Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-07-11
2004-01-06
Reamer, James H (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06673792
ABSTRACT:
FIELD OF THE INVENTION
The present invention comprises anti-emetic compositions and related methods for using same. More specifically, the present invention relates to compositions having more than one anti-emetic ingredient, which act synergistically and/or additively to relieve symptoms associated with emesis
BACKGROUND OF THE INVENTION
Emesis, also referred to as vomiting, is associated with myriad clinical conditions. For example, emesis is often associated with uncomplicated motion sickness, mild gastrointestinal upset caused by infections, food poisoning and adverse drug reactions including cancer chemotherapy. Additionally, emesis provides an elimination mechanism for ingested toxins and poisons. Moreover, the colors, smells tastes and textures associated with potentially toxic compounds results in a learned aversion to these substances, thus providing animals with a vital survival mechanism.
Emesis symptoms can range from an unpleasant inconvenience to a debilitating condition causing sever dehydration, weight loss, fatigue, torn esophagus, broken bones and reopening of surgical wounds. Moreover, many forms of chemotherapy and most radiation treatments can induce severe nausea and emesis. Patents that are particularly adversely affected with emesis can become severely dehydrated and malnourished requiring parenteral fluid and dietary supplementation. As a result, many patents find that their life quality is so compromised that they voluntarily remove themselves from life saving chemotherapy. In other patients, the emesis is so severe that physicians must temporarily, or permanently discontinue treatments. Often times the treating physician is without other therapeutic options, consequently the patient goes under treated, or in some cases, untreated.
Unfortunately, emesis is a complex, multifactorial process for which there is presently no therapeutic regime suitable for treating or preventing all underlying biological emesis-related processes. Emesis involves many different neuroreceptors and the biochemical pathways that regulate emesis are varied and complex. Emesis-associated neuroreceptors include neurochemical receptors such as dopamine receptors, 5-hydroxytrytamine (5-HT) receptors, aceytalcholine receptors, histamine receptors, opioid receptors, neurokinin (NK
1
) receptors, and cannabinoid receptors, as well as mechano-receptors.
Mechano-receptors are generally located in the stomach and small intestines and are activated in response to emetic stimuli and cause the expulsion of stomach and/or intestinal contents. The Mechano-receptors are tension sensors activated in response to the contraction and extension of the stomach and intestines and are the primary receptors associated with bowl occlusion-related emesis.
Neurochemical receptors are located in the stomach, the small intestines and the central nervous system (CNS). These respond to various chemical stimuli including toxins such as cholecystokinin (CCK) peptides, copper sulfate and 5-hydroxytrytamine (5-HT) among others. Copper sulfate-induced vomiting is mediated by 5-HT
4
receptors, CCK acts via CCK-A receptors and emesis associated with cancer therapies such as irradiation and chemotherapy are medicated by 5-HT
3
receptors.
There are four 5-HT receptors associated with emesis including 5-HT
3
, 5-HT
1a
, 5-HT
1D
and 5-HT
4
. Among the 5-HT receptors involved in emesis, the 5HT
3
has been identified as the most important receptor involved in cancer therapy-related emesis. 5-HT
3
receptors are located in the CNS and peripherally in the gut mucosa, nerve endings and primary afferent nerve fibers. Antagonism of the 5-HT
3
receptors can prevent emesis associated with increased local 5-HT concentrations. 5-HT
1a
, 5-HT
1D
, and 5-HT
4
receptors are primarily located in the CNS; however, they also occur in the periphery including the myocardium (5-HT
4
) and arterioles (5-HT
1a
). The primary dopamine receptor involved in emesis is the dopamine
2
(D
2
) receptor. Dopamine
2
antagonists include phenothiazies, butyrophenones, and benzamides; both CNS and gastrointestinal (GI) receptors are blocked.
It has been demonstrated that emesis can be controlled when specific receptor antagonists are administered prior and/or after onset of nausea or emesis. Receptor antagonists act as anti-emetics by blocking receptors in the central nerves CNS and/or GI tract and prevent binding of the target ligand. For example, a dopamine receptor antagonists block dopamine binding thus preventing the neuro-sensory activity associated with dopamine and its associated emetic effects.
Present anti-emetic therapies are composed of neuroreceptor antagonists that target one or two of the receptors that regulate emesis. However, as previously stated, emesis is a complex, multi-factorial process that involves a wide array of neuroreceptors. Therefore, there is a need for broad-spectrum anti-emetic compositions suitable for use with all patients, regardless of the underlying biological process associated with their particular emesis. An ideal broad spectrum anti-emetic composition will comprise a variety of receptor antagonists that block emesis associated receptors preventing them from initiating nausea and the vomiting reflex.
SUMMARY OF THE INVENTION
The present invention is a therapeutic composition for the treatment and prevention of emesis. In one embodiment of the present invention the therapeutic compositions include broad-spectrum medicaments containing specific neuroreceptor antagonists. The neuroreceptors targeted by the medicaments of the present invention include, but are not limited to, dopamine receptors, 5-hydroxytrytamine (5-HT) receptors, aceytalcholine receptors, histamine receptors, opioid receptors, neurokinin (NK
1
) receptors, and cannabinoid receptors.
The neuroreceptor antagonists of the present invention are selected from the group of compounds including, but not limited to, antihistamines, anti-dopaminergics, and anti-anxiety agents. In specific embodiments of the present invention the anti-emetic compositions comprise at least one benzodiapepine, at least one phenothiazine, at least one diphenhydramine, and at least one metoclopramide.
In one embodiment of the present invention the anti-emetic compositions comprise lorazepam, promethazine, diphenhydramine, and metoclopramide.
In another embodiment of the present invention the anti-emetic compositions comprise from approximately 0.1 to 100 mg/unit of lorazepam, from approximately 0.1 to 100 mg/unit promethazine, from approximately 0.1 to 100 mg/unit diphenhydramine, and from approximately 0.1 to 100 mg/unit metoclopramide, wherein a “unit” is defined as a single drug delivery form.
In yet another embodiment the compositions are drug delivery forms selected from the group consisting of compressed tablets, capsules, caplets, gelcaps, free flowing powders, compressed powders, suppositories, transdermal devices, implantable drug release depots, inhalants, liquids suitable for intravenous (parenteral) use, liquids suitable oral use, and multi-phasic slurries.
In another embodiment of the present invention the drug delivery forms are compounded to provide controlled delivery of the anti-emetic compositions over a predetermined time.
DEFINITION OF TERMS
Prior to setting forth the invention, it may be helpful to an understanding thereof to set forth definitions of certain terms that will be used hereinafter.
Approximately: The term approximately as used herein means an estimated amount of a compound or an estimated distance or temporal interval. When used to denote a numerical value the term approximately includes all values within a range that those having ordinary skill in the art would understand that range to include. For example, and not intended as a limitation, the phrase “from about 0.1 to 100 mg” would include a range of values included, at least from 0.009 to 110 mg and all values in between.
Broad-spectrum: As used herein, “broad-spectrum” refers to anti-emetic compositions that provides treatment or prevention of emesis caused by physical or chemical
Preston Gates & Ellis LLP
Reamer James H
Upchuck, LLC
Wallen III John W.
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