NZ719452B2 - High-speed centrifugal mixing devices and methods of use - Google Patents
High-speed centrifugal mixing devices and methods of use Download PDFInfo
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- NZ719452B2 NZ719452B2 NZ719452A NZ71945214A NZ719452B2 NZ 719452 B2 NZ719452 B2 NZ 719452B2 NZ 719452 A NZ719452 A NZ 719452A NZ 71945214 A NZ71945214 A NZ 71945214A NZ 719452 B2 NZ719452 B2 NZ 719452B2
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- canister
- pulley
- turret
- axis
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- 230000007704 transition Effects 0.000 claims description 36
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Classifications
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- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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Abstract
Preferred embodiments of the present invention seek to provide a lighter centrifugal device that is capable of achieving greater speeds. A centrifugal mixing device can include a shaft assembly that is operably coupled to a motor such that the motor rotates the shaft assembly about a first axis. The devices can further include a turret that is rotatably coupled to the shaft assembly such that the turret rotates about the first axis relative to the shaft assembly. The turret can include a first support, a first canister rotatably coupled to the first support such that the first canister rotates about a second axis, and a second canister rotatably coupled to the first support such that the second canister rotates about a third axis. The turret can further include a second support spaced from the first support along the first axis, the first and second canisters being rotatably coupled to both the first support and the second support. The turret is configured to rotate about the first axis in a first rotational direction and each of the first and second canisters is configured to rotate about the second and third axes, respectively, in a second rotational direction that is opposite the first rotational direction. e devices can further include a turret that is rotatably coupled to the shaft assembly such that the turret rotates about the first axis relative to the shaft assembly. The turret can include a first support, a first canister rotatably coupled to the first support such that the first canister rotates about a second axis, and a second canister rotatably coupled to the first support such that the second canister rotates about a third axis. The turret can further include a second support spaced from the first support along the first axis, the first and second canisters being rotatably coupled to both the first support and the second support. The turret is configured to rotate about the first axis in a first rotational direction and each of the first and second canisters is configured to rotate about the second and third axes, respectively, in a second rotational direction that is opposite the first rotational direction.
Description
HIGH-SPEED CENTRIFUGAL MIXING DEVICES AND METHODS OF USE
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims benefit of U.S. Ser. No. 14/059,837 filed October 22,
2013, the entire contents of which is hereby incorporated by reference herein.
TECHNICAL FIELD
The present inventions relate generally to centrifugal mixing devices, methods
of using them, and mixtures produced by such methods.
BACKGROUND
Centrifugal processing devices have been used to separate liquids and/or to
finish or otherwise smooth surfaces of different objects. Some of these processing devices have
an outer vessel and a turret within the outer vessel that is rotated about the axis of the outer
vessel. The turret includes at least one inner vessel that rotates about its own axis as the turret
rotates about the axis of the outer vessel. In particular, a frictional force between the inner vessel
and the outer vessel causes the inner vessel to rotate in a rotational direction that is opposite the
rotational direction of the turret as the turret is rotated about the outer vessels axis. The contents
of the inner vessels of such processing devices are subjected to an acceleration several hundred
times that associated with gravity (“g”). While these devices are useful for finishing objects
and/or separating liquids, their utility for applications such as processing particulate materials
such as pharmaceuticals could be improved by increasing the acceleration to which their contents
are subjected. Furthermore, there is a need for devices of this type in which substantially the
same forces and accelerations act on the contents of the mixing device.
SUMMARY
The present invention provides centrifugal mixing devices, particularly those
that are capable of repeatably forming mixtures of particulate materials.
In accordance with certain embodiments of the present invention, a centrifugal
mixing device comprises a shaft assembly that is elongate along a first axis and is configured to
be operably coupled to a motor such that the motor rotates the shaft assembly about the first axis.
The device further comprises a turret that is rotatably coupled to the shaft assembly such that the
turret is configured to rotate about the first axis relative to the shaft assembly. The turret can
include a first support, a first canister rotatably coupled to the first support on a first side of the
shaft assembly such that first canister rotates about a second axis, and a second canister rotatably
coupled to the first support on a second side of the shaft assembly such that the second canister
rotates about a third axis. The turret can further include a second support spaced from the first
support along the first axis, the first and second canisters being rotatably coupled to both the first
support and the second support. The turret can be configured to rotate about the first axis in a
first rotational direction and each of the first and second canisters are configured to rotate about
the second and third axes, respectively, in a second rotational direction that is opposite the first
rotational direction.
In accordance with other embodiments, the centrifugal mixing device comprises
a shaft assembly that includes a shaft body that is elongate along a first axis and is configured to
be operably coupled to a motor such that the motor rotates the shaft assembly about the first axis,
and a first shaft pulley that is rigidly fixed to the shaft body. The device further comprises a
turret that is rotatably coupled to the shaft body and includes a first canister that has a first
canister pulley and is rotatable about a second axis, and a second canister that has a second
canister pulley and is rotatable about a third axis. The turret further includes a first support and a
second support, and wherein the first canister is rotatably coupled to the first and second supports
on a first side of the shaft assembly and the second canister is rotatably coupled to the first and
second supports on a second side of the shaft assembly. The device further comprises a first
drive belt that is in communication with the first shaft pulley, the first canister pulley, and the
second canister pulley such that rotation of the shaft assembly by the motor causes the first and
second canisters to rotate about the second and third axes, respectively. The first shaft pulley,
the first canister pulley, and the second canister pulley are each sized such that an acceleration of
at least 600 g is imposed on material retained in the first and second canisters when the motor
rotates the shaft assembly about the first axis.
In accordance with other aspects of the invention, methods of operating the
device can comprise the steps of: providing a centrifugal mixing device according to the
previously described aspect; placing in said first canister at least three substantially spherical
members, a first particulate material, and at least a second particulate material; rotating the turret
about the first axis in a first direction at a first rotational speed; rotating the first canister about
the second axis in a second direction opposite the first direction at a second rotational speed;
causing each member to contact an inner surface within the first canister such that a substantially
constant force is applied against the inner side surface as the turret rotates at the first rotational
speed and as the first canister rotates at the second rotational speed; and causing the first and
606099049.2
second particulates to move between the members and inner surface such that at least one of the
first and second particulates is impregnated by the other.
Pharmaceutical compositions prepared by processes in accordance with the
invention are also provided.
BRIEF DESCRIPTION OF THE DRAWINGS
The foregoing summary, as well as the following detailed description, will be
better understood when read in conjunction with the appended drawings, which show exemplary
embodiments for the purposes of illustration. It should be understood, however, that the
application is not limited to the precise arrangements and systems shown. In the drawings:
Fig. 1A is a top perspective view of a centrifugal mixing device in accordance
with an embodiment of the invention, the centrifugal mixing device including a shaft assembly, a
motor coupled to the shaft assembly, and a turret rotatably coupled to the shaft assembly;
Fig. 1B is a side view of the centrifugal device shown in Fig. 1A;
Fig. 1C is a cross-sectional view of the centrifugal device shown in Fig. 1B
through the line 1C-1C and showing first and second canisters of the turret that are each
configured to retain material;
Fig. 2A is a perspective view of the turret and shaft assembly of the device
shown in Fig. 1A;
Fig. 2B is a side view of the turret and shaft assembly shown in Fig. 2A; and
Fig. 2C is a cross-sectional view of the turret and shaft assembly shown in Fig.
2B through the line 2C-2C.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
The present subject matter may be understood more readily by reference to the
following detailed description which forms a part of this disclosure. Unless otherwise defined
herein, scientific and technical terms used in connection with the present application shall have
the meanings that are commonly understood by those skilled in the art. Further, unless otherwise
required by context, singular terms shall include pluralities and plural terms shall include the
singular.
Certain terminology is used in the following description for convenience only
and is not limiting. The words "right", "left", "lower" and "upper" designate directions in the
drawings to which reference is made. The words “proximally” and “distally” refer to directions
606099049.2
toward and away from, respectively, the specific component being described. The terminology
includes the above-listed words, derivatives thereof, and words of similar import.
Referring to Figs. 1A-1C, a centrifugal mixing device 10 according to the
invention can include a motor 14, a shaft assembly 18 that is elongate along a first axis A and is
operably coupled to the motor 14 such that the motor 14 rotates the shaft assembly 18 about the
first axis A , and a turret 22 that is rotatably coupled to the shaft assembly 18 such that the turret
22 is configured to rotate about the first axis A relative to the shaft assembly 18. As shown in
Fig. 1C, the turret 22 includes a first support 26, a first canister 30 rotatably coupled to the first
support 26 on a first side of the shaft assembly 18 and a second canister 34 rotatably coupled to
the first support 26 on a second side of the shaft assembly 18. In the illustrated embodiment, the
first and second canisters 30 and 34 are on opposed sides of the shaft assembly 18. It should be
appreciated, however, that the first and second canisters 30 and 34 can be located on any side of
the shaft assembly 18 and that the centrifugal mixing device 10 can include any number of
canisters as desired. For example, the centrifugal mixing device 10 can include one canister or
two or more canisters as desired.
With continued reference to Fig. 1C, the first canister 30 is configured to rotate
about a second axis A and the second canister 34 is configured to rotate about a third axis A
both of which are parallel to the first axis A . Each of the first and second canisters 30 and 34 is
configured to receive at least three spherical members 38, a first particulate material, and at least
a second particulate material. The turret 22 is configured to rotate about the first axis A in a
first rotational direction at a first rotational speed and each of the first and second canisters 30
and 34 are configured to rotate about the second and third axes A and A , respectively, in a
second rotational direction that is opposite the first rotational direction at second and third
rotational speeds, respectively. Rotation of the turret 22 and the canisters 30 and 34 will cause
each spherical member 38 to contact an inner surface within each canister 30 and 34 such that a
substantially constant force is applied against the inner surfaces as the turret 22 rotates at the first
rotational speed and as the first and second canisters 30 and 34 rotate at the second and third
rotational speeds. The particulates within the first and second canisters 30 and 34 will move
between the members 38 and the inner surfaces such that at least one of the first and second
particulates is impregnated with the other. Typically, the softer of the particulates will be
impregnated by the other(s). It should be appreciated, however, that the potential exists for the
softer of two particulates to effect impregnation. In this regard, impregnation according to the
present invention can involve, but does not require, a portion of one type of particulate extending
606099049.2
into a portion of another type of particulate. For example, one type of particulate can be
impregnated by another by fully surrounding or partially surrounding it. Thus, impregnation
according to the present invention is effected where at least two different type of particulates are
sufficiently conjoined that they exhibit the physical properties of a single type of particulate
when exposed to normal material handling procedures such as sieving and pouring.
The centrifugal mixing device 10 is configured to reach high rotational speeds
and can thus subject the contents of the first and second canisters 30 and 34 to a high
accelerations. For example, the first rotational speed can be between about 100 rpm and about
1750 rpm and the second and third rotational speeds can be between about 140 rpm and about
2550 rpm. Preferably the first rotational speed is about 1750 rpm and the second and third
rotational speeds are about2500 rpm. It should be appreciated, however, that the first, second,
and third rotational speeds can be the same or different from each other. It should be further
appreciated that although it is preferred that the first and second canisters 30 and 34 rotate at the
same rotational speed, the first and second canisters 30 and 34 can be configured to rotate at
different speeds relative to teach other, as desired.
The centrifugal mixing device 10 is configured such that rotation of the turret 22
and the canisters 30 and 34 subjects the contents of the canisters 30 and 34 to an acceleration of
at least 600 g. For example, the centrifugal mixing device 10 can be configured such that the
contents of the canisters 30 and 34 are subjected to an acceleration of between about 600 g and
about 750 g and preferably to an acceleration of about 691 g. The high acceleration that the
contents experience and the substantially constant force provided by the spherical members 38
allow the centrifugal mixing device 10 to make certain pharmaceutical compositions. In certain
embodiments, for example, melanin and/or a melanin promoter can be processed with one or
more particulate cancer drugs. FDA-approved cancer drugs that are amenable to such processing
include selective estrogen receptor modulators such as tamoxifen, toremifene (Fareston®), and
fulvestrant (Faslodex®); aromatase inhibitors such as anastrozole (Arimidex®), exemestane
(Aromasin®), and letrozole (Femara®); signal transduction inhibitors such as imatinib mesylate
(Gleevec®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), lapatinib
(Tykerb®), gefitinib (Iressa®), erlotinib (Tarceva®), temsirolimus (Torisel®), everolimus
(Afinitor®), vandetanib (Caprelsa®), vemurafenib (Zelboraf®), and crizotinib (Xalkori®); drugs
that modify the function of proteins that regulate gene expression and other cellular functions,
such as vorinostat (Zolinza®), romidepsin (Istodax®), bexarotene (Targretin®), alitretinoin
(Panretin®), tretinoin (Vesanoid®); drugs that induce cancer cells to undergo apoptosis, such as
606099049.2
bortezomib (Velcade®), carfilzomib (Kyprolis™), and pralatrexate (Folotyn®); and drugs that
interfere with angiogenesis, such as sorafenib (Nexavar®), sunitinib (Sutent®), pazopanib
(Votrient®), Regorafenib (Stivarga®), and cabozantinib (Cometriq™). Additional cancer drugs
amenable to the present invention include denileukin diftitox (Ontak®), ziv-aflibercept
(Zaltrap®), cisplatin, cisplatinum, (cis-diamminedichloroplatinum(II)), carboplatin, oxaliplatin,
benzyl isothiocyanate, acetylcholine, and dihydrotestosterone (DHT). It should be appreciated,
however, that other drugs that exist in particulate form may be amenable to processing in
accordance with the present invention.
Now in reference to Figs. 2A-2C, the shaft assembly 18 includes a shaft body 42
that is elongate along the first axis A , a first shaft pulley 46 fixed to the shaft body 42, and a
second shaft pulley 50 fixed to the shaft body 42 and spaced from the first shaft pulley 46 along
the first axis A . The first shaft pulley 46 is configured to be operatively coupled to the first and
second canisters 30 and 34, for example, via a single belt such that as the shaft assembly 18 is
rotated about the first axis A by the motor 14, the first and second canisters 30 and 34 are driven
to be rotated about the second and third axes A and A , respectively, by the belt. Similarly, the
second shaft pulley 50 is operatively coupled to the turret 22, for example via a series of belts,
such that as the shaft assembly 18 is rotated about the first axis A by the motor 14, the turret 22
is driven to be rotated about the first axis A relative to the shaft body 42 by the series of belts.
In this way a single motor can be used to drive the turret 22 to rotate about the first axis A and
separately drive the first and second canisters 30 and 34 to rotate about the second and third axes
A and A . It should be appreciated, however, that in some embodiments the canisters 30 and 34
can be driven by a separate motor or motors than the motor that causes the turret 22 to rotate, and
that any number of belts can be used to transfer the rotational motion of the shaft assembly 18 to
the turret 22 and to the first and second canisters 30 and 34.
With continued reference to Figs. 2A-2C, the turret 22 further includes a second
support 44 spaced from the first support 26 along the first axis A and a turret pulley 48 that is
rigidly coupled to the first support 26 and rotatably coupled to the shaft assembly 18 such that
rotation of the turret pulley 48 causes the first and second supports 26 and 44 to rotate about the
first axis A relative to the shaft assembly 18. As shown in Fig. 2C, the first and second canisters
and 34 are rotatably coupled to the first and second supports 26 and 44. Thus, as the first and
first and second supports 26 and 44 are rotated about the first axis A the first and second
canisters 30 and 34 are also rotated about the first axis A .
606099049.2
As shown in Fig. 2C, while rotating about the first axis A the first canister 30 is
configured to rotate about the second axis A and the second canister 34 is configured to rotate
about the third axis A . As shown, the first canister 30 includes a first canister shaft 52 that is
rotatably coupled to the first support 26 and a first canister pulley 54 that is rigidly fixed to the
first canister shaft 52. Similarly, the second canister 34 includes a second canister shaft 58 that
is rotatably coupled to the first support 26 and a second canister pulley 62 that is rigidly fixed to
the second canister shaft 58. The first and second canister pulleys 54 and 62 are positioned such
that the first shaft pulley 46 is located between the first and second canister pulleys 54 and 62.
With continued reference to Fig. 2C, the centrifugal mixing device 10 further
includes a first drive belt 68 that is in communication with the first shaft pulley 46 and the first
and second canister pulleys 54 and 62 such that the first drive belt 68 drives the first and second
canister pulleys 54 and 62 to rotate the first and second canisters 30 and 34 about the second and
third axes A and A , respectively when the motor 14 causes the first shaft pulley 46 to rotate
about the first axis A . To maintain the first drive belt 68 in tension, the turret 22 further
includes a first tension pulley 72 and a second tension pulley 76 also in communication with the
first drive belt 68. As shown in Fig. 2C, the first tension pulley 72 is supported by the first
support 26 between the first shaft pulley 46 and the first canister pulley 54 and the second
tension pulley 76 is supported by the first support 26 between the first shaft pulley 46 and the
second canister pulley 62. As shown in Fig. 2A, the first drive belt 68 is maintained in tension
by the first and second tension pulleys 72 and 76 as it is placed in communication with the first
shaft pulley 46 and the first and second canister pulleys 54 and 62. Therefore, as the first shaft
pulley 46 drives the first drive belt 68, the first drive belt 68 will drive the first and second
canister pulleys 54 and 62. In this way, the motor 14 can drive the first and second canister
pulleys 54 and 62 to thereby cause the first and second canisters 30 and 34 to rotate about the
second and third axes A and A , respectively. Thus, rotation of the shaft assembly 18 is
transferred to the first and second canisters 30 and 34.
Referring back to Figs. 1A and 1B, the centrifugal mixing device 10 can further
include a transition member 80 configured to transfer rotational motion of the shaft assembly 18
to the turret 22 to thereby cause the turret 22 to rotate about the first axis A relative to the shaft
body 42. As shown in Fig. 1B, the transition member 80 can include a transition shaft 82, a first
transition pulley 84 fixed to the transition shaft 82, and a second transition pulley 88 fixed to the
transition shaft 82 such that both the first transition pulley 84 and the second transition pulley 88
together rotate about a fourth axis A when the shaft assembly 18 is driven by the motor 14. As
606099049.2
illustrated, the mixing device 10 can further include a second drive belt 92 that is in
communication with the second shaft pulley 50 and the first transition pulley 84 such that the
second drive belt 92 drives the first transition pulley 84 to rotate the transition member 80 about
the fourth axis A when the motor 14 causes the second shaft pulley 50 to rotate about the first
axis A . As further illustrated, the mixing device 10 can additionally include a third drive belt 96
that is in communication with the second transition pulley 88 and the turret pulley 48 such that
the third drive belt 96 drives the turret pulley 48 to rotate the turret 22 about the first axis A
when the motor 14 causes the transition member 80 to rotate about the fourth axis A . As shown
in Fig. 1B, the centrifugal mixing device 10 can further include a pair of tension pulleys 102 that
maintain the second and third drive belts 92 and 96 in tension.
In the illustrated embodiment, the turret pulley 48, the first and second transition
pulleys 84 and 88, the first and second shaft pulleys 46 and 50, and the first and second canister
pulleys 54 and 62 each has a respective diameter such that an acceleration of at least 600 g,
preferably between about 600 g and about 750 g, and even more preferably of about 691 g is
imposed on material (e.g. the spherical members and particulates) retained in the first and second
canister 30 and 34 when the motor 14 rotates the shaft assembly 18. Furthermore, the first,
second, and third belts 68, 92, and 96 are oriented such that the turret 22 rotates in a first
direction and the first and second canisters 30 and 34 rotate in a second direction that is opposite
the first direction. It should be appreciated, however, that in certain embodiments the pulleys 46,
48, 50, 54, 62, 84, and 88 can have respective diameters that result in other operating parameters
as desired and that the belts 68, 92, and 96 can be oriented such that the turret 22 and canisters 30
and 34 rotate in the same rotational direction. It should be further appreciated that the resultant
desired parameters may depend on the size, type, and/or number of particulate materials being
combined.
Referring back to Fig. 2C, the first canister 30 further includes a first canister
housing 106 that is rigidly coupled to the first canister shaft 52 and rotatably coupled to the
second support 44. Therefore, the first canister 30 can be rotatably supported by both the first
and second supports 26 and 44. As shown in Fig. 2C, the first canister 30 can further include a
first removable vessel 110 that is housed within the first canister housing 106 and a first lid 114
that is removably attached to the first canister housing 106 to thereby selectively retain the first
removable vessel 110 within the first canister housing 106. The first lid 114 can be fixed to the
first canister housing 106 with attachment members 118, illustrated as bolts. It should be
606099049.2
appreciated, however, that the first lid 114 can be fixed to the first canister housing 106 with any
attachment member as desired.
Similarly, the second canister 34 further includes a second canister housing 126
that is rigidly coupled to the second canister shaft 58 and rotatably coupled to the second support
44. Therefore, the second canister 34 can be rotatably supported by both the first and second
supports 26 and 44. As shown in Fig. 2C, the second canister 34 can further include a second
removable vessel 130 that is housed within the second canister housing 126 and a second lid 134
that is removably attached to the second canister housing 126 to thereby selectively retain the
second removable vessel 130 within the second canister housing 126. The second lid 134 can be
fixed to the second canister housing 126 with attachment members 118, illustrated as bolts. It
should be appreciated, however, that the second lid 134 can be fixed to the first canister housing
126 with any attachment member as desired.
In the illustrated embodiment and as shown in Figs. 1C and 2C, the first and
second vessels 110 and 130 are each configured to retain the spherical members 38 and the at
least two particulate materials. Each vessel 110 and 130 includes an inner surface 140 that
defines a cavity 144 in which the materials can be retained. As shown in Fig. 2C, each inner
surface 140 can be a side inner surface that defines a respective height H measured from a
bottom of the cavity 144 to a top of the cavity 144. The spherical members 38 are configured to
contact and apply a substantially constant force against the inner surfaces 140 as the turret 22
rotates at the first rotational speed and as the first and second canisters 30 and 34 rotate at their
respective rotational speeds. In particular the spherical members 38 are configured to contact the
inner surfaces 140 so as to form a column or columns of members 38 that extend from the
bottom of the inner surfaces 140 to the top of the inner surfaces 140 as shown in Fig. 1C. When
in operation, the spherical members 38 maintain contact with the inner surfaces 140 and thus the
force applied against the inner surfaces 140 by each spherical member 38 remains substantially
constant. The size, weight, and material of the spherical members 38 can be such that the
spherical members 38 form the columns and apply the desired force against the inner surfaces
140. The spherical members 38 can be made of ceramic and can each weigh about 25 grams. It
should be appreciated, however, that the spherical members 38 can be made of any material as
desired and can have any weight as desired. It should be further appreciated that the vessels 110
and 130 can be configured to retain any number of spherical members 38 as desired, so long as
the spherical members 38 form a column(s) against the inner surfaces 140 such that each
spherical member 38 contacts and applies a substantially constant force against the inner surface
606099049.2
140 of the canister in which it is retained. It should yet be further appreciated that the first and
second canisters 30 and 34 can be void of the removable vessels 110 and 130 such that the
canister housings 106 and 126 themselves receive the spherical members 38 and particulates.
In operation, as the turret rotates at the first rotational speed and as the first and
second canisters 30 and 34 rotate at their respective rotational speeds, the first and second
particulates within the canisters 30 and 34 will move between the spherical members 38 and
inner surfaces 140 such that at least one of the first and second particulates is impregnated by the
other. In particular, the particulates can continuously move between the spherical members 38
and the inner surfaces 140, and can have different orientations each time they move between the
spherical members 38 and inner surfaces 140 to thereby cause at least one of the first and second
particulates to impregnate the other. Because the forces applied by the members 38 are
substantially constant, the process for impregnation is repeatable. That is, the spherical members
38 remain in contact with the inner surfaces 140 and do not climb on top of each other as the
device 10 is operating at normal speeds. Therefore, the forces acting on the particulates will be
substantially constant.
In the illustrated embodiment, the turret 22 rotates about the first axis at a speed
of about 1750 rpm and the first and second canisters 30 and 34 each rotate about the second and
third axes, respectively, at a speed of about 2500 rpm. The canisters 30 and 34 are positioned
such that the most distant point of the inner surfaces 140 of each canister 30 and 34 from the first
axis is about 4.8 inches and each inner surface 140 defines a diameter of about 3.8 inches. The
spherical members 44 are stainless steel balls each having a diameter of about 0.5 inches and a
weight of about 0.29 oz. Therefore, in the illustrated embodiment the pressure applied to the
particulates is:
RPM 100 500 875 1000 1200 1500 1750
Pressure
0.025 0.627 1.919 2.506 3.609 5.639 7.676
(lbs)
In the illustrated embodiment, each ball 44 exerts a force of 7.676 lbs on the
particulates as it rolls against the inner surface 140 of the respective canister 30 and 34. With 23
balls 44 in a single canister, arranged in 3 columns of 8, 7, 8 rolling side by side against the inner
surface 140, at 1750 rpm, no particulate is ever exposed to more than 7,676 lbs of pressure at the
rolling contact point between the ball 44 and inner surface 140. It should be appreciated,
however, that centrifugal device 10 can have other configurations as desired. For example, the
606099049.2
spherical members 44 can have other dimensions, the inner surfaces 140 can define other
diameters, and the turret 22 and canisters 30 and 34 can rotate at other speeds as desired.
In one embodiment, the present invention can be used to make combination
therapies that alter the defenses of cancerous cells to oxidative stress. One class of such
therapies increases free radical availability to cancerous cells. A representative subclass of such
therapies involve administration of pharmaceutical compositions comprising a tyrosine
hydroxylase inhibitor, a melanin promoter, a p450 3A4 promoter, a leucine aminopeptidase
inhibitor, and, optionally, a growth hormone inhibitor. Therefore at least one of the particulate
materials retained by the first and second vessels 110 and 130 can include an active
pharmaceutical ingredient or can have particles that individually comprise two or more active
pharmaceutical ingredients.
While not intending to be bound by any particular mechanism of operation, at
least one of the particulate materials can include a tyrosine hydroxylase inhibitor, which is
believed to function by accumulating in cancer cells and preventing them from forming a coating
of either lipids or hyaluronan. By preventing the cancer cells from forming a coating of either
lipids or hyaluron, the cancer cells are believed to be made more accessible to oxidative stress.
Representative tyrosine hydroxylase inhibitors include tyrosine derivatives, which typically are
rapidly absorbed by most cancers and inflamed tissues. Representative tyrosine derivatives
include one or more of methyl (2R)amino(2-chlorohydroxyphenyl) propanoate, D-
tyrosine ethyl ester hydrochloride, methyl (2R) amino(2,6-dichloro-3,4-dimethoxyphenyl)
propanoate H-D-Tyr(TBU)-allyl ester HCl, methyl (2R)amino(3-chloro-4,5-
dimethoxyphenyl) propanoate, methyl (2R)amino(2-chlorohydroxymethoxyphenyl)
propanoate, methyl (2R)amino(4-[(2-chlorofluorophenyl) methoxy] phenyl) propanoate,
methyl (2R) amino(2-chloro-3,4-dimethoxyphenyl) propanoate, methyl (2R)amino(3-
chlorofluorohydroxyphenyl) propanoate, diethyl 2-(acetylamino)(4-[(2-chloro
fluorobenzyl) oxy] benzyl malonate, methyl (2R)amino(3-chloromethoxyphenyl)
propanoate, methyl (2R)amino(3-chlorohydroxymethoxyphenyl) propanoate, methyl
(2R)amino(2,6- dichlorohydroxymethoxyphenyl) propanoate, methyl (2R)amino-
3-(3-chlorohydroxyphenyl) propanoate, H-DL-tyr-OME HCl, H-3,5-diiodo-tyr-OME HCl, H-
D-3,5-diiodo-tyr-OME HCl, H-D-tyr-OME HCl, D-tyrosine methyl ester hydrochloride, D-
tyrosine-ome HCl, methyl D-tyrosinate hydrochloride, H-D-tyr-OMe·HCl, D-tyrosine methyl
ester HCl, H-D-Tyr-OMe-HCl, (2R)amino(4-hydroxyphenyl) propionic acid, (2R)
amino(4-hydroxyphenyl) methyl ester hydrochloride, methyl (2R)amino(4-
606099049.2
hydroxyphenyl) propanoate hydrochloride, methyl (2R)azanyl(4-hydroxyphenyl)
propanoate hydrochloride, 3-chloro-L-tyrosine, 3-nitro-L-tyrosine, 3-nitro-L-tyrosine ethyl ester
hydrochloride, DL-m-tyrosine, DL-o-tyrosine, Boc-Tyr (3,5-I )-OSu, Fmoc-tyr(3-NO )-OH, and
α-methyl-DL-tyrosine.
At least one of the particulate materials can include melanin, a melanin
promoter, or a combination thereof. Melanin promoters are chemical compounds that increase
the production and/or the activity of melanin. Increased melanin levels are believed to reduce
inflammation (through, for example, suppression of TNF) and exclude the sequestered lymph
system. Melanin also is a photo catalyst, and can therefore promote chemical reactions that
generate free radicals which, in turn, can become accessible to cancer cells. Representative
melanin promoters are methoxsalen and melanotan II.
At least one of the particulate materials can include tamoxifen, toremifene,
fulvestrant, anastrozole, exemestane, letrozole, imatinib mesylate, dasatinib, nilotinib, bosutinib,
lapatinib, gefitinib, erlotinib, temsirolimus, everolimus, vandetanib, vemurafenib, crizotinib,
vorinostat, romidepsin, bexarotene, alitretinoin, tretinoin, bortezomib, carfilzomib, pralatrexate,
sorafenib, sunitinib, pazopanib, regorafenib, cabozantinib, denileukin diftitox, ziv-aflibercept,
cisplatin, cisplatinum, (cis-diamminedichloroplatinum(II)), carboplatin, oxaliplatin, benzyl
isothiocyanate, acetylcholine, or dihydrotestosterone (DHT).
While the foregoing description and drawings represent the preferred
embodiment of the present invention, it will be understood that various additions, modifications,
combinations and/or substitutions may be made therein without departing from the spirit and
scope of the invention as defined in the accompanying claims. In particular, it will be clear to
those skilled in the art that the invention may be embodied in other specific forms, structures,
arrangements, proportions, and with other elements, materials, and components, without
departing from the spirit or essential characteristics thereof. One skilled in the art will appreciate
that the invention may be used with many modifications of structure, arrangement, proportions,
materials, and components, which are particularly adapted to specific environments and
operative requirements without departing from the principles of the invention. In addition,
features described herein may be used singularly or in combination with other features. For
example, features described in connection with one component may be used and/or interchanged
with features described in another component. The presently disclosed embodiment is therefore
to be considered in all respects as illustrative and not restrictive, the scope of the invention being
indicated by the appended claims, and not limited to the foregoing description.
606099049.2
It will be appreciated by those skilled in the art that various modifications and
alterations of the invention can be made without departing from the broad scope of the appended
claims. Some of these have been discussed above and others will be apparent to those skilled in
the art. For example, it should be appreciated that the first and second canisters 30 and 34 can be
configured to retain any material and is not limited to spherical members 38, particulates
including the active ingredients listed above, or even particulates at all.
606099049.2
Claims (44)
1. A centrifugal mixing device comprising: a shaft assembly that is elongate along a first axis and is configured to be operably coupled to a motor such that the motor rotates the shaft assembly about the first axis; and a turret that is rotatably coupled to the shaft assembly such that the turret is configured to rotate about the first axis relative to the shaft assembly, the turret including a first support, a first canister rotatably coupled to the first support on a first side of the shaft assembly such that first canister rotates about a second axis, a second canister rotatably coupled to the first support on a second side of the shaft assembly such that the second canister rotates about a third axis, and a second support spaced from the first support along the first axis, the first and second canisters being rotatably coupled to both the first support and the second support, wherein the turret is configured to rotate about the first axis in a first rotational direction and each of the first and second canisters are configured to rotate about the second and third axes, respectively, in a second rotational direction that is opposite the first rotational direction.
2. The centrifugal mixing device of claim 1, wherein: the first canister includes a first canister pulley, the second canister includes a second canister pulley, and the shaft assembly includes a shaft body that is elongate along the first axis and a first shaft pulley fixed to the shaft body between the first and second canister pulleys; and the mixing device further comprises a first drive belt that is in communication with the first shaft pulley and the first and second canister pulleys such that the first drive belt drives the first and second canister pulleys to rotate the first and second canisters about the second and third axes, respectively, when the motor causes the first shaft pulley to rotate about the first axis.
3. The centrifugal mixing device of claim 1 or 2, wherein (i) the first canister includes a first canister shaft that is rotatably coupled to the first support, (ii) the second canister includes a second canister shaft that is rotatably coupled to the first support, and (iii) the first canister pulley is rigidly fixed to the first canister shaft and the second canister pulley is rigidly fixed to the second canister shaft. 606099049.2
4. The centrifugal mixing device of claim 3, wherein (i) the first canister includes a first removable vessel, (ii) the second canister includes a second removable vessel, and (iii) the first and second vessels are each configured to retain the at least two materials.
5. The centrifugal mixing device of claim 3, wherein: the turret further includes a first tension pulley and a second tension pulley, the first tension pulley is supported by the first support between the first shaft pulley and the first canister pulley, the second tension pulley is supported by the first support between the first shaft pulley and the second canister pulley, and the first and second tension pulleys are configured to maintain the first drive belt in tension.
6. The centrifugal mixing device of claim 2, wherein the shaft assembly includes a second shaft pulley fixed to the shaft body, and the device further comprises a transition member configured to transfer rotational motion of the shaft assembly to the turret.
7. The centrifugal mixing device of claim 6, wherein: the transition member includes a first transition pulley and a second transition pulley, and the device further comprises a second drive belt that is in communication with the second shaft pulley and the first transition pulley such that the second drive belt drives the transition member to rotate the first and second transition pulleys about a fourth axis when the motor causes the second shaft pulley to rotate about the first axis.
8. The centrifugal mixing device of claim 7, wherein the turret includes a turret pulley rotatably coupled to the shaft assembly about the first axis.
9. The centrifugal mixing device of claim 8, further comprising a third drive belt that is in communication with the second transition pulley and the turret pulley such that the third drive belt drives the turret pulley to rotate the turret about the first axis when the motor causes the first and second transition pulleys to rotate about the fourth axis. 606099049.2
10. The centrifugal mixing device of claim 9, wherein the turret pulley, the first and second transition pulleys, the first and second shaft pulleys and the first and second canister pulleys each has a respective diameter such that an acceleration of at least 600 g is imposed on material retained in the first and second canisters when the motor rotates the shaft assembly.
11. The centrifugal mixing device of claim 9, wherein the turret pulley, the first and second transition pulleys, the first and second shaft pulleys and the first and second canister pulleys each has a respective diameter such that an acceleration of about 691 g is imposed on material retained in the first and second canisters when the motor rotates the shaft assembly,.
12. The centrifugal mixing device of claim 1, further comprising the motor.
13. The centrifugal mixing device of claim 1, wherein each canister comprises at least three substantially spherical members.
14. The centrifugal mixing device of claim 13, wherein the at least three members are made of ceramic.
15. The centrifugal mixing device of claim 1, wherein rotation of the shaft assembly (i) causes the turret to rotate about the first axis at a first rotational speed and (ii) causes each of the first and second canisters to rotate about the second and third axes, respectively, at a second rotational speed.
16. The centrifugal mixing device of claim 1, wherein one or both of said canisters comprises at least two different particulate materials.
17. The centrifugal mixing device of claim 16, wherein at least one of said particulate materials comprises an active pharmaceutical ingredient.
18. The centrifugal mixing device of claim 17, wherein at least one of said particulate materials comprises methyl (2R)amino(2-chloro-4 hydroxyphenyl) propanoate, D-tyrosine ethyl ester hydrochloride, methyl (2R) amino(2,6-dichloro-3,4-dimethoxyphenyl) propanoate H-D-Tyr(TBU)-allyl ester HCl, methyl (2R)amino(3-chloro-4,5- 606099049.2 dimethoxyphenyl) propanoate, methyl (2R)amino(2-chlorohydroxymethoxyphenyl) propanoate, methyl (2R)amino(4-[(2-chlorofluorophenyl) methoxy] phenyl) propanoate, methyl (2R) amino(2-chloro-3,4-dimethoxyphenyl) propanoate, methyl (2R)amino(3- chlorofluorohydroxyphenyl) propanoate, diethyl 2-(acetylamino)(4-[(2-chloro fluorobenzyl) oxy] benzyl malonate, methyl (2R)amino(3-chloromethoxyphenyl) propanoate, methyl (2R)amino(3-chlorohydroxymethoxyphenyl) propanoate, methyl (2R)amino(2,6- dichlorohydroxymethoxyphenyl) propanoate, methyl (2R)amino- 3-(3-chlorohydroxyphenyl) propanoate, H-DL-tyr-OME HCl, H-3,5-diiodo-tyr-OME HCl, H- D-3,5-diiodo-tyr-OME HCl, H-D-tyr-OME HCl, D-tyrosine methyl ester hydrochloride, D- tyrosine-ome HCl, methyl D-tyrosinate hydrochloride, H-D-tyr-OMe·HCl, D-tyrosine methyl ester HCl, H-D-Tyr-OMe-HCl, (2R)amino(4-hydroxyphenyl) propionic acid, (2R) amino(4-hydroxyphenyl) methyl ester hydrochloride, methyl (2R)amino(4- hydroxyphenyl) propanoate hydrochloride, methyl (2R)azanyl(4-hydroxyphenyl) propanoate hydrochloride, 3-chloro-L-tyrosine, 3-nitro-L-tyrosine, 3-nitro-L-tyrosine ethyl ester hydrochloride, DL-m-tyrosine, DL-o-tyrosine, Boc-Tyr (3,5-I )-OSu, Fmoc-tyr(3-NO )- OH, α-methyl-L-tyrosine, α-methyl-D-tyrosine, or α-methyl-DL-tyrosine.
19. The centrifugal mixing device of claim 17, wherein at least one of said particulate materials comprises α-methyl-DL-tyrosine.
20. The centrifugal mixing device of claim 18, wherein at least one of said particulate materials comprises melanin, a melanin promoter, or a combination thereof.
21. The centrifugal mixing device of claim 20, wherein at least one of said particulate materials comprises melanin.
22. The centrifugal mixing device of claim 21, wherein the melanin promoter is methoxsalen, melanotan II, or a combination thereof.
23. The centrifugal mixing device of claim 19, wherein at least one of said particulate materials comprises tamoxifen, toremifene, fulvestrant, anastrozole, exemestane, letrozole, imatinib mesylate, dasatinib, nilotinib, bosutinib, lapatinib, gefitinib, erlotinib, temsirolimus, everolimus, vandetanib, vemurafenib, crizotinib, vorinostat, romidepsin, bexarotene, alitretinoin, 606099049.2 tretinoin, bortezomib, carfilzomib, pralatrexate, sorafenib, sunitinib, pazopanib, regorafenib, cabozantinib, denileukin diftitox, ziv-aflibercept, cisplatin, cisplatinum, (cis- diamminedichloroplatinum(II)), carboplatin, oxaliplatin, benzyl isothiocyanate, acetylcholine, or dihydrotestosterone (DHT).
24. The centrifugal mixing device of claim 1, wherein one or both of said canisters comprises a particulate material having particles that individually comprises two or more active pharmaceutical ingredients.
25. A centrifugal mixing device comprising: a shaft assembly that includes: a shaft body that is elongate along a first axis and is configured to be operably coupled to a motor such that the motor rotates the shaft assembly about the first axis, and a first shaft pulley that is rigidly fixed to the shaft body; a turret that is rotatably coupled to the shaft body and includes: a first canister that has a first canister pulley and is rotatable about a second axis, a second canister that has a second canister pulley and is rotatable about a third axis; and a first support and a second support, and wherein the first canister is rotatably coupled to the first and second supports on a first side of the shaft assembly and the second canister is rotatably coupled to the first and second supports on a second side of the shaft assembly; and a first drive belt that is in communication with the first shaft pulley, the first canister pulley, and the second canister pulley such that rotation of the shaft assembly by the motor causes the first and second canisters to rotate about the second and third axes, respectively, wherein the first shaft pulley, the first canister pulley, and the second canister pulley are each sized such that an acceleration of at least 600 g is imposed on material retained in the first and second canisters when the motor rotates the shaft assembly about the first axis.
26. The centrifugal mixing device of claim 25, wherein rotation of the shaft assembly by the motor (i) causes the turret to rotate about the first axis in a first rotational direction and (ii) 606099049.2 causes each of the first and second canisters to rotate about the second and third axes, respectively, in a second rotational direction that is opposite the first rotational direction.
27. The centrifugal mixing device of claim 25, wherein the first shaft pulley is fixed to the shaft body between the first and second canister pulleys.
28. The centrifugal mixing device of claim 25, wherein (i) the first canister includes a first canister shaft that is rotatably coupled to the first support, (ii) the second canister includes a second canister shaft that is rotatably coupled to the first support, and (iii) the first canister pulley is rigidly fixed to the first canister shaft and the second canister pulley is rigidly fixed to the second canister shaft.
29. The centrifugal mixing device of claim 28, wherein each canister comprises at least three substantially spherical members.
30. The centrifugal mixing device of claim 25, wherein the shaft assembly further includes a second shaft pulley rigidly fixed to the shaft body, and wherein the turret further includes a turret pulley that is in communication with the second shaft pulley such that rotation of the shaft assembly causes the turret to rotate about the first axis.
31. The centrifugal mixing device of claim 30, further comprising a transition member configured to transfer rotational motion of the shaft assembly to the turret.
32. The centrifugal mixing device of claim 31, wherein the transition member includes a first transition pulley and a second transition pulley, and wherein the device further comprises a second drive belt that is in communication with the second shaft pulley and the first transition pulley such that when the motor causes the second shaft pulley to rotate about the first axis the second drive belt drives the transition member to thereby rotate the first and second transition pulleys about a fourth axis.
33. The centrifugal mixing device of claim 32, further comprising a third drive belt that is in communication with the second transition pulley and the turret pulley such that when the motor 606099049.2 causes the first and second transition pulleys to rotate about the fourth axis, the third drive belt drives the turret pulley to thereby rotate the turret about the first axis.
34. The centrifugal mixing device of claim 32, wherein the turret pulley, the first and second transition pulleys, the first and second shaft pulleys and the first and second canister pulleys are each sized such that an acceleration of about 691 g is imposed on material retained in the first and second canisters when the motor rotates the shaft assembly.
35. The centrifugal mixing device of claim 25, further comprising the motor.
36. A method comprising the steps of: providing a centrifugal mixing device according to claim 1; placing in said first canister at least three substantially spherical members, a first particulate material, and at least a second particulate material; rotating the turret about the first axis in a first direction at a first rotational speed; rotating the first canister about the second axis in a second direction opposite the first direction at a second rotational speed; causing each member to contact an inner surface within the first canister such that a substantially constant force is applied against the inner side surface as the turret rotates at the first rotational speed and as the first canister rotates at the second rotational speed; causing the first and second particulates to move between the members and inner surface such that at least one of the first and second particulates is impregnated by the other.
37. The method of claim 36, wherein said rotation of said turret and said first canister subjects its contents to an acceleration of at least 600 g.
38. The method of claim 36, wherein said rotation of said turret and said first canister subjects its contents to an acceleration of about 691 g.
39. The method of claim 36, wherein the first rotating step comprises rotating the turret about the first axis at a first rotational speed that is between about 100 rpm and about 1750 rpm and the second rotating step comprises rotating the first canister about the second axis at a second rotational speed that is between about 140 rpm and about 2550 rpm. 606099049.2
40. The method of claim 36, wherein the first rotating step comprises rotating the turret about the first axis at a first rotational speed that is about 1750 rpm and the second rotating step comprises rotating the first canister about the second axis at a second rotational speed that is about 2500 rpm.
41. The method of claim 36, wherein the turret further includes a second canister that is rotatably coupled to the support such that the second canister rotates about a third axis, the method further comprising the steps of: placing in said second canister at least three substantially spherical members, a first particulate material, and at least a second particulate material; rotating the second canister about the third axis in the second direction at a third rotational speed; causing each member to contact an inner surface within the second canister such that a substantially constant force is applied against the inner side surface as the turret rotates at the first rotational speed and as the second canister rotates at the third rotational speed; causing the first and second particulates to move between the members and inner surface such that at least one of the first and second particulates that is retained by the second canister is impregnated by the other.
42. The method of claim 41, further comprising driving the first and second canisters with a first drive belt so as to cause the first and second canisters to rotate about the second and third axes, respectively.
43. The method of claim 36, wherein the first causing step comprises causing each member to contact the inner side surface so as to form a column of members that extends from a bottom of the inner surface to a top of the inner surface.
44. The method of claim 36 wherein at least one of said particulate materials comprises an active pharmaceutical ingredient. 606099049.2
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14/059,837 US9724657B2 (en) | 2013-10-22 | 2013-10-22 | High-speed centrifugal mixing devices and methods of use |
US14/059,837 | 2013-10-22 | ||
PCT/US2014/061481 WO2015061256A1 (en) | 2013-10-22 | 2014-10-21 | High-speed centrifugal mixing devices and methods of use |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ719452A NZ719452A (en) | 2021-03-26 |
NZ719452B2 true NZ719452B2 (en) | 2021-06-29 |
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