KR20230109980A - Enzalutamide solid dispersion - Google Patents

Abstract

The present invention relates to a solid dispersion composition containing enzalutamide, copovidone and colloidal silicon dioxide and a method for preparing the same.

Description

Enzalutamide solid dispersion {Enzalutamide solid dispersion}

The present invention relates to a solid dispersion composition containing enzalutamide, copovidone and colloidal silicon dioxide and a method for preparing the same.

Enzalutamide, a compound with the chemical name “4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide, is an androgen receptor signaling inhibitor.

Enzalutamide is marketed as a soft capsule containing 40 mg of enzalutamide per capsule (Xtandi Soft Capsule 40mg ^® ), and is used for the treatment of asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer patients, the treatment of metastatic castration-resistant prostate cancer patients previously treated with docetaxel, the treatment of high-risk non-metastatic castration-resistant prostate cancer patients, and the treatment of hormone-responsive metastatic prostate cancer patients. .

Enzalutamide is a drug belonging to the biopharmaceutical classification system (BCS) class 2 and is a poorly soluble drug with low solubility. Since the daily dose of Xtandi soft capsules, a currently marketed formulation of enzalutamide, is 160 mg, the patient needs to take 4 capsules a day. A large amount of surfactant is added to the Xtandi soft capsules to solve the poor solubility of enzalutamide, which is a burden on the patient's body. In detail, if you take Xtandi soft capsules once a day at the recommended dose, you will take about 3600 mg of surfactant (Labrasol ^® ), which is more than 50 times the daily limit of the FDA's Inactive Ingredient Guide (IIG; 2013, 10).

Therefore, it is urgent to develop a formulation capable of exhibiting high bioavailability without using an excessive amount of surfactant while solving the problem of poor dissolution due to poor solubility of enzalutamide.

The present invention is to provide a solid dispersion composition containing enzalutamide, copovidone and colloidal silicon dioxide.

In addition, the present invention is a first step of dissolving enzalutamide in a pharmaceutically acceptable solvent; A second step of adding and dissolving copovidone in the solution of the first step; A third step of homogenizing by adding colloidal silicon dioxide to the solution of the second step; And it is to provide a method for producing a solid dispersion composition comprising a fourth step of preparing a solid dispersion by spray-drying the prepared solution.

The present invention provides a solid dispersion composition containing enzalutamide, copovidone and colloidal silicon dioxide.

In the present invention, enzalutamide is a compound having the chemical name "4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide", and refers to an androgen receptor signaling inhibitor. Enzalutamide is a drug used for the treatment of metastatic prostate cancer that is ineffective with treatments including docetaxel, and inhibits the growth of cancer cells by binding to androgen receptors and inhibiting male hormones from binding to the receptors.

Preferably the enzalutamide of the present invention is amorphous. Amorphous enzalutamide is more rapidly dissolved than crystalline enzalutamide in the in vivo environment, and thus exhibits high bioavailability.

Amorphous enzalutamide may be prepared by any known means including spray-drying, hot melt extrusion and precipitation from solution by non-solvent addition.

The solid dispersion of the present invention contains copovidone and colloidal silicon dioxide in addition to enzalutamide as an active ingredient.

In the present invention, the copovidone refers to a copolymer of vinylpyrrolidone-vinylacetate. Copovidone is a hydrophilic polymer and can increase water solubility when added to a solid dispersion containing poorly soluble drugs. Enzalutamide is also a poorly soluble drug that does not dissolve well in water, and as a result of screening the water solubility of enzalutamide through a comparative experiment, it was confirmed that copovidone has excellent solubilization ability.

The solid dispersion composition of the present invention is characterized in that copovidone and colloidal silicon dioxide exist inside the solid dispersion, including copovidone and colloidal silicon dioxide, during preparation of the solid dispersion.

The solid dispersion containing enzalutamide means that enzalutamide is evenly dispersed in copovidone and colloidal silicon dioxide, and the composition and structure of this solid dispersion prevent conversion of amorphous enzalutamide to crystalline form and suppress aggregation, thereby increasing the dispersing force. As enzalutamide is dispersed inside the copovidone and colloidal silicon dioxide solid dispersion, it is possible to obtain an effect of increasing water solubility and dissolution while changing drug properties to hydrophilic properties.

In one experimental example, a solid dispersion tablet containing enzalutamide and copovidone (Example 5) and a solid dispersion tablet containing enzalutamide, copovidone, and colloidal silicon dioxide (Example 8) were prepared and the dissolution rate was compared by a dissolution test according to Method 2 of the General Test Methods of the Korean Pharmacopoeia. As a result, the tablet of Example 8 had an initial dissolution rate of about 1 It was higher by 3%, and at 60 minutes of the dissolution test, the dissolution rate was about 18% higher, and at 60 minutes, enzalutamide dissolution of 60% or more was achieved, confirming the effect of showing fast initial dissolution and high dissolution rate (Table 6 and FIG. 2).

The solid dispersion composition of the present invention may preferably include 10 parts by weight to 400 parts by weight of copovidone based on 100 parts by weight of enzalutamide.

In addition, the solid dispersion composition of the present invention may preferably include 10 parts by weight to 100 parts by weight of colloidal silicon dioxide based on 100 parts by weight of enzalutamide.

In addition, the solid dispersion composition of the present invention may preferably include 50 parts by weight of copovidone and 50 parts by weight of colloidal silicon dioxide based on 100 parts by weight of enzalutamide.

The solid dispersion composition of the present invention may preferably not contain a surfactant. Compared to the capsule composition (Xtandi Soft Capsule 40mg ^® ) containing a large amount of surfactant Labrasol, the solid dispersion composition of the present invention maintains excellent solubility and dissolution characteristics and does not contain a surfactant, thereby reducing the burden on the body and at the same time reducing the size of the solid preparation.

In one experimental example, solid dispersion compositions (Comparative Examples 6 and 7) containing enzalutamide, copovidone, and surfactant were prepared, and a dissolution test was performed according to Method 2 of the General Test Methods of the Korean Pharmacopoeia. As a result, when the surfactant was included, the very early dissolution of enzalutamide was well achieved, but the dissolution rate began to decrease from around 15 to 30 minutes, resulting in a maximum dissolution rate of less than 40% (Fig. 4).

The solid dispersion composition of the present invention is characterized in that the initial dissolution rate is fast and the final dissolution rate is high by including copovidone and colloidal silicon dioxide together in the enzalutamide solid dispersion.

Preferably, the solid dispersion composition of the present invention can exhibit a dissolution rate of 40% or more in 10 minutes when tested at 50 rpm in 900 mL of 0.1N HCl according to Method 2 (paddle method) of the dissolution test of the General Test Methods of the Korean Pharmacopoeia.

In addition, preferably, the solid dispersion composition of the present invention can exhibit a dissolution rate of 60% or more in 60 minutes when dissolution test is performed at 50 rpm in 900 mL of 0.1N HCl according to the dissolution test method 2 (paddle method) of the General Test Methods of the Korean Pharmacopoeia.

The solid dispersion composition of the present invention may include a pharmaceutical additive selected from the group consisting of an excipient, a disintegrant, a binder, a lubricant, and any combination thereof.

The excipient may be any excipient known in the art, and may be, for example, selected from the group consisting of microcrystalline cellulose, lactose, low-substituted hydroxypropyl cellulose, calcium phosphate, light anhydrous silicic acid, pregelitinated starch, corn starch, potato starch, sucrose, mannitol, dextrin, precipitated calcium carbonate, and any combination thereof, but is not limited thereto.

The disintegrant may be any disintegrant known in the art, and may be selected from, for example, the group consisting of sodium starch glycolate, polyvinylpyrrolidone, crospovidone, croscarmellose sodium, pregelatinized starch, low-substituted hydroxypropyl cellulose, starch, alginic acid, sodium alginate, and combinations thereof, but is not limited thereto.

The binder may be any binder known in the art, and may be selected from the group consisting of, for example, hydroxypropylcellulose, polyvinylpyrrolidone, povidone, copovidone, macrogol, and any combination thereof, but is not limited thereto.

The lubricant may be any lubricant known in the art, and may be selected from the group consisting of, for example, stearic acid, metal stearate salts such as calcium stearate or magnesium stearate, talc, sucrose fatty acid esters, hydrogenated vegetable oils, high melting point waxes, glyceryl fatty acid esters, glycerol dibehenate, and any combination thereof, but is not limited thereto.

Preferably, the solid dispersion composition of the present invention may include mannitol, croscarmellose sodium, copovidone and magnesium stearate as additives.

Excipients, disintegrants, binders, and lubricants included in the solid dispersion composition of the present invention may be included in appropriate amounts as needed, and may include 100 parts by weight to 400 parts by weight of excipients, 5 parts by weight to 50 parts by weight of disintegrants, 5 parts by weight to 50 parts by weight of binders, and 1 to 10 parts by weight of lubricants based on 80 parts by weight of the solid dispersion.

Also preferably, the solid dispersion composition of the present invention may include 100 parts by weight of mannitol, 10 parts by weight of croscarmellose sodium, 5 parts by weight of copovidone, and 2 parts by weight of magnesium stearate based on 80 parts by weight of the solid dispersion.

The solid dispersion composition of the present invention may further include at least one selected from the group consisting of water-soluble polymers, sustained-release polymers, solid lipids, and phospholipids.

Preferably, the water-soluble polymer may be hydroxypropyl cellulose.

Also preferably, the water-soluble polymer may be low-substituted hydroxypropyl cellulose.

Preferably, the sustained-release polymer may be at least one selected from the group consisting of Eudragit RL, Eudragit RS, Kollidon SR, and ethyl cellulose.

Preferably, the solid dispersion composition of the present invention may further contain at least one selected from the group consisting of tricaprine, trilaurin, trimyristin, tripalmitin, tristearin, stearic acid, palmitic acid, decanoic acid, cetyl alcohol, stearyl alcohol, sodium taurocholate, cholic acid, cholesterol, lecithin, phosphatidylic acid, phosphatidylcholine, phosphatidylglycerol, phosphatidylserine, and phosphatidylethanolamine.

The solid dispersion composition of the present invention can be used as a pharmaceutical for oral administration as a solid dispersion, or can be prepared in the form of powder, granules, capsules, tablets, etc., preferably in the form of tablets.

In addition, the present invention is a first step of dissolving enzalutamide in a pharmaceutically acceptable solvent; A second step of adding and dissolving copovidone in the solution of the first step; A third step of homogenizing by adding colloidal silicon dioxide to the solution of the second step; and a fourth step of preparing a solid dispersion by spray drying the prepared solution.

The details of the preparation method of the solid dispersion composition can be applied as it is to the description of the solid dispersion composition of the present invention. Specifically, enzalutamide, copovidone, colloidal silicon dioxide, and the solid dispersion are as described above.

Any pharmaceutically acceptable solvent in which enzalutamide is dissolved may be used as the pharmaceutically acceptable solvent in the first step, and may be, for example, acetone.

In the second step, copovidone is added to and dissolved in the solution of the first step, and may be completely dissolved by stirring for 10 minutes, for example.

In the third step, the solution of the second step is homogenized by adding colloidal silicon dioxide.

In the fourth step, the solution prepared in the third step is spray-dried to prepare a solid dispersion. The fourth step is a process of removing the solvent from the third step solution, through which a substantially uniform solid dispersion is produced. Enzalutamide is uniformly dispersed throughout the copovidone and colloidal silicon dioxide solid dispersion during the solvent removal process.

The spray drying step is a step of drying the solvent, and the method is not particularly limited, and known methods such as spray drying using a spray dryer, fluidized bed granulator, CF granulator, vacuum dryer, vacuum drying, hot air drying, etc. can be used.

Preferably, in the fourth step in the production method of the present invention, a solid dispersion composition may be prepared using a spray dryer.

In the solid dispersion composition of the present invention, sparingly soluble enzalutamide is evenly dispersed in the copovidone and colloidal silicon dioxide solid dispersion to suppress aggregation of enzalutamide, and the amorphous form of enzalutamide is stably maintained. Through this, the solid dispersion composition according to the present invention has a fast initial dissolution rate of enzalutamide, high dissolution rate, and excellent bioavailability.

1 is the dissolution test results of Examples 4 to 6 and Comparative Examples 1 and 2.
Figure 2 is the dissolution test results of Examples 5, 8 and Comparative Examples 3 to 5.
Figure 3 is the dissolution test results of Examples 5 and 8, Comparative Examples 6 and 7.
Figure 4 is the dissolution test results of Comparative Examples 8 and 9.

Hereinafter, the present invention will be described in detail through examples and experimental examples. However, these Examples and Experimental Examples are only examples of the present invention, and the scope of the present invention is not limited only to these.

Examples 1 to 3 and Preparation Example 1: Preparation of Solid Dispersion

[Table 1]

According to the composition of Table 1, the solid dispersions of Examples 1 to 3 were prepared. Specifically, 1 g of enzalutamide was dissolved in 20 mL of acetone, copovidone was added to the solution in which enzalutamide was dissolved, stirred for 10 minutes to completely dissolve, and then 10 mL of purified water was added to prepare a transparent solution. The prepared solution was spray dried using a spray dryer (Yamato spray dryer, ADL311S; Tokyo, Japan) under the following conditions. In the case of Preparation Example 1, after dissolving 1 g of enzalutamide without copovidone in 20 mL of acetone, 10 mL of purified water was added to prepare a solution, and the prepared solution was spray-dried under the same conditions as below.

-Flow rate: 1.5

- Inlet temperature: 90℃

-Outlet temperature: 60-63℃

- Blower (average flow rate of drying air): 0.42 ㎥/min

- Atomizing air: 0.15 MPa

Examples 4 to 6, Comparative Examples 1 and 2: Preparation of tablets containing solid dispersion

Using the solid dispersions of Examples 1 to 3, enzalutamide (crystalline), and Preparation Example 1 (amorphous enzalutamide), tablets were prepared according to the quantities (mg) shown in Table 2 below. Specifically, a solid dispersion, enzalutamide (crystalline) or amorphous enzalutamide was mixed with mannitol, croscarmellose sodium and copovidone, and then magnesium stearate was added to the mixture. The obtained mixture was molded into tablets using a tablet press. The tablets of Examples 4 to 6 and Comparative Examples 1 and 2 in Table 2 below all contain 40 mg of enzalutamide.

[Table 2]

Experimental Example 1: Dissolution test of Examples 4 to 6 and Comparative Examples 1 and 2

The tablets of Examples 4 to 6 and Comparative Examples 1 and 2 were subjected to a dissolution test at 0.1 N, HCl 900 mL, 50 rpm according to the Korean Pharmacopoeia General Test Method 2, paddle method, and the results are shown in Table 3 and FIG. 1 below.

[Table 3]

As can be seen in Table 3 and FIG. 1 above, the tablets of Examples 4 to 6 containing copovidone in the solid dispersion showed a very good dissolution rate compared to the crystalline enzalutamide tablet (Comparative Example 1) and the amorphous enzalutamide not containing copovidone (Comparative Example 2).

Example 7, Preparation Examples 2 to 4: Preparation of Solid Dispersion

[Table 4]

Solid dispersions of Example 7 and Preparation Examples 2 to 4 were prepared according to the composition of Table 4 above. Specifically, 1 g of enzalutamide was dissolved in 20 mL of acetone, copovidone was added to the solution in which enzalutamide was dissolved, stirred for 10 minutes to completely dissolve, and then 10 mL of purified water was added to prepare a transparent solution. The clear solution was homogenized by adding colloidal silicon dioxide, calcium silicate or magnesium aluminometasilicate. The prepared solution was spray dried using a spray dryer (Yamato spray dryer, ADL311S; Tokyo, Japan) under the following conditions.

-Flow rate: 1.5

- Inlet temperature: 90℃

-Outlet temperature: 60-63℃

- Blower (average flow rate of drying air): 0.42 ㎥/min

- Atomizing air: 0.15 MPa

Example 8, Comparative Examples 3 to 5: Preparation of tablets containing solid dispersion

Tablets were prepared according to the amount (mg) of Table 5 below using the solid dispersions of Example 7 and Preparation Examples 2 to 4. Specifically, the solid dispersion was mixed with mannitol, croscarmellose sodium and copovidone, and then magnesium stearate was added to the mixture. The obtained mixture was molded into tablets using a tablet press. The tablets of Example 8 and Comparative Examples 3 to 5 were all containing 40 mg of enzalutamide.

[Table 5]

Experimental Example 2: Dissolution test of Examples 5 and 8 and Comparative Examples 3 to 5

The tablets of Examples 5 and 8 and Comparative Examples 3 to 5 were subjected to a dissolution test at 0.1 N, HCl 900 mL, 50 rpm according to the Korean Pharmacopoeia General Test Method 2, Paddle Method, and the results are shown in Table 6 and FIG. 2 below.

[Table 6]

As can be seen in Table 6 and FIG. 2 above, the initial dissolution rate and the dissolution rate at 60 minutes were low for the tablets prepared using the solid dispersion containing enzalutamide and copovidone but calcium silicate or magnesium aluminum metasilicate (Comparative Examples 3 and 4), and the tablet prepared using the solid dispersion not containing copovidone (Comparative Example 5) had very little initial dissolution. In addition, the dissolution rate at 60 minutes was less than 10%.

On the other hand, compared to the tablet prepared using the solid dispersion containing only enzalutamide and copovidone (Example 5), the initial dissolution rate of the tablet prepared using the solid dispersion further containing colloidal silicon dioxide (Example 8) was about 13% higher, and at 60 minutes of the dissolution test, the dissolution rate was about 18% higher, and at 60 minutes the enzalutamide was already 60% or more Elution was achieved. The tablet of Example 8 was about 1.4 times faster than the tablet of Example 5, about 1.9 times faster than the tablet of Comparative Example 3, about 3.1 times faster than the tablet of Comparative Example 4, and about 30 times faster than the tablet of Comparative Example 5. Through this, it was confirmed that the purification of the solid dispersion containing enzalutamide, copovidone and colloidal silicon dioxide (Example 8) can effectively improve the problem of low dissolution due to the low solubility of enzalutamide.

Comparative Examples 6 and 7: Preparation of tablets containing solid dispersion

Tablets of Comparative Examples 6 and 7 were prepared according to the amount (mg) of Table 7 below using the solid dispersion of Example 2. Specifically, the solid dispersion was mixed with colloidal silicon dioxide, mannitol, croscarmellose sodium and copovidone, and then magnesium stearate was added to the mixture. The obtained mixture was molded into tablets using a tablet press. The tablets of Comparative Examples 6 and 7 both contain 40 mg of enzalutamide. The amount of colloidal silicon dioxide used in the tablet molding of Comparative Example 6 is the same as the amount of colloidal silicon dioxide used in preparing the solid dispersion of Example 8, and Comparative Example 7 contained half the amount of colloidal silicon dioxide compared to the solid dispersion of Example 8.

[Table 7]

Experimental Example 3: Dissolution test of Examples 5 and 8 and Comparative Examples 6 and 7

The tablets of Examples 5, 8 and Comparative Examples 6 and 7 were subjected to a dissolution test at 0.1 N, HCl 900 mL, 50 rpm according to the Korean Pharmacopoeia General Test Method 2, paddle method, and the results are shown in Table 8 and FIG. 3 below.

[Table 8]

As can be seen from Table 8 and FIG. 3 above, when colloidal silicon dioxide was included in the solid dispersion (Example 2) containing only enzalutamide and copovidone as a lubricant for tablet molding (Comparative Examples 6 and 7), not only the initial dissolution rate was very low, but also the dissolution rate at 60 minutes was about 16% and about 14%, respectively.

Comparative Examples 8 and 9: Preparation of tablets containing solid dispersion

Solid dispersions of Comparative Examples 8 and 9 and tablets containing them were prepared. Specifically, 1 g of enzalutamide was dissolved in 20 mL of acetone, copovidone was added to the solution in which enzalutamide was dissolved, stirred for 10 minutes to completely dissolve, and then 10 mL of purified water was added to prepare a transparent solution. The clear solution was homogenized by adding sodium lauryl sulfate (SLS). The prepared solution was spray dried using a spray dryer (Yamato spray dryer, ADL311S; Tokyo, Japan) under the following conditions.

-Flow rate: 1.5

- Inlet temperature: 90℃

-Outlet temperature: 60-63℃

- Blower (average flow rate of drying air): 0.42 ㎥/min

- Atomizing air: 0.15 MPa

Thereafter, the prepared solid dispersions of Comparative Examples 8 and 9 were molded into tablets according to the quantities shown in Table 9 below.

[Table 9]

Specifically, the solid dispersion was mixed with mannitol, croscarmellose sodium and copovidone, and then magnesium stearate was added to the mixture. The obtained mixture was molded into tablets using a tablet press. The tablets of Comparative Examples 8 and 9 both contain 40 mg of enzalutamide.

Experimental Example 4: Dissolution test of Comparative Examples 8 and 9

The tablets of Comparative Examples 8 and 9 were subjected to a dissolution test at 0.1 N, HCl 900 mL, 50 rpm according to the Korean Pharmacopoeia General Test Method 2, paddle method, and the results are shown in FIG. 4 .

As a result, as shown in FIG. 4, in the tablets of Comparative Examples 8 and 9, enzalutamide was initially well eluted, but the dissolution rate decreased again after 15 to 30 minutes, and it was confirmed that the maximum dissolution rate was less than 40%.

Claims (15)

A solid dispersion composition comprising enzalutamide, copovidone and colloidal silicon dioxide. The solid dispersion composition according to claim 1, wherein the enzalutamide is amorphous. The solid dispersion composition according to claim 1, comprising 10 parts by weight to 400 parts by weight of the copovidone based on 100 parts by weight of the enzalutamide. The solid dispersion composition according to claim 1, comprising 10 parts by weight to 100 parts by weight of the colloidal silicon dioxide based on 100 parts by weight of the enzalutamide. The solid dispersion composition according to claim 1, comprising 50 parts by weight of the copovidone and 50 parts by weight of the colloidal silicon dioxide, based on 100 parts by weight of the enzalutamide. The solid dispersion composition according to claim 1, wherein the composition does not contain a surfactant. The solid dispersion composition according to claim 1, wherein the solid dispersion composition shows a dissolution rate of 40% or more in 10 minutes when a dissolution test is performed at 50 rpm in 900 mL of 0.1N HCl according to Method 2 (paddle method) of the dissolution test of the General Test Methods of the Korean Pharmacopoeia. The solid dispersion composition according to claim 1, wherein the solid dispersion composition exhibits a dissolution rate of 60% or more in 60 minutes when a dissolution test is performed at 50 rpm in 900 mL of 0.1N HCl according to Method 2 (paddle method) of the dissolution test of the General Test Methods of the Korean Pharmacopoeia. The solid dispersion composition according to claim 1, wherein the solid dispersion composition further comprises at least one selected from the group consisting of water-soluble polymers, sustained-release polymers, solid lipids, and phospholipids. 10. The solid dispersion composition according to claim 9, wherein the water-soluble polymer is hydroxypropyl cellulose. 10. The solid dispersion composition according to claim 9, wherein the water-soluble polymer is low-substituted hydroxypropyl cellulose. The solid dispersion composition according to claim 9, wherein the sustained-release polymer is at least one selected from the group consisting of Eudragit RL, Eudragit RS, Kollidon SR, and ethyl cellulose. The solid content of claim 1, wherein the solid dispersion composition further comprises at least one selected from the group consisting of tricaprine, trilaurin, trimyristin, tripalmitin, tristearin, stearic acid, palmitic acid, decanoic acid, cetyl alcohol, stearyl alcohol, sodium taurocholate, cholic acid, cholesterol, lecithin, phosphatidylic acid, phosphatidylcholine, phosphatidylglycerol, phosphatidylserine, and phosphatidylethanolamine. acid composition. The solid dispersion composition according to claim 1, wherein the solid dispersion composition is in the form of a tablet. A first step of dissolving enzalutamide in a pharmaceutically acceptable solvent;
A second step of adding and dissolving copovidone in the solution of the first step;
A third step of homogenizing by adding colloidal silicon dioxide to the solution of the second step; and a fourth step of preparing a solid dispersion by spray-drying the prepared solution.