SOLID COMPOSITES OF A CALCIUM RECEPTOR-ACTIVE COMPOUND
Cross-Reference to Related Applications
[0001] This application claims the benefit of U.S. Serial No. 60/841,689, filed
September 1,2006, which is incorporated herein by reference in its entirety.
Field of the Invention
[0002] The invention encompasses solid composites of the calcium receptor-active
compounds, processes for preparing the solid composites, immediate and controlled-release pharmaceutical formulations comprising the solid composites, and methods of treatment therewith.
Background of the Invention
[0003] Cinacalcet hydrochloride has the chemical name (R)-N-[l-(l-naphthyl)ethyl]-
3-[3-(trifluoromethyl)phenyl]propan-l-amine hydrochloride and is reported to have the following chemical structure:
(Structure Removed)
[0004] Cinacalcet hydrochloride is a calcium receptor-active compound that is
currently marketed under the trade name SENSIPAR® for the treatment of hyperparathyroidism in patients with chronic kidney disease on hemodialysis. Physicians' Desk Reference, 60th ed. (2006), pp. 603-605. The dosing of SENSIPAR® is expressed in terms of amount of cinacalcet free base, (R)-N-[l-(l-naphthyl)ethyl]-3-[3-(trifluoromethyl) phenyl]propan-l-amine, present in the tablet, rather than in terms of the amount of the hydrochloride salt. See id
[0005] Cinacalcet is a solid that is understood to be slightly soluble in water and very
soluble in some organic solvents, such as methanol and ethanol. For example, U.S. Patent Application No. 10/937,870, published as U.S. Patent Application Publication No. 2005/0147669 ("the '669 publication") reports that cinacalcet has a solubility in water of less than about 1 µg/ml at neutral pH. The '669 publication, p. 1,12. Further, the '669
publication reports that 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. Id.
[0006] Compounds having low water solubility typically demonstrate a low rate of
dissolution and, often, low bioavailability. See, e.g., Ansel, et al.. Pharmaceutical Dosage
Forms and Delivery Methods (6th ed., 1995), pp. 105, 108.
[0007] The '669 publication addresses the poor water solubility of cinacalcet by
providing pharmaceutical compositions comprising cinacalcet in the form of particles with a
D50 of less than or equal to about 50 µm. '669 publication, pp. 2-3, 26. The '669
publication discloses that these pharmaceutical compositions have a dissolution profile that
results in about 50 percent to about 125 percent of a target amount of cinacalcet being
released from the composition no later than about 30 minutes from the start of a dissolution
test that is conducted in 0.05 N HCl in a U.S.P. type 2 apparatus at a temperature of
37°C±0.5°C at a rotation speed of 75 r.p.m. Id. at p. 5, 61.
[0008] However, this technique of increasing the solubility in water, and, thus, the
bioavailability, of cinacalcet requires micronization of the cinacalcet to achieve the iesired
particle size distribution. Micronization poses a health risk during production on ar industrial
scale. Thus, there is a need for a method to reduce the health risks involved with nicronized
powders of active ingredients, such as cinacalcet, while maintaining an adequate dissolution
profile, and, thus, bioavailability.
[0009] There is also a need for a method of releasing drugs, such as cinacalcet, at a
position in the gastrointestinal tract where the pH is such that they are most soluble.
Summary of the Invention
[0010] The present invention is directed to a composition, comprising a solid
composite of cinacalcet in intimate association with at least one carrier. In preferred embodiments of the invention, the composition is the solid composite. In preferred embodiments, at least about 85 percent of the cinacalcet is in intimate association with the at least one carrier, at least about 85 percent of the cinacalcet is not in particulate form, at least about 85 percent of the cinacalcet is not in crystalline form, and/or the solid composite is a solid solution. Preferably, substantially all of the cinacalcet is in solution in the solid solution.
[0011] In preferred embodiments of the invention, the carrier comprises a polymer,
such as povidone, poloxamer, hydroxypropyl methylcellulose, polyethylene glycol.
colovidone, copolymers of methacrylate, copolymers of methacrylic acid, and mixtures
thereof Preferably, the polymer is povidone or a copolymer of methacrylic acid. In
preferred embodiments the carrier comprises a sugar or sugar derivative, such as sucrose,
mannitol, lactose, maltitol, sorbitol, xylitol, sucralose, and mixtures thereof.
[0012] In preferred embodiments of the invention, the solid composite is a particulate
having an average particle size of more than about 100 µm, preferably, from about 100 to
about 600 µm. In preferred embodiments of the invention, the composite has a drug to carrier
weight ratio of from about 1:0.5 to about 1:10, preferably, from about 1:2 to about 1:6.
[0013] In preferred embodiments of the invention, the composition is a
pharmaceutical formulation, comprising from about 10 percent to about 40 percent by weight of cinacalcet. In preferred embodiments of the invention, the composition further comprises about 0.5 percent to about 5 percent by weight relative to the total weight of the formulation of at least one glidant or lubricant and/or about 1 percent to about 6 percent by weight of at least one coating material.
[0014] In preferred embodiments of the invention, the composition is an immediate
release composition from which at least about 80 percent of the cinacalcet is released within about 30 minutes in 0.05 N HCI in a U.S.P. type 2 apparatus at a temperature of about 37°C and at a rotation speed of about 75 r.p.m
[0015] In preferred embodiments of the invention, the composition is a controlled
release pharmaceutical formulation, and wherein, when the formulation is exposed to a solution of 0.05 N HCl in a U.S.P. type 2 apparatus at a temperature of about 37°C and at a rotation speed of about 75 r.p.m. for about 30 minutes, followed by addition of a buffer in an amount sufficient to neutralize the solution and continued exposure to the neutralized solution, more than about 50 percent of the cinacalcet is released from the formulation within about the first 30 minutes of exposure, and not less than about 70 percent of the calcium receptor-active compound is released from the formulation within about the first 90 minutes of exposure. Preferably, at least about 50 percent of the cinacalcet is released within about the first 60 minutes of exposure, more preferably, not less than about 80 percent of the cinacalcet is released from the formulation during about the first 90 minutes of exposure, and, most preferably, not less than about 90 percent of the cinacalcet is released from the formulation during about the first 90 minutes of exposure.
[0016] In preferred embodiments of the invention, the invention is directed to a
method for preparing a solid composite, comprising combining cinacalcet, at least one carrier, and at least one liquid solvent to form a solution, and removing the solvent to obtain a
said composite of the cinacalcet and the at least one carrier. In preferred embodiments of the invention, the solid composite is a solid solution. In preferred embodiments of the invention, the carrier is selected from the group consisting of povidone, poloxamer, hydroxypropyl methylcellulose, polyethylene glycol, copovidone, copolymers of methacrylate, and copolymers of methacrylic acid, preferably at least one of lower aliphatic alcohols and C3-8 ketones. In preferred embodiments of the invention, the solvent is removed by evaporation, preferably under vacuum, in a fluidized bed drier, or by spray drying. In preferred embodiments of the invention, the composition is the cinacalcet and at least one carrier are dissolved in an organic or inorganic solvent to form the solution, a supercritical fluid is added to induce precipitation of a mixture of the cinacalcet and the carrier, and the solvent and the supercritical fluid are removed by evaporation. In preferred embodiments of the invention, the solvent is a supercritical fluid, preferably, at least one of carbon dioxide, water, methane, ethane, propane, ethylene, propylene, methanol, ethanol, and acetone, and, more preferably, carbon dioxide. In preferred embodiments of the invention, the supercritical fluid is removed by evaporation.
[0017] In preferred embodiments, the invention the invention is directed to a method
for preparing the solid composite, comprising combining cinacalcet and at least one carrier to form a mixture, heating the mixture to a temperature at which both the cinacalcet and the carrier melt to form a fusion product, and cooling the fusion product in a manner that does not allow crystallization of the cinacalcet out of the fusion product, in preferred embodiments of the invention, the method further comprises combining the cinacalcet and at least one carrier to form a mixture, heating the mixture to control its viscosity, and feeding the heated mixture through a hot melt extrusion system.
[0018] In preferred embodiments the invention, is directed to a method of treatment,
comprising administering an effective amount of a preferred composition of the invention to a mammal, such as a human.
Brief Description of the Drawings
[0019] Figure 1 illustrates an XRD difiractogram of cinacalcet raw material.
[0020] Figure 2 illustrates an XRD diffractogram of PVP K-30.
[0021] Figure 3 illustrates an XRD diffractogram of a 1:2 solid solution of cinacalcet
with PVP K-30.
[0022] Figure 4 illustrates an XRD diffractogram of EUDRAGIT® L-100-55.
[0023] Figure 5 illustrates an XRD diffractogram of a 1:2 solid solution of cinacalcet
with EUDRAGIT L-100-55.
[0024] Figure 6 illustrates a DSC thermogram of cinacalcet raw material.
[0025] Figure 7 illustrates a DSC thermogram of PVP K-30.
[0026] Figure 8 illustrates a DSC thermogram of a 1:2 solid solution of cinacalcet
with PVP K-30.
[0027] Figure 9 illustrates a DSC thermogram of EUDRAGIT® L-100-55.
[0028] Figure 10 illustrates a DSC thermogram of a 1:2 solid solution of cinacalcet
with EUDRAGIT L-100-55.
[0029] Figure 11 illustrates a dissolution profile of a solid solution of cinacalcet with
PVP (P-00709), of a physical mixture of cinacalcet with PVP (1:3), and of SENSIPAR® in
0.05 N HCl, USP apparatus 2, 37°C, 75 r.p.m.; and
[0030] Figure 12 illustrates a dissolution profile of a solid solution of cinacalcet with
PVP (P-00709), of a physical mixture of cinacalcet with PVP (1:3), and of SENSIPAR® in 6
g/L NaH2PO4, pH 6, 0.15% SLS, USP apparatus 2, 37°C, 75 r.p.m.
[0031] Figure 13 illustrates a dissolution profile of a 1:2 solid solution of cinacalcet
with EUDRAGIT® snd of SENSIPAR® in 0.05 N HCl, U.S.P. type 2 apparatus, 37°C, 75
r.p.m.; and in 6 g/L NaH2PO4, pH 6, 0.15% SLS, USP apparatus 2, 37°C, 75 r.p.m.
[0032] Figure 4 illustrates a dissolution profile of formulations of solid solutions of
cinacalcet in a simulated gastrointestinal environment.
Detailed Description of the Invention
[0033] As used herein, unless otherwise defined, "cinacalcet" means cinacalcet free
base and pharmaceutically acceptable salts and solvates thereof Preferably, "cinacalcet" means cinacalcet hydrochloride.
[0034] As used herein, unless otherwise defined, "intimate association" or "intimately
associated," when used with respect to a mixture of cinacalcet and at least one carrier, means that the carrier(s) and the cinacalcet interact on the molecular level, there being no easily detectable separate cinacalcet phase. A non-intimate association is, for example, a powder blend, or a compressed powder blend, as it is possible to discern between different phases using, for example, electron microscopy. Another example of a non-intimate association is an emulsion, where separate phases co-exist in the solution, and may be visualized using, for example, a light microscope. An example for an intimate associations is a liquid solution.
where there is no way to separate between the carrier and the solute by physical means, or to observe a phase of solute within the carrier.
[0035] As used herein, unless otherwise defined, "free drug" means solid particles
consisting essentially of cinacalcet that are not in intimate association with a carrier.
[0036] As used herein, unless otherwise defined, "non-crystalline" and "not in
crystalline form" means a material comprising cinacalcet that does not produce an X-ray powder diffraction pattern having peaks characteristic of crystalline cinacalcet, and that does not exhibit a discemable endotherm in differential scanning calorimetry using heating rates of 2 to 20 degrees per minute.
[0037] As used herein, unless otherwise defined, a "solid solution" means a solid,
homogenous mixture of at least two components (e.g. cinacalcet and a carrier) wherein the components are interspersed on a molecular level In solid solutions, the individual physical properties related to the crystalline structure of the components present in lesser amounts, commonly referred to as the solutes, are lost. Presence of the solutes can be detected spectroscopically or by measure of the colligative properties of the solid solution. Even in the solid solutions, some portion of the cinacalcet may come out of solution or remain undissolved in the carrier without departing from the scope of the invention. However, in the solid solutions, at least about 85 percent of the clnacalcet is in solution in the solid solution. Preferably, substantially all, and, most preferably, all, of the cinacalcet is in solution in the solid solution.
[0038] As used herein, the term "supercritical fluid" refers to substances at a
temperature and pressure above their thermodynamic critical point. A supercritical fluid
solution is a solution in which a supercritical fluid is the solvent. Such a substance has
unique properties, such as the ability to diffuse through a solid like a gas, and dissolve solids
like a liquid. Additionally, it is possible to change the density of such a substance by subtle
changes in temperature and/or pressure. Useful supercritical fluids are, for example, carbon
dioxide, water, methane, ethane, propane, ethylene, propylene, methanol, ethanol, and
acetone. Preferably, the supercritical fluid is selected from the group comprising carbon
dioxide, water, and ethanol. More preferably, the supercritical fluid is carbon dioxide.
[0039] As used herein, unless otherwise defined, "effective" and "therapeutically
effective" amount of a drug or pharmacologically active agent means an amount of the drug or agent that is nontoxic and sufficient to provide the desired effect, e.g., treatment of secondary hyperparathyroidism.
[0040] As used herein, unless otherwise defined, "treating," "treated," and
"treatment" means at least one of the following: reduction in severity and/or frequency of
symptoms, elimination of symptoms and/or underlying cause, prevention of the occurrence of
symptoms and/or their underlying cause, or improvement or remediation of damage.
[0041 ] The invention encompasses a solid composite comprising cinacalcet and at
least one carrier, wherein at least about 85 percent of the cinacalcet is in intimate association
with the carrier.
[0042] Preferably, the solid composite is a solid solution. Preferably, substantially all
of the cinacalcet is in solution in the solid solution. More preferably, all of the cinacalcet is
in solution in the solid solution.
[0043] Preferably, the solid composite is particulate and has an average particle size
larger than about 100 µm, more preferably between 100 and 600µm.
[0044] Preferably at least about 85 percent of the cinacalcet in the solid composite is
not in crystalline form. More preferably, the cinacalcet in the solid composite has no
detectable crystalline cinacalcet.
[0045] The carrier may be any pharmaceutically acceptable inert solid carrier known
to one of skill in the art, including, for example, sugars and polymers.
[0045] Preferably, the carrier is a hydrophilic polymer or a polymer precenting a pH
dependent solubility profile in aqueous media. The hydrophilic polymer may be selected
from the group consisting of povidone, poloxamer, hydroxypropyl methylcellulose,
polyethylene glycol, copovidone, and amino alkyl methacrylate type A NF.
[0047] The polymer presenting a pH dependent solubility profile in aqueous media
may be selected from copolymers of methacrylic acid. More preferably, the carrier is
povidone or a copolymer of methacrylic acid. Although hydroxypropyl methyl cellulose
phthalate, polymethylacrylate, and hydroxypropyl cellulose may be used in the present
invention as carriers, other carriers, particularly povidone and copolymers of methacrylic
acid, are more preferred in the present invention.
[0048] Preferably, the carrier is present in an amount sufficient to maintain at least
about 85 percent of the cinacalcet in intimate association with, and, more preferably, in solid
solution in, the carrier. One of skill in the art can easily determine by routine
experimentation such an amount of carrier. Typically, the drug-to-carrier weight ratio in the
solid composites is within a range of about 1:0.5 to about 1:10, preferably about 1:2 to about
1:6.
[0049] The invention further encompasses a process for preparing the solid composite
comprising: combining cinacalcet, at least one carrier, and at least one liquid solvent to form
a solution; and removing the liquid solvent to obtain the solid composite.
[0050] The cinacalcet may be prepared by any means known to one of skill in the art.
It will be appreciated that while preferably at least about 85 percent of the cinacalcet in the
solid composites of the present invention is not in crystalline form, cinacalcet in any form
(e.g. crystalline or amorphous) may be used to prepare the solid composites.
[0051] Liquid solvents suitable for preparing the solid composite include organic
solvents capable of dissolving at least about 85 percent of the cinacalcet and substantially all of the carrier. Preferably, the liquid solvent is capable of dissolving at least about 85 percent of the cinacalcet and at least about 85 percent of the carrier. More preferably, the liquid solvent is capable of dissolving substantially all of the cinacalcet and carrier. Most preferably, the liquid solvent is capable of dissolving all of the cinacalcet and carrier. Preferably, the liquid solvent is one in which cinacalcet has a solubility of at least about 5 mg of cinacalcet per 1 ml solvent at 25°C.
[0052] Examples of suitable liquid solvents include, but are not limited to, at least one
of lower aliphatic alcohols and C3 -8 ketones. "Lower aliphatic alcohols" as used herein means organic compounds having the general structure R-OH, wherein R is a linear or branched C1-6 alkyl group. Preferred lower aliphatic alcohols include methanol, ethanol, isopropyl alcohol ("IPA"), and butanol. Preferred C3-8 ketones include acetone, methylisobutyl ketone ("MIBK") and methylethyl ketone ("MEK"). More preferred liquid solvents are ethanol, acetone, isopropyl alcohol, and mixtures thereof. Most preferably, the liquid solvent is ethanol or mostly ethanol in combination with one or more of the above solvents.
[0053] The combining step may include mixing the liquid solvent with cinacalcet and
at least one carrier in any order. The cinacalcet, carrier, and liquid solvent may be mixed using any suitable mixing method known to one of skill in the art, such as by using magnetic stirrers, mixer stirrers, shakers, or sonification.
[0054] Preferably, at least about 85 percent of the cinacalcet and a majority of the
carrier are in solution in the at least one liquid solvent. More preferably, at least about 85 percent of the cinacalcet and about 85 percent of the carrier are in solution in the at least one liquid solvent. Even more preferably, substantially all of the cinacalcet and carrier are in
solution in the at least one solvent. In particularly preferred embodiments, all of the
cinacalcet and carrier are in solution in the at least one solvent.
[0055] The step of removing the liquid solvent may be performed by any method
known to one of skill in the art. Preferably, the liquid solvent is removed by evaporation.
More preferably, the liquid solvent is removed by evaporation under vacuum, by fluidized
bed drying, or by spray-drying. "Spray-drying" broadly refers to processes involving
breaking up liquid mixtures into small droplets (atomization) and rapidly removing solvent
from the mixture. In a typical spray-drying apparatus, there is a strong driving force for
evaporation of solvent from the droplets, which may be provided by providing a heated
drying gas. Spray-drying processes and equipment are described in Perry's Chemical
Engineer's Handbook, pp. 20-54 to 20-57 (6th ed. 1984). The obtained solid composite may
optionally be further dried.
[0056] Preferably, the obtained solid composite is in the form of a solid solution,
wherein substantially all, most preferably all, of the cinacalcet is in solid solution in the
carrier.
[0057] Optionally, the process further comprises the addition of at least one
pharmaceutically acceptable excipient. Suitable pharmaceutically acceptable excipients
include, for example, surfactants such as sodium lauryl sulfate,
[0058] The pharmaceutically acceptable excipient may be combined with the
cinacalcet, carrier, and liquid solvent in step a), or may be added to the obtained solid
composite of step b) after removal of the liquid solvent.
[0059] Alternatively, the pharmaceutically acceptable excipient may be added during
removal of the liquid solvent in step b), by, for example, spraying the solution containing the
cinacaclet, carrier and solvent onto a fluidized bed of the excipient while drying. As a result,
the solid composite will be formed on the excipient. In some cases, this process will prove
advantageous because it provides a solid composite with greater surface area, which can aid
in dissolution in aqueous media upon administration to a patient.
[0060] The invention further encompasses a process for preparing the solid composite
using supercritical fluid technology. The process may comprise: dissolving cinacalcet and at
least one carrier in a supercritical fluid; and removing the supercritical fluid by evaporation.
Preferably, the evaporation is accomplished under reduced pressure or by adjusting the
temperature of the solution to a temperature at which the supercritical fluid becomes a gas.
Alternatively, the process may comprise: dissolving cinacalcet and at least one carrier in an
organic or inorganic solvent to form a liquid solution; adding a supercritical fluid
(uti-solvent) to induce precipitation of a mixture of the cinacalcet and the carrier; and
removing the solvent and the supercritical fluid by evaporation. Preferably, the evaporation
is accomplished under reduced pressure or by adjusting the temperature of the solution.
[0061] The invention further encompasses a process for preparing the solid composite
comprising: combining cinacalcet and at least one carrier to form a mixture; heating the
mixture to a temperature at which both the cinacalcet and the carrier melt to form a fusion
product; and cooling the fusion product in a manner that does not allow for re-crystallization
of the cinacalcet out of the fusion product.
[0062] The invention further encompasses a process for preparing the solid composite
comprising: combining cinacalcet and at least one carrier to form a mixture, heating the
mixture to control its viscosity; and feeding the heated mixture through a hot melt extrusion
system.
[0063] It would be appreciated by one of skill in the art that the above-described solid
composites reduce the health risks involved in handling active pharmaceutical ingredients in
particulate form and specifically micronized particles.
[0064] In addition, because of the enhanced solubility of the solid composites relativ'e
to the active ingredient alone or in a physical mixture with the carrier, as described below, ,
larger particle size of the solid composite particles may be used in the formulation withou'
having an adverse effect on the dissolution profile of the cinacalcet.
[0065] Another method to improve the safety of the products is by using a bi-modal
distribution of particle sizes of the cinacalcet, wherein the population of large particle sizes,
above 70µm, avoids the need for micronization of the cinacalcet, and thus reduces production
of hazardous dust. The population of small particle sizes, smaller than about 5 µm,
preferably less than 2 µm, and even more preferably smaller than 1 µm, is prepared using a
high pressure homogenizer. This method involves micronizing the particles in a liquid
medium, thus avoiding production and dispersion of dust particles of the active ingredient.
[0066] The invention further encompasses pharmaceutical formulations comprising a
solid composite comprising cinacalcet and at least one carrier, and at least one
pharmaceutically acceptable excipient.
[0067] The pharmaceutical formulation may contain additional cinacalcet, meaning
free drug cinacalcet in addition to the cinacalcet in the solid composite, thus providing the
ability to manipulate the dissolution characteristics of the formulation.
[0068] The amount of the solid composite used in the pharmaceutical formulation is
preferably an amount that provides a therapeutically effective amount of cinacalcet. It will be
reciated that the amount of solid composite used will differ according to the cinacalcet: carrier ratio in the particles.
[0069] Preferably, the pharmaceutical formulation comprises: (a) from about 10
percent to about 40 percent by weight of a calcium receptor-active compound, such as cinacalcet; (b) from about 10 percent to about 50 percent of at least one binder, which may serve as the carrier or "solid solvent" of the solid composite; (c) from about 15 percent to about 45 percent by weight of at least one diluent; and (e) from about 10 percent to about 40 percent of at least one disintegrant; wherein the percentage by weight is relative to the total weight of the formulation.
[0070] The formulation may further comprise about 0.5 percent to about 5 percent by
weight relative to the total weight of the formulation of at least one glidant or lubricant and about 1 percent to 6 percent by weight of at least one coating material. It is understood by one of skill in the art that one or more inactiveintigredients can act in more than one capacity for example; the same material may function as both a diluent and a disintegrant. The formulation may further comprise a surfactant.
[0071] The pharmaceutical formulation can be processed into, for example, a unit
dosage form. In particular, the pharmaceutic al lormulation can be formulated into oral solid dosage forms such as capsules, tablets, or gel caps.
[0072] The solid composites and pharmaceutical formulation including them
preferably allow for the rapid absorption and onset of the calcium receptor-active compound cinacalcet in a mammal.
[0073] The invention further encompasses an immediate release formulation of a
calcium receptor-active compound, such as cinacalcet, wherein at least about 80 percent of the calcium receptor-active compound is released from the formulation within about 30 minutes in 0.05 N HCl in a U.S.P. type 2 apparatus at a temperature of about 37°C and at a rotation speed of about 75 r.p.m.
[0074] The invention fiirther encompasses a controlled release formulation of a
calcium receptor-active compound, such as cinacalcet, wherein the majority of the calcium receptor-active compound is released in the intestine, where the pH is slightly acidic to neutral, rather than in the stomach, where the pH is acidic.
[0075] When the controlled release formulation is exposed to a simulated gastric
environment for a period of about 30 minutes, followed by exposure to a simulated intestinal environment, more than about 50 percent of the calcium receptor-active compound is released from the formulation during about the first 30 minutes of exposure and not less than
about 70 percent of the calcium receptor-active compound is released from the formulation
during about the first 90 minutes of exposure.
[0076] Preferably, at least about 50 percent of the calcium receptor-active compound
is released within about the first 60 minutes of exposure, i.e., 30 minutes after the change in
environment.
[0077] Preferably, not less than about 80 percent of the calcium receptor-active
compound is released from the formulation during about the first 90 nunutes of exposure.
More preferably, not less than about 90 percent of the calcium receptor-active compound is
released from the formulation during about the first 90 minutes of exposure.
[0078] The simulated gastric environment is 800 ml of 0.05 N HCl in a U.S.P. type 2
apparatus at a temperature of about 37°C and at a rotation speed of about 75 r.p.m. The
simulated intestinal environment is 6 g/L NaH2pO4, pH 6, 0.15% sodium !auryl sulfate in a
U.S.P. type 2 apparatus at a temperature of about 37°C and at a rotation speed of about 75
r.p.m. These environments simulate the passage of the dosage forms through the
gastrointestinal pathway.
[0079] The invention further encompasses a method of treatment comprising
administering the pharmaceutical formulation to a mammal. Preferably, the mammal is a
buman. Preferably, the pharmaceutical formulation comprises cinacalcet and is administered
to treat secondary hyperparathyroidism, which is the approved use for SEN SEP AR®. As
discussed above, the method of "treating" secondary hyperparathyroidism described herein
encompasses both prevention of the disorder in a predisposed individual and treatment of the
disorder in a clinically symptomatic individual.
[0080] The amount of calcium receptor-active compound administered and the dosing
regimen used, will depend on the particular drug selected, the age and general condition of
the subject being treated, the severity of the subject's condition, and the judgment of the
prescribing physician.
[0081 ] Having described the invention with reference to certain preferred
embodiments, other embodiments will become apparent to one skilled in the art from
consideration of the specification. The invention is further defined by reference to the
following examples. It will be apparent to those skilled in the art that many modifications,
both to materials and methods, may be practiced without departing from the scope of the
invention.
Examples
[0082] In the following examples, a rotary evaporator equipped with a vacuum pump,
was used to remove the solvent from the liquid solutions. The liquid solutions were heated to about 50°C using a water bath during rotary evaporation.
[0083] In the following examples, dissolution profiles were determined in a
dissolution vessel using a U.S.P. type 2 apparatus (paddles) in a simulated gastrointestinal environment under conditions described in Table 1. See U.S. Pharamcopeia, pp. 2155-2156 (26th ed. 2003). Samples were analyzed on-line by a UV detector.
Table 1. Dissolution conditions.

(Table Removed)
Example 1: Cinacalcet Solid Solutions with Povidone
a) Cinacalcet HCl: povidone in 1:2 weight ratio
[0084] 1 g of cinacalcet HCl per 2 g of povidone (PVP K-30) were ground together
using a mortar and pestle. The resulting mixture was completely dissolved in ethanol in a round-bottom flask. The ethanol was then removed from the solution using a rotary evaporator under vacuum, and heating the solution to 50°C, until dry solid flakes formed on the flask. The dry solid was then collected.
[0085] X-ray diffraction ("XRD") and differential scanning calorimetry ("DSC")
were performed on the dry solid and compared to the XRD and DSC for the cinacalcet and povidone alone. The XRD and DSC for the dry solid are illustrated in Figures 3 and 8, respectively. The XRD and DSC for the cinacalcet are illustrated in Figures 1 and 6, respectively. The XRD and DSC for the povidone are illustrated in Figures 2 and 7, respectively.
b) Cinacalcet HCl: povidone in 1:3 weight ratio
[0086] 1 g of cinacalcet HCl per 3 g of povidone (PVP K-30) were ground together
using a mortar and pestle. The resulting mixture was completely dissolved in ethanol in a round-bottom flask. The ethanol was then removed from the solution using a rotary
carporator under vacuum, and heating the solution to 50°C, until dry solid flakes formed on the flask.
[0087] A sample of the dry solid was collected and its dissolution profile determined
according to the conditions in Table 1. The dissolution profile of the solid was compared with the dissolution profile of a commercial version of cinacalcet HCl tablets (SENSIPAR®, 30 mg) and with a simple mixture of cinacalcet HCl (average length of the needle-shaped crystals was ~20 micron) with povidone. The results of dissolution testing are illustrated in Figures 11 and 12.
[0088] The amount of cinacalcet dissolved at the 30 minute time point demonstrates
that cinacalcet in a solid solution form has a solubility greater than cinacalcet raw material in a physical mixture with lactose or starch. The percent of cinacalcet dissolved after 5 minutes demonstrates the greater dissolution rate of cinacalcet in a solid solution form, as compared with both SENSIPAR® and a physical mixture of particles with an average length of 20 µm with starch.
Example 2: Cinacalcet Solid Solution with EUDRAGIT® L 100-55 in 1:2 Weight Ratio
[0089] 1g of cinacalcet was dissolved in 10 ml of ethanol to form a first solution. 2 g
of EUDRAGIT® L-100-55 was dissolved in about 15 ml of ethanol to form a second solution.
The two solutions were then combined, and ethanol was evaporated from the combined
solution using a rotary evaporator to obtain dry solid flakes. The dry solid was then
collected.
[0090] XRD and DSC were performed on the dry solid and compared to the XRD and
DSC for the cinacalcet and EUDRAGIT® L-100-55 alone. The XRD and DSC for the dry
solid are illustrated in Figures 5 and 10, respectively. The XRD and DSC for the cinacalcet
are illustrated in Figures 1 and 6, respectively. The XRD and DSC for the EUDRAGIT®
L-100-55 are illustrated in Figures 4 and 9, respectively.
[0091] A sample of the dry solid was collected and its dissolution profile determined
according to the conditions in Table 1. The dissolution profile of the solid was compared
with the dissolution profile of a commercial version of cinacalcet HCl tablets (SENSIPAR ,
30 mg) in a simulated gastrointestinal environment. The results of dissolution testing are
shown in Figure 13.
[0092] As illustrated in Figure 13, in the simulated gastric environment of 0.05N HCl,
cinacalcet was released more quickly from the SENSIPAR® tablets than from the solid
solution of cinacalcet and EUDRAGIT® L-100-55. For example, about 95 percent of the
cinacalcet was released from the SENSIPAR® tablets during about the first 30 minutes of exposure to the 0.05N HCl, while only about 15 percent of the cinacalcet was released from the solid solution of cinacalcet and EUDRAGIT® L-100-55 the under the same conditions. In the more neutral simulated intestinal environment of buffer at pH 6, however, about 95
percent of the cinacalcet was released from both the SENSIPAR® tablets and from the solid solution of cinacalcet and EUDRAGIT® L-100-55 during about the first 30 minutes of exposure.
Example 3: Formulation including cinacalcet solid solution with povidone
[0093] Prepare a formulation of cinacalcet, with a target amount of 90 mg of
cinacalcet per tablet, having the following composition:
Table 2. Cinacalcet formulation prepared in Example 3.

(Table Removed)
[0094] Combine and mix cinacalcet HCl, povidone, microcrystalline cellulose,
crospovidone, and sodium carboxymethylcellulose. Then, add magnesium stearate to the mixture and press the mixture into tablets. Measure the dissolution profile of the tablets according to the procedure described in Example 6.
Example 4: Formulation including cinacalcet solid solution with povidone
[0095] A solid solution of cinacalcet with povidone (1:2 weight ratio) prepared
according to Example la was passed through a sieve equipped with a 30 mesh (-600 micron
aperture) screen on top of a 50 mesh screen (300 micron aperture).
[0096] The sample, which passed the 50 mesh screen, is estimated to have a particle
size distribution wherein approximately 100 percent of the particles are less than 300 microns
Size and an average particle size around 100µm. This sample was used to prepare a pharmaceutical formulation of cinacalcet, with a target amount of 90 mg of cinacalcet per tablet, having the following composition:
Table 3. Cinacalcet formulation prepared in Example 4.

(Table Removed)
[0097] The solid solution of cinacalcet with povidone was dry-mixed with
microcrystalline cellulose, crospovidone and sodium carboxymethylcellulose, followed by granulation with a 20 percent to 40 percent. ethanolic solution of EUDRAGIT L-100-55. The resulting granulate was then dried in a vacuum oven at 50°C. The granulate was then passed through an 8 mesh sieve (~2.4mm), followed by an 18 mesh sieve (~lmm). Magnesium stearate was then added to the granulate to form a lubricated blend, and the final lubricated blend was compressed into tablets using a manual press.
Example 5: Formulation including cinacalcet solid solution with EUDRAGIT L-100-55
[0098] A solid solution of cinacalcet in EUDRAGIT® L-100-55 (1:2 weight ratio)
prepared according to Example 2 was passed through a sieve equipped with a 30 mesh screen on top of a 50 mesh screen.
a) Cinacalcet HC1:EUDRAGIT® L-100-55 with Average Particle Size of-400 µm
[0099] The solid composite collected on top of the 50 mesh screen (having a particle
size between 300µm and 600µm) was used in a pharmaceutical formulation (average particle size estimated to be -400 µm).
b) Cinacalcet HCl:EUDRAGIT® L-100-55 with Average Particle Size of-100 µm
[00100] The solid composite which passed through the 50 mesh screen (having a
particle size distribution wherein 100 percent of the particles are less than 300|im in size) was
used in another pharmaceutical formulation (average particle size estimated to be -l0µm).
[00101] Each solid composite (5a and 5b) was used to prepare a pharmaceutical
formulation of cinacalcet, with a target amount of 90 mg of cinacalcet per tablet, having the following composition:
Table 4. Cinacalcet formulation prepared in Example 5.

(Table Removed)
[00102] The solid solution of cinacalcet with EUDRAGIT® L-100-55 was mixed with
microcrystalline cellulose, crospovidone, and sodium carboxymethylcellulose, followed by granulation. Magnesium stearate was then added to the granulate to form a lubricated blend, and the final lubricated blend was compressed into tablets using a manual press.
Example 6: Dissolution profile of tablet formulations of cinacalcet
[00103] The dissolution profiles of the formulations prepared in Examples 4 and 5
were measured with a U.S.P. type 2 apparatus at a temperature of about 37°C, and at a
rotation speed of about 75 r.p.m. The dissolution profiles are described in Table 5 and
illustrated in Figure 14. Percentage of dissolution was adjusted to change in medium volume.
[00104] The dissolution profile was measured in a complex medium designed to
imitate physiological conditions in the gastrointestinal tract. During the first 30 minutes of dissolution the medium was 800 ml 0.05N HCl, which was then neutralized with 120 ml of a
netralizing buffer (50 g/1 NaH2PO4 adjusted to pH 6, to which were added 35 ml/1 10N NaOH, and 11.25 g/1 SLS) for a final volume of 920 ml.
Table 5. Dissolution profiles for the formulations prepared in Examples 4, 5a, and 5b.

(Table Removed)
[00105] As illustrated in Table 5, in the simulated gastric environment of 0.05N HCl,
cinacalcet was released more quickly from the SENSIPAR® tablets than from the solid solution of cinacalcet and EUDRAGIT® L-100-55. 91.3 percent of the cinacalcet was released from the SENSIPAR® tablets during the first 30 minutes of exposure to the 0.05N HCl, while only 3.5 to 19.8 percent of the cinacalcet was released from the solid solution of cinacalcet and povidone the under the same conditions. In the more neutral simulated intestinal envirorument of buffer at pH 6, however, 90 percent to 97.7 percent of the cinacalcet was released from both the SENSIPAR® tablets and the solid solution of cinacalcet and povidone during the first 150 minutes. Thus, the solid solution allows for the controlled release of cinacalcet in an environment more neutral than the gastric environment.
Example 7: Method for improving the safety of cinacalcet production - Preparation of sub-micron scale population of particles
[00106] A suspension of cinacalcet hydrochloride in water is placed in a Microfluidics
M-1 10Y Laboratory Microfluidizer Processor, and processed until the D50 particle size is less
than about 1 µm. This population is mixed with a population of particles having a D50 of more than about 100 µm, so that the overall particle size D50 is larger than about 70 µm. This mixture is then used in a formulation, and the dissolution profile is examined.
Example 8: Preparation of cinacalcet solid solutions using supercritical fluid technology
[00107] A solution of cinacalcet in absolute ethanol, also containing PVP K-30, is
introduced in the particle formation vessel of a supercritical apparatus containing supercritical carbon dioxide at an appropriate flow through the inner nozzle passage. Supercritical carbon dioxide is introduced at an appropriate flow through the outer nozzle passage. A solid fluffy substance is formed, and the pressure lowered to remove the carbon dioxide and ethanol.

What is Claimed is:
1. A composition, comprising a solid composite of cinacalcet in intimate association with at least one carrier.
2. The composition of claim 1, wherein the composition is the solid composite.
3. The composition of either of claims 1 and 2, wherein at least about 85 percent of the cinacalcet is in intimate association with the at least one carrier.
4. The composition of any of claims 1 to 3, wherein at least about 85 percent of the cinacalcet is not in particulate form.
5 The composition of any of claims 1 to 4, wherein at least about 85 percent of
the cinecalcet is not in crystalline form.
6. The composition of any of claims 1 to 5, wherein the solid composition; is a solid solutic r
7- The composition of claim 6, wherein substantially all of the cinae. is in solut min the solid solution.
8. The composition of any of claims 1 to 7, wherein the carrier compries a polymer.
9. The composition of claim 8, wherein the polymer is selected from the group consisting of povidone, poloxamer, hydroxypropyl methylcellulose, polyethylene glycol, copovidone, copolymers of methacrylate, copolymers of methacrylic acid, and mixtures thereof.
10. The composition of claim 8, wherein the polymer is povidone or a copolymer of methacrylic acid.
11. The composition of any of claims 1 to 7, wherein the carrier comprises a sugar or a sugar derivative.
12. The composition of claim 11, wherein the sugar or sugar derivative is selected from the group consisting of sucrose, mannitol, lactose, maltitol, sorbitol, xylitol, sucralose, and mixtures thereof.
13. The composition of any of claims 1 to 12, wherein the solid composite is a particulate having an average particle size of more than about 100 µm.
14. The composition of any of claims 1 to 12, wherein the average particle size is from about 100 to about 600 µm.
15. The composition of any of claims 1 to 14, wherein composite has a drug-to-carrier weight ratio of from about 1:0.5 to about 1:10.
16. The composition of any of claims 1 to 14, wherein composite has a drug-to-carrier weight ratio of from about 1:2 to about 1:6.
17. The composition of any of claims 1 to 16, wherein the composition is a pharmaceutical formulation, comprising from about 10 percent to about 40 percent by weight of cinacalcet.
18. The composition of claim 17, further comprising about 0.5 percent to about 5 percent by weight relative to the total weight of the formulation of at least one glidant or lubricant and/or about 1 percent to about 6 percent by weight of at least one coating material.
19. The composition of either of claims 17 and 18, wherein the composition is an immediate release composition from which at least about 80 percent of the cinacalcet is released within about 30 minutes in 0.05 N HCl in a U.S.P. type 2 apparatus at a temperature of about 37°C and at a rotation speed of about 75 r.p.m.
20. The composition of either of claims 17 and 18, wherein the composition is a controlled release pharmaceutical formulation, and wherein, when the formulation is exposed to a solution of 0.05 N HCl in a U.S.P. type 2 apparatus at a temperature of about 37°C and at a rotation speed of about 75 r.p.m. for about 30 minutes, followed by addition of a buffer in an amount sufficient to neutralize the solution and continued exposure to the neutralized solution, more than about 50 percent of the cinacalcet is released from the formulation within
about the first 30 minutes of exposure, and not less than about 70 percent of the calcium receptor-active compound is released from the formulation within about the first 90 minutes of exposure.
21. The composition of claim 20 wherein at least about 50 percent of the cinacalcet is released within about the first 60 minutes of exposure.
22. The composition of claim 20, wherein not less than about 80 percent of the cinacalcet is released from the formulation during about the first 90 minutes of exposure.
23. The composition of claim 20, wherein not less than about 90 percent of the cinacalcet is released from the formulation during about the first 90 minutes of exposure.
24. A method for preparing a solid composite, comprisig:
combining cinacalcet, at least one carrier, and at least one liquid solvent to form a
solution; and
removing the solvent to obtain a solid composite of the cinacalcet and the at least one
carrier.
25. The method of claim 24, wherein the solid composite is a solid solution.
26 The method of either of claims 24 and 26, wherein the carrier is selected from; the group consisting of povidone, poloxamer, hydroxypropyl methylcellulose, polyethylene glycol, copovidone, copolymers of methacrylate, and copolymers of methacrylic acid.
27 The method of any of claims 24 to .26, wherein the solvent is selected from at least one of lower aliphatic alcohols and C3-8 ketones.
28 method of any of claims 24 to 26, further comprising removing solvent by evaporation.
29. The method of claim 28, wherein the solvent is evaporated under vacuum, in a fluidized bed drier, or by spray drying.
30 The method of any of claims 24to 26, Wther comprising dissolving the cinacalcet and at least one carrier in an organic or inorganic solvent to form the solution;
adding a supercritical fluid to induce precipitation of a mixture of the cinacalcet and the carrier; and
removing the solvent and the supercritical fluid by evaporation.
31. The method of claim 24, wherein the solvent is a supercritical fluid.
32. The method of either of claims 30 'and 31; wherein the supercritical fluid is
selected from the group consisting of carbon dioxide, water, methane, ethane, propane,
ethylene, propylene, methanol, ethanol, and acetone.
33. The method of claim 32, wherein the supercritical fluid is carbon dioxide.
34 The method of either of claims 30 and 31, further comprising removing the
supercritical fluid by reducing pressure.
35. A method for preparing a solid composite comprising:
combining cinacalcet and at least one carrier to form a mixture;
heating the mixture to a temperature at which both the cinacalcet and the carrier mel; to form a fusion product; and
cooling the, fusion product in a manner that does not allow crystallization of the cinacalcet out of the fusion product.
36. The method of claim 35 further comprising combining the cinacalcet and at least one carrier to form a mixture;
heating the mixture to control its viscosity; and feeding the heated mixture through a hot melt extrusion system.