Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
2000-01-24
2001-11-20
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Bacterium or component thereof or substance produced by said...
C424S236100, C435S071100, C435S071300, C514S002600, C530S350000
Reexamination Certificate
active
06319505
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides novel methods for treating various disorders and conditions, with Botulinum toxins. Importantly, the present invention provides methods useful in relieving pain related to muscle activity or contracture and therefore is of advantage in the treatment of, for example, muscle spasm such as Temporomandibular Joint Disease, low back pain, myofascial pain, pain related to spasticity and dystonia, as well as sports injuries, and pain related to contractures in arthritis.
BACKGROUND OF THE INVENTION
Heretofore, Botulinum toxins, in particular Botulinum toxin type A, has been used in the treatment of a number of neuromuscular disorders and conditions involving muscular spasm; for example, strabismus, 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 acetylcholine release. This results in local paralysis and hence relaxation of the muscle afflicted by spasm.
For one example of treating neuromuscular disorders, see U.S. Pat. No. 5,053,005 to Borodic, which suggests treating curvature of the juvenile spine, i.e., scoliosis, with an acetylcholine release inhibitor, preferably Botulinum toxin A.
For the treatment of strabismus with Botulinum toxin type A, see Elston, J. S., et al.,
British Journal of Ophthalmology,
1985, 69, 718-724 and 891-896. For the treatment of blepharospasm with Botulinum toxin type A, see Adenis, J. P., et al.,
J. Fr. Ophthalmol.,
1990, 13 (5) at pages 259-264. For treating squint, see Elston, J. S.,
Eye,
1990, 4(4):VII. For treating spasmodic and oromandibular dystonia torticollis, see Jankovic et al.,
Neurology,
1987, 37, 616-623.
Spasmodic dysphonia has been treated with Botulinum toxin type A. See Blitzer et al.,
Ann. Otol. Rhino. Laryngol,
1985, 94, 591-594. Lingual dystonia was treated with Botulinum toxin type A according to Brin et al.,
Adv. Neurol.
(1987) 50, 599-608. Finally, Cohen et al.,
Neurology
(1987) 37 (Suppl. 1), 123-4, discloses the treatment of writer's cramp with Botulinum toxin type A.
The term Botulinum toxin is a generic term embracing the family of toxins produced by the anaerobic bacterium
Clostridium botulinum
and, to date, seven immunologically distinct neurotoxins 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 and Brin,
The New England Journal of Medicine,
No. 17, 1990, pp. 1186-1194, and to the review by Charles L. Hatheway in Chapter 1 of the book entitled
Botulinum Neurotoxin and Tetanus Toxin,
L. L. Simpson, Ed., published by Academic Press Inc. of San Diego, Calif., 1989, the disclosures in which are incorporated herein by reference.
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, i.e., by interfering with the exocytosis of acetylcholine, by decreasing the frequency of acetylcholine release, and a larger polypeptide chain of about 100 kD which is believed to be necessary to enable the toxin to bind to the pre-synaptic membrane.
The “short” and “long” chains are linked together by means of a simple disulfide bridge. (It is noted that certain serotypes of Botulinum toxin, e.g., type E, may exist in the form of a single chain un-nicked protein, as opposed to a dichain. The single chain form is less active but may be converted to the corresponding dichain by nicking with a protease, e.g., trypsin. Both the single and the dichain are useful in the method of the present invention.)
In general, four physiologic groups of
C. botulinum
are recognized (I, II, III, IV). The organisms capable of producing a serologically distinct toxin may come from more than one physiological group. For example, Type B and F toxins can be produced by strains from Group I or II. In addition, other strains of clostridial species (
C. baratii,
type F;
C. butyricum,
type E;
C. novyi,
type C
1
or D) have been identified which can produce botulinum neurotoxins.
Immunotoxin conjugates of ricin and antibodies, which are characterized as having enhanced cytotoxicity through improving cell surface affinity, are disclosed in European Patent Specification 0 129 434. The inventors note that botulinum toxin may be utilized in place of ricin.
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.
Botulinum toxin type A, the toxin type generally utilized in treating neuromuscular conditions, is currently available commercially from several sources; for example, from Porton Products Ltd. UK, under the trade name “DYSPORT,” and from Allergan, Inc., Irvine, Calif., under the trade name BOTOX®.
It is one object of the invention to provide novel treatments of neuromuscular disorders and conditions with various Botulinum toxin types. It is another object of the present invention to relieve pain with various Botulinum toxin types.
SUMMARY OF THE INVENTION
The present invention provides a method for relieving pain, associated with muscle contractions, a composition and a method of treating conditions such as cholinergic controlled secretions including excessive sweating, lacrimation and mucus secretions and a method for treating smooth muscle disorders including, but not limited to, spasms in the sphincter of the cardiovascular arteriole, gastrointestinal system, urinary, gall bladder and rectum, which method comprises administering to the patient suffering from said disorder or condition a therapeutically effective amount of Botulinum toxin selected from the group consisting of Botulinum toxin types B, C, D, E, F and G.
Each serotype of Botulinum toxin has been identified as immunologically different proteins through the use of specific antibodies. For example, if the antibody (antitoxin) recognizes, that is, neutralizes the biological activity of, for example, type A it will not recognize types B,C,D, E, F or G.
While all of the Botulinum toxins appear to be zinc endopeptidases, the mechanism of action of different serotypes, for example, A and E within the neuron appear to be different than that of Type B. In addition, the neuronal surface “receptor” for the toxin appears to be different for the serotypes.
In the area of use of the Botulinum toxins in accordance with the present invention with regard to organ systems which involve the release of neurotransmitter, it is expected to introduce the toxins A, B, C, D, E, F, and G directly by local injections.
DETAILED DESCRIPTION
The Botulinum toxins used according to the present invention are Botulinum toxins type A, B, C, D, E, F and G.
The physiologic groups of
Clostridium botulinum
types are listed in Table I.
TABLE I
Physiologic Groups of
Clostridium botulinum
Phenotypically
Toxin
Glucose
Phages
Related
Sero-
Milk
Fermen-
&
Clostridium
Group
Type
Biochemistry
Digest
tation
Lipase
Plasmids
(nontoxigenic)
I
A, B, F
proteolytic saccharolytic
+
+
+
+
C. sporogenes
II
B, E, F
nonproteolytic saccharolytic
−
+
+
+
psychotrophic
III
C, D
nonproteolytic saccharolytic
±
+
+
+
C. novyi
IV
G
proteolytic nonsaccharolytic
+
−
−
−
C. subterminale
These toxin types may be produced by selection from the appropriate physiologic group of
Clostridium botulinum
organisms. the organisms designated as Group I are usually referred to as proteolytic and produce Botulinum toxins of types A, B and F. The organisms designated as Group II are saccharolytic and produce Botulinum toxins of types B, E and F. The organisms designated as Group III produce only Botuli
Aoki K. Roger
Carlson Steven R.
Grayston Michael W.
Leon Judith M.
Allergan Sales Inc.
Baran Robert J.
Donovan Stephen
Gupta Anish
Low Christopher S. F.
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