Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
• • 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
  • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
  • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
• • 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
  • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • 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
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • 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
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
• • 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
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
  • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants

Definitions

• the present invention belongs to the fields of pharmacology, medicine and medicinal chemistry, and provides antipsychotic methods and compositions.
• Psychoses are serious mental illnesses characterized by defective or lost contact with reality. Psychotic patients may also suffer hallucinations and delusions as part of their disease. Psychoses exact a tremendous emotional and economic toll on the patients, their families, and society as a whole. While the mechanisms underlying these diverse disease states are poorly understood, recently discovered therapies are offering new hope for the treatment of psychotic patients. Progress in the treatment of psychotic conditions has been achieved through the introduction of new, atypical antipsychotic agents. While the side effect profile of these atypical antipsychotics is far superior to that of traditional agents, weight gain is a side effect that has been observed in patients treated with the atypical antipsychotics .
• the invention provides a method for treating a patient suffering from or susceptible to psychosis, acute mania, mild anxiety states, or depression in combination with psychotic episodes, comprising administering to said patient an effective amount of a first component which is an atypical antipsychotic, in combination with an effective amount of a second component which is a serotonin reuptake inhibitor .
• the invention also provides a pharmaceutical composition which comprises a first component which is an atypical antipsychotic, and a second component which is a serotonin reuptake inhibitor.
• a pharmaceutical composition which comprises a first component which is an atypical antipsychotic, and a second component which is a serotonin reuptake inhibitor.
• the first component is a compound which acts as an atypical antipsychotic.
• the essential feature of an atypical antipsychotic is less acute extrapyra idal symptoms, especially dystonias, associated with therapy as compared to a typical antipsychotic such as haloperidol .
• Clozapine the prototypical atypical antipsychotic, differs from the typical antipsychotics with the following characteristics: (1) greater efficacy in the treatment of overall psychopathology in patients with schizophrenia nonresponsive to typical antipsychotics; (2) greater efficacy in the treatment of negative symptoms of schizophrenia; and (3) less frequent and quantitatively smaller increases in serum prolactin concentrations associated with therapy (Beasley, et al . ,
• Atypical antipsychotics include, but are not limited to:
• Olanzapine 2 -methyl-4- (4-methyl-l-piperazinyl ) - lOH-thieno [2 , 3-b] [1 , 5] benzodiazepine, is a known compound and is described in U.S. Patent No. 5,229,382 as being useful for the treatment of schizophrenia, schizophreniform disorder, acute mania, mild anxiety states, and psychosis.
• U.S. Patent No. 5,229,382 is herein incorporated by reference in its entirety; Clozapine, 8-chloro-ll- (4-methyl-l-piperazinyl ) -
• Quetiapine 5- [2- (4-dibenzo [b, f ] [1, 4] thiazepin-11- yl-1-piperazinyl) ethoxy] ethanol, and its activity in assays which demonstrate utility in the treatment of schizophrenia are described in U.S. Patent No. 4,879,288, which is herein incorporated by reference in its entirety.
• Quetiapine is typically administered as its (E) -2-butenedioate (2:1) salt; and
• Fluoxetine N-methyl-3- (p-trifluoro ethylphenoxy) - 3-phenylpropylamine, is marketed in the hydrochloride salt form, and as the racemic mixture of its two enantiomers.
• U.S. Patent 4,314,081 is an early reference on the compound. Robertson et al., J. Med. Chem. 31. 1412 (1988), taught the separation of the R and S enantiomers of fluoxetine and showed that their activity as serotonin uptake inhibitors is similar to each other.
• fluoxetine will be used to mean any acid addition salt or the free base, and to include either the racemic mixture or either of the R and S enantiomers
• Duloxetine N-methyl-3- ( 1-naphthalenyloxy) -3- (2- thienyl)propanamine, is usually administered as the hydrochloride salt and as the (+) enantiomer. It was first taught by U.S. Patent 4,956,388, which shows its high potency.
• the word “duloxetine” will be used here to refer to any acid addition salt or the free base of the molecule;
• Patent 4,136,193 as a serotonin reuptake inhibitor. Its pharmacology was disclosed by Christensen et al., Eur . J . Pharmacol . 41, 153 (1977), and reports of its clinical effectiveness in depression may be found in Dufour et al., Int. Clin. Psvchopharmacol . 2 . , 225 (1987), and Timmerman _____ _____. , ibid., 239;
• first and second component compounds While all combinations of first and second component compounds are useful and valuable, certain combinations are particularly valued and are preferred, as follows : olanzapine/ fluoxetine olanzapine/venlafaxine olanzapine/citralopram olanzapine/ fluvoxamine olanzapine/paroxetine olanzapine/sertraline olanzapine/milnacipran olanzapine/duloxetine clozapine/fluoxetine risperidone/fluoxetine sertindole/fluoxetine quetiapine/fluoxetine ziprasidone/fluoxetine
• combinations and methods of treatment using fluoxetine as the second component are preferred.
• combinations and methods of treatment using olanzapine as the first component and fluoxetine as the second component are preferred.
• the first component is olanzapine
• it will be the Form II olanzapine polymorph having a typical x-ray powder diffraction pattern as represented by the following interplanar spacings:
• a typical example of an x-ray diffraction pattern for Form II is as follows wherein d represents the interplanar spacing and I/Ii represents the typical relative intensities : d I/Il
• the x-ray diffraction patterns set out herein were obtained using a Siemens D5000 x-ray powder diffractometer having a copper K ⁇ radiation source of wavelength, ⁇
• Form II olanzapine polymorph will be administered as the substantially pure Form II olanzapine polymorph.
• substantially pure refers to Form II associated with less than about 5% Form I, preferably less than about 2% Form I, and more preferably less than about 1% Form I. Further, “substantially pure” Form II will contain less than about 0.5% related substances, wherein
• Form II refers to undesired chemical impurities or residual solvent or water.
• substantially pure Form II should contain less than about 0.05% content of acetonitrile, more preferably, less than about 0.005% content of acetonitrile.
• the polymorph of the invention should contain less than 0.5% of associated water.
• the polymorph obtainable by the process taught in the '382 patent will be designated as Form I and has a typical x-ray powder diffraction pattern substantially as follows, obtained using a Siemens D5000 x-ray powder diffractometer, wherein d represents the interplanar spacing :
• the interplanar spacings in the column marked “d” are in Angstroms.
• the typical relative intensities are in the column marked "I/Ii”.
• N-Methylpiperazine (reagent) 6 equivalents
• Intermediate 1 can be prepared using methods known to the skilled artisan. For example, the preparation of the Intermediate 1 is taught in the '382 patent.
• a sub-surface nitrogen sparge line was added to remove the ammonia formed during the reaction.
• the reaction was heated to 120°C and maintained at that temperature throughout the duration of the reaction.
• the reactions were followed by HPLC until 2 5% of the intermediate 1 was left unreacted.
• the mixture was allowed to cool slowly to 20°C (about 2 hours) .
• the reaction mixture was then transferred to an appropriate three neck round bottom flask and water bath.
• the reaction slurry was cooled to zero to 5°C and stirred for 30 minutes.
• the product was filtered and the wet cake was washed with chilled methanol .
• the wet cake was dried in vacuo at 45°C overnight.
• the product was identified as technical olanzapine.
• salts thus are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, aerylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenyl
• the dosages of the drugs used in the present invention must, in the final analysis, be set by the physician in charge of the case, using knowledge of the drugs, the properties of the drugs in combination as determined in clinical trials, and the characteristics of the patient, including diseases other than that for which the physician is treating the patient.
• General outlines of the dosages, and some preferred dosages, can and will be provided here. Dosage guidelines for some of the drugs will first be given separately; in order to create a guideline for any desired combination, one would choose the guidelines for each of the component drugs .
• Risperidone from about 0.25 to 16 mg daily; preferred from about 2-8 mg daily;
• Quetiapine from about 1.0 to 40 mg/kg given once daily or in divided doses;
• Ziprasidone from about 5 to 500 mg daily; preferred from about 50 to 100 mg daily;
• Venlafaxine from about 10 to about 150 mg once- thrice/day; preferred, from about 25 to about 125 mg thrice/day; Milnacipran: from about 10 to about 100 mg once- twice/day; preferred, from about 25 to about 50 mg twice/day; Citalopram: from about 5 to about 50 mg once/day; preferred, from about 10 to about 30 mg once/day;
• Sertraline from about 20 to about 500 mg once/day; preferred, from about 50 to about 200 mg once/day;
• the adjunctive therapy of the present invention is carried out by administering a first component together with the second component in any manner which provides effective levels of the compounds in the body at the same time.
• All of the compounds concerned are orally available and are normally administered orally, and so oral administration of the adjunctive combination is preferred. They may be administered together, in a single dosage form, or may be administered separately.
• adjunctive combination may be administered as a single pharmaceutical composition, and so pharmaceutical compositions incorporating both compounds are important embodiments of the present invention.
• Such compositions may take any physical form which is pharmaceutically acceptable, but orally usable pharmaceutical compositions are particularly preferred.
• Such adjunctive pharmaceutical compositions contain an effective amount of each of the compounds, which effective amount is related to the daily dose of the compounds to be administered.
• Each adjunctive dosage unit may contain the daily doses of all compounds, or may contain a fraction of the daily doses, such as one-third of the doses .
• each dosage unit may contain the entire dose of one of the compounds, and a fraction of the dose of the other compounds. In such case, the patient would daily take one of the combination dosage units, and one or more units containing only the other compounds.
• the amounts of each drug to be contained in each dosage unit depends on the identity of the drugs chosen for the therapy, and other factors such as the indication for which the adjunctive therapy is being given.
• compositions contain from about 0.5% to about 50% of the compounds in total, depending on the desired doses and the type of composition to be used.
• the amount of the compounds is best defined as the effective amount, that is, the amount of each compound which provides the desired dose to the patient in need of such treatment.
• adjunctive combinations do not depend on the nature of the composition, so the compositions are chosen and formulated solely for convenience and economy. Any of the combinations may be formulated in any desired form of composition. Some discussion of different compositions will be provided, followed by some typical formulations.
• Capsules are prepared by mixing the compound with a suitable diluent and filling the proper amount of the mixture in capsules.
• the usual diluents include inert powdered substances such as starch of many different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders .
• Tablets are prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants and disintegrators as well as the compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders.
• Enteric formulations are often used to protect an active ingredient from the strongly acid contents of the stomach. Such formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in acid environments, and soluble in basic environments. Exemplary films are cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate. It is preferred to formulate duloxetine and duloxetine-containing combinations as enteric compositions, and even more preferred to formulate them as enteric pellets.
• a preferred duloxetine enteric formulation is a pellet formulation comprising a) a core consisting of duloxetine and a pharmaceutically acceptable excipient; b) an optional separating layer; c) an enteric layer comprising hydroxypropylmethylcellulose acetate succinate (HPMCAS) and a pharmaceutically acceptable excipient; d) an optional finishing layer.
• HPMCAS hydroxypropylmethylcellulose acetate succinate
• Tablets are often coated with sugar as a flavor and sealant.
• the compounds may also be formulated as chewable tablets, by using large amounts of pleasant -tasting substances such as mannitol in the formulation, as is now well-established practice.
• Instantly dissolving tablet-like formulations are also now frequently used to assure that the patient consumes the dosage form, and to avoid the difficulty in swallowing solid objects that bothers some patients .
• Cocoa butter is a traditional suppository base, which may be modified by addition of waxes to raise its melting point slightly.
• Water-miscible suppository bases comprising, particularly, polyethylene glycols of various molecular weights are in wide use, also. Transdermal patches have become popular recently.
• Hard gelatin capsules are prepared using the following ingredients:
• Formulation 2 A tablet is prepared using the ingredients below:
• Formulation 3 An aerosol solution is prepared containing the following components:
• Tablets each containing 80 mg of active ingredient, are made as follows:
• the active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly.
• the aqueous solution containing polyvinyl- pyrrolidone is mixed with the resultant powder, and the mixture then is passed through a No. 14 mesh U.S. sieve.
• the granules so produced are dried at 50°C and passed through a No. 18 mesh U.S. Sieve.
• the sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No . 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 170 mg .
• Capsules each containing 130 mg of active ingredient, are made as follows:
• Formulation 6 Suppositories, each containing 45 mg of active ingredient, are made as follows:
• the active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.
• Formulation 7 Suspensions, each containing 70 mg of active ingredient per 5 ml dose, are made as follows:
• the active ingredient is passed through a No . 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste.
• the benzoic acid solution, flavor and color are diluted with a portion of the water and added, with stirring. Sufficient water is then added to produce the required volume.
• An intravenous formulation may be prepared as follows :
• the present invention also is useful for the treatment of premenstrual syndrome (PMS) and anorexia nervosa. Furthermore, the present invention is useful for the treatment of the agression/violence which may be associated with certain disorders. These disorders include, but are not limited to, mania, schizophrenia, schizoaffective disorders, substance abuse, head injury, and mental retardation.
• Psychotic conditions to be treated by the present method of adjunctive therapy include schizophrenia, schizophreniform diseases, acute mania, schizoaffective disorders, and depression with psychotic features.
• the titles given these conditions represent multiple disease states .
• the following list illustrates a number of these disease states, many of which are classified in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, published by the American Psychiatric Association (DSM) .
• the DSM code numbers for these disease states are supplied below, when available, for the convenience of the reader .
• Psychoses are often associated with other diseases and conditions, or caused by such other conditions. For example, they are associated with neurological conditions, endocrine conditions, metabolic conditions, fluid or electrolyte imbalances, hepatic or renal diseases, and autoimmune disorders with central nervous system involvement. Psychoses may also be associated with use or abuse of certain substances. These substances include, but are not limited to cocaine, methylphenidate, dexmethasone, amphetamine and related substances, cannabis, hallucinogens, inhalants, opioids, phencyclidine, sedatives, hypnotics and anxiolytics. Psychotic disorders may also occur in association with withdrawal from certain substances. These substances include, but are not limited to, sedatives, hypnotics and anxiolytics. The embodiments of the present invention are useful for treatment of psychotic conditions associated with any of these conditions.
• Sprague-Dawley rats (Harlan or Charles River) weighing 270-300 grams are surgically implanted with microdialysis probes under chloral hydrate/pentobarbital anesthesia (170 and 36 mg/kg i.p. in 30% propylene glycol, 14% ethanol) (Perry and Fuller, Effect of fluoxetine on serotonin and dopamine concentration in rat hypothalamus after administration of fluoxetine plus L-5-hydroxytrypto- phan, Life Sci .. 50, 1683-90 (1992)).
• a David Kopf stereotaxic instrument is used to implant the probe unilaterally in the hypothalamus at coordinates rostral -1.5 mm, lateral -1.3 mm, and ventral -9.0 mm (Paxinos and Watson, 1986) .
• rats are placed in a large plastic bowl with a mounted liquid swivel system (CMA/120 system for freely moving animals, Bioanalytical Systems, West Lafayette, IN) .
• Filtered artificial cerebrospinal fluid (CSF) 150 mM NaCl, 3.0 mM KCl, 1.7 mM CaC12, and 0.9 mM MgC12
• CSF cerebrospinal fluid
• the output dialysate line is fitted to a tenport HPLC valve with a 20 ⁇ l loop. At the end of each 30 minute sampling period, dialysate collected in the loop is injected on an analytical column (Spherisorb 3 ⁇ ODS2, 2X150 mm, Keystone Scientific) .
• the method used to measure monoamines is as described by Perry and Fuller (1992). Briefly, dialysate collected in the 20 ⁇ l loop is assayed for 5-HT, NE and DA. The 20 ⁇ l injection goes onto the column with a mobile phase which resolves NE, DA, and 5-HT: 75 M potassium acetate, 0.5 mM ethylenediaminetetraacetic acid, 1.4 mM sodium octanesulfonic acid and 8% methanol, pH 4.9.
• the mobile phase for the amine column is delivered with a flow programmable pump at an initial flow rate of 0.2 ml/min increasing to 0.3 ml/min at 5 in then decreasing back to
• the electrochemical detector (EG&G, Model 400) for the amine column is set at a potential of 400 mV and a sensitivity of 0.2 nA/V. Basal levels are measured for at least 90 minutes prior to drug administration.
• the drugs are prepared in filtered deionized water (volume 0.25-0.3 ml) for administration at the desired doses.

Landscapes

• Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Life Sciences & Earth Sciences (AREA)
• Public Health (AREA)
• Chemical & Material Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Neurology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Neurosurgery (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Biomedical Technology (AREA)
• Psychiatry (AREA)
• Pain & Pain Management (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Priority Applications (12)

Applications Claiming Priority (2)

Publications (1)

Family

ID=21834363

Family Applications (1)

Country Status (29)

Cited By (20)

Families Citing this family (55)

Family Cites Families (8)

• 1997
  • 1997-09-04 ZA ZA977967A patent/ZA977967B/xx unknown
  • 1997-09-09 UA UA99031565A patent/UA62937C2/uk unknown
  • 1997-09-09 IL IL16183397A patent/IL161833A0/xx not_active IP Right Cessation
  • 1997-09-09 RS YUP-152/99A patent/RS49828B/sr unknown
  • 1997-09-09 CN CNB971981132A patent/CN1162156C/zh not_active Expired - Lifetime
  • 1997-09-09 KR KR10-1999-7002422A patent/KR100532901B1/ko not_active Expired - Lifetime
  • 1997-09-09 WO PCT/US1997/015874 patent/WO1998011897A1/en not_active Ceased
  • 1997-09-09 CZ CZ0098799A patent/CZ301154B6/cs not_active IP Right Cessation
  • 1997-09-09 JP JP10514717A patent/JP2001503031A/ja active Pending
  • 1997-09-09 IL IL12873097A patent/IL128730A0/xx not_active IP Right Cessation
  • 1997-09-09 AU AU44112/97A patent/AU719033C/en not_active Expired
  • 1997-09-09 EA EA199900324A patent/EA001317B1/ru not_active IP Right Cessation
  • 1997-09-09 PL PL97332481A patent/PL190374B1/pl unknown
  • 1997-09-09 NZ NZ334168A patent/NZ334168A/xx not_active IP Right Cessation
  • 1997-09-09 CA CA002264941A patent/CA2264941C/en not_active Expired - Lifetime
  • 1997-09-09 BR BR9711530A patent/BR9711530A/pt active Search and Examination
  • 1997-09-09 HU HU9903905A patent/HU228178B1/hu unknown
  • 1997-09-12 TW TW086113280A patent/TW541178B/zh not_active IP Right Cessation
  • 1997-09-16 MY MYPI97004299A patent/MY125564A/en unknown
  • 1997-09-19 PE PE1997000840A patent/PE110198A1/es not_active Application Discontinuation
  • 1997-09-19 AR ARP970104324A patent/AR008462A1/es active IP Right Grant
  • 1997-09-19 CO CO97054849A patent/CO4900058A1/es unknown
  • 1997-09-22 AT AT97307375T patent/ATE231724T1/de active
  • 1997-09-22 ES ES97307375T patent/ES2191152T3/es not_active Expired - Lifetime
  • 1997-09-22 DK DK97307375T patent/DK0830864T3/da active
  • 1997-09-22 DE DE69718731T patent/DE69718731T2/de not_active Expired - Lifetime
  • 1997-09-22 EP EP97307375A patent/EP0830864B9/en not_active Expired - Lifetime
  • 1997-09-23 EG EG98197A patent/EG24660A/xx active
  • 1997-09-23 US US08/935,872 patent/US6147072A/en not_active Expired - Lifetime
• 1999
  • 1999-03-22 NO NO19991381A patent/NO319166B1/no not_active IP Right Cessation

Non-Patent Citations (3)

Also Published As

Similar Documents

Legal Events