U.S. patent application number 13/755310 was filed with the patent office on 2013-06-06 for botulinum toxin compositions and methods.
This patent application is currently assigned to ALLERGAN, INC.. The applicant listed for this patent is Allergan, Inc.. Invention is credited to Andrew M. Blumenfeld, Franklin D. Gaylis.
Application Number | 20130142770 13/755310 |
Document ID | / |
Family ID | 39689504 |
Filed Date | 2013-06-06 |
United States Patent
Application |
20130142770 |
Kind Code |
A1 |
Gaylis; Franklin D. ; et
al. |
June 6, 2013 |
BOTULINUM TOXIN COMPOSITIONS AND METHODS
Abstract
Disclosed herein are methods of using extracellular matrix
digesting enzymes and neurotoxins, such as a Clostridial
neurotoxins, to treat various medical conditions, such as
overactive bladder, benign prostatic hyperplasia, hyperhidrosis,
and cholecystitis for example.
Inventors: |
Gaylis; Franklin D.; (La
Mesa, CA) ; Blumenfeld; Andrew M.; (Del Mar,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Allergan, Inc.; |
Irvine |
CA |
US |
|
|
Assignee: |
ALLERGAN, INC.
Irvine
CA
|
Family ID: |
39689504 |
Appl. No.: |
13/755310 |
Filed: |
January 31, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12032057 |
Feb 15, 2008 |
8383103 |
|
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13755310 |
|
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60890052 |
Feb 15, 2007 |
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Current U.S.
Class: |
424/94.2 |
Current CPC
Class: |
A61P 13/08 20180101;
A61P 25/00 20180101; A61K 38/4893 20130101; A61K 38/54 20130101;
A61K 9/0053 20130101; A61P 25/02 20180101; A61K 38/49 20130101;
A61K 38/47 20130101; A61P 13/10 20180101; A61K 38/4886 20130101;
A61K 9/0019 20130101; A61P 43/00 20180101; A61P 35/00 20180101;
A61K 38/4886 20130101; A61K 2300/00 20130101; A61K 38/49 20130101;
A61K 2300/00 20130101; A61K 38/47 20130101; A61K 2300/00 20130101;
A61K 38/4893 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/94.2 |
International
Class: |
A61K 9/00 20060101
A61K009/00 |
Claims
1. A method for administering a botulinum toxin to a patient
suffering from cholecystitis, wherein the method excludes injection
of the botulinum toxin or an extracellular matrix digesting enzyme,
the method comprising the steps of: a) accessing a gall bladder of
the patient suffering from cholecystitis; b) administering a first
composition containing at least one extracellular matrix digesting
enzyme to a gall bladder surface area of the patient; and c)
administering the second composition containing a botulinum toxin
to the gall bladder surface area of the patient, wherein the first
composition containing at least one extracellular matrix digesting
enzyme and the second composition containing a botulinum toxin are
instilled into the gall bladder or a duct of the gall bladder to
contact the gall bladder surface area of the patient.
2. The method of claim 11, wherein the neurotoxin is a botulinum
toxin and is selected from the group consisting of botulinum toxin
types A, B, C.sub.1, D, E, F and G.
3. The method according to claim 26, wherein the neurotoxin is a
botulinum toxin type A.
4. The method according to claim 13, wherein the amount of
botulinum toxin type A administered is between about 10 units and
about 2750 units.
5. The method according to claim 14, wherein the at least one
extracellular matrix digesting enzyme is selected from the group
consisting of a hyaluronidase, a tissue plasminogen activator and a
collagenase.
6. The method according to claim 11, wherein the duct of the gall
bladder dilates sufficiently subsequent to instillation of the
first composition containing at least one extracellular matrix
digesting enzyme and the second composition containing a botulinum
toxin to allow a gall stone to pass through the duct of the gall
bladder.
7. The method according to claim 11, wherein the at least one
extracellular matrix digesting enzyme is a hyaluronidase and the
botulinum toxin is a botulinum toxin type A.
Description
CROSS-REFERENCE
[0001] This application is a divisional of application Ser. No.
12/032,057 filed Feb. 15, 2008, which claims the benefit of U.S.
Provisional Application No. 60/890,052, filed Feb. 15, 2007, the
contents of which are hereby incorporated by reference in their
entirety.
BACKGROUND
[0002] The present invention relates to the use of extracellular
matrix digesting enzymes and neurotoxins to treat various medical
conditions/disorders, such as overactive bladder, urinary
incontinence due to overactive bladder or unstable detrusor
sphincter, benign prostatic hyperplasia and associated bladder
voiding complications, urinary retention that is secondary to
having a spastic sphincter or a hypertrophied bladder neck,
neurogenic bladder dysfunction (e.g. secondary to for example,
Parkinson's disease, spinal cord injury, stroke or multiple
sclerosis), hyperhidrosis and gall bladder inflammation
(cholecystitis).
[0003] Neurotoxins, and in particular botulinum toxins, are
increasingly finding useful application in treating various medical
conditions. Such treatments are typically focally delivered via
injections that penetrate the skin or organ lining. This can lead
to difficulty in delivering the treatment due to complications from
needle penetration, patient concerns such as needle phobia, pain
and physician training issues. Neurotoxins such as botulinum toxin
are gaining significant application in the treatment of several
urological conditions including overactive bladder (OAB) and
detrusor hyperreflexia (DH) which cause bothersome symptoms such as
voiding urgency, excessive voiding frequency and incontinence, for
example. A detailed discussion of the use and techniques for
utilizing botulinum toxin to treat overactive bladder can be found
in "Botulinum toxin for the treatment of idiopathic and neurogenic
overactive bladder: State of the art" Nitti Victor W. Rev Urol
2006; 8(4):198-208. As detailed therein, botulinum toxin is
injected into the bladder wall and the number of injections
(between 15 to 50 injections of 100 to 1000 units of botulinum
toxin type A and 10 injections of 5000 units botulinum toxin type
B) depends on the well known effect and potency difference between
the serotype of botulinum toxin utilized, as well as the amount of
total toxin and dilution of toxin utilized, as detailed in therein
and known in the art.
[0004] Incontinence, one symptom of various urologic disorders,
includes urge incontinence and stress incontinence. Urge
incontinence involves a strong, sudden need to urinate, followed by
inappropriate bladder contraction, which then results in leakage.
What is troublesome is that it is often the case that these
contractions occur regardless of the amount of urine that is in a
sufferer's bladder, that is, the bladder does not necessarily have
to be so full and under pressure from urine contained therein to
result undesirable leakage. Urge incontinence can be a result of
neurological injuries (such as spinal cord injury or stroke),
neurological diseases (such as multiple sclerosis), infection,
bladder cancer, bladder stones, bladder inflammation, or bladder
outlet obstruction, for example. While these conditions can be
found both in men and women, men have an additional burden in that
urge incontinence may also be due to neurologic disease or bladder
changes caused by benign prostatic hypertrophy (BPH) or bladder
outlet obstruction from an enlarged prostate, for example.
[0005] Stress incontinence is an involuntary loss of urine that
occurs during physical activity, such as coughing, sneezing,
laughing, or exercise. A person can suffer from one or both types
of incontinence, and when suffering from both, it is called mixed
incontinence. Despite all of the knowledge associated with
incontinence, the majority of cases of urge incontinence are
idiopathic, which means a specific cause cannot be identified. Urge
incontinence may occur in anyone at any age, and it is more common
in women and the elderly.
[0006] The detrusor of the bladder is the muscle that expels urine
from the bladder. Consequences of detrusor hyperreflexia include
poor bladder compliance, high intravesical pressure, and reduction
in bladder capacity, all of which may result in deterioration of
the upper urinary tract.
[0007] It is thought that botulinum toxin exerts its effect on
bladder hyperactivity by paralyzing the detrusor muscle in the
bladder wall or possibly impacting afferent pathways in the bladder
and reducing sensory receptors in suburothelial nerves. These
effects possibly account for the improvement in urinary
incontinence, bladder capacity and reduction in bladder detrusor
pressures that are seen when the bladder walls are injected with
botulinum toxins. Examples of botulinum toxin use to treat various
urologic disorders can be found in "Botulinum Toxin Treatment of
Spastic Bladder", by Dott, C. et al., U.S. Patent App. Publication
No. US 2007/0275110A1and "Methods for the use of neurotoxin in the
treatment of urologic disorders", by Doshi, R., U.S. Patent App.
Publication No. 2004/0067235A1, both herein incorporated by
reference. Other known potential urological applications for
neurotoxins include the treatment of a variety of disorders of the
prostate including benign prostatic hyperplasia (BPH), prostatitis,
and prostate cancer (see, e.g., U.S. Pat. No. 6,365,164, herein
incorporated by reference in its entirety.)
[0008] To date, botulinum toxin has shown promising early results
for treatment of lower urinary tract symptoms including obstructive
and irritative voiding symptoms attributed to BPH. Both subjective
(symptoms) and objective (flow rates) improvements have been
observed. The prostate is a partially glandular and partially
fibromuscular gland of the male reproductive system. During aging,
the prostate tends to enlarge (hypertrophy). This prostatic
enlargement can lead to urethral obstruction and voiding
dysfunction. This is because the urethra passes through the
prostate (prostatic urethra) as it leads to the external urethral
orifice. A detailed discussion of prostate anatomy (including
lobes, stroma, nerve fiber types and innervation) can be found in
published U.S. patent application Ser. No. 09/978,982, filed Oct.
15, 2001, and entitled "Use of neurotoxin therapy for treatment of
urologic and related disorders", U.S. Published Patent Application
No. 20020025327 A1, herein incorporated by reference in its
entirety, in addition to standard anatomy texts.
[0009] Botulinum toxin is thought to affect nerve terminals in the
prostate and the release of neurotransmitters including
acetyicholine, sensory neuropeptides, and noradrenalin. These
effects may alter neural control within the prostate. Preliminary
reports suggest that botulinum toxin may also have a role in the
management of prostate cancer, possibly by inhibiting inflammation
and the down regulation of COX-2 expression.
[0010] In humans, the gall bladder is the organ that stores about
50 ml of bile (yellow or green alkaline fluid secreted by
hepatocytes from the liver of most vertebrates) until needed for
digestion. Bile is discharged into the duodenum where it aids the
process of digestion of lipids. The gallbladder is about 100 to 120
mm long in humans and is connected to the liver and the duodenum by
the biliary tract. A cystic duct connects the gallbladder to the
common hepatic duct to form the common bile duct, which then joins
the pancreatic duct, and enters through the hepatopancreatic
ampulla at the major duodenal papilla. The fundus of the
gallbladder is the part farthest from the duct, located by the
lower border of the liver at the same level as the transpyloric
plane.
[0011] Unfortunately, inflammation of the gall bladder, called
cholecystitis, can occur and is typically caused by the presence of
gall stones (choleliths, crystalline bodies formed by accretion or
concretion of normal or abnormal bile components in the
gallbladder) which commonly block the cystic duct directly leading
to a thickening of the bile, bile stasis, and even secondary
infection by gut organisms, predominantly E coli species. This
results in inflammation of the wall of the gallbladder. The
gallbladder can also become inflamed and infected in the absence of
galls stones. This is known as acute acalculous cholecystitis.
Chronic, low-level inflammation can lead to a chronic
cholecystitis, where the gallbladder is fibrotic and calcified.
[0012] In order to gain acess and visualize the gall bladder and
ducts, endoscopic retrograde cholangiopancreatography (ERCP) can be
utilized, a technique that combines the use of endoscopy and
fluoroscopy to diagnose and treat problems of the biliary systems.
Aided by a video endoscope, ERCP can utilize x-ray examination to
investigate and access bile ducts. The inside of the stomach and
duodenum can be seen through the endoscope, and dyes are commonly
injected by medical personnel into the ducts in the biliary tree so
they can be seen on x-rays. ERCP is used primarily to diagnose and
treat conditions of the bile ducts, including investigation of and
removal gallstones, inflammatory strictures (scars), leaks (from
trauma and surgery), and cancer. ERCP combines the use of x-rays
and endoscopy and is performed for diagnostic or therapeutic
reasons. In some instances, a second camera can be inserted through
the channel of the first endoscope (this technique is termed
duodenoscope-assisted cholangiopancreatoscopy (DACP) or
mother-daughter ERCP). The daughter scope can be used to administer
direct electrohydraulic lithotripsy to break up stones, or to help
in diagnosis by directly visualizing the duct (as opposed to
obtaining X-ray images).
[0013] The large size of the botulinum toxin molecule can limit its
ability to diffuse, and thus prohibits it from reaching both
afferent and efferent nerve fibers. As a result, current methods of
administration for OAB, for example, require many injections
(typically 20 to 50) of botulinum toxin into the bladder muscle
wall or into the prostate. Other examples of botulinum toxin uses
includes the treatment of chronic migraine with botulinum toxin,
which requires approximately 30 injections into the head and neck
musculature, and axillary hyperhidrosis, which requires numerous
injections to the dermal skin layer in the axilla (typically
anywhere from 10 to 40 injections per axilla, depending on the
severity of the condition, area overproducing sweat, size of the
patient and concentration, amount and type of botulinum toxin
used).
[0014] The genus Clostridium has more than one hundred and twenty
seven species, grouped according to their morphology and functions.
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 containers of
home based canneries, 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.
[0015] About 50 picograms of a commercially available botulinum
toxin type A (a purified neurotoxin complex available from
Allergan, Inc., of Irvine, Calif. under the trade name BOTOX.RTM.
in 100 unit vials) is a LD.sub.50 in mice (i.e. 1 unit). One unit
of BOTOX.RTM. contains about 50 picograms (about 56 attomoles) of
botulinum toxin type A complex. Interestingly, on a molar basis,
botulinum toxin type A is about 1.8 billion times more lethal than
diphtheria, about 600 million times more lethal than sodium
cyanide, about 30 million times more lethal than cobra toxin and
about 1 2 million times more lethal than cholera. Singh, Critical
Aspects of Bacteria/Protein Toxins, pages 63-84 (chapter 4) of
Natural Toxins II, edited by B. R. Singh et al., Plenum Press, New
York (1976) (where the stated LD.sub.50 of botulinum toxin type A
of 0.3 ng equals 1 unit is corrected for the fact that about 0.05
ng of BOTOX.RTM. equals 1 unit). 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.
[0016] 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 rate of
paralysis produced in the rat, than is 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. Moyer E et al.,
Botulinum Toxin Type 8: Experimental and Clinical Experience, being
chapter 6, pages 71-85 of "Therapy With Botulinum Toxin", edited by
Jankovic, J. et al. (1994), Marcel Dekker, Inc. Botulinum toxin
apparently binds with high affinity to cholinergic motor neurons,
is translocated into the neuron, and blocks the release of
acetylcholine. Additional uptake can take place through low
affinity receptors, as well as by phagocytosis and pinocytosis.
[0017] Regardless of stereotype, the molecular mechanism of toxin
intoxication appears to be similar and to involve at least three
steps or stages. In the first step of the process, the toxin binds
to the presynaptic membrane of the target neuron through a specific
interaction between the heavy chain, H chain, and a cell surface
receptor; the receptor is thought to be different for each type of
botulinum toxin and for tetanus toxin. The carboxyl end segment of
the H chain, H.sub.C, appears to be important for targeting of the
toxin to the cell surface.
[0018] In the second step, the toxin crosses the plasma membrane of
the poisoned cell. The toxin is first engulfed by the cell through
receptor-mediated endocytosis, and an endosome containing the toxin
is formed. The toxin then escapes the endosome into the cytoplasm
of the cell. This step is thought to be mediated by the amino end
segment of the H chain, H.sub.N, which triggers a conformational
change of the toxin in response to a pH of about 5.5 or lower.
Endosomes are known to possess a proton pump which decreases
intra-endosomal pH. The conformational shift exposes hydrophobic
residues in the toxin, which permits the toxin to embed itself in
the endosomal membrane. The toxin (or at a minimum the light chain)
then translocates through the endosomal membrane into the
cytoplasm.
[0019] The last step of the mechanism of botulinum toxin activity
appears to involve reduction of the disulfide bond joining the
heavy chain, H chain, and the light chain, L chain. The entire
toxic activity of botulinum and tetanus toxins is contained in the
L chain of the holotoxin; the L chain is a zinc (Zn.sup.2+)
endopeptidase which selectively cleaves proteins essential for
recognition and docking of neurotransmitter-containing vesicles
with the cytoplasmic surface of the plasma membrane, and fusion of
the vesicles with the plasma membrane. Tetanus neurotoxin,
botulinum toxin types B, D, F, and G, cause degradation of
synaptobrevin (also called vesicle-associated membrane protein
(VAMP)), a synaptosomal membrane protein. Most of the VAMP present
at the cytoplasmic surface of the synaptic vesicle is removed as a
result of any one of these cleavage events. Botulinum toxin
serotype A and E cleave SNAP-25. Botulinum toxin serotype C.sub.1
was originally thought to cleave syntaxin, but was found to cleave
syntaxin and SNAP-25. Each of the botulinum toxins specifically
cleaves a different bond, except botulinum toxin type B (and
tetanus toxin) which cleave the same bond. Each of these cleavages
block the process of vesicle-membrane docking, thereby preventing
exocytosis of vesicle content.
[0020] Botulinum toxins have been used in clinical settings for the
treatment of neuromuscular disorders characterized by hyperactive
skeletal muscles (i.e. motor disorders). Almost twenty years ago,
in 1989, a botulinum toxin type A complex was approved by the U.S.
Food and Drug Administration for the treatment of blepharospasm,
strabismus and hemifacial spasm. Subsequently, a botulinum toxin
type A was also approved by the FDA for the treatment of cervical
dystonia and for the treatment of glabellar lines, and a botulinum
toxin type B was approved for the treatment of cervical dystonia.
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, although significantly longer periods of
therapeutic activity have been reported.
[0021] 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 (VAMP, 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. Apparently, a substrate for a botulinum toxin can be
found in a variety of different cell types. See e.g. Biochem J
1;339 (pt 1):159-65.1999, and MovDisord, 10(3):376:1995 (pancreatic
islet B cells contains at least SNAP-25 and synaptobrevin).
[0022] 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 700 kD
or 500 kD complex. Botulinum toxin type D is produced as both 300
kD 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 non-toxin 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.
[0023] In vitro studies have indicated that botulinum toxin
inhibits potassium cation induced release of both acetylcholine and
norepinephrine from primary cell cultures of brainstem tissue.
Additionally, it has been reported that botulinum toxin inhibits
the evoked release of both glycine and glutamate in primary
cultures of spinal cord neurons and that in brain synaptosome
preparations botulinum toxin inhibits the release of each of the
neurotransmitters acetylcholine, dopamine, norepinephrine
(Habermann E., et al., Tetanus Toxin and Botulinum A and C
Neurotoxins Inhibit Noradrenaline Release From Cultured Mouse Brain
J Neurochem 51(2);522-527:1988)), CGRP, substance P, and glutamate
(Sanchez-Prieto, J., et al., Botulinum Toxin A Blocks Glutamate
Exocytosis From Guinea Pig Cerebral Cortical Synaptosomes, Eur J.
Biochem 165; 675-681:1897). Thus, when adequate concentrations are
used, stimulus-evoked release of most neurotransmitters is blocked
by botulinum toxin. See e.g. Pearce, L. B., Pharmacologic
Characterization of Botulinum Toxin For Basic Science and Medicine,
Toxicon 35(9);1 373-1 412 at 1393; Bigalke H., et al., Botulinum A
Neurotoxin Inhibits Non-Cholinergic Synaptic Transmission in Mouse
Spinal Cord Neurons in Culture, Brain Research 360;318-324:1985;
Habermann E., Inhibition by Tetanus and Botulinum A Toxin of the
release of [3H] Noradrenaline and [3H]GABA From Rat Brain
Homogenate, Experientia 44;224-226: 1988, Bigalke H., et al.,
Tetanus Toxin and Botulinum A Toxin Inhibit Release and Uptake of
Various Transmitters, as Studied with Particulate Preparations From
Rat Brain and Spinal Cord, Naunyn-Schmiedeberg's Arch Pharmacol 31
6;244-251 :1 981, and; Jankovic J. et al., Therapy With Botulinum
Toxin, Marcel Dekker, Inc., (1994), page 5.
[0024] 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 (and thus the
routine use of many thousands of units of botulinum toxin type B,
as known in the art, see e.g. "Long-term safety, efficacy, and
dosing of botulinum toxin type B (MYOBLOC.RTM.) in cervical
dystonia (CD) and other movement disorders" Kumar R and Seeberger
LC. Mov Disord 2002; 17(Suppl 5):S292-S293). 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.
[0025] High quality crystalline botulinum toxin type A can be
produced from the Hall A strain of Clostridium botulinum with
characteristics of .gtoreq.3.times.10.sup.7 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 Botuilnum toxin and
Other Microbial Neurotoxins in Medicine, Microbiol Rev.
56;80-99:1992. Generally, the botulinum toxin type A complex can be
isolated and purified from an anaerobic fermentation by cultivating
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 toxin type A with an approximately 150 kD
molecular weight with a specific potency of 1-2.times.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.times.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.
[0026] Botulinum toxins and/or botulinum toxin complexes can be
obtained from List Biological Laboratories, Inc., Campbell,
California; the Centre for Applied Microbiology and Research,
Porton Down, U.K.; Wako (Osaka, Japan), Metabiologics (Madison,
Wis.) as well as from Sigma Chemicals of St Louis, Mo. Pure
botulinum toxin can also be used to prepare a pharmaceutical
composition for use in accordance with the present disclosure.
[0027] As with enzymes generally, the biological activities of
botulinum toxins (which are intracellular peptidases) is dependant,
at least in part, upon their 3-dimensional conformation. Thus,
botulinum toxin type A is detoxified by heat, various chemicals,
surface stretching, and surface drying. Additionally, it is known
that dilution of the toxin complex obtained by the known culturing,
fermentation and purification to the much lower toxin
concentrations used for pharmaceutical composition formulation
results in rapid detoxification of the toxin unless a suitable
stabilizing agent is present. Dilution of the toxin from milligram
quantities to a solution containing nanograms per milliliter
presents significant difficulties because of the rapid loss of
specific toxicity upon such great dilution. Since the toxin may be
used months or years after the toxin containing pharmaceutical
composition is formulated, the toxin can be stabilized with a
stabilizing agent such as albumin and gelatin.
[0028] A commercially available botulinum toxin containing
pharmaceutical composition is sold under the trademark BOTOX.RTM.
(available from Allergan, Inc., of Irvine, Calif.). BOTOX.RTM.
consists of a purified botulinum toxin type A complex, albumin and
sodium chloride packaged in sterile, vacuum-dried form. Botulinum
toxin type A is made from a culture of the Hall strain of
Clostridium botulinum grown in a medium containing N-Z amine and
yeast extract. The botulinum toxin type A complex is purified from
the culture solution by a series of acid precipitations to a
crystalline complex consisting of the active high molecular weight
toxin protein and an associated hemagglutinin protein. The
crystalline complex is re-dissolved in a solution containing saline
and albumin and sterile filtered (0.2 microns) prior to
vacuum-drying. The vacuum-dried product is stored in a freezer at
or below -5.degree. C. BOTOX.RTM. can be reconstituted with
sterile, non-preserved saline prior to intramuscular injection.
Each vial of BOTOX.RTM. contains about 100 U of Clostridium
botulinum toxin type A purified neurotoxin complex, 0.5 milligrams
of human serum albumin and 0.9 milligrams of sodium chloride in a
sterile, vacuum-dried form without a preservative.
[0029] To reconstitute vacuum-dried BOTOX.RTM., sterile normal
saline without a preservative (0.9% Sodium Chloride Injection) is
used by drawing up the proper amount of diluent in the appropriate
size syringe. Since BOTOX.RTM. may be denatured by bubbling or
similar violent agitation, the diluent is gently injected into the
vial. For sterility reasons BOTOX.RTM. is preferably administered
within four hours after the vial is removed from the freezer and
reconstituted. During these four hours, reconstituted BOTOX.RTM.
can be stored in a refrigerator at about 2.degree. C. to about
8.degree. C. Reconstituted, refrigerated BOTOX.RTM. has been
reported to retain its potency for at least about two weeks
(Neurology, 48:249-53, 1997). It has been reported that botulinum
toxin type A has been used in clinical settings as follows: [0030]
(1) about 75-125 U of BOTOX.RTM. per intramuscular injection
(multiple muscles) to treat cervical dystonia; [0031] (2) 5-10 U of
BOTOX.RTM. per intramuscular injection to treat glabellar lines
(brow furrows) (5 units injected intramuscularly into the procerus
muscle and 10 units injected intramuscularly into each corrugator
supercilii muscle); [0032] (3) about 30-80 U of BOTOX.RTM. to treat
constipation by intrasphincter injection of the puborectalis
muscle; [0033] (4) about 1-5 U per muscle of intramuscularly
injected BOTOX.RTM. to treat blepharospasm by injecting the lateral
pre-tarsal orbicularis oculi muscle of the upper lid and the
lateral pre-tarsal orbicularis oculi of the lower lid; [0034] (5)
to treat strabismus, extraocular muscles have been injected
intramuscularly with between about 1-5 U of BOTOX.RTM., the amount
injected varying based upon both the size of the muscle to be
injected and the extent of muscle paralysis desired (i.e. amount of
diopter correction desired); [0035] (6) to treat upper limb
spasticity following stroke by intramuscular injections of
BOTOX.RTM. into five different upper limb flexor muscles, as
follows: [0036] (a) flexor digitorum profundus: 7.5 U to 30 U
[0037] (b) flexor digitorum sublimus: 7.5 U to 30 U [0038] (c)
flexor carpi ulnaris: 10 U to 40 U [0039] (d) flexor carpi
radialis: 15 U to 60 U [0040] (e) biceps brachii: 50 U to 200 U.
Each of the five indicated muscles has been injected at the same
treatment session, so that the patient receives from 90 U to 360 U
of upper limb flexor muscle BOTOX.RTM. by intramuscular injection
at each treatment session; [0041] (7) to treat migraine,
pericranial (injected symmetrically into glabellar, frontalis and
temporalis muscles) injection of 25 U of BOTOX.RTM. has showed
significant benefit as a prophylactic treatment of migraine
compared to vehicle as measured by decreased measures of migraine
frequency, maximal severity, associated vomiting and acute
medication use over the three month period following the 25 U
injection.
[0042] It is known that botulinum toxin type A can have an efficacy
for up to 12 months (European J. Neurology 6 (Supp 4): S111 -S1150:
1999), and in some circumstances for as long as 27 months, when
used to treat glands, such as in the treatment of hype rhydrosis.
See e.g. Bushara K., Botulinum toxin and rhinorrhea, Otolaryngol
Head Neck Surg 1996; 114(3):507, and The Laryngoscope
109:1344-1346:1999. However, the usual duration of effect of an
intramuscular injection of BOTOX .RTM. is typically about 3 to 4
months.
[0043] The success of botulinum toxin type A to treat a variety of
clinical conditions has led to interest in other botulinum toxin
serotypes. Two commercially available botulinum type A preparations
for use in humans are BOTOX.RTM. available from Allergan, Inc., of
Irvine, Calif., and DYSPORT.RTM. available from Beaufour Ipsen,
Porton Down, England. A botulinum toxin type B preparation
(MYOBLOC.RTM.) is available from Elan Pharmaceuticals of San
Francisco, Calif.
[0044] A botulinum toxin has also been proposed for or has been
used to treat otitis media of the ear (U.S. Pat. No. 5,766,605),
inner ear disorders (U.S. Pat. Nos. 6,265,379; 6,358,926), tension
headache, (U.S. Pat. No. 6,458,365), migraine headache pain (U.S.
Pat. No. 5,714,468), post-operative pain and visceral pain (U.S.
Pat. No. 6,464,986), hair growth and hair retention (U.S. Pat. No.
6,299,893), psoriasis and dermatitis (U.S. Pat. No. 5,670,484),
injured muscles (U.S. Pat. No. 6,423,319) various cancers (U.S.
Pat. No. 6,139,845), smooth muscle disorders (U.S. Pat. No.
5,437,291), and neurogenic inflammation (U.S. Pat. No. 6,063,768).
Controlled release toxin implants are known (see e.g. U.S. Pat.
Nos. 6,306,423 and 6,312,708) as is transdermal botulinum toxin
administration (U.S. patent application Ser. No. 10/194805).
[0045] Additionally, a botulinum toxin may have an effect to reduce
induced inflammatory pain in a rat formalin model. Aoki K., et al,
Mechanisms of the antinociceptive effect of subcutaneous
BOTOX.RTM.: Inhibition of peripheral and central nociceptive
processing, Cephalalgia 2003 Sep.;23(7):649. Furthermore, it has
been reported that botulinum toxin nerve blockage can cause a
reduction of epidermal thickness. Li Y, et al., Sensory and motor
denervation influences epidermal thickness in rat foot glabrous
skin, Exp Neurol 1997; 147:452-462 (see page 459). Finally, it is
known to administer a botulinum toxin to the foot to treat
excessive foot sweating (Katsambas A., et al., Cutaneous diseases
of the foot: Unapproved treatments, Clin Dermatol 2002
Nov.-Dec.;20(6):689-699; Sevim, S., et al., Botulinum toxin-A
therapy for palmar and plantar hyperhidrosis, Acta Neurol Belg 2002
Dec.;102(4):167-70), spastic toes (Suputtitada, A., Local botulinum
toxin type A injections in the treatment of spastic toes, Am J Phys
Med Rehabil 2002 Oct.; 81(10):770-5), idiopathic toe walking
(Tacks, L., et al., Idiopathic toe walking: Treatment with
botulinum toxin A injection, Dev Med Child Neurol 2002;44(Suppl
91):6), and foot dystonia (Rogers J., et al., Injections of
botulinum toxin A in foot dystonia, Neurology 1993 Apr.;43(4 Suppl
2)). Tetanus toxin, as wells as derivatives (i.e. with a non-native
targeting moiety), fragments, hybrids and chimeras thereof can also
have therapeutic utility. The tetanus toxin bears many similarities
to the botulinum toxins. Thus, both the tetanus toxin and the
botulinum toxins are polypeptides made by closely related species
of Clostridium (Clostridium tetani and Clostridium botulinum,
respectively).
[0046] Additionally, both the tetanus toxin and the botulinum
toxins are dichain proteins composed of a light chain (molecular
weight about 50 kD) covalently bound by a single disulfide bond to
a heavy chain (molecular weight about 100 kD). Hence, the molecular
weight of tetanus toxin and of each of the seven botulinum toxins
(non-complexed) is about 150 kD. Furthermore, for both the tetanus
toxin and the botulinum toxins, the light chain bears the domain
which exhibits intracellular biological (protease) activity, while
the heavy chain comprises the receptor binding (immunogenic) and
cell membrane translocational domains.
[0047] Additionally, both the tetanus toxin and the botulinum
toxins exhibit a high, specific affinity for gangliocide receptors
on the surface of presynaptic cholinergic neurons. Receptor
mediated endocytosis of tetanus toxin by peripheral cholinergic
neurons results in retrograde axonal transport, blocking of the
release of inhibitory neurotransmitters from central synapses and a
spastic paralysis.
[0048] Contrarily, receptor mediated endocytosis of botulinum toxin
by peripheral cholinergic neurons results in little if any
retrograde transport, inhibition of acetylcholine exocytosis from
the intoxicated peripheral motor neurons and a flaccid
paralysis.
[0049] Finally, the tetanus toxin and the botulinum toxins resemble
each other in both biosynthesis and molecular architecture. Thus,
there is an overall 34% identity between the protein sequences of
tetanus toxin and botulinum toxin type A, and a sequence identity
as high as 62% for some functional domains. Binz T. et al., The
Complete Sequence of Botulinum Neurotoxin Type A and Comparison
with Other Clostridial Neurotoxins, J Biological Chemistry 265(16);
9153-9158:1990.
[0050] Acetylcholine
[0051] Typically only a single type of small molecule
neurotransmitter is released by each type of neuron in the
mammalian nervous system. The neurotransmitter acetylcholine is
secreted by neurons in many areas of the brain, but specifically by
the large pyramidal cells of the motor cortex, by several different
neurons in the basal ganglia, by the motor neurons that innervate
the skeletal muscles, by the preganglionic neurons of the autonomic
nervous system (both sympathetic and parasympathetic), by the
postganglionic neurons of the parasympathetic nervous system, and
by some of the postganglionic neurons of the sympathetic nervous
system. Essentially, only the postganglionic sympathetic nerve
fibers to the sweat glands, the piloerector muscles and a few blood
vessels are cholinergic as most of the postganglionic neurons of
the sympathetic nervous system secret the neurotransmitter
norepinephine. In most instances acetylcholine has an excitatory
effect. However, acetylcholine is known to have inhibitory effects
at some of the peripheral parasympathetic nerve endings, such as
inhibition of heart rate by the vagal nerve.
[0052] The efferent signals of the autonomic nervous system are
transmitted to the body through either the sympathetic nervous
system or the parasympathetic nervous system. The preganglionic
neurons of the sympathetic nervous system extend from preganglionic
sympathetic neuron cell bodies located in the intermediolateral
horn of the spinal cord. The preganglionic sympathetic nerve
fibers, extending from the cell body, synapse with postganglionic
neurons located in either a paravertebral sympathetic ganglion or
in a prevertebral ganglion. Since, the preganglionic neurons of
both the sympathetic and parasympathetic nervous system are
cholinergic, application of acetylcholine to the ganglia will
excite both sympathetic and parasympathetic postganglionic
neurons.
[0053] Acetylcholine activates two types of receptors, muscarinic
and nicotinic receptors. The muscarinic receptors are found in all
effector cells stimulated by the postganglionic neurons of the
parasympathetic nervous system, as well as in those stimulated by
the postganglionic cholinergic neurons of the sympathetic nervous
system. The nicotinic receptors are found in the synapses between
the preganglionic and postganglionic neurons of both the
sympathetic and parasympathetic. The nicotinic receptors are also
present in many membranes of skeletal muscle fibers at the
neuromuscular junction.
[0054] Acetylcholine is released from cholinergic neurons when
small, clear, intracellular vesicles fuse with the presynaptic
neuronal cell membrane. A wide variety of non-neuronal secretory
cells, such as, adrenal medulla (as well as the PC12 cell line) and
pancreatic islet cells release catecholamines and parathyroid
hormone, respectively, from large dense-core vesicles. The PC12
cell line is a clone of rat pheochromocytoma cells extensively used
as a tissue culture model for studies of sympathoadrenal
development. Botulinum toxin inhibits the release of both types of
compounds from both types of cells in vitro, permeabilized (as by
electroporation) or by direct injection of the toxin into the
denervated cell. Botulinum toxin is also known to block release of
the neurotransmitter glutamate from cortical synaptosomes cell
cultures.
[0055] A variety of substances, termed proteolytic enzymes, degrade
or digest substances found in the extracellular matrix. These
include the family of hyaluronidases, plasminogen activators and
collagenase, for example. Hyaluronidase causes hydrolysis of
hyaluronic acid, a polysaccharide (nonsulfated glycosaminoglycan)
found in the intercellular matrix of connective tissue.
Hyaluronidase temporarily reduces the viscosity of the
extracellular matrix (tissue cement) by digesting hyaluronic acid
or hyaluronate, which is widely distributed throughout connective,
epithelial, and neural tissues. This effect promotes the diffusion
or spread of other drugs like anesthetic agents. Hyaluronidase may
be injected into connective tissue to enhance the effects of
co-injected drugs.
[0056] Hyaluroronidase can be obtained from a variety of sources
and is typically derived from testicular tissue extracts. For
example, ISTA Pharmaceuticals of Irvine, Calif., USA manufactures
and distributes VITRASE (a sheep sourced (ovine) form of
hyaluronidase), which is just one example of a hyaluronidase for
injection. VITRASE is an injectable drug approved by the U.S. FDA
as an adjunct to (in combination with) other injected drugs to
increase their absorption and dispersion. As stated previously,
hyaluronidase has been used most commonly in combination with local
anesthetics in the setting of ophthalmic (eye) surgery.
Hyaluronidase increases tissue permeability and promotes the spread
or dispersion of other drugs, for example, speeding the onset of
action for an anesthetic. VITRASE is also approved for use as an
adjunct to rehydrating agents, and for use with certain imaging
agents. Hyaluronidase is also available as a recombinant purified
preparation of the enzyme recombinant human hyaluronidase, an
example of which is HYLENEX, which is marketed by Baxter Healthcare
Corporation, Deerfield, Ill., USA. HYLENEX (a recombinant
hyaluronidase) is available as a sterile clear, colorless,
nonpreserved ready for use solution (each mL containing 150 USP
units of recombinant human hyaluronidase with 8.f mg sodium
chloride, 1.4 mg bibasic sodium phosphate, 1.0 mg human albumin,
0.9 mg edetate, 0.3 mg calcium chloride, and sodium hydroxide for
pH adjustment. Another exemplary hyaluronidase produced from sheep
testes is named HYALASE, by Aventis Pharma, Lane Cove, NSW,
Australia.
[0057] Hyaluronidase increases dispersion in the interstitial
matrix provided local pressure is adequate to furnish the necessary
mechanical impulse. Such an impulse is normally initiated by
injected solutions and the rate of diffusion is proportionate to
the amount of enzyme. The extent of diffusion is also proportionate
to the volume of solution, as known in the art.
[0058] Investigation of maintenance of efficacy, spread of effect
and decrease in required dose of botulinum toxin administered along
with hyaluronidase for treating axillary hyperhidrosis has been
reported ("Diffusion and short-term efficacy of botulinum toxin A
after the addition of hyaluronidase and its possible application
for the treatment of axillary hyperhidrosis" by Goodman G. Dermatol
Surg 2003 May; 29(5):533-8. Here a formulation/mixture containing a
botulinum toxin and a hyaluronidase is injected to treat
hyperhidrosis, as well as administration of botulinum toxin and
superadded hyaluronidase.
[0059] Other proteolytic enzymes include collagenase and
plasminogen activators which digest extracellular matrix proteins.
Plasminogen activators (PA) belong to a class of serine proteases
that have considerable substrate specificity and convert the
inactive zymogen plasminogen to plasmin. Plasmin is a general
protease which is capable of degrading many proteins including
laminin, fibronectin and activating latent collagenase
moieties.
[0060] What is needed therefore is a method for treating various
disorders that reduces the amount of botulinum toxin administered
to a patient. More particularly a method is needed that reduces, or
more preferably even eliminates, the number of, or need for,
injection of neurotoxins, such as botulinum toxins, to treat
various disorders.
SUMMARY
[0061] The present disclosure meets the need for a method by which
cholinerically-influenced disorders can be treated by reducing or
even eliminating the number of, and even the need for, injections
endured by a patient in order to treat the disorder that the
patient suffers from.
[0062] Definitions
[0063] As used herein, the words or terms set forth below have the
following definitions.
[0064] "About" means that the item, parameter or term so qualified
encompasses a range of plus or minus ten percent above and below
the value of the stated item, parameter or term.
[0065] "Target" or "target area" means that location/area or tissue
or gland of a patient's anatomy in which the desired effect of the
administered neurotoxin is exerted. A target can include, but is
not limited to a muscle, such as a detrusor muscle of a bladder, or
neurons that innervate a gland or muscle that is overactive, such
as the neurons that control sweat production of sweat glands in the
dermis of patient having hyperhidrosis, or contraction of a
targeted muscle, such a detrusor muscle and/or a urethral
sphincter, for example. Typically, the target is within 5 inches of
the locale of the administration of a composition of the instant
invention, preferably within 3 inches and even more preferably
within 1 inch.
[0066] "Administration", "administering" or "to administer" means
the step of giving (i.e. administering) a composition to a subject,
such as a pharmaceutical composition. The pharmaceutical
compositions disclosed herein are "locally administered" by e.g.
intramuscular (i.m.), intradermal, subcutaneous administration,
intraperitoneal (i.p.) administration, topical (transdermal),
instillation (e.g. intravesicular instillation) and implantation
(e.g. a slow-release device such as polymeric implant) routes of
administration.
[0067] "Botulinum toxin" means a neurotoxin produced by Clostridium
botulinum, as well as a botulinum toxin (or the light chain or the
heavy chain thereof) made recombinantly by a non-Clostridial
species. The phrase "botulinum toxin", as used herein, encompasses
the botulinum toxin serotypes A, B, C.sub.1, D, E, F and G.
Botulinum toxin, as used herein, also encompasses both a botulinum
toxin complex (i.e. the 300, 600 and 900 kDa complexes) as well as
the purified botulinum toxin (i.e. about 150 kDa). "Purified
botulinum toxin" is defined as a botulinum toxin that is isolated,
or substantially isolated, from other proteins, including proteins
that form a botulinum toxin complex. A purified botulinum toxin may
be greater than 95% pure, and preferably is greater than 99% pure.
The botulinum C.sub.2 and C.sub.3 cytotoxins, not being
neurotoxins, are excluded from the scope of the present
invention.
[0068] "Clostridial neurotoxin" means a neurotoxin produced from,
or native to, a Clostridial bacterium, such as Clostridium
botulinum, Clostridium butyricum or Clostridium beratti, as well as
a Clostridial neurotoxin made recombinantly by a non-Clostridial
species.
[0069] "Modified botulinum toxin" means a botulinum toxin that has
had at least one of its amino acids deleted, modified, or replaced,
as compared to a native botulinum toxin. Additionally, the modified
botulinum toxin can be a recombinantly produced neurotoxin, or a
derivative or fragment of a recombinantly made neurotoxin. A
modified botulinum toxin retains at least one biological activity
of the native botulinum toxin, such as, the ability to bind to a
botulinum toxin receptor, or the ability to inhibit
neurotransmitter release from a neuron. One example of a modified
botulinum toxin is a botulinum toxin that has a light chain from
one botulinum toxin serotype (such as serotype A), and a heavy
chain from a different botulinum toxin serotype (such as serotype
B). Another example of a modified botulinum toxin is a botulinum
toxin coupled to a neurotransmitter, such as substance P.
[0070] A "therapeutically effective" amount of the neurotoxin is
the dosage sufficient to inhibit neuronal activity for at least one
week, more preferably one month, most preferably for approximately
6 to 9 months or longer and up to 5 years. Dosing can be single
dosage or cumulative (serial dosing), and can be readily determined
by one skilled in the art. Neurotoxin, such a botulinum toxin, can
be delivered serially (i.e., one time per month, one time per every
six months) such that an optimal amount of toxin is administered in
accordance with the severity of the disorder treated and beneficial
results are maintained. Such a dosage schedule is readily
determined by one skilled in the art based on, e.g., patient size,
the neurotoxin selected, the condition to be treated, severity of
the disorder and other variables known in the art.
[0071] "Patient" means a human or non-human subject receiving
medical or veterinary care. Accordingly, as disclosed herein, the
compositions may be used in treating any animal, such as
mammals.
[0072] "Sufficient amount" means that amount of a substance,
composition of element of a composition that is enough to meet the
needs under the situation or a proposed end. For example, in
treating a particular disorder, it is that amount of botulinum
toxin that results in a desired outcome, e.g. a decrease in
detrusor muscle spasm or decrease in excessive sweat
production.
[0073] "Cholinergically-influenced disorder" is a disorder that
results from the dysfunction of a gland, organ or tissue that is
the result of over or under activity of the gland, organ or tissue,
or abnormal/disruptive enlargement of the gland organ or tissue,
wherein the gland organ of tissue is influenced/innervated by
acetylcholine releasing neurons. Non-limiting examples of
cholinergically-influenced disorders include, hyperhidrosis,
overactive bladder, and benign prostatic hyperplasia, for example.
The term "urologic disorder" includes, but is not limited to,
overactive bladder, detrusor hyperreflexia, detrusor instability,
neurogenic bladder, idiopathic bladder, benign prostate hyperplasia
and urinary incontinence.
[0074] An extracellular matrix digesting enzyme is an enzyme that
digests/breaks down at least one component of the extracellular
matrix. Exemplary extracellular matrix digesting enzymes include
hyaluronidase, which digests hyaluronic acid and has potential
application in both the bladder and prostate for disorders such as
overactive bladder, neurogenic bladder, benign prostatic
hyperplasia, prostitis, and prostate cancer. Other enzymes which
digest the extracelluar matrix including collagenase and
plasminogen activators such as tissue plasminogen activator and
urokinase which may have similar application by digesting the
extracellular matrix to thereby enhancing diffusion of neurotoxins,
and reduce the number of or eliminate the need for injection of
neurotoxin, in accordance with one aspect of the present
teachings.
[0075] A surface area is simply a particular area of a
subject/patient, such as a skin surface or internal surface, to
which compositions of the instant disclosure are administered.
Non-limiting examples of a surface area include an axillary skin
surface area, a palmar skin surface area, a gall bladder surface
area and a plantar skin surface area.
[0076] A "luminal surface area" of a patient/subject is an area
that faces a lumen, as well known in the art. Non-limiting examples
include a bladder luminal surface area, nasal luminal surface area,
a prostate luminal surface area, an esophageal luminal surface
area, stomach luminal surface area, gall bladder luminal surface
area, intestinal luminal surface area and a vascular luminal
surface area, for example.
[0077] "Intravesically administered" or "intravesical
administration" means instillation of a composition into a lumen to
contact a luminal surface area, such as a bladder luminal surface
area, for example, by any known suitable and appropriate means.
Intravesical administration excludes, however, injection into a
wall facing the lumen, such as a bladder wall.
[0078] "Alleviating" means a reduction in the occurrence of a
symptom that is associated with a cholinergically-influenced
disorder. For example, alleviating includes some reduction,
significant reduction, near total reduction, and total reduction of
at lease one symptom associated with hyperhidrosis, overactive
bladder, and benign prostate hyperplasia, for example, or any
disorder treated in accordance with the methods disclosed herein.
An exemplary symptom of hyperhidrosis is excessive sweating, for
overactive bladder and benign prostate hyperplasia, exemplary
symptoms can be incontinence or retention, for example. An
alleviating effect may not appear clinically for between 1 to 7
days after administration of a Clostridial toxin, such as a
botulinum toxin, to a patient.
[0079] "Treating" means to alleviate (or to eliminate) at least one
symptom of a cholinergically-influenced disorder, either
temporarily or permanently.
[0080] A method for treating a patient having a
cholinergically-influenced disorder, in accordance with the present
disclosure, can comprise the steps of administering a first
composition containing an extracellular matrix digesting enzyme to
a surface area of the patient, followed by allowing a sufficient
amount of time to pass for the extracellular matrix digesting
enzyme to diffuse through the surface area, then administering a
second composition containing a botulinum toxin to the surface
area, and subsequently allowing sufficient time for the botulinum
toxin to diffuse through the surface area to thereby alleviate at
least one symptom associated with the cholinergically-influenced
disorder and treat the patient having the
cholinergically-influenced disorder. In particular instances, the
surface area is a luminal surface area such as a bladder luminal
surface area. The extracellular matrix digesting enzyme is a
hyaluronidase, tissue plasminogen activator and collagenase, for
example, while the botulinum toxin is selected from the group
consisting of botulinum toxin type A, B, C, D, E, F, and G.
[0081] Various methods of administration can be utilized for
administration of the compositions useful in practicing the methods
disclosed herein. In one instance, administration of the
extracellular matrix digesting enzyme and botulinum toxin to a
bladder luminal surface area is achieved by instillation of a
composition containing an extracellular matrix digesting enzyme, as
well as instillation of a composition containing botulinum toxin,
into a bladder, for example.
[0082] Additionally, due to the synergistic effects provided by
methods practiced in accordance with the teachings disclosed
herein, administration of the extracellular matrix digesting enzyme
can be accomplished by injection, for example into a bladder wall,
or subdermally injected to a skin surface area (such as into an
armpit (axilla), palmer or plantar surface, for example), while
administration of a neurotoxin containing second composition is
accomplished by instillation into the bladder, or sprayed, swabbed
or smeared onto the skin surface area, respectively, thereby
avoiding any need for injection of the botulinum toxin. Conversely,
it is also contemplated that administration of the extracellular
matrix digesting enzyme (a first composition) can be accomplished
by instillation of the first composition into a bladder or sprayed,
swabbed or smeared onto the skin surface area, and administration
of the botulinum toxin is accomplished by injection of the second
composition (containing a neurotoxin, such as a botulinum toxin)
into a bladder wall or subdermally into the skin surface area,
respectively.
[0083] Accordingly, administration of the botulinum toxin can be
achieved by less than 20 injections into the bladder wall, more
preferably by less than 10 injections into the bladder wall and
most preferably by performing between 1 and 5 injections into the
bladder wall. For example, a total of 5 injections of neurotoxin,
such as botulinum toxin, after administration of the first
composition having the extracellular matrix digesting enzyme, can
be administered as follows: 1 injection to the dome of a bladder, 1
injection to an ventral wall of the bladder wall, 1 injection to a
dorsal wall of the bladder, and 1 injection each into each lateral
wall (left and right lateral wall of the bladder) for a total of
five injections. Particularly useful botulinum toxin include
botulinum toxin selected from the group consisting of botulinum
toxin types A, B, C.sub.1, D, E, F and G.
[0084] In particular embodiments, the methods disclosed herein can
include further steps of emptying the bladder prior to
administration of a composition containing an extracellular matrix
digesting enzyme and optionally emptying the bladder after
administration of the composition containing the extracellular
matrix digesting enzyme, and optionally emptying the bladder after
administration of the second composition that contains a
neurotoxin, such as a botulinum toxin. As stated above, the methods
disclosed herein can include removing the first composition
(containing at least one extracellular matrix digesting enzyme) and
removing the second composition (containing at least one
neurotoxin, such as a botulinum toxin).
[0085] Exemplary cholinergically-influenced disorders that can be
treated in accordance with the instant disclosure include a
urologic disorder such as a bladder disorder or a prostate
disorder. Exemplary bladder disorders include overactive bladder,
hypertrophied bladder neck and detrusor hyperreflexia, for example.
Exemplary prostate disorders include benign prostatic hyperplasia,
prostatitis and prostate cancer. An additional example of a
cholinergically-influenced disorder is hyperhidrosis and the
surface area of the patient, when treated accordingly, can is
selected from the group consisting of an axillary skin surface
area, a palmar skin surface area and a plantar skin surface
area.
[0086] A method for treating a patient suffering from cholecystitis
is also herein described, which can comprise the steps of
administering a first composition containing an extracellular
matrix digesting enzyme to a gall bladder surface area of the
patient, allowing sufficient time to pass for the extracellular
matrix digesting enzyme to diffuse through the gall bladder surface
area, administering a second composition containing a botulinum
toxin to the gall bladder surface area and allowing sufficient time
for the botulinum toxin to diffuse through the gall bladder surface
area to alleviate at least one symptom associated with
cholecystitis, thereby treating the patient suffering from
cholecystitis. Optionally the first composition can be removed
after the sufficient amount of time has passed, and similarly, the
second composition can also be optionally removed after a
sufficient amount of time has passed.
[0087] The gall bladder surface area can be within the gall bladder
proper and/or within a duct of the gall bladder, and useful
botulinum toxins can be selected from the group consisting of
botulinum toxin type A, B, C.sub.1, D, E, F and G. For example,
where the botulinum toxin is a botulinum toxin type A, it can be
administered in an amount from between about 1 unit to about 3000
units. Where the administered botulinum toxin is botulinum toxin
type B it can be administered in an amount from about between 50
units to about 25,000 units. Useful extracellular matrix digesting
enzymes are selected from the group consisting of a hyaluronidase,
a tissue plasminogen activator and a collagenase.
[0088] Symptoms associated with cholecystitis, and which can be
alleviated in accordance with the presently disclosed methods can
include gall bladder wall inflammation, intense pain in the upper
abdominal region that steadily increases, pain in the back,
ordinarily between the shoulder blades, or pain under the right
shoulder, pain in the lower region of the stomach, near the pelvis,
and nausea and vomiting. Additional symptoms can also include
abdominal bloating, intolerance of fatty foods, belching, gas, and
indigestion. Symptoms may most often be felt after a fatty meal and
at night. The cholecystitis can be due to the presence of at least
one gall stone.
[0089] In a particular embodiment, a method that excludes injection
of the botulinum toxin or an extracellular matrix digesting enzyme
for administering a botulinum toxin to a patient suffering from
cholecystitis can comprise the steps of accessing a gall bladder of
the patient suffering from cholecystitis and administering a first
composition containing at least one extracellular matrix digesting
enzyme to a gall bladder surface area of the patient and then
administering the second composition containing a botulinum toxin
to the gall bladder surface area of the patient, such that the
first composition containing at least one extracellular matrix
digesting enzyme and the second composition containing a botulinum
toxin are instilled into the gall bladder and/or a duct of the gall
bladder, in order to contact a gall bladder surface area of the
patient. As above, useful botulinum toxin types include A, B,
C.sub.1, D, E, F and G. For botulinum toxin type A, an exemplary
range of dosage can be between about 10 units and about 2750
units.
[0090] In still another aspect, method disclosed herein provide for
sufficient dilation of the duct of the gall bladder, subsequent to
instillation of the first composition containing at least one
extracellular matrix digesting enzyme and the second composition
containing a botulinum toxin, to allow a gall stone to pass through
the duct of the gall bladder and thus avoid surgical removal of the
stone. In one instance, the at least one extracellular matrix
digesting enzyme is a hyaluronidase and the botulinum toxin is a
botulinum toxin type A.
[0091] In particular embodiments, in addition to reducing the
number of injections utilized to treat cholinergically-influenced
disorders, the method for administering a neurotoxin to a patient
in need thereof can specifically exclude any injection of the
neurotoxin or an extracellular matrix digesting enzyme, where the
method comprises the steps of administering a first composition
containing at least one extracellular matrix digesting enzyme onto
a skin surface area or luminal surface area of the patient and
administering the second composition containing a neurotoxin onto
the skin surface area or luminal surface area of the patient, where
the neurotoxin diffuses to a greater extent that if administered
without the first composition containing at least one extracellular
matrix digesting enzyme, and further the administration excludes
injection of both the first and second compositions. In such
embodiments, the skin surface area can be an axillary skin surface
area, plantar skin surface area or palmar skin surface area. An
exemplary luminal surface area can be a bladder luminal surface
area, a urethral luminal surface area, a nasal luminal surface area
or a prostate luminal surface area.
[0092] For example, in methods that specifically exclude injection
of the neurotoxin or an extracellular matrix digesting enzyme, the
administration of one or both of the extracellular matrix digesting
enzyme and botulinum toxin is achieved by application via at least
one of spraying or rubbing onto the skin surface area or luminal
surface area of the patient. A method can further include the step
of drying the skin surface after administration of the first
composition (containing at least one extracellular matrix digesting
enzyme) to the skin surface. Drying the skin surface can include
the step of allowing sufficient time to pass to allow evaporation
of the first composition from the skin surface, before commencing
with administration of the second composition (containing a
neurotoxin, such as a botulinum toxin selected from the group
consisiting of botulinum toxin type A, B, C.sub.1, D, E, F or G),
onto the skin surface area.
[0093] Another non-injection method is provided in accordance with
the instant disclosure, for treating a urologic disorder in a
patient in need thereof, comprising the steps of instilling a first
composition containing hyaluronidase into to a bladder of the
patient in order to contact a bladder luminal surface area (which
has a glycosaminoglycan layer) to the first composition and
maintaining the first composition within the bladder to allow
sufficient time to pass such that the introduced (and instilled)
hyaluronidase interacts with the glycosaminoglycan layer and
diffuses through the bladder luminal surface area, optionally
draining the first composition from the bladder, instilling a
second composition containing a botulinum toxin type A to the
bladder in order to contact the bladder luminal surface area
previously contacted by the previously instilled and removed first
composition, and retaining the instilled second composition for a
sufficient time within the bladder so that a sufficient amount of
botulinum toxin type A diffuses through the bladder luminal surface
area to at least one layer of the muscularis propria (at least one
of the a inner longitudinal, middle circular, and outer
longitudinal layers) and optionally draining the second composition
from the bladder, thereby alleviating at least one symptom
associated with the urologic disorder and treating the urologic
disorder of the patient in need thereof. It is further contemplated
that a single composition/mixture that includes both an
extracellular matrix digesting enzyme and a botulinum toxin therein
can be instilled into a bladder.
[0094] Exemplary urologic disorders that can be so treated, that
is, by methods that do not require the use of injections, include
urologic disorders selected from the group consisting of overactive
bladder, hypertrophied bladder neck and detrusor hyperreflexia, for
example.
[0095] Each and every feature described herein, and each and every
combination of two or more of such features, is included within the
scope of the present invention provided that the features included
in such a combination are not mutually inconsistent.
DESCRIPTION
[0096] The present disclosure provides methods by which various
cholinergically-influenced disorders, such as urologic disorders
and hyperhidrosis can be treated. Urologic disorders include
overactive bladder, hypertrophied bladder neck and detrusor
hyperreflexia, for example, which can be treated by utilizing an
extracellular matrix digesting enzyme in conjunction with a
neurotoxin, such as botulinum toxin as taught herein. Such use
enhances the diffusion of botulinum toxin and as such can reduce,
and even eliminate, the need for injection protocols that are
typically utilized when treated these disorders with botulinum
toxin.
[0097] In accordance with the present disclosure, the methods are
described herein that take advantage of the synergistic effect of
utilizing at least one extracellular matrix digesting enzyme in
conjunction with a neurotoxin, preferably a botulinum toxin, in
order to treat various disorders, as more fully described below. An
advantageous aspect of the methods detailed herein is the reduction
in the number of, and even elimination of, injections to administer
therapeutically effective amounts of the neurotoxin to the patient
and thereby treat the disorder.
[0098] The neurotoxin can be formulated in any pharmaceutically
acceptable formulation/formulations such as a liquid, powder,
cream, emulsion, suspensions, solutions, and the like.
[0099] The amount of the Clostridial toxin, such as botulinum toxin
administered according to a method within the scope of the
disclosed herein can vary according to the particular
characteristics of the disorder being treated, for example, such a
urologic disorder or hyperhidrosis, including the severity and
other various patient variables including size, weight, age, and
responsiveness to therapy, as known in the art. To guide the
practitioner, typically, no less than about 1 unit and no more than
about 2500 units of a botulinum toxin type A (such as BOTOX.RTM.)
is administered per injection site if the toxin is injected, per
patient treatment session. For a botulinum toxin type A such as
DYSPORT.RTM., no less than about 2 units and no more about 4000
units of the botulinum toxin type A are administered per injection
site, per patient treatment session, if injected. For a botulinum
toxin type B such as MYOBLOC.RTM., no less than about 40 units and
no more about 25,000 units of the botulinum toxin type B are
administered per injection site, per patent treatment session.
Similar amounts of toxin can be utilized in accordance with methods
that do not utilize injection of toxin, such as instillation,
swabbing or spraying of neurotoxin containing compositions to areas
to which a composition containing an extracellular matrix digesting
enzyme has been or is/will be administered, either by injection or
non-injection. Of course, the amount of neurotoxin and
extracellular matrix containing enzyme to be utilized in a
particular patient to treat a particular disorder/condition will be
determined by the attending physician, as known in the medical
arts. For example, when treating a urologic disorder by
administration of neurotoxin to a patient's bladder, the volume of
the solution/dispersion and concentration of the neurotoxin may
depend upon the size of the patient, the severity of the disorder,
thickness of the bladder wall, concentration/amount of administered
extracellular matrix digesting enzyme and muscle, comorbidities,
and other factors.
[0100] For example, if treating a patient suffering from
hyperhidrosis, such as axillary hyperhidrosis, the hyperhidrotic
surface area to be treated (here an armpit) is first determined by
conducting a simple Minor's starch and iodine test, in order to
determine the area to be treated. The area is demarcated, and a
composition containing an extracellular matrix digesting enzyme,
such as a solution containing hyaluronidase, is applied to the
hyperhydrotic area. For example, the composition so applied can
contain about 150 U of hyaluronidase and is left on the patient's
skin surface to allow the hyaluronidase to be absorbed. Such
application can be simply accomplished by brushing, spraying or
swabbing a first composition containing an extracellular matrix
digesting enzyme onto the desired area. In some instances,
sufficient time is allowed to pass to allow the skin surface area
to dry. Subsequently, a composition that contains a neurotoxin,
such as a botulinum toxin, is applied to the area. Such a
composition can contain, for example, from about 50 to about 200
units of a botulinum toxin. Preferably, the composition containing
the botulinum toxin is similarly brushed, sprayed or swabbed to the
surface area to be treated and the patient can report a decrease in
excessive sweating and a return to euhidrosis in about 2 to about 7
days time.
[0101] Alternatively, for example, the botulinum toxin can be
administered by injection, such as by subdermal injection. However,
due to the topical application of the extracellular matrix
digesting enzyme, such as hyaluronidase, the number of necessary
injections is greatly reduced as compared to the typical number of
injections of botulinum toxin utilized to treat axillary
hyperhidrosis. As an example, between about 5 to about 10 injection
sites, having between about 5 to about 25 units of BOTOX.RTM.
(botulinum toxin type A) at each site, can be administered to the
area to which the extracellular matrix digesting enzyme is
administered. Preferably, up to about 5 injections of botulinum
toxin are administered to the area to which the extracellular
matrix digesting enzyme is administered. Typically, the injections
are evenly spaced from one another to as to cover the maximum
amount of hyperhidrotic area.
[0102] In another example, the methods disclosed herein provide for
methods to treat various urological disorders, for example, by
administering a neurotoxin such as a botulinum toxin to a bladder's
luminal surface area to which has been administered a composition
that contains an extracellular matrix digesting enzyme. Access to
the lumen of the bladder is easily accomplished by insertion of a
catheter or cannula into the urethra and to the bladder, as known
in the art. Once the catheter is so positioned, between 1 and 1000
ml of a first composition containing extracellular matrix digesting
enzyme, such as hyaluronidase, is instilled into the bladder. The
solution can contain anywhere from about 25 to about 50 Units of
hyaluronidase, the volume of the composition (for example a
solution) and concentration of the hyaluronidase may depend upon
the size of the patient, thickness of the bladder wall and muscle,
comorbidities, severity of the urologic disorder, weight of the
patient among other standard factors considered in the medical arts
when determining appropriate dosages/parameters for treating
particular patients. The first composition may then be drained from
the bladder after allowing a sufficient amount of time to pass,
such as from about 5 minutes to about 2 hours. In some embodiments,
where, for example, from about 10 ml to about 50 ml of the first
composition is instilled into the bladder, there may not be a need
to drain the bladder, as the composition can be absorbed. During
this time, the patient may be positioned (turned on their sides,
onto their stomach and back) in order to thoroughly establish
contact of the first composition with the bladder luminal surface.
The first composition can then be drained from the bladder
(utilizing known drainage techniques, and can include external,
manual depression of the bladder, for example). Subsequently, a
second composition containing a neurotoxin, preferably a botulinum
toxin, most preferably a botulinum toxin type A, is then
administered by instillation into the bladder to contact the
bladder luminal surface previously administered the first
composition containing the extracellular matrix digesting enzyme.
From about 25 to about 3000 units, more preferably from about 100
to about 2500 units of a botulinum toxin type A can be so
instilled, and from about 500 to about 50,000 units, and more
preferably from about 1000 to about 25,000 units of a botulinum
toxin type B can be so instilled into the bladder or a clinically
equivalent amount for other botulinum toxin serotypes, as known to
the skilled person in the art.
[0103] The dosage of neurotoxin agent that is intravesically
administered to the patient is one that is therapeutically
effective to achieve the desired treatment outcome. In the case of
botulinum toxin, the typical dose administered to the patient may
be any dose less than a toxic dose (for example less than 3000
units of BOTOX.RTM., a botulinum toxin type A, for a 70 kg man),
for example between 1 and 1,500 units and more preferably between
50 and 500 units per patient per treatment, although smaller or
larger doses may be administered as required. The doses can be
given as a single dose, or as divided doses over a span of time,
such as over a period of days or weeks or months, depending on the
length of effect for a given neurotoxin preparation.
[0104] Similar to the first composition, between about 1 and about
1000 ml of the second composition containing botulinum toxin can be
instilled into the bladder and the patient placed in various
positions as detailed above. Because the patient will likely be
instructed to empty his or her bladder prior to the procedure, the
bladder will likely not be full or markedly distended. In
particular embodiments, instillation of about 1 to about 100 mls of
solution/dispersion, and more preferably 10-50 ml of
solution/dispersion, may be sufficient to coat the inside of the
bladder (bladder luminal surface). Additionally, after a sufficient
amount of time (e.g. from about 5 minutes to about 2 hours) has
passed after instillation of the second composition into the
bladder, the second composition containing the botulinum toxin can
be drained from the bladder, although if a smaller volume of the
second composition is instilled (e.g. from about 1 to about 10
mls), the attending physician may not desire to drain the bladder
and rather allow for the second composition to be naturally drained
(expelled) by the patient. A composition (containing either/or a
botulinum toxin or an extracellular matrix digesting enzyme) for
bladder infusion according to the teaching of the present
disclosure typically is of a volume of about 80 to about 100 ml,
and more preferably 80 ml. Of course, the attending physician can
increase or decrease the concentration of the neurotoxin containing
composition and extracellular matrix digesting enzyme composition,
and volume of the instilled compositions, in accordance with the
patient's bladder size (children and young adults having smaller
bladders than adults) and severity of the disorder treated.
[0105] Draining of the instilled compositions can be accomplished
via catheter or naturally expelled, appropriate care being taken,
of course, associated with the disposable of neurotoxin containing
compositions. Within about 2 to about 7 days the patient can report
urological improvement and even a return towards a normal
urological state, which, for an adult, is having a flow rate of
about 25 cc/sec and a void volume of about 400 cc.
[0106] Draining of the first composition (containing the
extracellular matrix digesting enzyme) and the second composition
are described above for instillation into a bladder. If instilled
into a portion of a patient's GI tract or into a nasal lumen,
appropriate routes of removal/drainage can be employed, such as
simply tilting/positioning the patients head to instill or remove
compositions from a nasal luminal surface area, for example.
[0107] An exemplary method for intravesically administering the
first and second compositions utilizes a urinary catheter that
extends through the urethra into the bladder. The catheter may be a
"straight catheter" with a single lumen (simply a straight channel)
or alternatively might be a catheter that in some cases uses a
balloon or other mechanism to fix the catheter within the bladder
(such as a Foley catheter). Standard sizes for such a catheters are
known in the art, such as 10-16 French (3-5 mm), though larger or
smaller sizes might be used depending on size the patient and his
or her anatomy.
[0108] Once the catheter is in place, typically between 1 and 1000
ml of solution/dispersion containing neurotoxin and more preferably
in the range of 10-50 ml of solution/dispersion containing
neurotoxin can be instilled through the catheter into the bladder.
The volume of the solution/dispersion and concentration of the
neurotoxin may depend upon the size of the patient, thickness of
the bladder wall and muscle, comorbidities, and other factors.
[0109] Another representative means of intravesically administering
the neurotoxin involves the placement of a suprapubic needle or
catheter through the abdominal wall directly into the patient's
bladder. This is a more invasive method and is not the preferred
method of access to the bladder; however, due to urethral tract
infections, obstructions, etc. may be the best route that is
available to the attending physician to access the bladder luminal
surface. The required volume of compositions containing the
extracellular matrix digesting enzyme and the neurotoxin can then
be introduced into the bladder, either using direct vision,
endoscopic or fluoroscopic guidance, as known in the art.
Intravesical administration in accordance with the present
disclosure can also be accomplished utilizing a cystoscope which
facilitates viewing of intravesical delivery of the compositions.
Here, the compositions can be introduced into the bladder lumen
through the working channel of the cystoscope or through a catheter
or other tubular structure passed within or alongside the
cystoscope.
[0110] In some cases, the urethra or suprapubic catheter/needle may
have an inflatable component that can be inflated within the
bladder to "lock" the urethra or suprapubic catheter/needle in
place and prevent its removal. Inflating the balloon or other
inflatable device takes up volume within the bladder, and can
thereby require less of the extracellular matrix digesting enzyme
composition and neurotoxin containing composition to be
administered.
[0111] In accordance with once aspect, the extracellular matrix
digesting enzyme and a botulinum toxin can be serially administered
or administered at the same time. An exemplary mixture for
instillation or spreading to a surface area in can, for, example,
containing 100 units of botulinum toxin type A (BOTOX) diluted with
9 ml of preserved saline and 1 ml of hyaluronidase (1500 units,
here HYALASE).
[0112] Although examples of routes of administration and dosages
are provided, the appropriate route of administration and dosage
are generally determined on a case by case basis by the attending
physician. Such determinations are routine to one of ordinary skill
in the art (see for example, Harrison's Principles of Internal
Medicine (1998), edited by Anthony Fauci et al., 14th edition, and
published by McGraw Hill). For example, the route and dosage for
administration of a Clostridial neurotoxin, such as a botulinum
toxin, according to the present disclosed invention can be selected
based upon criteria such as the solubility characteristics of the
neurotoxin chosen as well as the intensity of the disorder
treated.
[0113] The following examples provide those of ordinary skill in
the art with specific preferred methods to practice methods that
are within the scope of the present invention and are not intended
to limit the scope of the invention.
EXAMPLES
Example 1
[0114] A 64-year old patient has an overactive bladder, and as a
result has urge and stress incontinence. He unfortunately
experiences from about 5-8 leakage accidents per day, requiring
necessary changes of the adult diapers that he is forced to wear
because of his condition. Upon presentation to his urologist, a
regimen of bladder instillation is decided upon, utilizing
botulinum toxin and an extracellular matrix digesting enzyme.
[0115] The patient is asked to relieve himself before lying on his
back upon an adjustable table or bed, after which a urethral
catheter is inserted into his urethra and to the patient's bladder.
A first composition containing an extracellular matrix digesting
enzyme, here 150 USP units of nonpreserved hyaluronidase (such as
HYLENEX) in 50 mls of nonpreserved saline, are instilled into the
man's bladder. The catheter is then removed and the surface upon
which the patient is lying is tilted so that his head is lower than
his feet, in order that the first composition contacts the bladder
luminal surface at the dome of the bladder. The patient remains in
such a position for 10 minutes, after which he is titled forward so
that his feet are lower than his head so that the first composition
is now in full contact with the floor of the bladder. The patient
remains so for 10 more minutes, and is then asked to roll onto his
left and right sides (for 10 minutes each, respectively) and then
onto his stomach, to more fully expose all of the bladder's lateral
luminal surface areas to the first composition that includes the an
extracellular matrix digesting enzyme. The patient is then
recatheterized and stood upright, to drain the bladder. Then a
second composition, which contains 500 units of a botulinum toxin
type A, such as BOTOX.RTM. reconstituted in 50 mls of non-preserved
saline, is then instilled into the patient's bladder and the
patient is then subjected to the same positioning regimen as for
the first composition. Subsequently, the patient is drained of the
second composition and discharged.
[0116] Weekly follow up visits show that the patient now has
control over his urination, and although he still wears adult
diapers out of abundance of caution, and does not have accidental
leakage episodes since the instillation treatment and can enjoy
running and other physical activities that his stress incontinence
forces him to avoid.
Example 2
[0117] A 72-year old man has suffers from urge incontinence due to
a neurogenic bladder dysfunction that is secondary to his
Parkinson's disease. His condition forces the patient to make, on
average, over 20 trips to the restroom per day to relieve his
bladder. The situation is presented to his physician and
administration of an extracellular matrix digesting enzyme and
botulinum toxin to his bladder walls is decided upon.
[0118] The patient is firstly asked to relive himself before
insertion of an appropriately sized catheter (3-5 mm) into his
urethra. A first composition containing 300 USP units of
nonpreserved hyaluronidase (such as HYLENEX) in 2 mls of solution
is instilled into the bladder and a positioning routine, however
the patient now remains in the various positions for 5 minutes.
After drainage of the patient's bladder, a cytoscope is utilized to
inject botulinum toxin at one site into each of the dome, dorsal,
ventral and lateral walls of the bladder, sparing the trigone. Thus
a total of five injections, of about 10 units of a botulinum toxin
type A complex at each injection site for a total of about 50 units
of botulinum toxin type A (e.g. BOTOX.RTM., or about 40 units of
DYSPORT.RTM. at each site, for a total of 200 units of botulinum
toxin type A) are so delivered, a great reduction from the
typically 20-40 injections of prior methods which utilizing toxin
alone. The instillation of the extracellular matrix digesting
enzyme into the bladder and to the bladder luminal surface
facilitates the greater diffusion of the toxin throughout the
muscularis propria (i.e. the three layers: inner longitudinal,
middle circular, and outer longitudinal muscles of the bladder's
muscular layer) while reducing the amount of injections that need
to be performed.
[0119] The patient rests after the procedure is completed and is
then taken home. During follow-up visits, the patient reports no
unwanted systemic or local side effects and shows an improvement in
bladder function, both subjectively (reduction in urgency to
urinate) and objectively (now only urinates 4 times/day on
average).
[0120] Injection of up to 5000 units of botulinum toxin type B, at
1000 units per injection site can also be performed and treats
neurogenic bladder dysfunction that is secondary to his Parkinson's
disease, similarly.
Example 3
[0121] A 58 year old woman suffers urinary retention that is
secondary to spastic sphincter and has a hypertrophied bladder
neck. The patient typically urinates only 2-3 times per week and
when so doing only manages to void approximately 50 mls of urine
per visit to the restroom. Her caretaker fears resultant high
intravesical pressure and reduction in bladder capacity will result
in deterioration of the upper urinary tract.
[0122] Accordingly, her urologist inserts a cytoscope and flexible
endoscopic needle into her urethra and into the bladder. A first
composition comprising a total of 100 units of hyaluronidase, such
as VITRASE, is injected into the detrusor muscle, at a total of 10
sites, 2 sites into each into of the dorsal, ventral and lateral
bladder walls (for a total of 8 injections to the bladder walls)
and 2 sites into the bladder neck and the cytoscope removed. After
10 minutes, a second composition of 100 mls of nonpreserved saline,
containing 750 units of a botulinum toxin type A (e.g.
DYSPORT.RTM.) is instilled into bladder and kept there for 30
minutes, after which the patent is recatherized and voided of the
second composition. Within 7 days, the caretaker reports improved
frequency of urination (1 to 2 times per day) and an increase in
the amount of urine voided (about 300 to 400 mls per visit to the
restroom).
Example 4
[0123] A 23 year old college student reports to her dermatologist
stating that her excessive axillary sweating is rendering her very
self conscience and as a result her grades are suffering and she
has become more and more introverted as time passes. The
dermatologist determines that the patient is suffering from
hyperhidrosis and suggests utilizing a neurotoxin to treat the
hyperhidrosis since roll-on antiperspirants have no effect on her
excessive sweating.
[0124] After wiping the axilla of the patient dry with a paper
towel, a Minor's iodine-starch test is performed to demarcate the
hyperhidrotic skin surface area to be treated (such as by utilizing
a vegetable-based ink). Applied to this axillary skin surface area
is a first composition that contains an extracellular matrix
digesting enzyme, here 1 ml containing 150 USP units of
nonpreserved hyaluronidase (such as HYLENEX) is applied by swabbing
the demarcated area with an applicator, such as a cotton swab. The
area is then allowed to air-dry, for about 10 minutes. Thereafter
and to the axillary skin surface area, about 25 units of botulinum
toxin type A (such as BOTOX.RTM., or about 100 units of
DYSPORT.RTM., or about 1250 units of MYOBLOC.RTM.) is applied,
utilizing another cotton swab and allowed to dry. The same
procedure is performed on the patient's other axilla.
[0125] Within one week, the patient reports that they no longer
experience the excessive sweating that pervaded their previous
days, and that there are no excessive local hypotonicity or
systemic adverse effects.
[0126] A similar approach can be utilized to treat other skin
surface areas that may also be hyperhidrotic, such as the palms of
the hands (palmar skin surface area) and/or the soles of the feet
(plantar skin surface area).
Example 5
[0127] A 42 year old single man reports to his dermatologist that
his excessive axillary sweating is rendering him very self
conscience to the point of no longer interacting with the opposite
sex. The dermatologist determines that the patient is suffering
from hyperhidrosis and suggests utilizing a neurotoxin to treat the
hyperhidrosis, since all of the topical antiperspirants he as tried
have not been effective.
[0128] After wiping the axilla of the patient dry with a paper
towel, a Minor's iodine-starch test is performed to demarcate the
hyperhidrotic skin surface area to be treated (such as by utilizing
a vegetable-based ink). Applied to this axillary skin surface area
is a first composition that contains an extracellular matrix
digesting enzyme, here 2 mls containing 300 USP units of
nonpreserved hyaluronidase (such as HYLENEX), applied by spraying
the demarcated area with a spray applicator, such as a non-aerosol
pump. The area is then allowed to air-dry, for about 10 minutes.
Thereafter and to the axillary skin surface area, about 1000 units
of botulinum toxin type B (such as MYOBLOC.RTM.) is sprayed
thereon, utilizing a spray applicator and allowed to dry. The same
procedure is performed on the patient's other axilla.
[0129] Within 10 days, the patient reports that he no longer
experiences the excessive sweating that pervaded their previous
lonely days, and further that there are no excessive local
hypotonicity or systemic adverse effects. The patient reports that
the procedure was effective for between about 2 to about 6 months,
at which time he returns to the dermatologist for another round of
treatment.
Example 6
[0130] A 15 year old high school student reports to his family
physician that his hyperhidrotic hands are a source of great
embarrassment. Accordingly, the doctor proceeds to perform a
Minor's iodine-starch test to demarcate the areas to be treated. It
appears that the excessive sweating mainly originates from the area
between the patient's wrists to the bases of the fingers.
[0131] Accordingly, 1 ml of hyaluronidase containing 150 USP units
is applied to the wrist to the base of the fingers (1 ml/150 USP
units per hand) and allowed to dry. After drying, 4 points of
injection in the palm (midline at the base of wrist, base of middle
finger, and between base of the thumb and base of the index finger,
and between base of the pinky and base of wrist) at which about 40
units of botulinum toxin type A (such as BOTOX.RTM., or about 80
units DYSPORT.RTM. or 200 units of a botulinum toxin type B, such
as MYOBLOC.RTM.) is injected intradermally at each of the four
points.
[0132] After 5 days, the teen reports that his palms are not longer
sweaty and there are no reports of excessive hypotonicity or
systemic effects. The hyperhidrosis abates for up to 8 months, at
which time the teen returns to have the procedure repeated. If
needed, the treatment is also applied to the ventral portions of
the patient's fingers, if exhibiting excessive sweating.
Example 7
[0133] A 76 year old man suffers from chronic urinary retention due
to the enlargement of his prostate due to benign prostatic
hyperplasia. It is decided by his physician that the patient
undergo administration of a botulinum toxin to the prostate in
order to alleviate his urinary retention and treat the benign
prostatic hyperplasia. In order to minimize the number of
injections of botulinum toxin to the prostate, an extracellular
matrix enzyme, such as hyaluronidase, is injected into the
transition zone of the lateral lobes of the prostate and the median
lobe. Three injections of hyaluronidase (50 units at injection
point) are made utilizing an injection cytoscope and a 23 gauge
needle, one injection into each of the lateral lobes and one
injection into the median lobe. After 5 minutes, three injections
of a botulinum toxin type A are similarly administered, where each
injection contains 50 units of botulinum toxin type A (BOTOX .RTM.)
for a total of 150 units.
[0134] After about 7 days, the patient reports an improvement in
spontaneous voiding after this treatment and decrease post voiding
residual volume and pressure are decreased. These beneficial
effects are maintained for about 5 months in this particular
patient and no adverse effects are reported. A type B botulinum
toxin can also be utilized, for example, from about 250 units to
1000 units per injection site.
Example 8
[0135] A 53 year old woman suffers from recurring bouts of pain the
upper abdominal region. The pain steadily increases over time (over
about 15 minutes to an hour) and sometimes is accompanied by pain
located in her back. Upon visiting her internist, he finds that she
suffers from cholecystitis as a result of the formation of
gallstones. The physician decides to remove the gall stones and
instill her gall bladder utilizing a combination of an
extracellular matrix digesting enzyme (hyaluronidase) and botulinum
toxin type A, utilizing common endoscopic retrograde
cholangiopancreatography (ERCP) techniques to gain access to her
gall bladder.
[0136] After sedation of the patient, a flexible camera (endoscope)
is inserted through her mouth, eventually through the pylorus and
into her duodenum where the ampulla of Vater (the opening of the
common bile duct and pancreatic duct) exists, at which the
sphincter of Odi controls the ampulla's opening. The region is
directly visualized with the endoscopic camera while a plastic
catheter (or cannula and the like) is inserted through the ampulla.
About 25 mls of a first composition comprising a total of 100 units
of hyaluronidase, such as VITRASE, is instilled into the gall
bladder through the inserted catheter. After 15 minutes, any
remaining first composition is removed via the same catheter.
Subsequently, 25 mls of a second composition containing 200 units
of botulinum toxin type A (BOTOX.RTM.) is also instilled into the
gall bladder through the catheter. After another 20 minutes, any
remaining second composition is then removed and the endoscope and
catheter is removed. During the instillation and removal of the
first and second compositions, two gall stones, having
circumferences of about 6 mm and 8 mm, are flushed out and
removed.
Example 9
[0137] A debilitated 78 year old man suffers from recurring bouts
of pain between the shoulder blades and under the right shoulder,
and his caregiver reports that he feels nauseated and vomits on
occasion. Upon inspection, his primary physician notes that his
gallbladder is inflamed, and since no gall stones are found, a
diagnosis of acute acalculous cholecystitis is made. His physician
proceeds to instill the gall bladder, utilizing a combination of an
extracellular matrix digesting enzyme (hyaluronidase) and botulinum
toxin type B.
[0138] After anaesthetizing the patient, ERCP can be performed to
insert a flexible camera (endoscope) through his mouth, and as in
example 8, a plastic catheter (or cannula and the like) is inserted
through the ampulla.
[0139] About 30 mls of a first composition comprising a total of
150 units of hyaluronidase, such as VITRASE, is instilled into the
gall bladder through the inserted catheter. After 25 minutes, any
remaining first composition is removed via the same catheter.
Subsequently, 30 mls of a second composition containing 5000 units
of botulinum toxin type B (MYOBLOC.RTM.) is also instilled into the
gall bladder through the catheter. After another 30 minutes, any
remaining second composition is removed and the endoscope and
catheter is removed.
[0140] After the anesthetic sufficiently wears off, the patient is
then sent home with his caretaker. Upon questioning at a follow up
visit with his 3 months later, the caretaker reports that the man
no longer suffers from any pain between the shoulder blades or
under the right shoulder, and does not vomit.
[0141] Although the present invention has been described in detail
with regard to certain preferred methods, other embodiments,
versions, and modifications within the scope of the present
invention are possible. For example, a wide variety of neurotoxins
can be effectively used in the methods of the present invention in
place of Clostridial neurotoxins. Additionally, the present
invention includes administration of two or more different
Clostridial toxin components and targeting moieties, administered
concurrently or consecutively. For example, administration of a
particular second composition containing botulinum toxin type A to
the bladder luminal surface or hyperhidrotic skin surface area can
be administered to the patient and if increased tolerance
resistance to it's effect is noted, a botulinum toxin of a
different serotype, such as botulinum toxin type B or F, can be
utilized in subsequent applications to treat the
cholinergically-influenced disorder. While this invention has been
described with respect to various specific examples and
embodiments, it is to be understood that the invention is not
limited thereto and that it can be variously practiced with the
scope of the following claims.
* * * * *