Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing
Reexamination Certificate
2000-12-29
2004-09-07
Riley, Jezia (Department: 1637)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
C514S002600, C514S014800
Reexamination Certificate
active
06787517
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to compositions and methods for treating pain. Particularly, the present invention relates to an agent comprising a neurotoxin, methods for making the agent and methods for treating pain using the agent.
“For all the happiness mankind can gain is not in pleasure, but rest from pain.” John Dryden (1631-1700).
It is convenient to divide the human pain experience into two general categories, acute and chronic. Any noxious stimulus, for example extreme heat or sharp objects, may elicit an acute pain. The pain resulting from such a stimulus usually subsides in a relatively short period of time. Acute pain may also present itself in the course of any disease. However, such pain is also self-limited and subsides with time or adequate treatment.
Chronic pain is the second major category of pain experience. It can be defined as significant pain persisting for more than a few weeks for which there is no adequate therapy available to treat the underlying problem. Globally, there are countless numbers of people who presently are victims of chronic pain. For example, just in the United States alone, the National Institute of Health estimates that more than 90 million Americans suffer from chronic pain stemming from migraine headaches, back pain, arthritis, trauma, allodynia or catastrophic illness.
In general, the transduction of acute or chronic pain signals from the periphery to sensation itself is achieved by a multi-neuronal pathway and the information processing centers of the brain. The first nerve cells of the pathway involved in the transmission of sensory stimuli are called primary sensory afferents. The cell bodies for the primary sensory afferents from the head and some of the internal organs reside in various ganglia associated with the cranial nerves, particularly the trigeminal nuclei and the nucleus of the solitary tract. The cell bodies for the primary sensory afferents for the remainder of the body lie in the dorsal root ganglia of the spinal column. The primary sensory afferents and their processes have been classified histologically; the cell bodies fall into two classes: A-types are large (60-120 micrometer in diameter) while B-types are smaller (14-30 micrometer) and more numerous. Similarly the processes fall into two categories: C-fibers lack the myelin sheath that A-fibers possess. A-fibers can be further sub-divided into A beta-fibers, that are large diameters with well-developed myelin, and A delta-fibers, that are thinner with less well developed myelin. It is generally believed that A beta-fibers arise from A-type cell bodies and that A delta- and C-fibers arise from B-type cell bodies.
After the activation of the primary sensory afferents the next step in the transduction of sensory signals is the activation of the projection neurons, which carry the signal, via the spinothalamic tract, to higher parts of the central nervous system such as the thalamic nuclei. The cell bodies of these neurons (other than those related to the cranial nerves) are located in the dorsal horn of the spinal cord, This is also where the synapses between the primary afferents and the projection neurons are located. The dorsal horn is organized into a series of laminae that are stacked, with lamina I being most dorsal followed by lamina II, etc. The different classes of primary afferents make synapses in different laminae. For cutaneous primary afferents, C-fibers make synapses in laminae I and II, A delta-fibers in laminae I, II, and V, and A beta-fibers in laminae III, IV, and V. Deeper laminae (V-VII, X) are thought to be involved in the sensory pathways arriving from deeper tissues such as muscles and the viscera.
The predominant neurotransmitters at the synapses between primary afferents and projection neurons are substance P, glutamate, calcitonin-gene related peptide (CGRP) and neuropeptide Y. The efficiency of transmission of these synapses can be altered via descending pathways and by local interneurons in the spinal cord. These modulatory neurons release a number of mediators that are either inhibitory (e.g. opioid peptides, glycine, norepinephrine) or excitatory (e.g. nitric oxide, cholecystokinin, norepinephrine), to provide a mechanism for enhancing or reducing awareness of sensations.
Although the present available treatments for acute pain are usually manageable, the treatments for chronic pain are inadequate and disappointing. For example, it is known that intraspinal administration of opioids, such as morphine and fentanyl can alleviate pain. See e.g. Gianno, J., et al.,
Intrathecal Drug Therapy for Spasticity and Pain
, Springer-Verlag (1996) (which publication is incorporated herein by reference in its entirety). However, these drugs used in intraspinal, or intrathecal, injections typically have only short lived antinociceptive effects. As a result, these drugs have to be frequently administered, such as by the aid of a pump for continuous infusion. For example, one frequently used pump is the SynchroMed® Infusion System, a programmable, implanted pump available from Medtronic, Inc., of Minneapolis, Minn. However, complications can arise due to the required surgical implantation procedure for the use of the pump and the known intrathecally administered drugs for pain, such as opioids, have the disadvantages of dependency and potential respiratory depression.
Longer acting analgesics are also known, for example, blocks by phenol injection. However, such treatments raise a considerable risk of irreversible functional impairment.
Botulinum Toxin
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.
Botulinum toxin type A is the most lethal natural biological agent known to man and has a very potent LD
50
. A specific dose of a toxin that would be lethal to 50% of the population of a certain species of animal is called an LD
50
. For example, the estimated LD
50
of botulinum toxin type A (available from Allergan, Inc., of Irvine, Calif. as a purified neurotoxin complex under the trade name BOTOX®) in humans is about 150,000 picograms or about 3,000 units. Interestingly, on a molar basis, botulinum toxin type A is about 1.8 billion times more lethal than diphtheria toxin, about 600 million times more lethal than sodium cyanide, about 3.0 million times more lethal than cobra toxin and about 12 million times more lethal than cholera toxin. Singh, Critical Aspects of Bacterial Protein Toxins, pages 63-84 (chapter 4) of Natural Toxins II, edited by B. R. Singh et al., Plenum Press, New York (1996).
Seven immunologically distinct botulinum neurotoxins have been characterized, these being respectively botulinum neurotoxin serotypes A, B, C
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. Botulinum toxin apparently binds with high affinity to cholinergic motor neurons, is translocated into the neuron and blocks the release of acetylcholine.
Without wishing to limit the invention to any theory
Aoki Kei R.
Gil Daniel W.
Allergan Inc.
Hollrigel Greg S.
Riley Jezia
Stout, Uxa Buyan & Mullins, LLP
Uxa Frank J.
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