CN113456588B - Abiraterone acetate solid self-microemulsion and preparation method thereof - Google Patents

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a solid self-microemulsion containing abiraterone acetate. The abiraterone acetate solid self-microemulsion is composed of the following components in mass percentage: 0.25%-1.5% abiraterone acetate, 5%-10% oil phase, 25-30% surfactant, 12.5% co-surfactant ‑15%, solid carrier 45‑55%. The invention realizes the solidification of the liquid medicine, and through the single-factor test for prescription screening and optimization, a self-microemulsion without preservatives, easy to store, easy to transport and more stable is obtained. The preparation method is simple and controllable, and the repeatability is good. The transmission electron microscope image of the emulsion of abiraterone acetate solid self-microemulsion shows that the particles are regular spherical, evenly distributed, and the particle size is less than 100nm.

Description

A kind of abiraterone acetate solid self-microemulsion and preparation method thereof

technical field

The invention relates to the technical field of pharmaceutical preparations, in particular to a solid self-microemulsion containing abiraterone acetate.

Background technique

Abiraterone acetate (AA) is an inhibitor of androgen synthase CYP17A1, which is clinically used to treat metastatic castration-resistant prostate cancer (mCRPC). Or precipitate discharge, so that many expensive drugs are discharged as crystals, precipitates or prototypes without being effective. At the same time, abiraterone acetate belongs to the IV class drug in the biopharmaceutical classification system (BCS), and has the characteristics of low permeability and low solubility. Its octanol-water partition coefficient is 5.12 (LogP), the pKa of aromatic nitrogen is 5.19, it is almost insoluble in water (less than 0.01mg/ml), and has poor permeability. extremely low.

Lipid preparation drug delivery system entered the pharmaceutical field in the form of a simple oil solution in 1981. Subsequently, most of the lipid preparation drug delivery systems on the market were self-emulsifying preparations. The self-emulsifying drug delivery system can be used as a An effective means to improve the bioavailability of poorly soluble drugs, self-emulsifying formulations highlight the importance of lipids in enhancing the oral absorption of lipophilic drugs. Patent document CN 110538150 relates to a self-microemulsion of abiraterone acetate, which includes: active ingredient: abiraterone acetate; auxiliary materials: at least one oil phase, at least one emulsifier, and at least one co-emulsifier. Although the invention improves the bioavailability, its liquid form limits the effect of transportation, storage and quantitative administration, and the liquid preparation is heavy, easy to leak, and prone to bacteria in wet conditions. When taking it, a measuring cup is required, and most patients are inconvenient to move. Therefore, it is difficult for elderly men to ensure accurate arrival of the scale line, and it is also inconvenient to carry. In addition, preservatives and antioxidants need to be added to the composition for long-term preservation.

Contents of the invention

The invention aims at the deficiencies in the prior art, realizes the solidification of the liquid medicine, and further solves the problems of inconvenient transportation, preservation and administration of the liquid preparation. At the same time, solid abiraterone acetate can reduce the precipitation of the drug in the stomach, thereby improving the bioavailability. Therefore, a kind of abiraterone acetate solid self-microemulsion and its preparation method are provided.

To achieve the above object, the technical scheme adopted in the present invention is as follows:

A kind of solid self-microemulsion of abiraterone acetate, is made of the component of following mass percentage:

The solid carrier is Aerosil 200 and/or cross-linked PVP.

The oil phase is any one or a combination of glycerol monooleate, Tween 80, ethyl oleate, and Labrafil M 1944CS.

The emulsifier is Labrasol or Tween 80.

The co-emulsifier is ethanol.

Furthermore, it is composed of the following raw materials in parts by weight:

The particle size of the abiraterone acetate solid self-microemulsion emulsion is 81.09nm, and the drug loading is 0.97%±0.05%.

The preparation method of abiraterone acetate solid self-microemulsion:

1) Mix the surfactant and the co-surfactant according to the above ratio to obtain a mixed solution for use;

2) adding abiraterone acetate to the above mixed solution and mixing, then adding the oil phase to obtain abiraterone acetate liquid self-microemulsion;

3) adding the solid carrier into the above-mentioned abiraterone acetate liquid self-microemulsion to obtain the abiraterone acetate solid self-microemulsion.

In the step 1), the surfactant and the co-surfactant are mixed in a mass ratio of 2:1.

The beneficial effects of the present invention are:

The solid self-microemulsion of the present invention solves the problem that abiraterone acetate is not easy to absorb, and at the same time, through a specific system, it enables the active substance to fully exert its activity and improves the defect that the liquid self-microemulsion separates out in the stomach, and then obtains the solid self-microemulsion to solve the problem of making the liquid solidification, thus reaching to solve the problem of inconvenient transportation and storage of liquid preparations and the reduction of bioavailability due to precipitation in the stomach, the quality research of the obtained abiraterone acetate solid self-microemulsion shows that the particle size of the abiraterone acetate solid self-microemulsion emulsion is 81.09nm, PDI is 0.204, uniform particle size. The drug loading is 0.97%±0.05%, and the content uniformity meets the requirements of the Pharmacopoeia. DSC, PXRD, and SEM images showed that abiraterone acetate existed in an amorphous state in abiraterone acetate solid self-microemulsion, and TEM images showed that the nanoparticles in the emulsion were spherically dispersed in water. The dissolution rates of abiraterone acetate solid self-microemulsion in media of pH 1.2 and 6.8 are 90.6% and 82.5%, respectively.

Simultaneously, the solid self-microemulsion of the present invention is stable in properties under high temperature and strong light irradiation conditions, and the accelerated stability test results show that 3 batches of abiraterone acetate self-microemulsion samples are placed under accelerated test conditions for 6 months. Content reduces 7%-8%, and abiraterone acetate solid self-microemulsion of the present invention all does not have obvious change in every investigation index under the same condition, and stability is significantly better than abiraterone acetate self-microemulsion, and the solid self-microemulsion of the present invention The choice of self-microemulsion system can achieve high encapsulation efficiency.

Description of drawings

Fig. 1 is the solubility effect diagram of abiraterone acetate in oil phase and emulsifier.

Fig. 2 is an effect diagram of the effect of the ratio of surfactant to co-surfactant on the self-emulsifying ability of the preparation provided by the embodiment of the present invention.

Fig. 3 is a graph showing the influence of the drugs provided by the examples of the present invention on the properties of the preparation.

Fig. 4 is the particle size distribution diagram of abiraterone acetate solid self-microemulsion provided by the embodiment of the present invention.

Fig. 5 is the DSC diagram of four samples provided by the embodiment of the present invention.

Fig. 6 is the XRD scan pattern of four samples provided by the embodiment of the present invention.

Fig. 7 is a scanning electron microscope image of four samples provided by the embodiment of the present invention.

Fig. 8 is a transmission electron microscope image of the abiraterone acetate solid self-microemulsion emulsion provided by the embodiment of the present invention.

Fig. 9 is a dissolution curve in a pH 1.2 medium provided by an embodiment of the present invention.

Fig. 10 is the dissolution curve in the pH6.8 medium provided by the embodiment of the present invention.

detailed description

The specific embodiments of the present invention will be further described below in conjunction with examples. It should be noted that the specific embodiments described here are only for illustrating and explaining the present invention, and are not intended to limit the present invention.

Instruments and reagents

instrument:

Reagent

The selection of each composition of embodiment 1 abiraterone acetate solid self-microemulsion

1.1. Solubility test

Take multiple 10mL EP tubes, add 1g of abiraterone acetate standard to each EP tube, add 5mL of different oils, emulsifiers and co-emulsifiers to different EP tubes and seal them. Fix the EP tube in a constant temperature water bath shaker, shake it for 48 hours at a water temperature of 37°C and 60 rpm, and then place it in a centrifuge for 10 minutes at a speed of 5000 rpm. Take out the centrifugate and filter it with a 0.45 μm microporous membrane, then dilute its volume 5 times with acetonitrile, and enter the liquid phase to detect the solubility of abiraterone acetate in different oils and surfactants (see Figure 1).

Among them, the chromatographic conditions are:

Chromatographic column: Promosil C18 (4.6mm×250mm, 5μm)

Detector: UV 254nm

Flow rate: 1.2mL/min

Mobile phase: phosphate buffer (0.01M KH2PO4, pH=3)-acetonitrile (25:75, v/v)

Injection volume: 10μL

Column temperature: 35°C

The different oils mentioned above are glyceryl oleate, glyceryl caprylate, ethyl soybean oleate, isopropyl myristate, Labrafac Lipophile 1349, Labrafil M 1944CS, Labrafil M 2125CS; different emulsifiers are Tween and Labrasol; Different co-emulsifiers ethanol, PEG400, 1,2-propanediol.

As shown in Figure 1, glycerol monooleate, ethyl oleate, and Labrafil M 2125CS in the oil phase have relatively high solubility to abiraterone acetate, which are 46.25mg/mL, 45.63mg/mL, and 48.02 mg/mL, respectively; The solubility of abiraterone acetate in the emulsifier Labrasol (40.36mg/mL) was not significantly different from that in Tween 80 (35.54mg/mL); while the solubility in ethanol (43.02mg/mL) was the largest among co-emulsifiers. The greater solubility of the drug in the excipients is beneficial to the stability of the self-microemulsion preparation, and at the same time can increase the unit drug loading of the preparation. Therefore, through the preliminary screening of this experiment, it was determined that the oil phase in the prescription was glycerol monooleate, ethyl oleate, Labrafil M 1944CS, the emulsifier was Labrasol, Tween 80, and the co-emulsifier was ethanol.

1.2. Phase separation experiment

The oil phase, emulsifier, and co-emulsifier that have been screened to obtain a drug with high solubility still need to be studied in compatibility.

Obtained 3 kinds of oil phases (namely monooleic acid, glyceride, ethyl oleate), 2 kinds of emulsifiers (namely Labrasol, Tween 80), 1 kind of co-emulsifier (namely ethanol) through the above-mentioned solubility test screening, will The screened oil phase, emulsifier, and co-emulsifier are combined one by one in a ratio of 10:80:10 (w/w). After matching one by one, 6 different combinations can be obtained (see Table 1). Take 1 mL of the self-emulsifying concentrated solution after compatibility and dilute it with 10 mL of distilled water, and observe after standing for 2 hours (see Table 1). The combinations with obvious phase separation phenomena such as a large number of oil droplets floating and stratification in the diluent should be discarded, and the stable compatibility combinations should be retained for subsequent pseudo-ternary phase diagram research.

Table 1 Compatibility test results

As shown in Table 1, among the 6 combinations, the compatibility solution composed of glycerol monooleate, Labrasol, and ethanol can form a clear and transparent light blue emulsion after being diluted with water, and it can still maintain a stable state after being placed at room temperature for 24 hours. Other compatible combinations all showed poor stability, turbidity, and oil droplets on the liquid surface within 2 hours. Therefore, glyceryl monooleate, Labrasol, and ethanol were selected as self-microemulsion formulations for optimization.

2.3 Drawing of pseudo-ternary phase diagram

A pseudo-ternary phase diagram of oil, water, and mixed surfactants was constructed using water titration. The consumption of oil phase and mixed surfactant is by the ratio of 1: 9, 2: 8, 3: 7, 4: 6, 5: 5, 6: 4, 7: 3, 8: 2, 9: 1 (v /v) configuration, first mix the two evenly, then add deionized water drop by drop, stir while adding, and monitor the conductivity of the liquid in real time with a conductivity meter. Initially, a water-in-oil (W/O) nanoemulsion is formed. At this time, the viscosity of the liquid is low and the electrical conductivity is the smallest; as the amount of water added continues to increase, the viscosity of the liquid begins to increase, and the electrical conductivity value also increases. Large; continue to drop deionized water into the system, it can be found that the liquid changes from viscous to dilute, and the conductivity rises to the maximum value. This is the critical point for the formation of oil-in-water (O/W) nanoemulsion. The amount of water added. Collect the data of each point to draw a pseudo-ternary phase diagram, and connect the points into a line to get two regions: the self-emulsifying region and the non-emulsifying region.

2.4 Selection of solid carrier

In this experiment, 5 kinds of materials were selected as alternative carriers, they were Aerosil 200, cross-linked PVP, micropowder silica gel, cross-linked CMC-Na and corn starch. The adsorption carrier mainly examines its adsorption capacity and desorption capacity for L-SEDDS.

Weigh 1 g of each of the above five carrier materials and place them in five small beakers, add the liquid self-microemulsion prepared in advance to the carrier powder dropwise, and stir while adding, and continue this operation until the powder shows poor fluidity. Take out a certain amount of powder and place it on white A4 paper. If there are oil marks on the powder paper after light pressing, it means that the adsorption capacity has reached saturation. Record the amount of liquid added when each carrier material is saturated, so as to judge the liquid adsorption capacity of the material. The specific method is:

Take a certain amount of adsorbed and saturated carrier material and place it in a beaker, add deionized water 10 times the volume of the adsorbed liquid, stir evenly and let stand for 30 minutes, observe the appearance change of the diluted solution. Then take a small amount of diluent to detect the content of abiraterone acetate according to the liquid phase method. The desorption capacity of each carrier material can be obtained by calculation, expressed in desorption rate (see Table 2).

The adsorption and desorption capacity of the carrier material can be seen from Table 2. Aerosil 200 has the best liquid adsorption performance. 1g of Aerosil 200 can absorb 2.956g of self-microemulsion; the second adsorption capacity is crospovidone, 1g It can absorb 1.262g of self-microemulsion, which is far from the adsorption capacity of Aerosil 200. The adsorption capacity of other materials is not good. 1g of material can only absorb 0.3-0.4 g of self-microemulsion on average. In terms of desorption capacity, Aerosil 200 is also very good, and the desorption rate of 92.6% is not much different from that of crospovidone (93.4%). The saturated Aerosil 200 powder diluted with water can form a clear and translucent light blue emulsion within 30 minutes, indicating that the self-microemulsion absorbed in Aerosil 200 meets water to form a microemulsion with a smaller particle size. Aerosil 200 is a silica powder with a specific surface area of 200m ² /g, which is prepared by the gas phase method and can form a colloidal solution with a particle size of 10-100nm after dilution with water ^[48] . In view of the better adsorption and desorption capacity of Aerosil200, it was selected as the solid phase carrier of solid self-microemulsion.

The performance test of table 2 carrier material

The ratio optimization of each component in the Abiraterone acetate solid self-microemulsion system of embodiment 2

In this experiment, the amount of oil phase, the ratio of surfactant to co-surfactant/Km, and the amount of drug added were screened, and the optimal system was obtained based on particle size, appearance and stability.

2.1 Amount of oil phase

The ratio of fixed surfactant and co-surfactant is 2: 1 (v/v), adding blank liquid self-microemulsion preparation (oil phase, emulsifier and co-emulsifier) total mass 10%, 15%, 20%, 25%, 30% oil phase, the three are mixed evenly to make a blank self-microemulsion preparation. Take 1 g of the blank preparation and add 10 mL of deionized water to dilute, observe the stability of the diluent within 48 hours, and take a small amount of the diluent to measure the particle size and its distribution (see Table 3).

The influence of table 3 oil phase dosage on preparation properties

The increase in the amount of oil phase in the blank liquid self-microemulsion preparation resulted in the increase of the particle size of the self-emulsifying diluent. At the same time, the appearance of the emulsion gradually changed from clear and transparent light blue to turbid milky white. The stability at room temperature also decreased. start lowering. The self-emulsifying ability of the solution decreases due to the increase of the specific gravity of the oil and the decrease of the specific gravity of the emulsifier. It can be seen from Table 3 that when the amount of oil phase increases from 10% to 20%, the particle size of the emulsion increases slowly, and the polydispersity index PDI does not change significantly; while when the amount of oil phase increases to 30%, the particle size increases sharply to 250.83nm , the degree of dispersion is also significantly increased, and the stability time of the emulsion is reduced to below 12h. The gravity of the oil phase in the blank liquid self-microemulsion preparation increases, and the proportion of the emulsifier decreases accordingly, which can avoid the irritation and toxicity of a large amount of surfactants to the gastrointestinal tract, thereby improving the safety of the preparation. Considering comprehensively, 20% oil phase dosage is selected as a better formulation in order to obtain a formulation with smaller particle size, longer stable time and higher safety.

2.2 Ratio of surfactant to co-surfactant/Km

The optimum oil phase dosage is fixed to be X% of the blank liquid self-microemulsion preparation in the solid self-microemulsion system, and the mixed surfactant dosage is 1-X%. Use the ternary phase diagram method described in 1.3 to investigate the self-emulsifying ability of the preparation when Km is 1, 1.5, 2, and 3. In the pseudo-ternary phase diagram, the larger the self-emulsifying area, the stronger the emulsifying ability of the preparation, and the Km value with stronger emulsifying ability should be selected as the optimized solid self-microemulsion system (see Figure 2).

The self-emulsifying abilities of self-microemulsion formulations with Km of 1, 1.5, 2, and 3 are shown in Figure 2 (the gray shaded area represents the microemulsion area). When Km is 1, the area of the microemulsion area is the smallest, and the self-emulsifying ability is the worst; when Km increases to 1.5, the microemulsion area also expands; when Km continues to increase to 2, the microemulsion area basically reaches the maximum , the area differs slightly from that when Km is 3. Select Km as 2 as the optimized solid self-microemulsion system of the preparation.

2.3 Drug addition amount

The above test results are used as the optimal adjuvant composition of the blank solid self-microemulsion system, and then 0.5%, 1%, 1.5%, 2%, and 3% of abiraterone acetate in the blank liquid self-microemulsion preparation are added to make drug-loaded preparations. The specific steps are as follows: first mix the quantitative abiraterone acetate and the surfactant mixture, accelerate the dissolution of the drug with the aid of ultrasound, then add the oil phase and shake well. Take 1 g of the drug-loaded preparation and add 10 mL of deionized water to dilute, and take a small amount of the diluted solution to measure the particle size. Take 1mL of the diluent to detect the drug content, and calculate the drug encapsulation efficiency (EE%) of drug-loaded preparations with different drug doses. The specific calculation formula is as follows:

The effect of the amount of drug added on the properties of drug-loaded preparations is shown in Figure 3. It was observed that the increase of the drug dosage led to the gradual increase of the particle size of the diluent and the decrease of the encapsulation efficiency, which was similar to the results of some related studies. In fact, the particle size only increased from 75.4nm to 84.7nm when the drug addition increased from 0.5% to 2.0%, and the encapsulation efficiency decreased from 99.3% to 96.8%, the difference was not significant. When the amount of drug added increased to 3.0%, the particle size of the diluent increased sharply and the encapsulation efficiency dropped suddenly, which indicated that 2.0%-3.0% was the critical region of the added amount. Considering that the low bioavailability of abiraterone acetate leads to high doses in clinical application, a prescription with a larger dosage and better loading effect should be selected, so 2.0% can be regarded as the optimal dosage of the drug.

2.4 The amount of solid carrier

The fluidity of solid self-microemulsion powder particles depends on the addition ratio of solid carrier in the unit preparation. Investigate the fluidity of the powder when the liquid self-microemulsion and the solid carrier adding ratio (v/v) are 1:2, 1:1.5, 1:1, 1.5:1, 2:1 in turn, the fluidity of the powder can be measured by its The angle of repose and degree of compression are evaluated (see Table 5), specifically:

The angle of repose of the powder can be measured with an angle of repose tester: load 100g of solid powder into the funnel, open the valve of the funnel to let the powder flow out naturally and fall on the plane of the receiver, the angle between the plane of the receiver and the generatrix of the powder cone is the angle of repose theta. It is generally believed that the powder flow performance is better when θ is below 30 degrees, and the smaller the θ value, the better the flowability.

The degree of compaction of the powder can be measured with a tap density tester: Weigh 50g of solid powder and fill it in a 100mL measuring cylinder to measure its loose volume V0, vibrate at a certain frequency and amplitude until the volume of the powder in the measuring cylinder is basically constant. The numerical value is expressed as the tapped volume VF, V0/VF represents the Hausner ratio, and the fluidity of the powder is inversely proportional to the numerical value of V0/VF.

The fluidity changes of the abiraterone acetate solid powder measured under different carrier addition ratios are shown in Table 5. The fluidity of the powder gradually deteriorated with the decrease of the amount of carrier added. When the ratio of the liquid self-microemulsion to the carrier is 1:1, the angle of repose is 29.3°, the V ₀ /V _F value is 1.14, the powder still shows good fluidity, and the preparation also has a high drug loading capacity. , so the amount of carrier added is 40%-60% as the solid self-microemulsion system.

Table 5 Fluidity test results of solid self-microemulsion powder (n=3)

Obtain the component system of abiraterone acetate solid self-microemulsion by above-mentioned.

Example 3

At room temperature, weigh 0.263 g of ethanol and 0.534 g of caprylic capric acid polyethylene glycol glyceride (Labrasol) and mix them in a small beaker to obtain a surfactant mixture.

Add 10.2 mg of abiraterone acetate to the surfactant mixture obtained above and mix evenly, and ultrasonically assists in accelerating the dissolution of the drug. After the drug is completely dissolved, add 0.207 g of glyceryl monooleate and shake well to obtain acetic acid Abiraterone Liquid Self Microemulsion.

Take 1.5g of abiraterone acetate liquid self-microemulsion and 1.5g of cross-linked PVP to mix and absorb, and obtain 3g of abiraterone acetate solid self-microemulsion.

Example 4

At room temperature, weigh 0.265g ethanol and 0.536g Labrasol and mix in a small beaker to obtain a surfactant mixture.

Then add 15.3 mg of abiraterone acetate to the mixed surfactant mixture obtained above and mix evenly. Ultrasound assists in accelerating the dissolution of the drug. After the drug is completely dissolved, add 0.217 g of glycerol monooleate and shake well to obtain Abiraterone Acetate Liquid Self Microemulsion.

Take 1.5 g of abiraterone acetate liquid self-microemulsion and 1.5 g of cross-linked Aerosil200 and mix and absorb to obtain 3 g of abiraterone acetate solid self-microemulsion.

The quality evaluation of embodiment 5 abiraterone acetate solid self-microemulsion

1) Particle size and polydispersity coefficient

Get 1g S-SEDDS abiraterone acetate solid self-microemulsion powder (composed of: abiraterone acetate 1%, oil phase glyceryl caprylate 9.8%, surfactant Labrasol26.15%, co-surfactant Ethanol 13.05%, solid carrier Aerosil 50%) plus 20 times its volume of water to dilute and emulsify completely, then let it stand for 10 minutes, use a dropper to absorb a small amount of the upper emulsion and analyze it with a dynamic laser scattering particle size analyzer The average particle size and dispersion of the particles in the liquid were measured in parallel three times (see Figure 4).

As shown in Figure 4, the average particle size is 81.09nm, and the polydispersity index (PDI) is 0.204, indicating that the particle dispersion is small and the particle size is uniform.

2) Determination of drug loading and content uniformity

Weigh the above-mentioned example 3 abitate acetate solid self-microemulsion powder with a mass of M (about 1g), add V (20ml) volume of deionized water and mix evenly, stir gently to make it emulsified and leave it for a period of time until the insoluble carrier After deposition, draw the supernatant, and detect the concentration C of abiraterone acetate. The formula for calculating the drug loading (W%) of the preparation is as follows:

W%=(C×V)/0.01M×100%

According to the method specified in the 2015 edition of the Chinese Pharmacopoeia (general rule 0941), the content uniformity of abitrate acetate solid self-microemulsion powder was determined. Get 3 batches (batch numbers are 20190405, 20190501, 20190603) samples of the solid self-microemulsion prepared in Example 4, each batch extracts 10 parts of 100mg samples as test sample. Determination of the relative content x of AA in each test sample, the labeled amount of the drug is counted as 100. Calculate the mean value X and standard deviation S of the same batch of test product x and the absolute value A of X-100. If 2.2S+A≤L (L=15) is measured, it can be considered that the batch of samples meets the regulations (see Table 6).

Table 6 Content Uniformity Measurement Results (n=3)

Calculated by the formula, the drug loading amount of the abiraterone acetate solid self-microemulsion is 0.97%±0.05%.

The measured A+2.2S values of three batches of test products are respectively 3.95, 5.89, 6.12, all less than 15. It can be considered that the content uniformity of the three batches of samples is qualified.

3) Research on drug molecular state and morphological evaluation

In order to observe the influence that the liquid is adsorbed on the solid phase carrier from the microemulsion on the crystal structure of the drug, this experiment is carried out on the raw material drug Abiraterone acetate (AA), the solid phase carrier Aerosil 200, the physical mixture (PM) and the Acetate Acetate of the embodiment. Differential scanning calorimetry (DSC) analysis and powder X-ray diffraction (PXRD) analysis of Bitone solid self-microemulsion were carried out (see 5-8).

Use a differential scanning calorimeter to obtain the DSC analysis graph of each sample, put about 5 mg of the sample into an aluminum pot with a cover, and use a blank aluminum pot without adding a sample as a reference. Under the blowing protection of a nitrogen flow rate of 20 mL/min, the aluminum pot was heated from 35 °C to 200 °C with a constant heating rate of 10 °C/min. X-ray diffractometer was used for powder diffraction analysis, with Cu as the target element, the scanning range 2θ was 5°-60°, the scanning speed was 5°/min, and the scanning step was 0.02°.

In order to visualize the microscopic morphology of the preparation, scanning electron microscopy (SEM) was carried out on the raw drug abiraterone acetate, solid phase carrier Aerosil 200, physical mixture (PM) and abiraterone acetate solid self-microemulsion (S-SEDDS). Analysis, meanwhile the abiraterone acetate solid self-microemulsion emulsion was analyzed by transmission electron microscope (TEM).

Use a scanning electron microscope to observe the morphological characteristics of each sample: evenly coat the sample powder on the conductive glue on the loading plate, remove the residual sample powder, spray gold for about 2 minutes, and then scan and observe at a voltage of 15KV. Use a transmission electron microscope to observe the morphological characteristics of the particles in the emulsion: Dilute the S-SEDDS powder with water to a certain number of times until the liquid appears light blue opalescent, take a small amount of emulsion and drop it on the copper grid coated with carbon film, and remove the residual liquid at the edge of the copper grid , and then use 2% phosphotungstic acid solution to carry out negative staining on the sample. After the sample is dried, take the copper grid and carry out transmission observation under the voltage of 200KV.

Thermal analysis can provide information related to melting, recrystallization, decomposition and changes in specific heat capacity, which determine the physicochemical properties of compounds. The thermal analysis results are shown in Figure 5. The DSC curve of abiraterone acetate has a sharp endothermic peak at a temperature of 146.44°C, indicating that the powder of the raw material drug is in a crystalline state, which is basically consistent with the melting point (146°C) reported in the literature . The solid phase carrier Aerosil 200 has no specific endothermic peak near the melting point of the API. A relatively smooth peak appeared in the physical mixture between 140°C and 150°C, indicating that the crystals of the raw material drug still existed. The endothermic peak of abiraterone acetate solid self-microemulsion at the melting point of the crude drug disappears completely, indicating that abiraterone acetate is completely dissolved in abiraterone acetate liquid self-microemulsion and adsorbed into a solid carrier, existing in an amorphous state. Simultaneously, in order to further study the crystallinity of abiraterone acetate in the preparation, the above-mentioned sample was carried out PXRD analysis again, and collection of illustrative plates is as shown in Figure 6. The diffraction pattern of the abiraterone acetate raw material drug has strong crystal diffraction characteristic peaks in many places. The crystal diffraction characteristic peaks at two positions in the physical mixture diffraction pattern still exist, and the peak intensity decreases, which further verifies the existence of abiraterone acetate crystals in the physical mixture. In contrast, in the diffraction pattern of the abiraterone acetate solid self-microemulsion prepared by the solid-phase carrier adsorption method, there is no obvious crystal diffraction peak, which also shows that the crystalline bulk drug is prepared into abiraterone acetate solid self-microemulsion. Has been transformed into an amorphous state.

In this study, the surface microstructures of four samples were observed using SEM. Figure 7 shows the morphology of various solid samples. Abiraterone acetate has an irregular crystal structure as a raw material drug; the solid carrier Aerosil 200 is a loose aggregate composed of very fine particles, with a particle size around 50 μm, and it can be observed that the composed aggregate has a rough and porous surface; the solid carrier The presence of abiraterone acetate crystals can still be seen in the scanning figure of the special mixture; but no obvious crystallization is observed in the abiraterone acetate solid self-microemulsion, indicating that abiraterone acetate is dissolved in the liquid lipid and adsorbed on the solid on the carrier.

As shown in Figure 8, the transmission electron microscope image of the abiraterone acetate solid self-microemulsion emulsion shows that the particles in the microemulsion are regular spherical, evenly distributed, and the particle size is less than 100nm.

4) Dissolution determination

The in vitro dissolution rate was determined by the second method (slurry method) of the Chinese Pharmacopoeia 2015 edition. 10 mg abiraterone acetate bulk drug and the liquid containing 10 mg abiraterone acetate bulk drug and the abiraterone acetate solid self-microemulsion preparation system prepared according to the embodiment containing 10 mg abiraterone acetate bulk drug Long solid self-microemulsions were filled into hard gelatin capsules with a size of 00 as the research object of in vitro dissolution. The two dissolution media are hydrochloric acid solution with pH 1.2 and phosphate buffer solution with pH 6.8, respectively, and the media volume is 500 mL. Adjust the parameters to control the temperature of the water bath to 37°C and the speed of the stirring blade to 100rpm. Put the drug-loaded gelatin capsules into the dissolution vessel and start timing. Samples are taken after 2, 5, 10, 20, 40, 60, and 120 minutes. Each sample is 5 mL and an equal amount of fresh medium is added. After filtering the sample solution, detect the content of abiraterone acetate, calculate the dissolution rate at each time point, and then draw the dissolution rate-time curve (see 9 and 10).

This study investigated the dissolution of abiraterone acetate API, abiraterone acetate liquid self-microemulsion (L-SEDDS) and abiraterone acetate solid self-microemulsion (S-SEDDS) in pH 1.2 and pH 6.8 media within 2h The results are shown in Figures 9 and 10. There is a huge difference in the cumulative dissolution rate of abiraterone acetate bulk drug under different pH conditions, about 36.7% in pH 1.2, and close to 0 in pH 6.8, this phenomenon shows that the dissolution effect of abiraterone acetate has a great influence on pH The environment has certain dependencies. After the drug is made into a self-emulsifying preparation, its dissolution rate is significantly improved, and can reach more than 80% in two different media. Among them, the dissolution rate of abiraterone acetate liquid self-microemulsion is the largest at pH 1.2, which can reach 96.1 %; secondly the dissolution rate (90.6%) of abiraterone acetate solid self-microemulsion in pH 1.2 environment, the dissolution rate of abiraterone acetate solid self-microemulsion in pH 6.8 medium also can reach 82.5%. Although the dissolution rate of abiraterone acetate solid self-microemulsion in the two media is slightly lower than that of abiraterone acetate liquid self-microemulsion, their overall behaviors are similar. The initial dissolution rate is faster in the first 20 minutes, and then the dissolution rate gradually slows down. After about 1 hour, it enters a stable period. The reason for the relatively low dissolution rate of abiraterone acetate solid from microemulsion may be that part of the drug was adsorbed on the solid carrier and failed to release into the dissolution medium. Self-microemulsion has a good drug solubilization effect, which can increase the probability of the drug being absorbed by the gastrointestinal tract in a dissolved state, thereby increasing the bioavailability and improving the efficacy of the drug.

Example 6

1) Influencing factor test

High temperature test:

Take the liquid self-microemulsion (composed of: abiraterone acetate 2%, oil phase glyceryl caprylate 19.6%, surfactant Labrasol 52.3%, co-surfactant ethanol 26.1% by mass percentage) and solid self-microemulsion respectively Milk (consisting of: 1% abiraterone acetate, 9.8% caprylic acid glycerin oil phase, 26.15% surfactant Labrasol, 13.05% ethanol co-surfactant, 50% solid carrier Aerosil) 10g was placed in a 30mL flat shape and weighed transfer the weighing bottle to a constant temperature drying oven, and let the sample stand at a temperature of 60°C for 10 days, take samples on the 5th and 10th days after the start, check whether the properties of the test product have changed, and follow the above chapters of this article The method is used to measure the drug content, clarity, and emulsified particle size of abiraterone acetate liquid self-microemulsion and the drug content, dissolution rate, and emulsified particle size of abiraterone acetate solid self-microemulsion (see Tables 7 and 8).

High humidity test:

Put 10g of the above-mentioned liquid and solid self-emulsifying preparations into 30mL flat weighing bottles, transfer the weighing bottles to a drug stability test box and let it stand for 10 days, while controlling the temperature and humidity in the test box to maintain at 25°C±0.5°C , 90% ± 3% relative humidity, take samples on the 5th and 10th day after the start, check whether the properties of the test product have changed, and measure the drug content, clarity, and The emulsified particle size and the drug content, dissolution rate, emulsified particle size and other indicators of abiraterone acetate liquid self-microemulsion.

Strong light exposure test:

Put 10 g of the above-mentioned liquid and solid self-emulsifying preparations into 30 mL flat weighing bottles respectively, transfer the weighing bottles to a drug stability test box and let it stand for 10 days. Samples were taken on the 5th and 10th days afterward to check whether the properties of the test product changed, and the drug content, clarity, emulsified particle size and abiraterone acetate solid self-microemulsion were determined according to the method in the above chapters. Milk drug content, dissolution rate, emulsified particle size and other indicators.

Experimental results:

The test results of the samples under high temperature, high humidity and strong light irradiation are shown in the table. The results showed that the self-microemulsion of abiraterone acetate liquid was placed for 10 days under the conditions of various influencing factors, and the inspection items such as sample properties, drug content, solution clarity, and emulsion particle size did not change significantly, and the sample properties were stable. Abiraterone acetate solid self-microemulsion was placed under the same conditions for 10 days, and the inspection items such as sample properties, content, dissolution rate, and emulsified particle size did not change significantly, and the weight gain and loss inspection items under high humidity conditions increased by 5.74%, indicating that the sample It is easy to absorb moisture and should be stored airtight.

Table 7 Abiraterone acetate liquid self-microemulsion influencing factors test results

Table 8 Abiraterone acetate solid self-microemulsion influencing factors test results

2) Accelerated stability test

Get 3 groups of liquid self-emulsifying preparations prepared at different times (composed of: abiraterone acetate 2%, oil phase 19.6%, surfactant 52.3%, co-surfactant 26.1%) and different time prepared solid self-emulsifying preparations ( Composed of: abiraterone acetate 1%, glyceryl caprylate 9.8%, surfactant Labrasol 26.15%, co-surfactant ethanol 13.05%, solid carrier Aerosil 200 50%) about 10g were transferred to 30mL flat-shaped plugs respectively In a measuring bottle (the batch numbers of liquid and solid self-emulsifying preparations prepared at different times are 20190513, 20190515, and 20190517, respectively). Transfer the weighing bottle containing the sample to the drug stability test box and let it stand for 6 months. , Take samples at the end of June to check whether the properties of the test product have changed, and measure the drug content, clarity, and emulsified particle size of abiraterone acetate liquid self-microemulsion and the drug content and dissolution of abiraterone solid self-microemulsion according to the methods in the above chapters. Degree, emulsified particle size and other indicators (see Table 9).

Table 9 Abiraterone liquid self-microemulsion accelerated stability test results

Table 10 Abiraterone solid self-microemulsion accelerated stability test results

The test results showed that when the Abiraterone liquid self-microemulsion was placed under accelerated test conditions for 6 months, the properties of the 3 batches of samples changed from light yellow viscous liquid to yellow viscous liquid, which may be caused by lipid denaturation. The drug content in the Chinese medicine is reduced by 7%-8%, and the clarity and emulsified particle size do not change significantly. Abiraterone solid self-microemulsion was placed under the same conditions for 6 months, and there was no significant change in each inspection item of the 3 batches of samples, indicating that the stability of abiraterone solid self-microemulsion was stronger than that of abiraterone liquid self-microemulsion under this condition. Microemulsion.

The abiraterone acetate solid self-microemulsion obtained in the present invention has the advantages of good emulsification ability of liquid self-microemulsion and good stability of solid preparation. It does not need to add preservatives, and can be stored for a long time only in dry conditions, which saves costs. The obtained Solid self-microemulsion can be further prepared into tablets, capsules, granules and other preparations, providing more choices for oral administration of self-microemulsion.

Claims (3)

1. The abiraterone acetate solid self-microemulsion is characterized by comprising the following components in percentage by mass:

0.25 to 1.5 percent of abiraterone acetate

5 to 10 percent of oil phase

25 to 30 percent of surfactant

Cosurfactant 12.5-15%

45-55% of a solid carrier;

the oil phase is glycerol monooleate;

the surfactant is Labrasol;

the cosurfactant is ethanol;

the solid carrier is Aerosil200 and/or cross-linked PVP;

the mass ratio of the surfactant to the cosurfactant is 2.

2. The preparation method of the abiraterone acetate solid self-microemulsion according to claim 1, which is characterized in that:

1) Mixing the surfactant and the cosurfactant according to the proportion to obtain a mixed solution for later use;

2) Adding the abiraterone acetate into the mixed solution, uniformly mixing, and adding the oil phase to obtain an abiraterone acetate liquid self-microemulsion;

3) And adding a solid carrier into the abiraterone acetate liquid self-microemulsion to obtain the abiraterone acetate solid self-microemulsion.

3. The preparation method of the abiraterone acetate solid self-microemulsion according to claim 2, which is characterized in that: in the step 1), the surfactant and the cosurfactant are mixed according to the mass ratio of 2.

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