U.S. patent application number 10/581671 was filed with the patent office on 2007-11-29 for botulinum toxin treatment of spastic bladder.
Invention is credited to John Batchelor, Pierre Bernard D'Arbigny, Chris Dott.
Application Number | 20070275110 10/581671 |
Document ID | / |
Family ID | 29764527 |
Filed Date | 2007-11-29 |
United States Patent
Application |
20070275110 |
Kind Code |
A1 |
Dott; Chris ; et
al. |
November 29, 2007 |
Botulinum Toxin Treatment Of Spastic Bladder
Abstract
The invention relates to the use of a liquid or semi-solid
formulation of botulinum toxin for the preparation of a medicament
intended to treat a disorder characterised by bladder spasms (e.g.
urinary incontinence due to unstable bladder or unstable detrusor
sphincter, voiding complications due to detrusor overactivity or
unstable detrusor sphincter, urinary retention secondary to spastic
sphincter or hypertrophied bladder neck and neurogenic bladder
dysfunction secondary to Parkinson's disease, spinal cord injury,
stroke or multiple sclerosis or characterised by a spasm reflex),
wherein said medicament is for administration by infusion into the
bladder or by other methods that do not involve injection into the
bladder wall.
Inventors: |
Dott; Chris; (Berkshire,
GB) ; Batchelor; John; (Berkshire, GB) ;
Bernard D'Arbigny; Pierre; (Courbevoie, FR) |
Correspondence
Address: |
JACOBSON HOLMAN PLLC
400 SEVENTH STREET N.W.
SUITE 600
WASHINGTON
DC
20004
US
|
Family ID: |
29764527 |
Appl. No.: |
10/581671 |
Filed: |
November 12, 2004 |
PCT Filed: |
November 12, 2004 |
PCT NO: |
PCT/GB04/04770 |
371 Date: |
April 2, 2007 |
Current U.S.
Class: |
424/780 |
Current CPC
Class: |
A61K 38/00 20130101;
A61K 38/4893 20130101; A61P 13/06 20180101; A61P 13/10
20180101 |
Class at
Publication: |
424/780 |
International
Class: |
A61K 35/74 20060101
A61K035/74; A61P 13/06 20060101 A61P013/06 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 4, 2003 |
GB |
0328060.9 |
Claims
1. A use of a solid, semi-solid or liquid formulation of botulinum
toxin for the preparation of a medicament intended to treat a
disorder characterised by bladder spasms wherein said medicament is
for administration without using an injection into the bladder
wall.
2. The use according to claim 1, wherein the disorder characterised
by bladder spasms is selected from the group consisting of urinary
incontinence due to unstable bladder or unstable detrusor
sphincter, voiding complications due to detrusor overactivity or
unstable detrusor sphincter, urinary retention secondary to spastic
sphincter or hypertrophied bladder neck and neurogenic bladder
dysfunction secondary to Parkinson's disease, spinal cord injury,
stroke or multiple sclerosis or characterised by a spasm
reflex.
3. The use according to claim 1, wherein the medicament prepared is
in the form of a liquid or semi-solid formulation intended to be
administered through infusion into the bladder or a solid, a gel
formulation intended to be deposited at the appropriate location of
the patient's bladder, a spray formulation intended to be
administered through spraying at the appropriate location of the
patient's bladder or a solid, semi-solid or liquid botulinum toxin
formulation spread on the outer wall of a balloon intended to be
inflated inside the bladder.
4. The use according to claim 3, wherein the medicament prepared is
a liquid or semi-solid formulation for administration through
infusion into the bladder.
5. The use according to claim 4, wherein the liquid or semi-solid
formulation has a volume of 20 to 80 ml.
6. The use according to claim 3, wherein the liquid or semi-solid
formulation contains from 100 to 2500 units of botulinum toxin type
A.
7. The use according to claim 3, wherein the liquid or semi-solid
formulation contains from 4,000 to 50,000 units of botulinum toxin
type B.
8. The use according to claim 3, wherein the medicament prepared is
in the form of a gel formulation.
9. The use according to claim 3, wherein the medicament prepared is
in the form of a spray formulation.
10. The use according to claim 3, wherein the medicament prepared
is in the form of a solid, semi-solid or liquid botulinum toxin
formulation spread on the outer wall of a balloon intended to be
inflated inside the bladder.
11. A method of treatment of a disorder characterised by bladder
spasms, wherein the disorder characterised by bladder spasms is
selected from the group consisting of urinary incontinence due to
unstable bladder or unstable detrusor sphincter, voiding
complications due to detrusor overactivity or unstable detrusor
sphincter, urinary retention secondary to spastic sphincter or
hypertrophied bladder neck and neurogenic bladder dysfunction
secondary to Parkinson's disease, spinal cord injury, stroke or
multiple sclerosis or characterised by a spasm reflex: wherein a
patient requiring said treatment is administered with a
therapeutically effective dose of a solid, semi-solid or liquid
formulation of botulinum toxin, wherein said formulation is
administered without using an injection into the bladder wall.
Description
[0001] The present invention relates to the use of botulinum toxin
for the preparation of a medicament intended to topically treat
urinary disorders and notably spastic bladder.
[0002] The anaerobic, gram positive bacterium Clostridium botulinum
produces a potent polypeptide neurotoxin, botulinum toxin, which
causes a neuroparalytic illness in humans and animals referred to
as botulism. The spores of Clostridium botulinum are found in soil
and can grow in improperly sterilized and sealed food tins, which
are the cause of many of the cases of botulism. The effects of
botulism typically appear 18 to 36 hours after eating the
foodstuffs infected with a Clostridium botulinum culture or spores.
The botulinum toxin can apparently pass unattenuated through the
lining of the gut and attack peripheral motor neurons. Symptoms of
botulinum toxin intoxication can progress from difficulty walking,
swallowing, and speaking to paralysis of the respiratory muscles
and death.
[0003] Botulinum toxin type A is the most lethal natural biological
agent known to man. About 50 picograms of a commercially available
botulinum toxin type A (purified neurotoxin complex) correspond to
the LD.sub.50 in mice.
[0004] Seven immunologically distinct botulinum neurotoxins have
been characterized, these being respectively botulinum neurotoxin
serotypes A, B, C.sub.1, D, E, F and G each of which is
distinguished by neutralization with type-specific antibodies. The
different serotypes of botulinum toxin vary in the animal species
that they affect and in the severity and duration of the paralysis
they evoke. For example, it has been determined that botulinum
toxin type A is 500 times more potent, as measured by the LD.sub.50
in mice, than botulinum toxin type B. Additionally, botulinum toxin
type B has been determined to be non-toxic in primates at a dose of
480 U/kg which is about 12 times the primate LD.sub.50 for
botulinum toxin type A. Botulinum toxin apparently binds with high
affinity to cholinergic motor neurons, is translocated into the
neuron and blocks the release of acetylcholine.
[0005] Although all the botulinum toxin serotypes apparently
inhibit release of the neurotransmitter acetylcholine at the
neuromuscular junction, they do so by affecting different
neurosecretory proteins and/or cleaving these proteins at different
sites. For example, botulinum types A and E both cleave the 25
kilodalton (kD) synaptosomal associated protein (SNAP-25), but they
target different amino acid sequences within this protein.
Botulinum toxin types B, D, F and G act on vesicle-associated
protein (V,AMP, also called synaptobrevin), with each serotype
cleaving the protein at a different site. Finally, botulinum toxin
type C.sub.1 has been shown to cleave both syntaxin and SNAP-25.
These differences in mechanism of action may affect the relative
potency and/or duration of action of the various botulinum toxin
serotypes. The molecular weight of the botulinum toxin protein
molecule, for all seven of the known botulinum toxin serotypes, is
about 150 kD. Interestingly, the botulinum toxins are released by
Clostridial bacterium as complexes comprising the 150 kD botulinum
toxin protein molecule along with associated non-toxin proteins.
Thus, the botulinum toxin type A complex can be produced by
Clostridial bacterium as 900 kD, 500 kD and 300 kD forms. Botulinum
toxin types B and C.sub.1 are apparently produced as only a 500 kD
complex. Botulinum toxin type D is produced as both 300 ka and 500
kD complexes. Finally, botulinum toxin types E and F are produced
as only approximately 300 kD complexes. The complexes (i.e.
molecular weight greater than about 150 kD) are believed to contain
a non-toxin hemaglutinin protein and a nontoxin and non-toxic
nonhemaglutinin protein. These two non-toxin proteins (which along
with the botulinum toxin molecule comprise the relevant neurotoxin
complex) may act to provide stability against denaturation to the
botulinum toxin molecule and protection against digestive acids
when toxin is ingested. Additionally, it is possible that the
larger (greater than about 150 kD molecular weight) botulinum toxin
complexes may result in a slower rate of diffusion of the botulinum
toxin away from a site of intramuscular injection of a botulinum
toxin complex.
[0006] Botulinum toxin type A can be obtained by establishing and
growing cultures of Clostridium botulinum in a fermenter and then
harvesting and purifying the fermented mixture in accordance with
known procedures. All the botulinum toxin serotypes are initially
synthesized as inactive single chain proteins which must be cleaved
or nicked by proteases to become neuroactive. The bacterial strains
that make botulinum toxin serotypes A and G possess endogenous
proteases and serotypes A and G can therefore be recovered from
bacterial cultures in predominantly their active form. In contrast,
botulinum toxin serotypes C.sub.1, D and E are synthesized by
nonproteolytic strains and are therefore typically unactivated when
recovered from culture. Serotypes B and F are produced by both
proteolytic and nonproteolytic strains and therefore can be
recovered in either the active or inactive form. However, even the
proteolytic strains that produce, for example, the botulinum toxin
type B serotype only cleave a portion of the toxin produced. The
exact proportion of nicked to unnicked molecules depends on the
length of incubation and the temperature of the culture. Therefore,
a certain percentage of any preparation of, for example, the
botulinum toxin type B toxin is likely to be inactive, possibly
accounting for the known significantly lower potency of botulinum
toxin type B as compared to botulinum toxin type A. The presence of
inactive botulinum toxin molecules in a clinical preparation will
contribute to the overall protein load of the preparation, which
has been linked to increased antigenicity, without contributing to
its clinical efficacy. Additionally, it is known that botulinum
toxin type B has, upon intramuscular injection, a shorter duration
of activity and is also less potent than botulinum toxin type A at
the same dose level. High quality crystalline botulinum toxin type
A can be produced form the Hall A strain of Clostridium botulinum
with characteristics of 3.107 U/mg, an A.sub.260/A.sub.278 of less
than 0.60 and a distinct pattern of banding on gel electrophoresis.
The known Schantz process can be used to obtain crystalline
botulinum toxin type A, as set forth in Schantz, E. J., et al,
Properties and use of Botulinum toxin and Other Microbial
Neurotoxins in Medicine, Microbiol Rev. (1992), 56, 80-99.
Generally, the botulinum toxin type A complex can be isolated and
purified from an anaerobic fermentation by culturing Clostridium
botulinum type A in a suitable medium. The known process can also
be used, upon separation out of the non-toxin proteins, to obtain
pure botulinum toxins, such as for example: purified botulinum
toxintype A with an approximately 150 kD molecular weight with a
specific potency of 1-2.10.sup.8 LD.sub.50 U/mg or greater,
purified botulinum toxin type B with an approximately 156 kD
molecular weight with a specific potency of 1-2.10.sup.8 LD.sub.50
U/mg or greater, and purified botulinum toxin type F with an
approximately 155 kD molecular weight with a specific potency of
1-2.times.10.sup.7 LD.sub.50 U/mg or greater.
[0007] Already prepared and purified botulinum toxins and toxin
complexes can be obtained from List Biological Laboratories, Inc.
(Campbell, Calif., USA); the Centre for Applied Microbiology and
Research (Porton Down, UK); Wako (Osaka, Japan), as well as from
Sigma Chemicals (St. Louis, Mo., USA).
[0008] Botulinum toxin of type A was first used in man in 1981. The
first therapeutic uses related to the treatment of certain
neuromuscular disorders that include blepharospasm, strabismus and
hemifacial spasm. Non-type A botulinum toxin serotypes apparently
have a lower potency and/or a shorter duration of activity as
compared to botulinum toxin type A. Clinical effects of peripheral
intramuscular botulinum toxin type A are usually seen within one
week of injection. The typical duration of symptomatic relief from
a single intramuscular injection of botulinum toxin type A averages
about three months.
[0009] Spastic bladder treatment by botulinum toxin was first
disclosed in U.S. Pat. No. 5,437,291. The method of administration
disclosed is the direct injection into the bladder wall.
[0010] PCT patent application WO 99/03483 further discloses the use
of botulinum toxin for the treatment of various urinary disorders.
The administration of toxin consists in an injection in the lateral
bladder wall by means of an endoscopic device introduced through
the urethra.
[0011] The Applicant has now surprisingly found that it is possible
to treat patients with urinary disorders and notably spastic
bladder without using such an injection. This can be achieved for
example by one of the following methods: [0012] infusing the
patients' bladder with a liquid or semi-solid formulation of
botulinum toxin; [0013] depositing a gel formulation containing
botulinum toxin at the appropriate location of the patients'
bladder; [0014] spraying a spray formulation containing botulinum
toxin at the appropriate location of the patients' bladder; or
[0015] topically applying a solid (e.g. lyophilised), semi-solid or
liquid botulinum toxin formulation that is put or spread on the
outer walls of a balloon which is then inflated in the bladder so
as to be in contact with said bladder's wall.
[0016] By spray formulation is understood in the present
application a solid or liquid formulation that is or can be split
into particles or droplets with a mean diameter of less than 1 mm,
preferably of less than 500 .mu.m and more preferably less than 100
.mu.m.
[0017] The invention therefore relates to the use of a liquid,
semi-solid, gel, spray or solid (e.g. lyophilised) formulation of
botulinum toxin for the preparation of a medicament intended to
treat a disorder characterised by bladder spasms wherein said
medicament is for administration by infusion into the bladder or
local administration without injection into the bladder wall.
[0018] Liquid formulations may in particular be a liquid
formulation that is not miscible with water and such that the
formulation is less dense than water; an advantage of this
execution mode is that the formulation tends to separate and
preferentially be in contact with the bladder. The liquid
formulations may also be water solutions (e.g. a saline water
solution) or suspensions.
[0019] Besides, the liquid or semi-solid formulation may be
replaced by a gel (including a double gel) or another adhering
formulation. This type of formulation will be particularly
advantageous as it will allow the selective application of the
formulation to the appropriate bladder wall locations, avoiding
administration to the trigone.
[0020] Alternatively, the formulation may be in the form of a spray
containing the botulinum toxin. This spray may notably be created
using a two-compartment capsule containing in one compartment
botulinum toxin powder and in the other explosives which will bring
about the spraying of botulinum toxin once explosion occurs; hence,
according to this particular variant, the capsule is first brought
at the appropriate location near the bladder wall and then the
explosion triggered to spray the botulinum toxin on said wall.
[0021] According to a further variant of the invention, a solid
(e.g. lyophilised), semi-solid or liquid botulinum toxin
formulation may be coated or spread over the outer walls of a
balloon. The balloon is brought into the bladder using an
endoscopic or cystoscopic apparatus or, more preferably, only a
cathether; it is then inflated in the bladder until it is in
contact with the bladder walls. In this manner, the botulinum toxin
can be delivered at the appropriate bladder wall locations,
avoiding administration to the trigone. A further object of the
invention is therefore the use of a solid (e.g. lyophilised),
semi-solid or liquid botulinum toxin formulation spread on the
outer wall of a balloon intended to be inflated inside the bladder
for the preparation of a medicament intended to treat a disorder
characterised by bladder spasms.
[0022] Preferably, the botulinum toxin formulation used for this
invention will comprise a penetration enhancer.
[0023] To summarise, according to the invention, the formulation of
botulinum toxin does not need to be injected but should simply be
put in contact with the bladder wall. This mode of administration
is much easier for the doctor.
[0024] According to this invention, disorders characterised by
bladder spasms include notably: [0025] urinary incontinence due to
unstable bladder or unstable detrusor sphincter; [0026] voiding
complications due to detrusor overactivity or unstable detrusor
sphincter; [0027] detrusor sphincter dyssynergia; [0028] urinary
retention secondary to spastic sphincter or hypertrophied bladder
neck; or [0029] neurogenic bladder dysfunction secondary to
Parkinson's disease, spinal cord injury, stroke or multiple
sclerosis or characterised by a spasm reflex.
[0030] In this application, unless stated otherwise, the words
"botulinum toxin" always refer to a botulinum toxin complex (made
from the toxin and one or more complexing proteins) or a high
purity botulinum toxin (botulinum toxin which is substantially free
from any complexing protein).
[0031] By botulinum toxin complex shall be notably understood the
active principles of the products Dysport.RTM. (registered
trademark of the Applicant), Botox.RTM. (registered trademark of
Allergan), Vistabel.RTM. (registered trademark of Allergan),
Neurobloc.RTM. (registered trademark of Elan) or Myobloc.RTM.
(registered trademark of Elan).
[0032] By high purity botulinum neurotoxin (type A, B, C.sub.1, D,
E, F or G) is meant, in the present application, botulinum
neurotoxin (type A, B, C.sub.1, D, E, F or G) free from complexes
including at least another protein. In other words, a high purity
botulinum neurotoxin (type A, B, C.sub.1, D, E, F or G) does not
contain significant quantities of any other Clostridium spp derived
protein than botulinum neurotoxin (type A, B, C.sub.1, D, E, F or
G).
[0033] Preferably, the invention will be such that the medicament
prepared is intended to treat a disorder selected from the group
consisting of urinary incontinence, urinary retention and
neurogenic bladder dysfunction.
[0034] A liquid or semi-solid formulation intended for bladder
infusion according to the invention will preferably not have a
volume exceeding 100 ml, and more preferably 80 ml. For example, a
volume of 20 to 80 ml, and notably a volume of 40 to 60 ml (e.g.
about 50 ml), will be appropriate. The same volumes will apply for
a gel formulation intended to be deposited in the patient's
bladder.
[0035] Preferably, the viscosity of the formulation according to
the invention will be greater than that of the corresponding water
solution thanks to the use of a thickening agent like gelatine,
carboxymethyl cellulose, polyethylene glycol, glycerol, mannitol or
a surfactant.
[0036] Furthermore, liquid formulations used for the invention will
preferably be such that they have a viscosity from 0.5 to 500
centipoises, and more preferably from 1 to 500 centipoises.
Semi-solid formulations used for the invention will preferably be
such that they have a viscosity from 500 to 10,000 centipoises, and
more preferably from 2,000 to 10,000 centipoises. Gel formulations
used for the invention will preferably be such that they have a
viscosity from 10,000 to 100,000 centipoises, and more preferably
from 50,000 to 100,000 centipoises.
[0037] For use in a bladder infusion, the liquid or semi-solid
formulation according to the invention will typically contain from
100 to 2,500 units of botulinum toxin type A or F, or from 4,000 to
50,000 units of botulinum toxin type B or a clinically equivalent
amount for other serotypes as is known to the skilled person.
[0038] Nevertheless, the dose of botulinum toxin to provide
according to the present invention for treatment of the
abovementioned diseases or disorders, varies depending on the age
and body weight of the subject to be treated, as well as the state
of the latter, and will be finally decided by the attending doctor
or veterinarian. Such a quantity determined by the attending doctor
or veterinarian is here called "therapeutically effective
quantity".
[0039] For the purposes of the instant patent application, one unit
(U) of botulinum toxin is defined as the LD.sub.50 upon
intraperitoneal injection into female Swiss Webster mice weighing
18 to 20 grams each.
[0040] Methods of treatment of disorders characterised by bladder
spasms comprising the administration by infusion of a liquid,
semi-solid or gel composition or spraying a spray composition
according to the invention into the bladder of a patient in need
thereof are also within the scope of this invention. These methods
of treatment can notably be carried out under cystoscope control,
but using flexible cystoscopes, mini-cystoscopes or even simple
catheters will be preferred. The use of the aforesaid devices can
be combined with a radioscopic control, but may also be carried out
without any such control.
[0041] For the case of a spray formulation, the injection nozzle
will preferably have an umbrella or conic shape in order to direct
the spray in an appropriate fashion.
[0042] According to the instant invention, the infusion or contact
with the botulinum toxin formulation should last any time between
10 minutes and 12 hours (overnight).
[0043] A preferred execution mode for this invention will involve
the use of a balloon whose outer wall is coated with a botulinum
toxin formulation, said balloon being intended to be inflated in
the bladder of the patient to be treated with the purpose of
releasing the toxin into the bladder wall.
[0044] The method uses a balloon that can be introduced, through
the urethra, into the bladder, that can be inflated in the bladder
in order to enter in contact with the bladder wall and that can
also be deflated afterwards. The surface of the balloon is
previously covered by a botulinum toxin formulation in order to,
later, transfer said formulation as a layer between balloon and
bladder wall.
[0045] The botulinum toxin formulation can be liquid, semisolid or
solid and can optionally comprise one or more penetration enhancers
to favour the botulinum toxin transfer from the surface to the
target of the drug.
[0046] The balloon is the transfer-target device and can play an
occlusive role or any other mechanical functions likely to increase
botulinum toxin penetration thanks to the process and/or to the
balloon surface, composition, etc.
[0047] One of the preferred device presentations is the one used in
balloon angioplasty. However, the skilled person may contemplate
any other where an inflated balloon is used in order to enter in
contact with the bladder wall to ensure botulinum toxin penetration
into the bladder wall.
[0048] Hence, as for angioplasty, the device will preferably be
thin and long for transluminal access to the bladder, the diameter
and length being adapted to urethra and bladder. The deflated total
diameter of the balloon could be less than 1 cm and preferably less
than 5 mm and the deflated total length less than 15 cm and
preferably less than 10 or even 5 cm.
[0049] The balloon device could come with a control guide wire
and/or a peripheral guide catheter. For example, a thin and
flexible balloon catheter can be positioned at rest in a reservoir
and when necessary expelled from the catheter (optionally through a
catheter guide), leaving the balloon to expand gently into the
bladder.
[0050] One may monitor the progress of the treatment on an X-ray
machine thanks to the metallic guide wire but it can also be
contemplated that the wire is used as a guide to determine the
appropriate position with contact on top of the bladder before
treatment application without any radiographic need, thus making
the treatment even simpler to perform. The device shape and working
process can be made in a way to offer contact in the target area
and for instance avoiding balloon contact in the trigone or urethra
area.
[0051] According to the invention method, the balloon's outer
surface is to be covered with the botulinum toxin formulation to be
delivered.
[0052] Different approaches with solid, semi-solid or liquid
compositions of the drug can be contemplated as detailed
hereafter.
[0053] For solid formulations, one can prepare concentrated liquid
aqueous or organic solutions of botulinum toxin, to wet the
deflated balloon in these solutions of the drug and to dry or
freeze-dry the preparation in order to obtain a solid layer of the
drug on top of the surface. If necessary, only one defined part of
the balloon's surface could enter in contact with the solution and
then be covered by the drug. It can also be contemplated to add one
or more excipients likely to enhance drying and/or penetration of
the toxin. For instance, alcoholic solutions and/or pH preparations
can be used to obtain local inflammation, creating micro-lesions
that will ease the transfer of the toxin through the epithelium
layer. Besides, surfactant or organic solvents can be incorporated
into the toxin formulation to improve the delivery. In the end,
aqueous medium and/or local humidity in the bladder could rehydrate
the solid composition and give the pH, concentration and liquid
vehicle to transfer the toxin.
[0054] Semi-solid or gel like compositions could also be used with
the balloon device. Here also one can wet the balloon surface in a
botulinum toxin gel preparation or semi-solid formulation to obtain
the botulinum toxin coating layer. The treatment could also be
realised just by putting on top of the balloon in the guide
catheter the semi-solid or gel preparation. During the process,
this layer will cover the balloon's surface as a result of the
balloon inflation and then be trapped, stuck and squeezed between
the balloon and the bladder wall.
[0055] A liquid preparation could also be used with the device.
This preparation can be already associated with the device as a
layer on a deflated balloon or a liquid reservoir in the tip of the
guide catheter. The liquid reservoir at the tip of the guide
catheter may as well be filled using a syringe just before use with
a high aqueous concentration of botulinum toxin in a small volume
(e.g. 500 units of Dysport.RTM. in 0.5 ml or less of saline
solution); pH modifying agents, organic solvents, viscosity and
penetration enhancers may be added if necessary. This tip part will
wet the balloon as it is pushed out of the guide catheter and cover
it when it inflates in the bladder, allowing the toxin composition
to enter in contact with the bladder wall.
[0056] Various methods of treatment can be contemplated thanks to
the invention's balloon device.
[0057] For example, the balloon can be inflated and deflated
several times, with a contact between the balloon's outer wall and
the bladder inner wall being maintained for a certain time in
between. The contact time will be chosen for optimising penetration
(in general less than one hour, for instance 10 minutes) as well as
the number of times the balloon will be inflated.
[0058] The pressure exerted on the bladder wall could also play a
favorable plastic and penetration role. It will therefore be
adapted by the treating physician to each patient. The balloon can
be inflated to a relatively high pressure that can be precisely
controlled (as it is normally prevented from blowing up thanks to
the bladder wall). In addition, the device can be inflated or
deflated several times during treatment and one can perform some
pressure jerks to improve toxin penetration.
[0059] Depending on the treatment conditions, the botulinum toxin
administration using the balloon dilatation on the tip of the
catheter works thanks to an occlusive phenomenon only or thanks to
both an occlusive phenomenon and the pressure exerted by the
balloon on the bladder wall.
[0060] After treatment, the balloon is deflated and withdrawn just
by removing the catheter and/or guide wire.
[0061] If by chance the bladder wall gets damaged because of
treatment, the healing would have the time it needs as treatments
could be spaced by time intervals of 6 months or more as the toxin
is effective for that duration when treating bladder disorders.
[0062] Other execution modes of the balloon device according to
this invention include having on the balloon surface rough patches
to improve botulinum toxin penetration. Those sharp elements can be
incorporated, similarly to coronary stents, on the balloon.
[0063] It could also be contemplated to use an elastic catheter
tipped with a balloon as a way to target local multi-injections,
similarly to what is described for example in U.S. Pat. No.
6,638,246. According to this variant, the balloon would be fitted
with small needles (e.g. microneedles of about 1 mm length and
about 130 .mu.m diameter) that would be attached and folded safely
into the balloon's surface. As the balloon is inflated, the
microneedle would penetrate the bladder wall and the botulinum
toxin formulation would be injected.
[0064] The execution modes wherein the balloon is fitted with rough
patches or microneedles present the advantage of allowing targeted
administration of the botulinum toxin formulation into defined
areas of the patient's bladder.
[0065] Thanks to this balloon device, the treatment dose can be
accurate, already fixed and associated to the device or easily
selected and prepared by the physician using standard procedures
for liquid injections.
[0066] It should be mentioned that the balloon system previously
described can be used for any kind of active substance that can be
formulated as a solid, semi-solid or liquid pharmaceutical
composition and that can be delivered through an epithelium surface
into an accessible body reservoir or vessel like for example the
bladder, the colon, the bowel, the stomach, the oesophagus, the
nose, the sinus, the ear, the eye or the blood vessels (veins or
arteries).
[0067] Possible uses of this balloon device therefore include for
example: [0068] introducing the invention balloon coated with an
anti-restenosic drug, an antithrombogenic agent, an
endothelialisation promoter, a radioactive isotope, a platelet
antiaggregant agent, a fibrinolytic agent, an anti-inflammatory
agent, an antiproliferation agent, a radio opaque substance, a gene
therapy agent, an inhibitor and/or promoter of cellular adhesion
and/or growth (e.g. somatostatin analogues like lanreotide or
octreotide, glucocorticoids, glycerol, heparin, botulinum toxin, a
cytotoxic agent, a cytostatic agent, etc.) into the appropriate
artery locations and inflating it to release said drug, agent,
inhibitor or promoter; [0069] introducing the invention balloon
coated with an anti-ulcer drug (e.g omeprazole, esomeprazole or the
like) into the stomach and inflating it to release said anti-ulcer
drug; or [0070] introducing the invention balloon coated with an
anti-inflammation drug into the colon, bladder or bowel and
inflating it to release said anti-inflammation drug.
[0071] Of course, the various general improvements indicated for
botulinum toxin formulations to be used on balloons according to
this invention (such as, among many other things, the use of
penetration enhancers) apply mutatis mutandis to the corresponding
other drug formulations.
[0072] The term "about" refers to an interval around the considered
value. As used in this patent application, "about X" means an
interval from X minus 10% of X to X plus 10% of X, and preferably
an interval from X minus 5% of X to X plus 5% of X.
[0073] Unless they are defined differently, all the technical and
scientific terms used here have the same meaning as that usually
understood by an ordinary specialist in the field to which this
invention belongs. Similarly, all publications, patent
applications, all patents and all other references mentioned here
are incorporated by way of reference.
[0074] The following example is presented to illustrate the above
and must in no case be considered as a limit to the scope of the
invention.
EXAMPLE
[0075] A woman in her sixties suffers from urinary incontinence due
to unstable bladder. She is infused in the bladder, through a
catheter introduced into the urethra and the bladder and with the
assistance of an endoscope apparatus, with 50 ml of a physiological
saline solution containing 2,000 units of botulinum toxin type A
(Dysport.RTM.; supplier: Ipsen Ltd, Wrexham, UK).
[0076] Pharmacological Procedures
[0077] Bladder Function
[0078] The bladder capacity (in ml) is measured in patients before
and after treatment at regular time intervals for up to 12 months.
Additionally voiding function is recorded over this period.
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