PCT
`
`WORLD INTELLECTUAL-PROPERTY ORGANIZATION
`International Bureau
`
`
`
`9 March 2000 (09.03.00)
`
`
`
`(22) International Filing Date:
`
`31 August 1999 (31.08.99)
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY(PCT)
`(51) International PatentClassification 7 :
`(11) International Publication Number:
`WO 00/12097
`A61K 31/64, 9/28 // (A61K 31/64, 31:155)
`.
`i.
`(43) International Publication Date:
`
`from the core.
`
`(21) International Application Number: PCT/US99/19978|(81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR,
`BY, CA, CH, CN, CU, CZ, DE, DK,EE, ES, FI, GB, GE,
`GH, GM, HR, HU,ID, IL, IS, JP, KE, KG, KP, KR, KZ,
`LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW,
`MX,NO, NZ, PL, PT, RO, RU, SD, SE, SG,SI, SK, SL, TJ,
`TM, TR, TT, UA, UG, UZ, VN, YU, ZW, ARIPO patent
`(GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), Eurasian
`patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
`patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR,
`IE, IT, LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF,
`CG, CI, CM, GA, GN, GW, ML, MR,NE,SN, TD, TG).
`
`(30) Priority Data:
`09/132,796
`
`31 August 1998 (31.08.98)
`
`US
`
`(71) Applicant: ANDRX PHARMACEUTICALS, INC. [US/US];
`Suite 201, 4001 S.W. 47th Avenue, Fort Lauderdale, FL
`33314 (US).
`
`(72) Inventors: CHEN, Chih-Ming; 10680 S.W. 40th Manor,|Published
`
`Davie, FL 33328 (US). CHENG, Xiu, Xiu; Apartment
`With international search report.
`506, 3150 W.Rolling Hills Circle, Davie, FL 33328 (US).
`Before the expiration of the time limit for amending the
`CHOU, Joseph; 5755 N.W. 54th Place, Coral Springs, FL
`claims and to be republished in the event of the receipt of
`33067 (US).
`JAN, Steve; 512 N.W. 120th Drive, Coral
`amendments.
`Springs, FL 33071 (US).
`
`(74) Agent: ENDRES, Martin, P.; Hedman, Gibson & Costigan,
`P.C., 1185 Avenue of the Americas,.New York, NY 10036
`(US).
`
`(54) Title) CONTROLLED RELEASE TABLET COMPRISING A HYPOGLYCEMIC DRUG AND AN ANTIHYPERGLYCEMIC
`DRUG
`
`METFORMIN HCI/GLIPIZIDE TABLETS,850/5
`
`100
`
`80
`
`amount 2
`DISSOLVED 40
`
`8
`DISSOLUTION TIME (HRS)
`
`(57) Abstract
`
`tablet containing antihyperglycemic drug and a hypoglycemic drug that does not contain
`A controlled release pharmaceutical
`an expanding or gelling polymer layer and comprising 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
`
`AUROBINDO EX1007, 1
`
`AUROBINDO EX1007, 1
`
`

`

`Singapore
`
`Albania
`Armenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`Cote d'Ivoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`ES
`FI
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`Lc
`LI
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Treland
`Tsrael
`Tceland
`Ttaly
`Japan
`Kenya
`Kyrgyzstan
`Democratic People’s
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`°
`Monaco
`Republic of Moldova
`Madagascar
`The former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`
`Slovenia
`SI
`Slovakia
`SK
`Senegal
`SN
`Swaziland
`SZ
`Chad
`TD
`Togo
`TG
`Tajikistan
`TJ
`™ Turkmenistan
`TR
`Turkey
`TT
`Trinidad and Tobago
`UA
`Ukraine
`UG
`Uganda
`US
`United States of America
`UZ
`Uzbekistan
`VN
`Viet Nam
`YU
`Yugoslavia
`ZW
`Zimbabwe
`
`AUROBINDO EX1007, 2
`
`AUROBINDO EX1007, 2
`
`

`

`WO 00/12097
`
`PCT/US99/19978
`
`CONTROLLED RELEASE TABLET COMPRISING A HYPOGLYCEMIC DRUG AND AN ANTIHYPERGLYCEMIC
`DRUG
`
`BACKGROUND OF THE INVENTION:
`
`The present invention relates to controlled release unit dose
`
`formulations containing an antihyperglycemic drug and a hypoglycemic
`
`drug. As usedin this specification the term "antihyperglycemic" refers to a
`drug that is useful in controlling or managing noninsulin-dependent diabetes
`
`mellitus (NIDDM) by decreasing hepatic glucose production, decreasing
`
`intestinal absorption of glucose and/or improving insulinsensitivity.
`
`10
`
`Biguanides are the preferred antihyperglycemic drugs. As usedin 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.
`
`15
`
`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 United States Patent Nos. 3,957,853 and
`
`20
`
`4,080,472 which are incorporated herein by reference. The sulfonylurea
`
`compoundis preferably glipizide as described in United States Patent No.
`
`9,545,413 or glyburide. Other possible sulfonylurea compounds such as
`
`glibornuride, glisoxepide, gliclazide acetohexamide, chlorpropamide,
`
`AUROBINDO EX1007, 3
`
`AUROBINDO EX1007, 3
`
`

`

`WwO 00/12097
`
`PCT/US99/19978
`
`tolazamide, tolbutamide and tolbutamide which are described in United
`
`States Patent 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.
`
`Ina 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 formsin order to maintain
`
`therapeutic serum levels of medicaments and to minimize the effects of
`
`missed doses of drugs caused bya 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,
`
`United States Patent Nos. 5,545,413, 5,591,454 and 5,091,190 disclose
`
`controlled release dosage forms containing only the drug glipizide and
`
`employ a hydrogel to push the active ingredient from the dosage form.
`
`20
`
`The 50th edition of the Physicians’ Desk Reference®, copyright 1996,
`
`suggests administering to a patient a metformin HCl dosage form
`
`commercially available from Bristol-Myers Squibb Co. under the tradename
`
`GLUCOPHAGE®and a dosage form of a sulfonylurea compound such as
`
`AUROBINDO EX1007, 4
`
`AUROBINDO EX1007, 4
`
`

`

`WO 00/12097
`
`PCT/US99/19978
`
`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 tolerance by different mechanism.
`
`According to the 50th edition of the Physicians’ Desk Reference, the
`
`GLUCOPHAGE®dosageform is believed to function by decreasing hepatic
`
`glucose production, decreasing intestinal absorption of glucose and
`
`improving insulin sensitivity, while the sulfonylurea compoundis believed to
`
`10
`
`lower the blood glucoselevels by stimulating the release of insulin from the
`
`pancreas.
`
`Although the 50th edition of the Physicians’ Desk Reference
`
`suggests the combined administration of metformin HCl and a sulfonyiurea
`
`compound, it fails to suggest a single unitary controlled release dosage
`
`15
`
`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 animalin need of
`
`such treatment over a twelve hour or twenty-four hour period.
`
`It is an object of the present invention to provide a controlled or
`
`20
`
`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
`
`AUROBINDO EX1007, 5
`
`AUROBINDO EX1007, 5
`
`

`

`WO 00/12097
`
`PCT/US99/19978
`
`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 homogeneouscore
`
`10
`
`wherein the core component may be madeusing 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)
`
`(ii)
`
`(iil)
`
`(iv)
`
`an antihyperglycemic drug;
`
`a hypoglycemic drug;
`
`a binding agent; and
`
`optionally, an absorption enhancer;
`
`20
`
`(b) optionally a seal coating layer around the core;
`
`(c) a semipermeable coating membrane surrounding the core; and
`
`AUROBINDO EX1007, 6
`
`AUROBINDO EX1007, 6
`
`

`

`WO 00/12097
`
`PCT/US99/19978
`
`(d) at least one passageway in the semipermeable membraneto allow
`
`release of the antihyperglycemic drug and the hypoglycemic drug.
`
`In the preferred embodiment the antihyperglycemic drugis 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
`
`10
`
`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 XXIll, 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
`
`15
`
`Example 2 as tested according to the procedure described in United States
`
`Pharmacopeia XXill, Apparatus 2 @ 75 rpm.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`The term antihyperglycemic drug as usedin this specification refers
`
`20
`
`to drugs that are useful in controlling or managing noninsulin-dependent
`diabetes mellitus (NIDDM) by decreasing hepatic glucose production,
`
`decreasing intestinal absorption of glucose and/or improving insulin
`
`sensitivity. Preferably the antihyperglycemic drug is a biguanide such as
`
`AUROBINDO EX1007, 7
`
`AUROBINDO EX1007, 7
`
`

`

`WO 00/12097
`
`PCT/US99/19978
`
`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 stimulating the release ofinsulin 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.
`
`10
`
`The binding agent may be any conventionally known
`
`pharmaceutically acceptable binder, butit 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,
`
`15
`
`hydroxyethyl cellulose, hydroxypropyl methylcellulose 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
`
`20
`
`absorption enhancer commonly knownin 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,
`
`AUROBINDO EX1007, 8
`
`AUROBINDO EX1007, 8
`
`

`

`WO 00/12097
`
`PCT/US99/19978
`
`such as sodium lauryl sulfate, sodium dodecyl sulfate and polysorbate 80,
`
`chelating agents such ascitric acid and phytic acid. The core comprises
`
`approximately 1 to about 20% absorption enhancer based onthetotal
`weight of the core and mostpreferably 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
`
`enhanceris preferably formed by mixing and tableting techniques commonly
`
`knownin the art. The core may also be formed by granulating 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.
`
`15
`
`The homogeneouscore is subsequently coated with a
`
`semipermeable membrane, preferably a modified polymeric membraneto
`
`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
`
`20
`
`antihyperglycemic drug and/orthe hypoglycemic drug in the core. Materials
`that are useful in forming the semipermeable membraneare cellulose
`
`esters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose
`
`ester-ether, cellulose acylate, cellulose diacylate, cellulose triacylate,
`
`AUROBINDO EX1007, 9
`
`AUROBINDO EX1007, 9
`
`

`

`WO 00/12097
`
`PCT/US99/19978
`
`cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate
`
`propionate, cellulose acetate butyrate and ethylcellulose. Other suitable
`
`polymers are described in United States Patent Nos. 3,845,770, 3,916,899,
`
`4,008,719, 4,036,228 and 4,11210 which are incorporated herein by
`
`reference. The most preferred semipermeable membrane materialis
`
`cellulose 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 membrane can be
`
`10
`
`formed from the above-described polymers and a flux enhancing agent.
`
`The flux enhancing agent increase the volumeoffluid imbibed into the core
`
`to enable the dosage form to dispense substantially all of the
`
`antihyperglycemic drug and hypoglycemic drug through both the
`
`passageway and the porous membrane. The flux enhancing agent is a
`
`15
`
`water-soluble component such as sodium chloride, potassium chloride,
`
`sugar, sucrose, sorbitol, mannitol, polyethylene glycol (weight av. molecular
`
`weight 380-3700), propylene glycol, hydroxypropyl cellulose, hydroxypropyl
`
`methylcellulose and mixtures thereof. The preferred flux enhancer is PEG
`
`400.
`
`20
`
`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 membrane to form paths in the semipermeable membrane
`
`AUROBINDO EX1007, 10
`
`AUROBINDO EX1007, 10
`
`

`

`WO 00/12097
`
`PCT/US99/19978
`
`for the fluid to enter the core and dispense the active ingredients from the
`
`core.
`
`The semipermeable membrane mayalso be formed with commonly
`
`known excipients such a plasticizer. Some commonly knownplasticizers
`
`include adipate, azelate, enzoate, citrate, stearate, isoebucate, sebacate,
`
`triethyl citrate, tri-n-buty! 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, dioctyiphthalate,
`
`dibutylsebacate, triethylcitrate, tributylcitrate, glyceroltributyrate, and thelike.
`Depending on the particular plasticizer, amounts of from 0% to 25%, and
`
`15
`
`preferably 2 to 15% of the plasticizer can be used based uponthetotal
`
`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
`
`20
`
`antihyperglycemic drug and hypoglycemic drug from the dosage form. A
`detailed description of the passageway can be found in United States
`
`Patent Nos. 3,845,770, 3,916,899, 4,034,758, 4,077,407, 4,783,337 and
`
`5,071,607.
`
`AUROBINDO EX1007, 11
`
`AUROBINDO EX1007, 11
`
`

`

`WO 00/12097
`
`PCT/US99/19978
`
`Generally, the membrane coating around the core will 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:
`
`Preferred
`
`Most Preferred
`
`CORE:
`antihyperglycemic cpd
`hypoglycemic cpd
`binder
`absorption enhancer
`
`15
`
`COATING:
`semipermeable polymer
`plasticizer
`flux enhancer
`
`50-96%
`0.05-3%
`0-40%
`1-20%
`
`50-99%
`0-25%
`0-40%
`
`75-93%
`0.25-2%
`3-15%
`2-10%
`
`75-95%
`2-15%
`2-20%
`
`20
`
`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 mlof simulated intestinal fluid (pH 7.5
`
`phosphate buffer) and at 37°C:
`
`25
`
`30
`
`Time (hours)
`
`2
`4
`8
`12
`16
`
`ANTIHYPERGLYCEMIC RELEASE
`
`Preferred
`
`Most Preferred
`
`0-30%
`10-50%
`30-90%
`NLT 50%
`NLT 60%
`
`0-25%
`20-45%
`45-90%
`NLT 60%
`NLT 70%
`
`NLT = NOT LESS THAN
`
`10
`
`AUROBINDO EX1007, 12
`
`AUROBINDO EX1007, 12
`
`

`

`WO 00/12097
`
`PCT/US99/19978
`
`HYPOGLYCEMIC RELEASE
`
`Preferred
`
`Most Preferred
`
`Time (hours)
`
`2
`4
`8
`12
`16
`
`10
`
`NLT = NOT LESS THAN
`
`0-30%
`10-50%
`30-90%
`NLT 50%
`NLT 60%
`
`0-25%
`20-45%
`45-90%
`NLT 60%
`NLT 70%
`
`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 disclosed
`
`in Remington’s Pharmaceutical Sciences, 1995 Edition 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
`
`20
`
`tablets.
`
`DESCRIPTION OF THE PREFERRED EMBODIMENTS
`
`EXAMPLE1
`
`25
`
`A once a day controlled release tablet containing 850 mg of metformin
`
`HCI and 5 mg ofglipizide and having the following formula is prepared as
`
`follows:
`
`11
`
`AUROBINDO EX1007, 13
`
`AUROBINDO EX1007, 13
`
`

`

`WO 00/12097
`
`PCT/US99/19978
`
`
`
` i Core
`
`metformin HCl
`
`glipizide
`
`povidone’, USP
`
`sodium lauryl sulfate
`
`Weight %
`
`88.10%
`
`0.52%
`
`6.33%
`
`4.56%
`
`magnesium stearate
`0.50%
`' approximate molecular weight = 1,000,000, dynamic viscosity (10%w/v solution at 20°C) = 300-
`
`700 m Pas.
`
`(a)
`
`Granulation
`
`10
`
`1321.46 g of metformin HC! 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 metformin HCl and sodium lauryl
`
`15
`
`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 driedin the fluidized bed
`
`20
`
`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.
`
`AUROBINDO EX1007, 14
`
`AUROBINDO EX1007, 14
`
`

`

`WO 00/12097
`
`PCT/US99/19978
`
`(b)
`
` Tableting
`
`7.50 g of magnesium stearate is passed through a 40 meshstainless
`
`steel screen and blended with the metformin HC\/glipizide granules for
`
`approximately five (5) minutes. After blending, the granules are compressed
`
`5
`
`ona rotary pressfitted with 15/32" 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 clearin purified water. The Opadry solution is then sprayed
`
`10
`
`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 sealcoating
`
`until a theoretical coating level of approximately 2% is obtained.
`
`15
`
`Il
`
`Sustained Release Coating
`
`Weight %
`
`cellulose acetate (398-10)*
`
`triacetin
`
`PEG 400°
`
`2 acetyl content 39.3 - 40.3%
`
`85%
`
`5%
`
`10%
`
`20
`
`°* weight av. molecular weight 380-420
`(d) Sustained Release Coating
`
`The cellulose acetate is dissolved in acetone while stirring with a
`
`homogenizer. The polyethylene glycol 400 andtriacetin are added to the
`
`13
`
`AUROBINDO EX1007, 15
`
`AUROBINDO EX1007, 15
`
`

`

`WO 00/12097
`
`PCT/US99/19978
`
`cellulose acetate solution and stirred until a homogenoussolution is obtained.
`
`The coating solution 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 approximately 1-2 bar; and a sprayrate of 10-
`
`30 mi/min. This coating process continues until a theoretical coating level of
`
`approximately 3% is obtained.
`
`Once the theoretical coating level
`
`is obtained, the sustained release
`
`coated tablets are dried in the fluidized bed coater for approximately 5 to 10
`
`minutes. Then onehole is either mechanically drilled or laser drilled onto each
`
`10
`
`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 XxXiIll,
`
`Apparatus 2 (paddle) @ 75 rpm and found to have the following release
`
`15
`
`20
`
`25
`
`30
`
`profile:
`
`TIME (hours)
`2
`4
`8
`12
`16
`
`TIME (hours)
`2
`4
`8
`12
`16
`
`METFORMIN HCI RELEASE
`
`% Released (pH 7.5)
`17
`32
`56
`76
`89
`
`GLIPIZIDE RELEASE
`
`% Released (pH 7.5)
`22
`37
`57
`76
`90
`
`AUROBINDO EX1007, 16
`
`AUROBINDO EX1007, 16
`
`

`

`WO 00/12097
`
`PCT/US99/19978
`
`The release profile in simulated intestinal fluid (pH 7.5) of the sustained
`
`release product prepared in this Example is shown in Figure 1.
`
`EXAMPLE 2
`
`A controlled release tablet containing 500 mg of metformin HCI and 5
`
`mg of glipizide and having the following formula is prepared as follows:
`
`|
`
`Core
`
`metformin HCI
`
`glipizide
`
`10
`
`povidone’, USP
`
`sodium lauryl sulfate
`
`magnesium stearate
`
`Weight %
`
`87.77%
`
`0.88%
`
`6.31%
`
`4.54%
`
`0.50%
`
`4 approximate molecular weight = 1,000,000 dynamic viscosity (10%w/v solution at 20°C) = 300-
`
`700 m Pas.
`
`15
`
`(a)
`
`Granulation
`
`5.266 kg of metformin HCI 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
`
`20
`
`dispersed in the solution. The mixture of metformin HCI and sodium lauryl
`sulfate is then added to a top-sprayfluidized 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;
`
`15
`
`AUROBINDO EX1007, 17
`
`AUROBINDO EX1007, 17
`
`

`

`WO 00/12097
`
`PCT/US99/19978
`
`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.
`
`5
`
`(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)
`
`10
`
`The tablets are seal coated with an Opadry material or other suitable
`
`water-soluble material according to the procedure outlined in Example 1.
`
`I
`
`Sustained Release Coating
`
`Weight %
`
`cellulose acetate (398-10)°
`
`15
`
`triacetin
`
`PEG 400°
`
`$ acetyl content 39.3 - 40.3%
`
`$ weight av. molecular weight 380-420
`
`85%
`
`5%
`
`10%
`
`20
`
`(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
`
`AUROBINDO EX1007, 18
`
`AUROBINDO EX1007, 18
`
`

`

`WO 00/12097
`
`PCT/US99/19978
`
`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 XXiIil,
`
`Apparatus 2 (paddle) @ 75 rpm and found to have the following release
`
`profile:
`
`TIME (hours)
`2
`4
`8
`12
`16
`
`TIME (hours)
`2
`4
`8
`12
`16
`
`10
`
`15
`
`20
`
`METFORMIN HCI RELEASE
`
`% Released (pH 7.5)
`23
`41
`70
`92
`98
`
`GLIPIZIDE RELEASE
`% Released (pH 7.5)
`23
`35
`56
`75
`90
`
`The releaseprofile in SIF of the sustained release product preparedin
`
`this Example is shown in Figure 2.
`
`25
`
`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 appendedclaimsare intendedto cover all embodiments of the
`
`invention and modifications thereof which do not depart from the spirit and
`
`30
`
`scope of the invention.
`
`AUROBINDO EX1007, 19
`
`AUROBINDO EX1007, 19
`
`

`

`WO 00/12097
`
`PCT/US99/19978
`
`Weclaim:
`
`1.
`
`A controlled release pharmaceutical tablet comprising:
`
`(a) a core comprising:
`
`(i)
`
`(il)
`
`(iii)
`
`(iv)
`
`an antihyperglycemic drug;
`
`a hypoglycemic drug,
`
`a binding agent; and
`
`optionally, an absorption enhancer;
`
`10
`
`(b) optionally a seal coating layer around the core;
`(c) a semipermeable membrane coating covering said core; and
`(d) at least one passageway in the semipermeable membraneto allow the
`
`release of the antihyperglycemic drug and the hypoglycemic drug from the
`
`core to the environment of use.
`
`15
`
`2.
`
`A controlled release pharmaceutical tablet as defined in claim 1 wherein
`
`the antihyperglycemic drug is a biguanide.
`
`3.
`
`A controlled release pharmaceutical tablet as defined in claim 2 wherein
`
`the antihyperglycemic drug is metformin or a pharmaceutically acceptable salt
`
`20
`
`thereof.
`
`AUROBINDO EX1007, 20
`
`AUROBINDO EX1007, 20
`
`

`

`WO 00/12097
`
`PCT/US99/19978
`
`4.
`
`Acontrolled release pharmaceutical tablet as defined in claim 2 wherein
`
`the antihyperglycemic drug is buformin or a pharmaceutically acceptable salt
`
`thereof.
`
`5.
`
`A controlled release pharmaceutical tablet as defined in claim 1 wherein
`
`the hypoglycemic drug is a sulfonylurea compound.
`
`6.
`
`Acontrolled release pharmaceutical tablet as defined in claim 5 wherein
`
`the hypoglycemic drugis glipizide.
`
`10
`
`7.
`
`A controlled release pharmaceutical tablet as defined in claim 5 wherein
`
`the hypoglycemic drug is glyburide.
`
`8.
`
`A controlled release pharmaceutical tablet as defined in claim 1 wherein
`
`15
`
`the binding agent is water-soluble.
`
`9,
`
`A controlled release pharmaceutical tablet as defined in claim 1 wherein
`
`the water-soluble binding agent
`
`is selcted from the group consisting of
`
`polyvinyl
`
`pyrrolidone,
`
`hydroxypropyl
`
`cellulose,
`
`hydroxyethyl
`
`cellose,
`
`20
`
`hydroxypropyl methycellulose or mixtures thereof.
`
`10.
`
`Acontrolled release pharmaceutical tablet as defined in claim 9 wherein
`
`the water-soluble binding agent is polyvinyl pyrrolidone.
`
`19
`
`AUROBINDO EX1007, 21
`
`AUROBINDO EX1007, 21
`
`

`

`WO 00/12097
`
`PCT/US99/19978
`
`141.|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.
`
`12.
`
`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 or their monoglycerides.
`
`13.
`
`Accontrolled release pharmaceutical as defined in claim 1 wherein the
`
`10
`
`absorption enhancer is a surfactant selected from the group consisting of
`
`sodium lauryl! sulfate, sodium dodecyl sulfate and polysorbate 80.
`
`14.
`
`Accontrolled release pharmaceutical as defined in claim 1 wherein the
`
`absorption enhanceris a chelating agent selected from the group consisting
`
`15
`
`of citric acid and phytic acid.
`
`15.
`
`Acontrolled release pharmaceutical as defined in claim 1 wherein the
`
`absorption enhanceris a bile salt.
`
`20
`
`16.
`
`Acontrolled release pharmaceutical tablet as defined in claim 1 wherein
`
`the absorption enhancer is sodium lauryl sulfate.
`
`20
`
`AUROBINDO EX1007, 22
`
`AUROBINDO EX1007, 22
`
`

`

`WO 00/12097 —
`
`PCT/US99/19978
`
`17.
`
`Acontrolled release pharmaceutical tablet as defined in claim 1 wherein
`
`the semipermeable membrane around the core is a water-insoluble cellulose
`
`derivative.
`
`18.
`
`A controlled release pharmaceutical
`
`tablet as defined in claim 17
`
`wherein the water-insoluble cellulose derivative is cellulose acetate.
`
`19.
`
`Acontrolled release pharmaceutical tablet as defined in claim 1 wherein
`
`semipermeable membrane comprises a flux enhancer.
`
`20.
`
`A controlled release pharmaceutical
`
`tablet as defined in claim 19
`
`wherein the flux enhancer is sodium chloride, potassium chloride, sugar,
`
`sucrose,
`
`sorbitol, mannitol,
`
`polyethylene
`
`glycol,
`
`propylene
`
`glycol,
`
`hydroxypropyl!cellulose or mixtures thereof.
`
`10
`
`15
`
`21.
`
`A controlled release pharmaceutical
`
`tablet as defined in claim 20
`
`wherein the flux enhanceris polyethylene glycol with an average molecular
`
`weight between 380 and 420.
`
`20
`
`22.
`
`Aconirolled release pharmaceutical tablet as defined in claim 1 wherein
`
`the semipermeable membrane comprisesa plasticizer.
`
`21
`
`AUROBINDO EX1007, 23
`
`AUROBINDO EX1007, 23
`
`

`

`WO 00/12097
`
`PCT/US99/19978
`
`23.
`
`A controlled release pharmaceutical
`
`tablet as defined in claim 22
`
`wherein the plasticizer is triacetin.
`
`24.
`
` Acontrolled release pharmaceutical tablet as defined in claim 1 wherein
`
`at least two passageways are formed in the semipermeable membrane.
`
`25.
`
`Acontrolled 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
`
`10
`
`buffer) and at 37°C:
`
`after 2 hours 0-30%of the antihyperglycemic drug is released;
`
`after 4 hours 10-50% of the antihyperglycemic drug is released;
`
`after 8 hours 30-90% of the antihyperglycemic drug is released;
`
`after 12 hours not less than 50% of the antihyperglycemic drug is released;
`
`and
`
`after 16 hours not less than 60%of the antihnyperclycemic drug is released;
`
`and
`
`after 2 hours 0-30% of the hypoglycemic drug is released;
`
`after 4 hours 10-50%of the hypoglycemic drug is released;
`
`20
`
`after 8 hours 30-90%of the hypogiycmic drug is released;
`
`after 12 hours not less than 50% of the hypoglycemic drug is released; and
`
`after 16 hours not less than 60%of the hypolycemic drug is released.
`
`22
`
`AUROBINDO EX1007, 24
`
`AUROBINDO EX1007, 24
`
`

`

`WO 00/12097
`
`PCT/US99/19978
`
`26.
`
`A controlled release pharmaceutical tablet as defined in claim 1 that
`
`exhibits the following dissolution prof