A drug controlled release system with chiral drug selective loading function, preparation method and application thereof

Abstract

The application relates to a drug controlled release system with a chiral drug selective loading function, a preparation method and application thereof, and belongs to the technical field of biological medicines. The drug controlled release system with the chiral drug selective loading function is prepared into a supermolecular hydrogel selective loading system after a gel factor is self-assembled into a supermolecular hydrogel, and chiral drugs with the same optical rotation as the supermolecular hydrogel are loaded into a three-dimensional network structure of the supermolecular hydrogel. The drug controlled release system with the chiral drug selective loading function prepared by the application can realize selective loading of different configurations of naproxen, and can realize controlled release of S-naproxen under alkaline conditions. The chiral selective controlled release system is simple in preparation, high in feasibility, and can be widely applied to the field of biological medicines.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of biological medicine, and particularly relates to a drug controlled release system with a chiral drug selective loading function, a preparation method and application thereof. BACKGROUND

[0002] Chiral drugs refer to a pair of enantiomers obtained by introducing a chiral center into a drug molecule structure, which are real and mirror images of each other. Because of the existence of such spatial differences, drugs with different optical activities have great differences in pharmacology, toxicology and pharmacokinetics. Therefore, the separation of chiral drugs is crucial. At the same time, some chiral drugs have the disadvantages of poor water solubility, low bioavailability and low targeting, and in order to overcome these disadvantages and fully exert the maximum use value of the drugs, the drugs are often made into controlled release preparations. Therefore, while studying the separation of chiral drugs, we also need to develop suitable controlled release carriers for drugs.

[0003] Supramolecular hydrogels are formed by self-assembly of small molecules through hydrogen bonding, π-π stacking, electrostatic interaction and host-guest complexation. Supramolecular hydrogels formed by self-assembly of chiral or non-chiral gelators can have helical nanostructures, thereby being endowed with macroscopic chirality and serving as a material with chiral selectivity. Supramolecular hydrogels also have excellent biocompatibility, biodegradability, responsiveness to external stimuli and other advantages, and are widely used in drug delivery systems, tissue engineering, wound healing and other biomedical fields. Therefore, we selected supramolecular hydrogels in the present application to realize selective loading of chiral drugs and controlled release of drugs in the dominant configuration. SUMMARY

[0004] In view of the problems existing in the prior art, the present application aims to provide a drug controlled release system with a chiral drug selective loading function, a preparation method and application thereof. The present application uses, for example, phenylalanine derivatives as gelators, and after self-assembly into supramolecular hydrogels, a drug controlled release system with a chiral drug selective loading function is prepared. The drug controlled release system uses its chirality to selectively load chiral drugs (such as naproxen), and loads chiral drugs with the same optical activity as the supramolecular hydrogel into the three-dimensional network structure of the supramolecular hydrogel. Meanwhile, the loaded chiral drugs (such as naproxen) can be released in response to an alkaline environment. The supramolecular hydrogel has both selective loading and controlled release capabilities, and can be used for separation and delivery of chiral drugs.

[0005] In order to achieve the above-mentioned purpose, the present application adopts the following technical solutions:

[0006] In one aspect, the present application provides a drug controlled release system with chiral drug selective loading function, after the gelator self-assembles into supramolecular hydrogel, a supramolecular hydrogel selective loading system is prepared, and a chiral drug with the same optical rotation as the supramolecular hydrogel is loaded into the three-dimensional network structure of the supramolecular hydrogel.

[0007] The drug controlled release system with chiral drug selective loading function, the gelator is a substance that can be combined by supramolecular forces, and the gelator is one or more of phenylalanine derivatives, glucose derivatives, lysine derivatives, and dimeric cholesterol derivatives; the chiral drug is S-naproxen.

[0008] In a second aspect, the present application provides a preparation method of the drug controlled release system with chiral drug selective loading function, comprising the following steps:

[0009] (1) preparing a gelator;

[0010] (2) preparing a supramolecular hydrogel selective loading system;

[0011] (3) placing the supramolecular hydrogel selective loading system in a solution of a chiral drug, and taking it out after standing for 18-36 hours to obtain a chiral drug / supramolecular hydrogel drug controlled release system.

[0012] In the preparation method, when the gelator is a phenylalanine derivative, the specific process of preparing the gelator is as follows: (a) weighing terephthaloyl chloride and L-phenylalanine methyl ester hydrochloride, and adding them into a mixed solvent of triethylamine and dichloromethane, stirring under ice bath conditions, removing the solvent by rotary evaporation to obtain a precipitate, washing the precipitate with anhydrous ethanol, and then performing suction filtration and vacuum drying, dissolving the precipitate in anhydrous methanol, slowly adding 2M sodium hydroxide aqueous solution dropwise at 0°C, stirring at room temperature to completely dissolve the solid, and adding 3M hydrochloric acid solution dropwise to acidify to pH < 3 to obtain a gel-like solid, thereby obtaining an intermediate product 1;

[0013] (b) repeatedly washing the intermediate product 1 with deionized water, performing suction filtration, and vacuum drying, adding the dried intermediate product 1 into a mixed solvent of diethylene glycol and 12M hydrochloric acid, stirring under reflux, pouring into an ice water mixture to obtain a gel-like precipitate, filtering, collecting the precipitate, washing it with a large amount of deionized water, and performing freeze-drying to obtain the gelator.

[0014] In the preparation method, the mass ratio of the terephthaloyl chloride and L-phenylalanine methyl ester hydrochloride in step (a) is 2.4-2.8:5.8-6.2 g; the volume ratio of triethylamine to dichloromethane is 5-10:90-120; and the volume ratio of the anhydrous ethanol, the anhydrous methanol, and the 2M sodium hydroxide is 80-120:10-30:5-15.

[0015] The stirring time under ice bath condition is 24h, the temperature of vacuum drying is 60℃, and the stirring time at room temperature is 24h.

[0016] In the preparation method, the mass and volume ratio of the dried intermediate product 1, diethylene glycol, 12M hydrochloric acid and the ice water mixture in step (b) is 1.2-1.6g:30-50mL:0.8-1.2mL:80-120mL.

[0017] The temperature of vacuum drying is 60℃; the stirring condition under reflux is that the temperature is 135℃ and the time is 4h; and the time of freeze drying is 24h.

[0018] In the preparation method, the preparation process of the supramolecular hydrogel selective loading system in step (2) comprises the following steps: weighing the gelator, adding the gelator into deionized water, heating to obtain a clear solution, cooling at room temperature, and obtaining the supramolecular hydrogel selective loading system after complete gelation.

[0019] Preferably, the mass and volume ratio of the gelator and deionized water is 80-120mg:40-60mL; preferably, the heating condition is that the temperature is 95℃ and the time is 5min; and preferably, the cooling time is 30min.

[0020] In the preparation method, the mass and volume ratio of the supramolecular hydrogel and the solution of chiral drugs in step (3) is 26g:50mL, and the concentration of the solution of chiral drugs is 20-100μg / mL.

[0021] The use of the drug controlled release system in selective loading of chiral drugs.

[0022] The use of any one of the preparation methods in the preparation of the drug controlled release system with chiral drug selective loading function.

[0023] Compared with the prior art, the present application has the following beneficial effects:

[0024] The drug controlled release system with chiral drug selective loading function can realize selective loading of drugs with different configurations, and can realize controlled release of drugs in an alkaline environment. The drug controlled release system with chiral drug selective loading function is simple to prepare, and can be widely applied to separation and controlled release of chiral drugs. BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1 The nuclear magnetic resonance spectrum of the gelator in Example 1;

[0026] Figure 2UV absorption spectra of the supramolecular hydrogel in sol and gel state in Example 1;

[0027] Figure 3 IR spectra of the supramolecular hydrogel in Example 1;

[0028] Figure 4 Field emission scanning electron micrographs of the supramolecular hydrogel prepared with the concentration of the gelator being 2 mg / mL (A) and 0.02 mg / mL (B) respectively in Example 1;

[0029] Figure 5 Circular dichroism spectra of R / S-naproxen (A) and the supramolecular hydrogel (B) in Example 1;

[0030] Figure 6 UV absorption spectra of the supramolecular hydrogel in Example 1 for selective loading of S-naproxen (A) and R-naproxen (B) at 50 μg / mL for different time;

[0031] Figure 7 Drug release curve of S-naproxen in the S-naproxen / supramolecular hydrogel drug controlled release system under different pH conditions in Example 1. DETAILED DESCRIPTION

[0032] The present application will be further described in conjunction with the accompanying drawings and examples, which are intended to illustrate the present application rather than further limit the present application.

[0033] Example 1:

[0034] A preparation method of a drug controlled release system with selective loading function of chiral drugs, comprising the following steps:

[0035] (1) Take 2.6 g of terephthaloyl chloride and 6 g of L-phenylalanine methyl ester hydrochloride, add to a mixed solvent of 8 mL of triethylamine and 100 mL of dichloromethane, stir the resulting mixed solution in an ice bath for 24 h, remove the solvent by rotary evaporation, add 100 mL of anhydrous ethanol to the resulting solid, suction filter, vacuum dry the undissolved solid at 60℃, disperse the dried solid in 20 mL of anhydrous methanol, slowly add 10 mL of a 2M sodium hydroxide aqueous solution at 0℃, stir at room temperature for 24 h to completely dissolve the solid, add a 3M hydrochloric acid solution to the resulting clear solution, acidify to pH < 3 to obtain a gel-like solid, wash repeatedly with deionized water, suction filter, vacuum dry at 60℃, then take 1.4 g of the dried intermediate 1 and add to 40 mL of diethylene glycol and 1.2 mL of a 12M hydrochloric acid mixture, stir the mixed solution at 135℃ under reflux for 4 h, pour the reacted solution into 100 mL of an ice water mixture to obtain a gel-like precipitate, filter and wash with a large amount of deionized water, and freeze-dry the washed product for 24 h to obtain the gelator.

[0036] As shown in Figure 1 the nuclear magnetic resonance spectrum of the gelator is shown in the following figure, and the nuclear magnetic resonance data is as follows: 1 H NMR (400 MHz, DMSO-d6) δ: 3.06-3.19 (m, 4H), 3.41-3.51 (m, 8H), 3.51-3.61 (m, 4H), 4.18 (m, 4H), 4.60 (m, 2H), 4.67 (m, 2H), 7.15-7.32 (m, 10H), 7.83 (s, 4H), 8.99 (d, 2H), according to the chemical shift, peak splitting and peak area in the nuclear magnetic resonance data, the chemical structure of the target product can be one-to-one corresponding, which proves that the gelator is successfully prepared.

[0037] (2) Take 100 mg of the gelator and add to 50 mL of deionized water, heat the resulting solution at 95℃ for 5 min to obtain a clear solution, cool the heated solution at room temperature for 30 min, and the solution is completely gelled to obtain the supramolecular hydrogel selective loading system.

[0038] As shown in Figure 2 the ultraviolet absorption spectrum of the supramolecular hydrogel in the sol and gel states, the ultraviolet absorption peak of the supramolecular hydrogel in the sol state is at 248.5 nm, and the ultraviolet absorption peak in the gel state is at 245.0 nm, and the blue shift of the ultraviolet absorption peak proves that the supramolecular hydrogel is self-assembled by intermolecular hydrogen bonds.

[0039] As shown in Figure 3The infrared spectrum of the supramolecular hydrogel is shown. It can be seen from Figure 3 that the absorption peak at 1544 cm – 1 The absorption peak at 1737 cm – 1 The absorption peak at 3550-3250 cm – 1 The absorption peak of N-H in the range of 3550-3250 cm – 1 The absorption peak of C-O at 1639 cm

[0040] As shown in Figure 1, the supramolecular hydrogel was prepared by mixing the gelator and the drug solution. Figure 4 (A) and (B) are field emission scanning electron microscope images of the supramolecular hydrogel prepared by using the gelator at concentrations of 2 mg / mL and 0.02 mg / mL, respectively. It can be seen from Figure 4 (A) that the supramolecular hydrogel has a three-dimensional network structure and good drug loading space, and from Figure 4 (B) that the nanofibers constituting the three-dimensional network structure are in a spiral shape and have a diameter of about 50-65 nm, proving that the supramolecular hydrogel system has macroscopic chirality.

[0041] (3) 26 g of the supramolecular hydrogel was placed in 50 mL of an S-naproxen solution with a concentration of 50 μg / mL, and was taken out after 24 h to obtain an S-naproxen / supramolecular hydrogel drug controlled release system.

[0042] Example 2:

[0043] A preparation method of a drug controlled release system with a chiral drug selective loading function, comprising the following steps:

[0044] (1) 2.4 g of terephthaloyl chloride and 5.8 g of L-phenylalanine methyl ester hydrochloride were weighed and added to a mixed solvent of 5 mL of triethylamine and 90 mL of dichloromethane, and the resulting mixed solution was stirred for 24 h under ice bath conditions, and the solvent was removed by rotary evaporation. 80 mL of anhydrous ethanol was added to the resulting solid, and the undissolved solid was vacuum dried at 60°C. The dried solid was dispersed in 10 mL of anhydrous methanol, and 5 mL of a 2M aqueous sodium hydroxide solution was slowly added dropwise at 0°C. The solid was completely dissolved by stirring at room temperature for 24 h, and a 3M hydrochloric acid solution was added dropwise to the resulting clear solution to acidify it to pH < 3, thereby obtaining a gel-like solid. The intermediate 1 was repeatedly washed with deionized water, filtered, and vacuum dried at 60°C. Then, 1.2 g of the dried intermediate 1 was weighed and added to a mixed solvent of 35 mL of diethylene glycol and 1.0 mL of a 12M hydrochloric acid solution. The mixed solution was stirred at 135°C under reflux for 4 h, and the reaction solution was poured into 90 mL of an ice water mixture to obtain a gel-like precipitate. The precipitate was collected by filtration and washed with a large amount of deionized water. The washed product was freeze-dried for 24 h to obtain a gelator.

[0045] (2) 80 mg of the gelator was weighed and added to 40 mL of deionized water. The resulting solution was heated at 95°C for 5 min to obtain a clear solution. The heated solution was cooled at room temperature for 30 min, and the solution was completely gelled to obtain a supramolecular hydrogel selective loading system.

[0046] (3) 26 g of the supramolecular hydrogel was placed in 50 mL of a S-naproxen solution having a concentration of 20 μg / mL, and was taken out after 24 h to obtain a S-naproxen / supramolecular hydrogel drug release system.

[0047] Example 3:

[0048] A method of preparing a drug release system having a chiral drug selective loading function, comprising the steps of:

[0049] (1) Take 2.8 g of terephthaloyl chloride and 6.2 g of L-phenylalanine methyl ester hydrochloride, add to a mixed solvent of 10 mL of triethylamine and 120 mL of dichloromethane, stir the resulting mixed solution in an ice bath for 24 h, remove the solvent by rotary evaporation, add 120 mL of anhydrous ethanol to the resulting solid, suction filter, vacuum dry the undissolved solid at 60°C, disperse the dried solid in 30 mL of anhydrous methanol, slowly drop 15 mL of a 2M sodium hydroxide aqueous solution at 0°C, stir at room temperature for 24 h to completely dissolve the solid, drop a 3M hydrochloric acid solution into the resulting clear solution to acidify to pH < 3 to obtain a gel-like solid, repeatedly wash with deionized water, suction filter, vacuum dry at 60°C, then take 1.6 g of the dried intermediate 1 and add to a mixed solvent of 45 mL of diethylene glycol and 0.8 mL of 12M hydrochloric acid, stir the mixed solution at 135°C under reflux for 4 h, pour the reacted solution into 110 mL of an ice water mixture to obtain a gel-like precipitate, filter and wash with a large amount of deionized water, and freeze dry the washed product for 24 h to obtain the gelator.

[0050] (2) Take 120 mg of the gelator and add to 60 mL of deionized water, heat the resulting solution at 95°C for 5 min to obtain a clear solution, cool the heated solution at room temperature for 30 min, and when the solution is completely gelled, the supramolecular hydrogel selective loading system is obtained.

[0051] (3) Place 26 g of the supramolecular hydrogel in 50 mL of a 100 μg / mL S-naproxen solution, take it out after 24 h to obtain the S-naproxen / supramolecular hydrogel drug controlled release system.

[0052] Example 4:

[0053] The preparation steps of the drug controlled release system are the same as steps (1) and (2) in Example 1, only step (3) is different, as follows: take 26 g of the supramolecular hydrogel selective loading system and place in 50 mL of a 50 μg / mL R / S-naproxen solution, respectively, to selectively load the drug, take out 4 mL of the solution every hour during the drug loading process to determine the amount of loaded R / S-naproxen, use an ultraviolet-visible spectrophotometer to measure the characteristic absorption peak intensity of R / S-naproxen at 331 nm, calculate the concentration, and then calculate the encapsulation efficiency of the supramolecular hydrogel for different configurations of naproxen.

[0054] As shown in Figure 5 (A) and (B) are the circular dichrograms of R / S-naproxen and the supramolecular hydrogel, Figure 5As can be seen in (A), R-naproxen exhibits a positive Cotton effect at 231 nm, while S-naproxen exhibits a negative Cotton effect at 231 nm. In Figure 5 As can be seen in (B), the supramolecular hydrogel exhibits a negative Cotton effect at 230 nm, proving the existence of chirality of the supramolecular hydrogel. By comparing Figure 5 As can be seen by comparing (A) and (B), S-naproxen exhibits the same optical rotation as the supramolecular hydrogel, and since substances with the same optical rotation interact more strongly with each other, it can be inferred that the supramolecular hydrogel has a stronger loading capacity for S-naproxen.

[0055] As shown in Figure 6 (A) and (B) are UV absorption spectra of the selective loading of the supramolecular hydrogel with 50 μg / mL of S-naproxen (A) and 50 μg / mL of R-naproxen (B) for different times. As can be seen from Figure 6 As can be seen from (A) and (B), the absorbance of both S-naproxen and R-naproxen gradually decreases with time, but the absorbance of S-naproxen decreases more significantly at the same loading time. When 24 h is reached, the maximum encapsulation efficiency of the supramolecular hydrogel for S-naproxen is calculated to be 49.69%, while the maximum encapsulation efficiency of the supramolecular hydrogel for R-naproxen is only 32.48%. The difference in encapsulation efficiency proves that the supramolecular hydrogel has a selective loading capacity for chiral naproxen.

[0056] Example 5:

[0057] The S-naproxen / supramolecular hydrogel drug release system prepared in Example 1 was subjected to S-naproxen release under different pH conditions: the S-naproxen / supramolecular hydrogel drug release system prepared in step (4) was placed in a dialysis bag with a molecular weight cut-off of 500, and the dialysis bag was placed in 50 mL of hydrochloric acid solution with a pH of 1.2, phosphate buffer solution with a pH of 7.4, and sodium hydroxide solution with a pH of 10.0, respectively, and was subjected to constant temperature drug release in a 37°C water bath. During the drug release process, 4 mL of solution was taken out every hour to determine the amount of S-naproxen released, and 4 mL of fresh solution was added at the same time. The characteristic absorption peak intensity of S-naproxen at 331 nm was measured using a UV-visible spectrophotometer, and the concentration was calculated, thereby calculating the cumulative drug release percentage of S-naproxen at different times under different pH values.

[0058] The S-naproxen / supramolecular hydrogel drug release system prepared in Example 1 was subjected to S-naproxen release under different pH conditions: the S-naproxen / supramolecular hydrogel drug release system prepared in step (4) was placed in a dialysis bag with a molecular weight cut-off of 500, and the dialysis bag was placed in 50 mL of hydrochloric acid solution with a pH of 1.2, phosphate buffer solution with a pH of 7.4, and sodium hydroxide solution with a pH of 10.0, respectively, and was subjected to constant temperature drug release in a 37°C water bath. During the drug release process, 4 mL of solution was taken out every hour to determine the amount of S-naproxen released, and 4 mL of fresh solution was added at the same time. The characteristic absorption peak intensity of S-naproxen at 331 nm was measured using a UV-visible spectrophotometer, and the concentration was calculated, thereby calculating the cumulative drug release percentage of S-naproxen at different times under different pH values. Figure 7As shown, the release of S-naproxen has obvious dependence on pH value. The greater the pH value, the greater the cumulative release percentage of S-naproxen within the same drug release time. When the drug release reaches 42 h, the cumulative release percentages of S-naproxen at pH values of 1.2, 7.4 and 10.0 are 4.51%, 44.74% and 70.22%, respectively. This is because alkaline conditions are conducive to the deprotonation of the terminal carboxylic acid group, which exists in the form of carboxylate ion. The strong electrostatic interaction between carboxylate ions leads to the destruction of the hydrogen bond between the carbonyl group and the amide, and the hydrogel is decomposed, so that S-naproxen can be released from the supramolecular hydrogel under alkaline conditions.

Claims

1. A drug controlled release system having a chiral drug selective loading function, characterized in that, After the gelator self-assembles into a supramolecular hydrogel, a supramolecular hydrogel selective loading system is prepared, and a chiral drug with the same optical activity as the supramolecular hydrogel is loaded into the three-dimensional network structure of the supramolecular hydrogel; The gelator is a phenylalanine derivative; the chiral drug is S-naproxen; and the drug controlled release system can realize the controlled release of S-naproxen in an alkaline environment. The preparation method of the drug controlled release system with the chiral drug selective loading function comprises the following steps: (1) preparing a gelator; (2) preparing a supramolecular hydrogel selective loading system; the preparation process of the supramolecular hydrogel selective loading system comprises the following steps: weighing the gelator, adding it into deionized water, heating to obtain a clear solution, cooling at room temperature, and obtaining the supramolecular hydrogel selective loading system after complete gelation; (3) placing the above supramolecular hydrogel selective loading system into a solution of a chiral drug, taking it out after standing for 18-36 hours, and obtaining a chiral drug / supramolecular hydrogel drug controlled release system; The specific process for preparing the gelator is as follows: (a) weighing terephthaloyl chloride and L-phenylalanine methyl ester hydrochloride, adding them into a mixed solvent of triethylamine and dichloromethane, stirring under ice bath conditions, removing the solvent by rotary evaporation to obtain a precipitate, washing the precipitate with anhydrous ethanol, and then performing suction filtration and vacuum drying, dissolving the precipitate in anhydrous methanol, slowly adding 2M sodium hydroxide aqueous solution dropwise at 0℃, stirring at room temperature until the solid is completely dissolved, adding 3M hydrochloric acid solution dropwise, and acidifying to pH<3 to obtain a gel-like solid, thereby obtaining an intermediate product 1; (b) repeatedly washing the intermediate product 1 with deionized water, performing suction filtration, and vacuum drying, adding the dried intermediate product 1 into a mixed solvent of diethylene glycol and 12M hydrochloric acid, stirring under reflux, pouring into an ice water mixture to obtain a gel-like precipitate, filtering, collecting the precipitate, washing it with a large amount of deionized water, and performing freeze drying, thereby obtaining the gelator.

2. The drug controlled release system having a chiral drug selective loading function according to claim 1, wherein, In step (a), the mass ratio of the terephthaloyl chloride and L-phenylalanine methyl ester hydrochloride is 2.4-2.8g:5.8-6.2g; the volume ratio of the triethylamine and dichloromethane is 5-10:90-120; and the volume ratio of the anhydrous ethanol, anhydrous methanol, and 2M sodium hydroxide is 80-120:10-30:5-15. The stirring time under ice bath conditions is 24h, the vacuum drying temperature is 60℃, and the stirring time at room temperature is 24h.

3. The drug controlled release system having a chiral drug selective loading function according to claim 1, wherein, In step (b), the mass and volume ratio of the dried intermediate product 1, diethylene glycol, 12M hydrochloric acid, and ice water mixture is 1.2-1.6g:30-50mL:0.8-1.2mL:80-120mL. The vacuum drying temperature is 60℃; the stirring condition under reflux is that the temperature is 135℃ and the time is 4h; and the freeze drying time is 24h.

4. The drug controlled release system having a chiral drug selective loading function according to claim 1, wherein, In step (2), the mass and volume ratio of the gelator and deionized water is 80-120mg:40-60mL.

5. The drug controlled release system having a chiral drug selective loading function according to claim 1, wherein, In step (2), the heating condition is that the temperature is 95℃ and the time is 5min.

6. The drug controlled release system having a chiral drug selective loading function according to claim 1, wherein, The cooling time in step (2) is 30 min.

7. The drug controlled release system having a chiral drug selective loading function according to claim 1, wherein, The mass and volume ratio of the supramolecular hydrogel selective loading system and the solution of chiral drugs in step (3) is 26 g:50 mL, and the concentration of the solution of chiral drugs is 20-100 μg / mL.

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