U.S. patent application number 16/227882 was filed with the patent office on 2019-04-25 for rapid dissolution formulation of a calcium receptor-active compound.
The applicant listed for this patent is Amgen Inc.. Invention is credited to Francisco J. Alvarez, Tzuchi R. Ju, Glen Gary Lawrence, Hung-Ren H. Lin.
Application Number | 20190117592 16/227882 |
Document ID | / |
Family ID | 34434844 |
Filed Date | 2019-04-25 |
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United States Patent
Application |
20190117592 |
Kind Code |
A1 |
Lawrence; Glen Gary ; et
al. |
April 25, 2019 |
RAPID DISSOLUTION FORMULATION OF A CALCIUM RECEPTOR-ACTIVE
COMPOUND
Abstract
The present invention relates to a pharmaceutical composition
comprising a therapeutically effective amount of a calcium
receptor-active compound and at least one pharmaceutically
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.
Inventors: |
Lawrence; Glen Gary;
(Thousand Oaks, CA) ; Alvarez; Francisco J.;
(Newbury Park, CA) ; Lin; Hung-Ren H.; (Oak Park,
CA) ; Ju; Tzuchi R.; (Vernon Hills, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Amgen Inc. |
Thousand Oaks |
CA |
US |
|
|
Family ID: |
34434844 |
Appl. No.: |
16/227882 |
Filed: |
December 20, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15966812 |
Apr 30, 2018 |
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16227882 |
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15163356 |
May 24, 2016 |
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15966812 |
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12942646 |
Nov 9, 2010 |
9375405 |
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15163356 |
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10937870 |
Sep 10, 2004 |
7829595 |
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12942646 |
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60502219 |
Sep 12, 2003 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 5/00 20180101; A61P
43/00 20180101; A61P 3/14 20180101; A61K 9/2866 20130101; A61K
31/137 20130101; A61P 5/20 20180101; A61K 31/135 20130101; A61K
9/2077 20130101; A61P 5/18 20180101; A61K 31/00 20130101; A61P 3/00
20180101 |
International
Class: |
A61K 31/135 20060101
A61K031/135; A61K 31/00 20060101 A61K031/00; A61K 9/20 20060101
A61K009/20; A61K 31/137 20060101 A61K031/137; A61K 9/28 20060101
A61K009/28 |
Claims
1. A pharmaceutical composition comprising an effective dosage
amount of a calcium receptor-active compound and at least one
pharmaceutically acceptable excipient, wherein at least one dosage
unit of the composition has a dissolution profile in 0.05 N HCl,
measured according to a dissolution test conducted in a USP 2
apparatus at a temperature of about 37.degree. 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.-118. (canceled)
Description
[0001] This application claims the benefit of priority of U.S.
Provisional Patent Application No. 60/502,219, filed Sep. 12,
2003.
[0002] Calcium receptor-active compounds are known in the art. One
example of a calcium receptor-active compound is cinacalcet 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 of less than about 1
.mu.g/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.
[0003] 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.
[0004] 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.
[0005] The invention also provides a method of manufacturing the
pharmaceutical composition to achieve the desired dissolution
profile, as well as a 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.
[0006] 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 HCl, 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.degree.
C..+-.0.5.degree. 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.
[0007] 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 HCl, 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.degree.
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.
[0008] 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.
[0009] 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 Ca.sup.2+, 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.
[0010] 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. 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 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.
[0011] In certain embodiments, the calcium receptor-active
compounds are chosen from compounds of formula (I) and
pharmaceutically acceptable salts thereof
##STR00001##
[0012] wherein:
[0013] X.sub.1 and X.sub.2, which may be identical or different,
are each a radical chosen from CH.sub.3, CH.sub.3O,
CH.sub.3CH.sub.2O, Br, Cl, F, CF.sub.3, CHF.sub.2, CH.sub.2F,
CF.sub.3O, CH.sub.3S, OH, CH.sub.2OH, CONH.sub.2, CN, NO.sub.2,
CH.sub.3CH.sub.2, propyl, isopropyl, butyl, isobutyl, t-butyl,
acetoxy, and acetyl radicals, or two of X.sub.1 may together form
an entity chosen from fused cycloaliphatic rings, fused aromatic
rings, and a methylene dioxy radical, or two of X.sub.2 may
together form an entity chosen from fused cycloaliphatic rings,
fused aromatic rings, and a methylene dioxy radical; provided that
X.sub.2 is not a 3-t-butyl radical;
[0014] n ranges from 0 to 5;
[0015] m ranges from 1 to 5; and
[0016] 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 thiodihydroindotyl groups, and 2-, 3-,
and 4-piperid(in)yl groups; and the stereoisomers thereof.
[0017] Calcium receptor-active compounds useful in the present
invention 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, alginate,
citrate, aspartate, benzoate, benzenesulfonate, bisulfate,
butyrate, camphorate, camphorsulfonate, digluconate,
cyclopentanepropionate, dodecylsulfate, ethanesulfonate,
giucoheptanoate, glycerophosphate, hemisulfate, heptanoate,
hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide,
2-hydroxy-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.
[0018] 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 HCl, and cinacalcet methanesulfonate. The cinacalcet HCl
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.
[0019] The therapeutically effective amount of the calcium
receptor-active compound in the compositions disclosed herein
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 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 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,
about 180 mg, about 210 mg, about 240 mg, about 300 mg, or about
360 mg.
[0020] 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.
[0021] As used herein, an "effective dosage amount" is an amount
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 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 at least one calcium
receptor-activecompound is administered by administering a portion
of the composition.
[0022] 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.
[0023] 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.
[0024] In some embodiments of the present invention, the
compositions disclosed herein comprise a therapeutically effective
amount of cinacalcet HCl 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 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.
[0025] 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.
[0026] The cinacalcet HCl 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 D.sub.50 of,
for example, less than or equal to about 50 .mu.m. As used herein,
the "particle D.sub.50" is the particle size of the active
pharmaceutical ingredient at the 50.sup.th percentile of a particle
size distribution. According to certain embodiments of the
invention, the active pharmaceutical ingredient in the formulation
has a particle D.sub.50 that is less than the granule D.sub.50 of
the formulation, discussed in detail below.
[0027] The particle D.sub.50 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 invention, the
particle D.sub.50 of the cinacalcet HCl 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.
[0028] Specifically, the particle size distribution of the active
pharmaceutical ingredient, for example, cinacalcet HCl, can be
determined according to the following procedure. The following
instrument conditions in a Malvern Mastersizer particle size
analyzer are specified in its software:
TABLE-US-00001 Refractive Index Sample 1.630 Absorptive Index 0.1
Refractive Index Dispersant 1.375 Analysis model General purpose
spherical Calculation sensitivity Enhanced Measurement snaps and
time 20,000 snaps over 20 seconds Background snaps and time 20,000
snaps over 20 seconds Stir speed 1750 rpm
[0029] While stirring, about 170 mL of a dispersion of about 0.1%
sorbitan trioleate (for example Span 85.RTM., 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.
[0030] The entire suspension containing the cinacalcet HCl 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-B, the dispersant-B is
drained, and the sampling unit is refilled with about 170 mL of
dispersant-B. 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.
[0031] The Obscuration, D(v,0.1), D(v,0.5), D(v,0.9) values are
then calculated from these measurements. The average, standard
deviation, and relative standard deviation (RSD) of the D(v,0.1),
D(v,0.5), 0(v,0.9) values is also calculated. The RSD (%) is
calculated as follows:
R S D ( % ) = 100 X [ i = I N ( X i - X _ ) 2 N = 1 ] 1 2
##EQU00001##
[0032] where X, is an individual measurement in a set of N
measurements and is the arithmetic mean of the set.
[0033] 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 D.sub.50 ranging from about 50
.mu.m to about 150 .mu.m, such as from about 80 .mu.m to about 130
.mu.m. As defined herein, the "granule D.sub.50" is the particle
size of the composition at the 50.sup.th percentile of a particle
size distribution. The granule D.sub.50 can readily be determined
by one of ordinary skill in the art using sieve analysis techniques
Specifically, the granule D.sub.50 is determined according to the
following procedure.
[0034] 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 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 ##EQU00002##
[0035] 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 .mu.m is 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-US-00002 TABLE 1 Particle size range of Hole size of retained
material Median particle each screen on each screen size of the
Screens (.mu.m) (.mu.m) screen (.mu.m) 40 mesh 425 425-1410 918 60
mesh 250 250-424 337 80 mesh 180 180-249 215 100 mesh 150 150-179
165 140 mesh 106 106-149 128 200 mesh 75 75-105 90 325 mesh 45
45-74 60 Bottom pan 0 1-44 23
[0036] 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 10 percentile
(D.sub.10), 50-percentile (D.sub.50), and 90-percentile (D.sub.90)
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 50-percentile (D.sub.50) is interpolated by,
D 50 ( m ) = [ ( 50 - X n ) * d n + 1 + ( X n + 1 - 50 ) * d n ] (
X n + 1 - X n ) ##EQU00003##
[0037] where,
[0038] X.sub.n=cumulative quantity of sample that is just below
50-percentile (in %);
[0039] d.sub.n=mean of the particle size range from the sieve
screen where X occurs (in mm);
[0040] X.sub.n+1=next cumulative quantity of sample that is above
50-percentile (in %).
[0041] d.sub.n+1=mean of the particle size range from the sieve
screen where 4.sub.+1 occurs (in mm).
[0042] 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.
[0043] 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.
[0044] The at least one pharmaceutically acceptable excipient can
be chosen from, for example, diluents such as starch,
microcrystalline cellulose, dicalcium 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.
[0045] 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.
[0046] 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 about
5% to about 25%, or from about 5% to about 10% by weight relative
to the total weight of the composition.
[0047] 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.
[0048] Certain compositions can comprise:
[0049] (a) from about 10% to about 40% by weight of a calcium
receptor-active compound chosen from cinacalcet HCl and cinacalcet
methanesulfonate;
[0050] (b) from about 45% to about 85% by weight of at least one
diluent;
[0051] (c) from about 1% to about 5% by weight of at least one
binder; and
[0052] (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,
[0053] In another embodiment, the composition disclosed herein
comprises:
[0054] (a) from about 10% to about 40% by weight of cinacalcet
HCl;
[0055] (b) from about 5% to about 10% by weight of starch;
[0056] (c) from about 40% to about 75% by weight of
microcrystalline cellulose;
[0057] (d) from about 1% to about 5% by weight of povidone; and
[0058] (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,
[0059] 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.
[0060] 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.
[0061] 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 HCl in a U.S.P. 2 apparatus at a
temperature of 37.degree. C..+-.0.5.degree. 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 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.degree.
C..+-.0.5.degree. 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.
[0062] 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.degree. 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.
[0063] 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.
[0064] 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 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 than 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%.
[0065] 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-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 mast 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.
[0066] Other embodiments of the present invention are directed to a
method of making a pharmaceutical composition comprising:
[0067] (a) forming a granule comprising a calcium receptor-active
compound and at least one pharmaceutically acceptable excipient as
disclosed herein; and
[0068] (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 HCl
according to a dissolution test conducted in a USP 2 apparatus at a
temperature of 37.+-.0.5.degree. C., and a rotation speed of 75
r.p.m.
[0069] Further embodiments of the present invention are directed to
a method of making a pharmaceutical composition comprising:
[0070] (b) forming a granule comprising a calcium receptor-active
compound and at least one pharmaceutically acceptable excipient as
disclosed herein; and
[0071] (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 HCl
according to a dissolution test conducted in a USP 2 apparatus at a
temperature of about 37.degree. C., and a rotation speed of about
75 r.p.m.
[0072] The granule can be formed by any known process, such as high
wet shear granulation, low wet shear granulation, fluid bed
granulation, rotary granulation, extrusion-spheronization, dry
granulation, roller compaction, and the like.
[0073] The particle size of the granule of the composition can be
controlled by various factors. In certain embodiments of the
present invention, the particle size of the granule of the
composition can be controlled by the amount of water added to the
materials present in a granulator. For example, a desired particle
size of the granule can be achieved when the granulator has a
volume ranging from about 1 L to about 1200 1, such as from about
65 L to about 1200 L, or from about 300 L to about 800 L, and the
amount of water added ranges from about 20% to about 40%, such as
from about 30% to about 35%, relative to the amount of dry powders
present in the granulator to form the granules.
[0074] The granulator's impeller tip speed can also affect the
particle size of the granules. In some embodiments, the impeller
tip speed, measured in meters per second (m/s), can range from
about 5 m/s to about 10 m/s, such as from about 7 m/s to about 9
m/s.
[0075] Other embodiments of the present invention are directed to a
method of making a pharmaceutical composition comprising
[0076] (a) forming a composition comprising a therapeutically
effective amount of particles of a calcium receptor-active compound
and at least one pharmaceutically acceptable excipient as disclosed
herein; and
[0077] (b) controlling the particle size of the calcium
receptor-active compound such that from about 50% to about 125% of
a target amount of the 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 HCl according to a dissolution test conducted
in a USP 2 apparatus at a temperature37.degree. C. .degree. C., and
a rotation speed of 75 r.p.m.
[0078] Additional embodiments of the present invention are directed
to a method of making a pharmaceutical composition comprising
[0079] (a) forming a composition comprising a therapeutically
effective amount of particles of a calcium receptor-active compound
and at least one pharmaceutically acceptable excipient as disclosed
herein: and
[0080] (b) controlling the particle size of the calcium
receptor-active compound such that from about 50% to about 125% of
a target amount of the 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 HCl according to a dissolution test conducted
in a USP 2 apparatus at a temperature of about 37.degree. C., and a
rotation speed of about 75 r.p.m.
[0081] The size of the particles is controlled during the
production of the active pharmaceutical ingredient, for example, by
use of a milling step, or a controlled crystallization process. For
example, the active pharmaceutical ingredient can be milled using a
stainless steel hammer mill with 5 mm screen and 12 hammers forward
at a mill speed of 8100.+-.100 rpm, with the feed speed is set at
90.+-.10 rpm.
[0082] Yet other embodiments of the present invention are directed
to a method for the treatment of a disease or disorder that can be
treated by altering a subject's calcium receptor activity. In some
embodiments, a method for the treatment of a disease chosen from
hyperparathyroidism, such as primary hyperparathyroidism and
secondary hyperparathyroidism, hyperphosphonia, hypercalcemia, and
elevated calcium-phosphorus product comprises administering to a
patient, such as human, an effective dosage amount of a
pharmaceutical composition comprising a calcium receptor-active
compound and at least one pharmaceutically acceptable excipient as
disclosed herein, wherein the composition has a dissolution profile
in 0.05 N HCl, measured, according to a dissolution test conducted
in a USP 2 apparatus at a temperature of 37.degree.
C..+-.0.5.degree. 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 in no later than about 30 minutes from the start of the
test.
[0083] A further embodiment of the present invention is directed to
a method for the treatment of a disease chosen from
hyperparathyroidism, hyperphosphonia, hypercalcemia, and elevated
calcium-phosphorus product comprises administering to a patient,
such as human, an effective dosage amount of a pharmaceutical
composition comprising a calcium receptor-active compound and at
least one pharmaceutically acceptable excipient as disclosed
herein, wherein the composition has a dissolution profile in 0.05 N
HCl, measured according to a dissolution test conducted in a USP 2
apparatus at a temperature of about 37.degree. 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 in no later than about
30 minutes from the start of the test.
[0084] Reference will now be made to the following examples which
are not intended to limit the invention. To the contrary, it will
be appreciated that various alternatives, modifications, and
equivalents may be included within the spirit and scrape of the
invention.
EXAMPLES
[0085] Three pharmaceutical formulations with target amounts of
30mg, 60mg, and 90 mg active pharmaceutical ingredient with the
following components were prepared:
TABLE-US-00003 30 mg 60 mg 90 mg Tablet Tablet Tablet Weight %
Amount Amount Amount (w/w) (mg) (mg) (mg) Cinacalcet HCl 18.367
33.06 66.12 99.18 Pregelatinized starch (Starch 33.378 60.08 120.16
180.24 1500) Microcrystalline cellulose 6.678 12.02 24.04 36.06
(Avicel PH102) Povidone (Plasdone K29/32) 2.044 3.68 7.36 11.04
Crospovidone (Polyplasdone 1.233 2.22 4.44 6.66 XL) Purified
Water.sup.1 -- -- -- -- Microcrystalline cellulose 34.300 61.74
123.48 185.22 (Avicel PH102) Magnesium stearate 0.500 0.90 1.80
2.70 Colloidal silicon dioxide 0.500 0.90 1.80 2.70 (Colloidal
anhydrous silica) (Cab-O-Sil M5P) Crospovidone (Polyplasdone 3.000
5.40 10.80 16.20 XL) Core Tablet 100.000 180.00 360.00 540.00
Purified Water.sup.1 -- -- -- -- Opadry .RTM. II (colored 4.000
7.20 14.40 21.60 film former) Purified Water.sup.1 -- -- -- --
Opadry .RTM. Clear (clear film 1.500 2.70 5.40 8.10 former)
Carnauba Wax Powder 0.010 0.018 0.036 0.054 Opacode .RTM. Ink
(Black).sup.2 -- -- -- -- .sup.1The purified Water was removed
during processing. .sup.2Trace quantities of ink were applied to
the coated tablet.
[0086] The 30-, 60- and 90-mg tablets were made according to the
process flow diagram depicted below.
TABLE-US-00004 Critical Process Equipment Components Unit Operation
Controls PMA 800L purified water and granulation.sup.b water level,
granulator intra-granular impeller speed, components.sup.a water
spray rate .dwnarw. Comil (In-line) wet mill .dwnarw. Aeromatic MP6
fluid bed dry .dwnarw. Quadro Mill 196S dry mill (Comil) .dwnarw.
Gallay tote blender extra-granular pre-blend (650 L)
components.sup.c .dwnarw. Gallay tote blender combine granulation
final blend blend time (1000 L) mix A and B and extra-granular mix
.dwnarw. Gallay tote blender magnesium stearate lubrication (1000
L) .dwnarw. Unipress 27 compression.sup.d tablet press speed,
tablet weight, thickness, hardness, friability, disintegration time
.dwnarw. 3 X Vector Hi-Coater pan color coat (Opadry .RTM. II),
film coating and spray rate, (3 spray guns) delivery clear coat
(Opadry .RTM. wax exhaust temperature (peristaltic pump) Clear),
carnauba Wax .dwnarw. Ackley ink-based offset Opacode .RTM. black
print printer .sup.acinacalcet HCl, pregelatinized starch,
microcrystalline cellulose, povidone, and crospovidone .sup.bThe
granulation step to dry milling step is repeated to generate 2
bowls of wet granulation (Mix A and B). .sup.cExtra-granular
components are microcrystalline cellulose, crospovidone, and
colloidal silicon dioxide .sup.dTooling dimension is dependent on
tablet size and strength, (30 mg; 0.2372'' .times. 0.3800'' oval
shape plain, 60 mg; 0.3000'' .times. 0.4800'' modified oval (double
radius) plain, 90 mg; 0.3420'' .times. 0.5480'' modified oval
(double radius) plain)
[0087] The wet granulation process was conducted in a PMA 800L
high-shear granulator with water serving as the granulation fluid.
The cinacalcet HCl and the intra-granulation excipients
(pregelatinized starch, microcrystalline cellulose, povidone, and
crospovidone) were dry-mixed for 1 to 2 minutes with an impeller
speed set point at 116.+-.10 rpm, followed by granulation with
30.0% to 36.0% wfw water (based on intra-granular lot size; target
was 34.9% wlw) with an impeller speed set point at 116.+-.10 rpm
and at a slow or fast chopper speed (target was slow speed). During
the granulation process water was delivered at 9.8 .+-.0.5
kg/min.
[0088] Following granulation, the mixture was wet-milled using an
in-line Comil equipped with a 0.375'' (0.953 cm) opening screen and
an impeller speed set point at 1400.+-.50 rpm. The mixture was then
discharged into a fluid-bed dryer.
[0089] After completion of the wet-milling process, the granulation
mixture was dried in an Aeromatic MP6 fluid bed dryer with an inlet
temperature set point at 70.degree..+-.5.degree. C. When the outlet
temperature reached 37.degree. C. to 41.degree. C., samples were
taken to determine moisture levels by loss on drying (LOD). The
granules were dried until the average moisture levels reached 1.0%
to 2.5%.
[0090] The dried granulation mixture was milled through a Ouadro MM
196S (Comil) equipped with a 0.055'' (0.140 cm) opening screen at
an impeller speed of 1650.+-.50 rpm into a 1000L Gallay tote.
[0091] Except for magnesium stearate, the extra-granular excipients
were blended in a 650 L Gallay tote blender for 7.+-.1 minutes at
12.+-.1 rpm. This mixture was further blended with the dry-milled
granulation in a 1000 L Galley tote blender for 15.+-.5 minutes at
12.+-.1 rpm, and then for 6.+-.1 minutes at 12.+-.1 rpm after
magnesium stearate was added for lubrication.
[0092] The final lubricated blend was compressed into tablets
containing 30-, 60-, or 90 mg of the free base equivalent of active
cinacalcet HCl using a Unipress 27 tablet press set to a speed of
2000.+-.300 tablets per minute and equipped with a force feeder.
Throughout the compression operation, individual tablet weights
(target weights of 180, 360, and 540 mg for 30-, 60-, and 90-mg
tablets, respectively), the average weight of 10 tablets, tablet
hardness and thickness were monitored at pre-determined
intervals.
[0093] The color-coating suspension and clear-coating solution were
prepared by slowly adding either the Opadry.RTM. II (green) or
Opadry.RTM. Clear into purified water while mixing until uniform
(.gtoreq.45 minutes). The color suspension and clear solution
deaerated for .gtoreq.45 minutes before the spraying process began,
and were used within a pre-determined time limit.
[0094] Each lot was film-coated with color and clear coats in a
Vector Hi-Coater 48'' pan. The color-coating suspension was applied
onto a moving core tablet bed (pan speed=4 to 7 rpm) and a spray
rate of 250.+-.50 grams per minute per 3 guns. The distance between
the spray guns and the tablet bed was approximately 8'' (20 cm) to
11'' (28 cm), and the air volume was 600.+-.200 ft.sup.3 per minute
(17.1.+-.5.7 m.sup.3 per minute) with a pan pressure differential
maintained between -0.1'' (-0.25 cm) to -0.3'' (-0.76 cm) of water.
Supply air temperature was adjusted to 80.+-.10.degree. C. to
maintain an exhaust temperature of 41.+-.3.degree. C.
[0095] When the clear-coating application was completed, the heater
and the air supply was turned off and the wax was spread evenly
over the moving tablet bed (after it reached .gtoreq.37.degree. C.)
with a pan speed of 4 to 7 rpm. The tablets were rotated for 5.+-.1
minutes, and after the supply air and exhaust fan were turned on,
the tablets were rotated for an additional 5.+-.1 minutes with a
pan speed of 4 to 7 rpm and supply air of 600.+-.200 ft.sup.3 per
minute (17.1.+-.5.7 m.sup.3 per minute). The pan was jogged until
the tablet bed temperature reached .ltoreq.30.degree. C.
[0096] An Ackley ink-based offset printer was used to produce
2-sided printed tablets.
[0097] The dissolution profile of the three formulations were
measured according the dissolution protocol described in the USP
26/NF 21, chapter 711 using a USP 2 apparatus at a temperature of
about 37.degree. C., and at a rotation speed of about 75 r.p.m. The
dissolution profile of the formulations in which at least about 75%
of the cinacalcet HCl was released from the composition in no later
than about 30 minutes from the start of the test is set forth in
Table 2.
TABLE-US-00005 TABLE 2 Time (min) 30 mg Tablet 60 mg Tablet 90 mg
Tablet 15 85.3 81.9 80.8 30 95.2 93.8 93.4 45 97.7 97.7 97.9 60
98.7 98.8 99.8
[0098] The content uniformity of the three formulations were
measured in accordance with USP 26/NF 21, chapter 905, described in
detail above. The content uniformity and for each of the three
formulations is set forth in Table 3.
TABLE-US-00006 TABLE 3 30 mg Tablet 60 mg Tablet 90 mg Tablet Mean
(10 % Mean % Mean % Container tablets) RSD (10 tablets) RSD (10
tablets) RSD 1 (beg.) 98.5 0.8 96.7 1.6 99.7 1.2 5 98.8 0.8 98.5
0.8 100.7 0.9 11 98.5 0.6 98.3 1.0 99.9 0.7 16 98.3 0.8 97.6 1.3
99.9 0.5 22 98.3 1.0 96.3 1.8 100.7 0.9 end 98.0 0.6 95.8 1.9 99.3
0.8
* * * * *