Amorphous lycorine composition based on solid dispersion technology and preparation method of amorphous lycorine composition

Abstract

The invention relates to the technical field of medicines, in particular to a lycorine amorphous composition based on a solid dispersion technology and a preparation method of the lycorine amorphous composition. The composition comprises lycorine and sorbitol, the lycorine exists in the pharmaceutical composition in an amorphous form, and compared with the lycorine, the prepared lycorine pharmaceutical composition has obviously superior solubility and dissolution rate in water. Under the condition of the same feeding amount of the lycorine content, the dissolution rate of the lycorine pharmaceutical composition can reach 80.44%, while the dissolution rate of the lycorine raw material medicine is only 10.22%. Meanwhile, compared with a lycorine raw material medicine, the AUC (0-t) of the lycorine amorphous composition is improved to 170%.

Description

Technical Field

[0001] The invention relates to the field of medical technology, and in particular to a lycorine amorphous composition based on solid dispersion technology and a preparation method thereof. Background Art

[0002] Lycorine is an isoquinoline alkaloid with important pharmacological activity. It was first isolated from the Amaryllis plant Narcissus in 1877. The molecular formula of the compound is C 16 H 17 NO4, with a molecular weight of 287.31, has a clear solvent dependence in its solubility characteristics: it is easily soluble in dilute acid and dimethyl sulfoxide, slightly soluble in methanol, ethanol, petroleum ether and water, but almost insoluble in chloroform. This unique solubility behavior is closely related to its molecular structure - Lycorine has a five-ring rigid skeleton containing four consecutive chiral centers. This highly hydrophobic structural feature leads to its extremely low water solubility (190 µg / mL), which in turn severely limits its bioavailability. Despite the limitations in solubility, Lycorine still exhibits a wide range of pharmacological activities, including significant antipyretic, analgesic, anti-inflammatory, and antibacterial effects. Of particular note is its antiviral and antitumor activity: multiple in vitro studies have confirmed that Lycorine can exert an antiviral effect by inhibiting the RNA polymerase activity of SARS-CoV-2; at the same time, it has shown significant proliferation inhibition on a variety of tumor cell lines such as breast cancer, pancreatic cancer, and leukemia. These excellent pharmacological properties make it of great development value in the field of medicine. However, the poor water solubility of lycorine and the resulting insufficient bioavailability have seriously restricted the full realization of its potential for clinical application. This key issue has become a core challenge that needs to be urgently addressed in the current research and development of lycorine, and is also the focus of researchers. Improving its solubility characteristics through formulation technology innovation will be an important breakthrough in promoting the transformation of lycorine into clinical applications.

[0003] In recent years, researchers have started to develop novel delivery systems for lycorine using modern formulation techniques, such as nanoparticles, cyclodextrin inclusion complexes, lipid nanoemulsions, etc. Existing research mainly focuses on physicochemical characterization of the formulations through techniques such as differential scanning calorimetry and Fourier transform infrared spectroscopy, determination of basic parameters such as drug loading and encapsulation efficiency, and preliminary cytotoxicity evaluation. However, the current research still has obvious limitations: First, the preparation schemes of the above-mentioned drug delivery systems are not feasible for industrial application. Second, the above research lacks systematic study on the in vitro dissolution behavior of the formulations. Third, a key in vivo bioavailability evaluation system has not been established, which directly affects the objective assessment of its clinical application potential. Therefore, the current research on lycorine dosage forms is still in the exploratory stage. In the prior art, sorbitol is mainly used as a filler for solid drug formulations, or in extremely rare special cases as a cosolvent (concentration range of 5% - 40%). An aqueous solution of sorbitol with a concentration lower than this will not have a solubilizing effect.

[0004] Different solid forms of poorly soluble drugs have an impact on their physicochemical properties, especially on solubility, which further affects their bioavailability. The molecules of the amorphous form of the drug are in a disordered arrangement state with high surface free energy, which can improve solubility and dissolution rate. The solid dispersion technology is a solid dispersion system formed by uniformly distributing the drug in a highly dispersed state such as molecular state, ionic state, microcrystalline state or amorphous state in a carrier material. This technology has important application value in the field of modern drug formulations, especially suitable for improving the dissolution performance and bioavailability of poorly soluble drugs.

[0005] In the present invention, a lycorine amorphous composition with high dissolution rate has been successfully developed by using the solid dispersion technology with lycorine and a low - concentration sorbitol solution. Summary of the Invention

[0006] The present invention aims to solve the technical defects existing in the prior art and provides a lycorine amorphous composition based on the solid dispersion technology and its preparation method. In this system, the introduction of sorbitol significantly enhances the dissolution rate of lycorine and also significantly enhances the bioavailability of the lycorine amorphous substance in rats. This technology provides an efficient and feasible new strategy for the development of lycorine formulations.

[0007] To achieve the above - mentioned purpose, the present invention provides the following technical solutions.

[0008] A lycorine composition based on the amorphous solid dispersion technology, comprising the following components: lycorine and a carrier material; the mass ratio of lycorine to the carrier material is 1:5 - 1:11.

[0009] Further, the carrier material is sorbitol.

[0010] A preparation method of lycorine composition based on amorphous solid dispersion technology, comprising the following steps: Step 1: Weigh sorbitol precisely and add it to absolute ethanol, stir at 50 °C until it dissolves to obtain a solution; Step 2: Weigh an appropriate amount of lycorine precisely, add it to the solution obtained in Step 1, and stir at room temperature until it dissolves completely; Step 3: Remove ethanol quickly, dry it in a vacuum drying oven, grind and pulverize it to obtain the lycorine composition.

[0011] Further, the vacuum drying temperature is 40 °C and the drying time is 12 h.

[0012] Compared with the prior art, the beneficial effects of the present invention are as follows.

[0013] 1. Different from the prior art, the present invention applies sorbitol to the preparation of amorphous lycorine. When the amorphous lycorine composition is completely dissolved during the dissolution process, the sorbitol concentration in water is about 0.2%, which is much lower than the above-mentioned concentration of 5% - 40%. The dissolution rate of the amorphous lycorine composition of the present invention is significantly improved. This technical solution breaks through the limitations of the traditional application of sorbitol and provides a new feasible solution for the application of the lycorine composition.

[0014] 2. The preparation method provided by the present invention has simple process, good reproducibility, low production cost, and can effectively improve the dissolution rate of lycorine.

[0015] 3. The dissolution rate determination result of the present invention (dissolution medium 900 mL, drug dosage equivalent to 270 mg of the active ingredient) can reach 80.44%. Compared with the dissolution rate of 10.22% of the lycorine raw material drug, the dissolution rate is significantly improved.

[0016] 4. The results of the pharmacokinetic experiment of the present invention in rats show that the lycorine raw material drug appears at T max of 0.33 ± 0.13 h, its C max is 5.14 ± 0.60 mg / L, MRT (0-t) is 3.87 ± 0.30 h, the elimination half-life t 1 / 2 is 4.40 ± 0.80 h, and the area under the drug-time curve AUC (0~t) is 16.70 ± 1.94 mg / L*h; while the amorphous lycorine composition appears at T max of 0.54 ± 0.25 h, its C max is 7.33 ± 0.78 mg / L, MRT (0-t) is 3.87 ± 0.35 h, the elimination half-life t 1 / 2 is 3.95 ± 0.62 h, and AUC (0~t)was 28.41 ± 2.89 mg / L*h; Generally speaking, compared with lycorine raw material drug, the AUC of the amorphous composition of lycorine (0-t) was increased to 170%. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 To show the molecular docking diagrams between the raw material drug and the excipients (A, Molecular docking structural model diagram of lycorine - Sorb; B, Molecular docking structural model diagram of lycorine - Eudragit ® L100; C, Molecular docking structural model diagram of lycorine - PVPK30; D, Molecular docking structural model diagram of lycorine - Eudragit ® EPO).

[0018] Figure 2 To show the polarized light microscope images of the raw material drug and the amorphous compositions of lycorine in various ratios in Example 1 (A, Lycorine; B, Lycorine - Sorb composition 1:3; C, Lycorine - Sorb composition 1:5; D, Lycorine - Sorb composition 1:7; E, Lycorine - Eudragit ® L100 composition 1:3; F, Lycorine - Eudragit ® L100 composition 1:5; G, Lycorine - Eudragit ® L100 composition 1:7; H, Lycorine - PVPK30 composition 1:3; I, Lycorine - PVPK30 composition 1:5; J, Lycorine - PVPK30 composition 1:7; K, Lycorine - Eudragit ® EPO composition 1:3; L, Lycorine - Eudragit ® EPO composition 1:5; M, Lycorine - Eudragit ® EPO composition 1:7).

[0019] Figure 3 To show the Fourier transform infrared spectroscopy diagrams of the raw material drug, excipients, Example 2, Comparative Examples 1 - 3, and the physical mixtures of Example 2 and Comparative Examples 1 - 3 in the same ratio (A, Lycorine - Sorb composition; B, Lycorine - Eudragit ® L100 composition; C, Lycorine - PVPK30 composition; D, Lycorine - Eudragit ® EPO composition; a, Composition; b, Physical mixture; c, Excipient; d, Lycorine).

[0020] Figure 4To show the differential scanning calorimetry diagrams of the active pharmaceutical ingredient, excipients, Example 2, Comparative Examples 1-3, and the physical mixtures of Example 2 and Comparative Examples 1-3 in the same proportion (A, lycorine - Sorb - composition; B, lycorine - Eudragit ® L100 composition; C, lycorine - PVPK30 composition; D, lycorine - Eudragit ® EPO composition; a, composition; b, physical mixture; c, excipient; d, lycorine).

[0021] Figure 5 To show the scanning electron microscope (SEM) images of the active pharmaceutical ingredient, Example 2, and Comparative Examples 1-3 (A, lycorine; B, lycorine - Sorb - composition; C, lycorine - Eudragit ® L100 composition; D, lycorine - PVPK30 composition; E, lycorine - Eudragit ® EPO composition).

[0022] Figure 6 To show the blood concentration - time curves of the active pharmaceutical ingredient and Example 2 in rats.

[0023] Figure 7 To show the dissolution curves of the active pharmaceutical ingredient, Example 2, and the compositions of Comparative Examples 1 - 3 in water. Detailed implementation manners

[0024] To facilitate the understanding of the present invention, the technical solutions of the present invention will be comprehensively described below in conjunction with the drawings and specific implementation manners. However, the following described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments, and are only used to illustrate the present invention, and should not be regarded as limiting the scope of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts belong to the scope of protection of the present invention.

[0025] A lycorine composition based on the amorphous solid dispersion technology, comprising the following components: lycorine and a carrier material; the mass ratio of lycorine to the carrier material is 1:5 - 1:11.

[0026] Further, the carrier material is sorbitol A preparation method of a lycorine composition based on the amorphous solid dispersion technology, comprising the following steps: Step 1: Weigh sorbitol precisely and add it to absolute ethanol, and stir at 50 °C to dissolve it to obtain a solution; Step 2: Weigh an appropriate amount of lycorine precisely, add it to the solution obtained in Step 1, and stir at room temperature until completely dissolved; Step 3: Quickly remove ethanol, dry in a vacuum drying oven at 40 °C for 12 h, grind and pulverize to obtain the lycorine composition.

[0027] Example 1.

[0028] 1. Judge the possibility of drug and excipient compatibility according to the solubility parameter (δ). When the solubility difference (Δδt) is less than 7 MPa 1 / 2 the compatibility between the drug and the carrier is good. When Δδt is greater than 10 MPa 1 / 2 the drug and the carrier are almost incompatible. When the value is between the two, there is a possibility of compatibility between the drug and the excipient. Calculate the solubility parameter differences of lycorine with sorbitol (Sorb), polyvinylpyrrolidone K30 (PVP K30), Eudragit ® L100 (Eudragit ® L100) and Eudragit ® EPO (Eudragit ® EPO). As a result, the solubility parameter differences between Sorb, Eudragit ® L100, PVP K30 and lycorine are less than 10, and the solubility difference between Sorb and lycorine is the smallest, only 3.29, while the solubility parameter difference between Eudragit ® EPO and lycorine is greater than 10. According to the solubility parameter calculation results, the order of compatibility between the drug and the carrier is Sorb > Eudragit ® L100 > PVP K30 > Eudragit ® EPO.

[0029] 2. Use AutoDock software to perform molecular docking on lycorine, Sorb, PVP K30, Eudragit ® L100 and Eudragit ® EPO, and calculate the docking energy. Use PyMol 2.5.2 software to visually analyze the docking results of AutoDock Vina. Figure 1 is the structural model diagram of the docking of lycorine and excipients. It can be observed that the hydroxyl group or ether bond of lycorine is connected to the excipient. The docking binding energies are Sorb (-3.0) > Eudragit ® L100 (-3.6) > PVP K30 (-4.2) > Eudragit ® EPO (-4.7). The binding energy is generally negative. The lower the energy, the more stable it is, indicating that the drug and the excipient are more tightly bound and the bond is more stable. In this experiment, the closer the drug and the excipient are bound, the less conducive to dissolution. Through the binding energy (E binding)To further quantitatively study the drug-polymer excipient binding in the system, as shown in Table 1, the E of lycorine and Sorb binding is 210.84 kcal / mol, and this energy is greater than the E of lycorine with the other three excipients binding , indicating that the energy possessed by the amorphous composition of lycorine-Sorb during dissolution is greater than that of the other three compositions, which is more conducive to drug dissolution.

[0030] Table 1 Binding energy E binding Docking molecule <![CDATA[E binding (kcal / mol)]]> Lycorine - Sorb 210.84 <![CDATA[Lycorine - Eudragit ® L100]]> 128.38 Lycorine - PVP K30 12.31 <![CDATA[Lycorine-Eudragit ® EPO]]> 123.64 3. Using Sorb, Eudragit ® L100, PVP K30 and Eudragit ® EPO as raw materials, amorphous compositions of lycorine were prepared by the solvent method at mass ratios of 1:3, 1:5, and 1:7 respectively. Weigh the excipients (Sorb, PVP K30, Eudragit ® L100 or Eudragit ® EPO) according to the prescription and add them to 100 mL of ethanol respectively. Stir at 50 °C until completely dissolved, then add lycorine and continue to stir to make it fully dissolved. Subsequently, ethanol was rapidly removed at room temperature and dried in a vacuum drying oven at 40 °C for 12 h, and then pulverized to obtain four amorphous compositions of lycorine with different ratios.

[0031] The polarized light microscope was used to observe lycorine and the amorphous compositions of lycorine with different ratios. The polarized light microscope images are as Figure 2 shown. Figure 2 A shows the polarized light image of the raw material of lycorine, and obvious crystal morphological characteristics and birefringence phenomenon can be seen. Figure 2 B, E, H, K correspond to the polarized light images of the four amorphous compositions at a mass ratio of 1:3 respectively, and all show significant birefringence phenomena, indicating that the amount of excipient at this ratio is not sufficient to completely transform the drug from the crystalline state to the amorphous state. Figure 2 C, F, I, L are the polarized light images of the amorphous compositions of lycorine at a mass ratio of 1:5. The birefringence phenomenon is weakened, but it still does not reach the best dispersion state. Therefore, amorphous compositions of lycorine at a mass ratio of 1:7 were further prepared, as Figure 2 shown in D, G, J, M. The results show that no birefringence phenomenon was observed in the amorphous compositions with Sorb and Eudragit ® L100 as excipients, confirming that the drug is compatible with these two excipients and the solid dispersion is in the amorphous state; while for PVPK30 and Eudragit ®There is still a small amount of birefringence in the amorphous composition with EPO as the excipient, indicating that there may be a trace amount of drug that is not fully dispersed. These results are consistent with the solubility parameter calculations and molecular docking studies, comprehensively indicating that a mass ratio of 1:7 is the optimal ratio for preparing the amorphous composition of lycorine. It can be inferred from the polarized light image results that an amorphous composition can be formed when the ratio of lycorine to the excipient reaches 1:5 - 1:11 or even higher.

[0032] Example 2.

[0033] 1. Preparation of the amorphous composition of lycorine (1:7): First, add 700 mg of Sorb to 100 mL of ethanol, stir at 50 °C until dissolved, then add 100 mg of lycorine and stir at room temperature until both are completely dissolved. Rapidly remove the ethanol at room temperature and dry in a vacuum drying oven at 40 °C for 12 h. Crush and grind to obtain the product.

[0034] 2. Dissolution test of the drug: According to the Chinese Pharmacopoeia (2020 Edition), the dissolution test was carried out using the paddle method on a ZRS-8GD dissolution system (Tianjin Tianda Tianfa Technology Co., Ltd., Tianjin, China). The dissolution medium was 900 mL of water, the rotation speed was 100 r·min -1 , the temperature of the dissolution medium was (37 ± 0.5) °C. Take 3 portions of Example 2 (equivalent to 270 mg of lycorine raw material) and place them in the dissolution cups respectively. Absorb 5 mL of the solution at 5, 10, 15, 30, 60, 90, and 120 min respectively, and simultaneously supplement the same volume and temperature of the dissolution medium. After the sample solution is filtered through a 0.45 μm microporous membrane, take the subsequent filtrate. Use a UV1600 ultraviolet spectrophotometer (Shanghai Mepuda Instrument Co., Ltd.) to analyze the filtrate at a wavelength of 289 nm. The results are as Figure 7 , when it comes to 2 h for this composition, the cumulative dissolution rate of lycorine reaches 80.44%, showing excellent dissolution performance.

[0035] Example 3.

[0036] 1. Use a Thermo Fisher / Nicolet iN10 infrared spectrometer (Thermo Fisher Scientific) to study the molecular interactions in Example 2. Take appropriate amounts of lycorine, excipient, and the physical mixture of Example 2 with the same ratio as Example 2, and prepare them by the KBr tablet pressing method. The test range is from 4000 cm -1 to 400 cm -1 , the resolution is 4 cm -1 , and each sample is scanned 32 times. From Figure 3 A (curve d), it can be seen that lycorine has a broad peak at 3329 cm -1 , which is the stretching vibration peak of the hydroxyl group; 1091 cm -1The peak at [position] is the stretching vibration peak of the carbon-oxygen single bond; 1622 cm -1 The peak at [position] is the characteristic peak of the double bond; 1130 cm -1 The peak at [position] is the characteristic peak of the ether bond. As Figure 3 Shown in A (curve c), the excipient has a broad peak at 3325 cm -1 The peak at [position] is the stretching vibration peak of the hydroxyl group; 1095 cm -1 、1046 cm -1 、1001 cm -1 The peak at [position] is the stretching vibration peak of the carbon-oxygen single bond; 872 cm -1 is the absorption peak of the carbon-carbon single bond, and the absorption is weak. Figure 3 A (curve b) is the physical mixture of the two, indicating that the physical mixture is just a simple superposition of the two. As Figure 3 Shown in A (curve a), it is the amorphous composition described in Example 2, in which the characteristic peak of lycorine at 3329 cm -1 is redshifted to 3385 cm -1 The peak at [position], 1622 cm -1 、1130 cm -1 and 1091 cm -1 The characteristic peaks at [position] disappear; the characteristic peaks of Sorb all change slightly. From this, it is inferred that there is an interaction between lycorine and Sorb molecules in Example 2, forming hydrogen bonds, and the amorphous composition is formed.

[0037] 2. Weigh about 5 mg of the composition prepared in Example 2 into an aluminum pan, and use a differential scanning calorimeter to detect the thermal behavior of the sample. The nitrogen gas flow rate is 70 mL / min, the heating rate is 10 °C / min, and the scanning range is 10 °C to 300 °C. Take another 5 mg each of the lycorine raw material drug, Sorb, and the physical mixture in the same proportion as in Example 2 and operate in the same way. The obtained spectra are shown in Figure 4 A (curve d). Lycorine has a sharp endothermic peak at 287 °C, and this peak is the melting point characteristic peak of lycorine, indicating that the drug exists in a crystalline form. Figure 4 In A (curve c), the endothermic peak of Sorb appears at 97 °C, Figure 4 In A (curve b), the endothermic peak of Sorb still exists, Figure 4 In A (curve a), the corresponding endothermic peak of lycorine disappears, and a new endothermic peak appears at 71 °C. This phenomenon that the melting temperature is lower than the melting point of any single component in the mixture indicates that a eutectic mixture is formed between lycorine and Sorb.

[0038] 3. The morphology of the lycorine raw material drug and Example 2 was analyzed using a scanning electron microscope. The sample was first fixed on a metal plate, and gold sputtering treatment was carried out for 30 s at a pressure of 8 - 10 Pa using an ion sputtering instrument, and then photographed. The obtained spectra are shown in Figure 5。 Figure 5 A It was observed that lycorine presented a prismatic crystal form. Figure 5 Irregular lumps were observed in the composition of B, indicating that the lycorine crystals had disappeared and were dispersed in the carrier material in an amorphous form.

[0039] 4. In this study, an HPLC method for the determination of lycorine was established (chromatographic column: Sepax C18 (4.6 mm×150 mm, 5 µm); detection wavelength: 203 nm; mobile phase: aqueous solution of 0.05% phosphoric acid - methanol (95:5); column temperature: 40 °C; flow rate: 1.2 mL / min). In the range of 0.1 - 10.0 µg / mL, the standard curve of lycorine concentration had a good linearity. And through precision and accuracy experiments, extraction recovery experiments, and stability experiments, it was proved that this detection and analysis method was stable and reliable and met the methodological requirements. Twelve healthy male SD rats were randomly divided into a lycorine intragastric administration group (control group) and an amorphous composition of lycorine intragastric administration group (experimental group), with 6 rats in each group. They were fasted for 12 h before administration and allowed free access to water. The control group and the experimental group were respectively made into suspensions by adding 1 mL of 0.5% CMC - Na aqueous solution, and the dose was 30 mg / kg (calculated based on lycorine), and a single - dose administration experiment was carried out. The experimental group and the control group were respectively bled from the orbital cavity at 0.05, 0.12, 0.17, 0.25, 0.5, 1, 2, 4, 8, 12 h after administration, and the blood was transferred to a heparin - containing centrifuge tube, and centrifuged at 3000 r·min -1 for 10 min, and the upper - layer plasma was taken and frozen at - 20 °C in the refrigerator for standby. 100 μL of the drug - containing rat plasma sample was placed in a 1.5 mL EP tube, 10 μL of the internal standard solution (50 µg / mL galanthamine) was added, vortex - shaken for 1 min, 500 µL of acetonitrile was added and vortex - shaken for 1 min, and centrifuged at 10000 r·min -1 for 10 min. 500 μL of the supernatant was taken, the solvent was air - dried at 40 °C, and the residue was dissolved with 100 μL of the mobile phase (0.05% phosphoric acid water: methanol = 95:5), vortex - shaken for 2 min, and centrifuged at 10000 r‧min -1 for 10 min. 30 μL of the supernatant was taken for injection analysis. The plasma drug concentration of the amorphous composition of lycorine in rats was significantly higher than that of the lycorine raw material drug group, and the drug - time curve is shown in Figure 6 。After being made into an amorphous composition, the drug was dispersed in the hydrophilic carrier in an amorphous form, which could significantly improve the dissolution rate of the drug. This rapid dissolution property contributed to the more effective absorption of the drug in the digestive tract. Lycorine combined with Sorb intermolecularly. Sorb has hydrophilicity, which promotes the dissolution and absorption of lycorine. The pharmacokinetic parameters of the lycorine raw material drug and the self - made amorphous composition in rats are as follows. The lycorine raw material drug appeared at T max of 0.33 ± 0.13 h, and its Cmax was 5.14 ± 0.60 mg / L, and the MRT (0-t) was 3.87 ± 0.30 h, and the elimination half-life t 1 / 2 was 4.40 ± 0.80 h, and the area under the drug-time curve AUC (0~t) was 16.70 ± 1.94 mg / L*h; while for the amorphous lycorine composition, at T max was 0.54 ± 0.25 h, and its C max was 7.33 ± 0.78 mg / L, and the MRT (0-t) was 3.87 ± 0.35 h, and the elimination half-life t 1 / 2 was 3.95 ± 0.62 h, and the AUC (0~t) was 28.41 ± 2.89 mg / L*h. The T of the amorphous lycorine composition max compared with that of lycorine max was extended by about 10 min. This may be because it takes a certain time for the drug to be released from the excipient and enter the blood circulation, as well as the influence of individual differences in rats. Generally speaking, compared with the lycorine raw material drug, the AUC of the amorphous lycorine composition (0-t) was increased to 170%.

[0040] Comparative Example 1

[0041] 1. Preparation of the lycorine composition: First, add 700 mg of Eudragit ® L100 to 100 mL of ethanol, stir at 50 °C until dissolved, then add 100 mg of lycorine and stir at room temperature until both are completely dissolved. Quickly remove the ethanol at room temperature and dry in a vacuum drying oven at 40 °C for 12 h. Crush and grind to obtain it.

[0042] 2. Use a Thermo Fisher / Nicolet iN10 infrared spectrometer (Thermo Fisher Scientific Inc.) to study the molecular interactions of Comparative Example 1. The experimental method is the same as that of Example 3. As Figure 3 shown in B, the stretching vibration peak of the ester group in Eudragit ® L100 is at 1729 cm -1 . In the physical mixture of the two, the stretching vibration peaks corresponding to lycorine are at 3329 cm -1 , 1130 cm -1 and 1091 cm -1 ; while 1729 cm -1 is the absorption peak corresponding to Eudragit ® L100, indicating that the physical mixture is just a simple superposition of the two. In Comparative Example 1 (curve a), the stretching vibration peak of lycorine is at 3329 cm -1The characteristic peak at [position] redshifts to 3347 cm -1 at [position], 1622 cm -1 、1130 cm -1 and 1091 cm -1 at [position] disappear; while in Eudragit ® L100, the characteristic peak at 1729 cm -1 at [position] shifts to 1725 cm -1 . From this, it is inferred that there is an interaction between the lycorine API in Comparative Example 1 and the molecules of Eudragit ® L100, forming a hydrogen bond.

[0043] 3. Weigh approximately 5 mg of the composition prepared in Comparative Example 1 into an aluminum pan, and use a differential scanning calorimeter to detect the thermal behavior of the sample. The experimental conditions are the same as in Example 3. As Figure 4 shown in ® B, the melting point of Eudragit

[0044] L100 is 198 °C. It can be seen from 4B (curve a) that the endothermic peaks corresponding to lycorine have disappeared, indicating that there is an interaction between lycorine and the carrier to form a hydrogen bond or chemical bond, and lycorine exists in the form of an amorphous solid dispersion. Figure 5 4. The morphology of the lycorine API and Comparative Example 1 was analyzed using a scanning electron microscope. The experimental conditions are the same as in Example 3. As

[0045] shown in Figure 7 C, Comparative Example 1 is in the shape of irregular flakes, and the characteristics of the crystalline lycorine API are no longer visible. Therefore, it indicates that lycorine has been transformed into an amorphous state through solid dispersion technology.

[0046] Comparative Example 2.

[0047] 1. Preparation of the lycorine composition: First, add 700 mg of PVP K30 to 100 mL of ethanol, stir at 50 °C until dissolved, then add 100 mg of lycorine and stir at room temperature until both are completely dissolved. Rapidly remove the ethanol at room temperature and dry in a vacuum drying oven at 40 °C for 12 h; pulverize and grind to obtain.

[0048] 2. Use a Thermo Fisher / Nicolet iN10 infrared spectrometer (Thermo Fisher Scientific) to study the molecular interaction of Comparative Example 2. The experimental method is the same as in Example 3. As Figure 3As shown in C, PVP K30 has a broad peak at 3456 cm -1 which is the stretching vibration peak of the hydroxyl group; at 2956 cm -1 is the stretching vibration peak of the carbon-hydrogen single bond; at 1673 cm -1 is the absorption peak of the carbon-oxygen double bond in the pyrrolidone ring; at 1422 cm -1 is the bending vibration peak of the methylene group; at 1287 cm -1 is the absorption peak of the amide bond. In the physical mixture, the absorption peaks corresponding to the excipient and lycorine both exist, indicating that there is only a simple superposition between the two and no interaction occurs. In Comparative Example 2 (curve a), the characteristic peaks of lycorine at 3329 cm -1 are all red-shifted to 3435 cm -1 , and the characteristic peaks at 1622 cm -1 , 1130 cm -1 and 1091 cm -1 disappear; while the characteristic peaks of PVP K30 all show slight shifts. From this, it is inferred that an interaction occurs between the lycorine API and PVP K30 molecules in Comparative Example 2, forming hydrogen bonds.

[0049] 3. Weigh about 5 mg of the composition prepared in Comparative Example 2 into an aluminum pan, and use a differential scanning calorimeter to detect the thermal behavior of the sample. The experimental conditions are the same as those in Example 3. As Figure 4 shown in C, the melting point of PVP K30 is 57 °C. Figure 4 It can be seen from C (curve a) that the endothermic peaks corresponding to lycorine all disappear, indicating that an interaction occurs between lycorine and the carrier to form hydrogen bonds or chemical bonds, and lycorine exists in the form of an amorphous solid dispersion.

[0050] 4. The morphology of lycorine API and Comparative Example 2 was analyzed using a scanning electron microscope. The experimental conditions are the same as those in Example 3. As Figure 5 shown in D, Comparative Example 2 is in the shape of irregular flakes, and the characteristics of the crystalline lycorine API are no longer visible. Therefore, it indicates that lycorine has been transformed into an amorphous state through solid dispersion technology.

[0051] 5. Dissolution test of the drug: Weigh 3 portions of Comparative Example 2 (equivalent to 270 mg of lycorine API) and add them to 900 mL of water respectively, and conduct a powder dissolution experiment according to the method of Example 2. The results are shown in Figure 7 . At 2 h for this composition, the cumulative dissolution of lycorine is 69.99%. The results show that the dissolution of this composition is higher than that of lycorine, but the dissolution is not as good as that of the composition using Sorb as the excipient.

[0052] Comparative Example 3.

[0053] 1. Preparation of lycorine composition: First, add 700 mg of Eudragit ® EPO to 100 mL of ethanol, stir at 50 °C until dissolved, then add 100 mg of lycorine and stir at room temperature until both are completely dissolved. Quickly remove the ethanol at room temperature and dry in a vacuum drying oven at 40 °C for 12 h. Crush and grind to obtain the product.

[0054] 2. Use a Thermo Fisher / Nicolet iN10 infrared spectrometer (Thermo Fisher Scientific) to study the molecular interaction of Comparative Example 3. The experimental method is the same as that of Example 3. As Figure 3 shown in D, Eudragit ® EPO has a broad peak at 3430 cm -1 , which is the stretching vibration peak of the amino group; the stretching vibration peak of the methyl group is at 2958 cm -1 ; the absorption peak of the ester group is at 1731 cm -1 . In the physical mixture, the corresponding absorption peaks of the excipient and lycorine all exist, indicating that there is only a simple superposition between the two and no interaction occurs. Figure 3 In D (curve a), the characteristic peaks of lycorine at 3329 cm -1 are all redshifted to 3435 cm -1 , and the characteristic peaks at 1622 cm -1 , 1130 cm -1 and 1091 cm -1 disappear; while the characteristic peaks in Eudragit ® EPO all show slight shifts. From this, it is inferred that there is an interaction between the lycorine API and Eudragit ® EPO molecules in Comparative Example 3, forming hydrogen bonds.

[0055] 3. Weigh about 5 mg of the composition prepared in Comparative Example 3 into an aluminum pan and use a differential scanning calorimeter to detect the thermal behavior of the sample. The experimental conditions are the same as those of Example 3. As Figure 4 shown in D, the melting point of Eudragit ® EPO is 52 °C. Figure 4 It can be seen from D (curve a) that the endothermic peaks corresponding to lycorine disappear, indicating that there is an interaction between lycorine and the carrier to form hydrogen bonds or chemical bonds, and lycorine exists in the form of an amorphous solid dispersion.

[0056] 4. Use a scanning electron microscope to analyze the morphology of the lycorine API and Comparative Example 3. The experimental conditions are the same as those of Example 3. As Figure 5 shown in E, Comparative Example 3 is in the shape of irregular flakes, and the characteristics of the crystalline lycorine API are no longer visible. Therefore, it indicates that lycorine has been transformed into an amorphous state through solid dispersion technology.

[0057] 5. Dissolution test of the drug: Weigh 3 portions of Comparative Example 3 (equivalent to 270 mg of lycorine raw material) and add them to 900 mL of water respectively, and conduct the powder dissolution experiment according to the method of Example 2. The results are shown in Figure 7 . At 2 h for this composition, the cumulative dissolution of lycorine is 60.19%. The results show that the dissolution of this composition is higher than that of lycorine, but the dissolution is not as good as that of the composition using sorbitol as the excipient.

[0058] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than limiting the protection scope of the present invention. Any simple modification or equivalent replacement made by those of ordinary skill in the art to the technical solution of the present invention shall not depart from the essence and scope of the technical solution of the present invention.

Claims

1. An lycorine composition based on the amorphous solid dispersion technology, characterized in that, It comprises the following components: lycorine and a carrier material; the mass ratio of lycorine to the carrier material is 1:5 - 1:

11.

2. The lycorine composition based on the amorphous solid dispersion technology according to claim 1, characterized in that The carrier material is sorbitol.

3. A preparation method of lycorine composition based on amorphous solid dispersion technology, characterized in that, It comprises the following steps: Step 1: Weigh sorbitol precisely and add it to absolute ethanol, and stir at 50 °C to dissolve it to obtain a solution; Step 2: Weigh an appropriate amount of lycorine precisely, and add it to the solution obtained in Step 1 and stir at room temperature until completely dissolved; Step 3: Rapidly remove ethanol, dry it in a vacuum drying oven, grind and pulverize it to obtain the lycorine composition.

4. The preparation method of the lycorine composition based on the amorphous solid dispersion technology according to claim 3, wherein, The vacuum drying temperature is 40 °C and the drying time is 12 h.

5. The lycorine amorphous composition according to any one of claims 1-2, characterized in that, The amorphous lycorine composition is used for preparing lycorine-related drugs.

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