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|United States Patent Application
;   et al.
October 2, 2008
SPACING DEVICES FOR RELEASING ACTIVE SUBSTANCES IN THE PARANASAL SINUS
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.
Gopferich; Achim; (Sinzing, DE)
; Hosemann; Werner; (Regensburg, DE)
STOUT, UXA, BUYAN & MULLINS LLP
4 VENTURE, SUITE 300
June 12, 2008|
|Current U.S. Class:
||606/109; 606/199; 623/23.7 |
|Class at Publication:
||606/109; 606/199; 623/23.7 |
||A61M 29/02 20060101 A61M029/02; A61F 11/00 20060101 A61F011/00; A61F 2/82 20060101 A61F002/82|
Foreign Application Data
|Feb 6, 2001||DE||10105592.7|
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; andB) 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
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.
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
The present invention relates to a spacing device (stent) for use in
fenestrations of the paranasal sinus.
BACKGROUND OF INVENTION
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.
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.
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).
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.
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)).
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).
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
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.
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).
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)).
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.
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
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).
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.
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.
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).
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.
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.
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.
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
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.
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
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.
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
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.
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
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.
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.
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
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
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.
It has been proposed to produce medical devices used in the body
from a material loaded with active substance or to coat them therewith.
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.
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.
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
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.
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.
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.
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
In contrast to this, for coronary stents the value q is typically in
a range of less than 1.2.
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.
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:
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.
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 ]
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
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
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
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.
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
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.
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.
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.
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.
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.
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.
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
The wall thickness of the cylinder may also be selected to be
Thus, in the drawings:
FIG. 1 shows a preferred configuration according to the invention of
the spacing device in cylindrical form,
FIG. 2 shows the top view of a cross-section through a spacing
device loaded with active substance according to the invention,
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,
FIG. 4 shows a further configuration of the spacing device according
to the invention with perforations in the sheath,
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,
FIG. 6 shows a further configuration of the spacing device according
to the invention as a matrix system with a plurality of layers, and
FIG. 7 is a graph with the release curve of an active substance from
a preferred layer material according to the invention.
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.
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
The at least two inner apertures 2 typically have a diameter in a
range of 0.5 to 25 mm.
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.
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.
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
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
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.
The inner wall 4 may consist here of a corresponding polymer
material but also of an inorganic material such as a metal etc.
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.
The form and number of perforations 7 can be freely selected here as
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.
As shown here, the wall thickness may also vary, wherein it
decreases in this case towards the end regions.
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.
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.
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.
If necessary, the stent according to the invention may be surrounded
by a suitable outer coating.
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
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.
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.
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).
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.
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.
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..
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.
To avoid any bacterial contamination the spacing device may also be
loaded with bactericidally or bacteriostatically active substances.
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
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.
The materials from which the spacing device can be produced may be
biodegradable or else non-biodegradable materials or a combination
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).
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.
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
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.
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
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.
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.
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.
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.
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
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.
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).
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.
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.
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.
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
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:
1. The spacing device acts as a physical barrier which mechanically
keeps the access to the frontal sinus open.
2. The spacing device releases medicinal substances which control
the growth of the tissue around the newly created access to the front
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.
Production of a Dexamethasone-Loaded Polymer Film
The film has the following composition:
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
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.
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.
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.
Release of Dexamethasone from the Polymer Film in Example 1
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
1 sheath 2 aperture 3 inner cavity 4 reservoir
area 5 membrane 6 layer impermeable to active substance
7 perforation 8 polymer layer loaded with active substance
9 deformable polymer layer
* * * * *