U.S. patent application number 13/143703 was filed with the patent office on 2011-12-01 for drug-eluting medical device.
Invention is credited to Magdalena Renke-gluszko, Silvio Schaffner, Ulrich Speck.
Application Number | 20110295200 13/143703 |
Document ID | / |
Family ID | 42060656 |
Filed Date | 2011-12-01 |
United States Patent
Application |
20110295200 |
Kind Code |
A1 |
Speck; Ulrich ; et
al. |
December 1, 2011 |
DRUG-ELUTING MEDICAL DEVICE
Abstract
The present invention relates to a drug-eluting medical device,
in particular a balloon for angioplasty catheters with drug elution
to prevent the restenosis of the vessel subjected to angioplasty.
More particularly, the present invention relates to a catheter
balloon completely or partially coated with paclitaxel in hydrated
crystalline form or in hydrated solvated crystalline form, having
an immediate release and bioavailability of a therapeutically
effective amount of paclitaxel at the site of intervention. The
balloon can be made of a polyether-polyamide block copolymer, or a
polyester amide, or polyamide-12.
Inventors: |
Speck; Ulrich; (Frauenfeld,
CH) ; Schaffner; Silvio; (Frauenfeld, CH) ;
Renke-gluszko; Magdalena; (Frauenfeld, CH) |
Family ID: |
42060656 |
Appl. No.: |
13/143703 |
Filed: |
January 8, 2010 |
PCT Filed: |
January 8, 2010 |
PCT NO: |
PCT/EP10/50162 |
371 Date: |
August 18, 2011 |
Current U.S.
Class: |
604/103.02 ;
118/503; 118/696; 427/2.28; 53/473 |
Current CPC
Class: |
A61M 2025/105 20130101;
A61M 2025/1031 20130101; A61L 2300/216 20130101; A61L 29/16
20130101; A61L 2300/63 20130101; A61M 25/1002 20130101; A61L
2300/416 20130101; A61L 2300/602 20130101; A61M 2025/1004 20130101;
A61L 29/06 20130101; A61M 25/1029 20130101; A61L 29/06 20130101;
C08L 77/00 20130101 |
Class at
Publication: |
604/103.02 ;
427/2.28; 118/696; 118/503; 53/473 |
International
Class: |
A61M 25/10 20060101
A61M025/10; B65B 1/04 20060101 B65B001/04; B05C 13/02 20060101
B05C013/02; A61M 29/00 20060101 A61M029/00; B05C 11/00 20060101
B05C011/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 9, 2009 |
IT |
MI2009A000014 |
Mar 12, 2009 |
US |
61/159503 |
Claims
1. A catheter balloon completely or partially coated with
paclitaxel in crystalline hydrated form, having an immediate
release and bioavailability of a therapeutically effective amount
of paclitaxel at the site of intervention.
2. The catheter balloon completely or partially coated with
paclitaxel in crystalline hydrated solvated form, having an
immediate release and bioavailability of a therapeutically
effective amount of paclitaxel at the site of intervention.
3. The catheter balloon according to claim 1, wherein said
crystalline hydrated form comprises water of crystallization in a
molar ratio expressed by an integer or a decimal ranging between 2
and 4 per molecule of paclitaxel.
4. The catheter balloon according to claim 2, wherein said
crystalline hydrated solvated form comprises water of
crystallization in a molar ratio expressed by an integer or a
decimal from 2 to 3, and solvating solvent in a molar ratio
expressed by an integer or a decimal from 1 to 3 per molecule of
paclitaxel.
5. The catheter balloon according to any one of the claims 1 to 4,
wherein said release of a therapeutically effective amount of
paclitaxel occurs in a period of time ranging between 1 second and
1.5 minutes, preferably between 20 seconds and 1 minute.
6. The catheter balloon according to any one of the claims 1 to 5,
wherein said bioavailability of a therapeutically effective amount
of paclitaxel occurs in periods of time ranging between 1 second
and 25 minutes, preferably between 20 seconds and 25 minutes.
7. The catheter balloon according to any one of the claims 1 to 6,
wherein said paclitaxel in crystalline hydrated or crystalline
solvated hydrated form can be obtained by means of a method
comprising: i) dissolving paclitaxel in an aqueous solvent so as to
form a paclitaxel solution; ii) completely or partially wetting the
balloon surface with such solution; and iii) letting the solvent to
evaporate.
8. The catheter balloon according to claim 7, wherein said aqueous
solvent is selected from acetone/ethanol/water,
tetrahydrofuran/water, methanol/water, acetone/water,
ethanol/water, acetonitrile/water, DMF/water mixtures for
crystalline hydrated paclitaxel, and from dioxane/water, DMF/water,
DMSO/water, N-methylpyrrolidone/water, acetonitrile/water,
N,N-dimethylacetamide/water,
1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone/water,
1,3-dimethyl-2-imidazolidinone/water mixtures, or mixtures thereof,
for crystalline hydrated solvated paclitaxel.
9. The catheter balloon according to claim 8, wherein said aqueous
solvent for the formation of paclitaxel in crystalline hydrated
form is selected from a 9:1 tetrahydrofuran/water mixture, or a
tetrahydrofuran/water mixture with ratios ranging between 9.5:0.5
and 65:35, or an acetone/ethanol/water mixture, in which the
organic solvent is present in an amount not less than 50% by volume
relative to water.
10. The catheter balloon according to any one of the claims 7 to 9,
wherein said balloon can be obtained by depositing said paclitaxel
solution on the folded balloon surface or on the surface of the
balloon in inflated condition by means of a syringe, micropipette,
or other similar dispensing means, and by making said dispensing
means to slide on the surface from an end to the other one, and
vice versa, while rotating the balloon around the longitudinal axis
thereof, so as to establish a zigzag path.
11. The catheter balloon according to any one of the claims 7 to
10, wherein said paclitaxel solution of the step i) comprises urea,
preferably in amounts ranging between 1 and 100 mg/mL, or between 4
and 10 mg per mL solvent, or about 7 mg per mL solvent.
12. The catheter balloon according to any one of claims 7 to 11,
wherein the said paclitaxel has a concentration between 4 and 6
mg/ml in the said paclitaxel solution.
13. The catheter balloon according to any one of the claims 1 to
12, wherein said balloon is made of a polyether-polyamide block
copolymer, or compound thereof with a polyamide.
14. The catheter balloon according to claim 13, wherein said
polyether-polyamide block copolymer can be obtained by
polymerization of a polyamide block-forming compound selected from
the group consisting of an aminocarboxylic acid according to the
formula (1), and a lactam according to the formula (2):
##STR00003## with a triblock polyetherdiamine compound of formula
(3): ##STR00004## and with a dicarboxylic acid according to the
formula (4): HOOC--(R3).sub.m-COOH (4) wherein each of the R1, R2,
and R3 groups represents linking groups comprising a hydrocarbon
chain therein, optionally interrupted by one or more amide
groups.
15. The catheter balloon according to claim 14, wherein: R1 and R2
independently comprise an alkylene group having 2 to 20 carbon
atoms and amide bonds; R3 comprises an alkylene group having 1 to
20 carbon atoms; x can vary between 1 and 20, or between 1 and 18,
or between 1 and 16; y can vary between 4 and 50, or between 5 and
45, or between 8 and 30; z can vary between 1 and 20, or between 1
and 18, or between 1 and 12; m is 0 or 1.
16. The catheter balloon according to claim 14 or 15, wherein said
polymerization is carried out by using 15 to 70% by weight of the
compound of formula (1) and/or (2), and a mixture of compounds of
formulae (3) and (4) in an overall weight percentage between 30 and
85%, at a temperature ranging between 150 and 300.degree. C., or
between 160 and 280.degree. C., or between 180 and 250.degree.
C.
17. The catheter balloon according to any one of the claims 13 to
16, wherein said compounds of the polyether-polyamide block
copolymer with a polyamide can be obtained by mixing the copolymer
in amounts from 10 to 90% by weight, or 75 to 25%, or 60 to 40% by
weight, with an amount of polyamide to completion of 100%.
18. The catheter balloon according to claim 17, wherein said
polyamide is polyamide-12.
19. The catheter balloon according to any one of the claims 1 to
12, wherein said balloon is made of polyamide-12.
20. The catheter balloon according to any one of the claims 1 to
12, wherein said balloon is made of polyester amide.
21. The catheter balloon according to claim 20, wherein said
polyester amide can be described by the following general formula:
H--(O--PF--OOC--PA--COO--PF--OOC--PA--CO).sub.n--OH wherein PA is a
polyamide segment, PF is a diol segment comprising OH-terminating
dimer diol segments, and n is a number ranging between 5 and
20.
22. The catheter balloon according to claim 21, wherein the content
of the diol component within the polyester-amide copolymer is 5-50%
by weight, or 10 to 30% by weight, or between 10 and 20% by weight
of the total formulation.
23. The catheter balloon according to any one of the claims 1 to
22, wherein said balloon has a surface which is hydrophilic or
hydrophilized by suitable hydrophilizing treatment.
24. The catheter balloon according to any one of the claims 1 to
23, wherein paclitaxel is present in the catheter balloon coating
layer in amounts ranging between 1 and 20 .mu.g/mm.sup.2, or
between 2 and 7 .mu.g/mm.sup.2, or between 3 and 5
.mu.g/mm.sup.2.
25. A method of coating a catheter balloon with a drug, the said
method comprising the following steps: (a) Providing a balloon; (b)
Inflating the said balloon to a predetermined pressure; (c) Coating
the said inflated balloon of step (b) with a paclitaxel solution;
(d) Deflating the coated balloon of step (c); (e) Folding the
deflated balloon of step (d) when still wet; (f) Optionally,
applying to the said folded balloon a protective cover.
26. A method of coating a catheter balloon with a drug, the said
method comprising the following steps: (g) Providing a folded
balloon, for example a balloon having 3 or 6 folds; (h) Inflating
the said folded balloon to a predetermined pressure; (i) Coating
the said inflated balloon of step (h) with a paclitaxel solution;
(j) Deflating the coated balloon of step (i); (k) Re-folding the
deflated balloon of step (j) when still wet; (l) Optionally,
applying to the said re-folded balloon a protective cover.
27. The method of claim 25 or 26, wherein in step (b) or (h) the
said predetermined pressure is a pressure below the RBP pressure of
the catheter balloon.
28. The method of claim 25 or 26, wherein the said predetermined
pressure is between 5 and 9 bar.
29. The method according to any one of claims 25 to 28, wherein the
said catheter balloon is disconnected from the pressurised air
source before coating.
30. The method according to any one of claims 25 to 29, wherein the
said inflating step (b) or (h) is prolonged for 20 to 40
seconds.
31. The method according to any one of claims 25 to 30, wherein
step (c) or (i) of coating is performed by delivering the drug
solution over the inflated balloon surface, starting delivery of
the solution from the mid of the balloon length and moving to an
end of the balloon, then to the opposite end, while the balloon is
rotated.
32. The method according to claim 31, wherein the balloon catheter
is rotated at a speed from about 5 rpm to about 30, preferably from
about 10 rpm to about 20 rpm and the delivery time of the drug
solution ranges from about 10 seconds to about 500 seconds.
33. The method according to any one of claims 25 to 32, wherein
step (d) or (j) of deflation of the coated balloon is accomplished
by applying vacuum to the catheter balloon opening and/or by
pressing the balloon from the exterior.
34. The method according to any one of claims 25 to 33, wherein
step (e) or (k) or folding or of re-folding, respectively, is
performed within 20 minutes from the end of the coating step (c),
or between 1 minute and 10 minutes, or between 1 minute and 5
minutes.
35. The method according to any one of claims 25 to 34, wherein
step (f) or (l) is accomplished by inserting over the re-folded
balloon a protective cover, typically a sleeve that envelops the
balloon surface that has been coated with the drug.
36. The method according to claim 35, wherein the said sleeve is
made of a low friction material having a friction coefficient below
the friction coefficient of the material of which the balloon is
made.
37. The method according to claim 36, wherein the said low friction
material is polytetrafluoroethylene (PTFE).
38. A device (1) for rotating a catheter balloon (2) during the
coating step with a drug, the said device (1) comprising a first
motor unit (5) and a second motor unit (6) that rotate
synchronously, the said first and second motor units (5, 6)
comprising respective clamp means (8, 8') to clamp opposite ends of
a catheter balloon (2).
39. The device of claim 38, comprising a command and control unit
(7) that operates synchronously the said first and second motor
units (5, 6).
40. The device according to claim 38 or 39, wherein the said first
and second motor units (5, 6) are brushless motors.
41. The device according to any one of claims 38 to 40, comprising
one or more supporting means (9) for the catheter balloon (2).
Description
[0001] The present invention relates to a drug-eluting medical
device, in particular a balloon for angioplasty catheters with drug
elution to prevent restenosis of the vessel subjected to
angioplasty.
BACKGROUND OF THE INVENTION
[0002] The treatment of vascular atherosclerotic lesions is a
widespread therapy. Such lesions are most often localized at
predetermined portions of the blood vessels, of which they cause
constrictions or also obstructions. Vascular atherosclerotic
lesions are typically treated in angioplasty procedures by means of
catheters provided with a balloon.
[0003] A catheter provided at the distal end thereof with a balloon
is advanced, following a guidewire, to the ostium of the narrowed
artery. Once the balloon has been arranged at the artery narrowing,
it is repeatedly inflated and deflated. The insufflation, with
successive deflation, of the balloon within the artery reduce the
extent of the arterial luminal narrowing, and restore a suitable
blood flow in the cardiac area, suffering from the stenosis. In
some cases, it is necessary to arrange a so-called stent, which
provides to maintain the artery patent also after withdrawal of the
catheter and the balloon.
[0004] In both cases, success of the intervention is not complete.
In fact, after a few months, some patients develop a new narrowing
of the vessel wall at the intervention point. Such narrowing, known
under the name of restenosis, is not due to the formation of new
atherosclerotic plaques, but to a cell hyperproliferation process,
particularly of the vascular smooth muscle cells, probably due to
the dilating action operated by the foreign body, stent or
balloon.
[0005] It has been observed that restenosis can be treated by
coating a stent with a drug having antiproliferative action. Among
the drugs usually employed to such aim, paclitaxel (taxol) has
proved to be particularly efficient. The drug must be released for
a sufficiently long time span, so as to inhibit the cell
hyper-proliferation process caused by the constant presence of the
stent implanted in the vessel. However, the drug also induces an
inhibition of the stent endothelization process, which is crucial
to avoid the formation of thrombi. For this reasons, the use of a
stent with drug elution ("drug eluting stent") has some
drawbacks.
[0006] More recently, antiproliferative drug-coated catheter
balloons have been proposed. However, in almost all cases, forms of
slow release of the drug at the site of intervention after the drug
has been transferred from the balloon to the vessel wall have been
described.
[0007] However, it has been noticed that a drug elution over a
prolonged time frame to inhibit the restenosis phenomenon is
neither necessary nor desirable, but that it is sufficient, and
rather more convenient, a time limited contact between drug and
vessel surface, for example, from a few seconds to one minute.
These are typically the contact times of a catheter balloon as
described before.
[0008] The patent publication WO 02/076509 discloses drug-coated
catheter balloons releasing such drug in an immediately
bioavailable form during the short contact time of the balloon with
the vessel wall.
[0009] It will be recognized that an approach such as the one
described herein above poses completely different problems compared
to those previously dealt with. In fact, while a prolonged drug
elution can be obtained by various solutions, such as, for example,
incorporation of the drug in a polymeric matrix or microcapsules,
the immediate release will depend on several factors, of which the
main ones are: [0010] The nature of the drug, in particular the
hydrophilicity or hydrophobicity thereof; [0011] The form in which
the drug is administered, in particular, the crystalline or
amorphous form thereof; [0012] The presence of possible excipients
or "enhancers"; [0013] Optionally, the nature of the balloon
surface on which the drug is deposited.
[0014] In fact, it should be understood that the drug has to be,
first of all, released from the balloon to the vessel wall in the
very short contact time available during an angioplasty procedure.
Once the drug has been released, it has to be absorbed by the cell
wall, before the blood flow washes it off. Ideally, it is therefore
desirable that the drug absorption occurs concomitantly to the
release thereof from the balloon.
[0015] However, it is just as well necessary that the drug is
retained by the balloon surface in a manner sufficient to resist to
all the handling operations which it is subjected to, both during
the production step and during the preparation and carrying out of
the angioplasty procedure, in any case, before the balloon reaches
the site of intervention. This requires a perfect balance of such
properties.
[0016] Therefore, it is an object of the present invention to
provide a catheter balloon coated with a drug which allows an
immediate release and bioavailability of the drug at the site of
intervention.
[0017] It is a further object of the present invention to provide a
method of coating of a catheter balloon with a drug in order to
reach a good adherence of the drug on the balloon surface and at
the same time a fast release of the drug upon contact of the said
balloon surface with a blood vessel wall.
SUMMARY OF THE INVENTION
[0018] The present invention relates to a catheter balloon coated
with paclitaxel in crystalline hydrated form, having an immediate
release and bioavailability of the drug at the site of
intervention.
[0019] A further object of the invention is a catheter balloon
coated with paclitaxel in crystalline hydrated solvated form,
having an immediate release and bioavailability of the drug at the
site of intervention.
[0020] According to another aspect of the invention, the catheter
balloon coated with paclitaxel in crystalline hydrated or solvated
hydrated form as defined before is made of a polyether-polyamide
block copolymer, or "compound" thereof with a polyamide.
[0021] According to a further aspect, the catheter balloon coated
with paclitaxel in crystalline hydrated or solvated hydrated form
as defined before is made of a polyester amide.
[0022] According to a further aspect, the catheter balloon coated
with paclitaxel in crystalline hydrated or crystalline solvated
hydrated form as defined before is made of polyamide-12.
[0023] According to a further aspect, the catheter balloon surface
is hydrophilic or made hydrophilic by treatment with a
hydrophilizing agent.
[0024] According to a further aspect of the invention, paclitaxel
in crystalline hydrated or solvated hydrated form as defined before
is deposited from a urea-containing solution.
[0025] According to an aspect of the invention, the balloon is
inflated before coating with the paclitaxel solution and then it is
folded when still wet.According to a further aspect of the
invention, the balloon is folded, then it is inflated before
coating with the paclitaxel solution and it is finally folded again
when still wet.
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] FIG. 1 shows a schematic side view of a device for rotating
a catheter balloon during coating, according to an aspect of the
invention.
DESCRIPTION OF THE INVENTION
[0027] The present invention relates in particular to a catheter
balloon completely or partially coated with paclitaxel in hydrated
crystalline form, having an immediate release and bioavailability
of a therapeutically effective amount of paclitaxel at the site of
intervention.
[0028] By the term "an immediate release and bioavailability" is
meant a release from the balloon surface in periods of time ranging
between 1 second and 1.5 minutes, preferably between 20 seconds and
1 minute, and an absorption by the vascular tissue in periods of
time ranging between 1 second and 25 minutes, preferably between 20
seconds and 25 minutes.
[0029] By the term "therapeutically effective amount" is meant a
drug amount capable of inducing a therapeutical or preventive
effect against the restenosis of the treated vascular tissue in the
patient.
[0030] By the term "site of intervention" is meant the section of
the blood vessel treated directly with the catheter balloon of the
invention, and the adjacent portion of the tissues in which the
post-procedure presence of paclitaxel can be detected. Generally,
such section will extend for 2-10 mm down- and upstream the contact
section with the balloon.
[0031] With "paclitaxel in hydrated crystalline form" is meant
paclitaxel with 2, 3 or 4 molecules of water of
crystallization.
[0032] This crystalline form of paclitaxel can be obtained by
dissolving paclitaxel in an aqueous solvent, by completely or
partially wetting the balloon surface with such solution, and by
letting the solvent to evaporate to a formation of a crystalline
layer having a white, homogeneous, or partially inhomogeneous
appearance.
[0033] As the aqueous solvent, a mixture of solvents selected from
acetone/ethanol/water, tetrahydrofuran/water, methanol/water,
acetone/water, ethanol/water, acetonitrile/water, DMF/water is
preferably used. More preferably, the solvent is a 9:1
tetrahydrofuran/water mixture or a tetrahydrofuran/water mixture
with ratios ranging between 9.5:0.5 and 65:35, or an
acetone/ethanol/water mixture in which the organic solvent is
present in amounts not less than 50% by volume relative to
water.
[0034] The concentration of paclitaxel in the solution may range
from 4 to 6 mg/ml, preferably about 5 mg/ml.
[0035] The balloon wetting step can be performed in several ways,
known to those skilled in the art, such as, for example, dipping
the balloon into the paclitaxel solution, spraying the paclitaxel
solution on the balloon, or depositing the paclitaxel solution on
the balloon by means of a syringe, a micropipette, or other similar
dispensing device.
[0036] The balloon can be wetted with the paclitaxel solution in a
deployed and inflated condition, or in a folded condition. It has
been observed that in this second case also, the paclitaxel
solution penetrates by capillarity under the folds, so as to form a
drug depot which remains protected during the introduction step of
the folded balloon into the blood vessel by means of the catheter,
until reaching the site of intervention and the inflation
thereof.
[0037] Methods are also known to selectively coat the area under
the balloon folds, leaving the outer surface substantially free
from the drug. Such methods can comprise, for example, the
introduction into the balloon folds of a cannula bearing a series
of micro-nozzles, through which the paclitaxel solution is
deposited on the inner surface of the folds. Such a method is
described, for example, in the international application No.
PCT/IT2007/000816, filed on Nov. 21 2007, the contents of which are
incorporated herein by reference.
[0038] The folded balloon will preferably have 3 to 6 folds.
[0039] A preferred wetting method for the balloon is the deposition
of the paclitaxel solution on the folded balloon surface by means
of a syringe, micropipette, or other similar dispensing means.
Typically, the dispensing means will be made to slide on the
surface from an end to the other one, and vice versa, while
rotating the balloon around the longitudinal axis thereof, so as to
establish a zigzag path. Alternatively, the dispensing means will
be made to slide on the balloon surface starting from a
substantially central position relative to the longitudinal extent
thereof, and it will be made to slide towards a first end thereof
and, subsequently, towards the second end thereof, so as to
establish a substantially zigzag path.
[0040] According to a further method, the following steps are
performed: [0041] (a) Providing a balloon; [0042] (b) Inflating the
said balloon to a predetermined pressure; [0043] (c) Coating the
said inflated balloon of step (b) with a paclitaxel solution;
[0044] (d) Deflating the coated balloon of step (c); [0045] (e)
Folding the deflated balloon of step (d) when still wet; [0046] (f)
Optionally, applying to the said folded balloon a protective
cover.
[0047] According to this method the coating step is performed
directly during the manufacturing process of the balloon catheter
and the coating step is indeed part of the balloon catheter
manufacturing process. Therefore, the production of a coated
balloon catheter according to this method is advantageously
quicker.
[0048] According to a further preferred method, the following steps
are performed: [0049] (g) Providing a folded balloon, for example a
balloon having 3 or 6 folds; [0050] (h) Inflating the said folded
balloon to a predetermined pressure; [0051] (i) Coating the said
inflated balloon of step (h) with a paclitaxel solution; [0052] (j)
Deflating the coated balloon of step (i); [0053] (k) Re-folding the
deflated balloon of step (j) when still wet; [0054] (l) Optionally,
applying to the said re-folded balloon a protective cover.
[0055] The use of an already folded balloon according to step (g)
is advantageous because the material may keep some memory of the
folds even after inflation in step (h), so that the subsequent
re-folding of step (k) can take place easily and in a short time,
without manipulating too much the coated balloon.
[0056] The said predetermined pressure in step (b) or (h) is a
pressure below the nominal pressure (RBP pressure) of the balloon.
For example, for balloon diameters between 4 and 7 mm and balloon
length between 40 and 80 mm, the said predetermined pressure is
between 5 and 9 bar.
[0057] The inflated balloon of step (b) or (h) is preferably
disconnected from the pressurised air source before coating. In
such a way, the balloon is still inflated, but it is not tensioned
and the coating step advantageously benefits from this state
condition. In the case of long balloons, inflation step (b) or (h)
is prolonged for less than 1 minute.
[0058] Coating of step (c) or (i) is preferably performed by
delivering the drug solution over the inflated balloon surface.
Typically, a micropipette can be used, as described above for the
coating of the folded balloons. The same protocol can be followed,
i.e. starting delivery of the solution from the mid of the balloon
length and moving to an end of the balloon, then to the opposite
end, while the balloon is rotated. It is important that
substantially the whole balloon surface is wetted.
[0059] Preferably, the rotation of the balloon is not too fast.
Typically, a rotational speed of the balloon during coating from
about 5 rpm to about 30, preferably from about 10 rpm to about 20
rpm, is used, but different values may be set without departing
from the scope of the invention. Preferably, the delivery time of
the drug solution may range from about 10 seconds to about 500
seconds.
[0060] The rotation of the balloon may preferably be accomplished
by means of a device as shown in FIG. 1 and as described below.
[0061] Step (d) or (j) of deflation of the coated balloon is
accomplished by applying vacuum to the catheter balloon opening
and/or by pressing the balloon from the exterior. Application of
vacuum is preferred, in particular for long balloons.
[0062] Step (e) or (k) of folding and re-folding respectively is
performed by means of conventional devices for folding
balloons.
[0063] According to the processes mentioned above, folding (e) and
re-folding (k) are performed when the balloon surface is still wet.
This allows a better adherence of drug onto the balloon surface to
be obtained.
[0064] Typically, the said folding (e) or re-folding (k) is
performed within 20 minutes from the end of the coating step (c) or
(i) respectively, preferably between 1 minute and 10 minutes, more
preferably between 1 minute and 5 minutes.
[0065] If performed, step (f) or step (l) are accomplished by
inserting over the folded or re-folded balloon a protective cover,
typically a sleeve that envelops the balloon surface that has been
coated with the drug. Such a sleeve is preferably made of a low
friction material. As a low friction material,
polytetrafluoroethylene (PTFE) may conveniently be used. The use of
a low friction material allows to minimize the removal of the drug
adhered onto the balloon surface. The low friction material should
have a friction coefficient below the friction coefficient of the
material of which the balloon is made.
[0066] In general, independently from the method used, it is
possible to repeat several times the balloon wetting step with the
paclitaxel solution, as a function of the drug amount which is
intended to be deposited.
[0067] As shown in FIG. 1, a suitable device for rotating a
catheter balloon 2 is indicated with the numeral 1. The catheter
balloon 2 comprises a catheter section 3 and a balloon section 4,
that is shown in the inflated condition.
[0068] The device 1 comprises a basement 4, a first motor unit 5
and a second motor unit 6. Each motor unit 5, 6 comprises clamping
means 8, 8' to clamp the two ends of the catheter balloon 2.
[0069] Preferably, the distal clamping means 8 acts upon the guide
wire (not shown) on which the catheter balloon is loaded.
Preferably, the proximal clamping means 8' acts upon the connector
(luer) (not shown) the catheter balloon is provided with.
[0070] The motor units 5, 6 are preferably brushless motors. The
motor units 5, 6 are synchronously operated. A command and control
unit 7 provides for the synchronous operation of the two motor
units 5, 6. This is important, in order to avoid torsion of the
catheter balloon 2.
[0071] One or more supporting means 9, depending on the balloon
length, are also provided in order to keep the catheter balloon 2
in an horizontal position.
[0072] According to another aspect, the invention relates to a
catheter balloon completely or partially coated with paclitaxel in
crystalline hydrated solvated form, having an immediate release and
bioavailability of a therapeutically effective amount of paclitaxel
at the site of intervention.
[0073] With "paclitaxel in crystalline hydrated solvated form" is
meant paclitaxel with 2 to 3 molecules of water of crystallization
and with 1 to 3 molecules of solvent.
[0074] It shall be noted that, both in the case of the hydrated
crystalline form and the hydrated solvated crystalline form as
defined before, paclitaxel tends to form dimers which take in water
and/or the solvent into the crystalline structure. Therefore, it is
possible that the number of molecules of water of crystallization
or solvent into the solvate per molecule of paclitaxel is not
defined by an integer, but by a decimal. For example, if a hydrated
solvate is formed by crystallization from a solvent such as
dioxane/water, a dimer can be obtained, which takes in 5 water
molecules and 3 dioxane molecules: in this case, therefore, there
will be 2.5 molecules of water of crystallization and 1.5 molecules
dioxane per molecule of paclitaxel.
[0075] The crystalline hydrated solvated form of paclitaxel can be
obtained from an aqueous solvent preferably selected from
dioxane/water, DMF/water, DMSO/water, N-methylpyrrolidone/water,
acetonitrile/water, N,N-dimethylacetamide/water,
1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone/water,
1,3-dimethyl-2-imidazolidinone/water mixtures, or mixtures thereof,
by operating under suitable conditions, such as those described in
the patent publication WO 03/0475078 in the name of Bristol-Myers
Squibb Co., the content of which, relatively to such preparation
methods, is incorporated herein by reference.
[0076] The preparation modes of the balloon completely or partially
coated with paclitaxel in crystalline hydrated solvated form are
completely similar to those described above for the hydrated
crystalline form; therefore, they will not be further
described.
[0077] According to a further aspect of the invention, a catheter
balloon completely or partially coated with paclitaxel in
crystalline hydrated or crystalline solvated hydrated form, having
an immediate release and bioavailability of a therapeutically
effective amount of paclitaxel at the site of intervention, can be
obtained by dissolving paclitaxel in an aqueous solvent, as defined
before, in the presence of urea, by completely or partially wetting
the balloon surface with such solution, and by letting the solvent
to evaporate to the formation of a crystalline layer having a
white, homogeneous, or partially inhomogeneous appearance.
[0078] It has been noticed that the presence of urea in the coating
layer of paclitaxel on the balloon surface promotes the release of
the drug from such surface. Urea can be used in amounts ranging
between 1 and 100 mg per mL solvent, preferably between 4 and 10 mg
per mL solvent, more preferably about 7 mg per mL solvent.
[0079] It is a further object of the present invention a catheter
balloon completely or partially coated with paclitaxel in
crystalline hydrated or crystalline solvated hydrated form, having
an immediate release and bioavailability of a therapeutically
effective amount of paclitaxel at the site of intervention, in
which said balloon is made of a polyether-polyamide block copolymer
or "compound" thereof with a polyamide.
[0080] The polyether-polyamide block copolymer according to the
invention is an elastomer comprising polyamide block-forming
monomers, representing the hard portion of the material, modified
with a group representing the soft portion.
[0081] This elastomer is obtained by polymerization of a polyamide
block-forming compound selected from the group consisting of an
aminocarboxylic acid according to the formula (1) and a lactam
according to the formula (2):
##STR00001##
with a triblock polyetherdiamine compound of formula (3):
##STR00002## [0082] and with a dicarboxylic acid according to the
formula (4):
[0082] HOOC--(R3).sub.m-COOH (4)
[0083] In the above-mentioned formulae, each of the R1, R2, and R3
groups represents linking groups comprising a hydrocarbon chain
therein, optionally interrupted by one or more amide groups.
[0084] Preferably, R1 and R2 independently comprise an alkylene
group having 2 to 20 carbon atoms and amide bonds, and R3 comprises
an alkylene group having 1 to 20 carbon atoms;
[0085] x can vary between 1 and 20, preferably between 1 and 18,
more preferably between 1 and 16; y can vary between 4 and 50,
preferably between 5 and 45, more preferably between 8 and 30, and
z can vary between 1 and 20, preferably between 1 and 18, more
preferably between 1 and 12;
[0086] m is 0 or 1.
[0087] Generally, the polymerization is carried out by using 15 to
70% by weight of the compound of formula (1) and/or (2), and a
mixture of compounds of formulae (3) and (4) in an overall weight
percentage between 30 and 85%. This polymerization is carried out
in a reactor at a temperature ranging between 150 and 300.degree.
C., preferably between 160 and 280.degree. C., more preferably
between 180 and 250.degree. C.
[0088] Compounds of such copolymers with polyamides can be obtained
by mixing, according to known techniques, the copolymer in amounts
from 10 to 90% by weight, preferably 75 to 25%, more preferably 60
to 40% by weight, with an amount of polyamide to completion of
100%.
[0089] Preferably, the polyamide is polyamide-12.
[0090] Such copolymers and the compounds thereof with polyamides
are known, and have been described in detail in the patent
publication WO 2007/132485 A1, the content of which, relatively to
the structure of such materials, and obtaining thereof, is
incorporated herein by reference.
[0091] It has been observed that the use of such material in the
construction of the catheter balloon of the invention provides
optimal characteristics of paclitaxel release, while balancing the
necessary ability of retaining the drug during the processing and
use steps far from the site of intervention with the easiness to
release the paclitaxel layer to the vascular cell wall in the short
contact time between this and the inflated balloon surface, at the
site of intervention.
[0092] It is a further object of the present invention a catheter
balloon completely or partially coated with paclitaxel in
crystalline hydrated or crystalline solvated hydrated form, having
an immediate release and bioavailability of a therapeutically
effective amount of paclitaxel at the site of intervention, in
which said balloon is made of polyamide-12.
[0093] It is a further object of the present invention a catheter
balloon completely or partially coated with paclitaxel in
crystalline hydrated or crystalline solvated hydrated form, having
an immediate release and bioavailability of a therapeutically
effective amount of paclitaxel at the site of intervention, in
which said balloon is made of polyester amide.
[0094] The polyester amide used in the present invention can be
described by the following general formula:
H--(O--PF--OOC--PA--COO--PF--OOC--PA--CO).sub.n--OH
[0095] in which PA is a polyamide segment, PF is a diol segment
comprising OH-terminating dimer diol segments, and n is a number
ranging between 5 and 20.
[0096] The content of the diol component within the polyester-amide
copolymer is 5-50% by weight. Preferably, the concentration of the
diol component ranges between 10 to 30% by weight, still more
preferably between 10 and 20% by weight of the total
formulation.
[0097] These polymers are known, and have been described in detail
in the patent publication WO 2005/037337 A1, the content of which,
relatively to the chemical structure and the preparation methods of
such materials, is incorporated herein by reference.
[0098] It is a further object of the present invention a catheter
balloon completely or partially coated with paclitaxel in
crystalline hydrated or crystalline solvated hydrated form, having
an immediate release and bioavailability of a therapeutically
effective amount of paclitaxel at the site of intervention, in
which said balloon has a surface which is hydrophilic or
hydrophilized by suitable hydrophilizing treatment.
[0099] For example, the catheter balloon surface according to the
invention can be made hydrophilic by treatment with
plasma-activated oxygen.
[0100] In all the above-described embodiments, paclitaxel is
present in the catheter balloon coating layer in amounts ranging
between 1 and 20 .mu.g/mm.sup.2, preferably between 2 and 7
.mu.g/mm.sup.2, more preferably between 3 and 5 .mu.g/mm.sup.2.
[0101] The invention will now be further described by means of the
following examples, given by way of non-limiting example.
EXAMPLE 1A
Coating of Catheter Balloons with Crystalline Hydrated or
Crystalline Hydrated Solvated Paclitaxel
[0102] Paclitaxel solutions have been prepared at a 50 mg/mL
concentration in the following solvents:
[0103] (1) 9:1 THF/water
[0104] (2) 9:1 THF/water with addition of 15 mg/mL urea
[0105] (3) 6.5:3.5 THF/water
[0106] (4) Acetone/ethanol/water
[0107] (5) Acetic acid (comparative solution)
[0108] (6) Dichloromethane (comparative solution)
[0109] It shall be noted that paclitaxel in a crystalline hydrated
or solvated hydrated form according to the invention is not
obtained by crystallization from acetic acid. Instead, amorphous
paclitaxel is obtained by precipitation from dichloromethane.
[0110] Some balloons--made of a polyamide-12+polyether-polyamide
block copolymer compound (70% UBESTA.RTM. XPA9063+30% UBESTA.RTM.
3030XA) and in a folded condition--have been coated with paclitaxel
by wetting the surface thereof with equal volumes of the solutions
(1)-(6) by means of a Hamilton syringe, according to the previously
described modes. For each solution, several balloons have been
used.
[0111] Then, the balloons have been dried under vacuum.
[0112] The appearance of the coating was white, not always
homogeneous.
EXAMPLE 1B
Coating of Catheter Balloons with Crystalline Hydrated or
Crystalline Hydrated Solvated Paclitaxel (Coating in an Unfolded
Condition)
[0113] The procedure of example 1A has been repeated using coating
solution (2), by inflating first the folded balloons at 7 bar, then
removing the pressurised air source and coating the inflated
balloons by means of a Hamilton syringe. The coated balloons have
then been re-folded after about 1 minute after the coating step,
while the surface thereof was still wet.
[0114] The appearance of the coating was white, substantially
homogeneous.
EXAMPLE 2
Assessment of Paclitaxel Adhesion on the Surface of the Catheter
Balloons
[0115] The balloons prepared according to the example 1 have been
subjected to some assessments, in order to determine the drug
adhesion under the various conditions.
[0116] Test A
[0117] First, the dry adhesion has been assessed, which is useful
to determine the paclitaxel loss which can occur in the production
or handling steps of the balloon. Such determination has been
carried out by dry expanding the balloon and shaking the inflated
balloon within a tube.
[0118] The paclitaxel content in the tube was determined by
HPLC/UV. The drug was taken up with ethanol, the tubes were closed
and vigorously vortexed for at least 30 seconds, followed by a
treatment in an ultrasound bath for 30 minutes. At least 70 .mu.l
of extract were injected into the HPLC, together with a paclitaxel
standard solution (concentration of about 20 .mu.g/mL). The results
are reported in Table I.
[0119] Test B
[0120] Release of paclitaxel at the site of intervention has been
assessed in experiments on castrated male pigs, approximately 3
months old, and weighing about 30 kg. The pigs were sedated by
intramuscular injection of ketamine and xylazine. Anaesthesia was
started by intravenous injection of propofol, followed by
orotracheal intubation, and was maintained with 1-2 vol %
isoflurane, vol % N.sub.2O.sub.2, and 30 vol % oxygen. All the
animals received 5.000 IU heparin, 250 mg aspirine, and 200 mg
nitroglicerine via the intracoronary route. The coronary arteries
were monitored by means of a standard angiography technique through
the left carotid artery.
[0121] The animals were treated with the paclitaxel-coated balloons
(solutions (1)-(6)) mounted on catheter.
[0122] Some balloons, once the site of intervention has been
reached, were kept floating in the blood flow for 1 minute without
expanding them, then they were retracted, introduced into suitable
tubes, inflated, and separated from the catheter. After that, they
were extracted with ethanol as described in test A, and finally
subjecting the tube to centrifugation for 10 minutes. The extracts
were analyzed by HPLC/UV as previously described, so as to
determine the paclitaxel amount which is dispersed in the blood
flow. The results are reported in Table I.
[0123] Other balloons, on which stents had been mounted, have
instead been introduced, inflated, and then deflated and retracted,
then undergoing the same extraction treatment of those
non-inflated. In this case, the residual paclitaxel amount left on
the balloon after contacting the vessel wall was determined.
[0124] After a period of time ranging between 15 and 25 minutes,
the animals were sacrificed by administration of 20% KCl under deep
anaesthesia. Hearts were quickly removed, and the arterial segments
on which the stent was arranged, plus a portion 5 mm down- and
upstream the stent, were sectioned, placed in pre-weighted tubes to
determine the weight thereof, and subjected to extraction with a
predetermined amount of ethanol to achieve a >50% concentration.
After 30 minutes of extraction at room temperature with ultrasounds
and centrifugation for 10 minutes, the extracts were analyzed by
HPLC/UV as described before, so as to determine the paclitaxel
amount absorbed by the vascular tissue. The results are reported in
Table I.
TABLE-US-00001 TABLE I Results of drug adhesion, release, and
uptake by the vascular tissue % paclitaxel % paclitaxel %
paclitaxel % paclitaxel lost in blood not released absorbed by
Deposition lost by dry flow (non- to the site of the vascular
solution expansion inflated ballon) intervention tissue (1) 4 .+-.
3 22 .+-. 3 32 .+-. 9 13.3 .+-. 7.3 (2)/EX. 1A 24 .+-. 1 42 .+-. 3
13 .+-. 3 19.7 .+-. 11.3 (2)/EX. 1B 7 .+-. 4 27 .+-. 17 16 .+-. 8
17.7 .+-. 11.9 (3) 10 .+-. 5 26 .+-. 11 30 .+-. 6 17.4 .+-. 5.5 (4)
11 .+-. 11 33 .+-. 13 9 .+-. 4 23.4 .+-. 8.1 (5) 3 .+-. 2 5 .+-. 4
64 .+-. 5 5.2 .+-. 3.2 (6) 4 .+-. 3 41 .+-. 26 11 .+-. 7 17.4 .+-.
7.2
[0125] Data reported in Table I show that paclitaxel release is
noticeably higher when the drug is present in crystalline hydrated
or solvated hydrated form (lines (1) to (4)) compared to the
non-hydrated form (line (5)). In fact, in the latter case, most
paclitaxel (64%.+-.5%) remains adhered to the balloon surface, and
the drug amount absorbed by the vascular tissue is only
5.2%.+-.3.2%.
[0126] As regards paclitaxel in the amorphous form (line (6)),
although data show a high amount of drug released by the balloon
and absorbed into the tissues, further experiments for the
restenosis inhibition assessment demonstrated an inactivity of such
form. In such further experiments, paclitaxel in crystalline
hydrated or solvated hydrated form (lines (1)-(4)) exhibited,
instead, a restenosis inhibition action in the animal.
[0127] Data also show that the presence of urea in the deposition
solution (line (2)) produces a higher paclitaxel release and a
higher amount of drug absorbed in the vascular tissue, compared to
the same solution without the presence of urea (line (1)).
[0128] The coating in the inflated state, followed by re-folding
while still wet, allows a better adherence of the drug onto the
balloon surface.
[0129] Further investigations demonstrated that the material of
which the balloon is made has also a considerable impact on the
paclitaxel release properties, the polyether-polyamide block
copolymer, or the compound thereof with polyamides giving the best
results for drug elution.
EXAMPLE 3
Determination of the Crystalline Rorm of Paclitaxel
[0130] Paclitaxel in crystalline hydrated form was identified by IR
analysis under the conditions reported in the literature, thus
obtaining a spectrum which was equivalent to what has been
described in Jeong Hoon Lee et al., Bull. Korean Chem. Soc. 2001,
vol. 22, No. 8, 925-928.
* * * * *