As an explanation and description, in the above-mentioned embodiments, 1 part by weight: 1 part by volume=1 g:1 mL.

In the pharmaceutical composition containing abiraterone acetate according to the present invention, preferably, the active ingredients also comprise prednisone.

The pharmaceutical composition of the invention has an excellent efficacy as a medicament, especially an excellent inhibitory activity on 17α-hydroxylase/C17,20-lyase (CYP17). Since the pharmaceutical composition of the invention can significantly reduce the difference between pre-meal and post-meal administration and improve the oral bioavailability, it can be used in conjunction with prednisone in the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) who ever received with polyene paclitaxel chemotherapy, and can achieve an outstanding efficacy.

The pharmaceutical composition containing abiraterone acetate provided by the present invention can be used alone for treating diseases, for example, diseases including but not limited to prostate cancer. In a specific administrating process, the pharmaceutical composition provided by the present invention can be administered in, for example but not limited to, the following manners.

An adult is administrated at intervals of one day, for example, once a day. Preferably, the effective dose of abiraterone acetate per administration is 25 mg to 200 mg, more preferably 50 mg to 150 mg, and further more preferably 75 mg to 100 mg.

The present invention also provides the use of the pharmaceutical composition in the manufacture of a pharmaceutical preparation, preferably in the manufacture of a pharmaceutical preparation for the treatment of prostate cancer. More preferably, the prostate cancer is selected from one or two of metastatic castration-resistant prostate cancer and high-risk metastatic castration-sensitive prostate cancer.

The present invention further provides a pharmaceutical preparation containing the pharmaceutical composition described in any one of the above. Preferably, the pharmaceutical preparation is a capsule.

The capsule of the invention comprises any one of the above-mentioned pharmaceutical composition containing abiraterone acetate and a capsule shell. The capsule shells are well-known hard capsule and/or soft capsule materials, such as that used in hard gelatin capsules or soft gelatin capsules, which is commercially available or produced and is not specially defined herein.

Each capsule of the capsule of the present invention preferably comprises no more than 100 mg of abiraterone acetate.

The present invention defines that the abiraterone acetate capsules have a single oral dose of 50 to 200 mg of abiraterone acetate.

The present invention further provides a pharmaceutical combination (manner), comprising:

- one of the pharmaceutical compositions according to any one of the embodiments described above and the abiraterone acetate capsules according to any one of the embodiments described above, and
- prednisone.

The said pharmaceutical combination (manner) of the invention described herein have an administration manner of, including but are not being limited to, using prednisone as one of the active ingredients, sequentially administrating the pharmaceutical compositions or capsules and prednisone, and the like. It can be administrated through common operations in the art.

The present invention further provides the use of the abiraterone acetate capsule according to any one of the embodiments described above, and/or the pharmaceutical combination according to any one of the embodiments in the manufacture of a medicament for the treatment of prostate cancer.

Preferably, the prostate cancer is selected from one or two of metastatic castration-resistant prostate cancer and high-risk metastatic castration-sensitive prostate cancer.

The present invention also provides a method of preparing the pharmaceutical composition containing abiraterone acetate according to any one of the embodiments described above, comprising mixing the oil phase, the emulsifier and the active ingredient, and adding the co-emulsifier (and may further adding antioxidants and/or preservatives).

It will be understood by one skilled in the art that the preparation method can include the steps of mechanical stirring, emulsificating, and sonicating. A preferred embodiment is provided as follows:

- stirring the oil phase and the emulsifier at room temperature or under heating condition to form a homogeneous mixture, then adding abiraterone acetate to the mixture and stirring the mixture in dark conditions, and finally adding co-emulsifier and optionally antioxidants and/or preservatives and mixing the mixture well to obtain the pharmaceutical composition.

More specifically, the method comprises the following steps:

- stirring the oil phase and the emulsifier at room temperature or under heating condition to form a homogeneous mixture, then adding abiraterone acetate to the mixture, sonicating the mixture for 10 to 20 minutes under dark conditions, mechanically stirring the mixture for 10 to 30 minutes at a speed of 100 to 400 rpm, and finally adding the co-emulsifier and mixing the mixture well to obtain the pharmaceutical composition.

The method for manufacturing the pharmaceutical preparations of the invention may also be operated by one skilled in the art according to conventional methods in the art. A preferred embodiment for preparing capsules is given herein as follows:

- preparing the pharmaceutical composition containing abiraterone acetate according to the aforementioned method; sealing the pharmaceutical composition in a soft capsule or a hard capsule. Preferably, each capsule contains 0.5 to 1 ml of the pharmaceutical composition.

In the pharmaceutical composition containing abiraterone acetate provided by the present invention, the concentration of abiraterone acetate can be controlled in the range of 50 to 100 mg/mL and a single oral dose is 75 to 100 mg. The pharmaceutical composition of the invention can spontaneously form an O/W nanoemulsion having a particle size of less than 250 nm with high clarity, uniform particle size and stable properties when mixed with water, biologically related media such as SGF, SGF, FessiF and FassiF media, or gastrointestinal fluid; can exist in the form of a stable solution when stored at room temperature; can possess a stable content even under the conditions of influencing factors (40° C.±2° C., or a relative humidity of 90%).

The difference between pre-meal and post-meal administration of the pharmaceutical composition of the invention is significantly reduced and the oral bioavailability is increased by several to ten times compared to the original drug Zytiga. The pharmaceutical composition can be further manufactured into a capsule, which is stable and the content has a uniform texture.

The present invention further relates to a method of treatment of prostate cancer, comprising administering the aforementioned pharmaceutical composition containing abiraterone acetate or abiraterone acetate capsules. Preferably, a single dose is 25 mg to 200 mg of abiraterone acetate, more preferably 50 mg to 200 mg, still more preferably 50 mg to 150 mg, further preferably 75 mg to 100 mg. Preferably, the pharmaceutical composition or capsule can be administered before or after meal. Preferably, the prostate cancer is selected from one or two of metastatic castration-resistant prostate cancer and high-risk metastatic castration-sensitive prostate cancer.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to explain the embodiments of the present invention or the prior art more clearly, the drawings that need to be used in the description of the embodiments or the prior art will be introduced briefly in the following. It is obvious that the drawings in the following description are merely part of the embodiments of the present invention. For one skilled in the art, other drawings can be obtained based on these drawings without creative efforts.

FIG. 1 is a particle size distribution diagram after the content of the abiraterone acetate capsule in Example 1 forming microemulsions in water.

FIG. 2 is a particle size distribution diagram after the content of the abiraterone acetate capsule in Example 2 forming microemulsions in water.

FIG. 3 is a particle size distribution diagram after the content of the abiraterone acetate capsule in Example 8 forming microemulsions in water.

FIG. 4 is a drug-time curve chart of the fasting test for tablet and capsule in Test Example 4.

FIG. 5 is a drug-time curve chart of the fasting and postprandial test for capsule in Test Example 4.

DETAILED DESCRIPTION OF THE INVENTION

The technical solutions in the examples of the present invention will be clearly and completely described below in conjunction with the accompanied drawings of the examples of the present invention. Obviously, the described examples are merely a part of the examples rather than all the examples of the present invention. Based on the examples of the present invention, all other examples obtained by one skilled in the art without creative effects fall within the scope of the present invention.

Example 1

This example provided a pharmaceutical composition containing abiraterone acetate comprising the following components:

abiraterone acetate
1.65
g

hydrogenated castor oil
4.0
mL

glyceryl monooleate
4.0
mL

polyoxyethylene castor oil EL35
8.0
mL

propylene glycol
2.0
mL

ethanol
4.0
mL

This example further provided an abiraterone acetate capsule, which used the above-mentioned pharmaceutical composition as the content, and the content was filled in a capsule shell.

The preparation method was provided as follows.

Hydrogenated castor oil, glyceryl monooleate, and polyoxyethylene castor oil EL35 were measured out, and then abiraterone acetate was added to form a mixture. The mixture was sonicated for 10 minutes under dark conditions and was stirred mechanically at 300 rpm for 20 minutes to allow it completely dissolved. Thereafter, propylene glycol and ethanol were added until it became a transparent and homogeneous self-emulsifying solution, which was filled in soft capsules or sealed in hard capsules under nitrogen atmosphere and stored.

Example 2

This example provided a pharmaceutical composition containing abiraterone acetate comprising the following components:

abiraterone acetate
4.00
g

Span 80
9.0
mL

polyoxyethylene castor oil EL35
7.0
mL

glyceryl monooleate
7.0
mL

hydrogenated castor oil
9.0
mL

propylene glycol
4.0
mL

ethanol
8.0
mL

BHA
0.009
g

BHT
0.014
g

This example further provided an abiraterone acetate capsule, which used the above-mentioned pharmaceutical composition as the content, and the content was filled in a capsule shell.

The preparation method was provided as follows.

Span 80, hydrogenated castor oil, glyceryl monooleate, and polyoxyethylene castor oil EL35 were measured out, and then abiraterone acetate was added to form a mixture. The mixture was stirred mechanically at 300 rpm for 25 minutes to allow it completely dissolved. Thereafter, BHA, BHT, propylene glycol and ethanol were added until it became a transparent and homogeneous self-emulsifying solution, which was filled in soft capsules or sealed in hard capsules under nitrogen atmosphere and stored.

Example 3

This example provided a pharmaceutical composition containing abiraterone acetate comprising the following components:

abiraterone acetate
1.17
g

glyceryl monolinoleate
4.4
mL

medium chain triglyceride
2.8
mL

polyoxyethylene 40 hydrogenated castor oil
3.6
mL

diethylene glycol monoethyl ether
4.8
mL

BHA
0.004
g

BHT
0.012
g

This example further provided an abiraterone acetate capsule, which used the above-mentioned pharmaceutical composition as the content, and the content was filled in a capsule shell.

The preparation method was provided as follows.

Medium chain triglyceride, glyceryl monolinoleate, and polyoxyethylene 40 hydrogenated castor oil were measured out, and then abiraterone acetate was added to form a mixture. The mixture was stirred mechanically at 300 rpm for 30 minutes to allow it completely dissolved. Thereafter, diethylene glycol monoethyl ether, BHT, and BHA were added until it became a transparent and homogeneous self-emulsifying solution, which was filled in soft capsules or sealed in hard capsules under nitrogen atmosphere and stored.

Example 4

This example provided a pharmaceutical composition containing abiraterone acetate comprising the following components:

abiraterone acetate
1.47
g

glyceryl monolinoleate
4.4
mL

polyoxyethylene 40 hydrogenated castor oil
3.6
mL

diethylene glycol monoethyl ether
7.6
mL

BHA
0.004
g

BHT
0.012
g

This example further provided an abiraterone acetate capsule, which used the above-mentioned pharmaceutical composition as the content, and the content was filled in a capsule shell.

The preparation method was provided as follows.

Glyceryl monolinoleate, and polyoxyethylene 40 hydrogenated castor oil were measured out, and then abiraterone acetate was added to form a mixture. The mixture was stirred mechanically at 300 rpm for 30 minutes to allow it completely dissolved. Thereafter, diethylene glycol monoethyl ether, BHT, and BHA were added until it became a transparent and homogeneous self-emulsifying solution, which was filled in soft capsules or sealed in hard capsules under nitrogen atmosphere and stored.

Example 5

This example provided a pharmaceutical composition containing abiraterone acetate comprising the following components:

abiraterone acetate
1.32
g

glyceryl monolinoleate
5.6
mL

medium chain triglyceride
2.8
mL

polyoxyethylene 40 hydrogenated castor oil
4.8
mL

propylene glycol
2.8
mL

ethanol
1.6
mL

BHA
0.004
g

BHT
0.009
g

This example further provided an abiraterone acetate capsule, which used the above-mentioned pharmaceutical composition as the content, and the content was filled in a capsule shell.

The preparation method was provided as follows.

Medium chain triglyceride, glyceryl monolinoleate, and polyoxyethylene 40 hydrogenated castor oil were measured out, and then abiraterone acetate was added to form a mixture. The mixture was stirred mechanically at 300 rpm for 30 minutes to allow it completely dissolved. Thereafter, ethanol, propylene glycol, BHT, and BHA were added until it became a transparent and homogeneous self-emulsifying solution, which was filled in soft capsules or sealed in hard capsules under nitrogen atmosphere and stored.

Example 6

This example provided a pharmaceutical composition containing abiraterone acetate comprising the following components:

abiraterone acetate
2.2
g

Tween 80
5.0
mL

polyoxyethylene 40 hydrogenated castor oil
8.0
mL

glyceryl monooleate
9.0
mL

corn oil
10.0
mL

propylene glycol
4.0
mL

ethanol
8.0
mL

This example further provided an abiraterone acetate capsule, which used the above-mentioned pharmaceutical composition as the content, and the content was filled in a capsule shell.

The preparation method was also provided as follows. Tween 80, corn oil, glyceryl monooleate, and polyoxyethylene 40 hydrogenated castor oil were measured out, and then abiraterone acetate was weighed and added to allow it fully mixed. Thereafter, propylene glycol and ethanol were added, and a transparent and homogeneous solution was obtained under heating under water bath. After the solution was cooled down to room temperature, the homogeneous phase was destroyed and the drug was crystallized out.

Example 7

This example provided a pharmaceutical composition containing abiraterone acetate comprising the following components:

abiraterone acetate
4.40
g

Tween 80
3.0
mL

polyoxyethylene castor oil EL35
5.0
mL

polyoxyethylene 40 hydrogenated castor oil
8.0
mL

glyceryl monooleate
8.0
mL

hydrogenated castor oil
8.0
mL

propylene glycol
2.0
mL

ethanol
10.0
mL

This example further provided an abiraterone acetate capsule, which used the above-mentioned pharmaceutical composition as the content, and the content was filled in a capsule shell.

The preparation method was also provided as follows. Tween 80, polyoxyethylene 40 hydrogenated castor oil, hydrogenated castor oil, glyceryl monooleate, and polyoxyethylene castor oil EL35 were measured out, and then abiraterone acetate was added to allow it completely dissolved. Thereafter, propylene glycol and ethanol were added until it became a transparent and homogeneous self-emulsifying solution, which was filled in soft capsules or sealed in hard capsules under nitrogen atmosphere and stored.

Example 8

This example provided a pharmaceutical composition containing abiraterone acetate comprising the following components:

abiraterone acetate
4.40
g

Span 80
8.4
mL

Solutol
2.6
mL

polyoxyethylene castor oil EL35
5.0
mL

glyceryl monooleate
8.0
mL

hydrogenated castor oil
8.0
mL

propylene glycol
2.0
mL

ethanol
10.0
mL

This example further provided an abiraterone acetate capsule, which used the above-mentioned pharmaceutical composition as the content, and the content was filled in a capsule shell.

The preparation method was also provided. Span 80, Solutol, hydrogenated castor oil, glyceryl monooleate, and polyoxyethylene castor oil EL35 were measured out, and then abiraterone acetate was added to allow it completely dissolved. Thereafter, propylene glycol and ethanol were added until it became a transparent and homogeneous self-emulsifying solution, which was filled in soft capsules or sealed in hard capsules under nitrogen atmosphere and stored.

Example 9

This example provided a pharmaceutical composition containing abiraterone acetate comprising the following components:

abiraterone acetate
4.40
g

Span 80
8.8
mL

polyoxyethylene castor oil EL35
4.4
mL

glyceryl monooleate
8.0
mL

hydrogenated castor oil
9.6
mL

propylene glycol
4.4
mL

ethanol
8.8
mL

This example further provided an abiraterone acetate capsule, which used the above-mentioned pharmaceutical composition as the content, and the content was filled in a capsule shell.

The preparation method was also provided. Span 80, hydrogenated castor oil, glyceryl monooleate, and polyoxyethylene castor oil EL35 were measured out, and then abiraterone acetate was added to allow it completely dissolved. Thereafter, propylene glycol and ethanol were added until it became a transparent and homogeneous self-emulsifying solution, which was filled in soft capsules or sealed in hard capsules under nitrogen atmosphere and stored.

Example 10

Same with Example 1, with the exceptions that 2.0 mL propylene glycol and 4.0 mL ethanol were replaced with 1.0 mL propylene glycol and 2.0 mL ethanol, respectively.

Example 11

Same with Example 3, with the exceptions that 4.8 mL diethylene glycol monoethyl ether was replaced with 1.6 mL diethylene glycol monoethyl ether.

Example 12

Same with Example 3, with the exceptions that 4.8 mL diethylene glycol monoethyl ether was replaced with 17.6 mL diethylene glycol monoethyl ether.

Example 13

Same with Example 3, with the exceptions that 4.8 mL diethylene glycol monoethyl ether was replaced with 36.8 mL diethylene glycol monoethyl ether.

Example 14

This example provided a pharmaceutical composition containing abiraterone acetate comprising the following components:

abiraterone acetate
50 mg

glyceryl monolinoleate
286.5 mg

medium chain triglyceride
84.89 mg

polyoxyethylene 40 hydrogenated castor oil
212.22 mg

diethylene glycol monoethyl ether
477.5 mg

Test Example 1

This Test example provided the dissolution test of abiraterone acetate capsules provided in Example 1-4 and original drug Zytiga tablet.

Test method: in accordance with the dissolution test method for abiraterone acetate from the “United States Pharmacopoeia (USP)”, the dissolution tests of abiraterone acetate capsules (prepared in Examples 1, 2, 3) and the original drug Zytiga tablet were carried out in 900 mL release medium 1 under 50 rpm at 37° C., respectively.

Among them, a phosphate buffer solution with a pH of 4.5 was prepared by the following method: adding 56.5 mM sodium dihydrogen phosphate to water, and adjusting the pH was to 4.5 with sodium hydroxide or phosphoric acid.

The specific method was as follows:

Dissolution
Medium 1: 900 ml phosphate buffer

conditions
solution containing 0.25%

sodium lauryl sulfate with pH 4.5 (USP condition)

Medium 2: 900 ml water

Rotation speed: 50 r/min

Time: 45 min

Test methods
UV-visible spectrophotometer

Test preparations
Commercial preparation: Trade name

(Zytiga) Specification:

250 mg tablet

Preparation of the present invention: abiraterone acetate

capsules of Examples 1, 2, 3 and 4

Test results
Dissolution test results: see Tables 1 and Table 2

TABLE 1

Dissolution of abiraterone acetate capsule and

Zytiga tablet in medium 1 (%)

Sampling

Example
Example
Example
Example

point/min
Zytiga
1
2
3
4

5
22
73
80
74
75

10
42
93
97
91
90

15
64
96
99
97
96

20
71
98
99
99
97

30
89
99
97
99
99

45
91
98
99
99
99

TABLE 2

Dissolution of abiraterone acetate capsule and

Zytiga tablet in medium 2 (%)

Sampling

point/min
Zytiga
Example 1
Example 2
Example 3
Example 4

5
0
86
72
70
75

10
0
95
84
84
82

15
1
99
92
90
97

20
1
98
96
94
96

30
2
99
97
99
97

45
2
97
99
99
99

The comparison results of Tables 1 and 2 showed that the abiraterone acetate capsules of the present invention (Examples 1, 2, 3, and 4) were substantially dissolved completely in medium 1 within 15 minutes, but the commercial abiraterone acetate tablet Zytiga was unable to be completely dissolved until 45 minute. The abiraterone acetate capsules of the present invention (Examples 1, 2, 3, and 4) were substantially dissolved completely in medium 2, but the commercial abiraterone acetate tablet Zytiga had an extremely low dissolution.

It can be seen from the experimental results described above that the abiraterone acetate capsule of the present invention is capable of effectively improving the dissolution of abiraterone acetate under both USP and non-UPS conditions, which facilitates to increase the oral bioavailability of abiraterone acetate and reduce individual differences.

Test Example 2

This Test example provided the stability test of the abiraterone acetate capsule provided by Examples 1-9.

(1) Long-term test: the abiraterone acetate capsule was charged into a polyethylene plastic bottle, and the sample was placed under a relative humidity of 60%±10% at a temperature of 25° C.±2° C. to observe the physical stability of the pharmaceutical composition inside the capsule. The test results were shown in Table 3.

TABLE 3

Physical stability of the pharmaceutical composition

Stability test
1 month
2 months
3 months
6 months

Example 1
−
−
−
−

Example 2
−
−
−
−

Example 3
−
−
−
−

Example 4
−
−
−
−

Example 5
−
−
−
−

Example 6
+
++
++
++

Example 7
−
++
++
++

Example 8
−
−
−
−

Example 9
−
−
−
−

Example 10
+
++
+++
+++

Example 11
+
++
+++
+++

Example 12
−
−
−
−

Example 13
−
−
−
−

Example 14
−
−
−
−

−: Clear solution, no drug precipitation

+: Clear solution, trace amount of drug precipitation

++: Clear solution, small amount of drug precipitation

+++: Clear solution, substantial amount of drug precipitation

It can be seen from Table 3 that the pharmaceutical composition formed by the specific emulsifier, oil phase, co-emulsifier and abiraterone acetate of the present invention has good physical stability. Particularly, the combination of 20% to 80% (percent by mass relative to the total mass of the composition) of specific co-emulsifiers and specific emulsifiers (polyoxyethylene castor oil EL35, polyoxyethylene 40 hydrogenated castor oil, Span 80, polyethylene glycol-15 hydroxystearate) achieves a significantly better physical stability. In addition, taking the factors such as drug safety, chemical stability, preparation production and so on into consideration, the percent of the co-emulsifier is preferably 60% or less by mass, particularly 20% to 60%.

(2) Accelerated test: the abiraterone acetate capsule was charged into a polyethylene plastic bottle, and then the sample was placed under a relative humidity of 60%±10% at a temperature of 40° C.±2° C. to test the content and related substances of the pharmaceutical composition. The results were shown in Table 4. The abiraterone acetate capsules prepared in Examples 1, 2, 3, and 4 possess stable content.

TABLE 4

Accelerated stability of the pharmaceutical composition

0 month
1 month
3 months

Exam-
Traits
Light yellow
Light yellow
Light yellow

ple 1

transparent
transparent
transparent

liquid
liquid
liquid

Content
99.9%
99.8%
99.2%

Total
0.05%
0.21%
0.78%

impurities

Dis-
passed
passed
passed

solution

Exam-
Traits
Light yellow
Light yellow
Light yellow

ple 2

transparent
transparent
transparent

liquid
liquid
liquid

Content
99.9%
99.8%
99.7%

Related
0.05%
0.15%
0.26%

substances

Dis-
passed
passed
passed

solution

Exam-
Traits
Light yellow
Light yellow
Light yellow

ple

transparent
transparent
transparent

3

liquid
liquid
liquid

Content
99.9%
99.9%
99.3%

Related
0.05%
0.11%
0.69%

substances

Dis-
passed
passed
passed

solution

Exam-
Traits
Light yellow
Light yellow
Light yellow

ple

transparent
transparent
transparent

4

liquid
liquid
liquid

Content
99.9%
99.9%
99.4%

Related
0.05%
0.11%
0.57%

substances

Dis-
passed
passed
passed

solution

Test Example 3

This Test example provided the self-emulsification ability and particle size test of the pharmaceutical compositions provided by Examples 1 to 9.

The pharmaceutical compositions prepared in Examples 1-9 were added to purified water, and the appearance and traits were observed after slight shaking. The particle size of the formed emulsion was measured with a nanoparticle size meter. Results is shown in Tables 5-1.

TABLE 5-1

Traits and particle size after emulsification

of the pharmaceutical composition

Nanoemulsion

Traits
particle size

Example 1
Clear and transparent nanoemulsion
about 100 nm

Example 2
Clear and transparent slightly blue
about 110 nm

opalescent nanoemulsion

Example 3
Clear and transparent slightly blue
about 70 nm

opalescent nanoemulsion

Example 4
Clear and transparent slightly blue
about 90 nm

opalescent nanoemulsion

Example 5
Clear and transparent slightly blue
about 90 nm

opalescent nanoemulsion

Example 6
Unable to form a homogeneous
Not tested

system, oil droplets always exist

Example 7
Opalescent nanoemulsion
Not tested

Example 8
Clear and transparent light blue
about 270 nm

opalescent nanoemulsion

Example 9
Clear and transparent light blue
about 140 nm

opalescent nanoemulsion

This Test example also provided the stability test of the obtained nanoemulsion after emulsifying the pharmaceutical compositions of Examples 1 to 9. The test method was as follows.

Long-term test: the samples were placed under a relative humidity of 60%±10% at a temperature of 25° C.±2° C. and the stability of the nanoemulsion after emulsification of the pharmaceutical composition was observed. The results were shown in Table 5-2.

TABLE 5-2

Nanoemulsion traits after emulsification

of the pharmaceutical composition

0 h
2 weeks
4 weeks

Example 1
Clear and transparent nanoemulsion
—
—

Example 2
Clear and transparent slightly blue
—
—

opalescent nanoemulsion

Example 3
Clear and transparent slightly blue
—
—

opalescent nanoemulsion

Example 4
Clear and transparent slightly blue
—
—

opalescent nanoemulsion

Example 8
Clear and transparent light blue
—
—

opalescent nanoemulsion

Example 9
Clear and transparent light blue
—
—

opalescent nanoemulsion

— Represents no difference

See the attached drawings. FIG. 1 is the particle size distribution diagram of the microemulsion formed by the content of abiraterone acetate capsule in Example 1 in water, FIG. 2 is the particle size distribution diagram of the microemulsion formed by the content of abiraterone acetate capsule in Example 2 in water, and FIG. 3 is the particle size distribution diagram of the microemulsion formed by the content of abiraterone acetate capsule in Example 8 in water.

Test Example 4

This Test example provided the pharmacokinetic test of Example 1, Example 14 and the original drug Zytiga of abiraterone acetate.

Test method and subject:

- Healthy beagle dogs were randomly divided into 3 groups, 2 in each group, and the washout period is 3 days between cycles. The test groups were shown in Table 6.

The tests were divided into fasting test and postprandial test.

Fasting test: fasting the subject for 10 h before the test, administrating the drug on an empty stomach, and feeding 4 hours after the administration.

Postprandial test: fasting the subject for 10 h before the test, and administering after feeding a high-fat meal (feeding and administration were completed within 30 minutes).

The tested tablet was the original drug Zytiga of abiraterone acetate, and a single tablet contained 250 mg of abiraterone acetate.

The tested capsule I was the abiraterone acetate capsule provided by Example 1, and a single capsule contained 50 mg of abiraterone acetate.

The tested capsule II was the abiraterone acetate capsule provided by Example 14, and a single capsule contained 50 mg of abiraterone acetate.

Sampling design: collecting 2 mL blood sample at 15 minutes, 30 minutes, 1 h, 1.5 h, 2.0 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, and 24 h after administration, and centrifuging the sample to separate plasma.

TABLE 6

Test grouping

Test
First
Second
Third
Fourth
Fifth

group
cycle
cycle
cycle
cycle
cycle

1
fasting, 2
postprandial, 1
fasting, 1
fasting, 1
postprandial, 1

tablets (T1)
capsule I (T3)
capsule I (T2)
capsule II (T4)
capsule II (T5)

2
fasting, 1
fasting, 2
postprandial, 1
fasting, 1
postprandial, 1

capsule I (T2)
tablets (T1)
capsule I (T3)
capsule II (T4)
capsule II (T5)

3
postprandial, 1
fasting, 1
fasting, 2
fasting, 1
postprandial, 1

capsule I (T3)
capsule I (T2)
tablets (T1)
capsule II (T4)
capsule II (T5)

In the table, T1 represents a group with fasting test-the original drug Zytiga (labeled as fasting tablet group in FIG. 4), T2 represents a group with fasting test-abiraterone acetate capsule of Example 1 (labeled as fasting capsule group in FIG. 4 and FIG. 5), and T3 represents a group with postprandial test-abiraterone acetate capsule (labeled as a postprandial capsule group in FIG. 5); T4 represents a group with fasting test-abiraterone acetate capsule of Example 14; T5 represents a group with postprandial test-abiraterone acetate capsule of Example 14.

TABLE 7

Fasting test: pharmacokinetic parameters for 500 mg of the original drug Zytiga

vs. 50 mg of the abiraterone acetate capsule

Tablet (T1)
Capsule (T2)
Capsule (T4)

C_max
AUC_last

C_max
AUC_last

C_max
AUC_last

T_1/2
T_max
(ng/
(h*ng/
T_1/2
T_max
(ng/
(h*ng/
T_1/2
T_max
(ng/
(h*ng/

Items
(h)
(h)
mL)
mL)
(h)
(h)
mL)
mL)
(h)
(h)
mL)
mL)

Average
2.11
0.96
316.65
563.09
8.34
0.83
275.94
553.29
8.44
0.67
383.15
756.39

value

Standard
0.48
0.51
316.04
666.00
2.80
0.26
107.63
244.76
0.56
0.22
175.75
204.19

deviation

Variable
22.88
53.25
99.81
118.27
33.57
30.98
39.00
44.24
26.52
32.48
45.87
28.11

coefficient

%

In the table, T_1/2represents the drug half-life, T_maxrepresents the peak time, C_maxrepresents the maximum plasma concentration (peak concentration), and AUC_lastrepresents the AUC (area under the drug-time curve) during the duration from the start of administration to the last point.

The results were shown in FIG. 4, which was the drug-time curve on 50 mg of abiraterone acetate capsule (T2) of Example 1 and 500 mg of original drug Zytiga (T1) for beagle dogs on an empty stomach in the fasting test.

It can be seen from Table 7 that the oral bioavailability of one abiraterone acetate capsule of Example 1 (containing 50 mg of abiraterone acetate) for beagle dogs on an empty stomach reached 98% compared to two tablets of the original drug Zytiga (250 mg/tablet). The oral bioavailability of one abiraterone acetate capsule of Example 14 (containing 50 mg of abiraterone acetate) for beagle dogs on an empty stomach reached 134% compared to two tablets of the original drug Zytiga (250 mg/tablet). It demonstrated that the oral bioavailability of the abiraterone acetate pharmaceutical composition of the present invention was 10 to 13 times of the original drug Zytiga (250 mg/tablet), and the variable coefficient of peak time, peak concentration and absorption level among individuals were significantly lower than that of the original drug Zytiga.

TABLE 8

Postprandial test: Pharmacokinetic parameters of 50 mg of the abiraterone acetate

capsule pre-meal and post-meal

Capsule (T2)
Capsule (T3)
Capsule (T5)

C_max
AUC_last

C_max
AUC_last

C_max
AUC_last

T_1/2
T_max
(ng/
(h*ng/
T_1/2
T_max
(ng/
(h*ng/
T_1/2
T_max
(ng/
(h*ng/

Items
(h)
(h)
mL)
mL)
(h)
(h)
mL)
mL)
(h)
(h)
mL)
mL)