WO1993000074A1 - Method and compositions for treating emesis, nausea and other disorders using optically pure r(+) ondansetron - Google Patents

Method and compositions for treating emesis, nausea and other disorders using optically pure r(+) ondansetron Download PDF

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Publication number
WO1993000074A1
WO1993000074A1 PCT/US1992/005376 US9205376W WO9300074A1 WO 1993000074 A1 WO1993000074 A1 WO 1993000074A1 US 9205376 W US9205376 W US 9205376W WO 9300074 A1 WO9300074 A1 WO 9300074A1
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Prior art keywords
ondansetron
administered
composition according
pharmaceutically acceptable
composition
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PCT/US1992/005376
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French (fr)
Inventor
James W. Young
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Sepracor, Inc.
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Priority to EP9292914873A priority Critical patent/EP0591434A4/en
Priority to CA002112487A priority patent/CA2112487C/en
Priority to JP5501664A priority patent/JPH06508836A/en
Publication of WO1993000074A1 publication Critical patent/WO1993000074A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/41641,3-Diazoles
    • A61K31/41781,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4151,2-Diazoles

Definitions

  • HT 3 including but not limited to disorders of gastrointestinal motility, depression, migraine, alcohol, nicotine or drug (benzodiazepine et al.) withdrawal, while
  • the active compound of this composition, and method is an optical isomer of the compound, ondansetron which is described in United States Patent No. 4,695,578.
  • the active compound is the R(+) isomer of 1,2,3,9-tetrahydro-9-meth l-3-[(2-methyl-lH-imidazol-l- yl) ethyl]-4H-carbazol-4-one.
  • This isomer will hereinafter be referred to as R(+) ondansetron.
  • -Stereochemical purity is of importance in the field of pharmaceuticals, where 12 of the 20 most prescribed drugs exhibit chirality.
  • a case in point is provided by the L-form of the ⁇ -adrenergic blocking agent, propranolol, which is known to be 100 times more potent than the D-enantiomer.
  • Ondansetron which is the subject of the present invention, is available commercially only as the 1:1 racemic mixture; i.e., it is a mixture of optical isomers, called enantiomers.
  • the racemic mixture of ondansetron is a dihydrate, that is administered as a hydrochloride salt.
  • the enantiomers of ondansetron are disclosed in Butler et al., Br.
  • ondansetron is an antagonist of the 5-hydroxytryptamine (5-HT 3 or serotonin) receptor.
  • 5-HT 3 or serotonin 5-hydroxytryptamine
  • serotonin a major site of production and storage of serotonin is the enterochromaffin cell of the gastrointestinal mucosa. It was also discovered that serotonin has a powerful stimulating action on intestinal motility by stimulating intestinal smooth muscle, speeding intestinal transit, and decreasing absorption time, as in diarrhea. This stimulating action is also associated with nausea and vomiting.
  • Chemo-and radio-therapy may induce nausea and vomiting by the release of serotonin from damaged enterochromaffin cells in the gastrointestinal tract. Release of the neurotransmitter serotonin, stimulates both afferent vagal nerve fibers (thus initiating the vomiting reflex) and serotonin receptors in the chemoreceptor trigger zone of the area postrema region of the brain.
  • One of the first agents used to prevent the nausea and vomiting associated with emetogenic cancer chemotherapy was etoclopramide.
  • Ondansetron is a competitive antagonist at serotonin 5-HT 3 receptor subtypes in both the gastrointestinal tract and the brain, where it blocks both sites of serotonin-induced e esis.
  • ondansetron appears to offer a dual mode of action through antagonism of serotonin at peripheral vagal nerve afferents, and antagonism of serotonin within the central nervous system, at or near the chemoreceptor trigger zone.
  • ondansetron may produce a significant 5 reduction, or a complete inhibition of nausea and vomiting in the majority of patients subsequently treated with cancer chemotherapeutics of moderate or high emetic potential. Similarly, the compound prevented radiation- induced nausea and emesis. Further, ondansetron appears
  • Ondansetron•s use as an antiemetic by either the intravenous or oral routes is disclosed in U.S. Patent No. 's 4,753,789 and 4,929,632. Furthermore, various researchers have tested the use of the racemic mixture of ondansetron to prevent nausea and vomiting caused by
  • ondansetron appears to be an effective antiemetic, although its dose-response relationships remain to be clarified.
  • the drug offers a moderate
  • Schizophrenic disorders are complex mental disorders which tend toward chronicity, and which impair functioning, and are characterized by psychotic symptoms of disturbed thinking, feeling and general behavior. Clear, goal directed thought becomes difficult, while blunting and inappropriate affect become the most characteristic emotional changes. Auditory hallucinations can be common, and delusions of opposition are frequent, as are threats of violence, and minor aggressive outbursts. Disturbances of movement can range from significant over-activity and excitement to retardation and stupor.
  • depression an affective disorder, is characterized by changes in mood, as a primary clinical feature. The most common of the significant mental illnesses, depression must be distinguished clinically from periods of normal grief, sadness, and disappointment, and the related dysphoria or demoralization frequently associated with medical illness. Depression is characterized by feelings of intense sadness, and despair, mental slowing and loss of concentration, pessimistic worry, agitation, and self- deprecation.
  • U.S. Patent No. 4,847,281 discloses the use of the racemic mixture of ondansetron to treat substance abuse. Disorders of substance use or abuse often involve both psychologic and physical dependence, accompanied by the development of tolerance (the need to increase the dose progressively so as to prod :_e the effect originally achieved by smaller amounts) , and manifested by a withdrawal or abstinence syndrome.
  • Alcohol withdrawal syndrome represents a continuum of symptoms including tremor, weakness, sweating and gastrointestinal symptoms usually beginning some hours after cessation of intake. Drugs which alter the serotonin system can modulate the alcohol consumption in humans. Some mutual, but incomplete cross-tolerance exists between alcohol and other drugs including the benzodiazepines, the sedative-hypnotic, and the anxiolytic muscle relaxant group. While benzodiazepine withdrawal symptoms are often considered moderate, in withdrawal, often anxiety returns, with dysphoria irritability, sweating, headache and sleep abnormalities. Nicotine withdrawal syndrome following cessation of tobacco use, varies significantly among subjects in intensity, and specific signs and symptoms.
  • Alzheimers-type dementia is thought to be due to a degenerative process, with a large loss of cells from the cerebral cortex and other brain areas. Acetylcholine- transmitting neurons and their target nerve cells are particularly affected. The brain shows marked atrophy with wide sulci and dilated ventricles. Senile plaques and neurofibrillary tangles are present. Memory loss is the most prominent early symptom. Disturbances of arousal do not occur early in the course. Alzheimer's presenile and senile onset dementias are similar in both clinical and pathologic features, with the former commonly beginning in the 5th and 6th decades and the latter in the 7th and 8th decades. The dementia usually progresses steadily, becoming well advanced in 2 to 3 years. Some cases of dementia occurring in the presenile period are hard to classify and are sometimes labelled idiopathic or simple presenile dementia.
  • Alzheimers-type dementia The signs and symptoms of dementia, in particular Alzheimers-type dementia, include depression, paranoia, anxiety or any of several other psychologic symptoms.
  • the most common clinical picture is slow disintegration of personality and intellect due to impaired insight and judgment and loss of affect.
  • Memory impairment increases, beginning with problems recalling recent events or finding names. The impairment varies greatly from time to time and often from moment to moment. Dementia generally is an insidious, slowly progressive, untreatable condition.
  • AAMI age-associated memory impairment
  • racemic mixture of ondansetron offers efficacy in treating a variety of diseased states and conditions, its use is associated with adverse effects (principally headache and constipation) which increase with the dose of the racemic mixture of ondansetron administered.
  • optically pure R(+) isomer of ondansetron is an effective anti-emetic agent, useful as an adjunctive therapy in cancer treatment to ameliorate nausea and vomiting induced by chemo- or radio-therapeutics, while decreasing the usual adverse effects including, but not limited to, headache, constipation and increases in transaminase levels which are associated with the racemic mixture of ondansetron.
  • the present invention also includes novel compositions of matter, containing optically pure R(+) ondansetron which are useful and effective as antiemetic adjunctive therapy in cancer treatment by chemo-or radio- therapeutics, and as agents for the aforementioned disorders.
  • novel compositions also avoid, or reduce the above described adverse effects associated with the administration of the racemic mixture of ondansetron.
  • clearer dose definitions of efficacy vis a vis adverse effects may be achieved.
  • the present invention encompasses a composition for the treatment of a human with behavior disorders such as mood anxiety or schizophrenia, which comprises an amount sufficient to alleviate behavioral disorders such as mood anxiety or schizophrenia, but insufficient to cause adverse effects, of R(+) ondansetron, or a pharmaceutically acceptable salt thereof, substantially free of its S(-) stereoisomer.
  • a further aspect of the present invention is a composition for treating a condition caused by disturbance of neuronal 5-HT function, which comprises an amount sufficient to alleviate said condition but insufficient to cause adverse effects, of R(+) ondansetron, or a pharmaceutically acceptable salt thereof, substantially free of its S(-) stereoisomer.
  • 'adverse effects* includes, but is not limited to headache, constipation, fatigue, sedation, lethargy, drowsiness, dry mouth, diarrhea and transient increases in transaminase levels. Increases in the serum activity of certain hepatocellular enzymes is also included within the term “adverse effects”.
  • substantially free of its S(-) stereoisomer as used herein means that the composition contains a greater proportion of the R(+) isomer of ondansetron in relation to the S(-) isomer of ondansetron.
  • an initial loading dose of between about 2 mg to about 10 mg given by slow intravenous injection or infusion over 15-30 minutes, immediately before the emetogenic chemotherapy, and followed by about 2 mg to about 8 mg given orally every eight hours for periods up to four to five days will elicit therapy and provide for a reduction of symptoms.
  • an initial loading dose of between about 2 mg to about 10 mg given by slow intravenous injection or infusion over 15-30 minutes, immediately before the emetogenic chemotherapy, and followed by about 2 mg to about 8 mg given orally every eight hours for periods up to four to five days will elicit therapy and provide for a reduction of symptoms.
  • an oral therapeutic for the other conditions described herein generally doses of between about 2 mg to about 8 mg orally every eight hours, should provide benefit to adult patients.
  • an amount sufficient to alleviate the nausea and vomiting but insufficient to cause said adverse effects is encompassed by the above described dosage amounts and dose frequency schedule.
  • an amount sufficient to alleviate said condition but insufficient to cause said adverse effects wherein said conditions include but are not limited to behavioral disorders such as mood anxiety and schizophrenia as well as disturbances of neuronal 5-HT function including, but not limited to, disorders of gastrointestinal motility, depression, migraine and alcohol, nicotine or drug (benzodiazepine et al.) withdrawal are also encompassed by the above described amounts.
  • an amount sufficient to alleviate said condition but insufficient to cause said adverse effects wherein said condition includes cognitive disorders such as dementia and age- associated memory impairment, is also encompassed by the above-described amounts.
  • compositions of the present invention comprise R(+) ondansetron as active ingredient, or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier, and optionally, other therapeutic ingredients.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids.
  • each tablet contains from about 2.0 mg to about 8.0 mg of the active ingredient
  • each cachet or capsule contains from about 2.0 mg to about 8.0 m_ of the active ingredient.
  • the tablet, cachet or capsule contains either one of three dosages: 2.0 mg, 4.0 mg and 8.0 mg (as scored tablets, the preferable dose form) of active ingredient.
  • each tablet or capsule can contain from about 0.001 mg to about 10.0 mg of the active ingredient.
  • the amount of active ingredient found in the composition may vary depending on the amount of active ingredient to be administered to the patient.
  • EXAMPLE 1 A pharmacological study to determine the relative potency and specificity of optically pure R(+) ondansetron and racemic ondansetron as competitive antagonists at serotonin receptor subtype 5-HT 3 present in gastrointestinal, brain, and other tissues.

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Abstract

Methods and compositions are disclosed utilizing the optically pure R(+) isomer of ondansetron. This compound is a potent drug for the treatment of nausea and vomiting associated with chemotherapy and radiation therapy, while avoiding the concomitant liability of adverse effects associated with the racemic mixture of ondansetron. The R(+) isomer of ondansetron is also useful for the treatment of behavioral disorders such as mood anxiety and schizophrenia, and such other conditions as may be related to R(+) ondansetron's activity as a competitive antagonist of serotonin receptor subtype 5-HT3 such as disorders of gastrointestinal motility, depression, migraine, and as an aid for alcohol withdrawal, nicotine withdrawal, and drug (benzodiazepine et al.) withdrawal, without the concomitant liability of adverse effects associated with the racemic mixture of ondansetron. Furthermore, the R(+) isomer of ondansetron is also useful for the treatment of cognitive disorders such as dementia or age-associated memory impairment, while avoiding the concomitant liability of adverse effects associated with the racemic mixture of ondansetron.

Description

METHODS AND COMPOSITIONS FOR TREATING
EMESIS, NAUSEA AND OTHER DISORDERS USING OPTICALLY PURE Rf+. ONDANSETRON
This application is a continuation-in-part of copending application serial no. 07/721,868, filed June 26, 1991. 5
1. BACKGROUND OF THE INVENTION This invention relates to novel compositions of matter containing optically pure R(+) ondansetron. These novel compositions have potent antiemetic activity and are
10 useful in ameliorating the nausea and vomiting otherwise induced by cancer chemotherapeutic agents and higher dose radiotherapeutic treatment procedures while avoiding adverse effects including but not limited to headache, constipation and increases in transaminase levels, which
15 are associated with the administration of the racemic mixture of ondansetron. Additionally, these novel compositions of matter containing optically pure R(+) ondansetron are useful in treating behavioral disorders such as mood anxiety and schizophrenia, and such other
20 conditions as may relate to R(+) ondansetron•s activity as a competitive antagonist of serotonin receptor subtype 5-
HT3, including but not limited to disorders of gastrointestinal motility, depression, migraine, alcohol, nicotine or drug (benzodiazepine et al.) withdrawal, while
25 avoiding adverse effects associated with the administration of the racemic mixture of ondansetron..
Furthermore, these novel compositions of matter containing optically pure R(+) ondansetron are useful in treating cognitive disorders such as dementia and age-associated
30 memory impairment, while avoiding the adverse effects associated with the administration of the racemic mixture of ondansetron. Also disclosed are methods for treating the above described conditions in a human while avoiding
„„ the adverse effects that are associated with the racemic 35 ixture of ondansetron, by administering the R(+) isomer of ondansetron to said human.
The active compound of this composition, and method is an optical isomer of the compound, ondansetron which is described in United States Patent No. 4,695,578.
Chemically, the active compound is the R(+) isomer of 1,2,3,9-tetrahydro-9-meth l-3-[(2-methyl-lH-imidazol-l- yl) ethyl]-4H-carbazol-4-one. This isomer will hereinafter be referred to as R(+) ondansetron.
1.1. Steric Relationships and Drug Action
Many organic compounds exist in optically active forms, i.e.. they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes (+) and (-) or d and 1 are employed to designate the sign of rotation of plane- polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixtv. e of such isomers is often called an enantiomeric or racemic mixture.
-Stereochemical purity is of importance in the field of pharmaceuticals, where 12 of the 20 most prescribed drugs exhibit chirality. A case in point is provided by the L-form of the β-adrenergic blocking agent, propranolol, which is known to be 100 times more potent than the D-enantiomer.
Furthermore, optical purity is important since certain isomers may actually be deleterious rather than simply inert. For example, it has been suggested that the D-enantiomer of thalido ide was a safe and effective sedative when prescribed for the control of morning sickness during pregnancy, and that the corresponding L- enantiomer, a potent teratogen. Ondansetron, which is the subject of the present invention, is available commercially only as the 1:1 racemic mixture; i.e., it is a mixture of optical isomers, called enantiomers. The racemic mixture of ondansetron is a dihydrate, that is administered as a hydrochloride salt. The enantiomers of ondansetron are disclosed in Butler et al., Br. J. Pharmacol.. 94, pg. 397-412 (1988). This reference states that the R and S isomers of ondansetron were approximately equipotent as 5-HT antagonists on rat vagus nerve. Furthermore, the reference alleges that the racemic mixture caused concentration-dependent parallel rightward displacement of the 2-methyl -5-HT concentration response curve when exposed to the longitudinal smooth muscle of the guinea-pig ileum, and that the R isomer was more potent than the S isomer when administered competitively against 2-methyl-5-HT.
The racemic mixture of ondansetron is an antagonist of the 5-hydroxytryptamine (5-HT3 or serotonin) receptor. The role of serotonin, and thus the pharmacology of ondansetron has been broadly implicated in a variety of conditions for many years (see, Phillis, J. ., The
Pharmacology of Synapses, Pergamon Press, Monograph 43, 1970; Frazer, A. et al. Annual Rev. of Pharmacology and Therapeutics 30, 307-348, 1990) . Thus, research has focused on locating the production and storage sites of serotonin as well as the location of serotonin receptors in the human body in order to determine the connection between these sites and various disease states or conditions.
In this regard, it was discovered that a major site of production and storage of serotonin is the enterochromaffin cell of the gastrointestinal mucosa. It was also discovered that serotonin has a powerful stimulating action on intestinal motility by stimulating intestinal smooth muscle, speeding intestinal transit, and decreasing absorption time, as in diarrhea. This stimulating action is also associated with nausea and vomiting.
Thus, researchers studied diseases and treatment of diseases where the above described effects were manifested. One such treatment is chemo-and radio-therapy of cancer using che otherapeutic and high dose radiotherapeutic agents. Chemo-and radio-therapy may induce nausea and vomiting by the release of serotonin from damaged enterochromaffin cells in the gastrointestinal tract. Release of the neurotransmitter serotonin, stimulates both afferent vagal nerve fibers (thus initiating the vomiting reflex) and serotonin receptors in the chemoreceptor trigger zone of the area postrema region of the brain. One of the first agents used to prevent the nausea and vomiting associated with emetogenic cancer chemotherapy was etoclopramide. This compound is an antagonist of central and peripheral dopamine receptors, and at high doses it also antagonizes serotonin receptors. Because it had this combined effect, researchers began to search for a more specific and safer, serotonin 5-HT3 antagonist to use to treat nausea and vomiting associated with chemo-and radio-therapv of cancer. This led to the development of ondansetron. Ondansetron is a competitive antagonist at serotonin 5-HT3 receptor subtypes in both the gastrointestinal tract and the brain, where it blocks both sites of serotonin-induced e esis. With respect to its anti-emetic potential, ondansetron appears to offer a dual mode of action through antagonism of serotonin at peripheral vagal nerve afferents, and antagonism of serotonin within the central nervous system, at or near the chemoreceptor trigger zone.
Consequently, ondansetron may produce a significant 5 reduction, or a complete inhibition of nausea and vomiting in the majority of patients subsequently treated with cancer chemotherapeutics of moderate or high emetic potential. Similarly, the compound prevented radiation- induced nausea and emesis. Further, ondansetron appears
j- to have an effect on gastrointestinal motility slowing the transit of material through portions of the tract. This decrease in motility may be beneficial in those patients undergoing the chemotherapy for cancer where diarrhea can provide an additional debilitating burden.
15 Ondansetron•s use as an antiemetic by either the intravenous or oral routes is disclosed in U.S. Patent No. 's 4,753,789 and 4,929,632. Furthermore, various researchers have tested the use of the racemic mixture of ondansetron to prevent nausea and vomiting caused by
20 anticancer chemotherapy. See. Green et al.. Cancer
Chemother. Pharmacol. , 24:137-139 (1989); Cubeddu et al.. New Enσl. J. Med.. Vol. 322; No. 12, pg. 810-815 (1990); De Mulder et al., Ann. Int. Med.. Vol. 113: No. 11, pg. 834-840 (1990) ; Marty, Eur. J. Cancer Clin. Oncol.. Vol.
25 25, Suppl. 1, pg. 541-545 (1989); Khojasteh et al..
Cancer. Vol. 66, No. 6, pg. 1101-1105 (1990); Schmoll, Eur. J.- Cancer Clin. Oncol.. Vol. 25, Suppl. 1, pg. 535- 539 (1989); Grunberger et al., J. Clin. Oncol.. Vol. 7, No. 8, pg. 1137-1141 (1989); Kris et al., J. Clin. Oncol..
30 Vol. 6, no. 4, pg. 659-662 (1988).
Thus, in the context of adjunctive therapy for cancer treatment, ondansetron appears to be an effective antiemetic, although its dose-response relationships remain to be clarified. The drug offers a moderate
35 potency, a half-life of some three hours, and the potential for prophylactic/therapeutic activity. Dosing 1-2 hours prior to cancer therapy or at the initiation of therapy can be accomplished by continuous infusion, or repeated oral or intravenous administrations. (see Smith, R.N., Safety of Ondansetron, European J. of Cancer and Clinical Oncology, 25 Suppl.1 547-50, 1989; and Smyth, J.F. ibid., 555-57, 1989).
As stated previously, stimulation of serotonin receptors has been postulated to be involved in a variety of disease states and conditions. Thus, it has been proposed that antagonizing serotonin receptors will assist in treating these conditions.
It has been proposed that the racemic mixture of ondansetron is useful in the treatment of anxiety disorders. Anxiety disorder has its etiology in both psychologic and physiologic factors, and it has been suggested that a genetic influence exists. Emotional stress can precipitate anxiety neurosis which represents the individual's fear of losing control of such emotional drives as aggression or dependency needs, and losing control of one's resulting actions. Physiologically, anxiety is associated with autonomic nervous' system discharge, and related neurohumoral processes. In acute anxiety attacks, lasting from a few minutes to an hour, the individual experiences a subjective sense of terror, for no evident reason, and perhaps a haunting dread of catastrophe. Chronic anxiety displays less intense symptoms of longer duration, characterized by uneasiness, nervousness, nagging uncertainty about future events, headache, fatigue and subacute autonomic symptoms. The use of the racemic mixture of ondansetron to treat anxiety disorders is disclosed in U.S. Patent No. 4,695,578.
It has also been proposed that the racemic mixture of ondansetron is useful to treat psychotic disorders such as schizophrenia. (See U.S. Patent No. 4,695,578). Schizophrenic disorders are complex mental disorders which tend toward chronicity, and which impair functioning, and are characterized by psychotic symptoms of disturbed thinking, feeling and general behavior. Clear, goal directed thought becomes difficult, while blunting and inappropriate affect become the most characteristic emotional changes. Auditory hallucinations can be common, and delusions of persecution are frequent, as are threats of violence, and minor aggressive outbursts. Disturbances of movement can range from significant over-activity and excitement to retardation and stupor. Treatment has often included tranguilizer and other antipsychotic drugs, • administered orally or by long acting depot injections (to offset problems of patient compliance) . The racemic mixture of ondansetron has also been proposed to be useful in the treatment of depression (see U.S. Patent No. 4,835,173). Depression, an affective disorder, is characterized by changes in mood, as a primary clinical feature. The most common of the significant mental illnesses, depression must be distinguished clinically from periods of normal grief, sadness, and disappointment, and the related dysphoria or demoralization frequently associated with medical illness. Depression is characterized by feelings of intense sadness, and despair, mental slowing and loss of concentration, pessimistic worry, agitation, and self- deprecation. Physical changes can also occur, including insomnia, anorexia, and weight loss, decreased energy and libido, and the disruption of circadian rhythms. Often the condition responds well to tricyclic or related antidepressant drugs, monoamine oxidase inhibitors, or in resistant cases or severe disease, to electro-convulsive shock treatment. Nevertheless, the treatment of depression would benefit from new therapy. It has also been proposed that the racemic mixture of ondansetron is useful to treat migraine (see U.S. Patent No. 4,695,578). Migraine is of unknown cause, although evidence suggests a functional disturbance of the cranial circulation. The condition is a paroxysmal disorder, characterized by recurrent attacks of headache, which can be associated with visual and gastrointestinal disturbances. Migraine headaches may be preceded by a short period of depression, irritability, restlessness or anorexia.
U.S. Patent No. 4,847,281 discloses the use of the racemic mixture of ondansetron to treat substance abuse. Disorders of substance use or abuse often involve both psychologic and physical dependence, accompanied by the development of tolerance (the need to increase the dose progressively so as to prod :_e the effect originally achieved by smaller amounts) , and manifested by a withdrawal or abstinence syndrome.
Alcohol withdrawal syndrome represents a continuum of symptoms including tremor, weakness, sweating and gastrointestinal symptoms usually beginning some hours after cessation of intake. Drugs which alter the serotonin system can modulate the alcohol consumption in humans. Some mutual, but incomplete cross-tolerance exists between alcohol and other drugs including the benzodiazepines, the sedative-hypnotic, and the anxiolytic muscle relaxant group. While benzodiazepine withdrawal symptoms are often considered moderate, in withdrawal, often anxiety returns, with dysphoria irritability, sweating, headache and sleep abnormalities. Nicotine withdrawal syndrome following cessation of tobacco use, varies significantly among subjects in intensity, and specific signs and symptoms. Apart from the craving for tobacco products, which begins within 24 hours of cessation and then subsides over a period of some days. other symptoms include, but are not limited to, irritability, anxiety, increased appetite and the gastrointestinal symptoms, and inability to concentrate. In addition, the racemic mixture of ondansetron could be useful in the treatment of cognitive disorders. Cognitive disorders include but are not limited to dementia and age-associated memory impairment. Dementia can occur at any age. It is a structurally caused permanent or progressive decline in several dimensions of intellectual function that interferes substantially with individual normal social or economic activity.
One particular type of dementia is Alzheimers-type dementia. Alzheimers-type dementia is thought to be due to a degenerative process, with a large loss of cells from the cerebral cortex and other brain areas. Acetylcholine- transmitting neurons and their target nerve cells are particularly affected. The brain shows marked atrophy with wide sulci and dilated ventricles. Senile plaques and neurofibrillary tangles are present. Memory loss is the most prominent early symptom. Disturbances of arousal do not occur early in the course. Alzheimer's presenile and senile onset dementias are similar in both clinical and pathologic features, with the former commonly beginning in the 5th and 6th decades and the latter in the 7th and 8th decades. The dementia usually progresses steadily, becoming well advanced in 2 to 3 years. Some cases of dementia occurring in the presenile period are hard to classify and are sometimes labelled idiopathic or simple presenile dementia.
The signs and symptoms of dementia, in particular Alzheimers-type dementia, include depression, paranoia, anxiety or any of several other psychologic symptoms. The most common clinical picture is slow disintegration of personality and intellect due to impaired insight and judgment and loss of affect. Memory impairment increases, beginning with problems recalling recent events or finding names. The impairment varies greatly from time to time and often from moment to moment. Dementia generally is an insidious, slowly progressive, untreatable condition.
However, the rate of progression varies widely and depends on the cause.
Another type of cognitive disorder is age- associated memory impairment (AAMI) . AAMI is used to describe healthy non-demented people who have experienced memory loss over the course of the person's life. Most commonly it is used to describe adults over the age of 50 who have experienced memory loss over the course of adult life. It has been estimated that between 25% and 50% of people over the age of 65 have this disorder.
While the racemic mixture of ondansetron offers efficacy in treating a variety of diseased states and conditions, its use is associated with adverse effects (principally headache and constipation) which increase with the dose of the racemic mixture of ondansetron administered.
Thus it would be particularly desirable to find a compound with the advantages of ondansetron which would not have the aforementioned disadvantages.
2. SUMMARY OF THE INVENTION It has now been discovered that the optically pure R(+) isomer of ondansetron is an effective anti-emetic agent, useful as an adjunctive therapy in cancer treatment to ameliorate nausea and vomiting induced by chemo- or radio-therapeutics, while decreasing the usual adverse effects including, but not limited to, headache, constipation and increases in transaminase levels which are associated with the racemic mixture of ondansetron. It has also been discovered that the optically pure R(+) isomer of ondansetron is a useful agent to treat such behavioral disorders as mood anxiety and schizophrenia, and such other conditions as may relate to the composition's activity as a competitive antagonist at serotonin receptor subtype 5-HT3, such as disorders of gastrointestinal motility, depression, migraine, and as a therapeutic aid in alcohol, nicotine, and benzodiazepine withdrawal, while decreasing the usual adverse effects associated with the racemic mixture of ondansetron. Furthermore, it has also now been discovered that the optically pure R(+) isomer of ondansetron is useful in treating cognitive disorders such as dementia and age- associated memory impairment, while decreasing the adverse effects associated with the racemic mixture of ondansetron.
The present invention also includes novel compositions of matter, containing optically pure R(+) ondansetron which are useful and effective as antiemetic adjunctive therapy in cancer treatment by chemo-or radio- therapeutics, and as agents for the aforementioned disorders. These novel compositions also avoid, or reduce the above described adverse effects associated with the administration of the racemic mixture of ondansetron. Thus, with the R(+) isomer of ondansetron, clearer dose definitions of efficacy vis a vis adverse effects, may be achieved.
3. DETAILED DESCRIPTION OF THE INVENTION
The present invention encompasses a method of eliciting an antiemetic effect while avoiding the concomitant liability of adverse effects which comprises administering to a human in need of such antiemetic therapy an amount sufficient to alleviate nausea and vomiting, but insufficient to cause said adverse effects, of R(+) ondansetron, or a pharmaceutically acceptable salt thereof, substantially free of its S(-) stereoisomer.
The present invention also encompasses an antiemetic composition for the treatment of a human in need of antiemetic therapy, which comprises an amount sufficient to alleviate nausea and vomiting but insufficient to cause adverse effects, of R(+) ondansetron, or a pharmaceutically acceptable salt thereof, substantially free of its S(-) stereoisomer. The present invention further encompasses a method of treating behavioral disorders such as mood anxiety or schizophrenia in a human while avoiding the concomitant liability of adverse effects, which comprises administering to said human in need of such therapy, an amount sufficient to alleviate said condition, but insufficient to cause said adverse effects, of R(+) ondansetron, or a pharmaceutically acceptable salt thereof, substantially free of its S(-) stereoisomer.
In addition, the present invention encompasses a composition for the treatment of a human with behavior disorders such as mood anxiety or schizophrenia, which comprises an amount sufficient to alleviate behavioral disorders such as mood anxiety or schizophrenia, but insufficient to cause adverse effects, of R(+) ondansetron, or a pharmaceutically acceptable salt thereof, substantially free of its S(-) stereoisomer.
Also included in the present invention is a method of treating a condition caused by disturbance of neuronal 5-HT function while avoiding the concomitant liability of adverse effects, which comprises administering to a human in need of such therapy an amount sufficient to alleviate said condition but insufficient to cause said adverse effects, of R(+) ondansetron, or a pharmaceutically acceptable salt thereof, substantially free of its S(-) stereoisomer. Conditions caused by a disturbance of neuronal 5-HT function include but are not limited to, disorders of gastrointestinal motility, depression, migraine, and alcohol, nicotine, or drug (benzodiazepine et al.) withdrawal. A further aspect of the present invention is a composition for treating a condition caused by disturbance of neuronal 5-HT function, which comprises an amount sufficient to alleviate said condition but insufficient to cause adverse effects, of R(+) ondansetron, or a pharmaceutically acceptable salt thereof, substantially free of its S(-) stereoisomer.
Furthermore, the present invention includes a method of treating cognitive disorders such as dementia or age-associated memory impairment, while avoiding the concomitant liability of adverse effects, which comprises administering to a human in need of such therapy an amount sufficient to alleviate said cognitive disorder but insufficient to cause said adverse effects, of R(+) ondansetron, or a pharmaceutically acceptable salt thereof, substantially free of its S(-) stereoisomer. A further aspect of the present invention is a composition ,for treating cognitive disorders such as dementia or age-associated memory impairment, which comprises an amount sufficient to alleviate said condition, but insufficient to cause adverse effects, of R(+) ondansetron, or a pharmaceutically acceptable salt thereof-, substantially free of its S(-) stereoisomer.
The available racemic mixture of ondansetron (i.e. a 1:1 racemic mixture of stereoisomers) causes antiemetic activity, and provides therapy and a reduction of symptoms in a variety of conditions and disorders; however this racemic mixture, while offering the expectation of efficacy, causes adverse effects. Utilizing the R(+) isomer of ondansetron alone results in dose related definitions of efficacy, diminished adverse effects, and accordingly, an improved therapeutic index. It is therefore, more desirable to use the R(+) isomer of ondansetron.
The term 'adverse effects* includes, but is not limited to headache, constipation, fatigue, sedation, lethargy, drowsiness, dry mouth, diarrhea and transient increases in transaminase levels. Increases in the serum activity of certain hepatocellular enzymes is also included within the term "adverse effects". The term "substantially free of its S(-) stereoisomer" as used herein means that the composition contains a greater proportion of the R(+) isomer of ondansetron in relation to the S(-) isomer of ondansetron. In one embodiment the term "substantially free of its S(-) stereoisomer" as used herein means that the composition contains at least 90 % by weight of R(+) ondansetron, and 10 % by weight or less of S(-) ondansetron. In the most preferred embodiment the term "substantially free of the S(-) stereoisomer" means that the composition contains at least 99 % by weight R(+) ondansetron, and 1 % or less of S(-) ondansetron.
The term, "eliciting an antiemetic effect" as used herein means providing relief from the symptoms of nausea and vomiting induced spontaneously or substantially free of its associated with emetogenic cancer chemotherapy or irradiation therapy.
The term, "behavioral disorders such as mood anxiety, and schizophrenia'1 as used herein means relief from the symptoms which include, but are not limited to, a subjective sense of terror, a dread of catastrophe, uneasiness, nervousness uncertainty, headache, fatigue, disturbed thinking inappropriate affect, auditory hallucinations, aggressive outbursts and the like.
The term, "a condition caused by disturbance of neuronal 5-HT function" includes but is not limited to disorders of gastrointestinal motility, depression, migraine and alcohol, nicotine or drug (benzodiazepine et al.) withdrawal. This includes relief from the symptoms which include, but are not limited to, diarrhea and related symptoms, as decreased absorption time, etc., intense sadness, despair, mental slowing, loss of concentration, worry, agitation, headache, irritability, restlessness, anorexia, sweating, sleep abnormalities, and the like. The term "treating cognitive disorders" as used herein means providing relief from the symptoms of cognitive disorders including but not limited to memory loss, disintegration of personality and intellect, depression, paranoia, anxiety and other psychologic symptoms.
The preparation of the mixture of enantiomers, (e.g., racemic mixture) of ondansetron is disclosed in U.S. Patent No. 4,695,578. The R(+) isomer of ondansetron, may be obtained by resolution of the mixture of enantiomers of ondansetron using conventional means such as an optically active resolving acid; see, for example, "Stereochemistry of Carbon Compounds", by E.L. Eliel (McGraw Hill 1962) and Lochmuller C.H. et al., J. Chromatoqr.. 1975, Vol. 113, No. 3, Pg. 283-302. The magnitude of a prophylactic or therapeutic dose of R(+) ondansetron in the acute or chronic management of disease will vary with the severity of the condition to be treated, and the route of administration. The dose, and perhaps dose frequency, will also vary according to the age, body weight, and response of the individual patient. In general, the total, .daily dose ranges, for the conditions described herein, from about 0.01 mg to about 35 mg administered in divided doses orally, or by a slow intravenous injection or infusion. In cases of moderate to highly emetogenic chemotherapy, it may be expected that, an initial loading dose of between about 2 mg to about 10 mg given by slow intravenous injection or infusion over 15-30 minutes, immediately before the emetogenic chemotherapy, and followed by about 2 mg to about 8 mg given orally every eight hours for periods up to four to five days will elicit therapy and provide for a reduction of symptoms. In cases of radiotherapy, and as an oral therapeutic for the other conditions described herein, generally doses of between about 2 mg to about 8 mg orally every eight hours, should provide benefit to adult patients. In the case of using R(+) ondansetron to treat cognitive disorders such as dementia and age- associated memory impairment, the total daily dosage ranges may be from about 0.001 mg to about 35 mg in divided doses orally or by a slow intravenous injection or infusion. Children generally will benefit from doses that are generally some 25-50 percent those of the adult for a given condition, while geriatric .patients generally tolerate adult doses. It may be necessary to use dosages outside these ranges in some conditions.
The term, "an amount sufficient to alleviate the nausea and vomiting but insufficient to cause said adverse effects" is encompassed by the above described dosage amounts and dose frequency schedule. In addition, the term "an amount sufficient to alleviate said condition but insufficient to cause said adverse effects" wherein said conditions include but are not limited to behavioral disorders such as mood anxiety and schizophrenia as well as disturbances of neuronal 5-HT function including, but not limited to, disorders of gastrointestinal motility, depression, migraine and alcohol, nicotine or drug (benzodiazepine et al.) withdrawal are also encompassed by the above described amounts. The term "an amount sufficient to alleviate said condition but insufficient to cause said adverse effects" wherein said condition includes cognitive disorders such as dementia and age- associated memory impairment, is also encompassed by the above-described amounts.
Any suitable route of administration may be employed for providing the patient with an effective dosage of R(+) ondansetron. For example, oral, rectal, parenteral, transdermal, subcutaneous, intramuscular, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, and the like.
The pharmaceutical compositions of the present invention comprise R(+) ondansetron as active ingredient, or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier, and optionally, other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids.
Since the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Such acids include acetic, benzene-sulfonic, benzoic camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic, and the like. Particularly preferred are hydrobromic, hydrochloric, phosphoric and sulfuric acids. The compositions include compositions suitable for oral, rectal or other mucosal routes, transdermal, parenteral (including subcutaneous, intramuscular, and intravenous) , although the most suitable route in any given case will depend on the nature and severity of the condition being treated. The most preferred routes of the present invention include both intravenous injections, and infusions and the oral route. They may be conveniently presented in unit dosage form, and prepared by any of the methods well known in the art of pharmacy. In the case where an oral composition is employed, a suitable dosage range for use is, e.g., from about 5 mg to about 35 mg total daily dose, administered as equally divided doses, three times a day. Preferably, a dose range of between about 10 mg to about 30 mg per day, administered as equally divided doses, three times a day, and most preferably from between about 12 mg to about 24 mg per day, administered as equally divided doses, three times a day. Patients may be upwardly titrated within this dose range to enable the satisfactory control of symptoms. In the case where an oral composition is employed to treat cognitive disorders such as dementia and age-associated memory impairment, a suitable dosage range for use is from about 0.001 mg to about 35 mg total daily dose administered as equally divided doses from one to three times a day. Preferably a dose range of between about 0.001 mg to about 20 mg per day administered as equally divided doses one to three times a day and most preferably from between 0.001 mg to about 10 mg per day administered as equally divided doses, one to three times a day.
In the case where an intravenous injection or infusion composition is employed, a suitable dosage range for use is, e.g. from about 0.01 mg to about 32 mg total daily dose, presented as a loading slow intravenous injection of about 2 mg to about 8 mg over 15-30 minutes, followed by an intravenous infusion of about 0.5 mg to about 1.0 g/hour for up to 24 hours. These regimens may be followed by oral doses of between about 1.5 mg to about
8.0 mg every eight hours for periods up to five days. In practical use, R(+) ondansetron can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (including intravenous injections or infusions) . In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, e.g., water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations, e.g., suspensions, solutions, and elixirs; or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like in the case of oral solid preparations e.g., powders, capsules, and tablets, with the solid oral preparations being preferred over the liquid preparations. The most preferred solid oral preparation is tablets.
Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
In addition to the common dosage forms set out above,the compounds of the present invention may also be administered by controlled release means and/or delivery devices such as those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, the disclosures of which are hereby incorporated by reference.
Another preferred route of administration, particularly to avoid problems associated with emesis, is transdermal delivery, for example, via an abdominal skin patch.
Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, or aerosol sprays, each containing a predetermined amount of the active ingredient, as a powder or granules, or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy, but all methods include the. step of bringing into association, the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound, moistened with an inert liquid diluent. Desirably, each tablet contains from about 2.0 mg to about 8.0 mg of the active ingredient, and each cachet or capsule contains from about 2.0 mg to about 8.0 m_ of the active ingredient. Most preferably, the tablet, cachet or capsule contains either one of three dosages: 2.0 mg, 4.0 mg and 8.0 mg (as scored tablets, the preferable dose form) of active ingredient. Furthermore, each tablet or capsule can contain from about 0.001 mg to about 10.0 mg of the active ingredient. However, the amount of active ingredient found in the composition may vary depending on the amount of active ingredient to be administered to the patient.
The invention is further defined by reference to the following examples describing in detail, the preparation of the compound, and the compositions of the present invention. It will be apparent to those skilled in the art, that many modifications, both to materials and methods, may be practiced without departing from the purpose and interest of this invention.
All temperatures are in degrees Celsius.
4. EXAMPLES
4.1. EXAMPLE 1 A pharmacological study to determine the relative potency and specificity of optically pure R(+) ondansetron and racemic ondansetron as competitive antagonists at serotonin receptor subtype 5-HT3 present in gastrointestinal, brain, and other tissues.
The optically pure and racemic compounds may be evaluated as a function of their molar concentration, for their relative abilities to inhibit the binding of 3H-5-HT in such selected preparations as nerves of guinea pig ileum and preparations of brain tissue from several species including rats and humans. The availability of 3H- 5-HT as a radioligand with relatively high specific activity, the development of other selective 5-HT3 antagonists, and the additional agonist, 2-methyl-5- hydroxy-tryptamine (2-methyl-5-HT) provide the pharmacologic tools for the characterization of the 5-HT3 receptor, and the evaluation of R(+) , and racemic ondansetron. (see Frazer, A. , et al. , Annu. Rev. Pharmacol. Toxicol. J3.0, 307-348, 1990). It has been suggested, (Bradley, P.B et al., Neurophar acology 25, 563-576, 1986) as part of the evolving characterization of serotonin receptor subtypes, that responses mediated by 5- HT3 receptors: be reduced by selective antagonists, not be inhibited by selective antagonists of other subtypes of serotonin receptors, and be mimicked by 2-methyl 5-HT at concentrations comparable to that of serotonin. Accordingly, the comparative ability of R(+) and racemic ondansetron, to inhibit the binding of 3H-5-HT and the agonist, 3H-2-methyl 5-HT, not to be inhibited as a radioligand for 5-HT3 receptors by selective antagonists of other subtypes and to be inhibited from selective binding as a function of concentration, by other 5-HT3 selective antagonists of possibly greater potency including zacopride, ICS 205-930, and granisetron, will serve a characterization of potency and specificity at 5-HT3 receptors.
4.2. EXAMPLE 2: ORAL FORMULATION
Tablet:
Formula Quantity per Tablet in mg
Active Ingredient R(+) ondansetron
Lactose BP
Starch BP
Pregelatinized Maize Starch BP
Magnesium Stearate BP
Figure imgf000025_0001
Compression Weight 200.0 200.0 200.0
The active ingredient, is sieved through a suitable sieve and blended with lactose, starch, and pregeatinised maize starch. Suitable volumes of purified water are added and the powders are granulated. After drying, the granules are screened and blended with the magnesium stearate. The granules are then compressed into tablets using 7 mm diameter punches.
Tablets of other strengths may be prepared by altering the ratio of active ingredient to lactose or the compression weight and using punches to suit. 4.3. EXAMPLE 3 ORAL FORMULATION
Capsules :
Formula g/capsule
Active Ingredient R(+) ondansetron
Starch 1500
Magnesium Stearate BP
Figure imgf000026_0001
Compression Weight 100.0 100.0 100.0
The active ingredient is sieved and blended with the excipients. The mix is filled into size No. 2 hard gelatin capsules using suitable machinery. Other doses may be prepared by altering the fill weight an if necessary changing the capsule size to suit.
4 .4 . . EXAMPLE 4
INTRAVENOUS FORMULATION
Formula jug/ml
Active Ingredient R(+) ondansetron 400
Dilute Hydrochloric Acid BP to pH 3.5 Sodium Chloride Injection BP 1 ml

Claims

What is claimed is:
1. A method of eliciting an antiemetic effect while avoiding the concomitant liability of adverse effects, which comprises administering to a human in need of antiemetic therapy, an amount sufficient to alleviate nausea and vomiting, but insufficient to cause said adverse effects, of R(+) ondansetron, or a pharmaceutically acceptable salt thereof, substantially free of its S(-) stereoisomer.
2. The method of claim 1, wherein R(+) ondansetron is administered by intravenous infusion, transdermal delivery, orally as a tablet or a capsule.
3. The method according to claim 2, wherein the amount administered is about 0.01 mg to about 35.0 mg.
4. The method according to claim 3, wherein the amount administered by intravenous infusion is about 2 mg to about 10 mg.
5. The method according to claim 3, wherein the amount administered orally is about 10.0 mg to about 30.0 mg.
6. The method according to claim 5, wherein the amount administered orally is about 12.0 mg to about 24.0 mg.
7. The method according to claim 1, wherein the amount of R(+) ondansetron or a pharmaceutically acceptable salt thereof is greater than approximately 90% by weight.
8. The method according to claim 1, wherein R(+) ondansetron or a pharmaceutically acceptable salt thereof, substantially free of its S(-) .stereoisomer, is administered together with a pharmaceutically acceptable carrier.
9. A method according to claims 2, 3, 4, 5, or 6, wherein R(+) ondansetron hydrochloride is administered.
10. An antiemetic composition adapted for the treatment of a human in need of antiemetic therapy which comprises an amount sufficient to alleviate nausea and vomiting, but insufficient to cause adverse effects, of R(+) ondansetron or a pharmaceutically acceptable salt thereof, substantially free of its S(-) stereoisomer.
11. A composition according to claim 10, wherein the amount is about 2.0 mg to about 8.0 mg.
12. A composition according to claim 11, wherein said composition is administered from one to four times a day.
13. A composition according to claim 12, wherein said composition is administered twice a day.
14. A composition according to claim 12, wherein said composition is administered once a day.
15. A composition according to claim 11, which comprises R(+) ondansetron hydrochloride.
16. A composition according to claim 15, adapted from oral administration.
17. A composition according to claim 15, adapted for intravenous delivery.
18. A composition according to claim 15, adapted for use in a transdermal delivery formulation.
19. A composition according to claim 18, adapted for use as a transdermal patch.
20. The composition according to claim 10, wherein R(+) ondansetron or a pharmaceutically acceptable salt thereof, substantially free of its S(-) stereoisomer, is administered together with a pharmaceutically acceptable carrier.
21. A method of treating behavioral disorders such as mood anxiety and schizophrenia while avoiding concomitant liability of adverse effects, which comprises administering to a patient in need of such therapy, an amount sufficient to alleviate said condition, but insufficient to cause said adverse effects, of R(+) ondansetron, or a pharmaceutically acceptable salt thereof, substantially free of its S(-) stereoisomer.
22. The method of claim 21, wherein R(+) ondansetron is administered by intravenous infusion, transdermal delivery, orally as a tablet or a capsule.
23. The method according to claim 22, wherein the amount admiristered is about 0.01 mg to about 35.0 mg.
24. The method according to claim 23, wherein the amount administered by intravenous infusion is about 2 mg to about 10 mg.
25. The method according to claim 23, wherein the amount administered orally is about 10.0 mg to about 30.0 mg.
26. The method according to claim 25, wherein the amount administered orally is about 12.0 mg to about 24.0 mg.
27. The method according to claim 21, wherein the amount of R(+) ondansetron or a pharmaceutically acceptable salt thereof is greater than approximately 90% by weight.
28. The method according to claim 21, wherein R(+) ondansetron or a pharmaceutically acceptable salt thereof, substantially free of its S(-) stereoisomer, is administered together with a pharmaceutically acceptable carrier.
29. A method according to claims 22, 23, 24, 25, or 26, wherein R(+) ondansetron hydrochloride is administered.
30. A composition for the treatment of a human with behavior disorders such as mood anxiety or schizophrenia, which comprises an amount sufficient to alleviate said behavior disorders such as mood anxiety or schizophrenia, but insufficient to cause adverse effects, of R(+) ondansetron or a pharmaceutically acceptable salt thereof, substantially free of its S(-) stereoisomer.
31. A composition according to claim 30, wherein the amount is about 2.0 mg to about 8.0 mg.
32. A composition according to claim 31, wherein said composition is administered from one to four times a day.
c
33. A composition according to claim 32, wherein said composition is administered twice a day.
34. A composition according to claim 32, wherein said composition is administered once a day.
35. A composition according to claim 31, which comprises R(+) ondansetron hydrochloride.
36. A composition according to claim 35, adapted from oral administration.
37. A composition according to claim 35, adapted for intravenous delivery.
38. A composition according to claim 35, adapted for use in a transdermal delivery formulation.
39. A composition according to claim 38, adapted for use as a transdermal patch.
40. The composition according to claim 30, wherein
R(+) ondansetron or a pharmaceutically acceptable salt thereof, substantially free of its S(-) stereoisomer, is administered together with a pharmaceutically acceptable carrier.
41. A method of treating a condition caused by disturbance of neuronal 5-HT function, while avoiding the concomitant liability of adverse effects, which comprises administering to a human in need of such therapy an amount sufficient to alleviate said condition but insufficient to cause said adverse effects, of R(+) ondansetron, or a pharmaceutically acceptable salt thereof, substantially free of its S(-) stereoisomer.
42. The method according to claim 41, wherein said disturbance of neuronal 5-HT function is selected from the group consisting of disorders of gastrointestinal mobility, depression, migraine, alcohol withdrawal, nicotine withdrawal, and drug withdrawal.
43. The method of claim 41, wherein R(+) ondansetron is administered by intravenous infusion, transdermal delivery, orally as a tablet or a capsule.
44. The method according to claim 43, wherein the amount administered is about 0.01 mg to about 35.0 mg.
45. The method according to claim 44, wherein the amount administered by intravenous infusion is about 2.0 mg to about 10.0 mg.
46. The method according to claim 44, wherein the amount administered orally is about 10.0 mg to about 30.0 mg.
47. The method according to claim 46, wherein the amount administered orally is about 12.0 mg to about 24.0 mg.
48. The method according to claim 41, wherein the amount of R(+) ondansetron or a pharmaceutically acceptable salt thereof is greater than approximately 90% by weight.
49. The method according to claim 41, wherein R(+) ondansetron or a pharmaceutically acceptable salt thereof, substantially free of its S(-) .stereoisomer is administered together with a pharmaceutically acceptable carrier.
50. The method according the claims 43, 44, 45, 46 or 47, wherein R(+) ondansetron hydrochloride is administered.
51. A composition for treating a condition caused by disturbance of neuronal 5-HT function, which comprises an amount sufficient to alleviate said condition, but insufficient to cause adverse effects, of R(+) ondansetron, or a pharmaceutically acceptable salt thereof, substantially free of its S(-) stereoisomer.
52. A composition according to claim 51, wherein said disturbance of neuronal 5-HT function is selected from the group consisting of disorders of gastrointestinal motility, depression, migraine, alcohol withdrawal, nicotine withdrawal, and drug withdrawal.
53. A composition according to claim 51, wherein the amount is about 2.0 mg to about 8.0 mg.
54. A composition according to claim 53, wherein said composition is administered from one to four times a day.
55. A composition according to claim 54, wherein said composition is administered twice a day.
56. A composition according to claim 54, wherein said composition is administered once a day.
57. A composition according to claim 53, which comprises R(+) ondansetron hydrochloride.
58. A composition according to claim 57, adapted from oral administration.
59. A composition according to claim 57, adapted for intravenous delivery.
60. A composition according to claim 57, adapted for use in a transdermal delivery formulation.
61. A composition according to claim 60, adapted for use as a transdermal patch. '
62. The composition according to claim 51, wherein R(+) ondansetron or a pharmaceutically acceptable salt thereof, substantially free of its S(-) stereoisomer, is administered together with a pharmaceutically acceptable carrier.
63. A method of treating cognitive disorders while avoiding the concomitant liability of adverse effects, which comprises administering to a human in need of such therapy an amount sufficient to alleviate said condition but insufficient to cause said adverse effects, of R(+) ondansetron, or a pharmaceutically acceptable salt thereof, substantially free of its S(-) stereoisomer.
64. The method according to claim 62, wherein said cognitive disorder is selected from the group consisting of dementia and age-associated memory impairment.
65. The method of claim 63, wherein R(+) ondansetron is administered by intravenous infusion, transdermal delivery, orally as a tablet or a capsule.
66. The method according to claim 65, wherein the amount administered is about 0.001 mg to about 35.0 mg.
67. The method according to claim 66, wherein the amount administered by intravenous infusion is about 0.001 mg to about 35.0 mg.
68. The method according to claim 66, wherein the amount administered orally is about 0.001 mg to about 35.0 mg.
69. The method according to claim 68, wherein the amount administered orally is about 0.001 mg to about 20.0 mg.
70. The method according to claim 63, wherein the amount of R(+) ondansetron or a pharmaceutically acceptable salt thereof is greater than approximately 90% by weight.
71. The method according to claim 63, wherein R(+) ondansetron or a pharmaceutically acceptable salt thereof, substantially free of its S(-) stereoisomer is administered together with a pharmaceutically acceptable carrier.
72. The method according to claims 65, 66, 67, 68 or 69, wherein R(+) ondansetron hydrochloride is administered.
73. A composition for treating cognitive disorders, which comprises an amount sufficient to alleviate said condition, but insufficient to cause adverse effects, of R(+) ondansetron, or a pharmaceutically acceptable salt thereof, substantially free of its S(-) stereoisomer.
74. A composition according to claim 73, wherein said cognitive disorders is selected from the group consisting of dementia and age-associated memory impairment.
75. A composition according to claim 74/ wherein the amount is about 0.001 mg to about 10.0 mg.
76. A composition according to claim 75, wherein said composition is administered from one to four times a day.
77. A composition according to claim 76, wherein said composition is administered twice a day.
78. A composition according to claim 76, wherein said composition is administered once a day.
79. A composition according to claim 75, which comprises R(+) ondansetron hydrochloride.
80. A composition according to claim 73, adapted from oral administration.
81. A composition according to claim 73, adapted for intravenous delivery.
82. A composition according to claim 73, adapted for use in a transdermal delivery formulation.
83. A composition according to claim 82, adapted for use as a transdermal patch.
84. The composition according to claim 73, wherein R(+) ondansetron or a pharmaceutically acceptable salt thereof, substantially free of its S(-) stereoisomer, is administered together with a pharmaceutically acceptable carrier.
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Families Citing this family (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5578628A (en) 1985-06-25 1996-11-26 Glaxo Group Limited Medicaments for the treatment of nausea and vomiting
EP1022025A3 (en) * 1991-06-26 2002-06-05 Sepracor, Inc. Method and compositions for treating emesis nausea and other disorders using optically pure R(+) ondansetron
CN1161118C (en) * 1998-12-22 2004-08-11 诺瓦提斯药物有限公司 Use of 5HT3 receptor antagouists for the treatment of chronic fatigue syndrome
EP1435238A1 (en) * 1999-03-01 2004-07-07 Sepracor Inc. Methods for treating apnea and apnea disorders using optically pure R (+) ondansetron
CA2371822A1 (en) * 1999-03-01 2000-09-08 Sepracor Inc. Methods for treating apnea and apnea disorders using optically pure r(+)ondansetron
FR2797399B1 (en) * 1999-08-13 2002-10-18 Aventis Pharma Sa USE OF CYAMEMAZINE IN THE TREATMENT OF BENZODIAZEPINES WITHDRAWAL
CA2416706C (en) * 2000-07-31 2009-04-07 Dainippon Pharmaceutical Co., Ltd. Dementia remedies containing 2-aryl-8-oxodihydropurine derivatives as the active ingredient
CA2426026A1 (en) * 2000-10-30 2002-05-10 Judith Aronhime Novel crystal and solvate forms of ondansetron hydrochloride and processes for their preparation
US20020115707A1 (en) * 2001-01-11 2002-08-22 Rami Lidor-Hadas Process for preparing pure ondansetron hydrochloride dihydrate
US6596686B2 (en) 2001-03-12 2003-07-22 International Flavors & Fragrances Inc. Use of dihydropyrans as fragrance Material
GB0216027D0 (en) * 2002-07-10 2002-08-21 Arachnova Therapeutics Ltd New therapeutic use
US20040048874A1 (en) * 2001-05-22 2004-03-11 Bardsley Hazel Judith New therapeutic use of 4-(2-fluorophenyl)-6-methyl-2-(1-piperazinyl)thieno[2,3-D]pyrimidine
AU2002354041A1 (en) * 2001-11-06 2003-05-19 John L. Haracz Antimnemonic therapy for hypermemory syndromes
KR20040104654A (en) * 2002-04-29 2004-12-10 비오갈 기오기스제르갸르 알티. Process for preparing 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1h-imidazol-1-yl)methyl]-4h-carbazol-4-one
US20050131045A1 (en) * 2002-04-30 2005-06-16 Judith Aronhime Novel crystal forms of ondansetron, processes for their preparation, pharmaceutical, compositions containing the novel forms and methods for treating nausea using them
WO2003093260A1 (en) * 2002-04-30 2003-11-13 Biogal Gyogyszergyar Rt. Novel crystal forms of ondansetron, processes for their preparation, pharmaceutical compositions containing the novel forms and methods for treating nausea using them
WO2003100091A1 (en) * 2002-05-24 2003-12-04 Epidauros Biotechnologie Ag Means and methods for improved treatment using 'setrones'
JP2006516977A (en) * 2003-01-13 2006-07-13 ダイノゲン ファーマシューティカルズ,インコーポレイテッド How to treat nausea, vomiting, retching, or any combination thereof
NZ541008A (en) * 2003-01-13 2007-09-28 Dynogen Pharmaceuticals Inc Method of treating functional bowel disorders
US20080213363A1 (en) * 2003-01-23 2008-09-04 Singh Nikhilesh N Methods and compositions for delivering 5-HT3 antagonists across the oral mucosa
DE602004007225T2 (en) * 2003-04-04 2008-03-06 Dynogen Pharmaceuticals Inc., Waltham METHOD FOR THE TREATMENT OF LOWER HARN PATTERNS
US7390503B1 (en) 2003-08-22 2008-06-24 Barr Laboratories, Inc. Ondansetron orally disintegrating tablets
DE602005015434D1 (en) * 2004-04-30 2009-08-27 Univ Chiba Nat Univ Corp MEANS FOR THE TREATMENT OF PSYCHONEUROTIC DISEASES
WO2006085497A1 (en) * 2005-02-09 2006-08-17 Kissei Pharmaceutical Co., Ltd. Tablet disintegrating in the oral cavity
WO2006105117A2 (en) * 2005-03-28 2006-10-05 Dynogen Pharmaceuticals, Inc. Method of treating disorders and conditions using peripherally-restricted antagonists and inhibitors
SI2124556T1 (en) 2006-10-09 2015-01-30 Charleston Laboratories, Inc. Pharmaceutical compositions
JP5156222B2 (en) * 2006-11-28 2013-03-06 エムキュア ファーマシューティカルズ リミテッド New process for producing antiemetic compounds
EP3090743A1 (en) 2008-01-09 2016-11-09 Charleston Laboratories, Inc. Pharmaceutical compositions for treating headache and eliminating nausea
US20100298397A1 (en) * 2009-05-19 2010-11-25 Singh Nikhilesh N Method of treatment of obsessive compulsive disorder with ondansetron
CA2767576C (en) 2009-07-08 2020-03-10 Charleston Laboratories Inc. Pharmaceutical compositions comprising an antiemetic and an opioid analgesic
CN104274426A (en) * 2013-07-03 2015-01-14 陆克塞纳医药公司 Novel aerosol formulations of ondansetron and uses thereof
US10172833B2 (en) 2015-08-11 2019-01-08 Insys Development Company, Inc. Sublingual ondansetron spray
WO2017152130A1 (en) 2016-03-04 2017-09-08 Charleston Laboratories, Inc. Pharmaceutical compositions
EA201992532A1 (en) * 2017-04-24 2020-04-03 Чейс Терапьютикс Корпорейшн COMPOSITIONS AND METHOD FOR TREATING DEPRESSION
CN115702894A (en) * 2021-08-11 2023-02-17 朱信红 A sustained-release composition for stopping emesis and its preparation method

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4695578A (en) * 1984-01-25 1987-09-22 Glaxo Group Limited 1,2,3,9-tetrahydro-3-imidazol-1-ylmethyl-4H-carbazol-4-ones, composition containing them, and method of using them to treat neuronal 5HT function disturbances
US4753789A (en) * 1985-06-25 1988-06-28 Glaxo Group Limited Method for treating nausea and vomiting
US4835173A (en) * 1986-12-17 1989-05-30 Glaxo Group Limited Method of medical treatment
US4847281A (en) * 1986-11-21 1989-07-11 Glaxo Group Limited Method of medical treatment of addiction

Family Cites Families (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1438268A (en) * 1974-03-25 1976-06-03 Nelson Research Dev Co Antidepressant
GR75395B (en) * 1980-11-14 1984-07-13 Lilly Co Eli
FR2528046B1 (en) * 1982-06-08 1985-06-21 Delalande Sa OPTICALLY ACTIVE OXAZOLIDINONE-2 N-ARYLATED DERIVATIVES, SPECIFIC AND REVERSIBLE INHIBITORS OF TYPE B MONOAMINE OXYDASE AND PROCESS FOR THEIR PREPARATION
NL8202810A (en) * 1982-07-12 1984-02-01 Duphar Int Res SPASMOLYTIC EFFICACY (+) - SECOVERINE.
IT1203721B (en) * 1983-12-29 1989-02-23 Dompe Farmaceutici Spa OPTICALLY ACTIVE COMPOUNDS WITH ANTITOSSE AND CENTRAL SEDATIVE ACTIVITIES, PROCEDURE FOR PREPARATION AND COMPOSITIONS CONTAINING THEM
KR920003064B1 (en) * 1984-01-25 1992-04-13 글락소 그룹 리미티드 Process for preparing hetero cyclic compounds
EP0201165B1 (en) * 1985-03-14 1994-07-20 Beecham Group Plc Medicaments for the treatment of emesis
GB8518745D0 (en) * 1985-07-24 1985-08-29 Glaxo Group Ltd Heterocyclic compounds
GB8617994D0 (en) 1986-07-23 1986-08-28 Glaxo Group Ltd Heterocyclic compounds
HU202108B (en) * 1986-07-30 1991-02-28 Sandoz Ag Process for producing pharmaceutical compositions containing serotonine antqgonistic derivatives of indol-carboxylic acid or imidazolyl-methyl-carbazol
DK662687A (en) * 1986-12-17 1988-06-18 Glaxo Group Ltd USE OF TRICYCLIC CARBAZOLONES
DE3822792C2 (en) * 1987-07-11 1997-11-27 Sandoz Ag New use of 5HT¶3¶ antagonists
US5198459A (en) * 1987-07-11 1993-03-30 Sandoz Ltd. Use of 5HT-3 antagonists in preventing or reducing dependency on dependency-inducing agents
US5098909A (en) * 1987-11-14 1992-03-24 Beecham Group, P.L.C. 5-ht3 receptor antagonists for treatment of cough and bronchoconstriction
GB8816187D0 (en) * 1988-07-07 1988-08-10 Glaxo Group Ltd Medicaments
GB8917556D0 (en) * 1989-08-01 1989-09-13 Glaxo Group Ltd Medicaments
DE3928287A1 (en) * 1989-08-26 1991-02-28 Knoll Ag USE OF THE (+) - ENANTIOMER OF ANIPAMIL
WO1991006295A1 (en) * 1989-11-06 1991-05-16 Sepracor, Inc. Analgesic composition containing optically pure s(+) flurbiprofen
CA2069404A1 (en) * 1989-11-21 1991-05-22 Timothy J. Barberich Use of optically pure s(-) atenolol for the treatment of cardiovascular disorders
JPH06509073A (en) * 1991-06-26 1994-10-13 セプラコア,インコーポレーテッド Methods and compositions for the treatment of emesis, nausea and other disorders using optically pure S(-)ondansetron
EP1022025A3 (en) * 1991-06-26 2002-06-05 Sepracor, Inc. Method and compositions for treating emesis nausea and other disorders using optically pure R(+) ondansetron

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4695578A (en) * 1984-01-25 1987-09-22 Glaxo Group Limited 1,2,3,9-tetrahydro-3-imidazol-1-ylmethyl-4H-carbazol-4-ones, composition containing them, and method of using them to treat neuronal 5HT function disturbances
US4753789A (en) * 1985-06-25 1988-06-28 Glaxo Group Limited Method for treating nausea and vomiting
US4929632A (en) * 1985-06-25 1990-05-29 Glaxo Group Limited Medicaments
US4847281A (en) * 1986-11-21 1989-07-11 Glaxo Group Limited Method of medical treatment of addiction
US4835173A (en) * 1986-12-17 1989-05-30 Glaxo Group Limited Method of medical treatment

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0591434A4 *

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EP1022025A3 (en) 2002-06-05
EP0591434A4 (en) 1994-09-14
US5712302A (en) 1998-01-27
EP0591434A1 (en) 1994-04-13
CA2112487C (en) 2003-04-15
US5962494A (en) 1999-10-05
US5629333A (en) 1997-05-13
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