WO2016066611A1

WO2016066611A1 - Pharmaceutical compositions containing cinacalcet and methods for their preparation and use

Info

Publication number: WO2016066611A1
Application number: PCT/EP2015/074808
Authority: WO
Inventors: Pietro TREVISO; Prashant Agarwal; Hywel Williams; Eduardo JULE
Original assignee: Capsugel Belgium N.V.
Priority date: 2014-10-31
Filing date: 2015-10-27
Publication date: 2016-05-06

Abstract

The instant disclosure provides pharmaceutical compositions containing cinacalcet and methods for their preparation and use.

Description

PHARMACEUTICAL COMPOSITIONS CONTAINING CINACALCET AND METHODS

FOR THEIR PREPARATION AND USE

[0001] The present disclosure relates to oral pharmaceutical compositions containing the drug cinacalcet, or acceptable salts thereof, and methods for their preparation and use.

BACKGROUND

[0002] Cinacalcet is a drug designed to lower parathyroid hormone levels (PTH) in the body. It works directly at the parathyroid gland by increasing the sensitivity of calcium-sensing receptors to extracellular calcium, which, in turn, suppresses PTH secretion.

[0003] The drug cinacalcet has the following chemical structure:

[0005] Sensipar® tablets containing the hydrochloride salt form of cinacalcet base was developed by Amgen, and approved in 2004 by the FDA for the treatment of secondary Hyperparathyroidism (HPT), hypercalcemia in patients with parathyroid carcinoma, and severe hypercalcemia in patients with primary HPT who are unable to undergo parathyroidectomy. [0006] Since cinacalcet works in the parathyroid gland (Kruse AE et al. Nephrol. Dial. Transplant. (2005) 20 (7): 131 1 -1314), it needs to be absorbed from the

gastrointestinal (Gl) tract following oral administration in order to be effective. A critical step in drug absorption from the small intestine (often the primary site of drug

absorption) is achieving a high dissolved drug concentration in Gl fluids - a high drug concentration will promote drug permeation across the intestinal epithelium either passively or actively (via transporters) before drug enters the systemic circulation. It can therefore be understood that low drug solubility in the Gl fluids can be limiting to drug absorption, and in these instances, there is a risk that the level of drug absorption is highly variable between patients and also affected by the presence of food in the Gl tract. In the latter case, the presence of food can improve drug absorption by several different mechanisms, such as improving drug solubilization by promoting the release of natural solubilizers in the small intestine (i.e., bile salts and phospholipids) and by slowing Gl transit time, which results in greater time for a drug to dissolve in the stomach.

[0007] Due to its relatively low solubility (<1 μg/mL in water), cinacalcet suffers from a sub-linear increase in absorption with increasing dose and increased absorption when administered with meals (Padhi D & Harris R Clin Pharmacokinet 2009; 48 (5): 303-31 1 ). Specifically, it has been found that when Sensipar® is coadministered with a high fat meal in healthy subjects, cinacalcet Cmax and AUC°° values increase by 82% and 68%, respectively, when compared to fasted state values. Also, when administered with a low fat meal, Cmax and AUC°° values increased by 65% and 50%, respectively. These findings confirm that food will significantly affect cinacalcet absorption, and that meal composition will introduce variability in this level of absorption.

[0008] As cinacalcet shows a positive food effect (as described above), the product label states that Sensipar® should be taken with food or shortly after a meal, to achieve a maximal level of drug absorption using this tablet dosage form (Sensipar®

(cinacalcet) tablets: US prescribing information, URL:

http://pi.amgen.com/united_states/sensipar/sensipar_pi_hcp_english.pdf).

[0009] Requiring patients to administer their daily medication with meals to boost drug absorption does however introduce compliance issues, particularly if patients are also taking other medications that, for example, require administration on an empty stomach. In addition, there is also the fact that the type of meal will also affect how much cinacalcet is absorbed, creating an additional source of variability.

[0010] There is therefore a benefit in developing a formulation that improves cinacalcet bioavailability in the fasted state in turn reducing the food effect so that patients requiring cinacalcet can take their medication independent of meals. This will result in better patient compliance, reduced absorption variability, in turn resulting in the possibility of improved therapeutic outcomes.

SUMMARY

[001 1] The present disclosure generally relates to oral pharmaceutical compositions containing cinacalcet or an acceptable salt form thereof, and methods for their preparation and use. More specifically, formulation approaches to address solubility limited absorption of cinacalcet are disclosed. [0012] The pharmaceutical compositions described herein comprise cinacalcet, a lipid component of either a medium-chain glyceride (MCG) or long-chain glyceride (LCG), or a propylene glycol fatty acid ester, or a suitable blend of these lipid

components, and a non-ionic surfactant having a HLB of at least 6.

[0013] In one embodiment, the lipid component is chosen from the group consisting of mono-, di- and triglycerides of 6-12 carbon fatty acids, and blends thereof.

[0014] In another embodiment, the lipid component is chosen from the group consisting of mono-, di- and tri caprylic and capric glycerides, and blends thereof.

[0015] In another embodiment, the lipid component is chosen from the group consisting of mono-, di- and triglycerides of 14 - 22 carbon fatty acids, and blends thereof.

[0016] In another embodiment, the lipid component is chosen from the group consisting of propylene glycol monocaprylate, propylene glycol monolaurate, propylene glycol dicaprate, propylene glycol dilaurate or propylene glycol heptanoate.

[0017] In another embodiment, the non-ionic surfactant has a HLB of at least 8.

[0018] In another embodiment, the non-ionic surfactant is chosen from the group consisting of polyoxyethylated mono- and di-fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylated mono- and di-fatty acid esters, glycerol macrogolglycerides, DL-a-tocopheryl polyethylene glycol succinate, polyoxyethylene-polyoxypropylene copolymers, polyglycerol esters of fatty acids, and ethoxylated fatty alcohols.

[0019] In another embodiment, the non-ionic surfactant is selected from the group consisting of polyoxyethylated mono- and di-fatty acid esters of castor oil or hydrogenated castor oil, and polyethylene glycol ester of caprylic/capric glycerides, and sorbitan monolaurate, and blends thereof.

[0020] In another embodiment, the ratio of lipid component to non-ionic surfactant is at least 0.25:1.

[0021] In another embodiment, the ratio of lipid component to non-ionic surfactant is at least 0.5: 1.

[0022] In another embodiment, the ratio of lipid component to non-ionic surfactant is at least 1 :1.

[0023] In another embodiment, the cinacalcet is completely dissolved in the formulation.

[0024] In another embodiment, the cinacalcet is partly dispersed in the

formulation, forming a suspension.

[0025] In another embodiment, the cinacalcet is present in an amount of at least 27.2 mg/g (2.72% w/w).

[0026] In another embodiment, the cinacalcet is present in an amount of at least 54.4 mg/g (5.44 % w/w).

[0027] In another embodiment, the cinacalcet is present in the formulation in an amount of at least 108.8 mg/g (10.8% w/w).

[0028] In another embodiment, the cinacalcet is in the form of a hydrochloride salt, or another pharmaceutically acceptable salt form.

[0029] In another embodiment, the cinacalcet is in the form of a free base.

[0030] In another embodiment, the formulation contains between 5-75% w/w lipid component and 25-75% non-ionic surfactant. [0031] In another embodiment, the formulation contains between 20-75% w/w lipid component and 20-50% non-ionic surfactant.

[0032] In another embodiment, the formulation optionally contains a

pharmaceutically acceptable cosolvent, where said cosolvent is propylene glycol, polyethylene glycol, isorpropyl myristate, triacetin, glycerol, ethanol, or diethylene glycol monoethyl ether.

[0033] In another embodiment, the formulation containing cinacalcet is delivered in pharmaceutically acceptable dosage form including capsules, sachets and bottles.

[0034] In another embodiment, the formulation containing cinacalcet is delivered in the form of a capsule.

[0035] One advantage of the instant disclosure is to provide a formulation that has a reduced food effect relative to prior art cinacalcet formulations, by improving compound solubility and dissolution rate in the Gl tract, and / or by enhancing uptake of the compound into the lymphatic system following oral administration.

[0036] Other advantages include increased bioavailability and potential dose reduction of the active ingredient and the dosage formulation as a whole, compared to conventional forms.

[0037] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the claimed subject matter.

DETAILED DESCRIPTION

[0038] Definitions [0039] As used herein, reference to an element by the indefinite article "a" or "an" does not exclude the possibility that more than one of the elements is present, unless the context clearly requires that there is one and only one of the elements. The indefinite article "a" or "an" thus usually means "at least one." The disclosure of numerical ranges should be understood as referring to each discrete point within the range, inclusive of endpoints, unless otherwise noted. The term "about" as used in the disclosure of numerical ranges indicates that deviation from the stated value is acceptable to the extent that the deviation is the result of measurement variability and/or yields a product of the same or similar properties.

[0040] As used herein, "w/w %" and "wt%" means by weight as a percentage of the total weight of the composition.

[0041] The pharmaceutical compositions here are lipid-based formulations intended to be administered orally either in a hard capsule or soft gelatin capsule. In the broadest sense, the lipid-based formulations comprise cinacalcet, a lipid component, a nonionic surfactant and optionally a cosolvent in which the drug is completely or partly dissolved. Thus, the formulation may either be in the form of a solution or a

suspension. The formulations may be administered as single unit dosage forms (i.e., liquid or semi-solid fills) filled into hard or soft capsules, sachets or bottles.

[0042] The compound cinacalcet means both the free base form of the drug as well as pharmaceutically acceptable salts, including acid addition salts such as those containing sulfate, hydrochloride, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate, cyclohexylsulfamate and quinate. (See e.g., PCT/US92/03736, hereby incorporated by reference herein.)

[0043] Cinacalcet has the following properties:

[0044] In one aspect, the instant disclosure provides a lipid formulation comprising a lipid component and a non-ionic surfactant. The lipid component may consist of a medium-chain glyceride, a long-chain glyceride, a propylene glycol fatty acid ester or a mixture of these excipients.

[0045] Medium-chain glycerides (MCGs) contain 6 -12 carbon fatty acid esters of glycerol. The MCG may be a mono-, di- or triglyceride. Preferred MCGs are caprylic and capric mono- and diglycerides, and blends thereof, including glyceryl monocaprylate, glyceryl dicaprylate, glyceryl monocaprate and glyceryl dicaprate. Examples are sold under the trade names Imwitor® and Capmul®. Other MCGs include caprylic/capric triglycerides, sold under trade names such as Miglyol™, Labrafac® and Captex®, glycerol esters of lauric acid, such as glyceryl monolaurate, glyceryl dilaurate and glycerol trilaurate, and polyglycerol esters of caprylic acid, sold under the trade names such as Caprol®.

[0046] Long-chain glycerides (LCGs) contain 14 - 22 carbon fatty acid esters of glycerol. The LCG may be a mono-, di- or triglyceride. Examples of LCGs include glyceryl behenate, glyceryl monolinoleate, glycerol monooleate, glycerol monostearate, glycerol monopalmitate, glyceryl dilinoleate, glycerol diooleate, glycerol distearate, glycerol dipalmitate, glyceryl trilinoleate, glyceryl triolein, glyceryl tristearate, glyceryl tripalmitate, sold under trade names such as Peceol™, Maisine™ 35-1 , Geleol™ and Capmul®. Other examples of LCGs include simple oils including, but not limited to the following: almond oil, canola oil, castor oil, cod liver oil, corn oil, cottonseed oil, evening primrose oil, fish oil, grape seed oil, olive oil, palm kernel oil, palm oil, peanut oil, rapeseed oil, safflower oil, sesame oil, soybean oil, sunflower oil, hydrogenated castor oil, hydrogenated coconut oil, hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated soybean oil, partially hydrogenated soybean oil and hydrogenated vegetable oil.

[0047] Example propylene glycol fatty acid esters that may be used in the formulation as the lipid phase include propylene glycol monocaprylate, propylene glycol dicaprate, propylene glycol monolaurate, propylene glycol dilaurate , and propylene glycol heptanoate . Examples are sold under the trade names Capmul®, Capryol®, Lauroglycol® and Labrafac® PG. These propylene glycol fatty acid esters may also be used in the formulations as surfactants when a more lipophilic excipient is included.

[0048] When targeting the development of a lipid solution, preferred lipid components in the present invention are those that can dissolve the compound at concentrations greater than 25 mg active (free base equivalent) per gram of excipient ("mg/g" hereinafter), and more preferably, above 50 mg/g, and more preferably, above 100 mg/g, which may be determined via solubility assays. For cinacalcet, preferred lipid components include LCGs, namely glycerol monooleate (Peceol®) or glycerol monolinoleate (Maisine™ 35-1 ), and more preferably, MCGs such as glycerol monocaprylate (e.g., Capmul® MCM EP or Imwitor® 308) or propylene glycol fatty acid esters such as propylene glycol monocaprylate (Capryol® 90 or Capryol® PGMC).

[0049] The non-ionic surfactant has a capacity to emulsify the lipid component of the formulation and has a hydrophilic-lipophilic balance ("HLB") of at least 6. The hydrophilic-lipophilic balance of a surfactant is a measure of the degree to which it is hydrophilic or lipophilic, determined by calculating values for the different regions of the molecule. An HLB value of 0 corresponds to a completely lipophilic/hydrophobic molecule, and a value of 20 corresponds to a completely hydrophilic/lipophobic molecule. HLB values for various surfactants are well known in the art.

[0050] The non-ionic surfactant may be selected from propylene glycol mono- or diesters of 8 - 22 carbon fatty acids, sorbitan fatty acid esters including sorbitan monolaurate; polyoxyethylene sorbitan fatty acid esters such as polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80, polysorbate 85; polyoxyethylated mono- and di-fatty acid esters such as esters of castor oil (Kolliphor® EL), hydrogenated castor oil (Kolliphor® RH40), hydroxystearic acid (Kolliphor® HS-15); glycerol macrogolglycerides such as Labrasol®, Gelucire® 44/14, Gelucire® 50/13, Labrafil®; DL-a-tocopheryl polyethylene glycol succinate; polyoxyethylene- polyoxypropylene copolymers such as poloxamer 124, poloxamer 188, poloxamer 407; polyglycerol esters of fatty acids such as polyglycerol-6-caprylate, polyglycerol-3-oleate; and ethoxylated fatty alcohols such as the Brij® surfactants.

[0051 ] Of the above list, the preferred surfactants in the present invention are those with a capacity to emulsify the lipid component of the formulation, namely those surfactants with a HLB greater than 8 for example Span 20 and polysorbate 85 (Tween 85), or, more preferably, a HLB greater than 12, for example, Kolliphor RH40, Kolliphor EL, Solutol HS-15, polysorbate 20, polysorbate 60, polysorbate 80, , Gelucire® 44/14, Labrasol®, Gelucire® 50/13 or DL-a-tocopheryl polyethylene glycol succinate. In one embodiment, the non-ionic surfactant is selected from the group consisting of polyoxyethylated mono- and di-fatty acid esters of castor oil or hydrogenated castor oil, and polyethylene glycol ester of caprylic/capric glycerides, and sorbitan monolaurate, and blends thereof. It is also possible to utilize a single non-ionic surfactant or a combination of non-ionic surfactants in a cinacalcet lipid formulation.

[0052] The amount of lipid and non-ionic surfactant in the lipid-based formulation are chosen so as to enable relatively high compound loadings of cinacalcet with optimal formulation dispersibility. In general, the formulation contains between 5-75% w/w, typically 6-70% w/w, typically 7-65% w/w, typically 8-60% w/w, lipid component and 25- 75% w/w non-ionic surfactant. [0053] In general the ratio of lipid component to non-ionic surfactant is at least 0.25:1. The ratio may be at least 0.5:1 , may be at least 1 :1 , may be at least 1.5:1 , may be at least 2:1 , or may be at least 3:1.

[0054] The amount of cinacalcet in the lipid formulations is preferably at least 27.2 mg/g (27.2 mg cinacalcet free base equivalent per g of lipid formulation), may be at least 40.8 mg/g, or may be at least 54.4 mg/g. When using other lipids such as LCG and propylene glycol fatty acid esters, similar lipid:surfactant ratios are employed, though when developing a lipid solution it is generally found that stable cinacalcet loadings in the formulation are lower when compared to equivalent formulations containing MCG or propylene glycol fatty acid esters. For suspension type formulations, since the drug is partly suspended in the formulation, there are fewer constraints in terms of the amount of lipid component in the final formulation. In addition, the amount of cinacalcet in suspension-type lipid formulations can be higher than that of lipid solutions, preferably at least 108.8 mg/g.

[0055] The lipid formulation may contain other optional excipients to improve emulsification of the lipid component in the formulation and overall drug solubility, and may include phospholipids, free fatty acids, fatty acid alcohols or synthetic fatty acid derivatives including isopropyl myristate and isopropyl palmitate. Isopropyl myristate and isopropyl palmitate may also be added to the lipid formulation as a cosolvent, for the purpose of improving drug solubility in the formulation. Other example cosolvents may include propylene glycol, polyethylene glycol, triacetin, glycerol, ethanol and diethylene glycol monoethyl ether, or other pharmaceutically acceptable cosolvents. [0056] It should be understood that the embodiments described herein are not limited thereto. Other embodiments of the present disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the disclosed embodiments. The following examples should be considered as exemplary only, with a true scope and spirit of the present disclosure being indicated by the following claims.

57] Table of excipients:

[0058] Examples

[0059] Example Formulations 1 , 2 and 3 were prepared as follows. The target compound mass was initially weighed into a glass vial before the addition of compound- free formulation, followed by mixing at 30°C until the compound was completely dissolved, which was confirmed by the absence of any drug crystals in the formulation using a polarized light microscope.

[0060] Dispersion of the formulation into aqueous solution was evaluated as follows: 1 g of compound containing formulation was added directly to a glass beaker followed by 250 mL aqueous medium (pre-equilibrated to 37°C) under constant stirring. Samples were periodically analyzed over a 24 hour period by polarized light microscopy to detect potential compound precipitation. Since cinacalcet is a poorly water-soluble compound, precipitation to form crystals following dispersion in an aqueous medium was considered an indicator of poor lipid formulation performance.

3 Capmul® MCM EP / 54.4 No compound

Kolliphor®EL crystals over 24

Cloudy

75 / 25 hour dispersion emulsion

[0061] Examples 1 , 2, 3 formed homogenous dispersions in water with no evidence of compound precipitation over 24 hours. Following HPLC analysis, the amount of compound solubilized within the aqueous-rich colloidal phase was 93.5%, 103.3% and 98.3% for Examples 1 , 2 and 3, respectively.

[0062] Effect of surfactant and surfactant-type

[0063] Examples 1 , 2 and 3 described above all contain a notable amount of a high HLB non-ionic surfactant which was included to facilitate dispersion of the lipid formulation oil phase.

[0064] Additional cinacalcet lipid formulations were prepared and tested to explore the importance of including a surfactant and surfactant type, and were as follows:

Example 4 Isopropyl myristate 54.4 Milky dispersion

/ Span 20 / with distinct

99.1 %

Imwitor 308, phase-separated

25 / 25 / 50 oil droplets

[0065] These formulations were prepared and tested for performance on dispersion in a manner as described for Examples 1 -3 above and there was no evidence of compound precipitation over 24 hours for these formulations. When compared to Example 2, however, there was visual evidence of poorer dispersibility of the lipid component on removing surfactant from cinacalcet lipid formulation (i.e., Control 1 ) or using a lower HLB surfactant, namely sorbitan monoleate (Span 80) of HLB = 4.3 (i.e., Control 2). This poorer dispersibility was confirmed by HPLC following centrifugation of samples of the dispersion removed after 3 hours; the % of cinacalcet solubilized within the aqueous-rich colloidal phase in Control formulations 1 and 2 is lower (<90%) than that of Example 2 (>90% at 93.5% and 103.3%), with the remainder of the dose solubilized in a poorly dispersed oil phase. Compound in a poorly dispersed oil phase is less available for absorption when compared to compound present in smaller colloids that are well dispersed in an aqueous phase (e.g., micelles and small, emulsified oil droplets),

[0066] The results therefore indicate that a high HLB surfactant is needed for optimal dispersion and solubilization of cinacalcet by lipid formulations. While all surfactants tested were able to provide substantial compound solubilization in the aqueous-rich colloidal phase (i.e., >75%), based on the results, preferred surfactants are those with a HLB greater than 8, since Example 4 containing the surfactant sorbitan monolaurate (Span 20, HLB 8.6) provided >95% compound solubilization in the aqueous phase, whereas Control 2 containing sorbitan monooleate (Span 80, HLB 4.3) provided <85%.

[0067] Effect of lipid type

[0068] Examples 1 -4 described above all contain a MCG, glycerol monocaprylate (Imwitor 308 or Capmul® MCM) as the lipid component of the formulation for effective cinacalcet solubilization following dispersion.

[0069] Additional cinacalcet lipid formulation examples were prepared and tested to determine the utility of other lipid components, and were as follows:

[0070] In Example 5, Capryol® 90, which consists of propylene glycol fatty acid esters of caprylic acid, is used as the lipid component. On dispersion, Example 5 showed no evidence of precipitation over 24 hours and provided a high level (>94.1 %) of cinacalcet solubilization in the aqueous-rich colloidal phase. The performance of Example 5 containing a propylene glycol fatty acid ester as the lipid component was therefore consistent with Examples 1-4 described above that contained MCG.

[0071] Peceol® was investigated as an example LCG. It consists of a mono, di and triester mixture of oleic acid. In Example 6 containing Peceol®, it was necessary to lower the compound loading to 40.8 mg/g to produce stable lipid solutions due to a decrease in cinacalcet solubility in this lipid component relative to MCG and propylene glycol fatty acid esters. On dispersion of Example 6 in water, there was no evidence of compound precipitation over 24 hours. Example 6 also provided substantial

solubilization of the compound in the aqueous-rich colloidal phase (>75%).

[0072] For cinacalcet, it appears that good compound solubilization post- dispersion may be achieved using different types of lipid component, including MCG, LCG and propylene glycol fatty acid esters. The use of glycerol monocaprylate (e.g., Imwitor® 308, Capmul® MCM) and propylene glycol fatty acid esters (e.g., Capryol® 90) as the lipid component have the additional advantage of being able to support higher loadings of dissolved cinacalcet in a lipid formulation.

[0073] Effect of cinacalcet physical form

[0074] Examples described above all contain dissolved cinacalcet in the formulation. To investigate the effect of compound physical form on the performance of cinacalcet lipid formulations, Example 7 was prepared as follows:

Example Isopropyl 108.8 Compound was mixed Lipid formulation

7 myristate / with the placebo lipid containing suspended

Labrasol® / formulation at 30°C compound crystals

Kolliphor® EL until compound was (lipid suspension)

/ Imwitor 308 uniformly dispersed

12.5 / 12.5 /

25 / 50

[0075] Example 7 is an example of a lipid suspension for the compound cinacalcet. For performance comparison purposes, Example 7 is consistent in composition to Example 1 described earlier, but differing in the compound/formulation ratio, and differing in terms of the physical form of the compound in the formulation.

[0076] Example 7 was tested on dispersion similarly to the Example 1 described above, both in water and in pH 6.5 phosphate buffered saline (PBS), but where the mass of formulation was reduced to 0.5 g to deliver the same cinacalcet dose in 250 ml dispersion medium. The pH of the PBS medium mimics that of the pH of the small intestine, the primary site of drug absorption. As cinacalcet is weakly basic with an apparent pKa of 8.72, it will show decreasing aqueous solubility with increasing pH, thus higher solubility in the acidic stomach compared to the more neutral small intestine. Dispersion testing of cinacalcet formulations in pH 6.5 PBS will therefore be more stressful to solubilization in comparison to water (where an acidic salt counterion can shift pH to a more acidic value) and in an acidic simulated gastric fluid.

[0077] As shown in the table below, Example 7 offered complete (>95%) cinacalcet solubilization in both water and in PBS. This example lipid suspension therefore provides similar performance to Example 1 , despite it containing cinacalcet dispersed in a crystalline form in the formulation. Since it was not possible to completely solubilize the same dose of cinacalcet in PBS in the absence of lipid formulation, it is apparent that the dispersed lipid formulation is able to increase cinacalcet solubility in the dispersed state.

[0078] Formulation stability

[0079] Example cinacalcet formulations were tested for their ability to solubilize the compound at 54.4 mg/g, and then placed on storage at ICH conditions

(25°C/60%RH, 40°C/75%RH). At regular, pre-defined intervals, formulations were inspected for evidence of compound recrystallization that would indicate physical instability on storage.

[0080] Digestion testing

[0081] 1 g of each formulation was dispersed in 40 ml_ fasted intestinal medium (2 mM Tris-maleate, 1 .4 mM CaCI₂-2H₂0, and 150 mM NaCI, 3 mM sodium

taurodeoxycholate and 0.75 mM phosphatidylcholine, 37°C) using a pH-stat titrator as described by the LFCS Consortium (Williams, HD. et al., J. Pharm. Sci.101 (2012), p. 3360-3380). Digestion was initiated on addition of 4 ml_ porcine pancreatic extract, prepared as described previously (1 ), and continuously monitored and maintained at pH 6.5 with NaOH for 60 min during which period samples were removed, centrifuged and solubilized compound concentrations determined by HPLC. Digestion however applied greater stress on the formulations, resulting in compound precipitation in the case of Example 3 (44% compound solubilized after 60 min digestion), but not Example 1 or Example 2 (providing at least 79% or 89% compound solubilized after 60 min digestion.

Claims

WHAT IS CLAIMED IS:

1. A pharmaceutical composition, comprising:

a) cinacalcet;

b) a lipid component of either a medium-chain glyceride (MCG) or long-chain glyceride (LCG), or a propylene glycol fatty acid ester, or a suitable blend of these lipid components

c) a non-ionic surfactant having a HLB of at least 6.

2. The pharmaceutical composition of claim 1 wherein said lipid component is chosen from the group consisting of mono-, di- and triglycerides of 6 - 12 carbon fatty acids, and blends thereof.

3. The pharmaceutical composition of any of the preceding claims wherein said lipid component is chosen from the group consisting of mono-, di- and tri caprylic and capric glycerides, and blends thereof.

4. The pharmaceutical composition of any of the preceding claims wherein said lipid component is chosen from the group consisting of mono-, di- and triglycerides of 14 - 22 carbon fatty acids, and blends thereof.

5. The pharmaceutical composition of any of the preceding claims wherein said lipid component is chosen from the group consisting of propylene glycol monocaprylate, propylene glycol monolaurate, propylene glycol dicaprate, propylene glycol dilaurate and propylene glycol heptanoate.

6. The pharmaceutical composition of any of the preceding claims wherein said non-ionic surfactant has a HLB of at least 8.

7. The pharmaceutical composition of any of the preceding claims wherein said non-ionic surfactant is chosen from the group consisting of, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylated mono- and di-fatty acid esters, glycerol macrogolglycerides, DL-a-tocopheryl polyethylene glycol succinate, polyoxyethylene-polyoxypropylene copolymers, polyglycerol esters of fatty acids, and ethoxylated fatty alcohols.

8. The pharmaceutical composition of any of the preceding claims wherein said non-ionic surfactant is selected from the group consisting of polyoxyethylated mono- and di-fatty acid esters of castor oil or hydrogenated castor oil, and polyethylene glycol ester of caprylic/capric glycerides, and sorbitan monolaurate, and blends thereof.

9. The pharmaceutical composition of any of the preceding claims wherein said ratio of lipid component to non-ionic surfactant is at least 0.25:1 , preferably at least 0.5:1 , more preferably at least 1 :1.

10. The pharmaceutical composition of any of the preceding claims wherein said cinacalcet is completely dissolved in the formulation or is partly dispersed in the formulation, forming a suspension.

1 1. The pharmaceutical composition of any of the preceding claims wherein said cinacalcet is present in an amount of at least 27.2 mg/g (2.72% w/w), preferably, least 54.4 mg/g (5.44 % w/w), more preferably least 108.8 mg/g (10.8% w/w).

12. The pharmaceutical composition of any of the preceding claims wherein said cinacalcet is in the form of a hydrochloride salt, or another pharmaceutically acceptable salt form, or in the form of a free base.

13. The pharmaceutical composition of any of the preceding claims wherein the formulation contains between 5-75% w/w lipid component and 25-75% non-ionic surfactant, preferably between 20-75% w/w lipid component and 20-50% non-ionic surfactant.

14. The pharmaceutical composition of any of the preceding claims wherein the formulation contains a pharmaceutically acceptable cosolvent, preferably wherein said cosolvent is selected from the group consisting of propylene glycol, isopropyl myristate, polyethylene glycol, triacetin, glycerol, ethanol, diethylene glycol monoethyl ether, and mixtures thereof.

15. The pharmaceutical composition of any of the preceding claims wherein the formulation containing cinacalcet is contained, and preferably delivered, in a pharmaceutically acceptable dosage form selected from capsules, sachets and bottles, preferably a capsule.