A water-soluble paeonol derivative and preparation method thereof

Abstract

The present invention discloses a water-soluble paeonol derivative and a preparation method thereof, comprising the following steps: step 1, adding a certain amount of commercial paeonol powder into a container and dispersing it with water in proportion; adding a certain amount of silane coupling agent in proportion at reflux temperature; cooling to room temperature after refluxing for 3 to 10 hours; centrifuging, washing, and drying at room temperature to obtain a paeonol-grafted silane coupling agent; step 2, taking a certain amount of the paeonol-grafted silane coupling agent obtained in step 1 and placing it into a flask, dispersing it with water in proportion; then sequentially adding an ethanol solution of an initiator and an N-vinyl pyrrolidone monomer and stirring evenly; then reacting under reflux conditions for 10 to 20 hours, stopping the reaction and cooling to room temperature; and centrifuging and drying to obtain a polymer-grafted paeonol derivative. The water-soluble paeonol derivative prepared by this scheme has a solubility in water (based on paeonol) of up to 0.88%; it not only has the properties of paeonol itself, but also improves the solubility of paeonol in water and the bioavailability of paeonol.

Description

Technical Field

[0001] The invention belongs to the technical field of preparation and surface modification of paeonol derivatives, and particularly relates to a water-soluble paeonol derivative and a preparation method thereof. Background Art

[0002] Paeonol (Paeonolum, Pae) is the main active ingredient of the root bark of the Ranunculaceae plant Paeonia suffruticosa and the whole herb of the Asclepiadaceae plant Cynanchum chinense, with antiallergic, anti-inflammatory, vasodilatory, antiarrhythmic, antibacterial, sedative, hypnotic, antipyretic, analgesic, tumor cell proliferation inhibition and other pharmacological activities, clinically used to treat rheumatic pain, stomachache and other pain, eczema, allergic dermatitis, etc. Pae is a phenolic compound with low melting point, volatile, poor water solubility (solubility in water 350 μg / mL), and the characteristics of easy decomposition when exposed to light, resulting in its low bioavailability. Therefore, it is necessary to further improve its water solubility and increase its stability in the hope of improving its bioavailability.

[0003] In recent years, researchers have adopted two main methods to improve the bioavailability of paeonol: one is chemical modification, which introduces specific functional groups into a certain functional group on the paeonol structure to prepare paeonol derivatives; such as paeonol sulfonated derivatives, Mannich base derivatives, arsenic-containing derivatives, ester derivatives, halogenated derivatives, flavonoid derivatives, cyclophosphamide derivatives, and glycoside derivatives; the other is physical coating, such as liposomes, nanocapsules, microemulsions, MOFs and other carriers, to improve its water solubility. Compared with chemical modification, physical coating methods are relatively simple, but have poor stability.

[0004] The current preparation of paeonol derivatives mainly focuses on the modification of the active ingredient structure of the drug; while not much attention is paid to the water solubility of paeonol derivatives. The preparation of paeonol derivatives mainly focuses on the modification of the active ingredient structure of paeonol drugs by chemical methods; the introduced active ingredients can synergistically improve the activity of paeonol, but cannot effectively improve the water solubility of paeonol. In addition, the current process for preparing paeonol derivatives is cumbersome, and it takes five or six steps or even dozens of steps to prepare the derivatives. Strong acids, organic solvents, etc. are required during the reaction process, which will inevitably affect the purity and yield of the derivatives. How to prepare paeonol derivatives with a simpler and more effective method, while retaining its biological activity and improving its bioavailability, is one of the key issues in the current modification of paeonol. Summary of the Invention

[0005] To address at least one of the aforementioned technical problems, the present invention provides a water-soluble paeonol derivative and a method for preparing the same. Polyvinylpyrrolidone is covalently grafted onto the surface of paeonol to produce a water-soluble paeonol derivative. This water-soluble paeonol derivative not only retains the properties of paeonol itself but also improves its solubility in water and bioavailability.

[0006] One of the objects of the present invention is to provide a method for preparing a water-soluble paeonol derivative, comprising the following steps:

[0007] Step 1: adding a certain amount of paeonol powder into a container and dispersing it with water in proportion; adding a certain amount of silane coupling agent into the container in proportion at reflux temperature; cooling to room temperature after refluxing for 3 to 10 hours; centrifuging, washing, and drying at room temperature to obtain a paeonol-grafted silane coupling agent;

[0008] Step 2: Take a certain amount of the paeonol-grafted silane coupling agent obtained in step 1 and put it into a container, add water according to the proportion to disperse it; then add the ethanol solution of the initiator and the N-vinyl pyrrolidone monomer into the container in sequence and stir evenly; then react under reflux conditions for 10 to 20 hours, stop the reaction and cool to room temperature; centrifuge, wash, and dry at room temperature to obtain a polymer-grafted paeonol derivative.

[0009] As a preferred embodiment, in step 1, the mass ratio of the silane coupling agent to paeonol is 0.5 to 1.5:1.

[0010] As a preferred embodiment, in step 1, the silane coupling agent is one of vinyltri(2-methoxyethoxy)silane, vinyltrichlorosilane, vinyltriethoxysilane, vinyltrimethoxysilane or γ-methacryloxypropyltrimethoxysilane.

[0011] As a preferred solution, in step 2, the initiator is an azo initiator or a peroxide initiator.

[0012] As a preferred embodiment, in the step 2, the mass ratio of the initiator to N-vinyl pyrrolidone is 1:10-30.

[0013] As a preferred solution, in the step 2, the mass ratio of N-vinyl pyrrolidone to the paeonol grafted silane coupling agent is 1 to 4:1, preferably, the mass ratio is 1 to 2.5:1.

[0014] As a preferred embodiment, in step 2, the ethanol solution of the initiator is prepared by pre-dissolving 0.0034 to 0.04 g of azobisisobutyronitrile in 1 mL of ethanol.

[0015] Polyvinylpyrrolidone (PVP) is a typical representative of medical polymers. As a synthetic water-soluble polymer, it possesses the general properties of water-soluble polymers: colloid protection, film-forming properties, adhesion, hygroscopicity, solubilization or coagulation, and excellent solubility. PVP is physiologically inert and does not participate in human metabolism. It also has excellent biocompatibility, causing no irritation to the skin, mucous membranes, eyes, etc., and does not cause significant adverse reactions when in contact with organisms. It is precisely these advantages that give PVP a wide range of applications in the fields of medicine, food, cosmetics, etc.

[0016] To address the low solubility and poor bioavailability of existing paeonol, the present invention utilizes commercial paeonol as a matrix, a silane coupling agent as a bridge, and a water-soluble polymer as a modifier. The polymer is covalently grafted onto the surface of the paeonol via in-situ polymerization to prepare a paeonol derivative. The paeonol derivative prepared by the present invention not only retains the properties of the original paeonol, but also improves its solubility in water and enhances its bioavailability.

[0017] The second object of the present invention is to provide a water-soluble paeonol derivative, which uses paeonol powder as a matrix, forms a silane coupling layer on the surface of the paeonol by grafting modification, and performs a polymerization reaction on the grafted paeonol surface to form a polymer layer.

[0018] As a preferred embodiment, its structural formula is as follows:

[0019]

[0020] Among them, m and n are integers between 8000 and 700000.

[0021] The paeonol derivative prepared by the raw materials and method of the present invention can give full play to the advantages of the combination of paeonol and polymer; on the one hand, it retains the excellent pharmacological activity of commercial paeonol, and on the other hand, it gives paeonol excellent water solubility and improves its bioavailability.

[0022] The reaction mechanism of the preparation scheme of the present invention is as follows: First, the silane coupling agent is hydrolyzed to form hydroxyl groups, which undergo dehydration condensation with the hydroxyl groups on the surface of paeonol, successfully grafting the silane coupling agent onto the surface of paeonol. Azobisisobutyronitrile (AIBN) is used as an initiator to initiate the polymerization reaction. First, under the action of AIBN, the double bond of the silane coupling agent is opened to form free radicals; then, monomers are triggered, causing repeated rapid addition between the NVP monomer and the free radicals, grafting polyvinyl pyrrolidone onto the paeonol. Compared with the existing technology, the present invention has at least one of the following beneficial effects:

[0023] First, the present invention addresses the problems of poor water solubility and poor bioavailability of existing paeonol, and provides a water-soluble paeonol derivative based on the inventive concept of combining chemical modification and physical coating. The paeonol derivative prepared by the present invention, on the one hand, retains the excellent pharmacological activity of commercial paeonol, and on the other hand, gives paeonol excellent water solubility, effectively improving its bioavailability; the paeonol derivative formed by this scheme not only has the properties of paeonol itself, but also improves the solubility of paeonol in water, thereby improving the bioavailability of paeonol; the paeonol derivative of the present invention has high stability; it is not easy to phase separate during the application process, and has stable performance.

[0024] Secondly, the present invention optimizes the preparation process of paeonol derivatives. The present invention uses commercial paeonol as a matrix, a silane coupling agent as a bridge, and a water-soluble polymer as a modifier; the polymer is covalently grafted onto the surface of paeonol through in-situ polymerization, and the paeonol derivatives are prepared using the above-mentioned raw material ratio. By strictly controlling various process indicators such as temperature and time, the process steps of the preparation process are simplified, it is easy to realize industrialization, and the production cost is low. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 The infrared spectrum of the paeonol derivative in Example 1 of the present invention; (1) PVP; (2) PVP-Pae-Si (3) Pae-Si; (4) Pae;

[0026] Figure 2 This is a scanning electron micrograph of commercial paeonol (Pae), a raw material used in the examples;

[0027] Figure 3 This is a scanning electron micrograph of the paeonol derivative (PVP-Pae-Si) in Example 2 of the present invention;

[0028] Figure 4 This is a comparison chart of the dispersibility experiment of paeonol before and after modification in Example 3 of the present invention;

[0029] Figure 5 This is the UV-visible absorption spectrum of the paeonol derivative (PVP-Pae-Si) prepared in Example 1 of the present invention; (1), Pae; (2), PVP-Pae-Si; (3), PVP;

[0030] Figure 6 This is a standard working curve diagram of commercial paeonol pae in an embodiment of the present invention;

[0031] Figure 7 The UV-visible absorption spectra of the paeonol derivative (PVP-Pae-Si) prepared in Example 7 of the present invention after being placed for the same time; (1), fresh preparation; (2), 1 month; (3), 3 months; (4), 5 months. DETAILED DESCRIPTION

[0032] In order to make the technical means, creative features, objectives and beneficial effects achieved by the present invention easier to understand, the present invention is further described below in conjunction with specific implementation methods.

[0033] In addition, in order to better illustrate the present invention, numerous specific details are given in the specific embodiments below. Those skilled in the art should understand that the present invention can also be implemented without certain specific details. In other embodiments, methods, means, equipment and steps well known to those skilled in the art are not described in detail in order to highlight the main purpose of the present invention.

[0034] The present invention provides a method for preparing a water-soluble paeonol derivative, comprising the following steps:

[0035] Step 1: adding a certain amount of paeonol powder into a container and dispersing it with water in proportion; adding a certain amount of silane coupling agent into the container in proportion at reflux temperature; cooling to room temperature after refluxing for 3 to 10 hours; centrifuging, washing, and drying at room temperature to obtain a paeonol-grafted silane coupling agent;

[0036] Step 2: Take a certain amount of the paeonol-grafted silane coupling agent obtained in step 1 and put it into a container, add water according to the proportion to disperse it; then add the ethanol solution of the initiator and the N-vinyl pyrrolidone monomer into the container in sequence and stir evenly; then react under reflux conditions for 10 to 20 hours, stop the reaction and cool to room temperature; centrifuge, wash, and dry at room temperature to obtain a polymer-grafted paeonol derivative.

[0037] Preferably, in step 1, the mass ratio of the silane coupling agent to paeonol is 0.5 to 1.5:1.

[0038] Preferably, in step 1, the silane coupling agent is one of vinyltri(2-methoxyethoxy)silane, vinyltrichlorosilane, vinyltriethoxysilane, vinyltrimethoxysilane or γ-methacryloxypropyltrimethoxysilane.

[0039] Preferably, in step 2, the initiator is an azo initiator or a peroxide initiator.

[0040] Preferably, in step 2, the mass ratio of the initiator to N-vinyl pyrrolidone is 1:10-30.

[0041] Preferably, in step 2, the mass ratio of N-vinyl pyrrolidone to the paeonol grafted silane coupling agent is 1 to 4:1.

[0042] Preferably, in the step 1, 1 g of paeonol is dispersed in 100 ml of water.

[0043] Preferably, in the step 2, 0.5 g of paeonol-grafted silane coupling agent is dispersed in 100 ml of water.

[0044] Preferably, in step 2, the ethanol solution of the initiator is prepared by pre-dissolving 0.0034-0.04 g of azobisisobutyronitrile in 1 ml of ethanol.

[0045] The present invention also provides a paeonol derivative, which uses paeonol as a matrix, forms a silane coupling layer on the surface of the paeonol through grafting modification, and performs polymerization reaction on the grafted paeonol surface to form a polymer layer.

[0046] Preferably, its structural formula is as follows:

[0047]

[0048] Among them, m and n are integers between 8000 and 700000.

[0049] The present invention uses commercial paeonol as a matrix, a silane coupling agent as a bridge, and a water-soluble polymer as a modifier. The polymer is covalently grafted onto the surface of paeonol by in-situ polymerization to prepare a water-soluble paeonol derivative. The solubility of the modified paeonol in water can reach 0.88%. The derivative prepared by the present invention fully utilizes the advantages of the compounding of paeonol and the polymer; on the one hand, the polymer grafted with paeonol does not change the pharmacological activity of paeonol and still retains the excellent pharmacological activity of commercial paeonol; on the other hand, the grafted polymer gives paeonol excellent water solubility, thereby improving its bioavailability. The preparation method of the present invention has a simpler process, is easy to industrialize, and has a low production cost; it provides a new idea for the preparation of water-soluble paeonol derivatives. The following is an illustration with reference to specific embodiments:

[0050] Example 1

[0051] The present embodiment provides a method for preparing a water-soluble paeonol derivative, comprising the following steps: (1) paeonol grafted silane coupling agent: 1 g of paeonol was added to a round-bottom flask and dispersed in 100 mL of water, and 1 g of γ-methacryloyloxypropyltrimethoxysilane (KH570) was added at reflux temperature; the mixture was refluxed for 6 h and then cooled to room temperature; the mixture was centrifuged and washed with water, and then dried under vacuum at 50°C to obtain 0.8 g of paeonol grafted silane coupling agent, which was recorded as Pae-Si; (2) paeonol grafted polymer: 0.5 g of Pae-Si was added to a flask and dispersed in 100 mL of water; 1 g of N-vinyl pyrrolidone monomer and a solution of 0.05 g of azobisisobutyronitrile pre-dissolved in 5 mL of ethanol were then added in sequence and stirred evenly; the reaction was stopped under reflux for 15 h and then cooled to room temperature; the mixture was centrifuged and washed with water, and then dried under vacuum at 50°C to obtain 0.7 g of polymer-grafted paeonol derivative, which was recorded as Poly-Si-Pae.

[0052] Example 2

[0053] The present embodiment provides a method for preparing a water-soluble paeonol derivative, comprising the following steps: (1) paeonol grafted silane coupling agent: 1 g of paeonol was added to a round-bottom flask and dispersed in 100 mL of water, and 1.5 g of γ-methacryloyloxypropyltrimethoxysilane (KH570) was added at reflux temperature; the mixture was refluxed for 3 h and then cooled to room temperature; the mixture was centrifuged and washed with water, and then dried under vacuum at 50°C to obtain 0.8 g of paeonol grafted silane coupling agent, which was recorded as Pae-Si; (2) paeonol grafted polymer: 0.5 g of Pae-Si was added to a flask and dispersed in 100 mL of water; 2 g of N-vinyl pyrrolidone monomer and a solution of 0.2 g of azobisisobutyronitrile pre-dissolved in 5 mL of ethanol were then added in sequence and stirred evenly; the reaction was stopped after 10 h under reflux conditions and the mixture was cooled to room temperature; the mixture was centrifuged and washed with water, and then dried under vacuum at 50°C to obtain 0.8 g of polymer-grafted paeonol derivative, which was recorded as Poly-Si-Pae.

[0054] Example 3

[0055] The present embodiment provides a method for preparing a water-soluble paeonol derivative, comprising the following steps: (1) paeonol grafted silane coupling agent: 1 g of paeonol was added to a round-bottom flask and dispersed in 100 mL of water, and 0.5 g of γ-methacryloyloxypropyltrimethoxysilane (KH570) was added at reflux temperature; after 10 h of reflux, the mixture was cooled to room temperature; centrifuged and washed with an appropriate amount of water, and then vacuum-dried at 50° C. to obtain 0.8 g of paeonol grafted silane coupling agent, which was designated as Pae-Si; (2) paeonol grafted polymer: 0.5 g of Pae-Si was placed in a flask and dispersed in 100 mL of water; and then 0.5 g of γ-methacryloyloxypropyltrimethoxysilane (KH570) was added in sequence. A solution of N-vinyl pyrrolidone monomer and 0.017 g of azobisisobutyronitrile pre-dissolved in 5 mL of ethanol was stirred evenly; the reaction was then stopped after 20 hours under reflux, and the mixture was cooled to room temperature; the mixture was centrifuged and washed with an appropriate amount of water, and then dried in a vacuum at 50° C. to obtain 0.6 g of a polymer-grafted paeonol derivative, which was recorded as Poly-Si-Pae.

[0056] The structural formulas of Examples 1-3 are as follows:

[0057]

[0058] Example 4

[0059] The present embodiment provides a method for preparing a water-soluble paeonol derivative, comprising the following steps: (1) paeonol grafted silane coupling agent: 1 g of paeonol was added to a round-bottom flask and dispersed in 100 mL of water, and 1 g of vinyltri(2-methoxyethoxy)silane was added at reflux temperature; the mixture was refluxed for 6 h and then cooled to room temperature; the mixture was centrifuged and washed with water, and then dried under vacuum at 50°C to obtain 0.8 g of paeonol grafted silane coupling agent, which was recorded as Pae-Si; (2) paeonol grafted polymer: 0.5 g of Pae-Si was added to a flask and dispersed in 100 mL of water; 1 g of N-vinylpyrrolidone and 5 mL of ethanol in which 0.05 g of azobisisobutyronitrile was pre-dissolved were then added in sequence and stirred evenly; the reaction was stopped after 15 h of reflux, and the mixture was cooled to room temperature; the mixture was centrifuged and washed with water, and then dried under vacuum at 50°C to obtain 0.7 g of polymer grafted paeonol derivative, which was recorded as Poly-Si-Pae.

[0060] Example 5

[0061] This embodiment provides a method for preparing a water-soluble paeonol derivative, comprising the following steps: (1) paeonol grafted silane coupling agent: 1 g of paeonol was added to a round-bottom flask and dispersed in 100 mL of water, and 1 g of vinyltrichlorosilane was added at reflux temperature; after refluxing for 6 h, the mixture was cooled to room temperature; after centrifugation and washing with water, the mixture was dried at room temperature to obtain 0.8 g of paeonol grafted silane coupling agent, which was recorded as Pae-Si; (2) paeonol grafted polymer: 0.5 g of Pae-Si was added to a flask and dispersed in 100 mL of water; then 1 g of N-vinyl pyrrolidone and 5 mL of ethanol in which 0.05 g of azobisisobutyronitrile was pre-dissolved were added in sequence, and the mixture was stirred evenly; the reaction was stopped after 15 h under reflux conditions, and the mixture was cooled to room temperature; after centrifugation and washing with water, the mixture was dried at room temperature to obtain 0.7 g of polymer-grafted paeonol derivative, which was recorded as Poly-Si-Pae.

[0062] Example 6

[0063] This embodiment provides a preparation method of a water-soluble paeonol derivative, comprising the following steps: (1) paeonol grafted silane coupling agent: 1 g of paeonol was added to a round-bottom flask and dispersed in 100 mL of water, and 1 g of vinyltriethoxysilane was added at reflux temperature; after refluxing for 6 hours, the mixture was cooled to room temperature; after centrifugation and washing with water, the mixture was dried at room temperature to obtain 0.7 g of paeonol grafted silane coupling agent, which was recorded as Pae-Si; (2) paeonol grafted polymer: 0.5 g of Pae-Si was put into a flask and dispersed in 100 mL of water; then 1 g of N-vinyl pyrrolidone and 5 mL of ethanol in which 0.05 g of azobisisobutyronitrile was pre-dissolved were added in sequence and stirred evenly; then the reaction was stopped after 15 hours under reflux conditions and the mixture was cooled to room temperature; after centrifugation and washing with water, the mixture was dried at room temperature to obtain 0.7 g of polymer-grafted paeonol derivative, which was recorded as Poly-Si-Pae.

[0064] Example 7

[0065] The present embodiment provides a method for preparing a water-soluble paeonol derivative, comprising the following steps: (1) paeonol grafted silane coupling agent: 1 g of paeonol was added to a round-bottom flask and dispersed in 100 mL of water, and 1 g of vinyltrimethoxysilane was added at reflux temperature; after refluxing for 6 h, the mixture was cooled to room temperature; after centrifugation and washing with water, the mixture was dried at room temperature to obtain 0.8 g of paeonol grafted silane coupling agent, which was recorded as Pae-Si; (2) paeonol grafted polymer: 0.5 g of Pae-Si was put into a flask and dispersed in 100 mL of water; then 1 g of N-vinyl pyrrolidone and 5 mL of ethanol in which 0.05 g of azobisisobutyronitrile was pre-dissolved were added in sequence and stirred evenly; then the reaction was stopped after 15 h under reflux conditions and the mixture was cooled to room temperature; after centrifugation and washing with water, the mixture was dried at room temperature to obtain 0.7 g of polymer-grafted paeonol derivative, which was recorded as Poly-Si-Pae.

[0066] The structural formulas of Examples 4-7 are as follows:

[0067]

[0068] The prepared paeonol derivatives were characterized by the following methods: Figure 1 These are the infrared spectra of commercial paeonol (Pae), polyvinyl pyrrolidone (PVP), silane coupling agent-modified paeonol (Pae-Si), and polyvinyl pyrrolidone-modified paeonol (Poly-Pae-Si) in the preparation process of paeonol derivatives.

[0069] Figure 1 The infrared spectra of Pea, PVP, Pae-Si and PVP-Pae-Si in Example 1 are shown. (1) PVP; (2) PVP-Pae-Si; (3) Pae-Si; (4) Pea; Figure 1 It can be seen that the characteristic peaks of the infrared spectrum of pure PVP (curve 1) are mainly: 3400cm -1 The broad absorption band at 2900 cm-1 is attributed to the stretching vibration of the OH bond of H2O in the sample. -1 The absorption band is the stretching vibration of CH in methylene, 1655cm -1 is the stretching vibration of C=O; 1435cm -1 The infrared spectrum of pure Pae (curve 4) has the following characteristic peaks: 2900cm -1 The absorption band is the stretching vibration of CH in methyl group; 1620cm -1 It is the characteristic vibration of vinyl ether or vinyl ketone, 1255cm -1 The absorption band near 1620 cm is the vibration of C=C of benzene ring. -1 In addition to the characteristic absorption peaks of Pae at 1255 cm-1, the wave number is 1016 cm -1 The characteristic vibration peak of Si-OC appeared at 1 016 cm-1, proving that the silane coupling agent was combined with Pae. When the polymer PVP molecules were introduced into the Poly-Pae-Si composite (curve 2), not only the peak at 1 016 cm-1 -1 The characteristic vibration peak of Si-OC appears at 1620cm -1 and 1255cm -1 The characteristic absorption peak of Pae appeared at 1655cm -1 and 1435cm -1The characteristic vibration peak of PVP also appears at 3400cm. According to the infrared results, the Poly-Pae-Si composite contains not only the characteristic peaks of Pae, but also the characteristic peaks of PVP and KH570. In addition, it can be seen from the infrared spectrum that after the PVP molecules are introduced into the Pae surface, the characteristic peak at 3400cm -1 The obvious water peak appears at the surface of Pae, which also shows that the surface becomes hydrophilic due to the introduction of PVP. Figure 1 The infrared spectrum results in the figure show that the grafting of PVP to Pae has been successfully achieved using this scheme.

[0070] Figure 5 The UV-visible absorption spectra of Pae, PVP-Pae-Si and PVP are respectively; Structural analysis of paeonol derivatives: In the preparation of polyvinylpyrrolidone-modified paeonol derivatives, whether the structure of paeonol is destroyed is verified by UV-visible absorption spectrum. The results are as follows Figure 5 As shown. Figure 5 It can be seen that pure commercial paeonol Pae has absorption peaks at 213nm, 228nm, 274nm, and 314nm; pure polyvinylpyrrolidone (PVP) only has an absorption peak near 213nm. When polyvinylpyrrolidone and paeonol form a derivative (Poly-Pae-Si) in Example 1, it exhibits almost identical characteristic absorption peaks of Pae, indicating that the structure of paeonol is not destroyed during the preparation of the derivative.

[0071] The microstructure of polyvinyl pyrrolidone and paeonol was observed by scanning electron microscopy. Figure 2 and Figure 3 As shown. Figure 2 It can be seen that pure paeonol is in a block state, and there are also a small number of small particles that are aggregated into spherical shapes. Figure 3 The scanning electron microscope image of the paeonol derivative (PVP-Pae-Si) in Example 2 is shown, which is different from the morphology of the uncoated paeonol ( Figure 2 ) Compared with the results of the experiment, polyvinyl pyrrolidone grafted with paeonol ( Figure 3 ) after the main spherical morphology, spherical particle size in the micrometer scale of 10-40μm; no obvious large agglomerate morphology was found, compared with the appearance of pure paeonol, there is a great difference, indicating that the introduction of the polymer has changed the morphology of paeonol. Figure 2 and 3 The results of scanning electron microscopy show that after the paeonol on the surface of commercial paeonol crystals was modified with PVP, the dispersibility was greatly improved and the morphology changed from blocky to spherical.

[0072] To further demonstrate the success of polymer grafting, energy spectrum analysis was performed on the polymer-modified paeonol derivatives described in the examples. Data for commercial paeonol are shown in Table 1. Data for polyvinylpyrrolidone-modified paeonol (Poly-Pae-Si) are shown in Table 2.

[0073] Table 1 Elemental composition of commercial paeonol

[0074]

[0075] Table 2 Elemental composition of polyvinylpyrrolidone modified paeonol

[0076]

[0077] Compared to the commercial paeonol data in Table 1, Table 2 shows that the nitrogen and silicon contents of the polyvinylpyrrolidone-modified paeonol increased after the polymer and silane coupling agent were introduced onto the paeonol surface, indicating that the polymer and silane coupling agent were successfully introduced onto the paeonol surface. The energy spectrum test results combined with scanning electron microscopy analysis demonstrate that the process provided by the present invention successfully covalently grafted the polymer and silane coupling agent onto the paeonol surface, yielding polyvinylpyrrolidone-modified paeonol.

[0078] Dispersion evaluation

[0079] Whether the modification of paeonol is successful is verified by the following dispersion experiment. Figure 4 The dispersion test of the paeonol derivative (PVP-Pae-Si) obtained in Example 3 of the present invention is as follows: a certain amount of paeonol before modification and the modified paeonol derivative are dispersed into two deionized water samples respectively, and their dispersion states in the two water samples are observed; the results are shown in FIG. Figure 4 As shown. Figure 4 It can be seen that the modified paeonol can be evenly dispersed in an aqueous solution and the solution remains clear and transparent after being placed for 3 days; for the unmodified paeonol, paeonol can only be suspended in the bottle at the beginning, and during the same period of time, paeonol is still in a suspended state. The evaluation method is as follows: take 0.1g of the modified paeonol derivative; disperse it into a water sample of 10mL deionized water. The steps of the dispersion comparison experiment are as follows: take 0.045g of commercial paeonol before modification and disperse it into a water sample of 10mL deionized water (the loading amount of paeonol in the modified paeonol derivative corresponding to Example 3 is 45%: the loading amount data is calculated by ultraviolet-visible absorption spectroscopy, so the 0.1g paeonol derivative in the comparative experiment contains 0.045g of paeonol).

[0080] The above-mentioned dispersibility experiment shows that: using the preparation method of the present invention, polyvinyl pyrrolidone molecules have been successfully grafted onto the surface of paeonol, and the modified paeonol has good dispersibility in water.

[0081] Evaluation of paeonol loading

[0082] Analysis of the paeonol loading amount in the paeonol derivative prepared in Example 7: After polyvinyl pyrrolidone was grafted onto the surface of paeonol, the paeonol loading amount was also tested using UV-visible absorption spectroscopy.

[0083] First, it is necessary to draw a working curve of Pae. The specific method is as follows: accurately pipette an appropriate amount of Pae stock solution (100 μg / mL), dilute to 50 ml with anhydrous ethanol, and prepare a series of reference solutions with concentrations of 2.0, 4.0, 6.0, 8.0, and 10.0 μg / mL. Use anhydrous ethanol as a blank to test the absorbance A at the characteristic absorption peak of paeonol at 274 nm; perform linear regression with A as the ordinate and concentration c as the abscissa. The results are as follows: Figure 6 As shown. Figure 6 It can be seen that the regression equation of paeonol is A=0.0818c-0.0027(R 2 =0.9992), indicating that the concentration of paeonol had a good linear relationship with the absorbance in the range of 2.0-10.0 μg / mL.

[0084] The paeonol derivative prepared in Example 7 was selected, and then a certain concentration of ethanol solution of the paeonol derivative was prepared. The absorbance A at 274 nm was measured, and then compared with the standard curve to determine the concentration of pure paeonol, and then the paeonol loading was calculated. The specific method was as follows: 0.01 g of the paeonol derivative was dissolved in 20 mL of anhydrous ethanol, 0.2 mL was taken and the volume was made up to 10 mL with anhydrous ethanol. Using anhydrous ethanol as a reference, the absorbance at 274 nm was measured to be 0.4109. Then, the working curve of paeonol was applied to obtain 5 μg / mL. The paeonol concentration before dilution was determined to be 252.5 μg / mL; thus, the paeonol loading was determined to be 50.5%.

[0085] Stability evaluation

[0086] The following is a test of the stability of paeonol derivatives in water: Whether the stability of paeonol derivatives is improved, a stability test is conducted. The specific method is: prepare a certain concentration of paeonol derivative aqueous solution, then test its absorbance at different times, and observe the changes in its characteristic peak. The longest test time in the experiment is 5 months; the preparation method of paeonol derivatives is as follows: take 0.01g of the paeonol derivative prepared in Example 7 and dissolve it in 20mL of water, take 1mL and dilute it to 50mL. Measure the absorbance. The results are as follows Figure 7shown.

[0087] from Figure 7 It can be seen that during the 5-month storage of the sample, the UV-visible absorption spectrum did not undergo significant changes. Only the peak intensity at 213 nm decreased slightly with time, while the peak intensities of other characteristic peaks did not decrease at all. This shows that the stability of paeonol was greatly improved after being modified with polyvinylpyrrolidone molecules.

[0088] Solubility evaluation

[0089] Solubility test: The polymer modification of paeonol improves its solubility in water. The solubility of paeonol before and after modification was tested. The method was as follows: at 50°C, a certain amount of paeonol before and after modification was dissolved in 10 mL of water. 50 mg of the modified paeonol was added at a time, stirring to dissolve. Additional additions were made after complete dissolution. If insoluble matter appeared, the experiment was stopped, the amount added was recorded, and the solubility was calculated. The test results are shown in Table 3.

[0090] Table 3 Solubility of modified paeonol in water

[0091]

[0092] In the related prior art, the solubility of commercial paeonol in water is known to be approximately 300 μg / mL, or 0.03%. When paeonol is modified using the present invention, taking the paeonol derivative obtained in Example 7 as an example, the solubility is 0.28% at room temperature; when the temperature is raised to 50°C, the solubility reaches 0.56%; and when the temperature is raised to 75°C, the solubility reaches 0.83%. The concentration of paeonol added to ointments or cosmetics is generally around 0.1 to 0.3%. This shows that the method provided by the present invention greatly improves the solubility of paeonol in water, reaching the concentration range of commercial paeonol.

[0093] The solubility comparison analysis of the derivatives obtained in Examples 1-7 was carried out below. According to the above solubility experiments, the solubility of paeonol in Examples 1-7 under different temperature conditions was obtained.

[0094] Table 4 Solubility of modified paeonol in water at different temperatures (mass percentage)

[0095]

[0096] As can be seen from the above table: the solubility of unmodified paeonol in water is 0.03% to 0.04%; while the solubility of modified paeonol in water is 0.25% to 0.88%. The solubility of the modified paeonol is about 8 to 30 times higher than that of the unmodified paeonol. The paeonol derivatives of this scheme will not affect the original physical and chemical properties of paeonol after modification, and according to the above-mentioned spectral analysis of this application, it can be seen that the spectrum of paeonol before and after modification has not changed, which further proves the above conclusion. According to the fact that the added concentration of paeonol in ointments or cosmetics is generally 0.1 to 0.3% by mass, the modified paeonol of the present invention reaches more than 0.25% at room temperature, thus meeting the added concentration of commercial paeonol.

[0097] In the related prior art, the current application of paeonol in cosmetics or some ointments for treating eczema generally uses physically encapsulated paeonol or directly adds paeonol; due to the poor solubility of paeonol in water, it can only be made into cream-type cosmetics or ointments; or ethanol or a large amount of surfactant is added to the cosmetics to improve the dispersion of paeonol; but it is highly irritating to the skin. Using the modified paeonol derivatives of the present invention, not only can high concentrations of paeonol be easily added to lotions, creams, or eczema ointments, but it can also be made into lotions or sprays. For example, the modified paeonol of the present application is used to prepare a lotion, wherein the lotion includes the following components, calculated by mass fraction: water: 90%, the modified paeonol derivative of the present application: 0.2% to 0.8%, essence: 1%, moisturizer: 2%, stabilizer: 0.1%, pH adjuster: 0.2%, preservative: 0.1% to 0.5%, and other additives: 5.4% to 6.4%. The formula of the lotion here is only to illustrate that the solubility of the modified paeonol has reached the addition amount for the prepared product, and the preparation process and various additives of this type of lotion are all existing technologies and will not be repeated here. The only difference between the preparation of the lotion here and the existing technology is that paeonol is replaced by the modified paeonol derivative prepared in this application.

[0098] The above description is merely a preferred embodiment of the present invention and does not constitute any form of limitation to the present invention. Although the present invention has been disclosed as a preferred embodiment, it is not intended to limit the present invention. Any technician familiar with the present profession can make some changes or modifications to equivalent embodiments of equivalent changes using the technical contents disclosed above without departing from the scope of the technical solution of the present invention. However, any simple modifications, equivalent changes and modifications made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solution of the present invention are still within the scope of the technical solution of the present invention.

Claims

1. A method for preparing a water-soluble paeonol derivative, characterized in that: The steps include: Step 1: Add a certain amount of paeonol powder to a container and disperse it with water in proportion; add a certain amount of silane coupling agent to the container in proportion at reflux temperature; reflux for 3 to 10 hours and then cool to room temperature; obtain the paeonol-grafted silane coupling agent after solid-liquid separation; the silane coupling agent is one of vinyltri(2-methoxyethoxy)silane, vinyltrichlorosilane, vinyltriethoxysilane, vinyltrimethoxysilane or γ-methacryloxypropyltrimethoxysilane; Step 2: Take a certain amount of the paeonol-grafted silane coupling agent obtained in step 1 and put it into a container, add water according to the proportion to disperse it; then add the ethanol solution of the initiator and the N-vinyl pyrrolidone monomer to the container in sequence and stir evenly; then react under reflux conditions for 10 to 20 hours, stop the reaction and cool to room temperature; after solid-liquid separation, obtain a polymer-grafted paeonol derivative.

2. The method for preparing a water-soluble paeonol derivative according to claim 1, wherein: In the step 1, the mass ratio of the silane coupling agent to paeonol is 0.5-1.5:

1.

3. The method for preparing a water-soluble paeonol derivative according to claim 1 or 2, characterized in that: In the step 2, the initiator is an azo initiator or a peroxide initiator.

4. The method for preparing a water-soluble paeonol derivative according to claim 1 or 2, characterized in that: In the step 2, the mass ratio of the initiator to N-vinyl pyrrolidone is 1:10~30.

5. The method for preparing a water-soluble paeonol derivative according to claim 1 or 2, characterized in that: In the step 2, the mass ratio of N-vinyl pyrrolidone to paeonol grafted silane coupling agent is 1-4:

1.

6. The method for preparing a water-soluble paeonol derivative according to claim 1 or 2, characterized in that: In the step 2, the ethanol solution of the initiator is prepared by pre-dissolving 0.0034-0.04 g of azobisisobutyronitrile in 1 ml of ethanol.

7. The paeonol derivative prepared by the method for preparing a water-soluble paeonol derivative according to any one of claims 1 to 6, characterized in that: Paeonol powder is used as a matrix, a silane coupling layer is formed on the surface of the paeonol by grafting modification, and a polymerization reaction is carried out on the surface of the grafted paeonol to form a polymer layer.

8. The paeonol derivative according to claim 7, characterized in that: Its structural formula is as follows: ; or Wherein, m and n are integers between 8000 and 700000.

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