KR20170088783A - Wetgranulation composition containing mirabegron - Google Patents

Abstract

The present invention relates to a formulation comprising a uniform granule made by using mirabegron and polyethylene oxide, a silicate compound, and to a manufacturing method thereof. When manufacturing the mirabegron and polyethylene oxide as granules according to the prior art, irregularly uneven deformation flakes, thread shapes, and the like were formed, and it was found that it was impossible to manufacture granules having uniform quality. However, it has been surprisingly found that when a silicate compound is used in the production of granules, it is possible to produce granules having uniform properties and contents, and thus a formulation having uniform quality can be manufactured.

Description

[0001] WET GRANULATION COMPOSITION CONTAINING MIRABEGRON [0002]

Drugs are generally prepared using granules containing active pharmaceutical ingredients, although these may vary depending on the classification of the form of the solid, semi-solid or liquid formulations. The reason for this is that, even in the case of mass production, the uniformity and quality of the drug product are required to be maintained, and it is important to secure the density and fluidity of the drug powder, and from this point of view, it is a considerable advantage to formulate the drug into granules. For example, the tablet may be prepared by tableting the granules containing the drug, the capsule may be filled with the capsule containing the drug, and the granules may be prepared by packing the dispersed granules containing the drug.

The present invention relates to granules of mirabegron. Specifically, the present invention relates to granules suitable for the preparation of sustained-release preparations of mirabegron.

Mirabegron is a drug that selectively acts on the? 3-adrenergic receptor and is used in the treatment of overactive bladder (see KR10-0606568, KR10-0967070).

Mirabegron has been shown to have effects on dietary development during the formulation process and development of a sustained-release formulation is essential to minimize this effect (see KR10-1524164).

In the development of the sustained release agent, the composition was prepared by combining a hydrophilic agent containing polyethylene glycol having a solubility of 200 mg / mL or more for penetration of water into the preparation and a polyethylene oxide forming a hydrogel having a molecular weight of 2,000,000 or more (See KR10-0507400).

For reference, polyethylene glycol and polyethylene oxide, which are polymers used to develop a sustained-release preparation with minimized dietary effects of mirabegron, are classified according to the same parent structure or molecular weight. In the case of less than 100,000, polyethylene glycol And polyethylene oxide (hereinafter referred to as "polyethylene oxide"). Thus, in the present specification, the term "polyethylene oxide" means a polymer having a molecular weight of 100,000 or more.

Korean Patent Registration No. 10-0606568 Korean Registered Patent No. 10-0967070 Korean Registered Patent No. 10-1524164 Korean Patent Publication No. 10-0507400 Korean Patent Publication No. 10-0161394

According to the results of experiments conducted by the present inventors, the combination of mirabegron and polyethylene oxide employed in the prior art described above for the sustained release of mirabegron has shown limitations in the manufacturing process. Specifically, when granules were prepared by blending polyethylene oxide having a molecular weight of 100,000 or more with mirabegron, the following serious problems occurred. Particularly, the following phenomenon became more severe when a high-shear mixer was used in the production of granules or when the molecular weight of polyethylene oxide was less than 2,000,000.

In the high shear mixer, polyethylene oxide and mirabegron were used to produce a very large, nonuniform uneven agglomerate in the form of yarn or flakes, and the resulting agglomerates were irreversibly mixed with finished drug Making subsequent processing for fabrication impossible. Therefore, in order to carry out the subsequent process based on the prior art idea, it is necessary to remove the uneven agglomerate separately from the sieve, and as a result, the recovery rate is low and the homogeneity of the drug is remarkably decreased, .

Particularly, when granules having such a low recovery rate and low uniformity are produced, the risk is extremely high in terms of safety, efficacy, and economy as a finished drug, and therefore improvement is necessarily required.

The cause of the formation of such uneven agglomerates is not clear, but it is presumed that they are formed by the interaction of the drug with the polyethylene oxide during the physical mixing process.

KR 10-0161394 also recognizes that it is very difficult to carry out the granulation by using polyethylene oxide which is water-soluble thermoplastic resin of white powder or granular form having a molecular weight of several hundred thousand to several millions. Particularly, when the direct method or the dry granulation method is used, loss of the content and uniformity due to scattering of the drug may be reduced, and when the wet granulation using water, a nonuniform thread type Lt; RTI ID = 0.0 > of < / RTI > In order to avoid such problems, wet granules are produced using an organic solvent. However, in this case, there is a concern about safety and stability due to organic solvents.

The present inventors have struggled to overcome the new granules of Mirabegron that can overcome the limitations of the prior art. Specifically, it has been recognized that non-uniform agglomerates are formed in the production of controlled release formulations using mirabegron and polyethylene oxide. Particularly when a high shear mixer is used, or when the molecular weight of polyethylene oxide is less than 2 million, And it has been found that by preventing the phenomenon, it is possible to manufacture a stable and uniform granule.

That is, the present invention relates to a method for producing a sustained-release oral pharmaceutical preparation comprising mirabegron and polyethylene oxide, which can be used in the production of granules suitable for the production of finished pharmaceutical products, The present invention aims to provide a novel granule capable of inhibiting the generation of uneven agglomerates and obtaining a stable and uniform mixture.

The present invention solves the above-mentioned problems by the following means.

1. A granular composition comprising mirabegron, characterized in that it comprises polyethylene oxide and a silicate compound.

2. The granule composition of 1 above, wherein the granular composition is a wet granulate.

3. The granule composition according to 1 or 2, wherein the granular composition is wet granulated using a solvent and a binder of alcohol, purified water or a mixture thereof.

4. The granule composition according to 3 above, wherein the binding agent is hypromellose or hydroxypropylcellulose.

5. A pharmaceutical sustained-release preparation comprising the granular composition according to any one of the above 1 to 3.

According to the present invention, it is possible to improve the economical efficiency of the process and the like in the production of granules suitable for the preparation of a preparation comprising mirabegron and polyethylene oxide. In particular, unlike the prior art, the granules of the present invention inhibit the production of uneven agglomerates in the process of obtaining the granules, so that it is possible to realize uniform granules without any separate sieving process. Especially, the value according to the present invention can be maximized when the wet granules of Mirabegron are formed by using a high shear mixer with less than 2 million polyethylene oxides.

And granulating the mixture of powders into agglomerates. Simply put, it is granules that make any powder larger. Making large particles in the final formulation has several advantages. The main purpose of granulating the drug together with excipients, especially in the final formulation, is to prevent separation of the flowable components and the mixed components. For example, when the tablets are tableted to prepare the desired final preparation, or when the particles are filled into vials or capsules, the amount of the particles must be quantified uniformly and reproducibly. At this time, the flowability of the particles is very important. The reason is that filling the components into the tablet die to fix the tablet or filling the components into the vial or capsule is not a manipulation by mass measurement but filling the space by taking a certain volume so as to increase the process speed reproducibly This is because the flow of each component is important.

Therefore, it is common to granulate the drug with an excipient in advance when preparing the preparation. In the preparation of a sustained-release preparation containing mirabegron as described above, the prior art first prepared granules containing mirabegron, and tried to implement the final formulation using the granules.

The present invention relates to granules of mirabegron. And more particularly to granules of Mirabegron suitable for the preparation of sustained release formulations comprising mirabegron.

Mirabegron has been shown to be effective in demonstrating the desired efficacy of implementation in a sustained release drug delivery system. The prior art utilizes polyethylene oxide for the sustained release of Mirabegron. Polyethylene oxide is a polymeric substance that forms a hydrogel, and is a typical sustained-release agent that slowly releases a drug while swelling upon contact with a digestive tract liquid and eroded. KR10-1524164 discloses a process for preparing a final preparation by granulating mirabegron with polyethylene oxide.

However, the present inventors have found that, as in the prior art, when granules are formed by combining mirabegron and polyethylene oxide, granules of undesirable properties in the form of uneven yarns or pieces are produced. This phenomenon was more frequent in high shear mixers or when the molecular weight of polyethylene oxide was less than 2 million. Since the granules have different densities when the unintended uneven granular granule is obtained, the granules are filled with the components to fix the tablet, or the components are charged into the vial or capsule. I can not. Therefore, when the final preparation is obtained according to the prior art, it is necessary to carry out a separate course for eliminating unintended non-uniform granules after granules are formed.

However, the present inventors have surprisingly found that when a silicate compound such as colloidal silicon dioxide is added to an initial granulation process of a mixture comprising mirabegron and polyethylene oxide, the production of a nonuniform thread or a mixture in the form of a piece is remarkably reduced, In addition, it has been found that very homogeneous granules are formed in the form of the granulated material, so that it is possible to easily prepare the finished product through a subsequent process.

The type of the silicate compound used in the present invention is not particularly limited, and examples thereof are as follows. At least one of magnesium aluminosilicate, calcium silicate, magnesium silicate, magnesium trisilicate hydrate, or colloidal silicon dioxide can be used .

The silicate compound used in the present invention is listed on the Generally Regarded As Safe list in the US FDA and is not particularly limited in its amount. However, in order to prevent generation of a non-uniform thread or a mixture in the form of a granule, The amount used in the preparation is preferably in the range of 0.5 to 10.0% by weight, more preferably 1.0 to 5.0% by weight, still more preferably 2.0 to 5.0% by weight, based on the total weight of the granules, 3.0 wt% is preferably used.

The blending amount of mirabegron used in the present invention is not particularly limited as long as it is an amount that can be used for pharmaceutical treatment or prevention, but is preferably 15 to 55% by weight, 30% by weight.

The amount of polyethylene oxide used in the present invention for preparing granules is not particularly limited as long as it is an amount for controlling the release of the drug from the preparation, but is preferably 25 to 80% by weight, more preferably 50 to 75% % to be. Such polyethylene oxide (hereinafter sometimes abbreviated as PEO) is not particularly limited, but polyethylene oxide having an average molecular weight of 100,000 or more and less than 2,000,000 can be used. For example, polyethylene oxide poly Ox (Polyox ^®), which WSR N-10 (molecular weight 100,000, 12 ~ 50 cps (5 % aqueous solution viscosity)), poly Ox WSR N-80 (molecular weight of 200,000 and a viscosity of 65 ~ 115 cP (5% aqueous solution)), Polyox WSR-205 (molecular weight viscosity 600,000, 4500-8800 cP (5% aqueous solution)), Polyox WSR-1105 (molecular weight 300,000, viscosity 600-1200 cP (Molecular weight: 1,000,000, viscosity: 400 to 800 cP (2% aqueous solution)), and the like can be used. Particularly, the polyethylene oxide used in the present invention may be used in combination of one or more of those having different molecular weights and grades.

In the pharmaceutical composition of the present invention, a binder may be used if necessary, and for example, hypromellose, hydroxypropylcellulose and the like are exemplified, but the present invention is not limited thereto.

The amount of binder used in the production of the granules in the present invention is not limited as long as it is an amount which allows the formation of the fine powder to be prepared at a level of, for example, 50% by weight or less in accordance with the physical properties for preparation of the finished product, 0.5 to 9.0% by weight, more preferably 1.0 to 6.0% by weight, based on water. Particularly, although not limited in the method of introducing the binder, it is possible to add the binder through a method of dissolving in a solvent, a method of adding it into a dried material without dissolving it in a solvent, and a mixing method thereof.

There is no particular limitation on the solvent that can be used in preparing the binding solution. For example, alcohol, purified water or a mixed solvent thereof may be used. Specifically, methanol, ethanol, isopropyl alcohol, purified water, The bonding liquid can be prepared by using the mixed liquid, and the mixing ratio in the mixed solvent is not particularly limited. However, in the formulation using polyethylene oxide, the use of ethanol, purified water or a mixture thereof may be more preferable in manifesting the objective effect of the present invention.

The granulation process is most commonly used as a high shear granulation method using a high shear mixer and a low shear granulation method using a low shear mixer.

The low-shear mixer includes a mechanical stirring mixer in which a container containing a powder is contained, a stirring blade is present therein, and a rotary mixer in which the container itself rotates. Generally, the low shear granulation method requires a longer drying time and longer heat exposure time because it uses a larger amount of binder solution than the high shear granulation method. In addition, it is difficult to manufacture granules of high density, and because of the disadvantage of low productivity, high shear granulation method using high shear mixer is used.

The high-shear mixer is composed of three or more impellers and choppers in a mixing vessel. The stirring blades are generally rotated at a speed of 50 to 500 rpm, So it is not limited to the above range. The separator serves as a countercurrent to granulate the mixture wetted by the solvent and is generally rotated at a speed of 500-4000 rpm, but is not limited thereto.

The granules produced through the above composition and method should be passed through additional process as required and then passed the process intermediate quality evaluation (evaluation of granule content, standard 95 ~ 105%). Here, the content of 95% to 105% of drug refers to the ratio of the remaining amount (mg) of the drug contained in the granule or the finished product to the desired drug input amount (mg).

Thereafter, an additional process such as post-mixing for preparing the final product of the medicament may be performed. The thus-prepared mixture is not limited to the formulations, but may be prepared into final formulations such as tablets, capsules or granules.

Further, the post-mixing process can be carried out by adding an appropriate amount of known additives. Since the present invention is characterized by the granules of mirabegron, suitable combinations for post-mixing are not separately described. Those parts which are not described in the present invention may employ known general techniques. For example, the granulate according to the present invention may be mixed with an additive or the like known in KR10-1524164 to form a final formulation.

Hereinafter, the present invention will be described in more detail by way of comparative examples and examples. However, it should not be construed that the present invention is construed to be construed to limit the present invention. If uniformity in granules is ensured, additional processing may be performed depending on the purpose.

Colloidal silicon dioxide, hydroxypropylcellulose, purified water and ethanol were mixed in a high shear mixer under conditions of stirring blades and sieves of 170, 3500 rpm, and sieved with 10 mesh sieves to confirm the agglomerates. The agglomerates were then dried in a flat drier at 40 ° C and dried to form a 30 mesh sieve, thereby evaluating the physical properties of the granules. Then, 1.0 wt% of magnesium stearate, which is a lubricant, was added and mixed to prepare tablets, and the tablets were prepared by tabletting on a rotary tablet machine. After that, the contents of the tablets and the uniformity of the preparation were evaluated.

Composition of Granular Water Ingredients Comparative Example Example Furtherance Mirabegron 23 wt% 22 wt% Polyethylene oxide 73 wt% 72 wt% Hydroxypropylcellulose 4 wt% 4 wt% Colloidal silicon dioxide - 2 wt% Total 100 wt% 100 wt% Gross weight 250 g 250 g

In order to confirm the formation of uneven agglomerates in the granulation process in the compositions of the comparative examples and the examples, 10-mesh sieves were sieved to confirm the amount remaining on the sieves, and the uniformity was confirmed by evaluating the contents of the residues. Typically, a non-uniform lump refers to a non-spherical shape of the prepared mixture granules, which has a different physical property from other mixtures. Having different physical properties from other mixtures means that irreversible properties as well as the content of the drug in the mixture are contained at different concentrations than other mixtures, resulting in problems with uniformity. Therefore, it is not meaningful to distinguish the size of the mixture using 10 mesh or 30 mesh sieve.

That is, when the content of the drug in the granule produced in the process intermediate quality evaluation is within the range of 95 to 105%, it is judged that it is suitable to proceed with the next step. After the drying process, 30 mesh sieves were sieved to confirm the remaining amount of non - uniform agglomerates, and the amount remaining in the sieve was confirmed. In order to control the size of particles required for the preparation of the finished product, 30 mesh sieves are selected for the sizing process. It does not have any special significance depending on the mesh size. When the content of granules is within 95 ~ 105% The evaluation of the content was carried out because the subsequent process was possible. In order to confirm the uniformity of the contents of the active ingredients in each formulation according to the formulation uniformity test method of the Korean Pharmacopoeia, each active ingredient content was measured and found that the content of the active ingredient in each formulation was within the acceptable range of 95 to 105% And confirmed whether it exceeded the maximum allowable limit value of 15% according to the criteria of Korea Pharmacopoeia.

Item Comparative Example Example Ten residue after granulation 21% No residue. 10 Tissue Residual Aggregate Content 113.3% - After formation 30 remaining taurine 18.3% No residue 30 Tissue Residual Aggregate Content 118.5% - 30 Tissue Size 87.7% 98.2% Refined content 85.5% 99.6% Formulation uniformity Average 85.3% 100.3% Determination value 18% 4%

The granules and the tablets obtained by preparing Comparative Examples and Examples were evaluated, and the results are as follows.

In the case of the comparative example, uneven agglomerates were overproduced, and the percentage of the unusable agglomerates that were not used after the granulation and sizing process was close to 40%, and the non-uniform agglomerates thus produced had a drug content of 110% or more. On the other hand, in the case of the intended formulation, the content of the drug is less than 90% because of the loss of the drug due to the uneven agglomerates formed during the granulation process, and the criticality of the tablet, It became a cause. In particular, it was not within the range of 95 ~ 105%, which is the basic standard of the drug composition prescribed in the Korean Pharmacopoeia, and it deviated from the maximum allowable limit value of 15% of the uniformity determination value of the drug, .

On the other hand, in the case of the examples, there was no residue due to uneven agglomeration during the granulation and sizing process, and thus all of the granules produced could be put into an additional process for producing the finished product, As a result, the drug can be used as a drug of very high quality.

Claims (5)

A granular composition comprising Mirabegron, wherein the granular composition comprises polyethylene oxide and a silicate compound. The granule composition of claim 1, wherein the granule composition is a wet granulate. The granular composition of claim 1, wherein the granular composition is wet granulated using a solvent and a binder of alcohol, purified water or a mixture thereof. The granule composition according to claim 3, wherein the binding agent is hypromellose or hydroxypropylcellulose. A pharmaceutical sustained-release preparation comprising the granular composition according to any one of claims 1 to 3.