Biocompatible ionic liquid and use thereof

Abstract

The application discloses a kind of biocompatibility ionic liquid and its application, by as the matrine or choline of positive ion donor, as the valproic acid of negative ion donor and anhydrous ethanol mixed reaction, then, by rotary evaporation and vacuum drying and made into.The application is used as the solubilizer of poorly soluble active ingredient, compared with traditional organic solvent, toxicity is lower, more green environmental protection, biological friendly, and can greatly improve the solubility of poorly soluble active ingredient, improve the bioavailability of poorly soluble drug, ensure the safety of drug-loaded composition, improve the drug property of poorly soluble drug, widen the adaptive range of drug-loaded composition.

Description

Technical Field

[0001] This invention belongs to the field of ionic liquid technology, specifically relating to a biocompatible ionic liquid and its applications. Background Technology

[0002] Drug discovery and development face various challenges related to active pharmaceutical ingredients (APIs), including low solubility, poor permeability, physical transformation, and stability. Statistics show that over 40% of new chemical entities (NCEs) exhibit poor water solubility, severely limiting their bioavailability. Currently, 40% of marketed drugs and nearly 90% of drugs under development are poorly soluble, significantly hindering the progress of new drug development and market launch. Therefore, solubilization and absorption enhancement of drug molecules are crucial research topics in the pharmaceutical industry.

[0003] In recent years, an increasing number of studies have focused on developing more efficient drug delivery systems using ionic liquids (ILs) to improve the solubility and loading of poorly soluble drugs. Ionic liquids (ILs) are liquid mixtures formed under certain conditions by organic cations and inorganic or organic anions, typically with melting points below 100°C. ILs are simple to prepare and possess characteristics such as low volatility, high stability, high conductivity, and non-flammability. These characteristics highly align with the pharmaceutical philosophy of "green chemistry." Furthermore, ILs are "tunable," meaning their physical, chemical, and biological properties can be altered by selecting different anions and cations or different ratios of anions and cations. Due to their unique tunable physical, chemical, and biological properties, cosolvents or materials are used in drug delivery and active pharmaceutical ingredients (API) formulation.

[0004] These two characteristics give ILs a natural advantage in the pharmaceutical field. In drug synthesis, ILs can replace volatile organic solvents to extract active pharmaceutical ingredients (APIs) from natural products. In drug analysis, ILs can serve as mobile phases in various chromatographic systems, creating polar gradients by adjusting the polarity of the constituent ions. Currently, two-phase solvent systems containing ILs have been successfully applied to separate mixtures of natural products. In drug delivery, ILs increase drug solubility, improve drug stability, and enhance drug permeability. Furthermore, ILs can also serve as active pharmaceutical ingredients, forming novel API-ILs drug delivery systems to address the problems of low solubility, low bioavailability, and polymorphism in traditional drugs.

[0005] However, currently widely used traditional ionic liquids are not as environmentally friendly and sustainable as expected, making the development of a new generation of more environmentally friendly and sustainable ionic liquids a challenging task. To achieve this goal, using anion and cation counterparts derived entirely or partially from natural compounds is an ideal and sustainable approach. In recent years, research has primarily focused on the development of choline-based biorenewable ILs (Bio-ILs), resulting in a family of choline-based ILs. In addition, many bioactive natural compounds exist that can serve as raw materials for the synthesis of Bio-ILs, but these have not yet been fully explored.

[0006] Therefore, developing a new ionic liquid using bioactive natural compounds to solve the problem of drug solubilization, and simultaneously using it as an active pharmaceutical ingredient to form a novel API-ILs drug delivery system, is of great significance in the development of drug delivery technology. Summary of the Invention

[0007] The purpose of this invention is to overcome the shortcomings of the prior art and provide a biocompatible ionic liquid.

[0008] Another object of the present invention is to provide applications of the above-mentioned biocompatible ionic liquid.

[0009] The technical solution of the present invention is as follows:

[0010] A biocompatible ionic liquid is prepared by reacting matrine or choline as a cation donor, valproic acid as an anion donor, and anhydrous ethanol, followed by rotary evaporation and vacuum drying.

[0011] In a preferred embodiment of the present invention, the molar ratio of the cation donor to the anion donor is 1:1.

[0012] The above-mentioned biocompatible ionic liquids are used in the preparation of solubilizers for poorly soluble drugs.

[0013] In a preferred embodiment of the present invention, the poorly soluble drug solubilizer further includes deionized water in an amount equal to that of the biocompatible ionic liquid.

[0014] The use of the above-mentioned biocompatible ionic liquid in the preparation of antitumor compositions.

[0015] A poorly soluble drug solubilizer, the active ingredient of which includes the above-mentioned biocompatible ionic liquid.

[0016] In a preferred embodiment of the present invention, the active ingredient further includes deionized water in an amount equal to that of the biocompatible ionic liquid.

[0017] An antitumor composition comprising the above-mentioned biocompatible ionic liquid as its active ingredient.

[0018] A pharmaceutical composition comprising the above-mentioned poorly soluble drug solubilizer and a poorly soluble drug dissolved in the poorly soluble drug solubilizer.

[0019] In a preferred embodiment of the present invention, the poorly soluble drug includes verteporfen, PpIX, and nirored.

[0020] The beneficial effects of this invention are:

[0021] 1. As a solubilizer for poorly soluble active ingredients, this invention has lower toxicity compared to traditional organic solvents, is more environmentally friendly and bio-friendly, and can significantly improve the solubility of poorly soluble active ingredients, improve the bioavailability of poorly soluble drugs, ensure the safety of drug-loaded compositions, improve the drug-likeness of poorly soluble drugs, and broaden the scope of application of drug-loaded compositions.

[0022] 2. The synthesis method of this invention is simple, convenient and readily available, and can effectively increase the solubility of poorly soluble active ingredients. Furthermore, a large number of previous studies have confirmed that ionic liquids are also a good chemical penetration enhancer. Attached Figure Description

[0023] Figure 1 These are photographs of the choline-based ionic liquid and the matrine-based ionic liquid prepared in Example 1 of this invention.

[0024] Figure 2 The choline valproic acid in Example 2 of this invention 1 H NMR spectrum.

[0025] Figure 3 The matrine and valproic acid in Example 2 of this invention 1 H NMR spectrum.

[0026] Figure 4 Matrine oleic acid in Example 2 of this invention 1 H NMR spectrum.

[0027] Figure 5 Matrine and linoleic acid in Example 2 of this invention 1 H NMR spectrum.

[0028] Figure 6 This is a graph showing the effect of different ILs on the survival rate of HaCaT cells in Example 4 of the present invention.

[0029] Figure 7 This is a graph showing the effect of different ILs on the survival rate of B16 cells in Example 5 of the present invention. Detailed Implementation

[0030] The technical solution of the present invention will be further explained and described below with reference to specific embodiments and accompanying drawings.

[0031] Example 1

[0032] (1) Preparation of choline-based ionic liquids (choline valproic acid, choline oleic acid, choline linoleic acid, and choline ursolic acid): At room temperature, an equimolar amount of choline bicarbonate solution was slowly added to an equimolar amount of the corresponding fatty acid solution (solvent: anhydrous ethanol), dissolved, and stirred for 24 h. Then, the mixture was placed in a rotary evaporator and evaporated at 60°C and 100 rpm for 2 h to remove the anhydrous ethanol. The resulting product was placed in a vacuum drying oven and dried under vacuum at 60°C for 48 h to obtain the choline-based ionic liquid. Finally, it was placed in a desiccator and stored in a cool, dark place for later use. (See also...) Figure 1 .

[0033] (2) Preparation of matrine-based ionic liquids (matrine valproic acid, matrine oleic acid, matrine linoleic acid, matrine ursolic acid): Equimolar amounts of matrine and the corresponding fatty acids were dissolved in anhydrous ethanol (nitrogen gas was purged for 10 min before use to remove air from the ethanol) to obtain matrine and fatty acid solutions, respectively. The matrine solution was then slowly added to the fatty acid solution while stirring. The mixture was then stirred for 24 h at room temperature under a nitrogen atmosphere to ensure complete reaction between the matrine and fatty acids. The solvent was then removed by rotary evaporation at 60°C and 100 rpm for 2 h. The resulting product was placed in a vacuum drying oven and dried under vacuum at 60°C for 48 h to obtain the matrine-based ionic liquid. Finally, it was placed in a desiccator and stored in a cool, dark environment for later use. (See also...) Figure 1 .

[0034] Example 2

[0035] In this preferred embodiment, the ionic liquid synthesized in Example 1, which is liquid at room temperature, was used for proton NMR spectroscopy detection. Before measurement, the ionic liquid was placed in a vacuum drying oven at 60°C for 48 hours. Using a deuterated reagent as a solvent, the ionic liquid was measured using a Bruker AVANCE NEO 500 fully digital NMR spectrometer (Bruker GmbH, Germany). 1 The H spectrum was then analyzed using MestReNova software.

[0036] Choline, valproic acid, matrine, valproic acid, matrine, oleic acid, matrine, linoleic acid 1 See H NMR spectrum Figure 2 , 3 4, 5. Previous studies have found that ionic liquids synthesized from matrine and fatty acids, when analyzed by 1H NMR spectroscopy, show that the H atom on the carboxyl group of the fatty acid combines with the N atom far from the O atom on the matrine, producing a protonated amine group. Figure 3 For example, from top to bottom, the images show the 1H NMR spectra of valproic acid, matrine, and the ionic liquid synthesized from matrine and valproic acid. Figure 3 As can be seen in Figure a, the broad peak shift of the acidic proton in valproic acid is 9.41 ppm; Figure 3 The C-ray discrepancy (C-C) shows that in the synthetic product of matrine and valproic acid, the acidic proton peak of the fatty acid disappears, and a new structure is generated, corresponding to the protonated amino group, with a shift of 8.43 ppm. The 1H NMR spectrum indicates that the matrine-valproic acid ionic liquid was successfully synthesized.

[0037] Example 3

[0038] In this embodiment, verteporfin, PpIX, and nirored were selected as poorly soluble drug models to investigate the solubilizing effect of the ionic liquid prepared in Example 1 on poorly soluble drugs.

[0039] Excess drug was weighed and added to 1g of water, anhydrous ethanol, and ionic liquid respectively. After stirring evenly, the mixture was irradiated with ultrasound for 1 hour to ensure complete drug dissolution. The solution was centrifuged at 10000 rpm for 10 minutes, and the supernatant was the saturated drug solution. The solubility of the poorly soluble drug in different solutions was read using a multi-functional microplate reader based on the detection wavelengths of verteporfin (excitation wavelength: 689 nm and emission wavelength: 720 nm), protoporphyrin IX (excitation wavelength: 409 nm and emission wavelength: 633 nm), and Nile red (excitation wavelength: 555 nm and emission wavelength: 636 nm).

[0040] The results showed that the synthesized matrine valproic acid ionic liquid could significantly improve the solubility of poorly soluble drugs. See Table 1 for the solubility of three poorly soluble drugs—verteporfen, protoporphyrin IX, and nilored—in water, anhydrous ethanol, choline valproic acid, matrine valproic acid, matrine oleic acid, matrine linoleic acid, and matrine decanoic acid, respectively. The results indicated that the solubility of these three poorly soluble drugs in water was less than 0.5 μg / g, and the ionic liquid had a solubilizing effect on all three drugs. The solubilizing effect of matrine ILs was particularly significant, far exceeding that of anhydrous ethanol.

[0041] Table 1. Solubility of lipid-soluble drugs in different solvents (μg / g)

[0042]

[0043]

[0044] Example 4

[0045] This embodiment describes a method for detecting the cytotoxicity of the ionic liquid prepared in Example 1, including the following steps:

[0046] 1. Cell Culture

[0047] 1.1 Cell resuscitation

[0048] (1) Take out the DMEM complete culture medium from the 4℃ refrigerator and preheat it in a 37℃ constant temperature water bath for 30 min;

[0049] (2) Remove the frozen HaCaT cells from liquid nitrogen, quickly place them in a 37°C constant temperature water bath, gently shake them to thaw until there are no crystals in the cryovial, and then wipe the outer wall of the cryovial with 75% alcohol.

[0050] (3) Take 5 mL of complete culture medium into a 15 mL centrifuge tube, transfer the melted cell suspension from (2) into the centrifuge tube, and centrifuge at 1000 rpm for 5 min;

[0051] (4) Discard the supernatant, resuspend the precipitate in 10 mL of complete culture medium, inoculate it into a cell culture dish (d = 10 cm), and culture it in a 37°C, 5% CO2 cell culture incubator;

[0052] (5) On the second day, the culture was continued using fresh complete culture medium.

[0053] 2) Cell exchange medium

[0054] (1) Remove the cell culture dish from the incubator and remove the old complete culture medium from the culture dish;

[0055] (2) Add 3 mL of sterile 0.01 M PBS solution, gently shake, and wash twice to remove dead cells;

[0056] (3) Add 10 mL of fresh complete culture medium to the culture dish and continue to culture in the cell culture incubator.

[0057] 3) Cell passage

[0058] (1) When the cells have grown to cover 80% of the area of ​​the culture dish, remove the cell culture medium from the culture dish;

[0059] (2) Add 3 mL of sterile 0.01 M PBS solution, gently shake, and wash the cells twice;

[0060] (3) Add 1 mL of 0.25% trypsin digestion solution to the culture dish, digest for 4-5 min, observe under a microscope, and add 5 mL of complete culture medium to stop digestion after the cells shrink and become round.

[0061] (4) Gently pipette the cells to detach them, then transfer the suspension to a 15mL centrifuge tube and centrifuge at 1000rpm for 5min.

[0062] (5) Discard the supernatant, resuspend the precipitated cells in 2 mL of complete culture medium, and then passage them at a ratio of 1:4 (4 culture dishes). Add new complete culture medium to 10 mL, pipette a few times to disperse the cells evenly in the culture dishes, and finally place them in a 37°C, 5% CO2 cell culture incubator for culture. Change the medium once every 1 to 2 days.

[0063] 4) Cell cryopreservation

[0064] (1) When the cells have grown to cover 80% of the culture dish, collect the cells by centrifugation according to the cell digestion method in “Cell Passage” (steps (1) to (4));

[0065] (2) Discard the supernatant, add 1 mL of serum-free cryopreservation solution to the precipitated cells, mix well and add to the cryopreservation tube;

[0066] (3) Place the cryovial in a -20°C freezer for 2 hours, then quickly transfer it to a -80°C freezer, and after 24 hours place it in a liquid nitrogen tank for long-term storage.

[0067] 2. MTT assay for detecting the cytotoxic effects of ionic liquids

[0068] (1) Collect HaCaT cells in the logarithmic growth phase and adjust the cell suspension concentration to 1×10⁻⁶. 5 Cells / mL were aliquoted into 96-well plates, with 100 μL of cell suspension added to each well. Sterile PBS solution was then added to a ring of wells around the perimeter of the 96-well plate to reduce evaporation. Finally, the plates were incubated in a cell culture incubator for 24 hours.

[0069] (2) Preparation of ionic liquid solutions of different concentrations

[0070] Accurately weigh 50 mg of ionic liquid (choline valproic acid, matrine valproic acid, matrine oleic acid, matrine linoleic acid, and matrine decanoic acid), dissolve it in 5 mL of complete culture medium, and then filter it through a 0.22 μm filter membrane to remove bacteria and other impurities. Use this as a stock solution and add it to fresh complete culture medium to make the final concentrations of the ionic liquids 10 mg / mL, 8 mg / mL, 6 mg / mL, 5 mg / mL, 4 mg / mL, 3 mg / mL, 2 mg / mL, and 1 mg / mL, respectively.

[0071] (3) Remove the old culture medium from the 96-well plate and add 100 μL of the ionic liquid solutions of different concentrations prepared in (2). At the same time, set up control wells (cells, complete culture medium, MTT, Formazan lysate) and zeroing wells (complete culture medium, MTT, Formazan lysate). Set up 6 replicates for each group. Then put the cells into an incubator and incubate until the cells cover 80% of the bottom area of ​​the well.

[0072] (4) Carefully aspirate the supernatant, add 90 μL of fresh culture medium, then add 10 μL of MTT solution, and continue culturing for 4 h;

[0073] (5) Then carefully aspirate the supernatant (be careful not to aspirate the purple crystals at the bottom), and add 110 μL of Formazan solution to each well;

[0074] (6) Place the 96-well plate on a shaker and shake it at low speed for 10 minutes to fully dissolve the purple crystals. Finally, use an ELISA reader to measure the absorbance of each well at 490 nm.

[0075] (7) Calculate the survival rate of HaCaT cells at different IL concentrations and use GraphPad Prism 8.0.2 software to calculate the IC50 value of IL on HaCaT cells.

[0076] Table 2 IC50 values ​​of different ILs on HaCaT cells

[0077]

[0078] The toxicity of different ILs to human immortalized epidermal cells (HaCaT) was determined using the MTT assay. The effects of different ILs on HaCaT cell survival are shown in [link to MTT assay]. Figure 6 The results show that the toxicity of ILs to HaCaT cells gradually increases with increasing concentration. The cell survival rates at different IL concentrations were fitted to obtain the IC50 values ​​of each IL for HaCaT cells, as shown in Table 2. Numerous studies have demonstrated the safety of choline geranilic acid (CAGE) in transdermal drug delivery systems. In previous experiments, the IC50 value of CAGE for HaCaT cell toxicity was 3.06 mg / mL, while the IC50 value of matrine valproic acid was 4.12 mg / mL. The IC50 value of matrine valproic acid is higher than that of CAGE, indicating that matrine valproic acid has better cytotoxicity than CAGE. This suggests that matrine valproic acid has good biocompatibility and can be safely used in transdermal drug delivery systems. However, matrine oleic acid and matrine linoleic acid exhibit greater toxicity.

[0079] Example 5

[0080] This embodiment describes a method for detecting the anticancer activity of the ionic liquid prepared in Example 1, comprising the following steps:

[0081] 1. Cell Culture

[0082] 1.1 Cell resuscitation

[0083] (1) Take out the DMEM complete culture medium from the 4℃ refrigerator and preheat it in a 37℃ constant temperature water bath for 30 min;

[0084] (2) Remove the frozen B16 cells from the liquid nitrogen, quickly place them in a 37°C constant temperature water bath, gently shake them to thaw until there are no crystals in the cryovial, and then wipe the outer wall of the cryovial with 75% alcohol.

[0085] (3) Take 5 mL of complete culture medium into a 15 mL centrifuge tube, transfer the melted cell suspension from (2) into the centrifuge tube, and centrifuge at 1000 rpm for 5 min;

[0086] (4) Discard the supernatant, resuspend the precipitate in 10 mL of complete culture medium, inoculate it into a cell culture dish (d = 10 cm), and culture it in a 37°C, 5% CO2 cell culture incubator;

[0087] (5) On the second day, the culture was continued using fresh complete culture medium.

[0088] 2) Cell exchange medium

[0089] (1) Remove the cell culture dish from the incubator and remove the old complete culture medium from the culture dish;

[0090] (2) Add 3 mL of sterile 0.01 M PBS solution, gently shake, and wash twice to remove dead cells;

[0091] (3) Add 10 mL of fresh complete culture medium to the culture dish and continue to culture in the cell culture incubator.

[0092] 3) Cell passage

[0093] (1) When the cells have grown to cover 80% of the area of ​​the culture dish, remove the cell culture medium from the culture dish;

[0094] (2) Add 3 mL of sterile 0.01 M PBS solution, gently shake, and wash the cells twice;

[0095] (3) Add 1 mL of 0.25% trypsin digestion solution to the culture dish, digest for 2-3 min, observe under a microscope, and add 5 mL of complete culture medium to stop digestion after the cells shrink and become round.

[0096] (4) Gently pipette the cells to detach them, then transfer the suspension to a 15mL centrifuge tube and centrifuge at 1000rpm for 5min.

[0097] (5) Discard the supernatant, resuspend the precipitated cells in 2 mL of complete culture medium, and then passage them at a ratio of 1:4 (4 culture dishes). Add new complete culture medium to 10 mL, pipette a few times to disperse the cells evenly in the culture dishes, and finally place them in a 37°C, 5% CO2 cell culture incubator for culture. Change the medium once every 1 to 2 days.

[0098] 4) Cell cryopreservation

[0099] (1) When the cells have grown to cover 80% of the culture dish, collect the cells by centrifugation according to the cell digestion method in “Cell Passage” (steps (1) to (4));

[0100] (2) Discard the supernatant, add 1 mL of serum-free cryopreservation solution to the precipitated cells, mix well and add to the cryopreservation tube;

[0101] (3) Place the cryovial in a -20°C freezer for 2 hours, then quickly transfer it to a -80°C freezer, and after 24 hours place it in a liquid nitrogen tank for long-term storage.

[0102] 2. MTT assay for detecting the cytotoxic effects of ionic liquids

[0103] (1) Collect B16 cells in the logarithmic growth phase and adjust the cell suspension concentration to 1×10⁻⁶. 5 Cells / mL were aliquoted into 96-well plates, with 100 μL of cell suspension added to each well. Sterile PBS solution was then added to a ring of wells around the perimeter of the 96-well plate to reduce evaporation. Finally, the plates were incubated in a cell culture incubator for 24 hours.

[0104] (2) Preparation of ionic liquid solutions of different concentrations

[0105] Accurately weigh 50 mg of ionic liquid (choline valproic acid, matrine valproic acid, matrine oleic acid, matrine linoleic acid, and matrine decanoic acid), dissolve it in 5 mL of complete culture medium, and then filter it through a 0.22 μm filter membrane to remove bacteria and other impurities. Use this as a stock solution and add it to fresh complete culture medium to make the final concentrations of the ionic liquids 10 mg / mL, 8 mg / mL, 6 mg / mL, 5 mg / mL, 4 mg / mL, 3 mg / mL, 2 mg / mL, and 1 mg / mL, respectively.

[0106] (3) Remove the old culture medium from the 96-well plate and add 100 μL of the ionic liquid solutions of different concentrations prepared in (2). At the same time, set up control wells (cells, complete culture medium, MTT, Formazan lysate) and zeroing wells (complete culture medium, MTT, Formazan lysate). Set up 6 replicates for each group. Then put the cells into an incubator and incubate until the cells cover 80% of the bottom area of ​​the well.

[0107] (4) Carefully aspirate the supernatant, add 90 μL of fresh culture medium, then add 10 μL of MTT solution, and continue culturing for 4 h;

[0108] (5) Then carefully aspirate the supernatant (be careful not to aspirate the purple crystals at the bottom), and add 110 μL of Formazan solution to each well;

[0109] (6) Place the 96-well plate on a shaker and shake it at low speed for 10 minutes to fully dissolve the purple crystals. Finally, use an ELISA reader to measure the absorbance of each well at 490 nm.

[0110] (7) Calculate the survival rate of B16 cells at different IL concentrations. Use GraphPad Prism 8.0.2 software to calculate the IC50 values ​​of different ILs on B16 cells.

[0111] The toxicity of ILs to mouse melanoma B16 cells was determined using the MTT assay. The effects of different ILs on B16 cell survival are shown in [reference needed]. Figure 7 The results show that the toxicity of ILs to B16 cells gradually increases with increasing concentration. The IC50 values ​​of each IL for B16 cells were obtained by fitting the survival rates of B16 cells at different IL concentrations, as shown in Table 3. The biocompatible matrine valproic acid had an IC50 value of 6.07 mg / mL for B16 cells. When the concentration of matrine valproic acid reached 10 mg / mL, the survival rate of B16 cells was less than 10%, indicating a certain anti-melanoma activity.

[0112] Table 3 IC50 values ​​of different ILs against B16 cells

[0113]

[0114] Example 6

[0115] This embodiment measures the solubility of sparingly soluble active ingredients in aqueous solutions of ionic liquids with different proportions, including the following steps:

[0116] 1. Preparation of aqueous solutions of matrine / valproic acid / choline / valproic acid ionic liquids with different ratios.

[0117] Matrine valproic acid / choline valproic acid was mixed with pure water in three mass ratios of 1:1, 1:2, and 2:1, respectively, and the mixture was vortexed to ensure complete miscibility, thus obtaining three different ratios of matrine valproic acid / choline valproic acid aqueous solutions.

[0118] 2. Preparation of ionic liquid solutions of poorly soluble active ingredients

[0119] Weigh out an excess of verteporfen and add it to 1g of the above three ratios of matrine / valproic acid / choline / valproic acid aqueous solution. After stirring evenly, irradiate with ultrasound for 1 hour to ensure complete drug dissolution. Centrifuge at 10000 rpm for 10 minutes, and the supernatant is the ionic liquid solution of the poorly soluble active ingredient.

[0120] 3. Determine the solubilizing ability of ionic liquid aqueous solutions for poorly soluble drugs.

[0121] At room temperature, a multifunctional microplate reader was used to read the solubility of poorly soluble drugs in different solutions based on the detection wavelength of verteporfen (excitation wavelength: 689 nm and emission wavelength: 720 nm).

[0122] The results showed that the solubility of verteporfen was highest in aqueous solutions of both ionic liquids at a mass ratio of 1:1. The solubility of verteporfen in a 1:1 solution of matrine and valproic acid was 4180.14 ± 95.35 μg / g, and the solubility in a 1:1 solution of choline and valproic acid was 3226.86 ± 80.61 μg / g. Overall, matrine and valproic acid showed better solubility of verteporfen than choline and valproic acid.

[0123] Table 4. Solubility of verteporfen in aqueous solutions of ionic liquids with different proportions (μg / g)

[0124]

[0125] Example 7

[0126] This embodiment prepares an ionic liquid solution of a poorly soluble active ingredient, including the following steps:

[0127] 1. Preparation of matrine / valproic acid / choline / valproic acid ionic liquid aqueous solution

[0128] Matrine valproic acid / choline valproic acid was mixed with pure water at a mass ratio of 1:1 and vortexed to achieve complete miscibility, resulting in a 50% aqueous solution of matrine valproic acid / choline valproic acid.

[0129] 2. Preparation of ionic liquid solutions of poorly soluble active ingredients

[0130] Weigh out an excess of verteporfen and add it to 1g of the above-mentioned 50% matrine / valproic acid / choline / valproic acid aqueous solution. After stirring evenly, irradiate with ultrasound for 1 hour to ensure complete dissolution of the drug. Centrifuge at 10000 rpm for 10 minutes, and the supernatant is the ionic liquid solution of the poorly soluble active ingredient.

[0131] The solubility of vertepofen in a 50% matrine-valproic acid aqueous solution is 4180.14±95.35 μg / g, and the solubility in a 50% choline-valproic acid aqueous solution is 3226.86±80.61 μg / g. Compared with the solubility in pure IL, the solubility is increased, which greatly improves the bioavailability of the drug.

[0132] Verteporfen is a second-generation potent photosensitizer derived from porphyrins. The lipid formulation of verteporfen (Visudyne) has been approved for the treatment of age-related macular degeneration (AMD). Verteporfen exists as an equal mixture of two regioisomers, BPD-MAC and BPD-MAD, each consisting of a racemic mixture of the two enantiomers. BPD-MA has shown potential not only as an antiviral agent or for treating psoriasis but also as a photosensitizer for photodialysis (PDT) in non-melanoma skin cancers.

[0133] However, verteporfen is highly lipophilic and is a poorly soluble component. Therefore, ionic liquid solutions of this poorly soluble active ingredient can greatly increase its solubility and improve the drug's bioavailability.

[0134] The above description is merely a preferred embodiment of the present invention and should not be construed as limiting the scope of the present invention. All equivalent changes and modifications made in accordance with the scope of the patent and the contents of the specification should still fall within the scope of the present invention.

Claims

1. Use of an ionic liquid for the preparation of a solubilizer for poorly soluble drugs, characterized in that: The poorly soluble drug solubilizer also includes deionized water in an equal mass to the ionic liquid, wherein the ionic liquid is matrine valproic acid and the poorly soluble drug is vertepofen. The structural formula of matrine valproic acid is: .

Images