throbber
1300 I Street, NW c Washin~on,'Dt 20005-3315 c 202.408.4000 c Fax 202.408.4400
`www.finnegan.com
`
`FINNEGAN
`HENDERSON
`FARABOW
`GARRETT &
`DUNNER!J!
`
`MARK D. SWEET
`202.408.4162
`mark.sweet@finnegan.com
`
`September 10, 2004
`
`ATTORNEY DOCKET NO. 06843.0057 o
`CUSTOMER NO. 22,852 ~~
`cricx:> -
`.q(cid:173)
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`0
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`-
`...-
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`New U.S. Patent Application
`Title: RAPID DISSOLUTION FORMULATION OF
`A CALCIUM RECEPTOR-ACTIVE COMPOUND
`Inventors: Glen LAWRENCE. Francisco J. ALVAREZ. Hung-Ren H. LIN.
`and Tzuchi R. JU
`
`Sir:
`
`We enclose the following papers for filing in the United States Patent and
`Trademark Office in connection with the above patent application.
`
`Application- 55 pages, including title page, 11 independent claims with 118
`claims total, and Abstract.
`
`Applicants claim the right to priority based on Provisional Patent Application No.
`60/502,219 filed September 12, 2003.
`
`This application will be completed iri accordance with 37 C.F.R. § 1.53(f) upon
`receiving a Notice to File Missing Parts of Application.
`
`Please accord this application an application number and filing date.
`
`Respectfully submitted,
`
`FINNEGAN, HENDERSON, FARABOW,
`GAR
`NER L.L.P.
`
`Mak D. Sweet
`Reg. No. 41,469
`
`MDS/raa
`Enclosures
`
`Washington, DC c Atlanta, GA c Cambridge, MA c Palo Alto, CA c Reston, VA c Brussels c Taipei c Tokyo
`
`1
`
`EX 1002
`IPR of U.S. Pat. No. 7,829,595
`
`

`
`.·
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`.,;_
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`\
`
`Attorney Docket No. 06843.0057..00
`Customer No. 22.852
`
`UNITED STATES PATENT APPLICATION
`
`FOR
`
`RAPID DISSOLUTION FORMULATION OF
`A CALCIUM RECEPTOR-ACTIVE COMPOUND
`
`BY
`
`GLEN LAWRENCE, FRANCISCO J. ALVAREZ, HUNG-REN H. LIN, AND
`TZUCHI R. JU
`
`2
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`

`
`,,
`
`Attorney Docket No. 06843.0057-00
`
`·
`
`[001] This application claims the benefit of priority of U.S. Provisional Patent
`
`Application No. 60/502,219, filed September 12, 2003.
`
`[002] Calcium receptor-active compounds are known in the art. One example
`
`of a calcium receptor-active compound is cinacalcet HCI, which is described, for
`
`example, in U.S. Patent 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 of less 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 solubility can reduce the number of formulation and delivery
`
`options available for these calcium receptor-active compounds. Limited water solubility
`
`can also result in low bioavailability of the compounds.
`
`[003] 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.
`
`[004] One aspect of the present invention provides a pharmaceutical
`
`composition comprising at least one calcium receptor active compound in combination
`
`with at least one pharmaceutically acceptable carrier. Certain embodiments of the
`
`present invention are directed to a pharmaceutical composition with a defined
`
`dissolution profile.
`
`(005] The invention also provides a method of manufacturing the.
`
`pharmaceutical composition to achieve the desired dissolution profile, as well as a
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`3
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`

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`Attorney Docket No. 06843.0057-00
`
`method of treating a disease using the pharmaceutical composition. In addition, certain
`
`embodiments of the present invention are directed to a method for controlling
`
`dissolution rate of a formulation comprising the pharmaceutical composition.
`
`[006] According to one aspect of the invention, the invention provides a
`
`pharmaceutical composition comprising an effective 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 HCI, measured
`
`according to a dissolution test conducted in United States Pharmacopeia (USP) -
`
`National Formulary (NF) (USP 26/NF 21 ), chapter 711 using a USP 2 apparatus at a
`
`temperature of 37 °C ±0.5 °C, and at a rotation speed of 75 r.p.m., which comprises
`
`from about 50% to about 125% of a target amount of the calcium receptor-active
`
`.
`
`compound being released from the composition no later than about 30 minutes from the
`
`start of the test.
`
`[007] According to another aspect of the invention, the invention provides a
`
`pharmaceutical composition comprising an effective 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 HCI, measured
`
`according to a dissolution test conducted in USP 26/NF 21, chapter 711 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 compound being released from the composition no later than about 30
`
`minutes from the start of the test.
`
`2
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`4
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`·~ ,,
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`Attorney Docket No. 06843.0057-00
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`·
`
`[008] The invention also provides a method of controlling the dissolution rate of
`
`a formulation comprising an effective dosage amount of a calcium receptor-active
`
`compound and at least one pharmaceutically acceptable excipient, the method
`
`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.
`
`[009] 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 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 considered allosteric
`
`modulators of the calcium receptor. As used herein, the term "calcilytic compounds"
`
`refers to compounds that act as calcium receptor antagonists, and stimulate PTH
`
`secretion.
`
`[01 O]
`
`The calcimimetic compounds and calcilytic compounds useful in the
`
`present invention include those disclosed in, for example, European Patent No. 933
`
`354; International Publication Nos. WO 01/34562, WO 93/04373, WO 94/18959, WO
`
`95/11221, WO 96/12697, WO 97/41090; U.S. Patent 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 U.S. Patent Application Publication No. 2002/0107406. The
`
`calcimimetic compounds and/or calcilytic compounds disclosed in these patents and
`
`published applications are incorporated herein by reference.
`
`3
`
`5
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`l,
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`Attorney Docket No. 06843.0057 -00
`
`[011]
`
`In certain embodiments, the calcium receptor-active compounds are.
`
`chosen from compounds of formula (I) and pharmaceutically acceptable salts thereof
`
`(X2)n--
`
`0-
`
`H
`
`H
`{alkyl)--N
`
`wherein:
`
`(I)
`
`X1 and X2, which may be identical or different, are each a radical chosen from
`
`CN, N02, CH3CH2, propyl, isopropyl, butyl, isobutyl, t-butyl, acetoxy, and acetyl radicals,
`
`or two of X1 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 Oto 5;
`
`m ranges from 1 to 5; and
`
`the alkyl radical is chosen from C1-C3 alkyl radicals, which are optionally
`
`substituted with at least one group chosen from saturated and unsaturated, linear,
`
`branched, and cyclic C1-C9 alkyl groups, dihydroindolyl and thiodihydroindolyl groups,
`
`and 2-, 3-, and 4-piperid(in)yl groups; and the stereoisomers thereof.
`
`[012] Calcium receptor-active compounds useful in the presentinvention can
`
`be used in the form of pharmaceutically acceptable salts derived from inorganic or
`
`organic acids. The salts include, but are not limited to, the following: acetate, adipate,
`
`4
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`6
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`

`
`Attorney Docket No. 06843.0057 -00
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`alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,
`
`camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,
`
`.ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate,
`
`hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy(cid:173)
`
`ethanesulfonate, lactate, maleate, mandelate, methansulfonate, nicotinate, 2-
`
`naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 2-phenylpropionate,
`
`picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate,
`
`mesylate, and undecanoate. When compounds of the invention include an acidic
`
`function such as a carboxy group, then suitable pharmaceutically 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 "pharmacologically acceptable salts," see infra and Berge et al.,
`
`J. Pharm. Sci. 66:1 (1977). In certain embodiments of the invention salts of
`
`hydrochloride and salts of methanesulfonic acid can be used.
`
`[013]
`
`In some embodiments of the present invention, the calcium-receptor
`
`active compound can be chosen from cinacalcet, i.e., N-(1-(R)-(1-naphthyl)ethyl]-3-[3-
`
`(trifluoromethyl)phenyl]-1-aminopropane, cinacalcet HCI, and cinacalcet
`
`methanesulfonate. The cinacalcet HCI and cinacalcet methanesulfonate 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, micromeretics, and particle morphology.
`
`[O 14]. The therapeutically effective amount of the calcium receptor-active
`
`compound in the compositions disclosed herein ranges from about 1 mg to about 360
`
`5
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`7
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`Attorney Docket No. 06843.0057 ·00
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`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 manner at least one of the calcium level, the phosphorus level, the PTH level,
`
`and the calcium phosphorus product in a subject. In some embodiments, the
`
`therapeutically effective amount of cinacalcet HCI 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, about120 mg, about 150 mg, about 180 mg, about 210 mg,
`
`about 240 mg, about 300 mg, or about 360 mg.
`
`[015] 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 composition. Thus, a pharmaceutical composition of the invention may
`
`comprise a therapeutically effective amount of at least one calcium receptor-active
`
`compound, or an effective dosage amount of at least one calcium receptor-active ·
`
`compound.
`
`[016] As used herein, an "effective dosage amount" is an amount that provides
`
`a therapeutically effective amount ofthe 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 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
`
`composition, such as powders, liquids and the like, in which an effective amount of the
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`Attorney Docket No. 06843.0057 -00
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`at least one calcium receptor-active compound is administered by administering a
`
`portion of the composition.
`
`[017] · 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 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 readjustment or depletion of one or
`
`more other therapeutics administered to an individual subject, and/or the like.
`
`[018] The effective dosage amount of the pharmaceutical composition
`
`disclosed herein ranges 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.
`
`[019]
`
`In some embodiments of the present invention, the compositions
`
`disclosed herein comprise a therapeutically effective amount of cinacalcet HCI for the
`
`treatment of hyperparathyroidism, such as primary hyperparathyroidism and secondary
`
`hyperparathyroidism, hyperphosphonia, hypercalcemia, and elevated
`
`calcium-phosphorus product. For example, in certain embodiments, the cinacalcet HCI
`
`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.
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`Attorney Docket No. 06843.0057 -00
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`[020] The compositions of the invention may contain one or more active
`
`ingredients in addition to the calcium receptor·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.
`
`[021] The cinacalcet HCI or other calcium receptor·active compound that can
`
`be used in the composition is typically present in the form of particles. These particles
`
`can have a particle 050 of, for example, less than or equal to about 50 µm. As used
`
`herein, the "particle Dso" is the particle size of the active pharmaceutical ingredient at
`
`the 5oth percentile of a particle size distribution. According to certain embodiments of
`
`the invention, the active pharmaceutical ingredient in the formulation has a particle D5o
`
`that is less than the granule 050 of the formulation, discussed in detail below.
`
`[022] The particle D5o of the cinacalcet HCI particles can be determined by one
`
`of ordinary skill in the art using known light scattering techniques. In one embodiment
`
`of the invention, the particle Dso of the cinacalcet HCI particles is determined 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 detectors: smaller
`
`particles diffract light at larger angles, while larger particles diffract light at smaller
`
`angles. The light intensities 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.
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`Attorney Docket No. 06843.0057-00
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`·
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`[023] Specifically, the particle size distribution of the active pharmaceutical
`
`ingredient, for example, cinacalcet HCI, can be determined according to the following
`
`procedure. The following instrument conditions in a Malvern Mastersizer particle size
`
`analyzer are specified in its software:
`
`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
`
`[024] While stirring, about 170 ml of a dispersion of about 0.1 % sorbitan
`
`trioleate (for example Span 85®, available from Kishida Chemical) in hexane
`
`("dispersant-8"), is added to the sampling unit, and the laser is aligned to take a
`
`background measurement of the dispersant-8.
`
`[025] The entire suspension containing the cinacalcet HCI is added until a
`
`suitable obscuration range ranging from about 10 to about 20% is obtained. The
`
`sample is measured after the obscuration value has stabilized. After the measurement,
`
`the system is drained and rinsed once with about 170 ml of dispersant-8, the
`
`dispersant-8 is drained, and the sampling unit is refilled with about 170 ml of
`
`dispersant-8. The measurement are repeated two more times with different riffled
`
`fractions. The riffling is performed on large samples to obtain small representative
`
`particle size fractions about 15 mg in size.
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`Attorney Docket No. 06843.0057-00
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`[026] The Obscuration, O(v,0.1), O(v,0.5), O(v,0.9) values are then calculated
`
`from these measurements. The average, standard deviation, and relative standard
`
`deviation (RSO) of the O(v,0.1), O(v,0.5), O(v,0.9) values is also calculated. The RSO
`
`(%)is calculated as follows:
`
`N
`
`100 I rxi- xi
`RSD 1% )= -
`,. 01 x
`N-1
`
`..:.-'=.:.......! - - -
`
`1
`2
`
`where X, is an individual measurement in a set of N measurements and is
`
`the arithmetic mean of the set.
`
`[027] 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 050 ranging from about 50 µm to about 150 µm, such as from about 80 µm to
`
`about 130 µm. As defined herein, the "granule 050" is the particle size of the
`
`composition at the 501
`h percentile of a particle size distribution. The granule 0 50 can
`
`readily be determined by one of ordinary skill in the art using sieve analysis techniques.
`
`Specifically, the granule 050 is determined according to the following procedure.
`
`(028] 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 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
`
`10
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`Attorney Docket No. 06843.0057-00
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`normalized to generate sieve weight fraction. The individual sieve weight fraction is
`
`calculated by dividing each sieve weight with the sum of all sieve weights.
`
`Weight Fraction of each sieve
`
`Weight of each sieve
`Sum of all sieves
`
`[029] 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 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 the particle size range.
`
`Table 1
`
`Particle size
`Hole· size of
`. range of
`each screen retained material
`(µm)
`on each screen
`(um)
`425 -1410
`250 -424
`180 - 249
`150 - 179
`106-149
`75-105
`45-74
`1-44
`
`425
`250
`180
`150
`106
`75
`45
`0
`
`Screens
`
`40 mesh
`60 mesh
`80 mesh
`100 mesh
`140'mesh
`200 mesh
`325 mesh
`Bottom pan
`
`Median particle
`size of the
`screen (µm)
`
`918
`337
`215
`165
`128
`90
`60
`23
`
`[030] 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 distribution is generated, the corresponding particle size at
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`Attorney Docket No. 06843.0057-00
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`10 percentile (010), 50-percentile (Dso), and 90-percentile (Ogo) are determined. The
`
`particle size of the corresponding percentile is determined by linear interpolation
`
`between two consecutive data from the cumulative frequency distribution. For example,
`
`particle size of SO-percentile (Dso) is interpolated by,
`
`[ ( 5 0 - Xn) * dn + 1 + { Xn + I - 5 0) * dn]
`(Xn+I-Xn)
`
`Dso{µm) -
`
`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+1 = next cumulative quantity of sample that is above 50-percentile (in%).
`
`dn+1 = mean of the particle size range from the sieve screen where Xn+1 occurs
`
`(in mm).
`
`[031] 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.
`
`[032] 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.
`
`[033] The at least one pharmaceutically acceptable excipient can be chosen
`
`from, for example, diluents such as starch, microcrystalline cellulose, dicalcium
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`Attorney Docket No. 06843.0057~00
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`phosphate, lactose, sorbitol, mannitol, sucrose, methyl dextrins; binders such as
`
`povidone, hydroxypropyl methylcellulose, dihydroxy propylcellulose, and sodium
`
`carboxyl methylcellulose; 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 dioxide, and
`
`mixtures thereof. In some embodiments of the present invention, the at least one
`
`pharmaceutically acceptable excipient is chosen from microcrystalline cellulose, starch,
`
`talc, povidone, crospovidone, magnesium stearate, colloidal silicon dioxide, sodium
`
`dodecyl sulfate, and mixtures of any of the foregoing. The excipients of the present
`
`invention, can be intragranular, intergranular, or mixtures thereof.
`
`[034]
`
`In some embodiments of the present invention, the composition and/or
`
`. the granules within the composition can comprise 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 cellulose 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 weight
`
`ratio of the microcrystalline cellulose and starch can range from about 1: 1 to about 10: 1,
`
`'
`
`such as about 5: 1.
`
`[035] 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 75% by 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
`
`13
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`Attorney Docket No. 06843.0057-00
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`about 5% to about 25%, or from about 5% to about 10% by weight relative to the total
`
`weight of the composition.
`
`[036] 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 methylcellulose.
`
`[037] Certain compositions can comprise:
`
`(a)
`
`from about 10% to about 40% by weight of a calcium receptor-
`
`active compound chosen from cinacalcet HCI 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 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 to the total weight of the
`
`composition.
`
`[038]
`
`In another embodiment, the composition disclosed herein comprises:
`
`(a)
`
`from about 10% to about 40% by weight of cinacalcet HCI;
`
`(b)
`
`from about 5% to about 10% by weight of starch;
`
`(c)
`
`from about 40% to about 75% by weight of microc;rystalline
`
`cellulose;
`
`(d)
`
`from about 1% to about 5% by weight of povidone; and
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`Attorney Docket No. 06843.0057-00
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`( e) ·
`
`from about 1 % to about 10% by weight of crospovidone;
`
`wherein the percentage by weight is relative to the total weight of the composition.
`
`[039] 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.
`
`[040] The composition can 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 colloidal silicon dioxide, magnesium stearate, talc, and the like, and mixtures of
`
`any of the foregoing. In certain embodiments of the invention, 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 composition 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.
`
`[041] As mentioned above, the compositions of certain embodiments 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 HCI in a U.S.P. 2 apparatus at a temperature of 37°C ± 0.5°C at a
`
`rotation speed of75 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,
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`Attorney Docket No. 06843.0057-00
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`which is incorporated herein by reference. According to this embodiment using this.
`
`dissolution protocol, a stated volume of the dissolution 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 amount of active pharmaceutical ingredient that is released as a
`
`function of time is measured.
`
`[042] 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 dissolution medium is equilibrated to about 37°C, the thermometer 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.
`
`[043] The dissolution profile represents the percentage of the active
`
`pharmaceutical ingredient released based on a target amount of the active
`
`pharmaceutical ingredient in the formulation. As used herein "target amount" refers to
`
`the amount of active pharmaceutical ingredient in each formulation. In certain
`
`embodiments, the target amount refers to the label amount and/or label claim.
`
`[044] USP 26/NF 21, chapter 905, defines a protocol used to determine the
`
`dosage-unit conformity according to the present invention, and this content uniformity
`
`protocol is incorporated .herein by reference. According to this protocol, the content
`
`uniformity is determined by measuring the amount of active pharmaceutical ingredient in
`
`10 dosage unit samples, and calculating whether the amount of active pharmaceutical
`
`ingredient in all the dosage unit samples falls within a range of 85% .to 115% of the
`
`target amount. If one dosage unit sample is outside the range of 85% to 115% of the
`
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`Attorney Docket No. 06843.0057 -00
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`target amount and no unit is outside a range of 75% to 125% of the target amount, or if
`
`the Relative Standard Deviation (RSD), which is the sample standard deviation
`
`expressed as a percentage of the mean, is not greater thari 6%, then 20 additional
`
`dosage unit samples are tested. After treating at least 30 dosage units, the content
`
`uniformity requirement is met if not more than one dosage unit sample is outside the
`
`range of 85% to 115% of the target amount, and no unit is outside a range of 75% to
`
`125% of the target amount, and the RSD of the at least 30 dosage units does not
`
`exceed 7.8%.
`
`[045]
`
`In certain embodiments, the dissolution profile of the compositions
`
`disclosed herein can result in, for example, at least about 50%, at least about 70%, at
`
`least about 75%, or at least about 85%, of the target amount of the calcium receptor(cid:173)
`
`active compound ·being released from the composition no later than about 30 minutes
`
`from the start of the test. In certain embodiments, the dissolution profile of the
`
`.compositions disclosed herein can comprise at most about 125%, for example at most
`
`about 115%, at most about 110%, or at most about 100% of the target amount of the
`
`calcium receptor-active compound being released from the composition no later than
`
`about 30 minutes from the start of the test.
`
`In additional embodiments, the dissolution
`
`profile of the compositions disclosed herein can comprise from about 50% to about
`
`125%, for example from about 70% to about 110%, of the target amount of the calcium
`
`receptor-active compound being released from the composition no later than about 30
`
`minutes from the start of the test.
`
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`Attorney Docket No. 06843.0057 -00
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`[046] Other embodiments of the present invention are directed to a methocJ of
`
`making a pharmaceutical composition comprising:
`
`(a)
`
`forming a granule comprising a calcium receptor-active compound
`
`and at least one pharmaceutically acceptable excipient as disclosed herein; and
`
`(b)
`
`controlling the particle size of the granule such that from about 50%
`
`to about 125% of a target amount of calcium receptor-active compound is released from
`
`the composition no later than about 30 minutes from the start of a test in 0.05 N HCI
`
`according to a dissolution test conducted in a USP 2 apparatus at a temperature of 37
`
`0c ±0.5 °C, and a rotation speed of 75 r.p.m.
`
`[047] Further embodiments of the present invention are directed to a method
`
`of making a pharmaceutical composition comprising:
`
`(b)
`
`forming a granule comprising a calcium receptor-active compound
`
`and at least one pharmaceutically acceptable excipient as disclosed herein; and
`
`(b)
`
`controlling the particle size of the granule such that from about 50%
`
`to about 125% of a target amount of calcium receptor-active compound is released from
`
`the composition no later than about 30 minutes from the start of a test in 0.05 N HCI
`
`according to a dissolution test conducted in a USP 2 apparatus at a temperature of
`
`about 37 °C, and a rotation speed of about 75 r.p.m.
`
`[048] The granule can be formed

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