KR20200007604A - Amorphous state of New mirabegron cocrystal or complex with improved water solubility - Google Patents

Abstract

Since polyethylene glycol, which is a hydrophilic substrate that damages mucosa in a body during a process of preparing an oral formulation due to insolubility which is a problem of mirabegron, is used, and oral absorption in small intestine is also not good, the present invention provides a mirabegron/fumaric acid, mirabegron/L-pyroglutamic acid, mirabegron/citric acid co-crystal or complex of an amorphous state having an improved water solubility, solubility or dissolution speed and dissolution rate in pH 6.8 of small intestine, and having excellent thermodynamic stability due to no phase transition to a crystalline form. The mirabegron co-crystal or complex of an amorphous state is a new solid form with an improved solubility of mirabegron, and is very useful as an optimal source medical substance which can maximize use as a drug.

Description

Amorphous state of New mirabegron cocrystal or complex with improved water solubility

The present invention is to provide a mirabegron co-crystal or a complex of amorphous form with improved poor solubility. More specifically, in the present invention, the water solubility of Mirabegron is only 0.082 mg / ml, and in order to increase the oral absorption in the preparation of oral preparations, a hydrophilic base polyethylene glycol 8000 is used. In order to improve this problem, the water solubility of Mirabegron must be increased to improve this problem, and the present inventors have improved the water solubility and solubility of small intestine pH 6.8 or more by 57 times, and the elution rate is also high. It is possible to develop oral drugs without a mechanism. In addition, the amorphous form does not phase change into a crystalline form to provide a novel amorphous form of Mirabegron co-crystal or composite having excellent thermodynamic stability.

Cocrystals form new crystal structures by combining them at regular ratios through hydrogen bonds with co-formers having rich functional groups capable of forming hydrogen bonds such as O, OH, N, etc. or pKa differences of 3 or less. It means having a crystalline solid. Since these co-crystals contain more than two molecules of compounds, they can be expressed in complex form. Since the formation of co-crystals is a crystal structure through new hydrogen bonds of two or more molecules, solubility and dissolution rate of the drug can be increased. This may change the bioavailability by changing the absorption rate of the drug in the human body. The co-molecule selection of co-crystals to overcome poor solubility must first be water-soluble molecules that are well soluble in water. If such co-molecules are not compatible with water and poorly soluble, the choice of co-molecules will not overcome the poor solubility of the drug, but will lead to a decrease in solubility. Therefore, the selection of common molecules is a very important requirement. Cocrystals include amorphous polymorphs, hydrates, and solvates.

Crystals generally have the property of precipitating metastable crystals in the course of crystallization and then transferring them to a more stable crystal structure in the solvent medium and in the solid state to maintain thermodynamic stability. Through transformation, the molecules are rearranged to form a more stable crystal structure. This creates a polymorph, which is called ostwald's rule of stage. Therefore, the physicochemical characteristics of metastable and stable crystals are changed. Thus, it causes a change in solubility that represents the thermodynamic energy of the most important crystal as a drug. The co-molecules of the co-crystals can confirm the change of the crystal structure or the presence of the crystal polymorph of the co-crystal itself through the phase transition phenomenon that is generally replaced with the solvent molecules in the solvent. Therefore, in water, the co-crystal can be phase-changed as a hydrate, which can cause a change in the solubility of the co-crystal to the solubility of the hydrate. The reason why the solubility does not improve even when the co-crystal is prepared in the poorly soluble hydrate crystal form is that the co-crystal has been phase-changed as a hydrate. Therefore, the selection of co-molecules is very important. Depending on which comolecules are used, phase transitions can be suppressed or promoted (Crystal Growth & Design (2011) 11, 887-895, Recrystallization in Materials Processing Intech: Vienna, Austria, 2015; pp. 173-74, Drug Discovery Today (2008) 13, 440-446).

The formation of cocrystals is achieved through cocrystallization. Co-crystallization methods include solvent evaporation technique, anti-solvent method, solvent drop grinding, slurry technique, solid state grinfing, etc. (Recrystallization in Materials Processing Intech: Vienna, Austria, 2015; pp. 173-74).

Amorphous refers to a solid state where molecular interactions exist but do not form a crystal array. Therefore, it has a higher energy level than the crystalline form, and solubility is higher than the crystalline form. However, due to the high energy level, the thermodynamic stability is low, so there is a problem in that the phase changes very quickly. Amorphous co-amorphous forms an amorphous solid through a new hydrogen bond between two or more molecules, which can suppress phase transition to crystalline form, and can overcome poor solubility through high solubility. In a solid state. The reason why the phase transition to the crystalline form can be suppressed is because the amorphous glass transition temperature is higher than that of the drug itself (Advanced Drug Delivery Reviews (2016) 100, 116-125). And the formation of amorphous co-crystal should be used to crystallization method to control the crystallization rate very fast to reach high supersaturation quickly. Representative methods such as reduced pressure evaporation crystallization, supercritical crystallization, liquid nitrogen crystallization, freeze evaporation crystallization, etc. are used. However, hydrogen bonds due to the interaction between drug molecules and comolecules in the formation of co-crystals are very diverse, so it is very difficult to design and control amorphous materials even with these extreme crystallization methods (From Molecules to Crystallizers An Introduction to Crystallization 2000; pp. 2-14).

Mirabegron has the chemical name (R) -2- (2-aminothiazol-4-yl) -4 '-[2-[(2-hydroxy-2-phenylethyl) Amino] ethyl] anile acetate is developed by Astellas Seiyacu. According to WO99 / 20607 and Korean Patent No. 10-0506568, the compound has both insulin secretion promoting action and insulin sensitivity enhancing action, and also has anti-obesity action and antihyperlipidemic action based on selective β3 receptor stimulation and is useful for treating diabetes. It was reported to be a compound.

[Formula 1]

The same compound can also be used as a therapeutic agent for overactive bladder in WO 2004/041276 and is useful as a therapeutic agent for overactive bladder with urinary urgency, urinary incontinence or urinary frequency, in addition to overactive bladder due to enlarged prostate, for example. have. Therefore, it is currently sold as a treatment for urination disorder under the trade name Betmiga.

The crystalline polymorph of Mirabegron is disclosed in WO 2003/037881, anhydrous crystalline form α or β. Currently, it is α type that is used as a drug substance. It is reported that the α-form is a stable crystalline form, in which hydrochloride reported in WO 2003/037881 occurs by moisture absorption in the presence of moisture, but α-form does not absorb moisture. In addition, it was reported that the crystal form is excellent in stability that does not phase with other crystal forms.

However, according to the FDA / Draft Guidance on Mirabegron Active Ingredient, Mirabegron α was reported as BCS class II with poor water solubility of 0.082 mg / ml, which is poorly absorbed. Therefore, EP 2857389 discloses acetate in an effort to this end, and bromate, tartaric acid salt, benzate salt, oxalic acid salt, and sulphate salt are disclosed in WO 2016/049749. However, these patents do not disclose the results of accurate solubility or stability.

In addition, in Patent Publication No. 10-2015-0045500, in order to improve the problem of Mirabegron α-type poor solubility, the beta is manufactured and sold in a sustained-release tablet dosage of 50 mg by adding hydrophilic polyethylene glycol 8000 to increase the water solubility during oral preparation. . However, the addition of polyethylene glycol has a problem of damaging the mucous membranes of the body, so a new solid form is required to increase the water solubility of Mirabegron.

Throughout this specification, many papers and patent documents are referenced and their citations are indicated. The disclosures of cited papers and patent documents are incorporated herein by reference in their entirety, and the level of the technical field to which the present invention belongs and the contents of the present invention are more clearly described.

The present inventors are preparing oral preparations using polyethylene glycol, a hydrophilic base having a problem of damaging the mucosal membranes due to poor solubility of Mirabegron α-type, thereby increasing the absorption rate in the body. Therefore, in order to overcome this problem, when appropriate solvents and reaction conditions are used while controlling the equivalent weight of pharmaceutically acceptable co-molecule fumaric acid, L-pyroglutamic acid, and citric acid Mirabegron / fumaric acid of Formula 2, Mirabegron / L-pyroglutamic acid of Formula 3, Mirabegron / cimaric acid of Formula 4 / citric acid) A method of producing amorphous amorphous Mirabegron co-crystals, which are hydrogen-bonded at a ratio of 1: 1, to form an amorphous form, is reproducibly produced in an excellent yield. It increases the solubility of Begron water solubility and solubility of small intestine pH 6.8 times by 57 times, eliminating the need for hydrophilic agents and increasing the dissolution rate. The present invention has been completed by identifying a novel amorphous form of co-crystal or co-formulation of Mirabegron, which is a pharmaceutically useful formulation that can overcome the problems of Mirabegron.

It is therefore an object of the present invention to provide a novel amorphous Mirabegron / fumaric acid cocrystal or combination.

It is therefore an object of the present invention to provide a novel amorphous form of Mirabegron / L-Pyroglutamic acid cocrystal or co-agent.

It is therefore an object of the present invention to provide a novel amorphous Mirabegron / citric acid co-crystal or combination.

It is another object of the present invention to provide a method of preparing the above-described amorphous form of Mirabegron / fumaric acid, Mirabegron / L-pyroglutamic acid, Mirabegron / citric acid co-crystal or composite.

Other objects and advantages of the present invention will become apparent from the following detailed description, claims and drawings.

According to an aspect of the present invention, the present invention provides an amorphous co-crystal or a combination of one molecule of Mirabegron and one molecule of fumaric acid, L-pyroglutamic acid, and citric acid.

The present inventors have used amorphous organic salts of fumaric acid, L-pyroglutamic acid, and citric acid, not basic inorganic salts, to form amorphous Mirabegron / fumaric acid, Mirabegron / L-pyroglutamic acid, Mirabegron / citric acid Cocrystals or composites were prepared.

Therefore, the present inventors have very high water solubility to prepare co-crystals having high water solubility to overcome the extreme solubility of Mirabegron, and have two or more carboxylic acids, so that the fumaric acid rich in O, OH, L- Pyroglutamic acid and citric acid were selected to design and manufacture amorphous co-crystals. Experimental optimization established a method for reproducibly producing amorphous Mirabegron co-crystals or composites. The amorphous Mirabegron co-crystals or composites prepared in this way have improved water solubility and solubility of small intestine pH by 57 times or more than the existing Mirabegron α-type, and can be sufficiently dissolved in 250 ml of water injected during oral ingestion. As a result, the polyethylene glycol 8000 used to increase the oral absorption of the Mirabegron was improved. Therefore, while the hydrophilic base of polyethylene glycol, which is a hydrophilic base that can damage the mucous membrane in the preparation process due to the poor solubility of Mirabegron, is added, the amorphous form of the Mirabegron co-crystal or complex of the present invention does not require the addition of a hydrophilic base. It is possible to improve the oral absorption by improving the solubility of Mirabegron, and do not phase change into a crystalline form is excellent thermodynamic stability. Therefore, when the co-crystal or a combination of Mirabegron / fumaric acid, Mirabegron / L-pyroglutamic acid, Mirabegron / citric acid amorphous form of the present invention is used, it is suitable to be used as an improved new drug which improves the solubility of Mirabegron. Do.

According to one embodiment of the invention, the amorphous form of the Mirabegron / fumaric acid co-crystals or complex is a compound represented by the following formula (2):

In the formula, the dotted line represents a hydrogen bond.

In the amorphous form of the Mirabegron / fumaric acid co-crystal or complexing agent as shown in Formula 2, one molecule of the Mirabegron and one molecule of fumaric acid forms a co-crystal in a 1: 1 ratio by hydrogen bonding. Since fumaric acid having such a high water solubility is in an amorphous form due to hydrogen bonding with Mirabegron, the Mirabegron is also dissolved in water when phosphorus fumaric acid is dissolved by interaction with fumaric acid. Small intestine pH 6.8 increases solubility. Therefore, it can be sufficiently absorbed and dissolved in the body even without adding a hydrophilic base polyethylene glycol 8000 during oral preparation, and thus, the ease of preparation can be increased without adding a hydrophilic base.

According to one embodiment of the invention, the amorphous form of the Mirabegron / L-pyroglutamic acid co-crystal or compound is a compound represented by the following chemical room 3:

In the formula, the dotted line represents a hydrogen bond.

In the amorphous form of the Mirabegron / L-pyroglutamic acid co-crystal or the complexing agent, a one-way Mirabegron and one molecule of L-pyroglutamic acid are co-crystallized in a 1: 1 ratio by hydrogen bonding, as shown in Formula 2 above. To form. The high water solubility of L-pyroglutamic acid forms an amorphous form due to hydrogen bonding with mirabegron, and the mirabegron also dissolves in water when L-pyroglutamic acid is dissolved due to interaction with L-pyroglutamic acid. As a result, the solubility in water and the solubility of small intestine pH 6.8 are increased. Therefore, it can be sufficiently absorbed and dissolved in the body even without adding a hydrophilic base polyethylene glycol 8000 during oral preparation, and thus, the ease of preparation can be increased without adding a hydrophilic base.

According to one embodiment of the invention, the amorphous form of the Mirabegron / citric acid co-crystal or complex is a compound represented by the following formula (4):

In the formula, the dotted line represents a hydrogen bond.

Mirabegron / citric acid co-crystal or complex of the amorphous form of Formula 4 forms a co-crystal in a 1: 1 ratio of one molecule of Mirabegron and one molecule of citric acid by hydrogen bonding as shown in the formula (2). Since citric acid having such a high water solubility is in an amorphous form due to hydrogen bonding with Mirabegron, the Mirabegron also dissolves in water when phosphoric acid is dissolved by interaction with citric acid. Small intestine pH 6.8 increases solubility. Therefore, it can be sufficiently absorbed and dissolved in the body even without the addition of the hydrophilic polyethylene glypol 8000 during the preparation of oral preparations, so that the ease of preparation can be increased without adding a hydrophilic base.

Therefore, the solubility in water and small intestine pH 6.8 increased 57 times as compared to Mirabegron, solubilized in 250 ml of water, so that the solubility was increased so that the hydrophilic base polyethylene glycol 8000 was not used. This not only increases the oral absorption of Mirabegron, but also overcomes the poor solubility of Mirabegron, and does not require the addition of polyethylene glycol 8000, a hydrophilic base that can damage the mucous membranes of the body. It is an appropriate form that can be enhanced to have an optimized form, the amorphous form of the present invention Mirabegron / fumaric acid, Mirabegron / L- pyroglutamic acid, Mirabegron / citric acid co-crystals or complexes are reported anywhere Bar is a novel solid form.

According to an embodiment of the present invention, the amorphous mirabegron / fumaric acid cocrystal or composite agent exhibits an amorphous form with a 2θ diffraction angle in X-ray diffraction (PXRD) analysis, and solid state carbon nuclear magnetic resonance spectroscopy (solid state) CP / MAS ¹³ C-NMR) Spectrum 31.74 ppm, 37.35 ppm, 38.69 ppm, 50.02 ppm, 69.46 ppm, 104.23 ppm, 119.37 ppm, 128.16 ppm, 136.59 ppm, 170.12 ppm to show the change in hydrogen bond, Hydrogen nuclear magnetic resonance spectroscopy ( ¹ H-NMR) is an amorphous co-crystal or complex with a molecular weight of 1: 1 formed through characteristic peaks at 6.29 ppm and 6.52 ppm.

According to an embodiment of the present invention, the amorphous Mirabegron / L-pyroglutamic acid co-crystal or composite agent exhibits an amorphous form of 2θ diffraction angle in X-ray diffraction (PXRD) analysis, and solid-state carbon nuclear magnetic resonance spectroscopy ( solid state CP / MAS ¹³ C-NMR) Spectrum 25.43 ppm, 30.07 ppm, 39.50 ppm, 48.83 ppm, 57.82 ppm, 68.99 ppm, 103.32 ppm, 119.59 ppm, 127.98 ppm, 137.89 ppm, 144.48 ppm, 169.51 ppm, 178.79 ppm The characteristic peaks indicate the change of hydrogen bonds, and the ratio of molecules is 1: 1 by the characteristic peaks shown at 3.89 ppm, 3.90 ppm, 3.91 ppm, and 6.29 ppm of hydrogen nuclear magnetic resonance spectroscopy ( ¹ H-NMR) spectrum In amorphous form.

According to an embodiment of the present invention, the amorphous Mirabegron / citric acid cocrystal or composite agent exhibits a 2θ diffraction angle in an amorphous form in X-ray diffraction (PXRD) analysis, and solid state carbon nuclear magnetic resonance spectroscopy (solid state) CP / MAS ¹³ C-NMR) Spectrum 31.68 ppm, 46.19 ppm, 69.21 ppm, 74.26 ppm, 104.31 ppm, 119.05 ppm, 128.33 ppm, 135.12 ppm, 170.18 ppm, 178.41 ppm to show the change in hydrogen bond, Hydrogen nuclear magnetic resonance spectroscopy ( ¹ H-NMR) is an amorphous co-crystal or complex with a 1: 1 ratio of its molecules through characteristic peaks represented at 2.57 ppm, 2.59 ppm, and 6.29 ppm.

According to another aspect of the present invention, the present invention provides a method for preparing an amorphous form of Mirabegron / fumaric acid, Mirabegron / L-pyroglutamic acid, Mirabegron / citric acid co-crystal or a composite comprising the following steps do.

(a) mixing the Mirabegron and the organic solvent and adding fumaric acid, L-pyroglutamic acid and citric acid, respectively;

(b) heating and refluxing the product of step (a);

(c) cooling and stirring the resultant of step (b);

(d) evaporating half of the solvent of step (c); And

(e) vacuum drying the resultant of step (d) to obtain amorphous Mirabegron / fumaric acid, Mirabegron / L-pyroglutamic acid, Mirabegron / citric acid co-crystals or complex crystals.

The inventors of the present invention have prepared a novel crystalline co-crystal and a complex of pharmaceutically useful amorphous form of Mirabegron. Established a method that can be produced in yield. This method is called solvent evaporation during cocrystallization.

The method of the present invention is the Mirabegron / fumaric acid of the amorphous form of the present invention described above. Since the preparation of Mirabegron / L-pyroglutamic acid, Mirabegron / citric acid co-crystals or complexes, common content between the two is omitted to avoid excessive complexity of the specification according to the repeated description. .

Hereinafter, a detailed description of the method of the present invention for preparing the amorphous form of Mirabegron / fumaric acid, Mirabegron / L-pyroglutamic acid, Mirabegron / citric acid co-crystal or co-formulation is as follows;

(a) Mirabegron and organic solvent mixture and addition of fumaric acid, L-pyroglutamic acid and citric acid

First, the process of the present invention comprises the step of mixing the solid powder of the mirabegron and the organic solvent and adding fumaric acid, L-pyroglutamic acid, and citric acid, respectively.

According to one embodiment of the present invention, the mirabegron of step (a) is added at 1-30 (w / v)% based on the volume of the organic solvent, more preferably 6-25 (w / v) %, Still more preferably 10-20 (w / v)%.

In the preparation of the amorphous form of Mirabegron / fumaric acid, Mirabegron / L-pyroglutamic acid, Mirabegron / citric acid co-crystals or composites in a high yield in the amorphous form of Mirabegron / fumaric acid, Mirabegron / Organic solvents that produce L-pyroglutamic acid, Mirabegron / citric acid co-crystals or complexes and are proven to be effective solvents for the removal of fumaric acid, L-pyroglutamic acid and citric acid used in excess are preferably methanol, ethanol At least one selected from organic solvents consisting of isopropyl alcohol, acetone, tetrahydrofuran, dimethyl acetamide, dimethyl sulfoxide, dimethyl formamide, chloroform, methyl ethyl ketone, ethyl acetate, methylene chloride and acetonitrile, ie A single solvent or a mixed solvent thereof is selected, more preferably methanol, ethanol, isopropyl alcohol, or acet And, most preferably methanol.

According to another embodiment of the present invention, fumaric acid, L-pyroglutamic acid and citric acid of step (a) are added in a molar ratio of 1 to 1.5 equivalents relative to Mirabegron.

It was confirmed by hydrogen nuclear magnetic resonance spectroscopy ( ¹ H-NMR) according to the equivalent of fumaric acid, the peak of the mirabegron remains only in the case of 1.1 equivalents of L-pyroglutamic acid, and a novel amorphous mirabegron. This is because / fumaric acid, Mirabegron / L-pyroglutamic acid and Mirabegron / citric acid peaks appear 1: 1.

Therefore, fumaric acid, L-pyroglutamic acid, and citric acid are preferably added in a molar ratio of 1 to 1.5 equivalents relative to Mirabegron, respectively. The amorphous Mirabegron co-crystals or complexes thus obtained are amorphous Mirabegron / fumaric acid, Mirabegron / L-pyroglutamic acid, Mirabegron / citric acid co-crystals or complexes in combination with Mirabegron. I become

According to another embodiment of the present invention, fumaric acid, L-pyroglutamic acid, and citric acid of step (a) are added to the mixed Mirabegron and the organic solvent in an amount of 1/3.

It is a mixture of the solid powder Mirabegron and fumaric acid, L-pyroglutamic acid, citric acid in the preparation of the Mirabegron / fumaric acid, Mirabegron / L- pyroglutamic acid, Mirabegron / citric acid co-crystal or composite This is because the mixing ratio of cifumaric acid, L-pyroglutamic acid, and citric acid is important in forming 1: 1 ratio with Mirabegron.

Therefore, fumaric acid, L-pyroglutamic acid, and citric acid mixed with the solid powder Mirabegron are added to each of the fumaric acid, L-pyroglutamic acid, and citric acid by 1/3 of the total mixing equivalent, respectively. It can be formed most effectively when dividing and mixing.

More preferably, each of fumaric acid, L-pyroglutamic acid and citric acid of step (a) is added to the mixed mirabegron and the organic solvent in an amount of 1/3 and added at intervals of 20 minutes.

(b) stirring the elevated temperature and reflux of the resultant

The process of the present invention is then subjected to a step of raising the temperature of the result of step (a) and stirring under reflux.

The temperature rise time of the resultant of step (a) requires adjustment of the temperature so that it takes more than 1 hour to reach the reflux temperature, and the stirring time at the reflux temperature should not exceed three hours.

According to another embodiment of the present invention, the temperature raising in step (b) is carried out for 1 hour to 3 hours.

According to another embodiment of the invention, the reflux agitation of step (b) is carried out for 1 hour to 3 hours, more preferably for 30 minutes to 2 hours, even more preferably 30 minutes to 1 hour To be carried out.

(c) cooling and stirring the resulting product

The method of the present invention then comprises cooling and stirring the product of step (b), ie the refluxed reaction solution.

According to another embodiment of the invention, the cooling in step (c) is carried out at 15-40 ℃, more preferably at a temperature of 15-30 ℃, most preferably at 15-20 ℃. .

According to another embodiment of the invention, the stirring in step (c) is carried out for 1-12 hours, more preferably for 1 to 8 hours, even more preferably for 3 to 5 hours do.

(d) evaporating and stirring the resultant

The process of the present invention then comprises stirring the product of step (c), i.e., half of the solvent of the cooled reaction solution.

According to another embodiment of the invention, the evaporation of step (d) is carried out at 30-60 ° C., more preferably at a temperature of 30-50 ° C., most preferably at 30-40 ° C. .

According to another embodiment of the invention, the stirring in step (d) is carried out for 1-12 hours, more preferably for 1 to 8 hours, even more preferably for 3 to 5 hours do.

According to another embodiment of the present invention, after the step (d) (d-1) further comprises the step of washing the resultant of the step (d) with an organic solvent after filtration under reduced pressure.

According to another embodiment of the invention, the organic solvent of the step (d-1) is methanol, ethanol, isopropyl alcohol, acetone, tetrahydrofuran, dimethyl acetamide, dimethyl sulfoxide, dimethyl formamide, chloroform, methyl ethyl At least one is selected from organic solvents consisting of ketones, ethyl acetate, methylene chloride and acetonitrile, ie a single solvent or a mixed solvent thereof is selected, more preferably methanol, ethanol, isopropyl alcohol or acetone, most preferred It is acetone.

According to another embodiment of the present invention, the organic solvent of step (c-1) is added at 1-30 (v / v)% based on the volume of the organic solvent of step (a), more preferably 1-10 (v / v)%, even more preferably 2-5 (v / v)%.

(e) vacuum drying of the resultant and the amorphous form of Mirabegron / Fumaric acid Obtaining Mirabegron / L -Pyroglutamic Acid Mirabegron / Citric Acid Cocrystal and Co-crystal

Finally, the process of the present invention is subjected to the vacuum drying of the resultant of step (e) to obtain the Mirabegron / L-pyroglutamic acid co-crystal and the composite crystal.

According to another embodiment of the invention, the vacuum drying of step (e) is carried out for 8 to 12 hours at a temperature of 30-65 ℃.

More preferably, the vacuum drying is performed at a temperature of 40-55 ° C, even more preferably at a temperature of 45-50 ° C.

Amorphous Mirabegron / fumaric acid Mirabegron / L-pyroglutamic acid Mirabegron / citric acid co-crystals or complexes obtained by vacuum drying at the temperature and time above 1% and purity is HPLC More than 99.5%.

In this way, Mirabegron's poor solubility and body can be used as a therapeutic agent for overactive bladder and used as a therapeutic agent for overactive bladder with urinary urgency, urinary incontinence or urinary frequency, in addition to overactive bladder due to enlarged prostate Mirabegron / fumaric acid, a new amorphous solid that overcomes the problems of Mirabegron by improving water solubility and small intestine pH 6.8 so that the oral preparation can be prepared without using polyethylene glycol 8000, a damaging hydrophilic base of the mucosa, Mirabegron / L-pyroglutamic acid, Mirabegron / citric acid co-crystals or composites can be prepared and prepared in the amorphous form of Mirabegron / fumaric acid, Mirabegron / L-pyroglutamic acid, Mirabegron / Sheet The lyric acid cocrystal or complex is an amorphous form in which one equivalent of Mirabegron is combined with one equivalent of fumaric acid, L-pyroglutamic acid, and citric acid. ABBE GRONLUND / Puma acid, Mira GRONLUND Entebbe / L- glutamic acid blood, the Miramar bay GRONLUND / citric acid crystals or complexes ball.

The features and advantages of the present invention are summarized as follows;

(a) The present invention is an amorphous form of Mirabegron / fumaric acid, Mirabegron / L-Pyroglutamic acid, Mira, in which one molecule of Mirabegron and one molecule of Fumaric acid, L-pyroglutamic acid, and citric acid are respectively bound Begron / citric acid co-crystals or composites and methods for making the same are provided.

(b) Mirabegron / fumaric acid, Mirabegron / L-pyroglutamic acid, Mirabegron / citric acid cocrystals or complexes of the amorphous form of the present invention are prepared in a special solvent environment through cocrystallization in the preparation of fumaric acid. , By adjusting the L-pyroglutamic acid, the equivalent of citric acid, the amount of evaporation of the stirring solvent, the evaporation temperature and time of the solvent. Optimal proportions of novel cocrystal can be obtained with good purity and yield.

(c) Mirabegron / fumaric acid, Mirabegron / L-pyroglutamic acid, Mirabegron / citric acid cocrystals or combination agents of the amorphous form of the present invention have a very low water solubility of Mirabegron in the amorphous form of the present invention. Polyglycol 8000, a hydrophilic agent that damages the mucous membrane of the body during oral preparation of Mirabegron, has increased by 57 times because of water solubility and solubility of small intestine pH 6.8. It is very useful as a Mirabegron complex drug substance that does not need to be used and can also increase oral absorption.

Figure 1 shows the powder X-ray diffraction (PXRD) pattern results of the amorphous form of Mirabegron / fumaric acid co-crystal or composite prepared according to an embodiment of the present invention.
FIG. 2 shows the solid state CP / MAS ¹³ C-NMR spectra of amorphous Mirabegron / fumaric acid cocrystal or composite prepared according to an embodiment of the present invention.
FIG. 3 is a solid state CP / MAS ¹³ C-NMR of the amorphous form of Mirabegron / Fumaric acid cocrystal or composite, Mirabegron, Fumaric acid prepared according to an embodiment of the present invention ) Show spectral results.
Figure 4 shows the results of the hydrogen nuclear magnetic resonance spectroscopy ( ¹ H-NMR) spectrum of the amorphous form of the Mirabegron / fumaric acid co-crystal or prepared in accordance with an embodiment of the present invention.
Figure 5 shows the powder X-ray diffraction (PXRD) pattern results of the amorphous form of Mirabegron / L- pyroglutamic acid co-crystal or composite prepared according to an embodiment of the present invention.
FIG. 6 shows solid state CP / MAS ¹³ C-NMR spectra of amorphous Mirabegron / L-Pyroglutamic acid co-crystals or composites prepared according to an embodiment of the present invention. .
FIG. 7 is a solid state carbon / magnetic resonance spectroscopy of the amorphous form of Mirabegron / L-Pyroglutamic acid co-crystal or composite, Mirabegron, L-Pyroglutamic acid prepared according to an embodiment of the present invention. ¹³ C-NMR) spectrum results are shown.
Figure 8 shows the results of the hydrogen nuclear magnetic resonance spectroscopy ( ¹ H-NMR) spectrum of the amorphous form of the Mirabegron / L- pyroglutamic acid co-crystal or prepared in accordance with an embodiment of the present invention.
Figure 9 shows the powder X-ray diffraction (PXRD) pattern results of the amorphous form of Mirabegron / citric acid co-crystal or composite prepared in accordance with an embodiment of the present invention.
FIG. 10 shows the solid state CP / MAS ¹³ C-NMR spectra of amorphous Mirabegron / citric acid cocrystals or composites prepared according to an embodiment of the present invention.
FIG. 11 is a solid state CP / MAS ¹³ C-NMR of Mirabegron / citric acid co-crystal or composite, Mirabegron, citric acid prepared in accordance with an embodiment of the present invention ) Show spectral results.
12 shows the results of hydrogen nuclear magnetic resonance spectroscopy ( ¹ H-NMR) spectrum of the amorphous form of Mirabegron / citric acid cocrystal or composite prepared according to an embodiment of the present invention.
FIG. 13 is a photograph showing the solubility in an amorphous form of Mirabegron cocrystal or composite agent and Mirabegron in 250 ml of water prepared according to the present invention and an embodiment.
Figure 14 shows the dissolution rate graph of the amorphous form of the Mirabegron co-crystals or composites and Mirabegron and Mirabegron amorphous prepared in accordance with an embodiment of the present invention.
FIG. 15 shows Mirabegron amorphous and Mirabegron α dissolution rate graphs and monitored phase change results through PXRD.
FIG. 16 shows PXRD patterns of amorphous Mirabegron co-crystals or composites, Mirabegron α-type and Mirabegron amorphous after 12 hours in the dissolution test procedure of FIG. 14.
17 shows the DSC calorimetry results of Mirabegron / fumaric acid, Mirabegron / L-pyroglutamic acid and Mirabegron / citric acid of the present invention.
The DSC calorie curve result of the Mirabegron crystal form cocrystal shown in the comparative example is shown.

Through the following examples will be described the present invention in more detail. These examples are only for illustrating the present invention in more detail, it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples in accordance with the gist of the present invention. .

[ Example  One] Mirabegron Of Fumaric acid Crystal  Or composite preparation

Add 10 g of Mirabegron and 100 ml of methanol and stir at room temperature for 20 minutes. Thereafter, 1.2 equivalents of fumaric acid were added one by one, and the temperature was gradually raised for 1 hour to reach reflux, followed by further stirring for 30 minutes. After slowly cooling to 15 ℃-20 ℃ and stirred for 3 hours. Thereafter, 50 ml of methanol was evaporated while the temperature was stirred at 30 ° C.-40 ° C. for 3 hours to precipitate crystals. The precipitated crystals were filtered under reduced pressure, washed with 10 ml of acetone, and vacuum-dried at 45 ° C. for at least 16 hours to obtain a novel amorphous Mirabegron / fumaric acid cocrystal or complex (purity 99.2%, HPLC) in 90% yield. It was confirmed by DSC calorimetry curve that the amorphous form of the Mirabegron cocrystal (Fig. 17).

[ Example  2] Mirabegron / L-pyroglutamic acid Crystal  Or composite preparation

Add 10 g of Mirabegron and 100 ml of methanol and stir at room temperature for 20 minutes. Thereafter, 1.2 equivalents of L-pyroglutamic acid were added one by one, and the temperature was gradually raised for 1 hour to reach reflux, followed by further stirring for 30 minutes. After slowly cooling to 15 ℃-20 ℃ and stirred for 3 hours. Thereafter, 50 ml of methanol was evaporated while the temperature was stirred at 30 ° C.-40 ° C. for 3 hours to precipitate crystals. The precipitated crystals were filtered under reduced pressure, washed with 10 ml of acetone, and vacuum-dried at 45 ° C. for at least 16 hours to form a novel amorphous Mirabegron / L-pyroglutamic acid co-crystal or complex (purity 99.5%, HPLC) in 86% yield. Got it. It was confirmed by DSC calorimetry curve that the amorphous form of the Mirabegron cocrystal (Fig. 17).

[ Example  3] Mirabegron Of Citric acid Crystal  Or composite preparation

Add 10 g of Mirabegron and 100 ml of methanol and stir at room temperature for 20 minutes. Then, 1.2 equivalents of citric acid were added one by one, and the temperature was gradually raised for 1 hour to reach reflux, followed by further stirring for 30 minutes. After slowly cooling to 15 ℃-20 ℃ and stirred for 3 hours. Thereafter, 50 ml of methanol was evaporated while the temperature was stirred at 30 ° C.-40 ° C. for 3 hours to precipitate crystals. The precipitated crystals were filtered under reduced pressure, washed with 10 ml of acetone, and vacuum-dried at 45 ° C. for at least 16 hours to obtain a novel amorphous Mirabegron / citric acid cocrystal or complex (purity 99.4%, HPLC) in 88% yield. It was confirmed by DSC calorimetry curve that the amorphous form of the Mirabegron cocrystal (Fig. 17).

[ Experimental Example  1] powder X-ray diffraction ( PXRD )

PXRD analysis (see FIG. 1) was performed on an X-ray powder diffractometer using Cu Kα radiation (D8 Advance). The instrument was equipped with tubular power and the amount of current was set to 45 kV and 40 mA. The divergence and scattering slits were set to 1 ° and the light receiving slit was set to 0.2 mm. A θ-2θ continuous scan of 3 ° min. (0.4 sec / 0.02 ° interval) from 5 to 35 ° 2θ was used.

[ Experimental Example  2] solid state carbon NMR spectrum analysis (Solid state CP / MAS ¹³ C-NMR)

Solid-state CP / MAS ¹³ C-NMR was measured by cross polarization (CP) / magic angle spinning (MAS) using a 500 MHz solid-state NMR (Avance II, Bruker, Billerica, Massachusetts, USA). Measurement conditions were spinning 5 KHz, pulse delay 10s, contact time 2 ms and measurement time was 24 hours per sample (see Fig. 2).

[ Experimental Example  3] Mirabegron Crystal  Or solubility evaluation of the combination

Since Mirabegron is poorly soluble with a water solubility of 0.082 mg / ml, the absorption of oral formulations is enhanced by adding polyethylene glycol 8000, a hydrophilic base, during the preparation of oral formulations. However, the addition of the hydrophilic base polyethylene glycol 8000 has a problem that damages the mucous membranes in the body, it is a trend to refrain from adding polyethylene glycol in the formulation process. However, polyethylene glycol was used in the Mirabegron oral preparation. Therefore, it is urgent to improve the solubility and accordingly, it is combined with fumaric acid, L-pyroglutamic acid, and citric acid to prepare new amorphous co-crystals and complexes to improve the water solubility and gastrointestinal pH solubility of Mirabegron. It was. The results are summarized in Table 2 below, and the analysis conditions are shown in Table 1 below.

Mobile phase A: B = 90:10 (v / v) A 10 mmol / LK ₂ HPO ₄ solution B Methanol Flow rate 1 ml / min UV 250 nm Run time 35 min diluent Methanol Injection volume 5 μl Column X-Bridge C18 25cm × 4.6cm × 5μm

HPLC Analysis Method for Determination of Amorphous Mirabegron Cocrystal or Co-Solubility

H ₂ O pH6.8 250 ml of H ₂ O Mirabegron α type 0.082 mg / ml 0.092 mg / ml 20.5 mg Mirabegron / Fumaric Acid 4.88 mg / ml 4.92 mg / ml 1220 mg Mirabegron / L-pyroglutamic acid 10.02 mg / ml 10.11 mg / ml 2528 mg Mirabegron / citric acid 7.51 mg / ml 7.68 mg / ml 1878 mg

Solubility of Mirabegron Cocrystal or Complex with Mirabegron in Amorphous Form

As shown in Table 2, it was confirmed that the water solubility and solubility in the small intestine pH 6.8 or more increased about 57 times compared to the Mirabegron of the present invention in the amorphous form of the Mirabegron cocrystal or composite. And Mirabegron (brand name Beta-Mega Western Formula) contains 50 mg of Mirabegron. Therefore, 50 mg in 250 ml of water must be well dissolved and thus absorbed in the small intestine to show its efficacy. However, as shown in Table 2, since the Mirabegron α-type can only dissolve 20.5 mg in 250 ml of water, 50 mg is absorbed into the body using a hydrophilic polyethylene glycol 8000. However, this hydrophilic base polyethylene glycol has a problem that causes damage to the mucous membrane of the body. However, all of the amorphous form of the Mirabegron co-crystal or the present invention is dissolved in more than 500 mg in 250 ml of water, has the advantage of not using a hydrophilic base.

Additionally, in order to confirm that 50 mg of the amorphous form of the Mirabegron co-crystal of the present invention is dissolved in 250 ml of water without the use of this hydrophilic base, the amorphous form of the Mirabegron co-crystal of the present invention or Three kinds of complexes and Mirabegron α-type were added to confirm solubility and are shown in FIG. 13. As a result, it was confirmed that 50 mg of all of the Mirabegron co-crystals or complexes of the amorphous form of the present invention were dissolved in 250 ml of water, but Mirabegron α was not dissolved. Therefore, the results confirmed the possibility of dissolving well in the body without the use of the hydrophilic base polyethylene glycol by using the amorphous form of the Mirabegron co-crystal or the composite of the present invention, ensuring the ease of preparation, oral The absorption was also predicted to be improved.

[ Experimental Example  4] in amorphous form at small intestine pH 6.8 Mirabegron Crystal  Or evaluating dissolution rate of composites and monitoring phase transition through PXRD

In order to determine the oral absorption of the amorphous form of the Mirabegron co-crystal or co-formulation, the amorphous form of Mirabegron / fumaric acid (MBR-FA), Mirabegron / L-pyroglutamic acid (MBR-PG), Co-crystals or composites of Mirabegron / citric acid (MBR-CA), Mirabegron α-type (MBR crystalline) and Mirabegron Self-Amorphous (MBR amorphous) were tested by using a dissolution tester. The dissolution rate was analyzed by HPLC analysis and presented in FIG. 14. As shown in FIG. 14, it was confirmed that the dissolution rate and dissolution rate of the amorphous form of the Mirabegron cocrystal or composite of the present invention were increased by 57 times or more than the Mirabegron α type. However, in Figure 15, the Mirabegron amorphous itself showed a dissolution rate of 6.7 times higher than the Mirabegron α type, but after 35 minutes it was confirmed that the phase transition to the Mirabegron α type after one hour. Since the time that Mirabegron is present in the body is 3.5 hours, it has been found that the use of Mirabegron's own amorphous form results in a very dangerous result of recrystallization into crystals. However, it was confirmed that the amorphous form of the Mirabegron co-crystals are thermodynamically stable as shown in FIG. Therefore, it was confirmed that the amorphous form of the Mirabegron co-crystal can solve the problem of poor solubility of the Mirabegron α type and the thermodynamic stability of the amorphous Mirabegron itself.

Therefore, the Mirabegron cocrystal or composite agent of the amorphous form of the present invention is expected to be a novel drug substance that overcomes the poor solubility of Mirabegron.

[ Comparative example  1] in amorphous form Mirabegron Crystal  Screening

The co-molecules, edisilic acid, napadisilic acid, histidine, aspartic acid, fumaric acid, L-pyroglutamic acid, and citric acid, were selected and screened in an amorphous form of Mirabegron co-crystal. As a result, co-crystal Mirabegron / Edisilic acid (MBR_EFA) and Mirabegron / Nafadisilic acid (MBR_NDA) of noncrystalline form were formed, Mirabegron / Histidine (MBR_His), Mirabegron / In aspartic acid (MBR_AA), it was confirmed by DSC calorimetry that even co-crystals were not formed (FIG. 18). As described above, the formation of co-crystals is very simple and not carried out through conventional experimental methods. The formation of co-crystals in the form of crystals is required when hydrogen bonds, which are intermolecular interactions between many drug molecules and co-molecules, must be properly formed and there is no ionic environment. do. Amorphous co-crystals use a crystallization method that controls the rate of all crystallization rapidly to reach supersaturation very quickly or induces a very high degree of supersaturation. The reduced pressure evaporation crystallization method, which is the crystallization method used in the present example and the comparative example, is a crystallization method which rapidly controls the crystallization rate to reach supersaturation or induces a very high degree of supersaturation. However, not all of these crystallization methods form amorphous crystals. The reason for this is that co-crystals are formed by various hydrogen bonds through intermolecular interactions with various co-molecules. However, even if the crystallization rate is rapidly controlled, the degree of supersaturation for the formation of the amorphous form is different for each co-crystal formed. Therefore, exploring, designing, and controlling amorphous co-crystals is very complex and requires engineering thoughts and views. Thus, this amorphous Mirabegron co-crystal is a very unusual invention that cannot be designed and controlled without understanding crystallization engineering ideas and opinions.

Having described the specific part of the present invention in detail, it is apparent to those skilled in the art that such a specific technology is merely a preferred embodiment, and the scope of the present invention is not limited thereto. Therefore, the substantial scope of the present invention will be defined by the appended claims and equivalents thereof.

Claims (12)

A co-crystal or a complex combined with one molecule of mirabegron and one molecule of fumaric acid. The amorphous amorphous Mirabegron / fumaric acid cocrystal according to claim 1, wherein the Mirabegron / fumaric acid cocrystal or complex is a compound represented by the following Chemical Formula 2:
Formula 2

In the above formula, the dotted line represents a hydrogen bond. The method of claim 1, wherein the Mirabegron / fumaric acid co-crystals or composites exhibit an amorphous form of 2θ diffraction angle in the X-ray diffraction (PXRD) analysis, solid state CP / MAS ¹³ C- NMR) shows changes in hydrogen bonding through characteristic peaks of 31.74 ppm, 37.35 ppm, 38.69 ppm, 50.02 ppm, 69.46 ppm, 104.23 ppm, 119.37 ppm, 128.16 ppm, 136.59 ppm, 170.12 ppm ¹ H-NMR) Amorphous co-crystals or composites characterized by a peak appearing at 6.29 ppm, 6.52 ppm. The Mirabegron / fumaric acid co-crystal according to claim 1, wherein the Mirabegron / fumaric acid co-crystal or co-agent is an amorphous form in which one equivalent of fumaric acid is combined with one equivalent of Mirabegron. Cocrystals or complexes combined with one molecule of mirabegron and one molecule of L-pyroglutamic acid. 6. The amorphous Mirabegron / L-pyroglutamic acid cocrystal according to claim 5, wherein the Mirabegron / L-pyroglutamic acid cocrystal or a complexing agent is a compound represented by the following Chemical Formula 3:
Formula 3

In the above formula, the dotted line represents a hydrogen bond. 6. The amorphous Mirabegron / L-Pyroglutamic acid co-crystal or composite agent exhibits an amorphous form with 2θ diffraction angles in X-ray diffraction (PXRD) analysis, wherein the solid state CP / MAS ¹³ C-NMR) Spectra of 25.43 ppm, 30.07 ppm, 39.50 ppm, 48.83 ppm, 57.82 ppm, 68.99 ppm, 103.32 ppm, 119.59 ppm, 127.98 ppm, 137.89 ppm, 144.48 ppm, 169.51 ppm, 178.79 ppm Amorphous co-crystals or complexes that exhibit a change in hydrogen bonds and are characterized by peaks at 3.89 ppm, 3.90 ppm, 3.91 ppm, 6.29 ppm of hydrogen nuclear magnetic resonance spectroscopy ( ¹ H-NMR) spectrum. 6. The Mirabegron / L-Pyroglutamic acid cocrystal according to claim 5, wherein the Mirabegron / L-pyroglutamic acid co-crystal or a combination agent is an amorphous form in which 1 equivalent of L-pyroglutamic acid is bound to 1 equivalent of Mirabegron. A co-crystal or complex agent combined with one molecule of mirabegron and one molecule of citric acid. 10. The amorphous Mirabegron / citric acid cocrystal according to claim 9, wherein the Mirabegron / citric acid cocrystal or complex is a compound represented by the following Chemical Formula 4:
Formula 4

In the above formula, the dotted line represents a hydrogen bond. 10. The solid state CP / MAS of claim 9, wherein the amorphous Mirabegron / citric acid co-crystal or composite exhibits a 2θ diffraction angle in an amorphous form in X-ray diffraction (PXRD) analysis, and the solid state CP / MAS ¹³ C-NMR) Spectrum 31.68 ppm, 46.19 ppm, 69.21 ppm, 74.26 ppm, 104.31 ppm, 119.05 ppm, 128.33 ppm, 135.12 ppm, 170.18 ppm, 178.41 ppm to show the change in hydrogen bonds Amorphous co-crystals or complexes characterized by peaks appearing at 2.57 ppm, 2.59 ppm, 6.29 ppm in resonance spectroscopy ( ¹ H-NMR) spectrum. 10. The Mirabegron / citric acid cocrystal according to claim 9, wherein the Mirabegron / citric acid co-crystal or complex is an amorphous form in which one equivalent of citric acid is bound to one equivalent of Mirabegron.

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