Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-08-07
2002-03-05
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S810000, C514S811000, C514S812000, C424S451000, C424S464000
Reexamination Certificate
active
06352984
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to methods of treating psychosis, acute mania, mild anxiety states, schizophrenia, bipolar disorder, autistic disorder, excessive aggression, substance abuse, depressive signs and symptoms, tic disorder, functional bowel disorder and fungal dermatitis.
BACKGROUND OF THE INVENTION
Olanzapine I is an orally active, potent, antipsychotic agent.
It is commercially available as Zyprexa® from Eli Lilly Co. The antipsychotic effect of olanzapine is ascribed by the literature to blocking of the dopamine D
2
receptor and to 5-HT antagonism.
One of the main serum metabolites of olanzapine is olanzapine-4′-N-oxide H, formed by oxidation of the nitrogen at the 4-position of the piperazinyl ring. The chemical name of II is 2-methyl-4-(4-methyl-4-oxido-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiszepine and hereinafter is referred to as olanzapine-N-oxide.
Because olanzapine is oxidized to olanzapine-N-oxide in the liver by P450 enzymes, drug-drug interactions arise from the concomitant administration of other drugs that stimulate or inhibit P450 or rely on P450 enzymes for their disposition. The human liver flavin-containing monooxygenase (FMO3) is involved in the metabolism of olanzapine-N-oxide. Exemplary drugs metabolized by the FMO3 enzyme include cimetidine and tamoxifen.
It is therefore desirable to find a compound with the advantages of olanzapine which would provide a more predictable dosage regimen in the patient population and that would decrease the chances for drug-drug interaction.
SUMMARY OF THE INVENTION
The present invention relates to use of olanzapine-N-oxide for treating psychosis, acute mania, mild anxiety states, anxiety disorders, schizophrenia, bipolar disorder, nautistic disorder, attention deficit hyperactivity disorder (“ADHD”), excessive aggression, substance abuse, depressive signs and symptoms, tic disorder, functional bowel disorder and fungal dermatitis. It provides this effective treatment while exhibiting fewer or less severe adverse effects than olanzapine, a lessened liability toward drug-drug interactions than olanzapine and a more predictable dosing regimen than olanzapine.
The invention also relates to pharmaceutical compositions comprising olanzapine-N-oxide. In one embodiment, said pharmaceutical compositions comprise solid unit dosage forms such as tablets or capsules, containing olanzapine-N-oxide.
DETAILED DESCRIPTION OF THE INVENTION
The active compound of the compositions and methods of the present invention is olanzapine-N-oxide. It may be prepared as described by Calligaro et al., [
Biorg.
&
Med. Chem. Letters,
25-30, (1997)], the disclosure of which is incorporated herein by reference. Calligaro concludes that the “data demonstrate that all metabolites are significantly less active than olanzapine. It is therefore unlikely that the activity of these agents contributes to the overall pharmacological profile of the parent compound.” Galatsis [
Annual Reports in Medicinal Chemistry
32, 313, (1997)] also states that olanzapine's “ten metabolic products are inactive.” Kando et al. [
The Annals of Pharmacotherapy,
31, 1325-1334, (1997)] report that the metabolites “lack antipsychotic activity at the concentrations that have been observed.”
It has now been discovered that olanzapine-N-oxide is a superior agent for treating psychoses such as acute mania and schizophrenia, mild anxiety states, anxiety disorders, bipolar disorder, autistic disorder, excessive aggression, attention deficit hyperactivity disorder (“ADHD”), substance abuse, depressive signs and symptoms, tic disorder, functional bowel disorder and fungal dermatitis. In particular, the methods and compositions of the present invention may be used to treat humans suffering from such conditions. Olanzapine-N-oxide provides this effective treatment while exhibiting fewer or less severe adverse effects than olanzapine, a lessened liability toward drug-drug interactions than olanzapine and a more predictable dosing regimen than olanzapine.
Adverse effects of olanzapine include postural hypotension, constipation, dry mouth, weight gain, dizziness, fast heart beat, personality disorder and akathisia. Other side effects of olanzapine include tachycardia, irregular pulse, diaphoresis, cardiac dysrhythmia, flu syndrome, nausea, vomiting, hematuria, metrorrhagia, urinary. incontinence, abdominal pain, premenstrual syndrome, somnolence, agitation, insomnia, nervousness, headache, dyspnea, tremors, myoglobinuria (rhabdomyolysis), drug-induced Parkinsonism, amblyopia, and asthenia.
The present invention encompasses a method of treating psychosis which comprises administering to a human in need of such therapy, an amount of olanzapine-N-oxide or a pharmaceutically acceptable salt thereof, said amount being sufficient to alleviate the symptoms of the psychotic condition. Psychotic conditions of particular interest in humans include, but are not limited to, ADHD, schizophrenia and acute mania.
The present invention also encompasses an oral composition which comprises a pharmaceutically acceptable carrier for oral administration and a therapeutically effective amount of olanzapine-N-oxide or a pharmaceutically acceptable salt thereof. Preferably the composition is in the form of a tablet or capsule, and the amount of olanzapine-N-oxide in the tablet or capsule is preferably about 1 to 150 mg.
A pharmaceutical composition of the present invention may also contain a therapeutically effective amount of a selective serotonin reuptake inhibitor in addition to a therapeutically effective amount of olanzapine-N-oxide or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier for oral administration. Selective serotonin reuptake inhibitors include, but are not limited to paroxetine (PAXIL®), fluoxetine (PROZAC®), sertaline (ZOLOFT®), fluvoxamine (LUVOX®), venlafaxine (EFFEXOR®), and nefazodone (SERZONE®), as well as any optically pure isomers or metabolites of any of these compounds.
The present invention further encompasses a method of treating bipolar disorder, anxiety disorder, tic disorder, autistic disorder, excessive aggression, ADHD, substance abuse, and signs and symptoms of depression and of treating conditions caused or contributed to by any of these. The method comprises administering to a human in need of such therapy, an amount of olanzapine-N-oxide or a pharmaceutically acceptable salt thereof, said amount being sufficient to alleviate the symptoms of the particular condition.
The present invention further encompasses a method of treating fungal dermatitis and functional bowel disorder. The method comprises administering to a human in need of such therapy, an amount of olanzapine-N-oxide or a pharmaceutically acceptable salt thereof, said amount being sufficient to alleviate the symptoms of the particular condition.
Utilizing olanzapine-N-oxide results in enhanced dosage predictability and an improved therapeutic index. In particular, olanzapine-N-oxide exhibits less potential for drug-drug interaction than does olanzapine, where flavin-containing monooxygenase inhibitors or inducers are coadministered. Olanzapine-N-oxide may also be used to treat various conditions or disorders while minimizing or avoiding adverse cardiac events associated with administration of olanzapine. Furthermore, olanzapine-N-oxide can be administered to treat various conditions or disorders while minimizing or avoiding impact on hepatic function (e.g., liver enzyme abnormalities).
The term “psychotic condition” as used herein means pathologic psychological conditions which are psychoses or may be associated with psychotic features. Such conditions include, but are not limited to the psychotic disorders which have been characterized in the DSM-IV-R,
Diagnostic and Statistical Manual of Mental Disorders Revised,
4th Ed. (1994), including schizophrenia and acute mania. The DSM-IV-R was prepared by the Task Force on Nomenclature and Statistics of the American Association, and provides
Heslin Rothenberg Farley & & Mesiti P.C.
Krass Frederick
Sepracor Inc.
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