I lllll llllllll Ill lllll lllll lllll lllll lllll 111111111111111111111111111111111
`US007829595B2
`
`c12) United States Patent
`Lawrence et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,829,595 B2
`Nov. 9, 2010
`
`(54) RAPID DISSOLUTION FORMULATION OF A
`CALCIUM RECEPTOR-ACTIVE COMPOUND
`
`(75)
`
`Inventors: Glen Gary Lawrence, Thousand Oaks,
`CA (US); Francisco J. Alvarez,
`Newbury Park, CA (US); Hung-Ren H.
`Lin, Oak Park, CA (US); Tzuchi R. Ju,
`Vernon Hills, IL (US)
`(73) Assignee: Amgen Inc., Thousand Oaks, CA (US)
`( *) Notice:
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 742 days.
`(21) Appl. No.: 10/937,870
`Sep.10,2004
`Filed:
`(22)
`Prior Publication Data
`(65)
`
`Jul. 7, 2005
`US 2005/0147669 Al
`Related U.S. Application Data
`
`(51)
`
`(60) Provisional application No. 60/502,219, filed on Sep.
`12, 2003.
`Int. Cl.
`A61K 31144
`(2006.01)
`A61K 311135
`(2006.01)
`(52) U.S. Cl. ....................................... 514/579; 514/649
`( 58) Field of Classification Search . ... ... ... ... .. ... ... 514/2,
`514/307,320, 167, 168,456,256,275, 557,
`514/567, 579, 607, 614, 646, 649; 424/464,
`424/465, 476, 490
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5,126,145 A
`5,981,599 A
`6,001,884 A
`6,0ll,068 A
`6,031,003 A *
`6,172,091 Bl
`6,2ll,244 Bl*
`6,228,807 Bl
`6,277,788 Bl
`6,313,146 Bl
`6,316,460 Bl *
`6,342,532 Bl
`6,363,231 Bl
`6,387,404 B2
`6,399,100 Bl
`6,419,954 Bl*
`6,432,656 Bl
`6,447,809 Bl*
`6,495,165 Bl
`200110051636 Al*
`200210015735 Al
`200210107406 Al
`2002/0123459 Al*
`2003/0035836 Al
`2003/0054041 Al
`2005/0147670 Al*
`
`611992 Evenstad et al.
`1111999 Moe et al.
`12/1999 Nemeth et al.
`112000 Nemeth et al.
`212000 Nemeth et al. .............. 514/579
`112001 Cohen et al.
`412001 Van Wagenen et al ....... 514/649
`512001 Kuchikata et al.
`8/2001 Wright
`1112001 Van Wagenen et al.
`1112001 Creekmore et al .......... 514/275
`112002 Moe et al.
`3/2002 Manzer et al.
`512002 Oshlack et al.
`612002 Clancy et al.
`712002 Chu et al.
`................... 424/465
`8/2002 Del Mar et al.
`912002 Krumhar et al.
`12/2002 Thosar et al.
`12/2001 Black et al. ................. 514/320
`212002 Hedden et al.
`8/2002 Sakai et al.
`912002 Ault et al. ... ... .. ... ... ... ... .. 514/2
`212003 Shanghvi et al.
`3/2003 Lemmens et al.
`7/2005 Hsu et al.
`................... 424/464
`
`............ 424/602
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`WO
`
`0 933 354
`WO 93/04373
`
`8/1999
`3/1993
`
`WO
`WO
`WO
`WO
`WO
`
`WO 94/18959
`WO 95/ll221
`WO 96/12697
`WO 97/41090
`WO 01134562
`
`9/1994
`4/1995
`5/1996
`1111997
`5/2001
`
`OTHER PUBLICATIONS
`
`William G Goodman, Gerald A. Hladik, Stewar A. Turner, Peter W.
`Blaisdell, David A. Goodkin, Wei Liu, Yousir M. Barri, Raphael M
`Cohen and jack W. Coburn, The Calcimimetic Agent AMG 073
`Lowers Plasma parathryoid Hormone levels in Hemodialysis patients
`with secondary hyperparathyroidism, J. Am. Soc. Nephrology, 13,
`1017-1024, 2002.*
`Amgen News Release, Internet Article: "Amgen Submitted New
`Drug Application for Cinecalcet HCl", XP002313388, URL: http://
`www.amgen.com/news/news03/pressRelease030908a.pdf, Sep. 8,
`2003, 2 pages.
`Berge, Stephen, et al., "Pharmaceutical Salts," J Pharm. Sci., vol. 66,
`No. 1, pp. 1-19, Jan. 1977.
`Drugs in R&D, "Cinecalcet: AMG 073, Calcimimetics- Amgen/
`NPS Pharmaceuticals, KRN 1493, NPS 1493," vol. 4, No. 6, pp.
`349-351, 2003.
`Goodman, William G., et al., "The Calcimimetic Agent AMG 073
`Lowers Plasma Parathyroid Hormone Levels in Hemodialysis
`Patients with Secondary Hyperparathyroidism," J Am. Soc. Nephrol,
`vol. 13, pp. 1017-1024, Apr. 2002.
`Nemeth, Edward F., et al., Pharmacodynamics of the Type II
`Calcimimetic Compound Cinacalcet HCl, J Pharmacol. Exp Thera(cid:173)
`peutics, vol. 308, No. 2, pp. 627-635, Feb. 2004.
`Pattaragarn, Anirut, et al., "Effect of the Calcimimetic NPS R-467 on
`Furosemide- Induced Nephrocalcinosis in the Young Rat," Kidney
`Internationa, vol. 65, pp. 1684-1689, 2004.
`U.S. Food and Drug Administration, Internet Article: "FDA
`Approves First in a New Class of Drugs to Treat Hyperparathyroid(cid:173)
`ism Associated with Renal Failure and in Patients with Parathyroid
`Cancer," FDA Talk Paper, XP-002313389, http://www.fda.gov/bbs/
`topics/ANSWERS/2004/ANS01282.htrnl), Mar. 8, 2004. 1 page,
`(retrieved by EPO Searching Authority on Jan. 11, 2005).
`RxList, Inc., Internet Article: "Sensipar (Cinacalcet HCI) Tablets,"
`XP-002313390, www.rxlist.com/cgi/generic3/sensipar.htrn), Aug.
`12, 2004, 2 pages, (retrieved by EPO Searching Authority on Jan. 10,
`2005.
`NPS Pharmaceuticals, Internet Article: "NPS Drug Development:
`Product Development Pipeline," XP-002313391, www.npsp.com/
`drug-development/pipline.php, Sep. 8, 2003, 2 pages, (retrieved by
`EPO Searching Authority on Jan. 12, 2005).
`* cited by examiner
`Primary Examiner-Michael G Hartley
`Assistant Examiner-Jagadishwar R Samala
`(74) Attorney, Agent, or Firm-Foley & Lardner LLP
`
`(57)
`
`ABSTRACT
`
`The present invention relates to a pharmaceutical composi(cid:173)
`tion comprising a therapeutically effective amount of a cal(cid:173)
`cium receptor-active compound and at least one pharmaceu(cid:173)
`tically acceptable excipient, wherein the composition has a
`controlled dissolution profile. The present invention further
`relates to a method of manufacturing the pharmaceutical
`composition, as well as a method of treating a disease using
`the pharmaceutical composition.
`
`25 Claims, No Drawings
`
`1
`
`EX 1001
`IPR of U.S. Pat. No. 7,829,595
`
`

`
`1
`RAPID DISSOLUTION FORMULATION OF A
`CALCIUM RECEPTOR-ACTIVE COMPOUND
`
`US 7,829,595 B2
`
`2
`comprising producing the formulation in a granulator which
`has a volume ranging from about 1 L to about 2000 L, and
`contains water in a granulation level ranging from about 10%
`to about 50% relative to the weight of the dry powders in the
`granulator.
`The calcium receptor-active compound useful in the
`claimed invention may be a calcimimetic compound or a
`calcilytic compound. As used herein, the term "calcimimetic
`compounds" refers to compounds that bind to a calcium
`1 o receptor, and induce a conformational change that reduces the
`threshold for calcium receptor activation by the endogenous
`ligand Ca2+, thereby reducing parathyroid hormone ("PTH")
`secretion. These calcimimetic compounds can also be con(cid:173)
`sidered allosteric modulators of the calcium receptor. As used
`15 herein, the term "calcilytic compounds" refers to compounds
`that act as calcium receptor antagonists, and stimulate PTH
`secretion.
`The calcimimetic compounds and calcilytic compounds
`useful in the present invention include those disclosed in, for
`20 example, European Patent No. 933 354; International Publi(cid:173)
`cation Nos. WO 01/34562, WO 93/04373, WO 94/18959,
`WO 95/11221, WO 96/12697, WO 97/41090; U.S. Pat. Nos.
`5,981,599, 6,001,884, 6,011,068, 6,031,003, 6,172,091,
`6,211,244, 6,313,146, 6,342,532, 6,363,231, 6,432,656, and
`25 U.S. Patent Application Publication No. 2002/0107406. The
`calcimimetic compounds and/or calcilytic compounds dis(cid:173)
`closed in these patents and published applications are incor(cid:173)
`porated herein by reference.
`In certain embodiments, the calcium receptor-active com-
`30 pounds are chosen from compounds of formula (I) and phar(cid:173)
`maceutically acceptable salts thereof
`
`This application claims the benefit of priority of U.S. Pro(cid:173)
`visional Patent Application No. 60/502,219, filed Sep. 12,
`2003.
`Calcium receptor-active compounds are known in the art.
`One example of a calcium receptor-active compound is cina(cid:173)
`calcet HCl, which is described, for example, in U.S. Pat. No.
`6,001,884. Such calcium receptor-active compounds may be
`insoluble or sparingly soluble in water, particularly in their
`non-ionized state. For example, cinacalcet has a solubility in
`water ofless than about 1 µg/mL at neutral pH. The solubility
`of cinacalcet can reach about 1.6 mg/mL when the pH ranges
`from about 3 to about 5. However, when the pH is about 1, the
`solubility decreases to about 0.1 mg/mL. Such limited solu(cid:173)
`bility can reduce the number of formulation and delivery
`options available for these calcium receptor-active com(cid:173)
`pounds. Limited water solubility can also result in low bio(cid:173)
`availability of the compounds.
`There is therefore a need to maximize the dissolution of the
`calcium receptor-active compound from a dosage form, and
`potentially during in vivo exposure. There is also a need to
`improve the bioavailability of the calcium receptor-active
`compound during in vivo exposure.
`One aspect of the present invention provides a pharmaceu(cid:173)
`tical composition comprising at least one calcium receptor
`active compound in combination with at least one pharma(cid:173)
`ceutically acceptable carrier. Certain embodiments of the
`present invention are directed to a pharmaceutical composi(cid:173)
`tion with a defined dissolution profile.
`The invention also provides a method of manufacturing the
`pharmaceutical composition to achieve the desired dissolu(cid:173)
`tion profile, as well as a method of treating a disease using the
`pharmaceutical composition. In addition, certain embodi- 35
`ments of the present invention are directed to a method for
`controlling dissolution rate of a formulation comprising the
`pharmaceutical composition.
`According to one aspect of the invention, the invention
`provides a pharmaceutical composition comprising an effec- 40
`tive dosage amount of at least one calcium receptor-active
`compound and at least one pharmaceutically acceptable
`excipient, wherein the composition has a dissolution profile
`in 0.05 N HCl, measured according to a dissolution test con(cid:173)
`ducted in United States Pharmacopeia (USP)-National For- 45
`mulary (NF) (USP 26/NF 21 ), chapter 711 using a USP 2
`apparatus at a temperature of37° C. ±0.5° C., andat a rotation
`speed of75 r.p.m., which comprises from about 50% to about
`125% of a target amount of the calcium receptor-active com(cid:173)
`pound being released from the composition no later than 50
`about 30 minutes from the start of the test.
`According to another aspect of the invention, the invention
`provides a pharmaceutical composition comprising an effec(cid:173)
`tive dosage amount of at least one calcium receptor-active
`compound and at least one pharmaceutically acceptable 55
`excipient, wherein the composition has a dissolution profile
`in 0.05 N HCl, measured according to a dissolution test con(cid:173)
`ducted in USP 26/NF 21, chapter711 using a USP 2 apparatus
`at a temperature of about 37° C., and at a rotation speed of
`about 75 r.p.m., which comprises from about 50% to about
`125% of a target amount of the calcium receptor-active com(cid:173)
`pound being released from the composition no later than
`about 30 minutes from the start of the test.
`The invention also provides a method of controlling the
`dissolution rate of a formulation comprising an effective dos(cid:173)
`age amount of a calcium receptor-active compound and at
`least one pharmaceutically acceptable excipient, the method
`
`(I)
`
`(X2)n--
`
`0- +01
`
`H H
`-1-(Xi)m
`(alkyl)-N
`~ ~
`
`CH3
`
`wherein:
`X 1 and X2 , which may be identical or different, are each a
`radical chosen from CH3 , CH30, CH3 CH20, Br, Cl, F, CF3 ,
`CHF 2 , CH2 F, CF 3 0, CH3 S, OH, CH2 0H, CONH2 , CN, N02 ,
`CH3CH2 , propyl, isopropyl, butyl, isobutyl, t-butyl, acetoxy,
`and acetyl radicals, or two ofX 1 may together form an entity
`chosen from fused cycloaliphatic rings, fused aromatic rings,
`and a methylene dioxy radical, or two of X2 may together
`form an entity chosen from fused cycloaliphatic rings, fused
`aromatic rings, and a methylene dioxy radical; provided that
`X2 is not a 3-t-butyl radical;
`n ranges from 0 to 5;
`m ranges from 1 to 5; and
`the alkyl radical is chosen from Cl-C3 alkyl radicals,
`which are optionally substituted with at least one group cho(cid:173)
`sen from saturated and unsaturated, linear, branched, and
`cyclic Cl-C9 alkyl groups, dihydroindolyl and thiodihy-
`60 droindolyl groups, and 2-, 3-, and 4-piperid(in)yl groups; and
`the stereoisomers thereof.
`Calcium receptor-active compounds useful in the present
`invention can be used in the form of pharmaceutically accept(cid:173)
`able salts derived from inorganic or organic acids. The salts
`65 include, but are not limited to, the following: acetate, adipate,
`alginate, citrate, aspartate, benzoate, benzenesulfonate, bisul(cid:173)
`fate, butyrate, camphorate, camphorsulfonate, digluconate,
`
`2
`
`

`
`US 7,829,595 B2
`
`25
`
`3
`cyclopentanepropionate, dodecylsulfate, ethanesulfonate,
`glucoheptanoate, glycerophosphate, hemisulfate, hep(cid:173)
`tanoate, hexanoate, fumarate, hydrochloride, hydrobromide,
`hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate,
`mandelate, methansulfonate, nicotinate, 2-naphthalene(cid:173)
`sulfonate, oxalate, palmoate, pectinate, persulfate, 2-phenyl(cid:173)
`propionate, picrate, pivalate, propionate, salicylate, succi(cid:173)
`nate, sulfate, tartrate, thiocyanate, tosylate, mesylate, and
`undecanoate. When compounds of the invention include an
`acidic function such as a carboxy group, then suitable phar- 10
`maceutically acceptable salts for the carboxy group are well
`known to those skilled in the art and include, for example,
`alkaline, alkaline earth, ammonium, quaternary ammonium
`cations and the like. For additional examples of"pharmaco(cid:173)
`logically acceptable salts," see infra and Berge et al., J. 15
`P harm. Sci. 66: 1 (1977). In certain embodiments of the inven(cid:173)
`tion salts of hydrochloride and salts ofmethanesulfonic acid
`can be used.
`In some embodiments of the present invention, the cal(cid:173)
`cium-receptor active compound can be chosen from cinacal(cid:173)
`cet, i.e., N-(l-(R)-(l-naphthyl)ethyl]-3-[3-(trifluoromethyl)
`phenyl]-1-aminopropane, cinacalcet HCl, and cinacalcet
`methanesulfonate. The cinacalcet HCl and cinacalcet meth(cid:173)
`anesulfonate can be in various forms, such as amorphous
`powders, crystalline powders, and mixtures thereof. For
`example, the crystalline powders can be in forms including
`polymorphs, psuedopolymorphs, crystal habits, micromer(cid:173)
`etics, and particle morphology.
`The therapeutically effective amount of the calcium recep(cid:173)
`tor-active compound in the compositions disclosed herein 30
`ranges from about 1 mg to about 360 mg, for example from
`about 5 mg to about 240 mg, or from about 20 mg to about 100
`mg. As used herein, the "therapeutically effective amount" is
`an amount that changes in a desired marmer at least one of the
`calcium level, the phosphorus level, the PTH level, and the 35
`calcium phosphorus product in a subject. In some embodi(cid:173)
`ments, the therapeutically effective amount of cinacalcet HCl
`in the composition disclosed herein can be chosen from about
`5 mg, about 15 mg, about 30 mg, about 50 mg, about 60 mg,
`about 75 mg, about 90 mg, about 120 mg, about 150 mg, 40
`about 180 mg, about 210 mg, about 240 mg, about 300 mg, or
`about 360 mg.
`While it may be possible to administer a compound of the
`invention alone, the compound administered will normally be
`present as an active ingredient in a pharmaceutical composi- 45
`tion. Thus, a pharmaceutical composition of the invention
`may comprise a therapeutically effective amount of at least
`one calcium receptor-active compound, or an effective dos(cid:173)
`age amount of at least one calcium receptor-active compound.
`As used herein, an "effective dosage amount" is an amount 50
`that provides a therapeutically effective amount of the at least
`one calcium receptor active compound when provided as a
`single dose, in multiple doses, or as a partial dose. Thus, an
`effective dosage amount of the at least one calcium receptor
`active compound of the invention includes an amount less 55
`than, equal to or greater than an effective amount of the
`compound; for example, a pharmaceutical composition in
`which two or more unit dosages, such as in tablets, capsules
`and the like, are required to administer an effective amount of
`the compound, or alternatively, a multidose pharmaceutical 60
`composition, such as powders, liquids and the like, in which
`an effective amount of the at least one calcium receptor-active
`compound is administered by administering a portion of the
`composition.
`Alternatively, a pharmaceutical composition in which two
`or more unit dosages, such as in tablets, capsules and the like,
`are required to administer an effective amount of the at least
`
`4
`one calcium receptor active compound may be administered
`in less than an effective amount for one or more periods of
`time (i.e, a once-a-day administration, and a twice-a-day
`administration), for example to ascertain the effective dose
`for an individual subject, to desensitize an individual subject
`to potential side effects, to permit effective dosing readjust(cid:173)
`ment or depletion of one or more other therapeutics admin(cid:173)
`istered to an individual subject, and/or the like.
`The effective dosage amount of the pharmaceutical com(cid:173)
`positiondisclosedhereinranges from about 1 mg to about 360
`mg from a unit dosage form, for example about 5 mg, about 15
`mg, about 30 mg, about 50 mg, about 60 mg, about 75 mg,
`about 90 mg, about 120 mg, about 150 mg, about 180 mg,
`about 210 mg, about 240 mg, about 300 mg, or about 360 mg
`from a unit dosage form.
`In some embodiments of the present invention, the com(cid:173)
`positions disclosed herein comprise a therapeutically effec(cid:173)
`tive amount of cinacalcet HCl for the treatment of hyperpar-
`20 athyroidism, such as primary hyperparathyroidism and
`secondary hyperparathyroidism, hyperphosphonia, hypercal(cid:173)
`cemia, and elevated calcium-phosphorus product. For
`example, in certain embodiments, the cinacalcet HCl can be
`present in an amount ranging from about 1 % to about 70%,
`such as from about 5% to about 40%, from about 10% to
`about 30%, or from about 15% to about 20%, by weight
`relative to the total weight of the composition.
`The compositions of the invention may contain one or
`more active ingredients in addition to the calcium receptor(cid:173)
`active compound. The additional active ingredient may be
`another calcium receptor-active compound, or it may be an
`active ingredient having a different therapeutic activity.
`Examples of such additional active ingredients include, for
`example, vitamins and their analogs, such as vitamin D and
`analogs thereof, antibiotics, and cardiovascular agents.
`The cinacalcet HCl or other calcium receptor-active com(cid:173)
`pound that can be used in the composition is typically present
`in the form of particles. For instance, the cinacalcet HCl can
`be in a form chosen from needle-shaped particles, rod-shaped
`particles, plate-shaped particles, and mixtures of any of the
`foregoing. These particles can have a particle D50 of, for
`example, less than or equal to about 50 µm. As used herein,
`the "particle D50" is the particle size of the active pharmaceu(cid:173)
`tical ingredient at the 50'h percentile of a particle size distri(cid:173)
`bution. According to certain embodiments of the invention,
`the active pharmaceutical ingredient in the formulation has a
`particle D50 that is less than the granule D50 of the formula-
`tion, discussed in detail below.
`The particle D50 of the cinacalcet HCl particles can be
`determined by one of ordinary skill in the art using known
`light scattering techniques. In one embodiment of the inven(cid:173)
`tion, the particle D50 of the cinacalcet HCl particles is deter(cid:173)
`mined by using a particle size analyzer, such as a Malvern
`Mastersizer analyzer, that uses a laser to scan a suspension of
`particles. The particles diffract the incoming light to detec(cid:173)
`tors: smaller particles diffract light at larger angles, while
`larger particles diffract light at smaller angles. The light inten(cid:173)
`sities observed at each detector are translated into a particle
`size distribution based on the diameter of a sphere that has an
`equivalent volume to that of the measured particles.
`Specifically, the particle size distribution of the active phar(cid:173)
`maceutical ingredient, for example, cinacalcet HCl, can be
`65 determined according to the following procedure. The fol(cid:173)
`lowing instrument conditions in a Malvern Mastersizer par(cid:173)
`ticle size analyzer are specified in its software:
`
`3
`
`

`
`US 7,829,595 B2
`
`5
`
`6
`
`Weight of each sieve
`Weight Fraction of each sieve = Sum of all sieves
`
`Refractive Index Sample
`Absorptive Index
`Refractive Index Dispersant
`Analysis model
`Calculation sensitivity
`Measurement snaps and time
`Background snaps and time
`Stir speed
`
`1.630
`0.1
`1.375
`General purpose spherical
`Enhanced
`20,000 snaps over 20 seconds
`20,000 snaps over 20 seconds
`1750 rpm
`
`While stirring, about 170 mL ofa dispersion ofabout 0.1 %
`sorbitan trioleate (for example Span 85®, available from
`Kishida Chemical) in hexane ("dispersant-B''), is added to the
`sampling unit, and the laser is aligned to take a background
`measurement of the dispersant-B.
`The entire suspension containing the cinacalcet HCl is
`added until a suitable obscuration range ranging from about
`!Oto about 20% is obtained. The sample is measured afterthe 20
`obscuration value has stabilized. After the measurement, the
`system is drained and rinsed once with about 170 mL of
`dispersant-B, the dispersant-B is drained, and the sampling
`unit is refilled with about 170 mL of dispersant-B. The mea(cid:173)
`surement are repeated two more times with different riffled 25
`fractions. The riffling is performed on large samples to obtain
`small representative particle size fractions about 15 mg in
`size.
`The Obscuration, D(v, 0.1), D(v, 0.5), D(v, 0.9) values are 30
`then calculated from these measurements. The average, stan(cid:173)
`dard deviation, and relative standard deviation (RSD) of the
`D(v, 0.1), D(v, 0.5), D(v, 0.9) values is also calculated. The
`RSD (%)is calculated as follows:
`
`Before the particle size calculation, the mean size range
`must be determined for each sieve and the bottom pan. This
`mean size of each sieve screen represents the mean particle
`size retained on the screen. The mean size of each sieve screen
`10 is determined by the hole size of the screen (lower limit) and
`one sieve size larger (upper limit). In the case of the 40 mesh
`sieve screen, the hole size of about 1410 µmis used as an
`upper limit. Table 1 set forth below shows the particle size
`range of any retained material on each screen and the mean of
`15 the particle size range.
`
`TABLE 1
`
`Hole size of
`each screen
`(µrn)
`
`Particle size
`range of
`retained material
`on each screen
`(µrn)
`
`Median particle
`size of the
`screen (µrn)
`
`425
`250
`180
`150
`106
`75
`45
`0
`
`425-1410
`250-424
`180-249
`150-179
`106-149
`75-105
`45-74
`1-44
`
`918
`337
`215
`165
`128
`90
`60
`23
`
`Screens
`
`40 mesh
`60 mesh
`80 mesh
`100 mesh
`140 mesh
`200 mesh
`325 mesh
`Bottom pan
`
`The weight fraction of each sieve is added to generate
`cumulative frequency distribution starting from the bottom
`pan to 40 mesh screen. Once the cumulative frequency dis-
`35 tribution is generated, the corresponding particle size at 10
`percentile (D 10), 50-percentile (D50), and 90-percentile (D90 )
`are determined. The particle size of the corresponding per(cid:173)
`centile is determined by linear interpolation between two
`consecutive data from the cumulative frequency distribution.
`40 For example, particle size of 50-percentile (D50) is interpo(cid:173)
`lated by,
`
`N
`~ (X;-X)
`100 ;~1
`RSD(o/o) = X --N---1-
`
`2
`
`45
`
`where X, is an individual measurement in a set ofN mea-
`surements and is the arithmetic mean of the set.
`The composition disclosed herein can be in various forms,
`for example, in granular form. The granules that can be used
`in the present invention can have a granule D50 ranging from
`about 50 µm to about 150 µm, such as from about 80 µm to 50
`about 130 µm. As defined herein, the "granule D50" is the
`particle size of the composition at the 50'h percentile of a
`particle size distribution. The granule D50 can readily be
`determined by one of ordinary skill in the art using sieve
`analysis techniques. Specifically, the granule D50 is deter- 55
`mined according to the following procedure.
`Approximately 100 g of sample is added to sieve shaker
`equipped with 40 mesh, 60 mesh, 80 mesh, 100 mesh, 140
`mesh, 200 mesh, 325 mesh, and the bottom pan. The sieve 60
`shaker is then turned on for about 10 minutes to separate the
`sample according to particle size. Each sieve is weighed to
`determine the amount of sample retained on each sieve and
`the bottom pan. The individual sieve weight is normalized to
`generate sieve weight fraction. The individual sieve weight 65
`fraction is calculated by dividing each sieve weight with the
`sum of all sieve weights.
`
`Dso(µm) =
`
`[(50 - Xn) * dn+! + (Xn+! - 50) * dn]
`(Xn+! - Xn)
`
`where,
`xn =cumulative quantity of sample that is just below
`50-percentile (in%);
`dn =mean of the particle size range from the sieve screen
`where xn occurs (in mm);
`xn+l =next cumulative quantity of sample that is above
`50-percentile (in%).
`dn+l =mean of the particle size range from the sieve screen
`where xn+l occurs (in mm).
`According to all embodiments of the present invention, the
`particle size of active pharmaceutical ingredient is measured
`according to light scattering techniques, and the particle size
`of the granules of composition is measured according to sieve
`analysis.
`The compositions disclosed herein can be in a form chosen
`from, for example, tablets, capsules, and powders. The tablets
`can be made by pressing the granules into the form of tablets.
`The capsules can also be made using the granules.
`The at least one pharmaceutically acceptable excipient can
`be chosen from, for example, diluents such as starch, micro-
`
`4
`
`

`
`US 7,829,595 B2
`
`7
`crystalline cellulose, dicalcium phosphate, lactose, sorbitol,
`mannitol, sucrose, methyl dextrins; binders such as povidone,
`hydroxypropyl methylcellulose, dihydroxy propylcellulose,
`and sodium carboxylmethylcellulose; and disintegrants such
`as crospovidone, sodium starch glycolate, croscarmellose
`sodium, and mixtures of any of the foregoing. The at least one
`pharmaceutically acceptable excipient can further be chosen
`from lubricants such as magnesium stearate, calcium stearate,
`stearic acid, glyceryl behenate, hygrogenated vegetable oil,
`glycerine fumerate and glidants such as colloidal silicon 10
`dioxide, and mixtures thereof. In some embodiments of the
`present invention, the at least one pharmaceutically accept(cid:173)
`able excipient is chosen from microcrystalline cellulose,
`starch, talc, povidone, crospovidone, magnesium stearate,
`colloidal silicon dioxide, sodium dodecyl sulfate, and mix- 15
`tures of any of the foregoing. The excipients of the present
`invention, can be intragranular, intergranular, or mixtures
`thereof.
`In some embodiments of the present invention, the com(cid:173)
`position and/or the granules within the composition can com(cid:173)
`prise microcrystalline cellulose and starch in a weight ratio
`ranging from about 1:1 to about 15:1. For example, in the
`composition, the weight ratio of the microcrystalline cellu(cid:173)
`lose and starch can range from about 1: 1 to about 15: 1, such
`as about 10: 1, and in the granules within the composition, the 25
`weight ratio of the microcrystalline cellulose and starch can
`range from about 1: 1 to about 10: 1, such as about 5: 1.
`The microcrystalline cellulose can be present in an amount
`ranging from about 25% to about 85%, for example from
`about 50% to about 80%, or from about 60% to about 7 5% by 30
`weight relative to the total weight of the composition. The
`starch can be present in an amount ranging from about 5% to
`about 35%, for example, from about 5% to about 25%, or
`from about 5% to about 10% by weight relative to the total
`weight of the composition.
`The compositions disclosed herein can further comprise at
`least one ingredient chosen from coating materials that are
`known in the art such as, for example, hydroxypropyl meth(cid:173)
`ylcellulose.
`Certain compositions can comprise:
`(a) from about 10% to about 40% by weight of a calcium
`receptor-active compound chosen from cinacalcet HCl and
`cinacalcet methanesulfonate;
`(b) from about 45% to about 85% by weight of at least one
`diluent;
`( c) from about 1 % to about 5% by weight of at least one
`binder; and
`( d) from about 1 % to about 10% by weight of at least one
`disintegrant; wherein the percentage by weight is relative to
`the total weight of the composition. The compositions can 50
`further comprise from about 0.05% to about 5% by weight,
`relative to the total weight of the composition, of at least one
`additive chosen from glidants, lubricants, and adherents. The
`composition can additionally comprise from about 1 % to
`about 6% by weight of at least one coating material, relative 55
`to the total weight of the composition.
`In another embodiment, the composition disclosed herein
`comprises:
`(a) from about 10% to about 40% by weight of cinacalcet
`HCl;
`(b) from about 5% to about 10% by weight of starch;
`( c) from about 40% to about 75% by weight of microcrys(cid:173)
`talline cellulose;
`( d) from about 1 % to about 5% by weight of povidone; and
`( e) from about 1 % to about 10% by weight of crospovi(cid:173)
`done; wherein the percentage by weight is relative to the total
`weight of the composition.
`
`8
`The povidone can be present in an amount ranging from
`about 1 % to about 5%, for example, from about 1 % to about
`3% by weight relative to the total weight of the composition.
`The crospovidone can be present in an amount ranging from
`about 1 % to about 10%, for example from about 3% to about
`6%, by weight relative to the total weight of the composition.
`The composition can further comprise from about 0.05% to
`about 5% by weight, relative to the total weight of the com(cid:173)
`position, of at least one additive chosen from colloidal silicon
`dioxide, magnesium stearate, talc, and the like, and mixtures
`of any of the foregoing. In certain embodiments of the inven-
`tion, the composition comprises from about 0.05% to about
`1.5% of colloidal silicon dioxide, from about 0.05% to about
`1.5% of magnesium stearate, from about 0.05% to about
`1.5% of talc, or mixtures of any of the foregoing. The com(cid:173)
`position can even further comprise from about 1 % to about
`6% by weight of at least one coating material, relative to the
`total weight of the composition.
`As mentioned above, the compositions of certain embodi-
`20 ments of the present invention have a dissolution profile that
`results in about 50% to about 125% of a target amount of the
`calcium receptor-active compound being released from the
`composition no later that about 30 minutes from the start of a
`dissolution test that is conducted in 0.05 N HCl in a U.S.P. 2
`apparatus at a temperature of 37° C. ±0.5° C. at a rotation
`speed of 75 r.p.m. The dissolution test is conducted using a
`USP 2 apparatus, and according to the dissolution protocol
`described in USP 26/NF 21, chapter 711, which is incorpo(cid:173)
`rated herein by reference. According to this embodiment
`using this dissolution protocol, a stated volume of the disso(cid:173)
`lution medium (±1 %) is placed in the vessel of the USP 2
`apparatus, the apparatus is assembled, the dissolution
`medium is equilibrated to 37° C. ±0.5° C., the thermometer is
`removed, the dosage form is placed in the vessel, and the
`35 amount of active pharmaceutical ingredient that is released as
`a function of time is measured.
`According to another embodiment of the invention, a stated
`volume of the dissolution medium is placed in the vessel of
`the USP 2 apparatus, the apparatus is assembled, the disso-
`40 lution medium is equilibrated to about 37° C., the thermom(cid:173)
`eter is removed, the dosage form is placed in the vessel, and
`the amount of active pharmaceutical ingredient that is
`released as a function of time is measured.
`The dissolution profile represents the percentage of the
`45 active pharmaceutical ingredient released based on a target
`amount of the active pharmaceutical ingredient in the formu(cid:173)
`lation. As used herein "target amount" refers to the amount of
`active pharmaceutical ingredient in each formulation. In cer-
`tain embodiments, the target amount refers to the label
`amount and/or label claim.
`USP 26