Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-14
2001-09-25
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06294553
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the topical application of brimonidine for treating ocular pain and neurogenic inflammation and compositions useful for such application.
BACKGROUND OF THE ART
Pain is a well known phenomenon as an indicator of injury or tissue damage due to inflammation, ischemia, mechanical or other irritation.
The first step leading to the sensation of pain is the activation of nociceptive primary afferents by intense thermal, mechanical or chemical stimuli. Indirect studies of nociceptive transduction (activation) indicate that it involves chemical mediators that are released or synthesized in response to tissue damage. These chemical mediators include lactic acid, hypertonic saline, histamine, 5-hydroxytyptamine, potassium chloride, acetylcholine, purines, bradykinin and substance P which are referred to as algesic agents. In recent years it has been shown that prostaglandins and leukotrienes can contribute to the activation of primary afferent nociceptors. Prostaglandins are uniquely distinguished from the other chemical mediators in that they induce a state of hyperalgesia by elevating the sensitivity of pain receptors to other painful or algesic stimuli.
The stimulation of primary afferents leads to action potentials in their axons which propagate to the spinal cord. In addition, excited primary afferents release neuropeptides (substance P, calcitonin gene-related peptide, neurokinin A) at their peripheral terminals. Neuropeptides enhance inflammatory reactions in the injured tissue, contributing to vasodilation, edema, and increased vascular permeability, this phenomenon is called ‘neurogenic inflammation’.
In the spinal cord, the nociceptors enter the gray matter of the superficial dorsal horn to synapse on nerve cells contributing to pain-transmission pathways such as the spinothalamic and spinoreticulothalamic tracts which terminate in two separate regions in the thalamus. The two thalamic regions in turn project to different cortical sites.
The pain transmitting and modulating system depicted so far depends on numerous chemical moieties for its integrated function.
Anesthetics block neuronal transmission and affect sensation as well as pain. Analgesics act by interfering with the activity of chemical mediators of nociception without affecting sensory input.
According to Remington's Pharmaceutical Sciences, 17th Ed., analgesics can be classified as falling into at least three loose groups: 1) the opiate-based (narcotic) analgesics; 2) the non-opiate analgesics; and 3) analgesics and antipyretics.
The opiate-based analgesics include opium derived alkaloids, including morphine, codeine, and their various derivatives, opiate antagonists, the several morphine derivatives which have morphine antagonist activity, but have analgesic activity.
Since these narcotic type drugs are addictive, a number of nonaddictive, non-opiate analgesics have been developed in an attempt to produce an analgesic which is highly efficient but not addictive.
In the third broad category, the analgesics and antipyretics, are the salicylates and acetamide-containing compounds and the so-called non-steroidal anti-inflammatory drugs. They are non-addictive pain killers.
As to their mode of action, drugs that block perception of pain may be said to act either centrally (such as narcotics) or peripherally.
The non-steroidal anti-inflammatory agents (NSAIAs) have been described as peripheral pain relievers. It was further suggested that the analgesic properties of these drugs are independent of their antiedema or anti-inflammatory actions.
The action of NSAIAs as pain relievers is associated with the biosynthesis of prostanoids.
Inflammation or trauma and resultant tissue injuries cause the release of arachidonic acid which is degraded by cyclo-oxygenase and lipoxygenase. The cyclo-oxygenase pathway leads to the synthesis of prostaglandin E
2
(PGE
2
) and other mediators. PGE
2
release increases the cyclic AMP and ionic calcium levels at the nociceptor membrane resulting in a lowered activation threshold, resulting in the relay to the central nervous system of augmented pain perception (hyperalgesia). Inhibitors of prostaglandin synthesis, such as NSAIAs, act by avoiding the sensitizing effects of prostaglandins on nociceptive endings and therefore, the decrease in pain threshold.
In animal models and human studies non-steroidal antiinflammatory agents have been shown to inhibit inflammatory pain.
Ophthalmic applications of various NSAIAs are also known, including the utilization of their anti-inflammatory properties for control of various ocular inflammations.
NSAIAs have been used for the treatment of non-inflammatory, localized pain, such as non-inflammatory ocular pain.
Calcium channel blockers have been suggested as useful for treating pain, including ocular pain.
SUMMARY OF THE INVENTION
As will be appreciated from the above, various peripherally-acting analgesics, anesthetics, etc. have been used to treat ocular pain. However, nowhere is it suggested that the compound utilized in the method of the present invention, i.e. brimonidine that is a centrally-acting analgesic in animal models, may be used to treat ocular pain.
The present invention is based on the unexpected finding that brimonidine efficiently relieves ocular pain, including ocular pain associated with corneal injuries.
The use of a topical composition, including brimonidine, for the relief of eye pain offers several benefits over the use of systemic agents because of the decreased systemic absorption, which may decrease side-effects, and increased ocular absorption that can increase efficacy.
Alpha-2 agonists including brimonidine have been shown to alleviate systemic pain in animal models, including hot plate, tail flick and nerve ligation. One alpha-2 agonist, clonidine, is administered epidurally for treating chronic pain in humans.
The sites of action are presumed to be in the spinal cord and in the brain, where they can reduce the perception of pain. One potential mechanism for the alleviation of pain at the level of the spinal cord is the inhibition of release of the chemical mediators of pain, including substance P and calcitonin gene-related peptide. This mechanism has been demonstrated in vitro for the alpha-2 agonist, dexmedetomidine, acting on rat spinal cord slices (M. Takano, Y. Takano and T. Yaksh, 1993, Release of calcitonin gene-related peptide, substance P, and vasoactive intestinal polypeptide from rat spinal cord: modulation by alpha-2 agonists, Peptides 14, 371-378), and for brimonidine (UK 14304) acting on cultured dorsal root ganglion cells (S. Supowit et al., 1998, Alpha-2 adrenergic receptor activation inhibits calcitonin gene-related peptide expression in cultured dorsal root ganglia neurons, Brain Res. 782, 184-193).
Accordingly, the present invention relates to a method for treating ocular pain in a mammal afflicted by such pain, which method comprises applying to the eye of said mammal an effective amount of brimonidine in a pharmaceutically acceptable vehicle.
REFERENCES:
patent: 6242442 (2001-06-01), Dean et al.
patent: 6248741 (2001-06-01), Wheeler et al.
Donello John E.
Gil Daniel W.
Stern Michael E.
Allergan Sales Inc.
Baran Robert J.
Fisher Carlos A.
Henley III Raymond
Voet Martin A.
LandOfFree
Method for treating ocular pain does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method for treating ocular pain, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for treating ocular pain will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2484587