MX2008004862A

MX2008004862A - Stable pharmaceutical formulations containing escitalopram and bupropion

Info

Publication number: MX2008004862A
Application number: MX/A/2008/004862A
Authority: MX
Inventors: G Dedhiya Mahendra; Chhettry Anil; Mani Narasimhan
Original assignee: Chhettry Anil; G Dedhiya Mahendra; Forest Laboratories Inc; Mani Narasimhan
Priority date: 2005-10-14
Filing date: 2008-04-14
Publication date: 2008-10-03

Abstract

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

Description

STABLE PHARMACEUTICAL FORMULATIONS CONTAINING ESCITALOPRAM AND BUPROPION FIELD OF THE INVENTION The present invention relates to stable pharmaceutical formulations of escitalopram and bupropion and their use for the treatment of a central nervous system disorder, such as a mood disorder (e.g., severe depressive disorder) or a disorder of anxiety (for example, general anxiety disorder, social anxiety disorder, post-traumatic stress disorder, or panic disorder).

BACKGROUND OF THE INVENTION Selective serotonin reuptake inhibitors (hereinafter called SSRIs), such as citalopram and racemic escitalopram, have become the therapeutics of first choice in the treatment of depression primarily because of their superior efficacy in comparison to tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs). SSRIs work by inhibiting the reuptake of the neurotransmitter serotonin (5-hydroxy t riptamine, 5-HT) by nerve cells in synapses. As a result, serotonin persists in the synaptic opening and has the opportunity to stimulate the receptors of the recipient cells. Escitalopram is the S enantiomer of citalopram and has the following structure: The escitalopram preparation methods are described in, for example, U.S. Pat. U.U Nos. Re. 34,712 and 6,566,540 and International Applications Nos. WO 03/000672, WO 03/006449, WO 03/051861, and WO 2004/083197, all of which are hereby incorporated by reference. International Publications Nos. WO 01/03694 and WO 02/087566, which are hereby incorporated by reference, describe the use of escitalopram in the treatment of various mental disorders including severe depressive disorder, general anxiety disorder, disordered social anxiety, post-traumatic stress disorder, panic attacks, acute stress disorder, eating disorders (such as bulimia, anorexia and obesity), phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, hyperactivity disorder of attention deficit and abuse of drugs. International Application No. WO 02/087566 also describes the use of escitalopram for the treatment of patients who have failed to respond to initial treatment with a conventional SSRI, in particular patients with severe depression disorder who have failed to respond to initial treatment with a conventional SSRI. Escitalopram oxalate is currently marketed in the United States as Lexapro® for the treatment of severe depressive disorder and generalized anxiety disorder. Lexapro® is available in 5, 10 and 20 mg immediate release tablets of escitalopram (as an oxalate salt) and in 5 rag / mL of an oral solution. A modified release formulation of escitalopram oxalate prepared by melt granulation is described in International Publication No. WO 01/22941. Modified release formulations of SSRIs, such as citalopram hydrobromide and escitalopram oxalate, having particular dissolution configurations are described in International Publication No. WO 2004/058299. Side effects associated with escitalopram include nausea, insomnia, drowsiness, increased sweating, fatigue, and sexual dysfunction (including, but not limited to, ejaculation disorder, anorgasmia, and reduced libido). Bupropion hydrochloride, which is described in U.S. Pat. Nos. 3,819,706 and 3,885,046, it is currently marketed as Wellbutrin®, Wellbutrin SR®, and Wellbutrin XL® for the treatment of severe depressive disorder and Zyban® as an aid to treatment for cessation of smoking. Bupropion is an amino ketone derivative chemically unrelated to other currently available antidepressants (eg, serotonin reuptake inhibitors, tricyclics, and tetracyclics). While the neurochemical mechanisms of the antidepressant and smoking cessation effects are unknown, the noradrenergic trajectories and / or dopaminergic effects appear to be mainly included. Bupropion does not inhibit monoamine oxidase and is a weak serotonin blocker and norepinephrine reuptake. Wellbutrin® (a formulation of bupropion hydrochloride immediate release) is supplied as tablets of 75 and 100 mg which will be administered three times a day, preferably with at least 6 hours between successive doses. Controlled release formulations of bupropion hydrochloride have been developed. For example, U.S. Pat. Do not.

Re. 33,994 discloses a controlled release bupropion tablet formulation comprising a core of bupropion hydrochloride and a coating comprised of a water-permeable film-forming coating, insoluble in water and a water-soluble pore-forming material. , particulate. However, because 25-70% of the bupropion is released within 4 hours and 40-90% within 6 hours, at least the dose of twice daily is typically still required. U.S. Pat. Nos. 5,358,970, 5,763,493, and 5,731,000 describe formulations of bupropion hydrochloride containing a stabilizer to prevent degradation of bupropion hydrochloride. U.S. Pat. No. 5,427,798 discloses a controlled release bupropion tablet formulation containing hydroxypropylmethylcellulose. More than half of bupropion is released preferentially in distilled water in 4 hours. Due to this rapid release rate, the formulation is typically administered multiple times in a day. U.S. Pat. Nos. 6,096,341 and 6,143,327 describe a controlled release tablet of bupropion hydrochloride, free of stabilizers and pore-forming agents. The tablet is comprised of a core consisting essentially of bupropion hydrochloride, a binder, and a lubricant, and a coating consisting essentially of a water-permeable, water-permeable, water-permeable film-forming polymer, a binder, and a binder. water soluble polymer. U.S. Pat. No. 6,905,708 and the U.S. Patent Application Publications. Nos. 2003/0161874 and 2005/0147678 describe the formulation of bupropion hydrochloride once a day comprising tablets coated with bupropion hydrochloride. In DeVane, J. Clin. Psychiatry 2003, 64 (suppl.18): 14-19, the results of clinical studies of controlled release formulations and immediate release of antidepressants were compared in relation to nausea leading to discontinuation of the drug. The author stated that "the most stable pharmacokinetic profiles could be the cause for the low occurrence of nausea with some newer controlled-release antidepressants" but "a connection has not been proven".

According to Gerner et al., Biol. Psychiatry, 1998, 43.101S, abstract 336 ("Gerner I"), "[b] upropion has been added to the SSRIs for the treatment of inadequate clinical response, sexual dysfunction by SSRI, and for comorbid ADD and depression associated with [p] aic or [d] ompul sive [c] structions [ojbsesivo. See also Kennedy et al., J. Clin Psychiatry, 2002, 63: 181-186 (study regarding the effects of sexual dysfunction, therapeutics, pharmacokinetics of bupropion SR combinations with venlafaxine, paroxetine, or fluxetine); Gerner et al., Biol. Psychiatry, 1998, 43: 99S, abstract 329 ("Gerner II"); Ashton et al., J. Clin. Psychiatry, 1998, 59 (3): 112-115 (study regarding the use of bupropion as an antidote for sexual dysfunction induced by the serotonin reuptake inhibitor (paroxetine, fluoxetine, sertraline, venlafaxine, or fluvoxamine); Gitlin et al. ., J. Sex &Marital Therapy 2002, 28: 131-138 (study regarding a sustained release formulation of bupropion as a treatment for sexual side effects induced by SSRI) .However, the treatment of induced sexual dysfunction by SSRI with bupropion has not been proven to be effective According to Sturpe et al., J. Family Practice August 2002, 51 (8): 1681, a double-blind placebo-controlled trial comparing augmentation therapy with bupropion showed improvement In addition, bupropion has increased the incidence of attack compared to other antidepressants Gerner II, supra (reported in 3 cases of severe motor berthing in previously depressed patients). you free of attacks after combining bupropion with fluoxetine or fluvoxamine); see also Gerner J, upra. Studies suggest that between 29% and 46% of depressed patients fail to respond fully with the antidepressant treatment of the appropriate duration and dose. 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, reported the results of a clinical study comparing the combination of bupropion SR and citalopram against exchange to monotherapy in patients with treatment-resistant depression. According to the authors, "[t] he results of this cohort study suggest that the combination of bupropion SR and citalopram is more effective than exchange to monotherapy." U.S. Pat. No. 6,342,496 describes the metabolites of bupropion for treatment of disorders lessen by the inhibition of neuronal monoamine retake. The metabolite of bupropion may be administered in an adjunct manner with an additional pharmacologically active compound, such as an SSRI, 5-HT3 inhibitor, or nicotine. There is a need for methods of treating disorders of the central nervous system which have fewer side effects than the previous methods and which are effective in patients resistant to treatment.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to stable oral dosage forms containing escitalopram (or a pharmaceutically acceptable salt thereof) and bupropion (or a pharmaceutically acceptable salt thereof). Preferably, the oral dosage forms are formulations once a day, ie, it is only required to provide the patient once a day with a therapeutic effect for the entire day (24 hours). The amount of bupropion of a pharmaceutically acceptable salt thereof in the oral dosage forms preferably ranges from about 50 to about 450 mg and more preferably from about 75 to about 225 mg (calculated on the basis of the weight of one molar equivalent of hydrochloride of bupropion) (for example, 75, 150, or 225 mg). The amount of escitalopram or a pharmaceutically acceptable salt thereof in the oral dosage forms preferably ranges from about 2.5 to about 40 mg of escitalopram and more preferably 2.5 to 20 mg (calculated on the basis of the weight of a molar equivalent of base escitalopram. free) (for example, 2.5, 5, 10, or 20 mg). According to a preferred embodiment, the oral dosage form comprises 4 mg of escitalopram or a pharmaceutically acceptable salt thereof and 150 mg of bupropion or a pharmaceutically acceptable salt of mime. The oral dosage form can provide immediate release or modified release of each active component. Preferably, bupropion and escitalopram in the oral dosage form are physically separated. The inventors have discovered that the conventional formulations of escitalopram hydrobromide and escitalopram oxalate unexpectedly degrade under storage conditions. In particular, escitalopram oxalate, which is stable in commercial formulations up to about 12 months, degrades significantly faster when stored in intimate contact with bupropion hydrochloride. It has been found that when the two are in intimate contact, each is degraded by more than 10% in potency after one month of storage at 40 ° C and 75% relative humidity. Escitalopram and bupropion can be separated by having separate discrete zones of the dosage form (such as different layers) for each component.

- - Alternatively, the dosage form may include a plurality of sitalitalia tablets or beads and a plurality of bupropion tablets or beads, wherein one or both escitalopram tablets / beads and bupropion tablets / beads are coated. Preferably, the oral dosage form contains (1) at least about 80% w / w of non-degraded escitalopram or pharmaceutically acceptable salt thereof (relative to the initial amount of escitalopram or pharmaceutically acceptable salt thereof) after storage for 6 hours. weeks at about 40 ° C and 75% relative humidity, (2) at least about 80% w / w degraded bupropion or pharmaceutically acceptable salt thereof after storage for 6 weeks at about 40 ° C and 75% relative humidity , or both. The oral dosage form more preferably contains at least about 90% w / w and even more preferably 95% w / w degraded bupropion or a pharmaceutically acceptable salt thereof and / or unreacted escitalopram or a pharmaceutically acceptable salt thereof after storage for 6 weeks under the same conditions. According to still another preferred embodiment, the oral dosage form contains (1) at least about 90% w / w of non-degraded escitalopram or pharmaceutically acceptable salt thereof (in relation to the initial amount - of escitalopram or pharmaceutically acceptable salt of the same) after storage for 1, 3, or 6 months at about 40 ° C and 75% relative humidity, (2) at least about 90% w / w of non-degraded bupropion or pharmaceutically acceptable salt thereof after storage by 1, 3, or 6 months at approximately 40 ° C and 75% relative humidity, or both. The oral dosage form more preferably contains at least about 95% w / w of non-degraded bupropion or a pharmaceutically acceptable salt thereof and / or non-degraded escitalopram or a pharmaceutically acceptable salt thereof after storage by 1, 3, or 6 months under the same conditions. According to another preferred embodiment, the oral dosage form contains (1) at least about 80% w / w of non-degraded escitalopram or pharmaceutically acceptable salt thereof (in relation to the initial amount of escitalopram or pharmaceutically acceptable salt thereof) after storage for 6 months, 9 months, or 1 year at approximately 25 ° C and 60% relative humidity, (2) at least approximately 80% w / w of non-degraded bupropion or pharmaceutically acceptable salt thereof after storage by 6 months, 9 months, or 1 year at approximately 25 ° C and 60% relative humidity, or both. The oral dosage form more preferably contains at least about 90% w / w and even more preferably 95% w / w of non-degraded bupropion or a pharmaceutically acceptable salt thereof and / or unsubdued escitalopram or a pharmaceutically acceptable salt thereof after Storage for 6 months, 9 months, or 1 year under the same conditions. According to another embodiment, the oral dosage form provides modified release of the bupropion or pharmaceutically acceptable salt thereof. Preferably, the oral dosage form, upon ingestion by a patient, provides one or more of the following: (a) a statistically significant lower average fluctuation index for bupropion or a pharmaceutically acceptable salt thereof (preferably bupropion hydrochloride) in the plasma that an immediate release tablet containing the same amount of bupropion or a pharmaceutically acceptable salt thereof, and (b) bupropion bioavailability is substantially equivalent to that of three immediate release tablets of the same form of bupropion administered a tablet every 6 or more hours, for a day (for example, the AUC of bupropion provided by the oral dosage form is 75% to 130% of that provided by the three immediate release tablets). According to yet another embodiment, less than about 30% of the bupropion (or pharmaceutically acceptable salt thereof) (based on 100% bupropion in the oral dosage form) is released within 2 hours after administration, and more About 60% of the bupropion is released 12 hours after administration. According to still another embodiment, the oral dosage form provides sustained or pulsed release, including delayed release and extended release, of the bupropion or pharmaceutically acceptable salt thereof. According to one embodiment, the oral dosage form, upon ingestion by a patient, releases the bupropion or pharmaceutically acceptable salt thereof in two or more pulses and preferably in three pulses. Each pulse is released at a different time after administration with time intervals between the release of the pulses during which substantially no bupropion or pharmaceutically acceptable salt thereof is released from the oral dosage form. Each pulse can be released under different conditions, for example. at different times and / or at different pHs. For example, according to one embodiment, the release of bupropion (or pharmaceutically acceptable salt thereof) is delayed by approximately 2 hours of ingestion, eg, less than 20% is released and more than 60% of bupropion is released in approximately 2 to approximately 12 hours after ingestion. According to yet another embodiment, the oral dosage form includes bupropion modified release tablets or beads (or a pharmaceutically acceptable salt thereof) to be provided for their modified release. Tablets and / or beads can provide single-phase or multi-phase release of bupropion. According to a modality, 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 tablets have a diameter ranging from about 4.5 to about 15 mm. The beads and / or tablets can be incorporated into a capsule. According to one embodiment, the oral dosage form includes beads and / or bupropion tablets (or a pharmaceutically acceptable salt thereof) having at least two different configurations. For example, the oral dosage form may include beads and / or immediate release tablets of bupropion and beads and / or modified release tablets of bupropion. According to yet another embodiment, the oral dosage form has an In vitro dissolution profile as measured by the Paddle USP method at (a) 75 rpm in 900 mL of water at 37 ° C or (b) 100 rpm in 900 mL 0.1N HC1 at 37 ° C, such that (i) after 2 hours, less than about 30% by weight of the bupropion (or a pharmaceutically acceptable salt thereof) is released, (ii) after 8 hours, Approximately 40% to about 90% is released, and (iii) after 24 hours, more than about 70% is released. The aforementioned oral dosage forms can provide immediate or modified release of escitalopram or pharmaceutically acceptable salt thereof. Dosage forms formulated for the immediate release of escitalopram oxalate preferably provide a Tmax ranging from about 1 to about 8 hours, and more preferably about 5 hours. The modified release of escitalopram oxalate preferably provides a Tmax of about 4 to 24 hours. According to a preferred embodiment, the oral dosage form, upon ingestion by a subject, provides at least one of the following: (a) an average Cmax for escitalopram (or pharmaceutically acceptable salt thereof) which is about 50 to about 85% of that for an immediate release tablet containing the same amount of escitalopram (or pharmaceutically acceptable salt thereof), (b) a Tmax for escitalopram (or pharmaceutically acceptable salt thereof) of from about 4 to about 12 hours, (c) bioavailability for escitalopram (or pharmaceutically acceptable salt thereof) substantially equivalent to that of an immediate release tablet containing the same amount of escitalopram (or pharmaceutically acceptable salt thereof) (eg, the AUC of escitalopram provided by the oral dosage form is 75% to 130% of that provided by the immediate-release tablet), (d) an index of f mean lower statistically significant difference (difference between Cmax and Crain) in the plasma for escitalopram than an immediate release tablet containing the same amount of escitalopram (or pharmaceutically acceptable salt thereof), (e) an average minimum plasma concentration (Cmin) ) for escitalopram (or pharmaceutically acceptable salt thereof) its substantially equivalent to that of an immediate release tablet containing the same amount of escitalopram (or pharmaceutically acceptable salt thereof), and (f) an area under a plasma concentration vs. . time curve (AUC) for escitalopram (or pharmaceutically acceptable salt thereof) within the range of from about -25% to about + 30% of that produced by an immediate release tablet containing the same amount of escitalopram (or pharmaceutically salt) acceptable of it). According to a more preferred embodiment, for example, 8 mg of the oral dosage form provides an AUC0-24 for escitalopram oxalate of from about 200 to about 350 ng »hr / ml. The comparative immediate-release tablet is preferably 4 and 8 mg and the 5, 10, or 20 mg of escitalopram oxalate tablet which is the subject of the New Drug Application No. 21-323 Approved by the United States Food and Drug Administration. • The immediate release dosage form preferably has an in vitro dissolution profile for escitalopram (as measured by the Basket USP Method at 100 rpm in 900 ml 0.1N HC1 at 37 ° C) such that more than 80% of the drug is released in approximately 30 minutes. The release dosage form preferably has an in vitro dissolution profile for escitalopram (as measured when used by the Basket USP Method at 100 rpm in 900 ml 0. IN HC1 at 37 ° C) such that within 2 hours , from about 10% to about 50% by weight of escitalopram is released, and after 8 hours, more than about 70% by weight of escitalopram is 1 lb. According to a preferred embodiment, the oral dosage form, for example, comprising about 8 mg of escitalopram or a pharmaceutically acceptable salt thereof and, when ingested by a patient, provides a maximum plasma concentration (C max) of the escitalopram of about 2 to about 25 ng / ml, and more desirably about 3 to about 15 ng / ml. According to yet another embodiment, the oral dosage form includes the modified release tablets or beads of escitalopram (or a pharmaceutically acceptable salt thereof) to be provided for their modified release. Tablets and / or beads can provide single phase or multiple phase release of escitalopram. According to one embodiment, the beads and / or tablets comprise a modified release escitalopram core and one or more escitalopram release layers. For example, the beads and / or tablets may have a layer of such an immediate release opram and a modified release escitalopram core. According to one embodiment, the tablets have a diameter ranging from about 4.5 to about 15 mm. The beads and / or tablets can be incorporated into a capsule. According to one embodiment, the oral dosage form includes beads and / or tablets of escitalopram (or a pharmaceutically acceptable salt thereof) having at least two different release configurations. For example, the oral dosage form may include beads and / or immediate release tablets of escitalopram and beads and / or modified release tablets of escitalopram. Yet another embodiment is a method of treating a central nervous system (CNS) disorder, (such as an anxiety or mood disorder) in a patient in need thereof by daily administration of an oral dosage form of the present invention. invention. Examples of CNS disorders that can be treated include, but are not limited to, severe depressive disorder, general anxiety disorder, social anxiety disorder, post-traumatic stress disorder, panic attacks, acute stress disorder, eating disorders ( such as 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 effectively treat patients who have failed to respond to initial treatment with a conventional SSRI, particularly patients with severe depression disorder who have failed to respond to initial treatment with a conventional SSRI. The combination can also treat or reduce suicidal thoughts in a patient in need thereof, and improve disability-free survival following stroke. Yet another embodiment is a method of treating a patient suffering from depression resistant to treatment by administering the oral dosage form of the present invention. Another embodiment of the invention is a method of treating a patient suffering from nausea, insomnia, drowsiness, increased sweating, fatigue, or a combination thereof due to 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 includes (a) discontinuing treatment with the antidepressant; and treating the patient with an oral dosage form of the present invention. According to one embodiment, the antidepressant is an immediate-release escitalopram oxalate formulation. Yet another embodiment is a method of treating sexual dysfunction in a patient suffering from sexual dysfunction due to treatment with an antidepressant other than a combination of escitalopram or a pharmaceutically acceptable salt thereof and bupropion or a pharmaceutically acceptable salt thereof. Sexual dysfunction may be ejaculation disorder, anorgasmia, and / or reduced libido. The method includes (a) discontinuing treatment with the antidepressant; and (b) treating the patient with an oral dosage form of the present invention. According to one embodiment, the oral dosage form provides bupropion release in such a way that a first release of bupropion (or pharmaceutically salt thereof) is delayed by approximately 2 hours of ingestion, eg, less than 20% is released and More than 60% of bupropion is released from approximately 2 to approximately 12 hours. Optionally, additional pulses can be released such that bupropion hydrochloride is released (> 80%) approximately 4 to 24 hours after ingestion.

BRIEF DESCRIPTION OF DRAWINGS Figure 1 shows the simulated dissolution profile of the escitalopram core beads (200 mg / g) and the modified release beads (194.1 mg / g and 188.7 mg / g) described in Example 1.

Figure 2 shows the simulated dissolution profile of the bupropion core beads (600 mg / g) and the modified release beads (545.5 mg / g and 500 mg / g) described in Example 3. Figure 3 shows the bupropion dissolution profile of the three capsules described in Table 14 of Example 15 as determined by the USP basket method at 100 rpm in 0.1 N HC1. Figure 4 shows the dissolution profile of pulsatile escitalopram beads of those prepared by (1) mixing the modified release and immediate release beads and (2) unitary beads comprising modified and immediate release described in Table 14 of Example 5 as determined by the USP basket method at 100 rpm in 0.1N HC1.

DETAILED DESCRIPTION OF THE INVENTION Definitions The term "escitalopram" as used herein includes 1- [3- (dimethyl-amino) propi 1] -1- (p-fluorophenyl) -5-phthalancarbonitrile preferably containing less than 3.2. , 1, 0.5, or 0.2% by weight of its R-enantiomer (based on 100% total weight of 1 - [3- (dimethylamino) propylJ -1- (p-fluorophenyl) -5-phthalancarbonitrile), i.e. , S-citalopram having an enantomeric purity (by weight) of 97, 98, 99, 99.5, or 99.8%. The 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 are maleic, fumaric, benzoic, ascorbic, pamoic, succinic, oxalic, salicylic, methanesulfonic, ulonic, acetic, propionic, tartaric, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-amino-benzoic, glutamic, benzene sulfonic and acetic acid of theophylline, as well as the 8-haloteofilines, for example, 8 -bromoteofilina. Non-limiting examples of suitable inorganic acids 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 term "escitalopram" also includes polymorphic, hydrate, solvate, and amorphous forms of escitalopram and its pharmaceutically acceptable salts. Escitalopram and the pharmaceutically acceptable salts thereof can be prepared as described in U.S. Pat. No. Re. 34,712 and 6, 566, 540 and the International Publications Nos. WO 03/000672, WO 03/006449, WO 03/051861, and WO 2004/083197, each of which is hereby incorporated by reference. The crystals of escitalopram oxalate and escitalopram hydrobromide such as those described in Publication International No. WO 03/011278, U.S. Patent Application Publication No. 2004/0167209, and U.S. Patent Applications. Nos. 10 / 851,763 and 10 / 984,594, all of which are hereby incorporated by reference, may also be used. ' The "immediate release" tablets of comparative escitalopram referred to herein are preferably those of the Approved Request for New Drug No. 21-323 of the United States Food and Drug Administration of equal quantity (5, 10 and 20 mg. escitalopram as oxalate). Unless otherwise specified, all weight values of escitalopram salts are given as the free base equivalent weight of escitalopram. For example, 4 mg of escitalopram oxalate refers to an amount of escitalopram oxalate which is a molar equivalent to 4 mg 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 and inorganic acids, for example, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, formate, mesylate, citrate, benzoate, fumarate, maleate and succinate. The term "bupropion" also includes polymorphous, hydrate, solvate, and amorphous forms of bupropion and their pharmaceutically acceptable salts. A preferred pharmaceutically acceptable salt of bupropion is bupropion hydrochloride. The "immediate release" tablets of comparative bupropion referred to herein are preferably those of the New Drug Application No. 018-644 of equal amount (50, 75, and 100 mg of bupropion hydrochloride). An "effective amount" means the amount of an active ingredient or a combination of active ingredients which, when administered to a mammal for treatment of a condition, disorder or condition, is sufficient to effect such treatment. The "effective amount" will vary depending on the active ingredient, the condition, disorder, or condition to be treated and its severity, and the age, weight, physical condition and responsiveness of the mammal to be treated. According to one embodiment of the present invention, an effective amount of escitalopram is an amount effective to treat a disorder of the central nervous system (CNS), such as, severe depressive disorder, general anxiety disorder, social anxiety disorder, disorder of post-traumatic stress, or panic attacks. The term "pharmaceutically acceptable" generally means biologically or pharmacologically compatible for in vivo use in animals or humans, and preferably means approved by a regulatory agency of the state or Federal government or listed in the US Pharmacopoeia. or another pharmacopoeia generally recognized 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, including, for example, disorders of the central nervous system (CNS) , (such as mood disorders, severe depressive disorder, general anxiety disorder, social anxiety disorder, post-traumatic stress disorder, and panic attacks, including panic attacks); (b) reducing or alleviating the intensity and / or duration of a manifestation of a disorder experienced by a subject including, but not limited to, those that are in response to a given stimulus (e.g., tissue injury pressure, and cold temperature) ); and (c) arresting, delaying the onset (ie, the period prior to the clinical manifestation of a disorder) and / or reducing the risk of developing or worsening a disorder. The term "panic attacks" includes, but is not limited to, any disease, which is associated with panic attacks including panic disorder, specific phobias, social phobia and agoraphobia where panic attacks occur. These disorders are also described in the Statistical and Diagnostic Manual of Mental Disorders, 4a. Ed. Text Review (DSM-IV-TR), A. French (ed.), American Psychiatric Association, Washington, D.C., 2000). A panic attack is a discrete period in which there is a sudden onset of intense apprehension, fright or terror, often associated with feelings of impending doom. During the attack, symptoms such as palpitations, sweating, tremors, sensations of shortness of breath, feeling of shock, chest pain or discomfort, nausea, feeling dizzy, feelings of no reality, fear of losing control or going crazy, fear of dying, paresthesias and cold or hot flushes present themselves. Panic disorders are characterized by recurrent, unexpected panic attacks about which there is persistent interest. Agoraphobia is anxiety about, or evasion from, places or situations from which it might be difficult to escape or in which help may not be available in the event of a panic attack. Specific phobia and social phobia (together formerly simple phobia) are characterized by persistent and marked fear that is excessive or unreasonable, indicated by the presence or anticipation of a specific situation or object (flying, heights, animals, seeing blood, etc.). ) or situations of social functioning. The disorders in which panic attacks occur differ from each other due to the foreseeable capacity of the attacks case, for example, in the panic disorder the attacks are not predictable and are not associated with any particular case, whereas in the specific phobia attacks are activated by specific stimuli. The phrase "panic disorder treatment" may include a reduction in the number or prevention of panic attacks and / or relief of the severity of panic attacks. The term "mood disorder" as used herein includes the mood disorders specified in the DSM-IV-TR, but not limited to, depressive disorders, such as depressive disorder s ero. The term "anxiety disorder" as used herein includes the anxiety disorders specified in the DSM-IV-TR, including, but not limited to, panic disorder without agoraphobia, panic disorder with agoraphobia, social phobia (previously known as social anxiety disorder), obsessive-compulsive disorder, post-traumatic stress disorder, and generalized anxiety disorder. Patients suffering from "treatment-resistant depression" include (1) those who fail to respond to standard doses (ie, significantly superior to placebo in double-blind studies) of antidepressants (such as SSRIs) administered continuously for a minimum duration 6 weeks, and (2) those who fail to respond to standard doses of an antidepressant (such as an SSRI) (monotherapy) administered continuously for a minimum duration of 12 weeks. One criterion for determining whether a patient's depression is resistant to treatment for an antidepressant is whether a Global Clinical Impression Improvement (CGI-I) record of 1 (much greatly improved) or 2 (greatly improved) is not achieved by the end of an essay of 6, 8, or 12 weeks. The CGI-I record is defined in Guy,. (ed.): ECDEU Assesment Manual for Psychopharmacology, Revised, DHEW Pub. (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 an active ingredient over an extended period of time leading to lower maximum plasma concentrations and a prolonged Tmax as compared to the immediate release formulations. These terms also include the release for a period of time by means of a series of pulses of immediate release. The pharmacokinetic profile for 100 mg tablets of ellbutrin® (immediate-release bupropion hydrochloride tablets) shows a maximum plasma concentration at approximately 1-2 hours following administration. The pharmacokinetic profile for 20 mg of escitalopram oxalate tablets (immediate release tablets) shows a maximum plasma concentration at approximately 5 hours (Physician's Desk Reference 2005, Thomson Healthcare; 59th ed. 2004). By "pulsatile" it is meant that a plurality of drug doses are released at separate separate time intervals. The term "bioavailability" refers to the rate and degree to which the active ingredient or active residue, for example, is citalopram, is absorbed from a drug product and becomes available therapeutically. The term "about" or "about" means within a range of error acceptable to the particular value as determined by a person skilled in the art, which will depend in part on how the value is measured or determined, i.e. limitations of the measurement system. For example, "around" can mean within 1 or more than 1 standard deviation, per practice in the subject. Alternatively, "around" with respect to the compositions can mean a range of up to 10%, preferably up to 5%. Combinations of Bupropion and Escitalopram The oral dosage form preferably includes about 75, 150, or 225 mg of bupropion hydrochloride and about 2.5, 4, 5, 10, 15 or 20 mg of escitalopram or a pharmaceutically acceptable salt thereof ( such as escitalopram oxalate or escitalopram hydrobromide). In another embodiment, the oral dosage form preferably includes about 75, 150, or 300 mg of bupropion hydrochloride and about 4, 8, 12 or 24 mg of 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. Do not . Amount of Amount of Escitalopram (or Bupropion Salt (or Pharmaceutically Acceptable Pharmaceutically acceptable salt thereof)) 1 4 mg 150 mg 2 16 mg 300 mg The unit dosage forms containing both escitalopram and bupropion are preferably formulated in such a way that escitalopram and bupropion are not in contact with one another. Modified Release Formulations Preferably, oral dosage forms containing bupropion and / or escitalopram can be formulated to provide modified release of bupropion and immediate and / or modified release of escitalopram. Modified release profiles for bupropion, escitalopram, or both, may be achieved by sustained, delayed and extended release, pulsatile formulations. Pulsatile Formulations Pulsatile release profiles can be achieved with dosage forms that are closed, such as sealed tablets or capsules, that contain two or more dose units containing drug. The dosage form may include one, two, three, or four or more types of dose units, each having a different drug release profile. Each dose unit can provide the multi-phase release of bupropion and / or escitalopram. Preferably, the dosage form includes at least two types of dose units, and more preferably, includes two or three types of dose units. For example, according to one embodiment, the first type of dose unit releases the drug substantially immediately following ingestion of the dosage form, the second type releases the drug approximately 1 to 8 hours after ingestion, and the third optional type releases the drug approximately 2 to 24 hours after ingestion. According to another embodiment, approximately 20 to 60% of escitalopram and about 10 to 50% of bupropion is released in a first pulse. The release of the remaining bupropion and any remaining escitalopram occurs in one or more pulses following the first pulse. The number of pulses and the amount of drugs released preferably result in a Tmax of from about 4 to about 24 hours for escitalopram and from about 4 to about 12 hours for bupropion. Each dose unit can be, for example, a tablet (e.g., compressed or molded), bead, or particle. Alternatively, the dose units may be different layers in the dosage form (e.g., a multilayer tablet). Suitable pulsatile systems are described in U.S. Pat. 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 the publications of US Pat. Nos. 2003-124196, 2004-028729, and 2003-0133978, the descriptions of which are incorporated herein by reference in their entirety. The tablet dose units may be of any size. According to a preferred embodiment, the tablets have an axis of greater diameter varying from about 4.5 to about 15 mm. According to one embodiment, the dosage form (e.g., a capsule) contains two or three tablets. Generally, the bead dose units comprise an inert support with a drug coated thereon and / or a core-containing drug. The inert support can be, for example, a sugar bead or microcrystalline cellulose. The drug can be coated on the inert support by methods known in the art. Individual dose units (such as beads and particles) can be compacted or compressed into a single tablet or capsule by methods known in the art. Sustained Release Formulations Sustained release profiles for a dosage form can be achieved by coatings and / or the use of the above-mentioned beads, particles, and tablets as dosage units within the dosage form. Dose Units As will be appreciated by those skilled in the art and as described in the relevant texts and literatureA number of methods are available to prepare tablets containing drugs or other dosage units that provide a variety of drug release profiles. Such methods include coating a drug or a drug-containing composition, increasing the particle size of the drug, placing the drug within a binder, and complexing the drug with a suitable complexing agent. The modified release dosage units for the sustained release and pulsatile formulations can be prepared, for example, by coating a drug or a drug containing composition with one or more membrane coating materials, such as one or more polymeric materials. When a coating is used to provide the delayed release dose units, particularly preferred coating materials include,. but are not limited to bioerodible polymers, which are gradually hydrolysable and / or gradually soluble in water. The "coating weight", or relative amount of coating material per dosage unit, generally dictates the time interval between ingestion and drug release. Suitable membrane coating materials for effecting delayed release include, but are not limited to: cellulosic polymers such as cellulose acetate, cellulose acetate phthalate, hydroxypropyl cellulose, cellulose acetate trimellitate, cellulose phthalate, hydroxypropylmethyl, phthalate cellulose ether-ester, hydroxypropyl cellulose phthalate, alkaline earth salts of cellulose acetate phthalate, hydroxypropylmethyl cellulose hexahydrophthalate, cellulose acetate hexahydrophthalate, and sodium of carboxymethylcellulose; acrylic acid polymers and preferably formed copolymers of acrylic acid, methacrylic acid, alkyl esters of acrylic acid, alkyl esters of methacrylic acid, and the like, for example, copolymers of acrylic acid, methacrylic acid, methyl acrylate, acrylate ethyl, methyl methacrylate and / or ethyl methacrylate (such as ethyl acrylate terpolymer, methyl methacrylate and trimethylammonioethyl methacrylate chloride (available as Eudragit® RS from Rohm America, LLC, Piscataway, NJ); polymers and copolymers of vinyl such as polyvinyl pyrrolidone, polyvinyl acetate, polyvinylacetate phthalate, vinyl acetate crotonic acid copolymer, and ethylene-vinyl acetate copolymers, and lacquer, ammonia lacquer, acetyl alcohol 1-yl, and n-butyl stearate lacquer. some cases, it may be desirable for a tablet, bead, or particle to be provided for drug release into the colon, in which case it is They hoist polymeric materials or others that allow the release of the drug into the colon. These may be selected from the aforementioned list, or other materials may be used as will be known to those skilled in the art of pharmaceutical formulation and drug delivery. For example, hydrocolloid gums may be effective to provide for colonic delivery, for example, guar gum, lobster gum, bena gum, tragacanth gum, and karaya gum (see for example, U.S. Patent No. 5,656,294). Other materials suitable for effecting the colonic drug delivery include polysaccharides, mucopolysaccharides, and related compounds, for example, pectin, arabinogalactose, chitosan, chondroitin sulfate, dextran, galactomannan, and xylan. The desired pulsatile profile can be achieved by a dosage form comprised of a plurality of tablets. The first tablet is provided with little or no coating material, the second tablet is provided with some degree of coating material, the third tablet is provided with even more coating material, and so on. Analogically, for the encapsulated dosage forms in which the dose units containing drug are beads or particles, a first fraction of beads or particles is provided with little or no coating material, a second fraction is provided with a certain degree of sustained release coating material, the third fraction is provided with even more coating material, and so on. For example, when the dose form contains three tablets (or, analogously, three types of beads or drug-containing particles), the first tablet, which releases the drug substantially immediately, may have a total coating weight of less than about 5% (preferably less than about 3%) (based on the total weight of the tablet), the second tablet can have a total coating weight in the range of about 5% to 50% (preferably 5% to 40%) and the third tablet, if present, may have a total coating weight in the range of about 25% to 60% (preferably 25% to 50%). The preferred coating weights for the particular coating materials can be readily determined by those skilled in the art when evaluating individual release profiles for dose units prepared with different amounts of various coating materials. Alternatively, delayed release dose units, e.g., tablets or particles, may be formulated by using a polymer coating that imparts delayed release properties. Insoluble plastic binders may be comprised of, for example, polyvinyl chloride or polyethylene. Useful hydrophilic polymers to provide a binder for a delayed release dosage unit include, but are not limited to, those described above as suitable coating materials. The particle mixture can be compressed into tablets or processed into particles containing individual drugs. The individual dose units may be provided with colored coatings, with a single color used to identify a tablet or bead or particle fraction having a corresponding delayed release profile. That is, for example, a blue coating can be used for the tablet or bead or immediate release particle fraction, a red coating can be used for the tablet or bead or "medium" release particle fraction, and so on. In this way, mistakes can easily be avoided during processing. The color is introduced by incorporating a pharmaceutically acceptable dye into the coating during the coating preparation. The colorant can be either natural or synthetic. Natural colorants include, but are not limited to, pigments such as chlorophyll, anattenes, beta-carotene, alizarin, indigo, rutin, hesperidin, quercetin, carminic acid, and 6,6'-dibromoindigo. Synthetic dyes include, but are not limited to, dyes, including both acidic dyes and basic dyes, such as nitrous dyes, nitro dyes, azo dyes, oxazines, thiamines, pyrazolones, xanthenes, indigoids, antirquinones, acridines, rosanilins, phthaleins , and quinolines. For encapsulated tablets, the weight of each individual tablet in the capsule is typically in the range of about 50 mg to about 750 mg, preferably in the range of about 50 mg to about 600 mg, and more preferably in the range of about 60 mg to about 450 mg. Individual tablets can be prepared by methods known in the art. A preferred method for forming tablets herein is by direct compression of a powdery, crystalline or granular drug containing composition, alone or in combination with diluents, binders, lubricants, disintegrants, colorants or other excipients. Compressed tablets can also be prepared by wet granulation or dry granulation processes. The tablets can also be molded instead of compressed, starting with a moist material containing a suitable water-soluble lubricant. Beads or particles containing drug can also be prepared by methods known in the art, such as with a fluid dispersion. The coating methods and equipment known in the art can be used to coat the dosage units, for example, tablets, beads or drug-containing particles. For example, a delayed release coating composition can be applied using a coating tray, or fluidized bed coating equipment. Materials, equipment and processes for preparing tablets, beads, drug particles, and delayed-release dosage forms are described in Pharmaceutical Dosage Forms: Tablets, eds. , Lieberman et al. (New York: Marcel Dekker, Inc., 1989), and Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 6a. Ed., (Media, Pa: Williams &; Wilkins, 1995). Optional components present in individual drug-containing dosage units include, but are not limited to, diluents, binders, lubricants, disintegrants, stabilizers, surfactants, and coloring agents. Diluents (also referred to as "fillers") are typically included to increase the volume of a tablet such that a practical size is provided for compression. Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, hydrolyzed starches, silicon dioxide, titanium oxide, aluminum, talc. , my cellulose, cellulose, powdered sugar, and mixtures thereof. The binders are used to impart the cohesive qualities to a tablet formulation, and in this way ensure that a tablet remains intact after compression. Suitable binders include, but are not limited to, starch (including corn starch and initialed pregelatin starch), gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, synthetic and natural gums (for example, acacia, tragacanth, sodium alginate, polyvinylpyrrolidone, celluloses and Veegum), and synthetic polymers (such as polymethacrylates and poly inylpyrrolidone) ), and mixtures thereof. Lubricants are used to facilitate the manufacture of tablets. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, and polyethylene glycol.

Preferably, a dose unit contains no more than about 1% by weight (based on the weight of the dose unit) of lubricant. The disintegrants are used to facilitate the disintegration of tablets or "break" after administration. Suitable disintegrants include, but are not limited to, starches, clays, celluloses, algines, gums, degraded polymers, and mixtures thereof. The stabilizers are used to inhibit or retard drug decomposition reactions which include, by way of example, hydrolysis, such as those including 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 5,358,370. The stabilizer can be an organic acid, a carboxylic acid, an acid salt of an amino acid, sodium metabisulphite, or a mixture thereof. Examples of acidic salts of amino acids include, but are not limited to, hydrochloride salts such as cistern hydrochloride, L-cysteine hydrochloride, glycine hydrochloride, and cysteine 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, oral dosage forms of bupropion can be prepared using non-organic solvents. According to another embodiment of the present invention, the dosage form contains less than 0.2% BHT, anti-oxidant. 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, associated with cations such as sodium, potassium and ammonium ions. Other suitable surfactants include, but are not limited to, long alkyl chain sulfonates and aryl alkyl sulfonates, such as sodium dodecyl benzene sulfonate; dialkyl sodium 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 emulsifying agents or humectants, pH regulating agents, and preservatives. As noted hereinabove, tablets, beads or drug particles, in one embodiment, are contained within a closed capsule. The capsule material can be either hard or soft, and as will be appreciated by those skilled in the art of pharmaceutical science, typically comprises an insipid, easily administered and water soluble compound such as gelatin, starch or cellulose. A preferred capsule material is gelatin. The capsules are preferably sealed, such as with gelatin bands. See, for example, Remington: The Science and Practice of Pharmacy, 20th Edition (Easton, Pa .: Mack Publishing Co., 2000), which describes materials and methods for preparing encapsulated pharmaceuticals designed to dissolve shortly after ingestion. . Dosage Form The dosage form may also include one or more release modifiers in the form of polymeric binders or coatings. The dosage form can also include one or more vehicles, excipients, anti-adhesives, fillers, stabilizing agents, binders, colorants, glidants, and lubricants. Depending on the hydrophilic or hydrophobic nature of the binder, this may be a material that swells upon contact with gastric fluid to a size that is large enough to promote retention in the stomach while the subject is in the digestive state. The digestive state is induced by dietary intake and begins with a rapid and profound change in the motor model of the upper gastrointestinal (GI) tract. The change consists of a reduction in the amplitude of the contractions that the stomach overcomes and a reduction in the pyloric opening to a partially closed state. The result is a screening process that allows liquids and small particles to pass through the partially open pylorus while non-digestible particles that are larger than the pylorus are retropelled and retained in the stomach. The biological fluids migrate through the binder and dissolve the active ingredient which is released by diffusion through the binder, which simultaneously modulates the release flow. The controlled release binder in these embodiments of the invention is therefore selected as one that can swell to a size large enough to retropelled and thereby retain in the stomach, causing prolonged release of the drug to occur in the stomach instead of in the intestines. Descriptions of oral dosage forms that swell to sizes that will prolong residence time in the stomach are found in U.S. Pat. Nos. 5,007,790, 5,582,837, and 5,972,389, as well as Nos. Of International Publications WO 98/55107 and WO 96/26718. Each of the documents cited in this paragraph is hereby incorporated by reference in its entirety. The binder may be composed of an insoluble hydrophilic polymer, such as cellulose ester, carboxyvinyl ester, or methacrylic or acrylic ester. In contact with biological fluids, the hydrophilic binder becomes hydrated and swollen, forming a very dense network of polymers, through which the soluble active principles diffuse. In addition, the lipids, in particular glyceryl esters, can be added in order to modulate the swelling of the binder. These compositions can be obtained by granulation and then compression of the mixture formed of the polymer, active ingredients and various adjuvants. The hydrophobic binders can be composed of a lipid binding agent of natural origin, for example, beeswaxes, which is highly innocuous. These compositions can be obtained by granulation, by a solvent or wet way, and then by compression including the high proportions of each of the constituents. In general, inflatable binders contain binders that are non-toxic polymers, inflatable in water, swell in a manner, dimensionally unrestricted in water inhibitions, and release the drug gradually over time. Examples of polymers that meet this description include, but are not limited to the following: cellulose polymers and their derivatives including, but not limited to, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethylcellulose, and polysaccharides. microcrystalline cellulose and its derivatives, polyalkylene oxides, polyethylene glycols, chitosan, poly (vinyl alcohol), xanthan gum, copolymers of maleic anhydride, poly (vinyl pyrrolidone), starch and polymers based on starch, maltodextrins, poly (2-ethyl- 2-oxazoline), poly (ethyleneimine), polyurethane hydrogels, and degraded polyacrylic acids and their derivatives. Additional non-limiting examples are copolymers of the polymers listed above, including blocking polymers and graft polymers. The specific examples of copolymers are PLURONIC® and TECTONIC®, which are copolymer blocking polypropylene oxide-polyethylene oxide and available from BASF Corporation, Chemicals Div., Yandotte, Mich., USA. Additional examples are polyacrylonitrile graft copolymers of hydrolyzed starch, commonly known as "Super Slurper" and available from Illinois Corn Growers Association, Bloomington, III, USA. Other suitable polymers for the binders are poly (ethylene oxide), hydroxypropyl 1 methyl cellulose, and combinations of poly (ethylene oxide) and hydroxypropyl 1 methyl cellulose. A preferred polymer is hydroxypropyl methyl cellulose. In one embodiment, modified release formulations, such as the 24-hour modified release formulation, contain such polymers in amounts ranging from about 10% w / w to about 50% w / w, and preferably from about 15% to about 45%. % p / p. The prolongation in time of the maximum plasma concentration values (Tmax) as compared to the immediate release is related to the in vitro dissolution release rate of the drug. The in vitro dissolution release rate of the drug depends on the composition of the binder. When using different cellulosic binders, the in vitro release rates (drug solution of more than about 70% to about 80%) can be manipulated anywhere from about 4 hours to 24 hours. The formulations have a maximum plasma concentration time (average Tmax) ranging from about 1 to about 35 hours for both drugs, preferably from about 4 to about 30 hours and an in vitro release rate of more than about 70% to about 80% in approximately 4 to approximately 24 hours. Preferably, the formulations have a release rate for escitalopram of about more than 80% in about 30 minutes to about 12 hours. More preferably, the formulations have a release rate of from about 10% to about 40% within the first hour following entry to an environment of use (such as the gastrointestinal tract) followed by extended release; and more preferably, the formulations have a release rate of more than 70% within the next 12 hours. Tablets according to this invention can be prepared by conventional mixing, spraying, and tabletting techniques that are well known in the pharmaceutical formulating industry. The modified release tablet, for example, can be manufactured by direct compression by perforations and punches fitted to a rotary tablet forming press, compression or ejection molding, granulation followed by compression, or paste formation and extrusion of the paste towards a mold or cut of the extrudate in short lengths. Fillers such as lactose (for example, monohydrate or lactose) are used to modify the dissolution profile. When hydroxypropyl methylcellulose or ethyl cellulose are used, dissolution rates may be much slower than the target modified release rate. The slow release is because the hydrophobic binder tablets that are formed release the drug by the polymer erosion mechanism. Since the erosion of a hydrophobic binder is very slow, the dissolution rate of the readily soluble active ingredient is also slow. However, lactose is also an important filler ingredient useful in improving powder flow and compressibility for escitalopram and bupropion tablets. When the tablets are made by direct compression, the addition of lubricants can be useful and sometimes it is important to promote the flow of powder and to prevent the cap of the tablet (the detachment of a part of the tablet) when the pressure is mitigated . Useful lubricants include magnesium stearate, and hydrogenated vegetable oil (preferably refined and hydrogenated triglycerides of stearic and palmitic acids). In a preferred embodiment, the lubricant is magnesium stearate. For the 24 hour release formulations, magnesium stearate is preferably present in amounts ranging from about 0.5% w / w to about 3% w / w, and preferably from about 0.5% w / w to about 2% w / w. Additional excipients may be added to improve tablet hardness, powder flowability, and friability of the tablet and to reduce the adhesion to the die wall.

EXAMPLE 1 Escitalopram Core and Modified Release Beads Tables 1 and 2 show the formulation ingredients and percentage weight ranges for the elaboration of escitalopram core and modified release beads, respectively. Each modified release bead is a core bead of citalopram coated with a modified release coating. Table 1: Formulation Ranges of the Pearl Escitalopram Nucleus * - Compitrol 888 is glyceryl behenate (tribehenin) and is available from Gattefosse Corp. De Paramus, N.J. ** - Avicel® PH 101 is microcrystalline cellulose and is available from FMC Corporation of Philadelphia, PA. *** _ pYp K-30 is polyvinylpyrrolidone having a K value of about 30. Table 2: Modified Release Coating Formulation Formulations of Escitalopram Surelease is an aqueous ethylcellulose dispersion and is available from Colorcon, Inc. Of West Point, PA. The escitalopram core beads (200 mg / g) having the formulation in Table 3 have been prepared. Table 3: Escitalopram Core Beads (200 mg / g) The beads can be prepared by mixing ingredients 1-5 of Table 3 in a high-cut granulator (DÃsona, Fluid Air, Chicago, IL). The granulated material is extruded with an extruder (Niro, Model E-140, Columbia MD), and then subjected to fermentation in beads using a spheronizer (Niro Model S450, Columbia, MD). The beads are dried optionally at 50 ° C for up to 12 hours. The escitalopram core beads of Table 3 have been coated with a modified release coating according to Table 4 (Profile I) or 5 (Profile II). Table 4: Escitalopram Modified Release Beads (194.1 mg / g) Table 5: Modified Release Beads of Es cit alopram (188.7 mg / g) The simulated dissolution profiles of the escitalopram core beads (200 mg / g) of Table 3 and the modified release beads of Tables 4 and 5 are shown in Figure 1.

EXAMPLE 2 Dosage Form of Pulsatile Escitalopram Capsule The modified release beads and escitalopram core described in Example 1 can be filled into capsules to deliver pulsatile release profiles.

For example, the predetermined weights of beads can be filled into a capsule using a capsule filling machine (MG-2, MG America, Fairfield, NJ). The amounts of beads per capsule for a 4 mg resistant pulsatile escitalopram capsule are shown in Table 6. Table 6: Pulsatile Escitalopram Capsule Dosage Formulations Capsules containing different amounts of beads of a given strength will generate different dissolution profiles. Also, different dose proportional resistances can be generated by using more beads, such as for 5, 8, 10, 15, 16, 20, and 40 mg by the total filler weight.

EXAMPLE 3 Modified Release and Bupropion Core Beads Tables 7 and 8 show the formulation ingredients and weight percent ranges for bupropion core and modified release beads, respectively. Each modified release bead includes a bupropion core bead coated with a modified release coating. Table 9 shows the formulation ingredients and weight percent ranges for the Bupropion Core Beads (600 mg / g). Table 7: Bupropion Core Pearl Formulation Ranges INGREDIENTS% p / p BUPROPION HCL 3.0-70.0 COMPRITOL® 888 5.0-50.0 MONOESTEARATE 1.0-15.0 SORBITAN AVICEL® PH 101 3.0-50.0 HPMC 0-30.0 PVP K-30 1.0-7.0 TALCO, USP 1.0-6.0 OLEATE OF SORBITAN 3.0-15.0 TOTAL 100.0 Table 8: Bupropion Modified Release Coating Formulation Ranges INGREDIENTS% p / p 20-95 HCL NUCLEO PEARLS BUPROPION EUDRAGIT® 5-40.0 PURIFIED WATER QS TOTAL 100.0 Table 9: Bupropion Core Beads (600 mg / g) # INGREDIENTS% P / P GRAM WEIGHT 1. BUPROPION HCL 60.0 600 2. COMPRITOL® 888 17.0 170 3. AVICEL® PH 101 7.0 70 4. PVP K-30 2.0 20 . TALCO, USP 4.0 40 6. OLEATO DE SORBITAN 10.0 100 TOTAL 100.0 1000 The beads can be prepared by mixing ingredients 1-5 of Table 9 in a high cut granulator (DÃsona, Fluid Air, Chicago, IL). The granulated material is extruded with an extruder (Niro, Model E-140, Columbia MD), and then put into fermentation in beads using a spheronizer (Niro Model S450, Columbia, MD). The beads are optionally dried at 50 ° C for up to 12 hours. The bupropion core beads of Table 9 have been coated with a modified release coating according to Table 10 (Profile I) or Table 11 (Profile II). Table 10: Bupropion Modified Release Beads (545.5 mg / g) INGREDIENTS% P / P BUPROPION NUCLEUS PEARL 600 90 MG / G EUDRAGIT® RS / RL (95%: 5%) * 10 PURIFIED WATER QS TOTAL 100.00 * - Eudragit® RS / RL (95%: 5%) is a mixture containing 95% of Eudragit® RS and 5% of Eudragit® RL, both are available from Rohm America Inc. of Piscataway, NJ Table 11: Bupropion Modified Release Beads (500 mg / g) INGREDIENTS% p / p PEARL OF BUPROPION NUCLEUS 600 MG / G 80 EUDRAGIT® RS / RL (95%: 5%) * 20 PURIFIED WATER QS TOTAL 100.00 The simulated dissolution profiles of the bupropion core beads (600 mg / g) of Table 9 and the modified release beads of Tables 10 and 11 are shown in 1 to Figure 2. Tables 12A-12D show the ingredients of formulation and the ranges of percentage by weight for the elaboration of IR, MI R, MR II and pulsatile formulations. Pearls can be prepared by mixing the ingredients in a high-cut granulator (Dísona, Fluid Air, Chicago, IL). The granulated material is extruded with an extruder (Niro, Model E-140, Columbra MD), and then spheronized into beads using a spheronizer (Niro Model S450, Columbia, MD). The beads are optionally dried at 50 ° C for up to 12 hours. The beads are thus coated with seal coating polymer in a fluid bed coater (Glatt AIR, Ramsey, NJ) at 25 to 30 ° C. Table 12A. Release Formulations Immediate Release Bupropion Mg / dose Mg / g Immediate (596 mg / g) Extruded Pearls HCL BUPROPION 300 595.9 BEHENATO DE GLYCERILO, NF 73.1 145.4 (COMPRITOL® 888 ATO) - TT - CELLULOSE MY CROCRI S ALINA 33.2 66.0 (AVICEL® PH101) CITRIC ACID, ANHYDRO 23.7 47.2 HIDROXI BUT I SIDE ANISOL 0.05 0.1 (BHA) SORBITAN MONOOLEATE, 57.0 113.2 (SPAN 80) TALK, USP (PHARMA M) 14.1 28.0 Total (extruded pearls ) 501 995.7 Seal Reversal: KLUCEL EF 21 4.2 ANISOL HIDROXI BUT I SIDE 0.042 0.1 WATER Q. S. Total 503.1 1000.0 Table 12B. Modified Release Formulation I Release Formula Mg / dos i s Mg / g Modified I (544 mg / g) Release beads 503.1 904.2 immediate (596 mg / g) EUDRAGIT NE 30D Dispersion 52.1 93.7 (Solids) TALCO 1.2 2.1 ANISOL HIDROXI BUTILADO < 0.05 < 0.05 WATER - Q. S.

Total 556.4 1000.0 Modified release beads I can be coated using suspension Eudragit in a fluid bed coater (Glatt AIR, Ramsey, NJ) at 25 to 30 ° C. Table 12C. Modified Release Formulation II Release Formula Mg / two i s Mg / g Modified (Delayed / Extended) II (414) mg / g) Release Pearl 556. Modified 4 796.2 (54 4 mg / g) ACRYLEZE (Solid Continuous Cont.) 167. 0 230.8 WATER - QS.

Total 723. 4 1000.0 The modified release beads II are coated using Eudragit suspension in a fluid bed coater (Glatt AIR, Ramsey, NJ) at 30 to 40 ° C. Table 12D. Pulsatile Formulations Two-Pulse Formulation (300 mg) mg / dos i s Bupropion Immediate Release 100 6 mg (596 mg / g) Modified Release Formula 578 7 mg II (414 mg / g) Total 679 3 mg Capsules containing two-pulse beads are prepared by mixing different beads during the encapsulation process using a capsule filling machine (MG-2, MG America, Fairfield, NJ).

EXAMPLE 4 Dosage Form of Pulsatile Bupropion Capsule The bupropion core and the modified release beads described in Example 3 can be filled into capsules to deliver pulsatile release profiles. For example, the predetermined weights of beads can be filled into a capsule using a capsule filling machine (MG-2, MG America, Fairfield, NJ). The amounts of beads per capsule for a 150 mg strength pulsatile bupropion capsule are shown in Table 13. Table 13: Pulse Bupropion Capsule Dose Formulations PROFILE PEARL OF PEARL OF PEARL CORE RELEASE RELEASE (MG / COVER) MODIFIED MODIFIED 1 (MG / COVER) 2 (MG / COVER) PULSE 250 MG 0 0 UNIQUE DOS 137.5 MG 150 MG PULSOS THREE 300 MG PULSES Capsules containing different amounts of beads of a given strength will generate different dissolution profiles. Also, the different dose proportional resistances can be generated by using more beads, such as by 75 to 450 mg by the weight of total filler.

EXAMPLE 5 Dosage Form of Bupropion Capsule and Pulsatile Citalopram A pulsatile capsule dose form is prepared by packing a plurality of escitalopram beads and bupropion beads in a capsule. A pulsatile capsule dose formulation for a 4 mg / 150 mg escitalopram resistance capsule of bupropion is shown in Table 14. Table 14: Pulsatile Capsule Dosage Form of 150 mg Bupropion / 4 mg Escitalopram PULSO PULSO PULSE PULSE PULSO PULSO MR OF MR OF MR DE MR NUCLEO BUPROBUPRONUCLEO ESCITA ESCITA DE PION 1 PION 2 DE - - BUPRO (MG / TA (MG / TA ESCITALOPRAM LOPRAM PION PA) PA) LOPRAM 1 2 (MG / TA (MG / TA (MG / TA (MG / TA PA) PA ) PA) PA) TWO 250 MG 0 0 25.6 MG 0 0 PULSES (ONE PER API) (CAPSULE A) PULSE MR 0 MG 300 MG 0 MG 27.2 UNIQUE MG (CAPSULE B) TWO 137.5 150 MG 13.2 13.6 PULSES MG MG MG MR (CAPSULE C) Multiple combinations of beads can be made to meet the desired solution release profiles. The beads can be filled with a bead mixture or multiple funnels with an encapsulator (such as an MG-2, MG America, Fairfield, NJ). Figures 3 and 4 show the dissolution rates of bupropion and escitalopram of the three capsules shown in Table 13, respectively. The dissolution test for both figures was according to the USP basket method at 100 rpm in 0.1 NHC1. Proportional dose resistances can be prepared by altering the fill weight. Formulations of modified release and core beads that combine bupropion and escitalopram in a system (bead) are susceptible to degradation of both molecules. It was observed that more than 10% loss of potency for each was observed when stored for 1 month at 40 ° C and 75% relative humidity. The formulation of the present invention shows excellent stability under the same conditions. The beads of both bupropion and escitalopram used in this example show less than 10% loss in potency and in most cases less than 5% potency loss when stored for 1 raes at 40 ° C and 75% humidity relative. Patents, patent applications, publications, product descriptions, and protocols are cited throughout this application, the descriptions of which are incorporated herein by reference in their entireties for all purposes.

Claims

REVIVAL ICATIONS 1. An oral dosage form comprising bupropion or a pharmaceutically acceptable salt thereof and escitalopram or a pharmaceutically acceptable salt thereof.
2. Oral dosage form of rei indication 1, wherein the bupropion or pharmaceutically acceptable salt thereof and escitalopram or pharmaceutically acceptable salt thereof are physically separated in the oral two form.
3. The oral dosage form of claim 1, wherein the oral dosage form comprises from about 50 to about 450 mg of bupropion or a pharmaceutically acceptable salt thereof. (calculated on the basis of the weight of a molar equivalent of bupropion hydrochloride).
4. Oral dosage form of rei indication 1, wherein the oral dosage form comprises from about 75 to about 225 mg of bupropion or a pharmaceutically acceptable salt thereof (calculated on the basis of the weight of a molar equivalent of bupropion hydrochloride).
5. Oral dosage form of claim 1, wherein the oral dosage form comprises 150 mg of bupropion or a pharmaceutically acceptable salt thereof.
6. The oral dosage form of claim 1, wherein the oral dosage form comprises 225 mg of bupropion or a pharmaceutically acceptable salt thereof.
7. The oral dosage form of claim 1, wherein the oral dosage form comprises bupropion hydrochloride.
The oral dosage form of claim 1, wherein the oral dosage form comprises from about 2.5 to about 40 mg of escitalopram or a pharmaceutically acceptable salt thereof (calculated based on the weight of one molar equivalent of free base escitalopram) ).
9. The oral dosage form of claim 1, wherein the oral dosage form comprises 2.5 mg escitalopram or a pharmaceutically acceptable salt thereof.
10. The oral dosage form of claim 1, wherein the oral dosage form comprises 4 mg escitalopram or a pharmaceutically acceptable salt thereof.
11. The oral dosage form of claim 1, wherein the oral dosage form comprises 5 mg escitalopram or a pharmaceutically acceptable salt thereof.
12. The oral dosage form of claim 1, wherein the oral dosage form comprises 10 mg of escitalopram or a pharmaceutically acceptable salt thereof.
13. Oral dosage form of rei indication 1, wherein the oral dosage form comprises 20 mg 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 the bupropion or pharmaceutically acceptable salt of the same.
17. The oral dosage form of claim 1, wherein the oral dosage form provides immediate release of escitalopram or pharmaceutically acceptable salt thereof.
18. The oral dosage form of claim 1, wherein the oral dosage form provides modified release of escitalopram or pharmaceutically acceptable salt thereof.
The oral dosage form of claim 1, wherein the oral dosage form, upon ingestion by a patient, induces a statistically significant lower average fluctuation index for the bupropion or pharmaceutically acceptable salt thereof in the plasma than in a Immediate-release tablet containing the same amount of the bupropion or pharmaceutically acceptable salt thereof, and provides bioavailability of the bupropion or pharmaceutically acceptable salt thereof substantially equivalent to that of three immediate-release tablets of the bupropion or pharmaceutically acceptable salt thereof by administering a tablet every 6 or more hours, for a 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) 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 pulsed release of the bupropion or pharmaceutically acceptable salt of the same.
22. The oral dosage form of claim 1, wherein the oral dosage form comprises modified release beads of bupropion or a pharmaceutically acceptable salt thereof having at least two different release profiles.
23. The oral dosage form of claim 1, wherein the dosage form comprises modified release tablets of bupropion or a pharmaceutically acceptable salt thereof.
24. Oral dosage form of claim 1, having an in vitro dissolution profile as measured by the Paddle USP Method at 75 rpm in 90 ml of water at 37 ° C such that (i) after 2 hours, less than about 20% by weight of the bupropion or pharmaceutically acceptable salt thereof is released, (ü) after 8 hours, from about 10% to about 60% is released, and (iii) after 24 hours, more than 70% it is released.
25. Oral dosage form of claim 1, having an in vitro dissolution profile as measured by the Paddle USP Method at 100 rpm in 900 ml 0. IN HC1 at 37 ° C such that (i) after 2 hours, less than about 20% by weight of the bupropion or pharmaceutically acceptable salt thereof is released, (ii) after 8 'hours, from about 10% to about 60% is released, and (iii) after 24 hours, more 70% is released.
26. The oral dosage form of claim 1, wherein the oral dosage form, upon ingestion by a patient, provides a Tmax for the escitalopram or pharmaceutically acceptable salt thereof varying from about 4 to about 35 hours.
27. The oral dosage form of claim 1, wherein the oral dosage form, upon ingestion by a patient, provides a Tmax for the escitalopram or pharmaceutically acceptable salt thereof of about 5 hours.
28. The oral dosage form of claim 1, wherein the oral dosage form, upon ingestion by a patient, provides: (a) an average Cmax for the escitalopram or pharmaceutically acceptable salt thereof which is about 50 to about 85% of that for an immediate release tablet containing the same amount of escitalopram or pharmaceutically acceptable salt thereof; (b) a Troax for escitalopram or pharmaceutically acceptable salt thereof from about 1 about 8 hours, and; (c) bioavailability for escitalopram or pharmaceutically acceptable salt thereof substantially equivalent to that of an immediate release tablet containing the same amount of escitalopram or pharmaceutically acceptable salt thereof.
29. The oral dosage form of claim 1, wherein the oral dosage form, upon ingestion by a patient: (a) induces a statistically significant lower mean fluctuation index in plasma for escitalopram or pharmaceutically acceptable salt thereof. that an immediate release tablet containing the same amount of escitalopram or pharmaceutically acceptable salt thereof; (b) it provides an average minimum plasma concentration (Cmin) for escitalopram or pharmaceutically acceptable salt thereof substantially equal to that of an immediate release tablet containing the same amount of escitalopram or pharmaceutically acceptable salt thereof; (c) provides an area under a plasma concentration vs. time curve (AUC) for escitalopram or pharmaceutically acceptable salt thereof within the range of from about 20% to about + 25% of that produced by an immediate release tablet containing the same amount of escitalopram or pharmaceutically acceptable salt thereof , or; (d) any combination of the foregoing.
30. The oral dosage form of claim 1, wherein the oral dosage form has an AUCo-24 for escitalopram or pharmaceutically acceptable salt thereof from about 320 to about 400 ng-hr / ml.
31. The oral dosage form of claim 1, wherein the oral dosage form has an in vitro dissolution profile as measured by the Basket USP Method at 100 rpm in 900 ml 0.1N HCl at 37 ° C such that after about 30 minutes, more than about 80% by weight of the escitalopram or pharmaceutically acceptable salt thereof is released.
32. Oral dosage form of claim 1, wherein the oral dosage form has an in vitro dissolution profile as measured by the Basket USP Method at 100 rpm in 900 ml of 0.1 N HCl at 37 ° C such that ( i) after 2 hours, from about 10% to about 50% by weight of the escitalopram or 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 10 mg escitalopram or a pharmaceutically acceptable salt thereof (calculated based on the weight of a molar equivalent of free base escitalopram), and, in ingestion by a patient, provides a mean maximum plasma concentration (Cmax) of escitalopram or pharmaceutically acceptable salt thereof from about 1 ng / ml to about 50 ng / ml.
34. The oral dosage form of claim 1, wherein the oral dosage form, upon ingestion by a patient, provides an average maximum plasma concentration (Cmax) of escitalopram or pharmaceutically acceptable salt thereof of about 10 ng / ml. at approximately 18 ng / ml.
35. Oral dosage form of rei indication 1, wherein the oral dosage form provides a therapeutic effect for at least about 24 hours after administration to a patient.
36. 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 the oral dosage form is administered once. up to date.
38. The method of claim 36, wherein the disorder is a mood disorder.
39. The method of claim 38, wherein the mood disorder is severe depressive disorder.
40. The method of claim 39, wherein the disorder is an anxiety disorder.
41. Method of treating a sexual dysfunction in a patient in need thereof comprising administering the oral dosage form of claim 1.
42. The method of claim 41, wherein the sexual dysfunction is ejaculation disorder.
43. The method of claim 41, wherein the sexual dysfunction is anorgasmia.
44. The method of claim 41, wherein the sexual dysfunction is reduced libido.
45. Method of treatment of a patient suffering from treatment-resistant depression comprising administering to the patient an effective amount of the oral dosage form of claim 1.