U.S. patent application number 16/339922 was filed with the patent office on 2020-02-13 for compositions and devices to administer pharmaceutical compositions nasally.
The applicant listed for this patent is BOARD OF REGENTS, THE UNIVERSITY OF TEXAS SYSTEM. Invention is credited to Yang LU, Hugh D.C. SMYTH, Zachary WARNKEN, Robert O. WILLIAMS, III.
Application Number | 20200046919 16/339922 |
Document ID | / |
Family ID | 61831232 |
Filed Date | 2020-02-13 |
![](/patent/app/20200046919/US20200046919A1-20200213-D00000.png)
![](/patent/app/20200046919/US20200046919A1-20200213-D00001.png)
![](/patent/app/20200046919/US20200046919A1-20200213-D00002.png)
![](/patent/app/20200046919/US20200046919A1-20200213-D00003.png)
![](/patent/app/20200046919/US20200046919A1-20200213-D00004.png)
![](/patent/app/20200046919/US20200046919A1-20200213-D00005.png)
![](/patent/app/20200046919/US20200046919A1-20200213-D00006.png)
![](/patent/app/20200046919/US20200046919A1-20200213-D00007.png)
![](/patent/app/20200046919/US20200046919A1-20200213-D00008.png)
![](/patent/app/20200046919/US20200046919A1-20200213-D00009.png)
![](/patent/app/20200046919/US20200046919A1-20200213-D00010.png)
View All Diagrams
United States Patent
Application |
20200046919 |
Kind Code |
A1 |
SMYTH; Hugh D.C. ; et
al. |
February 13, 2020 |
COMPOSITIONS AND DEVICES TO ADMINISTER PHARMACEUTICAL COMPOSITIONS
NASALLY
Abstract
Devices and methods for nasal administration of a pharmaceutical
composition. In certain embodiments, the devices comprises a
reservoir, a conduit in fluid communication with the reservoir, and
an anatomic positioning device configured to position the conduit
in a nasal cavity of a user. Particular embodiments include an
actuator configured to transfer the pharmaceutical composition from
the reservoir to the conduit and emit the pharmaceutical
composition from the conduit.
Inventors: |
SMYTH; Hugh D.C.; (West Lake
Hills, TX) ; WILLIAMS, III; Robert O.; (Austin,
TX) ; WARNKEN; Zachary; (Austin, TX) ; LU;
Yang; (Austin, TX) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BOARD OF REGENTS, THE UNIVERSITY OF TEXAS SYSTEM |
Austin |
TX |
US |
|
|
Family ID: |
61831232 |
Appl. No.: |
16/339922 |
Filed: |
October 3, 2017 |
PCT Filed: |
October 3, 2017 |
PCT NO: |
PCT/US17/54861 |
371 Date: |
April 5, 2019 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
62404928 |
Oct 6, 2016 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/32 20130101;
A61K 49/06 20130101; G16H 20/10 20180101; A61K 49/0043 20130101;
A61M 15/08 20130101; A61M 2205/3327 20130101; A61K 9/0043 20130101;
A61K 9/122 20130101; A61K 31/4184 20130101; A61M 2205/3306
20130101; A61B 6/032 20130101; A61M 2202/064 20130101; A61M
2210/0618 20130101; A61M 31/005 20130101; A61B 5/055 20130101; G16H
40/63 20180101; A61K 9/146 20130101; A61K 9/0085 20130101; A61K
9/124 20130101; A61M 11/02 20130101 |
International
Class: |
A61M 15/08 20060101
A61M015/08; A61K 9/00 20060101 A61K009/00; A61K 9/12 20060101
A61K009/12; A61K 9/14 20060101 A61K009/14; A61K 47/32 20060101
A61K047/32; A61K 31/4184 20060101 A61K031/4184; A61K 49/06 20060101
A61K049/06; A61K 49/00 20060101 A61K049/00; A61M 31/00 20060101
A61M031/00; G16H 20/10 20060101 G16H020/10; G16H 40/63 20060101
G16H040/63 |
Claims
1. An apparatus for nasal administration of a pharmaceutical
composition, the apparatus comprising: a reservoir; a conduit in
fluid communication with the reservoir; an actuator configured to
transfer a pharmaceutical composition from the reservoir to the
conduit and emit the pharmaceutical composition from the conduit;
and an anatomic positioning device configured to position the
conduit in a nasal cavity of a user.
2. The apparatus of claim 1 wherein the anatomic positioning device
is modeled after anatomic features of an individual user.
3. The apparatus of claim 1 wherein the anatomic positioning device
is modeled after a computerized tomography (CT) scan of an
individual user.
4. The apparatus of claim 1 wherein the anatomic positioning device
is modeled after a magnetic resonance imaging (MRI) scan of a nasal
cavity of an individual user.
5. The apparatus of claim 1 wherein the anatomic positioning device
comprises: an adjustable member coupled to the conduit, wherein:
the adjustable member can be adjusted to control a depth at which
the conduit is inserted into the nasal cavity; and the adjustable
member can be adjusted to control an angle at which the conduit is
inserted into the nasal cavity.
6. The apparatus of claim 5 wherein the conduit is threaded and the
adjustable member is threadably coupled to the conduit.
7. The apparatus of claim 5 wherein the anatomic positioning device
further comprises: a dial mechanism for controlling the depth and
the angle at which the conduit is inserted into the nasal
cavity.
8. The apparatus of claim 1 wherein further comprising a sensor
configured to detect an angle at which the conduit is
positioned.
9. The apparatus of claim 8 wherein the sensor is a mechanical
sensor.
10. The apparatus of claim 8 wherein the sensor is an electronic
sensor.
11. The apparatus of claim 1 wherein the anatomic positioning
device comprises an anatomical nostril insert.
12. The apparatus of claim 1 wherein the anatomic positioning
device comprises an external frame structure.
13. The apparatus of claim 12 wherein the external frame structure
is configured to be placed outside a nose and configured to guide
the conduit into the nasal cavity.
14. The apparatus of claim 1 wherein the actuator is configured to
increase pressure in the reservoir.
15. The apparatus of claim 1 wherein the actuator is configured to
compress the reservoir.
16. The apparatus of claim 1 wherein the pharmaceutical composition
comprises: (A) a therapeutic agent; and (B) a pharmaceutical
excipient, wherein: the pharmaceutical composition is formulated
for administration intranasally for delivery to the brain; and the
pharmaceutical composition is formulated as a solid dispersion.
17. The apparatus of claim 16, wherein the solid dispersion is
amorphous.
18. The apparatus of claim 16, wherein the solid dispersion is in a
nanocrystalline state.
19. The apparatus according to any one of claims 16-18, wherein the
therapeutic agent is a chemotherapeutic compound.
20. The apparatus of claim 19, wherein the therapeutic agent is
mebendazole.
21. The apparatus according to any one of claims 16-20, wherein the
pharmaceutical excipient is a polymer.
22. The apparatus of claim 21, wherein the pharmaceutical excipient
is a polyvinylpyrrolidone copolymer.
23. The apparatus of claim 22, wherein the pharmaceutical excipient
is a polyvinylpyrrolidone and vinyl acetate copolymer.
24. The apparatus of claim 23, wherein the pharmaceutical excipient
is Kollidon.RTM. VA64.
25. The apparatus of claim 1 wherein the pharmaceutical composition
comprises: (A) a therapeutic agent; and (B) a pharmaceutical
excipient, wherein: the pharmaceutical composition is formulated
for administration intranasally for delivery to the brain; and the
pharmaceutical composition is formulated as a foam.
26. The apparatus of claim 25, wherein the pharmaceutical excipient
is a composition comprising a first polymer and a second
polymer.
27. The apparatus of claim 26, wherein the first polymer is a
polyether.
28. The apparatus of claim 27, wherein the first polymer is a
triblock polyether.
29. The apparatus of claim 28, wherein the first polymer is a
polyethylene-polypropylene-polyethylene polymer.
30. The apparatus of claim 29, wherein the first polymer is
Poloxamer.RTM. 407.
31. The apparatus according to any one of claims 25-30, wherein the
therapeutic agent is a contrast agent.
32. The apparatus of claim 31, wherein the therapeutic agent is
perfluorooctylbromide.
33. The apparatus according to any one of claims 25-32, wherein the
pharmaceutical composition comprises an imaging agent.
34. The apparatus of claim 33, wherein the imaging agent is
fluorescein.
35. The apparatus according to any one of claims 25-34, wherein the
pharmaceutical composition further comprises a basic solution.
36. The apparatus of claim 35, wherein the basic solution is a
hydroxide solution.
37. The apparatus of claim 36, wherein the basic solution is a
sodium hydroxide solution.
38. The apparatus according to any one of claims 25-37 wherein the
pharmaceutical composition comprises a propellant.
39. The apparatus of claim 38, wherein the propellant is a
haloalkane.sub.(C.ltoreq.12).
40. The apparatus of claim 39, wherein the propellant is a
haloalkane.sub.(C.ltoreq.6).
41. The apparatus of claim 40, wherein the propellant is
1,1,1,2,3,3,3-heptafluoropropane.
42. A method of developing individualized administration of a
pharmaceutical composition to a person, the method comprising:
obtaining one or more images of a nasal cavity of the person;
creating a three-dimensional model of the nasal cavity; and
determining person-specific parameters for a device configured to
administer the pharmaceutical composition to the person, wherein
the person-specific parameters are based on the three-dimensional
model of the nasal cavity.
43. The method of claim 42 wherein the one or more images comprise
computed tomography (CT) scans of the nasal cavity of the
person.
44. The method of claim 42 wherein the three-dimensional model of
the nasal cavity is created by image processing software utilizing
the one or more images obtained of the nasal cavity of the
person.
45. The method of claim 44 wherein the image processing software is
segmentation software.
46. The method of claim 42 wherein the person-specific parameters
include an administration angle of the device.
47. The method of claim 42 wherein the person-specific parameters
include an insertion depth of the device.
48. The method of claim 42 wherein the person-specific parameters
include a head tilt angle.
49. The method of claim 42 wherein the person-specific parameters
include an actuation force of the device.
50. The method of claim 42 further comprising creating a
three-dimensional casting of the nasal cavity from the
three-dimensional model of the nasal cavity.
51. The method of claim 50 wherein creating a three-dimensional
casting of the nasal cavity comprises: obtaining computed
tomography (CT) scans of the nasal cavity; using image processing
software to generate cross-section views of the CT scans in the
coronal, sagittal and axial positions; creating a three-dimensional
model of the nasal cavity with the image processing software; and
printing the three-dimensional casting from the three-dimensional
model via stereolithography.
52. The method of claim 51 wherein the three-dimensional casting is
printed in multiple anatomical segments.
53. The method of claim 52 wherein the multiple anatomical segments
include an anterior segment, an upper segment, a middle segment, a
lower segment and a naso-pharynx segment.
54. The method of claim 53 wherein the three-dimensional model
comprises a superior turbinate, a middle turbinate, and an inferior
turbinate.
55. The method of claim 54 wherein the anterior segment comprises a
boundary at a coronal slice made directly anterior to the superior
turbinate, the middle turbinate, and the inferior turbinate.
56. The method of claim 54 wherein the upper segment comprises a
lower boundary between the superior turbinate and the middle
turbinate.
57. The method of claim 54 wherein the middle segment comprises a
first boundary between the middle turbinate and the superior
turbinate and a second boundary between the middle turbinate and
the inferior turbinate.
58. The method of claim 54 wherein the lower segment comprises an
upper boundary between the inferior turbinate and the middle
turbinate.
59. The method of claim 54 wherein a boundary of the naso-pharynx
segment is a coronal slice made directly posterior to the superior
turbinate, the middle turbinate, and the inferior turbinate.
60. The method of claim 52 further comprising: (1) providing an
initial administration of a test compound into the anterior segment
of the three-dimensional casting; and (2) observing an initial
amount of the test compound deposited in the upper segment of the
three-dimensional casting after the initial administration of the
test compound into the anterior segment.
61. The method of claim 60 further comprising: (3) altering one or
more parameters of the initial administration of the test compound
into the anterior segment; (4) providing a subsequent
administration of the test compound into the anterior segment of
the three-dimensional casting; (5) observing a subsequent amount of
the test compound deposited in the upper segment of the
three-dimensional casting after the subsequent administration of
the test compound into the anterior segment; and (6) comparing the
subsequent amount of the test compound deposited to the initial
amount of the test compound deposited; (7) repeating steps (3)-(6)
to maximize the subsequent amount of the test compound deposited in
the upper segment of the three-dimensional casting.
62. The method of claim 61 wherein providing an initial
administration of the test compound into the anterior segment
comprises: inserting a device with a conduit into the anterior
segment of the three-dimensional model; and directing the test
compound from the conduit into the anterior segment.
63. The method of claim 62 wherein altering the one or more
parameters comprises altering an insertion depth of the device into
the anterior segment of the three-dimensional model.
64. The method of claim 62 wherein altering the one or more
parameters comprises altering an insertion angle of the device into
the anterior segment of the three-dimensional model.
65. The method of claim 63 wherein the insertion angle is measured
from a vertical reference line extending from a nostril of the
anterior segment when viewed from the front.
66. The method of claim 63 wherein the insertion angle is measured
from a vertical reference line extending from a nostril of the
anterior segment when viewed from the side.
67. The method of claim 60 wherein the test compound comprises a
fluorescent agent.
68. The method of claim 42 wherein computer software is utilized to
determine the person-specific parameters based on the
three-dimensional model of the nasal cavity.
69. A pharmaceutical composition comprising: (A) a therapeutic
agent; and (B) a pharmaceutical excipient, wherein: the
pharmaceutical composition is formulated for administration
intranasally for delivery to the brain; and the pharmaceutical
composition is formulated as a solid dispersion.
70. The pharmaceutical composition of claim 69, wherein the solid
dispersion is amorphous.
71. The pharmaceutical composition of claim 69, wherein the solid
dispersion is in a nanocrystalline state.
72. The pharmaceutical composition according to any one of claims
69-71, wherein the therapeutic agent is a chemotherapeutic
compound.
73. The pharmaceutical composition of claim 72, wherein the
therapeutic agent is mebendazole.
74. The pharmaceutical composition according to any one of claims
69-73, wherein the pharmaceutical excipient is a polymer.
75. The pharmaceutical composition of claim 74, wherein the
pharmaceutical excipient is a polyvinylpyrrolidone copolymer.
76. The pharmaceutical composition of claim 75, wherein the
pharmaceutical excipient is a polyvinylpyrrolidone and vinyl
acetate copolymer.
77. The pharmaceutical composition of claim 76, wherein the
pharmaceutical excipient is Kollidon.RTM. VA64.
78. A pharmaceutical composition comprising: (A) a therapeutic
agent; and (B) a pharmaceutical excipient, wherein: the
pharmaceutical composition is formulated for administration
intranasally for delivery to the brain; and the pharmaceutical
composition is formulated as a foam.
79. The pharmaceutical composition of claim 78, wherein the
pharmaceutical excipient is a composition comprising a first
polymer and a second polymer
80. The pharmaceutical composition of claim 79, wherein the first
polymer is a polyether.
81. The pharmaceutical composition of claim 80, wherein the first
polymer is a triblock polyether.
82. The pharmaceutical composition of claim 81, wherein the first
polymer is a polyethylene-polypropylene-polyethylene polymer.
83. The pharmaceutical composition of claim 82, wherein the first
polymer is Poloxamer.RTM. 407.
84. The pharmaceutical composition according to any one of claims
78-83, wherein the therapeutic agent is a contrast agent.
85. The pharmaceutical composition of claim 84, wherein the
therapeutic agent is perfluorooctylbromide.
86. The pharmaceutical composition according to any one of claims
78-85, wherein the pharmaceutical composition comprises an imaging
agent.
87. The pharmaceutical composition of claim 86, wherein the imaging
agent is fluorescein.
88. The pharmaceutical composition according to any one of claims
78-87, wherein the pharmaceutical composition further comprises a
basic solution.
89. The pharmaceutical composition of claim 88, wherein the basic
solution is a hydroxide solution.
90. The pharmaceutical composition of claim 89, wherein the basic
solution is a sodium hydroxide solution.
91. The pharmaceutical composition according to any one of claims
78-90 further comprising a propellant.
92. The pharmaceutical composition of claim 91, wherein the
propellant is a haloalkane.sub.(C.ltoreq.12).
93. The pharmaceutical composition of claim 92, wherein the
propellant is a haloalkane.sub.(C.ltoreq.6).
94. The pharmaceutical composition of claim 93, wherein the
propellant is 1,1,1,2,3,3,3-heptafluoropropane.
95. A method of delivering a pharmaceutical composition to a
subject, the method comprising: inserting an apparatus into a nasal
cavity of the subject, wherein the apparatus is anatomically
modeled after the nasal cavity of the subject; and emitting the
pharmaceutical composition from the apparatus into the nasal cavity
of the subject.
96. A method of delivering a pharmaceutical composition to a
subject, the method comprising: inserting an apparatus according to
any of claims 1-41 into a nasal cavity of the subject; and emitting
the pharmaceutical composition from the apparatus into the nasal
cavity of the subject.
Description
[0001] This application claims the benefit of U.S. Provisional
Patent Application No. 62/404,928, filed Oct. 6, 2016, the entirety
of which is incorporated herein by reference.
BACKGROUND INFORMATION
[0002] Currently, oral administration is the most common method of
drug delivery, and is most often used for absorption into the
systemic circulation..sup.1 However, when the disease in question
is a CNS related disorder, there are several additional barriers
that a drug must overcome to reach its site of action and provide a
pharmacological response such as the blood-brain barrier (BBB) and
the blood-cerebrospinal fluid barrier..sup.2 Over the last several
decades, it has been discovered that materials can be transported
directly to the brain interstitial fluid and cerebrospinal fluid
when administered intranasally..sup.34 By using intranasal
administration, it is possible to circumvent the barriers of the
BBB by taking advantage of the only place the CNS is in direct
contact with the environment, the olfactory epithelium..sup.4 In
the past, invasive methods such as intraparenchymal, intrathecal,
and intracerebroventricular injections have been used to achieve
clinically relevant brain concentrations for therapeutic efficacy.
Limitations of nose-to-brain delivery have also been identified,
and include a relatively small volume for administration of the
drug, limited surface area of the olfactory epithelium and short
retention time for drug absorption..sup.5
[0003] Accordingly, several studies have attempted different
formulation techniques to improve brain delivery by direct
nose-to-brain mechanisms. Studies have shown that by increasing the
residence time of the drug in the nasal cavity, it is possible to
increase the amount delivered to the brain. While mucoadhesives are
effective at increasing brain concentrations, experiments combining
their use with other formulation techniques have produced even
greater brain uptake. The formulation composition appears to have a
significant effect on drug uptake into the brain. However, as not
all formulation strategies have shown to produce significant
increases in brain delivery, there remains a need to improve the
formulation design and standardization on in vitro and in vivo
experimental conditions. By maximizing brain concentrations and
limiting systemic exposure, this pathway offers the ability to
decrease systemic side effects while producing therapeutic effects
that otherwise would not be possible using other non-invasive
routes of administration.
[0004] Despite these potential limitations, the nasal route of
administration for brain delivery has shown promise for therapeutic
efficacy based on animal models and clinical trials in
humans.sup.6,7 Existing methods and devices for administering
therapeutic agents nasally include shortcomings that have not been
adequately addressed. For example, traditional methods of
therapeutic agent nasal administration utilize generic devices
inserted into a subject's nasal cavity. Such generic devices do not
account for unique anatomical structures of individual subjects.
Accordingly, these differences in anatomical structures can affect
the amount of therapeutic agent that is deposited to the olfactory
region and can present challenges in nasally administering a
desired dosage of a particular therapeutic agent.
[0005] Currently, many of the commercial nasal preparations are
delivered with metered-dose pump sprays. Of the relatively small
volume that is administrable utilizing metered-dose spray pumps,
only around 2.5% is deposited in the area which corresponds to the
olfactory region.sup.8. One of the oldest nasal delivery systems is
nasal drops.sup.9. When administered properly, nasal drops spread
over a larger area than nasal sprays, however, are often cleared
faster than nasal sprays as well.sup.10. An important limitation of
nasal drops is that their efficacy can be affected by patient
administration technique, requiring complex maneuvers to achieve
correct head positioning.sup.9.
[0006] Successful targeting of nose-to-brain drug delivery requires
a formulation to be administered in such a way that the amount
deposited on the olfactory epithelium is maximized. Yet there are
only a limited number of examples of such devices described in the
art.
[0007] Many different delivery devices and methods have been
developed in attempts to overcome the issues relating to targeting
the olfactory region. Vianase.TM. is an electronic atomizer device
developed by Kurve Technology.RTM. which consists of a nebulizer
attached to a vortex chamber. Nebulized drug particles move in a
vortex in the vortex chamber and continue to exhibit this flow when
leaving the device.sup.11. This reportedly promotes a larger area
for deposition compared to conventional pump nasal sprays,
including deposition on the olfactory region.sup.7.
[0008] The Opt-Powder device by Optinose.RTM. is a bi-directional
delivery device which uses the patient's own exhalation force to
emit the dose from the device. Closure of the soft palate ensures
that none of the flowing powder can be deposited into the lungs.
Djupesland and Skretting compared the deposition of radiolabeled
lactose from the Opt-Powder device to the deposition of a
radiolabeled liquid formulation from a conventional pump nasal
spray in seven subjects. They report just over 18% of the powder
from the Opt-Powder deposited in the upper region of the nasal
cavity while only about 2.4% of the liquid from the spray was
deposited in the same region.sup.8.
[0009] There is presently a shortage of methods and devices that
provide for effective nasal administration of therapeutic agents to
treat diseases and disorder such as neurological pathologies to
patients.
SUMMARY
[0010] Exemplary embodiments of the present disclosure address the
issues described above. Exemplary embodiments include an apparatus
for nasal administration of a pharmaceutical composition, where the
apparatus comprises: a reservoir; a conduit in fluid communication
with the reservoir; an actuator configured to transfer a
pharmaceutical composition from the reservoir to the conduit and
emit the pharmaceutical composition from the conduit; and an
anatomic positioning device configured to position the conduit in a
nasal cavity of a user.
[0011] In certain embodiments, the anatomic positioning device is
modeled after anatomic features of an individual user. In
particular embodiments, the anatomic positioning device is modeled
after a computerized tomography (CT) scan of an individual user. In
some embodiments, the anatomic positioning device is modeled after
a magnetic resonance imaging (MRI) scan of a nasal cavity of an
individual user. In specific embodiments, the anatomic positioning
device comprises: an adjustable member coupled to the conduit,
where: the adjustable member can be adjusted to control a depth at
which the conduit is inserted into the nasal cavity; and the
adjustable member can be adjusted to control an angle at which the
conduit is inserted into the nasal cavity.
[0012] In certain embodiments, the conduit is threaded and the
adjustable member is threadably coupled to the conduit. In
particular embodiments, the anatomic positioning device further
comprises: a dial mechanism for controlling the depth and the angle
at which the conduit is inserted into the nasal cavity. Some
embodiments further comprise a sensor configured to detect an angle
at which the conduit is positioned, and in specific embodiments the
sensor is a mechanical sensor or an electronic sensor.
[0013] In specific embodiments, the anatomic positioning device
comprises an anatomical nostril insert. In certain embodiments, the
anatomic positioning device comprises an external frame structure.
In particular embodiments, the external frame structure is
configured to be placed outside a nose and configured to guide the
conduit into the nasal cavity. In some embodiments, the actuator is
configured to increase pressure in the reservoir. In specific
embodiments, the actuator is configured to compress the
reservoir.
[0014] In certain embodiments, the pharmaceutical composition
comprises: (A) a therapeutic agent; and (B) a pharmaceutical
excipient, where: the pharmaceutical composition is formulated for
administration intranasally for delivery to the brain; and the
pharmaceutical composition is formulated as a solid dispersion. In
particular embodiments, the solid dispersion is amorphous. In some
embodiments, the solid dispersion is in a nanocrystalline state. In
specific embodiments, the therapeutic agent is a chemotherapeutic
compound. In certain embodiments, the therapeutic agent is
mebendazole. In particular embodiments, the pharmaceutical
excipient is a polymer. In some embodiments, the pharmaceutical
excipient is a polyvinylpyrrolidone copolymer. In specific
embodiments, the pharmaceutical excipient is a polyvinylpyrrolidone
and vinyl acetate copolymer. In certain embodiments, the
pharmaceutical excipient is Kollidon.RTM. VA64.
[0015] In particular embodiments, the pharmaceutical composition
comprises: (A) a therapeutic agent; and (B) a pharmaceutical
excipient, where: the pharmaceutical composition is formulated for
administration intranasally for delivery to the brain; and the
pharmaceutical composition is formulated as a foam. In some
embodiments, the pharmaceutical excipient is a composition
comprising a first polymer and a second polymer. In specific
embodiments, the first polymer is a polyether. In certain
embodiments, the first polymer is a triblock polyether. In
particular embodiments, the first polymer is a
polyethylene-polypropylene-polyethylene polymer. In some
embodiments, the first polymer is Poloxamer.RTM. 407. In specific
embodiments, the therapeutic agent is a contrast agent. In certain
embodiments, the therapeutic agent is perfluorooctylbromide. In
particular embodiments, the pharmaceutical composition comprises an
imaging agent. In some embodiments, the imaging agent is
fluorescein. In specific embodiments, the pharmaceutical
composition further comprises a basic solution. In certain
embodiments, the basic solution is a hydroxide solution. In
particular embodiments, the basic solution is a sodium hydroxide
solution. In some embodiments, the pharmaceutical composition
comprises a propellant. In specific embodiments, the propellant is
a haloalkane.sub.(C.ltoreq.12). In certain embodiments, the
propellant is a haloalkane.sub.(C.ltoreq.6). In particular
embodiments, the propellant is
1,1,1,2,3,3,3-heptafluoropropane.
[0016] Certain embodiments, include a method of developing
individualized administration of a pharmaceutical composition to a
person, where the method comprises: obtaining one or more images of
a nasal cavity of the person; creating a three-dimensional model of
the nasal cavity; and determining person-specific parameters for a
device configured to administer the pharmaceutical composition to
the person, where the person-specific parameters are based on the
three-dimensional model of the nasal cavity.
[0017] In particular embodiments, the one or more images comprise
computed tomography (CT) scans of the nasal cavity of the person.
In some embodiments, the three-dimensional model of the nasal
cavity is created by image processing software utilizing the one or
more images obtained of the nasal cavity of the person. In specific
embodiments, the image processing software is segmentation
software. In certain embodiments, the person-specific parameters
include an administration angle of the device. In particular
embodiments, the person-specific parameters include an insertion
depth of the device. In some embodiments, the person-specific
parameters include a head tilt angle. In specific embodiments, the
person-specific parameters include an actuation force of the
device. Certain embodiments, further comprise creating a
three-dimensional casting of the nasal cavity from the
three-dimensional model of the nasal cavity.
[0018] In particular embodiments, creating a three-dimensional
casting of the nasal cavity comprises: obtaining computed
tomography (CT) scans of the nasal cavity; using image processing
software to generate cross-section views of the CT scans in the
coronal, sagittal and axial positions; creating a three-dimensional
model of the nasal cavity with the image processing software; and
printing the three-dimensional casting from the three-dimensional
model via stereolithography. In some embodiments, the
three-dimensional casting is printed in multiple anatomical
segments. In specific embodiments, the multiple anatomical segments
include an anterior segment, an upper segment, a middle segment, a
lower segment and a naso-pharynx segment. In certain embodiments,
the three-dimensional model comprises a superior turbinate, a
middle turbinate, and an inferior turbinate. In particular
embodiments, the anterior segment comprises a boundary at a coronal
slice made directly anterior to the superior turbinate, the middle
turbinate, and the inferior turbinate. In some embodiments, the
upper segment comprises a lower boundary between the superior
turbinate and the middle turbinate. In specific embodiments, the
middle segment comprises a first boundary between the middle
turbinate and the superior turbinate and a second boundary between
the middle turbinate and the inferior turbinate. In certain
embodiments, the lower segment comprises an upper boundary between
the inferior turbuinate and the middle turbinate. In particular
embodiments, a boundary of the naso-pharynx segment is a coronal
slice made directly posterior to the superior turbinate, the middle
turbinate, and the inferior turbinate.
[0019] Specific embodiments further comprise: (1) providing an
initial administration of a test compound into the anterior segment
of the three-dimensional casting; and (2) observing an initial
amount of the test compound deposited in the upper segment of the
three-dimensional casting after the initial administration of the
test compound into the anterior segment. Certain embodiments,
further comprise: (3) altering one or more parameters of the
initial administration of the test compound into the anterior
segment; (4) providing a subsequent administration of the test
compound into the anterior segment of the three-dimensional
casting; (5) observing a subsequent amount of the test compound
deposited in the upper segment of the three-dimensional casting
after the subsequent administration of the test compound into the
anterior segment; (6) comparing the subsequent amount of the test
compound deposited to the initial amount of the test compound
deposited; and (7) repeating steps (3)-(6) to maximize the
subsequent amount of the test compound deposited in the upper
segment of the three-dimensional casting.
[0020] In certain embodiments, providing an initial administration
of the test compound into the anterior segment comprises: inserting
a device with a conduit into the anterior segment of the
three-dimensional model; and directing the test compound from the
conduit into the anterior segment. In particular embodiments,
altering the one or more parameters comprises altering an insertion
depth of the device into the anterior segment of the
three-dimensional model. In some embodiments, altering the one or
more parameters comprises altering an insertion angle of the device
into the anterior segment of the three-dimensional model. In
specific embodiments, the insertion angle is measured from a
vertical reference line extending from a nostril of the anterior
segment when viewed from the front. In certain embodiments, the
insertion angle is measured from a vertical reference line
extending from a nostril of the anterior segment when viewed from
the side. In some embodiments, the test compound comprises a
fluorescent agent. In specific embodiments, computer software is
utilized to determine the person-specific parameters based on the
three-dimensional model of the nasal cavity.
[0021] Certain embodiments include a pharmaceutical composition
comprising: (A) a therapeutic agent; and (B) a pharmaceutical
excipient, where: the pharmaceutical composition is formulated for
administration intranasally for delivery to the brain; and the
pharmaceutical composition is formulated as a solid dispersion. In
particular embodiments, the solid dispersion is amorphous. In some
embodiments, the solid dispersion is in a nanocrystalline state. In
specific embodiments, the therapeutic agent is a chemotherapeutic
compound. In certain embodiments, the therapeutic agent is
mebendazole. In particular embodiments, the pharmaceutical
excipient is a polymer. In some embodiments, the pharmaceutical
excipient is a polyvinylpyrrolidone copolymer. In specific
embodiments, the pharmaceutical excipient is a polyvinylpyrrolidone
and vinyl acetate copolymer. In certain embodiments, the
pharmaceutical excipient is Kollidon.RTM. VA64.
[0022] Particular embodiments include a pharmaceutical composition
comprising: (A) a therapeutic agent; and (B) a pharmaceutical
excipient, where: the pharmaceutical composition is formulated for
administration intranasally for delivery to the brain; and the
pharmaceutical composition is formulated as a foam. In some
embodiments, the pharmaceutical excipient is a composition
comprising a first polymer and a second polymer. In specific
embodiments, the first polymer is a polyether. In certain
embodiments, the first polymer is a triblock polyether. In
particular embodiments, the first polymer is a
polyethylene-polypropylene-polyethylene polymer. In some
embodiments, the first polymer is Poloxamer.RTM. 407. In specific
embodiments, the therapeutic agent is a contrast agent. In certain
embodiments, the therapeutic agent is perfluorooctylbromide. In
particular embodiments, the pharmaceutical composition comprises an
imaging agent, and in certain embodiments the imaging agent is
fluorescein.
[0023] In some embodiments, the pharmaceutical composition further
comprises a basic solution. In specific embodiments, the basic
solution is a hydroxide solution. In certain embodiments, the basic
solution is a sodium hydroxide solution. Some embodiments further
comprise a propellant. In specific embodiments, the propellant is a
haloalkane.sub.(C.ltoreq.12). In certain embodiments, the
propellant is a haloalkane.sub.(C.ltoreq.6). In particular
embodiments, the propellant is
1,1,1,2,3,3,3-heptafluoropropane.
[0024] Specific embodiments include a method of delivering a
pharmaceutical composition to a subject, where the method
comprises: inserting an apparatus into a nasal cavity of the
subject, wherein the apparatus is anatomically modeled after the
nasal cavity of the subject; and emitting the pharmaceutical
composition from the apparatus into the nasal cavity of the
subject.
[0025] Certain embodiments include a method of delivering a
pharmaceutical composition to a subject, where the method
comprising: inserting an apparatus according to the present
disclosure (e.g. an apparatus according to any of claims 1-41) into
a nasal cavity of the subject; and emitting the pharmaceutical
composition from the apparatus into the nasal cavity of the
subject.
[0026] In the present disclosure, the term "coupled" is defined as
connected, although not necessarily directly, and not necessarily
mechanically.
[0027] The use of the word "a" or "an" when used in conjunction
with the term "comprising" in the claims and/or the specification
may mean "one," but it is also consistent with the meaning of "one
or more" or "at least one." The terms "approximately, "about" or
"substantially" mean, in general, the stated value plus or minus
10%. The use of the term "or" in the claims is used to mean
"and/or" unless explicitly indicated to refer to alternatives only
or the alternative are mutually exclusive, although the disclosure
supports a definition that refers to only alternatives and
"and/or."
[0028] The terms "comprise" (and any form of comprise, such as
"comprises" and "comprising"), "have" (and any form of have, such
as "has" and "having"), "include" (and any form of include, such as
"includes" and "including") and "contain" (and any form of contain,
such as "contains" and "containing") are open-ended linking verbs.
As a result, a method or device that "comprises," "has," "includes"
or "contains" one or more steps or elements, possesses those one or
more steps or elements, but is not limited to possessing only those
one or more elements. Likewise, a step of a method or an element of
a device that "comprises," "has," "includes" or "contains" one or
more features, possesses those one or more features, but is not
limited to possessing only those one or more features. Furthermore,
a device or structure that is configured in a certain way is
configured in at least that way, but may also be configured in ways
that are not listed.
[0029] Other objects, features and advantages of the present
invention will become apparent from the following detailed
description. It should be understood, however, that the detailed
description and the specific examples, while indicating specific
embodiments of the invention, are given by way of illustration
only, since various changes and modifications within the spirit and
scope of the invention will be apparent to those skilled in the art
from this detailed description.
BRIEF DESCRIPTION OF THE FIGURES
[0030] FIG. 1 illustrates graphs of amount vs. time profiles for
vasoactive intestinal peptide after intranasal administration in
the olfactory bulb and olfactory tract (A), cerebrum (B) and
cerebellum (C).
[0031] FIG. 2 illustrates a graph of brain risperidone
concentration vs. time following administration.
[0032] FIG. 3 illustrates a flowchart of steps performed in an
exemplary method for developing individualized administration of a
pharmaceutical composition to a person.
[0033] FIG. 4 illustrates a computed tomography (CT) scan of a
nasal cavity.
[0034] FIG. 5 illustrates a three-dimensional model of a nasal
cavity in a section view.
[0035] FIG. 6 illustrates a three-dimensional casting of a nasal
cavity printed in multiple anatomical segments.
[0036] FIG. 7 illustrates a flowchart of steps performed in an
exemplary method to determine the person-specific parameters used
for individualized administration of a pharmaceutical composition
to a person.
[0037] FIG. 8 illustrates insertion angles and an insertion depth
of an apparatus used in the individualized administration of a
pharmaceutical composition to a person.
[0038] FIG. 9 illustrates a schematic of an apparatus used in the
individualized administration of a pharmaceutical composition to a
person according to a first exemplary embodiment.
[0039] FIG. 10 illustrates a schematic of an apparatus used in the
individualized administration of a pharmaceutical composition to a
person according to a second exemplary embodiment.
[0040] FIG. 11 illustrates a schematic of an apparatus used in the
individualized administration of a pharmaceutical composition to a
person according to a third exemplary embodiment.
[0041] FIG. 12 illustrates a schematic of an apparatus used in the
individualized administration of a pharmaceutical composition to a
person according to a fourth exemplary embodiment.
[0042] FIG. 13 illustrates a schematic of an apparatus used in the
individualized administration of a pharmaceutical composition to a
person according to a fifth exemplary embodiment.
[0043] FIG. 14 illustrates a table showing administration angle and
percent deposition in an upper region of a nasal cavity.
[0044] FIG. 15 illustrates a graph of concentration of a solid
dispersion powder formulation for personalized delivery to the
olfactory region of a human.
[0045] FIG. 16 illustrates the powder X-ray diffraction spectra for
the spray dried mebendazole and Kollidon VA 64.RTM. formulation, a
physical mixture of mebendazole and Kollidon VA 64.RTM., and
crystalline mebendazole (from top to bottom).
[0046] FIG. 17 illustrates a formulation table for a
fluorescein-labeled foam formulation for delivery to the olfactory
region of a human.
[0047] FIG. 18 illustrates an illustrative example of an
anatomically correct nasal cast developed based on CT-scans of
patients (left) followed by 3D printing (right). The casts were
segmented into five different sections (A=anterior, U=upper
turbinate region, M=middle turbinate region, L=lower turbinate
region, N=nasopharynx) to quantitate the deposition pattern within
the nasal cavity.
[0048] FIG. 19 illustrates deposition results for the formulation
of FIG. 17.
[0049] FIG. 20 illustrates an example of nasal geometry
measurements to compare nasal casts.
[0050] FIG. 21 illustrates a coronal plane CT slice of a nasal
cavity.
[0051] FIG. 22 illustrates a sagittal plane CT slice of a nasal
cavity.
[0052] FIG. 23 illustrates a schematic of a testing apparatus of a
nasal cavity.
[0053] FIG. 24 illustrates a schematic of administration angles and
deposition efficiency.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0054] The present disclosure provides an apparatus that may be
used to deliver a pharmaceutical composition to specific locations
of the nasal cavity. The apparatus may preferably be formed using a
subject's own imaging scans of the nasal cavity to prepare an
anatomically formulated apparatus and the composition contained in
the apparatus for delivering the pharmaceutical composition to the
brain via the nasal cavity. Also, provided herein are compositions
which are formulated as solid dispersions that can be administered
to the nasal cavity for delivery to the brain. In particular, these
compositions may show beneifical properties such as increased
concentrations when formulated or improved absorption into the
brain.
[0055] A. Anatomical Intranasal Delivery Device
[0056] Provided herein are intranasal delivery devices which have
been anatomically formed to deliver the therapeutic agent to
specific areas of the nasal cavity. In order to properly form the
intranasal delivery device, it is important to understand the
general anatomy of the naval cavity.
[0057] i. Nasal Cavity Anatomy
[0058] The nasal cavity is defined by three main regions: the
vestibule, olfactory region and the respiratory region. The
respiratory region comprises the largest surface area of the nasal
cavity and makes up a majority of the posterior area of the nasal
cavity..sup.12 The olfactory region is located at the roof of the
nasal cavity and makes up nearly 10% of the total 150 cm.sup.2
surface area..sup.13 The different regions in the nasal cavity have
varying epithelial layers which help support their individual
functions. The respiratory epithelium is comprised of ciliated and
non-ciliated columnar cells. The ciliated cells of the respiratory
region contain hair-like extensions that beat at 1000 strokes per
minute in a single direction to clear particles towards the
nasopharynx region. This process is known as the mucociliary
clearance..sup.13 The olfactory epithelium is comprised of
supporting cells and olfactory receptor neurons which are
responsible for our sense of smell..sup.14 The cilia found in the
olfactory region are non-motile since they lack the dynein arms
required for movement..sup.15 For a more detailed discussion of the
nasal cavity anatomy the reader is referred to Clerico et
al..sup.16, Mygind et al..sup.17 and Thomas et al..sup.12
[0059] While much of the initial studies on this manner of delivery
has been carried out in animals, there are important anatomical
differences between the typically studied animal models and humans
that are expected to be important when predicting the expected
response in humans. The nasal cavity of rats is composed of about
50% olfactory epithelium, which makes up around 6.75 cm.sup.2. In
mice the olfactory epithelium makes up about 47% of the nasal
cavity, which is about 1.37 cm.sup.2. This is much larger than the
8-10% of the nasal cavity that is comprised of olfactory epithelium
in humans. This makes up around 12.5 cm.sup.2, although the
olfactory epithelium area can vary slightly from
person-to-person..sup.18,19 The location of the olfactory
epithelium in humans may also add additional challenges to drug
delivery. For effective brain targeting by the intranasal route,
drug needs to be delivered to the olfactory epithelium. This may
require specialized delivery devices, or subject positioning, that
are designed to maximize this deposition pattern. For all of these
reasons, Ruigrok and Lange.sup.18 expect that nose-to-brain
delivery in humans is overestimated based on animal studies,
especially those conducted in rats. Ruigrok and Lange.sup.18
explained that pharmacodynamic-pharmacokinetic studies in animals
may provide better predictive models for assessing drugs undergoing
direct nose-to-brain transport in humans.
[0060] Exemplary embodiments of the present disclosure comprise
methods and apparatus for delivering a pharmaceutical composition
to a subject. In exemplary embodiments, the method comprises
inserting an apparatus that is anatomically modeled after the nasal
cavity of the subject into the nasal cavity of the subject.
Exemplary methods further comprise emitting the therapeutic agent
from the device into the nasal cavity of the subject. Exemplary
embodiments further comprise methods for developing individualized
administration of a pharmaceutical composition to a person.
[0061] Referring now to FIG. 3, a flowchart of steps is shown
performed in an exemplary method 100 for developing individualized
administration of a pharmaceutical composition to a person. In this
embodiment, method 100 comprises a first step 110 of obtaining one
or more images of a nasal cavity of the person. In certain
embodiments, the images may comprise magnetic resonance imaging
(MRI) scans or computed tomography (CT) scans. One example of such
a nasal cavity image from a CT scan is shown in FIG. 4 as image
115. Referring back now to FIG. 3, method 100 may also comprise a
second step 120 of creating a three-dimensional model of the nasal
cavity (e.g. by converting the images obtained in step 130 into a
three-dimensional model). One example of such a three-dimensional
model 300 in a section view is illustrated in FIG. 5. As shown in
FIG. 5, model 300 comprises a superior turbinate 310, a middle
turbinate 320, and an inferior turbinate 330.
[0062] As shown in FIG. 3, step 130 comprises determining
person-specific parameters (based on three-dimensional model 300 of
the nasal cavity) for a device configured to administer the
therapeutic agent to the person. In certain embodiments,
three-dimensional model 300 of the nasal cavity can be created by
image processing software (e.g. segmentation software) utilizing
the one or more images obtained of the nasal cavity of the
person.
[0063] As explained in further detail below, the person-specific
parameters may include an administration angle, insert depth,
and/or an actuation force of the device. The person-specific
parameters may also include a head tilt angle of the person during
administration of the therapeutic agent.
[0064] In certain embodiments, the method may include creating a
three-dimensional casting of the nasal cavity from the
three-dimensional model of the nasal cavity. For example, the
three-dimensional casting can be created by printing
three-dimensional model 300 via stereolithography. In specific
embodiments, computed tomography (CT) scans of the nasal cavity can
be obtained and image processing software used to generate
cross-section views of the CT scans in the coronal, sagittal and
axial positions. The image processing software can then create the
three-dimensional model of the nasal cavity that can be printed via
stereolithography.
[0065] Referring now to FIG. 6, one example of a three-dimensional
casting 400 is shown printed in multiple anatomical segments. In
this embodiment, casting 400 comprises an anterior segment 410, an
upper segment 420, a middle segment 430, a lower segment 440 and a
naso-pharynx segment 450. Anterior segment 410 comprises a boundary
411 at a coronal slice made directly anterior to the superior
turbinate, the middle turbinate, and the inferior turbinate (shown
in FIG. 5). As shown in FIG. 6, upper segment 420 comprises a lower
boundary 421 between the superior turbinate and the middle
turbinate. In addition, middle segment 430 comprises boundary 421
and a boundary 431 between the middle turbinate and the inferior
turbinate (e.g. middle segment is located between boundaries 421
and 431). Furthermore, lower segment 440 comprises boundary 431
(e.g. lower segment 440 is located below boundary 431). Finally,
naso-pharynx segment 450 comprises a boundary 451 at a coronal
slice made directly posterior to the superior turbinate, the middle
turbinate, and the inferior turbinate.
[0066] In certain embodiments, simulations via computer software
can be used to determine the person-specific parameters used to
administer the therapeutic agent. In other embodiments,
experimental testing can be performed on casting 400 to determine
the person-specific parameters used to administer the therapeutic
agent. For example referring now to FIG. 7, a method 500 comprises
a first step 510 of providing an initial administration of a test
compound into the anterior segment of the three-dimensional
casting. Method 500 also comprises a second step 520 of observing
an initial amount of the test compound deposited in the upper
segment of the three-dimensional model after the initial
administration of the test compound into the anterior segment. This
initial amount of the test compound deposited can then be compared
to subsequent amounts using different parameters, as explained
further below.
[0067] For example, method 500 can include third and fourth steps
530 and 540 comprising altering one or more parameters of the
initial administration of the test compound into the anterior
segment and providing a subsequent administration of the test
compound into the anterior segment of the three-dimensional model.
Step 550 comprises observing a subsequent amount of the test
compound deposited in the upper segment of the three-dimensional
casting after the subsequent administration of the test compound
into the anterior segment. In step 560, the subsequent amount of
the test compound deposited can be compared to the initial amount
of the test compound deposited. Steps 530-560 can be repeated to
maximize the subsequent amount of the test compound deposited in
the upper segment of the three-dimensional casting.
[0068] For example, administration of the test compound into the
anterior segment may comprise inserting a device with a conduit
into the anterior segment of the three-dimensional model, and
directing the test compound from the conduit into the anterior
segment. If the insertion depth of the device is decreased in a
subsequent administration and the test compound deposited is also
decreased, the insertion depth can be increased in further
administrations in an effort to maximize the amount of the test
compound deposited in the upper segment.
[0069] Similarly, the angle at which a device is inserted into the
anterior segment can be altered based on the comparison of the
amount of the test compound deposited. Referring now to FIG. 8, an
insertion depth D is shown as well as insertion angles A and B used
during administration. As shown in FIG. 8 insertion angle A is
measured from a vertical reference line extending from a nostril of
the anterior segment when viewed from the front. Insertion angle B
is measured from a vertical reference line extending from a nostril
of the anterior segment when viewed from the side.
[0070] Certain embodiments also include an apparatus for nasal
administration of therapeutic agents. Referring now to FIG. 9, an
apparatus 700 comprises a reservoir 710 containing a pharmaceutical
composition 715, and a conduit 720 in fluid communication with
reservoir 710. Apparatus 700 can also comprise an actuator 730
configured to transfer pharmaceutical composition 715 from
reservoir 710 to the conduit 720 and emit pharmaceutical
composition 715 from conduit 720. In addition, apparatus 700 may
comprise an anatomic positioning device 740 configured to position
conduit 720 in a nasal cavity of a user (e.g., in a manner shown in
FIG. 8) in a way to maximize the amount of pharmaceutical
composition 715 deposited in the upper segment of the nasal cavity.
Anatomic positioning device 740 can comprise dimensions or features
that are obtained based on experimental testing of castings or
computer simulation of models based on specific features of the
subject nasal cavity.
[0071] In certain embodiments, anatomic positioning device 740 can
be modeled after anatomic features of an individual user, including
for example, the shape of the anterior segment of the nasal cavity.
In particular embodiments, anatomic positioning device 740 may
comprise an adjustable member coupled to conduit 720 that can be
adjusted to control a depth and/or an angle at which the conduit
720 is inserted into the nasal cavity. In specific embodiments,
conduit 720 is threaded and the adjustable member is threadably
coupled to conduit 720. Apparatus 700 may also comprise a
mechanical or electronic sensor 750 configured to detect an angle
at which the conduit 720 is positioned. As shown in FIG. 10, in
certain embodiments anatomic positioning device 740 may comprise a
dial mechanism 741 for controlling the depth and the angle at which
conduit 720 is inserted into the nasal cavity. As shown in FIG. 11,
in particular embodiments, anatomic positioning device 740 may
comprise an anatomical nostril insert 742. Referring now to FIG.
12, in other embodiments, anatomic positioning device may comprise
an external frame structure 743 that is configured to be placed
outside a nose and configured to guide conduit 720 into the nasal
cavity. As shown in FIG. 13, certain embodiments may comprise a
chamber 745 for loading a dose-containing portion of
formulation.
[0072] Referring now to FIG. 14, a table illustrates how angle
optimization can affect deposition of a test compound in the upper
region of a three-dimensional cast (e.g. upper segment 420 shown in
FIG. 6). In the table, "Angle A" and "Angle B" refer to the angles
shown in FIG. 8. As shown in FIG. 14, an "A" angle of 7 degrees and
and a "B" angle of 23 degrees resulted in the maximum amount of the
test compound deposited in the upper segment of the cast.
[0073] B. Pharmaceutical Compositions for Use in Intranasal
Device
[0074] In some aspects, the present disclosure provides
pharmaceutical compositions comprising a therapeutic agent and a
pharmaceutical excipient. In certain embodiments, the
pharmaceutical composition is formulated as a solid dispersion or
foam, and is formulated for administration intranasally for
delivery to the brain. Because navigating the human nasal cavity to
target the upper region can be difficult, foam formulation can
provide certain advantages by expanding to fill the target region
of the nasal cavity.
[0075] i. Solid Dispersions
[0076] These compositions may contain a solid dispersion which is a
mixture of an excipient and a therapeutic agent where these
components are mixed at the solid state which has been prepared
using a melting, solvent, or combination method. These compositions
are known to increase the solubility of poorly soluble drugs,
reduce the particle size, improve the wettability, improve the
porosity of the drug, mask the taste, or decrease the amount of
crystalline forms of the drug in the composition. Several methods
of preparing solid dispersions are known to a person of skill in
the art and contemplated herein..sup.20-26
[0077] ii. Foam Formulations
[0078] It is also contemplated that the therapeutic agent may be
formulated as a foam. A pharmaceutical foam is an emulsion which
contains one or more therapeutic agents along with a surfactant, a
liquid and/or a propellant. These compositions are classified as
aerosols, which may be used to direct the therapeutic agent towards
a specific area within the nasal cavity. These foam compositions
may be formulated with the therapeutic agent as a solid dispersion.
Foam formulations may incorporate nanoparticulate, suspension,
solubilized and emulsion type dosage forms in exemplary
embodiments. Foam compositions often may have an added benefit of
increasing the concentration of the therapeutic agent or increasing
the resident time of the composition within the nose. Methods of
preparing foam formulations are taught by Arzhavitina and
Steckel.sup.27 and Zhao et al..sup.28-30
[0079] iii. Other Pharmaceutical Compositions
[0080] In addition to the solid dispersion formulations and foam
compositions prepared herein, the device used herein may also be
used with other pharmaceutical compositions which have been
prepared in the art. Table 1 provides a list of non-limiting
examples that have so far been reported in the literature on
formulations and their effects on nose-to-brain delivery. As can be
seen in Table 1 below, formulations that have so far been utilized
to enhance nose-to-brain delivery include: solutions,
microemulsion, mucoadhesive formulations, polymeric nanoparticles,
lipid-based nanoparticles as well as novel combination therapies.
As would be known to a person of skill in the art, the choice of
the formulation may be greatly influenced by the physicochemical
properties of the drug.
TABLE-US-00001 TABLE 1 Drugs and Their Formulations Reported for
Nose-to-Brain Delivery Animal Disease State Drug Formulation Model
Being Treated Results Reference 5-FU Solution Rats pre- CNS
malignancy 104% 31 dosed with increased acetazolamide brain uptake
compared to i.v. Bromocriptine Chitosan Mice Parkinson's Showed 32
Nanoparticles Disease significant increase in dopamine levels
Buspirone Chitosan/HP-.beta.- Rats Depression DTE--4.13 33 CD
solution compared with 3.38 for i.n. plain solution Carbamazepine
Hypromellose/ Rats Epilepsy Significantly 34 Carbopol Gel higher
brain uptake compared to i.v. Carbamazepine Thermoreversible Mice
Epilepsy DTE--0.98 35 Gel i.n. and i.v. provide similar
blood/plasma ratios Curcumin In Situ Gelling Rats Brain tumor/
DTE--6.5 36 Microemulsion Alzheimer's Disease Donepezil Chitosan
Rats Alzheimer's Significantly 37 Nanoparticles Disease higher
brain concentrations from nanoparticles Doxepin Thermoreversible
Mice Depression No difference in 38 Gel pharmacodynamic endpoint
Duloxetine Lipid Nanocarrier Rats Depression DTE--757.14% 39
compared to 287.34% from solution Estradiol Cyclodextrin Rats
Alzheimer's AUC.sub.CSF/ 40 Disease AUC.sub.plasma 1.60 which was
significantly higher than 0.61 from i.v. GDF-5 Microemulsion Rats
Parkinson's Significantly 41 Disease higher midbrain concentrations
compared to acidic solution Methotrexate Mucoadhesive Rats pre- CNS
malignancy 195% increase 42 Solution dosed with in uptake
acetazolamide compared to i.n. without acetazolamide; 75% reduction
in brain tumor weight Methotrexate Solution Rats CNS malignancy
DTE--21.7% 43 Morphine Solution (PBS Rats Pain Brain/Plasma 44
buffer at pH 7.4) AUC ratio of 3 after i.n. use and 0.1 after i.v.
use Nimodipine Microemulsion Rats Stroke, reduce Higher AUC 45
dementia in olfactory bulb but lower AUC in rest of brain after
i.n. compared with i.v. treatment Olanzapine Nanomicellar Rats
Schizophrenia/ DTE--520.26% 46 Carrier Bipolar Disorder Olanzapine
PLGA Rats Schizophrenia/ 10.86 times 47 Nanoparticles Bipolar
Disorder higher brain uptake compared to i.n. solution alone
Olanzapine Mucoadhesive Rats Schizophrenia/ DTE--890% 48
Nanoemulsion Bipolar Disorder compared to 550% from i.n. solution
Paliperidone Mucoadhesive Rats Schizophrenia/ DTE--320.69%; 49
Microemulsion Bipolar 1.74-fold higher than nasal solution alone
Raltitrexed Solution (PBS pH Rats CNS malignancy DTE for 50 8)
Olfactory Bulb, Cerebrum and cerebellum was 127,120 and 71
respectively Rasagiline Thermosensitive Rabbits Parkinson's
Significant 51 Gel Disease improvement in brain uptake from gel
formulations Remoxipride Solution (Normal Rats Psychosis ~50%
increase 52 Saline) in brain/ plasma AUC Risperidone Mucoadhesive
Rats Schizophrenia/ DTE--476% 53 Nanoemulsion Bipolar Disorder
Risperidone Solid Lipid Mice Schizophrenia/ 10-fold 54
Nanoparticles Bipolar Disorder higher brain AUC compared to i.v.
solution Ropinirole Temperature Rats Parkinson's DTE--10.4 55
sensitive in situ Disease compared to 5.3 gel with for solution
alone Chitosan and HPMC Saquinavir Nanoemulsion Rats CNS involved
~62 times 56 HIV infection higher drug accumulation compared to
i.v. suspension Tacrine Solution of Mice Alzheimer's DTE--207.23%
57 Propylene glycol Disease and Normal Saline Tacrine Mucoadhesive
Mice Alzheimer's DTE--295.87% 58 Microemulsion Disease Testosterone
Noseafix .RTM. Mice CNS Hormone Significantly 59 Mucoadhesive
Replacement higher brain system levels except frontal cortex UH-301
Solution (Normal Rats Depression No difference 60 Saline) in CSF
concentrations between i.n. or i.v. Zidovudine- Solid Lipid Rats
CNS involved 6-fold higher 61 prodrug Microparticles HIV infection
CSF uptake Zolmitriptan Micellar Rats Migraine Significant 62
Nanocarrier increase brain concentrations as soon as 30 min. up to
120 min.
[0081] i. Solution Based Formulations
[0082] In some aspects, it is contemplated that the instant
intranasal delivery devices may be used with compositions which are
formulated as a solution. When formulating drugs as a solution such
as a molecular dispersion for use herein, the physicochemical
properties of the drug will be the driving factor for absorption.
Studies on direct nose-to-brain delivery with solutions have taken
place on a number of drugs, as can be seen in Table 1; including
elements like manganese.sup.63,64 and cobalt,.sup.65 to more
complex small molecules like remoxipride.sup.52 and UH-301.sup.60,
and even proteins.sup.6,66,67. Formualtions reported by Kandimalla
et al. showed that passive diffusion plays a role in the delivery
of small lipophilic molecules through diffusion cell permeability
studies with hydroxyzine..sup.69 Pardeshi et al..sup.15 compared
the delivery of dopamine.sup.70, a small molecule, to that of nerve
growth factor, a small secreted protein (MW=26,500 Da), and
observed that brain concentrations were fivefold higher for
dopamine than the protein when dosed at the same concentration.
Even though small lipophilic drugs are found to have the highest
brain levels after intranasal administration, formulations with
hydrophilic drugs often show the largest improvement in brain
levels compared to other routes of administration. Raltitrexed, a
hydrophilic small molecule with a log P of -0.98, was studied to
assess brain levels after intranasal and intravenous
administration. It was found that, depending on the section of
brain, a 54-121 fold increase in the AUC was found after intranasal
use compared to intravenous use in rats..sup.50 Wang et al.
performed similar experiments with methotrexate, another
hydrophilic drug with log P -1.98, and found that it provided
greater than 13 fold higher CSF AUC after nasal administration
compared to intravenous administration..sup.43 When comparing the
CSF concentrations from the Wang et al. study to those that use a
brain tumor model.sup.42, it can be inferred that the increase in
CSF concentration may be sufficient for pharmacological
activity.
[0083] Remarkably, the nose-to-brain route also seems applicable to
macromolecules.sup.15,71 as evidenced by animal studies with
plasmids.sup.72, IGF-I.sup.67 and Nerve Growth Factor.sup.4.
Research with arginine vasopressin.sup.73, insulin.sup.7,
oxytocin.sup.6 and melanocortin melanocyte-stimulating
hormone/adrenocorticotropin.sub.4-10.sup.74 supports the delivery
of macromolecules in humans. While only a limited number of the
current studies in humans provide pharmacokinetic evidence for the
paracellular drug transportation pathway, many of the experiments
have compared pharmacodynamic endpoints after intranasal and
intravenous administration. Pietrowsky et al..sup.73 reported the
event-related potentials, which are a measure of the brain's
electrical response to a stimulus, after administration with either
intranasal or intravenous arginine vasopressin. In a double-blind
crossover study, subjects had a significant increase in the P3
component, the component of the event-related potentials that is
task related, after intranasal administration, while intravenous
administration did not show significant differences compared to
placebo. Additionally, the plasma concentrations after intravenous
administration were higher than that after intranasal use, which
led Pietrowsky et al. to conclude that the peptide was delivered in
a direct nose-to-brain transport pathway, and not merely being
absorbed systemically and crossing the BBB. In rats, substances as
large as mesenchymal stem cells have been delivered by direct
nose-to-brain pathways.sup.75. The wide variety of substances that
can be transported to the brain through these mechanisms gives
promise to many treatment options for CNS-related disorders.
[0084] ii. Mucoadhesive/Viscosity Increasing Agents
[0085] Additionally, the intranasal administration methods and
devices described herein may be used with different formulation
techniques have been reported to overcome some of the barriers to
nasal drug delivery in hopes of increasing the amount delivered to
the brain. A large barrier that is unique to nasal delivery is the
mucociliary clearance. Mucoadhesive and viscosity increasing agents
have been used to increase drug residence time in the nasal cavity
for better absorption..sup.76 By increasing the viscosity of the
formulation, with polymers such as hypromellose or polyvinyl
alcohol, it is possible to decrease mucociliary
clearance..sup.77,78 Even though the cilia in the olfactory
epithelium are non-motile, mucus clearance is still evident and
most likely caused by gravity and continuous mucus production by
the Bowman's gland. Charlton et al..sup.79 studied how some
mucoadhesive agents can affect deposition and clearance to the
olfactory region in humans. Their experiments compared the
clearance of different low-molecular weight pectin and chitosan
formulations in 12 human subjects administered as either liquid
drops or atomized from a nasal spray device. The formulations
contained fluorescein so that the deposition could be visually
examined by endoscopy. Charlton et al. found no statistical
difference in the clearance from the olfactory region between the
formulations given as liquid drops. However, the residence time and
deposition were significantly reduced after nasal spray
administration, which was similar to the control buffer solution
without a mucoadhesive agent. Formations with mucoadhesive agents
are effective at extending residence times at the olfactory
epithelium, but they are not the only factor for successful drug
delivery in humans.
[0086] It has been shown that mucoadhesive and viscosity increasing
agents are effective at increasing bioavailability from nasal
formulations designed for systemic delivery..sup.80 To determine
how the addition of a mucoadhesive agent can influence the
absorption of drugs into the brain.sup.81, Khan et al..sup.33
compared brain concentrations of buspirone after administration
intravenously, intranasally as a solution and intranasally as a
solution with 1% chitosan and 5% hydroxypropyl-3-cyclodextrin. They
found that the AUC in the brain was 2.5-times higher for buspirone
in the mucoadhesive formulation than in the intravenous solution,
and 2-times as high as buspirone solution delivered intranasally.
The excipients may have also contributed to the increase in brain
concentration by increasing the permeability of the drug through
the tight junctions of the nasal epithelium..sup.33
[0087] Utilizing a novel formulation to increase nasal residence
time and improve brain delivery, Bank et al..sup.59 compared brain
concentrations after nasal delivery of testosterone in
Noseafix.RTM. gel, which is comprised of castor oil, oleoyl
polyoxyglycerides and amorphous silicon dioxide, to those measured
after intravenous administration. They found significantly higher
brain levels in all parts of the brain except the frontal cortex
following intranasal administration. However, since the authors did
not compare intranasal administration of testosterone without
Noseafix.RTM., no conclusion was stated about the effect the
formulation had on increasing brain delivery. The increase in brain
concentration may be attributed to intranasal administration
alone.
[0088] Barakat et al..sup.34 studied nose-to-brain delivery of
carbamazepine with the use of hypromellose and Carbopol 974P to
form a gel to reduce clearance. They found the brain AUC-to-plasma
AUC ratio was 4.31-times higher than from intravenous therapy.
Carbamazepine has also been formulated in an in situ gelling
formulation for direct nose-to-brain delivery..sup.35 The
formulation consisted of carbamazepine, 18% Pluronic F-127 and 0.2%
Carbopol 974P, which is a thermoreversible gel. A thermoreversible
gel is liquid at room temperature, but quickly turns into a gel at
body temperature, which provides an extended residence time in the
nasal cavity.
[0089] When compared to intravenous administration of carbamazepine
solution, Barakat et al. found that the intranasal formulation
provided 100% systemic bioavailability. Even at early time points,
they were unable to detect significantly higher brain levels in the
intranasal group. Intranasal administration was performed on rats
that were lying either on their side or in the supine position.
Body position during intranasal administration plays a significant
role on the deposition of formulation in the nasal cavity,
targeting the respiratory region instead of the olfactory.
[0090] Other studies have reported on the effects that
thermoreversible gels can have on direct nose-to-brain drug
delivery. Ravi et al..sup.51 used poloxamer 407 and poloxamer 188
(1:1) with chitosan and Carbopol to develop a thermoreversible gel
with rasagiline mesylate. Compared to a nasal solution of
rasagiline in normal saline, the gel formulations exhibited
significantly higher brain uptake. In a different formulation that
also exhibited gelling at body temperature, Khan et al..sup.55
formed an in situ gel formulation comprised of chitosan and
hypromellose to deliver ropinirole, and found that the AUC in the
brain was 8.5-times higher compared to intravenous administration
and nearly four times greater than ropinirole solution alone given
intranasally.
[0091] Doxepin has been formed into a thermoreversible gel
formulated with chitosan and glycerophosphate. Instead of accessing
brain concentrations from homogenated brain tissue, the
investigators assessed efficacy by a forced swim test, yet they saw
no significant difference in duration of immobility when
tested.sup.38. In situ gel preparations active in the presence of
ions have also been developed and show the ability to form a gel in
the presence of nasal secretions..sup.82 These studies, also shown
in Table 1, describe that altering a formulation to increase the
drug's residence time, allowing an increase in the time the
formulation is in contact with the olfactory epithelium, generally
lead to an increase in the amount of drug delivered to the
brain.
[0092] iii. Polymeric Nanoparticles
[0093] A favorable formulation method for many routes of
administration is the formation of nanosuspensions of drug
encapsulated in polymeric carriers. These carriers may provide
favorable characteristics to the drug like enhanced absorption,
mucoadhesion and increased stability. Bhavna et al..sup.37
developed a nanosuspension formulation of donepezil, a
cholinesterase inhibitor, for enhancing brain targeting to treat
Alzheimer's disease. The nanosuspension is formed by crosslinking
chitosan with tripolyphosphate to form nanoparticles that
encapsulate donepezil. When tested in rats against donepezil
suspension, the authors reported significantly higher AUC and
maximum concentration in the brain after administration with the
nanosuspension. The authors also observed significantly higher
bioavailability with the nanosuspension so whether or not the
increase in brain concentrations was due to direct nose-to-brain
mechanisms is difficult to conclude.
[0094] In another paper, the authors tested chitosan nanoparticles
loaded with bromocriptine..sup.32 In this study they compared
bromocriptine-loaded nanoparticles given intranasally,
bromocriptine-loaded nanoparticles given intravenously, and
bromocriptine solution given intranasally. They found that
bromocriptine-loaded nanoparticles given intranasally produced
brain AUCs that were over two-fold greater than intravenous
administration of the nanoparticles. Both nanoparticle formulations
showed higher brain and plasma AUC values.
[0095] A novel polymeric carrier developed by Gao et al..sup.83 is
comprised of wheat germ agglutinin conjugated to poly (ethylene
glycol)-poly (lactic acid) (PEG-PLA) in an effort to increase
absorption of nanoparticles to the brain. They used the
nanoparticle carrier to encapsulate coumarin and found a two-fold
increase in brain concentrations after intranasal administration
compared to intranasal administration of unmodified PEG-PLA
nanoparticles. In a later study, Gao et al. determined whether or
not the nanoparticle carrier would be applicable to transport
peptides to the brain..sup.84 They incorporated vasoactive
intestinal peptide into the wheat germ agglutinin conjugated
PEG-PLA nanoparticles.
[0096] When given intranasally, the authors reported 5.6-7.7 fold
higher brain levels from the conjugated nanoparticles compared to
vasoactive intestinal peptide given intranasally as a solution.
Additionally, they also found higher brain levels from the
conjugated nanoparticles compared to the peptide delivered in
unmodified nanoparticles. The results from this study are displayed
in FIG. 1, which shows the concentrations of vasoactive intestinal
peptide measured in the olfactory bulb and olfactory tract (FIG.
1A), cerebrum (FIG. 1B) and cerebellum (FIG. 1C) after
administration with the wheat germ agglutinin conjugated PEG-PLA
nanoparticles, unmodified nanoparticles, or as a solution. Higher
concentrations in the olfactory region (FIG. 1A) and the cerebellum
(FIG. 1C) provide some evidence that the pathway for transport of
the nanoparticles into the brain is along both the olfactory and
trigeminal nerves. The novel carrier was assessed for toxicity
issues during intranasal use by analyzing concentrations of
surrogate markers, such as tumor necrosis factor alpha and wheat
germ agglutinin specific antibodies, and concluded that the
nanoparticles were a safe agent for use in intranasal therapy
targeting the brain..sup.85 Seju et al..sup.47 used one of the most
commonly used biodegradable polymers for nanoparticles,
poly(lactic-co-glycolic acid) (PLGA)..sup.47,86 The authors loaded
olanzapine, an atypical antipsychotic, into the PLGA nanoparticles
for intranasal delivery. The authors performed ex vivo permeation
studies along with pharmacokinetic studies in rats and found the
nanoparticles were slower to the diffuse the sheep nasal mucosa in
the ex vivo study. However, in the pharmacokinetic study, they
found 10.86 times higher drug accumulation in the brain after
nanoparticle administration than olanzapine solution given
intranasally, and 6.35 times higher than after drug solution given
intravenously. Studies with polymeric nanoparticles are not yet
conclusive on whether or not the particles are being absorbed into
the brain or if the particles are adhering to the mucosal surface,
followed by release of the drug. Gao et al..sup.83 discussed that
the enhanced brain concentrations from the wheat germ agglutinin
conjugated nanoparticles allowed binding with the nasal mucosal
surface and then release of the drug. Bhavna et al. predicted that
enhancements in brain delivery are also due to the mucoadhesive
nature of chitosan. However, Fazil et al..sup.87 performed confocal
laser scanning microscopy with rhodamine loaded chitosan
nanoparticles and reported that intact particles were found in the
brain. Seju et al..sup.47 predicted that olanzapine PLGA
nanoparticles were transported as intact particles by endocytotic
processes. Future studies are required to determine if the
transport of the individual nanoparticle takes place for all
nanoparticles, or if this is an advantage of a select few
nanoparticle types. These studies, summarized in Table 1, show the
promise that polymeric nanoparticle carriers can have on the
delivery of both small molecules and peptides into the brain.
[0097] iv. Co-Administration Methods for Improved Delivery
[0098] The olfactory region receives its blood supply from small
branches off the ophthalmic artery, while the respiratory region
receives its blood supply from a large arterial branch from the
maxillary artery. As a result, the respiratory region is highly
innervated with blood vessels, making it an ideal target for
systemic drug absorption..sup.14. Often researchers target the
olfactory region for nose-to-brain delivery, since this has fewer
blood vessels contributing to plasma concentrations, while
providing access to the olfactory nerve pathways. Dhuria et
al..sup.88 studied the effect phenylephrine, a vasoconstrictor used
for nasal decongestion, would have on increasing the brain to
plasma AUC ratio. They tested brain concentrations after nasal
administration of one of two neuropeptides, hypocretin-1 or
dipeptide L-Tyr-D Arg. The use of the vasoconstrictor significantly
decreased the amount of drug absorbed into the systemic circulation
(as shown in FIG. 1); it also significantly increased the amount
delivered to the olfactory bulb. However, this resulted in a
decreased amount in the trigeminal nerve and about 50% decrease in
whole brain concentrations of the neuropeptides. Use of a
vasoconstrictor to modify drug absorption may be applicable for
delivering some therapeutics to the brain depending on the risks of
systemic exposure and location of the target for therapy. The CSF
originates at the choroid plexus and eventually flows across the
cribriform plate and into the nasal lymphatics.
[0099] Shingaki et al. tested the use of acetazolamide to increase
brain concentrations of drugs delivered nasally..sup.31,42
Acetazolamide, a carbonic anhydrase inhibitor, functions to
decrease the production of CSF. When rats were dosed with 5-FU with
and without pre-administration of acetazolamide, Shingaki et al.
found significantly higher CSF levels with the concomitant use of
acetazolamide..sup.31 Similar studies with methotrexate produced
similar results..sup.42 Co-administration with acetazolamide leads
to a decrease in CSF secretion, which provides an increase in
direct transport of drugs into the CSF.
[0100] v. Solubility and Permeability Enhancing
[0101] For drugs to take advantage of the extracellular mechanisms
of drug transport they must cross the nasal epithelium. Since the
trigeminal nerve ending is located in the lamina propria, it is
necessary for drugs to cross the nasal epithelium to access this
pathway. In targeting drug delivery to the system circulation, many
agents have been used to increase the permeation of drugs across
the epithelium..sup.89-94 Agents used to increase the permeability
across a membrane are referred to as permeation enhancers. Since
the nasal epithelial layer is connected by tight junctions,
permeation enhancers that open tight junctions may be useful in
improving drug delivery to the brain. Some studies have used
bomeol.sup.95, chitosan and cyclodextrins.sup.33,40 to help improve
direct nose-to-brain drug transport. Other methods to increase
delivery of drugs to the brain use lipid components like
microemulsions. Microemulsions can increase the concentration of
hydrophobic drugs to be delivered, as well as increase the
permeability across membranes..sup.96 Jogani et al..sup.58
developed a microemulsion formulation of tacrine for delivery to
the brain.
[0102] Firstly, they prepared a solution of tacrine in propylene
glycol and water and compared its brain delivery after intranasal
and intravenous administration. They found that the direct
transport efficiency (DTE) was 207.23..sup.57 DTE is a comparison
of ratios of the AUC in the brain compared to plasma after
intranasal administration compared to intravenous administration,
and is described by the following equation:
% DTE = [ AUC brain / AUC blood i . n . ] [ AUC brain = AUC blood i
. v . ] .times. 100 % ##EQU00001##
[0103] Values greater than one, indicate that a higher brain/plasma
ratio is obtained from intranasal administration as compared to
intravenous administration. Jogani et al. then incorporated tacrine
into a microemulsion formulation and a mucoadhesive microemulsion
using the mucoadhesive agent Carbopol 934P.
[0104] The authors then compared brain delivery to mice from
tacrine solution given intranasally and intravenously to tacrine
microemulsion and tacrine mucoadhesive microemulsion given
intranasally. The tacrine mucoadhesive microemulsion showed the
highest DTE of 295.87%, followed by the tacrine microemulsion (DTE
242.82%) and then tacrine solution (DTE 207.23%). Many different
investigators have looked at the effects microemulsion and
nanoemulsions with and without the use of mucoadhesive agents can
have on direct nose-to-brain delivery (Table
1)..sup.41,45,46,48,56,97,98 For instance, Patel et al..sup.49
studied the pharmacokinetics from a paliperidone microemulsion
formulation intended for delivery to the brain. Instead of Carbopol
934P, Patel et al. used polycarbophil as a mucoadhesive agent in
the formulation.
[0105] When given in rats, the mucoadhesive microemulsion
formulation gave the highest DTE, 320.69%, which was 1.74-fold
higher than paliperidone given intranasally as a solution.
Additionally, the intranasal mucoadhesive microemulsion produced
brain AUCs that were 2.43 times higher than after intravenous
administration of the microemulsion. One study used an in situ
gelling agent to increase the residence time in the nasal cavity
after the microemulsion is administered. Wang et al..sup.36
developed a microemulsion using deacytylated gellan gum for ion
activated in situ gelling. When testing with curcumin, they found
the DTE to be 6.50 and a brain AUC three times that after curcumin
injection.
[0106] Curcumin has also been used to study the effects of an
optimized mucoadhesive nanoemulsion ex vivo permeation through
sheep nasal mucosal as well as in vitro toxicity studies. The
mucoadhesive agent used with the nanoemulsion was chitosan. The
investigators found that their nanoemulsion did not cause
noticeable toxicity issues and increased curcumin permeation across
the nasal mucosal..sup.99
[0107] Risperidone has also been formulated into a mucoadhesive
nanoemulsion..sup.53 The mucoadhesive agent added to the
nanoemulsion was 0.5% chitosan. The DTE was found to be 476 when
tested in rats. The intravenous control in the experiment was
risperidone nanoemulsion, which shows higher brain intake was not
due to the nanoemulsion alone, but also contributed to by direct
nose-to-brain pathways, as shown in FIG. 2. The locomotor activity
was significantly reduced in mice when treated with any of the
tested formulations of risperidone. There was a significant
reduction in activity from the risperidone nanoemulsion and
mucoadhesive nanoemulsion given intranasally compared to the
risperidone nanoemulsion given intravenously.
[0108] Risperidone has also been formulated as solid lipid
nanoparticles for nose-to-brain delivery..sup.54 Solid lipid
nanoparticles reportedly provide many advantages over solution and
drug suspension dosage forms. They can entrap the drug, giving the
ability to control release and to improve stability. Additionally,
they possess many of the advantages of microemulsion and
nanoemulsions. Solid lipid nanoparticles have recently received a
lot of attention in delivery therapeutics using direct
nose-to-brain drug delivery, as seen in table 1..sup.54,61,100,101
Patel et al..sup.54 entrapped risperidone into solid lipid
nanoparticles (SLNs) and gave them intranasally and
intravenously.
[0109] Risperidone solution was also given intravenously. It was
shown that the SLNs given intranasally produced a brain to plasma
AUC ratio fivefold higher than the SLN formulation given
intravenously and tenfold higher than the risperidone solution
given intravenously. The brain AUC values after risperidone SLNs
were administered intranasally and intravenously were similar;
however, the plasma AUC after intranasal administration was lower.
In theory, this would allow for equal efficacy while reducing
systemic side effects by lowering the plasma concentration.
Similarly, Alam et al..sup.39 studied the effects that a lipid
nanocarrier of duloxetine would have on brain delivery. They found
the lipid nanocarrier formulations provided about eight times
higher brain concentrations when compared to intravenous
administration of duloxetine solution and a DTE of 757.14%.
[0110] Intranasal administration of duloxetine solution produced a
DTE of 287.34%, showing that the lipid nanocarrier formulation was
able to significantly influence the amount delivered to the brain.
Many of the above-mentioned studies took place using psychiatric
medications, but another area for therapeutic improvement using
this pathway is the treatment of migraines. Jain et al..sup.62
produced a micellar formulation of zolmitriptan, a medication
indicated for migraine treatment. The goal of the formulation would
be to maintain the rapid onset of action provided by intranasal
zolmitriptan while improving its efficacy and duration of action.
They found that after administering the micellar formulation, there
was about fivefold higher brain concentrations in rats as soon as
30 minutes after administration, and the formulation continued to
show significantly higher brain concentrations up to 120 minutes.
Further clinical study is required to see how this could affect
treatment of migraines, however it has been observed that it is
possible to increase zolmitriptan brain uptake in this manner.
EXAMPLES
Example 1: The Nasal Implant Requires Solutions which can Achieve
Sufficient
[0111] concentrations of the active therapeutic agents to delivery
an effective amount to the appropriate nasal surfaces. To achieve a
sufficient concentration, the therapeutic agents were formulated as
a solid dispersion powder. To form the solution of the solid
dispersion components, mebendazole and Kollidon VA 64.RTM. were
dissolved at a 1:4 ratio in 0.62% HCl: 49.7% methanol: 49.7%
tetrahydrofuran. This solution was spray dried in a Buchi B-290 at
inlet temperature 100.degree. C., Pump 15% and Qflow 40 mm. The
resulting solid dispersion was amorphous according to PXRD spectra
(FIG. 16) and exhibited supersaturation upon dissolution in
deionized water (FIG. 15). As a comparison, FIG. 16 shows the PXRD
spectra of a physical mixture as well as crystalline mebendazole.
The amorphous nature as well as the supersaturated characteristic
of the solution indicated favorable solution characteristic for the
use in an intranasal delivery device.
Example 2: The Following Process was Used to Produce a Solid
Dispersion of Mebendazole
TABLE-US-00002 [0112] TABLE 2 Parts by weight No. Mebendazole
Povidone K30 Kollidon VA 64 .RTM. 1 1 1 0 2 1 2 0 3 1 3 0 4 1 0 1 5
1 0 2 6 1 0 3
[0113] Solutions of the solid dispersion components were prepared
by dissolving the component in 20% formic acid: 80% acetone. The
resulting solutions was spray dried in a Buchi B-290 at inlet
temperature of 100.degree. C., pump 15%, Aspirator 100% and a Qflow
of 55 mm. The resulting solid dispersion were analysed by PXRD for
detection of crystallinity. Crystallinity was observed in all
preparations except No. 3 and No. 6.
Example 3
[0114] In order to determine the delivery location of the
preparation using the intranasal delivery device, a foam
formulation was prepared using fluorescein. The composition
components and amounts are shown in FIG. 17. All of the components
except HFA 227 were added into a canister and a continuous spray
valve was crimped on followed by addition of HFA 227 by pressure
filling. Actuation of foam was performed with a prototype device as
disclosed herein, with an actuator adapted from an 18 gauge syringe
for directing foam deposition. In order to quantitate the drug
deposition in different regions of the nasal casts, they were each
divided into five separate parts based on anatomy, as shown in FIG.
18. As shown in FIG. 19, the percent deposited in the upper region
was 27.9 percent, compared to 9.0 percent for the anterior region,
29.5 percent for the middle region, 33.6 percent for the lower
region and 0 percent for the nasopharynx region.
Example 4
[0115] Nasal replica casts that anatomically represent the nasal
cavities of individuals were fabricated to study the regional
deposition of compositions within the nasal cavity. CT-scans of
individuals were uploaded into 3D Slicer software
(http://www.slicer.org). FIG. 4 shows an example of the CT-scan of
an individual before segmentation of the nasal cavity. Threshold
effects within the editor module of the software were used to
segment the region of the nasal cavity. Manual edits were used to
remove the sinuses from the nasal cavity segment. The model feature
of the editor module was used to create a model of the segmented
nasal cavity from the CT-scan in a format that could be 3D-printed.
The 3D model was printed by W. M. Keck Center for 3D innovation (El
Paso, USA) using a Viper.TM. HA SLA.RTM. system (3D Systems Corp.,
Valencia, USA) with build layer thickness of 0.004 inches and
resolution of 0.010 inches using Somos.RTM. Watershed XC 11122 (DSM
Somos.RTM., Elgin, USA) as the material. The age, gender and basic
geometric parameters are provided in Table 3. The measurements used
to depict the geometric parameters of the nasal cast replicas is
presented in FIG. 20.
TABLE-US-00003 TABLE 3 Area.sub.min Length.sub.n-t Cast Age Gender
(mm.sup.2) (mm) C1 12 Female 258.344 75.884 C2 7 Female 113.969
59.159 C3 7 Female 217.201 59.791 C4 9 Female 173.471 63.609 C5 14
Female 299.155 68.990 C6 48 Male 249.173 88.000 C7 33 Male 279.347
86.680 C8 44 Female 218.720 80.730 C9 48 Male 249.300 86.000 C10 31
Female 213.241 78.207 Pediatric (n = 5) Adult (n = 5) Age (yrs.)
9.8 (3.1) 40.8 (8.2) Area.sub.min (mm.sup.2) 212.428 (72.223)
241.956 (26.780) Length.sub.n-t 65.487 (7.007) 83.923 (4.225)
Area.sub.min = minimum coronal cross-section area; Length.sub.n-t =
length from nostrils to the end of the turbinates Averages
presented as mean (standard deviation)
Example 5
[0116] Deposition studies, in nasal replica cast C3 from Example 4,
were used to compare the effect of administration angles on
deposition to the to the upper region of the nasal cavity. The
device used in this example was a prototype device resembling FIG.
11. The device consisted of a propellant canister connected to a
dosing chamber modified from a 2 mL microcentrifuge tube which was
further connected to the top 1.5 inches of a 5000 mL pipette tip
(Eppendorf, Germany) with an anatomically-positioning insert. HFA
134a was used as propellant to propel the powder from the device.
The anatomically-positioning insert was developed by creating a
negative mold of the nostrils of the individuals from the
3D-printed models using Copyflex.RTM. (MakeYourOwnMolds,
Cincinnati, USA) around the device fixed at a specific
position.
[0117] Deposition in each region of the nasal cavity was performed
using a powder comprised of 5% (w/w) fluorescein in InhaLac.RTM. 70
(MEGGLE, Germany). 5 mg of the powder was loaded into the device,
which was dispensed by actuation of the Metered Dose Inhaler
canister fitted with a valve set to deliver 100 .mu.L of
propellant. The insertion depth of the device was set at 10 mm. The
deposition in each region was measured by washing each region of
the nasal cast with 5 mL of 3% w/v sodium hydroxide aqueous
solution and measuring UV absorbance at 494 nm for each cast. FIG.
6 illustrates the individual regions of the nasal cast.
[0118] The deposition study results are shown in Table 4. The
sagittal angle is presented with respect to the base of the nasal
cavity. The coronal angle is depicted as being positive towards the
septum. The coronal angle and sagittal angles are depicted with
respect to the nasal cavity in FIG. 8 as A and B respectively.
[0119] Changes in the angle of administration created differences
in the deposition to the upper region of the nasal cavity. As
differences in the administration angle affect the deposition
pattern of the powder, controlling the angle of administration
affects the deposition pattern. As evident, by controlling the
sagittal and coronal angles for nasal replica cast C3, the
anatomical positioning is important to optimize its upper region
deposition, and therefore the upper region deposition must be
optimized for individualized administration.
TABLE-US-00004 TABLE 4 Sagittal Angle Coronal Angle Upper region
deposition (degrees) (degrees) (% deposited) 62.0 34.8 6.7% 65.0
7.6 13.6% 60.0 1.0 15.6%
Example 6
[0120] The anatomical positioning device can be modeled based on
the CT scan of the individuals. In this example, the device used
for deposition experiments was the same as that described in
Example 2 except that the anatomically-positioning insert was
developed by 3D-printing the negative model of the nostril with a
hole placed near the middle of the insert, which allows the device
tip to be inserted at a specified depth and angle into the nostril
of the cast.
[0121] Deposition in each region of the nasal cavity (C3 from Table
1, Example 1)) was performed with a powder comprised of 5% (w/w)
fluorescein in InhaLac.RTM. 70 (MEGGLE, Germany). 5 mg of the
powder was loaded into the device which was activated by actuation
of the Metered Dose Inhaler canister fitted with a valve set to
deliver 100 .mu.L of liquid propellant. The insertion depth of the
device was set at 10 mm. The sagittal angle with respect to the
base of the nasal cast was 60.7 degrees and the coronal angle with
respect to the septum was 6.6 degrees. Deposition in each region
was quantified using the method described in Example 2. The
percentage of deposited fluorescein measured in the upper region
compared to the entire cast was 22.0% with a standard deviation of
3.6%. As evident, by controlling the sagittal and coronal angle for
nasal replica cast C3, the anatomical positioning is important to
obtain reproducible upper region deposition.
Example 7
[0122] Individualized administration parameters can be obtained by
use of the CT-scan images. The angles for administration to target
the upper region of the nasal cavity were determined based on
factors found in the specific CT-scan for each individual. The
angles in the coronal and sagittal planes were determined based on
the positioning of two points. Point 1 was placed in the center of
the nostril at the beginning of the nasal cavity. Point 2 was
placed in the coronal plane CT slice that was located at 0.3
multiplied by the length (L) of the nasal cavity (FIG. 21), zero
defined at the anterior portion of the cavity comprising the
nostril region. Point 2 was placed at 0.7 multiplied by the height
(H) of the nasal cavity at the previously determined coronal place
slice (FIG. 22). The coronal and sagittal angles were calculated
based on equation 1 and equation 2, respectively. Where x, y, and z
points correspond to their coordinates in the Cartesian plane found
in 3D Slicer software's view of the CT-scans. Table 5 presents the
angles of administration determined for the left nostril of each
individual. The angles determined from this example are referred to
as the CT-scan based angle.
Coronal angle = tan - 1 y 2 - y 1 ( x 2 - x 1 ) . Equation 1
Sagittal angle = tan - 1 y 2 - y 1 ( z 2 - z 1 ) . Equation 2
##EQU00002##
TABLE-US-00005 TABLE 5 Individual Sagittal Angle (degrees) Coronal
Angle (degrees) 1 53.3 -1.9 2 61.1 7.2 3 55.9 9.7 4 60.6 5.2 5 64.3
4.3 6 60.4 5.8 7 58.5 1.2 8 61.0 2.5 9 60.0 1.0
Example 8
[0123] Individualized administration parameters can be obtained by
use of the three-dimensional model of the nasal cavity. The angles
for administration to target the upper region of the nasal cavity
were determined based on the relative force of airflow that passed
to the upper region of the nasal cavity. The upper region of the
nasal cavity was removed from the nasal cast, which was otherwise
assembled and placed over an analytical balance (Mettler Toledo,
Columbus, USA) with the nostril opening facing away from the
balance plate. (FIG. 23) Airflow was produced using a jet nebulizer
compressor (Pari, Midlothian, VA) and directed through a nozzle
developed with a 5 mL pipette tip (Eppendorf, Germany). The nozzle
was placed in to a nostril of the nasal cast and airflow was
allowed to flow through the cast and impact on the balance. The
relative force produced by the airflow was logged using the serial
port on the analytical balance.
[0124] To obtain the angle in which the nozzle was placed into the
nasal casts over time, two cameras were set up on adjacent sides of
the nasal cast. One camera captured the sagittal plane of the nasal
cast, providing the sagittal angle of the nozzle, while the other
captured the coronal plane of the nasal cast, providing the coronal
angle of the nozzle. The picture frames corresponding to the time
at which the relative force of the airflow was at its maximum were
used to measure the sagittal and coronal angles using ImageJ angle
tool. Table 6 depicts the administration angles found using this
method for the left nostril of each individual. The angles used in
this method are henceforth referred to as the airflow based
angle.
TABLE-US-00006 TABLE 6 Individual Sagittal Angle (degrees) Coronal
Angle (degrees) 1 46.0 -5.2 2 67.1 23.1 3 55.8 14.4 4 56.0 4.3 5
67.5 16.8 6 50.3 -3.8 7 60.0 9.2 8 71.5 6.7 9 60.7 6.6
Example 9
[0125] The deposition to the upper region of the nasal cavities
described in Example 1 was produced with the device described in
Example 2, with anatomical--positioning inserts created for each
individual controlling for the CT-scan based angles presented in
Table 3. Deposition experiments were performed in the left nostril
of each cast. Deposition in each region of the nasal cavity was
performed with a powder comprised of 5% (w/w) fluorescein in
InhaLac 70 (MEGGLE, Germany). 5 mg of the powder was loaded into
the device which was activated by actuation of the Metered Dose
Inhaler canister fitted with a valve set to delivery 100 .mu.L. The
insertion depth of the device was set at 10 mm. The percentage of
deposited fluorescein found in the upper region for each cast is
depicted in Table 7 as determined based on the quantification
method presented in Example 2.
TABLE-US-00007 TABLE 7 Cast of individual described Upper region
deposition in Table 3 (% of detected) 1 35.5% 2 9.1% 3 3.2% 4 35.0%
5 7.1% 6 3.1% 7 54.2% 8 41.1% 9 15.8%
Example 10
[0126] The deposition to the upper region of the nasal cavities
described in Example 1 was produced with the device described in
Example 2, with anatomical--positioning inserts created for each
individual controlling for the airflow based angles presented in
Table 3. Deposition experiments were performed in the left nostril
of each cast. Deposition in each region of the nasal cavity was
performed with a powder comprised of 5% (w/w) fluorescein in
InhaLac.RTM. 70 (MEGGLE, Germany). 5 mg of the powder was loaded
into the device which was activated by actuation of the Meteredd
Dose Inhaler canister fitted with a valve set to delivery 100
.mu.L. The insertion depth of the device was set at 10 mm. The
percentage of deposited fluorescein found in the upper region for
each cast is depicted in Table 8 as determined based on the
quantification method presented in Example 2.
TABLE-US-00008 TABLE 8 Cast of individual described Upper region
deposition in Table 3 (% of detected) 1 11.9% 2 15.8% 3 10.7% 4
50.3% 5 16.7% 6 5.3% 7 48.8% 8 26.7% 9 12.4%
Example 11
[0127] The deposition to the upper region of the nasal cavities
described in Example 1 was produced with the device described in
Example 2, with anatomical--positioning inserts created for each
individual controlling the administration angles to a sagittal
angle of 55.0 degrees and coronal angle of 5.0 degrees for all
casts. Deposition experiments were performed in the left nostril of
each cast. Deposition in each region of the nasal cavity (C3 from
Example 1)) was performed with a powder comprised of 5% (w/w)
fluorescein in InhaLac.RTM. 70 (MEGGLE, Germany). 5 mg of the
powder was loaded into the device, which was activated by actuation
of the Metered Dose Inhaler canister fitted with a valve set to
deliver 100 .mu.L. The insertion depth of the device was set at 10
mm. The percentage of deposited fluorescein found in the upper
region for each cast is depicted in Table 9 as determined based on
the quantification method presented in Example 2. The angle used in
this test is henceforth referred to as the common use angle.
TABLE-US-00009 TABLE 9 Cast Upper region deposition (% of detected)
1 46.6% 2 8.1% 3 18.4% 4 33.4% 5 18.4% 6 2.9% 7 41.3% 8 36.7% 9
2.0%
Example 12
[0128] The individualized administration to a person can be further
optimized by testing the deposition to a particular region using
the parameters determined by various methods. The selection for the
patient-specific angle for targeting to upper region of the nasal
cast is determined based on the relative improvement in deposition
using the CT-Scan based angles and the airflow based angles
compared to all casts using the common use angle is compared in
TABLE 10. The percentage of deposited fluorescein to the upper
region of the cast for CT-scan based angle, airflow based angles
and common use angle is divided by the results found for each cast
using the common use angle to compare the relative improvement in
deposition to this region. The olfactory targeting patient-specific
angle for targeting the upper region of the nasal cavity is taken
as the administration angle method presenting the highest value for
each patient.
TABLE-US-00010 TABLE 10 Relative deposition compared to common use
angle CT-scan Airflow based Cast based angle angle Common use angle
1 0.25 0.76 1.00 2 1.95 1.12 1.00 3 0.58 0.18 1.00 4 1.51 1.05 1.00
5 0.91 0.38 1.00 6 1.85 1.09 1.00 7 1.18 1.31 1.00 8 0.73 1.12 1.00
9 6.17 7.86 1.00
Example 13
[0129] The use of patient-specific administration angles for
targeting the upper region is compared to all casts using the
common use angle. Table 11 depicts the relative deposition using
the olfactory targeting patient-specific angle compared to the
common use angle for each individual. There was an average
improvement of 2.07-fold using the olfactory targeting
patient-specific angle compared to the common use angle for
targeting the upper region of the nasal cast. By individualizing
the administration to each individual, the upper region targeting
was improved compared to all individuals using the same
parameters.
TABLE-US-00011 TABLE 11 Relative deposition compared Cast to common
use angle 1 1.00 2 1.95 3 1.00 4 1.51 5 1.00 6 1.85 7 1.31 8 1.12 9
7.86 Average 2.07
Example 14
[0130] In this example, the device used was a metered dose pump
spray device, VP7 (Aptar Pharma, Le Vaudreuil, France). Cromolyn
sodium nasal solution, USP was formulated with the addition of
hypromellose E4M at 0.8% w/v. The nasal spray was actuated into the
nasal casts described in Example 1. To evaluate the effect of
patient-specific angles, which are designed for turbinate drug
delivery, a central-composite design of experiments was conducted.
The output variable for optimization was percentage of deposited
cromolyn sodium in the turbinate region. The inputs studied were
the coronal plane and sagittal plane angles of administration of
the nasal spray device. Table 12 depicts the coronal and sagittal
angle ranges used in the design of experiments for each cast. The
central composite design was developed with an axial value that
allowed the design to be rotatable and contained three central
points. The statistical design of experiments were generated and
analyzed by standard least squares regression using JMP.RTM. Pro 13
(SAS Institute, Inc., Cary, USA). The predicted angle for each cast
that maximized the turbinate deposition efficiency was tested, and
it was considered the patient-specific angle. The predicted optimal
angles for each cast are presented in Table 13.
[0131] To quantitate cromolyn sodium deposition in each region of
the nasal cast, the cast was dissembled and each part of the cast
was washed with 5 mL of deionized water. The concentration of
cromolyn sodium in the wash fluid of each part was assessed by UV
absorbance at 326 nm.
[0132] The administration angles of the nasal spray device were
controlled by mechanically fixing the position of the MightyRunt
actuator with the use of a rotatable vice.
TABLE-US-00012 TABLE 12 Coronal angle range Sagittal angle range
Cast (degrees) (degrees) C1 0-20 30-45 C2 0-20 30-45 C3 0-20 35-50
C4 0-20 35-50 C5 0-20 30-45 C6 0-20 30-45 C7 0-20 35-50 C8 0-20
35-50 C9 0-20 35-50 C10 0-20 35-50
TABLE-US-00013 TABLE 13 Patient-Specific Angle (degrees) Coronal
Angle Sagittal Angle Cast (degrees) (degrees) C1 20.0 30.0 C2 20.0
34.4 C3 20.0 35.0 C4 20.0 35.0 C5 15.7 30.0 C6 18.5 35.3 C7 14.7
35.0 C8 0.0 35.0 C9 10.3 35.0 C10 14.0 35.0
Example 15
[0133] To optimize the percentage of deposited cromolyn sodium in
the turbinateregion, the determined patient-specific angles from
Example 7 were compared with the percent drug deposited when all
casts used an administration angle of 30 degrees from horizontal in
the sagittal plane and zero degrees from the septum in the coronal
plane as a comparative example. The results of the turbinate
deposition efficiency are presented in Table 14. As shown in FIG.
24, the use of the patient-specific angle significantly increased
the turbinate deposition efficiency compared to that found for all
subjects using an administration angle of 30.degree., around 90%
compared to about 73%. When the administration angle was maintained
in all the replicas, we found turbinate deposition increased with
decreases in the administration angle. Deposition to the upper
regions of the replica was poor with any formulation or
administration angle tested. Personalized delivery using
patient-specific angles increases the turbinate targeting of the
tested formulation compared to each cast using the comparative
administration angle.
TABLE-US-00014 TABLE 14 % deposited cromolyn sodium in turbinate
region Patient-specific angle 30 degrees/0 degrees Cast (degrees)
(degrees) C1 97.1% 73.0% C2 93.8% 76.8% C3 97.8% 85.8% C4 97.0%
69.9% C5 95.8% 81.7% C6 86.9% 87.9% C7 75.7% 46.4% C8 81.5% 62.9%
C9 81.4% 65.5% C10 97.7% 79.5% Average 90.5%(8.3%) 72.9%(12.4%)
(standard deviation)
[0134] All of the devices, systems and/or methods disclosed and
claimed herein can be made and executed without undue
experimentation in light of the present disclosure. While the
devices, systems and methods of this invention have been described
in terms of particular embodiments, it will be apparent to those of
skill in the art that variations may be applied to the devices,
systems and/or methods in the steps or in the sequence of steps of
the method described herein without departing from the concept,
spirit and scope of the invention. All such similar substitutes and
modifications apparent to those skilled in the art are deemed to be
within the spirit, scope and concept of the invention as defined by
the appended claims.
REFERENCES
[0135] The contents of the following references are incorporated by
reference herein: [0136] 1. Sakr, A. & Alanazi, F. in
Remington: The Science and Practice of Pharmacy (eds. Allen, L. V.,
Jr., Ph D., Adejare, A., Ph D., Desselle, S. P., Ph D. &
Felton, L. A., Ph D.) (Pharmaceutical Press, 2012). [0137] 2.
Lockhead, J. & Thome, R. G. in Drug Delivery to the Brain:
Physiological Concepts, Methodologies and Approaches (Springer
Science & Business Media, 2013). [0138] 3. Thome, R. G., Emory,
C. R., Ala, T. A. & Frey II, W. H. Quantitative analysis of the
olfactory pathway for drug delivery to the brain. Brain Res. 692,
278-282 (1995). [0139] 4. Frey, W. H. et al. Delivery of 125I-NGF
to the Brain via the Olfactory Route. Drug Deliv. 4, 87-92 (1997).
[0140] 5. Wu, H., Hu, K. & Jiang, X. From nose to brain:
understanding transport capacity and transport rate of drugs.
Expert Opin. Drug Deliv. 5, 1159-1168 (2008). [0141] 6. Striepens,
N. et al. Elevated cerebrospinal fluid and blood concentrations of
oxytocin following its intranasal administration in humans. Sci.
Rep. 3, (2013). [0142] 7. Craft S, Baker L D, Montine T J & et
al. Intranasal insulin therapy for alzheimer disease and amnestic
mild cognitive impairment: A pilot clinical trial. Arch. Neurol.
69, 29-38 (2012). [0143] 8. Djupesland, P. G. & Skretting, A.
Nasal deposition and clearance in man: comparison of a
bidirectional powder device and a traditional liquid spray pump. J.
Aerosol Med. Pulm. Drug Deliv. 25, 280-289 (2012). [0144] 9.
Kublik, H. & Vidgren, M. T. Nasal delivery systems and their
effect on deposition and absorption. Adv. Drug Deliv. Rev. 29,
157-177 (1998). [0145] 10. Hardy, J. G., Lee, S. W. & Wilson,
C. G. Intranasal drug delivery by spray and drops. J. Pharm.
Pharmacol. 37, 294-297 (1985). [0146] 11. Giroux, M. Particle
dispersion device for nasal delivery. (2007). [0147] 12. Thomas, C.
& Ahsan, F. in Pharmaceutical Manufacturing Handbook:
Production and Processes (ed. Gad, S. C.) 591-650
(Wiley-Interscience, 2008). [0148] 13. Illum, L. Nasal drug
delivery--possibilities, problems and solutions. J. Controlled
Release 87, 187-198 (2003). [0149] 14. Dhuria, S. V., Hanson, L. R.
& Frey, W. H. Intranasal delivery to the central nervous
system: Mechanisms and experimental considerations. J. Pharm. Sci.
99, 1654-1673 (2010). [0150] 15. Pardeshi, C. V. & Belgamwar,
V. S. Direct nose to brain drug delivery via integrated nerve
pathways bypassing the blood-brain barrier: an excellent platform
for brain targeting. Expert Opin. Drug Deliv. 10, 957-972 (2013).
[0151] 16. Clerico, D., To, W. & Lanza, D. in Handbook of
Olfaction and Gustation 1-16 (CRC Press, 2003). [0152] 17. Mygind,
N. & Dahl, R. Anatomy, physiology and function of the nasal
cavities in health and disease. Adv. Drug Deliv. Rev. 29, 3-12
(1998). [0153] 18. Ruigrok, M. J. R. & de Lange, E. C. M.
Emerging Insights for Translational Pharmacokinetic and
Pharmacokinetic-Pharmacodynamic Studies: Towards Prediction of
Nose-to-Brain Transport in Humans. AAPS J. (2015). doi:
10.1208/s12248-015-9724-x [0154] 19. Lochhead, J. J. & Thorne,
R. G. Intranasal delivery of biologics to the central nervous
system. Adv. Drug Deliv. Rev. 64, 614-628 (2012). [0155] 20.
Verreck, G. et al. Characterization of solid dispersions of
itraconazole and hydroxypropylmethylcellulose prepared by melt
extrusion--part I. Int. J. Pharm. 251, 165-174 (2003). [0156] 21.
Weuts, I. et al. Physicochemical properties of the amorphous drug,
cast films, and spray dried powders to predict formulation
probability of success for solid dispersions: Etravirine. J. Pharm.
Sci. 100, 260-274 (2011). [0157] 22. DiNunzio, J. C. et al. Fusion
production of solid dispersions containing a heat-sensitive active
ingredient by hot melt extrusion and Kinetisol.RTM. dispersing.
Eur. J. Pharm. Biopharm. 74, 340-351 (2010). [0158] 23. Betageri,
G. V. & Makarla, K. R. Enhancement of dissolution of glyburide
by solid dispersion and lyophilization techniques. Int. J. Pharm.
126, 155-160 (1995). [0159] 24. Zhang, M. et al. Formulation and
delivery of improved amorphous fenofibrate solid dispersions
prepared by thin film freezing. Eur. J. Pharm. Biopharm. 82,
534-544 (2012). [0160] 25. Shah, N. et al. Improved human
bioavailability of vemurafenib, a practically insoluble drug, using
an amorphous polymer-stabilized solid dispersion prepared by a
solvent-controlled coprecipitation process. J. Pharm. Sci. 102,
967-981 (2013). [0161] 26. Won, D.-H., Kim, M.-S., Lee, S., Park,
J.-S. & Hwang, S.-J. Improved physicochemical characteristics
of felodipine solid dispersion particles by supercritical
anti-solvent precipitation process. Int. J. Pharm. 301, 199-208
(2005). [0162] 27. Arzhavitina, A. & Steckel, H. Foams for
pharmaceutical and cosmetic application. Int. J. Pharm. 394, 1-17
(2010). [0163] 28. Zhao, Y., Brown, M. B. & Jones, S. A.
Engineering novel topical foams using hydrofluroalkane emulsions
stabilised with pluronic surfactants. Eur. J. Pharm. Sci. 37,
370-377 (2009). [0164] 29. Zhao, Y., Brown, M. B. & Jones, S.
A. Pharmaceutical foams: are they the answer to the dilemma of
topical nanoparticles? Nanomedicine Nanotechnol. Biol. Med. 6,
227-236 (2010). [0165] 30. Zhao, Y., Moddaresi, M., Jones, S. A.
& Brown, M. B. A dynamic topical hydrofluoroalkane foam to
induce nanoparticle modification and drug release in situ. Eur. J.
Pharm. Biopharm. 72, 521-528 (2009). [0166] 31. Shingaki, T. et al.
The transnasal delivery of 5-fluorouracil to the rat brain is
enhanced by acetazolamide (the inhibitor of the secretion of
cerebrospinal fluid). Int. J. Pharm. 377, 85-91 (2009). [0167] 32.
Md, S. et al. Optimised nanoformulation of bromocriptine for direct
nose-to-brain delivery: biodistribution, pharmacokinetic and
dopamine estimation by ultra-HPLC/mass spectrometry method. Expert
Opin. Drug Deliv. 11, 827-842 (2014). [0168] 33. Khan, M. S.,
Patil, K., Yeole, P. & Gaikwad, R. Brain targeting studies on
buspirone hydrochloride after intranasal administration of
mucoadhesive formulation in rats. J. Pharm. Pharmacol. 61, 669-675
(2009). [0169] 34. Barakat, N. S., Omar, S. A. & Ahmed, A. a.
E. Carbamazepine uptake into rat brain following intra-olfactory
transport. J. Pharm. Pharmacol. 58, 63-72 (2006). [0170] 35.
Serralheiro, A., Alves, G., Fortuna, A. & Falcao, A. Intranasal
administration of carbamazepine to mice: A direct delivery pathway
for brain targeting. Eur. J. Pharm. Sci. 60, 32-39 (2014). [0171]
36. Wang, S., Chen, P., Zhang, L., Yang, C. & Zhai, G.
Formulation and evaluation of microemulsion-based in situ
ion-sensitive gelling systems for intranasal administration of
curcumin. J. Drug Target. 20, 831-840 (2012). [0172] 37. Bhavna et
al. Donepezil nanosuspension intended for nose to brain targeting:
In vitro and in vivo safety evaluation. Int. J. Biol. Macromol. 67,
418-425 (2014). [0173] 38. Naik, A. & Nair, H. Formulation and
Evaluation of Thermosensitive Biogels for Nose to Brain Delivery of
Doxepin. BioMed Res. Int. 2014, e847547 (2014). [0174] 39. Alam, M.
I. et al. Pharmacoscintigraphic evaluation of potential of lipid
nanocarriers for nose-to-brain delivery of antidepressant drug.
Int. J. Pharm. 470, 99-106 (2014). [0175] 40. Wang, X., He, H.,
Leng, W. & Tang, X. Evaluation of brain-targeting for the nasal
delivery of estradiol by the microdialysis method. Int. J. Pharm.
317, 40-46 (2006). [0176] 41. Hanson, L. R. et al. Intranasal
delivery of growth differentiation factor 5 to the central nervous
system. Drug Deliv. 19, 149-154 (2012). [0177] 42. Shingaki, T. et
al. Transnasal Delivery of Methotrexate to Brain Tumors in Rats: A
New Strategy for Brain Tumor Chemotherapy. Mol. Pharm. 7, 1561-1568
(2010). [0178] 43. Wang, F., Jiang, X. & Lu, W. Profiles of
methotrexate in blood and CSF following intranasal and intravenous
administration to rats. Int. J. Pharm. 263, 1-7 (2003). [0179] 44.
Westin, U. E., Bostrdm, E., Grisjd, J., Hammarlund-Udenaes, M.
& Bjork, E. Direct Nose-to-Brain Transfer of Morphine After
Nasal Administration to Rats. Pharm. Res. 23, 565-572 (2006).
[0180] 45. Zhang, Q. et al. Preparation of nimodipine-loaded
microemulsion for intranasal delivery and evaluation on the
targeting efficiency to the brain. Int. J. Pharm. 275, 85-96
(2004). [0181] 46. Abdelbary, G. A. & Tadros, M. I. Brain
targeting of olanzapine via intranasal delivery of core-shell
difunctional block copolymer mixed nanomicellar carriers: In vitro
characterization, ex vivo estimation of nasal toxicity and in vivo
biodistribution studies. Int. J. Pharm. 452, 300-310 (2013). [0182]
47. Seju, U., Kumar, A. & Sawant, K. K. Development and
evaluation of olanzapine-loaded PLGA nanoparticles for
nose-to-brain delivery: In vitro and in vivo studies. Acta
Biomater. 7, 4169-4176 (2011). [0183] 48. Kumar, M., Misra, A.,
Mishra, A. K., Mishra, P. & Pathak, K. Mucoadhesive
nanoemulsion-based intranasal drug delivery system of olanzapine
for brain targeting. J. Drug Target. 16, 806-814 (2008). [0184] 49.
Patel, M. R., Patel, R. B., Bhatt, K. K., Patel, B. G. &
Gaikwad, R. V. Paliperidone microemulsion for nose-to-brain
targeted drug delivery system: pharmacodynamic and pharmacokinetic
evaluation. Drug Deliv. 1-9 (2014). doi:
10.3109/10717544.2014.914602 [0185] 50. Wang, D., Gao, Y. &
Yun, L. Study on brain targeting of raltitrexed following
intranasal administration in rats. Cancer Chemother. Pharmacol. 57,
97-104 (2006). [0186] 51. Ravi, P. R., Aditya, N., Patil, S. &
Cherian, L. Nasal in-situ gels for delivery of rasagiline mesylate:
improvement in bioavailability and brain localization. Drug Deliv.
1-8 (2013). doi:10.3109/10717544.2013.860501 [0187] 52. Stevens,
J., Ploeger, B. A., Graaf, P. H. van der, Danhof, M. & Lange,
E. C. M. de. Systemic and Direct Nose-to-Brain Transport
Pharmacokinetic Model for Remoxipride after Intravenous and
Intranasal Administration. Drug Metab. Dispos. 39, 2275-2282
(2011). [0188] 53. Kumar, M. et al. Intranasal nanoemulsion based
brain targeting drug delivery system of risperidone. Int. J. Pharm.
358, 285-291 (2008). [0189] 54. Patel, S. et al. Brain targeting of
risperidone-loaded solid lipid nanoparticles by intranasal route.
J. Drug Target. 19, 468-474 (2011). [0190] 55. Khan, S., Patil, K.,
Bobade, N., Yeole, P. & Gaikwad, R. Formulation of intranasal
mucoadhesive temperature-mediated in situ gel containing ropinirole
and evaluation of brain targeting efficiency in rats. J. Drug
Target. 18, 223-234 (2010). [0191] 56. Mahajan, H. S., Mahajan, M.
S., Nerkar, P. P. & Agrawal, A. Nanoemulsion-based intranasal
drug delivery system of saquinavir mesylate for brain targeting.
Drug Deliv. 21, 148-154 (2013). [0192] 57. Jogani, V. V., Shah, P.
J., Mishra, P., Mishra, A. K. & Misra, A. R. Nose-to-brain
delivery of tacrine. J. Pharm. Pharmacol. 59, 1199-1205 (2007).
[0193] 58. Jogani, V. V. Mp., Shah, P. J. Mp., Mishra, P., Mishra,
A. K. & Misra, A. R. P. *. Intranasal Mucoadhesive
Microemulsion of Tacrine to Improve Brain Targeting. Alzheimer Dis.
Assoc. Disord. April. 2008 22, 116-124 (2008). [0194] 59. Banks, W.
A., Morley, J. E., Niehoff, M. L. & Mattern, C. Delivery of
testosterone to the brain by intranasal administration: Comparison
to intravenous testosterone. J. Drug Target. 17, 91-97 (2009).
[0195] 60. Dahlin, M. & Bjork, E. Nasal absorption of
(S)-UH-301 and its transport into the cerebrospinal fluid of rats.
Int. J. Pharm. 195, 197-205 (2000). [0196] 61. Dalpiaz, A. et al.
Brain Uptake of a Zidovudine Prodrug after Nasal Administration of
Solid Lipid Microparticles. Mol. Pharm. 11, 1550-1561 (2014).
[0197] 62. Jain, R., Nabar, S., Dandekar, P. & Patravale, V.
Micellar Nanocarriers: Potential Nose-to-Brain Delivery of
Zolmitriptan as Novel Migraine Therapy. Pharm. Res. 27, 655-664
(2010). [0198] 63. Brenneman, K. A. et al. Direct Olfactory
Transport of Inhaled Manganese (54MnCl2) to the Rat Brain:
Toxicokinetic Investigations in a Unilateral Nasal Occlusion Model.
Toxicol. Appl. Pharmacol. 169, 238-248 (2000). [0199] 64.
Henriksson, J., Tallkvist, J. & Tjalve, H. Transport of
Manganese via the Olfactory Pathway in Rats: Dosage Dependency of
the Uptake and Subcellular Distribution of the Metal in the
Olfactory Epithelium and the Brain. Toxicol. Appl. Pharmacol. 156,
119-128 (1999). [0200] 65. Persson, E., Henriksson, J. &
Tjalve, H. Uptake of cobalt from the nasal mucosa into the brain
via olfactory pathways in rats. Toxicol. Lett. 145, 19-27 (2003).
[0201] 66. Wolf, D. A. et al. Lysosomal enzyme can bypass the
blood-brain barrier and reach the CNS following intranasal
administration. Mol. Genet. Metab. 106, 131-134 (2012). [0202] 67.
Thorne, R. G., Pronk, G. J., Padmanabhan, V. & Frey II, W. H.
Delivery of insulin-like growth factor-I to the rat brain and
spinal cord along olfactory and trigeminal pathways following
intranasal administration. Neuroscience 127, 481-496 (2004). [0203]
68. Pardridge, W. M. Drug transport across the blood-brain barrier.
J. Cereb. Blood Flow Metab. 32, 1959-1972 (2012). [0204] 69.
Kandimalla, K. K. & Donovan, M. D. Transport of hydroxyzine and
triprolidine across bovine olfactory mucosa: Role of passive
diffusion in the direct nose-to-brain uptake of small molecules.
Int. J. Pharm. 302, 133-144 (2005). [0205] 70. Dahlin, M., Jansson,
B. & Bjork, E. Levels of dopamine in blood and brain following
nasal administration to rats. Eur. J. Pharm. Sci. 14, 75-80 (2001).
[0206] 71. Mistry, A., Stolnik, S. & Illum, L. Nanoparticles
for direct nose-to-brain delivery of drugs. Int. J. Pharm. 379,
146-157 (2009). [0207] 72. Han, I.-K. et al. Enhanced brain
targeting efficiency of intranasally administered plasmid DNA: an
alternative route for brain gene therapy. J. Mol. Med. 85, 75-83
(2007). [0208] 73. Pietrowsky, R., Strtiben, C., Molle, M., Fehm,
H. L. & Born, J. Brain potential changes after intranasal vs.
intravenous administration of vasopressin: evidence for a direct
nose-brain pathway for peptide effects in humans. Biol. Psychiatry
39, 332-340 (1996). [0209] 74. Fehm, H. L. et al. The Melanocortin
Melanocyte-Stimulating Hormone/Adrenocorticotropin4-10 Decreases
Body Fat in Humans. J. Clin. Endocrinol. Metab. 86, 1144-1148
(2001). [0210] 75. Danielyan, L. et al. Therapeutic Efficacy of
Intranasally Delivered Mesenchymal Stem Cells in a Rat Model of
Parkinson Disease. Rejuvenation Res. 14, 3-16 (2011). [0211] 76.
Touitou, E. & Illum, L. Nasal drug delivery. Drug Deliv.
Transl. Res. 3, 1-3 (2013). [0212] 77. Nakamura, F., Ohta, R.,
Machida, Y. & Nagai, T. In vitro and in vivo nasal mucoadhesion
of some water-soluble polymers. Int. J. Pharm. 134, 173-181 (1996).
[0213] 78. Pennington, A. K., Ratcliffe, J. H., Wilson, C. G. &
Hardy, J. G. The influence of solution viscosity on nasal spray
deposition and clearance. Int. J. Pharm. 43, 221-224 (1988). [0214]
79. Charlton, S., Jones, N. S., Davis, S. S. & Illum, L.
Distribution and clearance of bioadhesive formulations from the
olfactory region in man: Effect of polymer type and nasal delivery
device. Eur. J. Pharm. Sci. 30, 295-302 (2007).
[0215] 80. Chaturvedi, M., Kumar, M. & Pathak, K. A review on
mucoadhesive polymer used in nasal drug delivery system. J. Adv.
Pharm. Technol. Res. 2, 215-222 (2011). [0216] 81. Jose, S. et al.
Thermo-sensitive gels containing lorazepam microspheres for
intranasal brain targeting. Int. J. Pharm. 441, 516-526 (2013).
[0217] 82. Cai, Z. et al. Formulation and Evaluation of In Situ
Gelling Systems for Intranasal Administration of Gastrodin. AAPS
PharmSciTech 12, 1102-1109 (2011). [0218] 83. Gao, X. et al.
Lectin-conjugated PEG-PLA nanoparticles: Preparation and brain
delivery after intranasal administration. Biomaterials 27,
3482-3490 (2006). [0219] 84. Gao, X. et al. Brain delivery of
vasoactive intestinal peptide enhanced with the nanoparticles
conjugated with wheat germ agglutinin following intranasal
administration. J. Controlled Release 121, 156-167 (2007). [0220]
85. Liu, Q. et al. In vivo toxicity and immunogenicity of wheat
germ agglutinin conjugated poly(ethylene glycol)-poly(lactic acid)
nanoparticles for intranasal delivery to the brain. Toxicol. Appl.
Pharmacol. 251, 79-84 (2011). [0221] 86. Sharma, D. et al.
Formulation and Optimization of Polymeric Nanoparticles for
Intranasal Delivery of Lorazepam Using Box-Behnken Design: In Vitro
and In Vivo Evaluation. BioMed Res. Int. 2014, e156010 (2014).
[0222] 87. Fazil, M. et al. Development and evaluation of
rivastigmine loaded chitosan nanoparticles for brain targeting.
Eur. J. Pharm. Sci. 47, 6-15 (2012). [0223] 88. Dhuria, S. V.,
Hanson, L. R. & Frey, W. H. Novel vasoconstrictor formulation
to enhance intranasal targeting of neuropeptide therapeutics to the
central nervous system. J. Pharmacol. Exp. Ther. 328, 312-320
(2009). [0224] 89. Drejer, K. et al. Intranasal Administration of
Insulin With Phospholipid as Absorption Enhancer: Pharmacokinetics
in Normal Subjects. Diabet. Med. 9, 335-340 (1992). [0225] 90.
Gordon, G. S., Moses, A. C., Silver, R. D., Flier, J. S. &
Carey, M. C. Nasal absorption of insulin: enhancement by
hydrophobic bile salts. Proc. Natl. Acad. Sci. 82, 7419-7423
(1985). [0226] 91. Behl, C. R. et al. Optimization of systemic
nasal drug delivery with pharmaceutical excipients. Adv. Drug
Deliv. Rev. 29, 117-133 (1998). [0227] 92. Arora, P., Sharma, S.
& Garg, S. Permeability issues in nasal drug delivery. Drug
Discov. Today 7, 967-975 (2002). [0228] 93. Karasulu, E., Yava
oglu, A., Evren anal, Z., Uyanlkgil, Y. & Karasulu, H. Y.
Permeation Studies and Histological Examination of Sheep Nasal
Mucosa Following Administration of Different Nasal Formulations
with or without Absorption Enhancers. Drug Deliv. 15, 219-225
(2008). [0229] 94. Karasulu, H. Y., Sanal, Z. E., Sdzer, S.,
Gtineri, T. & Ertan, G. Permeation Studies of Indomethacin from
Different Emulsions for Nasal Delivery and Their Possible
Anti-Inflammatory Effects. AAPS PharmSciTech 9, 342-348 (2008).
[0230] 95. Lu, Y. et al. Bioavailability and Brain-Targeting of
Geniposide in Gardenia-Bomeol Co-Compound by Different
Administration Routes in Mice. Int. J. Mol. Sci. 13, 14127-14135
(2012). [0231] 96. Jadhav, K. R., Shaikh, I. M., Ambade, K. W.
& Kadam, V. J. Applications of Microemulsion Based Drug
Delivery System. Curr. Drug Deliv. 3, 267-273 (2006). [0232] 97.
Shah, B. M., Misra, M., Shishoo, C. J. & Padh, H. Nose to brain
microemulsion-based drug delivery system of rivastigmine:
formulation and ex-vivo characterization. Drug Deliv. 1-13 (2014).
doi:10.3109/10717544.2013.878857 [0233] 98. Hosny, K. M. &
Hassan, A. H. Intranasal in situ gel loaded with saquinavir
mesylate nanosized microemulsion: Preparation, characterization,
and in vivo evaluation. Int. J. Pharm. 475, 191-197 (2014). [0234]
99. Sood, S., Jain, K. & Gowthamarajan, K. Optimization of
curcumin nanoemulsion for intranasal delivery using design of
experiment and its toxicity assessment. Colloids Surf. B
Biointerfaces 113, 330-337 (2014). [0235] 100. Montenegro, L. et
al. In vitro evaluation of idebenone-loaded solid lipid
nanoparticles for drug delivery to the brain. Drug Dev. Ind. Pharm.
37, 737-746 (2011). [0236] 101. Pardeshi, C. V., Rajput, P. V.,
Belgamwar, V. S., Tekade, A. R. & Surana, S. J. Novel surface
modified solid lipid nanoparticles as intranasal carriers for
ropinirole hydrochloride: application of factorial design approach.
Drug Deliv. 20, 47-56 (2013). [0237] 102. Behl, C. R.; Pimplaskar,
H. K.; Sileno, A. P.; deMeireles, J.; Romeo, V. D. Effects of
physicochemical properties and other factors on systemic nasal drug
delivery. Advanced Drug Delivery Reviews 1998, 29, (1-2), 89-116.
[0238] 103. Newman, S. P.; Pitcaim, G. R.; Dalby, R. N. Drug
delivery to the nasal cavity: in vitro and in vivo assessment.
Critical Reviews.TM. in Therapeutic Drug Carrier Systems 2004, 21,
(1). [0239] 104. Wamken, Z.; Smyth, H. D.; Williams III, R. O.,
Route-Specific Challenges in the Delivery of Poorly Water-Soluble
Drugs. In Formulating Poorly Water Soluble Drugs, Springer: 2016;
pp 1-39. [0240] 105. Hoekman, J. D.; Ho, R. J. Y. Enhanced
Analgesic Responses After Preferential Delivery of Morphine and
Fentanyl to the Olfactory Epithelium in Rats: Anesthesia &
Analgesia 2011, 1. [0241] 106. Wamken, Z. N.; Smyth, H. D. C.;
Watts, A. B.; Weitman, S.; Kuhn, J. G.; Williams Iii, R. O.
Formulation and device design to increase nose to brain drug
delivery. Journal of Drug Delivery Science and Technology 2016, 35,
213-222. [0242] 107. Illum, L. Nasal drug delivery-possibilities,
problems and solutions. Journal of Controlled Release 2003, 87,
187-198. [0243] 108. Djupesland, P. G. Nasal drug delivery devices:
characteristics and performance in a clinical perspective--a
review. Drug Delivery and Translational Research 2013, 3, 42-62.
[0244] 109. Cheng, Y.; Yeh, H.; Guilmette, R.; Simpson, S.; Cheng,
K.; Swift, D. Nasal deposition of ultrafine particles in human
volunteers and its relationship to airway geometry. Aerosol Science
and Technology 1996, 25, (3), 274-291. [0245] 110. Kundoor, V.;
Dalby, R. N. Effect of formulation- and administration-related
variables on deposition pattern of nasal spray pumps evaluated
using a nasal cast. Pharmaceutical Research 2011, 28, (8),
1895-1904. [0246] 111. Foo, M. Y.; Cheng, Y. S.; Su, W. C.;
Donovan, M. D. The influence of spray properties on intranasal
deposition. Journal of aerosol medicine: the official journal of
the International Society for Aerosols in Medicine 2007, 20, (4),
495-508. [0247] 112. Doughty, D. V.; Hsu, W.; Dalby, R. N.
Automated actuation of nasal spray products: effect of hand-related
variability on the in vitro performance of Flonase nasal spray.
Drug Dev Ind Pharm 2014, 40, (6), 711-8. [0248] 113. Guo, C.;
Stine, K. J.; Kauffman, J. F.; Doub, W. H. Assessment of the
influence factors on in vitro testing of nasal sprays using
Box-Behnken experimental design. European Journal of Pharmaceutical
Sciences 2008, 35, (5), 417-426. [0249] 114. Cheng, Y.; Holmes, T.;
Gao, J.; Guilmette, R.; Li, S.; Surakitbanham, Y.; Rowlings, C.
Characterization of nasal spray pumps and deposition pattern in a
replica of the human nasal airway. Journal of Aerosol Medicine
2001, 14, (2), 267-280. [0250] 115. Guo, Y.; Laube, B.; Dalby, R.
The effect of formulation variables and breathing patterns on the
site of nasal deposition in an anatomically correct model. Pharm
Res 2005, 22, (11), 1871-8. [0251] 116. Swift, D. Inspiratory
inertial deposition of aerosols in human nasal airway replicate
casts: implication for the proposed NCRP lung model. Radiation
Protection Dosimetry 1991, 38, (1-3), 29-34. [0252] 117.
Samoliliski, B. K.; Grzanka, A.; Gotlib, T. Changes in Nasal Cavity
Dimensions in Children and Adults by Gender and Age. The
Laryngoscope 2007, 117, (8), 1429-1433. [0253] 118. Hsu, D.-J.;
Chuang, M.-H. In-Vivo Measurements of Micrometer-Sized Particle
Deposition in the Nasal Cavities of Taiwanese Adults. Aerosol
Science and Technology 2012, 46, (6), 631-638. [0254] 119. Liu, Y.;
Johnson, M. R.; Matida, E. A.; Kherani, S.; Marsan, J. Creation of
a standardized geometry of the human nasal cavity. Journal of
Applied Physiology 2009, 106, (3), 784-795. [0255] 120. Fedorov,
A.; Beichel, R.; Kalpathy-Cramer, J.; Finet, J.; Fillion-Robin,
J.-C.; Pujol, S.; Bauer, C.; Jennings, D.; Fennessy, F.; Sonka, M.;
Buatti, J.; Aylward, S.; Miller, J. V.; Pieper, S.; Kikinis, R. 3D
Slicer as an Image Computing Platform for the Quantitative Imaging
Network. Magnetic resonance imaging 2012, 30, (9), 1323-1341.
[0256] 121. Doughty, D. V.; Vibbert, C.; Kewalramani, A.;
Bollinger, M. E.; Dalby, R. N. Automated actuation of nasal spray
products: determination and comparison of adult and pediatric
settings. Drug Development and Industrial Pharmacy 2011, 37, (3),
359-366. [0257] 122. Schindelin, J.; Arganda-Carreras, I.; Frise,
E.; Kaynig, V.; Longair, M.; Pietzsch, T.; Preibisch, S.; Rueden,
C.; Saalfeld, S.; Schmid, B. Fiji: an open-source platform for
biological-image analysis. Nature methods 2012, 9, (7), 676-682.
[0258] 123. Zhou, Y.; Guo, M.; Xi, J.; Irshad, H.; Cheng, Y.-S.
Nasal deposition in infants and children. Journal of aerosol
medicine and pulmonary drug delivery 2014, 27, (2), 110-116. [0259]
124. Garcia, G. J.; Tewksbury, E. W.; Wong, B. A.; Kimbell, J. S.
Interindividual variability in nasal filtration as a function of
nasal cavity geometry. Journal of aerosol medicine and pulmonary
drug delivery 2009, 22, (2), 139-156. [0260] 125. D., S.
Inspiratory inertial deposition of aerosols in human nasal airway
replicate casts: Implication for the proposed NCRP lung model.
Radiation Protection Dosimetry 1991, 38, (1/3), 29-34. [0261] 126.
Sadee, W. Personalized Therapeutics and Pharmacogenomics: Integral
to Personalized Health Care. Pharmaceutical Research 2017, 34, (8),
1535-1538. [0262] 127. Inthavong, K.; Fung, M. C.; Yang, W.; Tu, J.
Measurements of droplet size distribution and analysis of nasal
spray atomization from different actuation pressure. Journal of
aerosol medicine and pulmonary drug delivery 2015, 28, (1), 59-67.
[0263] 128. Pu, Y.; Goodey, A. P.; Fang, X.; Jacob, K. A Comparison
of the Deposition Patterns of Different Nasal Spray Formulations
Using a Nasal Cast. Aerosol Science and Technology 2014, 48, (9),
930-938. [0264] 129. Kimbell, J. S.; Segal, R. A.; Asgharian, B.;
Wong, B. A.; Schroeter, J. D.; Southall, J. P.; Dickens, C. J.;
Brace, G.; Miller, F. J. Characterization of Deposition from Nasal
Spray Devices Using A Computational Fluid Dynamics Model of The
Human Nasal Passages. Journal of Aerosol Medicine 2007, 20, (1),
59-74. [0265] 130. Xi, J.; Yuan, J. E.; Zhang, Y.; Nevorski, D.;
Wang, Z.; Zhou, Y. Visualization and Quantification of Nasal and
Olfactory Deposition in a Sectional Adult Nasal Airway Cast.
Pharmaceutical Research 2016, 33, (6), 1527-1541. [0266] 131.
Aggarwal, R.; Cardozo, A.; Homer, J. J. The assessment of topical
nasal drug distribution. Clinical Otolaryngology & Allied
Sciences 2004, 29, (3), 201-205. [0267] 132. Kelly, J. T.;
Asgharian, B.; Kimbell, J. S.; Wong, B. A. Particle Deposition in
Human Nasal Airway Replicas Manufactured by Different Methods. Part
I: Inertial Regime Particles. Aerosol Science and Technology 2004,
38, 1063-1071. [0268] 133. Kelly, J. T.; Asgharian, B.; Kimbell, J.
S.; Wong, B. A. Particle deposition in human nasal airway replicas
manufactured by different methods. Part I: Inertial regime
particles. Aerosol Science and Technology 2004, 38, (11),
1063-1071. [0269] 134. Schroeter, J. D.; Garcia, G. J.; Kimbell, J.
S. Effects of surface smoothness on inertial particle deposition in
human nasal models. Journal of aerosol science 2011, 42, (1),
52-63.
* * * * *
References