Application of sponge spicule and ionic liquid aqueous solution in preparation of permeation enhancing composition

Abstract

The invention discloses application of a sponge spicule and an ionic liquid aqueous solution in preparation of a penetration enhancing composition, the ionic liquid is matrine valproic acid, and the sponge spicule is a bee sponge spicule. According to the invention, the ionic liquid aqueous solution and the sponge spicule are combined for application, so that the skin cuticle barrier effect is overcome, the percutaneous absorption of the insoluble active component is effectively improved by utilizing the synergistic effect of the ionic liquid aqueous solution and the sponge spicule, and the toxicity of in-vivo administration of the insoluble active component is reduced at the same time.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical compositions, and in particular relates to the use of sponge spicules and ionic liquid aqueous solutions in preparing penetration-enhancing compositions. Background Art

[0002] During drug discovery and development, active pharmaceutical ingredients (APIs) often face problems such as low solubility, poor permeability, physical transformation and stability. These challenges are particularly evident in many new chemical entities (NCEs). These NCEs usually have poor water solubility, which limits their bioavailability. According to research, more than 40% of NCEs have poor solubility, and among the drugs already on the market, 40% are poorly soluble drugs.

[0003] To address these challenges, researchers have been exploring the use of ionic liquids (ILs) to improve drug solubility and bioavailability. ILs are a class of salts with unique physicochemical properties. They are liquid at room temperature and have low volatility, high stability, high conductivity, and are non-flammable, which is in line with the pharmaceutical concept of green chemistry.

[0004] In drug synthesis, ILs can replace volatile organic solvents to extract APIs from natural products. In drug analysis, ILs can be used as the mobile phase of the chromatographic system to form a polarity gradient by adjusting the polarity of the constituent ions. In drug delivery, ILs can increase the solubility, stability and permeability of drugs, and can even be used as active ingredients of drugs to form a new API-ILs drug delivery system.

[0005] However, although ILs have shown great potential in drug delivery, their biotoxicity remains a concern. Some traditional ILs have shown considerable toxicity in animal experiments, which limits their application in drug delivery. Therefore, the development of a new generation of more environmentally friendly and sustainable ILs is an important research direction in the field of medicine. In particular, the development of choline-based biorenewable ILs (Bio-ILs) has received widespread attention due to their good biocompatibility, low toxicity and high biodegradability.

[0006] Overall, ILs have promising applications in medicine, but further research is needed to reduce their toxicity and improve their safety and efficacy in drug delivery. Summary of the invention

[0007] The present invention aims to overcome the defects of the prior art and provide the use of sponge spicules and ionic liquid aqueous solution in preparing a penetration-enhancing composition.

[0008] The technical solution of the present invention is as follows:

[0009] The invention discloses use of sponge spicules and ionic liquid aqueous solution in preparing a penetration-enhancing composition. The ionic liquid is matrine valproic acid, and the sponge spicule is bee sponge spicule.

[0010] In a preferred embodiment of the present invention, in the ionic liquid aqueous solution, the mass ratio of the ionic liquid to pure water is 1:1.

[0011] A penetration-promoting composition comprises bee sponge spicules and an ionic liquid aqueous solution, wherein the ionic liquid is matrine and valproic acid.

[0012] In a preferred embodiment of the present invention, in the ionic liquid aqueous solution, the mass ratio of the ionic liquid to pure water is 1:1.

[0013] Use of the penetration-enhancing composition in preparing a percutaneous absorbent.

[0014] An active composition comprises bee sponge spicules and an ionic liquid aqueous solution containing an active ingredient that is poorly soluble in water, wherein the ionic liquid is matrine and valproic acid.

[0015] In a preferred embodiment of the present invention, in the ionic liquid aqueous solution, the mass ratio of the ionic liquid to pure water is 1:1.

[0016] In a preferred embodiment of the present invention, the poorly water-soluble active ingredients include verteporfin, protoporphyrin IX and Nile red.

[0017] Use of the above active composition in preparing a percutaneous absorption preparation.

[0018] The beneficial effect of the present invention is that the present invention combines the ionic liquid aqueous solution with the sponge bone needle, and while overcoming the barrier effect of the skin stratum corneum, utilizes the synergistic effect of the ionic liquid aqueous solution and the sponge bone needle to effectively increase the percutaneous absorption of the poorly soluble active ingredients, while reducing the toxicity of the poorly soluble active ingredients when administered in vivo. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 Shows the actual picture and state of the synthesized ionic liquid in Example 1 of the present invention.

[0020] Figure 2 The hydrogen nuclear magnetic resonance spectra of valproic acid (a), choline (b) and choline valproic acid (c) in Example 2 of the present invention are shown.

[0021] Figure 3 The nuclear magnetic resonance hydrogen spectra of valproic acid (a), matrine (b) and matrine valproic acid (c) in Example 2 of the present invention are shown.

[0022] Figure 4The nuclear magnetic resonance hydrogen spectra of oleic acid (a), matrine (b) and matrine oleic acid (c) in Example 2 of the present invention are shown.

[0023] Figure 5 The nuclear magnetic resonance hydrogen spectra of linoleic acid (a), matrine (b) and matrine linoleic acid (c) in Example 2 of the present invention are shown.

[0024] Figure 6 The effects of different ionic liquids in Example 3 of the present invention on the survival rate of HaCaT cells are shown.

[0025] Figure 7 The in vitro percutaneous PpIX absorption rate in Example 6 of the present invention is shown. DETAILED DESCRIPTION

[0026] The technical solution of the present invention is further illustrated and described below through specific implementation modes in combination with the accompanying drawings.

[0027] Example 1

[0028] This embodiment relates to a method for preparing and characterizing an ionic liquid, comprising the following steps:

[0029] (1) Preparation of choline fatty acid ionic liquids (choline valproate, choline oleic acid, choline linoleic acid, choline ursolic acid): At room temperature, slowly add an equimolar choline bicarbonate solution to an equimolar organic acid solution (if the organic acid is solid at room temperature, dissolve the organic acid in an appropriate amount of anhydrous ethanol to prepare an organic acid solution for use), dissolve, and stir for 24 hours. Then place the mixture in a rotary evaporator at 60°C, 100 rpm, and rotary evaporate for 2 hours to remove the solvent. The obtained product is placed in a vacuum drying oven and vacuum dried at 60°C for 48 hours to obtain a choline fatty acid ionic liquid. Finally, place it in a drying dish and store it in a cool, dark environment for use. The specific process is as follows Figure 1 shown.

[0030] (2) Preparation of matrine fatty acid ionic liquid (matrine valproic acid, matrine oleic acid, matrine linoleic acid, matrine ursolic acid): dissolve equimolar matrine and fatty acid in anhydrous ethanol (nitrogen was passed for 10 minutes before use to remove air in ethanol), and then slowly add the matrine solution to the fatty acid solution while stirring. Thereafter, stir the mixture in a nitrogen atmosphere at room temperature for 24 hours to allow matrine and fatty acids to fully react. Then place the mixture in a rotary evaporator at 60°C and 100 rpm, and rotary evaporate for 2 hours to remove the solvent. The obtained product was placed in a vacuum drying oven and vacuum dried at 60°C for 48 hours to obtain matrine fatty acid ionic liquid. Finally, place it in a drying dish and store it in a cool, dark environment for later use. The specific process is as follows Figure 1 shown.

[0031] (3) Nuclear magnetic resonance hydrogen spectrum detection of ionic liquids:

[0032] The ionic liquid that is successfully synthesized and in liquid form at room temperature is preferably subjected to nuclear magnetic resonance hydrogen spectrum detection. Before the measurement, the ionic liquid is placed in a vacuum drying oven at 60°C and vacuum dried for 48 hours. The deuterated reagent is used as the solvent and the Bruker AVANCE NEO 500 fully digital nuclear magnetic resonance spectrometer of the German Bruker company is used to measure the ionic liquid. 1 H spectrum, and then the spectrum analysis was performed using MestReNova software.

[0033] Choline valproate, matrine valproate, matrine oleate, matrine linoleate 1 H NMR spectrum Figure 2 , Figure 3 , Figure 4 and Figure 5 Previous studies have found that the ionic liquid synthesized from matrine and fatty acids, the nuclear magnetic resonance hydrogen spectrum shows that the H atom on the carboxyl group of the fatty acid will combine with the N atom far away from the O atom on matrine to produce a protonated amine group. Figure 3 For example, from top to bottom are the nuclear magnetic resonance hydrogen spectra of valproic acid, matrine, and the ionic liquid synthesized from matrine and valproic acid. In Figure a, it can be seen that the broad peak of acidic protons in valproic acid is shifted by 9.41ppm; in Figure c, in the synthetic product of matrine and valproic acid, the acidic proton peak of fatty acids disappears, and a new structure is generated, corresponding to the protonated amine group, with a shift of 8.43ppm. The nuclear magnetic resonance hydrogen spectrum shows that the matrine valproic acid ionic liquid was successfully synthesized.

[0034] Example 2

[0035] This embodiment relates to measuring the solubility of a poorly soluble drug, comprising the following steps:

[0036] Verteporfin, PpIX and Nile red were selected as models of poorly soluble drugs to explore the solubilization effect of ionic liquids on poorly soluble drugs.

[0037] Weigh an excess of the drug and add it to 1g of water, anhydrous ethanol, and ionic liquid, stir evenly, and then irradiate with ultrasound for 1h to fully dissolve the drug. Centrifuge at 10000rpm for 10min, and the supernatant is the saturated solution of the drug. A multifunctional microplate reader is used to read the solubility of poorly soluble drugs in different solutions according to the detection wavelengths of verteporfin (excitation wavelength: 689nm and emission wavelength: 720nm), protoporphyrin IX (excitation wavelength: 409nm and emission wavelength: 633nm), and Nile red (excitation wavelength: 555nm and emission wavelength: 636nm).

[0038] The results show that the synthesized matrine valproate ionic liquid can significantly improve the solubility of poorly soluble drugs. Table 1 shows the solubility of the three poorly soluble drugs, verteporfin, protoporphyrin IX and Nile red in Example 3 in water, anhydrous ethanol, choline valproate, matrine valproate, matrine oleic acid, matrine linoleic acid and matrine decanoic acid, respectively. The results show that the solubility of these three poorly soluble drugs in water is less than 0.5 μg / g, and the ionic liquid has a solubilizing effect on these three poorly soluble drugs, among which the solubilizing effect of matrine-based ILs is particularly significant, and the solubilizing effect on poorly soluble drugs is far greater than that of anhydrous ethanol.

[0039] Table 1 Solubility of fat-soluble drugs in different solvents (μg / g)

[0040]

[0041] Example 3

[0042] This embodiment relates to a method for detecting the cytotoxicity of an ionic liquid, comprising the following steps:

[0043] 1. Cell culture

[0044] 1.1 Cell recovery

[0045] (1) Take out DMEM complete medium from the 4°C refrigerator and preheat it in a 37°C constant temperature water bath for 30 min;

[0046] (2) Take out 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 cryotube, and then wipe the outer wall of the cryotube with 75% alcohol;

[0047] (3) Take 5 mL of complete culture medium and place it in a 15 mL centrifuge tube. Transfer the thawed cell suspension in (2) to the centrifuge tube and centrifuge at 1000 rpm for 5 min.

[0048] (4) Discard the supernatant, resuspend the precipitate in 10 mL of complete culture medium, inoculate into a cell culture dish (d = 10 cm), and culture in a cell culture incubator at 37°C and 5% CO2;

[0049] (5) The next day, fresh complete medium was used to continue the culture.

[0050] 2) Cell culture medium replacement

[0051] (1) Take out the cell culture dish from the incubator and remove the old complete culture medium in the dish;

[0052] (2) Add 3 mL of sterile 0.01 M PBS solution, shake gently, and wash twice to remove dead cells;

[0053] (3) Add 10 mL of fresh complete culture medium to the culture dish and continue to culture in the cell culture incubator.

[0054] 3) Cell passaging

[0055] (1) When the cells grow to cover 80% of the culture dish, remove the cell culture medium in the culture dish;

[0056] (2) Add 3 mL of sterile 0.01 M PBS solution and gently shake to wash the cells twice;

[0057] (3) Add 1 mL of 0.25% trypsin digestion solution to the culture dish and digest for 4 to 5 min. Observe under a microscope. When the cells shrink and become round, add 5 mL of complete culture medium to terminate the digestion.

[0058] (4) Gently blow the cells to dislodge them, then transfer the suspension to a 15 mL centrifuge tube and centrifuge at 1000 rpm for 5 min;

[0059] (5) Discard the supernatant and resuspend the precipitated cells in 2 mL of complete medium. Then, subculture them at a ratio of 1:4 (4 culture dishes). Add new complete medium to 10 mL and pipette several times to evenly disperse the cells in the culture dishes. Finally, culture the cells in a 37°C, 5% CO2 cell culture incubator. Change the medium every 1 to 2 days.

[0060] 4) Cell cryopreservation

[0061] (1) When the cells grow to cover 80% of the culture dish, collect the cells by centrifugation according to the cell digestion method in "Cell Passaging" (steps (1) to (4));

[0062] (2) Discard the supernatant, add 1 mL of serum-free freezing solution to the precipitated cells, mix well, and add to the cryopreservation tube;

[0063] (3) Place the cryovials in a -20°C refrigerator for 2 h, then quickly transfer to a -80°C refrigerator, and after 24 h place in a liquid nitrogen tank for long-term storage.

[0064] 2. MTT assay to detect the toxic effect of ionic liquids on cells

[0065] (1) Collect HaCaT cells in the logarithmic phase and adjust the cell suspension concentration to 1×10 5 cell / mL, divided into 96-well plates, 100 μL of cell suspension was added to each well, and sterile PBS solution was added to the wells around the 96-well plate to ease evaporation, and finally placed in a cell culture incubator for 24 h;

[0066] (2) Preparation of ionic liquid solutions of different concentrations

[0067] Accurately weigh 50 mg of ionic liquid (choline valproate, matrine valproate, matrine oleic acid, matrine linoleic acid and matrine decanoic acid), dissolve it in 5 mL of complete culture medium, then filter with a 0.22 μm filter membrane to remove impurities such as bacteria, use this as the mother liquor, add it to fresh complete culture medium, and 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, 1 mg / mL, respectively.

[0068] (3) removing the old culture medium in the 96-well plate, and then adding 100 μL of the ionic liquid solution of different concentrations prepared in (2), setting control wells (cells, complete culture medium, MTT, Formazan solution), zeroing wells (complete culture medium, MTT, Formazan solution), and setting 6 replicate wells for each group; then placing the cells in an incubator and incubating them until the cells cover 80% of the bottom area of ​​the well;

[0069] (4) Carefully remove the supernatant, add 90 μL of fresh culture medium, then add 10 μL of MTT solution, and continue culturing for 4 h;

[0070] (5) Then carefully aspirate the supernatant (be careful not to aspirate the purple crystalline substance at the bottom) and add 110 μL of Formazan solution to each well;

[0071] (6) Place the 96-well plate on a shaker and shake at low speed for 10 min to allow the purple crystalline substance to fully dissolve. Finally, use an ELISA reader to measure the absorbance of each well at 490 nm.

[0072] (7) The survival rate of HaCaT cells at different IL concentrations was calculated, and the IC50 value of IL for HaCaT cells was calculated using GraphPad Prism 8.0.2 software.

[0073] Table 2 IC50 values ​​of different ILs on HaCaT cells

[0074]

[0075] The toxicity of different ILs to human immortalized epidermal cells HaCaT was determined by MTT assay. Figure 6As shown. From the results, it can be seen that the toxicity of ILs to HaCaT cells gradually increases with the increase of concentration. The survival rate of cells under different IL concentrations was fitted to obtain the IC50 value of each IL for HaCaT cells (as shown in Table 2). A large number of studies have demonstrated the safety of choline geranyl acid (CAGE) in transdermal delivery systems. In previous experiments, the IC50 value of CAGE toxicity to HaCaT cells was 3.06 mg / mL, while the IC50 value of matrine valproate was 4.12 mg / mL. The IC50 value of matrine valproate is higher than that of CAGE, so the cytotoxicity of matrine valproate is better than that of CAGE, which means that matrine valproate has good biocompatibility and can be safely used in transdermal delivery systems. However, matrine oleic acid and matrine linoleic acid are more toxic.

[0076] Example 4

[0077] This example measures the solubility of the poorly soluble active ingredient in aqueous ionic liquid solutions at different ratios, comprising the following steps:

[0078] 1. Preparation of different ratios of matrine valproate / choline valproate ionic liquid aqueous solutions

[0079] Matrine valproate / choline valproate and pure water were mixed in three mass ratios of 1:1, 1:2 and 2:1, respectively, and vortexed to fully dissolve each other, thereby obtaining three aqueous solutions of matrine valproate / choline valproate in different ratios.

[0080] 2. Preparation of ionic liquid solutions of poorly soluble active ingredients

[0081] An excess amount of verteporfin was weighed and added to 1 g of the above three ratios of matrine valproate / choline valproate aqueous solution, stirred evenly, and then ultrasonically irradiated for 1 hour to fully dissolve the drug. Centrifuged at 10000 rpm for 10 minutes, and the supernatant was the ionic liquid solution of the poorly soluble active ingredient.

[0082] 3. Determination of the solubilization ability of ionic liquid aqueous solutions for poorly soluble drugs

[0083] At room temperature, a multifunctional microplate reader was used to read the solubility of the poorly soluble drugs in different solutions according to the detection wavelength of verteporfin (excitation wavelength: 689 nm and emission wavelength: 720 nm).

[0084] The results are shown in Table 3. For both ionic liquids, the solubility of verteporfin is the maximum in the ionic liquid aqueous solution with a mass ratio of 1:1. It can be seen that the ionic liquid aqueous solution with a mass ratio of 1:1 can increase the solubility of poorly soluble active ingredients. The solubility of verteporfin in the matrine valproic acid aqueous solution with a mass ratio of 1:1 is 4180.14±95.35μg / g, and the solubility in the choline valproic acid aqueous solution with a mass ratio of 1:1 is 3226.86±80.61μg / g. In general, the dissolution effect of matrine valproic acid on verteporfin is better than that of choline valproic acid.

[0085] Table 3 Solubility of verteporfin in aqueous solutions of ionic liquids at different ratios (μg / g)

[0086]

[0087]

[0088] Example 5

[0089] The present embodiment prepares the sponge spicule solution and the sponge spicule gel, comprising the following steps:

[0090] 1. Prepare sponge spicule solution

[0091] 1 mL of deionized water was added to 50-100 mg of bee sponge spicules to prepare a 5-10% bee sponge spicule solution.

[0092] 2. Preparation of sponge spicule gel

[0093] First, prepare carbomer gel. Weigh 94.36g of ultrapure water into a beaker, add 5g of propylene glycol, stir and mix evenly, then add 0.5g of carbomer, stir thoroughly until the carbomer is completely swollen, and finally add 0.14g of sodium hydroxide, stir until it becomes a gel, and store at 4°C. Bee sponge spicules can be added in any proportion to prepare sponge spicule gel.

[0094] Example 6

[0095] This embodiment combines sponge spicules and ionic liquid aqueous solution to synergistically deliver verteporfin in vitro, including the following steps:

[0096] 1. Preparation of aqueous solution of poorly soluble drug ionic liquid:

[0097] (1) Preparation of 50% ionic liquid aqueous solution (IL-H2O): 1 g of matrine-valproate ionic liquid was placed in a 5 mL centrifuge tube, 1 g of pure water was added, vortexed, ultrasonicated for 30 min, and mixed to obtain a 50% ionic liquid aqueous solution.

[0098] (2) Preparation of poorly soluble drug ionic liquid aqueous solution: Weigh 1 mg of PpIX into a 5 mL centrifuge tube, then add 2 g of 50% ionic liquid aqueous solution, and use a disposable inoculating loop to stir so that PpIX is evenly dispersed in the ILs; then place the centrifuge tube at 30°C for 30 min, stir evenly with an inoculating loop, and sonicate again for 30 min to help PpIX completely dissolve in IL-H2O. The final concentration of PpIX in IL-H2O is 500 μg / g.

[0099] 2. In vitro transdermal test

[0100] The experimental material for in vitro transdermal transfection was selected from in vitro pig skin with intact stratum corneum. First, the pig skin was taken out of the refrigerator and thawed naturally at room temperature. The pig skin was pretreated, and the fat tissue below the dermis was carefully scraped off with a scalpel, and then the hair on the surface of the pig skin was shaved to less than 5 mm with an electric shaver. After the pig skin was processed, it was cleaned with ultrapure water. A piece of pig skin was knocked off with a circular punch with a diameter of 40 mm and fixed on the Franz diffusion transdermal device, with the stratum corneum facing up and the dermis in contact with the receiving pool solution (0.2M PBS solution).

[0101] In order to detect the integrity of the skin barrier, the skin conductivity was measured by ex vivo transcutaneous resistance test. That is, a waveform generator was used to detect the current through the pig skin under the conditions of 100mV and 100Hz, and the pig skin with a current value less than 5μA (intact skin barrier) was selected. The drug delivery area of ​​the Franz diffusion cell was 1.77cm 2 The volume of the receiving pool was 12 mL, and the solution added to the receiving pool was a 0.2 M PBS solution containing 1% Tween 80. The in vitro transdermal experiment was divided into 4 experimental groups, each with 3 parallels.

[0102] Blank group: 0.20 g of drug-free ILs aqueous solution (matrine valproate, choline valproate) was added to the administration cavity;

[0103] Control group: a saturated solution of 0.20 g PpIX in 30% ethanol was added to the administration cavity;

[0104] ILs group: 0.20 g of the prepared PpIX ionic liquid aqueous solution was added into the administration cavity;

[0105] SHS+ILs group: According to the contour of the dosing cavity, a wide tape was cut and covered on the pig skin, 100 μL of a 100 mg / mL SHS aqueous solution (prepared in Example 5) was added to the skin surface of the dosing area, and massaged evenly with fingers for 5 min. The dosing cavity was then rinsed with ultrapure water 5 times to wash away the residual spicules, and the pig skin surface was wiped dry with a paper towel, and 0.20 g of the above-prepared PpIX ionic liquid aqueous solution was added to the dosing cavity.

[0106] After the drug is added to the dosing cavity, the Franz diffusion transdermal device is gently rotated so that the drug is evenly spread on the dosing site, a magnetic stirring rotor is added to the receiving pool, and the dosing cavity and the receiving pool outlet are sealed with a sealing film. Then each group of Franz diffusion transdermal devices is placed in a 37°C circulating water bath, and the receiving pool solution is stirred at a speed of 600r / min, and the light-proof permeation is performed for 16 hours. After the transdermal operation, the dosing cavity is cleaned 5 times with anhydrous ethanol to remove the residual drug, and then the pig skin is removed, wrapped with aluminum foil and stored in a -20°C refrigerator for future use. Take 2mL of the solution in the receiving pool into a 2mL centrifuge tube, store it in a 4°C refrigerator, and reserve it.

[0107] 3. Extraction of drugs from various layers of the skin

[0108] The tape stripping method was used to separate the stratum corneum and measure the drug content in each skin layer. The permeated pig skin was placed on the stripping device and fixed. The stratum corneum was peeled off 10 times with transparent tape, and the peeled stratum corneum was placed in a brown glass bottle; after the stratum corneum was peeled off, the active epidermis was separated with a scalpel and placed in a brown glass bottle; the remaining dermis was punched with a 5mm diameter punch to take 2 pieces of dermis, which were chopped with a scalpel and placed in a brown glass bottle. 4mL of methanol was added to each glass bottle, and then the glass bottle was placed in a shaker at 25℃ and 180rpm for 24h to fully extract PpIX in the cortex. After the extraction was completed, the extract was collected, centrifuged at 5000rpm for 5min, and 1mL of supernatant was taken to measure the content of PpIX.

[0109] 4. Detection and calculation of drug content in each cortex

[0110] Determine the standard curve, put the extracts of different cortical layers and the solutions of the receptor pool into the ELISA instrument to detect the fluorescence values, and then substitute them into the standard curves of the extracts and the receptor pool respectively to calculate the drug content.

[0111] The results are as follows Figure 7 As shown, the penetration-enhancing effect of ionic liquid aqueous solution alone on protoporphyrin IX is relatively small, and protoporphyrin IX can hardly reach the dermis; however, after the combined use of ionic liquid aqueous solution and sponge spicules, the penetration depth and percutaneous absorption rate of protoporphyrin IX are greatly improved, and the penetration-enhancing effect is better than the previous pure ionic liquid synergistically used bee sponge spicules to deliver PpIX.

[0112] Example 7

[0113] This embodiment combines sponge bone needles and ionic liquid aqueous solution to administer drugs to live mice, including the following steps:

[0114] C57BL / 6 female mice aged 5-6 weeks were purchased and kept in an animal center for one week. The experiment was performed when the mice were in good condition. The mice were randomly divided into 3 groups, 4 in each group. After the mice were anesthetized, the hair on the back of the mice was shaved with an electric shaver. Be careful not to shave the skin and keep it intact. Then a 1.77cm bottom area was placed on the 2 The hollow drug delivery pool was fixed on the shaved back of the mouse to ensure that the drug delivery area was 1.77 cm 2 .

[0115] Blank group: no treatment;

[0116] SHS+ionic liquid group: 200 mg of SHS gel (prepared in Example 5, containing 10 mg of SHS) was added to the dosing pool, and massaged manually for 2 min, and then the SHS gel remaining on the skin surface was carefully wiped off with saline wipes; 50 μL of matrine valproate solution with a PpIX content of 500 μg / g was added to the dosing pool;

[0117] SHS+ionic liquid aqueous solution group: 200 mg SHS gel (containing 10 mg SHS) was added to the dosing pool, and the skin was manually massaged for 2 min, and then the SHS gel remaining on the skin surface was carefully wiped off with saline wipes; 50 μL of matrine valproate aqueous solution with a content of 500 μg / g of PpIX was added to the dosing pool (preparation method see Example 6);

[0118] After the administration, the mice were kept away from light for 24 hours and then observed. It was found that all the mice in the SHS+ionic liquid group died, while the mice in the SHS+ionic liquid aqueous solution group were in good condition. After four administrations in a three-day cycle, the mice in the SHS+ionic liquid aqueous solution group grew healthily. It can be seen that the ionic liquid aqueous solution combined with bee sponge spicules can not only improve the solubility and bioavailability of drugs, improve drug delivery efficiency, but also ensure the safety and effectiveness of drug administration in animal experiments.

[0119] The above description is only a preferred embodiment of the present invention, and therefore cannot be used to limit the scope of the present invention. That is, equivalent changes and modifications made according to the patent scope of the present invention and the contents of the specification should still fall within the scope of the present invention.

Claims

1. Use of sponge spicules and ionic liquid aqueous solution in preparing a penetration-enhancing composition, characterized in that: The ionic liquid is matrine valproic acid, and the sponge spicule is a bee sponge spicule.

2. The use according to claim 1, characterized in that: In the ionic liquid aqueous solution, the mass ratio of the ionic liquid to pure water is 1:

1.

3. A penetration-enhancing composition, characterized in that: The invention comprises bee sponge spicules and an ionic liquid aqueous solution, wherein the ionic liquid is matrine valproic acid.

4. A penetration-enhancing composition according to claim 3, characterized in that: In the ionic liquid aqueous solution, the mass ratio of the ionic liquid to pure water is 1:

1.

5. Use of the penetration-enhancing composition according to claim 3 or 4 in the preparation of a percutaneous absorption agent.

6. An active composition, characterized in that: The invention comprises bee sponge spicules and an ionic liquid aqueous solution containing an active component which is hardly soluble in water, wherein the ionic liquid is matrine and valproic acid.

7. An active composition according to claim 6, characterized in that: In the ionic liquid aqueous solution, the mass ratio of the ionic liquid to pure water is 1:

1.

8. An active composition according to claim 6 or 7, characterized in that: The poorly water-soluble active ingredients include verteporfin, protoporphyrin IX and Nile red.

9. Use of the active composition according to any one of claims 6 to 8 in the preparation of a percutaneous absorption preparation.

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