JP2007535557A - Controlled release metformin composition - Google Patents

Abstract

  A method of treating a patient with an antidiabetic agent comprising administering to the patient a high dose of an antidiabetic agent, wherein the diabetic agent is one or more pharmacokinetic parameters proportional to the dose. Is shown.

Description

  The present invention relates to controlled release unit dose formulations containing anti-diabetic drugs such as hypoglycemic drugs. More particularly, the present invention relates to biguanides, such as metformin or buformin, or metformin salts or metformin hydrochloride as described in US Pat. Nos. 3,957,853 and 4,080,472, which are hereby incorporated by reference. And a pharmaceutically acceptable salt thereof.

  In the prior art, controlled and sustained release using a number of techniques to maintain blood levels of therapeutically effective drugs and minimize the effects of drug forgetting caused by patient non-compliance Types of pharmaceutical dosage forms have been provided.

  In the prior art, sustained release tablets have a permeable drug core surrounded by a semipermeable membrane. These tablets function by allowing liquids such as gastric juice or intestinal fluid to permeate the coating membrane and dissolve the active ingredient, thereby allowing the release of the active ingredient through the passage of the coating membrane. If the active ingredient is insoluble in the infiltrated liquid, it can be pushed through the passageway by a swelling agent such as a hydrogel. Representative examples of such osmotic tablet systems can be found in US Pat. Nos. 3,845,770, 3,916,899, 4,034,758, 4,077,407 and 4,783,337. U.S. Pat.No. 3,952,741 presents an osmotic device in which the perimeter is covered with a semi-permeable membrane only after sufficient pressure has been generated inside the membrane to rupture the membrane in a weak part of the membrane. The active substance is released from the broken core.

  The basic osmotic devices described in the above patents have been improved over time to provide better controlled release of active ingredients. For example, U.S. Pat. Nos. 4,777,049 and 4,851,229 describe osmotic dosage forms comprising a semipermeable wall surrounding a core. The core contains an active ingredient and a modulator, which triggers the release of the active ingredient through the passage of the semipermeable membrane in a pulsatile manner. Other improvements include an improvement in the semipermeable membrane around the active core, eg, changing the proportion of components that make up the membrane; ie, US Pat. Nos. 5,178,867, 4,587,117 and 4,522,625, or around the active core No. 5,650,170 and 4,892,739.

  A great deal of research has been done on controlled release or sustained release compositions, especially on osmotic dosage forms, but little has been done in the field of controlled release or sustained release compositions using hypoglycemic drugs. .

  Metformin is an oral hypoglycemic agent used to treat non-insulin dependent diabetes mellitus (NIDDM). This is chemically and pharmacologically independent of oral sulfonylureas. Metformin improves glucose tolerance in NIDDM patients by lowering both basal and postprandial blood glucose levels. Metformin hydrochloride is currently commercially available from Bristol-Myers Squibb as a Glucophage (GLUCOPHAGE®) tablet. Glucophage tablets contain 500, 850, or 1000 mg of metformin hydrochloride, respectively. There is no fixed dosing regimen for managing diabetic hyperglycemia with glucophage. The dosage of glucophage is set individually based on efficacy and tolerability, but does not exceed the maximum recommended dose of 2550 mg per day.

  Metformin has been widely prescribed to lower blood glucose levels in NIDDM patients. However, because it is a short-acting drug, metformin requires administration twice a day (b.i.d.) or three times a day (t.i.d.). Adverse events associated with the use of metformin often occur in the gastrointestinal tract (eg anorexia, nausea, vomiting, and in some cases diarrhea). Such adverse events can be avoided to some extent by reducing the initial dose and / or maintenance dose or by using a sustained release dosage form. Another obvious advantage of sustained release dosage forms is a reduction in the number of doses. All of these findings suggest that metformin sustained release dosage forms may improve the quality of treatment and improve the safety profile of patients with NIDDM compared to conventional dosage forms.

  Limited studies on controlled-release or sustained-release or sustained-release formulations using hypoglycemic drugs such as metformin hydrochloride include hypoglycemic drugs and swelling agents or gels that control drug release from the dosage form. Concomitant use with agents. Such studies are illustrated by the teachings of WO 96/08243 and the GLUCOPHAGE® metformin hydrochloride product.

  As reported in the US Pharmaceutical Handbook, 50th edition, 1996 edition, page 753, food reduces the extent of metformin delivery by glucophage dosage forms and delays absorption somewhat. These reductions include a single 850 mg metformin hydrochloride-containing glucophage tablet with food, followed by a reduction of about 40% in the maximum concentration compared to similar tablets administered under fasting conditions, with a bioavailability of 25 % Reduction and the time to peak plasma concentration is increased by 35 minutes.

  Controlled release metformin dosage forms are also described in WO 99/47128. This document describes a controlled release delivery system for metformin, which is substantially homogeneous, containing metformin and one or more hydrophilic polymers, one or more hydrophobic polymers and one or more hydrophobic materials. Including an inner solid particle phase in the form of a smooth granule, as well as an outer continuous phase in which the 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 (assigned to the assignee of the present invention) discloses a controlled release metformin formulation that gives a Tmax of 8 to 12 hours.

  It is an object of the present invention to provide controlled release or sustained release of hypoglycemic drugs that effectively control blood glucose levels in humans.

  It is another object of the present invention to provide a method for treating non-insulin dependent diabetes mellitus (NIDDM) patients once a day with a hypoglycemic agent that effectively controls blood glucose levels in humans. It is.

  Formulations for treating non-insulin dependent diabetes mellitus (NIDDM) patients, which provide advantages over the state of the art and can be administered alone or with other antidiabetic drugs once daily Providing a method is another object of the present invention.

  It is also an object of the present invention to provide a controlled or sustained release formulation of a hypoglycemic drug in which the bioavailability of the drug is not reduced by the presence of food.

  It is another object of the present invention to provide a controlled or sustained release formulation of a hypoglycemic drug that does not use an expandable polymer.

  Controlled or sustained release formulations of hypoglycemic drugs that can provide sustained and non-pulsed therapeutically effective drug levels to animals or humans in need of such treatment over a 12-24 hour period It is another object of the present invention.

  It is still a further embodiment of the present invention to provide a controlled release or sustained release formulation for hypoglycemic drugs that achieves maximum plasma levels from 5.5 hours to 7.5 hours after administration under various conditions. One purpose. Also, the time to reach the maximum plasma level is 6.0 to 7.0 hours, 5.5 to 7.0 hours, or 6.0 to 7.5 hours.

  It is also an object of the present invention to provide a controlled release or sustained release formulation that has a uniform core and whose core components can be produced by conventional tableting molding methods.

  In accordance with the above objectives and the like, the present invention provides a control comprising a hypoglycemic drug, preferably a biguanide drug (eg, metformin or a pharmaceutically acceptable salt thereof) suitable for administration of a drug once daily. A release oral dosage form is provided, which results in an average maximum plasma concentration attainment time (Tmax) of the drug between 5.5 and 7.5 hours after administration. This dosage form consists of a drug and a membrane. In certain preferred embodiments, the dosage form is a tablet.

In a preferred embodiment, the controlled release oral dosage form of the present invention is a tablet comprising:
a core comprising (a) (i) a hypoglycemic agent, (ii) optionally a binder, and (iii) optionally an absorption enhancer;
(b) a membrane surrounding the core; and
(c) at least one passage in the membrane.

  When the drug is metformin or a pharmaceutically acceptable salt thereof and is administered on a once-daily basis, the daily dose can vary, for example, from about 500 mg to about 2500 mg. This daily dose may be included in one controlled release dosage form of the invention, but can also be included in two or more such dosage forms. For example, a controlled release metformin dosage form can be formulated to contain about 1000 mg of drug, although two such dosage forms can be administered simultaneously to provide a once-daily metformin treatment. Good. The daily dose of the drug (ie, metformin or a pharmaceutically acceptable salt thereof) can be about 500 mg to about 2500 mg, about 1000 mg to about 2500 mg, or about 2000 mg to about 2000 mg, depending on the clinical needs of the patient. It can range up to 2500mg.

  In certain preferred embodiments, the solid controlled release oral dosage form of the present invention is about 50% of the mean plasma concentration / time-curve height of the drug (eg, metformin), from about 4.5 to about 13 hours, More preferably from about 5.5 to about 10 hours, even more preferably from about 6 hours to about 8 hours.

  In certain embodiments, a controlled release oral dosage form of the invention provides an average maximum plasma concentration (Cmax) of the drug that is greater than about 7 times the average plasma level of a hypoglycemic drug at about 24 hours after administration. . In preferred embodiments, the controlled release oral dosage form of the present invention is about 7 to about 14 times the plasma level of the drug at about 24 hours after administration, more preferably at about 24 hours after administration. Gives a mean maximum plasma concentration (Cmax) of the drug from about 8 to about 12 times the plasma level of the drug.

  In certain embodiments of the invention, when the drug is metformin or a pharmaceutically acceptable salt thereof, the controlled release oral dosage form has an average maximum plasma concentration (Cmax) of the drug of about 1500 ng / ml to about 3000 ng / ml. ml (based on metformin 2000 mg once daily), more preferably from about 1700 ng / ml to about 2000 ng / ml (based on metformin 2000 mg once daily).

In certain embodiments of the invention, when the drug is metformin or a pharmaceutically acceptable salt thereof, the controlled release dosage form is from about 17200 ng.hr/ml to about 33900 ng, based on metformin 2000 mg once daily. up to .hr / ml; preferably from about 17200 ng.hr/ml to about 26500 ng.hr/ml based on metformin 2000 mg once daily; more preferably about 19800 ng.hr based on metformin 2000 mg once daily Give an average AUC _0-24hr from / ml to about 33900ng.hr/ml.

In certain embodiments of the invention, administration of a hypoglycemic drug, eg, at least one metformin dosage form, is at least 80% of the average AUC _0-24hr given by twice daily administration of a reference drug (GLUCOPHAGE), Preferably an average AUC _0-24hr of at least 90% is given, but the daily _dose of this reference drug is the same as the once-daily dose of metformin administered as a controlled release oral dosage form of the present invention. .

  In certain embodiments of the invention, the controlled release dosage form is as follows when tested in 900 ml artificial gastrointestinal fluid (pH 7.5 phosphate buffer) at 37 rpm at 37 ° C. in a USP type 2 device: Shows dissolution profile of hypoglycemic drugs (eg metformin): 0-30% drug release after 2 hours; 10-45% drug release after 4 hours; 30-90% drug release after 8 hours; 50 after 12 hours % Drug release; more than 60% drug release after 16 hours; and more than 70% drug release after 20 hours.

  In one preferred embodiment of the present invention, the solid controlled release oral dosage form is as follows when tested in 900 ml artificial gastrointestinal fluid (pH 7.5 phosphate buffer) at 37 rpm at 37 ° C. in a USP type 2 device: Dissolution profile of: 0-25% drug release (eg metformin or a pharmaceutically acceptable salt thereof) after 2 hours; 20-40% drug release after 4 hours; 45-90% drug after 8 hours Release; more than 60% drug release after 12 hours; more than 70% drug release after 16 hours; and more than 80% drug release after 20 hours.

  With respect to embodiments of the invention in which the hypoglycemic agent is metformin, it has been shown that drugs such as metformin provide approximately linear pharmacokinetics up to a level of about 2 g per day. Thus, for the purposes of the present invention, the plasma level of metformin (eg, Cmax) given for each specified dose is considered to be directly proportional to other doses of metformin. Such proportional doses and plasma levels are within the scope of the present invention and are considered to be within the scope of the appended claims.

  The dosage form of the present invention can provide a therapeutically effective concentration of a hypoglycemic drug for 12 to 24 hours and does not show reduced bioavailability when taken with food. In fact, a slight increase in the bioavailability of hypoglycemic drugs is observed when the controlled release dosage form of the present invention is administered with food. In preferred embodiments, the dosage form can be administered once daily, ideally with meals, or after meals, preferably with dinner, or after dinner, resulting in a therapeutically effective drug concentration throughout the day. Maximum plasma levels are obtained between 5.5 and 7.5 hours after administration.

  The invention also relates to a method of lowering blood glucose levels in a human patient in need of treatment for non-insulin dependent diabetes mellitus (NIDDM), the method comprising a biguanide drug (eg, metformin or a pharmaceutically acceptable Salt)) orally administered to a human patient once daily, said drug being included in at least one controlled release solid oral 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. it can.

  The controlled release dosage form of the present invention gives a delayed Tmax compared to the Tmax given by GLUCOPHAGE. Delayed Tmax is between 5.5 and 7.5 hours after administration. If a drug (eg, metformin) is administered at dinner, Tmax is usually the time when gluconeogenesis is maximal (eg, around 2 am).

  The present invention also encompasses a method of treating a NIDDM patient, wherein the method involves administering a single dose of a drug, including a biguanide drug (eg, metformin or a pharmaceutically acceptable salt thereof) once daily to a human patient. Orally, wherein the drug is included in at least one controlled release oral 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. it can. In certain embodiments, the treatment method of the present invention comprises metformin monotherapy administered once a day as a dietary supplement to reduce blood glucose levels in NIDDM patients whose hyperglycemia cannot be adequately managed by diet alone. Use therapy. In certain other embodiments, for example, once daily metformin therapy of the present invention is used in combination with sulfonylurea when diet and sulfonylurea monotherapy alone do not result in adequate glycemic control. can do. In other specific embodiments, once daily metformin therapy of the present invention is used in combination with glitazone, for example, when diet and monotherapy with glitazone alone do not result in adequate glycemic control. be able to.

  The present invention further relates to a method of controlling blood glucose levels in human NIDDM patients, which method comprises administering at least one controlled release oral administration of the present invention to a NIDDM patient in a once-daily manner, preferably at dinner. Administering an effective dose of a biguanide drug (eg, metformin) contained in the dosage form.

  The invention further encompasses a controlled release dosage form of a drug comprising a biguanide drug (eg, metformin) suitable for once daily administration to human NIDDM patients, the dosage form being up to about 24 Containing an effective amount of drug to control blood glucose levels over time, as well as an amount of controlled release carrier effective to provide controlled release of the drug, the average peak plasma concentration time (Tmax) of the drug administered About 5.5 to 7.5 hours later, the mean plasma concentration / time of the drug at 50% of the height of the curve is about 6 to about 13 hours wide. In a preferred embodiment, the administration of the controlled release dosage form is performed with a meal, preferably at dinner.

In certain preferred embodiments, controlled release administration of a drug of the invention (eg, metformin or a pharmaceutically acceptable salt thereof) is provided by one or more controlled release tablets comprising:
(a) (i) a hypoglycemic agent (eg, metformin or a pharmaceutically acceptable salt thereof),
(ii) an optional binder, and
(iii) optionally an absorption enhancer,
A core comprising:
(b) a membrane surrounding the core; and
(c) at least one passage in the membrane.

  In certain preferred embodiments, the average time to maximum plasma concentration of the drug is 6.5 to 7.5 hours after administration at dinner.

  In certain embodiments of the invention where the drug is a biguanide drug (eg, metformin or a pharmaceutically acceptable salt thereof), the controlled release dosage form is administered in a single dose, equally as two divided doses (1 One divided dose is administered at the start of the dosing interval and the other dose is administered 12 hours later) giving an average plasma variability index higher than the same dose immediate release composition, preferably of the immediate release composition Maintain bioavailability of at least 80%, preferably at least 90%.

  In certain embodiments of the invention, the average variation index of the dosage form is from about 1 to about 4, preferably from about 2 to about 3, and more preferably about 2.5.

  In certain embodiments of the invention, which exhibit a higher mean variability index in plasma than the same dose immediate release composition administered as an evenly divided dose, in one embodiment of the invention, the mean variability index of the dosage form of the invention and the immediate release composition The ratio is about 3: 1, preferably about 2: 1, and more preferably 1.5: 1.

  When the drug is metformin or a pharmaceutically acceptable salt thereof, the dose of the drug exhibiting the above mean variability index can be any effective dose that is administered to NIDDM patients to lower blood glucose levels. For example, the dose can be metformin or a pharmaceutically acceptable salt thereof, about 500 mg to about 2500 mg, about 1000 mg to about 2000 mg, or about 850 mg to about 1700 mg.

  Drugs that can be used with the present invention include drugs useful for the treatment of non-insulin dependent diabetes mellitus (NIDDM), including biguanides such as metformin or buformin, or pharmaceutically acceptable salts thereof. Is not limited to them. When the drug used in the present invention is metformin, the metformin is preferably present in the form of a salt, preferably as metformin hydrochloride.

  Further contemplated as part of the present invention is a method of treating a patient with an antidiabetic agent, the method comprising administering to the patient a high dose of an antidiabetic agent. The antidiabetic agent exhibits one or more pharmacokinetic parameters proportional to the dose.

  The term “metformin” as used herein means metformin or any pharmaceutically acceptable salt, such as metformin hydrochloride.

  The term “dosage form” as used herein means at least one unit dosage form of the invention (eg, a daily dose of a hypoglycemic agent is administered in a single dose once a day). Can be included in the two unit dosage forms of the present invention).

  The term “morning” as used herein with respect to the administration of a controlled release formulation of the present invention, generally from about 6 am to 11 am early in the day after the patient wakes up from an overnight sleep. By the time, it means that the controlled release formulation is administered orally (unless you give breakfast at that time unless otherwise indicated).

  The terms “at dinner” or “at dinner” as used herein with respect to the administration of a controlled release formulation of the invention are usually at the time of having dinner (in fact at that time unless otherwise indicated). Regardless of whether or not you have a meal), it generally means that the controlled release formulation is administered orally from about 4 pm to about 8 pm.

  The term “sleeping” as used herein with respect to the administration of a controlled release formulation of the present invention is controlled release, usually between about 8 pm and about 12 pm, at night before the patient goes to bed. It means that the formulation is administered orally.

  The term “therapeutically effective decrease” as used herein refers to an immediate release reference drug (eg, when a controlled release formulation is orally administered to a human patient in a once daily regimen (eg, GLUCOPHAGE (registered trademark)) means that the blood glucose level is reduced to the same extent or more.

  The terms “sustained release” and “controlled release” are used interchangeably herein and are defined for the purposes of the present invention as releasing a drug from a dosage form at the following rate: However, the rate is such that when a once daily dose of the drug is administered as a sustained or controlled release dosage form, the blood (eg, plasma) concentration (level) of the drug is from about 12 hours to about 24 hours. Over a period of time such that it is within a therapeutically effective range but remains below a toxic level. When the drug used in the present invention is metformin (preferably metformin hydrochloride), the solid controlled release oral dosage form containing such drug is referred to as “metformin XT”.

  The term “Cmax” is the maximum plasma concentration of the drug that is reached during the dosing interval, ie about 24 hours.

  The term “Cmin” is the lowest plasma concentration of the drug that is reached during the dosing interval, ie about 24 hours.

  The term “Cavg”, as used herein, refers to the dose interval, ie, the plasma concentration of the drug within the range of about 24 hours, calculated as AUC / dose interval.

  The term “Tmax” is the time that elapses after dosage form administration, at which time the plasma concentration of the drug reaches the highest drug plasma concentration reached during the dosing interval (ie, about 24 hours).

  The term “AUC” as used herein means the area under the plasma concentration-time curve, calculated by the trapezoidal rule over the entire 24-hour interval.

  The term “steady state” means that the blood concentration curve for a given drug does not substantially vary after repeated administration of the formulation.

  The term “single dose” means that a human patient has received a single dose of a drug formulation and the plasma concentration of the drug has not achieved a steady state.

  The term “multiple doses” means that a human patient has received the formulation more than once according to the administration interval of the drug formulation (eg, in a once daily regimen). A patient who receives multiple doses of the controlled release formulation of the invention may or may not reach steady state drug plasma levels, but the term multiple dose is as defined herein.

  The term “patient” means that the discussion (or claim) is directed to individual patient pharmacokinetic parameters and / or mean pharmacokinetic values obtained from the patient population unless otherwise indicated. means.

  The term “mean”, when preceded by a pharmacokinetic value (eg, mean Tmax), unless otherwise specified, is an arithmetic mean (eg, geometric value) of pharmacokinetic values obtained from a patient population. Mean).

  The term “variability” represents (Cmax−Cmin) / Cavg.

  The term “high dose” is commonly used in the medical and pharmaceutical fields and indicates the relative dosage concentration. For example, on certain embodiments of the invention, the term high dose is any dose of 500 mg or more when referring to metformin.

  As used herein, the term anti-diabetic drug, hypoglycemic drug, refers to a drug useful for controlling or managing non-insulin dependent diabetes mellitus (NIDDM). Preferably, the hypoglycemic drug is a biguanide drug, for example, metformin or buformin, or a pharmaceutically acceptable salt thereof such as metformin hydrochloride. Other anti-diabetic drugs can include sulfonylureas such as glipizide, and thiazolidinediones such as glitazones (eg, pioglitazone).

  Surprisingly, when a biguanide drug such as metformin is administered orally in a “fed” state, preferably at dinner, in a controlled release dosage form suitable for once daily administration, it is in a “fast” state. It was found that bioavailability was improved compared to administration in dosage form. This is in contrast to GLUCOPHAGE® and shows the opposite characteristics. The methods and dosage forms of the present invention have resulted in improved results for patients suffering from NIDDM, compared to administering GLUCOPHAGE® in accordance with accepted protocols, eg, twice daily dosing regimen ( For example, it has been found that a reduction in blood glucose level) is achieved.

  In the method and dosage form of the present invention, when administered at dinner, the controlled release formulation of the present invention provides a Tmax (5.5 to 7.5 hours) after oral administration (this Tmax is compared to the reference drug GLUCOPHAGE®). As a result, it provides an additional advantage in that the drug concentration is maximized when the human patient is producing glucose at the highest level. It is well known to those skilled in the art that gluconeogenesis is greatest at night. Thus, according to the present invention, based on a dose administered at 6:00 pm, the Tmax of the drug is, for example, between 11:30 pm and 1:30 am. Similarly, administration of such dosage forms results in a decrease in drug concentration during the day (eg, afternoon) when gluconeogenesis is lower than at night. The present invention also advantageously provides the additional benefit of reducing insulin levels. Insulin is considered to be a risk factor for cardiovascular disease by itself in NIDDM.

  Compared to twice-daily administration of a reference drug (GLUCOPHAGE®), the plasma level of metformin is preferably lower in the afternoon. This is particularly advantageous in patients undergoing combination therapy with one or more additional antidiabetic agents such as sulfonylureas. It is known to those skilled in the art that about 60% of patients previously treated with metformin have been treated with at least one additional antidiabetic agent (eg, sulfonylurea). Sulfonylurea drugs can cause hypoglycemia, but metformin does not, and therefore patients may have hypoglycemia, so having a low blood metformin level during the afternoon There are advantages.

  Accordingly, the present invention also encompasses a method of treating a human NIDDM patient, wherein the method is a once daily administration method wherein a therapeutically effective dose of metformin is administered in a controlled release oral dosage form ( In combination with an effective amount of a sulfonylurea. In a preferred embodiment, metformin is supplied from a controlled release dosage form comprising metformin or a pharmaceutically acceptable salt thereof, which is useful for providing once-daily oral administration of a drug. And such dosage forms provide a metformin mean peak plasma concentration arrival time of 5.5 to 7.5 hours after administration.

  In certain embodiments, combination therapy can be provided as follows. If patients do not respond to monotherapy for 4 weeks with the highest dose of metformin XT (2500 mg / day), metformin XT, even if major or secondary failures have previously occurred for sulfonylureas The sulfonylurea can be added in stages while maintaining the highest dose of. Examples of sulfonylureas are glyburide (glibenclamide), chlorpropamide, tolbutamide, glipizide, acetohexamide, and tolazamide. Metformin XT is preferably administered once daily, but the sulfonylurea can be administered in different dosage forms and at different frequencies.

  The desired glycemic control can be obtained by adjusting the dose of each drug using a combination therapy of metformin XT and sulfonylurea.

In certain embodiments, the above objective is accomplished by a controlled release dosage form comprising:
(a) (i) hypoglycemic agent,
(ii) an optional binder, and
(iii) optionally an absorption enhancer,
A core comprising:
(b) a membrane surrounding the core; and
(c) at least one passage in the membrane.

  The binder may be any conventionally known pharmaceutically acceptable binder, such as polyvinylpyrrolidone, hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose, polymethacrylate, wax, and the like. Mixtures of the binders can also be used. Preferred binders are water soluble, such as polyvinylpyrrolidone having an average molecular weight of 25,000 to 3,000,000. The binder comprises about 0 to about 40% of the total weight of the core, but preferably comprises about 3% to about 15% of the total weight of the core.

  The core may contain an absorption enhancer depending on the situation. The absorption enhancer can be any type of absorption enhancer that is widely known, such as fatty acids, surfactants, chelating agents, bile salts, or mixtures thereof. Examples of preferred absorption enhancers include fatty acids such as capric acid, oleic acid and their monoglycerides, surfactants such as sodium lauryl sulfate, sodium taurocholate and polysorbate 80, citric acid, phytic acid, ethylenediaminetetraacetic acid (EDTA) And ethylene glycol-bis (β-aminoethyl ether) -N, N, N, N-tetraacetic acid (EGTA). The core comprises from about 0 to about 20% of an absorption enhancer based on the total weight of the core, with about 2% to about 10% of the total weight of the core being most preferred.

  In this embodiment, the core comprising a hypoglycemic agent, a binder (preferably a pharmaceutically acceptable water-soluble polymer) and an absorption enhancer preferably wet granulates the core component and rotates the granules. It is formed by adding a lubricant with a compressor and compressing it into tablets. It is also possible to dry-granulate the core component and form the core by compressing the granules into tablets with the addition of a lubricant or by direct compression.

  Other commonly known additives can also be included in the core, such as lubricants, pigments, or colorants.

  The uniform core is coated with a membrane, preferably a polymeric membrane, to form the controlled release tablet of the present invention. The membrane is permeable to the passage of outside liquids such as water and biological fluids, but is impermeable to the passage of hypoglycemic drugs in the core, making it a semipermeable membrane be able to. Materials useful for forming the membrane are cellulose ester, cellulose diester, cellulose triester, cellulose ether, 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 US Pat. Nos. 3,845,770, 3,916,899, 4,008,719, 4,036,228 and 4,11210, which are hereby incorporated by reference. The most preferred membrane material is cellulose acetate having an acetyl content of 39.3% to 40.3% and is commercially available from Eastman Fine Chemicals.

  In yet another embodiment, the membrane can be formed from the polymer and a glidant. Glidants increase the volume of liquid absorbed by the core and allow the dosage form to disperse nearly all of the hypoglycemic agent through the passageway and / or through the porous membrane. The glidant can be a water soluble material or an enteric material. Examples of preferred materials useful as glidants include sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycol (PEG), propylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, There are cellulose acetate phthalate, polyvinyl alcohol, methacrylic acid copolymers and mixtures thereof. A preferred glidant is PEG 400.

  The glidant may be a water soluble drug, such as metformin or a pharmaceutically acceptable salt thereof, or may be a drug that is soluble under intestinal conditions. When the glidant is a drug, the dosage form of the present invention has the additional advantage of providing immediate release of the drug selected as the glidant.

  The glidant comprises about 0 to about 40% of the total weight of the coating, but preferably comprises about 2 to about 20% of the total weight of the coating. The glidant dissolves or leaches from the membrane and forms a passageway in the membrane for the liquid to enter the core and dissolve the active ingredient.

  In another embodiment, the film can also be formed using commonly known additives such as plasticizers. Commonly known plasticizers include adipic acid ester, azelaic acid ester, benzoic acid ester, citric acid ester, stearic acid ester, isoebucate, sebacic acid ester, triethyl citrate, tri-n-butyl citrate , Acetyltri-n-butyl citrate, citrate esters, and plasticizers described in John Wiley & Sons, Encyclopedia of Polymer Science and Technology, Volume 10 (1969). Preferred plasticizers are triacetin, acetylated monoglyceride, grape seed oil, olive oil, sesame oil, acetyl tributyl citrate, acetyl triethyl citrate, glycerin, sorbitol, diethyl oxalate, diethyl malate, diethyl fumarate, dibutyl succinate, malon Examples include diethyl acid, dioctyl phthalate, dibutyl sebacate, dibutyl sebacate, triethyl citrate, tributyl citrate, and glyceryl tributyrate. Depending on the individual plasticizer, amounts from 0 to about 25%, preferably from about 2% to about 15% of the plasticizer can be used, based on the total coating weight.

  As used herein, the term passageway refers to gaps, openings, holes, holes, weak areas, or erodible parts, such as osmotic pressure to erod and release a hypoglycemic drug from a dosage form. Includes a gelatin plug that forms the passage. Detailed descriptions of the passages can be found in U.S. Pat.Nos. 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. Included in this specification).

  In some embodiments, the passage is formed by laser drilling. In other embodiments, the passageway is formed by creating a jagged surface on the core prior to membrane coating and creating a weak portion of the membrane at the jagged point. In a preferred embodiment of the invention, the dosage form contains two passages to provide the desired pharmacokinetic parameters of the formulation.

  Generally, the membrane surrounding the core will account for about 1% to about 7%, 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 body fluids and active drugs or drug components (eg, the formulations of Examples 1-3). Thus, the membrane is porous permeable to the drug, and in preferred embodiments, the drug is released through the holes or passages, through the porous membrane, into solution, or in vivo. The term “membrane” also encompasses the term “semi-permeable membrane” as generically defined.

In yet another embodiment, the dosage form of the invention can also comprise an effective amount of a hypoglycemic agent that can be utilized for immediate release. An effective amount of an antihyperglycemic agent for immediate release may be coated on the membrane of the dosage form, or may be incorporated within the membrane. In certain preferred embodiments of the invention in which the dosage form is prepared according to the above, the dosage form will have the following composition:
Ingredients Suitable proportions Optimal proportion Core:
Drug 50-98% 75-95%
Binder 0-40% 3-15%
Absorption accelerator 0-20% 2-10%
coating:
Membrane polymer 50-99% 75-95%
Glidants 0-40% 2-20%
Plasticizer 0-25% or 0-30% 2-15%

A dosage form prepared in accordance with an embodiment of the present invention preferably has the following dissolution profile when tested at 37 rpm in an artificial intestinal fluid (pH 7.5 phosphate buffer) in a USP type 2 device: Show:
Time (time) suitable optimum
2 0-30% 0-15% or 0-25%
4 10-45% 20-40%
8 30-90% 45-90%
12 50% or more 60% or more
16 60% or more 70% or more
20 70% or more 80% or more

  In preparing the tablets of the present invention, various well-known solvents can be used to prepare the granules and apply an outer coating to the tablets of the present invention. In addition, various diluents, excipients, lubricants, dyes, colorants, dispersants and the like described in the 1995 edition of Remington's Pharmaceutical Sciences can be used to optimize the formulations of the present invention.

  Known to those skilled in the art to obtain a controlled release formulation of the invention, ie, a formulation that, when administered orally to a human patient, provides the mean Tmax and / or other pharmacokinetic parameters of the drug described herein. Other controlled release technologies can be used. Such formulations can be prepared as controlled release oral formulations in the form of suitable tablets or multiparticulate formulations well known to those skilled in the art. In either case, the controlled release dosage form can optionally include a controlled release carrier, which is incorporated into the matrix with the drug or added as a controlled release coating.

  The oral dosage forms of the present invention can be provided, for example, as granules, spheres, beads, pellets (hereinafter collectively referred to as multiparticulates) and / or particles. A quantity of multiparticulates effective to deliver the desired dose of drug over an extended period of time may be encapsulated, but may be incorporated into any other suitable oral dosage form.

  In certain preferred embodiments, the drug-containing tablet core or multiparticulate is coated with a hydrophobic material selected from (i) alkylcellulose, and (ii) glycol polymers. The coating can be applied in the form of an organic or aqueous solution or a dispersion. A coating can be applied to obtain a desired sustained release profile to obtain a weight gain of about 2 to about 25% of the substrate. The sustained release coating of the present invention can include a release device comprising at least one passageway, opening, etc., as has already been clarified.

  Further considered as part of the invention is a method of treating a patient with an anti-diabetic agent, the method comprising administering to the patient a high dose of an anti-diabetic agent, the anti-diabetic agent Diabetic drugs exhibit one or more dose-related pharmacokinetic parameters. Advantageously, this method provides a predictable dosing regime for high dose administration. Preferably, the antidiabetic agent is administered once a day. Antidiabetic drugs of this method can include, but are not limited to, biguanides, hormone analogs, sulfonylureas, and thiazolidinediones, or their salts, derivatives, prodrugs or metabolites as antidiabetics. Not. In certain preferred embodiments, the antidiabetic agent is metformin, or a salt, derivative, prodrug or metabolite thereof.

  In yet another preferred embodiment, the method of the invention can be used to lower blood glucose and / or be performed on a patient in need of treatment for non-insulin dependent diabetes mellitus (NIDDM). Can do. In this method, a dose-related pharmacokinetic parameter can be selected from the group consisting of AUC and Cmax.

  The methods of the present invention can be practiced by dosing such that the antidiabetic agent is released in a controlled manner. Controlled mode of drug release means released from the dosage form in some controlled manner, including delayed release, sustained release, sustained release, and the like. Controlled release dosage forms are well known in the art and can include, but are not limited to, any administration as a solid, semi-solid, liquid, suspension or solution. Such dosage forms can be administered by a variety of routes known in the art, including oral, buccal, sublingual, intravenous, parenteral, transdermal, iontophoresis and the like. It is. In certain preferred embodiments, the dosage form is administered orally as a solid formulation.

  The following examples illustrate various aspects of the present invention. These examples should in no way be construed as limiting the claims.

Example 1
Controlled release tablets containing 500 mg of metformin hydrochloride and having the following formulation are prepared as follows:
I. Core
Ingredient amount (mg / tablet)
Metformin hydrochloride 500.0
Povidone ³ , USP 36.0
Sodium lauryl sulfate 25.8
Magnesium stearate 2.8
³ Approximate molecular weight = 1,000,000; Kinematic viscosity (10% w / v solution, 20 ° C) = 300-700 m Pa s

(a) Granulation Eliminate lumps by passing metformin hydrochloride and sodium lauryl sulfate through a 400 mesh sieve and collecting in a clean container covered with polyethylene inside. Dissolve povidone, K-90-F in pure water. Next, granulate by adding the lump-free metformin hydrochloride and sodium lauryl sulfate to a top spray (spray from the top) fluid bed granulator and spraying with a povidone binding solution under the following conditions: Temperature 50-70 ° C; spraying pressure 1-3 bar; spraying rate 10-100 ml / min.

  When the binder is used up, the granules are dried in a granulator until the loss on drying is less than 2%. Pass the dried granules through a Comil equipped with an 18 mesh screen equivalent.

(b) Tableting Magnesium stearate is passed through a 40 mesh stainless steel sieve and blended with metformin hydrochloride particles for about 5 minutes. After blending, the granules are compressed in a rotary compressor equipped with a 15/32 inch circular standard concave punch.

(c) Seal coating (optional)
First, the Opadry material, preferably Opadry Clear (YS-1-7006), is dissolved in pure water to seal coat the core tablet with the Opadry material or other suitable water-soluble material. The Opadry solution is then sprayed onto the core tablets using a pan coater under the following conditions: exhaust temperature 38-42 ° C .; spray pressure 28-40 psi; spray rate 10-15 ml / min. The coating Opadry Clear constitutes about 11.5 mg / tablet.

II. Controlled release coating
Ingredient amount (mg / tablet)
Cellulose acetate (398-10) ² 21.5
Triacetin 1.3
PEG 400 2.5
² Acetyl content 39.3-40.3%
While stirring with a homogenizer, cellulose acetate is dissolved in acetone. Polyethylene glycol 400 and triacetin are added to the cellulose acetate solution and stirred until a clear solution is obtained. Tablets are coated by spraying a clear coating solution onto seal-coated tablets in a fluid bed coater using the following conditions: product temperature 16-22 ° C; spray pressure, about 3 bar; spray rate 120 -150 ml / min.

(d) Laser drilling Two holes were drilled in the coated tablets with a laser drill (one hole on one side of the tablet).

Example 2
A controlled release tablet containing 850 mg of metformin hydrochloride and having the following formulation is prepared as follows:
I. Core
Ingredient amount (mg / tablet)
Metformin hydrochloride 850.0
Povidone ³ , USP 61.1
Sodium lauryl sulfate 43.9
Magnesium stearate 4.8
³ Approximate molecular weight = 1,000,000; Kinematic viscosity (10% w / v solution, 20 ° C) = 300-700 m Pa s

(a) Granulation Eliminate lumps by passing metformin hydrochloride and sodium lauryl sulfate through a 400 mesh sieve and collecting in a clean container covered with polyethylene inside. Dissolve povidone, K-90-F in pure water. The agglomerated metformin hydrochloride and sodium lauryl sulfate are then granulated by adding them to a top spray fluid bed granulator and spraying with a combined solution of povidone under the following conditions: intake air temperature 50-70 ° C; Spray pressure 1-3 bar; spray rate 10-100 ml / min.

  When the binder is used up, the granules are dried in a granulator until the loss on drying is less than 2%. Pass the dried granules through a Comil equipped with an 18 mesh screen equivalent.

(b) Tableting Magnesium stearate is passed through a 40 mesh stainless steel sieve and blended with metformin hydrochloride particles for about 5 minutes. After blending, the granules are compressed in a rotary compressor equipped with a 15/32 inch circular standard concave punch.

(c) Seal coating (optional)
First, an Opadry material, preferably Opadry Clear (YS-1-7006) is dissolved in pure water to seal coat the core tablet with an Opadry material or other suitable water soluble material. The Opadry solution is then sprayed onto the core tablets using a pan coater under the following conditions: exhaust temperature 38-42 ° C .; spray pressure 28-40 psi; spray rate 10-15 ml / min. The coating Opadry Clear is about 11.5 mg / tablet.

II. Controlled release coating
Ingredient amount (mg / tablet)
Cellulose acetate (398-10) ² 24.0
Triacetin 1.4
PEG 400 2.8
² Acetyl content 39.3-40.3%
While stirring with a homogenizer, cellulose acetate is dissolved in acetone. Polyethylene glycol 400 and triacetin are added to the cellulose acetate solution and stirred until a clear solution is obtained. Tablets are coated by spraying a clear coating solution onto seal-coated tablets in a fluid bed coater using the following conditions: product temperature 16-22 ° C; spray pressure, about 3 bar; spray rate 120 -150 ml / min.

(d) Laser drilling Two holes were drilled in the coated tablets with a laser drill (one hole on one side of the tablet).

Example 3
Controlled release tablets containing 1000 mg of metformin hydrochloride and having the following formulation are prepared as follows:
I. Core
Ingredient amount (mg / tablet)
Metformin hydrochloride 1000.0
Povidone ³ , USP 71.9
Sodium lauryl sulfate 51.7
Magnesium stearate 5.6
³ Approximate molecular weight = 1,000,000; Kinematic viscosity (10% w / v solution, 20 ° C) = 300-700 m Pa s

(a) Granulation Eliminate lumps by passing metformin hydrochloride and sodium lauryl sulfate through a 400 mesh sieve and collecting in a clean container covered with polyethylene inside. Dissolve povidone, K-90-F in pure water. Next, granulate by adding the lump-free metformin hydrochloride and sodium lauryl sulfate to a top spray (spray from the top) fluid bed granulator and spraying with a povidone binding solution under the following conditions: Temperature 50-70 ° C; spraying pressure 1-3 bar; spraying rate 10-100 ml / min.

  When the binder is used up, the granules are dried in a granulator until the loss on drying is less than 2%. Pass the dried granules through a Comil equipped with an 18 mesh screen equivalent.

(b) Tableting Magnesium stearate is passed through a 40 mesh stainless steel sieve and blended with metformin hydrochloride particles for about 5 minutes. After blending, the granules are compressed in a rotary compressor equipped with a 15/32 inch circular standard concave punch.

(c) Seal coating (optional)
First, an Opadry material, preferably Opadry Clear (YS-1-7003) is dissolved in pure water to seal coat the core tablet with an Opadry material or other suitable water soluble material. The Opadry solution is then sprayed onto the core tablets using a pan coater under the following conditions: exhaust temperature 38-42 ° C .; spray pressure 28-40 psi; and spray rate 10-15 ml / min. The core tablet is coated with a sealing solution until the tablet is coated with 23.0 mg / tablet of Opadry material.

II. Controlled release coating
Ingredient amount (mg / tablet)
Cellulose acetate (398-10) ² 19.0
Triacetin 1.1
PEG 400 2.2
² Acetyl content 39.3-40.3%
While stirring with a homogenizer, cellulose acetate is dissolved in acetone. Polyethylene glycol 400 and triacetin are added to the cellulose acetate solution and stirred until a clear solution is obtained. Tablets are coated by spraying a clear coating solution onto seal-coated tablets in a fluid bed coater using the following conditions: product temperature 16-22 ° C; spray pressure, about 3 bar; spray rate 120 -150 ml / min.

(d) Laser drilling Two holes were drilled in the coated tablets with a laser drill (one hole on one side of the tablet).

(e) Color coating (optional)
Following the sustained release coating, the laser drilled tablets are covered with a color coating using Opadry White (24 mg / tablet) and waxed with Candelilla wax powder (0.4 mg / tablet).

Clinical trial
Test 1
In Study 1, a total of 12 healthy subjects (6 men and 6 women) were randomized and either a single oral dose of 850 mg of metformin sustained release formulation prepared according to Example 2 or GLUCOPHAGE for the assigned study period. Of one of the following groups: Group A-Metformin sustained release formulation (2 x 850 mg tablets) around 8:00 am, after breakfast Take immediately; Group B-Metformin sustained release formulation (2 x 850 mg tablets) around 6:00 pm, immediately after dinner; Group C-GLUCOPHAGE (1 x 850 mg tablets) around 8:00 am, immediately after breakfast , And around 6:00 pm, take immediately after dinner. Each drug administration had a 7 day washout period. In this study, one male subject was excluded from the study prior to stage II due to mononucleosis unrelated to treatment. Therefore, 11 subjects (5 men, 6 women) completed the study.

For metformin sustained release, plasma samples were collected from subjects at 0 hours (prior to administration), 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, and 24 hours after administration. For GLUCOPHAGE, 0 hours (before administration), 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 15, 16, 18, 20, 22, and 24 hours after the first administration in the morning Plasma samples were collected from subjects. The plasma concentration of metformin was measured using an effective HPLC method. The minimum quantification limit for this method is 10 ng / ml. The mean plasma concentration-time profile is shown in FIG. 1, and the average pharmacokinetic parameters of metformin obtained from this study are shown in Table 1.

  As shown in FIG. 1 and Table 1, when metformin XT is administered immediately after either breakfast or dinner, the relative bioavailability of the metformin XT formulation to GLUCOPHAGE is approximately 100%.

  Using the results of Test 1, the degree of variability (Cmax-Cmin / Cavg) of the preparation was estimated.

  Cmax was obtained directly from this test (see Table 1). Cavg was obtained by dividing the AUC value by the dosing interval, ie 24 hours. The value of Cmin was extrapolated from FIG.

The results are shown in Table 2 below:

  As shown in FIG. 1 and Table 2, a single dose of metformin XT formulation is administered at substantially the same dose of GLUCOPHAGE (divided doses, one at the beginning of the dosing interval and the other 12 hours later). ) Gives a higher mean variability index in plasma.

Test 2
The study plan for study 2 was formulated and dosed (in this second study, 4 x 500 mg once a day for metformin XT prepared according to Example 1 for a total dose of 2000 mg and for GLUCOPHAGE: 2 x 500 mg twice a day for a total dose of 2000 mg). In this study, 12 healthy subjects (5 men and 7 women) were randomized, treated, and completed the study. The mean plasma concentration-time profile and the average value of metformin pharmacokinetic parameters obtained from this study are shown in FIG.

As shown in FIG. 2 and Table 3, when the metformin XT formulation (500 mg) is administered immediately after dinner, the relative bioavailability of this formulation to GLUCOPHAGE is approximately 100%, and the mean Cmax value is approximately the same. However, when administered immediately after breakfast, the relative bioavailability of metformin XT is approximately 80%. The long-term profile showed that metformin was released continuously in vivo with metformin XT after administration of metformin XT, with a Tmax slower than GLUCOPHAGE and a similar Cmax (FIG. 2).

  Using the results of Test 2, the variability of the formulation was estimated according to the calculation used in Test 1 (extrapolated value of Cmin was obtained using FIG. 2).

The results are shown in Table 4 below:

  As shown in FIG. 2 and Table 4, a single administration of metformin XT formulation is a bisected dose, one at the beginning of the dosing interval and the other at 12 hours later than the same dose of GLUCOPHAGE. Resulting in a high mean variability index in plasma.

Test 3
In Study 3, multiple doses, open-label, single-stage studies were conducted to evaluate the short-term tolerability (drug resistance) and steady state pharmacokinetics of the 500 mg metformin XT formulation used in Study 2. In this study, 8 healthy subjects (4 men and 4 women) were randomized and received 2000 mg metformin XT (4 x 500 mg tablets) at around 6:00 pm immediately after dinner for 14 days. .

  Blood samples were collected from each subject at 0 hours (prior to administration), 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, and 24 hours after the first administration on day 1. Collected and collected at 0 hours (pre-dose), 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 24, 38, and 48 hours after the last administration on day 14 . Blood samples were also collected from each subject immediately prior to administration on days 10-13. Urine samples were also collected from each subject at the following time intervals: 6 hours before the first dose; 0-6, 6-12 and 12-24 hours after the first dose; and 0-6, 6 after the last dose. -12, 12-24 and 24-48 hours later.

The average plasma profile and pharmacokinetic parameters of metformin are shown in Table 5 below:

  Metformin XT, 4 x 500 mg once daily for 14 days after oral administration, difference in plasma concentration-time profile of metformin between day 1 and day 14 in 8 healthy subjects There was little or no (Figure 3). On average, troph plasma concentrations of metformin are almost constant in the range of 188.8 to 205.1 ng / ml on days 10-14, indicating that a steady state of metformin was achieved quickly. An average accumulation ratio of 1.01 indicates that metformin XT once daily do not cause accumulation.

  After oral administration of metformin XT in a single dose (4 x 500 mg), approximately 31% of the dose was excreted in the urine within the first 24 hours. On average, renal clearance of metformin was 366 ml / min. After high doses of metformin XT, 4 x 500 mg once a day, slightly higher renal clearance (454 ml / min) was observed.

  Gastrointestinal symptoms (diarrhea, nausea, vomiting, abdominal distension, flatulence, and anorexia) are the most common side effects of GLUCOPHAGE. In controlled clinical trials, GLUCOPHAGE was gradually increased to higher doses, starting with a low dose that would not be treated. Despite these escalations, GLUCOPHAGE was discontinued due to gastrointestinal reactions in approximately 4% of patients. In contrast, metformin XT, starting with a therapeutically effective initial dose of 2000 mg once a day at dinner, was well accepted by all healthy subjects in a multiple dose study. Diarrhea and nausea are the most common gastrointestinal reactions that are likely or suspected to be related to metformin XT. However, these reactions were mild or moderate. This suggests that metformin treatment may be begun at an effective dose rather than using the slowly increasing method required from GLUCOPHAGE for non-therapeutic doses.

Test 4
Study 4 was designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of metformin XT compared to GLUCOPHAGE after NIDDM patients were treated with multiple doses. Metformin XT tablets prepared according to Example 3 were used for this test. This study was conducted in a single center randomized binary crossover study. A total of 24 NIDDM patients who were continuously taking doses of GLUCOPHAGE from 1000 to 2550 mg / day for at least 12 weeks were selected for this study. For treatment trials, there was a pretreatment period of at least 3 weeks prior to randomization. At the beginning of the pretreatment period, all patients stopped taking all other hypoglycemic drugs except GLUCOPHAGE, and the dose of GLUCOPHAGE was adjusted to 1000 mg twice a day (breakfast and dinner) . After the pre-treatment period, treatment period I was started and continued for 4 weeks. During period I, a total of 12 patients were randomized and received 2 1000 mg metformin XT tablets once a day (immediately after dinner) around 6:00 pm, 12 randomized One tablet of 1000 mg GLUCOPHAGE was administered twice a day (with breakfast and dinner). Immediately after period I, each patient was switched to the other drug treatment over a 4 week period II. There was no washout period between the two treatment periods.

  Plasma metformin concentrations were measured over the course of 24 hours at the end of stage I and II as follows: just before administration, and 1, 2, 3, 4, 5, 6, 8, 10, After 12, 14, 15, 16, 17, 18, 19, 20, 22, and 24 hours. Pharmacokinetic data was obtained from 23 patients because one subject withdrew from the study for personal reasons after 2 weeks of treatment period I.

The mean plasma profile and pharmacokinetic parameter values for metformin are shown in FIG. As shown in FIG. 4 and Table 6, when metformin XT is administered immediately after dinner, the bioavailability of metformin XT against GLUCOPHAGE at steady state is close to 100%. The dose of metformin XT at dinner was twice that of GLUCOPHAGE, but the average Cmax value was only 32% higher.

  When metformin XT is administered immediately after dinner, the bioavailability of metformin XT against GLUCOPHAGE in steady state is close to 100%. However, when metformin XT was administered immediately after breakfast, the relative bioavailability of the corresponding metformin XT was about 80%. The safety profile of metformin XT, 2000 mg administered once daily after dinner or after breakfast was comparable to the safety of the same dose of GLUCOPHAGE administered twice daily. The efficacy profile of metformin XT, 2000 mg administered once daily after dinner was similar to the efficacy of the same dose of GLUCOPHAGE administered twice daily. However, the efficacy of metformin XT, 2000 mg administered once daily after breakfast, appeared to be comparable or slightly lower than that of GLUCOPHAGE administered twice daily.

Test 5
The pharmacokinetics and dose-exposure relationship of a metformin sustained release formulation (ER) produced according to the examples given herein was compared in a randomized single-dose cross in 24 healthy male subjects. The over test was considered. During each study period, subjects received a randomly assigned dose containing 1000, 1500, 2000 or 2500 mg metformin. Blood samples were taken periodically from 0 to 72 hours after dosing for pharmacokinetic analysis and assessment of dose-proportionality for the above dosages. Multiple pairwise comparisons between dose groups were significant for dose-standardized C _max , AUC _0-72hr , and AUC _∞ (p <0.05), but the magnitude of the difference across the dose range was , AUC _0-72hr and AUC _∞ were <20% and C _max was ≦ 30%. This result shows a consistent and predictable increase in metformin exposure with metformin sustained release formulations from about 1000 to about 2500 mg.

Metformin has been widely used for the treatment of type 2 non-insulin dependent diabetes mellitus (NIDDM). Immediate-release (IR) metformin is typically administered with meals in divided doses to minimize gastrointestinal side effects (Dunn CJ, Peters DH. Metformin: A review of its pharmacological Properties and therapeutic use in non-insulin-depended diabetes mellitus. Drugs 1995; 49: 721-749, and Scheen AJ. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 1996; 30 (5): 359-371).

Oral administration of 500 mg typically results in about 50% bioavailability, and proportionally more drug is absorbed after administration of 500 mg than after administration of higher doses above 500 mg (Scheen AJ Clinical pharmacokinetics of metformin. Clin 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 Phamecol 1979; 16: 195 -202).

Materials and Methods A single dose, open-label, randomized, 4-stage crossover study was performed on 24 subjects enrolled in this study based on selection / exclusion criteria for healthy male volunteers. Subjects received the following four metformin doses in any order, in the order specified: 1000 mg (1 x 1000 mg tablet), 1500 mg (1 x 1000 mg + 1 x 500 mg tablet), 2000 mg (2 x 1000 mg tablet) ), And 2500 mg (2 × 1000 mg + 1 × 500 mg tablets). 500 mg tablets were prepared according to Example 1 and 1000 mg tablets were prepared according to Example 3. Each medication was separated by a 7 day washout period. Dosing was performed with 240 ml of ambient temperature water immediately after the standardized dinner.

  To quantify metformin concentration in plasma, 0 hour (before administration), 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 24, 38, 48, and 72 after administration At time, blood samples (10 ml) were collected in heparinized Vacutainer blood collection tubes. Plasma samples were assayed using high performance liquid chromatograph (HPLC) analysis with ultraviolet detection. The standard curve for metformin covered a range from 10 to 2500 ng / ml; the lower limit of quantification (LOQ) was 10 ng / ml. Quality control standards (25, 160, and 1600 ng / ml) and LOQ were used to assess the accuracy and accuracy of daily and intraday assays at the time of validation. The daily assay variability (accuracy) ranged from 4.82 to 8.23% and the theoretical percentage difference (accuracy) ranged from -2.08 to 2.72%, while the daily accuracy ranged from 6.16 to 9.56% The accuracy ranged from -17.7 (LOQ) to 5.76%.

The pharmacokinetic parameters of metformin include the highest concentration observed (Cmax), the time to Cmax (Tmax), the delay time (T _lag ), and the area under the blood concentration-time curve (AUC). AUC is calculated from 0 to 72 hours using a straight trapezoidal rule (AUC _0-72hr ). The AUC from 0 to infinity is equal to the sum of AUC _0-t and C (t) / ke, where C (t) is the plasma concentration at 72 hours and ke is the final elimination rate constant . The final elimination half-life (t1 / 2) was calculated as ln (2) / ke, and ke was determined from linear regression of the terminal part of the ln-concentration-time curve.

  A summary statistical table on pharmacokinetic and safety data was created. Dose proportionality was assessed by comparing dose-standardized pharmacokinetic parameters using statistical models, including variables related to duration, dose and sequence of administration, and linear regression analysis of AUC or Cmax and dose Included.

Results Of the 24 healthy men enrolled and selected for safety assessment, 23 subjects (96%) completed the study and participated in the pharmacokinetic and dose proportionality assessment. One subject withdrew consent for personal reasons.

  There were no serious adverse events during the course of the study. There were nine signs or symptoms (TESS) that occurred during the treatment, which may be related to treatment.

Plasma metformin concentration-time profiles were measured for each subject (n = 23) at each dose level. Mean (± SD) metformin pharmacokinetic parameters are summarized in Table 7. In most subjects, the _{extrapolation} from AUC _0-72hr to AUC _∞ was less than 5%, resulting in a reliable estimate of AUC _∞ . Dose proportionality is explained by some of the pharmacokinetic parameters in Table 7 below:

Pairwise comparisons between doses every dose normalized Cmax, was significant for AUC _0-72Hr and AUC _∞ (p <0.05), but the comparison between the two highest dose excluded. The size of the difference over the dose range, on average, ≦ 30% for Cmax, and was <20% Both the AUC _0-72Hr and AUC _∞. There were no detectable differences between doses for model-independent pharmacokinetic parameters such as Tmax and half-life (t1 / 2). As a result of linear regression of the mean of the four treatments, the coefficient of determination (r ² ) was> 0.99 for Cmax, AUC _0-72hr and AUC _∞ , and the deviation from zero was significant for all three parameters (p <0.05). The linear regression for AUC _∞ is shown in FIG.

Although considerable overlap exposure was observed, Cmax, as indicated by the AUC _0-72Hr and AUC _∞, predictable and consistent, increase in metformin exposure due to dose was observed. Dose - relationship exposure, especially noteworthy for AUC _∞ (Fig. 9), minimum mean square regarding doses of 1500,2000 and 2500 mg (LSM) are both within 20% of the dose-normalized values to 1000mg (Table 7).

The pharmacokinetic properties of metformin have been investigated using a variety of formulations, including intravenous and oral aqueous solutions, rapidly dissolving tablets, and modified release formulations (Karttunen P, Unsitupa M, and Lamminsivu U. The pharmacokinetics of metformin: a comparison 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 Scheen and Pentikainen, supra). Overall, the pharmacokinetic features of metformin are slow and incomplete absorption (40-60%) combined with rapid elimination. Oral absorption was estimated to be completed within 6 hours after administration of metformin immediate release dosage form, but there is no dose-proportionality at doses higher than 500 mg, which may involve a saturating absorption process This may significantly limit high-dose oral absorption (Scheen and Pentikainen, supra, 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 latest study, sustained release tablets developed by Andrx showed no evidence that metformin bioavailability was impaired at these high doses. On the contrary, there was a consistent and predictable increase in metformin exposure with dose as dose increased. Thus, the results of this study are likely to support the claim made from previous studies that the majority of the intestine can be involved in the absorption of metformin (Scheen, supra, and Vidon N, Chaussade S, Noel M et al., Metformin in the digestive tract. Diabetes Res Clin Pract 1988; 4: 223-229). This study showed that metformin sustained release formulations showed a predictable and consistent increase in metformin exposure with doses in the dose range above 500 mg, especially at doses from about 1000 to about 2500 mg.

Test 6
Tolerability of sustained-release metformin (ERM) produced according to the examples herein, in a phase II, single center, dual crossover comparative study with two 4 week treatment periods incorporated The pharmacokinetics and pharmacodynamics (HbA1c, plasma insulin concentration and 24-hour plasma glucose concentration) were evaluated relative to commercial immediate release metformin (IRM). Patients were randomized to receive either 2000 mg ERM with dinner at 6:00 pm, or 1000 mg IRM with breakfast at 8:00 am and 1000 mg IRM with dinner at 6:00 pm, then the other Switched to treatment. Metformin mean ± SD AUC _0-24hr (ng · hr / ml) was 26811 ± 7055 for ERM and 27371 ± 5781 for IRM. For HbA1c, there was no significant difference between ERM and IRM. ERM resulted in significantly lower fasting plasma insulin levels (p <0.05) compared to IRM and maintained lower plasma glucose levels between 6:00 pm and 6:00 am. ERM administered at dinner numerically reduced insulin levels.

  The hypoglycemic drug metformin is commercially available as immediate release (IR) and ER metformin tablets (Glucophage® / Glucophage XR-Bristol-Meyers Squibb, Princeton, NJ). There is no routine use to manage hyperglycemia of diabetes with metformin. The usual starting dose for IR tablets is one 500 mg tablet twice a day, or one 850 mg tablet given once a day with meals, then up to a therapeutically effective amount up to 2500-2550 mg per day The dose is gradually increased by dividing into twice daily administration or three times daily administration. Current ER formulations (available as 500 mg and 750 mg tablets) start with 500 mg once a day and gradually increase to a maximum dose of about 2000 mg once a day. If efficacy is not achieved, it is generally recommended to administer the maximum dose (2000 mg) as two divided doses per day.

  The most common adverse events associated with the use of metformin are in fact related to the gastrointestinal tract such as anorexia, nausea, vomiting and diarrhea. These adverse events can be avoided to some extent by either reducing the starting and / or maintenance dose, taking the drug with meals, or using sustained release dosage forms (Schein & Pentikan, supra). .

The purpose of this test was to evaluate:
1) Compare ERM pharmacodynamics (PD) and efficacy with IRM after treating type 2 diabetic patients for 4 weeks,
2) Compare ERM pharmacokinetics (PK) with IRM after treating type 2 diabetes patients for 4 weeks,
3) Compare the short-term safety and tolerability of ERM with IRM in patients with type 2 diabetes.

Test plan
Materials and methods / patients received the following treatments in no particular order:
1. Treatment A: 2000 mg metformin XT, (2 × 1000 mg) prepared according to Example 3 is administered immediately after dinner.
2. Treatment B: 1000 mg IR metformin is given immediately after breakfast and dinner.
-The summary of the test is shown in Table 8. This trial had no washout period.

Sample collection • Plasma samples for PK and PD assessment were collected at visits 5, 9, and 13.
• Sampling time for plasma metformin concentration measurement and plasma glucose • AUC _0-24 was as follows: 1, 2, 3, 4, 5, 6, 8, 10 immediately before administration and after administration at 6 pm , 12, 14, 15, 16, 17, 18, 19, 20, 22, and 24 hours.
Fasting plasma samples were collected approximately 13 hours after evening administration for measurement of plasma insulin, fasting plasma glucose, and hemoglobin A1c.

Safety assessment • Safety variables assessed during this study included health checks, changes in electrocardiogram (ECG) or vital signs, incidence and frequency of adverse events, and laboratory values.

Pharmacokinetic analysis • Heparinized plasma samples were analyzed for metformin using an effective high performance liquid chromatography (HPLC) method with ultraviolet detection.
• Concentration-time profiles were measured for individual subjects.
• PK parameters were calculated using non-compartmental analysis and WinNonlin version 1.1 (Pharsight-mountainview, CA).

The PD variables to be evaluated and evaluated for pharmacodynamics were changes from baseline in the following parameters: glucose AUC _0-24 , fasting plasma glucose (FPG), hemoglobin A1c concentration, and fasting plasma insulin (FPI) concentration .

Statistical analysis. The main null hypothesis was that there was no difference in treatment.
• Comparison of Cmax, AUC _0-24 , glucose AUC _0-24 , FPG, hemoglobin A1c and FPI between treatments using log-transformed and non-transformed values using a standard crossover model.

The patient population / 24 patients were randomly assigned to treatment groups. One patient withdrew from the study for personal reasons and did not complete Period I. All randomly assigned patients (n = 24) are included in the safety analysis, and 23 patients who completed the study are included in the PK / PD analysis in the comprehensive analysis.
・ There were 10 males and 14 females. Most were white (95.8%). The age range was 39 to 70 years. The average of total body weight and height was 91.8 kg and 171.8 cm, respectively.

Signs and symptoms (TESS) developed under study treatment that may be related to safety and treatment were generally mild to moderate in severity; however, one patient was severe I experienced severe TESS. The patient developed severe diarrhea while taking metformin XT, which was resolved. The patient successfully completed the study.
・ 7/24 (29%) of TESS considered to be related to treatment is related to metformin XT treatment (diarrhea, abdominal pain, pain, hypertension, dyspepsia, and rash), and 1/24 (4.3%) is It was related to IR metformin (dyspepsia).

The results for pharmacokinetic pharmacokinetics are given in Table 9 below.
The average plasma concentration-time curve created from the data is shown in FIG.

-Cmax of metformin XT was significantly higher than IR metformin (p <0.05). However, this increase in Cmax of metformin XT was not as high as expected from the same dose of IR metformin.
Longer Tmax and similar dose-free Cmax with similar metformin exposure (ie AUC) is consistent with the sustained release characteristics of metformin XT.
The least mean square ratio for AUC _0-24 (Metformin XT vs. IR Metformin) (shown in Table 9) showed that there was no significant difference in overall metformin exposure under steady state conditions.

Pharmacodynamics

  The average of 24-hour plasma glucose levels for the two treatment groups is shown in FIG.

The effects of the two treatments (Metformin XT vs. IR Metformin) on fasting plasma glucose (FPG), hemoglobin A1c, glucose AUC _0-24h and fasting plasma insulin levels are shown in Table 10.

_{Changes in} glucose AUC _0-24h (p = 0.291) or fasting plasma glucose levels (p = 0.154) were not significantly different between treatment groups.
• There was a slight change in hemoglobin A1c from baseline to week 4, which was not statistically or clinically significant.
Fasting plasma insulin levels decreased by 1.3 μIU / ml with metformin XT treatment from baseline to the end of the fourth week and increased by 1.5 μIU / ml with IR metformin treatment. This difference between the two treatment groups was not clinically significant but statistically significant (p = 0.012).

Conclusion / Pharmacokinetic analysis confirmed the sustained release characteristics of metformin XT formulation.
• Type 2 diabetic patients are usually in relative insulin deficiency rather than absolute insulin deficiency and may have normal or normal levels of insulin or elevated insulin levels as a result of hyperglycemia. FPI is used as a surrogate marker for insulin resistance. Normal / high insulin levels in these patients have been attributed to several causes. This may be due to excessive secretion of basal insulin to compensate for persistent fasting hyperglycemia. Others, elevated insulin levels or hyperinsulinemia are said to be associated with other metabolic abnormalities found in NIDDM patients, such as hyperlipidemia, abnormal fibrinolysis and hypertension. This study revealed a statistically significant decrease in FPI. However, this is not clinically significant, which may be due to the short study period (4 weeks for each treatment).

・ Despite the difference in plasma metformin concentrations between treatment groups, plasma glucose concentrations follow a similar trend throughout the 24-hour collection period (although 12 to 24 hours are more prominent). Reflects morning and lunch consumption and absorption, and associated changes. Metformin postprandial control is statistically similar between metformin XT and IR metformin as assessed by total glucose concentration (glucose AUC _0-24 ), and the metformin concentration-time profile is Although different, the postprandial glucose control was shown to be similar.

Linking individual plasma metformin concentration trends to glucose levels is of limited value, but examining total exposure from plasma metformin AUC and the corresponding plasma glucose level AUC Take into account the variability associated with absorption. There was no significant difference between the AUC for the 24-hour collection period in either the plasma metformin concentration profile or the plasma glucose concentration profile.

In conclusion, both Metformin XT and IR Metformin are safe and well tolerated. Metformin XT, administered once daily at a dose of 2000 mg, is as effective in glycemic control as IR metformin, administered twice daily at 1000 mg, and is statistically measured for fasting plasma insulin in patients with type 2 diabetes. Showed a significant decrease.

Test 7
This double-blind, multicenter, parallel group, randomized trial included 115 patients (24 in the metformin XT 2000 mg group, 32 in the XT 2500 mg group, 33 in the immediate release metformin (IRM) 2000 mg group, and the IRM The efficacy and tolerability of metformin XT once a day (26 people in the 2500 mg group) was compared to an immediate release metformin (IRM) twice a day. The patient was treated for 6 months. The primary efficacy variable was mean HbA1c change from baseline at endpoint. The average change in HbA1c was 0.19% (p = 0.3027) for XT and 0.33% (p = 0.00218) for IRM. In the 2500 mg group, the change in hemoglobin A1c was -0.02% for the XT group and 0.61% for the IRM group. Diarrhea and nausea were the most common signs or symptoms that occurred during treatment, related to study drug, but this was not a statistically significant difference between the groups.

  The sustained release formulation of metformin used in this study was manufactured as 500 mg tablets and 1000 mg tablets according to Examples 1 and 3. The dose range from 1000 mg to 2500 mg administered once daily with dinner was studied.

  The following is another Phase III study of metformin XT that collects safety and tolerability data for patients with type 2 diabetes (including those who have never received metformin) at daily doses of 2000 and 2500 mg Was made for.

  The primary objective of this study was to determine the tolerability and safety of 2000 mg and 2500 mg metformin XT once daily over the 6 month treatment period in NIDDM patients with the same dose of IRM (Glucophage®) twice daily. ). A secondary objective was to evaluate the effectiveness of the treatment over a 6 month treatment period.

Materials and methods
Study design • This study is a Phase III, double-blind, double-dummy, multicenter, randomized, parallel group comparison study in patients with type 2 diabetes, who are treated with hypoglycemic drugs. However, it does not necessarily contain metformin.

• Patients were assigned to the 2000 mg group or 2500 mg group to obtain at least 100 patients in each group in two Phase III protocols. A series of dose assignments (2000 mg or 2500 mg) was sent to each facility. Patients were then randomized and treated with either metformin XT or IRM.

• A summary of the test is given in Table 11 below.

• Subjects gradually increased by 500 mg over 2-3 weeks depending on assigned dose and starting dose.

Antidiabetics Concomitant drugs continues, or after enabling adjustment to metformin administration protocol led to visit 2-4 was as constant up visit 5-9.

Safety assessment / health checkup, 12-lead electrocardiogram (ECG) and vital signs were performed at screening and at Visit 9, and any changes from screening were noted.
• Adverse events and signs and symptoms (TESS) that occurred during treatment were recorded.

Efficacy assessment • Fasting blood samples were taken at every visit to measure fasting plasma glucose (FPG).
• Hemoglobin A1c concentration was measured during visits 1, 6 and 9 after fasting at night.
・ Baseline FPG is the average of FPG values for Visits 1 and 2.
・ Baseline hemoglobin A1c, body weight and BMI are the values at Visit 2.
The endpoint was the final measurement obtained by 3 days (under fasting conditions) after the last dose of study drug.

Change from baseline in fasting plasma glucose (FPG) at efficacy variable Visit 3-9 and endpoint.
• Changes in baseline hemoglobin A1c at visits 6 and 9 and endpoint.
• Changes in baseline and endpoint body weight and BMI from baseline.

Patient population • 115 subjects were randomly assigned to treatment groups (56 received metformin XT (sustained release) and 59 received immediate release metformin (IRM)). 83 subjects completed the study. 113 were included in the safety population because they had at least one safety observation after randomization. 112 subjects had at least one baseline efficacy measurement and at least one post-baseline efficacy measurement and were included in the global analysis population.
Average (± SD) age, body weight and BMI were 55.3 ± 10 years at baseline, 92.6 ± 17.1 kg and 31.0 ± 4.6 kg / m ² .
• Of the 115 patients, 26 (22.6%) had never received metformin and had not been exposed to metformin prior to the start of the trial. 89 (77.4%) patients had previously been exposed to metformin / Glucophage.

Randomized concomitant medications or oral hypoglycemic drugs were used at study time by 38/56 (67.9%) patients in the metformin XT group and 46/59 (78.0%) patients in the IRM group.
Insulin and similar drugs 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 • During this study, 43/54 (79.6%) patients in the metformin XT group and 39/59 (66.1%) patients in the IRM group experienced at least one TESS.
1/54 patients in the metformin XT group died of acute coronary artery failure during the course of the study. This was considered unrelated to the study treatment.

A total of 9/113 patients were reported to have serious adverse events (SAE): 4/54 in the metformin XT group and 5/59 in the IRM group. The investigator determined that none of these TESS events were related to study drug except for diarrhea in one patient in the IRM group, but patients in this IRM group may be related to study drug. It was regarded. This patient completed the study.

• 15/56 (26.8%) and 17/59 (28.8%) patients randomly assigned to metformin XT and IRM, respectively, were discontinued after random assignment. Of these, 9 patients (3/56 in the metformin XT group and 6/59 in the IRM group) withdrew due to adverse events that occurred during treatment. These events included abdominal pain, coronary artery disease, and hypoglycemia in the metformin XT group, and somnolence, angina, anorexia, diarrhea, dyspepsia, thrombocytopenia, and hypoglycemia in the IRM group. Of these nine, two in the metformin XT group and four in the IRM group were considered related to study drug.

Of the patients in the safety group, 14/54 (25.9%) patients in the metformin XT group and 15/59 (25.4%) patients in the IRM group have investigators involved in the study drug Experienced TESS to think (Table 13). The two most common occurrences of TESS, diarrhea and nausea, considered to be related to the study drug, were found to be comparable between treatment groups as calculated from chi-square (p = 0.2913).

SAE was reported in 5/113 patients (5 SAE): 4/54 (4 SAE) in the metformin XT group and 1/59 (1 SAE) in the IRM group. The investigator determined that all SAEs were not related to study drug.

None of the patients discontinued the trial due to lack of efficacy or efficacy.
Overall compliance rates were 94.3% of subjects in the metformin XT group and 95.4% of patients in the IRM group.
Table 12 lists the change in hemoglobin A1c (%) from baseline at the endpoint with the assigned dose.

The mean change in FPG from baseline at the 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. It was. These changes from baseline at the endpoint were statistically significant (p = 0.0201 metformin XT, p = 0.0236 IRM). FIG. 11 shows the average change in FPG over time from baseline for the ITT population.

The average change in body weight from baseline at the 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).

Average change in BMI from baseline at endpoint for Metformin XT group was 0.2 kg / m ^2, for the IRM group was 0.5 kg / m ^2. The change in BMI for the metformin XT group was not statistically significant (p = 0.2741), but the change for the IRM group was statistically significant (p = 0.0023).

• In both groups, a large number of patients experienced gastrointestinal TESS associated with study drug, but diarrhea and nausea were the two most common events among these symptoms. Although statistically similar between treatment groups was found, the frequency of diarrhea was 14.8% and 8.5% of patients in the metformin XT and IRM groups, respectively, and the frequency of nausea was metformin XT 5.6% and 6.8% of patients in the group and IRM group, respectively. The relatively high incidence of gastrointestinal TESS associated with study drug was the expected effect of metformin and was similar to that reported in the IRM.1 package insert.

• There was no meaningful difference in the number of TESS associated with study drug between treatment groups. The most frequently confirmed adverse events related to study drug, confirmed by investigators, were diarrhea and nausea.

• Both metformin XT and IRM were safe and well tolerated. The number of patients who showed SAE and / or inconvenient dropout (ADO) was similar between treatment groups. The AE, SAE and ADO patterns did not suggest any new findings for high dose metformin in either of the two high dose treatment groups. There were no clinically significant safety differences at higher doses of metformin XT (2000 mg and 2500 mg) compared to IRM.

• This study primarily compared tolerability and safety between metformin XT and IRM, however, efficacy was also analyzed.

• The two doses of the Fortamet group (one-day formulation of metformin) and the lower dose of IR metformin (2000 mg) did not show any change from baseline (p> 0.05). Although the statistically significant increase in the 2500 mg Glucophage group appears to be due to a lack of dose proportionality for IRM1, Fortamet was reported to show an increase in exposure with a predictable and consistent dose. Four similar mean percent changes were observed for FP, body weight, and BMI with metformin XT and IRM.

The overall conclusion of this study is that treatment with 2000 mg or 2500 mg metformin XT administered once daily compared to treatment with 2000 mg or 2500 mg IRM administered twice daily in patients with type 2 diabetes. , Shown to give similar efficacy and safety profiles.

  For the purpose of illustrating the invention, preferred and other aspects of the invention have been described, but modifications of the disclosed embodiments can occur to those skilled in the art. Accordingly, the appended claims are intended to cover all embodiments of the invention and all such modifications that do not depart from the spirit and scope of the invention.

CROSS REFERENCE TO RELATED APPLICATIONS This application is the United States Patent those claims priority to Provisional Application No. 60 / 566,491 (filed Apr. 29, 2004), also U.S. Patent Nov. 3, 2000 Also a continuation-in-part of US patent application Ser. No. 10 / 796,411, filed Mar. 9, 2004, which is a continuation of application 09 / 705,630 (now US Pat. No. 6,866,866). The contents are included herein for reference.

It is a graph which shows the relative bioavailability of the metformin XT formulation of Example 2 with respect to GLUCOPHAGE (trademark) about the clinical trial 2. FIG. It is a graph which shows the relative bioavailability of the metformin XT formulation (500 mg) of Example 1 with respect to GLUCOPHAGE (trademark) about the clinical trial 3. FIG. For clinical study 4, metformin XT formulation of Example 1 was orally administered 4 × 500 mg once daily for 14 days, followed by metformin in 8 healthy subjects between day 1 and day 14. It is a graph which shows the difference in a plasma concentration-time profile. 4 is a graph showing the mean plasma profile and pharmacokinetic parameter values of the metformin XT formulation of Example 3 for clinical trial 5. FIG. 6 is a graph showing the mean plasma glucose concentration-time profile for clinical trial 5 after 4 weeks of treatment with the metformin XT formulation of Example 3 and GLUCOPHAGE®. It is a graph which shows the dissolution profile of 500 mg of controlled release metformin formulation of Example 1 of this invention. It is a graph which shows the dissolution profile of 850 mg of controlled release metformin formulation of Example 2 of this invention. It is a graph which shows the dissolution profile of 1000 mg of controlled release metformin formulations of Example 3 of this invention. 1 is a graph showing the relationship between mean (SD) sustained release metformin AUC _0-∞ and dose. 1 is a graph showing the average plasma concentration of metformin versus time. 2 is a graph showing average plasma glucose concentration versus time.

Claims (21)

  A method of treating a patient with an antidiabetic agent comprising administering a high dose of an antidiabetic agent, wherein the antidiabetic agent exhibits one or more dose-proportional pharmacokinetic parameters. , Said method.   The method of claim 1, wherein the antidiabetic agent is selected from the group consisting of biguanides, hormone analogs, sulfonylureas, and thiozolidinediones, or salts, derivatives, prodrugs or metabolites thereof.   The method of claim 1, wherein the antidiabetic agent is a biguanide agent.   4. The method of claim 3, wherein the biguanide drug is metformin.   The method of claim 1, wherein the antidiabetic agent is administered once a day.   The method of claim 1, wherein the antidiabetic agent is administered to lower blood sugar.   The method of claim 1, wherein the antidiabetic agent is administered to a patient in need of treatment for non-insulin dependent diabetes mellitus (NIDDM).   2. The method of claim 1, wherein the dose-related pharmacokinetic parameter is selected from the group consisting of AUC and Cmax.   4. The method of claim 3, wherein the biguanide drug is administered at a dose greater than about 500 mg.   4. The method of claim 3, wherein the biguanide drug is administered at a dose greater than about 750 mg.   4. The method of claim 3, wherein the biguanide drug is administered at a dose greater than about 850 mg.   4. The method of claim 3, wherein the biguanide drug is administered at a dose greater than about 1000 mg.   4. The method of claim 3, wherein the biguanide drug is administered at a dose greater than about 1500 mg.   4. The method of claim 3, wherein the biguanide drug is administered at a dose greater than about 2000 mg.   4. The method of claim 3, wherein the biguanide drug is administered at a dose greater than about 2500 mg. After administration of metformin from about 500 mg to about 2500 mg,
(a) a Cmax from about 1 to about 3.1 μg / ml; and
(b) about 9 to about 29 μg · h / ml of AUC;
5. The method of claim 4, wherein the pharmacokinetic parameter selected from the group consisting of is indicated by administration of metformin. After administration of about 1000 mg metformin,
(a) from about 1 to about 2 μg / ml of Cmax; and
(b) about 9 to about 15 μg · h / ml of AUC;
17. The method of claim 16, wherein a pharmacokinetic parameter selected from the group consisting of is indicated by administration of metformin. After administration of about 1500 mg metformin,
(a) a Cmax from about 1.2 to about 2.4 μg / ml; and
(b) about 12 to about 21 μg · h / ml of AUC;
17. The method of claim 16, wherein a pharmacokinetic parameter selected from the group consisting of is indicated by administration of metformin. After administration of about 2000 mg metformin,
(a) a Cmax from about 1.5 to about 2.7 μg / ml; and
(b) AUC from about 17 to about 25 μg · h / ml;
17. The method of claim 16, wherein a pharmacokinetic parameter selected from the group consisting of is indicated by administration of metformin. After administration of about 2500 mg metformin,
(a) a Cmax from about 1.9 to about 3.1 μg / ml; and
(b) about 20 to about 29 μg · h / ml of AUC;
17. The method of claim 16, wherein a pharmacokinetic parameter selected from the group consisting of is indicated by administration of metformin.   2. The method of claim 1, wherein the high dose antidiabetic agent is released in a controlled manner.

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