. WORLD INTELLECTUAL PROPERTY ORGANIZATION
`Intematlonal Bureau
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) International Patent Classification 7 =
`
`(11) International Publication Number:
`
`WO 00/28989
`
`A61K 31/353, 3114439, 9/32, 9/52, 45/06,
`A611) 3/10
`
`.
`_
`_
`(43) International Publlcatlon Date:
`
`25 May 2000 (25.05.00)
`
`(21) International Application Number:
`
`PCT/EP99/O8704
`
`(22) International Filing Date:
`
`8 November 1999 (08.11.99)
`
`BE Vincenzo [GB/GB]; .SmithKline Beecham .Pharmaceu'
`tlcals, New Frontlers Solence Park South, Thlrd Avenue,
`HaflOW’ Essex CM19 SAW (GB).
`
`(74) Agent: RUTTER, Keith; SmithKline Beecham Corporate
`Intellectual Property, Two New Horizons Court, Brentford,
`Mlddlesex TW8 9EP (GB)-
`
`(30) Priority Data:
`98248669
`98248677
`98248693
`9912193.]
`99121907
`99121915
`
`12 November 1998 (12.11.98)
`12 November 1998 (12.11.98)
`12 November 1998 (12.11.98)
`25 May 1999 (25.05.99)
`25 May 1999 (25.05.99)
`25 May 1999 (25.05.99)
`
`(71) Applicant (for all designated States except US): SMITHKLINE
`BEECHAM P.L.C. [GB/GB]; New Horizons Court, Brent—
`ford, Middlesex TW8 9EP (GB).
`
`amendments.
`
`'GB
`GB
`GB
`GB (81) Designated States: AE, AL, AM, AT, AU, AZ, BA, BB, BG,
`GB
`BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE,
`GB
`ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP,
`KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA,
`MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU,
`SD, SE, SG, SI, SK, SL, TJ, TM, TR, Tl“, TZ, UA, UG,
`US, UZ, VN, YU, ZA, ZW, ARIPO patent (GH, GM, KE,
`LS, MW, SD, SL, SZ, TZ, 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).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): LEWIS, Karen [GB/GB];
`SmithKline Beecham Pharmaceuticals, New Frontiers
`Science Park South, Third Avenue, Harlow, Essex CM19
`SAW (GB). LILLIOTI‘, Nicola, Jayne [GB/GB]; SmithK-
`line Beecham Pharmaceuticals, New Frontiers Science Published
`Park South, Third Avenue, Harlow, Essex CM19 SAW
`With international search report.
`(GB). MACKENZIE, Donald, Colin [GB/GB]; SmithKline
`Before the expiration of the time limit for amending the
`Beecham Pharmaceuticals, New Frontiers Science Park
`claims and to be republished in the event of the receipt of
`South, Third Avenue, Harlow, Essex CM19 SAW (GB).
`
`(54) Title: PHARMACEUTICAL COMPOSITION FOR MODIFIED RELEASE OF AN INSULIN SENSITISER AND ANOTHER
`ANTIDIABETIC AGENT
`
`(57) Abstract
`
`an insulin sensitiser and another antidiabetic agent and a
`A pharmaceutical composition, which composition comprises:
`pharmaceutically acceptable carrier therefor, wherein the composition is arranged to provide a modified release of at least one of the
`insulin sensitiser and the other antidiabetes agent, and the use of such composition in medicine.
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`AUROBINDO EX. 1003, ‘l
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`AUROBINDO EX. 1003, 1
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`Zimbabwe
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`Albania
`Armenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`cote d’lvoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`ES
`FI
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`[L
`IS
`IT
`JP
`KE
`KG
`KP
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`KR
`KZ
`LC
`LI
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People's
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
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`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
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`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.
`
`SI
`SK
`SN
`SZ
`TD
`TG
`TJ
`TM
`TR
`TT
`UA
`UG
`US
`UZ
`VN
`YU
`ZW
`
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Turkmenistan
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Viet Nam
`Yugoslavia
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`WO 00/28989
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`PCT/EP99/08704
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`PHARMACEUTICAL COMPOSITION FOR MODIFIED RELEASE OF AN INSULIN SENSITISER AND ANOTHER
`ANTIDIABETIC AGENT
`
`This invention relates to a novel composition, in particular to a modified release
`
`composition and its use in medicine, especially its use for the treatment of diabetes
`
`mellitus, preferably Type 2 diabetes, and conditions associated with diabetes mellitus.
`
`Alpha glucosidase inhibitor antihyperglycaemic agents (or alpha glucosidase
`
`inhibitors) and biguanide antihyperglycaemic agents (or biguanides) are commonly used
`
`in the treatment of Type 2 diabetes. Acarbose, voglibose, emiglitate and miglitol are
`
`examples of alpha glucosidase inhibitors.1,1 — Dimethylbiguanidine (or metformin) is a
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`particular example of a biguanide.
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`Insulin secretagogues are compounds that promote increased secretion of insulin
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`by the pancreatic beta cells. The sulphonylureas are well known examples of insulin
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`secretagogues. The sulphonylureas act as hypoglycaemic agents and are used in the
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`treatment of Type 2 diabetes. Examples of sulphonylureas include glibenclamide (or
`
`glyburide), glipizide, gliclazide, glimepiride, tolazamide and tolbutamide.
`
`European Patent Application, Publication Number 0,306,228 relates to certain
`
`thiazolidinedione derivatives disclosed as having antihyperglycaemic and hypolipidaemic
`
`activity. One particular thiazolidinedione disclosed in EP 0306228 is 5—[4—[2—(N-methyl-
`
`N—(2—pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4—dione (hereinafter ’Compound (I)’).
`
`WO94/05659 discloses certain salts of Compound (1) including the maleate salt at
`
`example 1 thereof.
`
`Compound (I) is an example of a class of anti—hyperglycaemic agents known as
`
`’insulin sensitisers’. In particular Compound (I) is a thiazolidinedione insulin sensitiser.
`
`European Patent Applications, Publication Numbers: 0008203, 0139421,
`
`0032128, 0428312, 0489663, 0155845, 0257781, 0208420, 0177353, 0319189, 0332331,
`
`0332332, 0528734, 0508740; International Patent Application, Publication Numbers
`
`92/18501, 93/02079, 93/22445 and United States Patent Numbers 5104888 and 5478852,
`
`also disclose certain thiazolidinedione insulin sensitisers.
`
`Another series of compounds generally recognised as having insulin sensitiser
`
`activity are those typified by the compounds disclosed in International Patent
`
`Applications, Publication Numbers WO93/21166 and WO94/01420. These compounds
`
`are herein referred to as ’acyclic insulin sensitisers’. Other examples of acyclic insulin
`
`sensitisers are those disclosed in United States Patent Number 5232945 and International
`
`Patent Applications, Publication Numbers WO92/03425 and WO91/ 19702.
`
`Examples of other insulin sensitisers are those disclosed in European Patent
`
`Application, Publication Number 0533933, Japanese Patent Application Publication
`
`Number 05271204 and United States Patent Number 5264451.
`
`The above mentioned publications are incorporated herein by reference.
`_1_
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`It is now indicated that certain modified release pharmaceutical compositions
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`allow administration of a single daily dose of Compound (I) and another antidiabetic
`
`agent, such as an alpha glucosidase inhibitor, a biguanide or an insulin secretagogue, to
`
`provide an advantageous delivery of drug for maintaining effective glycaemic control
`
`with no observed adverse side effects. Such modified release is therefore considered to
`
`be particularly useful for the delivery of insulin sensitisers in combination with other
`
`antidiabetic agents for the treatment of diabetes mellitus, especially Type 2 diabetes and
`
`conditions associated with diabetes mellitus.
`
`Accordingly, the invention provides a pharmaceutical composition, suitable for
`
`the treatment of diabetes mellitus, especially Type 2 diabetes and conditions associated
`
`with diabetes mellitus in a mammal, such as a human, which composition comprises: an
`
`insulin sensitiser, such as Compound (I), and another antidiabetic agent, such as an alpha
`
`glucosidase inhibitor, a biguanide or an insulin secretagogue, and a pharmaceutically
`
`acceptable carrier therefor, wherein the composition is arranged to provide a modified
`
`release of at least one of the insulin sensitiser and the other antidiabetic agent.
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`In another aspect, the invention provides a modified release pharmaceutical
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`composition, suitable for the treatment of diabetes mellitus, especially Type 2 diabetes
`
`and conditions associated with diabetes mellitus in a mammal, such as a human, which
`
`composition comprises: an insulin sensitiser, such as Compound (I), and another
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`antidiabetic agent, such as an alpha glucosidase inhibitor, a biguanide or an insulin
`
`secretagogue, and a pharmaceutically acceptable carrier therefor, wherein the carrier is
`
`arranged to provide a modified release of at least one of the insulin sensitiser and the
`
`other antidiabetic agent
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`Suitably, the release of both the insulin sensitiser and the other antidiabetic agent
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`is modified.
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`However, it is envisaged that the release of only the insulin sensitiser is
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`modified. It is also envisaged that the release of only the other antidiabetic agent is
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`modified. The remaining active agent would of course be subject to non-modified release.
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`Suitably, the modified release is delayed, pulsed or sustained release.
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`In one aspect the modified release is a delayed release.
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`Delayed release is conveniently obtained by use of a gastric resistant formulation
`
`such as an enteric formulation, such as a tablet coated with a gastric resistant polymer, for
`
`example Eudragit L100—55. Other gastric resistant polymers include methacrylates,
`
`cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose
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`phtahlate, in particular, Aquateric, Sureteric, HPMCP—HP—SSS.
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`The enteric coated tablet may be a single layer tablet, where the active agents are
`
`admixed prior to compression into tablet form, or a multi-layer tablet, such as a bi-or tri-
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`layer tablet, wherein each active agent is present in a discrete layer within the compressed
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`WO 00/28989
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`,PCT/EP99/08704
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`tablet form. The discrete table layers can be arranged as required to provide modified or
`
`non—modified release of each active agent.
`
`In a further aspect the modified release is a sustained release, for example
`
`providing effective release of active agents over a time period of up to 26 hours, typically
`
`in the range of 4 to 24 hours.
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`Sustained release is typically provided by use of a sustained release matrix,
`
`usually in tablet form, such as disintegrating, non—disintegrating or eroding matrices.
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`Sustained release is suitably obtained by use of a non disintegrating matrix tablet
`
`formulation, for example by incorporating Eudragit RS into the tablet. Alternative non
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`disintegrating matrix tablet formulations are provided by incorporating methacrylates,
`
`cellulose acetates, hydroxypropyl methylcellulose phtahlate, in particular Eudragit L and
`
`RL , Carbopol 971P, HPMCP-HP-SSS into the tablet.
`
`Sustained release is further obtained by use of a disintegrating matrix tablet
`
`formulation, for example by incorporating methacrylates, methylcellulose, in particular
`
`Eudragit L, Methocel K4M into the tablet.
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`Sustained release can also be achieved by using a semi-permeable membrane
`
`coated tablet for example by applying methacrylates, ethylcellulose, cellulose acetate, in
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`particular Eudragit RS, Surelease to the tablet.
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`Sustained release can also be achieved by using a multi layer tablet, where each
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`active ingredient is formulated together or as a separate layer, for example as a matrix
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`tablet, with the other layers providing further control for sustained release of either one or
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`both active agents.
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`In yet a further aspect the modified release is a pulsed release, for example
`
`providing up to 4, for example 2, pulses of active agent per 24 hours.
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`One form of pulsed release is a combination of non—modified release of active
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`agent and delayed release.
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`Suitable modified release includes controlled release. The composition of the
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`invention also envisages a combination of pulsed, delayed and/or sustained release for
`
`each of the active agents, thereby enabling for example the release of the reagents at
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`different times. For example, where the composition comprises an insulin sensitiser and a
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`biguanide, such as metformin, the composition can be arranged to release the metforrnin
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`overnight.
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`A suitable alpha glucosidase inhibitor is acarbose.
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`Other suitable alpha glucosidase inhibitors are emiglitate and miglitol. A further
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`suitable alpha glucosidase inhibitor is voglibose.
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`Suitable biguanides include metformin, buforrnin or phenformin, especially
`metforrnin.
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`Suitable insulin secretagogues include sulphonylureas.
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`WO 00/28989
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`Suitable sulphonylureas include glibenclamide, glipizide, gliclazide, glimepiride,
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`tolazamide and tolbutamide. Further sulphonylureas include acetohexamide,
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`carbutamide, chlorpropamide, glibornuride, gliquidone, glisentide, glisolamide,
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`glisoxepide, glyclopyamide and glycylamide. Also included is the sulphonylurea
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`glipentide.
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`Further suitable insulin secretagogues include repaglinide. An additional insulin
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`secretagogue is nateglinide.
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`A preferred thiazolidinedione insulin sensitiser is Compound (1).
`
`Other suitable thiazolidinedione insulin sensitisers include (+) -5-[[4-[(3,4—
`
`dihydro-6-hydroxy—2,5 ,7,8—tetramethyl-2H—1~benzopyran-2-yl)methoxy]phenyl]rnethyl]-
`
`2,4-thiazolidinedione (or troglitazone), 5—[4-[(1—methylcyclohexyl)methoxy]benzyl]
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`thiazolidine—2,4—dione (or ciglitazone), 5-[4—[2—(5—ethylpyridin-2—yl)ethoxy]benzyl]
`
`thiazolidine-2,4—dione (or pioglitazone) or 5—[(2—benzyl—2,3-dihydrobenzopyran)-5-
`
`ylmethyl)thiazolidine—2,4—dione (or englitazone).
`
`A particular thiazolidinedione insulin sensitiser is 5-[4—[2—(5—ethylpyridin—2-
`
`yl)ethoxy]benzyl] thiazolidine-2,4—dione (or pioglitazone).
`
`A particular thiazolidinedione insulin sensitiser is (+) —5-[[4-[(3,4—dihydro—6—
`
`hydroxy—2,5,7,8-tetramethyl-2H-1—benzopyran—2-yl)methoxy]phenyl]methyl]-2,4-
`
`thiazolidinedione (or troglitazone).
`
`Suitable dosages, preferably unit dosages, of the insulin sensitiser and the other
`
`antidiabetic agent, such as the alpha glucosidase inhibitor, a biguanide or insulin
`
`secretagogue, include the known permissible doses for these compounds as described or
`
`referred to in reference texts such as the British and US Pharmacopoeias, Remington’s
`
`Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia
`
`(London, The Pharmaceutical Press) (for example see the 3 lst Edition page 341 and
`
`pages cited therein) or the above mentioned publications.
`
`The dosages of each particular active agent in any given composition can as
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`required vary within a range of doses known to be required in respect of accepted dosage
`
`regimens for that compound. Dosages of each active agent can also be adapted as
`
`required to take into account advantageous effects of combining the agents as mentioned
`herein.
`
`In one particular aspect, the composition comprises 2 to 12 mg of Compound (I).
`
`Suitably the composition comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 mg of
`
`Compound (I).
`
`Particularly, the composition comprises 2 to 4 , 4 to 8 or 8 to 12 mg of
`
`Compound (I).
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`Particularly, the composition comprises 2 to 4mg of Compound (I).
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`Particularly, the composition comprises 4 to 8mg of Compound (I).
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`Particularly, the composition comprises 8 to 12 mg of Compound (I).
`
`Preferably, the composition comprises 2 mg of Compound (I).
`
`Preferably, the composition comprises 4 mg of Compound (I).
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`Preferably, the composition comprises 8 mg of Compound (I).
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`Suitable unit dosages of other insulin sensitisers include from 100 to 800mg of
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`troglitazone such as 200, 400, 600 or 800mg or from 5 to 50mg, including 10 to 40mg, of
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`pioglitazone, such as 20, 30 or 40 mg and also including 15, 30 and 45mg of pioglitazone.
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`As indicated above the unit doses of the additional antidiabetic agents including
`
`the alpha glucosidase inhibitor, the biguanide and the insulin secretagogue include those
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`found in the reference texts mentioned herein and include the doses set out below.
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`For the alpha glucosidase inhibitor, a suitable amount of acarbose is in the range
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`of from 25 to 600 mg, including 50 to 600 mg, for example 100mg or 200mg.
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`For the the biguanide, a suitable dosage of metforrnin is between 100 to 3000mg,
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`for example 250, 500mg, 850mg or lOOOmg.
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`For the insulin secretagogue, a suitable amount of glibenclamide is in the range
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`of from 2.5 to 20 mg, for example 10mg or 20mg; a suitable amount of glipizide is in the
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`range of from 2.5 to 40 mg; a suitable amount of gliclazide is in the range of from 40 to
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`320 mg; a suitable amount of tolazamide is in the range of from 100 to 1000 mg; a
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`suitable amount of tolbutamide is in the range of from 1000 to 3000 mg; a suitable
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`amount of chlorpropamide is in the range of from 100 to 500 mg; and a suitable amount
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`of gliquidone is in the range of from 15 to 180 mg. Also a suitable amount of glimepiride
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`is 1 to 6mg and a suitable amount of glipentide is 2.5 to 20mg.
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`A suitable amount of repaglinide is in the range of from 0.5mg to 20mg, for
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`example 16mg. Also a suitable amount of nateglinide is 90 to 360mg, for example
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`270mg.
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`The compounds mentioned herein, in particular the thiazolidinediones such as
`
`Compound (I), may exist in one of several tautomeric forms, all of which are
`
`encompassed by the invention as individual tautomeric forms or as mixtures thereof. The
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`compounds mentioned herein may contain one or more chiral carbon atoms and hence can
`
`exist in two or more stereoisomeric forms, all of which are encompassed by the invention
`
`either as individual isomers or as mixtures of isomers, including racemates.
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`It will be understood that the insulin sensitiser, such as Compound (I) and the
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`other antidiabetic agent are in a pharmaceutically acceptable form, including
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`pharmaceutically acceptable derivatives such as pharmaceutically acceptable salts, esters
`
`and solvates thereof, as appropriate to the relevant pharmaceutically active agent chosen.
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`In certain instances herein the names used for the antidiabetic agent may relate to a
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`particular pharmaceutical form of the relevant active agent: It will be understood that all
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`pharmaceutically acceptable forms of the active agents per se are encompassed by this
`invention.
`
`Suitable pharmaceutically acceptable forms of the insulin sensitiser and other
`
`antidiabetic agent depend upon the particular agent used but included are known
`
`pharmaceutically acceptable forms of the particular agent chosen. Such derivatives are
`
`found or are referred to in standard reference texts such as the British and US
`
`Pharrnacopoeias, Remington’s Pharmaceutical Sciences (Mack Publishing Co.), The
`
`Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 3 lst
`
`Edition page 341 and pages cited therein) and the above mentioned publications. For
`
`example, a particular form of metformin is metformin hydrochloride, a particular form of
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`repaglinide is a benzoic acid salt form and a particular form of tolbutamide is a sodium
`
`salt form.
`
`Suitable pharmaceutically acceptable forms of Compound (I) include those
`
`described in EP 0306228 and WO94/05659, especially pharmaceutically acceptable salted
`
`or solvated forms. A preferred pharmaceutically acceptable salt form of Compound (I) is
`
`a maleate. A preferred pharmaceutically acceptable solvated form of Compound (I) is a
`
`hydrate. A preferred form of pioglitazone is as the hydrochloride salt.
`
`The insulin sensitiser or the alpha glucosidase inhibitor antihyperglycaemic agent
`
`of choice is prepared according to known methods, such methods are found or are
`
`referred to in standard reference texts, such as the British and US Pharrnacopoeias,
`
`Remington’s Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra
`
`Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31st Edition
`
`page 341 and pages cited therein) or as described in the above mentioned publications.
`
`Compound (I) or, a pharmaceutically acceptable salt thereof, or a
`
`pharmaceutically acceptable solvate thereof, may be prepared using known methods, for
`
`example those disclosed in EP 0306228 and WO94/05659. The disclosures of EP
`
`0306228 and WO94/05659 are incorporated herein by reference.
`
`When used herein the term ’conditions associated with diabetes’ includes those
`
`conditions associated with the pre-diabetic state, conditions associated with diabetes
`
`mellitus itself and complications associated with diabetes mellitus.
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`When used herein the term ’conditions associated with the pre-diabetic state’
`
`includes conditions such as insulin resistance, including hereditary insulin resistance,
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`impaired glucose tolerance and hyperinsulinaemia.
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`’Conditions associated with diabetes mellitus itself’ include hyperglycaemia,
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`insulin resistance, including acquired insulin resistance and obesity. Further conditions
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`associated with diabetes mellitus itself include hypertension and cardiovascular disease,
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`especially atherosclerosis and conditions associated with insulin resistance. Conditions
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`WO 00/28989
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`PCT/EP99/08704
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`associated with insulin resistance include polycystic ovarian syndrome and steroid
`
`induced insulin resistance and gestational diabetes.
`
`’Complications associated with diabetes mellitus’ includes renal disease, especially
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`renal disease associated with Type 2 diabetes, neuropathy and retinopathy.
`
`Renal diseases associated with Type 2 diabetes include nephropathy,
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`glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive
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`nephrosclerosis and end stage renal disease.
`
`As used herein the term ’pharmaceutically acceptable’ embraces both human and
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`veterinary use: for example the term ’pharmaceutically acceptable’ embraces a veterinarin
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`acceptable compound.
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`15
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`20
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`25
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`30
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`For the avoidance of doubt, unless other wise stated, when reference is made
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`herein to scalar amounts, including mg amounts, of the active compound such as
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`Compound (I), in a pharmaceutically acceptable form, the scalar amount referred to is
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`made in respect of the active compound per se: For example 2 mg of Compound (I) in
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`the form of the maleate salt is that amount of maleate salt which provides 2 mg of
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`Compound (I).
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`Diabetes mellitus is preferably Type 2 diabetes.
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`Glycaemic control may be characterised using conventional methods, for
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`example by measurement of a typically used index of glycaemic control such as fasting
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`plasma glucose or glycosylated haemoglobin (Hb Alc). Such indices are determined
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`using standard methodology, for example those described in: Tuescher A, Richterich, P.,
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`Schweiz. med. Wschr. 101 (1971), 345 and 390 and Frank P., ’Monitoring the Diabetic
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`Patent with Glycosolated Hemoglobin Measurements’, Clinical Products 1988.
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`In a preferred aspect, the dosage level of each of the active agents when used in
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`accordance with the treatment of the invention will be less than would have been required
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`from a purely additive effect upon glycaemic control.
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`There is also an indication that the treatment of the invention will effect an
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`improvement, relative to the non-modified release of the individual agents, in the levels
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`of advanced glycosylation end products (AGES), leptin and serum lipids including total
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`cholesterol, HDL—cholesterol, LDL-cholesterol including improvements in the ratios
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`thereof, in particular an improvement in serum lipids including total cholesterol, HDL—
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`cholesterol, LDL—cholesterol including improvements in the ratios thereof.
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`Usually the compositions are adapted for oral administration. However, they
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`may be adapted for other modes of administration, for example parenteral administration,
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`sublingual or transdermal administration.
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`In a further aspect the invention also provides a process for preparing a
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`pharmaceutical composition, suitably for the treatment of diabetes mellitus, especially
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`Type 2 diabetes and conditions associated with diabetes mellitus in a mammal, such as a
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`-7-
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`human, which composition comprises an insulin sensitiser, such as Compound (I), and
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`another antidiabetic agent, such as an alpha glucosidase inhibitor, a biguanide or an
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`insulin secretagogue, and a pharmaceutically acceptable carrier therefor, which process
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`comprises formulating the insulin sensitiser, the other antidiabetic agent and the
`pharmaceutically acceptable carrier so as to enable a modified release of at least one of
`
`the insulin sensitiser and the other antidiabetic agent.
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`In afurther aspect, the invention provides a process for preparing a modified
`
`release pharmaceutical composition, suitably for the treatment of diabetes mellitus,
`especially Type 2 diabetes and conditions associated with diabetes mellitus in a mammal,
`such as a human, which composition comprises an insulin sensitiser, such as Compound
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`10
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`(I) and another antidiabetic agent, such as an alpha glucosidase inhibitor, a biguanide or
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`an insulin secretagogue and a pharmaceutically acceptable carrier therefor, which process
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`comprises formulating the insulin sensitiser, the other antidiabetic agent and the
`pharmaceutically acceptable carrier so as to enable a modified release of at least one of
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`15
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`the insulin sensitiser and the other antidiabetic agent.
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`The compositions are formulated to provide the modified release of active agents
`
`according to the appropriate methods required, for example those disclosed in Sustained
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`and Controlled Release Drug Delivery Systems, Editor Joe R Robinson, Volume 7,
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`published by Marcel Dekker under the title Drugs and the Pharmaceutical Sciences,
`Controlled Drug Delivery, 2nd Edition’ edited by Joe Robinson and Vince Lee, Marcel
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`20
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`Dekker, 1987 and ’Drug Delivery to the Gastrointestinal Tract’ Editors: J G Hardy, S S.
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`Davis and C G Wilson also with reference to texts such as the British and US
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`Pharmacopoeias, Remington’s Pharmaceutical Sciences (Mack Publishing Co.),
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`Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example
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`see the 3lst Edition page 341 and pages cited therein) and Harry’s Cosmeticology
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`(Leonard Hill Books).
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`Preferably, the compositions are in unit dosage form. Unit dosage presentation
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`forms for oral administration may be in tablet or capsule form and may as necessary
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`contain conventional excipients such as binding agents, fillers, lubricants, glidants,
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`disintegrants and wetting agents.
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`Examples of binding agents include acacia, alginic acid, carboxymethylcellulose
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`calcium, carboxymethylcellulose sodium, dextrates, dextrin, dextrose, ethylcellulose,
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`gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose,
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`hydroxypropyl methylcellulose, magnesium aluminium silicate, maltodextrin, methyl
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`cellulose, polymethacrylates, polyvinylpyrrolidone, pregelatinised starch, sodium alginate,
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`sorbitol, starch, syrup, tragacanth.
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`Examples of fillers include calcium carbonate, calcium phosphate, calcium
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`sulphate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, compressible
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`sugar, confectioner’s sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate
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`dihydrate, dibasic calcium phosphate, fructose, glyceryl palmitostearate, glycine,
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`hydrogenated vegetable oil—type l, kaolin, lactose, maize starch, magnesium carbonate,
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`magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylates,
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`potassium chloride, powdered cellulose, pregelatinised starch, sodium chloride, sorbitol,
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`starch, sucrose, sugar spheres, talc, tribasic calcium phosphate, xylitol.
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`Examples of lubricants include calcium stearate, glyceryl monostearate, glyceryl
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`palmitostearate, magnesium stearate, microcrystalline cellulose, sodium benzoate, sodium
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`chloride, sodium lauryl sulphate, stearic acid, sodium stearyl fumarate, talc, zinc stearate.
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`Examples of glidants include colloidal silicon dioxide, powdered cellulose,
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`magnesium trisilicate, silicon dioxide, talc.
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`Examples of disintegrants include alginic acid, carboxymethylcellulose calcium,
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`carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium,
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`crospovidone, guar gum, magnesium aluminium silicate, microcrystalline cellulose,
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`methyl cellulose, polyvinylpyrrolidone, polacrilin potassium, pregelatinised starch,
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`sodium alginate, sodium lauryl sulphate, sodium starch glycollate.
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`An example of a pharmaceutically acceptable wetting agent is sodium lauryl
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`sulphate.
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`As required the solid oral compositions may be prepared by conventional
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`methods of blending, filling or tabletting. Repeated blending operations may be used to
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`distribute the active agent throughout those compositions employing large quantities of
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`fillers. Such operations are of course conventional in the art. The tablets may be coated
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`according to methods well known in normal pharmaceutical practice.
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`Compositions may, if desired, be in the form of a pack accompanied by written
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`or printed instructions for use.
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`No adverse toxicological effects are expected for the compositions of the
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`invention in the above mentioned dosage ranges.
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`AUROBINDO EX. 1003, 11
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`EXAMPLES COMPRISING AN INSULIN SENSITISER AND A BIGUANIDE
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`Example 1, Delayed Release Composition
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`Delayed release is achieved by coating single or bilayer tablets comprising 4mg or 8mg
`of Compound (I) as pure free base (pfb) and 500, preferably, or 1000 or 1500mg of
`metformin HCl with Eudragit L100-55, a gastric resistant polymer
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`10
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`The enteric coat consists of:
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`Eudragit L30 D-55 (30% aqueous dispersion)
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`76.8
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`Triethyl Citrate
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`15
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`Talc Alphafil 500
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`7.7
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`15.5
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`%w/w
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`Example 2, Sustained release by use of a semi—permeable membrane
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`The semi—permeable membrane consists of:
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`Eudragit RS30D (30% aqueous dispersion)
`Triethyl Citrate
`Talc
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`%w/w
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`90
`1
`9
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`This membrane is applied to a single or bilayer tablets each comprising 4mg or 8mg of
`Compound (I) and 500, preferably, or 1000 or 1500mg of metformin HCl
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`Example 3, Sustained Release by use of a non disintegrating matrix tablet
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`A matrix tablet is formed by tabletting the following mixture as:
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`(a) a single layer tablet:
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`Compound (I)
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`Metformin HCl
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`Eudragit L100-55
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`Lactose monohydrate
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`mg/tablet
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`4 (pfb)
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`500
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`150
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`50
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`Eudragit RS powder to
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`1000
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`20
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`25
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`30
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`35
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`40
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`(b) a bilayer tablet to provide sustained release of Compound I and immediate (i.e non-
`modified) release of metformin HCl.
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`Layer A
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`45
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`Compound (I)
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`mg/tablet
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`4 (pfb)
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`-10-
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`Eudragit L100-55
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`Lactose monohydrate
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`Eudragit RS powder to
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`150
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`50
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`500
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`mg/tablet
`500
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`15
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`520
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`M M
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`etformin HCl
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`Polyvinyl pyrollidone
`Magnesium stearate to
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`Example 4, Sustained Release by use of a Mixed Eudragit matrix tablet
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`A matrix tablet is formed by tabletting the following mixture as:
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`10
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`15
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`(a) a single layer tablet:
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`Compound (I)
`Metformin HCl
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`Eudragit L100—5 5
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`Eudragit RS powder
`Colloidal Silicon dioxide
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`20
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`Magnesium stearate
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`Lactose monohydrate to
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`(b) a trilayer tablet:
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`25
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`Layer A
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`Compound (I)
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`Eudragit L100—55
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`Eudragit RS powder
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`mg/tablet
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`4 <pfb>
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`500
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`74
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`18.5
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`2.6
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`3 .25
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`650
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`mg/tablet
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`4 (pfb)
`74
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`18.5
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`Colloidal Silicon dioxide
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`0.6
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`30
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`Magnesium stearate
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`Lactose monohydrate to
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`1.5
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`150
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`Layer B
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`Metformin HCl
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`35
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`Eudragit L100-55
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`Eudragit RS powder to
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`Layer C
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`Metformin HCl
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`40
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`Polyvinyl pyrrolidone
`Magnesium stearate to
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`mg/tablet
`250
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`74
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`345
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`mg/tablet
`250
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`7.5
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`260
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`-11-
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`AUROBINDO EX. 1003, 13
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`W9 00/28989
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`Example 5, Sustained Releas