Solifenacin succinate bilayer tablet formulation

Abstract

The present invention relates to pharmaceutical compositions, specifically bilayer tablet formulations containing mirabegron and solifenacin succinate. The invention particularly addresses improvements in in-vitro release of solifenacin succinate in immediate release layer by improved manufacturing processes.

Description

[0001] DESCRIPTION

[0002] SOLIFENACIN SUCCINATE BILAYER TABLET FORMULATION

[0003] Technical Field

[0004] The present invention relates to pharmaceutical compositions, specifically bilayer tablet formulations containing mirabegron and solifenacin succinate. The invention particularly addresses improvements in in-vitro release of solifenacin succinate in immediate release layer by improved manufacturing processes.

[0005] State of Art

[0006] Mirabegron and solifenacin succinate are widely recognized pharmaceutical agents used in the treatment of overactive bladder (OAB). Their complementary mechanisms of action generate an effective combination therapy for managing urinary frequency, urgency, and incontinence.

[0007] Mirabegron, as being a beta-3 adrenergic receptor agonist, enhances bladder storage capacity by relaxing the detrusor muscle during the filling phase. Its use has significantly improved the treatment of OAB, offering a well-tolerated alternative to anticholinergic therapies.

[0008] Chemically known as 2-(2-Amino-l,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2- phenylethyl]amino} ethyl) phenyl] acetamide with the following structure Formula II, mirabegron has the empirical formula C21H24N4O2S and a molecular weight of 396.506 g / mol.

[0009] Formula II

[0010] Mirabegron is a white crystalline powder, non-hygroscopic, and soluble in dimethyl sulfoxide, methanol, and water under neutral to acidic pH conditions. With one chiral center, it exhibits stereoisomerism, and the R-enantiomer is used in the final product.

[0011] Mirabegron and its pharmaceutically acceptable salts thereof were first described in patent document EP10281 11 by Yamanouchi Pharmaceutical Co. This document discloses the preparation of mirabegron and its salts, particularly focusing on its hydrochloride form, as detailed in Example 41. Subsequently, patent document EP1559427 was the first to outline a pharmaceutical composition containing mirabegron, intended for use as a therapeutic agent in OAB, including OAB with prostatic hyperplasia, urinary urgency, urinary incontinence, and urinary frequency. The R-enantiomer, used in the manufacture of the final product, was further disclosed in patent document EP2298752.

[0012] Solifenacin succinate, a muscarinic receptor antagonist, mitigates the effects of acetylcholine on smooth muscle contraction, thereby reducing bladder overactivity. It is particularly effective in alleviating symptoms of urgency and frequency, making it a preferred choice in managing OAB when combined with other agents.

[0013] Its chemical name is butanedioic acid, compound with l(S)-3(R)-l-azabicyclo[2.2.2]oct-3-yl 3,4-dihydro-l-phenyl-2(lH)-isoquinolinecarboxylate (1 : 1), with an empirical formula of C23H26N2O2C4H6O4 and a molecular weight of 480.55 g / mol. The structural formula for solifenacin succinate is represented by Formula I.

[0014] F s nta I

[0015] Solifenacin succinate is a white to pale-yellowish-white crystal or crystalline powder. It is freely soluble at room temperature in water, glacial acetic acid, dimethyl sulfoxide, and methanol. Initially described in the patent document EP0801067 by Yamanouchi Pharmaceutical Co., solifenacin and its pharmaceutically acceptable salts were developed for conditions like urinary incontinence, neurogenic bladder, and chronic cystitis. The pharmaceutical product containing solifenacin, marketed as VESICARE®, was first approved in the Netherlands in 2003 and is available in 5 mg and 10 mg film-coated tablets for oral use.

[0016] Based on this knowledge, several patents or patent applications in the state of art aim to develop a pharmaceutical composition comprising mirabegron and solifenacin in separate layers which are summarized below.

[0017] EP2891493 relates to a pharmaceutical composition for oral administration comprising; a modified release portion comprising mirabegron or a pharmaceutically acceptable salt thereof, and an immediate release portion comprising solifenacin or a pharmaceutically acceptable salt thereof. In the document, the modified release portion contains hydrogel forming polymer (polyethylene oxide) and an additive allowing water to penetrate into the modified release portion. Furthermore, in the document, the immediate release portion contains calcium stearate because the combination product may negatively effect the release rate of solifenacin.

[0018] EP4159199 relates to a pharmaceutical form comprising an immediate-release solifenacin in the second component and modified-release mirabegron in the first component wherein polyethylene oxide with the average molecular weight of 100,000 to 900,000 is included in an amount preferably 2 to 20% by weight, based on the total weight of the mirabegron-containing composition.

[0019] W02020097328 relates to a fixed dose pharmaceutical composition comprising a core comprising about 50 mg to 100 mg mirabegron and optionally one or more pharmaceutically acceptable excipients; and a coating layer comprising about 5 mg to 10 mg solifenacin and a pharmaceutically acceptable excipient. In the document, the pharmaceutically acceptable excipient of the coating layer is selected from the group consisting of Opadry, lactose monohydrate, com starch, hypromellose 2910, magnesium stearate, talc, polyethylene glycol 8000, and titanium dioxide with yellow ferric oxide or red ferric oxide, or combinations thereof. Additionally, it may optionally further comprise an outer layer of the composition comprising a non-pH-dependent water-soluble coating film.

[0020] EP3448367 relates to a multi-layer tablet comprising a controlled release part comprising mirabegron and an immediate release part comprising solifenacin succinate, along with a water insoluble diluent in an amount ranging from 50 to 99% w / w relative to the total weight of the immediate-release part of the tablet.

[0021] Another prior art document is the patent application of Santa Farma company with number of EP4419087. In this document, patentee describes a matrix formulation of mirabegron prolonged-release tablet in detail and this formulation will be the same in current bilayer tablet as being the part of mirabegron containing prolonged-release layer.

[0022] Bilayer compositions comprising mirabegron and solifenacin succinate represent a key innovation in pharmaceutical industry. They provide the advantage of delivering both active pharmaceutical ingredients (APIs) in a single dosage form, optimizing patient compliance and therapeutic outcomes. However, achieving consistent performance, particularly in terms of dissolution and uniformity, remains a significant challenge. This is critical particularly for the layer comprising solifenacin succinate as being a low-amount drug load composition. Despite being included in BCS Class I, solifenacin succinate comprising layer’s formulation design and manufacturing process surprisingly identified as significant factors affecting dissolution behavior. Despite advancements in bilayer tablet formulations, the impact of PSD on homogeneity of in vitro dissolution performance has not been sufficiently addressed in the prior art. This gap creates variability in product quality and limits the reliability of existing formulations in bilayer tablet formulations.

[0023] The current invention builds upon this state of the art by optimizing PSD through granulation step. A surprising improvement in homogeneity of in vitro dissolution profile observed as the invention addresses a critical unmet need in the field and sets a new standard for bilayer tablet formulations containing mirabegron and solifenacin succinate.

[0024] Summary of The Invention

[0025] The present invention relates to a pharmaceutical formulation comprising mirabegron or its pharmaceutically acceptable salts, and solifenacin or its pharmaceutically acceptable salts, formulated as a bilayer tablet dosage form by presenting homogenous in-vitro release.

[0026] The object of the present invention is to provide a bilayer tablet formulation where mirabegron is present in its free form in the prolonged-release layer, while solifenacin is incorporated as the succinate salt in the immediate-release layer.

[0027] In one object, the immediate release layer of the present invention contains solifenacin succinate in its crystal form.

[0028] In another object, the immediate release layer of the present invention contains solifenacin succinate in its amorphous form.

[0029] Particularly, the immediate release layer of the present invention contains solifenacin succinate in crystal form I with presenting characterized 2-theta angles of 3.9 °, 11.2 °, 14.3 °, and 18.80±0.2°.

[0030] In the present invention, solifenacin succinate in the immediate-release layer belongs to BCS Class I and presents high solubility and high permeability.

[0031] In the present invention, solifenacin succinate is in micronized particle size distribution and the size of 90% of solifenacin succinate particles is 90-microns or below. In the present invention, the immediate-release layer comprising solifenacin succinate is incorporated with powder blend homogeneity due to flowability problem in its physicochemical properties.

[0032] Another object of the present invention is to provide an immediate-release pharmaceutical formulation comprising solifenacin succinate manufactured by using wet granulation process.

[0033] A further object of the present invention is to provide a bilayer tablet formulation in which immediate-release layer comprising solifenacin succinate with improved homogeneity at in- vitro release profiles in physiological media.

[0034] Detailed Description of The Invention

[0035] The object of the present invention relates to a bilayer tablet formulation comprising solifenacin or a pharmaceutically acceptable salt and mirabegron or a pharmaceutically acceptable salt thereof, designed to achieve prolonged-release of mirabegron and immediate release of solifenacin succinate in a single form.

[0036] A "biphasic delivery system" involves a single dosage form with immediate release and prolonged release. This system combines immediate-release solifenacin for rapid therapeutic action with prolonged-release mirabegron for extended efficacy.

[0037] The term "prolonged-release" refers to dosage forms that release the active ingredient over an extended period, ensuring sustained therapeutic effects. In the preferred embodiment, mirabegron or its pharmaceutically acceptable salt is used, preferably in its free form.

[0038] In the present formulation, the total weight of the mirabegron-containing prolonged-release layer ranges between 200 mg to 300 mg, with mirabegron comprising less than 25% w / w of the layer.

[0039] The term "immediate-release" refers to dosage forms that dissolve and act quickly after administration. In the preferred embodiment, solifenacin or its pharmaceutically acceptable salt, preferably solifenacin succinate, is selected for the immediate-release layer.

[0040] In one object, the immediate release layer of the present invention contains solifenacin succinate in its crystal form.

[0041] In another object, the immediate release layer of the present invention contains solifenacin succinate in its amorphous form. Particularly, the immediate release layer of the present invention contains solifenacin succinate in crystal form I with presenting characterized 2-theta angles of 3.9 °, 11.2 °, 14.3 °, and 18.80±0.2°.

[0042] In the present formulation, the total weight of the solifenacin-containing immediate-release layer ranges between 100 mg to 200 mg, with solifenacin succinate comprising less than 4% w / w of the layer. Due to this low concentration, solifenacin is classified as a low-dose drug. However, this low dosage poses specific challenges, particularly in achieving complete and consistent release of active substance in time meeting immediate release requirements.

[0043] In the present invention, low-dose solifenacin presents challenges not only in achieving uniform distribution but also in ensuring adequate flowability due to its hygroscopic nature and tendency to adhere to equipment surfaces. These characteristics complicate the manufacturing process, necessitating careful management for an effective bilayer tablet formulation.

[0044] According to an embodiment, prolonged-release layer comprising mirabegron is manufactured according to EP4419087 based on the formulation identified as Example 4 in the document. The manufacturing method is also kept same and the release profile of Example 4 is valid.

[0045] Table 1: Unit Formula of Example 4 declared in EP4419087

[0046] The detailed manufacturing steps of Example 4 presenting prolonged release of mirabegron were presented below: i. Mirabegron and polyethylene oxide are screened through a proper sieve and transferred into cubic mixer and stirred, ii. ii. Microcrystalline cellulose, hydroxypropyl methylcellulose and hydroxypropyl cellulose are screened through a proper sieve and added to the preparation in Step (i) to perform granulation process, iii. iii. Butylated hydroxytoluene is dissolved in sufficient quantity of an organic solvent and added to the preparation in Step (ii) to perform granulation process, iv. iv. The granules prepared in Step (iii) are dried in high-shear mixer and shifted through a 0.63 mm mesh sieve, v. v. Magnesium stearate is screened through a proper sieve and added to the granules prepared in Step (iv), vi. vi. Colloidal silicon dioxide is screened through a proper sieve and added to the granules prepared in Step (v) and stirred to obtain a uniform final blend.

[0047] According to an embodiment, immediate-release layer comprising solifenacin succinate manufactured by using wet granulation method.

[0048] According to the embodiment, first prolonged-release layer is compressed and secondly the immediate release layer compressed on prolonged-release layer subsequently. Tablet is coated with a film coating finally.

[0049] According to the present invention, a bilayer tablet composed of immediate-release layer comprising solifenacin succinate indicating homogeneous in-vitro releases in physiological media.

[0050] The immediate-relase layer comprising solifenacin succinate as the proposed composition, Example 1 is provided in Table 2 below, showing the unit formula of the immediate-release solifenacin succinate layer in w / w%.

[0051] Table 2: Unit Formula of Example 1

[0052] Another objective of the Example 1 relates to the preparation of the immediate-release layer using a wet granulation process, which includes the following steps: i. Solifenacin succinate, the specified amount of pregelatinized starch, the specified amount of lactose and specified amount of the hydroxypropyl methylcellulose are screened through a proper sieve, transferred into high-shear mixer, and stirred, ii. The rest of the lactose is screened through a proper sieve and added to the powder mixture prepared in Step a, iii. The rest of the hydroxypropyl methylcellulose is dissolved in sufficient amount of deionized water and added to the mixture from Step a to perform granulation process, iv. The granule from Step c - granulation step - is dried in fluid bed dryer till to max. water content value of 2.0% and screened through 0.63 mm mesh sieve to ensure uniform particle size, v. The remaining amount of pregelatinized starch and magnesium stearate are screened through 0.63 mm mesh sieve and added to the prepared granules in Step d, then mixed for 3 minutes to obtain a uniform final blend,

[0053] In the Example 1, the flowability of the final blend was not sufficient, ensuring an efficient tablet compression process. A sticking problem was observed during tablet compression process. However, the tablets could be compressed with challenging.

[0054] The mesh size of sieve is important to get a uniform blend as well as to obtain a uniform bilayer tablet. The closer the particle sizes are, the more applicable to obtain a homogeneous bilayer tablet regarding tablet compression process, because the similar powder blends can be compressed under similar conditions. Therefore, 0.63 mm mesh size is preferred in immediate- release layer comprising solifenacin succinate, which is the same with the powder blend in prolonged-release layer comprising mirabegron.

[0055] As a result, a bilayer tablet compression was performed by using Example 1 and Example 4 mentioned above.

[0056] The compressed bilayer tablets were then, subjected to an in vitro dissolution study to evaluate the disintegration and release profile considering absorption site of the gastrointestinal (GI) tract.

[0057] 0.1N HC1, pH 4.5 acetate buffer and pH 6.8 phosphate buffer were used to simulate gastric conditions, with a dissolution medium volume of 900 ml. The temperature was maintained at 37°C±0.5, with a rotation speed of 100 rpm using a basket apparatus, and the duration of the dissolution study was 60 minutes. The amount of dissolved solifenacin succinate as the active ingredient over time in the in-vitro dissolution study was determined by HPLC.

[0058] Table 3: In-vitro dissolution profiles of prolonged-release layer in physiological media Table 4: In-vitro dissolution profiles of immediate-release layer in physiological media

[0059] The in-vitro release pattern of solifenacin succinate in the immediate-release layer of the bilayer tablet presented dissolution profiles along with high variations in all three media since mirabegron dissolution profiles were convenient.

[0060] Actually, the inhomogeneity issue at in-vitro release profiles of immediate-release solifenacin succinate was an unexpected problem due to its high solubility property and being in micronized form. Thus, the process and formulation details were examined to find out the source of variation.

[0061] The variations in dissolution profiles could be sourced from solifenacin succinate itself and qualitative formulation. Since the active substance solifenacin succinate was used in micronized form and classified as BCS Class I (highly soluble), it could not be the cause of this kind of variation. The qualitative formulation was also not the source of this kind of release problem, regarding the approximately 100% release of solifenacin succinate was achieved at the targeted dissolution duration at absorption site medium which is 0.1N HCI.

[0062] Thus, the problem to be solved was investigated in detail to get the proper approach for further processes. A close examination on individual dissolution profiles at 10th, 15thtime durations were investigated as tabulated below.

[0063] Table 5: Individual dissolution profile results of solifenacin succinate in 0.1N HCI medium at 10thminute duration Table 6: Individual dissolution profile results of solifenacin succinate in pH 4.5 acetate buffer medium at 10thminute and 15thminute durations Table 7: Individual dissolution profile results of solifenacin succinate in pH 6.8 phosphate buffer medium at 10thminute duration

[0064] The individual releases of solifenacin succinate could arise due to manufacturing processes in which homogeneous blending was not achieved. Also the sticking problem was present.

[0065] Thus, an investigation study employed to find out the source of sticking issue.

[0066] First of all, active substance was analysed to get information about physicochemical properties such as powder flowability and compressibility index.

[0067] Flowability and compressibility of solifenacin succinate active substance alone evaluated (Hausner ratio value is 1.37 which means the flowability property is poor) and concluded that solifenacin succinate active substance presents strong aggregation based on the analytical characterization studies.

[0068] As a result of the investigation studies, active substance solifenacin succinate does not present proper flow properties and the it is understand that pharmaceutical composition should be designed to overcome sticking problem.

[0069] During the designing manufacturing process of the further embodiments, physicochemical data of active substance was evaluated testing water content of the granule after drying step (fluidbed dryer process) completed during the granulation process.

[0070] The mixing conditions during manufacturing process were differentiated in solifenacin succinate layer in two new embodiments. The quantitative and qualitative compositions kept constant and manufacturing process was redesigned by changing the size of sieve from 0.63 mm to 1.00 mm during manufacturing process and mixing durations of final powder blend.

[0071] Mirabegron prolonged-release layer was completely kept same. The mixing durations of solifenacin succinate immediate-release layer powder blend before compression process, and size of sieve were changed to avoid variations in in-vitro releases.

[0072] Table 8: Mixing process durations and the water content values after drying step in the manufacturing process

[0073] The hardness of the bilayer tablet is also a critical parameter in bilayer tablet effective on physicochemical and in-vitro release characterizations. Thus, the experienced values during the process was between 130N - 250N. However, the convenient tablet hardness was between 180-250N. No sticking problem was observed during manufacturing process of Embodiment l . Embodiment ! presented similar sticking affinity with Example 1.

[0074] The bilayer tablets manufactured with above mentioned process details were subjected to dissolution studies under the same media and conditions with Example 1. Table 9: In-vitro dissolution profiles of New embodiment ! at immediate-release layer in physiological media

[0075] Table 10: In-vitro dissolution profiles of New embodiment l at immediate-release layer in physiological media

[0076] According to the results presented in Table 9 and Table 10, the in-vitro profiles of solifenacin succinate and variations in these in-vitro results in physiological media were improved with Embodiment ! . Embodiment_2 with higher mixing duration and final blend sieved through 1.00 mm sieve, does not overcome variations in solifenacin succinate release. Further, solifenacin succinate amount in Embodiment_2 was not released completely in absorption site medium, which is 0. IN HCI.

[0077] It is surprising that, in comparison of Embodiment ! and Embodiment_2, the mixing durations along with higher sieve size bypassed both variations in solifenacin succinate release. It was also observed that solifenacin succinate releases were improved. Tablet compression was completed without any sticking issue by controlling water content of the granule.

[0078] In the present invention, bilayer tablet composition comprises immediate release layer comprising solifenacin succinate and prolonged-release layer comprising mirabegron, wherein

[0079] The final blend in solifenacin succinate layer is sieved through 1.00 mm sieve, and - The final blend in immediate-release layer is mixed for 5-10 minutes.

[0080] The water content of granule after drying step is between 0.7-1.5%.

Claims

CLAIMS1. A bilayer tablet pharmaceutical composition comprising an immediate-release layer comprising solifenacin succinate and at least one pharmaceutically acceptable excipient, a prolonged-release layer comprising mirabegron and at least one pharmaceutically acceptable excipient, wherein;The final blend in immediate-release layer is sieved through 1.00 mm sieve, and The final blend in immediate-release layer is mixed for 5-10 minutes.The water content of granule after drying step is between 0.7-1.5%.

2. A bilayer tablet pharmaceutical composition according to claim 1, wherein at least one pharmaceutically acceptable excipient in the immediate-release layer is a disintegrant which is pregelatinized starch.

3. A bilayer tablet pharmaceutical composition according to any one of the preceeding claims, wherein at least one pharmaceutically acceptable excipient in the immediate-release layer is a binder which is hydroxypropyl methylcellulose.

4. A bilayer tablet pharmaceutical composition according to any one of the preceeding claims, wherein the immediate-release layer is prepared by wet granulation method.

5. A bilayer tablet pharmaceutical composition according to any one of the preceeding claims, wherein at least one pharmaceutically acceptable excipient in the immediate-release layer is selected from the group comprising a diluent, a lubricant and a granulation solvent.

6. A bilayer tablet pharmaceutical composition according to claim 5, wherein the diluent is selected from dibasic calcium phosphate dehydrate, polysaccharides, primarily microcrystalline cellulose, lactose, mannitol, sugars, sorbitol, sucrose, inorganic salts, primarily calcium salts, and mixtures thereof.

7. A bilayer tablet pharmaceutical composition according to claim 5, wherein the lubricant is selected from sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid, hydrogenated castor oil, and mixtures thereof.

8. A bilayer tablet pharmaceutical composition according to claim 5, wherein the granulation solvent is selected from deionized water, ethanol, methanol, isopropanol, and mixtures thereof.

9. A bilayer tablet pharmaceutical composition according to any one of the preceding claims, wherein the amount of immediate-release layer comprising solifenacin succinate is between 100 mg to 200 mg.

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