Flutamine inclusion compound ultrafine particle and preparation method thereof

Abstract

The preparation method comprises the following steps: dissolving flutamide and a water-soluble carrier in absolute ethyl alcohol, and then preparing the flutamide inclusion compound with the particle size range of 174-306 nm by virtue of a supercritical CO2 anti-solvent method. The preparation method comprises the following steps: step 1, weighing flutamide and a water-soluble carrier which are equal in mole, and dissolving the flutamide and the water-soluble carrier in absolute ethyl alcohol to obtain a mixed solution; 2, CO2 is introduced into the crystallization kettle, the temperature is set to be 37-49 DEG C, and the pressure is set to be 9-19 Mpa; step 3, when the temperature and the pressure in the crystallization kettle are stable, introducing the mixed solution into the crystallization kettle; 4, after sample introduction is completed, CO2 continues to be introduced, the residual solvent is completely discharged, pressure relief is conducted, the crystallization kettle is opened, and a product is collected. The method has the advantages of mild operation conditions, one-step granulation, green and efficient process, and no pollution in solution recovery; the dissolution rate reaches 48.43% at the time of 5 min, and the cumulative dissolution rate reaches 78.25% or above at the time of 60 min.

Description

Technical Field

[0001] The invention relates to a pharmaceutical method, in particular to ultrafine flutamide inclusion compound particles and a preparation method thereof. Background Art

[0002] Flutamide is an oral nonsteroidal antiandrogen used to treat prostate cancer. It mainly interferes with the action of testosterone by inhibiting the uptake of testosterone or binding to target cell receptors, affecting the level of prostate-specific antigen in the blood; Flutamide belongs to BCS Class II drugs, and its clinical efficacy has obvious disadvantages, such as its low water solubility, short half-life, rapid liver metabolism and severe liver toxicity, and its biological activity cannot be fully exerted. Therefore, the development of new formulations with improved solubility and dissolution rate will help achieve a higher level of therapeutic effect at the absorption site and may overcome the low bioavailability caused by the first-pass effect.

[0003] Existing methods for preparing flutamide inclusion compounds include grinding method, spray drying method, etc., all of which have disadvantages such as uneven mixing, large particle size, and solvent residue pollution. Summary of the invention

[0004] Purpose of the invention: In order to overcome the deficiencies in the prior art, the purpose of the present invention is to provide a flutamide-based inclusion compound ultrafine particles with high solubility. Another purpose of the present invention is to provide a method for preparing flutamide-based inclusion compound ultrafine particles.

[0005] Technical solution: The flutamide-based inclusion compound of the present invention is prepared by dissolving flutamide and a water-soluble carrier in anhydrous ethanol and then passing through a supercritical CO 2 Flutamide-based inclusion complexes with particle sizes ranging from 174 to 306 nm were prepared by the antisolvent method.

[0006] Furthermore, the water-soluble carrier is hydroxypropyl-β-cyclodextrin (HP-β-CD).

[0007] The method for preparing ultrafine particles of flutamide-based inclusion compound of the present invention comprises the following steps:

[0008] Step 1, weighing equimolar amounts of flutamide and a water-soluble carrier and dissolving them in anhydrous ethanol to obtain a mixed solution;

[0009] Step 2: CO 2 Pass into the crystallization kettle, set the temperature to 37-49°C and the pressure to 9-19Mpa;

[0010] Step 3, when the temperature and pressure in the crystallization kettle are stable, introducing the mixed solution into the crystallization kettle;

[0011] Step 4: After the injection is completed, continue to introduce CO 2, drain the residual solvent, release the pressure, open the crystallization kettle and collect the product.

[0012] Furthermore, in step 1, the mass concentration of the mixed solution is 3 to 8 mg / mL. Preferably, the mass concentration of the mixed solution is 5 to 7 mg / mL.

[0013] Furthermore, in step 2, CO 2 The inlet flow rate is 2-4 L / min. Preferably, the temperature in the crystallization kettle is 41-45° C. Preferably, the pressure in the crystallization kettle is 9-13 Mpa.

[0014] Furthermore, in step three, the flow rate of the mixed solution is 1 to 1.4 mL / min.

[0015] Further, in step 4, CO is continuously introduced 2 90~100min.

[0016] Preparation principle: dissolve the solute in a suitable solvent to form a solution of a certain concentration, and then make the solution react with supercritical CO 2 When the solvent contacts the solid, rapid mutual diffusion occurs between them, causing the volume of the solvent to expand, the density to decrease, and the solubility of the solution for the solute to decrease, thus forming an extremely high supersaturation in a short period of time, and ultrafine particles with high purity and uniform particle size distribution can be precipitated.

[0017] Beneficial effects: Compared with the prior art, the present invention has the following significant features: supercritical CO 2 The antisolvent method has mild operating conditions, one-step granulation, a green and efficient process, and no pollution in solution recovery. The prepared flutamide / HP-β-CD inclusion complex has a small and uniform particle size. FTIR, DSC and XRD tests have proved that flutamide is completely included in HP-β-CD. In vitro dissolution test shows that compared with the raw material drug, the dissolution characteristics of the flutamide / HP-β-CD inclusion complex ultrafine particles have been significantly improved. Specifically, the solubility can reach 48.43% at 5 minutes, and the cumulative dissolution can reach more than 78.25% at 60 minutes. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 is a diagram of an experimental device of the present invention;

[0019] Figure 2 is a graph showing the relationship between the crystallization temperature of the present invention and the recovery rate and drug loading of the flutamide / HP-β-CD inclusion compound;

[0020] Figure 3 is a graph showing the relationship between the crystallization pressure of the present invention and the recovery rate and drug loading of the flutamide / HP-β-CD inclusion complex;

[0021] Figure 4is a graph showing the relationship between the mass concentration of the present invention and the recovery rate and drug loading of the flutamide / HP-β-CD inclusion complex;

[0022] Figure 5 is a graph showing the relationship between the volume flow rate and the recovery rate and drug loading of the flutamide / HP-β-CD inclusion complex of the present invention;

[0023] Figure 6 It is a DSC comparison diagram of flutamide bulk drug and flutamide / HP-β-CD inclusion complex prepared by the present invention;

[0024] Figure 7 It is a FTIR comparison diagram of flutamide bulk drug and flutamide / HP-β-CD inclusion complex prepared by the present invention;

[0025] Figure 8 It is an XRT comparison diagram of flutamide bulk drug and flutamide / HP-β-CD inclusion complex prepared by the present invention;

[0026] Fig. 9 The SEM comparison diagrams of the flutamide bulk drug and the flutamide / HP-β-CD inclusion complex prepared by the present invention are shown in Figure 1, wherein (a) is the flutamide bulk drug; (b) is HP-β-CD; (c) is a physical mixture of the flutamide bulk drug and HP-β-CD; (d) is the flutamide / HP-β-CD inclusion complex prepared in Example 5;

[0027] Fig.10 The present invention provides a 180-min in vitro dissolution curve of the flutamide bulk drug and the flutamide / HP-β-CD inclusion compound prepared by the present invention. DETAILED DESCRIPTION

[0028] The materials and reagents used in the following examples, unless otherwise specified, can be obtained from commercial sources. The experimental methods in the examples without specifying specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer. Flutamide with a purity of ≥99% was purchased from Shanghai Yuanye Zhiyuan Biotechnology Co., Ltd. HP-β-CD with a purity of ≥98% was purchased from Shanghai Yuanye Zhiyuan Biotechnology Co., Ltd. CO 2The purity of the product was >99%, purchased from Nanjing Shangyuan Industrial Gas Plant. Anhydrous ethanol was analytical grade and purchased from Shanghai Titan Technology Co., Ltd. Distilled water was homemade. Helix supercritical particle preparation system was purchased from Applied Separations, USA. Helix Series 1500 high-pressure infusion pump was purchased from Applied Separations, USA. TYW-2 air compressor pump was purchased from Suzhou Tongyi Electromechanical Co., Ltd. SDC-6 low-temperature constant temperature bath was purchased from Nanjing Xinchen Biotechnology Co., Ltd. UV-1800 ultraviolet visible spectrophotometer was purchased from Shimadzu Corporation, Japan. DSC 204F1 differential scanning calorimeter was purchased from NETZSCH, Germany. FT / IR-4100 Fourier transform infrared spectrometer was purchased from JASCO, Japan. SEM scanning electron microscope was purchased from Hitachi Regulus8100, Japan. XRD D8 Advance X-ray diffractometer was purchased from Beuker, Germany. ZRS-8L intelligent dissolution tester was purchased from Tianjin Tianda Tianfa Technology Co., Ltd.

[0029] like Figure 1 The supercritical CO used 2 CO in antisolvent preparation units 2 Gas cylinder 1, low temperature constant temperature tank 2, CO 2 The pump 3, the supercritical particle preparation host 4, the preheater 5, and the crystallization kettle 6 are connected in sequence, the crystallization kettle 6, the high-efficiency liquid phase injection pump 7, and the mixed solution storage bottle 8 are connected in sequence, the bottom of the crystallization kettle 6 is connected to the solvent collection bottle 9, and the solvent collection bottle 9 is connected to the rotor flowmeter 10. 2 Gas cylinder 1, low temperature constant temperature tank 2, CO 2 Pump 3, supercritical particle preparation host 4, preheater 5 pipeline is for preparing supercritical CO 2 The pipeline of high-performance liquid phase injection pump 7 and mixed solution storage bottle 8 is the passage for the flutamide / HP-β-CD mixed solution to enter the crystallization kettle, and the pipeline of crystallization kettle 6, high-performance liquid phase injection pump 7, mixed solution storage bottle 8, solvent collection bottle 9 and rotor flowmeter 10 is the discharge passage of the crystallization kettle. The dynamic balance of the pressure value in the crystallization kettle is mainly controlled by the rotor flowmeter.

[0030] Example 1

[0031] A method for preparing ultrafine particles of flutamide-based inclusion compounds comprises the following steps:

[0032] (1) Flutamide API and HP-β-CD were accurately weighed in a molar ratio of 1:1 and dissolved in 50 mL of anhydrous ethanol, and ultrasonically dissolved to obtain a flutamide / HP-β-CD mixed solution with a mass concentration of 3 mg / mL.

[0033] (2) Check the air tightness of the entire system to ensure that there is no leakage. Turn on the heating device of the low-temperature thermostatic bath 2 and the crystallization kettle 6. When the temperature reaches the set value of 37°C, turn on the CO 2 The inlet valve of the 2 The crystallization reactor 6 was introduced at a flow rate of 2.0 ± 0.2 L / min, and CO was turned on. 2 The pump increases the pressure of the entire system and adjusts the pressure in the crystallization kettle 6 to 9 MPa.

[0034] (3) Continue to introduce CO 2 When the pressure and temperature of the crystallizer 6 are stable, open the CO 2 The outlet valve controls the CO 2 Flow rate, observe the rotor flowmeter 10 changes to make CO 2 The flow rate is stabilized in the set range. The temperature and pressure in the crystallization kettle 6 are maintained unchanged, and the mixed solution prepared in step (1) is sprayed into the crystallization kettle 6 from the nozzle at the top of the crystallization kettle 6 through the high-efficiency liquid phase injection pump 7, and the volume flow rate of the solution is 1 mL / min.

[0035] (4) After the injection is completed, continue to introduce CO 2 90min, exhaust the residual solvent, and finally turn off the CO 2 Inlet valve and CO 2 Pump, release the pressure, open the crystallization kettle 6, and collect the product.

[0036] Example 2

[0037] A method for preparing ultrafine particles of flutamide-based inclusion compounds comprises the following steps:

[0038] (1) Flutamide API and HP-β-CD were accurately weighed in a molar ratio of API to carrier of 1:1 and dissolved in 50 mL of anhydrous ethanol, and ultrasonically dissolved to obtain a flutamide / HP-β-CD mixed solution with a mass concentration of 8 mg / mL.

[0039] (2) Check the air tightness of the entire system to ensure that there is no leakage. Turn on the heating device of the low-temperature thermostatic bath 2 and the crystallization kettle 6. When the temperature reaches the set value of 49°C, turn on the CO 2 The inlet valve of the 2 The crystallization reactor 6 was introduced at a flow rate of 4.0 ± 0.2 L / min, and CO was turned on. 2 The pump increases the pressure of the entire system and adjusts the pressure in the crystallization kettle 6 to 19 MPa.

[0040] (3) Continue to introduce CO 2 When the pressure and temperature of the crystallizer 6 are stable, open the CO 2The outlet valve controls the CO 2 Flow rate, observe the rotor flowmeter 10 changes to make CO 2 The flow rate is stabilized in the set range. The temperature and pressure in the crystallization kettle 6 are maintained unchanged, and at the same time, the mixed solution prepared in step (1) is sprayed into the crystallization kettle 6 from the nozzle at the top of the crystallization kettle 6 through the high-efficiency liquid phase injection pump 7, and the volume flow rate of the solution is 1.4 mL / min.

[0041] (4) After the injection is completed, continue to introduce CO 2 100min, exhaust the residual solvent, and finally turn off the CO 2 Inlet valve and CO 2 Pump, release the pressure, open the crystallization kettle 6, and collect the product.

[0042] Example 3

[0043] This example aims to investigate the influence of various factors on the recovery rate and drug loading of ultrafine particles of flutamide / HP-β-CD inclusion complex by single factor.

[0044] Single factor experiment: Effect of crystallization temperature on the recovery rate and drug loading of ultrafine particles of flutamide / HP-β-CD inclusion complex

[0045] The crystallization pressure was 10 MPa, the mass concentration of flutamide was 5 mg / mL, the molar ratio of flutamide to HP-β-CD was 1:1, the injection volume flow rate was 1.0 mL / min, and CO 2 Under the condition of flow rate of 3.5±0.2L / min, the effects of crystallization temperature of 37, 39, 41, 43, 45, and 47℃ on the recovery rate and encapsulation efficiency of ultrafine particles of flutamide / HP-β-CD inclusion complex were investigated. Figure 2 As shown, the recovery rates were 77.79%, 83.82%, 84.5%, 88.21%, 85.73%, and 85.32%, respectively, and the drug loadings were 4.41%, 4.36%, 4.95%, 5.14%, 4.92%, and 5.28%, respectively. After comprehensive comparison and consideration, the crystallization temperature was finally determined to be 41, 43, and 45°C for orthogonal optimization.

[0046] Single factor experiment: Effect of crystallization pressure on the recovery rate and drug loading of flutamide / HP-β-CD inclusion complex ultrafine particles.

[0047] When the crystallization temperature was 45 °C, the mass concentration of flutamide was 5 mg / mL, the molar ratio of flutamide to HP-β-CD was 1:1, the injection volume flow rate was 1.0 mL / min, and CO 2Under the condition of flow rate of 3.5±0.2L / min, the effects of crystallization pressures of 9, 11, 13, 15, 17, and 19MPa on the recovery rate and encapsulation efficiency of ultrafine particles of flutamide / HP-β-CD inclusion complex were investigated. Figure 3 As shown, the recovery rates were 85.67%, 83.22%, 81.61%, 80.28%, 75.18%, and 72.19%, respectively, and the drug loadings were 6.14%, 5.66%, 5.49%, 5.79%, 5.58%, and 4.81%, respectively. After comprehensive comparison and consideration, the crystallization pressure was finally determined to be 9, 11, and 13 MPa for orthogonal optimization.

[0048] Single factor experiment: Effect of API concentration on the recovery rate and drug loading of flutamide / HP-β-CD inclusion complex ultrafine particles.

[0049] The crystallization pressure was 10 MPa, the crystallization temperature was 45 °C, the molar ratio of flutamide to HP-β-CD was 1:1, the injection volume flow rate was 1.0 mL / min, and CO 2 Under the condition of flow rate of 3.5±0.2L / min, the effects of flutamide concentration of 3, 4, 5, 6, 7, 8 mg / mL on the recovery rate and encapsulation efficiency of ultrafine particles of flutamide / HP-β-CD inclusion complex were investigated. Figure 4 As shown, the recoveries were 73.76%, 79.95%, 85.73%, 83.48%, 83.03%, and 77.68%, respectively, and the drug loadings were 3.89%, 4.64%, 4.91%, 5.21%, 5.28%, and 5.49%, respectively. After comprehensive comparison and consideration, the final orthogonal optimization was carried out by determining the mass concentration of flutamide at three levels of 5, 6, and 7 mg / mL.

[0050] Single factor experiment: Effect of solution volume flow rate on the recovery rate and drug loading of flutamide / HP-β-CD inclusion complex ultrafine particles.

[0051] When the crystallization pressure was 10 MPa, the crystallization temperature was 45 °C, the mass concentration of flutamide was 5 mg / mL, the molar ratio of flutamide to HP-β-CD was 1:1, CO 2 Under the condition of flow rate of 3.5±0.2L / min, the effects of solution volume flow rate of 0.6, 0.8, 1.0, 1.2, 1.4, and 1.6mL / min on the recovery rate and encapsulation efficiency of ultrafine particles of flutamide / HP-β-CD inclusion complex were investigated. Figure 5As shown, the recovery rates are 79.52%, 81.59%, 85.73%, 85.34%, 92.77%, and 82.24% respectively, and the drug loadings are 6.67%, 6.48%, 5.92%, 6.04%, 5.14%, and 4.94% respectively. After comprehensive comparison and consideration, the solution volume flow rates of 1.0, 1.2, and 1.4 mL / min are finally determined for three levels of orthogonal optimization.

[0052] Example 4

[0053] Taking the recovery rate as the index, an orthogonal experiment was designed to investigate the crystallization pressure (A), crystallization temperature (B), solution mass concentration (C), and solution volume flow rate (D). Table 1 is the factor level design table, and Table 2 is the orthogonal experiment design and results.

[0054] The direct weighting method in the comprehensive scoring method was used for single-index integration. Under the same experimental conditions, the sum of the weights of the two indexes is 1. Among them, the recovery rate is the main investigation index with a weight of 0.6, and the drug loading is the auxiliary index with a weight of 0.4; according to the formula comprehensive score = recovery rate * 0.6 + drug loading / theoretical drug loading * 0.4, the following orthogonal experiment results, range analysis table, and variance analysis table were calculated, as shown in Tables 1 to 3.

[0055] From the orthogonal design and results table, it can be seen that the influence of each factor on the flutamide / HP-β-CD inclusion complex from large to small is D > A > C > B, that is, solution volume flow rate > crystallization temperature > solution mass concentration > crystallization pressure, and the optimal process combination is A 1 B 2 C 2 D 3 , and the SPSS software was used to perform variance analysis on the orthogonal experiment. Among them, the range of factor B (crystallization pressure) is relatively the smallest and has little influence on the comprehensive result, so it is set as the error factor. From the variance analysis result table, it can be obtained that the significance of factor D is the smallest among other factors and there is a certain gap, indicating that factor D has a significant influence on the entire experimental result, while other factors have little influence, and the influence order is D > A > C, which is consistent with the range analysis result.

[0056] Table 1 Factor level table

[0057]

[0058] Table 2 Orthogonal design and results

[0059]

[0060] Table 3 Variance analysis results

[0061]

[0062] Example 5

[0063] In this example, the optimal process conditions were used to prepare the flutamide / HP-β-CD inclusion complex.

[0064] A method for preparing ultrafine particles of flutamide-based inclusion compounds comprises the following steps:

[0065] (1) Flutamide API and HP-β-CD were accurately weighed in a molar ratio of API to carrier of 1:1 and dissolved in 50 mL of anhydrous ethanol, and ultrasonically dissolved to obtain a flutamide / HP-β-CD mixed solution with a mass concentration of 6 mg / mL.

[0066] (2) Check the air tightness of the entire system to ensure that there is no leakage. Turn on the heating device of the low-temperature thermostatic bath 2 and the crystallization kettle 6. When the temperature reaches the set value of 41°C, turn on the CO 2 The inlet valve of the 2 The crystallization reactor 6 was introduced at a flow rate of 3.0 ± 0.2 L / min, and CO was turned on. 2 The pump increases the pressure of the entire system and adjusts the pressure in the crystallization kettle 6 to 11 MPa.

[0067] (3) Continue to introduce CO 2 When the pressure and temperature of the crystallizer 6 are stable, open the CO 2 The outlet valve controls the CO 2 Flow rate, observe the rotor flowmeter 10 changes to make CO 2 The flow rate is stabilized in the set range. The temperature and pressure in the crystallization kettle 6 are maintained unchanged, and at the same time, the mixed solution prepared in step (1) is sprayed into the crystallization kettle 6 from the nozzle at the top of the crystallization kettle 6 through the high-efficiency liquid phase injection pump 7, and the volume flow rate of the solution is 1.4 mL / min.

[0068] (4) After the injection is completed, continue to introduce CO 2 90min, exhaust the residual solvent, and finally turn off the CO 2 Inlet valve and CO 2 Pump, release the pressure, open the crystallization kettle 6, and collect the product.

[0069] The optimal process combination is verified, as shown in Table 4, that is, A 1 B 2 C 2 D 3 ; crystallization temperature is 41 ° C, crystallization pressure is 11 MPa, solution mass concentration is 6 mg / mL, solution volume flow rate is 1.4 mL / nin, CO 2The flow rate was 3.0±0.2L / min. The results of three parallel experiments are shown in the table. The recovery rate and drug loading were 88.31%, 87.39%, 86.61% and 7.68%, 7.53%, 7.47%, respectively. The average values ​​were 87.44% and 7.56%, and the RSD values ​​were 0.97% and 1.43%, respectively. The RSD values ​​were all less than 2%, indicating that supercritical CO 2 The optimal process stability of preparing ultrafine particles of flutamide / HP-β-CD inclusion complex by antisolvent technology is feasible.

[0070] Table 4 Optimal process verification

[0071]

[0072] Characterization and analysis of ultrafine particles of flutamide / HP-β-CD inclusion complex:

[0073] DSC analysis: DSC comparison of flutamide API, HP-β-CD carrier, physical mixture, and flutamide / HP-β-CD inclusion complex. Figure 6 As shown in the figure, the characteristic melting point peak of flutamide API is at 112℃. The characteristic melting point peak of flutamide API also exists in the physical mixture, while the characteristic melting point peak of flutamide / HP-β-CD inclusion complex, i.e., the API in the supercritical group, almost completely disappears and is consistent with that of HP-β-CD carrier. Therefore, it is shown that the supercritical CO 2 The flutamide / HP-β-CD inclusion complex prepared by antisolvent technology was in an amorphous state, which also proved that flutamide was successfully included in HP-β-CD.

[0074] FTIR analysis: FTIR comparison of flutamide API, HP-β-CD carrier, physical mixture, and flutamide / HP-β-CD inclusion complex. Figure 7 As shown in the figure, the infrared absorption of the physical mixture group is a superposition of the peaks of flutamide and HP-β-CD, such as the wavelength of 3355 cm -1 , 1175cm -1 The characteristic peak of flutamide is present at the IR absorption peak of flutamide / HP-β-CD inclusion complex, while the characteristic absorption peak of flutamide is weakened or disappears in the infrared absorption of flutamide / HP-β-CD inclusion complex, which proves that flutamide is included in HP-β-CD.

[0075] XRD analysis: XRD comparison of flutamide API, HP-β-CD carrier, physical mixture, and flutamide / HP-β-CD inclusion complex is shown in Figure 2. Figure 8 As shown in the figure, the diffraction pattern of flutamide / HP-β-CD inclusion complex shows that the characteristic diffraction peak of flutamide raw material drug almost completely disappears, indicating that the supercritical CO 2 The flutamide / HP-β-CD inclusion complex prepared by antisolvent technology is in an amorphous state.

[0076] SEM analysis: SEM comparison of flutamide API, HP-β-CD carrier, physical mixture, and flutamide / HP-β-CD inclusion complex. Fig. 9 As shown, the flutamide / HP-β-CD inclusion complex is more uniformly spherical and has a significantly smaller particle size than the raw material.

[0077] In vitro dissolution test

[0078] Take appropriate amount of flutamide API and flutamide / HP-β-CD inclusion complex prepared under the optimal process, apply paddle method at temperature (37±0.5℃), rotation speed 100r / min, dissolution medium is phosphate buffer solution (pH6.8), and cumulative dissolution within 180min. The results are as follows: Fig.10 As shown by Fig.10 It can be seen that the cumulative dissolution performance of flutamide / HP-β-CD inclusion complex within 180 min is significantly higher than that of flutamide API, indicating that the application of supercritical CO 2 The dissolution performance of flutamide / HP-β-CD inclusion complex prepared by antisolvent technology was significantly improved.

[0079] The above experimental results show that the supercritical CO 2 Antisolvent technology can prepare flutamide / HP-β-CD inclusion complexes with smaller particle size, more uniform distribution and significantly improved dissolution performance, thereby increasing the bioavailability of flutamide and improving its drugability. It can also overcome the common problem of organic solvent residues in traditional technologies. The operating conditions are easy to control, the biological components are not easily inactivated, and the process is green and efficient with high safety.

Claims

1. A flutamide-based inclusion compound, characterized in that: Flutamide and a water-soluble carrier are dissolved in anhydrous ethanol, and then a flutamide-based inclusion compound with a particle size ranging from 174 to 306 nm is prepared by a supercritical CO2 antisolvent method.

2. A flutamide-based inclusion compound according to claim 1, characterized in that: The water-soluble carrier is hydroxypropyl-β-cyclodextrin.

3. A method for preparing the ultrafine particles of flutamide-based inclusion compound according to claim 1, characterized in that: The steps include: Step 1, weighing equimolar amounts of flutamide and a water-soluble carrier and dissolving them in anhydrous ethanol to obtain a mixed solution; Step 2: Pass CO2 into the crystallization kettle, set the temperature to 37-49°C and the pressure to 9-19Mpa; Step 3, when the temperature and pressure in the crystallization kettle are stable, introducing the mixed solution into the crystallization kettle; Step 4: After the injection is completed, continue to introduce CO2 to exhaust the residual solvent, release the pressure, open the crystallization kettle, and collect the product.

4. The method for preparing the ultrafine particles of flutamide-based inclusion compound according to claim 3, characterized in that: In the step 1, the mass concentration of the mixed solution is 3-8 mg / mL.

5. The method for preparing the ultrafine particles of flutamide-based inclusion compound according to claim 3, characterized in that: In the step 1, the mass concentration of the mixed solution is 5-7 mg / mL.

6. The method for preparing the ultrafine particles of flutamide-based inclusion compound according to claim 3, characterized in that: In the step 2, the CO2 introduction rate is 2 to 4 L / min.

7. The method for preparing ultrafine particles of flutamide-based inclusion compound according to claim 3, characterized in that: In the step 2, the temperature in the crystallization kettle is 41-45°C.

8. The method for preparing the ultrafine particles of flutamide-based inclusion compound according to claim 3, characterized in that: In the step 2, the pressure in the crystallization kettle is 9-13Mpa.

9. The method for preparing ultrafine particles of flutamide-based inclusion compound according to claim 3, characterized in that: In the step 3, the flow rate of the mixed solution is 1 to 1.4 mL / min.

10. The method for preparing ultrafine particles of flutamide-based inclusion compound according to claim 3, characterized in that: In step 4, continue to introduce CO2 for 90 to 100 minutes.

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