U.S. patent application number 12/254925 was filed with the patent office on 2009-04-16 for injectable depot formulation comprising crystals of iloperidone.
Invention is credited to Markus Ahlheim, Alexandra Glausch, Dierk Wieckhusen.
Application Number | 20090099232 12/254925 |
Document ID | / |
Family ID | 9940486 |
Filed Date | 2009-04-16 |
United States Patent
Application |
20090099232 |
Kind Code |
A1 |
Wieckhusen; Dierk ; et
al. |
April 16, 2009 |
INJECTABLE DEPOT FORMULATION COMPRISING CRYSTALS OF ILOPERIDONE
Abstract
An injectable depot formulation comprising crystals having
structure (I) wherein R is (FII) and the X50 value of the crystals
is from 1 to 200 microns. Depot formulations containing crystals of
iloperidone or its metabolites have the following advantages: (i)
release of the crystals in plasma can be correlated with the size
of the crystals; (ii) absorption of the crystals in plasma can be
correlated with the size of the crystals; (iii) the particle size
of the crystals can be controlled by crystal engineering and/or
milling; and (iv) the crystals are stable upon storage, and stable
to sterilization procedures, such as gamma irradiation.
Inventors: |
Wieckhusen; Dierk; (Binzen,
DE) ; Glausch; Alexandra; (Weil am Rhein, DE)
; Ahlheim; Markus; (Staufen, DE) |
Correspondence
Address: |
HOFFMAN WARNICK LLC
75 STATE STREET, 14TH FLOOR
ALBANY
NY
12207
US
|
Family ID: |
9940486 |
Appl. No.: |
12/254925 |
Filed: |
October 21, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10521064 |
Jan 12, 2005 |
|
|
|
PCT/EP03/07619 |
Jul 14, 2003 |
|
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12254925 |
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Current U.S.
Class: |
514/321 |
Current CPC
Class: |
A61K 47/38 20130101;
A61P 25/18 20180101; A61K 47/26 20130101; A61P 25/28 20180101; A61K
9/0019 20130101; A61K 31/454 20130101; A61K 47/10 20130101 |
Class at
Publication: |
514/321 |
International
Class: |
A61K 31/454 20060101
A61K031/454 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 15, 2002 |
GB |
0216416.8 |
Claims
1. An injectable depot formulation comprising crystals of
iloperidone or its metabolite or a pharmaceutically acceptable
salt, hydrate, solvate, polymorph or stereoisomer of iloperidone or
its metabolite, wherein the X.sub.50 value of the crystals is from
1 to 200 microns.
2. An injectable depot formulation comprising crystals having
Structure (I) ##STR00009## wherein R is ##STR00010## and the
X.sub.50 value of the crystals is from 1 to 200 microns.
3. The depot formulation according to claim 2 wherein the crystals
have Structure (II) ##STR00011##
4. The depot formulation according to claim 2 wherein the crystals
have Structure (III) ##STR00012##
5. The depot formulation according to claim 2 wherein the crystals
are a combination of crystals having Structure (II) ##STR00013##
and crystals having Structure (III) ##STR00014##
6. The depot formulation according to claim 1 wherein the X.sub.50
value of the crystals is from 10 to 170 microns.
7. The depot formulation according to claim 6 wherein the X.sub.50
value of the crystals is from 15 to 70 microns.
8. The depot formulation according to claim 1 wherein a suitable
vehicle is used to form a suspension of the crystals.
9. The depot formulation according to claim 8 wherein the suitable
vehicle is water.
10. The depot formulation according to claim 1 which additionally
comprises an additional ingredient selected from the group
consisting of a surfactant, solubilizer, emulsifier, preservative,
isotonicity agent, dispersing agent, wetting agent, filler,
solvent, buffer, stabilizer, lubricant, thickening agent, and
combinations thereof.
11. The depot formulation according to claim 10 wherein the
surfactant is selected from the group consisting of a sorbitan
fatty acid ester, phosphatide, polyoxyethylated sorbitan
monooleate, polyoxyalkylene derivatives of propylene glycol,
polyoxyethylated fat, polyoxyethylated oleotriglyceride,
linolizated oleotriglyceride, polyethylene oxide condensation
products of fatty alcohol, and an alkylphenol.
12. The depot formulation according to claim 11 wherein the
surfactant is a polyoxyalkylene derivative of propylene glycol.
13. The depot formulation according to claim 10 wherein the
concentration of surfactant is in the range of about 0.5 to about
10 mg/mL.
14. The depot formulation according to claim 10 wherein the
thickening agent is selected from the group consisting of sodium
carboxymethyl cellulose, hydroxypropyl cellulose, calcium
carboxymethyl cellulose, and crosslinked carboxymethyl
cellulose.
15. The depot formulation according to claim 14 wherein the
thickening agent is sodium carboxymethylcellulose.
16. The depot formulation according to claim 10 wherein the
concentration of thickening agent is in the range of about 2 to
about 25 mg/mL.
17. The depot formulation according to claim 10 wherein the
isotonicity agent is selected from the group consisting of salts
such as sodium chloride; sugars such as dextrose, mannitol, and
lactose.
18. The depot formulation according to claim 17 wherein the
isotonicity agent is mannitol.
19. The depot formulation according to claim 1 wherein the amount
of iloperidone or its metabolite administered in one injection is
from about 10 mg to about 1000 mg.
20. The depot formulation according to claim 19 wherein the amount
of iloperidone or its metabolite administered in one injection is
from about 100 mg to about 750 mg.
21. A package comprising a container containing an injectable depot
formulation comprising crystals of iloperidone or its metabolite or
a pharmaceutically acceptable salt, hydrate, solvate, polymorph and
stereoisomer of iloperidone or its metabolite, wherein the X.sub.50
value of the crystals is from 1 to 200 microns.
22. A package comprising a container containing an injectable depot
formulation comprising crystals having Structure (I) ##STR00015##
wherein R is ##STR00016## and the X.sub.50 value of the crystals is
from 1 to 200 microns.
23. Crystals of iloperidone or its metabolite or a pharmaceutically
acceptable salt, hydrate, solvate, polymorph and stereoisomer of
iloperidone or its metabolite, wherein the X.sub.50 value of the
crystals is from 1 to 200 microns.
24. Crystals having Structure (I) ##STR00017## wherein R is
##STR00018## and the X.sub.50 value of the crystals is from 1 to
200 microns.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of co-pending
U.S. patent application Ser. No. 10/521,064, filed 12 Jan. 2005,
which is a 35 USC 371 application claiming the benefit of PCT
Patent Application No. PCT/EP03/07619, filed 14 Jul. 2003, which in
turn claims the benefit of British Patent Application No.
GB0216416, filed 15 Jul. 2002, each of which is incorporated
herein.
FIELD OF THE INVENTION
[0002] This invention relates to an injectable depot formulation
comprising crystals of iloperidone or its metabolite wherein the
release and absorption of the crystals in plasma can be correlated
with the crystal size.
BACKGROUND OF THE INVENTION
[0003] The controlled release of an active agent from
poly(d,l-lactide-co-glycolide) microspheres and the general status
of such lactide use is discussed in the article "Controlled Release
of a Luteininizing Hormone-Releasing Hormone Analogue from
Poly(d,l,-lactide-co-glycolide) Microspheres" by L. M. Sanders et
al., J. of Pharm. Sci., 73, No. 9, September (1984).
[0004] Microencapsulated depot formulations of iloperidone and a
poly-glycolide polylactide glucose star polymer are disclosed in
U.S. Patent Application Nos. 60/339,036, filed Oct. 30, 2001, and
60/339,037, filed Oct. 30, 2001.
[0005] U.S. Pat. No. 5,955,459 describes compositions for treating
schizophrenia containing conjugates of a fatty acid and
iloperidone. A preferred fatty acid is cis-docosahexanoic acid.
[0006] It would be advantageous to develop an iloperidone or its
metabolite depot formulation that is as chemically-pure as
possible, and which is stable to sterilization procedures, such as
gamma irradiation. Furthermore, the depot formulation should
provide a reliable, reproducible and constant plasma concentration
profile of iloperidone or its metabolite following administration
to a patient.
SUMMARY OF THE INVENTION
[0007] The present invention provides an injectable depot
formulation comprising crystals of iloperidone or its metabolite or
a pharmaceutically acceptable salt, hydrate, solvate, polymorph and
stereoisomer thereof, wherein the mean particle size (X.sub.50
value) of the crystals is from 1 to 200 microns.
[0008] According to another aspect the invention provides an
injectable depot formulation comprising crystals having Structure
(I)
##STR00001##
[0009] wherein R is
##STR00002##
[0010] and the X.sub.50 value of the crystals is from 1 to 200
microns.
[0011] According to a further aspect the invention provides
crystals of iloperidone or its metabolite or a pharmaceutically
acceptable salt, hydrate, solvate, polymorph and stereoisomer
thereof, wherein the X.sub.50 value of the crystals is from 1 to
200 microns.
[0012] The present inventors have unexpectedly determined that
depot formulations containing crystals of iloperidone or its
metabolite have the following advantages: (i) release of the
crystals in plasma can be correlated with the size of the crystals;
(ii) absorption of the crystals in plasma can be correlated with
the size of the crystals; (iii) the particle size of the crystals
can be controlled by crystal engineering and/or milling; and (iv)
the crystals are stable upon storage, and stable to sterilization
procedures, such as gamma irradiation.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] FIG. 1 is a photomicrograph of iloperidone crystals wherein
1 grid is equal to 100 microns.
[0014] FIG. 2 is a photomicrograph of iloperidone crystals after
milling wherein 1 grid is equal to 250 microns.
[0015] FIG. 3 is a graph of mean plasma concentrations in female
rabbits of an iloperidone crystal depot formulation having an
X.sub.50 value of 16 microns and 30 microns over a period of
time.
[0016] FIG. 4 is a graph of mean plasma concentrations in female
rabbits of an iloperidone crystal depot formulation having an
X.sub.50 value of 170 microns over a period of time.
DESCRIPTION OF THE INVENTION
[0017] Iloperidone is
1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-meth-
oxyphenyl]ethanone. As used herein, "iloperidone" includes any
salts, hydrates, solvates, polymorphs such as amorphous polymorphs,
and/or stereoisomers thereof. The metabolite of iloperidone is
1-[4[3-[4(6-fluoro(d)isoxazol-3-yl)-piperidin-1-yl]propoxy]-3-methoxyphen-
yl]ethanol. As used herein, "metabolite of iloperidone" includes
any salts, hydrates, solvates, polymorphs such as amorphous
polymorphs, and/or stereoisomers thereof.
[0018] Preferably, the crystals have Structure (I)
##STR00003##
[0019] wherein R is
##STR00004##
[0020] It is noted that when R is
##STR00005##
[0021] the crystals may exist as either the (R) or (S) enantiomer,
or as a racemic mixture thereof. The (S) enantiomer has Structure
II
##STR00006##
[0022] The (R) enantiomer has Structure (III)
##STR00007##
[0023] The crystals may be in the form of needles, trigonal forms,
tetragonal forms, flat rod shaped, cubes, parallelepipeds, or
plate-like. The mean particle size (X.sub.50 value) of the crystals
is preferably from about 1 to about 200 microns, more preferably 10
to 170 microns, whereby application of the depot formulation to a
patient can be carried out using a standard gauge (typically 18 or
20 gauge) needle. Most preferably, the mean particle size (X.sub.50
value) of the crystals is from 15 to 70 microns.
[0024] The crystals may be prepared by crystal growth or
engineering directly to a desired crystal size. In the alternative,
the crystals may be prepared to a larger crystal size than is
desired in the depot formulations. In such a situation, the
crystals may be milled or ground to achieve crystals having a size
in the desired range. Such a milling step, for example, is
important for achieving the desired crystal size distribution. In
principle any mill can be used, for example, a pinmill. Following
milling, the crystals may optionally be passed through a screen
stack or sieve with crystals of the desired size retained while the
crystals falling outside of the desired range (either too small or
too large) are discarded.
[0025] It is also within the scope of the invention to provide the
depot formulations of the invention as suspensions in a suitable
vehicle. Aqueous suspensions are preferred such as the crystals
suspended in water. The present inventors have determined that in
the case of a suspension, the crystals are preferable administered
with one or more additional ingredients.
[0026] Additional ingredients which may be used in the depot
formulations of the invention include natural and/or artificial
ingredients which are commonly used to prepare pharmaceutical
compositions. Examples of additional ingredients include a
surfactant, solubilizer, emulsifier, preservative, isotonicity
agent, dispersing agent, wetting agent, filler, solvent, buffer,
stabilizer, lubricant, and thickening agent. A combination of
additional ingredients may also be used. Preferred additional
ingredients are a surfactant, isotonicity agent, and thickening
agent. Generally, such ingredients and their concentrations in
parenteral formulations are known to those skilled in the art, and
thus, only examples of the preferred additional ingredients are
described. The depot formulations of the invention should not be
limited to the following examples of preferred additional
ingredients.
[0027] Examples of surfactants include: sorbitan fatty acid esters
such as sorbitan trioleate, phosphatides such as lecithin, acacia,
tragacanth, polyoxyethylated sorbitan monooleate and other
ethoxylated fatty acid esters of sorbitan, polyoxyalkylene
derivatives of propylene glycol, such as those available under the
trademark PLURONIICS, especially PLURONICS F68; polyoxyethylated
fats, polyoxyethylated oleotriglycerides, linolizated
oleotriglycerides, polyethylene oxide condensation products of
fatty alcohols, alkylphenols or fatty acids or
1-methyl-3-(2-hydroxyethyl)imidazolidone-(2). As used herein,
"polyoxyethylated" means that the substances in question contain
polyoxyethylene chains, the degree of polymerization of which
generally is between 2 and 40, and preferably, between 10 and 20. A
preferred surfactant is a polyoxyalkylene derivative of propylene
glycol, such as PLURONICS F68 which is available from BASF.
[0028] The amount of surfactant in the depot formulations of the
invention is in the range known in the art for parenteral
formulations, preferably from about 0.5 to about 10 mg/mL.
[0029] Examples of thickening agents include: croscarmellose
sodium, sodium carboxymethyl cellulose, and hydroxypropyl
cellulose. A preferred thickening agent is sodium carboxymethyl
cellulose.
[0030] The amount of thickening agent in the depot formulations of
the invention is in the range known in the art for parenteral
formulations, preferably from about 2 to about 25 mg/mL.
[0031] Examples of isotonicity agents which may impart tonicity to
the depot formulations to prevent the net flow of water across a
cell membrane, include: salts such as sodium chloride; sugars such
as dextrose, mannitol, and lactose. Mannitol is a preferred
isotonicity agent.
[0032] The amount of isotonicity agent in the depot formulations of
the invention is in the range known in the art for parenteral
formulations.
[0033] The amount of iloperidone or its metabolite in the depot
formulations will vary depending upon the severity of the condition
to be treated. The depot formulations of the invention are
preferably injectable and may be administered by intramuscular or
subcutaneous injection. The depot formulations administered by
injection provide an effective treatment of diseases over an
extended period, for example, from about 2 to about 8 weeks. The
depot formulation allows a controlled release of iloperidone or its
metabolite by dissolution of the crystals, and therefore, steady
state levels of the iloperidone or its metabolite are obtained over
the extended period.
[0034] The amount of iloperidone or its metabolite administered in
one injection is preferably from about 10 mg to about 1000 mg. More
preferably, the amount of iloperidone or its metabolite
administered in one injection is from about 100 mg to about 750
mg.
[0035] In one embodiment of the invention, the crystals of defined
size are filled into a glass vial, purged with nitrogen and sealed
with a rubber stopper. The vial may be terminal sterilized by gamma
irradiation, preferably, in a range of 25-35 kGy or manufactured
under aseptic conditions.
[0036] In one embodiment of the invention, the iloperidone crystals
are injected into the body.
[0037] In one embodiment of the invention, the crystals of the
metabolite of iloperidone are injected into the body.
[0038] In another embodiment of the invention, the iloperidone
crystals are suspended in water, and the suspension is injected
into the body.
[0039] In another embodiment of the invention, the crystals of the
metabolite of iloperidone are suspended in water, and the
suspension is injected into the body.
[0040] The depot formulation of the invention is useful for
treating central nervous system disorders, for example, psychotic
disorders such as schizophrenia. The invention also provides a
package comprising a container containing the depot formulation and
instructions for using the depot formulation for treating
schizophrenia in a patient.
[0041] The following examples further describe the materials and
methods used in carrying out the invention. The examples are not
intended to limit the invention.
Example 1
[0042] Preparation of
1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxyl]-3-met-
hoxyphenyl]ethanone having the structure:
##STR00008##
[0043] Into a 2 L Erlenmeyer flask with magnetic stirrer and reflux
cooler under nitrogen atmosphere and an external temperature of
20-25.degree. C., 250 g of iloperidone and 1050 g of butylacetate,
were added. The light brown suspension was heated to an internal
temperature of 80.degree. C. until a brownish solution was formed.
The solution was filtered over Cellflock into a preheated 2.5 L
glass vessel with a blade-stirrer and reflux-cooler under nitrogen
atmosphere. The Erlenmeyer flask and filter were washed with warm
butylacetate (ca. 70.degree. C.). The brownish solution was
reheated to an internal temperature of 80.degree. C. and stirred
for 5 to 10 minutes. The solution was cooled with 0.75 K/min to an
internal temperature of 65.degree. C. and seeded with 2.5 g of
iloperidone milled, which was suspended and ultrasonicated in 7.5 g
of butylacetate.
[0044] The suspension was cooled to an internal pressure of
0.degree. C. with a rate of 0.25 K/min and stirred for 2 to 12
hours at an internal temperature of 0.degree. C. The suspension was
filtered over a glass nutsche (0=110 mm) for 15 seconds. The filter
cake (cake thickness=4 cm) was flushed with motherliquor and 275 g
of cold butylacetate (0.degree. C.) in two portions.
[0045] Iloperidone, 315 g, was obtained as wet, light brownish
filtercake. The wet product was dried at an external temperature of
50-60.degree. C. under a vacuum of less than 2 mbar for about 16-24
hours. Iloperidone, 238.3 g, was obtained. Theoretical yield was
determined to be 94.4%.
Example 2
[0046] The iloperidone crystals prepared in Example 1, 120 mg,
having a particle size X.sub.50=32 .mu.m were reconstituted with 1
ml of a mixture containing sodiumcarboxymethylcellulose, Pluronics
F68, and mannitol, by shaking resulting in a homogeneous
suspension. The suspension was withdrawn from the vial with a
syringe and injected into rabbits.
Example 3
[0047] The iloperidone crystals prepared in Example 1, 850 mg,
having a particle size X.sub.50=15 .mu.m were reconstituted with 2
ml of a mixture containing sodiumcarboxymethylcellulose, Pluronics
F68, and mannitol, by shaking or swirling until a homogeneous
suspension was obtained. This pastelike suspension was withdrawn
from the vial with a syringe and injected into rabbits.
Example 4
[0048] The iloperidone crystals prepared in Example 1, 850 mg,
having a particle size X.sub.50=51 .mu.m were reconstituted with 2
ml of a mixture containing sodiumcarboxymethylcellulose, Pluronics
F68, and mannitol, by shaking resulting in a homogeneous
suspension. The suspension was withdrawn from the vial with a
syringe and injected into rabbits.
Example 5
[0049] Regarding the drawings, FIG. 3 is a graph of mean plasma
concentrations in female rabbits of an iloperidone crystal depot
formulation having an X.sub.50 value of 16 microns and 30 microns
over a period of time. The formulations were dose normalized to 20
mg of iloperidone per kg of each rabbit. Each formulation was
injected into six rabbits. FIG. 3 shows that the depot formulations
prepared with iloperidone crystals having a X.sub.50=16 remained in
the plasma of the rabbits for at least 16 days. The depot
formulations prepared with iloperidone crystals having a
X.sub.50=30 remained in the plasma of the rabbits for at least 25
days. The mean dose normalized pharmacokinetic parameters of
iloperidone in plasma for each crystal size are summarized in Table
I.
TABLE-US-00001 TABLE I Actual dose Iloperidone t.sub.max,d [mg/kg]
C.sub.max,d [d] Formulation mean [ng/mL] mean median 16 um 16.7
53.2 6 30 um 17.0 35.3 9
[0050] The results in Table I and graph of FIG. 3 clearly show that
the mean plasma concentration of iloperidone can be correlated with
the particle size of the iloperidone crystals.
Example 6
[0051] Regarding the drawings, FIG. 4 is a graph of mean plasma
concentrations in female rabbits of an iloperidone crystal depot
formulation having an X.sub.50 value of 170 microns over a period
of time. The formulations were dose normalized to 20 mg of
iloperidone per kg of each rabbit The formulation was injected into
six rabbits. FIG. 4 shows that the depot formulations prepared with
iloperidone crystals having a X.sub.50=170 microns remained in the
plasma of the rabbits for at least 30 days. The mean dose
normalized pharmacokinetic parameters of iloperidone in plasma are
summarized in Table II.
TABLE-US-00002 TABLE II Actual dose Iloperidone T.sub.max,e (mg/kg)
C.sub.max,e [d] Formulation Mean [ng/mL] (median) 170 um 15.7 .+-.
1.9 37.4 .+-. 11.2 10.5
[0052] Depot formulations containing crystals of iloperidone or its
metabolite have the following advantages: (i) release of the
crystals in plasma can be correlated with the size of the crystals;
(ii) absorption of the crystals in plasma can be correlated with
the size of the crystals; (iii) the particle size of the crystals
can be controlled by crystal engineering and/or milling; and (iv)
the crystals are stable upon storage, and stable to sterilization
procedures, such as gamma irradiation.
[0053] While the invention has been described with particular
reference to certain embodiments thereof, it will be understood
that changes and modifications may be made by those of ordinary
skill within the scope and spirit of the following claims:
* * * * *