AU2003275855B2

AU2003275855B2 - Sustained-release tramadol formulations with 24-hour efficacy

Info

Publication number: AU2003275855B2
Application number: AU2003275855A
Authority: AU
Inventors: Jonathan Bacon; Sonia Gervais; Vincent Lenaerts; Patricia Laure Ouadji-Njiki; Rachid Ouzerourou; Miloud Rahmouni; Damon Smith
Original assignee: Paladin Labs Barbados Inc; Paladin Labs Inc; Paladin Labs Europe Ltd
Current assignee: Paladin Labs Barbados Inc; Paladin Labs Inc; Paladin Labs Europe Ltd
Priority date: 2002-10-25
Filing date: 2003-10-27
Publication date: 2009-04-23
Anticipated expiration: 2023-10-27
Also published as: AU2003275855A1; NO20052479D0; IL168114A; CA2503155A1; UA84277C2; WO2004037222A2; NO20052479L; RU2328275C2; JP2006507277A; PT1594460E; WO2004037222A3; AR045972A1; KR20050083816A; RU2005115855A

Description

WO 2004/037222 PCT/CA2003/001638 SUSTAINED-RELEASE TRAMADOL FORMULATIONS WITH 24-HOUR EFFICACY FIELD OF THE INVENTION 5 [0001]This invention relates to a novel once daily oral pharmaceutical composition for controlled release of tramadol or a salt thereof. BACKGROUND OF THE INVENTION Tramadol Pharmaceutical Formulations [0002]Tramadol hydrochloride (HCI) was developed by GrOnenthal GmbH, Germany. 10 It has been marketed in Germany since 1977 (eg. Tramal

TM

), and in the United States as Ultram@ since 1995. The efficacy and safety profile of tramadol HCI make it highly suitable as a long-term treatment for chronic pain. [0003]Tramadol HCI is a synthetic, centrally acting analgesic that has been shown to be effective in a variety of acute and chronic pain states. In particular, tramadol HCI, 15 in both immediate and slow-release formulations, in conjunction with non-steroidal anti-inflammatory drugs (NSAIDs) (Roth SH. "Efficacy and safety of tramadol HCI in breakthrough musculoskeletal pain attributed to osteoarthritis". J. Rheumatol 1998; 25:1358-1363. Wilder-Smith CH et a. "Treatment of severe pain from osteoarthritis with slow-release tramadol or dihydrocodeine in combination with NSAID's: a 20 randomized study comparing analgesia, antinociception and gastrointestinal effects". Pain 2001; 91:23-31.), has been demonstrated to reduce pain attributed to osteoarthritis (OA). After oral administration, tramadol HCI is rapidly and almost completely absorbed, and it is extensively metabolized. The major metabolic pathways appear to be N- and 0- demethylation and glucuronidation or sulfonation in 25 the liver. Only one metabolite, mono-O-desmethyltramadol (Ml), is pharmacologically active, which has an approximate 200-fold higher affinity for the p.

opioid receptor than racemic tramadol (DeJong R. "Comment on the hypoalgesic effect of tramadol in relation to CYP2D6" (comment) Pain Dig 1997; 7:245; Kogel B. et al "Involvement of metabolites in the analgesic action of tramadol" Proc. 9 th World 30 Congress on Pain, Vienna, 1999). In healthy humans, tramadol is demethylated by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6) to the M1 metabolite. 1 WO 2004/037222 PCT/CA2003/001638 [0004]The mechanism of action of tramadol HCI is not completely understood. Animal models indicate that the drug (and its active M1 metabolite) acts as an opiate agonist, apparently by selective activity at the p-receptor. In addition to opiate agonist activity, tramadol HCI inhibits re-uptake of certain monoamines 5 (norepinephrine, serotonin) which appears to contribute to the drug's analgesic effect. The antinociceptic effect of tramadol HCI is only partially antagonized by naloxone in some tests in animals and humans. In addition, because of the drug's opiate agonist activity, it has been suggested that tramadol HCI may produce dependence; however, its abuse potential appears to be low, and tramadol HCI is not "subject to 10 control" under the United States Federal Controlled Substances Act of 1970 as a scheduled drug. [0005] Immediate release formulations of tramadol HCI are well known in the art. Such formulations, however, require frequent dosing in order to provide effective pain relief. Lack of compliance with high frequency dosing regimens can result in 15 inconsistent plasma drug concentrations and accordingly less consistent analgesia. Twice daily formulations are available and are desirable over immediate release formulations as they provide longer periods of analgesia after administration and require less frequent dosing. A once daily formulation is even more desirable for increased effectiveness, safety and convenience. 20 [0006]A critical factor influencing the rate of absorption, and thereby the safety and efficacy, of an active pharmaceutical ingredient by the body following oral administration in a tablet or other solid dosage form is the rate of release of the active pharmaceutical ingredient from that dosage form post ingestion. [0007] It is thus the ability of the dosage form components to control the release rate 25 that constitutes the basis for the so-called controlled-release, extended-release, sustained-release or prolonged-action pharmaceutical preparations that are designed to produce slow, uniform release and absorption of active pharmaceutical ingredients over a period of hours, days, weeks or months. The advantages of such controlled release formulations include: a reduction in the required administration frequency of 30 the drug as compared to conventional immediate release dosage forms, often resulting in improved patient compliance; the maintenance of a stable concentration of the drug in the body and thereby a sustained therapeutic effect over a set period of time; and a decreased incidence and intensity of undesired side effects of the active 2 WO 2004/037222 PCT/CA2003/001638 agent caused by the high plasma concentrations that occur after administration of immediate-release dosage forms. [0008]Many materials have been proposed and developed as matrices for the controlled release of active pharmaceutical ingredients. These include, for example, 5 polymeric materials such as polyvinyl chloride, polyethylene amides, ethyl cellulose, silicone and poly (hydroxymethyl methacrylate). See e.g., U.S. Patent No. 3,087,860 to Endicott et al.; U.S. Patent No. 2,987,445 to Levesque et a!.; Salomon et al. Pharm. Acta Helv., 55, 174-182 (1980); Korsmeyer, Diffusion Controlled Systems: Hydrogels, Chap. 2, pp 15-37 in Polymers for Controlled Drug Delivery, Ed Tarcha, 10 CRC Press, Boca Raton, Fla. USA (1991); and Buri et al., Pharm. Acta Helv. 55, 189 197 (1980). [0009]High amylose starch has also been used for controlled-release purposes and, in particular, recent advances have been made using cross-linked high amylose starch. For example, United States Patent No. 6,284,273 (Lenaerts et al.), which 15 issued September 4, 2001, and No. 6,419,957 (Lenaerts et al.), which issued July 16, 2002, teach a solid controlled release oral pharmaceutical dosage unit in the form of tablets comprising a dry powder of a pharmaceutical product and a dry powder of cross-linked high amylose starch, wherein said cross-linked high amylose starch is a matrix comprising a mixture of about 10-60% by weight of amylopectin and about 40 20 90% amylose. United States Patent No. 6,607,748 (Lenaerts et al.) which issued on August 19, 2003 describes a process for making a cross-linked high amylose starch which is known under the name Contramid*. Extended Release Formulations Known in the Art [0010]Extended and controlled release formulations relating to tramadol HCI have 25 been suggested, examples being described in: United States Patent Application Publication No. 2003/0143270, (Deboeck et aL.) published July 31, 2003; United States Patent No. 6,254,887 (Miller et aL) issued July 3, 2001; United States Patent Application Publication No. 2001/0036477 (Miller et aL.) published November 1, 2001; United States Patent No. 6,326,027 (Miller et al.) issued December 4, 2001; and 30 United States Patent No. 5,591,452 (Miller et a!) issued January 7, 1997; and European Patent No. 1 190 712 (Vanderbist) published March 27, 2002. 3 WO 2004/037222 PCT/CA2003/001638 [0011]Although there are some controlled release tramadol HCI formulations on the market which purport to be once-daily formulations, none of these has successfully replaced twice-daily tramadol HCI formulations. [0012]Articles have been published in which comparative data between putative 5 "once-daily" tramadol HCI formulations and immediate release tramadol HCI formulations are presented: Adler et al., "A Comparison of Once-Daily Tramadol with Normal Release Tramadol in the Treatment of Pain in Osteoarthritis," The Journal of Rheumatology (2002) 29(10): 2195-2199; and Bodalia et al., "A Comparison of the Pharmacokinetics, Clinical Efficacy, and Tolerability of Once-Daily Tramadol Tablets 10 with Normal Release Tramadol Capsules," Journal of Pain and Symptom Management (2003) 25(2): 142-149. Adverse Events from Administration of Tramadol HCI [0013] The most frequently reported side effects of tramadol observed in clinical trials in the United States are constipation, nausea, dizziness/vertigo, headache, 15 somnolence and vomiting. These are typical adverse effects of opiate drugs. Seizures and anaphylactoid reactions have also been reported, though the estimated incidence of seizures in patients receiving tramadol HCI is less than 1% (Kazmierczak, R., and Coley, K.: "Doctor letters on prescribing: evaluation of the use of tramadol HCI." Formulary 32: 977-978, 1997). 20 [0014]Adler et al., supra, reports on the results of a clinical study comparing a once daily tramadol formulation to immediate release tramadol in the treatment of pain in osteoarthritis. The authors report similar adverse event profiles for individuals in both treatment groups. Table 2 of Adler et aL indicates that a greater percentage of people who were in the once daily treatment group withdrew due to adverse events 25 than did those in the other treatment group. [0015]In Bodalia et aL, supra, the authors report comparable tolerability with a 150 mg once daily dose, a 200 mg once daily dose and three doses of a 50 mg normal release tramadol formulation. This article does not however include any information on how to make the formulations which are purported to be "once daily" nor does the 30 article disclose any pharmacokinetic data after a single dose. [0016]Citation or identification of any reference in this section shall not be construed as an admission that such reference is available as prior art to the present invention. 4 SUMMARY OF THE INVENTION An object of the present invention is to provide an improved sustained-release tramadol formulation with 24 5 hour effective analgesia. According to the present invention there is provided a solid dosage formulation comprising a core, comprising an active pharmaceutical ingredient and a matrix, and a coat comprising a physical mixture of polyvinyl acetate 10 and polyvinyl pyrrolidone and an active pharmaceutical ingredient, in which the formulation, upon initial administration of one dose, provides an onset of analgesic effect within 2 hours, which analgesic effect continues for at least 24 hours after administration, and/or release 15 from the formulation of the active ingredient located in the core is slower than the release of the active ingredient located in the matrix of the coat. In accordance with one aspect of the present invention, there is provided a once daily oral 20 pharmaceutical composition for controlled release of tramadol or a salt thereof, in which the composition, upon initial administration, provides an onset of analgesic effect within 2 hours, which analgesic effect continues for at least 24 hours after administration. 25 In accordance with another aspect of the present invention, there is provided a once daily oral pharmaceutical composition for controlled release of tramadol or a salt thereof, wherein the composition, upon initial administration of one dose, provides a mean plasma 30 concentration of at least 100 ng/mL within 2 hours of administration and continues to provide a mean plasma concentration of at least 100 ng/mL for at least 22 hours after administration. In an embodiment of the present invention, there is 35 provided a once daily oral pharmaceutical composition for controlled release of tramadol or a salt thereof, wherein the composition, upon initial administration of one dose, 5 provides a mean plasma concentration of at least 100 ng/mL within 2 hours of administration and continues to provide a mean plasma concentration of at least 100 ng/mL for at least 22 hours after administration and wherein the mean 5 maximum plasma concentration (Cmax) is less than 2.2 times the mean plasma concentration obtained 24 hours after administration (C24h). The term "X,.a is the apparent terminal elimination rate constant, determined by the slope of the regression 10 during the log-linear phase. The term "AUCoTn" is the mean area under the plasma concentration-time curve from time 0 to Tmax and is used as an indicator of the rate of drug absorption, or metabolite formation. It is calculated as the arithmetic mean of the 15 area under the plasma concentration-time curve from time 0 to Tmax calculated for each individual participating in the bioavailability study. The term "AUCo..o" is the mean area under the plasma concentration-time curve extrapolated to infinity. It is 20 calculated as the arithmetic mean of the area under 5a WO 2004/037222 PCT/CA2003/001638 the plasma concentration-time curve from time 0 extrapolated to infinity, calculated for each individual participating in the bioavailability study. [0024]The term "analgesic effect" is defined for the purposes of the present invention as providing a mean blood plasma concentration of at least about 100 ng/mL of 5 tramadol. [0025]The term "C'max" is the maximum observed plasma concentration, calculated as the mean of the individual maximum blood plasma concentrations. [0026] The term "controlled release" is defined for purposes of the present invention as a method of oral drug delivery where the rate of release of the active 10 pharmaceutical ingredient from the formulation is not solely dependent on the concentration of active pharmaceutical ingredient remaining in the formulation and/or the solubility of the active pharmaceutical ingredient in the medium surrounding the formulation, and where the time course and/or location of release of an active ingredient from a pharmaceutical formulation are chosen to accomplish therapeutic or 15 convenience objectives not offered by conventional dosage forms. [0027]The term "half-life" is the apparent terminal elimination half-life. [0028]The term "HVD" is the half value duration, that is, the time during which tramadol concentrations are above one half the C'm.. This parameter is an indicator of the shape of the plasma concentration time curve. 20 [0029]The term "immediate release" is defined for purposes of the present invention as the release of an active ingredient from a pharmaceutical formulation where the rate of release of the active pharmaceutical ingredient from the pharmaceutical formulation is not retarded by means of a controlled release matrix and where the components of the pharmaceutical formulation are designed such that, upon 25 ingestion, maximum exposure of said active pharmaceutical ingredient to body tissues occurs in the minimum period of time. [0030]The term "initial administration" is defined for purposes of the present invention as the first single dose of a formulation containing an active ingredient administered to a patient or subject or the first dose administered to a patient or subject after a 30 suitable washout period. 6 WO 2004/037222 PCT/CA2003/001638 [0031]The term "MRT" is the mean residence time, which is an estimate of the average time that a tramadol molecule resides in the body following oral administration. [0032]The term "mean maximum plasma concentration" (Cmax) is defined for the 5 purposes of the present invention as the maximum mean plasma concentration. [0033]The term "mean plasma concentration" is defined for purposes of the present invention as the arithmetic mean blood plasma concentration. 0026a] [0034]The term "tmax" is the time at which Cmax is achieved. [0035]The term "Tmax " is the time at which the maximum blood plasma concentration 10 is observed for each individual participating in the bioavailability study. [0036]The term "Rstart" is the time at which plasma concentrations begin to decline in a log-linear fashion, that is, the time at which either drug absorption or metabolite formation is complete. [0037]The word "tramadol", as used herein shall refer to tramadol, its stereoisomers 15 and its pharmaceutically acceptable salts. [0038]The term "steady state" is defined for purposes of the present invention as the state, following multiple dose administration, where the rate of drug elimination matches the rate of input and the plasma drug concentrations at a given time within a dosing interval are approximately the same from one dosing interval to another. 20 BRIEF DESCRIPTION OF THE FIGURES [0039]Various features and advantages of the present invention will become clear from the more detailed description given below with reference to the accompanying drawings, in which: [0040] Figure 1: Flow diagram showing manufacturing process for tablets. 25 [0041]Figure 2: Dissolution profiles of formulations A, B and C: In vitro performance of formulations A, B and C: under USP Type 1 Conditions; sodium phosphate buffer, 50 mM, pH 6.8, 100 rpm. 6 tablets were tested per time point. [0042] Figure 3: Mean tramadol plasma concentrations following single-dose administration of (i) a 100 mg dose of the inventive controlled release composition 7 WO 2004/037222 PCT/CA2003/001638 (9), (ii) a 200 mg dose of the inventive controlled release composition (m), and (iii) a 300 mg dose of the inventive controlled release composition (A). [0043] Figure 4: Mean 0-desmethyltramadol plasma concentrations of following single dose administration of either 100 mg (+), 200 mg (0), and 300 mg (A) 5 strength tramadol formulations (A, B, and C, respectively). [0044] Figure 5: Mean tramadol plasma concentrations following single-dose administration of (i) 2 x 200 mg doses of the inventive controlled release composition (A); and (ii) Topalgic@ LP 200 mg BID q12h (A). [0045] Figure 6: Mean 0-desmethyltramadol plasma concentrations following 10 single-dose administration of (i) 2 x 200 mg doses of the inventive controlled release composition (A); and (ii) Topalgic@ LP 200 mg BID q12h (A). [0046] Figure 7: Mean steady-state tramadol and 0-desmethyltramadol plasma concentration following administration of (i) a 200 mg dose of the inventive controlled release composition (e & o); and (ii) Topalgic@ LP 100 mg BID q12h (A & A). 15 DETAILED DESCRIPTION OF THE INVENTION CORE [0047]The core of a tablet of the invention includes at least one active ingredient and a matrix, these components associated in such a way that release of the pharmaceutical ingredient from the matrix is controlled. In a specific embodiment, 20 the matrix of the core is a cross-linked high amylose starch known under the name Contramid*, and described most recently in U.S. Patent No. 6,607,748 (Lenaerts et al.), which issued August 19, 2003. A preferred formulation in the context of this invention is provided in the specification of U.S. Patent No. 6,607,748. [0048] Preferably, the core is formed by admixing the ingredients (in granular or 25 powder form) and then compressing the mixture to form the core over which the coat is subsequently formed. The weight of the core can be any percentage of the weight of the total composition between 10% and 80%. The preferred percentage depends, upon other things, the total dosage of the pharmaceutical agent. In a particular embodiment described further below, a tablet contains 100 mg tramadol 30 hydrochloride and the core is about 26% of the total weight of the tablet. In another embodiment, a tablet contains 200 mg tramadol hydrochloride and the core makes 8 WO 2004/037222 PCT/CA2003/001638 up about 33% of the total weight of the tablet. In yet another embodiment, a tablet contains 300 mg tramadol hydrochloride, and the core contributes 33% to the total weight of the tablet. Active Agent in the Core 5 [0049]An active pharmaceutical ingredient is present in the core of the composition of the present invention. A suitable pharmaceutical ingredient of the present invention is any such ingredient that is desired to be delivered in a sustained-release dosage form. A comprehensive list of suitable pharmaceutical agents can be found in The Merck Index, 12th Ed. Preferably, the pharmaceutical ingredient is, but not 10 limited to, isonicotinic acid hydrazide, sodium salicylate, pseudoephedrine hydrochloride, pseudoephedrine sulfate, acetaminophen or diclofenac sodium, verapamil, glipizide, nifedipine, felodipine, betahistine, albuterol, acrivastine, omeprazole, misoprostol, tramadol*, oxybutynin, trimebutine, ciprofloxacin, and salts thereof. In addition, the pharmaceutical agent can be an antifungal agent, such as 15 ketoconazole, or an analgesic agent such as acetylsalicylic acid, acetaminophen, paracetamol, ibuprofen, ketoprofen, indomethacin, diflunisal, naproxen, ketorolac, diclofenac, tolmetin, sulindac, phenacetin, piroxicam, mefamanic acid, dextromethorphan, other non-steroidal anti-inflammatory drugs including salicylates, pharmaceutically acceptable salts thereof or mixtures thereof. Pro-drugs are part of 20 the invention. [0050]The solubility of the pharmaceutical agent in aqueous solution can be a wide variety of values. The aqueous solubility of the pharmaceutical agent can be less than 10-3 g/L, more than 10- g/L, more than 10-2 g/L, more than 10- g/L, more than 1 g/L, more than 10 g/L, more than 100 g/L, more than 500 g/L, more than 1000 g/L, 25 or more than 2000 g/L. Preferably, the solubility is more than 100 g/L. More preferably, the solubility is more than 500 g/L. Most preferably, the solubility is more than 1000 g/L. [0051]The pharmaceutical agent can meet a variety of dosage requirement. For example, the dosage requirement of the pharmaceutical agent can be less than 1 30 mg/dosage unit, more than 1 mg/dosage unit, more than 10 mg/dosage unit, more than 100 mg/dosage unit, more than 200 mg/dosage unit, more than 300 mg/dosage unit, more than 400 mg/dosage unit, more than 500 mg/dosage unit, or more than 9 WO 2004/037222 PCT/CA2003/001638 1000 mg/dosage unit. Preferably, the pharmaceutical agent is more than 50 mg/dosage unit. More preferably, the pharmaceutical agent is 100 mg/dosage unit, or more, e.g. 150 mg/dosage unit, or 200 mg/dosage unit, or 250 mg/dosage unit, or 300 mg/dosage unit, or more. 5 [0052] Particular embodiments include a core containing tramadol hydrochloride in which the core contains between about 10% and 90% of the total tramadol present in the tablet, e.g. about 45 mg of a 100 mg strength tablet (45% of the tablet total), or about 90 of a 200 mg strength tablet (45% of the tablet total), or about 151 mg of a 300 mg strength tablet (50% of the tablet total). 10 Matrix of the Core [0053]The release from the formulation of an active pharmaceutical ingredient located in the core is slower than the release of an active pharmaceutical ingredient located in the matrix of the coat. A preferred matrix of the core is cross-linked high amylose starch, known under the name Contramid* and described in U.S. Patent No. 15 6,607,748. In particular embodiments, the matrix makes up between about 10% and about 90% by weight of the core i.e., the ratio of the matrix of the core to the active ingredient of the core (w/w) is between about 0.1 and about 10, or between about 0.2 and about 9, or between about 0.2 and about 8, or between about 0.3 and about 7, or between about 0.4 and about 6, or between about 0.5 and about 5, or between about 20 0.6 and about 4, or between about 0.7 and about 4 or between about 1 and about 4, or between about 1 and about 3 and about 1.5 and about 2.5. In one particular embodiment, the core totals about 90 mg, of which about 44 mg is Contramid*, and 45 mg is tramadol hydrochloride. In this case, Contramid* thus makes up about 49 weight percent of the core. 25 Optional Components [0054]The core composition of the present invention may optionally include a pharmaceutically acceptable carrier or vehicle. Such carriers or vehicles are known to those skilled in the art and are found, for example, in Remingtons's Pharmaceutical Sciences, 14 th Ed. (1970). Examples of such carriers or vehicles 30 include lactose, starch, dicalcium phosphate, calcium sulfate, kaolin, mannitol and powdered sugar. Additionally, when required, suitable binders, lubricants, and 10 WO 2004/037222 PCT/CA2003/001638 disintegrating agents can be included. If desired, dyes, as well as sweetening or flavoring agents can be included. [0055]The core composition of the present invention may optionally include accessory ingredients including, but not limited to dispersing agents such as 5 microcrystalline cellulose, starch, cross-linked starch, cross-linked poly(vinyl pyrrolidone), and sodium carboxymethyl cellulose; flavoring agents; coloring agents; binders; preservatives; surfactants and the like. [0056]The core can, optionally, also include one or more suitable binders known to one of ordinary skilled in the art. 10 [0057]Suitable forms of microcrystalline cellulose, for example, MCC-PH101, MCC 102, MCC-105, etc. [0058]Suitable lubricants, such as those known to the skilled person, may also be included. For example, magnesium stearate, vegetable oil, talc, sodium-stearyl fumarate, calcium stearate, stearic acid, etc. 15 [0059]Suitable glidants, known in the art, may also be included. Examples of such glidants include, but are not limited to talc, colloidal silicon dioxide, etc. Proportion [0060]The active agent is present at levels ranging from about 1 to about 90 wt.% of the total weight of the core, preferably from about 10 to about 70 wt.% of the total 20 composition of the core, more preferably from about 20 to about 60 wt.% of the total composition of the core, and probably most often between about 30 to about 50 wt.% of the total composition of the core. [0061]Of course, the total amount of all components is 100 wt.%, and those of ordinary skill in the art can vary the amounts within the stated ranges to achieve 25 useful compositions. COAT [0062]The coat of the dosage form includes a physical mixture of polyvinyl acetate and polyvinylpyrrolidone and the active pharmaceutical ingredient(s) of the coat. The coat can also include a cross-linked high amylose starch, e.g., Contramid*, and other 30 optional components. In a preferred embodiment, the coat is formed by dry compression. The weight of the coat can be any percentage of the weight of the total 11 WO 2004/037222 PCT/CA2003/001638 composition between about 10% and about 90%, but is preferably in the higher part of this range. The coat thus usually makes up between about 20% to about 90%, (w/w) of a tablet of the invention, or about 25% to about 90%, or about 30% to about 85%, or about 35 % to about 85%, or about 40% to about 85%, or about 45% to 5 about 85%, or about 45% to about 90%, or about 50% to about 90% or about 50% to about 85 %, or about 55% to about 90%, or about 55% to about 85%, or about 55% to about 80%, or about 60% to about 90%, or about 60% to about 85%, or about 60% to about 80%, or about 60% to about 75%, or about 65% to about 90%, or about 65% to about 85%, or about 65% to about 80%, or about 65% to about 75%, or about 65% 10 or about 70% or about 75%. The coat often includes an optional binding agent. Polyvinyl Acetate and Polyvinylpyrrolidone of the Coat [0063]The weight percentage of the polyvinyl acetate/polyvinylpyrrolidone mixture in the coat can be anywhere within a wide range of values. Depending on the solubility 15 in water of the active ingredient in the coat, the amount of the polyvinyl acetate/polyvinylpyrrolidone mixture in the coat can be adjusted. United States Patent Publication No. 2001/0038852 describes ways in which such adjustments can be made. For example, for active ingredients that are soluble to extremely soluble in water, polyvinyl acetate/polyvinylpyrrolidone mixture can be about 20 to about 20 80 wt.% of the coat, preferably about 30 to about 65 wt.%, or about 40 to about 55 wt.%. In a particular embodiment described below, KollidonTM SR makes up about 45% by weight of a coat that is about 31% by weight tramadol hydrochloride and about 23% xanthan gum. For active ingredients that are sparingly soluble to slightly soluble in water, the amount of polyvinyl acetate/polyvinylpyrrolidone mixture 25 is often lower, as described in United States Patent Publication No. 2001/0038852. [0064]The weight ratio of polyvinyl acetate to polyvinylpyrrolidone in the polyvinyl acetate/polyvinylpyrrolidone mixture can be a wide range of values. Preferably, such ratio is between about 6:4 and 9:1; more likely between about 7:3 and 6:1, even more preferably about 8:2. 30 [0065]The molecular weight of the polyvinyl acetate component in the polyvinyl acetate/polyvinylpyrrolidone mixture can be a wide range of values. Preferably, the average molecular weight of the polyvinyl acetate is about 100 to about 10,000,000; 12 WO 2004/037222 PCT/CA2003/001638 or about 1,000 to about 1,000,000; or about 10,000 to about 1,000,000; or about 100,000 to about 1,000,000; or about 450,000. [0066]The molecular weight of the polyvinylpyrrolidone component in the polyvinyl acetate/polyvinylpyrrolidone mixture can be a wide range of values. The average 5 molecular weight of the polyvinylpyrrolidone can be from about 100 to about 10,000,000; or about 1,000 to about 1,000,000; or about 5,000 to about 500,000; or about 10,000 to about 100,000; or about 50,000. [0067]The polyvinyl acetate and polyvinylpyrrolidone mixture can be prepared by a variety of processes including simply mixing powders of polyvinylpyrrolidone and 10 polyvinyl acetate. In a preferred embodiment, such mixture is spray dried powder of a colloidal dispersion of polyvinyl acetate and polyvinylpyrrolidone solution. Optionally, sodium lauryl sulfate is used as a stabilizer in order to prevent agglomeration during spray drying process and/or colloidal silica is used to improve the flow properties of the polyvinyl acetate/polyvinylpyrrolidone mixture. Optionally, 15 polyvinyl acetate and polyvinylpyrrolidone can be formed in a random or a block copolymer. Optional Components [0068] Suitable binding agents for the present invention include, but are not limited to, plant extracts, gums, synthetic or natural polysaccharides, polypeptides, alginates, 20 synthetic polymers, or a mixture thereof. [0069]Suitable plant extracts to be used as gelling agents include, but are not limited to, agar, ispaghula, psyllium, cydonia, ceratonia or a mixture thereof. [0070]Suitable gums to be used as gelling agents include, but are not limited to, xanthan gum, guar gum, acacia gum, ghatti gum, karaya gum, tragacanth gum or a 25 mixture thereof. [0071]Suitable synthetics or natural hydrophilic polysaccharides to be used as gelling agents include, but are not limited to, hydroxyalkylcelluloses, cellulose ethers, cellulose esters, nitrocelluloses, dextrin, agar, carrageenan, pectin, furcellaran, starch or starch derivatives, cross-linked high amylose starch, or a mixture thereof. 30 [0072]Suitable polypeptides to be used as gelling agents include, but are not limited to, gelatin, collagen, polygeline or a mixture thereof. 13 WO 2004/037222 PCT/CA2003/001638 [0073] Suitable alginates to be used as gelling agents include, but are not limited to, alginic acid, propylene glycol alginate, sodium alginate or a mixture thereof. [0074]Suitable synthetic polymers to be used as gelling agents include, but are not limited to, carboxyvinyl polymer, polyvinyl alcohol, polyvinyl pyrrolidone, polyethelene 5 oxide, polyethylene glycols, copolymers of ethylene oxide and propylene oxide and their copolymers or a mixture thereof. [0075] In a preferred embodiment, the gelling agent is a gum such as xanthan gum, guar gum, acacia gum, ghatti gum, karaya gum, tragacanth gum or a mixture thereof, PEO 7,000,000 and HPMC K100 M. 10 [0076] In a most preferred embodiment, the gelling agent is xanthan gum. Active agent of the Coat [0077]A suitable active pharmaceutical ingredient of the present invention is any active agent that it is desired to be delivered in a sustained-release dosage form. A comprehensive list of suitable pharmaceutical agents can be found in The Merck 15 Index, 12 th Ed. Preferably, the pharmaceutical agent is, but not limited to, isonicotinic acid hydrazide, sodium salicylate, pseudoephedrine hydrochloride, pseudoephedrine sulfate, acetaminophen or diclofenac sodium, verapamil, glipizide, nifedipine, felodipine, betahistine, albuterol, acrivastine, omeprazole, misoprostol, tramadol*, oxybutynin, trimebutine, ciprofloxacin, and salts thereof. In addition, the 20 pharmaceutical agent can be an antifungal agent, such as ketoconazole, or an analgesic agent such as acetylsalicylic acid, acetaminophen, paracetamol, ibuprofen, ketoprofen, indomethacin, diflunisal, naproxen, ketorolac, diclofenac, tolmetin, sulindac, phenacetin, piroxicam, mefamanic acid, dextromethorphan, other non-steroidal anti-inflammatory drugs including salicylates, pharmaceutically 25 acceptable salts thereof or mixtures thereof. [0078]The solubility of the pharmaceutical agent in aqueous solution can be a wide variety of values. The aqueous solubility of the pharmaceutical agent can be less than 10~3 g/L, more than 10-3 g/L, more than 10-2 g/L, more than 10-1 g/L, more than 1 g/L, more than 10 g/L, more than 100 g/L, more than 500 g/L, more than 1000 g/L, 30 or more than 2000 g/L. Preferably, the solubility is more than 100 g/L. More preferably, the solubility is more than 500 g/L. or even 1000 g/L. 14 WO 2004/037222 PCT/CA2003/001638 [0079]The pharmaceutical agent can meet a variety of dosage requirements. For example, the dosage requirement of the pharmaceutical agent can be less than 1 mg/dosage unit, more than 1 mg/dosage unit, more than 10 mg/dosage unit, more than 100 mg/dosage unit, more than 200 mg/dosage unit, more than 300 mg/dosage 5 unit, more than 400 mg/dosage unit, more than 500 mg/dosage unit, or more than 1000 mg/dosage unit. Preferably, the pharmaceutical agent is more than 50 mg/dosage unit. More preferably, the pharmaceutical agent is more than 100 mg/dosage unit. Most preferably, the pharmaceutical agent is more than 200 mg/dosage unit. 10 [0080]The coat can be between about 5% and about 90% by weight active pharmaceutical ingredient, or between about 5% and about 80% by weight api, or between about 10% and about 70% by weight api, or between about 10% and about 60% by weight api, or between about 15% and about 50% by weight api, or between about 15% and about 45% by weight api, or between about 15% and about 40% by 15 weight api, or between about 20% and about 35% by weight api, or between about 20% and about 30% by weight api. [0081]In particular embodiments, described further below, the weight of tramadol from a 100 mg tramadol tablet is about 21% by weight of the coat. The weight of tramadol from a 200 mg tablet is about 31 % by weight of the coat. The weight of 20 tramadol from a 300 mg tablet is about 30% by weight of the coat. ROUTES OF ADMINISTRATION [0082]The tablet composition of the present invention can be administered through, but not limited to, a number of routes such as oral, sublingual, and rectal. The preferred route of administration of the compositions of the present invention is oral. 25 [0083] Compositions of the present invention that are suitable for oral administration may be presented as discrete units such as tablets or granules. Preferably, the compositions of the present invention are presented in a tablet form. Such tablets may be conventionally formed by compression or molding. Compressed tablets may be prepared by compressing in a suitable machine the mixture of one or more 30 components described above. Molded tablets may be made by molding in a suitable machine the above components, which can be optionally moistened with an inert liquid diluent. The tablets may optionally be coated and/or have other identifying indicia visible to the consumer. A tablet can also be in a variety of forms, 15 WO 2004/037222 PCT/CA2003/001638 e.g., uncoated , dry coated, or film coated, etc. A tablet can also be in a variety of shapes (e.g., oval, sphere, etc.) and sizes. A comprehensive discussion of tablets can be found in references such as The Theory and Practice of Industrial Pharmacy by Lachman et al., 3 rd Ed. (Lea & Febiger, 1986). 5 Dissolution Profile of Sustained-Release Composition [0084]The active agent of the composition exhibits the following in vitro dissolution 10 profile when measured with a USP Type I apparatus in 50 mM phosphate, pH 6.8, and stirring between 50 and 150 rpm: an average rate of between 10% and 30% per hour of the agent is released between 0 and 2 hours when tested in vitro using a USP Type I apparatus in 50 mM phosphate, pH 6.8, and stirring between 50 and 150 rpm; or 15 between 10% and 40% of the agent is released from the formulation between 0 and about 2 hours of measurement, between about 30% and 60% of the agent is released from the formulation between 2 and about 7 hours of the measurement, between about 50% and 80% of the agent is released from the formulation between 7 and about 12 hours of measurement, and between about 80% and 100% of the 20 agent is released from the formulation after about 20 hours of measurement; or more preferably between 15% and 35% of the agent is released from the formulation between at 2 hours of measurement, between about 40% and 60% of the agent is released from the formulation between at 7 hours of the measurement, between about 60% and 25 80% of the agent is released from the formulation at 12 hours of measurement, and between about 85% and 100% of the agent is released from the formulation after about 20 hours of measurement, or between 20% and 40% of the agent is released from the formulation between at 2 hours of measurement, between about 40% and 60% of the agent is released from 30 the formulation between at 7 hours of the measurement, between about 60% and 80% of the agent is released from the formulation at 12 hours of measurement, and 16 WO 2004/037222 PCT/CA2003/001638 between about 85% and 100% of the agent is released from the formulation after about 20 hours of measurement. [0085]The present invention will be more readily understood by referring to the following examples which are given to illustrate the invention rather than to limit its 5 scope. EXAMPLES [0086]The cross-linked high amylose starch used in the these examples is made by a process comprising the steps of crosslinking and chemically modifying, followed by gelatinization and drying. Such process is described in more detail in U.S. Patent 10 No. 6,607,748 (Lenaerts et al.), which issued August 19, 2003, and known in the marketplace under the name Contramid*. and described in Examples 1 and 2. Example 1 A. Cross-Linking [0087]High amylose starch (30.0 kg) containing about 70% w/w of amylose (CI 15 AmyloGel 03003) is placed in a reactor. To this reactor is added water (55.0 1) containing sodium hydroxide (30.0 g) and sodium sulfate (2.40 kg). The resulting slurry is heated to a temperature of 300C. Phosphorus oxychloride (22.5 g) is added to the reaction mixture which is reacted for one hour. B. Chemical Modification, Hydroxyproylation 20 [0088] The crude reaction mixture from Part A is transferred into a hydroxypropylation reactor. The reaction mixture is heated to 40'C. over 30 minutes and the reaction is purged with nitrogen. After a full purge, propylene oxide (1.80 kg) is added. The reaction mixture is kept at 400C. for 20 hours. The reaction mixture is neutralized with 0.1 N H 2

SO

4 (1:2 v/v) to a pH of 5.5. The starch slurry is washed with 25 a basket-centrifuge at a speed of 1200 rpm. The obtained starch cake is re-slurrified in 35 1 of water and centrifuged a second time. The resulting starch cake is dried in a flash dryer at an inlet temperature of 1600C. and an outlet temperature of 600C. 30 C. Gelatinization [0089]The modified granular starch cake is diluted in demineralized water in order to form a slurry at a concentration of about 8% calculated on dry substance. The resulting slurry has a relative density of 1.032 kg/l compared to water. The pH of the 17 WO 2004/037222 PCT/CA2003/001638 modified starch slurry is adjusted to 6.0. The slurry is then heated to 1600C. by direct steam injection (Schlick Model 825). The temperature variation is not higher than ±10C. The slurry is held in a holding column for a period of 4 minutes at a temperature of 1600C. and a pressure of about 5.5 bar. The pressUre is then 5 reduced to atmospheric by passing through a flash. The slurry is then contained at 950C. in a hold tank. D. Spray-Drying [0090]The drying of the slurry from Part C is carried out using a Niro FSD 4 spray drying tower equipped with a 0.8 mm nozzle and fed at 10 I/hour. The inlet 10 temperature is fixed at 3000C. and the outlet temperature of 120'C. The obtained powder is a controlled release excipient with the following properties: Properties Moisture Content 4.5% Bulk Density 150 g/l Packed Density 210 g/l pH 5.4 Particle Size Peak Value 50 pm (Laser Particle Sizer-Sympatec) Example 2 A. Cross-Linking 15 [0091]High amylose starch (30.0 kg) containing about 70% w/w of amylose (Cl AmyloGel 03003) is placed in a reactor. To this reactor is added water (55.01) containing sodium hydroxide (30.0 g) and sodium sulfate (2.40 kg). The resulting slurry is heated to a temperature of 300C. Sodium trimetaphosphate (45 g) is added to the reaction mixture which is reacted for one hour. 20 B. Chemical Modification, Hydroxyproylation [0092]The crude reaction mixture from Part A is transferred into a hydroxypropylation reactor. The reaction mixture is heated to 400C. over 30 minutes and the reaction is purged with nitrogen. After a full purge, propylene oxide (1.80 kg) is added. The reaction mixture is kept at 400C. for 20 hours. The reaction mixture is neutralized 25 with 0.1 N H 2

SO

4 (1:2 v/v) to a pH of 5.5. The starch slurry is washed with a basket centrifuge at a speed of 1200 rpm. The obtained starch cake is re-slurrified in 35 I of 18 WO 2004/037222 PCT/CA2003/001638 water and centrifuged a second time. The resulting starch cake is dried in a flash dryer at an inlet temperature of 1600C. and an outlet temperature of 600 C. C. Gelatinization [0093]The modified granular starch cake is diluted in demineralized water in order to 5 form a slurry at a concentration of about 8% calculated on dry substance. The resulting slurry has a relative density of 1.032 kg/I compared to water. The pH of the modified starch slurry is adjusted to 6.0. The slurry is the heated to 1600C. by direct steam injection (Schlick Model 825). The temperature variation is not higher than ±10C. The slurry is held in a holding column for a period of 4 minutes at a 10 temperature of 1600C. and a pressure of about 5.5 bar. The pressure is then reduced to atmospheric by passing through a flash. The slurry is then contained at 950C. in a hold tank. D. Spray-Drying [0094]The slurry from Part C is carried out using a Niro FSD 4 spray-drying tower 15 equipped with a 0.8 mm nozzle and fed at 10 I/hour. The inlet temperature is fixed at 3000C. and the outlet temperature of 1200C. The obtained powder is a controlled release excipient with the following properties: Properties Moisture Content 5.2% Bulk Density 103 g/I Packed Density 155 g/l pH 5.3 Particle Size Peak Value 70 pm (Laser Particle Sizer-Sympatec) 20 [0095] Lubritab* is a product sold by Penwest Pharmaceuticals Co. (Cedar Rapids, IA, USA). KollidonTM SR is a product produced by BASF (Germany). Encompress TM is a dicalcium phosphate dihydrate which can be purchased from Mendell (Patterson, NY). Tramadol hydrochloride can be obtained from Chemagis Ltd., 3 Hashlosha 25 Street, P.O. Box 9091, 61090, Tel Aviv, Israel. Methods of synthesis and purification of tramadol are described in, for example, U.S. Patent Nos., 3,652,589, 5,414,129, 5,672,755, 5,874,620, 5,877,351, and 6,169,205. 19 WO 2004/037222 PCT/CA2003/001638 Manufacturing Procedure [0096]Tablets of the invention can be manufactured according to the process set out generally in the flow chart of Figure 1, and described in more detail below. [0097]Weighing: Raw materials are dispensed into clearly labeled containers. 5 [0098]Core Pre-Blend: Blend a portion of the Contramid@ and Colloidal Silicon Dioxide and pass through #30 mesh screen into a suitable container. [0099]Core Blend: Place a portion of the Contramid@ into a blender. Pass Tramadol Hydrochloride through a #30 mesh screen and add to blender. Rinse container with a portion of Contramid@ and add to blender. Sieve Hydrogenated 10 Vegetable Oil Type I through a #30 mesh screen and add to the blender. Add the Core Pre-Blend into the blender. Add the remaining Contramid@ into the blender, and blend all ingredients. Sieve the Magnesium Stearate through a #30 mesh screen and add blend with other ingredients. Dispense blend in suitable container and identify as Core Blend. 15 [00100] Dry Coated Pre-Blend: Blend a portion of the Xanthan Gum and all of the Colloidal Silicon Dioxide and pass through #30 mesh screen. [00101] Dry Coated Blend: Place a portion of the Kollidon@ SR into a blender. Pass Tramadol Hydrochloride through Kason Separator with a #30 mesh screen into suitable container and add to blender. Rinse container with remaining xanthan gum 20 and add to blender. Sieve Hydrogenated Vegetable Oil Type 1 through a #30 mesh screen and add to the blender. Place Dry Coated Pre-Blend and the remainder of the Kollidon@ SR into the blender, and blend with all ingredients. Sieve the magnesium stearate through a #30 mesh screen and blend with other ingredients. Dispense granulation in suitable container and identify as Dry Coated Blend. 25 [00102] Compression: Use a Manesty Dry-Cota press to produce compression-coated tablets. Example 3 [00103] Formulations A, B, and C, as shown in Table 1, were manufactured according to the process set out above. 20 WO 2004/037222 PCT/CA2003/001638 00 LOC )0 0 t )-tL -L *'4 c, co 0.4a) o s ~ \-1ic~ CO 0'J .~ E OR 96 LCj ,- 5- 6 C C C L - -. I I--I OCD C~ Cc; co (000LO

E

CC CLO \,LO ~ C.0 c o00 00 t 0 ci 0 c' Lqcm LO' 0 LO 0) " 0 LO' r P LO C .0 .e 0~ 0~ r cr) 0) C) (D ,qc') .0O c .CD co tmdC c)C E 0 LL 0) 0 OC DcmL N7C ~0 a) C: L a) a a) a, a , o1- c _0 -oL.0 4 - cu '' CO a) 0) 0~ a) 0Cc 090 z' 0 ~ w C)~ 0 > a) > - a) Iw I ®) E a ) ( -- o CD = ~ ~ =o @ a)~ 3: 03 E0 0 0C~ 0 EC rPC -d EIOD C

--------------------------------------------

ca O C C Cd 0 0a 021 WO 2004/037222 PCT/CA2003/001638 Dissolution profiles of formulations A, B and C are shown in Figure 2. Tramadol Once Daily Formulation [00104] The present invention relates to a controlled release tablet composition which provides analgesic effect within 2 hours of oral administration and lasts for at 5 least 24 hours after administration. [00105] The 200 mg dose of the inventive controlled release composition surprisingly provides a rapid onset of analgesic effect within 2 hours after oral administration, and a mean tramadol plasma concentration between 100 ng/mL and 200 ng/mL for at least 24 hours after a single dose. 10 [00106] Furthermore, at steady-state, the mean tramadol plasma concentration remains between 100 ng/mL and 350 ng/mL. The inventive controlled release compositions have surprisingly been shown to provide full clinical effect for at least 24 hours after oral administration. Bioavailability Studies 15 [00107] An object of the present invention is to provide flexible dosing options for patients with different analgesic requirements, with a once daily formulation. [00108] One embodiment of the present invention is to provide a once daily formulation which upon initial ingestion of a dose of 100 mg would provide the desired early onset of action but achieve mean tramadol plasma concentrations of at 20 least 45 ng/mL between 2 and 24 hours. [00109] A further embodiment of the present invention is to provide a once daily formulation which upon initial ingestion of a dose of 200 mg would provide the desired early onset of action but achieve mean tramadol plasma concentrations of at least 100 ng/mL between 2 and 24 hours. 25 [00110] A further embodiment of the present invention is to provide a once daily formulation which upon initial ingestion of a dose of 300 mg would provide the desired early onset of action but achieve mean tramadol plasma concentrations of at least 150 ng/mL between 2 and 24 hours. [00111] A further embodiment of the present invention is to provide a once daily 30 formulation which upon initial ingestion of a dose of 400 mg would provide the desired early onset of action but achieve mean tramadol plasma concentrations of at least 180 ng/mL between 2 and 24 hours. 22 WO 2004/037222 PCT/CA2003/001638 [00112] further embodiment of the present invention is to provide a once daily formulation which upon initial ingestion of a dose would provide a C'max to dose ratio of from about 0.90 to about 1.0. [00113] A further embodiment of the present invention is to provide a once daily 5 formulation which upon initial ingestion of a dose would provide a tramadol plasma concentration which rises steadily until peak tramadol concentrations are attained at a Tmax of about 4 hours to about 6 hours. Preferably, the Tmax occurs at about 5 hours to about 5.5 hours. [00114] A further embodiment of the present invention is to provide a once daily 10 formulation which upon initial ingestion of a dose would provide a tramadol plasma concentration which, after Tmax, declines in a slow but steady manner, reflecting continuing absorption in addition to elimination processes. Preferably, the decline in the tramadol plasma concentration after Tmax occurs in a log-linear fashion with a mean apparent terminal elimination half-life of between about 5.5 hours and about 15 6.5 hours. [00115] A further embodiment of the present invention is to provide a once daily formulation which upon initial ingestion of a dose would provide a tramadol plasma concentration which, after Tmax, declines in a slow but steady manner, reflecting continuing absorption in addition to elimination processes, and which absorption 20 continues for at least 20 hours from the time when absorption of the ingested dose begins. [00116] A further embodiment of the present invention is to provide a once daily formulation which upon initial ingestion of a dose provides a tramadol plasma concentration which, after Tma, declines in a log-linear fashion with an apparent 25 terminal elimination rate constant (Xz) of about 0.12 hW. [00117] A further embodiment of the present invention is to provide a once daily formulation which upon initial ingestion of a dose would provide a mean residence time (MRT) of tramadol ranging from about 15 hours to about 18 hours. [00118] A further embodiment of the present invention is to provide a once daily 30 formulation which upon initial ingestion of a dose would provide a half value duration (HVD) of tramadol which ranges from about 22.5 hours to about 25.4 hours. [00119] A further embodiment of the present invention is to provide a once daily formulation which upon initial ingestion of a dose would provide a C'max to AUCo 23 WO 2004/037222 PCT/CA2003/001638 ratio of from about 0.04 h" to about 0.06 h 1 . Preferably, the C'max to AUCo.. ratio is from about 0.04 h 1 to about 0.05 h 1 . The ratio C'max/AUCo- is used for evaluating the rate of drug absorption. [00120] A further embodiment of the present invention is to provide a once daily 5 formulation which upon initial ingestion of a dose would provide a mean AUCO- 24 with respect to the tramadol plasma concentration which increases proportionally with dose over the range of dosage strengths of 100 mg to 300 mg of the controlled release composition. [00121] A further embodiment of the present invention is to provide a once daily 10 formulation which upon initial ingestion of a dose of 100 mg would provide a mean AUCo-Tmax of from about 610 ng-h/mL to about 630 ng-h/mL. [00122] A further embodiment of the present invention is to provide a once daily formulation which upon initial ingestion of a dose of 200 mg would provide a mean AUCO-Tmax of from about 910 ng-h/mL to about 920 ng-h/mL. 15 [00123] A further embodiment of the present invention is to provide a once daily formulation which upon initial ingestion of a dose of 300 mg would provide a mean AUC-Tmax of from about 1570 ng-h/mL to about 1590 ng-h/mL. [00124] A further embodiment of the present invention is to provide a once daily formulation which upon initial ingestion of a dose provides a mean ratio of 20 AUCo-24/AUCo.- of tramadol plasma concentration which ranges between about 70% and about 85%. Preferably, the mean ratio of AUCO.

2 4 /AUCo- of tramadol plasma concentration ranges between about 74% and about 80%. As a result, about 15% to about 30% of the administered dose is still circulating in the plasma 24 hours post dose, depending on the dose administered. 25 [00125] A further embodiment of the present invention is to provide a once daily formulation which upon initial ingestion of a dose would provide a ratio of the C'max to the dose released to the blood plasma in the first 24 hours (AUCo-24/AUC.- multiplied by the dose) of from about 1.10 to about 1.35. Preferably the ratio is from about 1.15 to about 1.31. 30 [00126] A further embodiment of the present invention is to provide a once daily formulation which upon initial ingestion of a dose, would provide a ratio of the C'max /Tmax to the dose administered of from about 0.10 to about 0.20. Preferably the ratio is from about 0.12 to about 0.19. 24 WO 2004/037222 PCT/CA2003/001638 [00127] A further embodiment of the present invention is to provide a once daily formulation which upon initial ingestion of a dose would provide a slope in ng/ml-hr following the peak blood plasma concentration level, which does not exceed a factor of about 0.035 of the total dose administered in mg. Preferably, the factor is about 5 0.03. [00128] Tramadol pharmacokinetic parameters of the controlled release composition are presented in Table 2. 25 WO 2004/037222 PCT/CA2003/001638 CfD 0o co ) Mo c N) -Uf o0 0 Z Z m co CD CD CN co 0a 00 C\ (D cm 0 CO CD CDO) CM o Cl cm CO~- N co) a) U 0 0L IqD zCo o C C o o C I- 0 ~ N CD 0 Co D cm 30 cd N DN co -) co 0 LO N ~ Io co N Co U _ C - CD LO LO - 2 C7 0) co LO No U D CD LO CD U) CD N) ON 0MoIT~ C) a) 0) a) 0 0 0 4.

0(n CC 00 C2 00 C D ~ U CoD C U) 0 0o CoCDoCD C ) C 0) C i U)) C 0 - C . E oa~ 2 2 0 00 c 2o E, ''e 00 LL z 266 WO 2004/037222 PCT/CA2003/001638 [00129] A further embodiment of the present invention is to provide a once daily formulation which upon initial ingestion of a dose would provide a ratio of the C'max calculated with respect to the blood plasma concentration of O-desmethyltramadol, to the dose of tramadol of from about 0.19 to about 0.22. Preferably the ratio is from 5 about 0.20 to 0.21. [00130] A further embodiment of the present invention is to provide a once daily formulation which upon initial ingestion of a dose would provide an 0 desmethyltramadol plasma concentration which rises steadily until peak tramadol concentrations are attained at a Tmax of about 8 hours to about 16 hours. 10 [00131] A further embodiment of the present invention is to provide a once daily formulation which upon initial ingestion of a dose would provide an 0 desmethyltramadol plasma concentration which, after Tmax, declines in a slow but steady manner, reflecting continuing tramadol absorption and subsequent metabolite formation in addition to elimination processes. Preferably, the decline in the 0 15 desmethyltramadol plasma concentration occurs in a log-linear fashion with a mean apparent terminal elimination half-life of between about 6.7 hours and about 8.1 hours. [00132] A further embodiment of the present invention is to provide a once daily formulation which upon initial ingestion of a dose would provide the formation of 20 metabolite for at least 18 hours. [00133] A further embodiment of the present invention is to provide a once daily formulation which upon initial ingestion of a dose would, after Tmax, provide a decline in the O-desmethyltramadol plasma concentration in a log-linear fashion with an apparent terminal elimination rate constant (X,) of about 0.1 h 1 . 25 [00134] A further embodiment of the present invention is to provide a once daily formulation which upon initial ingestion of a dose would provide a half value duration (HVD) of 0-desmethyltramadol which ranges from about 25.6 hours to about 28.1 hours. [00135] A further embodiment of the present invention is to provide a once daily 30 formulation which upon initial ingestion of a dose would provide a C'max to AUCo.

ratio calculated with respect to the 0-desmethyltramadol plasma concentration, of about 0.04 h. The ratio C'max/AUCo-_ is used for evaluating the rate of metabolite formation. 27 WO 2004/037222 PCT/CA2003/001638 [00136] A further embodiment of the present invention is to provide a once daily formulation which upon initial ingestion of a dose would provide a mean AUCO- 2 4 calculated with respect to the 0-desmethyltramadol plasma concentration, which increases proportionally with dose over the range of dosage strengths of 100 mg to 5 300 mg of the controlled release composition. [00137] A further embodiment of the present invention is to provide a once daily formulation which upon initial ingestion of a dose of 100 mg would provide a mean AUCO-Tmax with respect to the O-desmethyltramadol plasma concentration of from about 175 ng-h/mL to about 180 ng-h/mL. 10 [00138] A further embodiment of the present invention is to provide a once daily formulation which upon initial ingestion of a dose of 200 mg would provide a mean AUCo-Tmax with respect to the 0-desmethyltramadol plasma concentration of from about 530 ng-h/mL to about 550 ng-h/mL. [00139] A further embodiment of the present invention is to provide a once daily 15 formulation which upon initial ingestion of a dose of 300 mg would provide a mean AUCo-Tmax with respect to the O-desmethyltramadol plasma concentration of from about 580 ng-h/mL to about 590 ng-h/mL. [00140] A further embodiment of the present invention is to provide a once daily formulation which upon initial ingestion of a dose provides a mean ratio of 20 AUCo-24/AUCo-- of 0-desmethyltramadol plasma concentration which ranges between about 65% and about 80%. Preferably, the mean ratio of AUCo- 2 4 /AUCo-- of 0-desmethyltramadol plasma concentration ranges between about 68% and about 75%. As a result, about 25% to about 32% of the active metabolite is still circulating in the plasma 24 hours post-dose. 25 [00141] A further embodiment of the present invention is to provide a once daily formulation which upon initial ingestion of a dose would provide a ratio of the C'max calculated with respect to the 0-desmethyltramadol plasma concentration, to the 0 desmethyltramadol blood plasma concentration in the first 24 hours (AUCo-24/AUComultiplied by the dose of tramadol) of from about 0.0025 to about 0.0035. Preferably 30 the ratio is from about 0.0027 to about 0.0031. [00142] 0-desmethyltramadol pharmacokinetic parameters of the controlled release composition are presented in Table 3. 28 WO 2004/037222 PCT/CA2003/001638 3 O 0) cq cq CD 0q C 0) N- m N 0) -o m co 0 2 CD N - co 0) CD wDN CD C 0 ~0 CD z S s CDl - l N- N . D CD C to 7D co CO 0q '-0 oqI E oCD CD l CDl cu CD LO N CD Q 0) CDl C_ 7D C4 C N C) 0 0 C) C- j 0 't (r - C O 0a VD - Lo C 00 0 00 0 0w E CD 0 CD 0 CD 0 0o 0 o 0 O 00 0 l 0 0 E 6 6 0 06 06 0 0 q 0 0 0 (1 CD ' D C E. E E -c CD E) a) .

E 0 ' 0 0 0 0 C6 as 29 WO 2004/037222 PCT/CA2003/001638 Example 4 (i) Dose Proportionality - Single Dose [00143] A bioavailability study was conducted to assess the dose-proportionality 5 between three dosage strengths (100 mg, 200 mg and 300 mg). This study was conducted with a suitable washout period between each administration. The doses were taken by 27 healthy human volunteers under fasting conditions. [00144] Figure 3 depicts the mean plasma concentration time-profiles of tramadol obtained in the subjects after the administration of the inventive controlled 10 release composition (dosed at 100 mg, 200 mg and 300 mg of tramadol HC). The data used to create Figure 3 is included in Table 4. Table 4 Mean (±SD) Tramadol Plasma Concentrations (nq/mL) 100 mg dose 200 mg dose 300 mg dose of the of the of the inventive inventive inventive Time controlled controlled controlled release release release composition composition composition 0 0 0 0 1 41.8 ±14.1 82.5 24.1 110.2 ±36.7 2 60.0 ± 14.6 129.2 *25.7 168.6 ± 52.1 3 69.2 ±20.2 156.5 37.0 218.1 ± 82.3 4 72.5 ±21.8 164.0 44.9 242.0 ± 96.2 5 81.7 ± 24.2 177.2 61.8 277.1 ± 153.8 6 77.9 ± 24.7 169.2 58.1 260.3 ± 134.8 8 83.0 ±25.6 164.1 52.7 243.6 ± 127.1 10 81.0 ±24.7 157.8 57.8 219.8 ±101.6 12 84.4 ± 25.3 156.4 ± 55.9 223.4 ± 85.1 16 73.0 ± 24.1 152.8 42.0 209.9 ± 70.2 20 56.4 ± 19.4 121.0 ±34.4 185.7 ± 62.7 24 47.2 ± 20.9 101.6 38.2 157.0 ± 60.4 30 26.8 ± 15.0 56.4 ± 28.3 99.9 ± 50.3 36 13.2 *9.4 29.1 ± 18.7 55.9 ± 37.9 48 3.7 3.5 8.5 ±6.7 15.7 ±13.1 15 [00145] The results from this study indicated that the 100 mg, 200 mg and 300 mg formulations of the inventive controlled release composition are dose proportional with respect to the rate and extent of absorption of tramadol and the rate and extent of formation of O-desmethyltramadol. 30 WO 2004/037222 PCT/CA2003/001638 [00146] Bioavailability studies were conducted in order to characterize the pharmacokinetic properties of the inventive controlled release composition and to demonstrate similar exposure of the drug and/or its active metabolite when compared to a reference product. 5 Example 5 (ii) Comparison to a Twice-Daily Formulation - Single Dose [00147] The 2 x 200 mg dosage of the inventive controlled release composition was compared to the twice daily formulation, Topalgic@ LP (200 mg) tablets manufactured by Laboratoires Hoechst Houde in a comparative bioavailability study 10 after administration under fasting conditions in 24 healthy human volunteers. [00148] The pharmacokinetic results from the inventive controlled release composition were compared to those obtained following twice daily administration (at 12-hour intervals) of the reference formulation in order to assess bioequivalence between the test and the reference product. Based on calculation of the 90% 15 confidence interval of the test versus reference ratios of geometric means, the extent of exposure (determined by assessment of AUCo- and AUCo_ of tramadol following dose normalization) was within the conventional bioequivalence interval of 80-125% for the log-transformed parameters. Thus the inventive controlled release composition and the twice daily formulation were found to be bioequivalent in terms 20 of the overall exposure to tramadol. Results for tramadol AUCo._. are presented in Table 5. Table 5 Comparison of AUCo. (Single-dose versus twice-daily formulation) Treatment Arithmetic Mean ± SD Geometric Mean Ratio (ng-h/mL) (90% Confidence Interval) 2 x 200 mg dose of the 9332 ±3767 inventive controlled 103 (98 - 109) release composition 1 x 200 mg 89 32 Topalgic@ LP BID 8897 * 3124 25 [00149] Figure 5 depicts the arithmetic mean plasma concentration time-course profiles of tramadol obtained after the administration of the inventive controlled 31 WO 2004/037222 PCT/CA2003/001638 release composition once a day and of the reference product in one day at 12-hour intervals in the 24 healthy volunteers. The data used to create Figure 5 is included in Table 6. Table 6 5 Mean Tramadol Plasma Concentrations (nq/mL) Test formulation Reference formulation Conc. Conc. 2x200 mg dose of the inventive Time composition Time 200 mg BID 0 0 0 0 1 138.49 ±58.62 1 101.93 ±43.72 2 257.56 ± 81.20 2 226.89 ± 72.90 3 350.21 166.42 3 296.35 ± 99.46 4 373.93 124.33 4 318.22 ± 91.27 5 427.66 * 166.90 5 330.88 ± 98.68 6 424.72± 176.20 6 281.67 85.95 9 408.61 * 196.28 9 236.39 + 87.89 12 357.88 ±162.48 12- 167.41 65.49 16 312.70± 153.34 13 181.96 70.51 20 243.94 ± 117.93 14 284.67 126.76 24 184.96 ± 102.90 15 378.82 136.23 30 99.78 ±61.60 16 396.87 146.56 36 51.01 ± 43.33 17 388.83 142.32 48 0 18 396.38 ±140.65 21 331.81 ±121.52 24 275.00 110.61 30 118.69 64.92 36 54.04 39.07 48 0 [00150] Figure 6 depicts the arithmetic mean plasma concentration time-course profiles of O-desmethyltramadol obtained after the administration of the inventive 10 controlled release composition once-a-day and of the reference product in one day at 12-hour intervals in the 24 healthy volunteers. The data used to create Figure 6 is included in Table 7. 32 WO 2004/037222 PCT/CA2003/001638 Table 7 Mean (±SD) 0-desmethyltramadol Plasma Concentrations (nq/mL) Test formulation Reference formulation Conc. Conc. 2x200 mg dose of the inventive Time composition Time 200 mg BID 0 0 0 0 1 29.82 17.0 1 17.7 14.6 2 57.8±17.0 2 48.3 17.5 3 76.3 31.6 3 66.2 25.9 4 84.9 30.9 4 74.3 26.2 5 98.0 41.4 5 80.64 ±29.2 6 100.6 41.7 6 74.3 26.1 9 99.9 *41.7 9 68.1 24.6 12 96.52 38.8 12 56.6 22.1 16 83.9 32.6 13 59.1 23.8 20 68.2 28.8 14 75.1 32.6 24 57.6 28.0 15 92.6 38.0 30 33.2 ± 20.0 16 96.7 37.0 36 0 17 97.0 34.5 48 0 18 100.4 33.6 21 93.0 32.4 24 83.3 37.8 30 44.4 21.6 36 18.1 16.8 48 0 5 Example 6 (iii) Comparison to a Twice Daily Formulation - Steady State [00151] The 200 mg dosage of the inventive controlled release composition was compared to the twice daily formulation, Topalgic@ LP (100 mg) tablets, manufactured by Laboratoires Hoechst Houd6, in a comparative bioavailability study 10 after multiple administration under fasting conditions in 26 healthy human volunteers. [00152] The results from this study indicated that the inventive controlled release composition is equivalent to the reference product with respect to the rate and extent of absorption of tramadol and the rate and extent of formation of 0 desmethyltramadol. The comparative bioavailability of the two products was 15 assessed on the basis of the confidence interval for the primary variable AUCs for 33 WO 2004/037222 PCT/CA2003/001638 tramadol and 0-desmethyltramadol in relation to the conventional bioequivalence range of 80% to 125%. Results for tramadol AUCss are presented in Table 8. Table 8 Comparison of AUCq,_(Once-a-day versus twice-daily formulation) Treatment Arithmetic Mean ± SD Geometric Mean Ratio (ng-h/mL) (90% Confidence Interval) 200 mg dose of the 5185 ±1460 inventive controlled 92.4 (87.5 - 97.5) release composition Topalgic@ LP 100 mg 5538 ± 1214 BID 5 [00153] Figure 7 depicts the arithmetic mean plasma concentration time-course profiles of tramadol and O-desmethyltramadol following administration of a 200 mg dose of the inventive controlled release composition once a day and of the reference product (Topalgic@ LP 100 mg BID) in one day at 12 hour intervals. The data used 10 to create Figure 7 is included in Table 9. 34 WO 2004/037222 PCT/CA2003/001638 Table 9 Mean (±SD) Tramadol and 0-desmethyltramadol Plasma Concentrations (nq/mL) Test formulation (200 mg dose of the inventive controlled release composition) Reference formulation (100 mg BID) Time Tramadol Metabolite Time Tramadol Metabolite 0 113.3 ±48.8 37.6 9.0 0 157.8 ± 48.8 49.1 ± 10.7 1 195.4 ±58.4 49.9 13.9 1 220.2 ± 61.1 58.1 ± 12.9 2 249.5 ± 61.0 58.9 14.4 2 251.6 ± 60.9 63.1 ± 14.6 3 285.0 ± 66.0 65.4 16.3 2.5 282.7 ± 65.3 68.0 ± 14.7 4 290.6 ± 65.5 66.2 16.0 3 290.8 ± 59.7 69.4 ± 15.6 5 298.9 ± 81.1 67.3 16.7 3.5 290.9 ±70.6 69.6 ± 15.7 6 280.0 ±70.7 67.7 17.5 4 297.3 ±71.3 71.3 ± 15.3 9 244.9 ± 58.4 63.9 16.8 4.5 305.2 ± 75.2 72.8 ± 15.6 12 226.0 ±70.2 59.8 17.2 5 281.8 ±65.5 69.1 ± 15.7 16 209.4 ± 73.4 57.3 14.8 6 262.8 ±55.5 67.4 ± 17.3 20 161.5 ±68.9 47.9 12.1 7 243.9 ±60.2 64.9±15.2 24 119.9 ±59.1 37.1 8.9 9 198.0 ± 54.4 57.0 ±12.8 12 154.6 ± 47.8 46.2 ±10.5 13 203.5 ± 55.4 53.2 ± 12.8 14 260.7 ± 54.2 63.7 ± 15.0 14.5 307.2 ± 59.9 72.2 ± 16.5 15 303.7 ±60.5 73.2 ±17.1 15.5 290.7 ± 54.3 71.3 ± 16.8 16 289.0 ±54.6 72.1 ± 15.6 16.5 276.4 ± 53.2 72.1 ± 16.8 17 267.6 ±55.2 71.6 ±16.8 18 244.6 ± 58.4 68.2 ± 15.0 19 237.1 ±59.4 66.4 ± 14.8 21 201.5 ±52.7 57.9 ± 12.0 24 156.9 ±49.9 49.6 ± 10.1 [00154] The present invention is not limited in scope by the specific 5 embodiments disclosed in these examples which are intended to illustrate the most preferred embodiments of the invention. Indeed, various modifications of the invention or other embodiments which are functionally equivalent to those shown and described herein will become apparent to those skilled in the art and are intended to be.covered by the appended claims. 10 [00155] A number of references have been cited, the entire disclosures of which are incorporated herein by reference. [00156] Although various examples of combined elements of the invention have been described, it will also be understood that these are not intended to be exhaustive and features of one embodiment may be combined with those of another, 35 and such other combinations are contemplated to be within the scope of the invention disclosed therein. In the claims which follow and in the preceding 5 description of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but 10 not to preclude the presence or addition of further features in various embodiments of the invention. It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute is an admission that the publication forms a part of the common general knowledge in the art, in Australia or any other country. 36

Claims

1. A solid dosage formulation comprising: a core comprising an active pharmaceutical ingredient 5 and a matrix and a coat comprising a physical mixture of polyvinyl acetate and polyvinyl pyrrolidone and an active pharmaceutical ingredient, in which 10 the formulation, upon initial administration of one dose, provides an onset of analgesic effect within 2 hours, which analgesic effect continues for at least 24 hours after administration, and/or release from the formulation of the active ingredient located in the core 15 is slower than the release of the active ingredient located in the matrix of the coat.

2. The solid dosage formulation according to claim 1, wherein the formulation, upon initial administration of 20 one dose, provides a mean plasma concentration of at least 100 ng/mL within 2 hours of administration and continues to provide a mean plasma concentration of at least 100 ng/mL for at least 22 hours after administration. 25

3. The solid dosage formulation according to claim 1, wherein the formulation, upon initial administration of one dose, provides a mean plasma concentration of at least 100 ng/mL within 2 hours of administration and continues to provide a mean plasma concentration of at least 100 30 ng/mL for at least 23 hours after administration.

4. The solid dosage formulation according to claim 1, wherein the formulation, upon initial administration of one dose, provides a mean plasma concentration of at least 35 100 ng/mL within 2 hours of administration and continues to provide a mean plasma concentration of at least 100 ng/mL for at least 24 hours after administration. 37

5. The solid dosage formulation according to any one of claims 1 to 4, wherein the active pharmaceutical ingredient of the core and of the coat is the same and is 5 tramadol or a stereoisomer or a pharmaceutically acceptable salt thereof.

6. The solid dosage formulation according to claim 5, wherein the formulation comprises about 200 mg of tramadol 10 or a salt thereof.

7. The solid dosage formulation according to claim 5, comprising 100 mg of tramadol or a salt thereof, wherein the composition, upon initial administration of one dose, 15 provides a mean plasma concentration of at least 50 ng/mL within 2 hours of administration and continues to provide a mean plasma concentration of at least 50 ng/mL for at least 22 hours after administration. 20

8. The solid dosage formulation according to claim 5, comprising 100 mg of tramadol or a salt thereof, wherein the composition, upon initial administration of one dose, provides a mean plasma concentration of at least 50 ng/mL within 2 hours of administration and continues to provide 25 a mean plasma concentration of at least 50 ng/mL for at least 23 hours after administration.

9. The solid dosage formulation according to claim 5, comprising 300 mg of tramadol or a salt thereof, wherein 30 the composition, upon initial administration of one dose, provides a mean plasma concentration of at least 150 ng/mL within 2 hours of administration and continues to provide a mean plasma concentration of at least 150 ng/mL for at least 22 hours after administration. 35

10. The solid dosage formulation according to claim 5, comprising 300 mg of tramadol or a salt thereof, wherein 38 the composition, upon initial administration of one dose, provides a mean plasma concentration of at least 150 ng/mL within 2 hours of administration and continues to provide a mean plasma concentration of at least 150 ng/mL for at s least 23 hours after administration.

11. The solid dosage formulation according to claim 5, comprising 300 mg of tramadol or a salt thereof, wherein the composition, upon initial administration of one dose, 10 provides a mean plasma concentration of at least 150 ng/mL within 2 hours of administration and continues to provide a mean plasma concentration of at least 150 ng/mL for at least 24 hours after administration. 15

12. The solid dosage formulation according to claim 5, comprising 200 mg of tramadol or a salt thereof, wherein upon initial administration of 400 mg, the composition provides a mean plasma concentration of at least 200 ng/mL for at least 22 hours after administration. 20

13. The solid dosage formulation according to claim 5, comprising 200 mg of tramadol or a salt thereof, wherein upon initial administration of 400 mg, the composition provides a mean plasma concentration of at least 190 ng/mL 25 for at least 23 hours after administration.

14. The solid dosage formulation according to claim 5, comprising 200 mg of tramadol or a salt thereof, wherein upon initial administration of 400 mg, the composition 30 provides a mean plasma concentration of at least 180 ng/mL for at least 24 hours after administration.

15. The solid dosage formulation according to claim 7 or 8. wherein the mean maximum plasma concentration (Cmax) is 35 less than 100 ng/mL.

16. The solid dosage formulation according to claim 7 or 39 8, wherein the mean maximum plasma concentration (Cmax) is less than 300 ng/mL.

17. The solid dosage formulation according to claim 7 or 5 8, wherein the mean maximum plasma concentration (Cmax) is less than 200 ng/mL.

18. The solid dosage formulation according to claim 7 or 8, wherein the mean maximum plasma concentration (Cmax) is 10 less than 2.2 times the mean plasma concentration obtained 24 hours after administration (C24h).

19. The solid dosage formulation according to claim 9, 10 or 11, wherein the mean maximum plasma concentration is (Cmax) is less than 300 ng/mL.

20. The solid dosage formulation according to claim 9, 10 or 11, wherein the mean maximum plasma concentration (Cmax) is less than two times the mean plasma 20 concentration obtained 24 hours after administration (C24h).

21. The solid dosage formulation according to claim 12, 13 or 14, wherein the mean maximum plasma concentration 25 (Cmax) is less than 2.3 times the mean plasma concentration obtained 24 hours after administration (C24h).

22. The solid dosage formulation according to any one of 30 claims 2 to 4 and 7 to 21, wherein median time to the mean maximum plasma concentration (tmax) is between 2 and 10 hours.

23. The solid dosage formulation according to claim 22, 35 wherein the tmax is between 3 and 6 hours.

24. The solid dosage formulation according to claim 23, 40 wherein the tmax is between 5 and 6 hours.

25. The solid dosage formulation according to claim 5, comprising 200 mg of tramadol or a salt thereof, wherein 5 the composition, upon initial administration of one dose, provides an 0-desmethyltramadol mean plasma concentration of at least 24 ng/mL within 2 hours of administration and continues to provide an 0-desmethyltramadol mean plasma concentration of at least 25 ng/mL for at least 24 hours 10 after administration.

26. The solid dosage formulation according to claim 5, comprising 100 mg of tramadol or a salt thereof, wherein the composition, upon initial administration of one dose, 15 provides an 0-desmethyltramadol mean plasma concentration of at least 11 ng/mL within 2 hours of administration and continues to provide an 0-desmethyltramadol mean plasma concentration of at least 12 ng/mL for at least 24 hours after administration. 20

27. The solid dosage formulation according to claim 5, comprising 300 mg of tramadol or a salt thereof, wherein the composition, upon initial administration of one dose, provides an 0-desmethyltramadol mean plasma concentration 25 of at least 32 ng/mL within 2 hours of administration and continues to provide an O-desmethyltramadol mean plasma concentration of at least 32 ng/mL for at least 24 hours after administration. 30

28. The solid dosage formulation according to claim 5, comprising 200 mg of tramadol or a salt thereof, wherein upon initial administration of 400 mg, the composition provides an 0-desmethyltramadol mean plasma concentration of at least 50 ng/mL within 2 hours of administration and 35 continues to provide an 0-desmethyltramadol mean plasma concentration of at least 50 ng/mL for at least 24 hours after administration. 41

29. The solid dosage formulation according to any one of claims 1 to 28, wherein said formulation is a tablet. 5

30. The solid dosage formulation according to any one of claims 5 to 21, wherein between 10% and 40% of tramadol is released from the formulation between 0 and about 2 hours of measurement, between about 30% and 60% of tramadol is released from the formulation between 2 and about 7 hours 10 of the measurement, between about 50% and 80% of tramadol is released from the formulation between 7 and about 12 hours of measurement, and between about 80% and 100% of tramadol is released from the formulation after about 20 hours of measurement. 15

31. The solid dosage formulation according to any one of claims 1 to 28, wherein the formulation, upon initial administration, provides an onset of analgesic effect within 2 hours, which therapeutic effect continues for at 20 least 24 hours after administration and having a dissolution rate in vitro when measured with HPLC-USP apparatus Type 1 at 100 rpm in 50mM sodium phosphate buffer at pH 6.8, from about 5% to about 30% after 1 hour; from about 15% to about 40% after 2 hours; from about 20% 25 to about 50% after 4 hours, from about 30% to about 70% after 8 hours; from about 40% to about 90% after 12 hours; from about 50% to about 100% after 16 hours; from about 60% to about 100% after 24 hours. 30

32. The solid dosage formulation according to any one of claims 1 to 28, wherein the formulation, upon initial administration, provides an onset of analgesic effect within 2 hours, which therapeutic effect continues for at least 24 hours after administration and having a 35 dissolution rate in vitro when measured with HPLC-USP apparatus Type 1 at 100 rpm in 50mM sodium phosphate buffer at pH 6.8, from about 10% to about 25% after 1 42 hour; from about 15% to about 30% after 2 hours; from about 25% to about 40% after 4 hours; from about 40% to about 55% after 8 hours; from about 60% to about 75% after 12 hours; from about 70% to about 90% after 16 hours; from 5 about 90% to about 100% after 24 hours.

33. The solid formulation of claims 31 or 32, wherein the composition comprises 200 mg of tramadol or a salt thereof. 10

34 A solid dosage formulation comprising: a core comprising an active pharmaceutical ingredient and a matrix and a coat comprising a physical mixture of polyvinyl 15 acetate and polyvinylpyrrolidone and an active pharmaceutical ingredient, wherein the active pharmaceutical ingredient and the matrix of the core are associated in such a way that release of 20 the pharmaceutical ingredient from the matrix of the core is controlled, so that release from the formulation of the active ingredient located in the core is slower than the release of the active pharmaceutical ingredient located in the matrix of the coat. 25

35. The formulation according to claim 34, having an in vitro dissolution profile when measured with a USP Type I apparatus in 50 mM phosphate at a pH 6.8 and while stirring between 50 and 150 rpm as follows: Elapsed Time in Hours Weight-percent release of active ingredient 0 - 2 10 - 40 2 - 7 30 - 60 7 - 12 50 - 80 20 80 - 100 30 43

36. The formulation according to claim 34 or 35, wherein the composition, upon initial administration of one dose, provides a mean plasma concentration of at least 100 ng/mL within two hours of administration and continues to s provide a mean plasma concentration of at least 100 mg/mL for at least 22 hours after administration.

37. The formulation according to any one of claims 34 to 36, wherein the active pharmaceutical ingredient is 10 present in the core in an amount between 30 and 50 weight percent of the total composition of the core.

38. The formulation according to any one of claims 34 to 37, wherein the active ingredient is present in the coat 15 in an amount in the range between 15 and 40 weight percent.

39. The formulaion according to any one of claims 34 to 38, wherein the polyvinyl acetate of the coat has a 20 molecular weight in the range from 100,000 to 1,000,000.

40. The formulation according to any one of claims 34 to 39, wherein the polyvinylpyrrolidone of the coat has a molecular weight in the range from 10,000 to 100,000. 25

41. The formulation according to any one of claims 34 to 40, wherein the coat further comprises xanthan.

42. The formulation according to any one of claims 34 to 30 41, wherein the matrix of the core is cross-linked high amylose starch.

43. The formulation according to any one of claims 34 to 42, wherein the active ingredient of the core has a 35 solubility greater than 500 g/L.

44. The formulation according to any one of claims 34 to 44 43, wherein the active ingredient of the coat has a solubility greater than 500 g/L.

45. The formulation according to any one of claims 34 to 5 44, wherein the pharmaceutical ingredient of the core and of the coat is the same and is tramadol or a stereoisomer or pharmaceutically acceptable salt thereof.

46. The formulation according to any one of claims 34 to 10 45, wherein the formulation is a once daily oral pharmaceutical composition for controlled release of tramadol or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the composition upon initial administration of one dose, provides a tramadol plasma is concentration of at least 100 ng/mL within two hours of administration and continues to provide a tramadol mean plasma concentration of at least 100 ng/mL for at least 22 hours after administration. 20

47. The formulation according to claim 46, wherein the mean maximum plasma concentration (Ca,) is less than 2.2 times the mean plasma concentration obtained 24 hours after administration (C24h). 25

48. A tablet comprising the formulation according to any one of claims 34 to 47.

49. A solid dose formulation substantially as herein described with reference to the accompanying examples 30 apart from the comparative examples.

50. A tablet substantially as herein described with reference to the accompanying examples apart from the comparative examples. 35

51. A solid dose formulation substantially as herein 45 described with reference to the accompanying drawings.

52. A tablet substantially as herein described with reference to the accompanying drawings. 46