Modified release mirabegron formulations

Abstract

The present invention relates to prolonged-release tablet compositions comprising 25 mg mirabegron, polyethylene oxide and hydroxypropyl methylcellulose as release modifying agents.

Description

[0001]DESCRIPTION MODIFIED RELEASE MIRABEGRON FORMULATIONS Technical Field The present invention relates to a prolonged-release pharmaceutical composition for oral administration comprising mirabegron or a pharmaceutically acceptable salt thereof with at least two release modifying polymers for use in the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency, wherein a dose of mirabegron per tablet is 25 mg. State of Art Overactive bladder is a chronic distressing condition that has a tremendous impact on the health-related quality of life of the inflicted individuals (daily activities and social functions). According to the International Continence Society, the overactive bladder syndrome is characterized by urgency, with or without urinary incontinence, usually associated with increased daytime frequency and nocturia. 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. There are many options for the treatment of overactive bladder such as; bladder training and drug therapy using antimuscarinic drugs. However, antimuscarinic drugs are not always effective in controlling an overactive bladder due to the adverse effects, including dry mouth, nausea, constipation, and central nervous system adverse effects, that cause poor long-term adherence to treatment. Then, a novel active substance mirabegron developed by Astellas Pharmac Inc. has been reported that this compound has not only both an activity of promoting insulin secretion and an activity of enhancing insulin sensitivity, but also an antiobestic activity and an antihyperlipemic activity based on an activity of selectively stimulating a β3 receptor, and is useful in treating diabetes. Further, it has been reported as an alternative option to antimuscarinic drugs for patients with overactive bladder accompanied by prostatic hyperplasia, or overactive bladder accompanied by urinary urgency, urinary incontinence, and urinary frequency. Mirabegron is an active substance that chemical name 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 I. The empirical formula is C21H24N4O2S. The compound has a molecular weight of 396.506 g / mol. 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 for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency. In the state of the art, there are many patents / patent applications, which are summarized below. EP2554168 relates to modified release pharmaceutical composition comprising mirabegron or a pharmaceutically acceptable salt thereof, and a carrier for a sustained release pharmaceutical composition, wherein the dissolution rate of the drug from the composition is 75% or less after 1.5 hours from the beginning of the dissolution test, and also wherein the pharmaceutical composition is not a sustained release hydrogel formulation which contains an additive that allows water to penetrate into the formulation, and a hydrogel-forming polymer. EP2345410 relates to modified release pharmaceutical composition comprising mirabegron, at least one additive having a solubility such that the volume of water required for dissolving 1 g of the additive is 10 mL or less to ensure penetration of water into the pharmaceutical composition, and a hydrogel-forming polymer having an average molecular weight of approximately 100.000 or more, or viscosity of 12 cP or more at a 5% aqueous solution at 25°C. EP2832730 relates to a pharmaceutical composition for modified release comprising mirabegron dodecyl sulfate wherein a molar ratio of mirabegron to alkyl sulfuric acid is 1:1 to 1:2. WO2011122523 relates to a pharmaceutical composition comprising mirabegron or a pharmaceutically acceptable salt thereof, and a carrier for a sustained release pharmaceutical composition, and the drug dissolution rate after 30 minutes from the beginning of the dissolution test is less than 85%. EP3345600 relates to a pharmaceutical composition comprising mirabegron, hypromellose, and polyvinylpyrrolidone, wherein the spray-dried granulated product contains 100% or more by mass of the hypromellose, and the polyvinylpyrrolidone in total with respect to a content of the mirabegron. WO2019072404 relates to a pharmaceutical composition for modified release comprising mirabegron presenting 5-25 weight% to the total weight of the uncoated tablet, polyethylene oxide having an average molecular weight of approximately 7,000,000 or viscosity of 7500 to 10000 cps at a 1% aqueous solution at 25°C and polyethylene glycol having an average molecular weight of approximately 6000 to 10000, preferably 8000, wherein the weight ratio polyethylene oxide to polyethylene glycol ranges from 1:3 to 1:4.5. EP3448366 relates to a pharmaceutical composition for modified release comprising; 5 to 25 wt% relative to the total weight of mirabegron, 15 to 40 w%, relative to the total weight, of a mixture of one or more polyethylene oxides having a viscosity of 100 to 800, preferably 400 to 10800 cP at a 2% aqueous solution at 25°C, and a water-insoluble hydrophilic excipient. EP3554480 relates to a solid prolonged release solid pharmaceutical oral dosage form comprising mirabegron or a pharmaceutically acceptable salt thereof wherein mirabegron is distributed in a sustained release matrix comprising a hydrogel generator selected from the group consisting of a mixture of at least two different hydroxypropyl methylcellulose, of alginate, alginic acid, poly (meth) acrylate-based polymer and carrageenan, and wherein dissolution rate of the drug from the composition is 20% to 40% in 3 hours, 44% to 64% in 5 hours and more than 80% in 8.5 hours. WO2018169325 relates to a controlled-release pharmaceutical composition comprising mirabegron or a pharmaceutically acceptable salt thereof and a polyethylene oxide as a sustained-release agent. WO2022125007 relates to a prolonged release formulation comprising mirabegron or a pharmaceutically acceptable salt thereof as an active ingredient in which the release profile of the active ingredient is controlled by using a specific hydrophobic polymer and a plasticizer at a specific range of ratio between 1:0.5 to 1:1 in the coating formulation. Mirabegron absorption is dose-dependent due to increasing the absolute bioavailability with increasing doses. In other words, the absolute bioavailability increases from 29% at a dose of 25 mg to 35% at a dose of 50 mg. In addition, the AUC and Cmax of mirabegron are affected by the presence or absence of food in the gastrointestinal tract. If it is taken with a high-fat meal, the AUC and Cmax will decrease by 17% and 45% lower, respectively; and if it is taken with low-fat meals, the AUC and Cmax values will decrease by 51% and 75%. Based on the prior arts shown above, many studies have been conducted to provide a pharmaceutical composition comprising mirabegron designed in prolonged-released film- coated tablet dosage form to control the drug release throughout the gastrointestinal tract. Present invention is related to a pharmaceutical composition comprising mirabegron or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient in the prolonged-release dosage form, which extends the release of mirabegron into 12 hours through a design comprising at least two release modifying polymers in a specified ratio with mirabegron in the matrix core. Summary Of The Invention The present object of this invention is to develop a pharmaceutical composition comprising a therapeutically effective amount of mirabegron or one of its pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient in prolonged-release dosage form with an improved release profile. Another object of the invention is to develop a pharmaceutical composition comprising mirabegron or one of its pharmaceutically acceptable salts used in the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency. Another object of the present invention is to a pharmaceutical composition comprising mirabegron or one of its pharmaceutically acceptable salts, wherein the mirabegron is free of salt, preferably it is in crystalline form, more preferably it is in alpha crystalline form characterized by an X-ray powder diffraction pattern having peaks expressed as 2θ at about 5.32, 8.08, 15.28, 17.88, 19.04, 20.20, 23.16 and 24.34 degrees. Another object of the present invention relates to a pharmaceutical composition comprising mirabegron wherein the release of mirabegron is controlled by a matrix core tablet. Another object of the invention is to prepare a pharmaceutical composition comprising 25 mg to 50 mg mirabegron without performing the dose-proportional strategy. Another object of the present invention relates to a pharmaceutical composition comprising mirabegron in the matrix with at least two release modifying polymers to form a gel layer to present prolonged release throughout the gastrointestinal tract, wherein the amount ratio between these polymers is 1.0:3.0. A further object of the present invention relates to a pharmaceutical composition comprising mirabegron in the matrix core with at least two release modifying polymers, wherein the amount ratio between Mirabegron and the release modifying agents is in the range of 1:1.5 - 1:1.7 respectively. Detailed Description Of The Invention The present invention provides a pharmaceutical composition comprising of mirabegron or one of its pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient wherein at least two types of hydrogel-forming polymers are used to exhibit a prolonged-release profile of mirabegron. The term "prolonged-release" herein refers to any composition or dosage form which comprises an active drug and which is formulated to provide a longer duration of pharmacological response after administration of the dosage form than is ordinarily experienced after administration of a corresponding immediate release composition comprising the same drug in the same amount. In the preferred embodiment of the present invention, the prolonged-release pharmaceutical composition comprising 25 mg mirabegron drug substance. Mirabegron is a human β3-adrenoceptor agonist, 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. Therefore, it should be released into the intestinal tract. However, mirabegron is a weakly basic drug that demonstrates pH-dependent solubility; such as 0.15 mg / mL in deionized water, 3.9 mg / mL in pH 6.8, and 18.68 mg / mL in pH 1.2. The resulting release from conventional tablets could decrease with increasing pH-milieu of the gastrointestinal tract. Thus, in the preferred embodiments of the present invention, the prolonged-release pharmaceutical composition is provided by modifying the solubility and dissolution profile of mirabegron during its passage through the gastrointestinal tract by using at least two types of hydrogel-forming polymers in the matrix core. Hence, the performance of mirabegron does not depend on the pH of the environment it encounters. In the preferred embodiment of the present invention, at least two hydrogel-forming agents may include but are not limited to, polyethylene, polyethylene oxide, ethyl cellulose, hydroxypropyl methylcellulose, and hydroxypropyl cellulose and their copolymers. Preferably, the hydrogel- forming agents are selected as hydroxypropyl methylcellulose and polyethylene oxide. Polyethylene oxide (PEO) is one of the thickening agents that provides delayed drug release via the hydrophilic matrix approach having in the molecular weight range of 100,000 to 7,000,000 g / mole. There is a relationship between swelling capacity and molecular weight to obtain desired prolonged-release matrix formulation. In the preferred embodiment, the average molecular weight of polyethylene oxide is approximately 2,000,000 g / mole. Hydroxypropyl methylcellulose (HPMC) is another thickening agent used to form swellable- soluble matrices. It provides decreased drug release rate of the drug via decreasing its viscosity at low pH aqueous solutions, hence the matrices including them exhibit pH-independent drug release profiles. In the preferred embodiment of the present invention, the viscosity of PEO in 1% aqueous solution at 25^C is between 1000-2000 mPa.s. In the preferred embodiment of the present invention, the viscosity of HPMC in 1% aqueous solution at 25^C is between 5-15 mPa.s. In the preferred embodiment of the present invention, the amount ratio between release modifying polymers is 2:1 – 3:1, PEO and HPMC. In the preferred embodiment relates to the pharmaceutical composition comprising a therapeutically effective amount of mirabegron or one of its pharmaceutically acceptable salts with at least two hydrogel-forming agents, binder, filler, antioxidant, lubricant, glidant, and an organic solvent selected as to be the most suitable ones with respect to the intended form of administration. In the preferred embodiment of the present invention, the binder may include but is not limited to hydroxypropyl cellulose, cellulose or cellulose derivatives, povidone, starch, or mixtures thereof. Preferably, the binder is hydroxypropyl cellulose. In a preferred embodiment of the present invention, the filler may include but is not limited to dibasic calcium phosphate dehydrate, polysaccharides, microcrystalline cellulose, lactose, or mixtures thereof. Preferably, the filler is microcrystalline cellulose. In the preferred embodiment of the present invention, the antioxidant may include but is not limited to butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, sodium sulfite, sodium thiosulfate, monothioglycerol, tert-butyl hydroquinone, ethoxyquin, dithiothreitol, and derivatives thereof. Preferably, the antioxidant is butylated hydroxytoluene. In the preferred embodiment of the present invention, the lubricant may include but is not limited to magnesium stearate, zinc stearate, calcium stearate, talc, sodium stearyl fumarate sodium laurel sulfate, and as well as other known lubricants. Preferably, the lubricant is magnesium stearate. In a preferred embodiment of the present invention, the glidant may include but is not limited to silicon dioxide, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc, and thereof. Preferably, the glidant is colloidal silicon dioxide. The proposed embodiment was already designed for 50 mg strength and at first the formulation details along with the manufacturing method is presented. The approach is to achieve a successful embodiment for 50 mg strength and by using dose proportional strategy 25 mg would be determined also. The embodiment identified as Example 1 is given in Table 1 below. The proposed embodiment based on the invention provided a prolonged release solid pharmaceutical composition. Table 1: Unit formula of Example 1 The declared embodiment was manufactured by a wet granulation process includes the steps of: i. Mirabegron and Polyethylene oxide, Hydroxypropyl methylcellulose, Microcrystalline cellulose, and Hydroxypropyl cellulose were screened through a proper sieve and transferred into the high-shear mixer and stirred, ii. Butylated hydroxytoluene was dissolved in a sufficient quantity of acetone and added to the powder blend in Step (i) to perform the granulation process, iii. The granules prepared in Step (ii) were dried and shifted through a proper sieve, iv. Magnesium stearate and Colloidal silicon dioxide were screened through a proper sieve and added to the granules prepared in Step (iii) and stirred, v. Tablet compression was performed with the final blend in Step (iv). Compressed tablets were subjected to in-vitro dissolution study. The conditions of the dissolution study are set by US&FDA, based on the information that the main dissolution medium is phosphate buffer, pH 6.8. Other conditions are defined as; the volume of the dissolution medium being 900 ml, the temperature of the study being 37°C±0.5, the rotation speed being 100 rpm, the apparatus being basket, and the duration of the dissolution study being 12 hours. The amount of dissolved active ingredient over time was determined by HPLC. Table 2: Comparative dissolution profile for Example 1 and reference product comprising 50 mg mirabegron in pH 6.8 phosphate buffer The total tablet weight comprising 50 mg mirabegron was 250 mg. Based on the results presented in Table 2 above, the release pattern of Example 1 was quite similar to the reference product, which presents an in-vivo release pattern approved by the international health authorities. According to The Guideline on the Investigation of Bioequivalence, the in vitro dissolution profile of two drug products is evaluated based on the value of similarity factor f2, if that value is higher than 50, the two compositions in comparison show similar dissolution profiles. The similarity factor f2 of Example 1 and the reference product was calculated as 68.3 since this value was above 50, the products were similar. Currently, the compositions comprising 50 mg mirabegron in prolonged-release tablet dosage form were supplied. The main objective is to obtain 25 mg strength. Thus, compositions comprising 25 mg was manufactured by using dose proportionality strategy. According to the state of the art, the dose-proportional strategy is one of the common strategies for providing multiple dose strengths without changing the formulation. In this strategy, multiple doses are designed in the same composition in w / w% and manufactured in the same manufacturing method. To investigate the effectiveness of the dose-proportional strategy, the amount of mirabegron in the pharmaceutical composition of Example 1 was redesigned by reducing it from 50 mg to 25 mg. In other words, all excipients and active substance were reduced in half regarding the amounts but kept same in the same proportions in Table 1, with w / w% unit. In addition, the manufacturing process was also applied as the same in Example 1. The obtained compressed tablets were subjected to in-vitro dissolution study set by US&FDA given above. Table 3: Comparative dissolution profile for Example 2 and Example 1 comprising pH 6.8 phosphate buffer Based on the results presented in Table 3 above, unexpectedly the release pattern of Example 2 was faster than Example 1. Although the amount of mirabegron and release modifying polymers were kept in the same proportion in w / w%, it was observed that no linear correlation exists between the amounts of mirabegron, release modifying polymers and the release pattern. The dose proportional strategy was not suitable for 25 mg strength mirabegron compositions. Thus, another example was proposed to obtain a composition comprising 25 mg mirabegron presenting in-vitro release pattern similar to 50 mg strength as the highest dose. The mechanism of action was investigated regarding the relationship between release modifying polymers and the mirabegron release pattern. The excipients that have impact on mirabegron release pattern are hydroxypropylmethyl cellulose and polyethylene oxide as release modifying polymers. Polyethylene oxide (PEO) is a water-soluble polymer which presents the release by its swelling ability comprising mirabegron in the holes formed as a result of the swelling action. However, it enhances the water penetration into the matrix since PEO is more soluble in water and this action accelerates the swelling rate, which leads to faster drug release. At this point, HPMC takes the responsibility of regulating drug release. Although HPMC has hydrophilic characteristics, it contains more hydrophobic substituents, which lead to the reduction of water penetration. Thus, polymer-water connections in the matrix causes slower hydration and thus slower drug release. Consequently, the mirabegron drug release is affected by two different release modifying polymers with two different mechanisms of action. In addition, the importance of quantitative composition was observed and demonstrated that mirabegron release pattern is not only directly related with the amount of mirabegron and release modifying polymers themselves, surprisingly the ratio of the release modifying polymers were found critical (not similar to 50 mg) and unforeseen by the person skilled in the art over the prior art documents and / or general technological know-how. The modifications in amounts were designed based on the composition of Example 1. The amount of mirabegron was adjusted to 25 mg in the total composition, therefore the tablet weight was 225 mg in total by keeping the amounts of other excipients constant. Hence, the proportions in w / w% by the total weight of the composition was changed. The proposed quantitative formulation (Example 3) is presented in Table 4 in comparison with the formulation of Example 1. Table 4: The comparison of Example 1 and Example 3 formulations The obtained compressed tablets of Example 3 were subjected to in-vitro dissolution study under the conditions set by US&FDA given in above. Table 5: Comparative dissolution profiles for Example 3 and Example 1 in pH 6.8 phosphate buffer Based on the results presented in Table 5, the release pattern of Example 3 was quite similar to 50 mg strength drug release pattern. According to “Guideline on the Investigation on Bioequivalence” published by EMA, to establish bioequivalence of the test product with that of reference product, 90% Confidence Interval (CI) for the ratio (Test / Reference) of Least Square Means of the Ln transformed PK parameters (AUCt and Cmax) must fall between 80.00% to 125.00%. In vivo fasting bioequivalence study results of Example-3 are presented on below table. As a result, the present invention provides a pharmaceutical composition comprising 25 mg mirabegron and at least two release modifying polymers wherein - the amount ratio of polyethylene oxide and hydroxypropyl methylcellulose is between 1:2 and 1:3 respectively, - the amount ratio between mirabegron and two release modifying polymers is between 1:1.5 and 1:1.7 respectively in the matrix structure to obtain successful drug release pattern. 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 prolonged-release tablet composition comprising 25 mg mirabegron or a pharmaceutically acceptable salt thereof, polyethylene oxide and hydroxypropyl methylcellulose as release modifying agents, wherein - the amount ratio between Mirabegron and the release modifying agents is in the range of 1:1.5 - 1:1.7 respectively, and - the amount ratio of polyethylene oxide and hydroxypropyl methylcellulose is in the range of 1:2 - 1:3 respectively.

2. A prolonged-release tablet composition according to claim 1, wherein the composition comprises mirabegron in crystalline form of alpha characterized by an X-ray powder diffraction pattern having peaks expressed as 2θ at about 5.32º, 8.08º, 15.28º, 17.88º, 19.04º, 20.20º, 23.16º and 24.34º.

3. A prolonged-release tablet composition according to any one of the preceding claims, wherein the composition further comprises at least one pharmaceutically acceptable excipient selected from fillers, binders, glidants, lubricants, granulation solvent and mixtures thereof.

4. A prolonged-release tablet composition according to claim 3, wherein the filler is selected from dibasic calcium phosphate dehydrate, polysaccharides, microcrystalline cellulose, lactose and mixtures thereof.

5. A prolonged-release tablet composition according to claim 4, wherein the filler is microcrystalline cellulose.

6. A prolonged-release tablet composition according to claim 3, wherein the binder is selected from hypromellose, sodium carboxymethyl cellulose, povidone, starch, sucrose and mixtures thereof.

7. A prolonged-release tablet composition according to claim 6, wherein the binder is hypromellose.

8. A prolonged-release tablet composition according to claim 3, wherein the antioxidant is selected from butylated hydroxytoluene, propyl gallate, butyl hydroxyanisole, ascorbic acid, sodium ascorbate, erythorbic acid, sodium nitrite, sodium bisulfite, sodium pyrosulfite, citric acid and mixtures thereof.

9. A prolonged-release tablet composition according to claim 8, wherein the antioxidant is butylated hydroxytoluene.

10. A prolonged-release tablet composition according to claim 3, wherein the lubricant is selected from magnesium stearate, calcium stearate, talc, colloidal silica and mixtures thereof.

11. A prolonged-release tablet composition according to claim 10, wherein the lubricant is magnesium stearate.

12. A prolonged-release tablet composition according to claim 3, wherein the glidant is selected from silicon dioxide, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc and mixtures thereof.

13. A prolonged-release tablet composition according to claim 12, wherein the glidant is colloidal silicon dioxide.

14. A prolonged-release tablet composition according to claim 3, wherein the granulation solvent is selected from deionized water, methanol, ethanol, isopropyl alcohol, dichloromethane, acetone, and mixtures thereof.

15. A prolonged-release tablet composition according to claim 14, wherein the granulation solvent is acetone.

16. A wet granulation method for the preparation of a prolonged-release tablet composition according to any one of the preceding claims, wherein the process comprising the steps of; i. Mirabegron and Polyethylene oxide, Hydroxypropyl methylcellulose, Microcrystalline cellulose, and Hydroxypropyl cellulose were screened through a proper sieve and transferred into the high-shear mixer and stirred, ii. Butylated hydroxytoluene was dissolved in a sufficient quantity of acetone and added to the powder blend in Step (i) to perform the granulation process, iii. The granules prepared in Step (ii) were dried and shifted through a proper sieve, iv. Magnesium stearate and Colloidal silicon dioxide were screened through a proper sieve and added to the granules prepared in Step (iii) and stirred, v. Tablet compression was performed with the final blend in Step (iv).

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