Preparation method and application of transdermal preparation membrane capable of selectively permeating superior enantiomers
Polyclastic membranes prepared by surface molecular printing technology can selectively release the supernatural alien structure of hand -pharmaceutical ammloping, solve the problem of difficulty in achieving high efficiency and selective release in existing technology, and achieve efficient and economical economy. , Environmental drug release effect.
Patent Information
- Application Number
- CN202411371772.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-29
- Publication Date
- 2025-01-24
AI Technical Summary
The prior art is difficult to prepare a simple, stable, environmentally friendly permeable membrane that can selectively release the superior enantiomers in chiral drugs.
Using surface molecular printing technology, using polyphonic membranes containing derivative silicon microspheres as the base membrane, pre -effect through functional monomers and template molecules to prepare to selectively release surface molecular imprints that can selectively release the heterogeneous structure. membrane.
Achieve the selective release of the superior pharmaceutin of the opponent drug to the alien structure (S) -odipine), the cumulative release rate reaches 77%, rather than the superior opposite structure (R) -emida-ammonia-ammonia-ammonia The release rate of chlorine is only 5%. At the same time, the process is simple, the price is low, and the environment is friendly.
Abstract
Description
Technical Field
[0001] The present invention relates to the field of selectively releasing the superior enantiomer of chiral drugs. Background Art
[0002] Chiral drugs are relatively common in daily life. Currently, 60% of the total human drugs are chiral. During the absorption, distribution, metabolism and excretion process, chiral drugs will produce different pharmacological effects and adverse reactions by binding to different stereochemical macromolecules in the body. Amlodipine exists in two isomers, consisting of levorotatory amlodipine ((S)-amlodipine) and dextrorotatory amlodipine ((R)-amlodipine). It is a commonly used calcium channel blocker for the treatment of hypertension and is widely used in the long-term treatment of hypertension, arrhythmias, angina pectoris and other heart diseases. Studies have shown that (S)-amlodipine exhibits calcium channel blocking activity that is 1,000 times stronger than (R)-amlodipine, and (R)-amlodipine stimulates the release of nitric oxide in the veins, reduces the oxygen consumption of cardiac tissue, and produces adverse reactions such as edema and palpitations (Si DY, He YQ, Yang CY, NiLJ, Li B, Ding M, Yang P, American Journal of Hypertension, 2014, 27: 27). Therefore, the use of a single superior enantiomer (S)-amlodipine can improve the efficacy of the drug, reduce the incidence of peripheral edema and other side effects, reduce adverse drug reactions, and achieve better therapeutic effects. Currently, the methods for separating amlodipine enantiomers include crystallization, chromatography and capillary electrophoresis, but they each have their own shortcomings, such as: the steps are time-consuming and expensive, and they are not suitable for large-scale industrial production (Zhang LS, Song P, Long H, Meng M, Yin YM, Xi RM, Sensors and Actuators B-Chemical, 2017, 248, 682).
[0003] Polysulfone materials have excellent mechanical properties, good thermal stability, chemical stability and excellent membrane processing performance. In addition, polysulfone materials are inexpensive and the membrane making method is simple (Serbanescu OS, Voicu SI, Thakur VK, Materials Today Chemistry, 2020, 17, 100302). Therefore, polysulfone is widely used in the membrane industry and can be made into polymer membranes with various different needs.
[0004] Surface molecular imprinted polymers have a large number of imprinted cavities that are highly matched with the template molecules in terms of size, spatial structure, binding sites, etc., and show strong specific recognition of the template molecules. Chen Xiaoming's research group at Xiangtan University (Lai SZ, Chen CY, Ouyang XL, Qin YR, Cai CQ, Chen XM, Journal of Separation Science, 2016, 39: 4354) prepared surface imprinted polymer microspheres by core-shell precipitation polymerization for the enantioselective separation of amlodipine. The present invention uses surface molecular imprinting technology to design a transdermal preparation permeation membrane with specific recognition performance for the chiral drug amlodipine. The permeation membrane only selectively releases or mostly releases the superior enantiomer, which can avoid chiral separation or chiral synthesis. The design process is simple, low-cost, highly selective and environmentally friendly. The imprinted membrane shows excellent specific recognition and selective release capabilities for (S)-amlodipine. Summary of the invention
[0005] The technical problem to be solved by the present invention is: how to provide a permeable membrane which has simple preparation process, stable performance and is environmentally friendly and can selectively release the superior enantiomer in a chiral drug.
[0006] The technical solution adopted by the present invention is: a method for preparing a transdermal preparation membrane capable of selectively permeating the superior enantiomer, which is carried out according to the following steps: Step 1: Prepare a polysulfone-based membrane containing modified silica microspheres, modify silica microspheres using 3-aminopropyltrimethoxysilane KH-540 to obtain modified silica microspheres, place polysulfone particles, porogen PEG-400 and modified silica microspheres in a 1,2-dichloroethane solvent, stir to complete the reaction, and then use a phase inversion method to prepare a membrane to obtain a polysulfone-based membrane SiO2-NH2 / PSF containing modified silica microspheres; Step 2: pre-reacting the functional monomer with the template molecule, dissolving the template molecule (S)-amlodipine (S)-ADP and the functional monomer methacrylic acid MAA in a methanol aqueous solution and reacting them for 8-12 hours to obtain a prepolymer; Step 3, preparing a surface molecular imprinting membrane, soaking the polysulfone-based membrane SiO2-NH2 / PSF containing modified silica microspheres in a methanol aqueous solution to swell, adding a prepolymer, then adding a crosslinking agent, passing nitrogen to exhaust air, adding an initiator, and reacting under nitrogen protection to obtain a surface molecular imprinting membrane; Step 4: Elute the template molecules. Repeatedly wash the surface molecular imprinting membrane with an eluent to completely elute the template molecules, and vacuum dry to constant weight to obtain the (S)-amlodipine molecular surface imprinted polysulfone membrane PMAA@SiO2-NH2 / PSF-SMIM, which is a transdermal preparation membrane that can selectively permeate the dominant enantiomer.
[0007] In step 1, 0.2 mL of porogen PEG-400, 0.6 g to 1.8 g of modified silica microspheres and 25 mL of 1,2-dichloroethane solvent were paired for every 5.58 g of polysulfone particles; the stirring time was 8-12 h. In step 2, the volume ratio of methanol to water in the methanol-water solution was 5:2, and every 0.5 g of the template molecule (S)-amlodipine (S)-ADP corresponded to 1 mL to 2 mL of the functional monomer methacrylic acid MAA and 70 mL of methanol-water solution.
[0008] In step three, the cross-linking agent is N,N'-methylenebisacrylamide MBA, the initiator is ammonium persulfate Aps, the reaction temperature is 70°C to 80°C, and the reaction time is 8 h to 10 h.
[0009] In step 3, 0.3 g of polysulfone-based membrane SiO2-NH2 / PSF containing modified silica microspheres corresponds to 1.70 g to 2.06 g of crosslinking agent and 0.0132 g to 0.0265 g of initiator. In step 4, the eluent is a mixed solution of methanol / acetic acid, and the volume ratio of methanol to acetic acid in the mixed solution of methanol / acetic acid is 4:1.
[0010] The invention discloses an application of a transdermal preparation membrane capable of selectively permeating superior enantiomers. The transdermal preparation membrane capable of selectively permeating superior enantiomers can selectively permeate superior enantiomers of chiral drugs.
[0011] The transdermal preparation membrane capable of selectively permeating the superior enantiomer can selectively permeate the superior enantiomer (S)-amlodipine. For (R)-amlodipine, the selectivity coefficient of the imprinted membrane for (S)-amlodipine is 4.18. When the racemate passes through the permeable membrane, the cumulative release rate of (S)-amlodipine is 77%, and the cumulative release rate of (R)-amlodipine is 5%.
[0012] The invention uses a polysulfone membrane containing modified silica microspheres as a base membrane and adopts a surface molecular imprinting technology to prepare a surface molecular imprinting membrane capable of selectively releasing a chiral drug amlodipine. The imprinted membrane can be used as a permeation membrane for transdermal preparations, has good selective release performance for the chiral drug amlodipine, can selectively allow the superior enantiomer (S)-amlodipine to be permeated and released, and is a good transdermal preparation membrane capable of selectively permeating the superior enantiomer.
[0013] The beneficial effects of the present invention are as follows: (1) The surface molecular imprinting membrane PMAA@SiO2-NH2 / PSF-SMIM is used as a permeable membrane to selectively release the superior enantiomer. The surface molecular imprinting membrane PMAA@SiO2-NH2 / PSF-SMIM prepared by the method can selectively permeate the superior enantiomer, and the permeated superior enantiomer has a high cumulative release rate. The selectivity coefficient of PMAA@SiO2-NH2 / PSF-SMIM prepared by the method for (S)-amlodipine is 4.18 (relative to (R)-amlodipine). When the racemate passes through the permeable membrane, the cumulative release rate of (S)-amlodipine within 24 hours is 77%, while the cumulative release rate of (R)-amlodipine is only 5%. (2) The preparation process of the present invention uses a polysulfone membrane containing KH-540 modified silica microspheres as a base membrane, and adopts surface molecular imprinting technology to prepare the permeable membrane, which is low in price, easy to control, has high stability and is environmentally friendly. (3) The surface molecular imprinted membrane prepared by the present invention can be used as a permeation membrane for transdermal preparations, and only or mostly releases the superior enantiomer (S)-amlodipine during the drug permeation process, thereby avoiding chiral resolution or chiral synthesis. DETAILED DESCRIPTION
[0014] Example 1: 5.58 g of polysulfone particles, 0.2 mL of porogen PEG-400 and 1.2 g of modified silica microspheres modified with 3-aminopropyltrimethoxysilane KH-540 were placed in 25 mL of 1,2-dichloroethane solvent and mechanically stirred for 12 h. The polysulfone-based membrane SiO2-NH2 / PSF containing silica microspheres was obtained by phase inversion method. In a four-necked bottle, 0.3 g of the prepared polysulfone-based membrane SiO2-NH2 / PSF was soaked and swollen overnight in a mixed solution of 70 mL of methanol / water with a volume ratio of 5:2. 0.5 g of the template molecule (S)-amlodipine (S)-ADP and 1 mL of the functional monomer methacrylic acid MAA were dissolved in a mixed solution of 70 mL of methanol / water with a volume ratio of 5:2 and interacted for 12 h to obtain a prepolymer, which was added to the above four-necked bottle. Then add 1.88 g of cross-linking agent N,N'-methylenebisacrylamide MBA, and pass nitrogen for 30 minutes to exhaust the air. Dissolve 0.0198 g of initiator ammonium persulfate Aps in 5 mL of distilled water and slowly add it to the above four-necked bottle. Heat to 75 ° C and stir for 9 h under nitrogen protection. After the reaction, take out the membrane and soak and clean the membrane repeatedly with a methanol / acetic acid mixed solution with a volume ratio of 4:1 to completely elute the template molecules. Vacuum dry to constant weight to obtain (S)-amlodipine surface molecular imprinted polysulfone membrane PMAA@SiO2-NH2 / PSF-SMIM. Take 25 mL of 2.0 mg / mL amlodipine racemic solution and add it to a conical flask containing 0.05 g PMAA@SiO2-NH2 / PSF-SMIM imprinted membrane for S-ADP and R-ADP competitive adsorption experiment, and the selectivity coefficient is 4.18. 3 mL of 2.0 mg / mL amlodipine racemate was loaded into the supply pool of the drug transdermal diffusion instrument, PMAA@SiO2-NH2 / PSF-SMIM was used as the permeable membrane, 20% ethanol-normal saline was used as the receiving medium, and samples were taken from the receiving pool at certain time intervals. The cumulative release rate of (S)-amlodipine was 77% in 24 hours, while the cumulative release rate of (R)-amlodipine was only 5%.
[0015] Example 2: 5.58 g of polysulfone particles, 0.2 mL of porogen PEG-400 and 0.6 g of modified silica microspheres modified with 3-aminopropyltrimethoxysilane KH-540 were placed in 25 mL of 1,2-dichloroethane solvent and mechanically stirred for 12 h. The polysulfone-based membrane SiO2-NH2 / PSF containing silica microspheres was obtained by phase inversion method. In a four-necked bottle, 0.3 g of the prepared polysulfone-based membrane SiO2-NH2 / PSF was soaked and swollen overnight in a mixed solution of 70 mL of methanol / water with a volume ratio of 5:2. 0.5 g of the template molecule (S)-amlodipine (S)-ADP and 1.5 mL of the functional monomer methacrylic acid MAA were dissolved in a mixed solution of 70 mL of methanol / water with a volume ratio of 5:2 and interacted for 12 h to obtain a prepolymer, which was added to the above four-necked bottle. Then add 1.70 g of cross-linking agent N,N'-methylenebisacrylamide MBA, and pass nitrogen for 30 minutes to exhaust the air. Dissolve 0.0132 g of initiator ammonium persulfate Aps in 5 mL of distilled water and slowly add it to the above four-necked bottle. Heat to 70 ° C and stir for 8 h under nitrogen protection. After the reaction, take out the membrane and soak and clean the membrane repeatedly with a methanol / acetic acid mixed solution with a volume ratio of 4:1 to completely elute the template molecules. Vacuum dry to constant weight to obtain (S)-amlodipine surface molecular imprinted polysulfone membrane PMAA@SiO2-NH2 / PSF-SMIM. Take 25 mL of 2.0 mg / mL amlodipine racemic solution and add it to a conical flask containing 0.05 g PMAA@SiO2-NH2 / PSF-SMIM imprinted membrane for S-ADP and R-ADP competitive adsorption experiment, and the selectivity coefficient is 3.97. 3 mL of 2.0 mg / mL amlodipine racemate was loaded into the supply pool of the drug transdermal diffusion instrument, PMAA@SiO2-NH2 / PSF-SMIM was used as the permeable membrane, 20% ethanol-normal saline was used as the receiving medium, and samples were taken from the receiving pool at certain time intervals. The cumulative release rate of (S)-amlodipine was 70% in 24 hours, while the cumulative release rate of (R)-amlodipine was only 8%.
[0016] Example 3: 5.58 g of polysulfone particles, 0.2 mL of porogen PEG-400 and 1.8 g of modified silica microspheres modified with 3-aminopropyltrimethoxysilane KH-540 were placed in 25 mL of 1,2-dichloroethane solvent and mechanically stirred for 12 h. The polysulfone-based membrane SiO2-NH2 / PSF containing silica microspheres was obtained by phase inversion method. In a four-necked bottle, 0.3 g of the prepared polysulfone-based membrane SiO2-NH2 / PSF was soaked and swollen overnight in a mixed solution of 70 mL of methanol / water with a volume ratio of 5:2. 0.5 g of the template molecule (S)-amlodipine (S)-ADP and 2.0 mL of the functional monomer methacrylic acid MAA were dissolved in a mixed solution of 70 mL of methanol / water with a volume ratio of 5:2 and interacted for 12 h to obtain a prepolymer, which was added to the above four-necked bottle. Then add 2.06 g of cross-linking agent N,N'-methylenebisacrylamide MBA, and pass nitrogen for 30 minutes to exhaust the air. Dissolve 0.0265 g of initiator ammonium persulfate Aps in 5 mL of distilled water and slowly add it to the above four-necked bottle. Heat to 80 ° C and stir for 10 h under nitrogen protection. After the reaction, take out the membrane and soak and clean the membrane repeatedly with a methanol / acetic acid mixed solution with a volume ratio of 4:1 to completely elute the template molecules. Vacuum dry to constant weight to obtain (S)-amlodipine surface molecularly imprinted polysulfone membrane PMAA@SiO2-NH2 / PSF-SMIM. Take 25 mL of 2.0 mg / mL amlodipine racemic solution and add it to a conical flask containing 0.05 g PMAA@SiO2-NH2 / PSF-SMIM imprinted membrane for S-ADP and R-ADP competitive adsorption experiment, and the selectivity coefficient is 3.85. 3 mL of 2.0 mg / mL amlodipine racemate was loaded into the supply pool of the drug transdermal diffusion instrument, PMAA@SiO2-NH2 / PSF-SMIM was used as the permeable membrane, 20% ethanol-normal saline was used as the receiving medium, and samples were taken from the receiving pool at certain time intervals. The cumulative release rate of (S)-amlodipine was 68% in 24 hours, while the cumulative release rate of (R)-amlodipine was only 6%.
[0017] Example 4: 5.58 g of polysulfone particles, 0.2 mL of porogen PEG-400 and 1.8 g of modified silica microspheres modified with 3-aminopropyltrimethoxysilane KH-540 were placed in 25 mL of 1,2-dichloroethane solvent and mechanically stirred for 12 h. The polysulfone-based membrane SiO2-NH2 / PSF containing silica microspheres was obtained by phase inversion method. In a four-necked bottle, 0.3 g of the prepared polysulfone-based membrane SiO2-NH2 / PSF was soaked and swollen overnight in a mixed solution of 70 mL of methanol / water with a volume ratio of 5:2. 0.5 g of the template molecule (S)-amlodipine (S)-ADP and 1.0 mL of the functional monomer methacrylic acid MAA were dissolved in a mixed solution of 70 mL of methanol / water with a volume ratio of 5:2 and interacted for 12 h to obtain a prepolymer, which was added to the above four-necked bottle. Then add 1.70 g of cross-linking agent N,N'-methylenebisacrylamide MBA, and pass nitrogen for 30 minutes to exhaust the air. Dissolve 0.0265 g of initiator ammonium persulfate Aps in 5 mL of distilled water and slowly add it to the above four-necked bottle. Heat to 70 ° C and stir for 10 h under nitrogen protection. After the reaction, take out the membrane and soak and clean the membrane repeatedly with a methanol / acetic acid mixed solution with a volume ratio of 4:1 to completely elute the template molecules. Vacuum dry to constant weight to obtain (S)-amlodipine surface molecularly imprinted polysulfone membrane PMAA@SiO2-NH2 / PSF-SMIM. Take 25 mL of 2.0 mg / mL amlodipine racemic solution and add it to a conical flask containing 0.05 g PMAA@SiO2-NH2 / PSF-SMIM imprinted membrane for S-ADP and R-ADP competitive adsorption experiment, and the selectivity coefficient is 3.77. 3 mL of 2.0 mg / mL amlodipine racemate was loaded into the supply pool of the drug transdermal diffusion instrument, PMAA@SiO2-NH2 / PSF-SMIM was used as the permeable membrane, 20% ethanol-normal saline was used as the receiving medium, and samples were taken from the receiving pool at certain time intervals. The cumulative release rate of (S)-amlodipine was 66% in 24 hours, while the cumulative release rate of (R)-amlodipine was only 7%.
Claims
1. A method for preparing a transdermal preparation membrane capable of selectively permeating superior enantiomers, characterized in that: Follow the steps below Step 1: Prepare a polysulfone-based membrane containing modified silica microspheres, modify silica microspheres using 3-aminopropyltrimethoxysilane KH-540 to obtain modified silica microspheres, place polysulfone particles, porogen PEG-400 and modified silica microspheres in a 1,2-dichloroethane solvent, stir to complete the reaction, and then use a phase inversion method to prepare a membrane to obtain a polysulfone-based membrane SiO2-NH2 / PSF containing modified silica microspheres; Step 2: pre-reacting the functional monomer with the template molecule, dissolving the template molecule (S)-amlodipine (S)-ADP and the functional monomer methacrylic acid MAA in a methanol aqueous solution and reacting them for 8-12 hours to obtain a prepolymer; Step 3, preparing a surface molecular imprinting membrane, soaking the polysulfone-based membrane SiO2-NH2 / PSF containing modified silica microspheres in a methanol aqueous solution to swell, adding a prepolymer, then adding a crosslinking agent, passing nitrogen to exhaust air, adding an initiator, and reacting under nitrogen protection to obtain a surface molecular imprinting membrane; Step 4: Elute the template molecules. Repeatedly wash the surface molecular imprinting membrane with an eluent to completely elute the template molecules, and vacuum dry to constant weight to obtain the (S)-amlodipine molecular surface imprinted polysulfone membrane PMAA@SiO2-NH2 / PSF-SMIM, which is a transdermal preparation membrane that can selectively permeate the dominant enantiomer.
2. The method for preparing a transdermal preparation membrane capable of selectively permeating the superior enantiomer according to claim 1, characterized in that: In step 1, 0.2 mL of porogen PEG-400, 0.6 g to 1.8 g of modified silica microspheres and 25 mL of 1,2-dichloroethane solvent are mixed with every 5.58 g of polysulfone particles; the stirring time is 8-12 h.
3. The method for preparing a transdermal preparation membrane capable of selectively permeating the superior enantiomer according to claim 1, characterized in that: In step 2, the volume ratio of methanol to water in the methanol-water solution is 5:2, and every 0.5 g of the template molecule (S)-amlodipine (S)-ADP corresponds to 1 mL to 2 mL of the functional monomer methacrylic acid MAA and 70 mL of the methanol-water solution.
4. The method for preparing a transdermal preparation membrane capable of selectively permeating the superior enantiomer according to claim 1, characterized in that: In step three, the cross-linking agent is N,N'-methylenebisacrylamide MBA, the initiator is ammonium persulfate Aps, the reaction temperature is 70°C to 80°C, and the reaction time is 8 h to 10 h.
5. The method for preparing a transdermal preparation membrane capable of selectively permeating the superior enantiomer according to claim 4, characterized in that: In step three, 0.3 g of the polysulfone-based membrane SiO2-NH2 / PSF containing modified silica microspheres corresponds to 1.70 g to 2.06 g of a cross-linking agent and 0.0132 g to 0.0265 g of an initiator.
6. The method for preparing a transdermal preparation membrane capable of selectively permeating the superior enantiomer according to claim 1, characterized in that: In step 4, the eluent is a mixed solution of methanol / acetic acid, and the volume ratio of methanol to acetic acid in the mixed solution of methanol / acetic acid is 4:
1.
7. Use of a transdermal preparation membrane that selectively permeates the superior enantiomer prepared by the method for preparing a transdermal preparation membrane that selectively permeates the superior enantiomer according to any one of claims 1 to 6, characterized in that: The transdermal preparation membrane capable of selectively permeating the superior enantiomer can selectively permeate the superior enantiomer of the chiral drug.
8. Use of a transdermal preparation membrane capable of selectively permeating the superior enantiomer according to claim 7, characterized in that: The transdermal preparation membrane capable of selectively permeating the superior enantiomer can selectively permeate the superior enantiomer (S)-amlodipine. For (R)-amlodipine, the selectivity coefficient of the imprinted membrane for (S)-amlodipine is 4.
18. When the racemate passes through the permeable membrane, the cumulative release rate of (S)-amlodipine is 77%, and the cumulative release rate of (R)-amlodipine is 5%.