The subject matter of the invention are pharmaceutical compositions comprising ziprasidone free base or ziprasidone hydrochloride and the method for their preparation.

Ziprasidone free base is a compound with the chemical formula as follows:

Ziprasidone is typically administered as hydrochloride acid addition salt, hydrochloride or monohydrate of this salt with the chemical formula:

The method for preparation of ziprasidone hydrochloride was presented in the US patent specification No. US 4 831 031, where also its application as a neuroleptic agent useful inter alia in the treatment of schizophrenia was disclosed. Ziprasidone free base and ziprasidone hydrochloride are hereinafter collectively referred to as "ziprasidone" for convenience.

Ziprasidone belongs to the class Il of Biopharmaceutical Classification System (BCS), which indicates that the active ingredient is poorly soluble in water but highly permeable across biological barriers. Therefore, the factor having a decisive influence on bioavailability of the drugs belonging to this class is their solubility. The size of active ingredient crystals is a parameter which helps to control the solubility. The size of active ingredient crystals directly influences its absorption rate into the organism. This is particularly essential for ziprasidone, which is a highly active drug characterized by narrow therapeutic range.

As it was disclosed in patent No. PL 196 867 B ziprasidone is administered orally as hydrochloride acid addition salt. The drug containing ziprasidone in form of ziprasidone hydrochloride monohydrate is characterized with high permeability through biological barriers but it is poorly soluble in water, what negatively affects its bioavailability.

The formulation of pharmaceutical compositions containing active ingredients poorly soluble in water is difficult. The adequate preparation of pharmaceutical composition allows for increase of drug solubility what results in improvement of bioavailability. The use of various methods for preparation of pharmaceutical compositions containing active ingredients poorly soluble in water is known in the pharmaceutical industry It was disclosed in the international patent application No. WO 2006/024944 A that implementation of polymers in the pharmaceutical composition improves solubility of the drugs which are poorly soluble. This effect is achieved as a result of partial coating of the drug particles with polymer that preferably contains hydrophilic and hydrophobic groups. The polymer used in this invention was Hydroxypropyl Methylcellulose Acetate Succinate (HMPCAS) which contains low amount of carboxylic acid groups.

In turn, it was disclosed in the international patent application No. WO 2007/027273 A that the use of surface stabilizers such as hydroxypropyl methylcellulose, gelatin or sodium lauryl sulfate in pharmaceutical compositions allows for obtaining composition that in FAST (on an empty stomach) and FED (during or after the meal) studies has comparable pharmacokinetics. The method for preparation of this composition consists in contact of ziprasidone with at least one surface stabilizer in suitable conditions and for suitable time in order to receive ziprasidone particles of size lower than 2,000 nm. Emulsion polymerization processes, precipitation or supercritical extraction provide suitable conditions. The use of technologically advanced methods for preparation of the composition is expensive and may be problematic in the large- scale processes. The similar solution was presented in the US patent application No. US 2008/0305161 A where a ziprasidone depot formulation (pharmaceutical composition with prolonged action) for intramuscular and hypodermic administration is in the form of nanoparticles. The composition contains at least two surfactants, i.e. cetylpiridine chloride, gelatin, casein, phosphatides, etc.

There are also other methods for improvement of ziprasidone solubility such as use of cyclodextrins in pharmaceutical compositions described in the patent No. PL 189 324 B.

In turn, in the patent No. PL 195 209 B the pharmaceutical composition was disclosed that contains crystalline ziprasidone free base or crystalline ziprasidone hydrochloride in form of particles of size at most 85 μm, preferably particles of average size between 5-50 μm. Apart from ziprasidone the composition contains known pharmaceutically acceptable excipients, such as carboxymethyl cellulose, pregelatinized starch and others. The pharmaceutical composition is in a form of capsules and that is why the granulate volume is an important parameter that determines capsule size and patient comfort of medication administration. In the patent No. PL 195 209 B pharmaceutical compositions were disclosed that contain relatively low amount of active ingredient in the granulate (about 23% according to Example 3 (a)). Thus, a large capsule has to be used for relatively small drug dose. Such solution makes it necessary to use large capsules which can house the proper dosage unit which in turn can be uncomfortable for the patients when taking the drug.

The purpose of the present invention is to provide new pharmaceutical compositions containing ziprasidone and the method for their preparation.

As a result of work on pharmaceutical composition containing ziprasidone it was unexpectedly noticed that the use of ziprasidone in micronized form, adequately crosslinked polymer and disintegrant guarantees development of pharmaceutical composition with desired release profile parameters.

The term "adequately crosslinked polymer" refers to the polymer that forms hydrogel in aqueous environment and, while surrounding particles of the active ingredient, creates suitable environment favoring dissolution of ziprasidone. During research and development work on optimal drug formulation it was observed that ziprasidone in micronized form with the average particle size D[4.3] below 2 μm is dissolved worse than the larger particles. This observation is surprising as usually particles of a small size due to a larger solvent accessible surface area are more readily dissolved than the larger particles.

Thus, it was necessary to find the excipients which could increase rate of micronized ziprasidone dissolution.

As a result of work on development of pharmaceutical composition containing ziprasidone hydrochloride it was surprisingly found out that crospovidone perfectly meets above-mentioned requirements.

Crospovidone (polyvinylpyrrolidine) is a substance insoluble in water and is usually used in pharmaceutical compositions as a disintegrant.

Because of use of the micronized ziprasidone hydrochloride in the pharmaceutical composition according to the invention, crospovidone of average particle size within the range of 5-10 microns and large specific surface area about 2.0-2.5 m ² /g was advantageously used (an example of crospovidone of this type is known under the trade name Polyplasdone INF-IO, ISP). This polyvinylpyrrolidine has very high capillary activity what results in the increase of amount of water provided to the system, which in turn facilitates increase in substance dissolution rate. Moreover, during compression of crospovidone with other ingredients of the pharmaceutical composition they are significantly concentrated and intermolecular interactions are generated. Crospovidone when in contact with water forms a loose gel which surrounds ziprasidone particles and creates a local environment that facilitates dissolution of ziprasidone hydrochloride. Additionally, this phenomenon prevents ziprasidone particles from floating to the surface of acceptor fluid, forming agglomerates or adhering of substance particles to the vessel walls. Elimination of those phenomena increases contact surface area of ziprasidone and acceptor fluid and, as a consequence, the pharmaceutical drug availability is increased. Because of the tendency of crospovidone to form loose gels in aqueous environment the use of disintegrant is advantageous. It is especially preferable to use modern compounds belonging to the group of the so-called superdisintegrants. In the pharmaceutical composition according to the invention sodium carboxymethyl starch with sodium content in the range of 2.8-4.2% was used (it is known under the trade name Ultraamylopectin of type A, JRS Pharma).

The generally used pharmaceutically acceptable auxiliary substances such as lactose monohydrate (known under the trade name Flowlac-100), microcrystalline cellulose

(known under the trade name Avicel PHlOl) and magnesium stearate are used besides the carrier for preparation of the pharmaceutical composition according to the invention.

The pharmaceutical composition according to the invention contains ziprasidone hydrochloride in the form of micronized particles, wherein average particle size can be characterized by volume weighted mean D[4.3], which is less than 2 μm or by Sauter diameter D[3.2], which is less than 1 μm.

The term "average particle size" expressed by D [4.3] parameter lower than 2 μm or D

[3.2] parameter lower than 1 μm, measured by means of a method of particle size laser measurement by Malvern, means that the particles size of 90% is lower than 5 μm.

During research and development work on optimal drug form a great difference between aqueous solubility of ziprasidone free base and ziprasidone hydrochloride was observed. This phenomenon is compliant with data available on substances of low solubility, whose addition salts are dissolved to a larger extent -Table 1.

Table 1. Comparison of ziprasidone hydrochloride and ziprasidone free base solubility in water at 37°C.

However, it was surprisingly noticed that in the case of acetate buffer solution of pH 4.5, containing acetyl groups, reverse phenomenon is observed; solubility of ziprasidone base is much higher than solubility of ziprasidone hydrochloride which is presented in Table 2 and in Fig. 1.

Table 2. Comparison of ziprasidone hydrochloride and ziprasidone free base solubility in the solution containing acetyl groups and phosphate groups and at 37°C.

Physicochemical properties of both substances, i.e. ziprasidone hydrochloride and ziprasidone free base, significantly differ from each other (Table 3). Thus, it is obvious for persons skilled in the art that substances of such different physicochemical properties need quite different approach when developing the optimal pharmaceutical composition.

Table 3. Comparison of physicochemical properties of ziprasidone hydrochloride and ziprasidone free base.

When developing the optimal drug formulation an appropriate excipients was searched for, which could provide suitable amount of acetyl groups, forming the environment facilitating ziprasidone dissolution. It turned out unexpectedly during the investigations that the use of a polymer, polyacrylic acid of specific linear crosslinking, allows for obtaining pharmaceutical composition of the desired release profile. In the pharmaceutical composition according to the invention, polymer, polyacrylic acid (known as carbopol), was advantageously used. The polymer is characterized with high content of acetyl groups originating from residues of the solvent, ethyl acetate (max. residue level of the solvent ethyl acetate is 0.5%), which is used during synthesis of this polymer. The viscosity of the polymer is within the range 29,400-39,400 cp (viscosity measured for 0.5% w/w aqueous solution at 25°C, according to the European Pharmacopoeia). This type of carbopol is available under the trade name Carbopol 974P, Noveon.

It may seem surprising for persons skilled in the art of development of technologies of drug form preparation that polymer, polyacrylic acid, was used in order to increase the dissolution rate, as conventionally this polymer is used in slow release formulations because it forms hydrogels which gradually release an active ingredient to the solution. However, in case of ziprasidone free base, during investigations of pharmaceutical availability carbopol, on the one hand, forms hydrophilic matrix surrounding particles of active ingredient and on the other hand, it provides suitable microenvironment containing acetyl groups that facilitate dissolution of the drug.

Because polyacrylic acid forms hydrogel of high viscosity it is preferable to use disintegrant. It is especially preferable to use new compounds belonging to the group of the so-called superdisintegrants. In the pharmaceutical composition according to the invention sodium carboxymethyl starch with sodium content in the range 2.8-4.2% (known inter alia under the trade name Ultraamylopectin of type A, JRS Pharma) was used. The generally used pharmaceutically acceptable excipients such as lactose (known under the trade name Flowlac-100), microcrystalline cellulose (known under the trade name Avicel PHlOl) and magnesium stearate are used besides the carrier for preparation of the pharmaceutical composition according to the invention. The pharmaceutical composition according to the invention contains ziprasidone free base in the form of micronized particles, wherein average particle size can be characterized by volume weighted mean D[4.3], which is less than 2 μm or by Sauter diameter D[3.2], which is less than 1 μm.

The term "average particle size" expressed by D [4.3] parameter lower than 2 μm or D [3.2] parameter lower than 1 μm, measured by means of a method of particles size laser measurement by Malvern, means that the particles size of 90% is lower than 5 μm.

The method of investigation of drug pharmaceutical availability was chosen based on the methodology published in the FDA internet service (http://www.accessdata.fda.gov/scripts/cder/dissolution/inde x.cfm). The method comprises investigation of therapeutic substance release from the drug form with the help of apparatus Il (blade apparatus) with the rotational speed of 75 rpm. As the acceptor fluid 0.05M phosphate buffer solution of pH 7.5 containing 2% of sodium lauryl sulfate and pancreatin was added. The addition of pancreatin reduces the influence of hard gelatin capsule on degradation time and release rate of therapeutic substance. Additionally, in order to avoid floating of the drug onto the acceptor fluid surface capsules were placed in sinkers. The investigation of pharmaceutical availability consists of two stages. During the first stage the capsules are macerated for 15 minutes in 700 ml of 0.05M phosphate buffer solution containing 0.5% w/w pancreatin. In the second stage 200 ml of phosphate buffer solution of pH 7.5 and containing 9% w/w of sodium lauryl sulfate is added.

The amount of the dissolved ziprasidone can be determined using any common method, e.g. UV/Vis spectroscopic method, by comparing absorbance of investigated and standard solution in 1 cm layer at the wavelength of 319 nm in relation to acceptor fluid as a reference. It is typical of the pharmaceutical composition according to the invention that if the dosage form is placed in the apparatus Il according to the Ph. Eur. (blade apparatus) containing 0.05M phosphate buffer solution of pH 7.5 as acceptor fluid with 1% sodium lauryl sulfate and with pancreatin, equipped with blades stirring with speed equal to 75 rpm, at least 75% of ziprasidone contained in the dosage form is dissolved within 30 minutes.

It is obvious for persons skilled in the art that when developing the optimal technology of drug form preparation specific problems may occur in the case of substances in the form of micronized particles. The micronized substance tends to form large compact agglomerates which remain intact during mixing with excipients and during encapsulation. As a result, the granulate is not homogeneous, which negatively affects uniformity of dosage units. Moreover, the substance is not fully accessible for acceptor fluid, which can result in decrease of substance solubility and in limiting the drug bioavailability. Moreover, micronized ziprasidone has high bulk volume, which makes technological processes difficult and it can easily form dust. Additionally, high bulk volume of the granulate containing micronized ziprasidone makes it necessary to use very large capsules that can house the proper dosage unit. This may be uncomfortable for the patients taking the drug.

Unexpectedly, it was found out that the use of roller compaction method for granulate preparation for production of pharmaceutical composition containing micronized ziprasidone causes that bulk volume of the granulate is significantly lowered, flow properties are improved, the phenomenon of dusting and losses due to adhesion of active ingredient to the production devices are eliminated.

The use of roller compaction technique of micronized ziprasidone with at least one crosslinked polymer as a carrier allows for effective compression of ziprasidone particles and for obtaining granulate of high integration of the active ingredient with the carrier.

The method for preparation of pharmaceutical composition containing ziprasidone hydrochloride according to the invention is characterized by the following stages: a. the active ingredient (micronized ziprasidone) is subjected to granulation with at least one pharmaceutically acceptable carrier, b. obtained granules are calibrated , c. calibrated granulate is mixed with excipients, d. the granulate is subjected to encapsulation.

Preferably, the granulation process is conducted dry with use of roller compaction method.

The pharmaceutical composition according to the invention obtained in this way is characterized by high concentration of ziprasidone up to 60% w/w of the active ingredient in the granulate. As a result, a smaller capsule size for high doses of the preparation can be used and thus increasing patient's comfort in taking the drug.

This invention is illustrated with the following examples that do not limit the invention in any way:

Example 1

In the below described examples the powder for compaction containing 3.0 kg of substances mentioned in the following tables was prepared in the 20-L bin blender by Zanchetta. Dry granulation process was conducted in the roller compactor by Alexanderwerk WP 150 Pharma. During the process the pressing force of 8 kN/cm ² and sieve of 1.0 mm diameter were used for milling of the "ribbons" formed. The proportional granulate content was used for doses 20 and 40 mg as well as for 60 and 80 mg.

I Total J I 75.8 I

^(A) substance of average particle size D[4.3] below 2 μm (D[2,3] below 1 μm)

Example 2.

The following example illustrates influence of compaction process on the active ingredient release rate.

substance of average particle size D[4.3] below 2 μm (D[2,3] below 1 μm) * Prepared according to the scheme presented in Fig. 2 ** Prepared according to the scheme presented in Fig. 4

Based on the results presented in Fig. 5, it can be concluded that the use of compacting process for preparation of pharmaceutical composition according to the invention allows for obtaining the desired release profile.

Example 3.

The following example illustrates the influence of the polymer type used in the composition on active ingredient release rate.

* Composition prepared according to the scheme presented in Fig. 2 Based on the results presented in Fig. 6, it may be concluded that in the pharmaceutical composition only the use of crospovidone as a pharmaceutically acceptable carrier of high capillary activity being able to form loose gel in aqueous environment allows for obtaining the desired release profile.

In the below described examples, the powder for compaction containing 3.0 kg of substances mentioned in the following tables was prepared in the 20-L bin blender, by Zanchetta. Dry granulation process was conducted in the roller compactor by Alexanderwerk WP 150 Pharma. During the process the pressing force of 8 klM/cm ² and sieve of 1.0 mm diameter were used for milling of the "ribbons" formed. The proportional granulate content was used for doses 20 and 40 mg as well as for 60 and 80 mg.

Example 4.

The following example illustrates the influence of the polymer type used in the composition according to the invention.

Example 5.

The following example illustrates the comparison of ziprasidone release rate from the pharmaceutical composition containing ziprasidone free base and ziprasidone hydrochloride.

Composition No. 4* Composition No. 6*

Substance name mg / tablet

Ziprasidone free base 40.00 -

* Composition prepared according to the scheme presented in Fig. 7

According to the results presented in Fig. 9, the use of carbopol leads to obtaining the pharmaceutical composition consistent with the desired release profile only for ziprasidone free base.

Example 6.

The following example illustrates the influence of compacting process on ziprasidone release rate.

* Composition prepared according to the scheme presented in Fig. 7 ** Composition prepared according to the scheme presented in Fig. 10

Example 7.

The following example illustrates the influence of active ingredient particles size on ziprasidone release rate.

substance of average particle size D[4.3] below 2 μm (D[2,3] below 1 μm)

^(B) substance of average particle size D[4.3] about 20 μm

** Composition prepared according to the scheme presented in Fig. 10

Example 8.

The following example illustrates the influence of granulate particle size on active ingredient release profile from the capsules.

** Composition prepared according to the scheme presented in Fig. 9 Composition No. 10 - granulate particle size: D[v,0.9] - 97 μm Composition No. 9 - granulate particle size: D[v,0.9] - 170 μm

The subject matter of the invention is visualized in the figures, in which:

Fig. 1. Comparison of ziprasidone hydrochloride and ziprasidone free base solubility within the pH range of 1 to 7.5.

Fig. 2 presents the flow chart of preparation of composition No. 1

Fig. 3 presents obtained release profiles of the active ingredient

Fig. 4 presents the flow chart of preparation of composition No. 2

Fig. 5 presents obtained release profiles of the active ingredient from the composition No. 1 and composition No. 2

Fig. 6 presents the comparison of release profiles of the active ingredient from composition No. 1 and composition No. 3

Fig. 7 presents the flow chart of preparation of composition No. 4 and composition

No. 5

Fig. 8 presents the comparison of ziprasidone release profiles from compositions No.

4 and composition No. 5

Fig. 9 presents the comparison of ziprasidone release profiles from compositions No.

4 and composition No. 6

Fig. 10 presents the flow chart of preparation of composition No. 7

Fig. 11 presents the comparison of ziprasidone release profiles from compositions No.

4 and composition No. 7

Fig. 12 presents the comparison of ziprasidone release profiles from compositions No.

7 and composition No. 8

Fig. 13 presents the comparison of ziprasidone release profiles from compositions No.

9 and composition No. 10.