Patent Application
20150328172
The present invention relates to a pharmaceutical composition, particularly a tablet composition comprising a high drug load of cinacalcet hydrochloride, having improved bioavailability.
Cinacalcet, having the chemical structure shown above, is a calcimimetic agent, and as such it increases the sensitivity to extracellular calcium of the calcium-sensing receptors of the parathyroid gland, leading to reduced levels of parathyroid hormone, serum calcium, and phosphate. It is indicated for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis.
Cinacalcet free base and pharmaceutically acceptable salts thereof are disclosed in European Patent application EP1203761.
A cinacalcet hydrochloride-containing pharmaceutical product is approved in many countries of the world under the brand name Mimpara® (Amgen) in the EU and Sensipar® (Amgen) in the US. Generally, the marketed cinacalcet hydrochloride tablets comprise 30, 60 or 90 mg of cinacalcet hydrochloride.
Cinacalcet hydrochloride is poorly soluble in water and has a pH dependent solubility. At basic pH it is practically insoluble (<0.001 mg/ml). The solubility is about 1.6 mg/ml at a pH range of from about 3-5, however at pH 1 the solubility decreases to approx. 0.1 mg/ml. In the state of the art, various proposals have been made on how to formulate this active pharmaceutical ingredient.
The marketed formulation of cinacalcet hydrochloride is described in WO2005034928. The tablet composition disclosed therein contains cinacalcet hydrochloride with a particle size distribution D50 less than or equal to 50 μm (see paragraph [021]) in an amount of approx. 18% by weight based on the total weight of the tablet composition (see paragraphs [019] and [057]).
The tablet of WO2005034928 contains a high amount (i.e. 70% by weight) of diluent among other pharmaceutical excipients, having a tablet weight of up to 540 mg for the cinacalcet 90 mg tablet strength. The incorporation of a relatively high amount of excipients (e.g., diluents and disintegrants) into the formulation of a solid oral dosage form can improve the dissolution rate of active pharmaceutical ingredients, especially those that are relatively hydrophobic and poorly soluble in water like cinacalcet. Increasing the amount of excipients in the composition, however, entails a number of disadvantages. Notably, tablet size will increase significantly causing patient compliance problems. In addition, content uniformity can be problematic as well as stability problems can occur related to interaction of the active pharmaceutical ingredient with one or more of the excipients.
The objective of the present invention was therefore to overcome the above-mentioned disadvantages.
The present invention relates to a pharmaceutical composition containing a high amount of cinacalcet hydrochloride having a particle size distribution D90 equal to or less than 30 μm, preferably equal to or less than 25 μm, more preferably equal to or less than 10 μm, exhibiting good drug release and bioavailability profile. The preferred tablet composition has a high drug load, a reduced size and is bioequivalent as compared to the commercially available tablet.
In one embodiment, the present invention relates to a tablet composition comprising a therapeutically effective dose of cinacalcet hydrochloride having a particle size distribution D90 equal to or less than 30 μm, preferably equal to or less than 25 μm, more preferably equal to or less than 10 μm, in an amount of from 40% to 60%, preferably from 45% to 55% by weight based on the total weight of the composition, and one or more pharmaceutically acceptable excipients.
The D90 value of the particle size distribution is defined as the particle diameter at which 90% by volume of the particles have a smaller diameter than the diameter which corresponds to the D90 value measured by laser diffractometry. Specifically, a Malvern Instruments Mastersizer was used to determine the particle size distribution.
The one or more pharmaceutically acceptable excipients to be used in accordance with the present invention can be chosen from, for example, diluents, binders, disintegrants, lubricants, and glidants.
Diluents are fillers which are used to increase the bulk volume of a tablet or capsule. Generally, by combining a diluent with the active pharmaceutical ingredient, the final product is given adequate weight and size to assist in production and handling. Binders hold the excipients that are present in a tablet together. Binders ensure that tablets and granules can be formed having the desired or required mechanical strength, and they give volume to low active dose tablets. Suitable examples of diluents to be used in accordance with the present invention include starch, pregelatinized starch, microcrystalline cellulose, and calcium phosphate, lactose, sorbitol, mannitol and sucrose.
The tablet composition of the present invention preferably contains at least one hydrophilic diluents. Starch, pregelatinized starch, lactose, sorbitol, mannitol and sucrose are suitable hydrophilic diluents.
In a preferred embodiment of the present invention, the at least one hydrophilic diluent is pregelatinized starch.
The tablet composition of the invention preferably comprises:
Binders which are suitable for use in accordance with the present invention include povidone, hydroxypropyl methylcellulose, dihydroxy propylcellulose, and sodium carboxyl methylcellulose. Binders are preferably used in an amount of from 1% to 5% by weight based on the total weight of the composition. A preferred binder is povidone.
The tablet composition of the present invention may also contain a disintegrant. Disintegrants are added to a tablet composition to promote the breakup of the tablet into smaller fragments in an aqueous environment, thereby increasing the available surface area and promoting a more rapid release of the active pharmaceutical ingredient. Suitable examples of disintegrants to be used in accordance with the present invention include crospovidone, sodium starch glycolate, croscarmellose sodium, and mixtures of any of the foregoing. Disintegrants preferably are used in an amount of from 1% to 10% by weight based on the total weight of the composition.
The tablet composition of the invention may also contain a lubricant. Lubricants are generally used in order to reduce sliding friction. In particular, to decrease friction at the interface between a tablet's surface and the die wall during ejection, and reduce wear on punches and dies. Suitable lubricants to be used in accordance with the present invention include magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, hydrogenated vegetable oil, and glycerine fumarate. The tablet composition of the invention may also contain a glidant. Glidants enhance product flow by reducing interparticulate friction. A suitable example is colloidal silicon dioxide.
Lubricants and glidants preferably are used in a total amount of from 0.05% to 5% by weight based on the total weight of the composition.
In a preferred embodiment, the tablet composition of the present invention contains the following ingredients, based on the total weight of the composition:
In one embodiment of the present invention, the therapeutically effective dose of cinacalcet hydrochloride is 30 mg, 60 mg or 90 mg.
The pharmaceutically acceptable excipients to be used in accordance with the present invention, can be used only intragranularly, only extragranularly, or both.
The present invention further relates to a tablet composition as described hereinabove, prepared by a wet-granulation process, which process comprises:
The present invention still further relates to a granulate suitable for making a tablet composition as described hereinabove, prepared by a wet-granulation process, which process comprises:
In a preferred embodiment, the granulate of the invention contains an hydrophilic diluent. More preferably it contains pregelatinized starch and optionally other hydrophilic diluents. Pregelatinized starch is an excipient that generally can act as a diluent but also as binder improving cohesion of the granulate. We have found that surprisingly by adding pregelatinized starch intragranularly to our formulation, the dissolution profile is improved. This improvement is significant when compared to other known diluents and binders. Pregelatinized starch creates a hydrophilic environment that facilitates tablet disintegration and improves the dissolution of Cinacalcet significantly more than any other similar hydrophilic diluents.
The granules of the present invention typically have a particle size distribution D50 of from 200-300 μm.
The present invention also relates to a pharmaceutical composition comprising a granulate as described hereinabove in the form of a capsule or a tablet, preferably a tablet.
The pharmaceutical compositions described herein can be made using conventional methods and equipment well-known in the art.
The pharmaceutical (tablet) compositions of the present invention have a high load of cinacalcet hydrochoride and show an in vitro dissolution profile wherein at least 75% of cinacalcet is released at thirty minutes when the composition is subjected to a dissolution study in 900 ml HCl 0.05N (pH 1.3) using a USP apparatus II at 75 rpm at 37° C. Preferably, at least 85% of cinacalcet is released from the pharmaceutical composition at thirty minutes and the tablet compositions in accordance with the present invention are bioequivalent in vitro and in vivo to the commercially available cinacalcet hydrochloride tablets.
The present invention is illustrated by the following Examples.
Three strengths of cinacalcet hydrochloride tablets were prepared in a conventional way as described further herein below, and have the following compositions:
Cinacalcet hydrochloride 90 mg tablets
The 30, 60 and 90 mg tablets of Example 1 and 2 were made according to the process depicted in
| Number | Date | Country | Kind |
|---|---|---|---|
| PCT/EP2012/076732 | Dec 2012 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2013/077523 | 12/19/2013 | WO | 00 |
