U.S. patent application number 14/109633 was filed with the patent office on 2014-06-05 for for injectable formulations containing asenapine and method of treatment using same.
The applicant listed for this patent is Werenfridus Adrianus Faassen, Gerardus Johannes Kemperman, Johannes Antonius van Laarhoven. Invention is credited to Werenfridus Adrianus Faassen, Gerardus Johannes Kemperman, Johannes Antonius van Laarhoven.
Application Number | 20140154322 14/109633 |
Document ID | / |
Family ID | 43386952 |
Filed Date | 2014-06-05 |
United States Patent
Application |
20140154322 |
Kind Code |
A1 |
Faassen; Werenfridus Adrianus ;
et al. |
June 5, 2014 |
FOR INJECTABLE FORMULATIONS CONTAINING ASENAPINE AND METHOD OF
TREATMENT USING SAME
Abstract
The present invention provides a formulation comprising
asenapine hemipamoate suspended particles, which formulation can be
administered via a Depot provided by an IM injection of the
formulation, and which depot does not display a particle-size
dependent release rate. The present invention provides also methods
of treatment using the same.
Inventors: |
Faassen; Werenfridus Adrianus;
(Oss, NL) ; Kemperman; Gerardus Johannes; (Oss,
NL) ; van Laarhoven; Johannes Antonius; (Oss,
NL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Faassen; Werenfridus Adrianus
Kemperman; Gerardus Johannes
van Laarhoven; Johannes Antonius |
Oss
Oss
Oss |
|
NL
NL
NL |
|
|
Family ID: |
43386952 |
Appl. No.: |
14/109633 |
Filed: |
December 17, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13378118 |
Jun 5, 2012 |
8658687 |
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PCT/EP10/58960 |
Jun 24, 2010 |
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14109633 |
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61220027 |
Jun 24, 2009 |
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Current U.S.
Class: |
424/489 ;
514/410 |
Current CPC
Class: |
A61K 31/407 20130101;
A61P 25/00 20180101; A61K 9/19 20130101; A61K 31/40 20130101; C07D
491/044 20130101; A61K 9/0019 20130101; A61P 25/18 20180101; A61K
9/10 20130101; A61K 47/10 20130101 |
Class at
Publication: |
424/489 ;
514/410 |
International
Class: |
A61K 9/19 20060101
A61K009/19; A61K 31/407 20060101 A61K031/407 |
Claims
1-20. (canceled)
21. A pharmaceutical formulation comprising an aqueous suspension
of particles of crystalline Form II of asenapine hemipamoate,
wherein said asenapine hemipamoate is present at a concentration of
5 wt. % or greater of the suspension, and wherein, said particles
comprise less than about 10 vol % of particles having a mean
diameter of less than 1 micron and have a d.sub.50-value of from
about 1.5 microns to about 40 microns.
22. The formulation of claim 21 which is further characterized by
providing a consistent release profile of asenapine from a depot
injection consistent with that illustrated in FIGS. 9a to 9c.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is the National Stage of International
Application No. PCT/EP2010/058960 filed on Jun. 24, 2010, which
claims the benefit under 35 U.S.C. 119(e) of U.S. Provisional
Application No. 61/220,027 filed Jun. 24, 2009, each of which
applications are incorporated by reference as if fully set forth
herein.
FIELD OF THE INVENTION
[0002] This application discloses a novel formulation comprising
asenapine hemipamoate which is suitable for depot administration of
asenapine and methods of treatment using the same.
BACKGROUND OF THE INVENTION
[0003] Identification of any publication in this section or any
section of this application is not an admission that such
publication is prior art to the present invention.
[0004] U.S. Pat. No. 4,145,434 (the '434 patent), in Example IV
therein, describes the preparation of
trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz-[2,3;6,7]oxepino--
[4,5c]pyrolle (known also as asenapine, see Merck Index monograph
no. 832), which has the structure of the compound of Formula I,
##STR00001##
[0005] The compound of Formula I is known to have activity in the
treatment of patients afflicted with central nervous system
disorders (CNS disorders). As described in the '434 patent, Col. 1,
lines 45 to 50, compounds like the compound of Formula I show in
general a marked CNS-depressant activity, which can be used in the
treatment of states of tension, excitation and anxiety, and in the
treatment of psychotic and schizophrenic conditions and show as
well excellent antihistamine and antiserotonin activities. As
described in U.S. Pat. No. 5,763,476 (the '476 patent), filed Mar.
9, 1995 as international application. no. PCT/EP95/00765, in Col.
1, lines 43 to 46, sublingual or buccal administration of an
asenapine maleic acid salt is useful for use in treating or
managing diseases including mental disorders, such as tension,
excitation, anxiety, psychosis, and schizophrenia. Each of the
aforementioned applications and patents are incorporated by
reference as if fully set forth herein in their entirety. Treatment
of bipolar disorders and associated symptoms with administration of
asenapine is described in a U.S. patent application published Apr.
20, 2006 under publication no. 2006/0084692, which application is
incorporated by reference as if fully set forth herein in its
entirety.
[0006] Sublingual administration of a formulation comprising
asenapine or a salt thereof to a patient to whom it is administered
is effective in providing treatment for many CNS diseases, but
requires at least regular daily administration to maintain
acceptable therapeutic levels of asenapine in patients.
[0007] One serious problem to be overcome in providing effective
asenapine therapy is lack of dosing compliance, particularly when
the medicament is self-administered and more particularly when it
must be administered daily or several times daily. Accordingly, in
addressing this compliance issue, it would be preferable to have a
medicament administered in a clinical setting to a patient in a
form providing a therapeutically effective plasma level in the
patient for a sustained period of time, thus eliminating the
compliance problems associate with self-administration. This
treatment modality would also require fewer dosing treatments in a
given period of time.
[0008] In an effort to increase the amount of time between doses of
a medicament while maintaining a therapeutically effective plasma
level of the active compound, some workers have attempted to
administer some CNS active agents by intramuscular injection of a
depot (Depot administration) of a composition containing the active
pharmaceutical agent (API), which releases a therapeutic compound
systemically over time. One example of such a dosage form reported
pertains to the pamoate salt of olanzapine, an atypical
antipsychotic compound unrelated to asenapine. Olanzapine pamoate
has been described in U.S. Pat. Nos. 6,169,084 and 7,303,764 for
use in IM administration. Depot administration of a composition
containing this salt was tested in clinical trials by Eli Lilly
(see for example clinical trial NCT00320489 listed on the U.S.
National Institutes of Health web site at "clinicaltrials.gov"). In
these trials a depot of a formulation comprising particles of
olanzapine pamoate as an active pharmaceutical agent (API)
suspended in a liquid was administered by intramuscular injection
(Depot administration). Initially, based on the results of these
trials, the FDA declined to approve the formulation for sale citing
incidents in the trials of extreme sedation and reversible coma
associated with the administration of the formulation. The cause of
these adverse events has not been verified, but is believed to be
related to unexpectedly rapid dissolution of the suspended API in
the injected depot and concomitant rapid systemic absorption of the
dissolved material. Subsequently the FDA has approved this
formulation for Depot injection subject to strict conditions of
patient monitoring. Accordingly, the risks associated with the use
of this formulation remain. As this example illustrates, the
provision of a salt having apparently suitable characteristics for
use in a depot formulation, for example, a pamoate salt, does not
necessarily by itself provide a formulation for depot
administration which is free of undesirable complications.
[0009] In depot administration of a medicament comprising a
particle suspension, particle size and particle size distribution
of suspended API has been observed to be a factor in the release of
drug from the injected depot. This point is illustrated by the
study of Miller and Fincher reported in The Journal of
Pharmaceutical Sciences, (November 1971) Vol. 60, No. 11, pp. 1733
to 1736. In their study, Miller and Fincher observed plasma levels
of phenobarbitol following IM-injections of suspensions of
different fractions of classified phenobarbitol particles into
dogs. Accordingly, Miller et al. prepared separate suspensions from
particle fractions having a mean particle diameter of either 6.63
microns, 10.68 microns, 17.16 microns or 29.96 microns as
determined using a Coulter counter. As shown in FIG. 1, plasma
concentrations of phenobarbitol observed by Miller et al. following
depot injection of these suspensions tracked inversely with the
mean particle diameter of the phenobarbitol particle fraction used
to prepare the suspension. This is to say that for equivalent
weight percentages of API in a suspension, injection of equal
amounts of API in suspensions made with particles having a smaller
mean particle size provided higher C.sub.max in a shorter time post
injection than those suspensions prepared from particle fractions
having a larger mean particle size.
[0010] From the foregoing it can be seen that the attempt to
provide a formulation suitable for depot administration implicates
issues not addressed by merely identifying a salt form of the drug
which has acceptable solubility and melting point properties. As
mentioned above, depot formulations are subject to unexpected
release profiles due to particle size and other factors described
above.
[0011] Another aspect of the problem which can interfere with
success in the provision of a formulation suitable for use in depot
administration, especially in the provision of a depot formulation
having extended release properties, is the stability of the active
pharmaceutical ingredient (API) used in the formulation.
Instability of the formulation can adversely impact the
effectiveness of the formulation when subjected to the
physiological environment in which it is used as well as impact the
ability to store the formulation for long periods or under ambient
conditions. For example, where the API is in a crystalline form,
loss of crystallinity or a change in crystalline morphology has
been observed to have a profound effect on release rates from a
depot injection administered using such a formulation.
[0012] As described in Published European application publication
no. EP0569096, published Nov. 10, 1993 (the '096 publication),
which is incorporated by reference as if fully set forth herein in
its entirety, pamoate salts of
trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz-[2,3;6,7]oxepino--
[4,5c]pyrolle (asenapine, the compound of Formula I) are known,
including a 1:1 pamoate salt (comprising equimolar amounts of
pamoic acid and asenapine free base reacted together) and a 2:1
hemipamoate salt (comprising a 2:1 mole ratio of asenapine and
pamoic acid reacted together). Published international application
no. WO98/54186 (published Dec. 3, 1998, applicant Akzo-Nobel)
characterizes the asenapine hemipamoate salt described in the '096
publication (which is also referred to as "the Form I hemipamoate
salt", as comprising a mixture of amorphous and crystalline
material with a melting point of from about 167.degree. C. to about
168.degree. C.
[0013] The two aforementioned publications, which describe various
depot formulations containing aromatic acid salts of asenapine, do
not indicate that the hemipamoate mentioned therein is suitable for
use in a depot formulation. The provision of asenapine salts of
pamoic acid (pamoate and hemipamoate Form I) has here-to-fore not
resulted in the provision of a form of asenapine which is
sufficiently stable and possessed of suitable dissolution
characteristics for use in a formulation intended for depot
administration, particularly for use in the provision of an
extended release administration from a depot provided by IM
injection of the formulation.
Objectives and Summary of the Invention
[0014] In view of the foregoing, what is needed is an
asenapine-containing formulation which is suitable for Depot
administration of asenapine, particularly administration of a Depot
which provides therapeutic plasma levels of asenapine over a
prolonged period, for example, a period of at least about 2 weeks
or longer. Moreover, what is needed is a method of treating
diseases amenable to treatment by asenapine utilizing a formulation
adapted for Depot administration. These and other objectives and/or
advantages are provided by the present invention which in one
aspect is a pharmaceutical formulation comprising particles of
crystalline Form II of asenapine hemipamoate (defined herein)
suspended in an aqueous suspending medium, wherein the particles of
asenapine hemipamoate are present in the formulation in a
concentration of at least about 5 mg asenapine hemipamoate/mL of
formulation, more preferably the concentration is at least about 50
mg asenapine hemipamoate/mL of formulation, more preferably the
concentration is at least about in excess of 100 mg asenapine
hemipamoate/mL of formulation. In some embodiments it is preferred
for the concentration to be at least about 200 mg asenapine
hemipamoate/mL of formulation. In some embodiments it is preferred
for the concentration to be from about 50 mg asenapine
hemipamoate/mL of formulation to about 300 mg asenapine
hemipamoate/mL of formulation. In some embodiments it is preferred
for the concentration to be from about in excess of 100 mg
asenapine hemipamoate/mL of formulation to about 300 mg asenapine
hemipamoate/mL of formulation, more preferably the concentration is
from about 200 mg asenapine hemipamoate/mL of formulation to about
300 mg asenapine hemipamoate/mL of formulation.
[0015] In some embodiments it is preferred to prepare the
formulation of the invention using particles of crystalline Form II
of asenapine hemipamoate which have a d.sub.50-value, as determined
by laser diffractometry, of from about 3.5 microns to about 28
microns. In some embodiments it is preferred to provide particles
of crystalline Form II of asenapine hemipamoate by micronizing
precipitated crystalline material. In some embodiments it is
preferred to provide particles of crystalline Form II of asenapine
hemipamoate by precipitating crystals under controlled
crystallization conditions. In some embodiments it is preferred to
employ unclassified particulate crystalline Form II of asenapine
hemipamoate. In some embodiments, it is preferred to classify
particulate crystalline Form II of asenapine hemipamoate to remove
particles smaller than about 0.3 microns prior to being
incorporated into a formulation of the invention. In some
embodiments, it is preferred to classify particulate crystalline
Form II of asenapine hemipamoate to remove particles larger than
about 200 microns prior to being incorporated into a formulation of
the invention. In some embodiments it is preferred to classify the
particle fraction to remove both particles smaller than about 0.3
microns and particles larger than about 200 microns prior to being
incorporated into a formulation of the invention.
[0016] In some embodiments, preferably the aqueous suspending media
used in the formulation comprises a buffer. In embodiments
employing a buffer as the suspending media, preferably the buffer
is a phosphate buffer. In embodiments employing a buffer,
preferably the buffer has a physiologically compatible pH, more
preferably it has a pH of from about pH 4 to about pH 8, more
preferably the buffer has a pH of about pH 7. In some embodiments
it is preferred to employ a buffer having a buffering strength of
from about 0.5 mM to about 100 mM.
[0017] In some embodiments, optionally the formulation comprises
also a surfactant that can act as a dispersing agent to aid in
dispersing solids in the formulation, or re-dispersing the solids
in the formulation after storage and settling has occurred. In some
embodiments employing a dispersing agent it is preferred to use a
medium chain length polyethylene glycol, for example, macrogol
3400, as a dispersing agent.
[0018] In another aspect the present invention provides a method of
using the formulation of the invention in the treatment of a
patient, the method comprising administering an amount of the
formulation to a patient in need of asenapine therapy by
intramuscular injection (IM) of a sufficient volume of the
formulation to provide a depot which maintains a therapeutic plasma
concentration of asenapine for a period of at least about 2 weeks,
preferably from about 2 to about 4 weeks. In some patient
populations it will be desirable to administer a sufficient depot
volume that the patient will be provided thereby a therapeutic
plasma concentration of asenapine for a period of up to 6 weeks or
even up to 8 weeks.
[0019] In some embodiments, it is preferred to administer
contemporaneous injections at multiple sites to form multiple
depots to achieve the desired volume of the depot to provide for
extended periods of therapeutic plasma concentration. In some
embodiments it is preferred to inject an amount of the formulation
to provide a depot volume (either as one or more than one depot)
containing the equivalent to up to about 280 mg of asenapine free
base to achieve the maximum desired period of maintenance of a
therapeutic plasma concentration of asenapine. In some embodiments
it is preferred to inject a volume of the formulation which
contains an amount of Crystalline Form II of asenapine hemipamoate
equivalent to from about 14 mg asenapine free base to about 280 mg
of asenapine free base, more preferably, a depot volume comprising
an amount of Crystalline Form II of asenapine hemipamoate
equivalent to up to about 140 mg asenapine free base is
administered.
[0020] Optionally, injection(s) are repeated as needed to maintain
a therapeutically effective plasma concentration of asenapine. In
some embodiments it is preferred to inject a volume of the
formulation sufficient to provide an amount of crystalline Form II
of asenapine hemipamoate which produces therapeutic plasma levels
of asenapine for a period of at least two weeks, thus injections
are repeated about every two weeks. In some embodiments it is
preferred to inject a volume of the formulation sufficient to
provide an amount of crystalline Form II of asenapine hemipamoate
which produces therapeutic plasma levels of asenapine for a period
of at least three weeks, thus injections are repeated about every
three weeks. In some embodiments it is preferred to inject a volume
of the formulation sufficient to provide an amount of Crystalline
Form II of asenapine hemipamoate which produces therapeutic plasma
levels of asenapine for a period of at least four weeks, thus
injections are repeated about every four weeks. The volume of
injections will depend upon the concentration of crystalline Form
II of asenapine hemipamoate present in the formulation and the
aggregate volume of all of the depots administered when the
formulation is administered in more than one depot formed by
multiple contemporaneous injections. Accordingly, in some
embodiments it is preferred to administer a volume of the
formulation which provides a 2 week, 3 week, or 4 week, or longer,
sustained therapeutic plasma level of asenapine. In some
embodiments it is preferred to administer a volume of the
formulation which will provide up to about 4 weeks of sustained
therapeutic plasma level of asenapine. In some embodiments it is
preferred to administer a volume of the formulation which will
provide up to about 8 weeks of sustained therapeutic plasma level
of asenapine. In some embodiments it is preferred to administer a
volume of the formulation which will provide up to about 12 weeks
of sustained therapeutic plasma level of asenapine.
[0021] The present invention further provides methods for treating
a CNS disease, for example, schizophrenia or bipolar disorders. In
some embodiments the method comprises administering a formulation
of the invention at 2 week, 3 week, or 4 week intervals by IM
injection, wherein an amount of the formulation administered
provides a depot of sufficient volume to provide a therapeutically
effective plasma concentration of asenapine over the selected
interval. In some embodiments it is preferred to administer a
volume comprising the equivalent to up to about 280 mg of asenapine
free base. In some embodiments it is preferred to administer a
depot volume comprising the equivalent to up to about 140 mg of
asenapine freebase.
[0022] Other aspects and advantages of the invention will become
apparent from the Figures and following Detailed Description.
BRIEF DESCRIPTION OF THE FIGURES
[0023] The present invention is more fully described in the
following detailed description and the appended figures in
which:
[0024] FIG. 1 is adapted from Miller et al., J. Pharm. Sci.,
November 1971, Vol. 60, No. 11, pp 17333 to 1736, and illustrates
the results of a prior art study of plasma levels of phenobarbital
in dogs resulting from depot administration of suspensions having
various particle sizes of Phenobarbital (see Background section
above).
[0025] FIG. 2a presents DSC data obtained on samples of crystalline
Form I of asenapine hemipamoate before and after storage in a pH 7
phosphate buffer at 30.degree. C.
[0026] FIG. 2b presents X-Ray Powder Diffraction (XRPD) data
obtained on samples of crystalline Form I of asenapine
hemipamoate.
[0027] FIG. 3a presents DSC data obtained on samples of crystalline
Form II of asenapine hemipamoate before and after storage in a pH 7
phosphate buffer at 30.degree. C.
[0028] FIG. 3b presents X-Ray Powder Diffraction (XRPD) data
obtained on samples of crystalline Form II of asenapine
hemipamoate.
[0029] FIG. 4 illustrates plasma levels attained after Depot
administration of suspensions of crystalline Form II of asenapine
hemipamoate having a laser diffractometry d.sub.50-value of 3.5
microns, 12 microns, or 28 microns.
[0030] FIG. 5 graphically presents the particle size distribution
in classified particle fractions having d.sub.50-values (measured
by laser diffractometry) of 3.5 microns, 12 microns, or 28
microns.
[0031] FIG. 6 schematically presents the dissolution system used to
study the in vitro dissolution behavior of crystalline Form II of
asenapine hemipamoate particles.
[0032] FIGS. 7a-7d illustrate the rate of dissolution of particles
of crystalline Form II of asenapine hemipamoate in a buffer
solution under various test conditions.
[0033] FIG. 7e illustrates the particle size distribution of the
fractions used in providing the data in FIGS. 7a to 7d.
[0034] FIGS. 8a and 8b illustrate a comparison of the rate of
dissolution of particles having similar particle size and size
distribution of crystalline Form II of asenapine hemipamoate and of
crystalline Form I of asenapine hemipamoate in a buffer solution
under various test conditions.
[0035] FIGS. 9a to 9c illustrate plasma concentration observed
after IM injection of New Zealand White Rabbits with a 1 mL depot
comprising 5 wt % or 20 wt % asenapine hemipamoate Form II.
[0036] FIG. 9d illustrates the particle size distribution in the
particle fractions used in providing the data in FIGS. 9a to
9c.
[0037] FIG. 10 illustrates a comparison of plasma concentration
observed after IM injection of New Zealand White Rabbits with a 1
mL depot comprising 20 wt % asenapine hemipamoate Form I and Form
II.
[0038] FIG. 11 illustrates median plasma concentrations observed
after IM injection of patients with a 1.0 mL depot comprising 20 wt
% asenapine hemipamoate Form II.
[0039] FIG. 12 illustrates a simulation of the plasma concentration
levels expected in administering depot injections comprising a
formulation of the invention at regular intervals.
[0040] FIG. 13 illustrates plasma levels observed in test animals
injected with a depot comprising a formulation of the invention
comprising Form II asenapine hemipamoate particle fractions having
d.sub.50 values of 3.5 microns, 12 microns, and 27 microns, present
in the formulation at a level of 1 wt. %.
DETAILED DESCRIPTION OF THE INVENTION
[0041] Formulations of the present invention comprise particles of
crystalline Form II of asenapine hemipamoate as an active
pharmaceutical ingredient (API) suspended in an aqueous suspension
medium, wherein the concentration of Crystalline Form II of
asenapine hemipamoate is maintained within a particular range,
described herein in greater detail.
[0042] As used herein, where particle size and particle
distribution measurements are described by a numerical value,
implicit in stating a numerical value is the understanding that
these values reflect a precision of measurement which contemplates
the normal variability experienced for a given sample when
measurements are compared among different measuring techniques,
different sample preparation techniques and measurements obtained
by different operators of a given piece of equipment. Accordingly,
as will be appreciated by those of ordinary skill in particle size
and particle size distribution measurement, the stated values do
not reflect absolute numerical precision but are rather indicative
of particle size and particle size distribution values that are
within the ordinary range of values typically observed when
measuring a given sample having a particular mean particle size and
particle size distribution considering the generally recognized
precision and accuracy which is obtainable using a given
measurement technique by those of ordinary skill in measuring
particle size and particle size distribution. Accordingly, it will
be understood that the values stated herein which describe a
collection of particles in terms of "d-values" reflect the accuracy
and precision typically available from the measuring technique
employed (the details of which are described herein) and are not
intended to imply greater accuracy or greater precision than is
understood by those of ordinary skill in the art of particle
measurement.
[0043] The inventors have surprisingly found that asenapine
hemipamoate can be provided in crystalline Form II (described
herein as "crystalline Form II of asenapine hemipamoate") which,
unlike previously reported forms of asenapine hemipamoate
(amorphous and Crystalline Form I), is surprisingly useful for
preparing formulations suitable for depot administration. As
illustrated in FIG. 3a, Crystalline Form II of asenapine
hemipamoate is stable and has a melting point of about 218.degree.
C. determined by DSC analysis and, with reference to FIG. 3b,
provides X-Ray Powder Diffraction (XRPD) data that indicates it is
a wholly different crystalline modification of asenapine
hemipamoate from any previously reported form of asenapine
hemipamoate salt. For example, comparison of XRPD FIG. 2b, which is
of previously reported crystalline Form I of asenapine hemipamoate,
is easily distinguished from the XRPD of FIG. 3b. The procedures
and results of these determinations are discussed more fully herein
below. Crystalline Form II of asenapine hemipamoate has a
solubility in an aqueous phosphate buffer at pH 7 of about 3
micrograms/mL.
[0044] Crystalline Form I of asenapine hemipamoate, which was
previously reported in published international application
publication no. WO98/54186 and published European patent
application No. EP0569096 (see Example II therein) yields the XRPD
spectrum presented in FIG. 2b, and its differences when compared
with the XRPD of Crystalline Form II of asenapine hemipamoate (FIG.
3b) are readily apparent. FIG. 2a (bottom trace) presents DSC
analysis of the previously reported crystalline Form I of asenapine
hemipamoate and indicates that it has a melting point of about
167.degree. C. (centroid of the large endothermic event) with a
span of from about 162.degree. C. to about 172.degree. C. The
solubility of crystalline Form I of asenapine hemipamoate in an
aqueous phosphate buffer maintained at pH 7 is about 12.6
micrograms/mL, approximately 4 times that of crystalline Form II of
asenapine hemipamoate.
[0045] With reference to FIG. 8a, surprisingly, particles of
crystalline Form II of asenapine hemipamoate (lower traces)
suspended in an aqueous dissolution medium dissolve much slower
than an equivalent particle size fraction of previously reported
crystalline Form I of asenapine hemipamoate (FIG. 8a, upper
traces). Moreover, particles of crystalline Form I of asenapine
hemipamoate suspended in a phosphate buffer at pH 7 and stored at
30.degree. C. and 40.degree. C. were found to convert from
crystalline Form I of asenapine hemipamoate to crystalline Form II
of asenapine hemipamoate based on melting point observed by DSC.
With reference to FIG. 2a, the conversion of Form I to Form II was
monitored by periodically taking aliquots of the stored suspension,
isolating the suspended solids by filtration and drying the
isolated solids at room temperature. DSC analysis was performed on
the isolated, dried solids using a 10 mg sample of the solids and a
Mettler DSC 822e programmed to heat at a rate of 10.degree. C./min.
from 25.degree. C. to 250.degree. C. The results of this study are
presented in, with the result shown in the upper traces of FIG. 2a.
These data clearly show that crystalline Form I of asenapine
hemipamoate is slowly converted to crystalline Form H of asenapine
hemipamoate. Unless noted differently, the method described for
providing the DSC data shown in FIG. 2a was employed in generating
all of the DSC data presented herein.
[0046] Surprisingly, when this stability test was repeated starting
with only crystalline Form II of asenapine hemipamoate present, the
results of DSC analysis of solids recovered from a stored
suspension of particles in a buffer solution indicate that under
these conditions (storage at 30.degree. C. and 40.degree. C.)
crystalline Form II of asenapine hemipamoate does not decompose or
convert to any other crystalline form when stored for extended
periods of time.
[0047] Taken together, all of the foregoing indicate that the
previously reported crystalline Form I of asenapine hemipamoate is
unsuitable for use in a depot formulation. Based on its solubility,
the facile conversion of its crystalline form and its dissolution
properties it is particularly unsuitable for use in a formulation
for administering a depot to provide sustained release of
therapeutic levels of asenapine. Moreover, the foregoing indicate
that crystalline Form II of asenapine hemipamoate has distinct and
unexpected crystalline morphology, stability properties, solubility
properties, and dissolution properties, which make surprisingly
well suited for use in preparing a formulation for depot
administration.
[0048] The inventors have surprisingly found that a suspension
comprising crystalline Form II of asenapine hemipamoate can provide
formulations suitable for depot administration. In accordance with
the present invention crystalline Form II of asenapine hemipamoate
can provide a formulation suitable for administration of a depot
providing sustained release of therapeutic levels of asenapine
without unwanted side effects, for example, those described above
for olanzapine.
[0049] The inventors have surprisingly discovered that crystalline
Form II of asenapine hemipamoate can be prepared by introducing
aliquots of an ethanol solution of asenapine maleate into an
ethanol solution of disodium pamoate salt, and cooling the mixture
slowly (process details further described herein in the Examples
which follow). The inventors have also found that this
crystallization process can be carried out on a small scale to
provide "seeds" which can be used to "seed" the preparation on a
larger scale. Accordingly, once seeds of crystalline Form II of
asenapine hemipamoate are obtained by this method, they can be
employed as "seeds" to precipitate large batches of crystalline
Form II of asenapine hemipamoate in a scaled-up process.
[0050] An X-Ray Powder Diffraction spectrum of crystalline Form II
of asenapine hemipamoate is presented in FIG. 3b. The spectrum of
FIG. 3b contains 5 most significant diffraction peaks appearing at
the diffraction angle (in .degree. 2-theta) and correspondingly
calculated "d-spacing" shown in Table I, below.
TABLE-US-00001 TABLE I Significant Diffraction Peaks XRPD
Crystalline Form II of Asenapine Hemipamoate Diffraction d-spacing
(.degree.2-theta) (Angstroms - calculated) 11.9 7.5 16.5 5.4 18.8
4.7 19.4 4.6 23.4 3.8
[0051] With reference to FIG. 3a, a micronized sample of
crystalline Form II of asenapine hemipamoate has been characterized
by differential scanning calorimetry (DSC) on a Mettler DSC 822e in
accordance with the above-described procedure, and was found to
have a melting point of about 218.degree. C. The melting point was
taken as the centroid in the endothermic event observed within the
heating range. The span of the endothermic event observed under
these conditions was 213.degree. C. to 223.degree. C.
[0052] Asenapine maleate suitable for use in preparing crystalline
Form II of asenapine hemipamoate may conveniently be prepared by
following the procedures described in any of published
international application publication Nos. WO2006/106136 (see for
example, Schemes II and IV and Example 7 therein), WO2008/003460
(see for example, Examples 1 and 7 therein), or WO2009/087058. Each
of these publications is incorporated specifically by reference as
if fully set forth herein.
[0053] In accordance with the foregoing, formulations of the
invention provide asenapine in a form which can be administered as
a depot (Depot administration) to a patient in need of asenapine
therapy. As shown below, in Example 4, when administered in a
sufficient volume, preferably by intramuscular (IM) injection,
administration of a depot comprising a formulation of the invention
is expected to provide sustained plasma levels of asenapine in the
patient without producing a "burst release" that is sometimes
observed with depot injections. Accordingly, depot administration
of a formulation of the invention can be carried out using a
sufficient amount of the formulation to provide therapeutic plasma
levels of asenapine over an extended period of time without
untoward release of drug from the depot.
[0054] Moreover, with reference to FIG. 12, when administered as a
depot of sufficient volume at regular intervals, it will be found
that a formulation of the invention provides therapeutic asenapine
plasma levels in a subject to whom it is administered over an
extended period, for example, two weeks, three weeks or four weeks.
In some embodiments, and with some patient populations, a
sufficient depot volume of the formulation is administered can be
accomplished using an amount of the formulation sufficient to
provide up to 8 weeks of a therapeutic asenapine plasma level.
[0055] In some embodiments, it will be useful to utilize a depot
loading dose, followed by smaller depot volumes for maintenance.
For example, in some embodiments it will be preferred to administer
a loading dose of an amount of the formulation comprising up to
about 210 mg of crystalline Form II of asenapine hemipamoate, which
will be sufficient to provide therapeutic asenapine plasma levels
for a period of up to about 8 weeks, followed by periodic
administration of a maintenance depot in an amount comprising up to
about 140 mg of crystalline Form II of asenapine hemipamoate, which
will be sufficient to provide therapeutic asenapine plasma levels
for additional periods of up to about 8 weeks. In some embodiments
utilizing a formulation of the invention comprising 200 mg/mL of
asenapine, it will be preferred to supply a loading dose
comprising, for example, 1 mL of depot volume or 1.5 mL of depot
volume, and administer maintenance doses at intervals thereafter
which comprise a smaller volume, for example, 0.75 mL of depot
volume, or 0.5 mL of depot volume. It will be appreciated that by
continuing this administration schedule, continuous therapy can be
provided to a patient. This administration is illustrated in FIG.
12, which provides a simulation of the plasma levels which can be
experienced by a patient receiving a formulation of the invention
in accordance with this dosing regime based on the response seen in
patients and repeated administration in test animal subjects. As
mentioned above, the provision of therapeutic asenapine plasma
levels is useful in the treatment or management of certain CNS
diseases, for example, schizophrenia.
[0056] The inventors have surprisingly found that formulations
prepared using crystalline Form II of asenapine hemipamoate,
wherein the concentration of crystalline Form II of asenapine
hemipamoate in a formulation is maintained in according to the
present invention, permit depot administration of the formulation
to a subject which provides plasma levels which are independent of
the particle size and particle distribution present in the aliquot
of the crystalline Form II of asenapine hemipamoate from which the
formulation is prepared.
[0057] With reference to FIG. 4, depot administration of 2
formulations of the invention, one prepared with a particle
fraction having a d.sub.50 value of 3.5 micron and 10 wt % of
particle fines having a diameter of less than 0.8 micron (d.sub.10
value of 0.8 microns) and the other prepared using a particle
fraction having a d.sub.50 value of 28 microns with almost
negligible wt % of particles less than 1 micon (d.sub.10 value of
11 microns) showed no significant differences in plasma
concentration of asenapine among experimental animal subjects
(details reported in Example 3, herein). This study was carried out
over multiple weeks observation following depot administration.
Accordingly, these data show that a formulation of the invention
provides in vivo an extended release of asenapine having PK
parameters which are not dependent upon the particle size or
particle size distribution present in the formulation.
[0058] Although for use in a formulation of the invention it is not
necessary to classify particulates into narrow particle fractions,
it is preferred to prepare a formulation of the invention using a
particle fraction of crystalline Form II of asenapine hemipamoate
having a d.sub.50 value, as determined by laser diffractometry, of
from about 3.5 microns to about 28 microns. In some embodiments it
is preferred to employ asenapine hemipamoate Form II which has been
micronized to provide particulate having a d.sub.50 value within
the desired size range. Although it is not required, in some
embodiments it is preferred to classify the asenapine particles
used in the composition to substantially remove particles smaller
than about 0.3 micron. Although it is not required, in some
embodiments it is preferred to classify the particles used in the
composition to substantially remove particles greater than about
200 microns. However, with reference to FIG. 4, the inventors have
surprisingly found that the presence of even 10 wt. % of fines (a
particle fraction having a d.sub.10 value of less than 1 micron,
for example, Sample 1 of Table 1) does not influence the plasma
levels observed in experimental animal subjects to whom a depot of
the formulation was administered by injection. The details of this
study will be explained in greater detail in Example 3, below.
[0059] Preferably a formulation of the invention comprises an
amount of crystalline Form II of asenapine hemipamoate sufficient
to provide a concentration of at least about 10 mg of crystalline
Form II of asenapine hemipamoate/mL of formulation. With reference
to FIG. 13, it can be seen that formulations of the invention
comprising 1 wt. % of Form II of asenapine hemipamoate prepared
separately using particle fractions having d.sub.50 values of 3.5,
12, and 27 microns, when injected into a test animal in a 1.0 mL
depot volume produced substantially the same plasma profile for all
formulations, but the profiles suggest that when lower
concentrations are employed the plasma levels produced will be
differentiated with respect to the particle size employed. In some
embodiments it is preferred to employ an amount of crystalline Form
II of asenapine hemipamoate to provide a concentration of at least
about 50 mg of crystalline Form II of asenapine hemipamoate/mL of
formulation, more preferably the formulation comprises an amount of
crystalline Form II of asenapine hemipamoate to provide a
concentration of at least about in excess of 100 mg of crystalline
Form II of asenapine hemipamoate/mL of formulation. In some
embodiments it is preferred to include in the formulation an amount
of crystalline Form II of asenapine hemipamoate sufficient to
provide a concentration of at least about 200 mg of crystalline
Form II of asenapine hemipamoate/mL of formulation. In some
embodiments it is preferred to include in the formulation an amount
of crystalline Form II of asenapine hemipamoate sufficient to
provide a concentration of from at least about 50 mg of crystalline
Form II of asenapine hemipamoate/mL of formulation to about 300 mg
of crystalline Form II of asenapine hemipamoate/mL of formulation.
In some embodiments it is preferred to include in the formulation
an amount of crystalline Form II of asenapine hemipamoate
sufficient to provide a concentration of in excess of from about
100 mg of crystalline Form II of asenapine hemipamoate/mL of
formulation to about 300 mg of crystalline Form II of asenapine
hemipamoate/mL of formulation, more preferably the formulation
includes an amount of crystalline Form II of asenapine hemipamoate
sufficient to provide a concentration of from about 200 mg of
crystalline Form II of asenapine hemipamoate/mL of formulation to
about 300 mg of crystalline Form II of asenapine hemipamoate/mL of
formulation. In some embodiments it is especially preferred to
employ a formulation which is about 200 mg of crystalline Form II
of asenapine hemipamoate/mL of formulation.
[0060] Formulations of the invention comprise particles of
crystalline Form II of asenapine hemipamoate suspended in an
aqueous suspending medium. The aqueous suspending medium can be
sterile water alone, preferably the aqueous suspending medium
comprises a buffer. In some embodiments it is preferred for the
formulation to comprise crystalline Form II of asenapine
hemipamoate, a buffer and a dispersing agent, and optionally one or
more additional excipient which contributes to the stability of the
suspension or its utility as an injectable formulation.
[0061] In some embodiments it is preferred to prepare a formulation
of the invention by combining a particle form of crystalline Form
II of asenapine hemipamoate and an aqueous suspending medium with
mixing or blending until a homogeneous mixture is provided. It will
be appreciated that the method of dispersing crystalline Form II of
asenapine hemipamoate in the aqueous suspending medium is not
critical and any suitable means of providing a homogeneous mixture
of a solid suspended in a liquid can be employed.
[0062] In some embodiments where the aqueous suspending medium
comprises a buffer, it is preferred to prepare the buffer to the
desired pH and buffering strength and then add, with stirring, the
desired amount of particulate crystalline Form II of asenapine
hemipamoate. In some embodiments where the aqueous suspending
medium comprises additionally a suspending agent, it is preferred
to prepare the buffer, add the desired amount of suspending agent,
and then add the desired amount of particulate crystalline Form II
of asenapine hemipamoate. While the order of addition is not
critical, in some embodiments utilizing a dispersing agent it is
preferred to add the dispersing agent to the suspending medium, for
example, a buffer, prior to adding particles of crystalline Form II
of asenapine hemipamoate to the suspending medium.
[0063] In some embodiments where the aqueous suspending medium
comprises a buffer, preferably the buffer solution provides a
physiologically compatible pH, more preferably a pH of from about
pH 5 to about pH 9, more preferably it provides a pH of about pH 7.
In some embodiments wherein the aqueous suspending medium comprises
a buffer it is preferred to employ an aqueous phosphate buffer
solution as the aqueous suspending medium. It will be appreciated
that other buffer materials can be employed, for example, citrate
or carbonate buffers and be within the scope of the invention. It
will be appreciated also that though exemplified below using a
phosphate buffer prepared in a particular manner, other means of
providing a buffer solution can be employed to provide a suitable
aqueous suspending medium for use in preparing a formulation of the
invention.
[0064] In some embodiments it is preferred to prepare a buffer by
combining, for each mL of buffer prepared: up to about 60 mg of
polyethylene glycol, preferably from about 5 mg of polyethylene
glycol to about 60 mg of polyethylene glycol, more preferably from
about 5 mg polyethylene glycol to about 30 mg of polyethylene
glycol; an amount of disodium hydrogen phosphate and sodium
dihydrogen phosphate that provides a phosphate moiety concentration
of from about 2 mM to about 50 mM in the final buffer solution,
preferably a phosphate moiety concentration of about 10 mM, wherein
the ratio of each of the disodium hydrogen phosphate species and
sodium dihydrogen phosphate species will depend upon the pH of the
finished buffer solution; and an amount of sodium chloride
sufficient to provide up to about a 0.13 M concentration of sodium
chloride.
[0065] As mentioned above, in some embodiments a formulation of the
invention includes one or more surfactants that have the ability to
act as a dispersing agent to aid in dispersion of the asenapine
hemipamoate Form II particles in the suspending medium used in
preparing a formulation of the invention. In such embodiments the
dispersing agent can also help to stabilize the formulation after
dispersion and improve redispersion of the particles if some
particle settling has occurred after storage of the formulation.
Hydrophilic polymers, for example, carboxymethyl cellulose polymers
and polyethylene glycol polymers, are suitable surfactants for use
as dispersing agents in a formulation of the invention. Examples of
polyethylene glycol polymers which are suitable include, but are
not limited to, medium weight polyethylene glycol polymers, for
example, macrogols, for example, macrogol 3400, macrogol 4000, and
macrogol 6000, preferably macrogol 3400.
[0066] In accordance with the foregoing, it is expected that
administrating a suitable amount of a formulation of the invention
comprising at least about 100 mg crystalline Form II of asenapine
hemipamoate/mL of formulation to a human as a depot of suitable
volume, a sustained release of asenapine that provides a constant
therapeutic plasma level of asenapine of from about 1 ng/mL to
about 8 ng/mL, preferably from about 1 ng/mL to about 3 ng/mL will
be observed. In some embodiments it is preferred to provide an
amount of formulation containing the equivalent of from about 50 mg
crystalline Form II of asenapine hemipamoate, more preferably 100
mg crystalline Form II of asenapine hemipamoate, to about 300 mg of
crystalline Form II of asenapine hemipamoate, more preferably at
least about 200 mg of Form II of asenapine hemipamoate. In some
embodiments it is preferred to provide a depot by administering the
formulation by injection into the deltoid muscle of the upper arm
in an amount providing from about 50 mg, more preferably 100 mg of
crystalline Form II of asenapine hemipamoate, to about 300 mg of
crystalline Form II of asenapine hemipamoate, preferably an amount
providing about 200 mg of crystalline Form II of asenapine
hemipamoate. In some embodiments it is preferred to administer a
depot by injection into the gluteal muscle or into the vastus
lateralis muscle an amount of the formulation comprising from about
100 mg of crystalline Form II of asenapine hemipamoate to about 300
mg of crystalline Form II of asenapine hemipamoate, preferably 200
mg of crystalline Form II of asenapine hemipamoate.
EXAMPLES
[0067] In the following examples, all reagents are USP grade
articles of commerce unless otherwise noted.
Example 1
Preparation of Asenapine Hemipamoate and Asenapine Hemipamoate
Crystalline Form II Therefrom
[0068] Asenapine maleate for use in preparing crystalline Form II
of asenapine hemipamoate was prepared in accordance with the
procedures described in published international application No
WO2008/003460 (see Examples 1 and 6 therein).
[0069] Seeds of crystalline Form II of asenapine hemipamoate were
prepared by titrating aliquots of an ethanol solution of asenapine
maleate into an ethanol solution of disodium pamoate and
crystallizing crystalline Form II of asenapine hemipamoate
therefrom. Accordingly, 201 gram of asenapine maleate prepared as
described in published international application publication no.
WO08/003460 was dissolved in 3.0 L of USP grade ethanol at
75.degree. C. Disodium pamoate (108.7 g, USP grade used as
received) was dissolved in 13.5 L of ethanol (USP grade) at
75.degree. C. Aliquots of the asenapine maleate solution were added
to the solution of disodium pamoate while maintaining the mixture
at 75.degree. C. After all of the asenapine maleate solution had
been added, the mixture was slowly cooled to room temperature with
continued stirring. The crystals which formed were collected by
filtration, washed with ethanol (4 L, ambient temperature) and
dried at 45.degree. C. under house vacuum. The asenapine
hemipamoate thus provided (210 gram, 87%) was examined by XPRD
(FIG. 3b) and DSC (melting point 223.degree. C. using the DSC
procedure described herein) and determined to be crystalline Form
II of asenapine hemipamoate.
[0070] A larger quantity of crystalline Form II of asenapine
hemipamoate was prepared by seeding a solution of asenapine maleate
with the seeds of crystalline Form II of asenapine hemipamoate
prepared above, and then treating the seeded solution with a
solution of pamoic acid in accordance with the following
procedure.
[0071] An ethanol/water solvent was prepared by combining 58 L of
USP grade ethanol and 3.2 L of purified water in a vessel equipped
with a stirring apparatus. The solvent was heated to about
70.degree. C. Into this solvent was added 2703 g of asenapine
maleate previously prepared (as described above) and the mixture
was stirred and the temperature of the mixture maintained at about
70.degree. C. until the solids had dissolved. The asenapine maleate
solution was seeded with seeds of crystalline Form II of asenapine
hemipamoate prepared in accordance with the procedure described
above, and with continued stirring, a solution of 1486 g of pamoic
acid dissolved in 28 L of water was added over about 1 hour, while
stirring was continued and the temperature of the mixture was
maintained at 70.degree. C. The mixture was stirred at 70.degree.
C. for an additional hour during which crystals of crystalline Form
II of asenapine hemipamoate were formed. After 1 hour of stirring,
the mixture was cooled to ambient temperature (about 20.degree. C.)
by removing the heat source and allowing the batch to cool with
stirring. Stirring was continued for an additional 16 hours. At the
end of 16 hours, the precipitated crystals were recovered by
filtration, washed with water at ambient temperature and dried at
45.degree. C. under house vacuum. The identity and purity of the
crystalline material produced was confirmed by DSC, which shows a
sharp endotherm at 223.degree. C., and by XRPD, which produces a
spectrum conforming with the reference spectrum (FIG. 3b) for
crystalline Form II of asenapine hemipamoate.
Example 2
Preparation of Injectable Composition Comprising Crystalline Form
II of Asenapine Hemipamoate
[0072] A phosphate buffer was prepared by placing into a vessel
equipped with a mechanical stirring apparatus 1000 g of sterile
water, 30 g of macrogol 3400, 1.18 g of disodium hydrogen
phosphate, 0.47 g of sodium dihydrogen phosphate, and 7.6 g of
sodium chloride. The vessel was stirred for one hour at ambient
temperature (about 20.degree. C.), until dissolution was complete.
After all of the contents had dissolved, the pH of the buffer was
adjusted by adding aliquots of 1M aqueous phosphoric acid and 1M
aqueous sodium hydroxide as needed (with aliquots of the buffer
being withdrawn and tested using a standard laboratory pH meter
after the addition of each aliquot) until the buffer attained a pH
of 7.0.
[0073] Aliquots of crystalline Form II of asenapine hemipamoate,
prepared in Example 1, above, were micronized and classified into
fractions having various d.sub.50 values as determined by laser
diffractometry using a Malvern particle sizer. Diffractometry was
performed on samples prepared by adding 20 mg of the crystalline
Form II of asenapine hemipamoate sample to be measured to 1 mL of a
dispersing medium comprising an aqueous 0.05 wt. % Tween 80
solution, and adding a suitable amount of the dispersion to the
apparatus' measuring vessel which contained a 0.05 wt. % Tween 80
aqueous solution saturated with asenapine hemipamoate. Measurements
were taken in accordance with the manufacturers operating
instructions.
[0074] Using this method, the following characteristics were
measured on three different particle fractions obtained by
micronizing samples of crystalline Form II of asenapine hemipamoate
(Table II).
TABLE-US-00002 TABLE II Particle Size Analysis (d values given
Sample in microns) No. d.sub.10 d.sub.90 d.sub.50 1 0.8 11.9 3.5 2
1.45 56.9 12 3 11 51.6 28
[0075] As used herein, the term "d.sub.50" means a value
representing the particle size wherein half of the sample weight
comprises particles smaller than d.sub.50 and half of the sample
weight comprises particles larger than d.sub.50. In a similar
manner, d.sub.10 is the value representing the particle size
wherein 10% of the particles in the sample are smaller than
d.sub.10, and d.sub.90 is the value wherein 90% of the particles in
the sample are smaller than d.sub.90. Accordingly, sample 1
comprises relative small particles, sample 2 comprises intermediate
size particles, and sample 3 comprises large particles, as
reflected by their relative d.sub.50 values. The particle fractions
described in Table 1 are referred to herein further as sample 1
(d.sub.50=3.5 micron), sample 2 (d.sub.50=12 micron), and sample 3
(d.sub.50=28 micron). FIG. 5 further illustrates the particle size
and particle size distribution found in these samples.
[0076] Into each of three vessels equipped with a mechanical
stirrer was placed a 4800 mg aliquot of the buffer prepared above.
A 1200 mg aliquot of each of particulate samples 1, 2, and 3 was
weighed out. Into each vessel containing the buffer solution was
added, with stirring, one of these 1200 mg aliquots, providing a
formulation of the invention made from each of the particle
fractions characterized, each of which formulation had a
concentration of 215 mg of crystalline Form II of asenapine
hemipamoate/mL of formulation.
Example 3
In Vivo Studies of Depot Administration of Asenapine Hemipamoate
Composition Using Rabbits
[0077] Each of the formulations prepared in Example 2 were
administered to a series of experimental animal subjects (New
Zealand white rabbits) as a depot injection. A depot of 1 mL volume
of the formulation selected was administered into the left limb of
the subject. At time intervals following injection, blood samples
were collected from the subject's ear artery in 0.03 mL of 0.2M
EDTA. Samples were collected at 1, 3, and 6 hours post injection,
then 1, 2, 3, and 6 days post injection, then on days 10, 13, 17,
20, 24 and 25. Once collected, blood samples were centrifuged for 2
min. at room temperature (125,000 N/kg). Plasma samples thus
obtained were analyzed by LC/MS after adding an internal standard.
The asenapine and internal standard were isolated from the sample
by solid phase extraction. The extracted components were separated
by liquid chromatography in accordance with published methodology
and the eluent was conducted to a triple quadrapole mass
spectrometer which employed electrospray ionization in
multi-reaction monitoring mode to determine asenapine content. The
results of this study are presented in FIG. 4, which shows that
plasma levels of asenapine observed in experimental animal subjects
is approximately the same for each of the formulations studied,
designated by the d.sub.50 value of the particle fraction which was
employed in preparing each formulation studied. The particle
fraction used in preparing each of the formulations studied
provided differing d.sub.50 values and different particle size
distributions, as shown in FIG. 5. Accordingly, these data indicate
that the release rate of asenapine provided by a depot of a
formulation of the invention is independent of the mean particle
size or particle size distribution used to prepare the formulation.
These studies indicate also that a composition of the invention can
be employed to provide acceptable therapeutic levels of asenapine
without untoward release of asenapine to a patient to whom it is
administered.
[0078] It will be appreciated from FIG. 5 that the formulation
prepared from the Sample 1 particle fraction contained 10 wt. %
fines (particles less than 1 micron, in the case of Sample 1,
d.sub.10 was measured to be 0.8 microns). However, the information
presented in FIG. 4 demonstrates that even this loading of fines,
depot administration of a formulation of the invention does not
result in a release profile which is particle-size dependent.
[0079] With reference to FIGS. 9a to 9c, additional studies were
conducted using New Zealand White rabbits using the methodology
described above. Accordingly, test subjects were administered an IM
injection to provide a depot comprising a suspension of asenapine
hemipamoate Form II prepared as described above using particulate
API having: (i) a mean particle size of 1.5 microns, 20 microns, or
40 microns and a concentration of 20 wt % (FIG. 9a); (ii) a mean
particle size of 1.5 microns, 10 microns, 20 microns, or 40 microns
and a concentration of 5 wt % (FIG. 9b); and (iii) a mean particle
size of 0.25 microns, 3.5 microns, 5 microns, 12 microns, and 28
microns and a concentration of 20 wt % (FIG. 9c).
[0080] With reference to FIG. 9a through 9d, these data indicate
that at 20 wt % concentration, formulations of the invention
comprising API particle fractions having less than about 10 vol %
particles of less than 1 micron and a d.sub.50 value of 28 microns
or less yields a release profile that provides a consistent plasma
concentration of asenapine regardless of the d.sub.50 value of the
particle fraction employed. These data indicate also that at a 5 wt
% concentration, formulations of the invention comprising API
particle fractions having less than about 10 vol % particles of
less than 1 micron and exhibiting a d.sub.50 value of greater than
1.5 microns and less than about 40 microns provide a consistent
release profile across the range of formulations tested that yields
a sustained plasma concentration of asenapine consistent with the
provision of a therapeutic level of asenapine.
[0081] As can be seen in FIGS. 9c and 9a, particle fractions
yielding small d.sub.50 values (e.g. 0.25 microns, 9c) or which
have a large "fines" content (10 vol % or greater of particles with
less than 1 micron particle size (e.g., 1.5 micron, 9a) tend to
exhibit a "bursting effect" (also termed a "Burst Release") upon
injection, and are accordingly unacceptable for use as a
formulation for depot administration of asenapine.
[0082] In additional animal studies, and with Reference to FIG. 10,
using the same procedures described above, suspensions comprising
20 wt % of asenapine hemipamoate of Form I (mean particle size of
20 micron) and Form II (mean particle size 16 micron) were
prepared. Aliquots of each suspension were administered as a 1 mL
IM injection to New Zealand White rabbits using the same procedure
described above. Plasma levels of asenapine were determined using
the above-described procedure. As can be seen from FIG. 10, this
illustrates that Form I of asenapine hemipamoate is unsuitable for
use in providing a controlled release of asenapine in that it
exhibits an undesirable "burst release", e.g. high initial plasma
levels in the first week after administration in comparison to the
plasma levels provided by the depot comprising Form II asenapine
hemipamoate. Accordingly, formulations prepared in this manner from
crystalline Form I asenapine hemipamoate are unsuitable for use in
depot administration.
Example 4
In Vivo Study of Depot Administration of Asenapine Hemipamoate
Composition In Patients
[0083] Formulations of the invention were studied in human patients
diagnosed with stable chronic schizophrenia. Using the same
procedure described above, a suspension was prepared comprising 20
wt % of crystalline Form II of asenapine hemipamoate. The Form II
particle fraction employed to prepare the suspension yielded a
d.sub.10 value of 3 microns, a d.sub.90 value of 27 microns and a
d.sub.50 value of 10 microns. An injection of 1.0 mL volume of the
suspension was administered in the deltoid muscle of the upper arm
by inserting the needle in the thickest part of the deltoid muscle
at a 90 degree angle to the skin, followed by aspiration for 5 to
10 seconds, followed by injection of the depot over a 10 second
interval. The plasma concentration of asenapine provided by the
depot was observed using the above-described procedure. The results
of this study are presented in FIG. 11 which shows that the
composition can provide a controlled release of asenapine over a
period of about 4 weeks.
[0084] It will be observed that by changing the injection volume
used to provide the depot different plasma levels can be
obtained.
Example 5
In Vitro Studies of Dissolution of Selected Particle Fractions of
Crystalline Form II of Asenapine Hemipamoate
[0085] In vitro studies of the dissolution behavior of particle
fractions comparable to each of those reported in Table II above
were conducted in a USP paddle stirring dissolution apparatus (see
FIG. 6). To carry out these studies, particle fractions of
crystalline Form II of asenapine hemipamoate having d.sub.50 values
of 3.5 microns, 7 microns, and 20 microns respectively, (see FIG.
7e) were obtained and placed into one of the dissolution vessels of
the apparatus. Prior to charging a dissolution vessel with an
aliquot of particles, each of the vessels was filled with 1 L of
phosphate buffered saline (10 mM, adjusted to pH 7.0) and fitted
with a probe that contained a mirror and optical arrangement in its
tip defining a fixed sample path. Each probe was optically
connected to a central light source and detector permitting
real-time photometric monitoring of the concentration of asenapine
in solution as dissolution proceeded during the investigation.
Using this system the investigators were able to observe over time
the rate of dissolution under standard conditions and compare the
dissolution behavior of the various particle fractions as selected
variables (temperature, paddle speed, pH) were altered in the
dissolution apparatus.
[0086] The particle fractions were prepared for use in the
apparatus by dispersing the sample (20 mg) in 1 mL of an aqueous
solution comprising 3 wt. % macrogol 3400, 0.118 wt. % of disodium
hydrogen phosphate, 0.047 wt. % sodium dihydrogen phosphate and
0.76 wt. % sodium chloride. Each determination was carried out by
adjusting the apparatus to the desired dissolution conditions
(temperature, paddle speed, pH of dissolution media) and injecting
50 microliter of the selected crystalline Form II of asenapine
hemipamoate dispersion (equivalent to 1 mg of crystalline Form II
of asenapine hemipamoate) into a dissolution vessel filled with the
desired dissolution medium. Asenapine hemipamoate concentration in
the dissolution medium was monitored optically using the probe
system described above during the course of the dissolution. The
results of these investigations are reported in FIGS. 7a through
7d, which illustrate the dissolution behavior of various fractions
of the crystalline Form II of asenapine hemipamoate suspensions
under various test conditions. As can be seen from the FIG. 7c
(observing the dissolution behavior of suspensions of particle
fractions having a d.sub.50 value of either 3.5 microns or 20
microns) variation of the dissolution medium pH (from pH 6 to pH 8)
does not significantly vary the rate of dissolution of a given
particle fraction, that is, neither the 3.5 micron fraction nor the
20 micron fraction appreciably change their dissolution rate with
variation in the pH of the dissolution medium. In the same manner,
with reference to FIG. 7d, the dissolution behavior observed for a
given particle fraction is also reasonably insensitive to variation
in the paddle speed of the apparatus (50 rpm to 150 rpm). Moreover,
with reference to FIG. 7b, the dissolution behavior observed for a
given particle fraction is reasonably insensitive to variation in
temperature of the dissolution medium (35.degree. C. to 39.degree.
C.). However, with reference to FIG. 7a, when the dissolution rate
of various particle fractions are compared under the same
conditions, it was observed that the rate of particle dissolution
is greatly influenced by the d.sub.50 value of the particle
fraction studied. These results indicate that a depot
administration of asenapine hemipamoate prepared by suspending an
unclassified particle fraction in a carrier could result in
non-linear release of asenapine from the depot due to the faster
dissolution rate of small particles in comparison with the slower
dissolution rate of large particles.
[0087] The above-described in vitro testing methodology was used to
compare the dissolution of crystalline crystalline Form I of
asenapine hemipamoate hemipamoate (as precipitated) and crystalline
Form II of asenapine hemipamoate (as precipitated). Accordingly, 20
mg of a particle fraction of crystalline Form I of asenapine
hemipamoate having a d.sub.50 value of 19 microns, a d.sub.90 value
of 41 microns and a d.sub.10 value of 3 microns was dispersed into
2 mL of a polysorbate 80 solution. An aliquot of 100 microliter of
the dispersion was introduced into dissolution medium contained in
a paddle stirring apparatus as described above. For these tests the
dissolution vessels of the apparatus were filled with 1 L of
phosphate buffered saline (10 mM, adjusted to pH 7.0). The
temperature of the dissolution medium was maintained at 37.degree.
C. and the apparatus paddle speed was set at 100 RPM. The
dissolution results for the crystalline Form I of asenapine
hemipamoate sample are shown in the upper trace of FIG. 8a.
[0088] For comparison, a 100 microliter sample of a dispersion
comprising 100 mg of crystalline Form II of asenapine hemipamoate
particle fraction having a d.sub.50 value of 16 microns, a d.sub.90
value of 50 microns, and a d.sub.10 value of 2 microns, dispersed
in 1 mL of a polysorbate 80 solution, as described above was
studied under the same conditions and dissolution medium used to
study the sample containing crystalline Form I of asenapine
hemipamoate. The results of this study are shown in the lower trace
of FIG. 8a. The results presented in FIG. 8a indicate that the rate
of dissolution observed for crystalline Form I of asenapine
hemipamoate is significantly higher under the same conditions in
comparison with that observed for crystalline Form II of asenapine
hemipamoate. These results demonstrate that a formulation
comprising crystalline Form I of asenapine hemipamoate is
unacceptable for depot administration. FIG. 8b presents the
classification characteristics of the particle fraction used in the
studies described above.
[0089] The above description of the invention is intended to be
illustrative and not limiting. Various changes or modifications in
the embodiments described herein may occur to those skilled in the
art. These changes can be made without departing from the scope or
spirit of the invention
* * * * *