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`APPLICATION NO.
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`ISSUING CLASSIFICATION
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`D The terminal -months
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`this patent have been disclaimed.
`
`NOTICEbOF ALLOWANCE MAILED
`
`ISSUE BATCH NUMBER
`
`WARNING:
`The informallon disclosed hereln ma! be restrlcied. Unauthorized dlsclosure may be prohlblted by the Unlted states Code Tltle 95, Sectlone 122,181 and 388.
`Posaewion outside the U.S. Patent &Trademark Office le restricted to authorized-employees and cintracton onty.
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`FILED WITH: n DISK (CRF) (-J FICHE
`
`(AttaGMd In
`
`CD-ROM
`on mfll InSfde Rap)
`
`AUROBINDO EX1005, 1
`
`

`

`*B I I3DP,TASHEET'*
`
`SERIAL UU h4B ER
`09/7 C15,6:10
`
`FILING DATE
`1 1 I0312000
`
`RULE
`c-
`
`r
`
`Page 1 o f 2
`
`CONFIRMATION NO. 8707
`
`I
`
`ATTORN E)'
`,Jc)
`
`300.3 005 -.
`
`GROUP ART UNIT
`1615
`
`1
`
`cz?
`
`I
`
`Xiu X u Cheng, Davie, FL;
`
`Chih-Ming Chen, Davie, FL;
`Steve Jan, Coral Springs, FL;Joseph Chou. Manassas, VA;
`
`** FC)REIGN AJJPIJCAT~I~NS * ' " * t * * * C f * C f * t * * * * *
`
`IF HEQUIf?ED, FOREIGN FILING LlCElJSE GRANTED
`** 02/01/2001
`
`Fcmiyn Priority clalmed
`35 US: 11!3 (a-d)
`me1
`hrified and
`rzki iorvl8dlje:l
`
`~ ~ ~ i & 3 O N . ClAVlDSON & KAF'PEL, LLC
`
`85 SEVENTH AVENUE, 14TH FLOOR
`
`TITLE
`
`RECEIVED
`
`FEES: Atifhority has been given in Paper
`lo chargeIc;redit DEPOSIT ACCOUNT
`for following:
`
`---
`
`P A l l Fees
`
`-(
`
`--
`-___----.
`/=ilin(j
`.__-..--...
`I____p--.-
`.l . I 7 Fees ( Processing Ext. of
`time )
`
`- I_.__--.
`
`11 t tp: //nee : S000/preexatn/Javaf'roxy/j sph i bdatdt ransfom .j sp
`
`1211 5/'03
`
`AUROBINDO EX1005, 2
`
`

`

`Date Received , .
`(Incl. C. of M.)
`or
`Date Malled
`
`49.
`50.
`
`j’
`
`58.
`59.
`60.
`61.
`62.
`63.
`
`64.
`65.
`66.
`
`67.
`68.
`69.
`70.
`
`7 4
`I I .
`72.
`
`73.
`74.
`75.
`76.
`77.
`78.
`79.
`
`80.
`81.
`
`82.
`
`1
`
`AUROBINDO EX1005, 3
`
`

`

`(12) United States Patent
`Chen et al.
`
`(io) Patent No.:
`(45) Date of Patent:
`
`US 6,866,866 B1
`*Mar. 15,2005
`
`(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 of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 162 days.
`
`This patent is subject to a terminal dis-
`claimer.
`
`(21) Appl. No.: 09/705,630
`Nov. 3, 2000
`(22) Filed:
`.............................
`A61K 9/22; A61K 9/52
`(51) Int. CI.'
`(52) US. CI. .......................
`4241468; 424t457; 424t474;
`424/480
`(58) Field of Search .................................
`424/473, 468,
`424t474, 475, 479, 480, 482; 514t635,
`588, 591, 592, 593
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`3,845,770 A * 1111974 Theeuwes et al. .......... 4241427
`1111997 Ayer et al. .................. 4241422
`5,688,518 A
`1111997 lnman et al. ............... 5141691
`5,691,386 A
`111999 Cho ...........................
`5,858,398 A
`4241450
`5,955,106 A * 911999 Moeckel el at. ............ 4241464
`112000 A-Razzak et al. ......... 4241464
`6,010,718 A
`
`wo
`wo
`wo
`wo
`wo
`
`6,099,859 A * 8DOoO Cheng et al. ............... 4241464
`8/20oO Chen et al. ................. 4241473
`6,099,862 A
`6,284,275 B1 * 9/2001 Chen et al. ................. 4241473
`6,475,521 B1 11D002 Timmins et al. ............ 4241469
`FOREIGN PATENT DOCUMENTS
`* 911999
`WO 99147125
`............ A61W9/20
`WO 9947125 A1 * 911999
`............ A6 1 W9120
`9947125
`911999
`* 512fXJO
`WO 00128989
`......... A61 W31/353
`WO 0028989 A1 * 512000
`OTHER PUBLICATIONS
`Chiao, C. Sustained-Release Drug Delivery Sysrcms Rem-
`ington: The Science and Practice of Pharmacy, 1995, Mack
`Publishing Company, Easton, PA pp. 1660-1669.*
`* cited by examiner
`
`Primary Examiner-Thurman K. Page
`Assistanr E x a m i n e r a i c a h Paul Young
`(74) Attorney, Agent, or Finn-Davidson, Davidson 1G
`Kappel, LLC
`(57)
`
`ABSTRACT
`
`A composition for treating patients having non-insulin-
`dependent diabetes mellitus (NIDDM) by administering a
`controlled release oral solid dosage form containing prefer-
`ably a biguanide drug such a s metformin, on a once-a-day
`basis. The dosage form provides a mean time to maximum
`plasma concentration (Tmm) 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.
`
`25 Claims, 8 Drawing Sheets
`
`m-
`
`2500 -
`
`0
`
`3
`8
`12
`TIME (hr)
`-METFORMIN
`XT qd. AFTER BREAK
`- o - MET FORMlN XT 9.d. AFTER D[NNER
`
`9
`
`15
`
`18
`
`21
`
`24
`
`--+-GLUCOPHAGE
`
`b.l.d.
`
`AUROBINDO EX1005, 4
`
`

`

`U.S. Patent
`
`Mar. 15,2005
`
`Sheet 1 of 8
`
`US 6,866,866 B1
`
`-cn
`
`-cD
`
`AUROBINDO EX1005, 5
`
`

`

`U S . Patent
`
`Mar. 15,2005
`
`Sheet 2 of 8
`
`US 6,866,866 B1
`
`AUROBINDO EX1005, 6
`
`

`

`U*S* Patent
`
`Mar. 15,2005
`
`Sheet 3 of 8
`
`US 6,866,866 B1
`
`*"
`c
`. u
`w
`2
`F
`0
`
`0
`
`AUROBINDO EX1005, 7
`
`

`

`U.S. Patent
`
`Mar. 15,2005
`
`Sheet 4 of 8
`
`US 6,866,866 B1
`
`I i
`
`0
`I
`
`d
`
`/
`/
`
`/ d
`
`I .
`
`AUROBINDO EX1005, 8
`
`

`

`120’
`
`,
`0
`6 Pm
`
`1
`4
`
`I
`8
`
`I
`12
`6 am
`TIME (hr)
`
`I
`
`16
`
`I
`
`20
`
`1
`.24
`6 Pm
`
`FIG. 5
`
`+METFORMIN
`
`XT,(n=23)
`
`- -u - GLUCOPHAGE (n=23)
`
`d
`m
`o\
`00
`o\ a!
`u
`00
`o\
`
`Y
`
`o\ w
`
`CI
`
`AUROBINDO EX1005, 9
`
`

`

`METFORMIN HCI DISSOLUTION PROFILES
`PADDLE AT 75rpm, IN pH7.5
`
`120.
`
`I
`
`0
`
`0
`
`I
`I
`
`5
`
`-
`
`I
`1
`
`10
`TIME (HOUR)
`
`L
`I
`15
`
`.
`
`20
`
`500ma
`
`FIG. 6
`
`W
`F
`
`AUROBINDO EX1005, 10
`
`

`

`METFORMIN HCI DISSOLUTION PROFILES
`PADDLE AT 75rprn, IN pH7.5
`
`80
`
`60
`
`40
`1
`
`20
`
`0
`
`0
`
`1
`I
`
`5
`
`I
`I
`
`10
`
`TIME (HOUR) -
`
`850mg
`
`FIG, 7
`
`I
`I
`
`15
`
`20
`
`4 s
`
`00
`
`Y
`
`c
`m
`ut
`00 ut
`ut
`00
`el el
`w
`c
`
`Y
`
`AUROBINDO EX1005, 11
`
`

`

`METFORMIN HCI DISSOLUTION PROFILES
`PADDLE AT 75rpm,.lN pH7.5
`
`120
`
`I
`
`t r ,
`OY
`0
`
`I I
`5
`
`I I
`
`15
`
`20
`
`I I
`
`10
`TIME (HOUR)
`
`lOOOmg
`FIG. 8
`
`c
`pi
`
`00
`0
`c*
`00
`
`cl
`m
`01
`"
`Qb 01
`01
`"50
`01 of
`W
`Y
`
`AUROBINDO EX1005, 12
`
`

`

`US 6,866,866 B1
`
`1
`CONTROLLED RELEASE METFORMIN
`COMPOSITIONS
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`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 U S . 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 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 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; Le., 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 MDDM patients by lowering both basal and postprandial
`plasma glucose. Metformin hydrochloride is currently mar-
`keted as GLUCOPHAGEB tablets by Bristol-Myers Squibb
`Co. Each GLUCOPHAGEB 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 CLUCOPHAGEQ. Dosage of GLU-
`COPHAGEQ is individualized on the basis of both effec-
`
`2
`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 (1.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 advanlage 0 1
`an extended release dosage form is a reduction in the
`frequency of administration. All of these findings suggest
`that an extended-release dosage form of metformin may
`improve the quality of therapy in patients with NIDDM and
`the safety profile relative to a conventional dosage form.
`The limited work on controlled or sustained release
`formulations that employ antihyperglycemic drugs such as
`metformin hydrochloride includes the combination of the
`antihyperglycemic drug and an expanding or gelling agent to
`control the release of the drug from the dosage form. This
`research is exemplified by the teachings of WO 96108243
`and by the GLUCOPHAGEB metformin HCI product.
`It is reported in the 50‘” Edition of the Physicians’ Desk
`Reference, copyright 1996, p. 753, that food decreascs 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-minule
`prolongation of time to peak plasma concentration following
`administration of a single GLUCOPHAGEB tablet contain-
`ing 850 mg of metformin HCI with food compared to the
`similar tablet administered under fasting conditions.
`A controlled release metformin dosage form is also
`described in WO 99147128. This a 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, ancl an outer
`continuous phase in which the above granules are embcddccl
`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
`It is an object of the present invention to provide a
`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 10 proviclc: a
`method of
`treating human patients with non-insulin-
`dependent diabetes mellitus (NIDDM) on a once-a-day Ixisis
`with an antihyperglycemic drug which provides clfective
`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.
`It is a further object of the present invention to provide a
`controlled or sustained release formulation of an antihyper-
`
`50
`
`5s
`
`60
`
`65
`
`AUROBINDO EX1005, 13
`
`

`

`US 6,866,866 B1
`
`5
`
`3
`4
`preferred embodiments, the controlled release oral dosage
`glycernic drug wherein the bioavailability of the drug is not
`form of the present invention provides a mean maximum
`decreased by the presence of food.
`It is a further object of the present invention to provide a
`plasma concentration (Cmux) of the drug which is from about
`7 times 10 about 14 times the plasma 1cvel of the drug at
`controlled or sustained release formulation of an antihyper-
`glycemic drug that does not employ an expanding polymer.
`about 24 hours after the administration, morc preferably
`is also a further object of the present invention to
`from about 8 times to about 12 times the plasma level of thc
`drug at about 24 hours after administration.
`provide a controlled or sustained release formulation of an
`In certain embodiments of the present invenlion, when thc
`antihyperglycemic drug that can provide continuous and
`drug is metformin or a pharmaceutically acceptable salt
`non-pulsating therapeutic levels of the drug to an animal or
`human in need of such treatment Over a twelve hour to IO thereof, the controlled release oral dosage form provides a
`mean maximum plasma concentration (C,,,,,,) of the drug
`twenty-four hour period.
`that is about I5O0 ndml to about 3000 ng/ml,
`It is an additional object of other embodiments of the
`On
`present invention to provide a controlled or sustained release
`administration of a 2000 mg once-a-day dose of metformin,
`more preferably about l7O0 ng/ml lo about 2000 'gim1>
`formulation for an antihyperglycemic drug that obtains peak
`plasma levels from 5.5 to 7.5 hours after administration 15 based on administration of a 2000 mg once-a-day dose of
`metformin'
`under various conditions. Alternatively, the time to peak
`In certain embodiments Of the present invention, when lhe
`plasma levels are from 6.0 to 7.0, frorn 5.5 to 7.0 or from 6.0
`drug is metformin or a pharmaceutically acceptable salt
`to 7.5.
`thereof, the controlled release dosage form provides a mean
`It is also an object of this invention to provide a controlled
`20 AUC,,,,
`that is about 17200 ng.hr/ml to about 33900
`having a
`ng.hr/ml, based on administration of a 2000 mg once-a-day
`phamaceutical
`Or sustained
`homogeneous core wherein the core component may be
`dose of metformin; preferably about 17200 og.hr/ml to
`made using ordinary tablet compression techniques.
`about 26500 ng.hr/ml, based on administration ol a 20(W mg
`In accordance with the above-mentioned Objects and
`once-a-day dose of metformin; more preferably about 198(tO
`the present invention provides a
`2s ng.hr/ml to about 33900 ng.hr/ml, based on administration
`Others*
`comprising an antihyperglycemic drug,
`Ora' dosage
`of a 2000 mg once-a-day dose of metformin,
`preferably a bipanide
`(e.g'p metformin Or a phamaceuti-
`In certain embodiments of [he invention, the adminislra-
`that is
`for providing
`tion of the antihyperglycemic drug, e,g., at least one met-
`wherein the dosage
`once-a-day administration Of the
`formin dosage form provides a mean AUCO-24h, from at least
`form provides a mean lime
`plasma
`30 80%, preferably at least 90% of the mean AUC,.,, provided
`lion (Tm~r) Of the drug from 5.5 lo 7.5 hours after admin-
`of [he r e f e r e n c e
`b y
`hation. The dosage form comprises the
`and a Inem-
`(GLUCOPHAGE) twice a day, wherein [he daily dose of the
`brane. In certain preferred embodiments, the dosage form
`reference standard is equal to the once-a day dose
`comprises a tablet.
`metformin administered in the controtled release oral dosage
`In preferred embodiments, the controlled release oral 35 form of the present invention.
`dosage form of the present invention is a tablet comprising:
`ln certain embodiments of the present invention, the
`(a) a core comprising:
`controlled release dosage form exhibits the following dis-
`(i) the antihyperglycemic drug;
`solution profiles of the antihyperglycemic drug (e.g.,
`(ii) optionally a binding agent; and
`metformin) when tested in a USP type 2 apparatus a1 75 rpm
`(iii) optionally an absorption enhancer;
`in 900 ml of simulated intestinal gastric h i d (pl-1 7.5
`phosphate buffer) at 37" C.: 0-30% of the drug released alter
`(b) a membrane coating surrounding the core; and
`2 hours; 1045% of the drug released after 4 hours; 30-90%
`(c) at least one passageway in the membrane.
`When the drug is metformin or a pharmaceutically accept-
`of the drug released after 8 hours; not less than 50% of the
`able salt thereof and is administered on a once-a-day basis,
`drug released after 12 hours; not less than 60% of the drug
`the daily dose may vary, e.g., from about 500 mg to about 45 released after 16 hours; and not less than 70% of the drug
`2500 mg. Such daily dose may be contained in one
`released after 20 hours.
`In certain preferred embodiments, the controlled release
`controlled-release dosage form of the invention, or may be
`contained in more than one such dosage form. For example,
`solid oral dosage form exhibits the following dissolution
`profiles when tested in USP type 2 apparatus at 75 rpm in
`a controlled-release metformin dosage form may be fonnu-
`lated to contain about 1000 mg of the drug, and two of said SO 900 ml of simulated intestinal gastric fluid (pH 7.5 phos-
`phate buffer) at 37" C.: 0-25% of the drug (e.g., metformin
`dosage form may be administered together to provide once-
`a-day metformin therapy. The daily dose of the drug (Le.
`or a pharmaceutically acceptable salt thereof) released after
`metformin or pharmaceutically acceptable salt thereof) may
`2 hours; 2 0 4 0 % of the drug released after 4 hours; 45-90%
`range from about 500 mg to about 2500 mg, from about
`of the drug released after 8 hours; not less than 60% of thc
`1000 mg to about 2500 mg, or from about 2000 mg to about ss drug released after 12 hours; not less than 70% of the drug
`2500 mg, depending on the clinical needs of the patient.
`released after 16 hours; and not less than 80% of the drug
`released after 20 hours.
`In certain preferred embodiments, the controlled release
`solid oral dosage form of the present invention provides a
`With respect to embodiments of the present invention
`width at 50% of the height of a mean plasma concentration/
`where the antihyperglycemic drug is metformin, it has ticen
`time curve of the drug (e.g., of metformin) from about 4.5 60 found that drugs such as metformin provide substantially
`to about 13 hours, more preferably from about 5.5 to about
`linear pharmacokinetics up to a level of about 2 grams per
`10 hours, more preferably from about 6 to about 8 hours.
`day. Therefore, it is contemplated for purpcws of thc prescnt
`In certain embodiments, the controlled release oral dosage
`invention that a given plasma level (e.g., C,,J of metformin
`form of the present invention provides a mean maximum
`per specified dose will be directly proportional to other
`plasma concentration (Cmox) of the antihyperglycemic drug 65 doses of metformin. Such proportional doses and plasma
`levels are contemplated to be within the scope of the
`which is more than about seven times the mean plasma level
`of said drug at about 24 hours after administration. In
`invention and to be within the scope of the appended claims.
`
`40
`
`AUROBINDO EX1005, 14
`
`

`

`US 6,866,866 B1
`
`25
`
`6
`5
`for up to about 24 hours and an effective amount of a
`The dosage form of the present invention can provide
`controlled-release carrier to provide controlled release of the
`therapeutic levels of the antihyperglycemic drug for twelve
`drug with a mean time to maximum plasma concentration
`to twenty-four hour periods and does not exhibit a decrease
`(T,,,,J of the drug from 5.5 to 7.5 hours after administration
`in bioavafiabfity if taken with food, In fact, a slight increase
`in the bioavailability of the antihyperglycemic drug is 5 and a width at 50% of the height of a mean plasma
`observed when the controlled release dosage form of the
`concentration/time curve of the drug from about 6 to about
`present invention is administered with food,
`a preferred
`13 hours. In preferred embodiments, the administration of
`the dosage form can be administered once-a-
`the controlled-release dosage form occurs at fed state, more
`day, ideally with or after a meal, preferably with or after the
`preferably at dinner time.
`evening meal, and provides therapeutic levels of the drug 10
`In Certain preferred embodiments, the controlkd-release
`dose of the drug (e.g., metformin Or a pharmaceutically
`throughout the day with peak plasma levels being obtained
`acceptable salt thereof) according to the present invention is
`between 5.5 to 7.5 hours after administration.
`ne present invention is also directed to a method of
`provided by one or more of a controlled-release tablet
`lowering blood glucose levels in human patients needing
`comprising
`(a) a core comprising:
`treatment for non-insulin-dependent diabetes mellitus IS
`(i) the antihyperglycemic drug (e.g., metformin or 21
`(NIDDM), comprising orally administering to human
`pharmaceutically acceptable salt thereof);
`patients on a once-a-day basis a dose of a drug comprising
`(ii) optionally a binding agent; and
`a biguanide (e.g., metformin or a pharmaceutically accept-
`(iii) optionally an absorption enhancer;
`able salt thereof), said drug being contained in at least one
`(b) a membrane coating surrounding the core; and
`solid oral controlled release dosage form of the present 20
`invention. When the drug is metformin, the daily dose of the
`(c) at least one passageway in the membrane.
`In certain preferred embodiments, the mean time to mnxi-
`drug may be from about 500 mg to about 2500 mg, from
`mum plasma concentration of the drug is reached from 6.5
`about 1000 mg to about 2500 mg, or from about 2000 mg to
`to 7.5 hours after administration at dinner time.
`about 2500 mg, depending on the clinical needs of the
`In certain embodiments of the invention when thc drug is
`patient.
`a biguanide (e.g. metformin or a pharmaceutically accept-
`The controlled release dosage form of the present inven-
`tion provides a delayed T,,,
`able salt thereof), the controlled release dosage form pro-
`as compared to the T,,
`provided by GLUCOPHAGE. The delayed T,,
`vides upon single administration, a higher mean fluctuation
`occurs
`from 5.5 to 7.5 hours after administration. If the drug (eg.,
`index in the plasma than an equivalent dose of an immediate
`metformin) is administered at dinner time, the T,,
`would 30 release composition administered as two equal divided
`doses, one divided dose at the start of the dosing interval and
`occur during the time when gluconeogenesis is usually at its
`highest (e.g., around 2 a.m.).
`the other divided dose administered 12 hours later, prefer-
`The present invention also includes a method of treating
`ably maintaining bioavailability from at least 80% prefer-
`ably from at least 90% of the immediate release composi-
`patients with NIDDM comprising orally administering to
`human patients on a once-a-day basis a dose of a drug 35 tion.
`comprising a biguanide (e.g., metformin or a pharmaceuti-
`In certain embodiments of the present invention, the mean
`fluctuation index of the dosage form is from about 1 to about
`cally acceptable salt thereof), contained in at least one oral
`4, preferably about 2 to about 3, more preferably about 2.5.
`controlled release dosage form of the present invention.
`When the drug is metformin, the daily dose of the drug
`In certain embodiments of the invention which exhibit a
`maybe from about 500 mg to about 2500 mg, from about 40 higher mean fluctuation index in the plasma than an rquiva-
`lent dose of an immediate release composition administered
`1000 mg to about 2500 mg, or from about 2000 mg to about
`2500 mg, depending on the clinical needs of the patient. In
`as two equal divided doses, the ratio of the mean fluctuation
`certain embodiments, the method of treatment according to
`index between the dosage form and the immediate release
`composition is about 3:1, preferably about 2: 1, more prel‘-
`the present invention involves once-per-day metformin
`monotherapy as an adjunct to diet to lower blood glucose in 45 erably 1.5:l.
`When the drug is metformin or a pharmaceutically accept-
`patients with NIDDM whose hyperglycemia may not be
`satisfactorily managed on diet alone. In certain other
`able salt thereof, the doses of drug which exhibit the above
`disclosed mean fluctuation indexes can bc any cEective close
`embodiments, the once-a-day metformin therapy of the
`present invention may be used concomitantly with a
`administered to a patient with NIDDM for the reduction of
`sulfonylurea, e.g., when diet and monotherapy with a sul- SO serum glucose levels. For example, the dose can Cram about
`500 mg to about 2500 mg, from about 1000 mg to about
`fonylurea alone do not result in adequate glycemic control.
`2000 mg or from about 850 mg to about 1700 mg metformin
`In certain other embodiments, the once-a-day metformin
`or pharmaceutically acceptable salt thereof.
`therapy of the present invention may be used concomitantly
`The drugs which may used in conjunction with the present
`with a glitazone, e.g., when diet and monotherapy with a
`glitazone alone do not result in adequate glycemic control. ss invention include those drugs which are useful for the
`treatment of non-insulin-dependent diabetes mellitus
`The present invention is further directed to a method of
`(NIDDM), including but not limited to biguinides such as
`controlling the serum glucose concentration in human
`metformin or buformin or pharmaceutically acceptable salts
`patients with NIDDM, comprising administering to patients
`having NIDDM on a once-a-day basis, preferably at dinner
`thereof. When the drug used in the present invention is
`time, an effective dose of a biguanide (e.g., metformin) 60 metformin, it is preferred that the metformin be present in a
`contained in at least one oral controlled release dosage form
`salt form, preferably as metformin hydrochloride.
`The term “metformin” as it is used herein means met-
`of the present invention.
`formin base or any pharmaceutically acceptable salt e.g.,
`The present invention further includes a controlled-
`release dosage form of a drug comprising a biguanide (e.g.,
`metformin hydrochloride.
`The term “dosage form” as it is used herein means at least
`metformin) suitable for once-a-day administration to human 65
`patients with NIDDM, the dosage form comprising an
`one unit dosage form of the present invention (e.g. the daily
`dose of the antihyperglycemic agent can be contained in 1
`effective amount of the drug to control blood glucose levels
`
`AUROBINDO EX1005, 15
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`

`

`US 6,866,866 B1
`
`15
`
`7
`unit dosage forms of the present invention for single once-
`a d a y 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 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 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 .
`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 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 amount as an immediate
`release reference standard (e.g., GLUCOPHAGEB) 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 drug is also referred to as “Metformin XT.”
`The term “Cmax” is the highest plasma concentration of
`the drug attained within the dosing interval, Le., about 24
`hours.
`The term “Cmin” is the minimum plasma concentration of
`the drug attained within the dosing interval, i.e. about 24
`hours.
`The term ‘‘CaVg” 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 ‘‘TmaX’’ 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 (Le.,
`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” means that the human patient 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-aday basis). Patients who have received
`multiple doses of the controlled release formulations of the
`
`30
`
`8
`invention may or may not have attained steady slate drug
`plasma levels, as the term multiple dose is defined herein.
`The term “a patient” means that the discussion (or claim)
`is directed to the pharmacokinetic parameters of a n indi-
`5 vidual patient and/or the mean pharmacokinetic valucs
`obtained from a population of patients, unless I’urthcr speci-
`fied.
`The term “mean”, when preceding a pharmacokinetic
`value (e.g. mean TmJ represents the arithmetic mcan value
`IO of the pharmacokinetic value taken from a popuhlion of
`patients unless otherwise specified (e.g. geometric