Modified release formulations of at least one form of tramadol

Abstract

The present invention provides for a modified release pharmaceutical composition comprising at least one form of tramadol selected from the group consisting of tramadol, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof, the composition exhibiting an in vitro dissolution profile (measured using the USP Basket Method at 75 rpm in 900 ml 0.1 N HCl at 37° C.) such that after 2 hours, from about 0% up to about 30% (by weight) of the at least one form of tramadol is released, after 4 hours, from about 5% to about 22% (by weight) of the at least one form of tramadol is released, after 6 hours, from about 15% to about 38% (by weight) of the at least one form of tramadol is released, after 8 hours, more than about 40% (by weight) of the at least one form of tramadol is released.

Description

FIELD OF INVENTION

[0002] The present invention relates to modified release formulations for oral administration, to processes for their preparation and to their medical use. In particular, the present invention relates to modified release formulations of at least one form of tramadol, selected from the group consisting of tramadol, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof.

BACKGROUND OF THE INVENTION

[0003] Tramadol, which was first described in U.S. Pat. No. 3,652,589, is a class of analgesic cycloalkanol-substituted phenol esters having a basic amine group in the cycloalkyl ring and having the chemical name trans-(±)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol. Tramadol is believed to produce an analgesic effect through a mechanism that is neither fully opioid-like nor non-opioid-like because clinical data suggests that tramadol lacks many of the typical side effects of opioid antagonists such as respiratory depression, constipation, tolerance and abuse liability but can produce hot flashes and sweating. Due to the combination of non-opioid and opioid activity, tramadol is a very unique analgesic and many attempts have been made to prepare oral formulations of the drug.

[0004] Conventional or immediate release preparations in the form of tablets, capsules, drops and suppositories containing tramadol, or more particularly its hydrochloride salt, have been commercially available for many years for use in the treatment of moderate to severe pain. The clinical efficacy of immediate release tramadol preparations has been well established in numerous single dose and multiple dose studies, with 70% to 90% of patients obtaining satisfactory pain relief depending on the etiology of the pain. Immediate release tramadol preparations have demonstrated efficacy in obstetrical, gynecologic, orthopedic, abdominal and oral surgery. Immediate release tramadol preparations have also been studied in long-term clinical trials in patients with chronic pain of varying etiology, including low-back pain, osteoarthritis, cancer pain, neuropathic pain and orthopedic pain.

[0005] Immediate release tramadol preparations, however, do not provide a controlled release of the tramadol. For example, an immediate release oral formulation of tramadol is commercially available in the United States, from McNeil Pharmaceuticals under the tradename ULTRAM® as tramadol hydrochloride tablets. The 53rd Edition of the Physician's Desk Reference, copyright 1999, p. 2255, states that peak plasma levels of tramadol for the ULTRAM® product occur at about 1.6 hours after a single oral dose (100 mg) and at about 2.3 hours after multiple oral dosing (100 mg q.i.d). The short elimination half-life of tramadol necessitates dosing of patients with immediate release tramadol preparations every 4-6 hours in order to maintain optimal levels of analgesia in chronic pain.

[0006] To overcome the difficulties associated with the required dosing frequency of immediate release tramadol preparations, various attempts have been made to formulate tramadol into modified release formulations. For example, see U.S. Pat. Nos. 5,395,626, 5,474,786, 5,645,858, 5,478,577, 5,591,452, 6,254,887, 5,601,842, 5,580,578, 5,639,476, 5,811,126, 5,849,240, 5,891,471, 5,965,163, 5,958,452, 5,965,161, 5,478,577, 5,580,578, 5,648,096, 5,672,360, 5,811,126, 5,879,705, 5,968,551, 5,980,941, 6,068,858, 6,077,532, 6,077,533 and 6,254,887. Such modified release tramadol preparations purport to control the rate of release of tramadol within the gastrointestinal tract, with the purported result that tramadol is delivered at a specific, predetermined rate.

SUMMARY OF THE INVENTION

[0007] It is an object of the present invention to prepare a modified release pharmaceutical composition comprising at least one form of tramadol.

[0008] It is a further object of the present invention to prepare a modified release pharmaceutical composition comprising at least one form of tramadol wherein the composition is suitable for oral administration to patients which provides effective relief from pain.

[0009] Further and other objects of the present invention will be realized by those skilled in the art from the following summary of the invention and detailed description of embodiments thereof.

[0010] 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 at least one form of tramadol selected from the group consisting of tramadol, 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 at least one form of tramadol while maintaining bioavailability substantially equivalent to that of the immediate release composition.

[0011] 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 at least one form of tramadol selected from the group consisting of tramadol, 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 (Cmax) of the at least one form of tramadol that is lower than that produced by an immediate release pharmaceutical composition of the at least one form of tramadol, and the area under the concentration-time curve (AUC) and the mean minimum plasma concentration (Cmin) are substantially equivalent to that of the immediate release pharmaceutical composition.

[0012] 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 at least one form of tramadol selected from the group consisting of tramadol, 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, produces a mean maximum plasma concentration (Cmax) of the at least one form of tramadol having both a maximum concentration (Cmax) and an area under a plasma concentration vs. time curve (AUC) within the range from about −20% to about +25% of that produced by an immediate release pharmaceutical composition of the at least one form of tramadol.

[0013] In an embodiment of the present invention, the at least one form of tramadol is tramadol hydrochloride and the immediate release pharmaceutical composition is the subject of the United States Food and Drug Administration Approved New Drug Application number N20281, N75963, N75980, N75974, N76003, N75968, N75983, N76100, N75986, N75960, N75982, N75977, N75981, or N75962.

[0014] 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 at least one form of tramadol selected from the group consisting of tramadol, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof, in combination with at least one pharmaceutically acceptable excipient, the composition exhibiting an in vitro dissolution profile (measured using the USP Basket Method at 75 rpm in 900 ml 0.1 N HCl at 37° C.) such that after 2 hours, from about 0% up to about 30% (by weight) of the at least one form of tramadol is released, after 4 hours, from about 5% to about 22% (by weight) of the at least one form of tramadol is released, after 6 hours, from about 15% to about 38% (by weight) of the at least one form of tramadol is released, after 8 hours, more than about 40% (by weight) of the at least one form of tramadol is released.

[0015] 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 at least one form of tramadol selected from the group consisting of tramadol, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof, in combination with at least one pharmaceutically acceptable excipient, the composition exhibiting an in vitro dissolution profile (measured using the USP Basket Method at 75 rpm in 900 ml 0.1 N HCl at 37° C.) such that after 2 hours, from about 2% to about 10% (by weight) of the at least one form of tramadol is released, after 4 hours, from about 12% to about 20% (by weight) of the at least one form of tramadol is released, after 6 hours, from about 30% to about 38% (by weight) of the at least one form of tramadol is released, after 8 hours, from about 48% to about 56% (by weight) of the at least one form of tramadol is released, after 10 hours, from about 64% to about 72% (by weight) of the at least one form of tramadol is released, and after 12 hours, more than about 76% (by weight) of the at least one form of tramadol is released.

[0016] 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:

[0017] (i) a core comprising at least one form of tramadol selected from the group consisting of tramadol, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof and at least one pharmaceutically acceptable excipient; and

[0018] (ii) a coating comprising at least one water-insoluble, water-permeable film-forming polymer, at least one plasticizer and at least one water-soluble polymer.

[0019] In accordance with another aspect of the present invention, there is provided a modified release pharmaceutical composition comprising:

[0020] (i) a core comprising at least one form of tramadol selected from the group consisting of tramadol, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof, and combinations thereof and at least one pharmaceutically acceptable excipient; and

[0021] (ii) a coating comprising at least one water-insoluble, water-permeable film-forming polymer, at least one plasticizer and at least one water-soluble polymer, wherein the proportion of the at least one water-insoluble, water-permeable film-forming polymer varies from about 20% to about 90% of the coating dry weight, the proportion of the at least one plasticizer varies from about 5% to about 30% of the coating dry weight, and the proportion of the at least one water-soluble polymer varies from about 10% to about 75% of the coating dry weight.

[0022] 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:

[0023] (i) a core comprising at least one form of tramadol selected from the group consisting of tramadol, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof and at least one pharmaceutically acceptable excipient; and

[0024] (ii) a coating comprising at least one water-insoluble, water-permeable film-forming polymer, at least one plasticizer and at least one water-soluble polymer, wherein the composition exhibits an in vitro dissolution profile (measured using the USP Basket Method at 75 rpm in 900 ml 0.1 N HCl at 37° C.) such that after 2 hours, from about 0% up to about 30% (by weight) of the at least one form of tramadol is released, after 4 hours, from about 5% to about 22% (by weight) of the at least one form of tramadol is released, after 6 hours, from about 15% to about 38% (by weight) of the at least one form of tramadol is released, and after 8 hours, more than about 40% (by weight) of the at least one form of tramadol is released.

[0025] 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:

[0026] (i) a core comprising at least one form of tramadol selected from the group consisting of tramadol, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof and at least one pharmaceutically acceptable excipient; and

[0027] (ii) a coating comprising at least one water-insoluble, water-permeable film-forming polymer, at least one plasticizer and at least one water-soluble polymer, wherein the composition exhibits an in vitro dissolution profile (measured using the USP Basket Method at 75 rpm in 900 ml 0.1 N HCl at 37° C.) such that after 2 hours, from about 2% to about 10% (by weight) of the at least one form of tramadol is released, after 4 hours, from about 12% to about 20% (by weight) of the at least one form of tramadol is released, after 6 hours, from about 30% to about 38% (by weight) of the at least one form of tramadol is released, after 8 hours, from about 48% to about 56% (by weight) of the at least one form of tramadol is released, after 10 hours, from about 64% to about 72% (by weight) of the at least one form of tramadol is released, and after 12 hours, more than about 76% of the at least one form of tramadol is released.

[0028] 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:

[0029] (i) a core comprising at least one form of tramadol selected from the group consisting of tramadol, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof, and combinations thereof and at least one pharmaceutically acceptable excipient; and

[0030] (ii) a coating comprising at least one water-insoluble, water-permeable film-forming polymer, at least one plasticizer and at least one water-soluble polymer, wherein the proportion of the at least one water-insoluble, water-permeable film-forming polymer varies from about 20% to about 90% of the coating dry weight, the proportion of the at least one plasticizer varies from about 5% to about 30% of the coating dry weight, and the proportion of the at least one water-soluble polymer varies from about 10% to about 75% of the coating dry weight, and wherein the composition exhibits an in vitro dissolution profile (measured using the USP Basket Method at 75 rpm in 900 ml 0.1 N HCl at 37° C.) such that after 2 hours, from about 0% up to about 30% (by weight) of the at least one form of tramadol is released, after 4 hours, from about 5% to about 22% (by weight) of the at least one form of tramadol is released, after 6 hours, from about 15% to about 38% (by weight) of the at least one form of tramadol is released, and after 8 hours, more than about 40% (by weight) of the at least one form of tramadol is released.

[0031] 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:

[0032] (i) a core comprising at least one form of tramadol selected from the group consisting of tramadol, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof, and combinations thereof and at least one pharmaceutically acceptable excipient; and

[0033] (ii) a coating comprising at least one water-insoluble, water-permeable film-forming polymer, at least one plasticizer and at least one water-soluble polymer, wherein the proportion of the at least one water-insoluble, water-permeable film-forming polymer varies from about 20% to about 90% of the coating dry weight, the proportion of the at least one plasticizer varies from about 5% to about 30% of the coating dry weight, and the proportion of the at least one water-soluble polymer varies from about 10% to about 75% of the coating dry weight, and wherein the composition exhibits an in vitro dissolution profile (measured using the USP Basket Method at 75 rpm in 900 ml 0.1 N HCl at 37° C.) such that after 2 hours, from about 2% to about 10% (by weight) of the at least one form of tramadol is released, after 4 hours, from about 12% to about 20% (by weight) of the at least one form of tramadol is released, after 6 hours, from about 30% to about 38% (by weight) of the at least one form of tramadol is released, after 8 hours, from about 48% to about 56% (by weight) of the at least one form of tramadol is released, after 10 hours, from about 64% to about 72% (by weight) of the at least one form of tramadol is released, and after 12 hours, more than about 76% (by weight) of the at least one form of tramadol is released.

[0034] 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 at least one form of tramadol selected from the group consisting of tramadol, 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 (Cmax) of the at least one form of tramadol from about 80 ng/ml to about 500 ng/ml.

[0035] 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 at least one form of tramadol selected from the group consisting of tramadol, 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 time to mean peak plasma concentration (Tmax) of the at least one form of tramadol ranging from about 4 hours to about 14 hours.

[0036] 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 at least one form of tramadol selected from the group consisting of tramadol, 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 administered to a patient, provides a plasma concentration time curve with an area under the curve (AUC) ranging from about 1000 ng.hr/ml to about 10000 ng.hr/ml.

[0037] In an embodiment of the present invention, the at least one form of tramadol is present in the pharmaceutical composition in an amount effective for the management of moderate to moderately severe pain.

[0038] In an embodiment of the present invention, the pharmaceutical composition comprises from about 25 mg to about 800 mg or more of the at least one form of tramadol.

[0039] In an embodiment of the present invention, the pharmaceutical composition comprises from about 50 mg to about 400 mg or more of the at least one form of tramadol.

[0040] In an embodiment of the present invention, the pharmaceutical composition comprises from about 100 mg to about 300 mg or more of the at least one form of tramadol.

[0041] In an embodiment of the present invention, the at least one form of tramadol is tramadol hydrochloride.

[0042] In an embodiment of the present invention, the core is in a form selected from the group consisting of a granule, a spheroid, a microsphere, a bead, a seed, a pellet, a microtablet, a tablet, a capsule, and combinations thereof.

[0043] In an embodiment of the present invention, the core is in the form of a tablet.

[0044] In an embodiment of the present invention, the modified release pharmaceutical composition is suitable for once daily dosing.

[0045] In an embodiment of the present invention, the at least one pharmaceutically acceptable excipient is selected from the group consisting of at least one release rate controlling pharmaceutically acceptable carrier, at least one diluent, at least one lubricant, at least one binder, at least one filler and combinations thereof.

[0046] In an embodiment of the present invention, the at least one pharmaceutically acceptable excipient is at least one diluent.

[0047] In an embodiment of the present invention, the at least one diluent is selected from the group consisting of lactose, microcrystalline cellulose, mannitol and combinations thereof.

[0048] In an embodiment of the present invention, the at least one pharmaceutically acceptable excipient is at least one lubricant.

[0049] In an embodiment of the present invention, the at least one lubricant is selected from the group consisting of stearic acid, magnesium stearate, glyceryl behenate, talc, sodium stearyl fumarate and combinations thereof.

[0050] In an embodiment of the present invention, the at least one lubricant is sodium stearyl fumarate.

[0051] In an embodiment of the present invention, the at least one pharmaceutically acceptable excipient is at least one binder.

[0052] In an embodiment of the present invention, the at least one binder is selected from the group consisting of modified starch, gelatin, polyvinylpyrrolidone, polyvinyl alcohol and combinations thereof.

[0053] In an embodiment of the present invention, the at least one binder is polyvinyl alcohol.

[0054] In an embodiment of the present invention, the at least one pharmaceutically acceptable excipient is at least one filler.

[0055] In an embodiment of the present invention, the at least one filler is selected from the group consisting of lactose, microcrystalline cellulose and combinations thereof.

[0056] In an embodiment of the present invention, the at least one filler is microcrystalline cellulose.

[0057] There are at least three types of modified release pharmaceutical compositions in the pharmaceutical art; namely those that are delayed release, those that are extended release, and those that are both delayed and extended release. Delayed release pharmaceutical compositions are often designed to prevent drug release in the upper part of the gastrointestinal tract. Modified release coatings used to prepare this type of pharmaceutical composition are commonly called enteric coatings in the pharmaceutical art. Extended release pharmaceutical compositions are designed to extend drug release over a period of time, a result which is often achieved by the application of a sustained or controlled release coating.

[0058] In an embodiment of the present invention, the modified release pharmaceutical composition is an extended release pharmaceutical composition.

[0059] In an embodiment of the present invention, the at least one pharmaceutically acceptable excipient is at lease one release rate controlling pharmaceutically acceptable carrier.

[0060] In an embodiment of the present invention, the at least one release rate controlling pharmaceutically acceptable carrier may be incorporated into a matrix along with the at least one form of tramadol and/or may be applied as a release rate controlling coating.

[0061] In an embodiment of the present invention, the matrix is a normal release matrix having a coating which provides for modified release of the at least one form of tramadol.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] In an embodiment of the present invention, the modified release coating is semi-permeable.

[0067] In an embodiment of the present invention, the modified release coating comprises at least one water-insoluble, water-permeable film-forming polymer.

[0068] In an embodiment of the present invention, the at least one water-insoluble, water-permeable film-forming polymer is ethylcellulose.

[0069] In an embodiment of the present invention, the modified release coating further comprises at least one water-soluble polymer.

[0070] In an embodiment of the present invention, the at least one water-soluble polymer is polyvinylpyrrolidone.

[0071] In an embodiment of the present invention, the modified release coating further comprises at least one plasticizer.

[0072] In an embodiment of the present invention, the at least one plasticizer is dibutyl sebacate.

[0073] In an embodiment of the present invention, the at least one water-insoluble, water-permeable film-forming polymer is ethylcellulose, the at least one water-soluble polymer is polyvinylpyrrolidone and the at least one plasticizer is dibutyl sebacate.

[0074] In an embodiment of the present invention, the modified release pharmaceutical composition is in the form of a tablet.

[0075] In accordance with another aspect of the present invention, there is provided a modified release pharmaceutical composition comprising:

[0076] (i) a core comprising at least one form of tramadol selected from the group consisting of tramadol, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof, polyvinyl alcohol, silicon dioxide and sodium stearyl fumarate; and

[0077] (ii) a coating comprising ethylcellulose, polyvinylpyrrolidone and dibutyl sebacate, wherein the proportion of ethylcellulose varies between about 20% and about 90% of the coating dry weight, the proportion of dibutyl sebacate varies between about 5% and about 30% of the coating dry weight, and the proportion of polyvinylpyrrolidone varies between about 10% and about 75% of the coating dry weight, and wherein the composition exhibits an in vitro dissolution profile (measured using the USP Basket Method at 75 rpm in 900 ml 0.1 N HCl at 37° C.) such that after 2 hours, from about 0% up to about 30% of the at least one form of tramadol is released, after 4 hours, from about 5% to about 22% of the at least one form of tramadol is released, after 6 hours, from about 15% to about 38% of the at least one form of tramadol is released, after 8 hours, more than about 40% of the at least one form of tramadol is released.

[0078] In accordance with another aspect of the present invention, there is provided a modified release pharmaceutical composition comprising:

[0079] (i) a core comprising at least one form of tramadol selected from the group consisting of tramadol, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof, polyvinyl alcohol, silicon dioxide and sodium stearyl fumarate; and

[0080] (ii) a coating comprising ethylcellulose, polyvinylpyrrolidone and dibutyl sebacate, wherein the proportion of ethylcellulose varies between about 20% and about 90% of the coating dry weight, the proportion of dibutyl sebacate varies between about 5% and about 30% of the coating dry weight, and the proportion of polyvinylpyrrolidone varies between about 10% and about 75% of the coating dry weight, and wherein the composition exhibits an in vitro dissolution profile (measured using the USP Basket Method at 75 rpm in 900 ml 0.1 N HCl at 37° C.) such that after 2 hours, from about 2% to about 10% of the at least one form of tramadol is released, after 4 hours, from about 12% to about 20% of the at least one form of tramadol is released, after 6 hours, from about 30% to about 38% of the at least one form of tramadol is released, after 8 hours, from about 48% to about 56% of the at least one form of tramadol is released, after 10 hours, from about 64% to about 72% of the at least one form of tramadol is released, and after 12 hours, more than about 76% of the at least one form of tramadol is released.

[0081] In an embodiment of the present invention, the pharmaceutical composition is further coated with an immediate release coating comprising at least one form of tramadol.

BRIEF DESCRIPTION OF THE DRAWINGS

[0082] The present invention will be further understood from the following description with references to the drawings in which:

[0083] FIG. 1 compares the in vitro dissolution profiles of 100 mg Tramadol HCl ER Tablets formulated according to Lot Nos. 2159, 2162 and 2165.

[0084] FIG. 2 illustrates the mean plasma Tramadol concentrations (ng/ml) over time following once a day Tramadol HCl ER Tablet (100 mg×2) formulated according to Lot Nos. 2159, 2162 and 2165 vs Ultram® (50 mg×2) q.i.d.

[0085] FIG. 3 illustrates the mean plasma Desmethyltramadol concentrations (ng/ml) following once a day Tramadol HCl ER Tablet (100 mg×2) formulated according to Lot Nos. 2159, 2162 and 2165 vs Ultram® (50 mg×2) q.i.d.

[0086] FIG. 4 illustrates the mean plasma Tramadol concentrations on Day 1 following once a day Tramadol HCl ER Tablets (100 mg×2) formulated according to Lot#2162 for 5 Days vs. Ultram® (50 mg×2) q.i.d.

[0087] FIG. 5 illustrates the mean plasma Tramadol concentrations on Day 5 following once a day Tramadol HCl ER Tablets (100 mg×2) formulated according to Lot#2162 for 5 Days vs. Ultram® (50 mg×2) q.i.d.

[0088] FIG. 6 illustrates the mean plasma Desmethyltramadol concentrations on Day 1 following once a day Tramadol HCl ER Tablets (100 mg×2) formulated according to Lot#2162 for 5 Days vs. Ultram® (50 mg×2) q.i.d.

[0089] FIG. 7 illustrates the mean plasma Desmethyltramadol concentrations on Day 5 following once a day Tramadol HCl ER Tablets (100 mg×2) formulated according to Lot#2162 for 5 Days vs. Ultram® (50 mg×2) q.i.d.

[0090] FIG. 8 illustrates the mean plasma Tramadol concentrations on Day 1 following once a day Tramadol HCl ER Tablets (100 mg×3) formulated according to Lot Nos. 2162 and 2165 for 5 Days vs. Ultram® (50 mg×2) t.i.d.

[0091] FIG. 9 illustrates the mean plasma Tramadol concentrations on Day 5 following once a day Tramadol HCl ER Tablets (100 mg×3) formulated according to Lot Nos. 2162 and 2165 for 5 Days vs. Ultram® (50 mg×2) t.i.d.

[0092] FIG. 10 illustrates the mean plasma Desmethyltramadol concentrations on Day I following once a day Tramadol HCl ER Tablets (100 mg×3) formulated according to Lot Nos. 2162 and 2165 for 5 Days vs. Ultram® (50 mg×2) t.i.d.

[0093] FIG. 11 illustrates the mean plasma Desmethyltramadol concentrations on Day 1 following once a day Tramadol HCl ER Tablets (100 mg×3) formulated according to Lot Nos. 2162 and 2165 for 5 Days vs. Ultram® (50 mg×2) t.i.d.

[0094] FIG. 12 illustrates the in vitro dissolution profiles of Tramadol HCl 100 mg ER Tablets formulated according to Lot Nos. 1-4.

[0095] FIG. 13 illustrates the in vitro dissolution profile of a 200 mg Tramadol HCl ER Tablet formulated according to Example 4.

[0096] FIG. 14 illustrates the in vitro dissolution profiles of 200 mg Tramadol HCl ER Tablets formulated according to Lot Nos. 5 to 7.

[0097] FIG. 15 illustrates the comparison of the mean tramadol plasma concentration-time profiles resulting from the oral administration of Tramadol HCl 100 mg ER tablets (2×100 mg once a day) and Tramadol HCl 200 mg ER tablets (1×200 mg once a day) formulated according to an embodiment of the present invention.

[0098] FIG. 16 illustrates the comparison of the mean M1 plasma concentration-time profiles resulting from the oral administration of Tramadol HCl 100 mg ER tablets (2×100 mg once a day) and Tramadol HCl 200 mg ER tablets (1×200 mg once a day) formulated according to an embodiment of the present invention.

[0099] FIG. 17 illustrates the mean plasma Tramadol concentrations (ng/ml) over time after two 100 mg Tramadol HCl ER Tablets formulated according to an embodiment of the present invention or after one 200 mg Tramadol HCl ER Tablet formulated according to an embodiment of the present invention following a 10 hour overnight fast.

[0100] FIG. 18 illustrates the mean plasma M1 concentrations (ng/ml) over time after two 100 mg Tramadol HCl ER Tablets formulated according to an embodiment of the present invention or after one 200 mg Tramadol HCl ER Tablet formulated according to an embodiment of the present invention following a 10 hour overnight fast.

[0101] FIG. 19 illustrates the mean plasma M5 concentrations (ng/ml) over time after two 100 mg Tramadol HCl ER Tablets formulated according to an embodiment of the present invention or after one 200 mg Tramadol HCl ER Tablet formulated according to an embodiment of the present invention following a 10 hour overnight fast.

[0102] FIG. 20 illustrates the mean plasma Tramadol concentrations (ng/ml) over time after a single dose of one 200 mg Tramadol HCl ER Tablet formulated according to an embodiment of the present invention under fasting or fed conditions.

[0103] FIG. 21 illustrates the mean plasma M1 concentrations (ng/ml) over time after a single dose of one 200 mg Tramadol HCl ER Tablet formulated according to an embodiment of the present invention under fasting or fed conditions.

[0104] FIG. 22 illustrates the mean plasma M5 concentrations (ng/ml) over time after a single dose of one 200 mg Tramadol HCl ER Tablet formulated according to an embodiment of the present invention under fasting or fed conditions.

[0105] FIG. 23 compares the LS mean change from baseline to average of weeks 1-12 in arthritis pain intensity VAS scores (primary variables) for Tramadol HCl ER Tablets and placebo.

[0106] FIG. 24 compares the LS mean change from baseline to different study time points in arthritis pain intensity VAS scores (primary variables) for Tramadol HCl ER Tablets and placebo.

[0107] FIG. 25 compares the LS mean changes from baseline to Week 12 for the Tramadol HCl ER Tablets and placebo for each of the secondary variables.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0108] The present invention consists of a controlled release pharmaceutical composition, in one embodiment a tablet, comprising at least one form of tramadol, wherein the pharmaceutical composition comprises a core and a coating.

[0109] The core comprises at least one form of tramadol selected from the group consisting of tramadol, enantiomers thereof, pharmaceutically acceptable salts thereof, and combinations thereof, in one embodiment tramadol hydrochloride; and at least one pharmaceutically acceptable excipient, in one embodiment a lubricant, a binder and/or a filler, and optionally a glidant as well as other pharmaceutically acceptable excipients.

[0110] The at least one form of tramadol used in the present invention may be any form of tramadol conventional in the pharmaceutical art. The at least one form of tramadol used in the present invention may be tramadol. The at least one form of tramadol used in the present invention may be the individually optically active enantiomers of tramadol, such as for example, (+)-tramadol and (−)-tramadol. The at least one form of tramadol used in the present may be pharmaceutically acceptable salts of tramadol. Suitable pharmaceutically acceptable salts of tramadol for use as the at least one form of tramadol according to the present invention are those conventionally known in the art such as, for example, pharmaceutically acceptable acid addition salts. Suitable pharmaceutically acceptable acid addition salts of tramadol for use as the at least one form of tramadol according to the present invention may be the hydrochloride salt, the hydrobromide salt, the hydroiodide salt, the saccharinate salt etc. In one embodiment, the at least one form of tramadol is tramadol hydrochloride.

[0111] The at least one lubricant used in the present invention may be any lubricant conventional in the pharmaceutical art. The at least one lubricant used in the present invention may be stearic acid, magnesium stearate, glyceryl behenate, talc, mineral oil (in PEG), sodium stearyl fumarate, etc. In one embodiment, the at least one lubricant is sodium stearyl fumarate.

[0112] The at least one binder used in the present invention may be any binder conventional in the pharmaceutical art. The at least one binder used in the present invention may be a water-soluble polymer, such as modified starch, gelatin, polyvinylpyrrolidone, polyvinyl alcohol, etc. In one embodiment, the at least one binder is polyvinyl alcohol.

[0113] The at least one filler used in the present invention may be any filler conventional in the pharmaceutical art. The at least one filler used in the present invention may be lactose, microcrystalline cellulose, etc. In one embodiment, the at least one filler is microcrystalline cellulose.

[0114] The at least one glidant used in the present invention may be any glidant conventional in the pharmaceutical art. In one embodiment, the at least one glidant is colloidal silicon dioxide. The colloidal silicon dioxide may suitably be, for example, AEROSIL® as supplied by Degussa. Similar colloidal silicon dioxides are also available from other suppliers. Preferably, the colloidal silicon dioxide used is AEROSIL® 200.

[0115] The above binders, lubricants, fillers, glidants, and any other pharmaceutically acceptable excipient that may be present can further be found in the relevant literature, for example in the Handbook of Pharmaceutical Additives: An International Guide to More Than 6000 Products by Trade Name, Chemical, Function, and Manufacturer, Michael and Irene Ash (Eds.); Gower Publishing Ltd.; Aldershot, Hampshire, England, 1995.

[0116] The relative amounts of ingredients in the core are preferably as follows. The proportion of the at least one form of tramadol in the core may vary between about 70% and about 98% of the core dry weight. The proportion of the at least one lubricant in the core may vary between about 0.5% and about 10% of the core dry weight. The proportion of the at least one binder or at least one filler in the core may vary between about 1% and about 25% of the core dry weight.

[0117] The manufacturing process of the core can be as follows. The at least one form of tramadol is first granulated with the at least one binder, in one embodiment a granulator, but not necessarily a fluidized bed granulator. The at least one binder is first dissolved or dispersed in a suitable solvent, in one embodiment water. The solution or suspension of the at least one binder is then sprayed onto the at least one form of tramadol in a granulator, in one embodiment a fluidized bed granulator. For example, fluidized bed granulators manufactured by Glatt (Germany) or Aeromatic (Switzerland) can be used for this operation. An alternative process can be to use a conventional or high shear mixer to proceed granulation. If necessary, the at least one form of tramadol can be mixed with a filler, prior to the granulation step. Granules once dried can be mixed with the other pharmaceutically acceptable excipients, especially with the at least one lubricant, but also with at least one glidant and any other pharmaceutically acceptable excipient suitable to improve processing. The mixture of granules (in one embodiment with the at least one lubricant), and optionally at least one glidant is pressed into tablets. Alternatively, the at least one form of tramadol and the at least one lubricant can be mixed in a granulator, in one embodiment a fluidized bed granulator, and heated to the melting point of the at least one lubricant to form granules. This mixture can then be mixed with at least one suitable filler and compressed into tablets. Also, it is possible to mix the at least one form of tramadol and the at least one lubricant (in one embodiment polyvinyl alcohol) in a granulator, in one embodiment a fluidized bed granulator, and then to press the resulting granules into tablets. Tablets can be obtained by standard techniques, in one embodiment on a (rotary) press (for example Manesty Betapress®) fitted with suitable punches. The resulting tablets are hereinafter referred as tablet cores.

[0118] These tablet cores are then coated with the semi-permeable coating designed to achieve a controlled release of the at least one form of tramadol.

[0119] The coating comprises at least one water-insoluble, water-permeable film-forming polymer, together with at least one plasticizer and at least one water-soluble polymer.

[0120] The at least one water-insoluble, water-permeable film-forming polymer used in the present invention, may be any water-insoluble, water-permeable film-forming polymer conventional in the pharmaceutical art. The at least one water-insoluble, water-permeable film-forming polymer used in the present invention may be a cellulose ether, such as ethylcellulose, a cellulose ester, such as cellulose acetate, polyvinyl alcohol, etc. In one embodiment, the at least one water-insoluble, water-permeable film-forming polymer is ethylcellulose. The ethylcellulose may suitably be, for example, ETHOCEL® as supplied by Dow Chemical Company. Similar ethylcelluloses are also available from other suppliers. Preferably, the ethylcellulose used is ETHOCEL® PR, more preferably ETHOCEL® PR100.

[0121] The at least one plasticizer used in the present invention, may be any plasticizer conventional in the pharmaceutical art. The at least one plasticizer used in the present invention may be an ester such as a citrate ester, an oil such as castor oil, a polyalkylene glycol of various molecular weights, such as polyethylene glycol. In one embodiment, the at least one plasticizer is dibutyl sebacate.

[0122] The at least one water-soluble polymer used in the present invention, may be any water-soluble polymer conventional in the pharmaceutical art. In one embodiment, the at least one water-soluble is polyvinylpyrrolidone. The polyvinylpyrrolidone may suitably be, for example, KOLLIDON® as supplied by BASF AG. Similar polyvinylpyrrolidones are also available from other suppliers. Preferably, the polyvinylpyrrolidone used is KOLLIDON® 90F.

[0123] Other pharmaceutically acceptable excipients can be used in the coating, such as for example, acrylic acid derivatives (available from Röhm Pharma under the trade name EUDRAGIT®), pigments, etc.

[0124] The relative amounts of ingredients in the coating are preferably as follows. The proportion of the at least one water-insoluble, water-permeable polymer (in one embodiment ethylcellulose) in the coating may vary between about 20% and about 90% of the coating dry weight. The proportion of the at least one water-soluble polymer (in one embodiment polyvinylpyrrolidone) in the coating may vary between about 10% and about 75% of the coating dry weight. The proportion of the at least one plasticizer (in one embodiment dibutyl sebacate) in the coating may vary between about 5% and about 30% of the coating dry weight. The relative proportions of ingredients, notably the ratio of the at least one water-insoluble, water-permeable film-forming polymer to the at least one water-soluble polymer, can be varied depending on the desired release profile (where a more delayed release is desired, it is generally obtained with a higher amount of the at least one water-insoluble, water-permeable film-forming polymer).

[0125] The coating process can be as follows. Ethylcellulose, dibutyl sebacate and polyvinylpyrrolidone are dissolved in a solvent such as denatured alcohol using a propeller stirrer until complete dissolution is achieved. The resulting solution is sprayed onto the tablet cores, using a perforated coating pan.

[0126] The weight ratio coating/tablet core is comprised e.g. between about 1/30 and about 3/10, preferably about 1/10.

[0127] The tablet comprises an amount of the at least one form of tramadol of from about 25 mg to about 800 mg or more per tablet.

[0128] The present invention thus provides a controlled release pharmaceutical composition comprising at least one form of tramadol selected from the group consisting of tramadol, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof, the composition exhibiting a dissolution profile such that after 2 hours, from about 0% up to about 30% (by weight) of the at least one form of tramadol is released, after 4 hours, from about 5% to about 22% (by weight) of the at least one form of tramadol is released, after 6 hours, from about 15% to about 38% (by weight) of the at least one form of tramadol is released, after 8 hours, more than about 40% (by weight) of the at least one form of tramadol is released.

[0129] In an embodiment of the present invention, the controlled release pharmaceutical composition is an extended release tablet, the tablet comprising:

[0130] (i) a core comprising tramadol hydrochloride, polyvinyl alcohol, colloidal silicon dioxide and sodium stearyl fumarate; and

[0131] (ii) a coating comprising ethylcellulose, polyvinylpyrrolidone and dibutyl sebacate.

[0132] Further details of the preferred embodiments of the present invention are illustrated in the following examples which are understood to be non-limiting.

EXAMPLE 1

100 mg Tramadol HCl ER Tablets

[0133] The following 100 mg Tramadol HCl ER Tablet formulations were prepared:

TABLE 1a
Tablet Core Formulation
	Ingredients	Quantity (mg)	%
	Tramadol HCl	100.00	96.15
	Polyvinyl Alcohol	2.00	1.92
	Colloidal Silicon Dioxide	1.00	0.96
	(AEROSIL ® 200)
	Sodium Stearyl Fumarate	1.00	0.96
	Purified Water	41.60 *
	Core Total Weight	104.00	99.99
	* evaporated during process

[0134] Tablet Core Preparation

[0135] Tramadol HCl and colloidal silicon dioxide were mixed and passed through a 1.0 mm screen. Polyvinyl alcohol was dissolved in purified water. The mixed tramadol HCl and colloidal silicon dioxide powder was granulated with the aqueous solution of polyvinyl alcohol in a fluidized bed granulator, Glatt GPCG1 and then dried. After granulation, the granules were blended with sodium stearyl fumarate and then passed through a 1.0 mm screen. The blend was then compressed into tablet cores using a Manesty Betapress.

TABLE 1b
Coating Formulation
	mg/tablet
	Lot#2159	Lot#2162	Lot#2165
	Quantity	Quantity	Quantity
Ingredients	(mg)	(mg)	(mg)
Ethylcellulose	9.20	9.81	9.54
(ETHOCEL ® PR 100)
Polyvinylpyrrolidone	4.14	3.53	3.80
(KOLLIDON ® 90 F)
Dibutyl Sebacate	2.66	2.66	2.66
Denatured Alcohol	170.00 *	170.00 *	170.00 *
* evaporated during process

[0136] Coating Preparation

[0137] The ethyl alcohol and isopropanol were weighed and mixed. Dibutyl sebacate and ethylcellulose were added to and dissolved in the ethyl alcohol and isopropyl alcohol while stirring using a propeller stirrer, Coframo RZR1. The ethylcellulose and dibutyl sebacate were allowed to dissolve completely. The polyvinylpyrrolidone was added. The solution was stirred until all components were dissolved. The solution was passed through a high pressure homogenizer, Mini DeBee 2000 with #7 nozzle, Bee International. The tablet cores were coated using the coating solution in a perforated coating pan, O'Hara Labcoat III 36″ Pan, Vector LCDS.

[0138] Coating Parameters

	Inlet Temperature:	48.5-49.5°	C.
	Outlet Temperature:	38.5-39.5°	C.
	Bed Temperature:	37.5-38.5°	C.
	Spray Rate:	300	g/min
	Atomizing Air/Patterm:	25/25	psi
	Distance gun/Bed:	6″
	Distance between guns:	6″
	Pan speed:	12.0	rpm

[0139] Coating Amount

	Diameter:	6	mm
	Thickness:	4.65	mm
	Cup Height:	1.02	mm
	Surface:	112	mm2
	Percentage:	100%
	Amount:	16	mg

[0140] Dissolution Method

[0141] In vitro dissolution studies were conducted on 100 mg Tramadol HCl ER Tablets formulated according to Lot#2159, Lot#2162 and Lot#2165. The following dissolution conditions were used for all of the in vitro dissolution studies conducted herein for determining the in vitro dissolution profiles of Tramadol HCl ER Tablets:

	Apparatus:	USP Basket (10 mesh)
	Dissolution medium:	0.1	N HCl
	Volume (vessels):	900	ml
	Bath temperature:	37°	C.
		(±0.5°	C.)
	Wavelength:	271	nm
	Flow cell thickness:	1	cm
	Rotation speed:	75	rpm
	Total run time:	900	min
	Sampling interval:	30	min

[0142]

TABLE 2
Dissolution Profile
	% Dissolved
	Time (min.)	Lot#2159	Lot#2162	Lot#2165
	0	0	0	0
	30	1.1	0.1	0.3
	60	5.7	0.3	2.0
	90	12.8	1.4	5.1
	120	21.3	2.9	9.1
	180	41.6	7.0	19.8
	240	62.4	12.8	33.4
	300	77.8	20.2	48.7
	360	87.3	29.4	62.7
	420	92.6	40.3	73.5
	480	95.9	50.8	81.7
	540	97.5	59.9	87.2
	600	98.7	67.6	91.1
	660	99.2	73.7	94.1
	720	99.6	78.2	96.0
	780	99.9	81.9	97.2
	840		84.9	97.8
	900		86.9	98.5
	960		88.5	99.0

[0143] FIG. 1 compares the in vitro dissolution profiles of 100 mg Tramadol HCl ER Tablets formulated according to Lot Nos. 2159, 2162 and 2165.

[0144] Study No. 401 (B99-401 PK-TRAP03)

[0145] A pilot four-way, single-dose, open-label, fasting, comparative bioavailability study of three formulations of Tramadol Hydrochloride Extended-Release Tablets (2×100 mg) Versus Ultram® Tablets (50 mg q.i.d) in normal, healthy, Non-smoking male volunteers was conducted.

[0146] This pilot study evaluated the bioavailability of three novel Tramadol HCl Extended-Release Tablets (2×100 mg) against Ultram® (Ortho-McNeil Pharmaceuticals) Tablets (50 mg q.i.d.) under fasting conditions.

[0147] This pilot study was a randomized, balanced, four-period, four-treatment, four-sequence crossover study design in sixteen (16) normal, healthy, non-smoking male volunteers and two (2) alternates.

[0148] Eighteen (18) subjects were entered into the study. Fourteen (14) subjects completed the study; there were fourteen (14) evaluable subjects. All subjects were non-smoking, between 18 and 45 years of age (inclusive), and with body weights no more than ±15% of the ideal weight for the subject's height and frame as determined by the Table of Desirable Weights for Men and Women.

[0149] The study periods were separated by a one-week washout period. Blood sampling for drug content analysis was carried out at 0.0 (pre-drug), 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0, 16.0, 20.0, 24.0, 30.0, 36.0, and 48.0 hours post-drug when each test drug was administered. Blood sampling for drug content analysis was carried out at 0.0 (pre-drug), 1.0, 2.0, 3.0, 4.0, 5.0 (pre-drug), 6.0, 7.0, 8.0, 9.0, 10.0, 11.0 (pre-drug), 12.0, 13.0, 14.0, 15.0 (pre-drug), 16.0, 17.0, 18.0, 20.0, 24.0, 30.0, 36.0, and 48.0 hours post-drug when the reference drug was administered.

Treatments:	A:	Tramadol HCl ER 200 mg Tablets
		Lot Number: 2159
	B:	Tramadol HCl ER 200 mg Tablets
		Lot Number: 2162
	C:	Tramadol HCl ER 200 mg Tablets
		Lot Number: 2165
	D:	Ultram ® 50 mg Tablets
		Control Number: CDA 2225; Expiry Date: 4/01
		(Ortho-McNeil Pharmaceuticals, U.S.A.)

[0150] The three 100 mg extended release tramadol formulations tested (2×100 once a day) demonstrated prolonged tramadol and mono-O-desmethyltramadol plasma concentration-time profiles relative to the Ultram® tablet (1×50mg) when administered 4 times a day (2nd, 3rd and 4th doses at 5, 11 and 15 hours post-1st dose, respectively) (See FIGS. 2 and 3). In addition, the ER formulations yielded equivalent AUCs relative to an equivalent dose of the Ultram® immediate release tablet. The 90% geometric mean confidence intervals for AUCt and AUC∞ were within the 80%-125% range for all three test formulations. Formulations 2162 and 2165 also yielded equivalent Cmax values versus Ultram® as evidenced by 90% geometric confidence intervals within the 80-125% range. The mean pharmacokinetic parameters and 90% confidence interval for ratio of the geometric mean AUC and Cmax are presented in Tables 3a and 3b for tramadol and in Tables 4a and 4b for O-desmethyltramadol. Table 3a also shows that overall there was no apparent difference in the ratio of metabolite (AUC∞ of M1/tramadol) among the ER tramadol formulations and the immediate release tablet. The half-life following Ultram® treatment was slightly shorter compared to the extended release formulations.

TABLE 3a
Pharmacokinetic Parameters Study 401PK (n = 14)
Study 401PK Mean Pharmacokinetic Parameters for Plasma Tramadol (n = 14)
	Lot# 2159	Lot# 2162	Lot# 2165	Ultram 50 mg
	1 × 200 mg	1 × 200 mg	1 × 200 mg	q.i.d
Parameter	Mean (CV %)	Mean (CV %)	Mean (CV %)	Mean (CV %)
AUCt (hr*ng/mL)	4796.83 (42.92)	4663.89 (34.42)	4827.94 (44.08)	4915.71 (43.81)
AUC∞ (hr*ng/mL)	4936.23 (45.71)	4897.97 (38.96)	5028.36 (46.36)	5118.72 (47.88)
Cmax(ng/mL)	351.60 (28.89)	246.46 (32.13)	298.30 (38.34)	284.70 (36.17)
Tmax (hr)	5.86 (21.02)	9.86 (21.74)	8.43 (19.03)	14.07 (37.03)
Half-life (hr)	6.90 (32.10)	7.94 (32.96)	7.49 (37.02)	6.73 (37.46)
M1/Tramadol	0.29 (50.96)	0.30 (45.62)	0.29 (49.35)	0.29 (52.92)
MRT (hr)	13.70 (24.08)	19.48 (18.19)	16.57 (22.61)	17.79 (19.03)
Lag Time (hr)	0.00 (0.00)	1.00 (0.00)	0.64 (77.35)	0.00 (0.00)

[0151] FIG. 2 illustrates the mean plasma Tramadol concentrations (ng/ml) over time following once a day Tramadol HCl ER ablet (100 mg×2) formulated according to Lot Nos. 2159, 2162 and 2165 vs Ultram® (50 mg×2) q.i.d.

TABLE 3b
Ratio of Means & 90% Confidence Interval for Plasma Tramadol
	AUC(0-t)	AUC(0-□)	Cmax
		Ratio of			Ratio of			Ratio of
	90% CI	Means	CV(%)	90% CI	Means	CV(%)	90% CI	Means	CV(%)
Formulation A	90.1-105.1	97.3	11.5	89.2-104.4	96.5	11.7	114.2-140.0	126.5	15.2
(Lot # 2159)
Formulation B	93.1-109.6	101	11.5	93.7-110.7	101.9	11.7	80.5-101.1	90.7	15.2
(Lot # 2162)
Formulation C	94.0-109.6	101.5	11.5	94.0-110.1	101.7	11.7	99.0-121.4	109.6	15.2
(Lot # 2165)

[0152]

TABLE 4a
Pharmacokinetic Parameters Study 401 (401PK) (n = 14)
Study 401PK: Mean Pharmacokinetic Parameters for Plasma O-desmethyltramadol (n = 12)
	Lot# 2159	Lot# 2162	Lot# 2165	Ultram 50 mg
	1 × 200 mg	1 × 200 mg	1 × 200 mg	q.i.d
Parameter	Mean (CV %)	Mean (CV %)	Mean (CV %)	Mean (CV %)
AUCt (hr*ng/mL)	1193.78 (44.84)	1230.54 (40.02)	1169.03 (39.15)	1166.74 (33.21)
AUC∞ (hr*ng/mL)	1226.20 (44.26)	1295.76 (41.06)	1218.22 (39.68)	1201.62 (32.42)
Cmax(ng/mL)	68.91 (39.65)	56.49 (36.64)	61.75 (39.92)	60.72 (35.05)
Tmax (hr)	7.29 (23.11)	13.29 (21.78)	10.14 (29.41)	16.71 (4.35)
Half-life (hr)	7.56 (30.98)	8.80 (36.96)	8.16 (28.65)	7.50 (32.79)

[0153] FIG. 3 illustrates the mean plasma Desmethyltramadol concentrations (ng/ml) following once a day Tramadol HCl ER Tablet (100 mg×2) formulated according to Lot Nos. 2159, 2162 and 2165 vs Ultram® (50 mg×2) q.i.d.

TABLE 4b
Ratio of Means & 90% Confidence Interval for Plasma O-desmethyltramadol
	AUC(0-t)	AUC(0-□)	Cmax
	90% CI	Ratio of Means	90% CI	Ratio of Means	90% CI	Ratio of Means
Formulation A	87.8-109.7	98.1	87.6-108.9	97.7	98.3-124.6	110.7
(Lot # 2159)
Formulation B	91.0-115.2	102.4	93.0-117.1	104.3	80.7-103.7	91.4
(Lot # 2162)
Formulation C	89.0-111.2	99.5	89.7-111.6	100.1	89.4-113.3	100.7
(Lot # 2165)

[0154] Study No. 99103 (B99416PK-TRAP03)

[0155] A pilot two-way, multiple-dose, open-label, Fasting, comparative bioavailability study of Tramadol Hydrochloride Extended-Release Tablets (2×100 mg) versus Ultram® in normal, healthy, non-smoking male and female volunteers was conducted.

[0156] The objective of this study was to compare the rate and extent of absorption of a new extended-release formulation of tramadol hydrochloride (2×100 mg) against Ultram® (50 mg q.i.d.) under steady-state conditions in normal healthy male and female volunteers. This comparison reflects the administration of Ultram® under clinical conditions.

[0157] This pilot steady-state study was a randomized, two-way crossover study design in sixteen (16) normal, healthy, non-smoking male and female volunteers and four (4) alternates (total 11 males and 9 females).

[0158] Twenty (20) subjects were entered into the study. Fifteen (15) subjects completed the study; there were fifteen (15) evaluable subjects. All subjects were non-smoking, between 18 and 45 years of age (inclusive), and with body weights no more than ±15% of the ideal weight for the subject's height and frame as determined by the Table of Desirable Weights for Men and Women. All female subjects were non-lactating, had negative pregnancy tests, and were taking an acceptable method of contraception.

[0159] The study periods were separated by a one-week washout period. Blood sampling for drug content analysis was carried out as follows for the test product (Tramadol ER tablets (2×100 mg), treatment A, Lot#2162): Day 1—0.0 (pre-dose), 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0, 16.0, 20.0, 24.0; Day 2, 3, and 4—0.0 (pre-dose); Day 5—0.0 (pre-dose), 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0, 16.0, 20.0, 24.0, 30.0, 36.0, and 48.0 hours post-drug administration.

[0160] Blood sampling for drug content analysis was carried out as follows for the reference product (Ultram® 50 mg tablets q.i.d., treatment B, Lot#CDA2225): Day 1—0.0 (pre-dose), 1.0, 2.0, 3.0, 4.0, 5.0 (pre-dose), 6.0, 7.0, 8.0, 9.0, 10.0, 11.0 (pre-dose), 12.0, 13.0, 14.0, 15.0 (pre-dose), 16.0, 17.0, 18.0, 20.0 and 24.0; Days 2, 3, and 4—0.0 (pre-dose); Day 5—0.0 (pre-dose), 1.0, 2.0, 3.0, 4.0, 5.0 (pre-dose), 6.0, 7.0, 8.0, 9.0, 10.0, 11.0 (pre-dose), 12.0, 13.0, 14.0, 15.0 (pre-dose), 16.0, 17.0, 18.0, 20.0, 24.0, 30.0, 36.0, and 48.0 hours post-drug administration.

Treatments:	A:	2 Tablets of Tramadol HCl ER 100 mg Tablets
		(Lot# 2162 - Biovail Corporation International,
		Canada) once a day (approximately 7 AM) for 5
		consecutive days.
	B:	Ultram ® (Tramadol HCl 50 mg tablet, Ortho-
		McNeil Pharmaceutical, USA) (Lot# CDA2225)
		q.i.d. (approximately 7 AM, 12 PM, 6 PM and 10
		PM) for 5 consecutive days.

[0161] In the current study, Lot#2162 was compared to immediate release Ultram® under multiple-dose conditions. The extended release formulation performed consistently under both single and multiple doses. The overall half-life after multiple-dose for tramadol was 7.3 hours and 6.7 hours, respectively, following Tramadol HCl ER Tablets and Ultram®. Steady state levels of tramadol were achieved by the third dose (day 3 of the study) for Tramadol HCl ER Tablets, and by the fifth dose (Day 2 of the study) for Ultram®. The mean pharmacokinetic data for single dose and multiple dose of tramadol and the M1 are presented in tables 5a-5b and 6a-6b, respectively. Steady-state bioequivalence between Tramadol HCl ER Tablets (Lot#2162) and immediate-release Ultram® (Lot #CDA2225) was established. The 90% confidence intervals for AUC and Cmax were within the 80-125% limits for both unchanged drug and 0-desmethyltramadol. Tramadol HCl ER Tablets (Lot#2162) given once daily exhibited lower percent fluctuation at steady state (70%) than Ultram® given four times a day.

TABLE 5a
Pharmacokinetic Parameters Study 99103 (416PK) (n = 15)
Study 416PK Mean Pharmacokinetic Parameters for Plasma Tramadol
(n = 15)
	Tramadol ER
	(2 × 100 mg) q.d.	Ultram 50 mg q.i.d.
Parameter	Day 1	Day 5	Day 1	Day 5
AUC0-□	5089.010	7715.89	5000.73	7004.37
(ng · hr/mL)	(37.55)	(35.69)	(37.94)	(27.81)
Cmax (ng/mL)	365.62	431.58	348.23	406.95
	(40.34)	(34.06)	(36.73)	(26.88)
Tmax (hr)	13.47	12.80	16.00	15.80
	(19.82)	(21.13)	(10.02)	(26.23)
t½ el (hr)		7.32		6.67
		(16.41)		(20.24)
% Fluctuation		70.19		81.82
		(24.19)		(20.28)
		Tramadol ER
	Cmin (ng/mL)	(2 × 100 mg) q.d.	Ultram 50 mg q.i.d.
	Day 1	161.37 (70.23)	147.52 (49.96)
	Day 2	213.43 (52.38)	178.52 (47.03)
	Day 3	235.13 (56.41)	183.89 (36.33)
	Day 4	231.44 (44.66)	176.41 (44.24)
	Day 5	253.55 (46.44)	201.20 (26.12)

[0162] FIG. 4 illustrates the mean plasma Tramadol concentrations on Day 1 following once a day Tramadol HCl ER Tablets (100 mg×2) formulated according to Lot#2162 for 5 Days vs. Ultram® (50 mg×2) q.i.d.

[0163] FIG. 5 illustrates the mean plasma Tramadol concentrations on Day 5 following once a day Tramadol HCl ER Tablets (100 mg×2) formulated according to Lot#2162 for 5 Days vs. Ultram® (50 mg×2) q.i.d.

TABLE 5b
Ratio of Means & 90% Confidence Interval for Plasma Tramadol
Statistical		90% Geometric
Analysis	Treatment	C.I. 2
(ANOVA)	Comparisons	Ratio 1	Lower	Upper
AUC0-t	Tramadol HCl ER	108.6%	104.2%	113.2%
	(Lot#2162) vs Ultram ®
	(Lot# CDA2225)
Cmax	Tramadol HCl ER	104.9%	98.6%	111.6%
	(Lot#2162) vs Ultram ®
	(Lot# CDA2225)
1 Ratio of least squares means
2 Calculated from log-transformed data

[0164]

TABLE 6a
Pharmacokinetic Parameters Study 99103 (416PK) (n = 15)
Study 416PK: Mean Pharmacokinetic Parameters for
Plasma O-desmethyltramadol (n = 15)
	Tramadol ER
	(2 × 100 mg) q.d.	Ultram 50 mg q.i.d.
Parameter	Day 1	Day 5	Day 1	Day 5
AUC0-□	1037.71	1550.55	1105.30	1540.17
(ng · hr/mL)	(40.22)	(37.21)	(37.74)	(39.07)
Cmax (ng/mL)	70.85	79.75	72.82	80.97
	(39.87)	(36.94)	(37.02)	(41.13)
Tmax (hr)	14.27	13.73	16.87	13.47
	(21.76)	(16.39)	(8.34)	(41.43)
t½ el (hr)		8.49		7.15
		(14.28)		(12.75)
% Fluctuation		49.46		55.08
		(22.71)		(33.22)
		Tramadol ER
	Cmin (ng/mL)	(2 × 100 mg) q.d.	Ultram 50 mg q.i.d.
	Day 1	40.05 (45.16)	41.34 (38.83)
	Day 2	54.73 (39.72)	49.41 (37.52)
	Day 3	56.67 (36.46)	50.03 (37.94)
	Day 4	56.55 (37.43)	47.35 (40.18)
	Day 5	55.19 (38.43)	50.86 (39.67)

[0165] FIG. 6 illustrates the mean plasma Desmethyltramadol concentrations on Day 1 following once a day Tramadol HCl ER Tablets (100 mg×2) formulated according to Lot#2162 for 5 Days vs. Ultram® (50 mg×2) q.i.d.

[0166] FIG. 7 illustrates the mean plasma Desmethyltramadol concentrations on Day 5 following once a day Tramadol HCl ER Tablets (100 mg×2) formulated according to Lot#2162 for 5 Days vs. Ultram® (50 mg×2) q.i.d.

TABLE 6b
Ratio of Means & 90% Confidence Interval
for Plasma O-desmethyltramadol
Statistical		90% Geometric
Analysis	Treatment	C.I. 2
(ANOVA)	Comparisons	Ratio 1	Lower	Upper
AUC0-t	Tramadol HCl ER	101.5%	97.2%	106.0%
	(Lot#2162) vs Ultram ®
	(Lot# CDA2225)
Cmax	Tramadol HCl ER	100.0%	94.2%	106.2%
	(Lot#2162) vs Ultram ®
	(Lot# CDA2225)
1 Ratio of least squares means
2 Calculated from log-transformed data

[0167] Study No. 2282 (B99-424PK-TRAP03)

[0168] A pilot three-way, multiple-dose, open-label, fasting, comparative bioavailability study of two formulations of Tramadol Hydrochloride Extended-Release Tablets (3×100 mg) administered once a day versus Ultram® Tablets (2×50 mg) administered three times a day in normal, healthy, non-smoking male and female volunteers was conducted.

[0169] The objective of this study was to compare the rate and extent of absorption of two new extended-release formulations of tramadol hydrochloride (3×100 mg) administered once daily against Ultram® (2×50 mg) administered three times a day under steady-state conditions in normal healthy male and female volunteers. This comparison reflects the administration of Ultram® under clinical conditions.

[0170] This pilot steady-state study was a randomized, three-way crossover study design in fifteen (15) normal, healthy, non-smoking male and female volunteers and three (3) alternates (total 11 males and 9 females). Eighteen (18) subjects were entered into the study. Fourteen (14) subjects completed the study; there were fourteen (14) evaluable subjects. All subjects were non-smoking, between 18 and 45 years of age (inclusive), and with body weights no more than ±15% of the ideal weight for the subject's height and frame as determined by the Table of Desirable Weights for Men and Women. All female subjects were non-lactating, had negative pregnancy tests, and were taking an acceptable method of contraception.

[0171] The study periods were separated by a one-week washout period. Blood sampling for drug content analysis was carried out as follows for the two test products (Tramadol ER tablets (3×100 mg), treatment A (Lot#2162) and treatment B (Lot#2165)): Day 1—0.0 (pre-dose), 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0, 16.0, 20.0, Day 2, 3, and 4—0.0 (pre-dose); Day 5—0.0 (pre-dose), 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0, 16.0, 20.0, 24.0, 30.0, 36.0 and 48.0 hours post-drug administration.

[0172] Blood sampling for drug content analysis was carried out as follows for the reference product (Ultram® 50 mg tablets q.i.d., treatment C): Day 1—0.0 (pre-dose), 1.0, 2.0, 3.0, 4.0, 5.0 (pre-dose), 6.0, 7.0, 8.0, 9.0, 10.0, 11.0 (pre-dose), 12.0, 13.0, 14.0, 16.0, and 20.0 hours; Days 2, 3, and 4—0.0 (pre-dose); Day 5—0.0 (pre-dose), 1.0, 2.0, 3.0, 4.0, 5.0 (pre-dose), 6.0, 7.0, 8.0, 9.0, 10.0, 11.0 (pre-dose), 12.0, 13.0, 14.0, 16.0, 20.0, 24.0, 30.0, 36.0, and 48.0 hours post-drug administration.

Treatments:	A:	3 Tablets of Tramadol HCl ER 100 mg Tablets
		(Lot# 2162 - Biovail Corporation International,
		Canada) once a day (approximately 7 AM) for 5
		consecutive days.
	B:	3 Tablets of Tramadol HCl ER 100 mg Tablets
		(Lot# 2165 - Biovail Corporation International,
		Canada) once a day (approximately 7 AM) for 5
		consecutive days.
	C:	2 Tablets of Ultram ® (Tramadol HCl 50 mg tablet,
		Ortho-McNeil Pharmaceutical, USA) (Lot#
		CDA2225) t.i.d. (approximately 7 AM, 12 PM and
		6 PM) for 5 consecutive days.

[0173] The current study was undertaken to compare the two lead Tramadol HCl ER Tablet formulations (Lot#2162 and Lot#2165) (3×100 mg) administered once daily against Ultram® (2×50 mg) administered three times a day under steady-state conditions in normal healthy male and female volunteers. This comparison reflects the administration of Ultram® under clinical conditions.

[0174] The extended release formulations performed consistently both under single and multiple dose conditions. The overall half-life after multiple-dose for tramadol was 7.3 hours following Tramadol HCl ER Tablets (Lot#2162), 6.9 hours following Tramadol HCl ER Tablets (Lot#2165), and 6.4 hours immediate release Ultram®. Steady state levels of tramadol were achieved by the third dose (day 3 of the study) for Tramadol HCl ER Tablets, (Lot#2162 and Lot#2165) and by the seventh dose (day 3 of the study) for Ultram®. The mean pharmacokinetic data for single dose and multiple doses of tramadol and the M1 are presented in tables 7a-7b and 8a-8b, respectively. Steady-state bioequivalence between Tramadol HCl ER tablets (Lot#2162 and Lot#2165) and immediate-release Ultram® (Lot #CDA2225) was established. The 90% confidence intervals for unchanged drug and O-desmethyltramadol AUC and Cmax for Tramadol HCl ER Tablets (Lot#2162), and the 90% confidence intervals for unchanged drug and O-desmethyltramadol AUC for Tramadol HCl ER Tablets (Lot#2165) were within the 80-125% limits. O-desmethyltramadol Cmax for Lot#2165 was within the limits.

[0175] Lot#2162 demonstrates steady-state bioequivalence versus both t.i.d. and q.i.d. administration of Ultram® as evidenced by 90% C.I. values for AUC and Cmax within 80-125% limits for both tramadol and O-desmethyltramadol. Lot#2162 also exhibited lower percent fluctuation versus Ultram® when given t.i.d. and q.i.d.

TABLE 7a
Pharmacokinetic Parameters Study 2282 (424PK) (n = 15)
Study 424PK Mean Pharmacokinetic Parameters for Plasma Tramadol (n = 15)
	Tramadol ER (2 × 100 mg) q.d.	Tramadol ER (2 × 100 mg) q.d.	Ultram 50 mg q.i.d.
	Lot # 2162	Lot # 2165	Lot #
Parameter	Day 1	Day 5	Day 1	Day 5	Day 1	Day 5
AUC0-□(ng · hr/mL)	6407.95 (27.03)	9849.28 (23.65)	6977.91 (27.97)	10116.75 (23.97)	6854.57 (25.77)	9611.88 (19.12)
Cmax (ng/mL)	457.65 (28.37)	585.17 (21.58)	540.76 (24.05)	699.76 (22.32)	464.67 (23.46)	621.66 (20.06)
Tmax (hr)	10.40 (20.80)	10.90 (27.70)	7.90 (18.6)	8.40 (21.20)	12.20 (34.20)	9.60 (36.10)
t½ el (hr)		7.32 (23.58)		6.91 (17.33)		6.40 (14.20)
% Fluctuation		84.73 (36.04)		125.39 (24.96)		114.47 (15.79)
	Tramadol ER (2 × 100 mg) q.d.	Tramadol ER (2 × 100 mg) q.d.	Ultram 50 mg q.i.d.
Cmin (ng/mL)	Lot # 2162	Lot # 2165	Lot #
Day 2	174.56 (40.90)	134.96 (51.01)	142.63 (36.88)
Day 3	213.73 (41.07)	156.63 (37.89)	154.99 (39.36)
Day 4	218.78 (44.50)	175.36 (46.91)	150.46 (32.52)
Day 5	250.77 (43.26)	186.04 (47.41)	166.85 (31.67)

[0176]

TABLE 7b
Ratio of Means & 90% Confidence Interval for Plasma Tramadol
Statistical		90% Geometric
Analysis	Treatment	C.I. 2
(ANOVA)	Comparisons	Ratio 1	Lower	Upper
AUC0-t	Tramadol ER (Lot#2162)	101.9%	95.4%	108.8%
	vs Ultram ® (Lot# CDA2225)
	Tramadol ER (Lot# 2165)	104.9%	98.2%	112.0%
	vs Ultram ® (Lot# CDA2225)
Cmax	Tramadol ER (Lot#2162)	93.1%	83.9%	103.4%
	vs Ultram ® (Lot# CDA2225)
	Tramadol ER (Lot#2165)	114.1%	102.8%	126.7%
	vs Ultram ® (Lot# CDA2225)
1 Ratio of least squares means
2 Calculated from log-transformed data

[0177]

TABLE 8a
Pharmacokinetic Parameters Study 2282 (424PK) (n = 15)
Study 424PK: Mean Pharmacokinetic Parameters for Plasma O-desmethyltramadol (n = 15)
	Tramadol ER (2 × 100 mg) q.d.	Tramadol ER (2 × 100 mg) q.d.	Ultram 50 mg q.i.d.
	Lot # 2162	Lot # 2165	Lot #
Parameter	Day 1	Day 5	Day 1	Day 5	Day 1	Day 5
AUC0-□(ng · hr/mL)	1896.02 (26.07)	2554.04 (26.68)	2133.71 (32.64)	2478.46 (32.46)	2096.32 (24.41)	2475.64 (25.10)
Cmax (ng/mL)	130.64 (30.58)	138.37 (24.02)	150.67 (33.05)	145.57 (29.10)	127.43 (24.32)	138.26 (26.73)
Tmax (hr)	11.60 (19.80)	12.60 (22.00)	9.60 (14.60)	9.20 (18.80)	13.20 (29.90)	13.20 (14.30)
Cmin (ng/mL)	Tramadol ER (2 × 100 mg) q.d.	Tramadol ER (2 × 100 mg) q.d.	Ultram 50 mg q.i.d.
Day 2	64.24 (34.32)	52.92 (46.34)	57.74 (25.59)
Day 3	70.48 (33.65)	55.29 (41.81)	56.61 (28.78)
Day 4	76.09 (41.83)	60.05 (44.08)	57.67 (28.81)
Day 5	76.87 (38.41)	59.65 (45.35)	58.82 (30.95)

[0178]

TABLE 8b
Ratio of Means & 90% Confidence Interval
for Plasma O-desmethyltramadol
Statistical		90% Geometric
Analysis	Treatment	C.I. 2
(ANOVA)	Comparisons	Ratio 1	Lower	Upper
AUC0-t	Tramadol ER (Lot# 2162)	102.4%	96.9%	108.1%
	vs Ultram ® (Lot# CDA2225)
	Tramadol ER (Lot# 2165)	98.6%	93.4%	104.2%
	vs Ultram ® (Lot# CDA2225)
Cmax	Tramadol ER (Lot# 2162)	100.4%	95.0%	106.0%
	vs Ultram ® (Lot# CDA2225)
	Tramadol ER (Lot# 2165)	105.3%	99.7%	111.3%
	vs Ultram ® (Lot# CDA2225)
1 Ratio of least squares means
2 Calculated from log-transformed data

[0179] FIG. 8 illustrates the mean plasma Tramadol concentrations on Day 1 following once a day Tramadol HCl ER Tablets (100 mg×3) formulated according to Lot Nos. 2162 and 2165 for 5 Days vs. Ultram® (50 mg×2) t.i.d.

[0180] FIG. 9 illustrates the mean plasma Tramadol concentrations on Day 5 following once a day Tramadol HCl ER Tablets (100 mg×3) formulated according to Lot Nos. 2162 and 2165 for 5 Days vs. Ultram® (50 mg×2) t.i.d.

[0181] FIG. 10 illustrates the mean plasma Desmethyltramadol concentrations on Day 1 following once a day Tramadol HCl ER Tablets (100 mg×3) formulated according to Lot Nos. 2162 and 2165 for 5 Days vs. Ultram® (50 mg×2) t.i.d.

[0182] FIG. 11 illustrates the mean plasma Desmethyltramadol concentrations on Day 1 following once a day Tramadol HCl ER Tablets (100 mg×3) formulated according to Lot Nos. 2162 and 2165 for 5 Days vs. Ultram® (50 mg×2) t.i.d.

EXAMPLE 2

100 mg Tramadol HCl ER Tablets

[0183] The following 100 mg Tramadol HCl ER Tablet formulation was prepared:

[0184] Tablet Core Formulation

[0185] The tablet core formulation was that of Example 1. The tablet core was prepared according to the process described in Example 1.

TABLE 9
Coating Formulation
		Quantity
	Ingredients	(mg)	%
	Ethylcellulose	9.73	73.00 (of coating
	(ETHOCEL ® PR 100)		polymer)
	Polyvinylpyrrolidone	3.60	27.00 (of coating
	(KOLLIDON ® 90 F)		polymer)
	Dibutyl Sebacate	2.67	20.00 (of above
			polymer)
	Total dry material: 8.5% of the solution
	Ethyl Alcohol 200 Proof	163.62 *	95% (of total
			solvent)
	Isopropyl Alcohol 99%	8.61 *	5% (of total
	Coated Tablet	120.00
	* evaporated during process

[0186] The coating process was carried out with the following parameters:

[0187] 30 psi spray pressure

[0188] 40° C. product temperature

[0189] 5 g/min/kg spray rate

EXAMPLE 3

100 mg Tramadol HCl ER Tablets

[0190] The following 100 mg Tramadol HCl ER Tablet formulation was prepared:

[0191] Tablet Core Formulation

[0192] The tablet core formulation was that of Example 1.

[0193] Tablet Core Preparation

[0194] The tablet core was prepared according to the process described in Example 1.

TABLE 10
Coating Formulation
	mg/tablet
	Lot#1	Lot#2	Lot#3	Lot#4
	Quantity	Quantity	Quantity	Quantity
Ingredients	(mg)	(mg)	(mg)	(mg)
Ethylcellulose	9.87	9.87	9.60	9.60
(ETHOCEL ® PR 100)
Polyvinylpyrrolidone	3.47	3.47	3.73	3.73
(KOLLIDON ® 90 F)
Dibutyl Sebacate	2.67	2.67	2.67	2.67
Ethyl Alcohol 200 Proof	153.94 *	153.94 *	153.94 *	153.94 *
Isopropyl Alcohol 99% USP	8.09 *	8.09 *	8.09 *	8.09 *
* evaporated during process

[0195] Coating Preparation

[0196] The tablet core coating solution was prepared according to the process described in Example 1.

TABLE 10
Coating Parameters:
Parameter	Lot #1	Lot#2	Lot #3	Lot #4
Inlet	41-42	56-57	56-57	48.5-49.5
Temperature ° C.
Outlet	32-33	44-45	44-45	38.5-39.5
Temperature ° C.
Bed	N/A	45-46	45-46	37.5-38.5
Temperature ° C.
Spray Rate g/min	300	300-310	300-310	300
Atomizing	25/20	25/25	25/25	25/25
Air/Pattern Psi
Distance gun/Bed	6″	6″	6″	6″
Distance	6″	6″	6″	6″
between guns
Pan speed rpm	12.0	12.0	12.0	12.0

[0197]

TABLE 11
Dissolution Profile
	% Dissolved
Time (min.)	Lot #1	Lot#2	Lot #3	Lot #4
0	0	0	0	0
120	0.5	3.34	7.81	5.13
240	0.85	7.94	26.68	15.23
360	1.39	13.06	50.97	34.94
480	2.43	20.72	70.16	54.58
600	4.04	30.15	83.27	70.10
720	6.89	41.77	91.40	81.89

[0198] FIG. 12 illustrates the in vitro dissolution profiles of Tramadol HCl 100 mg ER Tablets formulated according to Lot Nos. 1-4.

EXAMPLE 4

200 mg Tramadol HCl ER Tablets

[0199] The following 200 mg Tramadol HCl ER Tablet formulation was prepared:

TABLE 12a
Tablet Core Formulation
Ingredients               Quantity (mg)
Tramadol HCl              200.00
Polyvinyl Alcohol         4.00
Colloidal Silicon Dioxide 2.00
(AEROSIL ® 200)
Sodium Stearyl Fumarate   2.00
Purified Water            83.20 *
Core Total Weight         208.00
* evaporated during process

[0200] Tablet Core Preparation

[0201] The tablet core was prepared according to the process described in Example 1.

TABLE 12b
Coating Formulation
Ingredients                      Quantity (mg)
Ethylcellulose (ETHOCEL ® PR100) 12.28
Polyvinylpyrrolidone             6.05
(KOLLIDON ® K90)
Dibutyl Sebacate NF              3.67
Ethyl Alcohol 200 Proof          154.24 *
Isopropyl Alcohol USP            8.12 *
* evaporated during process

[0202] Coating Preparation

[0203] The tablet core coating solution was prepared according to the process described in Example 1.

TABLE 13
Dissolution Profile
Time (min.) % Dissolved
0           0
60          1.13
120         6.05
180         13.80
240         22.87
300         32.18
360         41.17
420         49.43
480         56.85
540         63.33
600         68.87
660         73.55
720         77.55
780         80.72
840         83.43
900         85.77
960         87.75
1020        89.20
1080        90.70
1140        91.62

[0204] FIG. 13 illustrates the in vitro dissolution profile of a 200 mg Tramadol HCl ER Tablet formulated according to Example 4.

EXAMPLE 5

200 mg Tramadol HCl Tablets

[0205] The following Tramadol HCl formulation was prepared:

[0206] Tablet Core Formulation

[0207] The tablet core formulation was that of Example 4.

[0208] Tablet Core Preparation

[0209] The tablet core was prepared according to the process described in Example 1.

TABLE 14
Coating Formulation
	Ingredients	Quantity (mg)	%
	Ethylcellulose	13.38	73.00 (of coating
	(ETHOCEL ® PR 100)		polymer)
	Polyvinylpyrrolidone	4.95	27.00 (of coating
	(KOLLIDON ® 90 F)		polymer)
	Dibutyl Sebacate	3.67	20.00 (of above
			polymer)
	Total dry material: 9% of the solution
	Ethyl Alcohol 200 Proof	211.32 *	95% (of total
			solvent)
	Isopropyl Alcohol 99%	11.12 *	5% (of total
	Coated Tablet	230.00
	* evaporated during process

[0210] The coating process was carried out with the following parameters:

[0211] 30 psi spray pressure

[0212] 40° C. product temperature

[0213] 5 g/min/kg spray rate

EXAMPLE 6

200 mg Tramadol HCl ER Tablets

[0214] The following Tramadol HCl formulation was prepared:

[0215] Tablet Core Formulation

[0216] The tablet core formulation was that of Example 4.

[0217] Tablet Core Preparation

[0218] The tablet core was prepared according to the process described in Example 1.

TABLE 15
Coating Formulation
	Ingredient	Lot #5	Lot#6	Lot #7
	Ethylcellulose	15.60	15.60	15.60
	(ETHOCEL ® PR 100)
	Polyvinylpyrrolidone	6.07	6.07	6.07
	(KOLLIDON ® 90 F)
	Dibutyl Sebacate	4.33	4.33	4.33
	Ethyl Alcohol 200 Proof	249.75*	249.75*	249.75*
	Isopropyl Alcohol 99%	13.15*	13.15*	13.15*
	*evaporated during process

[0219] Coating Preparation

[0220] The tablet core coating solution was prepared according to the process described in Example 1.

TABLE 16
Coating Parameters
Parameter	Lot #5	Lot#6	Lot #7
Inlet Temperature ° C.	49-50	50-51.5	50-51.5
Outlet Temperature ° C.	38.5-39.5	39.5-40.5	39.5-40.5
Bed Temperature ° C.	37.5-38.5	37.5-39	37.5-39
Spray Rate g/min	300	300	300
Atomizing Air/Pattern Psi	25/25	25/25	25/25
Distance gun/Bed	6″	6″	6″
Distance between guns	6″	6″	6″
Pan speed rpm	12.0	12.0	12.0

[0221] Dissolution Method

[0222] The dissolution method was performed according to the method described in Example 1.

TABLE 17
Dissolution Profile
	% Dissolved
	Time (min.)	Lot #5	Lot#6	Lot #7
	0	0	0	0
	120	5.54	4.13	5.37
	240	14.71	14.29	15.76
	360	29.25	31.83	33.48
	480	46.40	50.16	51.62
	600	N/A	65.64	66.42
	720	N/A	76.8	77.49

[0223] FIG. 14 illustrates the in vitro dissolution profiles of 200 mg Tramadol HCl ER Tablets formulated according to Lot Nos. 5 and 7.

EXAMPLE 7

[0224]

TABLE 17a
200 mg Tramadol HCl ER Tablet Formulation
                               Tramadol 200 mg
                               Lot # 2883
Ingredients                    Mg/tablet
Tramadol HCl                   200
Aerosil 200, NF                2
Polyvinyl Alcohol USP/NF       4
Sodium Stearyl Fumarate        2
Ethyl cellulose 100 NF         12.28
Povidone, K 90, NF (BASF)      6.05
Dibutyl Sebacate, NF (Morflex) 3.67
Total weight of coated Tablet  230

[0225] A two-way, crossover, open-label, single-dose, fasting, comparative biovailability study of Tramadol HCl Extended-Release Tablets (2×100 mg vs 1×200 mg) in normal healthy non-smoking male subjects was conducted.

[0226] 7.1: Synopsis

[0227] Based on preliminary data from 12 completing subjects, the 200 mg strength Tramadol HCl ER Tablets are proportional to the 100 mg strength given as 2×100 mg.

[0228] 7.2: Purpose of Study

[0229] This study was designed to determine the dosage strength proportionality of two strengths of Tramadol HCl ER Tablets (2×100 mg vs 1×200 mg) under single dose fasting conditions.

[0230] 7.3: Study Design

[0231] A single-dose, open-label, two-way, two-sequence, crossover design. The treatments were separated by a one (1) week washout period. On day 1 of each period, subjects received one of the following treatments on two (2) separate occasions according to the randomization scheme

Treatment A: Two Tramadol HCl Extended Release 100 mg Tablets (Lot
             #000103-scale-up) with 240 mL of water at 0.0 hour
             following a 10 hour overnight fast (Total Daily Dose =
             200 mg)
Treatment B: One Tramadol HCl Extended Release 200 mg Tablet (Lot
             #2883) with 240 mL of water at 0.0 hour following a 10
             hour overnight fast (Total Daily Dose = 200 mg)

[0232] 7.4: Summary and Conclusions

[0233] This study was intended to determine the dosage strength proportionality of two strengths of Tramadol HCl ER Tablets (2×100 mg vs 1×200 mg) under single dose fasting conditions. A total of 12 male subjects were dosed at Biovail Contract Research. Pharmacokinetic and statistical analyses were conducted with preliminary plasma data from 12 completing subjects for Tramadol, and M1 metabolite. The mean plasma concentrations vs time plots based on 12 completing subjects for tramadol, and M1 metabolite are presented in FIGS. 15 and 16, respectively. Individual pharmacokinetic parameters are shown in Tables 18a, 18b, 19a and 19b.

[0234] With all subjects, the ratio of geometric means (1×200 mg/2×100 mg) for tramadol AUC0-t and Cmax were 1.11 and 1.17, respectively. The corresponding 90% confidence intervals were 97%-125% and 103%-133%, respectively. For the M1 metabolite, the ratio of geometric means (1×200 mg/2×100 mg) for AUC0-t and Cmax were 1.05 and 1.11, respectively. The corresponding 90% confidence intervals were 96%-116% and 102%-121%, respectively.

[0235] In conclusion, the 200 mg strength Tramadol HCl ER Tablets were proportional to the 100 mg strength given as 2×100 mg since the 90% confidence intervals for AUC0-t and Cmax for all analytes were found to be within 80%-125.

TABLE 18a
Tramadol PK (n = 12)
	TRAMADOL ER	200 mg/
CMAX	200 mg	2 × 100 mg	2 × 100 mg
Subject	Tmax	Cmax	In Cmax	Tmax	Cmax	In Cmax	Cmax Ratio
1	8	244.69	5.50	8	258.32	5.55	0.95
2	10	277.87	5.63	12	339.09	5.83	0.82
3	8	243.47	5.50	10	330.78	5.80	0.74
4	10	268.04	5.59	10	226.90	5.42	1.18
5	6	227.80	5.43	8	200.75	5.30	1.13
6	8	259.13	5.56	10	216.91	5.38	1.19
7	5	261.09	5.56	10	155.44	5.05	1.68
8	8	226.11	5.42	8	98.86	4.59	2.29
9	8	278.90	5.63	10	232.96	5.45	1.20
10	10	195.36	5.27	8	148.30	5.00	1.32
11	8	353.25	5.87	8	330.44	5.80	1.07
12	10	435.46	6.08	10	404.39	6.00	1.08
Mean	8.25	272.60	5.59	9.33	245.26	5.43	1.22
SD	1.60	64.10	0.21	1.30	90.97	0.41	0.41
CV	19.42	23.51	3.77	13.96	37.09	7.50	33.90
Min	5.00	195.36	5.27	8.00	98.86	4.59	0.74
Max	10.00	435.46	6.08	12.00	404.39	6.00	2.29
Geo Mean	8.09	266.71	5.58	9.25	228.55	5.42	1.17
				90% C.I.
Cmax Ratio	Mean	Geo Mean	90% C.I.	(Excluding Subject 8)
200 mg/2 × 100 mg	1.11	1.17(SAS)	103-133	100-123

[0236]

TABLE 18b
Tramadol PK (n = 12)
	TRAMADOL ER	200 mg/
AUCT	200 mg	2 × 100 mg	2 × 100 mg
Subject	AUCt	In AUCt	AUCt	In AUCt	AUCt Ratio
1	4604.23	8.43	4446.02	8.40	1.04
2	6485.28	8.78	6343.27	8.76	1.02
3	5324.71	8.58	6067.74	8.71	0.88
4	6975.11	8.85	6292.41	8.75	1.11
5	4284.83	8.36	4045.08	8.31	1.06
6	3919.08	8.27	3944.65	8.28	0.99
7	4096.54	8.32	3521.10	8.17	1.16
8	3279.62	8.10	1382.53	7.23	2.37
9	4260.44	8.36	4423.57	8.39	0.96
10	2923.70	7.98	2714.23	7.91	1.08
11	4911.47	8.50	4882.50	8.49	1.01
12	8824.82	9.09	8323.14	9.03	1.06
Mean	4990.82	8.47	4698.85	8.37	1.14
SD	1687.36	0.32	1852.43	0.47	0.39
CV	33.81	3.73	39.42	5.60	34.34
Min	2923.70	7.98	1382.53	7.23	0.88
Max	8824.82	9.09	8323.14	9.03	2.37
Geo Mean	4759.37	8.46	4307.55	8.36	1.10
				90% C.I.
		Geo	90%	(Excluding
AUCt Radio	Mean	Mean	C.I.	Subject 8)
200 mg/2 × 100 mg	1.06	1.11(SAS)	97-125	99-107

[0237] FIG. 15 illustrates the comparison of the mean tramadol plasma concentration-time profiles resulting from the oral administration of Tramadol HCl 100 mg ER tablets (2×100 mg once a day) and Tramadol HCl 200 mg ER tablets (1×200 mg once a day) formulated according to an embodiment of the present invention.

TABLE 19a
M1 PK (n = 12)
	TRAMADOL ER	200 mg/
CMAX	200 mg	2 × 100 mg	2 × 100 mg
Subject	Tmax	Cmax	In Cmax	Tmax	Cmax	In Cmax	Cmax Ratio
1	10	104.54	4.65	12	110.02	4.70	0.95
2	10	98.85	4.59	12	105.22	4.66	0.94
3	10	96.35	4.57	10	97.49	4.58	0.99
4	20	23.51	3.16	16	25.50	3.24	0.92
5	12	75.83	4.33	20	66.86	4.20	1.13
6	10	142.03	4.96	10	118.45	4.77	1.20
7	10	110.74	4.71	10	84.57	4.44	1.31
8	10	102.54	4.63	8	58.72	4.07	1.75
9	8	127.10	4.84	10	135.05	4.91	0.94
10	10	93.51	4.54	10	90.31	4.50	1.04
11	10	139.85	4.94	10	107.20	4.67	1.30
12	16	30.01	3.40	16	27.27	3.31	1.10
Mean	11.33	95.40	4.44	12.00	85.56	4.34	1.13
SD	3.34	37.38	0.57	3.52	34.68	0.55	0.24
CV	29.47	39.18	12.91	29.30	40.53	12.66	21.07
Min	8.00	23.51	3.16	8.00	25.50	3.24	0.92
Max	20.00	142.03	4.96	20.00	135.05	4.91	1.75
Geo Mean	10.98	85.03	4.40	11.59	76.53	4.30	1.11
				90% C.I.
Cmax Ratio	Mean	Geo Mean	90% C.I.	(Excluding Subject 8)
200 mg/2 × 100 mg	1.12	1.11	102-121	100-115

[0238]

TABLE 19b
M1 PK (n = 12)
	TRAMADOL ER	200 mg/
AUCT	200 mg	2 × 100 mg	2 × 100 mg
Subject	AUCt	In AUCt	AUCt	In AUCt	AUCt Ratio
1	2386.29	7.78	2404.81	7.79	0.99
2	2367.19	7.77	2244.63	7.72	1.05
3	2150.65	7.67	2139.59	7.67	1.01
4	718.62	6.58	750.69	6.62	0.96
5	1862.16	7.53	1773.47	7.48	1.05
6	2474.58	7.81	2359.88	7.77	1.0
7	2079.14	7.64	2137.31	7.67	0.97
8	1717.15	7.45	958.31	6.87	1.79
9	2262.49	7.72	2661.79	7.89	0.85
10	1657.30	7.41	1800.10	7.50	0.92
11	2373.89	7.77	2072.75	7.64	1.15
12	722.24	6.58	666.77	6.50	1.08
Mean	1897.64	7.48	1830.84	7.42	1.07
SD	611.42	0.44	674.61	0.48	0.24
CV	32.22	5.87	36.85	6.45	22.33
Min	718.62	6.58	666.77	6.50	0.85
Max	2474.58	7.81	2661.79	7.89	1.79
Geo Mean	1766.50	7.46	1676.26	7.41	1.05
				90% C.I.
				(Excluding
AUCt Ratio	Mean	Geo Mean	90% C.I.	Subject 8)
200 mg/2 × 100 mg	1.04	1.05	96-116	96-105

[0239] FIG. 16 illustrates the comparison of the mean M1 plasma concentration-time profiles resulting from the oral administration of Tramadol HCl 100 mg ER tablets (2×100 mg once a day) and Tramadol HCl 200 mg ER tablets (1×200 mg once a day) formulated according to an embodiment of the present invention.

EXAMPLE 8

[0240]

	TABLE 19c
	mg/tablet
	Tramadol 100 mg	Tramadol 200 mg
Ingredients	Lot # 010206	Lot # 010704
Tramadol HCl	100	200
Aerosil 200, NF	1	2
Polyvinyl Alcohol USP/NF	2	4
Sodium Stearyl Fumarate	1	2
Ethyl cellulose 100 NF	10.25	15.60
Povidone, K 90, NF (BASF)	4.00	6.07
Dibutyl Sebacate, NF (Morflex)	2.85	4.33
Total weight of coated Tablet	121.1	234

[0241] A two-way, crossover, open-label, single-dose, fasting, comparative biovailability study of Tramadol HCl Extended-Release Tablets (2×100 mg vs 1×200 mg) in normal healthy non-smoking male subjects was conducted.

[0242] 8.1: Synopsis

[0243] Based on preliminary data from 23 completing subjects, the 200 mg strength Tramadol HCl ER Tablets are proportional to the 100 mg strength given as 2×100 mg.

[0244] 8.2: Purpose of Study

[0245] This study was designed to determine the dosage strength proportionality of two strengths of Tramadol HCl ER Tablets (2×100 mg vs 1×200 mg) under single dose fasting conditions.

[0246] 8.3: Study Design

[0247] A single-dose, open-label, two-way, two-sequence, crossover design. The treatments were separated by a one (1) week washout period. On day 1 of each period, subjects received one of the following treatments on two (2) separate occasions according to the randomization scheme

Treatment A: Two Tramadol HCl Extended Release 100 mg Tablets
             (Lot # 010206) with 240 mL of water at 0.0 hour
             following a 10 hour overnight fast (Total Daily
             Dose = 200 mg)
Treatment B: One Tramadol HCl Extended Release 200 mg Tablet
             (Lot #010704) with 240 mL of water at 0.0 hour
             following a 10 hour overnight fast (Total Daily
             Dose = 200 mg)

[0248] 8.4: Summary and Conclusions

[0249] This study was intended to determine the dosage strength proportionality of two strengths of Tramadol HCl ER Tablets (2×100 mg vs 1×200 mg) under single dose fasting conditions. A total of 24 male subjects were dosed at Biovail Contract Research. Pharmacokinetic and statistical analyses were conducted with preliminary plasma data from 23 completing subjects for Tramadol, M1 and M5 metabolites. The mean plasma concentrations vs time plots based on 23 completing subjects for tramadol, M1 and M5 metabolites are presented in FIGS. 17, 18 and 19, respectively. Individual pharmacokinetic parameters are shown in Tables 20, 21 and 22.

[0250] With all subjects, the ratio of geometric means (1×200 mg/2×100 mg) for tramadol AUC0-t and Cmax were 1.00 and 1.00, respectively. The corresponding 90% confidence intervals were 96.3 %-104.17 % and 92.2%-109.12%, respectively. For the M1 metabolite, the ratio of geometric means (1×200 mg/2×100 mg) for AUC0-t and Cmax were 1.00 and 0.97, respectively. The corresponding 90% confidence intervals were 95.6 %-104.61 % and 90.3%-104.39%, respectively. For the M5 metabolite, the ratio of geometric means (1×200 mg/2×100 mg) for AUC0-t and Cmax were 0.98 and 0.99, respectively. The corresponding 90% confidence intervals were 92.6%-104.72 % and 90.9%-107.25%, respectively.

[0251] In conclusion, the 200 mg strength Tramadol HCl ER Tablets were proportional to the 100 mg strength given as 2×100 mg since the 90% confidence intervals for AUC0-t and Cmax for all analytes were found to be within 80%-125%.

TABLE 20
Summary of Pharmacokinetic Parameters for Tramadol
Tramadol
	B	A
	Tramadol HCl ER	Tramadol HCl ER
	1 × 200 mg	2 × 100 mg	B/A Ratio
Subject	AUC	Cmax	Tmax	AUC	Cmax	Tmax	AUC	Cmax
1	3772.72	125.97	24.00	4465.15	207.76	8.00	0.84	0.61
2	6989.42	361.35	14.00	7563.59	416.83	12.00	0.92	0.87
3	9967.41	440.03	14.00	8773.22	374.54	16.00	1.14	1.17
4	10503.26	528.11	16.00	10727.13	517.12	14.00	0.98	1.02
5	4315.08	244.26	12.00	4439.38	209.95	16.00	0.97	1.16
7	3539.99	151.93	16.00	4128.98	234.12	8.00	0.86	0.65
8	7752.67	368.21	14.00	6369.64	369.49	8.00	1.22	1.00
9	5413.87	281.50	14.00	5561.14	244.18	16.00	0.97	1.15
10	3640.04	162.12	12.00	4354.42	179.31	14.00	0.84	0.90
11	3442.46	147.72	20.00	3394.52	162.28	16.00	1.01	0.91
12	2763.51	190.15	10.00	2722.78	150.02	10.00	1.01	1.27
13	3746.10	203.07	8.00	4084.60	183.27	16.00	0.92	1.11
14	6394.67	311.42	16.00	5107.43	239.83	8.00	1.25	1.30
15	3093.78	178.86	12.00	2806.92	128.49	16.00	1.10	1.39
16	8363.96	465.15	10.00	7811.02	369.66	14.00	1.07	1.26
17	2410.07	130.62	14.00	2647.52	135.74	14.00	0.91	0.96
18	9336.37	469.34	8.00	9475.49	409.69	16.00	0.99	1.15
19	9125.11	437.92	14.00	8440.88	322.16	14.00	1.08	1.36
20	4983.63	209.73	10.00	4444.82	226.82	12.00	1.12	0.92
21	3337.64	151.75	12.00	3818.74	220.36	12.00	0.87	0.69
22	2868.24	164.88	16.00	2595.66	163.49	8.00	1.11	1.01
23	4233.82	179.29	16.00	4310.37	238.80	16.00	0.98	0.75
24	7311.78	329.98	20.00	7105.46	307.21	20.00	1.03	1.07
Mean	5535.03	271.02	14.00	5441.25	261.35	13.22	1.01	1.03
SD	2591.09	128.34	3.86	2376.20	104.90	3.45	0.11	0.22
CV	46.81	47.36	27.58	43.67	40.14	26.10	11.32	21.60
Geo	4992.59	244.00	13.51	4979.67	242.83	12.74	1.00	1.00
Mean
Min	2410.07	125.97	8.00	2595.66	128.49	8.00	0.84	0.61
Max	10503.26	528.11	24.00	10727.13	517.12	20.00	1.25	1.39
	1 × 200 mg/2 × 100 mg Ratio
	Means	Geo Means	LS Means %	90% CI
AUC	1.02	1.00	100.11	96.3-104.17
Cmax	1.04	1.00	100.29	92.2-109.12

[0252] FIG. 17 illustrates the mean plasma Tramadol concentrations (ng/ml) over time after two 100 mg Tramadol HCl ER Tablets formulated according to an embodiment of the present invention or after one 200 mg Tramadol HCl ER Tablet formulated according to an embodiment of the present invention following a 10 hour overnight fast.

TABLE 21
Summary of Pharmacokinetic Parameters for M1
M1
	B	A
	Tramadol HCl ER	Tramadol HCl ER
	1 × 200 mg	2 × 100 mg	B/A Ratio
Subject	AUC	Cmax	Tmax	AUC	Cmax	Tmax	AUC	Cmax
1	1672.89	57.88	24.00	2022.04	80.50	16.00	0.83	0.72
2	970.95	43.44	14.00	1156.80	54.21	12.00	0.84	0.80
3	1774.74	69.27	20.00	1789.62	70.05	20.00	0.99	0.99
4	1076.19	48.16	16.00	1050.38	44.32	16.00	1.02	1.09
5	1979.48	96.47	14.00	1657.77	72.52	14.00	1.19	1.33
7	953.92	36.57	24.00	1330.47	68.82	8.00	0.72	0.53
8	1414.94	61.68	24.00	1116.16	53.67	12.00	1.27	1.15
9	2484.11	113.99	14.00	2406.74	108.07	20.00	1.03	1.05
10	1721.50	73.76	14.00	1906.22	74.23	16.00	0.90	0.99
11	1829.82	80.76	24.00	1850.88	88.60	16.00	0.99	0.91
12	2144.82	109.30	10.00	2095.44	101.89	14.00	1.02	1.07
13	2111.31	90.98	10.00	2036.17	89.08	20.00	1.04	1.02
14	2130.45	93.13	16.00	2122.92	91.06	16.00	1.00	1.02
15	2360.46	115.08	12.00	2128.12	97.80	16.00	1.11	1.18
16	3234.30	130.32	12.00	3507.19	134.18	20.00	0.92	0.97
17	1922.21	90.47	16.00	1977.41	91.02	14.00	0.97	0.99
18	3490.68	135.80	12.00	3521.34	138.38	16.00	0.99	0.98
19	1154.33	49.30	16.00	991.16	38.21	20.00	1.16	1.29
20	2303.91	96.21	14.00	2269.27	110.63	14.00	1.02	0.87
21	1853.29	72.48	16.00	1983.58	95.39	12.00	0.93	0.76
22	2637.81	153.39	16.00	2464.84	144.41	8.00	1.07	1.06
23	1970.96	81.98	24.00	1870.67	96.76	16.00	1.05	0.85
24	1867.23	89.74	20.00	1673.09	78.73	20.00	1.12	1.14
Mean	1959.14	86.53	16.61	1953.40	87.94	15.48	1.01	0.99
SD	639.46	30.56	4.69	647.00	27.94	3.58	0.12	0.18
CV	32.64	35.32	28.23	33.12	31.77	23.12	12.11	18.40
Geo	1857.57	81.15	16.00	1855.19	83.46	15.03	1.00	0.97
Mean
Min	953.92	36.57	10.00	991.16	38.21	8.00	0.72	0.53
Max	3490.68	153.39	24.00	3521.34	144.41	20.00	1.27	1.33
	1 × 200 mg/2 × 100 mg Ratio
	Means	Geo Means	LS Means %	90% CI
AUC	1.00	1.00	100.01	95.6-104.61
Cmax	0.98	0.97	97.06	90.3-104.39

[0253] FIG. 18 illustrates the mean plasma M1 concentrations (ng/ml) over time after two 100 mg Tramadol HCl ER Tablets formulated according to an embodiment of the present invention or after one 200 mg Tramadol HCl ER Tablet formulated according to an embodiment of the present invention following a 10 hour overnight fast.

TABLE 22
Summary of Pharmacokinetic Parameters for M5:
M5
	B	A
	Tramadol HCl ER	Tramadol HCl ER
	1 × 200 mg	2 × 100 mg	B/A Ratio
Subject	AUC	Cmax	Tmax	AUC	Cmax	Tmax	AUC	Cmax
1	586.48	19.01	30.00	669.49	26.43	16.00	0.88	0.72
2	1011.03	39.82	20.00	1156.49	43.27	16.00	0.87	0.92
3	479.82	18.04	20.00	606.97	21.98	24.00	0.79	0.82
4	597.78	23.35	24.00	709.78	25.47	24.00	0.84	0.92
5	638.62	28.06	12.00	652.44	28.32	16.00	0.98	0.99
7	505.59	18.07	20.00	794.87	34.53	14.00	0.64	0.52
8	1105.91	49.06	24.00	1022.61	39.84	14.00	1.08	1.23
9	765.91	32.10	14.00	860.60	35.68	20.00	0.89	0.90
10	986.85	41.59	14.00	973.22	38.01	16.00	1.01	1.09
11	492.42	20.37	24.00	565.44	24.25	16.00	0.87	0.84
12	1566.17	75.38	16.00	1481.53	71.45	14.00	1.06	1.06
13	1044.20	43.60	16.00	974.90	39.62	20.00	1.07	1.10
14	843.42	35.36	16.00	809.01	33.16	16.00	1.04	1.07
15	967.94	46.14	14.00	867.23	36.72	16.00	1.12	1.26
16	987.92	44.60	20.00	1019.98	38.32	20.00	0.97	1.16
17	630.21	29.71	16.00	607.88	25.47	20.00	1.04	1.17
18	1889.26	66.43	14.00	1865.13	67.08	20.00	1.01	0.99
19	813.41	31.21	20.00	584.26	19.99	20.00	1.39	1.56
20	841.90	34.50	14.00	640.29	27.74	14.00	1.31	1.24
21	829.00	33.19	16.00	940.72	42.90	14.00	0.88	0.77
22	617.32	33.20	16.00	639.87	37.09	10.00	0.96	0.90
23	908.93	38.57	24.00	759.38	40.38	16.00	1.20	0.96
24	743.29	33.02	20.00	717.33	30.83	20.00	1.04	1.07
Mean	863.19	36.28	18.43	866.06	36.02	17.22	1.00	1.01
SD	334.21	14.20	4.51	308.56	12.52	3.45	0.17	0.22
CV	38.72	39.15	24.47	35.63	34.76	20.04	16.59	21.38
Geo	812.38	33.87	17.94	825.19	34.29	16.88	0.98	0.99
Mean
Min	479.82	18.04	12.00	565.44	19.99	10.00	0.64	0.52
Max	1889.26	75.38	30.00	1865.13	71.45	24.00	1.39	1.56
	1 × 200 mg/2 × 100 mg Ratio
	Means	Geo Means	LS Means %	90% CI
AUC	1.00	0.98	98.45	92.6-104.72
Cmax	1.01	0.99	98.77	90.9-107.25

[0254] FIG. 19 illustrates the mean plasma M5 concentrations (ng/ml) over time after two 100 mg Tramadol HCl ER Tablets formulated according to an embodiment of the present invention or after one 200 mg Tramadol HCl ER Tablet formulated according to an embodiment of the present invention following a 10 hour overnight fast.

EXAMPLE 9

[0255] A two-way, crossover, open-label, single-dose, food effect, comparative biovailability study of Tramadol HCl Extended-Release 200 mg Tablets in normal healthy non-smoking male subjects was conducted.

[0256] 9.1: Synopsis

[0257] Based on preliminary data from 20 completing subjects, the presence of food significantly decreased the rate and extent of absorption of tramadol, M1 and M5 metabolites of Tramadol HCl ER tablets 200 mg following single dose administration.

[0258] 9.2: Purpose of Study

[0259] This study was designed to evaluate the effect of food on Tramadol HCl ER 200 mg Tablets following single dose administration.

[0260] 9.3: Study Design

[0261] A single-dose, open-label, two-way, two-sequence, crossover design. The treatments were separated by a one (1) week washout period. On day 1 of each period, subjects received one of the following treatments following a 10 hour overnight fast on two (2) separate occasions according to the randomization scheme

Treatment A: One Tramadol HCl Extended Release 200 mg Tablet
             (Lot #010704) with 240 mL of water at 0.0 hour
             within 5 minutes of complete ingestion of a high
             fat content breakfast.
Treatment B: One Tramadol HCl Extended Release 200 mg Tablet
             (Lot #010704) with 240 mL of water at 0.0 hour
             following a 10 hour overnight fast.

[0262] 9.4: Summary and Conclusions

[0263] This study was intended to evaluate the effect of food on Tramadol HCl ER 200 mg Tablets following single dose administration. A total of 24 male subjects were dosed at Biovail Contract Research. Pharmacokinetic and statistical analyses were conducted with preliminary plasma data from 22 completing subjects. The mean plasma concentrations vs time plots based on 20 completing subjects for tramadol, M1 and M5 metabolites are presented in FIGS. 20, 21 and 22, respectively. Individual pharmacokinetic parameters are shown in Tables 23, 24 and 25.

[0264] With all subjects, the ratio of geometric means (Fed/Fasting) for tramadol AUC0-t and Cmax were 0.76 and 0.73, respectively. For the M1 metabolite, the ratio of geometric means (Fed/Fasting) for AUC0-t and Cmax were 0.75 and 0.76, respectively. For the M5 metabolite, the ratio of geometric means (Fed/Fasting) for AUC0-t and Cmax were 0.73 and 0.73, respectively.

[0265] When data analysis was carried out in the absence of subject #12 and #18, the ratio of geometric means for tramadol AUC0-t and Cmax were 0.79 and 0.73, respectively. For the M1 metabolite, the ratio of geometric means (Fed/Fasting) for AUC0-t and Cmax were 0.78 and 0.76, respectively. For the M5 metabolite, the ratio of geometric means (Fed/Fasting) for AUC0-t and Cmax were 0.75 and 0.72, respectively.

[0266] Based on the results, it was concluded that a significant food effect was observed for Tramadol HCl ER 200 mg Tablets. In the presence of food, the rate and extent of absorption of tramadol and its metabolites resulting from a single dose of Tramadol HCl ER 200 mg Tablet were significantly lower when compared to administration without food.

TABLE 23
Summary of Pharmacokinetic Parameters for Tramadol
Tramadol
		Framadol ER 200 mg,
	Tramadol ER 200 mg, Fed	Fasting	Fed/Fasting
Subject	AUC	Cmax	Tmax	AUC	Cmax	Tmax	AUC	Cmax
1	3944.30	149.33	24.00	4013.96	205.64	14.00	0.98	0.73
2	4078.64	139.34	24.00	6969.14	355.35	14.00	0.59	0.39
3	6818.20	251.76	20.00	6939.38	342.62	10.00	0.98	0.73
4	2021.34	72.15	24.00	4218.92	234.01	14.00	0.48	0.31
5	2330.34	142.73	20.00	2848.84	140.20	16.00	0.82	1.02
6	4636.19	225.35	20.00	5154.28	340.84	12.00	0.90	0.66
7	1901.40	128.41	14.00	3554.14	173.63	16.00	0.53	0.74
8	4585.55	137.09	14.00	5674.75	263.32	14.00	0.81	0.52
9	7727.96	320.14	14.00	7827.31	290.33	20.00	0.99	1.10
10	3783.07	170.80	14.00	4258.28	203.68	16.00	0.89	0.84
11	7079.58	263.39	14.00	7252.23	285.04	14.00	0.98	0.92
13	3342.06	171.38	16.00	3019.69	138.26	12.00	1.11	1.24
15	4424.02	190.87	16.00	4935.58	255.62	14.00	0.90	0.75
16	7296.94	328.00	16.00	6632.83	342.80	12.00	1.10	0.96
17	1070.08	43.56	4.00	8377.65	384.17	10.00	0.13	0.11
20	4209.33	215.06	14.00	5340.01	288.25	12.00	0.79	0.75
21	3451.99	173.23	14.00	3886.46	205.50	10.00	0.89	0.84
22	3937.39	155.94	16.00	3596.43	152.88	14.00	1.09	1.02
23	4539.31	200.08	20.00	5569.65	244.83	16.00	0.82	0.82
24	8472.81	669.76	24.00	6400.85	312.84	16.00	1.32	2.14
Mean	4482.52	207.42	17.10	5323.52	257.99	13.80	0.85	0.83
SD	2042.83	130.14	4.96	1647.23	75.37	2.50	0.26	0.41
CV	45.57	62.74	29.02	30.94	29.21	18.15	30.93	49.48
Geo	3999.75	178.85	16.16	5076.49	246.69	13.59	0.79	0.73
Mean
Min	1070.08	43.56	4.00	2848.84	138.26	10.00	0.13	0.11
Max	8472.81	669.76	24.00	8377.65	384.17	20.00	1.32	2.14
		Fed/Fasting Ratio (Including Subject #12 and
	Fed/Fasting Ratio	#18 who vomited during post-dose)
	Geo Means	LS Means %		Geo Means	LS Means %
AUC	0.79	78.93	AUC	0.76	75.62
Cmax	0.73	72.27	Cmax	0.73	72.38

[0267] FIG. 20 illustrates the mean plasma Tramadol concentrations (ng/ml) over time after a single dose of one 200 mg Tramadol HCl ER Tablet formulated according to an embodiment of the present invention under fasting or fed conditions.

TABLE 24
Summary of Pharmacokinetic Parameters for M1:
M1
	Tramadol ER	Tramadol ER 200 mg,
Sub-	200 mg, Fed	Fasting	Fed/Fasting
ject	AUC	Cmax	Tmax	AUC	Cmax	Tmax	AUC	Cmax
1	1921.05	75.67	24.00	2116.84	90.06	20.00	0.91	0.84
2	1278.59	45.95	24.00	2158.62	86.81	20.00	0.59	0.53
3	1159.73	42.64	20.00	1183.17	46.50	10.00	0.98	0.92
4	542.48	19.92	24.00	1223.87	58.17	14.00	0.44	0.34
5	1894.84	117.77	20.00	1982.93	96.08	20.00	0.96	1.23
6	1887.04	91.91	20.00	1761.13	105.91	12.00	1.07	0.87
7	1130.02	60.88	16.00	1901.17	77.45	16.00	0.59	0.79
8	1674.77	51.91	24.00	2013.76	75.57	16.00	0.83	0.69
9	1511.07	52.51	24.00	1487.99	53.84	24.00	1.02	0.98
10	1322.65	54.89	16.00	1702.91	70.92	16.00	0.78	0.77
11	1335.58	51.01	20.00	1286.31	46.10	24.00	1.04	1.11
13	2269.80	100.16	16.00	1796.92	70.38	14.00	1.26	1.42
15	1018.82	46.97	20.00	1168.38	52.96	16.00	0.87	0.89
16	1270.79	56.22	16.00	1382.61	71.49	16.00	0.92	0.79
17	183.63	5.70	24.00	1555.20	63.67	14.00	0.12	0.09
20	2275.30	101.30	20.00	2439.33	116.53	14.00	0.93	0.87
21	1257.39	60.38	20.00	1339.50	64.90	12.00	0.94	0.93
22	1749.84	66.63	20.00	2118.35	79.93	24.00	0.83	0.83
23	2201.99	91.33	24.00	2577.88	107.78	20.00	0.85	0.85
24	1373.21	77.04	24.00	1575.86	65.39	20.00	0.87	1.18
Mean	1462.93	63.54	20.80	1738.64	75.02	17.10	0.84	0.84
SD	543.09	27.58	3.07	419.16	20.30	4.18	0.25	0.29
CV	37.12	43.40	14.76	24.11	27.07	24.44	29.56	34.89
Geo	1311.89	55.00	20.57	1691.12	72.48	16.61	0.78	0.76
Mean
Min	183.63	5.70	16.00	1168.38	46.10	10.00	0.12	0.09
Max	2275.30	117.77	24.00	2577.88	116.53	24.00	1.26	1.42
		Fed/Fasting Ratio (Including
		Subject #12and #18 who
	Fed/Fasting Ratio	vomited during post-dose)
	Geo	LS		Geo	LS
	Means	Means %		Means	Means %
AUC	0.78	77.89	AUC	0.75	75.27
Cmax	0.76	76.07	Cmax	0.76	76.25

[0268] FIG. 21 illustrates the mean plasma M1 concentrations (ng/ml) over time after a single dose of one 200 mg Tramadol HCl ER Tablet formulated according to an embodiment of the present invention under fasting or fed conditions.

TABLE 25
Summary of Pharmacokinetic Parameters for M5:
M5
	Tramadol ER	Tramadol ER 200 mg,
	200 mg, Fed	Fasting	Fed/Fasting
Subject	AUC	Cmax	Tmax	AUC	Cmax	Tmax	AUC	Cmax
1	748.53	27.50	20.00	897.15	39.14	20.00	0.83	0.70
2	511.56	16.27	24.00	915.79	36.24	20.00	0.56	0.45
3	658.62	21.94	24.00	678.13	22.05	24.00	0.97	1.00
4	536.16	20.64	36.00	1281.12	58.25	20.00	0.42	0.35
5	371.79	21.38	20.00	406.02	17.27	20.00	0.92	1.24
6	851.56	38.97	20.00	732.06	40.97	12.00	1.16	0.95
7	298.02	16.33	16.00	535.16	21.77	16.00	0.56	0.75
8	764.80	21.96	24.00	1100.54	38.46	24.00	0.69	0.57
9	1066.70	31.87	24.00	1054.70	33.20	24.00	1.01	0.96
10	547.25	21.77	20.00	674.38	26.28	16.00	0.81	0.83
11	582.46	22.11	24.00	565.57	19.86	24.00	1.03	1.11
13	446.45	19.72	16.00	399.37	16.12	14.00	1.12	1.22
15	629.68	26.27	20.00	746.10	30.50	16.00	0.84	0.86
16	943.41	33.73	20.00	1024.16	44.47	16.00	0.92	0.76
17	41.47	1.49	24.00	341.34	12.37	14.00	0.12	0.12
20	939.16	36.75	20.00	1125.74	52.09	14.00	0.83	0.71
21	599.05	26.91	20.00	617.38	26.32	14.00	0.97	1.02
22	674.58	23.94	20.00	782.20	28.83	16.00	0.86	0.83
23	555.68	21.00	24.00	755.53	30.14	20.00	0.74	0.70
24	644.69	24.87	24.00	826.43	31.25	20.00	0.78	0.80
Mean	620.58	23.77	22.00	772.94	31.28	18.20	0.81	0.80
SD	236.47	8.13	4.21	259.24	11.96	3.89	0.25	0.28
CV	38.10	34.21	19.11	33.54	38.23	21.36	30.63	35.05
Geo	542.98	21.07	21.67	728.60	29.09	17.81	0.75	0.72
Mean
Min	41.47	1.49	16.00	341.34	12.37	12.00	0.12	0.12
Max	1066.70	38.97	36.00	1281.12	58.25	24.00	1.16	1.24
		Fed/Fasting Ratios (Including
		Subject #12 and#18 who
	Fed/Fasting Ratios	vomited during post-dose)
	Geo	LS		Geo	LS
	Means	Means %		Means	Means %
AUC	0.75	74.62	AUC	0.73	73.24
Cmax	0.72	72.23	Cmax	0.73	73.45

[0269] FIG. 22 illustrates the mean plasma M5 concentrations (ng/ml) over time after a single dose of one 200 mg Tramadol HCl ER Tablet formulated according to an embodiment of the present invention under fasting or fed conditions.

EXAMPLE 10

Tramadol ER Osteoarthritis Study

[0270] 10.1: Overall Study Design and Plan

[0271] A 12-week, multi-center double blind, randomized, dose-titration, parallel-group comparison of the efficacy and safety of Tramadol ER tablets and placebo in the treatment of osteoarthritis of the knee was conducted. Approximately 245 patients from 18 to 75 years of age with moderate to severe pain associated with Functional Class I-III osteoarthritis of the knee were planned for study enrollment to ensure that a minimum of 140 patients completed the study. After signing the informed consent, patients who met the inclusion and exclusion criteria at screening entered a 2 to 7 day washout period during which all analgesic use was discontinued. At the start of the first week of the study (Baseline, Visit 2), eligible patients who reported pain intensity ≧40 mm on a visual analog scale (VAS) in the index knee joint were randomly assigned to either Tramadol ER tablets or placebo.

[0272] Patients assigned to Tramadol ER tablets were initiated on 100 mg QD and maintained on their dose for at least 3 days. On Day 4, and for the remainder of the week (until their return to the clinic for Visit 3), patients were permitted to have their dose increased to 200 mg QD, based upon the tolerability of side effects. Beginning at Visit 3, patients must have been maintained on a minimum Tramadol ER tablet dose of 200 mg QD, and the dose titrated upwards if required based upon the adequacy of pain relief and tolerability of side effects. Patients randomized to the placebo group underwent sham dose increases. Further dose escalation and de-escalation was permitted provided that a minimum dose of 200 mg QD was maintained from Week 1 (Visit 3) to Week 12 (Visit 7). In patients with pain unresponsive to appropriate dosage adjustments, or with unacceptable side effects, treatment was discontinued and alternate analgesia therapy initiated, as appropriate. Patients returned for efficacy and safety evaluations at Week 1 (Visit 3), Week 2 (Visit 4), Week 4 (Visit 5), Week 8 (Visit 6) and Week 12 (Visit 7) or at Early Termination.

[0273] 10.2: Efficacy Variables

[0274] The primary measure of efficacy was the Arthritis Pain Intensity VAS (visual analog scale) Score from patient visits. The arthritis VAS is the most commonly used, validated tool to assess pain intensity and one recommended by FDA to evaluate the analgesic potential of a drug product.

[0275] Pain was also assessed as a secondary measure of efficacy using the WOMAC Osteoarthritis Index. The WOMAC is a validated, internationally recognized and widely used multidimensional instrument for assessing response to therapy in osteoarthritis. It assesses pain, joint stiffness and physical function, the three major bothersome symptoms in osteoarthritis. In addition, patients and physicians provided a Global assessment of disease and patients recorded their response on a sleep questionnaire as other secondary measures of efficacy.

[0276] 10.3: Results

[0277] A total of 246 patients were randomized and evaluable for safety. Of these, 219 were evaluable for the intent-to-treat (ITT) population. The ITT population included all safety evaluable patients who had primary efficacy information recorded at the baseline visit (Visit 2) and at the Week 1 visit (Visit 3), the first primary efficacy variable collection point on treatment. The ITT population also included all patients who dropped out before the Week 1 visit due to lack of treatment efficacy. The mean daily dose of Tramadol ER following the flexible dosing regimen was approximately 300 mg. The median age of patients who enrolled was 61 years and the median duration of osteoarthritis was 10 years.

[0278] Tramadol ER produced statistically significant and clinically meaningful reductions in pain intensity associated with osteoarthritis of the knee compared to placebo for the primary efficacy variable and all secondary variables evaluated.

[0279] 10.4: Response to Primary Variable

[0280] FIG. 23 compares the LS mean change from baseline in VAS score for Tramadol ER and placebo based upon the average of Weeks 1-12. On the primary endpoint (LS Mean change from baseline over 12 weeks), there was a 39.5% (30.4 mm) and 21.5% (17.7 mm) change from baseline in the arthritis pain intensity VAS in the Tramadol ER and placebo groups, respectively (LS Mean Difference 12.7 mm, p<0.001). FIG. 24 shows the weekly LS mean changes from baseline for the two treatment groups. Treatment differences emerged at the first return visit (Week 1) when patients were receiving either a 100 mg or 200 mg dose of Tramadol ER (change from baseline 24.8% [19.6 mm] vs. 14.0% [11.1 mm], LS mean difference 8.5 mm, p=0.003). At the end of the second week of treatment, the response to Tramadol ER increased relative to placebo (change from baseline 35.7% [27.4 mm] vs. 19.3% [15.7 mm], LS mean difference 11.7 mm, p<0.001). By Week 12, the response to Tramadol ER (LS mean change from baseline) was 48.6% [37.4 mm] while that for placebo was 27.0% [22.1 mm]. The LS Mean difference was 15.3 mm, p<0.001).

[0281] 10.5: Response on the Secondary Variables

[0282] FIG. 25 compares the LS mean changes from baseline to Week 12 for the Tramadol ER and placebo for each of the secondary variables.

[0283] 10.5.1: WOMAC Subscales

[0284] Results on the three dimensions of the WOMAC, namely pain, stiffness and physical function were similar to the main findings. Tramadol ER tablets was significantly better than placebo in improving pain, stiffness and physical function on the WOMAC.

[0285] At Week 12, on the WOMAC Pain Subscale, Tramadol ER was significantly different from placebo (change from baseline 44.6% [155.9 mm] vs. 24.8% [86.9 mm], LS mean difference on 0-100 mm Scale 13.8 mm, p<0.001).

[0286] At Week 12, on the WOMAC Stiffness Subscale, Tramadol ER was significantly different from placebo (change from baseline 43.4% [63.9 mm] vs. 18.1% [33.8 mm], LS mean difference on 0-100 mm Scale 15.0 mm, p<0.001).

[0287] At Week 12, on the WOMAC Physical Function Subscale, Tramadol ER was significantly different from placebo (change from baseline 43.8% [518.3 mm] vs. 21.3% [270.4 mm], LS mean difference on 0-100 mm Scale 14.6 mm, p<0.001).

[0288] At Week 12, on the WOMAC Composite Score, Tramadol ER was significantly different from placebo (change from baseline 42.2% [737.9 mm] vs. 22.8% [391.2 mm], LS mean difference on 0-100 mm Scale 14.4 mm, p<0.001).

[0289] 3.5.2: WOMAC Pain Walking on a Flat Surface

[0290] In the past, some studies have utilized one item from the WOMAC pain subscale as the primary endpoint. Since some of the questions on the WOMAC subscale relate to walking “up” or “down stairs” (and some areas of the country preferred by the elderly have few stairs, e.g., Arizona, New Mexico, Florida, etc), the WOMAC pain subscale question, “Pain Walking on a Flat Surface” is preferred by some biometricians.

[0291] At Week 12, on the WOMAC Pain Walking on Flat Surface, Tramadol ER was significantly different from placebo (change from baseline 40.9% [29.9 mm] vs. 15.7% [15.9 mm], LS Mean Difference 14 mm, p<0.001). This is also shown in FIG. 25.

[0292] 10.5.3: Patient Global Assessment of Osteoarthritis

[0293] At Week 12, on the Patient Global Assessment of Arthritis, Tramadol ER was significantly different from placebo (change from baseline 33.0% [33.2 mm] vs. 24.4% [18.5 mm], LS Mean Difference 14.7 mm, p<0.001).

[0294] 10.6: Safety Results

[0295] This was a placebo-controlled study without a positive control. Consequently, direct comparison with data on ULTRAM® product are not possible. However, indirect comparisons with the ULTRAM® product package insert are possible. Table 1 provides data on the cumulative incidence of adverse events on ULTRAM® in chronic non-malignant pain. The 90-day comparison is the most appropriate, given the 12 weeks duration of the present study. Adverse events were qualitatively similar. However, the incidence of the most commonly observed adverse events were generally lower for Tramadol ER after up to 90 days compared to only 7 days of treatment with ULTRAM®.

TABLE 26
Cumulative Incidence of Adverse Reactions for ULTRAM in
Chronic Trials of Nonmalignant Pain (N = 427). Data
on Tramadol HCl ER from the 12-Week OA Study (N = 124)
are Provided in Parenthesis for Comparison
	Up to	Up to	Up to
	7 Days	30 Days	90 Days
	Dizziness/Vertigo	26%	31%	33% (33%)
	Nausea	24%	34%	40% (24.2%)
	Constipation	24%	38%	46% (25.8%)
	Headache	18%	26%	32% (14.5%)
	Somnolence	16%	23%	25% (8.1%)
	Vomiting	9%	13%	17% (6.5%)
	Pruritus	8%	10%	11% (6.5%)
	“CNS Stimulation” 1	7%	11%	14% (TBD)
	Asthenia	6%	11%	12% (TBD)
	Sweating	6%	7%	9% (4%)
	Dyspepsia	5%	9%	13% (1.6%)
	Dry Mouth	5%	9%	10% (1.6%)
	Diarrhea	5%	6%	10% (9.7%)
	1 “CNS Stimulation” is a composite of nervousness, anxiety, agitation, tremor, spasticity, euphoria, emotional lability and hallucinations.

[0296] 10.7: Conclusion:

[0297] Tramadol ER produced statistically significant and clinically meaningful reductions in pain associated with osteoarthritis compared to placebo following a flexible dosing regimen in which the once-daily tablet formulation was titrated upward or downward over 12 weeks in doses of 200 mg, 300 mg or 400 mg based upon adequacy of pain relief and tolerability of side effects. The mean daily dose of Tramadol ER was estimated to be about 300 mg. The primary efficacy variable was pain relief as measured on a visual analog scale (VAS). Secondary measures of efficacy were the pain intensity, stiffness and physical function subscales of WOMAC Osteoarthritis Index, the Patient's and Physician's Global Assessment of Arthritis, patient withdrawal due to inadequate pain relief, and patient assessment of sleep.

[0298] At the end of the first week of treatment and at all subsequent weeks, Tramadol ER was statistically superior to placebo in reducing pain. The magnitude pain improvement (change from baseline) for the Tramadol ER cohort increased weekly throughout the 12 weeks of therapy (25% at Week 1 and 47% at Week 12). By Week 12, patient's treated with Tramadol reported a clinically important 15 mm difference in mean pain relief score compared to placebo. This difference was highly significant (p<0.001). Based upon the average of Weeks 1 through 12, the Tramadol ER treated patients achieved a highly statistically significant and clinically meaningful 14 mm difference in mean pain relief score compared to placebo (p<0.001). The results for the secondary variables paralleled those of the primary with all results statistically significant in favor or Tramadol ER.

[0299] The adverse events reported were qualitatively similar to that for Ultram. However, the incidence was generally lower for Tramadol ER than for that previously reported for ULTRAM®.

[0300] The results of this 12 week placebo controlled study demonstrate that Tramadol ER, when given at a dose of 200 to 400 mg QD, results in significant improvements in the cardinal symptoms of osteoarthritis, namely pain, stiffness and physical function. The safety profile of Tramadol ER is consistent with that for ULTRAM®, although the frequency of some adverse events appears to be lower than historical controls.

[0301] 10.8: Clinical Implications

[0302] In the present study, using conventional endpoints for evaluating efficacy, Tramadol ER demonstrated a 30.4 mm and 37.4 mm change from baseline in Arthritis Pain Intensity VAS, when expressed as a mean over 12 weeks (primary endpoint) and at the 12-Week time point, respectively. However, consistent with most such studies, the placebo treatment demonstrates a 17.7 mm and 22.1 mm change from baseline in Arthritis Pain Intensity VAS, when expressed as a mean over 12 weeks (primary endpoint) and at the 12-Week time point, respectively. Consequently, the actual treatment difference (response on Tramadol ER less response on placebo) is a 12.7 mm and 15.3 mm change from baseline in Arthritis Pain Intensity VAS, when expressed as a mean over 12 weeks (primary endpoint) and at the 12-Week time point, respectively.

[0303] A close examination of the time course and magnitude of the pharmacological response (on the primary and secondary variables) following treatment with Tramadol ER indicates that this is a clear drug effect: the magnitude of the response increases over time and all of the effects (pain, stiffness, physical function, patient global) are directionally consistent and generally of comparable size.

[0304] There are two available benchmarks for determining the robustness of the analgesic response to Tramadol ER in osteoarthritis. One approach involves using the perspectives from the academic rheumatology community. The other involves using the results of pivotal studies in osteoarthritis from recently approved and commercially successful drugs.

[0305] In a consensus development (3-round Delphi exercise) involving academic rheumatologists, a 15 mm treatment difference in patients overall assessment of pain was considered to be the minimum clinically important difference (MCID) for clinical trial purposes (Bellamy N, Carette S, Ford P M et al. Osteoarthritis Antirheumatic Drug Trials. II. Tables for calculating sample size for clinical trials. J Rheumatol 1992;19:444-50; Bellamy N, Carette S, Ford P M et al. Osteoarthritis Antirheumatic Drug Trials. Ill. Delta for Clinical Trials—Results of a Consensus Development (Delphi) Exercise. J Rheumatology 1992; 19:3, 451-457). However, in a recently published study, the minimum clinically perceptible improvement (MCPI) on the three dimensions of WOMAC pain, stiffness and physical function subscale scores (expressed using a 0-100 mm scale) were 9.7, 9.3 and 10 mm, respectively (Beaton D E, Bombardier C, Katz J et al. Looking for important change/difference in studies of responsiveness. J Rheumatol 2001 ;28;400-405.).

[0306] Data from other approved analgesics for which the NDA contained pivotal clinical trials in osteoarthritis were obtained under from the FDA under Freedom of Information (FOI). Although a direct comparison with other drugs is not possible and no drugs exist in the Tramadol class (combined serotonergic, noardrenergic and opioidergic effects), data on other analgesics provide a context for the results of the Tramadol ER study.

[0307] Rofecoxib (VIOXX®) is approved for the treatment of osteoarthritis at a daily dose of 12.5 mg; with the comment that some patients may derive a benefit from an increase in does to 25 mg per day (maximum dose). The efficacy studies with rofecoxib in osteoarthritis were 6 weeks in duration. The WOMAC variable “pain walking on a flat surface” was used as the primary endpoint. In most cases, the LS mean change from baseline over 6-weeks formed the basis of comparison. The mean difference between rofecoxib 12.5 mg and placebo was 14.3 mm (Study No. 029), 12.4 mm (Study No. 033),15.4 mm (Study No. 040) and 9.0 (Study No. 058). Similarly, the mean difference between the positive control and placebo was 13.5 mm (Ibuprofen, 2400 mg, Study No. 033), 14.6 mm (Ibuprofen, 2400 mg, Study No. 040) and 10 mm (Nabumetone [Relafen®], 1500 mg, Study No. 058).

[0308] Celecoxib (CELEBREX®) is approved for the treatment of osteoarthritis at a daily dose of 200 mg. Pivotal clinical trials were placebo controlled studies of either 6 or 12 weeks duration and used naproxen as the positive control. Study No. 020 and 054 served as pivotal clinical trials and Studies 040 and 087 were placebo controlled evaluations of celecoxib 100 mg BID vs. 200 mg QD. There were multiple primary endpoints in each of the studies, including Patients Assessment of Arthritis Pain VAS. The LS mean difference in pain VAS change from baseline between celecoxib 100 mg BID and placebo was 8.0 mm (12 weeks; Study No. 020), 12.2 mm (12 weeks; Study No. 054),13.9 mm (6 weeks; Celecoxib 100 mg BID; Study No. 040) and 13.1 mm (6 weeks; Celecoxib 200 mg QD; Study No. 040), 6.2 mm (6 weeks; Celecoxib 100 mg BID; Study No. 087) and 8.5 mm (6 weeks; Celecoxib 100 mg BID; Study No. 087). Similarly, the mean difference between the positive control and placebo was 7.6 mm (Naproxen 500 mg BID, Study No. 020) and 11.2 mm (Naproxen 500 mg BID, Study No. 054).

[0309] The results of the present study demonstrate that Tramadol ER at an approximate dose of 300 mg QD (range 200 to 400 mg) provides a robust analgesic response in OA. The magnitude of the response is at least equal, if not superior to that of NSAIDs and COX-2 inhibitors. With its advantage of once daily dosing, Tramadol ER will be an important addition to the therapeutic armamentarium of clinicians treating chronic pain.

EXAMPLE 11

[0310] A double-blind, placebo-controlled, parallel-group comparison of the efficacy and safety of 200 mg and 300 mg Tramadol HCl Extended-Release Tablets to placebo in the treatment of chronic low back pain was conducted.

[0311] 11.1: Study Overview

[0312] A multicenter, multiple-dose, randomized, placebo-controlled, parallel-group study involving a minimum of 360 patients designed to compare the analgesic efficacy and safety of extended release tramadol (Tramadol ER) 300 mg and 200 mg orally (PO) once-daily (QD) to placebo in patients with chronic low back pain.

[0313] 11.2: Subjects

[0314] Patients with chronic (≧6 months) low back pain requiring daily treatment with an analgesic.

[0315] 11.3: Design

[0316] An open-label run-in period followed by a double-blind, randomized, multiple-dose, placebo-controlled study. Patients may roll-over into an ongoing 1-year open-label extension study.

[0317] 11.4: Treatment Regimen:

[0318] A 3-week, open-label run-in period, including 2 weeks of dose titration on Tramadol ER, beginning with 100 mg, to attain a tolerable dose of 300 mg QD, followed by 1 week on a stable maintenance dose of Tramadol ER 300 mg QD. Following the run-in period, patients were randomized to one of the following double-blind treatments:

[0319] Tramadol ER 300 mg QD at 8:00 A.M.;

[0320] Tramadol ER 200 mg QD at 8:00 A.M.;

[0321] Placebo QD at 8:00 A.M.

[0322] 11.5: Enrollment Period

[0323] 5 months

[0324] 11.6: Treatment Period

[0325] At Screening (Visit 1), eligible patients underwent laboratory testing, and then entered a 2 to 7 day washout period during which all analgesic use was discontinued. At Visit 2 (Week-3), eligible patients who reported a pain intensity of ≧40 mm on a visual analog scale entered a 3-week, open-label run-in period. Patients were initiated on Tramadol ER 100 mg QD and maintained at their dose for at least 3 days. On Day 4, and for the remainder of the week (until their return to the clinic for Visit 3, Week-2), patients had their dose increased to 200 mg QD, based on the tolerability of side effects. Beginning at Visit 3 (Week-2), patients were maintained on a minimum Tramadol ER dose of 200 mg QD, and the dose titrated upwards (i.e. to 300 mg QD) based on the tolerability of side effects. Beginning at Visit 4 (Week-1), patients escalated their Tramadol ER dose to 300 mg QD and maintained that dose for 1 week. No further dose adjustments were permitted during the remainder of the run-in period. In patients with pain unresponsive to appropriate dosage adjustments, or with unacceptable side effects, treatment was discontinued and alternate analgesic therapy initiated, as appropriate. Eligible patients receiving Tramadol ER 300 mg QD at the end of the 3-week run-in period were entered into a 12-week, double-blind, randomized study. At Visit 5 (Week 0), patients were randomly assigned to receive Tramadol ER 300 mg QD, Tramadol ER 200 mg QD, or placebo QD. Study medication dosing occurred daily at 8:00 A.M. No dose adjustments were permitted in the double-blind period. Patients unable to tolerate the double-blind study medication and those with unacceptable pain control were dropped from the study. Patients returned for efficacy and safety evaluations at Week 1 (Visit 6), Week 2 (Visit 7), Week 4 (Visit 8), Week 8 (Visit 9), and Week 12 (Visit 10), or Early Termination. Study medication was discontinued at Visit 10 and patients were treated with nonopioid analgesics until they returned to the clinic after 1 week for a post-study medication visit (Visit 11, Week 13). Patients were contacted by telephone between Visit 10 and Visit 11 to ensure that they were not taking opioid analgesics, including tramadol. Visit 11 was scheduled earlier than 1 week after Visit 10, in the event that patient pain could not be managed with nonopioid analgesics, and intervention with opioid analgesics or tramadol was necessary. At Visit 11, patients completed assessments for physical dependence and adverse events.

[0326] 11.7: No. of Centers

[0327] 30 centers

[0328] 11.8: No. of Subjects

[0329] Approximately 600 patients were enrolled to provide a minimum of 360 patients (120 patients per treatment).

[0330] 11.9: Efficacy

[0331] At each visit, patients were asked to rate their current pain intensity and their pain intensity since their previous visit, using a visual analog scale (VAS), and they provided an overall global assessment of study medication. The primary efficacy measure was the patient's pain intensity VAS score since the previous visit. Secondary measures included the patient's current pain intensity, the patient's global assessment, the Roland Disability Index, the patient's assessment of sleep and premature study termination due to inefficacy.

[0332] 1 1.10: Safety

[0333] Safety was assessed at each visit by vital signs (heart rate, respiratory rate, supine or sifting and standing blood pressure) and a non-directed adverse events questionnaire. At Screening and at each visit, including Early Termination, patients were evaluated for the occurrence of syncope, orthostasis, dizziness, drop attacks and flushing (vasodilation). Adverse events were monitored throughout the study. Physical examination was performed at Screening (Visit 1) and at the Final Visit (Visit 11), or at Early Termination. Clinical laboratory testing was performed at Screening (Visit 1), at Week-3 (Visit 2), at Baseline (Week 0, Visit 5), at Week 1 (Visit 6), and at Week 12 (Visit 10) or Early Termination. In females of childbearing potential, serum pregnancy tests were performed at Screening (Visit 1), at Week-3 (Visit 2), at Baseline (Week 0, Visit 5), at Week 1 (Visit 6), at Week 4 (Visit 8), at Week 8 (Visit 9), and at Week 12 (Visit 10) or Early Termination. If the Screening (Visit 1) serum pregnancy results were not available from the central laboratory at the start of the run-in period (Visit 2), then the site obtained a urine pregnancy test locally. EKGs were performed at Screening (Visit 1), at Baseline (Week 0, Visit 5) and at Week 12 (Visit 10) or at Early Termination. The Addiction Research Center Inventory (ARCI) Short-form was completed by patients at each visit following the Screening Visit. The Physical Dependence Questionnaire was completed by patients at the start of the run-in period (Visit 2), at Week 12 (Visit 10), and at Week 13 (Visit 11) or at Early Termination.

EXAMPLE 12

[0334] A Two-Way, Crossover, Open-Label, Fasting, Single-Dose And Multiple-Dose Bioavailability Study Of Tramadol Hydrochloride Extended Release 200 mg Tablets (Once Daily) Versus Ultram® 50 mg Tablets (Four Times Daily) In Normal Healthy Non-Smoking Male And Female Subjects was conducted.

[0335] Objectives:

[0336] The objectives of this study were to determine the relative bioavailability of Tramadol HCl 200 mg Extended Release Tablets administered as a 200 mg dose (once daily) compared to Ultram® 50 mg Tablets administered as 50 mg (four times daily) under single-dose and steady-state conditions, and to investigate the extended release characteristics of the novel formulation.

[0337] Experimental Design:

[0338] A two-way, crossover, open-label, single-dose and multiple-dose, fasting design.

[0339] Subjects:

[0340] Thirty-six (36) normal, healthy, non-smoking male and female subjects.

[0341] Drug Administration:

[0342] Subjects received one of the following treatments, specific to the study dosing day, during each of the two (2) 12-day study periods, according to the dosage regimen in Appendix VI:

[0343] Treatment A: One (1) Tramadol HCl Extended Release 200 mg Tablet (Once Daily)

[0344] Treatment B: One (1) Ultram® 50 mg Tablet (Four Times Daily)

[0345] Day 1:

[0346] Treatment A (Once Daily):

[0347] One (1) Tramadol HCl Extended Release 200 mg Tablet at 0.0 hour with 240 mL of ambient temperature water following an overnight fast of at least ten (10) hours.

[0348] (Total dose=200 mg).

[0349] Treatment B (Four Times Daily):

[0350] One (1) Ultram® 50 mg Tablet at 0.0 hour with 240 mL of ambient temperature water following an overnight fast of at least ten (10) hours.

[0351] A second dose of one (1) Ultram® 50 mg tablet will be given at 6.0 hours with 240 mL of ambient temperature water after a fast of at least one (1) hour.

[0352] A third dose of one (1) Ultram® 50 mg tablet will be given at 12.0 hours with 240 mL of ambient temperature water after a fast of at least one (1) hour.

[0353] A fourth dose of one (1) Ultram® 50 mg tablet will be given at 18.0 hours with 240 mL of ambient temperature water after a fast of at least one (1) hour.

[0354] (Total daily dose=200 mg).

[0355] Day 2:

[0356] No drug administration.

[0357] Days 3-10:

[0358] Treatment A (Once Daily):

[0359] One (1) Tramadol HCl Extended Release 200 mg Tablet at 0.0 hour with 240 mL of ambient temperature water following an overnight fast of at least ten (10) hours.

[0360] (Total dose=200 mg).

[0361] Treatment B (Four Times Daily):

[0362] One (1) Ultram® 50 mg Tablet at 0.0 hour with 240 mL of ambient temperature water following an overnight fast of at least ten (10) hours.

[0363] A second dose of one (1) Ultram® 50 mg tablet will be given at 6.0 hours with 240 mL of ambient temperature water after a fast of at least one (1) hour.

[0364] A third dose of one (1) Ultram® 50 mg tablet will be given at 12.0 hours with 240 mL of ambient temperature water after a fast of at least one (1) hour.

[0365] A fourth dose of one (1) Ultram® 50 mg tablet will be given at 18.0 hours with 240 mL of ambient temperature water after a fast of at least one (1) hour.

[0366] (Total daily dose=200 mg).

[0367] Washout Period:

[0368] At least a two (2) week washout period between the last dose of Period I to the first dose of Period II.

[0369] Sample Collection:

[0370] Treatment A had a total of twenty-nine (29) blood samples (7 mL each) drawn in each period. Treatment B had a total of fifty-five (55) blood samples (7 mL each) drawn in each period for drug content analysis at the following times and relative to the 0.0 hour drug administration of each study dosing day, as follows:

[0371] Treatment A:

[0372] Days 1-3:

[0373] 0.0 (re-dose), 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0, 16.0, 20.0, 24.0 (Day 2), 36.0 and 48.0 (Day 3) hours post-drug administration.

[0374] Days 7, 8, 9:

[0375] 0.0 (pre-dose)

[0376] Day 10:

[0377] 0.0 (pre-dose), 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0, 16.0, 20.0 and 24.0 (Day 11) hours post-drug administration.

[0378] Treatment B:

[0379] Days 1-3:

[0380] 0.0 (pre-dose), 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 6.5, 7.0, 7.5, 8.0, 10.0, 12.0, 12.5, 13.0, 13.5, 14.0, 16.0, 18.0, 18.5, 19.0, 19.5, 20.0, 22.0, 24.0 (Day 2), 36.0 and 48.0 (Day 3) hours post-drug administration.

[0381] Days 7, 8, 9:

[0382] 0.0 (pre-dose). Pre-Dose samples not required for 6.0, 12.0 and 18.0 drug administration.

[0383] Day 10:

[0384] 0.0 (pre-dose), 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 6.5, 7.0, 7.5, 8.0, 10.0, 12.0, 12.5, 13.0, 13.5, 14.0, 16.0, 18.0, 18.5, 19.0, 19.5, 20.0, 22.0 and 24.0 (Day 11) hours post-drug administration.

[0385] All blood samples which coincide with drug administration were be drawn within 10 minutes prior to dosing.

[0386] There were no blood draws for drug content analysis on Days 4, 5, and 6.

[0387] Thirty-six subjects completed the study. Steady state plasma levels of all analytes were attained by Day 7 of dosing for each treatment. Both products demonstrated similar AUC for Tramadol under single dose (Ratio=90%; 90% C.I.=83-99%) and at steady state (Ratio=89%; 90% C.I.=84-94%). Tmax from T-ER was significantly longer (p<0.05). In conclusion, a novel once daily product, T-ER, was found to demonstrate similar AUC relative to Ultram® given four times daily. The plasma concentration vs time profile demonstrated prolonged systemic delivery of Tramadol. This product is suitable for once daily administration.

TABLE 27A
Mean (±SD) Plasma Concentration-Time Profiles
for Tramadol (ng/mL) (Single-Dose)
	TREATMENT A		TREATMENT B
SAMPLE TIME	1 × 200 mg		4 × 50 mg
(HOURS)	Mean Value	SD	Mean Value	SD
0.000	0.000 ± 0.000	0.000 ± 0.000
0.500	— ± —	39.661 ± 40.840
1.000	0.167 ± 0.659	114.496 ± 47.058
1.500	— ± —	132.150 ± 34.078
2.000	6.711 ± 4.128	132.958 ± 31.526
3.000	17.604 ± 8.289	— ± —
4.000	32.372 ± 15.414	102.362 ± 24.944
6.000	95.112 ± 73.170	81.425 ± 23.267
6.500	— ± —	85.634 ± 36.967
7.000	— ± —	113.144 ± 70.267
7.500	— ± —	140.204 ± 74.667
8.000	144.273 ± 85.625	158.469 ± 70.587
10.000	176.680 ± 78.128	172.499 ± 46.685
12.000	210.190 ± 75.483	131.122 ± 38.911
12.500	— ± —	137.865 ± 53.363
13.000	— ± —	166.699 ± 70.529
13.500	— ± —	181.891 ± 68.216
14.000	— ± —	203.898 ± 77.579
16.000	214.278 ± 92.105	184.824 ± 58.359
18.000	— ± —	154.686 ± 57.060
18.500	— ± —	150.269 ± 52.568
19.000	— ± —	182.943 ± 68.067
19.500	— ± —	205.774 ± 86.967
20.000	173.782 ± 82.192	205.561 ± 81.945
22.000	— ± —	198.821 ± 66.916
24.000	132.108 ± 64.445	156.779 ± 55.024
36.000	46.269 ± 28.195	35.899 ± 21.273
48.000	16.538 ± 11.611	10.854 ± 8.540
TREATMENT A: TRAMADOL HCl EXTENDED RELEASE TABLET, 1 × 200 mg, Martec. Lot #: 010704
TREATMENT B: ULTRAM ® TABLETS, 4 × 50 mg, Control #: 91P0789E

[0388]

TABLE 27B
Mean (±SD) Plasma Concentration-Time Profiles for
O-desmethyltramadol (M1) (ng/mL) (Single-Dose)
	TREATMENT A		TREATMENT B
SAMPLE TIME	1 × 200 mg		4 × 50 mg
(HOURS)	Mean Value	SD	Mean Value	SD
0.000	0.037 ± 0.206	0.112 ± 0.357
0.500	— ± —	11.053 ± 9.212
1.000	0.142 ± 0.639	27.751 ± 13.640
1.500	— ± —	35.973 ± 14.295
2.000	1.731 ± 1.809	40.539 ± 15.659
3.000	5.041 ± 2.820	— ± —
4.000	10.055 ± 5.107	40.038 ± 12.828
6.000	25.784 ± 19.323	35.316 ± 9.899
6.500	— ± —	34.500 ± 10.271
7.000	— ± —	38.802 ± 14.763
7.500	— ± —	46.329 ± 18.867
8.000	42.046 ± 26.865	50.819 ± 18.902
10.000	56.091 ± 29.637	60.828 ± 17.240
12.000	69.206 ± 28.447	53.430 ± 13.917
12.500	— ± —	53.748 ± 14.135
13.000	— ± —	58.758 ± 16.934
13.500	— ± —	62.088 ± 18.937
14.000	— ± —	67.873 ± 19.433
16.000	78.978 ± 27.318	68.941 ± 18.913
18.000	— ± —	63.529 ± 16.684
18.500	— ± —	62.565 ± 16.374
19.000	— ± —	69.658 ± 22.827
19.500	— ± —	74.614 ± 23.383
20.000	71.897 ± 23.204	77.648 ± 22.610
22.000	— ± —	80.164 ± 22.591
24.000	57.593 ± 18.702	72.071 ± 21.221
36.000	21.983 ± 9.678	20.144 ± 7.539
48.000	8.883 ± 4.982	6.728 ± 3.447

[0389] TREATMENT A: TRAMADOL HCl EXTENDED RELEASE TABLET, 1×200 mg, Martec. Lot #: 010704

[0390] TREATMENT B: ULTRAM® TABLETS, 4×50 mg, Control #: 91P0789E

TABLE 27C
Mean (±SD) Plasma Concentration-Time Profiles for
O,N-di-desmethyltramadol (M1) (ng/mL) (Single-Dose)
	TREATMENT A		TREATMENT B
SAMPLE TIME	1 × 200 mg		4 × 50 mg
(HOURS)	Mean Value	SD	Mean Value	SD
0.000	0.035 ± 0.198	0.000 ± 0.000
0.500	— ± —	3.098 ± 2.980
1.000	0.000 ± 0.000	7.527 ± 3.531
1.500	— ± —	9.681 ± 3.242
2.000	0.037 ± 0.209	11.296 ± 4.092
3.000	1.113 ± 0.926	— ± —
4.000	2.601 ± 1.299	12.490 ± 3.697
6.000	7.334 ± 4.693	12.705 ± 4.030
6.500	— ± —	12.164 ± 4.144
7.000	— ± —	13.729 ± 5.616
7.500	— ± —	15.904 ± 6.562
8.000	12.755 ± 7.109	17.113 ± 6.973
10.000	18.183 ± 8.743	20.775 ± 6.235
12.000	22.901 ± 9.137	20.422 ± 6.731
12.500	— ± —	20.205 ± 7.432
13.000	— ± —	21.781 ± 8.533
13.500	— ± —	22.008 ± 9.527
14.000	— ± —	24.100 ± 9.418
16.000	27.475 ± 9.428	25.002 ± 8.947
18.000	— ± —	24.097 ± 8.027
18.500	— ± —	23.184 ± 7.930
19.000	— ± —	25.554 ± 8.895
19.500	— ± —	26.620 ± 9.318
20.000	25.968 ± 9.122	28.049 ± 9.668
22.000	— ± —	29.282 ± 9.248
24.000	22.063 ± 8.843	26.052 ± 9.107
36.000	9.968 ± 5.073	9.631 ± 4.623
48.000	4.225 ± 2.774	3.387 ± 2.289
TREATMENT A: TRAMADOL HCl EXTENDED RELEASE TABLET, 1 × 200 mg, Martec. Lot #: 010704
TREATMENT B: ULTRAM ® TABLETS, 4 × 50 mg, Control #: 91P0789E

[0391]

TABLE 27D
Mean (±SD) Plasma Concentration-Time Profiles
for Tramadol (ng/mL) (Multiple-Dose)
	TREATMENT A	TREATMENT B
SAMPLE TIME	1 × 200 mg	4 × 50 mg
(HOURS)	Mean Value	SD	Mean Value	SD
Day 7	172.260 ± 86.654	222.253 ± 74.822
Day 8	165.631 ± 89.639	208.205 ± 69.644
Day 9	178.611 ± 70.424	208.345 ± 67.377
(DAY 10	181.080 ± 75.681	217.318 ± 73.031
0.0
0.5	— ± —	239.237 ± 81.718
1.0	169.850 ± 76.343	305.008 ± 82.624
1.5	— ± —	324.188 ± 79.985
2.0	168.811 ± 73.497	322.966 ± 79.327
3.0	176.662 ± 77.092	— ± —
4.0	185.678 ± 76.516	278.551 ± 83.145
6.0	244.557 ± 100.530	227.146 ± 74.007
6.5	— ± —	250.215 ± 69.072
7.0	— ± —	295.069 ± 72.288
7.5	— ± —	309.479 ± 81.004
8.0	291.578 ± 117.818	317.119 ± 87.116
10.0	311.004 ± 107.742	294.493 ± 94.117
12.0	311.222 ± 103.406	228.819 ± 75.602
12.5	— ± —	240.710 ± 88.065
13.0	— ± —	272.966 ± 109.605
13.5	— ± —	286.259 ± 113.756
14.0	— ± —	303.417 ± 107.971
16.0	290.068 ± 98.332	269.550 ± 90.764
18.0	— ± —	220.034 ± 77.524
18.5	— ± —	230.974 ± 78.174
19.0	— ± —	298.965 ± 97.855
19.5	— ± —	317.634 ± 86.238
20.0	232.071 ± 83.494	314.616 ± 86.295
22.0	— ± —	270.906 ± 82.463
24.0	186.538 ± 69.511	227.680 ± 72.362
TREATMENT A: TRAMADOL HCl EXTENDED RELEASE TABLET, 1 × 200 mg, Martec. Lot #: 010704
TREATMENT B: ULTRAM ® TABLETS, 4 × 50 mg, Control #: 91P0789E

[0392]

TABLE 27E
Mean (±SD) Plasma Concentration-Time Profiles for
O-desmethyltramadol (M1) (ng/mL) (Multiple- Dose)
	TREATMENT A		TREATMENT B
SAMPLE TIME	1 × 200 mg		4 × 50 mg
(HOURS)	Mean Value	SD	Mean Value	SD
Day 7	64.165 ± 23.744	81.109 ± 22.933
Day 8	64.118 ± 27.384	80.275 ± 22.049
Day 9	70.204 ± 20.574	80.300 ± 21.690
(DAY 10	66.667 ± 20.879	77.732 ± 21.598
0.0
0.5	— ± —	81.556 ± 19.798
1.0	62.713 ± 19.753	90.092 ± 19.924
1.5	— ± —	93.349 ± 19.781
2.0	61.044 ± 19.222	94.693 ± 20.198
3.0	61.783 ± 19.580	— ± —
4.0	62.575 ± 19.225	90.586 ± 22.032
6.0	70.432 ± 19.820	80.339 ± 20.357
6.5	— ± —	83.446 ± 22.673
7.0	— ± —	89.370 ± 25.446
7.5	— ± —	88.847 ± 25.183
8.0	80.975 ± 23.261	91.298 ± 25.550
10.0	87.936 ± 24.747	92.109 ± 24.126
12.0	89.795 ± 23.229	79.121 ± 24.414
12.5	— ± —	79.632 ± 25.149
13.0	— ± —	82.772 ± 28.524
13.5	— ± —	85.220 ± 29.459
14.0	— ± —	86.631 ± 28.178
16.0	90.703 ± 23.351	84.720 ± 25.744
18.0	— ± —	77.673 ± 23.522
18.5	— ± —	79.629 ± 24.830
19.0	— ± —	90.084 ± 26.437
19.5	— ± —	94.817 ± 24.915
20.0	81.932 ± 21.785	96.805 ± 25.489
22.0	— ± —	90.633 ± 23.673
24.0	69.142 ± 20.703	81.981 ± 22.364
TREATMENT A: TRAMADOL HCl EXTENDED RELEASE TABLET, 1 × 200 mg, Martec. Lot #: 010704
TREATMENT B: ULTRAM ® TABLETS, 4 × 50 mg, Control #: 91P0789E

[0393]

TABLE 27F
Mean (±SD) Plasma Concentration-Time Profiles for
O,N-di-desmethyltramadol (M1) (ng/mL) (Multiple-Dose)
	TREATMENT A		TREATMENT B
SAMPLE TIME	1 × 200 mg		4 × 50 mg
(HOURS)	Mean Value	SD	Mean Value	SD
Day 7	35.089 ± 14.474	42.440 ± 12.849
Day 8	31.976 ± 13.547	38.980 ± 12.616
Day 9	34.426 ± 14.884	39.204 ± 12.311
(DAY 10	36.667 ± 15.036	41.238 ± 14.662
0.0
0.5	— ± —	42.378 ± 13.491
1.0	33.625 ± 13.860	44.544 ± 13.517
1.5	— ± —	45.317 ± 14.018
2.0	32.958 ± 13.611	45.891 ± 13.966
3.0	32.519 ± 12.585	— ± —
4.0	32.455 ± 12.388	45.654 ± 14.599
6.0	35.541 ± 13.014	42.998 ± 13.319
6.5	— ± —	44.058 ± 14.122
7.0	— ± —	45.558 ± 14.828
7.5	— ± —	44.926 ± 15.465
8.0	39.531 ± 13.868	45.444 ± 14.043
10.0	44.265 ± 15.256	47.752 ± 13.720
12.0	44.814 ± 15.160	42.781 ± 14.071
12.5	— ± —	43.175 ± 14.871
13.0	— ± —	43.881 ± 15.852
13.5	— ± —	44.448 ± 15.400
14.0	— ± —	45.590 ± 15.522
16.0	46.887 ± 15.866	44.679 ± 15.591
18.0	— ± —	42.633 ± 14.258
18.5	— ± —	42.781 ± 14.482
19.0	— ± —	45.742 ± 14.501
19.5	— ± —	47.028 ± 14.852
20.0	45.335 ± 17.055	47.271 ± 14.722
22.0	— ± —	45.744 ± 15.384
24.0	38.305 ± 17.317	43.580 ± 15.859

[0394] TREATMENT A: TRAMADOL HC1 EXTENDED RELEASE TABLET, 1×200 mg, Martec. Lot #: 010704

[0395] TREATMENT B: ULTRAM® TABLETS, 4×50 mg, Control #: 91P0789E

TABLE 27G
Pharmacokinetic Parameters for Tramadol Single-Dose
	Tramadol HCl 200 mg
	Extended Release	Ultram ® 50 mg
	Tablets (A)	Tablets (B)
Pharmacokinetic	n = 32	n = 32
Parameter	Mean ± SD	Mean ± SD
AUC0-t (ng · hr/mL)	4792.17 ± 2017.83	5095.20 ± 1595.42
AUC0-inf (ng · hr/mL)	4999.94 ± 2139.00	5174.38 ± 1687.68
Cmax (ng/mL)	234.23 ± 90.43	257.98 ± 69.04
Tmax (hour)	13.57 ± 3.76	2.22 ± 1.36
t1/2 (hour)	7.66 ± 1.76	5.76 ± 1.15
Kel (hour−1)	0.096 ± 0.024	0.125 ± 0.025
MRT (hours)	2.22 ± 1.47	1.03 ± 0.69

[0396]

TABLE 27H
Pharmacokinetic Parameters for Tramadol Multiple-Dose
	Tramadol HCl 200 mg
	Extended Release	Ultram ® 50 mg
	Tablets (A)	Tablets (B)
Pharmacokinetic	n = 32	n = 32
Parameter	Mean ± SD	Mean ± SD
AUCτ (ng · hr/mL)	5975.03 ± 2027.42	6612.66 ± 1790.04
Cmax (ng/mL)	335.44 ± 116.11	382.49 ± 79.86
Cmin (ng/mL)	186.54 ± 69.51	227.68 ± 72.36
Tmax (hour)	11.88 ± 3.17	1.49 ± 0.63
Degree of Fluctuation (%)	61.03 ± 34.51	59.36 ± 20.77
Degree of Swing (%)	103.76 ± 103.14	76.30 ± 34.17
Cavg (ng/mL)	248.96 ± 84.48	275.53 ± 74.59

[0397]

TABLE 27I
Pharmacokinetic Parameters for O-desmethyltramadol
(M1) Single-Dose
	Tramadol Hcl 200 mg
	Extended Release	Ultram ® 50 mg
	Tablets (A)	Tablets (B)
Pharmacokinetic	n = 32	n = 32
Parameter	Mean ± SD	Mean ± SD
AUC0-t (ng · hr/mL)	1856.01 ± 596.66	2063.81 ± 501.78
AUC0-inf (ng · hr/mL)	1984.59 ± 636.68	2168.12 ± 527.97
Cmax (ng/mL)	83.42 ± 27.52	88.79 ± 21.21
Tmax (hour)	15.57 ± 3.16	2.97 ± 1.57
t1/2 (hour)	8.95 ± 2.20	6.90 ± 1.22
Kel (hour−1)	0.082 ± 0.022	0.104 ± 0.020
MRT (hours)	3.91 ± 2.70	1.85 ± 1.10
M/P ratio	0.4747 ± 0.2121	0.4901 ± 0.2056

[0398]

TABLE 27J
Pharmacokinetic Parameters for O-desmethyltramadol
(M1) Multiple-Dose
	Tramadol HCl 200 mg
	Extended Release	Ultram ® 50 mg
	Tablets (A)	Tablets (B)
Pharmacokinetic	n = 32	n = 32
Parameter	Mean ± SD	Mean ± SD
AUCτ (ng · hr/mL)	1889.96 ± 481.47	2095.37 ± 539.58
Cmax (ng/mL)	95.44 ± 23.09	104.35 ± 24.57
Cmin (ng/mL)	69.14 ± 20.70	81.98 ± 22.36
Tmax (hour)	14.63 ± 3.92	1.94 ± 1.10
Degree of Fluctuation (%)	33.50 ± 24.21	26.10 ± 12.23
Degree of Swing (%)	45.56 ± 46.27	30.03 ± 20.41
Cavg (ng/mL)	78.75 ± 20.06	87.31 ± 22.48
M/P ratio	0.3610 ± 0.1192	0.3510 ± 0.1041

[0399]

TABLE 27K
Pharmacokinetic Parameters for O,N-di-desmethyltramadol
(M5) Single-Dose
	Tramadol HCl 200 mg
	Extended Release	Ultram ® 50 mg
	Tablets (A)	Tablets (B)
Pharmacokinetic	n = 32	n = 32
Parameter	Mean ± SD	Mean ± SD
AUC0-t (ng · hr/mL)	684.84 ± 244.04	765.01 ± 239.00
AUC0-inf (ng · hr/mL)	757.34 ± 282.87	804.97 ± 264.89
Cmax (ng/mL)	29.00 ± 9.09	31.03 ± 9.03
Tmax (hour)	16.82 ± 3.44	2.92 ± 1.48
t1/2 (hour)	10.07 ± 2.48	8.24 ± 2.07
Kel (hour−1)	0.074 ± 0.021	0.089 ± 0.021
MRT (hours)	5.53 ± 3.43	3.42 ± 2.49
M/P ratio (based on	0.1901 ± 0.0771	0.1926 ± 0.0712
AUC0-inf)

[0400]

TABLE 27L
Pharmacokinetic Parameters for O,N-di-desmethyltramadol
(M5) Multiple-Dose
	Tramadol HCl 200 mg
	Extended Release	Ultram ® 50 mg
	Tablets (A)	Tablets (B)
Pharmacokinetic	n = 32	n = 32
Parameter	Mean ± SD	Mean ± SD
AUCτ (ng · hr/mL)	984.90 ± 345.84	1078.57 ± 341.59
Cmax (ng/mL)	49.74 ± 16.87	51.13 ± 15.15
Cmin (ng/mL)	38.31 ± 17.32	43.58 ± 15.86
Tmax (hour)	16.69 ± 3.50	2.89 ± 1.41
Degree of Fluctuation (%)	30.43 ± 21.23	18.40 ± 10.52
Degree of Swing (%)	38.59 ± 35.35	19.82 ± 12.08
Cavg (ng/mL)	41.04 ± 14.41	44.94 ± 14.23
M/P ratio	0.1998 ± 0.0758	0.1944 ± 0.0708

[0401]

TABLE 27M
Relative Bioavailability Analysis of Tramadol HCl 200
mg Extended Release Tablets (A) versus Ultram ® 50
mg Tablets (B) for Tramadol Single-Dose
	TRAMADOL
Parameter	90% C.I.	Ratio of Means	Intra-Subject CV
AUC0-t	82.69%-98.46%	90.23%	20.56%
AUC0-inf	83.28%-99.46%	91.01%	20.56%
Cmax	81.21%-95.84%	88.23%	19.52%

[0402]

TABLE 27N
Relative Bioavailability Analysis of Tramadol HCl 200
mg Extended Release Tablets (A) versus Ultram ® 50
mg Tablets (B) for Tramadol Multiple-Dose
	TRAMADOL
Parameter	90% C.I.	Ratio of Means	Intra-Subject CV
AUCτ	83.97%-93.75%	88.73%	12.98%
Cmax	78.63%-91.63%	84.88%	18.02%

[0403]

TABLE 27O
Relative Bioavailability Analysis of Tramadol HCl 200 mg
Extended Release Tablets (A) versus Ultram ® 50
mg Tablets (B) for O-Desmethyltramadol (M1) Single-Dose
	O-DESMETHYLTRAMADOL (M1)
Parameter	90% C.I.	Ratio of Means	Intra-Subject CV
AUC0-t	79.19%-94.98%	86.73%	21.42%
AUC0-inf	80.03%-98.87%	88.95%	23.19%
Cmax	83.50%-98.17%	90.54%	19.07%

[0404]

TABLE 27P
Relative Bioavailability Analysis of Tramadol HCl 200 mg
Extended Release Tablets (A) versus Ultram ® 50
mg Tablets (B) for O-Desmethyltramadol (M1) Multiple-Dose
	O-DESMETHYLTRAMADOL (M1)
Parameter	90% C.I.	Ratio of Means	Intra-Subject CV
AUCτ	85.18%-95.85%	90.35%	13.90%
Cmax	85.05%-97.75%	91.18%	16.40%

[0405]

TABLE 27Q
Relative Bioavailability Analysis of Tramadol HCl 200 mg Extended
Release Tablets (A) versus Ultram ® 50 mg Tablets
(B) for O,N-di-Desmethyltramadol (M5) Single-Dose
	O,N-DI-DESMETHYLTRAMADOL (M5)
Parameter	90% C.I.	Ratio of Means	Intra-Subject CV
AUC0-t	78.52%-95.44%	86.56%	23.00%
AUC0-inf	81.19%-100.64%	90.39%	23.87%
Cmax	83.11%-100.02%	91.17%	21.83%

[0406]

TABLE 27R
Relative Bioavailability Analysis of Tramadol HCl 200 mg Extended
Release Tablets (A) versus Ultram ® 50 mg Tablets
(B) for O,N-di-Desmethyltramadol (M5) Multiple-Dose
	O,N-DI-DESMETHYLTRAMADOL (M5)
Parameter	90% C.I.	Ratio of Means	Intra-Subject CV
AUCτ	85.55%-95.76%	90.51%	13.28%
Cmax	90.28%-102.31%	96.10%	14.74%

EXAMPLE 13

[0407] A Three-Treatment, Open-Label, Multiple-Dose, Fasting, Dose-Escalation Study of Tramadol Hydrochloride Extended Release Tablets (100 mg, 200 mg And 400 mg Doses) Given Once Daily In Normal Healthy Non-Smoking Male And Female Subjects was conducted.

[0408] Objectives:

[0409] The objective of this study was to investigate the dose-proportionality of tramadol over the 100 mg-400 mg dose range for Biovail Corporation's novel formulation of Tramadol HCl 100 mg Extended Release Tablets, given once daily under multiple-dose, fasting conditions.

[0410] Experimental Design:

[0411] A three-treatment, open-label, multiple-dose, dose-escalation, fasting design.

[0412] Subjects:

[0413] Thirty (30) normal, healthy, non-smoking male and female subjects.

[0414] Drug Administration:

[0415] Subjects received the following treatments at 0.0 hour, (once daily), specific to each study Dosing Day during the one (1) study period.

[0416] Treatment A: Tramadol HCl Extended Release 1×100 mg Tablet (Days 1 to 6).

[0417] Treatment B: Tramadol HCl Extended Release 1×200 mg Tablet (Days 7 to 12).

[0418] Treatment C: Tramadol HCl Extended Release 2×200 mg Tablets (Days 13 to 18).

[0419] Days 1 to 6—Treatment A:

[0420] One (1) Tramadol HCl Extended Release 100 mg Tablet at 0.0 hour with 240 mL of ambient temperature water following an overnight fast of at least ten (10) hours.

[0421] (Total Daily Dose=100 mg).

[0422] Days 7 to 12—Treatment B:

[0423] One (1) Tramadol HCl Extended Release 200 mg Tablet at 0.0 hour with 240 mL of ambient temperature water following an overnight fast of at least ten (10) hours.

[0424] (Total Daily Dose=200 mg).

[0425] Days 13 to 18—Treatment C:

[0426] Two (2) Tramadol HCl Extended Release 200 mg Tablets at 0.0 hour with 240 mL of ambient temperature water after an overnight fast of at least ten (10) hours.

[0427] (Total Daily Dose=400 mg).

[0428] Washout Period:

[0429] Not applicable. Subjects were confined for the entire 20-day study period.

[0430] Sample Collection:

[0431] Fifty-two (52) blood samples (10 mL each) were be drawn for the entire study period for drug content analysis relative to the 0.0 hour drug administration at the following times:

[0432] Day 1: 0.0 hour (pre-dose)

[0433] Day 2: No blood samples

[0434] Day 3, 4, 5: 0.0 hour (pre-dose)

[0435] Day 6: 0.0 (pre-dose), 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, 12.0, 14.0, 16.0 and 20.0 hours post-0.0 hour drug administration

[0436] Day 7: 24.0 hours after 0.0-hour drug administration of Day 6

[0437] Day 8: No blood samples

[0438] Days 9, 10, 11: 0.0 hour (pre-dose)

[0439] Day 12: 0.0 (pre-dose), 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, 12.0, 14.0, 16.0 and 20.0 hours post-0.0 hour drug administration

[0440] Day 13: 24.0 hours after 0.0-hour drug administration of Day 12

[0441] Day 14: No blood samples

[0442] Days 15, 16, 17: 0.0 hour (pre-dose)

[0443] Day 18: 0.0 (pre-dose), 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, 12.0, 14.0, 16.0 and 20.0 hours post-0.0 hour drug administration

[0444] Day 19: 24.0 hours after 0.0-hour drug administration of Day 18

[0445] All blood samples which coincided with drug administration were drawn within 10 minutes prior to dosing.

[0446] The “Days” referred to in the above section are “Treatment Days” as opposed to “Calendar Days”.

[0447] The Treatment Day started at the time of each 0.0 hour drug administration. Twenty-five subjects completed the study. Steady state was achieved by Day 3 of dosing for all doses studied. Within the dose range of 100 mg to 400 mg, tramadol Cmax, Cmin and AUC0-τ ranged from 179.24 ng/mL - 910.05 ng/mL, 73.84 ng/mL-438.70 ng/mL, and 2778.41 hr*ng/mL-15212.75 hr*ng/mL, respectively. For all analytes, Cmax, and AUC0-τ increased linearly with increasing doses (R2>0.85), while Tmax did not differ significantly among doses. In conclusion, linear pharmacokinetics of tramadol and its metabolites were observed with the administration of T-ER within the investigated dose range of 100 mg to 400 mg.

TABLE 28A
Mean (±SD) Plasma Concentration-Time Profiles for Tramadol
(ng/mL) Mean Plasma TRAMADOL Concentrations (ng/mL)
	TREATMENT A	TREATMENT B	TREATMENT C
SAMPLE TIME	1 × 100 mg	1 × 200 mg	2 × 200 mg
(DAY & HOURS)	Mean Value	SD	Mean Value	SD	Mean Value	SD
Day 1	0.000 ± 0.000	ND ± ND	ND ± ND
Day 3	63.926 ± 45.807	141.248 ± 66.083	396.043 ± 175.679
Day 4	75.826 ± 40.715	169.240 ± 87.832	437.835 ± 187.946
Day 5	73.139 ± 41.564	166.284 ± 79.160	477.906 ± 228.788
0.00	74.128 ± 36.540	175.916 ± 87.745	430.698 ± 203.442
1.00	68.521 ± 33.278	163.362 ± 83.751	405.745 ± 193.451
2.00	68.194 ± 34.949	163.204 ± 85.311	390.998 ± 185.584
3.00	70.866 ± 36.217	171.674 ± 88.248	416.134 ± 190.845
4.00	81.087 ± 41.819	187.108 ± 91.527	453.308 ± 200.774
5.00	103.448 ± 52.495	236.551 ± 110.006	543.522 ± 236.038
6.00	112.255 ± 63.429	254.467 ± 133.270	614.884 ± 255.501
8.00	145.486 ± 71.863	295.138 ± 177.216	733.924 ± 310.137
10.00	162.731 ± 65.861	340.792 ± 189.825	789.231 ± 290.949
12.00	156.023 ± 54.938	364.161 ± 156.391	835.051 ± 312.331
14.00	157.853 ± 59.931	372.045 ± 152.390	848.514 ± 297.779
16.00	133.296 ± 54.713	319.281 ± 138.002	740.597 ± 278.615
20.00	97.272 ± 43.901	233.513 ± 95.802	588.186 ± 245.444
24.00	73.843 ± 42.634	168.584 ± 72.580	438.695 ± 213.201
ND = No Data
TREATMENT A: TRAMADOL HCl EXTENDED RELEASE TABLET, 100 mg. Lot # 010206
TREATMENT B: TRAMADOL HCl EXTENDED RELEASE TABLET, 200 mg, Lot # 010704
TREATMENT C: TRAMADOL HCl EXTENDED RELEASE TABLETS, 2 × 200 mg, Lot # 010704

[0448]

TABLE 28B
Mean (±SD) Plasma Concentration-Time Profiles for O-Desmethyltramadol
(M1) (ng/mL) Mean Plasma O-DESMETHYLTRAMADOL Concentrations (ng/mL)
	TREATMENT A	TREATMENT B	TREATMENT C
SAMPLE TIME	1 × 100 mg	1 × 200 mg	2 × 200 mg
(DAY & HOURS)	Mean Value	SD	Mean Value	SD	Mean Value	SD
Day 1	0.000 ± 0.000	ND ± ND	ND ± ND
Day 3	26.516 ± 10.390	52.815 ± 17.983	115.649 ± 37.750
Day 4	29.056 ± 8.917	56.595 ± 25.362	115.547 ± 33.011
Day 5	29.139 ± 10.952	56.077 ± 20.859	122.361 ± 41.044
0.00	28.773 ± 8.524	57.516 ± 21.407	113.312 ± 38.296
1.00	26.845 ± 8.062	53.918 ± 20.241	108.733 ± 39.405
2.00	25.654 ± 7.869	51.821 ± 19.008	101.652 ± 36.696
3.00	25.255 ± 7.943	51.812 ± 18.567	103.915 ± 37.701
4.00	26.921 ± 8.324	54.077 ± 19.696	107.460 ± 39.010
5.00	30.337 ± 9.433	59.949 ± 20.636	113.205 ± 34.186
6.00	30.788 ± 9.515	62.006 ± 21.209	122.902 ± 38.384
8.00	37.764 ± 10.913	68.038 ± 27.448	138.077 ± 43.086
10.00	44.136 ± 12.527	76.477 ± 30.728	148.722 ± 44.515
12.00	42.521 ± 11.377	81.970 ± 31.776	153.975 ± 46.779
14.00	44.707 ± 11.479	86.644 ± 33.491	163.923 ± 52.479
16.00	41.353 ± 11.488	82.636 ± 33.655	153.983 ± 47.657
20.00	33.732 ± 10.466	66.544 ± 23.300	131.849 ± 43.884
24.00	26.954 ± 10.713	53.423 ± 19.003	107.232 ± 39.879
TREATMENT A: TRAMADOL HCl EXTENDED RELEASE TABLET, 100 mg. Lot # 010206
TREATMENT B: TRAMADOL HCl EXTENDED RELEASE TABLET, 200 mg, Lot # 010704
TREATMENT C: TRAMADOL HCl EXTENDED RELEASE TABLETS, 2 × 200 mg, Lot # 010704

[0449]

TABLE 28C
Mean (±SD) Plasma Concentration-Time Profiles for O,N-Di-Desmethyltramadol
(M5) (ng/mL) Mean Plasma O,N-di-DESMETHYLTRAMADOL Concentrations (ng/mL)
	TREATMENT A	TREATMENT B	TREATMENT C
SAMPLE TIME	1 × 100 mg	1 × 200 mg	2 × 200 mg
(DAY & HOURS)	Mean Value	SD	Mean Value	SD	Mean Value	SD
Day 1	0.000 ± 0.000	ND ± ND	ND ± ND
Day 3	10.757 ± 5.068	26.523 ± 10.271	67.814 ± 20.900
Day 4	12.955 ± 4.787	30.241 ± 13.316	74.874 ± 21.311
Day 5	13.510 ± 5.582	31.326 ± 11.601	80.068 ± 26.097
0.00	13.689 ± 5.158	32.873 ± 12.450	80.708 ± 26.820
1.00	12.869 ± 4.670	30.384 ± 11.541	75.860 ± 26.041
2.00	12.156 ± 4.498	29.290 ± 10.938	72.371 ± 24.547
3.00	11.722 ± 4.031	28.836 ± 10.691	72.605 ± 26.205
4.00	12.273 ± 3.938	28.919 ± 10.603	72.155 ± 25.176
5.00	13.276 ± 4.321	30.832 ± 10.362	73.872 ± 23.095
6.00	13.550 ± 4.445	32.396 ± 11.466	75.743 ± 24.242
8.00	16.066 ± 4.904	34.301 ± 13.155	80.791 ± 23.099
10.00	19.062 ± 5.577	38.951 ± 14.763	87.193 ± 24.138
12.00	19.061 ± 5.141	41.394 ± 15.960	91.068 ± 25.275
14.00	20.147 ± 5.199	44.586 ± 16.952	95.843 ± 27.591
16.00	19.325 ± 4.624	45.079 ± 17.894	94.608 ± 26.571
20.00	16.486 ± 4.510	39.116 ± 14.174	87.653 ± 27.320
24.00	13.452 ± 4.882	32.661 ± 12.159	78.518 ± 27.409
TREATMENT A: TRAMADOL HCl EXTENDED RELEASE TABLET, 100 mg, Lot # 010206
TREATMENT B: TRAMADOL HCl EXTENDED RELEASE TABLET, 200 mg, Lot # 010704
TREATMENT C: TRAMADOL HCl EXTENDED RELEASE TABLETS, 2 × 200 mg, Lot # 0107040 mg, Lot # 010704

[0450]

TABLE 28D
Mean (±SD) Plasma Concentration-Time Profiles for Tramadol (ng/mL)(With Dose-Corrected Data)
Mean Plasma TRAMADOL Concentrations (ng/mL) Dose-corrected to 1 × 100 mg strength
	TREATMENT A	TREATMENT B	TREATMENT C
SAMPLE TIME	1 × 100 mg	1 × 200 mg	2 × 200 mg
(HOURS)	Mean Value	SD	Mean Value	SD	Mean Value	SD
Day 1	0.000 ± 0.000	ND ± ND	ND ± ND
Day 3	63.926 ± 45.807	70.624 ± 33.041	99.011 ± 43.920
Day 4	75.826 ± 40.715	84.620 ± 43.916	109.459 ± 46.986
Day 5	73.139 ± 41.564	83.142 ± 39.580	119.476 ± 57.197
0.00	74.128 ± 36.540	87.958 ± 43.873	107.674 ± 50.861
1.00	68.521 ± 33.278	81.681 ± 41.875	101.436 ± 48.363
2.00	68.194 ± 34.949	81.602 ± 42.655	97.749 ± 46.396
3.00	70.866 ± 36.217	85.837 ± 44.124	104.033 ± 47.711
4.00	81.087 ± 41.819	93.554 ± 45.764	113.327 ± 50.194
5.00	103.448 ± 52.495	118.275 ± 55.003	135.880 ± 59.010
6.00	112.255 ± 63.429	127.234 ± 66.635	153.721 ± 63.875
8.00	145.486 ± 71.863	147.569 ± 88.608	183.481 ± 77.534
10.00	162.731 ± 65.861	170.396 ± 94.913	197.308 ± 72.737
12.00	156.023 ± 54.938	182.080 ± 78.196	208.763 ± 78.083
14.00	157.853 ± 59.931	186.023 ± 76.195	212.128 ± 74.445
16.00	133.296 ± 54.713	159.641 ± 69.001	185.149 ± 69.654
20.00	97.272 ± 43.901	116.757 ± 47.901	147.047 ± 61.361
24.00	73.843 ± 42.634	84.292 ± 36.290	109.674 ± 53.300
ND = No Data
TREATMENT A: TRAMADOL HCl EXTENDED RELEASE TABLET, 100 mg, Lot # 010206
TREATMENT B: TRAMADOL HCl EXTENDED RELEASE TABLET, 200 mg, Lot # 010704
TREATMENT C: TRAMADOL HCl EXTENDED RELEASE TABLETS, 2 × 200 mg, Lot # 010704

[0451]

TABLE 28E
Mean (±SD) Plasma Concentration-Time Profiles for O-Desmethyltramadol
(M1) (ng/mL) (With Dose-Corrected Data) Mean Plasma O-DESMETHYLTRAMADOL
Concentrations (ng/mL) Dose-corrected to 1 × 100 mg strength
	TREATMENT A	TREATMENT B	TREATMENT C
SAMPLE TIME	1 × 100 mg	1 × 200 mg	2 × 200 mg
(DAY & HOURS)	Mean Value	SD	Mean Value	SD	Mean Value	SD
Day 1	0.000 ± 0.000	ND ± ND	ND ± ND
Day 3	26.516 ± 10.390	26.408 ± 8.991	28.912 ± 9.437
Day 4	29.056 ± 8.917	28.298 ± 12.681	28.887 ± 8.253
Day 5	29.139 ± 10.952	28.038 ± 10.430	30.590 ± 10.261
0.00	28.773 ± 8.524	28.758 ± 10.703	28.328 ± 9.574
1.00	26.845 ± 8.062	26.959 ± 10.121	27.183 ± 9.851
2.00	25.654 ± 7.869	25.911 ± 9.504	25.413 ± 9.174
3.00	25.255 ± 7.943	25.906 ± 9.284	25.979 ± 9.425
4.00	26.921 ± 8.324	27.038 ± 9.848	26.865 ± 9.753
5.00	30.337 ± 9.433	29.975 ± 10.318	28.301 ± 8.547
6.00	30.788 ± 9.515	31.003 ± 10.604	30.725 ± 9.596
8.00	37.764 ± 10.913	34.019 ± 13.724	34.519 ± 10.771
10.00	44.136 ± 12.527	38.238 ± 15.364	37.180 ± 11.129
12.00	42.521 ± 11.377	40.985 ± 15.888	38.494 ± 11.695
14.00	44.707 ± 11.479	43.322 ± 16.746	40.981 ± 13.120
16.00	41.353 ± 11.488	41.318 ± 16.827	38.496 ± 11.914
20.00	33.732 ± 10.466	33.272 ± 11.650	32.962 ± 10.971
24.00	26.954 ± 10.713	26.711 ± 9.501	26.808 ± 9.970
ND = No Data
TREATMENT A: TRAMADOL HCl EXTENDED RELEASE TABLET, 100 mg, Lot # 010206
TREATMENT B: TRAMADOL HCl EXTENDED RELEASE TABLET, 200 mg, Lot # 010704
TREATMENT C: TRAMADOL HCl EXTENDED RELEASE TABLETS, 2 × 200 mg, Lot # 010704

[0452]

TABLE 28F
Mean (±SD) Plasma Concentration-Time Profiles for O,N-Di-Desmethyltramadol
(M5) (ng/mL) (With Dose-Corrected Data) Mean Plasma O,N-di-DESMETHYLTRAMADOL
Concentrations (ng/mL) Dose-corrected to 1 × 100 mg strength
	TREATMENT A	TREATMENT B	TREATMENT C
SAMPLE TIME	1 × 100 mg	1 × 200 mg	2 × 200 mg
(DAY & HOURS)	Mean Value	SD	Mean Value	SD	Mean Value	SD
Day 1	0.000 ± 0.000	ND ± ND	ND ± ND
Day 3	10.757 ± 5.068	13.262 ± 5.135	16.953 ± 5.225
Day 4	12.955 ± 4.787	15.120 ± 6.658	18.718 ± 5.328
Day 5	13.510 ± 5.582	15.663 ± 5.800	20.017 ± 6.524
0.00	13.689 ± 5.158	16.437 ± 6.225	20.177 ± 6.705
1.00	12.869 ± 4.670	15.192 ± 5.770	18.965 ± 6.510
2.00	12.156 ± 4.498	14.645 ± 5.469	18.093 ± 6.137
3.00	11.722 ± 4.031	14.418 ± 5.345	18.151 ± 6.551
4.00	12.273 ± 3.938	14.460 ± 5.301	18.039 ± 6.294
5.00	13.276 ± 4.321	15.416 ± 5.181	18.468 ± 5.774
6.00	13.550 ± 4.445	16.198 ± 5.733	18.936 ± 6.060
8.00	16.066 ± 4.904	17.151 ± 6.577	20.198 ± 5.775
10.00	19.062 ± 5.577	19.475 ± 7.381	21.798 ± 6.034
12.00	19.061 ± 5.141	20.697 ± 7.980	22.767 ± 6.319
14.00	20.147 ± 5.199	22.293 ± 8.476	23.961 ± 6.898
16.00	19.325 ± 4.624	22.539 ± 8.947	23.652 ± 6.643
20.00	16.486 ± 4.510	19.558 ± 7.087	21.913 ± 6.830
24.00	13.452 ± 4.882	16.330 ± 6.079	19.630 ± 6.852
ND = No Data
TREATMENT A: TRAMADOL HCl EXTENDED RELEASE TABLET, 100 mg, Lot # 010206
TREATMENT B: TRAMADOL HCl EXTENDED RELEASE TABLET, 200 mg, Lot # 010704
TREATMENT C: TRAMADOL HCl EXTENDED RELEASE TABLETS, 2 × 200 mg, Lot # 01070410704

[0453]

TABLE 28G
Pharmacokinetic Parameters for Tramadol
(Without Dose-Corrected Data)
	Tramadol HCl 100 mg	Tramadol HCl 200 mg	Tramadol HCl 200 mg
	Extended Release	Extended Release	Extended Release
	Tablets	Tablets	Tablets
	1 × 100 mg (A)	1 × 200 mg (B)	2 × 200 mg (C)
Pharmacokinetic	n = 25	n = 25	n = 25
Parameter	Mean ± SD	Mean ± SD	Mean ± SD
AUCτ (ng · hr/mL)	2778.41 ± 1141.24	6364.89 ± 2755.19	15212.75 ± 5754.59
Cmax (ng/mL)	179.24 ± 62.68	408.99 ± 177.71	910.05 ± 319.71
Cmin (ng/mL)	73.84 ± 42.63	168.58 ± 72.58	438.70 ± 213.20
Tmax (hours)	11.68 ± 2.43	12.16 ± 2.23	12.00 ± 2.38
Degree of Fluctuation (%)	98.979 ± 41.628	94.697 ± 36.879	81.785 ± 38.392
Cave (ng/mL)	115.77 ± 47.55	265.20 ± 114.80	633.86 ± 239.77

[0454]

TABLE 28H
Pharmacokinetic Parameters for O-desmethyltramadol (M1)
(Without Dose-Corrected Data)
	Tramadol HCl 100 mg	Tramadol HCl 200 mg	Tramadol HCl 200 mg
	Extended Release	Extended Release	Extended Release
	Tablets	Tablets	Tablets
	1 × 100 mg (A)	1 × 200 mg (B)	2 × 200 mg (C)
Pharmacokinetic	n = 25	n = 25	n = 25
Parameter	Mean ± SD	Mean ± SD	Mean ± SD
AUCτ (ng · hr/mL)	846.73 ± 210.51	1640.53 ± 574.72	3189.17 ± 973.87
Cmax (ng/mL)	48.01 ± 11.53	91.29 ± 34.19	169.06 ± 48.75
Cmin (ng/mL)	26.95 ± 10.71	53.42 ± 19.00	107.23 ± 39.88
Tmax (hours)	12.32 ± 2.50	13.16 ± 2.70	14.00 ± 2.83
Degree of Fluctuation (%)	62.399 ± 32.222	56.637 ± 33.742	49.717 ± 26.325
Cave (ng/mL)	35.28 ± 8.77	68.36 ± 23.95	132.88 ± 40.58

[0455]

TABLE 28I
Pharmacokinetic Parameters for O, N-di- desmethyltramadol (M5)
(Without Dose-Corrected Data)
	Tramadol HCl 100 mg	Tramadol HCl 200 mg	Tramadol HCl 200 mg
	Extended Release	Extended Release	Extended Release
	Tablets	Tablets	Tablets
	1 × 100 mg (A)	1 × 200 mg (B)	2 × 200 mg(C)
Pharmacokinetic	n = 25	n = 25	n = 25
Parameter	Mean ± SD	Mean ± SD	Mean ± SD
AUCτ (ng · hr/mL)	388.96 ± 99.59	888.78 ± 314.74	2022.09 ± 589.81
Cmax (ng/mL)	21.23 ± 5.30	47.19 ± 17.49	100.03 ± 27.51
Cmin (ng/mL)	13.45 ± 4.88	32.66 ± 12.16	78.52 ± 27.41
Tmax (hours)	13.36 ± 3.09	13.44 ± 3.93	15.36 ± 2.81
Degree of Fluctuation (%)	49.959 ± 30.658	40.952 ± 29.437	28.403 ± 20.472
Cave (ng/mL)	16.21 ± 4.15	37.03 ± 13.11	84.25 ± 24.58

[0456]

TABLE 2J
Pharmacokinetic Parameters for Tramadol
(With Dose-Corrected Data)
	Tramadol HCl 100 mg	Tramadol HCl 200 mg	Tramadol HCl 200 mg
	Extended Release	Extended Release	Extended Release
	Tablets	Tablets	Tablets
	1 × 100 mg (A)	1 × 200 mg (B)	2 × 200 mg(C)
Pharmacokinetic	n = 25	n = 25	n = 25
Parameter	Mean ± SD	Mean ± SD	Mean ± SD
AUCτ (ng · hr/mL)	2778.41 ± 1141.24	3182.45 ± 1377.60	3803.19 ± 1438.65
Cmax (ng/mL)	179.24 ± 62.68	204.50 ± 88.85	227.51 ± 79.93
Cmin (ng/mL)	73.84 ± 42.63	84.29 ± 36.29	109.67 ± 53.30
Tmax (hours)	11.68 ± 2.43	12.16 ± 2.23	12.00 ± 2.38
Degree of Fluctuation (%)	98.979 ± 41.628	94.697 ± 36.879	81.785 ± 38.392
Cave (ng/mL)	115.77 ± 47.55	132.60 ± 57.40	158.47 ± 59.94

[0457]

TABLE 28K
Pharmacokinetic Parameters for O-desmethyltramadol (M1)
(With Dose-Corrected Data)
	Tramadol HCl 100 mg	Tramadol HCl 200 mg	Tramadol HCl 200 mg
	Extended Release	Extended Release	Extended Release
	Tablets	Tablets	Tablets
	1 × 100 mg (A)	1 × 200 mg (B)	2 × 200 mg (C)
Pharmacokinetic	n = 25	n = 25	n = 25
Parameter	Mean ± SD	Mean ± SD	Mean ± SD
AUCτ (ng · hr/mL)	846.73 ± 210.51	820.27 ± 287.36	797.29 ± 243.47
Cmax (ng/mL)	48.01 ± 11.53	45.65 ± 17.09	42.26 ± 12.19
Cmin (ng/mL)	26.95 ± 10.71	26.71 ± 9.50	26.81 ± 9.97
Tmax (hours)	12.32 ± 2.50	13.16 ± 2.70	14.00 ± 2.83
Degree of Fluctuation (%)	62.399 ± 32.222	56.637 ± 33.742	49.717 ± 26.325
Cave (ng/mL)	35.28 ± 8.77	34.18 ± 11.97	33.22 ± 10.14
M/P Ratio	0.3555 ± 0.1165	0.2980 ± 0.0982	0.2441 ± 0.0831

[0458]

TABLE 28L
Pharmacokinetic Parameters for O,N-di-desmethyltramadol (M5)
(With Dose-Corrected Data)
	Tramadol HCl 100 mg	Tramadol HCl 200 mg	Tramadol HCl 200 mg
	Extended Release	Extended Release	Extended Release
	Tablets	Tablets	Tablets
	1 × 100 mg (A)	1 × 200 mg (B)	2 × 200 mg (C)
Pharmacokinetic	n = 25	n = 25	n = 25
Parameter	Mean ± SD	Mean ± SD	Mean ± SD
AUCτ (ng · hr/mL)	388.96 ± 99.59	444.39 ± 157.37	505.52 ± 147.45
Cmax (ng/mL)	21.23 ± 5.30	23.59 ± 8.74	25.01 ± 6.88
Cmin (ng/mL)	13.45 ± 4.88	16.33 ± 6.08	19.63 ± 6.85
Tmax (hours)	13.36 ± 3.09	13.44 ± 3.93	15.36 ± 2.81
Degree of Fluctuation (%)	49.959 ± 30.658	40.952 ± 29.437	28.403 ± 20.472
Cave (ng/mL)	16.21 ± 4.15	18.52 ± 6.56	21.06 ± 6.14
M/P Ratio	0.1734 ± 0.0653	0.1723 ± 0.0666	0.1667 ± 0.0682

[0459]

TABLE 28M
Regression Analysis Results for AUC□ and Cmax After Three Doses
of Tramadol With Y = a X + b Using Un-Weighted Data
	Parameter	Slope	95% CI	P
	Cmax	2.4459	(2.0531, 2.8387)	<0.0001
	AUC□	41.8466	(34.9723, 48.7208)	<0.0001

[0460]

TABLE 28N
P Value For Paired Comparisons Among
Treatments A, B, And C For Tramadol
	Parameter	Trt A-Trt B	Trt A-Trt C	Trt B-Trt C
	Cmax	0.4532	0.0627	0.2597
	AUC□	0.4675	0.0319	0.1491

[0461]

TABLE 28O
P Value For Paired Comparisons Among Treatments
A, B, And C For O-Desmethyltramadol (m1)
	Parameter	Trt A-Trt B	Trt A-Trt C	Trt B-Trt C
	Cmax	0.3011	0.1267	0.6162
	AUC□	0.4490	0.4168	0.9560

[0462]

TABLE 28P
P Value For Paired Comparisons Among Treatments
A, B, And C For O,N-Di-Desmethyltramadol (M5)
	Parameter	Trt A-Trt B	Trt A-Trt C	Trt B-Trt C
	Cmax	0.5122	0.1035	0.3254
	AUC□	0.3743	0.0152	0.1155

EXAMPLE 14

100 mg Tramadol HCl ER Tablets

[0463] The following 100 mg Tramadol HCl ER Tablet formulation was prepared.

TABLE 29
                                 Tramadol 100 mg
                                 Lot # 99H059
Ingredients                      mg/tablet
Tramadol HCl                     100
Hydroxypropylmethyl Cellulose (Premium K 100 224.40
M CR), USP
Lactose Anhydrous, NF            57.23
Microcrystalline Cellulose (Avicel PH 101), NF 26.99
Ethylcellulose (Ethocel Premium 100 FP) NF 26.99
Magnesium Stearate, NF           4.35
Opadry II White Y-22-7719        15.43
Weight of Coated tablet          455.39

[0464] Study No. 992088 (B99-402PK-TRAP03)

[0465] A three-way, single-dose, open-label, fasting and food effect, comparative bioavailability study of tramadol hydrochloride extended-release tablets (100 mg) in normal, healthy, non-smoking male volunteers was conducted.

[0466] This study evaluated the effect of food and the time of administration on the relative bioavailability of a novel Tramadol HCl Extended-Release Tablet (100 mg) formulation.

[0467] This study was a randomized, three-way crossover study design in twenty-four (24) normal, healthy, non-smoking male volunteers and three (3) alternates.

[0468] Twenty-seven (27) subjects were entered into the study. Twenty-seven (27) subjects completed the study; and as per the protocol, there were twenty-four (24) evaluable subjects. All subjects were non-smoking, between 18 and 45 years of age (inclusive), and with body weights no more than ±15% of the ideal weight for the subject's height and frame as determined by the Table of Desirable Weights for Men.

[0469] The study periods were separated by a one-week washout period. Blood sampling for drug content analysis was carried out at 0.0 (pre-drug), 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0, 16.0, 20.0, 24.0, 30.0, 36.0, and 48.0 hours post-drug administration.

[0470] Treatments: A: Single dose of Tramadol HCl Extended-Release Tablets, 100 mg (Lot #99H059), with 240 mL potable water, administered in the morning beginning at approximately 7 AM after an overnight fast of at lease 10 hours.

[0471] B: Single dose of Tramadol HCl Extended-Release Tablets, 100 mg (Lot #99H059), with 240 mL potable water, administered in the morning beginning at approximately 7 AM the intake of a high fat-content breakfast.

[0472] C: Single dose of Tramadol HCl Extended-Release Tablets, 100 mg (Lot #99H059), with 240 mL potable water, administered beginning at approximately 10 PM the night before the dosing date of regimens A and B. Food intake was not permitted for 2 hours before and 2 hours after dosing.

[0473] In the current study, the effect of food and time of administration on the formulation used in the pre-emptive dental pain study (Lot #99H059) was evaluated.

[0474] Results presented in Tables 30a, 31a and 32a indicate that there is no effect of food on the extended-release formulation. Similar tramadol, O-desmethyltramadol and M5 pharmacokinetic profiles were achieved when the formulation was administered in the morning or night. Equivalent AUCs and Cmax values were observed as evidenced by the 90% confidence intervals for the ratio of geometric means falling within 80-125% limits. Table 30a also shows that there was no apparent difference in the ratio of the metabolite (AUC∞ of M1/tramadol) between the different treatments. The half life of tramadol was slightly decreased after food (6.18 hours) and night time administration (6.74 hours) compared to morning administration (7.64 hours).

[0475] FIG. 28 shows that comparable tramadol, O-desmethyltramadol and M5 levels are obtained regardless of whether the extended-release tramadol formulation was administered in the morning (fasting), morning (fed) or night (fasting).

TABLE 30a
Pharmacokinetic Parameters Study 992088 (402PK) (n = 27)
Study 402PK Mean Pharmacokinetic Parameters for Plasma Tramadol (n = 27)
			Lot # 99H059
	Lot # 99H059	Lot # 99H059	PM Dosing
	AM Dosing	AM Dosing	(at least 2 hrs
	(Fasting)	(Fed)	after food)
Parameters	Mean (CV (%) )	Mean (CV (%) )	Mean (CV (%) )
AUC0-t	2655.9 (29.1)	2691.8 (30.9)	2622.5 (28.3)
(ng · h/mL)
AUC0-inf	2731.5 (30.2)	2728.0 (32.0)	2660.3 (28.8)
(ng · h/mL)
Cmax (ng/mL)	144.5 (21.7)	160.0 (20.3)	152.5 (24.5)
Tmax (h)	5.41 (37.4)	5.85 (32.4)	5.96 (30.3)
T1/2 el (h)	7.64 (29.6)	6.18 (22.8)	6.74 (18.1)
M1/Tramadol Ratio	0.37 (50.1)	0.37 (48.7)	0.38 (51.3)

[0476]

TABLE 30b
Ratio of Means & 90% Confidence Interval for Plasma Tramadol
Statistical		90% Geometric
Analysis	Treatment	C.I. 2
(ANOVA)	Comparisons	Ratio 1	Lower	Upper
AUC0-t	AM Fasting vs AM Fed	98.64	94.03%	103.47%
	AM Fasting vs PM	100.99	96.28%	105.94%
	Fasting
AUC0-inf	AM Fasting vs AM Fed	100.05	95.40%	104.92%
	AM Fasting vs PM	102.18	97.43%	107.15%
	Fasting
Cmax	AM Fasting vs AM Fed	90.01	84.41%	95.97%
	AM Fasting vs PM	95.49	89.55%	101.81%
	Fasting
1 Ratio of least squares means
2 Calculated from log-transformed data

[0477]

TABLE 31a
Pharmacokinetic Parameters Study 992088 (402PK) (n = 27)
Study 402PK: Mean Pharmacokinetic Parameters for
Plasma O-desmethyltramadol (n = 27)
			Lot # 99H059
	Lot # 99H059	Lot # 99H059	PM Dosing
	AM Dosing	AM Dosing	(at least 2 hrs
	(Fasting)	(Fed)	after food)
Parameters	Mean (CV (%) )	Mean (CV (%) )	Mean (CV (%) )
AUC0-t	870.9 (29.1)	872.0 (30.0)	871.4 (30.3)
(ng · h/mL)
AUC0-inf	909.5 (28.2)	892.2 (29.5)	898.5 (28.7)
(ng · h/mL)
Cmax (ng/mL)	40.4 (38.2)	45.0 (15.7)	46.9 (37.1)
Tmax (h)	7.41 (40.2)	8.37 (28.1)	7.81 (31.8)
T1/2 el (h)	8.53 (29.1)	6.89 (18.2)	7.68 (23.5)

[0478]

TABLE 31b
Ratio of Means & 90% Confidence Interval
for Plasma O-desmethyltramadol
Statistical		90% Geometric
Analysis	Treatment	C.I. 2
(ANOVA)	Comparisons	Ratio 1	Lower	Upper
AUC0-t	AM Fasting vs AM Fed	99.88	96.19%	103.72%
	AM Fasting vs PM	100.49	96.78%	104.34%
	Fasting
AUC0-inf	AM Fasting vs AM Fed	102.15	98.11%	106.35%
	AM Fasting vs PM	101.31	97.31%	105.48%
	Fasting
Cmax	AM Fasting vs AM Fed	87.96	82.56%	93.72%
	AM Fasting vs PM	85.38	80.13%	90.96%
	Fasting
1 Ratio of least squares means
2 Calculated from log-transformed data

[0479]

TABLE 32a
Pharmacokinetic Parameters Study 992088 (402PK) (n = 27)
Study 402PK: Mean Pharmacokinetic Parameters for Plasma M5 (n = 27)
			Lot # 99H059
		Lot # 99H059	PM Dosing
		AM Dosing	(at least 2 hrs
		(Fasting)	after food)
	Parameters	Mean (CV (%) )	Mean (CV (%) )
	AUC0-t	917.96 (37.4)	938.24 (36.4)
	(ng · h/mL)
	AUC0-inf	985.84 (35.4)	979.38 (35.9)
	(ng · h/mL)
	Cmax (ng/mL)	40.59 (40.9)	44.47 (41.2)
	Tmax (h)	9.0 (43.1)	9.7 950.1)

EXAMPLE 15

[0480] Study No.99105 (B99-415PK-TRAP03)

[0481] A pilot three-way, single-dose, open-label, fasting and fed, comparative bioavailability study of two formulations of tramadol hydrochloride extended-release tablets (2×100 mg) in normal, healthy, non-smoking male and female volunteers was conducted.

[0482] This pilot study evaluated the relative bioavailability of two novel Tramadol HCl Extended-Release Tablets (2×100 mg) against Ultram® (Ortho-McNeil Pharmaceuticals) Tablets (50 mg q.i.d.) under fasting (both formulations) and fed (one formulation) conditions.

[0483] This pilot study was a randomized, three-way crossover study design in fifteen (15) normal, healthy, non-smoking male and female volunteers and three (3) alternates (total 11 males and 7 females).

[0484] Eighteen (18) subjects were entered into the study. Seventeen (17) subjects completed the study; there were seventeen (17) evaluable subjects. All subjects were non-smoking, between 18 and 45 years of age (inclusive), and with body weights no more than ±15% of the ideal weight for the subject's height and frame as determined by the Table of Desirable Weights for Men and Women. All female subjects were non-lactating, had negative pregnancy tests, and were taking an acceptable method of contraception.

[0485] The study periods were separated by a one-week washout period. Blood sampling for drug content analysis was carried out at 0.0 (pre-drug), 1.0, 2.0, 3.0,4.0, 6.0, 8.0, 10.0, 12.0, 16.0, 20.0, 24.0, 30.0, 36.0, and 48.0 hours post-drug administration.

[0486] Treatments: A: 2 Tablets of Tramadol HCl ER 100 mg Tablets (Lot #2165) after a 10-hour overnight fast

[0487] B: 2 Tablets of Tramadol HCl ER 100 mg Tablets (Lot #2165) after a high-fat high-calorie content breakfast.

[0488] C: 2 Tablets of Tramadol HCl ER 100 mg Tablets (Lot #99H059) after a 10-hour overnight fast

[0489] Lot #2165 from a previous pilot biostudy (Study 401PK) exhibited AUC and Cmax values comparable to an equivalent dose of Ultram given q.i.d. for one day. This formulation was evaluated under fasting and fed conditions compared to the formulation (Lot #99H059) used in a previously conducted Phase II pre-emptive dental pain study.

[0490] The 100 mg extended release tramadol formulation tested (2×100 once a day) in treatments A and B (Lot #2165) demonstrated that there was no effect of food on the pharmacokinetics of tramadol and O-desmethyltramadol (M1). The test formulation (Lot #2165) had a higher Cmax and a delayed Tmax compared to Lot #99H059. However, the 90% geometric mean confidence intervals for AUCt and AUC∞ were within the 80%-125% range when the two formulations (Lot #2165 and 99H059) were compared. The mean pharmacokinetic parameters and 90% confidence interval for the ratio of the geometric mean AUC are presented in Table 33a and 33b for Tramadol and 34a and 34b for mono-O-desmethyltramadol.

[0491] FIGS. 29 a and 29b depict the tramadol and mono-O-desmethyltramadol plasma levels, respectively, when administered after fasting and fed conditions.

[0492] Based upon a longer Tmax and higher Cmax, Lot #2165 exhibits a desirable pharmacokinetic profile for use in pre-emptive dental pain.

TABLE 33a
Pharmacokinetic Parameters Study 99105 (415PK) (n = 15)
Study 415PK Mean Pharmacokinetic Parameters
for Plasma Tramadol (n = 15)
	Test-1 Fast (A)	Test-1 Fed (B)	Test-2 Fast (A)
	(Lot # 2165)	(Lot # 2165)	(Lot# 99H059)
Parameters	Mean (CV (%) )	Mean (CV (%) )	Mean (CV (%) )
AUC0-t	5078.97 (19.59)	5391.64 (19.80)	4892.42 (22.37)
(ng · h/mL)
AUC0-inf	5159.41 (19.91)	5454.67 (20.05)	4996.98 (22.99)
(ng · h/mL)
AUCt/inf (%)	98.51 (1.05)	98.89 (0.59)	98.07 (1.48)
Cmax (ng/mL)	339.00 (25.85)	338.47 (18.75)	273.81 (16.95)
Tmax (h)	7.53 (17.64)	8.88 (17.75)	5.12 (25.74)
Tlag (h)	0.765 (57.18)	0.824 (64.19)	0.000 (—)
T1/2 el (h)	6.43 (17.65)	6.18 (12.50)	6.92 (21.51)

[0493]

TABLE 33b
Ratio of Means & 90% Confidence Interval for Plasma Tramadol
Statistical		90% Geometric
Analysis	Treatment	C.I. 2
(ANOVA)	Comparisons	Ratio 1	Lower	Upper
AUC0-t	Test-1 Fast (A) vs Test-1	93.50%	86.69%	100.85%
	Fed (B)
	Test-1 Fast (A) vs Test-2	105.37%	97.69%	113.65%
	Fast (C)
AUC0-inf	Test-1 Fast (A) vs Test-1	93.97%	87.14%	101.34%
	Fed (B)
	Test-1 Fast (A) vs Test-2	105.10%	97.46%	113.34%
	Fast (C)
Cmax	Test-1 Fast (A) vs Test-1	100.55%	89.90%	112.46%
	Fed (B)
	Test-1 Fast (A) vs Test-2	121.00%	108.19%	135.33%
	Fast (C)
1 Ratio of least squares means
2 Calculated from log-transformed data

[0494]

TABLE 34a
Pharmacokinetic Parameters Study 99105 (415PK) (n = 15)
Study415PK: Mean Pharmacokinetic Parameters for Plasma
O-desmethyltramadol (n = 15)
Para-	Test-1 Fast (A)	Test-1 Fed (B)	Test-2 Fast (A)
met-	(Lot # 2165)	(Lot # 2165)	(Lot # 99H059)
ers	Mean	CV (%)	Mean	CV (%)	Mean	CV (%)
AUC0-t (ng · h/mL)	1973.29	(21.35)	1976.17	(23.84)	1880.16	(25.04)
AUC0-inf	2027.59	(21.38)	2021.39	(23.95)	1945.83	(25.47)
(ng · h/mL)
Cmax (ng/ mL)	108.24	(31.94)	104.09	(26.53)	87.41	(27.11)
Tmax (h)	9.41	(18.04)	9.65	(15.08)	6.71	(46.79)
Tlag (h)	0.941	(25.77)	1.059	(22.91)	0.000	—
T1/2 el (h)	7.29	(16.14)	6.96	(14.86)	7.71	(23.43)

[0495]

TABLE 34b
Ratio of Means & 90% Confidence Interval
for Plasma O-desmethyltramadol
Statistical		90% Geometric
Analysis	Treatment	C.I. 2
(ANOVA)	Comparisons	Ratio 1	Lower	Upper
AUC0-t	Test-1 Fast (A) vs Test-1	100.27%	93.97%	106.98%
	Fed (B)
	Test-1 Fast (A) vs Test-2	107.32%	100.58%	114.51%
	Fast (C)
AUC0-inf	Test-1 Fast (A) vs Test-1	100.79%	94.52%	107.46%
	Fed (B)
	Test-1 Fast (A) vs Test-2	106.87%	100.23%	113.95%
	Fast (C)
Cmax	Test-1 Fast (A) vs Test-1	104.76%	95.62%	114.76%
	Fed (B)
	Test-1 Fast (A) vs Test-2	123.59%	112.81%	135.39%
	Fast (C)
1 Ratio of least squares means
2 Calculated from log-transformed data

[0496] While the foregoing provides a detailed description of preferred embodiments of the present invention, it is to be understood that this description is only illustrative of the principles of the invention and is not limitative. Numerous modifications, variations and adaptations may be made to the particular embodiments of the invention described above without departing from the scope of the invention, which is defined in the claims.

Claims

1. A modified release pharmaceutical composition comprising at least one form of tramadol selected from the group consisting of tramadol, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof, wherein the 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 at least one form of tramadol while maintaining bioavailability substantially equivalent to that of the immediate release composition.

2. A modified release pharmaceutical composition comprising at least one form of tramadol selected from the group consisting of tramadol, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof, wherein the composition, when orally administered to a patient, produces a mean maximum plasma concentration (Cmax) of the at least one form of tramadol that is lower than that produced by an immediate release pharmaceutical composition of the at least one form of tramadol, and the area under the concentration-time curve (AUC) and the mean minimum plasma concentration (Cmin) are substantially equivalent to that of the immediate release pharmaceutical composition.

3. A modified release pharmaceutical composition comprising at least one form of tramadol selected from the group consisting of tramadol, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof, wherein the composition, when orally administered to a patient, produces a mean maximum plasma concentration (Cmax) of the at least one form of tramadol 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 at least one form of tramadol.

4. The pharmaceutical composition of claim 1, 2 or 3 wherein the at least one form of tramadol is tramadol hydrochloride and the immediate release pharmaceutical composition is the subject of the United States Food and Drug Administration Approved New Drug Application number N20281.

5. A modified release pharmaceutical composition comprising at least one form of tramadol selected from the group consisting of tramadol, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof, wherein the composition exhibits an in vitro dissolution profile (measured using the USP Basket Method at 75 rpm in 900 ml 0.1 N HCl at 37° C.) such that after 2 hours, from about 0% up to about 30% (by weight) of the at least one form of tramadol is released, after 4 hours, from about 5% to about 55% (by weight) of the at least one form of tramadol is released, after 12 hours, more than about 50% (by weight) of the at least one form of tramadol is released, and after 24 hours, more than about 80% (by weight) of the at least one form of tramadol is released.

6. A modified release pharmaceutical composition comprising at least one form of tramadol selected from the group consisting of tramadol, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof, the composition exhibiting an in vitro dissolution profile (measured using the USP Basket Method at 75 rpm in 900 ml 0.1 N HCl at 37° C.) such that after 2 hours, from about 0% up to about 30% (by weight) of the at least one form of tramadol is released, after 4 hours, from about 5% to about 22% (by weight) of the at least one form of tramadol is released, after 6 hours, from about 15% to about 38% (by weight) of the at least one form of tramadol is released, after 8 hours, more than about 40% (by weight) of the at least one form of tramadol is released.

7. The modified release pharmaceutical composition of claim 6 the composition exhibits an in vitro dissolution profile (measured using the USP Basket Method at 75 rpm in 900 ml 0.1 N HCl at 37° C.) such that after 2 hours, from about 2% to about 10% of the at least one form of tramadol is released, after 4 hours, from about 12% to about 20% of the at least one form of tramadol is released, after 6 hours, from about 30% to about 38% of the at least one form of tramadol is released, after 8 hours, from about 48% to about 56% of the at least one form of tramadol is released, after 10 hours, from about 64% to about 72% of the at least one form of tramadol is released, and after 12 hours, more than about 76% of the at least one form of tramadol is released.

8. A modified release pharmaceutical composition comprising at least one form of tramadol selected from the group consisting of tramadol, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof, wherein the pharmaceutical composition, when orally administered to a patient, provides a mean maximum plasma concentration (Cmax) of the at least one form of tramadol from about 80 ng/ml to about 500 ng/ml.

9. A modified release pharmaceutical composition comprising at least one form of tramadol selected from the group consisting of tramadol, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof, wherein the pharmaceutical composition, when orally administered to a patient, provides a time to mean maximum plasma concentration (Tmax) of the at least one form of tramadol ranging from about 4 hours to about 14 hours.

10. A modified release pharmaceutical composition comprising at least one form of tramadol selected from the group consisting of tramadol, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof, wherein the pharmaceutical composition, when orally administered to a patient, provides a plasma concentration time curve with an area under the curve ranging from about 1000 ng.hr/ml to about 10000 ng.hr/ml.

11. A modified release pharmaceutical composition comprising: (i) a core comprising at least one form of tramadol selected from the group consisting of tramadol, enantiomers thereof, pharmaceutically acceptable salts thereof and combinations thereof and at least one pharmaceutically acceptable excipient; and (ii) a coating comprising at least one water-insoluble, water-permeable film-forming polymer, at least one plasticizer and at least one water-soluble polymer.

12. The modified release pharmaceutical composition of claim 11, wherein the proportion of the at least one water-insoluble, water-permeable film-forming polymer varies from about 20% to about 90% of the coating dry weight, the proportion of the at least one plasticizer varies from about 5% to about 30% of the coating dry weight, and the proportion of the at least one water-soluble polymer varies from about 10% to about 75% of the coating dry weight.

13. The modified release pharmaceutical composition of claim 11, wherein the at least one water-insoluble, water-permeable film-forming polymer is ethylcellulose.

14. The modified release pharmaceutical composition of claim 11, wherein the at least one water-soluble polymer is polyvinylpyrrolidone.

15. The modified release pharmaceutical composition of claim 11, wherein the at least one plasticizer is dibutyl sebacate.

16. The modified release pharmaceutical composition of claim 11, wherein the at least one water-insoluble, water-permeable film-forming polymer is ethylcellulose, the at least one water-soluble polymer is polyvinylpyrrolidone and the at least one plasticizer is dibutyl sebacate.

17. The modified release pharmaceutical composition of claim 11, wherein the at least one pharmaceutically acceptable excipient in the core is selected from the group consisting of at least one lubricant, at least one binder, at least one glidant and combinations thereof.

18. The modified release pharmaceutical composition of claim 16, wherein the at least one pharmaceutically acceptable excipient in the core is selected from the group consisting of at least one lubricant, at least one binder, at least one glidant and combinations thereof.

19. The modified release pharmaceutical composition of claim 17, wherein the at least one lubricant is sodium stearyl fumarate, the at least one binder is polyvinyl alcohol, and the at least one glidant is colloidal silicon dioxide.

20. The modified release pharmaceutical composition of claim 18, wherein the at least one lubricant is sodium stearyl fumarate, the at least one binder is polyvinyl alcohol, and the at least one glidant is colloidal silicon dioxide.

21. The modified release pharmaceutical composition of claim 11, wherein the at least one form of tramadol is tramadol hydrochloride and wherein the tramadol hydrochloride is present in an amount of from about 50 mg to about 400 mg.

22. The modified release pharmaceutical composition of claim 16, wherein the at least one form of tramadol is tramadol hydrochloride and wherein the tramadol hydrochloride is present in an amount of from about 50 mg to about 400 mg.

23. The modified release pharmaceutical composition of claim 19, wherein the at least one form of tramadol is tramadol hydrochloride and wherein the tramadol hydrochloride is present in an amount of from about 50 mg to about 400 mg.

24. The modified release pharmaceutical composition of claim 20, wherein the at least one form of tramadol is tramadol hydrochloride and wherein the tramadol hydrochloride is present in an amount of from about 50 mg to about 400 mg.

25. The modified release pharmaceutical composition of claim 24, wherein the composition is in the form of a tablet.

26. A modified release pharmaceutical composition comprising: (i) a core comprising tramadol hydrochloride, polyvinyl alcohol, colloidal silicon dioxide and sodium stearyl fumarate; and (ii) a coating comprising ethylcellulose, polyvinylpyrrolidone and dibutyl sebacate.

27. The modified release pharmaceutical composition of claim 26, wherein the at least one form of tramadol is tramadol hydrochloride and wherein the tramadol hydrochloride is present in an amount of from about 50 mg to about 400 mg.

28. The modified release pharmaceutical composition of claim 27, wherein the composition is in the form of a tablet.