Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2806—Coating materials
  • A61K9/2833—Organic macromolecular compounds
  • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
  • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
  • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

• the present invention relates to controlled release unit dose formulations containing an antihyperglycemic drug. More specifically, the present invention relates to an oral dosage form comprising a biguanide such as metformin or buformin or a pharmaceutically acceptable salt thereof such as metformin hydrochloride or the metformin salts described in United States Patent Nos. 3,957,853 and 4,080,472 which are incorporated herein by reference.
• a biguanide such as metformin or buformin or a pharmaceutically acceptable salt thereof
• metformin hydrochloride or the metformin salts described in United States Patent Nos. 3,957,853 and 4,080,472 which are incorporated herein by reference.
• the prior art are extended release tablets which have an osmotically active drug core surrounded by a semipermeable membrane. These tablets function by allowing a fluid such as gastric or intestinal fluid to permeate the coating membrane and dissolve the active ingredient so it can be released through a passageway in the coating membrane or if the active ingredient is insoluble in the permeating fluid, pushed through the passageway by an expanding agent such as a hydrogel.
• a fluid such as gastric or intestinal fluid
• an expanding agent such as a hydrogel.
• United States Patent No. 3,952,741 teaches an osmotic device wherein the active agent is released from a core surrounded by a semipermeable membrane only after sufficient pressure has developed within the membrane to burst or rupture the membrane at a weak portion of the membrane.
• Metformin is an oral antihyperglycemic drug used in the management of non-insulin- dependent diabetes mellitus (NIDDM). It is not chemically or pharmacologically related to oral sulfonylureas. Metformin improves glucose tolerance in NIDDM patients by lowering both basal and postprandial plasma glucose. Metformin hydrochloride is currently marketed as GLUCOPHAGE® tablets by Bristol-Myers Squibb Co. Each GLUCOPHAGE® tablet contains 500, 850 or 1000 mg of metformin hydrochloride. There is no fixed dosage regimen for the management of hyperglycemia in diabetes mellitus with GLUCOPHAGE®. Dosage of GLUCOPHAGE® is individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended dose of 2550 mg per day.
• Metformin has been widely prescribed for lowering blood glucose in patients with NIDDM. However, being a short acting drag, metformin requires twice-daily (b.i.d.) or three- times-a-day (t.i.d.) dosing. Adverse events associated with metformin use are often gastrointestinal in nature (e.g., anorexia, nausea, vomiting and occasionally diarrhea, etc.). These adverse events may be partially avoided by either reducing the initial and/or maintenance dose or using an extended-release dosage form. Another clear advantage of an extended release dosage form is a reduction in the frequency of administration. All of these findings suggest that an extended-release dosage form of metformin may improve the quality of therapy in patients with NTDDM and the safety profile relative to a conventional dosage form.
• the limited work on controlled or sustained release formulations that employ antihyperglycemic drugs such as metformin hydrochloride includes the combination of the antihyperglycemic drug and an expanding or gelling agent to control the release of the drug from the dosage form.
• This research is exemplified by the teachings of WO 96/08243 and by the GLUCOPHAGE® metformin HCl product.
• a controlled release metformin dosage form is also described in WO 99/47128.
• This reference describes a controlled release delivery system for metformin which includes an inner solid particulate phase formed of substantially uniform granules containing metformin and one or more hydrophilic polymers, one or more hydrophobic polymers and one or more hydrophobic materials, and an outer continuous phase in which the above granules are embedded and dispersed throughout.
• the outer continuous phase includes one or more hydrophilic polymers, one or more hydrophobic polymers and one or more hydrophobic materials.
• NIDDM non-insulin-dependent diabetes mellitus
• NIDDM non-insulin-dependent diabetes mellitus
• the time to peak plasma levels are from 6.0 to 7.0, from 5.5 to 7.0 or from 6.0 to 7.5.
• the present invention provides a controlled release oral dosage form comprising an antihyperglycemic drug, preferably a biguanide (e.g., metformin or a pharmaceutically acceptable salt thereof) that is suitable for providing once-a-day administration of the drug, wherein the dosage form provides a mean time to maximum plasma concentration (T max ) of the drug from 5.5 to 7.5 hours after administration.
• the dosage form comprises the drug and a membrane, h certain preferred embodiments, the dosage form comprises a tablet.
• the controlled release oral dosage form of the present invention is a tablet comprising:
• the antihyperglycemic drug (i) the antihyperglycemic drug; (ii) optionally a binding agent; and (iii) optionally an absorption enhancer;
• the daily dose may vary, e.g., from about 500 mg to about 2500 mg.
• Such daily dose may be contained in one controlled-release dosage form of the invention, or may be contained in more than one such dosage form.
• a controlled- release metformin dosage form may be formulated to contain about 1000 mg of the drug, and two of said dosage form may be administered together to provide once-a-day metformin therapy.
• the daily dose of the drug i.e. metformin or pharmaceutically acceptable salt thereof
• the controlled release solid oral dosage form of the present invention provides a width at 50% of the height of a mean plasma concentration time curve of the drug (e.g., of metformin) from about 4.5 to about 13 hours, more preferably from about 5.5 to about 10 hours, more preferably from about 6 to about 8 hours.
• a mean plasma concentration time curve of the drug e.g., of metformin
• the controlled release oral dosage form of the present invention provides a mean maximum plasma concentration (C max ) of the antihyperglycemic drug which is more than about seven times the mean plasma level of said drug at about 24 hours after administration.
• the controlled release oral dosage form of the present invention provides a mean maximum plasma concentration (C max ) of the drug which is from about 7 times to about 14 times the plasma level of the drug at about 24 hours after the administration, more preferably from about 8 times to about 12 times the plasma level of the drug at about 24 hours after administration.
• the controlled release oral dosage form when the drug is metformin or a pharmaceutically acceptable salt thereof, provides a mean maximum plasma concentration (C max ) of the drag that is about 1500 ng/ml to about 3000 ng/ml, based on administration of a 2000 mg once-a-day dose of metformin, more preferably about 1700 ng/ml to about 2000 ng/ml, based on administration of a 2000 mg once-a-day dose of metformin.
• C max mean maximum plasma concentration
• the controlled release dosage form when the drag is metformin or a pharmaceutically acceptable salt thereof, provides a mean AUC 0.24hr that is about 17200 ng.hr/ml to about 33900 ng.hr/ml, based on administration of a 2000 mg once-a-day dose of metformin; preferably about 17200 ng.hr/ml to about 26500 ng.hr/ml, based on administration of a 2000 mg once-a-day dose of metformin; more preferably aboutl9800 ng.hr/ml to about 33900 ng.hr/ml, based on administration of a 2000 mg once-a-day dose of metformin.
• the administration of the antihyperglycemic drug e.g., at least one metformin dosage form provides a mean AUC 0 . 24hr from at least 80%, preferably at least 90% of the mean AUC 0 _ 24 provided by administration of the reference standard (GLUCOPHAGE) twice a day , wherein the daily dose of the reference standard is equal to the once-a day dose of metformin administered in the controlled release oral dosage form of the present invention.
• the controlled release dosage form exhibits the following dissolution profiles of the antihyperglycemic drug (e.g., metformin) when tested in a USP type 2 apparatus at 75 rpm in 900 ml of simulated intestinal gastric fluid (pH 7.5 phosphate buffer) at 37° C: 0-30% of the drag released after 2 hours; 10-45% of the drug released after 4 hours; 30-90% of the drug released after 8 hours; not less than 50% of the drug released after 12 hours; not less than 60% of the drug released after 16 hours; and not less than 70% of the drug released after 20 hours.
• the antihyperglycemic drug e.g., metformin
• the controlled release solid oral dosage form exhibits the following dissolution profiles when tested in USP type 2 apparatus at 75 rpm in 900 ml of simulated intestinal gastric fluid (pH 7.5 phosphate buffer) at 37° C: 0-25% of the drug (e.g., metformin or a pharmaceutically acceptable salt thereof) released after 2 hours; 20-40%) of the drug released after 4 hours; 45-90% of the drug released after 8 hours; not less than 60% of the drag released after 12 hours; not less than 70% of the drug released after 16 hours; and not less than 80%) of the drug released after 20 hours.
• the drug e.g., metformin or a pharmaceutically acceptable salt thereof
• the antihyperglycemic drag is metformin
• drugs such as metformin provide substantially linear pharmacokinetics up to a level of about 2 grams per day. Therefore, it is contemplated for purposes of the present invention that a given plasma level (e.g., C max ) of metformin per specified dose will be directly proportional to other doses of metformin. Such proportional doses and plasma levels are contemplated to be within the scope of the invention and to be within the scope of the appended claims.
• the dosage form of the present invention can provide therapeutic levels of the antihyperglycemic drug for twelve to twenty-four hour periods and does not exhibit a decrease in bioavailability if taken with food, hi fact, a slight increase in the bioavailability of the antihyperglycemic drag is observed when the controlled release dosage form of the present invention is administered with food.
• the dosage form can be administered once-a-day, ideally with or after a meal, preferably with or after the evening meal, and provides therapeutic levels of the drag throughout the day with peak plasma levels being obtained between 5.5 to 7.5 hours after administration.
• the present invention is also directed to a method of lowering blood glucose levels in human patients needing treatment for non-insulin-dependent diabetes mellitus (NIDDM), comprising orally administering to human patients on a once-a-day basis a dose of a drag comprising a biguanide (e.g., metformin or a pharmaceutically acceptable salt thereof), said drug being contained in at least one solid oral controlled release dosage form of the present invention.
• NIDDM non-insulin-dependent diabetes mellitus
• the daily dose of the drag may be from about 500 mg to about 2500 mg, from about 1000 mg to about 2500 mg, or from about 2000 mg to about 2500 mg, depending on the clinical needs of the patient.
• the controlled release dosage form of the present invention provides a delayed T max , as compared to the T max provided by GLUCOPHAGE.
• the delayed T max occurs from 5.5 to 7.5 hours after administration. If the drug (e.g., metformin) is administered at dinner time, the T max would occur during the time when gluconeogenesis is usually at its highest (e.g., around 2 a.m.).
• the present invention also includes a method of treating patients with NIDDM comprising orally administering to human patients on a once-a-day basis a dose of a drug comprising a biguanide (e.g., metformin or a pharmaceutically acceptable salt thereof), contained in at least one oral controlled release dosage form of the present invention.
• a drug comprising a biguanide (e.g., metformin or a pharmaceutically acceptable salt thereof) contained in at least one oral controlled release dosage form of the present invention.
• a biguanide e.g., metformin or a pharmaceutically acceptable salt thereof
• the daily dose of the drug may be from about 500 mg to about 2500 mg, from about 1000 mg to about 2500 mg, or from about 2000 mg to about 2500 mg, depending on the clinical needs of the patient, h certain embodiments, the method of treatment according to the present invention involves once-per-day metformin monotherapy as an adjunct to diet to lower blood glucose in patients with NIDDM whose hyperglycemia may not be satisfactorily managed on diet alone.
• the once-a-day metformin therapy of the present invention may be used concomitantly with a sulfonylurea, e.g., when diet and monotherapy with a sulfonylurea alone do not result in adequate glycemic control.
• the once-a-day metformin therapy of the present invention may be used concomitantly with a glitazone, e.g., when diet and monotherapy with a glitazone alone do not result in adequate glycemic control.
• the present invention is further directed to a method of controlling the serum glucose concentration in human patients with NIDDM, comprising administering to patients having NIDDM on a once-a-day basis, preferably at dinner time, an effective dose of a biguanide (e.g., metformin) contained in at least one oral controlled release dosage form of the present invention.
• a biguanide e.g., metformin
• the present invention further includes a controlled-release dosage form of a drag comprising a biguanide (e.g., metformin) suitable for once-a-day administration to human patients with NIDDM, the dosage form comprising an effective amount of the drug to control blood glucose levels for up to about 24 hours and an effective amount of a controlled-release carrier to provide controlled release of the drag with a mean time to maximum plasma concentration (T max ) of the drag from 5.5 to 7.5 hours after administration and a width at 50% of the height of a mean plasma concentration/time curve of the drug from about 6 to about 13 hours.
• T max mean time to maximum plasma concentration
• the administration of the controlled-release dosage form occurs at fed state, more preferably at dinner time.
• the controlled-release dose of the drug e.g., metformin or a pharmaceutically acceptable salt thereof
• a controlled-release tablet comprising
• the antihyperglycemic drag e.g., metformin or a pharmaceutically acceptable salt thereof
• optionally a binding agent e.g., metformin or a pharmaceutically acceptable salt thereof
• optionally an absorption enhancer e.g., metformin or a pharmaceutically acceptable salt thereof
• the mean time to maximum plasma concentration of the drag is reached from 6.5 to 7.5 hours after administration at dimier time.
• the controlled release dosage form provides upon single administration, a higher mean fluctuation index in the plasma than an equivalent dose of an immediate release composition administered as two equal divided doses, one divided dose at the start of the dosing interval and the other divided dose administered 12 hours later, preferably maintaining bioavailability from at least 80% preferably from at least 90% of the immediate release composition.
• a biguanide e.g. metformin or a pharmaceutically acceptable salt thereof
• the mean fluctuation index of the dosage form is from about 1 to about 4, preferably about 2 to about 3, more preferably about 2.5.
• the ratio of the mean fluctuation index between the dosage form and the immediate release composition is about 3:1, preferably about 2:1, more preferably 1.5:1.
• the doses of drag which exhibit the above disclosed mean fluctuation indexes can be any effective dose administered to a patient with NIDDM for the reduction of serum glucose levels.
• the dose can from about 500mg to about 2500mg, from about lOOOmg to about 2000 mg or from about 850mg to about 1700mg metformin or phannaceutically acceptable salt thereof.
• the drugs which may used in conjunction with the present invention include those drags which are useful for the treatment of non-insulin-dependent diabetes mellitus (NIDDM), including but not limited to biguinides such as metformin or buformin or pharmaceutically acceptable salts thereof.
• NIDDM non-insulin-dependent diabetes mellitus
• the drag used in the present invention is metformin, it is preferred that the metformin be present in a salt form, preferably as metformin hydrochloride.
• metformin as it is used herein means metformin base or any pharmaceutically acceptable salt e.g., metformin hydrochlori.de.
• dosage form means at least one unit dosage form of the present invention (e.g. the daily dose of the antihyperglycemic agent can be contained in 2 unit dosage forms of the present invention for single once-a-day administration).
• the term "morning" as it is used herein with respect to the dosing of the controlled release formulations of the invention means that the controlled release formulation is orally administered early in the day after the patient has awakened from overnight sleep, generally between about 6 a.m. and 11 a.m. (regardless of whether breakfast is eaten at that time, unless so specified herein).
• dinner or “at dinner” as it is used herein with respect to the dosing of the controlled release formulations of the invention means that the controlled release formulation is orally administered at a time when dinner is normally eaten (regardless of whether a meal is actually eaten at that time, unless so specified herein), generally between about 4 p.m. and 8 p.m.
• bedtime as it is used herein with respect to the dosing of the controlled release formulations of the invention means that the controlled release formulation is orally administered before the patient goes to bed in the evening, generally between about 8 p.m. and 12 p.m.
• therapeutically effective reduction when used herein is meant to signify that blood glucose levels are reduced by approximately the same amount as an immediate release reference standard (e.g., GLUCOPHAGE ) or more, when the controlled release dosage form is orally administered to a human patient on a once-a-day basis.
• sustained release and "controlled release” are used interchangeably in this application and are defined for purposes of the present invention as the release of the drag from the dosage form at such a rate that when a once-a-day dose of the drag is administered in the sustained release or controlled-release form, blood (e.g., plasma) concentrations (levels) of the drug are maintained within the therapeutic range but below toxic levels over a period of time from about 12 to about 24 hours.
• blood e.g., plasma
• concentrations levels
• the drug used in the present invention is metformin (preferably metformin hydrochloride)
• Metalformin XT the controlled release solid oral dosage form containing such drag is also referred to as "Metformin XT.”
• C max is the highest plasma concentration of the drug attained within the dosing interval, i.e., about 24 hours.
• C min is the minimum plasma concentration of the drug attained within the dosing interval, i.e. about 24 hours.
• C avg as used herein, means the plasma concentration of the drug within the dosing interval, i.e. about 24-hours, and is calculated as AUC/dosing interval.
• T max is the time period which elapses after administration of the dosage form at which the plasma concentration of the drag attains the highest plasma concentration of drug attained within the dosing interval ( i.e., about 24 hours).
• AUC as used herein, means area under the plasma concentration-time curve, as calculated by the trapezoidal rale over the complete 24-hour interval.
• steady state means that the blood plasma concentration curve for a given drag does not substantially fluctuate after repeated doses to dose of the formulation.
• single dose means that the human patient has received a single dose of the drug formulation and the drag plasma concentration has not achieved steady state.
• multiple dose means that the human patient has received at least two doses of the drug formulation in accordance with the dosing interval for that formulation (e.g., on a once- a-day basis). Patients who have received multiple doses of the controlled release formulations of the invention may or may not have attained steady state drag plasma levels, as the term multiple dose is defined herein.
• a patient means that the discussion (or claim) is directed to the pharmacokinetic parameters of an individual patient and/or the mean pharmacokinetic values obtained from a population of patients, unless further specified.
• mean when preceding a pharmacokinetic value (e.g. mean T max ) represents the arithmetic mean value of the pharmacokinetic value taken from a population of patients unless otherwise specified (e.g. geometric mean).
• FIG. 1 is a graph showing the relative bioavailability of the metformin XT formulation of Example 2 to GLUCOPHAGE® for Clinical Study 2.
• FIG. 2 is a graph showing the relative bioavailability of the metformin XT formulation of Example 1 (500 mg) to GLUCOPHAGE® for Clinical Study 3.
• FIG. 3 is a graph showing the difference in plasma concentration-time profiles of metformin in eight healthy volunteers between Day 1 and Day 14 dosing following oral administration of the metformin XT formulation of Example 1, 4 x 500 mg q.d. for 14 days for Clinical Study 4.
• FIG. 4 is a graph showing the mean plasma profiles and values of pharmacokinetic parameters of the metformin XT formulation of Example 3 for Clinical Study 5.
• FIG. 5 is a graph showing the mean plasma glucose concentration-time profiles after 4 weeks of treatment with the metformin XT formulation of Example 3 and GLUCOPHAGE® for Clinical Study 5.
• FIG. 6 is a graph showing the dissolution profile of a 500 mg controlled release metformin formulation of Example 1 of the present invention.
• FIG. 7 is a graph showing the dissolution profile of a 850 mg controlled release metformin formulation of Example 2 of the present invention.
• FIG. 8 is a graph showing the dissolution profile of a 1000 mg controlled release metformin formulation of Example 3 of the present invention.
• antihyperglycemic drugs refers to drugs that are useful in controlling or managing noninsulin-dependent diabetes mellitus (NIDDM).
• NIDDM noninsulin-dependent diabetes mellitus
• the antihyperglycemic drug is a biguanide such as metformin or buformin or a pharmaceutically acceptable salt thereof such as metformin hydrochloride.
• the controlled release formulations of the invention provide a T max (from 5.5 to 7.5 hours) after oral administration (which T max is delayed relative to the reference standard, GLUCOPHAGE®), such that the level of drag is greatest at the time when human patients are manufacturing glucose at highest levels.
• Gluconeogenesis is well known to those skilled in the art to be greatest at night.
• the T max of the drug occurs for example between 11 :30 p.m. and 1 :30a.m., based on a dose administered at 6:00 p.m.
• such admimstration of the dosage form provides lower drag levels during the day (e.g. the afternoon) when gluconeogenesis is lower than at night.
• the invention preferably provides the added benefit of lowering insulin levels. Insulin is considered a risk factor in NIDDM, in and of itself, for cardiovascular disease.
• the plasma levels of metformin are preferably lower in the afternoon.
• This is an advantage particularly in patients who are under concomitant therapy with one or more additional antidiabetic agents, such as for example, a sulfonylurea.
• additional antidiabetic agents such as for example, a sulfonylurea.
• Sulfonylureas can possibly cause hypoglycemia, whereas metformin cannot, so there is a benefit to having lower metformin levels in the blood during the afternoon due to the potential for the patient to have hypoglycemia.
• the present invention also includes a method of treating human patients with NIDDM comprising administering on a once-a-day basis a therapeutically effective dose of metformin in a controlled-release oral dosage form ("Metformin XT"), in combination with administering an effective amount of a sulfonylurea.
• metformin is provided by a controlled release dosage form comprising metformin or a pharmaceutically acceptable salt thereof, the dosage form being useful for providing a once-a-day oral administration of the drug, wherein the dosage form provides a mean time to maximum plasma concentration (T max ) of metformin from 5.5 to 7.5 hours after administration.
• the combination therapy may be provided as follows. If patients do not respond to four weeks of the maximum dose of Metformin XT (2500 mg/ day) monotherapy, a sulfonylurea may be gradually added while maintaining the maximum dose of Metformin XT, even if prior primary or secondary failure to a sulfonylurea has occurred.
• the sulfonylurea include glyburide (glibenclamid), chloropropamide, tolbutamide, glipizide, acetohexamide and tolazamide.
• Metformin XT is preferably administered on once-a-day basis, the sulfonylurea may be administered in a different dosage form and at a different frequency. With concomitant Metformin XT and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug.
• the foregoing objectives are met by a controlled release dosage form comprising:
• the binding agent may be any conventionally known pharmaceutically acceptable binder such as polyvinyl pyrrohdone, hydroxypropyl cellulose, hydroxyethyl cellulose, ethylcellulose, polymethacrylate, waxes and the like. Mixtures of the aforementioned binding agents may also be used.
• the preferred binding agents are water soluble such as polyvinyl pyrrohdone having a weight average molecular weight of 25,000 to 3,000,000.
• the binding agent comprises approximately about 0 to about 40% of the total weight of the core and preferably about 3% to about 15% of the total weight of the core.
• the core may optionally comprise an absorption enhancer.
• the absorption enhancer can be any type of absorption enhancer commonly known in the art such as a fatty acid, a surfactant, a chelating agent, a bile salt or mixtures thereof.
• examples of some preferred absorption enhancers are fatty acids such as capric acid, oleic acid and their monoglycerides, surfactants such as sodium lauryl sulfate, sodium taurocholate and polysorbate 80, chelating agents such as citric acid, phytic acid, ethylenediamine tetraacetic acid (EDTA) and ethylene glycol-big (B- aminoethyl ether -N,N,N,N-tetraacetic acid (EGTA).
• fatty acids such as capric acid, oleic acid and their monoglycerides
• surfactants such as sodium lauryl sulfate, sodium taurocholate and polysorbate 80
• chelating agents such as citric acid
• the core comprises approximately 0 to about 20% of the absorption enhancer based on the total weight of the core and most preferably about 2% to about 10% of the total weight of the core.
• the core which comprises the antihyperglycemic drug, the binder which preferably is a pharmaceutically acceptable water soluble polymer and the absorption enhancer is preferably formed by wet granulating the core ingredients and compressing the granules with the addition of a lubricant into a tablet on a rotary press.
• the core may also be formed by dry granulating the core ingredients and compressing the granules with the addition of a lubricant into tablets or by direct compression.
• excipients may also be included into the core such as lubricants, pigments or dyes.
• the homogeneous core is coated with a membrane, preferably a polymeric membrane to form the controlled release tablet of the invention.
• the membrane can be a semipermeable membrane by being permeable to the passage of external fluid such as water and biological fluids and being impermeable to the passage of the antihyperglycemic drug in the core.
• Materials that are useful in fo ⁇ ning the membrane are cellulose esters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ester-ether, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate propionate, and cellulose acetate butyrate.
• Other suitable polymers are described in United States Patent Nos.
• the most preferred membrane material is cellulose acetate comprising an acetyl content of 39.3 to 40.3%, commercially available from Eastman Fine Chemicals.
• the membrane can be formed from the above-described polymers and a flux enhancing agent.
• the flux enhancing agent increases the volume of fluid imbibed into the core to enable the dosage form to dispense substantially all of the antihyperglycemic drag through the passageway and/or the porous membrane.
• the flux enhancing agent can be a water soluble material or an enteric material.
• Some examples of the preferred materials that are useful as flux enhancers are sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycol (PEG), propylene glycol, hydroxypropyl cellulose, hydroxypropyl methycellulose, hydroxyprophy methycellulose phthalate, cellulose acetate phthalate, polyvinyl alcohols, methacrylic acid copolymers and mixtures thereof.
• the preferred flux enhancer is PEG 400.
• the flux enhancer may also be a drug that is water soluble such as metformin or its pharmaceutically acceptable salts or a drag that is soluble under intestinal conditions. If the flux enhancer is a drag, the present dosage form has the added advantage of providing an immediate release of the drag which is selected as the flux enhancer.
• the flux enhancing agent comprises approximately 0 to about 40% of the total weight of the coating, most preferably about 2% to about 20% of the total weight of the coating.
• the flux enhancing agent dissolves or leaches from the membrane to form paths in the membrane for the fluid to enter the core and dissolve the active ingredient.
• the membrane may also be formed with commonly known excipients such as a plasticizer.
• plasticizers include adipate, azelate, enzoate, citrate, stearate, isoebucate, sebacate, triethyl citrate, tri-n-butyl citrate, acetyl tri-n-butyl citrate, citric acid esters, and those described in the Encyclopedia of Polymer Science and Technology, Vol.
• the preferred plasticizers are triacetin, acetylated monoglyceride, grape seed oil, olive oil, sesame oil, acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol, diethyloxalate, diethylmalate, diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacate, triethylcitrate, tributylcitrate, glyceroltributyrate, and the like.
• amounts of from 0 to about 25%, and preferably about 2% to about 15% of the plasticizer can be used based upon the total weight of the coating.
• passageway includes an aperture, orifice, bore, hole, weakened area or an erodible element such as a gelatin plug that erodes to form an osmotic passageway for the release of the antihyperglycemic drag from the dosage form.
• erodible element such as a gelatin plug that erodes to form an osmotic passageway for the release of the antihyperglycemic drag from the dosage form.
• the passageway is formed by laser drilling, hi other embodiments, the passageway is formed by making an indentation onto the core prior to the membrane coating to form a weakened area of the membrane at the point of the indentation, h preferred embodiments of the invention, the dosage form contains two passageways in order provide the desired pharmacokinetic parameters of the formulation.
• the membrane coating around the core will comprise from about 1% to about 7%, preferably about 1.5% to about 3%, based on the total weight of the core and coating.
• membrane means a membrane that is permeable to both aqueous solutions or bodily fluids and to the active drag or pharmaceutical ingredient (e.g. the formulations of Examples 1-3). Thus, the membrane is porous to drug and, in a preferred embodiment, drag is released through the hole or passageway and through the porous membrane in solution or in vivo.
• membrane also generically encompasses the term “semipermeable membrane” as heretofore defined.
• the dosage form of the present invention may also comprise an effective amount of the antihyperglycemic drug that is available for immediate release.
• the effective amount of antihyperglycemic drug for immediate release may be coated onto the membrane of the dosage form or it maybe incorporated into the membrane.
• the dosage forms prepared according to certain embodiments of the present invention preferably exhibit the following dissolution profile when tested in a USP type 2 apparatus at 75 rpms in 900 ml of simulated intestinal fluid (pH 7.5 phosphate buffer) and at 37°C:
• various conventional well known solvents may be used to prepare the granules and apply the external coating to the tablets of the invention.
• various diluents, excipients, lubricants, dyes, pigments, dispersants, etc. which are disclosed in Remington's Pharmaceutical Sciences, 1995 Edition maybe used to optimize the formulations of the invention.
• controlled release formulations of the present invention i.e., formulations which provide a mean T max of the drag and/or other pharmacokinetic parameters described herein when orally administered to human patients.
• formulations can be manufactured as a controlled oral formulation in a suitable tablet or multiparticulate formulation known to those skilled in the art.
• the controlled release dosage form may optionally include a controlled release carrier which is incorporated into a matrix along with the drug, or which is applied as a controlled release coating.
• An oral dosage form according to the invention may be provided as, for example, granules, spheroids, beads, pellets (hereinafter collectively referred to as Amultiparticulates@) and/or particles.
• An amount of the multiparticulates which is effective to provide the desired dose of drag over time may be placed in a capsule or may be incorporated in any other suitable oral form.
• the tablet core or multiparticulates containing the drag are coated with a hydrophobic material selected from (i) an alkylcellulose and (ii) a polymeric glycol.
• the coating may be applied in the form of an organic or aqueous solution or dispersion.
• the coating may be applied to obtain a weight gain from about 2 to about 25% of the substrate in order to obtain a desired sustained release profile.
• the sustained release coatings of the present invention may also include an exit means comprising at least one passageway, orifice, or the like as previously disclosed.
• a controlled release tablet containing 500 mg of metformin HCl and having the following formula is prepared as follows:
• metformin HCl and sodium lauryl sulfate are delumped by passing them through a 40 mesh screen and collecting them in a clean, polyethylene-lined container.
• the povidone, K-90-F is dissolved in purified water.
• the delumped metformin HCl and sodium lauryl sulfate are then added to a top-spray fluidized bed granulator and granulated by spraying with the binding solution of povidone under the following conditions: inlet air temperature of 50-70 ° C; atomization air pressure of 1-3 bars; and spray rate of 10-100 ml/min.
• the granules are dried in the granulator until the loss on drying is less than 2%.
• the dried granules are passed through a Comil equipped with the equivalent of an 18 mesh screen.
• the magnesium stearate is passed through a 40 mesh stainless steel screen and blended with the metformin HCl granules for approximately five (5) minutes. After blending, the granules are compressed on a rotary press fitted with 15/32" round standard concave punches.
• the core tablet is seal coated with an Opadry material or other suitable water-soluble material by first dissolving the Opadry material, preferably Opadry Clear (YS- 1-7006), in purified water.
• the Opadry solution is then sprayed onto the core tablet using a pan coater under the following conditions: exhaust air temperature of 38-42°C; atomization pressure of 28-40 psi; and spray rate of 10-15 ml/min.
• the Opadry Clear of the coating constitutes about 11.5 mg/tablet.
• the cellulose acetate is dissolved in acetone while stirring with a homogenizer.
• the polyethylene glycol 400 and triacetin are added to the cellulose acetate solution and stirred until a clear solution is obtained.
• the tablet is coated by spraying the clear coating solution onto the seal coated tablets in a fluidized bed coater employing the following conditions: product temperature of 16-22 ° C; atomization pressure of approximately three bars; and spray rate of 120-150 ml/min.
• the coated tablets were laser drilled two holes (one hole on each side of the tablet).
• a controlled release tablet containing 850 mg of metformin HCl and having the following formula is prepared as follows:
• the metformin HCl and sodium lauryl sulfate are delumped by passing them through a 40 mesh screen and collecting them in a clean, polyethylene-lined container.
• the povidone, K-90-F is dissolved in purified water.
• the delumped metformin HCl and sodium lauryl sulfate are then added to a top-spray fluidized bed granulator and granulated by spraying with the binding solution of povidone under the following conditions: inlet air temperature of 50- 70 ° C; atomization air pressure of 1-3 bars; and spray rate of 10-100 ml/min.
• the binding solution is depleted, the granules are dried in the granulator until the loss on drying is less than 2%.
• the dried granules are passed through a Comil equipped with the equivalent of an 18 mesh screen.
• the magnesium stearate is passed through a 40 mesh stainless steel screen and blended with the metformin HCl granules for approximately five (5) minutes. After blending, the granules are compressed on a rotary press fitted with 15/32" round standard concave punches.
• the core tablet is seal coated with an Opadry material or other suitable water-soluble material by first dissolving the Opadry material, preferably Opadry Clear (YS-1-7006), in purified water.
• the Opadry solution is then sprayed onto the core tablet using a pan coater under the following conditions: exhaust air temperature of 38-42°C; atomization pressure of 28-40 psi; and spray rate of 10-15 ml/min.
• the Opadry Clear of the coating constitutes about 11.5 mg/tablet.
• the cellulose acetate is dissolved in acetone while stirring with a homogenizer.
• the polyethylene glycol 400 and triacetin are added to the cellulose acetate solution and stirred until a clear solution is obtained.
• the tablet is coated by spraying the clear coating solution onto the seal coated tablets in a fluidized bed coater employing the following conditions: product temperature of 16-22°C; atomization pressure of approximately three bars; and spray rate of 120-150 ml/min.
• the coated tablets were laser drilled two holes (one hole on each side of the tablet).
• a controlled release tablet containing 1000 mg of metformin HCl and having the following formula is prepared as follows:
• metformin HCl and sodium lauryl sulfate are delumped by passing them through a 40 mesh screen and collecting them in a clean, polyethylene-lined container.
• the povidone, K-90-F is dissolved in purified water.
• the delumped metformin HCl and sodium lauryl sulfate are then added to a fluidized bed granulator and granulated by spraying with the binding solution of povidone under the following conditions: inlet air temperature of 50- 70 °C; atomization air pressure of 1-3 bars; and spray rate of 10-100 ml/min.
• the granules are dried in the granulator until the loss on drying is less than 2%.
• the dried granules are passed through a Comil equipped with a screen equivalent to 18 mesh.
• the magnesium stearate is passed through a 40 mesh stainless steel screen and blended with the metformin HCl granules for approximately five (5) minutes. After blending, the granules are compressed on a rotary press fitted with V" round standard concave punches. ( c) Seal Coating (optional)
• the core tablet is seal coated with an Opadry material or other suitable water-soluble material by first dissolving the Opadry material, preferably Opadry Clear (YS- 1-7003), in purified water.
• the Opadry solution is then sprayed onto the core tablet using a pan coater under the following conditions: exhaust air temperature of 38-42 ° C; atomization pressure of 28-40 psi; and spray rate of 10-15 ml/min.
• the core tablet is coated with the sealing solution until the tablet is coated with 23.0 mg/tablet of the Opadry material.
• the cellulose acetate is dissolved in acetone while stirring with a homogenizer.
• the polyethylene glycol 400 and triacetin are added to the cellulose acetate solution and stirred until a clear solution is obtained.
• the tablet is coated by spraying the clear coating solution onto the seal coated tablets in a fluidized bed coater employing the following conditions: product temperature of 16-22°C; atomization pressure of approximately three bars; and spray rate of 120-150 ml/min.
• the coated tablets were laser drilled two holes (one hole on each side of the tablet).
• the laser drilled tablet is coated with a color coating using Opadry White (24 mg/tablet) and waxed with Candelilla wax powder (0.4 mg/tablet).
• Study 1 hi study 1 a total of twelve (12) healthy subjects (six males, six females) were randomized to receive either a single oral dose of metformin XT, 850mg, prepared in accordance with Example 2 or b.i.d. doses of GLUCOPHAGE in assigned study periods which consisted of one of the following groups: Group A - metformin XT (2 x 850 mg tablets) taken at approximately 8:00 a.m., immediately following breakfast, Group B - metformin XT (2 x 850 mg tablets) taken at approximately 6:00 p.m., immediately following dinner; and Group C - GLUCOPHAGE (1 x 850 mg tablet) taken at approximately 8:00 a.m., immediately following breakfast, and at approximately 6:00 p.m., immediately following dinner. Each drag administration was separated by a washout period of seven days. In this study, one male subject was removed from the study prior to Period II due to non-treatment- related mononucleosis. Thus, 11 (five males and six
• metformin XT plasma samples were obtained from subjects at 0 (predose), 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, and 24 hour(s) after dosing.
• GLUCOPHAGE plasma samples were obtained from subjects at 0 (predose), 1, 2, 3, 4, 5, 6, 8, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, and 24 hour(s) after the first dose in the morning.
• Plasma concentrations of metformin were determined using a validated HPLC method. The lower quantitation limit of this method is 10 ng/ml.
• Mean plasma concentration-time profiles are shown in Fig. 1 and mean values of pharmacokinetic parameters of metformin obtained from this study are presented in Table 1.
• the C max was directly obtained from the study (see Table 1).
• the C avg was obtained by dividing the AUC value by the dosing interval, i.e. 24 hours.
• the value for C min was extrapolated from Figure 1.
• a single administration of the metformin XT formulation provides a higher mean fluctuation index in the plasma than a substantially equal dose of Glucophage administered as two equal divided doses, one divided dose at the start of the dosing interval and the other divided dose administered 12 hours later.
• Study 2 The study design of Study 2 is the same as Study 1 except for the formulation and the dose (4 x 500 mg q.d., total dose 2000mg, for metformin XT prepared according to Example 1 and 2 x 500 mg b.i.d., total dose 2000mg, for GLUCOPHAGE in the second study), h this study, 12 healthy volunteers (five males and seven females) were randomized to receive treatments and completed the study. Mean plasma concentration-time profiles and mean values of pharmacokinetic parameters of metformin obtained from this study are presented in Figure 2 and Table 3.
• a single administration of the metformin XT formulation provides a higher mean fluctuation index in the plasma than an equivalent dose of Glucophage administered as two equal divided doses, one divided dose at the start of the dosing interval and the other divided dose administered 12 hours later.
• Study 3 a multiple-dose, open-label, one-period study was conducted to evaluate the short-term tolerability and steady-state pharmacokinetics of the 500 mg metformin XT formulation used in Study 2.
• eight healthy volunteers four males and four females were randomized to receive 2000 mg of metformin XT (4 x 500 mg tablets) at approximately 6:00 p.m., immediately following dinner, for 14 days.
• Blood samples were obtained from each subject at 0 (predose), 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16 and 24 hour(s) following the first dose on Day 1 and at 0 (predose), 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 24, 38 and 48 hour(s) following the last dose on Day 14. Blood samples were also drawn from each subject immediately prior to dosing on Days 10-13. Urine samples were collected from each subject at the following time intervals: six hours prior to the first dose; 0-6, 6-12 and 12-24 hours after the first dose; and 0-6, 6-12, 12-24 and 24-48 hours after the last dose.
• metformin XT Following oral administration of a single dose (4 x 500 mg) of metformin XT, approximately 31% of the dose was excreted in the urine within the first 24 hours. On average, the renal clearance of metformin was 366 ml/min. A slightly higher renal clearance (454 ml/min) was found after multiple-dose administration of 4 x 500 mg q.d. of metformin XT.
• Gastrointestinal symptoms diarrhea, nausea, vomiting, abdominal bloating, flatulence and anorexia
• GLUCOPHAGE was started at low, nontherapeutic doses and gradually titrated to higher doses.
• metformin XT begun at a therapeutic initial dose of 2000 mg once daily with dinner was well tolerated by all healthy volunteers. Diarrhea and nausea were the most common gastrointestinal reactions probably or possibly related to metformin XT. These reactions, however, were either mild or moderate. This suggests that it may be possible to initiate metformin XT treatment with effective doses rather than using the slow titration from non- therapeutic doses required for GLUCOPHAGE.
• Study 4 was a study designed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of metformin XT compared to GLUCOPHAGE after multiple-dose treatment in patients with NIDDM.
• Metformin XT tablets prepared according to Example 3 were used in this study. This study had a single-center, randomized, two-way crossover design.
• a total of 24 NIDDM patients who were on a stable dose of GLUCOPHAGE, between 1000 and 2550 mg/day, for at least 12 weeks were selected for the study.
• Plasma metformin concentrations were determined over a 24-hour period at the end of Treatment Periods I and II as follows: immediately prior to dosing and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 15, 16, 17, 18, 19, 20, 22, and 24 hours after the evening dose.
• metformin XT When the metformin XT was administered immediately after dinner, the bioavailability of metformin XT relative to GLUCOPHAGE at steady state was close to 100%. However, when metformin XT was administered immediately after breakfast, the corresponding relative bioavailability of metformin XT was approximately 80%.
• the safety profile of metformin XT, 2000 mg given once daily either after dinner or after breakfast was comparable to that of an equal dose of GLUCOPHAGE given b.i.d.
• the efficacy profile of metformin XT, 2000 mg given once daily after dinner was similar to that of an equal dose of GLUCOPHAGE given b.i.d.
• the efficacy of metformin XT, 2000 mg given once daily after breakfast however, appeared to be comparable to or slightly less than that of GLUCOPHAGE given b.i.d.

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