U.S. patent application number 14/167937 was filed with the patent office on 2014-05-29 for nasal administration.
This patent application is currently assigned to OptiNose AB. The applicant listed for this patent is OptiNose AB. Invention is credited to Per Gisle Djupesland, Peter Roderick Hafner.
Application Number | 20140144443 14/167937 |
Document ID | / |
Family ID | 36096409 |
Filed Date | 2014-05-29 |
United States Patent
Application |
20140144443 |
Kind Code |
A1 |
Djupesland; Per Gisle ; et
al. |
May 29, 2014 |
NASAL ADMINISTRATION
Abstract
A delivery device for and method of providing for delivery of
substance to the central nervous system (CNS) of a subject, the
delivery device comprising: a nosepiece unit for insertion into a
nasal airway of a subject and comprising an outlet unit which
includes a nozzle for delivering substance into the nasal airway of
the subject; and a substance supply unit which is operable to
deliver a dose of substance to the nozzle; wherein the delivery
device is configured such that at least 30% of the dose as
initially deposited in the nasal airway is deposited in an upper
posterior region of the nasal airway, thereby providing a CNS
concentration of the substance, and hence CNS effect, which is
significantly greater than that which would be predicted from a
counterpart blood plasma concentration of the substance.
Inventors: |
Djupesland; Per Gisle;
(Oslo, NO) ; Hafner; Peter Roderick; (Wiltshire,
GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
OptiNose AB |
Oslo |
|
NO |
|
|
Assignee: |
OptiNose AB
Oslo
NO
|
Family ID: |
36096409 |
Appl. No.: |
14/167937 |
Filed: |
January 29, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12161466 |
Feb 1, 2011 |
|
|
|
PCT/GB2006/000182 |
Jan 19, 2006 |
|
|
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14167937 |
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Current U.S.
Class: |
128/203.15 ;
128/203.18 |
Current CPC
Class: |
H01M 2008/1293 20130101;
A61M 15/0098 20140204; A61M 15/009 20130101; A61M 16/0493 20140204;
H01M 4/8657 20130101; A61M 15/0065 20130101; A61M 16/20 20130101;
H01M 4/9066 20130101; H01M 4/861 20130101; A61M 15/0021 20140204;
A61M 16/049 20140204; H01M 8/023 20130101; H01M 2004/8684 20130101;
H01M 8/2425 20130101; A61M 2202/04 20130101; A61M 2202/064
20130101; H01M 8/0247 20130101; A61K 31/404 20130101; A61M 15/0091
20130101; A61M 15/08 20130101; A61M 11/00 20130101; H01M 4/8642
20130101; Y02E 60/50 20130101 |
Class at
Publication: |
128/203.15 ;
128/203.18 |
International
Class: |
A61M 15/00 20060101
A61M015/00; A61M 15/08 20060101 A61M015/08 |
Claims
1. A method of delivering substance to the central nervous system
(CNS) of a subject, the method comprising the steps of: inserting a
nosepiece unit into a nasal airway of a subject, wherein the
nosepiece unit comprises an outlet unit which includes a nozzle for
delivering substance into the nasal airway of the subject; and
delivering a dose of substance to the nozzle; wherein at least 30%
of the dose as initially deposited in the nasal airway is deposited
in an upper posterior region of the nasal airway which is posterior
of the nasal valve and above the inferior meatus, thereby providing
a CNS effect which is significantly greater than that predicted
from a counterpart blood plasma concentration of the substance;
wherein the substance comprises sumatriptan or its
pharmaceutically-acceptable derivatives or analogues.
2. The method of claim 1, wherein the nozzle is configured to
deliver a powder aerosol.
3. The method of claim 1, further comprising the step of: the
subject exhaling through a mouthpiece to cause closure of the
oropharyngeal velum of the subject.
4. The method of claim 3, wherein the outlet unit is fluidly
connected to the mouthpiece, whereby exhaled air from an exhalation
breath of the subject is delivered through the nosepiece unit into
the nasal airway of the subject to entrain the delivered
substance.
5. The method of claim 1, wherein a dose of the substance is
delivered in response to exhalation by the subject.
6. The method of claim 1, wherein at least 40% of the dose as
initially deposited in the nasal airway is deposited in the upper
posterior region of the nasal airway.
7. The method of claim 6, wherein at least 50% of the dose as
initially deposited in the nasal airway is deposited in the upper
posterior region of the nasal airway.
8. The method of claim 1, wherein a fluid communication remains
between a region of the nasal airway which is anterior of the nasal
valve and a region of the nasal airway which is posterior of the
nasal valve.
9. The method of claim 8, wherein the region posterior of the nasal
valve represents the posterior two-thirds of the nasal airway and
the region anterior of the nasal valve represents the anterior
one-third of the nasal airway.
10. The method of claim 1, wherein the ratio of the peak CNS effect
to the peak blood plasma concentration is at least 2 times that
achieved using intravenous (IV) delivery.
11. The method of claim 1, wherein the ratio of the peak CNS effect
to the peak blood plasma concentration is at least 3 times that
achieved using intravenous (IV) delivery.
12. The method of claim 1, wherein the substance is for the
treatment of a condition which requires a rapid onset of action in
order to ameliorate or abort a CNS event.
13. The method of claim 1, wherein the substance is for the
treatment of migraine.
14. A method of delivering substance to the central nervous system
(CNS) of a subject, the method comprising the steps of: inserting a
nosepiece unit into a nasal airway of a subject, wherein the
nosepiece unit comprises an outlet unit which includes a nozzle for
delivering substance into the nasal airway of the subject, wherein
the nozzle is configured to deliver a powder aerosol; and the
subject exhaling through a mouthpiece to cause closure of the
oropharyngeal velum of the subject, wherein the outlet unit is
fluidly connected to the mouthpiece, whereby exhaled air from an
exhalation breath of the subject is delivered through the nosepiece
unit into the nasal airway of the subject to entrain and deliver a
dose of substance to the nozzle; wherein the substance comprises
sumatriptan or its pharmaceutically-acceptable derivatives or
analogues; wherein at least 30% of the dose as initially deposited
in the nasal airway is deposited in an upper posterior region of
the nasal airway which is posterior of the nasal valve and above
the inferior meatus, thereby providing a CNS effect which is
significantly greater than that predicted from a counterpart blood
plasma concentration of the substance.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Continuation of U.S. patent
application Ser. No. 2/161,466, filed on Feb. 1, 2011, which is a
U.S. National phase application of PCT/GB2006/000182 filed Jan. 19,
2006, the disclosure of which applications are incorporated herein
by reference.
FIELD OF INVENTION
[0002] The present invention relates to the nasal administration of
substances, in particular drugs, to the central nervous system
(CNS) via the nasal airway.
BACKGROUND
[0003] Referring to FIG. 1(a), the nasal airway 1 comprises the two
nasal cavities separated by the nasal septum, which airway 1
includes numerous ostia, such as the paranasal sinus ostia 3 and
the tubal ostia 5, and olfactory cells, and is lined by the nasal
mucosa. The nasal airway 1 can communicate with the nasopharynx 7,
the oral cavity 9 and the lower airway 11, with the nasal airway 1
being in selective communication with the anterior region of the
nasopharynx 7 and the oral cavity 9 by opening and closing of the
oropharyngeal velum 13. The velum 13, which is often referred to as
the soft palate, is illustrated in solid line in the closed
position, as achieved by providing a certain positive pressure in
the oral cavity 9, such as achieved on exhalation through the oral
cavity 9, and in dashed line in the open position.
[0004] In existing administration systems which provide for the
administration of drugs to the CNS, which include pulmonary,
parenteral, transdermal and oral administration systems, the
concentration of drug that is attained within the CNS is mediated
by the blood plasma concentration in the systemic, peripheral
circulation. For many drugs, the concentration attainable within
the CNS is much less than 10% of the blood plasma
concentration.
[0005] Consequently, high blood plasma concentrations are required
in order to achieve effective concentrations in the CNS. However,
high blood plasma concentrations can cause unwanted effects,
notably, systemic side effects. Thus, it is necessary to provide
for a balance of the CNS efficacy against the peripheral side
effect.
[0006] This may be particularly problematic in systems which
require a rapid onset of action, as such systems rely on achieving
high blood plasma concentrations in order to create a significant
driving gradient for the rapid uptake of drug into the CNS.
[0007] Examples of drugs which exhibit systemic side effects
include dopamine agonists, such as apomorphine and its derivatives
and analogues, which can cause nausea as a side effect, triptans,
such as sumatriptan and its derivatives and analogues, which can
cause an angina-like side effect, vasopressin and desmopressin
analogues which have activity on the learning pathway and can cause
enuresis as a side effect, acetylcholinesterase inhibitors which
can cause gastro-intestinal (GI) disorders as a side effect, and
insulin which exhibits a reduced blood glucose level as a side
effect.
[0008] It is one aim of the present invention to provide for the
administration of substances, in particular drugs, at greater
concentrations to the CNS for the same or reduced blood plasma
concentrations, which has the benefit of at least reducing any
peripheral side effects, which may be undesired. Such
administration has particular benefit in relation to rescue
situations.
[0009] It is another aim of the present invention to achieve a
faster onset of action as compared to at least ones of the existing
administration systems, and in particular existing nasal spray
administration systems.
[0010] It is a further aim of the present invention to achieve a
relatively rapid onset of action, but where avoiding the sharp peak
plasma profiles associated with existing administration systems,
such as in pulmonary, intravenous and transdermal systems.
SUMMARY OF THE INVENTION
[0011] The present inventors have recognized that an increased
delivery of substance to the posterior region of the nasal airway,
and in particular the upper posterior region of the nasal airway,
as illustrated in FIG. 1(b), relative to the anterior region of the
nasal airway, surprisingly provides for a disproportionately
greater CNS effect, which is suggestive of a greater uptake of
substance into the CNS than would be predicted from the blood
plasma concentration of the substance.
[0012] The posterior region of the nasal airway is that region
which is posterior of the nasal valve NV, as illustrated in FIG.
1(b). The nasal valve comprises the anterior bony cavum which
contains inferior turbinate erectile tissue and septal erectile
tissue, which are supported respectively by compliant ala tissue
and the rigid cartilaginous septum (Mosby). These elements combine
to form a dynamic valve, which extends over several millimetres,
that adjusts nasal airflow, and is stabilized by cartilage and
bone, modulated by voluntary muscle and regulated by erectile
tissue. The lumen of the nasal valve is the section of narrowest
cross-sectional area between the posterior and anterior regions of
the nasal airway, and is much longer and narrower dorsally than
ventrally, and this lumen defines a triangular entrance which
extends to the piriform region of the bony cavum. The nasal valve
is lined in its anterior part with transitional epithelium, with a
gradual transition posterior to respiratory epithelium. The nasal
valve and anterior vestibule define roughly the anterior one-third
of the nose.
[0013] The posterior region of the nasal airway is that region
which is lined with respiratory epithelium, which is ciliated, and
olfactory epithelium, which comprises nerves which extend downwards
through the cribiform plate CP from the olfactory bulb, whereas the
anterior region of the nasal airway is that region which is lined
with squamous epithelium, which is not ciliated, and transitional
epithelium. The olfactory epithelium extends on both the lateral
and medial sides of the nasal airway, and typically extends
downwards about 1.5 to 2.5 cm.
[0014] The upper posterior region is the region above the inferior
meatus IM, as illustrated in FIG. 1(b), and encompasses the middle
turbinate, the sinus ostia in infundibulum (ostia to maxillary,
frontal and ethmoidal sinuses), the olfactory region, and the upper
branches of the trigeminal nerve, and is that region which includes
veins which drain to the venous sinuses that surround the
brain.
[0015] As illustrated in FIG. 1(b), the posterior region of the
nasal airway is the nasal region posterior of an imaginary vertical
plane VERT1 which is located at a position corresponding to
one-quarter of the distance between the anterior nasal spine AnS,
which is a pointed projection at the anterior extremity of the
intermaxillary suture, and the posterior nasal spine PnS, which is
the sharp posterior extremity of the nasal crest of the hard palate
and represents the transition between the nose and the nasopharynx,
which corresponds to a distance posterior of the anterior nasal
spine AnS of between about 13 mm and about 14 mm (Rosenberger
defines the distance between the anterior nasal spine AnS and the
posterior nasal spine PnS as being 56 mm in eighteen year old boys
and 53.3 mm in eighteen year old girls). As again illustrated in
FIG. 1(b), the posterior nasal region is bounded posteriorly by an
imaginary vertical plane VERT2 which extends through the posterior
nasal spine PnS.
[0016] As further illustrated in FIG. 1(b), the upper region of the
nasal airway is an upper segment of the nasal airway which is
bounded by the cribiform plate CP and a horizontal plane HORIZ
which is located at a position corresponding to one-third of the
distance between the nasal floor NF of the nasal airway and the
cribiform plate CP, which corresponds to a height of typically
between about 13 and about 19 mm above the nasal floor NF (Zacharek
et at define the distance from the nasal floor NF to the cribiform
plate CP as 46+/-4 mm).
[0017] The upper posterior region is thus that upper posterior
region which is bounded by the above-defined vertical and
horizontal planes VERT1, HORIZ.
[0018] The present inventors have postulated that this increased
concentration within the CNS arises as a result of the veins in the
upper posterior region of the nasal airway draining backwards to
the venous sinuses that surround the brain, which leads to a higher
local concentration in the cerebrovasculature. Although the sinus
cavernous is outside the blood-to-brain barrier, animal models have
shown that substances can be transported by a counter-current
mechanism from the veins therein to the carotid artery which passes
through the sinus cavernous. Other mechanisms have been proposed
which include extra axonal transport along the surface of the
olfactory and trigeminal nerves. This mode of transport is
apparently quite rapid as compared to intra axonal transport.
[0019] The improved efficacy as achieved by the present invention
as compared to existing nasal spray administration systems can
apparently be explained in that such nasal spray administration
systems have been determined to deliver largely to the anterior
one-third of the nasal airway, that is, the nasal region anterior
of the nasal valve, from which region drainage is mainly along the
floor of the nose and in which region the veins drain to the
external facial vein, which in turn drains to the external carotid
and in turn to the peripheral circulation.
[0020] Recently, there has been a growing interest in alternative
forms of drug administration, and in particular nasal
administration. Nasal administration, with transmucosal absorption,
can offer advantages, such as ease of administration, rapid onset
and patient control. Also, in bypassing gastrointestinal and
hepatic pre-systemic elimination, nasal administration is
applicable in nauseated and vomiting patients who may have problems
in taking oral medication.
[0021] Several techniques and devices for intranasal drug
administration have been developed. However, the use of
manually-actuated spray pumps still dominates.
[0022] The present applicant has developed a novel nasal delivery
system, as disclosed in WO-A-2000/051672, the content of which is
herein incorporated by reference, which provides for the delivery
of drugs and vaccines in a bi-directional air flow through the two
nasal passages when connected in series by closure of the
oropharyngeal velum.
[0023] In one embodiment this delivery system includes a mouthpiece
through which the subject exhales, a nosepiece which is in fluid
communication with the mouthpiece, and a spray pump which is
actuated in response to exhalation through the mouthpiece to
deliver an aerosol spray containing a substance from the nosepiece,
such that an aerosol spray is delivered from the nosepiece together
with an air flow which acts to entrain the delivered aerosol spray.
In exhaling through the mouthpiece, the oropharyngeal velum closes
the communication between the oral and nasal cavities to establish
a bi-directional air flow which enters one nostril and exits the
other nostril.
[0024] In one aspect the present invention provides a delivery
device for providing for delivery of substance to the central
nervous system (CNS) of a subject, the delivery device comprising:
a nosepiece unit for insertion into a nasal cavity of a subject and
comprising an outlet unit which includes a nozzle for delivering
substance into the nasal cavity of the subject; and a substance
supply unit which is operable to deliver a dose of substance to the
nozzle; wherein the delivery device is configured such that at
least 30% of the dose as initially deposited in the nasal cavity is
deposited in an upper posterior region of the nasal cavity which is
posterior of the nasal valve and above the inferior meatus, thereby
providing a CNS concentration of the substance, and hence CNS
effect, which is significantly greater than that which would be
predicted from a counterpart blood plasma concentration of the
substance.
[0025] In one embodiment the nozzle is configured to deliver an
aerosol spray.
[0026] In one embodiment the aerosol spray is a liquid aerosol.
[0027] In another embodiment the aerosol spray is a powder
aerosol.
[0028] In another embodiment the nozzle is configured to deliver a
liquid jet.
[0029] In a further embodiment the nozzle is configured to deliver
a powder jet.
[0030] In one embodiment the delivery device further comprises: a
mouthpiece through which the subject in use exhales to cause
closure of the oropharyngeal velum of the subject.
[0031] In one embodiment the outlet unit further comprises a
delivery channel which is fluidly connected to the mouthpiece,
whereby exhaled air from an exhalation breath of the subject is
delivered through the nosepiece unit into the nasal cavity of the
subject.
[0032] In another embodiment the outlet unit further comprises a
delivery channel through which a gas flow, separate to an exhaled
air flow from an exhalation breath of the subject, is in use
delivered to the nasal cavity of the subject, and the delivery
device further comprises: a gas supply unit for supplying a gas
flow to the delivery channel.
[0033] In one embodiment the substance supply unit is breath
actuated.
[0034] In another embodiment the substance supply unit is manually
actuated.
[0035] Preferably, the delivery device is configured such that at
least 40% of the dose as initially deposited in the nasal cavity is
deposited in the upper posterior region of the nasal cavity.
[0036] More preferably, the delivery device is configured such that
at least 50% of the dose as initially deposited in the nasal cavity
is deposited in the upper posterior region of the nasal cavity.
[0037] In one embodiment the outlet unit further comprises a cuff
member which acts to obstruct a region of the nasal cavity which is
anterior of the nasal valve, such that substantially all of the
delivered dose is delivered to a region of the nasal cavity which
is posterior of the nasal valve.
[0038] In one embodiment the cuff member acts to close the nasal
valve.
[0039] In another embodiment the outlet unit includes no cuff
member which obstructs a region of the nasal cavity which is
anterior of the nasal valve.
[0040] In one embodiment the region posterior of the nasal valve
represents the posterior two-thirds of the nasal cavity and the
region anterior of the nasal valve represents the anterior
one-third of the nasal cavity.
[0041] In one embodiment the ratio of the peak CNS effect to the
peak blood plasma concentration is at least 2 times that achieved
using intravenous (IV) delivery.
[0042] Preferably, the ratio of the peak CNS effect to the peak
blood plasma concentration is at least 3 times that achieved using
intravenous (IV) delivery.
[0043] In another aspect the present invention provides a method of
delivering substance to the central nervous system (CNS) of a
subject, the method comprising the steps of: inserting a nosepiece
unit into a nasal cavity of a subject, wherein the nosepiece unit
comprises an outlet unit which includes a nozzle for delivering
substance into the nasal cavity of the subject; and delivering a
dose of substance to the nozzle; wherein at least 30% of the dose
as initially deposited in the nasal cavity is deposited in an upper
posterior region of the nasal airway which is posterior of the
nasal valve and above the inferior meatus, thereby providing a CNS
concentration of the substance, and hence CNS effect, which is
significantly greater than that which would be predicted from a
counterpart blood plasma concentration of the substance.
[0044] In one embodiment the nozzle is configured to deliver an
aerosol spray.
[0045] In one embodiment the aerosol spray is a liquid aerosol.
[0046] In another embodiment the aerosol spray is a powder
aerosol.
[0047] In another embodiment the nozzle is configured to deliver a
liquid jet.
[0048] In a further embodiment the nozzle is configured to deliver
a powder jet.
[0049] In one embodiment the method further comprises the step of:
the subject exhaling through a mouthpiece to cause closure of the
oropharyngeal velum of the subject.
[0050] In one embodiment the outlet unit is fluidly connected to
the mouthpiece, whereby exhaled air from an exhalation breath of
the subject is delivered through the nosepiece unit into the nasal
cavity of the subject, such as to entrain the delivered
substance.
[0051] In another embodiment a gas flow, separate to an exhaled air
flow from an exhalation breath of the subject, is delivered to the
nasal cavity of the subject, such as to entrain the delivered
substance.
[0052] In one embodiment a dose of the substance is delivered in
response to exhalation by the subject.
[0053] In another embodiment a dose of the substance is delivered
in response to a manual operation by the subject.
[0054] Preferably, at least 40% of the dose as initially deposited
in the nasal cavity is deposited in the upper posterior region of
the nasal cavity.
[0055] More preferably, at least 50% of the dose as initially
deposited in the nasal cavity is deposited in the upper posterior
region of the nasal cavity.
[0056] In one embodiment the method further comprises the step of:
obstructing a region of the nasal cavity which is anterior of the
nasal valve, such that substantially all of the delivered dose is
delivered to a region of the nasal cavity which is posterior of the
nasal valve.
[0057] In one embodiment the obstructing step comprises the step
of: closing the nasal valve.
[0058] In another embodiment a fluid communication remains between
a region of the nasal cavity which is anterior of the nasal valve
and a region of the nasal cavity which is posterior of the nasal
valve.
[0059] In one embodiment the region posterior of the nasal valve
represents the posterior two-thirds of the nasal cavity and the
region anterior of the nasal valve represents the anterior
one-third of the nasal cavity.
[0060] In one embodiment the ratio of the peak CNS effect to the
peak blood plasma concentration is at least 2 times that achieved
using intravenous (IV) delivery.
[0061] Preferably, the ratio of the peak CNS effect to the peak
blood plasma concentration is at least 3 times that achieved using
intravenous (IV) delivery.
[0062] In one embodiment the substance is a pharmaceutical
drug.
[0063] In one embodiment the substance exhibits one or more
systemic side effects.
[0064] In one embodiment the substance is a dopamine agonist.
[0065] Preferably, the substance comprises apomorphine or its
pharmaceutically-acceptable derivatives or analogues.
[0066] In another embodiment the substance is a triptan.
[0067] Preferably, the substance comprises sumatriptan or its
pharmaceutically-acceptable derivatives or analogues.
[0068] In a further embodiment the substance has activity on the
learning pathway.
[0069] In one embodiment the substance comprises vasopressin or its
pharmaceutically-acceptable derivatives or analogues.
[0070] In another embodiment the substance comprises desmopressin
or its pharmaceutically-acceptable derivatives or analogues.
[0071] In a still further embodiment the substance is an
acetylcholinesterase inhibitor.
[0072] Preferably, the substance comprises rivastigmine or its
pharmaceutically-acceptable derivatives or analogues.
[0073] In one embodiment the substance is for the treatment of a
condition which requires a rapid onset of action in order to
ameliorate or abort a CNS event.
[0074] In one embodiment the substance is a benzodiazepine for the
treatment of a panic disorder.
[0075] In another embodiment the substance is a triptan for the
treatment of migraine.
[0076] In a further embodiment the substance is a gaba agonist for
the treatment of neuropathic pain or to abort a partial or full
epilepsy seizure.
[0077] In a still further embodiment the substance is insulin which
is administered to regulate the satiety center.
[0078] In a yet further embodiment the substance is an insulin-like
growth factor or its pharmaceutically-acceptable analogues which is
administered to regulate the satiety center.
[0079] In yet another embodiment the substance is a peptide which
is administered to regulate the satiety center.
[0080] In a still yet further embodiment the substance is a
memory-enhancing agent which is administered prior to a learning
episode.
[0081] In still yet another embodiment the substance is a
sedative.
[0082] In one embodiment the substance is for the treatment of a
panic disorder.
[0083] In another embodiment the substance is for the treatment of
migraine.
[0084] In a further embodiment the substance is for the treatment
of neuropathic pain.
[0085] In a still further embodiment the substance is for aborting
a partial or full epilepsy seizure.
[0086] In yet another embodiment the substance is for regulating
the satiety center.
[0087] In still yet another embodiment the substance is a
memory-enhancing agent which is administered prior to a learning
episode.
[0088] In a yet further embodiment the substance is for the
treatment of a neurological disease, such as multiple sclerosis
(MS), Alzheimer's disease or Parkinson's disease.
[0089] In still another embodiment the substance is for the
treatment of sexual dysfunction.
[0090] In yet another embodiment the substance is a therapeutic
vaccine, such as for the treatment of intracerebral tumours.
[0091] In a still further embodiment the substance is an
angiotensin-converting enzyme (ACE) inhibitor, such as for the
treatment of hypertension.
[0092] In a yet further embodiment the substance is for the
treatment of insomnia.
[0093] In one embodiment the substance is a benzodiazepine.
[0094] In another embodiment the substance is a substance which
acts on benzodiazepine receptors.
[0095] In a still further embodiment the substance is for the
treatment of depression.
[0096] In one embodiment the substance is a selective serotonin
re-uptake inhibitor.
[0097] In another embodiment the substance is a tricyclic
anti-depressant.
[0098] In a yet further embodiment the substance is for the
treatment of agrophobia.
[0099] In still another embodiment the substance is for the
treatment of social anxiety disorder.
[0100] In still yet another embodiment the substance is for the
treatment of obsessive compulsive disorder.
[0101] In yet still another embodiment the substance is for use in
a treatment of smoking cessation.
[0102] In one embodiment the substance comprises nicotine.
[0103] In a still further embodiment the substance is a selective
serotonin re-uptake inhibitor.
BRIEF DESCRIPTION OF THE DRAWINGS
[0104] The present invention will now be described hereinbelow by
way of example only with reference to the accompanying drawings, in
which:
[0105] FIG. 1(a) schematically illustrates the anatomy of the upper
respiratory tract of a human subject;
[0106] FIG. 1(b) illustrates the segmentation of a nasal cavity in
accordance with a preferred embodiment of the present
invention;
[0107] FIG. 2 illustrates a nasal delivery device in accordance
with a first embodiment of the present invention;
[0108] FIG. 3 illustrates the nasal delivery device of FIG. 2,
where operative in delivering substance to the nasal cavity of the
subject;
[0109] FIG. 4 illustrates a nasal delivery device in accordance
with a second embodiment of the present invention;
[0110] FIG. 5 illustrates the nasal delivery device of FIG. 4,
where operative in delivering substance to the nasal cavity of the
subject;
[0111] FIG. 6 illustrates a nasal delivery device in accordance
with a third embodiment of the present invention;
[0112] FIG. 7 illustrates the nasal delivery device of FIG. 6,
where operative in delivering substance to the nasal cavity of the
subject;
[0113] FIG. 8 illustrates the time course for the measured blood
plasma concentrations of midazolam for the three exemplified
administration systems as employed in Example #1;
[0114] FIG. 9 illustrates the time course for the reported median
sedation scores on a numeric rating scale (NRS) following
administration of midazolam by the three exemplified administration
systems as employed in Example #1;
[0115] FIG. 10 illustrates a plot of the reported median sedation
scores as a function of the measured blood plasma concentration for
the intravenous administration system and the bi-directional
administration system as employed in Example #1;
[0116] FIG. 11 illustrates a plot of the reported median sedation
scores as a function of the measured blood plasma concentration for
the bi-directional administration system and the conventional nasal
spray administration system as employed in Example #1;
[0117] FIG. 12(a) illustrates the cumulative deposition as obtained
by the conventional nasal spray administration system as employed
in Example #2;
[0118] FIG. 12(b) illustrates the cumulative deposition by obtained
by the bi-directional administration system as employed in Example
#2;
[0119] FIG. 13 graphically illustrates the mean deposition
fractions in the four segmented nasal regions for both the
conventional nasal spray administration system and the
bi-directional administration system as employed in Example #2;
and
[0120] FIG. 14 graphically illustrates the mean deposition
fractions in the four segmented nasal regions for both the
conventional nasal spray administration system and the
bi-directional administration systems as employed in Example
#3.
DETAILED DESCRIPTION OF THE INVENTION
[0121] FIGS. 2 and 3 illustrate a nasal delivery device in
accordance with a first embodiment of the present invention.
[0122] The delivery device comprises a housing 15, a nosepiece unit
17 for fitting in a nasal passage of a subject, a substance supply
unit 18 for delivering substance to the nosepiece unit 17, and a
mouthpiece 19 through which the subject exhales to actuate the
delivery device.
[0123] The nosepiece unit 17 comprises a nosepiece 20, in this
embodiment a frusto-conical element, for guiding the nosepiece unit
17 into a nasal passage of the subject and providing a fluid-tight
seal with the nares of the nostril, and an outlet unit 21 for
delivering substance, in this embodiment a CNS-active drug, to an
upper posterior region of the nasal passage of the subject, in this
embodiment an upper posterior region as bounded by a vertical plane
which is located posterior of the anterior nasal spine AnS at a
position corresponding to one-quarter of the distance between the
anterior and posterior nasal spines AnS, PnS and a horizontal plane
which is located above the nasal floor at a height one-third of the
distance between the nasal floor and the cribiform plate. As
discussed hereinabove, the present inventors have recognized that
an increased delivery of substance to the upper posterior region of
the nasal passage surprisingly provides for a disproportionately
greater uptake of substance into the CNS than would be predicted
from the blood plasma concentration of the substance.
[0124] In this embodiment the outlet unit 21 comprises a delivery
channel 23 which is in fluid communication with the mouthpiece 19
such that an air flow is delivered into and through the nasal
airway of the subject on exhalation by the subject through the
mouthpiece 19, and a nozzle 25 which is in fluid communication with
the substance supply unit 18 and provides for delivery of substance
into the nasal passage of the subject.
[0125] In this embodiment the substance supply unit 18 comprises a
mechanical delivery pump, in particular a liquid delivery pump or a
powder delivery pump, which delivers metered doses of substance, on
actuation thereof.
[0126] In another alternative embodiment the substance supply unit
18 could comprise a dry powder delivery unit which delivers metered
doses of a substance, as a dry powder, on actuation thereof. In one
embodiment the substance supply unit 18 could provide for delivery
of substance from a capsule.
[0127] In yet another alternative embodiment the substance supply
unit 18 could comprise an aerosol canister which delivers metered
volumes of a propellant, preferably a hydrofluoroalkane (HFA)
propellant or the like, containing substance, either as a
suspension or solution.
[0128] In yet another alternative embodiment the substance supply
unit 18 could comprise a nebulizer which delivers metered doses of
a substance, as an aerosol spray, on actuation thereof.
[0129] In this embodiment the nozzle 25 is configured to deliver a
significant fraction of substance to the upper posterior region of
the nasal passage, here an initial deposition of greater than 30%
of the delivered dose.
[0130] In this embodiment the nozzle 25 is configured to deliver
substance as an aerosol spray.
[0131] In an alternative embodiment the nozzle 25 could be
configured to deliver substance as a jet, for example, as a column
of liquid or powder. In delivering the substance as a jet, the
substance can be more readily targeted at the upper posterior
region of the nasal passage.
[0132] In this embodiment the substance supply unit 18 is a
multi-dose unit for delivering a plurality of metered doses of the
substance. In another embodiment the substance supply unit 18 could
be a single-dose unit for delivering a single metered dose of the
substance.
[0133] The substance supply unit 18 is pre-primeable, in this
embodiment by loading a resilient element, and includes a
breath-actuated release mechanism 31 which, when triggered,
releases the resilient element and actuates the substance supply
unit 18 to deliver a metered dose of the substance through the
nozzle 25.
[0134] In this embodiment the trigger mechanism 31 is configured to
cause actuation of the substance supply unit 18 on generation of a
predetermined pressure at the delivery channel 23.
[0135] In an alternative embodiment the trigger mechanism 31 could
be configured to cause actuation of the substance supply unit 18 on
generation of a predetermined flow rate through the delivery
channel 23.
[0136] Operation of the delivery device will now be described
hereinbelow with reference to FIG. 3 of the accompanying
drawings.
[0137] The nosepiece unit 17 is first inserted into one of the
nasal passages of a subject until the nosepiece 20 abuts the nares
of the nostril such as to establish a fluid-tight seal therewith,
at which point the distal end of the outlet unit 21 extends about 2
cm into the nasal passage of the subject, and the mouthpiece 19 is
gripped in the lips of the subject.
[0138] The subject then begins to exhale through the mouthpiece 19,
which exhalation acts to close the oropharyngeal velum of the
subject and drive an air flow through the delivery channel 23 of
the outlet unit 21, with the air flow passing into the one nasal
passage, around the posterior margin of the nasal septum and out of
the other nasal passage, thereby achieving a bi-directional air
flow through the nasal airway of the subject.
[0139] In this embodiment, when the pressure developed at the
delivery channel 23 reaches a predetermined value, the release
mechanism 31 is triggered to actuate the substance supply unit 18
to deliver a metered dose of the substance to the nozzle 25 and
into the nasal passage of the subject.
[0140] In an alternative embodiment the release mechanism 31 could
be triggered in response to the generation of a predetermined flow
rate through the delivery channel 23.
[0141] In this embodiment, where the delivery device is a
multi-dose device, the device is ready for further use following
priming of the substance supply unit 18.
[0142] FIGS. 4 and 5 illustrate a nasal delivery device in
accordance with a second embodiment of the present invention.
[0143] The delivery device comprises a housing 115, a nosepiece
unit 117 for fitting in a nasal passage of a subject, a substance
supply unit 118 for delivering substance to the nosepiece unit 117,
and a mouthpiece 119 through which the subject exhales to actuate
the delivery device.
[0144] The nosepiece unit 117 comprises a nosepiece 120, in this
embodiment a frusto-conical element, for guiding the nosepiece unit
117 into a nasal passage of the subject and being configured both
to provide a fluid-tight seal with the nares of the nostril and
obstruct, in this embodiment close, the nasal passage at a position
therealong, in this embodiment at a position corresponding
substantially to the nasal valve, thereby obstructing the anterior
one-third of the nasal passage and leaving open the posterior
two-thirds of the nasal passage, as illustrated in FIG. 5, and an
outlet unit 121 for delivering substance, in this embodiment a
CNS-active drug, to an upper posterior region of the nasal passage
of the subject, in this embodiment an upper posterior region as
bounded by a vertical plane which is located posterior of the
anterior nasal spine AnS at a position corresponding to one-quarter
of the distance between the anterior and posterior nasal spines
AnS, PnS and a horizontal plane which is located above the nasal
floor at a height one-third of the distance between the nasal floor
and the cribiform plate. As discussed hereinabove, the present
inventors have recognized that an increased delivery of substance
to the upper posterior region of the nasal passage surprisingly
provides for a disproportionately greater uptake of substance into
the CNS than would be predicted from the blood plasma concentration
of the substance.
[0145] In this embodiment the outlet unit 121 comprises a delivery
channel 123 which is in fluid communication with the mouthpiece 119
such that an air flow is delivered into and through the nasal
airway of the subject on exhalation by the subject through the
mouthpiece 119, and a nozzle 125 which is in fluid communication
with the substance supply unit 118 and provides for delivery of
substance into the nasal passage of the subject.
[0146] In this embodiment the nosepiece 120 is formed of a
substantially rigid material, but in other embodiments could be
formed of a soft compressible and/or flexible material.
[0147] In this embodiment the substance supply unit 118 comprises a
mechanical delivery pump, in particular a liquid delivery pump or a
powder delivery pump, which delivers metered doses of substance, on
actuation thereof.
[0148] In another alternative embodiment the substance supply unit
118 could comprise a dry powder delivery unit which delivers
metered doses of substance, as a dry powder, on actuation thereof.
In one embodiment the substance supply unit 118 could provide for
delivery of substance from a capsule.
[0149] In yet another alternative embodiment the substance supply
unit 118 could comprise an aerosol canister which delivers metered
volumes of a propellant, preferably a hydrofluoroalkane (HFA)
propellant or the like, containing substance, either as a
suspension or solution.
[0150] In yet another alternative embodiment the substance supply
unit 118 could comprise a nebulizer which delivers metered doses of
substance, as an aerosol spray, on actuation thereof.
[0151] In this embodiment the nozzle 125 is configured to deliver
substance as an aerosol spray.
[0152] In an alternative embodiment the nozzle 125 could be
configured to deliver substance as a jet, for example, as a column
of liquid or powder. In delivering the substance as a jet, the
substance can be more readily targeted at the posterior region of
the nasal passage.
[0153] In this embodiment the substance supply unit 118 is a
multi-dose unit for delivering a plurality of metered doses of the
substance. In another embodiment the substance supply unit 118
could be a single-dose unit for delivering a single metered dose of
the substance.
[0154] The substance supply unit 118 is pre-primeable, in this
embodiment by loading a resilient element, and includes a
breath-actuated release mechanism 131 which, when triggered,
releases the resilient element and actuates the substance supply
unit 118 to deliver a metered dose of the substance through the
nozzle 125.
[0155] In this embodiment the trigger mechanism 131 is configured
to cause actuation of the substance supply unit 118 on generation
of a predetermined pressure at the delivery channel 123.
[0156] In an alternative embodiment the trigger mechanism 131 could
be configured to cause actuation of the substance supply unit 118
on generation of a predetermined flow rate through the delivery
channel 123.
[0157] Operation of the delivery device will now be described
hereinbelow with reference to FIG. 5 of the accompanying
drawings.
[0158] The nosepiece unit 117 is first inserted into one of the
nasal passages of a subject until the nosepiece 120 abuts the nares
of the nostril such as to establish a fluid-tight seal therewith,
at which point the distal end of the nosepiece 120 extends about 2
cm into the nasal passage of the subject and closes the nasal
valve, and the mouthpiece 119 is then gripped in the lips of the
subject.
[0159] The subject then begins to exhale through the mouthpiece
119, which exhalation acts to close the oropharyngeal velum of the
subject and drive an air flow through the delivery channel 123 of
the outlet unit 121, with the air flow passing into the one nasal
passage, around the posterior margin of the nasal septum and out of
the other nasal passage, thereby achieving a bi-directional air
flow through the nasal airway of the subject.
[0160] In this embodiment, when the pressure developed at the
delivery channel 123 reaches a predetermined value, the release
mechanism 131 is triggered to actuate the substance supply unit 118
to deliver a metered dose of the substance to the nozzle 125 and
into the nasal passage of the subject.
[0161] In an alternative embodiment the release mechanism 131 could
be triggered in response to the generation of a predetermined flow
rate through the delivery channel 123.
[0162] In this embodiment, where the delivery device is a
multi-dose device, the device is ready for further use following
priming of the substance supply unit 118.
[0163] FIGS. 6 and 7 illustrate a nasal delivery device in
accordance with a third embodiment of the present invention.
[0164] The delivery device of this embodiment is very similar to
the delivery device of the above-described second embodiment, and
thus, in order to avoid unnecessary duplication of description,
only the differences will be described in detail, with like
reference signs designating like parts.
[0165] The delivery device of this embodiment differs from that of
the above-described second embodiment in omitting the mouthpiece
119 and the release mechanism 131 being manually actuated.
[0166] Operation of this delivery device is similar to that of the
above-described second embodiment, except in that a bi-directional
air flow is not generated through the nasal airway and the release
mechanism 131 is actuated manually by the subject.
[0167] The present invention will now be described hereinbelow with
reference to the following non-limiting Examples.
EXAMPLE #1
[0168] The purpose of this study was to determine the relative
sedative effect of midazolam where intranasally delivered using the
novel, bi-directional administration system of the present
applicant.
[0169] In this study, twelve healthy subjects, 4 male and 8 female,
were studied. In separate sessions, the subjects received 3.4 mg of
midazolam by one of three different administration systems, these
being: an intravenous administration system in which a midazolam
formulation was intravenously administered; conventional nasal
spray administration system in which a midazolam formulation was
conventionally nasally administered using a spray pump as supplied
by Ing Erich Pfeiffer GmbH (Radolfsee, Germany) which is specified
to generate a liquid spray with a mean particle size of 43 .mu.m,
with 100 .mu.l of the formulation being delivered to each nostril;
and the bi-directional administration system of the first-described
embodiment, and incorporating the same spray pump as the
conventional nasal spray administration system, in which a
midazolam formulation was nasally administered, with 100 .mu.l of
the formulation being delivered to each nostril.
[0170] Each study session was six hours in duration, and the
sessions were separated by at least one week.
[0171] The intravenous formulation was a commercial midazolam HCl
formulation (1 mg/ml (free base)) as supplied by Alpharma Inc (New
Jersey, USA).
[0172] The nasal formulation was an aqueous solution containing
midazolam base (1.7% w/v), sulfobutylether-.beta.-cyclodextrin
sodium salt with a molar substitution of 6.2 (Captisol.RTM.) (14%
w/v) as supplied by CyDex Inc (Kansas, USA), hydroxypropyl
methylcellulose (0.1% w/v), benzalkonium chloride (0.02% w/v),
ethylene diaminetetraacetic acid (0.1% w/v) and phosphoric acid
(0.73% w/v). The pH of the formulation was adjusted to a pH of
between 4.20 and 4.35 with sodium hydroxide.
[0173] Venous blood samples, each having a volume of 9 ml, were
drawn just prior to administration and at 2, 5, 10, 15, 20, 25, 30,
35, 45, 60, 90, 120, 240 and 360 minutes after administration, in
order to allow for a determination of the blood plasma
concentration of midazolam.
[0174] The blood plasma concentration of midazolam was determined
according to Martens et al.
[0175] Samples, spiked with diazepam as an internal standard, were
alkalised and extracted by toluene containing 0.1% w/v amyl
alcohol. The resulting organic phase for each of the samples was
then evaporated and the residue for each of the samples was
derivatized with TBDMSTFA
(tert/-Butyldimethylsilyl)-/N/-methyltrifluoroacetamide with 1% w/v
tert-butyldimethylsilyllchloride) at 60.degree. C. After the excess
of TBDMSTFA was evaporated, the residue for each of the samples was
dissolved in ethyl acetate and analyzed in a gas chromatograph, in
this embodiment an HP 5890 gas chromatograph equipped with an HP
5972 mass-spectrometry detector as supplied by Hewlett Packard Inc
(USA). The midazolam and diazepam components were quantified by the
mass ions 310 and 256, respectively.
[0176] FIG. 8 shows the time course for measured blood plasma
concentrations of midazolam for the three different administration
systems.
[0177] The curves for the two nasal administration systems are
quite similar, whereas the curve for the intravenous administration
system exhibits a blood plasma concentration which is always
higher, although it has a parallel time-concentration curve to that
of the nasal administration systems. These curves do not seem to be
log-linear, indicating that a true elimination phase was not
reached within the study session.
[0178] Table I below shows the pharmacokinetic characteristics of
midazolam for the three administration systems.
[0179] In this study, the midazolam clearance, the volume of
distribution, the elimination rate, the maximum plasma
concentration Cmax, the time maximum plasma concentration Tmax, and
the area under the curve AUC (linear trapezoidal rule) were
calculated by computerized curve fitting using the Win-Nonlin
Standard 4.1 as supplied by Pharsight Corporation (California,
USA). The systemic clearance (Cl)=dose/AUC.sub.iv, the apparent
nasal clearances (Cl.sub.n)=dose/AUC.sub.n, and the respective
bioavailabilities
(F.sub.x)=(AUC.sub.x/dose.sub.y)/(AUC.sub.y/dose.sub.x) were
determined from the calculated values.
[0180] As can be seen, the two nasal administration systems
exhibited similar pharmacokinetics, including a rapid mean
T.sub.max of 15/16 minutes. The intravenous administration system
exhibited a shorter T.sub.max, and a significantly larger area
under the curve AUC. The bio-availabilities for the nasal
administration systems were similar, in being 0.68 (0.57, 0.80) and
0.69 (0.57, 0.81) for the conventional spray administration system
and the bi-directional spray administration system,
respectively.
TABLE-US-00001 TABLE I Administration T.sub.max C.sub.max T.sub.1/2
AUClast AUCinf Vz .sup.#(obs) Cl .sup.#(obs) System min ng/ml min
min*ng/ml min*ng/ml ml ml/min Intravenous 2.5 152 104 7349 8164
65378 451 2; 3 73; 232 87; 121 5953; 8744 6486; 9842 54383; 76373
374; 527 Bi-directional 16 44 119 4615 5364 98551 589 13; 19 34; 53
98; 139 3877; 5354 4476; 6252 64598; 132504 373; 805 Conventional
15 53 114 4628 5267 90691 551 11; 18 39; 66 96; 133 4211; 5044
4792; 5742 59419; 12964 376; 726 .sup.#The calculations for the
conventional nasal spray and bi-directional administration systems
are not corrected for bio-availability.
[0181] In the results, the data is given as a median (min-max) or a
mean (95% confidence interval (CI)). Regression analysis and ANOVA
were used as appropriate. A bi-variate correlation (Pearson) was
used to determine associations between variables. A paired sample
t-test was used for group comparisons.
[0182] Subjective sedation was scored by a numeric rating scale
(NRS) 0-10, where 0 is fully awake and 10 is falling asleep or as
tired as you can imagine at 0, 2, 5, 10, 15, 20, 25, 30, 35, 45,
60, 90, 120 and 360 minutes after administration.
[0183] FIG. 9 represents the time course for subjective reporting
of median sedation scores.
[0184] As can be seen, the bi-directional administration system
achieved sedation scores which were equivalent to those of the
intravenous administration system and yet unexpectedly had a much
lower Cmax than that of the intravenous administration system. In
addition, the bi-directional administration system has an onset of
action which is considerably faster than the conventional nasal
spray administration system and almost as fast as the intravenous
administration system, and a markedly longer Tmax than the
intravenous administration system.
[0185] FIG. 10 illustrates a plot of the reported median sedation
scores as a function of blood plasma concentration for the
intravenous administration system and the bi-directional
administration system.
[0186] This plot clearly illustrates that the bi-directional
administration system achieves the same peak CNS effect as the
intravenous administration system, but with a substantially lower
C.sub.max. In this embodiment the ratio of peak CNS effect to
C.sub.max as achieved by the bi-directional administration system
is about 3.5 times that achieved by intravenous administration.
[0187] FIG. 11 illustrates a plot of the reported median sedation
scores as a function of blood plasma concentration for the
bi-directional administration system and the conventional nasal
spray administration system.
[0188] This plot clearly illustrates the marked effect as achieved
by the bi-directional administration system as compared to the
conventional nasal spray administration system, insofar as the
bi-directional administration system achieves a substantially
greater CNS effect than the conventional nasal spray administration
system for a reduced C.sub.max.
[0189] As discussed hereinabove, the present inventors have
postulated that this increased concentration within the CNS arises
as a result of the veins in the upper posterior region of the nasal
passage draining backwards to the venous sinuses that surround the
brain, which leads to a higher local concentration in the
cerebrovasculature.
EXAMPLE #2
[0190] This study provides for characterization of the deposition
as achieved by the nasal administration systems of the
above-described study.
[0191] In this study, nine healthy subjects, 4 females and 5 males,
were studied.
[0192] In separate sessions, the subjects received a test solution
by one of two different nasal administration systems, these
corresponding to the nasal administration systems of the above
study and being: [0193] (i) a conventional nasal spray
administration system in which a labeled test solution was
conventionally nasally administered using a spray pump as supplied
by Ing Erich Pfeiffer GmbH (Radolfsee, Germany) which is specified
to generate a liquid spray with a mean particle size of 43 .mu.m,
with 100 .mu.l of the test solution being delivered to one nostril;
and [0194] (ii) the bi-directional administration system of the
first-described embodiment, and incorporating the same spray pump
as the conventional nasal spray administration system, in which a
labeled test solution was nasally administered, with 100 .mu.l of
the test solution being delivered to one nostril.
[0195] The two study sessions were performed two days apart to
secure complete washout and decay.
[0196] The test solution was a .sup.99mTc-DTPA solution, which was
made by adding 120-150 MBq .sup.99mTcO.sub.4.sup.- (IFETEC
generator) as supplied by Isopharma (Kjeller, Norway) in 6 ml of
eluate to a vial containing freeze-dried diethylene triamine
pentaacetic acid DTPA as supplied by Isopharma (Kjeller,
Norway).
[0197] The deposition of the test solution in the nasal cavity was
imaged using a scintillation camera system, here a VERTEX camera as
supplied by ADAC Laboratories (USA) which was equipped with a low
energy parallel hole high resolution VXGP collimator.
[0198] The aerosol was administered with the subjects sitting in
the upright position, and, following administration, the subjects
sat back such that the floor of the nasal cavity was projected at
between 30 and 45 degrees with respect to the y-axis of the camera
detector. This re-positioning took approximately 1 minute from the
dose administration and imaging was initiated immediately
thereafter. A total of 16 images, each containing 128.times.128
pixels, were acquired at two minute intervals. The subjects were
instructed not to sniff during the imaging procedure.
[0199] As a consequence of the variation in administered activity,
the acquired images were normalized so that the first image in each
series, which represents the initial deposition, had a total image
intensity equal to 100,000 within a region drawn around the nose as
appearing in the cumulative images. As the floor of the nose and
the curvature of the pharynx were clearly visible in the cumulative
images as derived from each of the series, each series of images
could conveniently be aligned.
[0200] Nasal dimensions were measured by acoustic rhinometry using
Rhin2000 anatomic nose adaptors as supplied by RhinoMetrics (Lynge,
Denmark), to verify normal nasal dimensions and to assist in nasal
segmentation. Acoustic rhinometry identified the location of the
minimal cross-sectional area corresponding to the head of the
inferior turbinate (mean/SD: 2.3+/-0.25 cm), the head of the middle
turbinate (mean/SD: 3.78+/-0.24 cm) and the transition to the
epipharynx (mean/SD: 7.6+/-0.48 cm).
[0201] In order to allow for characterization of the deposition,
the nose region was segmented into four rectangular nasal regions,
namely, a lower anterior region (LowAnt), an upper anterior region
(UpAnt), a lower posterior region (LowPost) and an upper posterior
region (UpPost), and one pharyngeal region. The horizontal
segmentation was fixed at a distance of 19 mm (4 pixels) from the
nasal floor as determined from the most intense contour in the
gradient image, and approximates the lower border of the middle
turbinate. The vertical segmentation was fixed at a distance of 38
mm (8 pixels) anterior to the transition between the nose and
nasopharynx, as visible in the cumulative images and lies between
the nasal valve and head of the middle turbinate. Because of the
limited spatial resolution of the camera system, the lower regions
were extended caudally and the upper regions cranially, in order to
include all counts originating from activity within the respective
regions.
[0202] FIGS. 12(a) and 12(b) illustrate respectively the cumulative
deposition as obtained by the two administration systems, with FIG.
12(a) illustrating the cumulative deposition as obtained by the
conventional nasal spray administration system and FIG. 12(b)
illustrating the cumulative deposition as obtained by the
bi-directional administration system.
[0203] As will be clearly seen, the bi-directional administration
system provides for a much greater fraction of the deposition to
the upper posterior region as compared to the conventional nasal
spray administration system.
[0204] Table II below shows the measured values for the initial
deposition in the four nasal segments and the nasopharynx, as
represented by the first in the series of images for each of the
subjects.
[0205] Table II below shows the measured values for the initial
deposition in the four nasal segments and the nasopharynx, as
represented by the first in the series of images for each of the
subjects.
TABLE-US-00002 TABLE II Conven- Conven- Conven- Conven- Conven-
Inven- Inven- Inven- Inven- Inven- tional tional tional tional
tional tive tive tive tive tive Difference Image Mean SD CV Nasal %
All % Mean SD CV Nasal % All % P-value Upper 32704 20205 0.62 43 38
12991 8095 0.62 19 17 p < 0.02 Anterior Lower 24172 14099 0.58
32 28 9228 6184 0.67 13 12 p < 0.004 Anterior Upper 8346 7242
0.87 11 10 22083 7599 0.34 32 28 p < 0.004 Posterior Lower 10983
7840 0.71 14 13 24997 8468 0.34 36 32 p < 0.02 Posterior
Nasopharynx 8899 10469 1.18 10 8992 7871 0.88 11 NS Sum Nasal 76205
21448 0.28 69299 8635 0.12 NS Regions Sum All 85104 14716 0.17
78290 8566 0.11 NS Regions
[0206] FIG. 13 graphically illustrates the mean deposition
fractions in the four segmented nasal regions for both the
conventional nasal spray administration system and the
bi-directional administration system.
[0207] As can be seen, the bi-directional administration system
provides for initial deposition of 68% to the posterior nasal
segments beyond the nasal valve of the total dose as deposited in
the nasal cavity, whereas only 25% of the total dose as deposited
in the nasal cavity is initially deposited in these segments
following delivery with the conventional nasal spray administration
system. In particular, following administration, the conventional
nasal spray administration system provides for initial deposition
of only 11% (SD 10%) of the total dose as deposited in the nasal
cavity in the upper posterior region of the nasal cavity, whereas
the bi-directional administration system provides for initial
deposition of 32% (SD 11%) of the total dose as deposited in the
nasal cavity in the upper posterior region of the nasal cavity.
[0208] The results of this study thus support the postulation of
the present inventors that the increased concentration of the
delivered substance to the CNS for any given blood plasma
concentration could at least in part be a function of the relative
fractions of substance which are delivered to the anterior and
posterior regions of the nasal cavity, and in particular the upper
posterior region.
EXAMPLE #3
[0209] The purpose of this study was to characterize the deposition
as achieved by powder aerosol and liquid jet administration systems
in accordance with embodiments of the present invention.
[0210] In this study, nine healthy subjects, 4 females and 5 males,
were studied.
[0211] In separate sessions, the subjects received a test substance
by one of three different nasal administration systems, these
being: [0212] (i) a conventional nasal spray administration system
in which a labeled test solution was conventionally nasally
administered using a single-dose spray pump as supplied by Ing
Erich Pfeiffer GmbH (Radolfsee, Germany) which is specified to
generate a liquid spray with a mean particle size of 43 .mu.m, with
100 .mu.l of the test solution being delivered to one nostril;
[0213] (ii) the bi-directional administration system of the
first-described embodiment where configured to deliver a labeled
test powder from a conventional gelatine capsule, with
approximately 4 mg of the test powder being nasally administered to
one nostril; and [0214] (iii) the bi-directional administration
system of the first-described embodiment where incorporating the
same single-dose spray pump as the conventional nasal spray
administration system but with the nozzle modified, here truncated,
to deliver a liquid jet, in which a labeled test solution was
nasally administered, with 100 .mu.l of the test solution being
delivered to one nostril.
[0215] The three study sessions were performed two days apart to
secure complete washout and decay.
[0216] The test solution was a .sup.99mTc-DTPA solution, which was
made by adding 120-150 MBq .sup.99mTcO.sub.4.sup.- (IFETEC
generator) as supplied by Isopharma (Kjeller, Norway) in 6 ml of
eluate to a vial containing freeze-dried diethylene triamine
pentaacetic acid DTPA as supplied by Isopharma (Kjeller,
Norway).
[0217] The test powder was a .sup.99mTc-labelled powder as supplied
by the Institute for Energy Technology (IFE) (Kjeller, Norway).
[0218] The deposition of the test solution and powder in the nasal
cavity was imaged using a scintillation camera system, here a
VERTEX camera as supplied by ADAC Laboratories (USA) which was
equipped with a low energy parallel hole high resolution VXGP
collimator.
[0219] The test samples were administered with the subjects sitting
in the upright position, and, following administration, the
subjects each turned their head to the side and positioned their
cheek and the tip of their nose in an alignment device which was
attached to the camera. In this study, the floor of the nasal
cavity was projected close to the horizontal, corresponding to the
x-axis of the camera detector. This re-positioning took between
approximately 10 and 30 seconds from the dose administration and
imaging was initiated immediately thereafter. A total of 16 images,
each containing 128.times.128 pixels, were acquired at two minute
intervals. The subjects were instructed not to sniff during the
imaging procedure.
[0220] As a consequence of the variation in administered activity,
the acquired images were normalized so that the first image in each
series, which represents the initial deposition, had a total image
intensity equal to 100,000 within a region drawn around the nose as
appearing in the cumulative images. As the floor of the nose and
the curvature of the pharynx were clearly visible in the cumulative
images as derived from each of the series, each series of images
could conveniently be aligned.
[0221] Nasal dimensions were measured by acoustic rhinometry using
Rhin2000 anatomic nose adaptors as supplied by RhinoMetrics (Lynge,
Denmark), to verify normal nasal dimensions and to assist in nasal
segmentation.
[0222] In order to allow for characterization of the deposition,
the nose region was segmented into four rectangular nasal regions,
namely, a lower anterior region (LowAnt), an upper anterior region
(UpAnt), a lower posterior region (LowPost) and an upper posterior
region (UpPost), and one pharyngeal region. The horizontal
segmentation was fixed at a distance of approximately 19 mm (4
pixels) from the nasal floor as determined from the most intense
contour in the gradient image, and approximates the lower border of
the middle turbinate. The vertical segmentation was fixed at a
distance of approximately 38 mm (8 pixels) anterior to the
transition between the nose and nasopharynx, as visible in the
cumulative images and lies between the nasal valve and head of the
middle turbinate. Because of the limited spatial resolution of the
camera system, the lower regions were extended caudally and the
upper regions cranially, in order to include all counts originating
from activity within the respective regions.
[0223] Tables III(a) to (c) below show the measured values for the
initial deposition in the four nasal segments and the nasopharynx,
as represented by the first in the series of images for each of the
subjects, for each of the adminisatration systems.
TABLE-US-00003 TABLE III(a) Conven- Conven- Conven- Conven- Conven-
tional tional tional tional tional Image Mean SD CV Nasal % All %
Upper 25565 16531 0.65 26 26 Anterior Lower 31935 26981 0.84 33 32
Anterior Upper 12893 8377 0.65 13 13 Posterior Lower 27999 19622
0.70 28 28 Posterior Nasopharynx 1579 4293 2.72 1 Sum Nasal 98392
Regions Sum All 99971 Regions
TABLE-US-00004 TABLE III(b) Liquid Jet Liquid Jet Liquid Jet Liquid
Jet Liquid Jet Image Mean SD CV Nasal % All % Upper 13993 8493 0.61
15 14 Anterior Lower 8409 7893 0.94 9 8 Anterior Upper 47518 9150
0.19 52 48 Posterior Lower 21598 11179 0.52 24 22 Posterior
Nasopharynx 8105 10310 1.27 8 Sum Nasal 91518 Regions Sum All 99623
Regions
TABLE-US-00005 TABLE III(c) Powder Powder Powder Powder Powder
Image Mean SD CV Nasal % All % Upper 20019 13147 0.66 21 20
Anterior Lower 8115 5445 0.67 8 8 Anterior Upper 54281 14196 0.26
56 54 Posterior Lower 14917 10682 0.72 15 15 Posterior Nasopharynx
2515 3501 1.39 3 Sum Nasal 97332 Regions Sum All 99847 Regions
[0224] FIG. 14 graphically illustrates the mean deposition
fractions in the four segmented nasal regions for both the
conventional nasal spray administration system and the
bi-directional administration systems.
[0225] As can be seen, the bi-directional liquid jet administration
system provides for initial deposition of 76% of the dose as
initially deposited in the nasal cavity to the posterior segments
beyond the nasal valve and the powder administration system
provides for initial deposition of 71% of the dose as initially
deposited in the nasal cavity to the posterior segments beyond the
nasal valve, whereas the conventional nasal spray administration
system provides for initial deposition of only about 41% of the
dose as initially deposited in the nasal cavity in these segments.
In particular, following administration, the conventional nasal
spray administration system provides for initial deposition of only
about 13% of the dose as initially deposited in the nasal cavity in
the upper posterior region of the nasal cavity, whereas the
bi-directional liquid jet administration system provides for
initial deposition of about 52% (SD 9%) of the dose as initially
deposited in the nasal cavity to the upper posterior region of the
nasal cavity and the bi-directional powder administration system
provides for initial deposition of about 56% (SD 14%) of the dose
as initially deposited in the nasal cavity to the upper posterior
region of the nasal cavity.
[0226] The results of this study thus support the postulation of
the present inventors that the increased concentration of the
delivered substance to the CNS for any given blood plasma
concentration could at least in part be a function of the relative
fractions of substance which are delivered to the anterior and
posterior regions of the nasal cavity, and in particular the upper
posterior region.
[0227] Finally, it will be understood that the present invention
has been described in its preferred embodiments and can be modified
in many different ways without departing from the scope of the
invention as defined by the appended claims. [0228] The following
references are herein incorporated in their entirety by reference.
[0229] 1. Born, J et al, Sniffing neuropeptides: a transnasal
approach to the human brain, Nature Neuroscience, 2002, pages 514
to 516. [0230] 2. Cole, P, The Respiratory Role of the Upper
Airway, Mosby, 1992, pages 7 and 8. [0231] 3. Einer-Jensen, N et
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cavities to the brain arterial blood in rats, Pharmacol and
Toxicol, 2000, Vol 87, pages 276 to 278. [0232] 4. Einer-Jensen, N
et al, Transfer of titrated water, tyrosine and propanol from the
nasal cavity to cranial arterial blood in rats, Experimental Brain
Research, 2000, vol 130, pages 216 to 220. [0233] 5. Martens, J et
al, Simultaneous determination of midazolam and its metabolites
1-hydroxymidazolam and 4-hydroxymidazolam in human serum using gas
chromatography-mass spectrometry, Journal of Chromatography B,
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and Development of the Naso-Respiratory Area in Childhood, PhD
Thesis, Laboratory of Anatomy, School of Medicine, Western Reserve
University, Presented to the Annual Meeting of the American
Laryngological, Rhinological and Otological Society, Charleston,
S.C., USA, 1934. [0235] 7. Zacharek, M A et al, Sagittal and
Coronal Dimensions of the Ethmoid Roof: A Radioanatomic Study, Am J
Rhinol 2005, Vol 19, pages 348 to 352.
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