KR20190117072A - Controlled Release Pharmaceutical Composition comprising Mirabegron - Google Patents

Abstract

The present invention relates to a controlled release pharmaceutical composition comprising mirabegron or a pharmaceutically acceptable salt thereof, and a sustained-release agent. More specifically, the present invention relates to the controlled release pharmaceutical composition and a method for manufacturing the same, in which the sustained-release agent combines gums with a polymer material forming hydrogel.

Description

Controlled Release Pharmaceutical Composition comprising Mirabegron

The present invention relates to a pharmaceutical composition comprising Mirabegron or a pharmaceutically acceptable salt thereof, while controlling the release of Mirabegron so that there is no restriction on dietary intake, and improving stability according to packaging and storage conditions. To a pharmaceutical composition and a method for preparing the same.

Mirabegron (chemical name: (R) -2- (2-aminothiazol-4-yl) -4 '-{2-[(2-hydroxy-2-phenylethyl) amino] ethyl} acetanilide) As a compound represented by the following structural formula, it has a function of promoting insulin secretion and enhancing insulin sensitivity, and selectively acts on the β3-adrenergic receptor.

[Formula 1]

In addition, Mirabegron or a pharmaceutically acceptable salt thereof is known to have anti-obesity action and antihyperlipidemic action and to be useful for treating diabetes. Furthermore, it is also known to be useful as a therapeutic agent for overactive bladder.

However, during the development of pharmaceutical formulations of Mirabegron or its pharmaceutically acceptable salts, the effects of dietary intake of Mirabegron have been identified, and to minimize this effect, Development and further development of preparations that avoid the effects of dietary intake are desired.

In this regard, in the case of betami commercially available sustained-release tablets in Korea, polyethylene oxide (PEO) is used as a sustained release agent. However, when PEO is used as a sustained release agent, the stability period is due to polymer chain decomposition by photolysis and oxidation. There is a problem that the bursting of the drug (bursting) may occur, and commercially available beta-mi is estimated to use iron oxide pigment and dibutyl hydroxytoluene (BHT) to improve this problem in the case of sustained-release tablets.

Moreover, when polyethylene oxide is used as a sustained release agent, there exists a problem that a glass transition temperature (Tg) may exist in semisolid form at normal temperature about -22 degreeC according to the molecular weight. Furthermore, in particular, considering that the melting point of the PEO is a polymer material having a maximum of 67 ° C., there is a problem that a part is likely to cause a phase change to a liquid phase under high temperature conditions. As such, in the case of using PEO as a sustained release agent of Mirabegron, there is a risk of dissolution due to phase change during storage.

Korean Patent Publication No. 10-2011-0071103 (published on June 28, 2011)

Accordingly, the present invention provides a pharmaceutical composition and a method for producing the pharmaceutical composition capable of controlling the stable release of Mirabegron or a pharmaceutically acceptable salt thereof regardless of the solubility of the additive and at the same time maintaining a stable release regardless of storage conditions and packaging containers. To provide.

In order to solve the above problems, the present invention is a controlled release pharmaceutical composition comprising a mirabegron or a pharmaceutically acceptable salt thereof and a sustained release agent, the sustained release agent is used in combination with a polymer and a gum to form a hydrogel To provide a controlled release pharmaceutical composition.

According to a preferred embodiment of the present invention, it is preferable that the polymer material forming the hydrogel has a 2 wt% aqueous solution viscosity of 50-1500 mPa · s at 20 ° C.

According to another suitable embodiment of the present invention, in the controlled release pharmaceutical composition, the polymer material forming the hydrogel is 27 to 57% by weight relative to the total weight of the pharmaceutical composition, and the gum is the pharmaceutical composition. It is preferably included 0.5 to 5% by weight relative to the total weight, more preferably 35 to 52% by weight of the polymer forming the hydrogel, the gum is 0.5 to 4% by weight, more preferably hydrogel 40 to 50% by weight of the polymer to be formed, the gum comprises 1 to 3% by weight.

According to another suitable embodiment of the present invention, in the controlled release pharmaceutical composition, the polymer material forming the hydrogel is hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose and hydroxyethylcellulose It is preferable that it is 1 or more types chosen from the group which consists of these.

According to another suitable embodiment of the present invention, the gum is preferably at least one gum selected from the group consisting of xanthan gum, locust bean gum, gum arabic and carrageenan.

According to another suitable embodiment of the present invention, it is preferable that the sustained-release agent is a controlled release pharmaceutical composition, characterized in that hydroxypropylmethylcellulose is used in combination with xanthan gum or locust bean gum.

According to another suitable embodiment of the invention, the controlled release pharmaceutical composition preferably further comprises a pharmaceutically acceptable excipient.

According to another suitable embodiment of the present invention, with respect to the total weight of the pharmaceutical composition, 7 to 25% by weight of Mirabegron or a pharmaceutically acceptable salt thereof, 30 to 60% by weight of a sustained release agent, pharmaceutically acceptable It is preferred to include 25 to 50% by weight of excipients.

According to another suitable embodiment of the present invention, it is preferred that the pharmaceutically acceptable excipient has a solubility of 1 L or more in the amount of water required to dissolve 1 g.

According to another suitable embodiment of the present invention, the pharmaceutically acceptable excipient is preferably selected from the group consisting of microcrystalline cellulose, starch, gelatinized starch, talc, titanium oxide, calcium phosphate and calcium carbonate.

In addition, in order to solve the above problems, in the Mirabegron or a pharmaceutically acceptable salt thereof, the polymer material for forming a hydrogel, and the gum is 30 to 60% by weight relative to the total weight of the pharmaceutical composition, and pharmaceutically acceptable Provided are methods for the preparation of controlled release pharmaceutical compositions comprising mixing 25 to 50% by weight of possible excipients relative to the total weight of the pharmaceutical composition.

Furthermore, in order to solve the above problems, the present invention also provides a granule by first mixing Mirabegron or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable excipient, and after the granulation is established, a sustained-release agent It provides a method for producing a controlled release pharmaceutical composition comprising the step of secondary mixing.

According to a suitable embodiment of the present invention, it is preferable to include a step of additionally adding a lubricant to the final mixing after the step.

According to the present invention, there can be provided a stable controlled release pharmaceutical composition without restriction of dietary intake and without risk of change in dissolution profile over time.

In addition, according to the present invention, it is possible to reduce the influence of the storage conditions and the packaging container to the pharmaceutical composition, it is easy to carry, and further can provide a pharmaceutical composition that can improve the medication compliance of the patient.

1 is a diagram schematically showing a method for producing a controlled release pharmaceutical composition according to the present invention.
FIG. 2 is a diagram in which the elution patterns of Examples 1, 3-1, and 4 and Comparative Examples 2 to 5 are plotted in comparison with that of Comparative Example 1. FIG.
3 is a diagram in which the elution patterns of Examples 9, 11, 13 and 15 are plotted in comparison with the elution patterns of Examples 1, 2 and Comparative Example 1. FIG.
4 is a diagram in which the elution pattern in the pH 3.0 citric acid buffer of Example 1 is compared with the elution patterns of Comparative Examples 1 and 7. FIG.
FIG. 5 is a diagram visually showing changes in properties of the initial sample of Comparative Example 6 and the sample after storage at 80 ° C. for 6 hours.

Hereinafter, the present invention will be described in detail with reference to embodiments. However, this is presented as an example, and the present invention is not limited by this, and the present invention is defined only by the scope of the following claims. In addition, even if it is the structure which is essential for implementing this invention, detailed description is abbreviate | omitted about the structure which a person skilled in the art can easily implement from a well-known technique.

A pharmaceutical composition comprising Mirabegron or a pharmaceutically acceptable salt thereof, which has an anti-obesity action and an antihyperlipidemic effect and is known as a drug useful for treating diabetes and the treatment of overactive bladder, has a commercially available beta Likewise, it is used as a sustained release preparation using PEO as a sustained release agent. However, when PEO is a sustained release agent, dissolution collapse of the drug may occur due to photolysis and oxidation during the stability period, a problem that the drug may exist in a semisolid form at room temperature, and even a part of the PEO may be removed under high temperature conditions. There is a problem that the phase can be changed into a liquid phase. In order to solve this problem, the present inventors are more stable in the pharmaceutical composition comprising a mirabegron or a pharmaceutically acceptable salt thereof by using a combination of a polymer material forming a hydrogel as a sustained release agent and a gum. Release control is possible, and furthermore, it was found that the influence of the storage conditions and the packaging container can be reduced to complete the present invention.

In the present invention, the term "release control pharmaceutical composition" means a dissolution test under conditions of 100 rpm paddle rotation using 900 mL of a pH 6.8 phosphate buffer solution according to the US Pharmacopeia Elution Test Method 2 (paddle method). Means an agent having a dissolution rate of 25% or less from the formulation after 1 hour from the start of the test, 50 to 70% after 4 hours, and 75% or more after 6 hours.

According to the present invention, there is provided a controlled release pharmaceutical composition comprising a mirabegron or a pharmaceutically acceptable salt thereof and a sustained release agent.

In the present invention, Mirabegron (chemical name: (R) -2- (2-aminothiazol-4-yl) -4 '-{2-[(2-hydroxy-2-phenylethyl) amino] ethyl } Acetanilide) is represented by the following structural formula.

[Formula 2]

Mirabegron, in addition to embodiments of the vitreous that do not have salts, in other embodiments forms salts with acids. Such salts include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, or formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, And acid addition salts with organic acids such as tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid and glutamic acid.

The dosage of Mirabegron is appropriately determined depending on the individual case in consideration of symptoms, age, sex, etc. of the subject, but in the case of oral administration, it is usually 0.01 mg / kg or more and 100 mg / kg or less per adult. Administration is performed once or divided into two to four times.

The blending amount per formulation of Mirabegron or its pharmaceutically acceptable salt is, for example, 1% by weight or more and 70% by weight or less, preferably 5% by weight or more and 70% by weight or less, and more preferably 5% by weight. It is more than 50 weight%.

In the present invention, as a sustained-release agent, a combination of a polymer material forming a hydrogel and a gum is used so that the release rate of the mirabegron drug can be controlled to such an extent that the blood concentration profile of the drug is not affected by dietary intake or not. It is preferable. As a sustained-release agent, when using a high molecular substance that forms a hydrogel based on hydroxypropylmethylcellulose (HPMC) or the like, there is a problem that initial dissolution of the drug is likely to occur. The occurrence of initial dissolution collapse can be suppressed. In addition, by using the gum in this manner, it is also possible to suppress the change in hardness under high temperature storage, which is a disadvantage of the sustained release agent capable of exhibiting zero emission such as PEO.

In addition, the polymer material forming the hydrogel preferably has a 2% aqueous solution viscosity of 50 to 1500 mPa · s at 20 ° C., more preferably 50 to 1000 mPa · s, and is 50 to 500 mPa · s. Most preferred. The controlled release pharmaceutical composition of the present invention can suppress the occurrence of the initial dissolution collapse of a drug by using a polymer material forming a hydrogel having a viscosity within the above range with a gum, and also suppresses the hardness change under high temperature storage. can do.

Moreover, even if the viscosity of the high molecular substance which forms a hydrogel does not fall into the predetermined viscosity range in this invention, when combining several types and mixing, when measuring viscosity before use and showing the viscosity within the said range, it is suitable. It can also be used in combination.

Furthermore, the polymer material forming the hydrogel constituting the sustained release agent according to the present invention is preferably 27 to 57% by weight, more preferably 30 to 55% by weight based on the total weight of the pharmaceutical composition. The gum is preferably 0.5 to 5% by weight, more preferably 1 to 4% by weight based on the total weight of the pharmaceutical composition. By including the high molecular weight and the gum forming the hydrogel in the above range with respect to the total weight of the pharmaceutical composition, it is possible to suppress the occurrence of the initial dissolution of the drug, to achieve the desired zero-order release, under high temperature storage The change in hardness can also be suppressed. By securing the zero-order release behavior, it is expected that blood concentration in the body can be properly maintained, thereby minimizing side effects of patients.

Although it does not restrict | limit especially as a polymeric material which forms the hydrogel contained in the slow-release agent which concerns on this invention, For example, in the group which consists of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, and hydroxyethyl cellulose. At least 1 sort (s) selected can be mentioned, Especially, hydroxypropyl methylcellulose and hydroxypropyl cellulose are preferable, and hydroxypropyl methyl cellulose is especially preferable.

Although it is not limited as hydroxypropyl methyl cellulose (HPMC) if it is the said viscosity range, As a specific example, Metolose 60SH-50 (brand name, the Shin-Etsu Chemical Co., Ltd. make) (the viscosity of 2% aqueous solution in 20 degreeC) : About 50 mPa · s), Metolose 65SH-50 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C .: about 50 mPa · s), metolose 90SH-100 ( (Trade name, the Shin-Etsu Chemical Co., Ltd. make) (the viscosity of the 2% aqueous solution in 20 degreeC: about 100 mPa * s), the Metolose 90SH-100SR (brand name, the Shin-Etsu Chemical Co., Ltd. make) (20 Viscosity of a 2% aqueous solution at 0 ° C .: about 100 mPa · s, Metolose 65SH-400 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of a 2% aqueous solution at 20 ° C .: about 400 mPa · s) ), Metolose 90SH-400 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C .: about 400 mPa · s), metolose 65SH-1500 (trade name, Shin-Etsu Chemical Co., Ltd.) Kogyo Co., Ltd.) (20 ° C 2% aqueous solution viscosity of the stand: and the like and about 1500 mPa s).

As hydroxypropyl cellulose, HPC-M (brand name, the Nippon Soda Co., Ltd. product) (the viscosity of 2% aqueous solution in 20 degreeC: 150-400 mPa * s) etc. are mentioned, for example.

The gum according to the present invention is not particularly limited as long as the sustained release agent can control the release rate of the Mirabegron drug to such an extent that the blood concentration profile of the drug is not affected by dietary intake. It is preferable to use a gum which does not have a large influence of the viscosity. Specific examples include one or more gums selected from the group consisting of xanthan gum, locust bean gum, gum arabic and carrageenan. Among them, xanthan gum or locust bean gum is preferred, and xanthan gum is particularly preferred.

The controlled release pharmaceutical composition according to the present invention may further include a pharmaceutically acceptable excipient as necessary. Examples of such pharmaceutically acceptable excipients include microcrystalline cellulose, starch, gelatinized starch, talc, titanium oxide, calcium phosphate and calcium carbonate as insoluble excipients, and propylene glycol alginate (PG Alginate), Polyoxyl 40 stearate (PEG-40 stearate), glycol monostearate (GMS), polyethyleneglycol (PEG), etc. are mentioned. Such pharmaceutically acceptable excipients do not limit water-soluble or insoluble excipients, but the amount of water required to dissolve 1 g preferably exhibits solubility of 1 L or higher, and the amount of water required to dissolve 1 g of solubility of 1.2 L or higher More preferably.

Insoluble excipients can serve as a nucleus to hold the two substances more firmly between the polymer and the gum forming the hydrogel used as a sustained release agent, and have better gel strength after gelling than when water-soluble excipients are used. Therefore, it is possible to reduce the effects of food erosion at the time of taking, it is possible to reduce the difference in the rate of postprandial absorption of the drug.

The pharmaceutically acceptable excipient included in the controlled release pharmaceutical composition according to the present invention may be included in an amount of 25 to 50% by weight based on the total weight of the pharmaceutical composition, and any of water-soluble excipients or insoluble excipients may be used. When using a water-soluble excipient, it is preferable to use the usage-amount about 30 to 80 weight% of an insoluble excipient.

The controlled release pharmaceutical composition according to the present invention comprises, based on the total weight of the pharmaceutical composition, 7 to 25% by weight of Mirabegron or a pharmaceutically acceptable salt thereof, 30 to 60% by weight of a sustained release agent, and a pharmaceutically acceptable excipient. It is preferred to include 25 to 50% by weight.

The controlled release pharmaceutical composition according to the present invention may further include any pharmaceutically acceptable ingredient as necessary. Examples of the optional component include binders, lubricants, antioxidants, coating bases, and the like.

As a binder, hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), etc. are mentioned, for example. The binder may be present in an amount from 0% to 40% by weight relative to the total weight of the pharmaceutical composition.

Examples of the lubricant include talc, magnesium stearate (Mg.St.) calcium stearate (Ca.St.), hydrogenated castor oil, talc powder, solid polyethylene glycol, and the like, but are not limited thereto. Glidants can be present in amounts of 0.1% to 5% by weight relative to the total weight of the pharmaceutical composition.

As antioxidant, For example, dibutylhydroxytoluene (BHT), propyl gallate (PG), butylhydroxyanisole (BHA), ascorbic acid, sodium ascorbate, erythorbic acid, sodium nitrite, sodium hydrogen sulfite, pyrothiane Sodium sulfate, and the like, but is not limited thereto.

The coating base is not particularly limited, and known coating bases such as PVA-based coating bases and HPMC-based coating bases may be used, and specific examples thereof include Kollicoat IR and Opadry II 85F grade.

The formulation of the controlled release pharmaceutical composition of the present invention may be, for example, tablets or capsules, and specifically, oral complex tablets, drug coated tablets, bilayer tablets, inner core tablets, etc. together with solifenacin and tamsulosin. It may be designed as a dosage form for administration.

The controlled release pharmaceutical composition according to the present invention can be prepared by known manufacturing methods such as, for example, a direct tableting process, dry granulation (compacting), wet granulation (high shear assembly, fluid bed granulation). Through the input of raw materials for each step of manufacturing, it does not show a difference in products according to the manufacturing method, but it is preferable to proceed directly to tableting or dry granules from the viewpoint of production convenience.

When the controlled release pharmaceutical composition according to the present invention is prepared by a direct tableting process, Mirabegron or a pharmaceutically acceptable salt thereof, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose and hydroxyethyl A polymer material forming at least one hydrogel selected from the group consisting of cellulose, at least one gum selected from the group consisting of xanthan gum, locust bean gum, gum arabic and carrageenan, and a pharmaceutically acceptable excipient Can be mixed, compressed, molded and manufactured. At this time, the polymer material forming the hydrogel and the gum are added at 30 to 60% by weight based on the total weight of the pharmaceutical composition, and the pharmaceutically acceptable excipient is 25 to 50% by weight based on the total weight of the pharmaceutical composition. It is preferable to add. Furthermore, after the mixing step, it is preferable to further add a lubricant and finally mix, compress and tablet.

The tableting device is not particularly limited as long as it is a device in which a compression molded product is usually produced in a pharmaceutical form, and a known tableting device can be used, such as a rotary tableting machine, a single tableting machine, and the like.

When the controlled release pharmaceutical composition according to the present invention is prepared by a dry granulation or wet granulation process, the influence of the process on the medicament can be minimized by adjusting the order of addition of excipients. For example, in the dry granulation process (compacting process), after the first mixing of the mirabegron and the pharmaceutically acceptable excipients, binders, glidants, if necessary, after the compacted granules are established It is preferable to prepare a medicament by adding a sustained-release agent and an antioxidant as necessary and mixing it secondly. In addition, in the wet granulation step, the mirabegron and the pharmaceutically acceptable excipient are mixed firstly, a binder liquid (a liquid containing a binder or purified water) is added to prepare wet granules, and the granules thus prepared are established. Later, the sustained-release agent may be mixed to prepare the drug sequentially. At this time, antioxidants, lubricants or other stabilizers may be added together as necessary. For uniform distribution of the antioxidant and stabilizer, it may be prepared by dissolving in the binder solution, or may be added by mixing in the step of mixing the sustained release agent. Furthermore, after the said secondary mixing process, you may further add a lubricant as needed. Detailed preparation of the controlled release pharmaceutical composition according to the invention is shown in FIG. 1.

The granulation device is not particularly limited as long as it can produce the controlled release pharmaceutical composition according to the present invention. Examples thereof include a fluidized bed granulator, a dry granulation device, and the like.

As long as a granulated material is also established as a sizing process and an apparatus, a well-known apparatus, such as a sieve and a wet dry sizer, can be used on the conditions which a granulated material is established to a desired size, without a restriction | limiting.

Example

Below, this invention is demonstrated concretely by an Example and a comparative example. However, the following Examples and Comparative Examples are only for illustrating the present invention, the present invention is not limited by the following Examples. In addition, it will be apparent to those skilled in the art that modifications and variations can be made without departing from the spirit of the present invention.

Example 1

50 g of Mirabegron, 80 g of Hypromellose (HPMC) 2910 (50 cPs), 10 g of xanthan gum, 115 g of microcrystalline cellulose (MCC) and 5 g of magnesium stearate (Mg.St.) are mixed well, By direct tableting process, controlled release pharmaceutical compositions were obtained. Using the prepared controlled release pharmaceutical composition, the following dissolution test was conducted.

Examples 2-8

With the composition as shown in Table 1, the release control pharmaceutical composition was obtained in the same manner as in Example 1. Using the prepared controlled release pharmaceutical composition, the following dissolution test was conducted.

Examples 9-16

With the composition shown in Table 2, it carried out similarly to Example 1, and obtained the release control pharmaceutical composition. Using the prepared controlled release pharmaceutical composition, the following dissolution test was conducted.

Comparative Examples 1 to 7

Comparative Example 1 represents a commercial betmiga sustained-release tablet, and Comparative Examples 2 to 7 have the composition as shown in Table 3 below, similarly to Example 1 to obtain a pharmaceutical composition. Using the prepared pharmaceutical composition, the following dissolution test, stability test, and light stability evaluation were performed.

Example 3-1 to 3-4

In Examples 3-1 to 3-4, the pharmaceutical composition having the composition of Example 3 was directly compressed into a tableting process (Example 3-1), a compacting process (Example 3-2), and a fluidized bed granulation process (Example 3-3), a high shear mixed granulation process (Example 3-4). The prepared granules were compressed to 8-15 kp using an autotap tablet press after the final mixing process. Using the prepared controlled release pharmaceutical composition, the following dissolution test, stability test, and light stability evaluation were performed.

Examples 17-20 and Comparative Example 8

Examples 17-20 were prepared by the controlled release pharmaceutical composition prepared in Example 3-2, respectively, in HDPE bottles (Example 17), PVC-Al (Example 18), and Al-Al blister (Example 19). It was packaged in a medicine wrapping paper (Example 20). In Comparative Example 8, the pharmaceutical composition prepared in Comparative Example 6 was packaged with a drug wrapping paper. With these packaged pharmaceutical compositions, stability tests were conducted.

Dissolution Experiment 1

For Examples 1, 4, 5, 8, and Examples 3-1 to 3-4 and Comparative Examples 1 to 6, the dissolution test was conducted according to the US Pharmacopeia Elution Test 2 Method (paddle method). As a test solution, 900 mL of pH 6.8 phosphate buffer was used, and it evaluated using the sinker at the conditions of the paddle rotation speed 100 rpm at 37 degreeC. The results are shown in Table 4 and FIG. 2.

As shown in FIG. 2, it was confirmed that Examples 1, 4, and 3-1 exhibited zero order emission similar to that of Comparative Example 1 (commercially available beta is sustained-release tablet). In addition, from the results of Comparative Examples 2 and 3, it can be seen that the initial dissolution collapse of the drug occurred when only HPMC having a high viscosity was used without using gum. Furthermore, from the results of Comparative Examples 4 and 5, when the xanthan gum was used in combination with HPMC of high viscosity grade, zero-order emission was seen, but it was found that the final dissolution rate of the desired degree was not obtained. As such, it can be seen that early dissolution disintegration of the drug can be prevented when the polymer material forming the hydrogel and the gum are used together as the sustained release agent.

Dissolution Test 2

In Example 1, 2, 9, 13, 15, and the comparative example 1, the dissolution test was advanced according to the US Pharmacopeia Elution Test 2 method (paddle method). As the test solution, 900 mL of a pH 6.8 phosphate buffer was used and evaluated using a sinker under conditions of a paddle rotation speed of 200 rpm at 37 ° C. The results are shown in Table 5 and FIG. 3.

As shown in FIG. 3, it turns out that Examples 9, 13, and 15 also show the elution pattern (zero order emission) of the grade similar to Example 1, 2, and Comparative Example 1. FIG. These results show that HPMC having a viscosity range of 50 to 400 cPs and zero-tans release regardless of the type of excipient when xanthan gum is used at a specific weight percentage.

Dissolution Test 3

About Example 1 and Comparative Examples 1 and 7, the dissolution test was conducted according to the US Pharmacopeia Elution Test 2 method (paddle method). As the test solution, 900 mL of pH3.0 citric acid buffer was used and evaluated using a sinker under conditions of paddle rotational speed of 100 rpm at 37 ° C. The results are shown in FIG. 4.

As shown in FIG. 4, in the case of Example 1 using xanthan gum, the dissolution pattern (0th order release) similar to that of Comparative Example 1 was observed even in pH 3.0 citric acid buffer, but the early dissolution was faster than that of Comparative Example 7 using guar gum. You can see that. This is presumed to be due to the property of guar gum to decrease viscosity at low pH conditions of 3.5 or less, using gums such as xanthan gum, locust bean gum, gum arabic, carrageenan, etc. In this case, it can be seen that the dissolution of the drug can be more stably controlled.

Stability test

For Example 20, Comparative Examples 1 and 8, after storage for 6 hours at 40 ℃ / 75% RH, 60 ℃, 70 ℃, 80 ℃ in consideration of harsh storage conditions, such as when stored in a car in the summer, 2 at room temperature After leaving for time, the hardness change was confirmed, respectively. The results are shown in Table 6 below. In addition, in FIG. 5, the change of the property after 6-hour storage at 80 degreeC with an initial sample was visually confirmed.

As a result of storage at a high temperature, Example 20 (release controlled pharmaceutical composition of Example 3-2 using HPMC and xanthan gum as a sustained release agent) did not change the hardness according to the high temperature storage, but compared with using PEO as a sustained release agent For Example 1, and Comparative Example 8 (pharmaceutical composition of Comparative Example 6) it can be seen that the hardness increases during high temperature storage. It is assumed that the melting point of PEO is a maximum of 67 ° C., and it becomes harder (hardened) by filling the voids between the excipients while melting at high temperature. In addition, as shown in FIG. 5, as a result of visually confirming the change in the properties of the initial sample of Comparative Example 6 and the sample after storage at 80 ° C. for 6 hours, it was confirmed that the initial sample was composed of fine opaque white particles, but was stored at 80 ° C. It is evident that the sample is a translucent white with a slight increase in the size of the granules. Furthermore, the dissolution results are shown in Table 7 below.

As a result of the dissolution test, both Example 20 and Comparative Example 8 used a packaging material (medicine wrapping paper) that was very vulnerable to water permeation under high temperature / high humidity conditions (40 ° C./75% RH), but a large change in dissolution rate was observed when exposed for a short time. You can see that there is no. On the other hand, in the condition of 80 ℃ still no big change in the case of Example 20, in Comparative Example 7 it can be seen that even if a short exposure to 80 ℃ initial dissolution rate shows a large change.

Optical stability evaluation

The tablets of Example 3-2 and Comparative Example 6 were irradiated at 1.2 million Lux hr using an optical chamber, and then the dissolution test was carried out according to the test method of Dissolution Test 1. The change rate (after initial sample → 1.2 million Luxhr irradiation) of the dissolution rate after 1 hour and 4 hours passed is shown in Table 8 below.

As a result of the dissolution test on the sample irradiated with light, when HPMC and xanthan gum were used as a sustained release agent, the effect of the light of the drug had little effect, but when PEO was used as in Comparative Example 6, after 1 hour, after 4 hours After all, the rate of change of about 15% compared to the dissolution rate of the initial sample (no light irradiation). Therefore, in the case of the controlled release pharmaceutical composition according to the present invention, it can be seen that a stable dissolution rate can be obtained without a light-shielding coating using an inorganic dye or an inorganic substance.

Claims (13)

A controlled release pharmaceutical composition comprising Mirabegron or a pharmaceutically acceptable salt thereof, and a sustained release agent,
The sustained release agent is a release control pharmaceutical composition, which uses a combination of a polymer material and a gum to form a hydrogel. The method of claim 1,
Release control pharmaceutical composition, characterized in that the viscosity of 2% by weight aqueous solution at 20 ℃ of the polymer material forming the hydrogel is 50 ~ 1500 mPa · s. The method of claim 1,
The polymer material forming the hydrogel is 27 to 57% by weight based on the total weight of the pharmaceutical composition,
Wherein said gum comprises 0.5 to 5% by weight, relative to the total weight of the pharmaceutical composition. The method of claim 1,
The polymer substance forming the hydrogel is at least one member selected from the group consisting of hydroxypropyl methyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, and hydroxyethyl cellulose. The method of claim 1,
Wherein said gum is at least one gum selected from the group consisting of xanthan gum, locust bean gum, gum arabic, and carrageenan, controlled release pharmaceutical composition. The method of claim 1,
The controlled release agent is characterized in that the hydroxypropyl methyl cellulose and xanthan gum or locust bean gum in combination. The method according to any one of claims 1 to 6,
A controlled release pharmaceutical composition, further comprising a pharmaceutically acceptable excipient. The method of claim 7, wherein
To the total weight of the pharmaceutical composition, it comprises 7 to 25% by weight of Mirabegron or a pharmaceutically acceptable salt thereof, 30 to 60% by weight of a sustained release agent, 25 to 50% by weight of a pharmaceutically acceptable excipient Controlled release pharmaceutical composition. The method of claim 7, wherein
Wherein the amount of water needed for the pharmaceutically acceptable excipient to dissolve 1 g represents at least 1 L solubility. The method of claim 7, wherein
Wherein said pharmaceutically acceptable excipient is selected from the group consisting of microcrystalline cellulose, magnesium stearate, starch, gelatinized starch, talc, titanium oxide, calcium phosphate and calcium carbonate. Miravegron or a pharmaceutically acceptable salt thereof,
30 to 60% by weight of the polymer material forming the hydrogel and the gums based on the total weight of the pharmaceutical composition, and
A process for preparing a controlled release pharmaceutical composition, comprising admixing 25 to 50 weight percent of a pharmaceutically acceptable excipient with respect to the total weight of the pharmaceutical composition. Granules are prepared by first mixing Mirabegron or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable excipient,
After the granules are established, a method of preparing a controlled release pharmaceutical composition comprising the step of secondary mixing the sustained release agent. The method according to claim 11 or 12,
After said process, further comprising adding a glidant and finally mixing.

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