CN110016022A - A kind of palmatine hydrochloride-naringenin drug co-crystal with sustained release effect - Google Patents

Abstract

The invention discloses a palmatine hydrochloride-naringenin drug co-crystal with sustained-release effect, belonging to the technical field of drug crystallization. The structural unit of the drug co-crystal contains palmatine hydrochloride molecule and naringenin molecule, the molar ratio between the two is 1:1, and the molecular formula is [C ₂₁ H ₂₂ ClNO ₄ ]·[C ₁₅ H ₁₂ O ₅ ]. In the present invention, palmatine hydrochloride and naringenin are mixed in proportion, and the palmatine hydrochloride drug co-crystal is formed by solvent evaporation, stirring or grinding. The preparation method of the invention is simple and easy to implement, and the yield of the co-crystal is high; and the prepared palmatine hydrochloride-naringenin drug co-crystal has no hygroscopicity, high thermal stability and light stability, and has the advantages of high thermal stability and light stability for palmatine hydrochloride. The sustained-release effect can be used to develop its application in palmatine hydrochloride sustained-release preparations.

Description

A kind of palmatine hydrochloride-naringenin drug co-crystal with sustained release effect

technical field

The invention belongs to the technical field of drug crystallization, in particular to a palmatine hydrochloride-naringenin drug co-crystal with sustained-release effect.

Background technique

Palmatine hydrochloride (patinarin) is an important isowaline alkaloid, which is an active ingredient in traditional Chinese medicine Huang vine. It has anti-inflammatory and broad-spectrum antibacterial effects, and is known as "natural plant antibiotics". Clinically, palmatine hydrochloride is mainly used for the treatment of enteritis, bacillary dysentery, respiratory and urinary tract infections, gynecological inflammation, surgical infection and conjunctivitis. Recent studies have shown that palmatine hydrochloride also has significant pharmacological activities such as anti-tumor, anti-depression and anti-Alzheimer's disease (BBA-Gen. Subjects, 2018, 1862, 1565-1575.). Although palmatine hydrochloride has high medicinal value, its medicinal properties are limited due to its own shortcomings. First of all, palmatine hydrochloride has strong hygroscopicity, and under different humidity, the number of crystal water in the molecule will change, resulting in poor humidity stability. Secondly, although palmatine hydrochloride has good water solubility, it is not easy to permeate through biofilms, so its gastrointestinal absorption is poor, and its oral bioavailability is low. In addition, pharmacokinetic data show that palmatine hydrochloride has a short in vivo half-life and large fluctuations in plasma concentrations. Therefore, the development of a new solid preparation of palmatine hydrochloride with low hygroscopicity, easy absorption and sustained release has become a research hotspot.

Naringenin is a dihydroflavonoid compound with anti-inflammatory, antibacterial, antioxidant, hypolipidemic, antitussive, protective liver function, prevention and treatment of aortic dissection, anti-platelet aggregation, anti-tumor, protection of brain damage and anti-Alz A variety of pharmacological activities such as hammer's disease. However, due to its poor water solubility and fat solubility, poor absorption in vivo and low oral bioavailability limit its clinical application.

Drug co-crystal is a new type of drug solid form, which is a crystal formed by non-covalent bonds such as hydrogen bonds and other active pharmaceutical ingredients and other physiologically acceptable co-crystal formers in a certain stoichiometric ratio. Drug co-crystals can improve the physical and chemical properties of drugs such as solubility, dissolution, bioavailability and stability without changing the molecular structure of drugs, and have a very positive effect on the development of oral pharmaceutical preparations (Chem. Commun., 2016 , 52, 8342-8360. ).

In summary, the co-crystallization of palmatine hydrochloride with better water solubility and naringenin, which is insoluble in water, is expected to balance the water solubility of palmatine hydrochloride and naringenin, that is, reduce the solubility and dissolution of palmatine hydrochloride. The solubility and dissolution rate of naringenin are improved while the rate achieves the sustained release effect. Taking advantage of the non-hygroscopic properties of naringenin, it is also expected to reduce the hygroscopicity of palmatine hydrochloride and improve its humidity stability. In addition, given that palmatine hydrochloride and naringenin have many similar pharmacological activities, from the perspective of the synergistic effect of drug combination, the formation of drug-drug co-crystals has important clinical application value.

At present, there is no public report on the drug-drug co-crystal of palmatine hydrochloride and naringenin.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a palmatine hydrochloride-naringenin drug co-crystal with sustained-release effect. The palmatine hydrochloride drug co-crystal crystal structure of the invention is clear, contains two medicinal active ingredients of palmatine hydrochloride and naringenin at the same time, and has high thermal stability, light stability and humidity stability. The dissolution rate of palmatine hydrochloride in the co-crystal is significantly lower than that of pure palmatine hydrochloride, and has an obvious sustained-release effect. To achieve the above object, the present invention adopts the following technical solutions:

A palmatine hydrochloride-naringenin drug co-crystal with sustained-release effect is characterized in that: its X-ray powder diffraction (Cu Kα radiation) pattern, at the diffraction angle 2θ°±0.2 is: 6.1, 7.7, 10.0, 12.4, 12.9, 13.6, 14.7, 15.3, 15.8, 16.7, 17.2, 17.9, 18.2, 19.0, 19.7, 19.8, 20.2, 20.6, 21.2, 21.3, 22.3, 22.8, 23.1, 23.4, 23.9, 24.2, 24.7 There are characteristic diffraction peaks at 25.5, 26.2, 27.6, 29.9, 30.6, 31.2, 31.6, 32.0, 34.0, 36.0, and 36.9.

The above-mentioned palmatine hydrochloride-naringenin drug co-crystal with sustained-release effect comprises a palmatine hydrochloride molecule and a naringenin molecule in its structural unit, and the molar ratio between the two is 1:1. The eutectic belongs to the triclinic system, space group P-1, and the unit cell parameters are: a = 7.8611(4) Å, b = 14.3547(6) Å, c = 14.4770(6) Å, α = 74.534(4) º , β = 86.337(4) º , γ = 74.321(4) º , V = 1515.84(12) Å ³ , Z = 2, D _c = 1.446 g/cm ³ , the formula is [C ₂₁ H ₂₂ ClNO ₄ ] • [C ₁₅ H ₁₂ O ₅ ].

In the above-mentioned palmatine hydrochloride drug co-crystal with sustained-release effect, palmatine hydrochloride and naringenin molecules are combined together through the hydrogen bond between the hydroxyl group of naringenin and the chloride ion of palmatine hydrochloride. The naringenin molecule and the chloride ion in palmatine hydrochloride were assembled into a supramolecular layered structure, and the palmatine cation was uniformly distributed between the supramolecular layer formed by the naringenin molecule and the chloride ion.

The above-mentioned palmatine hydrochloride-naringenin drug co-crystal with sustained-release effect, the crystal color is orange-yellow; measured by differential scanning calorimetry, it has a melting peak between 210-240 ℃, and the peak temperature is 227 ℃; under the condition of 25 ℃, 95%RH, the weight percentage of the absorbed moisture is 0.4%.

A preparation method of palmatine hydrochloride-naringenin drug co-crystal with sustained-release effect is as follows: palmatine hydrochloride and naringenin are completely dissolved in an organic solvent at a molar ratio of 1:1 to prepare a mixed solution, After the mixed solution is evaporated to dryness, the palmatine hydrochloride-naringenin drug co-crystal with sustained-release effect is obtained; or the palmatine hydrochloride and naringenin are mixed in an organic solvent with a molar ratio of 1:1, and after sealing Stirring at room temperature, gained precipitation obtains the palmatine hydrochloride-naringenin drug co-crystal with slow-release effect after filtration, washing, and drying; Or palmatine hydrochloride and naringenin are 1 with mol ratio: 1 Put it in a grinding jar after mixing, add an organic solvent and grind to obtain a palmatine hydrochloride-naringenin drug co-crystal with slow-release effect.

In the above preparation method, the organic solvent is one or a mixture of ethanol, methanol, acetone, ethyl acetate and acetonitrile.

A palmatine hydrochloride-naringenin drug co-crystal with sustained-release effect has sustained-release effect on palmatine hydrochloride in simulated gastric juice and simulated intestinal juice.

A palmatine hydrochloride-naringenin drug co-crystal with sustained-release effect is used in palmatine hydrochloride sustained-release preparations.

The significant advantages of the present invention are:

(1) The palmatine hydrochloride-naringenin drug co-crystal is prepared for the first time by this method. The preparation method is simple and easy to implement, the crystal structure is clear, and it contains two medicinal active components, palmatine hydrochloride and naringenin.

(2) In the palmatine hydrochloride-naringenin drug co-crystal, the palmatine hydrochloride and naringenin molecules are combined through the hydrogen bond between the hydroxyl group of naringenin and the chloride ion of palmatine hydrochloride. The naringenin molecule and the chloride ion in palmatine hydrochloride are assembled into a supramolecular layered structure, and the palmatine cation is uniformly distributed between the supramolecular layer formed by the naringenin molecule and the chloride ion. This special structure makes the At 25 ℃ and 95 % RH, the weight percentage of adsorbed moisture is only 0.4%, that is, no hygroscopicity. The eutectic was stored at 60°C (60% RH, no light) for 20 days, 90% RH (25°C, no light) for 20 days, light intensity 6000 Lx (40°C, 75% RH) After 10 days, no crystal transformation occurred, indicating that the cocrystal has excellent thermal stability, light stability and humidity stability.

(3) The special crystal structure of the palmatine hydrochloride-naringenin drug co-crystal significantly reduces the dissolution rate of palmatine hydrochloride, that is, naringenin acts as a sustained-release carrier.

Description of drawings

1 is an X-ray powder diffraction (XRD) pattern of the palmatine hydrochloride-naringenin drug co-crystal prepared in Example 1.

2 is the crystal structure unit of the palmatine hydrochloride-naringenin drug co-crystal prepared in Example 1.

3 is the stacking mode of palmatine hydrochloride molecules and naringenin molecules in the unit cell in the palmatine hydrochloride-naringenin drug co-crystal prepared in Example 1.

4 is a differential scanning calorimetry (DSC) diagram of the palmatine hydrochloride-naringenin drug co-crystal prepared in Example 1.

Figure 5 is the dynamic water vapor adsorption (DVS) diagram of the palmatine hydrochloride-naringenin drug co-crystal prepared in Example 1 at 25 °C.

Figure 6 is the XRD pattern of the palmatine hydrochloride-naringenin drug co-crystal prepared in Example 1 after being stored at 60 °C (60% RH, no light) for 20 days.

7 is the XRD pattern of the palmatine hydrochloride-naringenin drug co-crystal prepared in Example 1 after being stored for 20 days under 90% RH relative humidity (temperature 25° C., no light).

Figure 8 is the XRD pattern of the palmatine hydrochloride-naringenin drug co-crystal prepared in Example 1 after being stored for 10 days at a light intensity of 6000 Lx (temperature 40°C, humidity 75%).

Figure 9 is the dissolution curve of palmatine hydrochloride, naringenin and the palmatine hydrochloride-naringenin drug co-crystal prepared in Example 1 in simulated gastric juice (pH=1.2 hydrochloric acid solution).

Figure 10 shows the dissolution curves of palmatine hydrochloride, naringenin and the palmatine hydrochloride-naringenin drug co-crystal prepared in Example 1 in simulated intestinal fluid (pH=6.8 phosphate solution).

11 is the XRD pattern of the palmatine hydrochloride-naringenin drug co-crystal prepared in Example 2.

12 is the XRD pattern of the palmatine hydrochloride-naringenin drug co-crystal prepared in Example 3.

13 is the XRD pattern of the palmatine hydrochloride-naringenin drug co-crystal prepared in Example 4.

14 is the XRD pattern of the palmatine hydrochloride-naringenin drug co-crystal prepared in Example 5.

15 is the XRD pattern of the palmatine hydrochloride-naringenin drug co-crystal prepared in Example 6.

16 is the XRD pattern of the palmatine hydrochloride-naringenin drug co-crystal prepared in Example 7.

Detailed ways

In order to make the content of the present invention easier to understand, the technical solutions of the present invention will be further described below with reference to specific embodiments, but the present invention is not limited thereto.

Example 1

0.3 mmol palmatine hydrochloride and 0.3 mmol naringenin were completely dissolved in 200 mL of absolute ethanol to prepare a mixed solution; the above mixed solution was placed in a room temperature environment to naturally volatilize and dry to obtain palmatine hydrochloride with sustained-release effect. Tintin-naringenin drug co-crystal.

Fig. 1 is the XRD pattern of the palmatine hydrochloride-naringenin drug co-crystal prepared in this example. As shown in Figure 1, the prepared drug co-crystals at the diffraction angle 2θ° ± 0.2 are: 6.1, 7.7, 10.0, 12.4, 12.9, 13.6, 14.7, 15.3, 15.8, 16.7, 17.2, 17.9, 18.2, 19.0, Features at 19.7, 19.8, 20.2, 20.6, 21.2, 21.3, 22.3, 22.8, 23.1, 23.4, 23.9, 24.2, 24.7, 25.5, 26.2, 27.6, 29.9, 30.6, 31.2, 31.6, 32.0, 34.0, 36.0, 36.9 Diffraction peaks.

Figure 2 is the crystal structure unit of the palmatine hydrochloride-naringenin drug co-crystal prepared in this example. As can be seen from Figure 2, the prepared drug co-crystal includes palmatine cation, chloride ion and naringenin neutral molecule in its structural unit, and the molar ratio between them is 1:1:1. Palmatine hydrochloride and naringenin are bound together by hydrogen bonding between the hydroxyl groups of naringenin and chloride ions.

Figure 3 is the stacking mode of palmatine hydrochloride molecules and naringenin molecules in the unit cell in the palmatine hydrochloride-naringenin drug co-crystal prepared in this example. As shown in Figure 3, naringenin molecules and chloride ions in palmatine hydrochloride are assembled into a supramolecular layered structure, and palmatine cations are uniformly distributed between the supramolecular layers formed by naringenin molecules and chloride ions.

Figure 4 is the DSC chart of the palmatine hydrochloride-naringenin drug co-crystal prepared in this example. It can be seen from Figure 4 that the palmatine hydrochloride-naringenin drug co-crystal has a melting peak between 210 and 240 °C, and the peak temperature is 227 °C.

Figure 5 is the DVS diagram of palmatine hydrochloride and the palmatine hydrochloride-naringenin drug co-crystal prepared in this example at 25°C. It can be seen from FIG. 5 that the weight percentage of the water adsorbed by the palmatine hydrochloride-naringenin drug co-crystal is only 0.4%, that is, there is no hygroscopicity.

Figure 6 is the XRD pattern of the palmatine hydrochloride-naringenin drug co-crystal prepared in this example after being stored at 60°C (60% RH, no light) for 20 days. It can be seen from Figure 6 that all diffraction peak angles of the palmatine hydrochloride-naringenin drug co-crystal remain unchanged after 20 days at 60 °C, indicating that the co-crystal has excellent thermal stability.

Fig. 7 is the XRD pattern of the palmatine hydrochloride-naringenin drug co-crystal prepared in the present embodiment after being stored for 20 days under 90% RH relative humidity (temperature 25°C, no light). It is known from Figure 7 that after storage for 20 days under 90% RH relative humidity, all diffraction peak angles of the palmatine hydrochloride-naringenin drug co-crystal remain unchanged, indicating that the co-crystal has excellent humidity stability.

Figure 8 is the XRD pattern of the palmatine hydrochloride-naringenin drug co-crystal prepared in this example after being stored for 10 days at a light intensity of 6000 Lx (temperature 40°C, humidity 75%). It can be seen from Figure 8 that all diffraction peak angles of the palmatine hydrochloride-naringenin drug co-crystal remain unchanged after being stored for 10 days at 6000 Lx light intensity, indicating that the co-crystal has excellent photostability.

Figure 9 shows the dissolution profiles of palmatine hydrochloride, naringenin and palmatine hydrochloride-naringenin drug co-crystals in simulated gastric juice (pH = 1.2 hydrochloric acid solution). As can be seen from Figure 9, compared with palmatine hydrochloride, the dissolution rate of palmatine hydrochloride in the palmatine hydrochloride-naringenin drug co-crystal in the simulated gastric juice was significantly reduced, and the dissolution rate reached 97% after 6 hours. It shows that naringenin plays a role in controlling the sustained release of palmatine hydrochloride. This is related to the structure that palmatine is wrapped by the supramolecular layer formed by naringenin molecules and chloride ions shown in Figure 3. It can also be seen from Figure 9 that, compared with naringenin, the dissolution rate of naringenin in the palmatine hydrochloride-naringenin drug co-crystal is significantly increased, which is also similar to the palmatine hydrochloride and naringenin shown in Figure 3. It is related to the layered packing structure of naringenin, that is, the introduction of palmatine reduces the density of naringenin molecular packing.

Figure 10 shows the dissolution curves of palmatine hydrochloride, naringenin and palmatine hydrochloride-naringenin drug co-crystals in simulated intestinal fluid (pH=6.8 phosphate solution). As shown in Figure 10, compared with palmatine hydrochloride, the dissolution rate of palmatine hydrochloride in the palmatine hydrochloride-naringenin drug co-crystal in intestinal fluid is also significantly reduced, and the dissolution rate only reaches 62% after 24 hours. It shows that naringenin also has a sustained-release effect on palmatine hydrochloride in simulated intestinal fluid.

Example 2

Put 0.3 mmol palmatine hydrochloride and 0.3 mmol naringenin into 5 mL of absolute ethanol and mix, seal the beaker containing the mixture, and stir at room temperature for 48 hours. The obtained precipitate is filtered, washed with a small amount of ethanol, and dried in the air. The palmatine hydrochloride-naringenin drug co-crystal with sustained-release effect is obtained.

Figure 11 is the XRD pattern of the palmatine hydrochloride-naringenin drug co-crystal prepared in this example. It can be seen from Figure 11 that the palmatine hydrochloride-naringenin drug co-crystal prepared in this example has peaks at the same 2θ angle as Example 1, indicating that the two have the same crystal structure.

Example 3

Put 0.3 mmol of palmatine hydrochloride and 0.3 mmol of naringenin into 5 mL of methanol and mix, seal the beaker containing the mixture and stir at room temperature for 48 hours. The obtained precipitate is filtered, washed with a small amount of methanol, and dried to obtain a Sustained release palmatine hydrochloride-naringenin drug co-crystal.

Figure 12 is the XRD pattern of the palmatine hydrochloride-naringenin drug co-crystal prepared in this example. It can be seen from FIG. 12 that the palmatine hydrochloride-naringenin drug co-crystal prepared in this example has peaks at the same 2θ angle as Example 1, indicating that the two have the same crystal structure.

Example 4

Put 0.3 mmol palmatine hydrochloride and 0.3 mmol naringenin into 5 mL of acetone and mix, seal the beaker containing the mixture, and stir at room temperature for 48 hours. The obtained precipitate is filtered, washed with a small amount of acetone, and dried to obtain a Sustained release palmatine hydrochloride-naringenin drug co-crystal.

Figure 13 is the XRD pattern of the palmatine hydrochloride-naringenin drug co-crystal prepared in this example. It can be seen from Figure 13 that the palmatine hydrochloride-naringenin drug co-crystal prepared in this example has peaks at the same 2θ angle as Example 1, indicating that the two have the same crystal structure.

Example 5

Put 0.3 mmol palmatine hydrochloride and 0.3 mmol naringenin into 5 mL of ethyl acetate and mix, seal the beaker containing the mixture, and stir at room temperature for 48 hours. After drying, palmatine hydrochloride-naringenin drug co-crystal with sustained release effect is obtained.

Figure 14 is the XRD pattern of the palmatine hydrochloride-naringenin drug co-crystal prepared in this example. It can be seen from Figure 14 that the palmatine hydrochloride-naringenin drug co-crystal prepared in this example has peaks at the same 2θ angle as Example 1, indicating that the two have the same crystal structure.

Example 6

Put 0.3 mmol of palmatine hydrochloride and 0.3 mmol of naringenin into 5 mL of acetonitrile and mix, seal the beaker containing the mixture, and stir at room temperature for 48 hours. The obtained precipitate is filtered, washed with a small amount of acetonitrile, and dried to obtain a Sustained release palmatine hydrochloride-naringenin drug co-crystal.

Figure 15 is the XRD pattern of the palmatine hydrochloride-naringenin drug co-crystal prepared in this example. It can be seen from Figure 15 that the palmatine hydrochloride-naringenin drug co-crystal prepared in this example has peaks at the same 2θ angle as Example 1, indicating that the two have the same crystal structure.

Example 7

Put 0.3 mmol of palmatine hydrochloride and 0.3 mmol of naringenin in a grinding jar, add 100 μL of absolute ethanol, and grind for 30 minutes to obtain a palmatine hydrochloride-naringenin drug co-crystal with sustained-release effect.

Figure 16 is the XRD pattern of the palmatine hydrochloride-naringenin drug co-crystal prepared in this example. It can be seen from Figure 16 that the palmatine hydrochloride-naringenin drug co-crystal prepared in this example has peaks at the same 2θ angle as Example 1, indicating that the two have the same crystal structure.

The above descriptions are only preferred embodiments of the present invention, and all equivalent changes and modifications made according to the scope of the patent application of the present invention shall fall within the scope of the present invention.

Claims (8)

1. a palmatine hydrochloride-naringenin drug co-crystal with sustained-release effect, is characterized in that: its X-ray powder diffraction pattern is at diffraction angle 2 θ ° ± 0.2: 6.1, 7.7, 10.0, 12.4 , 12.9, 13.6, 14.7, 15.3, 15.8, 16.7, 17.2, 17.9, 18.2, 19.0, 19.7, 19.8, 20.2, 20.6, 21.2, 21.3, 22.3, 22.8, 23.1, 23.4, 23.9, 24.2, 24.7, 25.5, 26.2 , 27.6, 29.9, 30.6, 31.2, 31.6, 32.0, 34.0, 36.0, 36.9 have characteristic diffraction peaks; Described palmatine hydrochloride-naringenin drug co-crystal, its structural unit comprises palmatine hydrochloride molecule and naringenin molecule, and the molar ratio between the two is 1:1; the co-crystal belongs to triclinic crystal system, P-1 space group, unit cell parameters are: a = 7.8611(4) Å, b = 14.3547(6) Å, c = 14.4770(6) Å, α = 74.534(4) º , β = 86.337(4 ) º , γ = 74.321(4) º , V = 1515.84(12) Å ³ , Z = 2, D _c = 1.446 g/cm ³ , the molecular formula is [C ₂₁ H ₂₂ ClNO ₄ ]·[C ₁₅ H ₁₂ O ₅ ]. 2. the palmatine hydrochloride-naringenin drug co-crystal with sustained-release effect according to claim 1, is characterized in that: described palmatine hydrochloride molecule and naringenin molecule pass through the hydroxyl group of naringenin and hydrochloric acid The hydrogen bonds between the chloride ions of palmatine combine together, the naringenin molecule and the chloride ion in palmatine hydrochloride assemble into a supramolecular layered structure, and the palmatine cations are evenly distributed in the naringenin molecule and the chloride between supramolecular layers formed by ions. 3. the palmatine hydrochloride-naringenin drug co-crystal with sustained-release effect according to claim 1, is characterized in that: the drug co-crystal color is orange-yellow; There is a melting peak between 210-240 ℃, The peak temperature is 227 °C; under the condition of 25 °C and 95% relative humidity, the weight percentage of the adsorbed water is 0.4%. 4. the preparation method of the palmatine hydrochloride-naringenin drug co-crystal with slow-release effect as claimed in claim 1, it is characterized in that: palmatine hydrochloride and naringenin are 1 with mol ratio: 1. Completely dissolve in an organic solvent to obtain a mixed solution; evaporate the mixed solution to dryness to obtain a palmatine hydrochloride-naringenin drug co-crystal. 5. a preparation method of the palmatine hydrochloride-naringenin drug co-crystal with sustained-release effect as claimed in claim 1, is characterized in that: palmatine hydrochloride and naringenin are 1 with mol ratio: 1 Mix in an organic solvent, seal and stir at room temperature, and the obtained precipitate is filtered, washed and air-dried to obtain palmatine hydrochloride-naringenin drug co-crystal. 6. a preparation method of the palmatine hydrochloride-naringenin drug co-crystal with sustained-release effect as claimed in claim 1, is characterized in that: palmatine hydrochloride and naringenin are 1 with mol ratio: 1 Put it in a grinding tank after mixing, add an organic solvent and grind to obtain a palmatine hydrochloride-naringenin drug co-crystal. 7. the preparation method of palmatine hydrochloride-naringenin drug co-crystal according to any one of claims 4～6, is characterized in that: described organic solvent is in ethanol, methyl alcohol, acetone, ethyl acetate, acetonitrile one or a mixture of several. 8. A palmatine hydrochloride-naringenin drug co-crystal with sustained-release effect as claimed in claim 1, application in palmatine hydrochloride sustained-release preparation.