US006099859A
`6,099,859
`(114) Patent Number:
`United States Patent 55
`Chenget al.
`[45] Date of Patent:
`Aug. 8, 2000
`
`
`[54] CONTROLLED RELEASE ORAL TABLET
`HAVING A UNITARY CORE
`
`[75]
`
`Inventors: Xiu Xiu Cheng; Chih-Ming Chen,
`both of Davie; Steve Jan; Joseph
`Chou, both of Coral Springs, all of Fla
`;
`Prings,
`.
`.
`[73] Assignee: Andrx Pharmaceuticals, Inc., Fort
`Lauderdale, Fla.
`
`.
`
`[21] Appl. No.: 09/045,330
`
`[22]
`
`Filed:
`
`Mar. 20, 1998
`
`4
`Tmt, Cenc ec eeeceeeeeeeeeeneensenenseenees A61K 9/22
`(SL)
`[52] U.S. Cheee 424/464; 424/469; 424/484;
`424/468; 424/489
`[58] Field of Search occ 424/464, 489,
`424/450, 456
`
`[56]
`
`.
`References Cited
`U.S. PATENT DOCUMENTS
`
`.
`
`10/1990 Eckenhoff .
`4,963,141
`6/1991 Kuczynskietal. .
`5,024,843
`5,071,607 12/1991 Ayeretal. .
`5,091,190
`2/1992 Kuczynskiet al.
`5,110,597
`5/1992 Wongetal. .
`5,120,548
`6/1992 McClelland etal. .
`5,141,752
`8/1992 Ayeret al.
`.
`5,178,867
`1/1993 Guittard etal. .
`5,185,158
`2/1993 Ayeret al.
`.
`5,308,348
`5/1994 Balaban etal. .
`5,413,572
`5/1995 Wong etal. .
`5,512,293
`4/1996 Landrauetal. .
`5,543,156
`8/1996 Roorda et al.
`.
`5,545,413
`8/1996 Kuczynskietal. .
`5,591,454
`1/1997 Kuczynskiet al.
`.
`5,614,578
`3/1997 Dongetal. .
`5,629,319
`5/1997 Luoetal. .
`5,631,224
`5/1997 Efendic etal. .
`oe ji1007 wright ct al
`067,
`ong et al.
`.
`5,668,117
`9/1997 Shapiro .
`5,674,900 10/1997 Ubillaset al.
`5,688,518 11/1997 Ayeret al.
`.
`5,691,386
`11/1997 Inman etal. .
`5,858,398
`1/1999 ChO veecccccsscsssssssssssevseseesesseeeeeee 424/450
`
`.
`
`11/1974 Theeuwesetal. .
`3,845,770
`11/1975 Theeuwesetal. .
`3,916,899
`4/1976 Baker.
`3,952,741
`5/1976 Bohuon.
`3,957,853
`7/1977 Theeuwes .
`4,034,758
`3/1978 Theeuwesetal. .
`4,077,407
`3/1978 Bohoun.
`4,080,472
`6/1985 Edgren.
`4,522,625
`5/1986 Edgrenetal. .
`4,587,117
`9/1986 Ayer .
`4,609,374
`9/1986 Wongetal. .
`4,612,008
`4,615,698 10/1986 Guittard et al.
`4,624,847
`11/1986 Ayeretal. .
`.
`4,627,850 12/1986 Deterset al.
`4,692,336
`9/1987 Eckenhoff etal. .
`4,704,118
`11/1987 Eckenhoff .
`4,777,049
`10/1988 Magruderetal. .
`4,851,229
`7/1989 Magruderetal. .
`4,865,598
`9/1989 Eckenhoff .
`4,892,739
`1/1990 Shahetal. .
`
`.
`
`FOREIGN PATENT DOCUMENTS
`
`9608243
`
`3/1996 WIPO.
`
`Primary Examiner—Thurman K. Page
`Assistant Examiner—William E. Benston,Jr.
`Attorney, Agent, or Firm—Hedman, Gibson & Costigan,
`PC
`—
`[57]
`
`ABSTRACT
`
`A controlled release antihyperglycemic tablet that does not
`contain an expanding polymer and comprising a core con-
`taining the antihyperglycemic drug, a semipermeable mem-
`brane coating the core and at least one passageway in the
`membrane
`,
`
`29 Claims, 8 Drawing Sheets
`
`Metformin HCL Tablets, 850mg
`Lot# P97444A
`
`8
`12
`10
`Dissolution Time (Hr)
`-e-SGF
`-= pH 7.5 (SIF)
`
`14
`
`16
`
`18
`
`20
`
`AUROBINDO EX1004, 1
`
`(%) ao
`
`100
`
`80
`
`Amount 69
`Dissolved
`
`2
`
`4
`
`6
`
`AUROBINDO EX1004, 1
`
`

`

`Aug. 8, 2000
`
`Sheet 1 of 8
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`6,099,859
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`U.S. Patent
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`Aug. 8, 2000
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`Aug. 8, 2000
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`Aug. 8, 2000
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`Aug. 8, 2000
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`U.S. Patent
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`Aug. 8, 2000
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`6,099,859
`
`1
`CONTROLLED RELEASE ORAL TABLET
`HAVING A UNITARY CORE
`
`BACKGROUND OF THE INVENTION
`
`The present invention relates to controlled release unit
`dose formulations containing an antihyperglycemic drug.
`Morespecifically, the present invention relates to an oral
`dosage form comprising a biguanide such as metformin or
`buformin or a pharmaceutically acceptable salt thereof such
`as metformin hydrochloride or the metformin salts described
`in USS. Pat. Nos. 3,957,853 and 4,080,472 which are incor-
`porated herein by reference.
`In the prior art, many techniques have been used to
`provide controlled and extended-release pharmaceutical
`dosage forms in order to maintain therapeutic serum levels
`of medicaments and to minimize the effects of missed doses
`
`of drugs caused by a lack of patient compliance.
`In the priorart are extended release tablets which have an
`osmotically active drug core surrounded by a semipermeable
`membrane. These tablets function by allowing a fluid such
`as gastric or intestinal fluid to permeate the coating mem-
`brane and dissolve the active ingredient so it can be released
`through a passageway in the coating membraneor if the
`active ingredientis insoluble in the permeating fluid, pushed
`through the passageway by an expanding agent such as a
`hydrogel. Some representative examples of these osmotic
`tablet systems can be found in U.S. Pat. Nos. 3,845,770,
`3,916,899, 4,034,758, 4,077,407 and 4,783,337. U.S. Pat.
`No. 3,952,741 teaches an osmotic device wherein the active
`agent is released from a core surrounded by a semiperme-
`able membraneonly after sufficient pressure has developed
`within the membraneto burst or rupture the membraneat a
`weak portion of the membrane.
`The basic osmotic device described in the above cited
`patents have been refined over time in an effort to provide
`greater control of the release of the active ingredient. For
`example U\S. Pat. Nos. 4,777,049 and 4,851,229 describe an
`osmotic dosage form comprising a semipermeable wall
`surrounding a core. The core contains an active ingredient
`and a modulating agent wherein the modulating agent causes
`the active ingredient to be released through a passageway in
`the semipermeable membrane in a pulsed manner. Further
`refinements have included modifications to the semiperme-
`able membrane surrounding the active core such as varying
`the proportions of the components that form the membrane,
`Le U.S. Pat. Nos. 5,178,867, 4,587,117 and 4,522,625 or
`increasing the number of coatings surrounding the active
`core, i.e U.S. Pat. Nos. 5,650,170 and 4,892,739.
`Although vast amounts of research has been performed on
`controlled or sustained release compositions and in particu-
`lar on osmotic dosage forms, very little research has been
`performed in the area of controlled or sustained release
`compositions that employ antihyperglycemic drugs.
`The limited work on controlled or sustained release
`formulations that employ antihyperglycemic drugs such as
`metformin hydrochloride has been limited to the combina-
`tion of the antihyperglycemic drug and an expanding or
`gelling agent to control the release of the drug from the
`dosage form. This limited research is exemplified by the
`teachings of WO 96/08243 and by the GLUCOPHAGE®
`product which is a commercially available product from
`Bristol-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
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`decrease is shown by approximately a 40% lower peak
`concentration and a 25% lower AUC in plasma and a 35
`minute prolongation of time to peak plasma concentration
`following administration of a single GLUCOPHAGE®tab-
`let containing 850 mg of metformin HCI with food com-
`pared to the similar tablet administered under fasting con-
`ditions.
`
`invention to provide a
`is an object of the present
`It
`controlled or sustained release formulation for an antihy-
`perglycemic 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 antihy-
`perglycemic drug that does not employ an expanding poly-
`mer.
`
`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 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.
`invention to
`It
`is an additional object of the present
`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 having only a
`homogeneous osmotic core wherein the osmotic core com-
`ponent may be made using ordinary tablet compression
`techniques.
`
`SUMMARYOF THE INVENTION
`
`The foregoing objectives are met by a controlled release
`dosage form comprising:
`(a) a core comprising:
`(i) an antihyperglycemic drug;
`(ii) optionally a binding agent; and
`(iii) optionally an absorption enhancer;
`(b) a semipermeable membrane coating surrounding the
`core; and
`(c) at least one passageway in the semipermeable mem-
`brane.
`
`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 antihypoglycemic 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 mostpreferably 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 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 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.
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`AUROBINDO EX1004, 10
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`6,099,859
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`3
`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 and the in
`vivo metformin plasmaprofile of the 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 plasmaprofile of the commercially available
`metformin HCl product GLUCOPHAGE® under fasting
`conditions.
`
`FIG. 6 is a graph depicting the in vivo metformin plasma
`profile of the formulation described in Example 2 and the in
`vivo metformin plasmaprofile of the commercially available
`metformin HCl product GLUCOPHAGE® under fed con-
`ditions.
`
`FIG. 7 is a graph depicting the in vivo metformin plasma
`profile of the formulation described in Example 3 and the in
`vivo metformin plasmaprofile of the commercially available
`metformin HCl product GLUCOPHAGE® under fed con-
`ditions (after breakfast).
`FIG. 8 is a graph depicting the in vivo metformin plasma
`profile of the formulation described in Example 3 and the in
`vivo metformin plasmaprofile of the commercially available
`metformin HCl product GLUCOPHAGE® under fed con-
`ditions (after dinner).
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`The term antihyperglycemic drugs as used in this speci-
`fication refers to drugs that are useful in controlling or
`managing noninsulin-dependent diabetes mellitus
`(NIDDM). Preferably, the antihyperglycemic drugis a bigu-
`anide such as metformin or buformin or a 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
`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 binding agent
`comprises approximately about 0 to about 40% ofthe total
`weightof the core and preferably about 3% to about 15% of
`the total weight of the core.
`The core may optionally comprise an absorption
`enhancer. The absorption enhancer can be any type of
`absorption enhancer commonly known in the art such as a
`fatty acid, a surfactant, a chelating agent, a bile salt or
`mixtures thereof. Examples of some preferred absorption
`enhancers are fatty acids such as capric acid, oleic acid and
`their monoglycerides, surfactants such as sodium lauryl
`sulfate, sodium taurocholate and polysorbate 80, chelating
`agents such as citric acid, phytic acid, ethylenediamine
`tetraacetic acid (EDTA) and ethylene glycol-bis(p-
`aminoethyl ether)-N,N,N,N-tetraacetic acid (EGTA). The
`core comprises approximately 0 to about 20% of the absorp-
`tion enhancerbased onthe total weight of the core and most
`preferably about 2% to about 10% of the total weight of the
`core.
`
`The core of the present invention which comprises the
`antihyperglycemic drug, the binder which preferably is a
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`pharmaceutically acceptable water soluble polymer and the
`absorption enhanceris 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 knownexcipients may also be included
`into the core such as lubricants, pigments or dyes.
`The homogeneouscore is coated with a semipermeable
`membrane, preferably a modified polymeric membrane to
`form the controlled release tablet of the invention. The
`semipermeable membraneis 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 semi-
`permeable membraneare cellulose esters, cellulose diesters,
`cellulose triesters, cellulose ethers, cellulose ester-ether,
`cellulose acylate, cellulose diacylate, cellulose triacylate,
`cellulose acetate, cellulose diacetate, cellulose triacetate,
`cellulose acetate propionate, and cellulose acetate butyrate.
`Other suitable polymers are described in U.S. Pat. Nos.
`3,845,770, 3,916,899, 4,008,719, 4,036,228 and 4,612,008
`which are incorporated herein by reference. The most pre-
`ferred 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 mem-
`brane 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 antihyper-
`glycemic drug through the passageway and/or the porous
`membrane. Theflux enhancing agent can be a water soluble
`material or an enteric material. Some examples of the
`preferred materials that are useful as flux enhancers are
`sodium chloride, potassium chloride, sucrose, sorbitol,
`mannitol, polyethylene glycol (PEG), propylene glycol,
`hydroxypropyl cellulose, hydroxypropyl methycellulose,
`hydroxypropyl methycellulose phthalate, cellulose acetate
`phthalate, polyvinyl alcohols, methacrylic acid copolymers
`and mixtures thereof. The preferred flux enhancer is PEG
`400.
`
`The flux enhancer mayalso be a drugthat is water soluble
`such as metforminorits pharmaceutically acceptable salts or
`a drug that is soluble under intestinal conditions. If the flux
`enhanceris a drug, the present dosage form has the added
`advantage of providing an 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 weightof the coating, most preferably
`about 2% to about 20% of the total weight of the coating.
`The flux enhancing agent dissolves or leaches from the
`semipermeable membrane to form paths in the semiperme-
`able membraneforthe fluid to enter the core and dissolve the
`
`active ingredient.
`The semipermeable membrane may also be formed with
`commonly knownexcipients such a plasticizer. Some com-
`monly knownplasticizers include adipate, azelate, enzoate,
`citrate, stearate, isoebucate, sebacate, triethyl citrate, tri-n-
`butyl citrate, acetyl tri-n-butyl citrate, citric acid esters, and
`those described in the Encyclopedia of Polymer Science and
`Technology, Vol. 10 (1969), published by John Wiley &
`Sons. The preferred plasticizers are triacetin, acetylated
`monoglyceride, grape seed oil, olive oil, sesame oil,
`acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol,
`
`AUROBINDO EX1004, 11
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`6,099,859
`
`5
`diethyloxalate, diethylmalate, diethylfumarate,
`dibutylsuccinate, diethylmalonate, dioctylphthalate,
`dibutylsebacate,
`triethylcitrate,
`tributylcitrate,
`glyceroltributyrate, and the like. Depending onthe 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 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 drug from the
`dosage form. A detailed description of the
`II Sustained Release Coating passageway can be found in
`U.S. Pat. Nos. 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
`comprise from about 1% to about 5% and preferably about
`2% to about 3% based on the total weight of the core and
`coating.
`the dosage form of the
`In an alternative embodiment,
`present invention may also comprise an effective amount of
`the antihyperglycemic drug that is available for immediate
`release. The effective amount of antihyperglycemic drug for
`immediate release may be coated onto the semipermeable
`membraneof the dosage form or it may be incorporated into
`the semipermeable membrane.
`In a preferred embodiment the dosage form will have the
`following composition:
`
`
`CORE:
`
`drug
`binder
`absorption enhancer
`COATING:
`
`semipermeable polymer
`flux enhancer
`plasticizer
`
`Preferred
`
`Most Preferred
`
`50-98%
`040%
`0-20%
`
`50-99%
`040%
`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
`whentested in a USP type 2 apparatus at 75 rpms in 900 ml
`of simulated intestinal fluid (pH 7.5 phosphate buffer) and at
`37° C.:
`
`Time (hours)
`2
`4
`8
`12
`16
`20
`
`Preferred
`0-25%
`10-45%
`30-90%
`NTL 50%
`NTL 60%
`NTL 70%
`
`Most Preferred
`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 tablets of
`the invention.
`In addition, various diluents, excipients,
`lubricants, dyes, pigments, dispersants etc. which are dis-
`closed in Remington’s Pharmaceutical Sciences, 1995 Edi-
`tion may be used to optimize the formulations of the
`invention.
`
`6
`DESCRIPTION OF THE PREFERRED
`EMBODIMENTS
`
`EXAMPLE1
`
`A controlled release tablet containing 850 mg of met-
`formin HC] and having the following formula is prepared as
`follows:
`
`I Core
`
`metformin HCl
`povidone*, USP
`sodium tribasic phosphate
`magnesium stearate
`
`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 Pas.
`
`(a) Granulation
`The metformin HCl is delumped by passing it through a
`40 mesh screen and collecting it in a clean, polyethylene-
`lined container. The povidone, K-30, and sodium tribasic
`phosphate are dissolved in purified water. The delumped
`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 fol-
`lowing conditions: inlet air temperature of 50-70° C.; atomi-
`zation air pressure of 1-3 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 meshscreen.
`(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 blending,
`the granules are compressed on a rotary press fitted with
`15/32" round standard concave punches(plain lower punch,
`upper punch with an approximately 1 mm indentation pin).
`(c) Seal Coating (optional)
`The core tablet is seal coated with an Opadry material or
`other suitable water-soluble material by first dissolving the
`opadry material, preferably Opadry Clear, in purified water.
`The Opadry solution is then sprayed onto the core tablet
`using a pan coater under the following conditions: exhaust
`air temperature of 38-42° C.; atomization pressure of 28-40
`psi; and spay rate of 10-15 ml/min. Thecoretablet is coated
`with the sealing solution until a theoretical coating level of
`approximately 2% is obtained.
`
`II Sustained Release Coating
`
`cellulose acetate (398-10)?
`triacetin
`PEG 400
`
`85%
`5%
`10%
`
`acetyl content 39.3-40.3%
`
`(d) Sustained Release Coating
`The cellulose acetate is dissolved in acetone whilestirring
`with a homogenizer. The polyethylene glycol 400 andtri-
`acetin are added to the cellulose acetate solution andstirred
`
`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 tem-
`
`10
`
`15
`
`20
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`AUROBINDO EX1004, 12
`
`AUROBINDO EX1004, 12
`
`

`

`6,099,859
`
`7
`perature of 16-22° C.; atomization pressure of approxi-
`mately 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
`16
`20
`
`% Released (SGF)
`9
`27
`62
`82
`88
`92
`
`% Released (pH 7.5)
`12
`32
`82
`100
`105
`108
`
`The release profile in pH 7.5 and SGFof the sustained
`ease product prepared in this Example is shown in FIG. 1.
`FIG. 4 depicts the in vivo metformin plasmaprofile the
`sustained release product prepared in this Example. Also
`shownin FIG. 4 is the in vivo metformin plasmaprofile of
`GLUCOPHAGE®,a commercially available pharmaceuti-
`cal product containing the drug metformin HCl.
`
`EXAMPLE 2
`
`A controlled release tablet containing 850 mg of met-
`formin HCI and having the following formula is prepared as
`follows:
`
`I Core
`
`metformin HCl
`povidone®, USP
`sodium lauryl sulfate
`magnesium stearate
`
`88.555%
`6.368%
`4.577%
`0.5%
`
`Sapproximate molecular weight = 1,000,000, dynamic viscosity (10% w/v
`solution at 20° C.) = 300-700 m Pa s.
`
`(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 underthe
`following conditions:
`inlet air temperature of 50-70° C.;
`atomization air pressure of 1-3 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 meshscreen.
`(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 blending,
`the coated granules are compressed on a rotary pressfitted
`with 15/32" round standard concave punches(plain lower
`punch, upper punch with an approximately 1 mm indenta-
`tion pin).
`
`8
`(c) Seal Coating (optional)
`The core tablet is seal coated with an Opadry material or
`other suitable water-soluble material by first dissolving the
`Opadry material, preferably Opadry Clear in purified water.
`The Opadry solution is then sprayed onto the core tablet
`using a pan coater under the following conditions: exhaust
`air temperature of 38-42° C.; atomization pressure of 28-40
`psi; and spay rate of 10-15 ml/min. Thecoretablet is coated
`with the sealing solution until a theoretical coating level of
`approximately 2% is obtained.
`
`II Sustained Release Coating
`
`cellulose acetate (398-10)*
`triacetin
`PEG 400
`
`85%
`5%
`10%
`
`‘acetyl content 39.3-40.3%
`
`(d) Sustained Release Coating
`The cellulose acetate is dissolved in acetone whilestirring
`with a homogenizer. The polyethylene glycol 400 andtri-
`acetin are added to the cellulose acetate solution andstirred
`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 tem-
`perature of 16-22° C.; atomization pressure of approxi-
`mately 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
`16
`20
`
`% Released (SGF)
`13
`29
`55
`72
`81
`87
`
`% Released (pH 7.5)
`12
`27
`52
`71
`83
`91
`
`The release profile in pH 7.5 and SGFof the sustained
`release product prepared in this Example is shown in FIG.
`2.
`
`FIG. 5 depicts the in vivo metformin plasmaprofile of the
`sustained release product prepared in this Example under
`fasting conditions. FIG. 5 also showsthe in vivo metformin
`plasmaprofile of the GLUCOPHAGE®product underfast-
`ing conditions.
`FIG. 6 depicts the in vivo metformin plasmaprofile of the
`sustained release product prepared in this Example under fed
`conditions. FIG. 6 also showsthe in vivo metformin plasma
`profile of the GLUCOPHAGE®product under fed condi-
`tions.
`
`FIGS. 5 and 6 clearly show that the dosage forms pre-
`pared in accordance with the present
`invention exhibit
`consistent bioavailability under both fed and fasting condi-
`tions while the GLUOPHAGE® product’s bioavailability
`decreases in the presence of food.
`EXAMPLE3
`
`A controlled release tablet containing 850 mg of met-
`formin HC] and having the same formula as in Example 2 is
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`55
`
`60
`
`65
`
`AUROBINDO EX1004, 13
`
`AUROBINDO EX1004, 13
`
`

`

`6,099,859
`
`9
`prepared as described in Example 2 except that an additional
`hole was drilled on the plain side of the coated 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 XXIII,
`Apparatus 2@75 rpm and found to have the following
`release profile:
`
`TIME(hours)
`2
`4
`8
`12
`16
`20
`
`% Released (SGF)
`13
`27
`50
`67
`84
`97
`
`% Released (pH 7.5)
`14
`28
`63
`84
`95
`102
`
`The release profile in pH 7.5 and SGFof the sustained
`release product prepared in this Example is shown in FIG.
`3.
`
`FIG. 7 depicts the in vivo metformin plasmaprofile of the
`sustained release product prepared in this Example when
`administered shortly after breakfast. FIG. 7 also shows the
`in vivo metformin plasmaprofile of the GLUCOPHAGE®
`product administered shortly after breakfast.
`FIG. 8 depicts the in vivo metformin plasmaprofile of the
`sustained release product prepared in this Example when
`administered shortly after dinner. FIG. 8 also shows the in
`vivo metformin plasma profile of the GLUCOPHAGE®,
`product administered shortly after dinner.
`Table 1 is a summary of the bioavailability comparision
`data, test/reference ratio, shown in FIGS. 4-8 wherein the
`GLUCOPHAGE®product is the reference product in a two
`way crossover biostudy with n=6.
`
`wn
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`10
`of water and biologicalfluids and is impermeable to the
`passage of the antihyperglycemic drug wherein said
`coating comprises 50-99% of a polymer; 0-40% of a
`flux enhancer and 0-25% of a plasticizer; and
`(c) at least one passageway in the semipermeable mem-
`brane for the release of the antihyperglycemic drug.
`2. Acontrolled release pharmaceutical tablet as defined in
`claim 1 wherein the antihyperglycemic drugis a biguanide.
`3. Acontrolled release pharmaceutical tablet as defined in
`claim 2 wherein the antihyperglycemic drug is metformin or
`a pharmaceutically acceptable salt thereof.
`4. Acontrolled release pharmaceutical tablet as defined in
`claim 2 wherein the antihyperglycemic drug is buformin or
`a pharmaceutically acceptable salt thereof.
`5. Acontrolled release pharmaceutical tablet as defined in
`claim 1 wherein the binding agent is water soluble.
`6. Acontrolled release pharmaceutical tablet as defined in
`claim 1 wherein the water soluble binding agentis polyvinyl
`pyrrolidone, hydroxypropyl cellulose, hydroxyethyl
`cellulose, waxes or mixtures thereof.
`7. Acontrolled release pharmaceutical tablet as defined in
`claim 6 wherein the water soluble binding agent is polyvinyl
`pyrrolidone.
`8. Acontrolled release pharmaceutical tablet as defined in
`claim 1 wherein the absorption enhanceris selected from the
`group consisting of fatty acids, surfactants, chelating agents,
`bile salts or mixtures thereof.
`9. Acontrolled release pharmaceutical tablet as defined in
`claim 1 wherein the absorption enhancer is a fatty acid
`selected from the group consisting of capric acid,oleic acid
`or their monoglycerides.
`10. A controlled release pharmaceutical tablet as defined
`in claim 1 wherein the absorption enhanceris a surfactant
`selected from the group consisting of sodium lauryl sulfate,
`sodium taurocholate and polysorbate 80.
`11. A controlled release pharmaceutical tablet as defined
`in claim 1 wherein the absorption enhanceris a chelating
`agent selected from the group consisting of citric acid,
`phytic acid, ethylene diamine tetraacetic acid and ethylene
`glycol-bis(B-aminoethyl ether)-N,N,N,N-tetraacetic acid.
`12. A controlled release pharmaceutical tablet as defined
`in claim 1 wherein the abso