U.S. patent application number 17/153962 was filed with the patent office on 2021-07-22 for nasal delivery.
The applicant listed for this patent is OptiNose AS. Invention is credited to Per Gisle Djupesland.
Application Number | 20210220262 17/153962 |
Document ID | / |
Family ID | 1000005493253 |
Filed Date | 2021-07-22 |
United States Patent
Application |
20210220262 |
Kind Code |
A1 |
Djupesland; Per Gisle |
July 22, 2021 |
NASAL DELIVERY
Abstract
A nasal delivery device for and method of delivering a
substance, preferably comprising oxytocin, non-peptide agonists
thereof and antagonists thereof, preferably as one of a liquid, as
a suspension or solution, or a powder, to the nasal airway of a
subject, preferably the posterior region of the nasal airway, and
preferably the upper posterior region of the nasal airway which
includes the olfactory bulb and the trigeminal nerve, and
preferably in the treatment of neurological conditions and
disorders.
Inventors: |
Djupesland; Per Gisle;
(Oslo, NO) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
OptiNose AS |
Oslo |
|
NO |
|
|
Family ID: |
1000005493253 |
Appl. No.: |
17/153962 |
Filed: |
January 21, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15918169 |
Mar 12, 2018 |
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17153962 |
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14005363 |
Nov 22, 2013 |
9949923 |
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PCT/IB2012/000564 |
Mar 15, 2012 |
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15918169 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/198 20130101;
A61M 15/08 20130101; A61K 31/4174 20130101; A61M 2202/0468
20130101; A61M 15/0098 20140204; A61K 38/12 20130101; A61K 31/551
20130101; A61K 9/0043 20130101; A61K 38/17 20130101; A61M 2202/064
20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61M 15/08 20060101 A61M015/08; A61K 31/198 20060101
A61K031/198; A61K 31/4174 20060101 A61K031/4174; A61K 31/551
20060101 A61K031/551; A61K 38/12 20060101 A61K038/12; A61K 38/17
20060101 A61K038/17 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 15, 2011 |
GB |
1104450.0 |
May 4, 2011 |
GB |
1107477.0 |
May 4, 2011 |
GB |
1107478.8 |
Sep 14, 2011 |
GB |
1115972.0 |
Claims
1-63. (canceled)
64. A method of delivering a dose of powdered oxytocin to an upper
posterior, olfactory region of a nasal airway of a subject with a
nasal delivery device, the method comprising: causing a nosepiece
of the device to be fitted in a nostril of the subject, the device
further including a mouthpiece, a medicament supply unit, and a
tubular section coupling the nosepiece and the mouthpiece; causing
the subject to exhale through the mouthpiece and generate an
exhalation flow that flows (a) through the tubular section and
creates a positive pressure in an oral cavity of the subject
sufficient to cause closure of an oropharyngeal velum of the
subject and (b) through the nosepiece and creates a bi-directional
flow of exhalation breath through a nasal cavity of the subject
when the nosepiece is fitted in the nostril; causing a flow of gas
from the medicament supply unit to entrain the dose of powdered
oxytocin within the flow of gas and expel the dose of powdered
oxytocin and flow of gas through the nosepiece; and causing a flow
of liquid from the medicament supply unit through the nosepiece
after causing the flow of gas from the medicament supply unit.
65. The method of claim 64, further including causing a thickening
agent to be expelled through the nosepiece with the dose of
powdered oxytocin.
66. The method of claim 65, wherein the thickening agent thickens
after exposure to moisture, providing for increased residency at
the upper posterior, olfactory region of the nasal airway of the
subject.
67. The method of claim 65, wherein the thickening agent comprises
at least one of pectin, agar-agar, lignin, algin, gums, or
cellulose.
68. The method of claim 64, further including causing lactose to be
expelled through the nosepiece with the dose of powdered
oxytocin.
69. The method of claim 64, wherein the dose of powdered oxytocin
ranges from about 1 IU to about 100 IU.
70. The method of claim 64, wherein the dose of powdered oxytocin
ranges from about 5 IU to about 80 IU.
71. The method of claim 64, wherein the dose of powdered oxytocin
ranges from about 5 IU to about 50 IU.
72. The method of claim 64, wherein the dose of powdered oxytocin
ranges from about 5 IU to about 20 IU.
73. The method of claim 64, wherein the dose of powdered oxytocin
is delivered once daily.
74. The method of claim 64, wherein the dose of powdered oxytocin
is delivered twice daily.
75. The method of claim 64, wherein the method is performed to
provide for treatment of 22q11.2 deletion syndrome.
76. A method of delivering a dose of powdered oxytocin to an upper
posterior, olfactory region of a nasal airway of a subject with a
nasal delivery device, the method comprising: fitting a nosepiece
of the device in a nostril of the subject, the device including a
mouthpiece, a medicament supply unit, and a tubular section
coupling the nosepiece and the mouthpiece; exhaling through the
mouthpiece to generate an exhalation flow that flows (a) through
the tubular section and creates a positive pressure in an oral
cavity of the subject sufficient to cause closure of an
oropharyngeal velum of the subject and (b) through the nosepiece
and creates a bi-directional flow of exhalation breath through a
nasal cavity of the subject when the nosepiece is fitted in the
nostril; and supplying, via a medicament supply unit, (1) a gas
flow that entrains the dose of powdered oxytocin within the flow of
gas and expels the dose of powdered oxytocin and flow of gas
through the nosepiece and (2) a liquid flow through the nosepiece,
subsequent to expulsion of the flow of gas from the medicament
supply unit.
77. The method of claim 76, further including expelling a
thickening agent through the nosepiece with the dose of powdered
oxytocin.
78. The method of claim 77, wherein the thickening agent thickens
after exposure to moisture, providing for increased residency at
the upper posterior, olfactory region of the nasal airway of the
subject.
79. The method of claim 77, wherein the thickening agent comprises
at least one of pectin, agar-agar, lignin, algin, gums, or
cellulose.
80. The method of claim 76, further including expelling lactose
through the nosepiece with the dose of powdered oxytocin.
81. The method of claim 76, wherein the dose of powdered oxytocin
ranges from about 1 IU to about 100 IU.
82. The method of claim 76, wherein the dose of powdered oxytocin
ranges from about 5 IU to about 80 IU.
83. The method of claim 76, wherein the dose of powdered oxytocin
is delivered once daily.
84. The method of claim 76, wherein the dose of powdered oxytocin
is delivered twice daily.
85. The method of claim 76, wherein the method is performed to
provide for treatment of 22q11.2 deletion syndrome.
Description
[0001] The present invention relates to a nasal delivery device for
and a method of delivering a substance comprising oxytocin,
non-peptide agonists thereof and antagonists thereof, in particular
as one of a liquid, as a suspension or solution, or a powder, to
the nasal airway of a subject, in particular the posterior region
of the nasal airway, and in particular the upper posterior region
of the nasal airway, which includes the olfactory bulb and the
trigeminal nerve, in particular in the treatment of neurological
conditions and disorders.
[0002] Referring to FIG. 1, 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.
[0003] The posterior region of the nasal airway is that region
which is posterior of the nasal valve NV, as illustrated in FIG. 2.
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 (Cole). 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.
[0004] 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.
[0005] The upper posterior region is the region above the inferior
meatus IM, as illustrated in FIG. 2, and encompasses the middle
turbinate, the middle meatus, 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.
[0006] As illustrated in FIG. 2, the posterior region of the nasal
airway is the nasal region posterior of an imaginary vertical plane
VERT which is located at a position corresponding to the lower
angle of the anterior nasal aperture (aperture piriformis), which
corresponds substantially 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).
[0007] As further illustrated in FIG. 2, 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 al define the distance from the nasal floor NF to the cribiform
plate CP as 46+/-4 mm).
[0008] The upper posterior region is thus that upper posterior
region which is bounded by the above-defined vertical and
horizontal planes VERT, HORIZ.
[0009] The present invention is directed to the delivery of a
substance to the nasal airway of a subject, particularly in the
treatment of neurological conditions and disorders, using the
delivery technique of WO-A-2000/051672 and WO-A-2003/000310, the
contents of which are each herein incorporated by reference.
[0010] WO-A-2000/51672 and WO-A-2003/000310 disclose delivery
devices for delivering a substance, in particular a medicament, in
a bi-directional flow through the nasal cavities, that is, an air
flow which passes into one nostril, around the posterior margin of
the nasal septum and in the opposite direction out of the other
nostril.
[0011] The nasal delivery technique of the present invention
provides for delivery to the olfactory region, the trigeminal nerve
and other structures of the limbic system which interface at the
nasal airway, which features are located in the superior region of
the nasal cavities and represents the only region where it is
possible to circumvent the blood-to-brain barrier (BBB) and enable
communication with the cerebrospinal fluid (CSF) and the brain.
[0012] In one embodiment the substance is delivered as a powder,
preferably containing from about 1 IU to 100 IU, more preferably
from about 5 IU to about 80 IU, still more preferably from about 5
IU to about 50 IU, yet more preferably from about 5 IU to about 20
IU, still more preferably from about 20 IU to about 100 IU, yet
more preferably from about 40 IU to about 100 IU, and preferably
less than about 15 IU or greater than about 50 IU.
[0013] In one embodiment the active ingredient is mixed with a
bulking agent, such as lactose.
[0014] In one embodiment the substance includes a thickening agent,
which thickens following delivery and on exposure to a moist
environment, such as in the nasal airway, thereby providing for
increased residency at the target region.
[0015] In one embodiment the thickening agent comprises pectin,
agar-agar, lignin, algin, gums, such as vegetable gums, and
cellulose.
[0016] In one embodiment the substance can be delivered as a
powder, followed by application of a liquid, typically as a liquid
spray, to promote dissolution and transfer of the active
ingredient.
[0017] In another embodiment the substance is delivered as a
liquid, preferably containing from about 1 IU to about 10 IU, more
preferably from 3 IU to 10 IU, still more preferably from about 3
IU to about 5 IU or greater than 5 IU.
[0018] In one embodiment the substance is delivered in a once-daily
administration.
[0019] In another embodiment the substance is delivered in a
twice-daily administration.
[0020] In one embodiment the active ingredient comprises
oxytocin.
[0021] In another embodiment the active ingredient comprises a
non-peptide oxytocin agonist, such as WAY-267,464.
[0022] In one embodiment the active ingredient can comprise both
peptide and non-peptide oxytocin.
[0023] In a further embodiment the active ingredient comprises an
oxytocin antagonist.
[0024] In other embodiments the active ingredient can instead be an
analogue or derivative or oxytocin, such as carbetocin or
demoxytocin.
[0025] In one embodiment the active ingredient can comprise
desglycinamide oxytocin.
[0026] In a further embodiment the active ingredient can further
comprise another neurohypophysial hormone, including vasopressin
and lypressin, or their analogues or derivatives.
[0027] In a still further embodiment the active ingredient can
further comprise another stress hormone, including adrenalin,
adrenocorticocotropin or a corticotropin-releasing hormone, or
their analogues or derivatives.
[0028] In an alternative embodiment the active ingredient can
comprise another neurohypophysial hormone, including vasopressin
and lypressin, or their analogues or derivatives.
[0029] In another alternative embodiment the active ingredient can
comprise another stress hormone, including adrenalin,
adrenocorticocotropin or a corticotropin-releasing hormone, or
their analogues or derivatives.
[0030] In one embodiment the vasopressin comprises desglycinamide
vasopressin.
[0031] In yet another alternative embodiment the active ingredient
can comprise ketamin or another NMDA receptor antagonist, including
dextromethorphan (DXM) and phencyclidine (PCP), or their analogues
or derivatives.
[0032] In still another alternative embodiment the active
ingredient can comprise metyrosine (Demser) or its analogues or
derivatives.
[0033] In one embodiment the administration can be targeted to
provide for both N28 and systemic delivery.
[0034] In one embodiment the substance can be formulated
selectively to provide for greater N28 or systemic delivery.
[0035] In another embodiment the substance can comprise two
substance components, one formulated for N2B delivery and the other
formulated for systemic delivery.
[0036] In one embodiment the substance comprises a decongestant,
such as oxymetazoline.
[0037] In another embodiment the substance could comprise a
neuropeptide, such as hypocretin-1 (Orexin-A) or an orexin receptor
agonist or antagonist, or their analogues or derivatives.
[0038] In a further embodiment the substance could comprise an
analeptic, such as modafinil, armodafinil and adrafinil, or their
analogues or derivatives.
[0039] The nasal delivery technique of the present invention
provides for the treatment of neurological diseases and conditions,
including: neurodegenerative diseases and conditions, including
Alzheimer's disease, Huntington's disease, Parkinson's disease,
dementia and stroke, bi-polar disorder, including juvenile bipolar
disorder, diabetes, neuropsychiatric disorders, including
obsessive-compulsive disorder (OCD), autism, eating disorders,
addiction, schizophrenia, psychosis, post traumatic stress disorder
(PTSD), depression, chronic depression, disorders associated with
abuse and mood disorders, promoting well-being, promoting overall
calm, anxiety, including modulating anxiety, increasing trust,
reducing fear, hair loss, cancer, obesity, atherosclerotic
cardiovascular disease, essential hypertension, polycystic ovary
syndrome, syndrome X, ischemia, especially cerebral ischemia,
traumatic brain injury, immunodeficiency, sexual dysfunction,
promoting an orgasm, regulation of maternal behaviour, including
mother-infant bonding, regulation of sexual behaviour, including
regulation of female sexual behaviour and regulation of male sexual
behaviour, promoting social behaviour, including regulation of
social behaviour, including regulation of male and female
aggression, promoting social memory, including social recognition,
love bonding and pair bonding, promoting social recognition,
promoting intelligence, including non-verbal intelligence,
promoting learning, promoting memory, promoting cognition, lowering
sympathoadrenal tone ("flight and fight response"), enhancing
digestive activity, enhancing anabolic activity, decreasing blood
pressure, inhibiting salt-appetite, and improving wound
healing.
[0040] In other embodiments the nasal delivery technique of the
present invention provides for suppression of fever, and by way of
pain relief, such as in the treatment of breakthrough pain, for
example, in cancer patients.
[0041] The nasal delivery technique of the present invention also
provides for the treatment of 22q11.2 deletion syndrome, including
DiGeorge syndrome (DGS), DiGeorge anomaly, velo-cardlo-facal
syndrome (VCFS), Shprintzen syndrome, conotruncal anomaly face
syndrome, Strong syndrome, congenital thymic aplasla and thymic
hypoplasia, particularly when using any oxytocin-related active
ingredient or metyrosine (Demser) or its analogues or
derivatives.
[0042] The nasal delivery technique of the present invention also
provides for the treatment of bi-polar disorder, especially
juvenile bi-polar disorder, particularly when using ketamin or its
analogues or derivatives.
[0043] The nasal delivery technique of the present invention also
provides for the treatment of pheochromocytoma or phaeochromocytoma
(PCC), which is a neuroendocrine tumor of the medulla of the
adrenal glands, particularly when using metyrosine (Demser) or its
analogues or derivatives.
[0044] Differently from oral delivery techniques which utilize
gastro-intestinal (GI) absorption and exhibit a high first-pass
metabolism, the delivery technique of the present invention avoids
this effect, thus delivering more substance to the blood.
[0045] The delivery technique of the present invention, which
provides for nose-to-brain (N2B) delivery, enables the delivery of
substances to the brain in an amount significantly higher than
other conventional delivery routes, such as that achieved by the
oral route.
[0046] Finally, it will be understood that the present invention
has been described in its preferred embodiments and can be modified
in many different ways.
REFERENCES
[0047] 1. Cole, P, The Respiratory Role of the Upper Airways, a
selective clinical and pathophysiological review. 1993, Mosby-Year
Book Inc. ISBN1.55664-390-X. [0048] 2. Rosenberger, H, Growth 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. [0049] 3. 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.
Nasal Delivery Device
[0050] The present invention relates to a delivery device for and a
method of delivering a substance, in particular one of a liquid, as
a suspension or solution, or a powder containing a medicament,
especially a topical pharmaceutical, a cleansing agent, or an
irrigating agent, as a liquid, preferably combined with a cleansing
agent, to the nasal airway of a subject. In particular, the present
invention relates to the delivery of medicament to and the
irrigation of the nasal mucosa, the anterior region of nasopharynx,
the paranasal sinus ostia, the tubal ostia of the auditory tubes,
the sinus tubes, the auditory tubes, the tympanic cavities and the
paranasal sinuses.
[0051] Referring to FIG. 3, 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, 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.
[0052] There are many nasal conditions which require treatment. One
such condition is nasal inflammation, specifically rhinitis, which
can be allergic or non-allergic and is often associated with
infection and prevents normal nasal function. By way of example,
allergic and non-allergic inflammation of the nasal airway can
typically effect between 10 and 20% of the population, with nasal
congestion of the erectile tissues of the nasal concha,
lacrimation, secretion of watery mucus, sneezing and itching being
the most common symptoms. As will be understood, nasal congestion
impedes nasal breathing and promotes oral breathing, leading to
snoring and sleep disturbance. Worryingly, the incidence of such
allergic and non-allergic inflammatory diseases is increasing.
Other nasal conditions include nasal polyps which arise from the
paranasal sinuses, hypertrophic adenoids, secretory otitis media,
sinus disease and reduced olfaction.
[0053] In the treatment of certain nasal conditions, the topical
administration of medicaments is preferable, particularly where the
nasal mucosa is the prime pathological pathway, such as in treating
or relieving nasal congestion. Indeed, topical administration is
advantageous in minimising the possible side effects of systemic
administration. Medicaments that are commonly topically delivered
include decongestants, anti-histamines, cromoglycates, steroids and
antibiotics.
[0054] There are now an increasing number of adults and children
who rely on pharmaceuticals to relieve symptoms associated with
nasal conditions. At present, among the known anti-inflammatory
pharmaceuticals, topical steroids have been shown to have an effect
on nasal congestion. Topical decongestants have also been suggested
for use in relieving nasal congestion. The treatment of
hypertrophic adenoids and chronic secretory otitis media using
topical decongestants, steroids and anti-microbial agents, although
somewhat controversial, has also been proposed. Further, the
topical administration of pharmaceuticals has been used to treat or
at least relieve symptoms of inflammation in the anterior region of
the nasopharynx, the paranasal sinuses and the auditory tubes.
[0055] Aside from the delivery of medicaments, the irrigation of
the nasal mucosa with liquids, in particular saline solutions, is
commonly practised to remove particles and secretions, as well as
to improve the mucociliary activity of the nasal mucosa. These
solutions can be used in combination with active
pharmaceuticals.
[0056] Furthermore, medicaments are now increasingly systemically
delivered through the nasal pathway, the nasal pathway offering a
good administration route for the systemic delivery of
pharmaceuticals, such as hormones, for example oxytocin, and
anti-migraine compositions, as the high blood flow and large
surface area of the nasal mucosa advantageously provides for rapid
systemic uptake.
[0057] A variety of delivery systems have been developed to deliver
substances to the nasal airways of subjects.
[0058] Conventionally, spray bottles have been used to deliver a
medicament-containing liquid or an irrigating liquid to the nasal
airways of subjects. However, the distribution of the delivered
substance, in particular to the posterior region of the nasal
airway, is less than ideal, especially in the cases of moderate and
severe nasal obstruction. This poor distribution is often further
exacerbated by a subject inhaling through the nasal airway during
delivery, as is often prescribed, in an attempt to deliver the
substance to the posterior region of the nasal airway. Indeed, an
amount of the substance can be drawn into the lungs or swallowed in
each delivery, which could be problematic in paediatric subjects if
the medicament is a potent pharmaceutical, such as a steroid, which
has to be administered frequently. In addition, the spray is
frequently directed against the nasal septum which can undesirably
lead to localised deposition. Further, the mechanical action of the
delivery mechanism of the spray bottles can cause irritation and
bleeding.
[0059] GB-A-408856 discloses a delivery device, which in one mode
of use, apparently allows for the delivery of two separate air
flows entraining medicament into respective ones of the nasal
cavities of a subject. This delivery device comprises a chamber
containing a sponge saturated with medicament, a mouthpiece
connected to the chamber and first and second nosepieces connected
to the chamber. In one mode of use, the mouthpiece is taken in the
mouth of a subject and the nosepieces fitted into respective ones
of the nostrils of the subject, and on exhalation through the
mouthpiece separate air flows entraining medicament are apparently
driven into the nasal cavities of the subject.
[0060] It is not seen, however, how this delivery device could
function properly in this mode of use, since, as is now understood,
the velum of the subject would close on exhalation through his or
her mouth and hence close the nasal airway, thereby preventing any
significant air flow into the nasal cavities.
[0061] WO-A-98/53869 discloses a delivery device for delivering a
powder containing a medicament to the nasal mucosa in one of the
nasal cavities of a subject. This device comprises a tubular
section which contains a metered dose of powdered medicament. In
use, the ends of the tubular section art respectively located in
the nostril of one of the nasal cavities and the mouth of a
subject, and on exhalation by the subject through his or her mouth
the exhaled air entrains the powdered medicament and delivers the
same into the one nasal cavity, with the exhaled air backflowing
out of the one nostril around the tubular section. In one
embodiment the tubular section includes a flexible portion upstream
of the dose of powdered medicament. The provision of this flexible
portion allows the subject to close the tubular section at a point
upstream of the medicament, such that, on release of the closed
flexible portion during exhalation, a short explosive air flow
entraining medicament is delivered into the one nasal cavity. In
another embodiment the end of the tubular section located in the
nostril can be shaped to act to locate the tubular section in a
position in the nostril which allows for the deposition of the
powdered medicament on the nasal mucosa.
[0062] Whilst this delivery device is simple in-construction, the
operation of the device still does not provide for the effective
delivery of substances, in particular one of a liquid or powder
containing medicament, to the posterior region of the nasal airway,
since medicament is delivered separately to each of the nasal
cavities and the air flow into and out of each nasal cavity is
through the same opening, namely the respective nostril, with the
closed posterior region of the respective nasal cavity acting as a
pressure reflecting surface which causes the exhaled air to
backflow out of the one nostril before ever adequately reaching the
posterior region of the respective nasal cavity. Further, in
providing a short explosive burst of air flow into one of the nasal
cavities, it is not possible to achieve a sustained and controlled
bi-directional air flow through the nasal cavities which has been
found necessary to deliver a substance effectively to the posterior
region of the nasal airway.
[0063] For any substance to be delivered effectively to the nasal
airway, it is highly desirable that the administration is efficient
and simple. However, there can be problems in attempting to achieve
this goal. In particular, the pathological changes observed with
nasal inflammation make administration of substances, such as
liquids or powders, tricky, particularly to the posterior region of
the nasal airway and the posterior margins of the nasal structures.
Indeed, as a consequence of the complex geometry of the narrow
slit-like passages in the nasal airway, these passages become
partially occluded when the nasal mucosa is inflamed and congested,
making the distribution of topical pharmaceuticals to the nasal
airway difficult.
[0064] It is thus an aim of the present invention to provide a
delivery device for and a method of achieving a more optimally
distributed deposition of a substance, especially topical
pharmaceuticals, in the nasal airway, particularly the posterior
region of the nasal airway, and in particular the anterior region
of the nasopharynx where the adenoid and tubal ostia are
located.
[0065] Accordingly, the present invention provides a delivery
device for delivering a substance to the nasal airway of a subject,
comprising: a closure unit for causing the closure of the
oropharyngeal velum of the subject; and a delivery unit for
delivering a gas flow entraining a substance to one of the nostrils
of the subject at such a driving pressure as to flow around the
posterior margin of the nasal septum and out of the other nostril
of the subject, wherein the delivery unit comprises a nosepiece
which includes an outlet through which the gas flow is in use
delivered to the one nostril and a sealing member for sealing the
one nostril to the outlet such as in use to prevent the escape of
the gas flow through the one nostril.
[0066] In one embodiment the substance comprises a dry powder.
[0067] In another embodiment the substance comprises liquid
droplets.
[0068] Preferably, the particle size distribution of the substance
is principally in the range of about 1 to 10 .mu.m.
[0069] In one embodiment the substance contains a medicament,
particularly for the treatment of a nasal condition. In a preferred
embodiment the particle size distribution of the substance can
include a smaller fraction of larger particles, typically in the
range of about 10 to 30 .mu.m, and preferably in the range of about
20 to 30 .mu.m.
[0070] In other embodiments the substance can be a cleansing agent,
as a powder or liquid, for cleansing the nasal airway, or a liquid,
which may preferably contain a cleansing agent, for irrigating the
nasal airway. By way of example, the delivery device could be used
to administer saline or other solutions to the nasal airway to
remove particles and secretions, in particular from the posterior
region of the nasal airway, which resulting solution could be
analysed for diagnostic or research purposes. In a preferred
embodiment the particle size distribution of the cleansing or
irrigating agents can include a fraction of larger particles,
particularly in relation to the mechanical action of the
particles.
[0071] The present invention also provides a method of delivering a
substance to the nasal airway of a subject, comprising the steps
of: sealing one of the nostrils of a subject to an outlet of a
delivery unit such as to prevent the escape of a gas flow through
the one nostril; closing the oropharyngeal velum of the subject;
and delivering a gas flow entraining a substance through the outlet
at such a pressure as to flow around the posterior margin of the
nasal septum and out of the other nostril of the subject.
[0072] In one embodiment the closure of the velum is achieved
directly by the use of an instrument for pressing against the velum
to close the same or a bung for temporarily closing the opening
behind the velum between the nasal airway and the oral cavity.
[0073] In a preferred embodiment the closure of the velum is
achieved indirectly by the creation of a positive pressure in the
oral cavity, or more correctly a positive pressure differential
between the oral cavity and the nasal airway, such as achieved on
exhalation.
[0074] Preferably, the velum is closed simultaneously with the
onset of the delivery of the substance to the nasal airway.
[0075] In a preferred embodiment closure of the velum is achieved
automatically by the subject exhaling against a flow resistor,
which flow resistor may be operably connected to a tubular section
held between the lips of the subject. The flow resistor can be
configured to provide the required intra-oral positive
pressure.
[0076] It has been established that flow rates of about 1 to 20
litres per minute, and particularly about 3 to 15 litres per
minute, can be easily achieved by a subject and that and a fairly
constant air flow can be maintained for up to 20 seconds depending
on the flow rate. For some treatment regimes, it is important that
a stable flow of relatively high flow rate be maintained for a
period of a few seconds, preferably 3 to 10 seconds, in order to
enable the substance to penetrate to the more remote parts of the
nasal airway.
[0077] In one embodiment the air flow of exhalation by a subject is
used to power a mechanism which disperses the substance into a
volume of air and delivers that dispersed substance into the nasal
airway.
[0078] Preferably, the mechanism is so arranged that the substance
is delivered into the nasal airway after the velum has been closed
or simultaneously with velum closure. In this respect, it will be
understood that bi-directional flow through the nasal cavities is
possible only when the velum is closed and that any substance
delivered prior to closure of the velum would undesirably be
delivered to the lower airway or the gut.
[0079] Preferably, the release of the substance into the nasal
airway is triggered by the air flow created on exhalation.
[0080] In a preferred embodiment a pressure-sensitive valve is
utilised to trigger release of the substance when a predetermined
flow rate has been developed. It should be understood that control
of the flow rate of the gas in which the substance is delivered is
important, as this flow rate; along with the particle size
distribution of the substance, are the significant factors
determining the particle deposition efficiency.
[0081] In a preferred embodiment the pressure-sensitive valve is
not opened until the subject has maintained a predetermined flow
rate, and can be closed when the flow rate drops below the
predetermined flow rate so as to stop the delivery of the
substance.
[0082] In a preferred embodiment, where medicament is delivered in
a driving gas, one or both of the timing and duration of the
opening of the pressure-sensitive valve and the dose released are
carefully controlled to ensure a standardised dosage.
[0083] In one embodiment, where the substance is released into a
chamber and a gas flow, in one embodiment the exhalation flow, is
provided to induce the mixing of a metered dose of the substance,
the delivery of the gas flow can be prolonged to flush the nasal
airway as this prolonged flushing does not effect the delivered
dose. A mechanical device powered by a hand-chargeable spring,
pressurised air or similar, may be used to provide the driving
gas.
[0084] Regardless of the system employed, the flow characteristics
can be optimised to improve the deposition of the substance and the
comfort factor, such as to avoid an abrupt onset which is likely to
induce withdrawal reflexes.
[0085] Preferably, a metered dose of the substance is dispensed
into a delivery chamber by a dosing mechanism. This dosing
mechanism can be constructed in such a way as to allow for a
gradual release of the substance. This gradual release will better
enable the substance to be entrained by the gas flow and thereby
improve delivery to all ventilated parts of the nasal airway, in
particular in the contralateral nasal cavity.
[0086] In a preferred embodiment the exhalation air flow developed
by the subject, which closes the velum, provides the gas flow for
entraining the substance and providing the bi-directional flow.
This configuration is advantageous in that a separate driving gas
flow need not be developed.
[0087] Preferably, the nosepiece is configured to extend about 1 cm
into the one nasal cavity so as to expand the valve region, a
region located about 2 to 3 cm within a nasal cavity which is
usually the flow limiting region, and reduce the resistance which
may be high in the case of nasal inflammation.
[0088] The shape of the nosepiece can be tailored to suit specific
needs. For example, the internal shape of the nosepiece may be
optimised to promote turbulence and achieve a more optimal
dispersion of the substance.
[0089] The nosepiece may include a tight fitting nasal olive, which
can aid the creation of a suitable physiological gas flow. The
olive may be detachable such as to allow for other olives of the
same or different dimensions to be fitted. In the case of severe
nasal obstruction, a nasal olive can be introduced into the other
nostril to reduce resistance and facilitate flow therethrough.
[0090] As mentioned above, a gas flow of at least 20 litres per
minute can easily be achieved by the delivery device. By providing
a sufficiently high gas flow, all parts, or at least a larger part,
of the complex nasal airway can be penetrated by the substance. In
one embodiment the delivery device can include an indicator for
indicating the magnitude of the gas flow.
[0091] The dimensions of the posterior passage and opening behind
the nasal septum are almost always larger than the opening in the
flow resistor. Thus, it is only in very rare cases of complete
occlusion of the outlet nostril that the pressure in the posterior
region of the nasal airway will approach the positive pressure in
the oral cavity and jeopardise the velum closure. In the case of
severe obstruction, insertion of the nosepiece in the occluded
nostril may reduce the resistance and allow successful
flushing.
[0092] After having flushed the nasal airway in one direction, the
same procedure can be repeated from the other nostril. In this way
both nasal cavities are irrigated in both directions. This is a
unique feature of this device. This embodiment secures an improved
distribution of the substance to all parts of the nasal mucosa, and
in particular to the posterior region which is difficult to access
using current techniques.
[0093] In a preferred embodiment, where the substance is in solid
form, such as a powder, then a filter can be employed if high
humidity represents a problem for administration of the solid.
[0094] The substance can be a single compound or a mixture of
compounds, which compounds can be in any suitable form, such as a
powder form, a solution, or a suspension.
[0095] The substance can be any suitable substance for delivery to
a human or in some cases an animal. The substance may be for
delivery for action in any part of the nasal airway, or in any of
the surrounding tissues or organs. Also, the substance may be for
delivery for action in a region remote from the nasal airway.
[0096] Preferably, the substance is for delivery for subsequent
action in any part of the nasal airway, or in any of the
surrounding tissues or organs.
[0097] The substance may have a beneficial medical effect, which
can include a diagnostic effect, a therapeutic effect, a
prophylactic effect, and a cleansing effect such as the removal of
particles, crusts, secretions, debris, etc. Preferably, the
substance has a therapeutic effect.
[0098] Preferably, the substance is a pharmaceutical. The
pharmaceutical can be admixed with any suitable carrier, diluent,
excipient or adjuvant.
[0099] Preferably, the pharmaceutical is for the treatment of any
one or more of the above-mentioned conditions. By way of example,
the pharmaceutical may be for the treatment of any allergic and
non-allergic inflammatory disease.
[0100] Typical pharmaceuticals for administration include, but are
not limited to, steroids, anti-histamines, cromoglycates,
anti-allergic pharmaceuticals, anti-inflammatory pharmaceuticals,
anti-leucotriens, lactation promoters such as oxytocin, and
anti-migraine pharmaceuticals.
[0101] By achieving a more optimal delivery, the delivery device of
the present invention improves the effect of topical
pharmaceuticals in the treatment of upper airway pathologies, such
as hypertrophic adenoids and chronic sectretory otitis media.
[0102] Aside from pharmaceuticals, the device can also be used to
irrigate or cleanse the nasal airway with saline or other
solutions, preferably containing oils or herbs.
[0103] The device of the present invention can be tailored to suit
particular needs. For example, balloons or pop-up figures can
easily be integrated to provide a semi-quantitative indication of
the flow rate and to improve the acceptability and ease of
administration in small children.
[0104] Only in the rare circumstances when the nasal resistance is
too high to achieve a gas flow through the nasal airway, even after
attempting to expand the nasal cavities, would insufflation be
jeopardised. In those cases, pre-treatment with decongestants may
be necessary.
[0105] The delivery device may also be used as a nasal lavage means
in the collection of mediators and cells that originate from the
nasal mucosa for, for example, diagnostic analysis or research
purposes. In this respect, the mediators and cells can be expelled
into a suitable collecting vessel after the nasal airway has been
exposed to a suitable solution, such as a saline solution, for a
sufficient period of time to ensure sufficient transfer of the
mediators and cells into the solution. This use of the device may
require the use of a gas flow separate to the exhaled air flow as
the flow used to flush the nasal airway. For this lavage purpose,
use of the exhaled air may not be possible as the lower airways may
contain mediators, secretions and cells originating from the lower
airways which would contaminate the nasal sample. For this
particular use, and as indicated, the fluid escaping from the
outlet nostril may be collected in a vessel. Alternatively, the
fluid escaping from the outlet nostril may be absorbed onto a
filter for direct or delayed analysis. Indeed, such filters and the
like may even yield an almost immediate detection result of certain
organisms, such as bacteria, viruses or mediators.
[0106] The delivery device of the present invention is advantageous
for a number of reasons.
[0107] Notably, the delivery device provides a very simple and
efficient means of delivering substances, such as pharmaceuticals,
saline solutions, etc, into the nasal airway. In this respect, the
device utilises very simple technology with few movable parts,
making the device relatively inexpensive to mass produce. In
addition, the device of the present invention can be made in a
disposable form, thus avoiding the need for the delivered substance
to include any preservatives.
[0108] The present invention also eliminates the need for the
subsequent flushing or spraying methods that are associated with
some of the prior art devices. However, for some applications it
may still be desirable to perform a subsequent flushing or spraying
operation.
[0109] The delivery device of the present invention is advantageous
as, in use, the tight seal between the nosepiece and the one
nostril ensures a prolonged penetration of the complex nasal
airway, a bi-directional gas flow through the nasal cavities and
deposition of the substance in the contralateral nasal passage.
[0110] In accordance with the present invention, closure of the
velum will normally be maintained. The delivered gas flow enters
one nasal cavity, passes beyond the posterior margin of the nasal
septum, making a 180 degree turn behind the posterior margin of the
nasal septum, and passes out the other nasal cavity. This
re-direction of the gas flow results in a better deposition of
substance, notably pharmaceuticals, to the posterior regions of the
nasal turbinates and the nasal mucosa.
[0111] In addition, the bi-directional deposition of substances,
typically pharmaceuticals, and irrigation will also better reach
all sinus ostia due to the anatomic locations and orientation of
the sinus ostia, which can improve sinus ventilation and drainage
which is essential to treat sinusitis and frequently accompanies
inflammation of the nasal mucosa. In this respect, the ostia and
tubes to the ethmoidal and sphenoidal sinuses are located in the
posterior region of the nasal airway and the uncinate projections
covering the infundibulum, housing the maxillary, frontal and
anterior ethmoid ostia, are tilted backwards. Furthermore, the
driving positive pressure used will increase the deposition of
pharmaceuticals at the sinus ostia, the sinus tubes leading into
the sinuses and even in the sinuses themselves.
[0112] In addition, the 180 degree re-direction of the flow behind
the nasal septum particularly increases the deposition of substance
on the roof of the nasopharynx where the adenoid is located and in
proximity to the location of the tubal ostia to the auditory tubes
connecting the nasopharynx and the middle ears. By way of example,
steroids have been shown to reduce the size of
hypertrophic-adenoids which are commonly found in paediatric
subjects and can have a positive effect on secretory otitis media.
Deposition of topical decongestants closer to the tubal ostia may
also more efficiently decongest the auditory tubes and relieve the
negative pressure in the middle ears which accompanies rhinitis and
predisposes paediatric subjects to secretory otitis media and the
consequential reduced hearing. Surgery for enlarged adenoids is
frequently performed in children and the improved medical therapy
of the present invention should reduce the necessity for
surgery.
[0113] A further advantage is that possible surplus substance, that
is, substance which is not deposited, will be expelled out of the
contralateral nostril, where it may be collected, if desired, and
consequently not continue to the oral cavity and down into the gut
as is the case with many other delivery techniques. In this way,
the discomfort, and more importantly, the undesirable systemic
exposure to the substance, where the substance is a medicament,
will be reduced.
[0114] Also, with the present invention, irrigation by saline or
other solutions can be performed more efficiently and with less
spill and discomfort than the current techniques used for
irrigation and flushing of the nasal airway.
[0115] Further, the present invention provides for simple and
comfortable irrigation of the nasal mucosa with solutions, such as
saline solutions, and other oils to remove secretions from the
nasal mucosa and promote mucocilary function.
[0116] Still further, the present invention provides a simple and
effective means for the lavage of the nasal mucosa, such as to
collect and diagnose mucosal entities, such as bacteria, viruses,
cell components and inflammatory mediators.
[0117] Still yet further, the exposure of the nasal mucosa to a
positive pressure, particularly a dynamic positive pressure, will
open the narrow, and sometimes occluded, parts of the nasal
passages, rather than cause a dynamic collapse which may happen
during sniffing and inhalation. The dynamic positive pressure is at
least 5 cm H.sub.2O, preferably at least 50 cm H.sub.2O, more
preferably at least 100 cm H.sub.2O, still more preferably at least
200 cm H.sub.2O, yet more preferably 400 cm H.sub.2O and still yet
more preferably 500 cm H.sub.2O. The dynamic positive pressure
achieved by the present invention can be contrasted with the static
pressure provided by the Valsalva procedure where there is no flow
through the nasal airway.
[0118] In addition, the use of warm and humid air as the gas flow
is likely to be better tolerated and cause less irritation than
room air or outdoor air, especially in cold climates.
[0119] Where the substance is a dry powder, then the humidity of
the exhaled air may, in some instances, cause agglomeration of the
powder. Naturally, this will depend on the properties of the powder
and the construction of the device, in particular the dispersion
chamber. In order to alleviate this specific problem, the surface
properties of the powder could be modified, or the device could
include a moisture-absorbing element, typically containing a
desiccant such as silica, disposed upstream of the dispersion
chamber. In a preferred embodiment the moisture-absorbing element
could be provided as a filter which acts as the flow resistor.
[0120] In a preferred embodiment, in order to ensure that
agglomeration of powder would not impede the use of direct
insufflation of warm, humid exhaled air, the delivery device
comprises transfer means which creates a gas flow of drier air,
such as atmospheric air, as the delivery flow to the nasal airway.
Such transfer means, which could be mechanical in nature, utilizes
the energy of the exhaled air to drive the atmospheric room air at
the required flow rate, if necessary, to disperse the substance in
the delivered air flow. In this embodiment agglomeration will be
prevented or at least reduced to the same level as currently
exhibited by dry powder inhalers.
[0121] If desired, the distribution of the substance delivered to
the nasal airway could be studied using standard techniques. By way
of example, use could be made of acoustic rhinometry or coloured
fluids. The distribution of the delivered substance could even be
determined by video endoscopy. In addition, or in the alternative,
distribution studies could also be performed by using appropriate
radioactive materials and following the passage in the nasal
cavities. The results of these studies could be used to optimise
the flow rate, the shape or dimension of the device, in particular
the nosepiece geometry, and the particle size distribution of the
substance. The results of these studies could even be used to
optimise subject acceptance.
[0122] As already indicated, the delivery device may include a
balloon or a similar pop-up device for indicating that the desired
positive pressure has been attained, which balloon or pop-up device
may improve the compliance in small children who are reluctant to
use the device.
[0123] Alternatively, for particularly young children, the
entraining gas flow can be provided by the exhalation air flow of
another person, such as a parent, or even by the use of a pump or
the like, while the child creates the required positive pressure in
the oral cavity by inflating a balloon or pop-up device.
[0124] Preferred embodiments of the present invention will now be
described hereinbelow by way of example only with reference to the
accompanying drawings, in which:
[0125] FIG. 3 schematically illustrates the anatomy of the upper
respiratory tract of a human subject;
[0126] FIG. 4 schematically illustrates a delivery device in
accordance with a first embodiment of the present invention;
[0127] FIG. 5 schematically illustrates a delivery device in
accordance with a second embodiment of the present invention;
[0128] FIG. 6 schematically illustrates a delivery device in
accordance with a third embodiment of the present invention;
[0129] FIG. 7 schematically illustrates a modified delivery unit
for the above-described first to third embodiments of the present
invention;
[0130] FIG. 8 schematically illustrates a delivery device in
accordance with a fourth embodiment of the present invention;
[0131] FIG. 9 schematically illustrates a delivery device in
accordance with a fifth embodiment of the present invention;
[0132] FIG. 10 schematically illustrates a delivery device in
accordance with a sixth embodiment of the present invention;
and
[0133] FIG. 11 schematically illustrates a delivery device in
accordance with a seventh embodiment of the present invention.
[0134] FIG. 4 illustrates a delivery device in accordance with a
first embodiment of the present invention.
[0135] The delivery device comprises an oral exhalation unit 20 and
a substance delivery unit 22. In this embodiment the oral
exhalation unit 20 and the delivery unit 22 are provided as
separate components, but alternatively could be detachably coupled,
for example by means of Velcro.TM. fasteners, connected, for
example by means of screws and/or rivets, or even integrally
formed.
[0136] The oral exhalation unit 20 comprises a tubular section 24
and a mouthpiece 26 attached to one end of the tubular section 24.
The mouthpiece 26, which in use is gripped in the lips of a user,
is formed separately of the tubular section 24 to allow for
replacement, but could alternatively be integrally formed. In this
embodiment the mouthpiece 26 is a snap fit on the tubular section
24, but could equally be a screw fit. The tubular section 24
includes a flow resistor 28, in this embodiment a fixed baffle
plate, configured to provide a sufficient resistance to exhalation
therethrough by a subject as to cause the generation of a positive
pressure in the oral cavity of the subject and the closure of the
velum on exhalation by the subject. In alternative embodiments the
flow resistor 28 could be a movable member, such as a biased flap,
a resilient membrane or a damped wheel.
[0137] The delivery unit 22 comprises a nosepiece 30, in this
embodiment formed of a resilient material such as a polymeric
material, for providing a tight scaling fit in one of the nostrils
of the subject, a medicament supply unit 32 for supplying a gas
flow entraining medicament at a predetermined pressure sufficient
to open a flow path beyond the posterior margin of the nasal septum
when delivered into one of the nasal cavities of the subject, and a
tubular section 34 coupling the nosepiece 30 and the medicament
supply unit 32. In a preferred embodiment the nosepiece 30 can
include an external olive or be shaped to cause the anterior region
of the nasal cavity into which the nosepiece 30 is inserted to be
enlarged. In a particularly preferred embodiment the nosepiece 30
can be shaped, for example by including swirl-inducing projections,
to provide the exiting gas flow with an optimal flow pattern and
particle size distribution. The nosepiece 30 is formed separately
of the tubular section 34 to allow for replacement, but could
alternatively be integrally formed. In this embodiment the
nosepiece 30 is a snap fit on the tubular section 34, but could
equally be a screw fit. The medicament supply unit 32 can comprise
an aerosol spray generator for generating an aerosol spray of
liquid droplets containing medicament, such as provided by a
pressurised metered dose inhaler, or a pressurised gas source for
entraining a metered dose of a dry powder containing medicament
loaded thereinto, which powder could alternatively be loaded into a
compartment in the tubular section 34.
[0138] In use, a subject grips the mouthpiece 26 in his or her lips
and fits the nosepiece 30 into one of his or her nostrils. The
subject then exhales through the mouthpiece 26, the flow of which
exhaled air is resisted by the flow resistor 28 in the tubular
section 24 such as to develop a positive pressure in the oral
cavity of the subject, with the positive pressure being such as to
develop a pressure differential across the velum sufficient to
cause closure of the velum of the subject. The applicant has
established that a positive pressure differential between the oral
cavity and the nasal airway of about 5 cm H.sub.2O is required to
maintain the velum in the closed position. The applicant has
further established that a subject should be able to maintain a
flow rate of about 3 to 30 litres per minute for about 1 to 20
seconds, with flow rates of about 10 to 20 litres per minute and
delivery times of about 2 to 5 seconds being considered as optimal.
After closure of the velum, the medicament supply unit 32 is then
actuated to deliver a gas flow entraining medicament through the
nosepiece 30 and into the nasal airway of the subject. As mentioned
above, this gas flow is at such a pressure as to open a
communication path beyond the posterior margin of the nasal septum
such that the gas flow flows through the one nasal cavity, around
the posterior margin of the nasal septum, in effect being
re-directed through an angle of 180 degrees, and out of the other
nasal cavity. Again, as already described, this bi-directional flow
provides for a much enhanced deposition of the medicament in the
posterior region of the nasal airway.
[0139] In one modification, the medicament supply unit 32 can be
omitted from the delivery unit 22, and instead a metered dose of
dry powder loaded into a compartment in the tubular section 34,
with the delivery air flow being provided by another person, such
as the parent of a paediatric subject, blowing into the distal end
of the tubular section 34.
[0140] FIG. 5 illustrates a delivery device in accordance with a
second embodiment of the present invention.
[0141] The delivery device comprises the oral exhalation unit 20
and the delivery unit 22 of the above-described first embodiment,
and an outlet unit 36 for fitting to the other nostril of a subject
to which the delivery unit 22 is fitted.
[0142] The outlet unit 36 comprises a tubular section 38 and a
nosepiece 40, in this embodiment formed of a resilient material
such as a polymeric material, attached to one end of the tubular
section 38 for providing a light sealing fit in the other nostril
of the subject. The nosepiece 40 is formed separately of the
tubular section 38 to allow for replacement, but could
alternatively be integrally formed. In this embodiment the
nosepiece 40 is a snap fit on the tubular section 38, but could
equally be a screw fit. As with the nosepiece 30 of the delivery
unit 22, in a preferred embodiment the nosepiece 40 can include an
external olive or be shaped to cause the anterior region of the
other nasal cavity into which the nosepiece 40 is inserted to be
enlarged. The tubular section 38 includes a flow resistor 41, in
this embodiment a baffle plate, configured to provide a sufficient
flow resistance to an exhalation flow therethrough as to cause the
generation of a dynamic positive pressure in the nasal airway. In a
preferred embodiment the flow resistor 41 is adjustable to allow
for adjustment of the level of the resistance and hence provide
control of the dynamic pressure in the nasal airway. In alternative
embodiments the flow resistor 41 could be a movable member, such as
a biased flap, a resilient membrane or a damped wheel.
[0143] In a preferred embodiment the outlet unit 36 includes an
indicator for providing at least one of a visual or audible signal
on achieving a predetermined positive pressure upstream thereof,
that is, in the nasal airway. Preferably, the indicator comprises a
whistle. In this way, the subject is provided with positive
feedback of proper use of the device.
[0144] Use of the delivery device of this embodiment is the same as
for the above-described first embodiment. However, as mentioned
above, by the provision of the flow resistor 41 in the outlet unit
36 downstream of the outlet nostril of the subject, a positive
dynamic pressure is maintained in the nasal airway. This positive
pressure advantageously acts to dilate the various ostia in the
nasal airway, such as the sinus ostia and the tubal ostia, and the
associated tubes, namely the sinus tubes and the auditory tubes, so
as to promote the delivery of medicament thereto. Further, this
positive pressure acts to improve deposition on the adenoid which
can often obstruct the tubal ostia, the middle meatus which is a
common location of nasal polyps, and the cleft to the olfactory
cells.
[0145] FIG. 6 illustrates a delivery device in accordance with a
third embodiment of the present invention.
[0146] The delivery device is very similar to that of 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 parts being
designated by like reference signs. This delivery device differs
only in further comprising a pressure sensor 43, in this embodiment
a pressure-sensitive spring or membrane, located in the tubular
section 34 of the delivery unit 22 downstream of the medicament
supply unit 32, and a control unit 44 coupled to the sensor 43 and
the medicament supply unit 32.
[0147] The control unit 44 is configured to control the flow rate
of the delivery gas supplied by the medicament supply unit 32 in
order to optimise the particle deposition efficiency in the nasal
airway regardless of the degree of nasal congestion. As mentioned
hereinabove, by maintaining an optimum flow rate in the nasal
airway, the deposition efficiency of the medicament-containing
particles is increased, referred to as the particle deposition
efficiency. If, ordinarily, a flow rate of about 15 litres per
minute is required to maximise the particle deposition efficiency,
then in a congested nasal airway a lower flow rate, possibly 10
litres per minute, would be required and in an open nasal airway a
higher flow rate, possibly 20 litres per minute, would be
required.
[0148] Operation of this delivery device is otherwise the same as
that of the above-described second embodiment.
[0149] FIG. 7 illustrates a modified oral exhalation unit 20 for
the delivery devices of the above-described embodiments.
[0150] This modified oral exhalation unit 20 differs in that the
tubular section 24 includes a lateral opening 45 upstream of the
flow resistor 28 and in further comprising, as an indicator, an
inflatable FIG. 46 connected to the lateral opening 45, which FIG.
46 when inflated assumes a prominent position in the field of
vision of the subject. In FIG. 6, the FIG. 46 is shown inflated. By
providing such a display feature, subject compliance, particularly
in paediatric subjects, should be improved. The oral exhalation
unit 20 further comprises an inflation line 48 connected to the
FIG. 46 which allows the FIG. 46 to be further inflated by another
person, typically the parent of a paediatric subject, or a pump. In
an alternative embodiment, instead of being inflatable, the FIG. 46
could be of any kind which is brought into a prominent position on
exhalation by the subject, typically a mechanically or
electrically-operated figure. In a preferred embodiment the FIG. 46
can be configured so as to be inflated on the subject achieving an
optimum exhalation flow rate. In this way, the FIG. 46 acts as an
indicator.
[0151] Use of the delivery device of this embodiment is the same as
that of the above-described first embodiment. However, on exhaling
through the mouthpiece 26, the developed pressure causes the FIG.
46 to be inflated and assume a prominent position in the field of
vision of the subject. This appearance of the FIG. 46 is
particularly appealing for paediatric subjects as the fun element
of inflating the FIG. 46 can alleviate any unnecessary anxiety.
[0152] FIG. 8 illustrates a delivery device in accordance with a
fourth embodiment of the present invention.
[0153] The delivery device comprises a chamber 50 which includes an
inlet 52 and an outlet 54, a mouthpiece 56 connected to the inlet
52 and a nosepiece 58 connected to the outlet 54. The nosepiece 58
is configured to provide a tight sealing fit in one of the nostrils
of a subject. The chamber 50 includes a flow resistor 60, in this
embodiment a plurality of baffle plates, and a medicament-receiving
compartment 62 downstream of the flow resistor 60 for containing a
metered dose of a dry powder containing medicament to be delivered
to the nasal airway of a subject. In this embodiment the nosepiece
58 is formed of a resilient material such as a polymeric material.
In a preferred embodiment the chamber 50 may include a desiccant.
In a preferred embodiment the flow resistor 60 can be provided by a
moisture-absorbing filter.
[0154] In use, a subject grips the mouthpiece 56 in his or her lips
and fits the nosepiece 58 into one of his or her nostrils. The
subject then exhales through the mouthpiece 56, the flow of which
exhaled air is resisted by the flow resistor 60 in the chamber 50
and the resistance of the nasal airway such as to develop a
positive pressure in the oral cavity of the subject sufficient to
cause closure of the velum. The exhaled air, after passing the flow
resistor 60, then entrains the powdered medicament in the
medicament-receiving compartment 62, and this air flow entraining
medicament then passes through the nosepiece 58 into the nasal
airway of the subject. The exhaled air entering the nasal airway is
at a pressure sufficient to open a communication path beyond the
posterior margin of the nasal septum such that the air flow flows
through the one nasal cavity, around the posterior margin of the
nasal septum, in effect being re-directed through an angle of 180
degrees, and out of the other nasal cavity. Again, as already
described, this bi-directional flow provides for a much enhanced
deposition of the medicament in the posterior margin of the nasal
airway.
[0155] In a preferred embodiment the delivery device includes a
pressure-triggered valve, preferably located in the mouthpiece 56,
which is configured to open only when a predetermined positive
pressure has been developed by the exhalation of the subject,
typically at a positive pressure of about 10 cm H.sub.2O. This
configuration advantageously avoids the possibility of medicament
being delivered to the nasal airway with the velum in the open
position and thereby reduces the risk of undesirably depositing
medicament outside the nasal airway.
[0156] In another preferred embodiment, similarly to
third-described embodiment, the delivery device can include an
outlet unit for providing a flow resistor downstream of the other
nostril of the subject such as to maintain a positive dynamic
pressure in the nasal airway.
[0157] FIG. 9 illustrates a delivery device in accordance with a
fifth embodiment of the present invention.
[0158] The delivery device comprises an oral exhalation unit 70
through which a subject exhales to close his or her velum and a
medicament delivery unit 72 for supplying an air flow entraining
medicament to the nasal airway of the subject.
[0159] The oral exhalation unit 70 comprises a tubular section 74
and a mouthpiece 76 attached to one end of the tubular section 74.
The mouthpiece 76, which is gripped in the lips of the subject, is
formed separately of the tubular section 74 to allow for
replacement, but could alternatively be integrally formed
therewith. In this embodiment the mouthpiece 76 is a snap fit on
the tubular section 74, but could equally be a screw fit. The
tubular section 74 includes a flow resistor 78, in this embodiment
a gearwheel, configured to rotate on exhalation by the subject and
yet provide sufficient resistance to the exhalation flow as to
cause the generation of a positive pressure in the oral cavity of
the subject sufficient to maintain the required positive pressure
differential between the oral cavity and the nasal airway and
thereby maintain the velum in the closed position.
[0160] The delivery unit 72 comprises a tubular section 80 and a
nosepiece 82, in this embodiment formed of a resilient material
such as a polymeric material, for providing a tight sealing fit in
one of the nostrils of the subject, attached to one end of the
tubular section 80. The nosepiece 82 is formed separately of the
tubular section 80 to allow for replacement, but could
alternatively be integrally formed therewith. In this embodiment
the nosepiece 82 is a snap fit on the tubular section 80, but could
equally be a screw fit. In a preferred embodiment the nosepiece 82
can include an external olive or be shaped to cause the anterior
region of the nasal cavity, into which the nosepiece 82 is
inserted, to be enlarged. In a particularly preferred embodiment
the nosepiece 82 can be shaped for example by including
swirl-inducing projections, to provide the exiting air flow with an
optimal flow pattern and particle size distribution. The tubular
section 80 includes an impeller 84 coupled to the gearwheel 78 in
the tubular section 74 of the oral exhalation unit 70, such as to
be rotated on rotation of the gearwheel 78 to draw air into the
tubular section 80 and provide an air flow therethrough at a
pressure sufficient to open the flow path beyond the posterior
margin of the nasal septum when delivered into one of the nasal
cavities of the subject.
[0161] The delivery unit 72 further comprises a dispensing unit 86
for dispensing a metered dose of a dry powder containing medicament
to the tubular section 80 upstream of the impeller 84. In this
embodiment the dispensing unit 86 is manually actuated to supply a
metered dose of dry powder containing medicament into the tubular
section 80, but could alternatively be configured to the driven by
the gearwheel 78 so as to avoid the need for any manual
intervention on the part of the subject.
[0162] In use, a subject grips the mouthpiece 76 in his or her lips
and fits the nosepiece 82 into one of his or her nostrils. The
subject then exhales through the mouthpiece 76, the flow of which
exhaled air is resisted by the gearwheel 78 such as to develop a
positive pressure in the oral cavity of the subject sufficient to
cause the velum of the subject to close. The exhaled air causes
rotation of the gearwheel 78 which in turn causes rotation of the
impeller 84, and the rotation of the impeller 84 develops an air
flow through the tubular section 80 which entrains the metered dose
of dry powder containing medicament and delivers the same through
the nosepiece 82 to the nasal airway of the subject. As mentioned
above, this air flow is at a pressure sufficient to open a
communication path beyond the posterior margin of the nasal septum
such that the air flow flows through the one nasal cavity, around
the posterior margin of the nasal septum, in effect being
re-directed through an angle of 180 degrees, and out of the other
nasal cavity. Again, as already described, this bi-directional flow
provides for a much enhanced deposition of the medicament in the
posterior region of the nasal cavity.
[0163] In a preferred embodiment the gearwheel 78 is configured
such that rotation thereof is prevented until a predetermined flow
rate has been developed which is sufficient to ensure that the
entraining gas flow developed by the impeller 84 is optimal. This
configuration advantageously ensures an optimal particle deposition
efficiency and avoids the possibility of medicament being delivered
to the nasal airway with the velum in the open position so as to
reduce the risk of undesirably depositing medicament outside the
nasal airway.
[0164] FIG. 10 illustrates a delivery device in accordance with a
sixth embodiment of the present invention.
[0165] The delivery device comprises a housing 90 for housing a
blister pack element 92 which includes a plurality of blisters 94
therein, each containing powder containing medicament, and a
tubular section 96 in communication with one of the blisters 94
when open, one end of which tubular section 96 provides a
mouthpiece 98 which in use is gripped in the lips of a subject. The
tubular section 96 includes an element 100 movably disposed therein
between a first, normally closed position and a second, open
position. In this embodiment the element 100 comprises a propeller
or the like rotatably mounted on a threaded shaft and normally
biased to the closed position by a compression spring. The element
100 is configured both to function as a flow resistor and a valve.
In this embodiment the element 100 is configured to move to the
medicament-releasing open position by rotation along the threaded
shaft against the bias of the compression spring, with the powder
being entrainable by an air flow only when the exhalation flow
exceeds a predetermined flow rate. The flow rate, preferably in the
range of about 5 to 20 litres per minute, at which the powder
containing medicament is entrained by the air flow is a function,
in inverse relation, to the driving pressure which is itself a
function of the nasal resistance as described hereinabove. As will
be understood, this configuration advantageously provides for an
optimal particle deposition efficiency in releasing the powder
containing medicament at the optimal flow rate, and avoids the
possibility of medicament being delivered to the nasal airway with
the velum in the open position.
[0166] The delivery device further comprises a nosepiece 102, in
this embodiment formed of a resilient material such as a polymeric
material, for providing a tight sealing fit in one of the nostrils
of the subject attached to the other end of the tubular section 96
downstream of the element 100. The nosepiece 102 is formed
separately of the tubular section 96 to allow for replacement, but
could alternatively be integrally formed therewith. In this
embodiment the nosepiece 102 is a snap fit on the tubular section
96, but could equally be a screw fit. In a preferred embodiment the
nosepiece 102 can include an external olive or be shaped to cause
the anterior region of the nasal cavity into which the nosepiece
102 is inserted to be enlarged. In a particularly preferred
embodiment the nosepiece 102 can be shaped, for example by
including swirl-inducing projections, to provide the exiting air
flow with an optimal flow pattern and particle size
distribution.
[0167] The delivery device further comprises a blister opening
mechanism 104 for opening the blister 94 in communication with the
tubular section 96. In this embodiment the blister opening
mechanism 104 is manually operated by the subject prior to
delivery.
[0168] In use, a subject grips the mouthpiece 98 in his or her lips
and fits the nosepiece 102 into one of his or her nostrils. The
subject then exhales through the mouthpiece 98, the flow of which
exhaled air is resisted by the element 100 until a predetermined
flow rate has been achieved. Once this predetermined flow rate has
been achieved, at which flow rate the velum is in the closed
position, the element 100 is in the open position and the exhaled
air flow entrains the powdered medicament in the blister 94 and
delivers the same through the nosepiece 102 to the nasal airway.
The driving pressure of this air flow is at a level sufficient to
maintain a communication path beyond the posterior margin of the
nasal septum such that the air flow flows through the one nasal
cavity, around the posterior margin of the nasal septum, in effect
being re-directed through an angle of 180 degrees, and out of the
other nasal cavity. Again, as already described, this
bi-directional flow provides for a much enhanced deposition of the
medicament in the posterior margin of the nasal cavity.
[0169] In a preferred embodiment the delivery device includes a
blister pack advancement mechanism, operated by movement of the
mouthpiece 98, for rotating the blister pack element 92 such that
another unused blister 94 is located at the delivery position. In a
particularly preferred embodiment the blister pack advancement
mechanism can be coupled to the blister opening mechanism 104 such
as automatically to open the blister 94, and thereby avoid the need
for any further intervention by the subject.
[0170] In one modification, similarly to the above-described
modification of the first embodiment as illustrated in FIG. 5, the
delivery device can include an outlet unit for providing a flow
resistor downstream of the other nostril of the subject such as to
maintain a positive dynamic pressure in the nasal airway.
[0171] In another modification, the blister pack element 92 can be
omitted and the housing 90 instead provided with a chamber which is
in communication with the tubular section 96 and into which a
metered dose of dry powder containing medicament can be loaded.
With this configuration, the powder in the chamber is entrained on
the element 100 being driven to the second position and the blister
pack advancement mechanism is configured to meter a dose of powder
containing medicament into the chamber on operation thereof.
[0172] As will be understood, in essence, the present invention can
be broadly based on any dry powder inhaler, such as the
Turbuhaler.TM. as manufactured by AstraZeneca PLC, the
Accuhaler.TM. as manufactured by Glaxo PLC or the Twisthaler.TM. as
manufactured by Schering AG, where the usual mouthpiece is replaced
by a nosepiece and a mouthpiece is provided in communication with
the air inlet of the inhaler such as to utilise the air exhaled by
a subject as the entraining delivery air.
[0173] FIG. 11 illustrates a delivery device in accordance with a
seventh embodiment of the present invention.
[0174] The delivery device comprises a housing 110 and a tubular
section 112 extending through the housing 110, one end of which
provides a mouthpiece 114 which in use is gripped in the lips of a
subject.
[0175] The tubular section 112 includes an element 116 movably
disposed therein between a first, normally closed position and a
second, trigger position. In this embodiment the element 116
comprises a propeller or the like rotatably mounted on a threaded
shaft and normally biased to the closed position by a compression
spring. The element 116 is configured to function as a flow
resistor, a valve and a trigger for the delivery of an aerosol
spray into the tubular section 112 as will be described in detail
hereinbelow. In this embodiment the element 116 is configured to
move to the medicament-releasing open position, by rotation along
the threaded shaft against the bias of the compression spring, only
when the exhalation flow exceeds a predetermined flow rate. The
flow rate at which the medicament is released, preferably in the
range of about 5 to 20 litres per minute, is a function, in inverse
relation, to the driving pressure which is itself a function of the
nasal resistance as described hereinabove. As will be understood,
this configuration advantageously provides for an optimal particle
deposition efficiency in releasing the medicament at the optimal
flow rate, and avoids the possibility of medicament being delivered
to the nasal airway with the velum in the open position.
[0176] The tubular section 112 further includes a nozzle block 117
for providing an aerosol spray through the tubular section 112
along the longitudinal axis thereof. As will be described in detail
hereinbelow, the nozzle block 117 receives the valve stem 122 of an
aerosol canister 120.
[0177] The delivery device further comprises a known aerosol
canister 120 used to deliver metered volumes of a propellant,
preferably a hydrofluoroalkane (HFA) propellant or the like,
containing medicament, either as a suspension or as a solution. The
aerosol canister 120 comprises a main body 121 which contains a
volume of propellant under pressure containing medicament, a valve
stem 122 through which the propellant containing medicament is in
use delivered on relative movement of the main body 121 and the
valve stem 122, and a metering valve 124 for metering a
predetermined volume of propellant containing medicament to the
valve stem 122 on movement thereof.
[0178] The delivery device further comprises a trigger mechanism
126 for relatively moving the main body 121 and the valve stem 122
of the aerosol canister 120 to effect the delivery of a metered
volume of propellant containing medicament through the nozzle block
117. In this embodiment the trigger mechanism 126 comprises a
resilient element 128 for loading the main body 121 with an
actuation force, and a lever assembly 130 coupled to the movable
element 116 to cause the release of the actuation force provided by
the resilient element 128 on movement of the movable element 116
from the closed position to the trigger position.
[0179] The delivery device further comprises a nosepiece 132, in
this embodiment formed of a resilient material such as a polymeric
material, for providing a tight seating fit in one of the nostrils
of the subject, attached to the other end of the tubular section
112 downstream of the movable element 116. The nosepiece 132 is
formed separately of the tubular section 112 to allow for
replacement, but could alternatively be integrally formed
therewith. In this embodiment the nosepiece 132 is a snap fit on
the tubular section 112, but could equally be a screw fit. In a
preferred embodiment the nosepiece 132 can include an external
olive or be shaped to cause the anterior region of the nasal cavity
into which the nosepiece 132 is inserted to be enlarged. In a
particularly preferred embodiment the nosepiece 132 can be shaped,
for example by including swirl-inducing projections, to provide the
exiting air flow with an optimal flow pattern and particle size
distribution.
[0180] In use, a subject primes the trigger mechanism 126, grips
the mouthpiece 114 in his or her lips and fits the nosepiece 132
into one of his or her nostrils. The subject then exhales through
the mouthpiece 114, the flow of which exhaled air is resisted by
the movable element 116 until a predetermined flow rate has been
achieved. Once this predetermined flow rate has been achieved, at
which flow rate the velum is in the closed position, the movable
element 116 is in the open position, triggering the movement of the
lever assembly 130 and hence the relative movement of the main body
121 and the valve stem 122 of the canister 120 to deliver a metered
volume of propellant containing medicament to the nozzle block 117
to generate an aerosol spray of liquid droplets containing
medicament through the nosepiece 132 to the nasal airway. This
aerosol flow is at a pressure sufficient to maintain a
communication path beyond the posterior margin of the nasal septum
such that the flow flows through the one nasal cavity, around the
posterior margin of the nasal septum, in effect being re-directed
through an angle of 180 degrees, and out of the other nasal cavity.
Again, as already described, this bi-directional flow provides for
a much enhanced deposition of the medicament in the posterior
margin of the nasal cavity.
[0181] As will be understood, in essence, the present invention can
be broadly based on any breath-actuated pressurised metered dose
inhaler, where the usual mouthpiece is replaced by a nosepiece and
a mouthpiece is provided in communication with the air inlet of the
inhaler such as both to trigger the triggering mechanism and
utilise the air exhaled by a subject as the entraining delivery
air.
[0182] 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.
Nasal Devices
[0183] The present invention relates to a nasal delivery device for
and a method of delivering a substance, in particular one of a
liquid, as a suspension or solution, or a powder containing a
medicament, especially systemic or topical pharmaceuticals, or a
vaccine to the nasal airway of a subject.
[0184] Referring to FIG. 12, 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.
[0185] There are many nasal conditions which require treatment. One
such condition is nasal inflammation, specifically rhinitis, which
can be allergic or non-allergic and is often associated with
infection and prevents normal nasal function. By way of example,
allergic and non-allergic inflammation of the nasal airway can
typically effect between 10 and 20% of the population, with nasal
congestion of the erectile tissues of the nasal concha,
lacrimation, secretion of watery mucus, sneezing and itching being
the most common symptoms. As will be understood, nasal congestion
impedes nasal breathing and promotes oral breathing, leading to
snoring and sleep disturbance. Other nasal conditions include nasal
polyps which arise from the paranasal sinuses, hypertrophic
adenoids, secretory otitis media, sinus disease and reduced
olfaction.
[0186] In the treatment of certain nasal conditions, the topical
administration of medicaments is preferable, particularly where the
nasal mucosa is the prime pathological pathway, such as in treating
or relieving nasal congestion. Medicaments that are commonly
topically delivered include decongestants, anti-histamines,
cromoglycates, steroids and antibiotics. At present, among the
known anti-inflammatory pharmaceuticals, topical steroids have been
shown to have an effect on nasal congestion. Topical decongestants
have also been suggested for use in relieving nasal congestion. The
treatment of hypertrophic adenoids and chronic secretory otitis
media-using topical decongestants, steroids and anti-microbial
agents, although somewhat controversial, has also been proposed.
Further, the topical administration of pharmaceuticals has been
used to treat or at least relieve symptoms of inflammation in the
anterior region of the nasopharynx, the paranasal sinuses and the
auditory tubes.
[0187] Medicaments can also be systemically delivered through the
nasal pathway, the nasal pathway offering a good administration
route for the systemic delivery of pharmaceuticals, such as
hormones, for example, oxytocin and calcitionin, and analgetics,
such as anti-migraine compositions, as the high blood flow and
large surface area of the nasal mucosa advantageously provides for
rapid systemic uptake.
[0188] Nasal delivery is also expected to be advantageous for the
administration of medicaments requiring a rapid onset of action,
for example, analgetis, anti-emetics, insulin, anti-epileptics,
sedatives and hypnotica, and also other pharmaceuticals, for
example, cardio-vascular drugs. It is envisaged that nasal
administration will provide for a fast onset of action, at a rate
similar to that of injection and at a rate much faster than that of
oral administration. Indeed, for the treatment of many acute
conditions, nasal administration is advantageous over oral
administration, since gastric stasis can further slow the onset of
action following oral administration.
[0189] It is also expected that nasal delivery could provide an
effective delivery route for the administration of proteins and
peptides as produced by modern biotechnological techniques. For
such substances, the metabolism in the intestines and the
first-pass-effect in the liver represent significant obstacles for
reliable and cost-efficient delivery.
[0190] Furthermore, it is expected that nasal delivery using the
nasal delivery technique of the present invention will prove
effective in the treatment of many common neurological diseases,
such as Alzheimer's, Parkinson's, psychiatric diseases and
intracerebral infections, where not possible using existing
techniques. The nasal delivery technique of the present invention
allows for delivery to the olfactory region, which region is
located in the superior region of the nasal cavities and represents
the only region where it is possible to circumvent the
blood-to-brain barrier (BBB) and enable communication with the
cerebrospinal fluid (CSP) and the brain.
[0191] Also, it is expected that the nasal delivery technique of
the present invention will allow for the effective delivery of
vaccines.
[0192] Aside from the delivery of medicaments, the irrigation of
the nasal mucosa with liquids, in particular saline solutions, is
commonly practised to remove particles and secretions, as well as
to improve the mucociliary activity of the nasal mucosa. These
solutions can be used in combination with active
pharmaceuticals.
[0193] For any kind of drug delivery, accurate and reliable dosing
is essential, but it is of particular importance in relation to the
administration of potent drugs which have a narrow therapeutic
window, drugs with potentially serious adverse effects and drugs
for the treatment of serious and life-threatening conditions. For
some conditions, it is essential to individualize the dosage to the
particular situation, for example, in the case of diabetes
mellitus. For diabetes, and, indeed, for many other conditions, the
dosage of the pharmaceutical is preferably based on actual
real-time measurements. Currently, blood samples are most
frequently used, but the analysis of molecules in the exhalation
breath of subjects has been proposed as an alternative to blood
analysis for several conditions. Breath analysis is currently used
for the diagnosis of conditions such as Helicobacter pylori
infections which cause gastric ulcers.
[0194] WO-A-00/51672 discloses a delivery device for delivering a
substance, in particular a medicament, in a bi-directional flow
through the nasal cavities, that is, an air flow which passes into
one nostril, around the posterior margin of the nasal septum and in
the opposite direction out of the other nostril. This
bi-directional air flow advantageously acts to stimulate the
sensory nerves in the nasal mucosa, thereby conditioning the
subject for the delivery and providing a more comfortable delivery
situation.
[0195] It is an aim of the present invention to provide improved
nasal delivery devices and nasal delivery methods for providing for
the improved delivery of a substance to a nasal cavity of
subject.
[0196] In one aspect the present invention provides a nasal
delivery device for delivering substance to a nasal airway of a
subject, comprising: a nosepiece for fitting to a nostril of a
subject, the nosepiece including a nozzle through which substance
is in use delivered to the nasal airway, and at least one
inflatable cuff member which is configured to be inflated
subsequent to exhalation by the subject; and a delivery unit for
delivering substance through the nozzle of the nosepiece.
[0197] In another aspect the present invention provides a nasal
delivery device for delivering substance to a nasal cavity of a
subject, comprising: a nosepiece including a nozzle through which
substance is in use delivered to the nasal cavity, and at least one
inflatable cuff member which is configured such as, when inflated,
to provide a fluid-tight seal between the nosepiece and an inner
wall of the nasal-cavity of the subject; and a delivery unit for
delivering substance through the nozzle of the nosepiece.
[0198] In a further aspect the present invention provides a nasal
delivery device for delivering substance to a nasal airway of a
subject, comprising: a nosepiece for fitting to a nostril of a
subject, the nosepiece including a nozzle through which substance
is in use delivered to the nasal airway, and at least one cuff
member which is configured such as, when fitted in a nasal cavity
of the subject, to engage an inner wall of the nasal cavity of the
subject and direct at least a distal end of the nozzle towards a
site in the nasal airway of the subject; and a delivery unit for
delivering substance through the nozzle of the nosepiece.
[0199] In yet another aspect the present invention provides a nasal
delivery device for delivering substance to a nasal airway of a
subject, comprising: a nosepiece for fitting to a nostril of a
subject, the nosepiece including a nozzle through which substance
is in use delivered to the nasal airway, and at least one cuff
member, at least one of the at least one cuff member including at
least one lobe which, when the at least one of the at least one
cuff member is fitted in the nasal cavity of the subject, extends
into a region of the nasal cavity of the subject such as to at
least partially obstruct the same and prevent flow thereinto, and a
delivery unit for delivering substance through the nozzle of the
nosepiece.
[0200] In a yet further aspect the present invention provides a
nasal delivery device for delivering substance to a nasal airway of
a subject, comprising: a nosepiece for fitting to a nasal cavity of
a subject, the nosepiece including a first delivery outlet through
which substance is in use delivered to the nasal airway of the
subject, and at least one second delivery outlet through which at
least one gas flow, separate to an exhalation breath of the
subject, is in use delivered to the nasal airway of the subject; a
delivery unit for delivering substance through the first delivery
outlet of the nosepiece; and a gas supply unit for supplying a flow
of gas through the at least one second delivery outlet of the
nosepiece.
[0201] In yet another further aspect the present invention provides
a method of delivering substance to a nasal airway of a subject,
comprising: fitting a nosepiece to a nasal cavity of a subject, the
nosepiece including a nozzle through which substance is delivered
to the nasal airway, and at least one inflatable cuff member;
inflating the at least one cuff member subsequent to exhalation by
the subject; and delivering substance through the nozzle of the
nosepiece.
[0202] In a still further aspect the present invention provides a
method of delivering substance to a nasal cavity of a subject,
comprising the steps of: fitting a nosepiece to a nasal cavity of a
subject, the nosepiece including a nozzle through which substance
is delivered to the nasal cavity, and at least one inflatable cuff
member which is configured such as, when inflated, to provide a
fluid-tight seal between the nosepiece and an inner wall of the
nasal cavity of the subject; and delivering substance through the
nozzle of the nosepiece.
[0203] In still yet another further aspect the present invention
provides a method of delivering substance to a nasal airway of a
subject, comprising the steps of: fitting a nosepiece to a nasal
cavity of a subject, the nosepiece including a nozzle through which
substance is delivered to the nasal airway, and at least one cuff
member which is configured such as, when fitted in the nasal cavity
of the subject, to engage an inner wall of the nasal cavity of the
subject and direct at least a distal end of the nozzle towards a
site in the nasal airway of the subject; and delivering substance
through the nozzle of the nosepiece.
[0204] In a still yet further aspect the present invention provides
a method of delivering substance to a nasal airway of a subject,
comprising the steps of: fitting a nosepiece to a nasal cavity of a
subject, the nosepiece including a nozzle through which substance
is delivered to the nasal airway, and at least one cuff member, at
least one of the at least one cuff member including at least one
lobe which, when the at least one of the at least one cuff member
is fitted in the nasal cavity of the subject, extends into a region
of the nasal cavity of the subject such as to at least partially
obstruct the same and prevent flow thereinto; and delivering
substance through the nozzle of the nosepiece.
[0205] In a still yet another further aspect the present invention
provides a method of delivering substance to a nasal airway of a
subject, comprising the step of: delivering substance through a
first delivery outlet and at least one gas flow, separate to an
exhalation breath of a subject, through at least one second
delivery outlet into the nasal airway of the subject.
[0206] Preferred embodiments of the present invention will now be
described hereinbelow by way of example only with reference to the
accompanying drawings, in which:
[0207] FIG. 12 schematically illustrates the anatomy of the upper
respiratory tract of a human subject;
[0208] FIG. 13 schematically illustrates a nasal delivery device in
accordance with a first embodiment of the present invention;
[0209] FIG. 14 schematically illustrates the delivery device of
FIG. 13 inserted in a nasal cavity of a subject for operation;
[0210] FIG. 15 schematically illustrates the delivery device of
FIG. 3 during actuation;
[0211] FIG. 16 schematically illustrates the delivery device of
FIG. 3 following actuation;
[0212] FIG. 17 schematically illustrates a nasal delivery device in
accordance with a second embodiment of the present invention;
[0213] FIG. 18 schematically illustrates the delivery device of
FIG. 17 inserted in a nasal cavity of a subject for operation;
[0214] FIG. 19 schematically illustrates the delivery device of
FIG. 17 during actuation;
[0215] FIG. 20 schematically illustrates the delivery device of
FIG. 7 following actuation;
[0216] FIG. 21 schematically illustrates a nasal delivery device in
accordance with a third embodiment of the present invention;
[0217] FIG. 22 schematically illustrates the delivery device of
FIG. 21 inserted in a nasal cavity of a subject for operation;
[0218] FIG. 23 schematically illustrates the delivery device of
FIG. 21 during actuation;
[0219] FIG. 24 schematically illustrates the delivery device of
FIG. 21 following actuation;
[0220] FIG. 25 schematically illustrates a nasal delivery device in
accordance with a fourth embodiment of the present invention;
[0221] FIG. 26 schematically illustrates the delivery device of
FIG. 25 inserted in a nasal cavity of a subject for operation;
[0222] FIG. 27 schematically illustrates the delivery device of
FIG. 25 during actuation;
[0223] FIG. 28 schematically illustrates a nasal delivery device in
accordance with a fifth embodiment of the present invention;
[0224] FIG. 29 schematically illustrates the delivery device of
FIG. 28 inserted in a nasal cavity of a subject for operation;
[0225] FIG. 30 schematically illustrates the delivery device of
FIG. 28 during actuation;
[0226] FIG. 31 schematically illustrates a nasal delivery device in
accordance with a sixth embodiment of the present invention;
[0227] FIG. 32 schematically illustrates the delivery device of
FIG. 31 inserted in a nasal cavity of a subject for operation;
[0228] FIG. 33 schematically illustrates the delivery device of
FIG. 31 during actuation;
[0229] FIG. 34 schematically illustrates a nasal delivery device in
accordance with a seventh embodiment of the present invention;
[0230] FIG. 35 schematically illustrates the delivery device of
FIG. 34 inserted in a nasal cavity of a subject for operation;
[0231] FIG. 36 schematically illustrates the delivery device of
FIG. 34, during actuation;
[0232] FIG. 37 schematically illustrates the delivery device of
FIG. 34 following actuation;
[0233] FIG. 38 schematically illustrates a nasal delivery device in
accordance with an eighth embodiment of the present invention;
[0234] FIG. 39 schematically illustrates the delivery device of
FIG. 38 inserted in a nasal cavity of a subject for operation;
[0235] FIG. 40 schematically illustrates the delivery device of
FIG. 38 during actuation;
[0236] FIG. 41 schematically illustrates the delivery device of
FIG. 38 following actuation;
[0237] FIG. 42 schematically illustrates a nasal delivery device in
accordance with a ninth embodiment of the present invention;
[0238] FIG. 43 schematically illustrates the delivery device of
FIG. 42 inserted in a nasal cavity of a subject for operation;
[0239] FIG. 44 schematically illustrates the delivery device of
FIG. 42 during actuation;
[0240] FIG. 45 schematically illustrates the delivery device of
FIG. 42 following actuation;
[0241] FIG. 46 schematically illustrates a nasal delivery device in
accordance with a tenth embodiment of the present invention,
illustrated in the inoperative configuration;
[0242] FIG. 47 schematically illustrates the delivery device of
FIG. 46 where the driving unit is primed for actuation;
[0243] FIG. 48 schematically illustrates the delivery device of
FIG. 46 inserted in a nasal cavity of a subject for operation;
[0244] FIG. 49 schematically illustrates the delivery device of
FIG. 46 during actuation where the subject has commenced exhaling
and the delivery device is at the point of actuation;
[0245] FIG. 50 schematically illustrates the delivery device of
FIG. 46 during actuation;
[0246] FIG. 51 schematically illustrates a nasal delivery device in
accordance with an eleventh embodiment of the present invention,
illustrated in the inoperative configuration;
[0247] FIG. 52 schematically illustrates the delivery device of
FIG. 51 where the driving unit is primed for actuation;
[0248] FIG. 53 schematically illustrates the delivery device of
FIG. 51, inserted in a nasal cavity of a subject for operation;
[0249] FIG. 54 schematically illustrates the delivery device of
FIG. 51 where the subject has commenced exhaling and the delivery
device is at the point of actuation;
[0250] FIG. 55 schematically illustrates the delivery device of
FIG. 51 where the driving unit has been actuated, the driving unit
having initiated actuation of the gas delivery unit and being at
the point of initiating actuation of the substance-supply unit;
[0251] FIG. 56 schematically illustrates the delivery device of
FIG. 51 during full actuation;
[0252] FIG. 57 schematically illustrates a nasal delivery device in
accordance with a twelfth embodiment of the present invention,
illustrated in the inoperative configuration;
[0253] FIG. 58 schematically illustrates the delivery device of
FIG. 57 where the driving unit is primed for actuation;
[0254] FIG. 59 schematically illustrates the delivery device of
FIG. 67 inserted in a nasal cavity of a subject for operation;
[0255] FIG. 60 schematically illustrates the delivery device of
FIG. 57 where the subject has commenced exhaling and the delivery
device is at the point of actuation;
[0256] FIG. 61 schematically illustrates the delivery device of
FIG. 57 where the driving unit has been actuated, the driving unit
having initiated actuation of the gas delivery unit and being at
the point of initiating actuation of the substance supply unit;
and
[0257] FIG. 62 schematically illustrates the delivery device of
FIG. 67 during full actuation.
[0258] FIGS. 13 to 16 illustrate an exhalation breath-actuated
nasal delivery device in accordance with a first embodiment of the
present invention.
[0259] The delivery device comprises a housing 15, a nosepiece 17
for fitting in a nasal cavity of a subject, and a mouthpiece 19
through which the subject exhales to actuate the delivery
device.
[0260] The nosepiece 17 comprises a guide member 20, in this
embodiment a frusto-conical element, for guiding the nosepiece 17
into a nasal cavity of the subject, and an outlet unit 21 for
delivering substance into the nasal airway of the subject. In this
embodiment the nosepiece 17 is a replaceable unit.
[0261] 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 for delivering substance to the
nasal airway of the subject. In this embodiment the nozzle 25 is
disposed in the delivery channel 23 co-axially with the same. In
this embodiment the nozzle 25 is configured to provide an aerosol
spray. In an alternative embodiment, for the delivery of a liquid,
the nozzle 25 could be configured to deliver a liquid jet as a
column of liquid.
[0262] In this embodiment the outlet unit 21 is movably coupled to
the housing 15, here as provided by a flexible coupling, such as to
allow for the positioning of the outlet unit 21 in the nasal cavity
of the subject, as will be described in more detail
hereinbelow.
[0263] In an alternative embodiment the outlet unit 21 could be
fixed to the housing 15, and the mouthpiece 19 instead movably
coupled to the housing 15, here as provided by a flexible coupling,
such as to allow for the positioning of the outlet unit 21 in the
nasal cavity of the subject.
[0264] In this embodiment at least the tip of the delivery channel
23 comprises a tubular section of a flexible, preferably resilient,
material. In a preferred embodiment the material is a semi-soft
plastics material, such as silicone rubber.
[0265] In this embodiment at least the tip of the delivery channel
23 has a tapering section which narrows to the distal end thereof.
The delivery channel 23, in having a narrowing taper, acts, on
insertion, to expand the narrow nasal valve of the nasal cavity of
the subject. In a preferred embodiment the delivery channel 23 has
an elliptical section, preferably an oval section.
[0266] In a preferred embodiment the distal end of the outlet unit
21 is configured to extend at least about 2 cm, preferably at least
about 3 om, and more preferably from about 2 cm to about 3 cm, into
the nasal cavity of the subject.
[0267] The nosepiece 17 further comprises at least one expandable
cuff member 27 for expansion in the nasal cavity of the subject. In
this embodiment the at least one cuff member 27 comprises an
inflatable member.
[0268] In this embodiment the at least one cuff member 27 is in
fluid communication with the delivery channel 23, whereby the air
flow generated by the subject on exhalation through the mouthpiece
19 acts to inflate the at least one cuff member 27. In an
alternative embodiment the delivery device could include a separate
pump unit for inflating the at least one cuff member 27 subsequent
to fitting of the nosepiece 17, and in a preferred embodiment
subsequent to, preferably in response to, exhalation through the
mouthpiece 19.
[0269] In this embodiment the at least one cuff member 27 is an
inflatable member which is inflated on exhalation by the subject.
In an alternative embodiment the at least one cuff member 27 could
be inflated on the nosepiece 17 being located in the correct
position.
[0270] In this embodiment the at least one cuff member 27 comprises
a flexible balloon element which is inflated by the generation of a
pressure in the delivery channel 23, with the at least one cuff
member 27 deflating on the release of pressure from the delivery
channel 23. In the alternative embodiment, where the at least one
cuff member 27 is inflated by a separate pump unit, the at least
one cuff member 27 could equally be deflated by the evacuation of
gas therefrom using the same pump unit.
[0271] In one embodiment the at least one cuff member 27 could
comprise a resilient balloon element which is inflated by the
generation of a pressure in the delivery channel 23, with the at
least one cuff member 27 returning to the original, deflated
configuration on the release of pressure from the delivery channel
23.
[0272] In another embodiment the at least one cuff member 27 could
comprise an inflatable sponge element, in one embodiment a foam
element having an encapsulating sealing layer, which can be
compressed, in this embodiment by evacuation, to adopt a compact
configuration to allow for insertion into a nasal cavity of the
subject and inflated, in this embodiment by breaking the vacuum, to
allow for the introduction of a gas into the porous structure of
the sponge element. In one embodiment such a cuff member 27 could
be in selective fluid communication with the atmosphere. In another
embodiment such a cuff member 27 could be in selective fluid
communication with the delivery channel 23, whereby the pressure
developed in the delivery channel 23 would assist in the inflation
of the cuff member 27. In the alternative embodiment which includes
a separate pump unit, the pump unit could be employed to assist in
inflating such a cuff member 27 and in deflating the cuff member 27
by the evacuation of gas therefrom. In one embodiment the inflation
could be triggered on exhalation by the subject. In another
embodiment the inflation could be triggered on the nosepiece 17
being located in the correct position in the nasal cavity of the
subject.
[0273] The at least one cuff member 27 is disposed to an outer
surface of the outlet unit 21 such as, on expansion, to engage the
inner wall of the nasal cavity of the subject. The at least one
cuff member 27, in being expandable, provides for the expansion of
the narrow nasal valve of the nasal cavity of the subject, the
sealing of the nosepiece 17 in the nasal cavity of the subject, and
the positioning, in particular the direction, of the outlet unit 21
in the nasal cavity of the subject.
[0274] In this embodiment the at least one cuff member 27 comprises
a single annular cuff member 27 which is located about the outlet
unit 21 such as to provide a seal between the delivery channel 23
and the inner wall of the nasal cavity of the subject when
inflated.
[0275] In an alternative embodiment the at least one cuff member 27
could comprise a plurality of cuff members 27 which together
provide a seal between the delivery channel 23 and the inner wall
of the nasal cavity of the subject when inflated.
[0276] The delivery device further comprises a substance supply
unit 29 for delivering metered doses of a substance, in this
embodiment an aerosol canister for delivering metered volumes of a
propellant, preferably a hydrofluoroalkane (HFA) propellant or the
like, containing medicament, either as a suspension or solution,
which is fluidly connected to the nozzle 25 to deliver substance
from the nosepiece 17, in this embodiment as an aerosol spray.
[0277] In this embodiment the substance supply unit 29 is a
multi-dose unit for delivering a plurality of metered doses of
substance. In another embodiment the substance supply unit 29 could
be a single-dose unit for delivering a single metered dose of
substance.
[0278] The substance supply unit 29 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 29 to deliver a metered dose of a substance through the nozzle
25.
[0279] In this embodiment the trigger mechanism 31 is configured to
cause actuation of the substance supply unit 29 on generation of a
predetermined flow rate through the delivery channel 23.
[0280] In another embodiment the trigger mechanism 31 could be
configured to cause actuation of the substance supply unit 29 on
generation of a predetermined pressure within the delivery channel
23.
[0281] In a further embodiment the trigger mechanism 31 could be
configured to cause actuation of the substance supply unit 29 on
generation of either one of a predetermined flow rate through the
delivery channel 23 or a predetermined pressure within the delivery
channel 23.
[0282] In an alternative embodiment the substance supply unit 29
could comprise a mechanical delivery pump, in particular a liquid
delivery pump or a powder delivery pump, which delivers metered
doses of a substance on actuation thereof.
[0283] In another alternative embodiment the substance supply unit
29 could comprise a dry powder delivery unit which delivers metered
doses of a substance, as a dry powder, on actuation thereof.
[0284] In yet another alternative embodiment the substance supply
unit 29 could comprise a nebulizer which delivers metered doses of
a substance, as an aerosol spray, on actuation thereof.
[0285] Operation of the delivery device will now be described
hereinbelow with reference to FIGS. 14 to 15 of the accompanying
drawings.
[0286] Referring to FIG. 14, the nose piece 17 is first inserted
into one of the nasal cavities of a subject until the guide member
20 abuts the nares of the nostril, at which point the distal end of
the outlet unit 21 extends about 2 cm into the nasal cavity of the
subject, and the mouthpiece 19 is gripped in the lips of the
subject.
[0287] 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
cavity, around the posterior margin of the nasal septum and out of
the other nasal cavity, thereby achieving a bi-directional air flow
through the nasal airway of the subject. Exhalation through the
mouthpiece 19 acts to develop a pressure in the delivery channel
23, which pressure acts to inflate the at least one cuff member 27.
As illustrated in FIG. 15, the expansion of the at least one cuff
member 27 acts to expand the nasal valve in the nasal cavity, seal
the delivery channel 23 to the inner wall of the nasal cavity, and
position the outlet unit 21 in relation to the nasal cavity of the
subject. As will be noted from FIG. 15, the outlet unit 21 is
forced to adopt the required position by the at least one cuff
member 27, in this embodiment as accommodated by flexing of the
outlet unit 21.
[0288] In this embodiment, when the flow rate developed through the
delivery channel 23 reaches a predetermined value, the release
mechanism 31 is triggered to actuate the substance supply unit 29
to deliver a metered dose of a substance to the nozzle 25 and into
the nasal cavity of the subject. In the alternative embodiment the
release mechanism 31 could be triggered on the generation of a
predetermined pressure in the delivery channel 23.
[0289] Following exhalation, the pressure in the delivery channel
23 decreases and the at least one cuff member 27 deflates, as
illustrated in FIG. 16, at which point the mouthpiece 19 is
released and the nosepiece 17 withdrawn from the nasal cavity of
the subject.
[0290] In one embodiment, where the delivery device is a
single-dose device, the device can be discarded.
[0291] In another embodiment, where the delivery device is a
multi-dose device, the device is ready for further use following
priming of the substance supply unit 29. In a preferred embodiment,
where the nosepiece 17 is replaceable, the nosepiece 17 can be
replaced with anew nosepiece 17.
[0292] FIGS. 17 to 24 illustrate an exhalation breath-actuated
nasal delivery device in accordance with a second embodiment of the
present invention.
[0293] The delivery device of this embodiment is very similar to
the delivery device of the above-described first 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.
[0294] The delivery device of this embodiment differs from that of
the above-described first embodiment in further comprising an oral
exhalation breath-actuatable gas supply unit 33 for delivering a
gas flow through the delivery channel 23 of the outlet unit 21 in
response to exhalation by a subject, and in that the mouthpiece 19
is in fluid communication with the gas supply unit 33 and not the
delivery channel 23 of the outlet unit 21, whereby a gas flow is
delivered to the delivery channel 23 of the outlet unit 21, and
hence the nasal airway of the subject, in response to exhalation
through the mouthpiece 19.
[0295] Operation of the delivery device is the same as for the
above-described first embodiment, with a gas flow being delivered
to the delivery channel 23 of the outlet unit 21 in response to
exhalation through the mouthpiece 19.
[0296] FIGS. 21 to 24 illustrate an exhalation breath-actuated
nasal delivery device in accordance with a third embodiment of the
present invention.
[0297] The delivery device of this embodiment is very similar to
the delivery device of the above-described first 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.
[0298] The delivery device of this embodiment differs from that of
the above-described first embodiment only in that the nosepiece 17
comprises a plurality of, in this embodiment two, inflatable cuff
members 27a, 27b. This arrangement of cuff members 27a, 27b enables
the distalmost cuff member 27b to have a reduced size, and thereby
facilitates insertion of the outlet unit 21 through the narrow
nasal valve in the nasal cavity of the subject.
[0299] Operation of the delivery device is the same as for the
above-described first embodiment.
[0300] FIGS. 25 to 27 illustrate an exhalation breath-actuated
nasal delivery device in accordance with a fourth embodiment of the
present invention.
[0301] The delivery device comprises a housing 35, a nosepiece 37
for fitting in a nasal cavity of a subject, and a mouthpiece 39
through which the subject exhales to actuate the delivery
device.
[0302] The nosepiece 37 comprises a guide member 40, in this
embodiment a frusto-conical element, for guiding the nosepiece 37
into the nasal cavity of the subject, and an outlet unit 41 for
delivering substance into the nasal airway of the subject. In this
embodiment the nosepiece 37 is a replaceable unit.
[0303] In this embodiment the outlet unit 41 comprises a delivery
channel 43 which is in fluid communication with the mouthpiece 39
such that an air flow is delivered into and through the nasal
airway of the subject on exhalation by the subject through the
mouthpiece 39, and a nozzle 45 for delivering substance into the
nasal cavity of the subject. In this embodiment the nozzle 45 is
disposed in the delivery channel 43 co-axially with the same. In
this embodiment the nozzle 45 is configured to provide an aerosol
spray. In an alternative embodiment, for the delivery of a liquid,
the nozzle 45 could be configured to deliver a liquid jet as a
column of liquid.
[0304] In this embodiment at least the tip of the delivery channel
43 comprises a tubular section of a flexible, preferably resilient,
material. In a preferred embodiment the material is a semi-soft
plastics material, such as silicone rubber.
[0305] In this embodiment at least the tip of the delivery channel
43 has a tapering section which narrows to the distal end thereof.
The delivery channel 43, in having a narrowing taper, acts, on
insertion, to expand the narrow nasal valve of the nasal cavity of
the subject. In a preferred embodiment the delivery channel 43 has
an elliptical section, preferably an oval section.
[0306] In a preferred embodiment the outlet unit 41 is configured
to extend at least about 2 cm, preferably at least about 3 cm, and
more preferably from about 2 cm to about 3 cm, into the nasal
cavity of the subject.
[0307] The nosepiece 37 further comprises at least one cuff member
47 for fitting in the nasal cavity of the subject. In this
embodiment the at least one cuff member 47 is a resilient member
which is deformable to allow for insertion into the nasal cavity of
the subject and, on insertion, expansion to adopt the required
position in the nasal cavity, in which position the outlet unit 41
is correctly positioned. When so positioned, the at least one cuff
member 47 provides for the expansion of the narrow nasal valve in
the nasal cavity, the sealing of the outlet unit 41 in the nasal
cavity, and the positioning, in particular the direction, of the
outlet unit 41 in the nasal cavity of the subject. In this
embodiment the at least one cuff member 47 comprises a sponge
member, here a foam member. In an alternative embodiment the at
least one cuff member 47 could comprise a gel-filled member, such
as a silicone-filled member.
[0308] In this embodiment the at least one cuff member 47 is
configured such that, when inserted in the nasal cavity, the outlet
unit 41 is directed at a lower region of the nasal cavity of the
subject. In preferred embodiments the at least one cuff member 47
can be configured to direct the outlet unit 41 at any region of the
inferior meatus and the inferior region of the middle meatus,
whereby substance can be targeted in particular at the inferior
nasal concha, and the adenoids and tubal ostia in the superior
region of the epipharynx.
[0309] Regions in the nasal airway adjacent the inferior meatus and
the inferior region of the middle meatus represent the regions in
the nasal airway which provide the path of least flow resistance
therethrough. With existing nasal spray systems, the delivery is
such that the delivered substance flows along the floor of the
nasal cavity, with the result that the substance does not reach the
adenoids or the tubal ostia.
[0310] In this embodiment the at least one cuff member 47 includes
at least one lobe 54, here a single lobe 54, which is configured
such as to extend into, and thereby obstruct, an upper region of
the nasal cavity of the subject, the at least one lobe 54 acting to
force the delivered flow to follow a flow path defined by the
inferior meatus and the inferior region of the middle meatus. The
achievement of such a flow path, allied with an optimization of the
particle size distribution, provides that a much larger fraction of
substance can be delivered to sites in the inferior meatus and the
inferior region of the middle meatus.
[0311] In this embodiment the at least one cuff member 47 comprises
a single annular cuff member 47 which is disposed about the outlet
unit 41.
[0312] In an alternative embodiment the at least one cuff member 47
could comprise a plurality of cuff members 47 which are disposed
about the outlet unit 41.
[0313] The delivery device further comprises a substance supply
unit 49 for delivering metered doses of a substance, in this
embodiment an aerosol canister for delivering metered volumes of a
propellant, preferably a hydrofluoroalkane (HFA) propellant or the
like, containing medicament, either as a suspension or solution,
which is fluidly connected to the nozzle 45 to deliver substance
from the nosepiece 37, in this embodiment as an aerosol spray.
[0314] In this embodiment the substance supply unit 49 is a
multi-dose unit for delivering a plurality of metered doses of
substance. In another embodiment the substance supply unit 49 could
be a single-dose unit for delivering a single metered dose of
substance.
[0315] The substance supply unit 49 is pre-primeable, in this
embodiment by loading a resilient element, and includes a
breath-actuated release mechanism 51 which, when triggered,
releases the resilient element and actuates the substance supply
unit 49 to deliver a metered dose of a substance through the nozzle
45.
[0316] In this embodiment the trigger mechanism 51 is configured to
cause actuation of the substance supply unit 49 on generation of a
predetermined flow rate through the delivery channel 43.
[0317] In another embodiment the trigger mechanism 51 could be
configured to cause actuation of the substance supply unit 49 on
generation of a predetermined pressure within the delivery channel
43.
[0318] In a further embodiment the trigger mechanism 51 could be
configured to cause actuation of the substance supply unit 49 on
generation of either one of a predetermined flow rate through the
delivery channel 43 or a predetermined pressure within the delivery
channel 43.
[0319] In an alternative embodiment the substance supply unit 49
could comprise a mechanical delivery pump, in particular a liquid
delivery pump or a powder delivery pump, which delivers metered
doses of a substance on actuation thereof.
[0320] In another alternative embodiment the substance supply unit
49 could comprise a dry powder delivery unit which delivers metered
doses of a substance, as a dry powder, on actuation thereof.
[0321] In yet another alternative embodiment the substance supply
unit 49 could comprise a nebulizer which delivers metered doses of
a substance, as an aerosol spray, on actuation thereof.
[0322] Operation of the delivery device will now be described
hereinbelow with reference to FIGS. 26 and 27 of the accompanying
drawings.
[0323] Referring to FIG. 26, the nosepiece 37 is first inserted
into a nasal cavity of a subject until the guide member 40 abuts
the nares of the nostril, at which point the distal end of the
outlet unit 41 extends about 2 cm into the nasal cavity of the
subject, and the mouthpiece 39 is gripped in the lips of the
subject.
[0324] The subject then begins to exhale through the mouthpiece 39,
which exhalation acts to close the oropharyngeal velum of the
subject and drive an air flow through the delivery channel 43 of
the outlet unit 41, with the air flow passing into the one nasal
cavity, around the posterior margin of the nasal septum and out of
the other nasal cavity, thereby achieving a bi-directional air flow
through the nasal airway of the subject.
[0325] In this embodiment, when the flow rate developed through the
delivery channel 43 reaches a predetermined value, the release
mechanism 51 is triggered to actuate the substance supply unit 49
to deliver a metered dose of a substance to the nozzle 45 and into
the nasal cavity of the subject. In the alternative embodiment the
release mechanism 51 could be triggered on the generation of a
predetermined pressure in the delivery channel 43.
[0326] Following exhalation, the mouthpiece 39 is released and the
nosepiece 37 withdrawn from the nasal cavity of the subject.
[0327] In one embodiment, where the delivery device is a
single-dose device, the device can be discarded.
[0328] In another embodiment, where the delivery device is a
multi-dose device, the device is ready for further use following
priming of the substance supply unit 49. In a preferred embodiment,
where the nosepiece 37 is replaceable, the nosepiece 37 can be
replaced with a new nosepiece 37.
[0329] FIGS. 28 to 30 illustrate an exhalation breath-actuated
nasal delivery device in accordance with a fifth embodiment of the
present invention.
[0330] The delivery device of this embodiment is very similar to
the delivery device of the above-described fourth 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.
[0331] The delivery device of this embodiment differs from that of
the above described fourth embodiment only in the configuration of
the outlet unit 41 and the at least one cuff member 47.
[0332] In this embodiment the at least one cuff member 47 is
configured such that, when inserted in the nasal cavity of the
subject, the outlet unit 41 is directed at a middle region of the
nasal cavity of the subject. In a preferred embodiment the at least
one cuff member 47 can be configured to direct the outlet unit 41
at any region of the middle meatus and the inferior region of the
superior meatus, whereby substance can be targeted in particular at
the middle nasal conchs, the sinus infundibulum and the sinus
ostia.
[0333] The middle meatus is the region of the nasal cavity located
under and lateral to the middle nasal concha, with the sinus
infundibulum and the sinus ostia representing the sites of the main
pathologies in many very common diseases, such as chronic
sinusitis, which affects about 10 to 15% of the population and has
no FDA approved treatment, and nasal polyposis. The only known
treatment of these conditions is the application of drops during a
rigorous and complex procedure involving severe neck extension and
the so-called "Mecca" position. As will be appreciated, however,
owing to the complicated and often painful procedure, compliance is
very poor. Existing nasal spray systems are ineffective in
delivering substance to this region of the nasal cavity.
[0334] In this embodiment the at least one cuff member 47 includes
upper and lower lobes 54a, 54b which are configured such as to
extend into, and thereby obstruct, respective ones of the upper and
lower regions of the nasal cavity of the subject, the lobes 54a,
54b acting to force a delivered flow to follow a flow path defined
by the middle meatus and the inferior region of the superior
meatus. The achievement of such a flow path, allied with an
optimization of the particle size distribution, provides that a
much larger fraction of substance can be delivered to sites in the
middle meatus and the inferior region of the middle meatus.
[0335] Operation of the delivery device is the same as for the
above-described fourth embodiment.
[0336] FIGS. 31 to 33 illustrate an exhalation breath-actuated
nasal delivery device in accordance with a sixth embodiment of the
present invention.
[0337] The delivery device of this embodiment is very similar to
the delivery device of the above-described fourth 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.
[0338] The delivery device of this embodiment differs from that of
the above-described fourth embodiment only in the configuration of
the outlet unit 41 and the at least one cuff member 47.
[0339] In this embodiment the at least one cuff member 47 is
configured such that, when inserted in the nasal cavity of the
subject, the outlet unit 41 is directed at a superior region of the
nasal cavity of the subject. In a preferred embodiment the at least
one cuff member 47 can be configured to direct the outlet unit 41
at any region of the superior meatus, and in particular provide for
the targeting of the superior nasal concha and the olfactory
region.
[0340] The olfactory region is located in the superior region of
the nasal cavity and typically has a surface area of from about 4
to 6 cm.sup.2. The olfactory region represents the only region
where it is possible to circumvent the blood-to-brain barrier (BBB)
and enable communication with the cerebrospinal fluid (CSF) and the
brain. Such delivery is necessary to enable effective treatment of
neurological diseases, such as Alzheimer's and Parkinson's disease,
psychiatric diseases and intracerebral infectious.
[0341] The olfactory region is reached through narrow slit-like
passages and the delivery of substance to this region is not
possible using existing nasal delivery systems.
[0342] In existing nasal spray systems, substantially all of the
particles are far too large to pass through the passages in
communication with the olfactory region. Indeed, such spray systems
are specifically designed to deliver particles having an average
diameter of greater than 10 .mu.m in order to comply with the FDA
requirements which require that the maximum fraction of particles
having a diameter of less than 10 .mu.m be 5% of the total
fraction. The reason for this requirement is that, where the velum
is not closed, as would be the case where a subject inhales through
the nose as prescribed for delivery, particles having a diameter of
less than 10 .mu.m could escape from the nasal cavity and be
inhaled into the lungs.
[0343] In addition, in existing nasal spray systems, the flow
characteristics of particles delivered into the nasal cavity are
not suited to enable delivery through the passages communicating
with the olfactory region.
[0344] Furthermore, the sniffing action by a subject during
delivery causes the particles to be drawn into the inferior and
middle regions of the nasal cavity, where the flow resistance is
the lowest, with only a minimal fraction, if any, of the particles
being delivered to the olfactory region.
[0345] In this embodiment, by ensuring closure of the velum in
delivery and optimizing both the particle size distribution so as
to include a larger fraction of smaller particles, typically having
a particle size of less than 10 .mu.m, and the aerodynamic delivery
conditions, the delivery device provides for the effective delivery
of substance to the olfactory region. Such a delivery regime has
not previously been known, and has been recognised by the present
applicant as providing an improved delivery device and delivery
method.
[0346] In this embodiment the at least one lobe 54 of the at least
one cuff member 47 is configured such as to extend into, and
thereby obstruct, a lower region of the nasal cavity of the
subject, the at least one lobe 54 acting to force a delivered flow
to follow a flow path defined by the superior meatus and in
particular the olfactory region. The achievement of such a flow
path, allied with an optimization of the particle size
distribution, provides that a much larger fraction of substance can
be delivered to sites in the superior meatus and in particular the
olfactory region.
[0347] Operation of the delivery device is the same as for the
above-described fourth embodiment.
[0348] FIGS. 34 to 37 illustrate an exhalation breath-actuated
nasal delivery device in accordance with a seventh embodiment of
the present invention.
[0349] The delivery device comprises a housing 55, a nosepiece 57
for fitting in a nasal cavity of a subject, and a mouthpiece 59
through which the subject exhales to actuate the delivery
device.
[0350] The nosepiece 57 comprises a guide member 60, in this
embodiment a frusto-conical element, for guiding the nosepiece 57
into a nasal cavity of the subject, and an outlet unit 61 for
delivering substance into the nasal airway of the subject. In this
embodiment the nosepiece 57 is a replaceable unit.
[0351] In this embodiment the outlet unit 61 comprises a delivery
channel 63 which is in fluid communication with the mouthpiece 59
such that an air flow is delivered into and through the nasal
airway of the subject on exhalation by the subject through the
mouthpiece 59, and a nozzle 65 for delivering substance to the
nasal airway of the subject. In this embodiment the nozzle 65 is
disposed in the delivery channel 63 co-axially with the same. In
this embodiment the nozzle 65 is configured to provide an aerosol
spray. In an alterative embodiment, for the delivery of a liquid,
the nozzle 65 could be configured to deliver a liquid jet as a
column of liquid.
[0352] In this embodiment the outlet unit 61 is movably coupled to
the housing 55, here as provided by a flexible coupling, such as to
allow for the positioning of the outlet unit 61 in the nasal cavity
of the subject, as will be described in more detail
hereinbelow.
[0353] In an alternative embodiment the outlet unit 61 could be
fixed to the housing 55, and the mouthpiece 59 instead movably
coupled to the housing 55, here as provided by a flexible coupling,
such as to allow for the positioning of the outlet unit 61 in the
nasal cavity of the subject.
[0354] In this embodiment at least the tip of the delivery channel
63 comprises a tubular section of a flexible, preferably resilient,
material. In a preferred embodiment the material is a semi-soft
plastics material, such as silicone rubber.
[0355] In this embodiment at least the tip of the delivery channel
63 has a tapering section which narrows to the distal end thereof.
The delivery channel 63, in having a narrowing taper, acts, on
insertion, to expand the narrow nasal valve of the nasal cavity of
the subject. In a preferred embodiment the delivery channel 63 has
an elliptical section, preferably an oval section.
[0356] In a preferred embodiment the distal end of the outlet unit
61 is configured to extend at least about 2 cm, preferably at least
about 3 cm, and more preferably from about 2 cm to about 3 cm, into
the nasal cavity of the subject.
[0357] The nosepiece 57 further comprises at least one expandable
cuff member 67 for expansion in the nasal cavity of the subject. In
this embodiment the at least one cuff member 67 comprises an
inflatable member.
[0358] In this embodiment the at least one cuff member 67 is in
fluid communication with the delivery channel 63, whereby the air
flow generated by the subject on exhalation through the mouthpiece
59 acts to inflate the at least one cuff member 67. In an
alternative embodiment the delivery device could include a separate
pump unit for inflating the at least one cuff member 67 subsequent
to fitting of the nosepiece 57, and in a preferred embodiment
subsequent to, preferably in response to, exhalation through the
mouthpiece 59.
[0359] In this embodiment the at least one cuff member 67 is an
inflatable member which is inflated on exhalation by the subject.
In an alternative embodiment the at least one cuff member 67 could
be inflated on the nosepiece 57 being located in the correct
position.
[0360] In this embodiment the at least one cuff member 67 comprises
a flexible balloon element which is inflated by the generation of a
pressure in the delivery channel 63, with the at least one cuff
member 67 deflating on the release of pressure from the delivery
channel 63. In the alternative embodiment, where the at least one
cuff member 67 is inflated by a separate pump unit, the at least
one cuff member 67 could equally be deflated by the evacuation of
gas therefrom using the same pump unit.
[0361] In one embodiment the at least one cuff member 67 could
comprise a resilient balloon element which is inflated by the
generation of a pressure in the delivery channel 63, with the at
least one cuff member 67 returning to the original, deflated
configuration on the release of pressure from the delivery channel
63.
[0362] In another embodiment the at least one cuff member 67 could
comprise an inflatable sponge element, in one embodiment a foam
element having an encapsulating sealing layer, which can be
compressed, in this embodiment by evacuation, to adopt a compact
configuration to allow for insertion into a nasal cavity of the
subject and inflated, in this embodiment by breaking the vacuum, to
allow for the introduction of a gas into the porous structure of
the sponge element. In one embodiment such a cuff member 67 could
be in selective fluid communication with the atmosphere. In another
embodiment such a cuff member 67 could be in selective fluid
communication with the delivery channel 63, whereby the pressure
developed in the delivery channel 63 would assist in the inflation
of the cuff member 67. In the alternative embodiment which includes
a separate pump unit, the pump unit could be employed to assist in
inflating such a cuff member 67 and in deflating the cuff member 67
by the evacuation of gas therefrom. In one embodiment the inflation
could be triggered on exhalation by the subject. In another
embodiment the inflation could be triggered on the nosepiece 57
being located in the correct position in the nasal cavity of the
subject.
[0363] The at least one cuff member 67 is disposed to an outer
surface of the outlet unit 61 such as, on expansion, to engage the
inner wall of the nasal cavity of the subject. The at least one
cuff member 67, in being expandable, provides for the expansion of
the narrow nasal valve of the nasal cavity of the subject, the
sealing of the nosepiece 57 in the nasal cavity of the subject, and
the positioning, in particular the direction, of the outlet unit 61
in the nasal cavity of the subject.
[0364] In this embodiment the at least one cuff member 67 comprises
a single annular cuff member 67 which is located about the outlet
unit 61 such as to provide a seal between the delivery channel 63
and the inner wall of the nasal cavity of the subject when
inflated.
[0365] In an alternative embodiment the at least one-cuff member 67
could comprise a plurality of cuff members 67 which together
provide a seal between the delivery channel 63 and the inner wall
of the nasal cavity of the subject when inflated.
[0366] In this embodiment the at least one cuff member 67 is
configured such that, when inserted in the nasal cavity, the outlet
unit 61 is directed at a lower region of the nasal cavity of the
subject. In preferred embodiments the at least one cuff member 67
can be configured to direct the outlet unit 61 at any region of the
inferior meatus and the inferior region of the middle meatus,
whereby substance can be targeted in particular at the inferior
nasal concha, and the adenoids and tubal ostia in the superior
region of the epipharynx.
[0367] Regions in the nasal airway adjacent the inferior meatus and
the inferior region of the middle meatus represent the regions in
the nasal airway which provide the path of least flow resistance
therethrough. With existing nasal spray systems, the delivery is
such that the delivered substance flows along the floor of the
nasal cavity, with the result that the substance does not reach the
adenoids or the tubal ostia.
[0368] In this embodiment the at least one cuff member 67 includes
at least one lobe 74, here a single lobe 74, which is configured
such as to extend into, and thereby obstruct, an upper region of
the nasal cavity of the subject, the at least one lobe 74 acting to
force the delivered flow to follow a flow path defined by the
inferior meatus and the inferior region of the middle meatus. The
achievement of such a flow path, allied with an optimization of the
particle size distribution, provides that a much larger fraction of
substance can be delivered to sites in the inferior meatus and the
inferior region of the middle meatus.
[0369] In this embodiment the at least one cuff member 67 comprises
a single annular cuff member 67 which is disposed about the outlet
unit 61.
[0370] In an alternative embodiment the at least one cuff member 67
could comprise a plurality of cuff members 67 which are disposed
about the outlet unit 61.
[0371] The delivery device further comprises a substance supply
unit 69 for delivering metered doses of a substance, in this
embodiment an aerosol canister for delivering metered volumes of a
propellant, preferably a hydrofluoroalkane (HFA) propellant or the
like, containing medicament, either as a suspension or solution,
which is fluidly connected to the nozzle 65 to deliver substance
from the nosepiece 57, in this embodiment as an aerosol spray.
[0372] In this embodiment the substance supply unit 69 is a
multi-dose unit for delivering a plurality of metered doses of
substance. In another embodiment the substance supply unit 69 could
be a single-dose unit for delivering a single metered dose of
substance.
[0373] The substance supply unit 69 is pre-primeable, in this
embodiment by loading a resilient element, and includes a
breath-actuated release mechanism 71 which, when triggered,
releases the resilient element and actuates the substance supply
unit 69 to deliver a metered dose of a substance through the nozzle
65.
[0374] In this embodiment the trigger mechanism 71 is configured to
cause actuation of the substance supply unit 69 on generation of a
predetermined flow rate through the delivery channel 63.
[0375] In another embodiment the trigger mechanism 71 could be
configured to cause actuation of the substance supply unit 69 on
generation of a predetermined pressure within the delivery channel
63.
[0376] In a further embodiment the trigger mechanism 71 could be
configured to cause actuation of the substance supply unit 69 on
generation of either one of a predetermined flow rate through the
delivery channel 63 or a predetermined pressure within the delivery
channel 63.
[0377] In an alternative embodiment the substance supply unit 69
could comprise a mechanical delivery pump, in particular a liquid
delivery pump or a powder delivery pump, which delivers metered
doses of a substance on actuation thereof.
[0378] In another alternative embodiment the substance supply unit
69 could comprise a dry powder delivery unit which delivers metered
doses of a substance, as a dry powder, on actuation thereof.
[0379] In yet another alternative embodiment the substance supply
unit 69 could comprise a nebulizer which delivers metered doses of
a substance, as an aerosol spray, on actuation thereof.
[0380] Operation of the delivery device will now be described
hereinbelow with reference to FIGS. 35 to 37 of the accompanying
drawings.
[0381] Referring to FIG. 35, the nosepiece 57 is first inserted
into one of the nasal cavities of a subject until the guide member
60 abuts the nares of the nostril, at which point the distal end of
the outlet unit 61 extends about 2 cm into the nasal cavity of the
subject, and the mouthpiece 59 is gripped in the lips of the
subject.
[0382] The subject then begins to exhale through the mouthpiece 59,
which exhalation acts to close the oropharyngeal velum of the
subject and drive an air flow through the delivery channel 63 of
the outlet unit 61, with the air flow passing into the one nasal
cavity, around the posterior margin of the nasal septum and out of
the other nasal cavity, thereby achieving a bi-directional air flow
through the nasal airway of the subject. Exhalation through the
mouthpiece 59 acts to develop a pressure in the delivery channel
63, which pressure acts to inflate the at least one cuff member 67.
As illustrated in FIG. 36, the expansion of the at least one cuff
member 67 acts to expand the nasal valve in the nasal cavity, seal
the delivery channel 63 to the inner wall of the nasal cavity, and
position the outlet unit 61 in relation to the nasal cavity of the
subject. As will be noted from FIG. 36, the outlet unit 61 is
forced to adopt the required position by the at least one cuff
member 67, in this embodiment as accommodated by flexing of the
outlet unit 61.
[0383] In this embodiment, when the flow rate developed through the
delivery channel 63 reaches a predetermined value, the release
mechanism 71 is triggered to actuate the substance supply unit 69
to deliver a metered dose of a substance to the nozzle 65 and into
the nasal cavity of the subject. In the alternative embodiment the
release mechanism 71 could be triggered on the generation of a
predetermined pressure in the delivery channel 63.
[0384] Following exhalation, the pressure in the delivery channel
63 decreases and the at least one cuff member 67 deflates, as
illustrated in FIG. 37, at which point the mouthpiece 59 is
released and the nosepiece 57 withdrawn from the nasal cavity of
the subject.
[0385] In one embodiment, where the delivery device is a
single-dose device, the device can be discarded.
[0386] In another embodiment, where the delivery device is a
multi-dose device, the device is ready for further use following
priming of the substance supply unit 69. In a preferred embodiment,
where the nosepiece 57 is replaceable, the nosepiece 57 can be
replaced with a new nosepiece 57.
[0387] FIGS. 38 to 41 illustrate an exhalation breath-actuated
nasal delivery device in accordance with an eighth embodiment of
the present invention.
[0388] The delivery device of this embodiment is very similar to
the delivery device of the above-described seventh 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.
[0389] The delivery device of this embodiment differs from that of
the above-described seventh embodiment only in the configuration of
the outlet unit 61 and the at least one cuff member 67.
[0390] In this embodiment the at least one cuff member 67 is
configured such that, when inserted in the nasal cavity of the
subject, the outlet unit 61 is directed at a middle region of the
nasal cavity of the subject. In a preferred embodiment the at least
one cuff member 67 can be configured to direct the outlet unit 61
at any region of the middle meatus and the inferior region of the
superior meatus, whereby substance can be targeted in particular at
the middle nasal concha, the sinus infundibulum and the sinus
ostia.
[0391] The middle meatus is the region of the nasal cavity located
under and lateral to the middle nasal concha, with the sinus
infundibulum and the sinus ostia representing the sites of the main
pathologies in many very common diseases, such as chronic
sinusitis, which affects about 10 to 15% of the population and has
no FDA approved treatment, and nasal polyposis. The only known
treatment of these conditions is the application of drops during a
rigorous and complex procedure involving severe neck extension and
the so-called "Mecca" position. As will be appreciated, however,
owing to the complicated and often painful procedure, compliance is
very poor. Existing nasal spray systems are ineffective in
delivering substance to this region of the nasal cavity.
[0392] In this embodiment the at least one cuff member 67 includes
upper and lower lobes 74a, 74b which are configured such as to
extend into, and thereby obstruct, respective ones of the upper and
lower regions of the nasal cavity of the subject, the lobea 74a,
74b acting to force a delivered flow to follow a flow path defined
by the middle meatus and the inferior region of the superior
meatus. The achievement of such a flow path, allied with an
optimization of the particle size distribution, provides that a
much larger fraction of substance can be delivered to sites in the
middle meatus and the inferior region of the middle meatus.
[0393] Operation of the delivery device is the same as for the
above-described seventh embodiment.
[0394] FIGS. 42 to 45 illustrate an exhalation breath-actuated
nasal delivery device in accordance with a ninth embodiment of the
present invention.
[0395] The delivery device of this embodiment is very similar to
the delivery device of the above-described seventh 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.
[0396] The delivery device of this embodiment differs from that of
the above-described seventh embodiment only in the configuration of
the outlet unit 61 and the at least one cuff member 67.
[0397] In this embodiment the at least one cuff member 67 is
configured such that, when inserted in the nasal cavity of the
subject, the outlet unit 61 is directed at a superior region of the
nasal cavity of the subject. In a preferred embodiment the at least
one cuff member 67 can be configured to direct the outlet unit 61
at any region of the superior meatus, and in particular provide for
the targeting of the superior nasal concha and the olfactory
region.
[0398] The olfactory region is located in the superior region of
the nasal cavity and typically has a surface area of from about 4
to 6 cm.sup.2. The olfactory region represents the only region
where it is possible to circumvent the blood-to-brain barrier (BBB)
and enable communication with the cerebrospinal fluid (CSF) and the
brain. Such delivery is necessary to enable effective treatment of
neurological diseases, such as Alzheimer's and Parkinson's disease,
psychiatric diseases and intracerebral infections.
[0399] The olfactory region is reached through narrow slit-like
passages and the delivery of substance to this region is not
possible using existing nasal delivery systems.
[0400] In existing nasal spray systems, substantially all of the
particles are far too large to pass through the passages in
communication with the olfactory region. Indeed, such spray systems
are specifically designed to deliver particles having an average
diameter of greater than 10 .mu.m in order to comply with the FDA
requirements which require that the maximum fraction of particles
having an average diameter of less than 10 .mu.m be 5% of the total
fraction. The reason for this requirement is that, where the velum
is not closed, as would be the case where a subject inhales through
the nose as prescribed for delivery, particles having an average
diameter of less than 10 .mu.m could escape from the nasal cavity
and be inhaled into the lungs.
[0401] In addition, in existing nasal spray systems, the flow rate
of particles delivered into the nasal cavity is too great to enable
delivery through the passages communicating with the olfactory
region.
[0402] Furthermore, inhalation by a subject during delivery causes
the particles to be drawn into the inferior and middle regions of
the nasal cavity, where the flow resistance is the lowest, with
only a minimal fraction, if any, of the particles being delivered
to the olfactory region.
[0403] In this embodiment, by ensuring closure of the velum in
delivery and optimizing both the particle size distribution so as
to include a larger fraction of smaller particles, typically having
a particle size of less than 10 .mu.m, and the aerodynamic delivery
conditions, the delivery device provides for the effective delivery
of substance to the olfactory region. Such a delivery regime has
not previously been known, and has been recognised by the present
applicant as providing an improved delivery device and delivery
method.
[0404] In this embodiment the at least one lobe 74 of the at least
one cuff member 67 is configured such as to extend into, and
thereby obstruct, a lower region of the nasal cavity of the
subject, the at least one lobe 74 acting to force a delivered flow
to follow a flow path defined by the superior meatus and in
particular the olfactory region. The achievement of such a flow
path, allied with an optimization of the particle size
distribution, provides that a much larger fraction of substance can
be delivered to sites in the superior meatus and in particular the
olfactory region.
[0405] Operation of the delivery device is the same as for the
above-described seventh embodiment.
[0406] FIGS. 36 to 50 illustrate an exhalation breath-actuated
nasal delivery device in accordance with a tenth embodiment of the
present invention.
[0407] The delivery device comprises a housing 75, a nosepiece 77
for fitting in a nasal cavity of a subject, and a mouthpiece 79
through which the subject exhales to actuate the delivery
device.
[0408] The nosepiece 77 comprises a cuff member 80, in this
embodiment a frusto-conical element, for positioning the nosepiece
77 in the nasal cavity of the subject and providing a fluid-tight
seal therewith, and an outlet unit 81 for delivering substance into
the nasal airway of the subject.
[0409] In this embodiment the outlet unit 81 comprises a nozzle 82
from which substance is delivered into the nasal cavity of the
subject, and a delivery channel 83 through which a gas flow,
separate from the exhalation breath of the subject, is delivered to
interact with the substance delivered from the nozzle 82. This
configuration, in interacting with the substance and altering the
characteristics of the delivered substance, advantageously provides
for improved delivery of the substance.
[0410] In this embodiment the nozzle 82 is configured to provide an
aerosol spray. In an alternative embodiment, for the delivery of a
liquid, the nozzle 82 could be configured to deliver a liquid jet
as a column of liquid.
[0411] In this embodiment the nozzle 82 is disposed in the delivery
channel 83 co-axially with the same. In this embodiment the
delivery channel 83 is an annular channel which surrounds the
nozzle 82 such as to define an annular gas flow-which interacts
with the substance delivered from the nozzle 82.
[0412] The delivery device further comprises a substance supply
unit 85 which is fluidly connected to the nozzle 82 such as to
deliver a metered dose of a substance on actuation thereof. In this
embodiment the substance supply unit 85 comprises a mechanical pump
for delivering a metered dose of a substance on actuation
thereof.
[0413] The delivery device further comprises a gas supply unit 87
which is fluidly connected to the delivery-channel 83 for supplying
a gas flow therethrough. The gas supply unit 87 comprises a
cylinder 89, a piston 91 which is movably disposed within the
cylinder 89 and defines a chamber 93 forward thereof which contains
a gas, with a volume of the contained gas, typically about 5 ml,
being expelled from the chamber 93 on actuation of the gas supply
unit 87.
[0414] The delivery device further comprises a driving unit 95
which is actuatable to actuate the substance supply unit 85 and the
gas supply unit 87.
[0415] The driving unit 95 comprises a drive member 97, in this
embodiment a block, which is coupled, here commonly coupled, to the
body of the substance supply unit 85 and the piston 91 of the gas
supply unit 87 and movable between a first, rest position (as
illustrated in FIGS. 46 to 49) in which the substance supply unit
85 and the gas supply unit 87 are in the non-actuated positions and
a second, actuated position (as illustrated in FIG. 50) in which
the body of the substance supply unit 85 and the piston 91 of the
gas supply unit 87 are advanced to the actuated positions, and a
return biasing element 99, in this embodiment a resilient element,
particularly a compression spring, for returning the drive member
97 to the rest position.
[0416] The driving unit 95 further comprises a load biasing element
101, in this embodiment a resilient element, particularly a
compression spring, for biasing the drive member 97 in an actuating
direction when in the rest position, and a loading member 103, in
this embodiment a lever, for loading the load biasing element 101
such as to bias the drive member 97 when in the rest position with
an actuation force. The loading member 103 is movable between a
first, inoperative position (as illustrated in FIG. 46) in which
the load biasing element 101 is not loaded thereby, and a second,
operative position (as illustrated in FIGS. 47 to 49) in which the
biasing element 101, when restrained, loads the drive member 97
with the actuation force.
[0417] The delivery device further comprises a trigger mechanism
105 which is configured normally to lock the drive member 97 of the
driving unit 95 in the rest position and release the same on
exhalation by the subject through the mouthpiece 79, which drive
member 97, when loaded by the load biasing element 101, once
released acts commonly to actuate the substance supply unit 85 and
the gas supply unit 87.
[0418] In this embodiment the trigger mechanism 105 is configured
to cause actuation of the driving unit 95 on generation of a
predetermined flow rate through the mouthpiece 79.
[0419] In another embodiment the trigger mechanism 105 could be
configured to cause actuation of the driving unit 95 on generation
of a predetermined pressure within the mouthpiece 79.
[0420] In this embodiment the trigger mechanism 105 comprises a
linkage assembly 107 which includes first and second link elements
109, 111, and a biasing element 112, in this embodiment a resilient
element, particularly a tension spring, for biasing the linkage
assembly 107 to a looking configuration (as illustrated in FIGS. 46
to 48) in which the linkage assembly 107 acts to lock the drive
member 97 of the driving unit 95 in the rest position and prevent
movement thereof when loaded by the load biasing element 101.
[0421] One of the link elements 109 includes a pivot 113 about
which the same is rotatable, and first and second arms 115, 117.
One of the arms 115 extends into the mouthpiece 79 and, when the
linkage assembly 107 is in the locking configuration, is biased to
a rest position (as illustrated in FIGS. 46 to 48) in which the
flow path through the mouthpiece 79 is substantially closed, the
one arm 115 thereby providing a vane to be acted upon by the
exhalation breath of the subject.
[0422] The other of the link elements 111 is pivotally coupled at
one end to the distal end of the other, second arm 117 of the first
link element 109 and at the other end to the drive member 97 of the
driving unit 95; the second arm 117 of the first link element 109
being angularly positioned relative to the first arm 115 thereof
such that, when the linkage assembly 107 is in the locking
configuration, the second arm 117 of the first link element 109 and
the second link element 111 enclose an angle of less than 180
degrees on the side opposite to the first arm 115 of the first link
element 109, whereby the second arm 117 of the first link element
109 and the second link element 111 are over-centered and support
the drive member 97 of the driving unit 95 when loaded.
[0423] Operation of the delivery device will now be described
hereinbelow with reference to FIGS. 47 to 50 of the accompanying
drawings.
[0424] In a first step, as illustrated in FIG. 47 the loading
member 103 is operated to bias the biasing element 101 and load the
drive member 97 of the driving unit 95 with the actuation
force.
[0425] Referring to FIG. 48, the nosepiece 77 is then first
inserted into a nasal cavity of a subject until the cuff member 80
is fitted in the nares of the nostril, at which point the distal
end of the outlet unit 81 extends about 2 cm into the nasal cavity
of the subject, and the mouthpiece 79 is gripped in the lips of the
subject.
[0426] The subject then begins to exhale through the mouthpiece 79,
which exhalation acts to close the oropharyngeal velum of the
subject and drive an air flow over the first arm 115 of the first
link element 109 of the linkage assembly 107 which extends into the
mouthpiece 79. While the flow rate developed is not sufficient to
actuate the trigger mechanism 105, the linkage assembly 107 of the
trigger mechanism 105 acts to retain the drive member 97 of the
driving unit 95 in the locked position, whereby the substance
supply unit 85 and the gas supply unit 87 are not actuated. When
the flow rate developed reaches a predetermined value, as
illustrated in FIG. 49, the rotation of the first arm 115 of the
first link element 109 is such as to rotate the second arm 117 of
the first link element 109 to a position in which the support
provided together with the second link element 111 is unstable and
collapses. Referring to FIG. 0, this collapse of the linkage
assembly 107 enables the drive member 97 of the driving unit 95 to
be moved by the load biasing element 101 to the actuated position,
which movement actuates the substance supply unit 85 to deliver a
metered dose of a substance through the nozzle 82 and the gas
supply unit 87 to deliver a metered volume of a gas through the
delivery channel 83, which gas flow interacts with the delivered
substance to modify the characteristics of the delivered substance,
and thereby provide for improved delivery to the nasal airway of
the subject.
[0427] Following actuation, the mouthpiece 79 is released and the
nosepiece 77 is withdrawn from the nasal cavity of the subject.
[0428] The loading member 103 of the driving unit 95 is then
returned to the inoperative position, and the drive member 97 of
the driving unit 95 is returned to the rest position by the return
biasing element 99. The return of the drive member 97 to the rest
position causes the body of the substance supply unit 85 and the
piston 91 of the gas supply unit 87 to be returned to the rest
positions.
[0429] Following the return of the drive member 97 to the rest
position, the linkage assembly 107 again adopts the locking
configuration, with the linkage assembly 107 being maintained in
the locking configuration by the linkage biasing element 112. In
this configuration, the delivery device is ready for further
use.
[0430] FIGS. 51 to 56 illustrate an exhalation breath-actuated
nasal delivery device in accordance with an eleventh embodiment of
the present invention.
[0431] The delivery device of this embodiment is very similar to
the delivery device of the above-described tenth 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.
[0432] The delivery device of this embodiment differs from that of
the above-described tenth embodiment only in the configuration of
the driving unit 95.
[0433] In this embodiment the drive member 97 of the drive unit 95
is not configured to commence actuation of the substance supply
unit 85 and the gas supply unit 87 at the same instant as in the
above-described tenth embodiment, but rather is configured such
that actuation of the gas supply unit 87 is commenced prior to the
actuation of the substance supply unit 85, whereby an interacting
gas flow is delivered from the delivery channel 83 of the outlet
unit 81 prior to the delivery of substance from the nozzle 82 and
then during the delivery of substance from the nozzle 82 such as to
interact with the same.
[0434] In this embodiment the delayed actuation of the substance
supply unit 85 is achieved by configuring the drive member 97 such
as to be spaced from the body of the substance supply unit 85 when
the drive member 97 is in the rest position, whereby the drive
member 97 has to be advanced a predetermined distance,
corresponding to a predetermined time period, prior to common
actuation of the substance supply unit 85 and the gas supply unit
87. In this embodiment the substance supply unit 85 includes a
biasing element 119 for returning the substance supply unit 85 to
the rest position following actuation. With this configuration, the
interval between actuation of the gas supply unit 87 and the common
actuation of the substance supply unit 85 and the gas supply unit
87 can be controlled by altering the spacing between the drive
member 97 and the body of the substance supply unit 85.
[0435] Operation of the delivery device is the same as for the
above-described tenth embodiment.
[0436] FIGS. 57 to 62 illustrate an exhalation breath-actuated
nasal delivery device in accordance with a twelfth embodiment of
the present invention.
[0437] The delivery device of this embodiment is very similar to
the delivery device of the above-described tenth 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.
[0438] The delivery device of this embodiment differs from that of
the above-described tenth embodiment only in the configuration of
the outlet unit 81 and in the integration of the substance supply
unit 85 and the gas delivery unit 87.
[0439] In this embodiment the outlet unit 81 includes a second
delivery channel 120, here an annular channel which is disposed
co-axially about the nozzle 82, through which an air flow from an
exhalation breath of a subject is delivered, such as to entrain
with the substance delivered from the nozzle 82. In this embodiment
the second delivery channel 120 is fluidly connected to the
mouthpiece 79 downstream of the trigger mechanism, and the
mouthpiece 79 includes a pressure-release valve which allows for
the development of a flow above the release pressure of the
pressure-release valve where a flow, or at least not a sufficient
flow, cannot be developed through the nasal airway of the
subject.
[0440] In this embodiment the substance supply unit 85 comprises a
piston unit which is disposed within the chamber 93 of the gas
supply unit 87. The substance supply unit 85 comprises a cylinder
121 which defines a chamber 122 and into one, forward end of which
a hollow needle 123 extends as an extension of the nozzle 82. The
substance supply unit 85 further comprises first and second pistons
124, 125 which contain a volume of substance therebetween and are
movably disposed within the chamber 122.
[0441] With this configuration, the forward, piston 125 is driven
forwardly on the rear, piston 124 being driven-forwardly, the
substance contained between the pistons 124, 125 being
substantially incompressible. The forward piston 125 is a
puncturable member which is punctured by the needle 123 of the
nozzle 82 on being driven onto the same, with the needle 123 of the
nozzle 82 being in fluid communication with the substance contained
between the pistons 124, 125 on puncturing the forward piston
125.
[0442] In this embodiment the forward piston 125 of the substance
supply unit 85 is spaced from the needle 123 of the nozzle 82 by a
predetermined distance such that the piston 91 of the gas supply
unit 87, which drives the rear piston 124 of the substance supply
unit 85, is required to be driven a predetermined distance before
the forward piston 125 of the substance supply unit 85 is ruptured
and substance is delivered through the nozzle 82. In this way,
actuation of the gas supply unit 87 is initiated prior to the
actuation of the substance supply unit 85, whereby an interacting
gas flow is delivered from the delivery channel 83 of the outlet
unit 81 prior to the delivery of substance from the nozzle 82 and
then during the delivery of substance from the nozzle 82 such as to
interact with the same. In this embodiment the interval between
actuation of the gas supply unit 87 and the common actuation of the
substance supply unit 85 and the gas supply unit 87 can be
controlled by altering the spacing between the forward piston 125
of the substance supply unit 85 and the needle 123 of the nozzle
82.
[0443] Operation of the delivery device is the same as for the
above-described tenth embodiment.
[0444] 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.
[0445] In particular, it should be understood that features of any
of the embodiments could be incorporated in any other of the
embodiments. For example, the second and third embodiments could
incorporate features of the first embodiment, in particular the at
least one expandable cuff member 23 as in the first embodiment.
[0446] Also, in embodiments where an entraining gas flow is not
required through the nasal airways of subjects, ones of the
embodiments could be modified to include no such gas flow. For
example, the first-described embodiment could be modified such that
the outlet unit 21 includes only the nozzle 23 and no delivery
channel 23.
[0447] In the described embodiments the mouthpieces are configured
to be gripped in the lips of a subject. In alternative embodiments
the mouthpieces could be configured to be gripped by the teeth of a
subject and sealed by the lips of the subject. In preferred
embodiments the mouthpieces could be specifically configured to
have one or both of a shape or geometry which allows the delivery
devices to be gripped repeatedly in the same position, thereby
providing for the respective nosepieces to be reliably inserted in
the same position in the nasal cavity.
[0448] In preferred embodiments the delivery devices are configured
to deliver substance through one nostril of a subject at such a
pressure as to flow around the posterior margin of the nasal septum
and out of the other nostril of the subject, thereby achieving
bi-directional delivery through the nasal cavities as disclosed in
WO-A-00/51672. In alternative embodiments the delivery device could
be configured to deliver substance at a reduced pressure which is
not sufficient to achieve bi-directional delivery through the nasal
cavities. Such embodiments are still advantageous as compared to
known delivery devices in providing for velum closure and being
capable of achieving targeted delivery, particularly when certain
regions of the nasal cavity are obstructed by cuff members.
[0449] Also, in another modification, the delivery devices could
include two nosepiece, in one embodiment configured for the
simultaneous delivery to each of the nasal cavities. Such
embodiments would advantageously provide for three-point fixation
of the delivery devices via the nosepieces and the mouthpieces.
* * * * *