Modified Release Formulations Of Selective Serotonin Re-Uptake Inhibitors

BACKGROUND OF THE INVENTION

Clinical depression (unipolar depression) is a disturbance of mood that is distinguishable from the usual mood fluctuations of everyday life. There are several approaches to the treatment of depression depending on the severity of the condition and the risks to the patient. Antidepressants are classified into different groups either structurally or depending on which central neurotransmitters they act upon. The older tricyclic and related cyclic antidepressants and the monoamine oxidase inhibitors (MAOIs) have now been joined by the highly selective neuronal erotonin (5HT) reuptake inhibitors (SSRIs) which provide important improvements in adverse effect profile and safety. The mechanism of action of the SSRIs as anti-depressants is presumed to be linked to potentiation of serotonergic activity in the central nervous system resulting from their inhibition of central nervous system (CNS) neuronal reuptake of serotonin. There are currently seven SSRIB available on the market today, namely Fluoxetine HCl, Fluvoxamine maleate, Paroxetine HCl, Sertraline HCl, Venlafaxine HCl, Citalopram HBr and Escitalopram oxalate.

Fluoxetine HCl, which was first described in U.S. Pat. No. 4,314,081, is designated as (±)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)oxy)propylamine hydrochloride. Conventional immediate release preparations of Fluoxetine HCl are commercially available in the United States from Eli Lilly and Company under the proprietary name PROZAC® as 10 mg, 20 mg or 40 mg PULVULES®, 10 mg tablets and a 20 mg/5 ml oral solution. Each PULVULE® contains starch, gelatin, silicone, titanium dioxide, iron oxide and other inactive ingredients. The 10 mg and 20 mg PULVULES® also contain FD&C Blue No. 1, and the 40 mg PULVULE® also contains FD&C Blue No. 1 and FD&C Yellow No. 6. Each tablet contains microcrystalline cellulose, magnesium stearate, crospovidone, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, yellow iron oxide, FD&C Blue No. 1 aluminum lake, and polysorbate 80. The oral solution contains alcohol 0.23%, benzoic acid, flavoring agent, glycerin, purified water, and sucrose. The 56^thEdition (2002) of the Physician's Desk Reference (PDR), page 1238, states that following a single oral 40 mg dose, peak plasma concentrations of Fluoxetine from 15 to 55 mg/ml are observed after 6 to 8 hours. The PULVULE®, tablet and oral solution dosage forms of Fluoxetine are bioequivalent. Food does not appear to affect the systemic bioavailability of Fluoxetine, although it may delay its absorption by one to two hours, which is probably not clinically significant. Thus, Fluoxetine may be administered with or without food. Such conventional immediate release preparations, however, do not provide a modified release of Fluoxetine HCl.

A delayed release preparation of Fluoxetine HCl is also commercially available in the United States from Ely Lilly and Company under the proprietary name PROZAC® WEEKLY™ as 90 mg delayed release capsules, containing enteric coated pellets of Fluoxetine HCl. The capsules also contain FD&C Yellow #10, FD&C Blue #2, gelatin, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium dioxide, triethylcitrate and other inactive ingredients. PROZAC® WEEKLY™ capsules contain enteric coated pellets that resist dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. The enteric coating delays the onset of absorption of Fluoxetine one to two hours relative to the immediate release formulations. The PROZAC® WEEKLY™ delayed release capsule dosage form of Fluoxetine is bioequivalent to the PULVULE®, tablet and oral solution dosage forms of Fluoxetine. The PROZAC® WEEKLY™ delayed release capsule formulation is disclosed in U.S. Pat. No. 5,910,319.

Fluvoxamine maleate, which was first described in U.S. Pat. No. 4,085,225, is an SSRI belonging to a new chemical series, the 2-aminoethyl oxime ethers of aralkylketones and is designated as 5-methoxy-4′-(trifluoromethyl)valerophenone-(E)-O-(2-aminoethyl)oxime maleate. A conventional immediate release preparation of Fluvoxamine maleate is commercially available in the United States from Solvay Pharmaceuticals, Inc. under the proprietary name LUVOX® as 25 mg, 50 mg and 100 mg tablets for oral administration. Each tablet contains the following inactive ingredients: carnauba wax, hydroxypropyl methylcellulose, mannitol, polyethylene glycol, polysorbate 80, pregelatinized starch (potato), silicon dioxide, sodium stearyl fumarate, starch (corn), and titanium dioxide. The 50 mg and 100 mg tablets also contain synthetic iron oxides. The 56^thEdition of the PDR, page 3257, states that the absolute bioavailability of Fluvoxamine maleate is 53%. Oral bioavailability is not significantly affected by food. In a dose proportionality study involving Fluvoxamine maleate at 100, 200 and 300 mg/day for 10 consecutive days in 30 normal volunteers, steady state was achieved after about a week of dosing. Maximum plasma concentrations at steady state occurred within 38 hours of dosing and reached concentrations averaging 88, 283 and 546 ng/ml, respectively. Such a conventional immediate release preparation, however, does not provide a modified release of Fluvoxamine maleate.

Paroxetine HCl, which was first described in U.S. Pat. Nos. 3,912,743, 4,007,196 and 4,721,723, is an orally administered antidepressant in the hemihydrate form with a chemical structure unrelated to other SSRIs or to tricyclic, tetracyclic or other available antidepressant agents. It is the hydrochloride salt of a phenylpiperidine compound identified chemically as (−)-trans-4R-(4′-fluorophenyl)-3S[(3′,4′-methylenedioxyphenoxy)methyl]piperidine hydrochloride (hemihydrate). Conventional immediate release preparations of Paroxetine HCl are commercially available in the United States from GlaxoSmithKline under the proprietary name PAXIL® as 10 mg, 20 mg, 30 mg and 40 mg film coated tablets and as a 10 mg/5 ml suspension for oral administration. Each film coated tablet contains the inactive ingredients dibasic calcium phosphate dihydrate, hydroxypropyl methylcellulose, magnesium stearate, polyethylene glycols, polysorbate 80, sodium starch glycolate, titanium dioxide and one or more of the following: D&C Red No. 30, D&C Yellow No. 10, FD&C Blue No. 2 and FD&C Yellow No. 6. The oral suspension contains the inactive ingredients polacrilin potassium, microcrystalline cellulose, propylene glycol, glycerin, sorbitol, methyl paraben, propyl paraben, sodium citrate dihydrate, citric acid anhydrate, sodium saccharin, flavourings, FD&C Yellow No. 6 and simethicone emulsion, USP. The 56^thEdition of the PDR, page 1609 states that in a study in which normal male subjects received 30 mg tablets daily for 30 days, steady state Paroxetine concentrations were achieved by approximately 10 days for most subjects. At steady state, mean values of C_max, T_max, C_minand t_1/2were 61.7 ng/ml (CV 45%), 5.2 hours (CV 10%), 30.7 ng/ml (CV 67%) and 21.0 hours (CV 32%), respectively. The steady state C_maxand C_minvalues were about 6 and 14 times what would be predicted from single dose studies. Steady state drug exposure based on AUC_0-24was about 8 times greater than would have been predicted from single dose data in these subjects. The effects of food on the bioavailability of Paroxetine were studied and subjects were administered a single dose with and without food. AUC was only slightly increased (6%) when drug was administered with food, but the C_max29% greater, while the time to reach peak plasma concentration decreased from 6.4 hours post dosing to 4.9 hours. Such conventional immediate release preparations, however, do not provide a modified release of Paroxetine HCl.

A controlled release preparation of Paroxetine HCl is also commercially available in the United States from GlaxoSmithKline under the proprietary name PAXIL® CR™ as 12.5 mg, 25 mg and 37.5 mg enteric film coated, controlled release tablets. One layer of the tablet consists of a degradable barrier layer and the other contains the active material in a hydrophilic matrix. Inactive ingredients consist of hydroxypropyl, methylcellulose, polyvinyl pyrolidone, lactose monohydrate, magnesium stearate, colloidal silicon dioxide, glyceryl behenate, methacrylic acid copolymer type C, sodium lauryl sulfate, polysorbate 80, talc, triethyl citrate, and one or more of the following colorants: yellow ferric oxide, red ferric oxide, D&C Red #30, D&C Yellow #6, D&C Yellow #10, FD&C Blue #2. PAXIL® CR™ tablets contain a degradable polymer matrix (GEOMATRIX™, a trademark of Jago Pharma Muttenz, Switzerland) designed to control the dissolution rate of Paroxetine over a period of approximately 4 to 5 hours. In addition to controlling the rate of drug release in vivo, an enteric coat delays the start of drug release until PAXIL® CR™ tablets have left the stomach. In a study in which normal male and female subjects (n=23) received single oral doses of PAXIL® CR™ at 4 dosage strengths (12.5 mg, 25 mg, 37.5 mg and 50 mg), Paroxetine mean C_maxand AUC_0-infvalues at these doses were 2.0, 5.5, 9.0 and 12.5 mg/ml and 121, 261, 338 and 540 ng.hr./ml, respectively. T_maxwas observed typically between 6 and 10 hours post dose, reflecting a reduction in absorption rate compared with immediate release formulations. The mean elimination half life of Paroxetine was 15 to 20 hours throughout this range of single PAXIL® CR™ doses. The bioavailability of 25 mg PAXIL® CR™ is not affected by food. During repeated administration of PAXIL® CR™ (25 mg once daily), steady state was reached within two weeks (i.e., comparable to immediate release formulations). In a repeat dose study in, which normal male and female subjects (n=23) received PAXIL® CR™ (25 mg daily), mean steady state C_max, C_minand AUC_0-24values were 30 ng/ml, 20 ng/ml and 550 ng.hr./ml, respectively. According to the United States Food and Drug Administration (FDA) Approved Drug Products Publication (the “FDA Orange Book”), U.S. Pat. No. 4,522,123 relates to the PAXIL® CR™ controlled release tablet formulation.

Sertraline HCl, which was first described in U.S. Pat. No. 4,536,518, is chemically unrelated to other SSRIs, tricyclic, tetracyclic, or other available antidepressant agents. Sertraline HCl has the following chemical name: (1S-cis)-4(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride. Conventional immediate release preparations of Sertraline HCl are commercially available in the United States from Pfizer Inc. under the trade name ZOLOFT® as 25 mg, 50 mg and 100 mg scored tablets and as 20 mg/ml oral concentrate. The tablets contain the following inactive ingredients: dibasic calcium phosphate dihydrate, D&C Yellow #10 aluminum lake (in 25 mg tablet), FD&C Blue #1 aluminum lake (in 25 mg tablet), FD&C Red #40 aluminum lake (in 25 mg tablet), FD&C Blue #2 aluminum lake (in 50 mg tablet), hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, synthetic yellow iron oxide (in 100 mg tablet), and titanium dioxide. The solution contains the following inactive ingredients: glycerine, alcohol (12%), menthol and butylated hydroxytoluene (BHT). The 56^thEdition of the PDR, on page 2751, states that in man, following oral once daily dosing over the range of 50-200 mg for 14 days, mean peak plasma concentrations (C_max) of Sertraline occurred between 4.5-8.4 hours post dosing. The affects of food on the bioavailability of the Sertraline tablet and oral concentrate were studied in subjects administered a single dose with and without food. For the tablet, area under the plasma concentration time curve (AUC) was slightly increased when drug was administered with food but the C_maxwas 25% greater, while the time to reach peak plasma concentration (T_max) decreased from 8 hours post dosing to 5.5 hours. For the oral concentrate, T_maxwas slightly prolonged from 5.9 hours to 7.0 hours with food. Such conventional immediate release preparations, however, do not provide a modified release of Sertraline HCl.

Venlafaxine HCl, which was first described in U.S. Pat. No. 4,535,186, is chemically unrelated to tricyclic, tetracyclic, or other available antidepressant agents. It is designated as (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloride or (±)-1-[α-[(dimethylamino)methyl]-p-methoxybenzyl]cyclohexanol hydrochloride. A conventional immediate release preparation of Venlafaxine HCl is commercially available in the United States from Wyeth-Ayerst under the proprietary name EFFEXOR® as 25 mg, 37.5 mg, 50 mg, 75 mg or 100 mg compressed tablets. Inactive ingredients consist of cellulose, iron oxides, lactose, magnesium stearate, and sodium starch glycolate. Such a conventional immediate release preparation does not provide a modified release of Venlafaxine HCl.

An extended release preparation of Venlafaxine HCl is also available from Wyeth-Ayerst under the proprietary name EFFEXOR® XR as 37.5 mg, 75 mg or 150 mg extended release capsules for once a day oral administration. Drug release is controlled by diffusion through the coating membrane on the spheroids and is not pH dependent. Inactive ingredients consist of cellulose, ethylcellulose, gelatin, hydroxypropyl methylcellulose, iron oxide and titanium dioxide. The 37.5 mg capsule also contains D&C Red #28, D&C Yellow #10, and FD&C Blue #1. The 56^thEdition of the PDR, page 3499, states that administration of EFFEXOR® XR (150 mg q24 hours) generally resulted in lower C_max(150 ng/ml) and later T_max(5.5 hours) than for immediate release Venlafaxine tablets (C_maxfor immediate release 75 mg q12 hours was 225 ng/ml; T_maxwas 2 hours). The FDA Orange Book states that U.S. Pat. Nos. 6,274,171, 6,419,958 and 6,403,120 all relate to the EFFEXOR® XR extended release capsule formulation.

Citalopram HBr, which was first described in U.S. Pat. No. 4,136,193, is a racenic bicyclic phthalane derivative designated as (RS)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-5-phthalancarbonitrile hydrobromide. Conventional immediate release preparations of Citalopram HBr are commercially available in the United States from Forest Laboratories, Inc. under the proprietary name CELEXA™ as 20 mg and 40 mg film coated tablets and as 2 mg/ml oral solution. The tablets contain the following inactive ingredients: copolyvidone, corn starch, cross-carmellose sodium, glycerin, lactose monohydrate, magnesium stearate, hydroxypropyl methylcellulose, microcrystalline cellulose, polyethylene glycol and titanium dioxide. Iron oxides are used as colouring agents in the 10 mg and 20 mg tablets. The oral solution contains the following inactive ingredients: sorbitol, purified water, propylene glycol methylparaben, natural peppermint flavour and propylparaben. The 56^thEdition of the PDR, page 1365, states that following a single oral dose (40 mg tablet) of Citalopram, peak blood levels occur at about 4 hours. The absolute bioavailability of Citalopram was about 80% relative to an intravenous dose and absorption is not affected by food. Such conventional immediate release preparations, however, do not provide a modified release of Citalopram HBr.

Escitalopram oxalate, which was first described in U.S. Pat. No. RE 34712, is the pure S-enantiomer (single isomer) of the racemic bicyclic phthalane derivative of Citalopram. Escitalopram oxalate is designated as S-(+)-1-[3-(dimethyl-amino)propyl]-1-(β-fluorophenyl)-5-phthalancarbonitrile oxalate. A conventional immediate release preparation of Escitalopram oxalate is commercially available in the United States from Forest Laboratories, Inc. under the proprietary name LEXAPRO™ as 10 mg and 20 mg film coated tablets. The tablets contain the following inactive ingredients: talc, croscarmellose sodium, microcrystalline cellulose/colloidal silicon dioxide and magnesium stearate. The film coating contains hydroxypropyl methylcellulose, titanium dioxide and polyethylene glycol. The single and multiple dose pharmacokinetics of Escitalopram are linear and dose proportional in a dose range of 10 to 30 mg per day. Biotransformation of Escitalopram is mainly hepatic with a mean terminal half life of about 27 to 32 hours. With once daily dosing, steady state plasma concentrations are achieved within approximately one week. At steady state, the extent of accumulation of Escitalopram in plasma in young healthy subjects was 2.2 to 2.5 times the plasma concentrations observed after a single dose. Following a single oral dose (20 mg tablet) of Escitalopram, the mean T_maxwas 5±1.5 hours. Absorption of Escitalopram is not affected by food. The FDA Orange Book states that U.S. Pat. No. RE 34712 relates to the LEXAPRO™ formulation. Such a conventional immediate release preparation, however, does not provide a modified release of Escitalopram oxalate.

SUMMARY OF THE INVENTION

In accordance with one aspect of the present invention, there is provided a modified release pharmaceutical composition for oral administration, suitable for once daily dosing, comprising a form of at least one selective serotonin re-uptake inhibitor (SSRI) selected from the group consisting of SSRIs, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof, and combinations thereof in combination with at least one pharmaceutically-acceptable excipient, wherein the pharmaceutical composition, when orally administered to a patient, induces a statistically significant lower mean fluctuation index in the plasma than an immediate release composition of the form of the at least one SSRI while maintaining bioavailability substantially equivalent to that of the immediate release composition.

In accordance with another aspect of the present invention, there is provided a modified release pharmaceutical composition for oral administration, suitable for once daily dosing, comprising a form of at least one selective serotonin re-uptake inhibitor (SSRI) selected from the group consisting of SSRIs, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof, and combinations thereof in combination with at least one pharmaceutically-acceptable excipient, wherein the pharmaceutical composition, when orally administered to a patient, produces a mean maximum plasma concentration (C_max) of the form of the at least one SSRI that is lower than that produced by an immediate release pharmaceutical composition of the form of the at least one SSRI, and the area under the plasma concentration-time curve (AUC) and the mean minimum plasma concentration (C_min) are substantially equivalent to that of the immediate release pharmaceutical composition.

In accordance with another aspect of the present invention, there is provided a modified release pharmaceutical composition for oral administration, suitable for once daily dosing, comprising a form of at least one selective serotonin re-uptake inhibitor (SSRI) selected from the group consisting of SSRIs, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof, and combinations thereof in combination with at least one pharmaceutically-acceptable excipient, wherein the pharmaceutical composition, when orally administered to a patient, produces a mean maximum plasma concentration (C_max) of the form of the at least one SSRI and an area under a plasma concentration vs. time curve (AUC) within the range of from about −20% to about +25% of that produced by an immediate release pharmaceutical composition of the form of the at least one SSRI.

In an embodiment of the present invention, the form of the at least one SSRI is Citalopram HBr and the immediate release pharmaceutical composition is the subject of the United States Food and Drug Administration Approved New Drug Application number N20822 or N21046.

In an embodiment of the present invention, the form of the at least one SSRI is Escitalopram oxalate and the immediate release pharmaceutical composition is the subject of the United States Food and Drug Administration Approved New Drug Application number N21323.

In an embodiment of the present invention, the form of the at least one SSRI is Fluoxetine HCl and the immediate release pharmaceutical composition is the subject of the United States Food and Drug Administration ‘Approved New Drug Application’ number N18936, N20101, N20974, or N75755.

In an embodiment of the present invention, the form of the at least one SSRI is Fluvoxamine maleate and the immediate release pharmaceutical composition is the subject of the United States Food and Drug Administration Approved New Drug Application number N20243 or N75888.

In an embodiment of the present invention, the form of the at least one. SSRI is Sertraline HCl and the immediate release pharmaceutical composition is the subject of the United States Food and Drug Administration Approved New Drug Application number N20990 or N19839.

In an embodiment of the present invention, the form of the at least one SSRI is Verlafaxine HCl and the immediate release pharmaceutical composition is the subject of the United States Food and Drug Administration Approved New Drug Application number N20151.

In an embodiment of the present invention, the form of the at least one SSRI is Paroxetine HCl and the immediate release pharmaceutical composition is the subject of the United States Food and Drug Administration Approved New Drug Application number N20710 or N20031.

In accordance with another aspect of the present invention, there is provided a modified release pharmaceutical composition for oral administration, suitable for once daily dosing, comprising a form of at least one selective serotonin re-uptake inhibitor (SSRI) selected from the group consisting of SSRIS, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof, and combinations thereof in combination with at least one pharmaceutically-acceptable excipient wherein the pharmaceutical composition exhibits the following in vitro dissolution profile when measured using the USP Paddle Method at 100 rpm in 900 mL of a buffered medium having a pH between about 5.5 and about 7.5 at 37.0±0.5° C.:

- (a) between about 0% and about 50% (by wt) of the form of the at least one SSRI is released after about 1 hour;
- (b) between about 0% and about 75% (by wt) of the form of the at least one SSRI is released after about 2 hours;
- (c) between about 3% and about 95% (by wt) of the form of the at least one SSRI is released after about 4 hours;
- (d) between about 10% and about 100% (by wt) of the form of the at least one SSRI is released after about 8 hours;
- (e) between about 20% and about 100% (by wt) of the form of the at least one SSRI is released after about 12 hours;
- (f) between about 30% and about 100% (by wt) of the form of the at least one SSRI is released after about 16 hours;
- (g) between about 50% and about 100% (by wt) of the form of the at least one SSRI is released after about 24 hours; and
- (h) in excess of about 80% (by wt) of the form of the at least one SSRI is released after about 36 hours.

In an embodiment of the present invention, the composition exhibits the following in vitro dissolution profile when measured using the USP paddle method at 100 rpm in 900 ml of a buffered medium having a pH from about 5.5 to about 7.5 at 37.0±0.5° C.:

- (a) from about 20% to about 50% (by weight) of the form of the at least one SSRI is released after about 1 hour;
- (b) from about 40% to about 75% (by weight) of the form of the at least one SSRI is released after about 2 hours;
- (c) from about 60% to about 95% (by weight) of the form of the at least one SSRI is released after about 4 hours;
- (d) from about 80% to about 100% (by weight) of the form of the at least one SSRI is released after about 8 hours; and
- (e) from about 90% to about 100% (by weight) of the form of the at least one SSRI is released after about 12 hours.

- (a) from about 0% to about 50% (by weight) of the form of the at least one SSRI is released after about 1 hour;
- (b) from about 0% to about 75% (by weight) of the form of the at least one SSRI is released after about 2 hours;
- (c) from about 10% to about 95% (by weight) of the form of the at least one SSRI is released after about 4 hours;
- (d) from about 35% to about 100% (by weight) of the form of the at least one SSRI is released after about 8 hours;
- (e) from about 55% to about 100% (by weight) of the form of the at least one SSRI is released after about 12 hours;
- (f) from about 70% to about 100% (by weight) of the form of the at least one SSRI is released after about 16 hours; and
- (g) in excess of about 90% (by weight) of the form of the at least one SSRI is released after about 24 hours.

- (a) from about 0% to about 30% (by weight) of the form of the at least one SSRI is released after about 1 hour;
- (b) from about 0% to about 45% (by weight) of the form of the at least one SSRI is released after about 2 hours;
- (c) from about 3% to about 55% (by weight) of the form of the at least one SSRI is released after about 4 hours;
- (d) from about 10% to about 65% (by weight) of the form of the at least one SSRI is released after about 8 hours;
- (e) from about 20% to about 75% (by weight) of the form of the at least one SSRI is released after about 12 hours;
- (f) from about 30% to about 88% (by weight) of the form of the at least one SSRI is released after about 16 hours;
- (g) from about 50% to about 100% (by weight) of the form of the at least one SSRI is released after about 24 hours; and
- (h) in excess of about 80% (by weight) of the form of the at least one SSRI is released after about 36 hours.

- (a) from about 5% to about 50% (by weight) of the form of the at least one SSRI is released after about 1 hour;
- (b) from about 10% to about 75% (by weight) of the form of the at least one SSRI is released after about 2 hours;
- (c) from about 20% to about 95% (by weight) of the form of the at least one SSRI is released after about 4 hours;
- (d) from about 40% to about 100% (by weight) of the form of the at least one SSRI is released after about 8 hours;
- (e) more than about 50% (by weight) of the form of the at least one SSRI is released after about 12 hours;
- (f) more than about 70% (by weight) of the form of the at least one SSRI is released after about 18 hours; and
- (g) more than about 80% (by weight) of the form of the at least one SSRI is released after about 24 hours.

- (a) from about 15% to about 25% (by weight) of the form of the at least one SSRI is released after about 1 hour;
- (b) from about 25% to about 35% (by weight) of the form of the at least one SSRI is released after about 2 hours;
- (c) from about 30% to about 45% (by weight) of the form of the at least one SSRI is released after about 4 hours;
- (d) from about 40% to about 60% (by weight) of the form of the at least one SSRI is released after about 8 hours;
- (e) from about 55% to about 70% (by weight) of the form of the at least one SSRI is released after about 12 hours; and
- (f) from about 60% to about 75% (by weight) of the form of the at least one SSRI is released after about 16 hours.

- (a) from about 10% to about 30% (by weight) of the form of the at least one SSRI is released after about 1 hour;
- (b) from about 46% to about 66% (by weight) of the form of the at least one SSRI is released after about 4 hours;
- (c) from about 70% to about 90% (by weight) of the form of the at least one SSRI is released after about 8 hours; and
- (d) in excess of about 80% (by weight) of the form of the at least one SSRI is released after about 12 hours.

In an embodiment of the present invention, the pharmaceutical composition exhibits the following in vitro dissolution profile when measured using the USP Paddle Method at 100 rpm in 900 ml of a buffered medium, having a pH between about 5.5 and about 7.5 at 37.0±0.5° C.:

- (a) from about 3% to about 20% (by weight) of the form of the at least one SSRI is release after about 1 hour;
- (b) from about 7% to about 32% (by weight) of the form of the at least one SSRI is released after about 2 hours;
- (c) from about 17% to about 50% (by weight) of the form of the at least one SSRI is released after about 4 hours;
- (d) from about 30% to about 75% (by weight) of the form of the at least one SSRI is released after about 8 hours;
- (e) from about 55% to about 90% (by weight) of the form of the at least one SSRI is released after about 12 hours;
- (f) from about 68% to about 98% (by weight) of the form of the at least one SSRI is released after about 16 hours; and
- (g) in excess of about 85% (by weight) of the form of the at least one SSRI is released after about 24 hours.

- (a) from about 18% to about 30% (by weight) of the form of the at least one SSRI is release after about 1 hour;
- (b) from about 28% to about 43% (by weight) of the form of the at least one SSRI is released after about 2 hours;
- (c) from about 45% to about 78% (by weight) of the form of the at least one SSRI is released after about 4 hours;
- (d) from about 68% to about 98% (by weight) of the form of the at least one SSRI is released after about 8 hours;
- (e) from about 82% to about 100% (by weight) of the form of the at least one SSRI is released after about 12 hours;
- (f) from about 90% to about 100% (by weight) of the form of the at least one SSRI is released after about 16 hours; and
- (g) in excess of about 95% (by weight) of the form of the at least one SSRI is released after about 24 hours.

- (a) from about 10% to about 22% (by weight) of the form of the at least one SSRI is release after about 1 hour;
- (b) from about 16% to about 35% (by weight) of the form of the at least one SSRI is released after about 2 hours;
- (c) from about 28% to about 55% (by weight) of the form of the at least one SSRI is released after about 4 hours;
- (d) from about 48% to about 80% (by weight) of the form of the at least one SSRI is released after about 8 hours;
- (e) from about 62% to about 100% (by weight) of the form of the at least one SSRI is released after about 12 hours;
- (f) from about 73% to about 100% (by weight) of the form of the at least one SSRI is released after about 16 hours; and
- (g) in excess of about 80% (by weight) of the form of the at least one SSRI is released after about 24 hours.

- (a) from about 20% to about 24% (by weight) of the form of the at least one SSRI is release after about 1 hour;
- (b) from about 30% to about 38% (by weight) of the form of the at least one SSRI is released after about 2 hours;
- (c) from about 50% to about 58% (by weight) of the form of the at least one SSRI is released after about 4 hours;
- (d) from about 75% to about 85% (by weight) of the form of the at least one SSRI is released after about 8 hours;
- (e) from about 90% to about 100% (by weight) of the form of the at least one SSRI is released after about 12 hours; and
- (f) in excess of about 90% (by weight) of the form of the at least one SSRI is released after about 16 hours.

- (a) from about 20% to about 25% (by weight) of the form of the at least one SSRI is release after about 1-hour;
- (b) from about 32% to about 38% (by weight) of the form of the at least one SSRI is released after about 2 hours;
- (c) from about 50% to about 60% (by weight) of the form of the at least one SSRI is released after about 4 hours;
- (d) from about 75% to about 85% (by weight) of the form of the at least one SSRI is released after about 8 hours;
- (e) from about 90% to about 100% (by weight) of the form of the at least one SSRI is released after about 12 hours; and
- (f) in excess of about 90% (by weight) of the form of the at least one SSRI is released after about 16 hours.

In accordance with another aspect of the present invention, there is provided a modified release pharmaceutical composition for oral administration, suitable for once daily dosing, comprising about 20 mg of a form of at least one selective serotonin re-uptake inhibitor (SSRI) selected from the group consisting of SSRIs, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof in combination with at least one pharmaceutically-acceptable excipient, wherein the composition when orally administered to a patient, provides a mean maximum plasma concentration (C_max) of the form of the at least one SSRI from about 5.0 ng/ml to about 28.0 ng/ml.

In an embodiment of the present invention, the composition when orally administered to a fasting patient, provides a C_maxof the form of the at least one SSRI from about 5.0 ng/ml to about 28.0 ng/ml.

In an embodiment of the present invention, the composition when orally administered to a fasting patient, provides a C_maxof the form of the at least one SSRI from about 7.0 ng/ml to about 14.0 ng/ml.

In an embodiment of the present invention, the composition when orally administered to a fasting patient, provides a C_maxof the form of the at least one SSRI from about 8.0 ng/ml to about 12.0 ng/ml.

In an embodiment of the present invention, the composition when orally administered to a fasting patient, provides a C_maxof the form of the at least one SSRI from about 10.0 ng/ml to about 14.0 ng/ml.

In an embodiment of the present invention, the composition when orally administered to a fasting patient, provides a C of the form of the at least one SSRI from about 13.0 ng/ml to about 21.0 ng/ml.

In an embodiment of the present invention, the composition when orally administered to a fasting patient, provides a C_maxof the form of the at least one SSRI from about 15.0 ng/ml to about 19.0 ng/ml.

In an embodiment of the present invention, the composition when orally administered to a fasting patient, provides a C_maxof the form of the at least one SSRI from about 9.0 ng/ml to about 13.0 ng/ml.

In an embodiment of the present invention, the composition when orally administered to a fasting patient, provides a C_maxof the form of the at least one SSRI from about 12.0 ng/ml to about 19.0 ng/ml.

In an embodiment of the present invention, the composition when orally administered to a fasting patient, provides a C_maxof the form of the at least one SSRI from about 13.0 ng/ml to about 17.0 ng/ml.

In an embodiment of the present invention, the composition when orally administered to a fasting patient, provides a C_maxof the form of the at least one SSRI from about 14.0 ng/ml to about 21.0 ng/ml.

In an embodiment of the present invention, the composition when orally administered to a fasting patient, provides a C_maxof the form of the at least one SSRI from about 16.0 ng/ml to about 20.0 ng/ml.

In an embodiment of the present invention, the composition when orally administered to a fasting patient, provides a C_maxof the form of the at least one SSRI from about 6.0 ng/ml to about 28.0 ng/ml.

In an embodiment of the present invention, the composition when orally administered to a fed patient, provides a C_maxof the form of the at least one SSRI from about 9.0 ng/ml to about 18.0 ng/ml.

In an embodiment of the present invention, the composition when orally administered to a fed patient, provides a C_maxof the form of the at least one SSRI from about 9.0 ng/ml to about 16.0 ng/ml.

In an embodiment of the present invention, the composition when orally administered to a fed patient, provides a C_maxof the form of the at least one SSRI from about 11.0 ng/ml to about 15.0 ng/ml.

In an embodiment of the present invention, the composition when orally administered to a fed patient, provides a C_maxof the form of the at least one SSRI from about 11.0 to about 18.0 ng/mL.

In an embodiment of the present invention, the composition when orally administered to a fed patient, provides a C_maxof the form of the at least one SSRI from about 13.0 ng/ml to about 17.0 ng/ml.

In accordance with another aspect of the present invention, there is provided a modified release pharmaceutical composition for oral administration, suitable for once daily dosing, comprising a form of at least one selective serotonin re-uptake inhibitor (SSRI) selected from the group consisting of SSRIs, racemic mixtures thereof, enantiomers thereof pharmaceutically acceptable salts thereof and combinations thereof in combination with at least one pharmaceutically-acceptable excipient, wherein the pharmaceutical composition when orally administered to a patient, provides a medicament plasma concentration-time curve wherein the mean maximum plasma concentration (C_max) in a fasted patient divided by C_maxin a fed patient ranges from about 0.20 to about 1.55.

In an embodiment of the present invention, the composition, when orally administered to a patient, provides a medicament plasma concentration time curve wherein the C_maxin a fasted patient divided by the C_maxin a fed patient ranges from about 0.30 to about 1.55.

In an embodiment of the present invention, the composition, when orally administered to a patient, provides a plasma concentration-time curve wherein the C_maxof the form of the at least one SSRI in a fasted patient divided by the C_maxof the form of the at least one SSRI in a fed patient ranges from about 0.25 to about 1.45.

In accordance with another aspect of the present invention, there is provided a modified release pharmaceutical composition for oral administration, suitable for once daily dosing, comprising about 20 mg of a form of at least one selective serotonin re-uptake inhibitor (SSRI) selected from the group consisting of SSRIs, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof in combination with at least one pharmaceutically-acceptable excipient, wherein the composition when orally administered to a patient, provides a mean maximum plasma concentration (C_max) of the form of the at least one SSRI from about 6.0 ng/ml to about 28.0 ng/ml.

In an embodiment of the present invention, the composition, when orally administered to a fasting patient, provides a C_maxof the form of the at least one SSRI ranging from about 6.0 ng/ml to about 28.0 ng/ml.

In an embodiment of the present invention, the composition, when orally administered to a fed patient, provides a C_maxof the form of the at least one SSRI ranging from about 15.0 ng/ml to about 19.0 ng/rn1.

In accordance with another aspect of the present invention, there is provided a modified release pharmaceutical composition for oral administration, suitable for once daily dosing, comprising about 40 mg of a form of at least one selective serotonin re-uptake inhibitor (SSRI) selected from the group consisting of SSRIs, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof in combination with at least one pharmaceutically acceptable excipient, wherein the composition when orally administered to a patient, provides a mean maximum plasma concentration (C_max) of the form of the at least one SSRI from about 20.0 ng/ml to about 36.0 ng/ml.

In an embodiment of the present invention, the composition, when orally administered to a fasting patient, provides a C_maxof the form of the at least one SSRI ranging from about 20.0 ng/ml to about 36.0 ng/ml.

In an embodiment of the present invention, the composition, when orally administered to a fasting patient, provides a T_maxranging from about 4 hours to about 22 hours.

In an embodiment of the present invention, the composition, when orally administered to a fasting patient, provides a T=ranging from about 17 hours to about 21 hours.

In an embodiment of the present invention, the composition, when orally administered to a fasting patient, provides a T_maxranging from about 15 hours to about 19 hours.

In an embodiment of the present invention, the composition, when orally administered to a fasting patient, provides a T_maxranging from about 7 hours to about 11 hours.

In an embodiment of the present invention, the composition, when orally administered to a fasting patient, provides a T_maxranging from about 12 hours to about 16 hours.

In an embodiment of the present invention, the composition, when orally administered to a fasting patient, provides a T_maxranging from about 11 hours to about 15 hours.

In an embodiment of the present invention, the composition, when orally administered to a fasting patient, provides a T_maxranging from about 7 hours to about 13 hours.

In an embodiment of the present invention, the composition, when orally administered to a fasting patient, provides a T_maxranging from about 8 hours to about 12 hours.

In an embodiment of the present invention, the composition, when orally administered to a fasting patient, provides a T_maxranging from about 5 hours to about 11 hours.

In an embodiment of the present invention, the composition, when orally administered to a fasting patient, provides a T_maxranging from about 6 hours to about 10 hours.

In an embodiment of the present invention, the composition, when orally administered to a fed patient, provides a T_maxranging from about 14 to about 21 hours.

In an embodiment of the present invention, the composition, when orally administered to a fed patient, provides a T_maxranging from about 17 hours to about 21 hours.

In an embodiment of the present invention, the composition, when orally administered to a fed patient, provides a T_maxranging from about 14 hours to about 18 hours.

In accordance with another aspect of the present invention, there is provided a modified release pharmaceutical composition for oral administration, suitable for once daily dosing, comprising a form of at least one selective serotonin re-uptake inhibitor (SSRI) selected from the group consisting of SSRIs, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof in combination with at least one pharmaceutically-acceptable excipient, wherein the composition, when orally administered to a patient, provides a plasma concentration-time curve wherein the time to mean maximum plasma concentration (T_max) of the form of the at least one SSRI in a fasted patient divided by the T_maxof the form of the at least one SSRI in a fed patient ranges from about 0.50 to about 1.10.

In an embodiment of the present invention, the composition when orally administered to a patient, provides a medicament plasma concentration-time curve wherein the T_maxin a fasted patient divided by the T_maxin a fed patient ranges from about 0.50 to about 0.95.

In an embodiment of the present invention, the composition when orally administered to a patient, provides a medicament plasma concentration-time curve wherein the T_maxin a fasted patient divided by the T in a fed patient ranges from about 0.60 to about 1.10.

In an embodiment of the present invention, the composition, when orally administered to a fasting patient, provides a T_maxranging from about 4 hours to about 9 hours.

In an embodiment of the present invention, the composition, when orally administered to a fasting patient, provides a T_maxranging from about 5 hours to about 8 hours.

In an embodiment of the present invention, the composition, when orally administered to a fasting patient, provides a T_maxranging from about 5 hours to about 14 hours.

In an embodiment of the present invention, the composition, when orally administered to a fasting patient, provides a T_maxranging from about 7 hours to about 13 hours.

In an embodiment of the present invention, the composition, when orally administered to a fasting patient, provides a T_maxranging from about 8 hours to about 12 hours.

In an embodiment of the present invention, the composition, when orally administered to a fasting patient, provides a T_maxranging from about 6 hours to about 10 hours.

In an embodiment of the present invention, the composition, when orally administered to a fasting patient, provides a T_maxranging from about 5 hours to about 12 hours.

In accordance with another aspect of the present invention, there is provided a modified release pharmaceutical composition for oral administration, suitable for once daily dosing, comprising about 20 mg of a form of at least one selective serotonin re-uptake inhibitor (SSRI) selected from the group consisting of SSRIS, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof in combination with at least one pharmaceutically-acceptable excipient, wherein the composition when orally administered to a patient provides a plasma concentration time curve with an area under the curve from zero to infinity (AUC_(0-inf)) ranging from about 400 ng.hr/ml to about 1500 ng.hr/ml.

In an embodiment of the present invention, wherein the composition, when orally administered to a fasting patient, provides a plasma concentration time curve with an AUC_(0-inf)ranging from about 400 ng hr/ml to about 1500 ng.hr/ml.

In an embodiment of the present invention, the composition, when orally administered to a fasting patient, provides a plasma concentration time curve with an AUC_(0-inf)ranging from about 400 ng.hr/ml to about 800 ng.hr/ml.

In an embodiment of the present invention, the composition, when orally administered to a fasting patient, provides a plasma concentration-time curve of the form of the at least one SSRI with an AUC_(0-inf)ranging from about 600 ng.hr/ml to about 1000 ng.hr/ml. In an embodiment of the present invention, the composition, when orally administered to a fasting patient, provides a plasma concentration-time curve of the form of the at least one SSRI with an AUC_(0-inf)ranging from about 700 ng.hr/ml to about 1100 ng.hr/ml.

In an embodiment of the present invention, the composition, when orally administered to a fasting patient, provides a plasma concentration-time curve of the form of the at least one SSRI with an AUC_(0-inf)ranging from about 1100 ng.hr/ml to about 1500 ng.hr/ml. In an embodiment of the present invention, the composition, when orally administered to a fed patient, provides a plasma concentration-time curve of the form of the at least one SSRI with an AUC_(0-inf)ranging from about 600 ng.hr/ml to about 1000 ng.hr/ml.

In an embodiment of the present invention, the composition, when orally administered to a fed patient, provides a plasma concentration-time curve of the form of the at least one SSRI with an AUC_(0-inf)ranging from about 700 ng.hr/ml to about 1100 ng.hr/ml.

In accordance with another aspect of the present invention, there is provided a modified release pharmaceutical composition for oral administration, suitable for once daily dosing, comprising a form of at least one selective serotonin re-uptake inhibitor (SSRI) selected from the group consisting of SSRIs, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof in combination with at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition, when orally administered to a patient, provides an area under the curve from zero to infinity (AUC_(0-inf)) in a fasted patient, divided by AUC_(0-inf)in a fed patient ranges from about 0.60 to about 0.80.

In accordance with another aspect of the present invention, there is provided a modified release pharmaceutical composition for oral administration, suitable for once daily dosing, comprising about 20 mg of a form of at least one selective serotonin re-uptake inhibitor (SSRI) selected from the group consisting of SSRIs, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof in combination with at least one pharmaceutically-acceptable excipient, wherein the composition when orally administered to a patient provides a plasma concentration time curve with an area under the curve (AUC) ranging from about 100 ng.hr/ml to about 1000 ng.hr/ml.

In accordance with another aspect of the present invention, there is provided a modified release pharmaceutical composition for oral administration, suitable for once daily dosing, comprising about 40 mg of a form of at least one selective serotonin re-uptake inhibitor (SSRI) selected from the group consisting of SSRIs, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof in combination with at least one pharmaceutically-acceptable excipient, wherein the composition when orally administered to a patient provides a plasma concentration time curve with an area under the curve from zero to infinity (AUC_(0-inf)) ranging from about 600 ng.hr/ml to about 12000 ng.hr/ml.

In an embodiment of the present invention, the composition, when orally administered to a fasting patient, provides a plasma concentration-time curve of the form of the at least one SSRI with an AUC_(0-inf)ranging from about 600 ng.hr/ml to about 2200 ng.hr/ml. In an embodiment of the present invention, the composition, when orally administered to a fasting patient, provides a plasma concentration-time curve of the form of the at least one SSRI with an AUC_(0-inf)ranging from about 1200 ng.hr/ml to about 1600 ng.hr/ml.

In accordance with another aspect of the present invention, there is provided a modified release pharmaceutical composition for oral administration, suitable for once daily dosing, comprising a form of at least one selective serotonin re-uptake inhibitor (SSRI) selected from the group consisting of SSRIs, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof in combinations thereof in combination with at least one pharmaceutically acceptable excipient, wherein the composition, when orally administered to a patient, provides a plasma concentration time curve with an area under the curve from zero to t hours (AUC_(0-t)) ranging from about 400 ng.hr/ml to about 1500 ng.hr/ml.

In an embodiment of the present invention, the composition, when orally administered to a fasting patient, provides a plasma concentration time curve with an AUC_(0-t)ranging from about 400 ng.hr/ml to about 1500 ng.hr/ml.

In an embodiment of the present invention, the composition, when orally administered to a fed patient, provides a plasma concentration time curve with an AUC_(0-t)ranging from about 600 ng.hr/ml to about 1000 ng.hr/ml.

In accordance with another aspect of the present invention, there is provided a modified release pharmaceutical composition for oral administration, suitable for once daily dosing, comprising a form of at least one selective serotonin re-uptake inhibitor (SSRI) selected from the group consisting of SSRIs, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof in combination with at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition, when orally administered to a patient, provides a medicament plasma concentration time curve wherein the area under the curve from zero to t hours (AUC_(0-t)) in a fasted patient divided by the AUC_(0-t)in a fed patient ranges from about 0.60 to about 0.80.

In accordance with another aspect of the present invention, there is provided a modified release pharmaceutical composition for oral administration, suitable for once daily dosing, comprising about 40 mg of a form of at least one selective serotonin re-uptake inhibitor (SSRI) selected from the group consisting of SSRIs, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof in combinations thereof in combination with at least one pharmaceutically acceptable excipient, wherein the composition, when orally administered to a patient, provides a plasma concentration time curve with an area under the curve from zero to t hours (AUC_(0-t)) ranging from about 500 ng.hr/ml to about 6500 ng.hr/ml.

In accordance with another aspect of the present invention, there is provided a modified release pharmaceutical composition for oral administration, suitable for once daily dosing, comprising about 20 mg of a form of at least one selective serotonin re-uptake inhibitor (SSRI) selected from the group consisting of SSRIs, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof in combination with at least one pharmaceutically-acceptable excipient, wherein the composition when orally administered to a patient provides a plasma concentration time curve with an area under the curve from zero to 24 hours (AUC_(0-24)) ranging from about 100 ng.hr/ml to about 500 ng.hr/ml.

In accordance with another aspect of the present invention, there is provided a modified release pharmaceutical composition for oral administration, suitable for once daily dosing, comprising a form of at least one selective serotonin re-uptake inhibitor (SSRI) selected from the group consisting of SSRIs, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof in combination with at least one pharmaceutically-acceptable excipient, wherein the pharmaceutical composition when orally administered to a patient as a single dose, releases the form of the at least one SSRI in vivo such that the duration over which the plasma level of the form of the at least one SSRI is equal to or greater than 50% of the mean maximum plasma concentration (C_max) is about 20 hours or greater.

In an embodiment of the present invention, the composition, when orally administered to a patient as a single dose, releases the form of the at least one SSRI in vivo such that the duration over which the plasma level of the form of the at least one SSRI is equal to or greater than 50% of the C_maxis about 24 hours or greater.

In accordance with another aspect of the present invention, there is provided a modified release pharmaceutical composition for oral administration, suitable for once daily dosing, comprising a form of at least one selective serotonin re-uptake inhibitor (SSRI) selected from the group consisting of SSRIs, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof in combination with at least one pharmaceutically-acceptable excipient, wherein the pharmaceutical composition, when orally administered to a patient as a single dose, releases the form of the at least one SSRI in vivo such that the duration over which the plasma level of the form of the at least one SSRI is equal to or greater than 75% of the mean maximum plasma concentration (C_max) is about 6 hours or greater.

In an embodiment of the present invention, the pharmaceutical composition, when orally administered to a patient as a single dose, releases the form of the at least one SSRI in vivo such that the duration over which the plasma level of the form of the at least one SSRI is equal to or greater than 75% of the C_maxis about 12 hours or greater.

In accordance with another aspect of the present invention, there is provided a modified release pharmaceutical composition for oral administration, suitable for once daily dosing, comprising a form of at least one selective serotonin re-uptake inhibitor (SSRI) selected from the group consisting of SSRIs, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof in combination with at least one pharmaceutically-acceptable excipient, wherein the pharmaceutical composition, when orally administered to a patient releases the form of the at least one SSRI in vivo at steady state such that the plasma level of the form of the at least one SSRI over the 24 hour dosing period is equal to or greater than 50% of the mean maximum plasma concentration (C_max).

In an embodiment of the present invention, the pharmaceutical composition, when orally administered to a patient releases the form of the at least one SSRI in vivo at steady state such that the duration over which the plasma level of the form of the at least one SSRI over the 24 hour dosing period is equal to or greater than 75% of the C_maxis about 12 hours or greater.

In accordance with another aspect of the present invention, there is provided a modified release pharmaceutical composition for oral administration, suitable for once daily dosing, comprising a form of at least one selective serotonin reuptake inhibitor selected from the group consisting of SSRIS, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof in combination with at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition, when orally administered to a patient, provides a mean maximum plasma concentration (C_max) which is more than twice the plasma level of said form of said at least one SSRI at about 16 hours after administration of the pharmaceutical composition.

In an embodiment of the present invention, the composition, when orally administered to a patient, provides a C_maxwhich is more than twice the plasma level of said form of said at least one SSRI at about 20 hours after administration of the pharmaceutical composition.

In an embodiment of the present invention, the composition, when orally administered to a patient, provides a C_maxwhich is more than twice the plasma level of said form of said at least one SSRI at about 24 hours after administration of the pharmaceutical composition.

In an embodiment of the present invention, the composition, when orally administered to a patient, provides a C_maxwhich is more than twice the plasma level of said form of said at least one SSRI at about 36 hours after administration of the pharmaceutical composition.

In an embodiment of the present invention, the composition, when orally administered to a patient, provides a C_maxwhich is more than twice the plasma level of said form of said at least one SSRI at about 48 hours after administration of the pharmaceutical composition.

In accordance with another aspect of the present invention, there is provided a method of effectively treating depression in humans, comprising orally administering to a human patient on a once a day basis an oral sustained release dosage form containing a form of at least one selective serotonin re-uptake inhibitor (SSRI) selected from the group consisting of SSRIs, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof in combination with at least one pharmaceutically acceptable excipient which upon administration provides a time to maximum plasma concentration (T_max) of said form of said at least one SSRI in about 6 to about 20 hours and a maximum plasma concentration (C_max) which is more than twice the plasma level of said form of said at least one SSRI at about 48 hours after administration of the dosage form, and which dosage form provides effective treatment of depression for about 24 hours or more after administration to the patient. In accordance with another aspect of the present invention there is provided a method of effectively treating depression in a human patient, comprising orally administering to a human patient on a once a day basis an oral sustained release dosage form containing a form of at least one selective serotonin reuptake inhibitor selected from the group consisting of SSRIs, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof in combination with at least one pharmaceutically acceptable excipient, which provides a maximum plasma concentration (C_max) which is more than twice the plasma level of said form of said at least one SSRI at about 48 hours after administration of the dosage form, and which provides effective treatment of depression for about 24 hours or more after administration to the patient.

In an embodiment of the present invention, the form of the at least one SSRI is selected from the group consisting of Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Venlafaxine, Citalopram, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof.

In an embodiment of the present invention, the form of the at least SSRI is Citalopram HBr.

In an embodiment of the present invention, the form of the at least SSRI is Escitalopram oxalate.

In an embodiment of the present invention, the form of the at least SSRI is Fluvoxamine maleate.

In an embodiment of the present invention, the form of the at least SSRI is Paroxetine HCl.

In an embodiment of the present invention, the form of the at least SSRI is Sertraline HCl.

In an embodiment of the present invention, the form of the at least SSRI is Venlafaxine HCl.

In an embodiment of the present invention, the form of the at least one SSRI is present in the pharmaceutical composition in an amount effective to treat at least one condition selected from the group consisting of depression, major depressive disorder, obsessive compulsive disorder, panic disorder, social anxiety disorder, generalized anxiety disorder, posttraumatic stress disorder and combinations thereof.

In an embodiment of the present invention, the form of the at least one SSRI is present in the pharmaceutical composition in the range of from about 5 mg to about 1000 mg (calculated as the pharmaceutically-acceptable salt) per dosage unit.

In an embodiment of the present invention the form of the least one SSRI is present in the pharmaceutical composition in an amount in the range of from about 10 mg to about 200 mg (calculated as the pharmaceutically acceptable salt) per dosage unit.

In an embodiment of the present invention, the form of the at least one SSRI is present in the pharmaceutical composition in an amount in the range of from about 10 mg to about 100 mg (calculated as the pharmaceutically acceptable salt) per dosage unit.

In an embodiment of the present invention, the at least one pharmaceutically acceptable excipient is selected from the group comprising at least one release rate controlling pharmaceutically acceptable carrier, at least one diluent, at least one binder, at least one filler, at least one solubility enhancer, at least one bioavailability enhancer, at least one lubricant, at least one solubilizing agent, at least one surface active agent, at least one surfactant, at least one acidifying agent and combinations thereof.

In an embodiment of the present invention, the at least one release rate controlling pharmaceutically acceptable carrier is at least one sustained release pharmaceutically acceptable carrier.

In an embodiment of the present invention, the at least one sustained release pharmaceutically acceptable carrier is at least one solid sustained release pharmaceutically acceptable carrier.

In an embodiment of the present invention, the at least one solid sustained release pharmaceutically acceptable carrier is at least one solid sustained release pharmaceutically-acceptable polymer.

In an embodiment of the present invention, the at least one solid sustained release pharmaceutically-acceptable polymer is selected from the group consisting of at least one hydrophilic water-soluble polymer, at least one hydrophobic water-insoluble polymer and combinations thereof.

Any suitable hydrophilic water-soluble polymer conventional in the pharmaceutical art may be used. Examples of hydrophilic polymers suitable for use in the present invention include, but are not limited to, cellulose derivatives, dextrans, starches, carbohydrates, base polymers, natural or hydrophilic gums, xanthans, alginates, gelatins, polyacrylic acids, polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), carbomers or the like. The hydrophilic polymers can be used individually, as well as in mixtures of two or several hydrophilic polymers. In the case of the cellulose derivatives, the alkyl or hydroxyalkyl cellulose derivatives, the alkyl or hydroxyalkyl cellulose derivatives preferably come into consideration such as example, methyl cellulose, ethylcellulose (EC), hydroxy methylcellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), methylhydroxy ethylcellulose, methylhydroxy ethylcellulose, methylhydroxy propylcellulose or sodium carboxymethyl cellulose.

Suitable cellulose based hydrophilic polymers may have various degrees of substitution and/or different molecular weights corresponding to a different degree of viscosity of the aqueous solution.

In an embodiment of the present invention, the release rate controlling polymer may be selected from the group consisting of hydroxypropylmethyl cellulose, hydroxyethyl cellulose, ethylcellulose, carbomer and combinations thereof.

The hydroxypropyl methylcellulose (HPMC) used as the release rate controlling polymer in the present invention may suitably be any HPMC conventional in the pharmaceutical art. The HPMC used may suitably be, for example, HPMC substitution types 1828, 2208, 2906 and 2910 as described on page 843 of the 24^thEdition (2000) of the United States Pharmacopeia (USP XXIV). The hydroxypropyl methylcellulose used may suitably be, for example, METHOCEL® as supplied by Dow Chemical Company. Similar HPMCs are also available from other suppliers. Preferably, the HPMC used is HPMC 2208, more preferably METHOCEL® K4M Premium CR.

The ethylcellulose (EC) used as the release rate controlling polymer in the present invention may suitably be any EC conventional in the pharmaceutical art. The EC used may suitably be, for example, ETHOCEL® as supplied by Dow Chemical Company. Similar ECs are also available from other suppliers. Preferably, the EC used is EIHOCEL® FP, more preferably ETHOCEL® FP 100.

The carbomer used as the release rate controlling polymer in the present invention may suitably be any carbomer conventional in the pharmaceutical art. The carbomer used may suitably be, for example, carbomer 910, carbomer 934 and 934P, carbomer 941 and carbomer 1342 as described on pages 2426 to 2428 of the 19^thEdition (2000) of the United States National Formulary (USNFXIX). The carbomer used may suitably be, for example, CARBOPOL® as supplied by B.F. Goodrich. Similar carbomers are also available from other, suppliers. Preferably, the carbomer used is carbomer 941, more preferably CARBOPOL® 971P.

In an embodiment of the present invention, the modified release pharmaceutical composition may also comprise other pharmaceutically acceptable ingredients which are conventional in the pharmaceutical arts, such as at least one diluent, at least one lubricant, at least one binder, at least one granulating aid, at least one colourant, at least one flavourant, at least one surfactant, at least one pH adjuster, at least one anti-adherent, at least one glidant, at least one disintegrant, at least one solubility enhancer, at least one bioavailability enhancer, at least one solubilizing agent, at least one surface active agent, at least one surfactant and the like and combinations thereof.

In an embodiment of the present invention, the pharmaceutical composition may further comprise at least one diluent. Any suitable diluent conventional in the pharmaceutical art may be used. Examples of diluents suitable for use in the present invention include, but are not limited to, lactose, microcrystalline cellulose, mannit61 and combinations thereof. The lactose used may suitably be lactose anhydrous (direct tabletting) as supplied by Quest International. The microcrystalline cellulose used may suitably bes for example, AVICEL® as supplied by FMC Corporation, preferably AVICEL® PH 101 or AVICEL® PH 102.

In an embodiment of the present invention, the pharmaceutical composition may further comprise at least one binder. Any suitable binder conventional in the pharmaceutical art may be used. An example of a suitable binder for use in the present invention is polyvinyl pyrrolidone, for example KOLLIDON® as supplied by BASF AG, preferably KOLLIDON® 29/32 and/or KOLLIDON® 90F.

In an embodiment of the present invention, the pharmaceutical composition may further comprise at least one lubricant. Any suitable lubricant conventional in the pharmaceutical art may be used. Examples of suitable lubricants for use in the present invention include, but are not limited to, magnesium stearate, stearic acid and combinations thereof.

In an embodiment of the present invention, the pharmaceutical composition may further comprise at least one surfactant. Any surfactant conventional in the pharmaceutical art may be used. Examples of suitable surfactants for use in the present invention include, but are not limited to, a bile salt, sodium lauryl sulphate (SLS), polyoxyethylene/polyoxypropylene block copolymers, polyethylene glycol hydrogenated castor oils, polyethylene glycols, saturated polyglycolized glycerides from hydrogenated vegetable oils, saturated polyglycolized glycerides, water soluble derivatives of natural source vitamins, sucrose stearate, mannitol, mono- and diglycerides. The polyoxyethylene/polyoxypropylene block polymers used as the surfactant in the present invention may suitably be, for example, poloxamers, preferably poloxamer 407 or poloxamer 188 such as LUTROL® F127 or LUTROL® F68, respectively as supplied by BASF AG. The polyethylene ethylene glycol hydrogenated castor oils used as the surfactant in the present invention may suitably be, for example, PEG40 hydrogenated castor oil, such as CREMOPHOR® RH40 as supplied by BASF AG. The polyethylene glycols used as the surfactant in the present invention may suitably be, for example, PEG-3350, PEG-600, PEG8000 such as CARBOWAX® as supplied by Union Carbide and PEG-32 such as LUTROL® E1500 as supplied by BASF AG. The saturated polyglycolized glycerides from hydrogenated vegetable oils used as the surfactant in, the present invention may suitably be, for example, lauroyl macrogol-32 glycerides such as GELUCIRE® 44/14 as supplied by Gattefosse SA. The saturated polyglycolized glycerides used as the surfactant in the present invention may suitably be, for example, stearoyl macrogol-32 glycerides such as GELUCIRE® 50/13 as supplied by Gattefosse SA. The water soluble derivatives of natural source vitamins used as the surfactant in the present invention may suitably be, for example, Vitamin E d-∝-tocopheryl polyethylene glycol. 1000 succinate (IPGS) as supplied by Eastman. The sucrose stearate used as the surfactant in the present invention may suitably be, for example, CRODESTA® F160 as supplied by Croda Inc., The mono- and diglycerides used as the surfactant in the present invention may suitably be, for example, a propylene glycol monoester of medium chain fatty acids such as CAPMUL® PG8 as supplied by Abitec Corporation.

In an embodiment of the present invention, the pharmaceutical composition may further comprise at least one acidifying agent. Any acidifying agent conventional in the pharmaceutical art may be used. An example of a suitable acidifying agent for use in the present invention includes, but is not limited to, L-tartaric acid.

In an embodiment of the present invention, the form of the at least one SSRI may be incorporated into a matrix. The matrix may be any matrix conventional in the pharmaceutical art.

In an embodiment of the present invention the matrix is a modified release matrix that affords modified release of the form of the at least one SSRI over at least a 12 hour period and preferably that affords in vitro dissolution rates and in vivo absorption rates of the form of the at least one SSRI within the ranges specified above.

In an embodiment of the present invention, the matrix is selected from the group consisting of a sustained release matrix and a controlled release matrix.

In an embodiment of the present invention wherein the matrix is a sustained release matrix or a controlled release matrix, the pharmaceutical composition further comprises a modified release coating.

In an embodiment of the present invention, the matrix is a normal release matrix having a coating which provides for modified release of the form of the at least one SSRI.

In an embodiment of the present invention, the pharmaceutical composition further comprises a film coating. Any film coating material conventional in the pharmaceutical art may be used. Preferably, an aqueous film coating is used. The film coating functions to seal all surface pores and to provide a smooth and uniform surface. The film coat is obtained by preferably spray coating film coating dispersions onto the surface of uncoated cores using appropriate coating equipment. Usually these dispersions contain low viscosity hydrophilic polymers such as hydroxypropyl methylcellulose and hydroxypropyl cellulose, and plasticizers such as polyethylene glycol 400. These dispersions are commercially available as OPADRY® from Colorcon, West Point, Pa. Similar film coating dispersions are also available from other suppliers. Preferably the optional seal coating membrane is present in a concentration of about 0-5% W/W of the core. An example of a suitable film coating for use in the present invention is OPADRY® II White, preferably OPADRY® II White Y-22-7719. OPADRY® II White Y-22-7719 consists of hydroxypropylmethyl cellulose, titanium dioxide, polydextrose, triacetin and polyethylene glycol. Similar film coating materials are also available from other suppliers.

In an embodiment of the present invention the pharmaceutical composition further comprises a modified-release film coating. Any modified-release film coating material conventional in the pharmaceutical art may be used. The modified release film coating is applied to pharmaceutical products in order to modify drug release. There are two types of modified-release dosage forms, namely those that are delayed release and those that are extended release. Delayed-release products often are designed to prevent drug release in the upper part of the gastrointestinal (GI) tract. Modified release film coatings used to prepare this type of dosage form are commonly called enteric coatings. Extended-release products are designed to extend drug release over a period of time, a result which can be achieved by the application of a sustained- or controlled-release film coating. Modified release film coating is obtained by preferably spraying modified release film coating dispersions onto the surface of seal coated cores. However, these modified release film coating dispersions can also be coated straight onto the surface of the uncoated cores. In an embodiment of the present invention, the modified release film coating comprises as an aqueous dispersion, preferably with appropriate coating ingredients dispersed therein.

In an embodiment of the present invention, the modified release film coating further comprises plasticizers, film extenders, diffusion enhancers and other excipients such as detackifiers or opacifiers, etc. The hydrophobic polymer is mixed with a film extender/diffusion enhancer to give the hydrophobic polymer some degree of hyrophilicity. The plasticizer is added to reduce the glass transition temperature (T_g) of the polymer so that it can be coalesced at a lower temperature (such as 60° C.). The plasticizer also makes the functional coating membrane flexible so that it can stretch to some degree without breaking. Preferably, the ratio of the polymer to film extender in the aqueous polymeric dispersion of the functional coating membrane is from about 0.25-0.75 to 0.99-0.01.

The aqueous dispersions of hydrophobic polymers used as modified release film coatings in the present invention may be used in conjunction with tablets, spheroids (or beads), microspheres, seeds, pellets, ion-exchange resin beads, and other multi-particulate systems in order to obtain a desired controlled-release of the therapeutically active agent. Granules, spheroids, or pellets, etc., prepared in accordance with the present invention can be presented in a tablet, a capsule or in any other suitable dosage form. The tablets of the present invention may be any suitable shape, such as round, oval, biconcave, hemispherical, any polygonal shape such as square, rectangular, and pentagonal, and the like.

In order to obtain a modified-release formulation, it is usually necessary to overcoat the pharmaceutical composition with a sufficient amount of the aqueous dispersion of the hydrophobic polymer, to obtain a weight gain level from about 2 to about 25%, although the overcoat may be lesser or greater depending upon the physical properties of the form of the at least one SSRI and the desired release rate, the inclusion of plasticizer in the aqueous dispersion and the manner of incorporation of the same, for example.

In an embodiment of the present invention, the hydrophobic polymer is selected from the group consisting of ethylcellulose, an acrylic polymer and combinations thereof.

Although ethylcellulose is one preferred hydrophobic polymer which may be used for coating the pharmaceutical composition of the present invention, those skilled in the art will appreciate that other cellulosic polymers, including other alkyl cellulosic polymers, may be substituted for part or all of the ethylcellulose included in the hydrophobic polymer coatings of the present invention.

One commercially-available aqueous dispersion of ethylcellulose is AQUACOAT® (FMC Corp., Philadelphia, Pa., U.S.A.). AQUACOAT® is prepared by dissolving the ethylcellulose in a water-immiscible organic solvent and then emulsifying the same in water in the presence of a surfactant and a stabilizer. After homogenization to generate submicron droplets, the organic solvent is evaporated under vacuum to form a pseudolatex. The plasticizer is not incorporated in the pseudolatex during the manufacturing phase. Thus, prior to using the same as a coating, it is necessary to intimately mix the AQUACOAT® with a suitable plasticizer prior to use.

Another aqueous dispersion of ethylcellulose is commercially available as SURELEASE® (Colorcon, Inc., West Point, Pa., U.S.A.). This product is prepared by incorporating plasticizer into the dispersion during the manufacturing process. A hot melt of a polymer, plasticizer (dibutyl sebacate), and stabilizer (oleic acid) is prepared as a homogeneous mixture, which is then diluted with an alkaline solution to obtain an aqueous dispersion which can be applied directly into substrates.

Examples of pharmaceutically-acceptable acrylic polymers suitable for use in the present invention, include but are not limited to acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyan oethyl methacrylate, methyl methacrylate, copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, methyl methacrylate copolymers, methyl methacrylate copolymers, methacrylic acid copolymer, aminoalkyl methacrylate copolymer, methacrylic acid copolymers, methyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid, methacrylic acid alkylamide copolymer, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), methyl methacrylate, polymethacrylate, methyl methacrylate copolymer, poly(methyl methacrylate), poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.

In order to obtain a desirable dissolution profile, it may be necessary to incorporate two or more pharmaceutically-acceptable acrylic polymers having differing physical properties.

In an embodiment of the present invention, the modified-release coating is an enteric coating. An example of a suitable enteric coating material for use in the present invention is a methacrylic acid copolymer. The methacrylic acid copolymers used may suitably be any methacrylic acid copolymer conventional in the pharmaceutical art such as methacrylic acid copolymer Types A, B and C as described on page 2477 to page 2479 of USNFXIX.

In an embodiment of the present invention, the hydrophobic acrylic polymer is a polymer whose permeability is pH dependent, such as anionic polymers synthesized from methacrylic acid and methacrylic acid methyl ester. Such polymers are commercially available, e.g., from Rohm Pharma GmbH under the tradename EUDRAGIT® L and EUDRAGIT® S. The ratio of free carboxyl groups to the esters is said to be 1:1 in EUDRAGIT® L and 1:2 in EUDRAGIT® S. EUDRAGIT® L is insoluble in acids a pure water, but becomes increasingly permeable above pH 5.0 EUDRAGIT® S is similar, except that it becomes increasingly permeable above pH 7. Preferably, the methacrylic acid copolymer is methacrylic acid copolymer Type A and/or Type B, more preferably EUDRAGIT® L100 and/or EUDRAGIT® S100.

In one preferred embodiment, the acrylic coating is an acrylic resin lacquer used in the form of an aqueous dispersion, such as that which is commercially available from Rohm Pharma under the Tradename EUDRAGIT®. In further preferred embodiments, the acrylic coating comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma under the Tradenames EUDRAGIT® L100 and EUDRAGIT® S100, respectively.

EUDRAGIT® L100 and EUDRAGIT® S100 are anionic copolymers based on methacrylic acid and methyl methacrylate. The ratio of free carboxyl groups to the ester groups is about 1:1 in EUDRAGIT® L100 and about 1:2 in EUDRAGIT® S100. The average molecular weight is about 135,000. The films are insoluble below pH5 and thus resistant to gastric fluid. By salt formation in the neutral to weakly alkaline medium of intestinal fluid, the films dissolve step-wise at pH values above 5.5.

The EUDRAGIT® L/S dispersions of the present invention may be mixed together in any desired ratio in order to ultimately obtain a controlled-release formulation having a desirable dissolution profile. Desirable controlled-release formulations may be obtained, for instance, from an enteric coating derived from 100% EUDRAGIT® L100, 100% EUDRAGIT® S100, 50% EUDRAGIT® L100 and 50% EUDRAGIT® S100, and 90% EUDRAGIT® L100 and 10% EUDRAGIT® S100. Of course, one skilled in the art will recognize that other acrylic polymers may also be used.

In an embodiment of the present invention wherein the modified release film coating comprises an aqueous dispersion of a hydrophobic polymer, the inclusion of an effective amount of a plasticizer in the aqueous dispersion of hydrophobic polymer will further improve the physical properties of the film. For example, because ethylcellulose has a relatively high glass transition temperature and does not form flexible films under normal coating conditions, it is necessary to plasticize the ethylcellulose before using the same as a coating material. Generally, the amount of plasticizer included in a coating solution is based on the concentration of the film-former, e.g., most often from about 1 to about 50 percent by weight of the film-former. Concentration of the plasticizer, however, can only be properly determined after careful experimentation with the particular coating solution and method of application.

Examples of suitable plasticizers for ethylcellulose include water insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, and triacetin, although it is possible that other water-insoluble plasticizers (such as acetylated monoglycerides, phthalate esters, castor oil, etc.) may be used. Triethyl citrate is an especially preferred plasticizer for the aqueous dispersions of ethyl cellulose of the present invention.

Examples of suitable plasticizers for the acrylic polymers of the present invention include, but are not limited to citric acid esters such as triethyl citrate, tributyl citrate, dibutyl phthalate, and possibly 1,2-propylene glycol. Other plasticizers which have proved to be suitable for enhancing the elasticity of the films formed from acrylic films such as EUDRAGIT® L/S lacquer solutions include polyethylene glycols, propylene glycol, diethyl phthalate, castor oil, and triacetin. Triethyl citrate is an especially preferred plasticizer for the aqueous dispersions of ethyl cellulose of the present invention.

It has further been found that the addition of a small amount of talc reduces the tendency of the aqueous dispersion to stick during processing, and acts as a polishing agent.

In addition to modifying the dissolution profile by altering the relative amounts of different acrylic resin lacquers, the dissolution profile of the ultimate product may also be modified, for example, by increasing or decreasing the thickness of the retardant coating.

In an embodiment of the present invention, the at least one selective SSRI is selected from the group consisting of Fluoxetine HCl, Fluvoxamine maleate, Paroxetine HCl, Sertraline HCl, Venlafaxine HCl, Citalopram HBr, Escitalopram oxalate and combinations thereof.

In accordance with another aspect of the present invention, there is provided a modified release pharmaceutical composition comprising:

Ingredients
% w/w

(a)
SSRI
4.0-8.0

(b)
Hydroxypropylmethylcellulose 2208
10.0-40.0

(METHOCEL ® K4M Premium CR)

(c)
Lactose Anhydrous (DT)
40.0-60.0

(d)
Microcrystalline Cellulose (AVICEL ® PH 101)
6.0-10.0

(e)
Polyvinylpyrrolidone (KOLLIDON ® 29/32)
0.0-4.0

(f)
Polyvinylpyrrolidone (KOLLIDON ® K90F)
0.0-4.0

(g)
Magnesium Stearate
0.0-2.0

(h)
Stearic Acid
0.0-2.0

(i)
Carbomer 941 (CARBOPOL ® 971P)
0.0-2.0

(j)
Bile Salt
0.0-3.0

(k)
Sodium Lauryl Sulphate
0.0-3.0

(l)
Poloxamer 407 (LUTROL ® F127)
0.0-6.0

(m)
Poloxamer 188 (LUTROL ® F68)
0.0-6.0

(n)
PEG-40 hydrogenated castor oil
0.0-6.0

(CREMOPHOR ® RH40)

(o)
PEG-3350
0.0-6.0

(p)
PEG-600
0.0-6.0

(q)
PEG-8000
0.0-6.0

(r)
Saturated Polyglycolized Glycerides from
0.0-6.0

hydrogenated vegetable oils (GELUCIRE ® 44/14)

(s)
Saturated Polyglycolized Glycerides
0.0-6.0

(GELUCIRE ® 50/13)

(t)
Vitamin E TPGS
0.0-6.0

(u)
PEG-32 (LUTROL ® E1500)
0.0-6.0

(v)
Sucrose stearate (CRODESTA ® F160)
0.0-6.0

(w)
Mannitol
0.0-6.0

(x)
Propylene glycol monoester of medium chain fatty
0.0-6.0

acids (CAPMUL ® PG8)

(y)
L-Tartaric Acid
0.0-6.0