U.S. patent application number 17/448862 was filed with the patent office on 2022-01-13 for freeze-dried aripiprazole formulation.
This patent application is currently assigned to Otsuka Pharmaceutical Co., Ltd.. The applicant listed for this patent is Otsuka Pharmaceutical Co., Ltd.. Invention is credited to Shogo HIRAOKA.
Application Number | 20220008341 17/448862 |
Document ID | / |
Family ID | |
Filed Date | 2022-01-13 |
United States Patent
Application |
20220008341 |
Kind Code |
A1 |
HIRAOKA; Shogo |
January 13, 2022 |
FREEZE-DRIED ARIPIPRAZOLE FORMULATION
Abstract
An object of the present invention is to provide a freeze-dried
aripiprazole powder formulation that exhibits good dispersibility
and is easily dispersed into a homogenous suspension when
reconstituted with water. The present invention provides a
freeze-dried aripiprazole formulation obtained by a process
comprising the steps of spraying for freezing an aripiprazole
suspension containing (I) aripiprazole, (II) a vehicle for the
aripiprazole, and (III) water for injection, and drying
Inventors: |
HIRAOKA; Shogo; (Osaka,
JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Otsuka Pharmaceutical Co., Ltd. |
Tokyo |
|
JP |
|
|
Assignee: |
Otsuka Pharmaceutical Co.,
Ltd.
Tokyo
JP
|
Appl. No.: |
17/448862 |
Filed: |
September 24, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14124459 |
Dec 6, 2013 |
11154507 |
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PCT/JP2012/065180 |
Jun 7, 2012 |
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17448862 |
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61494088 |
Jun 7, 2011 |
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International
Class: |
A61K 9/19 20060101
A61K009/19; A61K 9/16 20060101 A61K009/16; A61K 31/496 20060101
A61K031/496 |
Claims
1. A freeze-dried aripiprazole formulation obtained by a process
comprising the steps of spraying for freezing an aripiprazole
suspension containing (I) aripiprazole, (II) a vehicle for the
aripiprazole, and (III) water for injection; and drying.
2. The freeze-dried formulation according to claim 1, consisting
essentially of particles with a particle size of substantially 30
.mu.m or more.
3. The freeze-dried formulation according to claim 1, comprising
aripiprazole in an amount of 50 w/w % or more.
4. The freeze-dried formulation according to claim 1, which has a
bulk density of about 0.05 to about 0.5 g/mL.
5. The freeze-dried formulation according to claim 1 wherein the
aripiprazole has a mean particle size of about 1 to about 10
microns.
6. The freeze-dried formulation according to claim 5 wherein the
aripiprazole has a mean particle size of about 2.5 microns.
7. The freeze-dried formulation according to claim 1, comprising at
least one member selected from the group consisting of suspending
agents, bulking agents, and buffers.
8. The freeze-dried formulation according to claim 1, comprising
(II-a) one or more suspending agents, (II-b) one or more bulking
agents, and (II-c) one or more buffers.
9. The freeze-dried formulation according to claim 1, comprising
(II-a) carboxymethyl cellulose or a salt thereof, (II-b) mannitol,
and (II-c) sodium phosphate.
10. The freeze-dried formulation according to claim 1, further
comprising (IV) a pH adjusting agent.
11. The freeze-dried formulation according to claim 10, wherein the
pH adjusting agent is sodium hydroxide.
12. The freeze-dried formulation according to claim 1, comprising
(I) aripiprazole, (II-a) carboxymethyl cellulose or a sodium salt
thereof, (II-b) mannitol, (II-c) sodium phosphate, and optionally
(IV) sodium hydroxide.
13. The freeze-dried formulation according to claim 1, wherein the
aripiprazole is in the form of a monohydrate.
14. A process for producing a freeze-dried aripiprazole formulation
comprising the steps of (e'-1) spray-freezing an aripiprazole
suspension having a mean particle size in the range of about 1 to
about 10 microns to obtain spray-frozen particles; and (e'-2)
drying the spray-frozen particles to obtain spray-freeze-dried
particles.
15. The process for producing a freeze-dried aripiprazole
formulation according to claim 14, comprising the steps of (d')
reducing the mean particle size of aripiprazole in a primary
suspension formed by mixing aripiprazole, a vehicle for the
aripiprazole, and water to the range of about 1 to about 10 microns
to form a final suspension; (e'-1) spray-freezing the aripiprazole
suspension having a mean particle size of about 1 to about 10
microns to obtain spray-frozen particles; and (e'-2) drying the
spray-frozen particles to obtain spray-freeze-dried particles.
16. The process according to claim 15, wherein the reduction of the
mean particle size of aripiprazole in the sterile primary
suspension is carried out by wet milling.
17. The process according to claim 14, wherein the spraying in step
(e'-1) is either spraying at a low temperature for freezing or
spraying under reduced pressure for freezing.
18. The process according to claim 14, further comprising selecting
particles with a particle size of substantially 30 .mu.m or
more.
19. The freeze-dried formulation according to claim 1, which
exhibits good dispersibility and forms a homogenous aripiprazole
suspension upon reconstitution with water.
20. The freeze-dried formulation according to claim 1, comprising
particles with a particle size of less than 75 .mu.m in an amount
of 15 w/w % or less.
Description
[0001] This application claims priority to U.S. provisional
application Ser. No. 61/494,088, filed Jun. 7, 2011, entitled
"FREEZE-DRIED FORMULATION". The disclosure of the above referenced
application is incorporated by reference herein in its
entirety.
TECHNICAL FIELD
[0002] The present invention relates to a freeze-dried formulation
containing aripiprazole.
BACKGROUND ART
Background of the Invention
[0003] U.S. Pat. No. 5,006,528 (Oshiro et al.) discloses
7-[(4-phenylpiperazino)-butoxy]carbostyrils, which include
aripiprazole, as dopaminergic neurotransmitter antagonists.
Aripiprazole is an atypical antipsychotic agent useful in treating
schizophrenia and has the following structure.
##STR00001##
Aripiprazole is poorly soluble in water (<1 .mu.g/mL at room
temperature).
[0004] A long-acting aripiprazole sterile injectable formulation
has merit as a drug dosage form in that it increases compliance of
patients and thereby lowers the relapse rate in the treatment of
schizophrenia.
[0005] Examples of known long-acting drug products for the
treatment of schizophrenia include haloperidol decanoate and
fluphenazine decanoate, both of which have an ester compound of low
water solubility dissolved in sesame oil. Microcapsules containing
risperidone (WO95/13814) and olanzapine (WO99/12549) are also
known.
CITATION LIST
Patent Literature
[0006] PTL 1: U.S. Pat. No. 5,006,528 [0007] PTL 2: WO2005/041937
[0008] PTL 3: WO1995/13814 [0009] PTL 4: WO1999/12549 [0010] PTL 5:
WO2003/26659
Non-Patent Literature
[0010] [0011] NPL 1: Journal of Pharmaceutical Sciences, Vol. 92,
No. 2, 319-332 (2003)
SUMMARY OF INVENTION
Technical Problem
[0012] The present inventors attempted to develop a prefilled
syringe (a prefilled syringe for injection to be prepared
immediately before use) containing a freeze-dried aripiprazole
formulation and water for injection, which are mixed together
immediately before use to reconstitute a ready-to-use
suspension.
[0013] To produce such a prefilled syringe, a freeze-dried
aripiprazole formulation must be filled into a syringe. For the
sake of convenience of such filling, a freeze-dried aripiprazole
powder formulation is preferably used. In particular, to
efficiently weigh out the amount of pharmaceutical preparation to
be filled, a powder is preferably used.
[0014] To fill a powder into a syringe, methods using bulk powder
itself or a spray-dried powder are generally used. However, when
these methods are used, aripiprazole or particles containing
aripiprazole exhibit poor dispersibility, and forming a homogeneous
suspension within a syringe was impossible. Accordingly, an attempt
was made to fill into a syringe a powder obtained by crushing the
cake-form freeze-dried aripiprazole formulation disclosed in
WO2005/041937. However, the resulting freeze-dried aripiprazole
powder formulation exhibited poor dispersibility upon
reconstitution with water; therefore, forming a homogeneous
suspension was not easy. This result was unexpected, because the
cake-form freeze-dried aripiprazole formulation is easily
reconstituted into a homogeneous suspension by adding water
thereto. (The above result was found by the present inventors and
was previously unknown. The detail will be described below as a
comparative example.)
[0015] The term "dispersibility" as used herein refers to the level
of dispersion of the powder formulation in water when the water is
added to the filled powder formulation. Accordingly, the phrase
"exhibit poor dispersibility" or "poor dispersion" as used herein
refers to the property such that when water is added to the filled
powder formulation, water poorly penetrates into the powder, and
the powder formulation does not easily disperse in water. When
dispersed in water, the powder formulation obtained by crushing the
cake-form freeze-dried aripiprazole formulation had problems such
as formation of clumping and a portion remaining in a powder state
due to no penetration of water.
[0016] Therefore, there was a need to develop a freeze-dried
aripiprazole powder formulation that exhibits good dispersibility
and is easily dispersed into a homogenous suspension upon
reconstitution with water.
Solution to Problem
[0017] The invention of this application, for example, includes the
items listed below. Hereinafter, "w/w %" stands for
"(weight/weight) %", and "w/v %" stands for "(weight/volume)
%".
Item 1a. A freeze-dried aripiprazole formulation obtained by a
process comprising the steps of spraying for freezing an
aripiprazole suspension containing (I) aripiprazole, (II) a vehicle
for the aripiprazole, and (III) water for injection; and
drying.
[0018] More specifically, the freeze-dried formulation of Item 1a
can be described as in Item 1b below.
Item 1b. A freeze-dried formulation obtained by a process
comprising the steps of spray-freezing an aripiprazole suspension
containing (I) aripiprazole, (II) a vehicle for the aripiprazole,
and (III) water for injection to form spray-frozen particles; and
drying the spray-frozen particles to obtain spray-freeze-dried
particles. Item 2. The freeze-dried formulation according to Item
1a or 1b, consisting essentially of particles (spray-freeze-dried
particles) with a particle size of substantially 30 .mu.m or more
(preferably 50 .mu.m or more, more preferably 70 .mu.m or more, and
even more preferably 75 .mu.m or more). Item 3. The freeze-dried
formulation according to any one of Items 1a to 2, comprising
aripiprazole in an amount of 50 w/w % or more (preferably 60 w/w %
or more, and more preferably 70 w/w % or more). Item 4. The
freeze-dried formulation according to any one of Items 1a to 3,
which has a bulk density of 0.05 to 0.5 g/mL (preferably 0.08 to
0.4 g/mL, and more preferably 0.1 to 0.3 g/mL). Item 5. The
freeze-dried formulation according to any one of items 1a to 4,
wherein the aripiprazole has a mean particle size of about 1 to
about 10 microns. Item 6. The freeze-dried formulation according to
Item 5, wherein the aripiprazole has a mean particle size of about
2.5 microns. Item 7a. The freeze-dried formulation according to any
one of Item 1a to 6, comprising at least one member selected from
the group consisting of suspending agents, bulking agents, and
buffers. Item 7b. The freeze-dried formulation according to any one
of Item 1a to 7a, wherein the aripiprazole suspension contains as
the vehicle at least one member selected from the group consisting
of suspending agents, bulking agents, and buffers. Item 8a. The
freeze-dried formulation according to any one of Items 1a to 7b,
comprising (II-a) one or more suspending agents, (II-b) one or more
bulking agents, and (II-c) one or more buffers. Item 8b. The
freeze-dried formulation according to any one of Items 1a to 8a,
wherein the aripiprazole suspension contains, as the vehicle,
(II-a) one or more suspending agents, (II-b) one or more bulking
agents, and (II-c) one or more buffers. Item 9a. The freeze-dried
formulation according to any one of Items 1a to 8b, comprising
(II-a) carboxymethyl cellulose or a salt thereof, (II-b) mannitol,
and (II-c) sodium phosphate. Item 9b. The freeze-dried formulation
according to any one of Items 1a to 9a, wherein the aripiprazole
suspension contains, as the vehicle, (II-a) carboxymethyl cellulose
or a salt thereof, (II-b) mannitol, and (II-c) sodium phosphate.
Item 10a. The freeze-dried formulation according to any one of
Items 1a to 9b, further comprising (IV) a pH adjusting agent. Item
10b. The freeze-dried formulation according to any one of Items 1a
to 10a, wherein the aripiprazole suspension further comprises (IV)
a pH adjusting agent. Item 11. The freeze-dried formulation
according to Item 10a or 10b, wherein the pH adjusting agent is
sodium hydroxide. Item 12. The freeze-dried formulation according
to any one of Items 1a to 11, comprising (I) aripiprazole, (II-a)
carboxymethyl cellulose or a sodium salt thereof, (II-b) mannitol,
(II-c) sodium phosphate (to adjust pH to about 7), and optionally
(IV) sodium hydroxide (to adjust pH to about 7). Item 13. The
freeze-dried formulation according to any one of Items 1a to 12,
wherein the aripiprazole is in the form of a monohydrate. Item 14a.
A process for producing a freeze-dried aripiprazole formulation
comprising the steps of (e'-1) spray-freezing an aripiprazole
suspension having a mean particle size within the range of about 1
to about 10 microns to obtain spray-frozen particles; and (e'-2)
drying the spray-frozen particles to obtain spray-freeze-dried
particles. Item 14b. A process for producing a freeze-dried
aripiprazole formulation comprising the steps of (d') reducing the
mean particle size of aripiprazole in a primary suspension formed
by mixing aripiprazole, a vehicle for the aripiprazole, and water
to the range of about 1 to about 10 microns to form a final
suspension; (e'-1) spray-freezing the aripiprazole suspension
having a mean particle size of about 1 to about 10 microns to
obtain spray-frozen particles; and (e'-2) drying the spray-frozen
particles to obtain spray-freeze-dried particles. Item 14c. A
process for producing a freeze-dried aripiprazole formulation
comprising the steps of (c') mixing aripiprazole, a sterile vehicle
for the aripiprazole, and water to form a primary suspension; (d')
reducing the mean particle size of aripiprazole in the primary
suspension to the range of about 1 to about 10 microns to form a
final suspension; (e'-1) spray-freezing the aripiprazole suspension
having a mean particle size within the range of about 1 to about 10
microns to obtain spray-frozen particles; and (e'-2) drying the
spray-frozen particles to obtain spray-freeze-dried particles.
[0019] The processes of producing a freeze-dried-aripiprazole
formulation according to Items 14a to 14c are preferable as methods
for producing the freeze-dried formulation of any one of Items 1a
to 13.
Item 15. The process for producing a freeze-dried aripiprazole
formulation according to any one of Items 1a to 13 comprising the
steps of (a) preparing sterile bulk aripiprazole having a desired
particle size distribution; (b) preparing a sterile vehicle for the
sterile bulk aripiprazole; (c) mixing the aripiprazole and the
vehicle to form a sterile primary suspension containing the
aripiprazole; (d) reducing the mean particle size of the
aripiprazole in the sterile primary suspension to the range of
about 1 to about 10 microns to form a sterile final suspension; and
(e) spraying for freezing the final suspension, and drying. Item
16. The process according to any one of Items 14a to 15, wherein
the reduction of the mean particle size of aripiprazole in the
(sterile primary) suspension is carried out by wet milling. Item
17. The process according to any one of Items 14a to 16, wherein
the spraying in step (e) or (e'-1) is either spraying at a low
temperature for freezing or spraying under reduced pressure for
freezing. Item 18. The process according to any one of Items 14a to
17, further comprising selecting particles (spray-freeze-dried
particles) with a particle size of 30 .mu.m or more (preferably 50
.mu.m or more, more preferably 70 .mu.m or more, and even more
preferably 75 .mu.m or more). Item 19. The freeze-dried formulation
according to any one of Items 1a to 13, which exhibits good
dispersibility and forms a homogenous aripiprazole suspension upon
reconstitution with water. Item 20. The freeze-dried formulation
according to any one of Item 1a to 13 and 19, comprising particles
with a particle size of less than 75 .mu.m in an amount of 15 w/w %
or less. Item 21. A homogeneous aripiprazole suspension
reconstituted from the freeze-dried formulation of any one of Items
1a to 13, 19, and 20 by adding water thereto. Item 22. An
aripiprazole formulation, which comprises aripiprazole and a
vehicle for the aripiprazole and which is in the form of a powder
(preferably having a particle size of 1 mm or less), the particles
of the powder being spherical and porous. Item 23. The aripiprazole
formulation according to Item 22 comprising freeze-dried particles
(preferably spray-freeze-dried particles) having a particle size of
substantially 30 .mu.m or more (preferably 50 .mu.m or more, more
preferably 70 .mu.m or more, and even more preferably 75 .mu.m or
more). Item 24. The aripiprazole formulation according to Item 22
or 23, comprising the aripiprazole in an amount of 50 w/w % or more
(preferably 60 w/w % or more, and even more preferably 70 w/w % or
more). Item 25. The aripiprazole formulation according to any one
of Items 22 to 24, which has a bulk density of 0.05 to 0.5 g/mL,
more preferably 0.08 to 0.4 g/mL, and even more preferably 0.1 to
0.3 g/mL. Item 26. The aripiprazole formulation according to any
one of Items 22 to 25, wherein the aripiprazole has a mean particle
size of about 1 to about 10 microns. Item 27. The aripiprazole
formulation according to Item 26, wherein the aripiprazole has a
mean particle size of about 2.5 microns. Item 28. The aripiprazole
formulation according to any one of Items 22 to 27, comprising
particles with a particle size of 75 .mu.m or less in an amount of
15 w/w % or less. Item 29. The aripiprazole formulation according
to any one of Items 22 to 28, which is a freeze-dried formulation.
Item 30. The aripiprazole formulation according to item 29, which
is a spray-freeze-dried formulation.
BRIEF DESCRIPTION OF DRAWINGS
[0020] FIG. 1 shows the appearance (photo on the left) and surface
condition (photo on the right) of spray-freeze-dried particles
obtained by spray-freeze-drying a 10% suspension and collected
between sieves of 75 .mu.m and 250 .mu.m. The white bar at the
bottom right of the photo on the left indicates 1 mm, and the white
bar at the bottom left of the photo on the right indicates 20
.mu.m.
[0021] FIG. 2 shows the appearance (photo on the left) and surface
condition (photo on the right) of spray-freeze-dried particles
obtained by spray-freeze-drying a 10% suspension and collected
between sieves of 250 .mu.m and 500 .mu.m. The white bar at the
bottom right of the photo on the left indicates 1 mm, and the white
bar at the bottom right of the photo on the right indicates 20
.mu.m.
[0022] FIG. 3 shows the appearance (photo on the left) and surface
condition (photo on the right) of spray-freeze-dried particles
obtained by spray-freeze-drying a 10% suspension and collected
between sieves of 500 .mu.m and 1000 .mu.m. The white bar at the
bottom right of the photo on the left indicates 1 mm, and the white
bar at the bottom right of the photo on the right indicates 20
.mu.m.
[0023] FIG. 4 shows the appearance (photo on the left) and surface
condition (photo on the right) of spray-freeze-dried particles
obtained by spray-freeze-drying a 20% suspension and collected
between sieves of 75 .mu.m and 250 .mu.m. The white bar at the
bottom right of the photo on the left indicates 1 mm, and the white
bar at the bottom right of the photo on the right indicates 20
.mu.m.
[0024] FIG. 5 shows the appearance (photo on the left) and surface
condition (photo on the right) of spray-freeze-dried particles
obtained by spray-freeze-drying a 20% suspension and collected
between sieves of 250 .mu.m and 500 .mu.m. The white bar at the
bottom right of the photo on the left indicates 1 mm, and the white
bar at the bottom right of the photo on the right indicates 20
.mu.m.
[0025] FIG. 6 shows the appearance (photo on the left) and surface
condition (photo on the right) of spray-freeze-dried particles
obtained by spray-freeze-drying a 20% suspension and collected
between sieves of 500 .mu.m and 1000 .mu.m. The white bar at the
bottom right of the photo on the left indicates 1 mm, and the white
bar at the bottom right of the photo on the right indicates 20
.mu.m.
[0026] FIG. 7 shows the appearance (photo on the left) and surface
condition (photo on the right) of spray-freeze-dried particles
obtained by spray-freeze-drying a 30% suspension and collected
between sieves of 75 .mu.m and 250 .mu.m. The white bar at the
bottom right of the photo on the left indicates 1 mm, and the white
bar at the bottom left of the photo on the right indicates 20
.mu.m.
[0027] FIG. 8 shows the appearance (photo on the left) and surface
condition (photo on the right) of spray-freeze-dried particles
obtained by spray-freeze-drying a 30% suspension and collected
between sieves of 250 .mu.m and 500 .mu.m. The white bar at the
bottom right of the photo on the left indicates 1 mm, and the white
bar at the bottom right of the photo on the right indicates 20
.mu.m.
[0028] FIG. 9 shows the appearance (photo on the left) and surface
condition (photo on the right) of spray-freeze-dried particles
obtained by spray-freeze-drying a 30% suspension and collected
between sieves of 500 .mu.m and 1000 .mu.m. The white bar at the
bottom right of the photo on the left indicates 1 mm, and the white
bar at the bottom right of the photo on the right indicates 20
.mu.m.
[0029] FIG. 10 shows the appearance (photo on the left) and surface
condition (photo on the right) of spray-freeze-dried particles
obtained by spray-freeze-drying a 10% suspension and collected
between sieves of 75 .mu.m and 250 .mu.m. The white bar at the
bottom right of the photo on the left indicates 50 .mu.m, and the
white bar at the bottom left of the photo on the right indicates 4
.mu.m.
[0030] FIG. 11 shows the appearance (photo on the left) and surface
condition (photo on the right) of spray-freeze-dried particles that
were obtained by spray-freeze-drying a 10% suspension and that
passed through a sieve of 75 .mu.m. The white bar at the bottom
right of the photo on the left indicates 50 .mu.m, and the white
bar at the bottom left of the photo on the right indicates 4
.mu.m.
[0031] FIG. 12 shows the appearance (photo on the left) and surface
condition (photo on the right) of the powder obtained by crushing a
product freeze-dried in a vial ("vial-freeze-dried product") and
collected between sieves of 75 .mu.m and 250 .mu.m. The white bar
at the bottom right of the photo on the left indicates 50 .mu.m,
and the white bar at the bottom left of the photo on the right
indicates 4 .mu.m.
[0032] FIG. 13 shows the appearance (photo on the left) and surface
condition (photo on the right) of the powder that was obtained by
crushing a vial-freeze-dried product and that passed through a
sieve of 75 .mu.m. The white bar at the bottom right of the photo
on the left indicates 50 .mu.m, and the white bar at the bottom
left of the photo on the right indicates 4 .mu.m.
[0033] FIG. 14 shows the appearance of a suspension obtained by
dispersing an uncrushed (cake-form) vial-freeze-dried product in
water.
[0034] FIG. 15 shows the appearance of a suspension obtained by
sifting a spray-freeze-dried product to collect a powder obtained
between sieves of 75 .mu.m and 250 .mu.m and dispersing the powder
in water.
[0035] FIG. 16 shows the appearance of a suspension obtained by
sifting a spray-freeze-dried product to collect a powder that
passed through a sieve of 75 .mu.m and dispersing the powder in
water.
[0036] FIG. 17 shows the appearance of a suspension obtained by
crushing a vial-freeze-dried product in a vial, sifting the powder
to collect a powder that passed through a sieve of 75 .mu.m, and
dispersing the powder in water.
[0037] FIG. 18 shows the appearance of a suspension obtained by
crushing a vial-freeze-dried product in the vial, sifting the
powder to collect a powder obtained between sieves of 75 .mu.m and
250 .mu.m, and dispersing the powder in water.
DESCRIPTION OF EMBODIMENTS
[0038] The present invention is described below in more detail.
Naturally, "micron" indicates the same length as ".mu.m."
[0039] The present invention provides the following pharmaceutical
preparation:
a freeze-dried aripiprazole formulation obtained by a process
comprising the steps of spraying for freezing an aripiprazole
suspension containing (I) aripiprazole, (II) a vehicle for the
aripiprazole, and (III) water for injection; and drying.
[0040] This freeze-dried formulation is obtained by producing an
aripiprazole suspension containing components (I) to (III) and then
subjecting the suspension to spray-freeze-drying. The "aripiprazole
suspension" is a homogeneous suspension. The "final aripiprazole
suspension" obtained by the production process described below is
particularly preferable.
[0041] This-freeze-dried formulation is in the form of a powder,
and exhibits good dispersibility in water. Accordingly, the
freeze-dried formulation can be easily reconstituted into a
homogenous suspension by adding water. The obtained suspension has
the same properties as the suspension before being subjected to
spray-freeze-drying. In particular, when the amount of water added
for reconstitution is the same as the amount of water lost during
freeze-drying, the obtained suspension has the same constitution
and properties as the suspension before being subjected to
spray-freeze-drying.
[0042] More specifically, the freeze-dried formulation upon
reconstitution with water can form an injectable suspension that
can release aripiprazole in a therapeutic amount over a period of
at least 1 week, preferably 2, 3, or 4 weeks, and up to 6 weeks or
more, when injected (preferably intramuscularly). The injectable
suspension can release aripiprazole in a therapeutic amount for at
least 1 week, preferably at least 2 weeks, more preferably at least
3 weeks, and even more preferably at least 4 weeks.
[0043] This freeze-dried formulation is in the form of a powder.
This powder consists essentially of particles comprising (I)
aripiprazole and (II) a vehicle for the aripiprazole. Because the
freeze-dried formulation of the present invention is obtained by
spray-freeze-drying the suspension, the obtained particles usually
have a particle size of 1 mm or less. In the present specification,
the particles are sometimes referred to as "spray-freeze-dried
particles."
[0044] Although the reason is not clear, said spray-freeze-dried
particles with an excessively small particle size unexpectedly tend
to exhibit poor dispersibility, when water is added thereto for
reconstitution. The powder formulation obtained by
spray-freeze-drying usually does not contain particles with small
particle sizes in such an amount as to cause poor dispersibility,
and therefore removing the particles with small particle sizes is
not particularly required but is preferable.
[0045] That is, the freeze-dried formulation preferably consists of
particles with a particle size larger than a specific value. More
specifically, the freeze-dried formulation preferably consists of
particles with a particle size of substantially 30 .mu.m or more,
more preferably a particle size of substantially 50 .mu.m or more,
even more preferably a particle size of substantially 70 .mu.m or
more, and particularly preferably a particle size of 75 .mu.m or
more. Such a freeze-dried formulation can be obtained, for example,
by sifting the spray-freeze-dried formulation using a sieve having
a specific opening size. More specifically, for example, the
freeze-dried formulation obtained by spray-freeze-drying the
suspension is sifted using a sieve having an opening size of 30
.mu.m, and the powder that remained on the sieve was collected to
obtain a freeze-dried formulation with a particle size of
"substantially 30 .mu.m or more". The phrase "substantially 30
.mu.m or more" means "obtained by a procedure for selecting
particles of 30 .mu.m or more (e.g., sifting) and does not mean
containing no particles with a particle size of less than 30
.mu.m.
[0046] Furthermore, even if it is not a "freeze-dried formulation
consisting of particles with particle sizes larger than a specific
value", any freeze-dried formulation that does not contain
particles with small particle sizes in such an amount as to cause
poor dispersibility can be preferably used. As described above,
because the powder formulation obtained by spray-freeze-drying
usually does not contain particles with small particle sizes in
such an amount as to cause poor dispersibility, such a
spray-freeze-dried formulation is preferable. Specific examples of
such formulations include a freeze-dried formulation comprising
particles with a particle size of less than 75 .mu.m in an amount
of preferably 15 w/w % or less, more preferably 0.10 w/w % or less,
and even more preferably 8 w/w % or less. The proportion of the
particles in the formulation can be determined by sifting using a
sieve having an opening size of 75 .mu.m, collecting a portion of
the powder passing through the sieve, measuring the weight of the
portion collected, and calculating the proportion of the portion,
based on the total weight of the freeze-dried formulation.
[0047] The particle size of spray-freeze-dried particles depends on
the fineness of the mist (size of mist droplets) during spraying,
and thus can be suitably adjusted by adjusting the pressure for
spraying, orifice of the spray nozzle, etc. at the time of
spraying. Further, because the particles are produced by
spray-freeze-drying, the particles can be approximately
spherical.
[0048] The freeze-dried formulation (the spray-freeze-dried
particles) of the present invention preferably contains
aripiprazole in an amount of 50 w/w % or more, more preferably 60
w/w % or more, and even more preferably 70 w/w % or more.
[0049] The bulk density of the freeze-dried formulation of the
present invention (i.e., spray-freeze-dried particles) is
preferably 0.05 to 0.5 g/mL, more preferably 0.08 to 0.4 g/mL, and
even more preferably 0.1 to 0.3 g/mL. The bulk density herein
refers to a value obtained by pouring the freeze-dried formulation
(powder) into a graduated cylinder and measuring the volume and
weight of the formulation, and dividing the weight by the
volume.
[0050] The vehicle may include one or more suspending agents, one
or more bulking agents, and one or more buffers. More specifically,
the vehicle is at least one member selected from the group
consisting of suspending agents, bulking agents, and buffers.
[0051] The suspending agent is present in an amount of about 0.2 to
about 10 w/v %, and preferably about 0.5 to about 5 w/v %, based on
the sterile injectable formulation. The "sterile injectable
formulation" as used herein refers to a sterile homogeneous
aripiprazole suspension containing the above components (I) to
(III) (including the suspension before spray-freeze-drying and the
suspension obtained by reconstituting the freeze-dried formulation
with water). Examples of suspending agents suitable for use
include, but are not limited to, one, two, or more of the
following: sodium carboxymethyl cellulose, hydroxypropyl cellulose,
carboxymethyl cellulose, hydroxypropylethyl cellulose,
hydroxypropylmethyl cellulose, and polyvinylpyrrolidone. Among
these, sodium carboxymethyl cellulose and polyvinylpyrrolidone are
preferable.
[0052] Other suspending agents suitable for use in the vehicle for
the aripiprazole include various polymers, low-molecular-weight
oligomers, natural products, and surfactants (including nonionic
and ionic surfactants), such as cetyl pyridinium chloride, gelatin,
casein, lecithin (phosphatide), dextran, glycerol, gum acacia,
cholesterol, tragacanth, stearic acid, benzalkonium chloride,
calcium stearate, glycerol monostearate, cetostearyl alcohol,
cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene
alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000),
polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan
fatty acid esters (e.g., the commercially available Tweens
(trandemark), such as Tween 20 (trademark) and Tween 80 (trademark)
(ICI Specialty Chemicals); polyethylene glycols (e.g., Carbowaxs
3350 (trademark) and 1450 (trademark); and Carbopol 934 (Union
Carbide)), dodecyl trimethyl ammonium bromide, polyoxyethylene
stearates, colloidal silicon dioxide, phosphates, sodium
dodecylsulfate, carboxymethylcellulose ti calcium, hydroxypropyl
celluloses (e.g., HPC, HPC-SL, and HPC-L), methylcellulose,
hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl
methylcellulose phthalate, noncrystalline cellulose, magnesium
aluminum silicate, triethanolamine, polyvinyl alcohol (PVA),
4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and
formaldehyde (also known as tyloxapol, superione, and triton),
poloxamers (e.g., Pluronics F68 (trademark) and F108 (trademark),
which are block copolymers of ethylene oxide and propylene oxide);
poloxamines (e.g., Tetronic 908 (trademark), also known as
Poloxamine 908 (trademark), which is a tetrafunctional block
copolymer derived from sequential addition of propylene oxide and
ethylene oxide to ethylenediamine (BASF Wyandotte Corporation,
Parsippany, N.J.)); charged phospholipids such as dimyristoyl
phophatidyl glycerol, dioctylsulfosuccinate (DOSS); Tetronic 1508
(trademark) (T-1508) (BASF Wyandotte Corporation), dialkylesters of
sodium sulfosuccinic acid (e.g., Aerosol OT (trademark), which is a
dioctyl ester of sodium sulfosuccinic acid (American Cyanamid));
Duponol P (trademark), which is a sodium lauryl sulfate (DuPont);
Tritons X-200 (trademark), which is an alkyl aryl polyether
sulfonate (Rohm and Haas); Crodestas F-110, which is a mixture of
sucrose stearate and sucrose distearate (Croda Inc.);
p-isononylphenoxypoly-(glycidol), also known as Olin-10G
(trademark) or Surfactant 10-G (trademark)(Olin Chemicals,
Stamford, Conn.); Crodestas SL-400 (Croda, Inc.); and SA90HCO,
which is C.sub.18H.sub.37CH.sub.2
(CON(CH.sub.3))--CH.sub.2(CHOH).sub.4 (CH.sub.2OH).sub.2 (Eastman
Kodak Co.); decanoyl-N-methylglucamide; n-decyl
.beta.-D-glucopyranoside; n-decyl .beta.-D-maltopyranoside;
n-dodecyl .beta.-D-glucopyranoside; n-dodecyl .beta.-D-maltoside;
heptanoyl-N-methylglucamide; n-heptyl-.beta.-D-glucopyranoside;
n-heptyl-.beta.-D-thioglucoside; n-hexyl .beta.-D-glucopyranoside;
nonanoyl-N-methylglucamide; n-nonyl .beta.-D-glucopyranoside;
octanoyl-N-methylglucamide; n-octyl-.beta.-D-glucopyranoside; octyl
.beta.-D-thioglucopyranoside; and the like.
[0053] Most of these suspending agents are known pharmaceutical
excipients and are described in detail in the Handbook of
Pharmaceutical Excipients, published jointly by the American
Pharmaceutical Association and The Pharmaceutical Society of Great
Britain (The Pharmaceutical Press, 1986), specifically incorporated
by reference. The suspending agents are commercially available
and/or can be prepared by techniques known in the art. The
suspending agents may be used singly or in a combination of two or
more.
[0054] When the mean particle size of aripiprazole in the
suspension is about 1 micron or more, carboxymethyl cellulose or
sodium salts thereof are particularly preferable.
[0055] The bulking agent (also called "cryogenic/lyoprotectant")
can be used in such an amount as to make the sterile injectable
formulation approximately isotonic with blood at the time of
administration. More specifically, bulking agent is present in an
amount of about 1 to about 10 w/v %, preferably about 3 to about 8
w/v %, and more preferably about 4 to about 5 w/v %, based on the
sterile injectable formulation. The "sterile injectable
formulation" as used herein refers to a sterile homogeneous
aripiprazole suspension containing the above components (I) to
(III) (including the suspension before spray-freeze-drying and the
suspension obtained by reconstituting the freeze-dried formulation
with water). Examples of bulking agents suitable for use herein
include, but are not limited to, one, two, or more of the
following: mannitol, sucrose, maltose, xylitol, glucose, starches,
sorbital, and the like. When the mean particle size of aripiprazole
in the suspension is about 1 micron or more, mannitol is preferably
used.
[0056] The buffer is used in an amount to adjust the pH of the
aqueous suspension of the freeze-dried aripiprazole formulation to
about 6 to about 8, and preferably about 7. To achieve such a pH,
the buffer, depending on type, is usually used in an amount of
about 0.02 to about 2 w/v %, preferably about 0.03 to about 1 w/v
%, and more preferably about 0.1 w/v %, based on the total weight
of the sterile injectable formulation. The "sterile injectable
formulation" as used herein refers to a sterile homogeneous
aripiprazole suspension containing the above components (I) to
(III) (including the suspension before spray-freeze-drying and the
suspension obtained by reconstituting the freeze-dried formulation
with water). Examples of buffers suitable for use herein include,
but are not limited to, one, two, or more of the following: sodium
phosphate, potassium phosphate, and TRIS buffer. Among these,
sodium phosphate is preferable.
[0057] The freeze-dried formulation of the invention may optionally
contain a pH adjusting agent, which is used in an amount to adjust
the pH of the suspension before spray-freeze-drying and the aqueous
suspension of the freeze-dried aripiprazole (suspension obtained by
reconstituting the freeze-dried formulation with water) to the
range of about 6 to about 7.5, and preferably about 7, and may be
an acid or base depending upon whether the pH of the aqueous
suspension of the freeze-dried aripiprazole needs to be raised or
lowered to reach the desired neutral pH of about 7. Thus, when the
pH needs to be lowered, an acidic pH adjusting agent, such as
hydrochloric acid or acetic acid, preferably hydrochloric acid, may
be used. When the pH needs to be raised, a basic pH adjusting
agent, such as sodium hydroxide, potassium hydroxide, calcium
carbonate, magnesium oxide, or magnesium hydroxide, preferably
sodium hydroxide, is used. Such pH adjusting agents can be used
singly or in a combination of two or more.
[0058] The freeze-dried formulation of the present invention is
obtained by spray-freezing the aripiprazole suspension containing
the above components (I) to (III) to obtain spray-frozen
aripiprazole particles, and drying the spray-frozen particles.
[0059] The spray-frozen particles contain components (I) to (III)
(however, water for injection (III) is in the form of ice). When
the spray-frozen particles are further subjected to drying, the
water for injection (III) is removed from the particles to obtain
particles containing components (I) and (II) (spray-freeze-dried
particles). The spray-freeze-dried particles are porous (and may
also be described as being in the form of foams. This is presumably
because when the particles are dried, only the component
(III)-derived ice portions in the spray-frozen particles are
lost.
[0060] The spray-freeze-dried formulation is in the form of
particles comprising components (I) and (II) as described above.
The ratio of component (II) to component (I) in the particles is
the same as that in the freeze-dried suspension.
[0061] More specifically, the amount of the suspending agent is
preferably about 1 to about 5 parts by weight per 100 parts by
weight of aripiprazole, the amount of the bulking agent is
preferably about 5 to about 25 parts by weight per 100 parts by
weight of aripiprazole, and the amount of the buffer is preferably
about 0.05 to about 0.5 parts by weight per 100 parts by weight of
aripiprazole.
[0062] Porosity may presumably be one of the reasons why the
spray-freeze-dried particles have excellent dispersibility in
water. However, regardless of the particle size of
spray-freeze-dried particles, there is little difference in pore
size of the particles, etc., whereas spray-freeze-dried particles
with an excessively small particle size tend to have poor
dispersibility in water, as described above. Accordingly, it is
difficult to explain the dispersibility in water only from the
viewpoint of porosity of the particles.
[0063] The present invention further provides a process for
producing a freeze-dried formulation comprising the following
steps:
(a) preparing bulk aripiprazole having a desired particle size
distribution; (b) preparing a vehicle for the bulk aripiprazole;
(c) mixing the aripiprazole, the sterile vehicle, and water to form
a primary suspension; (d) reducing the mean particle size of
aripiprazole in the primary suspension to the range of about 1 to
about 10 microns to form a final suspension; and (e) spraying for
freezing the final suspension, and drying to form a freeze-dried
formulation.
[0064] Step (e) is a step of spray-freeze-drying the aripiprazole
suspension. More specifically, step (e) can be divided separated
into the following steps:
(e'-1) spray-freezing a suspension of aripiprazole with a mean
particle size of about 1 to about 10 microns (corresponding to the
final suspension) to obtain spray-frozen particles; and (e'-2)
drying the spray-frozen particles to obtain spray-freeze-dried
particles.
[0065] As described above, in the production process, after the
"primary aripiprazole suspension" is produced (step (c)), the mean
particle size of aripiprazole in the primary suspension is reduced
to obtain a "final aripiprazole suspension" (step (d)), and the
final suspension is spray-frozen and dried (step (e)) to obtain a
freeze-dried formulation.
[0066] The primary aripiprazole suspension as used herein simply
means a suspension obtained by mixing bulk aripiprazole with the
vehicle and water. The final aripiprazole suspension refers to a
suspension obtained by milling aripiprazole to adjust the mean
particle size of aripiprazole particles. The aripiprazole in the
final suspension has a mean particle size of about 1 to about 10
.mu.m. The final suspension is a homogeneous suspension. The
homogeneous suspension as used herein refers to a "deflocculated
suspension", which is a term used in the field of suspensions; it
does not refer to a "flocculated suspension".
[0067] In the above method, reduction of the mean particle size of
the primary suspension to a desired mean particle size is carried
out by using an aseptic wet milling procedure, which preferably is
aseptic wet ball milling. Aseptic wet milling is particularly
preferable to form a homogeneous, sterile aripiprazole formulation
of a desired mean particle size distribution.
[0068] The term "mean particle size" refers to volume mean diameter
as measured by laser-light scattering (LLS) methods. The particle
size distribution is measured by LLS methods, and the mean particle
size is calculated from the particle size distribution. The LLS
method is synonymous with the laser diffraction-scattering
method.
[0069] The present invention further encompasses a process for
producing a freeze-dried formulation comprising step (e) and a
process for producing a freeze-dried formulation comprising steps
(d) and (e), and a process for producing a freeze-dried formulation
comprising steps (c) to (e).
[0070] The "process for producing a freeze-dried formulation
comprising step (e)" can be paraphrased as follows:
a process for producing a freeze-dried aripiprazole formulation
comprising the steps of (e'-1) spray-freezing a suspension of
aripiprazole with a mean particle size of about 1 to about 10
microns to obtain spray-frozen particles; and (e'-2) drying the
spray-frozen particles to obtain spray-freeze-dried particles.
[0071] The "process for producing the freeze-dried formulation
comprising steps (d) and (e)" can be paraphrased as follows: a
process for producing a freeze-dried aripiprazole formulation
comprising
the step (d') of reducing the mean particle size of aripiprazole in
a primary suspension obtained by mixing aripiprazole, a sterile
vehicle for the aripiprazole, and water to the range of about 1 to
about 10 microns to obtain a final suspension; and the above steps
(e'-1) and (e'-2).
[0072] The "process for producing a freeze-dried formulation
comprising steps (c) to (e)" can be paraphrased as follows: a
process for producing a freeze-dried aripiprazole formulation
comprising
the step (c') of mixing aripiprazole, a sterile vehicle for the
aripiprazole, and water; and the above steps (d'), (e'-1), and
(e'-2).
[0073] The freeze-dried aripiprazole formulation of the present
invention preferably contains aripiprazole in an amount of about 1
to about 40 w/w %, more preferably about 5 to about 35 w/w %, and
even more preferably about 8 to about 30 w/w %, based on the weight
of the suspension formulation obtained by reconstitution with
water. That is, the amount of water used for reconstitution is
preferably adjusted to achieve an aripiprazole content within the
above mentioned range.
[0074] The aripiprazole preferably has a mean particle size of
about 1 to about 30 microns, more preferably about 1 to about 20
microns, and even more preferably about 1 to about 10 microns. As
described above, the "mean particle size" refers to volume mean
diameter as measured by laser diffraction-scattering methods. The
homogenous aripiprazole suspension containing components (I) to
(III) (including the suspension before spray-freeze-drying and the
suspension obtained by reconstituting the freeze-dried formulation
with water) is measured by a laser diffraction-scattering method to
determine the mean particle size of aripiprazole in the
suspension.
[0075] When the desired controlled release period is at least about
2 weeks, and preferably about 3 to about 4 weeks, the mean particle
size of the aripiprazole is within the range of about 1 to about 20
microns, preferably about 1 to about 10 microns, more preferably
about 2 to about 4 microns, and most preferably about 2.5 microns.
That is, when an injectable formulation is reconstituted from the
freeze-dried formulation of the present invention having a mean
particle size of aripiprazole within the specific range by adding
water thereto, and administered, the period of controlled release
of aripiprazole is at least 2 weeks, and may last for 6 weeks or
more. The controlled release period is preferably 2 to 4 weeks, and
more preferably 3 to 4 weeks. The aripiprazole contained in the
freeze-dried formulation of the present invention that exhibits the
above-mentioned controlled release period has a mean particle size
of about 1 to about 20 microns, preferably about 1 to about 10
microns, and more preferably about 2 to about 4 microns, and even
more preferably about 2.5 microns.
[0076] The aripiprazole having a mean particle size of about 2.5
microns has, for example, a particle size distribution as
follows:
TABLE-US-00001 TABLE 1 Preferred More Preferred 95% < 50 microns
95% < 30 microns 90% < 20 microns 90% < 15 microns 50%
< 10 microns 75% < 10 microns 10% < 2 microns 50% < 4
microns 10% < 1 micron
[0077] The method for producing the freeze-dried aripiprazole
formulation of the invention is preferably carried out with
everything being sterile. Accordingly, an aseptic procedure is used
to produce sterile bulk aripiprazole of a desired particle size
distribution. The sterile bulk aripiprazole has a mean particle
size of about 5 to about 1000 microns, and preferably about 110 to
about 500 microns.
[0078] The impinging jet crystallization method and the aseptic
crystallization method are preferably used to produce bulk sterile
aripiprazole.
[0079] The vehicle for sterile bulk aripiprazole, which contains a
suspending agent, a bulking agent, a buffer, and water and may
optionally contain a pH adjusting agent, is prepared and
sterilized. The sterile bulk aripiprazole and the sterile vehicle
are then aseptically mixed to form a sterile primary suspension.
The particle size of the aripiprazole is reduced to a desired level
by wet milling. This is preferably carried out by an aseptic wet
milling procedure wherein sterile particles of aripiprazole
dispersed in the sterile vehicle are subjected to grinding means in
the presence of grinding media to reduce the particle size of
aripiprazole to the range of preferably about 1 to about 20
microns, more preferably about 1 to about 10 microns, even more
preferably about 2 to 4 microns, and particularly preferably about
2.5 microns, depending on the desired controlled release
period.
[0080] The aseptic wet milling procedure is preferably a
high-pressure homogenizer method or wet ball milling. A
high-pressure homogenizer method is more preferable. The desired
mean particle size of aripiprazole is preferably achieved by
reducing the mean particle size in a high-shear pre-milling step
prior to wet milling using a high-pressure homogenizer, and then
reducing the mean particle size by a high-pressure homogenizer to a
desired particle size.
[0081] In addition to ball mills (such as Dyno mills) and the
high-pressure homogenizer method, other low-energy and high-energy
mills (such as a roller mill) may be used, and high-energy mills
(such as Netzsch mills, DC mills, and Planetary mills) may be used.
However, the milling procedure and equipment used are required to
be able to produce a sterile aripiprazole formulation of a desired
mean particle size.
[0082] Other techniques for particle size reduction that may be
used include aseptic controlled crystallization, high shear
homogenization, and microfluidization to produce particles having a
mean particle size in the range of about 1 to about 100 microns
(preferably about 1 to about 20 microns, more preferably about 1 to
about 10 microns, even more preferably about 2 to about 4 microns,
and particularly preferably about 2.5 microns).
[0083] The spray-freezing step of the present invention (i.e.,
spraying for freezing) may be performed according to known methods.
Examples of usable methods include, but are not limited to, a
method of spraying into liquid nitrogen, a method of spraying at
low temperatures for freezing, and a method of spraying under
reduced pressure for freezing due to heat of vaporization of the
liquid.
[0084] The step of drying the spray-frozen particles obtained by
the spray-freezing step can also be performed according to known
methods. However, drying is preferably performed while the
particles are maintained in a frozen state. Accordingly, the drying
step is preferably performed at low temperatures (the temperature
at which ice sublimes: for example, at about -5.degree. C. or
less). Furthermore, lowering the pressure in the dryer can promote
drying and is thus preferable. For example, adjusting the air
pressure to 50 Pa or less, preferably 20 Pa or less, is preferable.
More specifically, for example, the spray-frozen particles are
placed in a freeze dryer and maintained at -5.degree. C. at 20 Pa
or less for at least 24 hours to achieve drying. Before the drying,
a step of maintenance in a frozen state may be performed. For
example, before drying, spray-frozen particles may be maintained at
a low temperature (e.g., about -40.degree. C.) for about 1 to about
5 hours, and then dried. By maintaining the frozen state, even the
inside of the frozen particles can be firmly frozen. (The
spray-freeze-dried particles, including the inside thereof, are
flash-frozen when spray-dried, but just to be safe, a step of
maintaining the frozen state may be included.)
[0085] Aripiprazole may be used in a desired crystalline form.
Examples thereof include a monohydrate form (aripiprazole hydrate
A) and a number of anhydrous forms, namely, Anhydride Crystals B,
Anhydride Crystals C, Anhydride Crystals D, Anhydride Crystals E,
Anhydride Crystals F, and Anhydride Crystals G. The above crystal
forms and other crystal forms of aripiprazole and methods for
making such crystal forms are disclosed in WO 2003/26659, published
on Apr. 4, 2003.
[0086] As described above, the aripiprazole is present in an amount
of about 1 to about 40 w/v %, preferably about 5 to about 35 w/v %,
and more preferably about 8 to about 30 w/v %, in the aqueous
injectable formulation, i.e., suspension. In preferred embodiments,
the freeze-dried aripiprazole formulation is constituted with water
for injection in an amount to provide about 10 to about 800 mg,
preferably about 200 to about 600 mg of aripiprazole in a volume of
2.5 mL or less, preferably 2 mL of the formulation. More
specifically, the aripiprazole is preferably present in the aqueous
injectable formulation, i.e. suspension, in an amount of about 50
to about 800 mg/2 mL of the formulation, more preferably about 100
to about 700 mg/2 mL of the formulation, even more preferably about
160 to about 600 mg/2 mL of the formulation, and still even more
preferably about 200 to about 600 mg/2 mL of the formulation. Such
a suspension is administered-once every 2 to 6 weeks (i.e., once
every 2, 3, 4, 5 or 6 weeks), as described above. The suspension as
used herein includes the suspension before spray-freeze-drying and
the suspension obtained by reconstituting the freeze-dried
formulation with water. However, as described above, the
concentration of the reconstituted suspension varies depending on
the amount of water used for reconstitution. Accordingly, the
suspension before spray-freeze-drying, and the suspension obtained
by reconstituting the freeze-dried formulation with water do not
necessarily have the same concentration, and may have different
concentrations.
[0087] In the above process for producing the freeze-dried
formulation, the mean particle size of aripiprazole in the
aripiprazole suspension is described. Because the freeze-dried
formulation of the present invention is obtained by
spray-freeze-drying the aripiprazole suspension as described above,
the mean particle size of aripiprazole contained in the
freeze-dried formulation is the same as that of aripiprazole
contained in the suspension used for the production of the
formulation.
[0088] Accordingly, the mean particle size of aripiprazole
contained in the freeze-dried formulation (spray-freeze-dried
particles) of the present invention is preferably about 1 to about
20 microns, more preferably about 1 to about 10 microns, even more
preferably about 2 to about 4 microns, and particularly preferably
about 2.5 microns.
[0089] In the suspension obtained by reconstituting the
freeze-dried formulation of the present invention with water, the
vehicle is dissolved in water. Therefore, the mean particle size of
aripiprazole contained in the freeze-dried formulation can be
easily obtained by measuring the mean particle size of aripiprazole
in the suspension by a laser diffraction-scattering method. The
mean particle size of aripiprazole contained in the freeze-dried
formulation of the present invention is measured in this
manner.
[0090] Preferable examples of reconstituted suspension formulations
obtained by the present invention are as follows:
TABLE-US-00002 TABLE 2 Aripiprazole 100 mg 200 mg 400 mg
Carboxymethyl 9 mg 9 mg 9 mg cellulose Mannitol 45 mg 45 mg 45 mg
Sodium 0.8 mg 0.8 mg 0.8 mg phosphate Sodium q.s. to adjust q.s. to
adjust q.s. to adjust hydroxide pH to 7 pH to 7 pH to 7 Water for
q.s. to 1 ml q.s. to 1 ml q.s. to 1 ml injection
[0091] After reconstitution of the suspension formulation with
water, the aripiprazole formulation of the invention is used to
treat schizophrenia and related disorders (such as bipolar disorder
and dementia) in human patients. A preferable dosage for the
injectable formulation of the invention is about 100 to about 400
mg of aripiprazole per dose. This amount of aripiprazole is
administered by a single injection or multiple injections. The
formulation can be administered once or twice monthly. More
specifically, a preferable dosage is a single injection or multiple
injections containing about 100 to about 400 mg aripiprazole/mL
given once or twice monthly. The injectable formulation is
preferably administered intramuscularly, although subcutaneous
injection is acceptable as well.
[0092] The following Examples represent preferred embodiments of
the invention. The unit "%" for the concentration of the suspension
means "w/v %".
EXAMPLES
Preparation of 10%, 20%, and 30% Aripiprazole Suspensions
[0093] First, a 30% suspension was prepared. More specifically,
each component was dissolved or suspended in water to prepare a
suspension (primary suspension) finally containing 12.48 mg of
carboxymethyl cellulose, 62.4 mg of mannitol, and 1.11 mg of sodium
dihydrogen phosphate monohydrate, and 312.0 mg of aripiprazole
hydrate per mL of the suspension. The pH of the primary suspension
was adjusted to about 7 with sodium hydroxide. The primary
suspension was pre-milled with a shear rotary homogenizer
(Clearmix, a product of M Technique Co., Ltd.), and then repeatedly
subjected to wet milling at about 550 bar using a high-pressure
homogenizer (a product of Niro) to achieve a mean particle size of
aripiprazole of 3 .mu.m or less, thus providing a suspension (final
suspension) of about 30% aripiprazole. The 30% aripiprazole
suspension was diluted with water to prepare a 10% suspension and a
20% suspension.
Spray-Freeze-Drying of the Suspensions
[0094] About 100 mL of each suspension of these different
concentrations was placed into each spraying bottle (product
number: 4-5002-01, a product of AS ONE Corporation, type that
sprays by squeezing a trigger by hand). Liquid nitrogen was placed
on an aluminum tray of about 250 mm.times.about 300 mm to a depth
of about 10 mm. Each suspension was sprayed over the liquid
nitrogen surface from a height of about 200 mm until each spraying
bottle was empty. As a result, each of the suspensions sprayed into
liquid nitrogen was frozen in the form of grains to form
spray-frozen particles. After spraying and before liquid nitrogen
had volatilized off from the aluminum tray, the tray over which
each suspension of the different concentrations was sprayed was
transferred to a shelf of a freeze dryer pre-cooled to -40.degree.
C. to start freeze-drying. The freeze-drying conditions were as
follows:
(a) Maintenance of the frozen state: the product was maintained at
-40.degree. C. for at least 3 hours. (b) Drying: the chamber
pressure was adjusted to about 20 Pa or less, the shelf temperature
was raised to about 5.degree. C., and drying was continued under
these conditions for at least 24 hours.
[0095] In this Example, the freezing step was performed by spraying
into liquid nitrogen. However, insofar as spray-freezing can be
performed, the method is not limited thereto. For example, a method
comprising spraying at a low temperature for freezing, and a method
comprising spraying under reduced pressure for freezing due to heat
of vaporization of the liquid can be used.
Sifting of the Obtained Freeze-Dried Products
[0096] After freeze-drying, each of the obtained freeze-dried
products was placed on a sieve with a diameter of 80 mm and with a
mesh size (i.e., an opening size) of 1000 .mu.m. Sieves with mesh
sizes of 500 .mu.m, 250 .mu.m, and 75 .mu.m were stacked together
below the sieve with a mesh size of 1000 .mu.m, and sifting was
performed. The freeze-dried products that remained between the
sieves of 75 .mu.m and 250 .mu.m, those that remained between the
sieves of 250 .mu.m and 500 .mu.m, and those that remained between
the sieves of 500 .mu.m and 1000 .mu.m were collected. Hereinafter,
the freeze-dried product (particles) that remained between sieves
of specific mesh sizes and collected therefrom may also be
described as "particles collected between sieves of a smaller mesh
size and a larger mesh size". For example, the freeze-dried product
that remained between the sieves of 75 .mu.m and 250 .mu.m and
collected therefrom is described as "particles collected between
sieves of 75 .mu.m and 250 .mu.m".
[0097] The sieves used herein are sieves of Japanese Pharmacopoeia
16th edition Sieve No. 200 (opening size: 75 .mu.m), No. 60
(opening size: 250 .mu.m), No. 30 (opening size: 500 .mu.m), and
No. 16 (opening size 1000 .mu.m).
Evaluation 1 of the Obtained Freeze-Dried Products
[0098] The obtained freeze-dried products were observed with a
scanning electron microscope. FIGS. 1 to 9 show the results. FIGS.
1 to 3 show the results of freeze-dried products obtained using the
10% suspension. FIGS. 4 to 6 show the results of freeze-dried
products obtained using the 20% suspension. FIGS. 7 to 9 show the
results of freeze-dried products obtained using the 30% suspension.
FIGS. 1, 4, and 7 show the appearance (photo on the left) and
surface condition (photo on the right) of the particles collected
between the sieves of 75 .mu.m and 250 .mu.m. FIGS. 2, 5, and 8
show the appearance (photo on the left) and surface condition
(photo on the right) of the particles collected between the sieves
of 250 .mu.m and 500 .mu.m. FIGS. 3, 6, and 9 show the appearance
(photo on the left) and surface condition (photo on the right) of
the particles collected between the sieves of 500 .mu.m and 1000
.mu.m. All of the freeze-dried products appeared to be
approximately spherical and porous. FIGS. 1 to 9 illustrate
50.times. magnifications of the appearance (photo on the left) and
2500.times. magnifications of the surface condition (photo on the
right).
[0099] The bulk density of the obtained freeze-dried products was
measured. More specifically, the freeze-dried product (powder) was
inserted into a 25-mL graduated cylinder up to the 5-mL mark, and
the inserted powder weight was measured to calculate the bulk
density. As a result, the bulk density was about 0.1 to about 0.3
g/mL.
[0100] About 325 mg of each powder (about 250 mg in terms of
aripiprazole) was weighed out and placed into glass vials. Water
for injection was added thereto in an amount to prepare an
aripiprazole suspension of approximately 20%. Each vial was capped
with a rubber stopper and shaken by hand to obtain a resuspension
(i.e., a suspension reconstituted by adding water for injection).
The powder was easily resuspended just like the vial-freeze-dried
product (corresponding to the cake-form freeze-dried aripiprazole
formulation disclosed in WO2005/041937) with no observation of
powder agglomerates due to poor dispersion.
[0101] The resuspension in the vial was sucked from the vial using
a needle-unattached plastic syringe having an orifice portion with
an inner diameter of about 1.7 mm to which a needle is to be
attached. No powder remaining due to poor dispersion was observed
in the vial after sucking. A 27 G needle (inner diameter: 0.22 mm)
was attached to this syringe to eject the suspension. The
suspension was ejected without needle clogging. The results
confirmed that the obtained resuspension of the freeze-dried
product contained no powder agglomerates with a size of 1.7 mm or
more, and no aggregates that may cause clogging of a needle with an
inner diameter of 0.22 mm were formed.
[0102] The mean particle size after resuspension was measured hy a
SALD-3100 laser diffraction particle size distribution analyzer,
produced by Shimadzu Corporation. The measurement was performed
using a circulation cell with a refractive index of 2.00-0.20i
using water as a medium for measurement. More specifically, 330 mL
of water was circulated through a sensing station within a
measuring apparatus, and about 0.05 mL of the suspension to be
measured was added thereto and measured. The suspension was
ultrasonically treated for 1 minute using an ultrasonic generator
accompanying the particle size distribution analyzer of the
suspension. The mean particle size of the suspension after the
ultrasonication was measured in the same manner as above. When a
reduction in mean particle size of 0.5 .mu.m or more was observed
in the measurement with ultrasonic treatment, it was assessed as
"aggregated". In the present invention, the term "mean particle
size" refers to a volume mean diameter as measured by a laser-light
scattering (LLS) method. i.e., a laser diffraction-scattering
method. Particle size distribution was measured by this method, and
mean particle size was calculated from the particle size
distribution. Table 3 shows the measurement results. The
measurement results indicate that no aggregation was observed in
any case and that all the freeze-dried products were resuspended
with good redispersibility.
TABLE-US-00003 TABLE 3 Mean particle size after re-dispersion
(.mu.m) Measured without Measured with Mesh sizes of the sieves
Bulk density ultrasonic ultrasonic Suspension used for collection
(g/mL) treatment treatment 10% 75 .mu.m and 250 .mu.m 0.131 1.92
1.98 250 .mu.m and 500 .mu.m 0.123 Not measured Not measured 500
.mu.m and 1000 .mu.m 0.107 Not measured Not measured 20% 75 .mu.m
and 250 .mu.m 0.178 1.97 1.96 250 .mu.m and 500 .mu.m 0.170 Not
measured Not measured 500 .mu.m and 1000 .mu.m 0.147 Not measured
Not measured 30% 75 .mu.m and 250 .mu.m 0.266 1.98 1.98 250 .mu.m
and 500 .mu.m 0.238 Not measured Not measured 500 .mu.m and 1000
.mu.m 0.200 2.06 2.06
Evaluation 2 of the Obtained Freeze-Dried Products
[0103] A 10% aripiprazole suspension was spray-freeze-dried in the
same manner as above to obtain a freeze-dried product. The
freeze-dried product was transferred onto a sieve with a mesh size
of 250 .mu.m and a diameter of 80 mm. A sieve with a mesh size of
75 .mu.m was placed below the sieve with a mesh size of the 250
.mu.m, and a tray was provided under the sieve with a mesh size of
75 .mu.m. The freeze-dried product was sifted thereby. The
freeze-dried product that remained between the sieves of 75 .mu.m
and 250 .mu.m, and the freeze-dried product that passed through the
sieve of 75 .mu.m and remained on the tray were collected.
[0104] As a comparative example, a freeze-dried product was
prepared by freeze-drying a suspension in a vial (vial-freeze-dried
product). More specifically, the freeze-dried product was produced
in the following manner.
[0105] First, a 10% suspension was prepared in the following
manner. More specifically, each component was dissolved or
suspended in water to prepare a suspension (primary suspension)
finally containing 4.16 mg of carboxymethyl cellulose, 20.8 mg of
mannitol, and 0.37 mg of sodium dihydrogen phosphate monohydrate,
and 104.0 mg of aripiprazole hydrate, per mL of the suspension. The
pH of the primary suspension was adjusted to about 7 with sodium
hydroxide. The primary suspension was pre-milled with a shear
rotary homogenizer (Clearmix, a product of M Technique Co., Ltd.),
and then repeatedly subjected to wet milling at about 550 bar using
a high-pressure homogenizer (a product of Niro) to achieve a mean
particle size of aripiprazole of 3 .mu.m or less. A suspension
(final suspension) of about 10% aripiprazole was thereby obtained.
The final suspension was the same as the 10% suspension obtained in
the above "preparation of the 10%, 20%, and 30% aripiprazole
suspensions".
[0106] A 4.75 mL quantity of this suspension was placed in a glass
vial with a diameter of 23 mm and a height of 43 mm and
freeze-dried under the following conditions:
(a) Maintenance of the frozen state: the product was maintained at
-40.degree. C. for at least 3 hours. (b) Drying: the chamber
pressure was adjusted to about 20 Pa or less, the shelf temperature
was raised to -5.degree. C., and drying was continued under these
conditions for at least 24 hours.
[0107] After freeze-drying, a vial-freeze-dried product was
obtained. The vial-freeze-dried product corresponds to the
cake-form freeze-dried aripiprazole formulation disclosed in
WO2005/041937.
[0108] The vial-freeze-dried product was crushed into a powder in
the vial with a spatula. The obtained powder was removed from the
vial and transferred onto a sieve with a mesh size of 250 .mu.m and
a diameter of 80 mm. A sieve with a mesh size of 75 .mu.m was
placed below the sieve with a mesh size of the 250 .mu.m, and a
tray was provided under the sieve with a mesh size of 75 .mu.m. The
freeze-dried product was sifted thereby. The freeze-dried product
that remained between the sieves of 75 .mu.m and 250 .mu.m, and the
freeze-dried product that passed through the sieve of 75 .mu.m and
remained on the tray were collected.
<Microscopic Observation>
[0109] Each of the freeze-dried products collected was observed
with a scanning electron microscope. FIGS. 10 to 13 show the
results. FIGS. 10 and 11 show the results of the spray-freeze-dried
product. FIGS. 12 and 13 show the results of the powder obtained
from the vial-freeze-dried product. FIGS. 10 and 12 show the
appearance (photo on the left) and surface condition (photo on the
right) of the particles collected between the sieves of 75 .mu.m
and 250 pin. FIGS. 11 and 13 show the appearance (left) and surface
condition (photo on the right) of the particles that passed though
the sieve of 75 .mu.m. FIGS. 10 to 13 illustrate 200.times.
magnifications of the appearance (photo on the left) and
2500.times. magnifications of the surface condition (photo on the
right).
[0110] The particles of the spray-freeze-dried product that passed
through the sieve of 75 .mu.m and those that remained on the sieve
of 75 .mu.m were both spherical and porous. There was no difference
therebetween in the surface condition.
[0111] With respect to the particles of the powder obtained by
crushing the vial-freeze-dried product, the particles that passed
through the 75 .mu.m sieve and those that remained on the sieve of
75 .mu.m were both irregularly shaped. There was no difference
therebetween in the surface condition.
<Evaluation of Dispersibility in Water>
[0112] The powders obtained by sifting were placed in vials with a
diameter of 23 mm and a height of 43 mm in an amount such that each
vial contained about 475 mg of aripiprazole. Each vial was capped
with a rubber stopper. The freeze-dried product obtained by
spray-freeze-drying contained only a very small amount of particles
that passed through the sieve of 75 .mu.m. Accordingly, sifting was
repeated many times to collect the particles in an amount of about
475 mg in terms of aripiprazole.
[0113] On the assumption that vibration would occur due to
transport, the bottom of each vial was lightly tapped 5 times.
Thereafter, the rubber stopper was removed and 1.9 mL of water was
added to the vial. After the vial was capped again with the rubber
stopper, the vial was gently shaken by hand 5 times. After shaking,
the rubber stopper was removed and the vial was inverted to remove
the contents from the vial. Air was lightly blown onto the contents
and the dispersibility in water was observed. The vial-freeze-dried
product before being crushed with a spatula (i.e., cake-form
freeze-dried product) was also investigated in the same manner as
above. FIGS. 14 to 17 show the observation results.
[0114] The (cake-form) vial-freeze-dried product was easily
redispersed without problems, and no agglomerates were observed in
the suspension removed from the vial (FIG. 14).
[0115] The powder obtained by sifting the spray-freeze-dried
product and collected between the sieves of 75 .mu.m and 250 .mu.m
was also easily redispersed without problems, and no agglomerates
were observed in the suspension removed from the vial (FIG. 15).
However, the powder that passed through the sieve of 75 .mu.m was
not completely redispersed and some remained in a powder state
(FIG. 16).
[0116] The powder obtained by crushing the vial-freeze-dried
product in the vial and sifting was not easily redispersed and some
of the powder remained in a powder state, whether the powder
particles passed through the sieve of 75 mm or were collected
between the sieve of 75 mm and 250 mm (FIG. 17: powder of less than
75 mm, FIG. 18: powder of 75 mm to 250 mm).
[0117] The above results indicated that the powder obtained by
crushing a vial-freeze-dried product exhibits poor dispersibility
in water, irrespective of the particle size, and that the powder
obtained by spray-freeze-drying the suspension exhibits good
dispersibility in water when the particles have a diameter larger
than a certain level. In the field of freeze-drying, it is thought
that as freezing speed increases and the volume of liquid to be
frozen decreases, smaller ice crystals are formed, which inhibits
agglomeration of particles (see, for example, Journal of
Pharmaceutical Sciences, Vol. 92, No. 2, 319-332 (2003)).
Therefore, in spray-freeze-drying that enables quick freeze-drying
of small droplets, it is predicted that as the size of the obtained
particles is smaller, agglomeration of particles is more
effectively inhibited. Therefore, the obtained results were
unexpected.
[0118] In the powder obtained by spray-freeze-drying, small
particles were scarcely present. Therefore, sifting to remove the
particles with a small particle size is not particularly necessary,
and the obtained powder exhibited practical dispersibility even
without sifting (i.e., the powder exhibited good dispersibility and
a homogeneous suspension was obtained).
* * * * *