U.S. patent application number 12/767462 was filed with the patent office on 2010-11-11 for drug-coated balloon catheter and method for the production thereof.
This patent application is currently assigned to BIOTRONIK VI PATENT AG. Invention is credited to Patrice Bachmann, Raimund Moehl, Bodo Quint, Alwin Schwitzer, Michael Tittelbach, Matthias Wesselmann.
Application Number | 20100286608 12/767462 |
Document ID | / |
Family ID | 42102799 |
Filed Date | 2010-11-11 |
United States Patent
Application |
20100286608 |
Kind Code |
A1 |
Tittelbach; Michael ; et
al. |
November 11, 2010 |
DRUG-COATED BALLOON CATHETER AND METHOD FOR THE PRODUCTION
THEREOF
Abstract
The invention relates to a drug-coated balloon catheter and to a
method for producing the same. The balloon of the catheter includes
(i) a main membrane, and (ii) an asymmetrical polymer membrane
which is applied to an outside of the main membrane and into which
at least one pharmaceutical active ingredient is introduced.
Inventors: |
Tittelbach; Michael;
(Nuernberg, DE) ; Moehl; Raimund; (Forch, CH)
; Schwitzer; Alwin; (Buelach, CH) ; Wesselmann;
Matthias; (Glattfelden, CH) ; Quint; Bodo;
(Oberglatt, CH) ; Bachmann; Patrice; (Winterthur,
CH) |
Correspondence
Address: |
BIOTECH BEACH LAW GROUP , PC
5677 OBERLIN DRIVE, SUITE 204
SAN DIEGO
CA
92121
US
|
Assignee: |
BIOTRONIK VI PATENT AG
Baar
CH
|
Family ID: |
42102799 |
Appl. No.: |
12/767462 |
Filed: |
April 26, 2010 |
Current U.S.
Class: |
604/103.01 ;
427/2.3 |
Current CPC
Class: |
A61L 29/16 20130101;
A61L 2420/02 20130101; A61L 2420/06 20130101; A61L 29/085 20130101;
A61L 29/085 20130101; A61L 2/085 20130101; A61L 2/085 20130101;
C08L 75/04 20130101; A61L 29/085 20130101; A61L 2300/606 20130101;
C08L 77/00 20130101; C08L 77/00 20130101; C08L 77/00 20130101 |
Class at
Publication: |
604/103.01 ;
427/2.3 |
International
Class: |
A61L 31/16 20060101
A61L031/16; A61M 25/10 20060101 A61M025/10; B05D 3/00 20060101
B05D003/00 |
Foreign Application Data
Date |
Code |
Application Number |
May 7, 2009 |
DE |
10 2009 002 893.5 |
Claims
1. A drug-coated balloon catheter having a balloon, comprising: (i)
a main membrane, and (ii) an asymmetrical polymer membrane which is
applied to an outside of the main membrane and into which at least
one pharmaceutical active ingredient is embedded.
2. The catheter according to claim 1, wherein the main membrane
comprises a polymer material at least on the side thereof facing
the polymer membrane.
3. The catheter according to claim 2, wherein the polymer material
of the main membrane is selected from the group consisting of
polyurethane, polyether-polyurethane, polyethylene terephthalate,
polybutylene terephthalate, polyamide, and copolymers and blends
thereof.
4. The catheter according to claim 3, wherein the polymer material
of the main membrane is polyamide.
5. The catheter according to claim 1, wherein the polymer membrane
comprises polyurethane or polyether-polyurethane.
6. The catheter according to claim 1, wherein at least one
pharmaceutical active ingredient is embedded into the polymer
membrane.
7. A method for producing a drug-coated balloon catheter,
comprising the following steps: a) providing a balloon blank having
a main membrane; b) wetting the main membrane with a homogeneous
polymer solution comprising a solvent and a polymer; c) inducing a
phase separation of the polymer from the polymer solution by a
measure selected from the group consisting of: (i) Temperature
change, (ii) immersing the wetted balloon blank in a bath of a
liquid which can be mixed with the solvent of the polymer solution,
but which does not dissolve, or hardly dissolves, the polymer, and
(iii) exposing the wetted balloon blank to an atmosphere which
comprises a gaseous constituent which can be mixed with the solvent
of the polymer solution, but does not dissolve, or hardly
dissolves, the polymer.
8. The method according to claim 7, wherein step c) is carried out
in an expanded state of the balloon blank.
9. The method according to claim 8, wherein the polymer solution
comprises a pharmaceutical active ingredient.
10. The method according to claim 7, wherein the balloon is dried
after the phase separation, and subsequently a pharmaceutical
active ingredient is embedded by applying an active ingredient
solution, or a pure active ingredient, onto the polymer membrane in
the expanded state of the balloon blank.
11. The method according to claim 7, wherein the main membrane of
the balloon comprises polyamide at least on the side thereof facing
the polymer membrane, and the polymer solution is a solution of
polyurethane or polyether-polyurethane in tetrahydrofurane (THF) or
dimethylformamide (DMF).
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This invention claims benefit of priority to Germany patent
application serial number DE 10 2009 002 893.5, filed on May 7,
2009; the contents of which is herein incorporated by reference in
its entirety.
FIELD OF THE INVENTION
[0002] The invention relates to a drug-coated balloon catheter and
to a method for producing the same.
BACKGROUND OF THE INVENTION
[0003] The use of balloon catheters is a preferred therapeutic
method for a wide variety of indications in many areas of medical
technology. In angioplasty and cardiology, for example, a dilation
of constricted blood vessels by way of balloon dilation is
proposed, releasing restenosis-inhibiting drugs at the same time.
According to one variant, for this purpose the drugs are applied
directly onto the balloon to be dilated. However, it has been found
that in practice up to 80% of the adhering drug is not applied at
the desired location of the vessel, but instead is dissolved
beforehand by the body fluid present in the lumen and carried away.
This increases the risk of undesirable systemic side effects of the
drugs.
[0004] As a counter measure, it has been proposed, for example, to
conduct the expansion of the balloon catheter over a
dumbbell-shaped intermediate stage, in which the two ends of the
balloon catheter shield the intermediate region coated with drugs
from the lumen of the vessel. Thereafter, the balloon is fully
expanded. Such a dumbbell-shaped balloon catheter used as an
intermediate stage, however, is very complex to produce and handle
and therefore prone to failure. In addition, it is impossible to
prevent the drug from being rinsed out when irregular vessel
geometries came into play.
[0005] A different approach would be to apply a coating receiving
or covering the drug. The production of such a coating, however, is
complex and catheters coated in this manner generally have short
shelf lives. The coating material must be biocompatible, and the
properties of the drug and the coating system must be matched to
each other in each individual case. In practice, this makes the
implementation of such a drug-coated balloon catheter very complex,
and it still does not provide the desired extent of safety for the
local administration of the drug.
SUMMARY OF THE INVENTION
[0006] It is therefore the object of the invention to provide a
drug-coated catheter, which solves or at least mitigates one or
more the problems addressed above.
[0007] A first aspect of the present invention is a drug-coated
balloon catheter having a balloon, comprising (i) a main membrane,
and (ii) an asymmetrical polymer membrane which is applied to an
outside of the main membrane and into which at least one
pharmaceutical active ingredient is embedded.
[0008] Another aspect of the present invention is a method for
producing a drug-coated balloon catheter, comprising the following
steps: (a) providing a balloon blank having a main membrane; (b)
wetting the main membrane with a homogeneous polymer solution
comprising a solvent and a polymer; (c) inducing a phase separation
of the polymer from the polymer solution by a measure selected from
the group consisting of (i) Temperature change, (ii) immersing the
wetted balloon blank in a bath of a liquid which can be mixed with
the solvent of the polymer solution, but which does not dissolve,
or hardly dissolves, the polymer, and (iii) exposing the wetted
balloon blank to an atmosphere which comprises a gaseous
constituent which can be mixed with the solvent of the polymer
solution, but does not dissolve, or hardly dissolves, the
polymer.
DESCRIPTION OF THE DRAWINGS
[0009] The invention is described based on the attached
drawings.
[0010] FIG. 1 shows an illustration of the balloon membrane of a
balloon catheter modified using the method according to the
invention.
[0011] FIG. 2 shows an enlarged section of the surface of the
balloon membrane of FIG. 1.
DETAILED DESCRIPTION OF THE INVENTION
[0012] A first aspect of the invention is to provide a drug-coated
balloon catheter, the balloon of which includes: (i) a main
membrane, and (ii) an asymmetrical polymer membrane which is
present on an outside of the main membrane and into which at least
one pharmaceutical active ingredient is introduced.
[0013] The balloon catheter according to the invention therefore
includes a microporous asymmetrical polymer membrane on the outside
of the balloon wall. This polymer membrane has a plurality of pores
and micro-furrows, into which the drug to be applied is embedded in
solute form or pure form. With respect to morphology, asymmetrical
polymer membranes stand out in that they have a higher thickness at
the outsides thereof than at the bases thereof, which is to say on
the side facing the main membrane. Accessibility of the cavities of
the polymer membrane in the non-expanded state of the balloon is so
low that any rinsing out of the drug by body fluid is significantly
reduced or even prevented. It is only in the expanded state that
the pores and micro-furrows at the top of the polymer membrane are
dilated such that the incorporated active ingredient can be
released without difficulty.
[0014] Accordingly, asymmetrical polymer membranes have a thin
cover layer with suitable mechanical stability, which protects a
porous structured located underneath. The term "asymmetrical
membrane" summarizes this very morphology in one term and is also
used in the literature (see, for example, Membrane Technology in
the Chemical Industry, 2001 Wiley-VCH Verlag GmbH, Chapter 3, pages
6-11). The structure of asymmetrical polymer membranes is dependent
on the production method thereof. Consequently, another aspect of
the invention is directed at the production of such a drug-coated
balloon catheter. The method includes the following steps: (a)
providing a balloon blank having a main membrane; (b) wetting the
main membrane with a homogeneous polymer solution including a
solvent and a polymer; (c) inducing a phase separation of the
polymer from the polymer solution by one of the following measures:
(i) Temperature change, (ii) immersing the wetted balloon blank in
a bath of a liquid which can be mixed with the solvent of the
polymer solution, but which does not dissolve, or hardly dissolves,
the polymer (wet process), or (iii) exposing the wetted balloon
blank to an atmosphere which includes a gaseous constituent which
can be mixed with the solvent of the polymer solution, but does not
dissolve, or hardly dissolves, the polymer (dry method).
[0015] After step (a), the method is therefore based on a balloon
catheter having a balloon, the outer membrane wall is to be coated.
For the purpose of the invention, it is immaterial whether this is
a monolumen, multilumen, or multi-layer catheter. In any case, the
outside of the balloon, hereinafter referred to as the main
membrane, is modified by deposition of the asymmetrical polymer
membrane.
[0016] The main membrane, at least on the outside thereof,
preferably includes a polymer material that is commonly used for
these purposes, in particular the polymer material of the main
membrane is selected from the group including of polyurethane,
polyether-polyurethane, polyethylene terephthalate, polybutylene
terephthalate, polyamide, and also copolymers and blends thereof.
Polyamides are particularly preferred because they have
particularly high strength.
[0017] Typical balloon materials are usually semicrystalline
thermoplastic resins, wherein in the PTCA/PTA field primarily
polyamides, polyethylene terephthalate (PET), or polybutylene
terephthalate (PBT), and the copolymers and blends thereof are
used. Polyurethanes are gaining increasing importance as
alternative materials for expandable and adaptable balloon
applications. Typical occlusion balloons are frequently made of
latex.
[0018] Furthermore, a homogeneous polymer solution is provided,
including a solvent having a polymer that is suited for developing
the asymmetrical polymer membrane. Polyurethanes or
polyether-polyurethanes are polymers that are particularly
preferred. However, it is also possible to use other polymers which
can be homogeneously dissolved in a solvent, such as aromatic
polyimides, polyethersulfones, polypropylene, cellulose, and
cellulose derivatives.
[0019] The solvent should be selected such that a sufficiently high
concentration of the polymer for the method is possible. In
addition, the properties of the solvent significantly influence the
phase inversion. Suitable solvents include in particular
dimethylformamide (DMF) and tetrahydrofurane (THF). The latter is
particularly preferred, because it is easy to remove from the
product as a result of the relatively low boiling point thereof and
the excellent water solubility thereof. In the solvents mentioned
above, in particular polyurethane and polyether-polyurethane have
particularly high solubility.
[0020] The homogeneous polymer solution is applied in step (b) onto
the region of the balloon catheter to be coated, be it by immersion
into the solution or by spraying on the same, for example. Wetting
can take place in particular in the expanded state of the balloon
blank, so that the regions of the polymer membrane close to the
surface are further compacted upon deflation, making accessibility
to the inner structure from the outside more difficult.
[0021] The process of phase inversion of the initially homogeneous
polymer solution is initiated by a temperature change (alternative
(i) step (c)), by immersing the wetted balloon blank into a bath of
a fluid that can be mixed with the solvent of the polymer solution,
but which does not dissolve, or hardly dissolves, the polymer (wet
process; alternative (ii) step (c)), or by exposing the wetted
balloon blank to an atmosphere which includes a gaseous constituent
which can be mixed with the solvent, but which does not dissolve,
or hardly dissolves, the polymer (dry method; alternative (iii)
step c)).
[0022] During the thermal process, typically a low-molecular
compound acts as the solvent at high temperatures, but dissolves
the powder only insufficiently at lower temperatures. Such a
process lends itself whenever the polymer to be deposited has poor
solution properties, such as polypropylene.
[0023] Isothermal phase separation, in particular after the drying
process, is preferred in the present case. In this process, the
polymer solution is exposed to a liquid or gaseous constituent,
which gradually spreads in the polymer solution, starting from the
outside of the liquid polymer film. However, this constituent
cannot dissolve, or hardly dissolves, the polymer, so that the
polymer is precipitated by way of phase separation. Such a system
is particularly easy to implement, for example, when using a THF
polymer solution: here, water or a water/alcohol mixture can be
used as the non-solvent for the polymer.
[0024] The morphology of the asymmetrical polymer membrane forming
over the course of the method can be influenced by the selected
method parameters. The underlying mechanisms of the process are
complex and have so far not been conclusively clarified. For
practical applications, however, parameters are known, which result
in structures of a predominantly foam-like, microporous nature or
having finger-like cavities/micro-furrows. The foam-like structure
is preferably formed when the polymer concentration in the polymer
solution rises, the viscosity of the polymer solution is increased,
such as by adding a cross-linking agent, or mixtures of solvents
and non-solvents are used. For the present purposes, a structure
representing a mixture of both structure types is preferred.
[0025] In the simplest case, the pharmaceutical active ingredient
can already be present in the polymer solution. This drastically
simplifies the manufacturing process. However, it is also
conceivable to apply a solution of a pharmaceutical active
ingredient, or the pure active ingredient, onto the dried and
purified polymer membrane after the asymmetrical polymer membrane
has been produced. This application should be carried out in
particular in the expanded state of the balloon in order to
facilitate embedding of the material into the inner lumen of the
polymer layer. Ideally, the active ingredient, or the active
ingredient solution, has minimal interaction with the polymer
membrane in order to facilitate the release of the agent. This can
be achieved, for example, by adding suitable additives to the
polymer solution.
[0026] The invention will be explained in more detail hereinafter
based on one exemplary embodiment.
Example
Production of a Coated Balloon Catheter
[0027] A balloon catheter having a balloon membrane comprising
polyamide was closed distally with a silicone tube, inflated at low
pressure (3-5 bar), and immersed in a solution. The catheter was
pulled out of the immersion solution in a continuous and slow
movement, wherein it should be noted that the speed of pulling it
out and the viscosity of the polymer to solution influence the
applied layer thickness of the polymer membrane to be produced.
[0028] The coagulation of the polymer from the polymer solution is
done by introducing the balloon catheter coated with the polymer
solution into a conditioning chamber having an atmosphere of
isopropanol/water (produced by heating a 50/50 isopropanol/water
mixture at 70.degree. C.).
[0029] After 10 minutes, the balloon was removed from the
conditioning chamber, rinsed several times with distilled water,
and dried. FIGS. 1 and 2 illustrate the morphological changes on
the surface of the balloon catheter.
[0030] The conical region of the balloon, which is of interest for
the coating, is defined proximally by the depth of immersion into
the polymer solution and by the distal subsequent removal of the
polymer coating by way of a solvent.
[0031] In the inflated state, the balloon catheter can then be
wetted with an active ingredient solution, which is embedded into
the cavities of the polymer membrane that were produced.
* * * * *