Syringic acid-rotundine carrier-free co-amorphous substance as well as preparation method and pharmaceutical application thereof

Abstract

The invention provides a drug-drug co-amorphous substance co-carrying analgesic active components of syringic acid and rotundine. The prescription of the drug-drug co-amorphous substance does not contain any carrier or auxiliary material, the preparation method is simple, convenient and efficient, special processes and equipment are not needed, the cost is low, and industrialization is easy. The co-amorphous substance prepared by the invention not only can significantly improve the water solubility of syringic acid and rotundine, but also can improve the transdermal performance of drugs, and is beneficial to development of double-drug co-loaded efficient oral or external compound products.

Description

Technical Field

[0001] The present invention relates to the technical field of medicine, and in particular to a carrier-free co-amorphous syringic acid-rotundine, a preparation method thereof, and pharmaceutical use thereof. Background Art

[0002] Currently, there are many types of drugs used clinically to treat chronic pain. Among them, opioids have significant analgesic effects, but they have serious adverse reactions such as constipation, respiratory depression and addiction; and non-steroidal anti-inflammatory drugs also have the risk of adverse reactions such as gastrointestinal damage, increased blood pressure and increased heart failure.

[0003] Rotundine (RTD, C 21 H 25 NO4), also known as corydalis ethyl, or l-tetrahydropalmatine (l-THP), is a kind of Corydalis yanhusuo WT Wang ) is an alkaloid extracted from the dried tubers of the plant, which is its main active ingredient. Rotundine is slightly soluble in ethanol and ether, soluble in chloroform and dilute sulfuric acid, but nearly insoluble in water. This poor solubility limits its application in formulation development. Pharmacological studies have shown that rotundine has multiple effects, including sedation, tranquilization, analgesia, and central muscle relaxation. Its mechanism is primarily dopamine receptor blockade, which differs from the receptor agonism of traditional opioids. In clinical practice, rotundine is widely used to treat internal pain, dysmenorrhea, and labor analgesia, and was included in the 2000 edition of the Chinese Pharmacopoeia. Studies have shown that its analgesic effect is comparable to that of tramadol, but it is non-addictive and has a higher safety profile. Currently, rotundine is available in tablets and injections for clinical use. However, tablets require a 30–60 mg dose three times daily, which can cause gastrointestinal irritation and significant first-pass hepatic effects. Intramuscular injection can cause allergic reactions, and there is still room for optimization of its administration method.

[0004] Syringic acid (SA, C9H 10 Syringic acid (O5) is an important secondary metabolite phenolic compound in plants. It is widely available, primarily in a variety of edible and medicinal plants, including oats, isatis root, motherwort, dendrobium, and isatis indigotica. It exhibits multiple pharmacological actions, including antibacterial, antioxidant, and anti-endotoxin properties. It also possesses significant sedative and local anesthetic effects, as well as sleep-inducing properties. However, syringic acid's poor solubility, rapid metabolism, and low bioavailability hinder its full efficacy.

[0005] Co-amorphous technology is an effective means of improving the solubility and bioavailability of low-solubility drugs (BCS class II and IV). Co-amorphous compounds (CAMs) are formed by intermolecular interactions such as hydrogen bonding and π-π stacking between an active pharmaceutical ingredient and another small molecule drug or pharmaceutical excipient to form a single-phase amorphous system. These systems exhibit a single glass transition temperature (Tg), effectively inhibiting crystal formation and reducing the free energy of the system. Depending on their composition, CAMs are categorized as drug-drug (e.g., cimetidine-naproxen) or drug-excipient (e.g., repaglinide-saccharin). This technology not only enhances drug solubility and dissolution rate but also increases in vivo absorption through supersaturation, improving bioavailability and enhancing physical stability. Previous studies have demonstrated that co-amorphous systems such as lurasidone-shikimic acid, lenvatinib-baicalein, and favipiravir-nifedipine exhibit significant improvements in solubility, permeability, and stability.

[0006] Prior art CN1778300A discloses an orally disintegrating tablet of rotundine. By wet-mixing rotundine with a small amount of filler or disintegrant and then drying and tableting, the problems of water insolubility and residue after disintegration are solved. It is suitable for industrial production, but still relies on a large amount of excipients to improve tableting performance. CN112076153A acidifies and dissolves rotundine and mixes it with a solvent containing hydroxypropyl β-cyclodextrin and alcohol, and then adjusts the pH with alkali to improve water solubility and reduce acidity. However, it requires the introduction of a large amount of cosolvent, making the process more complicated. CN101906101A and CN10190610A respectively produce Type B and Type C crystal forms of rotundine by spray drying or recrystallization with organic solvents, which improves absorption rate and blood drug concentration, but has high requirements for process conditions and is difficult to scale up. CN103040795A increases the solubility of rotundine by adding 10% dilute sulfuric acid and enhances transdermal absorption with a cubeb-azone composite penetration enhancer, increasing the permeability by 13.48 times. However, the acidity and penetration enhancer may cause irritation and safety risks, and the drug still relies on exogenous excipients.

[0007] Prior art CN113717042A discloses a method for preparing a syringic acid / iohexol cocrystal. This method involves mixing the cocrystal in an organic solvent at a 2:1 molar ratio, heating to dissolve, and then vacuum drying to obtain the cocrystal. This significantly improves the solubility of syringic acid, enabling synergistic application of the two drugs. CN110818692A discloses a method for preparing a tegafur-syringic acid cocrystal. This method uses a 1:1 molar ratio of syringic acid in methanol via solvent evaporation or cooling to obtain a stable cocrystal. Its in vitro dissolution rate is 1.46 times higher than that of the original drug. While these technologies demonstrate that syringic acid can be used as a cocrystal ligand to improve drug solubility, they do not involve rotundine, nor do they provide technical information on the formation of a co-amorphous compound between syringic acid and rotundine.

[0008] Unlike the aforementioned technologies, the present invention utilizes the interaction between the poorly soluble traditional Chinese medicine active ingredient, rotundine, and syringic acid to produce a drug-drug co-amorphous compound. This significantly improves the solubility of both components and synergistically promotes the absorption and transdermal permeability of rotundine and syringic acid, thereby enhancing bioavailability. Furthermore, the process is simple and the product is stable, without the need for any carriers or dressings. Summary of the Invention

[0009] The present invention aims to provide a syringic acid-rotundine drug-drug co-amorphous body with synergistic solubilization and transdermal penetration enhancement. The system can maximize the drug loading to form an amorphous body without adding any excipients. The use of the co-amorphous body can significantly increase the water solubility of syringic acid and rotundine, and greatly improve the transdermal permeability of syringic acid and rotundine. When used for oral medication, the dissolution of the drug can be increased, thereby improving bioavailability. When used for transdermal administration, the gastrointestinal irritation, first-pass effect, and allergic reactions associated with oral and parenteral administration can be avoided, thereby providing good application prospects.

[0010] Another object of the present invention is to provide a method for preparing the above-mentioned co-amorphous material.

[0011] Specifically, the present invention provides the following technical solution: a syringic acid-rotundine drug-drug co-amorphous form with synergistic solubilization and transdermal penetration enhancement, comprising the natural active ingredients syringic acid and rotundine, without any added carrier, wherein the molar ratio of syringic acid to rotundine is 1:1 to 2:1. Preferably, the molar ratio of syringic acid to rotundine is 2:1. The syringic acid-rotundine drug-drug co-amorphous form of the present invention is amorphous, exhibits no birefringence under a polarizing microscope, and exhibits no characteristic peaks and no new characteristic diffraction peaks on a powder X-ray diffractometer.

[0012] The present invention also provides a method for preparing the aforementioned co-amorphous compound, namely, a solvent evaporation method. The solvent evaporation method involves dissolving syringic acid and rotundine in a solvent. Since the molecules of syringic acid and rotundine fully contact and interact in the dissolved state, a specific form of the co-amorphous compound of syringic acid and rotundine is formed upon solvent evaporation and removal, rather than individual crystallizations of syringic acid or rotundine. A suitable solvent is one that can dissolve both syringic acid and rotundine. The solvent can be either a single organic solvent or a mixture of organic solvents.

[0013] In one feasible embodiment, the solvent evaporation method comprises weighing appropriate amounts of syringic acid and rotundine, mixing them uniformly, adding a solvent until the entire system reaches a clear, transparent, and completely dissolved state, and then removing the solvent to collect the solid. In another feasible embodiment, the solvent evaporation method comprises dissolving syringic acid and rotundine separately in a suitable solvent, then mixing the two solutions to form a mixed solution containing syringic acid and rotundine, and then removing the solvent to collect the solid. The solvent removal method includes, but is not limited to, one or more of the following methods: heating, reducing pressure, evaporating to dryness with ventilation, and natural evaporation.

[0014] Preferably, the solvent is: 1) methanol, anhydrous ethanol, or a mixture of the two; or 2) a mixture of methanol and an organic solvent other than anhydrous ethanol, wherein the methanol content is not less than 30%; or 3) a mixture of anhydrous ethanol and an organic solvent other than methanol, wherein the anhydrous ethanol content is not less than 30%. Preferably, the other organic solvent is one or more of propanol, butanol, ethyl acetate, dichloromethane, acetone, butanone, ether, tetrahydrofuran, acetonitrile, and trifluoroacetic acid. More preferably, the mixed solvent system of methanol and another solvent is composed of methanol and any one solvent selected from anhydrous ethanol, dichloromethane, and ethyl acetate. More preferably, the solvent is methanol.

[0015] The inventors have verified through experiments that the co-amorphous material prepared by the solvent volatilization method has a high product yield and a simple process, and is most easily able to reach an amorphous state.

[0016] The syringic acid-rotundine drug-drug co-amorphous form provided by the present invention exhibited significantly improved water solubility of both components in equilibrium solubility experiments. Furthermore, the drug transdermal behavior of the syringic acid-rotundine drug-drug co-amorphous form provided by the present invention was significantly improved in in vitro transdermal permeation experiments.

[0017] Another object of the present invention is to provide a use of the carrier-free co-amorphous syringic acid-rotundine compound in the preparation of an oral medication, characterized in that the solubility of both syringic acid and rotundine in the co-amorphous compound is greater than that of syringic acid or rotundine in their non-amorphous state, thereby improving the in vivo dissolution and absorption of the medication. Also provided is a use of the carrier-free co-amorphous syringic acid-rotundine compound in the preparation of a topical medication, characterized in that the transdermal absorption of syringic acid and rotundine in the co-amorphous compound is greater than that of syringic acid or rotundine in their non-amorphous state, thereby improving the transdermal absorption of the medication. Furthermore, the medication is used for analgesia.

[0018] In summary, the inventors have unexpectedly discovered that syringic acid and rotundine can be prepared into a co-amorphous compound using only two active ingredients, without the use of any carrier, through a solvent volatilization method. This can significantly improve water solubility, far exceeding the solubility of syringic acid and rotundine alone in water. Furthermore, the co-amorphous compound can significantly improve the transdermal permeation behavior of the drug. Compared with the raw material drug and the physical mixture, the retention time and cumulative permeation amount of the co-amorphous compound are significantly improved. In short, after being prepared into a co-amorphous compound, syringic acid and rotundine produce a significant synergistic effect in their transdermal permeation behavior. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 Appearance images (first row), micrographs (second row), and polarized micrographs (third row) of the syringic acid API (a), the rotundine API (b), the syringic acid-rotundine (2:1) physical mixture (c), and the syringic acid-rotundine co-amorphous substance in Examples 1-10.

[0020] Figure 2 The following are appearance pictures (first row), micrographs (second row), and polarized micrographs (third row) of comparative examples 1-5.

[0021] Figure 3 The powder X-ray diffraction patterns of the co-amorphous form, the API, and the physical mixture of syringic acid and rotundine (2:1 / 1:1) in Example 1 and Example 2 are shown.

[0022] Figure 4 The differential scanning calorimeters of the co-amorphous body and the raw material in Example 1 and Example 2 are shown.

[0023] Figure 5 This is the Fourier transform infrared spectrum of the coamorphous form, the API, and the physical mixture of syringic acid and rotundine (2:1) in Example 1.

[0024] Figure 6 The saturated solubility bar graph of the coamorphous form, the API, and the physical mixture of syringic acid and rotundine (2:1) in Example 1 is shown.

[0025] Figure 7 The in vitro percutaneous cumulative permeation curves of the coamorphous form, the API, and the physical mixture of syringic acid and rotundine (2:1) in Example 1 are shown, including rotundine (A), syringic acid (B), and skin retention (C). Figure 8 This is the effect of oral administration, transdermal administration of the coamorphous form and oral administration of the raw material of Rotundine in Example 1 on the pain threshold of mice using the hot plate method. Specific embodiments

[0026] Example 1: Weigh appropriate amounts of syringic acid and rotundine (molar ratio of 2:1), mix and completely dissolve in methanol, recover the solvent under reduced pressure to reduce the volume to one-fourth, and evaporate the resulting concentrate to dryness at room temperature to obtain a syringic acid-rotundine co-amorphous compound (see attached Figure 1 d).

[0027] Example 2: Weigh appropriate amounts of syringic acid and rotundine (molar ratio of 1:1), mix them and completely dissolve them in methanol. Recover the solvent under reduced pressure to reduce the volume to one-fourth. The resulting concentrate is allowed to evaporate naturally at room temperature to obtain a syringic acid-rotundine co-amorphous compound (see attached Figure 1 e).

[0028] Example 3: Weigh appropriate amounts of syringic acid and rotundine (molar ratio of 2:1), mix them and completely dissolve them in ethanol. Recover the solvent under reduced pressure to reduce the volume to one-fourth. The resulting concentrate is allowed to evaporate naturally at room temperature to obtain a syringic acid-rotundine co-amorphous compound (see attached Figure 1 f).

[0029] Example 4: Weigh appropriate amounts of syringic acid and rotundine (molar ratio of 2:1), mix and completely dissolve in a mixed solvent of methanol and ethanol (9:1), recover the solvent under reduced pressure to reduce the volume to one-fourth, and evaporate the resulting concentrate to dryness at room temperature to obtain a syringic acid-rotundine co-amorphous compound (see attached). Figure 1 g).

[0030] Example 5: Weigh appropriate amounts of syringic acid and rotundine (molar ratio of 2:1), mix and completely dissolve in a mixed solvent of methanol and ethanol (1:1), recover the solvent under reduced pressure to reduce the volume to one-fourth, and evaporate the resulting concentrate to dryness at room temperature to obtain a syringic acid-rotundine co-amorphous compound (see attached Figure 1 h).

[0031] Example 6: Weigh appropriate amounts of syringic acid and rotundine (molar ratio of 2:1), mix and completely dissolve in a mixed solvent of methanol and ethanol (3:7), recover the solvent under reduced pressure to reduce the volume to one-fourth, and allow the resulting concentrate to evaporate naturally at room temperature to obtain a syringic acid-rotundine co-amorphous compound (see attached). Figure 1 i).

[0032] Example 7: Weigh appropriate amounts of syringic acid and rotundine (molar ratio of 2:1), mix and completely dissolve in a mixed solvent of methanol-ethyl acetate (1:1), recover the solvent under reduced pressure to reduce the volume to one-fourth, and evaporate the resulting concentrate to dryness at room temperature to obtain a syringic acid-rotundine co-amorphous compound (see attached). Figure 1 j).

[0033] Example 8: Appropriate amounts of syringic acid and rotundine (molar ratio of 2:1) were weighed, mixed, and completely dissolved in a mixed solvent of methanol and ethyl acetate (3:7). The solvent was recovered under reduced pressure to reduce the volume to one-fourth, and the resulting concentrate was naturally evaporated at room temperature to obtain a syringic acid-rotundine co-amorphous compound (see attached). Figure 1 k).

[0034] Example 9: Weigh appropriate amounts of syringic acid and rotundine (molar ratio of 2:1), mix and completely dissolve in a mixed solvent of methanol-dichloromethane (1:1), recover the solvent under reduced pressure to reduce the volume to one-fourth, and evaporate the resulting concentrate to dryness at room temperature to obtain a syringic acid-rotundine co-amorphous compound (see attached). Figure 1 l).

[0035] Example 10: Weigh appropriate amounts of syringic acid and rotundine (molar ratio of 2:1), mix and completely dissolve in a mixed solvent of methanol-dichloromethane (3:7), recover the solvent under reduced pressure to reduce the volume to one-fourth, and evaporate the resulting concentrate to dryness at room temperature to obtain a syringic acid-rotundine co-amorphous compound (see attached). Figure 1 m).

[0036] Example 11: Syringic acid API, Rotundine API, Syringic acid-Rotonidine (2:1) physical mixture, and the co-amorphous compound obtained in Example 1 were scanned using an X-ray powder diffraction analyzer. The measurement conditions were: scanning angle 2θ, step length 0.02°, scanning speed 2° / min, scanning range 5-90°, voltage 30 mA (see attached results). Figure 3 ). Figure 3 It shows that both groups of raw materials and physical mixtures have obvious characteristic diffraction peaks, while the product in Example 1 has no obvious characteristic diffraction peaks, indicating that the intermolecular interaction occurs, causing the crystal structure to change, proving that a co-amorphous substance is formed.

[0037] Example 12: 5 mg of syringic acid API, rotundine API and the co-amorphous obtained in Example 1 were placed in an aluminum crucible, and an empty aluminum crucible was used as a reference. The temperature was raised at a rate of 10°C / min in the range of 50-250°C, and differential scanning calorimetry analysis was performed (see the attached results). Figure 4 ). Figure 4 It is shown that the product in Example 1 has no obvious characteristic endothermic and exothermic peaks, and has thermodynamic behaviors different from those of single APIs and physical mixtures. Since the co-amorphous body is a single-phase amorphous binary system, its internal structure is long-range disordered, which results in it not undergoing obvious phase transition and melting point phenomena at a specific temperature like crystals during the heating process, further verifying the above conclusion that a co-amorphous body is formed.

[0038] Example 13: Syringic acid API, Rotundine API, Syringic acid-Rotonidine (2:1) physical mixture and the amorphous compound obtained in Example 1 were ground evenly with dried potassium bromide, pressed into transparent sheets, and measured in an infrared spectrometer at 4000-400 cm -1 The results are shown in the attached Figure 5 ). Figure 5 The co-amorphous material formed in Example 1 has the peaks at 1698.3, 1557.4, and 1231.2 cm -1 There is a significant shift in the characteristic absorption spectrum of the active pharmaceutical ingredient at the position, indicating the existence of intermolecular interaction.

[0039] Example 14: 1 mL of deionized water was placed in a 2 mL centrifuge tube, and an excess of syringic acid API, rotundine API, syringic acid-rotundine (2:1) physical mixture, and the co-amorphous material obtained in Example 1 were added to the tube, sealed, and shaken at 37°C and 120 rpm for 48 h. After completion, the tube was centrifuged at 4000 rpm / min for 10 min. After completion, the supernatant was immediately taken and appropriately diluted for HPLC determination (see the attached results). Figure 6 ). Figure 6 The solubility of syringic acid and rotundine in the co-amorphous form was significantly higher than that of the corresponding API. The solubility of syringic acid in the co-amorphous form was 7.6 times higher than that of the API. The solubility of rotundine in the co-amorphous form was 763 times higher than that of the API. (* indicates P < 0.05 for the API compared to the physical mixture; # indicates P < 0.05 for the API compared to the co-amorphous form).

[0040] Example 15: Syringic acid API, Rotundine API, syringic acid-rotundine (2:1) physical mixture, and the co-amorphous compound obtained in Example 1 were dissolved in deionized water to obtain 2% solutions and suspensions, respectively. A transdermal diffusion tester was used, with the upper chamber serving as the supply reservoir and the lower chamber as the receiving reservoir, and an effective diffusion area of ​​2.27 cm. 2 , (37±0.5)℃ constant temperature water bath, and magnetic constant stirring at 120r / min. The frozen mouse abdominal skin was taken out and thawed, fixed between the two chambers, with the stratum corneum facing up and sealed, a magnetic rotor was placed in the receiving pool, and ethanol-PEG400-normal saline (3:2:5) was added to allow the dermis to fully contact the receiving fluid, remove the bubbles, and add 1mL of the sample to be tested to the supply pool. 1.5mL of receiving fluid was taken out at 0.5, 1, 2, 4, 6, 8, 10, and 12 o'clock, respectively, and an equal amount of fresh receiving medium was added at the same time. The taken out receiving fluid was filtered through a 0.22μm microporous filter membrane, and the content was determined by HPLC. The in vitro cumulative permeation curve was drawn (see the attached results). Figure 7 ) and calculate the cumulative permeation (Q 12 ,μg.cm -2), steady-state permeation rate (Js, μg.cm -2 .h -1 ) and parameters such as permeability enhancement factor ER.

[0041] Table 1 Skin penetration parameters of different groups (n=6) equation <![CDATA[Js （μg.cm -2 .h -1 ） ]]> <![CDATA[T lg(h) ]]> <![CDATA[Q 12(μg•cm -2 ) ]]> ER <![CDATA[Qs (μg•cm -2 ) ]]> SA <![CDATA[Q n =253.18t+437.03]]> 253.18 1.73 3131.49±249.93 1 41.39±21.94 CAM-SA <h2 style=";text-align:left;direction:ltr"><![CDATA[Q <h2 style=";text-align:left;direction:ltr"> n <h2 style=";text-align:left;direction:ltr"> =219.89t+622.19]]><h2 style=";text-align:left;direction:ltr"> 219.89 2.83 3001.12±147.22 0.96 21.82±10.44 PM-SA <h2 style=";text-align:left;direction:ltr"><![CDATA[Q <h2 style=";text-align:left;direction:ltr"> n <h2 style=";text-align:left;direction:ltr"> =139.94t-5.56]]><h2 style=";text-align:left;direction:ltr"> 139.94 0.04 1561.23±360.16 0.50 49.07±10.82 RTD <![CDATA[Q n =16.86t-27.11]]> 16.86 1.61 193.15±58.11 1 10.34±5.25 CAM-RTD <h2 style=";text-align:left;direction:ltr"><![CDATA[Q <h2 style=";text-align:left;direction:ltr"> n <h2 style=";text-align:left;direction:ltr"> =175.96t+218.94]]><h2 style=";text-align:left;direction:ltr"> 175.96 1.24 2198.92±234.22 11.38 14.91±4.35 PM-RTD <![CDATA[Q n =66.26t-40.91]]> 66.26 0.62 722.14±191.86 3.74 30.74±21.19

[0042] Among them: SA is the syringic acid raw material; CAM-SA is the syringic acid in the co-amorphous material; PM-SA is the syringic acid in the physical mixture; RTD is the rotundine raw material; CAM-RTD is the rotundine in the co-amorphous material; PM-RTD is the rotundine in the physical mixture.

[0043] The results showed that the cumulative permeation of RTD in CAM over 12 hours was much higher than that of RTD and RTD in PM. The cumulative permeation of RTA in PM also significantly increased compared to RTD. SA, due to its inherently good skin permeability, showed a slight increase in its cumulative permeation in CAM compared to SA in the early stages. These results indicate that the combination of the two drugs in a co-amorphous form has a synergistic permeation-enhancing effect.

[0044] Example 16: Female Kunming mice (weighing 20±2 g) were used to establish a hot plate analgesia model. The animals were placed on a constant temperature (55±0.5)°C intelligent hot plate instrument. Licking the hind paw was used as an indicator of pain response. Baseline pain thresholds were measured three times at 5-minute intervals. Individuals with abnormal thresholds (<5 s or >30 s) were excluded. Qualified mice were randomly divided into three groups (n=12). The chest and abdomen of the mice were depilated before the experiment. After three days of acclimatization, they were fasted for 12 hours before dosing (with free access to water). The dosing schedule for each group was as follows: the oral rotundine group received the rotundine API by oral gavage; the oral CAM group received the co-amorphous compound obtained in Example 1 by oral gavage; the transdermal CAM group received the co-amorphous compound obtained in Example 1 loaded with sodium carboxymethylcellulose gel (1%); and the negative control group received sodium carboxymethylcellulose gel (1%). Dosing was performed once daily for three consecutive days. Pain thresholds were measured 1, 2, 4, 6, 8, 10, and 12 h after the last administration. The paw licking reaction time was recorded using an EVB-YLS hot plate instrument (temperature accuracy ±0.5°C). The maximum observation time was set to 60 s, and no reaction was counted as 60 s. The experimental results are detailed in Table 2 and the Appendix. Figure 8 .

[0045] Table 2 Effects of transdermal drug administration on the pain threshold of mice using the hot plate method (n=12)

[0046] Note: * P < 0.05 compared with negative control; # P < 0.05 compared with oral rotundine by one-way ANOVA.

[0047] The results showed that the transdermal CAM gel group showed significant analgesic effect 1 hour after administration (30.00±7.60 s, P<0.05 vs negative control group), and the drug effect lasted until 12 hours (20.37±4.49 s, P<0.05 vs negative control group). The oral Rotundine group reached the maximum analgesic effect two hours after administration, and there was no significant difference with the negative control 6 hours after administration.

[0048] The present application also conducted the following experiment, which is given here as a comparative example:

[0049] Comparative Example 1: Weigh appropriate amounts of syringic acid and rotundine (molar ratio of 1:2), mix them and completely dissolve them in methanol, recover the solvent under reduced pressure to reduce the volume to one-fourth, and naturally evaporate the resulting concentrate at room temperature to obtain no syringic acid-rotundine co-amorphous compound (see attached Figure 2 a).

[0050] Comparative Example 2: Weigh appropriate amounts of syringic acid and rotundine (molar ratio of 1:3), mix and completely dissolve in methanol, recover the solvent under reduced pressure to reduce the volume to one-fourth, and naturally evaporate the resulting concentrate at room temperature to obtain no syringic acid-rotundine co-amorphous compound (see attached Figure 2 b).

[0051] Comparative Example 3: Weigh appropriate amounts of syringic acid and rotundine (molar ratio 3:1), mix and completely dissolve in methanol, recover the solvent under reduced pressure to reduce the volume to one-fourth, and naturally evaporate the resulting concentrate at room temperature to obtain no syringic acid-rotundine co-amorphous compound (see attached Figure 2 c).

[0052] Comparative Example 4: Weigh appropriate amounts of syringic acid and rotundine (molar ratio 4:1), mix and completely dissolve in methanol, recover the solvent under reduced pressure to reduce the volume to one-fourth, and naturally evaporate the resulting concentrate at room temperature to obtain no syringic acid-rotundine co-amorphous compound (see attached Figure 2 d).

[0053] Comparative Example 5: Weigh appropriate amounts of syringic acid and rotundine (molar ratio of 2:1), mix and grind until the drugs are fully dispersed. A small amount of methanol solution can be added during this process. After grinding and evaporation, no syringic acid-rotundine co-amorphous compound is obtained (see attached Figure 2 e).

[0054] The above are merely preferred embodiments of the present invention. It should be noted that the above preferred embodiments should not be construed as limiting the present invention, and the scope of protection of the present invention should be determined by the scope defined in the claims. Persons skilled in the art will appreciate that improvements and modifications may be made without departing from the spirit and scope of the present invention, and such improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A carrier-free co-amorphous compound of syringic acid and rotundine, characterized in that: The amorphous substance consists of syringic acid and rotundine, wherein the molar ratio of syringic acid to rotundine is 1:1 to 2:

1.

2. The carrier-free co-amorphous syringic acid-rotundine according to claim 1, characterized in that: The molar ratio of syringic acid to rotundine is 2:

1.

3. The carrier-free co-amorphous compound of syringic acid and rotundine according to claim 1, characterized in that: It is amorphous, has no birefringence under a polarizing microscope, and its characteristic peak disappears and no new characteristic diffraction peak appears on a powder X-ray diffractometer.

4. A method for preparing the carrier-free co-amorphous syringic acid-rotundine according to claim 1, characterized in that: The preparation method is prepared by a solvent evaporation method, that is, syringic acid and rotundine are dispersed in a solvent in proportion, and after the drugs are completely dissolved, the solvent is removed to obtain the product.

5. The method for preparing the carrier-free co-amorphous syringic acid-rotundine according to claim 4, characterized in that: The solvent is: 1) Methanol, anhydrous ethanol or a mixture of the two; or 2) A mixed solvent consisting of methanol and an organic solvent other than anhydrous ethanol, wherein the methanol content is not less than 30%; or 3) A mixed solvent consisting of anhydrous ethanol and an organic solvent other than methanol, wherein the content of anhydrous ethanol is not less than 30%; The other organic solvents are one or more of propanol, butanol, ethyl acetate, dichloromethane, acetone, butanone, ether, tetrahydrofuran, acetonitrile, and trifluoroacetic acid.

6. The method for preparing the carrier-free co-amorphous syringic acid-rotundine according to claim 5, characterized in that: The other organic solvents are ethyl acetate and dichloromethane.

7. Use of the carrier-free co-amorphous syringic acid-rotundine according to any one of claims 1 to 3 in the preparation of an oral medicament, characterized in that: The solubility of syringic acid and rotundine in the co-amorphous material is greater than that of syringic acid or rotundine in the non-amorphous material state, thereby improving the in vivo dissolution and absorption of the drug.

8. Use of the carrier-free co-amorphous syringic acid-rotundine according to any one of claims 1 to 3 in the preparation of an external-use medicine, characterized in that: The transdermal absorption performance of syringic acid and rotundine in the co-amorphous material is greater than that of syringic acid or rotundine in the non-amorphous material state, thereby improving the transdermal absorption of the drug.

9. The use according to claim 7 or 8, characterized in that: The drug is used to relieve pain.

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