WO2008099160A1

WO2008099160A1 - Solid oral dosage form containing bicalutamide and method of preparation

Info

Publication number: WO2008099160A1
Application number: PCT/GB2008/000484
Authority: WO
Inventors: Ales Franc; Roman Gonec; Anna Petrovicova; Borek Zaludek
Original assignee: Pliva Hrvatska doo
Current assignee: Pliva Hrvatska doo
Priority date: 2007-02-14
Filing date: 2008-02-12
Publication date: 2008-08-21
Anticipated expiration: 2009-08-14
Also published as: GB0702826D0

Abstract

A tablet comprising bicalutamide and a method for its production.

Description

SOLID ORAL DOSAGE FORM CONTAINING BICALUTAMIDE AND METHOD OF PREPARATION

Field of the invention

The invention relates to a tablet comprising bicalutamide, whereby the formulation is a tablet, as well as a method for its production.

Background of the invention

Bicalutamide is an antiandrogen which influences the action of male sex hormones. It is used to treat prostate .tumours without metastases for which sterilisation or other treatment is inconvenient or unacceptable. It is also used as supporting treatment at irradiation or after a surgical removal of the prostate.

From the chemical point of view, bicalutamide is N-[4-cyano-3- (trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide Summary formula: Ci₈Hi₄F₄N₂O₄S

Bicalutamide is used in the form of coated tablets containing 50 or 150 mg of active substance sold under the trademark CASODEX. Besides the active substance, the tablet core also contains lactose, polyvinylpyrrolidone, sodium carboxymethylstarch and magnesium stearate. The coating consists of hypromellose, macrogol and titanium dioxide. Total weight of the tablet containing 50 mg of active substance is 128 mg and its diameter is 7 mm. Total weight of the tablet containing 150 mg of active substance is 384 mg and its diameter is 10 mm.

WO 95/19770 refers to optically pure bicalutamide R-enantiomer and its examples use compositions with the active substance content from 10 to 50 mg. Auxiliaries are granulated lactose, starch and magnesium stearate. Dosage forms are capsules and tablets.

WO 02/067893, WO 02/080902 and GB 2 372 444 resolves the low aqueous solubility of bicalutamide by preparing a solid dispersion using the method of cosolvent evaporation when a solid dispersion is created with higher solubility than that of the active substance itself. The solid dispersion is further processed to prepare tablets and capsules.

US 2005/0008691 describes a composition of a solid dosage form containing at least 50% by weight of bicalutamide in granulate form. This resolves the slow aqueous solubility of bicalutamide by micronization of the active substance to achieve surface area of up to 3 m²/g and a mean diameter of particles between 1 - 10 microns. Lactose is the main filler of tablets given in the examples and the granulate is dried in one step in a vacuum and/or by microwave radiation.

These above mentioned compositions and the methods of production try to remove inconveniences related to the low and slow aqueous solubility of bicalutamide, either by a low content of active substance (to 50 mg), or by creating a solid dispersion, or by micronizing the active substance. Each of the foregoing solutions has its disadvantages. A lower content of active substance leads to increased dosing of unit dosage forms to achieve higher plasma levels. We have found that when using micronized substance, when using the stated auxiliary substances (in this case, lactose as a filler), the rate of dissolution of the tablet depends on the radial strength hardness of tablets. The tablet compositions stated in the Figures (1-5) of US 2005/0008691 , produced by the method of wet granulation, release at medium hardness of tablets (54 - 77 N) a statistically significant lower quantity of the substance than at low hardnesses (28 N)₁ within the time interval up to 30 or 60 minutes. The tablets of the US 2005/0008691 Figures 1-5) achieved the required release (75% within 30 min) according to USP, monograph <711> apparatus Il - (paddled method) with a hardness up to 40 N and a 50 mg content of active substance. Therefore, to achieve the required dissolution it is necessary to use only tablets with lower hardness, which is not convenient and which restricts the range of producible tablets. Further, tablets with lower hardness are less robust than tablets with a higher hardness which creates problems in handling and a substantial loss in production. Tablets with lower hardness are fragile and toxic dust can be produced from tablets when manipulating them during manufacturing and packaging.

Summary of the Invention

The goal of this invention was to find a composition and technology of tablet preparation which would solve the disadvantages resulting from the prior art. That means to find a sufficiently simple technology of preparation with low power consumption, enabling a dosage with the same high content of active substance as the commercial tablets. Simultaneously, it must enable sufficiently robust parameters of pressed units, in particular tablets in order to avoid/reduce losses in production. In this case, one important technological aspect is to obtain a dosage form with sufficient release of active substance within a sufficiently wide range of tablet radial hardness. This may be achieved by suitable properties of granulate in combination with suitable excipients in respect of the characteristics of active substance.

The aim of the present invention is therefore solved by a tablet whereby the tablet comprises at least one intragranular water-insoluble disintegrant with at least one extragranular water-soluble or gel forming disintegrant and at least one pharmaceutically acceptable water-insoluble binder with at least one water-soluble binder.

In the resulting tablet the bicalutamide is, surprisingly, released statistically independently of the core radial hardness in particular a) within the limits 30 - 110 N, preferably 30 - 70 N from a tablet containing 50 mg of bicalutamide a dissolution of bicalutamide of at least 70% within 30 min, preferably at least 85% within 30 min is achieved and b) within the limits 30 - 150 N, preferably 80 - 130 N from a tablet containing 150 mg of bicalutamide a dissolution of bicalutamide of at least 70% within 60 min, preferably at least 85% within 60 min is achieved, both under the conditions of 1 I of water containing 1% of sodium laurylsulfate at 50 rpm and 37°C. The hardness is determined by conventional methods described in European Pharmacopoeia, monograph 2. 9. 8.

Dissolution is performed according to USP<711> apparatus Il - (paddle method), medium is 1 L of 1 % sodium laurylsulfate in water, stirring speed is 50 rpm and bath temperature is 37⁰C. Sampling time is 10, 20, 30, 45 and 60 min.

This method is recommended for Bicalutamide tablets by FDA (http://www.accessdata.fda.gov/scripts/cder/dissolution/)

The term "water-soluble" means "good soluble" and better (defined according to Pharmacopoeia Europea, 1.4). It means that in range 15 - 25⁰C is soluble more than 1g in 30 mL of water.

The term "water-insoluble" means "practically insoluble" (defined according to Pharmacopoeia Europea, 1.4). It means that in range 15 - 25⁰C is not soluble more than 1g in 10 000 mL of water. The advantage of the inventive tablet over the prior art tablets comprising bicalutamide is the dissolution rate which is independent of the radial hardness. This is particularly advantageous since it is possible with the inventive tablets to use a large scale compression force during pressing. Harder tablets have better physical properties which is important for tablet coating, packaging, manipulation with tablets, etc. Further, no toxic dust is produced during tablet manipulation. The inventive tablets have a low friability.

The resulting tablet, when in contact with an aqueous environment (or digestive juices), absorbs water quickly due to the extragranular water-soluble or gel-forming disintegrant in its surface layer and swells. Secondly, the intragranular, water- insoluble disintegrant is activated which causes rupture in the pressed tablet. Subsequently, the swelling gel created from the water-soluble or gel-forming extragranular disintegrant penetrates into the ruptures formed between pressed granules. This mechanism destroys the structure of entire tablets in a very short time. Thus, the combination of the water-soluble or gel-forming disintegrant and the water- insoluble disintegrant enables a very rapid collapse of the tablet structure. This is significantly enhanced by the presence of the above-mentioned water-insoluble, dry binder, which creates a porous capillary structure within the tablet. The capillary structure wicks into the tablet and further reduces the disintegration time and increase the speed of the destruction of the tablet structure, and reduces the activation time of the intragranular water-insoluble release agent.

Further, the combination of the water-insoluble and the water-soluble binder enables one to achieve high strength hardness whilst using a low pressing force in the tableting process.

The high strength of pressed tablets is achieved by a high compression ratio which is due to a relatively low powder density and a big difference between the bulk and tap density. The Hausner number (ratio of the two values) is around 1.5. Such a fine microgranulate with high compressibility releases the active substance independently of the core radial hardness within the limits 30 - 110 N, preferably 30 - 70 N at the dissolution velocity of 70% active substance release within 30 min, or better at the velocity of 85% release within 30 min in water containing 1% of sodium laurylsulfate (method required by FDA) for the strength of 50 mg. For the hardness of 150 mg, the range of radial hardness is 30 - 150 N, preferably 80 - 130 N at the velocity of 70% active substance release within 60 min, or better at the velocity of 85% release within 60 min in water containing 1% of sodium laurylsulfate (method required by FDA).

The preparation of granulate with different intra- and extragranular excipients is also useful due to the poor flow and pressing properties of bicalutamide and its high bulk volume. To achieve better pressing and flow properties, it proved better to use excipients with high compressibility in non-granulated state, which function as a dry binder at the same time. In general, the granulate compressibility is not influenced by the size of particles or the granulation rate and the binding capacity is not affected by granulation. To produce sufficiently hard tablets, a relatively low pressing strength will suffice and the tablet will preserve its adequate hardness, excellent and equal disintegration capacity and extremely fast and almost complete dissolution.

The granulate origin itself is enabled by a highly efficient binder, perfectly soluble in the granulation liquid. Thanks to this excellent property, the binder may be added in a dry condition. It is activated during granulation in contact with the granulation liquid. The combination of the water-soluble binder and the dry water-insoluble binder - performing the function of a majority filler - shows synergy and leads to a granulate of excellent pressing capacity.

The water-insoluble binder with its porosity creates the granulate capillary structure, due to which, in spite of a relatively high volume of granulating agent (water), the granulate needs a very short time to dry.

Besides the combination of water-soluble and water-insoluble binder, the combination of water-soluble disintegrant and highly efficient water-insoluble disintegrant proved good. The water-insoluble disintegrant is not - owing to the low volume of granulation liquid used - activated by water during granulation, and so it may be used in an intragranular form and its swelling capacity is neither lost nor reduced during granulation. Like this, the tablet mass preserves its excellent release effects. Extragranularly, another hydrophilic or water-soluble or gel-forming disintegrant is used. It does not participate in the granulation process, but improves wettability of tablets containing a high volume of hardly soluble medicament. Preferably, the water-insoluble binder is microcrystalline cellulose in the concentration 5 - 90% of core weight, preferably 40-60% of core weight, still preferred 50% of core weight. Microcrystalline cellulose very rapidly creates optimally the above mentioned porous structure which leads to the destruction of the tablet structure. The US 2005/0008691 for example describes a bicalutamide formulation using lactose as binder which proved to have disadvantages over microcrystalline cellulose: Lactose does not create independent capillary structure of tablets and natural porosity descends with the radial hardness of tablets. This phenomenon is documented in literature for example in JUPPO A. M Porosity parameters of lactose, glucose and mannitol tablets obtained by mercury porosimetry, International Journal of Pharmaceutics, 1996, vol. 129, no. 1-2, pp. 1- 12 . There exists a big variability between drying time, compression force, size of lactose particles, moisture content of wet granules and mechanical integrity of lactose tablets. If the tablet moreover contains micronized particles of an insoluble substance, the micro-pores are obstructed and dissolution is decreased. According to the drawings in the above mentioned publication, it is necessary to use less pressing force which causes less hard tablets of about 28N in order to achieve the requested dissolution rate: Harder tablets of about 54 or 77 N show significantly slower dissolution. When using microcrystalline cellulose, these disadvantages do not occur.

Tablets according to the US 2005/0008691 are then prepared by one-pot method, which means wet granulating and drying in one step. This method of drying is longer than usual fluid bed drying and therefore more expensive. The main problem of the preparation of such a composition is that the active substance - in this case Bicalutamide - is released dependently of the core radial hardness.

The water-soluble binder may advantageously be polyvinylpyrrolidone, hydroxypropylmethylcellulose, modified starch and/or polyvinylalcohol, preferably polyvinylpyrrolidone, in the concentration of 0.5 - 10% of core weight, preferably 1- 3%, still preferred in the concentration of 2% of core weight. These particular binders allow one to achieve a very high solidity using a very low pressing force.

The intragranular water-insoluble disintegrant is optimally crossed carboxymethylcellulose sodium salt, crossed polyvinylpyrrolidone and/or crossed hydroxypropylmethylcellulose, preferably crossed carboxymethylcellulose sodium salt, in the concentration of 1 - 10% of core weight, preferably 2-4%, still preferred in the concentration of 3 % of core weight. These disintegrants cause the above mentioned ruptures in an optimal way and enable a particularly fast collapse of the tablet structure. Preferably, the extragranular water-soluble or gel-forming disintegrant is sodium carboxymethylstarch and/or modified starch, preferably sodium carboxymethylstarch, in the concentration of 1 - 10% of core weight, preferably 2-4%, still preferred in the concentration of 3% of core weight. Also these disintegrants are particularly useful in order to achieve the rapid destruction of the tablet structure.

In the combination with bicalutamide a completely unique synergy of all properties of excipients was achieved and high-quality tablets were produced with extremely low disintegration time and fast release, independent of the radial hardness of pressed pieces. This entirely exceptional composition using a standard drying technology, like fluid bed drying, which has not been used so far for the production of original tablets and their generics according to the patent literature, provides quality tablets and the required dissolution profiles in an extreme range of radial hardness, which has not been documented in the literature so far.

When substances with a high electrostatic charge and low solubility are produced, material often sticks to a metal surface of manufacturing equipment - for example, to the inner side of a drier or to the surface of punches. These phenomena also occurred when bicalutamide was processed. That is why our goal was to reduce the adhesion of materials to metal contact surfaces. For this reason, wetting agents, incorporated in the granulation liquid, were used during the preparation. Excellent properties were reached with anion active surfactant like in particular sodium sulfosuccinate, sodium laurylsulfate, sodium hexadecylsulfate, sodium hexadecylsulfonane and/or sodium dioctylsulfo-succinate, preferably sodium laurylsulfate, in the total volume from 0.1% to 10% of the tablet weight, preferably 0.5-1%, still preferred in the concentration of 0.6%, of the tablet weight.

A further aspect of the present invention relates to a method of preparation of the inventive tablet as mentioned above whereby the tablet is prepared by wet granulation. Here, the same definitions, preferred embodiments and advantages apply as mentioned above.

Compared to the prior art where lactose is used as a filler the inventive composition comprises microcrystalline cellulose which has moreover a function as water- insoluble binder. Surprisingly by using microcrystalline cellulose we can reduce time of drying in comparison with the prior art. Microcrystalline cellulose, which is also effective in a non-granulated form and so may be used in a dry condition (intragranularly), proved good as a convenient, porous binder. Due to its insolubility in the granulation liquid (water) its crystallinity is not changed and the pressing capacities remain constant.

Thanks to the use of sodium laurylsulfate, it was possible to dry the granulate practically by all methods commonly used in the pharmaceutical technology, in particular on a multi-storey drier, a vacuum drier, microwave, infra-radiation and fluid bed drier. Preferably, fluid bed drying is used as it is fast and power saving. In the fluid stream used at drying, the granulate is dried very quickly due to its porous structure, with the drying time below 1 hour at common temperatures of input air - in this case, it is possible to achieve drying times of 15 - 20 minutes at input air temperatures of 50-70⁰C. This is a significant reduction in comparison to the times achieved using vacuum drying for the production technology as per US 2005/0008691.

Moreover, the unique granulate structure needs a very low drying time in this case, although a very high percentage of water is used for wetting (up to 50%).

Owing to the fact that a cytostatic agent is in question and personnel as well as patient environment must be protected when manipulating it, the tablets are advantageously coated with a hydrophilic mixture. OPADRY is preferably used, in particular in the concentration up to 5% of tablet weight, still preferred within 1-3% of tablet weight.

Examples

The method of preparation of bicalutamide solid dosage form according to the invention is explained in the following examples of execution, without limiting the invention range. The substances are given in weight parts in the examples. Figures 1 and 2 show graphs comparing the dissolution rates of tablets with different tablet hardnesses. Example no. 1 Preparation of tablets

The substances are iven in wei ht arts in the exam les.

Method of Preparation

o Weigh the ingredients (1-4), o Mix the ingredients (1-4) in a high-speed mixer for 2 minutes, o Dissolve laurylsulfate (5) in water (6), o Wet the mixture of ingredients (1-4) with the laurylsulfate solution (5+6), o Mix in a high-speed mixer for 5 minutes, o Dry the mixture by fluid method at the temperature 50-70⁰C, o Add the ingredient 7 and mix in a cubic mixer for 10 - 15 min, o Add the ingredient 8 and mix in a cubic mixer for 5 min, o Press the produced mixture into biconvex tablets of 7mm diameter and 126mg weight containing 50 mg of active substance in one tablet, or into biconvex tablets of 10mm diameter and 378mg weight containing 150 mg of active substance in one tablet. Example no. 2 Coating of tablets

Coat the tablets mentioned in the foregoing example by 10 to 15% aqueous, lacquer pigmented dispersion OPADRY Il up to the required volume of lacquer dry mass 3.17% per tablet.

Example no. 3

Comparison of dissolution profiles of tablets with various hardnesses

The dissolution profile of tablets produced according to the invention was compared to the dissolution profile of CASODEX . The dissolution test carried out was the paddle Il test (USP apparatus), rotation: 50 rpm, volume 1000 ml; medium: 1 % SLS (sodium laurylsulfate).

Figures 1 and 2 show large scale of independency between radial hardness tablets and dissolution.

As can be seen from the above mentioned figures, the dissolution is independent of the tablet hardness in the scale from 20 N - 120N (20; 43; 70; 100; 113; 120 N) in the case of Bicalutamide 150 mg, see Fig. 1. In the case of Bicalutamide 50 mg the dissolution is independent of the tablet hardness in the scale from 26 N - 115N (26 ; 38; 73; 115 N) see Fig. 2. None of the prior art tablets show such large scale of independency between radial hardness tablets and dissolution.

Claims

1. A tablet comprising bicalutamide, characterized in that it comprises at least one intragranular water-insoluble disintegrant, at least one extragranular water-soluble or gel forming disintegrant, at least one pharmaceutically acceptable water- insoluble binder, and at least one water-soluble binder.

2. The tablet according to claim 1 characterized in that the water-insoluble binder is microcrystalline cellulose in the concentration 5 - 90% of core weight, preferably 40 to 60% of core weight, still preferred 50% of core weight.

3. The tablet according to claim 1 or 2 characterized in that the intragranular water- insoluble disintegrant is crossed carboxymethylcellulose sodium salt, crossed polyvinylpyrrolidone and/or crossed hydroxypropylmethylcellulose, preferably crossed carboxymethylcellulose sodium salt, in the concentration of 1 - 10% of core weight, preferably 2-4%, still preferred in the concentration of 3% of core weight.

4. The tablet according to any of the claims 1 to 3 characterized in that the water- soluble binder is polyvinylpyrrolidone, hydroxypropylmethylcellulose, modified starch and/or polyvinylalcohol, preferably polyvinylpyrrolidone, in the concentration of 0.5 - 10% of core weight, preferably 1-3%, still preferred in the concentration of 2% of core weight.

5. The tablet according to any of the claims 1 to 4 characterized in that the extragranular water-soluble or gel-forming disintegrant is sodium carboxymethylstarch and/or modified starch, preferably sodium carboxymethylstarch, in the concentration of 1 - 10% of core weight, preferably 2-4%, still preferred in the concentration of 3% of core weight.

6. The tablet according any of the claims 1 to 5 characterized in that it further comprises an anionic surfactant which is preferably sodium sulfosuccinate, sodium laurylsulfate, sodium hexadecylsulfate, sodium hexadecylsulfonane and/or sodium dioctylsulfo-succinate, still preferred sodium laurylsulfate, in the total volume from 0.1% to 10%, of the tablet weight, preferably 0.5-1%, most preferred in the concentration of 0.6%, of the tablet weight.

7. A method of preparation of the tablet according to any of the claims 1 to 6 characterized in that the tablet is prepared by wet granulation.

8. The method of preparation according to claim 7 characterized in that the produced granulate is dried by the use of a multi-storey drier, a vacuum drier, or a fluid bed dryer, or by the use of microwave, or infra-radiation.

9. The method of preparation according to the claims 7 or 8 characterized in that the tablet is coated with a hydrophilic mixture, preferably OPADRY, in the concentration up to 5% of tablet weight, preferably 1-3% of tablet weight.