FIELD OF INVENTION

The present invention relates to a prolonged release formulation comprising mirabegron or a pharmaceutically acceptable salt thereof as active ingredient in which release profile of the active ingredient is controlled by using a specific hydrophobic polymer and a plasticizer at a specific range of ratio in the coating formulation.

BACKGROUND OF THE INVENTION

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.

There are many options for treatment of overactive bladder such as; bladder training and drug therapy using anticholinergic substances such as propiverine hydrochloride and oxybutynin hydrochloride have been mostly used at present. However, intractable cases and side effects could be occurred such as urinary dysfunction and dry mouth and, therefore, Mirabegron has been reported as one of the substance for the management of overactive bladder.

Mirabegron is a selective agonist for human beta 3 -adrenoceptor (beta 3 -AR) which is also dominant in the human detrusor muscle. However, Mirabegron has been firstly declared by the Astellas Pharma Inc to be used for the treatment for diabetes, due to having an activity of promoting insulin secretion and enhancing insulin sensitivity, and also having an antiobestic activity and an antihyperlipemic activity. But then, it has been reported that Mirabegron can be used as an overactive bladder, such as overactive bladder accompanied by prostatic hyperplasia, or overactive bladder accompanied by urinary urgency, urinary incontinence, and urinary frequency.

The chemical name of Mirabegron is 2-(2-Amino-l,3-thiazoI-4-yl)-N-[4-(2-{[(2R)-2-hydroxy- 2-phenylethyl] amino} ethyl )phenyl] acetamide and the empirical formula is C2JH24N4O2S. The compound has a molecular weight of 396.506 g/mol. The structural formula of Mirabegron is shown in the Formula I.

Formula I

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 categorized as BCS III Drug which means that Mirabegron exhibits high solubility and low permeability.

Mirabegron has one chiral center and exhibits stereoisomerism. The manufacture of the finish 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. for the treatment of the Diabetes Mellitus. In particular, Example 41 discloses the preparation of mirabegron and its pharmaceutically acceptable salt thereof, with hydrochloride salt.

Moreover, patent document numbered as EP1559427 was first disclosed a pharmaceutical composition comprising mirabegron that can be 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.

Furthermore, the marketed product contains R-enantiomer of mirabegron was first described in patent document numbered as EP2298752, wherein an a-form crystal of mirabegron R- enantiomer has a moisture holding amount of not more than 0.2% and has main peaks at around 5.32, 8.08, 15.28, 17.88, 19.04, 20.20, 23.16 and 24.34 in the terms of 29(°) in the powder X- ray diffraction.

A pharmaceutical final product comprising mirabegron as an active was first approved in Japan and has been launched under the brand name of 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 of the MYRBETRIQ® in the United States and BETMIGA® in the Europe. All of the approved products are available as modified release tablet dosage form in the strength of 25 mg or 50 mg of mirabegron for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency.

Mirabegron is in the prolonged released film coated tablet dosage form to control the drug release from the tablet which 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. For instance, the rate of decrease in Cmax and AUC is 45% and 17%, respectively, when there is a coadministration with high fat meal. However, that decreasing is not higher when there is a coadministration with low fat meal which decreased Mirabegron Cmax and AUC by 75% and 51%, respectively.

In the state of art there are many 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 mPa.s or more at a 5% aqueous solution at 25°C.

EP3278801 relates to a pharmaceutical composition comprising a complex of mirabegron with sodium polystyrene sulfonate, a thickener, and a hydrophobic substance, wherein the hydrophobic substance is magnesium stearate and/or calcium stearate.

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 wt% 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 wt%, relative to the total weight of mirabegron, 15 to 40 wt%, 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 h.

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.

Although there are many patent applications of various patent applications, there is a need to develop a pharmaceutical composition comprising mirabegron that capable of avoiding the effects of food intake with a prolonged release based on a functional film coating including hydrophobic polymer and a plasticizer.

In the present invention, the prepared pharmaceutical composition comprising mirabegron or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient in a prolonged release profile by using a hydrophobic polymer with a plasticizer in a range ratio of 1:0.5 - 1:1 in the film coating layer.

SUMMARY OF THE INVENTION

The object of this invention is to develop a prolonged release solid pharmaceutical composition comprising a therapeutically effective amount of mirabegron or one of its pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient.

It is an object of the present invention is to develop a prolonged release solid 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.

The present invention is to develop a prolonged release solid 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 preparation method of a pharmaceutical composition of Mirabegron wherein the pharmaceutical compositions herein disclosed can be manufactured into solid dosage forms, such as tablet, capsule, granule, powder.

Another object of the present invention is related to a pharmaceutical composition comprising mirabegron and at least one pharmaceutically acceptable excipient and a functional film coating including a hydrophobic polymer and a plasticizer.

Another object of the present invention relates to a pharmaceutical composition comprising a hydrophobic polymer and a plasticizer in a range ratio of 1:0.5 - 1:1 in the coating film layer to provide prolonged release of mirabegron throughout the entire gastrointestinal tract.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a prolonged release formulation comprising mirabegron or a pharmaceutically acceptable salt thereof as active ingredient.

Mirabegron is a human P3 -adrenoceptor agonist which has been used for the management of overactive bladder syndrome for decades. Mirabegron exhibits high solubility and low permeability. Thus, after oral administration it is rapidly absorbed, but its absolute bioavailability is low and it slightly increased 29% at a 25 mg dose and 35% at a 50 mg dose. Besides that, there is another restriction about its bioavailability when given with food or absence of food throughout gastrointestinal tract.

Therefore, in the present invention relates to a pharmaceutical composition comprising mirabegron or a pharmaceutically acceptable salt thereof, wherein the variation in bioavailability caused by the presence or absence of food intake throughout gastrointestinal tract is minimized by controlling the drug release. The composition comprising mirabegron or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient is presented as prolonged release tablet dosage form.

The term "prolonged release" herein refers to any composition or dosage form which comprises active ingredient 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. Prolonged release is a continuous release of the active ingredient in a period of time of greater than about 1 hour, preferably greater than about 4 hours, more preferably, greater than about 8 hours. The term “prolonged release” can be conveniently replaced by similar terms like modified release, controlled release, timed release, retarded release, extended release and delayed release, sustained release, programmed release and/or rate controlled dosage forms.

In a preferred embodiment of the present invention is to provide a pharmaceutical composition for oral administration. Suitable solid oral dosage forms are selected from the group comprising tablet, capsule, granule, powder, preferably the solid oral dosage form is tablet.

In a preferred embodiment of prolonged release solid dosage composition, a hydrophobic polymer is designated for continuous drug release in the human gastrointestinal tract with diffusion of dissolving drug through a network of channels that exist between compacted polymer particles. In the preferred embodiment of the present invention, the hydrophobic polymer may include, but are not limited to, polyethylene, polyvinyl chloride, ethyl cellulose and acrylate polymers and their copolymers. Preferably, the hydrophobic polymer is selected as ethyl cellulose.

In the development dosage forms with modified release, ethyl cellulose is the perfect polymer to ensure drug dissolution throughout gastrointestinal tract and provide constant drug concentration. As the mechanism of action of ethyl cellulose, being insoluble at any gastrointestinal fluid at any pH, it undergoes to swell in these environments. As a result, it plays a significant role to improve the therapeutic effectiveness. In the present invention, it is used to provide the release of a drug in a controlled manner by using as an agent in coating formulation.

Ethyl cellulose is a biocompatible, non-allergenic, nonirritant, colorless, odorless, and tasteless hydrophobic polymer soluble in a wide variety of organic solvents such as alcohols, ketones, and polycyclic aromatic hydrocarbons, or solvent mixture to produce water insoluble films, but it does not dissolve in water, glycerin, or propylene glycol.

Ethyl cellulose effect can be modified by using in combination with a proper plasticizer in a specific ratio. Moreover, wherein plasticizer molecules are built in amongst the polymer chains that may cause to shift along each other in order to increasing the elasticity of the polymer film.

The compatibility between the excipients is quite important in order to reduce potential reduction between excipients which may affect the chemical, physical, bioavailability and stability of the dosage form. According to the literature knowledge, ethyl cellulose is known to be quite compatible polymer with a wide array of excipients and most of the plasticizer. Thus, in the preferred embodiment of the present invention, the plasticizer may include, but are not limited triethyl citrate, acetyltriethyl citrate, tributyl citrate, and acetyltributyl citrate and the like and mixtures thereof. Preferably, the plasticizer is selected as triethyl citrate.

In one of the preferred embodiment of the present invention is to provide a pharmaceutical compositions comprising Mirabegron by using wet granulation process wherein provided for the manufacture of tablets containing the active ingredient, hydrophobic polymer binder, antioxidant, plasticizer, glidant and lubricant and 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 are not limited to dibasic calcium phosphate dihydrate, polysaccharides, microcrystalline cellulose, lactose and the like and mixtures thereof. Preferably, the binder is microcrystalline cellulose. In the preferred embodiment of the present invention, the antioxidant may include, but are 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 hydroxy toluene.

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.

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 solvent may include, but are not limited deionized water, methanol, ethanol, isopropyl alcohol, dichloromethane, acetone, ethyl acetate, dimethylsulfoxide and their mixtures thereof. Preferably, the solvent is deionized water.

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 embodiment identified as Example 1 was given in the Table- 1 below.

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

Table 1: Unit Formula of Example 1

Another object of the present invention relates to provide wet granulation process for preparing a prolonged release pharmaceutical composition, providing the steps of: i. Mirabegron, Microcrystalline cellulose and Butylated hydroxytoluene were screened through a proper sieve and transferred into high-shear mixer and stirred, ii. Ethyl cellulose was dissolved in sufficient quantity of deionized water and added to the preparation in Step i to perform granulation process, iii. The granules prepared in Step ii were dried in fluid bed dryer and shifted through a proper sieve, iv. Colloidal silicon dioxide was screened through a proper sieve and added to the granules prepared in Step iii and stirred, v. Magnesium stearate was screened through a proper sieve and added to the granules prepared in Step iv and stirred to obtain a uniform final blend, vi. Tablet compression was performed with the final blend in Step v. vii. The coating was formulated separately including 1:0.5 - 1:1 ratio of ethyl cellulose and triethyl citrate, then it was applied to tablets prepared in Step vi.

The coating film layer is applied after the core tablet is prepared by using wet granulation process wherein the coating consists of ethyl cellulose as a hydrophobic polymer which is insoluble in water and gastro-intestinal fluids and triethyl citrate as a plasticizer in the ratio of

1:0.5 - 1:1 by weight.

Table 2: Composition of Film coating layer for Example 1

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.