(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2004/0102486A1
`(43) Pub. Date:
`May 27, 2004
`Benincosa et al.
`
`US 2004.0102486A1
`
`(54)
`(75)
`
`(73)
`(21)
`(22)
`
`(63)
`
`NOVEL METHOD OF TREATMENT
`
`(30)
`
`Foreign Application Priority Data
`
`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)
`Assignee: SmithKline Beecham Corporation
`Appl. No.:
`10/705,606
`
`Filed:
`
`Nov. 10, 2003
`Related U.S. Application Data
`Continuation of application No. 09/831,652, filed on
`Jul. 11, 2001, now abandoned, filed as 371 of inter
`national application No. PCT/US99/26746, filed on
`Nov. 12, 1999.
`
`Nov. 12, 1998 (GB)......................................... 9824893.3
`
`Publication Classification
`
`(51) Int. Cl." .......................................... A61K 31/4439
`(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
`tions for use in Such method and methodology for deter
`mining plasma concentrations of active agent use in Such
`methods.
`
`MPI EXHIBIT 1078 PAGE 1
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`MPI EXHIBIT 1078 PAGE 1
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`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1078, p. 1 of 9
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`Patent Application Publication May 27, 2004 Sheet 1 of 2
`
`US 2004/0102486A1
`
`Figure 1: Simulated steady-state concentrations of Compound (I) (upper)
`and M10 (lower) over a 24 hour dosing interval following 4 mg and 8 mg
`total daily doses of Avandia
`
`4 mg
`
`8 mg
`
`500
`400
`
`300
`
`200
`
`OO
`
`O
`
`504 508 512 516 52O 524 528
`
`504 508 512 516 52O 524 528
`
`Time (hr)
`
`2400
`
`1800
`
`1200
`
`600
`
`g
`S
`C
`Na
`
`S
`cus
`h E
`g
`C
`d
`O
`
`
`
`1 2 O O
`
`BOO
`
`400
`
`O
`
`504 508 512 516 52O 524 528
`
`504 508 512 516 52O 524 528
`
`Time (hr)
`
`MPI EXHIBIT 1078 PAGE 2
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`MPI EXHIBIT 1078 PAGE 2
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`DR. REDDY’S LABORATORIES, INC.
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`Patent Application Publication May 27, 2004 Sheet 2 of 2
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`US 2004/0102486A1
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`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 Avandia
`
`Placebo
`4 mg OD
`2 mg BID
`8 mg QD
`4 mg BID
`
`240
`
`230
`
`220
`
`
`
`2OO
`
`19 O
`
`1 8 O
`
`170
`
`160
`
`O
`
`1OOO
`
`2000
`
`3000
`Time, hr
`
`4000
`
`5000
`
`6OOO
`
`Symbols represent observed FPG, lines represent predicted FPG.
`Time scale related to study definition:
`0 hrs -6 week
`1008 hrs 0 week (initiation of first dose)
`1680 hr = 4 week
`
`MPI EXHIBIT 1078 PAGE 3
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`MPI EXHIBIT 1078 PAGE 3
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`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
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`US 2004/0102486 A1
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`May 27, 2004
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`NOVEL METHOD OF TREATMENT
`
`FIELD OF THE INVENTION
`0001. This invention relates to a novel method of treat
`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
`benzylthiazolidine-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
`hyperglycaemic agents known as “insulin Sensitisers”. In
`particular Compound (I) is a thiazolidinedione insulin Sen
`Sitiser.
`0004 European Patent Applications, Publication Num
`bers: 0008203, O139421, 0032128, 0428312, 0489663,
`O155845,0257781, 0208420, 0177353,031.9189,0332331,
`0332332,0528734,0508740; International Patent Applica
`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/O1420.
`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
`ber 0533933, Japanese Patent Application Publication Num
`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
`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
`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
`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/mL 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
`tion (hereinafter “Minimum Threshold Plasma Concentra
`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 Apreferred Threshold Plasma Concentration (here
`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
`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
`ments wherein the plasma concentration of the insulin
`Sensitiser remains Substantially within the range of concen
`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)methoxyphenyl)methyl-2,4-thia
`Zolidinedione (or troglitaZone), 5-4-(1-methylcyclohexyl
`)methoxybenzylthiazolidine-2,4-dione (or ciglitaZone),
`5-4-2-(5-ethylpyridin-2-yl)ethoxybenzylthiazolidine-2,
`4-dione (or pioglitazone) or 5-(2-benzyl-2,3-dihydroben
`Zopyran)-5-ylmethyl)thiazolidine-2,4-dione (or englita
`Zone).
`
`MPI EXHIBIT 1078 PAGE 4
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`MPI EXHIBIT 1078 PAGE 4
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`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1078, p. 4 of 9
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`US 2004/0102486 A1
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`0.018. A particular thiazolidinedione insulin sensitiser is
`5-4-2-(5-ethylpyridin-2-yl)ethoxybenzylthiazolidine-2,
`4-dione (or pioglitaZone).
`0.019
`Aparticular thiazolidinedione insulin sensitiser is
`5-4-(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-
`benzopyran-2-yl)methoxyphenyl)methyl-2,4-thiazo
`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
`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 release compositions are
`delayed, pulsed or Sustained release compositions.
`0.025
`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
`Sitiser, Suitably over a Sustained period of time.
`0.026
`Suitably the carrier is adapted to provide the pro
`vide a plasma concentration of the insulin Sensitiser of at
`least a Threshold Plasma Concentration.
`0.027
`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
`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
`
`Threshold Plasma Concentration, that is for Compound (I),
`Substantially at or above 100 ng/mL, especially Substantially
`at or above 102.8 ng/mL.
`0031) Suitably the composition is a unit dose composi
`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
`ceutically active agent. It will be understood that all phar
`maceutically acceptable forms of the active agents perse 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
`rated herein by reference.
`0038 Compound (I) may exist in one of several tauto
`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
`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
`litus itself and complications associated with diabetes mel
`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 1078 PAGE 5
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`MPI EXHIBIT 1078 PAGE 5
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`DR. REDDY’S LABORATORIES, INC.
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`US 2004/0102486 A1
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`0.042 “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
`tional diabetes.
`0.043 “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
`rosis, nephrotic Syndrome, hypertensive nephrosclerosis and
`end Stage renal disease.
`0.045. As used herein the term pharmaceutically accept
`able embraces both human and Veterinary use: for example
`the term "pharmaceutically acceptable' embraces a veteri
`narily acceptable compound.
`0046) When used herein the term “SC50 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
`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).
`0.048
`Diabetes mellitus is preferably Type II diabetes.
`0049 Glycaemic control may be characterised using con
`ventional methods, for example by measurement of a typi
`cally 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., “Moni
`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
`tion end products (AGES), leptin and Serum lipids including
`total cholesterol, HDL-cholesterol, LDL-cholesterol includ
`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.
`0.052. Usually the compositions are adapted for oral
`administration. However, they may be adapted for other
`modes of administration, for example parenteral adminis
`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
`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
`lose Sodium, dextrates, dextrin, dextrose, ethylcellulose,
`gelatin, liquid glucose, guar gum, hydroxyethyl cellulose,
`hydroxypropyl cellulose, hydroxypropyl methylcellulose,
`magnesium aluminium Silicate, maltodextrin, methyl cellu
`lose, polymethacrylates, polyvinylpyrrollidone, pregelati
`nised Starch, Sodium alginate, Sorbitol, Starch, Syrup, traga
`canth.
`0057 Examples of fillers include calcium carbonate, cal
`cium phosphate, calcium Sulphate, carboxymethylcellulose
`calcium, carboxymethylcellulose Sodium, compressible
`Sugar, confectioner's Sugar, dextrates, dextrin, dextrose,
`dibasic calcium phosphate dihydrate, dibasic calcium phos
`phate, fructose, glyceryl palmitoStearate, glycine, hydroge
`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
`rolidone, polacrilin potassium, pregelatinised Starch, Sodium
`alginate, Sodium lauryl Sulphate, Sodium Starch glycollate.
`0061 An example of a pharmaceutically acceptable wet
`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
`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
`
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`DR. REDDY’S LABORATORIES, INC.
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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
`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
`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 filtersterilized 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
`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
`pound can be Sterilized by exposure to ethylene oxide before
`Suspending in the Sterile vehicle. Advantageously, a Surfac
`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.
`0.066 The present treatments and compositions may also
`contain other medicaments in addition to insulin Sensitisers
`including other anti diabetic agents, Such as insulin Secre
`tagogues, biguanide antihyperglycaemic agents and alpha
`glucosidase inhibitor antihyperglycaemic agents.
`0067. In the treatment the medicaments may be admin
`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
`Sc.
`0070 The method by which the Threshold Plasma Con
`centration, Such as the SC50 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
`cose can Suitably be determined using an indirect
`pharmacological response model (model IV), for
`example that described in (Dayneka NL, Garg Vand
`Jusko WJ, Comparison of Four Basic Models of
`Indirect Pharmacodynamic Responses. J of Pharma
`cokinetics and Biopharmaceutics. Vol 21, No 4.
`1993). This model yields estimates of glucose input
`rate (Kin) and output rate (Kout), maximal stimula
`tion of glucose output (Smax). Hill coefficient
`(gamma) and the Threshold Plasma Concentration,
`Such as the SC50 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
`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
`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
`lated according to appropriate methods disclosed in for
`example Sustained and Controlled Release Drug Delivery
`
`MPI EXHIBIT 1078 PAGE 7
`
`MPI EXHIBIT 1078 PAGE 7
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1078, p. 7 of 9
`
`

`

`US 2004/0102486 A1
`
`May 27, 2004
`
`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: JG
`Hardy, SS. Davis and C G Wilson also with reference to
`texts such as the British and US Pharmacopoeias, Reming
`ton's Pharmaceutical Sciences (Mack Publishing Co.). Mar
`tindale The Extra Pharmacopoeia (London, The Pharmaceu
`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 APK/PD model was developed to characterise the
`effect of Compound (I) on fasting plasma glucose (FPG)
`concentrations in diabetic patients. The model was devel
`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
`group design of 26 weeks duration. Dose regimens evalu
`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
`eling fittings were done using ADAPT II, Release 4
`(DArgenio and Schumitzky, 1979).
`0085. In the absence of Compound (I), plasma glucose
`levels are governed by formation (kin) and utilization (kout).
`The action of Compound (I) was described as stimulation
`(S(t)) of the utilization of plasma glucose (kout), described
`in text as FPG reduction (Eq. 1). S.
`represents the maxi
`mal Stimulation, SCso is the Compound (I) concentration
`asSociated with half-maximal Stimulation and Y represents a
`Sigmoidicity parameter in the Hill type function (Eq. 2).
`
`FPG
`- = k - knoS(t)o FPG.
`
`where
`
`S(t) = 1 + Smax o Ch
`(t) =
`SCo + C.
`
`Eq. 1
`
`Eq. 2
`
`0086 The mean fasting plasma glucose profiles from 6
`weeks prior to dosing (time 0) through 26 weeks of treat
`ment for the 5 treatment groups are shown in FIG. 2. The
`PK/PD model accommodates the full nature of the fasting
`plasma glucose response over the duration of the Study
`period as evidenced by the close agreement between
`observed and predicted fasting plasma glucose concentra
`tions (FIG. 2). An estimated lag-time (292 hours) between
`the first dose and onset of response was incorporated into the
`modeling. The lag-time allows the model to describe the
`slow onset of action of Compound (I) observed over the first
`4 weeks of dosing.
`0087. The fitted plasma glucose concentrations at steady
`State reflect the difference in response to varying total daily
`dose as well as different dosing frequencies (i.e. once VS
`twice daily) (FIG. 2). The estimated pharmacodynamic
`parameter values are shown in the table below:
`
`Parameter
`