WO1992013452A1 - Procedes d'utilisation et compositions de r(-) fluoxetine - Google Patents

Procedes d'utilisation et compositions de r(-) fluoxetine Download PDF

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Publication number
WO1992013452A1
WO1992013452A1 PCT/US1992/000833 US9200833W WO9213452A1 WO 1992013452 A1 WO1992013452 A1 WO 1992013452A1 US 9200833 W US9200833 W US 9200833W WO 9213452 A1 WO9213452 A1 WO 9213452A1
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Prior art keywords
fluoxetine
pharmaceutically acceptable
administered
composition
composition according
Prior art date
Application number
PCT/US1992/000833
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English (en)
Inventor
James W. Young
Timothy J. Barberich
Martin H. Teicher
Original Assignee
Young James W
Barberich Timothy J
Teicher Martin H
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Publication date
Application filed by Young James W, Barberich Timothy J, Teicher Martin H filed Critical Young James W
Publication of WO1992013452A1 publication Critical patent/WO1992013452A1/fr

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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline

Definitions

  • This invention relates to a novel composition of matter containing optically pure R(-) fluoxetine.
  • This composition possesses potent antidepressant and appetite suppressant activity as a serotonin uptake inhibitor while avoiding the usual adverse effects associated with the racemic mixture of fluoxetine.
  • this composition possesses potent activity as a serotonin uptake inhibitor which can be utilized in the treatment of migraine headaches, pain and obsessive compulsive disorders, while avoiding the usual adverse effects associated with the racemic mixture of fluoxetine. Also disclosed are methods to treat depression, migraine headaches, pain, obsessive compulsive disorders and cause appetite suppression in a human by administering pure R(-) fluoxetine. This also avoids the usual adverse effects associated with the racemic mixture of fluoxetine.
  • the active compound of this composition and method is an optical isomer of the compound fluoxetine which is described in U.S. Patent Nos. 4,018,895 and 4,194,009 to Molloy, et al. Chemically, the R(-) isomer is ( -) N-methyl-3-phenyl-3 - [ ( ⁇ , ⁇ , ⁇ -trifluoro-p-tolyl)-oxy]-propylamine, herein after referred to as R(-) fluoxetine.
  • 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 mixture 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 propranolol, which is known to be 100 times more potent than the D-enantiomer.
  • optical purity is important since certain isomers may actually be deleterious rather than simply inert. For example, it has been suggested that the
  • L-enantiomer was a potent teratogen.
  • Fluoxetine's primary use is in the treatment of depression, which along with mania falls under the heading of affective disorders.
  • Mania and depression are characterized by changes in mood as the primary symptom. Either of these two extremes of mood may be accompanied by psychosis with disordered thought and delusional perceptions.
  • Psychosis may have, as a secondary symptom, a change in mood, and it is this overlap with depression that causes much confusion in diagnosis. Severe mood changes without psychosis frequently occur in depression and are often
  • Depression is characterized by feelings of intense sadness or pessimistic worry, agitation, self-deprecation, neurovegetative changes and symptoms such as insomnia, anorexia, and loss of drive, enthusiasm, and libido, and mental slowing.
  • a tricyclic antidepressant agent is administered to depression.
  • Fluoxetine is not in the class of drugs known as tricyclic antidepressants. Its antidepressant action is presumed to be based on its highly specific inhibition of serotonin uptake in serotonergic ns in the brain. It is also chemically unrelated to
  • Fluoxetine can also be used to assist in weight loss as disclosed in U.S. Patent No. 4,895,845 to Seed.
  • the cause of excess body weight and/or obesity are complex, however a common denominator in the overweight person's diet is a caloric intake which exceeds that person's body expenditures.
  • One method of treating a person who is overweight and/or obese is to restrict that person's caloric intake, in combination with an exercise regimen. This method may be limited in its effectiveness since many overweight or obese people have developed eating and activity patterns which are counterproductive to achieving weight
  • Another method to treat overweight or obese patients is to administer appetite suppressant drugs in conjunction with a weight reduction program.
  • the drawback to this method is that many appetite
  • migraine headaches which are a paroxysmal disorder characterized by recurrent attacks of said headache, with or without associated visual and gastrointestinal disturbances.
  • the cause is unknown, but evidence suggests a genetically transmitted
  • Prodromal symptoms may be due to intracerebral
  • Migraine may occur at any age but usually beings between ages 10 and 30, more often in women than in men. Migraine headaches may be preceded by a short period of depression, irritability,
  • paresthesias or (rarely) hemiparesis. These symptoms may disappear shortly before the headache appears or may merge with it. Pain is either unilateral or generalized. Symptoms usually follow a pattern in each patient, except that unilateral headaches may not always be on the same side. The patient may have attacks daily or only once in several months.
  • Pain is a complex subjective phenomenon comprised of a sensation indicating real or potential tissue damage and the affective response this
  • Pain can be classified as either acute or chronic pain.
  • Acute pain is an essential biologic signal of the potential for or the extent of injury. It is usually short-lived and is associated with hyperactivity of the sympathetic nervous system; eg, tachycardia, increased respiratory rate and blood pressure, diaphoresis, and pupillary dilation. The concurrent affect is anxiety. Treatment involves removal of the underlying etiology if possible and the use of analgesic drugs. Chronic pain is defined as pain persisting for greater than six months. Pain of this duration loses its adaptive biologic role.
  • constipation A depressed affect predominates.
  • organic disease may be insufficient to explain the degree of pain or may be altogether absent.
  • the psychologic factors become the primary contributor to impairment. Therapy is often difficult and prognosis is guarded.
  • fluoxetine is effective in the treatment of obsessive-compulsive disorders.
  • This is a neurotic disorder characterized by the presence of recurrent ideas and concerns (obsessions) and repetitive impulses or actions (compulsions) that the patient recognizes as morbid and toward which he feels a strong inner resistance.
  • Anxiety is a central feature, but in contrast to the phobias (where the patient is anxious in the face of external dangers of which he perceives himself to be the passive victim), the anxiety arises in response to internally derived thoughts and urges that the patient fears he may actively carry out despite his wishes not to.
  • Obsessive-compulsive patients comprise less than 5% of those with neurotic disorders, and about 0.05% of the population at large. The neurosis affects men and women equally and tends to be found in individuals from upper socioeconomic levels and with higher intelligence.
  • fluoxetine is available only as a racemic mixture. That is, it is a mixture of optical isomers, called enantiomers.
  • racemic mixture of fluoxetine in addition to its use as an antidepressant and appetite suppressant, has been shown to have a wide spectrum of action which includes:
  • 5HT uptake cortical synaptasomes Ki 30 33 21 nM 1 5HT uptake cortical synaptasomes (IC50) 99.5 61 .5 nM 2 Inhibition of 3H-fluoxetine binding (IC50) 5.7 7.7 4.1 nM 1 Inhibition of 5HT uptake Ex Vivo brainstem (ED50) 9.3 8.7 7.4 mg/kg 1 Inhibition of PCPA effect on 5HT (full block) -1 0 -5 mg/kg 3 Inhibition of PCPA effect on 5HT (ED50) 2.1 1 .2 mg/kg 4 Inhibition of Feeding (meal fed, 2DG) (re). potency) R ⁇ S 2 Inhibition of Sachari ⁇ e payability (ED50) 6.1 4.9 mg/kg 4 inhibition of acetic acid writhing (ED50) 15.3 25.7 mg/kg 4
  • 5HT 1A 5HT 2 , ⁇ 1. ⁇ 2. ⁇ , D 1. D 2. H 1. and M 1 receptors, or the norepinephrine uptake port, relative to their effect on 5HT uptake.
  • racemic mixture of fluoxetine has been shown to have certain advantages over other antidepressant drugs.
  • Antagonism of muscarinic, histaminergic and ⁇ i adrenergic receptors has been hypothesized to be associated with various anticholinergic and
  • Fluoxetine binds to these and other membrane receptors from brain tissue much less potently than do these tricyclic antidepressants.
  • fluoxetine gives less anticholinergic side effects such as blurred vision, dry mouth, constipation and urinary retention. There is also less lowering of blood pressure, tachycardia and arrhythmias.
  • insomnia headaches, nervousness, anxiety and insomnia. These are reported by 10% to 15% of patients treated with fluoxetine. These symptoms led to drug discontinuation in 5% of the patients treated with the drug. With regard to insomnia, often patients being treated with fluoxetine must be administered sleep medication such as benzodiazepine hypnotics or sedating antidepressants in the evening to counteract the insomnia.
  • fluoxetine produces a state of inner restlessness (akathisia), which is one of its more significant side effects. In all likelihood this is a result of the effect fluoxetine has on dopomine
  • fluoxetine include nausea, diarrhea and drowsiness.
  • racemic mixture of fluoxetine Another disadvantage of the racemic mixture of fluoxetine is its long half-life and long duration of action. Since the S(+) isomer of fluoxetine has a half life approximately three times that of the R(-) isomer, the long half life of the racemic mixture in all likelihood can be attributable to the amount of the S(+) isomer found in the racemic mixture. This long half life can lead to a buildup of fluoxetine in the patient's body and a concomitant increase in the above described side effects when a patient is given multiple doses.
  • the R(-) isomer of fluoxetine is an effective antidepressant and appetite suppressant, which because of its short half life and short duration of action, will not accumulate in a patient's body, thus decreasing the incidence of adverse effects seen with the racemic mixture of fluoxetine. It has also been discovered that the R(-) isomer of fluoxetine is useful in the treatment of migraine headaches, the treatment of pain, in
  • administering the R(-) isomer of fluoxetine include but are not limited to headaches, nervousness, anxiety, insomnia, inner restlessness (akathisia) suicidal thoughts and self mutilation.
  • Novel compositions of matter containing optically pure R(-) fluoxetine which have antidepressant and appetite suppressant activity while avoiding the above described adverse effects associated with the racemic mixture of fluoxetine are also disclosed.
  • novel compositions of matter containing optically pure R(-) fluoxetine which are useful in the treatment of migraine headaches, the treatment of pain, in particular chronic pain, and the treatment of obsessive compulsive disorders.
  • the present invention further encompasses a method of suppressing the appetite of a patient while avoiding concomitant liability of adverse effects, comprising administering to a patient in need of
  • appetite suppression an amount sufficient to suppress the patient's appetite but insufficient to cause said adverse effects, of R(-) fluoxetine or a pharmaceutically acceptable salt thereof, substantially free of its S(+) stereoisomer.
  • the present invention encompasses a method of treating migraine headaches, pain or
  • concomitant liability of adverse effects comprising administering to a patient in need of treatment of migraine headaches, treatment of pain or treatment of obsessive compulsive disorders, an amount sufficient to treat the patient's migraine headache, pain or
  • R(-) fluoxetine or a pharmaceutically acceptable salt thereof substantially free of its S(+) stereoisomer.
  • the present invention also encompasses an
  • antidepressant composition adapted for the treatment of a patient in need of antidepressant therapy which comprises an amount sufficient to alleviate human depression but insufficient to cause adverse effects, of R(-) fluoxetine or a pharmaceutically acceptable salt thereof, substantially free of its S(+)
  • an appetite suppression composition adapted to be
  • compositions that are adapted for treating migraine headaches, pain, or obsessive compulsive disorders, comprising an amount sufficient to alleviate the above-described afflictions, but insufficient to cause adverse effects, of R(-) fluoxetine or a pharmaceutically acceptable salt thereof, substantially- free of its S(+) stereoisomer.
  • R(-) fluoxetine functions as an effective antidepressant with a shorter half life and shorter duration of action than the racemic mixture or the S(+) isomer of fluoxetine. Having a shorter half life and shorter duration of action results in less accumulation of R(-) fluoxetine in a patient's body. This in turn results in decreased adverse effects including
  • R(-) fluoxetine Because of its short half life and short duration of action, R(-) fluoxetine will have less effect at night since by this time a large portion of the compound will have been cleared from the patient's body, thus
  • MAOI monoamine oxidase inhibitors
  • pure R(-) fluoxetine is of greater use as an appetite suppressant, since as discussed above the short half life and short duration of action will lead to a decrease in adverse effects.
  • pure R(-) fluoxetine is a more effective appetite suppressant since the racemic mixture and both isomers of fluoxetine effectively suppress the appetite only when given before meals. Because of their long half life and duration of action this would lead to unnecessary accumulation of the racemic mixture or the S(+) isomer of fluoxetine if they are administered in multiple doses. By administering the pure R(-) isomer of fluoxetine, with its shorter half life, this unnecessary accumulation and adverse effects can be avoided.
  • pure R(-) fluoretine is also more effective for the treatment of migraine headaches, the treatment of pain, in particular chronic pain and to treat obsessive compulsive disorders, since as
  • the shorter half-life and short duration of action of the R(-) isomer of fluoxetine allows for treatment of the symptoms on an acute basis and also prophylactically, without the previously described adverse effects or complications.
  • Another advantage of the present invention is the purity of the R(-) isomer of fluoxetine. Using the pure R(-) isomer of fluoxetine as opposed to the racemic mixture or S(+) isomer, leads to a decrease in side effects also.
  • the term "substantially free of the S(+) stereoisomer” means that the composition contains at least 90% by weight of R(-) fluoxetine and 10% by weight or less of S(+) fluoxetine. In the most preferred embodiment the term "substantially free of the S(+) stereoisomer” means that the composition contains at least 99% by weight R(-) fluoxetine and 1% or less of S(+) fluoxetine.
  • depression which include but are not limited to feelings of intense sadness or pessimistic worry, agitation, self-deprecation, neurovegetative changes and symptoms such as insomnia, anorexia, and loss of drive, enthusiasm and libido and mental slowing.
  • headaches include but is not limited to headaches, nervousness, anxiety, insomnia, inner restlessness (akathisia), suicidal thoughts, self mutilation, manic behavior, nausea, diarrhea and drowsiness.
  • This method is disclosed in Gao, et al. J. Org. Chem. Vol. 53, No. 17, pp. 4081-4084 (1988). It involves the use of 1-phenyl-1,3-propanediols, which are key intermediates.
  • the 1-phenyl-1,3-propanediols are prepared from cinnamyl epoxy alcohols by Red - AL reduction.
  • the chiral cinnamyl epoxy alcohols are made by, asymmetric epoxidation of cinnamyl alcohols as disclosed in Gao, et al.
  • (S)-(+) fluoxetine hydrochloride is prepared from (2R) - Epoxycinnamyl alcohol obtained by the asymmetric epoxidation disclosed in Gao et al. utilizing (-)-DIPT.
  • This method is based on the asymmetric reduction of ketone with a chiral borane reagent as disclosed in U.S. Patent No. 4,868,344 to H.C. Brown.
  • R(-) fluoxetine The magnitude of a prophylactic or therapeutic dose of R(-) fluoxetine will, of course, vary with the nature of the severity of the condition to be treated and its route of administration. It will also vary according to the age, weight and response of the individual patient.
  • the daily dose range for use as an anti-depressant or appetite suppressant, and for the treatment of migraine headaches, treatment of pain, in particular chronic pain and treatment of obsessive compulsive disorders lie within the range of from about 1 mg to about 100 mg per day, preferably about 5 mg to about 60 mg per day, and most preferably from about 10 mg to about 40 mg per day, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.
  • an amount sufficient to alleviate said human's depression but insufficient to cause said adverse effects and “an amount sufficient to suppress the appetite of said human but insufficient to cause said adverse effects” are encompassed by the above-described amounts. Furthermore, the terms “an amount sufficient to alleviate said human's migraine headaches, pain or obsessive compulsive disorder but insufficient to cause said adverse effects” is encompassed by the above described amounts.
  • R(-) fluoxetine Any suitable route of administration may be employed for providing the patient with an effective dosage of R(-) fluoxetine.
  • oral, rectal, parenteral, transdermal, subcutaneous, intramuscular, inhalation 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 R(-) fluoxetine as an active
  • 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,
  • hydrobromic, hydrochloric, phosphoric and sulfuric acids are particularly preferred.
  • compositions include compositions suitable for oral, rectal, 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 route of the present invention is oral. 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 1 mg to about 100 mg of fluoxetine per day, preferably from about 5 mg to about 60 mg per day and most preferably from about 10 mg to about 40 mg per day.
  • R(-) fluoxetine 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).
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or
  • tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously 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;
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets 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
  • 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 binner, 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 1 mg to about 100 mg of the active ingredient and each cachet or capsule contains from about 1 to about 100 mg of the active ingredient. Most preferably the tablet, cachet or capsule contains about 1 mg to about 60 mg of active ingredient of active ingredient.
  • hydrochloride (8) as a white powder (1.90 g, 75%): mp 140-142°C (lit. 133b mp 140-141.5°C; [ ⁇ ] 23 D-2.16° (c 1.62, MeOH); (lit. 133b [ ⁇ ] 23 D-1.97° [c 1.00, MeOH]); [ ⁇ ] 23 D +7.08° (c 1.30, H 2 O); (lit.
  • (S)-Fluoxetine hydrochloride was prepared by the above procedure from (S)-N-methyl-3-phenyl-3-hydroxypropylamine: mp 140-142°C (lit 133b mp 135-137°C); [ ⁇ ] 23 D -7.12° (c 1.53, H 2 O) ; lit 133b [ ⁇ ] 23 D -10.85° [c 1.00, H 2 O]); Anal. Calcd. for C 17 H 19 ClF 3 NO: C, 59.05; H, 5.54; N, 4.05. Found: C, 59.19; H, 5.42; N, 3.89.
  • DA dopamine
  • NE norepinephrine
  • tissue is centrifuged for 10 minutes at 900 ⁇ g, and the resulting
  • Each assay tube contains 50 ⁇ l of cerebral homogenate, plus 3 H-monoamine and test agents
  • Tubes are incubated at 37°C for 10 minutes with 3 H-DA (26.0 Ci/mmol), and for 20 minutes with 3 H-5HT (23.4 Ci/mmol) and 3 H-NE (11.8
  • Blanks (incubated at 0°C, or with specific uptake inhibitors of DA [GBR-12909 10 ⁇ M], 5HT [zimelidine 10 ⁇ M], or NE [desipramine 10 ⁇ M ] are usually indistinguishable for assays without tissue, and average 2-3% of total CPM.
  • Tissue sections are removed from frontal cortex, striatum, hippocampus and hypothalamus. Tissue specimens are frozen at -70°C, and will then be assayed for levels of DA, NE, 5HT, DOPAC, HVA, and 5HIAA using High
  • Tissue sections are also obtained for measurement of brain levels of fluoxetine, to ascertain whether there are any significant acute pharmacokinetic differences in brain transport.
  • Tissue samples from one hemisphere are used to assay for residual 5HT concentrations.
  • Tissue samples from the other hemisphere, and plasma sample are used to determine levels of fluoxetine and its desmethyl metabolite. Drug levels are not measured at every time point, but these samples are collected and frozen at -70°C, so that drug levels can be
  • the active ingredient, lactose and corn starch are blended until uniform; then the magnesium stearate is blended into the resulting powder.
  • the resulting mixture is encapsulated into suitably sized two-piece hard gelatin capsules.
  • the active ingredient is blended with the lactose until a uniform blend is formed.
  • the smaller quantity of cornstarch is blended with the water to form the resulting corn starch paste. This is then mixed with said uniform blend and mixed until a uniform wet mass is formed.
  • the remaining corn starch is added to the resulting wet mass and mixed until uniform granules are obtained.
  • the granules are then screened through a suitable milling machine, using a 1/4 inch stainless steel screen.
  • the milled granules are then dried in a suitable drying oven until the desired moisture content is obtained.
  • the dried granules are then milled through a suitable milling machine using 1/4 mesh stainless steel screen.
  • the magnesium stearate is then blended and the resulting mixture is compressed into tablets of desired shape, thickness, hardness and disintegration.

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Abstract

Procédé et composition utilisant l'isomère R(-) pur de fluoxétine constituant un antidépresseur et un inhibiteur de l'appétit, sans effet secondaire indésirable. L'invention concerne également un procédé et une composition utilisant l'isomère R(-) pur de fluoxétine, lequel est utile dans le traitement de la migraine, de céphalée, de douleur, notamment de douleur chronique et de troubles compulsifs obsessionnels.
PCT/US1992/000833 1991-02-04 1992-02-03 Procedes d'utilisation et compositions de r(-) fluoxetine WO1992013452A1 (fr)

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US65038591A 1991-02-04 1991-02-04
US650,385 1991-02-04

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Cited By (4)

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LT4477B (lt) 1997-05-29 1999-03-25 Eli Lilly And Company Fluoksetino enterinės piliulės
WO1999061014A2 (fr) * 1998-05-28 1999-12-02 Sepracor Inc. Compositions et methodes utilisant de la r(-) fluoxetine et d'autres ingredients actifs
WO2003011272A1 (fr) * 2001-07-31 2003-02-13 Pharmacia & Upjohn Company Traitement des douleurs chroniques au moyen de 3-aryloxy-3-phenylpropanamines
US7229640B2 (en) 1995-07-20 2007-06-12 Smithkline Beecham P.L.C. Paroxetine controlled release compositions

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US4018895A (en) * 1974-01-10 1977-04-19 Eli Lilly And Company Aryloxyphenylpropylamines in treating depression
US4194009A (en) * 1974-01-10 1980-03-18 Eli Lilly And Company Aryloxyphenylpropylamines for obtaining a psychotropic effect
US4918242A (en) * 1988-03-30 1990-04-17 Aldrich Chemical Company, Inc. Novel optically 1,3-phenoxypropylhalides

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US4018895A (en) * 1974-01-10 1977-04-19 Eli Lilly And Company Aryloxyphenylpropylamines in treating depression
US4194009A (en) * 1974-01-10 1980-03-18 Eli Lilly And Company Aryloxyphenylpropylamines for obtaining a psychotropic effect
US4918242A (en) * 1988-03-30 1990-04-17 Aldrich Chemical Company, Inc. Novel optically 1,3-phenoxypropylhalides

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Title
ACTA PHARMACEUTICA NORDIZA, Vol. 2, Number 3, issued 1990, WONG et al., "Fluoxetine and its two enantiomers as selective serotonin uptake inhibitors", pages 171-180. *
DRUGS, Vol. 32, issued 1986, BENFIELD et al., "Flioxetine a review of its pharmacodynamic and Pharmacokinetic properties, and Therapeutic Efficacy in Repressive Illnes", pages 481-508. *
TETRAHEDRON LETTERS, Vol. 30, No. 39, issued 1989, COREY et al., "Enantioselective and Partial Synthesis of R - and S - Fluoxetines", pages 5207-5210. *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7229640B2 (en) 1995-07-20 2007-06-12 Smithkline Beecham P.L.C. Paroxetine controlled release compositions
LT4477B (lt) 1997-05-29 1999-03-25 Eli Lilly And Company Fluoksetino enterinės piliulės
US5910319A (en) * 1997-05-29 1999-06-08 Eli Lilly And Company Fluoxetine enteric pellets and methods for their preparation and use
US5985322A (en) * 1997-05-29 1999-11-16 Eli Lilly And Company Method for the treatment of CNS disorders
AT408068B (de) * 1997-05-29 2001-08-27 Lilly Co Eli Fluoxetinpellets
USRE39030E1 (en) 1997-05-29 2006-03-21 Eli Lilly And Company Fluoxetine enteric pellets and methods for their preparation and use
WO1999061014A2 (fr) * 1998-05-28 1999-12-02 Sepracor Inc. Compositions et methodes utilisant de la r(-) fluoxetine et d'autres ingredients actifs
WO1999061014A3 (fr) * 1998-05-28 2000-07-20 Sepracor Inc Compositions et methodes utilisant de la r(-) fluoxetine et d'autres ingredients actifs
WO2003011272A1 (fr) * 2001-07-31 2003-02-13 Pharmacia & Upjohn Company Traitement des douleurs chroniques au moyen de 3-aryloxy-3-phenylpropanamines

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