Mirabegron and solifenacin bilayer tablet

Abstract

The present invention relates to bilayer tablet pharmaceutical compositions comprising an immediate-release layer comprising solifenacin succinate as active ingredient, a binder, a distintegrant and at least one pharmaceutically acceptable excipient, a prolonged-release layer comprising mirabegron as active substance and at least one pharmaceutically acceptable excipient.

Description

[0001] DESCRIPTION

[0002] MIRABEGRON AND SOLIFENACIN BILAYER TABLET Technical Field

[0003] The present invention relates to a bilayer pharmaceutical formulation comprising an immediate-release layer of solifenacin succinate and at least one pharmaceutically acceptable excipient and a prolonged-release layer of mirabegron and at least one pharmaceutically acceptable excipient.

[0004] State of Art

[0005] Overactive bladder (OAB) syndrome is a prevalent condition, characterized by a sudden and intense urge to urinate, with or without urgency urinary incontinence. It is commonly associated with increased daytime frequency and nocturia in the absence of a detectable underlying pathology such as urinary tract infections or other obvious abnormalities. Studies suggest that OAB affects up to 16% of the adult population, with a significant impact on quality of life by disrupting daily activities and reducing social and workplace productivity. Pharmacotherapy commonly used to manage OAB symptoms by suppressing involuntary detrusor muscle contractions, ultimately aiming to improve patients' quality of life.

[0006] Solifenacin succinate is a well-known muscarinic receptor antagonist frequently prescribed for OAB management. It alleviates symptoms such as urinary urgency and frequency by targeting muscarinic M2 and M3 receptors, which regulate detrusor muscle contractions and modulate neural activity in the urothelium.

[0007] Its chemical name is butanedioic acid, compound with 1(S)-3(R)-1-azabicyclo[2.2.2]oct-3-yl 3,4-dihydro-1-phenyl-2(1H)-isoquinolinecarboxylate (1:1), with an empirical formula of C23H26N2O2C4H6O4and a molecular weight of 480.55 g / mol. The structural formula for solifenacin succinate is represented by Formula I.

[0008]

[0009] 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.

[0010] Despite its widespread use, its broad inhibition of muscarinic receptors can result in unwanted side effects, including dry mouth, constipation, dry eyes, and blurred vision. These adverse reactions are often cited as factors contributing to low treatment adherence, with some patients discontinuing use prematurely due to intolerability.

[0011] Recent advancements in OAB research have led to the discovery of β-adrenoceptor subtypes (β1, β2, and β3) in the detrusor muscle and urothelium. Among these, the β3-adrenoceptor plays a key role in relaxing detrusor smooth muscle during the bladder’s storage phase. This relaxation increases bladder capacity, offering a novel pathway to managing OAB symptoms.

[0012] Mirabegron, the first β3-adrenoceptor agonist, offers a promising alternative for patients who are intolerant to antimuscarinic agents like solifenacin. Mirabegron’ s distinct mechanism of action avoids muscarinic receptors, reducing the likelihood of common side effects while providing effective symptom control for OAB. Chemically known as 2-(2-Amino-1,3-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.

[0013] V* J? „.

[0014]

[0015] ii

[0016] 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. Mirabegron and its pharmaceutically acceptable salts thereof were first described in patent document EP1028111 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 later disclosed in patent document EP2298752.

[0017] The first pharmaceutical product containing mirabegron as the active substance was approved in Japan and has been launched under the brand name BETANIS®. In a similar way, it was commercially approved by the U. S. Food& Drug Administration (FDA) in June 2012 and by European Medicines Agency (EMA) in December 2012, and has been launched under the brand name MYRBETRIQ® in the U. S. and BETMIGA® in Europe. All approved products are available in prolonged-release tablets, offered in strengths of 25 mg and 50 mg of mirabegron.

[0018] Recent literature supports the use of β3-adrenoceptor agonists, like mirabegron, in combination with anticholinergic agents to treat OAB. In 2018, the U. S. FDA approved a supplemental New Drug Application (sNDA) for MYRBETRIQ®, allowing mirabegron to be used in combination with solifenacin succinate for the treatment of OAB symptoms such as urge urinary incontinence, urgency and urinary frequency. Combining these two medications offers a more comprehensive treatment approach, targeting different pathways involved in bladder overactivity.

[0019] Fixed-dose combination therapies are known to reduce the risk of non-compliance, which is particularly important for chronic conditions like OAB. To improve dosing compliance through a single formulation, the patent document EP2216021 introduced a combination pharmaceutical composition that contains both mirabegron and solifenacin, or their a pharmaceutical acceptable salt thereof. The pharmaceutical composition outlined in the patent comprises 10 mg to 100 mg of mirabegron and 0.5 mg to 10 mg solifenacin, specifically targeting the treatment of urinary urgency, pollakiuria and / or urinary incontinence related to OAB. The combination pharmaceutical composition is designed as a monolayer tablet using the fluidized bed granulation process. However, the drug dissolution profiles for mirabegron and solifenacin differ from each other; mirabegron is in a prolonged-release formulation, while solifenacin is in an immediate-release formulation. Despite being contained in a single formulation, the release profiles of the two drugs remain distinct and are not affected by each other adeversely.

[0020] 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.

[0021] 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.

[0022] 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.

[0023] 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.

[0024] 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. 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.

[0025] According to prior art documents, there are many patents and patent applications for bilayer tablet composition with two separated release layers comprising mirabegron or its pharmaceutically acceptable salts and solifenacin or its pharmaceutically acceptable salts, for treating overactive bladder in a single dosage form.

[0026] However, there is a need for a bilayer tablet composition comprising prolonged-release form of mirabegron or a pharmaceutically acceptable salt thereof, and an immediate-release form of solifenacin or a pharmaceutically acceptable salt thereof which overcomes non-homogenous release profile problems of solifenacin succinate due to be in low-dose in the formulation.

[0027] Summary of The Invention

[0028] The object of this invention is to provide a pharmaceutical formulation comprising mirabegron or its pharmaceutically acceptable salts, and solifenacin or its pharmaceutically acceptable salts, formulated as a bilayer tablet dosage form, in which both active ingredients exhibit distinct release profiles, being separated into different layers.

[0029] Another objective 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.

[0030] In one object, the immediate release layer of the present invention contains solifenacin succinate in its crystal form.

[0031] In another object, the immediate release layer of the present invention contains solifenacin succinate in its amorphous form.

[0032] 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°.

[0033] In the present invention, solifenacin succinate is incorporated as a low-dose component, with a concentration of less than 4% w / w in the immediate-release layer composition (low-dose composition). Another object of the present invention is to provide an immediate-release pharmaceutical formulation comprising solifenasin succinate manufactured by using wet granulation process. A further object of the present invention is to provide a bilayer tablet formulation in which immediate-release layer comprising solifenacin succinate used at specified concentrations and ratio of disintegrant and binder in the formulation to overcome solifenacin dissolution problem.

[0034] Detailed Description of The Invention

[0035] The present invention provides 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. Additionally, the polymorphic form of solifenacin succinate is crystal Form-I.

[0040] 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.

[0041] 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.

[0042] The interactions of both layers components and their effect on counter-layers’ release profile is the most challenging obstacle considering bilayer composition and manufacturing details.

[0043] To address these complexities, the invention incorporates excipients with both carrier and binding properties, which effectively mitigate processability issues and support a consistent formulation outcome.

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

[0045] Ingredients w / w, % Mirabegron 19.0 - 21.0 Polyethylene oxide 10.0 - 15.0 Hydroxypropyl methylcellulose 7.0 - 11.0 Microcrystalline cellulose 48.0 - 54.0 Hydroxypropyl cellulose 5.0 - 10.0

[0046] Butylated hydroxytoluene 0.0 - 1.0 Magnesium stearate 1.0 - 2.0

[0047] Colloidal silicon dioxide 0.0 - 1.0

[0048] Organic solvent 1.0 - 2.0

[0049]

[0050] Core tablet 100.0

[0051] The detailed manufacturing steps of Example 4 presenting prolonged release of mirabegron were presented below:

[0052] i. Mirabegron and polyethylene oxide are screened through a proper sieve and transferred into cubic mixer and stirred,

[0053] 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,

[0054] 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),

[0055] 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. According to an embodiment, immediate-release layer comprising solifenacin succinate is manufactured.

[0056] 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.

[0057] According to the embodiment, solifenacin succinate is classified as BCS I by presenting high solubility and high permeability properties. Moreover, the particle size distribution of 90% of solifenacin succinate particles is between 1-50 microns.

[0058] In one object, the immediate release layer of the present invention contains solifenacin succinate in its crystal form.

[0059] In another object, the immediate release layer of the present invention contains solifenacin succinate in its amorphous form.

[0060] 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°.

[0061] These properties were considered adequate to meet immediate-release dosage form release profile without using no disintegrant during proposing first example to investigate its dissolution behaviour.

[0062] Thus, the binder in the formulation is selected carefully and hydroxypropyl methylcellulose (HPMC) is used as a binder based on its water-soluble, non-ionic nature. HPMC assists enhancing granule cohesion and compressibility while ensuring uniform distribution of low-dose solifenacin throughout the tablet.

[0063] In the above mentioned embodiment, the present invention provides an immediate-layer pharmaceutical composition comprising solifenacin succinate, manufactured using wetgranulation method which is employed to manufacture tablets that include the active ingredient along with composition designed with qualitative and quantitative diluent, lubricant, and granulation water, chosen for their suitability to the intended form of administration.

[0064] In the embodiment, the pharmaceutical composition comprises at least one diluent, selected from the group consisting of dibasic calcium phosphate dehydrate, polysaccharides, primarily microcrystalline cellulose, lactose, mannitol, sugars, sorbitol, sucrose, inorganic salts, primarily calcium salts and mixtures thereof. Preferably, the diluent is lactose.

[0065] In the embodiment, the pharmaceutical composition comprises at least one lubricant, selected from the group consisting of sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid, hydrogenated castor oil and mixtures thereof. Preferably, the lubricant is sodium stearyl fumarate.

[0066] In the embodiment, the pharmaceutical composition comprises at least one granulation solvent, selected from the group consisting of deionized water, ethanol, methanol, isopropanol, and mixtures thereof. Preferably, the granulation solvent is deionized water.

[0067] In the embodiment of the present invention, pharmaceutical formulations compressed into a bilayer tablet form consisting of at least two separate layers, where immediate-release layer comprising solifenacin succinate is manufactured using wet granulation process.

[0068] The immediate release layer part of the embodiment of the present invention is designed with quantitative and qualitative composition of pharmaceutically acceptable ingredients, utilizing the wet granulation process to overcome the challenges of poor flowability and low-dose drug uniformity.

[0069] In Example 1, no disintegrant is included to the design of the composition regarding solifenacin succinate belongs to BCS Class I and presents high solubility and high permeability properties. These properties are suitable to design an immediate release formulation.

[0070] The proposed composition for Example 1 is provided in Table 2 below, showing the unit formula of the immediate-release solifenacin succinate layer in w / w%.

[0071] Table 2: Unit Formula of Example 1

[0072] Ingredients Example 1 (w / w, %)

[0073] Solifenacin succinate 2.0 - 5.0

[0074] 90.0 - 95.0

[0075]

[0076] Lactose Ingredients Example 1 (w / w, %) Hydroxypropyl methylcellulose 2.0 - 5.0

[0077] Magnesium stearate 0.1 - 2.0

[0078] Deionized water Sufficient quantity

[0079]

[0080] Core tablet 100.0

[0081] 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:

[0082] a) Solifenacin succinate, 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,

[0083] b) The rest of the lactose is screened through a proper sieve and added to the powder mixture prepared in Step a,

[0084] c) 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,

[0085] d) The granule from Step c is dried in fluid bed dryer and screened through a proper sieve to ensure uniform particle size,

[0086] e) Magnesium stearate are screened through a proper sieve and added to the prepared granules in Step d, then stirred to obtain a uniform final blend,

[0087] f) The tablet compression is performed with the final blend in Step e.

[0088] In the Example 1, the flowability of the final blend was sufficient, ensuring an efficient tablet compression process. The compressed tablets of Example 1 were then, subjected to an in vitro dissolution study to evaluate the disintegration and release profile considering absorption site of the gastrointestinal (GI) tract.

[0089] 0.1N HCl medium was 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.

[0090] The amount of dissolved active ingredient over time in the in-vitro dissolution study was determined by HPLC. Table 3: In-vitro dissolution profiles of solifenacin succinate in Example 1

[0091] Result, % in 0.1N HC1

[0092] Time, min.

[0093] Reference Drug Product Example 1

[0094] 5 19 23

[0095] 10 47 38

[0096] 15 70 49

[0097] 20 87 58

[0098] 30 100 70

[0099] 45 100 82

[0100]

[0101] 60 100 89

[0102] The in-vitro release pattern of solifenacin succinate in the immediate-release layer of Example 1 presented a slower dissolution profile and the amount of solifenacin succinate is not release completely (89%). Although Example 1 reached a slightly higher initial release (23% at 5 minutes compared to 19% for the reference), it fell behind as dissolution progressed, achieving only 70% dissolution at 30 minutes versus 100% for the reference.

[0103] Moreover, according to The Guideline on the Investigation of Bioequivalence, an f2similarity factor of 36.0 (below the threshold of 50) also confirms that Example 1 and the reference product are not similar in dissolution profile. These findings highlight a need for further formulation to achieve complete release of total solifenacin succinate amount in time.

[0104] In Example 1, the absence of a disintegrant in this formulation may have further contributed to the observed slower dissolution rate as a routine approach. This revealed a need to add a disintegrant to the formulation of Example 1. Therefore, further examples were designed including various concentrations of disintegrant.

[0105] Disintegrants are essential excipients that facilitate tablet matrix breakdown, allowing water penetration and enhancing active ingredient release. To address the slower dissolution rate observed compared to the reference product, a disintegrant was incorporated into subsequent formulations. Considering the release profile of solifenacin succinate in Example 1 and HPMC nature as binder, disintegrant was investigated. Pregelatinized starch, selected for its unique swelling properties, promotes rapid water uptake and matrix expansion, thereby supporting tablet disintegration and improving active ingredient release. Thus, in the present invention, the ratio between HPMC and pregelatinized starch was examined. A balanced ratio influences the disintegration process and overall release rate, ensuring consistent active ingredient delivery.

[0106] Thus, subsequent examples were formulated by varying only the disintegrant amount relative to the total tablet weight by keeping binder amount constant. The diluent quantity was adjusted accordingly to balance the changes in disintegrant content, while the remaining excipients, as well as the manufacturing process. This approach ensured that any observed differences in release profile resulted solely based on the changes in disintegrant concentrations.

[0107] Table 4: Disintegrant and Diluent Concentrations, with Binder-To-Disintegrant Ratios in Formulation Examples

[0108] Excipients Example 1 Example 2 Example 3 Binder - HPMC 2.0 - 5.0 2.0 - 5.0 2.0 - 5.0 Disintegrant - No disintegrant 4.0 - 8.0 8.0 - 10.0 Pregelatinized starch

[0109] Binder-To-Disintegrant

[0110] No disintegrant 0.5:0.6 0.025:0.5

[0111]

[0112] Ratio

[0113] Table 5: In-vitro dissolution profiles of solifenacin succinate in Example 2 and Example 3

[0114] Results, % in 0.1N HC1

[0115] Time, min. Reference Drug

[0116] Example 2 Example 3 Product

[0117] 5 19 21 12

[0118] 10 47 46 34

[0119] 15 70 75 47

[0120] 20 87 90 59

[0121] 30 100 99 79

[0122] 45 100 100 97

[0123]

[0124] 60 100 99 100

[0125] The in-vitro release profiles of solifenacin succinate in the immediate-release layers of Example 2 and Example 3 were evaluated. Example 2 and Example 3 released total amount of active substance in time. However, there was a distinct release profile variations between two examples. The acceleration in release profile of Example 3 did not properly behave as immediate release layer (a quick release was not achieved).

[0126] On the other hand, Example 2 presented a gradually increasing release in time as being immediate release (99% of active ingredient is release in 30 minutes). It is surprising, because use of higher amount disintegrant directly blocking the release of active substance in time and resulting in a slower dissolution rate.

[0127] Thus, further example was designed to reveal the fact of this surprising effect. Example 4 was proposed by only changing the amount of HPMC as binder in the quantitative formulation by keeping the amount of Pregelatinized starch as disintegrant same as in Example 2. The amount of HPMC raised to 5.0 - 8.0 to observe the its quantitative effect.

[0128] Total tablet weight kept same, the amount of diluent was adjusted accordingly, while the remaining excipients and manufacturing process were kept the same.

[0129] Table 6: Comparative Table of Binder-to-Disintegrant Ratios in Example 2 and Example 4 Excipients Example 2 Example 4

[0130] Binder - HPMC 2.0 - 5.0 5.0 - 8.0

[0131] Disintegrant - 4.0 - 8.0 4.0 - 8.0

[0132] Pregelatinized starch

[0133] Binder-to-Disintegrant

[0134] 0.5 - 0.625 1.25 - 1.0

[0135]

[0136] Ratio

[0137] Table 7: Comparative table of in-vitro dissolution profiles of solifenacin succinate in Example 2 and Example 4

[0138] Results, % in 0.1N HC1

[0139] Time, min.

[0140] Example 2 Example 4

[0141] 5 21 31

[0142] 10 46 57

[0143] 15 75 78

[0144] 20 90 90

[0145] 30 99 99

[0146] 45 100 99

[0147]

[0148] 60 99 99

[0149] The in-vitro release profiles of solifenacin succinate in the immediate-release layers of Example 2 and Example 4 did not differ remarkably. Thus, it was demonstrated that the specific ratio of HPMC and Pregelatinized starch has a strong equilibrium between their functional effect in immediate release composition comprising solifenacin succinate. The effective ratio of binder-to-disintegrant is found in formulation of Example 2. It is because in mechanism of action by gelation to some extent of both excipients while wetting solifenacin succinate, which is unforeseen or predictable for such an active substance presenting high solubility properties. In the present invention, bilayer tablet composition with biphasic release comprises two layers which are immediate release layer comprising solifenasin succinate and prolonged-release layer comprising mirabegron, wherein

[0150] The immediate-release layer has a binder-to-disintegrant ratio of 0.5:0.625

[0151] - The immediate-release layer comprises disintegrant in an amount between 4.0% – 8.0% w / w, and

[0152] The immediate-release layer comprises binder in an amount between 2.0% - 5.0% w / w.

Claims

CLAIMS1. A bilayer tablet pharmaceutical composition comprising an immediate-release layer comprising solifenacin succinate as active ingredient, a binder, a distintegrant and at least one pharmaceutically acceptable excipient, a prolonged-release layer comprising mirabegron as active substance and at least one pharmaceutically acceptable excipient, wherein;The immediate-release layer has a binder-to-disintegrant ratio of 0.5:0.625,The immediate-release layer comprises disintegrant in an amount between 4.0% – 8.0% w / w, andThe immediate-release layer comprises binder in an amount between 2.0% - 5.0% w / w.

2. A bilayer tablet pharmaceutical composition according to claim 1, wherein the disintegrant in the immediate-release layer is pregelatinized starch.

3. A bilayer tablet pharmaceutical composition according to claim 2, wherein the amount of pregelatinized starch in the immediate-release layer is between 4.0% - 8.0% by weight of the total composition.

4. A bilayer tablet pharmaceutical composition according to any one of the preceeding claims, wherein the binder in the immediate-release layer is hydroxypropyl methylcellulose.

5. A bilayer tablet pharmaceutical composition according to claim 4, wherein the amount of hydroxypropyl methylcellulose in the immediate-release layer is between 2.0% - 5.0% w / w.

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

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

8. A bilayer tablet pharmaceutical composition according to claim 7, 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.

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

10. A bilayer tablet pharmaceutical composition according to claim 7, wherein the granulation solvent is selected from deionized water, ethanol, methanol, isopropanol, and mixtures thereof.

11. 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.

12. A bilayer tablet pharmaceutical composition according to any one of the preceding claims, wherein solifenacin succinate is present less than 4% w / w of the immediate-release layer.

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