WO2009138224A1

WO2009138224A1 - Pharmaceutical composition comprising drospirenone

Info

Publication number: WO2009138224A1
Application number: PCT/EP2009/003409
Authority: WO
Inventors: Sonja Lieb
Original assignee: Helm Ag
Priority date: 2008-05-14
Filing date: 2009-05-13
Publication date: 2009-11-19

Abstract

The present invention relates to a pharmaceutical composition comprising drospirenone, to a solid pharmaceutical composition obtainable by direct compression of said pharmaceutical composition and to a process for the preparation of said pharmaceutical composition.

Description

Pharmaceutical composition comprising Drospirenone

Drospirenone, having the chemical name 6β,7β,15β,16β-Dimethylen-3-oxo-17α-pregn-4- en-21 ,17-carbolactone, is represented by the formula below.

Drospirenone is a synthetic gestagen that shows additional aldosterone-antagonistic and antiandrogen properties. It is known since 1976 and it is used as an oral contraceptive, e.g. in combination with ethinylestradiol. Drospirenone is hardly soluble in water or aqueous buffer solutions and thus shows a low dissolution rate and bioavailability.

Fotherby discloses that the disintegration rate and the dissolution rate, which are important aspects of bioavailability, can be improved by grinding the active component to a very fine state (micronization) to increase the surface area of the drug. This results in an increase in the dissolution rate and hence in absorption (Bioavailability of Orally Administered Sex Steroids Used in Oral Contraception and Hormone Replacement Therapy, Fotherby, Contraception 1996, 54, 59-69).

WO 2001/015701 A1 discloses to improve the dissolution profile of drospirenone by dissolving drospirenone in a suitable solvent and spraying this solution onto the surface of inert carrier particles. WO 2005/087194 A1 relates to pharmaceutical compositions comprising steroidal drugs, such as drospirenone, in a molecularly dispersed form.

WO 2005/087199 A2 relates to pharmaceutical compositions comprising a powder of lipophilic compounds, such as drospirenone, in molecularly dispersed form together with a carrier having a specific surface area of at least 250 m²/g.

However, micronization techniques are costly, difficult to handle and require special equipment. Moreover, micronization of highly active substances have to be carried out under special precautions to avoid contact of the environment with the highly active substance. These precautions are costly and, therefore, economically disadvantageous. Furthermore, due to the high surface area of the micronized particles, electrostatic charging often results in particles which show disadvantageous flow properties making these particles inapplicable for most formulation techniques, such as direct compression.

Furthermore, drospirenone has a low chemical stability. Under acidic conditions, drospirenone is rapidly degraded to a physiologically inactive substance. Under alkaline conditions, drospirenone undergoes hydrolysis. Such degradation reactions in particular occur in wet granulation processes or when drospirenone is dissolved and sprayed onto carrier particles. Moreover, molecularly dispersing drospirenone in carriers may reduce the availability of the drug due to interactions of drospirenone and the carrier matrix. Additionally, such processes are costly due to the required special technical equipment.

Therefore, there is still a need for pharmaceutical compositions comprising drospirenone, wherein the drospirenone is chemically and morphologically stable, fast dissolving and showing improved bioavailability.

It has now been found that the above mentioned problems can surprisingly be overcome by a pharmaceutical composition comprising drospirenone substantially in amorphous form and a certain pharmaceutically acceptable carrier and the drospirenone and the pharmaceutically acceptable carrier are present in a co-milled state. In such composition drospirenone exhibits good chemical stability, excellent dissolution properties and bioavailability. In particular, by co-milling drospirenone and the pharmaceutically acceptable carrier, an improved dissolution in aqueous systems is achieved, compared to the dissolution of known crystalline forms of drospirenone. Furthermore, the drospirenone particles can be easily and cost effectively prepared, show excellent flow properties and can thus be further processed in a simple manner, for example by direct compression, to obtain solid pharmaceutical dosage forms.

The present invention therefore relates to a pharmaceutical composition comprising drospirenone, wherein the drospirenone is present in the composition substantially in amorphous form, the composition comprises a pharmaceutically acceptable carrier selected from the group consisting of hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), and microcrystalline cellulose (MCC), and the drospirenone and the pharmaceutically acceptable carrier are present in a co-milled state.

Drospirenone is known in the art. It can, for example, be prepared according to the methods disclosed in DE 26 52 761 and DE 30 22 337. Drospirenone is present in the pharmaceutical composition of the present invention substantially in amorphous form. Preferably more than about 90 wt%, more preferably more than about 95 wt%, such as more than about 99 wt%_/ in particular about 100 wt% of drospirenone based on the total weight of the drospirenone is present in amorphous form. In other words, it is prefered that no crystalline drospirenone can be detected within the pharmaceutical composition of the present invention by any detection method known in the art, such as infrared spectroscopy (IR), Raman spectroscopy, differential scanning calorimetry (DSC) or measurement of the powder X-ray diffraction pattern, in particular X-ray diffraction and DSC. Therefore, as used herein, the term "amorphous" describes a solid devoid of long-range crystalline order. Such amorphous form of a solid can be identified by the lack of discrete peaks in an X-ray powder diffraction pattern and/or the observation of a glass transition point in a DSC diagram.

The pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier. The carrier is selected from the group consisting of hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), such as povidone K12, and povidone K30, and microcrystalline cellulose (MCC). Most preferred is HPMC.

Drospirenone and the pharmaceutically acceptable carrier are present in the pharmaceutical composition of the present invention in a co-milled state. The term "co- milled state" means that the drospirenone particles and the particles of the pharmaceutically acceptable carrier are mixed and the mixture is milled or both ingredients are milled together to from a mixture. Preferably, co-milling is conducted without addition of any further ingredients. The co-milling results in a two-phase system of distinct drospirenone and carrier particles wherein the particles are, however, in more intimate contact with each other than in a mere blend of the compounds. The difference between a co-milled product and a blend will be explained in more detail below.

The co-milled state of drospirenone and the pharmaceutically acceptable carrier can be obtained by intensively mixing drospirenone and the pharmaceutically acceptable carrier in a suitable milling equipment, for example a ball milling equipment, such as a planetary ball mill (e.g. Pulverisette^®) or an agitator ball mill. These and further suitable milling equipment and how to conduct the milling with this equipment is known to a person skilled in the art.

The pharmaceutical composition according to the present invention can comprise about 5 wt% to about 75 wt% of drospirenone, preferably about 20 wt% to about 75 wt% of drospirenone, in particular about 25 wt% to about 75 wt% of drospirenone, based on the total weight of the composition.

In one embodiment of the present invention, the ratio of drospirenone to the pharmaceutically acceptable carrier in the pharmaceutical composition of the present invention is about 3:1 to about 1 :10, more preferably about 1 :1 to about 1 :5, in particular about 1 :2 to about 1 :3, such as about 1 :2.5, based on parts per weight.

The pharmaceutical composition of the present invention may further comprise suitable pharmaceutically acceptable excipients and adjuvants, for example selected from the group consisting of fillers, disintegrants, binders, glidants and lubricants. Optionally, coloring and/or sweetening agents can be added. If the pharmaceutical composition of the present invention is intended to be subjected to direct compression to obtain a solid pharmaceutical composition, the excipients and adjuvants are selected such that they are suitable for direct compression. Which excipients and adjuvants are suitable for direct compression can be determined by standard methods and is known to a person skilled in the art.

As fillers celluloses and cellulose derivatives, such as microcrystalline cellulose, powder cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and methylcellulose; sugars, such as lactose, fructose, saccharose, glucose and maltose; sugar alcohols, such as lactitol, mannitol, sorbitol, and xylitol; inorganic fillers, such as calcium phosphates and calcium sulfates; and starches and starch derivatives, such as corn starch, potato starch, wheat starch, dextrins, and pregelatinized starches can be exemplified. The pharmaceutical composition of the present invention preferably contains about 0 wt% to about 95 wt% of a filler, more preferably about 1 wt% to about 85 wt% of a filler, most preferably about 20 wt% to about 80 wt% of a filler, based on the total weight of the composition.

As disintegrants starches, modified starches, sodium starch glycolate, pregelatinized starch, celluloses, such as microcrystalline cellulose, carboxymethyl cellulose, modified sodium carboxymethyl cellulose, e.g. crosscarmellose sodium, crospovidone and mixtures thereof can be exemplified. The pharmaceutical composition of the present invention preferably contains about 0 wt% to about 50 wt% of a disintegrant, more preferably about 1 wt% to about 25 wt% of a disintegrant, in particular about 3 wt% to about 20 wt% of a disintegrant, based on the total weight of the composition.

The pharmaceutical composition of the present invention may further comprise one or more suitable binders, for example povidone and its derivatives. Binders are preferably present in an amount of about 0 wt% to about 50 wt%, preferably about 1 wt% to about 25 wt%, in particular about 3 wt% to about 20 wt%, based on the total weight of the composition.

The pharmaceutical composition of the present invention may further comprise one or more glidants, such as talc and/or silicon dioxide, e.g. colloidal silicon dioxide. The pharmaceutical composition of the present invention preferably contains about 0 wt% to about 10 wt% of a glidant, more preferably about 0.1 wt% to about 7.5 wt% of a glidant, in particular about 0.1 wt% to about 5 wt% of a glidant, such as about 0.1 wt% to about 3 wt% of a glidant, based on the total weight of the composition.

The pharmaceutical composition of the present invention may further comprise one or more lubricants. Suitable lubricants are for example stearic acid and derivatives thereof, such as calcium stearate, sodium stearyl fumarate or magnesium stearate, as well as glycerol stearate and hydrogenated vegetable oil. The lubricant may be present in an amount of about 0 wt% to about 10 wt%, preferably about 0.1 wt% to about 10 wt%, in particular about 0.1 wt% to about 7.5 wt%, such as about 0.1 wt% to about 3 wt%, based on the total weight of the composition.

In one embodiment, the pharmaceutical composition of the present invention contains about 0 wt% to about 95 wt%, preferably about 1 wt% to about 85 wt%, in particular about 20 wt% to about 80 wt% of a filler, about 0 wt% to about 50 wt%, more preferably about 1 wt% to about 25 wt%, in particular about 3 wt% to about 20 wt% of a disintegrant, about 0 wt% to about 50 wt%, more preferably about 1 wt% to about 25 wt%, in particular about 3 wt% to about 20 wt% of a binder, about 0 wt% to about 10 wt%, more preferably about 0.1 wt% to about 5 wt%, in particular about 0.1 wt% to about 3 wt% of a glidant, and about 0 wt% to about 10 wt%, more preferably about 0.1 wt% to about 10 wt%, even more preferred about 0.1 wt% to about 7.5 wt%, in particular about 0.1 wt% to about 3 wt% of a lubricant, each based on the total weight of the composition.

The amounts of the ingredients of the pharmaceutical composition have to sum up to 100 wt%.

The present invention further relates to a solid dosage form, preferably a tablet, in particular an immediate release tablet, which is most preferably obtainable by direct compression.

In one embodiment of the present invention, the ratio of the pharmaceutically acceptable excipients and adjuvants to the co-milled composition comprising drospirenone and the pharmaceutically acceptable carrier is in the range from about 1 :10 to about 30:1 , more preferably in the range from about 1 :5 to about 10:1 , based on parts per weight.

The present invention further relates to a process for the preparation of a pharmaceutical composition as described above, i.e. comprising drospirenone which is substantially in amorphous form and a pharmaceutically acceptable carrier selected from the group consisting of hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), and microcrystalline cellulose (MCC), drospirenone and the pharmaceutically acceptable carrier being present in a co-milled state, the process comprising the step of

a) co-milling of drospirenone and the pharmaceutically acceptable carrier and b) optionally adding one or more pharmaceutically acceptable excipients or adjuvants, c) optionally using the mixture obtained in steps a) or b) for the preparation of a solid dosage form, preferably pressing the mixture obtained in steps a) or b) into a solid dosage form, preferably a tablet obtained by direct compression.

The co-milling step of the process of the present invention (step a)) can be carried out as described above to obtain an intimate mixture of drospirenone and the pharmaceutically acceptable carrier in a co-milled state, preferably without using any solvent, thus, it is preferred to provide a mixture of drospirenone and a pharmaceutically acceptable carrier and to intensively blend said mixture in a suitable milling equipment, such as a ball mill or agitator bail mill. How to conduct the co-milling step in the process for the present invention is known to a person skilled in the art.

In one embodiment of the present invention, the process further comprises the step of adding one or more pharmaceutically acceptable excipients or adjuvants (step b)), whereby the preferred excipients and adjuvants and the preferred amounts to be used are such as described above.

In a further embodiment of the process of the present invention, the mixture obtained in above steps a) or b) is used for the preparation of a solid dosage form, preferably a tablet, in particular an immediate release tablet. Preferably, the mixture obtained in step a) or step b) is subjected to direct compression. Devices and conditions how to conduct compression, in particular direct compression, of a pharmaceutical composition are known to a person skilled in the art.

Preferably, the solid pharmaceutical composition of the present invention, which is in particular a tablet, contains about 2 mg to about 4 mg of drospirenone per single dosage unit.

In one embodiment of the present invention, the pharmaceutical composition comprises as additional pharmaceutically active ingredient ethinylestradiol. Preferably, the pharmaceutical composition contains the additional pharmaceutically active ingredient in an amount of about 0.01 mg to about 0.05 mg per single dosage unit.

In one embodiment, the solid dosage form of the present invention is coated. Suitable coatings or films are for example prepared from polymethacrylates, such as Eudragit^®, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, cellulose acetate phthalate and/or shellac.

In the pharmaceutical composition of the present invention drospirenone exhibits a good chemical stability although it is in amorphous form. The chemical stability of a composition comprising drospirenone (DRSP) being co-milled with HPMC in a ratio of 1 :2 is demonstrated by storage of said composition at 25°C and 75 % relative humidity over 3 months. The results are summerized in the following table:

^* As is, ratio DRSP: HPMC 1 :2

Furthermore, the pharmaceutical composition shows improved and advantageous dissolution of drospirenone in aqueous systems as compared to known compositions comprising drospirenone in crystalline form. In particular, the pharmaceutical composition of the present invention releases drospirenone completely. These advantages are probably due to the fact that the composition of the present invention stabilizes the amorphous form of drospirenone. This is for example confirmed by powder X-ray diffraction patterns and DSC measurements conducted (cf. Figures 6, 7, 11 , 12 and 15). For comparison, Figures 1 and 2 show the powder X-ray diffraction pattern and DSC of the crystalline form of drospirenone.

To further illustrate the differences between the pharmaceutical composition of the present invention and the prior art compositions, i.e. micronized drospirenone, molecularly dispersed drospirenone and drospirenone sprayed onto a carrier, Raman measurements have been conducted. Figure 3 shows the Raman spectrum of pure drospirenone and Figure 4 shows the Raman spectrum of pure HPMC. In Figure 8, the Raman image of co- milled drospirenone/HPMC, i.e. a pharmaceutical composition according to the present invention, is shown. In this image, two positions are marked, one as cross (position at 67 μm, 85 μm) and one as circle (position at 137 μm, 16 μm). The Raman spectra at these positions are shown in Figures 9 and 10. From these spectra, it can be determined which material is mainly present at the specific position of the sample. Thus, the ratio of the concentration of drospirenone to HPMC can be determined for each position of the Raman image. Regarding the Raman image shown in Figure 8, it can be seen that there are small areas showing a high drospirenone signal, e.g. at the "cross" area, and areas showing a rather low drospirenone signal and an increase in the HPMC signal, e.g. the "circle" area. In general, the areas with high drospirenone / low HPMC and low drospirenone / high HPMC signals do not exceed roughly 10 by 10 μm each.

Contrary to that, Raman images of the prior art compositions are different. Figure 16 shows the Raman image of micronized drospirenone which was blended with HPMC. In this image, much larger areas are observed, wherein the drospirenone signal is constantly high (Figure 17) or the HPMC signal is constantly high (Figure 18), respectively. Further, Figure 19 shows a Raman image of molecularly dispersed drospirenone in HPMC. Due to the homogenous distribution of drospirenone in the HPMC, the Raman image does not show significant differences at different positions, i.e. the spectra at two positions of this map are rather similar (Figures 20 and 21). Figure 22 shows a Raman map of drospirenone sprayed onto HPMC. Similarly to the molecularly dispersed drospirenone in HPMC, no significant differences in the area of the sample can be observed (Figures 23 and 24) demonstrating a homogenous distribution of drospirenone and excipient throughout the sample where drospirenone is entrapped within the excipient matrix.

Thus, as it can be seen from the above described Raman images, the co-milled drospirenone/HPMC, i.e. the preferred pharmaceutical composition according to the present invention, exhibits well distributed small areas of high drospirenone / low carrier content and areas of low drospirenone / high carrier content. The comparative measurements demonstrate that such a distribution is not obtained by processes as described in the prior art, i.e. blending of micronized drospirenone with a carrier, molecularly dispersing drospirenone in a carrier or spraying drospirenone onto carrier particles. Moreover, drospirenone in a carrier after co-milling is present in amorphous form (see X- ray diffraction patterns, Figures 6, 11 , 15 and 25). This is in agreement with the X-ray diffraction patterns of the drospirenone in the solid solution and the drospirenone being sprayed onto a carrier described in the prior art. In contrary, after micronization drospirenone is still present in crystalline form, rendering the dissolution behavior dependent on the selected particle size.

Thus,

1) combining the results of the two methodologies, Raman and X-ray diffraction, it can be concluded that drospirenone in the composition according to the invention is present in amorphous fast dissolving form, and

2) drospirenone is not distributed homogeneously throughout a dissolution controlling matrix but new fast dissolving drospirenone / carrier particles are formed having areas rich and poor in drospirenone.

Hence the new co-milled particles combine the advantages of a fast release of drospirenone but avoid the disadvantages of other formulations known in the art for steroidal drugs. For example, the co-milling procedure avoids the need of solvents thus reducing the risk of decomposition of drospirenone and avoiding the problems associated with residual solvent molecules in pharmaceutical compositions. Furthermore, the co- milling procedure does not require technically sophisticated and expensive equipment as it is needed for the micronization procedure. Hence the co-milling has an economic advantage over the micronization process, too.

Furthermore, the pharmaceutical composition according to the present invention comprising drospirenone and a pharmaceutically acceptable carrier in a co-milled state combines the advantages of the fast release of drospirenone and the good chemical and morphological stability of drospirenone, in particular by avoiding destabilization of drospirenone due to the absence of any solvent. Furthermore, the pharmaceutical composition provides excellent flow properties and can thus easily be further processed into solid pharmaceutical compositions, such as tablets. These advantageous characteristics of the pharmaceutical composition are also fully retained when the composition is processed into solid dosage form, e.g. a tablet. In particular, direct compression, which is preferred according to the present invention, does not entail any negative change in morphology, dissolution and stability of drospirenone by the formulation process.

The present invention also relates to the use of a pharmaceutically acceptable carrier selected from the group consisting of hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), and microcrystalline cellulose (MCC) for the preparation of a pharmaceutical composition comprising drospirenone substantially in amorphous form and wherein the pharmaceutically acceptable carrier and drospirenone are present in a co- milled state.

Figure 1 shows the powder X-ray diffraction pattern of crystalline drospirenone.

Figure 2 shows the DSC of crystalline drospirenone.

Figure 3 shows the Raman spectrum of drospirenone.

Figure 4 shows the Raman spectrum of HPMC.

Figure 5 shows the overlaid Raman spectra of drospirenone (API) and HPMC.

Figure 6 shows the powder X-ray diffraction pattern of drospirenone/HPMC co-milled particles according to the present invention, Example 1.

Figure 7 shows the DSC of drospirenone/HPMC co-milled particles according to the present invention, Example 1.

Figure 8 shows the Raman image of drospirenone/HPMC co-milled particles according to the present invention, Example 1.

Figure 9 shows the Raman spectrum of drospirenone/HPMC co-milled particles at the "cross" area in Figure 8.

Figure 10 shows the Raman spectrum of drospirenone/HPMC co-milled particles at the "circle" area in Figure 8. Figure 11 shows the powder X-ray diffraction pattern of drospirenone/PVP co-milled particles according to the present invention, Example 3.

Figure 12 shows the DSC of drospirenone/PVP co-milled particles according to the present invention, Example 3.

Figure 13 shows the dissolution profiles of crystalline drospirenone (API) and several drospirenone co-milled formulations in 0.1 N HCL.

Figure 14 shows the dissolution profiles of crystalline drospirenone (API) and several drospirenone co-milled formulations in water.

Figure 15 shows the powder X-ray diffraction pattern of drospirenone/HPMC co-milled particles according to the present invention, Example 1, after open storage for 14 days at 40⁰C, 75 % rh (relative humidity).

Figure 16 shows the Raman image of micronized drospirenone blended in HPMC according to the prior art (WO 2001/015701).

Figure 17 shows the Raman spectrum of micronized drospirenone blended in HPMC at the "cross" area in Figure 16.

Figure 18 shows the Raman spectrum of micronized drospirenone blended in HPMC at the "circle" area in Figure 16.

Figure 19 shows the Raman image of molecularly dispersed drospirenone in HPMC (solid solution) according to the prior art (WO 2005/087194).

Figure 20 shows the Raman spectrum of molecularly dispersed drospirenone in HPMC (solid solution) at the "cross" area in Figure 19.

Figure 21 shows the Raman spectrum of molecularly dispersed drospirenone in HPMC (solid solution) at the "circle" area in Figure 19. Figure 22 shows the Raman image of drospirenone sprayed onto HPMC according to the prior art (WO 2005/087199).

Figure 23 shows the Raman spectrum of drospirenone sprayed onto HPMC at the "cross" area in Figure 22.

Figure 24 shows the Raman spectrum of drospirenone sprayed onto HPMC at the "circle" area in Figure 22.

Figure 25 shows the powder X-ray diffraction patterns of a prior art preparation obtained by spraying drospirenone (DRSP) onto HPMC granules, a prior art preparation being a solid solution of DRSP in HPMC₁ a prior art formulation being a blend of micronized DRSP and HPMC and a co-milled formulation of DRSP and HPMC according to the invention (from upper to lower diagram).

Methods:

HPLC

The details of the HPLC method used are outlined below:

Column: Zorbax C18, 3.5μ 100 x 2.1

Mobile phase: AcCN:H₂O=46:54

Flow rate: 0.5 ml/min.

Detection: UV, 270nm

Injection volume: 20 μL

Column temperature: 3O⁰C

A calibration curve was generated for drospirenone in the range of 22-54 μ/mL which was found to be linear with an r² value of 0.9987.

Differential Scanning Calorimetrv (DSC)

Thermal analysis of solid solutions and their components was carried out using a Perkin Elmer Diamond DSC equipped with a liquid nitrogen cooling unit. Samples of 3-7mg were accurately weighed into non-hermetically sealed aluminium DSC pans and analysed in hyper-DSC mode. Once a stable heat-flow response was seen, the sample was heated to just below the degradation temperatures at a scan rate of 200°C/min and the resulting heat flow response was monitored. A helium purge was used (flow rate = 20 ml min^'1) to prevent thermally induced oxidation of the sample during heating. Prior to analysis the instrument was temperature and heat-flow calibrated using an indium reference standard.

Initially a sample of the pure API was scanned to determine the position of any melting peak. The sample was then quench cooled, i.e. cooled rapidly to convert into an amorphous form, and re-scanned to determine the glass transition temperature (Tg) of the amorphous state. Samples of the 5 pure polymers were also scanned in order to determine their Tg values. These were taken into account when determining whether the solid solutions were successfully formed after the formulation process.

X-Rav Powder Diffraction (XRPD)

The sample (150 mg) was spread onto the sample holder. The sample was then loaded into a Philips X-Pert MPD diffractometer, and the sample was analysed using the following experimental conditions.

Tube anode: Cu

Generator tension: 42 kV

Tube current: 42 mA

Wavelength α1 : 1.5426 A

Wavelength α2: 1.5464 A

Start angle [2Θ]: 5

End angle [2Θ]: 50

Time per step: 2.5 seconds

Scan step size: 0.02

Dissolution testing

The conditions used for dissolution testing were as follows:

Configuration: Paddles Dissolution medium: 900 ml of 0.1 N HCI or 900 ml of water

Temperature: 39.0⁰C ± 0.5⁰C

Filter: 1 μm (and 0.2 μm)

Paddle speed: 100 rpm

Sample volume: 1 ml

Sample Time: 2, 7, 15, 30, 47, 60 and 120 minutes.

Sample quantity: Formulations were added so that each dissolution vessel equivalent of 3 mg of API.

The formulations and API were filled into size "1" hard gelatine capsules which were then placed into the dissolution vessels.

Raman Mapping

Raman mapping was carried out using a Nicolet Almega XR Dispersive Raman Microscope. Raman mapping parameters were as follows:

Exposure time 0.5 seconds

Pinhole range 25 μm

Laser Helium (633 nm)

Scanning spectral range 1700-900 cm^"1

Scanning area 16O x 160 μm²

Scanning step 5 μ

Objective lens 50x70.80

Each spot was measured ten times to give a good signal to noise ratio. Spectra of drospirenone and HPMC were measured initially and suitable peaks unique to each component were identified and used to produce the maps. Mapping of the individual components was carried out, however this is subject to variations by topography. By mapping based on the ratio of API to excipient, variations due to an uneven surface topography were corrected. Prior to mapping, the samples were compressed using a die and punch of surface area 1cm², applying a pressure of 5 tons for 20 - 30 seconds. Reference spectra of drospirenone and HPMC were taken. These as well as the overlaid spectra are shown in Figures 3, 4 and 5. A strong signal at -1590 cm^'1 was observed for the API, i.e. drospirenone, with no signal in this range of the HPMC Raman spectrum. A signal at ~1450 cm^"1 was chosen to indicate the HPMC, with only a low signal in this range of the API Raman spectrum. It can also be noted that the intensity (signal) of the API is -10 times stronger than the intensity (signal) of the HPMC.

The Raman images represent the intensities of the signals at the chosen wavelengths (i.e. ~1590 cm^"1 for the API, and ~1450 cm^"1 for the carrier). The absolute intensities of both signals correlate with each other and actually correlate with the physical topography of the sample. This is effectively the "background noise" from preparing the samples, i.e. the absolute intensity of the signals due to both the API and excipient correlate with the shape of the sample.

To correct for the topography, i.e. to determine the real data on the distribution of the API and excipient within the sample, the following method was applied. The ratio of the intensity of the signal due to the API to the intensity of the signal due to the excipient is determined.

From this analysis, the variation of absolute signal intensity due to height variations of the sample is averaged out, which therefore do not affect the resulting data anymore (map). Thus, a sample that shows uniform distribution of API and excipient across the mapped region with little or no change in the intensity ratio is obtained. In contrast, a sample that has regions of mostly API and regions of mostly excipient shows large changes in the intensity ratio across the mapped region. All of the samples have been prepared and analysed in identical manners, so any observed differences are due to the nature of the investigated composition.

Another relevant factor is that the intensity of the Raman signal is different between the API and the excipient. The API gives a strong Raman signal typically in the region of 1000 cm^"1 to 1500 cm^"1. The excipient gives a weak Raman signal, typically in the region of 50 cm^"1 to 100 cm^"1. The Raman probe provides a resolution of roughly 0.5 x 0.5 microns. Thus, regions of mostly API that are larger than 0.5 x 0.5 μm give a strong response in the Raman mapping, regions in the mapping that give weak Raman response indicate less API content. The invention will now be further illustrated by the following examples, which are not intended to be limiting.

Example 1

Drospirenone 3 mg

HPMC 6 mg

1 g of drospirenone and 2 g of HPMC were blended in a planetary ball mill (Pulverisette^®) for a period of 12 - 48 hours. The resulting co-milled composition was divided into single dosages containing 3 mg of drospirenone each.

Example 2

Drospirenone 3 mg

HPMC 6 mg

Povidone 4 mg

Co-milled particles from drospirenone were prepared by blending 1 g of drospirenone, 1.3 g of Povidone and 2 g of HPMC in an agitator ball mill for a period of 0.5 - 3 hours. The resulting co-milled composition was divided into single dosages containing 3 mg of drospirenone each.

Example 3

Drospirenone 3 mg

Povidone K12 6 mg

The formulation was prepared according to Example 1 or 2 using 1 g of drospirenone and

2 g of Povidone K12.

Example 4

Drospirenone 3 mg Povidone K30 9 mg

The formulation was prepared according to Example 1 or 2 using 1 g of drospirenone and 3 g of Povidone K30.

Example 5

Drospirenone 3 mg microcrystalline cellulose (MCC) 9 mg

The formulation was prepared according to Example 1 or 2 using 1 g of drospirenone and 3 g of microcrystalline cellulose.

Example 6

Drospirenone 3 mg

HPMC 6 mg

Ethinylestradiol 0.03 mg

Magnesium stearate 0.8 mg

Povidone 4 mg

Lactose monohydrate 41.17 mg

Maize starch 24 mg

Co-milled particles of drospirenone were prepared according to Example 1 or 2 (I). 1 g of lactose monohydrate was sieved, 10 mg of ethinylestradiol were added and both ingredients were premixed in a plastic bag (II). 12.7 g of lactose, 8 g of maize starch (and 1.3 g of povidone if co-milled particles are prepared according to Example 1) were sieved, added to the processor and bjended for 5 min. (I) and (II) were added to this excipient mixture and blended for another 15 - 20 min. The dry mixture was sieved, 0.3 g of magnesium stearate were added and the final mixture was blended for another 3 - 5 min. The mixture was further processed to tablets of the above composition by direct compression.

The obtained tablets may be coated using suitable pharmaceutically acceptable coating agents.

Claims

1. Pharmaceutical composition comprising drospirenone, characterized in that the drospirenone is present in the composition substantially in amorphous form, the composition comprises a pharmaceutically acceptable carrier selected from the group consisting of hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), and microcrystalline cellulose (MCC), and the drospirenone and the pharmaceutically acceptable carrier are present in a co-milled state.

2. Pharmaceutical composition according to claim 1 , comprising about 5 wt% to about 75 wt% of drospirenone, based on the total weight of the composition.

3. Pharmaceutical composition according to claims 1 or 2, wherein the ratio of the drospirenone to the pharmaceutically acceptable carrier based on parts per weight is about 3:1 to about 1 :10.

4. Pharmaceutical composition according to any of the preceding claims, wherein the ratio of drospirenone to the pharmaceutically acceptable carrier based on parts per weight is about 1 :2 to about 1 :3.

5. Pharmaceutical composition according to any of the preceding claims, characterized in that the composition comprises one or more pharmaceutically acceptable excipients or adjuvants, selected from the group consisting of fillers, disintegrants, binders, glidants and lubricants.

6. Pharmaceutical composition according to any of the preceding claims, characterized in that it further comprises about 0 wt% to about 95 wt% of a filler, about 0 wt% to about 50 wt% of a disintegrant, about 0 wt% to about 50 wt% of a binder, about 0 wt% to about 10 wt% of a glidant, about 0 wt% to about 10 wt% of a lubricant, each based on the total weight of the composition.

7. Pharmaceutical composition according to any of the preceding claims, which is in the form of a solid dosage form, in particular a tablet.

8. Solid pharmaceutical composition according to claim 7, obtainable by direct compression.

9. Process for the preparation of a pharmaceutical composition as defined in any of the preceding claims comprising

a) co-milling of drospirenone and a pharmaceutically acceptable carrier, selected from the group consisting of hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), and microcrystalline cellulose (MCC), b) optionally adding one or more pharmaceutically acceptable excipients or adjuvants, and c) optionally using the mixture obtained in steps a) or b) for the preparation of a solid dosage form.

10. Process according to claim 9, wherein the solid dosage form of step c) is a tablet.

11. Use of a pharmaceutically acceptable carrier selected from the group consisting of hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), and microcrystalline cellulose (MCC) for the preparation of a pharmaceutical composition comprising drospirenone substantially in amorphous form and wherein the pharmaceutically acceptable carrier and drospirenone are present in a co-milled state.