KR20180106185A - Pharmaceutical composition for controlled release comprising Mirabegron or its salts - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for release control, comprising mirabegron or a pharmaceutically acceptable salt thereof. Particularly, the present invention relates to the pharmaceutical composition for release control, which comprises polyethylene oxide for controlling the release of mirabegron as an active ingredient and is harmless to the human body and easy to be pharmaceutically prepared.

Description

[0001] The present invention relates to a pharmaceutical composition for controlling release comprising Mirabegron or its salts,

The present invention relates to a pharmaceutical composition for controlling the release comprising mirabegron or a pharmaceutically acceptable salt thereof. In particular, the present invention relates to a pharmaceutical composition for controlling release, which contains polyethylene oxide for controlling the release of mirabegron as an active ingredient, and which is harmless to humans and easy to formulate pharmaceuticals.

Mirabegron is a compound having the structure of the following formula (1), and its chemical name is (R) -2- (2-aminothiazol-4-yl) -4 '- {2- [ Phenylethyl) amino] ethyl} acetanilide.

Mirabegron or a pharmaceutically acceptable salt thereof has a? 3 adrenergic receptor agonist action. Mirabegron is used for the treatment of symptoms of urgency, urinary frequency or urge incontinence that may occur in patients with irritable bladder. In Korea, Betami is marketed as the product name of SUDANJIN®.

Mirabegron relaxes the bladder in the urinary storage phase of the bladder and improves the bladder's storage capacity by this bladder relaxation effect (Naunyn Schmiedebergs Arch Pharmacol 2013; 386: 71-8). In addition, studies using a rat model of ischemic bladder have shown that Mirabegron protects bladder function and morphology, thereby reducing bladder overactivity (Eur Urol 2013; 64: 664-71).

In order to maximize the pharmacological effect of Mirabegron, it was necessary to develop an agent for controlling release.

Korean Patent No. 1524164 discloses a pharmaceutical composition for controlling release comprising mirabegron, which comprises (a) a hydrophilic additive for invasion of water into the preparation, and (b) a polymer material forming a hydrogel, Wherein the drug release rate is 75% or less from the preparation at 1.5 hours and 75% or more and 100% or less at 7 hours.

(B) a polyethylene oxide having an average molecular weight of not less than 2,000,000; and (c) an antioxidant selected from the group consisting of iron oxide Or a pharmaceutically acceptable salt thereof.

All of the above patents include a hydrophilic base, and polyethylene glycol (PEG) is used as a representative material of the hydrophilic base.

However, when polyethylene glycol is used as a hydrophilic base, it has been found that polyethylene glycol causes delayed or immediate hypersensitivity (Sapna Shah MD, et al., Hypersensitivity to Polyethylene Glycols, The Journal of Clinical Pharmacology). In addition, polyethylene glycol has the potential to cause changes in pharmacokinetic behavior due to ABC phenomenon (accelerated blood clearance) (U.S. Schuber et al., Polyethylene glycol in drug delivery, Angewandte chemie).

Accordingly, the present inventors have sought to develop a pharmaceutical composition which is harmless and stable to the human body in the preparation of a controlled release formulation containing mirabegron.

Polyethylene glycols are generally regarded as biologically inert and safe. However, it causes hypersensitivity to a small number of people and has a disadvantage of changing the pharmacokinetic behavior.

Accordingly, the present inventors have completed the present invention as a result of developing a pharmaceutical composition and a preparation which are safe and formulated easily without formulation of a hydrophilic base such as polyethylene glycol.

The present invention relates to a pharmaceutical composition for controlling the release comprising mirabegron or a pharmaceutically acceptable salt thereof as an active ingredient and polyethylene oxide (PEO) as a sustained-release agent.

Preferably, when the polyethylene oxide (PEO) of the present invention comprises at least one of PEO 300,000 and PEO 100,000, the pharmacokinetics and dissolution rate for exhibiting the continuous effects of the drug are excellent. In addition, it is preferable, but not limited, to include only PEO 300 and PEO 100 at a ratio of 1: 0.1 to 1: 5.

The polyethylene oxide has an average molecular weight of about 300,000 or more. The average molecular weight of the polyethylene oxide is preferably not more than 1,000,000, but is not limited thereto.

Polyethylene oxides suitable for use in the present invention are commercially available. For example, Polyox WSR N-12K, Polyox N-60K, Polyox N-750, Polyox WSR 301 NF or Polyox WSR 303 NF may be used in the dosage form of the present invention. However, the present invention is not limited thereto.

The present invention may be a pharmaceutical composition characterized by containing less than 5% of a hydrophilic base.

Examples of the hydrophilic base include water-soluble polymers such as polyethylene glycol (PEG) and polyvinyl pyrrolidone (PVP); Sugar alcohols such as D-mannitol, sorbitol and xylitol; Sugars such as lactose, saccharose, maltose, D-fructose, dextran and glucose; Surfactants such as polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan higher fatty acid esters; Salts such as sodium chloride and magnesium chloride; Organic acids such as citric acid and tartaric acid; Amino acids such as glycine, alanine, and lysine hydrochloride; And amino acid saccharides such as meglumine.

The present invention may further comprise a colorant. The colorant may be carmin, caramel, beta -carotene, titanium oxide, talc, riboflavin sodium phosphate, yellow aluminum lake, and the like, preferably aluminum lake.

The pharmaceutical composition of the present invention is a pharmaceutical composition containing mirabegron or a pharmaceutically acceptable salt thereof as an active ingredient and may be formulated into tablets, capsules, beads, beads, granules, pills, For example, tablets for oral administration, such as tablets, capsules, solutions, suspensions, and the like, or tablets for oral administration.

In addition, the pharmaceutical preparation of the present invention may further contain a pH adjusting agent, a suspending agent, a preservative, a flavoring agent, a coloring agent, a sweetening agent, an absorbent and the like, if necessary. The content of such an additive is not particularly limited in the present invention and can be appropriately adjusted as needed.

The formulation of the present invention may be packaged in a container and is preferably packaged in a hermetically sealed package, which container includes both an airtight container and a sealed container.

The tablets for oral administration of the present invention are preferably packaged in an aluminum alu-alu packing container, but the present invention is not limited thereto.

The pharmaceutical composition comprising mirabegron or a pharmaceutically acceptable salt thereof according to the present invention has advantages of long-lasting drug efficacy through release control, being harmless to human body, and easy to prepare pharmaceutically.

Fig. 1 shows the dissolution test results in the paddle method (50 rpm, 37 캜) in the eluate of pH 6.8 of Examples 1 to 5 and Comparative Example.

The present invention relates to a pharmaceutical composition for controlling the release, comprising mirabegron or a pharmaceutically acceptable salt thereof as an active ingredient and polyethylene oxide (PEO) as a sustained-release agent. In addition, the polyethylene oxide (PEO) of the present invention may include at least one of PEO 100 million and PEO 30 alone. PEO 300 and PEO 100 at a ratio of 1: 0.1 to 1: 5.

The average molecular weight of polyethylene oxide (PEO) is preferably 1 million or less.

The present invention includes pharmaceutical compositions that do not contain more than 5% of a hydrophilic base.

Particularly, the present invention is characterized in that it does not contain polyethylene glycol (PEG) as a hydrophilic base.

The present invention includes formulations for controlled release wherein the pharmaceutical composition is formulated, which may be, but not limited to, tablets for oral administration. The formulation may be packaged in a plastic container, and the plastic container is preferably Alu-Alu.

Hereinafter, the present invention will be described more specifically by way of examples. However, these examples are provided only for illustrative purposes in order to facilitate understanding of the present invention, and the scope of the present invention is not limited by the following examples.

≪ Examples 1 to 5 and Comparative Example &

As shown in the following Table 1, the pharmaceutical preparations were prepared by the following production method while varying the molecular weight of the polyethylene oxide used in Examples 1 to 5 and Comparative Examples.

Preparation of granules

Mirabegron and polyethylene oxide (Polyox® WSR N-12K) were mixed homogeneously, and then a binding solution in which hydroxypropylcellulose and dibutylhydroxytoluene were dissolved was added to ethanol and granulated, dried and fixed .

Final mixing

The sized product was put into a mixer, and colloidal silicon dioxide and magnesium stearate were sieved and mixed, followed by mixing to prepare a final mixture.

Tableting

The final mixture was tableted using an automatic tablet press (XP1, Korsh, Germany) to obtain tablets having a total weight of 250 mg.

[Test Example 1]

Dissolution test

The tablets prepared in Examples 1 to 5 and Comparative Examples were subjected to a dissolution test at pH 6.8 (900 mL, 50 rpm), and their liquid chromatographic measurement methods were as follows.

- Detector: Ultraviolet absorptiometer (measuring wavelength: 250 nm)

- Column: C18 (4.6 mm x 150 mm, 5 m)

- Mobile phase: Mobile phase A and B are mixed with 7: 3 ratio.

이동상 A : 물 900 mL에 8.7 mL의 과염소산(70%)과 3.0g의 수산화나트륨을 첨가한 후, 0.1 N 수산화나트륨 수용액으로 pH 2.0을 조정한 다음 1000 mL로 맞춘다.

Mobile phase A: After adding 8.7 mL of perchloric acid (70%) and 3.0 g of sodium hydroxide to 900 mL of water, adjust the pH to 2.0 with 0.1 N sodium hydroxide solution and adjust to 1000 mL.

이동상 B : 아세토니트릴

Mobile phase B: acetonitrile

- Flow rate: Adjust the flow rate so that mirabegron is detected at 4 minutes

- Column temperature: 40 ° C

The results are shown in Fig. 1, and the dissolution rate was confirmed. That is, when PEO 100 alone and PEO 30 alone were mixed, PEO 100 showed better dissolution rate than PEO 100 alone.

Claims (11)

A pharmaceutical composition for controlled release, which comprises mirabegron or a pharmaceutically acceptable salt thereof as an active ingredient and polyethylene oxide (PEO) as a sustained-release agent. The pharmaceutical composition according to claim 1, wherein the polyethylene oxide (PEO) comprises at least one member selected from the group consisting of PEO 100,000 and PEO 30,000. The pharmaceutical composition according to claim 2, comprising only PEO 300 and PEO 100 in a ratio of 1: 0.1 to 1: 5. The pharmaceutical composition according to claim 1, wherein the polyethylene oxide (PEO) has an average molecular weight of not more than 1,000,000. The pharmaceutical composition according to claim 1, characterized in that it comprises less than 5% of a hydrophilic base. The pharmaceutical composition according to claim 5, wherein the hydrophilic base is polyethylene glycol (PEG). The pharmaceutical composition of claim 1, further comprising an aluminum rake as a colorant. A formulation for controlling release, wherein the composition according to any one of claims 1 to 7 is formulated. 9. The release-controlling agent according to claim 8, which is a tablet for oral administration. 9. The formulation of claim 8, wherein the formulation is packaged in a plastic container. The release-controlling agent according to claim 10, wherein the plastic container is Alu-Alu.

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