Low dose riociguat compositions

Abstract

The present invention relates to a pharmaceutical composition comprising therapeutically effective amount of low dose riociguat as active substance and a specified surfactant wherein the composition is developed by using dose proportional approach.

Description

[0001]DESCRIPTION LOW DOSE RIOCIGUAT COMPOSITIONS Technical Field The present invention relates to a pharmaceutical solid dispersion composition containing a poorly water-soluble active pharmaceutical ingredient and at least one pharmaceutically acceptable excipient. More specifically, the present invention relates to develop pharmaceutical formulations designed in dose-proportional manner comprising low dose riociguat and a surfactant. 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 ischaemia 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-emulsifier. 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. At doses ranging from 0.5 to 2.5 mg, riociguat exhibits dose-dependent increases in plasma concentrations with pronounced variability among individuals of approximately 60% and within-subject variability of about 30%. The absolute bioavailability of riociguat is about 94% and is rapidly absorbed with maximum concentrations (Cmax) occurring within 1-1.5 hours after tablet intake. Riociguat is a BCS Class II drug and accordingly has low solubility and high permeability. According to the literature knowledge, riociguat is a basic molecule (pKa 4.3), so highly soluble in aqueous acidic media, but low solubility in water. Besides its solubility challenge, riociguat is also recognized with a loading range of 0.5 mg to 2.5 mg in the original product ADEMPAS®. These various strengths of ADEMPAS®are all founded on the same fundamental qualitative composition, with variations solely in the pigment composition of the film coating. Moreover, the total tablet weight remains consistent across all strengths. However, the amount of riociguat varies in different proportions for each strength, leading to changes in the weight ratio of riociguat to the total tablet weight based on its strength. For instance, the weight ratio of riociguat ranges from 0.6% to 3% in the lowest and highest drug doses. Despite the known challenges in achieving solid dispersion with a small quantity of drug substance in blends, the inventors of the present invention have successfully developed a pharmaceutical composition with multiple strengths using the dose-proportional technique. In the dose-proportional technique, riociguat and all excipients are used exactly in the same proportions in different strengths by changing the total tablet weight wherein the amount of riociguat does not exceed 0.6% of the weight of the dosage form. In conclusion, the inventors of the present invention have developed a pharmaceutical composition comprising low dose riociguat incorporated with specified surfactants in the granulation solution to achieve proper dispersion and superior dissolution profiles. Summary Of The Invention The object of this invention is to develop a 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). According to the literature, challenges related to physicochemical characteristics can significantly affect solid dispersion and solubility, particularly when dealing with low solubility and low drug doses. However, the present invention surprisingly addresses these issues through the use of a dose- proportional technique. In this technique, the weight ratio of riociguat in the lowest and highest- strength drug doses is kept the same by adjusting the tablet weight based on the dose strength. One of the object of the present invention, the total amount of low-dose riociguat present in the pharmaceutical composition is maximum 0.6% w / w in respect of the total amount of the pharmaceutical composition. Another object of the present invention, the total tablet weight comprising riociguat maximum 0.6% w / w by the total weight of the formulation is between 85 mg to 425 mg. One of the object of the present invention, the riociguat present in the pharmaceutical composition is maximum 0.6% w / w in respect of the total amount of the pharmaceutical composition is in micronized form. Another object of the present invention is to provide a pharmaceutical composition comprising riociguat in micronized form with 90% ratio of the particle size distribution (PSD D90) value is less than 15 micrometers. The pharmaceutical composition may further comprise a surfactant from 0.25% to 2% by weight, preferably from 0.9 % to 1.3% by weight. As regards the surfactant, it is generally used to aid in wetting of poor water solubility drugs in a pharmaceutical composition to ensure efficient dissolution profile. Another objective of the present invention is to provide a pharmaceutical composition comprising low-dose riociguat in micronized form and a specified surfactant, developed by using dose-proportion technique. Detailed Description Of The Invention The present invention provides a pharmaceutical composition comprising low dose riociguat or pharmaceutically acceptable salt thereof used for the treatment in both pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) in immediate-release dosage form. Based on the prior art, riociguat is classified as BCS (Biopharmaceutics Classification System) class II compound which means that it exhibits low solubility and high permeability. It acts poor solubility in water as 4 mg / mL at 25°C and in buffer phosphate (pH 7) 3 mg / L, besides its solubility slightly increases in 0.1 M HCl (pH 1) 250 mg / L. In the development of pharmaceutical compositions, micronizing the active ingredient with a customized particle size can meet the solubility requirements for optimal dissolution profiles. Thus, in the preferred embodiment of the present invention relates to a pharmaceutical composition comprising riociguat particles have a D90 value 15 microns or less. 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 active substance particles having D90 value that doesn’t exceed 15 microns, preferably D90 value is less than 12 microns, more preferably D90 value is less than 10 microns. Riociguat (Adempas®) comprising drug products are available in five different strengths ranging from 0.5 mg to 2.5 mg per tablet, with the tablet composition and manufacturing principles remaining consistent. However, the amount of riociguat by weight altering, ranging in drug products from 0.6% to 3% in the total tablet weight. This range observed based on the lowest and highest drug doses of Adempas®. In the present invention, the formulation design is preferred by utilizing the dose proportional design. This technique ensures that the weight ratio of riociguat remains consistent across the lowest and highest strength by adjusting the tablet weight between 85 mg to 425 mg. Furthermore, as the tablet weight changes from 85 mg to 425 mg with dose proportional dosage form design the release profile of active substance riociguat is the same. In conclusion, there could be a problem considering the amount of total excipients in the composition varies in a very broad range, inventors achieved to get a dose proportional formulation presenting no deviation and / or variation in the release profile of low dose the active substance. Thus, in the present invention, the amount of riociguat is presented maximum 0.6% w / w of the total weight of the composition in all strengths and that makes it as a low dose drug. According to the literature, the formulating low dose drug in dose proportional design presents a challenge as it requires a relatively large ratio of excipients to the active drug substance with characterization BCS Class II due to low solubility. Therefore, the selection of proper manufacturing process has become an importance. In the preferred embodiment of the present invention, wet granulation process is selected that refers to a process involving granulating the powder with granulating solution to achieve the desired properties for subsequent processes in which granulating solution can be used alone or as a solvent comprising the low dose drug and surfactant. Surfactants are one of the common pharmaceutical excipients that are incorporated into developed pharmaceutical compositions to reduce the interfacial energy barrier between the dissolution medium and the active ingredient, which can improve wettability. Moreover, surfactants are capable of forming micelles above the critical micelle concentration (CMC) in aqueous liquids, such as the fluids found in the gastrointestinal tract. This property holds particular significance in pharmacy due to their ability to enhance the solubility of sparingly soluble substances in water. Thus, in the present invention, sodium lauryl sulfate is preferably chosen as the most commonly used surfactant to enhance the solubility and bioavailability of riociguat by facilitating its proper dispersion in the granulation solvent. In the present invention, preferred solvent in the granulation solution is deionized water, which contains low dose riociguat and surfactant. Moreover, the pharmaceutical composition is also provided for the immediate release solid dosage form containing the active ingredient, diluent, disintegrant, binder, lubricant, surfactant and solvent. In a preferred embodiment, the pharmaceutical composition comprising at least one diluent which can be selected from dibasic calcium phosphate dehydrate, polysaccharides, primarily microcrystalline cellulose, lactose anhydrous, lactose monohydrate, mannitol, primarily calcium salts and the like and mixtures thereof. Preferably, diluent is the combination of lactose monohydrate and microcrystalline cellulose. In a preferred embodiment, the pharmaceutical composition comprising at least one disintegrant which can be selected from croscarmellose sodium, sodium starch glycolate, crospovidone, corn starch, pregelatinized starch, low-substituted hydroxypropyl cellulose and microcrystalline cellulose. Preferably, the disintegrant is crospovidone. In a preferred embodiment, the pharmaceutical composition comprises at least a binder which 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 at least one lubricant which can be selected from sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid and mixtures thereof. Preferably, the lubricant is magnesium stearate. The embodiment in accordance with the present invention is designed with adjusted quantitative composition composed of pharmaceutically acceptable ingredients mentioned above by using wet granulation process. The embodiment identified as Example 1 is given in the Table 1 below. This example was manufactured based on the highest strength, which comprises 2.5 mg Riociguat as active substance. The proposed embodiment based on the invention provided pharmaceutical composition is as stated below: Table 1: Unit formula of Example 1 Ingredients w / w, % Riociguat 0.6 Lactose monohydrate 40.0 – 50.0 Microcrystalline cellulose 35.0 – 45.0 Crospovidone 5.0 – 10.0 Hypromellose 2.0 – 5.0 Sodium lauryl sulfate 1.0 – 2.0 Magnesium stearate 0.1 – 1.0 Deionized water Sufficient quantity Core tablet 100.0 Furthermore, in a preferred embodiment, the process for the preparation of a pharmaceutical composition was manufactured using a wet granulation process, including the following steps: i. Lactose monohydrate, microcrystalline cellulose, crospovidone and hypromellose were screened through a proper sieve and transferred into cubic mixer and stirred, ii. Riociguat and sodium lauryl sulfate were dispersed in sufficient quantity of deionized water and added to the preparation in Step (i) to perform granulation process, iii. The granules prepared in Step (ii) were dried in fluid-bed mixer and shifted through a proper sieve, iv. Magnesium stearate was screened through a proper sieve and added to the granules prepared in Step (iii) and stirred to obtain a uniform final blend, v. Tablet compression was performed with the final blend in Step (iv). Firstly, the powder characterizations of powder blend for the proposed embodiment were evaluated according to the in <1174> in U.S. Pharmacopeia to identify the flowability property particularly. The compressibility index and Hausner ratio were calculated as 20.00 and 1.25, respectively based on the results of bulk and tapped densities which were 0.454 g / ml and 0.568 g / ml. Based on the results of scale of flowability, the final blend had “fair” flow characteristic. It was observed that the final blend's flowability was suitable for successfully performing tablet compression of Example 1. The tablet hardness was 230-250N. Furthermore, the obtained tablets were subjected to in-vitro dissolution studies, with the dissolution conditions designated to mimic the gastrointestinal pathway of orally applied solid dosage forms. The dissolution test is carried out in pH 6.8 phosphate buffer medium containing sodium lauryl sulfate. Other conditions are defined as; volume of dissolution medium is 900 ml, temperature of study is 37°C±0.5°C, rotation speed is 75 rpm, apparatus is paddle and the duration of dissolution study is 60 minutes. Table 2: In-vitro dissolution results of Example 1 Example 1 Time, min 5 10 15 20 30 45 60 Release, % 24 66 79 84 88 88 91 According to Table 2 provided above, the value at 60thminute was only 91, which means that the active substance likely remained undissolved or as solid particles in the environment. In the present embodiment, the aim was to ensure complete dissolution of active substance by using specified various types of surfactant in the formulation. According to the literature, the selection of an appropriate surfactant used in the studies is highly crucial because each surfactant has its own unique properties. Surfactants are commonly classified into four types based on the nature of the hydrophilic group: anionic surfactants (negative charge; sodium lauryl sulfate, docusate sodium), cationic surfactants (positive charge; benzalkonium chloride), nonionic surfactants (no charge; polysorbates, poloxamer, tween), and zwitterionic surfactants (containing both positive and negative charges; polysorbates). The embodiments identified as Example 2, Example 3, and Example 4 designed by considering the effect of different types of surfactants given in Table 3. All other ingredients, manufacturing steps and the strength remained constant with the constant tablet weight 425 mg. Furthermore, the active substance in low dose riociguat was placed in the solvent along with surfactant as mentioned in the manufacturing method. The examination of the these solution comprising different surfactants with ricoiguat were also examined because of having direct impact in granulation stage. Table 3: Examples comprising different types of surfactant Example 1 Example 2 Example 3 Example 4 w / w, % w / w, % w / w, % w / w, % Sodium lauryl sulfate 1.0 – 2.0 x x x Docusate sodium x 0.9 – 1.3 x x Tween 80 x x 0.9 – 1.3 x Poloxamer x x x 0.9 – 1.3 Prior to tablet compression, the flowabilities of the final blends were assessed to examine the impact of the specified types of surfactants on flow characteristics. Table 4: Physical appearances of the granulation solution comprising different types of surfactants along with riociguat Aggregation Example 1 x x x initiated rapidly Example 2 x Foam occured x x Aggregation Example 3 x x x initiated rapidly Example 4 x x x Totally dispersed The results of the compressibility index and Hausner ratio, along with the bulk and tapped densities of each powder blend, are presented in Table 5. Table 5: Physicochemical properties of all proposed examples Example 1 Example 2 Example 3 Example 4 The compressibility index 20.00 18.00 16.00 15.00 Hausner ratio 1.25 1.22 1.19 1.176 Bulk density, g / ml 0.454 0.495 0.447 0.450 Tapped density, g / ml 0.568 0.567 0.532 0.529 The scale of flowability Fair Fair Fair Good Based on the examination of the results of each powder blend, poloxamer was the one that presented an improvement between various powder blend characterizations. The results of the disintegration and in-vitro dissolution studies of each proposed example are presented in Table 6 and Table 7 respectively. Table 6: Disintegration results of proposed examples Disintegration time, min. Example-1 8 Example-2 5 Example-3 6 Example-4 6 The disintegration results were almost the same obtained with the four embodiments separately. Table 7: In vitro dissolution results of proposed examples Time, min 5 10 15 20 30 45 60 Example-2 32 70 80 84 87 90 90 Release, % Example-3 51 86 91 92 95 95 95 Release, % Example-4 57 84 91 95 97 99 100 Release, % According to Table 6 and Table 7, the highest release at 60thminute among multiple types of embodiments was obtained via Example-4, in which Poloxamer was used as the surfactant. Furthermore, because the dose proportionality approach requires presenting the same release characteristics in all strengths although the tablet weights and tablet hardness change. The tablet weight of 0.5 mg strength, Example-5, was 85 mg. Tablet hardness was 60N. Table 8: In vitro dissolution results of Example-5 5 min. 10 min. 15 min. 20 min. 30 min. 45 min. 60 min. Example-5 55 80 88 94 98 98 100 Release, % The disintegration time of Example-5 is 6 minutes. Thus, a proper dissolution and disintegration profiles were obtained with the pharmaceutical composition which was developed to be comprising low dose, 0.6% riociguat as active ingredient, 0.9-1.3% poloxamer as surfactant and was designed with dose proportional approach. 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. A pharmaceutical composition comprising low dose riociguat as active substance, poloxamer as surfactant and at least one further pharmaceutically acceptable excipient, in dose proportional design, wherein - the amount of riociguat is 0.6% w / w by weight of the total formulation, and -the amount of poloxamer is between the range of 0.9 – 1.3% w / w by weight of the total formulation.

2. A pharmaceutical composition according to Claim 1, wherein the amount of riociguat is from 0.5 mg to 2.5 mg per composition.

3. A pharmaceutical composition according to any one of the previous claims, wherein the total weight of the composition is between 85 mg to 425 mg.

4. A pharmaceutical composition according to any one of the previous claims, wherein the riociguat have a D90 value 15 microns or less.

5. A pharmaceutical composition according to any one of the previous claims, wherein at least one further pharmaceutically acceptable excipient is selected from diluent, disintegrant, binder and lubricant.

6. A 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, primarily calcium salts and mixtures thereof.

7. A 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 and microcrystalline cellulose.

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

9. A pharmaceutical composition according to Claim 5, wherein the lubricant is selected from sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid and mixtures thereof.

10. A pharmaceutical composition according to any one of the preceding claims, wherein the quantitative composition in w / w % is as stated below: Riociguat 0.6 Lactose monohydrate 40.0 – 50.0 Microcrystalline cellulose 35.0 – 45.0 Crospovidone 5.0 – 10.0 Hypromellose 2.0 – 5.0 Poloxamer 0.9 – 1.3 Magnesium stearate 0.1 – 1.0 Deionized water q.s.

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