PCT
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) International Patent Classification 6;
`A61K 9/20
`
`(11) International Publication Number:
`
`WO 99/47125
`
`(43) International Publication Date:
`
`23 September 1999 (23.09.99)
`
`(21) International Application Number:
`
`PCT/US99/06024
`
`(22) International Filing Date:
`
`19 March 1999 (19.03.99)
`
`(30) Priority Data:
`09/045,330
`
`20 March 1998 (20.03.98)
`
`US
`
`(71) Applicant: ANDRX PHARMACEUTICALS, INC. [US/US];
`Suite 201, 4001 S.W. 47th Avenue, Fort Lauderdale, FL
`33314 (US).
`
`(72) Inventors: CHENG, Xiu, Xiu; Apartment 506, 3150 W.
`Rolling Hills Circle, Davie, FL 33328 (US).
`CHEN,
`Chih-Ming; 10680 S.W. 40th Manor, Davie, FL 33328
`(US). JAN, Steve; 512 N.W. 120th Drive, Coral Springs,
`FL 33071 (US). CHOU, Joseph; 5755 N.W. 54th Place,
`Coral Springs, FL 33067 (US).
`
`(74) Agent: ENDRES, Martin, P.; Hedman, Gibson & Costigan,
`P.C., 1185 Avenue of the Americas, New York, NY 10036
`(US).
`
`Published
`With international search report.
`
`(81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR,
`BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE,}
`GH, GM, HR, HU,ID,IL, IS, JP, KE, KG, KP, KR, KZ,
`LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW,
`MX, NO, NZ, PL, PT, RO, RU,SD, SE, SG,SI, SK, SL, TJ,
`TM,TR, TT, UA, UG, UZ, VN, YU, ZW, ARIPO patent
`(GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), Eurasian
`patent (AM,AZ, BY, KG, KZ, MD, RU, TJ, TM), European
`patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR,
`IE, IT, LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF,
`CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG).
`
`antihyperglycemic drug, a semipermeable membranecoating the core and at least one passageway in the membrane.
`
`(54) Title: CONTROLLED RELEASE ORAL TABLET HAVING A UNITARY CORE
`
`(57) Abstract
`
`A controlled release antihyperglycemic tablet that does not contain an expanding polymer and comprising a core containing the
`
`AUROBINDOEx. 1002, 1
`
`AUROBINDO EX. 1002, 1
`
`

`

`Singapore
`
`Albania
`Armenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`Céte d’Ivoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`ES
`FI
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`Lc
`Li
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Treland
`Israel
`Iceland
`Ttaly
`Japan
`Kenya
`Kyrgyzstan
`Democratic People’s
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`
`Slovenia
`SI
`Slovakia
`SK
`Senegal
`SN
`Swaziland
`SZ
`Chad
`TD
`Togo
`TG
`Tajikistan
`TJ
`™ Turkmenistan
`TR
`Turkey
`TT
`Trinidad and Tobago
`UA
`Ukraine
`UG
`Uganda
`US
`United States of America
`UZ
`Uzbekistan
`VN
`Viet Nam
`YU
`Yugoslavia
`ZW
`Zimbabwe
`
`AUROBINDOEx. 1002, 2
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`AUROBINDO EX. 1002, 2
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`

`

`WO 99/47125
`
`PCT/US99/06024
`
`CONTROLLED RELEASE ORAL TABLET HAVING A UNITARY CORE
`
`BACKGROUND OF THE INVENTION:
`
`The present
`
`invention relates to controlled release
`
`formulations containing an antihyperglycemic
`unit dose
`drug. More specifically,
`the present invention relates to
`
`an oral
`
`dosage
`
`form comprising a biguanide
`
`such
`
`as
`
`metformin or buformin or a pharmaceutically acceptable salt
`
`thereof such as metformin hydrochloride or the metformin
`
`salts described in United States Patent Nos. 3,957,853 and
`
`10
`
`4,080,472 which are incorporated 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
`
`15
`
`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
`
`20
`
`coating membrane and dissolve the active ingredient so it
`
`can be
`
`released through a passageway in the
`
`coating
`
`membrane or if the active ingredient
`
`is insoluble in the
`
`permeating fluid,
`
`pushed through the passageway by an
`
`expanding agent such as a hydrogel.
`
`Some representative
`
`25
`
`examples of
`
`these osmotic tablet systems can be found in
`
`United States Patent Nos. 3,845,770, 3,916,899, 4,034,758,
`
`4,077,407
`
`and
`
`4,783,337.
`
`United States Patent No.
`
`3,952,741 teaches
`
`an osmotic device wherein the active
`
`agent is released from a core surrounded by a semipermeable
`
`30
`
`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.
`
`35
`
`For
`
`example United States Patent Nos.
`
`4,777,049
`
`and
`
`4,851,229 describe an osmotic dosage
`
`form comprising a
`
`SUBSTITUTE SHEET(RULE 26)
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`AUROBINDO EX. 1002, 3
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`

`

`WO 99/47125
`
`PCT/US99/06024
`
`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 semipermeable membrane surrounding the
`
`active
`
`core
`
`such as varying the proportions
`
`of
`
`the
`
`components that form the membrane, i.e United States Patent
`
`Nos. 5,178,867, 4,587,117 and 4,522,625 or increasing the
`
`10
`
`number of
`
`coatings
`
`surrounding the
`
`active
`
`core,
`
`i.e
`
`5,650,170 and 4,892,739.
`
`Although vast amounts of research has been performed
`
`on controlled or sustained release compositions and in
`
`particular on osmotic dosage forms, very little research
`
`15
`
`has been performed in the area of controlled or sustained
`
`release compositions that employ antihyperglycemic drugs.
`
`The limited work on controlled or sustained release
`
`formulations that employ antihyperglycemic drugs such as
`
`metformin hydrochloride has been limited to the combination
`of the antihyperglycemic drug and an expanding or gelling
`
`20
`
`agent
`
`to control
`
`the release of
`
`the drug from the dosage
`
`the
`exemplified by
`limited research is
`This
`form.
`teachings of WO 96/08243 and by the GLUCOPHAGE® product
`which is a commercially available product
`from Bristol-
`
`25
`
`Myers Squibb Co. containing metformin HCl.
`
`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 and
`a 25% lower AUC in plasma and a 35 minute prolongation of
`
`30
`
`time to peak plasma concentration following administration
`of
`a
`single GLUCOPHAGE® tablet
`containing 850 mg of
`metformin HCl with food compared to the similar
`tablet
`
`35
`
`administered under fasting conditions.
`
`It is an object of the present
`
`invention to provide a
`
`controlled or
`
`sustained
`
`release
`
`formulation
`
`for
`
`an
`
`SUBSTITUTE SHEET(RULE 26)
`
`AUROBINDOEx. 1002, 4
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`AUROBINDO EX. 1002, 4
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`

`

`WO 99/47125
`
`PCT/US99/06024
`
`antihyperglycemic 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 for
`an antihyperglycemic 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
`
`for an antihyperglycemic drug that can provide continuous
`
`10
`
`and
`
`non-pulsating
`
`therapeutic
`
`levels
`
`of
`
`an
`
`antihyperglycemic 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 the present invention to
`
`15
`
`provide a controlled or sustained release formulation for
`
`an antihyperglycemic drug that obtains peak plasma levels
`
`approximately 8-12 hours after administration.
`
`It is also an object of
`
`this invention to provide a
`
`controlled or
`
`sustained release pharmaceutical
`
`tablet
`
`20
`
`having only a homogeneous osmotic core wherein the osmotic
`core
`component may
`be made
`using
`ordinary
`tablet
`
`compression techniques.
`
`SUMMARY OF THE INVENTION
`
`25
`
`The
`
`foregoing objectives are met by a controlled
`
`release dosage form comprising:
`
`(a)
`
`a core comprising:
`
`(i)
`
`(ii)
`
`(iii)
`
`an antihyperglycemic drug;
`
`optionally a binding agent;
`
`and
`
`optionally an absorption enhancer;
`
`30
`
`(b) a semipermeable membrane coating surrounding the core;
`
`and
`
`(c) at least one passageway in the semipermeable membrane.
`
`The dosage form of
`
`the present
`
`invention can provide
`
`35
`
`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
`
`SUBSTITUTE SHEET (RULE 26)
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`

`

`WO 99/47125
`
`PCT/US99/06024
`
`the antihypoglycemic
`increase in the bioavailability of
`drug is observed when the controlled release dosage form of
`the present
`invention is administered with food.
`In a
`
`preferred embodiment,
`
`the dosage form will be administered
`
`once
`
`a
`
`day,
`
`ideally with or after
`
`a meal
`
`and most
`
`preferably with or after the evening meal,
`
`and provide
`
`therapeutic levels of the drug throughout the day with peak
`plasma
`levels being obtained between 8-12 hours after
`
`administration.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG.
`
`1
`
`ais
`
`a graph which depicts
`
`the dissolution
`
`profile in simulated intestinal fluid (pH 7.5 phosphate
`
`buffer)
`
`and
`
`simulated gastric
`
`fluid
`
`(SGF)
`
`of
`
`the
`
`formulation described in Example 1 as tested according to
`
`the procedure described in United States Pharmacopeia
`
`XXIII, Apparatus 2 @ 75 rpm.
`
`FIG.
`
`2
`
`is a graph which depicts
`
`the dissolution
`
`profile in simulated intestinal fluid (pH 7.5 phosphate
`
`buffer)
`
`and
`
`simulated gastric
`
`fluid
`
`(SGF)
`
`of
`
`the
`
`formulation described in Example 2 as tested according to
`
`the procedure described in United States Pharmacopeia
`
`XXIII, Apparatus 2 @ 75 rpm.
`
`FIG.
`
`3
`
`is a graph which depicts
`
`the dissolution
`
`profile in simulated intestinal
`
`fluid (pH 7.5 phosphate
`
`buffer)
`
`and
`
`simulated gastric
`
`fluid
`
`(SGF)
`
`of
`
`the
`
`formulation described in Example 3 as tested according to
`
`the procedure described in United States Pharmacopeia
`
`XXIII, Apparatus 2 @ 75 rpm.
`
`FIG.
`
`4
`
`is a graph depicting the in vivo metformin
`
`plasma profile of
`
`the formulation described in Example 1
`
`the
`of
`plasma profile
`vivo metformin
`in
`the
`and
`commercially available metformin HCl product GLUCOPHAGE®
`under fasting conditions.
`
`FIG.
`
`5
`
`is a graph depicting the in vivo metformin
`
`plasma profile of
`
`the formulation described in Example 2
`
`and
`
`the
`
`in
`
`vivo metformin
`
`plasma profile
`
`of
`
`the
`
`SUBSTITUTE SHEET (RULE 26)
`
`AUROBINDOEX. 1002. 6
`
`AUROBINDO EX. 1002, 6
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`

`

`WO 99/47125
`
`PCT/US99/06024
`
`commercially available metformin HCl product GLUCOPHAGE®
`
`under fasting conditions.
`
`FIG.
`
`6
`
`is a graph depicting the in vivo metformin
`
`the formulation described in Example 2
`plasma profile of
`and
`the
`in
`vivo metformin
`plasma profile
`of
`the
`commercially available metformin HCl product GLUCOPHAGE®
`
`under fed conditions.
`
`FIG.
`
`7
`
`is a graph depicting the in vivo metformin
`
`plasma profile of
`
`the formulation described in Example 3
`
`10
`
`the
`of
`plasma profile
`vivo metformin
`in
`the
`and
`commercially available metformin HCl product GLUCOPHAGE®
`
`under fed conditions (after breakfast).
`
`FIG.
`
`8
`
`is a graph depicting the in vivo metformin
`
`plasma profile of
`
`the formulation described in Example 3
`
`15
`
`the
`of
`plasma profile
`vivo metformin
`in
`the
`and
`commercially available metformin HCl product GLUCOPHAGE®
`
`under fed conditions (after dinner).
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`20
`
`The
`
`term antihyperglycemic drugs
`
`as used in this
`
`specification
`
`refers
`
`to
`
`drugs
`
`that
`
`are
`
`useful
`
`in
`
`controlling or managing noninsulin-dependent
`
`diabetes
`
`mellitus (NIDDM).
`
`Preferably,
`
`the antihyperglycemic drug
`
`is
`
`a biguanide
`
`such
`
`as metformin or buformin or
`
`a
`
`25
`
`pharmaceutically acceptable salt thereof such as metformin
`
`hydrochloride.
`
`The binding agent may be any conventionally known
`
`pharmaceutically
`
`acceptable
`
`binder
`
`such
`
`as
`
`polyvinyl
`
`pyrrolidone,
`
`hydroxypropyl
`
`cellulose,
`
`hydroxyethyl
`
`30
`
`cellulose, ethylcellulose, polymethacrylate, waxes and the
`like. Mixtures of
`the aforementioned binding agents may
`
`also be used.
`
`The preferred binding agents are water
`
`soluble such as polyvinyl pyrrolidone having a weight
`
`average molecular weight of 25,000 to 3,000,000.
`
`The
`
`35
`
`Dinding agent comprises approximately about
`
`0 to about 40%
`
`of the total weight of the core and preferably about
`
`3% to
`
`about 15% of the total weight of the core.
`
`SUBSTITUTE SHEET (RULE 26)
`
`AUROBINDOEX.1002, 7
`
`AUROBINDO EX. 1002, 7
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`

`

`WO 99/47125
`
`PCT/US99/06024
`
`absorption
`an
`core may optionally comprise
`The
`any type of
`The absorption enhancer
`can be
`enhancer.
`absorption enhancer commonly known in the art such as a
`fatty acid, a surfactant, a chelating agent, a bile salt or
`mixtures thereof.
`Examples of
`some preferred absorption
`enhancers are fatty acids such as capric acid, oleic acid
`and their monoglycerides, surfactants such as sodium lauryl
`sulfate,
`sodium taurocholate and polysorbate 80, chelating
`agents such as citric acid, phytic acid, ethylenediamine
`tetraacetic
`acid
`(EDTA)
`and
`ethylene
`glycol-bis(f8£-
`aminoethyl ether)-N,N,N,N-tetraacetic acid (EGTA).
`The
`
`the
`20% of
`to about
`approximately 0
`comprises
`core
`absorption enhancer based on the total weight of the core
`and most preferably about
`2% to about
`10% of
`the total
`
`10
`
`15
`
`weight of the core.
`
`The core of the present invention which comprises the
`antihyperglycemic drug,
`the binder which preferably is a
`pharmaceutically acceptable water soluble polymer and the
`absorption enhancer is preferably formed by wet granulating
`the core ingredients and compressing the granules with the
`addition of a lubricant
`into a tablet on a rotary press.
`The core may also be formed by dry granulating the core
`ingredients and compressing the granules with the addition
`of a lubricant into tablets or by direct compression.
`Other commonly known excipients may also be included
`into the core such as lubricants, pigments or dyes.
`The homogeneous core is coated with a semipermeable
`membrane, preferably a modified polymeric membrane to form
`the controlled release tablet of
`the invention.
`The
`
`semipermeable membrane is permeable to the passage of an
`external fluid such as water and biological fluids and is
`impermeable to the passage of the antihyperglycemic drug in
`the core. Materials
`that are useful
`in forming the
`semipermeable membrane are cellulose esters,
`cellulose
`diesters, cellulose triesters, cellulose ethers, cellulose
`ester-ether,
`cellulose
`acylate,
`cellulose
`diacylate,
`cellulose
`triacylate,
`cellulose
`acetate,
`cellulose
`
`20
`
`25
`
`30
`
`35
`
`6
`
`SUBSTITUTE SHEET (RULE 26)
`
`AUROBINDOEx. 1002, 8
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`AUROBINDO EX. 1002, 8
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`

`

`WO 99/47125
`
`PCT/US99/06024
`
`diacetate,
`
`cellulose
`
`triacetate,
`
`cellulose
`
`acetate
`
`propionate, and cellulose acetate butyrate. Other suitable
`
`polymers
`
`are described in United States Patent Nos.
`
`3,845,770,
`
`3,916,899, 4,008,719,
`
`4,036,228 and 4,11210
`
`which are
`
`incorporated herein by reference.
`
`The most
`
`preferred semipermeable membrane material
`
`is cellulose
`
`acetate comprising an acetyl content of 39.3 to 40.3%,
`
`commercially available from Eastman Fine Chemicals.
`
`In
`
`an
`
`alternative
`
`embodiment,
`
`the
`
`semipermeable
`
`10
`
`membrane can be formed from the above-described polymers
`and a
`flux enhancing agent.
`The
`flux enhancing agent
`
`increases the volume of
`
`fluid imbibed into the core to
`
`enable the dosage form to dispense substantially all of the
`
`antihyperglycemic drug through the passageway and/or the
`
`15
`
`porous membrane.
`
`The flux enhancing agent can be a water
`
`soluble material or an enteric material.
`
`Some examples of
`
`the preferred materials that are useful as flux enhancers
`
`are sodium chloride, potassium chloride, sucrose, sorbitol,
`
`mannitol, polyethylene glycol
`
`(PEG), propyiene glycol,
`
`20
`
`hydroxypropyl
`
`cellulose,
`
`hydroxypropyl methycellulose,
`
`hydroxypropyl methycellulose phthalate, cellulose acetate
`
`phthalate, polyvinyl alcohols, methacrylic acid copolymers
`
`and mixtures thereof.
`
`The preferred flux enhancer is PEG
`
`400.
`
`25
`
`The flux enhancer may also be a drug that
`
`is water
`
`soluble
`
`such
`
`as metformin
`
`oor
`
`its
`
`pharmaceutically
`
`acceptable salts or a drug that is soluble under intestinal
`
`conditions.
`
`Tf
`
`the flux enhancer is a drug,
`
`the present
`
`dosage
`
`form has
`
`the
`
`added advantage of providing an
`
`30
`
`immediate release of the drug which is selected as the flux
`
`enhancer.
`
`The flux enhancing agent comprises approximately 0 to
`
`about
`
`40% of
`
`the
`
`total weight
`
`of
`
`the coating, most
`
`preferably about 2% to about 20% of the total weight of the
`
`35
`
`coating.
`
`The
`
`flux enhancing agent dissolves or
`
`leaches
`
`from the semipermeable membrane
`
`to form paths
`
`in the
`
`SUBSTITUTE SHEET (RULE 26)
`
`AUROBINDOEx. 1002, 9
`
`AUROBINDO EX. 1002, 9
`
`

`

`WO 99/47125
`
`PCT/US99/06024
`
`semipermeable membrane for the fluid to enter the core and
`
`dissolve the active ingredient.
`
`The
`commonly
`
`semipermeable membrane may also be formed with
`known excipients
`such
`a plasticizer.
`Some
`
`azelate,
`commonly
`known plasticizers
`include
`adipate,
`triethyl
`enzoate, citrate, stearate,
`isoebucate, sebacate,
`Citrate,
`tri-n-butyl citrate, acetyl tri-n-butyl citrate,
`
`citric
`
`acid
`
`esters,
`
`and
`
`those
`
`described
`
`in
`
`the
`
`Encyclopedia of Polymer Science and Technology, Vol.
`
`10
`
`10
`
`The preferred
`(1969), published by John Wiley & Sons.
`plasticizers are triacetin, acetylated monoglyceride, grape
`seed oil, olive oil,
`sesame oil, acetyltributylcitrate,
`
`acetyltriethylcitrate, glycerin sorbitol, diethyloxalate,
`diethylmalate,
`diethylfumarate,
`dibutylsuccinate,
`
`15
`
`diethylmalonate,
`
`dioctylphthalate,
`
`dibutylsebacate,
`
`triethylcitrate, tributylcitrate, glyceroltributyrate, and
`
`the like. Depending on the particular plasticizer, amounts
`
`of
`
`from 0
`
`to about 25%, and preferably about
`
`2% to about
`
`15% of
`
`the plasticizer can be used based upon the total
`
`20
`
`weight of the coating.
`
`As
`
`used herein the
`
`term passageway
`
`includes
`
`an
`
`aperture, orifice, bore, hole, weaken area or an erodible
`
`element
`
`such as
`
`a gelatin plug that erodes
`
`to form an
`
`osmotic passageway for the release of the antihyperglycemic
`
`25
`
`drug from the dosage form.
`
`A detailed description of the
`
`passageway can be found in United States Patents such as
`
`3,845,770, 3,916,899, 4,034,758, 4,077,407, 4,783,337 and
`
`5,071,607.
`
`Generally,
`
`the membrane coating around the core will
`
`30
`
`comprise from about
`
`1% to about 5% and preferably about 2%
`
`to about
`
`3% based on the total weight of
`
`the core and
`
`coating.
`
`In an alternative embodiment,
`
`the dosage form of the
`
`present invention may also comprise an effective amount of
`
`35
`
`the antihyperglycemic drug that is available for immediate
`
`release.
`
`The effective amount of antihyperglycemic drug
`
`for immediate release may be coated onto the semipermeable
`
`SUBSTITUTE SHEET (RULE 26)
`
`AUROBINDO EX. 1002, 10
`
`AUROBINDO EX. 1002, 10
`
`

`

`WO 99/47125
`
`PCT/US99/06024
`
`membrane of the dosage form or it may be incorporated into
`the semipermeable membrane.
`
`In a preferred embodiment
`the following composition:
`
`the dosage form will have
`
`Preferred
`
`Most Preferred
`
`CORE:
`drug
`binder
`absorption enhancer
`
`COATING:
`semipermeable polymer
`flux enhancer
`plasticizer
`
`10
`
`15
`
`50-98%
`0-40%
`0-20%
`
`50-99%
`0-40%
`0-25%
`
`75-95%
`3-15%
`2-10%
`
`75-95%
`2-20%
`2-15%
`
`The dosage forms prepared according to the present
`invention should exhibit the following dissolution profile
`when tested in a USP type 2 apparatus at 75 rpms in 900 ml
`
`20
`
`of simulated intestinal fluid (pH 7.5 phosphate buffer) and
`
`at 37°C:
`
`Time (hours)
`2
`4
`8
`12
`16
`20
`
`25
`
`30
`
`Preferred
`
`Most Preferred
`
`0-25%
`10-45%
`30-90%
`NTL 50%
`NTL 60%
`NTL 70%
`
`0-15%
`20-40%
`45-90%
`NTL 60%
`NTL 70%
`NTL 80%
`
`NTL = NOT LESS THAN
`
`In the preparation of
`
`the tablets of
`
`the invention,
`
`various conventional well known solvents may be used to
`
`prepare the granules and apply the external coating to the
`
`35
`
`tablets of the invention.
`
`In addition, various diluents,
`
`lubricants, dyes, pigments, dispersants etc.
`excipients,
`which are disclosed in Remington’s Pharmaceutical Sciences,
`
`1995 Edition may be used to optimize the formulations of
`
`the invention.
`
`40
`
`DESCRIPTION OF THE PREFERRED EMBODIMENTS
`
`EXAMPLE 1
`
`SUBSTITUTE SHEET(RULE 26)
`
`AUROBINDOEX. 1002, 11
`
`AUROBINDO EX. 1002, 11
`
`

`

`WO 99/47125
`
`PCT/US99/06024
`
`A controlled release tablet containing 850 mg of
`
`metformin HCl and having the following formula is prepared
`
`as follows:
`
`
`
` I Core
`
`metformin HCl
`
`povidone’, USP
`
`sodium tribasic phosphate
`
`magnesium stearate
`
`10
`
`90.54%
`
`4.38%
`
`4.58%
`
`0.5 %
`
`‘approximate molecular weight
`
`= 50,000; dynamic viscosity
`
`(10%w/v solution at 20°C)
`
`= 5.5-8.5 m Pa s.
`
`(a) Granulation
`
`The metformin HCl is delumped by passing it through a
`
`15
`
`40 mesh screen and collecting it in a clean, polyethylene-
`
`lined container.
`
`The povidone, K-30, and sodium tribasic
`
`The delumped
`phosphate are dissolved in purified water.
`metformin HCl
`is then added to a top-spray fluidized bed
`granulator and granulated by spraying the binding solution
`of
`povidone
`and
`sodium tribasic phosphate
`under
`the
`following conditions:
`inlet air temperature of 50-70°C;
`atomization air pressure of 1-3 bars;
`and spray rate of
`
`10-100 ml/min.
`
`the granules
`Once the binding solution is depleted,
`are dried in the granulator until
`the loss on drying is
`less than 2%.
`The dried granules are passed through a
`
`Comil equipped with the equivalent of an 18 mesh screen.
`
`(b) Tableting
`
`20
`
`25
`
`The magnesium stearate is passed through a 40 mesh
`Stainless steel screen and blended with the metformin HCl
`
`30
`
`After
`(5) minutes.
`approximately five
`for
`granules
`the granules are compressed on a rotary press
`blending,
`fitted with 15/32" round standard concave punches
`(plain
`
`lower punch,
`
`upper punch with an approximately 1
`
`mm
`
`35
`
`indentation pin).
`
`(c)
`
`Seal Coating (optional)
`
`10
`
`SUBSTITUTE SHEET(RULE 26)
`
`AUROBINDO Ex. 1002, 12
`
`AUROBINDO EX. 1002, 12
`
`

`

`WO 99/47125
`
`PCT/US99/06024
`
`The core tablet is seal coated with an Opadry material
`other
`suitable water-soluble material
`by
`first
`or
`dissolving the Opadry material, preferably Opadry Clear,
`in
`purified water.
`The Opadry solution is then sprayed onto
`the core tablet using a pan coater under
`the following
`conditions:
`exhaust
`air
`temperature
`of
`38-42°C;
`
`and spay rate of 10-15
`atomization pressure of 28-40 psi;
`mi/min.
`The
`core
`tablet
`is
`coated with the
`sealing
`solution until a theoretical coating level of approximately
`2% is obtained.
`
`10
`
`II
`
`Sustained Release Coating
`
`cellulose acetate (398-10)?
`
`triacetin
`
`15
`
`PEG 400
`
`85%
`
`5%
`
`10%
`
`“acetyl content 39.3 - 40.3%
`
`(d) Sustained Release Coating
`
`20
`
`The cellulose acetate is dissolved in acetone while
`
`stirring with a homogenizer.
`
`The polyethylene glycol 400
`
`and triacetin are added to the cellulose acetate solution
`
`and stirred until a clear solution is obtained.
`
`The clear
`
`coating solution is then sprayed onto the seal coated
`
`25
`
`tablets in a fluidized bed coater employing the following
`
`30
`
`35
`
`conditions:
`
`product
`
`temperature of 16-22°C;
`
`atomization
`
`pressure of approximately 3 bars;
`
`and spray rate of 120-
`
`150 ml/min.
`
`The sealed core tablet
`
`is coated until
`
`a
`
`theoretical coating level of approximately 3% is obtained.
`
`The resulting tablet is tested in simulated intestinal
`
`fluid (pH 7.5) and simulated gastric fluid (SGF) according
`
`to the procedure described in United States Pharmacopeia
`
`XXIII, Apparatus 2 @ 75 rpm and found to have the following
`
`release profile:
`
`TIME (hours)
`2
`4
`8
`12
`
`% Released (SGF)
`9
`27
`62
`82
`
`% Released H7.5
`12
`32
`82
`100
`
`11
`
`SUBSTITUTE SHEET (RULE 26)
`
`AUROBINDOEX. 1002, 13
`
`AUROBINDO EX. 1002, 13
`
`

`

`WO 99/47125
`
`16
`20
`
`PCT/US99/06024
`
`88
`92
`
`105
`108
`
`The release profile in pH 7.5 and SGF of the sustained
`
`release product prepared in this Example is shown in Figure
`1.
`
`Figure 4 depicts the in vivo metformin plasma profile
`
`of the sustained release product prepared in this Example.
`
`is the in vivo metformin plasma
`Also shown in Figure 4
`profile
`of
`GLUCOPHAGE®,
`a
`commercially
`available
`pharmaceutical product containing the drug metformin HCl.
`
`10
`
`A controlled release tablet containing 850 mg of
`
`metformin HCl and having the following formula is prepared
`
`EXAMPLE 2
`
`15
`
`as follows:
`
`I
`
`Core
`
`metformin HCl
`
`povidone’, USP
`
`sodium lauryl sulfate
`
`20
`
`magnesium stearate
`
`88.555%
`
`6.368%
`
`4.577%
`
`0.5
`
`%
`
`7approximate molecular weight = 1,000,000, dynamic viscosity
`(1lO%w/v solution at 20°C)
`= 300-700 m Pa s.
`
`12
`
`SUBSTITUTE SHEET (RULE 26)
`
`AUROBINDO EX. 1002. 14
`
`AUROBINDO EX. 1002, 14
`
`

`

`WO 99/47125
`
`PCT/US99/06024
`
`(a) Granulation
`
`The metformin HCl
`
`and sodium lauryl
`
`sulfate are
`
`delumped by passing them through a
`
`40 mesh screen and
`
`collecting them in a clean, polyethylene-lined container.
`
`The povidone, K-90F,
`
`is dissolved in purified water.
`
`The
`
`delumped metformin HCl and sodium lauryl sulfate are then
`
`added
`
`to
`
`a
`
`top-spray
`
`fluidized bed granulator
`
`and
`
`granulated by
`
`spraying with the binding solution of
`
`povidone
`
`under
`
`the
`
`following
`
`conditions:
`
`inlet
`
`air
`
`10
`
`atomization air pressure of 1-3
`temperature of 50-70°C;
`bars;
`and spray rate of 10-100 ml/min.
`
`Once the binding solution is depleted,
`
`the granules
`
`are dried in the granulator until
`
`the loss on drying is
`
`less than 2%.
`The dried granules are passed through a
`Comil equipped with the equivalent of an 18 mesh screen.
`(b) Tableting
`
`The magnesium stearate is passed through a 40 mesh
`
`stainless steel screen and blended with the metformin HCl
`
`granules
`
`for
`
`approximately five
`
`(5) minutes.
`
`After
`
`the coated granules are compressed on a rotary
`blending,
`press fitted with 15/32"
`round standard concave punches
`(plain lower punch, upper punch with an approximately 1 mm
`
`15
`
`20
`
`indentation pin).
`
`(c)
`
`Seal Coating (optional)
`
`25
`
`The core tablet is seal coated with an Opadry material
`
`or
`
`other
`
`suitable water-soluble material
`
`by
`
`first
`
`dissolving the Opadry material, preferably Opadry Clear in
`purified water.
`The Opadry solution is then sprayed onto
`the core tablet using a pan coater under
`the following
`
`30
`
`conditions:
`
`exhaust
`
`air
`
`temperature
`
`of
`
`38-42°C;
`
`and spay rate of 10-15
`atomization pressure of 28-40 psi;
`mi/min.
`The
`core
`tablet
`is
`coated with the sealing
`
`solution until a theoretical coating level of approximately
`
`2% is obtained.
`
`35
`
`13
`
`SUBSTITUTE SHEET(RULE 26)
`
`AUROBINDO EX. 1002, 15
`
`AUROBINDO EX. 1002, 15
`
`

`

`WO 99/47125
`
`PCT/US99/06024
`
`II
`
`Sustained Release Coating
`
`cellulose acetate (398-10)?
`
`triacetin
`
`PEG 400
`
`85%
`
`5%
`
`10%
`
`facetyl content 39.3 - 40.3%
`
`(d) Sustained Release Coating
`
`The cellulose acetate is dissolved in acetone while
`
`stirring with a homogenizer.
`
`The polyethylene glycol 400
`
`10
`
`and triacetin are added to the cellulose acetate solution
`
`and stirred until a clear solution is obtained.
`
`The clear
`
`coating solution is then sprayed onto the seal coated
`
`tablets in a fluidized bed coater employing the following
`conditions:
`product
`temperature of 16-22°C;
`atomization
`
`15
`
`pressure of approximately 3 bars;
`
`and spray rate of 120-
`
`150 ml/min.
`
`The sealed core tablet
`
`is coated until
`
`a
`
`theoretical coating level of approximately 3% is obtained.
`
`The resulting tablet is tested in simulated intestinal
`
`fluid (pH 7.5) and simulated gastric fluid (SGF) according
`
`20
`
`to the procedure described in United States Pharmacopeia
`
`XXIII, Apparatus 2 @ 75 rpm and found to have the following
`
`25
`
`30
`
`35
`
`release profile:
`
`TIME (hours)
`2
`4
`8
`12
`16
`20
`
`% Released (SGF)
`13
`29
`55
`72
`81
`87
`
`% Released H7.5
`12
`27
`52
`71
`83
`91
`
`The release profile in pH 7.5 and SGF of the sustained
`
`release product prepared in this Example is shown in Figure
`
`2.
`
`Figure 5 depicts the in vivo metformin plasma profile
`
`of the sustained release product prepared in this Example
`
`under fasting conditions. Figure 5 also shows the in vivo
`metformin plasma profile of the GLUCOPHAGE® product under
`fasting conditions.
`
`Figure 6 depicts the in vivo metformin plasma profile
`
`of the sustained release product prepared in this Example
`
`14
`
`SUBSTITUTE SHEET (RULE 26)
`
`AUROBINDO EX. 1002, 16
`
`AUROBINDO EX. 1002, 16
`
`

`

`WO99/47125
`
`PCT/US99/06024
`
`the in vivo
`Figure 6 also shows
`fed conditions.
`under
`metformin plasma profile of
`the GLUCOPHAGE® product under
`fed conditions.
`
`Figures S and 6 clearly show that
`
`the dosage forms
`
`prepared in accordance with the present
`
`invention exhibit
`
`fasting
`consistent bioavailability under both fed and
`conditions while the GLUOPHAGE® product’s bioavailability
`decreases in the presence of food.
`
`10
`
`EXAMPLE 3
`
`A controlled release tablet containing 850 mg of
`
`metformin HCl and having the same formula as in Example 2
`
`1s prepared as described in Example
`
`2 except
`
`that
`
`an
`
`additional hole was drilled on the plain side of the coated
`
`15
`
`tablet.
`
`The
`
`additional
`
`hole
`
`had
`
`a
`
`diameter
`
`of
`
`approximately 1 mm.
`
`The resulting tablet is tested in simulated intestinal
`
`fluid (pH 7.5) and simulated gastric fluid (SGF) according
`
`to the procedure described in United States Pharmacopeia
`
`20
`
`XXIII, Apparatus 2 @ 75 rpm and found to have the following
`
`release profile:
`
`25
`
`TIME (hours)
`2
`4
`8
`12
`16
`20
`
`% Released (SGF)
`13
`27
`50
`67
`84
`97
`
`% Released H7.5
`14
`28
`63
`84
`95
`102
`
`The release profile in pH 7.5 and SGF of the sustained
`
`30
`
`release product prepared in this Example is shown in Figure
`3.
`
`Figure 7 depicts the in vivo metformin plasma profile
`
`of the sustained release product prepared in this Example
`
`when administered shortly after breakfast.
`
`Figure 7 also
`
`35
`
`the
`of
`plasma profile
`in vivo metformin
`the
`shows
`GLUCOPHAGE® product administered shortly after breakfast.
`Figure 8 depicts the in vivo metformin plasma profile
`
`of the sustained release product prepared in this Example
`
`when administered shortly after dinner.
`
`Figure 8 also
`
`15
`
`SUBSTITUTE SHEET (RULE 26)
`
`AUROBINDOEX. 1002, 17
`
`AUROBINDO EX. 1002, 17
`
`

`

`WO 99/47125
`
`PCT/US99/06024
`
`of
`plasma profile
`in vivo metformin
`the
`shows
`GLUCOPHAGE® product administered shortly after dinner.
`Table
`1
`is
`a
`summary
`of
`the
`bioavailability
`comparision data, test/reference ratio, shown in Figures 4-
`8 wherein the GLUCOPHAGE® product is the reference product
`in a two way crossover biostudy with n = 6.
`
`the
`
`Formula
`
`Figure
`
`Study
`
`TABLE 1
`
`Tmax
`
`2.15
`
`1.73
`
`1.94
`
`1.82
`
`2.00
`
`10
`
`Ex.
`
`Ex.
`
`Ex.
`
`Ex.
`
`Ex.
`
`1
`
`2
`
`2
`
`3
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`bkft = breakfast
`
`Fasting
`
`Fasting
`
`Fed (bkft)
`
`AUC
`
`0,202
`
`0.369
`
`0.628
`
`
`Cmax
`
`0.12
`
`0.214
`
`0.305
`
`Fed (bkft)
`
`0.797
`
`0.528
`
`Fed (dinner)
`
`0.850
`
`0.751
`
`15
`
`The results reported in Table 1 and Figures 4-8 show
`
`that dosage forms prepared in accordance with the present
`invention exhibit an increase in the bioavailability of the
`antihyperglycemic drug in the presence of food, especially
`when taken with or shortly after the evening meal.
`
`20
`
`While certain preferred and alternative embodiments of
`
`of
`forth for purposes
`set
`been
`invention have
`the
`disclosing the invention, modifications to the disclosed
`
`embodiments may occur to those who are skilled in the art.
`
`Accordingly,
`
`the appended claims are intended to cover all
`
`25
`
`embodiments of
`
`the invention and modifications
`
`thereof
`
`which do not depart
`
`from the spirit
`
`and scope of
`
`the
`
`invention.
`
`16
`
`AUROBINDO EX. 1002, 18
`
`

`

`WO 99/47125
`
`We claim:
`
`PCT/US99/06024
`
`1.
`
`(a)
`
`(b)
`
`A controlled release pharmaceutical tablet comprising:
`
`a core comprising:
`
`an antihyperglycemic drug;
`(1)
`and
`optionally a binding agent;
`(ii)
`optionally an absorption enhancer; and
`(iii)
`a semipermeable membrane coating covering said core;
`
`10
`
`(c)
`
`at least one passageway in the semipermeable membrane.
`
`A controlled release pharmaceutical tablet as defined
`2.
`in claim 1 wherein the
`antihyperglycemic
`drug
`is
`a
`
`biguanide.
`
`A controlled release p