U.S. patent application number 14/689245 was filed with the patent office on 2015-08-06 for implantable devices and methods for delivering drugs and other substances to treat sinusitis and other disorders.
The applicant listed for this patent is Acclarent, Inc.. Invention is credited to John Y. Chang, Joshua Makower, Julia D. Vrany, Amrish Jayprakash Walke.
Application Number | 20150217097 14/689245 |
Document ID | / |
Family ID | 35907961 |
Filed Date | 2015-08-06 |
United States Patent
Application |
20150217097 |
Kind Code |
A1 |
Makower; Joshua ; et
al. |
August 6, 2015 |
IMPLANTABLE DEVICES AND METHODS FOR DELIVERING DRUGS AND OTHER
SUBSTANCES TO TREAT SINUSITIS AND OTHER DISORDERS
Abstract
Implantable devices and methods for delivering drugs and other
substances to locations within the body of a human or animal
subject to treat or diagnose sinusitis and a variety of other
disorders. The invention includes implantable substance delivery
devices that comprise reservoirs and barriers that control the rate
at which substances pass out of the reservoirs. The delivery
devices may be advanced into the body using guidewires, catheters,
ports, introducers and other access apparatus. In some embodiments
the delivery devices may be loaded with one or more desired
substance before their introduction into the body. In other
embodiments the delivery devices are loaded and/or reloaded with a
desired substance after the delivery device has been introduced
into the body.
Inventors: |
Makower; Joshua; (Los Altos,
CA) ; Chang; John Y.; (Los Altos, CA) ; Vrany;
Julia D.; (Los Altos, CA) ; Walke; Amrish
Jayprakash; (Milpitas, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Acclarent, Inc. |
Menlo Park |
CA |
US |
|
|
Family ID: |
35907961 |
Appl. No.: |
14/689245 |
Filed: |
April 17, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12553887 |
Sep 3, 2009 |
7939230 |
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14689245 |
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12107005 |
Apr 21, 2008 |
9039680 |
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12553887 |
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10912578 |
Aug 4, 2004 |
7361168 |
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12107005 |
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Current U.S.
Class: |
604/514 |
Current CPC
Class: |
G03G 5/0539 20130101;
A61B 17/320725 20130101; A61B 17/24 20130101; A61B 17/3478
20130101; A61B 5/06 20130101; A61M 2025/0037 20130101; G03G 5/0564
20130101; A61B 17/320783 20130101; A61B 17/320758 20130101; A61F
2/82 20130101; G03G 5/0535 20130101; A61M 31/005 20130101; G03G
5/14726 20130101; G03G 5/0696 20130101; A61M 25/0029 20130101; A61M
31/007 20130101; A61B 5/411 20130101; A61F 2/18 20130101; G03G
5/14791 20130101; A61F 2250/0039 20130101; A61M 25/10 20130101;
A61M 2025/105 20130101; A61M 2210/0681 20130101; A61M 31/002
20130101; A61B 5/064 20130101; A61M 2025/1052 20130101; A61M 25/007
20130101; A61F 2002/825 20130101; A61B 34/20 20160201; G03G 5/056
20130101; A61B 2017/22061 20130101; G03G 5/0614 20130101 |
International
Class: |
A61M 31/00 20060101
A61M031/00; A61M 25/10 20060101 A61M025/10 |
Claims
1. A method for delivering a diagnostic or therapeutic substance
into a paranasal sinus or paranasal sinus ostium of a human or
animal subject, said method comprising: advancing a substance
delivery device into a paranasal sinus or paranasal sinus ostium,
wherein the substance delivery device comprises: an expandable
reservoir having a collapsed configuration during advancement into
the paranasal sinus or paranasal sinus ostium, said reservoir being
thereafter expandable to an expanded configuration; a tube
extending from said reservoir, said tube having a lumen through
which the substance may be introduced into the reservoir; and a
barrier through which the substance passes from the reservoir,
thereby causing the substance to be delivered into the paranasal
sinus or paranasal sinus ostium; introducing a substance through
the tube and into the reservoir, thereby causing the reservoir to
assume the expanded configuration; and delivering the substance out
of the reservoir into the paranasal sinus or paranasal sinus ostium
by leaving the device implanted within the paranasal sinus or
paranasal sinus ostium for a period of time such that the substance
passes through the barrier.
2. A method as in claim 1, wherein the substance delivery device
further comprises a closure apparatus for preventing the substance
from backflowing out of the tube after the substance has been
introduced into the reservoir.
3. A method as in claim 2, wherein the closure apparatus comprises
apparatus for clamping, clipping, ligating, tying or compressing
the tube after the substance has been introduced into the
reservoir.
4. A method as in claim 1, wherein the reservoir comprises a cavity
into which the substance is introduced.
5. A method as in claim 4, wherein at least a portion of said
reservoir comprises a porous material that becomes laden with the
substance.
6. A method as in claim 5, wherein the porous material is selected
from the group consisting of: a sponge flexible polymer foams;
biodegradable polymer foams; non-biodegradable polymer foams;
porous PLLA; porous PLGA; porous hydrogel; polyvinyl alcohols;
silicone foams; polytetrafluoroethylene; expanded
polytetraflurorethylene; latex; and nylon.
7. A method as in claim 4, further comprising a porous material
disposed in the reservoir which will hold the substance.
8. A method as in claim 1, further comprising cutting away a
portion of the tube so that the tube does not protrude outside of
the subject's nose.
9. A method as in claim 1, further comprising removing the
substance delivery device.
10. A method as in claim 9, wherein removing the substance delivery
device comprises grasping and pulling a graspable member of the
substance delivery device.
11. A method as in claim 1, wherein the device is configured such
that, when in the expanded configuration, it includes at least one
flow channel through which mucus or other biological fluid may
drain, and wherein the device is advanced to a location such that
mucus or other biological fluid drains through said at least one
flow channel while the device is implanted.
12. A method as in claim 1, wherein the substance delivery device
further comprises: an intraostial portion including at least one
indentation for receiving at least a portion of tissue forming a
paranasal sinus ostium when the reservoir is in its expanded
configuration; and an intrasinus portion that resides within a
paranasal sinus when the intraostial portion resides within the
paranasal sinus ostium.
13. A method as in claim 1, wherein advancing the substance
delivery device comprises pushing the substance delivery device out
of a distal end of a catheter using a pusher member disposed within
the catheter.
Description
RELATED APPLICATION
[0001] This is a continuation of copending U.S. patent application
Ser. No. 12/107,005 filed Apr. 12, 2008 which is a division of Ser.
No. 10/912,578 filed Aug. 4, 2004 now issued as U.S. Pat. No.
7,361,168, the entire disclosures of which are expressly
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates generally to medical devices
and methods and more particularly to substance delivering implants
and methods for treating a broad range of disorders including but
not limited to sinusitis and other ear, nose and throat
disorders.
BACKGROUND
[0003] The paranasal sinuses are cavities formed within the bones
of the face. The paranasal sinuses include frontal sinuses, ethmoid
sinuses, sphenoidal sinuses and maxillary sinuses. The paranasal
sinuses are lined with mucous-producing epithelial tissue.
Normally, mucous produced by the linings of the paranasal sinuses
slowly drains out of each sinus through an opening known as an
ostium, and into the nasopharnyx. Disorders that interfere with
drainage of mucous (e.g., occlusion of the sinus ostia) can result
in a reduced ability of the paranasal sinuses to function normally.
This results in mucosal congestion within the paranasal sinuses.
Such mucosal congestion of the sinuses can cause damage to the
epithelium that lines the sinus with subsequent decreased oxygen
tension and microbial growth (e.g., a sinus infection).
[0004] The nasal turbinates are three (or sometimes four) bony
processes that extend inwardly from the lateral walls of the nose
and are covered with mucosal tissue. These turbinates serve to
increase the interior surface area of the nose and to impart warmth
and moisture to air that is inhaled through the nose. The mucosal
tissue that covers the turbinates is capable of becoming engorged
with blood and swelling or becoming substantially devoid of blood
and shrinking, in response to changes in physiologic or
environmental conditions. The curved edge of each turbinate defines
a passageway known as a meatus. For example, the inferior meatus is
a passageway that passes beneath the inferior turbinate. Ducts,
known as the nasolacrimal ducts, drain tears from the eyes into the
nose through openings located within the inferior meatus. The
middle meatus is a passageway that extends inferior to the middle
turbinate. The middle meatus contains the semilunar hiatus, with
openings or ostia leading into the maxillary, frontal, and anterior
ethmoid sinuses. The superior meatus is located between the
superior and medial turbinates.
[0005] Nasal polyps are benign masses that grow from the lining of
the nose or paranasal sinuses. Nasal polyps often result from
chronic allergic rhinitis or other chronic inflammation of the
nasal mucosa. Nasal polyps are also common in children who suffer
from cystic fibrosis. In cases where nasal polyps develop to a
point where they obstruct normal drainage from the paranasal
sinuses, they can cause sinusitis.
[0006] The term "sinusitis" refers generally to any inflammation or
infection of the paranasal sinuses. Sinusitis can be caused by
bacteria, viruses, fungi (molds), allergies or combinations
thereof.
[0007] Various drugs have been used to treat sinusitis, including
systemic antibiotics. Intranasal corticosteroid sprays and
intranasal decongestant sprays and drops have also been used.
However, the use of intranasal sprays and drops by most patients
does not result in the drug actually entering the affected
intranasal sinuses. Rather, such sprays and drops typically contact
only tissues located within the nasal cavity. The introduction of
drugs directly into the sinuses has been proposed by others, but
has not become a widely used treatment technique.
[0008] For example, U.S. Patent Application Publication
2004/0116958A1 (Gopferich et al.) describes a tubular sheath or
"spacer" formed of biodegradable or non-biodegradable polymer that,
prior to insertion in the patient's body, is loaded with a
controlled amount of an active substance, such as a corticosteroid
or anti-proliferative agent. Surgery is performed to create a
fenestration in a frontal sinus and the sheath is inserted into
such fenestration. Thereafter, the sheath which has been preloaded
with the active substance is inserted into the surgically created
fenestration where it a) deters closure of the surgically created
fenestration, b) serves as a conduit to facilitate drainage from
the sinus and d) delivers the active substance. The sheath of U.S.
Patent Application Publication 2004/0116958A1 (Gopferich et al.)
remains substantially in a single configuration (i.e., it does not
transition between a collapsed configuration and an expanded
configuration) although it may be coated with a material that
swells when in contact with mucous or body fluid. In some
embodiments, the sheath is formed of multiple layers of polymeric
material, one or more of which is/are loaded with the active
substance and one or more of which is/are free of the active
substance. In other embodiments, the sheath has a "hollow body"
which forms a reservoir system wherein the active substance is
contained and a membrane which controls the release of the active
substance from the reservoir. In some embodiments, the sheath may
be anchored by causing the end of the sheath that extends into the
sinus to swell or otherwise enlarge.
[0009] Also, Min, Yang-Gi, et al., Mucociliary Activity and
Histopathology of Sinus Mucosa in Experimental Maxilary Sinusitis:
A Comparison of Systemic Administration of Antibiotic and
Antibiotic Delivery by Polylactic Acid Polymer, Laryngoscope,
105:835-842 (August 1995) describes experiments wherein
experimental sinusitis was induced in three groups of rabbits by
"pasting" the natural sinus ostia, forming an incision and small
bore hole made in the anterior wall of the sinus, introducing
pathogenic microbes through the bore hole and then closing the
incision. Five days after introduction of the pathogenic microbes,
the natural sinus ostia were reopened and the rabbits were divided
into three (3) groups. Group 1 (control) received no treatment.
Group 2 received repeated intramuscular injections of ampicillin.
In the animals of Group 3, 1.5 cm.times.1.5 cm sheets of polylactic
acid polymer (PLA) film containing ampicillin (0.326 mg/sheet) were
rolled up and inserted through the natural ostia into the infected
sinuses. Thereafter, measurements of mucocilliary transport speed
were made and the tissues lining the affected sinuses were examined
histopathologically. The authors concluded that the therapeutic
effect observed in the animals that had received intrasinus
implants of PLA/Ampicillin film (Group 3) was significantly better
that that observed in the untreated control animals (Group1) or
those that has received repeated intramuscular doses of ampicillin
(Group 2).
[0010] U.S. Pat. No. 3,948,254 (Zaffaroni) describes implantable
drug delivery devices comprising a drug reservoir surrounded by a
microporous wall. The reservoir may be formed of a solid drug
carrier that is permeable to passage of the drug. The rate of
passage of the drug through the wall may be slower than the rate at
which the drug passes through the solid drug carrier that forms the
reservoir. U.S. Pat. No. 3,948,254 (Zaffaroni) describes a number
of applications for the implantable drug delivery devices including
placement in a nasal passage. Specifically, U.S. Pat. No. 3,948,254
(Zaffaroni) claimed a nasal delivery device for dispensing a drug
within a nasal passage at a controlled rate wherein the nasal
device is comprised of (a) a wall defining the device dimensioned
for insertion and placement within a nasal passage, with the wall
formed of a nasal acceptable microporous material, (b) a reservoir
surrounded by the wall and comprised of a solid carrier permeable
to drug and containing drug in an amount sufficient for the device
to meter it at a continuous and controlled rate for a prolonged
period of time from the device, (c) a liquid medium permeable to
the passage of drug by diffusion charged in the micropores, and (d)
wherein the device releases drug when in a nasal environment by
passage of drug from the carrier and through the liquid to the
exterior of the device to produce a useful result. The entire
disclosure of U.S. Pat. No. 3,948,254 (Zaffaroni) is expressly
incorporated herein by reference.
[0011] Other publications have also reported that introduction of
drugs directly into the paranasal sinuses is effective in the
treatment of sinusitis. See, Tarasov, D. I., et al., Application of
Drugs Based on Polymers in the Treatment of Acute and Chronic
Maxillary Sinusitis, Vestn Otorinolaringol. Vol. 6, Pages 45-7
(1978). Also, R. Deutschmann, et al., A Contribution to the Topical
Treatment of [Maxillary] Sinusitis Preliminary Communication,
Stomat. DDR 2.6 (1976), 585-592 describes the placement of a
resorbable drug delivery depot within the maxillary sinus for the
purposes of eluting drugs, specifically Chloramphenicol. In this
clinical series a water soluble gelatin was used as carrier and was
mixed with the drug prior to application and introduced as a mass
into the sinus. Since the substance had little mechanical integrity
and dissolved in a relatively short timeframe, to achieve a
therapeutic effect, the author suggested that it must be instilled
every 2 to 3 days. An alternative to gelatin could be a sponge
loaded with the therapeutic substance as suggested in U.S. Pat. No.
6,398,758 (Jacobsen, et al.). In this patent directed at delivering
a sustained release device against the wall of a blood vessel, a
hollow cylindrical sponge is loaded with drug and pressed against
the wall. This allows the drug to contact the wall while sustaining
blood flow within the center of the lumen. Further, a skin is
provided to direct the drug into the walls of the blood vessel and
prevent drug from flowing into the lumen. While sponges loaded with
drug at the time of their application do permit some degree of
sustained release, the time required to load them also correlates
closely the time over which they will elute substance. Thus, if
delivery is required for a longer period of time additional
mechanisms must be employed to regulate their release.
[0012] There are also several examples in the patent literature
where various sustained release mechanisms have generally been
proposed using systems with pre-incorporated drugs into matrices or
polymers. These include U.S. Pat. No. 3,948,254 (Zafferoni), US
2003/0185872A2 (Kochinke), WO 92/15286 (Shikani), and U.S. Pat. No.
5,512,055 (Domb, et al.). In general, these references discuss
various materials and structures that may be used to construct
sustained drug delivery vehicles and provide a good overview of the
state of sustained drug delivery art. While helpful in laying out
certain materials and schemes for creating sustained release
systems for drugs, each of these references, however, do not
describe specific methods, means or structures which would permit
them to be easily adapted for intended uses in the targeted in this
application.
[0013] There remains a need in the art for the development of new
devices and methods for delivering drugs and other therapeutic or
diagnostic substances into paranasal sinuses or other locations
within the body for the treatment of sinusitis or other diseases
and disorders.
SUMMARY OF THE INVENTION
[0014] In accordance with the present invention, there is provided
a method and device for delivering a substance to a location within
the body of a human or animal subject (e.g., within the nose,
paranasal sinus, ostium of a paranasal sinus, eustachian tube,
etc.) to diagnose or treat a disorder (e.g., sinusitis or another
disorder of the ear, nose or throat). In general, this method
comprises the steps of: A) providing an implantable substance
delivery device that comprises i) a substance reservoir that may
subsequently be loaded with a substance that is therapeutically
effective to diagnose or treat the disorder and ii) a barrier that
will limit the rate at which a substance will flow out of the
reservoir; B) providing a substance that is useable to diagnose or
treat the disorder; C) introducing a quantity of the substance into
the reservoir; and D) implanting the device at a location within
the subject's body such that the substance will be delivered by the
implanted device to a location within the subject's body. In some
applications, the physician may load a desired therapeutic or
diagnostic substance into the reservoir before the device is
implanted in the subject's body. In other applications, the
physician may load a desired therapeutic or diagnostic substance
into the reservoir after the device has been implanted in the
subject's body. The device may be biodegradable or
non-biodegradable and may or may not be removed from the body after
it has remained implanted for a desired period of time. The barrier
of the device may comprise an aperture, membrane (e.g.,
semi-permeable membrane) or other structure that allows one or more
substances having certain key property or properties to pass
through the barrier at approximately a known rate. Examples of the
key properties that may determine a substance's ability to pass
through the barrier at approximately the known rate include but are
not limited to viscosity or a range of viscosities, molecular
weight or range or molecular weights, osmolarity or range of
osmolarities, osmolality or range of osmolalities, electrical
charge, presence of a chemical group or atom, hydrophilic or
hydrophibic properties, the size and/or shape of molecules, etc.
Thus, a physician and/or pharmacist may, in some cases, select a
barrier and select or specially formulate a substance that possess
a particular key property relative to the selected barrier, such
that the substance will be delivered through the barrier at an
intended delivery rate.
[0015] Further in accordance with the invention the reservoir of
the device may comprise a hollow cavity, porous material (e.g., an
absorptive polymer foam) or combination thereof. The barrier may
comprise a membrane or opening that surrounds, substantially
surrounds, partially surrounds or is located next to the reservoir
such that substance contained within the reservoir will pass
through the barrier at a controlled rate.
[0016] Still further in accordance with the invention, the
implantable substance delivery device may be configured such that,
at least when the reservoir is loaded with the substance, the outer
surface of the device will have peaks and valleys such that the
peaks are in contact with adjacent tissues or other anatomical
structure(s) and the valleys remain spaced away from adjacent
tissues or other anatomical structures so as not to interfere with
the physiological function of those tissues or other anatomical
structures. Such embodiments of the device may be implanted in
areas of the nose or paranasal sinuses lined with ciliated mucosal
tissue and the surface(s) of the device within the valleys will
remain far enough away from the adjacent ciliated mucosa as to not
interfere with mucociliary transport by such tissue. The diameter
or cross-sectional configuration of the device may vary along its
length or may be shaped in a conical, frustoconical or curvilinear
(e.g., hourglass) shape. Also, the device may have region(s) of
differing hardness (e.g., durometer), flexural properties (e.g.,
stiffness or flexibility) or compliance and such properties may
change in response to the presence or absence of the therapeutic or
diagnostic substance and/or contact or non-contact with body fluids
(e.g., mucous) or other conditions present at the intended site of
implantation.
[0017] Further aspects, details and embodiments of the present
invention will be understood by those of skill in the art upon
reading the following detailed description of the invention and the
accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1 is a schematic cut-away showing of a human head
having a catheter-based substance delivery system of the present
invention inserted therein to deliver a substance delivery implant
into the left frontal sinus.
[0019] FIG. 2 is a longitudinal sectional view of one embodiment of
an implantable substance delivery device of the present invention
having a generally round cross-sectional configuration and a
self-sealing fill site.
[0020] FIG. 2A is a longitudinal sectional view of the device of
FIG. 2 as it is being filled with a substance.
[0021] FIG. 2B is a longitudinal sectional view of another
embodiment of an implantable substance delivery device of the
present invention having a fill tube that extends from its fill
site.
[0022] FIG. 2C is a sectional view of a paranasal sinus having an
implantable substance delivery device of the present invention
implanted therein.
[0023] FIG. 3 is a perspective view of another embodiment of an
implantable substance delivery device of the present invention
having a cross-sectional configuration that provides discrete
projections that contact the surrounding anatomical structure(s)
while space remains between the remainder of the device and the
surrounding anatomical structure(s).
[0024] FIG. 3A is a cross sectional view through line 3A-3A of FIG.
3.
[0025] FIG. 4 is a perspective view of another embodiment of an
implantable substance delivery device of the present invention
having a frame, a porous core, an outer barrier layer and a
cross-sectional configuration that provides for discrete areas of
contact between the implanted substance delivery device and the
surrounding anatomical structure(s).
[0026] FIG. 4A is an end view of the device of FIG. 4.
[0027] FIG. 4B is a partial cross sectional view of an implantable
substance delivery device having a frame, a porous core and an
outer barrier layer, wherein the porous core is disposed within the
frame and the barrier layer is subsequently applied over the
frame.
[0028] FIG. 4C is a partial cross sectional view of an implantable
substance delivery device having a frame, a porous core and an
outer barrier layer, wherein the frame is integral of the porous
core and the barrier layer is disposed on the outer surface of the
porous core.
[0029] FIG. 5 is a perspective view of a screw-shaped substance
delivery device of the present invention positioned within an
anatomical passageway.
[0030] FIG. 5A is a cross sectional view through line 5A-5A of FIG.
5.
[0031] FIG. 6A is a perspective view of a helical substance
delivery device of the present invention positioned within an
anatomical passageway.
[0032] FIG. 6B is a perspective view of another embodiment of a
substance delivery device of the present invention comprising a
plurality of substantially parallel substance eluting strut
members.
[0033] FIG. 6C is a schematic diagram showing the device of FIG. 6B
implanted within a paranasal sinus.
[0034] FIG. 6D is a schematic diagram showing a modified version of
the device of FIG. 6B implanted within a paranasal sinus.
[0035] FIG. 7 is a side view of a substance delivery device of the
present invention that is configured for implantation and retention
within a paranasal sinus.
[0036] FIG. 7A shows the substance delivery device of FIG. 7 after
it has been positioned within a paranasal sinus but before being
loaded with therapeutic or diagnostic substance.
[0037] FIG. 7B shows the substance delivery device of FIG. 7 after
it has been positioned within a paranasal sinus and after it has
been loaded with therapeutic or diagnostic substance.
[0038] FIG. 8A shows a fill tube for a substance delivery implant
device of the present invention having a fill tube with a valve for
preventing the substance from back-flowing out of the fill
tube.
[0039] FIG. 8B shows a substance delivery implant device of the
present invention having a fill tube with a clip for preventing the
substance from back-flowing out of the fill tube.
[0040] FIG. 8C shows a substance delivery implant device of the
present invention having a fill tube with a ligature for preventing
the substance from back-flowing out of the fill tube.
[0041] FIG. 8D shows a substance delivery implant device of the
present invention having a fill port with an adhesive applicator
for applying adhesive to plug the fill port thereby preventing the
substance from back-flowing out of the fill port.
[0042] FIG. 8E shows a substance delivery implant device of the
present invention having a fill tube that is doubled over and
clipped to prevent the substance from back-flowing out of the fill
tube.
[0043] FIG. 9 is a longitudinal sectional view of another
embodiment of an implantable substance delivery device according to
the present invention.
[0044] FIG. 9A is a perspective view of a system comprising the
implantable substance delivery device of FIG. 9 in combination with
a delivery catheter device that is useable for implantation of the
implantable substance delivery device within the body of a human or
animal subject.
[0045] FIG. 9B shows the system of FIG. 9A after the delivery
catheter device has been detached from the implanted substance
delivery device.
[0046] FIG. 10A is an exploded view of a system for delivery and
implantation of a substance eluting filament in accordance with the
present invention.
[0047] FIG. 10B is a schematic diagram showing an example of a
method by which the system of FIG. 10A may be used to implant the
substance eluting filament within a paranasal sinus.
[0048] FIG. 11A is a cut-away side view of a catheter system having
a second lumen that is useable for implanting an implantable
substance delivery device or drug eluting filament by tracking over
a previously inserted guidewire.
[0049] FIG. 11B is a cut-away side view of a catheter system
adapted for over-the-wire delivery of an implantable substance
delivery device or drug eluting filament that has a guidewire lumen
extending longitudinally therethrough.
[0050] FIGS. 12A-12F schematic diagrams showing steps in a
procedure for a) access to and enlargement of the ostium of a
paranasal sinus and b) implantation of an implantable substance
delivery device of the present invention within the enlarged ostium
and paranasal sinus.
DETAILED DESCRIPTION
[0051] The following detailed description and the accompanying
drawings are intended to describe some, but not necessarily all,
examples or embodiments of the invention only. This detailed
description and the accompanying drawings do not limit the scope of
the invention in any way.
[0052] The human nose has right and left nostrils or nares which
lead into separate right and left nasal cavities. The right and
left nasal cavities are separated by the intranasal septum, which
is formed substantially of cartilage and bone. Posterior to the
intranasal septum, the nasal cavities converge into a single
nasopharyngeal cavity. The right and left Eustachian tubes (i.e.,
auditory tubes) extend from the middle ear on each side of the head
to openings located on the lateral aspects of the nasopharynx. The
nasopharynx extends inferiorly over the uvula and into the pharynx.
As shown in FIG. 1, paranasal sinuses are formed in the facial
bones on either side of the face. The paranasal sinuses open,
through individual openings or ostia, into the nasal cavities. The
paranasal sinuses include frontal sinuses FS, ethmoid sinuses ES,
sphenoidal sinuses SS and maxillary sinuses MS.
[0053] The present invention provides implantable devices that may
be positioned within a naturally occurring or man-made anatomical
cavity or passageway such as a nostril, nasal cavity, meatus,
ostium, interior of a sinus, etc. to deliver a diagnostic or
therapeutic substance to tissues located adjacent to or near the
implanted device. Certain non-limiting examples of the present
invention are shown in FIGS. 1-12F and described in detail
herebelow. Although certain examples shown in these drawings are
targeted to the paranasal sinuses and nasal cavities, the devices
and methods of the present invention are useable in a wide range of
applications in various area of the body, including but not limited
to natural or man made orifices and passageways, subcutaneous
locations, intravascular or intracardiac locations and locations
within the gastrointestinal tract.
[0054] The term "diagnostic or therapeutic substance" as used
herein is to be broadly construed to include any feasible drugs,
prodrugs, proteins, gene therapy preparations, cells, diagnostic
agents, contrast or imaging agents, biologicals, etc. Such
substances may be in bound or free form, liquid or solid, colloid
or other suspension, solution or may be in the form of a gas or
other fluid or nan-fluid. For example, in some applications where
it is desired to treat or prevent a microbial infection, the
substance delivered may comprise pharmaceutically acceptable salt
or dosage form of an antimicrobial agent (e.g., antibiotic,
antiviral, antiparacytic, antifungal, etc.), a corticosteroid or
other anti-inflammatory (e.g., an NSAID), a decongestant (e.g.,
vasoconstrictor), a mucous thinning agent (e.g., an expectorant or
mucolytic), an agent that prevents of modifies an allergic response
(e.g., an antihistamine, cytokine inhibitor, leucotriene inhibitor,
IgE inhibitor, immunomodulator), etc.
[0055] Some nonlimiting examples of antimicrobial agents that may
be used in this invention include acyclovir, amantadine,
aminoglycosides (e.g., amikacin, gentamicin and tobramycin),
amoxicillin, amoxicillin/clavulanate, amphotericin B, ampicillin,
ampicillin/sulbactam, atovaquone, azithromycin, cefazolin,
cefepime, cefotaxime, cefotetan, cefpodoxime, ceftazidime,
ceftizoxime, ceftriaxone, cefuroxime, cefuroxime axetil,
cephalexin, chloramphenicol, clotrimazole, ciprofloxacin,
clarithromycin, clindamycin, dapsone, dicloxacillin, doxycycline,
erythromycin, fluconazole, foscarnet, ganciclovir, atifloxacin,
imipenem/cilastatin, isoniazid, itraconazole, ketoconazole,
metronidazole, nafcillin, nafcillin, nystatin, penicillin,
penicillin G, pentamidine, piperacillin/tazobactam, rifampin,
quinupristin-dalfopristin, ticarcillin/clavulanate,
trimethoprim/sulfamethoxazole, valacyclovir, vancomycin, mafenide,
silver sulfadiazine, mupirocin (e.g., Bactroban Nasal.RTM., Glaxo
SmithKline, Research Triangle Park, N.C.), nystatin,
triamcinolone/nystatin, clotrimazole/betamethasone, clotrimazole,
ketoconazole, butoconazole, miconazole, tioconazole, detergent-like
chemicals that disrupt or disable microbes (e.g., nonoxynol-9,
octoxynol-9, benzalkonium chloride, menfegol, and N-docasanol);
chemicals that block microbial attachment to target cells and/or
inhibits entry of infectious pathogens (e.g., sulphated and
sulponated polymers such as PC-515 (carrageenan), Pro-2000, and
Dextrin 2 Sulphate); antiretroviral agents (e.g., PMPA gel) that
prevent retroviruses from replicating in the cells; genetically
engineered or naturally occurring antibodies that combat pathogens
such as anti-viral antibodies genetically engineered from plants
known as "plantibodies;" agents which change the condition of the
tissue to make it hostile to the pathogen (such as substances which
alter mucosal pH (e.g., Buffer Gel and Acidform); non-pathogenic or
"friendly" microbes that cause the production of hydrogen peroxide
or other substances that kill or inhibit the growth of pathogenic
microbes (e.g., lactobacillus); antimicrobial proteins or peptides
such as those described in U.S. Pat. No. 6,716,813 (Lin et al,.)
which is expressly incorporated herein by reference or
antimicrobial metals (e.g., colloidal silver).
[0056] Additionally or alternatively, in some applications where it
is desired to treat or prevent inflammation the substances
delivered in this invention may include various steroids or other
anti-inflammatory agents (e.g., nonsteroidal anti-inflammatory
agents or NSAIDS), analgesic agents or antipyretic agents. For
example, corticosteroids that have previously administered by
intranasal administration may be used, such as beclomethasone
(Vancenase.RTM. or Beconase.RTM.), flunisolide (Nasalide.RTM.),
fluticasone proprionate (Flonase.RTM.), triamcinolone acetonide
(Nasacort.RTM.), budesonide (Rhinocort Aqua.RTM.), loterednol
etabonate (Locort) and mometasone (Nasonex.RTM.). Other salt forms
of the aforementioned corticosteroids may also be used. Also, other
non-limiting examples of steroids that may be useable in the
present invention include but are not limited to aclometasone,
desonide, hydrocortisone, betamethasone, clocortolone,
desoximetasone, fluocinolone, flurandrenolide, mometasone,
prednicarbate; amcinonide, desoximetasone, diflorasone,
fluocinolone, fluocinonide, halcinonide, clobetasol, augmented
betamethasone, diflorasone, halobetasol, prednisone, dexamethasone
and methylprednisolone. Other anti-inflammatory, analgesic or
antipyretic agents that may be used include the nonselective COX
inhibitors (e.g., salicylic acid derivatives, aspirin, sodium
salicylate, choline magnesium trisalicylate, salsalate, diflunisal,
sulfasalazine and olsalazine; para-aminophenol derivatives such as
acetaminophen; indole and indene acetic acids such as indomethacin
and sulindac; heteroaryl acetic acids such as tolmetin, dicofenac
and ketorolac; arylpropionic acids such as ibuprofen, naproxen,
flurbiprofen, ketoprofen, fenoprofen and oxaprozin; anthranilic
acids (fenamates) such as mefenamic acid and meloxicam; enolic
acids such as the oxicams (piroxicam, meloxicam) and alkanones such
as nabumetone) and Selective COX-2 Inhibitors (e.g.,
diaryl-substituted furanones such as rofecoxib; diaryl-substituted
pyrazoles such as celecoxib; indole acetic acids such as etodolac
and sulfonanilides such as nimesulide)
[0057] Additionally or alternatively, in some applications, such as
those where it is desired to treat or prevent an allergic or immune
response and/or cellular proliferation, the substances delivered in
this invention may include a) various cytokine inhibitors such as
humanized anti-cytokine antibodies, anti-cytokine receptor
antibodies, recombinant (new cell resulting from genetic
recombination) antagonists, or soluble receptors; b) various
leucotriene modifiers such as zafirlukast, montelukast and
zileuton; c) immunoglobulin E (IgE) inhibitors such as Omalizumab
(an anti-IgE monoclonal antibody formerly called rhu Mab-E25) and
secretory leukocyte protease inhibitor) and d) SYK Kinase
inhibitors such as an agent designated as "R-112" manufactured by
Rigel Pharmaceuticals, Inc, or South San Francisco, Calif.
[0058] Additionally or alternatively, in some applications, such as
those where it is desired to shrink mucosal tissue, cause
decongestion or effect hemostasis, the substances delivered in this
invention may include various vasoconstrictors for decongestant and
or hemostatic purposes including but not limited to
pseudoephedrine, xylometazoline, oxymetazoline, phenylephrine,
epinephrine, etc.
[0059] Additionally or alternatively, in some applications, such as
those where it is desired to facilitate the flow of mucous, the
substances delivered in this invention may include various
mucolytics or other agents that modify the viscosity or consistency
of mucous or mucoid secretions, including but not limited to
acetylcysteine (Mucomyst.TM., Mucosil.TM.) and guaifenesin.
[0060] In one particular embodiment, the substance delivered by
this invention comprises a combination of an anti-inflammatory
agent (e.g. a steroid or an NSAID) and a mucolytic agent.
[0061] Additionally or alternatively, in some applications such as
those where it is desired to prevent or deter histamine release,
the substances delivered in this invention may include various mast
cell stabilizers or drugs which prevent the release of histamine
such as cromolyn (e.g., Nasal Chrom.RTM.) and nedocromil.
[0062] Additionally or alternatively, in some applications such as
those where it is desired to prevent or inhibit the effect of
histamine, the substances delivered in this invention may include
various antihistamines such as azelastine (e.g., Astylin.RTM.),
diphenhydramine, loratidine, etc.
[0063] Additionally or alternatively, in some embodiments such as
those where it is desired to dissolve, degrade, cut, break or
remodel bone or cartilage, the substances delivered in this
invention may include substances that weaken or modify bone and/or
cartilage to facilitate other procedures of this invention wherein
bone or cartilage is remodeled, reshaped, broken or removed. One
example of such an agent would be a calcium chelator such as EDTA
that could be injected or delivered in a substance delivery implant
next to a region of bone that is to be remodeled or modified.
Another example would be a preparation consisting of or containing
bone degrading cells such as osteoclasts. Other examples would
include various enzymes of material that may soften or break down
components of bone or cartilage such as collagenase (CGN), trypsin,
trypsin/EDTA, hyaluronidase, and tosyllysylchloromethane
(TLCM).
[0064] Additionally or alternatively, in some applications, the
substances delivered in this invention may include other classes of
substances that are used to treat rhinitis, nasal polyps, nasal
inflammation, and other disorders of the ear, nose and throat
including but not limited to anti-cholinergic agents that tend to
dry up nasal secretions such as ipratropium (Atrovent Nasal.RTM.),
as well as other agents not listed here.
[0065] Additionally or alternatively, in some applications such as
those where it is desired to draw fluid from polyps or edematous
tissue, the substances delivered in this invention may include
locally or topically acting diuretics such as furosemide and/or
hyperosmolar agents such as sodium chloride gel or other salt
preparations that draw water from tissue or substances that
directly or indirectly change the osmolar content of the mucous to
cause more water to exit the tissue to shrink the polyps directly
at their site.
[0066] Additionally or alternatively, in some applications such as
those wherein it is desired to treat a tumor or cancerous lesion,
the substances delivered in this invention may include antitumor
agents (e.g., cancer chemotherapeutic agents, biological response
modifiers, vascularization inhibitors, hormone receptor blockers,
cryotherapeutic agents or other agents that destroy or inhibit
neoplasia or tumorigenesis) such as; alkylating agents or other
agents which directly kill cancer cells by attacking their DNA
(e.g., cyclophosphamide, isophosphamide), nitrosoureas or other
agents which kill cancer cells by inhibiting changes necessary for
cellular DNA repair (e.g., carmustine (BCNU) and lomustine (CCNU)),
antimetabolites and other agents that block cancer cell growth by
interfering with certain cell functions, usually DNA synthesis
(e.g., 6 mercaptopurine and 5-fluorouracil (5FU), antitumor
antibiotics and other compounds that act by binding or
intercalating DNA and preventing RNA synthesis (e.g., doxorubicin,
daunorubicin, epirubicin, idarubicin, mitomycin-C and bleomycin)
plant (vinca) alkaloids and other anti-tumor agents derived from
plants (e.g., vincristine and vinblastine), steroid hormones,
hormone inhibitors, hormone receptor antagonists and other agents
which affect the growth of hormone-responsive cancers (e.g.,
tamoxifen, herceptin, aromatase ingibitors such as
aminoglutethimide and formestane, trriazole inhibitors such as
letrozole and anastrazole, steroidal inhibitors such as
exemestane), antiangiogenic proteins, small molecules, gene
therapies and/or other agents that inhibit angiogenesis or
vascularization of tumors (e.g., meth-1, meth-2, thalidomide),
bevacizumab (Avastin), squalamine, endostatin, angiostatin,
Angiozyme, AE-941 (Neovastat), CC-5013 (Revimid), medi-522
(Vitaxin), 2-methoxyestradiol (2ME2, Panzem), carboxyamidotriazole
(CAI), combretastatin A4 prodrug (CA4P), SU6668, SU11248,
BMS-275291, COL-3, EMD 121974, IMC-1C11, IM862, TNP-470, celecoxib
(Celebrex), rofecoxib (Vioxx), interferon alpha, interleukin-12
(IL-12) or any of the compounds identified in Science Vol. 289,
Pages 1197-1201 (Aug. 17, 2000) which is expressly incorporated
herein by reference, biological response modifiers (e.g.,
interferon, bacillus calmette-guerin (BCG), monoclonal antibodies,
interluken 2, granulocyte colony stimulating factor (GCSF), etc.),
PGDF receptor antagonists, herceptin, asparaginase, busulphan,
carboplatin, cisplatin, carmustine, cchlorambucil, cytarabine,
dacarbazine, etoposide, flucarbazine, flurouracil, gemcitabine,
hydroxyurea, ifosphamide, irinotecan, lomustine, melphalan,
mercaptopurine, methotrexate, thioguanine, thiotepa, tomudex,
topotecan, treosulfan, vinblastine, vincristine, mitoazitrone,
oxaliplatin, procarbazine, streptocin, taxol, taxotere,
analogs/congeners and derivatives of such compounds as well as
other antitumor agents not listed here.
[0067] Additionally or alternatively, in some applications such as
those where it is desired to grow new cells or to modify existing
cells, the substances delivered in this invention may include cells
(mucosal cells, fibroblasts, stem cells or genetically engineered
cells) as well as genes and gene delivery vehicles like plasmids,
adenoviral vectors or naked DNA, mRNA, etc. injected with genes
that code for anti-inflammatory substances, etc., and, as mentioned
above, osteoclasts that modify or soften bone when so desired,
cells that participate in or effect mucogenesis or ciliagenesis,
etc.
[0068] Additionally or alternatively to being combined with a
device and/or a substance releasing modality, it may be ideal to
position the device in a specific location upstream in the mucous
flow path (i.e. frontal sinus or ethmoid cells). This could allow
the deposition of fewer drug releasing devices, and permit the
"bathing" of all the downstream tissues with the desired drug. This
utilization of mucous as a carrier for the drug may be ideal,
especially since the concentrations for the drug may be highest in
regions where the mucous is retained; whereas non-diseased regions
with good mucous flow will be less affected by the drug. This could
be particularly useful in chronic sinusitis, or tumors where
bringing the concentration of drug higher at those specific sites
may have greater therapeutic benefit. In all such cases, local
delivery will permit these drugs to have much less systemic impact.
Further, it may be ideal to configure the composition of the drug
or delivery system such that it maintains a loose affinity to the
mucous permitting it to distribute evenly in the flow. Also, in
some applications, rather than a drug, a solute such as a salt or
other mucous soluble material may be positioned at a location
whereby mucous will contact the substance and a quantity of the
substance will become dissolved in the mucous thereby changing some
property (e.g., pH, osmolarity, etc) of the mucous. In some cases,
this technique may be used to render the mucous hyperosmolar so
that the flowing mucous will draw water and/or other fluid from
polyps, edematous mucosal tissue, etc., thereby providing a drying
or desiccating therapeutic effect.
[0069] Additionally or alternatively to substances directed towards
local delivery to affect changes within the sinus cavity, the nasal
cavities provide unique access to the olfactory system and thus the
brain. Any of the devices and methods described herein may also be
used to deliver substances to the brain or alter the functioning of
the olfactory system. Such examples include, the delivery of energy
or the deposition of devices and/or substances and/or substance
delivering implant(s) to occlude or alter olfactory perception, to
suppress appetite or otherwise treat obesity, epilepsy (e.g.,
barbiturates such as phenobarbital or mephoobarbital;
iminostilbenes such as carbamazepine and oxcarbazepine;
succinimides such as ethylsuximide; valproic acid; benzodiazepines
such as clonazepam, clorazepate, diazepam and lorazepam,
gabapentin, lamotrigine, acetazolamide, felbamate, levetiraceam,
tiagabine, topiramate, zonisamide, etc.), personality or mental
disorders (e.g., antidepressants, antianxiety agents,
antipsychotics, etc.) , chronic pain, Parkinson's disease (e.g.,
dopamine receptor agonists such as bromocriptine, pergolide,
ropinitrol and pramipexole; dopamine precursors such as levodopa;
COMT inhibitors such as tolcapone and entacapone; selegiline;
muscarinic receptor antagonists such as trihexyphenidyl,
benztropine and diphenhydramine) and Alzheimer's disease,
Huntington's disease or other dementias, disorders of cognition or
chronic degenerative diseases (e.g. tacrine, donepezil,
rivastigmine, galantamine, fluoxetine, carbamazepine, clozapine,
clonazepam and proteins or genetic therapies that inhibit the
formation of beta-amyloid plaques), etc.
[0070] In certain applications, such as those intended for the
treatment of sinusitis or other disorders of the ear, nose or
throat, the implantable substance delivery devices and methods of
the present invention may satisfy one or more of the following
objectives:
[0071] 1. Clearing of mucous: The implantable substance delivery
devices of this invention may be configured such that, when
implanted in a nasal or perinasal passageway, they will allow at
least a portion of the adjacent anatomical wall(s) to maintain
muco-ciliary action. To accomplish this the devices may have
discrete areas which contact the adjacent anatomical wall(s) and
other areas that do not contact the adjacent anatomical wall(s)
and/or they may incorporate an internal hollow lumen. While some
embodiments of the invention include a central lumen, in most
cases, it may be impossible or impracticable for mucous to flow
through the lumen of the implanted device via gravity or sheer
pressure. Thus, this central lumen may not be a usable structure to
maintain patency of the anatomical passageway since in such cases
fluids may more easily be conducted around the device. Accordingly,
in other embodiments of the present invention as described herein,
the device may comprise spaced apart struts or members which allow
mucous to flow there-between, thus avoiding any need for the mucous
to enter a lumen or bore within the device. Also, there are other
embodiments of the current invention where the struts are
relatively thin and the device in composed of an open-cellular
structure such that the cilia are allowed to contact the inner
lumen of the device directly. In these circumstance the clearing of
mucous may be possible through the central lumen without relying on
pressure or gravity.
[0072] 2. Sustained Effect Drug saturated gauze or sponges, as may
be used to deliver drugs in some intranasal/intrasinus
applications, have little or no ability to regulate the dosage(s)
of drug(s) delivered or the dispersion of those drug(s). Further,
they may be either non-biodegradable or very quickly biodegradable.
At least some embodiments of the devices of the present invention
overcome these shortcomings by delivering predetermined dosages of
drugs for a predetermined treatment duration and then, after
conclusion of the predetermined treatment duration, may be removed
or may biodegrade and be eliminated.
[0073] 3. Minimally Invasive Placement Many of the instruments
currently used to perform sinus procedures require significant
obliteration of or damage to tissues within the nose or sinus in
order to gain access and place implants. However, the devices and
methods of the present invention may be carried out with minimal
iatrogenic damage to nasal and sinus tissues. Thus, the devices and
methods described herein may permit swollen tissues and obstructed
lumens to be reduced through the action of the drugs, and for
infections to be controlled, thereby resulting in a resolution of
symptoms without the need for invasive tissue-damaging therapy such
as traditional sinus surgery.
[0074] 4. Low risk of device infection: In accordance with this
invention, implantable substance delivery devices may be made of a
material that is naturally antiinfective or may be coated with such
a material. This may aid in avoidance of "toxic-shock" syndrome or
other similar device related infections. Alternatively they may be
removable or resistant to infection as a result of their mechanical
structure or integrity.
[0075] 5. Removable or biodegradable: In some embodiments, the
implantable substance delivery devices of the present invention may
be biodegradable and/or removable. In some applications, it will be
desirable for the device to be biodegradable over a desired time
period, yet be removable if conditions merit it's early removal
(e.g., before sufficient time has elapsed to allow the device to
fully biodegrade). To aid in the removability of the structure a
tail, or suture/string attachment point may be provided to permit
easy removal in the office.
[0076] 6. Ability to deliver one or more diagnostic or therapeutic
substances: Since sinus disease has many etiologies, it would be
ideal to allow the physician to customize the device to contain one
or more substances in order to treat an individual patient's
disorder. Alternatively, it may also be acceptable to have mixtures
or combinations of substances (e.g., a fixed dosage combination of
two or more drugs) pre-packaged for loading into the implantable
substance delivery device before or after it has been implanted.
Such prepackaged mixtures or combinations of substances may be in
liquid form suitable for direct loading into the device or may be
in dry form (e.g., lyophilized or powder) that may be easily
reconstituted with a specified volume of liquid (e.g., sterile
water, 0.9% NaCl solution, etc.). Alternatively the device may
contain two or more separated chambers that simultaneously or
sequentially release drug(s). Alternatively, one other embodiment
may include one or more drugs or substances that are pre-bound or
pre-loaded within the device without being mixed with any additive
or one or more drugs or substances may be added or mixed with other
additives at the time of use.
[0077] 7. Preventing scarring or adhesions: Any material placed in
the sinus should be designed of material such that adhesions or
scarring may be minimized to allow for the continued patency of the
channels in which they are placed. While simply having a mechanical
barrier to adhesion may be useful, it is also important that the
implant itself does not induce a tissue reaction. Inert materials
should be used to avoid this condition. In other embodiments it may
be necessary to release an agent capable of preventing the tissue
response to the implant. Nominally, although a vast array of
therapeutic substances may be used inside the device, it may also
have utility simply as a spacer to maintain the passageway in which
it is delivered, filled with an inert substance such as saline.
[0078] 8: Drug delivery kinetics: The devices of the present
invention can deliver therapeutic substances in a consistent or
predictable manner over the course of the therapy, and if possible,
this timing of delivery would be programmable based upon the
material chosen. In some circumstances it may be ideal to allow the
device to be refilled in situ, but in some embodiments the device
may be capable of containing enough therapeutic substance so that
refilling would not be necessary. To date there is no device
proposed or available which can satisfy these needs and thus the
need still exists for new devices and methods for delivering drugs
and other therapeutic or diagnostic substances into paranasal
sinuses or other locations within the body for the treatment of
sinusitis or other diseases and disorders.
[0079] Though the implantable substance delivery device may be
delivered to or removed from the sinuses or other regions in the
ear, nose, or throat via standard surgical techniques, it is of
particular interest that the substance delivery device may also be
delivered via minimally invasive means which may reduce bleeding,
tissue removal, post-operative care, and other surgical issues.
[0080] A catheter, which may be malleable, deflectable, and/or have
an appropriately shaped body and tip may be introduced into the
nose and near or into the location of interest, such as the ostia
of a sinus. The catheter may or may not be introduced through an
access port located in the nostril. Furthermore, the guide may be
positioned in the anatomy via such means, but not limited to:
direct visualization, endoscopic imaging, fluoroscopic imaging,
electro-magnetic sensing, etc. Once properly positioned near or
through the appropriate ostium, a guide wire may be advanced
through the catheter and into a sinus cavity. For example, in the
case of accessing the Maxillary or Frontal sinus, the catheter tip
may curve around the uncinate process (without the need to resect
the uncinate) and enter through or point toward the appropriate
sinus ostia. A guide wire can than be advanced into the sinus
cavity. These maneuvers may be done under fluoroscopic, endoscopic,
electro-magnetic sensing, etc. visualization methods. Appropriately
shaped, deflectable, and/or malleable catheters may also be used to
gain access to the frontal and sphenoidal sinuses. Once a wire is
advanced into the sinus, a balloon catheter may be introduced over
the wire in order to enlarge the ostia of the sinus in question if
it is deemed necessary. If desired, a second catheter may be
advanced over the wire and through the access catheter. This second
catheter may be used to exchange for a smaller guide wire--thus
allowing for the use of smaller catheters that are compatible with
the smaller guide wire.
[0081] Access to the Sphenoid sinus may be accomplished similarly
by advancing the access catheter medial to the middle turbinate and
placing the catheter through or close to the ostium of the sinus.
Similar techniques of advancing a guide wire into the sinus with
subsequent balloon dilation prior to delivery of the substance
delivery device may then follow.
[0082] Access to the Ethmoid sinuses may be accomplished similarly
by advancing the access catheter into or close to the retrobullar
and suprabullar recesses, which provide entry into the ethmoid
cells. Similar techniques of navigating and advancing a guide wire
through and into the cells with subsequent balloon dilation prior
to delivery of the substance delivery device may then follow.
[0083] Alternatively, it may be desirable to advance a catheter
near the anterior ethmoid (e.g. Ethmoid Bulla) under fluoroscopic,
endoscopic, electro-magnetic sensing, etc.
visualization/navigation. Subsequently, a piercing member such as a
needle or catheter may be advance through the access catheter, and
through the walls of the anterior and posterior ethmoid cells. Once
one or more walls are pierced, a guidewire may be advanced into the
ethmoid cells via the needle or other catheter member. Balloon
dilation of the pierced anterior and posterior ethmoid cells may be
conducted, if desired, prior to placement of the substance delivery
device. In general, minimally invasive access to the sinuses and
their surrounding areas is a key element to delivering a substance
delivery device.
[0084] Turning now to FIGS. 1-12F, it is to be understood that such
figures show specific examples of the devices and methods of the
present invention. Any elements, attributes, components,
accessories or features of one embodiment or example shown in these
figures may be eliminated from that embodiment or example, or may
be included in any other embodiment or example, unless to do so
would render the resultant embodiment or example unusable for its
intended purpose.
[0085] FIG. 1 generally shows a diagram of the head of a human
patient wherein a system 10 of the present invention is being
employed to implant a substance delivery device 12 of the present
invention within the left frontal sinus. As shown, this system 10
comprises a nasal access port device 14, a delivery catheter 16, an
elongate member 18 and the implantable substance delivery device
12. The port device 14 is positioned within the nostril, as shown.
Examples of nasal port devices that may be useable are described in
detail in parent application Ser. No. 10/829,917 entitled "Devices,
Systems and Methods for Diagnosing and Treating Sinusitis and Other
Disorders of the Ears, Nose and/or Throat," which is incorporated
herein by reference. The catheter 16 is advanced through the port
device 14 and through the nasal cavity to a location within or very
near the ostium to the left frontal sinus. Prior to or after
insertion of the catheter 16, the implantable substance delivery
device 12 is loaded into the lumen of the delivery catheter 16 and
the elongate member 18 is positioned in the lumen of the delivery
catheter 16 proximal to the implantable substance delivery device
12. It will be appreciated that, in some cases, a separate guide
catheter (not shown) may be advanced through port device 14 and to
a position near the ostium of the left frontal sinus and thereafter
the delivery catheter may be advanced through that guide catheter
to a position where the distal end of the delivery catheter is in
or immediately adjacent to the ostium of the left frontal sinus.
Thereafter, the elongate member 18 may be advanced in the distal
direction thereby pushing the implantable substance delivery device
12 out of the distal end of the delivery catheter 16.
Alternatively, the distal end of the elongate member 18 may be
positioned in contact with the proximal end of the drug delivery
device 12 within the lumen of the delivery catheter 16 and,
thereafter, the elongate member 18 may be held stationary while the
delivery catheter 16 is retracted in the proximal direction so as
to cause the implantable substance delivery device 12 to pass out
of the distal end of the delivery catheter 16. In either case, the
substance delivery device 12 will be positioned fully or partially
within the frontal sinus and, thereafter, the port device 14,
delivery catheter 16 and elongate member 18 may be removed. The
implantable substance delivery device 12 may be constructed in
various ways, examples of which are shown in FIGS. 2-12F and
described herebelow. In any of the embodiments of this invention,
the desired diagnostic or therapeutic substance may be loaded into
the implantable substance delivery device 12 before and/or after
the device 12 has been implanted within the body.
[0086] FIGS. 2-2C show one embodiment of an implantable substance
delivery device 12a which tube 20 having a lumen 22, a porous
matrix 24 and an outer barrier 26. One end of the tube 20 protrudes
through the outer barrier 26 and has a needle-penetrable,
self-sealing cap 27 thereon. The other end of the tube 20 is closed
such that the lumen 22 of the tube forms a hollow cavity within the
approximate center of the porous matrix 24. A solution containing
the desired therapeutic or diagnostic substance is introduced into
the lumen 22 of the tube 20 by a syringe and needle 28, as shown in
FIG. 2A. The tube 20 is constructed of porous or permeable material
such as expanded polytetrafluoroethylene (ePTFE) or a bioabsorbable
material such as porous poly (L-lactic acid) (PLLA) or poly
(L-glycolic acid) (PLGA,) etc. which allows the substance to pass
through the wall of the tube 20 and into the porous matrix 24. In
this manner, the porous matrix 24 becomes substantially saturated
or loaded with the substance such that the lumen 22 of tube 20 and
the porous matrix 24 combine to form a reservoir in which a
quantity of the substance is contained. The porous matrix may be
formed of a biodegradable or non-biodegradable porous material such
as a flexible or rigid polymer foam, cotton wadding, gauze,
hydrogel, collagen etc. Examples of biodegradable polymers that may
be foamed or otherwise rendered porous include poly (L-lactic acid)
(PLLA), poly (L-glycolic acid) (PLGA), polyglycolide,
poly-L-lactide, poly-D-lactide, poly(amino acids), polydioxanone,
polycaprolactone, polygluconate, polylactic acid-polyethylene oxide
copolymers, modified cellulose, collagen, polyorthoesters,
polyhydroxybutyrate, polyanhydride, polyphosphoester,
poly(alpha-hydroxy acid) and combinations thereof. This device 12a
may be fully or partially biodegradable or non-biodegradable. In
non-biodegradable embodiments of the device 12a, the tube 20,
porous body 24 and outer barrier 26 The tube 20 may be formed of
any suitable material, such as various commercially available
biocompatible polymers including but not limited to silicone
rubber, polyethylene terephthalate, ultra high molecular weight
polyethylene, expanded polytetrafloroethylene, polypropylene,
polycarbonate urethane, polyurethane, polyamides.
[0087] Any embodiment of this invention, such as that shown in FIG.
2-2B, could incorporate a means for assisting the transport of a
substance across the barrier. Such a device could take the form of
a mechanical pump, an electro-mechanical pump, a nanotechnology
pumping mechanism, or an electrical device that emits a current to
drive the transport. This means could be incorporated into the
barrier itself or into the porous matrix. A more specific example
of a mechanical embodiment would be to mechanically change the
reservoir size so that the volume of substance to be delivered is
continually under positive pressure to drive its transport across
the barrier. This mechanical change could be controlled via
micro-electronics and could be pre-programmed or remotely
controlled through various wireless communication technologies.
Another example of a mechanical means to maintain pressure within
the reservoir would be to incorporate a membrane barrier that
contracts or shrinks as the drug volume diminishes such as an
osmotic pump, or one activated by an internal chemical reaction.
This contraction could be achieved by creating the membrane barrier
from an elastic or shrinking polymer or by including movable
filaments or sections that decrease the reservoir volume.
[0088] In any embodiment of this invention, the wall of any tube 22
or other cavity formed within or next to the porous matrix 24 may
be constructed of material that controls the rate at which the
substance passes from the lumen 22 of the tube 20 into the porous
matrix 24. Also, the outer barrier 26 may be constructed of
material (e.g., a semi-permeable membrane or film) which will
control the rate at which the substance will pass from the porous
matrix 24 through the outer barrier 26 and out of the device 12.
There may be other embodiments of the substance delivery device
that utilize multiple chambers within the device to contain
multiple drugs. These chambers could be arranged in various
configurations, including, but not limited to being arranged
axially so that a strip of each chamber travels the length of the
device but the cross-section shows multiple compartments,
longitudinally so that the distal portion of the device could
contain a different drug than the middle or proximal portions, or
in layers (like an onion) such that the first drug that gets
delivered may be different than the next drug to treat various
afflictions at different times--i.e. first addressing inflammation,
then after a predetermined period to begin releasing antimicrobials
to combat infection. In the layered configuration, the dividing
membranes may or may not be biodegradable. The device 12 of this
invention may initially be provided without diagnostic or
therapeutic substance contained in the device 12. In such cases, a
physician may then select or formulate a particular therapeutic or
diagnostic substance or combination of such substances into the
device 12 before the device is implanted in the subject's body. In
other applications, the physician may load a desired therapeutic or
diagnostic substance or combination of such substances into the
device 12 after the device has been implanted in the subject's
body. To facilitate the physician's selection or formulation of the
diagnostic or therapeutic substance(s) to be loaded into the device
12, the device may be accompanied by a data compilation for
facilitating dilution of substance(s) and loading of the devices 12
such that desired dosage(s) of the substance(s) that have been
loaded into the device 12 will be delivered by the implanted device
12. Such data compilation may be in the form of tabular data,
algorhythm(s) etc. Also, such data compilation may be provided in
written form (e.g., as a table or list) as hard copy (e.g., a
package insert or booklet) or stored in electronic form (e.g., on
compact disc, accessible from a website, programmed into a computer
or microprocessor device such as a hand held electronic dosage
calculator that is programmed specifically for use in conjunction
with the devices 12 of the present invention). The dosage of
particular substance(s) delivered by the devices 12 will be
determined rate(s) at which certain substances, preparations,
mixtures or concentrations of solutes or substances having certain
defined key properties will pass through the barriers 26 of the
devices 12. The data compilation may include or comprise examples
or lists of certain key properties for which specific barrier
transition rates may be provided include a viscosity or a range of
viscosities, molecular weight or range of molecular weights, an
electrical charge, osmolarity or a range of osmolarities,
osmolality or a range of osmolalities, presence of a certain
chemical group or atom, relative hydrophilicity and/or hydrophobic
properties, etc.. An example of one type of data compilation that
may be provided to facilitate preparation and loading of a device
12 of the present invention with specific steroid or
steroid/antimicrobial formulations is a tabular presentation as
shown in Table 1 below:
TABLE-US-00001 TABLE 1 Concentration of Drug or Drug Combination in
Solution (mg of drug or Diffusion Rate Out of Device (Drug or Drug
drug Combination per ml (amount of each drug delivered
Combination/Solvent) of solution) per 24 hour period) fluticasone
proprionate X mg/ml 200 mcg fluticasone (as microfine aqueous
proprionate/24 hr suspension) Y mg/ml 230 mcg fluticasone
proprionate/24 hr .sup. Z mg/ml 260 mcg fluticasone proprionate/24
hr cefuroxime axetil + X mg/ml 200 mcg fluticasone proprionate +
fluticasone proprionate 8 mg cefuroxime axetil/24 hr in 0.9% saline
Y mg/ml 230 mcg fluticasone proprionate + 12 mg cefuroxime
axetil/24 hr .sup. Z mg/ml 260mcg fluticasone proprionate + 20 mg
cefuroxime axetil/24 hr triamcinolone acetonide X mg/ml 180 mcg
triamcinolone (as aqueous cetonide/24 hr microcrystalline Y mg/ml
220 mcg triamcinolone suspension). cetonide/24 hr .sup. Z mg/ml 260
mcg triamcinolone cetonide/24 hr amoxicillin + X mg/ml 180 mcg
triamcinolone cetonide + clavulanate + 40 mcg amoxicilin + 20 mcg
triamcinolone acetonide clavulanate/24 hr in 0.9% saline as Y mg/ml
220 mcg triamcinolone cetonide solution/aqueous cetonide + 60 mcg
amoxicilin + 40 microcrystalline mcg clavulanate/24 hr suspension
.sup. Z mg/ml 260 mcg triamcinolone cetonide cetonide + 80 mcg
amoxicilin + 60 mg clavulanate/24hr clotrimazole + X mg/ml 170 mcg
clotrimazole + 100 mcg betamethasone betamethasone dipropionate/24
hr dipropionate in Y mg/ml 200 mcg clotrimazole + 125 mcg
polyethylene glycol betamethasone dipropionate/24 hr .sup. Z mg/ml
125 mcg clotrimazole + 150 mcg betamethasone dipropionate/24 hr
mupirocin calcium X mg/ml 1 mg mupirocin calcium/24 hr Y mg/ml 4 mg
mupirocin calcium/24 hr .sup. Z mg/ml 8 mg mupirocin calcium/24 hr
mupirocin calcium + X mg/ml 1 mg mupirocin calcium + 200 mcg
fluticasone proprionate fluticasone proprionate/24hr (as
solution/microfine Y mg/ml 4 mg mupirocin calcium + 220 mcg aqueous
suspension) triamcinolone cetonide/24 hr .sup. Z mg/ml 8 mg
mupirocin calcium + 260 mcg fluticasone proprionate/24 hr
[0089] All percentages set forth in this table are expressed as
percent by weight. It is to be appreciated that this table is
merely an illustrative example provided to show one way in which
instructional information or data on substance release rates that
may accompany certain implantable substance delivery devices 12 of
the present invention to facilitate their loading and use with
different substances and/or differing concentrations of substances.
The actual substances used and actual delivery rates of those
substances will depend on the intended use of the device 12, the
key properties of the substance to be loaded into the device 12 and
the relative porosity or permeability of the porous matrix 24
and/or outer barrier 26 of the device 12. The above-set-forth table
shows several examples whereby a physician may use a starting
preparation that contains one or more drugs (e.g., the preparations
listed in the left column) to prepare different dilutions (e.g.,
concentrations X, Y or Z listed in the middle column) which will
deliver different topical doses of the agents contained in the
preparation (e.g., the daily dosages listed in the right column).
The starting preparation (e.g., the preparations listed in the left
column) may comprise a commercially available pharmaceutical
preparation that is approved and/or useable for intranasal
administration or topical administration to mucosal tissues
elsewhere in the body.
[0090] The starting preparation (e.g., the preparations listed in
the left column) may be a) packaged and/or provided along with the
devices 12 of the present invention, b) obtained by the physician
separately from the devices 12 of the present invention and/or c)
pre-loaded in concentrated (e.g., dry or lyophilized form) within
the devices 12 of the present invention, as described herein. In
some cases, the devices 12 may be provided with a dry (e.g,
lyophilized or powdered) diagnostic or therapeutic substance (e.g.,
a drug preparation) contained in the device (e.g. within the lumen
22 of the tube 20 and/or within the porous matrix 24) and the
physician may subsequently inject a measured amount of a solvent
(e.g., sterile water, 0.9% NaCl solution, basic salt solution,
etc.) to reconstitute or dissolve the substance and to expand or
activate the device 12. In such cases, the instructions or other
information provided with the device 12 may include information for
different concentrations of substance produced by injecting
different amounts of solvent. In other cases, the devices may be
provided in an expanded state and need to be compressed or
re-shaped for delivery then re-expanded fully, slightly, or not at
all depending upon the desired implantation location. As stated
above, in some cases, the starting preparation (e.g., the
preparations listed in the left column) may be commercially
available preparations. For example, fluticasone proprionate
referred to in the first 1, 2 and 7 of Table 1 is commercially
available as a preparation for intranasal spray administration as
Flonase.RTM. nasal spray (Glaxo-SmithKline, Research Triangle Park,
North Carolina). Fluticasone propionate, the active component of
Flonase.RTM. nasal spray, is a synthetic corticosteroid having the
chemical name S-(fluoromethyl)6<,
9-difluoro-11.RTM.-17-dihydroxy-16<-methyl-3-oxoandrosta-1,4-diene-17.-
RTM.-carbothioate, 17-propionate. It is provided as an aqueous
suspension of microfine fluticasone propionate containing
microcrystalline cellulose and carboxymethylcellulosesodium,
dextrose, 0.02% w/w benzalkonium chloride, polysorbate 80, and
0.25% w/w phenylethyl alcohol, and having a pH between 5 and 7.
This commercially available Flonase product may, in some cases,
serve as the base preparation (left column of Table 1) which may be
combined with one or more other substances and/or prepared in
various dilutions (e.g., middle column of Table 1) prior to being
loaded into the device 12 such that the device 12 will, when
subsequently implanted in the subject's body, deliver a desired
dosage of fluticasone propionate alone or in combination with other
agent(s) (right column of Table 1). In instances such as this where
the substance is in the form of a suspension, the suspension may be
formulated such that it will remain stable within the implanted
device 12 and the barrier 26 of the device 12 may comprise a
membrane that has pores which are large enough to allow the
particles (e.g., microparticles) of the suspension to pass through
the barrier at the desired rate.
[0091] Similarly, triamcinolone acetonide referred to in rows 3 and
4 of Table is commercially available as Nasacort.RTM. AQ nasal
spray (Aventis Pharmaceuticals, Inc., Bridgewater, N.J.).
Triamcinolone acetonide, the active ingredient in Nasacort.RTM. AQ
nasal spray, is 9-Fluoro-11.beta., 16.alpha.,
17,21-tetrahydroxypregna-1 ,4-diene-3,20-dione cyclic 16,17-acetal
with acetone (C.sub.24H.sub.31FO.sub.6). It is provided as a
microcrystalline suspension of triamcinolone acetonide in an
aqueous medium with microcrystalline cellulose,
carboxymethylcellulose sodium, polysorbate 80, dextrose,
benzalkonium chloride, and edetate disodium. Hydrochloric acid or
sodium hydroxide may be added to adjust the pH to a target of 5.0
within a range of 4.5 and 6.0.
[0092] Also, preparations of the antifungal agent clotrimazole
combined with the corticosteroid betamethasone dipropionate as
referred to in row 5 of Table 1 are commercially available as
Lotrisone.RTM. lotion (Schering Corporation, Kenilworth, New
Jersey) for topical application to treat fungal infections.
Chemically, clotrimazole is 1-(a-Chloro, a, a-diphenylbenzyl)
imid-azole, with the empirical formula C.sub.22H.sub.17ClN.sub.2
and a molecular weight of 344.8. Clotrimazole is an odorless, white
crystalline powder, insoluble in water and soluble in ethanol.
Betamethasone dipropionate has the chemical name 9-Fluoro-1, 16,
17,21-trihydroxy-16B-methylpregna-1,4-diene-3,20-dione-17,21-dipropio-
nate, with the empirical formula C.sub.28H.sub.37FO.sub.7 and a
molecular weight of 504.6. Betamethasone dipropionate is a white to
creamy white, odorless crystalline powder, insoluble in water. Each
gram of Lotrisone.RTM. lotion contains 10 mg clotrimazole and 0.643
mg betamethasone dipropionate (equivalent to 0.5 mg betamethasone),
in a hydrophilic base of purified water, mineral oil, white
petrolatum, cetyl alcohol plus stearyl alcohol, ceteareth-30,
propylene glycol, sodium phosphate monobasic monohydrate, and
phosphoric acid; benzyl alcohol as a preservative. For applications
where the device 12 of the present invention is to be implanted in
the nose, paranasal sinus or other location within the ear, nose or
throat, the base preparation (left column of Table 1) may comprise
low-viscosity forms of the Lotrisone.RTM. lotion or may comprise a
solution or suspension of microparticles containing the active
ingredients of Lotrisone.RTM. lotion absent the lotion base (e.g,
excluding some or all of the mineral oil, white petrolatum, cetyl
alcohol plus stearyl alcohol, ceteareth-30 and/or propylene
glycol).
[0093] Also, mupirocin calcium is an antibiotic that is
commercially available as Bactroban Nasal.RTM. ointment
(Glaxo-SmithKline, Research Triangle Park, N.C.) for intranasal
application. Bactroban Nasal.RTM. ointment contains 2.15% w/w
mupirocin calcium (equivalent to 2.0% pure mupirocin free acid) in
a soft white ointment base that contains paraffin and a mixture of
glycerin esters (Softisan.RTM. 649). The Mupirocin calcium is in
the form of the dihydrate crystalline calcium hemi-salt of
mupirocin. Chemically, it is (.alpha.E,2 S,3 R,4 R,5 S)-5-[(2 S,3
S,4 S,5
S)-2,3-Epoxy-5-hydroxy-4-methylhexyl]tetrahydro-3,4-dihydroxy-.beta.-meth-
yl-2 H-pyran-2- crotonic acid, ester with 9-hydroxynonanoic acid,
calcium salt (2:1), dihydrate. The molecular formula of mupirocin
calcium is (C26H43O9)2Ca.2 H2O, and the molecular weight is 1075.3.
The molecular weight of mupirocin free acid is 500.6. For
applications where the device 12 of the present invention is to be
implanted in the nose, paranasal sinus or other location within the
ear, nose or throat, the base preparation (left column of Table 1)
may comprise low-viscosity forms of the Bactroban Nasal.RTM.
ointment or may comprise a solution or suspension of microparticles
containing the active ingredients of Bactroban Nasal.RTM. ointment
absent the ointment base (e.g, excluding some or all of the
paraffin and/or glycerin esters (Softisan.RTM. 649)).
[0094] FIG. 2B shows a variant of the implantable substance
delivery device 12b comprising the same components as the device
12a of FIGS. 2 and 2A but, instead of the needle-penetrable,
self-sealing cap 27, this device 12b has a fill tube 32 connected
to the exposed end of the inner tube 22 by way of a removable
connector 30. A check valve 31 may be positioned in the lumen 22
just inside of the connector 30. This check valve may be a device
or may simply be the function resulting from the elasticity of the
materials chosen for its construction. A syringe or other substance
injecting or infusing apparatus may be connected to the free end of
the fill tube 32 and a diagnostic or therapeutic substance
comprising or consisting of a fluid may be introduced through the
fill tube 32, through check valve 31 and into the reservoir (i.e.,
in this embodiment the "reservoir" includes the lumen 22 as well as
the adjacent porous matrix 24). Thereafter, the connector cap 30
and fill tube 32 may be removed. Check valve 31 will prevent the
substance from backflowing out of the protruding end of the inner
tube 20. Alternatively, the fill tube 32 may remain connected to
the device 12 and may be closed (e.g., compressed, clamped,
clipped, sealed, cut, doubled over, ligated or otherwise
manipulated or sealed as shown in the examples of FIGS. 8A-8E and
described herebelow).
[0095] The outer barrier controls the rate at which the diagnostic
or therapeutic substance will diffuse or pass out of the device 12a
or 12b. In some applications of the invention, the device 12a or
12b may be provided to a physician in an empty state (i.e., without
diagnostic or therapeutic substance contained in lumen 22 or porous
matrix 24). The physician may then select or self-formulate one or
more diagnostic or therapeutic substances to be loaded into the
device 12a, 12b before or after the device 12a, 12b has been
implanted in the body.
[0096] FIG. 2C shows a general example where this implantable
substance delivery device 12, 12a, 12b is implanted within the
ostium OS of a paranasal sinus PS such that a portion of the device
12, 12a, 12b extends into the paranasal sinus PS. In such cases
where the device 12, 12a or 12b is implanted in a paranasal sinus
PS to treat sinusitis, the physician may load the lumen 22 and
porous matrix 24 with any drugs or other diagnostic or therapeutic
substance that he or she deems suitable for treatment of the
condition. For example, the device 12, 12a, 12b may be loaded with
a corticosteroid, such as one or more of those corticosteroids
listed hereabove that have been approved for intranasal use (e.g.,
approved for topical application as a nasal spray or for
intramucosal injection directly into the nasal turbinates or nasal
mucosa). One specific example is an aqueous solution of Fluticasone
Proprionate (Flonase, Glaxo-SmithKline). For intranasal or
paranasal applications, the empty device 12b shown in FIG. 2A may
be initially delivered and positioned within the paranasal sinus PS
and the fill tube 32 may extend into the nasal cavity or out of the
subjects nostril. The physician may then infuse the desired
substance through the fill tube 32 and into the device 12b. After
the lumen 22 and porous matrix 24 have been loaded with the desired
amount of substance, the connector 30 may be disconnected and the
fill tube 32 removed or, alternatively, the fill tube may be
allowed to remain attached to the device 12b to facilitation
subsequent in situ refilling of the device 12b. In one embodiment,
the fill tube is connected to a subcutaneous substance reservoir.
The subcutaneous substance reservoir may comprise a pumping
mechanism and is especially useful for chronic delivery of the
substance. The subcutaneous drug reservoir may be refillable.
[0097] FIGS. 3-4C show additional embodiments of implantable
substance delivery devices 12c and 12d. Like the embodiments 12a
and 12b shown in FIGS. 2-2c, these embodiments 12c, 12d comprise at
least a porous matrix 24 and an outer barrier 26, as described
above. Optionally, these embodiments 12c, 12d may also have an
inner tube 20 or other hollow cavity formed within or next to the
porous matrix 24. The outer surfaces of these devices 12c, 12d are
shaped to define peaks 34 and valleys 36. When the device 12c, 12d
is implanted in the body of a subject and loaded with the desired
diagnostic or therapeutic substance, the peaks 34 will contact
adjacent anatomical tissue and valleys 36 will remain a spaced
distance away from adjacent anatomical tissue. In this manner, the
surface to surface contact of the device is minimized and normal
flow of body fluids and/or function of anatomical tissues may
continue in the areas adjacent to the valleys 36 of the device 12c,
12d. For example, in cases where the device 12c, 12d is placed
within a nasal cavity, paranasal sinus, Eustachian tube,
nasolacrimal duct or other passageway lined with ciliated mucosa,
the peaks 34 will make firm abutting contact the mucosal tissue
thereby holding the device 12c, 12d in place but the valleys 36
will remain a spaced distance away from the mucosal tissue so as
not to substantially interfere with mucocillary transport by that
tissue or mucous flow past the implanted device 12c, 12d.
[0098] In the examples of FIGS. 3 and 4, the implantable substance
delivery devices 12c, 12d have a fill tube 38 that is connected to
the device 12c, 12d. In embodiments where there is no hollow cavity
or tube 20 within the porous matrix 24, the diagnostic or
therapeutic substance may be infused through the tube 38 such that
it will be absorbed into porous matrix 24 and no closure or the
tube or check valve will then be required as the substance will
substantially remain within the porous matrix 24. However, in
embodiments where the device 12c, 12d does have a hollow cavity
(e.g., a tube 20 as shown in FIGS. 2-2B) within or next to the
porous matrix 24, there may be a check valve or other means for
closing the tube 38 (e.g., compressing, clamping, clipping,
sealing, cutting, doubling over, ligating or otherwise manipulating
or sealing the tube as shown in the examples of FIGS. 8A-8E and
described herebelow) to prevent the substance from backflowing from
the hollow cavity through the tube 38.
[0099] FIGS. 4-4C show an embodiment of the implantable substance
delivery device 12d that further comprises a frame 40. Such frame
may impart structural rigidity or a specific shape to all or any
portion of the device 12d. Alternatively or additionally, such
frame may act as a scaffold or support structure and/or may be
self-expanding or pressure-expandable so as to exert outwardly
directed force against an adjacent anatomical tissue or structure.
Although FIG. 4 shows a frame 40 that extends over the entire
length of the device 12d, it is to be appreciated that the frame 40
may be confined to one or more specific region(s) of any device 12,
such as in the example of FIGS. 12D-12E described herebelow. The
frame 40 may be formed of any suitable material, including but not
limited to wire, mesh, polymer, etc. In the particular example
shown in FIGS. 4-4B, the frame 40 comprises a self-expanding stent
formed of wire members 42. In some embodiments, the wire members 42
may be positioned on the outer surface of the porous matrix 24
within or inside of the outer barrier 26, as shown in FIG. 4BA.
Such embodiments may be manufactured by initially placing the
porous matrix 24 (e.g. a sponge or mass of absorptive material)
within the frame 40 and then dipping, spray-applying, applying by
lay-up of a film or otherwise applying a polymer to from the outer
barrier 26 encapsulating the porous matrix 24 and the frame 40, as
shown in FIG. 4B. Alternatively, such embodiments may be
manufactured by forming (e.g., foaming in place) the porous matrix
24 about the frame 40 such that some or all of the frame members 42
are embedded within the porous matrix 24 as shown in FIG. 4C. The
outer barrier 26 may then be placed or formed (e.g., dip coated,
sprayed on, applied by lay-up of a film, etc.) on the outer surface
of the porous matrix 24 as further shown in FIG. 4C. Also, another
method of forming the device may include the initial creation of
the barrier film within a mold cavity, and subsequently forming the
foam within the film covered mold cavity.
[0100] In one embodiment, the device 12d comprises multiple,
substantially non-intersecting ridges on its outer surface. The
ridges enable only a portion of the device 12d to contact adjacent
anatomical tissue while keeping bulk of the device 12d spaced a
distance away from adjacent anatomical tissue. The ridges are
designed to be substantially parallel to the direction of flow of
fluids (e.g. mucous) along the walls of the adjacent anatomical
tissue. This design enables reduced interfere with mucociliary
transport by that tissue or the flow of fluids (e.g. mucous) past
the device 12d.
[0101] Some embodiments of the implantable substance delivery
devices 12 of the present invention may be configured to define at
lest one lumen of flow channel through which body fluid or
extraneously introduced fluid may flow after the device 12 has been
implanted in a natural or man made passageway of the body. Examples
of this concept include devices 12c, 12d having peaks 34 and
valleys 36 as shown in FIGS. 3 and 4, as well as 12e and 12f having
other flow-facilitating configurations, examples of which are shown
in FIGS. 5-6. The device 12e of FIGS. 5 and 5A comprises a porous
matrix 24 covered with an outer barrier 26 and is in the shape of a
helical strip (e.g., the shape of a screw or auger). When loaded
with the desired diagnostic or therapeutic substance and implanted
in a body lumen or passageway, this device 12e defines a helical
groove or flowpath 50 through which fluid (e.g., mucous, body
fluid, etc.) may flow. The device 12e of FIG. 5 also incorporates
an optional grasping member 52 to facilitate grasping of the device
12e by forceps, by hand or by other instruments while removing,
moving or manipulating the device 12e. In the particular example
shown, the grasping member 52 comprises a strand of suture thread
that extends from one end of the device 52 but it is to be
appreciated that such grasping member 52 may be of any suitable
design or construction and may be located over the entire length of
the device. For example, small threads or projections, a net or
other graspable structure may be located at numerous location on
the outer surface of the device so as to facilitate moving or
removing the entire device or portion(s) of the device after the
device has begun to break apart or biodegrade in situ.
[0102] FIG. 6A shows an implantable substance delivery device 12f
of the present invention that comprises a helical substance eluting
filament. This helical structure defines a hollow lumen 54 through
the center of the device 12f and open spaces 56 between individual
convolutions of the helix, through which fluids (e.g., mucous or
other body fluids) may flow. This helical filament may be formed of
any suitable biodegradable or nonbiodegradable material. Examples
of biodegradable polymers that may be used to form the filament
include poly (L-lactic acid) (PLLA), poly (L-glycolic acid) (PLGA),
polyglycolide, poly-L-lactide, poly-D-lactide, poly(amino acids),
polydioxanone, polycaprolactone, polygluconate, polylactic
acid-polyethylene oxide copolymers, modified cellulose, collagen,
polyorthoesters, polyhydroxybutyrate, polyanhydride,
polyphosphoester, poly(alpha-hydroxy acid) and combinations
thereof. This filament may contain or may be coated with the
diagnostic or therapeutic substance or a preparation that contains
the diagnostic or therapeutic substance such that the substance
will elute from the filament after the filament has been implanted
in the body.
[0103] FIGS. 6B-6D show In another embodiment of an implantable
substance delivering device 12m which comprises a plurality of
substance eluting struts 55 and may optionally include a spacing
member 53. When the device 12m is implanted, such as in the
examples of FIGS. 6C and 6D, the struts 55 may be substantially
parallel to the direction of flow of fluids (e.g. mucous) along the
walls of the adjacent anatomical tissue (e.g., a paranasal sinus,
sinus ostium, intranasal meatus, etc.) This design enables reduced
interference with the transport of fluids (e.g. mucociliary
transport) along the walls of the adjacent anatomical tissue and in
the spaces 57 between the struts 55. The device 12m can be placed
both in anatomical cavities (e.g. nasal sinus cavities) and in
anatomical passages (e.g. trachea, blood vessels etc.). The device
12m has a configuration that enables the struts 55 to substantially
come into direct contact with the flow of fluids (e.g. mucous) past
the stent. The device 12m may be delivered to the intended
implantation site while in a collapsed configuration and may
subsequently expand to an expanded configuration, as shown in the
figures. This device 12m may be self expanding or pressure
expandable (e.g., by inflation of a balloon within the collapsed
device). The thickness of the struts 55 may vary along the length
of the device 12m as shown in the example of FIG. 6D. In such
embodiments, the diagnostic or therapeutic substance may be
contained in and eluted from the thicker in regions 51 of the
struts 55 and such substance may subsequently be carried or
distributed by a natural flow of body fluid (e.g., mucous flow out
of the paranasal sinus). Also, in such embodiments, the thinner
regions of the struts 55 may be located near the drainage openings
of the anatomical tissue (e.g. ostia of a nasal sinus) to minimize
obstruction to fluid drainage. The device 12m may comprise a
spacing member 53, such as a tubular or cylindrical hub, and such
spacing member 53 may be positionable in an opening of the
anatomical tissue (e.g. ostium of a nasal sinus as shown in FIG.
6D). The spacing member 53 may or may not have drug eluting
properties. The spacing member 53 may be configured to perform a
scaffolding function such as to deter narrowing of a man made or
natural an anatomical opening or passage in which it is positioned
to ensure that fluid flow through the opening is not compromised.
The device 12m may be biodegradable or bioabsorbable.
[0104] FIGS. 7-7B show an example of an implantable substance
delivery device 12g of the present invention that is designed to be
implanted and subsequently retained within a paranasal sinus. This
device 12g may include the inner tube 20, porous matrix 24 and
outer barrier 26 as shown in FIGS. 2 and 2A and described above.
Additionally, this embodiment of the device 12g has an intrasinus
portion 56 intended to be positioned within the paranasal sinus, an
intraostial portion 58 intended to be positioned within the sinus
ostium OS and an intranasal portion 60 intended to protrude into
the nasal cavity. A fill tube 62 having a needle-penetrable,
self-sealing cap 64 is positioned on the end of the fill tube. It
will be appreciated from the foregoing discussion, however, that
various other fill site/closure apparatus or designs may be used in
place of this fill tube and cap arrangement 62, 64. The intraostial
portion 58 of device 12g has an annular groove formed therein. As
may be appreciated from FIGS. 7A and 7B this annular groove is
configured to receive the annulus of the ostium OS and frictionally
engage the underlying bone B, thereby helping to position or seat
and/or hold the device 12g in its intended implantation position.
Initially, the device 12g is in a collapsed configuration wherein
the device has a diameter or maximum cross dimension D1 that is
small enough to be advanced through the ostium OS and into the
paranasal sinus, as shown in FIGS. 7 and 7A. Thereafter, a syringe
and needle 66 are used to inject a known volume of a solution
containing the desired diagnostic or therapeutic substance 68 into
the device 12g. The loading of the substance containing solution
into the device 12g causes the intrasinus portion 56 to swell to a
larger diameter D2, which is too large to pass through the ostium
OS, thereby tending to retain the intrasinus portion 56 within the
paranasal sinus, as shown in FIG. 7B.
[0105] FIGS. 8A-8E show several non-limiting examples of the manner
in which the implantable substance delivery devices 12 of this
invention may be sealed or closed to prevent substantial backflow
of the diagnostic or therapeutic substance from the device 12 after
the device 12 has been loaded with substance.
[0106] In the embodiment of FIG. 8A, the device has a long fill
tube 70 and a one way check valve 72 within the neck of the fill
tube, immediately adjacent to the body of the device. After the
device has been implanted and the substance has been infused
through the fill tube into the device, the fill tube 70 may be cut
to a desired length such that it will not protrude from the
subject's body or interfere with the subject's daily
activities.
[0107] FIG. 8B shows a device that has a fill tube 70 and a clip 74
which is useable to clip the fill tube 70 to prevent substance from
backflowing out of the fill tube 70.
[0108] FIG. 8C shows a device that has a fill tube 70 and a
ligature 76, such as a length of suture material or draw string
which is useable to ligate the fill tube 70 to prevent substance
from backflowing out of the fill tube 70. An annular indentation or
groove may optionally be formed in the fill tube to receive and
prevent longitudinal slippage of the ligature 76.
[0109] FIG. 8D shows a device that has a fill port 78 through which
the substance is injected or otherwise loaded into device and an
adhesive applicator 80 that may be used to apply an adhesive to the
fill port 78 thereby sealing the fill port 78 such that substance
will not backflow out of the fill port 78.
[0110] FIG. 8E shows a device that has a fill tube 70 that is
doubled over and a clamp 82 that is useable to clamp the doubled
over fill tube 70 to prevent substance from backflowing out of the
fill tube 70.
[0111] FIGS. 9-9B are directed to another embodiment of an
implantable substance delivery device 12h of the present invention.
This device 12h comprises a container portion which comprises a
container body 90 and a lid 92. The interior of the container
portion is loaded with a desired diagnostic or therapeutic
substance. The lid 92 has a permeable barrier 94 which allows the
diagnostic or therapeutic substance to pass through the barrier 94
at approximately a known rate as described hereabove. An attachment
portion 98 attaches the container portion to bone and/or soft
tissue. Such attachment portion 98 may comprise any suitable type
of attachment apparatus or substance such as an adhesive, barb(s),
a screw, a suture or stitch, a clip, a suction apparatus, a stent,
a self-expanding portion that grip the walls of the anatomical
target etc. As shown in FIG. 9A, the device 12h may be mounted on a
delivery catheter 100 which is useable to deliver the device 12h to
its intended implantation location. In the example shown, the
delivery catheter 100 has engagement members 102 that engage
projections 96, 98 on the device 12h, as shown, to hold the device
12h on the end of the delivery catheter as it is advanced into the
body to the desired implantation location. The proximal end of the
delivery catheter 100 comprises a handpiece having a control knob
104. When the control knob 104 is retracted, the engagement members
102 will disengage the projections 96, 98, thereby releasing the
device 12h and allowing the delivery catheter 100 to be retracted
and removed as shown in FIG. 9B. In cases where the attachment
portion 98 comprises a screw, the delivery catheter 100 may be
braided or otherwise constructed in accordance with techniques well
known in the art such that the catheter may be rotated to screw the
screw into adjacent soft tissue or bone, before the device 12h is
released from the delivery catheter 100. As in other embodiments
discussed above, the substance may be loaded into this device 12h
before or after the device 12h has been implanted within the
subject's body.
[0112] In one embodiment, the device 12h is implanted in an
anatomical location having a mucous flow in such a way that the
eluted drug is distributed to a wider region by the mucous flow.
This is especially helpful in the enhancing the efficacy of agents
like mucolytics as they would accumulate at higher concentrations
in regions of higher mucous density. This also enables the
reduction in size of the substance delivery mechanism since it can
be limited to deliver substances only to particular regions from
where the drug can be distributed most efficiently.
[0113] FIGS. 10A and 10B show a system 110 for delivering another
implantable substance delivery device which comprises a substance
eluting filament 12j. This system 110 comprises the substance
eluting filament 12j, a catheter 114, a pusher 116 and a connector
118. The substance eluting filament 12j is advanced into the lumen
of the delivery catheter 114. The pusher 116 is advanced into the
lumen of the delivery catheter 114 behind the substance eluting
filament 12j and the connector 118 is connected to the proximal end
of the delivery catheter 114. As shown in FIG. 10B, the delivery
catheter 114 may then be advanced into the subject's body to a
position where the distal end of the delivery catheter is within or
near the location where the substance delivery device 12j is to be
implanted (e.g., within or near the ostium of a paranasal sinus).
Thereafter the pusher may be advanced in the distal direction or
the pusher may be held stationary and the catheter 114 may be
retracted in the proximal direction to push the substance delivery
device 12j out of the end of distal end of the catheter and into
the desired implantation site (e.g., paranasal sinus). The
substance eluting filament may or may not be biased to a specific
shape or coiled configuration. In one embodiment, the substance
eluting filament 12j assumes a random coiled shape within the
implant location.
[0114] The implantable substance delivery devices 12 of this
invention and/or the delivery catheter or delivery devices used to
deliver such devices 12 into the body may, in some instances, be
configured for over-the-wire or rapid exchange delivery. FIG. 11A
shows an illustrative example of a rapid exchange embodiment of
this invention and FIG. 11B shows an illustrative example of an
over-the-wire embodiment. In the rapid exchange embodiment shown in
FIG. 11A, the delivery catheter 120 has a first lumen within which
the implantable substance delivery device 12k and elongate delivery
member or pusher 126 are positioned. A side tube 124 having a
second lumen 122 is located on a side of the delivery catheter 120,
as shown. Thus, a guidewire GW may pass through the side lumen 122,
thereby allowing the system to be advanced over a previously
inserted guidewire.
[0115] FIG. 11B shows an over-the-wire embodiment comprising a
delivery catheter 130 having a lumen within which the implantable
substance delivery device 121 and elongate delivery member or
pusher 134 are positioned. The substance delivery device 121 and
elongate delivery member or pusher 134 have lumens 132 and 136
extending longitudinally therethrough. Thus, a guidewire GW may
pass through the lumens 132 and 136, thereby allowing the system to
be advanced over a previously inserted guidewire. Thus, it is to be
understood that, wherever feasible, the substance delivery devices
12 of the present invention may have guidewire lumens or
passageways extending therethrough.
[0116] FIGS. 12A-12E show one of many possible examples of
procedures that may be performed using the implantable substance
delivery devices 12 of the present invention. This particular
example shows a method for treating sinusitis in a human or animal
subject. In this subject, the sinusitis is due at least in part to
impaired drainage from the sinus as a result of an occlusion of the
ostium OS that leads into the paranasal sinus. The ostium OS
consists of thin bone B covered by mucosal tissue. As shown in FIG.
12A, a guidewire such as a Guidant Hi-Torque Supracore 35 Guide
Wire is advanced through the ostium OS and into the paranasal
sinus. As shown in FIG. 12B, a balloon catheter 200 such as the
Guidant Agiltrac 0.035 Peripheral Dilatation Catheter having a
balloon 202 formed of relatively strong material such as
polyethylene teraphthalate is then advanced over the guidewire GW
to a position where the balloon 202 is positioned within the ostium
OS. Thereafter, as shown in FIG. 12B, the balloon 202 is inflated
so as to dilate the ostium OS possibly breaking bone B that
surrounds the ostium OS and creating an enlarged ostium EOS.
Thereafter, as shown in FIG. 12C, the balloon 202 is deflated and
the balloon catheter 200 is withdrawn and removed, leaving the
guidewire GW in place. Thereafter, a delivery catheter of any of
the type described herein is advanced over the guidewire GW and to
deliver an empty implantable substance delivery device 12i of the
present invention within the enlarged ostium EOS such that a
portion of the device 121 extends into the sinus, as shown in FIG.
12D. In this example, the implantable substance delivery device 12i
is an over the wire type device 12i having a fill tube 204, an
intraostial portion 206 which includes a self-expanding frame 208
and intrasinus portion 210. As shown in FIG. 12E, after the
implantable substance delivery device 12i has been positioned such
that its intraostial portion is within the enlarged ostium EOS and
its intrasinus portion is within the paranasal sinus, the delivery
catheter and guidewire GW are removed and a quantity of the desired
diagnostic or therapeutic substance (e, g, a corticosteroid,
anti-inflammatory, antimicrobial, mucous modifying or mucolytic
agent, or other agent or substance effective to treat sinusitis) is
infused through the fill tube 204 into the device 12i. As shown in
FIG. 12E, this causes the intrasinus portion 210 of the device 12i
to swell or expand to an enlarged configuration that will not pass
out of the enlarged ostium EOS. Also, the intraostial portion 206
and frame 208 will enlarge to an expanded configuration that exerts
outward radial pressure against the enlarged ostium EOS for a
period of time sufficient to allow the enlarged ostium OS and any
broken bone BB therein to heal and remodel to the enlarged
diameter. Also, the substance(s) that was/were introduced into the
device 12i will diffuse out of the device 12 into the sinus at a
desired rate, thereby providing pharmacological treatment for the
infection, inflammation and/or other aspects of the sinusitis.
Thereafter the device 12i may biodegrade and/or may be removed and
the enlarged ostium will remain facilitating normal drainage from
the sinus thereafter.
[0117] Another embodiment of the substance delivery device
incorporates the addition of a micropump to one or all of the drug
containing chambers. The micropump would assist in active transport
of the drug across the membrane. The delivery rate of this pump
could be programmed ahead of time or via remote electronics. Other
methods of incorporating micromachinery or nanotechnology to enable
pressure assisted transport could be added to the substance
delivery device. Another example would include a semi-permeable
membrane where the reservoir volume continuously shrinks as drug is
eluted to maintain a certain driving pressure in the reservoir.
This shrinkage could be due to elastic properties of the membrane
or due to mechanically limiting and changing the space in the
reservoir. These devices could be refillable.
[0118] The abovementioned embodiments may be used as spacing
devices after a open surgical, laparoscopic surgical or an
interventional procedure. Further, these devices may be further
coated with an anti-infective agent or may be constructed of a
substance which is naturally bacteriostatic to reduce the
likelihood of toxic-shock syndrome or other device related
infections. Such a naturally bacteriostatic material would be a
biodegradable substance which, through the process of
biodegradation, undergoes hydrolysis, releasing bacteriostatic
substances such as hydrogen peroxide.
[0119] It is to be appreciated that the invention has been
described hereabove with reference to certain examples or
embodiments of the invention but that various additions, deletions,
alterations and modifications may be made to those examples and
embodiments without departing from the intended spirit and scope of
the invention. For example, any element or attribute of one
embodiment or example may be incorporated into or used with another
embodiment or example, unless to do so would render the embodiment
or example unsuitable for its intended use. All reasonable
additions, deletions, modifications and alterations are to be
considered equivalents of the described examples and embodiments
and are to be included within the scope of the following
claims.
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