Multi-layer pharmaceutical formulation of mirabegron and solifenacin succinate

Abstract

The present invention relates to a multi-layer pharmaceutical formulation comprising a prolonged-release mirabegron or a pharmaceutically acceptable salt thereof, an immediate- release solifenacin or a pharmaceutically acceptable salt thereof with a proper ratio of solifenacin succinate to binder in the immediate-release-layer for use in the treatment of overactive bladder.

Description

[0001]DESCRIPTION MULTI-LAYER PHARMACEUTICAL FORMULATION OF MIRABEGRON AND SOLIFENACIN SUCCINATE Technical Field The present invention relates to a multi-layer pharmaceutical formulation comprising a prolonged-release mirabegron or a pharmaceutically acceptable salt thereof, an immediate- release solifenacin or a pharmaceutically acceptable salt thereof with a proper ratio of solifenacin succinate to binder in the immediate-release-layer for use in the treatment of overactive bladder. Background Of The Invention Overactive bladder (OAB) syndrome is characterized by urgency, with or without urgency urinary incontinence, usually associated with increased daytime frequency and nocturia, in the absence of urinary incontinence or other obvious pathology. Irrespective of the pathophysiology, the aim of the pharmacotherapeutic treatment options indicated for the overactive bladder is to obtain the reduced or suppressed intensity of involuntary detrusor contraction and thus, reduce its interference with daily routines and significantly improve health-related quality of life (HRQL). Solifenacin is a competitive muscarinic receptor antagonist that plays an important role in several major cholinergically mediated functions, including contractions of urinary bladder smooth muscle. The chemical name of solifenacin is (R)-quinuclidin-3-yl (S)-1-phenyl-1,2,3,4- tetrahydroisoquinoline-2-carboxylate with the following structure Formula I. The compound has the empirical formula C23H26N2O2, and its relative molecular mass is 362.46 g / mol as a free base and 480.55 g / mol as the succinate salt. Solifenacin succinate is a white to pale-yellowish-white crystal or crystalline powder. It exhibits high solubility at room temperature in water, glacial acetic acid, dimethyl sulfoxide, and methanol. Solifenacin and its pharmaceutically acceptable salts thereof first have been described in the patent document EP1028111 by Yamanouchi Pharmaceutical Co. for the prevention or treatment of urinary incontinence or pollakiuria in neurogenic pollakiuria, neurogenic bladder, nocturnal enuresis, unstable bladder, cystospasm, chronic cystitis, chronic obstructive pulmonary diseases, chronic bronchitis, asthma or rhinitis. A pharmaceutical final product comprising solifenacin as an active substance was first approved in the Netherlands on 16 December 2003 under the trade name of VESICARE®5 mg and 10 mg film-coated tablets. Solifenacin, antimuscarinic agents, is one of the currently the most widely used pharmacological agents for the treatment of OAB symptoms. It blocks muscarinic M2 and M3 receptors to modulate detrusor and urothelial neural activity. However, it also inhibits muscarinic receptors in other parts of the body, such as the salivary glands, tear ducts, brain and heart that can result in unwanted effects such as dry mouth, constipation, dry eyes and blurred vision. Relative intolerability could be the cause of the low adherence, and may lead to early discontinuation of treatment. According to recent advances in the understanding of OAB, three β-adrenoceptor subtypes (mRNAs) - β1, β2 and β3 – have been identified in the detrusor muscle and urothelium. Among these, the β3-adrenoceptor stands out as the predominant β-receptor subtype in the human urinary bladder due to its role in relaxating detrusor smooth muscle during the bladder storage phase, thereby increasing bladder capacity. The first β3-adrenoceptor agonist mirabegron, is considered likely to be more useful in the treatment of patients experiencing intolerable side-effect to antimuscarinics due to its different action mechanism. The chemical name of mirabegron is 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. The compound has the empirical formula C21H24N4O2S, and its relative molecular mass is 396.506 g / mol as a free base. Mirabegron appears as a white crystalline powder and is non-hygroscopic. It can be freely soluble in dimethyl sulfoxide, soluble in methanol, and soluble in water between neutral to acidic pH. Mirabegron has one chiral center and exhibits stereoisomerism. The manufacture of the finished product consists of the R-enantiomer. Mirabegron and its pharmaceutically acceptable salts thereof first have been described in EP1028111 numbered patent document by Yamanouchi Pharmaceutical Co. in which the preparation of mirabegron and its pharmaceutically acceptable salt thereof, with hydrochloride salt, in particular, Example 41 is also disclosed. Further, a patent document numbered EP1559427 was the first to disclose a pharmaceutical composition comprising mirabegron that could be used as a therapeutic agent for overactive bladders, such as overactive bladder accompanied by prostatic hyperplasia, or overactive bladder accompanied by urinary urgency, urinary incontinence, and urinary frequency. Moreover, the R-enantiomer used in the manufacture of the finished product was disclosed in EP2298752 numbered patent document. A finished product comprising mirabegron as an active substance was first 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 in June 2012 and by European Medicines Agency in December 2012 and has been launched under the brand name MYRBETRIQ®in the United States and BETMIGA®in Europe. All of the approved products are available in prolonged-release tablet dosage form in the strengths of 25 mg and 50 mg of mirabegron. In the literature, several recent large studies have supported the use of beta-3 agonist medications in combination with anticholinergic medications to treat OAB. Thus, in 2018, the U.S. Food and Drug Administration (FDA) announced the approval of a supplemental New Drug Application (sNDA) for MYRBETRIQ®for the use of mirabegron in combination with the muscarinic antagonist solifenacin succinate for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency and urinary frequency. However, fixed-dose combinations are known to significantly reduce the risk of medication non-compliance, which is particularly important in patients with chronic diseases. Thus, to enhance drug dosing compliance through a single formulation, the patent document EP2216021B1 was the first to introduce to the medical filed both mirabegron or a pharmaceutical acceptable salt thereof and solifenacin or a pharmaceutical acceptable salt thereof. The pharmaceutical composition outlined in the document comprises 10 mg to 100 mg of mirabegron and 0.5 mg to 10 mg solifenacin, targeting the treatment of urinary urgency, pollakiuria and / or urinary incontinence accompanying overactive bladder. Furthermore, the pharmaceutical formulation involves designing mirabegron and solifenacin in a monolayer tablet dosage form, manufactured 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 dosage form, while solifenacin is in an immediate-release dosage form. Thus, the drug release profile in each component contained in the single formulation is not significantly affected. 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. 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. 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. WO2020097328 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. 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. Many pharmaceutical compositions for pharmaceutical formulations comprising mirabegron or pharmaceutically acceptable salt thereof, in combination with solifenacin or pharmaceutically acceptable salt thereof are explained in the prior art documents stated above. However, there is a need for a multi-layer pharmaceutical formulation comprising an prolonged-release mirabegron or a pharmaceutically acceptable salt thereof, an immediate- release solifenacin or a pharmaceutically acceptable salt thereof with improved processability. Summary Of The Invention The object of this invention is to provide a pharmaceutical formulation comprising therapeutically effective amounts of mirabegron or pharmaceutically acceptable salts thereof solifenacin as active ingredients in which both active ingredients exhibit distinct release profiles in different layers. The present invention relates to provide a pharmaceutical composition manufactured as multi- layered tablet dosage form. Another object of the present invention is to develop a multi-layered tablet formulation comprising two formulation layers wherein one of them is immediate release layer, other one is prolonged release layer. Mirabegron or a pharmaceutically acceptable salt is presented in the prolonged-release layer and solifenacin or a pharmaceutically acceptable salt thereof is presented in the immediate- release layer. Another object of the present invention relates to a multi-layer tablet formulation comprising prolonged-release mirabegron in its free form and immediate-release solifenacin as the succinate salt. Another object of the present invention is to provide an immediate-release pharmaceutical formulation comprising solifenacin succinate in amorphous form. Another object of the present invention is to provide an immediate-release pharmaceutical formulation comprising solifenacin succinate manufactured by using wet granulation process. Another object of the present invention is to provide an prolonged-release pharmaceutical formulation comprising mirabegron manufactured by using wet granulation process that maintains stable in-vitro release profile. Another object of the present invention is to provide a pharmaceutical formulation comprising solifenacin or a pharmaceutically acceptable salt thereof present in the immediate-release layer with a specific ratio of solifenacin succinate to binder, and mirabegron or a pharmaceutically acceptable salt thereof present in the prolonged-release layer with a release profile non- dependent to pH and at least one pharmaceutically acceptable excipient. Detailed Description of the Invention The present invention provides a multi-layer pharmaceutical composition comprising solifenacin or a pharmaceutically acceptable salt in immediate-release layer and mirabegron or a pharmaceutically acceptable salt thereof in prolonged-release layer. The term an "immediate-release" refers to dosage forms disintegrate rapidly after administration with enhancing rate of dissolution. Moreover, in the case of solid dosage it should dissolve or disintegrate in the stomach within a short period. It should present rapid dissolution and absorption of drug, which may produce rapid onset of action. Therefore, in the present invention the immediate release layer is designed by considering the general literature knowledge. In a preferred embodiment of the present invention is to provide an immediate-layer pharmaceutical composition comprising solifenacin succinate by using wet-granulation method. Another object of the present invention is to provide an immediate-release pharmaceutical formulation comprising solifenacin succinate in amorphous form. The term “amorphous form” refers to a state of a material which has no ordered molecular pattern, the opposite form of “crystalline”. Furthermore, due to non-regular molecular pattern no specific melting point can be dedicated. Besides, amorphous forms can only present glass transition temperature which it much lower value than a specific melting point temperature and this leads a critical challenge during processability regarding the temperature values exposed. Thus, pharmaceutical composition should significantly be considered intensively to overcome processability problems with a binder that has carrier properties. According to another embodiment of this aspect, the binder comprises a hydrophilic polymer and optionally one or more pharmaceutically acceptable excipients. In a preferred embodiment of the present invention is to provide an immediate-layer pharmaceutical composition comprising solifenacin succinate by using wet-granulation method wherein provided for the manufacture of tablets containing the active ingredient, diluent, binder, lubricant and disintegrant selected as to be the most suitable ones with respect to the intended form of administration. In a preferred embodiment, the pharmaceutical composition comprises binder can be selected from the group consisting of hypromellose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, cellulose or cellulose derivatives, pregelatinized starch, povidone, starch, sucrose, polyethylene glycol, or mixtures thereof. Preferably, the binder is povidone. In a preferred embodiment, the pharmaceutical composition comprises at least one diluent can be 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 the like and mixtures thereof. Preferably, the diluent is lactose. In a preferred embodiment, the pharmaceutical composition comprises at least one lubricant can be 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. In a preferred embodiment, the pharmaceutical composition comprises at least one disintegrant can be selected from the group consisting of starch, pregelatinized starch, sodium starch glycolate, povidone, croscarmellose sodium, crospovidone, sodium glycolate or mixture thereof. Preferably, the disintegrant is pregelatinized starch. However, the term “prolonged-release” refers to dosage forms provide a longer duration of pharmacological response after administration of the dosage form than are ordinarily experienced after administration of a corresponding immediate release composition comprising the same drug in the same amount. Therefore, in the present invention is related to provide to form the prolonged release dosage form by using at least one pharmaceutically acceptable excipients. The prolonged release layer comprising mirabegron or a pharmaceutically acceptable salt thereof as an active ingredient with at least one pharmaceutically acceptable excipient is manufactured by using wet granulation process. The amount of the immediate-release layer comprising solifenacin succinate as active ingredient is between 100 mg to 150 mg. The weight ratio between solifenacin succinate to binder is between 3:1 to 3:0.5 in the immediate-release layer comprising solifenacin succinate as active ingredient in an amount of 100 mg to 150 mg. Mirabegron is a human β3-adrenoceptor agonist which has been used as a therapeutic agent for overactive bladder, such as overactive bladder accompanied by prostatic hyperplasia, or overactive bladder accompanied by urinary urgency, urinary incontinence, and urinary frequency. According to the Biopharmaceutical Classification System (BCS), mirabegron is considered to be BCS Class 3 drugs, having a good solubility but poor permeability. Nevertheless, mirabegron presents poor solubility in water and aqueous solutions. Mirabegron is known to have poor bioavailability and can be affected by many factors like dose and gender wherein its oral bioavailability is in the range from 29% to %35 for 25 mg and 35 mg respectively and women have higher bioavailability than men. Besides that, it is also known that the presence of food in the gastrointestinal tract restrict the bioavailability of mirabegron wherein the fat content of food is also effective. The maximum concentration (Cmax) and the area under the concentration-time curve (AUC) are reduced following high or low fat meal compared to fasting. After oral administration of mirabegron from an immediate release dosage form, in fed state the absorption time is estimated approximately 4 hours. However, its terminal elimination half- life (t1 / 2) is quite long like about 50 hours. Thus, in the preferred embodiment, the release profile of mirabegron is prolonged to avoid the effect of food on bioavailability wherein the absorption time about 4 h in fed state can be reached with prolonged period of time for at least about 12 hours, as an indicative 8.5 hour is accepted critical. The term "prolonged release" herein refers to any composition or dosage form which comprises active ingredient and which is designed to achieve or extend therapeutic effect by continuously releasing over an prolonged period of time after administration corresponding to immediate release dosage form administered by the same route. In the embodiment of present invention, the term “prolonged release dosage form” involves a matrix form comprising homogenously dispersed the active ingredient throughout at least two release modifiers which ensure to control release rate of active ingredient by swelling. The release modifier is responsible for retarding of the prepared formulation by forming a gelling form. In the present invention, the selected release modifier is independent of pH, thus its mechanism does not depend on the pH of the environment it encounters. In the preferred embodiment of the present invention, the release modifier may include, but are not limited to, hydroxypropyl methylcellulose, polyvinyl alcohol (PVA), ethyl cellulose, methacrylic polymers, hydroxypropyl cellulose, starches, gums, cellulose ethers, protein derived materials, nylon, acrylic resins, polylactic acid, polyvinylchloride, polyvinylpyrrolidones, and cellulose acetate phthalate. Preferably, at least one release modifier is Hydroxypropyl methylcellulose. In the preferred embodiment of the present invention, the disintegrant may include, but are not limited to croscarmellose sodium, crospovidone, starch, potato starch, pregelatinized starch, corn starch, sodium starch glycolate, microcrystalline cellulose, low substituted hydroxypropyl cellulose and other known disintegrants. Preferably, the disintegrant is Microcrystalline cellulose. In the preferred embodiment of the present invention, the glidant may include, but are not limited to silicon dioxide, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc and other known glidant. Preferably, the glidant is Colloidal silicon dioxide. In the preferred embodiment of the present invention, the lubricant may include, but are not limited to magnesium stearate, zinc stearate, calcium stearate, talc, carnauba wax, stearic acid, sodium stearyl fumarate sodium laurel sulfate, glyceryl palmitostearate, and hydrogenated vegetable oils and fats, as well as other known lubricants. Preferably, the lubricant is Magnesium stearate. The prolonged-release layer comprises mirabegron as active ingredient in an amount of 250 mg. In preferred embodiments of the present invention, pharmaceutical formulations compressed into a multi-layered tablet form consisting of at least two separate layers. The multi-layer 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 embodiments identified as examples are given in the Table-1 below. The proposed embodiment based on the invention with the amounts in w / w% of the multi-layer pharmaceutical composition are as stated below: Table 1: Unit Formula of Examples Ingredients w / w, % Immediate-release layer Solifenacin succinate 3 Lactose 70 – 75 Povidone 0.5 – 1 Pregelatized starch 15 – 20 Sodium stearyl fumarate 2 – 3 Solvent Sufficient quantity Prolonged-release layer Mirabegron 19 – 21 Polyethylene oxide 25 – 30 Ingredients w / w, % Immediate-release layer Hydroxypropyl 45 – 50 methylcellulose Hydroxypropyl cellulose 1 – 4 Butylated hydroxytoluene 0 – 1 Magnesium stearate 1 – 2 Solvent Sufficient quantit 5y Another object of the present invention relates to a multi-layer pharmaceutical composition prepared by providing the steps of: Immediate-release layer; a) Lactose, Povidone were dissolved in sufficient quantity of water, and mixed, b) The granules prepared in Step a were dried and screened through a proper sieve, c) The pregelatinized starch was screened through a proper sieve and added to the granules prepared in Step b and stirred, d) Sodium stearyl fumarate was screened through a proper sieve and added to the granules prepared in Step c and stirred to obtain a uniform final blend, e) Tablet compression is performed with the final blend in Step d. Prolonged-release layer; i. Mirabegron, polyethylene oxide, hydroxypropyl methylcellulose and hydroxypropyl cellulose were screened through a proper sieve and transferred into cubic mixer and stirred, ii. Butylated hydroxytoluene was dissolved in sufficient quantity of an organic solvent and added to the preparation in Step (i) to perform granulation process, iii. The granules prepared in Step (ii) were dried in high-shear 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). In the present invention, the flowability of final blend was good that leads tablet compression process to be achieved. The average hardness value is between 180-200 N for each layer. Furthermore, release profile of prolonged-release layer should be stable regardless to immediate-release layer pharmaceutical composition design. Thus, a study was performed to demonstrate that multi-layer pharmaceutical composition is achieved with a successful manufacturing process. Compressed tablets were subjected to disintegration and in vitro dissolution study. The conditions of dissolution study are set by US&FDA, based on the information the main dissolution medium is phosphate buffer, pH 6.8. Other conditions are defined as; volume of dissolution medium is 900 ml, temperature of study is 37°C±0.5, rotation speed is 100 rpm, apparatus is basket and the duration of dissolution study is 12 hours. The amount of dissolved active ingredient over time in the in-vitro dissolution study was determined by HPLC. Disintegration times of both layers in Example 1 manufactured according to the invention were between 9-11 minutes. Table 2: In-vitro dissolution profiles of mirabegron in prolonged-release layer Results, % in pH 6.8 phosphate buffer Time, hour Reference Drug Product Example 1 1 7 10 3 27 35 5 53 57 7 80 76 8.5 96 87 10 100 95 12 100 102 The in-vitro release pattern of mirabegron as the active ingredient in the prolonged-release layer of Example 1 was very similar to the reference product. 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 multi-layer pharmaceutical formulation composed of an immediate-release layer comprising solifenacin succinate, an prolonged-relaease layer comprising mirabegron and at least one pharmaceutically acceptable excipient, wherein; - at least one pharmaceutically acceptable excipient present in the immediate-release layer is povidone as a binder, and - the ratio between solifenacin succinate to povidone is between 3:0.5 to 3:

1.

2. A multi-layer pharmaceutical formulation according to claim 1, wherein the immediate- release layer is prepared by wet granulation method.

3. A multi-layer pharmaceutical formulation according to the preceding claims, wherein at least one pharmaceutically acceptable excipient present in the immediate-release layer is selected from a diluent, a disintegrant, a lubricant and a solvent and mixtures thereof.

4. A multi-layer pharmaceutical formulation according to claim 3, wherein the diluent selected from dibasic calcium phosphate dehydrate, polysaccharides, primarily microcrystalline cellulose, lactose, mannitol, sugars, sorbitol, sucrose, inorganic salts, primarily calcium salts and mixtures thereof.

5. A multi-layer pharmaceutical formulation according to claim 3, wherein the disintegrant is selected from starch, pregelatinized starch, sodium starch glycolate, povidone, croscarmellose sodium, crospovidone, sodium glycolate and mixture thereof.

6. A multi-layer pharmaceutical formulation according to claim 3, wherein the lubricant is selected from sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid, hydrogenated castor oil and mixtures thereof.

7. A multi-layer pharmaceutical formulation according to claim 3, wherein the solvent is selected from deionized water, methanol, ethanol, isopropyl alcohol, dichloromethane, acetone, ethyl acetate, dimethylsulfoxide and mixtures thereof.

8. A multi-layer pharmaceutical formulation according to anyone of the preceding claims, wherein the amount of immediate-release layer is between 100 mg to 150 mg.

9. A multi-layer pharmaceutical formulation according to anyone of the preceding claims, wherein the amount of immediate-release layer comprising solifancin succinate is between 100 mg to 150 mg.

10. A multi-layer pharmaceutical formulation according to anyone of the preceding claims, wherein the amount of prolonged-release layer comprising mirabegron is 250 mg.

11. A multi-layer pharmaceutical formulation according to any one of the preceding claims for use in the treatment of overactive bladder.

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