United States Patent
`US 6,866,866 B1
`(10) Patent No.:
`(12)
`’
`Chen et al.
`45) Date of Patent:
`*Mar. 15, 2005
`
`
`US006866866B1
`
`8/2000 Cheng etal. 0... 424/464
`6,099,859 A *
`«. 424/473
`8/2000 Chenetal. ....
`6,099,862 A *
`
`w 424/473
`9/2001 Chen etal.
`....
`6,284,275 B1 *
`11/2002 Timminsetal. ............ 424/469
`6,475,521 Bl
`FOREIGN PATENT DOCUMENTS
`
`(54) CONTROLLED RELEASE METFORMIN
`COMPOSITIONS
`
`(75)
`
`Inventors: Chih-Ming Chen, Davie, FL (US);
`Xiu-Xiu Cheng, Davie, FL (US); Steve
`Jan, Coral Springs, FL (US); Joseph
`Chou, Manassas, VA (US)
`
`(73) Assignee: Andrx Labs, LLC, Davie, FL (US)
`
`(*) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`US.C. 154(b) by 162 days.
`
`This patent is subject to a terminal dis-
`claimer.
`(21) Appl. No.: 09/705,630
`(22)
`Filed:
`Nov.3, 2000
`
`wo
`WO
`wo
`WO
`wo
`
`9/1999
`*
`WO 99/47125
`9/1999 Le A61K/9/20
`WO 9947125 Al *
`9/1999
`aeeccccesee A61K/9/20
`9947125
`* —$/2000
`WO 00/28989
`......... A61K/31/353
`WO 0028989 Al *
`5/2000
`OTHER PUBLICATIONS
`Chiao, C. Sustained—Release Drug Delivery Systems Rem-
`ington: The Science and Practice of Pharmacy, 1995, Mack
`Publishing Company, Easton, PA pp. 1660-1669.*
`koe
`.
`cited by examiner
`Primary Examiner—Thurman K. Page
`Assistant Examiner—Micah Paul Young
`;
`(74) Attorney, Agent, or Firm—Davidson, Davidson &
`Tnnt. Clo! ooo ceeceeeeeceeccceeeee A61K 9/22; A61K 9/52
`(51)
`Kappel, LLC
`(52) U.S. Ch. eee 424/468; 424/457; 424/474;
`ABSTRACT
`57
`24/480
`(58) Field of Search ..ccccssscssscssssseseee 424/473, 468, ©)
`424/474, 475, 479, 480, 482; 514/635,
`A composition for treating patients having non-insulin-
`588, 591, 592, 593
`dependent diabetes mellitus (NIDDM) by administering a
`controlled release oral solid dosage form containing prefer-
`ably a biguanide drug such as metformin, on a once-a-day
`basis. The dosage form provides a mean time to maximum
`plasma concentration (T,,,...) of the drug which occurs at 5.5
`to 7.5 hours after oral administration on a once-a-day basis
`to human patients. Preferably, the dose of drug is adminis-
`tered at dinnertime to a patient in the fed state.
`
`(56)
`
`.
`References Cited
`U.S. PATENT DOCUMENTS
`
`3,845,770 A * 11/1974 Theeuwesetal. .......... 424/427
`11/1997 Ayeret al. oo... 424/422
`5,688,518 A
`
`11/1997 Inman etal... 514/691
`5,691,386 A
`5,858,398 A
`1/1999 Cho veeseseecseesseeesessees 424/450
`5,955,106 A *
`9/1999 Moeckelet al. oo... 424/464
`6,010,718 A
`1/2000 Al-Razzaket al.
`......... 424/464
`
`
`
`25 Claims, 8 Drawing Sheets
`
`MEAN PLASMA CONCENTRATION-TIME PROFILES OF METFORMIN IN ELEVEN SUBJECTS AFTER AN ORAL
`ADMINISTRATION OF METFORMINXT (2 x 850 mg q.d.) OR GLUCOPHAGE (850 mg b.i.d.)
`
`3000
`
`
`
`
`
` s8s8PLASMACONC.{ng/mL} 8
`
`500
`
`12 15
`
`9
`
`ra
`
`—-@-—- METFORMIN XT .d. AFTER BREAK
`~~ — METFORMIN XT q.d. AFTER DINNER
`
`TIME (hr)
`
`-ae~--GLUCOPHAGEb.ld.
`
`AUROBINDOEx. 1016, 1
`
`AUROBINDO EX. 1016, 1
`
`

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`U.S. Patent
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`Mar.15, 2005
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`US 6,866,866 B1
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`U.S. Patent
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`US 6,866,866 B1
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`U.S. Patent
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`Mar.15, 2005
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`US 6,866,866 B1
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`U.S. Patent
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`Mar.15, 2005
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`US 6,866,866 B1
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`U.S. Patent
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`US 6,866,866 B1
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`U.S. Patent
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`Mar.15, 2005
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`Mar.15, 2005
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`U.S. Patent
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`Mar.15, 2005
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`US 6,866,866 B1
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`US 6,866,866 B1
`
`1
`CONTROLLED RELEASE METFORMIN
`COMPOSITIONS
`
`BACKGROUND OF THE INVENTION
`
`The present invention relates to controlled release unit
`dose formulations containing an antihyperglycemic drug.
`Morespecifically, 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 US. Pat. Nos. 3,957,853 and 4,080,472 which are incor-
`porated herein by reference.
`In the prior art, many techniques have been used to
`provide controlled and extended-release pharmaceutical
`dosage forms in order to maintain therapeutic serum levels
`of medicaments and to minimize the effects of missed doses
`of drugs caused by a lack of patient compliance.
`In the priorart 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 mem-
`brane and dissolve the active ingredient so it can be released
`through a passageway in the coating membraneor if the
`active ingredientis insoluble in the permeating fluid, pushed
`through the passageway by an expanding agent such as a
`hydrogel. Some representative examples of these osmotic
`tablet systems can be found in U.S. 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 teaches an osmotic device wherein the active
`agent is released from a core surrounded by a semiperme-
`able membraneonly after sufficient pressure has developed
`within the membraneto burst or rupture the membraneat a
`weak portion of the membrane.
`The basic osmotic device described in the above cited
`
`patents have been refined over time in an effort to provide
`greater control of the release of the active ingredient. For
`example U\S. Pat. Nos. 4,777,049 and 4,851,229 describe an
`osmotic dosage form comprising a semipermeable wall
`surrounding a core. The core contains an active ingredient
`and a modulating agent wherein the modulating agent causes
`the active ingredient to be released through a passageway in
`the semipermeable membrane in a pulsed manner. Further
`refinements have included modifications to the semiperme-
`able membrane surrounding the active core such as varying
`the proportions of the components that form the membrane;
`Le., U.S. Pat. Nos. 5,178,867, 4,587,117 and 4,522,625 or
`increasing the number of coatings surrounding the active
`core; i.e., U.S. Pat. Nos. 5,650,170 and 4,892,739.
`Although vast amounts of research has been performed on
`controlled or sustained release compositions and in particu-
`lar on osmotic dosage forms, very little research has been
`performed in the area of controlled or sustained release
`compositions that employ antihyperglycemic drugs.
`Metformin is an oral antihyperglycemic drug used in the
`management of non-insulin-dependent diabetes mellitus
`(NIDDM). It is not chemically or pharmacologically related
`to oral sulfonylureas. Metformin improves glucose tolerance
`in NIDDMpatients by lowering both basal and postprandial
`plasma glucose. Metformin hydrochloride is currently mar-
`keted 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 GLU-
`COPHAGE®is individualized on the basis of both effec-
`
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`tiveness and tolerance, while not exceeding the maximum
`recommended dose of 2550 mg per day.
`Metformin has been widely prescribed for lowering blood
`glucose in patients with NIDDM. However, being a short
`acting drug, metformin requires twice-daily (b.i.d.) or three-
`times-a-day (t.i.d.) dosing. Adverse events associated with
`metformin use are often gastrointestinal
`in nature (e.g.,
`anorexia, nausea, vomiting and occasionally diarrhea,etc.).
`These adverse events may bepartially avoided by either
`reducing the initial and/or maintenance dose or using an
`extended-release dosage form. Another clear advantage of
`an extended release dosage form is a reduction in the
`frequency of administration. All of these findings suggest
`that an extended-release dosage form of metformin may
`improve the quality of therapy in patients with NIDDM and
`the safety profile relative to a conventional dosage form.
`The limited work on controlled or sustained release
`
`formulations that employ antihyperglycemic drugs such as
`metformin hydrochloride includes the combination of the
`antihyperglycemic drug and an expandingor gelling agentto
`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 HCI product.
`It is reported in the 50” Edition of the Physicians’ Desk
`Reference, copyright 1996, p. 753, that food decreases the
`extent and slightly delays the absorption of metformin
`delivered by the GLUCOPHAGE® dosage form. This
`decrease is shown by approximately a 40% lower peak
`concentration, a 25% lower bioavailability and a 35-minute
`prolongation of time to peak plasma concentration following
`administration of a single GLUCOPHAGE®tablet contain-
`ing 850 mg of metformin HCl with food compared to the
`similar tablet administered under fasting conditions.
`A controlled release metformin dosage form is also
`described in WO 99/47128. This a reference describes a
`controlled release delivery system for metformin which
`includes an innersolid particulate phase formed of substan-
`tially uniform granules containing metformin and one or
`more hydrophilic polymers, one or more hydrophobic poly-
`mers 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 mate-
`rials.
`Our own WO 99/47125 discloses controlled release met-
`formin formulations providing a Tmax from 8 to 12 hours.
`OBJECTS AND SUMMARYOF THE
`INVENTION
`
`invention to provide a
`is an object of the present
`It
`controlled or sustained release of an antihyperglycemic drug
`which provides effective control of blood glucose levels in
`humans.
`
`It is a further object of the present invention to provide a
`method of treating human patients with non-insulin-
`dependent diabetes mellitus (NIDDM)on a once-a-day basis
`with an antihyperglycemic drug which provides effective
`control of blood glucose levels in humans.
`It is a further object of the present invention to provide
`formulations for treating human patients with non-insulin-
`dependent diabetes mellitus (NIDDM) which provides
`advantages over the state-of-the-art, and which may be
`administered on a once-a-daybasis byitself or together with
`other antidiabetic agents, and methodsthereof.
`It is a further object of the present invention to provide a
`controlled or sustained release formulation of an antihyper-
`AUROBINDO EX. 1016, 10
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`US 6,866,866 B1
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`3
`glycernic drug wherein the bioavailability of the drug is not
`decreased by the presence of food.
`It is a further object of the present invention to provide a
`controlled or sustained release formulation of an antihyper-
`glycemic drug that does not employ an expanding polymer.
`It is also a further object of the present invention to
`provide a controlled or sustained release formulation of an
`antihyperglycemic drug that can provide continuous and
`non-pulsating therapeutic levels of the drug to an animal or
`human in need of such treatment over a twelve hour to
`
`twenty-four hour period.
`It is an additional object of other embodiments of the
`present invention to provide a controlled or sustained release
`formulation for an antihyperglycemic drug that obtains peak
`plasma levels from 5.5 to 7.5 hours after administration
`under various conditions. Altematively,
`the time to peak
`plasmalevels are from 6.0 to 7.0, from 5.5 to 7.0 or from 6.0
`to 7.5.
`
`It is also an object of this invention to provide a controlled
`or sustained release pharmaceutical formulation having a
`homogeneous core wherein the core component may be
`made using ordinary tablet compression techniques.
`In accordance with the above-mentioned objects and
`others, the present invention provides a controlled release
`oral dosage form comprising an antihyperglycemic drug,
`preferably a biguanide (e.g., metformin or a pharmaceuti-
`cally 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 concentra-
`tion (T,,,,.) of the drug from 5.5 to 7.5 hours after admin-
`istration. The dosage form comprises the drug and a mem-
`brane. In certain preferred embodiments, the dosage form
`comprises a tablet.
`the controlled release oral
`In preferred embodiments,
`dosage form of the present invention is a tablet comprising:
`(a) a core comprising:
`(i) the antihyperglycemic drug;
`(ii) optionally a binding agent; and
`(iii) optionally an absorption enhancer;
`(b) a membrane coating surrounding the core; and
`(c) at least one passageway in the membrane.
`Whenthe drug is metformin or a pharmaceutically accept-
`able salt thereof and is administered on a once-a-day basis,
`the daily dose may vary, e.g., from about 500 mg to about
`2500 mg. Such daily dose may be contained in one
`controlled-release dosage form of the invention, or may be
`contained in more than one such dosage form. For example,
`a controlled-release metformin dosage form may be formu-
`lated to contain about 1000 mgofthe drug, and two of said
`dosage form may be administered together to provide once-
`a-day metformin therapy. The daily dose of the drug (ie.
`metformin or pharmaceutically acceptable salt thereof) may
`range from about 500 mg to about 2500 mg, from about
`1000 mg to about 2500 mg,or from about 2000 mg to about
`2500 mg, depending on the clinical needs of the patient.
`In certain preferred embodiments, the controlled release
`solid oral dosage form of the present invention provides a
`width at 50% of the height of a mean plasma concentration/
`time curve of the drug (e.g., of metformin) from about 4.5
`to about 13 hours, more preferably from about 5.5 to about
`10 hours, more preferably from about 6 to about 8 hours.
`In certain embodiments,the controlled release oral dosage
`form of the present invention provides a mean maximum
`plasma concentration (C,,,,..) of the antihyperglycemic drug
`which is more than about seven times the mean plasmalevel
`of said drug at about 24 hours after administration. In
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`preferred embodiments, the controlled release oral dosage
`form of the present invention provides a mean maximum
`plasma concentration (C,,,,..) 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 plasmalevel ofthe
`drug at about 24 hours after administration.
`In certain embodimentsof the present invention, when the
`drug is metformin or a pharmaceutically acceptable salt
`thereof, the controlled release oral dosage form provides a
`mean maximum plasma concentration (C,,,,.) of the drug
`that is about 1500 ng/ml to about 3000 ng/ml, based on
`administration of a 2000 mg once-a-day dose of metformin,
`more preferably about 1700 ng/ml to about 2000 ng/ml,
`based on administration of a 2000 mg once-a-day dose of
`metformin.
`
`In certain embodimentsof the present invention, when the
`drug is metformin or a pharmaceutically acceptable salt
`thereof, the controlled release dosage form provides a mean
`AUC).54,, 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 about 19800
`ng.hr/ml to about 33900 ng.hr/ml, based on administration
`of a 2000 mg once-a-day dose of metformin.
`In certain embodiments of the invention, the administra-
`tion of the antihyperglycemic drug, e.g., at least one met-
`formin dosage form provides a mean AUC,_»,,,, from at least
`80%, preferably at least 90% of the mean AUC,,, 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
`invention,
`In certain embodiments of the present
`controlled release dosage form exhibits the following dis-
`solution 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 drug released after
`2 hours; 10-45% of the drug released after 4 hours; 30-90%
`of the drug released after 8 hours; not less than 50% of the
`drug released after 12 hours; not less than 60% of the drug
`released after 16 hours; and not less than 70% of the drug
`released after 20 hours.
`In certain preferred embodiments, the controlled release
`solid oral dosage form exhibits the following dissolution
`profiles when tested in USP type 2 apparatus at 75 rpm in
`900 ml of simulated intestinal gastric fluid (pH 7.5 phos-
`phate buffer) at 37° C.: 0-25% of the drug (e.g., metformin
`or a pharmaceutically acceptable salt thereof) released after
`2 hours; 20-40% of the drug released after 4 hours; 45-90%
`of the drug released after 8 hours; not less than 60% of the
`drug released after 12 hours; not less than 70% of the drug
`released after 16 hours; and not less than 80% of the drug
`released after 20 hours.
`
`With respect to embodiments of the present invention
`where the antihyperglycemic drug is metformin, it has been
`found that drugs such as metformin provide substantially
`linear pharmacokinetics up to a level of about 2 grams per
`day. Therefore, it is contemplated for purposesof the present
`invention that a given plasmalevel(e.g., C,,,,,..) 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.
`AUROBINDOEX. 1016, 11
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`AUROBINDO EX. 1016, 11
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`US 6,866,866 B1
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`5
`The dosage form of the present invention can provide
`therapeutic levels of the antihyperglycemic drug for twelve
`to twenty-four hour periods and does not exhibit a decrease
`in bioavailability if taken with food. In fact, a slight increase
`in the bioavailability of the antihyperglycemic drug is
`observed when the controlled release dosage form of the
`present invention is administered with food. In a preferred
`embodiment, the dosage form can be administered once-a-
`day, ideally with or after a meal, preferably with or after the
`evening meal, and provides therapeutic levels of the drug
`throughout the day with peak plasmalevels being obtained
`between 5.5 to 7.5 hours after administration.
`
`The present invention is also directed to a method of
`lowering blood glucose levels in human patients needing
`treatment for non-insulin-dependent diabetes mellitus
`(NIDDM), comprising orally administering to human
`patients on a once-a-day basis a dose of a drug comprising
`a biguanide (e.g., metformin or a pharmaceutically accept-
`able salt thereof), said drug being contained in at least one
`solid oral controlled release dosage form of the present
`invention. Whenthe drug is metformin,the daily dose of the
`drug may be from about 500 mg to about 2500 mg, from
`about 1000 mg to about 2500 mg,or from about 2000 mg to
`about 2500 mg, depending on the clinical needs of the
`patient.
`The controlled release dosage form of the present inven-
`max?
`max
`tion provides a delayed T,
`as compared to the T.
`provided by GLUCOPHAGE. The delayed T,,,. occurs
`from 5.5 to 7.5 hours after administration. If the drug (e.g.,
`metformin) is administered at dinner time, the T,,,,. would
`occur during the time when gluconeogenesisis usually at its
`highest (e.g., around 2 a.m.).
`The present invention also includes a methodoftreating
`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 pharmaceuti-
`cally acceptable salt thereof), contained in at least one oral
`controlled release dosage form of the present invention.
`When the drug is metformin, the daily dose of the drug
`maybe from about 500 mg to about 2500 mg, from about
`1000 mg to about 2500 mg,or from about 2000 mg to about
`2500 mg, depending on the clinical needs of the patient. In
`certain embodiments, the method of treatment according to
`the present
`invention involves once-per-day metformin
`monotherapy as an adjunct to diet to lower blood glucose in
`patients with NIDDM whose hyperglycemia may not be
`satisfactorily managed on diet alone.
`In certain other
`embodiments,
`the once-a-day metformin therapy of the
`present
`invention may be used concomitantly with a
`sulfonylurea, e.g., when diet and monotherapy with a sul-
`fonylurea alone do not result in adequate glycemic control.
`In certain other embodiments,
`the once-a-day metformin
`therapy of the present invention may be used concomitantly
`with a glitazone, e.g., when diet and monotherapy with a
`glitazone alone do not result in adequate glycemic control.
`The present invention is further directed to a method of
`controlling the serum glucose concentration in human
`patients with NIDDM, comprising administering to patients
`having NIDDM on a once-a-day basis, preferably at dinner
`time, an effective dose of a biguanide (e.g., metformin)
`contained in atleast one oral controlled release dosage form
`of the present invention.
`The present
`invention further includes a controlled-
`release dosage form of a drug comprising a biguanide(e.g.,
`metformin) suitable for once-a-day administration to human
`patients with NIDDM,
`the dosage form comprising an
`effective amountof the drug to control blood glucose levels
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`for up to about 24 hours and an effective amount of a
`controlled-release carrier to provide controlled release of the
`drug with a mean time to maximum plasma concentration
`(Tax) of the drug from 5.5 to 7.5 hours after administration
`and a width at 50% of the height of a mean plasma
`concentration/time curve of the drug from about 6 to about
`13 hours. In preferred embodiments, the administration of
`the controlled-release dosage form occurs at fed state, more
`preferably at dinner time.
`In certain preferred embodiments, the controlled-release
`dose of the drug (e.g., metformin or a pharmaceutically
`acceptable salt thereof) according to the present invention is
`provided by one or more of a controlled-release tablet
`comprising
`(a) a core comprising:
`(i) the antihyperglycemic drug (e.g., metformin or a
`pharmaceutically acceptable salt thereof);
`(ii) optionally a binding agent; and
`(iii) optionally an absorption enhancer;
`(b) a membrane coating surrounding the core; and
`(c) at least one passageway in the membrane.
`In certain preferred embodiments, the mean time to maxi-
`mum plasma concentration of the drug is reached from 6.5
`to 7.5 hours after administration at dinner time.
`
`In certain embodiments of the invention when the drug is
`a biguanide (e.g. metformin or a pharmaceutically accept-
`able salt thereof), the controlled release dosage form pro-
`vides upon single administration, a higher meanfluctuation
`index in the plasmathan an equivalent dose of an immediate
`release composition administered as two equal divided
`doses, one divided doseat the start of the dosing interval and
`the other divided dose administered 12 hours later, prefer-
`ably maintaining bioavailability from at least 80% prefer-
`ably from at least 90% of the immediate release composi-
`tion.
`
`In certain embodimentsof the present invention, the mean
`fluctuation index of the dosage form is from about 1 to about
`4, preferably about 2 to about 3, more preferably about 2.5.
`In certain embodiments of the invention which exhibit a
`higher mean fluctuation index in the plasma than an equiva-
`lent dose of an immediate release composition administered
`as two equal divided doses, the ratio of the mean fluctuation
`index between the dosage form and the immediate release
`composition is about 3:1, preferably about 2:1, more pref-
`erably 1.5:1.
`Whenthe drug is metformin or a pharmaceutically accept-
`able salt thereof, the doses of drug which exhibit the above
`disclosed meanfluctuation indexes can be any effective dose
`administered to a patient with NIDDM for the reduction of
`serum glucose levels. For example, the dose can from about
`500 mg to about 2500 mg, from about 1000 mg to about
`2000 mg or from about 850 mg to about 1700 mg metformin
`or pharmaceutically acceptable salt thereof.
`The drugs which mayused in conjunction with the present
`invention include those drugs which are useful for the
`treatment of non-insulin-dependent diabetes mellitus
`(NIDDM), including but not limited to biguinides such as
`metformin or buformin or pharmaceutically acceptable salts
`thereof. When the drug used in the present invention is
`metformin,it is preferred that the metformin be present in a
`salt form, preferably as metformin hydrochloride.
`The term “metformin” as it is used herein means met-
`formin base or any pharmaceutically acceptable salt e.g.,
`metformin hydrochloride.
`The term “dosage form”as it is used herein meansat least
`one unit dosage form of the present invention (e.g. the daily
`dose of the antihyperglycemic agent can be contained in 2
`AUROBINDOEX. 1016, 12
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`AUROBINDO EX. 1016, 12
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`US 6,866,866 B1
`
`7
`unit dosage forms of the present invention for single once-
`a-day administration).
`The term “morning”as it is used herein with respectto the
`dosing of the controlled release formulations of the inven-
`tion meansthat the controlled release formulation is orally
`administered early in the day after the patient has awakened
`from overnight sleep, generally between about 6 a.m. and 11
`a.m. (regardless of whether breakfast is eaten at that time,
`unless so specified herein).
`The term “dinnertime” or “at dinner”as it is used herein
`
`with respect to the dosing of the controlled release formu-
`lations of the invention means that the controlled release
`
`formulation is orally administered at a time when dinneris
`normally eaten (regardless of whether a meal is actually
`eaten at that time, unless so specified herein), generally
`between about 4 p.m. and 8 p.m.
`The term “bedtime”as it is used herein with respect to the
`dosing of the controlled release formulations of the inven-
`tion meansthat the controlled release formulation is orally
`administered before the patient goes to bed in the evening,
`generally between about 8 p.m. and 12 p.m.
`The term “therapeutically effective reduction” when used
`herein is meant to signify that blood glucose levels are
`reduced by approximately the same amountas an immediate
`release reference standard (e.g.. GLUCOPHAGE®) or
`more, when the controlled release dosage form is orally
`administered to a human patient on a once-a-day basis.
`The term “sustained release” and “controlled release” are
`
`used interchangeably in this application and are defined for
`purposes of the present invention as the release of the drug
`from the dosage form at such a rate that when a once-a-day
`dose of the drug is administered in the sustained release or
`controlled-release form, blood (e.g., plasma) concentrations
`(levels) of the drug are maintained within the therapeutic
`range but below toxic levels over a period of time from
`about 12 to about 24 hours. When the drug used in the
`present
`invention is metformin (preferably metformin
`hydrochloride) the controlled release solid oral dosage form
`containing such drugis also referred to as “Metformin XT.”
`The term “C,,,.” 1s the highest plasma concentration of
`the drug attained within the dosing interval, 1.e., about 24
`hours.
`
`The term “C,,,,,” 1s the minimum plasma concentration of
`the drug attained within the dosing interval, i.e. about 24
`hours.
`The term “C,,,,” as used herein, means the plasma con-
`centration of the drug within the dosing interval, i.e. about
`24-hours, and is calculated as AUC/dosing interval.
`The term “T,,,.” is the time period which elapses after
`administration of the dosage form at which the plasma
`concentration of the drug attains the highest plasma con-
`centration of drug attained within the dosing interval (i.e.,
`about 24 hours).
`The term “AUC” as used herein, means area under the
`plasma concentration-time curve, as calculated by the trap-
`ezoidal rule over the complete 24-hour interval.
`The term “steady state” means that the blood plasma
`concentration curve for a given drug does not substantially
`fluctuate after repeated doses to dose of the formulation.
`The term “single dose” meansthat the humanpatient has
`received a single dose of the drug formulation and the drug
`plasma concentration has not achieved steady state.
`The term “multiple dose” means that the human patient
`has received at least two doses of the drug formulation in
`accordance with the dosing interval for that formulation
`(e.g., on a once-a-day basis). Patients who have received
`multiple doses of the controlled release formulations of the
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`invention may or may not have attained steady state drug
`plasma levels, as the term multiple dose is defined herein.
`The term “a patient” meansthat the discussion (or claim)
`is directed to the pharmacokinetic parameters of an indi-
`vidual patient and/or the mean pharmacokinetic values
`obtained from a population of patients, unless further speci-
`fied.
`
`The term “mean”, when preceding a pharmacokinetic
`value (e.g. mean T,,,.) represents the arithmetic mean value
`of the pharmacokinetic value taken from a population of
`patients unless otherwise specified (e.g. geometric mean).
`The term “Degree of Fluctuation” is expressed as
`(Curax-Cmin/Carg-
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 is a graph showing the relative bioavailability of
`the metformin XT formulation of Example 2 to GLUCOPH-
`AGE® 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, 4x500 mg q.d. for 14 days for Clinical Study 4.
`FIG. 4 is a graph showing the mean plasmaprofiles 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 aft