United States Patent
`US 6,284,275 B1
`(10) Patent No.:
`(12)
`Chen etal.
`(45) Date of Patent:
`*Sep. 4, 2001
`
`
`US006284275B1
`
`(54) CONTROLLED RELEASE TABLET HAVING
`A UNITARY CORE
`
`(75)
`
`Inventors: Chih-Ming Chen; Xiu Xiu Cheng,
`‘ue
`.
`Jon or:OreJorsnChou;Steve
`;
`prings,
`(US)
`(73) Assignee: Andrx Pharmaceuticals, Inc., Davie,
`FL (US)
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`US.C. 154(b) by 0 days.
`
`(*) Notice:
`
`This patent is subject to a terminal dis-
`claimer.
`
`.
`
`4,587,117
`5/1986 _Edgrenetal. .
`4,609,374
`9/1986 Ayer .
`4,612,008
`9/1986 Wongetal. .
`.
`pees Ltose Guittard “ al.
`3624,
`yer et al.
`.
`4,627,850
`12/1986 Deters etal. .
`4,692,336
`9/1987 Eckenhoff et al.
`4,696,815
`9/1987 Schepky etal. .
`4,704,118
`11/1987 Eckenhoff .
`“em
`(List continued on next page.)
`FOREIGN PATENT DOCUMENTS
`0283369
`8/1993 (EP).
`2320735
`8/1975 (FR).
`1522179
`11/1976 (GB).
`9608243
`3/1996 (WO).
`9609823
`4/1996 (WO).
`9717975
`5/1997 (WO).
`9810786
`3/1998 (WO).
`
`(22)
`
`“4.
`Filed:
`
`Jun. 9, 2000
`Related U.S. Application Data
`
`WO200028990 *
`WO02000289989*
`
`5/2000 (WO).
`5/2000 (WO).
`OTHER PUBLICATIONS
`
`(63) Continuation of application No. 09/143,876, filed on Aug.
`31, 1998, now Pat. No. 6,099,862.
`
`(SL) UntC0 eeeeeecccssssesneeees A61K 9/20; A61K 9/24;
`A61K 9/36
`(52) U.S. C0. cee eceseeeeeeeee 424/473; 424/468; 424/474;
`424/475; 424/479; 424/480
`(58) Field of Search .cccccscscsssssssssssseen 424/468, 473,
`424/474, 475, 479, 480; 514/635, 588,
`591, 592, 593
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`~~
`11/1974 Theeuwesetal. .
`11/1975 Theeuwesetal. .
`4/1976 Baker .
`,tony penoun
`eeuwes .
`3/1978 Theeuweset al.
`3/1978 Bohoun .
`6/1985 Edgren .
`
`.
`
`3,845,770
`3,916,899
`3,952,741
`foodee
`034,
`4.077.407
`4,080,472
`4,522,625
`
`Clin. Ther. May 1996; 18 (3):pp. 360-371, Campell et al.
`Briscoe TA,et al.; Dept of Medicine Morehouse of Med-
`icince, Atlanta, GA.
`Ann. Intern Med. Feb. 1, 1998; 128 (3) pp. 165-175.
`Physicians’s Desk Reference 52th Ed. pp. 795-800;
`1217-1219 and 2182-2186.
`;
`;
`Primary Examiner—Thurman K. Page
`.
`Assistant Examiner—BrianK. Seidleck
`(74) Attorney, Agent, or Firm—Hedman & Costigan P.C.
`57
`ABSTRACT
`67)
`A controlled release pharmaceutical tablet containing anti-
`hyperglycemic drug and a hypoglycemic drug that does not
`contain an expandingor 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
`membraneto allow the drugs to be released from the core.
`
`39 Claims, 2 Drawing Sheets
`
`METFORMIN HCIV/GLIPIZIDE TABLETS, 850/5
`
`sfwounr
`-2 GLIPIZIDE
`(%)
`AO annnnerctratnnnentingyylcamanmninarinisinaniniuinnnannnnsin =+ METFORMIN
`
`100
`
`
`20 sassnstasrerseeeey
`
`Ow
`0
`
`2
`
`4
`
`10
`8
`6
`DISSOLUTION TIME (HRS)
`
`12
`
`14
`
`16
`
`AUROBINDO EX1015, 1
`
`AUROBINDO EX1015, 1
`
`

`

`US 6,284,275 B1
` Page 2
`
`U.S. PATENT DOCUMENTS
`
`4,708,868
`4,777,049
`4,803,076
`4,851,229
`4,863,724
`4,865,598
`4,871,549
`4,892,739
`4,963,141
`5,024,843
`5,030,452
`5,071,607
`5,082,668
`5,091,190
`5,108,756
`5,110,597
`5,120,548
`5,141,752
`5,178,867
`5,185,158
`
`11/1987 Brickl etal. .
`10/1988 Magruderetal. .
`2/1989 Ranade.
`7/1989 Magruderetal. .
`9/1989 Schepkyetal. .
`9/1989 Eckenhoff .
`.
`10/1989 Uedaet al.
`1/1990 Shahetal. .
`10/1990 Eckenhoff.
`6/1991 Kuczynskietal. .
`7/1991 Curatolo.
`12/1991 Ayeretal. .
`1/1992 Wonget al. .
`2/1992 Kucezyskiet al.
`4/1992 Curatolo .
`5/1992 Wongetal. .
`6/1992 McClelland etal. .
`8/1992 Ayeretal. .
`1/1993 Guittard et al.
`2/1993 Ayeret al.
`.
`
`.
`
`.
`
`5,260,275
`5,308,348
`5,356,913
`5,413,572
`5,512,293
`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
`5,922,769 *
`6,011,049 *
`6,031,004 *
`
`11/1993 Cooperetal. .
`5/1994 Balabanetal. .
`10/1994 Colca .
`5/1995 Wongetal. .
`4/1996 _Landrauetal. .
`8/1996 Roordaetal. .
`8/1996 _Kuczynskietal. .
`1/1997 Kuyezynski etal. .
`3/1997 Dongetal. .
`5/1997 Luo etal. .
`5/1997 Efendicetal. .
`7/1997 Wrightetal. .
`9/1997 Wonget al.
`.
`9/1997 Shapiro .
`10/1997 Ubillas etal. .
`11/1997 Ayeret al.
`.
`11/1997 Inmanetal. .
`.
`7/1999 Barelli et al.
`1/2000 Whitcombetal. .
`2/2000 Timminsetal. .
`
`* cited by examiner
`
`AUROBINDO EX1015, 2
`
`AUROBINDO EX1015, 2
`
`

`

`U.S. Patent
`
`Sep. 4, 2001
`
`Sheet 1 of 2
`
`US 6,284,275 B1
`
`9=U)dHSZ
`
`G’ZHONI G/0S8
`
`
`‘SLATAVLACIZIdI19/IOHNINWOSLAN
`
`A!OLg9v
`
`
`
`
`
`(SHH)SWILNOLLATOSSIA
`
`|“Old
`
`INNOWY
`
`daN10Ssid
`
`(%)
`
`AUROBINDO EX1015, 3
`
`AUROBINDO EX1015, 3
`
`

`

`U.S. Patent
`
`Sep. 4, 2001
`
`Sheet 2 of 2
`
`US 6,284,275 B1
`
`GLHONI
`
`(9=U)WdSZ
`
`cOld
`
`sen©‘ddvdSn G/00S
`OL6fk|6UtkhCUE:CQv
`
`
`“SLATEWLACIZIdD/IOHNINKOSLAW
`
`(SHH)SILNOLLNIOSSIC
`
`INNOWY
`
`G3N10SsIqd
`
`(%)
`
`AUROBINDO EX1015, 4
`
`AUROBINDO EX1015, 4
`
`

`

`US 6,284,275 B1
`
`1
`CONTROLLED RELEASE TABLET HAVING
`A UNITARY CORE
`
`This is a continuation application of Ser. No. 09/143,876
`filed Aug. 31, 1998 now U‘S. Pat. No. 6,099,862.
`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-dependentdiabetes 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 mefformin
`salts described in U.S. Pat. Nos. 3,957,853 and 4,080,472
`which are incorporated herein by reference. The sulfony-
`lurea compoundis preferably glipizide as described in U.S.
`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 U.S. 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, U.S. 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 synergisticeffect,
`since both active ingredients act to improve glucosetoler-
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`ance by different mechanism. According to the 50th edition
`of the Physicians’ Desk Reference, the GLUCOPHAGE®
`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 mefformin
`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 animalin 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.
`SUMMARYOF 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 drugis 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
`
`AUROBINDO EX1015, 5
`
`AUROBINDO EX1015, 5
`
`

`

`US 6,284,275 B1
`
`3
`the formulation described in Example 2 as tested according
`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 mefformin 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% ofthe 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% ofthe 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
`knownin 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
`
`4
`triesters, cellulose ethers, cellulose ester-ether, cellulose
`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 U.S. 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 materialis 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 componentsuch 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% ofthe total weight of the coating. The flux enhancing
`agent dissolves or leaches from the semipermeable mem-
`brane to form paths in the semipermeable membranefor the
`fluid to enter the core and dispense the active ingredients
`from the core.
`
`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 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 onthe 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.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`As used herein the term passage way includes an aperture,
`orifice, bore, hole, weaken area or an erodible element such
`55
`as a gelatin plug that erodes to form an osmotic passage way
`tableting can be performed onarotary press.
`for the release of the antihyperglycemic drug and hypogly-
`Other commonly knownexcipients may also be included
`cemic drug from the dosage form. A detailed description of
`into the core such as lubricants, pigments or dyes.
`the passageway can be found in US. Pat. Nos. 3,845,770,
`The homogeneous core is subsequently coated with a
`3,916,899, 4,034,758, 4,077,407, 4,783,337 and 5,071,607.
`semipermeable membrane, preferably a modified polymeric
`membrane to form the controlled release tablet of the
`
`60
`
`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
`
`65
`
`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 EX1015, 6
`
`AUROBINDO EX1015, 6
`
`

`

`US 6,284,275 B1
`
`
`CORE:
`
`antihyperglycemic cpd
`hypogfycemic cpd
`binder
`absorption enhancer
`COATING:
`
`semipermeable polymer
`plasticizer
`flux enhancer
`
`Preferred
`
`Most Preferred
`
`50-96%
`0.05-3%
`040%
`1-20%
`
`50-99%
`0-25%
`040%
`
`75-93%
`0.25-2%
`3-15%
`2-10%
`
`75-95%
`2-15%
`2-20%
`
`5
`
`10
`
`15
`
`The dosage forms prepared according to the present
`invention should exhibit the following dissolution profile
`whentested 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)
`Preferred
`Most Preferred
`2
`0-30%
`0-25%
`4
`10-50%
`20-45%
`8
`30-90%
`45-90%
`12
`NLT 50%
`NLT 60%
`16
`NLT 60%
`NLT 70%
`
`NLT = NOT LESS THAN
`
`10/23 HYPOGLYCEMIC RELEASE
`Time (hours)
`Preferred
`Most Preferred
`2
`0-30%
`0-25%
`4
`10-50%
`20-45%
`8
`30-90%
`45-90%
`12
`NLT 50%
`NLT 60%
`16
`NLT 60%
`NLT 70%
`
`NLT = 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. In the alternative, dry granulation techniques may
`be used to prepare the granules for making compressed
`tablets.
`
`DESCRIPTION OF THE PREFERRED
`EMBODIMENTS
`
`EXAMPLE1
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`A once a day controlled release tablet containing 850 mg 65
`of metformin HCl and 5 mg of glipizide and having the
`following formula is prepared as follows:
`
`Core
`metformin HCl
`glipizide
`povidone’, USP
`sodium lauryl sulfate
`magnesium stearate
`
`Weight %
`88.10%
`0.52%
`6.33%
`4.56%
`0.50%
`
`approximate molecular weight 1,000,000; dynamic viscosity (10% w/v
`solution at 20° C.) = 300-700 m Pa s.
`
`(a) Granulation
`1321.46 g of metformin HCl and 67.01 g of sodium lauryl
`sulfate are delumped by passing the compounds through a
`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 mefformin HC] 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 mimin. Once the granulating solution is depleted
`and the granules are dried in thefluidized 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 mefformin HCl/
`glipizide granules for approximately five (5) minutes. After
`blending,
`the granules are compressed on a rotary press
`fitted with 152"round standard concave punches.
`(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
`core using a pan coater under the following conditions:
`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
`coating level of approximately 2% is obtained.
`
`Sustained Release Coating
`cellulose acetate (398-10)
`triacetin
`PEG 400
`
`Weight %
`85%
`5%
`10%
`
`Zacetyl content 39.3-40.3%
`Sweight av. molecular weight 380-420
`
`(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 homogenoussolution is obtained. The coating solu-
`tion is then sprayed onto the seal coated tablets in a fluidized
`bed coater employing the following conditions: product
`temperature 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
`approximately 3% is obtained.
`Once the theoretical coating level is obtained, the sus-
`tained release coated tablets are dried in the fluidized bed
`
`coater for approximately 5 to 10 minutes. Then one hole is
`
`AUROBINDO EX1015, 7
`
`AUROBINDO EX1015, 7
`
`

`

`US 6,284,275 B1
`
`7
`either mechanically drilled or laser drilled onto each side of
`the sustained release tablet.
`
`Theresulting 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:
`
`TIME(hours)
`
`% Released (pH 7.5)
`METFORMIN HCl RELEASE
`
`ReANaANY
`ReANaABNY
`
`wna
`
`wn~
`
`Sustained Release Coating
`
`Weight %
`
`cellulose acetate (398-10)°
`triacetin
`PEG 400°
`
`85%
`5%
`10%
`
`“acetyl content 39.3-40.3%
`°weight 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:
`
`10
`
`15
`
`20
`
`Therelease profile in simulated intestinal fluid (pH 7.5) of
`the sustained release product prepared in this Example is
`shown in FIG. 1.
`
`25
`
`EXAMPLE 2
`
`A controlled release tablet containing 500 mg of met-
`formin HC] and 5 mgofglipizide and having the following
`formula is prepared as follows:
`
`Core
`metformin HCl
`glipizide
`povidone*, USP
`sodium lauryl sulfate
`magnesium stearate
`
`Weight %
`87.77%
`0.88%
`6.31%
`4.54%
`0.50%
`
`‘approximate molecular weight = 1,000,000 dynamic viscosity (10% w/v
`solution at 20° C.) = 300-700 m Pa 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 meshscreen 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 mefformin HCI 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
`granulesare 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
`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.
`
`30
`
`35
`
`40
`
`45
`
`55
`
`60
`
`TIME(hours)
`
`% Released (pH 7.5)
`METFORMIN HCl RELEASE
`
`ReANaANY
`ReANaANY
`
`~Oo
`
`wna
`
`Therelease 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 claimsare 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 consisting
`essentially of:
`(a) a core consisting essentially of:
`(i) buformin or a pharmaceutically acceptable salt
`thereof;
`(ii) glipizide;
`(iii) polyvinyl pyrrolidone; and
`(iv) sodium lauryl sulfate;
`(b) optionally, a seal coat around the core;
`(c) a semipermeable membranecoating 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 release of the buformin or a pharma-
`ceutically acceptable salt thereof and glipizide from the
`core to the environmentof use to provide therapeutic
`levels of buformin or a pharmaceutically acceptable
`salt thereof and glipizide for from 12 to 24 hours.
`
`AUROBINDO EX1015, 8
`
`AUROBINDO EX1015, 8
`
`

`

`US 6,284,275 B1
`
`9
`2. 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 and mixtures thereof.
`3. Acontrolled release pharmaceutical as defined in claim
`1 wherein the absorption enhanceris a fatty acid selected
`from the group consisting of capric acid,oleic acid and their
`monoglycerides.
`4. Acontrolled release pharmaceutical tablet as defined in
`claim 1 wherein the absorption enhanceris a chelating agent
`selected from the group consisting of citric acid and phytic
`acid.
`
`5. Acontrolled release pharmaceutical tablet as defined in
`claim 1 wherein the absorption enhancerisa bile salt.
`6. Acontrolled release pharmaceutical tablet as defined in
`claim 1 wherein the semipermeable membrane around the
`core is cellulose acetate.
`
`7. Acontrolled release pharmaceutical tablet as defined in
`claim 1 wherein the semipermeable membraneincludes a
`flux enhancer.
`8. Acontrolled release pharmaceutical tablet as defined in
`claim 1 wherein the flux enhancer is sodium chloride,
`potassium chloride, sugar, sucrose, sorbitol, mannitol, poly-
`ethylene glycol, propylene glycol, hydroxypropyl] cellulose
`and mixtures thereof.
`9. Acontrolled release pharmaceutical tablet as defined in
`claim 8 wherein the flux enhancer is polyethylene glycol
`with an average molecular weight between 380 and 420.
`10. A controlled release pharmaceutical tablet as defined
`in claim 1 wherein the semipermeable membrane comprises
`a plasticizer.
`11. A controlled release pharmaceutical tablet as defined
`in claim 1 wherein at least two passageways are formed in
`the semipermeable membrane.
`12. A controlled release pharmaceutical tablet as defined
`in claim 1 that exhibits the following dissolution profile
`when tested in a USP type 2 paddle apparatus at 75 rpm in
`900 ml of simulated intestinal fluid, pH 7.5 phosphate buffer,
`at 37° C.:
`
`after 2 hours 0O—-30% of the buformin is released;
`after 4 hours 10-50% of the buformin is released;
`after 8 hours 30-90% of the buformin is released;
`after 12 hours not
`less than 50% of the buformin is
`released;
`after 16 hours not
`released and
`
`less than 60% of the buformin is
`
`after 2 hours 0-30% of the glipizide is released;
`after 4 hours 10-50% of the glipizide is released;
`after 8 hours 30-90% of the glipizide is released;
`after 12 hours not
`less than 50% of the glipizide is
`released;
`after 16 hours not
`released.
`
`less than 60% of the glipizide is
`
`13. A controlled release pharmaceutical tablet as defined
`in claim 11 that exhibits the following dissolution profile
`whentested in a USP type 2 paddle apparatus at 75 rpms in
`900 of simulated intestinal fluid, pH 7.5 phosphate buffer, at
`37° C.:
`
`after 2 hours O-25% of the buformin is released;
`after 4 hours 20-45% of the buformin is released;
`after 8 hours 45-90% of the buformin is released;
`after 12 hours not
`less than 60% of the buformin is
`released;
`after 16 hours not
`released and
`
`less than 90% of the buformin is
`
`10
`
`15
`
`20
`
`25
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`less than 70% of the glipizide is
`
`10
`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;
`after 16 hours not
`released.
`14. A controlled release pharmaceutical tablet consisting
`essentially of:
`(a) a core consisting essentially of:
`(i) metformin or a pharmaceutically acceptable salt
`thereof;
`(ii) glyburide;
`(iii) polyvinyl pyrrolidone; and
`(iv) sodium lauryl sulfate;
`(b) optionally, a seal coat around the core;
`(c) a semipermeable membranecoating 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 release of the metformin or a pharma-
`ceutically acceptable salt thereof and glyburide from
`the core to the environment of use to provide thera-
`peutic levels of metformin or a pharmaceutically
`acceptable salt thereof and glyburide for from 12 to 24
`hours.
`
`15. A controlled release pharmaceutical tablet consisting
`essentially of:
`(a) a core consisting essentially of:
`(i) buformin or a pharmaceutically acceptable salt
`thereof;
`(ii) glyburide;
`(iii) polyvinyl pyrrolidone; and
`(iv) sodium lauryl sulfate;
`(b) optionally, a seal coat around the core;
`(c) a semipermeable membranecoating 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 release of the buformin or a pharma-
`ceutically acceptable salt thereof and glyburide from
`the core to the environment of use to provide thera-
`peutic levels of buformin or a pharmaceutically accept-
`able salt thereof and glyburide for from 12 to 24 hours.
`16. A controlled release pharmaceutical tablet as defined
`in claim 14 wherein the absorption enhanceris selected from
`the group consisting of fatty acids, surfactants, chelating
`agents, bile salts and mixtures thereof.
`17. A controlled release pharmaceutical as defined in
`claim 14 wherein the absorption enhancer is a fatty acid
`selected from the group consisting of capric acid,oleic acid,
`and their monoglycerides.
`18. A controlled release pharmaceutical tablet as defined
`in claim 14 wherein the absorption enhanceris a chelating
`agent selected from the