WO2005107750A1 - Compositions a base de metformine a liberation regulee - Google Patents

Compositions a base de metformine a liberation regulee Download PDF

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Publication number
WO2005107750A1
WO2005107750A1 PCT/US2005/014826 US2005014826W WO2005107750A1 WO 2005107750 A1 WO2005107750 A1 WO 2005107750A1 US 2005014826 W US2005014826 W US 2005014826W WO 2005107750 A1 WO2005107750 A1 WO 2005107750A1
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Prior art keywords
metformin
dose
drug
administered
study
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PCT/US2005/014826
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English (en)
Inventor
Xiu-Xiu Cheng
Edward I. Cullen
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Andrx Labs. Llc
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Priority to EP05742346A priority Critical patent/EP1746993A4/fr
Priority to CA002564750A priority patent/CA2564750A1/fr
Priority to JP2007511018A priority patent/JP2007535557A/ja
Publication of WO2005107750A1 publication Critical patent/WO2005107750A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones

Definitions

  • 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.
  • 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.
  • 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.
  • 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.
  • GLUCOPHAGE® contains 500, 850 or 1000 mg of metformin hydrochloride.
  • 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.
  • 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.
  • 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.
  • NIDDM non-insulin-dependent diabetes mellitus
  • NIDDM non-insulin-dependent diabetes mellitus
  • 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.
  • 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.
  • the dosage form comprises a tablet.
  • 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;
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • C max mean maximum plasma concentration
  • the controlled release oral dosage form when the drug is metformin or a pharmaceutically acceptable salt thereof, 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.
  • C max mean maximum plasma concentration
  • the controlled release dosage form when the drug is metformin or a pharmaceutically acceptable salt thereof, 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.
  • 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.
  • 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 ⁇ m 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.
  • the antihyperglycemic drug e.g., metformin
  • 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.
  • the drug e.g., metformin or a pharmaceutically acceptable salt thereof
  • the antihyperglycemic drug is metformin
  • drugs such as metformin provide substantially linear pharmacokinetics up to a level of about 2 grams per day. Therefore, it is contemplated for pu ⁇ oses 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.
  • the controlled release dosage form of the present invention is administered with food.
  • 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.
  • 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.
  • 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.
  • a biguanide e.g., metformin or a pharmaceutically acceptable salt thereof
  • 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 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.
  • 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.
  • 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.
  • a biguanide e.g., metformin
  • 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 ma ⁇ ) 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.
  • T ma ⁇ mean time to maximum plasma concentration
  • the administration of the controlled-release dosage form occurs at fed state, more preferably at dinner time.
  • the controlled-release dose of the drug e.g., metformin or a pharmaceutically acceptable salt thereof
  • 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 abso ⁇ tion enhancer;
  • the mean time to maximum plasma concentration of the drug is reached from 6.5 to 7.5 hours after administration at dinner time.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • NIDDM non-insulin-dependent diabetes mellitus
  • 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.
  • a method for treating a patient using an antidiabetic drug comprising administering to the patient a high dose of the antidiabetic drug wherein said antidiabetic drug exhibits one or more dose proportional pharmacokinetic parameters.
  • metalformin as it is used herein means metformin base or any pharmaceutically acceptable salt e.g., metformin hydrochloride.
  • drug “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.
  • 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.
  • 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.
  • sustained release and "controlled release” are used interchangeably in this application and are defined for pu ⁇ oses 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.
  • blood e.g., plasma
  • the controlled release solid oral dosage form containing such drug is also referred to as "Metformin XT."
  • C max is the highest plasma concentration of the drug attained within the dosing interval, i.e., about 24 hours.
  • C m is the minimum plasma concentration of the drug attained within the dosing interval, i.e. about 24 hours.
  • 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.
  • 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).
  • AUC as used herein, means area under the plasma concentration-time curve, as calculated by the trapezoidal rule over the complete 24-hour interval.
  • 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.
  • 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.
  • 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.
  • 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.
  • mean when preceding a pharmacokinetic value (e.g.
  • 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 m i n )/C av g.
  • the term "high dose” is commonly used in the medical and pharmaceutical arts to refer to relative dosing strengths. For example, for the pu ⁇ oses of certain embodiments of the subject invention, the term high dose, as it relates to metformin is any dose 500mg or greater.
  • FIG. 1 is a graph showing the relative bioavailability of the metformin XT formulation of Example 2 to GLUCOPHAGE® for Clinical Study 2.
  • FIG. 1 is a graph showing the relative bioavailability of the metformin XT formulation of Example 2 to GLUCOPHAGE® for Clinical Study 2.
  • FIG. 1 is a graph showing the relative bioavailability of the metformin XT formulation of Example 2 to GLUCOPH
  • 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. 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
  • 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.
  • antidiabetic drugs antihyperglycemic drugs as used in this specification refers to drugs that are useful in controlling or managing noninsulin-dependent diabetes mellitus (NIDDM).
  • NIDDM noninsulin-dependent diabetes mellitus
  • 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.
  • the controlled release formulations of the invention provide a T m ⁇ (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.
  • 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.
  • administration of the dosage form provides lower drug levels during the day (e.g.
  • 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.
  • 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).
  • 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.
  • NIDDM controlled-release oral dosage form
  • metformin is provided by a controlled release dosage fo ⁇ n 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.
  • T max mean time to maximum plasma concentration
  • 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.
  • sulfonylurea examples include glyburide (glibenclamid), chloropropamide, tolbutamide, glipizide, acetohexamide and tolazamide.
  • 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.
  • the desired control of blood glucose may be obtained by adjusting the dose of each drug.
  • the foregoing objectives are met by a controlled release dosage form comprising:
  • a core comprising: (i) an antihyperglycemic drug; (ii) optionally a binding agent; and (iii) optionally an abso ⁇ tion enhancer;
  • 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 abso ⁇ tion enhancer.
  • the abso ⁇ tion enhancer can be any type of abso ⁇ tion enhancer commonly known in the art such as a fatty acid, a surfactant, a chelating agent, a bile salt or mixtures thereof.
  • abso ⁇ tion 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).
  • 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, ethylened
  • the core comprises approximately 0 to about 20%) of the abso ⁇ tion enhancer based on the total weight of the core and most preferably about 2% to about 10%> of the total weight of the core.
  • the core which comprises the antihyperglycemic drug, the binder which preferably is a pharmaceutically acceptable water soluble polymer and the abso ⁇ tion 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.
  • 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.
  • cellulose esters 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 inco ⁇ orated 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.
  • 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.
  • 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.
  • the membrane may also be formed with commonly known excipients such as a plasticizer.
  • 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.
  • 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.
  • 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.
  • the passageway is formed by laser drilling.
  • 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.
  • the dosage form contains two passageways in order provide the desired pharmacokinetic parameters of the formulation.
  • 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.
  • 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).
  • 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.
  • membrane also generically encompasses the term “semipermeable membrane” as heretofore defined.
  • 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 inco ⁇ orated into the membrane.
  • the dosage form will have the following composition:
  • 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 ⁇ ms in 900 ml of simulated intestinal fluid (pH 7.5 phosphate buffer) and at 37°C:
  • NTL Not less than
  • various conventional well known solvents may be used to prepare the granules and apply the external coating to the tablets of the invention.
  • 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.
  • the controlled release dosage form may optionally include a controlled release carrier which is inco ⁇ orated 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 inco ⁇ orated in any other suitable oral form.
  • 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.
  • a method for treating a patient using an antidiabetic drug 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 method provides for a predictable dosing regimen for high dose administration.
  • 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.
  • the antidiabetic drug is metformin or a salt, derivative, prodrug or metabolite thereof.
  • 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).
  • NIDDM non-insulin-dependent diabetes mellitus
  • 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.
  • the dosage form is administered orally as a solid dosage.
  • (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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 Povidone 3 , USP 71.9 Sodium Lauryl Sulfate 51.7 Magnesium Stearate 5.6
  • 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.
  • 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.
  • 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).
  • 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.
  • 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).
  • 12 healthy volunteers five males and seven females
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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).
  • 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.
  • 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.)
  • metformin XT 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.
  • 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.
  • HPLC high-performance liquid chromatographic
  • 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
  • the LOQ were used to assess the interday and intraday assay precision and accuracy during validation.
  • the interday assay coefficient of variation 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 (T ⁇ 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' ⁇ ) was calculated as ln(2)/ke, and ke was determined from linear regression of the terminal portion of the In-concentration versus time curve.
  • 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.
  • TESS treatment-emergent signs or symptoms
  • LSM Least-squared means
  • metformin 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.
  • Pentikainen PJ Pentikainen PJ. Bioavailability of metformin: comparison of solution, rapidly dissolving tablet, and three sustained-release products.
  • J Clin Pharmacol Ther Toxicol 1986;24:213-220; and the Scheen and Pentikainen op cit. 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.
  • metformin pharmacokinetics of metformin are characterized by slow and incomplete (40-60%) abso ⁇ tion in combination with rapid elimination.
  • 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 abso ⁇ tion 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).
  • 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 (Glucophage ⁇ /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.
  • 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.
  • PD pharmacodynamics
  • PK pharmacokinetics
  • Treatment A 2000 mg metformin XT , (2 x l 000) prepared according to Example 3, administered immediately following the evening meal.
  • Treatment B 1000 mg IR metformin administered immediately following breakfast and immediately following the evening meal.
  • 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 AUC 0 . 2 4 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).
  • FPG fasting plasma glucose
  • FPI fasting plasma insulin
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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

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Abstract

L'invention concerne une méthode destinée à traiter un patient au moyen d'un médicament antidiabétique. Cette méthode consiste à administrer à ce patient une dose élevée de ce médicament antidiabétique, lequel présente un ou plusieurs paramètres pharmacocinétiques proportionnels à la dose.
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KR20030061392A (ko) * 2000-11-03 2003-07-18 안드렉스 코포레이션 방출 조절성 메트포민 조성물
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CA2564750A1 (fr) 2005-11-17
EP1746993A4 (fr) 2007-08-29
JP2007535557A (ja) 2007-12-06
EP1746993A1 (fr) 2007-01-31

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