WO2020175897A1

WO2020175897A1 - Controlled release formulation containing mirabegron or pharmaceutically acceptable salt thereof

Info

Publication number: WO2020175897A1
Application number: PCT/KR2020/002708
Authority: WO
Inventors: 권석영; 박윤상; 한종권; 구대환
Original assignee: 신일제약주식회사
Priority date: 2019-02-26
Filing date: 2020-02-25
Publication date: 2020-09-03
Also published as: KR102062791B1

Abstract

The present invention relates to a controlled release formulation comprising: Mirabegron or a pharmaceutically acceptable salt thereof; an isomalt; and a sustained release agent. Disclosed is a formulation in which Mirabegron, a medication, does not decompose, and thus the therapeutic effect thereof can be maintained constant during long-term storage. Moreover, Mirabegron can be released stably and sustainably in vivo, and thus a sufficient medicinal effect can be exhibited even when the formulation is administered once a day.

Description

2020/175897 1»（：1^1{2020/002708 specification

Title of Invention: Release Control Formulations Containing Mirabegron or Its Pharmaceutically Acceptable Salt

Technical field

[1] The present invention relates to a pharmaceutical preparation containing mirabegron or a pharmaceutically acceptable salt thereof. Specifically, to a release controlling preparation containing mirabegron, isomalt, and a sustained release agent, a drug. As the generation of harmful substances due to decomposition of the drug is suppressed, a certain therapeutic effect can be expected even for long-term storage. More specifically, it shows the drug release pattern and bioavailability equivalent to those of the currently marketed products not only in vitro but also in vivo. It is characterized by being able to secure sufficient drug efficacy only for recovery.

Background

[2] Mirabegron, the active ingredient of the present invention, is a compound represented by the following chemical formula, whose chemical name is

⑷ -2- (2 -Aminothiazole- 4 -yl)-4'-[2-[(2 -hydroxy -2 -phenylethyl) amino] ethyl] acetic acid anilide.

[5] In Japanese Patent No. 97-285778, a novel amide derivative compound to which mirabegron represented by the above formula (1) belongs simultaneously exhibits the action of promoting insulin secretion and enhancing insulin sensitivity, (33-showing a selective stimulating action on the receptor). It is disclosed as, and it is known that it can be useful in the treatment of diabetes, obesity and hyperlipidemia. In particular, International Patent Publication \¥02004/041276 discloses that Mirabegron is effective in treating bladder activity.

[6] Mirabegron has a half-life of 18 to 24 hours, and there is no need for a release-controlling agent to maintain continuous blood concentration. However, pharmacokinetic properties such as: 11 and Show 11 are significantly changed depending on the intake of food. have determined that there is a problem, it is possible to reduce this effect have been developed zero emission control claim to allow be the exercise correctly pharmacological effects. Republic of Korea registered currently associated with Micah ^® sustained-release tablet beta is commercially available from Korea Patent 1,524,164 No. and Republic of Korea Patent No. In No. 507400, a matrix-type release control containing a hydrophilic base and a polymer material forming a hydrogel And is a representative substance for hydrophilic

Polyethylene glycol (PEG) is used.

[7] However, as mentioned in Korean Patent Laid-Open No. 10-2018-0106924, additives such as polyethylene glycol are decomposition of Mirabegron due to the interaction with the drug. There is a problem that the efficacy of the drug decreases, and as mentioned in Korean Patent Laid-Open No. 10-2018-0106185, a case where ethylene glycol induces delayed or immediate hypersensitivity, and ABC Phenomenon (accelerated blood clearance) It has been reported that there is a possibility of causing a change in pharmacokinetics due to this.

[8] Attempts are being made to develop a release-controlling formulation that overcomes the above problems of polyethylene glycol, which is a representative hydrophilic base, for example, Korean Patent Application Publication No. 10-2018-0106924 and Korean Patent Publication No. 10-2018. -0106185 discloses a release-controlled pharmaceutical composition consisting only of a sustained fire retardant without using polyethylene glycol, and Korean Patent Publication No. 10-2018-0104259 discloses a release-controlled pharmaceutical composition through a hydrophobic non-hydrogel matrix. have. In addition, Korean Patent Laid-Open No. 10-2017-0088783 discloses a formulation containing a homogeneous granule using a silicate compound.

[9] However, the method of simply excluding polyethylene glycol or replacing polyethylene glycol with a water-insoluble compound phosphate silicate, the in-vitro drug release rate is described in the OCAS ^® system (International Publication No. WO 1994/06414). ）Applied Betami ^{® may be} similar to Western-release tablets, but water-soluble additives, a key component of the OCAS ^® system, that release drugs not only from the stomach and small intestine, but also from the large intestine.

Since it does not contain polyethylene glycol, betamy ^® is not desirable because it is unlikely to be bioequivalent to sustained-release tablets in real life.

[1] Thus, the drug mirabegrone and interactions of polyethylene glycol

This release regulator proposed development that can secure a beta Micah ^® sustained-release tablet and bioequivalence is required at the same time to solve the problem.

[11] [Prior technical literature]

[12] [Patent Literature]

[13] (Patent Document 1) Korean Patent Registration No. 057400

[14] (Patent Document 2) Korean Patent Registration No. 1524164

[15] (Patent Document 3) Korean Patent Publication No. 10-2018-0106924

[16] (Patent Document 4) Korean Patent Publication No. 10-2018-0106185

[17] (Patent Document 5) Korean Patent Publication No. 10-2018-0106924

[18] (Patent Document 6) Korean Patent Publication No. 10-2018-0104259

[19] (Patent Document 7) Korean Patent Publication No. 10-2017-0088783

Detailed description of the invention 2020/175897 1»（：1^1{2020/002708 Technical task

[2] As a result of research to solve the above problems, the present inventor is mutually compatible with the drug Mirabegron when using isomalt, which was not mentioned at all in the release control formulations containing the known Mirabegron. Since no action occurs, harmful substances due to decomposition of Mirabegron are not generated, and not only in vitro, but also

The present invention was completed by confirming that it was possible to manufacture a release-controlling formulation capable of securing a stable drug release pattern and excellent bioavailability in vivo.

[21] The present invention is for the prevention or treatment of overactive bladder, urinary urgency, urinary incontinence, and frequency

The solution is to provide an anti-inflammatory agent, and it contains Mirabegron as an active ingredient, and it does not generate harmful substances due to the decomposition of the drug Mirabegron using isomalt, so that a certain therapeutic effect can be expected even for long-term storage. Providing controlled-release formulations is a specific challenge.

[22] Furthermore, the present invention releases drugs similar to 00Show 3 ^® D !!! applied to commercial products

A special challenge is to provide a release-controlled formulation that can show a pattern and secure excellent bioavailability in vivo.

Problem solving means

[23] In order to solve the above problems, the following measures are disclosed in this invention.

[24] In one embodiment, a release-controlled preparation comprising mirabegrone or a pharmaceutically acceptable salt thereof, isomalt, and a sustained-release agent is disclosed.

[25] The sustained-release agent is polyethylene oxide, hydroxypropylmethylcellulose,

Hydroxypropyl cellulose, sodium carboxymethyl cellulose,

Hydroxyethylcellulose, polyvinylpyrrolidone, methylcellulose, and

It may be one or two or more selected from the group consisting of ethyl cellulose.

[26] The sustained-release agent may be polyethylene oxide.

[27] The isomalt is 20 to 90% by weight based on the total weight of the release control agent,

The sustained-release agent may be included in an amount of 5 to 50% by weight based on the total weight of the release control agent.

[28] The release-controlling formulation may further contain one or more selected from excipients, binders, disintegrants, antioxidants, surfactants, lubricants and coating bases.

[29] In another embodiment, the release controlling agent of the present invention is Mirabegron or its

Initiate a release-controlled formulation with a pharmaceutically acceptable salt dissolution rate of less than 30% in 2 hours, 30-80% in 5 hours, and 80% or more in 12 hours.

Effects of the Invention

[3] The release control formulation according to the present invention exhibits the effect of preventing or treating overactive bladder, urinary urgency, urinary incontinence, and frequent urination. More particularly, by using isomalt as a water-soluble additive, the drug Mirabegron is decomposed. Due to the fact that no harmful substances are generated, constant therapeutic effects can be maintained even for long-term storage. In particular, the release-controlled formulation of the present invention releases drugs similar to those of commercially available sustained-release tablets not only in vitro but also in vivo. The 2020/175897 PCT/KR2020/002708 pattern can be secured, indicating excellent bioavailability.

Brief description of the drawing

1 is a graph showing the dissolution patterns of Mirabegron from the release-controlling formulation of the present invention, a comparative example, and a commercial formulation.

[32] Figure 2 shows the dissolution pattern of Mirabegron from the release control formulation of the present invention

It is a graph.

3 is a graph showing a comparison of the concentration of Mirabegron in blood of the release control formulation of the present invention and a commercial product.

Best mode for carrying out the invention

[34] In the present invention, when using polyethylene glycol, which is a representative water-soluble base, the drug mirabegron is decomposed and the therapeutic effect is reduced during long-term storage due to the harmful substance, whereas the release control including the known mirabegron This is based on the fact that the use of Isomalt, which has not been mentioned in the formulation at all, prevents the decomposition of the drug Mirabegron, so that the therapeutic effect can be maintained during long-term storage. In particular, it is tested without causing a reaction with the drug. Not only in the hall

It is based on the fact that stable and continuous dissolution is possible in vivo, thus ensuring excellent bioavailability.

[35] In accordance with the present invention, release-controlled formulations for the prevention or treatment of overactive bladder, urinary urgency, urinary incontinence, and frequency of urine include Mirabegron or its pharmaceutically acceptable salts, isomalt and sustained-release agents.

[36] Usable mirabegron of the present invention is a free base of mirabegron or a pharmaceutically acceptable acid addition salt thereof (hereinafter, in the specification, unless otherwise indicated, mirabegron or a pharmaceutically acceptable salt thereof To'Miravegron'

(Collectively)) may be included, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, benzoic acid, methanesulfonic acid, hydroxyethanesulfonic acid, toluenesulfonic acid, ethanesulfonic acid, etc. Organic carboxylic acids such as folic acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, and glutamic acid.

[37] Isomalt, a water-soluble agent used in the release control formulation of the present invention, is non-toxic,

As a non-allergic substance, it is a safe additive that does not cause hypersensitivity reactions when used by the human body. It has a molecular weight of 344.32 to 380.32 (Handbook of Pharmaceutical Excipients. Food Sciences and Nutrition). In particular, the representative water-soluble base polyethylene glycol is very hygroscopic, while isomalt is non-topically moisturized up to 85% relative humidity (Handbook of Pharmaceutical Excipients. Sixth edition. 2009), and its melting point is also 141~171°Cof pharmaceutical Excipients. Sixth edition. 2009)

It reacts with the drug Mirabegron after high temperature compared to polyethylene glycol (37 63 ^O C) 2020/175897 1»（：1^1{2020/002708 The problem of decomposition products can be prevented.

[38] The sustained-release agent used in the release controlling agent of the present invention can be used as long as it is a pharmaceutically acceptable sustained-release agent, preferably polyethylene oxide, hydroxypropylmethylcellulose, hydroxypropylcellulose,

It may be one or two or more selected from the group consisting of sodium carboxymethylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, methylcellulose and ethylcellulose. More preferably, polyethylene oxide £0) can be used, molecular weight Is 100,000 7,000, 000.

[39] The controlled release formulation of the present invention may contain 1 to 50% by weight of Mirabegron, 20 to 90% by weight of isomalt, and 5 to 50% by weight of a sustained release agent based on the total weight of the composition.

Preferably, 30 to 80% by weight of isomalt, 10 to 40% by weight of a sustained-release agent, more

Preferably, it may contain 40 to 70% by weight of isomalt and ^ to 30% by weight of a sustained-release agent. The release control formulation of the present invention is the release rate of Mirabegron from the formulation by controlling the content of isomalt and the sustained-release agent. Can be adjusted.

[4] The content range of this isomalt is at the same time preventing the decomposition of the drug Mirabegron.

It is desirable to effectively control the dissolution rate of Mirabegron so that it can be used once a day.

[41] The release controlling agent of the present invention may additionally contain additives such as excipients, binders, disintegrants, antioxidants, surfactants, lubricants, and coating bases.

[42] The excipients include starch, lactose, anhydrous lactose, microcrystalline cellulose, silicified microcrystalline cellulose, hypromellose, anhydrous silicic acid, calcium phosphate, anhydrous calcium phosphate, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, calcium silicate, Dextrin, dextrose, dextrate, mannitol, maltose, sorbitol, sucrose, polyethylene glycol, sodium chloride, etc. can be mentioned, and these can be used in one or a combination of two or more.

[43] Examples of the binder include povidone, copovidone, methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose,

Hydroxyethyl cellulose, gelatin, guar gum, xan gum, etc. are mentioned, and these can be used in one type or in a combination of two or more.

[44] The disintegrants include crospovidone, croscarmellose sodium, sodium glycolate starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, grain starch, etc., which are one or two or more combinations Can be used as

[45] The antioxidants include dibutylhydroxytoluene, butylhydroxytoluene,

Butylhydroxyanisole, tertiary butyl hydroquinone, propyl molar acid, vitamin 0, etc. can be used, and these can be used in one type or a combination of two or more.

[46] The surfactant is sodium lauryl sulfate, sodium stearate,

Polysorbate 80, poloxamer, etc. are mentioned, and these can be used in one type or a combination of two or more. 2020/175897 1»（：1^1{2020/002708

[47] As the lubricant, magnesium stearate, stearic acid, talc, silicon dioxide, sodium stearyl fumarate, sodium lauryl sulfate, poloxamer, etc. may be mentioned, and these may be used in one or a combination of two or more. .

[48] As the coating base, hypromellose, methylcellulose,

Hydroxypropyl cellulose, povidone, polyvinyl alcohol,

Polyvinyl acetate phthalate, shellac, cellulose acetate phthalide, sugar, methacrylic acid amino ester copolymers, etc. can be mentioned, and these can be used in one or two or more combinations, and can be used together with an appropriate plasticizer and colorant.

[49] According to the present invention, using the first method of dissolution test method among general test methods of the Korean Pharmacopoeia, with a rotational speed of ^0 111, 37ᄋ（: dissolution test agent 2!! 6.8 solution) High-performance liquid after filtering the eluate obtained at a certain time after the start of the test at 900 11

As measured by chromatography, the dissolution rate of Mirabegron from the release controlling agent of the present invention was less than 30% in 2 hours, 30-80% in 5 hours, and 12 hours.

It is more than 80%.

[5 This invention also uses the conventional dry/wet granulation method,

It can be manufactured through a tablet manufacturing method such as a direct powder compression method. As one specific example, the manufacturing method of the controlled release formulation of the present invention is

[51] （幻miravegrones, isomalt, sustained release agents and pharmaceutically acceptable additives

Mixing step;

[52] ）Compress the above mixture by direct powder compression to produce uncoated tablets, or

Dry (or wet) granulation and compression to produce uncoated tablets; and

[53] (0) It may include the step of coating the uncoated tablet.

[54] Above (after dry/wet granulation in the non-step, it can be mixed with additional additives before making tablets, (this coating step can be omitted if necessary).

[55] Hereinafter, the present invention will be described in detail by examples. However, the following examples are only illustrative of the present invention, and the contents of the present invention are not limited to the following examples.

[56] Simulated example 1-10. Preparation of release control formulation by aerobic granules

[57] Step of preparing a blend by mixing the ingredients in the granules according to the composition of Tables 1 and 2 below; Compressing the blend; Sizing the pressurized material; Mixing the sizing material and the non-granular components ; Compressing the mixture into tablets to obtain uncoated tablets; And through the step of film-coating the uncoated tablets to prepare the release control formulations of Examples 1 to.

[58] 2020/175897 1»（：1/10公020/002708

[59] [Table 1]

[6 this

2020/175897 1»（：1^1{2020/002708

[61] [Table 2]

[62] Examination example 11. Manufacture of a release control formulation by direct powder compression

[63] According to the composition of Table 3 below, ingredients excluding the film coating base (Opadry)

Mixing; Compressing the mixture into tablets to obtain uncoated tablets; And through the step of film-coating the uncoated tablets to prepare the release control formulation of Example 11.

[64] [Table 3]

[65] Shim Si Example 12-16. Manufacture of a release control formulation by Shu-sik granules 2020/175897 1»(：1^1{2020/002708 Step of mixing the components in the granules according to the composition of Table 4 below; Step of mixing by adding a solvent to the mixture; Hot air of 60 ᄋ（: Drying for 2 hours and then sizing; mixing the sized material and non-granular components; compressing the mixture into tablets to obtain uncoated tablets; And through the step of film coating the uncoated tablets, Examples 14, 15 and The release control formulation of 16 was prepared. In the case of Example 13, the step of film coating on the uncoated tablet was not performed.

[Table 4]

Comparative Example 1. Preparation of a release control formulation that does not contain isomalt

Preparing a blend by mixing the ingredients in the granules according to the composition of Table 5 below; Compressing the blend; Sizing the crushed product; Mixing the sizing product and the extragranular components; Compressing the mixture with a tablet to obtain uncoated tablets; And through the step of film coating the uncoated tablets. The release control formulation of Comparative Example 1 was prepared that did not contain malt. Comparative Example 1 was the same water solubility as the commercial product. 2020/175897 1» (：1^1{2020/002708) It was prepared using a base (polyethylene glycol) and a sustained release agent (polyethylene oxide).

[7] [Table 5]

[Group] Test Example 1; Test for external use in vivo

[72] The release control formulations prepared in Examples 2 to 5 and Comparative Example 1 and currently on the market

The dissolution test was conducted on Beta Miga ^® Western-release tablets (501¾) (hereinafter referred to as the control treaty).

Specifically, using the first method (basket) of the dissolution test method among the general test methods of the Korean Pharmacopoeia, at a rotation speed of ^0 111, 37ᄋ（: dissolution test solution 2!! 6.8 amount) 900 at 11 止

Samples were taken 2, 3, 5, 6, 8, 10, 12 hours after the initiation of the test, and the released mirabegron was analyzed as (:), and the results are shown in Table 6, Figs. 1 and 2.

2020/175897 1»（：1^1{2020/002708 3] [Table 6]

4] As shown in Table 6 above, the release control formulation of the present invention is a commercial product,

It was confirmed that the dissolution pattern was similar to that of Comparative Example 1, which was prepared using the same water-soluble base and sustained release agent as the product. In addition, the release rate of Mirabegron can be easily controlled by adjusting the content of polyethylene oxide and isomalt. of

Confirmed.

[75] Test Example 2: Hygroscopicity evaluation

6] The same water solubility as the formulation and commercial product of the present invention prepared in Examples 2, 4, and 5

Comparative Example 1 prepared using the base and the commercial product Betamiga ^® Sustained-release tablet (5011¾) (hereinafter referred to as reference drug) was packaged in a bottle and administered to a stability test chamber under high temperature and humidity conditions (50 ᄋ (:, 75% relative humidity) ) To measure the hygroscopicity by observing the ratio of the increase in the tablet weight, and the results are shown in Table 7.

7] [Table 7]

2020/175897 1»（：1^1{2020/002708

[78] As shown in Table 7 above, hygroscopicity immediately results in high temperature and humidity conditions (50 ᄋ（:,

Relative humidity 75% by weight), the weight increase rate due to moisture after 4 weeks of storage is comparative example

Compared to 1 (polyethylene glycol as a water-soluble base), the commercially available product was found to be at 70% level, whereas the release control formulation of the present invention was found to be at 57-58% level. Through this, the release control formulation of the present invention may occur during distribution and sale of pharmaceuticals. It was confirmed that it is a more stable formulation than a commercial product in a high temperature and high humidity environment.

Test Example 3: Flexible matter generation test

The formulation of the present invention prepared in Examples 2, 4, and 5, Comparative Example 1 prepared using the same water-soluble base as the commercial product, and the commercial product, Betamiga ^® Sustained-release tablet (5011¾) (hereinafter referred to as reference) in a bottle After being administered to a stability test chamber and stored in a high temperature and high humidity condition (50° (:, 75% relative humidity)), the content and change of the related substances were observed with (:), and the results are shown in Table 8. Beta Micah ^®

For Western-release tablets (50 ¾) (hereinafter referred to as “Controversy Treaty”), additionally related material generation tests were conducted in the form of aluminum/aluminum packaging, which is a commercial packaging format.

[8 [Table 8]

]]

90 21

78

As shown in Table 8 above, the production amount of related substances is comparative example, polyethylene glycol is used as a water-soluble base), whereas the commercially available product is more than 90%, whereas the release control formulation of the present invention is 70%, the amount of related substances is significantly low In particular, in the case of the aluminum/aluminum packaging type applied to commercial products, moisture penetration is not easy, but the packaging unit cost is high and packaging time is required, whereas the packaging is a packaging type that is easy to manufacture. Controlled release formulations have better stability than commercial products in this packaging form. 2020/175897 1»（：1^1{2020/002708 Confirmed that it is visible

[83] Test Example 4: In vivo test

[84] For the calculation of pharmacokinetic parameters for in vivo blood concentration of Mirabegron

Beta Miga ^® Sustained-release tablet (5011¾) (hereinafter referred to as a control treaty) and the release-controlled formulation prepared in Examples 2, 4 and 6 were divided into 4 groups of 12 beagle dogs, and after cross-administration on an empty stomach over 4 periods, blood Mirabe The concentration of Gron was measured to calculate the pharmacokinetic parameters, Show 11 (:, (: 11), and the results are shown in Table 9 and Fig. 3 below.

[85] [Table 9]

[86] As shown in Table 9 and Fig. 3, it was confirmed that the release-controlling formulation of the present invention exhibits pharmacokinetic parameters similar to those of commercial products.

Industrial availability

[87] The release control agent according to the present invention is used for overactive bladder, urinary urgency, urinary incontinence, and

As it shows a preventive or therapeutic effect, it can be used as a medicine in the pharmaceutical industry and medical field.

Claims

2020/175897 1»（：1/10公020/002708 Claims

[Claim 1] Mirabegron or its pharmaceutically acceptable salt, isomalt, and

Release control formulations containing sustained-release agents

[Claim 2] In claim 1, the sustained release agent is polyethylene oxide,

Hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose,

One or more release control agents selected from the group consisting of polyvinylpyrrolidone, methylcellulose and ethylcellulose

[Claim 3] The release control agent according to claim 2, wherein the sustained release agent is polyethylene oxide

[Claim 4] The method of claim 1, wherein the isomalt is added to the total weight of the release controlling agent.

20 to 90% by weight, based on the total weight of the release control agent.

Release control agent containing 5 to 50% by weight

[Claim 5] The release controlling agent according to paragraph 1, further comprising at least one selected from excipients, binders, disintegrants, antioxidants, surfactants, lubricants and coating bases.

[Claim 6] According to any one of items 1 to 5, the dissolution rate of the Mirabegron or its pharmaceutically acceptable salt is less than 30% in 2 hours, 30-80% in 5 hours, 80 in 12 hours. Release control agent characterized by more than%