KR20240010280A - Pharmaceutical composition comprising abiraterone acetate or pharmaceutically acceptable salt thereof - Google Patents

Abstract

The present invention relates to a pharmaceutical composition comprising abiraterone acetate or a pharmaceutically acceptable salt thereof. More specifically, the pharmaceutical composition can improve medication convenience by minimizing the content of pharmaceutically acceptable additives and reducing the mass and size of the preparation.

Description

Pharmaceutical composition comprising abiraterone acetate or a pharmaceutically acceptable salt thereof {PHARMACEUTICAL COMPOSITION COMPRISING ABIRATERONE ACETATE OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF}

The present invention relates to a pharmaceutical composition containing abiraterone acetate or a pharmaceutically acceptable salt thereof.

Abiraterone ((3β)-17-(pyridin-3-yl)androsta-5,16-dien-3-ol; CAS #: 154229-19-3; Formula: C24H31NO; Molecular Weight: 349.5 g/mol) is an inhibitor of CYP17 and thus interferes with the synthesis of androgens in testicular, adrenal and prostate tumor tissues. Abiraterone acetate (17-(3-pyridyl)androsta-5, acetate; CAS #154229-18-2), a prodrug of abiraterone, is the leading cause of castration-resistant prostate cancer in the United States. Approved as a treatment.

Among prostate cancer, a malignant tumor that occurs in the prostate, localized prostate cancer is known to have a 10-year survival rate of about 65% if it can be cured with surgical resection or radiation therapy, but if the tumor metastasizes to bones, lymph nodes, etc. Because it reaches a stage where it cannot be completely cured, the presence or absence of metastasis has a significant impact on the prognosis. For patients who are found to have metastatic prostate cancer, chemotherapy is generally used secondarily after primary therapy to suppress male hormones, but there is no alternative after chemotherapy.

Therefore, Zytiga® tablets containing abiraterone acetate as the active ingredient, which can be used to treat patients with metastatic castrate-resistant prostate cancer (mCRPC) who previously received chemotherapy, have attracted attention. I'm receiving it.

In the case of Zytiga® tablets (tablet mass: 1153.6 mg), the recommended dose is 1000 mg once a day, which is equivalent to 2 tablets of 500 mg, so the convenience of taking medication is still poor, making it difficult for patients to take their medication. There is a problem of decreased compliance.

Therefore, in oral preparations containing abiraterone acetate as an active ingredient, there is an increasing demand for the development of oral preparations with excellent medication convenience and good medication compliance.

Korean Patent No. 2121404

The present invention relates to the production of a pharmaceutical composition containing abiraterone acetate as an active ingredient, instead of maintaining the content of abiraterone acetate and a solubilizing agent to complement the poorly soluble characteristics of the abiraterone acetate. The aim is to provide a pharmaceutical composition in the form of an oral preparation with improved medication convenience by minimizing the mass and size by reducing the content of additives, including excipients.

According to the first aspect of the present invention,

The present invention is a pharmaceutical composition comprising abiraterone acetate or a pharmaceutically acceptable salt thereof, wherein the abiraterone acetate or a pharmaceutically acceptable salt thereof is contained in the form of granules, and the apparent density of the granules is 0.35. g/mL or more, and the weight of the pharmaceutical composition is 600 mg to 1200 mg.

In an embodiment of the present invention, the abiraterone acetate or a pharmaceutically acceptable salt thereof may be included in an amount of 40% by weight to 75% by weight based on the total weight of the pharmaceutical composition.

In an embodiment of the present invention, the granules may be wet granules manufactured by a high speed mixer (HSM).

In an embodiment of the present invention, the pharmaceutical composition includes (1) a granule portion, and (2) an additive portion, and the abiraterone acetate or a pharmaceutically acceptable salt thereof may be included in the granule portion. there is.

In an embodiment of the present invention, the pharmaceutical composition may include a solubilizer.

In an embodiment of the present invention, the solubilizer may be included in an amount of 5% to 10% by weight based on the total weight of the pharmaceutical composition.

In an embodiment of the present invention, the (1) granule portion may include a first excipient, and/or the (2) additive portion may include a second excipient.

In an embodiment of the present invention, the first excipient and the second excipient may each include one or more selected from the group consisting of lactose hydrate and cellulose-based excipient, and the first excipient and the second excipient are the same or It may be different.

In an embodiment of the present invention, the second excipient may include a cellulose-based excipient.

In an embodiment of the present invention, the cellulose-based excipient may include one or more selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, and carboxymethyl cellulose.

In an embodiment of the present invention, the cellulose-based excipient may be included in an amount of 5 to 17% by weight based on the total weight of the pharmaceutical composition.

In an embodiment of the present invention, the pharmaceutical composition may be formulated as an oral preparation.

In an embodiment of the present invention, the oral preparation may be a tablet, capsule, or polycap.

In an embodiment of the present invention, the size of the oral preparation may be 9 mm to 20 mm.

Since the pharmaceutical composition according to the present invention must be used together with a solubilizing agent in consideration of the characteristics of abiraterone acetate, which is a poorly soluble drug, the weight of the active ingredient and solubilizing agent contained in the pharmaceutical composition is not reduced, and the pharmaceutical composition Medication convenience and medication compliance can be improved by minimizing the weight and size of the formulation by reducing the weight of additives such as excipients required to form the formulation.

In addition, the pharmaceutical composition can improve physical strength by reducing friability by containing abiraterone acetate, an active ingredient, in the form of wet granules.

In addition, the wet granules included in the pharmaceutical composition are manufactured using a high speed mixer (HSM), so their apparent density is increased, so their fluidity is good and tableting properties can be improved.

In addition, the pharmaceutical composition can improve the dissolution rate when formulated and reduce friability by including a certain amount of cellulose-based excipient, thereby improving the physical strength of the preparation.

Figures 1A and 1B are photographs showing the side and top surfaces of the tablets prepared in Comparative Example 1 and Example 6.

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

As used herein, the term “wet granule” refers to granules manufactured in a wet state, and may be manufactured by a wet granulation process. The wet granulation process has excellent fluidity and flowability compared to the direct compression process in which granules are directly compressed into tablets, resulting in excellent fillability and productivity. There is empty space between the granules, so they do not clump up when placed in water, increasing the surface area. Because it expands, it has the advantage of improved solubility. In addition, since all manufactured granules contain the same amount of drug, the drug content uniformity is good and there is an advantage in preventing separation of the drug from excipients, which can occur in the direct compression process or dry granulation process. In other words, wet granules have relatively increased powder cohesion and compressibility, and can maintain their shape even after drying, preventing separation of components. The wet granules can be manufactured by any wet granulation method, and a general wet granulation machine used to manufacture wet granules in the pharmaceutical field, such as a High Speed Mixer (HSM), or a Fluid Bed Granulator. , FBG).

The present invention relates to a pharmaceutical composition containing abiraterone acetate or a pharmaceutically acceptable salt thereof as an active ingredient.

The abiraterone acetate is an active ingredient in Zytiga ^® , a drug used to treat patients with metastatic castration-resistant prostate cancer, and can play a role in suppressing male hormones. Since abiraterone acetate is poorly soluble in water, a drug containing abiraterone acetate as an active ingredient must also contain a solubilizer. In order to obtain a pharmaceutical composition without reducing the efficacy of abiraterone acetate, a number of additives must be used to form a pharmaceutical composition while maintaining the effective content of abiraterone acetate and the content of the solubilizer. do. However, when formulating a pharmaceutical composition containing abiraterone acetate as an active ingredient, a solubilizer, and a number of additives, the medication convenience may be reduced due to the large mass and size of the preparation.

Therefore, in the pharmaceutical composition, the content of the active ingredient abiraterone acetate or a pharmaceutically acceptable salt thereof and the solubilizer are maintained, while the content of other additives is reduced, thereby producing the pharmaceutical composition. The aim is to improve the convenience of taking medication by reducing the mass and size of the preparation. At this time, the content of the active ingredient and solubilizer refers to an absolute weight value, and when the content of additives other than the active ingredient and solubilizer is reduced, the relative content of the active ingredient and solubilizer compared to the total weight of the pharmaceutical composition actually increases. It may be. In general, additives used when formulating pharmaceutical compositions serve to ensure that the formulation is well formed and improve the physical properties of the formulation itself, so if the content of the additive is excessively reduced, the physical properties of the formulation are deteriorated. There is a problem. Therefore, it is necessary to reduce the content of additives included in the pharmaceutical composition and appropriately adjust their content range in consideration of the physical properties of the preparation itself.

In the pharmaceutical composition according to the present invention, the abiraterone acetate or a pharmaceutically acceptable salt thereof may be contained in the form of granules, and preferably, the granules may be wet granules.

The wet granules may be manufactured by a wet granulation process. For example, the wet granulation process may be performed using a high speed mixer (HSM). In general, wet granules can be produced by a fluid bed granulator (FBG), but the strength of wet granules produced by the FBG may be reduced. When producing wet granules, when using the FBG compared to when using the HSM, many small-sized wet granules are produced, so it is difficult to formulate a pharmaceutical composition to a constant size, and the tableting properties are poor. The friability of the formulation may increase and its physical strength may decrease.

In the present invention, the apparent density of the granules may be 0.35 g/mL or more. Specifically, the apparent density may be 0.35 g/mL or more, 0.40 g/mL or more, or 0.45 g/mL or more. The upper limit of the apparent density is not particularly limited, and may be, for example, 0.5 g/mL or less or 0.6 g/mL or less. The apparent density is related to the fluidity of the granules, and the higher the apparent density, the lower the fluidity of the granules. If the fluidity of the granules is low, tabletting properties are not good, and the granules are not distributed uniformly within the tablet, resulting in mass deviation within the tablet, which may reduce reliability.

The apparent density may vary depending on the manufacturing method of the granules. For example, granules made with HSM have a higher apparent density than granules made with FBG, which may be good for tableting.

In the present invention, the weight of the pharmaceutical composition may be 600 mg to 1200 mg, specifically, 600 mg or more, 650 mg or more, 700 mg or more, or 750 mg or more, 1000 mg or less, 1050 mg or less, It may be 1100 mg or less, 1150 mg or less, or 1200 mg or less. If the weight of the oral preparation is less than 600 mg, the content of additives is relatively reduced compared to the active ingredient and solubilizer, which may reduce the physical properties of the preparation itself, such as dissolution rate and physical strength, and if it exceeds 1200 mg, the weight of the preparation increases. This may reduce the convenience of taking medication.

In the present invention, the pharmaceutical composition may be formulated as an oral preparation.

The oral preparation may be a tablet, capsule, or polycap. Preferably, it may be a tablet, but is not limited thereto as long as it is a solid preparation that can be ingested orally.

In the present invention, the size of the oral preparation may be 9 mm to 20 mm, specifically 9 mm or more, 10 mm or more, 13 mm or more, or 15 mm or more, 16 mm or less, 17 mm or less, It may be 18 mm or less or 20 mm or less. If the size of the oral preparation is less than 9 mm, it cannot be manufactured to contain an effective content of abiraterone acetate, and if it is more than 20 mm, the convenience of taking medication may decrease as the size of the preparation increases. At this time, the size of the oral preparation may mean the length of the longest axis of the oral preparation. Specifically, the oral preparation may have an oval cross-section, and the size of the oral preparation may refer to the length of the long axis of the oval shape.

In the present invention, the abiraterone acetate or a pharmaceutically acceptable salt thereof, which is an active ingredient of the pharmaceutical composition, may be included in an amount of 40% to 75% by weight based on the total weight of the pharmaceutical composition, specifically , may be 40% by weight or more, 45% by weight or more, 50% by weight or more, or 55% by weight or more, and may be 70% by weight or less, 72.6% by weight or less, or 75% by weight or less. If the content of abiraterone acetate or a pharmaceutically acceptable salt thereof is less than 40% by weight, the efficacy of the active ingredient, for example, the effect of suppressing male hormones, may be minimal, and if it is more than 75% by weight, abiraterone acetate is poorly soluble. As the content increases, the content of additives relatively decreases, resulting in lower dissolution rate and lower bioavailability.

In the present invention, the pharmaceutical composition may contain pharmaceutically acceptable additives necessary for formulation in addition to the active ingredient abiraterone acetate or a pharmaceutically acceptable salt thereof.

The pharmaceutically acceptable additives may be one or more selected from the group consisting of excipients, disintegrants, binders, solubilizers, fluidizers, and lubricants.

The above additives may be included in granules included in the pharmaceutical composition, or may be included in parts other than the granules within the pharmaceutical composition. At this time, the part containing the granules may be called the granule part, and the part other than the granule part may be called the additive part.

Among the pharmaceutically acceptable additives, excipients, disintegrants, and solubilizers are included in both the granule portion and the additive portion, so for the purpose of distinction, they are referred to as first and second excipients, respectively, and first and second excipients. It can be called release, and it can be called the first and second solubilizer.

The type and content of these additives can be appropriately selected by those skilled in the art according to the type of specific formulation to be manufactured.

For example, the excipients may be added to ensure that a formulation that is convenient to take is smoothly formed and to improve tabletting properties during molding. The excipients are selected from the group consisting of lactose, starch, mannitol, cellulose excipients, and combinations thereof, and the first and second excipients may be the same or different among the excipients. Preferably, the excipient may be a cellulose-based excipient, and the cellulose-based excipient may be selected from microcrystalline cellulose, silicified microcrystalline cellulose, and carboxymethyl cellulose. The content of the excipient is not particularly limited, and may be included in an amount of 5% to 40% by weight based on the total weight of the pharmaceutical composition to maximize the effect without affecting other ingredients.

Additionally, the disintegrant can improve the dissolution rate. The disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropylcellulose, and combinations thereof, and the first and second disintegrants are the same among these disintegrants. Or it may be different. The content of the disintegrant is not particularly limited, and may be included in an amount of 2% to 10% by weight based on the total weight of the pharmaceutical composition to maximize the effect without affecting other ingredients.

Additionally, the binder may be added to the granulation process to facilitate the formation of granules containing the active ingredient. The binder may be selected from the group consisting of povidone, hypromellose, hydroxypropylcellulose, copovidone, and combinations thereof. The content of the binder is not particularly limited, and may be included in an amount of 0.3% to 2% by weight based on the total weight of the pharmaceutical composition to maximize the effect without affecting other ingredients.

In addition, the solubilizer is intended to complement the poorly soluble characteristics of the active ingredient abiraterone acetate, and can improve the dissolution rate of the pharmaceutical composition. The solubilizer is sodium lauryl sulfate (SLS), and both the first and second solubilizers may be sodium lauryl sulfate. The content of the solubilizer is not particularly limited, and may be included in an amount of 5.0% by weight to 10% by weight based on the total weight of the pharmaceutical composition to maximize the effect without affecting other ingredients.

Additionally, the fluidizing agent can improve the flow characteristics of raw materials during the pharmaceutical composition manufacturing process. The fluidizing agent may be selected from the group consisting of silicon dioxide, colloidal silicon dioxide, talc, and combinations thereof. The content of the fluidizing agent is not particularly limited, and may be included in an amount of 0.1% to 1.0% by weight based on the total weight of the pharmaceutical composition to maximize the effect without affecting other ingredients.

Additionally, the lubricant may be added to improve the flowability and gloss of the pharmaceutical composition. The lubricant may be selected from the group consisting of magnesium stearate, talc, light anhydrous silicic acid, sodium stearyl fumarate, and combinations thereof. The content of the lubricant is not particularly limited, and may be included in an amount of 0.3% to 2.0% by weight based on the total weight of the pharmaceutical composition to maximize the effect without affecting other ingredients.

In the present invention, the pharmaceutical composition includes (1) a granule portion, and (2) an additive portion, wherein the (1) granule portion includes granules containing abiraterone acetate or a pharmaceutically acceptable salt thereof. It may be.

The granule part (1) includes granules, wherein the granules include the active ingredient abiraterone acetate or a pharmaceutically acceptable salt thereof, as well as pharmaceutically acceptable additives such as a first excipient, a first disintegrant, a binder, and an agent. 1 It may contain one or more types selected from the group consisting of solubilizers. Specific examples of the first excipient, first disintegrant, binder, and first solubilizer are as described above. Additionally, the granules may be wet granules. At this time, the first solubilizer may be essential to complement the poorly soluble characteristics of abiraterone acetate.

In addition, the (2) additive part may include pharmaceutically acceptable additives, and the pharmaceutically acceptable additives included in the additive part include a second excipient, a second disintegrant, a second solubilizer, and a fluidizing agent. And it may be one or more types selected from the group consisting of lubricants. Specific examples of the second excipient, second disintegrant, second solubilizer, fluidizer, and lubricant are as described above. At this time, the second solubilizer may be essential to complement the poorly soluble characteristics of abiraterone acetate.

In the present invention, among the additives included in the pharmaceutical composition, the dissolution rate of the active ingredient contained in the pharmaceutical composition and the strength of the pharmaceutical composition may vary depending on the content, type, and/or location of the excipient.

Additionally, the excipient may be a cellulose-based excipient, and the cellulose-based excipient may include one or more selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, and carboxymethyl cellulose. Generally, the cellulose-based excipient is used to improve flowability, but it can also serve as a disintegrant to improve dissolution rate. For example, the formulation of the pharmaceutical composition containing the cellulose-based excipient is disintegrated in the dissolution device and dissolution occurs. At this time, the cellulose-based excipient increases the penetration of the dissolution test solution into the matrix forming the formulation, increasing the initial dissolution rate. can be further improved. The elution test solution may be water.

The cellulose-based excipient may be included in an amount of 5% to 17% by weight based on the total weight of the pharmaceutical composition. Specifically, the content of the cellulose-based excipient may be 5% by weight or more, 5.2% by weight or more, or 5.5% by weight or more, and 10% by weight or less, 13% by weight or less, 15% by weight or less, 16% by weight or less, or 17% by weight. It may be below. If the content of the excipient is less than 5% by weight, the molding and tableting process does not proceed smoothly, making it difficult to manufacture an oral preparation in the desired form, and the effect of improving the initial dissolution rate may be minimal, and if it exceeds 17% by weight, the weight of the preparation and As the size increases, medication administration may be reduced. The content of the excipient means the sum of the content of the first and second excipients.

Additionally, the cellulose-based excipient may be included as a first excipient in the granule portion, a second excipient in the additive portion, or may be included as first and second excipients in the granule portion and the additive portion simultaneously.

Considering the dissolution rate of the active ingredient and the strength of the formulation, it may be desirable for the cellulose-based excipient to be included as a second excipient in the additive portion within the above content range.

The present invention also provides a method for producing a pharmaceutical composition containing abiraterone acetate or a pharmaceutically acceptable salt thereof as an active ingredient.

The method for producing a pharmaceutical composition according to the present invention includes the steps of (a) preparing abiraterone granules containing abiraterone acetate or a pharmaceutically acceptable salt thereof; and (b) mixing the abiraterone granules and pharmaceutically acceptable additives and compressing them into tablets. In addition, the step of coating the preparation after tableting may be additionally included.

At this time, the granules in step (a) may be wet granules manufactured by a high speed mixer (HSM).

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

[Example]

Example 1: Preparation of tablets containing abiraterone acetate by high speed mixer (HSM)

Coated tablets containing abiraterone acetate as an active ingredient were prepared according to the composition shown in Table 1 below.

(1) Formation of wet granules by high speed mixer (HSM)

Abiraterone acetate, lactose hydrate, and croscarmellose sodium were mixed in a high speed mixer (HSM, SM-5C, SE, JONG) to obtain a mixture. The above mixture and the binding solution were mixed to obtain a wet mixture. At this time, the binding solution is an aqueous solution containing hydroxypropyl methylcellulose (HPMC) and sodium lauryl sulfate.

The wet mixture was dried in an oven at 60°C, and then sieved through a sieve with 0.85 mm openings to prepare abiraterone acetate wet granules.

(2) Tablet formation

Silicified microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and colloidal silicon dioxide were added to the abiraterone acetate wet granules and mixed uniformly on the first stage, then magnesium stearate was added and mixed uniformly on the second stage for 5 minutes. Thus, a mixture was obtained.

The mixture was compressed using a tablet press (Autotab-200TR, ichihashi seiki) to obtain tablets with a hardness of about 18 kp.

(3) Tablet coating

Using a coating machine (SFC-30F, Sejong). The tablets were coated with the coating base listed in Table 1 below.

The total weight of coated tablets is 1153.6 mg.

Example 2: Preparation of tablets containing abiraterone acetate by high-speed mixer

Tablets were prepared in the same manner as in Example 1 by maintaining the contents of abiraterone acetate and sodium lauryl sulfate and adjusting the contents of other ingredients.

The weight of the tablet of Example 2 is 90% of the weight of the tablet of Example 1.

Example 3: Preparation of tablets containing abiraterone acetate by high-speed mixer

Tablets were prepared in the same manner as in Example 1 by maintaining the contents of abiraterone acetate and sodium lauryl sulfate and adjusting the contents of other ingredients.

The weight of the tablet of Example 3 is 80% of the weight of the tablet of Example 1.

Example 4: Preparation of tablets containing abiraterone acetate by high-speed mixer

Tablets were prepared in the same manner as in Example 1 by maintaining the contents of abiraterone acetate and sodium lauryl sulfate and adjusting the contents of other ingredients.

The weight of the tablet of Example 4 is 70% of the weight of the tablet of Example 1.

Example 5: Preparation of tablets containing abiraterone acetate by high-speed mixer

Tablets were prepared in the same manner as in Example 1 by maintaining the contents of abiraterone acetate and sodium lauryl sulfate and adjusting the contents of other ingredients.

The weight of the tablet of Example 5 is 65% of the weight of the tablet of Example 1.

Comparative Example 1: Preparation of tablets containing abiraterone acetate by fluid bed granulator (FBG)

Tablets were manufactured in the same manner as in Example 1, except that wet granules were manufactured using a fluidized bed granulator instead of a high-speed mixer.

Specifically, abiraterone acetate, lactose hydrate, and croscarmellose sodium were placed in a fluidized bed granulator (Dalton, NQ-160) to obtain a mixture. The binding solution was added here and a wet mixture was obtained. At this time, the binding solution is an aqueous solution containing hydroxypropyl methylcellulose (HPMC) and sodium lauryl sulfate.

The wet mixture was dried at 55°C and then sieved through a sieve with 0.85 mm openings to prepare abiraterone acetate wet granules.

The weight of the tablet of Comparative Example 1 was 1153.6 mg, which is the same as the weight of the tablet of Example 1.

Comparative Example 2: Preparation of tablets containing abiraterone acetate by fluid bed granulator

Tablets were prepared in the same manner as in Comparative Example 1 by maintaining the contents of abiraterone acetate and sodium lauryl sulfate and adjusting the contents of other ingredients.

The weight of the tablet of Comparative Example 2 is 70% of the weight of the tablet of Comparative Example 1.

Comparative Example 3: Preparation of tablets containing abiraterone acetate by fluid bed granulator

Tablets were prepared in the same manner as in Comparative Example 1 by maintaining the contents of abiraterone acetate and sodium lauryl sulfate and adjusting the contents of other ingredients.

The weight of the tablet of Comparative Example 3 was 60% of the weight of the tablet of Comparative Example 1.

The specific compositions of the tablets according to Examples 1 to 5 and Comparative Examples 1 to 3 are shown in Table 1 below.

process classification Ingredients Comparative Example 1 Comparative example 2 Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 3 wet granulation active ingredient Abiraterone Acetate 500.0 500.0 500.0 500.0 500.0 500.0 500.0 500.0 excipient lactose hydrate 253.2 93.7 253.2 202.6 151.9 93.7 76.0 50.6 disintegrant Croscarmellose Sodium 22.4 8.3 22.4 17.9 13.4 8.3 6.7 4.5 binder Hydroxypropyl methylcellulose 16.8 6.2 16.8 13.4 10.1 6.2 5.0 3.4 Solubilizer Sodium lauryl sulfate 5.6 5.6 5.6 5.6 5.6 5.6 5.6 5.6 solvent Water ^{Note 1)} (560.0) (208.0) (560.0) (448.0) (336.0) (208.0) (193.0) (112.0) Granule weight (mg) 798.0 613.8 798.0 739.5 798.0 613.8 593.3 564.1 additive excipient Silicified microcrystalline cellulose 184.8 85.0 184.8 147.8 110.9 85.0 55.4 37.0 disintegrant Croscarmellose Sodium 56.0 20.7 56.0 44.8 33.6 20.7 16.0 11.2 Solubilizer Sodium Lauryl Sulfate 56.0 56.0 56.0 56.0 56.0 56.0 56.0 56.0 Fluidizing agent colloidal silicon dioxide 8.4 3.1 8.4 6.7 5.0 3.1 2.5 1.7 lubricant stearic acid 16.8 6.2 16.8 13.4 10.1 6.2 5.0 3.4 Additive weight (mg) 1120.0 784.8 1120.0 1008.2 896.6 784.8 728.2 673.4 coating Coating mechanism Opadry II 85F 33.60 23.20 33.60 30.30 26.90 23.20 21.87 20.20 Total weight (mg) 1153.6 808.0 1153.6 1038.5 923.5 808.0 750.1 693.6 Active ingredient content compared to total weight (% by weight) ^{Note 2)} 43.3 61.9 43.3 48.1 54.1 61.9 66.7 72.1

Note 1) Water is removed during the process.

Note 2) The active ingredient content compared to the total weight is calculated as “(active ingredient/total weight) x 100”.

Experimental Example 1: Dissolution experiment

According to the following dissolution conditions, the dissolution rates of the tablets prepared in Examples 1 to 5 and Comparative Examples 1 to 3 were measured, respectively, and the results are shown in Table 2 below.

<Dissolution conditions>

Dissolution method: Korean Pharmacopoeia dissolution method 2 (paddle method)

Dissolution test solution: 56.5 mM sodium phosphate monobasic with 0.25% (w/v) SLS, pH4.5

Amount of dissolution test solution: 900 Ml

Dissolution test solution temperature: 37℃

Paddle speed: 75 rpm

Dissolution time: 5, 10, 15, 30, 45, 60 minutes

Dissolution rate (%) Comparative Example 1 Comparative example 2 Example 1 Example 2 Example 3 Example 4 Example 5 Comparative example 3 5 minutes 46 37.7 51.5 52.4 50.7 39.9 36.2 30.1 10 minutes 77 71.9 82.2 79.9 79.6 73.9 76.6 57.9 15 minutes 92 90.8 96.3 90.4 92.1 91.2 91.5 77.3 30 minutes 97 97.1 99.5 95.4 97.5 97.9 100.4 91.8 45 minutes 98 97.9 99.2 96.4 99.2 98.6 103.1 95.4 60 minutes 98 100.1 99.1 96.2 98.9 100.5 104.8 99.1

As specified in Table 2 above, the tablets of Example 1 and Comparative Example 1 were manufactured with the same tablet weight by different granulation methods using a high-speed mixer (HSM) and a fluidized bed granulator (FBG), respectively, but the dissolution rates were different. It didn't come out.

In addition, in Examples 2, 3, 4, and 5, the tablet weight was reduced by 10%, 20%, 30%, and 35%, respectively, compared to Example 1 and Comparative Example 1, and the active ingredient abiraterone acetate The content in the tablet is relatively increased.

The dissolution rates of Examples 2, 3, 4 and 5 were found to be similar to Example 1 and Comparative Example 1 (similarity factor f ₂ > 50). At this time, the similarity factor can be obtained from the similarity between the dissolution rate graphs obtained by the dissolution rate.

However, the dissolution rate of Comparative Example 3 showed a decrease in the initial dissolution rate from 5 to 15 minutes compared to Example 1 and Comparative Example 1 (similarity factor f ₂ < 50).

In the tablet prepared in Comparative Example 3, the content of abiraterone acetate, the active ingredient in the tablet, exceeds 70% by weight. Since the active ingredient, abiraterone acetate, is poorly soluble, it can be seen that the initial dissolution rate decreased due to the increase in the content of the poorly soluble active ingredient in the tablet prepared in Comparative Example 3.

Experimental Example 2: Friability experiment

A friability test was conducted according to the general information tablet friability test method in Annex 6 of the Korean Pharmacopoeia.

The tablet weight was measured before and after the friability test, the friability was calculated, and the results are shown in Table 3 below. Friability is a measure of the physical strength of a tablet. The smaller the calculated friability value, the better the physical strength of the tablet.

Comparative Example 1 Comparative example 2 Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 3 Masondo
(%) 0.39 0.51 0.17 0.28
(0.28±0.03) 0.31
(0.31±0.04) 0.27
(0.27±0.03) 0.38 0.54

As shown in Table 3, among Examples 1 to 5, the content of abiraterone acetate, the active ingredient, relative to the total weight of the tablet increases, and the friability also tends to increase from Example 1 to Example 5. It can be seen (in Example 4, there is no tendency for friability to increase, but the deviations in friability of Examples 2, 3, and 4 are 0.28 ± 0.03, 0.31 ± 0.04, and 0.27 ± 0.03, respectively, expanding to the range of deviation If interpreted accordingly, this tendency may be satisfied). Accordingly, it can be seen that as the content of the active ingredient in the total weight of the tablet increases, the strength decreases. This result is because as the content of the active ingredient increases in the total weight of the tablet, the content of the additive relatively decreases, thereby deteriorating the tableting properties. If the wear rate is at the level of Comparative Examples 1 to 3, it may be vulnerable to coating or packaging processes and may be dangerous.

In addition, when wet granules in tablets were manufactured with the same composition, it was found that tablets containing wet granules manufactured by a high-speed mixer had lower friability and superior physical strength compared to a fluidized bed granulator depending on the granulation method. For example, Comparative Example 1 and Example 1 had the same composition but were manufactured using a fluidized bed granulator and a high-speed mixer, respectively, and it was confirmed that Example 1 using a high-speed mixer had less attrition. Comparative Example 2 and Example 2 also had the same composition, but it was confirmed that the tablets of Example 2 manufactured using a high-speed mixer had less friability and thus had better physical strength.

Comparative Example 4

Coated tablets containing abiraterone acetate as an active ingredient were prepared according to the composition shown in Table 4 below, except that silicified microcrystalline cellulose, an excipient of the additive part, was not used. Tablets were prepared in the same manner as in Example 4. .

Example 6

Coated tablets containing abiraterone acetate as an active ingredient were prepared according to the composition shown in Table 4 below, except that the content of silicified microcrystalline cellulose used as an excipient in the additive section was reduced to 42.5 mg. Tablets were prepared in the same manner.

Example 7

Tablets were manufactured in the same manner as in Example 6, except that microcrystalline cellulose was used instead of silicified microcrystalline cellulose as an excipient in the additive section.

Example 8

Tablets were manufactured in the same manner as in Comparative Example 4, except that silicified microcrystalline cellulose was used instead of lactose hydrate as an excipient in the granule part.

Example 9

Tablets were manufactured in the same manner as in Comparative Example 4, except that microcrystalline cellulose was used instead of lactose hydrate as an excipient in the granule part.

process classification Ingredients Comparative Example 4 Example 6 Example 7 Example 8 Example 9 active ingredient Abiraterone Acetate 500.0 500.0 500.0 500.0 500.0 excipient
lactose hydrate 93.7 93.7 93.7 0 0 Silicified microcrystalline cellulose 0 0 0 42.5 0 Microcrystalline cellulose 0 0 0 0 42.5 disintegrant Croscarmellose Sodium 8.3 8.3 8.3 8.3 8.3 binder Hydroxypropyl methylcellulose 6.2 6.2 6.2 6.2 6.2 Solubilizer Sodium lauryl sulfate 5.6 5.6 5.6 5.6 5.6 solvent Water ^{Note 1)} (208.0) (208.0) (208.0) (208.0) (208.0) Granule weight (mg) 613.8 613.8 613.8 562.6 562.6 additive excipient
Silicified microcrystalline cellulose 0 42.5 0 0 0 Microcrystalline cellulose 0 0 42.5 0 0 disintegrant Croscarmellose Sodium 20.7 20.7 20.7 20.7 20.7 Solubilizer Sodium Lauryl Sulfate 56.0 56.0 56.0 56.0 56.0 Fluidizing agent colloidal silicon dioxide 3.1 3.1 3.1 3.1 3.1 lubricant Magnesium stearate 6.2 6.2 6.2 6.2 6.2 Additive weight (mg) 699.8 742.3 742.3 648.6 648.6 coating Coating mechanism Opadry II 85F 21.0 22.3 22.3 19.5 19.5 Total weight (mg) 720.8 764.6 764.6 668.1 668.1 Effective ingredient weight % compared to total weight ^{Note 2)} 69.4 65.4 65.4 74.8 74.8 Cellulose weight % compared to total weight Note ³⁾ 0 5.6 5.6 6.4 6.4

Note 1) Water is removed during the process.

Note 2) The weight of the active ingredient compared to the total weight is calculated as “(active ingredient/total weight) x 100.”

Note 3) The weight of cellulose compared to the total weight is calculated as “(cellulose excipient/total weight) x 100.”

Experimental Example 3: Dissolution experiment

The dissolution rates of the tablets prepared in Examples 6 to 9 and Comparative Example 4 were measured in the same manner as in Experimental Example 1, and the results are shown in Table 5 below.

Dissolution rate (%) Comparative Example 4 Example 6 Example 7 Example 8 Example 9 5 minutes 33.7 39.0 40.3 41.3 38.7 10 minutes 65.9 70.6 69.2 70.0 68.9 15 minutes 83.1 87.4 87.4 88.9 85.7 30 minutes 95.6 98.1 99.0 97.3 98.0 45 minutes 100.5 102.5 100.1 98.8 99.3 60 minutes 100.3 101.3 101.1 99.9 100.0

Referring to Table 5, Comparative Example 4 is a case in which no excipients, including cellulose-based excipients, were used in the additive portion, and it can be seen that the dissolution rate at the beginning (5 minutes) was low (about 8% low). In addition, in Examples 6 and 7, the content of silicified microcrystalline cellulose, a cellulose-based excipient, in the additive section was reduced compared to Example 4, and the dissolution rate was improved compared to Comparative Example 4 in which the amount of silicified microcrystalline cellulose was 0% by weight. You can see that Therefore, it can be seen that the dissolution rate is improved only when the content of the cellulose-based excipient is included within a certain range based on the total weight of the tablet.

Examples 8 and 9 contain a cellulose-based excipient instead of lactose hydrate as an excipient in the granule part and do not contain an excipient in the additive part. Comparative Example 4 contains lactose hydrate as an excipient in the granule part and does not contain an excipient in the additive part. It can be seen that the dissolution rate is improved compared to .

Experimental Example 4: Friability experiment

In the same manner as in Experimental Example 2, a friability test was performed on the tablets of Examples 6 to 9 and Comparative Example 4, and the results are shown in Table 6 below.

Comparative example 4 Example 6 Example 7 Example 8 Example 9 Friability (%) 0.44 0.34 0.38 0.35 0.37

Referring to Table 6, Comparative Example 4 is a case where the content of cellulose-based excipients in the tablet is 0% by weight, and it can be seen that the friability is higher than Examples 6 to 9, which contain cellulose-based excipients in the tablet.

In addition, Examples 6 and 7 contain a cellulose-based excipient in the additive portion, and Examples 8 and 9 include a cellulose-based excipient in the granule portion, regardless of which part of the tablet the cellulose-based excipient is contained in. , it can be seen that if it is included within a certain content range, it is advantageous in reducing the attrition of tablets.

Referring to Tables 5 and 6 above, in a tablet containing a granule portion and an additive portion, a certain content range of a cellulose-based excipient is included as an excipient, but when the cellulose-based excipient is included in the additive portion rather than the granule portion, the tablet's It can be seen that it can be more effective in improving dissolution rate and reducing friability.

Experimental Example 5: Tablet size measurement

The sizes of the tablets prepared in Comparative Example 1 and Example 6 were measured. The size of the tablet refers to the length of the longest axis of the tablet, and the size of the tablet was measured using a stick.

Figures 1A and 1B are photographs showing the side and top surfaces of the tablets prepared in Comparative Example 1 and Example 6.

Referring to Figures 1A and 1B, it can be seen that the length of the tablet prepared in Comparative Example 1 is larger than that of Example 6. At this time, the tablet has an oval cross-section, and the length of the tablet may mean the long axis of the oval. Specifically, the tablet of Comparative Example 1 had a cross section width x length of 18.9 x 9.1 mm, and the tablet of Example 6 had a cross section width x height of 16.0 x 9.0 mm.

Although the tablet weight of Example 6 was reduced compared to Comparative Example 1, the content of the active ingredient abiraterone acetate was high, the dissolution rate was excellent, and the size was reduced, so it can be seen that the convenience of taking medication will be good.

Experimental Example 6: Density measurement of granules

Density was measured according to the granule manufacturing method.

Approximately 20.0 g of the prepared granules were placed into a drying cylinder without being compressed. After reading the apparent unsettled volume within the cylinder, the apparent density was calculated by dividing by the weight. The cylinder was fixed to a tap density measuring device capable of producing 250 taps for 1 minute from a height of 3 ± 0.2 mm, then 500 taps were performed, the volume was read, and the tap density was calculated by dividing by weight. The calculated apparent density and tap density are as shown in Table 7 below.

Comparative Example 1 Comparative example 2 Comparative Example 3 Comparative Example 4 Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Granule manufacturing method FBG FBG FBG HSM HSM HSM HSM HSM HSM HSM HSM HSM HSM Apparent density (g/mL) 0.28 0.27 0.28 0.38 0.43 0.43 0.42 0.38 0.37 0.35 0.35 0.36 0.37 Tap density (g/mL) 0.48 0.49 0.47 0.49 0.52 0.53 0.54 0.48 0.49 0.45 0.43 0.46 0.47

Referring to Table 7, it can be seen that the tap density of the granules is similar regardless of the granule manufacturing method.

On the other hand, granules prepared with FBG were found to have a lower apparent density compared to granules prepared with HSM.

If the apparent density of the granules is low, it means that the fluidity of the granules is low. In this case, tabletting properties are not good, the uniformity of granule content within the compressed tablet is not good, and mass deviation may occur.

Therefore, in tablets containing granules, when the granules are manufactured with HSM, the apparent density of the granules is low, and the tableting properties of the granules are good. In addition, since the granules can be uniformly contained within the tablet, mass deviation can be minimized, thereby improving the reliability of the tablet.

In particular, among tablets containing granules prepared from HSM, tablets containing a cellulose-based excipient can also exhibit an effect of improving dissolution rate (Examples 1 to 9).

Claims (14)

A pharmaceutical composition comprising abiraterone acetate or a pharmaceutically acceptable salt thereof,
The abiraterone acetate or a pharmaceutically acceptable salt thereof is contained in granule form,
The apparent density of the granules is 0.35 g/mL or more,
A pharmaceutical composition, wherein the weight of the pharmaceutical composition is 600 mg to 1200 mg. According to paragraph 1,
A pharmaceutical composition wherein the abiraterone acetate or a pharmaceutically acceptable salt thereof is contained in an amount of 40% by weight to 75% by weight based on the total weight of the composition. According to paragraph 1,
A pharmaceutical composition, wherein the granules are wet granules prepared by a high speed mixer (HSM). According to paragraph 1,
The pharmaceutical composition includes (1) a granule portion, and (2) an additive portion,
A pharmaceutical composition wherein the abiraterone acetate or a pharmaceutically acceptable salt thereof is contained in the granule portion. According to paragraph 1,
A pharmaceutical composition, wherein the pharmaceutical composition includes a solubilizer. According to clause 5,
A pharmaceutical composition, wherein the solubilizer is contained in an amount of 5% to 10% by weight based on the total weight of the pharmaceutical composition. According to paragraph 4,
The (1) granule portion includes a first excipient, and/or
A pharmaceutical composition wherein the (2) additive part includes a second excipient. In clause 7,
The first excipient and the second excipient may each include one or more selected from the group consisting of lactose hydrate and cellulose-based excipient,
A pharmaceutical composition wherein the first excipient and the second excipient are the same or different from each other. According to clause 8,
A pharmaceutical composition wherein the second excipient includes a cellulose-based excipient. According to clause 8,
The cellulose-based excipient is a pharmaceutical composition comprising at least one selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, and carboxymethyl cellulose. According to clause 8,
A pharmaceutical composition wherein the cellulose-based excipient is contained in an amount of 5 to 17% by weight based on the total weight of the pharmaceutical composition. According to paragraph 1,
The pharmaceutical composition is formulated as an oral preparation. According to clause 12,
A pharmaceutical composition wherein the oral preparation is a tablet, capsule, or polycap. According to paragraph 1,
A pharmaceutical composition, wherein the size of the oral preparation is 9 mm to 20 mm.