EP1746993A1

EP1746993A1 - Controlled release metformin compositions

Info

Publication number: EP1746993A1
Application number: EP05742346A
Authority: EP
Inventors: Xiu-Xiu Cheng; Edward I. Cullen
Original assignee: Andrx Laboratories LLC
Current assignee: Andrx Laboratories LLC
Priority date: 2004-04-29
Filing date: 2005-04-29
Publication date: 2007-01-31
Also published as: CA2564750A1; WO2005107750A1; EP1746993A4; JP2007535557A

Abstract

A method for treating a patient using an antidiabetic drug, said method comprising administering to the patient a high dose of the antidiabetic drug wherein said antidiabetic drug exhibits one or more does proportional pharmacokinetic parameters is described.

Description

CONTROLLED RELEASE METFORMIN COMPOSITIONS

CROSS REFERENCE TO RELATED APPLICATIONS This application claims benefit to US Provisional Patent Application Serial No. 60/566,491 filed April 29, 2004 and is also a Continuation-In-Part of US Patent Application Serial No. 10/796,41 1 filed March 9, 2004 which is a continuation of US Patent Application Serial No. 09/705,630 filed November 3, 2000, now US Patent No. 6,866,866 the disclosures of all the aforementioned applications of which are hereby incorporated by reference.

Background of the Invention

The present invention relates to controlled release unit dose formulations containing an antidiabetic drug, e.g., antihyperglycemic drug. More specifically, the present invention relates to an oral dosage form comprising a biguanide such as metformin or buformin or a pharmaceutically acceptable salt thereof such as metformin hydrochloride or the metformin salts described in United States Patent Nos. 3,957,853 and 4,080,472 which are incorporated herein by reference. In the prior art, many techniques have been used to provide controlled and extended- release pharmaceutical dosage forms in order to maintain therapeutic serum levels of medicaments and to minimize the effects of missed doses of drugs caused by a lack of patient compliance. In the prior art are extended release tablets which have an osmotically active drug core surrounded by a semipermeable membrane. These tablets function by allowing a fluid such as gastric or intestinal fluid to permeate the coating membrane and dissolve the active ingredient so it can be released through a passageway in the coating membrane or if the active ingredient is insoluble in the permeating fluid, pushed through the passageway by an expanding agent such as a hydrogel. Some representative examples of these osmotic tablet systems can be found in United States Patent Nos. 3,845,770, 3,916,899, 4,034,758, 4,077,407 and 4,783,337. United States Patent No. 3,952,741 teaches an osmotic device wherein the active agent is released from a core surrounded by a semipermeable membrane only after sufficient pressure has developed within the membrane to burst or rupture the membrane at a weak portion of the membrane. The basic osmotic device described in the above cited patents have been refined over time in an effort to provide greater control of the release of the active ingredient. For example United States Patent Nos. 4,777,049 and 4,851,229 describe an osmotic dosage form comprising a semipermeable wall surrounding a core. The core contains an active ingredient and a modulating agent wherein the modulating agent causes the active ingredient to be released through a passageway in the semipermeable membrane in a pulsed manner. Further refinements have included modifications to the semipermeable membrane surrounding the active core such as varying the proportions of the components that form the membrane; i.e., United States Patent Nos. 5,178,867, 4,587,117 and 4,522,625 or increasing the number of coatings surrounding the active core; i.e., U.S. Patent Nos. 5,650,170 and 4,892,739. Although vast amounts of research has been performed on controlled or sustained release compositions and in particular on osmotic dosage forms, very little research has been performed in the area of controlled or sustained release compositions that employ antihyperglycemic drugs. Metformin is an oral antihyperglycemic drug used in the management of non-insulin- dependent diabetes mellitus (NIDDM). It is not chemically or pharmacologically related to oral sulfonylureas. Metformin improves glucose tolerance in NIDDM patients by lowering both basal and postprandial plasma glucose. Metformin hydrochloride is currently marketed as GLUCOPHAGE® tablets by Bristol-Myers Squibb Co. Each GLUCOPHAGE® tablet contains 500, 850 or 1000 mg of metformin hydrochloride. There is no fixed dosage regimen for the management of hyperglycemia in diabetes mellitus with GLUCOPHAGE®. Dosage of GLUCOPHAGE® is individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended dose of 2550 mg per day. Metformin has been widely prescribed for lowering blood glucose in patients with NIDDM. However, being a short acting drug, metformin requires twice-daily (b.i.d.) or three- times-a-day (t.i.d.) dosing. Adverse events associated with metformin use are often gastrointestinal in nature (e.g., anorexia, nausea, vomiting and occasionally diarrhea, etc.). These adverse events may be partially avoided by either reducing the initial and/or maintenance dose or using an extended-release dosage form. Another clear advantage of an extended release dosage form is a reduction in the frequency of administration. All of these findings suggest that an extended-release dosage form of metformin may improve the quality of therapy in patients with NIDDM and the safety profile relative to a conventional dosage form. The limited work on controlled or sustained release formulations that employ antihyperglycemic drugs such as metformin hydrochloride includes the combination of the antihyperglycemic drug and an expanding or gelling agent to control the release of the drug from the dosage form. This research is exemplified by the teachings of WO 96/08243 and by the GLUCOPHAGE® metformin HC1 product. It is reported in the 50^th Edition of the Physicians' Desk Reference, copyright 1996, p. 753, that food decreases the extent and slightly delays the absorption of metformin delivered by the GLUCOPHAGE® dosage form. This decrease is shown by approximately a 40% lower peak concentration, a 25% lower bioavailability and a 35-minute prolongation of time to peak plasma concentration following administration of a single GLUCOPHAGE® tablet containing 850 mg of metformin HC1 with food compared to the similar tablet administered under fasting conditions. A controlled release metformin dosage form is also described in WO 99/47128. This reference describes a controlled release delivery system for metformin which includes an inner solid particulate phase formed of substantially uniform granules containing metformin and one or more hydrophilic polymers, one or more hydrophobic polymers and one or more hydrophobic materials, and an outer continuous phase in which the above granules are embedded and dispersed throughout. The outer continuous phase includes one or more hydrophilic polymers, one or more hydrophobic polymers and one or more hydrophobic materials. WO 99/47125 (commonly assigned) discloses controlled release metformin formulations providing a Tmax from 8 to 12 hours.

Objects and Summary of the Invention It is an object of the present invention to provide a controlled or sustained release of an antihyperglycemic drug which provides effective control of blood glucose levels in humans. It is a further object of the present invention to provide a method of treating human patients with non-insulin-dependent diabetes mellitus (NIDDM) on a once-a-day basis with an antihyperglycemic drug which provides effective control of blood glucose levels in humans. It is a further object of the present invention to provide formulations for treating human patients with non-insulin-dependent diabetes mellitus (NIDDM) which provides advantages over the state-of-the-art, and which may be administered on a once-a-day basis by itself or together with other antidiabetic agents, and methods thereof. It is a further object of the present invention to provide a controlled or sustained release formulation of an antihyperglycemic drug wherein the bioavailability of the drug is not decreased by the presence of food. It is a further object of the present invention to provide a controlled or sustained release formulation of an antihyperglycemic drug that does not employ an expanding polymer. It is also a further object of the present invention to provide a controlled or sustained release formulation of an antihyperglycemic drug that can provide continuous and non-pulsating therapeutic levels of the drug to an animal or human in need of such treatment over a twelve hour to twenty-four hour period. It is an additional object of other embodiments of the present invention to provide a controlled or sustained release formulation for an antihyperglycemic drug that obtains peak plasma levels from 5.5 to 7.5 hours after administration under various conditions. Alternatively, the time to peak plasma levels are from 6.0 to 7.0, from 5.5 to 7.0 or from 6.0 to 7.5. It is also an object of this invention to provide a controlled or sustained release pharmaceutical formulation having a homogeneous core wherein the core component may be made using ordinary tablet compression techniques. In accordance with the above-mentioned objects and others, the present invention provides a controlled release oral dosage form comprising an antihyperglycemic drug, preferably a biguanide (e.g., metformin or a pharmaceutically acceptable salt thereof) that is suitable for providing once-a-day administration of the drug, wherein the dosage form provides a mean time to maximum plasma concentration (T_max) of the drug from 5.5 to 7.5 hours after administration. The dosage form comprises the drug and a membrane. In certain preferred embodiments, the dosage form comprises a tablet. In preferred embodiments, the controlled release oral dosage form of the present invention is a tablet comprising: (a) a core comprising: (i) the antihyperglycemic drug; (ii) optionally a binding agent; and (iii) optionally an absorption enhancer;

(b) a membrane coating surrounding the core; and

(c) at least one passageway in the membrane. When the drug is metformin or a pharmaceutically acceptable salt thereof and is administered on a once-a-day basis, the daily dose may vary, e.g., from about 500 mg to about 2500 mg. Such daily dose may be contained in one controlled-release dosage form of the invention, or may be contained in more than one such dosage form. For example, a controlled- release metformin dosage form may be formulated to contain about 1000 mg of the drug, and two of said dosage form may be administered together to provide once-a-day metformin therapy. The daily dose of the drug (i.e. metformin or pharmaceutically acceptable salt thereof) may range from about 500 mg to about 2500 mg, from about 1000 mg to about 2500 mg, or from about 2000 mg to about 2500 mg, depending on the clinical needs of the patient. In certain preferred embodiments, the controlled release solid oral dosage form of the present invention provides a width at 50% of the height of a mean plasma concentration/time curve of the drug (e.g., of metformin) from about 4.5 to about 13 hours, more preferably from about 5.5 to about 10 hours, more preferably from about 6 to about 8 hours. In certain embodiments, the controlled release oral dosage form of the present invention provides a mean maximum plasma concentration (C_max) of the antihyperglycemic drug which is more than about seven times the mean plasma level of said drug at about 24 hours after administration. In preferred embodiments, the controlled release oral dosage form of the present invention provides a mean maximum plasma concentration (C_max) of the drug which is from about 7 times to about 14 times the plasma level of the drug at about 24 hours after the administration, more preferably from about 8 times to about 12 times the plasma level of the drug at about 24 hours after administration. In certain embodiments of the present invention, when the drug is metformin or a pharmaceutically acceptable salt thereof, the controlled release oral dosage form provides a mean maximum plasma concentration (C_max) of the drug that is about 1500 ng/ml to about 3000 ng/ml, based on administration of a 2000 mg once-a-day dose of metformin, more preferably about 1700 ng/ml to about 2000 ng/ml, based on administration of a 2000 mg once-a-day dose of metformin. In certain embodiments of the present invention, when the drug is metformin or a pharmaceutically acceptable salt thereof, the controlled release dosage form provides a mean AUC_0-2 _hr that is about 17200 ng.hr/ml to about 33900 ng.hr/ml, based on administration of a 2000 mg once-a-day dose of metformin; preferably about 17200 ng.hr/ml to about 26500 ng.hr/ml, based on administration of a 2000 mg once-a-day dose of metformin; more preferably aboutl9800 ng.hr/ml to about 33900 ng.hr/ml, based on administration of a 2000 mg once-a-day dose of metformin. In certain embodiments of the invention, the administration of the antihyperglycemic drug, e.g., at least one metformin dosage form provides a mean AUCo_-2 hr from at least 80%), preferably at least 90%) of the mean AUC_0-2 provided by administration of the reference standard (GLUCOPHAGE) twice a day , wherein the daily dose of the reference standard is equal to the once-a day dose of metformin administered in the controlled release oral dosage form of the present invention. In certain embodiments of the present invention, the controlled release dosage form exhibits the following dissolution profiles of the antihyperglycemic drug (e.g., metformin) when tested in a USP type 2 apparatus at 75 φm in 900 ml of simulated intestinal gastric fluid (pH 7.5 phosphate buffer) at 37°C: 0-30%> of the drug released after 2 hours; 10-45%) of the drug released after 4 hours; 30-90% of the drug released after 8 hours; not less than 50%> of the drug released after 12 hours; not less than 60%> of the drug released after 16 hours; and not less than 70%> of the drug released after 20 hours. In certain preferred embodiments, the controlled release solid oral dosage form exhibits the following dissolution profiles when tested in USP type 2 apparatus at 75 m in 900 ml of simulated intestinal gastric fluid (pH 7.5 phosphate buffer) at 37° C: 0-25%> of the drug (e.g., metformin or a pharmaceutically acceptable salt thereof) released after 2 hours; 20-40%) of the drug released after 4 hours; 45-90% of the drug released after 8 hours; not less than 60%> of the drug released after 12 hours; not less than 70%) of the drug released after 16 hours; and not less than 80%) of the drug released after 20 hours. With respect to embodiments of the present invention where the antihyperglycemic drug is metformin, it has been found that drugs such as metformin provide substantially linear pharmacokinetics up to a level of about 2 grams per day. Therefore, it is contemplated for puφoses of the present invention that a given plasma level (e.g., C_max) of metformin per specified dose will be directly proportional to other doses of metformin. Such proportional doses and plasma levels are contemplated to be within the scope of the invention and to be within the scope of the appended claims. The dosage form of the present invention can provide therapeutic levels of the antihyperglycemic drug for twelve to twenty-four hour periods and does not exhibit a decrease in bioavailability if taken with food. In fact, a slight increase in the bioavailability of the antihyperglycemic drug is observed when the controlled release dosage form of the present invention is administered with food. In a preferred embodiment, the dosage form can be administered once-a-day, ideally with or after a meal, preferably with or after the evening meal, and provides therapeutic levels of the drug throughout the day with peak plasma levels being obtained between 5.5 to 7.5 hours after administration. The present invention is also directed to a method of lowering blood glucose levels in human patients needing treatment for non-insulin-dependent diabetes mellitus (NIDDM), comprising orally administering to human patients on a once-a-day basis a dose of a drug comprising a biguanide (e.g., metformin or a pharmaceutically acceptable salt thereof), said drug being contained in at least one solid oral controlled release dosage form of the present invention. When the drug is metformin, the daily dose of the drug may be from about 500 mg to about 2500 mg, from about 1000 mg to about 2500 mg, or from about 2000 mg to about 2500 mg, depending on the clinical needs of the patient. The controlled release dosage form of the present invention provides a delayed T_max, as compared to the T_max provided by GLUCOPHAGE. The delayed T_max occurs from 5.5 to 7.5 hours after administration. If the drug (e.g., metformin) is administered at dinner time, the T_max would occur during the time when gluconeogenesis is usually at its highest (e.g., around 2 a.m.). The present invention also includes a method of treating patients with NIDDM comprising orally administering to human patients on a once-a-day basis a dose of a drug comprising a biguanide (e.g., metformin or a pharmaceutically acceptable salt thereof), contained in at least one oral controlled release dosage form of the present invention. When the drug is metformin, the daily dose of the drug may be from about 500 mg to about 2500 mg, from about 1000 mg to about 2500 mg, or from about 2000 mg to about 2500 mg, depending on the clinical needs of the patient. In certain embodiments, the method of treatment according to the present invention involves once-per-day metformin monotherapy as an adjunct to diet to lower blood glucose in patients with NIDDM whose hyperglycemia may not be satisfactorily managed on diet alone. In certain other embodiments, the once-a-day metformin therapy of the present invention may be used concomitantly with a sulfonylurea, e.g., when diet and monotherapy with a sulfonylurea alone do not result in adequate glycemic control. In certain other embodiments, the once-a-day metformin therapy of the present invention may be used concomitantly with a glitazone, e.g., when diet and monotherapy with a glitazone alone do not result in adequate glycemic control. The present invention is further directed to a method of controlling the serum glucose concentration in human patients with NIDDM, comprising administering to patients having NIDDM on a once-a-day basis, preferably at dinner time, an effective dose of a biguanide (e.g., metformin) contained in at least one oral controlled release dosage form of the present invention. The present invention further includes a controlled-release dosage form of a drug comprising a biguanide (e.g., metformin) suitable for once-a-day administration to human patients with NIDDM, the dosage form comprising an effective amount of the drug to control blood glucose levels for up to about 24 hours and an effective amount of a controlled-release carrier to provide controlled release of the drug with a mean time to maximum plasma concentration (T_maλ) of the drug from 5.5 to 7.5 hours after administration and a width at 50% of the height of a mean plasma concentration/time curve of the drug from about 6 to about 13 hours. In preferred embodiments, the administration of the controlled-release dosage form occurs at fed state, more preferably at dinner time. In certain preferred embodiments, the controlled-release dose of the drug (e.g., metformin or a pharmaceutically acceptable salt thereof) according to the present invention is provided by one or more of a controlled-release tablet comprising (a) a core comprising: (ii) the antihyperglycemic drug (e.g., metformin or a pharmaceutically acceptable salt thereof); (ii) optionally a binding agent; and (iii) optionally an absoφtion enhancer;

(b) a membrane coating surrounding the core; and

(c) at least one passageway in the membrane. In certain preferred embodiments, the mean time to maximum plasma concentration of the drug is reached from 6.5 to 7.5 hours after administration at dinner time. In certain embodiments of the invention when the drug is a biguanide (e.g. metformin or a pharmaceutically acceptable salt thereof), the controlled release dosage form provides upon single administration, a higher mean fluctuation index in the plasma than an equivalent dose of an immediate release composition administered as two equal divided doses, one divided dose at the start of the dosing interval and the other divided dose administered 12 hours later, preferably maintaining bioavailability from at least 80% preferably from at least 90%> of the immediate release composition. In certain embodiments of the present invention, the mean fluctuation index of the dosage form is from about 1 to about 4, preferably about 2 to about 3, more preferably about 2.5. In certain embodiments of the invention which exhibit a higher mean fluctuation index in the plasma than an equivalent dose of an immediate release composition administered as two equal divided doses, the ratio of the mean fluctuation index between the dosage form and the immediate release composition is about 3:1, preferably about 2: 1, more preferably 1.5: 1. When the drug is metformin or a pharmaceutically acceptable salt thereof, the doses of drug which exhibit the above disclosed mean fluctuation indexes can be any effective dose administered to a patient with NIDDM for the reduction of serum glucose levels. For example, the dose can from about 500mg to about 2500mg, from about lOOOmg to about 2000 mg or from about 850mg to about 1700mg metformin or pharmaceutically acceptable salt thereof. The drugs which may used in conjunction with the present invention include those drugs which are useful for the treatment of non-insulin-dependent diabetes mellitus (NIDDM), including but not limited to biguinides such as metformin or buformin or pharmaceutically acceptable salts thereof. When the drug used in the present invention is metformin, it is preferred that the metformin be present in a salt form, preferably as metformin hydrochloride. Further contemplated as part of the invention is a method for treating a patient using an antidiabetic drug, said method comprising administering to the patient a high dose of the antidiabetic drug wherein said antidiabetic drug exhibits one or more dose proportional pharmacokinetic parameters. The term "metformin" as it is used herein means metformin base or any pharmaceutically acceptable salt e.g., metformin hydrochloride. The term "dosage form" as it is used herein means at least one unit dosage form of the present invention (e.g. the daily dose of the antihyperglycemic agent can be contained in 2 unit dosage forms of the present invention for single once-a-day administration). The term "morning" as it is used herein with respect to the dosing of the controlled release formulations of the invention means that the controlled release formulation is orally administered early in the day after the patient has awakened from overnight sleep, generally between about 6 a.m. and 11 a.m. (regardless of whether breakfast is eaten at that time, unless so specified herein). The term "dinnertime" or "at dinner" as it is used herein with respect to the dosing of the controlled release formulations of the invention means that the controlled release formulation is orally administered at a time when dinner is normally eaten (regardless of whether a meal is actually eaten at that time, unless so specified herein), generally between about 4 p.m. and 8 p.m. The term "bedtime" as it is used herein with respect to the dosing of the controlled release formulations of the invention means that the controlled release formulation is orally administered before the patient goes to bed in the evening, generally between about 8 p.m. and 12 p.m. The term "therapeutically effective reduction" when used herein is meant to signify that blood glucose levels are reduced by approximately the same amount as an immediate release reference standard (e.g., GLUCOPHAGE® ) or more, when the controlled release dosage form is orally administered to a human patient on a once-a-day basis. The term "sustained release" and "controlled release" are used interchangeably in this application and are defined for puφoses of the present invention as the release of the drug from the dosage form at such a rate that when a once-a-day dose of the drug is administered in the sustained release or controlled-release form, blood (e.g., plasma) concentrations (levels) of the drug are maintained within the therapeutic range but below toxic levels over a period of time from about 12 to about 24 hours. When the drug used in the present invention is metformin (preferably metformin hydrochloride) the controlled release solid oral dosage form containing such drug is also referred to as "Metformin XT." The term "C_max"" is the highest plasma concentration of the drug attained within the dosing interval, i.e., about 24 hours. The term "C_m " is the minimum plasma concentration of the drug attained within the dosing interval, i.e. about 24 hours. The term "C_avg" as used herein, means the plasma concentration of the drug within the dosing interval, i.e. about 24-hours, and is calculated as AUC/dosing interval. The term "T_max" is the time period which elapses after administration of the dosage form at which the plasma concentration of the drug attains the highest plasma concentration of drug attained within the dosing interval ( i.e., about 24 hours). The term "AUC" as used herein, means area under the plasma concentration-time curve, as calculated by the trapezoidal rule over the complete 24-hour interval. The term "steady state" means that the blood plasma concentration curve for a given drug does not substantially fluctuate after repeated doses to dose of the formulation. The term "single dose" means that the human patient has received a single dose of the drug formulation and the drug plasma concentration has not achieved steady state. The term "multiple dose" means that the human patient has received at least two doses of the drug formulation in accordance with the dosing interval for that formulation (e.g., on a once- a-day basis). Patients who have received multiple doses of the controlled release formulations of the invention may or may not have attained steady state drug plasma levels, as the term multiple dose is defined herein. The term "a patient" means that the discussion (or claim) is directed to the pharmacokinetic parameters of an individual patient and/or the mean pharmacokinetic values obtained from a population of patients, unless further specified. The term "mean", when preceding a pharmacokinetic value (e.g. mean T_max) represents the arithmetic mean value of the pharmacokinetic value taken from a population of patients unless otherwise specified (e.g. geometric mean).. The term "Degree of Fluctuation" is expressed as (C_ma -C_mi_n)/C_avg. The term "high dose" is commonly used in the medical and pharmaceutical arts to refer to relative dosing strengths. For example, for the puφoses of certain embodiments of the subject invention, the term high dose, as it relates to metformin is any dose 500mg or greater. Brief Description of the Drawings FIG. 1 is a graph showing the relative bioavailability of the metformin XT formulation of Example 2 to GLUCOPHAGE® for Clinical Study 2. FIG. 2 is a graph showing the relative bioavailability of the metformin XT formulation of Example 1 (500 mg) to GLUCOPHAGE® for Clinical Study 3. FIG. 3 is a graph showing the difference in plasma concentration-time profiles of metformin in eight healthy volunteers between Day 1 and Day 14 dosing following oral administration of the metformin XT formulation of Example 1, 4 x 500 mg q.d. for 14 days for Clinical Study 4. FIG. 4 is a graph showing the mean plasma profiles and values of pharmacokinetic parameters of the metformin XT formulation of Example 3 for Clinical Study 5. FIG. 5 is a graph showing the mean plasma glucose concentration-time profiles after 4 weeks of treatment with the metformin XT formulation of Example 3 and GLUCOPHAGE® for Clinical Study 5. FIG. 6 is a graph showing the dissolution profile of a 500 mg controlled release metformin formulation of Example 1 of the present invention. FIG. 7 is a graph showing the dissolution profile of a 850 mg controlled release metformin formulation of Example 2 of the present invention. FIG. 8 is a graph showing the dissolution profile of a 1000 mg controlled release metformin formulation of Example 3 of the present invention. FIG 9 is a graph showing relationship between Mean (SD) Extended Release Metformin AUCo-∞ and Dose. FIG. 10 is a graph showing mean plasma concentration of metformin vs. time. FIG. 1 1 is a graph showing mean plasma glucose concentration vs. time.

Detailed Description of the Invention The term antidiabetic drugs, antihyperglycemic drugs as used in this specification refers to drugs that are useful in controlling or managing noninsulin-dependent diabetes mellitus (NIDDM). Preferably, an antihyperglycemic drug is a biguanide such as metformin or buformin or a pharmaceutically acceptable salt thereof such as metformin hydrochloride. Other antidiabetic drugs can include sulfonylureas, such as glipizide or the like, thiazolidinediones, such as the glitazones, e.g. pioglitazone or the like. It has suφrisingly been found that when biguanides such as metformin are administered orally in a controlled release dosage form suitable for once-a-day dosing in the "fed" state, preferably at dinner, the bioavailability is improved as compared to the administration of the controlled release dosage form in the "fasted" state. This is in contrast to GLUCOPHAGE®, which exhibits opposite characteristics. In accordance with the methods and dosage forms of the present invention, it has been determined that the patients suffering from NIDDM achieve improved results (e.g., lowered blood glucose levels) than GLUCOPHAGE® administered according to accepted protocols, e.g., on a twice-a-day basis. The methods and dosage forms of the invention provide the further advantage in that when dosed at dinnertime, the controlled release formulations of the invention provide a T_m χ (from 5.5 to 7.5 hours) after oral administration (which T_max is delayed relative to the reference standard, GLUCOPHAGE®), such that the level of drug is greatest at the time when human patients are manufacturing glucose at highest levels. Gluconeogenesis is well known to those skilled in the art to be greatest at night. Thus, in accordance with the invention, the T_max of the drug occurs for example between 11 :30 p.m. and 1 :30a.m., based on a dose administered at 6:00 p.m. Likewise, such administration of the dosage form provides lower drug levels during the day (e.g. the afternoon) when gluconeogenesis is lower than at night. Also, the invention preferably provides the added benefit of lowering insulin levels. Insulin is considered a risk factor in NIDDM, in and of itself, for cardiovascular disease. In comparison to a twice-daily dose of the reference standard (GLUCOPHAGE®), the plasma levels of metformin are preferably lower in the afternoon. This is an advantage particularly in patients who are under concomitant therapy with one or more additional antidiabetic agents, such as for example, a sulfonylurea. It is known in the art that to date approximately 60%> of patients being treated with metformin are also being treated with at least one additional antidiabetic agent (such as a sulfonylurea). Sulfonylureas can possibly cause hypoglycemia, whereas metformin cannot, so there is a benefit to having lower metformin levels in the blood during the afternoon due to the potential for the patient to have hypoglycemia. Accordingly, the present invention also includes a method of treating human patients with NIDDM comprising administering on a once-a-day basis a therapeutically effective dose of metformin in a controlled-release oral dosage form ("Metformin XT"), in combination with administering an effective amount of a sulfonylurea. In preferred embodiments, metformin is provided by a controlled release dosage foπn comprising metformin or a pharmaceutically acceptable salt thereof, the dosage form being useful for providing a once-a-day oral administration of the drug, wherein the dosage form provides a mean time to maximum plasma concentration (T_max) of metformin from 5.5 to 7.5 hours after administration. In certain embodiments, the combination therapy may be provided as follows. If patients do not respond to four weeks of the maximum dose of Metformin XT (2500 mg/ day) monotherapy, a sulfonylurea may be gradually added while maintaining the maximum dose of Metformin XT, even if prior primary or secondary failure to a sulfonylurea has occurred. Examples of the sulfonylurea include glyburide (glibenclamid), chloropropamide, tolbutamide, glipizide, acetohexamide and tolazamide. Although Metformin XT is preferably administered on once-a-day basis, the sulfonylurea may be administered in a different dosage form and at a different frequency. With concomitant Metformin XT and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. In certain embodiments, the foregoing objectives are met by a controlled release dosage form comprising:

(a) a core comprising: (i) an antihyperglycemic drug; (ii) optionally a binding agent; and (iii) optionally an absoφtion enhancer;

(b) a membrane coating surrounding the core; and

(c) at least one passageway in the membrane. The binding agent may be any conventionally known pharmaceutically acceptable binder such as polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxyethyl cellulose, ethylcellulose, polymethacrylate, waxes and the like. Mixtures of the aforementioned binding agents may also be used. The preferred binding agents are water soluble such as polyvinyl pyrrolidone having a weight average molecular weight of 25,000 to 3,000,000. The binding agent comprises approximately about 0 to about 40%> of the total weight of the core and preferably about 3%> to about 15%) of the total weight of the core. The core may optionally comprise an absoφtion enhancer. The absoφtion enhancer can be any type of absoφtion enhancer commonly known in the art such as a fatty acid, a surfactant, a chelating agent, a bile salt or mixtures thereof. Examples of some preferred absoφtion enhancers are fatty acids such as capric acid, oleic acid and their monoglycerides, surfactants such as sodium lauryl sulfate, sodium taurocholate and polysorbate 80, chelating agents such as citric acid, phytic acid, ethylenediamine tetraacetic acid (EDTA) and ethylene glycol-big (B- aminoethyl ether -N,N,N,N-tetraacetic acid (EGTA). The core comprises approximately 0 to about 20%) of the absoφtion enhancer based on the total weight of the core and most preferably about 2% to about 10%> of the total weight of the core. In this embodiment, the core which comprises the antihyperglycemic drug, the binder which preferably is a pharmaceutically acceptable water soluble polymer and the absoφtion enhancer is preferably formed by wet granulating the core ingredients and compressing the granules with the addition of a lubricant into a tablet on a rotary press. The core may also be formed by dry granulating the core ingredients and compressing the granules with the addition of a lubricant into tablets or by direct compression. Other commonly known excipients may also be included into the core such as lubricants, pigments or dyes. The homogeneous core is coated with a membrane, preferably a polymeric membrane to form the controlled release tablet of the invention. The membrane can be a semipermeable membrane by being permeable to the passage of external fluid such as water and biological fluids and being impermeable to the passage of the antihyperglycemic drug in the core. Materials that are useful in forming the membrane are cellulose esters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ester-ether, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate propionate, and cellulose acetate butyrate. Other suitable polymers are described in United States Patent Nos. 3,845,770, 3,916,899, 4,008,719, 4,036,228 and 4,1 1210 which are incoφorated herein by reference. The most preferred membrane material is cellulose acetate comprising an acetyl content of 39.3 to 40.3%>, commercially available from Eastman Fine Chemicals. In an alternative embodiment, the membrane can be formed from the above-described polymers and a flux enhancing agent. The flux enhancing agent increases the volume of fluid imbibed into the core to enable the dosage form to dispense substantially all of the antihyperglycemic drug through the passageway and/or the porous membrane. The flux enhancing agent can be a water soluble material or an enteric material. Some examples of the preferred materials that are useful as flux enhancers are sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycol (PEG), propylene glycol, hydroxypropyl cellulose, hydroxypropyl methycellulose, hydroxyprophy methycellulose phthalate, cellulose acetate phthalate, polyvinyl alcohols, methacrylic acid copolymers and mixtures thereof. The preferred flux enhancer is PEG 400. The flux enhancer may also be a drug that is water soluble such as metformin or its pharmaceutically acceptable salts or a drug that is soluble under intestinal conditions. If the flux enhancer is a drug, the present dosage form has the added advantage of providing an immediate release of the drug which is selected as the flux enhancer. The flux enhancing agent comprises approximately 0 to about 40%> of the total weight of the coating, most preferably about 2%> to about 20%> of the total weight of the coating. The flux enhancing agent dissolves or leaches from the membrane to form paths in the membrane for the fluid to enter the core and dissolve the active ingredient. In alternate embodiments, the membrane may also be formed with commonly known excipients such as a plasticizer. Some commonly known plasticizers include adipate, azelate, enzoate, citrate, stearate, isoebucate, sebacate, triethyl citrate, tri-n-butyl citrate, acetyl tri-n-butyl citrate, citric acid esters, and those described in the Encyclopedia of Polymer Science and Technology, Vol. 10 (1969), published by John Wiley & Sons. The preferred plasticizers are triacetin, acetylated monoglyceride, grape seed oil, olive oil, sesame oil, acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol, diethyloxalate, diethylmalate, diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacate, triethylcitrate, tributylcitrate, glyceroltributyrate, and the like. Depending on the particular plasticizer, amounts of from 0 to about 25%, and preferably about 2%> to about 15%> of the plasticizer can be used based upon the total weight of the coating. As used herein the term passageway includes an aperture, orifice, bore, hole, weakened area or an erodible element such as a gelatin plug that erodes to form an osmotic passageway for the release of the antihyperglycemic drug from the dosage form. A detailed description of the passageway can be found in United States Patent Nos. such as 3,845,770, 3,916,899, 4,034,758, 4,063,064, 4,077,407, 4,088,864, 4,783,337 and 5,071,607 (the disclosures of which are hereby incoφorated by reference). In certain embodiments, the passageway is formed by laser drilling. In other embodiments, the passageway is formed by making an indentation onto the core prior to the membrane coating to form a weakened area of the membrane at the point of the indentation. In preferred embodiments of the invention, the dosage form contains two passageways in order provide the desired pharmacokinetic parameters of the formulation. Generally, the membrane coating around the core will comprise from about 1% to about 1%, preferably about 1.5% to about 3%>, based on the total weight of the core and coating. The term "membrane" means a membrane that is permeable to both aqueous solutions or bodily fluids and to the active drug or pharmaceutical ingredient (e.g. the formulations of Examples 1-3). Thus, the membrane is porous to drug and, in a preferred embodiment, drug is released through the hole or passageway and through the porous membrane in solution or in vivo. The term "membrane" also generically encompasses the term "semipermeable membrane" as heretofore defined. In an alternative embodiment, the dosage form of the present invention may also comprise an effective amount of the antihyperglycemic drug that is available for immediate release. The effective amount of antihyperglycemic drug for immediate release may be coated onto the membrane of the dosage form or it may be incoφorated into the membrane. In certain preferred embodiments of the invention where the dosage form is prepared in accordance with the above, the dosage form will have the following composition:

INGREDIENT Preferred Most Preferred CORE: Drug 50-98% 75-95% Binder 0-40% 3-15% Absoφtion Enhancer 0-20% 2-10%

COATING: Membrane Polymer 50-99% 75-95% Flux Enhancer 0-40% 2-20% Plasticizer 0-25% or 0-30% 2-15%

The dosage forms prepared according to certain embodiments of the present invention preferably exhibit the following dissolution profile when tested in a USP type 2 apparatus at 75 φms in 900 ml of simulated intestinal fluid (pH 7.5 phosphate buffer) and at 37°C:

Time (Hours) Preferred Most Preferred

2 0-30% 0-15% or 0-25% 4 10-45% 20-40% 8 30-90% 45-90% 12 NTL 50% NTL 60% 16 NTL 60% NTL 70% 20 NTL 70% NTL 80% NTL = Not less than

In the preparation of the tablets of the invention, various conventional well known solvents may be used to prepare the granules and apply the external coating to the tablets of the invention. In addition, various diluents, excipients, lubricants, dyes, pigments, dispersants, etc. which are disclosed in Remington's Pharmaceutical Sciences, 1995 Edition may be used to optimize the formulations of the invention. Other controlled release technologies known to those skilled in the art can be used in order to achieve the controlled release formulations of the present invention, i.e., formulations which provide a mean T_max of the drug and/or other pharmacokinetic parameters described herein when orally administered to human patients. Such formulations can be manufactured as a controlled oral formulation in a suitable tablet or multiparticulate formulation known to those skilled in the art. In either case, the controlled release dosage form may optionally include a controlled release carrier which is incoφorated into a matrix along with the drug, or which is applied as a controlled release coating. An oral dosage form according to the invention may be provided as, for example, granules, spheroids, beads, pellets (hereinafter collectively referred to as multiparticulates) and/or particles. An amount of the multiparticulates which is effective to provide the desired dose of drug over time may be placed in a capsule or may be incoφorated in any other suitable oral form. In certain preferred embodiments, the tablet core or multiparticulates containing the drug are coated with a hydrophobic material selected from (i) an alkylcellulose and (ii) a polymeric glycol. The coating may be applied in the form of an organic or aqueous solution or dispersion. The coating may be applied to obtain a weight gain from about 2 to about 25% of the substrate in order to obtain a desired sustained release profile. The sustained release coatings of the present invention may also include an exit means comprising at least one passageway, orifice, or the like as previously disclosed. Further contemplated as part of the invention is a method for treating a patient using an antidiabetic drug, said method comprising administering to the patient a high dose of the antidiabetic drug wherein said antidiabetic drug exhibits one or more dose proportional pharmacokinetic parameters. Advantageously, the method provides for a predictable dosing regimen for high dose administration. Preferably, the antidiabetic drug is administered once a day. Antidiabetic drugs of the method may include but are not limited to biguanides, hormone analogues, sulfonylureas, and thiazolidinediones or salts, derivatives, prodrugs or metabolites thereof as the antidiabetic drug. In one preferred embodiment, the antidiabetic drug is metformin or a salt, derivative, prodrug or metabolite thereof.

In yet another preferred embodiment the method may be used to lower blood sugar and/or administered to a patient in need of treatment of non-insulin-dependent diabetes mellitus (NIDDM). Dose proportional pharmacokinetic parameters in the present method may be selected from the group consisting of AUC and Cmax.

The method of the present invention may be performed by administering a dose such that the antidiabetic drug is released in a controlled manner. A controlled manner of drug release means release from a dosage form in any modified manner, including delayed release, sustained release, extended releae or the like. Controlled release dosage forms are well known in the art and may include but would not be limited to any administration as a solid, semi-solid, liquid, suspension or solution. Such dosage forms can be administered by various routes known in the art, including oral, buccal, sublingual, intravenous, parentemal, transdermal, iontophoretic routes and the like. In one preferred embodiment, the dosage form is administered orally as a solid dosage.

Description of Certain Preferred Embodiments The following examples illustrate various aspects of the present invention. They are not to be construed to limit the claims in any manner whatsoever.

Example 1 A controlled release tablet containing 500 mg of metformin HC1 and having the following formula is prepared as follows: I. Core Ingredients Amount (mg/tab) Metformin HCl 500.0 Povidone³, USP 36.0 Sodium Lauryl Sulfate 25.8 Magnesium Stearate 2.8 approximate molecular weight = 1,000,000; dynamic viscosity (10%>w/v solution at 20°C) = 300-700 m Pa s.

(a) Granulation The metformin HCl and sodium lauryl sulfate are delumped by passing them through a 40 mesh screen and collecting them in a clean, polyethylene-lined container. The povidone, K- 90-F is dissolved in purified water. The delumped metformin HCl and sodium lauryl sulfate are then added to a top-spray fluidized bed granulator and granulated by spraying with the binding solution of povidone under the following conditions: inlet air temperature of 50-70°C; atomization air pressure of 1-3 bars; and spray rate of 10-100 ml/min. Once the binding solution is depleted, the granules are dried in the granulator until the loss on drying is less than 2%. The dried granules are passed through a Comil equipped with the equivalent of an 18 mesh screen.

(b) Tableting The magnesium stearate is passed through a 40 mesh stainless steel screen and blended with the metformin HCl granules for approximately five (5) minutes. After blending, the granules are compressed on a rotary press fitted with 15/32" round standard concave punches. ( c) Seal Coating (optional) The core tablet is seal coated with an Opadry material or other suitable water-soluble material by first dissolving the Opadry material, preferably Opadry Clear (YS- 1-7006), in purified water. The Opadry solution is then sprayed onto the core tablet using a pan coater under the following conditions: exhaust air temperature of 38-42°C; atomization pressure of 28-40 psi; and spray rate of 10-15 ml/min. The Opadry Clear of the coating constitutes about 1 1.5 mg/tablet.

II. Sustained Release Coating Ingredients Amount (mg/tablet) Cellulose Acetate (398-10)² 21.5 Triacetin 1.3 PEG 400 2.5

2 acetyl content 39.3 - 40.3%

The cellulose acetate is dissolved in acetone while stirring with a homogenizer. The polyethylene glycol 400 and triacetin are added to the cellulose acetate solution and stirred until a clear solution is obtained. The tablet is coated by spraying the clear coating solution onto the seal coated tablets in a fluidized bed coater employing the following conditions: product temperature of 16-22°C; atomization pressure of approximately three bars; and spray rate of 120- 150 ml/min.

(d) Laser Drilling The coated tablets were laser drilled two holes (one hole on each side of the tablet).

Example 2 A controlled release tablet containing 850 mg of metformin HCl and having the following formula is prepared as follows: I. Core Ingredients Amount (mg/tab) Metformin HCl 850.0 Povidone³, USP 61.1 Sodium Lauryl Sulfate 43.9 Magnesium Stearate 4.8 approximate molecular weight = 1,000,000; dynamic viscosity (10%>w/v solution at 20°C) = 300-700 m Pa s. (a) Granulation The metformin HCl and sodium lauryl sulfate are delumped by passing them through a 40 mesh screen and collecting them in a clean, polyethylene-lined container. The povidone, K- 90-F is dissolved in purified water. The delumped metformin HCl and sodium lauryl sulfate are then added to a top-spray fluidized bed granulator and granulated by spraying with the binding solution of povidone under the following conditions: inlet air temperature of 50-70°C; atomization air pressure of 1-3 bars; and spray rate of 10-100 ml/min. Once the binding solution is depleted, the granules are dried in the granulator until the loss on drying is less than 2%>. The dried granules are passed through a Comil equipped with the equivalent of an 18 mesh screen.

( b) Tableting The magnesium stearate is passed through a 40 mesh stainless steel screen and blended with the metformin HCl granules for approximately five (5) minutes. After blending, the granules are compressed on a rotary press fitted with 15/32" round standard concave punches.

( c) Seal Coating (optional) The core tablet is seal coated with an Opadry material or other suitable water-soluble material by first dissolving the Opadry material, preferably Opadry Clear (YS-1-7006), in purified water. The Opadry solution is then sprayed onto the core tablet using a pan coater under the following conditions: exhaust air temperature of 38-42°C; atomization pressure of 28-40 psi; and spray rate of 10-15 ml/min. The Opadry Clear of the coating constitutes about 1 1.5 mg/tablet.

II. Sustained Release Coating Ingredients Amount (mg/tablef) Cellulose Acetate (398-10)² 24.0 Triacetin 1.4 PEG 400 2.8 acetyl content 39.3 - 40.3%

Example 3 A controlled release tablet containing 1000 mg of metformin HCl and having the following formula is prepared as follows: I. Core Ingredients Amount (mg/tablet) Metformin HCl 1000.0 Povidone³, USP 71.9 Sodium Lauryl Sulfate 51.7 Magnesium Stearate 5.6

approximate molecular weight = 1,000,000; dynamic viscosity (10%>w/v solution at 20°C) = 300-700 m Pa s. (a) Granulation The metformin HCl and sodium lauryl sulfate are delumped by passing them through a 40 mesh screen and collecting them in a clean, polyethylene-lined container. The povidone, K- 90-F is dissolved in purified water. The delumped metformin HCl and sodium lauryl sulfate are then added to a fluidized bed granulator and granulated by spraying with the binding solution of povidone under the following conditions: inlet air temperature of 50-70°C; atomization air pressure of 1-3 bars; and spray rate of 10-100 ml/min. Once the binding solution is depleted, the granules are dried in the granulator until the loss on drying is less than 2%. The dried granules are passed through a Comil equipped with a screen equivalent to 18 mesh.

( b) Tableting The magnesium stearate is passed through a 40 mesh stainless steel screen and blended with the metformin HCl granules for approximately five (5) minutes. After blending, the granules are compressed on a rotary press fitted with ^lΛ" round standard concave punches. ( c) Seal Coating (optional) The core tablet is seal coated with an Opadry material or other suitable water-soluble material by first dissolving the Opadry material, preferably Opadry Clear (YS- 1-7003), in purified water. The Opadry solution is then sprayed onto the core tablet using a pan coater under the following conditions: exhaust air temperature of 38-42°C; atomization pressure of 28-40 psi; and spray rate of 10-15 ml/min. The core tablet is coated with the sealing solution until the tablet is coated with 23.0 mg/tablet of the Opadry material.

II. Sustained Release Coating Ingredients Amount (mg/tablet) Cellulose Acetate (398-10)² 19.0 Triacetin 1.1 PEG 400 2.2

²acetyl content 39.3 - 40.3%)

(d Laser Drilling The coated tablets were laser drilled two holes (one hole on each side of the tablet).

(e) Color Coating (optional) Subsequent to the sustained release coating, the laser drilled tablet is coated with a color coating using Opadry White (24 mg/tablet) and waxed with Candelilla wax powder (0.4 mg/tablet).

Clinical Studies

Study 1 In study 1, a total of twelve (12) healthy subjects (six males, six females) were randomized to receive either a single oral dose of metformin extended release, 850mg, prepared in accordance with Example 2 or b.i.d. doses of GLUCOPHAGE in assigned study periods which consisted of one of the following groups: Group A - metformin extended release (2 x 850 mg tablets) taken at approximately 8:00 a.m., immediately following breakfast, Group B - metformin extended release (2 x 850 mg tablets) taken at approximately 6:00 p.m., immediately following dinner; and Group C - GLUCOPHAGE (1 x 850 mg tablet) taken at approximately 8:00 a.m., immediately following breakfast, and at approximately 6:00 p.m., immediately following dinner. Each drug administration was separated by a washout period of seven days. In this study, one male subject was removed from the study prior to Period II due to non-treatment-related mononucleosis. Thus, 11 (five males and six females) subjects completed the study. For metformin extended release, plasma samples were obtained from subjects at 0 (predose), 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, and 24 hour(s) after dosing. For GLUCOPHAGE, plasma samples were obtained from subjects at 0 (predose), 1, 2, 3, 4, 5, 6, 8, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, and 24 hour(s) after the first dose in the morning. Plasma concentrations of metformin were determined using a validated HPLC method. The lower quantitation limit of this method is 10 ng/ml. Mean plasma concentration-time profiles are shown in Fig. 1 and mean values of pharmacokinetic parameters of metformin obtained from this study are presented in Table 1.

Table 1 Mean (±SD, n = 11) values of pharmacokinetic parameters of metformin (Example 2) in 11 healthy subjects (metformin XT, 2 x 850 mg q.d. or GLUCOPHAGE, 1 x 850 mg b.i.d.)

*Ratio = Metformin XT/GLUCOPHAGE

As shown in Figure 1 and Table 1 , when metformin XT was administered immediately after either breakfast or dinner, the relative bioavailability of metformin XT formulation to GLUCOPHAGE is approximately 100%. The results of study 1 were used to calculate the approximate degree of fluctuation (C_max -C_mj_n/C_avg) of the formulations. The C_max was directly obtained from the study (see Table 1). The C_avg was obtained by dividing the AUC value by the dosing interval, i.e. 24 hours. The value for C_mi_n was extrapolated from Figure 1. The results are set forth in Table 2 below:

Table 2

Mean (±SD, n = 12) values of pharmacokinetic parameters of metformin XT in 12 healthy subjects (metformin XT, 2 x 850 mg q.d. and GLUCOPHAGE, 850 mg b.i.d.)

As shown in Figure 1 and Table 2, a single administration of the metformin XT formulation provides a higher mean fluctuation index in the plasma than a substantially equal dose of Glucophage administered as two equal divided doses, one divided dose at the start of the dosing interval and the other divided dose administered 12 hours later.

Study 2 The study design of Study 2 is the same as Study 1 except for the formulation and the dose (4 x 500 mg q.d., total dose 2000mg, for metformin XT prepared according to Example 1 and 2 x 500 mg b.i.d., total dose 2000mg, for GLUCOPHAGE in the second study). In this study, 12 healthy volunteers (five males and seven females) were randomized to receive treatments and completed the study. Mean plasma concentration- time profiles and mean values of pharmacokinetic parameters of metformin obtained from this study are presented in Figure 2 and Table 3. As shown in Figure 2 and Table 3, when the metformin XT formulation (500 mg) was administered immediately after dinner, the relative bioavailability of this formulation to GLUCOPHAGE is approximately 100%), while the mean C_max value is about the same. The relative bioavailability of metformin XT, however, is approximately 80%> when administered immediately after breakfast. A prolonged profile, together with later T_max and similar C_max of metformin following administration of metformin XT immediately after dinner compared to GLUCOPHAGE indicated that metformin was released in vivo in a sustained fashion (Figure 2).

Table 3

Mean (±SD, n = 12) values of pharmacokinetic parameters of metformin of Example 1 in 12 healthy subjects (metformin XT, 4 x 500 mg q.d. or GLUCOPHAGE, 2 x 500

* Ratio = Metformin XT/GLUCOPHAGE The results of study 2 were used to calculate the approximate degree of fluctuation of the formulations in accordance with the calculations used in study 1 (using Figure 2 to obtain the extrapolated value for C_mj_n). The results are set forth in Table 4 below:

Table 4

Mean (±SD, n = 12) values of pharmacokinetic parameters of metformin XT in 12 healthy subjects (metformin XT, 4 x 500 mg q.d. and GLUCOPHAGE, 2 x 500 mg b.i.d.)

As shown in Figure 2 and Table 4, a single administration of the metformin XT formulation provides a higher mean fluctuation index in the plasma than an equivalent dose of Glucophage administered as two equal divided doses, one divided dose at the start of the dosing interval and the other divided dose administered 12 hours later.

Study 3 In Study 3, a multiple-dose, open-label, one-period study was conducted to evaluate the short-term tolerability and steady-state pharmacokinetics of the 500 mg metformin XT formulation used in Study 2. In this study, eight healthy volunteers (four males and four females) were randomized to receive 2000 mg of metformin XT (4 x 500 mg tablets) at approximately 6:00 p.m., immediately following dinner, for 14 days. Blood samples were obtained from each subject at 0 (predose), 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16 and 24 hour(s) following the first dose on Day 1 and at 0 (predose), 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 24, 38 and 48 hour(s) following the last dose on Day 14. Blood samples were also drawn from each subject immediately prior to dosing on Days 10-13. Urine samples were collected from each subject at the following time intervals: six hours prior to the first dose; 0-6, 6-12 and 12-24 hours after the first dose; and 0-6, 6-12, 12-24 and 24-48 hours after the last dose. Mean plasma profiles and values of pharmacokinetic parameters of metformin- are presented in Table 5 below: Table 5 Mean Pharmacokinetic Parameters (Example 1) Day l

Following oral administration of metformin XT, 4 x 500 mg q.d., for 14 days, there was little or no difference in plasma concentration-time profiles of metformin in eight healthy volunteers between Day 1 and Day 14 dosing (Figure 3). On average, trough plasma concentrations of metformin were nearly constant, ranging from 188.8 to 205.1 ng/ml on Days 10-14, indicating that the steady state of metformin was attained rapidly. The mean accumulation ratio was 1.01, indicating that the once-daily dose regimen of metformin XT results in no accumulation. Following oral administration of a single dose (4 x 500 mg) of metformin XT, approximately 31%) of the dose was excreted in the urine within the first 24 hours. On average, the renal clearance of metformin was 366 ml/min. A slightly higher renal clearance (454^" rru7mιnj was found after multiple-dose administration of 4 x 500 mg q.d. of metformin XT. Gastrointestinal symptoms (diarrhea, nausea, vomiting, abdominal bloating, flatulence and anorexia) are the most common adverse reactions to GLUCOPHAGE. In controlled trials, GLUCOPHAGE was started at low, nontherapeutic doses and gradually titrated to higher doses. In spite of this gradual titration, GLUCOPHAGE was discontinued due to gastrointestinal reactions in approximately 4%> of patients. In contrast, in the multiple-dose study, metformin XT begun at a therapeutic initial dose of 2000 mg once daily with dinner was well tolerated by all healthy volunteers. Diarrhea and nausea were the most common gastrointestinal reactions probably or possibly related to metformin XT. These reactions, however, were either mild or moderate. This suggests that it may be possible to initiate metformin XT treatment with effective doses rather than using the slow titration from non-therapeutic doses required for GLUCOPHAGE. Study 4 Study 4 was a study designed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of metformin XT compared to GLUCOPHAGE after multiple- dose treatment in patients with NIDDM. Metformin XT tablets prepared according to Example 3 were used in this study. This study had a single-center, randomized, two-way crossover design. A total of 24 NIDDM patients who were on a stable dose of GLUCOPHAGE, between 1000 and 2550 mg/day, for at least 12 weeks were selected for the study. A Pretreatment Period of at least 3 weeks preceded randomization to study treatment. At the start of the Pretreatment Period, all patients stopped taking any other hypoglycemic agents besides GLUCOPHAGE, and the GLUCOPHAGE dose was adjusted to 1000 mg b.i.d. (with breakfast and with dinner). Following the pretreatment period, patients began Treatment Period I, which lasted 4 weeks. During Period I, a total of 12 patients were randomized to receive two 1000-mg metformin XT tablets q.d. (immediately after dinner), at approximately 6:00 p.m., and 12 were randomized to receive one 1000-mg GLUCOPHAGE tablet b.i.d. (immediately after breakfast and immediately after dinner). Immediately following Period I, each patient was switched to the alternate medication tor 4 weeks in Period II. There was no washout between treatment periods. Plasma metformin concentrations were determined over a 24-hour period at the end of Treatment Periods I and II as follows: immediately prior to dosing and at 1 , 2, 3, 4, 5, 6, 8, 10, 12, 14, 15, 16, 17, 18, 19, 20, 22, and 24 hours after the evening dose. One subject withdrew from the study for personal reasons after two weeks of treatment in Treatment Period I, thus pharmacokinetic data were obtained from 23 patients. Mean plasma profiles and values of pharmacokinetic parameters of metformin are presented in Figure 4 and Table 6. As shown in Figure 4 and Table 6, when metformin XT was administered immediately after dinner, the bioavailability of metformin XT relative to GLUCOPHAGE at steady state is close to 100%>. Although the dose of metformin XT was twice as large as the dose of GLUCOPHAGE at dinner, the mean C_max value was only 32%o higher.

Table 6 Mean (± SD) values of pharmacokinetic parameters of metformin of Example 3 in 23 NIDDM patients (metformin XT, 2 x 1000 mg q.d. with dinner or GLUCOPHAGE, 1 x 1000 mg b.i.d.)

* Ratio = Metformin XT/GLUCOPHAGE

When the metformin XT was administered immediately after dinner, the bioavailability of metformin XT relative to GLUCOPHAGE at steady state was close to 100%). However, when metformin XT was administered immediately after breakfast, the corresponding relative bioavailability of metformin XT was approximately 80%>. The safety profile of metformin XT, 2000 mg given once daily either after dinner or after breakfast was comparable to that of an equal dose of GLUCOPHAGE given b.i.d. The efficacy profile of metformin XT, 2000 mg given once daily after dinner was similar to that of an equal dose of GLUCOPHAGE given b.i.d. The efficacy of metformin XT, 2000 mg given once daily after breakfast, however, appeared to be comparable to or slightly less than that of GLUCOPHAGE given b.i.d.

Study 5

The pharmacokinetics and dose-exposure relationship of an extended-release formulation of metformin (ER) manufactured in accordance with the Examples provided herein was investigated in a randomized, single-dose, four-period crossover study in 24 healthy male volunteers. During each study period, subjects received a randomly assigned dose containing 1000, 1500, 2000, or 2500 mg metformin. Blood samples were drawn periodically from 0-72 hours after dosing for pharmacokinetic analysis and dose- proportionality assessment for these dosage amounts. Although several pairwise comparisons between dose groups were significant (p<0.05) with respect to dose- normalized C_maχ, AUC_{0- 2hr}, and AUC_∞ , the magnitude of the difference across the dose range was <20%> for AUCo-_72hr and AUCoo, and was <30%> for C_max. The results indicate a consistent and predictable increase in metformin exposure with an extended-release formulation of metformin from about 1000 to about 2500 mg.

Metformin has been widely used in the management of Type 2, non-insulin-dependent diabetes mellitus (NIDDM). Immediate-release (IR) metformin is typically administered in divided doses with meals to minimize gastrointestinal side effects (Dunn CJ, Peters DH. Metformin: A review of its pharmacological properties and therapeutic use in non- insulin-dependent diabetes mellitus. Drugs 1995;49:721-749 and Scheen AJ. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 1996;30(5):359-371). An oral dose of 500mg typcially provides a bioavailability of approximately 50%), with proportionally more drug being absorbed after a from a 500 mg dose than after higher doses of more than 500 mg. (Scheen AJ. Clinical pharmacokinetics of metformin. Chn Pharmacokinet 1996;30(5):359-371. and Pentikainen PJ, Neuvonen PJ; and Penttila A. Pharmacokinetics of metformin after intravenous and oral administration to man. Eur J Clin Pharmacol 1979;16: 195-202).

MATERIALS AND METHODS A single-dose, open-label, randomized, four-period crossover study was conducted on twenty-four subjects enrolled in the study based on inclusion/exclusion criteria for healthy male volunteers. Subjects received the following four metformin doses in random order according to assigned sequences: 1000 mg (1 1000 mg tablet), 1500 mg (1x1000 mg + 1x500 mg tablets), 2000 mg (2x1000 mg tablets), and 2500 mg (2x1000 mg + 1x500 mg tablets). 500mg tablets were prepared according to Example 1 and lOOOmg tablets were prepared according to Example 3. Each treatment was separated by a seven-day washout period. The treatments were administered immediately following a standardized dinner with 240 ml of ambient-temperature water.

Blood samples (10 ml) were collected in heparinized vacutainer tubes at 0 (pre-dose), 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 24, 38, 48, and 72 hours after dosing, for the purpose of quantitating the concentration of metformin in plasma. Plasma samples were assayed using a high-performance liquid chromatographic (HPLC) assay with ultraviolet detection. The standard curves for metformin covered a range of 10 to 2500 ng/ml; the lower limit of quantitation (LOQ) was 10 ng/ml. Quality control standards (25, 160, and 1600 ng/mL) and the LOQ were used to assess the interday and intraday assay precision and accuracy during validation. The interday assay coefficient of variation (precision) ranged from 4.82 to 8.23%) and percent difference from theoretical (accuracy) ranged from -2.08 to 2.72%, while the intraday precision ranged from 6.16 to 9.56%> and accuracy ranged from -17.7 (at the LOQ) to 5.76%>.

Pharmacokinetic parameters for metformin included the maximum observed concentration (Cmax), time at which Cmax occurred (T_max), lag time (Tι_ag), and area under the plasma concentration-time curve (AUC). AUC was calculated using the linear trapezoidal rule from time zero to 72 hours (AUCo-72hr)- AUC from time zero to infinity (AUCoo) was equal to the sum of AU _M and C(t)/ke, where C(t) was the plasma concentration at 72 hours and ke was the terminal elimination rate constant. The terminal elimination half-life (t'Λ) was calculated as ln(2)/ke, and ke was determined from linear regression of the terminal portion of the In-concentration versus time curve.

Summary statistics for pharmacokinetic and safety data were generated. Dose proportionality was assessed by comparing dose-normalized pharmacokinetic parameters (AUC and C_max) using a statistical model that included variables for period, dose, and sequence of administration, as well as linear regression analysis of AUC or C_max and dose.

RESULTS

Of the twenty-four healthy males enrolled and included in the safety assessment, twenty- three subjects (96%o) completed the study and were included in pharmacokinetic and dose proportionality assessment. One subject withdrew consent for personal reasons.

There were no serious adverse experiences during the course of the study. There were 9 treatment-emergent signs or symptoms (TESS) that were considered possibly related to treatment.

The plasma metformin concentration time profiles were determined for each subject (n=23) at each dose level. Mean (±SD) metformin pharmacokinetic parameters are summarized in Table 7. In the majority of subjects, extrapolation from AUCo-₇₂hr to AUCoo was less than 5%>, resulting in reliable estimates of AUC_∞. Dose proportionality is illustrated by certain of the pharmacokinetic parameters in Table 7 below:

Table 7. M t'formin Pharmacokinetic Parameters (Mean + SD) and Dose- Proportionality Analysis following a Single Oral Dose

Metformin Dose Dose Normalized (DN) b

Parameter lOOO mg 1500 mg 2000 mg 2500 mg 1000 mg 1500 mg 2000 mg 2500 mg

C_max (μg/ml) 1.42 ± 0.32 1.78 ± 0.37 2.11 ± 0.52 2.48 ± 0 53 1.42^c 1.19^c 1.05^d 0 99°

AUC₀.72hr 1 1.90 ± 2.76 16.68 ± 4.14 20.65 ± 3.82 24.18 ± 3.97 1 1.87° 1 1.10^c 10.30^d 9.65'

(μg-hr/ml)

AUC„ 1 1.94 ± 2.71 16.70 ± 4.15 20.81 ± 3.87 24.26 ± 4.10 1 1.91^c l l . l l^c 10.38" 9.71^e

(μg hr/ml)

T_ma* (hr) 6.3 ± 1.4 6.7 ± 1.6 7.8 ± 2.0 7.2 ± 2.1 - - - - ι_ag (hr) 0.4 ± 0.5 0.3 ± 0.6 0.2 ± 0.4 0.0 + 0.0 - - - - tin (hr)^a 5.0 5.6 7.4 7.5 - - - -

^a Harmonic mean ^b Least-squared means (LSM) estimates of pharmacokinetic parameters were dose normalized to 1000 mg. ^c There is a statistical difference (p<0.05) in DN LSM between dose group and other three dose groups ^d There is a statistical difference (p<0.05) in DN LSM between dose group and two dose groups (1000 mg and 1500 mg), however there is no difference 0P>0.05) from 2500 mg dose group.

'There is a statistical difference (p<0.05) in DN LSM between dose group and two dose groups (1000 mg and 1500 mg), however there is no difference (p>0.05) from 2000 mg dose group.

All pairwise comparisons between doses were significant (p<0.05) with respect to dose- normalized C_max, AUC_0-72hr) and AUC_∞ except for the comparison between the two highest doses. The magnitude of the differences across the dose range was on average <30% for C_max and^"<20% for both AUC₀._72h and AUCoo. There was no detectable difference in model-independent pharmacokinetic parameters including T_max and half-life (t'Λ) among doses. The linear regression of the mean values of the four treatments resulted in a coefficient-of-determination (r²) that was >0.99 for C_maXj AUC₀. _2h and AUCoo, and deviation from zero was significant (p<0.05) for all 3 parameters. The linear regression for AUCoo is shown in Figure 9.

Although considerable overlap in exposure was observed, there was a predictable and consistent dose-associated increase in metformin exposure as represented by C_max, AUC₀. ₂hr, and AUCoo. The dose-exposure relationship is particularly noteworthy for AUCoo (Figure 9) whereby the least-squares means for the 1500, 2000 and 2500 mg doses were all within 20%> of the values dose-normalized to 1000 mg (Table 7).

The pharmacokinetic properties of metformin have been investigated using a variety of formulations including intravenous and oral aqueous solution, rapidly dissolving tablets, and modified-release formulations (Karttunen P, Uusitupa M, and Lamminsivu U. The pharmacokinetics of metformin: a comparision of the properties of a rapid-release and a sustained-release preparation. Int J Clin Pharmacol Ther Toxicol 1983 ;21:31-36; Pentikainen PJ. Bioavailability of metformin: comparison of solution, rapidly dissolving tablet, and three sustained-release products. Int J Clin Pharmacol Ther Toxicol 1986;24:213-220; and the Scheen and Pentikainen op cit.). Generally, the pharmacokinetics of metformin are characterized by slow and incomplete (40-60%) absoφtion in combination with rapid elimination. Although oral absorption has been estimated to be complete within six hours of administering immediate release dosage forms of metformin, the lack of dose-proportionality at doses higher than 500 mg suggests the possible involvement of a saturable absorption process, which might significantly limit oral absoφtion at higher doses (Scheen and Pentikainen op cit. and Noel M. Kinetic study of normal and sustained release dosage forms of metformin in normal subjects. Res Clin For 1979;1:35-45).

In the current study the extended-release tablets developed by Andrx showed no evidence that metformin bioavailability was impaired at such high doses. On the contrary, there was a»eonsist nt dose-associated increase in metformin exposure with increasing dose. The results of this study therefore would support the assertion from an earlier trial that a large segment of the intestine can be involved in the absoφtion of metformin (Scheen op cit. and Vidon N, Chaussade S, Noel M, et al. Metformin in the digestive tract. Diabetes Res Clin Pract 1988;4:223-229). This study demonstrated that there was a predictable and consistent dose-associated increase in metformin exposure within the dose range of greater than 500 mg, and particularly at doses of about 1000 to about 2500 mg with an extended-release formulation of metformin.

Study 6

A Phase II, single-center, two-way crossover study involving two, four-week treatment periods was conducted to assess the tolerability, pharmacokinetics, and pharmacodynamics (HbAlc, plasma insulin levels and 24-hour plasma glucose levels) of extended-release metformin (ERM) manufactured in accordance with the Examples herein compared to immediate-release metformin (IRM), which is commercially available. Patients were randomized to receive either 2000 mg ERM administered at 6:00 p.m. with dinner, or 1000 mg IRM administered at 8:00 a.m. with breakfast and 1000 mg IRM at 6:00 p.m. with dinner and then switched to the other treatment. The metformin mean ± SD AUC_0-24h (ng hr/mL) was 26811 + 7055 for ERM and 27371 ± 5781 for IRM. There were no significant differences between ERM and IRM in HbAlc. ERM produced significantly lower fasting plasma insulin level, (p < 0.05) and ERM maintained lower plasma glucose levels between 6:00 pm and 6:00 am when compared to IRM. ERM administered at dinner numerically reduced insulin levels.

The anti-hyperglycemic agent metformin has been available commercially as immediate- release (IR) and ER metformin tablets (GlucophageΘ/Gucophage XR- Bristol- Meyers Squibb, Princeton, NJ). There is no fixed dosage regimen for the management of hyperglycemia in diabetes mellitus with metformin. The usual starting dose for IR tablets is one 500 mg tablet bid, or one 850 mg tablet given once daily with meals and titrated to a therapeutically effective dose up to a maximum of 2500-2550 mg per day divided in bid or tid dosing. Current ER formulations (available in 500 mg and 750 mg tablets) are started at 500 mg once daily and titrated to a maximum dose of about 2000mg once daily. If efficacy is not reached, it is typically recommended to be given at the maximum dose (2000mg) in divided doses bid. The most common adverse events associated with metformin use are gastrointestinal in nature, including anorexia, nausea, vomiting, and diarrhea. These adverse events may be partially avoided by either reducing the initial and/or maintenance dose, taking the drug with a meal or using an extended-release dosage form (Schein and Pentikan op cit.).

The objectives of this study were to assess: 1) The pharmacodynamics (PD) and efficacy of ERM compared with IRM after 4 weeks of treatment in patients with Type 2 diabetes. 2) The pharmacokinetics (PK) of ERM compared with IRM after 4 weeks of treatment in patients with Type 2 diabetes, 3) The short-term safety and tolerability of ERM compared with IRM in patients with Type 2 diabetes.

Study design Materials and Methods Patients received the following treatments in random order: 1. Treatment A: 2000 mg metformin XT , (2 x l 000) prepared according to Example 3, administered immediately following the evening meal. 2. Treatment B: 1000 mg IR metformin administered immediately following breakfast and immediately following the evening meal. • The Study schematic is listed in Table 8. There was no washout in this study. Table 8: Study Schematic

1 End-of-study visit 2 Study visits were conducted at the end of the listed study weeks At each scheduled visit, ± 3 days were allowed

Sample collections • Plasma samples for PK and PD assessments were collected at visit 5, 9, and 13. ^• The sampling times for plasma metformin concentration determination and plasma glucose AUC₀.₂4 were as follows: immediately prior to dosing and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 15, 16, 17, 18, 19, 20, 22, and 24 hours after the 6 PM dosing. A fasting plasma sample was obtained approximately 13 hours after the evening dose for determination of plasma insulin, fasting plasma glucose, and hemoglobin AIC. Safety evaluation The safety variables assessed during this study included physical examinations, changes in electrocardiogram (ECG) or vital signs, incidence and frequency of adverse events, and clinical laboratory values. Pharmacokinetic analysis • Heparinized plasma samples were analyzed for metformin utilizing validated high performance liquid chromatography (HPLC) method with ultraviolet detection. • Concentration-time profiles were determined for each individual subject. • PK parameters were calculated using noncompartmental analyses and WinNonlin version 1.1 (Pharsight- Mountainview, CA).

Pharmacodynamic assessments • The PD variables assessed were: the changes of the following parameters from baseline: glucose AUCn.₂ , fasting plasma glucose (FPG), hemoglobin Ale concentration and fasting plasma insulin (FPI) concentration.

Statistical analysis • The primary null hypothesis was that there was no difference between the treatments. • Comparisons of Cmax, AUC₀.₂₄, glucose AUCO-24, FPG, hemoglobin Ale and FPI between treatments were performed using a standard crossover model, with both untransformed and logarithmically-transformed values.

Patient Population Twenty-four patients were randomized to treatment groups. One subject withdrew from the study for personal reasons and did not complete Period I. All randomized patients (n=24) were included in the safety analysis, the 23 patients who completed the study were included in the intent-to-treat PK/ PD analysis. There were 10 men and 14 women. A majority were white (95.8%). The ages ranged from 39 to 70 years. The overall mean weight and height was 91.8 kg and 171.8 cm, respectively. Safety • Treatment- emergent signs and symptoms (TESS) that were considered possibly treatment-related were generally mild to moderate in severity; however, one patient experienced a severe TESS. This patient had severe diarrhea, while taking Metformin XT, which resolved. This patients successfully completed the study. Of the TESS that were considered related to treatment 7/24 (29%o) were for metformin XT treatment (diarrhea, abdominal pain, pain, hypertension, dyspepsia, and rash) and 1/24 (4.3%>) on IR metformin (dyspepsia). Pharmacokinetics The pharmacokinetic results are given in Table 9, below • The mean plasma concentration-time curves generated from the data presented in Figure 10.

Table 9: Pharmacokinetic Results

J. Ratio= Least square Means Metformin XT/ least square mean IR Metformin 2 significant for both untransformed and log- transformed data 3 Harmonic mean; t' for ER formulation is longer due to prolonged absorption of drug from dosage form a: Value presented is for the full 24 hour period on the last day of each treatment period. b: Value presented is for the first 12 hour period on the last day of each treatment period, which represents the value for the IR metformin dose administered at the same time as metformin XT.

• The Cmax of the metformin XT was significantly higher (p<0.05) than the IR metformin. However this increase in the metformin XT Cmax was not as high as what would be expected from the same dose of IR metformin. • The longer Tmax and non- dose proportionate Cmax with similar metformin exposure (i.e. AUC) is consistent with the extended-release properties of metformin XT. The least square mean ratio (metformin XT versus IR metformin) for AUC₀.₂4 (listed in Table 9) indicated that there was no significant difference in overall metformin exposure under steady state conditions. Pharmacodynamics Table 10: Pharmacodynamic Results

confidence interval

The mean 24 hour plasma glucose levels for the two treatment groups are depicted in Figure 11.

The effects of the two treatments (metformin XT versus IR metformin) on fasting plasma glucose (FPG), Hemoglobin Ale, Glucose AUC0-24h and fasting plasma insulin levels are given in Table 10

There was no significant difference between groups in the change in glucose AUCO-24 (p=0.291), or fasting plasma glucose levels (p = 0.154) There was minimal change from baseline to Week 4 in hemoglobin Ale which was neither statistically nor clinically significant. Fasting plasma insulin levels decreased from baseline to the end of week 4, by 1.3 μlU/ml with metformin XT treatment and increased by 1.5 μlU/ml with IR metformin treatment. This difference between the two treatment groups, while clinically insignificant, was statistically significant (p = 0.012). Conclusion Pharmacokinetic analyses confirmed the extended release nature of the metformin XT formulation. Patients with type 2 diabetes usually have relative rather than absolute insulin deficiency, and may have insulin levels that appear normal or are elevated as a result of their hyperglycemia. FPI has been used as a surrogate marker for insulin resistance. The normal/elevated insulin levels in these patients has been attributed to a number of causes. It is thought to be due to an excessive secretion of basal insulin to compensate for the persistent fasting hyperglycemia. Others state that elevated insulin levels or hyperinsulinemia is linked to the other metabolic abnormalities seen with NIDDM such as hyperlipidemia, fibrinolytic defects, and hypertension. This study found a statistically significant decrease in FPI. However, this was not clinically significant which may be due to the short duration (4 weeks for each treatment) of the trial. Despite the differences in plasma metformin concentrations between treatment groups, throughout the 24 hour collection period (more pronounced from hour 12 to hour 24), plasma glucose concentrations follow similar trends, reflecting the consumption and absorption of the morning and the afternoon meals, and the associated variability. Post-prandial control by metformin, as evaluated by overall glucose concentrations (Glucose AUC₀.₂ ) was statistically similar between Metformin XT and IR metformin, showing that despite different metformin concentration vs time profiles, post-prandial glucose control is similar. While relating the trends in individual plasma concentrations of metformin to glucose levels is of limited value, looking at overall exposure in terms of the AUC for plasma metformin concentrations with the corresponding AUC for plasma glucose levels takes into account the associated variability of the consumption and absoφtion of meals. In both the plasma metformin concentration profile and the plasma glucose concentration profile there is no significant difference between the AUC for the 24 hour collection period. In conclusion, Metformin XT and IR metformin were both found to be safe and well tolerated. Metformin XT, dosed at 2000 mg q.d. at 6 p.m., was as effective as IR metformin, dosed at 1000 mg b.i.d., for the control of blood glucose and showed a statistically greater decrease in fasting plasma insulin in patients with Type 2 diabetes.

Study 7

This double-blind, multicenter, parallel group, randomized study compared the efficacy and tolerability of Metformin XT qd to immediate-release metformin (IRM) bid in 1 15 patients (24 in the XT 2000 mg group, 32 in the XT 2500 mg group, 33 in the IRM 2000 mg group, and 26 in the IRM 2500 mg group). Patients were treated for 6 months. The primary efficacy variable was mean HbAlc change from baseline at endpoint. The mean change in HbAlc was 0.19% (p=0.3027) for the XT and 0.33% for the IRM (p=0.00218). In the 2500 mg dose groups, the change in hemoglobin Ale was -0.02% for the XT group and 0.61% for the IRM group. Diarrhea and nausea were the most common trial-drug related treatment emergent sign or symptom, which was not statistically significant difference between groups.

The extended-release formulation of metformin, used in this study was manufactured in accordance with examples 1 and 3 as 500 mg and 1000 mg strength tablets. It has been studied in doses ranging from 1000 mg- 2500 mg given once daily with the evening meal.

The following is the second Phase III study, for Metformin XT, conducted in order to collect safety and tolerability data on Type 2 diabetic patients (including metformin- naϊve patients) at the daily dose of 2000 mg and 2500 mg.

The primary objective of this study was to compare the tolerability and safety of 2000 mg and 2500 mg of Metformin XT once daily (q.d.) to the same dose of IRM (Glucophage®) twice daily (bid) in patients with NIDDM over a 6-month treatment period. The secondary objectives were to evaluate the efficacy of the treatments over the 6-month treatment period.

Materials and Methods Study design This study is a Phase III, double-blind, double-dummy, multicenter, randomized, parallel group study in patients with Type 2 Diabetes who were being treated with hypoglycemic agents, not necessarily including metformin. Patients were assigned to the 2000 mg or 2500 mg groups in order to achieve at least 100 patients in each of the groups between the 2 Phase III protocols. Each site was sent a sequential listing of dose assignments (2000 mg or 2500 mg). Patients were then randomized to receive treatment with either Metformin XT or IRM. The Study schematic is provided in Table 11 below.

Table 11: Study Schematic

The investigator had option of bringing the patient back to the clinic at Week 1, 3, and 5 for an assessment of fasting blood sugar and possible adjustment of concomitant anti-diabetic medications.

1 Study visits were conducted at the end of the listed study weeks. At each scheduled visit, ± days were allowed.

2 Week -2 was approximately 8 days prior to Day 1 of the Treatment Period. Subjects were titrated up in 500mg increments over two-three weeks, depending on assigned dose and starting dose. Anti-diabetic Medications Concomitant medications were continued or adjusted from visit 2 - 4 to allow for the protocol-driven metformin doses and then remained constant from visit 5-9.

Safety evaluation Physical examinations, 12-lead electrocardiogram (ECG) and vital signs were performed at Screening and at Visit 9 and any changes from screening were noted. Adverse experiences and treatment-emergent signs and symptoms (TESS) were recorded. Efficacy Assessment Fasting blood sample is taken on all visits for determination of fasting plasma glucose (FPG). • Hemoglobin Ale concentrations were assessed at Visit 1 , 6,and 9 after an overnight fast. Baseline FPG is the average of FPG values on Visit 1 and 2. Baseline hemoglobin Ale, body weight and BMI are the values at Visit 2. Endpoint was the value of the last measurement taken up to 3 days after the last dose of study medication (taken under fasting conditions). Efficacy Variables Change from baseline in fasting plasma glucose (FPG) at Visits 3-9 and endpoint. Change from baseline in hemoglobin Ale at Visit 6, 9, and endpoint. Change from baseline in body weight and BMI at Visit 9 and endpoint.

Patient Population One hundred and fifteen subjects were randomized to treatment groups (56 received Metformin XT (extended release) and 59 received immediate release metformin (IRM)). Eighty-three subjects completed the study. One hundred and thirteen had at least one safety observation after randomization and were included in the safety population. One hundred twelve subjects had at least one baseline and at least one post-baseline efficacy measurement and were included in the intent-to-treat population. ^• The mean (± SD) age, weight, and BMI was 55.3 ± 10 years, 92.6 ±17.1 kg, and 31.0±4.6 kg/m2 at baseline. Twenty-six of 1 15 (22.6%) patients were metformin -naive and had no exposure to metformin prior to the start of the trial. Eighty-nine (77.4%) patients had previous exposure to Metformin/Glucophage. Concomitant Medications After Randomization • Oral blood glucose lowering drugs were used during the study by 38/56 (67.9%) patients in the Metformin XT group and 46/59 (78.0%) patients in the IRM group. • Insulins and analogues were used during the study by 8/56 (14.3%) patients in the Metformin XT group and 9/59 (15.3%) patients in the IRM group.

Safety • At least one TESS was experienced during this study by 43/54 (79.6%) patients in the Metformin XT group and 39/59 (66.1%) patients in the IRM group. • There was 1/54 patient from the Metformin XT group who died due to acute coronary insufficiency during the course of the study. This was considered unrelated to study treatment. • A total of 9/113 patients were reported to have a severe serious adverse event (S AE): 4/54 in the Metformin XT group and 5/59 in the IRM group. None of these TESS events were considered by the investigator to be related to study drug except for diarrhea for one patient in the IRM group, which was considered by the investigator to be possibly related to study drug. This patient completed the study. • Fifteen of 56 (26.8%) and 17/59 (28.8%) patients randomized to metformin XT and IRM, respectively, discontinued after randomization. Of these, 9 patients (3/56 in the Metformin XT group and 6/59 in the IRM group) withdrew prematurely due to treatment- emergent adverse experiences. These included abdominal pain, coronary artery disease, and hypoglycemia in the Metformin XT group and somnolence, angina pectoris, anorexia, diarrhea, dyspepsia, thrombocytopenia, and hypoglycemia in the IRM group. Out of these 9 patients, 2 from the metformin XT and 4 from the IRM group were considered trial-drug related. Of the patients in the Safety Population, 14/54 (25.9%) patients in the Metformin XT group and 15/59 (25.4%) patients in the IRM group experienced a TESS that the investigator considered trial drug-related (Table 13). The occurrence of the two most common TESS considered to be trial drug related, diarrhea and nausea, were found to be comparable between treatment groups as determined by chi-square (p=0.2913). SAEs were reported in 5/113 patients (5 SAEs): 4/54 patients (4 SAEs) in the Metformin XT group and 1/59 patient (1 SAE) in the IRM group. None of the SAEs were considered by investigators to be related to study drug. Efficacy • No patients discontinued the study due to lack of efficacy. • The overall mean compliance rate was 94.3% for subjects in the Metformin XT group and 95.4% for patients in the IRM group. • Table 12 lists the change in hemoglobin Ale (%) from baseline at endpoint by assigned dose.

Table 12: Change in Hemoglobin Ale (%) from Baseline at Endpoint by assigned dose- ITT Population

The mean change in FPG from baseline at endpoint was 13.9 mg/dL [0.76 mmol/L] for the Metformin XT group and 13.8 mg/dL [0.76 mmol/L] for the IRM group. Both of these changes from baseline to endpoint were statistically significant (p=0.0201 Metformin XT, p=0.0236 IRM). Figure 1 displays the mean change in FPG from baseline over time for the ITT Population. The mean change in body weight from baseline at endpoint was 0.5 kg for the Metformin XT group and 1.3 kg for the IRM group. The change in body weight for the Metformin XT group was not statistically significant (p=0.4079), while the change for the IRM group was statistically significant (p=0.0007). The mean change in BMI from baseline at endpoint was 0.2 kg/m2 for the Metformin XT group and 0.5 kg/m2 for the IRM group. The change in BMI for the Metformin XT group was not statistically significant (p=0.2741), while the change for the IRM group was statistically significant (p=0.0023). Both groups had a large number of patients who experienced gastrointestinal TESS that were trial drug-related, with diarrhea and nausea being the two most common events in this category. While found to be statistically similar between treatment groups, the frequency of diarrhea was 14.8% and 8.5% of patients in the Metformin XT and IRM group, respectively, and the frequency of nausea was 5.6% and 6.8% in the Metformin XT and IRM group, respectively. The relatively high incidence of trial drug-related gastrointestinal TESS was an anticipated effect of metformin, and was similar to the event rate reported in the package insert for IRM.1 There were no meaningful differences between treatment groups in the number of trial drug-related TESS. The most frequent investigator- determined, trial drug-related adverse experiences were diarrhea and nausea. Metformin XT and IRM were both safe and well tolerated. The total number of patients with SAEs and/or adverse dropouts (ADOs) was similar between treatment groups. The pattern of AEs, SAEs, and ADOs did not suggest any new findings for higher doses of metformin in both high dose treatment groups. There were no clinically significant safety differences at the higher doses (2000 mg and 2500 mg) of Metformin XT compared to IRM. • This study was primarily a comparison of tolerance and safety between Metformin XT and IRM, however an efficacy analysis was performed. Both doses of the Fortamet group and the lower dose (2000 mg) of the IR metformin showed no difference from baseline (p>0.05). The statistically significant increase in the 2500 mg Glucophage group may be due to lack of dose proportionality associated with of IRM 1, whereas Fortamet has been reported to have a predictable and consistent dose associated increase in exposure.4 Similar mean percent changes were observed for Metformin XT and IRM for FPG, body weight, and BMI.

The overall conclusion of this study indicates that treatment with 2000 mg or 2500 mg Metformin XT administered once a day provides a similar efficacy and safety profile when compared to treatment with 2000 mg or 2500 mg IRM administered twice a day in Type 2 diabetic patients (including a sub-population of metformin-naϊve patients).

Tablel3: Number and Percentage of Patients With the Most Common (incidence > 5%) Trial Drug related TESS by Body System, Preferred Term, and Assigned Dose- Safety Population

While certain preferred and alternative embodiments of the invention have been set forth for purposes of disclosing the invention, modifications to the disclosed embodiments may occur to those who are skilled in the art. Accordingly, the appended claims are intended to cover all embodiments of the invention and modifications thereof which do not depart from the spirit and scope of the invention.

Claims

What is claimed is:

1. A method for treating a patient using an antidiabetic drug, said method comprising administering to the patient a high dose of the antidiabetic drug wherein said antidiabetic drag exhibits one or more dose proportional pharmacokinetic parameters.

2. The method of claim 1 wherein said antidiabetic drug is selected from the group consisting of biguanides, hormone analogues, sulfonylureas, and thiozolidinediones or salts, derivatives, prodrugs or metabolites thereof.

3. The method of claim 1 wherein said antidiabetic drug is a biguanide.

4. The method of claim 3 wherein said biguanide is metformin.

5. The method of claim 1 wherein said antidiabetic drug is administered once a day.

6. The method of claim 1 wherein said antidiabetic drug is administered to lower blood sugar.

7. The method of claim 1 wherein said antidiabetic drug is administered to a patient in need of treatment of non-insulin-dependent diabetes mellitus (NIDDM).

8. The method of claim 1 wherein the dose proportional pharmacokinetic parameter is selected from the group consisting of AUC and Cmax.

9. The method of claim 3 wherein said biguanide is administered at a dose of greater than about 500mg.

10. The method of claim 3 wherein said biguanide is administered at a dose of greater than about 750mg.

11. The method of claim 3 wherein said biguanide is administered at a dose of greater than about 850mg.

12. The method of claim 3 wherein said biguanide is administered at a dose of greater than about lOOOmg.

13. The method of claim 3 wherein said biguanide is administered at a dose of greater than about 1500mg.

14. The method of claim 3 wherein said biguanide is administered at a dose of greater than about 2000mg.

15. The method of claim 3 wherein said biguanide is administered at a dose of greater than about 2500mg.

16. The method of claim 4 wherein administration of metformin exhibits the pharmacokinetic parameters selected from the group consisting of (a) Cmax of about 1 to about 3.1 μg/ml; and (b) AUC of about 9 to about 29 μg ^• h/ml; after administration of about 500mg to about 2500mg of metformin.

17. The method of claim 16 wherein administration of metformin exhibits the pharmacokinetic parameters selected from the group consisting of (a) Cmax of about 1 to about 2 μg/ml; and (b) AUC of about 9 to about 15 μg ^■ h/ml; after administration of about l OOOmg of metformin.

18. The method of claim 16 wherein administration of metformin exhibits the pharmacokinetic parameters selected from the group consisting of (a) Cmax of about 1.2 to about 2.4 μg/ml; and (b) AUC of about 12 to about 21 μg ^• h/ml; after administration of about 1500mg of metformin.

19. The method of claim 16 wherein administration of metformin exhibits the pharmacokinetic parameters selected from the group consisting of (a) Cmax of about 1.5 to about 2.7 μg/ml; and (b) AUC of about 17 to about 25 μg ^• h ml; after administration of about 2000mg of metformin.

20. The method of claim 16 wherein administration of metformin exhibits the pharmacokinetic parameters selected from the group consisting of (a) Cmax of about 1.9 to about 3.1 μg/ml; and (b) AUC of about 20 to about 29 μg ^• h ml; after administration of about 2500mg of metformin.

21. The method of claim 1 wherein said high dose of the antidiabetic drug is released in a controlled manner.