HK1124265A - Stable pharmaceutical formulations containing escitalopram and bupropion - Google Patents

Description

Stable pharmaceutical formulation containing escitalopram and bupropion

Technical Field

The present invention relates to stable pharmaceutical formulations of escitalopram (escitalopram) and bupropion (bupropion) and their use for the treatment of central nervous system disorders, such as mood disorders (e.g. major depressive disorder) or anxiety disorders (e.g. generalized anxiety disorder, social anxiety disorder, post traumatic stress disorder or phobic disorder).

Background

Selective 5-hydroxytryptamine reuptake inhibitors (hereinafter SSRIs), such as racemic citalopram (citalopram) and escitalopram, have become the first therapy of choice in the treatment of depression, primarily because of their higher potency than tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs). SSRIs act by inhibiting reuptake of the neurotransmitter 5-hydroxytryptamine (5-hydroxytryptamine, 5-HT) by synaptic neurons. As a result, 5-hydroxytryptamine is present in the synaptic cleft and has an opportunity to stimulate receptors of the recipient cell.

Escitalopram is the S-enantiomer of citalopram and has the following structure:

processes for the preparation of escitalopram are disclosed, for example, in U.S. Pat. Nos. Re.34,712 and 6,566,540 and International publication Nos. WO 03/000672, WO03/006449, WO 03/051861 and WO 2004/083197, all of which are hereby incorporated by reference.

International publications WO 01/03694 and WO02/087566 disclose the use of escitalopram in the treatment of various psychiatric disorders including major depressive disorder, generalized anxiety disorder, social anxiety disorder, post traumatic stress disorder, phobic disorder, acute stress disorder, eating disorders (e.g., bulimia, anorexia and obesity), phobias (phobias), dysthymia (dysthymia), premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder and drug abuse, the disclosures of which are hereby incorporated by reference. International publication No. WO02/087566 also discloses the use of escitalopram for the treatment of patients who do not respond to conventional SSRI primary treatment, in particular patients with major depressive disorder who do not respond to conventional SSRI primary treatment. Escitalopram oxalate recently marketed in the United states under the trademark EscitalopramFor the treatment of major depressive disorder and generalized anxiety disorder. Can be obtainedAre 5, 10 and 20mg escitalopram immediate release tablets (in the form of the oxalate) and 5mg/mL oral liquid.

International publication No. WO 01/22941 discloses a modified release formulation of escitalopram oxalate prepared by melt granulation. International publication No. WO 2004/058299 discloses modified release formulations of SSRIs, such as citalopram hydrochloride and escitalopram oxalate, with a particular dissolution profile.

Side effects of escitalopram include nausea, insomnia, lethargy, sweating, fatigue and sexual dysfunction disorders (including, but not limited to, ejaculatory disorders, anorgasmia and hypoactive sexual desire).

Bupropion hydrochloride salt is recently marketed under the trademark Buchner @WellbutrinAnd WellbutrinThey are useful in the treatment of major depressive disordersAs an adjuvant for smoking cessation therapy, the bupropion hydrochloride is described in U.S. patent nos. 3,819,706 and 3,885,046. Bupropion is an aminoketone derivative that is chemically unrelated to other antidepressants currently available (e.g., selective 5-hydroxytryptamine reuptake inhibitors, tricyclic and tetracyclic). Although the neurochemical mechanisms of antidepressants and the effects of smoking cessation are unknown, it appears that norepinephrine channels and/or dopamine-like effects are primarily involved. Bupropion does not inhibit monoamine oxidase and is a weak uptake blocker of 5-hydroxytryptamine and norepinephrine.

(an immediate release bupropion hydrochloride formulation) is supplied in the form of 75 and 100mg tablets, which are administered three times daily, preferably with at least 6 hours between successive doses. Controlled release formulations of bupropion hydrochloride have also been developed.

For example, U.S. Pat. No. re.33,994 discloses a controlled release bupropion tablet formulation comprising a bupropion hydrochloride core and a coating consisting of a water-insoluble and water-permeable film-forming coating and a particulate and water-insoluble pore-forming material. However, since 25-70% of bupropion is released within 4 hours and 40-90% is released within 6 hours, it is still generally necessary to administer bupropion at least twice daily.

U.S. Pat. Nos. 5,358,970, 5,763,493, and 5,731,000 disclose a bupropion hydrochloride formulation containing a stabilizer to prevent degradation of bupropion hydrochloride.

U.S. patent No. 5,427,798 discloses a bupropion tablet formulation containing hydroxypropylmethylcellulose. In distilled water, more than half of the bupropion is preferably released within 4 hours. Because of this rapid release rate, the formulation is typically administered multiple times during the day.

U.S. patent nos. 6,096,341 and 6,143,327 disclose a controlled release tablet of bupropion hydrochloride that is free of stabilizers and pore formers. The tablet consists of a core consisting essentially of bupropion hydrochloride, a binder, and a lubricant, and a coating consisting essentially of a water-insoluble, water-permeable film-forming polymer, a plasticizer, and a water-soluble polymer.

U.S. patent No. 6,905,708 and U.S. patent application publication nos. 2003/0161874 and 2005/0147678 disclose a once daily bupropion hydrochloride formulation comprising coated bupropion hydrochloride pellets.

In DeVane, j.clin.psychiatyry 2003, 64 (suppl.18): 14-19, results of clinical testing of immediate release and controlled release formulations of antidepressants were compared in terms of nausea leading to drug withdrawal. The authors state that a "more stable pharmacokinetic profile may be the cause of less nausea of some controlled release new antidepressants," but that "the relationship between them has not been demonstrated.

According to Gerner et al, biol. psychiatry, 1998, 43: 101S, abstract 336 ("GernerI"), bupropion has been added to SSRIs for the treatment of malaise clinical responses, SSRI sexual dysfunction disorders, and for concurrent ADD and fear-related depression or obsessive-compulsive disorder. See also Kennedy et al j.clin.psychiatry, 2002, 63: 181- "186" (freezing the pharmaceutical, thermal, and Sexual dysfunction effects combinations of bupirion SR with venlafaxine, parooxetine, orflooxetine); gerner et al, biol. psychiatry, 1998, 43: 99S, abstract 329 ("Gerner II"); ashton et al, j.clin.psychiatry, 1998, 59 (3): 112-115 (styrageting the use of bupirion as an antagonist for serotonin reuptakeinhibing (parooxetine, fluorooxetine, sertraline, venlafaxine, or fluoroxamine) induced sextual dysfunction); gitlin et al, j.six & Marital Therapy 2002, 28: 131-. However, the treatment of SSRI-induced sexual disorders with bupropion has not proven effective. According to Sturpe et al, j.family Practice August 2002, 51 (8): 1681, double-blind placebo-controlled experiments showed that treatment with bupropion had the same sexual function improvement as placebo. In addition, bupropion has an increased incidence of epileptogenesis compared to other antidepressants. Gerner II, supra (reporting on 3 cases of major motor semiconductors in previous semiconductors-fresh compressed substrates after water combining bupirion with fluorooxitine or fluorooxamines); see also Gerner I, supra.

Studies have shown that 29% to 46% of depressed patients do not respond completely to treatment with adequate doses and durations of antidepressant. Fava et al, psychiatr. clin. north Am., 1996, 19 (2): 179-200; fava et al, ann. clin. psychiatry, 2003, 15 (1): 17-22; lam et al, j.clin.psychiatry, 2004, 65: 337-340, the results of clinical tests in patients with treatment-resistant depression using a combination of citalopram and bupropion SR in comparison to single agent treatment were reported. According to the authors, the results of this cohort test showed that the combined use of citalopram and bupropion SR was more effective than the use of single agent treatment.

U.S. patent No. 6,342,496 discloses the improvement of the treatment of disorders by bupropion metabolites by inhibiting reuptake of neuronal monoamines. The bupropion metabolite can be combined with other pharmacologically active compositions, such as SSRI,5-HT₃The inhibitor or nicotine is co-administered.

There is a need for a once-a-day formulation for treating central nervous system disorders that has fewer side effects than existing formulations and which is also effective in treatment-resistant patients.

Brief description of the invention

The present invention relates to stable oral dosage forms comprising escitalopram (or a pharmaceutically acceptable salt thereof) and bupropion (or a pharmaceutically acceptable salt thereof). Preferably, the oral dosage form is a once-a-day formulation, i.e., only needs to be administered once a day to provide therapeutic benefit to the patient throughout the day (24 hours). In the oral dosage form, the amount of bupropion or pharmaceutically acceptable salt thereof is preferably from about 50 to about 450mg and more preferably from about 75 to about 225mg (based on the weight of the bupropion hydrochloride salt in an amount of 1 molar equivalent) (e.g., 75, 150, or 225 mg). In the oral dosage form, the amount of escitalopram or a pharmaceutically acceptable salt thereof is preferably from about 2.5 to about 40mg and more preferably from about 2.5 to 20mg (calculated on the weight of escitalopram free base in an amount of 1 molar equivalent) (e.g. 2.5, 5, 10 or 20 mg). According to a preferred embodiment, the oral dosage form comprises 4mg escitalopram or a pharmaceutically acceptable salt thereof and 150mg bupropion or a pharmaceutically acceptable salt thereof. The oral dosage form can provide immediate release and modified release of various active ingredients.

Preferably, the bupropion and escitalopram in the oral dosage form are physically separated. The inventors have found that conventional formulations of escitalopram hydrobromide and escitalopram oxalate unexpectedly degrade under storage conditions. In particular, escitalopram oxalate, which is stable for up to about 12 months in commercial formulations, undergoes a significant increase in its rate of degradation when stored in intimate contact with bupropion hydrochloride. It has been found that when the two are in intimate contact, the respective efficacy decreases by more than 10% after one month of storage at 40 ℃ and 75% relative humidity. Escitalopram and bupropion can be separated by providing separate discrete regions (e.g., different layers) for each component in the dosage form. Alternatively, the dosage form may comprise a plurality of escitalopram tablets or beads and a plurality of bupropion tablets or beads, wherein one or both of the escitalopram tablets/beads and bupropion tablets/beads are coated.

Preferably, the oral dosage form contains (1) at least about 80% w/w of undegraded escitalopram or a pharmaceutically acceptable salt thereof (relative to the initial amount of escitalopram or a pharmaceutically acceptable salt thereof) after 6 weeks of storage at about 40 ℃ and 75% relative humidity, (2) at least about 80% w/w of undegraded bupropion or a pharmaceutically acceptable salt thereof (relative to the initial amount of bupropion or a pharmaceutically acceptable salt thereof) or both after 6 weeks of storage at about 40 ℃ and 75% relative humidity. More preferably, the oral dosage form contains at least about 90% w/w, even more preferably 95% w/w, of undegraded bupropion or a pharmaceutically acceptable salt thereof and/or undegraded escitalopram or a pharmaceutically acceptable salt thereof after storage for 6 weeks under the same conditions.

According to yet another preferred embodiment, the oral dosage form contains (1) at least about 90% w/w of undegraded escitalopram or a pharmaceutically acceptable salt thereof (relative to the initial amount of escitalopram or a pharmaceutically acceptable salt thereof) after 1, 3 or 6 months of storage at about 40 ℃ and 75% relative humidity, (2) at least about 90% w/w of undegraded bupropion or a pharmaceutically acceptable salt thereof (relative to the initial amount of bupropion or a pharmaceutically acceptable salt thereof) after 1, 3 or 6 months of storage at about 40 ℃ and 75% relative humidity, or both. More preferably, the oral dosage form contains at least about 95% w/w undegraded bupropion or a pharmaceutically acceptable salt thereof and/or undegraded escitalopram or a pharmaceutically acceptable salt thereof after 1, 3, or 6 months of storage under the same conditions.

According to another preferred embodiment, the oral dosage form contains (1) at least about 80% w/w of undegraded escitalopram or a pharmaceutically acceptable salt thereof (relative to the initial amount of escitalopram or a pharmaceutically acceptable salt thereof) after 6 months, 9 months or 1 year of storage at about 25 ℃ and 60% relative humidity, (2) at least about 80% w/w of undegraded bupropion or a pharmaceutically acceptable salt thereof (relative to the initial amount of bupropion or a pharmaceutically acceptable salt thereof) after 6 months, 9 months or 1 year of storage at about 25 ℃ and 60% relative humidity, or both. More preferably, the oral dosage form contains at least about 90% and even more preferably 95% w/w of undegraded bupropion or pharmaceutically acceptable salt thereof and/or undegraded escitalopram or pharmaceutically acceptable salt thereof after 6 months, 9 months or 1 year of storage under the same conditions.

According to another embodiment, the oral dosage form provides modified release of bupropion or a pharmaceutically acceptable salt thereof. Preferably, the oral dosage form provides one or more of the following after ingestion by a patient:

(a) bupropion or a pharmaceutically acceptable salt thereof (preferably bupropion hydrochloride) has a statistically significant reduced mean fluctuation index in plasma, and

(b) the bioavailability of bupropion is substantially equivalent to three immediate release tablets of the same form of bupropion (e.g., the AUC for bupropion provided by an oral dosage form is 75% to 130% of the AUC provided by the three immediate release tablets), which are administered one tablet every 6 hours or more per day.

According to yet another embodiment, less than about 30% of the bupropion (or pharmaceutically acceptable salt thereof) (based on 100% of the bupropion in the oral dosage form) is released within 2 hours after administration and more than about 60% of the bupropion is released within 12 hours after administration.

According to yet another embodiment, the oral dosage form provides for pulsed or sustained release, including delayed and extended (extended) release, of bupropion or a pharmaceutically acceptable salt thereof. According to one embodiment, the oral dosage form releases bupropion or a pharmaceutically acceptable salt thereof in two or more pulses, preferably three pulses, after ingestion by a patient. Each pulse is released at a different time after administration, with a time interval between pulse releases during which substantially no bupropion or pharmaceutically acceptable salt thereof is released from the oral dosage form. Each pulse may be released under different conditions, e.g., at different times and/or at different pH. For example, according to one embodiment, release of bupropion (or a pharmaceutically acceptable salt thereof) is delayed for about 2 hours after ingestion, e.g., less than 20% is released, and more than 60% of the bupropion is released from about 2 to about 12 hours after ingestion.

According to yet another embodiment, the oral dosage form comprises modified release beads or tablets of bupropion (or a pharmaceutically acceptable salt thereof) to provide their modified release. The beads and/or tablets may provide single or multiple phase release of bupropion. According to one embodiment, the beads and/or tablets comprise a modified release bupropion core and one or more bupropion release layers. For example, the beads and/or tablets may have an immediate release bupropion layer and a modified release bupropion core. According to one embodiment, the tablet has a diameter ranging from about 4.5 to about 15 mm. The beads and/or tablets may be incorporated into capsules.

According to one embodiment, the oral dosage form comprises beads and/or tablets of bupropion (or pharmaceutically acceptable salt thereof) having at least two release profiles. For example, the oral dosage form may comprise bupropion immediate release beads and/or bupropion modified release beads and/or tablets.

According to yet another embodiment, the oral dosage form has an in vitro dissolution profile measured by the USP propeller Method (USP Method) in 900mL of water at 37 ℃ at (a)75rpm or 900mL of 0.1N HCl at 37 ℃ at (b)100rpm such that (i) less than about 30% by weight of the bupropion (or pharmaceutically acceptable salt thereof) is released after 2 hours, (ii) about 40% to about 90% of the bupropion (or pharmaceutically acceptable salt thereof) is released after 8 hours, and (iii) more than about 70% of the bupropion (or pharmaceutically acceptable salt thereof) is released after 24 hours.

The oral dosage forms described above may provide immediate release or modified release of escitalopram or a pharmaceutically acceptable salt thereof. Dosage forms formulated for immediate release of escitalopram oxalate preferably provide a T in the range of about 1 to about 8 hours, more preferably about 5 hours_max. The modified release of escitalopram oxalate preferably provides a T of about 4 to 24 hours_max。

According to a preferred embodiment, the oral dosage form provides at least one of the following after ingestion by a patient:

(a) average C of escitalopram (or a pharmaceutically acceptable salt thereof)_maxIs about 50 to about 85% of an immediate release tablet containing the same dose of escitalopram (or a pharmaceutically acceptable salt thereof),

(b) t of escitalopram (or a pharmaceutically acceptable salt thereof)_maxFrom about 4 to about 12 hours,

(c) the bioavailability of escitalopram (or a pharmaceutically acceptable salt thereof) is substantially equivalent to an immediate release tablet containing the same dose of escitalopram (or a pharmaceutically acceptable salt thereof) (e.g., the AUC of escitalopram provided by an oral dosage form is 75% to 130% of the AUC provided by an immediate release tablet),

(d) in plasma, escitalopram has a statistically significant reduced mean fluctuation index (at C) compared to an immediate release tablet containing the same dose of escitalopram (or a pharmaceutically acceptable salt thereof)_maxAnd C_minIn between),

(e) mean minimum plasma concentration (C) of escitalopram (or a pharmaceutically acceptable salt thereof)_min) Substantially the same amount of escitalopram (or pharmaceutically acceptable salt thereof)Salt) of the compound, and

(f) the area under the plasma concentration versus time curve (AUC) of escitalopram (or a pharmaceutically acceptable salt thereof) is in the range of about-25% to about + 30% of the area produced by an immediate release tablet containing the same dose of escitalopram (or a pharmaceutically acceptable salt thereof).

According to a preferred embodiment, for example, an 8mg oral dosage form provides an AUC of escitalopram oxalate of about 200 to about 350ng h/ml_0-24. Comparable immediate release tablets are preferably 4 and 8mg, and 5, 10 or 20mg escitalopram oxalate tablets which are the subject of a new drug application number 21-323 approved by the U.S. food and drug administration.

The immediate release dosage form preferably has an in vitro dissolution profile of escitalopram (measured by the USP Basket Method (USP Basket Method) in 900mL 0.1N HCl at 37 ℃ at 100 rpm) such that more than 80% of the drug is released in about 30 minutes. The delivery dosage form preferably has an in vitro dissolution profile of escitalopram (measured by the USP Basket Method (USP Basket Method) in 900mL 0.1NHCl at 37 ℃ at 100 rpm) such that about 10% to about 50% by weight of escitalopram is released within 2 hours and more than about 70% by weight of escitalopram is released after 8 hours.

According to a preferred embodiment, for example, an oral dosage form containing about 8mg escitalopram or a pharmaceutically acceptable salt thereof provides a mean maximum plasma concentration (Cmax) of escitalopram from about 2 to about 25ng/ml, more desirably from about 3 to about 15ng/ml, after ingestion by a patient_max)。

According to yet another embodiment, the oral dosage form comprises modified release beads or tablets of escitalopram (or a pharmaceutically acceptable salt thereof) thereby providing their modified release. The beads and/or tablets may provide a single or multiple phase release of escitalopram. According to one embodiment, the beads and/or tablets comprise an inner core of modified release escitalopram and one or more release layers of escitalopram. For example, the beads and/or tablets may have an immediate release escitalopram layer and a modified release escitalopram core. According to one embodiment, the tablet has a diameter ranging from about 4.5 to about 15 mm. The beads and/or tablets may be encapsulated.

According to one embodiment, the oral dosage form comprises beads and/or tablets of escitalopram (or a pharmaceutically acceptable salt thereof) having at least two different release profiles. For example, the oral dosage form may comprise immediate release beads and/or tablets of escitalopram and modified release beads and/or tablets of escitalopram.

Yet another embodiment is a method of treating a Central Nervous System (CNS) disorder, such as a mood or anxiety disorder, in a patient in need thereof by daily administration of an oral dosage form of the invention. Examples of CNS disorders that can be treated include, but are not limited to, major depressive disorder, generalized anxiety disorder, social anxiety disorder, post traumatic stress disorder, panic attack (panicattacks), acute stress disorder, eating disorders (e.g., bulimia, anorexia, and obesity), phobias, dysthymia, premenstrual syndrome, premenstrual dysphoric disorder, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder, and drug abuse. The combination of escitalopram and bupropion can also treat patients who do not respond to conventional SSRI primary treatment, especially patients with major depressive disorder who do not respond to conventional SSRI primary treatment. The composition can further treat or reduce suicidal psychology in a patient in need of treatment and improve the psychology of survivors who have not been injured after the stroke.

Yet another embodiment is a method of treating a patient suffering from treatment-resistant depression by administering an oral dosage form of the present invention.

Another embodiment of the invention is a method of treating a patient suffering from nausea, insomnia, lethargy, sweating, fatigue, or a combination thereof, caused by treatment with an antidepressant other than a combination of bupropion or a pharmaceutically acceptable salt thereof and escitalopram or a pharmaceutically acceptable salt thereof. The method comprises (a) discontinuing treatment with the antidepressant; and (b) treating said patient with an oral dosage form of the invention. According to one embodiment, the antidepressant is an immediate release escitalopram oxalate formulation.

Yet another embodiment is a method of treating a sexual disorder resulting from treatment with an antidepressant other than a combination of bupropion or a pharmaceutically acceptable salt thereof and escitalopram or a pharmaceutically acceptable salt thereof in a patient suffering from the sexual disorder. The sexual disorder may be a ejaculatory disorder, anorgasmia, and/or hypoactive sexual desire. The method comprises (a) discontinuing treatment with the antidepressant; and (b) treating said patient with an oral dosage form of the invention. According to one embodiment, the oral dosage form provides a release of bupropion such that the first release of the bupropion (or pharmaceutically acceptable salt thereof) is delayed for about 2 hours, e.g., less than 20% of the release, and more than 60% of the bupropion is released within about 2 to about 12 hours after ingestion. Optionally, additional pulses may be released such that bupropion hydrochloride is released (> 80%) within about 4 to 24 hours after ingestion.

Brief Description of Drawings

FIG. 1 shows simulated dissolution profiles of escitalopram core beads (200mg/g) and modified release beads (194.1mg/g and 188.7mg/g) as described in example 1.

FIG. 2 shows simulated dissolution profiles of bupropion inner core beads (600mg/g) and modified release beads (545.5mg/g and 500mg/g) described in example 3.

Figure 3 shows the bupropion dissolution profiles of the three capsules as described in table 14 of example 5, as determined by the USP basket method in 0.1N HCl at 100 rpm.

Figure 4 shows the dissolution profiles of the pulsed escitalopram beads of three capsules prepared by (1) mixing immediate release and modified release beads and (2) forming a single bead comprising immediate release and modified release, as determined by the USP basket method in 0.1N HCl at 100rpm, as described in table 14 of example 5.

Detailed Description

Definition of

The term "escitalopram" as used herein includes 1- [3- (dimethyl-amino) propyl ] -1- (p-fluorophenyl) -5-isobenzofurancarbonitrile which preferably contains less than 3, 2, 1, 0.5 or 0.2% by weight of the R enantiomer (based on 100% total weight of 1- [3- (dimethyl-amino) propyl ] -1- (p-fluorophenyl) -5-isobenzofurancarbonitrile), i.e.S-citalopram enantiomeric purity (by weight) of 97, 98, 99, 99.5 or 99.8%. Pharmaceutically acceptable salts of escitalopram include, but are not limited to, acid addition salts formed with organic and inorganic acids. Non-limiting examples of suitable organic acids include maleic acid, fumaric acid, benzoic acid, ascorbic acid, pamoic acid, succinic acid, oxalic acid, salicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, and theophylline acetic acid, as well as 8-halotheophyllines, such as 8-bromotheophylline. Non-limiting examples of suitable inorganic acids are hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid. Preferred pharmaceutically acceptable salts of escitalopram include, but are not limited to, escitalopram oxalate and escitalopram hydrobromide. The term "escitalopram" also includes polymorphic forms, hydrates, solvates and amorphous forms of escitalopram and pharmaceutically acceptable salts thereof. Escitalopram and pharmaceutically acceptable salts thereof may be prepared as described in U.S. Pat. nos. re.34,712 and 6,566,540 and international publication nos. WO 03/000672, WO03/006449, WO 03/051861 and WO 2004/083197, each of which is hereby incorporated by reference in its entirety. Crystalline forms of escitalopram oxalate and escitalopram hydrobromide may also be used, such as those described in international publication No. WO 03/011278, U.S. patent application publication No. 2004/0167209 and U.S. patent application nos. 10/851,763 and 10/948,594, all of which are hereby incorporated by reference. The comparable escitalopram "immediate release" tablets described herein are preferably equivalent forms of new drug application numbers 21-323 approved by the U.S. food and drug administration (5, 10 and 20mg of escitalopram oxalate).

Unless otherwise indicated, all weight values of the salts of escitalopram are provided in weight form in an amount of 1 molar equivalent to the escitalopram free base. For example, 4mg of escitalopram oxalate means an amount of escitalopram oxalate of 1 molar equivalent to 4mg of escitalopram free base.

The term "bupropion" refers to (±) -1- (3-chlorophenyl) -2- [ (1, 1-dimethylethyl) amino ] -1-propanone. Pharmaceutically acceptable salts of bupropion include, but are not limited to, acid addition salts formed with organic or inorganic acids, such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, formate, methanesulfonate, citrate, benzoate, fumarate, maleate, and succinate. The term "bupropion" also includes polymorphic forms, hydrates, solvates, and amorphous forms of bupropion and pharmaceutically acceptable salts thereof. A preferred pharmaceutically acceptable salt of bupropion is bupropion hydrochloride. Comparable bupropion "immediate release" tablets described herein are preferably in equivalent form (50, 75 and 100mg bupropion hydrochloride) as in New drug application No. 018-644.

By "effective amount" is meant an amount of the active ingredient or active ingredient composition that is sufficient to produce such a therapeutic effect when administered to a mammal for the treatment of a condition, disorder or symptom. The "effective amount" will vary depending on the active ingredient, the condition, disorder or symptom to be treated and its severity, as well as the age, weight, physical condition and response of the mammal to be treated. According to one embodiment of the invention, an effective amount of escitalopram is an amount effective for the treatment of a Central Nervous System (CNS) disorder, e.g. major depressive disorder, generalized anxiety disorder, social anxiety disorder, post traumatic stress disorder or panic attack.

The term "pharmaceutically acceptable" generally means biologically or pharmacologically suitable for use in an animal or human body, and preferably means approved by a regulatory agency of the federal or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

As used herein, the term "treating" includes one or more of the following:

(a) alleviating or alleviating at least one symptom of a disorder in a subject, the disorder including, for example, a Central Nervous System (CNS) disorder, (e.g., a mood disorder, a major depressive disorder, a generalized anxiety disorder, a social anxiety disorder, a post traumatic stress disorder, and a panic attack, including a panic attack);

(b) reducing or alleviating the intensity and/or duration of the manifestation of the disease in the subject, including, but not limited to, the response to an administered stimulus (e.g., stress, tissue damage, and hypothermia); and

(c) prevent, delay onset (i.e., a time prior to clinical manifestation of the disorder), and/or reduce the risk of developing or worsening the disorder.

The term "panic attack" includes, but is not limited to, any disease associated with panic attacks, including panic disorders, specific phobias, social phobias, and agoraphobia in which panic attacks occur. These conditions are described in Diagnostic and Statistical Manual of Mental Disorders4^thEd. -Text review (DSM-IV-TR), A.France (ed.), American psychiatric Association, Washington, D.C., 2000. A panic attack is a discontinuous cycle in which there is a sudden onsetThe onset of intense uneasiness, fear, or fear is often accompanied by a feeling of impending death. During an attack, symptoms such as palpitations, sweating, trembling, feeling of shortness of breath, feeling oppressed, chest pain or discomfort, nausea, feeling vertigo, unreal feeling, fear of loss of control or crazy feeling, fear of death, paresthesia and chills or fever flushes occur.

Panic disorders are characterized by the repeated occurrence of unpredictable panic attacks for a constant matter of concern. Plaza phobias are worries about or avoidance of places or situations from which escape is difficult or where it may not be helpful if a panic attack occurs. Specific and social phobias (as well as previous simple phobias) are characterized by overt or unprovoked, obvious and persistent concerns that are implied by the presence or anticipation of a particular object or situation (flying, altitude, animal, blood, etc.) or a socially generated situation.

Conditions in which panic attacks occur are distinguished from each other by the predictability of the occurrence of the attacks, for example, in panic conditions, where the attacks are unpredictable and not associated with any particular event, whereas in particular panic conditions, the attacks are triggered by a particular stimulus.

The phrase "treatment of a panic disorder" may include preventing or reducing the number of panic attacks and/or reducing the severity of panic attacks.

The term "mood disorder" as used herein includes the mood disorders specified in DSM-IV-TR, including, but not limited to, depressive disorders, such as major depressive disorder.

The term "anxiety disorder" as used herein includes anxiety disorders as defined in DSM-IV-TR, including, but not limited to, panic disorder without agoraphobia, panic disorder with agoraphobia, social phobia (previously referred to as social anxiety disorder), obsessive compulsive disorder, post-traumatic stress disorder, and generalized anxiety disorder.

Patients with "treatment-resistant depression" include (1) patients who do not respond to standard doses of antidepressants (e.g., SSRIs) administered for at least 6 weeks in a row (i.e., the response is significantly better than placebo in a double-blind test), and (2) patients who do not respond to standard doses of antidepressants (e.g., SSRIs) (single-dose treatment) administered for at least 12 weeks in a row. One criterion for determining whether a patient's depression is resistant to antidepressant therapy is whether the clinical global impression improvement score (CGI-I) at the end of the 6, 8 or 12 week experiment did not reach 1 or 2. The scoring criteria for CGI are set forth in Guy, W. (ed.):ECDEU Assessment Manual for Psvchopharmacologyrevised, DHEW pub. No. (ADM)76-338, Rockville, Md, National Institute of Mental Health, 1976.

The terms "sustained release", "modified release" and "sustained or modified release" as used herein refer to the release of the active ingredient over an extended period of time, resulting in lower peak plasma concentrations and extended T relative to immediate release formulations_max. These terms also include release over a period of time by a series of immediate release pulses. 100mg ofThe pharmacokinetic profile of the tablets (immediate release bupropion tablets) showed that the peak plasma concentration occurred approximately 1-2 hours after administration. The pharmacokinetic profile of the 20mg escitalopram oxalate tablet (immediate release tablet) shows that the peak plasma concentration occurs at about 5 hours. (physicians' Desk Reference 2005, Thomson Healthcare; 59th ed.2004).

By "pulsed" is meant that multiple doses of drug are released over an interval of time.

The term "bioavailability" refers to the rate and extent to which an active ingredient or active moiety, such as escitalopram, is absorbed from a drug and becomes available systemically.

The term "about" or "approximately" means within an acceptable error range for the particular numerical value determined by one of ordinary skill in the art, which depends in part on how the numerical value is measured or determined, i.e., in part on the limitations of the measurement system. For example, "about" can mean within 1 standard deviation or over 1 standard deviation per practice in the art. Alternatively, about in the composition may mean a range of up to 10%, preferably up to 5%.

Compositions of bupropion and escitalopram

The oral dosage form preferably comprises about 75, 150 or 225mg bupropion hydrochloride and about 2.5, 4, 5, 10, 15 or 20mg escitalopram or a pharmaceutically acceptable salt thereof (e.g. escitalopram oxalate or escitalopram hydrobromide). In another embodiment, the oral dosage form preferably comprises about 75, 150 or 300mg bupropion hydrochloride and about 4, 8, 12, 16 or 24mg escitalopram or a pharmaceutically acceptable salt thereof.

More preferred amounts of each component in the oral dosage form include, but are not limited to, those shown in the table below.

Escitalopram (or its pharmaceutical bupropion (or its pharmaceutical)

Serial number

An upper acceptable salt) in an amount of an acceptable salt)

1 4mg 150mg

2 16mg 300mg

It is preferred to formulate a unit dosage form containing both escitalopram and bupropion such that escitalopram and bupropion do not contact each other.

Modified release formulations

Preferably, an oral dosage form containing bupropion and/or escitalopram may be formulated to provide a modified release of bupropion and an immediate or modified release of escitalopram. Modified release profiles of bupropion, escitalopram, or both can be achieved by sustained, including delayed and extended, as well as pulsed, formulations.

Pulse preparation

The pulsed release profile may be obtained from a closed dosage form, such as a sealed capsule or tablet, containing two or more dosage units containing the drug. The dosage form may comprise one, two, three or four or more dosage units, each dosage unit having a different drug release profile. Each dosage unit may provide multiple releases of bupropion and/or escitalopram.

Preferably, the pulsatile dosage form comprises at least two dosage units, more preferably two or three dosage units. For example, according to one embodiment, a first dosage unit releases drug substantially immediately upon ingestion of the dosage form, a second releases drug about 1 to 8 hours after ingestion, and optionally a third releases drug about 2 to 24 hours after ingestion.

According to another embodiment, about 20 to 60% of escitalopram and about 10 to 50% of bupropion are released in the first pulse. The release of bupropion and any remaining escitalopram occurs in one or more pulses after the first pulse. The number of pulses and the amount of drug released preferably results in an escitalopram T of about 4 to about 24 hours_maxAnd bupropion T for about 4 to about 12 hours_max。

The various dosage units may be, for example, tablets (e.g., compressed or molded), beads, or microparticles. Alternatively, the dosage units may be different layers on the dosage form (e.g., a multilayer tablet). Suitable pulse systems are described in U.S. patent nos. 6,217,904, 6,555,136, 6,793,936, 6,627,223, 6,372,254, 6,730,321, 6,500,457, 4,723,958, 5,840,329, 5,508,040 and 5,472,708 and U.S. patent application publication nos. 2003-124196, 2004-028729 and 2003-0133978, all of which are hereby incorporated by reference.

The tablet dosage units may be of any size. According to a preferred embodiment, the tablet has a large diameter shaft ranging from about 4.5 to about 15 mm. According to one embodiment, the dosage form (e.g., capsule) contains two or three tablets.

Typically, the bead dosage unit comprises an inert carrier and a drug coated thereon. The inert carrier may be, for example, beads of sugar or microcrystalline cellulose. The drug may be coated on an inert carrier by methods known in the art.

The individual dosage units (e.g., beads and microparticles) can be compacted or extruded into a single tablet or capsule using methods known in the art.

Sustained release preparation

Sustained release profiles of the dosage forms may be obtained by coating and/or using the beads, microparticles, and tablets described above as dosage units within the dosage form.

Dosage unit

As envisioned by those skilled in the art and as described in the relevant papers and documents, a variety of methods are available for preparing tablets or other dosage units containing a drug that provide a variety of drug release profiles. Such methods include coating the drug or drug-containing composition, increasing the particle size of the drug, placing the drug within a matrix and forming a complex of the drug with a suitable complexing agent.

Modified dosage units for pulsed and sustained release formulations may be prepared, for example, by coating the drug or drug-containing composition with one or more coating materials, such as one or more polymeric materials. When coating is used to provide a delayed release dosage unit, particularly preferred coating materials include, but are not limited to, bioerodible, gradually hydrolyzing and/or pH dependent dissolving polymers. The "coat weight" or relative amount of coating material per dosage unit generally represents the time interval between ingestion and drug release.

Suitable coating materials for effecting delayed release include, but are not limited to: cellulose polymers such as cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, phthalate-ether cellulose, hydroxypropyl cellulose phthalate, alkali metal salts of cellulose acetate phthalate, alkaline earth metal salts of cellulose acetate phthalate, hydroxypropyl methylcellulose hexahydrophthalate, cellulose acetate hexahydrophthalate and sodium carboxymethylcellulose; acrylic polymers and copolymers, preferably copolymers made from acrylic acid, methacrylic acid, alkyl acrylates, alkyl methacrylates, e.g. acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate (e.g. terpolymers of ethyl acrylate, methyl methacrylate and trimethylammonium ethylmethacryloyl chloride (to)RS slaveAmerica l.l.c., available from piscataway, NJ)), and the like; vinyl polymers and copolymers such as polyvinylpyrrolidone, polyvinyl acetate phthalate, vinyl acetate crotonic acid copolymer and ethylene-vinyl acetate copolymer; and shellac (shellac), ammoniated shellac, shellac acetyl alcohol and shellac n-butyl stearate.

In some cases it may be desirable for the tablets, beads or particles to be released in the colon, in which case polymers or other materials capable of releasing the drug in the colon may be used. These may be selected from those listed above or other materials known to those skilled in the art of pharmaceutical formulation and administration that may be used. For example, hydrocolloid gums are effective in providing colonic administration, e.g., guar gum, locust bean gum, bena gum, tragacanth gum, and karaya gum (see, e.g., U.S. patent No. 5,656,294). Other materials suitable for effecting colonic delivery include polysaccharides, mucopolysaccharides and related compounds, for example, gums, arabinogalactans, chitosans, chondroitin sulfates, dextrans, galactomannans and xylans.

The desired pulse profile can be obtained by a dosage form containing a plurality of tablets. A first tablet may be provided with little or no coating material, a second tablet may be provided with some degree of coating material, a third tablet may be provided with more coating material, and so on. Similarly, for encapsulated dosage forms in which the dosage unit containing the drug is a bead or microparticle, the bead or microparticle may be provided with little or no coating material in a first component, with a degree of coating material in a second component, with more coating material in a third component, and so on. For example, when the dosage form contains three tablets (or, similarly, three microparticles or beads containing a drug), a first tablet that releases the drug substantially immediately may have a total coat weight of less than about 5% (preferably less than about 3%) (based on the total weight of the tablet), a second tablet may have a total coat weight in the range of about 5% to 50% (preferably 5% to 40%) and a third tablet, if present, may have a total coat weight in the range of about 25% to 60% (preferably 25% to 50%). The preferred coating weight for a particular coating material can be readily determined by one skilled in the art by evaluating the release profile of each of the dosage units prepared with different amounts of the various coating materials.

Alternatively, delayed release dosage units, e.g., tablets, beads or microparticles, may be formulated by using a polymeric coating that imparts delayed release characteristics. The insoluble plastic matrix may be composed of, for example, polyvinyl chloride or polyethylene. Hydrophilic polymers useful for providing a delayed release dosage unit matrix include, but are not limited to, those described above as suitable coating materials. The mixture may be compressed into tablets or processed into individual drug-containing microparticles.

The individual dosage units may have a colored coating, each color corresponding to a tablet or bead or microparticle composition having a corresponding delayed release profile. That is, for example, a blue coating may be used for an immediate release tablet or bead or microparticle composition, a red coating may be used for a "medium" release tablet or bead or microparticle composition, and so forth. In this way, errors in production can be easily avoided. The color may be introduced by introducing a pharmaceutically acceptable colorant into the coating during its preparation. The colorant may be natural or synthetic. Natural colorants include, but are not limited to, pigments such as chlorophyll, anattenes, beta-carotene, alizarin, indigo, rutin, hesperidin, quercetin, pinoxanic acid, and 6, 6' -dibromoindigo. Synthetic colorants include, but are not limited to, dyes, including acid dyes and basic dyes, such as nitroso dyes, nitro dyes, azo dyes, oxazines, thiazines, pyrazolones, xanthenes, indigoids, anthraquinones, acridines, fuchsin bases, phthalones, and quinolines.

For encapsulated tablets, the weight of each individual tablet in the capsule is generally in the range of about 50mg to about 750mg, preferably in the range of about 50mg to about 600mg, and more preferably in the range of about 60mg to about 450 mg. Individual tablets may be prepared by methods known in the art. The preferred method of forming the tablets herein is by direct compression of a powdered, crystalline or granular drug-containing composition, either alone or in combination with diluents, binders, lubricants, disintegrants, colorants or other excipients. Compressed tablets may also be prepared by wet granulation or dry granulation processes. Tablets may also be molded in addition to compression, starting with a moist material containing a suitable water-soluble lubricant. The drug-containing microparticles or beads may also be prepared by methods known in the art, for example, using liquid dispersion.

Dosage units, e.g., tablets, beads or microparticles containing a drug, can be coated using coating procedures and equipment known in the art. For example, delayed release coating compositions may be used as coatingsPan coating or fluidized bed coating equipment. Materials, apparatus and methods for preparing tablets, beads, drug microparticles and delayed release dosage forms are describedPharmaceutical Dosage Forms：TabletsLieberman et al (New York: Marcel Dekker, Inc., 1989) and Ansel et al,Pharmaceutical Dosage Forms and Drug Delivery Systems，6^th Ed.(Media，Pa.：Williams &wilkins, 1995).

Optional components present in each drug-containing dosage unit include, but are not limited to, diluents, binders, lubricants, disintegrants, stabilizers, surfactants, and colorants.

Diluents (also known as "fillers") are typically used to increase the volume of the tablet, thereby providing a size that is practical for compression. Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dried starch, hydrolyzed starch, silicon dioxide, titanium dioxide, alumina, talc, microcrystalline cellulose, powdered sugar, and mixtures thereof.

Binders are used to impart cohesive properties to the tablet formulation and thereby ensure that the tablet remains intact after compression. Suitable binders include, but are not limited to, starches (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose, lactose, and sorbitol), polyethylene glycols, waxes, natural and synthetic gums (e.g., acacia, tragacanth, sodium alginate, polyvinylpyrrolidone, cellulose, and Veegum), and synthetic polymers (e.g., polymethacrylates and polyvinylpyrrolidone) and mixtures thereof.

Lubricants are used to facilitate tablet production. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, and polyethylene glycol. Preferably, the dosage unit contains no more than about 1 wt.% (relative to the weight of the dosage unit) of lubricant.

Disintegrants are used to facilitate disintegration or "disintegration" of a tablet after administration. Suitable disintegrants include, but are not limited to, starches, clays, celluloses, algins, gums, cross-linked polymers, and mixtures thereof.

Stabilizers are used to inhibit or delay drug degradation reactions, including, for example, oxidation reactions, such as those involving bupropion and pharmaceutically acceptable salts thereof (e.g., bupropion hydrochloride). Suitable stabilizers include those described in U.S. Pat. nos. 5,763,493, 5,731,000, and 5,358,970. The stabilizer may be an organic acid, a carboxylic acid, an acid salt of an amino acid, sodium bisulfite or a mixture thereof. Examples of acid salts of amino acids include, but are not limited to, hydrochloride salts such as cysteine hydrochloride, L-cysteine hydrochloride, glycine hydrochloride, and cystine dihydrochloride. Examples of other stabilizers include, but are not limited to, ascorbic acid, malic acid, isoascorbic acid, citric acid, and tartaric acid.

According to one embodiment, the oral dosage form may be prepared using non-organic solvents. According to another embodiment of the present invention, the dosage form contains less than 0.2% BHT, antioxidant.

Suitable surfactants include, but are not limited to, anionic, cationic, amphoteric, and nonionic surfactants. Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate, and sulfate ions in combination with cations such as sodium, potassium, and ammonium ions. Other suitable surfactants include, but are not limited to, long alkyl chain sulfonates and alkylaryl sulfonates such as sodium dodecylbenzene sulfonate; sodium dialkyl sulfosuccinates, such as sodium bis- (2-ethylhexyl) sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate.

If desired, the tablets may also contain non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and preservatives.

As previously described herein, in one embodiment, the individual pharmaceutical tablets,The beads or particles are contained within a closed capsule. The capsule material may be hard or soft and, as would be expected by those skilled in the art of pharmaceutical science, typically contains a compound that is tasteless, easy to administer and soluble in water, such as gelatin, starch or cellulose. The preferred capsule material is gelatin. The capsule is preferably sealed, for example with gelatin tape. See, for example,Remington：The Science and Practice of Pharmacy，20^thedition (Easton, Pa.: Mack Publishing Co., 2000) describes materials and methods for preparing encapsulated drugs that dissolve shortly after ingestion.

Dosage forms

The dosage form may also include one or more release modifying agents in the form of a polymeric coating or matrix. The dosage form may also include one or more carriers, excipients, anti-caking agents, fillers, stabilizers, binders, colorants, glidants, and lubricants.

Depending on the hydrophilic or hydrophobic nature of the matrix, the material may swell to a size large enough upon contact with gastric fluid to facilitate retention of the drug in the stomach while the subject is in a digestive state. The digestive state is caused by the ingestion of food and begins with rapid and large changes in the motor pattern of the upper Gastrointestinal (GI) tract location. The changes consist of a reduction in the amplitude of the contractions experienced by the stomach and a reduction in the opening of the pylorus to a partially closed state. The result is a sifting process that allows liquid and small particles to pass through the partially open pylorus, while indigestible particles larger than the pylorus are retrograde drained (retropelleted) and retained in the stomach. The biological fluid migrates through the matrix and dissolves the active ingredient, which is released by diffusion of the matrix, which simultaneously regulates the release flow. Thus, the controlled release matrix in these embodiments of the present invention is selected to be one that expands to a size large enough to retrograde and thereby remain in the stomach, thereby allowing delayed release of the drug to occur in the stomach rather than in the intestinal tract. U.S. Pat. Nos. 5,007,790, 5,582,837 and 5,972,389, and International publication Nos. WO 98/55107 and WO 96/26718 disclose oral dosage forms that expand to a size that prolongs residence time in the stomach. Each of the documents cited in this paragraph is incorporated herein by reference in its entirety.

The matrix may be composed of insoluble hydrophilic polymers, such as cellulose esters, carboxyvinyl esters or acrylates or methacrylates. On contact with biological fluids, the hydrophilic matrix becomes hydrated and swells, forming a very dense polymer network through which the soluble active ingredient diffuses. Furthermore, lipids, in particular glycerides, may be added in order to regulate the swelling of the matrix. These compositions can be obtained by granulating a mixture of the polymer, the active principle and various adjuvants and then compressing.

The hydrophobic matrix may consist of a lipid matrix agent of natural origin, such as beeswax, which is highly harmless. These compositions can be obtained by wet or solvent route granulation of the various components contained in high proportions, followed by compression.

Typically, the swellable matrix contains an adhesive that is a water-swellable, non-toxic polymer that swells in a spatially unrestricted manner after absorbing water and gradually releases the drug over time. Examples of polymers that meet this description include, but are not limited to, the following: cellulosic polymers and their derivatives, including, but not limited to, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose and microcrystalline cellulose polysaccharides and their derivatives, polyalkylene oxide based, polyethylene glycol, chitosan, poly (vinyl alcohol), xanthan gum, maleic anhydride copolymers, poly (vinyl pyrrolidone), starch and starch based polymers, maltodextrin, poly (2-ethyl-2-oxazoline), poly (ethyleneimine), polyurethane hydrogels and cross-linked polyacrylic acids and their derivatives. Further non-limiting examples are copolymers of the polymers listed above, including block copolymers and graft polymers. A specific example of the copolymer isAndthey are polyethylene oxide-polypropylene oxide block copolymers and are available from BASF Corporation, Chemicals div. A further example is a hydrolyzed starch polyacrylonitrile graft copolymer, commonly referred to as a "superabsorbent material" and available from Illinois corngrowers Association, Bloomington, il.

Other suitable polymers for the matrix are poly (ethylene oxide) -hydroxypropyl methylcellulose and combinations of poly (ethylene oxide) and hydroxypropyl methylcellulose. The preferred polymer is hydroxypropyl methylcellulose. In one embodiment, a modified release formulation, such as a 24 hour modified release formulation, contains such a polymer in an amount of about 10% w/w to about 50% w/w, preferably in a range of from about 15% to about 45% w/w.

Time of appearance of maximum plasma concentration value (T) relative to immediate release_max) The above extension is related to the in vitro dissolution release rate of the drug. The rate of release of the drug by dissolution in vitro depends on the composition of the matrix. By using different cellulose matrices, the in vitro release rate (drug dissolution over about 70% to about 80%) can be arbitrarily manipulated within about 4 hours to 24 hours. Maximum plasma concentration time of the formulation (mean T) for both drugs_max) Is in the range of between about 1 to about 35 hours, preferably from about 4 hours to about 30 hours, and an in vitro release rate of greater than about 70% to about 80% is within about 4 hours to about 24 hours. Preferably, the release rate of the formulation is greater than 80% for escitalopram within about 30 minutes to about 12 hours. More preferably, the release rate of the formulation is from about 10% to about 40% within the first hour after deep release into the environment of use (e.g., gastrointestinal tract); more preferably, the formulation has a release rate of more than 70% over the next 12 hours.

The tablets according to the invention may be prepared by conventional mixing, crushing and tabletting processes known in the pharmaceutical formulation industry. Modified release tablets may be prepared, for example, by direct compression, spraying or compression molding, granulation followed by compression by a punch and die suitable for rotary compression, or by forming a paste and extruding the paste into a die or cutting the extrudate into small pieces.

Fillers such as lactose (e.g., lactose monohydrate) are used to modify the dissolution profile. When hydroxypropyl methylcellulose or ethylcellulose is used, the dissolution rate may be much slower than the modified release rate target. This slow release is due to the fact that the hydrophobic matrix tablet formed releases the drug pair by a mechanism of polymer erosion. Since the erosion of the hydrophobic matrix is very slow, the dissolution rate of the readily soluble active ingredient is also slow. However, lactose is also an important filler component for improving the powder flow and compressibility of escitalopram and bupropion tablets.

When tablets are made by direct compression, the addition of a lubricant may be beneficial and is sometimes important to promote powder flow and to prevent tablet breakage (breaking of a portion of the tablet) after pressure is removed. Effective lubricants include magnesium stearate and hydrogenated vegetable oils (preferably hydrogenated and refined triglycerides of stearic and palmitic acids). In a preferred embodiment, the lubricant is magnesium stearate. For 24 hour release formulations, magnesium stearate is preferably present in an amount of about 0.5% w/w to about 3% w/w, preferably about 0.5% w/w to about 2% w/w. Additional excipients may be added to increase tablet hardness, powder flow and tablet friability and reduce sticking to the mold walls.

Example 1

Escitalopram core and modified release beads

Tables 1 and 2 show the formulation ingredients and weight percent ranges used to make the escitalopram core and modified release beads, respectively. Each modified release bead is an escitalopram core bead coated with a modified release coating.

Table 1: formula range of escitalopram core bead

^*-888 is glyceryl behenate (tribehenin) and is obtainable from gattefossecorp. of Paramus, NJ.

^**-PH101 is microcrystalline cellulose and is available from FMC Corporation of philiadelphia, PA.

^***PVP K-30 is polyvinylpyrrolidone with a K value of about 30.

Table 2: formula range of escitalopram modified release coating

^****-Is an aqueous dispersion of ethyl cellulose and is available from Colorcon, inc.

Escitalopram core beads (200mg/g) having the formulation of table 3 were produced.

Table 3: escitalopram core bead (200mg/g)

The beads may be prepared by mixing ingredients 1-5 from table 3 in a high shear granulator (Disona, Fluid Air, Chicago, IL). The granulated material was extruded by an extruder (Niro, model E-140, Columbia, MD) and then spheronized by a spheronizer (Niro, model S450, Columbia, MD) to prepare beads. Optionally drying the beads at 50 ℃ for up to 12 hours.

The escitalopram core beads in table 3 were coated with a modified release coating according to table 4 (curve I) or 5 (curve II).

Table 4: escitalopram modified release beads (194.1mg/g)

Table 5: escitalopram modified release beads (188.7mg/g)

The simulated dissolution profiles of the escitalopram core beads (200mg/g) of table 3 and the modified release beads of tables 4 and 5 are shown in figure 1.

Example 2

Pulsatile escitalopram capsule dosage form

The escitalopram core described in example 1 and modified release beads can be filled into capsules to give a pulsed release profile. For example, a predetermined weight of beads may be filled into a capsule using a capsule filling machine (MG-2, MG America, Fairfield, NJ). The number of beads per capsule for a 4mg strength pulsed escitalopram capsule is shown in table 6.

Table 6: prescription of pulse escitalopram capsule

Curve line	Inner core bead (mg/capsule)	Modified release bead 1 (mg/capsule)	Modified release bead 2 (mg/capsule)
				Single pulse	0	0	27.1mg
Double pulse	6.4mg	0	20.3mg
				Three pulses	6.4mg	6.6mg	13.6mg

Capsules containing different numbers of beads of a given strength will produce different dissolution profiles. Also, the strength corresponding to different doses can be produced by using more beads, e.g. 5,8, 10, 15, 16, 20 and 40mg in total fill weight.

Example 3

Bupropion core and modified release beads

Tables 7 and 8 show the formulation ingredients and weight percent ranges used to make the bupropion core and modified release beads, respectively. Each modified release bead comprises an inner core bead of bupropion coated with a modified release coating. Table 9 shows the formulation composition and weight percent ranges for bupropion core beads (600 mg/g).

Table 7: bupropion core bead formula range

Composition% w/w

Bupropion hydrochloride 3.0-70.0

888 5.0-50.0

Sorbitan monostearate 1.0-15.0

PH101 3.0-50.0

HPMC 0-30.0

PVP K-30 1.0-7.0

Talc, USP 1.0-6.0

Sorbitan oleate 3.0-15.0

Total of 100.0

Table 8: formula range of bupropion modified release coating

Composition% w/w

Bupropion HCl core bead 20-95

5-40.0

Purified water QS

Total of 100.0

Table 9: bupropion core bead (600mg/g)

# ingredient% w/w Wt. grams

1. Bupropion HCl 60.0600

2. 888 17.0 170

3. PH101 7.0 70

4. PVP K-30 2.0 20

5. Talc, USP 4.040

6. Sorbitan oleate 10.0100

Aggregate 100.01000

The beads may be prepared by mixing ingredients 1-5 from table 9 in a high shear granulator (Disona, Fluid Air, Chicago, IL). The pelletized material was extruded with an extruder (Niro, model E-140, Columbia, MD) and then spheronized with a spheronizer (Niro, model S450, Columbia, MD) to make beads. Optionally the beads are dried at 50 ℃ for up to 12 hours.

The inner bupropion beads in table 9 were coated with a modified release coating according to table 10 (curve I) or 11 (curve II).

Table 10: amphetanone modified Release beads (545.5mg/g)

Composition% w/w

600mg/g 90 bupropion core bead

RS/RL(95％:5％)^* 10

Purified water QS

Total of 100.0

^*RS/RL (95%: 5%) is 95%RS and 5%A mixture of RL, both of which are derived fromObtained from America Inc. of Piscataway, N.J.

Table 11: amphetanone modified Release beads (500mg/g)

Composition% w/w

Bupropion core bead 600mg/g 80

RS/RL(95％:5％) 20

Purified water QS

Total of 100.0

The simulated dissolution curves for the bupropion inner core beads of Table 9 (600mg/g) and the modified release beads of tables 10 and 11 are shown in FIG. 2.

Tables 12A-12D show formulation ingredients and weight percentages used to produce IR, MR I, MR II and pulse formulations.

The beads may be prepared by mixing the ingredients in a high shear granulator (Disona, Fluid Air, Chicago, IL). The granulated material was extruded by an extruder (Niro, model E-140, Columbia, MD) and then spheronized by a spheronizer (Niro, model S450, Columbia, MD) to prepare beads. Optionally drying the beads at 50 ℃ for up to 12 hours. The beads were then coated with a seal coat polymer in a fluidized bed applicator (Glatt AIR, Ramsey, NJ) at 25 to 30 ℃.

Table 12A: immediate release formulation

Immediate release bupropion (596mg/g) extruded bead mg/dose mg/g

Bupropion HCl 300595.9

Glyceryl behenate, NF 73.1145.4

888ATO)

Microcrystalline cellulose: ( PH101) 33.2 66.0

Anhydrous citric acid 23.747.2

Butylated Hydroxyanisole (BHA) 0.050.1

Sorbitan monooleate, NF (SPAN 80) 57.0113.2

Talc, USP (PHARMA M) 14.128.0

Total (extruded beads) 501995.7

Sealing coating:

KLUCEL EF 2.1 4.2

butylated hydroxyanisole 0.0420.1

water-Q.S.

Aggregate 503.11000.0

Table 12B: modified release formulation I

Modified release formulation I (544mg/g) mg/dose mg/g

Immediate release bead (596mg/g) 503.1904.2

EUDRAGIT NE 30D Dispersion (solid) 52.193.7

Talc 1.22.1

Butylated hydroxyanisole <0.05

water-Q.S.

Aggregate 556.41000.0

The modified release I beads can be coated using Eudragit suspensions in a fluidized bed applicator (Glatt AIR, Ramsey, NJ) at 25 to 30 ℃.

Table 12C: modified release formulation II

Modified (delayed/extended) Release formulation II (414mg/g) mg/dose mg/g

Modified release I beads (544mg/g) 556.4769.2

ACRYLENE (solids content) 167.0230.8

water-Q.S.

Aggregate 723.41000.0

The modified release II beads can be coated using Eudragit suspensions in a fluidized bed applicator (Glatt AIR, Ramsey, NJ) at 30 to 40 ℃.

Table 12D: pulse preparation

Double-pulse preparation (300mg/g) mg/dose

Immediate release bupropion (596mg/g) 100.6mg

Modified release formulation II (414mg/g) 578.7mg

Total 679.3mg

The bi-pulse beadcontaining capsules were prepared by mixing different beads using a capsule filling machine (MG-2, MG America, Fairfield, NJ) during the processing of the encapsulated capsules.

Example 4

Pulsatile bupropion capsule dosage forms

The bupropion core and modified release beads described in example 3 can be filled into capsules to give a pulsatile release profile. For example, a predetermined weight of beads may be filled into a capsule using a capsule filling machine (MG-2, MG America, Fairfield, NJ). For a 150mg strength pulsed bupropion capsule, the number of beads per capsule is shown in table 13.

Table 13: formulation of pulse bupropion capsule dosage form

Curve line	Inner core bead (mg/capsule)	Modified release bead 1 (mg/capsule)	Modified release bead 2 (mg/capsule)
				Single pulse	250mg	0	0
Double pulse	0	137.5mg	150mg
				Three pulses	0	0	300mg

Capsules containing different numbers of beads of a given strength will produce different dissolution profiles. Also, the strength corresponding to different doses can be produced by using more beads, for example 75 to 450mg in total fill weight.

Example 5

Pulsatile escitalopram and bupropion capsule dosage forms

The pulsed capsule dosage form is prepared by encapsulating a plurality of escitalopram beads and bupropion beads in a capsule. A pulsed capsule dose formulation of 150mg bupropion/escitalopram capsule at a concentration of 4mg is shown in table 14.

Table 14: 150mg bupropion/4 mg escitalopram pulse capsule dosage form

	Bupropion core pulse (mg/capsule)	Bupropion MR pulse 1 (mg/capsule)	Amphetanone MR pulse 2 (mg/capsule)	Escitalopram core pulse (mg/capsule)	Escitalopram MR pulse 1 (mg/capsule)	Escitalopram MR pulse 2 (mg/capsule)
							Double pulse (once per API) (capsule A)	250mg	0	0	25.6mg	0	0
Single MR pulse (Capsule B)	0	0mg	300mg	0	0mg	272mg
							Double MR pulse (Capsule C)	0	1375mg	150mg	0	13.2mg	13.6mg

A variety of bead compositions can be manufactured to meet a desired dissolution release profile. The beads may be filled in a bead mixer or multiple bins associated with an encapsulation machine (e.g., MG-2, MG America, Fairfield, NJ). Figures 3 and 4 show the bupropion and escitalopram dissolution rates, respectively, for the three capsules shown in table 13. The dissolution tests of both figures were carried out according to the USP basket method at 100rpm in 0.1N HCl.

Dose rate concentrations can be prepared by varying the fill weight.

Formulations of inner core and modified release beads, which mix bupropion and escitalopram in one system (beads), are susceptible to degradation of both molecules. It was observed that each lost more than 10% of its efficacy when stored for 1 month at 40 ℃ and 75% relative humidity. The formulations of the present invention show excellent stability under the same conditions. Both beads of bupropion and escitalopram used in this example showed less than 10% loss of potency, and in most cases less than 5% loss of potency after 1 month of storage at 40 ℃ and 75% relative humidity.

Patents, patent applications, publications, product descriptions, and protocols are cited throughout the application, and these publications are incorporated herein by reference in their entirety for all purposes.

Claims (45)

1. An oral dosage form comprising bupropion or a pharmaceutically acceptable salt thereof and escitalopram or a pharmaceutically acceptable salt thereof.

2. The oral dosage form of claim 1, wherein bupropion or a pharmaceutically acceptable salt thereof and escitalopram or a pharmaceutically acceptable salt thereof are physically separated in the oral dosage form.

3. The oral dosage form of claim 1, wherein said oral dosage form comprises from about 50 to about 450mg of bupropion or a pharmaceutically acceptable salt thereof (calculated based on the weight of 1 molar equivalent of bupropion hydrochloride).

4. The oral dosage form of claim 1, wherein the oral dosage form comprises from about 75 to about 225mg of bupropion or pharmaceutically acceptable salt thereof (calculated based on the weight of 1 molar equivalent of bupropion hydrochloride).

5. The oral dosage form of claim 1, wherein the oral dosage form comprises 150mg of bupropion or a pharmaceutically acceptable salt thereof.

6. The oral dosage form of claim 1, wherein the oral dosage form comprises 225mg of bupropion or a pharmaceutically acceptable salt thereof.

7. The oral dosage form of claim 1, wherein the oral dosage form comprises bupropion hydrochloride.

8. The oral dosage form of claim 1, wherein the oral dosage form comprises about 2.5 to about 40mg escitalopram or a pharmaceutically acceptable salt thereof (calculated on the weight of 1 molar equivalent of escitalopram free base).

9. The oral dosage form of claim 1, wherein the oral dosage form comprises 2.5mg escitalopram or a pharmaceutically acceptable salt thereof.

10. The oral dosage form of claim 1, wherein the oral dosage form comprises 4mg of escitalopram or a pharmaceutically acceptable salt thereof.

11. The oral dosage form of claim 1, wherein the oral dosage form comprises 5mg of escitalopram or a pharmaceutically acceptable salt thereof.

12. The oral dosage form of claim 1, wherein the oral dosage form comprises 10mg of escitalopram or a pharmaceutically acceptable salt thereof.

13. The oral dosage form of claim 1, wherein the oral dosage form comprises 20mg of escitalopram or a pharmaceutically acceptable salt thereof.

14. The oral dosage form of claim 1, wherein the oral dosage form comprises escitalopram oxalate.

15. The oral dosage form of claim 1, wherein the oral dosage form provides immediate release of the bupropion or pharmaceutically acceptable salt thereof.

16. The oral dosage form of claim 1, wherein the oral dosage form provides modified release of bupropion or a pharmaceutically acceptable salt thereof.

17. The oral dosage form of claim 1, wherein the oral dosage form provides immediate release of escitalopram or a pharmaceutically acceptable salt thereof.

18. The oral dosage form of claim 1, wherein the oral dosage form provides modified release of bupropion or a pharmaceutically acceptable salt thereof.

19. The oral dosage form of claim 1, wherein the oral dosage form, after ingestion by a patient, causes a mean fluctuation index of bupropion or a pharmaceutically acceptable salt thereof in plasma that is statistically significantly lower than an immediate release tablet containing the same dose of bupropion or a pharmaceutically acceptable salt thereof and provides bioavailability of bupropion or a pharmaceutically acceptable salt thereof that is substantially equivalent to three immediate release tablets of bupropion or a pharmaceutically acceptable salt thereof administered one tablet every 6 hours or more per day.

20. The oral dosage form of claim 1 wherein less than about 40% of the bupropion or pharmaceutically acceptable salt thereof (based on 100% bupropion or pharmaceutically acceptable salt thereof in the dosage form) is released 2 hours after administration and more than about 60% of the escitalopram or pharmaceutically acceptable salt thereof is released 12 hours after administration.

21. The oral dosage form of claim 1, wherein the oral dosage form provides pulsatile release of the bupropion or pharmaceutically acceptable salt thereof.

22. The oral dosage form of claim 1, wherein the oral dosage form comprises modified release beads of bupropion or acceptable salts thereof having at least two different release profiles.

23. The oral dosage form of claim 1, wherein the dosage form comprises a modified release tablet of bupropion or an acceptable salt thereof.

24. The oral dosage form of claim 1 having an in vitro dissolution profile measured by USP paddle method at 75rpm in 900ml of water at 37 ℃ such that (i) less than about 20% by weight of the bupropion or pharmaceutically acceptable salt thereof is released after 2 hours, (ii) from about 10% to about 60% of the bupropion or pharmaceutically acceptable salt thereof is released after 8 hours, and (iii) more than about 70% of the bupropion or pharmaceutically acceptable salt thereof is released after 24 hours.

25. The oral dosage form of claim 1, which has an in vitro dissolution profile measured by USP paddle method at 100rpm in 900ml 0.1N HCl at 37 ℃ such that (i) less than about 20% by weight of the bupropion or pharmaceutically acceptable salt thereof is released after 2 hours, (ii) from about 10% to about 60% of the bupropion or pharmaceutically acceptable salt thereof is released after 8 hours, and (iii) more than about 70% of the bupropion or pharmaceutically acceptable salt thereof is released after 24 hours.

26. The oral dosage form of claim 1, wherein the oral dosage form provides a T of escitalopram or a pharmaceutically acceptable salt thereof in the range of about 4 to about 35 hours after ingestion by a patient_max。

27. The oral dosage form of claim 1, wherein the oral dosage form provides a T of escitalopram or a pharmaceutically acceptable salt thereof for about 5 hours after ingestion by a patient_max。

28. The oral dosage form of claim 1, wherein the oral dosage form, upon ingestion by a patient, provides:

(a) average C of escitalopram or a pharmaceutically acceptable salt thereof_maxIs about 50 to about 85% of an immediate release tablet containing the same dose of escitalopram or a pharmaceutically acceptable salt thereof,

(b) t of escitalopram or a pharmaceutically acceptable salt thereof_maxFrom about 1 to about 8 hours, and

(c) the bioavailability of escitalopram or a pharmaceutically acceptable salt thereof is substantially equivalent to an immediate release tablet containing the same dose of escitalopram or a pharmaceutically acceptable salt thereof.

29. The oral dosage form of claim 1, wherein the oral dosage form, after ingestion by a patient,

(a) causes the mean fluctuation index of escitalopram or a pharmaceutically acceptable salt thereof in plasma to be statistically significantly lower than that of an immediate release tablet containing the same dose of escitalopram or a pharmaceutically acceptable salt thereof,

(b) there is provided escitalopram substantially equivalent to an immediate release tablet containing the same dose of escitalopram or a pharmaceutically acceptable salt thereofMean minimum plasma concentration (Cmax) of Lun or a pharmaceutically acceptable salt thereof_min)，

(c) There is provided an area under the plasma concentration versus time curve (AUC) of escitalopram or a pharmaceutically acceptable salt thereof in the range of about-20% to about 25% of the area produced by an immediate release tablet containing the same dose of escitalopram or a pharmaceutically acceptable salt thereof, or

(d) Any combination of the above.

30. The oral dosage form of claim 1, wherein the oral dosage form has an AUC of about 320 to about 400 ng-h/ml of escitalopram or a pharmaceutically acceptable salt thereof_0-24。

31. The oral dosage form of claim 1, wherein the oral dosage form has an in vitro dissolution profile measured by the USP basket method at 100rpm in 900ml 0.1N HCl at 37 ℃ such that after about 30 minutes more than about 80% by weight of escitalopram, or a pharmaceutically acceptable salt thereof, is released.

32. The oral dosage form of claim 1, wherein the oral dosage form has an in vitro dissolution profile measured by the USP basket method at 100rpm in 900ml 0.1N HCl at 37 ℃ such that (i) after 2 hours about 10% to about 50% by weight of escitalopram, or a pharmaceutically acceptable salt thereof, is released and (ii) after 8 hours more than about 60% is released.

33. The oral dosage form of claim 1, wherein the oral dosage form comprises 10mg escitalopram or a pharmaceutically acceptable salt thereof (calculated on the weight of escitalopram free base in an amount of 1 molar equivalent) and provides a mean maximum plasma concentration (Cmax) of escitalopram or a pharmaceutically acceptable salt thereof of about 1ng/ml to about 50ng/ml after ingestion by a patient_max)。

34. The oral dosage form of claim 1Wherein the oral dosage form provides a mean maximum plasma concentration (Cmax) of escitalopram or a pharmaceutically acceptable salt thereof from about 10ng/ml to about 18ng/ml after ingestion by a patient_max)。

35. The oral dosage form of claim 1, wherein the oral dosage form provides a therapeutic effect for at least about 24 hours after administration to a patient.

36. A method of treating a central nervous system disorder in a patient in need thereof, comprising administering the oral dosage form of claim 1.

37. The method of claim 36, wherein said oral dosage form is administered once daily.

38. The method of claim 36, wherein the disorder is a mood disorder.

39. The method of claim 38, wherein the mood disorder is a major depressive disorder.

40. The method of claim 39, wherein the disorder is an anxiety disorder.

41. A method of treating a sexual disorder in a patient in need thereof, the method comprising administering the oral dosage form of claim 1.

42. The method of claim 41, wherein said sexual disorder is an ejaculatory disorder.

43. The method of claim 41, wherein said sexual disorder is anorgasmia.

44. The method of claim 41 wherein said sexual disorder is hypoactive sexual desire.

45. A method of treating a patient suffering from treatment-resistant depression, the method comprising administering to the patient an effective amount of the oral dosage form of claim 1.