KR20210001710A - Mirabegron controlled release formulations and manufacturing process thereof - Google Patents

Abstract

The present invention, in a controlled release-type mirabegron formulation for drug delivery, relates to a controlled release-type mirabegron formulation comprising mirabegron, and a cellulose-based biocompatible polymer granulated together with the mirabegron. The controlled release-type mirabegron according to the present invention is less likely to induce hypersensitivity reactions, and it is possible to minimize a disadvantage of changing the pharmacokinetic behavior.

Description

TECHNICAL FIELD [Mirabegron controlled release formulations and manufacturing process thereof]

The technology disclosed in the present specification relates to a controlled release Mirabegron formulation and a method for preparing the same, and more specifically, there is no restriction on the length of the treatmentable concentration retention time of the drug concentration and dietary intake according to the extension of the release time. It relates to a controlled-release miramegron formulation capable of controlling stable release and a method for preparing the same.

Mirabegron ((R)-2-(2-iminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]anilide acetate) It has both an insulin secretion promoting action and an insulin sensitivity enhancing action, and also has an anti-obesity action and an antihyperlipidemia action based on a selective β3 receptor stimulating action, and has a therapeutic effect on diabetes (see International Publication No. WO99/20605).

Mirabegron can also be used as a therapeutic agent for overactive bladder, as disclosed and claimed in WO2004/041276. For example, in addition to the overactive bladder caused by an enlarged prostate, it has a useful effect as a therapeutic agent for the overactive bladder that hydrates urinary urgency, urinary incontinence or frequency. In addition, when mirabegron is administered orally, its concentration changes significantly due to its rapid absorption rate. Therefore, the prior art, for example, beta-free hypothesis on commercially available AstraZeneca provides a release control effect by using polyethylene oxide/polyethylene glycol as a combination of a water-infiltrating agent and a hydrophilic agent in the formulation.

However, a conventional formulation of (R))-2-(2-aminothiazol-4-yl)'4'-[2-[(2-hydroxy-2-pheniethyl)amino]ethyl]anilide acetate is used. Thus, when a clinical trial was conducted, unexpectedly, problems such as a significant change in the presence or absence of dietary intake and pharmacokinetic data in the presence or absence of diet were revealed.

Accordingly, it is desired to develop a formulation capable of controlling release while avoiding the effects of dietary intake.

Patent Document 1: Patent Publication No. 10-2011-0071103

Accordingly, the problem to be solved by the present invention is to provide a controlled release mirabegron formulation, in which the drug is continuously released to increase bioavailability, and a stable controlled release mirabegron formulation and a method for manufacturing the same are provided without restriction of dietary intake. To provide.

According to an aspect of the present invention,

In the controlled release mirabegron formulation for drug delivery,

It includes a Mirabegron and a biocompatible polymer granulated together with the Mirabegron, wherein the biocompatible polymer is a controlled release type Mirabegron, which is a polymer having a viscosity in the range of 15 to 4000 mPa.s in a 2% aqueous solution at 20°C. Provide a formulation.

According to another aspect of the present invention,

In the controlled release mirabegron formulation for drug delivery,

Mirabegron formulation; And

Comprising a fibrous biocompatible polymer matrix granulated with the Mirabegron,

The polymer matrix is a cellulose-based polymer and is formulated in a compacted or wet granular tableted form to provide a controlled release Mirabegron formulation.

According to another aspect of the present invention,

A method for producing a controlled release mirabegron formulation for drug delivery, the method comprising: (a) mixing a mirabegron and a fibrous biocompatible polymer having a plurality of pores; And (b) molding the mixture into a controlled release formulation,

The biocompatible polymer provides a method for preparing a controlled release mirabegron formulation of at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, and hydroxyethylcellulose.

According to the controlled release mirabegron formulation according to an embodiment of the present invention, the mirabegron fibrous formulation prepared using a biocompatible fibrous polymer is limited in dietary intake compared to Mirabegron prepared using a non-fibrous polymer. It shows an excellent dissolution rate in the therapeutic concentration range without any side effects of mirabegron, and can lengthen the residence time of Mirabegron and allow the drug to be released continuously. Therefore, the antibiotic effect of Mirabegron also appears continuously for more than 12 hours, reducing the number of doses and minimizing side effects.

In addition, the controlled release mirabegron formulation according to the present invention can obtain a gel layer having an appropriate swelling property upon elution, thereby minimizing the effect of dietary intake, low incidence of hypersensitivity reactions, and pharmacokinetic behavior. You can minimize the disadvantages that change.

1 and 2 are diagrams showing two different dissolution test results for Examples 1 to 8 and Comparative Example 1 of the present invention, respectively.
3 is a view comparing properties of Examples 1 and 2 of the present invention and Comparative Example 1 after being eluted for 3 hours according to the presence or absence of rice starch.

Hereinafter, the present invention will be described in more detail.

According to an aspect of the present invention, there is provided a controlled release mirabegron formulation for increasing the bioavailability of orally administered mirabegron. The controlled release mirabegron formulation may include mirabegron and a biocompatible polymer granulated with the mirabegron.

In the case of Mirabegron, dietary intake is limited by oral administration, so it is difficult to take medication or is often administered multiple times. Therefore, it is necessary to design the drug as a completely controlled release formulation so that the minimal drug spreads slowly and does not limit dietary intake.

In order for the controlled release mirabegron formulation to have a low variability and high bioavailability, it is necessary to have a certain amount of release rate. That is, it is necessary to improve absorption by allowing the drug to stay for a long time when administered.

In the controlled release mirabegron formulation, preferably, the biocompatible polymer may be provided in a fibrous form. The fibrous phase may gradually induce swelling, and thus the dissolution rate of Mirabegron may be improved. The fibrous form is pharmacologically acceptable that can improve the physical properties of Mirabegron such as solubility, dissolution rate, hygroscopicity (hydroscopicity) and pharmacological properties (Cmax, Tmax) and bioavailability at strong acid acidity (pH) Compound.

The fibrous form may be provided in a granulated form with Mirabegron from a solution mixed with Mirabegron, for example, may be an organic polymer that forms a fibrous form with the drug Mirabegron, which is insoluble in water, preferably It may be a biocompatible polymer capable of improving solubility and dissolution rate when administered orally. Due to the fibrous form, the dissolution rate of the formulation is controlled. In one embodiment, the controlled release mirabegron formulation may be controlled to show a dissolution rate of 25% or less in 1 hour, 35 to 65% in 3 hours, and 75% or more in 6 hours.

The biocompatible polymer is not particularly limited as long as it is a pharmaceutically acceptable polymer and has a viscosity in the range of 15 to 4000 mPa·s at 20° C. in 2% aqueous solution, but preferably may be a natural carbohydrate polymer having hydrophilicity and swelling properties. . By adjusting the viscosity of the biocompatible polymer material, the dissolution behavior of the drug can be appropriately adjusted to suit the intended purpose.

The biocompatible polymer may be specifically, for example, at least one selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, and hydroxyethylcellulose.

The weight of the mirabegron may be 1 to 40 wt%, preferably 5 to 40 wt%, more preferably 15 to 35 wt%, based on the total weight of the controlled release mirabegron formulation. If the weight of Mirabegron among the total weight of the formulation is less than the above range, the therapeutic effect of the drug may not appear, and if it exceeds the above range, the fibrous form may not be formed, or the drug may not be uniformly dispersed in the fibrous form, so drug loading Overdose may not be smoothly released.

The controlled release mirabegron formulation may have a release time of at least 6 hours or more. In the controlled release mirabegron formulation, the in vitro release of the mirabegron at the same pH condition as in the body is at least 60% or more, preferably 65%, more preferably after 6 hours. May be 75% or more. It may also exhibit an emission rate of at least 5% or more per hour.

The controlled release mirabegron formulation according to an embodiment of the present invention may be formulated in the form of a tablet.

According to another aspect of the present invention, there is provided a controlled release mirabegron formulation for drug delivery, comprising: a mirabegron formulation; And a fibrous biocompatible polymer matrix granulated with the Mirabegron, wherein the polymer matrix is a cellulose-based polymer and is formulated in a compacted or wet granulated tablet form. Is provided. Here, the polymer matrix is formulated in a fibrous form. The biocompatible polymer matrix may be various cellulose-based polymers. The polymer has advantages such as biocompatibility, biodegradability, simplicity of a manufacturing method, abundance of raw materials, and low cost. The above-described controlled-release mirabegron formulation can release the drug at an effective concentration at a constant rate from the initial stage after oral administration, and then continuously release the drug over a long period of time so that the drug effect can be maintained for 12 hours or more. In addition, the formulation can increase the therapeutic effect of the drug by maintaining a constant concentration of the active drug. As a result, the above-described controlled-release mirabegron formulation is a formulation that can be administered less than once a day, and the side effects of dietary intake of the mirabegron formulation can be minimized, thereby increasing patient convenience and therapeutic effect.

According to another aspect of the present invention, there is provided a method for producing a controlled release mirabegron formulation for drug delivery, comprising: (a) mixing a mirabegron and a fibrous biocompatible polymer having a plurality of pores; And (b) molding the mixture into a controlled release formulation, wherein the biocompatible polymer is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, and hydroxyethylcellulose. A method of preparing one or more controlled release mirabegron formulations is provided.

Looking at the method for preparing the controlled release mirabegron formulation according to the corresponding embodiment, first, mirabegron and a biocompatible polymer for fibrous formation, pharmaceutically acceptable additives, for example, a diluent, a binder, and the like are mixed. In the next step, the mixture is molded into a controlled release formulation. Molding may be performed by a dry granulation method or a wet granulation method.

In one embodiment, the molding step comprises compacting the mixture using a dry granulator; And mixing additives such as a lubricant and a coating base with the compacting treatment. Then, it may further include the step of tableting and coating.

In another embodiment, the shaping step may include granulating the mixture by wet granulation, for example a fluid bed granulation method, followed by drying; Mixing and tableting a lubricant to the dried product after the wet granulation; And it may include the step of coating by further mixing the coating base.

On the other hand, the granulated product may be sizing before tableting. As the sizing step, as long as the granulated product is sizing, the apparatus and means are not particularly limited, and a sieve, wet dry sizing or the like can be used. The sizing condition is not particularly limited as long as it is a condition in which the granulated product is usually established to a desired size.

Here, the lubricant may be a conventional lubricant, preferably magnesium stearate and sodium stearyl fumarate, but is not limited thereto.

In addition, the coating base can be PVA-based or HPMC-based coating base and coating formulation, and commercial Opadry is representative.

In addition, the biocompatible polymer for fibrous formation used in the present invention is a sustained-release agent, and commercially available ones can be used, for example, METOLOSE ^® SM having a viscosity of 15 to 4000 cPs when dissolved at 20°C and 2% by weight. , 60SH, 65SH, METOLOSE ^® SR 90SH, WALOCEL™ C, and the like may be used, but are not limited thereto.

The sustained-release agent may be preferably a combination of one to two or more sustained-release agents having a viscosity of 15 to 3000 cPs when dissolved at 20°C and 2% by weight, more preferably one to one having 50 to 1500 cPs. It may be a combination of two or more sustained-release agents.

In addition, the pharmaceutically acceptable excipient or diluent used in the present invention is preferably at least one selected from the group consisting of microcrystalline cellulose, starch, gelatinized starch, talc, titanium oxide, calcium phosphate and calcium carbonate, and is insoluble. It is preferable because the effect of dietary intake is small.

In addition, when assembling into wet granules in the present invention, a binder may be used and is not particularly limited as long as it is pharmaceutically acceptable. The binder can be dissolved in purified water or other coarse solvent and applied in the form of a binder.

Further, in the controlled release formulation according to the present invention, a pharmaceutically acceptable additive may be appropriately contained. Such additives are not particularly limited as long as they are pharmaceutically acceptable, and examples thereof include disintegrants, preservatives, antioxidants, stabilizers, colorants, and sweeteners.

In the present invention as described above, Mirabegron may be in the range of 5 to 40 wt%, preferably 10 to 35 wt%, and more preferably 15 to 30 wt%, based on the total weight of the controlled release formulation.

The sustained-release agent may be in the range of 20 to 60% by weight, preferably 25 to 60% by weight, and more preferably 30 to 55% by weight, based on the total weight of the controlled release formulation.

The binder used in the wet granulation may be in the range of 1 to 15% by weight, preferably 1 to 10% by weight, more preferably 1 to 5% by weight, based on the total weight of the controlled release formulation. The coarse solvent used with such a binder may be used in the range of 10 to 40% by weight, preferably 10 to 30% by weight, and more preferably 15 to 25% by weight, based on the total weight of the controlled release formulation.

The excipient may be in the range of 30 to 70% by weight, preferably 35 to 65% by weight, more preferably 40 to 60% by weight, based on the total weight of the controlled release formulation.

The lubricant may be in the range of 0.1 to 3% by weight, preferably 0.3 to 2.0% by weight, more preferably 0.5 to 1.5% by weight, based on the total weight of the controlled release formulation.

Hereinafter, the present invention will be described in more detail with reference to various embodiments, but this is only for helping understanding of the present invention, and the technical idea of the present invention is not limited by the following embodiments.

Example

A fibrous formulation containing Mirabegro was prepared as follows (Examples 1 to 8).

Specifically, it was prepared through dry granulation (compacting) or wet granulation (high shear mixer, fluidized bed granulation), and ethanol was used as the granulating solvent to minimize the change in the crystal form of the main component sensitive to moisture when applying the wet granulation process.

Example One

Mirabegron, excipients, sustained-release agents, and lubricants were mixed in each amount (see Table 1), and then compacted and formulated. After sizing, a lubricant was further mixed and tableted. When tableting, it was adjusted to have a tablet mass of about 250 mg/1 tablet and a hardness of 7 to 10 kp. After tableting, the tablets were coated with a coating base and a coating solution to prepare a Mirabegron-containing controlled release tablet. The coating was made of Opadry coating base and pure water as a coating solution, and a sample was produced through 3% by weight of the outer skin coating based on the tablet mass of each formulation.

At this time, a Turbula mixer (Wab, T2F) is used for mixing the main components including Mirabegron, and a roller compactor (FREUND VECTOR, TF-1-A60) is used for compacting. , For tableting, a rotary tablet press machine (Sejong, GRC-18), and a pan coater (Sejong, SFC-30) were used for coating.

Example 2~7

In the same manner as in Example 1, except that each component was used in the content shown in Table 1, about 250 mg/1 tablet, a Mirabegron-containing controlled release tablet having a hardness of 7 to 10 kp was prepared.

Example 8

Mirabegron, excipients, sustained-release agents, and binders were mixed in each amount (see Table 1). A binder and a binder were further added to the mixture as a granulating solvent, granulated and dried into wet granules, and then sized. After sizing, a lubricant was further added to perform tableting. At the time of tableting, tableting was performed by adjusting to have a tablet mass of about 257.7 mg/1 tablet and a hardness of 7 to 10 kp. After tableting, the tablets were coated with a coating base and a coating solution to prepare a Mirabegron-containing controlled release tablet. The coating was made of Opadry coating base and pure water as a coating solution, and a sample was produced through 3% by weight of the outer skin coating based on the tablet mass of each formulation.

At this time, a Turbula mixer (Wab, T2F) is used for mixing the main ingredients including Mirabegron, and a fluid bed granulator (GR, XP-70) is used for wet granulation, and high shear mixing It was prepared through a granulation process. For tableting, a rotary tablet press machine (Sejong, GRC-18) was used, and the coating was produced using a pan coater (Sejong, SFC-30).

The contents of materials used in each example are summarized in Table 1 below. The unit is mg/T.

Comparative example One

For comparison, a commercial sample of Mirabegron 50mg, Betamiga 50mg/1 tablet, was used as a comparative example.

<Experimental Example 1>

Dissolution test-1: USP Dissolution test

For Examples 1 to 8 and Comparative Example 1, a dissolution test was performed according to the USP dissolution test method (basket method). As the test solution, 900 mL of a pH 6.8 phosphate buffer solution was used, and the evaluation was performed under conditions of 37°C and 200 rpm, and the results are shown in Table 2 (unit %) and FIG.

As shown in Table 2 and FIG. 1, it was confirmed that Examples 1 to 8 exhibited zero order emission similar to Comparative Example 1.

Dissolution test-2: Rice starch test

For Examples 1 to 2 and Comparative Example 1, the USP dissolution test method (paddle method) experimental apparatus was used, and a dissolution test according to the presence or absence of rice starch was conducted in order to evaluate the physical erosion of tablets by food during administration after meals.

Rice starch test was conducted by weighing 5 g of rice prepared with white rice into the outlet containing the test solution before the test, and leaving it for 10 minutes to release the rice grains, and then the dissolution test was conducted.The test solution was a pH 6.8 phosphate buffer solution. 900 mL was used, and the evaluation was performed under conditions of 37° C. and 100 rpm, and the results are shown in Table 3 and FIG. 2 below. In addition, the swelling degree of the tablet was measured at the time point of 3 hours, and the results are shown in FIG. 3.

As shown in Table 3 and FIGS. 2 and 3, in the case of the comparative example, it can be seen that the degree of swelling is larger than that of the example, and the change in the dissolution rate is large depending on the presence or absence of rice starch. In particular, the dissolution rate of 3 hours increased from 50.3% to 70.6%, and the change was found to be remarkable. In contrast, in Examples 1 and 2, the dissolution rate of 3 hours before containing was 56.0% to 57.7%, and 48.1% to 51.2%, respectively, and there was little difference in the degree of change in the dissolution rate. It can be seen that it is hardly affected after dietary intake and shows a stable controlled release.

Similarity Factor

Similarity Factor

In order to confirm the similarity of the elution results of w/ rice and w/o rice of Example 2 and Comparative Example 1 of Table 3, a similarity factor was calculated. The similarity factor is a value to determine the similarity of the dissolution patterns of the test drug and the reference drug, and was obtained through the following equation according to the FDA Guidance for Industry's Model Independent Approach Using a Similarity Factor, and the results are shown in Table 4 below.

f2 = 50.log{[1+(1/n)Σnt=1(Rt-Tt)2]-0.5. 100}

As shown in Table 4, in the case of Example 2, it was confirmed that the difference in dissolution rate according to the presence or absence of rice starch was not shown, and the similarity factor value was also 50 or more, showing similar dissolution. However, in the case of Comparative Example 1, physical erosion by rice starch As a result, the dissolution rate increased by about 10% at the time point of 1 hour and by about 20% at the time point of 3 hours, and the similarity factor value was also less than 50, indicating that the dissolution behavior of the two materials was not similar.

From the above results, according to Comparative Example 1, it is determined that there is a risk of rapid drug release due to physical erosion by food when administering the drug after a meal, but in the formulation according to the present invention using HPMC and an insoluble excipient, It was confirmed that there was no difference in dissolution and showed stable dissolution. This is a composition using PEO/PEG as a sustained-release agent and a hydrophilic base in Comparative Example 1, and in the case of PEO, the degree of swelling is greater than that of HPMC, and the gel strength is also relatively strong, so that a thicker gel layer is formed, and is taken accordingly. It is interpreted to mean that the difference in absorption according to the presence or absence of physical erosion to food may be larger.

Claims (13)

In the controlled release mirabegron formulation for drug delivery,
It includes a Mirabegron and a biocompatible polymer granulated together with the Mirabegron, wherein the biocompatible polymer is a controlled release type Mirabegron, which is a polymer having a viscosity in the range of 15 to 4000 mPa.s in a 2% aqueous solution at 20°C. Formulation. The method of claim 1,
The biocompatible polymer is a controlled release Mirabegron formulation, which is a fibrous cellulose polymer having a plurality of pores. The method of claim 1,
Controlled release mirabegron formulation further comprising a pharmaceutically acceptable insoluble excipient. The method of claim 1,
A controlled release mirabegron formulation in which the in vitro release of the mirabegron is at least 75% or more after 6 hours under the same pH condition as in the body. The method of claim 1,
The biocompatible polymer is at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, and hydroxyethylcellulose. In the controlled release mirabegron formulation for drug delivery,
Mirabegron formulation; And
Comprising a fibrous biocompatible polymer matrix granulated with the Mirabegron,
The polymer matrix is a cellulose-based polymer, which is formulated in a compacted or wet granular tablet form. The method of claim 6,
The controlled release Mirabegron formulation, wherein the formulation further comprises a pharmaceutically acceptable insoluble excipient. The method of claim 6,
The polymer matrix is at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, and hydroxyethylcellulose. The method of claim 1 or 6,
The mirabegron is a controlled release mirabegron formulation of 5 to 40% by weight based on the total weight of the formulation. The method of claim 1 or 6,
The biocompatible polymer is 20 to 60% by weight based on the total weight of the formulation controlled release Mirabegron formulation. The method according to claim 3 or 7,
The pharmaceutically acceptable insoluble excipient is 30 to 70% by weight based on the total weight of the formulation controlled release Mirabegron formulation. A method for producing a controlled release mirabegron formulation for drug delivery, the method comprising: (a) mixing a mirabegron and a fibrous biocompatible polymer having a plurality of pores; And (b) molding the mixture into a controlled release formulation,
The biocompatible polymer is at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, and hydroxyethylcellulose. The method of claim 12,
The forming step
(b-1) compacting the mixture or drying the mixture after wet granulation; And
(b-2) The method for producing a controlled release Mirabegron formulation comprising the step of mixing, tableting and coating a lubricant and a coating base in the dried product after compacting or wet granulation.

Images