Note: Descriptions are shown in the official language in which they were submitted.
ABIRATERONE ACETATE-CONTAINING COMPOSITION AND APPLICATION
THEREOF
FIELD OF THE INVENTION
The invention relates to the technical field of abiraterone acetate
preparations, particularly to a
self-microemulsion system for loading abiraterone acetate, and a composition
and application
thereof.
BACKGROUND OF THE INVENTION
Abiraterone acetate is a white to off-white, non-hygroscopic crystalline
powder, which has a
chemical name of (313)-17-(3-pyridypandrosta-5,16-dien-3-y1 acetate and has a
molecular formula
of C26H33NO2. Abiraterone acetate can be converted in vivo to an inhibitor
against androgen
biosynthesis, namely abiraterone, which inhibits 17a-hydroxylase/C17,20-lyase
(CYP17). It can be
administered in combination with prednisone for the treatment of patients with
metastatic
castration-resistant prostate cancer (CRPC) who have previously received
chemotherapy involving
docetaxel. However, abiraterone acetate is a lipophilic compound with an
octanol-water partition
coefficient of 5.12 (LogP) and a pKa of aromatic nitrogen of 5.19. Abiraterone
acetate is almost
insoluble in water (less than 0.01 mg/ml), has a poor permeability, belongs to
BCS class IV drug,
and has a very low bioavailability when administered orally.
ittred--:1
H
j1 A
Formula I
Zytiga, the innovator drug of abiraterone acetate, is a tablet. Each tablet of
Zytiga contains 250
mg of abiraterone acetate and inactive ingredients comprising: colloidal
silicon dioxide,
croscarmellose sodium, lactose monohydrate, magnesium stearate,
microcrystalline cellulose,
polyvidone, and sodium dodecylsulfate. The oral bioavailability of Zytiga is
very low (less than
10%). A single dosage of Zytiga is up to 1000 mg, but only less than 10% of
the drug can work.
Moreover, the absorption of abiraterone acetate is largely affected by food,
and the
commercially available preparations need to be taken only at a specific time
period before meals.
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Date Recue/Date Received 2022-12-12
The package insert of Zytiga emphasizes that the systemic exposure of
abiraterone acetate is
increased when it is administered together with food. When abiraterone acetate
is given together
with a low-fat diet (7% fat, 300 calories), C. and AUC0-. of abiraterone
increase about 7 times
and 5 times, respectively. When abiraterone acetate is given together with a
high-fat diet (57% fat,
825 calories), Cmax and AUCo-. increase about 17 times and 10 times,
respectively. Taking into
account the normal variation in the content and composition of diet, it may
result in an increased
and highly variable exposure when abiraterone acetate is taken together with
diet. Therefore, in
order to control the abiraterone concentration in plasma, dose must be taken
on an empty stomach
and, no food should be taken for at least two hours before and at least 1 hour
after taking the said
dose. Accordingly, although abiraterone acetate has a good treatment effect on
advanced prostate
cancer orally, its natures of low solubility and poor permeability have
brought obstacles to
preparation designing.
Sun Pharmaceutical Industries Ltd., India provides an modified abiraterone
acetate tablet,
namely Yonsa, by SoluMatrix microparticle technology, which can promote the
dissolution of
abiraterone acetate and increases the oral bioavailability of the innovator
drug Zytiga by 1 times.
Although the dosage of Yonsa is reduced to 500 mg, it only changes the crystal
form and size of the
drug and increases the drug dissolution rate, and fails to increase the
permeability of abiraterone
acetate through gastrointestinal epithelial cells, and thus the oral
bioavailability of Yonsa remains
very low.
Patent document CN107278152A relates to a complex of abiraterone acetate,
preparation
method thereof and pharmaceutical composition containing the same. The complex
comprises 5 -
40 wt.% of abiraterone acetate, 5 - 80 wt.% of polyvinyl caprolactam-polyvinyl
acetate-polyethylene glycol graft copolymer, and 0.1 - 50 wt.% of sodium
deoxycholate. It can
reduce the effect of food and thus eliminate the requirement of taking
medicament on an empty
stomach. It can also increase the oral bioavailability by 5 times. However,
the preparation process
of the complex is complicated. Patent document W02021057042 discloses a self-
microemulsion
composition of abiraterone acetate, and preparation method and application
thereof. Said
composition comprises 5 - 20 wt.% of abiraterone acetate, 20 - 50 wt.% of an
oil phase, 20 - 60
wt.% of an emulsifier, and 20 - 80 wt.% of a co-emulsifier. The pharmaceutical
composition needs
strong mechanical stirring to be completely dissolved during the dissolution
process, and the
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Date Recue/Date Received 2022-12-12
bioavailability after oral administration still needs to be improved.
SUMMARY OF THE INVENTION
In view of the deficiencies of the prior art, an object of the present
invention is to provide a
self-microemulsion system for loading abiraterone acetate, and a method for
preparing the
abiraterone acetate composition using the system and application thereof. The
self-microemulsion
system for loading abiraterone acetate of the present invention has an
excellent solubility and
stability to abiraterone acetate, and the composition formed by dissolving
abiraterone acetate in the
system can significantly reduce the effect of food on abiraterone acetate
absorption, reduce the
difference between preprandial and postprandial administering, such that the
medicament can be
taken on both an empty stomach and a full stomach, thus reducing the time
limit for taking the
medicament.
To achieve the above object, the technical solutions adopted in the present
invention are as
follows.
According to the first embodiment of the present invention, a self-
microemulsion system for
loading abiraterone acetate is provided.
The self-microemulsion system for loading abiraterone acetate comprises an oil
phase and an
emulsion phase, wherein the ratio of the weight percentages of the oil phase
and the emulsion phase
is 30% - 38%:62% - 70%, preferably 31% - 35%:65% - 69%, more preferably 32% -
34%:66% -
68%. For example, the ratio can be any one of 30%:70%, 31%:69%, 32%:68%,
32.5%:67.5%,
33%:67%, 33.5%:66.5%, 34%:66%, 34.5%:65.5%, and 35%:65%.
Preferably, the oil phase comprises glycerol monolinoleate (CC) and medium
chain
triglyceride (MCT).
Preferably, the emulsion phase comprises PEG-40 hydrogenated castor oil (RH40)
and
2-(2-ethoxyethoxy)ethanol (HP).
Preferably, the weight ratio of glycerol monolinoleate to medium chain
triglyceride in the oil
phase is 2.5-3.63 : 1.
Preferably, the weight ratio of PEG-40 hydrogenated castor oil to 2-(2-
ethoxyethoxy)ethanol in
the emulsion phase is 1: 2.25-2.5.
Preferably, the weight ratio of glycerol monolinoleate to medium chain
triglyceride in the oil
phase is 2.8-3.5 : 1.
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Date Recue/Date Received 2022-12-12
Preferably, the weight ratio of PEG-40 hydrogenated castor oil to 2-(2-
ethoxyethoxy)ethanol in
the emulsion phase is 1: 2.28-2.45.
Preferably, the weight ratio of the glycerol monolinoleate to the medium chain
triglyceride in
the oil phase is 3.0-3.4 : 1.
Preferably, the weight ratio of PEG-40 hydrogenated castor oil to 2-(2-
ethoxyethoxy)ethanol in
the emulsion phase is 1: 2.25-2.4.
In the self-microemulsion system comprising the oil phase and the emulsion
phase of the
present invention, the ratio of 2-(2-ethoxyethoxy)ethanol (HP) to PEG-40
hydrogenated castor oil
(RH40) increases with the proportion of the emulsion phase (wt.%, based on the
total weight of the
self-microemulsion system comprising the oil phase and the emulsion phase).
Preferably, when the
proportion of the emulsion phase increases or decreases by 1 wt.%, the ratio
of
2-(2-ethoxyethoxy)ethanol (HP) to PEG-40 hydrogenated castor oil (RH40)
increases or decreases
by 0.05 correspondingly. That is to say, when the proportion of the emulsion
phase steps up from 65
wt.% to 70 wt.% (each step is 1 wt. %), the ratio of 2-(2-ethoxyethoxy)ethanol
(HP) to PEG-40
hydrogenated castor oil (RH40) steps up from 2.25 to 2.5 (each step is 0.05).
Conversely, when the
proportion of the emulsion phase steps down from 70 wt.% to 65 wt.% (each step
is 1 wt.%), then
the ratio of 2-(2-ethoxyethoxy)ethanol (HP) to PEG-40 hydrogenated castor oil
(RH40) also steps
down from 2.5 to 2.25 (each step is 0.05).
In the present invention, the self-microemulsion system can be obtained
through
homogeneously mixing glycerol monolinoleate, medium chain triglyceride, PEG-40
hydrogenated
castor oil, 2-(2-ethoxyethoxy)ethanol, and the like in proportion. For
example, the
self-microemulsion system can be obtained through firstly mixing glycerol
monolinoleate and
medium chain triglyceride in proportion to obtain an oil phase; secondly
mixing PEG-40
hydrogenated castor oil and 2-(2-ethoxyethoxy)ethanol in proportion to obtain
an emulsion phase,
and lastly mixing the oil phase and the emulsion phase.
According to the second embodiment of the present invention, an abiraterone
acetate-containing composition is provided.
The abiraterone acetate-containing composition comprises abiraterone acetate
and the
self-microemulsion system as described in the first embodiment, wherein the
ratio of weight
percentages of abiraterone acetate and self-microemulsion system is 4.3-4.8% :
95.2-95.7%,
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Date Recue/Date Received 2022-12-12
preferably 4.4-4.6% : 95.4-95.6%. For example, the ratio of weight can be any
one of 4.3%:95.7%,
4.4%:95.6%, 4.5%:95.5%, 4.6%:95.4%, 4.7%:95.3%, and 4.8%:95.2%.
Preferably, the content of each component of the composition is as follows.
Abiraterone acetate: 4.3 - 4.8 wt.%, preferably 4.4 - 4.6 wt.%, for example
any one of
4.3wt.%, 4.4wt.%, 4.5wt.%, 4.6wt.%, 4.7wt.%, and 4.8wt.%.
Glycerol monolinoleate: 21.4 - 26.2 wt.%, preferably 22.0 - 26.0 wt.%, for
example any one
of 21 wt.%, 21.2 wt.%, 21.4 wt.%, 21.6 wt.%, 21.8 wt.%, 22 wt.%, 22.2 wt.%,
22.5 wt.%, 22.8
wt.%, 23 wt.%, 23.3 wt.%, 23.5 wt.%, 23.8 wt.%, 24 wt.%, 24.3 wt.%, 24.5 wt.%,
24.8 wt.%, 25
wt.%, 25.2 wt.%, 25.4 wt.%, 25.6 wt.%, 25.8 wt.%, 26 wt.%, and 26.2 wt.%.
Medium chain triglyceride: 6.2 - 9.6 wt.%, preferably 6.8 - 8.8 wt.%, for
example any one of
6.2 wt.%, 6.3 wt.%, 6.4 wt.%, 6.5 wt.%, 6.6 wt.%, 6.7 wt.%, 6.8 wt.%, 6.9
wt.%, 7.0 wt.%, 7.1
wt.%, 7.2 wt.%, 7.3 wt.%, 7.4 wt.%, 7.5 wt.%, 7.6 wt.%, 7.7 wt.%, 7.8 wt.%,
7.9 wt.%, 8.0 wt.%,
8.2 wt.%, 8.3 wt.%, 8.4 wt.%, 8.5 wt.%, 8.6 wt.%, 8.7 wt.%%, 8.8 wt.%, 8.9
wt.%, 9.0 wt.%, 9.1
wt.%, 9.2 wt.%, 9.3 wt.%, 9.4 wt.%, 9.5 wt.%, and 9.6 wt.%.
PEG-40 hydrogenated castor oil: 17.7 - 19.7 wt.%, preferably 18.5 - 19.5 wt.%,
for example
any one of 17.7 wt.%, 17.8 wt.%, 17.9 wt.%, 18.0 wt.%, 18.1 wt.%, 18.2 wt.%,
18.3 wt.%, 18.4
wt.%, 18.5 wt.%, 18.6 wt.%, 18.7 wt.%, 18.8 wt.%, 18.9 wt.%, 19.0 wt.%, 19.1
wt.%, 19.2 wt.%,
19.3 wt.%, 19.4 wt.%, 19.5 wt.%, 19.6 wt.%, and 19.7 wt.%.
2-(2-ethoxyethoxy)ethanol: 42.8 - 47.8 wt.%, preferably 43.0 - 47.2 wt.%, for
example any
one of 42.8 wt.%, 43 wt.%, 43.2 wt.%, 43.3 wt.%, 43.4 wt.%, 43.5 wt.%, 43.6
wt.%, 43.7 wt.%,
43.8 wt.%, 44 wt.%, 44.3 wt.%, 44.5 wt.%, 44.8 wt.%%, 45 wt.%, 45.3 wt.%, 45.5
wt.%, 45.8
wt.%, 46.1 wt.%, 46.5 wt.%, 46.8 wt.%, 47.1 wt.%, 47.5 wt.%, and 47.8 wt.%.
Preferably, the composition further comprises optional antioxidants and/or
preservatives
comprising 0.005% - 0.1% of the total weight of the composition. In the
context of present
disclosure, an "optional" ingredient means the ingredient can be comprised or
not comprised in the
composition.
In the present invention, the abiraterone acetate-containing composition can
be obtained
through dissolving abiraterone acetate in the self-microemulsion system in
proportion, and then
optionally adding an antioxidant and/or preservative, and then homogeneously
mixing the mixture.
For example, the composition can be obtained through mixing glycerol
monolinoleate, medium
Date Recue/Date Received 2022-12-12
chain triglyceride, PEG-40 hydrogenated castor oil (at room temperature or
under heating) in
proportion, then adding abiraterone acetate and stirring in dark place, and
finally adding
2-(2-ethoxyethoxy)ethanol and optional an antioxidant and/or preservative and
mixing them
homogeneously.
According to the third embodiment of the present invention, an abiraterone
acetate preparation
is provided.
The abiraterone acetate preparation comprises a solid preparation and a liquid
preparation. The
solid preparation comprises, but is not limited to, one or more of tablet,
capsule, granule, powder,
dripping pill, and film. The liquid preparation comprises, but is not limited
to, one or more of
injection, soft capsule, ointment, suppository, and aerosol.
Preferably, the solid preparation is obtained by one or more steps of
crushing, sieving, mixing,
granulating, and tableting the content(s) and adjuvant(s). The adjuvant(s) is
selected from one or
more of filler, adsorbent, binder, lubricant, dispersant, disintegrant,
wetting agent, spice, and
colorant. The content(s) is the self-microemulsion system described in the
first embodiment
and abiraterone acetate, or the abiraterone acetate-containing composition
described in the
second embodiment.
The liquid preparation composes of content(s) and auxiliary agent(s). The
auxiliary agent is
selected from one or more of preservative, stabilizer, antioxidant,
aromatizer, osmotic pressure
regulator, and flavoring agent. The content is the self-microemulsion system
described in the first
embodiment and abiraterone acetate, or the abiraterone acetate-containing
composition described in
the second embodiment.
In the present invention, the abiraterone acetate preparation can be obtained
by those skilled in
the art according to the preparation method of conventional preparations in
the art. For example, it
can be obtained through preparing the abiraterone acetate-containing
composition according to the
aforementioned process; and sealing the abiraterone acetate-containing
composition in soft capsules
or hard capsules. Preferably, each capsule contains 0.5 - 1 mL of the
abiraterone acetate-containing
composition.
In the present invention, the concentration of abiraterone acetate in the
abiraterone
acetate-containing composition can range from 50 - 100 mg/mL, and the single
oral dosage can be
75-100 mg. The abiraterone acetate can form an 0/W nano emulsion with a high
clarity, an uniform
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Date Recue/Date Received 2022-12-12
particle size of less than 250 nm, and a stable nature spontaneously when
mixing with water,
biologically relevant media (such as SGF and FassiF medium) or
gastrointestinal fluid. The
content(s) can exist as a stable solution when stored at room temperature.
Furthermore, the
self-microemulsion composition of the present invention is stable even under
conditions of
influencing factors (e.g. at 30 C 2 C, at 4 C, addition of 10 wt.% of
water based on the total
weight of the composition, addition of 15 wt.% of water based on the total
weight of the
composition).
According to the fourth embodiment of the present invention, a pharmaceutical
composition is
provided.
The pharmaceutical composition comprises the abiraterone acetate-containing
composition
described in the second embodiment or the abiraterone acetate preparation
described in the third
embodiment, and prednisone. That is, pharmaceutical composition comprises the
combination of
abiraterone acetate-containing composition and prednisone, or the combination
of abiraterone
acetate preparation and prednisone.
According to the fifth embodiment of the present invention, an application of
the abiraterone
acetate-containing composition described in the second embodiment or the
abiraterone acetate
preparation described in the third embodiment or the pharmaceutical
composition described in the
fourth embodiment, wherein the abiraterone acetate-containing composition
described in the second
embodiment or the abiraterone acetate preparation described in the third
embodiment or the
pharmaceutical composition described in the fourth embodiment is used in the
manufacture of a
pharmaceutical preparation for treating prostate cancer.
Preferably, the prostate cancer is selected from one or both of metastatic
castration-resistant
prostate cancer and metastatic high-risk castration-sensitive prostate cancer.
Generally, the
medicament according to the present invention can be administered either
before meal or after meal.
In the prior art, abiraterone acetate, as a BSC class IV drug, has a low
solubility and a low
permeability. In the process of developing dosage forms, it is necessary to
address not only the
solubility of abiraterone, but more importantly, the transmembrane problem of
abiraterone in the
absorption process. The currently existing dosage forms of abiraterone acetate
can effectively solve
the problems of solubility and dissolution of abiraterone acetate, but fail to
solve the problem of the
transmembrane and absorption of the medicament in vivo, and thus the
bioavailability is not
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Date Recue/Date Received 2022-12-12
effectively improved. Moreover, the existing dosage forms also fail to
effectively solve the problem
of precipitation of abiraterone acetate due to moisture absorption, resulting
in its low stability.
Further, the self-microemulsion systems for loading abiraterone acetate in the
prior art do not
reasonably control the ratio of the oil phase and the emulsion phase, and
consequently the amount
of 2-(2-ethoxyethoxy)ethanol in the emulsion phase in either too much (which
can lead to toxic and
side effects) or too little (which makes it hard or unable to form a
microemulsion).
In the present invention, the abiraterone acetate-containing composition is a
solution system,
which will, after oral administration, spontaneously disperse to form an 0/W
nanoemulsion with a
high clarity, a uniform particle size and a stable nature in the presence of
gastrointestinal fluid under
gastrointestinal peristalsis. The nanoemulsion has a small particle size,
which can promote drug
dissolution, increase the membrane permeability of abiraterone in vivo, and
increase the
permeability to intestinal epithelial cells, thereby significantly promoting
absorption and
significantly improving drug bioavailability. The abiraterone acetate-
containing composition of the
present invention can also significantly reduce the effect of food on the
absorption of abiraterone
acetate and reduce the difference between preprandial and postprandial
administering, such that it
can be taken on both an empty stomach and a full stomach, and the time limit
for taking the
medicament is reduced.
In the present invention, the provided self-microemulsion system can be used
as a carrier for a
medicament that is hydrophobic, hard to absorb or easy to hydrolyze. While
improving the
solubility of abiraterone acetate at room temperature, the formed uniform and
stable abiraterone
acetate-containing medicament system can spontaneously disperse to form a
nanoemulsion after
entering the body, which can effectively solve the problem of transmembrane
and absorption of
abiraterone acetate in vivo. Through in-depth research, it is found that the
oral bioavailability of the
abiraterone acetate-containing composition prepared in the present invention
is greatly improved,
and the stability in a humid or excessively humid environment is also
excellent. Comparing with
microemulsion, the self-emulsification solution has a higher stability and can
meet the requirements
for long-term storage, and it can also be directly packed into soft capsules
or hard capsules.
Compared with the prior art, the beneficial technical effects of the present
invention are as
follows.
1. In the present invention, the oil phase and the emulsion phase are prepared
by selecting
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Date Recue/Date Received 2022-12-12
specific raw materials in a specific ratio, and then the self-microemulsion
system for loading
abiraterone acetate is obtained by mixing the oil phase and the emulsion phase
in a specific ratio.
The self-microemulsion system has a high solubility and a strong stability to
abiraterone acetate,
and spontaneously disperses to form 0/W nanoemulsion with a high clarity, a
uniform particle size
and a stable nature under gastrointestinal peristalsis. The membrane
permeability of abiraterone
acetate in vivo is greatly improved, and the penetration to intestinal
epithelial cells is increased,
such that the absorption and the drug bioavailability are significantly
promoted.
2. The abiraterone acetate-containing composition of present invention is
prepared with
abiraterone acetate and an inventive self-microemulsion system, which can
significantly reduce the
effect of food on the absorption of abiraterone acetate and reduce the
difference between
preprandial and postprandial administering, such that the medicament can be
taken on both an
empty stomach and a full stomach, reducing the time limit for taking the
medicament.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a ternary phase diagram drawn by proportionally adjusting the
amounts of HP,
RH40 and a mixture of (CC:MCT=1:0).
Figure 2 is a ternary phase diagram drawn by proportionally adjusting the
amounts of HP,
RH40 and a mixture of (CC:MCT=1:1).
Figure 3 is a ternary phase diagram drawn by proportionally adjusting the
amounts of HP,
RH40 and a mixture of (CC:MCT=2:1).
Figure 4 is a ternary phase diagram drawn by proportionally adjusting the
amounts of HP,
RH40 and a mixture of (CC:MCT=1:2).
Figure 5 is a ternary phase diagram drawn by proportionally adjusting the
amounts of HP,
RH40 and a mixture of (CC:MCT=3 :1).
Figure 6 is a ternary phase diagram drawn by proportionally adjusting the
amounts of HP,
RH40 and a mixture of (CC:MCT=1:3).
Figure 7 is a ternary phase diagram drawn by proportionally adjusting the
amounts of HP,
RH40 and a mixture of (CC:MCT=5 :1).
Figure 8 is a ternary phase diagram drawn by proportionally adjusting the
amounts of HP,
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Date Recue/Date Received 2022-12-12
RH40 and a mixture of (CC:MCT=1:5).
Figure 9 shows the sample photos of abiraterone acetate-containing
compositions of
Comparative examples 1-4 after being placed at 4 C for 24 h.
Figure 10 shows the sample photos of abiraterone acetate-containing
compositions of Example
2 and Comparative examples 1-4 after being placed at room temperature for 24 h
with 10 wt.% of
water added.
Figure 11 shows the sample photos of abiraterone acetate-containing
compositions of Example
2 and Comparative examples 1-4 after being placed at room temperature for 24 h
with 15 wt.% of
water added.
DETAILED DESCRIPTION
The technical solutions of the present invention are illustrated below by way
of example, and
the scope of the claimed protection of the present invention includes but is
not limited to the
following examples.
Experiment 1: Construction of self-microemulsion system
Glycerol monolinoleate (CC) and medium chain triglyceride (MCT) were mixed in
different
weight ratios (the weight ratios are 1:0, 1:1, 2:1, 1:2, 3:1, 1:3, 5:1, and
1:5) to obtain the oil phase.
PEG-40 hydrogenated castor oil (RH40) and 2-(2-ethoxyethoxy)ethanol (HP) were
mixed in
different weight ratios (the weight ratios are 1:1, 2:1, 1:2, 3:1, and 1:3) to
obtain the emulsion
phase. Then, the oil phase and the emulsion phase were mixed in different
weight ratios (the weight
ratios are 9:1, 8:2, 7:3, 6:4, 5:5, 4:6, 3:7, 2:8, and 1: 9) to obtain a mixed
system. Ternary phase
diagrams (see Figure 1-8) were obtained using a Karl Fischer method, and the
loading performance
of the mixed system to abiraterone acetate (API) was investigated.
It can be seen from figures 1-8 that, as the oil phase, the combination of
glycerol
monolinoleate and medium chain triglyceride is more effective than glycerol
monolinoleate alone
(See Figures 1-8, wherein Figure 1 represents the ternary phase diagram when
glycerol
monolinoleate was used alone as the oil phase, and Figures 2-7 represent the
ternary phase diagrams
when the combination of glycerol monolinoleate and medium chain triglyceride
in different weight
ratios were used as the oil phase. It can be seen that the area of the
microemulsion zone in Figure 1
is the smallest. For example, referring to Figure 1 and Figure 2, when a
combination of glycerol
monolinoleate and medium chain triglyceride is used, microemulsion can still
be achieved when the
Date Recue/Date Received 2022-12-12
amount of oil phase is 50%, but the microemulsion state cannot be achieved
when glycerol
monolinoleate is used alone in the amount of 50%, no matter how the ratio of
RH40 and HP is
adjusted). Therefore, the self-microemulsion system of the present invention
can choose the mixture
of glycerol monolinoleate (CC) and medium chain triglyceride (MCT) as the oil
phase. Besides, it is
found through experiments that the solubility of abiraterone acetate in
glycerol monolinoleate (CC)
(25 C) was about 62.9 mg/g, and the solubility in medium chain triglyceride
(MCT) (25 C) was
about 28.4 mg/g. Accordingly, when glycerol monolinoleate and medium chain
triglyceride are used
in combination as the oil phase, in order to ensure a larger drug loading
capacity, the amount of CC
in the oil phase should be as much as possible, while the amount of MCT should
be as little as
possible. During the research, it was found that, when the amount and ratio of
the emulsion phase
were constant, the area of the microemulsification region in the ternary phase
diagram gradually
decreases as the ratio of amount of glycerol monolinoleate to medium chain
triglyceride varying
from 2:1 to 5:1 (the area where the microemulsion exists decreases with the
area of the
microemulsification region, and the small area renders the amount of adjuvants
is restricted. This
further leads a restriction on API loading, while also affects the self-
emulsification effect of the
self-microemulsion system). Furthermore, through further experiments and
calculations, it was
found that when the value of CC:MCT in the oil phase was 2.5-3.63:1
(preferably 2.8-3.5:1, more
preferably 3.0-3.4:1), the loading of abiraterone acetate was excellent (an
excessive amount of MCT
will lead to a significant decrease in API loading, while too few MCT will
lead to a small
emulsification area), and the self-microemulsion system comprising the oil
phase and emulsion
phase can achieve a good self-emulsification effect.
Through experiments, it was found that using the combination of PEG-40
hydrogenated castor
oil (RH40) and 2-(2-ethoxyethoxy)ethanol (HP) as the emulsion phase can obtain
a better effect
than using PEG-40 hydrogenated castor oil (RH40) alone, because 2-(2-
ethoxyethoxy)ethanol (HP)
can assist the emulsification and also reduce the amount of PEG-40
hydrogenated castor oil (RH40)
and increase the loading capacity of abiraterone acetate. Through experiments,
it was found that the
solubility of abiraterone acetate in PEG-40 hydrogenated castor oil (RH40) (25
C) was about 24.7
mg/g, and the solubility in 2-(2-ethoxyethoxy)ethanol (HP) (25 C) was about
69.0 mg/g. When
PEG-40 hydrogenated castor oil (RH40) and 2-(2-ethoxyethoxy)ethanol (HP) are
used in
combination as the emulsion phase, in order to ensure the emulsification
effect of the
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Date Recue/Date Received 2022-12-12
self-microemulsion system and to ensure a large drug loading capacity, one
should increase the
amount of RH40 in the emulsion phase while also reduce the amount of HP as
much as possible.
During the research, it was found that, when the amount and ratio of the oil
phase were constant, the
area of the microemulsification region in the ternary phase diagram gradually
decreases as the ratio
of the amount of PEG-40 hydrogenated castor oil to 2-(2-ethoxyethoxy)ethanol
varying from 1:1 to
1:3. Meanwhile, through further experiments, it was also found that when the
ratio of RH40 to HP
in the emulsion phase is 1:2.25-2.5, an well loading of abiraterone acetate
and excellent
self-emulsification of the self-microemulsion system composed of abiraterone
acetate and the oil
phase can be achieved, while the co-emulsifier (i.e., HP) was accommodated and
shielded by the
self-microemulsion system, producing almost no toxic and side effect.
In a preferred embodiment of the present invention, an oil phase was obtained
by mixing CC
and MCT according to weight ratio CC:MCT=3.38:1, and an emulsion phase was
obtained by
mixing R1140 and HP according to weight ratio RH40:HP=1:2.25; and a series of
mixed systems
were obtained by mixing the oil phase and emulsion phase in different weight
ratios, and the
emulsification effect of the mixed systems were investigated. The mixing
ratios of the oil phase and
the emulsion phase are shown in Table 1.
Table 1. Experiments result I on Emulsification
Oil Emulsion Water required to
phase phase form microemulsi on Emulsion state
(g) (g) (g)
0.9 0.1 Not emulsified, significantly visible oil
droplets
0.8 0.2 Not emulsified, significantly visible oil
droplets
0.7 0.3 Gray-white turbid substance, visible oil
droplets
0.6 0.4 Gray-white turbid substance, visible oil
droplets
0.5 0.5 Milky-white turbid substance
0.4 0.6 748.6 Microemulsion with blue light, high
turbidity
0.3 0.7 18.2 Microemulsion with blue light
0.2 0.8 6.1 Microemulsion with slight blue light
0.1 0.9 6.3 Colorless and transparent microemulsion
It can be seen from the experiments results in Table 1 that the amount of
emulsion phase
should be > 60 wt.% (based on the total weight of oil phase and emulsion
phase) to allow the
self-emulsification of the mixed system composed of oil phase and emulsion
phase. Further, in
12
Date Recue/Date Received 2022-12-12
order to ensure the self-emulsification while also reduce the amount of
emulsifier (i.e. RH40), the
ratio of the amount of the oil phase to the emulsion phase were further
optimized. The results are
summarized in Table 2.
Table 2. Experiments results II on Emulsification
Emulsion
Oil phase Emulsion state after adding 100 g water to 1 g
P hase
(g) mixed system
(g)
0.30 0.70 Microemulsion with slight blue light
0.31 0.69 Microemulsion with slight blue light
0.32 0.68 Microemulsion with slight blue light
0.33 0.67 Microemulsion with blue light
0.34 0.66 Microemulsion with blue light
0.35 0.65 Microemulsion with blue light
0.36 0.64 Microemulsion with blue light, slight
turbidity
0.37 0.63 Microemulsion with blue light, high turbidity
0.38 0.62 Microemulsion with blue light, high turbidity
0.39 0.61 Milky-white turbid substance
0.40 0.60 Milky-white turbid substance
It can be seen from the experiments results in Table 2 that, when 100 g water
was added, the
total amount of the oil phase in the mixed system (i.e., the self-
microemulsion system) composed of
the oil phase and the emulsion phase should be less than or equal to 35 wt.%,
and the total amount
of the emulsion phase should be greater than or equal to 65 wt.%, such that a
good emulsification of
the self-microemulsion system can be obtained. In order to ensure the self-
emulsification and also
reduce the amount of emulsifier (i.e., RH40), the ratio of the weight
percentages (based on the total
weight of oil phase and emulsion phase) of oil phase to the emulsion phase in
the
self-microemulsion system can be 32 wt.%-35 wt.% : 65 wt.%-68 wt.%, preferably
33 wt.%-35
wt.% : 65 wt.%-67 wt.%, more preferably 35 wt.% : 65 wt.%.
Experiment 2: Investigation of drug loading in self-microemulsion system
2.1. An oil phase was obtained by mixing CC and MCT in the weight ratio of
CC:MCT=3.63:1, and an emulsion phase was obtained by mixing RH40 and HP in the
weight ratio
of RH40:HP= 1:2.5. A self-microemulsion system for loading abiraterone acetate
was obtained by
mixing the oil phase and the emulsion phase in the weight ratio of 30 wt.%:70
wt.%. The
13
Date Recue/Date Received 2022-12-12
self-microemulsion system was loaded with different amounts of abiraterone
acetate (API), and the
results are shown in Table 3.
Table 3: API Loading Experiment Results I
API API API capsule API
capsule
API
Formulation Placed at R.T. Placed at 4 C Placed at R.T. Placed at 4 C
content
for 24 h for 24 h for 24 h for 24 h
Formulation 1 4.0 wt.%
Unprecipitated Unprecipitated Unprecipitated Unprecipitated
Formulation 2 4.1
wt.% Unprecipitated Unprecipitated Unprecipitated Unprecipitated
Formulation 3 4.2 wt.%
Unprecipitated Unprecipitated Unprecipitated Unprecipitated
Formulation 4 4.3
wt.% Unprecipitated Unprecipitated Unprecipitated Unprecipitated
Formulation 5 4.4
wt.% Unprecipitated Unprecipitated Unprecipitated Unprecipitated
Formulation 6 4.5
wt.% Unprecipitated Unprecipitated Unprecipitated Unprecipitated
Formulation 7 4.6
wt.% Unprecipitated Unprecipitated Unprecipitated Unprecipitated
Formulation 8 4.7
wt.% Unprecipitated Unprecipitated Unprecipitated Unprecipitated
Formulation 9 4.8
wt.% Unprecipitated Unprecipitated Unprecipitated Unprecipitated
Formulation 10 4.9 wt.% Precipitated Precipitated
Precipitated Precipitated
Formulation 11 5.0 wt.% Precipitated
Precipitated Precipitated Precipitated
2.2. An oil phase was obtained by mixing CC and MCT in the weight ratio of
CC:MCT=2.5:1,
and an emulsion phase was obtained by mixing RH40 and HP in the weight ratio
of RH40:HP=
1:2.25. A self-microemulsion system for loading abiraterone acetate was
obtained by mixing the oil
phase and the emulsion phase in the weight ratio of 35 wt.%:65 wt.%. The self-
microemulsion
system was loaded with different amounts of abiraterone acetate (API), and the
results are shown in
Table 4.
Table 4: API Loading Experiment Results II
API API API API capsule API
capsule
Prescription Placed at R.T.
Placed at 4 C Placed at R.T. Placed at 4 C
content
for 24 h for 24 h for
24 h for 24 h
Prescription 1 4.0 wt.% Unprecipitated Unprecipitated Unprecipitated
Unprecipitated
Prescription 2 4.1 wt.% Unprecipitated Unprecipitated Unprecipitated
Unprecipitated
Prescription 3 4.2 wt.% Unprecipitated Unprecipitated Unprecipitated
Unprecipitated
Prescription 4 4.3 wt.% Unprecipitated Unprecipitated Unprecipitated
Unprecipitated
Prescription 5 4.4 wt.% Unprecipitated Unprecipitated Unprecipitated
Unprecipitated
Prescription 6 4.5 wt.% Unprecipitated Unprecipitated Unprecipitated
Unprecipitated
Prescription 7 4.6 wt.% Precipitated Precipitated
Unprecipitated Unprecipitated
Prescription 8 4.7 wt.% Precipitated Precipitated
Precipitated Precipitated
Prescription 9 4.8 wt.% Precipitated Precipitated
Precipitated Precipitated
Prescription 10 4.9 wt.% Precipitated Precipitated
Precipitated Precipitated
Prescription 11 5.0 wt.% Precipitated Precipitated
Precipitated Precipitated
14
Date Recue/Date Received 2022-12-12
Referring to Table 3 and Table 4, it can be seen that the maximum effective
drug loading
capacity of abiraterone acetate of the self-microemulsion system provided by
present embodiments
is in the range of 4.5 wt.% to 4.8 wt.% (based on the total weight of API and
self-microemulsion
system). Besides, to maintain a proper dosage of the medicament loaded, the
content of abiraterone
acetate was determined to be no less than 4.3 wt.% upon calculation (an
excessively low content of
abiraterone acetate increases the dosage of medicament the subject has to
take, leading to an
increase in the amount of adjuvants as a carrier taken by the subject, and
thus leading to a high risk
of occurrence of toxic and side effects).
Example 1
The abiraterone acetate-containing composition comprises the following
components:
abiraterone acetate: 1.118 portions by weight (comprising about 4.30 wt.% of
the total weight
of the composition);
glycerol monolinoleate: 6.722 portions by weight (comprising about 25.85 wt.%
of the total
weight of the composition);
medium chain triglyceride: 1.991 portions by weight (comprising about 7.66
wt.% of the total
weight of the composition);
PEG-40 hydrogenated castor oil: 4.973 portions by weight (comprising about
19.13 wt.% of
the total weight of the composition); and
2-(2-ethoxyethoxy)ethanol: 11.196 portions by weight (comprising about 43.06
wt.% of the
total weight of the composition).
The preparation process is as follows. Glycerol monolinoleate, medium chain
triglyceride,
PEG-40 hydrogenated castor oil were taken in proportion, stirred and mixed
homogeneously,
followed by adding abiraterone acetate in dark place. After being fully
dissolved,
2-(2-ethoxyethoxy)ethanol was added to form a transparent and homogeneous self-
emulsification
solution, namely the abiraterone acetate-containing composition.
Example 2
The abiraterone acetate-containing composition comprises the following
components:
abiraterone acetate: 1.170 portions by weight (comprising about 4.50 wt.% of
the total weight
of the composition);
glycerol monolinoleate: 6.704 portions by weight (comprising about 25.78 wt.%
of the total
Date Recue/Date Received 2022-12-12
weight of the composition);
medium chain triglyceride: 1.986 portions by weight (comprising about 7.64
wt.% of the total
weight of the composition);
PEG-40 hydrogenated castor oil: 4.966 portions by weight (comprising about
19.10 wt.% of
the total weight of the composition); and
2-(2-ethoxyethoxy)ethanol: 11.174 portions by weight (comprising about 42.98
wt.% of the
total weight of the composition).
The preparation process is as follows. Glycerol monolinoleate, medium chain
triglyceride,
PEG-40 hydrogenated castor oil were taken in proportion, stirred and mixed
homogeneously,
followed by adding abiraterone acetate in dark place. After being fully
dissolved,
2-(2-ethoxyethoxy)ethanol was added to form a transparent and homogeneous self-
emulsification
solution, namely the abiraterone acetate-containing composition.
Example 3
The abiraterone acetate-containing composition comprises the following
components:
abiraterone acetate: 1.248 portions by weight (comprising about 4.80 wt.% of
the total weight
of the composition);
glycerol monolinoleate: 6.683 portions by weight (comprising about 25.70 wt.%
of the total
weight of the composition);
medium chain triglyceride: 1.979 portions by weight (comprising about 7.61
wt.% of the total
weight of the composition);
PEG-40 hydrogenated castor oil: 4.950 portions by weight (comprising about
19.04 wt.% of
the total weight of the composition); and
2-(2-ethoxyethoxy)ethanol: 11.140 portions by weight (comprising about 42.85
wt.% of the
total weight of the composition).
The preparation process is as follows. Glycerol monolinoleate, medium chain
triglyceride,
PEG-40 hydrogenated castor oil were taken in proportion, stirred and mixed
homogeneously,
followed by adding abiraterone acetate in dark place. After being fully
dissolved,
2-(2-ethoxyethoxy)ethanol was added to form a transparent and homogeneous self-
emulsification
solution, namely the abiraterone acetate-containing composition.
Example 4
16
Date Recue/Date Received 2022-12-12
The abiraterone acetate-containing composition comprises the following
components:
abiraterone acetate: 1.170 portions by weight (comprising about 4.50 wt.% of
the total weight
of the composition);
glycerol monolinoleate: 6.523 portions by weight (comprising about 25.09 wt.%
of the total
weight of the composition);
medium chain triglyceride: 2.167 portions by weight (comprising about 8.33
wt.% of the total
weight of the composition);
PEG-40 hydrogenated castor oil: 4.966 portions by weight (comprising about
19.10 wt.% of
the total weight of the composition); and
2-(2-ethoxyethoxy)ethanol: 11.174 portions by weight (comprising about 42.98
wt.% of the
total weight of the composition).
The preparation process is as follows. Glycerol monolinoleate, medium chain
triglyceride,
PEG-40 hydrogenated castor oil were taken in proportion, stirred and mixed
homogeneously,
followed by adding abiraterone acetate in dark place. After being fully
dissolved,
2-(2-ethoxyethoxy)ethanol was added to form a transparent and homogeneous self-
emulsification
solution, namely the abiraterone acetate-containing composition.
Example 5
The abiraterone acetate-containing composition comprises the following
components:
abiraterone acetate: 1.170 portions by weight (comprising about 4.50 wt.% of
the total weight
of the composition);
glycerol monolinoleate: 6.207 portions by weight (comprising about 23.87 wt.%
of the total
weight of the composition);
medium chain triglyceride: 2.483 portions by weight (comprising about 9.55
wt.% of the total
weight of the composition);
PEG-40 hydrogenated castor oil: 4.966 portions by weight (comprising about
19.10 wt.% of
the total weight of the composition); and
2-(2-ethoxyethoxy)ethanol: 11.174 portions by weight (comprising about 42.98
wt.% of the
total weight of the composition).
The preparation process is as follows. Glycerol monolinoleate, medium chain
triglyceride,
PEG-40 hydrogenated castor oil were taken in proportion, stirred and mixed
homogeneously,
17
Date Recue/Date Received 2022-12-12
followed by adding abiraterone acetate in dark place. After being fully
dissolved,
2-(2-ethoxyethoxy)ethanol was added to form a transparent and homogeneous self-
emulsification
solution, namely the abiraterone acetate-containing composition.
Example 6
The abiraterone acetate-containing composition comprises the following
components:
abiraterone acetate: 1.170 portions by weight (comprising about 4.50 wt.% of
the total weight
of the composition);
glycerol monolinoleate: 6.760 portions by weight (comprising about 26.00 wt.%
of the total
weight of the composition);
medium chain triglyceride: 1.930 portions by weight (comprising about 7.42
wt.% of the total
weight of the composition);
PEG-40 hydrogenated castor oil: 4.966 portions by weight (comprising about
19.10 wt.% of
the total weight of the composition); and
2-(2-ethoxyethoxy)ethanol: 11.174 portions by weight (comprising about 42.98
wt.% of the
total weight of the composition).
The preparation process is as follows. Glycerol monolinoleate, medium chain
triglyceride,
PEG-40 hydrogenated castor oil were taken in proportion, stirred and mixed
homogeneously,
followed by adding abiraterone acetate in dark place. After being fully
dissolved,
2-(2-ethoxyethoxy)ethanol was added to form a transparent and homogeneous self-
emulsification
solution, namely the abiraterone acetate-containing composition.
Example 7
The abiraterone acetate-containing composition comprises the following
components:
abiraterone acetate: 1.170 portions by weight (comprising about 4.50 wt.% of
the total weight
of the composition);
glycerol monolinoleate: 6.704 portions by weight (comprising about 25.78 wt.%
of the total
weight of the composition);
medium chain triglyceride: 1.986 portions by weight (comprising about 7.64
wt.% of the total
weight of the composition);
PEG-40 hydrogenated castor oil: 4.747 portions by weight (comprising about
18.26 wt.% of
the total weight of the composition); and
18
Date Recue/Date Received 2022-12-12
2-(2-ethoxyethoxy)ethanol: 11.393 portions by weight (comprising about 43.82
wt.% of the
total weight of the composition).
The preparation process is as follows. Glycerol monolinoleate, medium chain
triglyceride,
PEG-40 hydrogenated castor oil were taken in proportion, stirred and mixed
homogeneously,
followed by adding abiraterone acetate in dark place. After being fully
dissolved,
2-(2-ethoxyethoxy)ethanol was added to form a transparent and homogeneous self-
emulsification
solution, namely the abiraterone acetate-containing composition.
Example 8
The abiraterone acetate-containing composition comprises the following
components:
abiraterone acetate: 1.170 portions by weight (comprising about 4.50 wt.% of
the total weight
of the composition);
glycerol monolinoleate: 6.704 portions by weight (comprising about 25.78 wt.%
of the total
weight of the composition);
medium chain triglyceride: 1.986 portions by weight (comprising about 7.64
wt.% of the total
weight of the composition);
PEG-40 hydrogenated castor oil: 4.638 portions by weight (comprising about
17.84 wt.% of
the total weight of the composition); and
2-(2-ethoxyethoxy)ethanol: 11.502 portions by weight (comprising about 44.24
wt.% of the
total weight of the composition).
The preparation process is as follows. Glycerol monolinoleate, medium chain
triglyceride,
PEG-40 hydrogenated castor oil were taken in proportion, stirred and mixed
homogeneously,
followed by adding abiraterone acetate in dark place. After being fully
dissolved,
2-(2-ethoxyethoxy)ethanol was added to form a transparent and homogeneous self-
emulsification
solution, namely the abiraterone acetate-containing composition.
Example 9
The abiraterone acetate-containing composition comprises the following
components:
abiraterone acetate: 1.170 portions by weight (comprising about 4.50 wt.% of
the total weight
of the composition);
glycerol monolinoleate: 6.322 portions by weight (comprising about 24.32 wt.%
of the total
weight of the composition);
19
Date Recue/Date Received 2022-12-12
medium chain triglyceride: 1.872 portions by weight (comprising about 7.20
wt.% of the total
weight of the composition);
PEG-40 hydrogenated castor oil: 4.966 portions by weight (comprising about
19.10 wt.% of
the total weight of the composition); and
2-(2-ethoxyethoxy)ethanol: 11.670 portions by weight (comprising about 44.88
wt.% of the
total weight of the composition).
The preparation process is as follows. Glycerol monolinoleate, medium chain
triglyceride,
PEG-40 hydrogenated castor oil were taken in proportion, stirred and mixed
homogeneously,
followed by adding abiraterone acetate in dark place. After being fully
dissolved,
2-(2-ethoxyethoxy)ethanol was added to form a transparent and homogeneous self-
emulsification
solution, namely the abiraterone acetate-containing composition.
Example 10
The abiraterone acetate-containing composition comprises the following
components:
abiraterone acetate: 1.170 portions by weight (comprising about 4.50 wt.% of
the total weight
of the composition);
glycerol monolinoleate: 6.130 portions by weight (comprising about 23.58 wt.%
of the total
weight of the composition);
medium chain triglyceride: 1.816 portions by weight (comprising about 6.98
wt.% of the total
weight of the composition);
PEG-40 hydrogenated castor oil: 4.966 portions by weight (comprising about
19.10 wt.% of
the total weight of the composition); and
2-(2-ethoxyethoxy)ethanol: 11.918 portions by weight (comprising about 45.84
wt.% of the
total weight of the composition).
The preparation process is as follows. Glycerol monolinoleate, medium chain
triglyceride,
PEG-40 hydrogenated castor oil were taken in proportion, stirred and mixed
homogeneously,
followed by adding abiraterone acetate in dark place. After being fully
dissolved,
2-(2-ethoxyethoxy)ethanol was added to form a transparent and homogeneous self-
emulsification
solution, namely the abiraterone acetate-containing composition.
Example 11
The abiraterone acetate-containing composition comprises the following
components:
Date Recue/Date Received 2022-12-12
abiraterone acetate: 1.170 portions by weight (comprising about 4.50 wt.% of
the total weight
of the composition);
glycerol monolinoleate: 5.747 portions by weight (comprising about 22.10 wt.%
of the total
weight of the composition);
medium chain triglyceride: 1.702 portions by weight (comprising about 6.55
wt.% of the total
weight of the composition);
PEG-40 hydrogenated castor oil: 4.966 portions by weight (comprising about
19.10 wt.% of
the total weight of the composition); and
2-(2-ethoxyethoxy)ethanol: 12.415 portions by weight (comprising about 47.75
wt.% of the
total weight of the composition).
The preparation process is as follows. Glycerol monolinoleate, medium chain
triglyceride,
PEG-40 hydrogenated castor oil were taken in proportion, stirred and mixed
homogeneously,
followed by adding abiraterone acetate in dark place. After being fully
dissolved,
2-(2-ethoxyethoxy)ethanol was added to form a transparent and homogeneous self-
emulsification
solution, namely the abiraterone acetate-containing composition.
Comparative example 1
The abiraterone acetate-containing composition comprises the following
components:
abiraterone acetate: 1.170 portions by weight (comprising about 7.11 wt.% of
the total weight
of the composition);
glycerol monolinoleate: 4.136 portions by weight (comprising about 25.13 wt.%
of the total
weight of the composition);
medium chain triglyceride: 2.632 portions by weight (comprising about 15.99
wt.% of the total
weight of the composition);
PEG-40 hydrogenated castor oil: 3.816 portions by weight (comprising about
23.19 wt.% of
the total weight of the composition); and
2-(2-ethoxyethoxy)ethanol: 4.704 portions by weight (comprising about 28.58
wt.% of the
total weight of the composition).
The preparation process is as follows. Glycerol monolinoleate, medium chain
triglyceride,
PEG-40 hydrogenated castor oil were taken in proportion, stirred and mixed
homogeneously,
followed by adding abiraterone acetate in dark place. After being fully
dissolved,
21
Date Recue/Date Received 2022-12-12
2-(2-ethoxyethoxy)ethanol was added to form a transparent and homogeneous self-
emulsification
solution, namely the abiraterone acetate-containing composition.
Comparative example 2
The abiraterone acetate-containing composition comprises the following
components:
abiraterone acetate: 1.170 portions by weight (comprising about 8.78 wt.% of
the total weight
of the composition);
glycerol monolinoleate: 4.136 portions by weight (comprising about 31.05 wt.%
of the total
weight of the composition);
medium chain triglyceride: 2.632 portions by weight (comprising about 19.76
wt.% of the total
weight of the composition);
PEG-40 hydrogenated castor oil: 3.816 portions by weight (comprising about
28.64 wt.% of
the total weight of the composition); and
2-(2-ethoxyethoxy)ethanol: 1.568 portions by weight (comprising about 11.77
wt.% of the
total weight of the composition).
The preparation process is as follows. Glycerol monolinoleate, medium chain
triglyceride,
PEG-40 hydrogenated castor oil were taken in proportion, stirred and mixed
homogeneously,
followed by adding abiraterone acetate in dark place. After being fully
dissolved,
2-(2-ethoxyethoxy)ethanol was added to form a transparent and homogeneous self-
emulsification
solution, namely the abiraterone acetate-containing composition.
Comparative example 3
The abiraterone acetate-containing composition comprises the following
components:
abiraterone acetate: 1.170 portions by weight (comprising about 4.03 wt.% of
the total weight
of the composition);
glycerol monolinoleate: 4.136 portions by weight (comprising about 14.26 wt.%
of the total
weight of the composition);
medium chain triglyceride: 2.632 portions by weight (comprising about 9.08
wt.% of the total
weight of the composition);
PEG-40 hydrogenated castor oil: 3.816 portions by weight (comprising about
13.16 wt.% of
the total weight of the composition); and
2-(2-ethoxyethoxy)ethanol: 17.248 portions by weight (comprising about 59.47
wt.% of the
22
Date Recue/Date Received 2022-12-12
total weight of the composition).
The preparation process is as follows. Glycerol monolinoleate, medium chain
triglyceride,
PEG-40 hydrogenated castor oil were taken in proportion, stirred and mixed
homogeneously,
followed by adding abiraterone acetate in dark place. After being fully
dissolved,
2-(2-ethoxyethoxy)ethanol was added to form a transparent and homogeneous self-
emulsification
solution, namely the abiraterone acetate-containing composition.
Comparative example 4
The abiraterone acetate-containing composition comprises the following
components:
abiraterone acetate: 1.170 portions by weight (comprising about 2.45 wt.% of
the total weight
of the composition);
glycerol monolinoleate: 4.136 portions by weight (comprising about 8.65 wt.%
of the total
weight of the composition);
medium chain triglyceride: 2.632 portions by weight (comprising about 5.50
wt.% of the total
weight of the composition);
PEG-40 hydrogenated castor oil: 3.816 portions by weight (comprising about
7.98 wt.% of the
total weight of the composition); and
2-(2-ethoxyethoxy)ethanol: 36.064 portions by weight (comprising about 75.42
wt.% of the
total weight of the composition).
The preparation process is as follows. Glycerol monolinoleate, medium chain
triglyceride,
PEG-40 hydrogenated castor oil were taken in proportion, stirred and mixed
homogeneously,
followed by adding abiraterone acetate in dark place. After being fully
dissolved,
2-(2-ethoxyethoxy)ethanol was added to form a transparent and homogeneous self-
emulsification
solution, namely the abiraterone acetate-containing composition.
Comparative example 5
The abiraterone acetate-containing composition comprises the following
components:
abiraterone acetate: 1.300 portions by weight (comprising about 5.0 wt.% of
the total weight of
the composition);
glycerol monolinoleate: 6.667 portions by weight (comprising about 25.64 wt.%
of the total
weight of the composition);
medium chain triglyceride: 1.975 portions by weight (comprising about 7.60
wt.% of the total
23
Date Recue/Date Received 2022-12-12
weight of the composition);
PEG-40 hydrogenated castor oil: 4.940 portions by weight (comprising about
19.00 wt.% of
the total weight of the composition); and
2-(2-ethoxyethoxy)ethanol: 11.118 portions by weight (comprising about 42.76
wt.% of the
total weight of the composition).
The preparation process is as follows. Glycerol monolinoleate, medium chain
triglyceride,
PEG-40 hydrogenated castor oil were taken in proportion, stirred and mixed
homogeneously,
followed by adding abiraterone acetate in dark place. After being fully
dissolved,
2-(2-ethoxyethoxy)ethanol was added to form a transparent and homogeneous self-
emulsification
solution, namely the abiraterone acetate-containing composition.
Comparative example 6
The abiraterone acetate-containing composition comprises the following
components:
abiraterone acetate: 1.170 portions by weight (comprising about 4.50 wt.% of
the total weight
of the composition);
glycerol monolinoleate: 6.822 portions by weight (comprising about 26.24 wt.%
of the total
weight of the composition);
medium chain triglyceride: 1.868 portions by weight (comprising about 7.18
wt.% of the total
weight of the composition);
PEG-40 hydrogenated castor oil: 4.966 portions by weight (comprising about
19.10 wt.% of
the total weight of the composition); and
2-(2-ethoxyethoxy)ethanol: 11.174 portions by weight (comprising about 42.98
wt.% of the
total weight of the composition).
The preparation process is as follows. Glycerol monolinoleate, medium chain
triglyceride,
PEG-40 hydrogenated castor oil were taken in proportion, stirred and mixed
homogeneously,
followed by adding abiraterone acetate in dark place. After being fully
dissolved,
2-(2-ethoxyethoxy)ethanol was added to form a transparent and homogeneous self-
emulsification
solution, namely the abiraterone acetate-containing composition.
Comparative example 7
The abiraterone acetate-containing composition comprises the following
components:
abiraterone acetate: 1.170 portions by weight (comprising about 4.50 wt.% of
the total weight
24
Date Recue/Date Received 2022-12-12
of the composition);
glycerol monolinoleate: 6.704 portions by weight (comprising about 25.78 wt.%
of the total
weight of the composition);
medium chain triglyceride: 1.986 portions by weight (comprising about 7.64
wt.% of the total
weight of the composition);
PEG-40 hydrogenated castor oil: 4.547 portions by weight (comprising about
17.49 wt.% of
the total weight of the composition); and
2-(2-ethoxyethoxy)ethanol: 11.593 portions by weight (comprising about 44.59
wt.% of the
total weight of the composition).
The preparation process is as follows. Glycerol monolinoleate, medium chain
triglyceride,
PEG-40 hydrogenated castor oil were taken in proportion, stirred and mixed
homogeneously,
followed by adding abiraterone acetate in dark place. After being fully
dissolved,
2-(2-ethoxyethoxy)ethanol was added to form a transparent and homogeneous self-
emulsification
solution, namely the abiraterone acetate-containing composition.
Comparative example 8
The abiraterone acetate-containing composition comprises the following
components:
abiraterone acetate: 1.170 portions by weight (comprising about 4.50 wt.% of
the total weight
of the composition);
glycerol monolinoleate: 5.747 portions by weight (comprising about 22.10 wt.%
of the total
weight of the composition);
medium chain triglyceride: 1.702 portions by weight (comprising about 6.55
wt.% of the total
weight of the composition);
PEG-40 hydrogenated castor oil: 5.348 portions by weight (comprising about
20.57 wt.% of
the total weight of the composition); and
2-(2-ethoxyethoxy)ethanol: 12.033 portions by weight (comprising about 46.28
wt.% of the
total weight of the composition).
The preparation process is as follows. Glycerol monolinoleate, medium chain
triglyceride,
PEG-40 hydrogenated castor oil were taken in proportion, stirred and mixed
homogeneously,
followed by adding abiraterone acetate in dark place. After being fully
dissolved,
2-(2-ethoxyethoxy)ethanol was added to form a transparent and homogeneous self-
emulsification
Date Recue/Date Received 2022-12-12
solution, namely the abiraterone acetate-containing composition.
Comparative example 9
The abiraterone acetate-containing composition comprises the following
components:
abiraterone acetate: 1.170 portions by weight (comprising about 4.50 wt.% of
the total weight
of the composition);
glycerol monolinoleate: 7.087 portions by weight (comprising about 27.26 wt.%
of the total
weight of the composition);
medium chain triglyceride: 2.100 portions by weight (comprising about 8.08
wt.% of the total
weight of the composition);
PEG-40 hydrogenated castor oil: 4.813 portions by weight (comprising about
18.51 wt.% of
the total weight of the composition); and
2-(2-ethoxyethoxy)ethanol: 10.830 portions by weight (comprising about 41.65
wt.% of the
total weight of the composition).
The preparation process is as follows. Glycerol monolinoleate, medium chain
triglyceride,
PEG-40 hydrogenated castor oil were taken in proportion, stirred and mixed
homogeneously,
followed by adding abiraterone acetate in dark place. After being fully
dissolved,
2-(2-ethoxyethoxy)ethanol was added to form a transparent and homogeneous self-
emulsification
solution, namely the abiraterone acetate-containing composition.
Comparative example 10
The abiraterone acetate-containing composition comprises the following
components:
abiraterone acetate: 1.170 portions by weight (comprising about 4.50 wt.% of
the total weight
of the composition);
glycerol monolinoleate: 6.130 portions by weight (comprising about 23.58 wt.%
of the total
weight of the composition);
medium chain triglyceride: 1.816 portions by weight (comprising about 6.98
wt.% of the total
weight of the composition);
PEG-40 hydrogenated castor oil: 5.195 portions by weight (comprising about
19.98 wt.% of
the total weight of the composition); and
2-(2-ethoxyethoxy)ethanol: 11.689 portions by weight (comprising about 44.96
wt.% of the
total weight of the composition).
26
Date Recue/Date Received 2022-12-12
The preparation process is as follows. Glycerol monolinoleate, medium chain
triglyceride,
PEG-40 hydrogenated castor oil were taken in proportion, stirred and mixed
homogeneously,
followed by adding abiraterone acetate in dark place. After being fully
dissolved,
2-(2-ethoxyethoxy)ethanol was added to form a transparent and homogeneous self-
emulsification
solution, namely the abiraterone acetate-containing composition.
Comparative example 11
The abiraterone acetate-containing composition comprises the following
components:
abiraterone acetate: 1.170 portions by weight (comprising about 4.50 wt.% of
the total weight
of the composition);
glycerol monolinoleate: 6.704 portions by weight (comprising about 25.78 wt.%
of the total
weight of the composition);
medium chain triglyceride: 1.986 portions by weight (comprising about 7.64
wt.% of the total
weight of the composition);
PEG-40 hydrogenated castor oil: 5.124 portions by weight (comprising about
19.71 wt.% of
the total weight of the composition); and
2-(2-ethoxyethoxy)ethanol: 11.016 portions by weight (comprising about 42.37
wt.% of the
total weight of the composition).
The preparation process is as follows. Glycerol monolinoleate, medium chain
triglyceride,
PEG-40 hydrogenated castor oil were taken in proportion, stirred and mixed
homogeneously,
followed by adding abiraterone acetate in dark place. After being fully
dissolved,
2-(2-ethoxyethoxy)ethanol was added to form a transparent and homogeneous self-
emulsification
solution, namely the abiraterone acetate-containing composition.
Comparative example 12
The abiraterone acetate-containing composition comprises the following
components:
abiraterone acetate: 1.170 portions by weight (comprising about 4.50 wt.% of
the total weight
of the composition);
glycerol monolinoleate: 5.364 portions by weight (comprising about 20.63 wt.%
of the total
weight of the composition);
medium chain triglyceride: 1.588 portions by weight (comprising about 6.11
wt.% of the total
weight of the composition);
27
Date Recue/Date Received 2022-12-12
PEG-40 hydrogenated castor oil: 5.501 portions by weight (comprising about
21.16 wt.% of
the total weight of the composition); and
2-(2-ethoxyethoxy)ethanol: 12.377 portions by weight (comprising about 47.60
wt.% of the
total weight of the composition).
The preparation process is as follows. Glycerol monolinoleate, medium chain
triglyceride,
PEG-40 hydrogenated castor oil were taken in proportion, stirred and mixed
homogeneously,
followed by adding abiraterone acetate in dark place. After being fully
dissolved,
2-(2-ethoxyethoxy)ethanol was added to form a transparent and homogeneous self-
emulsification
solution, namely the abiraterone acetate-containing composition.
Comparative example 13
The abiraterone acetate-containing composition comprises the following
components:
abiraterone acetate: 1.170 portions by weight (comprising about 4.50 wt.% of
the total weight
of the composition);
glycerol monolinoleate: 6.134 portions by weight (comprising about 23.59 wt.%
of the total
weight of the composition);
medium chain triglyceride: 2.556 portions by weight (comprising about 9.83
wt.% of the total
weight of the composition);
PEG-40 hydrogenated castor oil: 4.966 portions by weight (comprising about
19.10 wt.% of
the total weight of the composition); and
2-(2-ethoxyethoxy)ethanol: 11.174 portions by weight (comprising about 42.98
wt.% of the
total weight of the composition).
The preparation process is as follows. Glycerol monolinoleate, medium chain
triglyceride,
PEG-40 hydrogenated castor oil were taken in proportion, stirred and mixed
homogeneously,
followed by adding abiraterone acetate in dark place. After being fully
dissolved,
2-(2-ethoxyethoxy)ethanol was added to form a transparent and homogeneous self-
emulsification
solution, namely the abiraterone acetate-containing composition.
Experimental Example 1
Abiraterone acetate-containing compositions were obtained according to the
amount
configurations of the above-mentioned Examples 1-11 and Comparative examples 1-
13. The
composition proportion of the composition of each Example is shown in Table 5.
Each abiraterone
28
Date Recue/Date Received 2022-12-12
acetate-containing composition is subjected to stability test. Specifically,
the abiraterone
acetate-containing compositions obtained in Examples 1-11 and Comparative
examples 1-13 were
placed for 24 h under conditions of: at room temperature; at 4 C; at room
temperature with the
addition of 10 wt.% water; and at room temperature with the addition of 15
wt.% water. The
stability of each abiraterone acetate-containing composition was observed and
the results are shown
in Table 6.
Table 5. Composition proportions of abiraterone acetate-containing
compositions
API CC MCT RH40 HP Oil phase /
CC/MCT RH40/HP
(%) (%) (%) (%) (%) Emulsion phase
Example 1 4.30 25.85 7.66 19.13 43.06 35%:65% 3.38:1 1:2.25
Example 2 4.50 25.78 7.64 19.10 42.98 35%:65% 3.38:1 1:2.25
Example 3 4.80 25.70 7.61 19.04 42.85 35%:65% 3.38:1 1:2.25
Example 4 4.50 25.09 8.33 19.10 42.98 35%:65% 3.01:1 1:2.25
Example 5 4.50 23.87 9.55 19.10 42.98 35%:65% 2.50:1 1:2.25
Example 6 4.50 26.00 7.42 19.10 42.98 35%:65% 3.50:1 1:2.25
Example 7 4.50 25.78 7.64 18.26 43.82 35%:65% 3.38:1 1:2.40
Example 8 4.50 25.78 7.64 17.84 44.24 35%:65% 3.38:1 1:2.48
Example 9 4.50 24.32 7.20 19.10 44.88 33%:67% 3.38:1 1:2.35
Example 10 4.50 23.58 6.98 19.10 45.84 32%:68% 3.38:1 1:2.40
Example 11 4.50 22.10 6.55 19.10 47.75 30%:70% 3.38:1 1:2.50
Comparative
7.11 25.13 15.99 23.19 28.58 44%:56% 1.571:1 1:2.33
example 1
Comparative
8.78 31.05 19.76 28.64 11.77 56%:44% 1.571:1 1:0.41
example 2
Comparative
4.03 14.26 9.08 13.16 59.47 24%:76% 1.571:1 1:4.52
example 3
Comparative 2.45 8.65 5.50 7.98 75.42 15%:85% 1.571:1 1:9.45
example 4
Comparative
5.00 25.64 7.60 19.00 42.76 35%:65% 3.38:1 1:2.25
example 5
29
Date Recue/Date Received 2022-12-12
Comparative
4.50 26.24 7.18 19.10 42.98 35%:65% 3.65:1 1:2.25
example 6
Comparative
4.50 25.78 7.64 17.49 44.59 35%:65% 3.38:1 1:2.55
example 7
Comparative
4.50 22.10 6.55 20.57 46.28 30%:70% 3.38:1 1:2.25
example 8
Comparative
4.50 27.26 8.08 18.51 41.65 37%:63% 3.38:1 1:2.25
example 9
Comparative
4.50 23.58 6.98 19.98 44.96 32%:68% 3.38:1 1:2.25
example 10
Comparative
4.50 25.78 7.64 19.71 42.37 35%:65% 3.38:1 1:2.15
example 11
Comparative
4.50 20.63 6.11 21.16 47.60 28%:72% 3.38:1 1:2.25
example 12
Comparative
4.5 23.59 9.83 19.10 42.98 35%:65% 2.40:1 1:2.25
example 13
Note: The value of oil phase or emulsion phase is represented by the
percentages of the oil phase or
the emulsion phase based on the total weight of the oil phase and the emulsion
phase.
Table 6. Investigation on the stability of the abiraterone acetate-containing
compositions
wt.% water of the 15 wt.% water of the
R.T. 4 C total weight of total
weight of
composition added
composition added
Example 1 Unprecipitated Unprecipitated
Unprecipitated Unprecipitated
Example 2 Unprecipitated Unprecipitated
Unprecipitated Unprecipitated
Example 3 Unprecipitated Unprecipitated
Unprecipitated Unprecipitated
Example 4 Unprecipitated Unprecipitated
Unprecipitated Unprecipitated
Example 5 Unprecipitated Unprecipitated
Unprecipitated Unprecipitated
Example 6 Unprecipitated Unprecipitated
Unprecipitated Unprecipitated
Example 7 Unprecipitated Unprecipitated
Slightly precipitated Slightly precipitated
Example 8 Unprecipitated Unprecipitated
Slightly precipitated Slightly precipitated
Example 9 Unprecipitated Unprecipitated
Unprecipitated Unprecipitated
Example 10 Unprecipitated Unprecipitated Unprecipitated
Unprecipitated
Date Recue/Date Received 2022-12-12
Example 11 Unprecipitated Unprecipitated Unprecipitated
Unprecipitated
Comparative
Unprecipitated Precipitated Precipitated Precipitated
example 1
Comparative
Unprecipitated Precipitated Precipitated Precipitated
example 2
Comparative
Unprecipitated Unprecipitated Layers separated Layers separated
example 3
Comparative
Unprecipitated Unprecipitated Layers separated Layers separated
example 4
Comparative API largely API largely API largely API largely
example 5 precipitated precipitated precipitated precipitated
Comparative Oil droplets Oil droplets
Unprecipitated Unprecipitated
example 6 precipitated precipitated
Comparative API
API precipitated API precipitated API precipitated
example 7 precipitated
Comparative
Unprecipitated Unprecipitated Layers separated Layers separated
example 8
Comparative Oil droplets Oil droplets
Unprecipitated Unprecipitated
example 9 precipitated precipitated
Comparative
Unprecipitated Unprecipitated Layers separated Layers separated
example 10
Comparative
Unprecipitated Unprecipitated Layers separated Layers separated
example 11
Comparative API
API precipitated API precipitated API precipitated
example 12 precipitated
Comparative API
API precipitated API precipitated API precipitated
example 13 precipitated
In Comparative example 1, the API content was too high and exceeded the
maximum drug
loading capacity of the system, rendering the carrier and adjuvants
precipitated and the system
being turbid. In Comparative example 2, the HP content was too low while the
API content was too
high, resulting in the precipitation of API and the appearance of medicament
particle crystals at the
bottom of the composition. Further, API was precipitated in both Comparative
example 1 and
Comparative example 2 after adding a small amount of water. In general, the
prepared
pharmaceutical composition tends to absorb moisture during subsequent long-
term storage,
resulting in an increase in moisture content. In Comparative example 5, the
excessively high API
content results in the formation of a large amount of API precipitation. In
comparative example 6,
the excessive proportion of CC lead to an excessive amount of oil phase,
resulting in the
precipitation of oil droplets under humid or over-humid conditions (i.e. after
adding a small amount
31
Date Recue/Date Received 2022-12-12
of water). Comparative example 7 comprises a large proportion of HP that is
hydrophilic.
Accordingly, under humid or over-humid conditions, after being dispersed in
water, some
medicament could not be completely dissolved and was precipitated.. Besides,
the excessively high
content of HP leads to the increase of toxic and side effects of medicaments.
Comparative examples
8, 10 and 11 have a low content of HP, and cannot achieve a satisfying
emulsification effect
(wherein Comparative example 11 comprises an excessively low content of HP and
failed to form
microemulsion). Further, these compositions were layered under humid or over-
humid conditions.
In Comparative example 9, the content of the emulsion phase was so low that
the microemulsion
could not be formed, while the content of the oil phase was too high that a
large number of oil
droplets were precipitated under humid or over-humid conditions. In
Comparative example 12, due
to the lower oil phase content and the higher emulsion phase content, the
content of HP, which is
hydrophilic, was relatively high. Accordingly, after being dispersed in water,
some medicament
could not be completely dissolved and was precipitated. In comparative example
13, due to the
excessively low content of CC, the resulting self-microemulsion system has a
low loading capacity
of API, resulting in the precipitation of API. Moreover, in Examples 7 and 8,
with a specific ratio of
oil phase and emulsion phase, the percentage of HP in the emulsion phase was
slightly high, making
the HP content in these Examples slightly high. HP is hydrophilic, and thus
trace amount of
medicament, after being dispersed in water under humid or over-humid
conditions, could not be
completely dissolved and was precipitated.
Further, the self-microemulsion systems of Example 2 and Comparative examples
1-4 after
emulsification were placed under a temperature of 30 C 5 C for 24 h and 48
h, respectively. The
stability of the self-microemulsion systems were observed and summarized in
Table 7.
Table 7
Comparative Comparative Comparative Comparative
Example 2
example 1 example 2 example 3 example 4
24 h No obvious change was observed
Oil droplets Oil droplets
48 h No obvious change was observed
precipitated precipitated
Referring to the Table 7 above, it can be seen that there was cargo (API)
precipitated in both
Comparative examples 3 and 4 after forming the self-microemulsion system,
which indicates that
both the self-microemulsion systems have poor long-term stabilities. Due to
the low oil phase
32
Date Recue/Date Received 2022-12-12
content in Comparative example 4 was low, co-emulsifier (HP) was added in a
content of more than
70% in order to form a transparent solution. However, the co-emulsifier was
hydrophilic, and after
dispersing in water, part of API could not be completely dissolved and was
precipitated. Besides,
the excessively high content of the co-emulsifier leads to an increase of
toxic and side effects of the
medicament. The oil phase content in Comparative example 3 was relatively low,
and accordingly
leaded to large particles after emulsification, which hinders the subsequent
absorption. Besides,
there was drug precipitation after a period of storage.
Application Example 1
Pharmacokinetic experiments were performed on the abiraterone acetate-
containing
composition prepared according to the present disclosure and Example 1 in the
prior art document
W02021057042 (hereinafter referred to as "Comparative example 14").
Experiment methods and subjects: 6 healthy beagle dogs, randomly divided into
3 groups with
2 dogs in each group; interperiodic washout period being 3 days.
The experiments were designed as fasting experiment and postprandial
experiment.
Fasting test: fasted for 10 hours before the experiment; administered on an
empty stomach, and
fed 4 hours after administration.
Postprandial test: fasted for 10 hours before the experiment, and fed a high-
fat meal followed
by administering (feeding and administering were completed within 30 minutes).
The experiment was carried out with the abiraterone acetate-containing
capsules provided in
the examples of the present invention and the Comparative example 14, wherein
a single capsule
contains 50 mg of abiraterone acetate.
Sampling design: 2 ml blood sample was collected at each of 15 min, 30 min, 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 administering, and the
plasma was separated by
centrifugation. The results of the pharmacokinetic experiments of the
abiraterone acetate-containing
compositions of the present invention being prepared into capsule are shown in
Table 8.
33
Date Recue/Date Received 2022-12-12
Table 8. Results of pharmacokinetic parameters
Average AUCIast Average AUCIast Bioavailability ofAUCIast of
oral administration
in fasting test on in postprandial postprandial test
Examples in fasting
beagle dogs test on beagle /AUCIast of
test/Comparative
(h=ng/mL) dogs (h=ng/mL) example 14 fasting test
Comparative
553.29 669.2 1.21
example 14
Example 1 752.41 855.03 135.99% 1.14
Example 2 756.39 857.14 136.71% 1.13
Example 3 788.72 847.63 142.55% 1.07
Example 4 769.1 822.52 139.00% 1.07
Example 5 723.85 789.18 130.83% 1.09
Example 6 774.04 848.26 139.90% 1.10
Example 7 781.58 739.48 141.26% 0.95
Example 8 765.03 755.97 138.27% 0.99
Example 9 773.95 814.28 139.88% 1.05
Example 10 745.37 833.41 134.72% 1.12
Example 11 777.18 808.75 140.47% 1.04
As seen in Table 8, the oral bioavailability of abiraterone acetate capsules
of Example 2
administered orally to Beagle on an empty stomach was 136.71% of the oral
bioavailability of
abiraterone acetate capsule of Comparison example 14. This indicates that,
comparing with
Comparative example 14, the oral bioavailability of the abiraterone acetate
pharmaceutical
composition of the present invention increased to about 1.36 times, and have a
low inter-individual
variability in peak time, peak concentration and absorption level of the
medicaments. When the
abiraterone acetate capsule of Comparative example 14 (containing 50 mg of
abiraterone acetate)
were administered after fasting or high-fat meals, there was no significant
difference in peak time in
Beagle, and the oral bioavailability in postprandial test was 1.21 times that
of the preprandial test
(i.e. the fasting test). When abiraterone acetate capsule of Example 2
(containing 50 mg of
abiraterone acetate ) were administered after fasting and high-fat meals,
there was no significant
difference in peak time in Beagle, and the oral bioavailability in
postprandial test was only 1.13
times that of the preprandial test. It can be seen that the abiraterone
acetate capsules provided by the
present invention further reduced the differences between preprandial and
postprandial.
Furthermore, as seen in Table 8, the postprandial oral bioavailability of
abiraterone acetate
capsules provided by the present invention ranges from 0.95 to 1.14 times that
of the preprandial
34
Date Recue/Date Received 2022-12-12
oral bioavailability, indicating the difference between preprandial and
postprandial was reduced.
Meanwhile, the oral bioavailability of the present capsules for Beagle in a
fasting test is 130.83% -
142.55% of the oral bioavailability of the abiraterone acetate capsule of
Comparative example 14,
indicating that the abiraterone acetate capsules provided by the present
invention further improved
the oral bioavailability under fasting.
Application Example 2
1. Tissue distribution of abiraterone acetate capsules
1.1 Administration
Male rats were randomly divided into groups with each group 9 rats. The
specific
administration scheme is as follows.
9 male rats in group 1 were orally administered with the innovator drug Zytiga
at a dosage of
500 mg;
36 male rats in groups 2-5 were orally administered with the abiraterone
acetate capsules
prepared according the present disclosure (Comparative example 14, Example 2,
Example 6, and
Example 10) at a dosage of 50 mg.
1.2 Sample collection and treatment
Three rats were sacrificed at each time point of 0.5 h, 2 h and 4 h,
respectively, after gavage
administration of the innovator drug Zytiga, and three rats were sacrificed at
each time point of 0.5
h, 2 h and 4 h, respectively, after gavage administration of the abiraterone
acetate capsule. 0.5 mL
of venous blood was collected, and then the dissection was quickly carried out
to take heart, liver,
spleen, lung, kidney, stomach, intestine, sputum, brain, spine, spinal fluid,
nerve, thymus, lymph
nodes, arterial wall, pancreas, gallbladder, prostate, testis, thyroid,
adrenal gland, hypothalamus,
pituitary gland, eye, ear, bladder, muscle, skin, white blood cells, bone,
cartilage, joint tissue,
synovial fluid, adipose tissue, and the like. The taken tissues were washed
with normal saline to
remove the surface blood stains, then dried with filter paper and weighed
respectively. Besides,
fecal samples are collected from the rat intestines and weighed to determine
the amount of
unabsorbed medicament.
The collected blood samples were anticoagulated with sodium heparin and
centrifuged at 3500
rpm for 10 min at 2-8 C within 1 h after collection. The separated plasma was
stored at -80 C in a
refrigerator for subsequent tests, and the lymphocytes and erythrocytes at the
bottom are also
recovered and stored at -80 C in a refrigerator for subsequent tests.
A certain amount (about 0.2 g) of each tissue sample was taken, and 3 mL of
normal saline was
added for every 1 g tissue. The mixture was fully stir-crushed with an
electric homogenizer under
Date Recue/Date Received 2022-12-12
an ice bath, and stored in a refrigerator at -80 C for subsequent tests. The
rest of the tissue that were
not homogenized were recovered and stored in a -80 C refrigerator.
The procedure of the sample collection and treatment was performed in dark
place.
1.3 Sample Detection
LC-MS/MS method was used to detect the concentration of abiraterone acetate in
plasma
samples, tissue samples (including testis and prostate) and fecal samples of
rats respectively. The
results are summarized in Tables 9-10 below.
Table 9. Detection results of the ratios of rat tissue samples/plasma samples
Concentration of
abiraterone
acetate in tissue Medicaments 0.5 h 2 h 4 h
sample/in
plasma sample
Innovator drug
0.0468 0.1161 0.6621
Ratio of Zytiga
concentration in Comparative
0.0556 0.2518 1.5456
testis sample to example 14
that in plasma Example 2 0.1342 0.6792 2.3424
sample Example 6 0.1324 0.6270 1.8209
Example 10 0.1328 0.4931 2.3086
Innovator drug
0.08799 3.5926 6.4445
Ratio of Zytiga
concentration in Comparative
0.3779 10.2045 15.4813
prostate sample example 14
to that in plasma Example 2 2.7474 16.5699 17.2236
sample Example 6 1.4594 11.7562 16.4445
Example 10 2.5592 14.5396 16.9481
Referring to the results in Table 9, taking the concentration of abiraterone
acetate in plasma
samples as a baseline, the testicular and prostate samples taken from the rats
that administered with
the abiraterone acetate compositions of the present disclosure (Comparison
example 14, Example 2,
Example 6, Example 10) showed high medicament concentrations, indicating that
abiraterone
aggregated in the testis and prostate. Abiraterone acetate with a high
concentration in specific local
tissues facilitates it accessing to the target location and producing better
efficacy.
36
Date Recue/Date Received 2022-12-12
Table 10. Detection results of abiraterone concentration in fecal samples of
rats
Medicaments 4 h
Innovator drug Zytiga 13430
Abiraterone
Comparative example 14 163.1
concentration in
Example 2 50.7
fecal samples
Example 6 61.61
Example 10 32.77
The results in Table 10 shows that, after 4 h of administration, the
concentrations of
abiraterone in the fecal samples of rats that administered with the
abiraterone acetate composition of
the examples of the present invention were significantly lower than that in
equal weight of fecal
samples of rats given the control medicament, indicating that more abiraterone
in the abiraterone
acetate composition of the examples of the present invention was absorbed.
37
Date Recue/Date Received 2022-12-12
