EP0591395A1 - Methodes et compositions pour le traitement des vomissements, de la nausee et d'autres troubles faisant appel a l'ondansetron optiquement pur s(-) - Google Patents

Methodes et compositions pour le traitement des vomissements, de la nausee et d'autres troubles faisant appel a l'ondansetron optiquement pur s(-)

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Publication number
EP0591395A1
EP0591395A1 EP92914351A EP92914351A EP0591395A1 EP 0591395 A1 EP0591395 A1 EP 0591395A1 EP 92914351 A EP92914351 A EP 92914351A EP 92914351 A EP92914351 A EP 92914351A EP 0591395 A1 EP0591395 A1 EP 0591395A1
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EP
European Patent Office
Prior art keywords
ondansetron
administered
composition according
pharmaceutically acceptable
composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP92914351A
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German (de)
English (en)
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EP0591395A4 (fr
Inventor
James W. Young
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sunovion Pharmaceuticals Inc
Original Assignee
Sepracor Inc
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Publication date
Application filed by Sepracor Inc filed Critical Sepracor Inc
Publication of EP0591395A1 publication Critical patent/EP0591395A1/fr
Publication of EP0591395A4 publication Critical patent/EP0591395A4/xx
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic 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
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics

Definitions

  • This invention relates to novel compositions of matter containing optically pure S(-) ondansetron. These novel compositions have potent antiemetic activity and are
  • HT 3 including but not limited to disorders of gastrointestinal motility, depression, migraine, alcohol, nicotine or drug (benzodiazepine et al.) withdrawal, while
  • compositions of matter containing optically pure S(-) ondansetron are useful in treating cognitive disorders such as dementia and age-associated cognitive disorders
  • 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 S(-) isomer of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-lH-imidazol-l-yl) methyl]-4H-carbazol--4-one.
  • This isomer will hereinafter be referred to as S(-) 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. J.
  • 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 ucosa. 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 che oreceptor 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 metoclopramide.
  • 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 emesis.
  • 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 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.
  • the compound prevented radiation- induced nausea and ernesis.
  • ondansetron appears 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.
  • 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.
  • various researchers have tested the use of the racemic mixture of ondansetron to prevent nausea and vomiting caused by anticancer chemotherapy. See, Green et al.. Cancer
  • ondansetron appears to be an effective antiemetic, although its dose-response relationships remain to be clarified.
  • the drug offers a moderate 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).
  • 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. Treatment has often included tranquilizer and other antipsychotic drugs, administered orally or by long acting depot injections (to offset problems of patient compliance) .
  • 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.
  • 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 5 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 fj 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 5- development of tolerance (the need to increase the dose progressively so as to produce 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.
  • 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.
  • Alzheimers-type dementia One particular type of dementia is Alzheimers-type dementia.
  • Alzheimers-type of 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-trans itting 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 5 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 20 with the dose of the racemic mixture of ondansetron administered.
  • optically pure S(-) isomer of ondansetron is an effective anti-emetic agent, useful as an adjunctive therapy in cancer treatment 30 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.
  • optically pure S(-) 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-HT 3 , 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.
  • the optically pure S(-) 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 S(-) 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 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.
  • 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 S(-) ondansetron, or a pharmaceutically acceptable salt thereof, substantially free of its R(+) 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 S(-) ondansetron, or a pharmaceutically acceptable salt thereof, substantially free of its R(+) stereoisomer.
  • 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 S(-) ondansetron, or a pharmaceutically acceptable salt thereof, substantially free of its R(+) 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 S(-) ondansetron, or a pharmaceutically acceptable salt thereof, substantially free of its R(+) 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 S(-) ondansetron, or a pharmaceutically acceptable salt thereof, substantially free of its R(+) stereoisomer.
  • 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 S(-) ondansetron, or a pharmaceutically acceptable salt thereof, substantially free of its R(+) 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 S(-) ondansetron, or a pharmaceutically acceptable salt thereof., substantially free of its R(+) stereoisomer.
  • the available racemic mixture of ondansetron i.e. a 1:1 racemic mixture of stereoisomers
  • ondansetron 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 S(-) 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 S(-) 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”.
  • substantially free of its R(+) stereoisomer as used herein means that the composition contains a greater proportion of the S(-) isomer of ondansetron in relation to the R(+) isomer of ondansetron.
  • the term "substantially free of its R(+) stereoisomer” as used herein means that the composition contains at least 90 % by weight of S(-) ondansetron, and 10 % by weight or less of R(+) ondansetron. In the most preferred embodiment the term "substantially free of the R(+) stereoisomer” means that the composition contains at least 99 % by weight S(-) ondansetron, and 1 % or less of R(-r-) ondansetron.
  • eliciting an antiemetic effect means providing relief from the symptoms of nausea and vomiting induced spontaneously or associated with emetogenic cancer chemotherapy or irradiation therapy.
  • behavioral disorders such as mood anxiety., and schizophrenia
  • 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.
  • 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.
  • treating cognitive disorders 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 S(-) 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. Chromatoor.. 1975, Vol. 113, No. 3, Pg. 283-302.
  • the magnitude of a prophylactic or therapeutic dose of S(-) 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.
  • 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.
  • 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.
  • 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.
  • 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
  • Any suitable route of administration may be employed for providing the patient with an effective dosage of S(-) ondansetron.
  • 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.
  • compositions of the present invention comprise S(-) 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.
  • salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
  • 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.
  • 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 or ⁇ .1 route. They may be conveniently presented in unit dosage form, and prepared by any of the methods well known in the art of pharmacy.
  • 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.
  • Patients may be upwardly titrated within this dose range to enable the satisfactory control of- symptoms.
  • 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.
  • a suitable dosage range for use- is, e.g.
  • S(-) 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
  • 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
  • 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 5 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.
  • 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.
  • 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
  • transdermal delivery for example, via an abdominal skin patch.
  • 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.
  • 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.
  • 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.
  • 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 mg. 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 S(-) ondansetron and racemic ondansetron as competitive antagonists at o serotonin receptor subtype 5-HT 3 present in gastrointestinal, brain, and other tissues.
  • optically pure and racemic compounds may be evaluated as a function of their molar concentration, for their relative abilities to inhibit the binding of 3 H-5-HT 5 in such selected preparations as nerves of guinea pig ileum and preparations of brain tissue from several species- including rats and humans.
  • 3 H-5-HT as a radioligand with relatively high specific activity, the development of other selective 5-HT 3 0 antagonists, and the additional agonist,
  • 2-methyl-5-hydroxy-tryptamine (2-methyl-5-HT) provide the pharmacologic tools for the characterization of the 5-HT- receptor, and the evaluation of S(-), and racemic ondansetron. (see Frazer, A., et al., Annu. Rev. 5 Pharmacol. Toxicol. 3_0, 307-348, 1990).
  • the active ingredient is sieved through a suitable 0 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 5 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.
  • 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.

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Abstract

Méthodes et compositions faisant appel à l'isomère S(-) d'ondansetron optiquement pur. Ce composé est un médicament puissant utilisé pour le traitement de la nausée et des vomissements associés à la chimiothérapie et à la thérapie par rayonnement, et permet d'éviter les risques d'effets secondaires liés aux mélanges racémiques de l'ondansetron. L'isomère S(-) d'ondansetron est également utile pour le traitement des troubles du comportement tels que l'anxiété, la schizophrénie, et d'autres troubles qui peuvent être liés à l'activité de l'ondansetron S(-) come antagoniste de compétition du sous-type 5-HT3 du récepteur de la sérotonine tels que les troubles de transit gastro-intestinal, la dépression, la migraine, et comme adjuvant pour traiter le syndrome d'abstinence lors de l'arrêt de la consommation d'alcool, de nicotine et des médicaments (benzodiazépine etc.) sans le risque d'effets secondaires associés au mélange racémique d'ondansetron. L'isomère S(-) permet également de traiter les troubles de la cognition tels que la démence ou les troubles de la mémoire liés à l'âge, en évitant les risques d'effets secondaires liés au mélange racémique d'ondansetron.
EP92914351A 1991-06-26 1992-06-25 Methodes et compositions pour le traitement des vomissements, de la nausee et d'autres troubles faisant appel a l'ondansetron optiquement pur s(-) Withdrawn EP0591395A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US721723 1985-04-10
US72172391A 1991-06-26 1991-06-26
US75080191A 1991-08-27 1991-08-27
US750801 1991-08-27
PCT/US1992/005377 WO1993000075A1 (fr) 1991-06-26 1992-06-25 Methodes et compositions pour le traitement des vomissements, de la nausee et d'autres troubles faisant appel a l'ondansetron optiquement pur s(-)

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EP0591395A1 true EP0591395A1 (fr) 1994-04-13
EP0591395A4 EP0591395A4 (fr) 1994-08-31

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EP (1) EP0591395A1 (fr)
JP (1) JPH06509073A (fr)
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EP0591434A4 (en) * 1991-06-26 1994-09-14 Sepracor Inc Method and compositions for treating emesis, nausea and other disorders using optically pure r(+) ondansetron
CN1078465C (zh) * 1996-10-10 2002-01-30 沈阳药科大学 一种含奥坦西酮的透皮吸收制剂
AU779696B2 (en) 1999-03-01 2005-02-10 Sepracor, Inc. Methods for treating apnea and apnea disorders using optically pure R(+)ondansetron
US20030114475A1 (en) * 2001-10-31 2003-06-19 Addiction Therapies, Inc. Methods for the treatment of addiction
JP5004236B2 (ja) * 2005-02-09 2012-08-22 キッセイ薬品工業株式会社 口腔内崩壊錠
US20110288115A1 (en) * 2010-05-24 2011-11-24 Avmedis Llc Treatment of vagally-mediated spectrum disorders

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GB8516083D0 (en) * 1985-06-25 1985-07-31 Glaxo Group Ltd Heterocyclic compounds
GB8518745D0 (en) * 1985-07-24 1985-08-29 Glaxo Group Ltd Heterocyclic compounds
JP2608078B2 (ja) * 1986-12-17 1997-05-07 グラクソ、グループ、リミテッド 医 薬

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BR.J.PHARMACOL. vol. 94 , 1988 pages 397 - 412 A.BUTLER ET AL. 'Pharmacological properties of GR38032F, a novel antagonist at 5-HT3 receptors' *
See also references of WO9300075A1 *

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EP0591395A4 (fr) 1994-08-31
WO1993000075A1 (fr) 1993-01-07
JPH06509073A (ja) 1994-10-13
AU2254692A (en) 1993-01-25
CA2112488A1 (fr) 1993-01-07

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