(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY(PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`29 December 2011 (29.12.2011) (10) International Publication Number
`
`(43) International Publication Date
`
`WO 2011/163206 A2
`
`
`51)
`
`International Patent Classification:
`A61K 9/00 (2006.01)
`AG6IK 31/4965 (2006.01)
`A61K 31/155 (2006.01)
`A61K 31/403 (2006.01)
`A61K 31/426 (2006.01)
`A61K 31/702 (2006.01)
`A61K 38/26 (2006.01)
`AGIK 31/445 (2006.01)
`AG61K 38/28 (2006.01)
`AG6IK 31/4439 (2006.01)
`A61K 31/17 (2006.01)
`A61K 31/421 (2006.01)
`A61K 31/4015 (2006.01)
`—-A61K 31/4985 (2006.01)
`
`(21)
`
`International Application Number:
`PCT/US2011/041218
`
`(22)
`
`International Filing Date:
`
`21 June 2011 (21.06.2011)
`
`(25)
`
`(26)
`
`(30)
`
`(71)
`
`(72)
`(75)
`
`Filing Language:
`
`Publication Language:
`
`English
`
`English
`
`Priority Data:
`61/357,251
`
`22 June 2010 (22.06.2010)
`
`US
`
`Applicant (for afl designated States except US). TWI
`PHARMACEUTICALS, INC.; 4f, No. 41, Lane 221,
`Kang Chien Rd., Nei Hu Dist., Taipei, 114 (TW).
`Inventors; and
`Inventors/Applicants (or US only): CHEN, Shou-Chi-
`ung; No. 87, Lane 269, Linsen E. Rd., East Dist., Chiayi
`City, 600 (TW). LEE, Shao-Ming; 2f, No. 9, Ln. 122,
`Ren'ai Rd., Taipei County, Xizhi City, 221 (TW). JAN,
`Chaur-Ming [US/US]; 512 Nw 120th Dr., Coral Springs,
`FL 33071 (US).
`
`(74)
`
`(81)
`
`Agent: KATZ, Martin, I..; Wood, Phillips, Katz, Clark
`& Mortimer, 500 West Madison Street, Suite 3800,
`Chicago, IL 60661 (US).
`
`Designated States (unless otherwise indicated, for every
`kind ofnational protection available): AL, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, Dk, DM, DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HN, HR, HU, ID,IL, IN, IS, JP, KE, KG, KM, KN, KP,
`KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
`ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI,
`NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD,
`SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR,
`TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`(84)
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG,
`ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU,TJ,
`TM), European (AL, AT, BF, BG, CH, CY, CZ, DE, DK,
`EE, ES, FL FR, GB, GR, HR, HU,IE, IS, IT, LT, LU,
`LV, MC, MK, MT, NL, NO,PL, PT, RO, RS, SE, SL SK,
`SM, TR), OAPI (BF, BJ, CF, CG, CL CM, GA, GN, GQ,
`GW, ML, MR, NE, SN, TD, TG).
`Published:
`
`without international search report and to be republished
`upon receipt ofthat report (Rule 48.2(g))
`
`(54) Title: CONTROLLED RELEASE COMPOSITIONS WITH REDUCED FOOD EFFECT
`
`(57) Abstract: The present invention provides a controlled release pharmaceutical composition which exhibits reduced food ef-
`fect.
`
`
`
`WO2011/163206A2[IIITNITNNUINLANATUTTITEAMTELAT
`
`
`
`
`
`

`

`WO 2011/163206
`
`PCT/US2011/041218
`
`CONTROLLED RELEASE COMPOSITIONS
`
`WITH REDUCED FOOD EFFECT
`
`BACKGROUND OF THE INVENTION
`
`[0001]
`
`Oral administration of drugs is frequently affected by food-drug interactions,
`
`a phenomenon often described by the term “food effect”. As generally interpreted, food
`
`effect is a very broad term which refers to all aspects of interactions of food on drug
`
`dissolution, absorption, distribution, metabolism and elimination. The implications of
`
`food effect include changesin bioavailability, rate of on-set, duration of therapeutic effect
`
`and incidence and seriousness ofside effects.
`
`[0002]
`
`The food effect is an important issue during the development of a drug.
`
`In
`
`some cases where food-drug interactions lead to an increase of drug absorption, the
`
`drug formulation is recommended to be taken with food in order to be sufficiently
`
`absorbed and exert its expected clinical effect. However, such drug formulations are not
`preferred because drug absorption can vary with food types and quantity.
`For example,
`
`if a patient forgets to take the drug formulation with food,
`
`the drug may be poorly
`
`absorbed and therefore notclinically efficient. This problem may be avoided by a
`
`formulation without food effect.
`
`[0003]
`
`Thus, there is a need for new sustained release compositions with reduced
`
`or no significant food effect.
`
`[0004]
`
`Metformin is an oral antihyperglycemic drug of the biguanide class used in
`
`the management of non-insulin-dependent diabetes mellitus (NIDDM).
`
`It has been
`
`widely prescribed for lowering blood glucose in patients with NIDDM.
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`WO 2011/163206
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`PCT/US2011/041218
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`[0005]
`
`The benefits of a sustained release dosage form of metformin have been
`
`well known: it allows one to simplify the patient's administration scheme by reducing the
`
`amount of recommended daily intakes,
`
`improves patient compliance, and attenuates
`
`adverse events, e.g., related to high plasma peaks.
`
`Immediate release compositions of
`
`metformin exhibit negative food effect when orally administered to a subject.
`
`[0006]
`
`The commercially available sustained-release dosage forms of metformin,
`
`such as Glucophage® XR, Glumetza® and Fortamet®, havesignificant positive food
`
`effect.
`
`Thus,
`
`they are all recommended to be taken with food to increase drug
`
`bioavailabiltiy and maximum therapeutic benefits.
`
`[0007]
`
`Thus, there is a need for new sustained release compositions of metformin
`
`with reducedor no significant food effect.
`
`SUMMARY OF THE INVENTION
`
`[0008]
`
`In one embodiment, the present invention provides a controlled release
`
`pharmaceutical composition which exhibits
`
`reduced food effect as compared to
`
`conventional controlled release compositions, wherein said composition comprises an
`
`active agent (which may be referred to as a “drug”) which has a limited window of
`
`absorption and displays a negative food effect when an immediate release dosage form
`
`of the drug is orally administered to a subject.
`
`[0009]
`
`in one
`
`embodiment,
`
`the
`
`invention
`
`provides
`
`a
`
`controlled
`
`release
`
`pharmaceutical composition which exhibits
`
`reduced food effect as compared to
`
`conventional controlled release formulations, said composition comprising:
`
`(a)
`
`a sustained release layer comprising:
`
`

`

`WO 2011/163206
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`PCT/US2011/041218
`
`(i)
`
`an active agent, wherein said active agent has a limited window of
`
`absorption and displays a negative food effect when an immediate release
`
`formulation of said active agent is orally administered to a subject;
`
`(ii)
`
`(iii)
`
`optionally, at.least one release modifier; and
`
`atleast one sustained release agent; and
`
`(b) an immediate release layer comprising said active agent and at least one
`
`pharmaceutically acceptable excipient.
`
`[00010]
`
`In one embodiment, the active agent is metformin.
`
`[000711]
`
`In one embodiment,
`
`the invented controlled release pharmaceutical
`
`composition further comprises a second therapeutic agent.
`
`[00012]
`
`In another embodiment,
`
`the invention provides a controlled release
`
`pharmaceutical composition of metformin, wherein the bioavailability of metformin is not
`
`increased more than 50% when said controlled release composition is orally
`
`administered to a subject in the fed state.
`
`[00013]
`
`In yet another embodiment, the invention provides a method of reducing
`
`the food effect of a controlled release composition, said method comprising a step of
`
`formulating an active agent into a unit dosage form, wherein the unit dosage form
`
`comprises at least one sustained layer and one immediate release layer.
`
`[00014]
`
`In yet another embodiment, the invention provides a method of reducing
`
`the time necessary to reach steady state for metformin, said method comprising
`
`administering a controlled release composition of metformin to a subject in need thereof,
`
`wherein the controlled release composition has higher bioavailability than a comparable
`
`dose of Fortamet® (metformin hydrochloride) tablets.
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`

`

`WO 2011/163206
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`PCT/US2011/041218
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`[00015]
`
`In yet another embodiment, the invention provides a method of improving
`
`the bioavailability of a controlled release dosage form of metformin in a fasted mode, said
`
`method comprising formulating metformin into a dosage from comprising a sustained
`
`release layer and an immediate release layer, wherein metformin is present in both the
`
`sustained release layer and the immediate release layer.
`
`[00016]
`
`In yet another embodiment,
`
`the
`
`invention provides
`
`a method of
`
`manufacturing a matrix controlled release tablet, said method comprising: (a) mixing a
`
`portion of an acid salt form of an active ingredient with an alkaline agent to form a mixture;
`
`(b) granulating said mixture with a controlled release agent; and (c) compressing the
`
`granules from step (b) into tablets.
`
`DEFINITIONS
`
`[00017]
`
`The term “food effect”, as used herein, refers to a relative difference in AUC
`
`(Area under the curve), Cmax (Maximum plasma concentration), and/or Tmax (Time to
`
`maximum concentration) of an active substance, when said substance or a formulation
`
`thereof, such as a tablet or a capsule, is administered orally to a mammal, preferably a
`
`human, concomitantly with food or in a fed state as compared to the same values when
`
`the same formulation is administered in a fasted state. The food effect F is calculated
`
`as
`
`F=(Ytea-Ytasted)/Ytasted
`
`wherein Yieq aNd Yiasteq are the found values of AUC, Cmax Or Tmax in the fed and fasted
`
`state, respectively.
`
`[00018]
`
`The term “reduced food effect’, as used herein, refers to the food effect of a
`
`composition of an active substance whichis less than 50%, preferably less than 40%,
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`WO 2011/163206
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`PCT/US2011/041218
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`and more preferably less than 30%. The food effect is calculated by the formula defined
`
`above.
`
`[00079]
`
`The term “positive food effect”, as used herein, refers to a food effect where
`
`.the AUC and/or Cmax is higher when the drug is administered orally in a fed state than
`
`when it is administered in a fasted state.
`
`[00020]
`
`The term “negative food effect” refers to a food effect where the AUC and/or
`
`Cmax IS.
`
`lower when the drug is administered orally in the fed state than when it
`
`is
`
`administered in the fasted state. Drug-food interactions leading to a reduced incidence
`
`and/or severity of side effects are referred to as an “enhanced tolerability food effect”.
`
`[00021]
`
`The term “concomitantly with food” or “administration in the fed state”, as
`
`used herein, refers to administration from about 30 minutes before a meal to about 1 hour
`
`after a meal.
`
`[00022]
`The term “administration in the fasted state”, as used herein, refers to
`administration at least 4 hours after a meal. Moreover, the fasted state also requires
`
`continued fasting for at least 2 hours after the administration.
`
`[00023]
`
`The terms “sustained release” and “controlled release”, as used herein, are
`
`used interchangeably in this application and refer to the release of a drug from a dosage
`
`form at such a rate that when a once-a-day dose or twice-a-day dose of the drug is
`
`administered in the sustained release or controlled release form, blood (e.g., plasma)
`
`concentrations (levels) of the drug are maintained within the therapeutic range but below
`
`toxic levels over a period of time from about 4 to about 24 hours.
`
`[00024]
`
`The term “immediate release”, as used herein, refers to the release of a
`
`drug from a dosageform within sixty minutes after administration to a subject.
`
`

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`WO 2011/163206
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`PCT/US2011/041218
`
`[00025]
`
`The term “limited window of absorption”, as used herein, refers to an oral
`
`bioavailability of less than about 75%, usually less than about 60%, usually decreasing
`
`with the increasing dose of a drug, and almost invariably having permeability/transit time
`
`limited absorption.
`
`[00026]
`
`The term “release modifier’, as used herein, refers to any excipient which
`
`modulates the release rate of a drug from a dosageform.
`
`

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`WO 2011/163206
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`PCT/US2011/041218
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`DETAILED DESCRIPTION OF THE INVENTION
`
`[00027]
`
`in one embodiment, the present invention provides a controlled release
`
`pharmaceutical composition comprising an active agent, wherein said controlled release
`
`composition exhibits a reduced food effect as compared to conventional controlled
`
`release compositions of the active agent.
`
`[00028]
`
`The active agent generally has a limited window of absorption and displays
`
`a negative food effect when an immediate release formulation of said active agent is
`
`orally administered to a subject.
`
`[00029]
`
`The food. effect of the compositions may be measured by AUC, Ca, and/or
`
`Tmax Values.
`
`[00030]
`
`In
`
`a preferred embodiment,
`
`the active agent
`
`is metformin
`
`or a
`
`pharmaceutically acceptable salt of metformin.
`
`Surprisingly,
`
`the novel controlled
`
`release compositions of metformin of
`
`the invention exhibit
`
`reduced food effect.
`
`Specifically, the food effect as measured by AUC is less than 50%, preferably less than
`
`40%, and more preferably less than 30%.
`
`[00031]
`
`In one embodiment, the controlled release pharmaceutical composition of
`
`the invention comprises a sustained release layer and an immediate release layer.
`[00032]
`In a preferred embodiment,
`the invention provides a controlled release
`
`pharmaceutical composition comprising:
`
`(a)
`
`a sustained release layer comprising:
`
`(i)
`
`an active agent, wherein said active agent has a limited window of
`
`absorption and displays a negative food effect when an immediate release
`
`formulation of said active agent is orally administered to a subject;
`
`(ii)
`
`optionally, at least one release modifier; and
`
`7
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`WO 2011/163206
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`PCT/US2011/041218
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`(iii)
`
`at least one sustained release agent: and
`
`(b)
`
`an immediate release layer comprising said active agent and at least one
`
`pharmaceutically acceptable excipient,
`
`wherein said controlled release pharmaceutical composition exhibits reduced food
`
`effects.
`
`[00033]
`
`In a preferred embodiment,
`
`the pharmaceutical compositions of
`
`the
`
`invention have the following amounts of the ingredients:
`
`Ingred ient
`Preferred
`More preferred
`(w/w)
`(w/w)
`(weight % based on each layer)
`Sustained release layer:
`active agent
`(ex., metformin)
`release modifier
`
`30-90%
`
`0-20%
`
`50-90%
`
`1-10%
`
`sustained release agent
`Immediate release layer
`active agent
`(ex., metformin)
`
`excipients
`41-50%
`
`10-50%
`
`50-99%
`
`20-50%
`
`[00034]
`
`In one embodiment of the invention, the ratio of the active agent in the
`
`sustained release layer and the immediate release layer is between about 1:10 and
`
`about 10:1, preferably between about 2:8 and about 8:2, most preferably between about
`
`3:7 and about7:3.
`
`[00035]
`
`In some embodiments, the compositions of the invention maybe in the form
`
`of a bi-layer tablet. The immediate layer may either surround the sustained release
`
`layer or be located at the top or the bottom of the sustained release layer.
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`

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`WO 2011/163206
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`PCT/US2011/041218
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`[00036]
`
`In some embodimenis of the invention, the compositions may optionally
`
`contain at least one release modifier. Examples of release modifiers include but are not
`
`limited to alkaline agents and surfactants. Examples of the preferred alkaline agents
`
`include, but are not
`
`limited to, sodium phosphate, potassium phosphate, calcium
`
`phosphate, sodium hydroxide, sodium tartrate and sodium succinate. Examples of
`
`surfactants include, but are not limited to, sodium lauryl! sulfate and Polysorbate 80.
`
`Ina
`
`preferred embodiment, the release modifier is a phosphatesalt.
`
`[00037]
`
`In some embodiments of the invention, the compositions may optionally
`
`include at least one sustained release agent.
`
`[00038]
`
`Examples of sustained release agents include, but are not
`
`limited to,
`
`hydrophilic polymers, hydrophobic polymers and wax materials.
`
`[00039]
`
`Hydrophilic polymers which may be employed in the invention include, but
`
`are
`
`not
`
`limited
`
`to, hydroxypropylmethylcellulose,
`
`hydroxypropyicellulose,
`
`sodium
`
`carboxymethylcellulose, carboxymethylcellulose calcium, ammonium alginate, sodium
`
`alginate, potassium alginate, calcium alginate, propylene glycol alginate, alginic acid,
`
`polyvinyl alcohol, povidone, carbomer, potassium pectate, potassium pectinate, and the
`
`like,
`
`[00040]
`
`Hydrophobic polymers which may be employedin the invention include, but
`
`are not
`
`limited to, ethyl cellulose, hydroxyethylcellulose, ammonio methyacrylate
`
`copolymer (Eudragit® RL or Eudragit® RS), methyacrylic acid copolymers (Eudragit® L
`
`or Eudragit® S), methacrylic acid-acrylic acid ethyl ester copolymer (Eudragit® L 100-5),
`
`methacrylic
`
`acid
`
`esiers
`
`neutral
`
`copolymer
`
`(Eudragit®
`
`NE
`
`30D),
`
`dimethylaminoethylmethacrylate-methacrylic acid esters copolymer (Eudragit® E 100),
`
`vinyl methyl ether/maleic anhydride copolymers, their salts and esters (Gantrez®).
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`WO 2011/163206
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`[00041]
`
`Wax materials which may be employedin the invention include, but are not
`
`limited to, beeswax, carnauba wax, microcrystalline wax, and ozokerite; fatty alcohols
`
`such as cetostearyl alcohol, stearyl alcohol; cetyl alcohol and myristyl alcohol; and fatty
`
`acid
`
`esters
`
`such
`
`as_
`
`glyceryl monostearate,
`
`glycerol monooleate,
`
`acetylated
`
`monoglycerides, tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate, glycery!
`
`behenate, and hydrogenated castor oil.
`
`[00042]
`
`in a preferred embodiment, the sustained release agent is a hydrophilic
`
`polymer such as hydroxypropylmethyicelluiose.
`
`[00043]
`
`Other excipients which may function as fillers, binders,
`
`lubricants,
`
`disintegrants, and plasticizers may also be included within either the sustained release
`
`layer and/or the immediate release layer.
`
`[00044]
`
`In one embodiment, the composition of the invention may contain 0-20%
`
`w/w of a binder, 0-50% w/w offiller, 0-5% wiw of a lubricant, 0-5% w/w of a disintegrant or
`
`0-20% w/w ofa plasticizer in the sustained release layer and/or immediate release layer.
`
`[00045]
`
`When the active agent is metformin, the total dose of metformin in the
`
`compositions of the invention can be equivalent to 250-2500 mg metformin hydrochloride,
`
`preferably from 250 mg to 1500 mg, and more preferably from 500 mg to 1000 mg.
`
`[00046]
`
`When necessary, an additional active agent may be included to achieve the
`
`desired therapeutic effect.
`
`For example, when the active agent is metformin, another
`
`antihyperglycemic agent may be included with the immediate release layer with
`
`metformin.
`
`[00047]
`
`lt has been knownthatthe first line blood glucose lowering therapy of type
`
`it diabetes is metformin or sulfonylurea monotherapy.
`
`If
`
`first
`
`line treatment
`
`is
`
`unsatisfactory, patients may be moved to second line combination therapies such as
`
`10
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`metformin with sulfonylurea or other antihyperglycemic agents. Accordingly, a second
`
`drug may be addedto the formulations of invention to maximum the therapeutic efficacy.
`
`The second drug may be selected from currently available anti-hyperglycemic drugs
`
`and/or investigational anti-hyperglycemic drugs.
`
`[00048]
`
`Examples of currently available antihyperglycemic drugs include, but are
`
`not limited to, sulfonylurea, biguanides, alpha-glucosidase inhibitors, thiazolidinediones
`
`(TZDs), dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors), meglitinides, glucagon-like
`
`peptide-1 analogs (GLP-1 analogs) and insulin. More specifically, the antidiabetic drugs
`
`include, but are not
`
`limited to, metformin, glyburide, glimepiride, glipyride, glipizide,
`
`chlorpropamide, gliclazide, acarbose, miglito!, pioglitazone,
`
`troglitazone, rosiglitazone,
`
`isaglitazone, muraglitizar, peliglitazar,
`
`sitagliptin,
`
`saxagliptin, vildagliptin,
`
`alogliptin,
`
`linagliptin, dutogliptin,
`
`repaglinide, nateglinide, mitiglindine,
`
`exenatide,
`
`liraglutide,
`
`albig!utide and insulin.
`
`[00049]
`
`Examples of
`
`investigational anti-hyperglycemic drugs include, but not
`
`limited
`
`to,
`
`IL-1 modulators, Sodium-glucose
`
`transporter-2
`
`(SGLT-2)
`
`inhibitors,
`
`Dual-PPAR modulators, 11811-beta- hydroxysteroid dehydrogenase (HSD) inhibitors,
`
`CCR2 antagonists,
`
`selective
`
`inhibitors of
`
`fructose 1,6-bisphosphatase,
`
`immune
`
`modulators, cortisol synthesis inhibitors, Gastrin-Releasing Peptide (GRP):
`
`receptor
`
`agonists, G protein-coupled receptor 119 (GPR 119) agonists, Toll-like receptor-4 (TLR-4)
`
`agonists, FXR antagonists, and antisense drugs targeting glucagon receptors. More
`
`specifically,
`
`the investigational drugs include, but are not
`
`limited to, rhein, diacerein,
`
`monoacetyirhein, berberine, dapagliflozin,
`
`remogliflozin, etabonate, canaglifiozin, and
`
`Aleglitazar.
`
`11
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`
`[00050]
`
`The compositions of the invention may be administered twice-a-day or
`
`once-a-day.
`
`[00051]
`
`In some embodiments, the invention provides a method of reducing the
`
`food effect of a controlled release composition comprising formulating an active agent of
`
`said controlled release composition into a unit dosage form, wherein said unit dosage
`
`form comprises at least one sustained layer and one immediate release layer. The
`
`method of reducing food effect is especially suitable for an active agent which has a
`
`limited window of absorption and displays a negative food effect when an immediate
`
`release dosage form of the active agent is orally administered to a subject. Preferably,
`
`the ratio of the active agentin the sustained release layer and immediate release layer is
`
`‘between about 1:10 and about 10:1, more preferably between about 3:7 and about 7:3.
`
`[00052]
`
`lt was surprisingly found that when the compositions of
`
`the present
`
`invention which included metformin were administered to patients with food,
`
`the
`
`bioavailability of metformin did not
`
`increase more than 50% as compared to the
`
`controlled release composition of metformin orally administered to patients in the fasted
`
`state. This result is an improvement as compared to commercially available extended
`
`release compositions including metformin such as Fortamet®, Glucophage® XR and
`
`Glumetza®.
`
`[00053]
`
`It was also surprisingly found that when metformin was formulated into a
`
`dosage form comprising a sustained release layer and an immediate release layer, the
`
`bioavailability of metformin is improved in a fasted mode as compared to a comparable
`
`dose of a commercially available product such as Fortamet®, Glucophage® XR and
`
`Glumetza®.
`
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`
`[00054]
`
`Thus,
`
`in one embodiment,
`
`the present invention provides a method of
`
`improving bioavailability of a controlled release dosage form of metformin in a fasted
`
`state.
`
`[00055]
`
`In a preferred embodiment,
`
`the invention provides a controlled release
`
`composition of metfomin with improved bioavailability as compared to the administration
`
`of a comparable dose of a Fortamet® tablet
`
`in a fasted mode. Administering the
`
`inventive controlled release compositions of metformin allows one to reduce the time
`
`necessary to reach a steady state in a subject in need thereof.
`
`[00056]
`
`Thus,
`
`in one embodiment,
`
`the present invention provides a method of
`
`reducing the time necessary to reach a steady state for metformin in a subject in need
`
`thereof comprising administering to said subject
`
`the compositions of
`
`the present
`
`invention.
`
`In one embodiment, the present invention provides a method of reducing the
`
`time necessary to reach a steady state for metformin in a subject in need thereofin the
`
`fasted state.
`
`[00057]
`
`The controlled release compositions in accordance with this invention can
`
`be prepared by common methods well knownto thoseskilled in the art of manufacturing
`
`drug compositions.
`
`[00058]
`
`However, a traditional manufacturing process may be not applicable when
`
`a controlled release composition contains a higher dose of an active ingredient.
`
`For
`
`example, a traditional manufacturing process is not suitable for manufacturing a matrix
`
`controlled release tablet containing more than 750 mg of an active ingredient. A matrix
`
`controlled release table usually requires at least 10% by weight of total weight of a
`
`controlled release agent. A combination of high dose of active ingredients, controlled
`
`release agent(s) and other excipients results in a higher total weight of a tablet. When
`
`13
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`
`compressedbya traditional method, the tablet size may be too big and not suitable for
`
`swallow.
`
`[00059]
`
`The present invention surprisingly resulted in reduced tablet size of a matrix
`
`controlled release tabiet.
`
`in a preferred embodiment,
`
`the method of the invention
`
`comprisesthe following steps:
`
`(a) mixing an acid salt form of active ingredient with an alkaline agent to form a
`
`mixture:
`
`(b) granulating said mixture with a controlled release agent; and
`
`(c) compressing the granules from step (b)into tablets.
`
`[00060]
`
`The method of reducing tablet size of the invention is especially suitable for
`
`a controlled release tablet comprising more than 750 mg of an active ingredient. By
`
`mixing an alkaline agent with an acid salt form of an active ingredient, the required
`
`amountof the controlled release agent may be decreased but still able to achieve the
`
`desired controlled release results. Accordingly, the size of the controlled release tablet
`
`is reduced.
`
`Ina preferred embodiment, ihe method is suitable for a controlled release
`
`tablet comprising about 750-1250 mg of metformin HCI.
`
`[00061]
`
`The following Examples are provided solely for illustrative purposes and are
`
`not meantto limit the invention in any way.
`
`14
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`

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`
`A. Preparation of a controlled release composition
`
`Example 1
`
`[00062]
`
`A controlled release tablet containing 1000 mg of metformin HCl was
`
`prepared as follows:
`
`Sustained release layer
`(a)
`
`
`Sustained release layer
`
`Ingredients
`mg/ tabiet
`%
`
`
`Metformin HCl
`
`HPMC K100M CR (intra)
`
`HPMC K100LV CR
`
`NasHPOz
`
`HPMC K100M CR (extra)
`
`600.0
`
`50.0
`
`45
`
`50.0
`
`300.0
`
`59.4
`
`5.0
`
`0.4
`
`5.0
`
`29.7
`
`Magnesium stearate
`5.0
`0.5
`
`
`100.0
`1009.5
`Subtotal
`
`
`[00063}
`
`HPMC K100LV CR was dissolved in purified water as a binder solution.
`
`Metformin HCl, NagHPO, and partial HPMC K100M CR (intra) were blended and passed
`
`through a 30 mesh screen. The blended powders were wet granulated in a high shear
`
`mixer by sparing with the binder solution. The granules were dried in a fluidized bed
`
`granulator at 70°C until the loss on drying is not more than 3%. The dried granules were
`
`passed through a Comil equipped with a 20# mesh screen. The HPMC K100M CR
`
`(extra) was passed through 30# mesh screen and blended with the dried granules by a
`
`V-blender. Magnesium stearate was passed through 30# mesh screen and blended
`
`with the mixtures.
`
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`
`immediate release layer
`(b)
`
`
`immediate release layer
`
`Ingredients
`mq/ tablet
`%
`
`
`Metformin HCl
`
`Microcrystal cellulose
`
`Hydropropyl cellulose
`
`(Klucel® EF)
`
`Ac-Di-Sol
`
`400.0
`
`100.0
`
`15.0
`
`25.0
`
`73.4
`
`18.3
`
`2.8
`
`4.6
`
`Magnesium stearate
`5.0
`0.9
`
`
`Subtotal
`545.0
`100.0
`
`
`[00064]
`
`Kiucel® EF was dissolved in purified water as a binder
`
`solution.
`
`Metformin HCI and Microcrystal cellulose were blended and passed through a 30# mesh
`
`screen. The blended powders were wet granulated in a high shear mixer by sparing
`
`with the binder solution. The granules weredried in a fluidized bed granulator at 70°C
`
`until the loss on drying is not more than 3%. The dried granules were passed through a
`
`Comil equipped with a 20# mesh screen. Ac-Di-Sol was passed through 30# mesh
`
`screen and blended with the dried granules by a V-blender. Magnesium stearate was
`
`passed through 30# mesh screen and blended with the mixtures.
`
`(c)
`
`Compression
`
`[00065]
`
`The sustained release and immediate release mixtures were compressed
`
`to form a capsule shaped tablet.
`
`[00066]
`
`The size of the capsule shapedtable of the invention is 21.5mm x 12.0 mm.
`
`The thickness is 8.25mm. The shape of Fortamet® 1000mg is round.
`
`Its diameteris
`
`16
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`

`WO 2011/163206
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`
`8.73mm and thickness is 12.98 mm. The table size and shape ofthe invention is more
`
`suitable for swallow when comparedto Fortamet®.
`
`B.
`
`Dissolution test
`
`[00067]
`
`The tablets were tested in an USP type I! apparatus at 50 rpm in 900ml of
`
`simulated gastric fluid (0.1 HCl). The result was asfollows:
`
`0.1N HCI, 900mg, USP Apparatus [I with sinker, 50 rom
`
`
`
` Time(hr) % metformin released
`
`0
`
`0.5
`
`1
`
`2
`
`4
`
`6
`
`8
`
`0.0
`
`46.3
`
`57.5
`
`68.7
`
`82.7
`
`91.6
`
`97.1
`
`
`
`10 100.0
`
`Cc.
`
`Bioavailability study
`
`Study Design
`
`[00068]
`
`A crossover bioavailability study to compare metformin HCI 1000 mg
`
`controlled release tablets of the invention and Fortamet® in healthy subjects.
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`Blood Samples Schedule
`
`[00069]
`
`Pre-dose (0 h) and 1, 2, 3, 4, 5, 6, 8, 10, 12 and 14 hours post dosefor test
`
`drugs and reference drugs with heparinized tubes.
`
`
`Bioavailability study of the metformnCR formulation (1000mg) of
`
`the invention and Fortamet® (1000 mg)
`
`Fed (n=7)
`|
`
`
`
`Fasted (n=7)
`
`PK parameters
`
`Test
`Fortamet®
`Test
`Fortamet®
`
`Cmax
`1491.9
`1819.6
`1812.1
`1116.0
`
`(ng/ml)
`
`AUCo-14
`
`(13%)
`
`15270
`
`(13%)
`
`15015
`
`!
`
`(18%)
`
`11337
`
`(43%)
`
`6470
`
`(36%)
`(16%)
`|
`(12%)
`(10%)
`(ng * h/ml)
`
`AUCo...
`15579
`15358
`|
`11896
`7020
`
`
`
`
`
`
`
`
`
`
`
`(ng » h/ml)
`(10%)
`(11%)
`(15%)
`(36%)
`
`
`Tmax
`
`4.6
`
`5.4
`
`3.7
`
`3.9
`
`(hr)
`(4-6)
`(5-6)
`(2-4)
`(2-5)
`
`T42
`38. -
`4.0
`2.7
`3.2
`
`(hr)
`
`(3.3-4.4)
`
`(3.2-4.4)
`
`(2.3-3.1)
`
`(2.8-3.8)
`
`18
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`
`CLAIMS
`
`1.
`
`A controlled release pharmaceutical composition with a reduced food effect, said
`
`composition comprising an active agent and at least one pharmaceutically acceptable
`
`excipient, wherein said active agent has a limited window of absorption and displays a
`
`negative food effect when an immediate release dosage form of said active agent is
`
`orally administered to a subject.
`
`2..
`
`The controlled release pharmaceutical composition of claim 1, wherein said
`
`composition comprises a sustained release layer and an immediate release layer.
`
`3.
`
`The controlled release pharmaceutical composition of claim 2, wherein said active
`
`agentis incorporated into said sustained release layer and said immediate release layer
`
`at a weight ratio from about 1:10 to about 10:1.
`
`4,
`
`The controlled release pharmaceutical composition of claim 1, wherein the food
`
`effect is less than 50%.
`
`5,
`
`The controlled release pharmaceutical composition of claim 4, wherein the food
`
`effect is less than 40%.
`
`6.
`
`The controlled release pharmaceutical composition of claim 5, wherein the food
`
`effect is less than 30%.
`
`7.
`
`The controlied release pharmaceutical composition of claim 2, wherein the
`
`sustained release layer comprises(i) the active agent; (b) optionally, at least one release
`
`modifier; and (c) at least one sustained release agent.
`
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`
`8.
`
`The controlled release pharmaceutical composition of claim 2, wherein said
`
`composition further comprise a second active agent.
`
`9.
`
`The controlled release pharmaceutical composition of claim 1, wherein said active
`
`agent is metformin or a pharmaceutically acceptable salt thereof.
`
`10.
`
`The controlled release pharmaceutical composition of claim 8, wherein said
`
`second active agent is selected from currently available antihyperglycemic drugs and
`
`investigational antinyperglycemic drugs.
`
`11.
`
`The controlled release pharmaceutical composition of claim 10, wherein said
`
`currently available antihyperglycemic drugs include, but are not limited to, sulfonylurea,
`
`biguanides,
`
`alpha-glucosidase
`
`inhibitors,
`
`thiazolidinediones
`
`(TZDs),
`
` dipeptidyl
`
`peptidase-4 inhibitors (DPP-4 inhibitors), meglitinides, glucagon-like peptide-1 analogs
`
`(GLP-7 analogs) and insulin.
`
`12.
`
`The controlled release pharmaceutical composition of claim 10 wherein the
`
`antihyperglycemic drugs include, but are notlimited to, metformin, glyburide, glimepiride,
`
`glipyride,
`
`glipizide,
`
`chlorpropamide,
`
`gliclazide,
`
`acarbose, miglitol,
`
`pioglitazone,
`
`troglitazone, rosiglitazone,
`
`isaglitazone, muraglitizar, peliglitazar, sitagliptin, saxagliptin,
`
`vildagliptin,
`
`alogliptin,
`
`linagliptin, dutogliptin,
`
`repaglinide, nateglinide, mitiglindine,
`
`exenatide, liraglutide, albiglutide and insulin.
`
`13.
`
`The controlled release pharmaceutical composition of claim 10, wherein said
`
`investigational antihyperglycemic drugs include, but not
`
`limited to,
`
`IL-1 modulators,
`
`Sodium-glucose transporter-2 (SGLT-2) inhibitors, Dual-PPAR modulators, 11811-beta-
`
`hydroxysteroid dehydrogenase (HSD) inhibitors, CCR2 antagonists, selective inhibitors
`
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`
`of
`
`fructose 1,6-bisphosphatase,
`
`immune modulators, cortisol synthesis
`
`inhibitors,
`
`Gastrin-Releasing Peptide (GRP) receptor agonists, G protein-coupled receptor 119
`
`(GPR 119) agonists, Toll-like
`
`receptor-4 (TLR-4) agonists, FXR antagonists, and
`
`antisense drugs targeting glucagon receptors.
`
`14.
`
`The controlled release pharmaceutical composition of claim 13, wherein the
`
`investigational drugs include