JP2020510679A - Pharmaceutical composition for modified release containing mirabegron or a salt thereof - Google Patents

Abstract

The present invention relates to a modified release pharmaceutical composition comprising mirabegron or a pharmaceutically acceptable salt thereof. Specifically, it relates to a pharmaceutical composition for controlling release, which contains polyethylene oxide for controlling the release of mirabegron as an active ingredient, is harmless to the human body and is easily manufactured pharmaceutically.

Description

  The present invention relates to a modified release pharmaceutical composition comprising mirabegron or a pharmaceutically acceptable salt thereof. Specifically, the present invention relates to a pharmaceutical composition for controlling the release of mirabegron, which contains polyethylene oxide for controlling the release of mirabegron as an active ingredient, and is harmless to the human body and easy to manufacture pharmaceutically.

Mirabegron is a compound having the structure of the following chemical formula 1, and its chemical name is (R) -2- (2-aminothiazol-4-yl) -4 ′-{2-[(2-hydroxy-2-phenylethyl) ) Amino] ethyl diacetanilide.
Mirabegron or a pharmaceutically acceptable salt thereof has β3 adrenergic receptor agonistic action. Mirabegron has been used for the treatment of symptoms of urinary urgency, frequent urination or urge incontinence that can occur in patients with irritable bladder and is marketed in Korea under the product name Betmiga PR.
Mirabeglon relaxes the bladder during a storage phase in which urine accumulates in the bladder, and improves the bladder's storage capacity by such a bladder relaxation effect (Naunyn Schmiedebergs Arch Pharmacol 2013; 386: 71-8). In addition, studies using a rat model in which ischemia occurred in the bladder revealed that mirabegron protects bladder function and morphology and reduces bladder overactivity (Eur Urol 2013; 64: 664-71).
In order to maximize such pharmacological effects of mirabegron, it was necessary to develop a modified release formulation.
Korean Patent No. 1524164 discloses that (a) a hydrophilic additive for infiltrating water into a preparation and (b) a polymer material forming a hydrogel to provide a pharmaceutical composition for controlled release containing mirabegron. Which discloses a controlled release preparation having a drug dissolution rate of 75% or less from the preparation in 1.5 hours and 75% to 100% in 7 hours.
Also, Korean Patent No. 507400 discloses that (a) a hydrophilic base, and (b) a polymer having an average molecular weight of 2,000,000 or more in order to provide a pharmaceutical composition having no change in drug elution during storage under light irradiation. An oral pharmaceutical composition comprising ethylene oxide and (c) iron oxide is disclosed.
Each of the registered patents contains a hydrophilic base, and uses polyethylene glycol (PEG) as a representative substance of the hydrophilic base.
However, in the case of using polyethylene glycol as the hydrophilic base, a case was discovered in which polyethylene glycol induces delayed and immediate hypersensitivity reactions (Sapna Shah MD, et al., Hypersensitivity to Pharmacy toy Groupy). , The Journal of Clinical Pharmacology). At the same time, polyethylene glycol may induce changes in pharmacokinetic behavior due to ABC Phenomenon (accelerated blood clearance) (U.S. Schuber et al., Polyethylene glycol in Drug delivery, Ange.)
Therefore, the present inventors have sought to develop a pharmaceutical composition that is harmless to the human body and stable when preparing a modified release formulation containing mirabegron.

Polyethylene glycol is generally considered biologically inert and safe. However, it has the disadvantage of eliciting a hypersensitivity reaction in a small number of humans and altering the pharmacokinetic behavior.
Therefore, the present inventors have developed a pharmaceutical composition and a pharmaceutical composition that does not contain a hydrophilic base such as polyethylene glycol and that is safe and easy to produce pharmaceutically, and completed the present invention. .

The present invention relates to a pharmaceutical composition for controlling release containing mirabegron or a pharmaceutically acceptable salt thereof as an active ingredient and polyethylene oxide (PEO) as a sustained-release base.
Preferably, when the polyethylene oxide (PEO) of the present invention contains all 300,000 PEO and 1 million PEO, it has excellent pharmacokinetics and dissolution rate for exhibiting a sustained effect of the drug. Further, it is preferable to include 300,000 PEO and 1,000,000 PEO in a weight ratio of 1: 0.1 to 1: 5, but the present invention is not limited to this.
The polyethylene oxide has an average molecular weight of about 300,000 or more. In addition, the average molecular weight of polyethylene oxide is preferably 1,000,000 or less, 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 303NF can be used in the dosage form of the present invention. However, it is not limited to these.
The invention may also be a pharmaceutical composition, characterized in that it comprises less than 5% of a hydrophilic base.
The hydrophilic base is a water-soluble polymer such as polyvinylpyrrolidone (PVP); sugar alcohols such as D-mannitol, sorbitol, xylitol; sugars such as lactose, sucrose, anhydrous maltose, D-fructose, dextran, glucose; Surfactants such as oxyethylene hydrogenated castor oil and 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; Amino acid saccharides and the like.
The present invention may further include a coloring agent. The coloring agent may be carmine, caramel, β-carotene, titanium oxide, talc, sodium riboflavin phosphate, yellow aluminum lake, or the like, and preferably aluminum lake.
The pharmaceutical composition of the present invention contains mirabegron or a pharmaceutically acceptable salt thereof as an active ingredient, and is used in a usual formulation in the pharmaceutical field, for example, tablets, capsules, beads, beadlets, granules, It may be formulated into a formulation for oral administration such as pills, troches, solutions and suspensions or a formulation for parenteral administration, and particularly may be a tablet for oral administration.
In addition, the pharmaceutical preparation of the present invention may further include a pH adjuster, a suspending agent, a preservative, a flavoring agent, a coloring agent, a sweetener, an adsorbent, 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 preparation of the present invention may be packaged in a container, and is preferably packaged in an airtight package, and the container includes both an airtight container and a sealed container.
The tablet for oral administration of the present invention is preferably packaged in an aluminum foil (alu-alu) packaging container, but is not limited thereto.

  Pharmaceutical compositions comprising mirabegron or a pharmaceutically acceptable salt thereof according to the present invention have the advantages of maintaining drug efficacy for a long time through controlled release, being harmless to the human body, and being easy to manufacture pharmaceutically. Have.

The result of the dissolution test by the paddle method (50 rpm, 37 ° C.) using the pH 6.8 eluate of Examples 1 to 5 and Comparative Example is shown.

TECHNICAL FIELD The present invention relates to a pharmaceutical composition for controlling release containing mirabegron or a pharmaceutically acceptable salt thereof as an active ingredient and polyethylene oxide (PEO) as a sustained-release base. Further, the polyethylene oxide (PEO) of the present invention can simultaneously contain 1,000,000 PEO and 300,000 PEO. It is preferable to include 300,000 PEO and 1,000,000 PEO in a weight ratio of 1: 0.1 to 1: 5.
Further, the average molecular weight of polyethylene oxide (PEO) is preferably 1,000,000 or less.
The invention includes pharmaceutical compositions that do not contain more than 5% of a hydrophilic base.
In particular, the present invention is characterized in that it does not contain polyethylene glycol (PEG) as a hydrophilic base.
The present invention includes a modified release formulation in which the pharmaceutical composition is formulated, which may be a tablet for oral administration, but is not limited thereto. The formulation may be packaged in a plastic container, and the plastic container is preferably aluminum foil (alu-alu).
Hereinafter, the present invention will be described more specifically with reference to examples. However, these examples are provided for illustrative purposes only to assist 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 Table 1 below, pharmaceutical preparations were prepared by changing the molecular weight of the polyethylene oxide used in Examples 1 to 5 and Comparative Examples as follows.
Preparation of Granules After mixing Mirabegron and polyethylene oxide (Polyox (registered trademark) WSR N-12K) homogeneously, a binding solution in which hydroxypropylcellulose and dibutylhydroxytoluene are dissolved in ethanol is kneaded and granulated. Dried and sized.
Final Mixing The sized product was placed in a mixer, and colloidal silicon dioxide and magnesium stearate were sieved and charged, followed by mixing to produce a final mixture.
Tableting the final mixture automatic tablet press (XP1, Korsh, Germany) to give tablets total weight 250mg and tablets utilized.
[Test Example 1]
Dissolution test The tablets manufactured in Examples 1 to 5 and Comparative Example were subjected to a dissolution test at pH 6.8 (900 mL, 50 rpm), and the liquid chromatographic measurement method was as follows.
-Detector: UV absorption spectrophotometer (measuring wavelength: 250 nm)
-Column: C18 (4.6 mm x 150 mm, 5 m)
-Mobile phase: mobile phases A and B are mixed and used at a ratio of 7: 3.
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 a 0.1 N aqueous sodium hydroxide solution, and adjust to 1000 mL.
Mobile phase B: acetonitrile-Flow rate: Adjust flow rate so that mirabegron is detected in 4 minutes-Column temperature: 40 ° C
The results are shown in FIG. 1 and Table 2, and the elution rate was confirmed. In other words, even when PEO 1,000,000 and PEO 300,000 were used in combination, an even better dissolution rate was exhibited than when PEO 1,000,000 was used alone.

Claims (10)

  A controlled release pharmaceutical composition comprising mirabegron or a pharmaceutically acceptable salt thereof as an active ingredient and polyethylene oxide (PEO) as a sustained release base.   The pharmaceutical composition according to claim 1, wherein the polyethylene oxide (PEO) comprises 1 million PEO and 300,000 PEO.   Pharmaceutical composition according to claim 2, characterized in that it comprises 300,000 PEO and 1 million PEO in a weight 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 1,000,000 or less.   Pharmaceutical composition according to claim 1, characterized in that it further comprises less than 5% of a hydrophilic base.   The pharmaceutical composition according to claim 1, further comprising an aluminum lake as a coloring agent.   A controlled release formulation, wherein the composition according to claim 1 is formulated.   The controlled release preparation according to claim 7, wherein the preparation is a tablet for oral administration.   8. The controlled release formulation of claim 7, wherein the formulation is packaged in a plastic container.   The controlled release preparation according to claim 9, wherein the plastic container is an aluminum foil (alu-alu).