(12) United States Patent
`Desai et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,628,799 B2
`Jan. 14, 2014
`
`US008628799B2
`
`(75)
`
`(54) COATED TABLET FORMULATION AND
`METHOD
`Inventors: Divyakant S. Desai, Princeton, NJ (US);
`Bing V_ Ll, Princeton, NJ (US)
`,
`_
`.
`(73) Assignee: Bristol-Myers Squibb Company,
`Princeton, NJ (US)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U~S~C~ 15405’) by 49 daYS~
`
`(21) Appl. No.: 13/094,379
`
`(22) Filed,
`
`Ar,r_ 26, 2011
`
`(65)
`
`Prior Publication Data
`Us 2011/0200672 A1
`Aug. 18, 2011
`Related US_ Application Data
`
`(62) Division of application No. 1 1/137,068, filed on May
`25, 2005, now Pat. No. 7,951,400.
`(60) Provisional application No. 60/575,319, filed on May
`28, 2004.
`
`(51)
`
`IIlt- CL
`/161K 9/24
`AHK 9/32
`(52) U-S- CL
`USPC ......................................... .. 424/472; 424/482
`(58) Field of Classification Search
`None
`.
`.
`
`(200001)
`(200601)
`
`.
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`.......... .. 424/471
`
`3,696,188 A * 10/1972 Fernandez et al.
`4,800,084 A
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`4,847,265 A
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`5,428,048 A
`6/1995 Malamas et al.
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`12/1998 Fassler et al.
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`7/2000 Bauer et al.
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`6,3l6,438 Bl
`l l/2001 Ya er al.
`6,395,767 B2 *
`5/2002 Robl et al.
`5,414,002 B1 *
`7/2002 Cheng GU11
`5,605,300 B1
`8/2003 Burnside GU11,
`6,653,314 B2
`11/2003 Cheng et al.
`6,670,334 B2
`12/2003 Venlr er al.
`5,727,271 B2
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`6,753,012 B2
`6/2004 Cappola
`3.0
`63.11
`éfi
`§I0b1Let 31~
`................. .. 424/471
`2003/0035839 A1 *
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`2004/0022855 A1
`2/2004 Yoon et al.
`2005/0208133 A1*
`9/2005 Tsutsumi et al.
`........... .. 424/472
`2005/0214373 A1
`9/2005 Desai et al.
`
`.................. .. 514/412
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`,,,,,,,,,,,, ~ 424/452
`
`2005/0256202 A1
`2005/0256314 A1
`2005/0288343 A1
`
`11/2005 Kim et al.
`11/2005 Kim et al.
`USOWICZ C 3.
`12/2005 R
`'
`t
`
`.
`
`l
`
`EP
`Ep
`EP
`W0
`
`W0
`wo
`
`FOREIGN PATENT DOCUMENTS
`0177 355 B1
`7/1990
`1 186 293 A2
`3/2002
`1 243 266 A1
`9/2002
`WO 99/05027 A1
`2/1999
`
`W0 03/059330 A1
`wo 2004/043912 A2
`
`13;;
`7/2003
`5/2004
`
`OTHER PUBLICATIONS
`
`“1-[[(3-Hydr0Xy-1-
`al.,
`et
`Villhauer
`B.
`Edwin
`adamantyl)amin0]acetyl]-2-cyano-(s)-pyrrolidinez A Potent, Selec-
`tive, and Orally Bioavailable Dipeptidyl Peptidase IV Inhibitor with
`?7r1;i9hypelrg4l;Icemic Properties,” J. Med. Chem., 2003, pp. 2774.
`,v0 .
`.
`Goldstein, S.W. et al.: “Hydroxyurea Derivatives as Hypoglycemic
`Agents,” J. Med. Chem. (1993) vol. 36, N0. 15, pp. 2238-2240.
`Malamas, M.S. et al.: “Azole Phenoxy Hydroxyureas as Selective and
`Orally Active Inhibitors of 5-Lipoxygenase,” J. Med. Chem. (1996)
`VOL 39’ N0' 1’ pp 237-245
`(Continued)
`
`Primary Examiner — David J Blanchard
`Assistant Examiner — Tigabu Kassa
`(74) Attorney Agent
`or Firm — McDonnell Boehnen
`Hulbert and Berghoff LLP
`
`(57)
`A
`
`d
`
`bl
`
`f
`
`ABSTRACT
`.
`.
`l
`
`.
`
`d d
`
`.
`hi h
`
`.
`
`l d
`
`E“
`
`HO
`
`H N
`2
`
`N
`
`0
`
`NC
`
`or its HCI salt,
`
`.
`.
`.
`.
`.
`.
`.
`W111C111S subject to intra-molecular cyclization, which formu-
`lation includes a tablet corelcontaining one or more fillers,
`and other conventional excipients, which tablet core includes
`a coating thereon which may include two or more layers, at
`least erre layer of Wlrrelr rs arr rrrrrer Seal eear layer Whreh is
`f
`d f
`.
`1
`d 1
`f
`orrne . o one or more coating po ymers, a secon . ayer o
`which is formed of medicament which is the DPP4-inhibitor
`and one or more coating polymers, and an optional, but pref-
`'
`'
`erable third outer protective layer which is formed of one or
`mare .°°almg Polyéllgrs‘ A method for fmmmg the Coated
`‘a
`9115 a 50 Pm“ 9 ~
`
`11 Claims, No Drawings
`
`Page 1 of 9
`
`Astraleneca Exhibit 2126
`
`Mylan V. Astraleneca
`IPR2015-013-I0
`
`AstraZeneca Exhibit 2126
`Mylan v. AstraZeneca
`IPR2015-01340
`
`Page 1 of 9
`
`

`
`US 8,628,799 B2
`Page 2
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Abdel-Magid, A.F. et al.: “Reductive Amination of Aldehydes and
`Ketones with Sodium Triactoxyborohydride. Studies on Direct and
`Indirect Reductive Amination Procedures,” J. Org. Chem. (1996) vol.
`61, No. 11, pp. 3849-3862.
`Bennett, A.E. et al.: “Heteronuclear decoupling in rotating solids,” J.
`Chem. Phys. (1995) J. Chem. Phys. (1995) vol. 103, No. 16, pp.
`695 1-695 8.
`Cosier, J. et al.: “A Nitrogen-Gas-Stream Cryostat for General X-ray
`Diffraction Studies,” J. Appl. Cryst. (1986) vol. 19, pp. 105-107.
`Earl, W.L. et al. “Measurement of C Chemical Shifts in Solids,”
`Journal of Magnetic Resonance (1982) vol. 48, pp. 35-54.
`Johannsson, G. et al.: “Growth Hormone Treatment ofAbdominal1y
`Obese Men Reduces Abdominal Fat Mass, Improves Glucose and
`Lipoprotein Metabolism, and Reduces Diastolic Blood Pressure,”
`Journal of Clinical Endocrinology and Metabolism (1997) vol. 82,
`No. 3, pp. 727-734.
`
`Jones, A.G. et al.: “Programmed Cooling Crystallization of Potas-
`sium Sulphate Solutions,” Chemical Engineering Science (1974) vol.
`29, pp. 105-118.
`Metz, G. et al.: “Ramped-Amplitude Cross Polarization in Magic-
`Angle-Spinning NMR,” Journal of Magnetic Resonance, Series A
`(1994) vol. 110, pp. 219-227.
`Mullin, J.W. et al.: “Programmed cooling of batch crystallizers,”
`Chemical Engineering Science (1971) vol. 26, pp. 369-377.
`Otwinowski, Z. et al.: “Processing of X-Ray Diffraction Data Col-
`lected in Oscillation Mode,” Macromolecular Crystallography, Part
`A, Methods in Enzymology (1997) vol. 276, Academic Press, publ.,
`Carter, Jr. C.W. et al. eds. pp. 307-326.
`Xu, Z. et al.: “Process Research and Development for an Efficient
`Synthesis ofthe HIV Protease Inhibitor BMS-232632,” Organic Pro-
`cess Research & Development (2002) vol. 6, No. 3, pp. 323-328.
`Yin, S. et al.: “Simulated PXRD Pattersn in Studies of the Phase
`Composition and Thermal Behavior of Bulk Crystalline Solids,”
`American Pharmaceutical Review (2003) vol. 6, No. 2, pp. 80-85.
`
`* cited by examiner
`
`Page 2 of 9
`
`Page 2 of 9
`
`

`
`1
`COATED TABLET FORMULATION AND
`METHOD
`
`US 8,628,799 B2
`
`-continued
`OH
`
`FIELD OF THE INVENTION
`
`This application is a divisional of U.S. patent application
`Ser. No. 11/137,068, filed May 25, 2005, now U.S. Pat. No.
`7,951,400, which claims a benefit of priority from U.S. Pro-
`visional Application No. 60/575,319, filed May 28, 2004, the
`entire disclosure ofwhich is herein incorporated by reference.
`
`The present invention relates to a coated tablet formulation
`which includes a tablet core coated with a medicament such
`
`as a DPP4-inhibitor, such as saxagliptin, and to a method for
`preparing such coated tablet formulation.
`
`BACKGROUND OF THE INVENTION
`
`The compound of the structure
`
`H0
`
`HZN
`
`or its HCl salt,
`
`(hereinafter the above DPP4-inhibitor or saxaglipitin) is an
`orally active reversible dipeptidyl peptidase-4 (DPP4) inhibi-
`tor, which is a therapeutic agent for treatment of Type-2
`diabetes mellitus which is disclosed in U.S. Pat. No. 6,395,
`767.
`
`is
`insulinotropic hormone GLP-l
`After a meal intake,
`released which in turn induces insulin release from the pan-
`creas. Some of the GLP-l is inactivated by the DPP4 present
`in plasma and intestinal capillary endothelium. Therefore, if
`the DPP4 is inhibited, more GLP-l will be available to acti-
`vate insulin release from the pancreas. The advantage of this
`mechanism of insulin release is that insulin is secreted only in
`response to a meal. Therefore, problems of hypoglycemia
`associated with other diabetes drugs will be less likely with a
`DPP4 inhibitor.
`
`The above DPP4 inhibitor is a labile compound which is
`prone to an intra-molecular cyclization as shown below.
`
`Formation of Cyclic Amidine CA
`
`OH
`
`O
`
`N
`
`—>
`
`N
`H/ I \_/1
`
`N
`
`DPP4-inhibitor
`
`Page 3 of 9
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`O
`
`N
`
`HN
`
`NH
`
`Cyclic amidine
`
`The resultant degradant, cyclic amidine (mainly cis-cyclic
`amidine (CA)), is not therapeutically active and therefore, its
`formation is not desirable. This cyclization reaction can occur
`both in solid state and solution state. The rate of intra-mo-
`
`lecular cyclization is accelerated when formulations are sub-
`ject to commonly used processing activities such as wet
`granulation, roller compaction, or tabletting. In addition,
`most commonly used excipients, when mixed with this com-
`pound, can accelerate the rate of cyclization. Moreover, the
`level of cis-cyclic amidine increases when the drug to excipi-
`ent ratio increases posing more challenges for low strength
`dosage forms. Given these properties of the molecule, manu-
`facture of a conventional tablet dosage form for the DPP4-
`inhibitor, which is a preferred dosage form, is not a viable
`option.
`
`Currently, capsule formulations containing a dry mix ofthe
`DPP4-inhibitor and commonly used excipients are manufac-
`tured at a small scale and used for clinical studies. The scale
`
`up of capsule formulations containing the DPP4-inhibitor
`will also be problematic since it will involve milling to control
`the particle size of the DPP4-inhibitor so that capsules of
`lower strengths are manufactured without content unifomity
`problems.
`
`Additionally, most of the therapeutic agents as a single
`entity or as a combination product for diabetes treatments are
`available in a tablet dosage form. Since a tablet dosage form
`using traditional manufacturing process is not feasible for the
`DPP4-inhibitor,
`its manufacturing with other therapeutic
`agents, as a combination tablet will be even more problem-
`atic.
`
`Thus, it is seen that there is clearly a need for stable phar-
`maceutical formulations containing medicaments which are
`subject to intra-molecular cyclization which results in forma-
`tion of degradants such as cyclic arnidines which are not
`therapeutically active.
`
`U.S. Pat. No. 6,395,767 to Robl et al. (hereinafter Robl et
`al.) discloses cyclopropyl-fused pyrrolidine-based dipeptidyl
`peptidase IV inhibitors (DPP4 inhibitors) which include com-
`pounds having the structure
`
`N:
`
`CN,
`
`HO
`
`N>—\<
`
`CN,
`
`F
`
`NH2
`
`0
`
`HZN
`
`o
`
`Page 3 of 9
`
`

`
`US 8,628,799 B2
`
`-continued
`
`,
`
`F
`
`HZN
`
`NC
`
`$ HZN
`
`5
`
`NC
`
`N
`
`0
`
`N
`
`;
`
`NC
`
`0
`
`5
`
`HO
`
`N
`
`,
`
`N
`
`or
`
`HZN
`
`0
`
`CN
`
`0
`
`NC
`
`HO
`
`HZN
`
`H2N
`
`HO
`
`N
`
`HZN
`
`0
`
`CN,
`
`or a pharmaceutically acceptable salt thereof, wherein the
`pharmaceutically acceptable salt can be the hydrochloride
`salt or the trifluoroacetic acid salt.
`
`Robl et al. discloses that the DPP4 inhibitors including
`those set out above may be formulated as tablets, capsules,
`granules or powders.
`
`BRIEF DESCRIPTION OF THE INVENTION
`
`In accordance with the present invention a coated tablet is
`provided which may include a medicament which is subject
`to intra-molecular cyclization, but is surprisingly stable under
`normal storage conditions, that is at 30° C. and 60% relative
`humidity.
`The coated tablet of the invention includes a tablet core
`
`(also referred to as a “core”, “tablet core”, “placebo”, “pla-
`cebo core tablet”, “tablet core composition” or “core compo-
`sition”) and
`a) a coating layer coated on the core, which coating layer is
`an inner seal coat formed of at least one coating polymer;
`b) a second coating layer, disposed over the inner seal coat,
`formed of a medicament and at least one coating polymer
`which preferably is the same coating polymer in the inner seal
`coat; and optionally
`c) an outer protective coating layer, disposed over the sec-
`ond coating layer, formed of at least one coating polymer,
`which preferably is the same coating polymer in the second
`coating layer and inner seal coat, but need not necessarily
`include the same amounts of such polymer.
`The medicament will preferably be the DPP4-inhibitor of
`the structure
`
`Page 4 of 9
`
`HO
`
`HZN
`
`0
`
`NC
`
`or a pharmaceutically acceptable salt thereof, such as the HCl
`salt, also referred to as Compound A.
`In a preferred embodiment, the coated tablet of the inven-
`tion will include a tablet core which is formed of one or more
`
`bulking agents or fillers, optionally one or more binders,
`optionally one or more disintegrants, and optionally one or
`more tableting lubricants,
`a) an inner seal coating layer which includes at least one
`coating polymer which preferably is a polyvinyl alcohol
`(PVA) based polymer;
`b) a second coating layer disposed over the seal coating
`layer a) which includes at least one medicament and at least
`one coating polymer which is preferably a PVA based poly-
`mer, and preferably the same as the coating polymer of the
`inner seal coating layer.
`The above coating layers are applied to the tablet core
`preferably by spray coating on to the tablet core.
`In a more preferred embodiment of the invention, an outer
`protective or third coating layer will be coated over the second
`coating layer (containing the medicament) and will function
`as a protective layer. The third or protective coating layer may
`preferably include similar components as in the second coat-
`ing layer except that it will not include a medicament, but may
`optionally include one or more colorants, and may not nec-
`essarily include the same amounts of such components.
`Optionally, a fourth layer (which includes similar compo-
`nents as in the third layer) containing colorants and a coating
`polymer can also be applied to differentiate tablets of various
`strengths. The first, second, third and fourth coating layers
`may be formed of the same or different coating polymers.
`It has been found that the coated tablets of the invention
`
`exhibit superior chemical stability as compared to traditional
`tablets manufactured using conventional dry granulation or
`wet granulation techniques.
`The coating approach will also facilitate preparation of a
`combination formulation of a problematic medicament with
`another drug by using the other drug tablet as a starting tablet
`(instead of the tablet core or placebo mentioned above) and
`applying the inner seal coating and the second coating con-
`taining the problematic medicament and coating polymer,
`and optionally but preferably, the outer protective coating
`over the other drug tablet.
`The coated tablets of the invention may be prepared pref-
`erably using perforated pan coaters. Fluid bed coating and
`spray coating may be used as well.
`In addition, in accordance with the present invention, a
`method is provided for preparing the coated tablet of the
`invention, which method includes the steps of
`a) providing a tablet core;
`b) coating the tablet with an inner seal coating layer for-
`mulation which includes at least one coating polymer;
`c) drying the coated tablet to form an inner seal coating
`thereon;
`
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`Page 4 of 9
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`

`
`US 8,628,799 B2
`
`5
`d) coating the so-coated tablet with a second coating layer
`formulation which includes medicament and at least one
`
`coating polymer;
`e) drying the so-coated tablet to form a second coating
`layer (containing medicament) thereon;
`f) optionally, but preferably, coating the so-coated tablet
`with a third outer protective coating layer formulation which
`includes at least one coating polymer; and
`g) optionally, coating the so-coated tablet with a fourth
`outer protective coating layer which includes at least one
`coating polymer and colorant, and
`h) drying the so-coated tablet to form the coated tablet of
`the invention.
`
`In a preferred embodiment of the method of the invention
`the inner seal coating layer formulation, the second coating
`layer formulation and the outer protective coating layer(s)
`formulation(s) each will be applied as a suspension of the
`coating polymer in a coating solvent.
`The third and fourth outer protective coating layers need
`not include a medicament (although it may, if desired), and
`may be formed of the other components of the first coating
`layer and/or second coating layer. The second coating layer
`may be formed of the components of the first coating layer
`and/or third/and or fourth coating layer, but not necessarily
`the same amounts of such components.
`In preparing the coated tablet of the invention, coating
`suspensions which include coating polymer in water are pre-
`pared. Other coating solvents which may be employed
`include ethanol, methanol, and isopropyl alcohol, with water
`being preferred. Tablets which are placebos (contain no medi-
`cament) and form tablet cores are coated with the inner seal
`coating suspension and are dried. The second coating layer
`suspension containing medicament and coating polymer is
`applied over the so-coated tablets which are then dried.
`Where the coated tablet of the invention is to include an
`
`outer protective layer, a coating suspension is prepared as in
`the case of the inner seal coating suspension but without
`medicament. The coating suspension will then be coated onto
`the previously coated tablets as described for the inner seal
`coating and second coating to form a protective coating layer
`thereon.
`The coated tablets of the invention are useful in the treat-
`
`ment of mammals such as humans, dogs and cats for Type II
`diabetes.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`The tablet core or placebo employed in the coated tablet of
`the invention will
`include conventional pharmaceutical
`excipients to enable formation of a pharmaceutically accept-
`able solid tablet core. The tablet core may be in the form of a
`tablet, bead, beadlet, or pill, all ofthe above being collectively
`referred to as a tablet core.
`The coated tablet ofthe invention will contain medicament,
`such as the above DPP4-inhibitor, saxaglipitin, in an amount
`within the range from about 0.1 to about 70% by weight and
`preferably from about 1 to about 50% by weight of the tablet
`core.
`
`The tablet core employed in the coated tablet of the inven-
`tion will preferably contain
`a) at least one bulking agent or filler;
`b) optionally at least one binder;
`c) optionally at least one disintegrant; and
`d) preferably but optionally at least one lubricant.
`wherein
`
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`
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`
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`
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`
`65
`
`6
`a) the bulking agent or filler is present in an amount within
`the range from about 1 to about 95% by weight, preferably
`from about 10 to about 85% by weight;
`b) the binder is present in an amount within the range from
`about 0 to about 20% by weight, preferably from about 1 to
`about 10% by weight;
`c) the disintegrant is present in an amount within the range
`from about 0 to about 20% by weight, and preferably from
`about 0.25 to about 10% by weight; and
`d) the lubricant is present in an amount within the range
`from about 0 to about 5% by weight, preferably from about
`0.2 to about 2% by weight, all ofthe above % by weight being
`based on the weight of the tablet core.
`It is preferred that the bulking agents are microcrystalline
`cellulose and lactose monohydrate;
`the disintegrant is croscarmellose sodium; and
`the lubricant is magnesium stearate.
`The tablet cores present in the coated tablets of this inven-
`tion can be prepared by a variety of processes and order of
`addition of excipients. The utility of these formulations is not
`limited to a specific dosage form or manufacturing process.
`Tablet cores may be manufactured by wet granulation, dry
`granulation, direct blending or any other pharmaceutically
`acceptable process.
`invention, a preferred
`In accordance with the present
`method is provided for preparing the tablet cores employed in
`the coated tablets ofthe invention which includes the steps of
`blending the one or more excipients such as bulking agent,
`optionally binder and optionally disintegrant. A lubricant will
`be preferably added to the blend to facilitate tablet formation.
`The bulking agents or fillers will be present in the tablet
`core compositions of the invention in an amount within the
`range from about 1 to about 95% by weight and preferably
`from about 10 to about 85% by weight of the core composi-
`tion. Examples of bulking agents or fillers suitable for use
`herein include, but are not limited to, cellulose derivatives
`such as microcrystalline cellulose or wood cellulose, lactose,
`sucrose, starch, pregelatinized starch, dextrose, mannitol,
`fructose, xylitol, sorbitol, corn starch, modified corn starch,
`inorganic salts such as calcium carbonate, calcium phos-
`phate, dicalcium phosphate, calcium sulfate, dextrin/dex-
`trates, maltodextrin, compressible sugars, and other known
`bulking agents or fillers, and/or mixtures of two or more
`thereof, preferably microcrystalline cellulose.
`The binder will be optionally present in the pharmaceutical
`compositions of the invention in an amount within the range
`from about 0 to about 20% weight, preferably from about 1 to
`about 10% by weight of the core composition. Examples of
`binders suitable for use herein include, but are not limited to,
`hydroxypropyl cellulose, corn starch, pregelatinized starch,
`modified corn starch, polyvinyl pyrrolidone (PVP) (molecu-
`lar weight ranging from about 5,000 to about 1,000,000,
`preferably about 40,000), hydroxypropyl methylcellulose
`(HPMC),
`lactose, gum acacia, ethyl cellulose, cellulose
`acetate, as well as a wax binder such as camauba wax, paraf-
`fin, spermaceti, polyethylenes or microcrystalline wax, as
`well as other conventional binding agent and/or mixtures by
`two or more thereof, preferably hydroxypropyl cellulose.
`The disintegrant will be optionally present in the pharma-
`ceutical composition ofthe invention in an amount within the
`range from about 0 to about 20% by weight, preferably from
`about 0.25 to about 10% by weight of the core composition.
`Examples of disintegrants suitable for use herein include, but
`are not limited to, croscarmellose sodium, crospovidone,
`starch, potato starch, pregelatinized starch, corn starch,
`sodium starch glycolate, microcrystalline cellulose, low sub-
`
`Page 5 of 9
`
`Page 5 of 9
`
`

`
`US 8,628,799 B2
`
`7
`stituted hydroxypropyl cellulose or other known disintegrant,
`preferably croscarrnellose sodium.
`The lubricant will be optimally present in the pharmaceu-
`tical composition of the invention in an amount within the
`range from about 0.1 to about 5% by weight, preferably from
`about 0.2 to about 2% by weight of the core composition.
`Examples of tableting lubricants suitable for use herein
`include, but are not limited to, magnesium stearate, zinc stear-
`ate, calcium stearate, talc, carnauba wax, stearic acid, palm-
`itic acid, sodium stearyl fumarate or hydrogenated vegetable
`oils and fats, or other known tableting lubricants, and/or mix-
`tures of two or more thereof, preferably magnesium stearate.
`The inner seal coating layer formulation (also referred to as
`the first coating layer) will include up to 95% of polymer
`based on the weight ofthe inner seal coating layer, and may be
`prepared as described hereinbefore. The formulation will
`contain at least one coating layer polymer and a coating
`solvent as described above, which preferably is water, which
`is used for processing and removed by drying. The coating
`layer polymer may be hydroxypropyl methylcellulose, poly-
`vinyl alcohol (PVA), ethyl cellulose, methacrylic polymers or
`hydroxypropyl cellulose, preferably PVA. The coating layer
`may also optionally include a plasticizer such as triacetin,
`diethyl phthalate, tributyl sebacate or polyethylene glycol
`(PEG), preferably PEG; and an anti-adherent or glidant such
`as talc, fumed silica or magnesium stearate, opacifying agent
`such as titanium dioxide. The coating layer may also include
`iron oxide based colorants. The coating material is commer-
`cially available under the trade name Opadry® HP or
`Opadry® 11 white.
`The second coating layer formulation will preferably be
`similar in composition to the first coating layer formulation
`although it will include medicament, preferably the DPP4-
`inhibitor in an amount within the range from about 0.5 to
`about 70%, preferably from about 30 to about 50% by weight,
`based on the weight of the second coating layer.
`The third outer protective coating layer will preferably be
`similar in composition to the first coating layer.
`The fourth coating layer where present will preferably be
`similar in composition to the third outer protective coating
`layer and will include colorant as desired, such as within the
`range from about 0.5 to about 5.0% by weight, based on the
`weight of the fourth coating layer.
`The inner seal coating layer will preferably be formed of
`coating layer polymer in an amount within the range from
`about 10 to about 95%, preferably from about 20 to about
`90% by weight of the inner seal coating layer, optionally
`plasticizer in an amount within the range from about 10 to
`about 30%, preferably from about 15 to about 20% by weight
`ofthe coating layer, and anti-adherent or glidant in an amount
`within the range for about 15 to about 30%, preferably from
`about 10 to about 15% by weight of the inner seal coating
`layer.
`The second coating layer will be preferably formed of
`coating layer polymer in an amount within the range from
`about 30 to about 99.5%, preferably from about 40 to about
`60% by weight ofthe second coating layer and medicament in
`an amount within the range from about 0.25% to about 70%,
`preferably from about 20 to about 50% by weight of the
`second coating layer.
`The coating layer polymer in the second coating layer will
`be at least about 5 mg with a 200 mg tablet core, and the
`medicament will be at least about 0.5 mg.
`The third outer protective coating layer will preferably be
`of similar composition to the first coating layer.
`The inner seal coating layer will be present in an amount
`within the range from about 1 to about 5%, preferably from
`
`8
`about 1 to about 3% by weight of the finished coated tablet;
`the second coating layer (containing medicament) will be
`present in an amount within the range from about 0.25 to
`about 70%, preferably from about 1 to about 50% by weight
`of the finished coated tablet, depending on potency; and the
`third outer protective coating layer and fourth layer where
`present will each be present in an amount within the range
`from about 1 to about 10%, preferably from about 1 to about
`5% by weight of the finished coated tablet.
`Preferred coated tablet formulations in accordance with the
`invention are set out below.
`
`Material
`Tablet Placebo
`
`Bulking Agent
`Lactose
`Microcrystalline
`cellulose
`Disintegrant
`Croscatrnellose
`sodium
`Lubricant
`Magnesium
`Stearate
`
`Preferred Range
`Possible Range %/
`mg by weight of200 mg %/mg by weight of200 mg
`placebo core tablet
`placebo core tablet
`
`2 to 95%/4 to 190 mg
`0 to 95%/0 to 190 mg
`0 to 95%/0 to 190 mg
`
`10 to 85%/20 to 170 mg
`20 to 75%/40 to 150 mg
`20 to 75%/40 to 150 mg
`
`0 to 20%/0 to 40 mg
`0 to 20%/0 to 40 mg
`
`0.25 to 10%/0.5 to 20 mg
`2 to 10%/4 to 20 mg
`
`0.1 to 5%/0.2 to 10 mg
`0.1 to 5%/0.2 to 10 mg
`
`0.2 to 2%/0.4 to 4 mg
`0.2 to 2%/0.4 to 4 mg
`
`10
`
`15
`
`20
`
`25
`
`30
`
`First Inner
`Seal Coating Layer
`
`35
`
`Coating polymer, and
`optional plasticizer
`and glidants
`
`%/mg by weight
`%/mg by weight of200 mg of200 mg
`placebo core tablet
`placebo core tablet
`
`0.5 to 50%/1 to 100 mg
`
`1 to 3%/2 to 6 mg
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`%/mg by weight
`of 200 mg
`placebo core tablet
`
`%/mg by weight
`of 200 mg
`placebo core tablet
`
`0.1 to 70%/0.2 to 140 mg 1 to 50%/2 to 100 mg
`
`1 to 70%/2 to 140 mg
`
`1 to 50%/2 to 100 mg
`
`%/
`mg by weight of200 mg
`placebo core tablet
`
`%/mg
`by weight of200 mg
`placebo core tablet
`
`0.5 to 50%/1 to 100 mg
`
`1 to 5%/2 to 10 mg
`
`Second Coating Layer
`DPP4-inhibitor
`(free base or HCl salt)
`Coating polymer, and
`optional plasticizer
`and glidants
`
`Third Outer Protective
`Coating Layer
`
`Coating polymer, and
`optional plasticizer,
`glidants and color
`
`The following working Example represents a preferred
`embodiment of the invention.
`
`EXAMPLE
`
`A 500 g batch of 2.5 mg DPP4 coated tablets having the
`following composition were prepared as described below
`
`Page 6 of 9
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`Page 6 of 9
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`

`
`US 8,628,799 B2
`
`Tablet Core
`
`Lactose Monohydrate NF
`Microcrystalline Cellulose NF
`Croscarmellose Sodium NF
`Magnesium Stearate NF
`
`To al
`Inner Seal Coating Layer
`Opadty ® HP which contains the following
`ingredients
`
`Po yvinyl Alcohol 40%
`PEG 20%
`Ta c 15%
`Ti anium dioxide 25%
`Middle Layer
`
`D ’P4-inhibitor, Saxaglipitin
`Oaadty ® HP
`Outer Protective Layer
`
`Oaadty ® HP
`
`Weight (mg) % by weight
`of a 200 mg
`placebo core tablet
`
`99 mg (49.5%)
`90 mg (45%)
`10 mg (5%)
`1 mg (0.5%)
`
`200 mg (100.0%)
`4 mg (2%)
`
`2.5 mg (1.25%)
`20 mg (10%)
`
`4 mg (2%)
`
`The 500 g of tablet cores were prepared as follows.
`Lactose monohydrate, croscarmellose sodium, and micro-
`crystalline cellulose were blended in a planetary mixer. The
`blend was then lubricated by blending with pre-screened
`magnesium stearate using a Turbula mixer. The lubricated
`blend was compressed using a single station press or using a
`rotary press into 200 mg placebo tablets.
`Inner Seal Coating Layer
`The inner seal coating suspension was prepared as follows.
`0.1 N HCl (about 226.7 g) in a metal container was con-
`tinuously stirred with a lightening mixer. 40 g Opadry® HP
`powder was quickly added into the vortex. After the powder
`addition was completed, mixing was continued at a low speed
`until a uniform mixture was visually evident. pH ofthe result-
`ing suspension was measured and pH was adjusted to 2 using
`concentrated HCl or NaOH.
`
`A Glatt coater was set up according to the following param-
`eters
`
`Glatt Coater Parameter
`
`Pump rate
`Pan speed
`Air pressure
`Inlet air temperature
`Exhaust air temperature
`Air flow
`Gun to bed distance
`Nozzle size
`
`3.5-5 ml/min
`20 rpm
`1.5 bar
`50° C.
`about 38° C.
`80 m3/hour
`6.5 inch
`0.8 mm
`
`The tablet cores were preheated in a coating pan for about
`10 to 15 minutes. 30 heated tablets were weighed. Drying of
`the tablets was continued until the moisture was driven out of
`
`the tablet and tablet weight became constant. The final weight
`of 30 tablets was designed as A.
`
`10
`The 30 tablets were coated with the inner seal coating
`suspension as prepared above employing the Glatt coater.
`The 30 tablets were weighed every 10 minutes (and the
`weight recorded) until the tablet weight reached the targeted
`weight (Equation 1). The coated tablets were dried by heating
`until the tablet weight became constant. The final weight of
`the so-coated tablets was designated as B.
`
`Targeted weight:A><1.02:B
`
`Equation 1
`
`Middle (Drug) Coating Layer
`The middle drug-containing coating layer suspension was
`prepared as follows.
`12.5 g of the DPP4-inhibitor (free base) was added to 1000
`ml of 0.1 N HCl in a metal container. The pH was measured
`and adjusted to 2. The HCl was continuously stirred and 100
`g Opadry® HP was quickly added into the vortex. The mix-
`ture was then stirred at low speed until a uniform mixture was
`visually evident. The pH of the suspension was maintained at
`2 using either concentrated HCl or 1N HCl as necessary.
`The seal coated tablet cores prepared above were coated
`with the coating suspension containing the DPP4-inhibitor
`prepared above employing the Glatt coater. The 30 seal
`coated tablets were weighed, initially every 30 minutes, then
`every 15 minutes and the weight recorded until the targeted
`weight was reached (Equation 2). The so-coated tablets were
`dried by heating until the tablet weight became constant. The
`final weight of 30 tablets was designated as C.
`
`Targeted weight:B+30><(2.925 (equivalent to 2.5mg
`free base)+20mg):B+687.75mg:C
`
`Equation 2
`
`The amount of drug coated onto the tablets was determined
`using HPLC, fiber optic probe, or NIR or other suitable
`means. Coating was stopped when the targeted amount of
`drug was deposited.
`Outer Protective Coating Layer
`The so-coated tablets were then coated with a suspension
`of Opadry® HP as used in forming the inner seal coating. The
`30 tablets were weighed every 10 minutes and the weight
`recorded until tablet weight reached the targeted weight
`(Equation 3). The tablets were dried by heating until the tablet
`weight became constant.
`The final weight of 30 tablets was designed as D.
`
`Equation 2
`Targeted weight:C+30><4mg:C+120mg:D
`The so-coated tablets were transferred to a suitable con-
`tainer.
`
`The tablets of the invention so-prepared had superior sta-
`bility to conventional tablet formulations (wherein the drug
`was in the core) and capsule formulations.
`The above 2.5 mg potency coated tablets of the invention
`were stored at various storage conditions up to and including
`41 weeks and stability data related to presence of the
`degradant cyclic amidine (mainly cis-cyclic amidine (Cis-
`CA)) were collected. As shown in Table 1 set out below, no
`cis-CA was detected at 25° C./60% RH storage condition.
`The cis-CA levels were 0.22% and 0.32% at 30° C./60% RH
`
`and 40° C./75% RH storage conditions, respectively. These
`levels are significantly lower than those observed in the 5 mg
`and 20 mg potency capsule formulations shown in Table 2.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`Page 7 of 9
`
`Page 7 of 9
`
`

`
`US 8,628,799 B2
`
`TABLE 1
`
`Twenty-six weeks stability data on 2.5 mg potency tablets coated with Opadry ® HP,
`free base as starting material, and three coating layers.
`For stability evaluation, tablets were packaged in HDPE