A tetrahydropyrimidine derivative of formula (I) as a selective inhibitor of the enzyme dihydroorotate dehydrogenase (DHODH)

Abstract

The application discloses a tetrahydropalmatine-Imperatorin solid self-emulsifying drug composition and a preparation method thereof. The tetrahydropalmatine-Imperatorin solid self-emulsifying drug composition is made of tetrahydropalmatine, Imperatorin, an oil phase and an amphiphilic polymer. The application introduces the oil phase to improve the compatibility limitation between the traditional Chinese medicine component and the polymer matrix, so as to successfully prepare the traditional Chinese medicine amorphous solid dispersion by the hot melt extrusion technology. On one hand, the solubility and dissolution degree advantage of the amorphous solid dispersion is utilized, and on the other hand, the self-emulsifying drug release system formed in the dissolution process can promote the intestinal permeation and absorption of the traditional Chinese medicine component, so that the oral bioavailability of the low-solubility and / or low-permeation traditional Chinese medicine component is improved from two aspects.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine preparation technology, specifically relating to a solid self-emulsifying drug composition of corydalis ethylsin and imperatorin and its preparation method. Background Technology

[0002] Traditional Chinese medicine (TCM) possesses unique advantages in disease prevention and treatment; however, many pharmacologically active TCM components suffer from extremely low oral bioavailability due to their hydrophobicity and low permeability, limiting their clinical application. Current methods for improving the solubility of poorly soluble drugs include amorphous solid dispersion technology, nanoparticle technology, solid solution systems, ion-pairing strategies, and the use of surfactants. However, these methods all have drawbacks. For example, nanoparticle technology has high production costs and may exhibit nanotoxicity; solid solution systems have complex preparation processes and poor stability; ion-pairing strategies involve cumbersome salt formation processes; and the use of surfactants may lead to toxic side effects. Furthermore, the aforementioned solubilization strategies often struggle to simultaneously improve the physicochemical properties of multiple TCM active components.

[0003] Amorphous solid dispersion (ASD) technology is now widely used to improve poorly soluble drugs, thereby enhancing drug dissolution and bioavailability. Amorphous drugs have higher surface free energy and apparent solubility compared to crystalline drugs. Simultaneously, the dispersion effect of solid carriers on drugs increases the dissolution surface area, improving the dissolution rate of poorly soluble drugs and further enhancing their oral bioavailability. Currently, the main industrial methods for preparing amorphous solid dispersions are spray drying and hot melt extrusion (HME). Among these, hot melt extrusion has attracted much attention due to its advantages such as solvent-free preparation, continuous production, and environmental friendliness.

[0004] However, the preparation of amorphous solid dispersions using hot-melt extrusion is limited by two factors. First, the hot-melt extrusion process involves high-temperature operation, and some drugs lose their activity under high-temperature conditions, leading to thermal instability. Second, the preparation of amorphous solid dispersions is affected by the compatibility of the active pharmaceutical ingredient (API) and excipients. Especially for the active ingredients of traditional Chinese medicine (TCM), their diversity and complexity make it difficult to directly prepare a homogeneous amorphous solid dispersion with polymer excipients, or they may face the risk of crystal transformation during preparation and storage. Therefore, developing a novel formulation strategy with promising applications to expand the application of amorphous solid dispersion technology in the field of TCM is of great significance.

[0005] Self-Emulsifying Drug Delivery System (SEDDS) is a class of lipid-based technology that has attracted extensive attention in recent years for improving the solubility and bioavailability of poorly soluble drugs. The main drawbacks of traditional SEDDS are poor drug-loading capacity and unstable formulations, and the stability of SEDDS can be effectively improved by solidification technology. Among the existing SEDDS solidification technologies, hot-melt extrusion technology has received widespread attention due to its advantages such as no solvent addition and continuous manufacturability.

[0006] Yuanhu Zhitong prescription is a traditional Chinese medicine analgesic preparation, which has the effects of non-addictive analgesia, and equal emphasis on regulating qi and activating blood circulation, and is an ideal medication for long-term pain relief in chronic pain and elderly patients. The Yuanhu Zhitong prescription consists of two traditional Chinese medicines, vinegar-processed Rhizoma Corydalis and Radix Angelicae Dahuricae, and the active pharmaceutical ingredients exerting analgesic effect are clear, namely tetrahydropalmatine and imperatorin. However, both tetrahydropalmatine and imperatorin are low-solubility drugs, resulting in extremely low bioavailability. For patients taking Yuanhu Zhitong dripping pills, the single dose is large (20 to 30 pills at a time, three times a day), leading to poor patient medication compliance. In order to reduce the administration dose and administration frequency, it is necessary to improve the existing dosage forms of the Yuanhu Zhitong prescription to enhance its bioavailability. Therefore, taking tetrahydropalmatine and imperatorin from the Yuanhu Zhitong prescription as model drugs to explore the preparation process of traditional Chinese medicine solid self-emulsifying drug delivery system is of great significance, which provides a new idea for developing new traditional Chinese medicine preparation strategies with application prospects. Summary of the Invention

[0007] One of the objectives of the present invention is to provide a tetrahydropalmatine-imperatorin solid self-emulsifying pharmaceutical composition, which is made of tetrahydropalmatine, imperatorin, an oil phase and an amphiphilic polymer;

[0008] The mass ratio of tetrahydropalmatine to imperatorin is 1:0.5 to 1:5, preferably 1:1;

[0009] The mass ratio of the total mass of tetrahydropalmatine and imperatorin to the oil phase is 1:1 to 1:4, preferably 1:3;

[0010] The mass ratio of the total mass of tetrahydropalmatine and imperatorin to the amphiphilic polymer is 1:9.

[0011] Further, the oil phase is a small-molecule oil (such as eugenol, trans-anethole, nerol, carvacrol, cinnamaldehyde, benzyl alcohol, propylene glycol, etc.) or a medium / long-chain oil (such as corn oil, soybean oil, walnut oil, almond oil, camellia oil, etc.), preferably eugenol, trans-anethole, benzyl alcohol, and more preferably eugenol.

[0012] Further, the amphiphilic polymer is copovidone, preferably copovidone VA64.

[0013] The second objective of this invention is to provide a method for preparing the above-mentioned corydaline-imperatorin solid self-emulsifying pharmaceutical composition, specifically: first, corydaline and imperatorin are mixed and dissolved in the oil phase, then an amphiphilic polymer is added and mixed, and the mixture is extruded by hot melt extrusion technology to obtain the solid self-emulsifying pharmaceutical composition.

[0014] Furthermore, the temperature of the hot melt extrusion is 160-180℃, and the rotation speed is 30-50rpm.

[0015] The inventors discovered that the addition of an oil phase improves the compatibility between the traditional Chinese medicine components and the polymer, increasing the possibility of preparing amorphous solid dispersions. A physical mixture of corydaline and imperatorin was directly mixed with an amphiphilic polymer and then hot-melt extruded to obtain a physical mixture extrudate (PM extrudate). Observation of the PM extrudate under a polarizing microscope revealed the presence of a large number of crystals, proving that the product was not a single homogeneous amorphous solid dispersion. However, when the physical mixture of corydaline and imperatorin was first dissolved in an oil phase and then thoroughly mixed with the amphiphilic polymer before hot-melt extrusion, the resulting product, observed under a polarizing microscope, showed no birefringence. Characterization using differential scanning calorimetry (DSC) revealed a single glass transition temperature, demonstrating that adding the traditional Chinese medicine components dissolved in an oil phase improves the compatibility between the components and the amphiphilic polymer, increasing the possibility of preparing amorphous solid dispersions of traditional Chinese medicine.

[0016] Furthermore, the inventors discovered that the addition of the oil phase can promote the formation of SEDDS during drug release, thereby achieving the purpose of regulating drug release. Through the mediation of different oil phase types, corydaline and imperatorin can exhibit different dissolution behaviors, thus better regulating the analgesic efficacy of the Corydalis analgesic formula through a solid-state self-emulsifying drug release system. Amorphous solid dispersions were prepared using eugenol (Eug), trans-anisene (TA), and benzyl alcohol (BP) as mediators, and characterized accordingly. The results showed that the effect on improving the dissolution of corydaline and imperatorin was: eugenol system (Eug-VA64 ASD) > trans-anisene system (TA-VA64 ASD) > benzyl alcohol system (BP-VA64 ASD).

[0017] Furthermore, the inventors discovered in their research that adding different amounts of oil phase can also regulate drug release behavior. Within a certain range, the dissolution rate of corydaline and imperatorin increased significantly with increasing oil phase content. Amorphous solid dispersions were prepared using different amounts of eugenol (mass ratios of the herbal components to eugenol were 1:2, 1:2.5, and 1:3, respectively), and the dispersions were characterized accordingly. The results showed that the effect on improving the dissolution rate of corydaline and imperatorin was as follows: high eugenol content (1:3) system > medium eugenol content (1:2.5) system > low eugenol content (1:2) system.

[0018] This invention improves the compatibility limitations between traditional Chinese medicine components and polymer matrices by introducing an oil phase, thereby successfully preparing amorphous solid dispersions of traditional Chinese medicine using HME technology. On the one hand, it utilizes the solubility advantage of amorphous solid dispersions, and on the other hand, the SEDDS formed during the dissolution process can promote the intestinal permeation and absorption of traditional Chinese medicine components, thereby improving the oral bioavailability of traditional Chinese medicine components with low solubility and / or low permeability from two aspects.

[0019] Beneficial effects:

[0020] (1) This invention realizes the preparation of the solid self-emulsifying drug release system of corydalis ethylsin-imperatorin traditional Chinese medicine through hot melt extrusion technology. Compared with the traditional amorphous solid dispersion formulation strategy, the addition of oil phase increases the compatibility between the multi-component traditional Chinese medicine and the amphiphilic polymer, increases the possibility of preparing amorphous solid dispersion, and is simple and efficient.

[0021] (2) The oil phase used in this invention has the function of regulating the dissolution behavior of the active pharmaceutical ingredient. Through the mediation of different types of oil phases, or the mediation of different amounts of the same type of oil phase, corydalis ethylsin and imperatorin can exhibit different dissolution and release behaviors, thereby better regulating the analgesic effect of the Corydalis analgesic formula through the solid self-emulsifying drug release system and increasing the different dosage settings for the applicable population.

[0022] (3) The addition of the oil phase effectively improved the oral bioavailability of corydaline and imperatorin in rats. This was not only due to the significantly improved dissolution, but also because the addition of the oil phase promoted the formation of a self-emulsifying drug delivery system during drug release.

[0023] (4) The hot melt extrusion process can realize continuous production without the addition of solvents, which is in line with the concept of green environmental protection and has broad application prospects. It provides new methods and technologies for the development of new dosage forms of Chinese medicine and the continuous and modern production of Chinese medicine. Attached Figure Description

[0024] Figure 1 A polarized light microscope image of the extruded physical mixture of corydaline, imperatorin, and VA64.

[0025] Figure 2 Polarized light microscope images of extrudates of corydaline-imperatorin-VA64 with different oil phases.

[0026] Figure 3 DSC characterization diagrams of amorphous solid dispersions of traditional Chinese medicine prepared in three different oil phase systems.

[0027] Figure 4 DSC characterization diagrams of amorphous solid dispersions of traditional Chinese medicine prepared in three different oil phase dosage systems.

[0028] Figure 5 Supersaturated dissolution curves of amorphous solid dispersions of traditional Chinese medicine with different oil phases.

[0029] Figure 6 Dissolution curves of amorphous solid dispersions of traditional Chinese medicine prepared for three different oil phase dosage systems.

[0030] Figure 7 This is a Raman spectrum analysis of amorphous solid dispersions of traditional Chinese medicine mediated by eugenol.

[0031] Figure 8 This is a Raman spectrum analysis of amorphous solid dispersions of traditional Chinese medicine mediated by trans-anessenol.

[0032] Figure 9 This is a Raman spectrum analysis of amorphous solid dispersions of traditional Chinese medicine mediated by benzyl alcohol.

[0033] Figure 10 The results show the absorption of amorphous solid dispersions of traditional Chinese medicine in the jejunum over 4 hours.

[0034] Figure 11 Particle size distribution of amorphous solid dispersions of traditional Chinese medicine mediated by different amounts of eugenol.

[0035] Figure 12 Pharmacokinetic studies of Eug-VA64 ASD amorphous solid dispersion and PM extrudate extrudate. Detailed Implementation

[0036] In their preliminary research, the inventors discovered that the addition of an oil phase increased the compatibility between corydaline and imperatorin with amphiphilic polymers, thus successfully preparing acophoraline-imperatorin amorphous solid dispersions. Furthermore, the dissolution behavior of these amorphous solid dispersions can be effectively controlled by varying the type or amount of oil phase. Simultaneously, these amorphous solid dispersions have been shown to exhibit self-emulsification during dissolution, effectively improving the intestinal permeability of the traditional Chinese medicine. In vivo studies have demonstrated that the novel formulation strategy proposed in this invention effectively improves the oral bioavailability of the corydaline-imperatorin amorphous solid dispersion.

[0037] The preferred embodiments of the present invention will now be described in detail with reference to specific examples. It should be understood that the following examples are given for illustrative purposes only and are not intended to limit the scope of the invention. Those skilled in the art can make various modifications and substitutions to the present invention without departing from its spirit and essence.

[0038] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0039] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0040] Example 1

[0041] Effect of oil phase addition on the preparation of amorphous solid dispersions of traditional Chinese medicine

[0042] Take equal amounts of corydaline and imperatorin, and mix them thoroughly through a 40-mesh sieve five times to obtain a physical mixture.

[0043] Weigh 1.5g of the physical mixture of corydaline and imperatorin and 13.5g of copovidone VA64, and mix thoroughly through a 40-mesh sieve five times to obtain a total mixture. Then, the total mixture is hot-melt extruded through a hot-melt extruder at a temperature of 170℃ in zones two, three, and four to obtain the extrudate of the physical mixture of corydaline-imperatorin-VA64, denoted as sample 1 (PM extrudate).

[0044] Weigh 1g of the physical mixture of corydaline and imperatorin, dissolve it in 3g of eugenol (Eug) in a water bath at 80℃, and add it to 9g of copovidone VA64 after complete dissolution. Stir to mix thoroughly, and then extrude the mixture through a hot melt extruder at a temperature of 170℃ in zones two, three and four to obtain an amorphous solid dispersion of corydaline-imperatorin-eugenol-VA64, which is designated as sample 2 (Eug-VA64 ASD).

[0045] Example 2

[0046] Influence of different types of oils on the preparation and characterization of amorphous solid dispersions of traditional Chinese medicine

[0047] Equal amounts of corydaline and imperatorin were passed through a 40-mesh sieve five times and mixed thoroughly. 1 g of the physical mixture of corydaline and imperatorin was weighed and dissolved completely in 3 g of trans-anestin (TA) and benzyl alcohol (BP) respectively under an 80°C water bath. After complete dissolution, these were added to 9 g of copovidone VA64 and stirred thoroughly. The final mixture was then hot-melt extruded using a hot-melt extruder at 170°C in zones two, three, and four to obtain an amorphous solid dispersion of corydaline-imperatorin-oil phase-VA64, designated as Sample 3 (TA-VA64 ASD) and Sample 4 (BP-VA64 ASD), respectively.

[0048] Example 3

[0049] Effects of different oil phase amounts on the preparation and characterization of amorphous solid dispersions of traditional Chinese medicine

[0050] Equal amounts of corydaline and imperatorin were passed through a 40-mesh sieve five times and mixed thoroughly. 1 g of the physical mixture of corydaline and imperatorin was weighed and dissolved in 2 g or 2.5 g of eugenol respectively under an 80°C water bath. After complete dissolution, the solutions were added to 9 g of copovidone VA64 and stirred thoroughly. The mixture was then hot-melt extruded through a hot-melt extruder at 170°C in zones two, three, and four to obtain an amorphous solid dispersion of corydaline-imperatorin-oil phase-VA64, designated as Sample 5 (Eug-VA64 ASD(1:2)) and Sample 6 (Eug-VA64 ASD(1:2.5)).

[0051] The samples from the above embodiments were tested, as follows:

[0052] 1. Polarizing microscope

[0053] Instrument: Nikon Eclipse Ci-POL transmission and reflection polarizing microscope (Nikon, Japan)

[0054] Light source: polarized light

[0055] Objective lens magnification: 5X

[0056] The polarized light microscope images of samples 1-6 of the above-mentioned corydaline-imperatorin solid dispersions are shown below. Figure 1 and Figure 2As shown, the solid dispersion (PM extrudate) without the addition of the oil phase exhibits obvious birefringence, indicating that sample 1 is in crystalline form. After the addition of the oil phase for mediation, the prepared solid dispersions (samples 2-6) did not show birefringence when observed under a polarizing microscope, indicating that no crystals exist in the samples and the samples are in amorphous form.

[0057] 2. Differential scanning calorimetry

[0058] Instrument: DSC 3500 Differential Scanning Calorimeter (NETZSCH, Germany)

[0059] Sample tray type: solid tray

[0060] Temperature range: 20-200℃

[0061] Heating rate: 10℃ / min

[0062] The DSC spectra of samples 2-6 of the corydaline-imperatorin solid dispersion are as follows: Figure 3 (Solid dispersions with different oil phases) Figure 4 (Solid dispersions with different amounts of oil phase are shown). After the addition of the oil phase, the DSC spectra of the prepared solid dispersions all showed a single glass transition temperature, indicating that the addition of the oil phase increased the compatibility between the active pharmaceutical ingredient and the excipients, and amorphous solid dispersions were successfully prepared.

[0063] 3. Supersaturated dissolution test

[0064] Instrument: RC806ADK Intelligent Dissolution Tester (Tianjin Tianda Tianfa Technology Co., Ltd.)

[0065] Method: Following the second method (paddle method) for the determination of dissolution and release in General Chapter 0931 of the 2020 edition of the Chinese Pharmacopoeia, the dissolution medium was 150 mL of pure water.

[0066] Temperature: 37±0.5℃

[0067] Speed: 100 rpm

[0068] Test solution: Weigh 1.5 g each of the corydaline-imperatorin solid dispersion samples 1-6 and place them in a dissolution vessel. After the start of the test, take 2 mL samples at 5, 10, 15, 30, 45, 60, 90, 120, 180, 240, 360, 480, 720, and 1440 min respectively, and replenish with the same volume of medium at the same temperature in a timely manner. Filter the collected dissolution solution through a 0.45 μm PTFE aqueous filter membrane. Use the filtrate as the test solution. Determine the concentrations of corydaline and imperatorin using high performance liquid chromatography (HPLC).

[0069] Reference solutions: Imperatorin reference standard: Accurately weigh an appropriate amount of imperatorin reference standard and prepare a solution containing 9.8 μg of imperatorin per mL with methanol. Tetracycline reference standard: Accurately weigh an appropriate amount of tetracycline reference standard and prepare a solution containing 24.5 μg of tetracycline per mL with methanol.

[0070] The determination of corydaline and imperatorin was performed by high performance liquid chromatography (HPLC), using a column of [missing information - likely a specific column type]. The column was C18, 4.6*250mm, 5μm; the mobile phase was acetonitrile-0.1% phosphoric acid aqueous solution (adjusted to pH 6.0 with triethylamine), the ratio of organic phase to aqueous phase was 65:35, the flow rate was 1mL / min, the column temperature was 40℃, the detection wavelength was 280nm, and the injection volume was 20μL. The above solution was subjected to high-performance liquid chromatography (HPLC) for peak area determination to calculate its dissolution rate.

[0071] Supersaturated dissolution curves of solid dispersions with different oil phases (samples 1-4) are shown below. Figure 5 As shown, the dissolution behavior of the three oils differs from that of corydaline and imperatorin, with eugenol showing the best performance, followed by trans-anestinene, and benzyl alcohol showing the worst. The supersaturated dissolution curves of solid dispersions (samples 2, 5, and 6) with different amounts of the same oil phase are shown below. Figure 6 As shown, the dissolution rate increases with the increase of the oil phase mass, and the platform dissolution rate will improve. However, in order to ensure the drug loading, it is preferred to prepare the solid self-emulsifying drug release system of traditional Chinese medicine with a ratio of 1:3 between the traditional Chinese medicine and the oil phase.

[0072] 4. Investigation on the influence of different oil phase types on the interaction forces of amorphous solid dispersion systems of traditional Chinese medicine

[0073] The effects of different oil phases on the interaction forces of amorphous solid dispersions were determined using laser confocal Raman spectroscopy. The samples tested included ethyl corydaline, imperatorin, VA64, eugenol (Eug), trans-anestinene (TA), benzyl alcohol (BP), and ethyl corydaline-imperatorin-oil phase-VA64 amorphous solid dispersions (Eug-VA64 ASD, TA-VA64 ASD, BP-VA64 ASD). The laser used for the analysis was at a wavenumber of 780 nm, and the test range was 400-4000 cm⁻¹. -1 .

[0074] Test results as follows Figure 7 , 8As shown in Figures 9, it can be seen that in the eugenol-mediated amorphous solid dispersion system, four interaction sites show significant shifts; in the trans-anessenol-mediated system, two interaction sites show significant shifts; and in the benzyl alcohol-mediated system, one interaction site shows a significant shift. Therefore, in the three traditional Chinese medicine amorphous solid dispersion systems, the relative strength of intermolecular interactions is likely eugenol system > trans-anessenol system > benzyl alcohol system. Further verification confirms that during supersaturated dissolution, the eugenol system exhibits the best dissolution behavior and the most stable system, followed by the trans-anessenol system, while the benzyl alcohol system is the worst.

[0075] 5. Investigation on the effect of oil phase addition on the permeation and absorption of amorphous solid dispersions of traditional Chinese medicine

[0076] Intestinal tissue from male Sprague-Dawley (SD) rats was used to investigate osmotic absorption. Due to the small intestinal area of ​​SD rats, an intestinal eversion model was used to investigate the drug absorption. Microvilli and a mucus layer were observed on the donor side to increase the concentration of the receptor drug, facilitating intestinal osmotic measurements. A 5cm segment of the rat jejunum was taken and washed three times with PBS 6.8 buffer using a blunt-tipped syringe. After eversion, one end of the intestine was ligated with silk suture. 1mL of Hank's balanced salt solution (HBSS) was injected into the intestine using a pipette, and the other end of the intestinal sac was then ligated with silk suture. The intestinal sac was placed in a dissolution vessel containing 150mL of pure water, and 1.5g of Sample 1 (PM extrudate) and Sample 2 (Eug-VA64ASD) powder were added, respectively. The dissolution vessel containing the sample solution served as the donor chamber, and the everted intestinal sac containing HBSS served as the recipient chamber. The same dissolution conditions as for supersaturation dissolution assays were used. The intestinal sac was removed after 4 hours and rinsed three times with physiological saline. The sac was then cut open, and the intestinal fluid was placed in a 2 mL centrifuge tube. The slurry was centrifuged at 12000 rpm (TGL-16G, Shanghai Anting Scientific Instrument Factory) for 10 min. 100 μL of the supernatant was then transferred to 200 μL of acetonitrile and vortexed (Vortex-Genie2, Scientific Industries, USA) for 2 min to fully precipitate the protein. The mixture was then centrifuged at 12000 rpm for 10 min. The supernatant was used as the test solution, and corydaline and imperatorin were analyzed using the high-performance liquid chromatography method described above. Each sample was measured in triplicate.

[0077] The 4-hour jejunal osmotic absorption of the obtained sample is as follows: Figure 10As shown, compared to the PM extrudate system, the addition of eugenol improved the permeability and absorption of both THP and IMP, indicating that the addition of the oil phase improved the intestinal permeability of the two traditional Chinese medicine components to a certain extent.

[0078] 6. Investigation on the effect of oil phase addition on the time-particle size curve of amorphous solid dispersion of traditional Chinese medicine during dissolution and release.

[0079] Test solution: Weigh 1.5g of each of the powdered samples 1-2 and 5-6 of the corydaline-imperatorin solid dispersion. The test was conducted using an RC806ADK intelligent dissolution apparatus (Tianjin Tianda Tianfa Technology Co., Ltd.), following the second method (paddle method) for determination of dissolution and release rate in General Chapter 0931 of the 2020 edition of the Chinese Pharmacopoeia. 150mL of water was used as the dissolution medium, the test temperature was 37±0.5℃, and the rotation speed was 100rpm. After the start of the test, 5mL samples were taken at 10, 15, 30, 60, 120, 240, 360, 480, 720, and 1440 min to prepare the test solution, and the same volume and temperature of medium were replenished promptly. The particle size of the dissolved samples at each time point was determined using a dynamic light scattering particle size analyzer.

[0080] Eugenol-mediated time-particle size profiles of amorphous solid dispersions are shown below. Figure 11 As shown, the addition of eugenol promotes the formation of SEDDS during the dissolution and release of amorphous solid dispersions of traditional Chinese medicine (TCM). The amorphous solid dispersions mediated by eugenol exhibit small particle sizes and stable particle size distributions during dissolution and release. Furthermore, with increasing eugenol dosage, the particle size of the amorphous solid dispersions formed during dissolution and release decreases, the specific surface area of ​​the particles increases, the dissolution rate is faster, and the formed SEDDS system becomes more stable. However, to ensure drug loading, a 1:3 ratio of TCM to eugenol is preferred for preparing the solid-state self-emulsifying drug release system. In addition, the particle size of sample 1 (PM extrudate) during dissolution and release is too large, and its effective particle size cannot be detected by a dynamic light scattering particle size analyzer. This indicates that the addition of the oil phase promotes the formation of SEDDS during the dissolution and release of TCM, which can, to some extent, promote the penetration and absorption of TCM.

[0081] 7. Investigation on the effect of oil phase addition on pharmacokinetic parameters of amorphous solid dispersions of traditional Chinese medicine

[0082] The oral pharmacokinetics of SD rats were investigated using Eug-VA64 ASD and PM extrudate samples. Rats were fasted for 12 hours prior to administration and then weighed. Both corydaline and imperatorin were administered orally via gavage at a dose of 30 mg / kg. Blood samples (1 mL) were collected from the orbital venous plexus of the rats at 30, 60, 90, 120, 180, 240, 360, 480, and 600 minutes after gavage administration. The following methods were used to detect corydaline and imperatorin:

[0083] Corydaline B: Take 150 μL of plasma sample and place it in a 2 mL centrifuge tube. Add 20 μL of 45.2 μg / mL internal standard (corydaline A) methanol solution and 50 μL of 1 mol / L NaOH solution for alkalization. Vortex for 5 min. Add 1.5 mL of n-hexane:isopropanol (95:5) for extraction, vortex for 5 min, and centrifuge at 12000 rpm for 10 min. Take the upper organic phase and dry it in a nitrogen evaporator at 40℃. Redissolve the residue in 150 μL of the corresponding mobile phase.

[0084] Imperatorin: Take 150 μL of plasma sample and place it in a 2 mL centrifuge tube. Add 20 μL of 29.2 μg / mL internal standard (isoimperatorin) methanol solution, vortex for 5 min, add 1.5 mL of ethyl acetate:petroleum ether (1:1) for extraction, vortex for 5 min, centrifuge at 12000 rpm for 10 min. Take the upper organic phase and dry it in a nitrogen evaporator at 40℃. Redissolve the residue in 150 μL of the corresponding mobile phase.

[0085] High-performance liquid chromatography (HPLC) was used to detect the samples. The chromatographic column used was [missing information]. The column was C18, 4.6*250mm, 5μm; the mobile phase was acetonitrile-0.1% phosphoric acid aqueous solution (adjusted to pH 6.0 with triethylamine), the ratio of organic phase to aqueous phase was 60:40, the flow rate was 1mL / min, the column temperature was 40℃, the detection wavelength for corydaline was 280nm, and the detection wavelength for imperatorin was 300nm, with an injection volume of 20μL. The peak area of ​​the above solutions was determined by high-performance liquid chromatography (HPLC) to calculate the blood drug concentration.

[0086] The pharmacokinetic parameters of Eug-VA64 ASD and PM extrudate samples are shown in Table 1.

[0087] Table 1. Pharmacokinetic parameters of Eug-VA64 ASD and PM extrudate rats after oral gavage administration.

[0088]

[0089] It can be seen that, for corydaline, the AUC of Eug-VA64 ASD is... 0-10h and C max Compared to PM extrudate samples, the values ​​were increased by 4.34-fold and 4.33-fold, respectively; for imperatorin, the AUC of Eug-VA64 ASD was [missing value]. 0-10h and C max Compared to the PMextrudate sample, the concentrations increased by 3.74 times and 4.49 times, respectively, indicating that the addition of eugenol significantly improved the absorption of tetrahydropalmatine (THP) and imperatorin (IMP) in rats. Furthermore, the plasma concentration-time curves of tetrahydropalmatine and imperatorin are shown below. Figure 12 As shown, the blood drug concentration of the amorphous solid dispersion (Eug-VA64 ASD) mediated by eugenol was much higher than that of the PM extrudate sample within a specific time period, indicating that the addition of eugenol effectively improved the oral bioavailability of corydaline and imperatorin.

Claims

1. A solid self-emulsifying pharmaceutical composition of corydalis yanhusuo and imperatorin, characterized in that, It is made from corydaline, imperatorin, oil phase and amphiphilic polymer; The preparation method of the solid self-emulsifying drug composition of corydalis-imperatorin is as follows: first, corydalis and imperatorin are mixed and dissolved in the oil phase, then an amphiphilic polymer is added and mixed, and the mixture is extruded by hot melt extrusion technology to obtain the solid self-emulsifying drug composition. The mass ratio of corydaline and imperatorin is 1:0.5 to 1:5; The total mass ratio of the corydaline and imperatorin to the oil phase is 1:1 to 1:

4. The ratio of the total mass of the corydaline and imperatorin to the mass of the amphiphilic polymer is 1:9; The oil phase is eugenol, trans-anessenol, or benzyl alcohol, and the amphiphilic polymer is copolyvinyl ketone.

2. The method for preparing the corydalis-imperatorin solid self-emulsifying pharmaceutical composition according to claim 1, characterized in that, First, corydaline and imperatorin are mixed and dissolved in the oil phase. Then, an amphiphilic polymer is added and mixed. The mixture is then extruded using hot melt extrusion technology to obtain the solid self-emulsifying drug composition.

3. The preparation method according to claim 2, characterized in that, The temperature of the hot melt extrusion is 160-180℃, and the rotation speed is 30-50 rpm.

4. A pharmaceutical composition, characterized in that, The solid self-emulsifying pharmaceutical composition comprising corydalis ethylsin and imperatorin as described in claim 1.

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