CN115944742A - Ionic liquid for preparing nano-medicament and preparation method and application thereof - Google Patents

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and relates to an ionic liquid for preparing nano-drugs, a preparation method and application thereof. The invention takes choline, betaine, amino acid, nicotinamide and meglumine cation ionic liquid with good biocompatibility as a solvent of insoluble drugs, adopts a solvent-non-solvent mixed precipitation method to prepare nanoparticles of the insoluble drugs, and controls the particle size of the nanoparticles through the ionic liquid. The invention uses the biocompatible ionic liquid to replace the traditional organic solvent to prepare the drug nanoparticles, can reduce the environmental pollution, solves the potential safety hazard of organic solvent residue in the product, can recycle the ionic liquid, and accords with the green chemical development trend. The invention has good application prospect as a green pharmaceutical technology.

Description

Ionic liquid for preparing nano-medicament and preparation method and application thereof

Technical Field

The invention belongs to the technical field of pharmaceutical preparations, relates to an ionic liquid, a preparation method and application thereof, in particular to an ionic liquid for preparing nano-drugs, a preparation method and application thereof, and particularly relates to application of preparing drug nano-particles and controlling particle size by using the ionic liquid as a solvent.

Background

The prior art discloses that the drug nanoparticles are particles which mainly consist of drugs and have the particle size of 50-1000nm, and can be drug crystals or amorphous particles of the drugs. Studies have shown that when the particle size of the drug is reduced to the nanoscale, the specific surface area and curvature of the system are significantly increased, allowing for a faster dissolution rate of the drug. Therefore, for insoluble drugs, the nano-particle oral administration prepared from the insoluble drugs can improve the dissolution rate and the oral bioavailability of the insoluble drugs, and currently, more than ten kinds of pharmaceutical preparations based on the technology are applied to clinic, thereby achieving remarkable success. Due to the advantages of large drug-loading rate and stable in-vivo and in-vitro properties, the insoluble drug nanoparticles show great application prospects in the aspects of injection administration, transdermal administration, ocular administration and pulmonary administration. The exertion of the function of the nano-particles is closely related to the particle size and the particle size distribution, and the particle size also relates to the safety of medication for the administration route such as intravenous injection. Therefore, the development of controllable preparation technology of drug nanoparticles is crucial for its application.

The preparation technology of the drug nanoparticles mainly comprises top-down and bottom-up. The Top-down technology adopts high-energy mechanical force to crush drug crystals to a nano scale, and the currently marketed nanoparticle preparations are basically prepared by the technology. The technology has the advantages of simple method and strong production scale expansion capability. However, this technique is not ideal for particle size control, and often requires long (hours to days) milling and homogenization treatments to reduce the average particle size of the drug crystals to the nanometer scale, even though the particle size distribution may be broad; the continuous energy input also increases the risk of shedding of grinding media, contamination with impurities. This greatly limits the application prospects of nanoparticles and is also not suitable for thermally unstable drugs. The Bottom-up method is a technique for growing drug particles from a solution, and the most common method is a method in which a drug solvent and a non-solvent are mixed to precipitate out a precipitate. In contrast, the bottom-up method has the advantages of time saving, energy saving and suitability for temperature sensitive medicines. However, the use of organic solvents in the bottom-up process causes great burden to the environment, does not meet the development requirement of current 'green chemistry', and the residual organic solvents in the system also cause great damage to the stability and safety of the product. More importantly, the bottom-up process is extremely challenging in controlling particle size and its distribution, since the process involves nucleation and growth, with fast nucleation and slow growth being the key to obtaining small and uniform nanocrystals. In the bottom-up process, a drug solvent is mixed with a non-solvent to form a supersaturated solution of the drug, promoting the formation of drug nuclei, which then grow spontaneously until the drug concentration has decreased to its solubility. The faster the nucleation speed, the more nuclei are generated, the more solute is consumed, and the growth of the nuclei is inhibited; if these nuclei are formed simultaneously, they grow simultaneously, and a small and uniform crystal is obtained. The supersaturation is the only power for promoting nucleation, and more supersaturation is often needed for promoting nucleation, however, because the organic solvent diffuses faster, the supersaturated solution of the drug is already formed locally in the process of mixing with the non-solvent, and crystal nuclei are generated, and the unsynchronized nucleation process causes the crystal nuclei to grow successively, so that the uneven distribution of the crystal particle size is caused, and the phenomenon is more prominent under the condition of larger batch size.

Ionic Liquids (ILs) generally refer to salts that have a melting point below 100 ℃ and are composed entirely of anions and cations. ILs are generally regarded as green solvents and widely applied to the chemical field due to the advantages of non-volatility, nonflammability, stable thermochemical properties, strong solvating power, high designability and the like. ILs can also be used as drug solvents or non-solvents, drug crystals are prepared by solvent-non-solvent mixed precipitation methods (cryst engcomm,2014,16, 10797. The above studies mainly utilize the interaction between the drug and ILs during crystallization to obtain drug crystal forms that cannot be obtained in common organic solvents, and do not involve control of the crystal particle size.

Chinese patent (ZL 201611020389.1) discloses a novel crystal form of dihydroquercetin and a preparation method thereof, wherein 1-butyl-3-methylimidazole tetrafluoroborate is used as a solvent, dichloromethane is used as a non-solvent, and a solvent-non-solvent mixed precipitation method is adopted for preparation. Korean patent (KR 20130139256) discloses a process for preparing clopidogrel hydrogensulfate polymorph I by solvent-non-solvent precipitation using ethanol as a solvent and 1-allyl-3-ethylimidazole tetrafluoroboric acid as a non-solvent. The patent does not relate to the control of the particle size of drug particles, and the ion environment provided by ILs is mainly utilized to induce the generation of new crystal forms of drugs. In addition, the ionic liquids used in the above patents are all immiscible with water, organic solvents such as dichloromethane and ethanol are required to be used as non-solvents, and the development requirements of "green chemistry" are not met, and the organic solvents remaining in the system also cause great damage to the stability and safety of the product. More importantly, the insoluble drugs have certain solubility in the organic solvent and are not easy to crystallize and separate out, so that the dihydroquercetin and clopidogrel hydrogen sulfate in the patent have certain water solubility and do not belong to the category of the insoluble drugs.

The Chinese patent application (CN 201811347234.8) discloses a method for preparing a new taxol crystal form by solvent-non-solvent mixed precipitation by using brominated 1-hexyl-3-methylimidazole as a solvent and deionized water as a non-solvent. Compared with the solubility of the bulk drugs, the solubility of the new crystal form is increased by nearly 6 times, and the dissolution rate is remarkably improved. The ionic liquid imidazole has long carbon chains of substituted alkyl groups and certain surface activity, and can form micelles when mixed with water, thereby inducing the generation of new crystal forms. However, such ionic liquid with surface activity is not suitable for controlling the particle size of nanoparticles, because the formation of micelles rather hinders the formation of drug crystal nuclei, which is not beneficial to controlling the crystal particle size, so the new crystal form in the patent is a long strip with the size of several microns or more. In addition, although the patent uses water-soluble IL and avoids the use of organic solvents, imidazole-type ILs still have some toxicity.

Based on the current situation and existing defects of the prior art, the inventor of the present application intends to provide an ionic liquid, a preparation method and applications thereof, and in particular relates to an ionic liquid for preparing nano-drugs, a preparation method and applications thereof, and in particular relates to applications of preparing drug nanoparticles and controlling particle size by using an ionic liquid as a solvent.

Disclosure of Invention

The invention aims to provide an ionic liquid, a preparation method and a new application thereof based on the current situation and the existing defects of the prior art, in particular to the ionic liquid for preparing nano-drugs, the preparation method and the application thereof, and particularly the new application of preparing insoluble drug nano-particles by using the prepared ionic liquid as a solvent and a solvent-non-solvent mixed precipitation method.

The invention aims to provide an ionic liquid capable of preparing drug nanoparticles.

The research shows that compared with the traditional organic solvent, the ionic liquid can control the particle size of the drug nanoparticles. The reason for analyzing the ionic liquid is that the ionic liquid has good solubilizing capacity for the insoluble drug, can be used as a solvent of the insoluble drug and provides higher supersaturation degree in the solvent-non-solvent mixed precipitation process; meanwhile, the ionic liquid has higher viscosity, and can keep solubilization of insoluble drugs to a certain extent when being mixed with water, further dispersion enables the ionic liquid to be completely dissociated into anions and cations to lose solubilization capacity, crystal nuclei are synchronously formed and grow synchronously, and the supersaturation degree promotes nucleation, more solutes are consumed to inhibit the growth degree of crystals, so that small and uniform nanoparticles are obtained.

Experiments in the invention show that choline ILs (Ch-ILs) can be used as a solvent of paclitaxel which is an insoluble drug, water is used as a non-solvent, and paclitaxel nano crystals are prepared by mixing the solvent and the non-solvent, and the particle size and the distribution of the nano crystals can be controlled even under the condition of improved drug concentration. The conventional organic solvent ethanol can only prepare paclitaxel nanocrystal when the concentration of the drug is lower, and the particle size distribution of the paclitaxel nanocrystal are increased along with the increase of the concentration of the paclitaxel. The method is suitable for insoluble drugs such as quercetin, meloxicam, resveratrol, paclitaxel, silybin, sirolimus, simvastatin, ursodeoxycholic acid, betulinic acid, curcumin, nicardipine and the like, and also suitable for ILs taking natural products such as amino acid, betaine, nicotinamide, meglumine and the like and derivatives thereof as cations. The reason for this is that these ILs can dissolve poorly soluble drugs, but completely dissociate into anions and cations when they are in contact with water, and the anions and cations lose their solubilizing ability and precipitate, and a higher supersaturation can be obtained due to their stronger solubilizing ability, which is advantageous for promoting nucleation. More importantly, compared with the traditional organic solvent, the ILs have higher viscosity and poor water diffusibility, so that the ILs can be dispersed into tiny droplets in the process of mixing with water to continuously maintain the solubilizing capability of the insoluble drug, the interaction with the water is strengthened in the process of continuously mixing, so that the ILs are dissociated to lose the solubilizing capability, and meanwhile, crystal nuclei are formed and synchronously grow to obtain small and uniform nano crystals.

In the invention, ILs which take natural products such as choline, amino acid, betaine, nicotinamide, meglumine and the like and derivatives thereof as cations and take amino acid or organic acid as anions have good biological safety. Ch-ILs have at least one order of magnitude lower toxicity to human cells than anionic imidazole ILs, and also have low cytotoxicity to other eukaryotic cells. The research of the application shows that choline acetate, choline salicylic acid, choline bicarbonate and the like hardly cause environmental problems; some Ch-ILs such as choline propionic acid, choline butyric acid, choline citric acid and the like are only the third type of solvent in the global chemical uniform classification and labeling system, namely, low-toxicity solvent.

More specifically, the present invention is directed to a method for producing,

the invention provides an ionic liquid for preparing drug nanoparticles, which is composed of cations and anions, wherein the cations comprise one or more of choline, phosphorylcholine, phosphatidylcholine, sphingomyelin, betaine, lysine, arginine, histidine, proline, nicotinamide and meglumine, and the anions are one or more of glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, proline, aspartic acid, glutamic acid, asparagine, cysteine, serine, threonine, tyrosine, glutamine, lysine, arginine, histidine and organic acid.

Preferably, the cation is choline.

Preferably, the anion is one or more of organic acids with the carbon chain length less than or equal to 6.

Further preferably, the organic acid is one or more of acetic acid, glycolic acid, lactic acid, propionic acid, malonic acid, oxalic acid, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid, and gluconic acid.

Further preferably, the organic acid is one of lactic acid and acetic acid.

The surface tension of the ionic liquid is 20-70mN/m.

The surface tension is preferably 30 to 70mN/m, and more preferably 40 to 70mN/m.

The viscosity of the ionic liquid is 30-3000 mPa.s,

the viscosity is preferably from 50 to 700 mPas, most preferably from 90 to 450 mPas.

The molar ratio of the anion to the cation is 1.

The invention further aims to provide a method for preparing drug nanoparticles by using the ionic liquid, and the method takes the prepared ionic liquid as a drug solvent and adopts a solvent-non-solvent mixing method to prepare the drug particles.

Preferably, the method for preparing the drug nanoparticles by the ionic liquid comprises the following processes:

(1) The medicine is dissolved in the ionic liquid,

(2) The ionic liquid is used as a medicine solvent, the solvent is mixed with a non-solvent, so that the medicine is separated out and precipitated,

(3) Filtering, and removing ionic liquid to obtain the medicinal nanoparticles.

Further preferably, the method for preparing the drug nanoparticles comprises the following steps:

(1) The drug is dissolved in the ionic liquid and may be heated appropriately to increase solubility or speed dissolution.

(2) Mixing the ionic liquid solvent and the non-solvent of the medicine to precipitate out the medicine. To promote the efficiency of mixing, stirring, sonication, high shear, jet impingement, multi-inlet vortex mixing, high gravity controlled settling, and the like, or combinations thereof, may be employed.

(3) Filtering, washing the filter cake with a non-solvent, and removing the ionic liquid.

(4) The filter cake was replaced in water to disperse uniformly.

In the invention, the ionic liquid is prepared by the following method:

mixing compounds providing anions and cations according to a certain molar ratio, and stirring overnight; and then removing the by-product of the metathesis reaction.

The mass ratio of the medicine to the medicine solvent is 0.001-0.1.

Preferably, the drug is a poorly soluble drug.

Further preferably, the poorly soluble drug is selected from one of tetrahydropalmatine, carbamazepine, ibuprofen, aripiprazole, azithromycin, celecoxib, nicardipine, fenofibrate, indomethacin, ketoconazole, quercetin, meloxicam, resveratrol, paclitaxel, silibinin, sirolimus, simvastatin, ursodeoxycholic acid, betulinic acid, cinnarizine, griseofulvin, naproxen, curcumin, nabilone, aprepitant, dexmethylphenidate hydrochloride, paliperidone, megestrol acetate, and theophylline.

Further preferably, the insoluble drug is quercetin, meloxicam, resveratrol, paclitaxel, silibinin, sirolimus, simvastatin, ursodeoxycholic acid, betulinic acid, curcumin, nicardipine. Further preferably, the poorly soluble drug is paclitaxel.

In the method for preparing the drug nanoparticles, the non-solvent is a liquid which can be mixed with the ionic liquid and can reduce the solubility of the drug to precipitate the drug.

In the method for preparing the drug nanoparticles, the non-solvent may contain a stabilizer, and the stabilizer includes but is not limited to one or more of poloxamer, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyethylene glycol, tween and sodium dodecyl sulfate.

Preferably, in the method for preparing drug nanoparticles, the non-solvent is water.

In the method for preparing the drug nanoparticles, the drug solvent may further comprise a conventional organic solvent, and a mixed system of an ionic liquid and the conventional organic solvent is used as the drug solvent, wherein the organic solvent is one or more of ethanol, dimethyl sulfoxide, acetone, methanol and acetonitrile.

The method for preparing the drug nanoparticles has the particle size of less than 1000nm. In the invention, the prepared drug nanoparticles have the particle size of 50-1000nm, preferably 50-700nm, and most preferably 50-500nm, as shown in the attached drawings 1-3.

In the invention, the prepared drug nanoparticles are crystalline or amorphous, as shown in figures 4-6, and are preferably crystalline.

It is a further object of the present invention to provide a new use of an ionic liquid.

The invention further provides application of the ionic liquid in preparation of drug nanoparticles, and the ionic liquid can be used for preparing the drug nanoparticles.

Compared with the prior art, the invention has the following advantages:

the invention provides a green environment-friendly nano-crystalline preparation technology with controllable particle size by taking biocompatible ionic liquid as a medicinal solvent.

The new application and the using method of the ionic liquid are suitable for preparing nanoparticles of insoluble drugs such as paclitaxel, simvastatin, quercetin, ursodeoxycholic acid, silybin, sirolimus, betulinic acid and the like, the particle size of the nanoparticles is less than 1000nm, and the particle size of the nanoparticles is less than 0.4. Wherein, when the ionic liquid is used as a solvent, the concentration of the paclitaxel is increased from 3mg/mL to 18mg/mL, the particle size of the obtained nanoparticles is within 300nm, and the PDI is within 0.2; compared with the prior art that when ethanol is used as a solvent and the preparation is carried out by the same method, the particle size and PDI of the obtained nanoparticles are obviously increased along with the increase of the concentration of the paclitaxel, and when the concentration of the paclitaxel is increased to 10mg/mL, the nanoparticles cannot be prepared; when commercial ionic liquid brominated 1-hexyl-3-methylimidazole is used as a solvent and the concentration of paclitaxel is 3mg/mL, nano particles cannot be prepared, and the particle size of the obtained particles is micron.

Drawings

Fig. 1 is a particle size diagram of the prepared drug nanoparticles.

FIG. 2 is a graph of the particle size of paclitaxel nanoparticles prepared using choline ionic liquids as solvents.

FIG. 3 is a particle size diagram of paclitaxel nanoparticles prepared with choline lactate as a solvent under various drug concentration conditions.

Fig. 4 is an SEM image of the prepared drug nanoparticles.

Fig. 5 is a DSC diagram of the prepared drug nanoparticles.

Fig. 6 is a PXRD pattern of the prepared drug nanoparticles.

Detailed Description

The invention is further illustrated by the following examples. It should be understood that: the examples of the present invention are given for illustration only and not for limitation of the present invention, and therefore, the simple modifications of the present invention in the premise of the present invention are within the scope of the claimed invention.

Examples 1 to 6

Slowly dripping the choline bicarbonate aqueous solution into lactic acid, acetic acid, butyric acid, malonic acid, malic acid and succinic acid solutions respectively according to a certain molar ratio, and stirring overnight; then, the reaction solution is pre-frozen in a refrigerator at-80 ℃ for 12h, and then is freeze-dried for 48h, and finally the ionic liquid with low water content is obtained. During the freeze-drying process, the system pressure was 0.050mbar and the condenser temperature was-89 ℃.

TABLE 1 Choline organic acid Ionic liquids Structure and Properties

Examples 7 to 16

Slowly dripping lactic acid into aqueous solutions of choline dihydrogen phosphate, phosphatidylcholine, sphingomyelin, betaine, lysine, arginine, histidine, proline, nicotinamide, and meglumine according to a certain molar ratio, respectively, as examples 7-16, adding appropriate amount of ethanol if the system does not form a clear solution, and stirring overnight; then, the reaction solution was evaporated under reduced pressure at 60 ℃ and 90rpm to remove water and organic solvent in the system, and then placed in a vacuum oven at 60 ℃ for overnight drying to obtain the compound.

TABLE 2 other biocompatible Ionic liquid structures

Examples 17 to 18 equimolar amounts of the amino acid were added to aqueous choline hydroxide and stirred at room temperature for 48h; subsequently, the reaction solution was evaporated under reduced pressure at 60 ℃ and 90rpm to remove water in the system. Then, an equal volume of acetonitrile/methanol (9,v/v) mixed solvent was added to the system to precipitate the unreacted amino acid, and after magnetically stirring and mixing for 10min, filtration was performed. The organic solvent in the filtrate was removed by evaporation at 50 ℃ and 90rpm under reduced pressure to give choline aspartic acid (example 17) and choline glutamic acid (example 18).

Examples 19 to 24

A certain amount of paclitaxel was weighed and dissolved in choline lactic acid (example 1) to prepare drug solutions of paclitaxel at concentrations of 3, 5, 8, 9.7, 13 and 18mg/g as examples 19-24, respectively. Using 20mL of water as a non-solvent, quickly injecting the drug solution into the water under the conditions of water bath ultrasound and mechanical stirring at 1,200rpm, and continuously stirring and ultrasound for 10min. And after the reaction is finished, filtering the solution by using a polycarbonate membrane with the aperture of 50nm, washing a filter cake by using 30mL of deionized water, re-dispersing the collected crystals in 3mL of deionized water, and performing ultrasonic treatment to uniformly disperse the crystals to obtain the product.

Examples 25 to 39

Weighing paclitaxel, respectively dissolving in the ionic liquids of examples 2-18, respectively serving as examples 25-39, to prepare a 3mg/g drug solution, rapidly injecting the drug solution into a non-solvent under the conditions of water bath ultrasound and mechanical stirring at 1,200rpm with 20mL of water as the non-solvent, and continuously stirring and ultrasound for 10min; after the reaction is finished, filtering by using a polycarbonate membrane with the aperture of 50nm, and washing a filter cake by using 30mL of deionized water; and re-dispersing the collected crystals in 3mL of deionized water, and performing ultrasonic treatment to uniformly disperse the crystals to obtain the crystal.

Examples 40 to 57

Examples 40 to 41 thereof

100mg of the drug was weighed out and dissolved in 1g of choline acetic acid as a drug solution. Poloxamer 188, 20mg, was weighed out and dissolved in 10mL of water as a non-solvent. Rapidly injecting the medicinal solution into a non-solvent in an ice water bath under the ultrasonic condition of a 400W probe, wherein the ultrasonic working time is 5s every 5s, and the operation is carried out for 10min; filtering with 0.22 μm cellulose membrane, dispersing the filter cake in non-solvent with ultrasound to obtain simvastatin nanometer suspension (example 40) and tetrahydropalmatine nanometer suspension (example 41)

Example 42A pharmaceutical solution was prepared by dissolving 50mg of quercetin in 3g of choline acetic acid. 19.2mg of poloxamer 188 was weighed out and dissolved in 120mL of water as a non-solvent, and the solution was placed in a refrigerator at 4 ℃ for pre-cooling. Rapidly pouring the medicinal solution into 50mL of non-solvent under the conditions of water bath ultrasound at 4 ℃ and high shear speed of 20,000rpm, removing the high shear device after reacting for 5min, continuing water bath ultrasound for 10min, filtering by using a cellulose membrane with the pore diameter of 0.22 mu m to remove the solvent, and re-dispersing the filter cake in the non-solvent by ultrasound to obtain the nano-composite nano-particles.

Example 43A pharmaceutical solution was prepared by dissolving 0.1g ursodeoxycholic acid in 2g choline acetic acid. 0.14g of HPMC E50 was weighed out and dissolved in 20mL of water as a non-solvent. Rapidly pouring the medicinal solution into a non-solvent at room temperature under the conditions of magnetic stirring speed of 700rpm and high shear speed of 8,000rpm, reacting for 2min, filtering the suspension with a cellulose membrane with the pore diameter of 0.22 μm, and ultrasonically suspending the filter cake in the non-solvent to obtain the final product.

Example 44 Silibinin, 4mg, is weighed out and dissolved in 1g choline acetic acid as a pharmaceutical solution, poloxamer 188, 0.8mg/mL, in water is used as a non-solvent. Quickly injecting the medicine solution into 4mL of non-solvent, and stirring for 1min; and then performing ultrasonic treatment in a water bath at 4 ℃ for 15min, filtering the suspension by using a cellulose membrane with the pore diameter of 0.22 mu m, and performing ultrasonic treatment to resuspend a filter cake in a proper amount of non-solvent to obtain the nano-porous cellulose.

EXAMPLE 45A 10mg/mL solution of choline acetate sirolimus, 0.5mg/mL PVP K-17 and 0.025mg/mL SDS were prepared as non-solvents. Under the conditions of 16 ℃ water bath and 600rpm magnetic stirring, the medicine solution is quickly injected into 20mL of non-solvent, the stirring is carried out for 40min, the suspension is filtered by a cellulose membrane with the pore diameter of 0.22 mu m, and the filter cake is ultrasonically suspended in a proper amount of non-solvent, thus obtaining the medicine.

Example 46 weighing 0.012g of curcumin in 0.4mL of choline acetic acid, and dissolving by ultrasound to obtain a solvent phase; adding the solution to 4.6mL of 0.1% HPMC E5 solution under magnetic stirring.

Examples 47-48 20mg of drug was weighed into 2mL of choline acetic acid and dissolved by sonication to give a 10mg/mL solvent phase. Under the conditions of ice water bath and magnetic stirring at 270rpm, 1mL of the drug solution is added into 40mL of 0.3mg/mL HPMC E5 aqueous solution, and stirring is carried out for 5min, thus obtaining the resveratrol nano suspension (example 47) and the theophylline nano suspension (example 48).

In examples 49 to 51, the drugs are weighed to prepare a 3mg/g choline acetic acid solution of the drug, 20mL of water is used as a non-solvent, the drug solution is quickly injected into the non-solvent under the conditions of water bath ultrasound and mechanical stirring at 1,200rpm, and the ultrasound is continuously stirred for 10min; after the reaction is finished, filtering the mixture by using a polycarbonate membrane with the aperture of 50nm, and washing a filter cake by using 30mL of deionized water; the collected crystals were re-dispersed in 3mL of deionized water and dispersed uniformly by sonication to obtain betulinic acid nanocrystals (example 49), naproxen nanosuspension (example 50) and nicardipine nanocrystals (example 51).

Examples 52-53A 4% (w/w) solution of 200mg of a drug dissolved in 5g of choline acetic acid was prepared. Under the conditions of ice water bath and 400W probe ultrasound, 2mL of drug solution is quickly injected into 8mL of 0.5% (W/W) poloxamer 188 aqueous solution, the ultrasonic working time is 5s every 5s, and the operation is carried out for 10min; filtering with cellulose membrane with pore diameter of 0.22 μm, and dispersing the filter cake in non-solvent by ultrasound to obtain meloxicam nanometer suspension (example 52) and ibuprofen nanometer suspension (example 53).

Example 54 fenofibrate choline acetate solution at 10mg/mL as solvent phase; 10mg of poloxamer 188 and 3.5mg of lecithin (PC-98T) were dissolved in 10mL of deionized water and sonicated to dissolve as a non-solvent phase. Under the conditions of ice water bath and magnetic stirring at 600rpm, 1mL of the drug solution is quickly injected into 10mL of the non-solvent phase, and the mixture is stirred for 10min to obtain the compound.

Example 55 dissolving 50mg cinnarizine in 2mL choline acetic acid to prepare a 25mg/mL solution phase; 0.2% (w/w) aqueous PVA solution was used as the non-solvent phase. Injecting 1mL of the medicine solution into 40mL of the non-solvent under the condition of water bath ultrasound at the temperature of 3 ℃, and reacting for 15min to obtain the compound.

Example 56 a choline acetate solution of aripiprazole was injected into an aqueous hydroxypropyl cellulose solution at a rate of 0.5mL/min with magnetic stirring at 900rpm for a reaction time of 15min; the solvent phase/non-solvent is 1/10 (v/v) and the stabilizer/drug is 1/5 (w/w).

Comparative examples 1 to 5

Weighing a certain amount of paclitaxel, dissolving in ethanol, and making into medicinal solution with paclitaxel concentration of 3, 5, 8, 10 and 13 mg/mL. Taking 20mL of water as a non-solvent, quickly injecting the drug solution into the non-solvent under the conditions of water bath ultrasound and mechanical stirring at 1,200rpm, and continuously stirring and ultrasound for 10min; and after the reaction is finished, filtering the solution by using a polycarbonate membrane with the aperture of 50nm, washing a filter cake by using 30mL of deionized water, re-dispersing the collected crystals in 3mL of deionized water, and performing ultrasonic treatment to uniformly disperse the crystals to obtain the crystal.

Comparative example 6

Weighing a certain amount of paclitaxel, dissolving in brominated 1-hexyl-3-methylimidazole, and preparing into a medicinal solution with the paclitaxel concentration of 3 mg/mL. Taking 20mL of water as a non-solvent, quickly injecting the drug solution into the non-solvent under the conditions of water bath ultrasound and mechanical stirring at 1,200rpm, and continuously stirring and ultrasound for 10min; and after the reaction is finished, filtering the solution by using a polycarbonate membrane with the aperture of 50nm, washing a filter cake by using 30mL of deionized water, re-dispersing the collected crystals in 3mL of deionized water, and performing ultrasonic treatment to uniformly disperse the crystals to obtain the crystal.

Test example 1 particle size and distribution thereof

After diluting the prepared nanoparticle suspension by 10 times, 200 μ L of the suspension was added into a test dish, and the particle size and PDI were measured by a Malvern Zetasizer laser particle sizer. The measurement temperature was set at 25 ℃ and the equilibration time was 30s, and each sample was assayed in triplicate. Specific data of the test results are shown in tables 3 to 5, and the distribution diagrams are shown in fig. 1 to 3.

TABLE 3 nanoparticle size and PDI prepared at different paclitaxel concentrations

TABLE 4 paclitaxel nanoparticle size and distribution prepared with different IL as solvent

TABLE 5 particle size and distribution of nanoparticles of different poorly soluble drugs

Test example 4 SEM

40. Mu.L of freshly prepared samples from example 19 and examples 40, 42-45 were dropped onto a 50nm polycarbonate film and the dispersion was drained. Water washing three times to remove the stabilizer from the sample. The sample was air-dried at room temperature and adhered to a sample stand with a conductive adhesive, and metal spraying was carried out for 60s, the emission voltage was 5.0kV, and the morphology of the product observed by SEM is shown in FIG. 4.

Test example 5 DSC

The freshly prepared samples of example 19 and examples 40 and 42 to 45 were centrifuged at 15,000rpm for 10min, the precipitate was collected, dried, and 5 to 10mg of the sample was placed in a crucible and subjected to DSC analysis using the bulk drug, the stabilizer and the physical mixture thereof as controls. In all tests, the flow rate of the purge gas is 20mL/min, the heating rate is 10K/min, and the blank control is Al ₂ O ₃ . The specific temperature rise ranges are as follows: :

1) Paclitaxel: 45-320 deg.C

2) Simvastatin: 50-200 deg.C

3) And (3) quercetin: 40-350 deg.C

4) Ursodeoxycholic acid: 50-300 deg.C

5) Silybin: 40-250 deg.C

6) Sirolimus: 30-220 deg.C

The test results are shown in fig. 5.

Test example 6 XRD

Samples of freshly prepared example 19 and examples 40 and 42-45 were taken, centrifuged at 15,000rpm for 10min, the precipitate collected, dried at room temperature and analyzed by XRD, against the bulk drug, stabilizer and physical mixture thereof. Cu-Kalpha rays are adopted in all sample testing processes, the detection voltage and current are respectively 40kV and 60mA, and the scanning step length is fixed to be 0.02 degrees. The test 2 θ range and scan rate for each drug were as follows:

1) Paclitaxel: 3-60 degrees and 5 degrees/min

2) Simvastatin: 5-40 degrees and 5 degrees/min

3) And (3) quercetin: 3-60 degrees and 2 degrees/min

4) Ursodeoxycholic acid: 8-50 degrees and 5 degrees/min

5) Silybin: 5-60 degrees, 1 degree/min

6) Sirolimus: 3-60 degrees and 5 degrees/min

The test results are shown in fig. 6.

Claims (16)

1. The ionic liquid for preparing the nano-drugs is characterized by being composed of cations and anions, wherein the cations comprise one or more of choline, phosphorylcholine, phosphatidylcholine, sphingomyelin, betaine, lysine, arginine, histidine, proline, nicotinamide and meglumine, and the anions comprise one or more of glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, proline, aspartic acid, glutamic acid, asparagine, cysteine, serine, threonine, tyrosine, glutamine, lysine, arginine, histidine and organic acid.

2. The ionic liquid for preparing nano-drugs according to claim 1, wherein the cation is choline.

3. The ionic liquid for preparing nano-drugs according to claim 1, wherein the anion is one or more of organic acids with carbon chain length less than or equal to 6.

4. The ionic liquid for preparing nano-drugs according to claim 1, wherein the organic acid is one or more of acetic acid, glycolic acid, lactic acid, propionic acid, malonic acid, oxalic acid, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid, and gluconic acid.

5. The ionic liquid for preparing nano-drugs according to claim 4, wherein the organic acid is one of lactic acid and acetic acid.

6. A method for preparing drug nanoparticles by using the ionic liquid as claimed in any one of claims 1 to 5, wherein the ionic liquid is used as a drug solvent to prepare drug particles by a solvent-non-solvent mixing method.

7. The method according to claim 6, characterized in that the method comprises the following steps:

(1) The ionic liquid is used as a medicine solvent, and medicines are dissolved in the ionic liquid;

(2) Mixing the solvent and the non-solvent to separate out the medicine and precipitate;

(3) Filtering, and removing the ionic liquid to obtain the drug nanoparticles.

8. The method of claim 6, wherein the drug is a poorly soluble drug.

9. The method of claim 8, wherein the poorly soluble drug is one of tetrahydropalmatine, carbamazepine, ibuprofen, aripiprazole, azithromycin, celecoxib, nicardipine, fenofibrate, indomethacin, ketoconazole, quercetin, meloxicam, resveratrol, paclitaxel, silibinin, sirolimus, simvastatin, ursodeoxycholic acid, betulinic acid, cinnarizine, griseofulvin, naproxen, curcumin, nabilone, aprepitant, dexmethylphenidate hydrochloride, paliperidone, megestrol acetate, or theophylline.

10. The method of claim 9, wherein the poorly soluble drug is one of quercetin, meloxicam, resveratrol, paclitaxel, silibinin, sirolimus, simvastatin, ursodeoxycholic acid, betulinic acid, curcumin, or nicardipine.

11. The method of claim 6, wherein the non-solvent is a liquid that is miscible with the ionic liquid and precipitates out the drug with reduced solubility.

12. The method according to claim 6, wherein the non-solvent comprises a stabilizer selected from one or more of poloxamer, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyethylene glycol, tween, and sodium lauryl sulfate.

13. The method according to claim 6, wherein the pharmaceutical solvent further comprises a conventional organic solvent, and a mixed system of an ionic liquid and the conventional organic solvent is used as the pharmaceutical solvent, and the organic solvent is one or more of ethanol, dimethyl sulfoxide, acetone, methanol and acetonitrile.

14. The method of claim 11, wherein the non-solvent is water.

15. The method of claim 6, wherein the drug nanoparticles have a particle size of less than 1000nm.

16. Use of an ionic liquid according to any one of claims 1 to 15 in the preparation of a pharmaceutical nanoparticle.

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