(12) United States Patent
`(10) Patent N0.:
`US 6,790,459 B1
`
`Cheng et al.
`(45) Date of Patent:
`Sep. 14, 2004
`
`U50067904-59B1
`
`(54) METHODS FOR TREATING DIABETES VIA
`ggggggfiglgggggoNTROLLED
`
`(75)
`
`InVemorS Xi“ Xi“ Cheng> DaVie> FL (Us);
`Chill-Ming Chen, Dime, FL (US);
`Steve Jan, Coral Sprmgs, FL (US);
`Joseph Chou, Manassas, VA (US)
`
`(73) Assignee: Andrx Labs, LLC, Davie, FL (US)
`
`99
`WO
`
`W8
`W0
`W0
`W0
`W0
`
`FOREIGN PATENT DOCUMENTS
`99999/
`......... 9999999
`6/1999
`......... A61K/31/155
`
`9929314
`
`*
`
`WO 99994413125
`W0 9947125 A1 *
`9947128
`*
`WO 00/28989
`W0 0028989 A1 *
`
`31999
`9/1999
`9/1999
`5/2000
`5/2000
`
`............ A61K/9/20
`
`..... A61K/9/20
`............ A61K/9/24
`
`......... A61K/31/353
`
`OTHER PUBLICATIONS
`
`( * ) Notice:
`
`Subject. to any diisglaimecri, the 11991111591 fig;
`pjatsenct 1:5??an 130:; Juste un er
`’
`’
`’
`( ) y
`ays.
`
`.
`(21) Appl. No“ 09/705’625
`(22)
`Filed:
`Nov. 3, 2000
`
`7
`
`(51)
`
`Int. Cl.
`
`............................ A61K 9/14; A61K 9/16;
`A61K 9/20; A61K 9/22; A61K 9/27
`....................... 424/468; 424/464; 424/465;
`(52) US. Cl.
`424/469; 424/470; 424/472; 424/474; 424/489;
`424/490
`(58) Field of Search ................................. 424/473, 469,
`424/474, 475, 479, 480, 482; 514/6359
`5889 5919 5929 593
`
`(56)
`
`_
`References Clted
`U.S. PATENT DOCUMENTS
`
`3,845,770 A * 11/1974 Theeuwes et al.
`.......... 424/427
`3,916,899 A
`11/1975 Theeuwes et a1.
`.......... 424/424
`3,952,741 A
`4/1976 Baker .................. 424/405
`
`5/1976 Bohuon ............... 560/143
`3,957,853 A
`
`2/1977 Theeuwes et a1.
`..... 424/427
`4,008,719 A
`
`..... 424/427
`4,034,758 A
`7/1977 Theeuwes
`
`7/1977 Theeuwes ............ 424/473
`4,036,228 A
`12/1977 Saunders et a1.
`........ 219/121.7
`4,063,064 A
`3/1978 Theeuwes et a1.
`.......... 424/427
`4,077,407 A
`4,080,472 A
`3/1978 Bohuon ...................... 514/555
`4,088,864 A
`5/1978 Theeuwes et a1.
`..... 219/121.71
`9/1978 Theeuwes ................ 424/473
`4,111,201 A
`
`6/1985 Edgren ............. 424/473
`4,522,625 A
`
`..... 424/473
`4,587,117 A
`5/1986 Edgren et a1.
`.......................... 424/473
`4,609,374 A
`9/1986 Ayer
`
`Chiao, C. Sustained—Release Drug Delivery Systems Rem-
`ington: the Science and Practice of Pharmacy, 1995, Mack
`Publishing Company, Easton, PA pp. 1660—1669.*
`Drug Facts and Comparisons p. 635—642 1999.*
`Physicans Desk Reference (54 ”h Ed. 2000), pp. 831—835.
`Sheen, Andre J., Clinical Pharmacokinetics of Metformin,
`Clinical Pharmacokinetics, May 30, 1996, 5:359—371.
`Bailey, Clifford J., et al., Metformin, The New England
`Journal ofMea'icine, Feb. 29, 1996, 334574—579.
`Dunn, Christopher J., et al., Metformin: A Review of its
`Pharmacological Properties and Therapeutic Use in Non—
`Insulin—Dependent Diabetes Mellitas, Drugs
`(1995),
`49721—747.
`Kartunen, P., et al., The Pharmacokinetics of Metformin.‘ A
`Comparison of the Properties of a Rapid—Release and a
`Sustained—Release Preparation, pp. 31—36.
`
`Primary Examiner—James M. Spear
`Assistant Examiner—S. Tran
`
`(74) Attorney, Agent, or Firm—Davidson, Davidson &
`Kappel, LLC
`
`(57)
`
`ABSTRACT
`
`Amethod for treating patients having non-insulin-dependent
`diabetes mellitus (NIDDM) by administering a controlled
`release oral solid dosage form containing preferably a bigu-
`anide drug such as metformin, on a once-a-day basis. The
`dosage form provides a mean time to maximum plasma
`concentration (Tmax) of the drug Which occurs at a 5.5 to 7.5
`hours after oral administration on a once-a-day basis to
`human patients. Preferably, the dose of drug is administered
`at dinnertime to a patient in the fed state.
`
`(List continued on next page.)
`
`21 Claims, 8 Drawing Sheets
`
`MEAN PLASMA CONCENTRATION-TIME PROFILES OF METFORMIN IN ELEVEN SUBJECTS AFTER AN ORAL
`ADMINISTRATION OF METFORMIN XI (2 x I350 mg qd.) OR GLUCOPHAGE (350 mg hid.)
`3000‘
`
`
`
`
`
`PLASMACONC.(nglrnL)
`
`2500J
`
`2000—
`
`1500-
`
`1000-
`
`500' 1
`
`12
`TIME (hr)
`+METFORMIN XT q.d. AFTER BREAK
`A o — METFORMIN x1 q.d. AFTER DINNER
`
`-----sw- GLUCOPHAGE l7.|.d.
`
`AUROBINDO EX. 1001, 1
`
`AUROBINDO EX. 1001, 1
`
`

`

`US 6,790,459 B1
`
`Page 2
`
`US. PATENT DOCUMENTS
`
`5,512,293 A
`
`4/1996 Landrau et al.
`
`............. 424/449
`
`4 612 008 A
`,
`,
`2725722: 2
`4,627,850 A
`4,692,336 A
`4,704,118 A
`4,777,049 A
`4,783,337 A
`4,851,229 A
`4,865,598 A
`4892 739 A
`4963141 A
`5,024,843 A
`5,071,607 A
`5,091,190 A
`,
`,
`5 110 597 A
`5,120,548 A
`5 141 752 A
`7
`7
`5,178,867 A
`5 185 158 A
`5,308,348 A
`5,413,572 A
`
`604/892 1
`1
`t
`9/1986 W
`~
`0.11% e a~ ~~~~~~~~~~~~~
`3/132:
`igétrtfida‘ftfi ---------- “426/9426;
`
`12/1986 Deters et al.
`............ 604/8921
`9/1987 Eckenhoff etal.
`.......... 424/468
`
`11/1987 Eckenhoff .........
`424/438
`.......... 424/457
`10/1988 Magruder et al.
`................ 424/468
`11/1988 Wong etal.
`
`7/1989 Magruder et al.
`424/457
`9/1989 Eckenhofl ................ 604/8921
`1/1990 Shah et al.
`................. 424/473
`
`10/1990 Eckenhoff .........
`604/892.1
`6/1991 Kuczynskietal.
`514/25506
`12/1991 Ayer et al.
`.................. 264/112
`
`2/1992 Kuczynski et al.
`..
`424/473
`................
`.
`5/1992 Wong et al
`424/438
`6/1992 McClelland et al.
`........ 424/473
`
`8/1992 Ayer et al
`424/473
`.
`‘ ““““““
`............. 424/473
`1/1993 Gulttard etal.
`2/1993 Ayer et al
`424/473
`5/1994 Balaban et al.
`604/892.1
`
`5/1995 Wong et a1.
`............. 604/8921
`
`5,543,156 A
`5,545,413 A
`5,591,454 A
`5722499313 2
`’
`’
`5,631,224 A
`3722331332 2
`576687117 A
`7
`7
`5,674,900 A
`59688518 A
`5,691,386 A
`5,858,398 A *
`5,955,106 A
`6,010,718 A *
`*
`6,099,859 A
`670997862 A *
`6,270,805 B1
`6284 275 B1 *
`,
`,
`6,475,521 B1
`
`* cited by examiner
`
`.............. 424/484
`8/1996 Roorda et al.
`8/1996 Kuczynskietal.
`......... 424/473
`1/1997 Kuczynskietal.
`......... 424/486
`:33; ggggetezlal' """"""""" 514728471
`
`.
`‘ ““““
`5/1997 Efendlc et al.
`............... 514/12
`3/133; $91“:th """""""" iii/2;:
`
`41997 Shonge a'
`‘
`512/55
`a?“ ““““““““““““
`.............. 514/557
`10/1997 Ublllasetal.
`
`“/1997 AV“ et al‘ “““
`424/422
`11/1997 Inman et al.
`............... 514/691
`1/1999 Cho ........................... 424/450
`9/1999 Moed‘el et al'
`424/464
`
`1/2000 Al—Razzak et al.
`424/464
`
`......
`8/2000 Cheng et al.
`424/464
`8/2000 Chen et al'
`~~~~~
`424/473
`8/2001 Chen et al.
`.....
`424/497
`9/2001 Chen et al.
`.....
`424/473
`.
`.
`11/2002 Tlmmlns et al.
`
`
`
`............ 424/469
`
`AUROBINDO EX. 1001, 2
`
`AUROBINDO EX. 1001, 2
`
`

`

`US. Patent
`
`Sep.14,2004
`
`Sheet170f8
`
`US 6,790,459 B1
`
`
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`

`

`US. Patent
`
`Sep. 14, 2004
`
`Sheet 2 0f 8
`
`US 6,790,459 B1
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`US. Patent
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`Sep. 14, 2004
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`US 6,790,459 B1
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`US. Patent
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`Sep. 14, 2004
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`US 6,790,459 B1
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`US. Patent
`
`Sep. 14, 2004
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`US 6,790,459 B1
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`US. Patent
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`Sep. 14, 2004
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`US 6,790,459 B1
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`US. Patent
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`Sep. 14, 2004
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`US 6,790,459 B1
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`

`

`US 6,790,459 B1
`
`1
`METHODS FOR TREATING DIABETES VIA
`ADMINISTRATION OF CONTROLLED
`RELEASE METFORMIN
`
`BACKGROUND OF THE INVENTION
`
`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 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 on compliance.
`In the prior art are extended release tablets which have an
`osmotically active drug core surrounded by a semipermeable
`membrane. These tablets function by allowing a fluid such
`as gastric or intestinal fluid to permeate the coating mem-
`brane and dissolve the active ingredient so it can be released
`through a passageway in the coating membrane or if the
`active ingredient is insoluble in the permeating fluid, pushed
`through the passageway by an expanding agent such as a
`hydrogel. Some representative examples of these osmotic
`tablet systems can be found in US. Pat. Nos. 3,845,770,
`3,916,899, 4,034,758, 4,077,407 and 4,783,337. US. Pat.
`No. 3,952,741 teaches an osmotic device wherein the active
`agent is released from a core surrounded by a semiperme-
`able membrane only after sufficient pressure has developed
`within the membrane to burst or rupture the membrane at a
`weak portion of the membrane.
`The basic osmotic device described in the above cited
`
`patents have been refined over time in an effort to provide
`greater control of the release of the active ingredient. For
`example US. 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;
`i.e., US. Pat. Nos. 5,178,867, 4,587,117 and 4,522,625 or
`increasing the number of coatings surrounding the active
`core; i.e., US. 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 NIDDM patients 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 GLUCOPH-
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`AGE® is individualized on the basis of both effectiveness
`
`and tolerance, while not exceeding the maximum recom-
`mended dose of 2550 mg per day.
`Metformin has been widely prescribed for lowering blood
`glucose in patients with NIDDM. However, being a short
`acting drug, metformin requires twice-daily (b.i.d.) or three-
`times-a-day (t.i.d.) dosing. Adverse events associated with
`metformin use are often gastrointestinal
`in nature (e.g.,
`anorexia, nausea, vomiting and occasionally diarrhea, etc.).
`These adverse events may be partially avoided by either
`reducing the initial and/or maintenance dose or using an
`extended-release dosage form. Another clear advantage of
`an extended release dosage form is a reduction in the
`frequency of administration. All of these findings suggest
`that an extended-release dosage form of metformin may
`improve the quality of therapy in patients with NDDM 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.
`It is reported in the 50th 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 reference describes a
`controlled release delivery system for metformin which
`includes an inner solid 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 SUMMARY OF 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-day basis by itself or together with
`other antidiabetic agents, and methods thereof.
`
`AUROBINDO EX. 1001, 11
`
`AUROBINDO EX. 1001, 11
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`

`

`US 6,790,459 B1
`
`3
`It is a further object of the present invention to provide a
`controlled or sustained release formulation of an antihyper-
`glycemic 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. Alternatively, the time to peak
`plasma levels are from 6.0 to 7.0, from 5.5 to 7.0 or from 6.0
`to 7.5.
`
`It is also an object of this invention to provide a controlled
`or sustained release pharmaceutical formulation having a
`homogeneous core wherein the core component may be
`made using ordinary tablet compression techniques.
`In accordance with the above-mentioned objects and
`others, the present invention provides a controlled release
`oral dosage form comprising an antihyperglycemic drug,
`preferably a biguanide (e.g., metformin or a 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 (Tmax) 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.
`When the 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 mg of the drug, and two of said
`dosage form may be administered together to provide once-
`a-day metformin therapy. The daily dose of the drug (i.e.
`metformin or pharmaceutically acceptable salt thereof) may
`range from about 500 mg to about 2500 mg, from about
`1000 mg to about 2500 mg, or from about 2000 mg to about
`2500 mg, depending on the clinical needs of the patient.
`In certain preferred embodiments, the controlled release
`solid oral dosage form of the present invention provides a
`width at 50% of the height of a mean plasma concentration/
`time curve of the drug (e.g., of metformin) from about 4.5
`to about 13 hours, more preferably from about 5 .5 to about
`10 hours, more preferably from about 6 to about 8 hours.
`In certain embodiments, the controlled release oral dosage
`form of the present invention provides a mean maXimum
`plasma concentration (C
`of the antihyperglycemic drug
`max)
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`which is more than about seven times the mean plasma level
`of said drug at about 24 hours after administration.
`In
`preferred embodiments, the controlled release oral dosage
`form of the present invention provides a mean maXimum
`plasma concentration (Cmax) of the drug which is from about
`7 times to about 14 times the plasma level of the drug at
`about 24 hours after the administration, more preferably
`from about 8 times to about 12 times the plasma level of the
`drug at about 24 hours after administration.
`In certain embodiments of the present invention, when the
`drug is metformin or a pharmaceutically acceptable salt
`thereof, the controlled release oral dosage form provides a
`mean maXimum plasma concentration (Cmax) of the drug
`that is about 1500 ng/ml to about 3000 ng/ml, based on
`administration of a 2000 mg once-a-day dose of metformin,
`more preferably about 1700 ng/ml to about 2000 ng/ml,
`based on administration of a 2000 mg once-a-day dose of
`metformin.
`
`In certain embodiments of the present invention, when the
`drug is metformin or a pharmaceutically acceptable salt
`thereof, the controlled release dosage form provides a mean
`AUC0_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 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 AUC0_24hr from at least
`80%, preferably at least 90% of the mean AUCO_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
`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 h ours; 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 purposes of the present
`invention that a given plasma level (e.g., Cm”) of metformin
`per specified dose will be directly proportional to other
`doses of metformin. Such proportional doses and plasma
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`US 6,790,459 B1
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`5
`levels are contemplated to be within the scope of the
`invention and to be within the scope of the appended claims.
`The dosage form of the present invention can provide
`therapeutic levels of the antihyperglycemic drug for twelve
`to twenty-four hour periods and does not exhibit a decrease
`in bioavailability if taken with food. In fact, a slight increase
`in the bioavailability of the antihyperglycemic drug is
`observed when the controlled release dosage form of the
`present invention is administered with food. In a preferred
`embodiment, the dosage form can be administered once-a-
`day, ideally with or after a meal, preferably with or after the
`evening meal, and provides therapeutic levels of the drug
`throughout the day with peak plasma levels being obtained
`between 5.5 to 7.5 hours after administration.
`
`The present invention is also directed to a method of
`lowering blood glucose levels in human patients needing
`treatment for non-insulin-dependent diabetes mellitus
`(NIDDM), comprising orally administering to human
`patients on a once-a-day basis a dose of a drug comprising
`a biguanide (e.g., metformin or a pharmaceutically accept-
`able salt thereof), said drug being contained in at least one
`solid oral controlled release dosage form of the present
`invention. When the drug is metformin, the daily dose of the
`drug may be from about 500 mg to about 2500 mg, from
`about 1000 mg to about 2500 mg, or from about 2000 mg to
`about 2500 mg, depending on the clinical needs of the
`patient.
`The controlled release dosage form of the present inven-
`max)
`max
`tion provides a delayed T
`as compared to the T
`provided by GLUCOPHAGE. The delayed Tmax occurs
`from 5.5 to 7.5 hours after administration. If the drug (e.g.,
`metformin) is administered at dinner time, the Tmax would
`occur during the time when gluconeogenesis is usually at its
`highest (e.g., around 2 am.).
`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 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 may
`be from about 500 mg to about 2500 mg, from about 1000
`mg to about 2500 mg, or from about 2000 mg to about 2500
`mg, depending on the clinical needs of the patient. In certain
`embodiments,
`the method of treatment according to the
`present invention involves once-per-day metformin mono-
`therapy 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 at least one oral controlled release dosage form
`of the present invention.
`The present
`invention further includes a controlled-
`release dosage form of a drug comprising a biguanide (e.g.,
`metformin) suitable for once-a-day administration to human
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`the dosage form comprising an
`patients with NIDDM,
`effective amount of the drug to control blood glucose levels
`for up to about 24 hours and an effective amount of a
`controlled-release carrier to provide controlled release of the
`drug with a mean time to maximum plasma concentration
`(Tmax) 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.
`
`the administration of the
`In preferred embodiments,
`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 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 h ours later, prefer-
`ably maintaining bioavailability from at least 80% prefer-
`ably from at least 90% of the immediate release composi-
`tion.
`
`In certain embodiments of the present invention, the mean
`fluctuation index of the dosage form is from about 1 to about
`4, preferably about 2 to about 3, more preferably about 2.5.
`In certain embodiments of the invention which exhibit a
`
`higher mean fluctuation index in the plasma than an 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.
`When the drug is metformin or a pharmaceutically accept-
`able salt thereof, the doses of drug which exhibit the above
`disclosed mean fluctuation indexes can be any effective dose
`administered to a patient with NIDDM for the reduction of
`serum glucose levels. For example, the dose can from about
`500 mg to about 2500 mg, from about 200 mg to about 2000
`mg or from about 850 mg to about 1700 mg metformin or
`pharmaceutically acceptable salt thereof.
`The drugs which may used in conjunction with the present
`invention include those drugs which are useful for the
`treatment of non-insulin-dependent diabetes mellitus
`(NIDDM), including but not limited to biguinides such as
`metformin or buformin or pharmaceutically acceptable salts
`thereof. When the drug used in the present invention is
`metformin, it is preferred that the metformin be present in a
`salt form, preferably as metformin hydrochloride.
`The term “metformin” as it is used herein means met-
`
`formin base or any pharmaceutically if acceptable salt e.g.,
`metformin hydrochloride.
`
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`US 6,790,459 B1
`
`7
`The term “dosage form” as it is used herein means at least
`one unit dosage form of the present invention (e.g. the daily
`dose of the antihyperglycemic agent can be contained in 2
`unit dosage forms of the present invention for single once-
`a-day administration).
`The term “morning” as it is used herein with respect to the
`dosing of the controlled release formulations of the inven-
`tion 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 am. and 11
`am. (regardless of whether breakfast is eaten at that time,
`unless so specified herein).
`The term “dinnertime” or “at dinner” as it is used herein
`
`10
`
`with respect to the dosing of the controlled release formu-
`lations of the invention means that the controlled release
`
`15
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`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 pm. and 8 pm.
`The term “bedtime” as it is used herein with respect to the
`dosing of the controlled release formulations of the inven-
`tion means that the controlled release formulation is orally
`administered before the patient goes to bed in the evening,
`generally between about 8 pm. and 12 pm.
`The term “therapeutically effective reduction” when used
`herein is meant to signify that blood glucose levels are
`reduced by approximately the same amount as an immediate
`release reference standard (e.g., GLUCOPHAGETM) 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
`pr