventional coating
pan, an automatic coating machine, or a rotogranulator. The
production of these central cores is described in more detail in
Pharmaceutical Pelletization Technology, ed. I. Ghebre-Sellassie,
Marcel Dekker, Inc. New York, N.Y. (1989) which is hereby
incorporated by reference.
[0102] The second major component of the beads is the polymeric
coating. As noted above, the polymeric coating is responsible for
giving the beads their sustained release characteristics. The
polymeric coating may be applied to the central core using methods
and techniques known in the art. Examples of suitable coating
devices include fluid bed coaters, pan coaters, etc. The
application techniques are described in more detail in: 1) Aqueous
polymeric coatings for pharmaceutical dosage forms, ed.J. W.
McGinity, Marcel Dekker, Inc. New York, N.Y. (1997); and 2)
Pharmaceutical Dosage Forms: Tablets Vol. 3. ed. H. A. Lieberman,
L. Lachman and J. B. Schwartz, Marcel Dekker, Inc. New York, N.Y.
pp. 77-287, (1990), the contents of each which are hereby
incorporated by reference.
[0103] Examples of suitable polymers include ethylcellulose,
cellulose acetate, cellulose propionate (lower, medium or higher
molecular weight), cellulose acetate propionate, cellulose acetate
butyrate, cellulose acetate phthalate, cellulose triacetate,
poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl
methacrylate), poly(isobutyl methacrylate), poly(hexyl
methacrylate), po1y(isodecyl methacrylate), poly(lauryl
methacrylate), poly(phenyl methacrylate), poly(methyl acrylate),
poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl
acrylate), poly(ethylene), poly(ethylene) low density,
poly(ethylene) high density, poly(propylene), poly(ethylene oxide),
poly(ethylene terephthalate), poly(vinyl isobutyl ether),
poly(vinyl acetate), poly(vinyl chloride) or polyurethane or
mixtures thereof.
[0104] Once the beads have been prepared, they may be filled into
capsules as is known in the art. Alternately, they may be pressed
into tablets using techniques conventional in the art.
[0105] The following examples are presented in order to further
illustrate the invention. While all of the examples specifically
relate to matrix dosage forms, their relevance extends to any of
the dosage forms described above. One skilled in the art could use
their teachings to prepare reservoir systems or osmotic pumps
having the pharnacokinetic profile described above.
EXAMPLES
Example 1
[0106] The following example provides a summary of the experimental
work culminating in the formulation of the present invention.
[0107] One gram tablets containing 538 mg of divalproex sodium,
magnesium stearate, dicalcium phosphate, microcrystalline cellulose
(Avicel.RTM., FMC Corporation, Philadelphia, Pa., USA) and/or
lactose and various hydrophilic polymers were prepared. Hydrophilic
polymers tested included hydroxypropyl methylcellulose,
methylcellulose (Methocel.RTM. grades K100LVP CR, K4MP CR,K15MP CR
and K100MP CR, Dow Chemical, Midland, Mich.; USA); hydroxypropyl
cellulose (Klucel.RTM. LF, Hercules, Inc., Wilmington, Del.; USA);
and alginate (Keltone.RTM. grades LVCR and HVCR, Kelco Co., San
Diego, Calif.; USA).
[0108] Bulk drug was milled prior to use and was sized to pass a 40
mesh sieve (0.42 mm nominal mesh opening). The milled and sieved
bulk drug was dry-mixed with polymer and excipients in a Collette
Gral 10 high shear mixer for 5 min at a high chopper speed of 3000
rpm and impeller speed of 200 rpm. Granules were prepared by adding
70 ml/kg of granulation fluid (water or water/ethanol mixtures) to
the polymer/drug/excipient powder mixture over a 1-2 minute period
at high chopper speed of 3000 rpm and impeller speed of 500 rpm.
Additional fluid of 10-165 ml was added in one step as needed in
order to reach granulation end-point. Total granulation time ranged
from 2-18 min.
[0109] Tablet matrix ingredients included microcrystalline
cellulose, lactose, magnesium stearate, and silicon dioxide. The
resulting granules were tray dried at 50.degree. C.-55.degree. C.
overnight under reduced pressure. The dried granules were mixed
with lubricant (magnesium stearate) in a bag and then passed
through a 20 mesh (0.84 mm nominal opening) sieve. Tablets
weighing- 1 g were pressed in a Model C Carver Press tableting
machine using a 0.747 inch (1.9 cm).times.0.360 inch (0.91 cm)
ovaloid die at a compression force between about 2000 lbf (about
8.9.times.10.sup.3 Newtons) and about 10,000 lbf (about
4.45.times.10.sup.4 Newtons), preferably between about 2300 lbf
(1.02.times.10.sup.4 Newtons) to about 5000 lbf
(2.25.times.10.sup.4 Newtons). The tablet compositions are
presented in Table 1.
1TABLE 1 Test Divalproex Matrix Tablet Formulations
Ingredient.sup.1 A B C D E F G H I Divalproex sodium 50 50 50 50 50
53.8 53.8 53.8 53.8 Methocel .RTM. K100LVPCR 18 20 -- -- -- -- --
-- 10 Methocel .RTM. 8 -- -- -- -- -- -- -- -- K4MPCR Klucel .RTM.
LF -- 20 -- -- -- -- -- -- -- Keltone .RTM. -- -- 30 -- -- -- -- --
-- HVCR Methocel .RTM. -- -- -- -- 30 26 35 -- 16 K15MPCR Methocel
.RTM. -- -- -- 15 -- -- -- 30 -- K100MPCR Lactose 23 9.5 9.5 29.5
14.5 14.7 5.7 10.7 14.7 Avicel .RTM. -- 0 5 5 5 5 5 5 5 PH101
PVP.sup.2 -- -- 5 -- -- -- -- -- -- Magnesium Stearate 1 0.5 0.5
0.5 0.5 0.5 0.5 0.5 0.5 .sup.1Percent by weight, based upon the
total tablet weight .sup.1Poly(vinylpyrrolidone)
Initial Formulation Screening
[0110] Initial screening of the matrix tablet formulations was
performed using a number of tests. Tablet hardness for each
formulation was measured using a Model VK2000 VanKel tablet
hardness analyzer and recorded in units of kiloPounds (kP) as the
average of ten trials.
[0111] Friability of the tablets were tested by rotating the
tablets samples 100 times using a Erweka TA friabilator. Friability
of tablets for each formulation were calculated based on the weight
loss of the tablets in this test.
[0112] Bulk density of the formulation granules was measured by
carefully filling a glass graduated cylinder to the 100 ml mark.
Tap density was determined following 100 taps of the filled
cylinder.
[0113] Determination of granule size distribution was performed by
collecting granules larger than 140 mesh (about 0.105 mm nominal
mesh opening) and 40 mesh (about 0.42 mm nominal mesh opening) for
evaluation of the percentage of fines and large granules.
[0114] In vitro dissolution tests were conducted using Apparatus II
described in the United State Pharmacopoeia XXI/National Formulary
XVI. Samples aliquots of 1.5 ml were withdrawn and filtered through
a 0.45 .mu.m filter and assayed by TDX.RTM. fluorescent
polarization immunoassay. Upon withdrawal of each sample, an equal
volume of medium was added to the test mixture to maintain constant
volume. The test conditions were as follows:
2 Apparatus USP II, paddle Medium 1 M HCl for one hour; remaining
time pH 6.8 buffer Volume of medium 900 ml Temperature 37.degree.
C. .+-. 0.5.degree. C. Paddle speed 100 rpm Sampling volume 1.5 ml
Sampling times 0, 0.5, 1, 2, 4, 6, 8, 13, 24 hours
[0115] The results of these tests are presented in Table 2.
[0116] Based upon these initial studies, and the data appearing in
Table 2 above, the following conclusions were drawn:
[0117] (1) Effects on tablet hardness: The use of ethanol as a
granulation fluid tends to increase tablet hardness. There is a
strong interaction between ethanol and particle size of the bulk
drug. The increase in hardness was only observed for formulations
containing drug of larger particle size. The opposite effect was
found for drug of smaller particle size. (2) Effects on friability:
The use of drug having a small particle size reduced friability.
However, this effect was significant only for formulations using
water as granulation fluid.
[0118] (3) Effects on density: The use of ethanol as a granulation
fluid was shown to decrease the density of the granules. However,
significant interactions of ethanol with the use of Klucel.RTM.,
and of ethanol with drug particle size were observed. Ethanol
decreased the density only of formulations containing drug of
larger particle size and/or formulations without Klucel.RTM.
present. The opposite effects were found for formulations
containing smaller drug particles and/or Klucell.RTM.. The same
conclusions were obtained with either tap or bulk density as
response.
[0119] (4) Effects on size of granules: More granules of larger
size were obtained with the use of drug having a larger particle
size. Moreover, interaction between ethanol and Klucel.RTM. was
found to be significant i.e. use of ethanol tends to generate
larger granules when there is no Klucel.RTM. present in the
formulation. No effect was observed for formulations containing 4%
Klucel.RTM.. Factors that showed significant influences on the
percentage of fines in the granules included ethanol, drug particle
size, and their interaction. Using smaller drug particles tended to
yield more fines in the granules. More fines were generated when
ethanol was used as a granulation fluid. The effect of ethanol was
most significant for formulations containing drug of a small
particle size.
[0120] (5) Effects on granulation fluid volume: In order to obtain
granulation end-point, more fluid volume was needed for
formulations containing either drug of a smaller particle size or
with the use of ethanol as granulation fluid.
[0121] (6) In vitro drug release: In vitro percent release of
valproic acid from controlled-release tablets are shown in FIG. 1.
The difference in release profiles among formulations was small. In
the study, percent release at 8 hours (Q.sub.8hr) was used to
represent release rate for data analysis. It was found that the use
of Klucel.RTM. or drug of a larger particle size in the formulation
resulted in an increase in release rate. Similar results were
obtained when Q.sub.10hr or Q.sub.24hr was used to estimate the
release rate.
[0122] Formulations containing high load and high viscosity grades
of polymers often showed poor compressibility. This is believed to
be the result of the increase in polymer order and elasticity with
increasing molecular weight. Hardness of the tablets remained
almost unchanged under compression forces ranging from about 3000
lb (1.3.times.10.sup.4 Newtons) to about 10,000 lb
(4.45.times.10.sup.4 Newtons).
3TABLE 2 Granulating Tap Bulk % Granule Fluid Hardness Friability
Density Density Size >40 Q.sub.8 hr Formulation Volume (kP) (%
Loss) (g/ml) (g/ml) Mesh Fines.sup.1 (%).sup.2 A 100 11.9 0.049
0.504 0.429 22.6 6.1 27.6 B 80 7.2 0.16 0.515 0.438 31.3 9.8 29.0 C
115 12.2 0.025 0.459 0.39 30.2 3.3 28.6 D 80 8.4 0.162 0.459 0.406
38.2 6.6 30.4 E 235 10.4 0.060 0.599 0.509 21.5 40.7 27.0 F 110
12.2 0.006 0.400 0.340 49.2 1.8 28.0 G 200 9.4 0.085 0.596 0.506
24.0 29.7 29.7 H 150 12.9 0.142 0.593 0.504 35.0 22.8 30.0 I 130
9.5 0.015 0.475 0.404 33.8 1.2 28.8 .sup.1Defined as percent
granules passing a 0.105 mm nominal mesh opening .sup.2Defined as
percent drug released in an 8-hour period under the in vitro test
condition
[0123] In order to increase the hardness of tablets,
microcrystalline cellulose and colloidal silicon dioxide were
tested by externally adding small amounts to the granules at levels
of 1-5%. Table 3 shows the results from the test. It was found that
external addition of small amounts of microcrystalline cellulose or
colloidal silicon dioxide significantly increased tablet
hardness.
4TABLE 3 Effect of External Addition of Microcrystalline Cellulose
or Silicon Dioxide Hardness Test Hardness Formulation Additive (kP)
Ia None 6.2 Ib 5% Avicel .RTM. 9.6 Ic 5% Avicel .RTM. and 1%
silicon 13.8 dioxide.sup.1 Iia None -- Iib 1% Silicon dioxide.sup.1
10.9 Iic 5% Avicel .RTM. and 1% silicon 14.4 dioxide.sup.1 IIIa
None 5.8 IIIb 1% Silicon dioxide.sup.1 10.8 IIIc 5% Avicel .RTM.
and 1% silicon 14.8 dioxide.sup.1 .sup.1Silicon dioxide was
Cab-O-Sil M-5 fumed silica (Cabot Corp., Boyertown, PA, USA) having
average particle size of between about 0.2 and 0.3 microns
[0124] As shown by the data in Table 3, the addition of either 1%
silicon dioxide or 5% microcrystalline cellulose to the hydrophilic
matrix formulations of the invention almost doubled tablet
hardness, while adding both resulted in a greater than doubling of
tablet hardness. However, although the results shown above
demonstrated improvement of tablet hardness by the combined use of
the external addition of Avicel.RTM. microcrystalline cellulose and
Cab-o-sil.RTM. silicon dioxide, problems of sticking and relatively
low density persisted. The low bulk density (i.e. 40 g/l) of the
small particle size Cab-O-Sil.RTM. fumed silica led to the problem
of not being able to load sufficient material into the tablet
die.
[0125] In response to this problem, a different silicon dioxide
having a larger average particle. size ranging from about 1 micron
to about 10 microns, preferably ranging between about 2 microns to
about 5 microns, and most preferably about 2-3 microns was used.
One such material is available as Syloid 244, available from W. R.
Grace, Lexington, Mass., USA. When this material was used,
initially intended as a de-tackifying and hardening agent for
tableting, a surprising and unexpected benefit was conferred upon
the formulation, as shown below. The material was added
"externally" to the formulation: that is, the active ingredient,
polymer(s) and excipients were dry blended, wet granulated, and
then dried and sized. The silicon dioxide was then added to the
granular formulation and the resulting mixture blended prior to
pressing into tablets.
[0126] On the basis of the above findings, preferred tablet
formulations were chosen for an in vivo absorption study in healthy
human subjects; The ingredients of the formulations and in vitro
release rates are shown in Table 4 and FIG. 2, respectively. The
formulations were designed to have different release rates by using
high viscosity HPMC alone or blended with low viscosity HPMC. The
target in vitro release rates were chosen to release drug in vivo
for 16-20 hours.
5TABLE 4 Preferred Controlled Release Formulations of the Invention
Preferred Preferred Ingredient Formulation A Formulation B
Divalproex sodium 53.82%.sup.2 53.82% (milled).sup.1 Hydroxypropyl
8% 30% methylcellulose (Methocel .RTM. K15M, CR) Methyl cellulose
18% -- (Methocel .RTM. K100L, CR) Anhydrous lactose 12.18% 8.18%
Microcrystalline cellulose 5% 5% (Avicel .RTM. PH 101) Silicon
dioxide 3% 3% (Average particle size 1 m < >10 .mu.m) (Syloid
.RTM. 244) Total tablet weight 1 g 1 g .sup.1Bulk drug sized to
pass a 40 mesh sieve (0.42 mm nominal mesh opening .sup.2All
percentages in the Table expressed as weight percentages based upon
the total weight of the tablet
[0127] The controlled release tablet formulations of the present
invention thus provide an effective delivery system for the once
daily administration of valproic acid (divalproex sodium) to
patients in need of such treatment. The formulations of the
invention provide substantially level plasma concentrations of
valproic acid falling within the therapeutic range of the drug over
a period which permits administration once daily.
Example 2
[0128] This Example illustrate the manufacture of a preferred
dosage form of the present invention at a larger scale.
[0129] Divalproex sodium was milled through a 0.040" band with
impact forward (flat edge) using a Fluid Air Mill operating at
50-75 rpm feed rate and 3500 rpm mill speed. 81 kg of milled drug
was vacuum loaded directly into the Collette Gral-600 high shear
mixer and mixed with 12.3 kg of lactose, 7.5 kg of microcrystalline
cellulose and 45 kg of hydroxypropylmethycellulos for 5 minutes.
The mixture of drug and excipients was granulated using 18 kg of
purified water for a total of 7 minutes and dried in a fluid bed
dryer until the average moisture content of the granules, measured
by a gravimetric test, is below the in-process control limit of
1.0% w/w. The dried granules are sized using a speed sifter and the
oversize granules are milled through a 0.078" band with impact
forward (flat edge) using a Fluid Air Mill operating at 50 rpm feed
rate and 3500 rpm mill rate. The two fractions of granules are then
recombined and blended with 4.5 kg of silicon dioxide in a
twin-shell blender. The blended mixture is compressed into 1.00
gram tablets with approximately 0-12 kN precompression and 24 kN
main compression force using a rotary tableting machine (Fette
2090) operating at 35-50 rpm.
Example 3
Multiple Dose Study
[0130] The bioavailability and plasma concentration versus time
profile of valproate from an oral extended-release tablet
formulation of divalproex sodium (made as in Example 2) determined
under fasting and nonfasting conditions was compared to those of a
commercially available enteric coated divalproex sodium
delayed-release tablet formulation (Depakote.RTM., Abbott
Laboratories; reference) determined under fasting conditions in
healthy subjects. The study was conducted according to a
multiple-dose, open-label, three-period, randomized, complete
crossover design. In each period, a six-day regimen was
administered with a minimum of 16 days separating the first doses
of consecutive periods. The three regimens were:
[0131] Regimen A: Extended-release formulation 1000 mg q24h
administered under fasting conditions (test/invention)
[0132] Regimen B: Extended-release formulation 1000 mg q24h
administered 30 minutes after breakfast was served
(test/invention)
[0133] Regimen C: Depakote enteric coated tablet 500 mg ql2h
administered under fasting conditions (reference/bid
comparator)
[0134] A schedule of the doses and meal times for the three
regimens follows.
6TABLE 5 Regimen Formulation Time of Dose Breakfast Lunch Dinner
Snack A Test ER 6:00 a.m. 8:00 a.m. 12 N 8:00 pm 10:30 pm B Test ER
6:00 a.m. 5:30 a.m. 12 N 8:00 pm 10:30 pm C Reference DR 6:00 a.m.
8.00 a.m. 12 N 8:00 pm 10:30 pm 6:00 p.m. ER = Extended-Release; DR
= Delayed Release (enteric-coated).
[0135] Fourteen healthy adult subjects (11 male and 3 female
subjects) completed all phases of the study. The mean age was 27
years (range 19-51 years), mean height was 69 inches (range 63-74
inches) and weight was 161 pounds (range 120-200 pounds).
[0136] Blood samples (7 mL) were collected at 0, 12, 24, 36, 48,
60, 72, 84, 96, 108, 120, 121, 122, 123, 124.5, 126, 127.5, 129,
130.5, 132, 133, 134, 135, 136.5, 138, 139.5, 141, 142.5 and 144
hours after the first dose of each period. Plasma samples were
analyzed for valproic acid using a validated gas-liquid
chromatographic method with flame ionization detection at Oneida
Research Services, Inc., Whitesboro, N.Y.
Pharmacokinetic and Statistical Analyses
[0137] Pharmacokinetic parameters were estimated by
noncompartmental techniques. For Day 6 data, these included
C.sub.max, T.sub.max, C.sub.min, AUC.sub.0-24, and degree of
fluctuation DFL). If C.sub.max, for the reference occurred after
the second dose of Day 6, T.sub.max, was taken to be the time since
the second dose rather than the time from the first dose.
[0138] Analyses of variance (ANOVAs) appropriate for crossover
models were performed for T.sub.max, DFL, and for the natural
logarithms of C.sub.min, C.sub.max, and AUC.sub.0-24. Within the
framework of the ANOVA, the regimens were compared pair-wise, each
comparison done by a test at significance level of 0.05.
Equivalence of the two formulations with respect to AUC was
addressed by performing the two one-sided tests procedure at
significance level 0.05 within the framework of the ANOVA on the
logarithm of AUC. As a further aid for assessing the
characteristics of the ER formulation, 95% confidence intervals for
the ratios of the ER formulation central values to the reference
regimen central value were obtained from the ANOVAs for logarithms
of C.sub.min and C.sub.max. In addition, a two one-sided tests
procedure was carried out to compare the fasting and nonfasting
extended-release formulation regimens.
[0139] The mean valproic acid plasma concentration-time profiles
for the three regimens are shown in FIG. 3.
[0140] The pharmacokinetic results for Day 6 of each regimen are
summarized in the following Table 6.
7 TABLE 6 Mean (Standard Deviatian), n = 14 T.sub.max C.sub.max
C.sub.min AUC.sub.0-24 Regimen (hr) (.mu.g/mL) (.mu.g/mL) (.mu.g
.multidot. hr/mL) DFL A 13.6 (6.3)* 80.5 (18.6)* 48.2 (17.0) 1592
(402) 0.523 (0.231) B 15.9 (4.5)* 85.0 (12.5)* 55.1 (13.3) 1709
(276) 0.432 (0.127)* C 3.6 (0.9) 99.4 (15.7) 54.1 (13.1) 1789 (332)
0.623 (0.160) *Statistically significantly different from Regimen
C. Regimen A: Divalproex Sodium ER; 2 .times. 500 mg once daily,
fasting. Regimen B: Divalproex Sodium ER; 2 .times. 500 mg once
daily, nonfasting. Regimen C: Depakote Tablet; 500 mg twice daily,
fasting.
[0141] The mean T.sub.max for Regimens A and B were about
three-fold longer than that of Regimen C. The differences in
T.sub.max between Regimens A and C and between B and C were
statistically significant. Regimens A and B tended to have lower
C.sub.max than that of Regimen C, and these differences were
statistically significant. The regimens did not differ
statistically significantly with respect to C.sub.min The mean DFL
for both ER Regimens A and B was lower than that of the reference,
and the difference between Regimen B and the reference was
statistically significant.
[0142] The 95% confidence intervals for bioavailability of the ER
regimens relative to the reference for C.sub.max and C.sub.min are
given below. The point estimate for the ratio of the central values
for both C.sub.max and C.sub.min for Regimen A, and C.sub.max for
Regimen B, were lower than 1.0. The point estimate of the ratio for
C.sub.min for Regimen B was approximately unity.
8 TABLE 7 Relative Bioavailability C.sub.max C.sub.min 95% 95%
Regimen Point Confidence Point Confidence Test Reference Estimate
Interval Estimate Interval A C 0.811 0.742-0.887 0.847 0.672-1.067
B C 0.861 0.788-0.941 1.026 0.814-1.293 Regimen A: Divalproex
Sodium ER; 2 .times. 500 mg once daily, fasting. Regimen B:
Divalproex Sodium ER; 2 .times. 500 mg once daily, nonfasting.
Regimen C: Depakote Tablet; 500 mg twice daily, fasting.
[0143] The results for the two one-sided tests procedure for
equivalence assessment of the regimens via a 90% confidence
interval based on the natural logarithm of AUC.sub.0-24 are given
below.
9TABLE 8 Two One-Sided Tests Procedure for Equivalence Assessment,
Day 6 AUC Relative Bioavailability 90% Confidence Test Reference
Point Estimate Interval A C 0.891 0.817-0.971 B C 0.970 0.890-1.058
A B 0.918 0.842-1.001 Regimen A: Divalproex Sodium ER; 2 .times.
500 mg once daily, fasting. Regimen B: Divalproex Sodium ER: 2
.times. 500 mg once daily, nonfasting. Regimen C: Depakote Tablet:
500 mg twice daily, fasting.
[0144] The 900% confidence intervals for AUC on Day 6 for the test
ER formulation administered under fasting (A) and nonfasting (B)
conditions versus the reference fasting (C), both satisfied the
0.80-1.25 criterion for equivalence. Additionally, the 90%
confidence interval for the ratio of central values of AUC for the
test ER formulation fasting:nonfasting regimens also satisfied the
equivalence criterion.
[0145] The extended-release formulation performs well. The
extended-release regimens are equivalent to the reference regimen
with respect to extent of absorption as characterized by AUC. The
two test regimens did not differ statistically significantly from
the reference regimen with respect to C.sub.min The lower C.sub.max
and later T.sub.max central values of the extended-release regimens
compared the reference regimen suggest that the ER formulation
provides extended release of valproic acid in vivo under fasting
and nonfasting conditions. The mean DFL for the extended-release
formulation administered under nonfasting conditions is lower
(.about.31%) than that of the reference regimen (observed means of
0.432 and 0.623, p<0.05). The mean DFL for the extended-release
formulation administered under fasting conditions was also lower
(.about.16%) than that of the reference regimen although
statistical significance was not attained (observed means of 0.523
and 0.623, p=0.126).
Example 4
Multiple Dose Study
[0146] The bioavailability and plasma concentration-time profile of
valproic acid from a new oral extended-release tablet formulation
of divalproex sodium (invention, made as in Example 2) was compared
to that from the currently marketed divalproex sodium
enteric-coated delayed-release tablet (Depakote.RTM. Abbott
Laboratories; reference) under multiple-dose conditions.
[0147] Sixteen subjects enrolled in the study. They had a mean age
of 34 years (range 19-55 years), mean height of 69 inches (range
65-75 inches), and mean weight of 180 pounds (range 148-209
pounds). This was a multiple-dose, open-label, 2-period, crossover
study with no washout between periods in healthy adult male and
female subjects comparing the extended-release (ER/invention) test
formulation (2.times.500 mg qd) with the delayed-release
(DR/bid/prior art) Depakote enteric-coated tablet (500 mg ql 2h) as
the reference. In one part of the study (Groups I and II), 4
subjects started on the ER test tablet in the morning and switched
over to the 500 mg DR tablet bid on Day 7 (end of Period 1) and
continued on it through Day 12 (Period 2). The other four subjects
(Group II) started with the DR tablet and switched over to the ER
test tablet in the morning of Day 7 and continued through Day 12.
The second part of the study (Groups III and IV) was a repeat of
the first part except that the test formulation was given in the
evening instead of in the morning. The ER formulation was
administered after a meal, and the DR tablet was given under
fasting conditions.
[0148] A schematic of the formulations administered and the meal
times follows.
10TABLE 9 Formulation Time of Dose Breakfast Lunch Dinner Snack
Morning Dose for ER Formulations ER 6 am 5:30 am 12 N 5:30 pm 10:30
pm DR 6 am, 6 pm 8:00 am 12 N 8:00 pm 10:30 pm Evening Dose for ER
Formulations ER 6 pm 5:30 am 12 N 5:30 pm 10:30 pm DR 6 pm, 6 am
8:00 am 12 N 8:00 pm 10:30 pm ER = Extended-Release (Invention); DR
= Delayed-Release (prior art).
[0149] Regimens: The regimens administered were as follows.
[0150] A: Divalproex sodium extended-release tablets, 500 mg
valproic acid equivalents; 2.times.500 mg tablets once every 24
hours starting with a morning dose. (invention)
[0151] B: Divalproex sodium enteric-coated delayed-release tablets
(same as Depakote, Abbott Laboratories, reference); one 500 mg
tablet once every 12 hours starting with a morning dose.
[0152] C: Divalproex sodium extended-release tablets, 500 mg
valproic acid equivalents; 2.times.500 mg tablets once every 24
hours starting with an evening dose. (invention)
[0153] D: Divalproex sodium enteric-coated delayed-release tablets
(same as Depakote, Abbott Laboratories, reference; one 500 mg
tablet once every 12 hours starting with an evening dose.
[0154] Blood samples (7 mL) were taken at 0, 12, 24, 36,.48, 60,
72, 84, 96, 108, 120, 121, 122, 123, 124.5, 126, 127.5, 129, 130.5,
132, 133, 134, 135, 136.5, 138, 139.5, 141, 142.5 and 144 hours
from the first dose of each period. Blood samples were taken on the
same schedule for Groups III and IV except that they were 12 hours
later than for Groups I and II (i.e., first blood sample at 6 p.m.
instead of 6 a.m.). Plasma samples were analyzed for valproic acid
using a validated gas-liquid chromatographic method with flame
ionization detection at Oneida Laboratories, N.Y.
Pharmacokinetic and Statistical Analyses
[0155] Pharmacokinetic parameters were estimated by
noncompartmental techniques. For Day 6 and 12 data, C.sub.max,
T.sub.max, C.sub.min, AUC.sub.0-24 and DFL were calculated. If
T.sub.max, occurred after the second dose of Day 6 or 12, T.sub.max
was taken to be the time since the second dose rather than the time
from the first dose natural logarithms of C.sub.min, C.sub.max, and
AUC.sub.0-24. The model had effects for time (whether subject
received ER formulation in morning or evening), formulation
sequence, subjects nested within time by formulation sequence,
formulation period, and the interaction of time with each of
formulation sequence, formulation and period. Subject effects were
random and all other effects were fixed. Equivalence of the two
formulations with respect to AUC was addressed by performing the
two one-sided tests procedure within the framework of the ANOVA on
the logarithm of AUC. This confidence interval for relative
bioavailability was obtained by exponentiating the endpoints of a
90% confidence interval for the difference of logarithm means
(difference of formulation main effects). As a further aid for
assessing the characteristics of the ER formulation, 95% confidence
intervals for bioavailability relative to that of the reference
formulation were obtained from the ANOVAs for logarithms of
C.sub.min and C.sub.max. The mean plasma valproic acid
concentrations following administration of the 1000 mg test
formulation once every 24 hours (Regimnens A and C) or the 500 mg
reference formulation once every 12 hours (Regimnens B and D) for
Days 6 and 12 are shown in FIG. 4.
[0156] The pharmacokinetic results for Day 6 of each regimen are
summarized in the following table.
11 TABLE 10 Mean (% Coefficient of Variation) C.sub.max C.sub.min
AUC.sub.0-24 Regimen (.mu.g/mL) (.mu.g/mL) (.mu.g .multidot. hr/mL)
DFL ER formulation in morning (n = 8) A 0-24 hr 87 (17.3) 55.5
(38.7) 1771 (22.8) 0.46 (55.9) B 0-24 hr 102 (10.5) 53.3 (26.2)
1798 (16.6) 0.67 (31.2) ER formulation in evening (n = 8) C 0-24 hr
85 (10.0) 57.4 (14.9) 1728 (12.5) 0.39(19.7) D 0-24 hr 98 (10.2)
54.7 (13.9) 1747 (10.5) 0.60 (12.3) All groups combined A and C
0-24 hr 86 (13.8) 56.4 (28.1) 1749 (17.9) 0.42 (44.3) B and D 0-24
hr 100 (10.3) 54.0 (20.2) 1773 (13.6) 0.64 (24.8) Regimen A:
Divalproex Sodium ER; 2 .times. 500 mg in a.m., nonfasting. Regimen
B: Depakote DR Tablet; 500 mg in a.m. and 500 mg in p.m., fasting.
Regimen C: Divalproex Sodium ER; 2 .times. 500 mg in p.m.,
nonfasting. Regimen D: Depakote DR Tablet; 500 mg in p.m. and 500
mg in a.m., fasting.
[0157] There were no statistically significant differences in the
pharmacokinetic results between subjects who received the ER
formulation in the morning and those who received the ER
formulation in the evening. Hence, the conclusions are based on the
combined data of the groups.
[0158] The mean DFL of the ER formulation was statistically
significantly lower than that of the reference. The two
formulations differed statistically significantly-with respect to
C.sub.max, but not with respect to C.sub.min and AUC. For C.sub.max
and C.sub.min, the 95% confidence interval for bioavailability of
the ER formulation relative to that of the reference was 0.80 to
0.91 and 0.89 to 1.18, respectively. The 90% confidence interval by
which the two one-sided tests procedure was performed for AUC was
0.924 to 1.041, being entirely within the equivalence range of 0.80
to 1.25.
[0159] Mean C.sub.max for the test formulation on Day 6 for both
periods, when the plasma valproic acid concentrations were
characterized, was lower than the reference formulation and was
statistically significantly different. Mean AUC.sub.0-24 for Day 6
of each period was not significantly different between the test and
reference formulations. Relative bioavailability based on the ratio
(test:reference) of mean logarithm of AUC.sub.0-24 (90% confidence
interval) was 0.981 (0.924 to 1.041). The degree of fluctuation was
statistically significantly smaller for the test formulation (0.42)
than for the reference (0.64). The results demonstrate the
extended-release characteristics of the test formulation and its
similarity in bioavailability based on AUC when compared to the
reference formulation.
Example 5
[0160] Based on the results of one multicenter, randomized,
double-blind, placebo-controlled clinical trial, the formulation of
Example 2 (hereinafter "Depakote ER") was well tolerated in the
prophylactic treatment of migraine headache. Of the 122 patients
exposed to Depakote ER in the placebo-controlled study, 8%
discontinued for adverse events, compared to 9% for the 115 placebo
patients.
[0161] a) Invention
[0162] The study below describes the side effect profile of a qd
divalproex sodium dosage form according to this invention.
[0163] Table 11 includes those adverse events reported for patients
in the placebo-controlled trial where the incidence rate in the
Depakote ER-treated group was greater than 5% and was greater than
that for placebo patients.
12TABLE 11 Adverse Events R ported by >5% f D pakote Extended
Release (ER/Invention) Patients During the Migraine
Placebo-Extended Trial with a Greater Incidence than Patients
Taking Placebo.sup.1 Body System Depakote ER Placebo Event (N =
122) (N = 115) Gastrointestinal Nausea 15% 9% Dyspepsia 7% 4%
Diarrhea 7% 3% Vomiting 7% 2% Abdominal Pain 7% 5% Nervous System
Somnolence 7% 2% Other Infection 15% 14% .sup.1The following
adverse events occurred in greater than 5% of Depakote ER-treated
patients and at a greater incidence for placebo than for Depakote
ER: asthenia and flu syndrome.
[0164] The following additional adverse events were reported by
greater than 1% but not more than 5% of Depakote ER-treated
patients and with a greater incidence than placebo in the
placebo-controlled clinical trial for migraine prophylaxis:
[0165] Body as a Whole: Accidental injury, viral infection.
[0166] Digestive System: Increased appetite, tooth disorder.
[0167] Metabolic and Nutritional Disorders: Edema, weight gain.
[0168] Nervous System: Abnormal gait, dizziness, hypertonia,
insomnia, nervousness, tremor, vertigo.
[0169] Respiratory System: Pharyngitis, rhinitis.
[0170] Skin and Appendages: Rash.
[0171] Special Senses: Tinnitus.
[0172] b) Prior Art
[0173] The study below describes the side effect profile of
Depakote DR
[0174] Based on two placebo-controlled clinical trials and their
long term extension, Depakote DR tablets were generally well
tolerated with most adverse events rated as mild to moderate in
severity. Of the 202 patients exposed to Depakote DR tablets in the
placebo-controlled trials, 17% discontinued for intolerance. This
is compared to a rate of 5% for the 81 placebo patients. The
adverse events reported as the primary reason for discontinuation
by greater than or equal to 1% of 248 Depakote DR-treated patients
were alopecia.(6%), nausea and/or vomiting (5%), weight gain (2%),
tremor (2%), somnolence (1%), elevated SGOT and/or SGPT (1%), and
depression (1%).
[0175] Table 12 includes those adverse events reported for patients
in the placebo-controlled trials where the incidence rate in the
Depakote DR-treated group was greater than 5% and was greater than
that for placebo patients.
13TABLE 12 Adverse Events Reported by >5% of Depakote Delayed
Release (DR/prior art) Patients During Migraine Placebo-Extended
Trials with a Greater Incidence than Patients Taking Placebo.sup.1
Body System Depakote DR Placebo Event (N = 202) (N = 81)
Gastrointestinal System Nausea 31% 10% Dyspepsia 13% 9% Diarrhea
12% 7% Vomiting 11% 1% Abdominal Pain 9% 4% Increased Appetite 6%
4% Nervous System Asthenia 20% 9% Somnolence 17% 5% Dizziness 12%
6% Tremor 9% 0% Other Weight Gain 8% 2% Back Pain 8% 6% Alopecia 7%
1% .sup.1The following adverse events occurred in greater than 5%
of Depakote DR-treated patients and at a greater incidence for
placebo than for Depakote DR: flu syndrome and pharyngitis.
[0176] The following additional adverse events not referred to
above were reported by greater than 1% but not more than .sup.5% of
Depakote DR-treated patients and with a greater incidence than
placebo in the placebo-controlled clinical trials:
[0177] Body as a Whole: Chest pain.
[0178] Cardiovascular System: Vasodilatation.
[0179] Digestive System: Constipation, dry mouth, flatulence,
stomatitis.
[0180] Hemic and Lymphatic System: Ecchymosis.
[0181] Metabolic and Nutritional Disorders: Peripheral edema.
[0182] Musculoskeletal System: Leg cramps.
[0183] Nervous System: Abnormal dreams, confusion, paresthesia,
speech disorder,
[0184] thinking abnormalities.
[0185] Respiratory System: Dyspnea, sinusitis.
[0186] Skin and Appendages: Prumtus.
[0187] Urogenital System: Metrorrhagia.
[0188] Although the safety of ER and DR formulations were not
assessed in the same study, a cross-study comparison of the data
presented in Tables 11 and 12 suggest that the rate of adverse
events were similar in the placebo-treated patients of the three
well-controlled randomized studies. It is evident from Tables 11
and 12 that while the adverse events in the placebo-treated
subjects were similar, Depakote ER-treated patients had lower
number of adverse events compared to the Depakote DR-treated
patients. It can be deduced that the reduced adverse events seen
with Depakote ER treatment compared to Depakote DR treatment is
probably due to the expected lower maximal plasma concentrations
(C.sub.max) and DFL that would be achieved, as illustrated in
Examples 3 & 4, following administration of equal doses of two
the formulations. It is reasonably believed that the reduced
adverse effects, as well as lower frequency of dosing (once-a-day)
dosing achieved with Depakote ER, would lead to better
compliance.
[0189] The controlled release tablet formulations of the present
invention thus provide an effective delivery system for the once
daily administration of valproic acid (divalproex sodium) to
patients in need of such treatment. The formulations of the
invention provide substantially level plasma concentrations of
valproic acid falling within the therapeutic range of the drug over
a period which permits administration once daily. Further the
incidence of side effects associated with valproate therapy has
been reduced with this new formulation.
[0190] While there have been shown and described what are the
preferred embodiments of the invention, one skilled in the
pharmaceutical formulation art will appreciate that various
modifications in the formulations and process can be made without
departing from the scope of the invention as it is defined by the
appended claims.
* * * * *
References