Immediate release formulations of Cinacalcet

Introduction

Cinacalcet is a calcium receptor-active compound which is approved for the treatment of secondary hyperparathyroidism resulting from chronical kidney insufficiency and for the treatment of hypercalcaemia in patients with parathyroid carcinoma.

Cinacalcet in the form of its hydrochloric acid addition salt (cinacalcet HCI) is marketed under the brand names Mimpara ^® and Parareg ^® in Europe and Sensipar ^® in the US. The chemical name of cinacalcet HCI is (R)-N-[l-(l-naphthyl)ethyl]-3-[3- (trifluoromethyl)phenyl]propan-l-amine Hydrochloride and has the following structure:

A synthesis of cinacalcet is disclosed in WO 96/12697. The manufacturing process of the most stable polymorphic form I of cinacalcet HCI is disclosed in WO 2007/62147.

The currently marketed tablets with immediate release of the drug are basically described in patent application WO 2005/034928. In order to meet certain regulatory demands, WO 2005/034928 teaches the use of cinacalcet HCI compositions comprising:

(a) from 10% to 40% by weight of cinacalcet HCI

(b) from 45% to 85% by weight of at least one diluent;

(c) from 1% to 5% by weight of at least one binder;

(d) from 1% to 10% by weight of at least one disintegrant; and

(e) from 0.05% to 5% of at least one additive chosen from glidants, lubricants, and adherents; wherein the percentage by weight is relative to the total weight of the composition. Patent application WO 2005/034928 reports a very low solubility of cinacalcet HCI in water of between O.lmg/ml and 1.6mg/ml, depending on the pH value, resulting in a low bioavailability and limiting the formulation and delivery options available for this compound.

WO 2005/034928 also discloses a manufacturing process for cinacalcet formulations, indicating several "Critical Process Controls", i.e. parameters such as water level, impeller speed and water spray rate (during granulation), and blend time, tablet press speed, tablet weight, thickness, hardness and friability (during compression) etc. that might be adapted in order to achieve a desired result (i.e. meet the dissolution characteristics according to standards like USP 26/NF 21, chapter 711). As it appears from the application, also the quantitative composition of the tablets is a critical parameter which is meant to be adapted within the specified limits. According to WO 2005/034928, cinacalcet HCI particles may have a D ₅₀ of less or equal to about 50μηη. However, the application remains silent about any technical implication related to the particle size of cinacalcet HCI particles. In addition, the application remains silent about the D ₅₀ of the API that was actually used. Patent application WO 2010/071689 suggests mechanical methods for particle size reduction of crystalline cinacalcet HCI in order to obtain particle sizes with a D ₅₀ of less than or equal to 50μηη, but also remains silent about any technical consequence in doing so, let alone providing any information of the behavior of cinacalcet HCI when formulated into pharmaceutical compositions. WO 2010/034497 suggests that micronized cinacalcet HCI is hard to process and might be sensitive to oxidation. Example 4 of this application further indicates that formulations according to WO 2005/034928 with micronized cinacalcet HCI show inferior dissolution characteristics compared to those of non-micronized cinacalcet HCI with a D ₅₀ of lOlpm. In conclusion, the prior art teaches to preferably use cinacalcet HCI with a D ₅₀ of above ΙΟΟμηη, but remains silent about the implications of cinacalcet HCI particle sizes below ΙΟΟμιτι for the manufacture of pharmaceutical formulations.

One object of the present invention therefore is the investigation of the correlation of the particle size of cinacalcet HCI and its dissolution characteristics. In accordance with the teaching of WO 2010/071689, crystallization of cinacalcet HCI under controlled conditions leads to large needle-shaped crystals, as can be seen in figure 1. Figure 2 illustrates a sample of micronized cinacalcet HCI. It has been found that dissolution of cinacalcet HCI API is heavily influenced by its D ₅₀ . A decrease of the dissolution rate with decreasing D ₅₀ was observed (see figure 4).

Resulting from this observation, another object of the present invention is the provision of a formulation process which is flexible with respect to the use of cinacalcet HCI with particle sizes below ΙΟΟμηη.

In order obtain a market authorization for a generic drug development, it is essential to meet several regulatory requirements. Amongst them, the proof of bioequivalence is of major importance. The first step in aiming at bioequivalence is to approach the in-vitro dissolution profile of an existing market product. In order to do so, it is favorable to establish methods and processes that allow the selection and use of the active substance and all necessary ingredients and the adaption of relevant parameters within broad ranges. Therefore, the pharmaceutical formulation process shall be flexible over both a broad range of active drug load, but also with respect to the quantitative amounts of the excipients to be used. All the abovementioned objectives have been solved by the formulation process and pharmaceutical compositions described hereinafter and the claims. It has been found that advantageous formulations comprise from 5.1% to 7% of one or more binders. All amounts in percent (%) are weight-%.

Binders such as povidone are usually not used in amounts of less than 0.5%, because of failure of binding activity. On the other hand, amounts above 5% are unusual since the strong binding activity might decrease the dissolution of the tablet. Now taking into consideration that cinacalcet HCI is extremely insoluble in water, it was a big surprise when the inventors of the present invention found out that cinacalcet HCI may be formulated with more than 5% binder without affecting the dissolution profile of the resulting formulation.

Pharmaceutical compositions according to the present invention further comprise

(a) from 15% to 50% by weight cinacalcet HCI;

(b) from 33% to 80% by weight of one ore more fillers;

(c) from 5.1% to 7% by weight of one ore more binders;

and may comprise other pharmaceutical ingredients such as disintegrants, glidants or lubricants, wherein the percentage by weight is relative to the total weight of the composition. The terms fillers, disintegrants, binders, lubricants, glidants etc. shall be understood as including a single compound, but also mixtures of compounds. More preferred is a composition comprising component (c) from 5.5% to 7% by weight of one or more binders.

The preferred pharmaceutical composition is a tablet. Tablets may be manufactured according to processes well known in the art.

The cinacalcet HCI used in the pharmaceutical compositions is manufactured by known procedures indicated above, exhibiting a particle size with a D ₅₀ ranging from 5μηη to 95μηη. Preferably, the D ₅₀ ranges from 5μηη to 45μηη. More preferably, the D ₅₀ ranges from ΙΟμιτι to 30μηη. Also preferred is a D50-value for the particle size ranging from about 14μηη to 23μηη with standard deviation. Most preferred, the D ₅₀ -value ranges from 14μηη to 23μηη. The particle size of the cinacalcet HCI is measured according to light scattering techniques. The preferred crystal form is crystal form I as disclosed in WO 2007/62147.

Pharmaceutically acceptable fillers or diluents include starch, microcrystalline cellulose, dicalcium phosphate, lactose, calcium carbonate, magnesium carbonate, sorbitol, mannitol, sucrose, dextrine, kaolin, magnesium oxide, calcium sulfate, xylitol, isomalt, glucose, fructose, maltose, acids like citric acid, tartaric acid, fumaric acid, co-polymers such as those from vinyl pyrrolidone and vinyl acetate or those of polyethylene glycol, and mixtures thereof. Preferred diluents are pre-gelatinized maize starch and microcrystalline cellulose. Pharmaceutically acceptable binders include povidone, hydroxypropyl methylcellulose, dihydroxy propylcellulose, sodium carboxyl methylcellulose, and mixtures thereof. Preferred binder is povidone.

Pharmaceutically acceptable disintegrants include sodium starch glycolate, crospovidone, croscarmellose sodium, and mixtures thereof. Preferred disintegrant is sodium starch glycolate.

Pharmaceutical compositions according to the present invention may also comprise glidants such as colloidal silicon dioxide.

Pharmaceutically acceptable lubricants include magnesium stearate, calcium stearate, stearic acid, stearic acid, glyceryl behenate, hexanedioic acid, hygrogenated vegetable oil sodium stearyl fumarate and glycerine fumarate. Preferred lubricant is magnesium stearate. The tablets according to the invention may connprise further connnnon pharmaceutically acceptable excipients and may be film coated.

In general, the formulation process comprises the following steps:

(a) The drug substance, binders, and portions of fillers and disintegrants are mixed and blended.

(b) The pre-mixture is then wet granulated;

(c) The wet granules are passed through a sieve;

(d) The sieved wet granules are dried and the dried granules are calibrated;

(e) Remaining portions of fillers, disintegrants and glidants are mixed and sieved to form the external phase.

(f) The external phase mixture is blended with the granules.

(g) The lubricant is sieved and blended with the mixture of granules and external phase to form the final blend which is used for production of tablets.

Specifically, the formulation process comprises the following steps: (a) mixing and blending the cinacalcet HCI with povidone, pre-gelatinzed maize starch with portions of microcrystalline cellulose and sodium starch glycolate;

(b) the pre-mixture is then granulated with water.

(c) the wet granulate is passed through a sieve (1.4mm);

(d) granules are dried in a fluid bed drier until loss on drying is around 3%;

(e) the dried granules are calibrated through a 0.2mm sieve;

(f) the remaining portions of microcrystalline cellulose and sodium starch glycolate and colloidal silicon dioxide are mixed and sieved though 0.71mm sieve to form the external phase; (g) the external phase mixture is blended with the granules;

(h) Magnesium stearate is blended with the mixture of granules and external phase to form the final blend which is used for production of tablets.

Granules prepared in step (b) exhibited a D ₅₀ ranging between 50μηη and 150μηη, measured by sieve analysis according to WO 2005/034928.

The dissolution profile of the formulations were measured according to standard dissolution protocols (USP paddle, 37°C+/- 0.5°C, 75 rpm, 0.05 N HCI, 900ml).

The following figures illustrate the invention without limiting it to these examples FIG 1: Cinacalcet HCI crystals

FIG 2: Cinacalcet HCI crystals after micronization

FIG 3: Flow chart of the pharmaceutical formulation process

FIG 4: In vitro dissolution tests of cinacalcet HCI - API

FIG 5: In vitro dissolution tests of pharmaceutical compositions with cinacalcet HCI

Example 1: Dissolution characteristics of cinacalcet HCI

The particle size distribution of cinacalcet HCI was measured by laser diffraction analysis, using the equipment and procedure as displayed in table 1:

Table 1 200mg of cinacalcet HCI of different D ₅₀ values was dropped into a vessel containing 900ml of dissolution medium (0.1 N HCI) at 37.0 +/- 0.5°C and stirred at 75rpm. The results are displayed in table 2 and figure 4.

Table 2

* Dissolution rate of D ₅₀ =89 μηη after 60min is set to 100%

The results clearly show that the cinacalcet HCI with a very low D ₅₀ of 20μηη exhibits a much lower solubility, indicating that the solubility of cinacalcet HCI decreases with decreasing particle size.

Exannples 2-5: Pharnnaceutical fornnulations with cinacalcet HCI

Tablets containing cinacalcet HCI were manufactured according to the process as shown in figure 3, using equipment and settings used in the manufacturing process as described in table 3.

Table 3 The connposition of the resulting fornnulation for a tablet comprising 30mg Cinacalcet is displayed table 4:

Table 3

* corresponding to 30mg cinacalcet free base

¹¹ Intragranular phase

2 ⁾ Extragranular phase

Tablets containing 60 mg and 90mg of cinacalcet HCI may be prepared accordingly by compressing the same mixture to tablets of double or triple tablet weight. Dissolution characteristics of the pharmaceutical compositions

The in-vitro dissolution of tablets (30mg) according to examples 2 to 5 were analyzed according to Ph. Eur. 2.9.3 and USP <711> - Method 2 (Paddle Apparatus) with the settings as displayed in table 5.

Equipment: Varian

Medium: HCI 0.05N

Volume: 900ml

Temperature: 37.0°C ± 0.5°C

Stirring speed: 75 rpm

Table 5

The dissolution profiles of the formulations are displayed in table 6 and figure 5. Unlike the dissolution experiments with unformulated cinacalcet HCI with a very small particle size, all tested compositions release at least about 85% of the cinacalcet HCI from the composition in no later than 30 minutes from the start of the test. Furthermore, comparison with the original products Mimpara ^® from France (FR-Reference) and the United States (US- Reference) showed an almost identical dissolution profile.

Table 6 Stability testing of the pharmaceutical compositions

The tablets of example 3 were stored for 1 month period under standard accelerated temperature and relative humidity conditions (40°C/75%RH) and were then analyzed for assay and impurity profile. Conditions for assay and purity determination by HPLC were according to table 8.

Luna C5 (5μηη,

Analytical column:

250mm*4.6mm)

Mobile phase A: Acetonitrile

Mobile phase B: 0.02M Ammonium Acetate

Flow rate: l.OmL/min

Column oven temperature: 30°C

Detection wavelength: 220nm

Gradient:

Time %A %B

0 55 45

20 70 30

25 70 30

33 95 5"

Table 7

No influence of temperature or moisture on the impurity profile of the tablets was observed. Additionally, there seems to be no influence of oxygen on the stability of the formulation, as derives from the results of experiments with open in comparison to closed flasks (see table 8). time=0 time=l month

Specification closed open

flask flask

Total impurities

NMT 0.5 % < 0.1% < 0.1% < 0.1%

(HPLC)

Cinacalcet HCI Assay 95.0 - 105.0

99.3% 99.0% 99.2%

(HPLC) %

Table 8

In conclusion, the present formulations exhibited no degradation of the drug substance, thus a good stability, indicating the robustness of the present formulation process and pharmaceutical compositions.