WO2023080855A1

WO2023080855A1 - Pharmaceutical composition comprising mirabegron and calcium salts

Info

Publication number: WO2023080855A1
Application number: PCT/TR2021/051126
Authority: WO
Inventors: Erol KIRESEPI; Ersin Yildirim
Original assignee: Santa Farma Ilac Sanayii A.S.
Priority date: 2021-11-03
Filing date: 2021-11-03
Publication date: 2023-05-11

Abstract

The present invention relates to a pharmaceutical composition comprising therapeutically effective amount of mirabegron or its pharmaceutically acceptable salt thereof is developed in the prolonged release dosage form by loading calcium source with improved solubility and dissolution characteristics.

Description

PHARMACEUTICAL COMPOSITION COMPRISING MIRABEGRON AND

CALCIUM SALTS

FIELD OF INVENTION

BACKGROUND OF THE INVENTION

Mirabegron is a compound that its 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 non-hygroscopic. It can freely soluble in dimethyl sulfoxide, soluble in methanol and soluble in water between neutral to acidic pH, thus it is classified as BCS III Drug and exhibits high solubility and low permeability.

Mirabegron has one chiral center and exhibits stereoisomerism. The molecule used as active substance is in the form of R-enantiomer.

Mirabegron is P3 -adrenergic receptor agonist used for the treatment of overactive bladder.

Overactive bladder is defined by The International Continence as urgency, with or without urgency incontinence, usually with frequency and nocturia. There is lack of information why overactive bladder occurs, but it is known that it involves detrusor overactivity which is responsible for feeling urgency by involving afferent signaling conveyed as bladder sensations. Thus, even if overactive bladder is reported not to be life threating, its symptoms may affect quality of life.

Multiple types of medications are available for use in the treatment of overactive bladder for reducing or suppressing the intensity of involuntary detrusor contractions. Anticholinergic agents such as solifenacin, oxybutynin, trospium, darifenacin, tolterodine and fesoterodine are the most commonly used at present. However, the most frequent side effects may occur such as urinary dysfunction and dry mouth. Mirabegron has advantage to cause significantly lower incidence of dry mouth than such as solifenacin or tolterodine.

Mirabegron and its pharmaceutically acceptable salts thereof first have been described in EP1028111 numbered patent document by Yamanouchi Pharmaceutical Co. in which mirabegron presents to have both promotion action for insulin secretion and enhancing action for insulin sensitivity and further have anti-obese and anti-hyperlipemic actions whereby it is a useful compound for the treatment of diabetes mellitus. The mentioned patent also discloses the preparation of mirabegron and its pharmaceutically acceptable salt thereof, with hydrochloride salt, in particular, Example 41.

Further, patent document numbered as EP1559427 was first disclosed the use of mirabegron 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.

Moreover, R-enantiomer of mirabegron was first described in patent document numbered as EP2298752, wherein an alpha form crystal of mirabegron R-enantiomer. This crystal form is the form present in the original drug product.

A pharmaceutical drug product comprising mirabegron as an active substance was first approved in Japan and was launched in September 2011 under the brand name of BETANIS¹®. Later 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 of the MYRBETRIQ®' in the United States and BETMIGA^'®' in the Europe. The modified release tablet dosage form in the strengths of 25 mg and 50 mg of mirabegron for use in the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency. Pharmacokinetic properties of Mirabegron as being the prolonged released film coated tablet dosage form lead to more slower absorption rate in the gastrointestinal tract than immediate release formulations, even in fasted conditions, due to pharmacokinetic variation of mirabegron according to the presence or absence of food intake. If it is administered with high fat meal there is a decrease both Cmax and AUC 45% and 17%, respectively in comparison with low fat meal.

In the state of art there are a lot of patents/patent applications which are summarized below.

EP2554168 relates to a pharmaceutical composition for modified release 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 a pharmaceutical composition for modified release 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 a 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.

WO201 1122523 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. W02019072404 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 a 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 w%, 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 800 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.

In the present invention, the pharmaceutical composition comprising mirabegron or its pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient in the prolonged release profile by using calcium source providing calcium in amount range of 9.75%- 13% in the total composition.

SUMMARY OF THE INVENTION

The present object of this invention relates to a pharmaceutical composition comprising a therapeutically effective amount of mirabegron or one of its pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient with improved solubility and release profile in prolonged release dosage form. It is an object of the present invention is to develop a pharmaceutical composition comprising mirabegron or one of its pharmaceutically acceptable salts, which is 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 develop preparation method of a pharmaceutical composition of mirabegron wherein the pharmaceutical compositions herein disclosed can be manufactured into solid dosage forms, such as tablets having prolonged dissolution profiles.

Another object of the present invention is to develop a pharmaceutical composition comprising mirabegron and at least one pharmaceutically acceptable excipient manufactured by using wet granulation process.

Another object of the present invention is to develop a pharmaceutical composition comprising mirabegron and at least one pharmaceutically acceptable excipient by using wet granulation process wherein provided for the manufacture of tablets containing the active ingredient, water soluble polymers, binder, antioxidant, lubricant, glidant and granulation solvent selected as to be the most suitable ones with respect to the intended form of administration.

Another object of the present invention relates to a pharmaceutical composition comprising mirabegron and at least one pharmaceutically acceptable excipient manufactured by using wet granulation process wherein the amount range of calcium 9.75% - 13.0% of the total weight of the composition to provide a prolonged release.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a pharmaceutical composition comprising mirabegron or its pharmaceutically acceptable salt thereof used for the treatment of overactive bladder provided in prolonged release dosage form.

In the solubility investigation study, mirabegron exhibits different solubility profiles at different pH levels. For instance, it is practically insoluble in water such as 0.15 mg/mL in water, 3.19 mg/mL at pH 6.8. Besides that, its solubility is estimated as 18.68 mg/mL in acidic solutions such as 0.1N HC1.

Table 1: Solubility results of Mirabegron active substance

The given solubility results mean that there is nonlinear relationship between mirabegron solubility and pH values.

Moreover, it has an absorption window in the stomach or in the upper small approximately 29% as a result of its variation on the pharmacokinetics in the presence or absence of food intake.

Thus, in a preferred embodiment of the present invention, mirabegron or its pharmaceutically acceptable salt thereof was provided in prolonged release dosage form by achieving to overcome the varying mirabegron release patterns in different pH environments.

To overcome the variations of the release of mirabegron in different pH environments through the gastrointestinal tract, the solubility and dissolution profile of mirabegron is modified by using calcium source to get improved release characterizations in prolonged release dosage form.

Calcium source is the excipient providing calcium in desired amounts with the use of dedicated concentrations.

Many calcium salts, which can be the calcium sources have pH dependent solubility. pH dependent solubility of mirabegron and calcium sources are composed into a drug product with proper excipients to maintain the manner of pH independent release.

In the embodiment, different types of calcium sources in salt form may be the source of calcium. They are commonly used in solid oral dosage form as filler or diluent to bulk up formulations and facilitate the further processing. However, it is surprisingly observed that the proposed embodiments comprising mirabegron and specified amount of calcium can present pH independent solubility and release pattern.

In the embodiment of the present invention, calcium salts are selected from dibasic calcium phosphate, tribasic calcium phosphate and the mixtures thereof. In the embodiment, the desired dissolution profile of mirabegron or its pharmaceutically acceptable salt thereof is provided with developed pharmaceutical composition comprising water soluble polymer, diluent, binder, antioxidant, lubricant, glidant and granulation solvent selected as to be the most suitable ones with respect to the intended form of administration.

In a preferred embodiment of the present invention, at least one water soluble polymer may include, but are not limited to hydroxypropylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, xanthan gum, polyvinylpyrrolidone, polyethylene glycol and the like, and mixtures thereof. Preferably, the water soluble polymers are polyethylene glycol and hydroxypropyl methylcellulose.

In a preferred embodiment of the present invention, the binder may include, but is not limited to hypromellose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, cellulose or cellulose derivatives, povidone, starch, sucrose, polyethylene glycol, or mixtures thereof. Preferably, the binder is hypromellose.

In a preferred embodiment of the present invention, the antioxidant may include, but is not limited to butylated hydroxytoluene, propyl gallate, butylhydroxyanisol, ascorbic acid, sodium ascorbate, erythorbic acid, sodium nitrite, sodium bisulfite, sodium pyrosulfite, citric acid, and thereof. Preferably, the antioxidant is butylated hydroxy toluene.

In a preferred embodiment of the present invention, the lubricant may include, but is not limited to magnesium stearate, calcium stearate, talc, colloidal silica, and thereof. 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.

In the preferred embodiment of the present invention, the granulation solvent may include, but are not limited deionized water, methanol, ethanol, isopropyl alcohol, dichloromethane, acetone, and thereof. Preferably, the granulation solvent is acetone.

The embodiment in accordance with the present invention was designed with adjusted quantitative composition composed of pharmaceutically acceptable ingredients mentioned above by using wet granulation process. The embodiments identified as Example 1 and Example 2 are designed with the differentiation in the amount of calcium given in the Table-2.

The proposed embodiments based on the invention provides a prolonged release solid pharmaceutical composition is as stated below:

Table 2: Unit Formula of Example 1 and Example 2

The detailed manufacturing steps for Example 1 and Example 2 were presented below: i. Mirabegron and polyethylene glycol were screened through a proper sieve and transferred into high- shear mixer and stirred, ii. Calcium source and hydroxypropyl methylcellulose was screened through a proper sieve and added to the granules prepared in Step (i) and stirred, iii. Hypromellose was screened through a proper sieve and added to the granules prepared in Step (ii) and stirred to obtain a uniform final blend, iv. Butylated hydroxytoluene was dissolved in sufficient quantity of acetone and added to the preparation in Step (iii) to perform granulation process, v. The granules prepared in Step (iv) were dried and shifted through a proper sieve, vi. Colloidal silicon dioxide was screened through a proper sieve and added to the granules prepared in Step (v) and stirred, vii. Magnesium stearate was screened through a proper sieve and added to the granules prepared in Step (vi) and stirred to obtain a uniform final blend, viii. Tablet compression was performed with the final blend in Step (vii). Compressed tablets are subjected to in vitro dissolution study. The conditions of dissolution study are set by US FDA, based on the information available dissolution media is phosphate buffer, pH 6.8. Other conditions are defined as; volume of dissolution media 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.

Moreover, the dissolution study was performed in 0.1N HCI to observe the behaviour of proposed pH independent formulations with only difference in calcium amount.

Table 3: Comparative dissolution profiles for Example 1 and Example 2 in 0.1N HCI

Table 4: Comparative dissolution profiles for Example 1 and Example 2 in pH 6.8 phosphate buffer

Based on the results presented in Table 3 and Table 4 above, dissolution profiles of Example 1 and Example 2 are compared by using the similarity factor f₂

According to The Guideline on the Investigation of Bioequivalence, the similarity factor f₂ is a substantial comparison index in order not to compromise product bioequivalence between examples and reference drug product. If the value of similarity factor f₂ is greater than 50, it means that two drug products in comparison show similar dissolution profiles.

In the embodiment of present invention, the similarity factor f₂ of Example 1 was calculated as 74 and Example 2 was calculated as 48 for 0.1N HCI. Further, the similarity factor f₂ of Example 1 was calculated as 62 and Example 2 was calculated as 45 for 6.8 phosphate buffer.

According to the dissolution profile results presented above. Example 1 designed as pH independent formulation presents desired prolonged dissolution profile.

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

1. A pharmaceutical composition comprising mirabegron or a pharmaceutically acceptable salt thereof, at least one pharmaceutically acceptable excipient, and a calcium source, wherein the amount range of calcium is between 9.75% - 13% by the total weight of the composition.

2. A pharmaceutical composition according to Claim 1, wherein the calcium source is a calcium salt.

3. A pharmaceutical composition according to Claim 2, wherein the calcium salt is selected from dibasic calcium phosphate, tribasic calcium phosphate and the mixtures thereof.

4. A pharmaceutical composition according to any one of the preceding claims, wherein at least one pharmaceutically acceptable excipient is selected from water soluble polymers, diluent, binder, antioxidant, lubricant, glidant and granulation solvent.

5. A pharmaceutical composition according to claim 4, wherein the water soluble polymer is selected from hydroxypropylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, xanthan gum, polyvinylpyrrolidone, polyethylene glycol and mixtures thereof.

6. A pharmaceutical composition according to claim 4, wherein the binder is selected from hypromellose, sodium carboxymethyl cellulose, cellulose or cellulose derivatives, polyethylene glycol, povidone, starch, sucrose, hydroxypropyl methylcellulose and mixtures thereof.

7. A pharmaceutical composition according to claim 4, wherein the antioxidant is selected from butylated hydroxytoluene, propyl gallate, butylhydroxyanisol, ascorbic acid, sodium ascorbate, erythorbic acid, sodium nitrite, sodium bisulfite, sodium pyrosulfite, citric acid and mixtures thereof.

8. A pharmaceutical composition according to claim 4, wherein the lubricant is selected from magnesium stearate, calcium stearate, talc, colloidal silica and mixtures thereof.

9. A pharmaceutical composition according to claim 4, wherein the glidant is selected from silicon dioxide, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc and mixtures thereof.

10. A pharmaceutical composition according to claim 4, wherein the granulation solvent is selected from deionized water, methanol, ethanol, isopropyl alcohol, dichloromethane, acetone and mixtures thereof.

11. A pharmaceutical composition according to any one of the preceding claims for use in the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency.