`US 20040102486Al
`
`(19) United States
`
`(12) Patent Application Publication
`Benincosa et al.
`
`(10) Pub. No.: US 2004/0102486 Al
`May 27, 2004
`(43) Pub. Date:
`
`(54) NOVEL METHOD OF TREATMENT
`
`(30)
`
`Foreign Application Priority Data
`
`(75)
`
`Inventors: Lisa Benincosa, King of Prussia, PA
`(US); William Jusko, Buffalo, NY (US)
`
`Correspondence Address:
`GLAXOSMITHKLINE
`Corporate Intellectual Property - UW2220
`P.O. Box 1539
`King of Prussia, PA 19406-0939 (US)
`
`(73)
`
`Assignee: SmithKline Beecham Corporation
`
`(21)
`
`Appl. No.:
`
`10/705,606
`
`(22)
`
`Filed:
`
`Nov. 10, 2003
`
`Related U.S. Application Data
`
`(63)
`
`Continuation of application No. 09/831,652, filed on
`Jul. 11, 2001, now abandoned, filed as 371 of inter(cid:173)
`national application No. PCT/US99/26746, filed on
`Nov. 12, 1999.
`
`Nov. 12, 1998
`
`(GB) ......................................... 9824893.3
`
`Publication Classification
`
`Int. Cl.7 ................................................ A61K 31/4439
`(51)
`(52) U.S. Cl. .............................................................. 514/342
`
`(57)
`
`ABSTRACT
`
`A method for the treatment of Type 2 diabetes mellitus and
`conditions associated with diabetes mellitus, which method
`comprises the administration to a human or non-human
`mammal in need thereof, of an effective non-toxic amount of
`an insulin sensitiser so as to provide a plasma concentration
`of the insulin sensitiser of at least a threshold level (the
`"Threshold Plasma Concentration") from within the range of
`effective plasma levels of the insulin sensitiser, composi(cid:173)
`tions for use in such method and methodology for deter(cid:173)
`mining plasma concentrations of active agent use in such
`methods.
`
`MPI EXHIBIT 1043 PAGE 1
`
`MPI EXHIBIT 1043 PAGE 1
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1043-0001
`
`
`
`Patent Application Publication May 27, 2004 Sheet 1 of 2
`
`US 2004/0102486 Al
`
`Figure 1: Simulated steady-state concentrations of Compound (I) (upper)
`and MIO (lower) over a 24 hour dosing interval following 4 mg and 8 mg
`total daily doses of A vandia
`
`8 mg
`
`- -aD
`- - BID
`
`4 mg
`
`-QD
`- - BID
`
`500
`
`400
`
`300
`
`200
`
`100
`
`0
`
`C
`
`::J'
`_§ 200
`0) .s
`._g 100
`ro
`.... c
`Ql g
`0
`0
`
`0
`
`504
`
`508
`
`512
`
`516
`
`520
`
`524
`
`528
`
`504
`
`508
`
`512
`
`516
`
`520
`
`524 528
`
`-
`__J
`--
`E 1200
`Cl
`.s
`-C
`
`BOO
`
`400
`
`C
`0
`:.=;
`....
`(13
`
`Q)
`(.)
`C:
`0
`()
`
`4mg
`
`- aD
`- - 61D
`
`Time (hr)
`
`3000
`
`2400
`
`1800
`
`1200
`
`600
`
`0
`
`8mg
`
`-OD
`- - BID
`
`0
`
`504
`
`508
`
`512
`
`516
`
`520
`
`524
`
`528
`
`504
`
`508
`
`512
`
`516
`
`520
`
`524
`
`528
`
`Time (hr)
`
`MPI EXHIBIT 1043 PAGE 2
`
`MPI EXHIBIT 1043 PAGE 2
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1043-0002
`
`
`
`Patent Application Publication May 27, 2004 Sheet 2 of 2
`
`US 2004/0102486 Al
`
`Figure 2: Observed mean fasting glucose concentrations and predicted
`mean fasting plasma glucose concentrations vs time based on PK/PD
`modeling of the effect of Compound (I) concentrations by regimen
`following administration of A vandia
`
`240
`
`230
`
`•
`
`•
`
`:J' 220
`"CJ
`oi
`
`E -5; 210
`
`Placebo
`•
`4mgQD
`0
`v' 2 mg BIO
`T 8mgQ0
`■ 4mgBI0
`
`0
`0
`::J
`c, 200
`ro
`E
`<IS a. 190
`-~
`iii 180
`co
`lL
`
`c/)
`
`CJ)
`
`\
`
`...
`...
`II '
`-------------
`•
`•
`
`1000
`
`2000
`
`3000
`Time, hr
`
`4000
`
`5000
`
`6000
`
`170
`
`160
`
`0
`
`Symbols represent observed FPG, lines represent predicted FPG.
`Time scale related to study definition:
`0 hr= -6 week
`1008 hr= 0 week (initiation of first dose)
`
`1680 hr= 4 week
`
`MPI EXHIBIT 1043 PAGE 3
`
`MPI EXHIBIT 1043 PAGE 3
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1043-0003
`
`
`
`US 2004/0102486 Al
`
`May 27, 2004
`
`1
`
`NOVEL METHOD OF TREATMENT
`
`FIELD OF THE INVENTION
`
`[0001] This invention relates to a novel method of treat(cid:173)
`ment, in particular to a method for the treatment of Type 2
`diabetes mellitus and conditions associated with diabetes
`mellitus and a pharmaceutical composition for use in such a
`method.
`
`BACKGROUND OF THE INVENTION
`
`[0002] 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 (I)
`including the maleate salt at example 1 thereof.
`[0003] Compound (I) is an example of a class of anti(cid:173)
`hyperglycaemic agents known as "insulin sensitisers". In
`particular Compound (I) is a thiazolidinedione insulin sen(cid:173)
`sitiser.
`[0004] European Patent Applications, Publication Num(cid:173)
`bers: 0008203, 0139421, 0032128, 0428312, 0489663,
`0155845, 0257781,0208420, 0177353,0319189, 0332331,
`0332332, 0528734, 0508740; International Patent Applica(cid:173)
`tion, Publication Numbers 92/18501, 93/02079, 93/22445
`and U.S. Pat. Nos. 5,104,888 and 5,478,852, also disclose
`certain thiazolidinedione insulin sensitisers.
`[0005] 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 "cyclic insulin
`sensitisers". Other examples of acyclic insulin sensitisers are
`those disclosed in U.S. Pat. No. 5,232,945 and International
`Patent Applications, Publication Numbers WO92/03425 and
`WO91/19702.
`[0006] Examples of other insulin sensitisers are those
`disclosed in European Patent Application, Publication Num(cid:173)
`ber 0533933, Japanese Patent Application Publication Num(cid:173)
`ber 05271204 and U.S. Pat. No. 5,264,451.
`[0007] The above mentioned publications are incorporated
`herein by reference.
`
`[0008]
`It is now surprisingly indicated that the particular
`plasma concentrations of an anti-diabetic agent, such as
`Compound (I), which provide effective glycaemic control,
`indeed an optimum effect on glycaemic control, can be
`determined. This therefore enables optimization of the dos(cid:173)
`ing regimen for the anti-diabetic agent for a given dosing
`interval. Pharmaceutical compositions which provide
`plasma concentrations of an anti-diabetic agent, such as
`Compound (I), at these particular concentrations, especially
`over an extended period of time, are also envisaged by this
`invention.
`
`SUMMARY OF THE INVENTION
`
`[0009] Accordingly, in a first aspect, the present invention
`provides a method for the treatment of Type 2 diabetes
`mellitus and conditions associated with diabetes mellitus,
`
`which method comprises the administration to a human or
`non-human mammal in need thereof, of an effective non(cid:173)
`toxic amount of an insulin sensitiser, such as Compound (I),
`so as to provide a plasma concentration of the insulin
`sensitiser of at least a threshold level from within the range
`of effective plasma levels of the insulin sensitiser (herein(cid:173)
`after referred to as the "Threshold Plasma Concentration").
`
`DETAILED DESCRIPTION OF THE
`INVENTOIN
`
`[0010] The Threshold Plasma Concentration is suitably
`within the range of from 40 to 200 ng/nL including 50 to 200
`ng/nL, including 50 to 120 ng/mL, 60 to 120 ng/mL, 90 to
`110 ng/mL or 95 to 105 ng/mL.
`
`[0011] A suitable minimum Threshold Plasma Concentra(cid:173)
`tion (hereinafter "Minimum Threshold Plasma Concentra(cid:173)
`tion") is the SC50 concentration of the particular insulin
`sensitiser, which for Compound (I) is within the range of 40
`to 65 ng/mL, more suitably 41.1 to 61.7, for example 50 or,
`more suitably, 51.4 ng/mL.
`
`[0012] A preferred Threshold Plasma Concentration (here(cid:173)
`inafter "Preferred Threshold Plasma Concentration") is
`twice the SC50 concentration, which for Compound (I) is in
`the range of 80 to 130 ng/mL, more suitably 82.2 to 123.4,
`for example 100 ng/mL or 102.8 ng/mL.
`
`[0013] The invention particularly envisages treatments
`wherein the plasma concentration of the insulin sensitiser
`remains substantially within the range of concentrations
`from the Minimum Threshold Plasma Concentration to the
`Preferred Threshold Plasma Concentration, that is for Com(cid:173)
`pound (I) within the range of from 40 to 130 ng/mL, more
`suitably 41.1 ng/mL to 123.4 ng/mL, for example 50 ng/mL
`to 100 ng/mL or 51.4 ng/mL to 102.8 ng/mL.
`
`[0014] The invention also particularly envisages treat(cid:173)
`ments wherein the plasma concentration of the insulin
`sensitiser remains substantially within the range of concen(cid:173)
`trations from the Minimum Threshold Plasma Concentration
`to a level at or above the Preferred Threshold Plasma
`Concentration, that is for Compound (I) within the range of
`from 40 ng/mL to a level at or above 130 ng/mL, more
`suitably 41.1 ng/mL to a level at or above 123.4 ng/mL, for
`example 50 ng/mL to 100 ng/mL or 51.4 ng/mL to a level at
`or above 102.8 ng/mL.
`
`[0015]
`In its preferred form, the invention provides a
`treatment wherein the plasma concentration of the insulin
`sensitiser remains substantially at or above the Preferred
`Threshold Plasma Concentration, that is for Compound (I),
`substantially at or above 100 ng/mL, especially substantially
`at or above 102.8 ng/mL.
`
`[0016] A suitable thiazolidinedione insulin sensitiser is
`Compound (I).
`
`[0017] 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]methyl ]-2,4-thia(cid:173)
`zolidinedione ( or troglitazone ), 5-[ 4-[(1-methylcyclohexyl(cid:173)
`)methoxy ]benzyl]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-dihydroben(cid:173)
`zopyran)-5-ylmethyl)thiazolidine-2,4-dione
`( or
`englita(cid:173)
`zone ).
`
`MPI EXHIBIT 1043 PAGE 4
`
`MPI EXHIBIT 1043 PAGE 4
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1043-0004
`
`
`
`US 2004/0102486 Al
`
`May 27, 2004
`
`2
`
`[0018] A particular thiazolidinedione insulin sensitiser is
`5-[ 4-[2-(5-ethylpyridin-2-yl)ethoxy ]benzyl]thiazolidine-2,
`4-dione ( or pioglitazone ).
`
`Threshold Plasma Concentration, that is for Compound (I),
`substantially at or above 100 ng/mL, especially substantially
`at or above 102.8 ng/mL.
`
`[0019] 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-thiazo(cid:173)
`lidinedione ( or troglitazone ).
`
`[0020] When the insulin sensitiser is Compound (I), the
`unit dose suitably comprises 2 to 12 or preferably 4 to 8 mg
`of Compound (I) in a pharmaceutically acceptable form.
`
`[0021] Suitable unit dosages of other insulin sensitisers are
`those indicated in publications mentioned herein and include
`from 100 to 800 mg of troglitazone such as 200, 400, 600 or
`800 mg and for pioglitazone from 5 to 50 mg, including 10
`to 40 mg, such as 20, 30 or 40 mg and also including 15, 30
`and 45 mg of pioglitazone.
`
`[0022] As indicated above, the treatment of the invention
`is suitably effected by the administration of a pharmaceutical
`composition of the insulin sensitiser adapted so as to provide
`a plasma concentration of the insulin sensitiser of at least a
`Threshold Plasma Concentration of the insulin sensitiser.
`
`[0023] Accordingly, in a further aspect, the invention also
`provides a pharmaceutical composition comprising an insu(cid:173)
`lin sensitiser and a pharmaceutically acceptable carrier
`therefor, which composition is adapted to provide a plasma
`concentration of the insulin sensitiser of at least a Threshold
`Plasma Concentration of the insulin sensitiser, suitably over
`a sustained period of time.
`
`[0024] Suitable modified
`compos1t10ns
`release
`delayed, pulsed or sustained release compositions.
`
`are
`
`[0025] Accordingly, in a further aspect, the invention also
`provides a modified release pharmaceutical composition
`comprising an insulin sensitiser and a pharmaceutically
`acceptable carrier therefor, which composition is adapted to
`provide a plasma concentration of the insulin sensitiser of at
`least a Threshold Plasma Concentration of the insulin sen(cid:173)
`sitiser, suitably over a sustained period of time.
`
`[0026] Suitably the carrier is adapted to provide the pro(cid:173)
`vide a plasma concentration of the insulin sensitiser of at
`least a Threshold Plasma Concentration.
`
`[0027] Suitably the modified release is a sustained release,
`for example providing effective release of active agents of at
`least a Threshold Plasma Concentration over a time period
`of up to 24 hours.
`
`[0028] Suitably the modified release is a pulsed release,
`for example providing two pulses of release of active agents
`of at least a Threshold Plasma Concentration per 24 hours.
`
`[0029] The invention particularly envisages compositions
`adapted to provide a plasma concentration of the insulin
`sensitiser which remains substantially within the range of
`concentrations from the Minimum Threshold Plasma Con(cid:173)
`centration to the Preferred Threshold Plasma Concentration,
`that is for Compound (I) within the range of from 40 to 130
`ng/mL, more suitably 41.1 to 123.4 ng/mL, for example 50
`to 100 ng/mL or 51.4 to 102.8 ng/mL.
`
`[0030] The invention also envisages compositions adapted
`to provide a plasma concentration of the insulin sensitiser
`which remains substantially at or above the Preferred
`
`[0031] Suitably the composition is a unit dose composi(cid:173)
`tion.
`
`[0032] Suitably, the Threshold Plasma concentration of
`the insulin sensitiser is maintained or exceeded over several
`hours, for example 12, 16 or 24 hours, per dose of insulin
`sensitiser.
`
`[0033] Suitably, the treatment is such that the Threshold
`Plasma concentration of the insulin sensitiser is maintained
`or exceeded over a sustained period of time.
`
`[0034]
`It will be understood that the insulin sensitiser,
`such as Compound (I), is administered in a pharmaceutically
`acceptable form, including pharmaceutically acceptable
`derivatives such as pharmaceutically acceptable salts, esters
`and solvates thereof, as appropriate of the relevant pharma(cid:173)
`ceutically active agent. It will be understood that all phar(cid:173)
`maceutically acceptable forms of the active agents per se are
`encompassed by this invention.
`
`[0035] Suitable pharmaceutically acceptable salted forms
`of Compound (I) include those described in EP 0306228 and
`WO94/05659. A preferred pharmaceutically acceptable salt
`is a maleate.
`
`[0036] Suitable pharmaceutically acceptable solvated
`forms of Compound (I) include those described in EP
`0306228 and WO94/05659, in particular hydrates.
`
`[0037] 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 incorpo(cid:173)
`rated herein by reference.
`
`[0038] Compound (I) may exist in one of several tauto(cid:173)
`meric forms, all of which are encompassed by the term
`Compound (I) as individual tautomeric forms or as mixtures
`thereof. Compound (I) contains a chiral carbon atom, and
`hence can exist in up to two stereoisomeric forms, the term
`Compound (I) encompasses all of these isomeric forms
`whether as individual isomers or as mixtures of isomers,
`including racemates.
`
`[0039] The insulin sensitisers mentioned herein are pre(cid:173)
`pared in accordance with known methods, for example those
`disclosed in the above mentioned publications or 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).
`
`[0040] When used herein the term "conditions associated
`with diabetes" includes those conditions associated with the
`pre-diabetic state, conditions associated with diabetes mel(cid:173)
`litus itself and complications associated with diabetes mel(cid:173)
`litus.
`
`[0041] When used herein the term "conditions associated
`with the pre-diabetic state" includes conditions such as
`insulin resistance, including hereditary insulin resistance,
`impaired glucose tolerance and hyperinsulinaemia.
`
`MPI EXHIBIT 1043 PAGE 5
`
`MPI EXHIBIT 1043 PAGE 5
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1043-0005
`
`
`
`US 2004/0102486 Al
`
`May 27, 2004
`
`3
`
`[0042]
`"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
`associated with insulin resistance include polycystic ovarian
`syndrome and steroid induced insulin resistance and gesta(cid:173)
`tional diabetes.
`
`[0043]
`"Complications associated with diabetes mellitus"
`includes renal disease, especially renal disease associated
`with Type II diabetes, neuropathy and retinopathy.
`
`[0044] Renal diseases associated with Type II diabetes
`include nephropathy, glomerulonephritis, glomerular scle(cid:173)
`rosis, nephrotic syndrome, hypertensive nephrosclerosis and
`end stage renal disease.
`
`[0045] As used herein the term 'pharmaceutically accept(cid:173)
`able' embraces both human and veterinary use: for example
`the term "pharmaceutically acceptable" embraces a veteri(cid:173)
`narily acceptable compound.
`
`[0046] When used herein the term "SCS0 concentration"
`refers to the plasma concentration for a given compound
`required to produce a half-maximal effect on fasting plasma
`glucose for that compound.
`
`[0047] For the avoidance of doubt, when reference is made
`herein to scalar amounts, including mg amounts, of Com(cid:173)
`pound (I) in a pharmaceutically acceptable form, the scalar
`amount referred to is made in respect of Compound (I) per
`se: For example 2 mg of Compound (I) in the form of the
`maleate salt is that amount of maleate salt which contains 2
`mg of Compound (I).
`
`[0048] Diabetes mellitus is preferably Type II diabetes.
`
`[0049] Glycaemic control may be characterised using con(cid:173)
`ventional methods, for example by measurement of a typi(cid:173)
`cally used index of glycaemic control such as fasting plasma
`glucose or glycosylated haemoglobin (Hb Ale). 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., "Moni(cid:173)
`toring the Diabetic Patent with Glycosolated Hemoglobin
`Measurements", Clinical Products 1988.
`
`[0050] Preferably, the treatment of the invention will
`effect an improvement in the levels of advanced glycosyla(cid:173)
`tion end products (AGEs), leptin and serum lipids including
`total cholesterol, HDL-cholesterol, LDL-cholesterol includ(cid:173)
`ing improvements in the ratios thereof, in particular an
`improvement in serum lipids including total cholesterol,
`HDL-cholesterol, LDL-cholesterol including improvements
`in the ratios thereof.
`
`[0051] As indicated above, the active medicaments of the
`method of the invention are preferably administered in
`pharmaceutical composition form.
`
`[0052] Usually the compositions are adapted for oral
`administration. However, they may be adapted for other
`modes of administration, for example parenteral adminis(cid:173)
`tration, sublingual or transdermal administration.
`
`[0053] The compositions may be in the form of tablets,
`capsules, powders, granules, lozenges, suppositories, recon-
`
`stitutable powders or liquid preparations, such as oral or
`sterile parenteral solutions or suspensions.
`
`[0054]
`In order to obtain consistency of administration it
`is preferred that a composition of the invention is in the form
`of a unit dose.
`
`[0055] Unit dosage presentation forms for oral adminis(cid:173)
`tration may be in tablet or capsule form and may as
`necessary contain conventional excipients such as binding
`agents, fillers, lubricants, glidants, disintegrants and wetting
`agents.
`
`[0056] Examples of binding agents include acacia, alginic
`acid, carboxymethylcellulose calcium. carboxymethylcellu(cid:173)
`lose sodium, dextrates, dextrin, dextrose, ethylcellulose,
`gelatin, liquid glucose, guar gum, hydroxyethyl cellulose,
`hydroxypropyl cellulose, hydroxypropyl methylcellulose,
`magnesium aluminium silicate, maltodextrin, methyl cellu(cid:173)
`lose, polymethacrylates, polyvinylpyrrolidone, pregelati(cid:173)
`nised starch, sodium alginate, sorbitol, starch, syrup, traga(cid:173)
`canth.
`
`[0057] Examples of fillers include calcium carbonate, cal(cid:173)
`cium phosphate, calcium sulphate, carboxymethylcellulose
`calcium, carboxymethylcellulose sodium, compressible
`sugar, confectioner's sugar, dextrates, dextrin, dextrose,
`dibasic calcium phosphate dihydrate, dibasic calcium phos(cid:173)
`phate, fructose, glyceryl palmitostearate, glycine, hydroge(cid:173)
`nated 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.
`
`[0058] Examples of lubricants include calcium stearate,
`glyceryl monostearate, glyceryl palmitostearate, magnesium
`stearate, microcrystalline cellulose, sodium benzoate,
`sodium chloride, sodium lauryl sulphate, stearic acid,
`sodium stearyl fumarate, talc, zinc stearate.
`
`[0059] Examples of glidants include colloidal silicon
`dioxide, powdered cellulose, magnesium trisilicate, silicon
`dioxide, talc.
`
`[0060] 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, polyvinylpyr(cid:173)
`rolidone, polacrilin potassium, pregelatinised starch, sodium
`alginate, sodium lauryl sulphate, sodium starch glycollate.
`
`[0061] An example of a pharmaceutically acceptable wet(cid:173)
`ting agent is sodium lauryl sulphate.
`
`[0062] The solid oral compositions may be prepared by
`conventional methods of 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 conven(cid:173)
`tional in the art. The tablets may be coated according to
`methods well known in normal pharmaceutical practice, in
`particular with an enteric coating.
`
`[0063] Oral liquid preparations may be in the form of, for
`example, emulsions, syrups, or elixirs, or may be presented
`as a dry product for reconstitution with water or other
`
`MPI EXHIBIT 1043 PAGE 6
`
`MPI EXHIBIT 1043 PAGE 6
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1043-0006
`
`
`
`US 2004/0102486 Al
`
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`suitable vehicle before use. Such liquid preparations may
`contain conventional additives such as suspending agents,
`for example sorbitol, syrup, methyl cellulose, gelatin,
`hydroxyethylcellulose, carboxymethylcellulose, aluminium
`stearate gel, hydrogenated edible fats; emulsifying agents,
`for example lecithin, sorbitan monooleate, or acacia; non(cid:173)
`aqueous vehicles (which may include edible oils), for
`example almond oil, fractionated coconut oil, oily esters
`such as esters of glycerine, propylene glycol, or ethyl
`alcohol; preservatives, for example methyl or propyl p-hy(cid:173)
`droxybenzoate or sorbic acid; and if desired conventional
`flavouring or colouring agents.
`[0064] For parenteral administration, fluid unit dosage
`forms are prepared utilizing the compound and a sterile
`vehicle, and, depending on the concentration used, can be
`either suspended or dissolved in the vehicle. In preparing
`solutions the compound can be dissolved in water for
`injection and filter sterilized before filling into a suitable vial
`or ampoule and sealing. Advantageously, adjuvants such as
`a local anaesthetic, a preservative and buffering agent can be
`dissolved in the vehicle. To enhance the stability, the com(cid:173)
`position can be frozen after filling into the vial and the water
`removed under vacuum. Parenteral suspensions are prepared
`in substantially the same manner, except that the Compound
`(I) suspended in the vehicle instead of being dissolved, and
`sterilization cannot be accomplished by filtration. The com(cid:173)
`pound can be sterilized by exposure to ethylene oxide before
`suspending in the sterile vehicle. Advantageously, a surfac(cid:173)
`tant or wetting agent is included in the composition to
`facilitate uniform distribution of the compound.
`[0065] As indicated the compositions are preferably in a
`unit dosage form in an amount appropriate for the relevant
`daily dosage.
`[0066] The present treatments and compositions may also
`contain other medicaments in addition to insulin sensitisers
`including other anti diabetic agents, such as insulin secre(cid:173)
`tagogues, biguanide antihyperglycaemic agents and alpha
`glucosidase inhibitor antihyperglycaemic agents.
`
`[0067]
`In the treatment the medicaments may be admin(cid:173)
`istered from 1 to 6 times a day, suitably 1 or 2 times per day,
`preferably once per day.
`[0068] Compositions may contain from 0.1 % to 99% by
`weight, preferably from 10-60% by weight. of the active
`material, depending upon the method of administration.
`
`[0069] The composition may, if desired, be in the form of
`a pack accompanied by written or printed instructions for
`use.
`[0070] The method by which the Threshold Plasma Con(cid:173)
`centration, such as the SCS0 concentration, for a given
`compound can be determined is:
`
`[0071] 1) first to obtain plasma concentrations versus
`time data for the compound, preferably using data
`from humans, by using standard pharmacokinetic
`compartmental modelling methods (for example for
`Compound (I), concentrations were fit to a one
`compartment model.);
`
`[0072] 2) the model predicted concentrations for the
`compound are then fed back into the model and used
`to determine the change in fasting plasma glucose
`levels after various doses;
`
`[0073] 3) the relationship between predicted plasma
`concentrations of compound and fasting plasma glu(cid:173)
`cose can suitably be determined using an indirect
`pharmacological response model (model IV), for
`example that described in (Dayneka NL, Garg V and
`Jusko W J, Comparison of Four Basic Models of
`Indirect Pharmacodynamic Responses. J of Pharma(cid:173)
`cokinetics and Biopharmaceutics. Vol 21, No 4.
`1993). This model yields estimates of glucose input
`rate (Kin) and output rate (Kaut), maximal stimula(cid:173)
`tion of glucose output (Smax). Hill coefficient
`(gamma) and the Threshold Plasma Concentration,
`such as the SCS0 concentration (i.e the concentration
`associated with a half maximal response) to be
`determined for that compound. This method forms a
`further part of the present invention.
`
`[0074] For Compound (I), it was necessary to account for
`a time delay between the time of actual initiation of dosing
`(week 0) and the observed change in fasting plasma glucose.
`This delay factor was estimated through the modelling for
`each dose level. The mean delay across dose levels for
`Compound (I) was found to be 292 hours. The delay factor
`was incorporated into the model for deriving fasting plasma
`glucose by assuming that the first dose of drug occurred only
`after the time dictated by the delay factor. It is considered
`that for this model a delay factor would be required for other
`thiazolidinedione insulin sensitisers and that this factor will
`be substantially similar to that found for Compound (I).
`Delay factors for other compounds may also be required to
`be determined using similar methodology to that disclosed
`herein.
`[0075] The invention also comprises the above mentioned
`method, optionally including the step of introducing the
`delay factor into the model.
`
`[0076]
`In a further aspect, the invention provides a process
`for preparing a pharmaceutical composition comprising an
`insulin sensitiser and a pharmaceutically acceptable carrier
`therefor, the composition being adapted to provide a plasma
`concentration of the insulin sensitiser of at least a Threshold
`Plasma Concentration of the insulin sensitiser, which pro(cid:173)
`cess comprises formulating the insulin sensitiser and the
`pharmaceutically acceptable carrier so as to provide a
`plasma concentration of the insulin sensitiser of at least a
`Threshold Plasma Concentration of the insulin sensitiser.
`[0077] Suitably, the composition is a modified release
`composition.
`
`[0078] Suitably, the carrier is adapted so as to provide a
`plasma concentration of the insulin sensitiser of at least a
`Threshold Plasma Concentration.
`
`[0079] The compositions for the treatment are prepared
`and formulated according to conventional methods, such as
`those disclosed in standard reference texts, for example the
`British and US Pharmacopoeias, Remington's Pharmaceu(cid:173)
`tical Sciences (Mack Publishing Co.), Martindale The Extra
`Pharmacopoeia (London, The Pharmaceutical Press) (for
`example see the 31st Edition page 341 and pages cited
`therein) and Harry's Cosmeticology (Leonard Hill Books) or
`the above mentioned publications.
`
`[0080] The modified release compositions may be formu(cid:173)
`lated according to appropriate methods disclosed in for
`example Sustained and Controlled Release Drug Delivery
`
`MPI EXHIBIT 1043 PAGE 7
`
`MPI EXHIBIT 1043 PAGE 7
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1043-0007
`
`
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`Systems, Editor Joe R Robinson, Volume 7, 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 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, Reming(cid:173)
`ton's Pharmaceutical Sciences (Mack Publishing Co.). Mar(cid:173)
`tindale The Extra Pharmacopoeia (London, The Pharmaceu(cid:173)
`tical Press) (for example see the 31st Edition page 341 and
`pages cited therein) and Harry's Cosmeticology (Leonard
`Hill Books).
`
`[0081] No adverse toxicological effects are expected for
`the compositions or methods of the invention in the above
`mentioned dosage ranges.
`
`EXAMPLES
`
`Example
`
`Pharmacokinetic/Pharmacodynamic Modeling of
`Compound (I) in Type 2 Diabetes Patients
`
`[0082] A PK/PD model was developed to characterise the
`effect of Compound (I) on fasting plasma glucose (FPG)
`concentrations in diabetic patients. The model was devel(cid:173)
`oped using mean fasting plasma glucose data from a Phase
`III clinical trial which consisted of comparison of placebo
`and four doses/regimens of Compound (I) in a parallel(cid:173)
`group design of 26 weeks duration. Dose regimens evalu(cid:173)
`ated were: 4 mg once daily and 2 mg twice daily, and 8 mg
`once daily and 4 mg twice daily.
`
`Pharmacokinetics of Compound (I)
`
`[0083] The pharmacokinetics of Compound (I) were
`described using a one-compartment model with first order
`oral absorption. Individual bayesian estimates of Compound
`(I) oral clearance and steady-state volume of distribution
`were predicted for each patient in the same Phase III clinical
`trial utilizing the population parameter estimates (priors)
`from the Phase I population pharmacokinetic analysis. Mean
`concentration-time profiles (Cp) for each regimen for use in
`the pharmacodynamic modeling were predicted using the
`mean post hoc oral clearance (2.68 L/h) and Vss/F (15.4 L)
`values across these patients (FIG. 1).
`
`Pharmacodynamics of Compound (I)
`
`[0084] A modified indirect response model IV (Dayneka et
`al. 1993) was developed utilizing the pharmacokinetics of
`Compound (I) as the driving force for the change in fasting
`plasma glucose after various doses of Compound (I). Mod(cid:173)
`eling fittings were done using ADAPT II, Release 4
`(D' Argenio and Schumitzky, 1979).
`
`[0085]
`In the absence of Compound (I), plasma glucose
`levels are governed by formation (kin) and utilization (k