U.S. patent application number 14/053117 was filed with the patent office on 2014-02-13 for once-weekly oral administration of aripiprazole.
This patent application is currently assigned to ZYSIS LIMITED. The applicant listed for this patent is Zysis Limited. Invention is credited to Russell PENDLETON, Ian WILDING.
Application Number | 20140044786 14/053117 |
Document ID | / |
Family ID | 37421592 |
Filed Date | 2014-02-13 |
United States Patent
Application |
20140044786 |
Kind Code |
A1 |
WILDING; Ian ; et
al. |
February 13, 2014 |
ONCE-WEEKLY ORAL ADMINISTRATION OF ARIPIPRAZOLE
Abstract
An orally deliverable pharmaceutical composition provides
controlled release of aripiprazole. The composition includes a
therapeutically effective amount of aripiprazole and at least one
pharmaceutically acceptable excipient. The compositions of the
invention may exhibit one or more of the release profiles defined
in the specification.
Inventors: |
WILDING; Ian; (Beeston,
GB) ; PENDLETON; Russell; (Mortlake, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Zysis Limited |
Beeston |
|
GB |
|
|
Assignee: |
ZYSIS LIMITED
Beeston
GB
|
Family ID: |
37421592 |
Appl. No.: |
14/053117 |
Filed: |
October 14, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12443036 |
Mar 26, 2009 |
8575172 |
|
|
PCT/GB07/03677 |
Sep 26, 2007 |
|
|
|
14053117 |
|
|
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Current U.S.
Class: |
424/489 ;
424/400; 514/253.07 |
Current CPC
Class: |
A61P 19/10 20180101;
A61P 3/10 20180101; A61P 25/00 20180101; A61K 47/38 20130101; A61P
25/20 20180101; A61K 31/496 20130101; A61P 25/22 20180101; A61P
25/28 20180101; A61K 9/2054 20130101; A61P 25/14 20180101; A61P
25/16 20180101; A61P 43/00 20180101; A61P 25/24 20180101; A61P 1/00
20180101; A61P 25/18 20180101; A61K 45/06 20130101; A61P 25/08
20180101; A61P 25/30 20180101; A61P 11/06 20180101 |
Class at
Publication: |
424/489 ;
514/253.07; 424/400 |
International
Class: |
A61K 47/38 20060101
A61K047/38; A61K 45/06 20060101 A61K045/06; A61K 31/496 20060101
A61K031/496 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 26, 2006 |
GB |
0618879.1 |
Claims
1. A method of treating a patient with one or more of a
neurological and a psychiatric condition selected from the group
consisting of a depressive disorder, an affective disorder, an
addiction, attention deficit hyperactivity disorder and
combinations thereof, the method comprising orally administering to
the patient once weekly a pharmaceutical composition for the
controlled release of aripiprazole, the pharmaceutical composition
comprising a therapeutically effective amount of aripiprazole and
at least one release-retarding material that retards the release of
the aripiprazole such that the aripiprazole released from the
composition is effective in treating the neurological or
psychiatric condition for a period of one week.
2. The method of claim 1, wherein the composition is formulated as
a diffusion-controlled formulation, a dissolution-controlled
formulation, an erosion-controlled formulation, an osmotic pump
technology formulation, a sprinkle dosage formulation, an
enteric-coated formulation, an ion exchange resin, or a combination
thereof.
3. The method of claim 1, wherein the composition is in the form of
a capsule, tablet, liquid, powder, granule, suspension, matrix,
microsphere, seed, pellet, bead or a combination of any two or more
thereof.
4. The method of claim 1, wherein the release retarding material is
selected from the group consisting of a water-soluble synthetic
polymer, a cellulose-based polymer, a hydrocolloid, a fatty acid,
an alcohol, a wax, a water-insoluble biodegradable polymer, a
plastic, a rubber, an ion-exchange resin, or a combination of two
or more thereof.
5. The method of claim 4, wherein the water-soluble synthetic
polymer is selected from the group consisting of poly (acrylic
acid), poly (ethylene oxide), poly (ethylene glycol), poly (vinyl
pyrrolidone), poly (vinyl pyrrolidone) copolymers, poly (vinyl
alcohol), polyacrylamide, poly (isopropyl acrylamide), poly
(cyclopropyl methacrylamide), thermogelling acrylamide derivatives,
carbomers, Carbopol.RTM. polymers, polyacrylic acid cross-linked
with divinyl glycol, or a combination of two or more thereof.
6. The method of claim 4, wherein the cellulose-based polymer is
selected from the group consisting ethyl cellulose, hydroxyethyl
cellulose, hydroxypropyl cellulose, hydroxypropyl butylcellulose,
cellulose acetate phthalate, sodium carboxymethylcellulose,
cellulose acetate, cellulose acetate butyrate, hydroxypropyl
methycellulose phthalate, hydroxypropyl methycellulose succinate,
cellulose acetate methylcarbamate, cellulose acetate
ethylcarbamate, cellulose dimethylaminoacetate, or a combination of
two or more thereof.
7. The method of claim 4, wherein the hydrocolloid is selected from
the group consisting alginic acid, sodium alginate, xanthan gum,
carrageenan gum, hyaluronic acid, pectin, pectinic acid, guar gum,
xylan gum, chitosan, locust bean gum, gellan gum, welan gum,
rhamsan gum, algin gum, guar, acacia, karaya, tragacanth, starch,
or a combination of two or more thereof.
8. The method of claim 4, wherein the fatty acid, alcohol or wax is
selected from the group consisting hydrogenated castor oil,
hydrogenated vegetable oil, glyceryl behenate, glyceryl
monostearate, stearic acid, cetyl alcohol, cetostearyl alcohol,
carnauba wax, beeswax, polyoxyglycerides, glycerol esters, oleyl
glycerate, glyceryl monooleate, selachyl alcohol, cocoa butter,
cocoa butter propylene glycol monostearate, cocoa butter propylene
glycol distearate, hydrogenated fat, hardened oil or fat, stearyl
alcohol, glycowax, castor wax, dextran, shellac, tribehenin,
C.sub.16-30 fatty acid triglycerides, or a combination of two or
more thereof.
9. The method of claim 4, wherein the water-insoluble biodegradable
polymer is selected from the group consisting poly
(lactide-co-glycolide), polylactic acid, polyglycolic acid, or a
combination of two or more thereof.
10. The method of claim 4, wherein the plastic or rubber is
selected from the group consisting polyurethane, silicones,
polycarbonate, polychloroprene, polyisobutylene, polycyanoacrylate,
poly (vinyl acetate), poly (vinyl acetate) copolymers, poly (vinyl
acetate) phthalate, poly (vinyl chloride), polyethylene, poly
(methyl methacrylates), poly (methyl methacrylate) copolymers,
ethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkyl
methacrylate copolymer, poly(methacrylic acid), methacrylic acid
alkylamide copolymer, poly(methacrylic acid anhydride), poly
(hydroxyethyl methacrylate), polyacrylamide, acrylic acid and butyl
acrylate copolymer, 2-ethylhexyl acrylate and butyl acrylate
copolymer, vinyl acetate and methyl acrylate copolymer,
polyurethane hydrogel, semipermeable polyamide, semipermeable
polyurethane, semipermeable polysulfane, semipermeable sulfonated
polystyrene, semipermeable silicon rubber, semipermeable poly
(sodium styrenesulfonate), semipermeable poly(vinylbenzyltrimethyl)
ammonium chloride, or a combination of two or more thereof.
11. The method of claim 4, wherein the ion-exchange resin is
selected from the group consisting styrene/divinylbenzene resin and
methacrylic acid/divinylbenzene resin, or a combination of two or
more thereof.
12. The method of claim 1, wherein the composition comprises at
least one pharmaceutically active agent in addition to
aripiprazole.
13. The method of claim 12, wherein the at least one additional
pharmaceutically active agent is selected from the group consisting
of one or more atypical antipsychotic agent, antiparkinsonian
agent, sedative, anxiolytic, antidepressant, monoamine oxidase A or
B inhibitor, tetracyclic antidepressant, serotonin re-uptake
inhibitor, noradrenaline reuptake inhibitor, adrenaline reuptake
inhibitor, and mood stabilizer, or a combination of two or more
thereof.
14. The method of claim 1, wherein the treatment is associated with
the partial agonist properties of aripiprazole on neurotransmitter
pathways in the brain.
15. The method of claim 1, wherein one or more of the neurological
and a psychiatric condition is associated with dopamine
receptors.
16. A method of treating a patient with one or more of a
neurological and a psychiatric condition selected from the group
consisting of a depressive disorder, an affective disorder, an
addiction, attention deficit hyperactivity disorder and
combinations thereof, the method comprising orally administering to
the patient once weekly a pharmaceutical composition for the
controlled release of aripiprazole, the pharmaceutical composition
comprising a therapeutically effective amount of aripiprazole and
at least one release-retarding material comprising a
water-swellable polymer that forms a matrix that retards the
release of the aripiprazole such that the aripiprazole released
from the composition is effective in treating the neurological or
psychiatric condition for a period of one week.
17. A method of treating a patient with one or more of a
neurological and a psychiatric condition selected from the group
consisting of schizophrenia, bipolar disorder, schizoaffective
disorders, and combinations thereof, the method comprising orally
administering to the patient once weekly a pharmaceutical
composition for the controlled release of aripiprazole, the
pharmaceutical composition comprising a therapeutically effective
amount of aripiprazole and at least one release-retarding material
that retards the release of the aripiprazole such that the
aripiprazole released from the composition is effective in treating
the neurological or psychiatric condition for a period of one week,
wherein the release retarding material is selected from the group
consisting of a water-soluble synthetic polymer, a cellulose-based
polymer, a hydrocolloid, a fatty acid, an alcohol, a wax, a
water-insoluble biodegradable polymer, a plastic, a rubber, an
ion-exchange resin, or a combination of two or more thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a division of co-pending U.S. patent
application Ser. No. 12/443,036, filed Mar. 26, 2009, which in turn
was a Section 371 U.S. National Stage application of International
Application No. PCT/GB2007/003677, filed Sep. 26, 2007, which was
published in the English language on Apr. 3, 2008, under
International Publication No. WO/2008/038003 A2, the disclosures of
each of which are hereby incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] The invention relates to pharmaceutical formulations
comprising aripiprazole. More particularly, the invention relates
to orally deliverable pharmaceutical compositions for the
controlled release of aripiprazole.
[0003] Aripiprazole is
7-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]-3,4-dihydro-1H-quinoli-
n-2-one and has the following structure:
##STR00001##
[0004] Aripiprazole appears to mediate its antipsychotic effects
primarily by partial agonism at the D2 receptor. Partial agonism at
D2 receptors has been shown to modulate dopaminergic activity in
areas where dopamine activity may be high or low, such as the
mesolimbic and mesocortical areas of the schizophrenic brain,
respectively. In addition to partial agonist activity at the D2
receptor, aripiprazole is also a partial agonist at the 5-HT1A
receptor, and like the other atypical antipsychotics, aripiprazole
displays an antagonist profile at the 5-HT2A receptor. Aripiprazole
has moderate affinity for histamine and alpha adrenergic receptors,
and no appreciable affinity for cholinergic muscarinic receptors.
Aripiprazole is currently used for the treatment of schizophrenia
and acute manic/mixed episodes associated with Bipolar I
Disorder.
[0005] Clinical activity is thought to be primarily due to the
parent drug, aripiprazole, and to a lesser extent, to its major
metabolite, dehydro-aripiprazole, which has been shown to have
affinities for D2 receptors similar to the parent drug and
represents 40% of the parent drug exposure in plasma (see
ABILIFY.RTM. (aripiprazole) prescribing information, Otsuka
Pharmaceutical Co., Ltd, Tokyo, 101-8535, June 2006). The mean
elimination half-lives are about 75 hours and 94 hours for
aripiprazole and dehydro-aripiprazole, respectively. Steady-state
concentrations are attained within 14 days of initial dosing for
both active moieties. Aripiprazole accumulation is predictable from
single-dose pharmacokinetics. At steady state, the pharmacokinetics
of aripiprazole are dose-proportional. Elimination of aripiprazole
is mainly through hepatic metabolism involving two Cytochrome P450
isozymes, CYP2D6 and CYP3A4 (Kubo M et al Influence of itraconazole
co-administration and CYP2D6 genotype on the pharmacokinetics of
the new antipsychotic ARIPIPRAZOLE. Drug Metab Pharmacokinet. 2005
February; 20(1):55-64).
[0006] Aripiprazole is well absorbed after administration of the
immediate release (IR) tablet, with peak plasma concentrations
occurring within 3 to 5 hours after dosing; the absolute oral
bioavailability of the IR tablet formulation is 87%. Administration
of a 15-mg aripiprazole IR tablet with a standard high-fat meal
does not significantly affect the C.sub.max or AUC of aripiprazole
or its active metabolite, dehydro-aripiprazole, but delays
T.sub.max by 3 hours for aripiprazole and 12 hours for
dehydro-aripiprazole. Aripiprazole is also well absorbed when
administered orally as the solution. At equivalent doses, the
plasma concentrations of aripiprazole from the solution were higher
than that from an IR tablet formulation.
[0007] In a relative bioavailability study comparing the
pharmacokinetics of 30 mg aripiprazole as an oral solution to 30 mg
aripiprazole IR tablets in healthy subjects, the solution to tablet
ratios of geometric mean C.sub.max and AUC values were 122% and
114%, respectively. The steady-state volume of distribution of
aripiprazole following intravenous administration is high (404 L or
4.9 L/kg), indicating extensive extravascular distribution. At
therapeutic concentrations, aripiprazole and its major metabolite
are greater than 99% bound to serum proteins, primarily to albumin.
In healthy human volunteers administered 0.5 to 30 mg/day
aripiprazole for 14 days, there was dose-dependent D2 receptor
occupancy indicating brain penetration of aripiprazole in humans
(Swainston Harrison T and Perry C M. Aripiprazole: a review of its
use in schizophrenia and schizoaffective disorder. Drugs. 2004;
64(15):1715-36).
[0008] Aripiprazole is metabolized primarily by three
biotransformation pathways: dehydrogenation, hydroxylation, and
N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6
enzymes are responsible for dehydrogenation and hydroxylation of
aripiprazole, and N-dealkylation is catalyzed by CYP3A4.
Aripiprazole is the predominant drug moiety in the systemic
circulation. At steady state, dehydro-aripiprazole, the active
metabolite, represents about 40% of aripiprazole AUC in plasma.
[0009] Approximately 8% of Caucasians lack the capacity to
metabolize CYP2D6 substrates and are classified as poor
metabolizers (PM), whereas the rest are extensive metabolizers
(EM). PMs have about an 80% increase in aripiprazole exposure and
about a 30% decrease in exposure to the active metabolite compared
to EMS, resulting in about a 60% higher exposure to the total
active moieties from a given dose of aripiprazole compared to Ems.
The mean elimination half-lives are about 75 hours and 146 hours
for aripiprazole in EMs and PMs, respectively. Aripiprazole does
not inhibit or induce the CYP2D6 pathway.
[0010] Following a single oral dose of [.sup.14C]-labeled
aripiprazole, approximately 25% and 55% of the administered
radioactivity was recovered in the urine and feces, respectively.
Less than 1% of unchanged aripiprazole was excreted in the urine
and approximately 18% of the oral dose was recovered unchanged in
the feces.
[0011] The recommended starting and target dose for aripiprazole in
schizophrenia is 10 or 15 mg/day administered on a once-a-day
schedule without regard to meals. If an increased dosage is
required it is recommended that this should not be made before 2
weeks; the time needed to achieve steady state. In bipolar disease,
the starting dose is 30 mg given once a day. However, in a phase
III clinical trials, approximately 15% of patients had their dose
decreased to 15 mg based on assessment of tolerability (Drugs at
FDA; Abilify.RTM. (NDA#021436 Tablet Oral)).
[0012] The listing or discussion of a prior-published document in
this specification should not necessarily be taken as an
acknowledgement that that document is part of the state of the art
or is common general knowledge.
[0013] There are a number of disadvantages associated with the
dosage regimen for aripiprazole described above for treating
schizophrenia, bipolar disease and other CNS conditions. Market
research suggests that patients much prefer oral medications that
can be taken as infrequently as possible and that are well
tolerated. The once daily oral administration dosage regime may be
considered too frequent for many patients. In addition, a
significant subset of the target population for aripiprazole is
likely to be patients that are both elderly and forgetful. Such
patients often require time consuming and expensive supervised
administration.
BRIEF SUMMARY OF THE INVENTION
[0014] The subject invention seeks to address one or more of the
above-mentioned deficiencies by the provision of an orally
deliverable pharmaceutical composition for the controlled release
of aripiprazole. The composition comprises a therapeutically
effective amount of aripiprazole and at least one pharmaceutically
acceptable excipient. These compositions (hereinafter denoted "the
compositions of the invention" unless otherwise stated) may be used
for the treatment of schizophrenia, bipolar disease and a number of
other medical indications as described later in this
specification.
[0015] The compositions of the invention are believed to have
advantages such as (but not limited to) one or more of the
following advantages.
[0016] Typically, the compositions of the invention control (e.g.
delay, prolong or sustain) the release of an aripiprazole dose so
that after administration, the adverse event profile is reduced, or
at least not significantly increased, compared to the current
dosage regimen.
[0017] Put another way, the compositions of the invention allow
greater quantities of aripiprazole to be administered in one dose
without significantly increasing adverse events compared to the
current once daily conventional IR dosing regimen. Any reduction in
dosing frequency is thought to bring material improvements in
patient convenience and compliance.
[0018] Reduction in dosing frequency offers significant
pharmacoeconomic advantages over the current dosing regimen by
reducing the indirect human cost of drug treatment (e.g. by
reducing medical practitioners' time required for supervised drug
administration).
[0019] The compositions of the invention also provide a once daily
dosage regimen in which the release of aripiprazole is controlled.
It is thought that this to could reduce the adverse event profile
compared to currently available once daily dosage regimens and/or
provide a more efficient once daily dose regimen.
[0020] Unless otherwise indicated herein, the term "aripiprazole"
refers to
7-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]-3,4-dihydro-1H-quin-
olin-2-one, its pharmaceutically acceptable salts, and mixtures
thereof. "Pharmaceutically acceptable salts" includes derivatives
of aripiprazole, wherein aripiprazole is modified by making
non-toxic acid or base salts thereof, and further refers to
pharmaceutically acceptable solvates (including hydrates) of such
salts. Examples of pharmaceutically acceptable salts include, but
are not limited to, mineral or organic acid salts of the amine
functionality of aripiprazole. The pharmaceutically acceptable
salts include non-toxic salts and the quaternary ammonium salts of
aripiprazole formed, for example, from organic and inorganic acids.
Such salts include those derived from inorganic acid such
hydrochloric, hydrobromic, hydroiodic, sulphuric, phosphoric,
nitric, metal salts such as sodium salt, potassium salt and cesium
salt, alkaline earth metal salts such as calcium salt and magnesium
salt and combinations of the foregoing. Pharmaceutically acceptable
organic salts include salts prepared from organic acids such as
acetic, trifluoroacetic propionic, succinic, glycolic, stearic,
lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,
hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic,
esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric,
toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic,
isethionic, HO.sub.2C--(CH.sub.2).sub.n--CO.sub.2H (where n=0-4)
and salts prepared from amino acids such as arginate, asparginate
and glutamate. Preferred pharmaceutically acceptable organic salts
include salts prepared from organic acids such as acetic,
trifluoroacetic propionic, succinic, glycolic, stearic, lactic,
malic, tartaric, citric, ascorbic, maleic, hydroxymaleic,
phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic,
besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
methanesulfonic, ethanedisulfonic, oxalic, isethionic,
HO.sub.2C--(CH.sub.2).sub.n--CO.sub.2H (where n=0-4) and salts
prepared from amino acids such as arginate, asparginate and
glutamate. The term "pharmaceutically acceptable salts" also
includes mixtures of any of the foregoing derivatives of
aripiprazole.
[0021] By the term "orally deliverable", we include the meaning
suitable for oral, including peroral and intra-oral (e.g.
sublingual or buccal) administration. Preferably, the compositions
of the invention are designed for peroral administration to a
patient, i.e. by swallowing (e.g. eating or drinking).
[0022] By the term "controlled release", we include the meaning
that after administration, release of the aripiprazole is
controlled so that a dosage regimen in which aripiprazole can be
administered less frequently than the current dosage regimen, for
example less frequently than once daily can be provided (however,
improved release profiles for once daily administration are also
included in this regard). This may include delaying and/or
prolonging and/or sustaining the release of aripiprazole so that
the time between doses of aripiprazole can be increased. Such
delayed/prolonged/sustained release may also be accompanied by a
higher single dose of aripiprazole in the compositions of the
invention compared to the currently used once daily IR
formulations.
[0023] The compositions of the invention are suitable for a
controlled release once daily (OD) dose regimen, and dose regimens
less frequent than OD. By dose regimens less frequent than OD, we
include once every 2, 3, 4, 5 or 6 days, thrice weekly, twice
weekly (TW), once weekly (OW) and combinations thereof. A preferred
group of dose regimens are OD, once every 2 days (i.e. every other
day), TW and OW, for example once every 2 days, TW and OW.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] The foregoing summary, as well as the following detailed
description of the invention, will be better understood when read
in conjunction with the appended drawings. For the purpose of
illustrating the invention, there are shown in the drawings
embodiments which are presently preferred. It should be understood,
however, that the invention is not limited to the precise
arrangements and instrumentalities shown. In the drawings:
[0025] FIG. 1 is a graph showing the release of aripiprazole over
time as set forth in Table 3 of Example 2.
[0026] FIG. 2 is a graph showing the release of aripiprazole over
time as set forth in Table 4 of Example 2.
[0027] FIG. 3 is a graph showing the release of aripiprazole over
time as set forth in Table 5 of Example 2.
[0028] FIG. 4 is a graph showing the release of aripiprazole over
time as set forth in Table 6 of Example 2.
[0029] FIG. 5 includes graphs of simulated plasma concentrations of
aripiprazole following repeated once-daily oral doses of 5, 10, 15
and 20 mg IR as set forth in Example 3.
[0030] FIG. 6 includes graphs showing steady-state simulations of
aripiprazole following 30 mg IR orally administered every other day
as compared to simulations after once-daily oral dosing of 15 mg IR
as set forth in Example 3.
[0031] FIG. 7 includes graphs showing steady-state simulations of
aripiprazole following 15 mg IR orally administered every other day
as compared to simulations after once-daily oral dosing of 15 mg IR
as set forth in Example 3.
[0032] FIG. 8 includes graphs showing steady-state simulations of
aripiprazole in a 14 hour sustained release ("SR") formulation
following 30 mg orally administered every other day as compared to
simulations after once-daily oral dosing of 15 mg IR as set forth
in Example 3.
[0033] FIG. 9 includes graphs showing steady-state simulations of
aripiprazole in a 14 hour SR formulation following 60 mg orally
administered weekly as compared to simulations after once-daily
oral dosing of 15 mg IR as set forth in Example 3.
[0034] FIG. 10 includes graphs showing steady-state simulations of
aripiprazole in a 14 hour SR formulation following 30 mg orally
administered twice weekly as compared to simulations after
once-daily oral dosing of 15 mg IR as set forth in Example 3.
[0035] FIG. 11 includes graphs showing steady-state simulations of
aripiprazole in a 14 hour SR formulation following 45 mg orally
administered twice weekly as compared to simulations after
once-daily oral dosing of 15 mg IR as set forth in Example 3.
[0036] FIG. 12 includes graphs showing steady-state simulations of
aripiprazole in a 14 hour SR formulation following 60 mg orally
administered twice weekly as compared to simulations after
once-daily oral dosing of 15 mg IR as set forth in Example 3.
[0037] FIG. 13 includes graphs showing steady-state simulations of
aripiprazole in a 10 hour SR formulation following 30 mg orally
administered every other day as compared to simulations after
once-daily oral dosing of 15 mg IR as set forth in Example 3.
[0038] FIG. 14 includes graphs showing steady-state simulations of
aripiprazole in an 18 hour SR formulation following 30 mg orally
administered every other day as compared to simulations after
once-daily oral dosing of 15 mg IR as set forth in Example 3.
[0039] FIG. 15 includes graphs showing steady-state simulations of
aripiprazole in a 10 hour SR formulation following 60 mg orally
administered weekly as compared to simulations after once-daily
oral dosing of 15 mg IR as set forth in Example 3.
[0040] FIG. 16 includes graphs showing steady-state simulations of
aripiprazole in an 18 hour SR formulation following 60 mg orally
administered weekly as compared to simulations after once-daily
oral dosing of 15 mg IR as set forth in Example 3.
[0041] FIG. 17 includes graphs showing steady-state simulations of
aripiprazole in a 10 hour SR formulation following 45 mg orally
administered twice weekly as compared to simulations after
once-daily oral dosing of 15 mg IR as set forth in Example 3.
[0042] FIG. 18 includes graphs showing steady-state simulations of
aripiprazole in an 18 hour SR formulation following 45 mg orally
administered twice weekly as compared to simulations after
once-daily oral dosing of 15 mg IR as set forth in Example 3.
[0043] FIG. 19 includes graphs showing steady-state simulations of
aripiprazole in a 14 hour SR formulation following 15 mg orally
administered once-daily as compared to simulations after once-daily
oral dosing of 15 mg IR as set forth in Example 3.
[0044] FIG. 20 includes graphs showing steady-state simulations of
aripiprazole in a 10 hour SR formulation following 15 mg orally
administered once-daily as compared to simulations after once-daily
oral dosing of 15 mg IR as set forth in Example 3.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0045] The controlled release characteristics of the compositions
of the invention may be defined in relation to their in vitro or in
vivo release profile or related values such as C.sub.max, T.sub.max
and AUC, as described in more detail below.
[0046] For example, the compositions of the invention may exhibit
an in vitro release profile wherein on average no more than about
60% of the aripiprazole, preferably no more than about 50%, more
preferably no more than about 40% is dissolved within 3 hours after
placement in a standard dissolution test.
[0047] Unless otherwise indicated, as used herein, the term
"standard dissolution test", means a test conducted according to
the "Paddle Method" at 100 rpm in 900 ml of a dissolution medium of
aqueous physiological pH range between 1 and 7 at 37.degree. C., as
described in the United States Pharmacopoeia, or other test
conditions substantially equivalent thereto, e.g. 0.1 M
hydrochloric acid and pH 4.0 phosphate buffer.
[0048] As noted above, the subject invention is concerned with
providing dosage regimens with either less frequent dosing than the
current once daily dosage regimen or controlled delivery of the
daily dose. Compositions having the in vitro release profile
defined above may be suitable for both OD administration and dose
regimens requiring even less frequent administration of the drug
containing composition than OD, as explained in more detail
below.
[0049] For the avoidance of doubt, by the phrase "dose regimens
requiring even less frequent administration of the drug containing
composition than OD", as used herein in relation to the
compositions of the invention having the controlled release
characteristics described herein (e.g. in vitro release profile),
we include once every 2, 3, 4, 5 or 6 days, thrice weekly, twice
weekly (TW), once weekly (OW) and combinations thereof.
[0050] The compositions of the invention which may be suitable for
OD administration may typically exhibit an in vitro release profile
wherein on average from about 10 to about 50%, such as from about
15 to about 45%, for example from about 15 to about 30% of the
aripiprazole is dissolved within 3 hours after placement in a
standard dissolution test.
[0051] The compositions of the invention which may be suitable for
dose regimens requiring even less frequent administration of the
drug containing composition than OD may typically exhibit an in
vitro release profile wherein on average from about 2 to about 40%
(e.g. about 2 to about 30 or 35%), such as from about 5 to about
25%, for example from about 10 to about 20% of the aripiprazole is
dissolved within 3 hours after placement in a standard dissolution
test.
[0052] The compositions of the invention which may be suitable for
OD administration may typically exhibit an in vitro release profile
wherein on average from about 25 to about 100%, such as from about
30 to about 100%, for example from about 40 to about 100% or about
50 to about 100% of the aripiprazole is dissolved within 8 hours
after placement in a standard dissolution test.
[0053] The compositions of the invention which may be suitable for
dose regimens requiring even less frequent administration of the
drug containing composition than OD may typically exhibit an in
vitro release profile wherein on average no more than about 70% of
the aripiprazole, preferably no more than about 60%, more
preferably no more than about 50%, for example no more than about
40% is dissolved within 8 hours after placement in a standard
dissolution test. Typically, such compositions exhibit an in vitro
release profile wherein on average from about 10 to about 65%, such
as from about 15 to about 55%, for example from about 20 to about
45% of the aripiprazole is dissolved within 8 hours after placement
in a standard dissolution test.
[0054] The compositions of the invention may exhibit an in vitro
dissolution rate after placement in a standard dissolution test
wherein:
[0055] from about 2 to about 50% of the aripiprazole is released
after 2 hours;
[0056] from about 5 to about 80% of the of the aripiprazole is
released after 4 hours;
[0057] 25% or more of the aripiprazole is released after 8 hours;
and
[0058] 40% or more of the aripiprazole is released after 12
hours.
[0059] Preferably, the in vitro release rate is independent of pH
between 1 and 7.
[0060] Compositions having the in vitro release profile defined
above may be suitable for both OD administration and dose regimens
requiring even less frequent administration of the drug containing
composition than OD, as explained in more detail below.
[0061] The compositions of the invention which may be suitable for
OD administration may typically exhibit an in vitro dissolution
rate after placement in a standard dissolution test wherein:
[0062] from about 5 to about 40% (e.g. from 10 to 30%) of the
aripiprazole is released after 2 hours;
[0063] from about 15 to about 70% (e.g. from 20 to 50%) of the
aripiprazole is released after 4 hours; and
[0064] 50% or more (e.g. 60% or more) of the aripiprazole is
released after 8 hours.
[0065] Preferably, the in vitro release rate is independent of pH
between 1 and 7.
[0066] The compositions of the invention which may be suitable for
dose regimens requiring even less frequent administration of the
drug containing composition than OD may typically exhibit an in
vitro dissolution rate after placement in a standard dissolution
test wherein:
[0067] from about 2 to about 35%, such from about 2 to about 25%
(e.g. from 5 to 15%) of the aripiprazole is released after 2
hours;
[0068] from about 5 to about 50% (e.g. from 10 to 40) of the
aripiprazole is released after 4 hours;
[0069] from about 25 to about 80% (e.g. from 30 to 60) of the
aripiprazole is released after 8 hours; and
[0070] 40% or more (e.g. 50% or more) of the aripiprazole is
released after 12 hours.
[0071] Preferably, the in vitro release rate is independent of pH
between 1 and 7.
[0072] The compositions of the invention may exhibit an in vivo
aripiprazole plasma absorption profile following single dose oral
administration wherein the time for 50% of the aripiprazole to be
absorbed into the plasma (of a human or animal patient) is at least
2 hours, preferably at least 3 hours, more preferably at least 4
hours (e.g. at least about 5 or 6 hours).
[0073] The phrase "aripiprazole plasma absorption profile" is
intended to refer to the plasma concentration of aripiprazole over
time following administration to a human or animal patient. As
known to those skilled in the art, the plasma absorption profile
may be measured by deconvolution of continuous release
pharmacokinetics versus an immediate release reference.
[0074] Compositions having the in vivo release profile defined
above may be suitable for both OD administration and dose regimens
requiring even less frequent administration of the drug containing
composition than OD, as explained in more detail below.
[0075] The compositions of the invention which may be suitable for
OD administration may typically exhibit an in vivo aripiprazole
plasma absorption profile following single dose oral administration
wherein the time for 50% of the aripiprazole to be absorbed into
the plasma is from about 2 to about 12 hours, such as from about 3
to about 10 hours, for example from about 4 to about 9 hours or
from about 5 to about 7 hours (e.g. about 6 hours).
[0076] The compositions of the invention which may be suitable for
dose regimens requiring even less frequent administration of the
drug containing composition than OD may typically exhibit an in
vivo aripiprazole plasma absorption profile following single dose
oral administration wherein the time for 50% of the aripiprazole to
be absorbed into the plasma is from about 6 to about 24 hours, such
as from about 7 to about 20 hours, for example from about 8 to
about 18 hours or from about 10 to about 16 hours.
[0077] The compositions of the invention may also be defined in
terms of the amount of aripiprazole which is released from the
compositions in vivo at specified periods of time following oral
administration. For example, compositions of the invention may
typically exhibit a release profile wherein:
[0078] from about 2 to about 50% of the aripiprazole is released
within 2 hours following administration;
[0079] from about 5 to about 80% of the aripiprazole is released
within 4 hours following administration;
[0080] 25% or more of the aripiprazole is released within 8 hours
following administration; and
[0081] 40% or more of the aripiprazole is released within 12 hours
following administration.
[0082] Compositions having the in vivo release profile defined
above may be suitable for both OD administration and dose regimens
requiring even less frequent administration of the drug containing
composition than OD, as explained in more detail below.
[0083] The compositions of the invention which may be suitable for
OD administration may typically exhibit an in vivo aripiprazole
plasma absorption profile wherein:
[0084] from about 5 to about 40% (e.g. from 10 to 30%) of the
aripiprazole is released within 2 hours following
administration;
[0085] from about 15 to about 70% (e.g. from 20 to 50%) of the
aripiprazole is released within 4 hours following administration;
and
[0086] 50% or more (e.g. 60% or more) of the aripiprazole is
released within 8 hours following administration.
[0087] The compositions of the invention which may be suitable for
dose regimens requiring even less frequent administration of the
drug containing composition than OD typically exhibit an in vivo
aripiprazole plasma absorption profile wherein:
[0088] from about 2 to about 35%, such from about 2 to about 25%
(e.g. from 5 to 15%) of the aripiprazole is released within 2 hours
following administration;
[0089] from about 5 to about 50% (e.g. from 10 to 40%) by weight of
the aripiprazole is released within 4 hours following
administration;
[0090] from about 25 to about 80% (e.g. from 30 to 60%) of the
aripiprazole is released within 8 hours following administration;
and
[0091] 40% or more (e.g. 50% or more) of the aripiprazole is
released within 12 hours following administration.
[0092] The controlled release characteristics of the compositions
of the invention which may be suitable for OD administration may be
defined in relation to the peak plasma concentration (C.sub.max)
value of aripiprazole when administered to human or animal
patients. For example, the compositions of the invention which may
be suitable for OD administration typically exhibit a aripiprazole
C.sub.max value following oral administration of from about 10 to
about 99%, such as from about 20 to about 80%, for example from
about 25 to about 70% (e.g. from about 30 to about 60%) of the
C.sub.max value achieved using a conventional immediate release
(IR) dosage form of aripiprazole when administered orally at an
identical dose.
[0093] The phrase "conventional immediate release (IR) dosage form
of aripiprazole" includes the meaning that the dosage form releases
substantially all of the aripiprazole contained therein
immediately, for example within 30 minutes of administration. In
other words, such IR dosage forms typically have substantially no
component which acts to delay and/or prolong and/or sustain the
release of aripiprazole. This definition is intended to include the
compositions of aripiprazole described in the introductory pages of
this specification which are currently typically used for the
treatment of schizophrenia and bipolar disease.
[0094] The controlled release characteristics of the compositions
of the invention which may be suitable for OD administration may be
defined by the ratio of the peak plasma concentration (C.sub.max)
of aripiprazole to the plasma concentration of aripiprazole 24
hours following administration (C.sub.24) when administered to
human or animal patients and prior to the administration of any
further doses. The compositions of the invention typically exhibit
a C.sub.max to C.sub.24 ratio, preferably under steady state
conditions, that is less than about 3:1, preferably less than about
2:1, more preferably less than about 1.5:1, such as from 1.1:1 to
about 1.5:1 (e.g. about 1:1).
[0095] The compositions of the invention may exhibit one or more of
the controlled release profiles defined above.
[0096] The compositions of the invention comprise a therapeutically
effective amount of aripiprazole and at least one pharmaceutically
acceptable excipient. In order to achieve one or more of the
controlled release profiles described above, the therapeutically
effective amount of aripiprazole may be formulated in numerous
different ways, including, but not limited to diffusion-controlled
formulations (such as wax matrices or pellets),
dissolution-controlled formulations (such as press-coated
formulations), dissolution/diffusion-controlled formulations,
easily administrable formulations (such as chewable, fast
dissolving, sprinkle or taste-masked formulations), enteric-coated
formulations, osmotic pump technology formulations,
tamper-resistant formulations, erosion-controlled formulations, ion
exchange resins and combinations of the foregoing. The above
formulations will be described in more detail below.
[0097] The formulations described herein for the compositions of
the invention are designed primarily for oral administration.
Suitable oral dosage forms include, but are not limited to
capsules, tablets, liquids, powders, granules, suspensions,
matrices, microspheres, seeds, pellets and/or beads of the
foregoing formulations. Combinations of these dosage forms may also
be used in the invention. For example, an oral dosage form
containing aripiprazole may be in the form of microtablets enclosed
inside a capsule, e.g. a hydroxypropylmethylcellulose (HPMC)
capsule or a gelatin capsule. Any suitable gelatin capsule may be
used, for example the hard gelatin capsule known as CAPSUGEL.
[0098] The solid oral dosage forms described above may typically
utilise drug substance which may have an average particle size of
greater than 100 nm, preferably greater than 500 nm, 1000 nm or
2000 nm (e.g. greater than 2500 nm).
[0099] The compositions of the invention may be diffusion
controlled formulations. By the term "diffusion controlled
formulations", we include formulations in which diffusion of
dissolved aripiprazole from the formulation has a significant role
in the rate of controlled release of aripiprazole from that
formulation. However, dissolution processes may also be involved.
Typical diffusion controlled formulations include so-called
"reservoir systems", in which a core of aripiprazole is coated with
a polymer (typically a water-insoluble polymer), and so-called
"matrix systems", in which the aripiprazole is dispersed throughout
a matrix (e.g. a swellable matrix), which may optionally be coated.
In either system, flow and egress of the dissolved drug is
controlled so as to achieve one or more of the release profiles
defined above.
[0100] The compositions of the invention may be based on matrix
technology. In this technology, aripiprazole is embedded in an
excipient that makes a non-disintegrating core called a matrix.
Diffusion of (dissolved) aripiprazole occurs through the core.
[0101] Preferably, the controlled release compositions of the
invention are formulated so there is at least some time-delay
before significant plasma concentrations of aripiprazole are
achieved. In other words, the compositions of the invention may
have a delayed and/or sustained and/or prolonged release component.
Such compositions may avoid an initial burst of aripiprazole, or
may be formulated so that release of aripiprazole in a particular
part of the gastrointestinal tract (e.g. the stomach) is retarded.
This may be useful for minimizing the adverse event profiles
associated with aripiprazole.
[0102] Enteric coated formulations, which may protect the stomach
against any irritant effects of aripiprazole, are also desirable.
Such formulations can be coated with a composition that is
non-toxic and includes a pharmaceutically acceptable enteric
polymer, which is predominantly soluble in the intestinal fluid,
but substantially insoluble in the gastric juices.
[0103] Typically, the compositions of the invention extend the
aripiprazole release, e.g. by several hours, compared to
aripiprazole release in the known immediate release dosage
form.
[0104] The compositions of the invention may comprise a
release-retarding material. The release-retarding material can be,
for example, in the form of a matrix or a coating. The compositions
of the invention may comprise, for example, a particle of
aripiprazole that is combined with a release-retarding material.
The release-retarding material is typically a material that permits
release of aripiprazole at a sustained rate in an aqueous medium.
The release-retarding material can be selectively chosen so as to
achieve, in combination with the other stated properties, a desired
release rate.
[0105] Release-retarding materials may be hydrophilic and/or
hydrophobic polymers and/or materials. Suitable release-retarding
materials include but are not limited to acrylic polymers,
alkylcellulose, shellac, zein, hydrogenated vegetable oil,
hydrogenated caster oil, and combinations comprising one or more of
the foregoing materials. The compositions of the invention
typically may contain between about 1% and about 80% (by weight) of
the release-retarding material.
[0106] Suitable acrylic polymers include, for example, acrylic and
methacrylic acid copolymers, methyl methacrylate copolymers,
ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl
methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid),
methacrylic acid alkylamide copolymer, poly(methyl methacrylate),
poly(methacrylic acid anhydride), methyl methacrylate,
polymethacrylate, poly(methyl methacrylate) copolymer,
polyacrylamide, aminoalkyl methacrylate copolymer, glycidyl
methacrylate copolymers, and combinations comprising one or more of
the foregoing polymers.
[0107] Suitable alkylcelluloses include, for example,
ethylcellulose. Those skilled in the art will appreciate that other
cellulosic polymers, including other alkyl cellulosic polymers, can
be substituted for part or all of the ethylcellulose.
[0108] Other suitable hydrophobic materials are typically
water-insoluble and may have a melting point of from about
30.degree. C. to about 200.degree. C., preferably from about
45.degree. C. to about 90.degree. C. The hydrophobic material may
include neutral or synthetic waxes, fatty alcohols (such as lauryl,
myristyl, stearyl, cetyl or preferably cetostearyl alcohol), fatty
acids, including fatty acid esters, fatty acid glycerides (mono-,
di-, and tri-glycerides), hydrogenated fats, hydrocarbons, hardened
oils or fats (e.g. hardened rapeseed oil, caster oil, beef tallow,
palm oil, soya bean oil) waxes, stearic acid, stearic acid, stearyl
alcohol, polyethylene glycol, hydrophobic and hydrophilic materials
having hydrocarbon backbones, and combinations comprising one or
more of the foregoing materials.
[0109] Suitable waxes include beeswax, glycowax, castor wax,
carnauba wax and wax-like substances, e.g. materials which are
normally solid at room temperature and have a melting point of from
about 30.degree. C. to about 100.degree. C., and combinations
comprising two or more of the foregoing waxes.
[0110] The release-retarding material also may comprise digestible,
long chain (e.g., C.sub.8-C.sub.50, preferably C.sub.12-C.sub.40),
substituted or unsubstituted hydrocarbons, such as fatty acids,
fatty alcohols, glyceryl esters of fatty acids, mineral and
vegetable oils, waxes, and combinations comprising one or more of
the foregoing materials. Hydrocarbons having a melting point of
from about 25.degree. C. to about 90.degree. C. may be used. The
compositions of the invention may contain up to about 60% by weight
of at least one digestible, long chain hydrocarbon and/or up to 60%
by weight of at least one polyalkylene glycol.
[0111] The release-retarding material also may comprise polylactic
acid, polyglycolic acid, or a co-polymer of lactic acid and
glycolic acid. The release-retarding material optionally includes
other additives such as an erosion-promoting agent (e.g. starch and
gums) and/or a semi-permeable polymer.
[0112] Release-modifying agents, which affect the release
properties of the composition, may optionally be used in the
compositions of the invention. The release-modifying agent may, for
example, function as a pore-former. Typically, a pore-former
creates channels which facilitate (e.g., accelerate) drug release.
The pore former can be organic or inorganic, and may include
materials that can be dissolved, extracted or leached from the
coating in the environment of use. The pore-former can comprise one
or more hydrophilic polymers, such as hydroxypropylmethylcellulose,
lactose, metal stearates (e.g. alkali metal stearates such as
magnesium stearate), polycarbonates (linear polyesters of carbonic
acid in which carbonate groups reoccur in the polymer chain), and
combinations comprising two or more of the foregoing
release-modifying agents.
[0113] The release-retarding material can also include an exit
means comprising at least one passageway, orifice, or the like. The
passageway can have any shape, such as round, triangular, square or
elliptical. Such exit means may be used in osmotic pump
formulations, which are described in more detail herein.
[0114] In addition to the above ingredients, the compositions of
the invention may also contain suitable quantities of other
materials, e.g. diluents, lubricants, binders, granulating aids,
colorants, flavorants and glidants that are conventional in the
pharmaceutical art.
[0115] Examples of suitable lubricants include stearic acid,
magnesium stearate, glyceryl behenate, talc, mineral oil (in PEG).
Examples of suitable binders include water-soluble polymers, such
as modified starch, gelatine, polyvinylpyrrolidone, polyvinyl
alcohol, etc. Examples of suitable fillers include lactose,
microcrystalline cellulose. An example of a glidant is silicon
dioxide.
[0116] The compositions of the invention may include one or more
substrates comprising aripiprazole. Such substrates may be coated
with a sustained and/or delayed and/or prolonged release coating
comprising a release-retarding material. Such compositions may be
used in a multiparticulate system, such as beads, ion-exchange
resin beads, spheroids, microspheres, seeds, pellets, matrices,
granules, and other multiparticulate systems in order to obtain the
desired controlled release of aripiprazole. The multiparticulate
system can be presented in a capsule or other suitable unit dosage
form, such as a tablet or a sachet.
[0117] In certain cases, more than one multiparticulate system may
be used, each exhibiting different characteristics, such as pH
dependence of release, time for release in various media (e.g.
acid, base simulated intestinal fluid), release in vivo, size and
composition.
[0118] In some cases, excipients to encourage spheronization may be
used together with the active ingredient to form spheroids.
Microcrystalline cellulose and hydrous lactose impalpable are
examples of such spheronizing agents. Additionally (or
alternatively), the spheroids may contain a water insoluble
polymer, preferably an acrylic polymer, an acrylic copolymer, such
as a methacrylic acid-ethyl acrylate copolymer, or ethyl cellulose.
In such a formulation, any sustained release coating present may
include a water insoluble material such as a wax, either alone or
in admixture with a fatty alcohol, or shellac or zein.
[0119] Spheroids or beads, coated with an active ingredient may be
prepared, for example, by dissolving the aripiprazole in water and
then spraying the solution onto a substrate such as sugar spheres.
Optionally, additional ingredients may be added prior to coating
the beads in order to assist the active ingredient binding to the
substrates, and/or to colour the solution, etc. The resulting
substrate-active material may be overcoated with a barrier
material, to separate the aripiprazole from the next coat of
material, e.g. a release-retarding material. The barrier material
may be a material comprising hydroxypropyl methylcellulose.
However, any film-former known in the art may be used. Preferably,
the barrier material increases stability during processing and/or
shelf-life, without affecting the dissolution rate of the final
product.
[0120] In order to achieve the desired release characteristics,
aripiprazole may be coated with an amount of release-retarding
material sufficient to obtain a weight gain level from about 1 to
about 80% (e.g. from about 2 to about 40%), although more or less
release-retarding material may be used depending, for example, on
the desired release-rate. Moreover, there may be more than one
release-retarding material used in the coating, as well as various
other pharmaceutical excipients.
[0121] The release-retarding material may be in the form of a film
coating comprising a dispersion of a hydrophobic polymer. Solvents
typically used for application of the release-retarding coating
include pharmaceutically acceptable solvents, such as water,
alcohols (e.g. methanol or ethanol), methylene chloride, and
combinations comprising one or more of the foregoing solvents.
[0122] The in vivo and/or in vitro release profile of the
compositions of the invention may be altered, for example
optimised, by using more than one release-retarding material, by
varying the thickness of the release-retarding material, by
changing the particular release-retarding material used, by
altering the relative amounts of release-retarding material, by
altering the manner in which any plasticizer present is added, by
varying the amount of plasticizer relative to retardant material,
by the inclusion of additional ingredients or excipients, by
altering the method of manufacture, or by combinations of the
foregoing.
[0123] In addition to or instead of being present in a matrix, the
release-retarding agent can be in the form of coating. Optionally,
a core can be coated, or a gelatine capsule can be further coated,
with a sustained and/or delayed and/or prolonged release coating
such as those described herein. The coatings may include a
sufficient amount of a hydrophobic material to obtain increase the
weight of the dosage from about 1 to about 80% (e.g. from about 2
to about 40%), although the coating can increase the weight of the
dosage form by a larger percent depending on the desired release
rate, among other things.
[0124] The compositions of the invention preferably release
aripiprazole slowly, e.g., when ingested and exposed to gastric
fluids, and then to intestinal fluids. The controlled release
profile of the formulations may be altered, for example, by varying
the amount of release-retarding agent, e.g. hydrophobic material,
by varying the amount any plasticizer present relative to
hydrophobic material, by the inclusion of additional ingredients or
excipients, by altering the method of manufacture, or combinations
of the foregoing.
[0125] The compositions of the invention may be prepared in such a
way that, substantially all of aripiprazole is present in amorphous
form. The term "amorphous" is intended to mean consisting of
disordered arrangements of molecules which do not possess a
distinguishable crystal lattice. A typical process for forming a
composition comprising amorphous aripiprazole comprises mixing
aripiprazole with water and a pharmaceutically acceptable polymeric
carrier and drying the mixture to form a composition comprising
amorphous aripiprazole and the polymeric carrier.
[0126] Suitable pharmaceutically acceptable polymeric carriers
include, for example, hydroxypropyl cellulose, methyl cellulose,
carboxymethyl cellulose, sodium carboxymethyl cellulose, cellulose
acetate phthalate, cellulose acetate butyrate, hydroxyethyl
cellulose, ethyl cellulose, polyvinyl alcohol, polypropylene,
dextran, dextrins, hydroxypropyl-beta-cyclodextrin, chitosan,
lactic/glycolid copolymers, polyorthoester, polyanhydrate,
polyvinyl chloride, polyvinyl acetate, ethylene vinyl acetate,
lectins, carbopols, silicon elastomers, polyacrylic polymers,
maltodextrins, lactose, fructose, inositol, trehalose, maltose,
raffinose, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG),
and alpha-, beta-, and gamma-cyclodextrins, and combinations of the
foregoing carriers.
[0127] Preferred polymeric carriers are one or more of
polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl
cellulose, methyl cellulose, block copolymers of ethylene oxide and
propylene oxide, and polyethylene glycol. The polyvinylpyrrolidone
(PVP) typically has an average molecular weight of from about 2,500
to about 3,000,000, for example from about 10,000 to about
450,000.
[0128] The polymeric carrier is preferably (i) miscible with both
aripiprazole free base and its pharmaceutically acceptable salts
(especially the hydrochloride salt), (ii) capable of keeping the
salt in a homogeneous noncrystalline solid state dispersion after
the water has been removed by evaporation, (iii) chemically inert
with respect to aripiprazole and (iv) at least partially water
soluble, and more preferably is fully water soluble.
[0129] Aripiprazole, the polymeric carrier, and water may be
combined in any order. Typically, they are combined in a manner so
as to form a solution of aripiprazole and the polymeric carrier. In
forming a solution of the polymeric carrier and water, heating the
solution is not generally necessary at lower concentrations but is
preferred at higher concentrations, provided that the temperature
does not result in decomposition or degradation of any materials.
It is preferred to add aripiprazole after dissolving the polymeric
carrier in water, suitably at from about 25 to about 100.degree.
C., for example from about 45 to about 80.degree. C., in order to
form a clear solution.
[0130] The ratio of aripiprazole to the polymeric carrier can be
varied depending, for example, on the precise release profile
required. Typical weight ratios of polymeric carrier to
aripiprazole range from about 100:1 to about 0.5:1, preferably from
about 50:1 to about 1:1, such as from about 20:1 to about 2:1 (e.g.
about 5:1).
[0131] Upon formation of the (preferably clear) solution, the
process proceeds by recovering the water to form a solid state
dispersion of the aripiprazole in the polymeric carrier. Any method
of removal of the water which provides a homogeneous solid state
dispersion can be used, suitable methods including evaporation
under vacuum or spray drying. Methods of evaporation under vacuum
include rotary evaporation, static vacuum drying and the
combination thereof. One skilled in the art of pharmaceutical
formulations can readily determine a reasonable temperature at
which water can be removed, provided the temperature is not so high
as to cause degradation or decomposition of the materials.
Typically, evaporation occurs at from about 25.degree. C. to about
100.degree. C. Evaporation of water should provide a solid state
dispersion which is homogeneous and substantially free of water. By
substantially free it is meant that the solid state dispersion
typically contains less than 20% by weight of residual water,
preferably less than 10%, more preferably less than 5%, most
preferably less than 1%.
[0132] Any suitable pharmaceutically acceptable excipient can be
added to the compositions of the invention. Examples of
pharmaceutically acceptable excipients include diluents,
aripiprazole vehicles, binders, disintegrants, glidants,
sweeteners, compression aids, colouring agents, flavoring agents,
suspending agents, dispersing agents, film formers, printing inks,
lubricants and/or preservatives. These excipients may be used in a
conventional manner, and alone or in any combination.
[0133] The pharmaceutical composition may be formulated by
conventional methods of admixture such as blending, filling,
granulation and compressing. Direct compression and wet granulation
are two examples of methods which may be used to formulate the
compositions of the invention. These and other methods are
described and/or exemplified in more detail hereinafter.
[0134] Excipients may be added for numerous reasons, for example to
facilitate manufacture, enhance stability, control release, enhance
product characteristics, enhance bioavailability, enhance patient
acceptability and combinations thereof.
[0135] Exemplary binders, which may be used to help to hold the
dosage form together, include polyvinyl pyrrolidone, hydroxypropyl
cellulose, hydroxypropyl methylcellulose, methylcellulose,
hydroxyethyl cellulose, sugars, and combinations thereof.
Disintegrants (such as croscarmellose sodium) expand when wet
causing a tablet to break apart. Lubricants typically aid in the
processing of powder materials. Exemplary lubricants include
calcium stearate, glycerol behenate, magnesium stearate, mineral
oil, polyethylene glycol, sodium stearylfumarate, stearic acid,
talc, vegetable oil, zinc stearate, and combinations thereof. An
example of a glidant is silicon dioxide.
[0136] The formulations described herein may contain a filler, such
as a water insoluble or water soluble filler, or combinations
thereof. Typical water insoluble fillers include silicon dioxide,
titanium dioxide, talc, alumina, starch, kaolin, polacrilin
potassium, powdered cellulose, microcrystalline cellulose, and
combinations thereof. Typical water-soluble fillers include water
soluble sugars and sugar alcohols, preferably lactose, glucose,
fructose, sucrose, mannose, dextrose, galactose, the corresponding
sugar alcohols and other sugar alcohols, such as mannitol,
sorbitol, xylitol, and combinations thereof.
[0137] Aripiprazole and any optional additives may be prepared as
subunits or as pellets, for example by a melt pelletization
technique. In this technique, the aripiprazole in finely divided
form is combined with a binder and other optional inert
ingredients, and thereafter the mixture is pelletized, e.g. by
mechanically working the mixture in a high shear mixer to form the
pellets. By the term "pellets" we include pellets, granules,
spheres and beads. Thereafter, the pellets can be sieved in order
to obtain pellets of the requisite size.
[0138] The binder material may also be in particulate form and
typically has a melting point above about 40.degree. C. Suitable
binder substances include hydrogenated castor oil, hydrogenated
vegetable oil, other hydrogenated fats, fatty alcohols, fatty acid
esters, fatty acid glycerides, and combinations thereof.
[0139] Oral dosage forms may be prepared to include an effective
amount of subunits containing aripiprazole and optionally other
active agents in the form of multiparticles or multipellets within
a capsule. For example, a plurality of multiparticulates may be
placed in a gelatin capsule in an amount sufficient to provide a
release profile as defined above.
[0140] Subunits (e.g. in the form of multiparticulates) may be
compressed into an oral tablet using conventional tableting
equipment using standard techniques. The tablet formulation may
include excipients such as, for example, an inert diluent (e.g.
lactose) granulating and disintegrating agents (e.g. a cornstarch),
binding agents (e.g. starch) and lubricating agents (e.g. magnesium
stearate).
[0141] Alternatively, subunits containing aripiprazole and
optionally containing additional active agents may be subjected to
an extrusion process, the resulting extrudate then being shaped
into tablets by methods known in the art. The diameter of the
extruder aperture or exit port can be adjusted to vary the
thickness of the extruded strands. Furthermore, the exit part of
the extruder may have any suitable shape, for example round, oblong
or rectangular. The exiting strands can be reduced to particles
using any suitable method, for example with a hot wire cutter or a
guillotine.
[0142] A melt-extruded multiparticulate system can be, for example,
in the form of granules, spheroids, pellets, or the like, depending
upon the extruder exit orifice. The terms "melt-extruded
multiparticulate(s)" and "melt-extruded multiparticulate system(s)"
and "melt-extruded particles" are used interchangeably herein and
typically include a plurality of subunits, preferably of similar
size and/or shape. The melt-extruded multiparticulates are
typically from about 0.1 to about 12 mm in length and from about
0.1 to about 5 mm in diameter. In addition, the melt-extruded
multiparticulates can be any geometrical shape within this size
range. Alternatively, the extrudate can simply be cut into desired
lengths and divided into unit doses of aripiprazole without the
need of a pelletization step.
[0143] Many of the oral dosage forms described herein contain
aripiprazole and optionally additional active agents in the form of
particles. Such particles may be compressed into a tablet, present
in a core element of a coated dosage form, such as a taste masked
dosage form, a press coated dosage form, or an enteric coated
dosage form, or may be contained in a capsule, osmotic pump dosage
form, or other dosage form.
[0144] For particles (e.g. powder particles) present in the core
element of a coated dosage form, the particles may have a particle
size of from about 1 .mu.m to about 250 .mu.m, preferably from
about 25 .mu.m to about 200 .mu.m, more preferably from about 35
.mu.m to about 150 .mu.m. The core element typically has a particle
size distribution with a median of about 100 .mu.m.
[0145] Another parameter to consider is the shape of the particles
and/or any core element. For example, particle/core shape can
influence the coverage and stability of any coating that may be
used. Both the crystallinity of aripiprazole and the aspect ratio
of the particles are related to particle/core shape. If the
aripiprazole of the coated dosage has a crystalline morphology,
sharp angles on the crystal can cause weaknesses (e.g. stress
points) in the coat possibly leading to premature release of
aripiprazole from the dosage form. Furthermore, areas of thin
coating are susceptible to breaking and cracking and hence less
effective for sustained release and taste masking. This potential
problem may be offset somewhat by the particles/core having a
relatively low aspect ratio. The aspect ratio is a measure of the
length to breadth. For example, a low aspect ratio of about 1 would
be a box or sphere. Crystals with a high aspect ratio are more
pointed with needle-like crystals. Crystals with a high aspect
ratio may result in a relatively thin coat at the crystal needle
tips leading to a more rapid release rate of aripiprazole than is
preferred. A low aspect ratio spherical shape of the particle is
advantageous for both solubility of the coat and to increase the
chance of all the aripiprazole contained in the formulation being
released. Therefore, it is most preferable that the aspect ratio is
less than about 3, more preferably less than about 2, and most
preferably approximately 1 providing a substantially rounded shape.
This may be achieved, for example, by spheronization.
[0146] Inconsistencies in size and shape can lead to inconsistent
coating. Where the particles containing aripiprazole are of
different size and shape, polymeric coating materials such as ethyl
cellulose may deposit differently on each particle. Therefore it is
preferable for coated dosage forms that most if not all particles
of the dosage form have substantially the same size and shape so
that the coating process is better controlled and maintained.
[0147] The compositions described herein may be coated with a
coating material. The coating typically comprises from about 0 to
about 90% by weight of the composition. The coating material
typically includes a polymer, preferably a film-forming polymer,
for example, methyl cellulose, ethyl cellulose, hydroxypropyl
cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl
cellulose, cellulose acetate, cellulose propionate, cellulose
acetate propionate, cellulose acetate butyrate, cellulose acetate
phthalate, carboxymethyl cellulose, cellulose triacetate, cellulose
sulphate sodium salt, poly(methyl methacrylate), poly(ethyl
methacrylate), poly(butyl methacrylate), poly(isobutyl
methacrylate), poly(hexyl methacrylate), poly(phenyl methacrylate),
poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl
acrylate), poly(octadecyl acrylate), high or low density,
polyethylene, polypropylene, poly(ethyleneglycol), poly(ethylene
oxide), poly(ethylene terephthalate), poly(vinyl alcohol),
poly(vinyl isobutyl ether), poly(vinyl acetate), poly(vinyl
chloride), polyvinyl pyrrolidone, and combinations thereof.
[0148] The coating material may be water soluble or water
insoluble. For certain application such a taste-masking, it is
preferable to use a water insoluble polymer. Suitable water
insoluble polymers include ethyl cellulose or dispersions of ethyl
cellulose, acrylic and/or methacrylic ester polymers, cellulose
acetates, butyrates or propionates or copolymers of acrylates or
methacrylates having a low quaternary ammonium content, and
combinations of the foregoing polymers.
[0149] Preferred hydrophobic or water insoluble polymers for use in
the compositions of the invention include, for example, methacrylic
acid esters, ethyl cellulose, cellulose acetate, polyvinyl
alcohol-maleic anhydride copolymers, .beta.-pinene polymers,
glyceryl esters of wood resins, and combinations of the
foregoing.
[0150] The coating may also include one or more monomeric materials
such as sugars (e.g. lactose, sucrose, fructose and mannitol),
salts (e.g. sodium chloride and potassium chloride) and organic
acids (e.g. fumaric acid, succinic acid, tartaric acid and lactic
acid). The coating may also include a filler such as described
earlier herein.
[0151] The coating composition may include additives which improve
the physical properties of the coating film. For example, the
coating composition may comprise a plasticizer. For example,
because ethyl cellulose has a relatively high glass transition
temperature and does not form flexible films under normal coating
conditions, it may be advantageous to add plasticizer to the ethyl
cellulose before using it as a coating material. Generally, the
amount of plasticizer included in a coating solution is based on
the concentration of the polymer, typically ranging from 0 to about
50% by weight of the coating composition. Suitable concentrations
of the plasticizer may be determined by routine
experimentation.
[0152] Examples of plasticizers for ethyl cellulose and other
celluloses include plasticizers such as dibutyl sebacate, diethyl
phthalate, triethyl citrate, tributyl citrate, triacetin,
acetylated monoglycerides, phthalate esters, castor oil, and
combinations thereof.
[0153] Examples of plasticizers for acrylic polymers include citric
acid esters such as triethyl citrate 21, tributyl citrate, dibutyl
phthalate, 1,2-propylene glycol, polyethylene glycols, propylene
glycol, diethyl phthalate, castor oil, triacetin, acetylated
monoglycerides, phthalate esters, castor oil, and combinations
thereof.
[0154] A typical coating comprises (a) a poorly water-permeable
component such as an alkyl cellulose (e.g. ethylcellulose) such as
AQUACOAT (a 30% solution) or SURELEASE (a 25% solution) and (b) a
water-soluble component, e.g. an agent that can form channels
through the poorly water-permeable component upon the hydration or
dissolution of the soluble component.
[0155] Preferably, the water-soluble component (b) is a low
molecular weight, polymeric material, e.g. hydroxyalkylcellulose,
hydroxyalkyl (alkylcellulose), carboxymethylcellulose, or salts
thereof. Particular examples of these water soluble polymeric
materials include hydroxyethylcellulose, hydroxypropylcellulose,
hydroxyethylmethylcellulose, hydroxypropylmethyl cellulose (e.g.
METHOCEL), carboxymethylcellulose, sodium carboxymethyl cellulose,
and combinations thereof. The water-soluble component (b) is
preferably of relatively low molecular weight, preferably less than
about 25,000, preferably less about 21,000.
[0156] In the coating, the weight ratio of the water soluble
component (b) to the poorly water permeable portion (a) is
typically from about 1:4 to about 2:1, such as from about 1:2 to
about 1:1, for example about 2:3. The coating typically constitutes
from about 1 to about 90% by weight, such as from about 2% to about
50%, for example from about 5 to about 30%, of the weight of the
total composition.
[0157] Preferably, the coating may be a substantially continuous
coat and substantially hole-free. This is particularly
advantageous, for example, where the coating provides taste
masking. The phrase "substantially continuous coating" is meant to
include a coating, which retains a smooth and continuous appearance
when magnified 1000 times under a scanning electron microscope and
wherein no holes or breakage of the coating are evident. Typically,
the coating is from about 0.005 to about 25 .mu.m thick, preferably
from about 0.05 to about 5 .mu.m.
[0158] One or more of the coatings described herein may be used in
the compositions of the subject invention. If two or more coatings
are present, the coating material used for each coating may be the
same or different.
[0159] Any suitable method may be used to apply the coating.
Processes which may be used include simple or complex coacervation,
interfacial polymerization, liquid drying, thermal and/or ionic
gelation, spray drying, spray chilling, fluidized bed coating, pan
coating and electrostatic deposition. A substantially continuous
coating may be achieved, for example, by spray drying from a
suspension or dispersion of aripiprazole in a solution of the
coating composition including a polymer in a solvent in a drying
gas having a low dew point.
[0160] When a solvent is used to apply the coating, the solvent is
preferably an organic solvent which is good solvent for the coating
material and a poor solvent for aripiprazole. While aripiprazole
may partially dissolve in the solvent, it is preferred that the
active ingredient will precipitate out of the solvent during the
spray drying process more rapidly than the coating material. The
solvent may be selected from alcohols such as methanol, ethanol,
halogenated hydrocarbons such as dichloromethane (methylene
chloride), hydrocarbons such as cyclohexane, and combinations
thereof.
[0161] The concentration of polymer in the solvent will normally be
less than about 75% by weight, typically from about 10 to about 30%
by weight. After coating, the coated dosage forms are typically
allowed to cure for from about 1 to about 2 hours at a temperature
of from about 50.degree. C. to about 60.degree. C.
[0162] The dosage form (e.g. a tablet) can be prepared by various
conventional mixing, comminution and fabrication techniques readily
apparent to those skilled in the chemistry of drug formulations.
Examples of such techniques are direct compression (using
appropriate punches and dies fitted to a suitable rotary tableting
press), injection or compression molding using suitable molds
fitted to a compression unit, granulation followed by compression,
and extrusion into a mold or to an extrudate to be cut into
lengths.
[0163] When particles or tablets are made by direct compression,
the addition of lubricants to the particles/tablets may be helpful
and sometimes important to promote powder flow and to prevent
capping of the particle (breaking off of a portion of the particle)
when the pressure is relieved. Any of the lubricants previously
described herein may be used. Preferred lubricants include
magnesium stearate and/or sodium stearyl fumarate (typically in a
concentration of from about 0.1 to about 10%, e.g. from about 0.25
to about 3% by weight in the powder mix), and hydrogenated
vegetable oil, for example hydrogenated and refined triglycerides
of stearic and palmitic acids may be used at from about 1 to about
5% by weight in the powder mix. Additional excipients may be added
to enhance powder flowability and reduce adherence. Compositions of
the invention made by direct compression are described in more
detail in the Examples.
[0164] Oral dosage forms may be prepared by including an effective
amount of melt-extruded subunits in the form of multiparticles
within a capsule. For example, a plurality of the melt-extruded
multiparticulates can be placed in a gelatin capsule in an amount
sufficient to provide the desired release profile when administered
orally. Alternatively, the composition may be in the form of
microtablets enclosed inside a gelatin capsule. Microtablets
typically have a size of from 0.5 to 7 mm in their largest
dimension, such as from 1 to 6 mm, for example 3 to 4 mm.
[0165] A number of formulations are described below as having
preferred components. It is to be understood that any of the
components described as being used in one type of formulation may
also be used in another type of formulation, even though such
components may not be listed as being used in the other
formulation. Moreover, the formulations described below may also
contain any of the excipients described above, or indeed any of the
excipients known in the art.
[0166] The compositions of the invention may be in the form of a
wax formulation. A wax formulation is a solid dosage form
comprising the aripiprazole in a waxy matrix.
[0167] The wax material used in the composition of the invention
may be, for example, an amorphous wax, an anionic wax, an anionic
emulsifying wax, a bleached wax, a carnauba wax, a cetyl ester wax,
a beeswax, a castor wax, an emulsifying wax such as a cationic
emulsifying wax, a cetrimide emulsifying wax, or a nonionic
emulsifying wax, a glycerol behenate, a microcrystalline wax, a
nonionic wax, a paraffin, a petroleum wax, a spermaceti wax, a
white wax, and combinations of one or more of the foregoing
waxes.
[0168] A cetyl ester wax suitable for use in the invention
typically has a molecular weight of from about 470 to about 490,
and is a mixture containing primarily esters of saturated fatty
alcohols and saturated fatty acids. A wax matrix suitable for use
in the compositions of the invention contains carnauba wax and no
other waxy material. Another suitable wax matrix includes carnauba
wax and glycerol behenates. The wax matrices suitable for use in
the invention may be used with or without a coating.
[0169] The wax material may be used in the range of from about 30
to about 95%, preferably from about 40 to about 85%, more
preferably from about 45 to about 80%, most preferably about 50% to
about 75% by weight of the total weight of the matrix material. The
remainder of the matrix material is typically aripiprazole,
although other optional components (e.g. fatty acid soaps, see
below) may also be present. When a combination of waxes is used,
the component waxes can be used in any suitable ratio. For example,
if a combination of carnauba wax and glyceryl behenate is used, the
relative amounts of each wax typically is from about 99 to 60 parts
carnauba wax (for example from 99 to about 85 parts) and from about
1 to about 40 parts glyceryl behenate (for example from 1 to about
15 parts). In formulations that have a combination of carnauba wax
and castor wax, the relative amounts of each wax typically is from
about 99 to 60 parts carnauba wax (for example from 99 to about 85
parts) and from about 1 to about 40 parts castor wax (for example
from 1 to about 15 parts). When carnauba wax, glyceryl behenate,
and castor wax are present, the carnauba wax typically comprises at
least about 85% of the waxy material present, the balance being
made up of a combination of glyceryl behenate and castor wax.
[0170] Fatty acids and fatty acid soaps may be present in the waxy
dosage form. In some cases, the fatty acids and/or fatty acid soaps
can replace a portion of the wax material. These optional fatty
acids and fatty acid soaps can be those that are generally used in
the pharmaceutical industry as tableting lubricants. Such fatty
acids and fatty acid soaps include solid fatty acids (for example
fatty acids having from about 16 to about 22 carbon atoms), the
alkaline earth metal salts thereof, (particularly the magnesium and
calcium salts) and combinations of the foregoing. For example, the
fatty acid can be stearic acid. The optional fatty acids and fatty
soaps, when present, are typically used in amounts up to about 10%
of the total weight of the matrix material, such as from about 1 to
about 9%, for example from about 2 to about 8% or from about 3 to
about 6% of the total weight of the matrix material.
[0171] To prepare the wax formulation, the wax or waxes may be
melted and used to granulate aripiprazole using melt granulation
techniques. The granulate may be allowed to cool and then be milled
to a proper size. Advantageously, the granulate is milled to an
average particle size of about 75 microns to about 850 microns,
preferably about 150 microns to about 425 microns. The milled
granulate may be mixed with optional processing aids. The
processing aids include, for example, hydrophobic colloidal silicon
dioxide. Hydrophobic silicon dioxide may typically be used in
amounts of less than or equal to about 0.5% by weight of the matrix
material, but individual formulations can be varied as required.
The blend of the waxy granulate and the processing aids, if any,
may be compressed and then optionally coated.
[0172] The wax formulation may be formulated into any suitable
dosage form, for example, coated (e.g. with a functional coating
composition or a non-function related coating composition) or
uncoated tablets, compressed pellets contained in capsules, or
loose powder or powder filled capsules.
[0173] When the coating composition is a functional coating
composition, it typically comprises a water insoluble component and
a water soluble component. When the coating composition is a
non-functional coating composition, it typically comprises a water
soluble component, preferably in the absence of a water insoluble
component. The coating composition may comprise pharmaceutically
acceptable dyes, pigments, or mixtures thereof.
[0174] As described above, the compositions of the invention may
comprise one or more active agents in addition to aripiprazole.
Therefore, the wax formulation may also include an active agent in
addition to aripiprazole in the matrix.
[0175] The wax formulations described herein may be made by hot
melting a waxy material to form a melt and granulating aripiprazole
with the melt to form a granulate. The granulate is typically then
milled and compressed to form a matrix. The method may further
comprise blending the granulate with a processing aid prior to
compressing the granulate to form the matrix. The method may
further comprise coating the matrix with a functional and/or a
non-functional coating.
[0176] The compositions of the invention may be in the form of
press-coat formulations. Such formulations comprise a core
composition containing aripiprazole with a coating composition
press-coated on the core. The core composition typically comprises
a waxy material containing aripiprazole. The coating composition
typically comprises a hydrophilic polymer and optionally
aripiprazole.
[0177] The waxy material of the core composition is typically a
hydrophobic waxy material capable of providing controlled release
of aripiprazole. Such waxy materials may be, for example, carnauba
wax, tribehenin, fatty alcohols (particularly those having 12-24
carbon atoms, such as lauryl alcohol, myristyl alcohol, stearyl
alcohol, palmityl alcohol, etc.), fatty acids (particularly those
having 12-24 carbon atoms, such as lauric acid, myristic acid,
stearic acid, palmitic acid, etc), polyethylenes, castor wax,
C.sub.16-30 fatty acid triglycerides, beeswax, and combinations of
one or more of the foregoing waxes.
[0178] The hydrophilic polymer of the coating composition is
typically chosen so as to aid controlled release of aripiprazole.
An example of such a hydrophilic polymer is a film-forming polymer,
such as a hydrophilic cellulose polymer, in particular a
hydroxyalkyl cellulose polymer. Examples of such hydroxyalkyl
cellulose polymers include hydroxyethylcellulose (HEC),
hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HMPC),
hydroxypropylethylcellulose (HPEC), hydroxypropylpropylcellulose
(HPPC), hydroxypropylbutylcellulose (HPBC), and combinations of one
or more of the foregoing polymers.
[0179] Both the core composition and the coating composition may
independently include a filler, such as a water soluble or
insoluble filler, or a mixture thereof. Examples of water insoluble
fillers include talc and calcium salts such as a calcium phosphate,
e.g. a dicalcium phosphate. If there is a filler in the coating
composition, it can be the same or different as the filler in the
core composition, if any. For example, the core composition may
include a water-soluble filler while the coating composition may
include a water-insoluble filler.
[0180] Optional excipients can also be present in the core
composition and/or the coating composition. Such excipients include
lubricants (such as talc and magnesium stearate), glidants (such as
fumed or colloidal silica), pH modifiers (such as acids, bases and
buffer systems), pharmaceutically useful processing aids, and
combinations of one or more of the foregoing excipients. Excipients
in the compositions can be the same or different as those in the
core compositions.
[0181] In order to form the press-coat formulations, the core
composition components (aripiprazole, waxy material, and optional
excipients) are typically blended together and compressed into
suitable cores. The blending can take place in a suitable order of
addition. The cores may be blended by starting with the smallest
volume component and then successively adding the larger volume
components. An alternative process is to melt the wax and to blend
aripiprazole and optional excipients into the melted wax.
Alternatively, aripiprazole, wax and any optional excipients can be
blended together and then subjected to a temperature at which the
wax will melt. Once cooled, the solidified mass can be milled into
granules for compaction into cores.
[0182] Typically, the core composition is press-coated with the
coating composition to form a tablet. The tablet may be further
coated with optional additional coatings. The additional coatings
can be pH-dependent or pH-independent, aesthetic or functional, and
can contain aripiprazole or a different active agent.
[0183] If aripiprazole is present in the coating composition, the
molar ratio of aripiprazole in the core composition to aripiprazole
in the coating composition is from about 500:1 to about 1:10, such
as from about 100:1 to about 1:5, e.g. from about 10:1 to about
1:1.
[0184] A preferred press-coat formulation comprises a core
composition comprising aripiprazole coated with a coating
composition comprising hydroxypropylmethyl cellulose (HPMC). The
core composition optionally comprises one or more waxy materials,
e.g. carnauba wax and the coating composition optionally comprises
aripiprazole. Such press coat formulations may be prepared by
press-coating the coating composition onto the core
composition.
[0185] The compositions of the invention may be formulated using
osmotic pump technology. Osmotic pump technology uses osmotic
pressure to deliver aripiprazole at a controlled rate. Osmotic pump
dosage formulations typically include a semi-permeable membrane
surrounding a core that contains at least two components, one
component comprising aripiprazole, the other comprising an osmotic
push layer (an osmotically active expandable driving member), such
as an osmotically active polymer. After the dosage form is
swallowed, water enters the membrane at a rate primarily determined
by the nature of the membrane. This causes the push layer to swell,
releasing aripiprazole at a controlled rate through an exit means
comprising a passageway or orifice (e.g. a laser-drilled hole) by
the action of the osmotically active driving member.
[0186] The osmotic pump formulation typically comprises a
semipermeable membrane, for example a capsule or tablet or other
dosage form typically having an outer wall comprising a selectively
semipermeable material. The selectively permeable material
preferably has the following characteristics: (i) it does not
adversely affect a host or animal, (ii) it is permeable to the
passage of an external aqueous fluid, such as water or biological
fluids while remaining essentially impermeable to the passage of
aripiprazole, (iii) it is substantially insoluble in body fluids,
(iv) it is non-toxic, and (v) it is non-erodible in the
environments to which it is subjected.
[0187] Representative materials for forming the selectively
semipermeable wall include semipermeable homopolymers and
copolymers. Suitable materials include, for example, cellulose
esters, cellulose monoesters, cellulose diesters, cellulose
triesters, cellulose ethers, cellulose ester-ethers, and
combinations thereof. These cellulosic polymers have a degree of
substitution (DS) on their anhydroglucose unit from greater than 0
to about 3. The "degree of substitution" is the average number of
hydroxyl groups originally present on the anhydroglucose unit that
have been replaced by a substituting group, or converted into
another group. The anhydroglucose unit can be partially or
completely substituted with semipermeable polymer forming groups
such as acyl, alkanoyl, aroyl, alkenyl, alkoxy, halogen,
carboalkyl, alkylcarbamate, alkylcarbonate, alkylsulfonate and
alkylsulfamate.
[0188] Other selectively semipermeable materials include, for
example, cellulose acylate, cellulose diacylate, cellulose
triacylate, cellulose acetate, cellulose diacetate, cellulose
triacetate, mono-, di- and tri-cellulose alkanylates, mono-, di-
and tri-alkenylates, mono-, di- and tri-aroylates, and combinations
of the foregoing materials. Exemplary polymers include cellulose
acetate having a DS of 1.8 to 2.3 and an acetyl content of about 32
to about 40%, cellulose diacetate having a DS of 1 to 2 and acetyl
content of about 21 to about 35%, cellulose triacetate having a DS
of 2 to 3 and an acetyl content of about 34 to about 45%. Other
examples of cellulosic polymers include cellulose propionate having
a DS of 1.8 and a propionyl content of about 38.5%, cellulose
acetate propionate having an acetyl content of about 1.5 to about
7% and a propionyl content of about 39 to about 42%, cellulose
acetate propionate having an acetyl content of about 2.5% to about
3%, an average propionyl content of about 39 to about 45% and a
hydroxyl content of about 2.8% to about 5.4%. Still further
exemplary cellulosic polymers include cellulose acetate butyrate
having a DS of 1.8, an acetyl content of about 13 to about 15% and
a butyryl content of about 34% to about 39%, cellulose acetate
butyrate having an acetyl content of about 2 to about 29.5%, a
butyryl content of about 17 to about 53%, and a hydroxyl content of
about 0.5% to about 4.7%. Yet further examples of suitable
cellulosic polymers include cellulose triacylates have a DS of 2.9
to 3 such as cellulose trivalerate, cellulose trilaurate, cellulose
tripalmitate, cellulose trioctanoate, and cellulose tripropionate,
cellulose diesters having a DS of 2.2 to 2.6 such as cellulose
disuccinate, cellulose dipalmitate, cellulose dioctanoate,
cellulose dicarpylate, mixed cellulose esters such as cellulose
acetate valerate, cellulose acetate succinate, cellulose propionate
succinate, cellulose acetate octanoate, cellulose valerate
palmitate, cellulose acetate heptonate, and combinations of the
foregoing cellulosic polymers.
[0189] Other potentially suitable semipermeable polymers include,
for example, acetaldehyde dimethyl cellulose acetate, cellulose
acetate ethylcarbamate, cellulose acetate methylcarbamate,
cellulose dimethylaminoacetate, semipermeable polyamides,
semipermeable polyurethanes, semipermeable polysulfanes,
semipermeable sulfonated polystyrenes, cross-linked selectively
semipermeable polymers formed by the coprecipitation of a polyanion
and a polycation, semipermeable silicon rubbers, semipermeable
polystyrene derivatives, semipermeable poly(sodium
styrenesulfonate), semipermeable poly(vinylbenzyltrimethyl)ammonium
chloride polymers, and combinations comprising of the foregoing
polymers, including combinations with one or more of the
selectively permeable materials listed in the preceding
paragraph.
[0190] The osmotically expandable driving member (or osmotic push
layer) of the osmotic pump dosage form is typically a swellable and
expandable inner layer. The materials suitable for forming the
osmotic push layer, include polymeric materials and/or polymeric
materials blended with osmotic agents, both of which typically
interact with water or a biological fluid, absorb the fluid, and
swell or expand to an equilibrium state in the presence of the
fluid without dissolving. Preferably, the polymer should exhibit
the ability to retain a significant fraction of absorbed fluid in
the polymer molecular structure. Such polymers may be gel polymers
that can swell or expand to a very high degree, for example
exhibiting from about 2 to about 50-fold volume increase.
[0191] Suitable swellable, hydrophilic polymers, also known as
osmopolymers, can be non-cross-linked or lightly cross-linked. The
cross-links can be covalent or ionic bonds with the polymer. The
polymer may be of plant, animal or synthetic origin. Polymeric
materials useful for the present purpose include poly(hydroxyalkyl
methacrylate) having a molecular weight of from about 5,000 to
about 5,000,000, poly(vinylpyrrolidone) having a molecular weight
of from about 10,000 to about 360,000, anionic and cationic
hydrogels, poly(electrolyte) complexes, poly(vinyl alcohol) having
a low acetate residual, a swellable mixture of agar and
carboxymethyl cellulose, a swellable composition comprising methyl
cellulose mixed with a sparingly crosslinked agar, a
water-swellable copolymer produced by a dispersion of finely
divided copolymer of maleic anhydride with styrene, ethylene,
propylene, or isobutylene, water swellable polymers of N-vinyl
lactams, and combinations of the foregoing polymers.
[0192] Other gelable, fluid absorbing and retaining polymers useful
for 1 to forming the osmotic push layer include pectins having a
molecular weight ranging from about 30,000 to about 300,000,
polysaccharides such as agar, acacia, karaya, tragacanth, algins
and guar, poly (carboxylic acids) and their salt derivatives,
polyacrylamides, water-swellable indene maleic anhydride polymers,
polyacrylic acid having a molecular weight of from about 80,000 to
about 200,000, polyethylene oxide polymers having a molecular
weight of from about 100,000 to about 5,000,000 (but may be
higher), starch graft copolymers, polyanion and polycation exchange
polymers, starch-polyacrylonitrile copolymers, acrylate polymers
with water absorbability of from about 100 to about 600 times their
original weight, diesters of polyglucan, a mixture of cross-linked
polyvinyl alcohol and poly(N-vinyl-2-pyrrolidone), zein (available
as prolamine), poly(ethylene glycol) having a molecular weight of
from about 4,000 to about 100,000, and combinations of the
foregoing polymers.
[0193] The osmotically expandable driving layer of the osmotic pump
dosage form may further contain an osmotically effective compound
(osmagent) that can be used neat or blended homogeneously or
heterogeneously with the swellable polymer discussed above. Such
osmagents are typically osmotically effective solutes that are
soluble in the fluid absorbed into the swellable polymer, and
exhibit an osmotic pressure gradient across the semipermeable wall
against an exterior fluid.
[0194] Suitable osmagents include, for example, solid compounds
such as magnesium sulfate, magnesium chloride, sodium chloride,
lithium chloride, potassium sulfate, sodium sulfate, mannitol,
urea, sorbital, inositol, sucrose, glucose, and combinations
thereof. The osmotic pressure of the osmagents is typically from
about 0 to about 500 atm, but may be higher.
[0195] The swellable, expandable polymer of the osmotically
expandable driving layer, in addition to providing a driving source
for delivering aripiprazole from the dosage form, may also function
as a supporting matrix for an osmotically effective compound (or
osmagent). The osmotic compound may be homogeneously or
heterogeneously blended with the polymer to yield the desired
expandable wall or expandable pocket. A typical osmotic pump dosage
form may comprise from about 20 to about 90% by weight of polymer
and from about 80 to about 10% by weight of osmotic compound,
preferably from about 35 to about 75% by weight of polymer and from
about 65 to about 25% by weight of osmotic compound based on the
total weight of the formulation.
[0196] The aripiprazole in the osmotic pump dosage form may be
formulated in any suitable manner, for example as a
thermo-responsive formulation in which aripiprazole is dispersed in
a thermo-responsive composition. Alternatively, the osmotic pump
dosage form may contain a thermo-responsive element comprising a
thermo-responsive composition at the interface of the osmotic push
layer and aripiprazole composition. Representative
thermo-responsive compositions (including their melting points in
parentheses) are cocoa butter (32.degree. C.-34.degree. C.), cocoa
butter and 2% beeswax (35.degree. C.-37.degree. C.), propylene
glycol monostearate and distearate (32.degree. C.-35.degree. C.),
hydrogenated oils such as hydrogenated vegetable oil (36.degree.
C.-37.5.degree.), 80% hydrogenated vegetable oil and 20% sorbitan
monopalmitate (39.degree. C.-39.5.degree. C.), 80% hydrogenated
vegetable oil and 20% polysorbate 60, (36.degree. C.-37.degree.
C.), 77.5% hydrogenated vegetable oil, 20% sorbitan trioleate, 2.5%
beeswax and 5.0% distilled water, (37.degree. C.-38.degree. C.),
mono-di, and triglycerides of acids having from 8-22 carbon atoms
including saturated and unsaturated acids such as palmitic,
stearic, oleic, lineolic and archidonic; triglycerides of saturated
fatty acids with mono- and diglycerdies (34.degree. C.-35.5.degree.
C.), propylene glycol mono- and distearates (33.degree.
C.-34.degree. C.), partially hydrogenated cottonseed oil
(35.degree. C.-39.degree. C.), block copolymers of polyoxyalkylene
and propylene glycol, block copolymers of 1,2-butylene oxide and
ethylene oxide, block copolymers of propylene oxide and ethylene
oxide, hardened fatty alcohols and fats (33.degree. C.-36.degree.
C.), hexadienol and hydrous lanolin triethanolamine glyceryl
monostearate (38.degree. C.), eutectic mixtures of mono-, di-, and
triglycerides (35.degree. C.-39.degree. C.), WITEPSOL#15,
triglyceride of saturated vegetable fatty acid with monoglycerides
(33.5.degree. C.-35.5.degree. C.), WITEPSOL H32 free of hydroxyl
groups (31.degree. C.-33.degree. C.), WITEPSOL W25 having a
saponification value of 225-240 (33.5.degree. C.-35.5.degree. C.),
WITEPSOL E75 having a saponification value of 220-230 (37.degree.
C.-39.degree. C.), a polyalkylene glycol such as polyethylene
glycol 1000, a linear polymer of ethylene oxide (38.degree.
C.-41.degree. C.), polyethylene glycol 1500 (38.degree.
C.-41.degree. C.), polyethylene glycol monostearate (39.degree.
C.-42.5.degree. C.), 33% polyethylene glycol 1500, 47% polyethylene
glycol 6000 and 20% distilled water (39.degree. C.-41.degree. C.),
30% polyethylene glycol 1500, 40% polyethylene glycol 4000 and 30%
polyethylene glycol 400, (33.degree. C.-38.degree. C.), mixtures of
mono-, di- and triglycerides of saturated fatty acids having 11 to
17 carbon atoms, (33.degree. C.-35.degree. C.), and mixtures of the
foregoing.
[0197] The thermo-responsive compositions, including
thermo-responsive carriers, are thought to be useful for storing
aripiprazole in a solid composition at a temperature of about
20.degree. C. to about 33.degree. C., maintaining an immiscible
boundary at the swelling composition interface, and for dispensing
the agent in a flowable composition at a temperature greater than
about 33.degree. C. and preferably from about 33.degree. C. to
about 40.degree. C.
[0198] When the aripiprazole containing thermo-responsive
formulations described above are used, the integrity of the
semi-permeable membrane which is also present in such osmotic pump
formulations is preferably not compromised (e.g. melted or eroded)
by the presence of the thermo-responsive formulations.
[0199] Aripiprazole in the osmotic pump dosage form may be
formulated by any suitable techniques known in the art, for example
by wet granulation or fluid bed granulation, as described in more
detail below.
[0200] Firstly, aripiprazole and the ingredients comprising the
aripiprazole layer are blended using an organic solvent, such as
isopropyl alcohol-ethylene dichloride 80:20 v/v (volume:volume) as
the granulation fluid. Other granulating fluid such as denatured
alcohol 100% may be used for this purpose. The ingredients forming
the aripiprazole layer are individually passed through a screen
such as a 40-mesh screen and then thoroughly blended in a mixer.
Next, other ingredients comprising the aripiprazole layer are
dissolved in a portion of the granulation fluid. Then the latter
prepared wet blend is slowly added to the aripiprazole blend with
continual mixing in the blender. The granulating fluid is added
until a wet blend is produced, which wet mass then is forced
through a screen such as a 20-mesh screen and onto oven trays. The
blend is dried for about 18 to about 24 hours at about 30.degree.
C. to about 50.degree. C. The dry granules are sized then with a
screen such as a 20-mesh screen. Next, a lubricant is passed
through a screen such as an 80-mesh screen and added to the dry
granule blend. The mixture is put into milling jars and mixed on a
jar mill for about 1 to about 15 minutes. The push layer may also
be made by the same wet granulation techniques. The compositions
are pressed into their individual layers in a KILIAN press-layer
press.
[0201] Another manufacturing process that can be used for providing
the aripiprazole layer and the osmotically expandable driving layer
comprises blending the powered ingredients for each layer
independently in a fluid bed granulator. After the powered
ingredients are dry blended in the granulator, a granulating fluid
(e.g. poly(vinyl-pyrrolidone) in water, denatured alcohol, 95:5
ethyl alcohol/water, or blends of ethanol and water) is sprayed
onto the powders. Optionally, the ingredients can be dissolved or
suspended in the granulating fluid. The coated powders are then
typically dried in a granulator. This process granulates the
ingredients present therein while adding the granulating fluid.
After the granules are dried, a lubricant such as stearic acid or
magnesium stearate is added to the granulator. The granules for
each separate layer may then be pressed in the manner described
above for the wet granulation method.
[0202] The osmotic push aripiprazole formulation and osmotic push
layer of the osmotic push dosage form may also be manufactured by
mixing aripiprazole with composition forming ingredients and
pressing the composition into a solid lamina. In a further
alternative method of manufacture, aripiprazole, any other
composition-forming ingredients and a solvent are typically mixed
into a solid, or a semisolid, by methods such as ball milling,
calendaring, stirring or roll milling, and then pressed into a
preselected layer forming shape. Next, a layer of composition
comprising an osmopolymer and an optional osmagent are typically
placed in contact with the layer comprising aripiprazole. The
layering of the first layer comprising aripiprazole and the second
layer comprising the osmopolymer and optional osmagent composition
may be accomplished by using a conventional layer press
technique.
[0203] The semipermeable wall can be applied by molding, spraying
or dipping the pressed bilayer's shapes into wall forming
materials. An air suspension coating procedure which includes
suspending and tumbling the two layers in a current of air until
the wall forming composition surrounds the layers may also be used
to form the semi-permeable wall of the osmotic formulations.
[0204] The dispenser of the osmotic pump dosage form may be, for
example, in the form of a hard or soft capsule. The capsule may
also be osmotic.
[0205] The hard capsule may be composed of two parts, a cap and a
body, which are typically fitted together after the body (which is
generally larger than the cap) is filled with aripiprazole. The
hard capsule may be fitted together by slipping or telescoping the
cap section over the body section, thus completely surrounding and
encapsulating aripiprazole.
[0206] The soft capsule of the osmotic pump dosage form may be a
one-piece soft capsule. Typically, the soft capsule comprises a
sealed construction encapsulating aripiprazole. The capsule may be
made by various processes, such as the plate process, the rotary
die process, the reciprocating die process, and the continuous
process.
[0207] Materials useful for forming the capsule of the osmotic pump
dosage form may be commercially available materials including
gelatin (typically having a viscosity of about 5 to about 30
millipoises and a bloom strength up to about 150 grams or gelatin
having a bloom value of about 150 to about 250), a composition
comprising gelatin, glycerine, water and titanium dioxide, a
composition comprising gelatin, erythrosine, iron oxide and
titanium dioxide, a composition comprising gelatin, glycerine,
sorbitol, potassium sorbate and titanium dioxide, a composition
comprising gelatin, acacia, glycerine, and water and combinations
thereof. Commercially available gelatin capsules (e.g. CAPSUGEL)
may also be used.
[0208] The semipermeable wall forming composition may be applied to
the aripiprazole containing component and/or to the exterior
surface of the capsule in laminar arrangement by molding, forming,
air spraying, dipping or brushing. Alternative techniques that can
be used for applying the semipermeable wall include air suspension
procedures and pan coating procedures. For example, an air
suspension procedure includes suspending and tumbling the capsule
arrangement in a current of air and a semipermeable wall forming
composition until the wall surrounds and coats the capsule. The
procedure can be repeated with a different semipermeable wall
forming composition to form a semipermeable laminated wall.
[0209] Exemplary solvents suitable for manufacturing the
semipermeable wall include inert inorganic and organic solvents
that do not adversely harm the materials used in the osmotic pump
formulations, e.g. the capsule wall, aripiprazole, the
thermo-responsive composition, the expandable member, or the final
dispenser. Such solvents include aqueous solvents, alcohols,
ketones, esters, ethers alipathics hydrocarbons, halogenated
solvents, cycloaliphatics, aromatics, heterocyclic solvents, and
combinations thereof. Particular solvents include acetone,
diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl
alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl
acetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane,
n-heptane, ethylene glycol monoethyl ether, ethylene glycol
monoethyl acetate, methylene dichloride, ethylene dichloride,
propylene dichloride, carbon tetrachloride, nitroethane,
nitropropane, tetrachloroethane, ethyl ether, isopropyl ether,
cyclohexane, cyloocatane, benzene, toluene, naphtha, 1,4-dioxane,
tetrahydrofuran, water, and mixtures thereof such as acetone and
water, acetone and methanol, acetone and ethyl alcohol, methylene
dichloride and methanol, and ethylene dichloride, methanol, and
combinations of the foregoing.
[0210] The exit means or hole in the osmotic pump formulations for
releasing aripiprazole may be produced during manufacture or in
use. For example, the exit means or hole can be formed by
mechanical or laser drilling, or by eroding an erodible element in
the wall, such as a gelatine plug. The orifice can be a polymer
inserted into the semipermeable wall, which polymer is a
(micro)porous polymer which typically has at least one
(micro)pore.
[0211] An example of a formulation for the controlled release of
aripiprazole in the stomach and gastrointestinal tract is one in
which aripiprazole is dispersed in a polymeric matrix that is
water-swellable rather than merely hydrophilic. Such
water-swellable matrices typically also have an erosion rate that
is substantially slower than their swelling rate, and release
aripiprazole primarily by diffusion.
[0212] The rate of diffusion of aripiprazole from the matrix can be
modified by varying numerous characteristics of the formulation.
For example, the rate of diffusion of aripiprazole can be slowed by
increasing aripiprazole particle size, by the choice of polymer
used in the matrix, and/or by the choice of molecular weight of the
polymer. The matrix is typically a relatively high molecular weight
polymer that swells upon ingestion, preferably to a size that is at
least about twice its unswelled volume, and that might in addition
promote gastric retention. Upon swelling, the matrix may convert
over a prolonged period of time (such as from about 1 to about 48
hours, e.g. from about 2 to about 24 hours or from about 3 to about
12 hours) from a glassy or crystalline polymer to a polymer this
rubbery in consistency.
[0213] Typically, penetrating fluid causes release of aripiprazole
in a gradual and prolonged manner by the process of solution
diffusion, i.e. dissolution of aripiprazole in the penetrating
fluid and diffusion of the dissolved drug backed out of the
matrix.
[0214] Typically, the matrix itself is solid prior to
administration, and once administered, remains undissolved in (i.e.
is not eroded by) the gastric fluid for a period of time sufficient
to permit the majority of aripiprazole to be released in a
controlled manner (as defined by the release profiles described
above) by solution diffusion. Therefore, the rate-limiting factor
in the release of aripiprazole is believed to be controlled
diffusion of aripiprazole from the matrix rather than erosion,
dissolving or chemical decomposition of the matrix.
[0215] The water-swellable polymer which forms the matrix is a
polymer that is non-toxic, that swells in a dimensionally
unrestricted manner upon absorption of water (and/or other fluids)
and that provides for sustained release of incorporated
aripiprazole. Examples of suitable polymers include, for example,
cellulose polymers and their derivatives (such as
hydroxyethylcellulose, hydroxypropylcellulose,
carboxymethylcellulose, and microcrystalline cellulose),
polysaccharides and their derivatives, polyalkylene oxides,
polyethylene glycols, chitosan, poly(vinyl alcohol), polysaccharide
gums, maleic anhydride copolymers, poly(vinyl pyrrolidone), starch
and starch-based polymers, poly(2-ethyl-2-oxazoline),
poly(ethyleneimine), polyurethane hydrogels, crosslinked
polyacrylic acids and their derivatives, copolymers of the
foregoing polymers, including block copolymers and grafted polymers
(e.g. PLURONIC and TECTONIC, which are polyethylene
oxide-polypropylene oxide block copolymers) and mixtures
thereof.
[0216] As used herein, unless otherwise stated, the terms
"cellulose" and "cellulosic" denote a linear polymer of
anhydroglucose. Suitable cellulosic polymers include, for example,
alkyl-substituted cellulosic polymers that ultimately dissolve in
the gastrointestinal (GI) tract in a predictably delayed manner.
Specific examples are methylcellulose, hydroxymethyl-cellulose,
hydroxyethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, and carboxymethylcellulose. The
viscosity of suitable alkyl-substituted cellulosic polymers is
typically from about 100 to about 110,000 centipoise as a 2%
aqueous solution at 20.degree. C. or from about 1,000 to about
4,000 centipoise as a 1% aqueous solution at 20.degree. C.
Exemplary alkyl-substituted celluloses are hydroxyethylcellulose
and hydroxypropylmethylcellulose. A specific example of a
hydroxyethylcellulose is NATRASOL 250HX NF.
[0217] Suitable polyalkylene oxides are those having the properties
described above for alkyl-substituted cellulose polymers. An
example of a polyalkylene oxide is poly(ethylene oxide) (PEO),
which term is used herein to denote a linear polymer of
unsubstituted ethylene oxide. Suitable PEO polymers typically have
molecular weights of greater than about 4,000,000, preferably from
about 4,500,000 to about 10,000,000, more preferably about from
5,000,000 to about 8,000,000. Preferred polyethylene oxides are
those with a weight-average molecular weight ranging from about
1.times.10.sup.5 to about 1.times.10.sup.7, preferably from about
9.times.10.sup.5 to about 8.times.10.sup.6. Suitable PEOs typically
have a viscosity of from about 50 to about 2,000,000 centipoise as
a 2% aqueous solution at 20.degree. C. Two specific example of PEOs
are POLYOX NF, grade WSR Coagulant, molecular weight 5 million, and
grade WSR 303, molecular weight 7 million.
[0218] Examples of suitable polysaccharide gums are natural and
modified (semi-synthetic) polysaccharide gums such as dextran,
xanthan gum, gellan gum, welan gum and rhamsan gum.
[0219] Suitable crosslinked polyacrylic acids include those whose
properties are the same as or similar to those described above for
alkyl-substituted cellulose and polyalkylene oxide polymers.
Typically, such crosslinked polyacrylic acids have a viscosity of
about 4,000 to about 40,000 centipoise as a 1% aqueous solution at
25.degree. C. Three specific examples are CARBOPOL NF grades 971P,
974P and 934P. Further examples include polymers known as WATER
LOCK, which are starch/acrylates/acrylamide copolymers.
[0220] As mentioned above, the hydrophilicity and
water-swellability of the polymers discussed above cause
aripiprazole-containing matrices to swell in size in the gastric
cavity due to ingress of water and/or other fluids. This swelling
promotes retention of the matrices in the stomach during the fed
phase. The hydrophilicity and water-swellability also cause the
matrices to become slippery, which provides resistance to
peristalsis and further promotes their retention in the
stomach.
[0221] The release rate of aripiprazole from the matrix is
primarily dependent upon the rate of water absorption and the rate
at which aripiprazole dissolves and diffuses from the swollen
polymer, which in turn is related to the solubility and dissolution
rate of aripiprazole, aripiprazole particle size and aripiprazole
concentration in the matrix. Also, because these matrix-forming
polymers typically dissolve very slowly in gastric fluid, the
matrix maintains its physical integrity over at least a substantial
period of time, typically for at least 70 or 80% of the dosing
period, and in many cases at least 90% and even over 100% of the
dosing period. Generally, the particles then slowly dissolve or
decompose. Complete dissolution or decomposition may not occur
until 24 hours or more after administration, although in many
cases, complete dissolution or decomposition will occur within 10
to 24 hours after the dosing period.
[0222] The swellable matrix dosage forms may include additives that
impart a small degree of hydrophobic character, to further retard
the release rate of aripiprazole into the gastric fluid. Examples
of such release rate retardants are glyceryl monostearate, fatty
acids and salts of fatty acids, (e.g. sodium myristate). Typically,
the weight ratio of additive to aripiprazole is in the range of
from about 1:10 to about 10:1, for example from about 1:5 to about
5:1.
[0223] The amount of polymer relative to aripiprazole may vary,
depending on the precise nature of the desired release profile, its
molecular weight, and excipients that may be present in the
formulation. However, the amount of polymer will be sufficient so
that the polymeric matrix will remain substantially intact until
all of aripiprazole is released. The term "substantially intact" is
used herein to denote a polymeric matrix in which the polymer
portion substantially retains its size and shape without
deterioration due to becoming solubilized in the gastric fluid or
due to breakage into fragments or small particles.
[0224] The water-swellable polymers can be used individually or in
combination. Certain combinations will often provide a more
controlled release of aripiprazole than their components when used
individually. Such combinations include cellulose-based polymers
(e.g. hydroxyethyl cellulose or hydroxypropyl cellulose) or
poly(ethylene oxide) combined with gums, (e.g. xanthan gum).
[0225] The benefits of the swellable matrix dosage form are
typically achieved over a wide range of aripiprazole loadings, for
example weight ratios of aripiprazole to polymer of from about
0.001:1 to about 10:1. Typical loadings (expressed in terms of the
weight percent of aripiprazole relative to aripiprazole and polymer
combined) are from about 0.001% to about 50%, preferably from about
0.01% to about 40%, such as from about 0.1% to about 30%, for
example from about 1% to about 20%.
[0226] The swellable matrix formulations also find significant
utility when administered to a subject who is in the digestive
state (also referred to as the postprandial or "fed" mode). The
postprandial mode is distinguishable from the interdigestive (or
"fasting") mode by distinct patterns of gastroduodenal motor
activity, which determine the gastric retention or gastric transit
time of the stomach contents.
[0227] Thus, administration of the formulation during the digestive
state results in localisation of aripiprazole release in the
stomach and small intestine reduces and/or prevents substantial
colonic degradation, inactivation, or loss of bioavailability.
[0228] Juvenile and elderly patients often require dosage forms
that are easy to swallow, for example to reduce the risk of choking
upon administration, and/or to improve patient compliance. The
compositions of the invention may be in the form of easily
administrable dosage forms, making them more suitable for patient
compliance. Such easily administrable formulations include, for
example, sprinkle dosage forms, taste-masked liquid dosage forms,
fast-dissolve dosage forms and chewable dosage forms.
[0229] It is to be understood that any of the easily administrable
dosage forms described below may comprise any of the formulations
described above in order to provide a composition which has the
desired release profile of aripiprazole according to the subject
invention.
[0230] An example of a chewable dosage form is a
aripiprazole-containing chewable tablet. Such a chewable tablet
comprises a chewable base and optionally a sweetener. The chewable
base typically comprises an excipient such as mannitol, sorbitol,
lactose, or a combination thereof. The optional sweetener used in
the chewable dosage form may be, for example, sucrose, liquid
glucose, sorbitol, dextrose, isomalt, liquid maltitol, aspartame,
lactose, or a combination thereof. In certain cases, the chewable
base and the sweetener may be the same component. The chewable base
and optional sweetener typically comprise about 50% to about 90% by
weight of the total weight of the chewable dosage form.
[0231] The chewable dosage form may additionally contain
preservatives, agents that retard and/or prevent adhesion to the
oral cavity and crystallization of sugars, flavouring agents,
souring agents, colouring agents, and combinations of one or more
of the foregoing. Glycerin, lecithin, hydrogenated palm oil or
glyceryl monostearate may be used as a protecting agent of
crystallization of the sugars, typically in an amount of from about
0.01 to about 2% by weight of the total weight of the ingredients.
Such protecting agents help to prevent adhesion to oral cavity and
improve the soft property or chewability of the dosage form.
Additionally or alternatively, isomalt or liquid maltitol may be
used to enhance the chewing properties of the chewable dosage
form.
[0232] The method for making the chewable dosage form comprising
aripiprazole described above is similar to the method used to make
soft confectionary. Such a method typically involves the formation
of a boiled sugar-corn syrup blend to which is added a frappe
mixture. The boiled sugar-corn syrup blend may be prepared from
sugar and corn syrup blended in parts by weight ratio of 90:10 to
10:90. This blend may be heated to temperatures above 120.degree.
C. to remove water and to form a molten mass. The frappe mixture
may be prepared from gelatine, egg albumen, milk proteins such as
casein, and vegetables proteins such as soy protein, and the like
which are added to a gelatine solution and rapidly mixed at ambient
temperature to form an aerated sponge like mass. The frappe mixture
is then added to the molten candy base and mixed until homogenous,
typically at temperatures between 60.degree. C. to about
120.degree. C. A matrix, tablet or other formulation containing
aripiprazole may then be added to the mix at a temperature of from
about 60.degree. C. to about 90.degree. C., whereupon additional
ingredients such as flavours, colourants, and preservatives may be
added. The formulation is then typically cooled and formed to
pieces of desired dimensions.
[0233] Fast-dissolving dosage forms may comprise microparticles and
one or to more effervescent agents, enabling the dosage forms to
rapidly disintegrate in the mouth whilst providing adequate
taste-masking. Alternatively, rapidly dissolving dosage forms may
contain an active agent and a matrix that includes a nondirect
compression filler and a lubricant. U.S. Pat. No. 5,178,878 and
U.S. Pat. No. 6,221,392 provide teachings regarding fast-dissolve
dosage forms.
[0234] Typical fast dissolve dosage forms for use in the subject
invention include a mixture incorporating a water and/or saliva
activated effervescent agent, a disintegration agent, and
microparticles. The microparticles typically incorporate
aripiprazole together with a protective material substantially
encompassing the aripiprazole. The term "substantially
encompassing" includes the meaning that the protective material
substantially shields aripiprazole from contact with the
environment outside the microparticle. Thus, each microparticle may
incorporate a discrete mass of aripiprazole covered by a coating of
the protective material, in which case the microparticle can be
referred to as a "microcapsule" or a "microtablet". Alternatively
or additionally, each microparticle may have aripiprazole dispersed
or dissolved in a matrix of the protective material, optionally
coated by a coating composition as described herein.
[0235] The mixture including the microparticles and an effervescent
agent is typically present as a tablet of a size and shape adapted
for direct oral administration to a patient. The tablet is
substantially completely disintegrable upon exposure to water
and/or saliva. The effervescent disintegration agent is present in
an amount effective to aid disintegration of the tablet, and to
provide a distinct sensation of effervescence when the tablet is
placed in the mouth of a patient.
[0236] The effervescent sensation is typically not only pleasant to
the patient but also tends to stimulate saliva production, thereby
providing additional water to aid in further effervescent action.
Thus, once the tablet is placed in the patient's mouth, it will
generally disintegrate rapidly and substantially completely without
any voluntary action by the patient. Thus, even if the patient does
not chew the tablet, disintegration should proceed rapidly. Upon
disintegration of the tablet, the microparticles are released and
can be swallowed as a slurry or suspension of the microparticles.
The microparticles are thus transferred to the patient's stomach
for dissolution in the digestive tract and systemic distribution of
the aripiprazole.
[0237] The terms "effervescent agent" and "disintegration agent"
includes compounds which evolve gas. Such agents may evolve gas by
means of chemical reactions which take place upon their exposure to
water and/or to saliva in the mouth. The bubble or gas generating
reaction is most often the result of the reaction of a soluble acid
source and an (alkali metal) carbonate source. The reaction of
these two general classes of compounds produces carbon dioxide gas
upon contact with the water in saliva.
[0238] Such saliva/water-activated materials should be kept in a
generally anhydrous state with little or no absorbed moisture or in
a stable hydrated form since exposure to water will prematurely
disintegrate the tablet. For example, the dosage form may be stored
in substantially air-tight packaging prior to administration.
[0239] The acid source may be any which is safe for human
consumption and may generally include food acids, acid anhydrides
and acid salts. Food acids include citric acid, tartaric acid,
malic acid, fumaric acid, adipic acid, and succinic acids, etc.
Because these acids are directly ingested, their overall solubility
in water is less important than it would be if the formulations
were intended to be dissolved in a glass of water. Acid anhydrides
and acid salts of the above-described acids may also be used. Acid
salts may include sodium, dihydrogen phosphate, disodium dihydrogen
pyrophosphate, acid citrate salts and sodium acid sulfite.
[0240] The carbonate source includes dry solid carbonate and
bicarbonate salts such as sodium bicarbonate, sodium carbonate,
potassium bicarbonate and potassium carbonate, magnesium carbonate
and sodium sesquicarbonate, sodium glycine carbonate, L-lysine
carbonate, arginine carbonate, amorphous calcium carbonate, and
combinations thereof.
[0241] While the effervescent disintegration agent is typically one
which upon a reaction which forms carbon dioxide, this is not
essential. Effervescent disintegration agents which evolve oxygen
or other gasses which are safe for human patients may also be
used.
[0242] Where the effervescent agent included two mutually reactive
components, such as an acid source and a carbonate source, it is
preferred that both components react substantially completely.
Therefore, an equimolar ratio of acid and carbonate sources is
preferred. For example, if the acid used is diprotic, then either
twice the molar amount of a mono-reactive carbonate base, or an
equal molar amount of a di-reactive base should be used for
complete neutralization to be realized. However, the amount of
either acid or carbonate source may exceed the amount of the other
component. This may be useful to enhance taste and/or performance
of a tablet containing an excess of either component. In such
cases, it is acceptable that the additional amount of either
component may remain unreacted.
[0243] The fast-dissolving dosage forms (e.g. tablets) typically
contain an amount of effervescent disintegration agent effective to
aid rapid and complete disintegration of the tablet when orally
administered. By "rapid", it is understood that the tablets should
disintegrate in the mouth of a patient in less than 10 minutes,
such as from about 15 seconds and about 7 minutes, for example from
about 30 seconds and about 5 minutes. Disintegration time in the
mouth can be measured by observing the disintegration time of the
tablet in water at about 37.degree. C. The tablet is immersed in
the water without forcible agitation. The disintegration time is
the time from immersion for substantially complete dispersion of
the tablet as determined by visual observation. As used herein, the
term "complete disintegration" of the tablet does not require
dissolution or disintegration of the microcapsules or other
discrete inclusions.
[0244] In order to achieve such disintegration, the amount of
effervescent agent or disintegration agent typically used in the
fast-dissolve dosage forms is from about 5% to about 50% by weight
of the final composition, preferably from about 15% to about 40% by
weight, more preferably about 20% to about 30% by weight.
[0245] The tablets described above can be manufactured by
well-known tableting procedures.
[0246] As mentioned above, each microparticle typically
incorporates aripiprazole in conjunction with a protective
material. The microparticle may be provided as a microcapsule,
microtablet or as a matrix-type microparticle. Microcapsules may
incorporate a discrete mass of aripiprazole surrounded by a
discrete, separately observable coating of the protective material.
Conversely, in a matrix-type particle, aripiprazole is dissolved,
suspended or otherwise dispersed throughout the protective
material. Certain microparticles may include attributes of both
microcapsules and matrix-type particles. For example, a
microparticle may incorporate a core incorporating a dispersion of
aripiprazole in a first protective material and a coating of a
second protective material, which may be the same as or different
from the first protective material surrounding the core.
Alternatively, a microparticle may incorporate a core consisting
essentially of aripiprazole and a coating incorporating the
protective material, the coating itself having some aripiprazole
dispersed within it. The microparticles typically have a mean
diameter of from about 75 to about 600 microns, preferably from
about 150 to about 500 microns, for example from about 200 to about
450 microns. The microparticles may be from about 200 to about 30
mesh (US standard size), for example from about 100 to about 35
mesh.
[0247] The protective materials suitable for use in the fast
dissolve dosage forms described above typically include polymers
which are conventionally utilized in the formation of
microparticles such as matrix-type microparticles, microtablets and
microcapsules. Among these are cellulosic materials such as
naturally occurring cellulose, synthetic cellulose derivatives,
acrylic polymers and vinyl polymers. Other simple polymers
including may also be used, such as proteinaceous materials (e.g.
gelatine, polypeptides) and natural and synthetic shellacs and
waxes. Protective polymers may also include ethylcellulose,
methylcellulose, carboxymethyl cellulose and acrylic resin
material.
[0248] When a coating is used in the above fast dissolve dosage
forms, it typically comprises at least about 5% by weight based on
the total weight of the resulting particles, preferably at least
about 10% by weight. The upper limit of protective coating material
used is generally less critical. In certain embodiments it is
possible to use a coating that is greater than 100 percent of
weight of the core, providing a relatively thick coating. However,
the amount of coating material should not be so great that it
impedes the release of a therapeutically effective amount
aripiprazole before defecation of the dosage form.
[0249] An example of a fast-dissolve dosage form is a hard,
compressed, rapidly dissolvable dosage form adapted for direct oral
dosing. Such a dosage form typically includes aripiprazole, often
in the form of a protected particle, and a matrix. The matrix
typically includes a filler and a lubricant, although it may
include other additional ingredients. The dosage form is adapted to
rapidly dissolve in the mouth of a patient, yet it has a friability
of about 2% or less when tested according to the USP. Generally,
the dosage form will also have a hardness of at least about 1.5 or
2.0 kP. Not only does the dosage form dissolve quickly, it does so
in a way that provides a positive organoleptic sensation to the
patient. In particular, the dosage form dissolves with a minimum of
unpleasant grit, which is tactilely very inconsistent with
organoleptic sensation of the dosage form.
[0250] The filler typically comprises a non-direct compression
filler. Exemplary fillers include, for example, nondirect
compression sugars and sugar alcohols. Such sugars and sugar
alcohols include dextrose, mannitol, sorbitol, lactose, and
sucrose. Dextrose, for example, can exist as either a direct
compression sugar, i.e., a sugar that has been modified to increase
its compressibility or a nondirect compression sugar. The
percentage of filler is typically in the range of from about 25 to
about 98% by weight of the microparticles, preferably from about 50
to about 95%, for example from about 60 to about 90%.
[0251] In the fast-dissolve dosage forms discussed above, a
relatively high proportion of lubricant is typically used.
Lubricants, and in particular, hydrophobic lubricants such as
magnesium stearate, may be used in an amount of from about 0.25 to
about 5% by weight of the formulation, preferably from about 1 to
about 3% by weight, for example from about 1.5 to about 2% by
weight. Despite the use of this relatively high percentage weight
of lubricant, the formulations typically exhibit excellent
compressibility, hardness, and rapid dissolution within the
mouth.
[0252] Hydrophobic lubricants include, for example, alkaline earth
metal stearates, stearic acid, mineral and vegetable oils, glyceryl
behenate, sodium stearyl fumarate, and combinations thereof.
Hydrophilic lubricants may be also be used.
[0253] The hard, compressed fast-dissolve dosage forms typically
have a hardness of at least about 1.5 kP and are designed to
dissolve spontaneously and rapidly in the mouth of a patient in
less than about 90 seconds to thereby liberate the particles.
Preferably the dosage form will dissolve in less than about 60
seconds and even more preferably in about 30 to about 45 seconds.
This measure of hardness is based on the use of small tablets of
less than about 0.25 inches in diameter. A hardness of at least
about 2.0 kP is preferred for larger tablets. Direct compression
techniques are preferred for the formation of these tablets.
[0254] Sprinkle dosage forms are another form of easily
administered formulations that may be used in the compositions of
the invention. Sprinkle dosage forms typically comprise
aripiprazole in the form of pellets, granules, microtablets or
microcapsules, optionally having functional or non-functional
coatings. In use, the patient or caregiver can sprinkle the
particulate/pelletized dose into drink or onto soft food. A
sprinkle dosage form may comprise particles having a mean diameter
of from about 10 to about 100 Tm in their major dimension, for
example from about 50 to 70 Tm.
[0255] An example of a sprinkle dosage form is an easily openable
capsule enclosing a plurality of aripiprazole-containing
micropellets. Each of the micropellets typically comprises a seed
coated with a first coating mixture of aripiprazole and
polyvinylpyrrolidone and a second coating mixture of from about 90
to about 70% by weight of the mixture of a non-hydrophilic polymer
(e.g. ethyl cellulose) and from about 10 to about 30% by weight of
the mixture of a hydrophilic polymer (e.g. hydroxypropyl methyl
cellulose). For example, the second coating mixture may comprise
about 3 parts ethylcellulose to about 1 part
hydroxypropylcellulose. The weight of the second coating mixture is
about 5-10% of the weight of the micropellets before the second
coating is applied. Optionally, the second coating contains
aripiprazole.
[0256] The polyvinylpyrrolidone used in the first coating typically
has a molecular weight of from about 30,000 to about 50,000, e.g.
about 40,000. The seed of the sprinkle dosage form may be a sugar
seed and have a mesh size of 60/80.
[0257] Taste-masked dosage forms are another form of easily
administered formulations that may be used in the compositions of
the invention. The taste-masked dosage form may be liquid or
solid.
[0258] A solid taste masked dosage form typically comprises a core
element comprising aripiprazole and a coating material surrounding
the core element. The core element comprising aripiprazole is
typically in the form of a (micro)particle, (micro)tablet,
(micro)capsule, amorphous solid, pellet, granule, powder or a
matrix. The core element may include carriers or excipients,
fillers, flavouring agents, stabilizing agents and/or colourants in
addition to aripiprazole.
[0259] The taste-masked dosage form typically includes from about
50 to about 99% by weight, preferably from about 65 to about 95% by
weight, for example from about 80 to about 90% by weight of the
aripiprazole-containing core element, based on the total weight of
the dosage form. The taste-masked dosage form typically includes
from about 1 to about 50% by weight, preferably from about 5 to
about 35% by weight, for example from about 10 to about 20% by
weight of the coating material surrounding the core element, based
on the total weight of the dosage form.
[0260] The core element typically includes from about 20 to about
90% by weight of a supplementary component selected from waxes,
water insoluble polymers, enteric polymers, and partially water
soluble polymers, other suitable pharmaceutical excipients, and
combinations thereof.
[0261] The core element optionally includes carriers or excipients,
fillers, flavouring agents, stabilizing agents, colorants, and
combinations thereof. Suitable fillers include, for example,
insoluble materials such as silicon dioxide, titanium dioxide,
talc, alumina, starch, kaolin, polacrilin potassium, powdered
cellulose, and microcrystalline cellulose, and combinations
comprising one or more of the foregoing fillers. Soluble fillers
include, for example, mannitol, sucrose, lactose, dextrose, sodium
chloride, sorbitol, and combinations comprising one or more of the
foregoing fillers. The filler may be present in amounts of up to
about 75% by weight based on the total weight of the dosage
form.
[0262] The core element may be in the form of a powder, for
example, having a particle size range of about 35 Tm to about 125
Tm. Such small particle size facilitates a substantially non-gritty
feel in the mouth. Small particle size also minimizes break-up of
the particles in the mouth, e.g. by the teeth. When in form of a
powder, the taste masked dosage form may be administered directly
into the mouth or mixed with a carrier such as water, or
semi-liquid compositions such as syrups, yogurt, and the like.
However, the taste-masked aripiprazole may be provided in any
suitable unit dosage form.
[0263] The coating material of the taste-masked formulation may
take a form that provides a substantially continuous coating and
provides taste masking. The coating may also provide controlled
release of aripiprazole. The polymer used in taste masked dosage
form coating may be a water insoluble polymer such as, for example,
ethyl cellulose. The coating material of the taste masked dosage
form may further include a plasticizer.
[0264] A method of preparing taste-masked pharmaceutical
formulations such as powdered formulations typically includes
mixing a core element and a coating material in a diluent and spray
drying the mixture to form a taste-masked formulation. Spray drying
of the pharmaceutically active ingredient and polymer in the
solvent typically involves spraying a stream of air into an
atomized suspension, optionally in a drying chamber, so that
solvent is caused to evaporate leaving aripiprazole coated with the
polymer coating material.
[0265] For a solvent such as methylene chloride, the solvent
concentration in the drying chamber is typically maintained at from
about 40,000 to about 100,000 parts per million of organic solvent.
The spray-drying process for such solvents may be conducted at a
process temperature of about 5.degree. C. to about 35.degree. C.
Spray drying of the dosage forms may be undertaken utilizing either
rotary, pneumatic or pressure atomizers located in either a
co-current or mixed-flow spray dryer or variations thereof. The
drying gas may be heated or cooled to control the rate of drying. A
temperature below the boiling point of the solvent may be used.
Inlet temperatures may be from about 40 to about 120.degree. C. and
outlet temperatures from about 5.degree. C. and 35.degree. C.
[0266] The coat formation may be optimized to meet the needs of the
material or application. Controlling the process parameters such as
temperature, solvent concentration, spray dryer capacity, atomizing
air pressure, droplet size, viscosity, total air pressure in the
system and the solvent system, allows the formation of a range of
coats, ranging from dense, continuous, non-porous coats through to
more porous microcapsule/polymer matrices.
[0267] A post-treatment step may be used to remove any residual
solvent. The post treatment may include a post drying step
including drying the final product on a tray and/or at a bed
temperature sufficient to remove excess solvent, but not degrade
the aripiprazole. Preferably the drying temperature is in the range
of from about 35.degree. C. to about 40.degree. C. Once completed,
the product maybe collected by a suitable method, such as
collection by sock filters or cyclone collection.
[0268] An exemplary chewable taste-masked dosage form comprises a
microcapsule of about 10 Tm to about 1.5 mm in diameter having a
core comprising aripiprazole and a polymer mixture coating having
sufficient elasticity to withstand chewing. The polymeric mixture
coating typically comprises from about 30 to about 70% by weight of
a polymer that forms a polymeric film at temperatures of at least
about 30.degree. C. (e.g. ethylcellulose) and from about 30 to
about 70% by weight of a copolymer that forms a polymeric film at
temperatures less than about 25.degree. C. The polymeric mixture
coating is adapted so that the dosage form exhibits the release
profiles discussed earlier in this specification.
[0269] The copolymer that forms a polymeric film at temperatures
less than about 25.degree. C. is typically a methacrylic acid ester
copolymer (having, for example, a weight average molecular weight
of about 800,000) or a styrene acrylate copolymer.
[0270] The core of the taste-masked aripiprazole dosage form
described above may comprise a diluent and/or a plasticizer.
Suitable plasticizers, include, but are not limited to polyethylene
glycol, triacetin, vinylpyrrolidone, diethyl phthalate,
dibutylsebacate, a citric acid ester, and combinations thereof.
[0271] Solid taste-masked dosage forms (e.g. polymer coated
aripiprazole powder) may be reconstituted as suspensions in a
liquid vehicle such as water before usage. This has the advantage
that the reconstitutable solid taste-masked dosage forms typically
have a longer shelf life than many liquid taste-masked dosage forms
and the suspensions, once reconstituted, have adequate taste
masking.
[0272] Aripiprazole is considered to impart its clinical activity
via its partial agonist properties on post-synaptic dopamine
receptors in several dopamine pathways in the brain. It is
currently used for the treatment of both positive and negative
symptoms of all forms of schizophrenia and has an indication for
use as a short treatment of acute mania, or manic symptoms
associated with bipolar disorders. The subject invention seeks to
address the deficiencies of known aripiprazole-containing
formulations for the treatment of schizophrenia and bipolar
disorders by providing the orally deliverable pharmaceutical
compositions described herein. However, these compositions may be
used in the treatment of numerous other medical indications in
addition to schizophrenia and bipolar disorders, as described in
more detail below.
[0273] Partial agonism is an unusual mechanism of action, but not
unique to aripiprazole regarding neuromodulation of
neurotransmitter activity in the brain. Aripiprazole competes for
and binds to post synaptic receptors, mainly on the dopamine
pathways in the mammalian brain. The resultant effect of partial
agonism is a `dampening down` of the extremes of activation of
neuronal pathways--in a pathway where the neurones are not being
stimulated enough, the partial agonist acts as an agonist
(`stimulant`); in a pathway where there is over-activation, the
partial agonist acts as an antagonist (`inhibitory agent`).
Aripiprazole acts mainly on the dopamine pathways in the brain, in
particular those involved in reward mechanisms. It works on both
the positive and negative symptoms of schizophrenia due to its
balancing effect, and to date has also achieved an indication for
the control of acute mania as part of bipolar I disorder. Anecdotal
evidence exists of its utility in treating the depressive symptoms
of both schizophrenia and bipolar I disorder, this is predictable
by its mode of action. Clinical trials are ongoing and are expected
to result in further indications for long term use as a mood
stabiliser in bipolar disorders and as an antidepressant
product.
[0274] The subject invention provides the use of an orally
deliverable pharmaceutical composition as defined in the claims for
the treatment of a neurological and/or a psychiatric condition.
[0275] By the term "a neurological and/or a psychiatric condition",
we include all conditions deriving from a pathology of the nervous
system. Particular examples of such conditions are described in
more detail below.
[0276] The phrase "the treatment of a neurological and/or a
psychiatric condition" is intended to include use for the acute,
chronic and/or prophylactic treatment of neurological,
neuropsychiatric, psychiatric and neurodegenerative disease.
[0277] Accordingly, there are numerous conditions which may be
treated by administering or using the compositions of the
invention. The invention is particularly suited to all conditions
involving two extremes of activation of the dopamine pathways in
the brain. These include all bipolar disorders, schizoaffective
disorders, Generalised Anxiety disorder, obsessive compulsive
disorder, Post Traumatic Stress Disorder, Personality Disorder and
Borderline Personality Disorder, all types of cognitive impairment
(e.g. mild cognitive impairment of the elderly); psychiatric
complications of stroke (including haemorrhagic and ischaemic and
sequelae), epilepsy, transient ischaemic attacks, traumatic brain
injury, Parkinson's disease, Huntington's disease, amyotrophic
lateral sclerosis; neuropathic pain, idiopathic pain, all psychoses
(such as degenerative schizophrenia and catatonia), all addictions,
(e.g. addiction to alcohol, nicotine and opiates), all eating
disorders including bulimia and anorexia, affective disorders
including ADHD (attention deficit hyperactivity disorder), all
depressive disorders, personality disorders (including borderline
personality disorders), sleep disorders (including jet lag and
insomnia), Downs syndrome, meningitis, central nervous system
vasculitis, leukodystrophies and adrenoleukodystrophies (including
Alexander's disease, Canavan's disease, cerebrotendinous
xanthomatosis, Krabbes and metachromatic LD), fatigue,
hypoglycaemia, encephalopathy, (such as hepatic and septic
encephalopathy), tumours of the brain and spinal cord (including
primary tumours of glial, neuronal, schwann cell, pinealcyte,
meningioma, melanoma, sarcoma, lymphoma and multiple systemic
systemic malignancies which metasize), cerebellar degeneration and
ataxias (e.g. Friedrich's ataxia, cerebellar cortical atazia,
complicated cerebellar ataxia, which includes olivopontocerebellar
degeneration, spinocerebellar disease, dentatorubral degeneration
and autosomal dominant ataxias) vertigo, vestibular system damage,
cochlear disorders such as tinnitus, nystagmus, peripheral
neuropathy, (e.g. polyneuropathy, polyradiculopathy, motor
neuronopathy, sensor neuronopathy, multiple mononeuropathy and
plexopathies), metabolic bone diseases, osteoporosis, pulmonary
disorders, (such as pulmonary edema, neurogenic pulmonary edema,
bronchial asthma, adult respiratory distress syndrome (ARDS) and
pulmonary cell death by apoptosis or necrosis), obesity and
complications thereof, diabetes and prediabetes, and combinations
thereof.
[0278] The compositions of the invention may comprise one or more
active agents in addition to aripiprazole.
[0279] For example, the compositions of the invention may comprise
another atypical antipsychotic agent (e.g. olanzapine, quetiapine,
risperidone, amisulpride, clozepine, chlorpromazine, or haloperidol
decanoate), antiparkinsonian agents (e.g. L-DOPA, Dopamine
Agonists), sedatives (e.g. a benzodiazepine sedative or
non-barbituate sedative), anxiolytics (e.g. benzodiazepines such as
lorazepam, chlordiazepoxide, oxazepam, clorazepate, diazepam, and
alprazolam), antidepressants, and mood stabilisers (e.g.
lamotrigine, lithium, valproate, carbamazepine, oxcarbazepine).
[0280] The antiparkinsonian agents may be used to treat the tardive
dyskinesia associated with neuroleptic use. Also called
"side-effect medication" antiparkinsonians are indicated when
muscle side-effects of the atypical antipsychotics make patients
uncomfortable. Antiparkinsonian agents are typically
anticholinergic drugs, examples including benztropine mesylate,
trihexyphenidyl, procyclidine, and amantadine.
[0281] Suitable antidepressents include tricyclic antidepressants
(such as amitriptyline, imipramine, doxepin, and clomipramine),
monoamine oxidase A or B inhibitors (such as phenelzine and
tranylcypromine), tetracyclic antidepressants (e.g. maprotiline),
and serotonin re-uptake inhibitors such as fluoxetine, cipramil,
S-cipramil, paroxetine, and sertraline hydrochloride, serotonin and
nor adrenaline reuptake inhibitors such as venlafaxine and
duloxetine, nor adrenaline reuptake inhibitors such as reboxetine
and viloxazine and all other classes of antidepressants.
[0282] Compositions of the invention including one or more of the
compounds listed above in addition to aripiprazole are particularly
suitable for the treatment of certain patients suffering from
schizophrenia, such as those suffering from severe or unresponsive
symptoms of schizophrenia.
[0283] Of course, the aripiprazole formulations described herein
may be used for the treatment of numerous other conditions in
addition to schizophrenia. Such conditions may require treatment by
different additional active agents (in addition to aripiprazole)
than those described above in relation to the treatment of
schizophrenia.
[0284] The invention will now be illustrated by the following
non-limiting Examples.
Example 1
Aripiprazole Compositions
[0285] 30 mg direct compression (DC) and wet granulation (WG)
controlled release tablets were manufactured as described
below.
[0286] Direct Compression Tablets
[0287] The ingredients set out in Table 1 below were blended
together in a planetary mixer for 5 minutes. The blend was
compressed on a rotary tabletting machine, using 7.0 mm diameter
round n/c punches. The tablet breaking strength was 2.5 kp to 3.5
kp.
TABLE-US-00001 TABLE 1 Direct Compression Composition DJ/1/27/A DC
Ingredient % tablet mg batch g Aripiprazole 20 30 100 Methocel K4M
35 52.5 175 Avicel PH 200 44 66 220 Sodium Stearyl Fumarate 1 1.5 5
100 150 500
[0288] Wet Granulation Tablets
[0289] The ingredients set out in Table 2 below except for sodium
stearyl fumarate were blended together in planetary mixer for 5
minutes prior to wet granulation with purified water. The moist
powders were dried in a fluid bed drier at an inlet temperature of
70.degree. C. for 15 minutes. The dried granule had a loss on
drying value of 2.5% w/w. The granules were sieved through an 850
.mu.m screen and blended for 1 minute with the Sodium Stearyl
Fumarate. The blend was compressed at 150 mg on a rotary tabletting
machine, using 7.0 mm diameter round n/c punches. The tablet
breaking strength was 5.0 kp to 6.0 kp.
TABLE-US-00002 TABLE 2 Wet Granulation Composition DJ/1/27/C WG
Ingredient % tablet mg batch g Aripiprazole 20 30 100 Methocel K4M
35 52.5 175 Avicel PH 200 39 58.5 195 PVPK30 5 7.5 25 Sodium
Stearyl Fumarate 1 1.5 5 100 150 500
[0290] In the above tablets, the aripiprazole was obtained from LGM
Pharmaceuticals (US). The methocel K4M ((hydroxypropyl
methylcellulose 2208 (hypromellose)) was obtained from Colorcon
Limit (UK). Avicel PH 200 (microcrystalline cellulose) was obtained
from FMC BioPolymer (Ireland). PVPK30 (polyvinylpyrrolidine) was
obtained from Shanghai WellTone Material Co., Ltd, China. Sodium
Stearyl Fumarate, under the trade mark PRUV, was obtained from JRS
Pharma GMBH (Germany).
Example 2
In Vitro Release Experiments
[0291] The release profiles of Aripiprazole from the DC and WG
tablets described in Example 1 were studied in pH 4.0 phosphate
buffer and 0.1M HCl, as described in more detail below.
[0292] Dissolution System
TABLE-US-00003 Dissolution medium 0.05M Phosphate Buffer (pH 4.0)
or 0.1M Hydrochloric Acid Apparatus USP II (Paddles) Volume 900 ml
Speed 100 rpm Temperature 37.degree. C.
[0293] 7 litres 0.05M Phosphate buffer (pH 4.0) was prepared by
dissolving 47.8 g potassium phosphate in 6.75 litres of water, then
adding portions of 60% orthophosphoric acid solution to obtain a pH
of 4.0 (+/-0.05). The solution was made up to 7 litres with water
and the pH adjusted as necessary with sodium hydroxide or
phosphoric acid).
[0294] The 0.1M HCl was prepared by diluting 3.5 litres of 0.2M
hydrochloric acid to 7 litres with purified water.
[0295] Dissolution Procedure
[0296] Aliquots were taken from each dissolution vessel at the
indicated (e.g. hourly) hourly intervals. The UV absorbance of each
aliquot at 215 nm was measured against a blank solution of 0.05M
phosphate buffer and calibrated against three reference standards
(0.03, 0.0012 and 0.0006 mg/ml aripiprazole). The % aripiprazole
dissolved is calculated using the calibration curve created from
the reference standards: [0297] p=purity of reference standard as %
w/w (not required when the input batch of drug substance is used as
the reference standard) [0298] X=value obtained from graph in
mg/ml
[0298] % dissolved = X .times. 900 .times. p .times. 100 % Label
claim ( mg ) .times. 100 ##EQU00001##
[0299] Table 3 below shows the averaged hourly Aripiprazole release
percentages over 23 hours from the DC tablet of Example 1 in pH 4.0
phosphate buffer. The corresponding graph of Aripiprazole release
over time is shown in FIG. 1.
TABLE-US-00004 TABLE 3 % Aripiprazole (DC) release in pH 4.0
phosphate buffer over 23 hours Time/h 0 1 2 3 4 5 6 7 8 9 10 %
Release 0.0 10.4 14.6 20.6 26.3 32.4 38.3 43.7 48.1 52.9 56.5
Time/h 13 14 15 16 17 18 19 20 21 22 23 % Release 69.7 75.5 78.9
82.2 84.1 85.8 87.8 89.2 91.1 91.7 92.7
[0300] Table 4 below shows the averaged hourly Aripiprazole release
percentages over 20 hours from the direct compression tablet of
Example 1 in 0.1M HCl. The corresponding graph of Aripiprazole
release over time is shown in FIG. 2.
TABLE-US-00005 TABLE 4 Aripiprazole (DC) release in 0.1M HCl over
20 hours Time/h 0 1 2 3 4 5 6 7 8 9 % 0.0 6.5 10.7 15.8 21.5 27.4
33.9 40.4 46.7 54.0 Re- lease Time/h 10 11 12 13 14 16 17 19 20 %
60.7 67.6 71.5 80.4 81.4 89.5 90.1 91.1 95.8 Release
[0301] Table 5 below shows the averaged hourly Aripiprazole release
percentages over 23 hours from the WG tablet of Example 1 in 0.1M
HCl. The corresponding graph of Aripiprazole release over time is
shown in FIG. 3.
TABLE-US-00006 TABLE 5 Aripiprazole (WG) release in 0.1M HCl over
23 hours Time/h 0 1 2 3 4 5 6 7 8 9 10 % Release 0.0 6.7 12.5 17.1
24.3 32.0 40.0 45.9 52.9 60.7 65.1 Time/h 13 14 15 16 17 18 19 20
21 22 23 % Release 79.5 86.4 89.4 91.7 94.4 95.4 96.2 97.1 96.0
99.1 96.1
[0302] Table 6 below shows the averaged hourly Aripiprazole release
percentages over 15 hours from the WG tablet of Example 1 in pH 4.0
phosphate buffer. The corresponding graph of Aripiprazole release
over time is shown in FIG. 4.
TABLE-US-00007 TABLE 6 % Aripiprazole (WG) release in pH 4.0
phosphate buffer over 15 hours Time/h 0 1 2 3 4 5 6 7 % Release 0.0
14.4 20.4 25.1 29.7 34.0 37.5 40.9 Time/h 8 9 10 11 12 13 14 15 %
Release 45.2 47.5 51.0 53.6 56.6 58.8 61.1 62.9
Example 3
Pharmacokinetic Modelling
[0303] Multiexponential functions were fitted to the published
plasma concentration-time profiles of immediate-release (IR)
aripiprazole after repeated once-daily oral doses of 5, 10, 15 and
20 mg (Mallikaarjun S, Salazar D, Braner S, "Pharmacokinetics,
tolerability and safety of aripiprazole following multiple oral
dosing in normal healthy volunteers", J. Clin. Pharmacol., 2004;
44:179-187).
[0304] The function (representing first-order absorption with
two-compartment disposition) was of the form:
C(t)=Ae.sup.-.alpha.(t)+Be.sup.-.beta.(t)+Ce.sup.-k.sup.01.sup.(t)
where A, B, .alpha., .beta. and k.sub.01 are constants, C=-(A+B)
and C(t) is the plasma concentration at time, t.
[0305] The published model (Mallikaarjun et al, see above) was used
to simulate plasma concentrations of aripiprazole after various
dose regimens of the IR formulation. In addition, various dose
regimens of a sustained-release (SR) formulation were simulated
assuming that the release was zero-order for examples ranging from
10 h to 18 h. The simulated plasma profiles of aripiprazole from
the new SR formulations were compared to modelling of the currently
utilised IR regimen.
[0306] Plasma aripiprazole plasma concentration profiles after
repeated dosing were simulated, using the prescribed model, by
means of WinNonLin Pro Version 5.2 (Pharsight Corporation Inc.,
Mountain View, Calif., USA, 2006). 15 mg aripiprazole was the most
commonly used dose (Molden E, Lunde H, Lunder N, Refsum H,
"Pharmacokinetic variability of aripiprazole and the active
metabolite dehydroaripiprazole in psychiatric patients", Ther. Drug
Monit., 2006; 28:744-749). Therefore, the multiexponential function
fitted to the 15 mg IR data was selected as the comparative IR
dose. Linear kinetics were assumed for this analysis, consistent
with the dose-proportional kinetics observed (Mallikaarjun et al).
The SR formulation was represented by the multi-exponential
function fitted to the 5 mg IR data and assuming zero-order input
(absorption) for 10 or 14 h.
[0307] The prescribed mean functions fitted to the plasma
concentrations of aripiprazole following once-daily oral dosing of
5, 10, 15 and 20 mg of the IR formulation (Mallikaarjun et al) are
presented in Table 7.
TABLE-US-00008 TABLE 7 Mean parameters of the multi-exponential
model fitted to the plasma concentration profiles of aripiprazole
following administration of an IR formulation Dose (mg) Parameter 5
10 15 20 Parameters published for IR formulation A (ng/mL) 79.3 117
183 191 B (ng/mL) 15.8 35.5 48.6 63.1 t.sub.1/2 (ABS) (h) 1.50 1.20
1.20 1.60 t.sub.1/2 (.alpha.) (h) 2.60 2.10 4.50 2.40 t.sub.1/2
(.beta.) (h) 71.1 58.0 58.7 78.6 Parameters used for IR formulation
A (ng/mL) 79.3 117 183 191 B (ng/mL) 15.8 35.5 48.6 63.1 k.sub.01
(/h) 0.462 0.578 0.578 0.433 .alpha. (/h) 0.267 0.330 0.154 0.289
.beta. (/h) 0.00975 0.0120 0.0118 0.00882 Parameter Value
Parameters published for IR formulation (5 mg) V (L) 116 k.sub.21
(/h) 0.104 t.sub.1/2 (.alpha.) (h) 2.60 t.sub.1/2 (.beta.) (h) 71.1
Parameters used for SR formulation (5 mg) V (mL) 0.116 k.sub.21
(/h) 0.104 .alpha. (/h) 0.267 .beta. (/h) 0.00975 Input duration
(h) 10 or 14
[0308] The simulated concentrations of aripiprazole are illustrated
in FIG. 5. The simulated profiles are similar to those published
(Mallikaarjun et al).
[0309] Steady-state simulations of aripiprazole following 30 mg IR
administered every other day are compared to simulations after
once-daily dosing of 15 mg IR in FIG. 6.
[0310] Steady-state simulations of aripiprazole following 15 mg IR
administered every other day are compared to simulations after
once-daily dosing of 15 mg IR in FIG. 7.
[0311] Steady-state simulations of aripiprazole following 30 mg
14-h SR form administered every other day are compared to
simulations after once-daily dosing of 15 mg IR in FIG. 8.
[0312] Steady-state simulations of aripiprazole following 60 mg
14-h SR form administered weekly are compared to simulations after
once-daily dosing of 15 mg IR in FIG. 9.
[0313] Steady-state simulations of aripiprazole following 30 mg
14-h SR form administered twice-weekly (e.g. every Wednesday and
Sunday) are compared to simulations after once-daily dosing of 15
mg IR in FIG. 10.
[0314] Steady-state simulations of aripiprazole following 45 mg
14-h SR form administered twice-weekly (e.g. every Wednesday and
Sunday) are compared to simulations after once-daily dosing of 15
mg IR in FIG. 11.
[0315] Steady-state simulations of aripiprazole following 60 mg
14-h SR form administered twice-weekly (e.g. every Wednesday and
Sunday) are compared to simulations after once-daily dosing of 15
mg IR in FIG. 12.
[0316] Steady-state simulations of aripiprazole following 30 mg
10-h SR form administered every other day are compared to
simulations after once-daily dosing of 15 mg IR in FIG. 13.
[0317] Steady-state simulations of aripiprazole following 30 mg
18-h SR form administered every other day are compared to
simulations after once-daily dosing of 15 mg IR in FIG. 14.
[0318] Steady-state simulations of aripiprazole following 60 mg
10-h SR form administered weekly are compared to simulations after
once-daily dosing of 15 mg IR in FIG. 15.
[0319] Steady-state simulations of aripiprazole following 60 mg
18-h SR form administered weekly are compared to simulations after
once-daily dosing of 15 mg IR in FIG. 16.
[0320] Steady-state simulations of aripiprazole following 45 mg
10-h SR form administered twice-weekly (e.g. every Wednesday and
Sunday) are compared to simulations after once-daily dosing of 15
mg IR in FIG. 17.
[0321] Steady-state simulations of aripiprazole following 45 mg
18-h SR form administered twice-weekly (e.g. every Wednesday and
Sunday) are compared to simulations after once-daily dosing of 15
mg IR in FIG. 18.
[0322] Steady-state simulations of aripiprazole following 15 mg
14-h SR administered once daily are compared to simulations after
once-daily dosing of 15 mg IR in FIG. 19.
[0323] Steady-state simulations of aripiprazole following 15 mg
10-h SR administered once daily are compared to simulations after
once-daily dosing of 15 mg IR in FIG. 20.
[0324] The results in FIG. 6 suggest that the 30 mg IR dosed every
two days would have a significantly greater chance of adverse
events (due to the high C.sub.max) compared to the OD 15 mg IR
regimen. On the other hand, FIG. 7 shows that the aripiprazole
plasma concentrations of the 15 mg IR every other day regimen are
lower than the OD 15 mg IR regimen.
[0325] The results shown in FIGS. 8, 13 and 14 show that the 30 mg
SR formulation dosed every two days has very similar peak to trough
properties compared to 15 mg IR dosed daily. This suggests the
potential for comparable efficacy but with an improved dosing
schedule.
[0326] The 45 mg SR formulation dosed twice weekly (see FIGS. 11,
17 and 18) has similar peak to trough properties compared to 15 mg
IR dosed daily, which given the current lack of understanding in
the relationship between plasma exposure and drug effects (Drugs at
FDA; Abilify.RTM. (NDA#021436 Tablet Oral)) suggests the potential
for comparable efficacy but with an improved dosing schedule.
Similarly, the aripiprazole plasma concentration profile for the 60
mg SR formulation dosed weekly (see FIGS. 9, 15 and 16) is believed
to fall within tolerated and efficacious levels.
[0327] The results in FIGS. 19 and 20 also suggest that the once
daily 15 mg SR formulation would have a significantly decreased
chance of adverse events (due to the low C.sub.max) compared to the
analogous 15 mg IR regimen.
* * * * *