A stabilized formulation of fesoterodine

Technical Field

The invention relates to stable pharmaceutical formulations containing fesoterodine [2- [(lJ¾ -3-(di(propan-2-yl amino]-l-phenylpropyI]-4-(hydroxymethyl)phenyl3 2-methyl propanoate of formula I, or its salts, solvate or ester, and a method of their preparation.

Background Art

Fesoterodine is an antimuscarinic agent the use of which has been approved for the treatment of symptoms associated with the overactive bladder syndrome. In the market, fesoterodine is available as the product Toviaz® in the form of tablets with extended release for administration once a day in the strengths of 4 mg and 8 mg.

Fesoterodine (formula I), with the chemical name 2-[(lR)-3-(diisopropylamino)-

1-phenylpropyl] -4- [hydroxy methyl] phenyl isobutyrate is a new antimuscarinic agent, which functionally acts as a prodrug. It is quickly and extensively hydrolyzed in the body by ubiquitous non-specific esterases to 5-hydroxymethyl tolterodine (-HMT), which is an active metabolite responsible for all antimuscarinic activity.

Fesoterodine is an ester that is considerably prone to degradation after in vivo administration as well as during storage under stress conditions, e.g. in a wet environment and at high temperatures. Hydrolysis and oxidation are considered to be the main mechanisms leading to degradation of fesoterodine.

Fesoterodine was included in the generic application W01998043942 and it was specifically claimed in the application W01999/058478.

The application W02007/141298 deals with the problem of fesoterodine stabilization in pharmaceutical formulations for oral administration. Degradation of fesoterodine during stability testing was prevented with the use of a stabilizer selected from the group of xylitol, sorbitol, polydextrose, isomalt, dextrose and their combinations; xylitol being mentioned as especially preferable. These stabilizers were used in relatively high concentrations, namely in the ratio of the active substance to the stabilizer of 1:9 (by weight . The total content of impurities of formulations containing xylitol in the 1:9 concentration (fesoterodine : xylitol by weight) stored for 6 months at the room temperature in closed vials was 1.33% and 1.79%.

In the application WO2010/043408 the issue of fesoterodine stability is solved by micro-encapsulation of the active substance in coated pellets, which are subsequently compressed into tablets in a preferred embodiment. No specific auxiliary substances that should contribute to stabilization of fesoterodine are used. However, this application does not contain any data showing stability and the dissolution profile of the described formulation.

In the application WO2011/050961, stability of fesoterodine in the formulation is solved by addition of fibrous material in the quantity of 1:50 to 1:2 (fesoterodine : fibrous material, by weight). As preferred Fibrous materials alginate, gelatine, agar, Arabic gum, xanthan, carrageenan and tragacanth, especially kappa-carrageenan, are mentioned. In the examples of working the invention agar is used in the ratio of 1:10 and 1:20 (fesoterodine : fibrous material, by weight) and kappa-carrageenan in the ratio of 1:10 (fesoterodine : fibrous material, by weight). For two pharmaceutical formulations the total contents of impurities are mentioned, indicating degradation of fesoterodine, which achieved 0.39 to 0.44 after two weeks [probably in %, not specified). However, the storage conditions are not mentioned either, which means that the results cannot be compared to other results of stability tests. The use of natural fibrous materials is not convenient from the microbiological point of view as they may be a source of microbial contamination, and hence of microbial degradation of the pharmaceutical compositions they are contained in.

The issue of stability of fesoterodine in pharmaceutical formulations was also dealt with in the application WO2012/136838. Here, fesoterodine was first granulated with a stabilizer selected from the group of sucrose, polyethylene glycol, cyclodextrin and their combinations. This granulate was subsequently used for the preparation of a pharmaceutical formulation. According to the authors of the application WO2012/136838 the ratio between fesoterodine and the stabilizer should be preferably in the range of 1:1 to 1:20. In the mentioned embodiment examples, where sucrose, polyethylene glycol, maltodextrin and cyclodextrin were used as stabilizers, the ratio of fesoterodine to the stabilizer was always 1:9, i.e. the same ratio as in the above mentioned application W02007/141298 was used. Then, sucrose was also used in the 1:12 and 1:16 ratios. For these formulations the contents of impurities after two weeks' storage on an open dish at 60°C and 21% relative humidity varied between 1.8% and 7.8% [except the formulation containing maltodextrin, where the content of impurities was 15.9%).

The authors of the application WO2011/117884 described formulations of fesoterodine in which 80% of fesoterodine activity should be maintained after three months of storing at 40°C and the relative humidity of 75%, while these formulations do not contain any alcoholic sugar. However, the application only mentions results after one month's storing, namely in HDPE flasks with silica gel, the storage conditions being 1 month at 50°C and the relative humidity of 80%. After this period the total content of impurities was higher than 3% [by weight, related to fesoterodine fumarate). The formulations described in the examples contained commonly used pharmaceutical auxiliary substances (microcrystalline cellulose, lactose, corn starch, polyvinyl pyrrolidone, talc, magnesium stearate, hydroxypropyl methyl cellulose, polyethylene glycol, polyethylene oxide, silicon dioxide, magnesium stearate). However, a similar formulation prepared by the authors of the present application was surprisingly very instable (see Example B .

The application WO2012/136839 describes a dry formulation of fesoterodine free from stabilizers from the group of xylitol, sorbitol, polydextrose, isomalt and dextrose, in which fesoterodine is homogeneously mixed with at least one polymer controlling the release of fesoterodine from the formulation. A precondition for such formulations should be elimination of any humidity from the formulation process, as well as from the formulation itself, and at the same time homogeneous admixing of the polymer controlling releasing. For such formulations the contents of impurities after two weeks' storage on an open dish at 60°C and 21% relative humidity varied between 4.5% and 5.3%.

The aim of this invention was to prepare a stable pharmaceutical formulation containing fesoterodine that can be produced by standard pharmaceutical production processes and that will be stable under common storage conditions even with the use of a low concentration of the stabilizer (weight ratio of fesoterodine to the stabilizer 1:2 to 1:5).

Disclosure of Invention

The invention provides stable pharmaceutical formulations of fesoterodine, containing trehalose in a concentration weight ratio of fesoterodine or its pharmaceutically acceptable salt to trehalose of 1:0.5 to 1:5; wherein surprisingly high stabilization was achieved with the use of a low concentration of the stabilizer trehalose.

On the contrary, the higher concentration weight ratio of 1:9 (fesoterodine or its pharmaceutically acceptable salt : trehalose), commonly used in the prior art, has not manifested any positive effect on stability of the pharmaceutical formulations of fes otero dine.

The formulation in accordance with the present invention can be prepared by common methods, i.e. both wet granulation and dry granulation or direct tabletting. Description of figures

Fig. 1/1: Dissolution profile

1 - reference product Toviaz

2 - formulation in accordance with Example 1

3 - formulation in accordance with Example 4

4 - formulation in accordance with Example A

5 - formulation in accordance with Example B

Detailed description of the invention

The aim of the present invention was to find a composition of a pharmaceutical formulation containing fesoterodine that would be chemically stable, could be prepared by common pharmaceutical production methods and would exhibit excellent dissolution characteristics.

The term fesoterodine is meant to refer to the chemical structure 2-[(lR)-3- [diisopropylamino -l-phenylpropyl]-4-(hydroxymethyl^phenyl isobutyrate, or possibly its salts, especially the hydrogen fumarate. The concentration of fesoterodine, preferably in the hydrogen fumarate form, is in the pharmaceutical formulations in accordance with the invention in the range of 1 to 8 mg (related to fesoterodine), preferably 4 and 8 mg (related to fesoterodine) per drug form unit

It has been well known from the state of the art that fesoterodine has to be stabilized in a formulation. The application W02010/043408 solves the stabilization by micro-encapsulation, i.e. a complicated process that does not meet the requirement of commonly available pharmaceutical production technology. The application WO2011/050961 suggests natural fibrous material as the stabilizer, which can however be itself a source of chemical impurities and in addition it may be subject to microbial decay, to say nothing of the animal origin of some preferred substances (e.g. gelatine), which may be limiting for some patient groups (vegetarians, religious point of view).

In the applications WO2007/141298 a WO2012/136838 alcoholic sugars, polysaccharides, sucrose and polyethylene glycol were used, namely in relatively high concentrations of 1:9 (fesoterodine : stabilizer). However, another aim of the authors of this invention was to find a pharmaceutical formulation that would be stable under normal storage conditions even with the use of a low concentration of the stabilizer.

Trehalose has proved to be such a stabilizer as it surprisingly provided high stabilization achieved with a surprisingly low concentration of the stabilizer. On the contrary and quite unexpectedly, with the use of the concentration commonly used and preferred in documents known from the art (WO2007/141298, WO2012/136838), i.e. the 1:9 concentration (active substance to the stabilizer, by weight), no stabilization of the formulation by trehalose has occurred (see the comparative Example A and Example 7).

One aspect of this invention is a stabilized pharmaceutical formulation of fesoterodine or one of its pharmaceutically acceptable salts, wherein trehalose is used as the stabilizer in a concentration weight ratio of fesoterodine or its pharmaceutically acceptable salt to trehalose of 1:0.5 to 1:5 (by weight). The ability of trehalose to protect fesoterodine even at significantly lower concentrations than described in the reference patent applications also brings (besides excellent stabilization of the active substance) savings of financial costs related to the production of such a composition.

The formulation in accordance with the present invention can be prepared bycommon procedures, i.e. both wet granulation and dry granulation or direct tabletting. The composition containing fesoterodine, preferably in the form of fesoterodine hydrogen fumarate, which is described in this patent, can be generally used for dosage forms with immediate, extended, pulse or delayed release, or for their mutual combination. However, achievement of an extended release profile with the most suitable length of fesoterodine release of at least 24 hours, and hence for dosing once a day, is preferred. This dosing regimen ensures continuous supply to the drug to the blood stream, which allows to reduce the exposure of the organism to the active substance while maintaining the therapeutic efficiency. It is preferably also possible to achieve compensation of deviations in the plasmatic concentration of the drug, which leads to a better tolerance of the drug and to a reduction of the frequency of occurrence of undesirable effects.

The preferred stable pharmaceutical composition containing fesoterodine, preferably in the form of fesoterodine hydrogen fumarate, makes it possible to achieve a suitable dissolution profile in 900 ml of phosphate buffer with pH 6.8 at 75 rpm and the temperature of 37.0 ± O.S°C in the USPII dissolution device (paddles). The minimum rate of released drug in the first hour of the dissolution test is 20%, by the sixth hour at least 50% is released and by the twentieth hour at least 75% of the drug is released.

Optimum polymers controlling releasing of the drug are substances from the group of hydrophilic polymers, but hydrophobic polymers or their combinations may also be used.

Suitable hydrophilic polymers include, e.g.: hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, sodium salt of carboxymethyl cellulose, hydroxypropyl cellulose, polysaccharides, polyacrylates and other similar polymers and polymers known from the prior art

Suitable hydrophobic polymers include: ethyl cellulose, glyceryl palmitostearate, waxes (carnauba, montan glycol), hardened vegetable oil, glycerol monostearate, stearyl alcohol, glyceryl behenate and other similar polymers and polymers known from the prior art.

The list of usable polymers is not complete and any other polymer from the prior art which is known to those skilled in the art can be used. A stable pharmaceutical composition containing fesoterodine is prepared by homogeneous mixing of fesoterodine, preferably in the form of fesoterodine hydrogen fumarate, preferably with a representative of the group of hydrophilic polymers, preferably from the hydroxypropyl methyl cellulose group. The amount of this polymer that guarantees extended release of fesoterodine hydrogen fumarate from the dosage form is in the range of from 20% by weight to 70% by weight, related to the total weight of the dosage form.

The selected dosage form is preferably a tablet, coated tablet or hard capsule. Other possible dosage forms for oral administration are: a multi-layered tablet with controlled release, pellets, pellets in a capsule, mini-tablets in a hard or soft capsules, or other dosage forms issuing from the prior art which is known to those skilled in the art.

The selected dosage form is preferably coated with a coating layer ensuring minimization of the impact of humidity on the tablet core; coating systems containing polyvinyl alcohol, or hydroxypropyl cellulose as an integral constituent being suitable candidates for this purpose. The coating layer may further include softeners, fillers and colorants.

Humidity can be further reduced within the primary package by incorporation of a desiccant, e.g. based on silicates, which are, together with the dosage form, enclosed in a package with low permeability for air humidity. Suitable materials for the production of packages with such characteristics include, e.g., high-density polyethylene, or polychlorotrifluoroethylene or aluminium foil. Additionally, the space inside the primary package is filled with an inert gas, preferably nitrogen.

The final dosage form may be packed in an aluminium blister package with the thickness of 0.45 mm, closed with aluminium foil with the thickness of 0.025 mm and subsequently in a secondary package (paper box). Stability of the formulation can be further enhanced by packing in an inert protective atmosphere.

The preparation process of the stable pharmaceutical composition containing fesoterodine, preferably in the form of fesoterodine hydrogen fumarate, uses routine processes available for dosage form formulation, such as direct mixing of constituents, compacting, fluid granulation, high-speed granulation, tabletting and coating. Very advantageously, a process step can be incorporated that will ensure close contact of the stabilizer with the active substance, which can be achieved by methods of mixing, granulation, spray drying, pelletizing and other methods issuing from the prior art, which are known to those skilled in the art. The proposed stable pharmaceutical compositions containing fesoterodine hydrogen fumarate have been subjected to stability evaluation in the conditions of 40°C at 75% relative humidity for 3 months. These conditions can be considered as stress conditions since the recommended storage temperature of the active substance itself is 5°C under normal conditions. Similarly, the developed pharmaceutical compositions were stored for the long-term stability test under relatively demanding conditions at which accelerated (stress] stability studies of the active substance are conducted, i.e. under the conditions of 25°C at 60% relative humidity.

The selected stable compositions were prepared using the method of dry or wet granulation of fesoterodine hydrogen fumarate with the defined group of auxiliary substances and then admixing of other extragranular components that should add volume up to the desired tablet weight, lubricate the mixture during the tabletting process or further contribute to achievement of the desired dissolution profile.

The groups of substances compatible with the developed pharmaceutical composition comprise, besides the stabilizer: fillers, binders, glidants and disintegrants.

The stabilizer is, as discussed above, trehalose. The preferred content of this substance in the system is 0.5 to 40% by weight, conveniently 1 to 25, most conveniently 1 to 15% by weight, the weight ratio of fesoterodine or its pharmaceutically acceptable salt to trehalose being in the range of 1:0.5 to 1:5.

Fillers supporting stability of the suggested composition can be: microcrystalline cellulose, starch, calcium hydrogen phosphate, calcium carbonate, magnesium carbonate and other compounds known from the prior art. The preferred contents of these substances in the system are 1 to 50% by weight.

Binders supporting stability of the proposed composition can be: hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, ethyl cellulose, methyl cellulose, polyvinyl pyrrolidone, dextrin, polymethacrylates, pregelatinized starch, sodium alginate and other substances known from the prior art. The preferred contents of these substances in the system are 0.5-10% by weight.

Disintegrants supporting stability of the proposed composition can be: sodium salt of crosscarmellose, pregelatinized starch, starch sodium glycolate, sodium salt of carmoxymethyl cellulose, crospovidone and other substances known from the prior art. The preferred contents of these substances in the system are 0.5 to 5% by weight

Glidants supporting stability of the proposed composition can be: talc, magnesium and calcium stearate, colloidal silicon dioxide, stearic acid, hydrogenated vegetable oils, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, polyethylene glycol, sodium salt of stearyl fumarate, mineral oils, kaolin and other substances known from the prior art. The preferred contents of these substances in the system are 0.5 to 20% by weight.

An advantageous composition of a stable pharmaceutical formulation containing fesoterodine, preferably in the form of fesoterodine fumarate, is specified in the table:

Examples

The purpose of the following examples of composition of stable pharmaceutical formulations is to illustrate the focus of this invention and not to limit its scope. Any other modifications of the composition or production methods are possible if they are implemented in line with maintaining the stability of the composition.

Example no. 1

Fesoterodine was granulated with trehalose [weight ratio 1:5) in a high-speed mixer with the use of a mixture of water with ethanol and, after drying and screening through a sieve with the mesh size of 0.5 mm, the granulate was mixed with the rest of the auxiliary substances and homogenized. A rotary press was used to produce tablets that were coated with a coating based on methyl cellulose and hydroxypropyl cellulose.

Example no. 2

Fesoterodine was granulated with trehalose (weight ratio 1:2) in a high-speed mixer with the use of water and, after drying and screening through a sieve with the mesh size of 0.5 mm, the granulate was mixed with the rest of the auxiliary substances and homogenized. A rotary press was used to produce tablets that were coated with a coating based on methyl cellulose and hydroxypropyl cellulose.

Example no. 3

Fesoterodine was granulated with trehalose (weight ratio 1:1) in a high-speed mixer with the use of water and, after drying and screening through a sieve with the mesh size of 0.5 mm, the granulate was mixed with the rest of the auxiliary substances and homogenized. A rotary press was used to produce tablets that were coated with coating based on methyl cellulose and hydroxypropyl cellulose. Constituent % by

weight

Fesoterodine hydrogen fumarate 2.5

Trehalose

Lactose 2.5

Microcrystalline cellulose 40.0

Hydroxypropyl methyl cellulose 45.0

Talc 4.5

Colloidal silicon dioxide 0.5

Glycerol behenate 2.5

Total [table core) 100.0

Coating layer 3.0

Example no.4

In a high-speed mixer, fesoterodine was mixed with trehalose (weight ratio 1:0.5) and then with the other auxiliary substances. A rotary press was used to produce tablets that were covered with coating based on methyl cellulose and hydroxypropyl cellulose.

Constituent % by

weight

Fesoterodine hydrogen fumarate 2.5

Trehalose

Lactose 2.5

Microcrystalline cellulose 41.25

Hydroxypropyl methyl cellulose 45.0 Talc 4.5

Colloidal silicon dioxide 0.5

Glycerol behenate 2.5

Total (table core] 100.0

Coating layer 3.0

Example A - comparative

Fesoterodine was granulated with trehalose (weight ratio 1:9) in a high-speed mixer with the use of a mixture of water with ethanol and, after drying and screening through a sieve with the mesh size of 0.5 mm, the granulate was mixed with the rest of the auxiliary substances and homogenized. A rotary press was used to produce tablets that were coated with coating based on methyl cellulose and hydroxypropyl cellulose.

Constituent % by

weight

Fesoterodine hydrogen fumarate 2.5

Trehalose 22.5

Lactose 2.5

Macrocrystalline cellulose 20.0

Hydroxypropyl methyl cellulose 45.0

Talc 4.5

Colloidal silicon dioxide 0.5

Glycerol behenate 2.5

Total (table core) 100.0

Coating layer 3.0 Example B - comparative

Fesoterodine was homogenized with the rest of the auxiliary substances, which provided the tabletting matter. A rotary press was used to produce tablets that were coated with coating based on methyl cellulose and hydroxypropyl cellulose.

Example no. 6 - dissolution

The dissolution profiles of tablets prepared in Examples 1, 4, A and B were measured in 900 ml of phosphate buffer at pH 6.8 at 75 rpm and the temperature of 37.0±0.5°C in the USP II dissolution device [paddles) and were compared to the dissolution profile of the reference preparation Toviaz® measured at the same conditions. The dissolution curves are shown in Fig. 1.

All the curves were comparable, the minimum rate of released drug in the first hour of the dissolution test was 20%, by the sixth hour at least 50% was released and by the twentieth hour the amount of at least 75% of the drug was released. Example no. 7 - stability testing

Tablets prepared in Examples 1-4 and A-B were subjected to a stability test under the conditions of 25°C/60% humidity and 40°C/75% humidity. The total contents of impurities were measured using the HPLC method at the beginning of the testing, after three months and after six months.

The conditions of the HPLC measurement were as follows:

Column Gemini C18, 250 x 4.6 mm, 5 πι

Flow rate: 1.2 ml/min

Mobile phase A: Acetonitrile [60:40 vol.)

Mobile phase B: Acetonitrile:water (90:10 vol.)

Gradient:

Column temperature: 40°C

Injected quantity: ΙΟμΙ

Detector wavelength: 220 nm

Sample solvent: acetonitrile : water : phosphoric acid [95:5:1 vol.)

Stock solution of fesoterodine: 20 mg of fesoterodine were dissolved in 50 ml of the sample solvent [5 min ultrasound) and refilled to 100 ml.

Reference solution: 1 ml of the stock solution was diluted with the sample solvent to 100 ml. Sample solution: 10 tablets were thoroughly crushed and homogenized. 825 mg of crushed tablets [corresponding to 20 mg of fesoterodine fumarate) were dosed into a 20 ml volumetric flask and dissolved in 20 ml of the sample solvent.

The results were evaluated as the percentage of the area under the curve.

The table presents the percentage values of the total content of impurities (by weight]. The formulations in accordance with Examples 1-4 were significantly more stable than the formulations in accordance with the comparative examples. The concentrations of trehalose of 1:1 and 1:0.5 (fesoterodine fumarate : trehalose) have proved to be the most advantageous.

The resulting data clearly indicate that the proposed composition with trehalose is more stable than a composition without protection that provides the same results by several orders.