Long acting antidepressant microparticles

Details Long acting antidepressant microparticles Long acting antidepressant microparticles

2001-08-30

2002-11-19

Dees, Jose' G. (Department: 1616)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S401000

Reexamination Certificate

active

06482440

ABSTRACT:

TECHNICAL FIELD
The present invention relates to pharmaceutically-active compositions, particularly injectable compositions, which provide long-acting antidepressant activity.
BACKGROUND OF THE INVENTION
Mood and anxiety disorders, in their various forms and combinations, constitute a major source of personal suffering and impaired ability to engage in productive work and interpersonal relationships in the United States today. Between five and nine percent of women, and between two and three percent of men meet the diagnostic criteria for major depression at any time; ten to twenty-five percent of all women suffer major depression at some point in their lives, while five to ten percent of men will develop a major depressive disorder (American Psychiatric Association, 1994). Anxiety disorders, e.g., obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), panic disorder and generalized anxiety disorder (GAD), show lifetime prevalence rates of approximately 2.5%, 7%, 2.5% and 5%, respectively. Between 3% and 13% of individuals in community samples are regarded as meeting the diagnostic criteria for social phobia. Mood and anxiety disorders are common co-morbidities (American Psychiatric Association, 1994), and the most common antidepressant medications, including serotonin re-uptake inhibitors, mixed serotonin-catecholamine re-uptake inhibitors, tricyclic antidepressants, and monoamine oxidase inhibitors—are all effective treatments for anxiety and panic attacks.
Affective disorders, while characterized by depressed mood of varying degrees, exist in various forms. Thus, melancholic depression is characterized by continuously depressed mood and pervasive hopelessness, insomnia with early morning awakening (including the inability to return to sleep), loss of appetite and weight loss, and excessive feelings of guilt (American Psychiatric Association, 1994). In contrast, so-called “atypical” depression is characterized by hypersomnia (over sleeping), hyperphagia, weight gain and, often, mood reactivity. In general, regardless of whether or not the depressive syndrome is melancholic, atypical or some mixture of the two, a diagnosis of major depression is given when depressed mood, or loss of interest or pleasure in all activities, is present for at least two weeks (American Psychiatric Association, 1994). If less severe or incapacitating, depressed mood is considered dysthymia. Depressed mood can occur in the form of a cycling mood abnormality, such as bipolar mood disorder, cyclothymia, or menstrual-related mood disorder. Mood disorders include, for example, depression, major depression, melancholic depression, atypical depression, minor depression, seasonal depression, bipolar affective disorder, dysthymia disorder, menstrual-related dysphoria, chronic fatigue syndrome, depression associated with somatoform disorder, fibromyalgia, and treatment-resistant depression. Commonly seen anxiety disorders include post-traumatic stress disorder, generalized anxiety disorder, panic disorder with and without agoraphobia, social phobia, tics, Tourette's Syndrome, and obsessive-compulsive disorder.
Mood disorders are commonly seen in general medical practice and some general medical disorders resemble depression in important respects. In particular, both fibromyalgia and chronic fatigue syndrome are medical disorders that have clinical and pathophysiologic features in common with atypical depression.
Recently, 1-amino-4-phenyltetralin compounds have become widely used for the treatment of mood and anxiety disorders. See, for example, U.S. Pat. No. 4,029,731, Sarges, issued Jun. 14, 1977; U.S. Pat. No. 4,045,488, Sarges, issued Aug. 30, 1977; U.S. Pat. No. 4,536,518, Welch et al., issued Aug. 20, 1985, and U.S. Pat. No. 4,556,676, Welch et al., issued Dec. 3, 1985, all of which are incorporated herein by reference. An example of such a material is cis-(1S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine hydrochloride, also known as sertraline hydrochloride (Zoloft), commercially available from Pfizer, Inc., New York, N.Y., This material is of growing importance as a treatment modality for anxiety and mood disorders.
Although effective pharmaceuticals, including Zoloft, are known for the treatment of mood and anxiety disorders, compliance with treatment regimens (i.e., assuring that the patient take the prescribed medication as scheduled) is a significant issue, particularly with regard to the more serious mood disorders. Some studies suggest that non-compliance rates for antidepressants are between 30% and 60% of the patients being treated. See Markowitz, et al., AIDS, 8: 403-412 (1994); and Demyttenaere, J. Affective Disorders, 43: 27-39 (1997). In particularly serious cases, non-compliance can lead to intensification of the medical condition and even potential injury to the patient or to others. Accordingly, it would be highly desirable to have a dosage form of an effective antidepressant medication, such as sertraline, which provides long-acting efficacy after it is administered. For example, it would be highly desirable to be able to administer the pharmaceutical agent once a month, or even at longer frequencies, rather than relying on the patient to dose themselves once or multiple times each day.
Long lasting (sustained release) treatment modalities for mental disorders have been suggested. For example, U.S. Provisional Patent Application Serial No. 60/183,135, Zemlan, filed February 17, 2000, describes the use of certain long-chain derivatives of compounds such as fluoxetine, particularly fluoxetine decanamide, as single-dose long-lasting drugs for the treatment of depression-related disorders.
U.S. Pat. No. 5,955,459, Bradley, et al., issued Sep. 21, 1999, describes conjugates of fatty acid molecules, such as cis-docosahexaenoic acid, with anti-psychotic agents, such as clozapine. These conjugates are taught to be useful in treating psychotic conditions and are said to provide a longer period of action (a single dose per day, rather than multiple doses per day) when compared to the non-conjugate drug.
U.S. Pat. No. 5,770,231, Mesens, et al., issued Jun. 23, 1998; U.S. Pat. No. 5,650,173, Ramstack, et al., issued Jul. 22, 1997; and U.S. Pat. No. 5,654,008, Herbert, et al., issued Aug. 5, 1997, describe biodegradable and biocompatible microparticles which can be used for the sustained release delivery of a wide range of pharmaceutical materials. Antidepressant materials are not included in the pharmaceutical actives taught to be useful in these patents.
U.S. Pat. Nos. 5,622,657; 5,651,990; 5,723,269; 5,178,878; and 6,022,562 describe various types of microparticles that can be used to deliver pharmaceutically-active agents. Antidepressant materials are mentioned in some of the patents as being useful for delivery using the specifically disclosed microcapsules.
SUMMARY OF THE INVENTION
The present invention relates to pharmaceutically-active materials comprising an antidepressant compound selected from the group consisting of fluoxetine, paroxetine, sertraline, nefazodone, venlafaxine, trazodone, buproprion, mirtazapine, fluvoxamine, duloxetine, pharmaceutically-acceptable salts of those compounds, long-chain derivatives of those compounds, and mixtures thereof, contained in microparticles formulated so as to release the antidepressant compound, when introduced into the patient, over an extended period of time.
Preferred microparticles are produced by dissolving in a solvent the anti-depressant compound and a biodegradable and biocompatible polymer (such as poly(lactic) acid, poly(glycolic acid), copolymers of the foregoing, polyorthoesthers, and mixtures thereof) to form an organic phase, and extracting the solvent to form the microparticles. Preferred antidepressant compounds are sertraline, pharmaceutically-acceptable salts of sertraline, and long-chain derivatives of sertraline, particularly, sertraline hydrochloride and sertraline decanamide.
The present invention also encompasses pharmaceutical compositions comprising a safe and effective

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