Patent Application
20050101666
The present invention relates to a method of treating the symptoms of premenstrual dysphoric disorder (PMDD) in a patient in need thereof by administering an effective amount of escitalopram or a pharmaceutically acceptable salt thereof.
Escitalopram is an example of a class of drugs known as selective serotonin reuptake inhibitors (hereafter referred to as SSRIs). SSRIs are selective for the 5-HT-uptake of serotonin, and have been used for the treatment of depression. See, for example, U.S. Pat. No. Re. 34,712, which is hereby incorporated by reference.
Escitalopram is the S-enantiomer of citalopram and has the following structure:
International Publication No. WO 02/087566-A1, which is hereby incorporated by reference, discloses the use of escitalopram to treat depression (such as major depression disorder), neurotic disorders, acute stress disorder, eating disorders (e.g., bulimia, anorexia, and obesity), phobias, dysthymi, pre-menstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder, and drug abuse.
Women diagnosed with premenstrual dysphoric disorder (PMDD) have monthly symptoms which markedly interfere with work, school, usual social activities, and their relationships with others. The essential symptoms of PMDD according to the Diagnostic & Statistical Manual of Mental Diseases IV-TR (DSM IV-TR) include markedly depressed mood, marked anxiety, affective lability, and decreased interest in activities.
Wikander et al. report in the Journal of Clinical Psychopharmacology (1998, 18(5):390-398) that citalopram administered to women according to certain regiments in a clinical trial was found to be an effective treatment for PMDD.
There exists a continuing need for effective methods of treating the symptoms of premenstrual dysphoric disorder which have few, if any, side effects.
The present invention relates to a method of treating a patient (or woman) suffering from premenstrual dysphoric disorder (PMDD) by administering an effective amount of escitalopram or a pharmaceutically acceptable salt thereof. The daily dose of escitalopram or a pharmaceutically acceptable salt thereof administered preferably ranges from about 5 to about 20 mg (calculated on a weight basis of escitalopram base). The daily does may be, for example, from about 5 to about 10 mg, from about 10 to about 20 mg, from about 5 mg, about 10 mg, or about 20 mg (calculated on a weight basis of escitalopram base). According to one preferred embodiment, the escitalopram or salt thereof is administered as a solid. The escitalopram or pharmaceutically acceptable salt thereof may be administered continuously throughout the menstrual cycle of the patient intermittently or semi-intermittently during the patient's menstrual cycle. The escitalopram or salt thereof is preferably administered orally (e.g., as a solid dosage form such as a tablet or capsule) although other routes of administration may be used. According to a preferred embodiment, it is administered during the morning.
The term escitalopram refers to (S)-(+)-1-[3-dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile. Preferably, the escitalopram is at least 95, 96, 97, 98, 99, or 99.5% pure. More preferably, it contains less than 1 or 2% w/w of the corresponding R-enantiomer.
As used herein, the term “about” means within 10% of a given value, preferably within 5%, and more preferably within 1% of a given value. Alternatively, the term “about” means that a value can fall within a scientifically acceptable error range for that type of value, which will depend on how qualitative a measurement can be given the available tools.
As used herein, the term “premenstrual dysphoric disorder” or “PMDD” refers to a woman whose symptoms meet the criteria defined by DSM-IV-TR, which is hereby incorporated by reference. These criteria are reproduced below:
The terms “treating” or “treatment” as used herein refer to:
The term “pharmaceutically acceptable” refers to additives or compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a mammal.
The term “effective amount” refers to an amount of escitalopram or a pharmaceutically acceptable salt thereof which, when administered to a female patient for PMDD, is sufficient to treat the same (e.g., an amount sufficient to alleviate the symptoms (e.g., psychological symptoms) of PMDD).
Pharmaceutically acceptable salts of escitalopram include, but are not limited to, salts formed with organic and inorganic acids. Examples of such organic salts are maleic, fumaric, benzoic, ascorbic, pamoic, succinic, oxalic, salicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-amino-benzoic, glutamic, benzene sulfonic and theophylline acetic acid, as well as the 8-halotheophyllines, for example 8-bromotheophylline. Examples of such inorganic salts are hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. Preferred pharmaceutically acceptable salts of escitalopram include, but are not limited to, escitalopram oxalate and escitalopram hydrobromide.
The oxalate of escitalopram may be prepared as described in U.S. Pat. No. Re. 34,712 and the base and other pharmaceutically acceptable salts may be obtained therefrom by standard procedures.
Methods for the preparation of solid pharmaceutical preparations are well known in the art. Tablets may thus be prepared by mixing the active ingredients with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a convenient tabletting machine. Examples of adjuvants or diluents comprise: corn starch, lactose, talcum, magnesium stearate, gelatin, lactose, gums, and the like. Any other adjuvant or additive such as colorings, flavorings, preservatives, etc. may also be used provided that they are compatible with the active ingredients.
According to the invention, escitalopram or a pharmaceutically acceptable salt thereof may be administered in any suitable way e.g. orally or parenterally, and it may be presented in any suitable form for such administration, e.g. in the form of tablets, capsules, powders, syrups, or solutions or dispersions for injection. Preferably, and in accordance with the purpose of the present invention, the compound of the invention is administered in the form of a solid pharmaceutical entity, suitably as a tablet or a capsule or in the form of a suspension, solution, or dispersion for injection.
The pharmaceutical composition prepared according to the invention may comprise escitalopram in a daily dosage form containing 5-20 mg escitalopram, preferably 10-20 mg escitalopram, including 10 mg, 15 mg, and 20 mg, and most preferred 20 mg escitalopram.
“Menstrual cycle” refers to the reproductive cycle of female humans. The cycle is characterized by a monthly discharge of blood, mucus, and tissues from the uterus (called menstruation) and involves changes to the lining of the uterus (the endometrium) during the rest of the month including a few days of fertility after an ovum (egg) is released by an ovary.
“Luteal phase” refers to the segment of a patient's menstrual cycle beginning on the expected day of ovulation, as calculated individually from normal cycle length minus 14 days, and ending on the first day of full bleeding.
“Follicular phase” refers to the segment of a patient's menstrual beginning on the first day of full bleeding and ending the day before the expected day of ovulation, as calculated individually from normal cycle length.
“Continuously” refers in regards to dosage refers to administration of escitalopram or pharmaceutically acceptable salt thereof during every day of the menstrual cycle (i.e., throughout the menstrual cycle).
“Intermittently” in regards to dosage refers to administration of escitalopram or a pharmaceutically acceptable salt thereof for a number of sequential days that do not equal the total number of days in the patient's menstrual cycle. For example, a preferred intermittent dosage regiment is administration of the escitalopram or salt thereof during the luteal phase. A preferred regimen is the administration of escitalopram or salt thereof beginning at the expected day of ovulation as calculated individually from normal cycle length minus 14 days, and administering the last dose on the first day of full bleeding of the subsequent cycle. Examples of such a regimen are as follows:
“Semi-intermittently” in regards to dosage refers to administration of escitalopram or pharmaceutically acceptable salt thereof at a high dosage for a number of sequential days that corresponding to the patient's luteal phase, then administering a lower baseline dosage the days of the follicular phase of the patient's cycle. This may be a preferred embodiment in the case of a patient who exhibits symptoms of PMDD superimposed on other depressive disorders. Examples of such a regimen are as follows:
The following examples illustrate the invention without limitation. All parts and percentages are given by weight unless otherwise indicated.
A double-blind, randomized, placebo-controlled trial evaluating the efficacy and safety of 3 months of intermittent treatment with 10 mg and 20 mg escitalopram per day in patients with PMDD is performed.
Intermittent treatment with 10 mg and 20 mg escitalopram oxalate daily is compared with placebo in a single-site, randomized, double-blind, parallel-group design.
150 patients are required for the Full Analysis Set. Patients eligible for this trial are female outpatients aged at least 18 years with a regular menstrual cycle who meet the DSM-IV-TR criteria for PMDD. The trial consists of two periods, the screening period of 2 menstrual cycles and the treatment period of 3 cycles. During the entire trial period patients are to complete a diary with daily rating of symptoms by means of VAS (Visual Analog Scales, ranging from 0-100 mm).
During treatment, escitalopram is administered in the luteal phase of the menstrual cycle. Patient contacts are to be undertaken a) in the luteal phase prior to the screening period for pre-screening, b) in the follicular phase of the cycle following the screening cycles for randomization, c) in the luteal phase of each treatment cycle and d) 28 days after the last trial visit for safety follow-up.
Escitalopram oxalate 10 mg and 20 mg daily (calculated by weight of escitalopram base) and placebo will be administered intermittently during the luteal phase of 3 menstrual cycles. Patients will start taking the escitalopram oxalate at the expected day of ovulation as calculated individually from normal cycle length minus 14 days. The last dose of study drug will be taken at the first day of full bleeding of the subsequent cycle. Patients should take the escitalopram oxalate in the morning.
The escitalopram dose will be uptitrated at each treatment cycle as follows:
Escitalopram oxalate 5 mg, 10 mg and 20 mg tablets differ in size and shape. In order to achieve double-blinding of study drug, all escitalopram oxalate and placebo tablets will be encapsulated.
The treatment will consist of capsules, identical in appearance, taste and smell, which will contain escitalopram oxalate tablets with the strength 5 mg, 10 mg, 20 mg or placebo tablets.
A dose increase as a consequence of lack of efficacy is not planned, nor will the dose be down-regulated due to the appearance of adverse events. If the patient does not tolerate the dose administered, she will be withdrawn from the trial.
The following efficacy assessments will be carried out: 1) self-rated: VAS (Visual Analog Scales, ranging from 0-100 mm) of 10 premenstrual symptoms, SDS (Sheehan Disability Scale, a 3 item scale of impairment of functioning), PGE (Patient Global Evaluation, how ill the patient is feeling), and 2) observer-rated: CGI-S (Clinical Global Impression—Severity Scale), CGI-I (Clinical Global Impression—Improvement Scale) and PMTS-O (Premenstrual Tension Syndrome Scale—Observer Rating). The primary efficacy variable will be percent change from baseline (that is, average of 2 screening cycles) of mean of VAS of 4 key symptoms at treatment cycle 3. For the safety evaluation, vital signs (including weight) will be recorded and blood analyses carried out. Other assessments involve physical examination (including height), MINI (Mini-International Neuropsychiatric Interview, to screen for psychiatric disorders), MADRS (Montgomery-Asberg Depression Rating Scale, for depression), and self-assessment of sexual function parameters.
The procedure described in example 1 is repeated except the escitalopram oxalate is administered continuously throughout the menstrual cycle. The daily dose is 5, 10, 15, or 20 mg of escitalopram oxalate (calculated based on the weight of escitalopram base).
The procedure described in example 1 is repeated except the escitalopram oxalate is administered “semi-intermittently”, i.e., at a constant low dose during the follicular phase and a higher dose during the luteal phase. The regimen is:
All references cited herein are incorporated by reference. To the extent that a conflict may exist between the specification and the reference the language of the disclosure made herein controls.
This application claims the benefit of U.S. Provisional Application No. 60/518,276, filed Nov. 7, 2003, which is hereby incorporated by reference.
| Number | Date | Country | |
|---|---|---|---|
| 60518276 | Nov 2003 | US |
