U.S. patent application number 12/138364 was filed with the patent office on 2008-10-02 for spacing devices for releasing active substances in the paranasal sinus.
This patent application is currently assigned to Acclarent, Inc.. Invention is credited to Achim Gopferich, Werner Hosemann.
Application Number | 20080243140 12/138364 |
Document ID | / |
Family ID | 7673200 |
Filed Date | 2008-10-02 |
United States Patent
Application |
20080243140 |
Kind Code |
A1 |
Gopferich; Achim ; et
al. |
October 2, 2008 |
SPACING DEVICES FOR RELEASING ACTIVE SUBSTANCES IN THE PARANASAL
SINUS
Abstract
The invention relates to a spacing device (stent) for use in
fenestrations of the paranasal sinus. Said device consists of a
sheath which forms a hollow body, surrounding an internal cavity.
An active substance, which is released in a controlled manner by
the spacing device, is contained in the sheath or in at least one
layer of the sheath. The relationship q of the external diameter of
the hollow body to the internal diameter of the hollow body is
expressed by 1.2.ltoreq.q.ltoreq.3.0.
Inventors: |
Gopferich; Achim; (Sinzing,
DE) ; Hosemann; Werner; (Regensburg, DE) |
Correspondence
Address: |
STOUT, UXA, BUYAN & MULLINS LLP
4 VENTURE, SUITE 300
IRVINE
CA
92618
US
|
Assignee: |
Acclarent, Inc.
Menlo Park
CA
|
Family ID: |
7673200 |
Appl. No.: |
12/138364 |
Filed: |
June 12, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10470881 |
Feb 4, 2004 |
|
|
|
PCT/EP02/01228 |
Feb 6, 2002 |
|
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12138364 |
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Current U.S.
Class: |
606/109 ;
606/199; 623/23.7 |
Current CPC
Class: |
A61L 31/16 20130101;
A61L 2300/43 20130101; A61L 2300/434 20130101; A61L 2300/258
20130101; A61L 2300/602 20130101; A61K 9/0043 20130101; A61L
2300/432 20130101; A61L 31/10 20130101; A61F 2/186 20130101; A61L
2300/222 20130101; A61K 9/0092 20130101; A61L 2300/414
20130101 |
Class at
Publication: |
606/109 ;
606/199; 623/23.7 |
International
Class: |
A61M 29/02 20060101
A61M029/02; A61F 11/00 20060101 A61F011/00; A61F 2/82 20060101
A61F002/82 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 6, 2001 |
DE |
10105592.7 |
Claims
1. A method for treating a disorder that affects a paranasal sinus,
middle ear or trachea, said method comprising the steps of: A)
providing a substance delivering device that is implantable in an
opening of a paranasal sinus, middle ear or trachea, said device
comprising a tubular body having a wall, a lumen, first and second
open ends, an outer surface, an inner surface and a substance
containing layer, the substance containing layer comprising a
matrix that contains therapeutic substance such that a
therapeutically effective amount of the substance will elute from
the device while implanted, wherein said therapeutic substance
comprises at least one steroid; and B) implanting the device in an
opening of a paranasal sinus, middle ear or trachea such that a
therapeutic amount of the therapeutic substance is delivered to the
paranasal sinus, middle ear or trachea in which the device is
implanted.
2. A method according to claim 1 wherein Step B comprises
implanting the device in an opening of a paranasal sinus.
3. A method according to claim 1 wherein Step B comprises
implanting the device in an opening of a frontal sinus.
4. A method according to claim 1 wherein Step B comprises
implanting the device in an opening of a paranasal sinus that has
been dilated.
5. A method according to claim 1 wherein Step B comprises
implanting the device in an opening of a paranasal sinus that has
been surgically altered.
6. A method according to claim 5 wherein the device is implanted in
a surgically created fenestration.
7. A method according to claim 1 wherein the device is capable of
being radially expanded and wherein Step B comprises radially
expanding the device at an intended site of implantation.
8. A method according to claim 7 wherein the device is radially
expanded by inflating a balloon positioned within the device.
9. A method according to claim 1 further comprising the step of: C)
removing the device.
10. A method according to claim 9 wherein the device is removed
approximately 2 to 12 weeks after implantation.
Description
RELATED APPLICATIONS
[0001] This patent application is a division of copending U.S.
patent application Ser. No. 10/470,881 filed Feb. 4, 2004 which is
a national stage filing under 35 U.S.C. .sctn. 371 of
PCT/EP02/01228 filed Feb. 6, 2004, which claims priority to German
Patent Application No. DE10105592.7 filed Feb. 6, 2001, the entire
disclosure of each such application being expressly incorporated
herein by reference.
FIELD OF INVENTION
[0002] The present invention relates to a spacing device (stent)
for use in fenestrations of the paranasal sinus.
BACKGROUND OF INVENTION
[0003] About 5% of our population suffer from a chronic mucous
membrane inflammation of the paranasal sinuses. In the course of an
inflammation of this type, nasal polyps occur in every fifth
patient. If corresponding symptoms occur and an attempt at
medicinal treatment remains unsuccessful, the chronic sinusitis is
approached surgically.
[0004] The paranasal sinus system consists of a series of cavities
lined with mucous membrane and filled with air. The interruption of
the natural secretion drainage from the remote paranasal sinus
portions and the removal of natural ventilation are important in
the occurrence of chronic sinusitis. The remote, diseased paranasal
sinus portions are accordingly reventilated during cleaning-up
interventions through newly created or extended accesses
("windows"). After healing, the natural secretion drainage of these
reventilated compartments reappears.
[0005] Surgical treatment of chronic sinusitis has been transformed
after the introduction of modern optical aids (rigid endoscopes,
microscope). Nowadays, the "minimally invasive" clearing
exclusively of those mucous membrane parts which have undergone an
obviously irreversible change owing to the inflammation process
predominates. Other reversibly changed or unaffected mucous
membrane areas are spared as far as possible (Hosemann W G, Weber R
K, Keerl R E, Lund V J: Minimally invasive endonasal sinus surgery.
Thieme, Stuttgart, New York 2000).
[0006] If the frontal sinus mucous membrane is involved in the
inflammatory modification of the sinus a surgical fenestration
takes place towards the nose. This is carried out with special
instruments (bent sharp spoons, special stamps, drills). Accesses
of about 5 to a maximum of 10 mm in diameter are produced by
routine "fenestration" of the frontal sinus. During healing of the
wound these accesses narrow by about 1.5 mm.
[0007] If certain health factors are present, such as, for example
intolerance of analgesics, a disproportionate tendency to scarred
narrowing has to be taken into account (Hosemann W, Th. Kuhnel, P.
Held, W. Wagner, A. Felderhoff: Endonasal frontal sinusotomy in
surgical management of chronic sinusitis--a critical evaluation.
Am. J. Rhinology 11: 1-9 (1997)). In such cases it is advised to
maximise the surgical access as a precaution. This "widened frontal
sinus surgery" is subdivided into specific types (Draf W: Endonasal
micro-endoscopic frontal sinus surgery: the Fulda concept. Op Tech
Otolaryngol Head Neck Surg 2: 234-240 (1991); May M, Schaitkin B:
Frontal sinus surgery: endonasal drainage instead of an external
osteopolstic approach. Op Tech Otolaryngo Head Neck Surg 6: 184-192
(1995)).
[0008] As stated, the neo-ostium to the front sinus narrows to a
greater or lesser extent, according to experience. To prevent this
scarred stenosis it was already proposed at the start of the last
century, i.e. long before the introduction of minimally invasive
endoscopic surgery to insert a spacing device (stent). These
spacing devices usually had the form of a small tube and were made
of various materials: at the beginning rolled metal or metal
braided in wires was used (Fletscher Ingals E: New operation and
instruments for draining the frontal sinus. Ann Otol Rhinol
Laryngol 14: 515-519 (1905), Good R H: An intranasal method for
opening the frontal sinus establishing the largest possible
drainage. Laryngoscope 18: 266-274 (1908)). In the last two decades
silicone tubes were preferred (Stammberger H: Komplikationen
entzundlicher Nasennebenhohlenerkrankungen eischlie.beta.lich
iatrogen bedingter Komplikationen. Eur Arch Oto-Rhino-Laryngol
Suppl 1993/1: 61-186).
[0009] Experience with spacing devices for stabilising the newly
created frontal sinus access was not always, however, encouraging,
apart from individual reports (Jacobs J B: 100 years of frontal
sinus surgery. Laryngoscope 107: 1-36 (1997); Weber, R, W.
Hosemann, W. Draf, R. Keerl, B. Schick, S. Schinzel: Denonasale
Stirnhohlenchirugie mit Langzeiteinlage eines Platzhalters.
Laryngol. Rhinol. Otol. 76: 728-734 (1997).
[0010] Initially it remained unclear as to how long a spacing
device of this type was required in the area of the operation. From
animal experiments on wound healing, it became clear that a scarred
narrowing of the frontal sinus access for a post-operative period
of at least three months has to be assumed (Hosemann, M. E. Wigand,
U. Gode, F. Lnger, I. Dunker: Normal wound healing of the paranasal
sinuses--clinical and experimental investigations, Eur. Arch,
Otorhinolarylgol. 248: 390-394 (1991)). Accordingly, the spacing
device would have to be used over eight to twelve weeks. Even with
the correct duration in position a spacing device will often only
delay and possibly reduce in scope the undesired scarred narrowing,
without being able to prevent it completely. An additional
medicinal treatment to reduce excessive wound reactions would have
to take place here.
[0011] According to the present level of knowledge about wound
healing processes in the nose the administration of medicinal
substances such as, for example, corticosteroids, seems to be in a
position to counteract, with a certain reliability, this tendency
to regenerating mucous membrane for scarred stricture of the front
sinus nose passage (Hosemann, M. E. Wigand, U. Gode, F. Lnger, I.
Dunker: Normal wound healing of the paranasal sinuses--clinical and
experimental investigations. Eur. Arch. Otorhinolaryngol. 248:
390-394 (1991); Hosemann W, Gode U, Langer F, Wigan M E:
Experimentelle Untersuchungen zur Wundheilung in den
Nasennebenhohlen. II. Spontaner Wundschluss und medikamentose
Effekte im standardisierten Wundmodell. HNO 39''48-54 (1991);
Hosemann W, Kuhnel Th, Allert M H. Weiterbehandlung nach
Nasennebenhohleneingriffen, part 2: Theapeutische Ma.beta.nahmen,
HNO aktuell 7: 291-302 (1999).
[0012] Unfortunately, conventional medicine forms such as salves or
sprays do not reach into the problem region of the transition of
frontal sinus and nose during routine application (Prince M E P,
Lemckert R J: Analysis of the intranasal distribution of ointment.
J Otolaryngol 26: 357-360 (1997); Weber R. Keerl R, Radziwill R,
Schick B, Haspersen D, Dshambazov K, Mlynski G, Draf W:
Videoendoscopic analysis of nasal steroid distribution. Rhinology
37: 69-73 (1999)).
[0013] Postoperative systemic administration of corticosteroids is
certainly usual in rhinosurgery (Bumm P:
Hals-Nasen-Ohrenkrankheiten. In: Kaiser H, Kley H K (Hrsg.)
Cortizontherapie, Corticoide in Klinik und Praxis. Thieme,
Stuttgart 1992, pages 390-401), but the treatment plans do not
usually extend over the required duration of 8 weeks. Moreover,
with longer-term systemic corticosteroid administration side
effects of the treatment have to be increasingly taken into
account.
[0014] The presently described problems show the need for systems
which can in a controlled manner dispense the active substances
such as, for example, corticosteroids over a longer period directly
to the operation site.
[0015] A series of systems have been proposed for the controlled
release of medicinal substances such as, for example implants of
polymers loaded with a medicinal substance. U.S. Pat. No. 5,633,000
thus describes implants for the release of pain killers. The
polymers used there release the active substance via diffusion.
U.S. Pat. No. 5,019,372 describes that this release can be
modulated by incorporation of magnetic particles and by application
of alternating magnetic fields. If this formed body is designed
with a correspondingly defined geometry the release of the active
substances can be optimised such that they are released over the
application period at a constant speed (U.S. Pat. No.
4,803,076).
[0016] The polymers used for such applications include, apart from
biodegradable materials, non-biodegradable materials, i.e. those
which do not decompose on contact with body fluids. Examples of
such polymers are silicone, polyacrylate and ethylene vinyl acetate
copolymer (U.S. Pat. No. 4,069,307). The last polymer group, in
particular, was used for a series of systems for controlled release
of active substances.
[0017] U.S. Pat. No. 3,393,073 thus describes a so-called reservoir
system consisting of a medicinal substance reservoir which is
surrounded by a polymer sheath regulating the release rate of the
medicinal substance. Such systems were successfully used for the
development of "intra-uterine devices" which release the active
substance in the uterus (U.S. Pat. No. 3,967,618 and U.S. Pat. No.
4,016,251) and for producing therapeutic systems which release
medicinal substances to the eye (U.S. Pat. No. 4,052,505).
[0018] Such systems were also described, as carrier systems with a
microporous membrane controlling the discharge of the active
substance, for introduction into various body cavities, such as for
example, the ear, nose or the rectum (U.S. Pat. No. 3,948,254).
[0019] Those made of plastics are described in the area of "stents"
for the treatment of paranasal sinuses, such as, for example in
U.S. Pat. No. 5,693,065 or U.S. Pat. No. 5,336,163. U.S. Pat. No.
5,693,065 describes a stent for the nose area made of silicone
rubber having a cylindrical shaft of which the leading end to be
inserted into the nose is designed in the shape of the point of a
spear, the base of the point connected to the shaft having a wider
diameter than the shaft. The point is closed at the front and
laterally has ribs with slits therebetween, the ribs expanding in
the inserted state and thus ensuring the hold of the stent in the
nose area.
[0020] An external diameter of 0.157 inches and an internal
diameter of 0.118 inches is given as the dimensions for the shaft.
The firm seat of the stent in the nose passage is only ensured,
however, by the spreading of the spear-shaped point.
[0021] U.S. Pat. No. 5,336,163 relates to a stent for the nose area
formed from a porous material and having a non-adhering, but
slightly porous outer surface. The stent is formed from a material
here which expands on contact with liquid.
[0022] U.S. Pat. No. 5,601,594 describes a stent for insertion into
a nose aperture, the stent having a bent shape and being formed
from a compressible material.
[0023] However, these are systems which are free of medicinal
substances and the action of which only aims to keep open the
accesses to the frontal sinus by physical/mechanical effects.
[0024] Despite this progress in the area of controlled release of
active substances there has previously not been any indications
that this technology could be usable for the post-operative care of
sinus systems after minimally invasive clearing. Although so-called
"stents" which prevent a tissue reconstruction are known these are
described exclusively for the treatment of blood vessels and are
accordingly geared to other biological needs.
[0025] U.S. Pat. No. 5,980,551 describes a stent for blood vessels,
the stent having an inner support structure which may be formed
from a wire and the support structure is surrounded by a
biodegradable resorbable substrate. Biologically active
microparticles which release active substances in a controlled
manner can be embedded into this substrate.
[0026] Stents for suppressing the restenosis of coronary arteries
have design features which clearly differ from the subject of the
invention and therefore also make them unsuitable for application
in the frontal sinus.
[0027] In many cases the "coronary stents" also require application
aids. Such application aids are described in combination with a
stent in U.S. Pat. No. 6,080,190 and U.S. Pat. No. 5,843,089. A
serious problem of coronary stents to release active substances is
the construction of the medicinal substance release system.
Coronary stents generally consist of a stent body such as, for
example, a wire braiding covered with medicinal substance-carrying
polymers or sheathed in thin polymer films (U.S. Pat. No.
5,824,048, U.S. Pat. No. 5,700,286, U.S. Pat. No. 5,837,313, U.S.
Pat. No. 5,679,400). The mechanical stability of these stents is
geared to the needs of arteries and makes them unsuitable for
application in the nasal sinus, as they are not mechanically stable
enough.
[0028] Coronary stents are rotationally symmetrical hollow bodies
and preferably have the geometry of a hollow cylinder. They can
therefore not be fixed via thickenings at the cylinder end in a
fenestration of the paranasal sinus. Moreover, a fenestration of
the paranasal sinus is generally not uniformly round, but more or
less irregular which creates additional problems with respect to
anchoring. In general, coronary stents cannot have large wall
thicknesses so as not to impede the blood flow.
[0029] Moreover, coronary stents differ from spacing devices for
paranasal sinuses due to their function. The coronary stent is
intended to expand the vessel in many cases. The front sinus
spacing device, on the other hand, is inserted in a surgically
applied passage which has bony (stable) walls. This passage was
surgically newly formed; the coronary artery, on the other hand is
left as a tube, but expanded.
[0030] A coronary stent is a permanent implant, it is completely
absorbed by the body. The frontal sinus spacing device, on the
other hand, is removed after a period of about 8 weeks.
[0031] The coronary stent is completely absorbed by the body. Blood
flows in the interior of the coronary stent; the wall is completely
colonised in the most favourable case by the body's own cells
(endothelial cells). With the frontal sinus spacing device,
complete absorption into the body is not desirable. Secretion from
the mucous membrane surface should drain in the interior of the
frontal sinus spacing device and ventilation should simultaneously
be ensured. Colonisation of the interior of the spacing device with
the body's own cells is neither anticipated nor desired.
[0032] On the other hand, the mucous membrane should widen at the
outside of the frontal sinus spacing device. In this manner, once
the spacing device has been removed, a passage lined with intact
mucous membrane should remain.
[0033] A problem in the coronary stent is the formation of a clot
with the risk of an occlusion which has to be suppressed by the
administration of special medication. The frontal sinus spacing
device does not require the administration of special
medication.
[0034] It has been proposed to produce medical devices used in the
body from a material loaded with active substance or to coat them
therewith.
[0035] WO 96/29071 describes medical devices such as catheters or
stents, on the surface of which antibacterial means are applied,
the antibacterial means adhering to the surface owing to adhesive
forces, without further aids being required.
[0036] It is proposed in general in WO 92/15286 to form medical
devices from a polymer loaded with medicinal substance or to
provide them with a coating thereof, stents also being mentioned
for use in the nasal area, without more detail about the
configuration of a stent of this type.
[0037] It was the object of the invention to provide a spacing
device suitable, in particular, for use in the paranasal sinus
having not only adequate stability and a firm hold but
simultaneously able to release in situ a desired active substance
in a controlled manner, a controlled release of the required amount
of active substance with the desired time course also being ensured
over an adequately long period for the treatment.
[0038] In addition, the spacing device according to the invention
allows an adequately large quantity of active substance to be
received and stored, without impairment of the controlled release
owing to interactions of the active substance contents.
[0039] According to the invention, this object is achieved by a
spacing device as described in the independent claims 1 and 2.
Advantageous developments are the subject of the sub-claims.
[0040] To do justice to the above-mentioned requirements the ratio
q of the external diameter r.sub.a to the internal diameter r.sub.i
of the stent body is a value of 1.2 and more.
[0041] According to the invention the ratio q is selected in a
range of 1.2.ltoreq.q.ltoreq.3.0, in particular of
1.2.ltoreq.q.ltoreq.2.8, preferably of 1.5.ltoreq.q.ltoreq.2.5 and
particularly preferably 1.8.ltoreq.q.ltoreq.2.2.
[0042] In contrast to this, for coronary stents the value q is
typically in a range of less than 1.2.
[0043] It has been shown, however, that with the smaller wall
thicknesses of the coronary stent in comparison to the stent
according to the invention for the paranasal sinus, the controlled
release of active substance as desired according to the invention
cannot be achieved.
[0044] The quotient q can thus serve as the calculation basis here.
For example, for a hollow cylinder the volume V can be calculated
from the height h, the internal diameter r.sub.i and q:
V=.pi.hr.sub.i.sup.2(q.sup.2-1) [1]
[0045] Formula I makes it clear that the volume of a coronary stent
(with q=1.2), with the same internal diameter r.sub.i and the same
height h is a maximum of about 15% of the volume of a paranasal
sinus spacing device according to the invention (with q=2). It
follows from this that stents with q=1.2 or less can receive a
maximum of 1/7 of the active substance dose of a paranasal sinus
spacing device according to the invention.
[0046] The quotient q has serious consequences for the release
periods over which active substances can be released. To estimate
the release duration t as a function of the thickness of a material
I and the diffusion coefficients D, in the literature the
dimensionless expression:
t = I 2 D [ 2 ] ##EQU00001##
[0047] is used (Cussler, E. L.; Diffusion: Mass Transfer in Fluid
Systems, Cambridge Univ. Press, 1996). The diffusion section in a
hollow cylinder can be estimated as half the difference between
external diameter r.sub.a and external diameter r.sub.i. In a stent
with a constant internal diameter r.sub.i the release duration is
reduced to 4% when q is reduced from 2 to 1.2. For the
above-mentioned reasons, for the described paranasal sinus spacing
device the value q is preferably above 1.2 and in particular in a
range 1.2.ltoreq.q.ltoreq.2.8, particularly preferably
1.5.ltoreq.q.ltoreq.2.5 and particularly preferably the range is
1.8.ltoreq.q.ltoreq.2.2.
[0048] According to a further aspect, the invention relates to a
spacing device for the paranasal sinus in which the layer or layers
loaded with active substance are separated towards the inner cavity
by a layer consisting of a material which is impermeable or at
least virtually impermeable for the active substance. Active
substance losses are thus avoided and the duration over which the
active substance is released is simultaneously increased.
[0049] Serious differences also exist with respect to the
mechanical properties. Coronary stents which are introduced via a
catheter into the blood vessels have to be plastically, i.e.
irreversibly deformable. Owing to an irreversible widening of the
stent, they have to be fixed to the vessel wall.
[0050] The spacing device developed in the course of this invention
for use in the paranasal sinus, in contrast thereto, is
distinguished by elastic properties and therefore reversible
deformability; the paranasal sinus spacing device can be fixed
simply in the apertures to the paranasal sinus, inter alia owing to
this elasticity.
[0051] It is possible with the spacing device (stent) loaded with
active substance according to the invention to keep the frontal
sinus accesses open not only by a physical/mechanical mechanism,
but also by a pharmacological mechanism. These spacing devices are
adapted to the surgically created accesses to the paranasal sinus
and fulfil two functions:
[0052] 1. They keep physically open the newly created
"fenestration" of the front sinus in the course of the minimally
invasive clearing. On the one hand, this is achieved by the
application of the spacing device to the surgically changed tissue
and assisted by the encouragement of the secretion drainage from
the sinus.
[0053] 2. The developed spacing devices may release active
substances such as medicinal substances such as, for example
corticosteroids which suppress tissue formation or overshooting
wound healing and therefore keep open the surgically newly created
fenestration.
[0054] In order to be able to fulfil both functions in an optimal
manner, the "stent" has some design features which will be
described in more detail hereinafter with the aid of the
figures.
[0055] The spacing device according to the invention is a hollow
body which is composed of a sheath surrounding an inner cavity and
having a respective aperture at two opposing ends.
[0056] The hollow body is preferably based on a cylindrical shape
wherein it can deviate from the ideal cylindrical form with an in
particular uniform diameter along the shaft.
[0057] The external diameter along the cylinder shaft may thus
vary, for example the external diameter in the end regions close to
the apertures may be selected to be larger than in the central
shaft region.
[0058] Starting from the end regions, the external diameter may
continuously reduce in the direction of the central shaft region,
may be reduced in the manner of an hourglass in the central region,
wherein the specific shape of the cylindrical basic body can be
adapted in any way as necessary.
[0059] The wall thickness of the cylinder may also be selected to
be variable.
[0060] Thus, in the drawings:
[0061] FIG. 1 shows a preferred configuration according to the
invention of the spacing device in cylindrical form,
[0062] FIG. 2 shows the top view of a cross-section through a
spacing device loaded with active substance according to the
invention,
[0063] FIG. 3 shows the top view of a cross-section of another
preferred configuration of the spacing device according to the
invention as a reservoir system with a plurality of layers,
[0064] FIG. 4 shows a further configuration of the spacing device
according to the invention with perforations in the sheath,
[0065] FIG. 5 shows a configuration of the spacing device according
to the invention, wherein the external diameter of the cylindrical
shaft in the end regions is greater than towards the centre and
furthermore the wall thickness increases towards the centre of the
cylinder shaft,
[0066] FIG. 6 shows a further configuration of the spacing device
according to the invention as a matrix system with a plurality of
layers, and
[0067] FIG. 7 is a graph with the release curve of an active
substance from a preferred layer material according to the
invention.
[0068] The geometry of the spacing device is preferably that of a
hollow cylinder as can be seen in FIG. 1, wherein a sheath 1
surrounds an inner cavity having apertures 2 at the two opposing
ends of the cylinder shaft. This cylinder form encourages the
secretion drainage from the sinuses owing to its tubular
design.
[0069] The length of the cylinder is preferably selected here in a
range of 5 to 30 mm and its external diameter in a range of 1 to 30
mm. The wall thickness is to be selected according to need as a
function of the physical properties of the polymer materials used
and the active substances used and the desired release profile
within the above-mentioned ranges for the ratio q of external
diameter to internal diameter.
[0070] The at least two inner apertures 2 typically have a diameter
in a range of 0.5 to 25 mm.
[0071] FIG. 2 shows an example of a spacing device with a
monolithic construction, wherein the sheath 1 is composed of a
single layer and the layer material forms the matrix for the active
substance.
[0072] FIG. 3 shows an example of a configuration of the spacing
device according to the invention as a reservoir system, wherein
the active substance is contained in a reservoir 4. In this case
the active substance is not contained in a matrix material, unlike
in the matrix system. The active substance may here directly form
the layer forming the reservoir or the active substance may be
provided in a corresponding cavity. The latter case is suitable in
particular for liquid or semi-solid active substances or for liquid
or semi-solid carriers containing the active substance. The active
substance to be released may also be dissolved or suspended in the
reservoir system.
[0073] The release-controlling material forming the cavity, for
example a reservoir 4 is surrounded by an outer membrane 3 which
preferably consists of a polymer material through which the active
substance can diffuse.
[0074] The cavity forming the reservoir 4 is preferably separated
on the inside to the inner cavity 3 by an inner wall 4 preferably
consisting of a material which is impermeable or virtually
impermeable to the active substance.
[0075] An inner layer (inner wall 4) which is as impermeable as
possible to the active substance is suitable in principle for any
active substance-carrying systems for avoiding active substance
losses in the direction of the inner cavity 3.
[0076] The inner wall 4 may consist here of a corresponding polymer
material but also of an inorganic material such as a metal etc.
[0077] The sheath 1 may have perforations 7, as shown in FIG. 4,
which connect the inner cavity 3 to the outer surface of the stent.
The secretion drainage can also be assisted by this measure.
[0078] The form and number of perforations 7 can be freely selected
here as required.
[0079] A configuration according to the invention with a varying
external diameter is shown in FIG. 5. In the embodiment shown in
FIG. 5, the external diameter of the stent is selected to be
greater at the end regions with the apertures 2 than in the central
region and decreases continuously towards the centre.
[0080] As shown here, the wall thickness may also vary, wherein it
decreases in this case towards the end regions.
[0081] The wall thickness, in other words the ratio q of external
diameter to internal diameter may, as required, in particular in
the end regions or else in short central sections be outside the
value to be adjusted according to the invention for q, if the
usability of the stent is not impaired. Thus, at least in the wound
regions q should be within the above-mentioned value range
according to the invention of 1.2.ltoreq.q.ltoreq.3.0. In the event
that in individual regions of the hollow body the wall thickness
has a value q outside the value range according to the invention,
these regions or this range should not be more than 30% of the
hollow body.
[0082] The stent according to the invention may be formed from one
or more layers, wherein the layers may consist of the identical
and/or different polymers. Individual regions of a layer, for
example the end regions close to the apertures 2 may be
manufactured from a material which is different from the material
for the remaining layer regions. In other words one layer may
contain at least one region which is formed from a different
material than the remaining layer.
[0083] In addition, the stent according to the invention may have
layers which are free of active substance in addition to layers
which are loaded with active substance.
[0084] If necessary, the stent according to the invention may be
surrounded by a suitable outer coating.
[0085] In contrast to coronary stents, the spacing device according
to the invention does not necessarily lie homogenously and in a
planar manner on the tissue. This circumstance requires a
particular construction so that, for example, secretion cannot
build up in the long term between the spacing device and the sinus
wall. Secretion drainage can be facilitated by perforations 7 in
the wall of the spacing device (see cross-section shown in FIG. 4).
With respect to its form the spacing device may show an
"hourglass-shaped"transition zone from the front sinus to the nasal
interior (FIG. 5) and permits endoscopy of the sinus through a
central aperture.
[0086] According to a further configuration, the space holder may
have irregularities such as humps etc. on its outer surface. In
this case, contact with the nasal wall is via these irregularities,
wherein, on the one hand, the contact face can be reduced and an
adequately firm hold is nevertheless ensured. The developing
cavities between the outer surface of the stent and nasal wall
simultaneously encourage secretion drainage.
[0087] The spacing device is moreover advantageously provided such
that suction of the paranasal sinus remains possible owing to the
spacing device. This is made possible owing to a relatively small
length. The spacing device is therefore preferably constructed such
that it can be cut to the desired length directly prior to
application.
[0088] The spacing device must be "anchored" counter to gravity in
the frontal sinus entry. This anchoring can be achieved by a
"ballooning" of the implant, i.e. a widening of the spacing device
end in the frontal sinus or fixing by means of a seam on the nasal
septum. Moreover, the stent may consist of materials which favour
anchoring and shape adaptation. In this context "shape memory
polymers" (for example U.S. Pat. No. 5,139,832, U.S. Pat. No.
5,189,110) or swelling polymers can be used (for example DE 4 032
096).
[0089] While the former change their shape at body temperature,
with swelling substances there is a volume increase of the material
owing to water absorption and therefore an increase in the stent
diameter after its application. The materials adapt optimally here
to the defect and thus prevent slipping of the stent. Owing to
their good permeability to water, swelling polymers prevent a build
up of secretion at the contact face to the tissue.
[0090] An example of this is shown in FIG. 6, wherein the outer
layer 9 consists of a deformable polymer and surrounds a polymer
layer 8 loaded with active substance.
[0091] The spacing device in the nose, in contrast to spacing
devices in vessels, is exposed to a bacteria-loaded environment
(mucous membrane wounds with free contact to the outside air).
Owing to corresponding shaping, scab formation and bacterial
contamination is delayed. This may, for example, be achieved by an
adequately large internal diameter of the spacing device
encouraging secretion drainage. The materials used may moreover be
modified at the surface in such a way that secretion drainage is
encouraged and bacterial contamination is avoided. An example is
the hydrophilising of the surface. For this purpose the interior of
the hollow body can be lined with a polymer layer which is highly
wettable and preferably has water contact angles
<45.degree..
[0092] As an alternative thereto, polymers can be used, the surface
of which has been chemically modified, such as, for example, by the
chemical bonding of hydrophilic substances or by treatment with gas
plasma.
[0093] To avoid any bacterial contamination the spacing device may
also be loaded with bactericidally or bacteriostatically active
substances.
[0094] In order to ensure the diverse functions of the stent, the
design of the matrix system may above all consist of a plurality of
polymer layers as the cross-section in FIG. 6 shows by way of
example. The number of layers is not limited to 2 as shown in the
figure. Thus a plurality of layers which fulfil different functions
can be combined with one another. Individual layers may be free of
medicinal substance or be loaded with one or more medicinal
substances. In loading different layers with various medicinal
substances, the latter may be released from the spacing device with
different kinetics. The thickness of individual polymer layers may
be thin, as desired, for example in the range of a few
micrometres.
[0095] The spacing device may also be already preformed prior to
application or else be shaped to its final geometry by processing a
precursor. Methods, such as, for example, extrusion or injection
moulding are excellently suited to producing preformed spacing
devices. For production from precursors polymer films may for
example be rolled to form hollow bodies and fixed by a seam.
[0096] The materials from which the spacing device can be produced
may be biodegradable or else non-biodegradable materials or a
combination thereof.
[0097] Examples of possible biodegradable materials are polymers of
lactic acid or glycolic acid and their copolymers. Further suitable
examples are to be found in the literature (K. Park, W. S. W.
Shalaby, H. Park, Biodegradable Hydrogels for Medicinal substance
Delivery, Technomic Publishing Inc. Lancaster 1993; A. Domb, J.
Kost, D. M. Wiseman, Handbook of Biodegradable Polymers, Harwood
Academic Publishers, 1997).
[0098] While biodegradable materials have the advantage of not
having to be removed after application, non-biodegradable materials
can be better fixed in the region of use of the spacing device.
Examples of such materials are silicones, polyacrylates and
polymethacrylates and the copolymers thereof (Eudragit.RTM.)),
poly(ethylene vinyl acetate) copolymer and other compositions as
described in the polymer literature and known for medical
applications.
[0099] The polymers should preferably be flexible so that they
adapt to the wound area. Moreover, they should be elastic enough to
remain in the fenestration and should be biocompatible, in other
words have good tolerability with respect to cells and tissues. To
ensure the mechanical adherence of the spacing device to the
fenestration, the polymers mentioned can be combined with other
materials, such as for example metals to ensure a reliable seat of
the "stent" with smaller wall thicknesses. These metals can be
incorporated into the wall of the cylinder.
[0100] The polymers can be processed by various industrial methods
to form the spacing devices shown in FIGS. 1 and 2, thus, for
example by extrusion or injection moulding or by polymerisation in
suitable moulds.
[0101] The casting of polymer solutions is a simple production
method (solvent casting). For this purpose the polymers are
dissolved in organic solvents and the solution is poured or sprayed
onto an inert surface. After evaporation of the solvent dry polymer
films loaded with active substance are obtained which can be cut
into any, for example rectangular forms.
[0102] While tubes are directly obtained by extrusion or injection
moulding, small individually adapted tubes can be formed from
rectangular polymer films directly before insertion into the
patient. This may take place by repeated rolling of the polymer
film or by mechanical adhesion or sticking of opposing film
edges.
[0103] Owing to the type of production, the polymer properties can
be controlled such that either smooth or porous surfaces are
produced. This influences the rate of active substance
administration and optionally the interaction between the spacing
device and wound edges.
[0104] The surfaces of the spacing device towards the tissue and
the secretion side may also be changed such that they optimally do
justice to the requirements of their functions. The inside of the
cylinder to the cavity of the spacing device may, for example be
physico-chemically changed on its surface such that there can be
improved wetting with secretion and therefore improved secretion
drainage. Examples are the above-mentioned hydrophilising of
surfaces or the covalent bonding of hydrophilic substances to the
polymer surfaces.
[0105] The surface to the tissue side may be chemically changed
such that the tissue compatibility is improved. This can be
achieved by a coating with materials in the form of thin films or
connection or application of functional groups or whole molecules
which interact with the biological system. Thus the anchoring of
polyethylene glycol chains to the surface leads to a reduced cell
attachment and this facilitates the removal of the spacing device
and increases it compatibility with the wound tissue.
[0106] The active substances can be selected according to need,
application, desired property etc. They can also be used in
combination. In particular, the stents according to the invention
are loaded with medicinal substances.
[0107] Substances are generally used as medicinal substances which
may influence the behaviour of cells and tissues, in particular
they should prevent uncontrolled tissue growth. For this purpose,
representatives of the group of glycocorticosteroids are suitable,
such as for example cortisol, corisone, prednisone, prednisolone,
6-methylprednisolone, dexamethasone, fludrocortisone,
desoxycorticoacetate. Further examples are proteins from the area
of cytokines and growth factors which are also said to have some
cell growth-inhibiting properties. Moreover, tyrosine kinase
inhibitors, antisense-oligonucleotides and mitosis inhibitors such
as mitomycin are suitable for eliminating the proliferative
influence of growth factors during wound healing.
[0108] The active substances can be released from the spacing
device over a long time period. Depending on the design and the
material used, releases can be carried out for up to several years.
Release preferably extends over a time period of 2 to 12 weeks.
Principles controlling the release include, apart from the wall
thickness expressed as the ratio q, primarily diffusion and polymer
swelling for non-biodegradable polymers. When using biodegradable
materials, i.e. those which dissolve during use, polymer erosion
also plays an important part (Gopferich, Polymer Degradation and
Erosion: Mechanismus and Applications, Eur. J. Pharm. Biopharm., 42
(1996) 1-11).
[0109] If the spacing device is produced from the preferred
non-degradable materials, the active substance is preferably
released from the reservoir or a matrix system. In both cases, the
active substance is released in the process by diffusion. The
release of active substance can be influence by a plurality of
factors. By changing the geometry the active substance can be
released over different lengths of time. Furthermore, it is
possible to control the kinetics of the active substance release by
the degree of loading.
[0110] The loading, in particular in the embodiment as a matrix
system, is preferably in a range up to 30% by weight based on the
total system. The minimum loading depends inter alia on the potency
of the active substance and on the desired duration of release.
[0111] To further influence diffusion additives can be added to the
polymer matrix or the polymers. Inert inorganic materials such as,
for example silicone dioxide thus lead to a reduction in the rate
of release. Depending on the type of polymer the rate of release
can be increased by plasticiser additives. During polymer swelling,
swelling can be increased by osmotic additives into the polymer and
the rate of release can therefore be increased depending on the
active substance properties.
[0112] To control the active substance release by erosion, the type
of biodegradable polymer can be geared to the application. Thus,
for example, it is known with poly(D,L-lactide-co-glycolide) that
the rate of release and the rate of erosion can be controlled by
the increase in the glycolide content.
[0113] The subject of the invention is a spacing device (stent)
which after surgical opening of the paranasal sinus (mainly the
frontal sinus) is inserted into the created fenestration to the
nose. The newly developed spacing device prevents a post-operative
scarred narrowing in that it combines two conventional treatment
attempts for the surgically newly created frontal sinus access:
[0114] 1. The spacing device acts as a physical barrier which
mechanically keeps the access to the frontal sinus open.
[0115] 2. The spacing device releases medicinal substances which
control the growth of the tissue around the newly created access to
the front sinus.
[0116] The material of the spacing device preferably has the
mechanical properties of an elastomer such as, for example
silicone, a proven material in ENT surgery for spacing devices.
Owing to the preferred geometry which corresponds substantially to
that of a hollow cylinder, secretion can drain from the sinuses.
Moreover, the material acts as a local release system for medicinal
substances such as for example corticosteroids. Owing to the shape
and function the stent ensures a firm seat and simultaneously
allows optimum secretion drainage. The continuous release of a
defined quantity of medicinal substance is preferably ensured over
a period of 8 weeks. The anticipated duration in position of the
implant is preferably also 8 weeks. For production, films loaded
with medicinal material, for example, can be rolled to form a
cylinder and stabilised with a surgical seam. The spacing device is
inserted intra operationem into the newly created frontal sinus
access. If necessary, it is fixed in the operation area by its
particular form, the materials used, its construction and/or by a
surgical seam to prevent displacement. Apart from the use in
fenestrations to the paranasal sinus, use is possible in the middle
ear and the trachea.
EXAMPLE
[0117] Production of a Dexamethasone-Loaded Polymer Film
[0118] The film has the following composition:
TABLE-US-00001 Evatane 40-55 (purified with acetone) 17.955 g
Dexamethasone DAB 10/Ph. Eur. 0.045 g Dichloromethane p.A. 98 ml
Acetone p.A. 4.5 ml
[0119] The polymer used, a poly(ethylene-vinyl acetate) copolymer
is initially freed of additives which were added during the
production of Evatane 40-55. 50 g of Evatane 40-55 are also weighed
out into a 500 ml iodine measuring cylinder with a magnetic
stirring rod. 250 ml acetone p.a. are measured with a measuring
cylinder and added to the polymer. The batch is stirred on the
magnetic stirrer for about a week and the acetone is then decanted.
The polymer is washed 3 times with 80 ml acetone p.a. and the
washing liquid discarded. The extraction and washing procedure is
repeated once with acetone and twice with ethanol using the same
volumes. The polymer is then dried in a crystallising dish in a
laminar airflow box for 48 h and then in a desiccator under
vacuum.
[0120] 17.955 g Evatane 40-55 are then weighed out into a 250 ml
iodine value vessel. The dichloromethane is added thereto and
stirred on the magnetic stirrer over 12 h. The dexamethasone is
dissolved in acetone and added to the polymer solution. The batch
is then left to stand for 10 min without stirring to remove air
bubbles. The solution is poured into a planar Teflon mould with an
area of 15 cm.sup.2 and dried in a laminar airflow box over 4
days.
[0121] The dried film is drawn from the Teflon mould and cut into
pieces of any size. The film thickness is about 0.8 to 1 mm. The
polymer films are rolled to form a hollow cylinder and preferably
fixed by a seam with a biocompatible seam material at the contact
points in such a way that the cylinder does not unwind owing to the
elasticity of the material. The small tube formed in this way is
then inserted into the fenestration to the paranasal sinus.
EXAMPLE
Release of Dexamethasone from the Polymer Film in Example 1
[0122] Round pieces with a diameter of 1.2 cm in diameter were cut
from the film described in Example 1 and the release determined in
vitro. The polymer platelets loaded with 0.25% dexamethasone were
also stored in closable glass vessels in 10 ml phosphate buffer at
37.degree. C. Samples were removed from the batch at regular
intervals and replaced by fresh buffer. The dexamethasone content
was determined per HPLC. FIG. 7 shows the release of dexamethasone
over the time.
LIST OF REFERENCE NUMERALS
[0123] 1 sheath [0124] 2 aperture [0125] 3 inner cavity [0126] 4
reservoir area [0127] 5 membrane [0128] 6 layer impermeable to
active substance [0129] 7 perforation [0130] 8 polymer layer loaded
with active substance [0131] 9 deformable polymer layer
* * * * *