CN113197865A - Eutectic crystal of abiraterone acetate and trans-aconitic acid, preparation method thereof, pharmaceutical composition and application thereof - Google Patents

Eutectic crystal of abiraterone acetate and trans-aconitic acid, preparation method thereof, pharmaceutical composition and application thereof Download PDF

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CN113197865A
CN113197865A CN202110516600.3A CN202110516600A CN113197865A CN 113197865 A CN113197865 A CN 113197865A CN 202110516600 A CN202110516600 A CN 202110516600A CN 113197865 A CN113197865 A CN 113197865A
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abiraterone acetate
aconitic acid
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CN113197865B (en
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梅雪锋
杨泽恩
朱冰清
戴文娟
王建荣
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Shanghai Institute of Materia Medica of CAS
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Abstract

The invention relates to a cocrystal of abiraterone acetate and trans-aconitic acid, a preparation method thereof, a pharmaceutical composition and application thereof. The X-ray powder diffraction pattern of the eutectic of abiraterone acetate and trans-aconitic acid has characteristic peaks at diffraction angles 2 theta of 6.7, 7.3, 7.6, 13.6, 14.0, 15.0, 17.1, 17.9, 18.5, 19.5 and 24.9 degrees. Compared with the abiraterone acetate in the prior art, the eutectic of the abiraterone acetate and the trans-aconitic acid is remarkably improved in the aspects of medicine solubility, dissolution performance, medicine in-vivo absorption and the like.

Description

Eutectic crystal of abiraterone acetate and trans-aconitic acid, preparation method thereof, pharmaceutical composition and application thereof
Technical Field
The invention relates to the technical field of pharmaceutical chemistry and crystallization processes, in particular to a cocrystal of abiraterone acetate and trans-aconitic acid, a preparation method thereof, a pharmaceutical composition and application thereof.
Background
The chemical name of Abiraterone Acetate (Abiraterone Acetate) is: 17- (3-pyridine) androsta-5, 16-diene-3 β -acetate ((3 β) -17- (3-pyridine) androsta-5,16-dien-3-ol acetate) having the following chemical structure:
Figure BDA0003061726220000011
abiraterone acetate can be converted into abiraterone in vivo, and abiraterone is an androgen biosynthesis inhibitor, can inhibit 17 alpha-hydroxylase/C17, 20 lyase, and reduce androgen production in testis, adrenal gland and prostate tumor tissues. However, the clinical application of the abiraterone acetate is greatly limited because of poor water solubility and poor oral absorption of the abiraterone acetate.
Pharmaceutical co-crystals are defined as the association of molecules of the Active Pharmaceutical Ingredient (API) with other physiologically acceptable acids, bases, salts and non-ionic compounds in the same crystal lattice by hydrogen bonding, pi-pi stacking, van der waals forces and other non-covalent bonds.
The pharmaceutical co-crystal has greater advantages compared with other solid forms such as polymorphism or salt. The solubility difference of different crystalline forms of a drug is usually not more than 2-fold compared to polymorphic forms, while the solubility of co-crystals varies by tens of times. Compared with salt, salt formation requires that the compound has at least one ionization center, each component in the pharmaceutical co-crystal can be neutral molecules, the molecular range of the co-crystal can be greatly expanded, and the pharmaceutical co-crystal can be food additives, preservatives, auxiliary materials, vitamins, minerals, amino acids and the like, even can be other API, and provides diversified solid forms for molecules lacking ionizable functional groups.
So far, US 10045998B2 reports that the solubility of abiraterone acetate in acidic medium is improved to some extent compared with abiraterone acetate itself, with co-crystals and salts of adipic acid, citric acid, D, L-malic acid, maleic acid, methyl 4-hydroxybenzoate, saccharin, L-tartaric acid, vanillic acid, but no pharmacokinetic experiments have been carried out to demonstrate that the existing co-crystals or salts are improved in drug absorption.
However, there remains a need in the art to provide a pharmaceutical form of abiraterone acetate which has a greater enhanced solubility and also an enhanced bioavailability.
Disclosure of Invention
The invention aims to provide a co-crystal of abiraterone acetate and trans-aconitic acid, which has the advantages of good solubility, high inherent dissolution rate and high bioavailability, and a preparation method, a pharmaceutical composition and application thereof.
In order to achieve the above object, in one aspect, the present invention provides a co-crystal of abiraterone acetate and trans-aconitic acid, wherein the molar ratio of abiraterone acetate to trans-aconitic acid is 2:1, and the X-ray powder diffraction pattern of the co-crystal of abiraterone acetate and trans-aconitic acid has characteristic peaks at diffraction angles 2 θ of 6.7, 7.3, 7.6, 13.6, 14.0, 15.0, 17.1, 17.9, 18.5, 19.5 and 24.9 degrees, and the error is ± 0.2 degrees.
In a specific embodiment, the co-crystal of abiraterone acetate and trans-aconitic acid has an X-ray powder diffraction (XRPD) pattern substantially as shown in figure 1.
In a specific embodiment, the differential scanning calorimetry analysis of the co-crystal of abiraterone acetate and trans-aconitic acid has a characteristic melting peak at 139 ± 2 ℃, preferably the co-crystal of abiraterone acetate and trans-aconitic acid has a Differential Scanning Calorimetry (DSC) profile substantially as shown in figure 3.
In a specific embodiment, the infrared spectrum of the eutectic of abiraterone acetate and trans-aconitic acid is at least 2935cm-1、2848cm-1、1701cm-1、1599cm-1、1376cm-1、1246cm-1、1035cm-1、797cm-1Has a characteristic peak, and preferably the eutectic of abiraterone acetate and trans-aconitic acid has an infrared spectrum (IR) diagram substantially as shown in figure 4.
In a specific embodiment, the Raman spectrum of the eutectic of abiraterone acetate and trans-aconitic acid is at least 1668cm-1、1600cm-1、1442cm-1、1299cm-1、1246cm-1、1050cm-1、1027cm-1、846cm-1、703cm-1、581cm-1Preferably, the eutectic of abiraterone acetate and trans-aconitic acid has a Raman spectrum (Raman) substantially as shown in figure 5.
In a specific embodiment, the eutectic of abiraterone acetate and trans-aconitic acid is monoclinic system, and space group is P21The unit cell parameters are:
Figure BDA0003061726220000021
Figure BDA0003061726220000022
α is 90 °; β 95.330(3) °; gamma 90 DEG, unit cell volume of
Figure BDA0003061726220000023
On the other hand, the invention provides a preparation method of the eutectic crystal of abiraterone acetate and trans-aconitic acid, which comprises the following steps:
a. dissolving abiraterone acetate and trans-aconitic acid in an organic solvent to form a solution of the abiraterone acetate and the trans-aconitic acid;
b. crystallizing the abiraterone acetate and trans-aconitic acid solution to form an eutectic solution system of the abiraterone acetate and the trans-aconitic acid;
c. and separating the eutectic solution system to obtain the eutectic of abiraterone acetate and trans-aconitic acid.
In a specific embodiment, in step a, the abiraterone acetate and trans-aconitic acid are dissolved in the organic solvent in a molar ratio of 2:1 to 1: 1.
In a specific embodiment, in step a, the abiraterone acetate and trans-aconitic acid are dissolved in the organic solvent in a molar ratio of 2: 1.
In a specific embodiment, in step a, the organic solvent is selected from any one of methanol, ethanol, acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran, ethyl acetate, or a mixed solvent of any two of them.
In a specific embodiment, in step a, the organic solvent is: ethanol, methanol, acetone, methyl ethyl ketone, acetonitrile, a mixed solvent of ethanol and acetonitrile, a mixed solvent of acetone and acetonitrile, a mixed solvent of ethyl acetate and acetone, a mixed solvent of ethanol and acetone, or a mixed solvent of methanol and acetonitrile.
In a specific embodiment, the volume ratio of the mixed solvent may be in the range of 1:3 to 3:1, for example, the volume ratio may be 1: 1.
In a particular embodiment, in step b, the crystallization treatment comprises removing the organic solvent by evaporation, thereby forming a co-crystal of abiraterone acetate and trans-aconitic acid.
In a particular embodiment, in step b, the crystallization treatment comprises removing the organic solvent by volatilization at a temperature of between room temperature and 50 ℃.
In a specific embodiment, in the step b, the crystallization treatment comprises adding a seed crystal of the abiraterone acetate and trans-aconitic acid eutectic to the abiraterone acetate and trans-aconitic acid solution.
In a specific embodiment, the step c comprises one of the following steps:
c 1: filtering the eutectic solution system to obtain a eutectic of abiraterone acetate and trans-aconitic acid;
c 2: centrifuging the eutectic solution system to obtain a eutectic of abiraterone acetate and trans-aconitic acid;
c 3: and heating the eutectic solution system, and evaporating to remove the organic solvent to obtain the eutectic of abiraterone acetate and trans-aconitic acid.
In another aspect, the present invention provides a pharmaceutical composition, which comprises a therapeutically effective amount of the above-mentioned co-crystal of abiraterone acetate and trans-aconitic acid, and a pharmaceutically acceptable carrier.
In particular embodiments, the pharmaceutically acceptable carrier may include one, more or all of lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, PVP-K30, sodium lauryl sulfate, magnesium stearate, and silicon dioxide.
In particular embodiments, the pharmaceutical composition may be in the form of various dosage forms, including tablets, capsules, microcapsules, granules, solutions, emulsions, and the like.
In another aspect, the invention provides an application of the above-mentioned abiraterone acetate and trans-aconitic acid eutectic or the above-mentioned pharmaceutical composition in preparing a medicament for treating prostate cancer.
Advantageous effects
The preparation method of the eutectic crystal of abiraterone acetate and trans-aconitic acid provided by the invention is simple to operate, the crystallization process is easy to control, the reproducibility is good, and compared with abiraterone acetate, the eutectic crystal has the advantages of remarkably improved solubility, more excellent inherent dissolution rate, higher bioavailability and smaller individual difference. Compared with the eutectic crystal and salt of the abiraterone acetate, adipic acid, citric acid and the like in the prior art, the solubility of the eutectic crystal of the abiraterone acetate and the trans-aconitic acid is improved more obviously.
Compared with the prior art, the invention further carries out dissolution experiments of the eutectic and verifies the advantages of the eutectic in the aspect of absorption in animals through animal pharmacokinetic experiments, and the pharmacokinetic experiments prove that the eutectic has higher bioavailability compared with abiraterone acetate.
Therefore, the invention provides a feasible technical means for the clinical application of the abiraterone acetate.
Drawings
Figure 1 is an X-ray powder diffraction (XRPD) pattern of a co-crystal of abiraterone acetate and trans-aconitic acid as provided in example 1 of the invention.
Fig. 2 is a thermogravimetric analysis (TG) diagram of a co-crystal of abiraterone acetate and trans-aconitic acid provided in example 1 of the present invention.
Fig. 3 is a Differential Scanning Calorimetry (DSC) chart of the co-crystal of abiraterone acetate and trans-aconitic acid provided in example 1 of the present invention.
Fig. 4 is an infrared spectrum (IR) diagram of a cocrystal of abiraterone acetate and trans-aconitic acid provided in example 1 of the present invention.
Fig. 5 is a Raman spectrum (Raman) chart of the cocrystal of abiraterone acetate and trans-aconitic acid provided in example 1 of the present invention.
Fig. 6 is a graph comparing the intrinsic dissolution rate of the eutectic of abiraterone acetate and trans-aconitic acid and the abiraterone acetate in the dissolution medium with ph of 1.2, provided in example 1 of the present invention.
Fig. 7 is a graph comparing the intrinsic dissolution rate of the co-crystal of abiraterone acetate and trans-aconitic acid provided in example 1 of the present invention and the abiraterone acetate in a dissolution medium with a pH of 4.5.
Fig. 8 is a graph of drug concentration in blood of rats (N ═ 6) orally administered the co-crystals of abiraterone acetate and trans-aconitic acid of example 1 of the present invention, and abiraterone acetate (15mg/kg) at various times.
Fig. 9 is a graph of drug concentration in blood of beagle dogs (N ═ 4) after oral administration of the cocrystal of abiraterone acetate and trans-aconitic acid of example 1 of the present invention and abiraterone acetate (5mg/kg) at various times.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Experimental materials: abiraterone acetate was purchased from Shanghai Demer pharmaceutical science and technology, Inc., lot number 20200615, and had a purity of greater than 98%. Trans-aconitic acid was purchased from Shanghai Allantin Biotechnology Ltd, lot H1905111, and had a purity of greater than 98%.
Preparation examples: preparation of eutectic crystal of abiraterone acetate and trans-aconitic acid
Example 1
Adding 0.1mmol of abiraterone acetate and 0.05mmol of trans-aconitic acid into 4 ml of ethanol according to the stoichiometric ratio of 2:1, completely dissolving, and slowly volatilizing at room temperature to obtain the eutectic of abiraterone acetate and trans-aconitic acid.
Example 2
Adding 0.1mmol of abiraterone acetate and 0.05mmol of trans-aconitic acid into 4 ml of methanol according to the stoichiometric ratio of 2:1, completely dissolving, and slowly volatilizing at 50 ℃ to obtain the eutectic of the abiraterone acetate and the trans-aconitic acid.
Example 3
Adding 0.1mmol of abiraterone acetate and 0.05mmol of trans-aconitic acid into 4 ml of acetone according to the stoichiometric ratio of 2:1, completely dissolving, and slowly volatilizing at 50 ℃ to obtain the eutectic of the abiraterone acetate and the trans-aconitic acid.
Example 4
Adding 0.1mmol of abiraterone acetate and 0.05mmol of trans-aconitic acid into 4 ml of methyl ethyl ketone according to the stoichiometric ratio of 2:1, completely dissolving, and slowly volatilizing at room temperature to obtain the eutectic of the abiraterone acetate and the trans-aconitic acid.
Example 5
Adding 0.1mmol of abiraterone acetate and 0.05mmol of trans-aconitic acid into ethanol (2 ml) and acetonitrile (2 ml) according to the stoichiometric ratio of 2:1, completely dissolving, and slowly volatilizing at room temperature to obtain the eutectic of abiraterone acetate and trans-aconitic acid.
Example 6
Adding 0.1mmol of abiraterone acetate and 0.05mmol of trans-aconitic acid into acetone (3 ml) and acetonitrile (1 ml) according to the stoichiometric ratio of 2:1, completely dissolving, and slowly volatilizing at room temperature to obtain the eutectic of abiraterone acetate and trans-aconitic acid.
Example 7
Adding 0.1mmol of abiraterone acetate and 0.05mmol of trans-aconitic acid into ethyl acetate (2 ml) and acetone (2 ml) according to the stoichiometric ratio of 2:1, completely dissolving, and slowly volatilizing at room temperature to obtain the eutectic crystal of abiraterone acetate and trans-aconitic acid.
Example 8
Adding 0.1mmol of abiraterone acetate and 0.05mmol of trans-aconitic acid into ethanol (3 ml) and acetone (1 ml) according to the stoichiometric ratio of 2:1, completely dissolving, and slowly volatilizing at room temperature to obtain the eutectic of abiraterone acetate and trans-aconitic acid.
Example 9
Adding 0.1mmol of abiraterone acetate and 0.05mmol of trans-aconitic acid into methanol (3 ml) and acetonitrile (1 ml) according to the stoichiometric ratio of 2:1, completely dissolving, and slowly volatilizing at room temperature to obtain the eutectic of abiraterone acetate and trans-aconitic acid.
Example 10
Adding 0.1mmol of abiraterone acetate and 0.05mmol of trans-aconitic acid into acetonitrile (10 ml) according to the stoichiometric ratio of 2:1, completely dissolving, slowly volatilizing at room temperature, adding the eutectic crystal seed (1-2 mg) of the abiraterone acetate and the trans-aconitic acid prepared in the example 1 when the solution volatilizes to 5 ml, and continuously volatilizing to obtain the eutectic crystal of the abiraterone acetate and the trans-aconitic acid.
Example 11
Adding 0.1mmol of abiraterone acetate and 0.1mmol of trans-aconitic acid into ethanol (4 ml) according to the stoichiometric ratio of 1:1, completely dissolving, and slowly volatilizing at room temperature to obtain the eutectic of abiraterone acetate and trans-aconitic acid.
Example 12
Adding 0.1mmol of abiraterone acetate and 0.1mmol of trans-aconitic acid into ethyl acetate (4 ml) according to the stoichiometric ratio of 1:1, completely dissolving, and slowly volatilizing at room temperature to obtain the eutectic of abiraterone acetate and trans-aconitic acid.
Experimental example 1:
the eutectic crystal of abiraterone acetate and trans-aconitic acid provided by the invention is characterized by solid-state methods such as X-ray powder diffraction (XRPD), thermogravimetric analysis (TG), Differential Scanning Calorimetry (DSC), Infrared (IR) and Raman (Raman) spectroscopy.
The single crystal of the eutectic crystal of abiraterone acetate and trans-aconitic acid obtained in example 1 was subjected to single crystal X-ray diffraction analysis using a Bruker Smart Apex type II X-ray single crystal diffractometer under the following measurement conditions: graphite monochromators, Mo-Ka rays
Figure BDA0003061726220000071
The voltage was 50kV, the current was 30mA, and the temperature was 298K. The single crystal of the eutectic of abiraterone acetate and trans-aconitic acid in example 1 was monoclinic tested by single crystal X-ray diffractometer, and the space group was P21The unit cell parameters are:
Figure BDA0003061726220000072
Figure BDA0003061726220000073
α is 90 °; β 95.330(3) °; gamma 90 DEG, unit cell volume of
Figure BDA0003061726220000074
The molar ratio of the abiraterone acetate to the trans-aconitic acid is 2: 1.
A sample of the eutectic solid of abiraterone acetate and trans-aconitic acid obtained in example 1 was subjected to X-ray powder diffraction analysis using a diffractometer of the Bruker D8 advanced model, Bruker instruments, Inc. of Germany, using Cu-Ka radiation
Figure BDA0003061726220000075
Voltage is 40 kv, current is 40 ma, step diameter: 0.02 degree, 0.1 second for each step. The analysis results are shown in FIG. 1. As can be seen from fig. 1, the eutectic has characteristic peaks at diffraction angles 2 θ of 6.7, 7.3, 7.6, 13.6, 14.0, 15.0, 17.1, 17.9, 18.5, 19.5, 24.9 degrees with an error of ± 0.2 degrees.
X-ray powder diffraction analysis of the solid cocrystal of abiraterone acetate and trans-aconitic acid obtained in examples 2 to 12 was performed as described above, and the results showed that the diffraction peaks thereof were similar to those of fig. 1, that is, the cocrystals obtained in examples 2 to 12 were the same substance as the cocrystal obtained in example 1.
Thermogravimetric analysis was performed on the eutectic solid sample of abiraterone acetate and trans-aconitic acid obtained in example 1, using a model TG20F3 thermogravimetric analyzer from german chi-resistant scientific instruments ltd, in an atmosphere of nitrogen and at a temperature rise rate of 10 degrees celsius/minute. The analysis results are shown in FIG. 2.
Differential scanning calorimetry was performed on the eutectic solid sample of abiraterone acetate and trans-aconitic acid obtained in example 1 using a DSC 8500 differential scanning calorimeter from TA instruments of America under nitrogen at a heating rate of 10 deg.C/min. The analysis results are shown in FIG. 3.
The eutectic solid sample of abiraterone acetate and trans-aconitic acid prepared in example 1 was subjected to infrared analysis, which was measured at room temperature using a Nicolet-Magna FT-IR 750 infrared spectrometer from nikko corporation, in the following detection ranges: 4000-350cm-1Wave number. The analysis results are shown in FIG. 4.
The solid eutectic sample of abiraterone acetate and trans-aconitic acid prepared in example 1 was subjected to raman spectroscopy, which was performed at room temperature using a DXR micro raman spectrometer from the united states of america, and the detection range was: 3500-50cm-1And (4) Raman shift. The analysis results are shown in FIG. 5.
Experimental example 2: solubility comparison of Co-crystals of Abiraterone acetate and Trans-Aconitic acid with Abiraterone acetate itself
The source of the test sample is: the eutectic of abiraterone acetate and trans-aconitic acid is prepared by the method provided in preparation example 1 of the present invention; the abiraterone acetate raw material medicine is purchased from Shanghai Demer medicine science and technology limited company, and the purity is more than 98%.
The experimental method comprises the following steps: accurately weighing 20 mg of abiraterone acetate and 24.4 mg of eutectic crystal of the abiraterone acetate and trans-aconitic acid with corresponding contents, suspending the abiraterone acetate and the eutectic crystal in 4 ml of dissolution media at 25 ℃, filtering the suspension by a water-phase microporous filter membrane after 4 hours, and measuring the concentration of the abiraterone acetate in the solution by using a high performance liquid phase to obtain the solubility of the raw material and the eutectic crystal.
Dissolution medium: aqueous hydrochloric acid at pH 2.0 and 0.25% aqueous sodium lauryl sulfate monobasic sodium phosphate at pH 4.5.
Liquid phase conditions: the instrument comprises the following steps: agilent 1260
Mobile phase: 0.1% trifluoroacetic acid and acetonitrile, elution gradient as follows:
time (minutes) 0.1% trifluoroacetic acid (%) Acetonitrile (%)
0.00 80 20
6.00 10 90
8.00 10 90
8.10 80 20
12.00 80 20
Column temperature: 30 degree centigrade
Flow rate: 1mL/min
Sample introduction amount: 10 μ L
The results of the experiment are shown in table 1:
TABLE 1 Co-crystals of abiraterone acetate and trans-aconitic acid and abiraterone acetate solubility contrast study
Figure BDA0003061726220000091
From the comparison results, it can be seen that the eutectic of abiraterone acetate and trans-aconitic acid of the present invention has higher solubility than abiraterone acetate itself after suspending in aqueous hydrochloric acid solution of pH 2.0 and 0.25% sodium lauryl sulfate in sodium dihydrogen phosphate solution of pH 4.5 for 4 hours. In particular, the solubility of the co-crystals was improved by a factor of approximately 7 relative to the solubility of abiraterone acetate itself in aqueous hydrochloric acid at pH 2.0.
Experimental example 3: comparison of the intrinsic dissolution rates of the cocrystal of abiraterone acetate and trans-aconitic acid with abiraterone acetate
The source of the test sample is: the eutectic of abiraterone acetate and trans-aconitic acid is prepared by the method provided in preparation example 1 of the present invention; the abiraterone acetate raw material medicine is purchased from Shanghai Demer medicine science and technology limited company, and the purity is more than 98%.
The experimental method comprises the following steps: accurately weighing 15mg of abiraterone acetate and 18.3 mg of eutectic of the abiraterone acetate and trans-aconitic acid with corresponding contents, pressing a sample into sample pieces with the surface area of 0.07 cubic centimeter by adopting a Mini-IDR press type tablet press of the American pion company under the pressure of 40bar, respectively magnetically rotating in 15 ml of dissolution media, taking 0.2 ml of solution at intervals, filtering by a water-phase microporous filter membrane, and measuring the concentration of the abiraterone acetate in the solution at each time point by using a high-efficiency liquid phase to finally obtain the inherent dissolution rate of the raw material and the eutectic.
Dissolution conditions: the instrument comprises the following steps: micro-dissolving out instrument
Dissolution medium: aqueous hydrochloric acid solution at pH1.2 and 0.25% sodium lauryl sulfate in sodium dihydrogen phosphate aqueous solution at pH 4.5
Magnetic rotating speed: 75 revolutions per minute
Dissolution temperature: 37 degrees centigrade
Sampling time: 5, 10, 15, 20, 25, 30, 40, 50, 60 minutes
The experimental results are as follows:
as shown in fig. 6 and 7 and table 2 below, the dissolution rate and the cumulative amount of dissolution of the eutectic of abiraterone acetate and trans-aconitic acid of the present invention in the aqueous hydrochloric acid solution of pH1.2 and the aqueous sodium dihydrogen phosphate solution of 0.25% sodium lauryl sulfate of pH 4.5 were significantly improved as compared to abiraterone acetate.
TABLE 2 eutectic of abiraterone acetate and trans-aconitic acid and comparative study of inherent dissolution rate of abiraterone acetate
Figure BDA0003061726220000101
Experimental example 4: the blood concentration characteristics of the abiraterone acetate in rats are the cocrystal of the abiraterone acetate and trans-aconitic acid
The eutectic of abiraterone acetate and trans-aconitic acid prepared according to preparation example 1 of the present invention was sieved through a 500 mesh sieve, and then mixed according to the formulation in table 3 below.
TABLE 3 Experimental formulation
Figure BDA0003061726220000102
The reference preparation is abiraterone acetate tablet which is sold on the market, purchased from Zhengda Ningqing (approved document: national medicine standard H20193207), and ground into powder for later use.
The powder of the eutectic formula of the abiraterone acetate and the trans-aconitic acid and the powder of the abiraterone acetate tablet are filled in microcapsules according to the administration dose of 15mg/kg (calculated by the abiraterone acetate), the powder and the powder are respectively administrated to clean rats (N ═ 6) in stomach, and rat arterial blood is extracted at different time points after the administration to determine the abiraterone content.
As shown in fig. 8, the results demonstrate that: the concentration of the drug in blood and the time for reaching peak concentration of the eutectic formula prepared by the abiraterone acetate are different under the condition that rats take the same oral dose, wherein the blood concentration of the eutectic of the abiraterone acetate and the trans-aconitic acid is obviously higher than that of the abiraterone acetate, so that the higher bioavailability of the eutectic of the abiraterone acetate and the trans-aconitic acid is realized compared with that of the commercial abiraterone acetate drug.
Experimental example 5: the blood concentration characteristics of the abiraterone acetate in the beagle in the cocrystal of the abiraterone acetate and trans-aconitic acid
The eutectic ball milling of abiraterone acetate and trans-aconitic acid prepared according to preparation example 1 of the invention is carried out to control the particle size D 5010 microns, mixed according to the formulation in table 3.
The reference preparation is abiraterone acetate tablet which is sold on the market, purchased from Zhengda Ningqing (approved document: national medicine standard H20193207), and ground into powder for later use.
Powder of a cocrystal formula of abiraterone acetate and trans-aconitic acid and powder of an abiraterone acetate tablet are filled in capsules at a dosage of 5mg/kg (calculated as abiraterone acetate), and are respectively administered to a beagle dog (N ═ 4) in stomach, and the arterial blood of the beagle dog is extracted at different time points after administration to determine the content of the abiraterone.
As shown in fig. 9 and table 4, the results demonstrate that: the concentration of the drug in blood of the abiraterone acetate and the prepared eutectic formula is different under the condition that the same dose is orally taken by beagle dogs, wherein the area under the blood concentration-time curve (AUC) of the eutectic of the abiraterone acetate and the trans-aconitic acid is about 1.6 times of that of the abiraterone acetate, and the result shows that the eutectic of the abiraterone acetate and the trans-aconitic acid has higher bioavailability compared with the commercial abiraterone acetate drug.
TABLE 4 pharmacokinetic parameters
Formulation of Tmax(min) Cmax(ng/mL) AUC0-8(ng min/mL)
Abiraterone acetate 60 45.3 4699.0
Eutectic of the invention 60 66.1 7315.1
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements that fall within the spirit and principles of the present invention are intended to be included therein.

Claims (10)

1. A co-crystal of abiraterone acetate and trans-aconitic acid in which the molar ratio of abiraterone acetate to trans-aconitic acid is 2:1, which has an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2 theta of 6.7, 7.3, 7.6, 13.6, 14.0, 15.0, 17.1, 17.9, 18.5, 19.5, 24.9 degrees with an error of ± 0.2 degrees, preferably which has an X-ray powder diffraction (XRPD) pattern substantially as shown in figure 1, preferably which is a monoclinic system with a space group of P21Crystal ofThe cell parameters are:
Figure FDA0003061726210000011
α＝90°；β＝95.330°；γ＝90°。
2. a co-crystal of abiraterone acetate and trans-aconitic acid according to claim 1, wherein the differential scanning calorimetry spectrum of the co-crystal of abiraterone acetate and trans-aconitic acid has a characteristic melting peak at 139 ± 2 ℃, preferably the co-crystal of abiraterone acetate and trans-aconitic acid has a Differential Scanning Calorimetry (DSC) profile substantially as shown in figure 3.
3. The co-crystal of abiraterone acetate and trans-aconitic acid of claim 1, wherein the infrared spectrum of the co-crystal of abiraterone acetate and trans-aconitic acid is at least 2935cm-1、2848cm-1、1701cm-1、1599cm-1、1376cm-1、1246cm-1、1035cm-1、797cm-1Has a characteristic peak, and preferably the eutectic of abiraterone acetate and trans-aconitic acid has an infrared spectrum (IR) diagram substantially as shown in figure 4.
4. A co-crystal of abiraterone acetate and trans-aconitic acid as claimed in claim 1 wherein the raman spectrum of the co-crystal of abiraterone acetate and trans-aconitic acid is at least 1668cm-1、1600cm-1、1442cm-1、1299cm-1、1246cm-1、1050cm-1、1027cm-1、846cm-1、703cm-1、581cm-1Preferably, the eutectic of abiraterone acetate and trans-aconitic acid has a Raman spectrum (Raman) substantially as shown in figure 5.
5. A method of preparing a co-crystal of abiraterone acetate and trans-aconitic acid as claimed in any of claims 1 to 4, the method comprising the steps of:
a. dissolving abiraterone acetate and trans-aconitic acid in an organic solvent to form a solution of the abiraterone acetate and the trans-aconitic acid;
b. crystallizing the solution of the abiraterone acetate and the trans-aconitic acid to form an eutectic solution system of the abiraterone acetate and the trans-aconitic acid;
c. and separating the eutectic solution system to obtain the eutectic of abiraterone acetate and trans-aconitic acid.
6. The method of claim 5, wherein, in step a,
dissolving the abiraterone acetate and trans-aconitic acid in the organic solvent in a molar ratio of 2:1 to 1:1, preferably in a molar ratio of 2: 1;
the organic solvent is selected from any one of methanol, ethanol, acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran and ethyl acetate, or a mixed solvent of any two of the above.
7. The method of claim 5, wherein, in step b,
the crystallization treatment comprises removing the organic solvent by evaporation, preferably at room temperature to 50 ℃, thereby forming a co-crystal of abiraterone acetate and trans-aconitic acid;
optionally, the crystallization treatment comprises adding a seed crystal of the abiraterone acetate and trans-aconitic acid eutectic to the solution of the abiraterone acetate and trans-aconitic acid.
8. The method of claim 5, wherein the step c comprises one of:
c 1: filtering the eutectic solution system to obtain a eutectic of abiraterone acetate and trans-aconitic acid;
c 2: centrifuging the eutectic solution system to obtain a eutectic of abiraterone acetate and trans-aconitic acid;
c 3: and heating the eutectic solution system, and evaporating to remove the organic solvent to obtain the eutectic of abiraterone acetate and trans-aconitic acid.
9. A pharmaceutical composition comprising a therapeutically effective amount of a co-crystal of abiraterone acetate and trans-aconitic acid as claimed in any of claims 1 to 4, and a pharmaceutically acceptable carrier, preferably the pharmaceutically acceptable carrier comprises one, more or all of lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, PVP-K30, sodium lauryl sulphate, magnesium stearate and silicon dioxide.
10. Use of a co-crystal of abiraterone acetate and trans-aconitic acid as claimed in any of claims 1 to 4 or a pharmaceutical composition as claimed in claim 9 in the manufacture of a medicament for the treatment of prostate cancer.
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CN114948885A (en) * 2022-05-20 2022-08-30 广东西捷药业有限公司 Improved abiraterone acetate nanocrystal oral preparation and preparation method thereof

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Publication number Priority date Publication date Assignee Title
CN114948885A (en) * 2022-05-20 2022-08-30 广东西捷药业有限公司 Improved abiraterone acetate nanocrystal oral preparation and preparation method thereof
CN114948885B (en) * 2022-05-20 2023-11-28 广东西捷药业有限公司 Improved abirater acetate Long Nami crystal oral preparation and preparation method thereof

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