Estrogen-beta-cyclodextrin inclusion compound as well as preparation method and tablet thereof

Abstract

The invention discloses a preparation method of an estrogen-beta-cyclodextrin inclusion compound, which comprises the following steps: mixing an aqueous solution of cyclodextrin and an organic solution of estrogen, heating, carrying out rotary evaporation to remove a solvent, filtering to obtain a solid, and drying the solid to obtain the estrogen-beta-cyclodextrin inclusion compound. The preparation method of the estrogen-beta-cyclodextrin inclusion compound is simple to operate, short in preparation period and high in yield, and meanwhile, the estrogen-beta-cyclodextrin inclusion compound can be prepared by adopting conventional equipment, so that industrial enlarged production is facilitated; the estrogen and the beta-cyclodextrin are dissolved in the same system of the organic solvent and the water, the organic solvent is removed through reduced pressure evaporation, and the estrogen enters a hydrophobic cavity of the beta-cyclodextrin under the hydrophobic action based on the characteristics of the API and the characteristics of the cyclodextrin, so that the encapsulation efficiency of the product is improved; the estrogen content in the estrogen-beta-cyclodextrin inclusion compound can reach 99% or above, the loss in the technological process is small, and the encapsulation efficiency can reach 96% or above.

Description

Technical Field

[0001] The present application relates to the field of medical technology, and in particular to an estrogen-β-cyclodextrin inclusion compound and a preparation method and tablets thereof. Background Art

[0002] Ethinyl estradiol is a white or off-white crystalline powder. Its chemical name is 3-hydroxy-19-nor-17α-pregnane-1,3,5(10)-triene-20-yn-17-ol. Its molecular formula is C 20 H 24 O2, with a molecular weight of 296.41, is easily soluble in ethanol, propanol or ether, soluble in chloroform, and insoluble in water. As a powerful oral estrogen drug, ethinyl estradiol can be used to supplement estrogen deficiency, treat female gonadal dysfunction, amenorrhea, menopausal syndrome, etc.; it also has a certain therapeutic effect on advanced breast cancer (postmenopausal women) and advanced prostate cancer. However, as a steroid drug, ethinyl estradiol has the characteristics of poor water solubility and instability, which greatly reduces its bioavailability and limits its application value.

[0003] Inclusion complex is an important method to improve the solubility of drug molecules. The inclusion process can increase the solubility of poorly soluble drugs, improve drug stability, adjust drug release rate, mask odor, and reduce irritation. Among conventional encapsulation carriers, cyclodextrin shows certain advantages. Cyclodextrin is a general term for a series of cyclic carbohydrates generated by amylose under the action of glucosyltransferase produced by Bacillus. The most common ones are α-, β-, and γ-cyclodextrin, which are composed of 6, 7, and 8 glucose units connected by α-1,4-glycosidic bonds, respectively. β-cyclodextrin, as the most commonly used inclusion material, is a cyclic structure with hydrophilic exterior and hydrophobic interior. This unique structural property enables it to interact with a variety of compounds, especially hydrophobic compounds, through non-covalent forces, encapsulating the latter in the cavity to form a host-guest inclusion complex, thereby improving the solubility of poorly soluble compounds, and then improving the absorption and bioavailability of the corresponding drugs in the body.

[0004] There are currently a variety of preparation methods for ethinyl estradiol-β-cyclodextrin. CN1482921A discloses a method for preparing ethinyl estradiol-β-cyclodextrin inclusion complex using a coprecipitation method, but the coprecipitation method has a long process and the ethinyl estradiol content varies between 90.1% and 98.7%. CN114225050A discloses a method for preparing ethinyl estradiol-β-cyclodextrin inclusion complex using a freeze-drying method, among which only diethylenetriamine-β-cyclodextrin has a high encapsulation rate, while the encapsulation rates of other cyclodextrins are relatively low.

[0005] Therefore, developing a method for preparing a drug inclusion complex that can improve the cyclodextrin encapsulation efficiency is an urgent problem to be solved by those skilled in the art. Summary of the invention

[0006] In view of this, the present application provides a method for preparing an estrogen-β-cyclodextrin inclusion complex, which has simple operation, short preparation cycle, high yield, and an encapsulation rate of more than 96%, which significantly improves the dissolution effect of estrogen.

[0007] The present application provides a method for preparing an estrogen-β-cyclodextrin inclusion complex, comprising:

[0008] The aqueous solution of cyclodextrin and the organic solution of estrogen are mixed, heated, and the solvent is removed by rotary evaporation. The solid is filtered to obtain a solid, and the solid is dried to obtain an estrogen-β-cyclodextrin inclusion complex.

[0009] The present application uses an aqueous solution of cyclodextrin and an organic solution of estrogen as raw materials, mixes and heats, and then performs rotary evaporation, and obtains an estrogen-β-cyclodextrin inclusion complex by filtering and drying. The cyclodextrin in the aqueous solution of cyclodextrin includes, but is not limited to, one or more of β-cyclodextrin and / or hydroxypropyl-β-cyclodextrin, and the present application has no special requirements for the selection of cyclodextrin. The estrogen in the organic solution of estrogen includes, but is not limited to, one or more of ethinyl estradiol, estradiol, estradiol valerate, estradiol benzoate, or estradiol aminosulfonate, and the present application has no special requirements for the selection of estrogen.

[0010] The application first dissolves cyclodextrin in water to obtain an aqueous solution of cyclodextrin. In some specific implementations, the water includes purified water. In some specific implementations, the mass concentration of the aqueous solution of cyclodextrin is 16g / L to 34g / L, which can be 16g / L, 17g / L, 18g / L, 19g / L, 20g / L, 21g / L, 22g / L, 23g / L, 24g / L, 25g / L, 26g / L, 27g / L, 28g / L, 29g / L, 30g / L, 31g / L, 32g / L, 33g / L, 34g / L, preferably 20g / L to 30g / L.

[0011] The present application then dissolves the estrogen in an organic solvent to obtain an organic solution of estrogen, and adds it to an aqueous solution of cyclodextrin, and heats and stirs. In some specific implementations, the organic solution of estrogen is prepared by dissolving estrogen in an organic solvent; the organic solvent includes but is not limited to one or more of acetone, methyl ethyl ketone, methyl isobutyl ketone, methanol, ethanol, n-propanol, isopropanol, butanol, ethyl acetate or propyl acetate, and the present application has no special requirements for the selection of organic solvents. In some specific implementations, the mass concentration of the organic solution of estrogen is 3g / L to 5g / L, which can be 3g / L, 3.1g / L, 3.2g / L, 3.5g / L, 3.6g / L, 3.7g / L, 3.8g / L, 4g / L, 4.2g / L, 4.4g / L, 4.6g / L, 4.8g / L, 5g / L. In some specific implementations, the heating temperature is 40° C. to 60° C., and may be 40° C., 41° C., 42° C., 43° C., 44° C., 45° C., 46° C., 47° C., 48° C., 49° C., 50° C., 51° C., 52° C., 53° C., 54° C., 55° C., 56° C., 57° C., 59° C., 60° C., and preferably 55° C. In some specific implementations, the molar ratio of cyclodextrin in the aqueous solution of cyclodextrin to estrogen in the organic solution of estrogen is 1:1 to 1:5, and may be 1:1, 2:1, 3:1, 4:1, or 5:1.

[0012] The present application then performs rotary evaporation, filtration and drying on the solution after stirring and heating to obtain an estrogen-β-cyclodextrin inclusion complex. In some specific implementations, the temperature of the rotary evaporation is 40°C to 70°C, which can be 40°C, 41°C, 42°C, 44°C, 45°C, 46°C, 48°C, 50°C, 52°C, 54°C, 55°C, 56°C, 58°C, 60°C, 62°C, 64°C, 65°C, 66°C, 68°C, 70°C, preferably 50°C to 60°C. The organic solvent is removed by rotary evaporation, and based on the characteristics of API and cyclodextrin, ethinylestradiol enters the hydrophobic cavity of β-cyclodextrin under hydrophobic action, thereby improving the encapsulation rate of the product. In some specific implementations, the filter cake is retained after the filtration for drying. In some specific implementations, the drying includes but is not limited to vacuum drying, and the present application has no specific requirements for the drying method.

[0013] The present application also includes a tablet, which comprises, by weight, 9 to 12 parts of the estrogen-β-cyclodextrin inclusion complex prepared by the above preparation method, 30 to 50 parts of lactose, 20 to 40 parts of microcrystalline cellulose and 0.2 to 0.6 parts of magnesium stearate.

[0014] The present application uses 9 to 12 parts of estrogen-β-cyclodextrin inclusion complex, 30 to 50 parts of lactose, 20 to 40 parts of microcrystalline cellulose and 0.2 to 0.6 parts of magnesium stearate as raw materials to prepare tablets.

[0015] The mass fraction of the estrogen-β-cyclodextrin inclusion complex is 9 to 12 parts, which can be 9, 10, 11, 12 parts, preferably 10 to 12 parts, which can be 10, 11, 12 parts. The mass fraction of lactose is 30 to 50 parts, which can be 30, 35, 40, 45, 50 parts, preferably 35 to 45 parts, which can be 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 parts; the mass fraction of microcrystalline cellulose is 20 to 40 parts, which can be 20, 25, 30, 35, 40, 45, 50, preferably 35 to 45 parts, which can be 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 parts. parts, preferably 25 to 35 parts, can be 25 parts, 26 parts, 27 parts, 28 parts, 29 parts, 30 parts, 31 parts, 32 parts, 33 parts, 34 parts, 35 parts; the mass fraction of the magnesium stearate is 0.2 to 0.6 parts, can be 0.2 parts, 0.3 parts, 0.4 parts, 0.5 parts, 0.6 parts, preferably 0.3 to 0.5 parts, can be 0.3 parts, 0.4 parts, 0.5 parts.

[0016] In some specific implementations, the mass percentage of estrogen in the estrogen-β-cyclodextrin inclusion complex is 10% to 20%, and can be 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, and preferably 12% to 15%.

[0017] The estrogen-β-cyclodextrin inclusion complex described in the present application has a simple preparation method, a short preparation cycle, a high yield, and can be prepared using conventional equipment, which is convenient for industrial scale-up production. Estrogen and β-cyclodextrin are dissolved in the same system of an organic solvent and water, and the organic solvent is removed by reduced pressure evaporation. Based on the characteristics of API and cyclodextrin, the estrogen enters the hydrophobic cavity of β-cyclodextrin under the hydrophobic effect, thereby improving the encapsulation rate of the product. The estrogen content in the estrogen-β-cyclodextrin inclusion complex can reach more than 99%, the loss during the process is small, and the encapsulation rate can reach more than 96%, which significantly improves the dissolution effect of estrogen and has good comprehensive performance. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 This is the infrared spectrum of the estrogen-β-cyclodextrin inclusion complex provided in Example 1 of the present application;

[0019] Figure 2 The infrared spectrum of the physical mixture of ethinyl estradiol and β-cyclodextrin provided in Comparative Example 4 of the present application;

[0020] Figure 3 The infrared spectrum of β-cyclodextrin provided in Comparative Example 5 of the present application;

[0021] Figure 4 The infrared spectrum of ethinyl estradiol provided in Comparative Example 6 of the present application;

[0022] Figure 5 XRD spectra of the estrogen-β-cyclodextrin inclusion complex, the physical mixture of ethinyl estradiol and β-cyclodextrin, β-cyclodextrin and ethinyl estradiol provided in the present application, wherein A is the estrogen-β-cyclodextrin inclusion complex, B is the physical mixture of ethinyl estradiol and β-cyclodextrin, C is β-cyclodextrin, and D is ethinyl estradiol;

[0023] Figure 6 The DSC spectra of the estrogen-β-cyclodextrin inclusion complex, the physical mixture of ethinyl estradiol and β-cyclodextrin, β-cyclodextrin and ethinyl estradiol provided in the present application, wherein A is the estrogen-β-cyclodextrin inclusion complex, B is the physical mixture of ethinyl estradiol and β-cyclodextrin, C is ethinyl estradiol, and D is β-cyclodextrin;

[0024] Figure 7 This is a 20X microscope view of the estrogen-β-cyclodextrin inclusion complex provided in Example 1 of the present application;

[0025] Figure 8 This is a 20X microscope view of a physical mixture of ethinyl estradiol and β-cyclodextrin provided in Comparative Example 4 of the present application;

[0026] Fig. 9 The lower image of the 20X microscope field of view of β-cyclodextrin provided in Comparative Example 5 of the present application;

[0027] Fig.10 The 20X microscope view of ethinyl estradiol provided in Comparative Example 6 of the present application;

[0028] Fig.11 XRD spectra of the estrogen-β-cyclodextrin inclusion complex provided in Example 1, Comparative Example 1 and Comparative Example 2;

[0029] Fig.12 This is a graph showing the dissolution curve test results of the tablets provided in Example 4 and Comparative Example 3. DETAILED DESCRIPTION

[0030] It should be understood that the expression "one or more of..." includes each of the items recited after the expression individually and in various different combinations of two or more of the recited items, unless otherwise understood from the context and usage. The expression "and / or" in combination with three or more recited items should be understood to have the same meaning, unless otherwise understood from the context.

[0031] The use of the terms "comprising", "having" or "containing", including their grammatical synonyms, should generally be understood as open and non-restrictive, for example not excluding other unrecited elements or steps, unless otherwise specifically stated or otherwise understood from the context.

[0032] It should be understood that the order of steps or the order in which certain actions are performed is not important as long as the present application is still operable. In addition, two or more steps or actions can be performed simultaneously.

[0033] The use of any and all examples or exemplary language, such as "for example" or "including", herein is intended only to better illustrate the present application and does not limit the scope of the present application unless the claims are set forth. No language in this specification should be construed as indicating that any non-claimed element is essential to the practice of the present application.

[0034] In addition, the numerical ranges and parameters used to define the present application are approximate values, and the relevant values ​​in the specific embodiments have been presented as accurately as possible. However, any numerical value inherently inevitably contains standard deviations due to individual test methods. Therefore, unless otherwise expressly stated, it should be understood that all ranges, quantities, values ​​and percentages used in this disclosure are modified by "about". Here, "about" generally refers to the actual value within plus or minus 10%, 5%, 1% or 0.5% of a specific value or range.

[0035] The present application provides a method for preparing an estrogen-β-cyclodextrin inclusion complex, comprising:

[0036] The aqueous solution of cyclodextrin and the organic solution of estrogen are mixed, heated, and the solvent is removed by rotary evaporation. The solid is filtered to obtain a solid, and the solid is dried to obtain an estrogen-β-cyclodextrin inclusion complex.

[0037] The estrogen-β-cyclodextrin inclusion complex described in the present application has a simple preparation method, a short preparation cycle, a high yield, and can be prepared using conventional equipment, which is convenient for industrial scale-up production. Estrogen and β-cyclodextrin are dissolved in the same system of an organic solvent and water, and the organic solvent is removed by reduced pressure evaporation. Based on the characteristics of API and cyclodextrin, the estrogen enters the hydrophobic cavity of β-cyclodextrin under the hydrophobic effect, thereby improving the encapsulation rate of the product. The estrogen content in the estrogen-β-cyclodextrin inclusion complex can reach more than 99%, the loss during the process is small, and the encapsulation rate can reach more than 96%, which significantly improves the dissolution effect of estrogen and has good comprehensive performance.

[0038] The present application is further described below in conjunction with the following embodiments. The protection scope of the present application is not limited by the following embodiments.

[0039] Example 1

[0040] Preparation of estrogen-β-cyclodextrin inclusion complex:

[0041] Weigh 1.2 g of ethinyl estradiol and dissolve it in 225 mL of anhydrous ethanol. After 9.2 g of β-cyclodextrin is completely dissolved, add it into 275 mL of purified water, mix the two and heat to 50°C. After it is completely dissolved, use a rotary evaporator to slowly remove the ethanol in the solution, and the rotary evaporation temperature is 65°C. The solution after vacuum rotary evaporation is filtered, and the filtered solid is vacuum dried at 50°C to obtain the estrogen-β-cyclodextrin inclusion complex.

[0042] Example 2

[0043] Weigh 1.2 g of ethinyl estradiol and dissolve it in 225 mL of anhydrous ethanol. After completely dissolving 19.8 g of hydroxypropyl β-cyclodextrin, add it into 120 mL of purified water, mix the two and heat to 55°C. After it is completely dissolved, use a rotary evaporator to slowly remove the ethanol in the solution, the rotary evaporation temperature is 60°C, and then increase the rotary evaporation temperature to 70°C. The solution after vacuum rotary evaporation is filtered, and the filtered solid is vacuum dried at 50°C to obtain ethinyl estradiol-hydroxypropyl β-cyclodextrin inclusion complex.

[0044] Example 3

[0045] Weigh 1.2g of ethinyl estradiol and dissolve it in 225mL of acetone. After completely dissolving 18.4g of β-cyclodextrin, add it into 550mL of purified water, mix the two and heat to 60°C. After it is completely dissolved, use a rotary evaporator to slowly remove the acetone in the solution, and the rotary evaporation temperature is 70°C. The solution after vacuum rotary evaporation is filtered, and the filtered solid is vacuum dried at 60°C to obtain the estrogen-β-cyclodextrin inclusion complex.

[0046] Example 4

[0047] 9.60 mg of the estrogen-β-cyclodextrin inclusion complex provided in Example 1, 40.0 mg of lactose, 30.0 mg of microcrystalline cellulose and 0.4 mg of magnesium stearate were mixed, and then tableted using a rotary tablet press to obtain tablets.

[0048] Comparative Example 1

[0049] Dissolve 1.44 g of ethinyl estradiol in 1.4 mL of ethanol. After complete dissolution, slowly add the ethinyl estradiol ethanol solution to the β-cyclodextrin solution under stirring. Cool the solution to below 25° C. and stir at 25° C. for another 20 hours. Then filter and dry the filtered solid in a vacuum drying oven to obtain an estrogen-β-cyclodextrin inclusion complex.

[0050] Comparative Example 2

[0051] Dissolve 6.66g of β-cyclodextrin in 100mL of 40℃ deionized water, add 0.85g of ethinyl estradiol and 10mL of ethanol as a cosolvent and stir at 40℃ for 1h. Then stop heating, continue stirring at room temperature for 3h and place in a 4℃ refrigerator overnight. After 12h, filter the above solution and freeze-dry the filtrate for 12h to obtain an estrogen-β-cyclodextrin complex.

[0052] Comparative Example 3

[0053] 1.0 mg of ethinyl estradiol, 48.6 mg of lactose, 30.0 mg of microcrystalline cellulose, and 0.4 mg of magnesium stearate were mixed and then compressed using a rotary tablet press to obtain tablets.

[0054] Comparative Example 4

[0055] This comparative example provides a physical mixture of ethinyl estradiol and β-cyclodextrin.

[0056] Comparative Example 5

[0057] This comparative example provides a β-cyclodextrin.

[0058] Comparative Example 6

[0059] This comparative example provides an ethinyl estradiol.

[0060] The inclusion rate and yield of the estrogen-β-cyclodextrin inclusion complex obtained in Example 1-3 and Comparative Example 1-2 are shown in Table 1.

[0061] Table 1

[0062]

[0063] Structural characterization:

[0064] 1) FT-IR analysis was used to detect ethinyl estradiol, β-cyclodextrin, a physical mixture of ethinyl estradiol and β-cyclodextrin, and an estrogen-β-cyclodextrin inclusion complex. The infrared spectrum of the estrogen-β-cyclodextrin inclusion complex provided in Example 1 is as follows: Figure 1 As shown; Comparative Example 4 provides an infrared spectrum of a physical mixture of ethinyl estradiol and β-cyclodextrin as shown Figure 2 As shown; the infrared spectrum of β-cyclodextrin provided in Comparative Example 5 is as shown Figure 3 As shown; the infrared spectrum of ethinyl estradiol provided in Comparative Example 6 is as shown Figure 4 As shown, ethinyl estradiol is at 3607 cm -1 、3503 cm -1 The absorption band at 3293 cm-1 belongs to the stretching vibration of hydroxyl OH. -1 The absorption band at 2970 cm-1 belongs to the stretching vibration of alkynyl CH. -1 、2937 cm -1and 2866 cm -1 The absorption band at 1615 cm-1 belongs to the stretching vibration of saturated alkane CH. -1 、1586 cm -1 、1501 cm -1 and 1472 cm -1 The absorption band at 3000 cm belongs to the stretching vibration of C=C of benzene ring; the absorption band of estrogen-β-cyclodextrin inclusion complex at 3000 cm -1 -3600 cm -1 The absorption band at 2930 cm-1 belongs to the stretching vibration of hydroxyl OH. -1 The absorption band at belongs to the stretching vibration of saturated alkane CH, and the relevant peaks of ethinyl estradiol do not appear in the infrared spectrum of the inclusion complex, indicating that the characteristic functional groups or chemical bonds of the estrogen-β-cyclodextrin inclusion complex and ethinyl estradiol are obviously inconsistent.

[0065] 2) XRD analysis was used to detect ethinyl estradiol, β-cyclodextrin, the physical mixture of ethinyl estradiol and β-cyclodextrin, and the estrogen-β-cyclodextrin inclusion complex. The XRD spectra were as follows: Figure 5 As shown, the main diffraction peaks of ethinyl estradiol are 5.7°, 7.9°, 8.3°, 13.1°, 13.9°, 14.9°, 15.7°, 17.2°, 21.4°, and 24.3° (2θ); the main diffraction peaks of β-cyclodextrin are 6.1°, 8.9°, 10.6°, 12.4°, 12.6°, 17.6°, 17.8°, 18.7°, 22.6°, 27.0°, and 34.8° (2θ); the physical mixture contains both characteristic peaks; the inclusion complex shows a decrease in crystallinity and the corresponding characteristic peaks disappear, which is the basis for the formation of the inclusion complex.

[0066] 3) DSC analysis was used to detect ethinyl estradiol, β-cyclodextrin, the physical mixture of ethinyl estradiol and β-cyclodextrin, and the estrogen-β-cyclodextrin inclusion complex. The DSC spectra were as follows: Figure 6 As shown. In the DSC curve of β-cyclodextrin (C), there is a broad endothermic peak at 61.10℃-127.33℃, which is related to the loss of crystal water of cyclodextrin. The DSC curve of ethinyl estradiol (D) has an endothermic peak at 183.38℃. The DSC curve of the physical mixture (B) has a broad endothermic peak at 57.75℃-123.90℃ and an endothermic peak at 183.89℃. The inclusion complex of estrogen-β-cyclodextrin (A) has no obvious peak, indicating the formation of inclusion complex.

[0067] 4) Use a microscope to observe the morphology. The 20X microscope view of the estrogen-β-cyclodextrin inclusion complex is as follows: Figure 7 As shown; the physical mixture of ethinyl estradiol and β-cyclodextrin is shown under a 20X microscope field of view. Figure 8As shown; the 20X microscope view of β-cyclodextrin is as follows Fig. 9 As shown; the 20X microscope view of ethinyl estradiol is as follows Fig.10 As shown in Figure 2, at 20X magnification, ethinyl estradiol presents a fine agglomerate morphology with a particle size of about 10 μm, and β-cyclodextrin presents a block crystal morphology of about 20-100 μm, with obvious morphological differences between the two. In the micrograph of the physical mixture, both substances can be observed to exist, while in the micrograph of the inclusion complex, ethinyl estradiol is no longer observed, indicating the formation of an inclusion complex.

[0068] The difficulty of encapsulation rate detection as an inclusion complex detection project lies mainly in finding a suitable solvent to dissolve free ethinyl estradiol while trying not to destroy the formed inclusion complex. The encapsulation rate detection method is as follows:

[0069] HPLC conditions:

[0070] Chromatographic column: octadecylsilane bonded silica gel as filler (Agilent XDB- C18, 4.6 mm × 150 mm, 5 μm);

[0071] Excitation wavelength: 285nm Emission wavelength: 315nm;

[0072] Column temperature: 25°C;

[0073] Mobile phase: diamine phosphate buffer: water: acetonitrile;

[0074] Injection volume: 20 μL;

[0075] Flow rate: 1.2 mL / min;

[0076] The test sample needs to be added with an appropriate amount of a suitable organic solvent (methyl ethyl ketone), stirred and slurried for 1 hour, and the supernatant is filtered by centrifugation as the encapsulation efficiency sample test solution.

[0077] The samples of Example 1, Comparative Example 1 and Comparative Example 2 were subjected to XRD analysis. Fig.11 As shown in the figure, it can be observed that the estrogen-β-cyclodextrin inclusion complex prepared by different preparation methods is different. Among them, the crystallinity of the inclusion complex prepared by reduced pressure evaporation and freeze drying is significantly reduced, and the characteristic peak of ethinyl estradiol is absent, which is the proof of the formation of the inclusion complex. By comparison, it is found that the sample prepared by coprecipitation has obvious diffraction peaks, indicating that the degree of encapsulation of the coprecipitation method is not sufficient, and a good estrogen-β-cyclodextrin inclusion complex is not prepared.

[0078] The samples of Example 1, Comparative Example 1 and Comparative Example 2 were weighed. The yield of the freeze-drying method of Comparative Example 2 was low, mainly because when the heating was stopped, the solubility of cyclodextrin decreased and precipitated. Even if the estrogen-β-cyclodextrin inclusion complex was formed, its solubility in water was still low, and the solubility was less than 1 mg / mL. Therefore, the inclusion complex content in the filtrate was extremely low, resulting in a poor yield after freeze drying. Therefore, this method is not suitable for large-scale production. The yields of the rotary evaporation methods of the embodiments were all above 95%, which can be applied to large-scale industrial production.

[0079] The samples of Example 1-3 and Comparative Example 1-2 were subjected to ethinylestradiol content determination, encapsulation efficiency determination, and dissolution determination, and the test results are shown in Table 2. The results show that under the preparation method provided in the present application, the content of the estrogen-β-cyclodextrin inclusion complex is stable, substantially without significant loss, and the encapsulation efficiency is more than 98%, and the powder dissolution is significantly improved relative to ethinylestradiol. The content of the estrogen-β-cyclodextrin inclusion complex prepared by the coprecipitation method is also substantially stable, but the encapsulation efficiency is relatively low, and the degree of encapsulation is low. The freeze-drying method has a low yield, and the coprecipitation method has an insufficient encapsulation efficiency. The estrogen-β-cyclodextrin prepared by the preparation method described in the present application can achieve a stable high yield, and has a higher estrogen and a better encapsulation effect, and the process is simple, and production amplification can be achieved.

[0080] Table 2

[0081]

[0082] The estrogen-β-cyclodextrin inclusion complex provided in the present application is confirmed to be formed by Fourier transform infrared spectroscopy, XRD, and DSC analysis, and the yield can reach more than 95%. The content of ethinyl estradiol in the product is high, the loss during the process is small, and the encapsulation rate can reach more than 96%. In addition, the dissolution property of ethinyl estradiol with slow release is significantly improved after tableting. At the same time, the method is simple to operate and is conducive to industrial scale-up production.

[0083] The tablets prepared in Example 4 and Comparative Example 3 were subjected to dissolution tests. The tablets prepared in Example 4 dissolved significantly faster than those in Comparative Example 3 and dissolved completely. The dissolution test method and test results are shown in Table 3. The dissolution curve test results of the tablets provided in Example 4 and Comparative Example 3 are shown in Table 3. Fig.12 shown.

[0084] Table 3

[0085]

[0086] The estrogen-β-cyclodextrin inclusion complex provided in the present application is confirmed to be formed by Fourier transform infrared spectroscopy, XRD, and DSC analysis, and the yield can reach more than 95%. The estrogen content in the product is high, the loss during the process is small, and the encapsulation rate can reach more than 96%. After tableting, the dissolution property of the slow release of estrogen is significantly improved. At the same time, the method is simple to operate and is conducive to industrial scale-up production.

[0087] The above is only a preferred specific implementation manner of the present application, but the protection scope of the present application is not limited thereto. Any technician familiar with the technical field can make equivalent substitutions or changes within the technical scope disclosed in the present application according to the technical solution and application concept of the present application, which should be covered by the protection scope of the present application.

Claims

1. A method for preparing an estrogen-β-cyclodextrin inclusion complex, characterized in that: include: The aqueous solution of cyclodextrin and the organic solution of estrogen are mixed, heated, and the solvent is removed by rotary evaporation. The solid is filtered to obtain a solid, and the solid is dried to obtain an estrogen-β-cyclodextrin inclusion complex.

2. The preparation method according to claim 1, characterized in that: The temperature of the rotary evaporation is 40°C to 70°C.

3. The preparation method according to claim 1, characterized in that: The cyclodextrin in the aqueous solution of cyclodextrin includes β-cyclodextrin and / or hydroxypropyl-β-cyclodextrin.

4. The preparation method according to claim 1, characterized in that: The estrogen in the organic solution of estrogen includes one or more of ethinyl estradiol, estradiol, estradiol valerate, estradiol benzoate or estradiol aminosulfonate.

5. The preparation method according to claim 1, characterized in that: The molar ratio of cyclodextrin in the aqueous solution of cyclodextrin to estrogen in the organic solution of estrogen is 1:1 to 1:

5.

6. The preparation method according to claim 1, characterized in that: The mass concentration of the cyclodextrin aqueous solution is 16 g / L to 34 g / L, and the mass concentration of the estrogen organic solution is 3 g / L to 5 g / L.

7. The preparation method according to claim 1, characterized in that: The organic solution of estrogen is prepared by dissolving estrogen in an organic solvent; the organic solvent includes one or more of acetone, methyl ethyl ketone, methyl isobutyl ketone, methanol, ethanol, n-propanol, isopropanol, butanol, ethyl acetate or propyl acetate.

8. The preparation method according to claim 1, characterized in that: The heating temperature is 40° C. to 60° C.; and the drying comprises vacuum drying.

9. A tablet, characterized in that In parts by mass, it comprises 9 to 12 parts of the estrogen-β-cyclodextrin inclusion complex prepared by the preparation method according to any one of claims 1 to 8, 30 to 50 parts of lactose, 20 to 40 parts of microcrystalline cellulose and 0.2 to 0.6 parts of magnesium stearate.

10. The tablet according to claim 9, characterized in that The mass percentage of estrogen in the estrogen-β-cyclodextrin inclusion compound is 10% to 20%.

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