EP4780459A1

EP4780459A1 - Pharmaceutical compositions comprising riociguat as active ingredient and other relevant excipients

Info

Publication number: EP4780459A1
Application number: EP23953232.8A
Authority: EP
Inventors: Abdulhaluk SANCAK; Yunus SANCAK; Elif Zehra ATUKEREN; Hakan GURPINAR; Akif ERDOGAN; Koray YILMAZ
Original assignee: Adalvo Ltd; Humanis Sağlık AS
Current assignee: Adalvo Ltd; Humanis Sağlık AS
Priority date: 2023-09-20
Filing date: 2023-09-20
Publication date: 2026-07-29
Also published as: WO2025063911A1

Abstract

The present invention relates to a pharmaceutical composition comprising Riociguat or a pharmaceutically acceptable salt thereof, method of preparation thereof and its use in the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). The pharmaceutical composition has a specific weight ratio of a filler and a disintegrant, which are both present in an internal and an external phase.

Description

DESCRIPTION

PHARMACEUTICAL COMPOSITIONS COMPRISING RIOCIGUAT AS ACTIVE INGREDIENT AND OTHER RELEVANT EXCIPIENTS

Field of the invention

Background of the invention

Riociguat, represented by structural Formula I and chemically named as methyl A-[4,6- diamino-2-[l-[(2-fluorophenyl)methyl]pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl]-A^r-methyl carbamate, has a molecular weight of 422,424 g/mol.

Riociguat and its method of prepration was described in W003095451. Riociguat is a carbamate ester that is the methyl ester of {4,6-diamino-2-[l-(2-fluorobenzyd)-lH- pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}methylcarbamic acid. It is used for treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). It has a role as a soluble guanylate cyclase activator and an antihypertensive agent. Polymorphism has been observed for riociquat, it exists in two modifications (modification I and modification II) as well as several solvated forms of Riociguat, all of which have been described in W02014128109. The brand name of the marketed riociguat reference product is Adempas. Due to the rarity of CTEPH and PAH, Adempas was originally designated as an ‘orphan medicine’ (a medicine used for treatment of rare diseases).

There remains a need to develop a simple, reproducible and cost-effective manufacturing process and a stable pharmaceutical composition comprising Riociguat with an improved flowability, content uniformity and processability, while at the same time ensuring that the desired properties such as dissolution, stability, bioavailability are maintained and are comparable with respect to the Reference product Adempas.

An object of the present invention to solve the problems of the prior art and is to provide an improved pharmaceutical composition comprising Riociguat or a pharmaceutically acceptable salt thereof, while at the same time having comparable and satisfactory dissolution rates.

The present invention puts forward a pharmaceutical composition comprising Riociguat or a pharmaceutically acceptable salt thereof, which comprises a filler and a disintegrant having a specific weight ratio, where both are present in an internal and an external phase.

The pharmaceutical composition according to the present invention has suitable physical and chemical properties with the active ingredient and also other raw materials (excipients) present in the composition. These properties result into the composition being stable and reproducible, without any unwanted interaction with the active ingredient, and it has the desired functionality and its preparation is cost effective.

Detailed description of the invention

The present invention relates to a pharmaceutical composition comprising Riociguat or a pharmaceutically acceptable salt thereof, wherein the composition comprises lactose as a filler and crospovidone as a disintegrant both present in an intra-granular phase and an extra- granular phase.

Preferably, the present invention relates to the pharmaceutical composition of Riociguat or a pharmaceutically acceptable salt thereof, wherein the composition is for use in the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH).

Preferably, the pharmaceutical compositions comprising Riociguat or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, are prepared by a wet granulation process. Preferably, the present invention relates to the pharmaceutical composition comprising Riociguat or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein the excipients are selected from the group including, but are not limited to solvents, diluents, lubricants, fillers, disintegrants, binders, surfactants, and other materials known to one of ordinary skill in the art and the mixtures thereof.

Preferably, the present invention relates to the pharmaceutical composition comprising Riociguat or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein the excipients are preferably at least one or a mixture of a filler, a diluent, a disintegrant, a lubricant, a surfactant, and a binder.

Preferably, the present invention relates to the pharmaceutical compositions comprising Riociguat or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein the composition has an intra-granular phase and an extra-granular phase.

Preferably, the pharmaceutical compositions comprising Riociguat or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein active ingredient, a certain amount of filler, a certain amount of disintegrant, surfactant and binder are in the intra-granular phase.

Preferably, the pharmaceutical compositions comprising Riociguat or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein a certain amount of filler, a certain amount of disintegrant, diluent and lubricant are in the extra-granular phase.

One aspect of this invention, is the weight ratio of filler and disintegrant both in the intra- granular and extra-granular phase. The filler and disintegrant should be preferably selected according to this ratio.

Filler is used to increase the volume of the material to enable easier processing of the ingredients and make it into a size suitable for consumption. Moreover, they can stabilize the product and provide better during manufacturing. The filler is preferably selected from a group including but are not limited to lactose, starch, powdered sugar, dextrin, lactose, microcrystalline cellulose, inorganic salts, mannitol and mixtures and/or derivatives thereof. The filler for the inventive composition is preferably lactose and other suitable lactose derivatives, evem more preferably, it is lactose monohydrate.

Disintegrant, is used for disintegrating tablets into fine particles in gastric and intestinal fluid, so that the other components of the composition can be quickly dissolved and absorbed to have a desired effect. Most of these substances have good water absorption and expansion, so as to achieve the disintegration of tablets.

The disintegrant is preferably selected from a group including but are not limited to crospovidone, starch, pregelatinized starch, croscarmellose sodium, sodium starch glycolate, polacrilin potassium, alginic acid, calcium carboxymethylcellulose, magnesium aluminum silicate and mixtures thereof. The disintegrant for the inventive composition is preferably crospovidone.

Preferably, the present invention relates to the preparation of pharmaceutical compositions comprising Riociguat or pharmaceutically acceptable salts or esters thereof, a filler, a disintegrant and other excipients, wherein the composition has an intra-granular phase and an extra-granular phase.

Preferably, the present invention relates to the preparation of pharmaceutical compositions comprising Riociguat or pharmaceutically acceptable salts or esters thereof, wherein the composition comprises a filler and a disintegrant both in intra-granular phase and extra- granular phase.

The present invention relates to a pharmaceutical compositions comprising Riociguat or pharmaceutically acceptable salts or esters thereof, wherein the composition comprises lactose as a filler and crospovidone as a disintegrant both present in intra-granular phase and extra- granular phase. Preferably, the present invention relates to the pharmaceutical compositions comprising Riociguat or pharmaceutically acceptable salts or esters thereof, wherein the ratio of a filler present in both the intra-granular phase and in the extra-granular phase is from 30 to 60 % by total weight.

Preferably, the present invention relates to the pharmaceutical compositions comprising Riociguat or pharmaceutically acceptable salts or esters thereof, wherein the ratio of lactose as a filler present in the intra-granular phase is from 10 to 50 % by total weight, preferably from 15 to 30 % by total weight, even more preferably from 15 to 20 % by total weight.

Preferably, the present invention relates to the pharmaceutical compositions comprising Riociguat or pharmaceutically acceptable salts or esters thereof, wherein the ratio of lactose as a filler present in the extra-granular phase is from 10 to 50 % by total weight, preferably from 15 to 30 % by total weight, even more preferably from 15 to 20 % by total weight.

Prefarably, the present invention relates to the pharmaceutical compositions comprising Riociguat or pharmaceutically acceptable salts or esters thereof, wherein the ratio of disintegrant present in the intra-granular phase is from 1 to 20 % by total weight.

Preferably, the present invention relates to the pharmaceutical compositions comprising Riociguat or pharmaceutically acceptable salts or esters thereof, wherein the ratio of crospovidone as a disintegrant present in the intra-granular phase is from 1 to 20 % by total weight.

Preferably, the present invention relates to the pharmaceutical compositions comprising Riociguat or pharmaceutically acceptable salts or esters thereof, wherein the ratio of a disintegrant present in the extra-granular phase is from 1 to 10 % by total weight.

Preferably, the present invention relates to the pharmaceutical compositions comprising Riociguat or pharmaceutically acceptable salts or esters thereof, wherein the ratio of crospovidone as a disintegrant present in the extra-granular phase is from 1 to 10 % by total weight. Preferably, the present invention relates to the pharmaceutical compositions comprising Riociguat or pharmaceutically acceptable salts or esters thereof, wherein a total weight ratio of a filler to a disintegrant is from 8: 1 to 4: 1, more preferably it is selected from 8: 1, 7,5: 1, 7: 1, 6,5: 1, 6:1, 5,5: 1, 5: 1, 4,5: 1, and 4: 1.

Preferably, the present invention relates to the pharmaceutical compositions comprising Riociguat or pharmaceutically acceptable salts or esters thereof, wherein a total weight ratio of lactose to crospovidone is from 8: 1 to 4: 1, more preferably it is selected from 8: 1, 7,5: 1, 7: 1, 6,5: 1, 6:1, 5,5: 1, 5: 1, 4,5: 1, and 4: 1.

Preferably, the present invention relates to the pharmaceutical compositions comprising Riociguat, and one or more pharmaceutically acceptable excipients, wherein the composition has an intra-granular phase and an extra-granular phase. Preferably, the present invention relates to a pharmaceutical compositions comprising;

Riociguat as an active ingredient, a filler, a disintegrant, a surfactant and a binder in the intra-granular phase and

A filler, a disintegrant, a diluent and a lubricant in the extra-granular phase.

The present invention relates to a pharmaceutical compositions comprising:

Riociguat, lactose monohydrate as the filler, crospovidone as the disintegrant, sodium lauryl sulfate as the surfactant, and hypromellose as the binder in the intra-granular phase, and

Lactose monohydrate as the filler, crospovidone as the disintegrant, microcrystalline cellulose as the diluent, and magnesium stearate as the lubricant in the extra-granular phase.

The present invention relates to a wet granulation process for preparing a pharmaceutical composition comprising Riociguat, wherein a filler and a disintegrant are both present in an intra-granular phase and an extra-granular phase. Preferably, the wet granulation process comprising the steps of:

1) mixing Riociguat, half of the total amount of the filler and two thirds of the total amount of the disintegrant;

2) granulation of the mixture from step 1 with a granulatuion solution, preferably water, thereby forming the intra-granular phase;

3) drying the granules obtained in step 2 at a temperature range of about 30 - 40 °C until the drying loss is less than 2%;

4) mixing the granules from step 3 with the remaining half of the total amount of the filler and the remaining one third of the total amount of the disintegrant, thereby forming the extra-granular phase.

Preferably, step 1 also comprises mixing a binder, more preferably, the binder is hypromellose.

Preferably, the mixture from step 1 is mixed in a high shear mixer, more preferably, the mixing is performed at from about 50 to about of 250 rpm speed for a about 10 to about 20 minutes time. Preferably, the granulation solution is comprising water and a surfactant. More preferably the surfactant is Sodium Lauryl Sulfate.

Preferably, the granulation solution in step 2 is added slowly at a 10-50 rpm speed to the mix. The dried granules from step 3 are preferably sieved.

Preferably, step 4 also comprises mixing a diluent, more preferably, the diluet is microcrystalline cellulose. Preferably, the mixing in step 4 is performed at from about 10 to about 50 rpm speed for about 30 to about 60 minutes time.

Preferably, te wet granulation compries tablet compression process as another step. Even more preferably, a coating process is carried out as the last step.

Preferably, the present invention relates to the wet granulation process for preparing a pharmaceutical composition comprising Riociguat, wherein lactose monohydrate and/or any suitable lactose derivative is used as a filler and crospovidone is used as a disintegrant, wherein both are present in the intra-granular phase and the extra-granular phase.

Preferably, the present invention relates to the wet granulation process for preparing a pharmaceutical composition comprising Riociguat, wherein the total weight ratio of filler to disintegrant is from 4: 1 to 8: 1. Preferably, the present invention relates to the wet granulation process for preparing a pharmaceutical composition comprising Riociguat, wherein the total weight ratio of lactose to crospovidone is from 4: 1 to 8: 1.

Preferably, the pharmacefutical composition according to the present invention may be in the form of a tablet, capsule, caplet, film-coated tablet, enteric tablet, controlled-release tablet and any similar solid oral dosage forms. The preferred dosage form according to the present invention is the solid oral dosage form, preferably a tablet form. Most preferably, the composition is a film-coated tablet (FCT). Commonly available coating materials may be used for coating of tablets.

Suitable fillers according to the present invention include, but are not limited to, dibasic calcium phosphate, kaolin, microcrystalline cellulose, lactose, sugars such as dextrose, maltose, saccharose, glucose, fructose or maltodextrine, mannitol, maltitol, sorbitol, xylitol, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate and starch. Fillers which are slightly hygroscopic or non-hygroscopic are preferred, with non- hygroscopic fillers being particularly preferred, in particular when the dosage form is to be used for tropical countries. The preferred filler is lactose, more preferably lactose monohydrate.

Suitable disintegrants according to the present invention include, but are not limited to, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, polyvinylpyrrolidone, crospovidone (cross-linked homopolymer of N-vinyl-2-pyrrolidinone), alginic acid, microcrystalline cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, polacrillin potassium, sodium alginate, sodium starch glycolate, partially hydrolysed starch, sodium carboxymethyl starch, and starch. The preferred disintegrants is crospovidone (cross-linked homopolymer of N-vinyl-2-pyrrolidinone).

Suitable diluents can be selected from the group, but are not limited to, microcrystalline cellulose, powdered cellulose, sucrose, lactose, mannitol, dextrose, sorbitol, lactitol, saccharose, trehalose, fructose, dextranes, dried maize starch and its derivatives such as pregelatinized starch, calcium salts of phosphoric acid or a combination thereof. The preferred diluent is microcrystalline cellulose.

Suitable lubricants according to the present invention are selected from a group including, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, fumaric acid, sodium stearylfumarate, zinc stearate and polyethylene glycol and other materials known to one of ordinary skill in the art and mixtures thereof. The preferred lubricant is magnesium stearate.

Suitable surfactants according to the present invention are selected from a group including, but are not limited to, lecithins, sorbitol monooleate, polyoxyethylene stearate, benzalkonium chloride, polysorbates, sorbitan monopalmitate, sodium salts of fatty alcoholsulfates such as sodium lauryl sulfate (SLS), sodium dodecyl sulfate, ethoxylated triglycerides and other materials known to one of ordinary skill in the art and mixtures thereof. The preferred surfactant is sodium lauryl sulfate (SLS).

Suitable binders according to the present invention are selected from the group including, but are not limited to, microcrystalline cellulose, starches, lactose, sugar alcohols like mannitol, polymers like polyvinylpyrrolidone, polyethylene glycol, isomalt, hypromellose (hydroxypropyl methylcellulose) and other materials known to one of ordinary skill in the art and mixtures thereof. The preferred binder is hypromellose (hydroxypropyl methylcellulose).

The term “about” is used herein to mean approximately, roughly, or within a certain region of a specific value or a range, but not strictly and doctrinally limited to said value or a range, including the error margins as well. When the term “about” or similar terms as mentioned in this paragraph are used in conjunction with a numerical range or a value, it modifies that range by extending the boundaries both above and below the numerical values set by that range or a value. In general, this term is used herein to modify a numerical range or a value above and below the stated value by a variance of at least 10%.

The term “% wt ” or “% by weight” is used herein to mean the percentage by weight of each ingredient in an uncoated pharmaceutical composition, based on the total weight of the uncoated pharmaceutical composition. The pharmaceutical composition is prefrably in a form of a tablet, either uncoated or coated tablet.

Examples

The embodiment examples below are only provided to illustrate and to explain the invention and are not in any case intended to restrict the protection scope, which is only delimited by the wording of the patent claims. Any other modifications of the composition or production methods are possible if they are implemented in line with maintaining the stability of the composition and the dissolution profile of both the active substances. Example 1

Composition examples

Comparative example: Example la

The unit formula of Riociguat 2,5 mg Film Coated Tablet (FCT) pharmaceutical composition, wherein all of lactose is in the intragranular phase and all of crospovidone is in the extragranular phase is given in the flowing Table 1.

Table 1 : Riociguat 2,5 mg Film Coated Tablet (FCT) Unit Formula

The process for the preparation of Riociguat 2,5 mg Film Coated Tablet according to the comparative example la is carried out as specified below:

Step 1: Riociguat, Lactose Monohydrate and Hypromellose are sieved.

Step 2: The substances sieved in Step 1 are taken into high shear mixer and mixed at about 50-250 rpm speed for about 10-20 minutes time.

Step 3: Pure water is taken in a stainless steel container. Sodium Lauryl Sulfate is added into it and mixed till it dissolves completely.

Step 4: Granulation solution is added slowly at about 10-50 rpm speed to pre-mixed powder.

Powder is mixed at about 50-150 rpm speed.

Step 5: The granules in Step 4 are dried at a temperature range of about 30 - 40 °C until the drying loss is less than 2% (LOD). Step 6: Dried granulles are sieved.

Step 7: Microcrystalline cellulose & Crospovidone are sifted.

Step 8: The sized granules from Step 6 are mixed with sifted materials of Step 7 at about 10- 50 rpm speed for a 30-60 minutes time. Step 9: Sieved Magnesium Stearate is mixed with mixture from step 8 for about 2-10 minutes at about 10-50 rpm speed.

Step 10: Tablet compression process is performed.

Step 11: Preferably, a coating process is carried out. Composition according to the present invention: Example lb

The unit formula of the pharmaceutical composition according to the present invention comprising Riociguat or a pharmaceutically acceptable salt thereof, wherein lactose and crospovidone are present both in the intra-granular phase and the extra-granular phase is given in the following Table 2. Table 2: Riociguat 2,5 mg Film Coated Tablet (FCT) Unit Formula The process for the preparation of Riociguat 2,5 mg Film Coated Tablet according to the present invention is carried out as specified below:

Step 1: Riociguat, Lactose Monohydrate as the filler, 2/3 of the total amount of Crospovidone as the disintegrant and Hypromellose are sieved.

Powder is mixed at about 50-150 rpm speed, in order to form the intra-granular phase.

Step 5: The granules in Step 4 are dried at a temperature range of about 30 - 40 °C until the drying loss is less than 2% (LOD).

Step 6: Dried granulles are sieved.

Step 7: Lactose monohydrate as the filler, Microcrystalline cellulose & 1/3 of the total amount of Crospovidone as the disintegrant are sifted.

Step 8: The sized granules from Step 6 are mixed with sifted materials of Step 7 at about 10- 50 rpm speed for about 30-60 minutes time, in order to form the extra-granular phase.

Step 9: Sieved Magnesium Stearate is mixed with mixture from step 8 for about 2-10 minutes at about 10-50 rpm speed.

Step 10: Tablet compression process is performed.

Step 11: Preferably, a coating process is carried out.

The present invention provides a pharmaceutical composition comprising Riociguat prepared by a simple and manufacturing process and to yield a stable composition.

The advantages of the wet granulation method are:

- Preventing segregation of powders,

- Reducing dust hazards,

Improving flow property and compression characteristics and increases density of granules.

The pharmaceutical compositions of the present invention shows in particular similar properties to the Reference product in the dissolution, and it is therefore also very useful as a pharmaceutical product preparation method. Example 2: Dissolution Tests

The dissolution results of the Adempas 2,5 mg Riociguat film coated tablets (as the Reference product) and composition of Riociguat 2,5 mg film coated tablets according to example la (comparative example) and example lb (example of the composition according to the invention) were compared.

Example 2a

Comparative dissolution profiles of Adempas 2,5 mg FCT (Reference product) and Riociguat 2,5 mg FCT (composition according to comparative example la).

Figure 1. Comparative Dissolution Profiles of Adempas 2,5 mg FCT (Reference product) and Riociguat 2,5 mg FCT (composition according to comparative example la) in pH 6,8 Medium (0,1 % SLS) / (All of lactose in intragranular phase and all of crospovidone in extragranular phase)

In first trial, dissolution testing has been performed in pH 6,8 medium and with % 0,1 sodium lauryl sulfate (SLS)

The results of the Adempas 2,5 mg film coated tablet (Reference product) and Riociguat 2,5 mg film coated tablet (composition according to comparative example la) have been compared. It is shown in Figure 1 that the dissolution profile of the test product was considerably slow and not found to be satisfactory compared to the Reference product. In addition, it was also observed that content uniformity was not satisfactory as well. Example 2b

Comparative dissolution profiles of Adempas 2,5 mg FCT (Reference product) and Riociguat

2,5 mg FCT (composition according to example lb).

In another trial, dissolution testing has been performed in different pH mediums; in pH 6,8 medium with 0,1 % SLS (Figure 2) in pH 6,8 medium without SLS (Figure 3) in pH 4,5 medium without SLS (Figure 4) in pH 1,2 medium without SLS (Figure 5)

In-vitro comparative dissolution data and profiles has been demonstrated below in pH 1.2 without SLS, pH 4.5 without SLS, pH 6.8 with 0,1 % SLS and pH 6,8 medium without SLS. It has been surprisingly found, that all these multi media profiles were comparatively similar to that of the Reference product, as it is shown in Figures 2-5.

Figure 2. Comparative Dissolution Profiles of Adempas 2,5 mg FCT (Reference product) and Riociguat 2,5 mg FCT (composition according to example lb) in pH 6,8 Medium (0,1 % SLS) / (Lactose is partially in both intragranular and extragranular phase and crospovidone is partially in both intragranular and extragranular phase )

Figure 3. Comparative Dissolution Profiles of Adempas 2,5 mg FCT (Reference product) and Riociguat 2,5 mg FCT (composition according to example lb) in pH 6,8 Medium (without SLS) / (Lactose is partially in both intragranular and extragranular phase and crospovidone

Figure 4. Comparative Dissolution Profiles of Adempas 2,5 mg FCT (Reference product) and Riociguat 2,5 mg FCT (composition according to example lb) in pH 4,5 Medium (without SLS) / (Lactose is partially in both intragranular and extragranular phase and crospovidone is partially in both intragranular and extragranular phase )

Figure 5. Comparative Dissolution Profiles of Adempas 2,5 mg FCT (Reference product) and Riociguat 2,5 mg FCT (composition according to example lb) in pH 1,2 Medium (without SLS) / (Lactose is partially in both intragranular and extragranular phase and crospovidone is partially in both intragranular and extragranular phase )

Brief description of the figures

Figure 2. Comparative Dissolution Profiles of Adempas 2,5 mg FCT (Reference product) and Riociguat 2,5 mg FCT (composition according to example lb) in pH 6,8 Medium (without SLS) / (Lactose partially in both intragranular and extragranular phase and also crospovidone partially in both intragranular and extragranular phase )

Figure 3. Comparative Dissolution Profiles of Adempas 2,5 mg FCT (Reference product) and Riociguat 2,5 mg FCT (composition according to example lb) in pH 6,8 Medium (0,1 % SLS) / (Lactose partially in both intragranular and extragranular phase and also crospovidone partially in both intragranular and extragranular phase )

Figure 4. Comparative Dissolution Profiles of Adempas 2,5 mg FCT (Reference product) and Riociguat 2,5 mg FCT (composition according to example lb) in pH 4,5 Medium (without SLS) / (Lactose partially in both intragranular and extragranular phase and also crospovidone partially in both intragranular and extragranular phase ) Figure 5. Comparative Dissolution Profiles of Adempas 2,5 mg FCT (Reference product) and Riociguat 2,5 mg FCT (composition according to example lb) in pH 1,2 Medium (without SLS) / (Lactose partially in both intragranular and extragranular phase and also crospovidone partially in both intragranular and extragranular phase )

Claims

1. A pharmaceutical composition comprising Riociguat or a pharmaceutically acceptable salt thereof, wherein the composition comprises a filler and a disintegrant, wherein both the filler and the disintegrant are present in an intra-granular phase and an extra-granular phase.

2. A pharmaceutical composition according to claim 1, wherein the ratio of the filler present in the intra-granular phase is from 10 to 50 % by total weight.

3. A pharmaceutical composition according to any of the preceding claims, wherein the ratio of the filler present in the extra-granular phase is from 10 to 50 % by total weight.

4. A pharmaceutical composition according to any of the preceding claims, wherein the ratio of the disintegrant present in the intra-granular phase is from 1 to 10 % by total weight.

5. A pharmaceutical composition according to any of the preceding claims, wherein the ratio of the disintegrant present in the extra- granular phase is from 1 to 10 % by total weight.

6. A pharmaceutical composition according to any one of the preceding claims, wherein the total weight ratio of the filler to the disintegrant is from 8:1 to 4:1.

7. A pharmaceutical composition according to any one of the preceding claims, comprising lactose or a derivative thereof as the filler and crospovidone as the disintegrant.

8. A pharmaceutical composition according to claim 7, wherein the lactose is lactose monohydrate or a derivative thereof.

9. A pharmaceutical composition according to any one of the preceding claims, wherein the composition further comprises at least one excipient selected from a surfactant, a binder, a lubricant, a diluent, a solvent and any mixtures thereof.

10. A pharmaceutical composition according to claim 9, wherein the composition comprises:

11. A pharmaceutical composition according to any one of the preceding claims, wherein the composition is in the form of tablet.

12. A wet granulation process for preparing a pharmaceutical composition comprising Riociguat or pharmaceutically acceptable salt thereof comprising a filler and a disintegrant, wherein both the filler and the disintegrant are present in an intra-granular phase and an extra- granular phase.

13. A wet granulation process according to claim 12, comprising the steps of:

14. A wet granulation process according to any of the claims 12 to 13, wherein lactose or a derivative thereof is used as the filler and crospovidone is used as the disintegrant, and wherein preferably, the total weight ratio of lactose to crospovidone is from 8:1 to 4:1.

15. A pharmaceutical composition according to any of the claims 1 to 11, wherein the composition is for use in the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH).