U.S. patent application number 10/976507 was filed with the patent office on 2005-05-26 for botulinum toxin neurotoxic components formulations.
This patent application is currently assigned to ALLERGAN, INC.. Invention is credited to Graham, Herbert Kerr.
Application Number | 20050112146 10/976507 |
Document ID | / |
Family ID | 10701881 |
Filed Date | 2005-05-26 |
United States Patent
Application |
20050112146 |
Kind Code |
A1 |
Graham, Herbert Kerr |
May 26, 2005 |
Botulinum toxin neurotoxic components formulations
Abstract
The invention provides for the use of a presynaptic neurotoxin
(for example a bacterial neurotoxin such as botulinum toxin A) for
the manufacture of a medicament for the treatment of cerebral palsy
in juvenile patients. The juvenile patients are preferably
juveniles of up to 6 years in age.
Inventors: |
Graham, Herbert Kerr; (North
Balwyn, AU) |
Correspondence
Address: |
Stephen Donovan
Allergan, Inc.
2525 Dupont Drive
Irvine
CA
92612
US
|
Assignee: |
ALLERGAN, INC.
Irvine
CA
|
Family ID: |
10701881 |
Appl. No.: |
10/976507 |
Filed: |
October 29, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10976507 |
Oct 29, 2004 |
|
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10155280 |
May 22, 2002 |
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Current U.S.
Class: |
424/239.1 |
Current CPC
Class: |
A61P 21/02 20180101;
Y02A 50/469 20180101; A61K 9/19 20130101; Y02A 50/30 20180101; C12Y
304/24069 20130101; A61P 21/00 20180101; A61P 43/00 20180101; A61K
38/4893 20130101; A61P 19/00 20180101; C12N 9/52 20130101; A61P
25/00 20180101 |
Class at
Publication: |
424/239.1 |
International
Class: |
A61K 039/08 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 24, 1991 |
GB |
GB9120306.7 |
Claims
1-16. (canceled)
17. A vacuum dried, sterile, lyophilised, powdered formulation for
therapeutic use in humans comprising: (a) the neurotoxic component
of a botulinum toxin purified from a complex of non-toxic proteins
and haemagglutinins, wherein the neurotoxic component has a
molecular weight of about 150 kilodaltons and comprises a short
polypeptide chain of about 50 kD and a larger polypeptide chain of
about 100 kD; (b) saline, and; (c) pasteurised human serum
albumin.
18. A method for making a neurotoxic component botulinum toxin
formulation comprising the steps of: (a) establishing a culture of
an anaerobic bacterium of Clostridium botulinum; (b) growing a
culture of the Clostridium botulinum in a fermenter; (c) harvesting
a botulinum toxin type A mixture from the fermenter, wherein the
botulinum toxin type A harvested comprises; (i) a neurotoxic
polypeptide component with (1) a molecular weight of about 150
kilodaltons, (2) a short polypeptide chain of about 50 kD, and (3)
a larger polypeptide chain of about 100 kD, (4) the two chains
being linked together by a disulphide bridge, (ii) a complex
comprising (5) non-toxic proteins and (6) haemagglutinins, (7) the
complex having a molecular weight of about 900 kD; (d) purifying
the botulinum toxin type A neurotoxic component from the fermented
mixture; (e) adding human serum albumin as a stabilizer to the
botulinum toxin type A; (f) adding saline as a tonicity adjusting
agent to the botulinum toxin type A to form a solution; (g) sterile
filtering the solution; (h) vacuum drying the solution to form a
powder; (i) reconstituting the powder with sterile unpreserved
normal saline to form a sterile, pyrogen-free aqueous solution or
dispersion of a botulinum toxin type A neurotoxic component.
19. A product made by the method of claim 18.
Description
[0001] The present invention relates to the treatment of cerebral
palsy in a juvenile patient and in particular to the promotion of
normal muscle growth in a juvenile patient suffering from dynamic
contractures caused by cerebral palsy.
[0002] Cerebral palsy is a collective name given to a range of
conditions caused by brain injury caused at or around the time of
birth, or in the first year of an infant's life. The brain injury
may be caused, for example, by trauma during delivery. It may also
arise through such causes as trauma due to road traffic accidents
or meningitis during the first year of life. It has been found that
there is an increased risk of cerebral palsy in prematurely born
babies and, as a result of the improvements in technology which
enable premature babies to be kept alive from a much earlier age,
the incidence of cerebral palsy in many countries is actually
increasing rather than falling.
[0003] Although the brain injury causing cerebral palsy is a
non-progressive injury, its effects may change as the sufferer
grows older. The largest group of sufferers from cerebral palsy
suffer from spastic cerebral palsy. Spastic cerebral palsy is
characterised by dynamic contractures of the muscles which impair
or inhibit completely the sufferer's ability to use his or her
muscles. Moreover, muscle growth is impaired such that the
longitudinal muscles become shorter relative to their associated
bones as the infant grows older. Where the leg muscles are
affected, the mobility of the sufferer can be severely reduced.
Conventional attempts to cure this defect and to restore a measure
of normal mobility typically have involved surgical intervention to
alter the lengths of the tendons once the stage has been reached at
which the knee joint can no longer be straightened or the sufferer
can only walk on tiptoe.
[0004] There remains a need for a treatment which allows the
longitudinal muscles to grow normally, thereby removing, or at
least minimising the need to resort to surgical intervention.
Moreover, there remains a need for a treatment which can augment
surgical intervention to improve the mobility of the sufferer.
[0005] A bacterial toxin, botulinum toxin, has been used in the
treatment of a number of conditions involving muscular spasm, for
example blepharospasm, spasmodic torticollis (cervical dystonia),
oromandibular dystonia and spasmodic dysphonia (laryngeal
dystonia). The toxin binds rapidly and strongly to presynaptic
cholinergic nerve terminals and inhibits the exocytosis of
acetylcholine by decreasing the frequency of acetyl choline
release. This results in paralysis, and hence relaxation, of the
muscle afflicted by spasm.
[0006] The term Botulinum toxin as used herein is a generic term
embracing the family of toxins produced by the anaerobic bacterium
Clostridium botulinum and, to date, seven immunologically distinct
toxins have been identified. These have been given the designations
A, B, C, D, E, F and G. For further information concerning the
properties of the various botulinum toxins, reference is made to
the article by Jankovic & Brin, The New England Journal of
Medicine, pp 1186-1194, No 17, 1991 and to the review by Charles L
Hatheway, Chapter 1 of the book entitled Botulinum Neurotoxin and
Tetanus Toxin Ed. L. L. Simpson, published by Academic Press Inc.
of San Diego Calif. 1989, the disclosures in which are incorporated
herein by reference.
[0007] The neurotoxic component of botulinum toxin has a molecular
weight of about 150 kilodaltons and is thought to comprise a short
polypeptide chain of about 50 kD which is considered to be
responsible for the toxic properties of the toxin, and a larger
polypeptide chain of about 100 kD which is believed to be necessary
to enable the toxin to penetrate the nerve. The "short" and "long"
chains are linked together by means of disulphide bridges.
[0008] The neurotoxic polypeptide component is present in a complex
with non-toxic proteins and haemagglutinins, the molecular weight
of the complex being in the region of 900 kD.
[0009] Botulinum toxin is obtained commercially by establishing and
growing cultures of C. botulinum in a fermenter and then harvesting
and purifying the fermented mixture in accordance with known
techniques.
[0010] The "A" form of botulinum toxin is currently available
commercially from several sources, for example from Porton Products
Ltd UK under the tradename "DYSPORT", and from Allergan Inc,
Irvine, Calif. under the trade name "OCULINUM".
[0011] It has now been found by the present inventor that children
suffering from cerebral palsy related dynamic muscle contractures
exhibit improvements in function following treatment with botulinum
toxin and that such functional improvements persist when the tone
reducing effects of the toxin have worn off.
[0012] It has also been found that by administering botulinum toxin
to a juvenile spastic mammal during its growth phase, the
consequent reduction in tone of the spastic muscle enables
increased longitudinal growth of the muscle to take place.
[0013] In a first aspect, the present invention provides a method
of treating a juvenile patient suffering from arrested muscle
growth arising from the presence of dynamic contractures of the
muscle, which method comprises administering to the patient a
therapeutically effective amount of a substance which blocks the
release of synaptic vesicles containing acetylcholine.
[0014] The present invention also provides a method of treating a
juvenile patient suffering from cerebral palsy, which method
comprises administering to the patient a therapeutically effective
amount of a substance which blocks the release of synaptic vesicles
containing acetylcholine.
[0015] In a further aspect the invention provides a method of
treating a juvenile patient suffering from arrested muscle growth
arising from the presence of dynamic contractures of the muscle,
which method comprises administering to the patient a
therapeutically effective amount of a presynaptic neurotoxin, for
example a bacterial neurotoxin such as botulinum toxin.
[0016] In a still further aspect the invention provides a method of
treating a juvenile patient suffering from arrested muscle growth
due to cerebral palsy, which method comprises administering a
presynaptic neurotoxin (for example a bacterial neurotoxin such as
botulinum toxin) to the patient in a non toxic amount sufficient to
reduce muscle tone and promote improved muscle growth.
[0017] The botulinum toxin used according to the present invention
preferably is Botulinum toxin A. Botulinum toxin A is available
commercially from Porton Products Limited, UK, and from Allergan
Inc, Irvine, Calif.
[0018] Administration of the toxin preferably is by means of
intramuscular injection directly into a spastic muscle, in the
region of the neuromuscular junction, although alternative types of
administration (e.g. sub-cutaneous injection) which can deliver the
toxin directly to the affected muscle region may be employed where
appropriate. The toxin can be presented as a sterile pyrogen-free
aqueous solution or dispersion and as a sterile powder for
reconstitution into a sterile solution or dispersion.
[0019] Where desired, tonicity adjusting agents such as sodium
chloride, glycerol and various sugars can be added. Stabilisers
such as human serum albumin may also be included. The formulation
may be preserved by means of a suitable pharmaceutically acceptable
preservative such as a paraben, although preferably it is
unpreserved.
[0020] It is preferred that the toxin is formulated in unit dosage
form, for example it can be provided as a sterile solution in a
vial, or as a vial or sachet containing a lyophilised powder for
reconstituting a suitable carrier such as water for injection.
[0021] In one embodiment the toxin, e.g. botulinum toxin A is
formulated in a solution containing saline and pasteurised human
serum albumin, which stabilises the toxin. The solution is sterile
filtered (0.2 micron filter), filled into individual vials and then
vacuum dried to give a sterile lyophilised powder. In use, the
powder can be reconstituted by the addition of sterile unpreserved
normal saline (sodium chloride 0.9% for injection).
[0022] In order for the benefits of the invention to be realised,
administration of the botulinum toxin should commence before the
child has completed its growing period and fixed myostatic
contracture has occurred. The benefits of the invention can be
maximised by administering the botulinum toxin to the child at an
early stage in its growing period, for example before the child
reaches the age of six.
[0023] The dose of toxin administered to the patient will depend
upon the severity of the condition e.g. the number of muscle groups
requiring treatment, the age and size of the patient and the
potency of the toxin. The potency of the toxin is expressed as a
multiple of the LD.sub.50 value for the mouse, one "unit" of toxin
being defined as being the equivalent amount of toxin that kills
50% of a group of mice. The definition of potency as used
hereinafter is the definition currently used in relation to the
product marketed by Porton Products Limited. According to this
definition, the potency of the botulinum toxin A available from
Porton Products Ltd is such that one nanogram contains 40 mouse
units (units).
[0024] Typically, the dose administered to the patient will be up
to about 1000 units, for example up to about 500 units, and
preferably in the range from about 80 to about 460 units per
patient per treatment, although smaller or larger doses may be
administered in appropriate circumstances. The potency of botulinum
toxin, and its long duration of action, means that doses will tend
to be administered on an infrequent basis. Ultimately, however,
both the quantity of toxin administered, and the frequency of its
administration will be at the discretion of the physician
responsible for the treatment, and will be commensurate with
questions of safety and the effects produced by the toxin.
[0025] The invention will now be illustrated in greater detail by
reference to the following non-limiting examples which describe the
results of clinical studies with botulinum toxin A:
EXAMPLE 1
The Use of Botulinum Toxin A in the Management Children with
Cerebral Palsy
[0026] Thirty three children suffering from cerebral palsy, having
a mean age of seven years and an age range of two to seventeen
years, were selected for participation in a clinical study.
[0027] The criteria for inclusion in the study were the presence of
dynamic contractures interfering with function, without clinical
evidence of fixed myostatic contracture. Before entering the study,
all children underwent clinical evaluation, physiotherapist's
assessment and parental assessment. All ambulatory patients
underwent gait analysis using electrogoniometers. The children
entering the study were suffering from spastic tetraplegia,
diplegia, hemiplegia or monoplegia.
[0028] The hamstrings and/or calf muscles of each patient were
injected with a sterile solution containing the botulinum toxin A
(obtained from Porton Products Limited, UK). Total patient doses
ranged from 80 units to 460 units (one unit being equivalent to the
murine LD.sub.50). Before injecting any muscle group, careful
consideration was given to the anatomy of the muscle group, the aim
being to inject the area with the highest concentration of
neuromuscular junctions. Before injecting the muscle, the position
of the needle in the muscle was confirmed by putting the muscle
through its range of motion and observing the resultant motion of
the needle end. General anaesthesia, local anaesthesia and sedation
were used according to the age of the patient, the number of sites
to be injected and the particular needs of the patient.
[0029] Following injection, it was noted that the onset of effects
was complete within thirty six to seventy two hours and lasted from
six to eighteen weeks. There were no systemic or local
side-effects. All but one patient had some reduction in muscle
tone; the one failure occurred early in the study and was probably
the result of the toxin dosage administered (75 units) being
sub-therapeutic. None of the patients developed extensive local
hypotonicity. The majority of children had an improvement in
function both subjectively and when measured objectively with gait
analysis.
[0030] Following injection of the calf muscle groups, an assessment
was made of the passive dorsiflexion at the ankle. It was found
that the younger children displayed a marked improvement in passive
dorsiflexion, but that for children over six years there was little
improvement. This was probably due to the dynamic contracture being
replaced by a fixed contracture which was unresponsive to any
amount of paresis.
[0031] Case Study 1
[0032] A five year old girl with moderate right hemiplegia
underwent gait analysis and, on examination, was found to have
dynamic contractures of her calf and hamstrings. Gait analysis
recordings of saggital plane movements (with 95% confidence limits)
were made prior to injection and these revealed that throughout the
gait cycle, the knee was in excessive flexion. Gait analysis also
indicated that she was in equinus throughout the gait cycle.
[0033] Following injection, the knee could be extended nearly to
neutral during stance and the gait analysis pattern, although still
abnormal was much improved. The ankle traces recorded indicated
that she was able to dorsiflex her ankle in gait and had developed
a normal range of movements.
[0034] Gait analysis was also undertaken at four months. At this
stage the effects of the toxin had clinically worn off and it was
found that the knee flexed to the same extent in swing that it did
prior to injection. However, the gain of extension in stance was
largely preserved. At the ankle, there was some relapse but there
was still a lesser degree of equinus.
[0035] Case Study 2
[0036] Measurements were made of the maximal extension of the knee
in a group of patients who underwent hamstring injection. Prior to
injection, they all had some degree of dynamic knee flexion
contracture. Four weeks following injection, this showed a highly
significant improvement. However, the one patient who was least
affected developed recurvatum at the knee following injection.
After this, all patients who had a dynamic knee flexion contracture
of less than fifteen degrees were excluded from hamstring
injection. Only one local side-effect from the treatment was noted
and this was a small subcutaneous haematoma which resolved itself
in a few days.
Example 2
The Treatment of the Hereditary Spastic Mouse with Botulinum Toxin
A
[0037] In cerebral palsy there is frequently a failure of muscle
growth leading to fixed muscular contracture. This failure has also
been demonstrated in the hereditary spastic mouse (Wright J and
Rang M The Spastic Mouse. And the search for an animal model of
spasticity in human beings) Clin. Orthop. 1990, 253, 12-19.
[0038] A study has been carried out to ascertain the effect of
Botulinum Toxin A on the growth of longitudinal muscle in the
spastic mouse compared with normal siblings. Groups of spastic mice
at six days old had one calf muscle injected with either 1.2 units
of Botulinum toxin A or normal saline.
[0039] The mice were sacrificed at maturity and the hind limbs
dissected to allow measurement of the muscle and bones.
[0040] In the control group, the spastic mice had a 13% failure of
longitudinal muscle growth compared with their normal siblings.
However, the muscles of the spastic mice injected with Botulinum
had growth identical to that of their normal siblings. There was no
difference in growth between normal mice injected with saline or
Botulinum.
[0041] It can be concluded that the injection of intramuscular
Botulinum toxin during the growth period of the hereditary spastic
mouse allows normal longitudinal muscle growth to take place and it
is believed that this finding may have significance in the
management of cerebral palsy.
[0042] The invention has been illustrated by reference to Botulinum
toxin A but it should be understood that the invention is not
limited to the use of this toxin. For example, other Botulinum
toxins may be employed. Moreover, other presynapnatic neurotoxins
(e.g. of bacterial origin) which act in a manner similar to
botulinum toxin may also be used. Also, synthetic analogues of the
botulinum toxins may be envisaged wherein the 50 kd chain and/or
the 100 kd chain are subjected to amino acid insertions, deletions
and/or substitutions and, provided that such analogues retain the
general type of activity exhibited by Botulinum toxin A, their use
in the manner described hereinbefore is embraced by the present
invention. The invention is also considered to embrace the use of
substances structurally dissimilar to Botulinum toxin A, provided
that such substances possess a prolonged ability to inhibit or
block release of the synaptic vesicles containing
acetylcholine.
* * * * *