(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY(PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`11 September 2009 (11.09.2009) (10) International Publication Number
`
`(43) International Publication Date
`
`WO 2009/111200 Al
`
`
`51)
`
`International Patent Classification:
`AOIN 37/52 (2006.01)
`AG6IK 9/22 (2006.01)
`A61K 31/155 (2006.01)
`
`Q))
`
`International Application Number:
`PCT/US2009/034851
`
`(22)
`
`International Filing Date:
`
`23 February 2009 (23.02.2009)
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`(25)
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`(26)
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`(30)
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`(7)
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`(72)
`(75)
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`(74)
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`(81)
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`Filing Language:
`
`Publication Language:
`
`English
`
`English
`
`Priority Data:
`61/068,016
`
`4 March 2008 (04.03.2008)
`
`US
`
`Applicant (for all designated States except US): MER-
`CK & CO., INC. [US/US]; 126 East Lincoln Avenue,
`Rahway, New Jersey 07065-0907 (US).
`
`Inventor; and
`(for US only): POURKAVOOS,
`Inventor/Applicant
`Nazaneen [CA/US]; 126 East Lincoln Avenue, Rahway,
`New Jersey 07065-0907 (US).
`
`Common Representative: MERCK & CO., INC.; 126
`East Lincoln Avenue, Rahway, New Jersey 07065-0907
`(US).
`
`Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ,
`
`LC, LE, LG, ES, FL, GB, GD, GE, GI, GM,GT,IIN,
`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,PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG,
`SK, SL, SM, ST, SV, SY, 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, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`TM), European (AT, BE, 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, SE, SL SK, TR),
`OAPI(BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML,
`MR,NE, SN, TD, TG).
`Declarations under Rule 4.17:
`
`as to applicant's entitlement to apply for and he granted
`a patent (Rule 4.17(ii))
`
`as to the applicant's entitlement to claim the priority of
`the earlier application (Rule 4.17(iii))
`Published:
`
`with international search report (Art. 21(3))
`before the expiration of the time limit for amending the
`claims and to be republished in the event ofreceipt of
`amendments (Rule 48.2(h))
`
`(54) Title: PHARMACEUTICAL COMPOSITIONS OF A COMBINATION OF METFORMIN AND A DIPEPTIDYL PEPTI-
`DASE-IVINIIBITOR
`
`(57) Abstract: Disclased are pharmaceutical compositions comprising fixed-dose combinations of an extended-release form of
`metformin, or a pharmaceutically acceptablesalt thereof, coated with an immediate-release form of the DPP-4 inhibitorsitagliptin,
`or a pharmaceutically acceptablesalt thereof.
`
`
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`WoO2009/111200AX[IITTNITNNUININTANIINTIONMGTTELA
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`WO 2009/111200
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`PCT/US2009/034851
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`TITLE OF THE INVENTION
`
`PHARMACEUTICAL COMPOSITIONS OF A COMBINATION OF METFORMIN AND A
`
`DIPEPTIDYL PEPTIDASE-IV INHIBITOR
`
`WE
`
`BACKGROUND OF THE INVENTION
`
`Type 2 diabetes is a chronic and progressive disease arising from a complex
`pathophysiology involving the dual endocrine defects of insulin resistance and impaired insulin
`secretion. The treatment of Type 2 diabetes typically begins with diet and exercise, followed by
`oral antidiabetic monotherapy. For many patients, these regimens do not sufficiently control
`glycemia during long-term treatment, leading to a requirement for combination therapy within
`several years following diagnosis. However, co-prescription of two or more orai antidiabetic
`drugs may result in treatment regimens that are complex and difficult for many patients to
`follow. Combining two or moreoral antidiabetic agents into a single tablet provides a potential
`means of delivering combination therapy without adding to the complexity of patients’ daily
`regimens. Such formulations have been well accepted in other disease indications, such as
`hypertension (HYZAAR® which is a combination of losartan potassium and
`hydrochlorethiazide) and cholesterol lowering (VYTORIN® which is a combination of
`simvastatin and ezetimibe). The selection of effective and well-tolerated treatments is a key step
`in the design of a combination tablet. Moreover, it is essential that the components have
`complementary mechanisms of action and compatible pharmacokinetic profiles. Examples of
`marketed combination tablets containing two oral antidiabetic agents include Glucovance®
`(metformin and glyburide), Avandamet® (metformin and rosiglitazone), and Metaglip®
`(metformin and glipizide).
`Metformin represents the only oral antidiabetic agent proven to reduce the total
`burden of microvascular and macrovascular diabetic complications and to prolongthe lives of
`Type 2 diabetic patients. Furthermore, metformin treatment is often associated with reductions
`in body weight in overweight patients and with improvements in lipid profiles m dyslipidemic
`patients. Metformin hydrochloride is marketed in the U.S. and elsewhere as either immediate-
`release or extended-release formulations with tablet dosage strengths of 500, 750, 850, and 1000
`milligrams. Extended-release formulations of metformin have advantages over immediate-
`release in terms of affording a more uniform maintenance of blood plasmaactive drug
`concentrations and providing better patient compliance by reducing the frequency of
`administration required.
`Dipeptidyi peptidase-TV (DPP-4) inhibitors represent a newclass of agents that
`are being developedfor the treatment or improvement in glycemic control in patients with Type
`2 diabetes. Specific DPP-4 inhibitors either already approved for marketing or underclinical
`developmentfor the treatmentof Type 2 diabetes include sitagliptin, vildagliptin, saxagliptin,
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`melogliptin, P93/01 (Prosidion), alogliptin, denagliptin, Roche 0730699, TS021 (Taisho), and
`E3024 (Eisai). For example, oral administration ofsitagliptin, vildag]iptin, alogliptin, and
`saxagliptin to human Type 2 diabetics has been found to reduce fasting glucose and postprandial
`glucose excursion in association with significantly reduced HbA]¢ levels. For reviews on the
`
`application of DPP-4 inhibitors for the treatment of Type 2 diabetes, reference is made to the
`following publications: (1) A.H. Stonehouse, et al.,"Management of Type 2 diabetes: the role of
`incretin mimetics, Exp. Opin. Pharmacother., 7: 2095-2105 (2006); (2) B.D. Green, et al,
`"Inhibition of dipeptidy! peptidase-IV activity as a therapy of Type 2 diabetes," Exp. Opin.
`Emerging Drugs, 1 t: 525-539 (2006); (3) M.M.J. Combettes, "GLP-1 and Type 2 diabetes:
`physiology and new chnical advances," Curr. Opin. Pharmacol., 6: 598-605 (2006); and R.K.
`Campbell, "Rationale for Dipeptidyl Peptidase 4 Inhibitors: A NewClass of Oral Agents for the
`Treatment of Type 2 Diabetes Mellitus," Ann. Pharmacother., 41: 51-60 (2007).
`Sitagliptin phosphate having structural formula I below is the
`dihydrogenphosphatesalt of (22)-4-oxo-4-[3-(trifluoromethy}-5,6-dihydro 12,4|triazolo[4,3-
`a)|pyrazin-7(8)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine.
`
`F
`
`F OC)
`L
`
`NH; ©AyesN
`LON7N
`CFs
`
`0
`
`+HsPO,7
`
`In one embodimentsitagliptin phosphate is in the form of a crystalline monohydrate. Sitagliptin
`free base and pharmaceutically acceptable salts thereof are disclosed in U.S. Patent No.
`6,699,871, the contents of which are hereby incorporated by reference in their entirety.
`Crystalline sitagliptin phosphate monohydrate is disclosed in U.S. Patent No. 7,326,708, the
`contents of which are hereby incorporated by reference in their entirety. Sitagliptin phosphate
`has been approved for marketing in several countries, including the U.S., Europe, Canada, and
`Mexico,for the treatment of Type 2 diabetes and is branded as JANUVIA®in the U.S. and
`elsewhere. For reviews, see D. Drucker, et al., "Sitagliptin," Nature Reviews Drug Discovery,6:
`109-110 (2007); C.F. Deacon, "Dipeptidyl peptidase 4 inhibition with sitagliptin: a new therapy
`for Type 2 diabetes," Exp. Opin. Invest. Drugs, 16: 533-545 (2007); K.A. Lyseng-Williamson,
`"Sitagliptin," Drugs, 67: 587-597 (2007); and B. Gallwitz, "Sitagliptin: Profile of a Novel DPP-4
`Inhibitor for the Treatment of Type 2 Diabetes (Update),” Drugs of Today, 43: 801-814 (2007).
`The combination ofsitagliptin and metformin provides substantial and additive
`glycemic improvement in patients with Type 2 diabetes (BJ. Goldstein,et al., “Effect ofInitial
`Combination Therapy with Sitagliptin, a DPP-4 Inhibitor, and Metformin on Glycemic Contro!
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`in Patients with Type 2 Diabetes," Diabetes Care, 30: 1979-1987 (2007) and B. Gallwitz,
`"Sitagliptin with Metformin: Profile of a combination for the treatment of Type 2 diabetes,"
`Drugs of Today, 43: 681-689 (2007). A fixed-dose combination ef immediate-release of both
`metformin andsitagliptin has been approved for marketing in several countries, including U.S.
`and Mexico, for adult patients with Type 2 diabetes who are not adequately controlled on
`metformin or sitagliptin alone or in patients already being treated with the combination of
`sitaglptin and metformin. The combination is branded as JANUMET®in the U.S.
`JANUMET®tablets contain 50 mgsitagliptin and either 500, 850, or 1000 mg metformin.
`Pharmaceutical compositions comprising fixed-dose combinations of immediate-release
`sitagliptin and immediate-release metformin are disclosed in PCT international patent application
`WO 2007/078726 which published on July 12, 2007.
`Extended-release formulations of metformin are disclosed in US 6,340,475; US
`6,635,280; US 6,866,866; US 6,475,521; and US 6,660,300. Pharmaceutical formulations
`containing extended-release metformin and a thiazolidinedione antihyperglycemic agent are
`described in WO 2004/026241 (1 April 2004) and WO 2006/107528 (12 October 2006).
`Pharmaceutical compositions comprising a DPP-4 inhibitor and a slow-release form of
`metformin are disclosed in US 2007/0172525 (26 July 2007). Stable pharmaceutical
`compositions of an immediate-release form of the antihyperglycemic sulfonylurea glimepiride
`and extended-release metformin are disclosed in US 2007/0264331 (15 November 2007).
`The present invention provides for pharmaceutical compositions comprising a
`core tablet formulation ofa fixed-amount of metformin that is coated with a sustained-release
`
`(SR) polymerfilm whichis further coated with an immediate release form of a fixed amount of
`sitagliptin. The metformin core tablet is prepared by wet or dry processing methodsprior to
`coating with the SR polymer composition.
`The present invention also provides processes to prepare pharmaceutical
`compositions of a fixed-dose combination of inmediate-release sitagliptin and extended-release
`metformin by wet or dry processing methods. The wet processing methods include wet
`granulation.
`
`Another aspect of the present invention provides methods for the treatment of
`Type 2 diabetes by administering to a host in need of such treatment a therapeutically effective
`amount of a pharmaceutical composition ofthe present invention.
`These and other aspects of the invention will become readily apparent from the
`detailed description which follows.
`
`SUMMARYOF THE INVENTION
`
`The present invention is directed to novel pharmaceutical compositions
`comprising a core tablet formulation of metformin, or a pharmaceutically acceptable salt thereof,
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`coated with a sustained-release polymer film which is further coated with an immediate-release
`form of the DPP-4 inhibitor sitagliptin, or a pharmaceutically acceptable salt thereof, processes
`for preparing such compositions, and methodsoftreating Type 2 diabetes with such
`compositions. In particular, the invention is directed to pharmaceutical compositions comprising
`a core tablet formulation of metformin hydrochloride coated with a sustained-release polymer
`film which is further coated with an immediate-release form of sitagliptin phosphate.
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`BRIEF DESCRIPTION OF THE FIGURES
`
`FIG. 1 is a graph showing in vitro metformin dissolution profiles of an
`immediate-release (TR) 1000-mg metformin hydrochloride core tablet coated with cellulose
`acetate sustained-release polymerfilm compositions of varying porosity with 3, 5, or 7 weight
`percent gain relative to the core tablet weight.
`FIG. 2 is a graph comparing in vitro metformin dissolution profiles of an
`immediate-release (IR) 500-mg metformin hydrochloride tablet with metformin dissolution
`profiles of an immediate-release (IR) 1000-mg metformin hydrochloride core tablet coated with a
`high porosity cellulose acetate sustained-release polymerfilm composition with 3, 5, or 7 weight
`percentgain relative to the core tablet weight.
`FIG. 3 is a graph comparing im vitro metformin dissolution profiles of an
`immediate-release GR) 500-ng metformin hydrochloride tablet with metformin dissolution
`profiles of a 1000-mg immediate-release (IR) metformin hydrochloride core tablet coated with a
`"modified high porosity" cellulose acetate sustained-release polymer film composition with 3, 5,
`or 7 weight percent gain relative to the core tablet weight.
`FIG. 4 is a graph showingivitro dissolution profiles for sitagliptin phosphate
`from the drug film layer in a pharmaceutical composition of the present invention compared to
`sitagliptin phosphate m JANUMET™ whichis a marketed fixed-dose combination of
`immediate-release metformin hydrochloride and immediate-release sitagliptin phosphate.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`One aspect of the present invention is directed to pharmaceutical compositions
`comprising a core tablet formulation of a fixed-amount of metformin, or a pharmaceutically
`acceptable salt thereof, which core tablet is coated with a sustained-release polymer film whichis
`further coated with an immediate release form of a fixed amount of the DPP-4 inhibitor
`
`sitagliptin, or a pharmaceutically acceptablesalt thereof.
`A preferred pharmaceutically acceptablesalt of sitagliptin is the
`dihydrogenphosphatesalt of structural formula I above(sitagliptin phosphate). A preferred form
`of the dihydrogenphosphatesalt is the crystalline monohydrate disclosed in U.S. Patent No.
`7,326,708, the contents of which are hereby incorporated by referencein their entirety.
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`The preparation of sitagliptin, and pharmaceutically acceptable salts thereof, is
`disclosed in US Patent No. 6,699,871, the contents of which are herein incorporated by reference
`in their entirety. The preparation of sitagliptin phosphate monohydrate is disclosed in U.S.
`Patent No. 7,326,708, the contents of which are hereby incorporated by reference in their
`entirety.
`
`The unit dosage strength ofsitagliptin free base anhydrate (active moiety) for
`inclusion into the fixed-dose combination pharmaceutical compositions of the present invention
`is 25, 50, and 100 milligrams. An equivalent amountof sitagliptin phosphate monohydrate to the
`sitagliptin free base anhydrate is used in the pharmaceutical compositions, namely, 32.125, 64.25
`and 128.5 milligrams, respectively.
`The unit dosage strength of the metformin hydrochloride forcorporation into
`the fixed-dose combination of the present invention is 250, 500, 750, 850, and 1000 milligrams.
`These unit dosage strengths of metformin hydrochloride represent the dosage strengths approved
`in the U.S. for marketing to treat Type 2 diabetes.
`Specific embodiments of dosage strengths for sitagliptin and metformin
`hydrochloride in the fixed-dose combinations of the present invention are the following:
`(1)
`25 milligramsof sitagliptin (equivalent to 32.125 milligrams ofsitagliptin
`phosphate monohydrate) and 250 milligrams metformin hydrochloride;
`25 milligramsof sitagliptin (equivalent to 32.125 milligramsof sitagliptin
`phosphate monohydrate) and 500 milligrams metformin hydrochloride;
`25 milligramsof sitagliptin (equivalent to 32.125 milligrams of sitagliptin
`phosphate monohydrate) and 750 milligrams metformin hydrochloride;
`25 milligramsof sitagliptin (equivalent to 32.125 milligramsof sitagliptin
`phosphate monohydrate) and 850 milligrams metformin hydrochloride;
`25 milligrams of sitagliptin (equivalent to 32.125 milligramsof sitagliptin
`phosphate monohydrate) and 1000 milligrams metformin hydrochloride;
`50 milligrams of sitagliptin (equivalent to 64.25 milligramsof sitagliptin
`phosphate monohydrate) and 500 milligrams metformin hydrochloride;
`50 milligramsof sitagliptin (equivalent to 64.25 milligramsof sitagliptin
`phosphate monohydrate) and 750 milligrams metformin hydrochloride;
`50 milligramsofsitagliptin (equivalent to 64.25 milligramsofsitagliptin
`phosphate monohydrate) and 850 milligrams metformin hydrochloride;
`50 milligramsofsitagliptin (equivalent to 64.25 milligramsofsitagliptin
`phosphate monohydrate) and 1000 milligrams metformin hydrochloride;
`100 milligramsof sitagliptin (equivalent to 128.5 milligrams of sitagliptin
`phosphate monohydrate) and 500 milligrams metformin hydrochloride;
`
`(8)
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`(9)
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`(10)
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`(2)
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`G3)
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`(4)
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`(5)
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`(6)
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`(7)
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`100 milligrams of sitagliptin (equivalent to 128.5 milligramsofsitagliptin
`phosphate monohydrate) and 750 milligrams metformin hydrochloride;
`100 milligramsof sitagliptin (equivalent to 128.5 milligramsofsitagliptin
`phosphate monohydrate) and 850 milligrams metformin hydrochloride; and
`100 milligramsof sitagliptin (equivalent to 128.5 milligrams ofsitagliptin
`phosphate monohydrate} and 1000 milligrams metformin hydrochloride.
`In a particular aspect of the present invention, the phannaceutical compositions of
`the present invention comprise an inner core formulation of metformin hydrochioride. The
`formulation is compressed into a tablet form.
`The metformin core tablets are prepared by wet or dry processing methods. In one
`embodiment the metformin core tablets are prepared by wet processing metheds. In a class of
`this embodiment the metformin core tablets are prepared by wet granulation methods. With wet
`granulation either high-shear granulation or fluid-bed granulation is preferred, but other wet
`granulation methods mayalso be used.
`In the high-shear wet granulation process, metformin hydrochloride is first
`blended with a suitable binding agent using water or an aqueous alcohol mixture, such as
`aqueous ethanol, as the granulating solvent. In one embodimentthe high-shear granulation
`process uses a tip speed of 3.58 m/sec with a granulation fluid level of between 3 and 10%. The
`resulting granules are next dried and sized to produce a mean particle size range of about 500 to
`about 800 microns and have a tensile strength of about 2 to about 3 megapascals [MPa] over a
`compaction pressure range of about 200 to 400 MPa. Embodiments of suitable binding agents
`include hydroxypropylcellulose (HPC), hydroxypropylmethy! cellulose (HMPC), hydroxyethyl-
`cellulose, starch 1500, polyvinylpyrrolidone (povidone), and co-povidone. A preferred binding
`agent is polyvinylpyrrolidone.
`The sized metformin granulation is subsequently blended with an extragranular
`composition which consists of one or more diluents and optionally a suitable glidant and/or a
`suitable lubricant to afford a final metformin drug loading of about 50 to about 80 weight
`percent. The tensile strength of the final blend formulation is about 2.0 MPa to about 2.5 MPa
`over a range of about 200 MPa to about 400 MPa compaction pressure. The final blendis
`compressed on a rotary press at a compression force of about 30 kiloNewtons (KN) using
`modified capsule-shaped tooling resulting in a tablet hardness (breaking force) of about 30-35
`kiloponds(kp).
`Embodiments of diluents include, but are not limited to, mannitol, sorbitol,
`dibasic calcium phosphate dihydrate, microcrystalline cellulose, and powdered cellulose. A
`preferred diluent is microcrystalline cellulose. Microcrystalline cellulose is available from
`several suppliers and includes Avicel PH 101™, Avicel PH 102™, Avicel PH 103™, Avicel PH
`105™, and Avicel PH 200™), manufactured by the FMC Corporation.
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`Examples of lubricants include magnesiumstearate, calcium stearate, stearic acid,
`sodium steary] fumarate, hydrogenated castoroil, and mixtures thereof. A preferred lubricant is
`magnesium stearate or sodium stearyl fumarate or a mixture thereof. Examples of glidants
`include colloidal silicon dioxide, calcium phosphate tribasic, magnesium silicate, and talc. In
`one embodimentthe glidant is colloidal silicon dioxide and the lubricant is sodium stearyl
`fumarate.
`
`The composition of a representative metformin core tablet of the present invention
`is provided in Table1.
`
`Table 1
`
`Metformin Core Tablet Composition
`
`
`
`Final drug loading
`Cowlw)
`
`76.725
`
`
`
`dioxide
`
`|
`
`
`Granulation
`
`
`
`Metformin HCl
`93.0%
`
`PVP K 29/32
`
`
`Weight
`fe
`
`Intragranular
`100.0%
`
`
`
`
`
`
`
`
`fumarate
`
`Fotal
`
`15
`
`20
`
`In a second aspect of the present invention, the metformin coretablet is coated
`with a functional sustained-release (SR) polymer film that is designed to control the release of
`metformin from the soluble core tablet leaving a largely intact ghost polymershell. The polymer
`film is designed as a porous membrane. The sustained-release polymer film consists of an
`aqueous organic solution of a sustained-release (SR) polymer, one or moreplasticizers, and a
`pore-forming agent. In one embodiment, the aqueous organic solvent is aqueous acetone.
`Embodiments of sustained-release polymers are cellulose esters, cellulose
`diesters, cellulose triesters, cellulose ethers, mixed cellulose esters/ethers, ethylcellulose having
`viscosity grades from 10 to 50 cP, ethylcellulose aqueous dispersion, polyvinyl acetate, and
`methacrylic acid copolymers. In one embodiment, the sustained-release polymeris a cellulose
`ester selected from the group consisting of cellulose acetate, cellulose diacetate, cellulose
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`triacetate, cellulose acetate propionate, and cellulose acetate butyrate. In a subclass ofthis class
`the sustained-release polymeris cellulose acetate. In a subclass of this subclass the cellulose
`acetate is cellulose acetate (CA) having an acetyl content of about 39.8 weight percent as in the
`CA-398-10 which is commercially available from Eastman Fine Chemicals.
`Embodimentsofplasticizers include, but are not limited to, dibutyl sebacate,
`diethyl phthalate, triethyl citrate, tri-n-butyl citrate, acetyl tri-n-butyl citrate, acetylated
`monoglycerides, castor oil, olive oil, sesameoil, oleic acid, and triacetin (glyceryl triacetate}. In
`a particular class the plasticizeris triacetin.
`Embodiments of pore-forming agents include, but are notlimited to, sodium
`chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycols (PEG), propylene
`glycol, polyvinyl alcohols, and methacrylic acid copolymers. In one embodiment the
`polyethyleneglycol is PEG 3350. Inaparticular class the SR polymeris cellulose acetate and the
`plasticizer is triacetin.
`The amount of sustained-release polymer coated over the metformin core tabletis
`based on the percent weight gain and ranges from about | to about 10 weight percent. The total
`concentration of solids (SR polymer + plasticizer + pore-forming agent) in the aqueous organic
`solution is preferably kept at about 10 weight percent. The ratio of the organic solvent to water is
`about 3:1 (w/w). The percent level of plasticizers to cellulose acetate ranges from about 25 to
`about 150 weight percent resulting in low to high porosity membrane coatings to modulate the
`rate of metformin drug release. In one embodiment the amount of sustained-release polymer
`coated over the metformin core tablet is based on the percent weight gain and ranges from about
`3 to about 9 weight percent. In a class of this embodiment the amountof sustained-release
`polymer coated over the metformin core tablet ranges from about 3 to about 7 weight percent.
`The composition of representative sustained-release (SR) cellulose acetate
`polymerfilms of different porosities from low to high is provided in Table 2. The SR polymer
`coating solution is prepared with differing levels of cellulose acetate (4-8 weight percent of CA)
`and a 1:1 w/w ratio oftriacetin and PEG 3350. Thetotal solid concentrationis kept the same as
`well as the ratio of acetone to water. The modified high porosity composition (5 weight percent
`of CA) generally affords a more robust film in terms of processability and integrity of polymer.
`The cellulose acetate polymer solution is applied at various levels of weight gain ranging from
`about 3 to about 9 weight percent based on core tablet weight and results in different rates of
`metformin drug release as shown in the metformin in vitro dissolution profiles of Figures 1-3.
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`Sustained-Release Polymer Film Composition*
`
`Table 2
`
`Modified|Medium|Low
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`Porosi
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`
`
`CA-398-10"* dste
`PEG 3350 Heesjn
`
`Triacetin 25|2|1
`Acetone
`__}#__jee68
`Water 2ii
`
`Total 100[100foo—ftooSid
`* 10% solid concentration (CA + PEG 3350 +triacetin).
`** Grade of commercial cellulose acetate having an acetyl content of about 39.8 weight percent.
`
`Yo whw
`
`In one embodimentthe cellulose acetate aqueous organic coating solution is
`applied over the metformin core tablet to achieve weight gain of about 3 to about 9 percent
`resulting in variable metformin release profiles using the high to modified high porosity
`compositions shown in Table 2. The film coating of cellulose acetate polymeris carried out in a
`conventional perforated vented pan with baffles and is conducted at a controlled exhaust
`temperature range of about 25 to 35 °C.
`In a third aspect of the present invention, the SR coated metformin core tablet is
`further coated with an aqueous solution or suspension of a sitagliptin salt until the desired solid
`weight gain, typically corresponding to either 50 mg or 100 mgofsitagliptin, is obtained.
`Thesitagliptin coating solution or suspension is designed to producea stable
`solution in an immediate-release polymerfilmso that the drug is substantially present as an
`amorphous form to allowrapid dissolution and absorption of sitagliptin to take place following
`ingestion of the dosage form. Embodiments of the film-forming polymerare
`hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sodium
`carboxymethylcellulose, polyvinylpyrrolidone (PVP), and polyvinylalcohol/PEG 3350, A
`particular form of HPMCforuseas a film-forming polymer is HPMC 2910. The coating
`solution also optionally contains one or more excipients selected from the group consisting of a
`plasticizer, such as polyethylene glycol grades 400 to 3350 and triethylcitrate; a dispersing agent,
`such as hydrated aluminum silicate (Kaolin); a colorant; and an antioxidant to prevent oxidative
`degradation. The antioxidant is selected frorn the group consisting of a-tocopherol, y-tocopherol,
`5-tocopherol, extracts of natural origin rich in tocopherol, L-ascorbic acid and its sodium or
`calcium salts, ascorbyl palmitate, propyl gallate, octyl gallate, dodecyl gallate, butylated
`hydroxytoluene (BHT), and butylated hydroxyanisole (BHA), In one embodiment, the
`antioxidant is propyl gallate.
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`The sitagliptin coating solution or suspension is prepared in total concentration of
`about 12 to about 17 weight percent. The sitagliptin coating solution or suspension is applied to
`the metformin core tablet and the amountof sitagliptin phosphate deposited in the active
`pharmaceutical ingredient ("API") film layer is controlled by tablet weight gain or amount of
`coating suspension sprayed. The 50 mg sitagliptin phosphate film potency represents one-half
`the weight gain of the 100 mg potencies.
`The composition of a representative sitagliptin film coating solution or suspension
`is provided in Table 3.
`
`Table 3
`
`SitagHptin Aqueous Film Coating Solution Compositions
`
`
`
`Solid Concentration|Solid Concentration
`Ingredient
`
`
`at about 12% (w/w)_|at about 17% (w/w)
`12.0
`Sitagliptin phosphate
`
`monohydrate
`
`Opadry I Clear
`
`HPMC2910 (6 cP)
`PEG 3350 NF
`
`
`
`1.5
`
`|Propy!gallate | 0,0637 0.0637 |
`
`
`
`
`
` Kaolin (Compendial)
`
`0.10
`|FD& C blue lake dye
`82.936
`87.84
`Water
`
`| ToMake 100 | 100
`
`
`
`
`
`
`
`
`15
`
`20
`
`The film-coating operation is carried out in a conventional perforated vented pan
`with baffles and is conducted at a controlled exhaust temperature range of about 40 °C to about
`44°C. The sprayrate and air flow through the coating pan is adjusted to produce a uniform
`coating and coverage ofthe entire width of the tablet bed. The amountof the coating solution or
`suspensionappliedis controlled by percent weight gain of tablet cores and typically ranges from
`about 19 to about 22 weight percent. This range results in sitagliptin drug assay close to the
`desired 50 mg or 100 mg with a standard deviation of about 2-4% for content uniformityassay of
`sitagliptin, The duration ofthe coating step is about 4-7 hours but may vary depending on the
`type of equipmentused.
`The final pharmaceutical compositions of the present invention are tablets. The
`tablets may be further film-coated such as with a mixture of hydroxypropylceilulose and
`hydroxypropylmethylcellulose containing titanium dioxide and/or other coloring agents, such as
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`iron oxides, dyes, and lakes; a mixture of polyvinyl alcohol (PVA)and polyethylene glycol
`(PEG) containing titanium dioxide and/orother coloring agents, such as iron oxides, dyes, and
`lakes; or any other suitable immediate-release film-coating agent(s). A commercial film-coatis
`Opadry® which is a formulated powder blend provided by Colorcon.
`The pharmaceutical tablet compositions of the present invention may also contain
`one or more additional formulation ingredients selected from a wide variety of excipients known
`in the pharmaceutical formulation art. According to the desired properties of the pharmaceutical
`composition, any number of ingredients may be selected, alone or in combination, based upon
`their known uses in preparing tablet compositions. Such ingredients include, but are not limited
`to, diluents, compressionaids, glidants, disintegrants, lubricants, flavors, flavor enhancers,
`sweeteners, and preservatives.
`The term “tablet” as used herein is intended to encompass compressed
`pharmaceutical dosage formulations ofall shapes and sizes, whether coated or uncoated.
`In one embodiment the metformin core tablets are prepared by wet granulation
`(preferably high shear and/or fluid bed). The steps involved in the wet granulation method
`comprise the following:
`(1) the active pharmaceutical ingredient metformin hydrochloride is addedto the granulator
`bowl;
`(2) optional disintegrants are added to step 1;
`(3) for high-shear granulation, the binding agent (such as polyvinylpyrrolidone or
`hydroxypropylcellulose) is added dry to the granulator bowl and dry mixed for a short period
`followed by the addition of water with or without a surfactant (such as sodium lauryl sultate);
`for fluid bed granulation, the metformin hydrochloride is added to the granulator bowl, the
`powderis fluidized, and the granulating solution comprised of binding agent with or without
`surfactant in water is sprayed into the fluidized powder;
`(4) granules prepared by high-shear granulation are tray-dried in an oven or dried in a fluid bed
`dryer. For granules prepared by fluid-bed granulation, granules are dried in a fluid bed dryer,
`(5) dried granules are resized using a suitable mill;
`(6) optional diluents (such as microcrystalline cellulose and dibasic calctum phosphate
`dihydrate) are blended with dried and sized granulesin a suitable blender;
`(7) lubricants or glidants (such as magnesium stearate and sodium stearyl fumarate) are added to
`the blend from step 7 in a suitable blender; and
`(8) the lubricated granule mixture from step 8 is compressed into the desired tablet image.
`
`The present invention also provides methods for treating Type 2 diabetes by orally
`administering to a host in need of such treatment a therapeutically effective amount of one of the
`fixed-dose combination pharmaceutical compositions of the present invention. In one
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`embodiment the host in need of such treatment is a human. In another embodimentthe
`pharmaceutical composition is in the dosage form of a tablet. The pharmaceutical compositions
`comprising the fixed-dose combination may be administered once-daily (QD) or twice-daily