Mirabegron formulation

Abstract

To improve the storage stability of mirabegron formulations and mitigate changes in drug release behavior dependent on storage environment humidity.SOLUTION: A pharmaceutical composition contains mirabegron and isomalt hydrate. The pharmaceutical composition may further contain a macromolecular substance forming hydrogel. The macromolecular substance forming hydrogel may be polyethylene oxide, cellulose ether, or a combination of them.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present disclosure relates to pharmaceutical compositions, and in particular to formulations of the adrenergic β3 receptor agonist mirabegron. [Background technology]

[0002] Mirabegron is represented as 2-(2-amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide, or (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetic acid anilide, also called YM-178, and is a compound with adrenergic β3 receptor agonist activity. Mirabegron can be used as a therapeutic agent for overactive bladder, for example.

[0003] Patent Documents 1 to 3 describe controlled release pharmaceutical compositions containing mirabegron as an active ingredient, and Patent Document 4 also describes a formulation containing mirabegron as an active ingredient. The composition of Patent Document 1 contains at least polyethylene glycol as an "additive for allowing water to penetrate into the formulation" that has a solubility of 10 mL or less of water to dissolve 1 g of the composition, and contains at least a specific polyethylene oxide as a polymeric substance that forms a hydrogel.

[0004] The composition of Patent Document 2 contains "one or more selected from the group consisting of polyethylene glycol, polyvinylpyrrolidone, D-mannitol, D-sorbitol, xylitol, lactose, sucrose, anhydrous maltose, D-fructose, dextran, glucose, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, polyoxyethylene sorbitan higher fatty acid ester, citric acid, tartaric acid, glycine, β-alanine, lysine hydrochloride, and meglumine" as a similar "additive for allowing water to penetrate into the preparation", and contains "one or more selected from the group consisting of polyethylene oxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, and hydroxyethyl cellulose" as a polymeric substance that forms a hydrogel.

[0005] The composition of Patent Document 3 is a preparation using a swelling polymer or a matrix preparation using a water-soluble polymer, the preparation using a swelling polymer is a preparation containing polyalkylene oxide as a high molecular weight water-soluble polymer that swells when absorbing water, and the matrix preparation using a water-soluble polymer is a preparation in which a drug is uniformly dispersed in hypromellose, hydroxymethylcellulose, hydroxyethylcellulose or hydroxypropylcellulose. The preparation of Patent Document 4 is characterized by containing mirabegron, hypromellose and polyvinylpyrrolidone.

[0006] Tablets containing mirabegron are commercially available, for example, under the trade names Betanis®, Myrbetriq®, or Betmiga®. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Patent No. 4688089 [Patent Document 2] Patent No. 5625855 [Patent Document 3] Patent No. 5849946 [Patent Document 4] JP 2017-048136 A Summary of the Invention [Problem to be solved by the invention]

[0008] Conventional mirabegron formulations have room for improvement in terms of drug stability, and it has been observed that related substances (decomposition products) are generated over time and that the dissolution behavior of the tablets can change depending on the humidity during storage.

[0009] According to the embodiments of the present disclosure, the storage stability of a mirabegron formulation can be improved, and changes in drug dissolution behavior that depend on the humidity of the storage environment can be suppressed. [Means for solving the problem]

[0010] The present disclosure includes the following embodiments. [1] A pharmaceutical composition comprising mirabegron and isomaltulose hydrate. [2] The pharmaceutical composition described in [1], further comprising a polymeric substance that forms a hydrogel. [3] The pharmaceutical composition according to [2], wherein the polymeric substance that forms the hydrogel is polyethylene oxide, cellulose ether, or a combination thereof. [4] The pharmaceutical composition according to any one of [1] to [3], which is for oral administration. [5] The pharmaceutical composition according to any one of [1] to [4], which is in the form of a tablet. [6] The pharmaceutical composition according to any one of [1] to [5], further comprising a film coating. [Brief description of the drawings]

[0011] [Figure 1]FIG. 1 shows the total related substance content detected in the formulations before high temperature storage ("start", left) and after high temperature storage (right) as a weight percentage relative to mirabegron, comparing between the Comparative Example and the Example. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] In one aspect, the present disclosure provides a pharmaceutical composition comprising mirabegron and isomalt hydrate. Mirabegron itself is known as described above. Isomalt hydrate is also known. "Isomalt" is sometimes displayed or pronounced as "Isomalt" in Japanese. Isomalt hydrate is a mixture of 6-O-α-D-glucopyranosyl-D-sorbitol (GPS) and 1-O-α-D-glucopyranosyl-D-mannitol (GPM) and contains water of hydration. Isomalt hydrate can also be considered as a mixture of GPS and GPM dihydrate. GPS and GPM (or GMP dihydrate) in the mixture are usually equimolar, which is preferable, but the molar ratio of the two can be within the range of, for example, 9:1 to 1:9, 8:2 to 2:8, 7:3 to 3:7, or 6:4 to 4:6. In a preferred embodiment, the molar ratio of GPS to GPM (or GMP dihydrate) in the mixture is in the range of 2:1 to 5:1.

[0013] The pharmaceutical composition of this embodiment is typically a solid preparation. The content of mirabegron in the composition is typically 1 to 30% by mass, preferably 5 to 25% by mass, and more preferably 7 to 20% by mass. In the composition, the part by mass of isomaltulose hydrate relative to 1 part by mass of mirabegron is, for example, 0.1 to 10, preferably 0.3 to 3, more preferably 0.5 to 2, and particularly preferably 0.9 to 1.2. In other words, it is preferable to contain approximately equivalent amounts of mirabegron and isomaltulose hydrate. The content of isomaltulose hydrate in the composition is typically 1 to 40% by mass, preferably 5 to 30% by mass, and more preferably 10 to 25% by mass.

[0014] Isomaltulose hydrate usually has a water solubility of 0.1 g / ml or more, for example 0.25 to 0.42 g / ml, at room temperature. In other words, isomaltulose hydrate exhibits a solubility in which the amount of water required to dissolve 1 g of isomaltulose hydrate is 10 ml or less (for example, 4 ml or less, or 2.4 ml or less). Due to such basic properties, isomaltulose hydrate can at least play a role as a hydrophilic additive for allowing water to penetrate into the inside of the formulation. However, considering the stabilization of mirabegron and its effect on the stabilization of the dissolution behavior, isomaltulose hydrate is not merely a hydrophilic additive but is expected to provide a further unique effect.

[0015] The composition according to the preferred embodiment further comprises a polymeric substance that forms a hydrogel. As will be understood by those skilled in the art, a hydrogel is a gel formed by retaining a large amount of water (e.g., at least 10% by weight of the polymer) in a polymer network. By containing a polymeric substance that forms a hydrogel together with isomalt hydrate, the formulation of the present embodiment can be almost completely gelled by water penetrating into the inside during retention in the upper part of the digestive tract (specifically, the stomach and small intestine). For example, in the gelation test described below, the gelation rate after 3 hours, 4 hours, or 5 hours is preferably 70% or more, more preferably 80% or more. Polymers that can form hydrogels, i.e., polymeric substances, are known to those skilled in the art, and those described in Patent Document 2, for example, can be used. In a particularly preferred embodiment, the polymeric substance that forms a hydrogel can be polyethylene oxide, cellulose ether, or a combination thereof.

[0016] As known to those skilled in the art, cellulose ether is a cellulose ether in which the hydroxyl group of cellulose is modified to form an ether group. The hydroxyl group on the glucose ring of cellulose itself forms hydrogen bonds with adjacent hydroxyl groups, inhibiting hydration, but it is understood that by replacing the hydrogen of these hydroxyl groups with hydrocarbon groups to form ether groups, hydration is promoted and water solubility is obtained. Examples of cellulose ether suitable for this embodiment include hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), carboxymethylcellulose (CMC), hydroxyethylcellulose (HEC), and any combination thereof, as well as pharma- ceutically acceptable salts thereof (e.g., sodium salt or potassium salt).

[0017] Polyethylene oxide (PEO) is distinguished from polyethylene glycol (PEG), which has a molecular weight of 20,000 or less. The polymeric substance forming the hydrogel in this embodiment, for example, polyethylene oxide and / or cellulose ether, may have an average molecular weight of 100,000 or more (20,000 or more for cellulose ether), or a viscosity of 12 mPa·s or more in a 5% aqueous solution at 25°C. In the present disclosure, the average molecular weight may be an average molecular weight expressed as a viscosity average molecular weight unless otherwise specified. The average molecular weight of the polymeric substance forming the hydrogel may be 100,000 to 7 million (20,000 or more for cellulose ether), for example, 100,000 to 900,000, 1 million to 2 million, or 4 million to 7 million. The viscosity of a 5% aqueous solution at 25°C may be, for example, 30 to 17,600 mPa·s. Additionally or alternatively, the hydrogel-forming polymeric substance may have a viscosity of 400-4000 mPa·s in a 2% aqueous solution at 25° C., and / or a viscosity of 1650-10000 mPa·s in a 1% aqueous solution at 25° C.

[0018] The content of the hydrogel-forming polymeric substance in the composition may be, for example, 20 to 80% by mass, preferably 30 to 70% by mass, and more preferably 40 to 60% by mass. In the composition, the part by mass of the hydrogel-forming polymeric substance relative to 1 part by mass of isomaltulose hydrate may be, for example, 0.1 to 10, preferably 0.5 to 5, and more preferably 1 to 3. Preferably, both polyethylene oxide and cellulose ether are contained. In a preferred example, the polyethylene oxide may be contained in an amount of 10 to 30% by mass, and the cellulose ether may be contained in an amount of 10 to 50% by mass.

[0019] In a specific preferred embodiment, the composition contains mirabegron, isomaltulose hydrate, polyethylene oxide, and cellulose ether. In one embodiment, the composition contains 1-30% by mass of mirabegron, 5-35% by mass of isomaltulose hydrate, 10-30% by mass of polyethylene oxide, and 10-50% by mass of cellulose ether, the total of which is within a range not exceeding 100% by mass.

[0020] In addition to the above-mentioned components, the composition of the present embodiment may contain additional components that may be one or more of carriers, excipients, lubricants, binders, disintegrants, preservatives, antioxidants, stabilizers, colorants, sweeteners, etc., known to those skilled in the art of pharmaceuticals, and these additional components are collectively referred to as additives in the present disclosure. Specific examples of additives include, but are not limited to, magnesium stearate as a lubricant and dibutylhydroxytoluene (BHT) as an antioxidant. The total mass of mirabegron, isomaltulose hydrate, and the polymeric substance that forms the hydrogel is preferably 50% or more, more preferably 70% or more, and even more preferably 90% or more of the total mass of the composition.

[0021] The above-mentioned components can be compressed to prepare a tablet. A mixture containing at least mirabegron, isomaltulose hydrate, and a polymeric substance that forms a hydrogel may be granulated and then compressed. Granulation is preferable because it improves the flowability of the mixture and suppresses the weight variation per tablet in the compression molding process. The tablet of this embodiment may further include a film coating that is external to the uncoated tablet in addition to the uncoated tablet whose composition has been described above. Suitable film coating techniques and compositions are well known to those skilled in the art. In a particular example, the film coating includes any of the cellulose ethers (e.g., hydroxypropyl methylcellulose) and polyethylene glycol described above, and may further include any of the additives described above. Typically, the mass of the film coating accounts for 1 to 5% of the total mass of the composition.

[0022] The formulation of this embodiment may be provided as a suppository or the like, i.e., as a pharmaceutical composition for parenteral administration, but is more preferably provided as a pharmaceutical composition for oral administration. The dosage form may be, for example, a tablet, a capsule, or a granule. In order to maximize the advantage of the stabilization of the controlled release profile, the tablet form is particularly preferred.

[0023] In the formulation of this embodiment, when a dissolution test is performed using 900 mL of test solution (e.g., USP buffer pH 6.8, or McIlvaine buffer pH 7.5) at a paddle rotation speed of 200 rpm in the Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method), the drug (i.e., mirabegron) dissolution rate 30 minutes after the start of the test is preferably less than 85%. In the present disclosure, a formulation or composition that satisfies this drug dissolution rate condition is referred to as a "controlled release" formulation or composition. For a controlled release formulation or composition, the mirabegron dissolution rate under the above conditions may be 50% or less, or 20% or less.

[0024] In one aspect, the present disclosure provides a method for preparing the above-mentioned composition. The method includes mixing mirabegron, isomaltulose hydrate, and a hydrogel-forming polymeric substance to provide a mixture, and compressing the mixture to provide a tablet. In some embodiments, the method includes granulating the mixture prior to compressing. In some embodiments, the method includes applying a film coating to the compressed core tablet.

[0025] A preferred manufacturing method, i.e., a formulation method, of this embodiment is described in more detail. First, mirabegron, isomaltulose hydrate, and a polymeric substance that forms a hydrogel are mixed to provide a homogeneous mixture containing at least these. Then, the mixture is preferably granulated by a method known to those skilled in the art. For example, the mixture can be granulated by a fluidized bed granulation method (e.g., by adding ethanol). At this granulation stage, any one of mirabegron, isomaltulose hydrate, and a polymeric substance that forms a hydrogel can be further added (e.g., by being included in the spray liquid of the fluidized bed granulation method). At a stage before compression molding (e.g., after granulation, before compression molding), a lubricant is preferably added. A tablet can be obtained as a plain tablet by compressing the mixture that has been granulated or not. Then, a film coating can be applied to the plain tablet by a method known to those skilled in the art. The above-mentioned additives can be added at any stage of mixing, granulation, compression molding, and film coating application based on the general knowledge of those skilled in the art and depending on the type of specific additive.

[0026] In addition to formulating the pharmaceutical composition as a tablet, embodiments are also contemplated in which the granulated or non-granulated mixture is encapsulated into a capsule, or the granulated mixture is provided as granules.

[0027] The gelation rate of the tablet can be measured according to the method described in JP 2001-10951 A. Specifically, the gelation rate in the present disclosure is a value measured by the following gelation test method. The test fluid used was the Japanese Pharmacopoeia 12th Revised Edition (hereinafter referred to as JP) Disintegration Test Method No. 2 Fluid (pH 6.8), and the test was performed according to the JP Dissolution Test Method No. 2 (paddle method) at a paddle rotation speed of 25 rpm. After removing the tablet at each time point, the gel layer was peeled off and the diameter (longest diameter) of the ungelled part was measured to obtain the D obs Get the value. D obs The gelation rate (G) is calculated by substituting the above into the following formula 1. obs means the longest diameter of the remaining part that has not gelled after the test time has elapsed, and D ini means the major axis of the preparation before the start of the study. [Formula 1] Gel ratio (G,%) = (1- (D obs ) 3 / (D ini ) 3 ) × 100

[0028] In this specification, a numerical range indicated using the expression "A to B" (or "from A to B" or "between A and B") indicates a range including the numerical values ​​A and B described before and after "to" as the minimum and maximum values, respectively, and also includes a range excluding the minimum and / or maximum values. In addition, the description "A to B" is understood to disclose the range "A or more" or "greater than A" and the range "B or less" or "less than B". When multiple numerical ranges are described, the upper limit or lower limit of a described numerical range can be combined with the upper limit or lower limit of another described numerical range, and the numerical range obtained by such combination is also understood to be disclosed in this application. In this specification, the expression "including A" or "having A" means an object that includes other things besides A in addition to A, unless contrary to the context, and the disclosure of an object that includes only A and does not include other things than A, i.e., an object consisting of A, is also included in the description, and vice versa. Reference to a singular object is understood to encompass disclosure of embodiments in which plural objects are used. EXAMPLES

[0029] 50 parts by weight of mirabegron, 50 parts by weight of PEO (Colorcon, N60K, average molecular weight 2 million), 80 parts by weight of HPMC (Shin-Etsu Chemical Co., Ltd.: TC-5 E, ​​weight average molecular weight 20,000), and 54.5 parts by weight of isomalt hydrate (Beneo, galenIQ (trademark) 801) were mixed homogeneously to obtain a mixture. In a fluidized bed granulator, granulation was performed while spraying an ethanol solution containing 12.5 parts by weight of HPC (Nippon Soda Co., Ltd.: HPC-SL, weight average molecular weight 100,000) and 0.5 parts by weight of BHT to obtain a granulated product. This granulated product was further mixed with 2.5 parts by weight of magnesium stearate, and then compressed to obtain tablets as plain tablets. A film coating consisting of 5.6 parts by weight of HPMC, 1.0 part by weight of PEG, and 1.4 parts by weight of yellow ferric oxide was applied to this plain tablet according to a conventional method to obtain the formulation of the example. The content of mirabegron per formulation is 50 mg, and the total mass is 258 mg, of which the mass of the uncoated tablet is 250 mg and the mass of the film coating is 8 mg. Among the above components, PEO, HPMC, and HPC are polymeric substances that form hydrogels. The comparative formulation is a film-coated tablet containing 50 mg of mirabegron, which is essentially the same as the formulation of the embodiment, except that the uncoated tablet portion lacks the combination of isomaltulose hydrate and HPMC, but contains polyethylene glycol instead.

[0030] The first sample of each formulation of the Examples and Comparative Examples underwent high-temperature storage (60°C, 3W) with heating at 60°C for 3 weeks. The corresponding second sample is the formulation before this high-temperature storage, i.e., at the "start" stage. Figure 1 shows the total related substance content detected in the formulation at the start (left) and after high-temperature storage (right) as a weight percentage relative to mirabegron. The related substances correspond to degradation products corresponding to mirabegron itself, and their contents were quantified by analyzing each formulation by HPLC and measuring the respective peak areas by automatic integration. As shown in Figure 1, the formulation of the Examples containing isomaltulose hydrate showed a significant inhibition of accumulation of related substances after high-temperature storage.

[0031] In another experiment, the first sample of each formulation of the Example and Comparative Example was subjected to high humidity storage (75% RH, 1M) by placing it in an environment of 25°C and 75% RH (relative humidity) for one month. The corresponding second sample is the formulation before the high humidity storage, i.e., at the "start" stage. These samples were subjected to a dissolution test over time using 900 mL of pH 7.5 McIlvaine buffer solution according to the Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method) as the test liquid. The results are shown in Tables 1 and 2. Tables 1 and 2 show the results of the test using the paddle method with paddle rotation speeds of 50 rpm and 200 rpm, respectively. The dissolution rates of the "start" sample and the sample after high humidity storage at different time points (minutes) during the dissolution test and the difference between them are shown. In the formulation of the Comparative Example, a clear change occurred in the dissolution rate of mirabegron between the sample that had been subjected to high humidity storage and the sample that had not been subjected to high humidity storage. In other words, after high humidity storage, the samples showed a clear tendency for the release control to be partially lost and the rate of mirabegron dissolution to increase by about 6 to 7%. In contrast, the release control profile was substantially maintained in the preparations of the examples even after high humidity storage. The results shown in Figure 1 and Tables 1 and 2 illustrate the stabilization of mirabegron in the preparations and the stabilization of its release control by the inclusion of isomaltulose hydrate.

[0032] [Table 1]

[0033] [Table 2]

Claims

1. A pharmaceutical composition comprising mirabegron and isomaltulose hydrate.

2. The pharmaceutical composition according to claim 1 , further comprising a polymeric substance that forms a hydrogel.

3. The pharmaceutical composition according to claim 2 , wherein the hydrogel-forming polymeric substance is polyethylene oxide, cellulose ether, or a combination thereof.

4. The pharmaceutical composition according to any one of claims 1 to 3, which is for oral administration.

5. The pharmaceutical composition according to any one of claims 1 to 3, which is in the form of a tablet.

6. 6. The pharmaceutical composition of claim 5, further comprising a film coating.

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