PCT
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International 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, 31/4439, 9/32, 9/52, 45/06,
`A61P 3/10
`
`(43) International Publication Date:
`
`25 May 2000 (25.05.00)
`
`(21) International Application Number:
`
`PCT/EP99/08704
`
`(22) International Filing Date:
`
`8 November 1999 (08.11.99)
`
`RE, Vincenzo [GB/GB]; SmithKline Beecham Pharmaceu-
`ticals, New Frontiers Science Park South, Third Avenue,
`Harlow, Essex CM19 SAW (GB).
`
`(74) Agent: RUTTER, Keith; SmithKline Beecham Corporate
`Intellectual Property, Two New Horizons Court, Brentford,
`Middlesex TW8 9EP (GB).
`
`amendments.
`
`30) Priority Data:
`(30)
`Priority
`Data
`12 November 1998 (12.11.98) GB
`9824866.9
`12 November 1998 (12.11.98)
`GB
`9824867.7
`12 November 1998 (12.11.98)
`GB
`9824869.3
`
`
`9912193.1 GB|(81) Designated States: AE, AL, AM, AT, AU, AZ, BA, BB, BG,25 May 1999 (25.05.99)
`9912190.7
`25 May 1999 (25.05.99)
`GB
`BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE,
`9912191.5
`25 May 1999 (25.05.99)
`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, TT, 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, Cl, CM,
`GA, GN, GW, ML, MR, NE, SN, TD, TG).
`
`(71) Applicant(for all designated States except US): SMITHKLINE
`BEECHAMP.L.C. [GB/GB]; New Horizons Court, Brent-
`ford, Middlesex TW8 9EP (GB).
`
`(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). LILLIOTT, 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) Titles 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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`Singapore
`
`Albania
`Armenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`Céte dIvoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`ES
`FI
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`TE
`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
`Israel
`Iceland
`Ttaly
`Japan
`Kenya
`Kyrgyzstan
`Democratic People’s
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`
`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
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codesused 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
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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
`particular example of a biguanide.
`Insulin secretagogues are compoundsthat promote increased secretion of insulin
`by the pancreatic beta cells. The sulphonylureas are well known examplesof insulin
`secretagogues. The sulphonylureas act as hypoglycaemic agents and are usedin the
`treatment of Type 2 diabetes. Examples of sulphonylureas include glibenclamide (or
`glyburide), glipizide, gliclazide, glimepiride, tolazamide and tolbutamide.
`European Patent Application, Publication Number0,306,228 relates to certain
`thiazolidinedione derivatives disclosed as having antihyperglycaemic and hypolipidaemic
`activity. One particular thiazolidinedione disclosed in EP 0306228 is 5-[4-[2-(N-methy]-
`N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (hereinafterCompound (I)’.
`W094/05659 discloses certain salts of Compound(I) including the maleate salt at
`example | thereof.
`Compound(J) is an exampleof a class of anti-hyperglycaemic agents known as
`‘insulin sensitisers’. In particular Compound(J) 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 compoundsgenerally recognised as having insulin sensitiser
`activity are those typified by the compoundsdisclosed 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 5232945and 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.
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`It is now indicated that certain modified release pharmaceutical compositions
`allow administration of a single daily dose of Compound(I) and anotherantidiabetic
`agent, such as an alpha glucosidase inhibitor, a biguanide or an insulin secretagogue, to
`provide an advantageousdelivery of drug for maintaining effective glycaemic control
`with no observed adverseside 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 anotherantidiabetic 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.
`In another aspect, the invention provides a modified release 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 thecarrieris
`arranged to provide a modified release of at least one of the insulin sensitiser and the
`other antidiabetic agent
`Suitably, the release of both the insulin sensitiser and the other antidiabetic agent
`is modified.
`
`However,it is envisaged that the release of only the insulin sensitiseris
`modified. It is also envisaged that the release of only the other antidiabetic agentis
`modified. The remaining active agent would of course be subject to non-modifiedrelease.
`Suitably, the modified release is delayed, pulsed or sustainedrelease.
`In one aspect the modified release is a delayed release.
`Delayed release is conveniently obtained by use ofa 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
`phtahlate, in particular, Aquateric, Sureteric, HPMCP-HP-S55S.
`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-ortri-
`layer tablet, wherein each active agent is present in a discrete layer within the compressed
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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 overa time period of up to 26 hours, typically
`in the range of 4 to 24 hours.
`Sustained release is typically provided byuseof a sustained release matrix,
`usually in tablet form, such as disintegrating, non-disintegrating or eroding matrices.
`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
`disintegrating matrix tablet formulations are provided by incorporating methacrylates,
`cellulose acetates, hydroxypropyl methylcellulose phtahlate, in particular Eudragit L and
`RL , Carbopol 971P, HPMCP-HP-S5SSinto 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 K4Mintothetablet.
`Sustained release can also be achieved by using a semi-permeable membrane
`coated tablet for example by applying methacrylates, ethylcellulose, cellulose acetate, in
`particular Eudragit RS, Sureleaseto the tablet.
`Sustained release can also be achieved by using a multi layer tablet, where each
`active ingredient is formulated togetheror as a separate layer, for example as a matrix
`tablet, with the other layers providing further control for sustained release of either one or
`both active agents.
`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.
`One form of pulsed release is a combination of non-modified release of active
`agent and delayedrelease.
`Suitable modified release includes controlled release. The composition of the
`invention also envisages a combination of pulsed, delayed and/or sustained release for
`each of the active agents, thereby enabling for exampletherelease of the reagentsat
`different times. For example, where the composition comprises an insulin sensitiser and a
`biguanide, such as metformin, the composition can be arranged to release the metformin
`overnight.
`A suitable alpha glucosidase inhibitor is acarbose.
`Other suitable alpha glucosidase inhibitors are emiglitate and miglitol. A further
`suitable alpha glucosidase inhibitor is voglibose.
`Suitable biguanides include metformin, buformin or phenformin,especially
`metformin.
`
`Suitable insulin secretagogues include sulphonylureas.
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`Suitable sulphonylureasinclude glibenclamide, glipizide, gliclazide, glimepiride,
`tolazamide and tolbutamide. Further sulphonylureas include acetohexamide,
`carbutamide, chlorpropamide, glibornuride, gliquidone, glisentide, glisolamide,
`glisoxepide, glyclopyamide and glycylamide. Also includedis the sulphonylurea
`glipentide.
`Further suitable insulin secretagogues include repaglinide. An additional insulin
`secretagogueis nateglinide.
`A preferred thiazolidinedioneinsulin sensitiser is Compound(I).
`Other suitable thiazolidinedioneinsulin sensitisers include (+) -5-[[4-[(3,4-
`dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H- 1-benzopyran-2-yl)methoxy]phenyl}methy]]-
`2,4-thiazolidinedione (or troglitazone), 5-[4-[(1-methylcyclohexyl)methoxy]benzy]]
`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 orinsulin
`secretagogue, include the known permissible doses for these compoundsas 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 31st Edition page 341 and
`pagescited therein) or the above mentioned publications.
`The dosagesof each particular active agent in any given composition can as
`required vary within a range of doses knownto be required in respect of accepted dosage
`regimens for that compound. Dosagesof each active agent can also be adapted as
`required to take into account advantageouseffects 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(1).
`Particularly, the composition comprises 2 to 4mg of Compound(J).
`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(D.
`Preferably, the composition comprises 8 mg of Compound(I).
`Suitable unit dosages of other insulin sensitisers include from 100 to 800mgof
`troglitazone such as 200, 400, 600 or 800mg or from 5 to 50mg,including 10 to 40mg,of
`pioglitazone, such as 20, 30 or 40 mg andalso including 15, 30 and 45mgofpioglitazone.
`Asindicated above the unit doses of the additional antidiabetic agents including
`the alpha glucosidase inhibitor, the biguanide and the insulin secretagogue include those
`found in the reference texts mentioned herein and include the dosesset out below.
`
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`For the alpha glucosidase inhibitor, a suitable amount of acarboseis in the range
`of from 25 to 600 mg,including 50 to 600 mg,for example 100mg or 200mg.
`For the the biguanide, a suitable dosage of metformin is between 100 to 3000mg,
`for example 250, 500mg, 850mg or 1000mg.
`For the insulin secretagogue, a suitable amountof glibenclamideis in the range
`of from 2.5 to 20 mg, for example 10mg or 20mg;a suitable amountofglipizideis in the
`range of from 2.5 to 40 mg; a suitable amountof gliclazide is in the range of from 40 to
`320 mg; a suitable amountof tolazamideis in the range of from 100 to 1000 mg; a
`suitable amountof tolbutamide is in the range of from 1000 to 3000 mg;asuitable
`amount of chlorpropamideis in the range of from 100 to 500 mg; and a suitable amount
`20
`of gliquidoneis in the range of from 15 to 180 mg. Also a suitable amountof glimepiride
`is 1 to 6mg and a suitable amountof glipentide is 2.5 to 20mg.
`A suitable amountof repaglinideis in the range of from 0.5mg to 20mg,for
`example 16mg. Also a suitable amountof nateglinide is 90 to 360mg, for example
`270mg.
`
`25
`
`The compounds mentionedherein, in particular the thiazolidinediones such as
`Compound(1), 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
`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 encompassedbythe invention
`either as individual isomers or as mixtures of isomers, including racemates.
`It will be understood that the insulin sensitiser, such as Compound(I) and the
`other antidiabetic agent are in a pharmaceutically acceptable form, including
`pharmaceutically acceptable derivatives such as pharmaceutically acceptable salts, esters
`and solvates thereof, as appropriate to the relevant pharmaceutically active agent chosen.
`In certain instances herein the names used for the antidiabetic agent mayrelate to a
`particular pharmaceutical form of the relevant active agent: It will be understoodthat all
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`pharmaceutically acceptable forms of the active agents per se are encompassed bythis
`invention.
`
`Suitable pharmaceutically acceptable formsof the insulin sensitiser and other
`antidiabetic agent depend uponthe particular agent used but included are known
`pharmaceutically acceptable forms of the particular agent chosen. Such derivatives are
`found orare referred to in standard reference texts such as the British and US
`
`Pharmacopoeias, Remington’s Pharmaceutical Sciences (Mack Publishing Co.), The
`Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31st
`Edition page 341 and pagescited therein) and the above mentioned publications. For
`example,a particular form of metformin is metformin hydrochloride, a particular form of
`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 acceptablesalted
`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 methodsare foundor are
`referred to in standard 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 31st Edition
`page 341 and pagescited therein) or as described in the above mentioned publications.
`Compound(J) 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.
`Whenusedherein 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.
`Whenusedherein the term ‘conditions associated with the pre-diabetic state’
`includes conditions suchas insulin resistance, including hereditary insulin resistance,
`impaired glucose tolerance and hyperinsulinaemia.
`‘Conditions associated with diabetes mellitus itself’ include hyperglycaemia,
`insulin resistance, including acquired insulin resistance and obesity. Further conditions
`associated with diabetes mellitus itself include hypertension and cardiovascular disease,
`especially atherosclerosis and conditions associated with insulin resistance. Conditions
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`associated with insulin resistance include polycystic ovarian syndromeandsteroid
`induced insulin resistance and gestational diabetes.
`‘Complications associated with diabetes mellitus’ includes renal disease, especially
`renal disease associated with Type 2 diabetes, neuropathy and retinopathy.
`Renal diseases associated with Type 2 diabetes include nephropathy,
`glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive
`nephrosclerosis and end stage renal disease.
`Asused herein the term ‘pharmaceutically acceptable’ embraces both human and
`veterinary use: for example the term ‘pharmaceutically acceptable’ embracesa veterinarily
`acceptable compound.
`For the avoidance of doubt, unless other wise stated, when reference is made
`herein to scalar amounts, including mg amounts,of the active compound such as
`Compound(J), in a pharmaceutically acceptable form, the scalar amountreferred to is
`madein respect of the active compound per se: For example 2 mg of Compound(I) in
`the form of the maleate salt is that amount of maleate salt which provides 2 mg of
`Compound(J).
`Diabetes mellitus is preferably Type 2 diabetes.
`Glycaemic control may be characterised using conventional methods, for
`example by measurementofa typically used index of glycaemic control such as fasting
`plasma glucose or glycosylated haemoglobin (Hb Alc). Such indices are determined
`using standard methodology, for example those described in: Tuescher A, Richterich,P.,
`Schweiz. med. Wschr. 101 (1971), 345 and 390 and Frank P., Monitoring the Diabetic
`Patent with Glycosolated Hemoglobin Measurements’, Clinical Products 1988.
`In a preferred aspect, the dosage level of each of the active agents when used in
`accordance with the treatment of the invention will be less than would have been required
`from a purely additive effect upon glycaemic control.
`
`There is also an indication that the treatment of the invention will effect an
`
`improvement,relative to the non-modified release of the individual agents,in the levels
`of advanced glycosylation end products (AGEs), leptin and serum lipids including total
`cholesterol, HDL-cholesterol, LDL-cholesterol including improvementsin theratios
`thereof, in particular an improvementin serum lipids including total cholesterol, HDL-
`cholesterol, LDL-cholesterol including improvementsin the ratios thereof.
`Usually the compositions are adapted for oral administration. However, they
`may be adapted for other modes of administration, for example parenteral administration,
`sublingual or transdermal administration.
`In a further aspect the invention also provides a process for preparing a
`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
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`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, which process
`comprises formulating the insulin sensitiser, the other antidiabetic agent and the
`pharmaceutically acceptable carrier so as to enable a modified release ofat least one of
`the insulin sensitiser and the other antidiabetic agent.
`In a.further 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
`(1) and anotherantidiabetic agent, such as an alpha glucosidaseinhibitor, a biguanide or
`an insulin secretagogue and a pharmaceutically acceptable carrier therefor, which process
`comprises formulating the insulin sensitiser, the other antidiabetic agent and the
`pharmaceutically acceptable carrier so as to enable a modified release ofat least one of
`the insulin sensitiser and the other antidiabetic agent.
`The compositionsare formulated to provide the modified release of active agents
`according to the appropriate methodsrequired, for example those disclosed in Sustained
`and Controlied Release Drug Delivery Systems, Editor Joe R Robinson, Volume 7,
`published by Marcel Dekker underthetitle Drugs and the Pharmaceutical Sciences,
`Controlled Drug Delivery, 2nd Edition’ edited by Joe Robinson and Vince Lee, Marcel
`Dekker, 1987 and Drug Delivery to the Gastrointestinal Tract’ Editors: J G Hardy, S S.
`Davis and C G Wilson also with reference to 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 31st Edition page 341 and pagescited therein) and Harry’s Cosmeticology
`(Leonard Hill Books).
`Preferably, the compositions are in unit dosage form. Unit dosage presentation
`forms for oral administration may bein tablet or capsule form and mayas necessary
`contain conventional excipients such as binding agents,fillers, lubricants, glidants,
`disintegrants and wetting agents.
`Examples of binding agents includeacacia, alginic acid, carboxymethylcellulose
`calcium, carboxymethylcellulose sodium, dextrates, dextrin, dextrose, ethylcellulose,
`gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose,
`hydroxypropyl methylcellulose, magnesium aluminiumsilicate, maltodextrin, methyl
`cellulose, polymethacrylates, polyvinylpyrrolidone, pregelatinised starch, sodium alginate,
`sorbitol, starch, syrup, tragacanth.
`Examplesoffillers include calcium carbonate, calcium phosphate, calcium
`sulphate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, compressible
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`sugar, confectioner’s sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate
`dihydrate, dibasic calcium phosphate, fructose, glyceryl palmitostearate, glycine,
`hydrogenated vegetable oil-type 1, kaolin, lactose, maize starch, magnesium carbonate,
`magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylates,
`potassium chloride, powdered cellulose, pregelatinised starch, sodium chloride, sorbitol,
`starch, sucrose, sugar spheres,talc, tribasic calcium phosphate, xylitol.
`Examples of lubricants include calcium stearate, glyceryl monostearate, glycery]
`palmitostearate, magnesium stearate, microcrystalline cellulose, sodium benzoate, sodium
`chloride, sodium lauryl sulphate, stearic acid, sodium stearyl fumarate,talc, zinc stearate.
`Examplesof glidants include colloidal silicon dioxide, powderedcellulose,
`magnesium trisilicate, silicon dioxide,talc.
`Examples of disintegrants include alginic acid, carboxymethylcellulose calcium,
`carboxymethylcellulose sodium,colloidal silicon dioxide, croscarmellose sodium,
`crospovidone, guar gum, magnesium aluminium silicate, microcrystalline cellulose,
`methyl cellulose, polyvinylpyrrolidone, polacrilin potassium, pregelatinised starch,
`sodium alginate, sodium lauryl sulphate, sodium starch glycollate.
`An example of a pharmaceutically acceptable wetting agent is sodium lauryl
`sulphate.
`Asrequired the solid oral compositions may be prepared by conventional
`methodsof blending,filling or tabletting. Repeated blending operations may be used to
`distribute the active agent throughout those compositions employing large quantities of
`fillers. Such operations are of course conventionalin the art. The tablets may be coated
`according to methods well known in normal pharmaceutical practice.
`Compositions may, if desired, be in the form of a pack accompanied by written
`or printed instructions for use.
`Noadverse toxicological effects are expected for the compositions of the
`invention in the above mentioned dosage ranges.
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`EXAMPLES COMPRISING AN INSULIN SENSITISER AND A BIGUANIDE
`
`Example 1, Delayed Release Composition
`
`Delayed release is achieved by coating single or bilayer tablets comprising 4mg or 8mg
`of Compound(J) as pure free base (pfb) and 500, preferably, or 1000 or 1500mg of
`metformin HC] with Eudragit L100-55, a gastric resistant polymer
`
`10
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`The enteric coat consists of:
`
`Eudragit L30 D-55 (30% aqueous dispersion)
`Triethyl Citrate
`Talc Alphafil 500
`
`Jow!lw
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`76.8
`7.7
`15.5
`
`Example 2, Sustained release by use of a semi-permeable membrane
`
`The semi-permeable membraneconsistsof:
`
`Eudragit RS30D (30% aqueousdispersion)
`Triethyl Citrate
`Talc
`
`Jowlw
`90
`1
`
`This membraneis 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
`
`Example 3, Sustained Release by use of a non disintegrating matrix tablet
`
`A matrix tablet is formed by tabletting the following mixture as:
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`(a) a single layertablet:
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`35
`
`Compound(I)
`Metformin HCl
`
`mg/tablet
`4 (pfb)
`500
`
`Eudragit L100-55
`Lactose monohydrate
`Eudragit RS powder to
`
`150
`50
`1000
`
`40
`
`(b) a bilayer tablet to provide sustained release of CompoundI and immediate(i.e non-
`modified) release of metformin HCl.
`
`Layer A
`Compound(I)
`
`45
`
`mg/tablet
`4 (pfb)
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`Eudragit L100-55
`Lactose monohydrate
`Eudragit RS powder to
`
`150
`
`50
`
`500
`
`mg/tablet
`LayerB
`500
`Metformin HCl
`Polyvinyl] pyrollidone
`Magnesium stearate to
`
`520
`
`15
`
`10
`
`Example 4, Sustained Release by use of a Mixed Eudragit matrix tablet
`
`A matrix tablet is formed by tabletting the following mixtureas:
`
`(a) a single layer tablet:
`
`Compound(I)
`Metformin HC]
`
`meg/tablet
`4 (pfb)
`500
`
`Eudragit L100-55
`Eudragit RS powder
`Colloidal Silicon dioxide
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`18.5
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`2.6
`
`Magnesiumstearate
`Lactose monohydrate to
`
`3.25
`
`650
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`15
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`20
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`25
`
`(b) a trilayer tablet:
`Layer A
`Compound(I)
`Eudragit L100-55
`Eudragit RS powder
`Colloidal Silicon dioxide
`
`30
`
`Magnesium stearate
`Lactose monohydrate to
`
`mg/tablet
`4 (pfb)
`74
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`18.5
`
`0.6
`
`1.5
`
`150
`
`Layer B
`Metformin HCl
`
`mg/tablet
`250
`
`35
`
`Eudragit L100-55
`Eudragit RS powderto
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`345
`
`Layer C
`Metformin HCl
`Polyvinyl] pyrrolidone
`Magnesium stearate to
`
`mg/tablet
`250
`
`7.5
`260
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`40
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`Example 5, Sustained Release by use of a disintegrating matrix tablet
`
`A matrix tablet is formed by tabletting the following mixture as a single layertablet:
`
`Compound(J)
`Metformin HCl
`
`Eudragit L100-55
`Methocel K4M
`
`mg/tablet
`4 (pfb)
`500
`
`74
`18.5
`
`10
`
`Colloidal Silicon dioxide
`
`2.6
`
`3.25
`Magnesiumstearate
`Lactose monohydrate to 650
`
`15
`
`Example 6, Sustained Release by use of a Mixed Carbopol matrix tablet
`
`A matrix tablet is formed by tabletting the following mixture as single or bilayertablet:
`mg/tablet
`4 (pfb)
`500
`
`Compound(I)
`Metformin HCl
`
`20