6,099,862
`[11] Patent Number:
`[19]
`United States Patent
`
`Chen et al.
`[45] Date of Patent:
`Aug. 8, 2000
`
`USOO6099862A
`
`[54] ORAL DOSAGE FORM FOR THE
`CONTROLLED RELEASE OFA BIGUANIDE
`AND SULFONYLUREA
`
`[75]
`
`Inventors: Chih-Ming Chen; Xiu Xiu Cheng;
`both of Davie. Joseph Chou. Steve
`’
`.
`’
`Jan; both of Coral Springs; all of Fla.
`_
`.
`[73] Ass1gnee: ANDRX C0rp0rat10n; Fort Lauderdale;
`Fla.
`
`[21] Appl‘ No" 09/143376
`[22]
`Filed;
`Aug 31, 1993
`
`[51]
`
`Int. Cl.7 ............................. .. A61K 9/24; A61K 9/36;
`A61K 9/20
`
`[52] us. Cl.
`
`........................ .. 424/473; 424/468; 424/474;
`424/475; 424/479; 424/480
`of Search ................................... ..
`424/472; 473; 474; 475; 479; 480; 604/8901;
`8921
`
`[56]
`
`References Cited
`
`3 845 770
`3,916,899
`3,952,741
`3,957,853
`4,034,758
`
`US. PATENT DOCUMENTS
`11/1974 Theeuwes et a1.
`.
`11/1975 Theeuwes et a1.
`.
`4/1976 Baker.
`5/1976 Bohuon .
`7/1977 Theeuwes .
`ggiii‘zes et al'
`6/1985 Edgren I
`4,522,625
`5/1986 Edgren et a].
`4,587,117
`9/1986 Ayer.
`4,609,374
`.
`9/1986 Wong et al.
`4,612,008
`4,615,698 10/1986 Guittard et al.
`496249827
`11/1986 Ayer et al‘ 1’
`2’233’332
`Effifhztflaét’al
`4’696’815
`9/1987 schepky et a1
`4’704’118
`11/1987 Eckenhoff.
`4,708,868
`11/1987 Brick] et a1”
`4,777,049
`10/1988 Magruder et a1.
`4,803,076
`2/1989 Ranade .
`4,849,227
`7/1989 Cho .
`4,851,229
`7/1989 Magruder et a1.
`
`.
`
`.
`
`.
`
`'
`
`'
`
`'
`.
`
`.
`
`.
`
`4,863,724
`4,865,598
`4,871,549
`4,892,739
`
`9/1989 Schepky et a1.
`9/1989 ECkenhOff ~
`.
`10/1989 Ueda et al.
`1/1990 Shah et a1..
`
`.
`
`10/1990 Eckenhofl;
`499639141
`6/1991 Kuczynski et al.
`5,024,843
`7/1991 Curatolo .
`5,030,452
`5,071,607 12/1991 Ayer et a1.
`.
`5,082,668
`1/1992 Wong et a1..
`.
`.
`(List continued on next page.)
`FOREIGN PATENT DOCUMENTS
`
`.
`
`0283369
`2320735
`1522179
`9608243
`9609823
`
`97017975
`
`99/03477
`
`.
`
`8/1993 European Pat. Off.
`8/1975
`France .
`11/1976 United Kingdom .
`3/1996 WIPO .
`4/1996 WIPO .
`
`5/1997 W1P0~
`gig
`1/1999 WIPO
`
`OTHER PUBLICATIONS
`Diem; Drug Therapy of Type—II Diabetes: Tablets; Insulin or
`a Combination of These; Schweizerische Rundschau Fur
`Medizin PraXis; 83(2) pp68—71; Jan. 18; 1994.
`Clin. Ther. 1996 May; 18 (3) : pp. 360—371.
`By Briscoe TA; et al.; Dept. of Medicine Morehouse School
`0f Med1C1n6§A1tanta> GA
`Ann. Intern Med. 1998 Feb. 1; 128 (3) pp. 165—175.
`Physician’s Desk Reference 52th Edition pp. 795—800;
`1217—1219; and 2182—2186.
`Primary Examiner—Thurman K. Page
`Assistant Examiner—Brian K. Seidleck
`Attorney, Agent, or Firm—Hedman; Gibson & Costigan;
`RC.
`
`ABSTRACT
`[57]
`A controlled release pharmaceutical tablet containing anti-
`hyperglycemic drug and a hypoglycemic drug that does not
`contain an expanding or gelling polymer layer and compris-
`ing a core containing the antihyperglycemic drug and the
`hypoglycemic drug; a semipermeable coating membrane
`surrounding the core and at least one passageway in the
`membrane to allow the drugs to be released from the core.
`
`4 Claims, 2 Drawing Sheets
`
`METFORMIN HCl/GLIPIZIDE TABLETS, 850/5
`
`100
`
`80
`
`
`(%)
`
`40
`
`20
`
`o .
`0
`
`‘E— GLIPIZIDE
`_V_ METFORMIN
`
`2
`
`4
`
`1 0
`8
`6
`DISSOLUTlON TIME (HHS)
`
`1 2
`
`1 4
`
`1 6
`
`AUROBINDO EX. 1004, ‘l
`
`AUROBINDO EX. 1004, 1
`
`

`

`5,091,190
`5,108,756
`5,110,597
`5,120,548
`5,141,752
`5,178,867
`5,185,158
`5,260,275
`5,308,348
`5,356,913
`5,413,572
`5,512,293
`
`2/1992
`4/1992
`5/1992
`6/1992
`8/1992
`1/1993
`2/1993
`11/1993
`5/1994
`10/1994
`5/1995
`4/1996
`
`.
`
`.
`
`.
`
`Kuczynski et al.
`Curatolo .
`.
`Wong et al.
`McClelland et al.
`Ayer et al.
`.
`Guittard et al.
`Ayer et al.
`.
`Cooper et al.
`Balaban et al.
`Colca .
`.
`Wong et al.
`Landrau et al.
`
`.
`
`.
`
`.
`
`6,099,862
`
`Page 2
`
`US. PATENT DOCUMENTS
`
`5,543,156
`5,545,413
`5,591,454
`5,614,578
`5,629,319
`5,631,224
`5,650,170
`5,667,804
`5,668,117
`5,674,900
`5,688,518
`5,691,386
`
`8/1996
`8/1996
`1/1997
`3/1997
`5/1997
`5/1997
`7/1997
`9/1997
`9/1997
`10/1997
`11/1997
`11/1997
`
`Roorda et al.
`
`.
`
`.
`.
`
`Kuczynski et al.
`Kuczynski et al.
`Dong et al.
`.
`Luo et al.
`.
`Efendic et al.
`
`.
`
`Wright et al.
`Wong et al.
`Shapiro .
`Ubillas et al.
`
`.
`
`.
`
`.
`
`.
`Ayer et al.
`Inman et al.
`
`.
`
`AUROBINDO EX. 1004, 2
`
`AUROBINDO EX. 1004, 2
`
`

`

`US. Patent
`
`Aug. 8, 2000
`
`Sheet 1 0f 2
`
`6,099,862
`
`9
`
`20.55353e2wmw
`am;22:
`
`F.OE
`
`505_>_mBE:z_ £03@533.
`
`m_Q_N_n=._0\_oIz__>_mon_._.m_>_
`
`H2852
`
`E838%
`
`AUROBINDO EX. 1004, 3
`
`AUROBINDO EX. 1004, 3
`
`

`

`US. Patent
`
`Aug. 8, 2000
`
`Sheet 2 0f 2
`
`6,099,862
`
`CD
`,—
`
`zo_S._Omm_o3NF2wm¢
`am;22:
`
`NdE
`
`..........m.mn_<n_m3
`
`ms:2_
`
`6052m3
`
`
`
`z__>_mou_._.m__>_J»:
`
`mo_N_n__._0
`
`.m. mBom
`
`
`.mEJmE.mo_N_n__._o\_o_._z__>_mou_._.m=>_
`
`09
`
`ow
`
`om
`
`Hzaoz<
`
`E838%
`
`AUROBINDO EX. 1004, 4
`
`AUROBINDO EX. 1004, 4
`
`

`

`6,099,862
`
`1
`ORAL DOSAGE FORM FOR THE
`CONTROLLED RELEASE OF A BIGUANIDE
`AND SULFONYLUREA
`
`BACKGROUND OF THE INVENTION
`
`The present invention relates to controlled release unit
`dose formulations containing an antihyperglycemic drug
`and a hypoglycemic drug. As used in this specification the
`term “antihyperglycemic” refers to a drug that is useful in
`controlling or managing noninsulin-dependent diabetes mel-
`litus (NIDDM) by decreasing hepatic glucose production,
`decreasing intestinal absorption of glucose and/or improving
`insulin sensitivity. Biguanides are the preferred antihyperg-
`lycemic drugs. As used in this specification the term
`“hypoglycemic” refers to a drug that is useful in controlling
`or managing noninsulin-dependent diabetes mellitus
`(NIDDM) by stimulating the release of insulin from the
`pancreas. Sulfonylureas are the preferred hypoglycemic
`drugs.
`In a preferred embodiment, the present invention relates
`to an oral dosage form comprising a unique combination of
`a biguanide and a sulfonylurea. The biguanide is preferably
`metformin or buformin or a pharmaceutically acceptable salt
`thereof such as metformin hydrochloride or the metformin
`salts described in US. Pat. Nos. 3,957,853 and 4,080,472
`which are incorporated herein by reference. The sulfony-
`lurea compound is preferably glipizide as described in US.
`Pat. No. 5,545,413 or glyburide. Other possible sulfonylurea
`compounds such as glibornuride, glisoxepide, gliclazide
`acetohexamide, chlorpropamide,
`tolazamide,
`tolbutamide
`and tolbutamide which are described in US. Pat. Nos.
`
`5,674,900 and 4,708,868, which are incorporated herein by
`reference, may also be employed.
`The dosage form of the present invention can provide
`therapeutic levels of the drugs from twelve to twenty-four
`hour periods. In a preferred embodiment, the dosage form
`will be administered once a day and provide therapeutic
`levels of the drug throughout the day.
`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 employ
`either a biguanide drug alone or a sulfonylurea drug alone.
`For example WO 96/08243 discloses a controlled release
`dosage form containing only metformin HCl, a biguanide, as
`the active ingredient and employs a hydrogel to push the
`active ingredient from the dosage form. Similarly, US. Pat.
`Nos. 5,545,413, 5,591,454 and 5,091,190 disclose con-
`trolled release dosage forms containing only the drug glip-
`izide and employ a hydrogel to push the active ingredient
`from the dosage form.
`The 50th edition of the Physicians” Desk Reference®,
`copyright 1996, suggests administering to a patient a met-
`formin HCl dosage form commercially available from
`Bristol-Myers Squibb Co. under the tradename GLUCOPH-
`AGE® and a dosage form of a sulfonylurea compound such
`as glyburide. More specifically, page 753 of the 50th edition
`of the Physicians” Desk Reference states that if adequate
`glycemic control
`is not attained with GLUCOPHAGE®
`monotherapy, the combination of GLUCOPHAGE® and a
`sulfonylurea such as glyburide may have a synergistic effect,
`since both active ingredients act to improve glucose toler-
`ance by different mechanism. According to the 50th edition
`of the Physicians” Desk Reference, the GLUCOPHAGE®
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`dosage form is believed to function by decreasing hepatic
`glucose production, decreasing intestinal absorption of glu-
`cose and improving insulin sensitivity, while the sulfony-
`lurea compound is believed to lower the blood glucose
`levels by stimulating the release of insulin from the pan-
`creas.
`
`Although the 50th edition of the Physicians” Desk Ref-
`erence suggests the combined administration of metformin
`HCl and a sulfonylurea compound, it fails to suggest a single
`unitary controlled release dosage form comprising both an
`antihyperglycemic drug and a hypoglycemic drug that can
`provide continuous and non-pulsating therapeutic levels of
`an antihyperglycemic drug and a hypoglycemic drug to an
`animal in need of such treatment over a twelve hour or
`
`twenty-four hour period.
`invention to provide a
`It
`is an object of the present
`controlled or sustained release formulation that contains
`
`both an antihyperglycemic drug and a hypoglycemic drug.
`It is a further object of the present invention to provide a
`controlled or sustained release formulation that contains
`
`both an antihyperglycemic drug and a hypoglycemic drug
`that does not employ an expanding or gel forming material
`to push the drugs out.
`It is a further object of the present invention to provide a
`controlled or sustained release formulation that contains
`
`both an antihyperglycemic drug and a hypoglycemic drug
`that can provide continuous and non-pulsating therapeutic
`levels of an antihyperglycemic drug to an animal in need of
`such treatment over a twelve hour or twenty-four hour
`period.
`It is also an object of this invention to provide a controlled
`or sustained release pharmaceutical tablet having a homo-
`geneous core wherein the core component may be made
`using ordinary tablet compression techniques.
`
`SUMMARY OF THE INVENTION
`
`The foregoing objectives are meet by a controlled release
`dosage form which comprises:
`(a) a core which comprises:
`(i) an antihyperglycemic drug;
`(ii) a hypoglycemic drug;
`(iii) a binding agent; and
`(iv) optionally, an absorption enhancer;
`(b) optionally a seal coating layer around the core;
`(c) a semipermeable coating membrane surrounding the
`core; and
`
`(d) at least one passageway in the semipermeable mem-
`brane to allow release of the antihyperglycemic drug
`and the hypoglycemic drug.
`In the preferred embodiment the antihyperglycemic drug
`is a biguanide such as metformin or a pharmaceutically
`acceptable salt and the hypoglycemic drug is a sulfonylurea,
`such as glipizide or a pharmaceutically acceptable salt
`thereof.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 is a graph which depicts the dissolution profile in
`simulated intestinal fluid (SIF), pH 7.5 phosphate buffer 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 (SIF), pH 7.5 phosphate buffer of
`the formulation described in Example 2 as tested according
`
`AUROBINDO EX. 1004, 5
`
`AUROBINDO EX. 1004, 5
`
`

`

`6,099,862
`
`3
`to the procedure described in United States Pharmacopeia
`XXIII, Apparatus 2 @ 75 rpm.
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`The term antihyperglycemic drug as used in this specifi-
`cation refers to drugs that are useful
`in controlling or
`managing noninsulin-dependent diabetes mellitus (NIDDM)
`by decreasing hepatic glucose production, decreasing intes-
`tinal absorption of glucose and/or improving insulin sensi-
`tivity. Preferably the antihyperglycemic drug is a biguanide
`such as metformin or buformin or a pharmaceutically
`acceptable salt thereof such as metformin hydrochloride.
`The term hypoglycemic drug as used in this specification
`refers to drugs that are useful in controlling or managing
`noninsulin-dependent diabetes mellitus (NIDDM) by stimu-
`lating the release of insulin from the pancreas. Preferably the
`hypoglycemic drug is a sulfonylurea compound such as
`glyburide, glipizide, glibornuride, glisoxepide, gliclazide,
`acetohexamide, chlorpropamide,
`tolazamide,
`tolbutamide,
`tolbutamide or mixtures thereof.
`
`The binding agent may be any conventionally known
`pharmaceutically acceptable binder, but it is preferred that
`the binding agent be a water-soluble polymer such as
`polyvinyl pyrrolidone having a weight average molecular
`weight of 25,000 to 200,000. Other pharmaceutically
`acceptable water-soluble polymers include hydroxypropyl
`cellulose, hydroxyethyl cellulose, hydroxypropyl methylcel-
`lulose and the like. Mixtures of the water-soluble binders
`
`may also be used. The water-soluble binders comprise
`approximately about 0 to about 40% of the total weight of
`the core and preferably about 3—15% of the total weight of
`the core.
`
`The absorption enhancer employed in the core 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, especially alkyl sulfates,
`such as sodium lauryl sulfate, sodium dodecyl sulfate and
`polysorbate 80, chelating agents such as citric acid and
`phytic acid. The core comprises approximately 1 to about
`20% absorption enhancer based on the 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 hypoglycemic drug, the binder
`which preferably is a pharmaceutically acceptable water-
`soluble polymer and the absorption enhancer is preferably
`formed by mixing and tableting techniques commonly
`known in the art. The core may also be formed by granu-
`lating the core ingredients and compressing the granules
`with or without the addition of a lubricant into a tablet. The
`
`tableting can be performed on a rotary press.
`Other commonly known excipients may also be included
`into the core such as lubricants, pigments or dyes.
`The homogeneous core is subsequently 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 antihyper-
`glycemic drug and/or the hypoglycemic 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
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`acylate, cellulose diacylate, cellulose triacylate, cellulose
`acetate, cellulose diacetate, cellulose triacetate, cellulose
`acetate propionate, cellulose acetate butyrate and ethylcel-
`lulose. Other suitable polymers are described in US. Pat.
`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 cellu-
`lose acetate comprising an acetyl content of 39.3 to 40.3%,
`commercially available under the tradename CA 398-10 or
`CA 398-3 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 increase
`the volume of fluid imbibed into the core to enable the
`
`dosage form to dispense substantially all of the antihyper-
`glycemic drug and hypoglycemic drug through both the
`passageway and the porous membrane. The flux enhancing
`agent is a water-soluble component such as sodium chloride,
`potassium chloride, sugar, sucrose, sorbitol, mannitol, poly-
`ethylene glycol (weight av. molecular weight 380~3700),
`propylene glycol, hydroxypropyl cellulose, hydroxypropyl
`methylcellulose and mixtures thereof. The preferred flux
`enhancer is PEG 400.
`
`The flux enhancing agent comprises approximately 0 to
`40% of the total weight of the coating, most preferably
`2—20% of the total weight of the coating. The flux enhancing
`agent dissolves or leaches from the semipermeable mem-
`brane to form paths in the semipermeable membrane for the
`fluid to enter the core and dispense the active ingredients
`from the core.
`
`The semipermeable membrane may also be formed with
`commonly known excipients such a plasticizer. Some com-
`monly known plasticizers 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 plasticizer is triacetin but materials such
`as acetylated monoglyceride, rape seed oil, olive oil, sesame
`oil, acetyltributylcitrate, acetyltriethylcitrate, glycerin
`sorbitol, diethyloxalate, diethylmalate, diethylfumarate,
`dibutylsuccinate, diethylmalonate, dioctylphthalate,
`dibutylsebacate,
`triethylcitrate,
`tributylcitrate,
`glyceroltributyrate, and the like. Depending on the particular
`plasticizer, amounts of from 0% to 25%, and preferably 2 to
`15% of the plasticizer can be used based upon the total
`weight of the coating.
`
`As used herein the term passage way includes an aperture,
`orifice, bore, hole, weaken area or an erodible element such
`as a gelatin plug that erodes to form an osmotic passage way
`for the release of the antihyperglycemic drug and hypogly-
`cemic drug from the dosage form. A detailed description of
`the passageway can be found in US. Pat. Nos. 3,845,770,
`3,916,899, 4,034,758, 4,077,407, 4,783,337 and 5,071,607.
`
`the membrane coating around the core will
`Generally,
`comprise from about 1—10% (theoretically) and preferably
`about 2—6% (theoretically) based on the total weight of the
`core and coating.
`
`In a preferred embodiment the dosage form will have the
`following composition:
`
`AUROBINDO EX. 1004, 6
`
`AUROBINDO EX. 1004, 6
`
`

`

`5
`
`6
`
`6,099,862
`
`Preferred
`
`Most Preferred
`
`I Core
`
`Weight %
`
`
`CORE:
`
`antihyperglycemic cpd
`hypoglycemic cpd
`binder
`absorption enhancer
`COATING:
`
`semipermeable polymer
`plasticizer
`flux enhancer
`
`50—96%
`0.05—3%
`0—40%
`1—20%
`
`50—99%
`0—25%
`0—40%
`
`5
`
`75—95%
`2—15%
`2—20%
`
`88.10%
`metformin HCl
`0.52%
`glipizide
`6.33%
`povidonel, USP
`75—93%
`4.56%
`sodium lauryl sulfate
`0.25—2%
`0.50%
`magnesium stearate
`3—15%
`2—10% —
`10 1approximate molecular weight = 1,000,000; dynamic viscosity (10% w/v
`solution at 20° C.) = 300—700 mPa s.
`.
`(a) Granulanon
`1321.46 g of metformin HCl and 67.01 g of sodium lauryl
`sulfate are delumped by passing the compounds through a
`15 40 mesh screen and then mixed. 94.92 g of povidone, K-90,
`and 1.34 g of sodium lauryl sulfate are dissolved in 1,803.5
`g of purified water and then 7.76 g of glipizide is dispersed
`in the solution. The mixture of metformin HCl and sodium
`
`The dosage forms prepared according to the present
`invention should exhibit the following dissolution profile
`when tested in a USP type 2 (paddle) apparatus at 75 rpms
`in 900 ml of simulated intestinal fluid (pH 7.5 phosphate 20
`buffer) and at 37° C.:
`
`ANTIHYPERGLYCEMIC RELEASE
`
`Time (hours)
`2
`4
`8
`12
`16
`
`Preferred
`0_30%
`10—50%
`30—90%
`NLT 50%
`NLT 60%
`
`Most Preferred
`0_25%
`20—45%
`45—90%
`NLT 60%
`NLT 70%
`
`NLT = NOT LESS THAN
`
`HYPOGLYCEMIC RELEASE
`
`Time (hours)
`
`Preferred
`
`Most Preferred
`
`i
`g
`12
`16
`NLT = NOT LESS THAN
`
`18:28::
`30_90%
`NLT 50%
`NLT 60%
`
`28:31::
`45_90%
`NLT 60%
`NLT 70%
`
`30
`
`lauryl sulfate is then added to a top-spray fluidized bed
`granulator and granulated by spraying with the granulating
`solution of povidone, sodium lauryl sulfate and glipizide
`under the following conditions: product
`temperature:
`35—45° C.; atomization pressure:
`1—3 bar; spray rate:
`10—150 ml/min. Once. the granulating solution is depleted
`25 and the granules are dried in the fluidized bed coater until the
`loss on drying is less than 2%. The dried granules are then
`passed through a Comil equipped with a screen equivalent to
`18 mesh.
`(b) Tableting
`7.50 g of magnesium stearate is passed through a 40 mesh
`~
`.
`.
`stainless steel screen and blended With the metformin HCl/
`glipizide granules for approximately five (5) minutes. After
`blending,
`the granules are compressed on a rotary press
`fitted with 15/32" round standard concave punches.
`35 (c) Seal Coating (optional)
`The tablet or core 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 tablet or
`40 core using a pan coater under the followingconditions:
`exhaust air temperature of 38—42 C.; atomization pressure
`of 28—40 psi; and spray rate of 10—150 ml/min. The core
`tablets are coated with the seal coating until a theoretical
`45 coating level of approximately 2% is obtained.
`
`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, exc1pients, 50
`lubricants, dyes, pigments, dispersants etc. which are dis-
`closed in Remington 5 Pharmaceutical SCiences, 1995 Edi-
`tion may be used to optimize the formulations of the
`invention. In the alternative, dry granulation techniques may
`be used to prepare the granules for making compressed
`tablets.
`
`H Sustained Release Coating
`cellulose acetate (398_1O)2
`triacetin
`PEG 4003
`2acety1 content 39_3_40_3%
`3weight av. molecular weight 380—420
`
`Weight ‘70
`85%
`5%
`10%
`
`55 (d) Sustained Release Coating
`The cellulose acetate is dissolved in acetone while stirring
`with a homogenizer. The polyethylene glycol 400 and tri-
`acetin are added to the cellulose acetate solution and stirred
`
`DESCRIPTION OF THE PREFERRED
`EMBODIMENTS
`
`until a homogenous solution is obtained. The coating solu-
`60 tion is then sprayed onto the seal coated tablets in a fluidized
`bed coter employing the following conditions: product tem-
`perature of 15—25° C.; atomization pressure of approxi-
`mately 1—2 bar; and a spray rate of 10—30 ml/min. This
`coating process continues until a theoretical coating level of
`Aonce a day controlled release tablet containing 850 mg 65 approximately 3% is obtained.
`of metformin HCl and 5 mg of glipizide and haVing the
`Once the theoretical coating level is obtained, the sus-
`following formula is prepared as follows:
`tained release coated tablets are dried in the fluidized bed
`
`EXAMPLE 1
`
`AUROBINDO EX. 1004, 7
`
`AUROBINDO EX. 1004, 7
`
`

`

`6,099,862
`
`7
`coater for approximately 5 to 10 minutes. Then one hole is
`either mechanically drilled or laser drilled onto each side of
`the sustained release tablet.
`
`The resulting tablets are tested in simulated intestinal fluid
`(pH 7.5) according to the procedure described in United
`States Pharmacopeia XXIII, Apparatus 2 (paddle) @ 75 rpm
`and found to have the following release profile:
`
`8
`
`(b) Tableting
`The granules are pressed into tablets according to the
`procedure outlined in Example 1 with the exception that
`0.030 kg of magnesium stearate is employed.
`(c) Seal Coating (optional)
`The tablets are seal coated with an Opadry material or
`other suitable water-soluble material according to the pro-
`cedure outlined in Example 1.
`
`METFORMIN HCl RELEASE
`
`TIME (hours)
`2
`4
`8
`12
`16
`
`% Released (pH 7.5)
`17
`32
`56
`76
`89
`
`GLIPIZIDE RELEASE
`
`TIME (hours)
`2
`4
`8
`12
`16
`
`% Released (pH 7.5)
`22
`37
`57
`76
`90
`
`The release profile in simulated intestinal fluid (pH 7.5) of
`the sustained release product prepared in this Example is
`shown in FIG. 1.
`
`EXAMPLE 2
`
`A controlled release tablet containing 500 mg of met-
`formin HCl and 5 mg of glipizide and having the following
`formula is prepared as follows:
`
`I Core
`metformin HCl
`glipizide
`povidone“, USP
`sodium lauryl sulfate
`magnesium stearate
`
`Weight %
`87.77%
`0.88%
`6.31%
`4.54%
`0.50%
`
`4approximate molecular weight = 1,000,000 dynamic viscosity (10% w/v
`solution at 20° C.) = 300—700 mPa s.
`
`(a) Granulation
`5.266 kg of metformin HCl and 0.263 kg of sodium lauryl
`sulfate are delumped by passing the compounds through a
`40 mesh screen and then mixed. 0.379 kg of povidone, K-90,
`0.009 kg of sodium lauryl sulfate are dissolved in 7.201 kg
`of purified water and then 0.053 kg of glipizide is dispersed
`in the solution. The mixture of metformin HCl and sodium
`
`lauryl sulfate is then added to a top-spray fluidized bed
`granulator and granulated by spraying with the granulating
`solution of povidone, sodium lauryl sulfate and glipizide
`under the following conditions: product
`temperature:
`35—45° C.; atomization pressure:
`1—3 bar; spray rate:
`10—150 ml/min. Once the granulating solution is depleted
`and the granules are dried in the fluidized bed coater until the
`loss on drying is less than 2%. The dried granules are then
`passed through a Comil equipped with a screen equivalent to
`18 mesh.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`II Sustained Release Coating
`
`Weight %
`
`cellulose acetate (398-10)5
`triacetin
`PEG 4006
`
`85%
`5%
`10%
`
`5acetyl content 39.3—40.3%
`5weight av. molecular weight 380—420
`
`(d) Sustained Release Coating
`The sustained release coating solution is prepared and
`applied to the seal coated tablets according to the procedure
`outlined in Example 1, with the exception that the sustained
`release coating is applied to the seal coated tablets until a
`theoretical coating level of approximately 4.5% is obtained.
`The resulting tablet is tested in simulated intestinal fluid
`(pH 7.5) according to the procedure described in United
`States Pharmacopeia XXIII, Apparatus 2 (paddle) @ 75 rpm
`and found to have the following release profile:
`
`METFORMIN HCl RELEASE
`
`TIME (hours)
`2
`4
`8
`12
`16
`
`% Released (pH 7.5)
`23
`41
`70
`92
`98
`
`GLIPIZIDE RELEASE
`
`TIME (hours)
`2
`4
`8
`12
`16
`
`% Released (pH 7.5)
`23
`35
`56
`75
`90
`
`The release profile in SIF of the sustained release product
`prepared in this Example is shown in FIG. 2.
`While certain preferred and alternative embodiments of
`the invention have been set forth for purposes of 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 embodiments
`of the invention and modifications thereof which do not
`
`depart from the spirit and scope of the invention.
`We claim:
`
`1. A controlled release pharmaceutical tablet which con-
`sisting essentially of:
`(a) a core consisting essentially of:
`(i) metformin or a pharmaceutically acceptable salt
`thereof;
`(ii) glipizide
`
`AUROBINDO EX. 1004, 8
`
`AUROBINDO EX. 1004, 8
`
`

`

`6,099,862
`
`9
`
`(iii) polyvinyl pyrrolidone; and
`(iv) sodium lauryl sulfate;
`(b) optionally a seal coat around the core,
`(c) a semipermeable membrane coating covering said core
`comprising:
`(i) cellulose acetate;
`(ii) polyethylene glycol with an average molecular
`weight between 380 and 420; and
`(iii) a plasticizer; and
`(d) at least one passageway in the semipermeable mem-
`brane to allow the release of the metformin and glip-
`izide from the core to the environment of use to provide
`therapeutic levels of metformin and glipizide from
`twelve to twenty-four hour periods.
`2. A controlled release pharmaceutical tablet as defined in
`claim 1 that exhibits the following dissolution profile when
`tested in a USP type 2 apparatus, paddle, at 75 rpms in 900
`ml of simulated intestinal fluid, pH 7.5 phosphate buffer and
`at 37° C.:
`
`after 2 hours 0—30% of the metformin is released;
`after 4 hours 10—50% of the metformin is released;
`after 8 hours 30—90% of the metformin is released;
`after 12 hours not less than 50% of the metformin is
`released; and
`after 16 hours not less than 60% of the metformin is
`released; and
`after 2 hours 0—30% of the glipizide is released;
`after 4 hours 10—50% of the glipizide is released;
`
`10
`
`15
`
`20
`
`25
`
`10
`after 8 hours 30—90% of the glipizide is released;
`after 12 hours not
`less than 50% of the glipizide is
`released; and
`after 16 hours not
`released.
`
`less than 60% of the glipizide is
`
`3. Acontrolled release pharmaceutical tablet as defined in
`claim 1 that exhibits the following dissolution profile when
`tested 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.:
`
`after 2 hours 0—25% of the metformin is released;
`after 4 hours 20—45% of the metformin is released;
`after 8 hours 45—90% of the metformin is released;
`after 12 hours not less than 60% of the metformin is
`released; and
`after 16 hours not less than 70% of the metformin is
`released; and
`after 2 hours 0—25% of the glipizide is released;
`after 4 hours 20—45% of the glipizide is released;
`after 8 hours 45—90% of the glipizide is released;
`after 12 hours not
`less than 60% of the glipizide is
`released; and
`after 16 hours not
`released.
`
`less than 70% of the glipizide is
`
`4. Acontrolled release pharmaceutical tablet as defined in
`claim 1 wherein the plasticizer is triacetin.
`*
`*
`*
`*
`*
`
`AUROBINDO EX. 1004, 9
`
`AUROBINDO EX. 1004, 9
`
`