WO2025122075A1

WO2025122075A1 - Pharmaceutical compositions of riociguat

Info

Publication number: WO2025122075A1
Application number: PCT/TR2023/051449
Authority: WO
Inventors: Erol KIRESEPI; Ersin Yildirim
Original assignee: Santa Farma Ilac Sanayi AS
Current assignee: Santa Farma Ilac Sanayi AS
Priority date: 2023-12-04
Filing date: 2023-12-04
Publication date: 2025-06-12
Anticipated expiration: 2026-06-04

Abstract

The present invention provides an immediate-release oral pharmaceutical composition that includes micronized riociguat as an active substance, sodium lauryl sulfate as a surfactant within the range of 0.10% to 0.25% w/w, and at least one pharmaceutically acceptable excipient manufactured by using high shear granulation method.

Description

DESCRIPTION PHARMACEUTICAL COMPOSITIONS OF RIOCIGUAT Technical Field The present invention provides an immediate-release oral pharmaceutical composition that includes micronized riociguat as an active substance, sodium lauryl sulfate as a surfactant within the range of 0.10% to 0.25% w/w, and at least one pharmaceutically acceptable excipient manufactured by using high shear granulation method. State Of Art Pulmonary arterial hypertension (PAH) is a chronic and life-threatening disorder of the pulmonary arterial circulation that results in increased pulmonary vascular resistance limiting the ability of the right ventricle to pump blood through the lungs, causing shortness of breath and reduced physical performance. Also, PAH is a progressive disorder, which can ultimately lead to right heart failure and death. Riociguat is a first-in-class activator of the soluble form of the enzyme (sGC) exhibiting a dual mode of action: directly stimulating sGC independently of nitric oxide and sensitizing sGC to endogenous nitric oxide by stabilizing nitric oxide–sGC binding. This results in increased production of cyclic GMP. Riociguat is the first drug to demonstrate efficacy in that both PAH and chronic thromboembolic pulmonary hypertension (CTEPH). The chemical name of riociguat is methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazo- lo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate. The molecular formula is C₂₀H₁₉FN₈O₂ and the compound has a molecular weight of 422.42 g/mol. The structural formula of riociguat is shown in Formula I.

Formula I Riociguat is a white to yellowish crystalline powder and non-hygroscopic. It is practically insoluble in water and shows a strong pH-dependent solubility in aqueous media in the pH range of 2 to 4, slightly soluble in acetone and methanol, and freely soluble in dimethyl sulfoxide and dimethyl formamide. Riociguat and its pharmaceutically acceptable salts, isomers, and hydrates thereof first has been described in EP1506193 numbered patent document by Bayer Healthcare for treatment of cardiovascular disorders, hypertension, thromboembolic disorders and ischaemias and sexual dysfunction, especially of erectile dysfunction and of female sexual dysfunction. Riociguat has a non-chiral molecular structure. There have been two modifications of riociguat, i.e. modification I and modification II. Riociguat was first commercially authorized by the U.S. Food Drug Administration in August 2013. The medicinal product of has been launched in the film-coated tablet dosage form under the name of ADEMPAS^® in the strengths of 0.5 mg, 1 mg, 1.5 mg, 2 mg, and 2.5 mg. ADEMPAS^® is a soluble guanylate cyclase (sGC) stimulator indicated for the treatment of adults with Persistent Or Recurrent Chronic Thromboembolic Pulmonary Hypertension (CTEPH) (WHO Group 4) after surgical treatment or inoperable CTEPH to improve exercise capacity and WHO functional class and Pulmonary Arterial Hypertension (PAH) (WHO Group 1) to improve exercise capacity, improve WHO functional class and to delay clinical worsening. In the state of the art, many patents/patent applications are summarized below. EP2958914 relates to a pharmaceutical composition comprising riociguat in the form of Modification II characterized by an X-ray powder diffractogram and as well as the preparation of said composition that contains microcrystalline cellulose and lactose monohydrate as filler, crospovidone as a disintegrant, hypromellose as a binder, magnesium stearate as a lubricant and sodium lauryl sulfate as a wetting agent. EP2958914 also discloses various polymorphic forms of riociguat such as M, mono-DMSO solvate, sesqui-DMSO solvate, ¼-ethyl acetate solvate and the conversion of these polymorphs into other forms. EP2958914 patent document has a divisional application. Its divisional application that is EP3760629 relates to forms of riociguat comprising its Modification I, mono-DMSO solvate, sesqui-DMSO solvate, and 1/4-ethyl acetate solvate, and combinations thereof. CN110946826 relates to a pharmaceutical composition comprising 10-20% riociguat, 20-35% oil phase, 2-18% emulsifier and 30-65% co-emülsifier. WO2022144930 relates to an immediate release oral pharmaceutical suspension dosage form comprising riociguat in an amount of about 0.01 % to about 30% w/v of the dosage form, a suspending agent, a wetting agent, pH adjusting agent, a pharmaceutically acceptable liquid carrier and at least one or more other pharmaceutically acceptable excipients. In the dose range of 0.5 to 2.5 mg, riociguat demonstrates dose-dependent elevation in plasma concentrations. However, there is a significant variation among individuals, with approximately 60% variability between them and around 30% variability within-subject. Riociguat's absolute bioavailability is approximately 94%, and it is rapidly absorbed, reaching its maximum concentrations (Cmax) between 1 to 1.5 hours after the tablet is ingested. Riociguat belongs to BCS Class II, characterized by low solubility and high permeability. It's important to note that riociguat is a basic molecule with a pKa of 4.3, which means it is highly soluble in acidic aqueous media but exhibits low solubility in water. In addition to its solubility challenge, riociguat is considered a low-dose drug, with dosages ranging from 0.5 mg to 2.5 mg in the original product ADEMPAS®. These different dose strengths were all based on the same qualitative composition, in which all dose strengths have been formulated to same tablet weight, such as 85 mg for 2.5 mg dose strength, and same size, with a 6 mm diameter. Due to consistent tablet weight, the weight ratio of riociguat in the pharmaceutical composition varies among different dose strengths, ranging from approximately 0.6% to 3.0%. Despite the well-recognized challenges associated with achieving an optimal flowability and solubility in the pharmaceutical composition comprising a relatively small quantity of drug substance with poor-water solubility, the inventors of the present invention have successfully developed a pharmaceutical composition manufactured by using high shear granulation. Moreover, the present invention aims to develop an immediate-release oral pharmaceutical composition comprising micronized riociguat within the range of 0.1% to 1% w/w, sodium lauryl sulfate within the range of 0.10% to 0.25% w/w, and at least one pharmaceutically acceptable excipient wherein the composition is manufactured by using high shear granulation process with taking into consideration of the optimization of the amount of granulation solvent to achieve improved release profile and powder flowability. Summary Of The Invention The object of this invention is to develop an immediate-release oral pharmaceutical composition comprising therapeutically effective amount of riociguat or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. It is an object of the present invention is to develop a pharmaceutical composition comprising riociguat or pharmaceutically acceptable salt thereof which is used for the treatment in both pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). The marketing product containing riociguat is available in five different strength, ranging from 0.5 to 2.5 mg. In these products, the weight ratio of riociguat changes from 0.6 to 3.0% w/w. However, in one aspect of the present invention is to prepare a pharmaceutical composition comprising riociguat at concentration between 0.1% to 1% w/w for all strength, in which the tablet composition and manufacturing principles remain unchanged, except for the total tablet weight for each strength. Riociguat is known to exhibit low solubility in water. Therefore, another object of the present invention is to provide improve solubility of riociguat by utilizing its micronized form, with a 90% ratio of the particle sizes (PSD value D90) measuring less than 15 microns, preferably less than 12 microns, more preferably less than 10 microns. According to the state of the art, the amount of granulation solvent can significantly affect the flow properties of the resulting granules. However, in the present embodiment, its effect has been improved through the incorporation of a surface-active agent in the granulation solvent. Another object of the present invention is to provide an immediate-release oral pharmaceutical formulation comprising micronized riociguat at 0.6% w/w and at least one pharmaceutically acceptable excipient manufactured by using high shear granulation, wherein the amount of sodium lauryl sulfate within the range of 0.10% to 0.25% w/w to improve dissolution profile. Another object of the present invention is to provide an immediate-release oral pharmaceutical formulation comprising micronized riociguat between 0.1% to 1% w/w, sodium lauryl sulfate within the range of 0.10% to 0.25% w/w and at least one pharmaceutically acceptable excipient manufactured by using high shear granulation, wherein the amount of granulation solvent is particularly identified between 4% to 9% w/w to improve processability and release profile. Detailed Description Of The Invention The present invention provides an immediate-release oral pharmaceutical composition comprising micronized riociguat and at least one pharmaceutically acceptable excipient manufactured by using proper manufacturing process to get improved release and processability properties. According to the state-of-the-art, riociguat exhibits low solubility and high permeability, being practically insoluble in water at 4 mg/L at 24°C. Therefore, the specified particle size along with the appropriate manufacturing method plays a significant role in achieving the desired dissolution profile. In the preferred embodiment, the pharmaceutical composition comprising riociguat particles in micronized form, preferably, riociguat has a particle size volume distribution with a D90 under 15 microns. The term “D90” is defined as 90% of the volume of particles having a diameter less than a specified diameter. The value of D90 refers to the particle size distribution of riociguat particles. In the present invention, riociguat particles having D90 doesn’t exceed the 15 microns, preferably D90 is less than 12 microns, more preferably D90 is less than 10 microns. Riociguat is available as oral tablets in five different strengths (0.5, 1.0, 1.5, 2.0 and 2.5 mg), wherein all doses has same tablet weight. Therefore, weight ratio of micronized riociguat in all dosages varies within the range of 0.6% to 3.0% regarding to the total tablet weight. These values refer to the lowest and highest drug doses of ADEMPAS^®. In the preferred embodiment, the formulation is designed by keeping the constant of the weight ratio of riociguat and all excipients across the lowest and highest-strength drug doses wherein the tablet weight is adjusted within the range of 85 to 425 mg. In the preferred embodiment of the pharmaceutical composition as disclosed herein, the amount of riociguat per unit dose equivalent to 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg of the active ingredient as free base. Another preferred embodiment of the present invention, riociguat is present as a low dose drug as constituting at 0.1% to 1% w/w by the total tablet weight. In the preferred embodiment of the present invention, the wet granulation process is proposed as a manufacturing process that is widely used in pharmaceutical industry due to its known advantages, such as improving the cohesiveness and compressibility of the powders, achieving distribution. Wet granulation involves the conversion of a powder blend into granules with having suitable flow and being cohesive properties for tableting. The procedure consists of mixing the powders in a suitable blender followed by adding the granulating solution, which is either sprayed through a nozzle or poured under shear to the mixed powders, usually high shear or fluidized bed to obtain a granulation. In the high shear granulation, the direct pouring of the granulation solution onto the powder blend and shear can lead to more controlled and localized wetting of the powder, reducing the likelihood of drug particles adhering to the vessel walls or with spraying during fluid-bed granulation process. Therefore, to minimize the loss of dispersed low-dose riociguat with the concentration of 0.1% to 1% w/w, with a D90 less than 10 microns, in the granulation solvent during granulation, in the preferred embodiment, the granulation takes place in the high shear granulator. In the preferred embodiment, the pharmaceutical composition is also provided for the manufacture of tablets containing the active ingredient, diluent, disintegrant, binder, lubricant, surfactant and granulation solvent for the immediate release oral dosage form. In a preferred embodiment, the pharmaceutical composition comprising at least one diluent can be selected from dibasic calcium phosphate dehydrate, polysaccharides, primarily microcrystalline cellulose, lactose anhydrous, lactose monohydrate, mannitol, sugars, sorbitol, sucrose, inorganic salts, primarily calcium salts and mixtures thereof. Preferably, diluents are lactose monohydrate and microcrystalline cellulose. In a preferred embodiment, the pharmaceutical composition comprising a disintegrant can be selected from croscarmellose sodium, sodium starch glycolate, crospovidone, corn starch, pregelatinized starch, low-substituted hydroxypropyl cellulose and microcrystalline cellulose, and mixtures thereof Preferably, the disintegrant is crospovidone. In a preferred embodiment, the pharmaceutical composition comprising a binder can be selected from hypromellose, sodium carboxymethyl cellulose, cellulose or cellulose derivatives, povidone, starch, sucrose, polyethylene glycol, or mixtures thereof. Preferably, the binder is hypromellose. In a preferred embodiment, the pharmaceutical composition comprising a lubricant can be selected from sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid and mixtures thereof. Preferably, the lubricant is magnesium stearate. The selection of the granulation solvent is a critical step in the granulation process. Typical granulation solutions usually include deionized water, ethanol, isopropanol, acetone, and methylene chloride, either individually or in combination. In the preferred embodiment, deionized water is chosen as a granulation solvent. Furthermore, the quantity of granulation solution (w/w %) also has a significant impact on the flow properties of the resulting granules and their dissolution properties. In the preferred embodiment, the amount of water is preferred in the range of 4% to 9% w/w by the total tablet weight. Moreover, in the present invention, a surface-active agent is dispersed along with micronized riociguat in the granulation solvent. Surface-active agents are known to enhance drug release primarily by increasing the wettability and the solubilisation. In this process, the hydrophobic and hydrophilic blocks of the surfactant tend to form structures known as micelles in an aqueous solution, where the active substance can be solubilized inside the hydrophobic core of the miscelles. The most commonly used surfactants include polysorbate, sodium lauryl sulfate, and polyethylene-propylene glycol copolymer (poloxamer). In the preferred embodiment, sodium lauryl sulfate is chosen as surfactant. The embodiment in accordance with the present invention is designed by taking into account the qualitative information mentioned above and manufactured using high shear granulation to address the issues associated with being poor solubility and low-dose drug. In Example 1 of the proposed embodiment based on the invention, an immediate-release oral solid pharmaceutical composition is provided. The composition consists of the following components in w/w% by weight of the total composition: 0.1 - 1% micronized riociguat as the active substance, 35 - 45% microcrystalline cellulose, 40 - 50% lactose monohydrate, 5 – 10% crospovidone, 2 – 5% hypromellose, 1 – 2% sodium lauryl sulfate, 0.1 – 1% magnesium stearate, and a sufficient amount of deionized water. Further, in the preferred embodiment, the pharmaceutical composition of the present invention is manufactured using high-shear granulation. The process comprises the following steps: i. Microcrystalline cellulose and lactose monohydrate, hypromellose and crospovidone are screened through a proper sieve and stirred, ii. Sodium lauryl sulfate and riociguat are dispersed into the granulation solvent, iii. The granulation solution prepared in Step (ii) is added to the powder blend prepared in Step (i), iv. The granules prepared in Step (iii) are dried in the fluid-bed dryer and shifted through a proper sieve, v. Magnesium stearate are screened through a proper sieve and added to the dried granules prepared in Step (iv). vi. The final blend in Step (v) is stirred to obtain a uniform form. Then, in-vitro dissolution study for an immediate-release oral pharmaceutical composition comprising the active substance was conducted under the following conditions: Dissolution medium: pH 6.8 containing sodium lauryl sulfate Dissolution volume: 900 ml Temperature of study: 37°C±0.5, Rotation speed: 75 rpm, Apparatus: Paddle The duration of dissolution: 60-minute The amounts of dissolved active ingredients over time were determined by HPLC. Table 1: In-vitro dissolution results of Example 1 Example 1 Time, min Results, % 5 30 10 51 15 62 20 69 30 77 45 83 60 85 In a preferred embodiment of the first aspect of the present invention, the pharmaceutical composition is in the immediate release tablets. An immediate-release tablet is defined as a tablet that exhibits dissolution performance, releasing at least 85% of the active substance within 15 minutes. However, according to Table 1 provided above, the immediate-release composition released at least 62% of the active ingredient in 15 minutes. This means that the release pattern of Example 1 was remarkably slower and did not approach to 100% at 60-minute duration. Based on this information, it appears that the micronized riociguat in Example 1 was likely embedded within obtained granules with relatively larger particle sizes resulted in the micronized riociguat not being released over time. Afterwards, other examples were proposed by changing the amount of surfactant and also granulation solvent which were directly linked to active substance release profile. The composition consists of the following components in w/w% by weight of the total composition: 0.1 - 1% micronized riociguat as the active substance, 35 - 45% microcrystalline cellulose, 40 - 50% lactose monohydrate, 5 – 10% crospovidone, 2 – 5% hypromellose, 0.10 – 0.25% sodium lauryl sulfate, 0.1 – 1% magnesium stearate, and three different amounts of deionized water. The changes in water amount and sodium lauryl sulfate affected the granule attributes and processability of the powder blends. Table 2: Critical amounts of excipients in the examples E_{xcipients Example 2} ^{Example 3 Example 4} S_{odium lauryl sulfate, %} ^{0.10 – 0.25 0.10 – 0.25 0.10 – 0.25} Deionized water, % 10-14 4-9 2-3 The powder blend characterizations of powder final blend for the proposed embodiment was evaluated according to the <1174> in U.S. Pharmacopeia to identify the flowability property particularly. Table 3: Characteristic powder properties of the examples Example 2 Example 3 Example 4 Amount of Granulation 10-14 4-9 2-3 solvent, % Flow properties Hausner Ratio 1.149 1.266 1.370 Compressibility index 13 21 27 Bulk density, g/mL 0.480 0.458 0.475 Tapped density, g/mL 0.552 0.580 0.651 Powder flowability Good Passable Poor Disintegration test was conducted following the USP<701> Disintegration monograph, Table 4: Disintegration time results of the examples Example 2 Example 3 Example 4 Disintegration time, min. 6 2 1 Table 5: In-vitro dissolution results of the examples Results, % Time, min Example 2 Example 3 Example 4 5 41 47 68 10 72 85 77 15 80 91 78 20 84 95 82 30 86 97 84 45 88 98 88 60 88 98 89 According to tables provided above, tablets with different flow properties and dissolution rates, resulting different results in granule attributes and release profile. Although, Example 2 presents the most proper flowability and acceptable disintegration result, the release profile was still slow and uncompleted at the time point of 60-minute. Likewise, even though Example 4 presented the most proper disintegration time, the release profile was still slow and uncompleted at the time point of 60-minute. There were differences between dissolution profiles of Example 2, Example 3 and Example 4. Only Example 3 released 91% of the active ingredient in 15 minutes and very close to complete its drug dissolution at 60-minute. The inventors surprisingly found that the amount of water which was directly effective on granule attributes was observed also to be one of the critical excipient in the composition that presented noticeable effect on release profile as well as a granulation solvent for the granulation solution of riociguat and the sodium lauryl sulfate. According to all results, in embodiments of the present invention, the immediate-release oral pharmaceutical composition comprising micronized riociguat and at least one pharmaceutically acceptable excipient manufactured by using high shear granulation process, wherein it comprises - micronized riociguat at concentration between 0.1% to 1% w/w - sodium lauryl sulfate in amount between 0.10 to 0.25% w/w, and - water as granulation solvent in amount between 4 to 9% w/w. While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

Claims

CLAIMS 1. An immediate-release oral pharmaceutical composition comprising micronized riociguat and at least one pharmaceutically acceptable excipient manufactured by using high shear granulation process, wherein the composition comprises - micronized riociguat at amount between 0.1% to 1% w/w - sodium lauryl sulfate as surfactant in amount between 0.10% to 0.25% w/w, and - water as granulation solvent in amount between 4% to 9% w/w.

2. An immediate-release oral pharmaceutical composition according to claim 1, wherein the riociguat particles have a D90 value less than 15 microns, preferably D90 is less than 12 microns, more preferably D90 is less than 10 microns.

3. An immediate-release oral pharmaceutical composition according to any one of the previous claims, wherein the composition comprises different strengths of riociguat between 0.5 mg to 2.5 mg.

4. An immediate-release oral pharmaceutical composition according to any one of the previous claims, wherein the tablet weight of the pharmaceutical composition is between 85 to 425 mg.

5. An immediate-release oral pharmaceutical composition according to any one of the previous claims, wherein at least one pharmaceutically acceptable excipient is selected from diluents, disintegrant, binder, lubricant, granulation solvent, surfactant and mixtures thereof.

6. An immediate-release oral pharmaceutical composition according to Claim 5, wherein the diluent is selected from dibasic calcium phosphate dehydrate, polysaccharides, primarily microcrystalline cellulose, lactose anhydrous, lactose monohydrate, mannitol, sugars, sorbitol, sucrose, inorganic salts, primarily calcium salts and mixtures thereof.

7. An immediate-release oral pharmaceutical composition according to Claim 5, wherein the disintegrant is selected from croscarmellose sodium, sodium starch glycolate, crospovidone, corn starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, microcrystalline cellulose and mixtures thereof

8. An immediate-release oral pharmaceutical composition according to Claim 5, wherein the binder selected from hypromellose, sodium carboxymethyl cellulose, cellulose or cellulose derivatives, povidone, starch, sucrose, polyethylene glycol and mixtures thereof.

9. An immediate-release oral pharmaceutical composition according to claim 5, wherein the lubricant selected from sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid and mixtures thereof.

10. An immediate-release oral pharmaceutical composition according to claim 5, wherein the surfactant selected from polysorbate, sodium lauryl sulfate, and polyethylene-propylene glycol copolymer (poloxamer).

11. An immediate-release oral pharmaceutical composition according to any one of the previous claims, wherein the granulation solvent selected from deionized water, ethanol, isopropanol, acetone, and methylene chloride, either individually or in combination.

12. An immediate-release oral pharmaceutical composition according to any one of the previous claims, wherein the composition comprising by weight 0.1 - 1% micronized riociguat, 35 - 45% microcrystalline cellulose, 40 - 50% lactose monohydrate, 5 – 10% crospovidone, 2 – 5% hypromellose, 0.10 – 0.25% sodium lauryl sulfate, 0.1 – 1% magnesium stearate, and a sufficient amount of deionized water.

13. A high shear granulation method for the preparation of a pharmaceutical composition according to any one of the previous claims, wherein the process comprising the steps of; i. Microcrystalline cellulose and lactose monohydrate, hypromellose and crospovidone are screened through a proper sieve and stirred, ii. Sodium lauryl sulfate and riociguat are dispersed into the granulation solvent, iii. The granulation solution prepared in Step (ii) is added to the powder blend prepared in Step (i), iv. The granules prepared in Step (iii) are dried in the fluid-bed dryer and shifted through a proper sieve, v. Magnesium stearate are screened through a proper sieve and added to the dried granules prepared in Step (iv). vi. The final blend in Step (v) is stirred to obtain a uniform form.