Ionic liquid microemulsion system as well as preparation method and application thereof

Abstract

The invention discloses an ionic liquid microemulsion system as well as a preparation method and application thereof. The ionic liquid microemulsion system is prepared from a water phase, an oil phase, a surfactant and ionic liquid, wherein cations of the ionic liquid are hydrophilic cations, and anions of the ionic liquid comprise two hydrophobic anions with different chain lengths. The ionic liquid microemulsion system is established, the viscosity of the delivery system and the irritation of the ionic liquid to the skin are reduced, and the stability and the delivery effect of the delivery system are improved. Specifically, the ionic liquid is used as an additive of a microemulsion system, a short chain is used for improving the drug loading capacity of water and oil insoluble drugs, and a long chain is used for enhancing the stability of the system.

Description

Technical Field

[0001] This invention relates to the field of biomaterials technology, and in particular to an ionic liquid microemulsion system, its preparation method, and its application. Background Technology

[0002] Current medical drug delivery systems mainly include oral, injectable, and transdermal delivery methods. Transdermal delivery, which delivers drugs directly to the skin, avoids the cumulative toxicity drawbacks of drugs administered internally and offers greater autonomy and convenience. However, transdermal drug delivery systems still face many challenges, such as the affinity of the drug delivery system to human skin, compatibility with the drug, biotoxicity, and targeted delivery. These unresolved issues remain key obstacles to the clinical application of drugs, and the medical application of next-generation active ingredients urgently requires delivery methods that can meet a wider range of application scenarios.

[0003] Ionic liquids, as a new era of green solvents, can dissolve many organic and inorganic compounds that are insoluble or only slightly soluble in water, as well as most organic compounds and even some pharmacologically active compounds. Due to their solubilizing effect, ionic liquids are also used in the field of medical drug delivery as drug delivery carriers. However, because of the ionic nature of ionic liquids, they are incompatible with some drug delivery systems, and their inherent irritant properties make them unsuitable for direct application in oral, injectable, and transdermal drug delivery.

[0004] Microemulsions are emerging as a novel, multifunctional system due to their high affinity for skin, gentleness, and high efficiency. They possess excellent hydrophilic and lipophilic properties and demonstrate high safety and delivery efficiency in various applications. In cutting-edge research on microemulsion systems, traditional polar (water) and non-polar (oil) components are no longer the only options for forming microemulsions; targeted ionic liquids can be used instead. Due to the unique solvent properties and designability of ionic liquids, their use as the dispersed or continuous phase in microemulsions holds great promise. Existing ionic liquid microemulsion systems replace one component in traditional microemulsions, such as the aqueous phase, oil phase, or surfactant, with an ionic liquid. While this allows for targeted improvements in drug solubility and delivery through ionic liquid design, it disrupts the stability of the original system. Extensive experiments are needed to balance drug loading, release characteristics, and system stability, making it less universally applicable.

[0005] Therefore, existing technologies still need to be improved and developed. Summary of the Invention

[0006] In view of the shortcomings of the prior art, the present invention provides an ionic liquid microemulsion system, its preparation method and application, thereby solving the problem of poor stability of poorly soluble drugs in existing transdermal drug delivery systems.

[0007] The technical solution adopted by the present invention to solve the above-mentioned technical problems is as follows:

[0008] In a first aspect, the present invention provides an ionic liquid microemulsion system, the ionic liquid microemulsion system being prepared from an aqueous phase, an oil phase, a surfactant, and an ionic liquid;

[0009] The cation of the ionic liquid is a hydrophilic cation, and the anions of the ionic liquid include two hydrophobic anions with different chain lengths.

[0010] Preferably, the cation is derived from matrine or L-carnitine, and the anion is derived from short-chain fatty acids and long-chain fatty acids.

[0011] Preferably, the anion is derived from two of hexanoic acid, octanoic acid, decanoic acid, and lauric acid.

[0012] Preferably, the ionic liquid includes at least one of matrine-[hexanoic acid, lauric acid], matrine-[octanoic acid, lauric acid], matrine-[decanoic acid, lauric acid], and L-carnitine-[hexanoic acid, lauric acid].

[0013] Preferably, the mass ratio of the short-chain fatty acid to the long-chain fatty acid is 1:(1-12).

[0014] Preferably, the ionic liquid accounts for 10%-50% of the ionic liquid microemulsion system by weight.

[0015] Preferably, the oil phase is selected from one of isopropyl myristate, glyceryl stearate, glyceryl caprylate, medium-chain triglycerides, and squalane.

[0016] Preferably, the surfactant is a nonionic surfactant.

[0017] A second aspect of the present invention provides a method for preparing the above-described ionic liquid microemulsion system, the method comprising the following steps:

[0018] The target drug is dissolved in an ionic liquid to obtain a mixed liquid;

[0019] The oil phase and surfactant were dissolved in water and subjected to ultrasonic homogenization to obtain a microemulsion.

[0020] Under continuous stirring, the mixed liquid is added to the microemulsion to obtain the ionic liquid microemulsion system.

[0021] A third aspect of the present invention provides the application of the above-described ionic liquid microemulsion system in the preparation of drug transdermal delivery carriers.

[0022] Beneficial effects:

[0023] This invention discloses an ionic liquid microemulsion system, its preparation method, and its application. The ionic liquid microemulsion system established by this invention can reduce the viscosity of the delivery system and the irritation of the ionic liquid to the skin, improve the stability and delivery effect of the delivery system, and solve the delivery problem of drugs that are poorly soluble in both water and oil. This invention provides a simple, universal, stable, and safe drug delivery scheme for poorly soluble drugs with high drug administration efficiency and good efficacy. Attached Figure Description

[0024] Figure 1 To observe and test the stability of the microemulsions prepared in Examples 1-5 of this invention: (a) morphology; (b) stability.

[0025] Figure 2 To observe the stability of the microemulsions prepared in Examples 1, 6-17 of this invention: (a) stability of ionic liquid microemulsions with different fatty acid ratios; (b) drug loading performance of ionic liquid microemulsions with a 1:12 ratio (hexanoic acid / caprylic acid / decanoic acid, lauric acid); (c) stability observation of hexanoic acid-lauric acid ratios from 1:1 to 1:12; (d) particle size distribution of matrine-hexanoic acid, lauric acid (1:12) microemulsions; (e) particle size of ionic liquid microemulsions with a 1:12 ratio; (f) dispersion coefficient of ionic liquid microemulsions with a 1:12 ratio.

[0026] Figure 3 To construct pseudo-ternary phase diagrams for the microemulsions prepared in Examples 1, 18 and 19 of this invention: (a) various micelle structures that may appear in the microemulsions at the ratio of water, surfactant and oil

[79] ; the phase diagrams drawn in this experiment: (b) pseudo-ternary phase diagram with Tween 80 and Span 20 in a 1:1 ratio; (c) pseudo-ternary phase diagram with Tween 80 and Span 20 in a 1:2 ratio; (d) pseudo-ternary phase diagram with Tween 80 and Span 20 in a 2:1 ratio.

[0027] Figure 4 The graph shows the stability test results of the ionic liquid microemulsion systems prepared in Examples 20-23 of this invention.

[0028] Figure 5 To test the stability of the ionic liquid microemulsion systems prepared in Examples 20-23 of this invention: (a) particle size of the microemulsions under anionic conditions; (b) zeta potential test.

[0029] Figure 6 The infrared spectrum is that of the ionic liquid microemulsion system prepared in Example 1 of this invention.

[0030] Figure 7Transmission electron microscopy images of the ionic liquid microemulsion systems prepared for embodiments of the present invention: (a) matrine-hexanoic acid microemulsion; (b) matrine-hexanoic acid microemulsion; (c) matrine-hexanoic acid, decanoic acid (1:12) microemulsion; (d) matrine-hexanoic acid, decanoic acid (1:12) microemulsion; (e) microemulsion (without baicalin); (f) microemulsion (without baicalin).

[0031] Figure 8 The antioxidant performance indicators of the ionic liquid microemulsion system prepared in Example 1 of this invention are as follows: (a) Baicalin suspension ABTS + (a) Free radical scavenging test; (b) Baicalin microemulsion ABTS + (c) Detection of ROS content in baicalin microemulsion; (d) Detection of SOD activity in baicalin microemulsion.

[0032] Figure 9 The results of the TNF-α cell experiment are for the ionic liquid microemulsion system prepared in Example 1 of this invention.

[0033] Figure 10 This study tested the whitening efficacy of the ionic liquid microemulsion system prepared in Example 1 of the present invention.

[0034] Figure 11 Transdermal drug delivery performance of the short-chain fatty acid: long-chain fatty acid (1:12) ionic liquid microemulsion system prepared in Examples 1, 10-12 of this invention was tested. Detailed Implementation

[0035] This invention provides an ionic liquid microemulsion system, its preparation method, and its application. To make the objectives, technical solutions, and effects of this invention clearer and more explicit, the invention is further described in detail below. It should be understood that the specific embodiments described herein are only for explaining the invention and are not intended to limit the invention.

[0036] This invention provides an ionic liquid microemulsion system, which is prepared from an aqueous phase, an oil phase, a surfactant, and an ionic liquid.

[0037] The cation of the ionic liquid is a hydrophilic cation, and the anions of the ionic liquid include two hydrophobic anions with different chain lengths.

[0038] From the perspective of poorly soluble target drugs (baicalin), baicalin has poor solubility in both aqueous and oil phases, which is difficult to solve with traditional emulsion methods. Although existing ionic liquid microemulsion systems can be used to specifically improve the solubility and delivery of target drugs through ionic liquid design, they will disrupt the stability of the original system. The ionic liquid microemulsion system provided in this invention solves the compatibility problem between ionic liquids and microemulsion systems compared with existing ionic liquid microemulsion systems.

[0039] Generally speaking, the longer the ionic chain of an ionic liquid, the higher its viscosity and the worse its solubility for the target drug, but the enhanced surface activity contributes to the stability of the microemulsion system. This invention employs a ternary ionic liquid system (i.e., cation + two anions). Short-chain anions are used to solubilize the drug, increasing the drug loading of target drugs that are poorly soluble in both water and oil, while long-chain anions ensure system stability. Furthermore, the inherent compatibility of this ternary ionic liquid system with its combination of long and short chains effectively reduces the destructive impact of short-chain anions on the stability of the microemulsion system.

[0040] In some embodiments, the cation is derived from matrine or L-carnitine, and the anion is derived from short-chain fatty acids and long-chain fatty acids.

[0041] When selecting anions and cations for ionic liquids, in addition to the physicochemical properties of the ions themselves, their bioactivity and safety should also be considered. Using natural pharmaceuticals and other green raw materials to synthesize ionic liquids is a worthwhile research direction, as it can yield good biocompatibility and biodegradability.

[0042] First, in this embodiment of the invention, matrine is selected as the source of cations. Matrine is a quinoline alkaloid extracted from the roots of leguminous plants. It possesses various biological activities, including anti-inflammatory, antiviral, antitumor, anti-allergic, and immunomodulatory effects, and is widely used in food, cosmetics, and biomedicine. The molecular formula of matrine is C0. 15 H 24 N 2O It has a tetracyclic structure, low biotoxicity and good stability. Introducing matrine into ionic liquids and utilizing its functions and bioactivity can enhance the medicinal efficacy of ionic liquids. At the same time, the high compatibility of matrine with other anions further reduces the difficulty of preparing ionic liquids and improves the stability of ionic liquid systems.

[0043] L-carnitine is an amino acid derivative widely found in human cells. It exists as a zwitterion in a neutral environment, exhibiting good thermal stability and resistance to decomposition. The electrochemical properties and stability of L-carnitine are unaffected by pH levels. However, due to its polar electron density distribution and molecular structure, the carboxyl group of L-carnitine more readily acquires hydrogen ions than the amino group of matrine, resulting in higher electrochemical activity. Conductivity tests of ionic liquids show that ionic liquids prepared using L-carnitine have higher conductivity. This is because the carbon chain structure of L-carnitine is more flexible than the cyclic structure of matrine, leading to greater mobility and higher conductivity in ionic liquids formed with fatty acids within solvents. However, the higher conductivity of L-carnitine ionic liquids can disrupt the balance between the ionic liquid, oil phase, and aqueous phase, causing instability such as stratification in microemulsion systems. Furthermore, ionic liquids prepared using L-carnitine as a cation source have excessively high viscosity, resulting in inferior drug loading capacity compared to ionic liquids using matrine as a cation source.

[0044] As the anionic chain length increases, the viscosity of the ionic liquid increases significantly. In medical applications, low-viscosity ionic liquids are more conducive to improving drug delivery efficiency and also facilitate uniform mixing and synergistic effects with other components. In this invention, the anions are derived from short-chain and long-chain fatty acids. The short chains are used to increase the drug loading of the target drug, which is poorly soluble in both water and oil, while the long chains enhance the stability of the system. The introduction of short-chain ions can disrupt the stability of the microemulsion system; the addition of long chains can reduce this disruption and improve the system's stability. Furthermore, the same cation ensures the compatibility and synergistic effect of both long and short-chain anions.

[0045] In some embodiments, the anion is derived from two of hexanoic acid, octanoic acid, decanoic acid, and lauric acid.

[0046] In some embodiments, the ionic liquid includes at least one of matrine-[hexanoic acid, lauric acid], matrine-[octanoic acid, lauric acid], matrine-[decanoic acid, lauric acid], and L-carnitine-[hexanoic acid, lauric acid].

[0047] In some embodiments, the mass ratio of the short-chain fatty acid to the long-chain fatty acid is 1:1 to 1:12. The mass ratio of the short-chain fatty acid to the long-chain fatty acid can be 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, or 1:12.

[0048] If there is too much short-chain fatty acid, the stability of the ionic liquid microemulsion system will deteriorate (it will be prone to demulsification); if there is too much long-chain fatty acid, the drug loading capacity of the ionic liquid microemulsion system will deteriorate.

[0049] In some preferred embodiments, the mass ratio of the short-chain fatty acid to the long-chain fatty acid is 1:12.

[0050] In some embodiments, the preparation of the ionic liquid includes the following steps:

[0051] The cation and two anions with different chain lengths are dissolved in a solvent, and after the reaction is complete, the solvent is removed to obtain the ionic liquid.

[0052] The cation is selected from matrine or L-carnitine, and the anion is selected from two of the following: acetic acid, caprylic acid, decanoic acid, and lauric acid.

[0053] In some embodiments, the ionic liquid comprises 10%-50% of the microemulsion system by weight. The ionic liquid may comprise 10%, 20%, 30%, 40%, or 50% of the microemulsion system.

[0054] In this embodiment of the invention, the weight of the ionic liquid is controlled to be 10%-50% of the microemulsion system. If the amount of ionic liquid is too small, the drug loading and transdermal delivery efficiency cannot be effectively improved. If the amount of ionic liquid is too large, the viscosity of the ionic liquid microemulsion system will increase, which is also not conducive to improving the drug loading and transdermal delivery efficiency, and is prone to causing demulsification.

[0055] In some preferred embodiments, the ionic liquid comprises 40% of the microemulsion system by weight.

[0056] In some embodiments, the oil phase is selected from isopropyl myristate, glyceryl stearate, glyceryl caprylate, medium-chain triglycerides, and squalane.

[0057] The oil phase, being the non-polar component of a microemulsion system, can enhance the loading of lipid-soluble drugs and also possesses certain biological benefits. In some pharmaceutical and health research, natural plant oils, such as peony seed oil and flaxseed oil, are used in the preparation of microemulsion systems to leverage the natural biological benefits of the oil phase. In this embodiment, to ensure the stability of the ionic liquid microemulsion system and the drug loading capacity, isopropyl myristate (IPM) was selected as the oil phase component. IPM is a commonly used microemulsion oil phase in research literature. Due to its compatibility with active substances and its beneficial effect on the stability of the microemulsion system, it performs well when emulsified with various surfactants, exhibits low biotoxicity, and can dissolve a certain amount of lipid-soluble active substances. In research, it has been used to improve the drug loading capacity of active substances in microemulsions and the efficiency of transdermal drug delivery.

[0058] In some embodiments, the surfactant is a nonionic surfactant.

[0059] Regarding the selection of surfactants, there are different types of ionic and nonionic surfactants. Although ionic surfactants have better emulsification effects and can exert their activation effect to the maximum efficiency, and can better promote the formation of microemulsion systems, their ionic nature makes the microemulsion system prone to instability and demulsification and stratification. Therefore, nonionic surfactants are selected in this embodiment.

[0060] In some embodiments, the surfactant comprises sorbitan monooleate polyoxyethylene ether and sorbitan monolaurate (Tween 80 and Span 20) in a mass ratio of 1:1.

[0061] Surface activation of a system composed of two nonionic surfactants with similar structures (Tween 80 and Span 20) can improve emulsification, thereby reducing the amount of surfactant required. The combination of Tween 80 and Span 20 is a commonly used surfactant combination in the cosmetics industry. They can improve the stability of emulsion systems, enhance sensory properties, and help reduce potential skin irritation. Specifically, (1) they have a synergistic effect: Tween 80 is a nonionic surfactant with excellent emulsifying and wetting abilities. Span 20 is also a nonionic surfactant, usually used as a co-emulsifier. When used together, they can produce a synergistic effect, improving the stability of ionic liquid microemulsion systems. (2) reduced viscosity: Tween 80 can reduce the surface tension of the aqueous phase, while Span 20 helps reduce the viscosity of the oil phase. This combination helps to form a more uniform and easier-to-apply emulsion. (3) Improved emulsification: Tween 80 helps form oil-in-water (O / W) emulsions, while Span 20 enhances the emulsification effect, making oil droplets smaller and more evenly dispersed. (4) Increased stability: Span 20 increases the emulsion's resistance to temperature and pH changes, and when combined with Tween 80, it improves the long-term stability of the emulsion. (5) Reduced side effects: Although surfactants may be irritating to the skin at high concentrations, the combination of Tween 80 and Span 20 can achieve the desired emulsification effect at a lower total concentration, thereby reducing potential skin irritation. (6) Adaptability: Different cosmetics may require different emulsification systems, and the combination of Tween 80 and Span 20 provides a flexible way to adjust the properties of the emulsion to meet the needs of specific products.

[0062] This invention provides a method for preparing the above-mentioned microemulsion system, the method comprising the following steps:

[0063] The target drug is dissolved in an ionic liquid to obtain a mixed liquid;

[0064] The oil phase and surfactant were dissolved in water and subjected to ultrasonic homogenization to obtain a microemulsion.

[0065] Under continuous stirring, the mixed liquid is added to the microemulsion to obtain the ionic liquid microemulsion system.

[0066] In some embodiments, the target drug may be a poorly soluble drug in both water and oil, such as baicalin, baicalein, phloretin, berberine, or quercetin.

[0067] This invention provides the application of the above-described microemulsion system in the preparation of transdermal drug delivery carriers.

[0068] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are merely some embodiments of the present invention, not all embodiments, and are intended only to illustrate the present invention and not to limit it. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0069] Example 1

[0070] The preparation of an ionic liquid microemulsion system includes the following steps:

[0071] S1. Dissolve 13 mmol matrine, 1 mmol hexanoic acid, and 12 mmol lauric acid in 26 mL of ethanol and mix well (matrine-hexanoic acid, lauric acid (1:12)). React at 40 °C for 12 h under nitrogen protection, and then remove the ethanol by rotary evaporation to obtain an ionic liquid.

[0072] S2. Dissolve baicalin in the above ionic liquid to prepare a saturated solution;

[0073] S3. Mix 10 parts IPM, 10 parts Tween80 and 10 parts Span20 (1:1) and 50 parts water (by mass) to obtain a mixed liquid. Homogenize the mixed liquid with an ultrasonic probe for 1 hour under an input energy of 500 kW to obtain a microemulsion.

[0074] S4. Under continuous stirring, 20 parts of the ionic liquid prepared in S1 are added dropwise to the microemulsion prepared in S3 to obtain an ionic liquid microemulsion. The mass of the ionic liquid accounts for 40% of the components other than water, and is referred to as a 40% ionic liquid microemulsion system.

[0075] Example 2

[0076] The preparation of an ionic liquid microemulsion system is basically the same as that in Example 1, except that: in step S3, the amount of water added is 33.33 parts; in step S4, the amount of ionic liquid added is 3.33 parts, resulting in an ionic liquid microemulsion system with an ionic liquid content of 10%.

[0077] Example 3

[0078] The preparation of an ionic liquid microemulsion system is basically the same as that in Example 1, except that: in step S3, the amount of water added is 37.5 parts; in step S4, the amount of ionic liquid added is 7.5 parts, resulting in an ionic liquid microemulsion system with an ionic liquid content of 20%.

[0079] Example 4

[0080] The preparation of an ionic liquid microemulsion system is basically the same as that in Example 1, except that: in step S3, the amount of water added is 42.86 parts; in step S4, the amount of ionic liquid added is 12.86 parts, resulting in an ionic liquid microemulsion system with an ionic liquid content of 30%.

[0081] Example 5

[0082] The preparation of an ionic liquid microemulsion system is basically the same as that in Example 1, except that: in step S3, the amount of water added is 60 parts; in step S4, the amount of ionic liquid added is 30 parts, resulting in an ionic liquid microemulsion system with an ionic liquid content of 50%.

[0083] Example 6

[0084] The preparation of an ionic liquid microemulsion system is basically the same as that in Example 1, except that in step S1, 20 mmol matrine, 10 mmol hexanoic acid, and 10 mmol lauric acid (matrine-hexanoic acid, lauric acid (1:1)) are dissolved in 40 mL of ethanol and obtained by rotary evaporation.

[0085] Example 7

[0086] The preparation of an ionic liquid microemulsion system is basically the same as that in Example 1, except that in step S1, 14 mmol matrine, 2 mmol hexanoic acid, and 12 mmol lauric acid (matrine-hexanoic acid, lauric acid (1:6)) are dissolved in 28 mL of ethanol and obtained by rotary evaporation.

[0087] Example 8

[0088] The preparation of an ionic liquid microemulsion system is basically the same as that in Example 1, except that in step S1, 18 mmol matrine, 2 mmol hexanoic acid, and 16 mmol lauric acid (matrine-hexanoic acid, lauric acid (1:8)) are dissolved in 36 mL of ethanol and obtained by rotary evaporation.

[0089] Example 9

[0090] The preparation of an ionic liquid microemulsion system is basically the same as that in Example 1, except that in step S1, 11 mmol matrine, 1 mmol hexanoic acid, and 10 mmol lauric acid (matrine-hexanoic acid, lauric acid (1:10)) are dissolved in 22 mL of ethanol and obtained by rotary evaporation.

[0091] Example 10

[0092] The preparation of an ionic liquid microemulsion system is basically the same as that in Example 1, except that in step S1, 13 mmol matrine, 1 mmol octanoic acid, and 12 mmol lauric acid (matrine-octanoic acid, lauric acid (1:12)) are dissolved in 26 mL of ethanol and obtained by rotary evaporation.

[0093] Example 11

[0094] The preparation of an ionic liquid microemulsion system is basically the same as that in Example 1, except that in step S1, 13 mmol matrine, 1 mmol decanoic acid, and 12 mmol lauric acid (matrine-decanoic acid, lauric acid (1:12)) are dissolved in 26 mL of ethanol and obtained by rotary evaporation.

[0095] Example 12

[0096] The preparation of an ionic liquid microemulsion system is basically the same as that in Example 1, except that in step S1, 20 mmol matrine, 10 mmol decanoic acid, and 10 mmol lauric acid (matrine-decanoic acid, lauric acid (1:1)) are dissolved in 40 mL ethanol and obtained by rotary evaporation.

[0097] Example 13

[0098] The preparation of an ionic liquid microemulsion system is basically the same as that in Example 1, except that in step S1, 20 mmol matrine, 10 mmol octanoic acid, and 10 mmol lauric acid (matrine-octanoic acid, lauric acid (1:1)) are dissolved in 40 mL of ethanol and obtained by rotary evaporation.

[0099] Example 14

[0100] The preparation of an ionic liquid microemulsion system is basically the same as that in Example 1, except that in step S1, 20 mmol matrine, 4 mmol octanoic acid, and 16 mmol lauric acid (matrine-octanoic acid, lauric acid (1:4)) are dissolved in 40 mL ethanol and obtained by rotary evaporation.

[0101] Example 15

[0102] The preparation of an ionic liquid microemulsion system is basically the same as that in Example 1, except that in step S1, 20 mmol matrine, 4 mmol decanoic acid, and 16 mmol lauric acid (matrine-decanoic acid, lauric acid (1:4)) are dissolved in 40 mL ethanol and obtained by rotary evaporation.

[0103] Example 16

[0104] The preparation of an ionic liquid microemulsion system is basically the same as that in Example 1, except that in step S1, 13 mmol matrine, 1 mmol decanoic acid, and 12 mmol lauric acid (matrine-decanoic acid, lauric acid (1:12)) are dissolved in 26 mL of ethanol and obtained by rotary evaporation.

[0105] Example 17

[0106] The preparation of an ionic liquid microemulsion system is basically the same as that in Example 1, except that in step S1, 13 mmol matrine, 1 mmol octanoic acid, and 12 mmol lauric acid (matrine-octanoic acid, lauric acid (1:12)) are dissolved in 26 mL of ethanol and obtained by rotary evaporation.

[0107] Example 18

[0108] The preparation of an ionic liquid microemulsion system is basically the same as that in Example 1, except that in step S3, the amount of Tween80 added is 6.67 parts and the amount of Span20 added is 13.33 parts (1:2).

[0109] Example 19

[0110] The preparation of an ionic liquid microemulsion system is basically the same as that in Example 1, except that in step S3, the amount of Tween80 added is 13.33 parts and the amount of Span20 added is 6.67 parts (2:1).

[0111] Example 20

[0112] The preparation of an ionic liquid microemulsion system is basically the same as that in Example 1, except that in step S1, 20 mmol matrine and 20 mmol hexanoic acid are dissolved in 40 mL ethanol and obtained by rotary evaporation.

[0113] Example 21

[0114] The preparation of an ionic liquid microemulsion system is basically the same as that in Example 1, except that in step S1, 20 mmol of matrine and 20 mmol of octanoic acid are dissolved in 40 mL of ethanol and then rotary evaporated to obtain the ionic liquid.

[0115] Example 22

[0116] The preparation of an ionic liquid microemulsion system is basically the same as that in Example 1, except that in step S1, 20 mmol of matrine and 20 mmol of decanoic acid are dissolved in 40 mL of ethanol and obtained by rotary evaporation.

[0117] Example 23

[0118] The preparation of an ionic liquid microemulsion system is basically the same as that in Example 1, except that in step S1, 20 mmol matrine and 20 mmol lauric acid are dissolved in 40 mL ethanol and obtained by rotary evaporation.

[0119] Performance testing

[0120] The ionic liquid microemulsion systems prepared in Examples 1-5 were observed and their stability was tested (see...). Figure 1 The main effect of ionic liquids on ionic liquid microemulsion systems is the disruption of their stability. Stabilization of the ionic liquid microemulsion system can be achieved by adjusting the ratio of ionic liquid, oil phase, and surfactant. Experiments showed that ionic liquid microemulsion systems with ionic liquid ratios of 10%, 40%, and 50% exhibited good stability. However, to ensure the drug loading of baicalin (solubilization by ionic liquid) and to minimize the viscosity of the ionic liquid microemulsion system (ensuring transdermal absorption efficiency), considering the stability performance of the aqueous phase, oil phase, and emulsifier after preparation, a 40% ionic liquid ratio was selected for the microemulsion. The resulting ionic liquid microemulsion systems consistently showed baicalin drug loadings exceeding 10%.

[0121] The stability of the ionic liquid microemulsion systems prepared in Examples 1 and 6-17 was observed, see below. Figure 2In the 1:1 short-chain to long-chain fatty acid ratio group, only decanoic acid did not separate into layers; in the 1:4 short-chain to long-chain fatty acid ratio group, caprylic acid, lauric acid, and decanoic acid did not separate into layers; in the 1:12 short-chain to long-chain fatty acid ratio group, all components did not separate into layers. To refine the stability observation results of the short-chain to long-chain fatty acid ratio ionic liquids, stability observation was designed for matrine-hexanoic acid, lauric acid ionic liquids in ratios of 1:1 to 1:12 (stability observation groups with fatty acid ratios of 1:2, 1:6, 1:8, and 1:10 were added). The separation time gradually increased, and the stability gradually strengthened. The 1:12 sample did not separate into layers after one month, indicating a stable ionic liquid microemulsion system.

[0122] The baicalin saturation content of the matrine-caproic acid, lauric acid (1:12) ionic liquid microemulsion delivery system was determined to be 14.54% by ultraviolet absorption spectroscopy, which is 14-15 times higher than that of baicalin microemulsion drug-loaded systems studied in recent years (10 mg / ml). Comparison of the enhanced solubility effect of ionic liquids on baicalin revealed that the ionic liquid microemulsion system using caproic acid as the short-chain component in the anion had a better baicalin loading than the microemulsion system using lauric acid as the single anion (11.23%) and other microemulsion schemes. Furthermore, the 1:12 (short-chain:long-chain) fatty acid ionic liquids exhibited lower conductivity: among them, the matrine-decanoic acid, lauric acid had the lowest conductivity, having the least impact on the stability of the microemulsion system. The matrine-decanoic acid, lauric acid ionic liquid microemulsion system also showed the highest stability in particle size and dispersion coefficient, but its baicalin loading was lower (12.21%). Although the particle size and dispersion coefficient of matrine-hexanoic acid and lauric acid ionic liquids vary considerably, no stratification occurred after 30 days of storage, which meets the stability standards for practical microemulsion applications.

[0123] To determine the blending ratio of Tween80 and Span20, pseudo-ternary phase diagrams were constructed for the ionic liquid microemulsion systems prepared in Examples 1, 18, and 19. Figure 3 Ionic liquids were added dropwise to the other two phase solutions, and the critical composition of the microemulsion, i.e., the phase equilibrium data of the pseudo-ternary system, was obtained by observing the turbidity point during the addition process. The region above the curve is the microemulsion region, and the region below the curve is the two-phase region. The microemulsion region with a 1:1 ratio of Tween80 and Span20 is relatively large. Therefore, ionic liquid microemulsion systems with surfactants in this ratio are easier to form, and the surfactant content required to stabilize the system is also the lowest, which can effectively improve the biosafety and stability of the ionic liquid microemulsion system.

[0124] The stability of the ionic liquid microemulsion systems prepared in Examples 20-23 was tested, see below. Figure 4Stability observations were conducted on ionic liquid microemulsion systems based on single fatty acid ionic liquids. The results showed that, for ionic liquid microemulsion systems prepared with the same ionic liquid ratio, the system with hexanoic acid as the anionic component separated into layers after 48 hours at room temperature, the system with octanoic acid as the anionic component separated into layers after 7 days, while the systems with decanoic acid or lauric acid as the anionic components remained stable after one month at room temperature. Adjustments to the composition ratios and preparation processes of the hexanoic acid and octanoic acid microemulsion systems that showed separation revealed that the experimental methods used, including the type and ratio of surfactants, gas environment, precursor preparation methods, and input energy (shear rate and temperature), did not improve the stability of the systems. Only by reducing the proportion of the ionic liquid in the ionic liquid microemulsion system could the system be stabilized. This results in a maximum baicalin loading of 7.5% in a single ionic liquid microemulsion system with hexanoic acid as the anion and 8.31% in a single ionic liquid microemulsion system with caprylic acid as the anion, significantly lower than the loading of the microemulsion system with lauric acid as the sole anion. In terms of the solubility of baicalin in ionic liquids, the order is: hexanoic acid > caprylic acid > capric acid > lauric acid; however, because ionic liquid microemulsion systems prepared with ionic liquids containing shorter-chain fatty acid components are unstable, the baicalin loading in stable systems is actually lower.

[0125] The particle size of ionic liquid microemulsion systems varies with the composition of anions, specifically, the shorter the chain length of the anionic component (…). Figure 5 The smaller the particle size of the ionic liquid microemulsion system, the better. Ionic liquid microemulsion systems with hexanoic acid and octanoic acid as anions exhibited demulsification and stratification, with a significant increase in emulsion particle size after 30 days of stability storage. Lauric acid-based systems showed less particle size change and remained stable. Changes in zeta potential also reflect the stability of the ionic liquid microemulsion system: generally, a larger absolute value of the zeta potential indicates higher stability. Ionic liquid microemulsion systems using hexanoic acid and octanoic acid as anions showed the lowest zeta potential and lowest stability after 30 days of storage, thus exhibiting demulsification and stratification in less than 7 days.

[0126] Structure and morphology characterization of the ionic liquid microemulsion system prepared in Example 1

[0127] (1) Infrared spectral analysis of ionic liquid microemulsion system

[0128] Infrared spectroscopy analysis of the ionic liquid microemulsion system revealed characteristic absorption peaks for matrine and fatty acids. Figure 6 ), respectively at 2937cm -1 (antisymmetric stretching vibration of CH2 in the fatty acid carbon chain) and 1728 cm -1(Stretching vibration of the carbon-oxygen double bond in the carboxylic acid group of fatty acids). To verify whether the ionic liquid microemulsion system contained baicalin, the infrared spectra of the ionic liquid microemulsion system without baicalin were compared. It was found that the ionic liquid microemulsion system loaded with baicalin exhibited an additional absorption peak corresponding to the baicalin group: 881 cm⁻¹. -1 (CH stretching vibration of the benzene ring structure of baicalin) and 1510 cm -1 (C=C stretching vibration of the baicalin benzene ring skeleton).

[0129] (2) Transmission electron microscopy analysis of ionic liquid microemulsion system

[0130] Transmission electron microscopy analysis was performed on two baicalin-saturated ionic liquid microemulsion systems to compare them with the ionic liquid microemulsion system with hexanoic acid as the anionic component. Figure 7 In the ionic liquid microemulsion system of (a, b), hexanoic acid, and lauric acid (1:12), the droplet morphology is more clearly defined. Figure 7 (c, d) This may be because the ionic liquid microemulsion system with hexanoic acid as the anionic component undergoes demulsification and stratification shortly after preparation, resulting in a blurred transmission electron microscopy (TEM) image with a few flocculent substances. Baicalin, after demulsification in the ionic liquid microemulsion system, becomes flocculent and free in the emulsion, deteriorating the quality of the TEM image. In contrast, the hexanoic acid, lauric acid (1:12) ionic liquid microemulsion system remains stable and homogeneous after 30 days, so its droplet morphology has clear edges. The hexanoic acid, lauric acid (1:12) ionic liquid microemulsion system without baicalin... Figure 7 The particle sizes of e and f) are mainly distributed in the range of 20-60 nm, while the particle size of the ionic liquid microemulsion system after loading with baicalin increases significantly to 50-100 nm, indicating that the encapsulation effect of baicalin leads to the increase in particle size of the ionic liquid microemulsion system.

[0131] Tests of various bioefficacy indicators of the ionic liquid microemulsion system prepared in Example 1

[0132] (1) Antioxidant properties

[0133] Baicalin is a flavonoid compound extracted from the root of Scutellaria baicalensis, and its antioxidant properties have been scientifically confirmed. ABTS was performed on a baicalin suspension. + Free radical scavenging test Figure 8 In (a), it was found that when the concentration of baicalin increased from 2% to 30%, its ABTS... + The free radical scavenging rate increased from 11.93% to 100.00%; while the ABTS test was performed on the baicalin-supported matrine-hexanoic acid, lauric acid (1:12) ionic liquid microemulsion system. + Free radical scavenging test Figure 8In section b), it was found that when the concentration of scutellarin ionic liquid microemulsion increased from 0.01% to 0.1%, its ABTS... + The free radical scavenging rate increased from 21.27% to 100.00%. This indicates that loading baicalin into a ternary ionic liquid microemulsion system significantly improved its free radical scavenging ability. ROS cell assays were performed on the baicalin-loaded matrine-hexanoic acid, lauric acid (1:12) microemulsion. Figure 8 In the study (c), it was found that when the concentration of the microemulsion increased from 0.01% to 0.05%, its ROS inhibition rate increased from 66.3% to 72.1%, slightly lower than the 87.2% of the positive control group, achieving a better antioxidant effect; SOD cell assays were performed on the baicalin-loaded matrine-hexanoic acid, lauric acid (1:12) microemulsion. Figure 8 In study d), it was found that when the microemulsion concentration increased from 0.01% to 0.05%, the SOD activity upregulation rate increased from 6.4% to 13.2%, and when the microemulsion concentration was 0.02% and 0.05%, the SOD activity upregulation rate exceeded the 7.9% of the positive group. (Based on ABTS...) + Free radical scavenging and ROS / SOD cell assays showed that the ionic liquid microemulsion system exhibits high antioxidant properties.

[0134] (2) Soothing efficacy test

[0135] Based on the TNF-α expression level of macrophages, the anti-inflammatory effect of the baicalin-loaded matrine-hexanoic acid, lauric acid (1:12) ionic liquid microemulsion system was detected. Figure 9 The results showed that the microemulsions at concentrations of 0.05 mg / mL and 0.025 mg / mL exhibited anti-inflammatory effects. Compared with the NC group, the relative content of TNF-α in the M group was significantly increased (P<0.05), indicating that the stimulation conditions in this experiment were effective. Compared with the M group, when the concentration of the baicalin ionic liquid microemulsion system was 0.1 mg / mL, the relative content of TNF-α did not change significantly, indicating that the baicalin ionic liquid microemulsion system had no significant anti-inflammatory effect at a concentration of 0.1 mg / mL. However, at the test concentrations of 0.05 mg / mL and 0.025 mg / mL, the relative content of TNF-α was significantly decreased (P<0.05), with inhibition rates of 3.54% and 13.21%, respectively, indicating that the baicalin ionic liquid microemulsion system could significantly inhibit TNF-α secretion at lower concentrations, achieving a soothing effect.

[0136] (3) Whitening efficacy test (tyrosinase inhibition)

[0137] The inhibition results of baicalin ionic liquid microemulsion system on tyrosinase (bisphenol) activity at concentrations of 0.001% and 0.01% are shown in Table 1. The highest tyrosinase inhibition effect was 12.62%, which was lower than the 50% inhibition in the positive control group (e.g., ...). Figure 10 However, compared with the negative control group, it still showed a certain inhibitory effect on tyrosinase. Analysis using the t-test showed that when the sample concentration was 0.01%, P > 0.05, indicating no statistical difference; while when the sample concentration was 0.1%, P < 0.05, indicating a statistical difference.

[0138] Table 1

[0139]

[0140]

[0141] Transdermal drug delivery efficiency test of ionic liquid microemulsion system

[0142] The drug loading of baicalin was set at 10%, and the transdermal delivery efficiency of baicalin in ionic liquid microemulsion systems and ionic liquid systems was compared. Compared with ionic liquids of the same composition, the baicalin transdermal delivery efficiency of the matrine-hexanoic acid, lauric acid (1:12) ionic liquid microemulsion system was superior to that of the ionic liquid group. Figure 11 For ionic liquid microemulsion systems with a short-chain fatty acid: long-chain fatty acid ratio of 1:12, the transdermal effects are as follows: hexanoic acid, lauric acid > caprylic acid, lauric acid > decanoic acid, lauric acid. Based on the above transdermal drug delivery results, the matrine-hexanoic acid, lauric acid (1:12) ionic liquid microemulsion system is the group with the best transdermal drug delivery effect among stable ionic liquid microemulsion systems.

[0143] Safety assessment of the ionic liquid microemulsion system prepared in Example 1

[0144] (1) Antibacterial test

[0145] The minimum inhibitory concentration (MIC) of the matrine-hexanoic acid, lauric acid (1:12) ionic liquid microemulsion system against Staphylococcus aureus was 0.25%, against Escherichia coli it was 3%, and against Candida albicans it was 0.5%. The MIC and inhibition zone experimental data are shown in Table 2. Among these, the ionic liquid microemulsion system exhibited the largest inhibition zone diameter against Staphylococcus aureus and showed the best antibacterial effect.

[0146] Table 2

[0147]

[0148]

[0149] (2) Human patch test

[0150] As shown in Table 3, the matrine-hexanoic acid, lauric acid (1:12) ionic liquid microemulsion system showed 0 adverse skin reactions in 31 human skin patch tests, indicating that it has excellent skin affinity and safety.

[0151] Table 3

[0152]

[0153] In summary, the matrine-hexanoic acid, lauric acid (1:12) ionic liquid microemulsion system achieved high levels in drug loading, stability, safety, and bioefficacy. This invention addresses the challenge of transdermal delivery of baicalin-type drugs, which are poorly soluble in both water and oil, by innovatively designing a microemulsion drug delivery system based on a long-short chain ternary ionic liquid. First, by optimizing the anion and cation structures of the ionic liquid, the solubilization effect of baicalin was significantly improved. Second, by constructing a ternary phase diagram model of the microemulsion, the key influencing factors on the baicalin loading and the stability of the microemulsion system were explored, and the optimal formulation was established. Finally, through a series of bioefficacy tests, the system's high antioxidant, anti-inflammatory, antibacterial, whitening effects, and safety were verified.

[0154] The innovation of this invention lies in combining the solubilizing properties of ionic liquids with the affinity advantages of microemulsions, providing a simple and universally applicable innovative strategy for the transdermal delivery of active ingredients in poorly soluble drugs such as baicalin. This research not only lays a solid foundation for the clinical application of baicalin but also provides valuable experience and insights for the design of drug delivery systems for other poorly soluble drugs.

[0155] It should be understood that the application of the present invention is not limited to the examples above. Those skilled in the art can make improvements or modifications based on the above description, and all such improvements and modifications should fall within the protection scope of the appended claims.

Claims

1. An ionic liquid microemulsion system, characterized in that, The ionic liquid microemulsion system is prepared by comprising an aqueous phase, an oil phase, a surfactant, and an ionic liquid. The cation of the ionic liquid is a hydrophilic cation, and the anions of the ionic liquid include two hydrophobic anions with different chain lengths.

2. The ionic liquid microemulsion system according to claim 1, characterized in that, The cation is derived from matrine or L-carnitine, and the anion is derived from short-chain fatty acids and long-chain fatty acids.

3. The ionic liquid microemulsion system according to claim 2, characterized in that, The anion is derived from two of the following: hexanoic acid, octanoic acid, decanoic acid, and lauric acid.

4. The ionic liquid microemulsion system according to claim 1, characterized in that, The ionic liquid includes at least one of matrine-[hexanoic acid, lauric acid], matrine-[octanoic acid, lauric acid], matrine-[decanoic acid, lauric acid], and L-carnitine-[hexanoic acid, lauric acid].

5. The ionic liquid microemulsion system according to claim 2, characterized in that, The mass ratio of the short-chain fatty acid to the long-chain fatty acid is 1:(1-12).

6. The ionic liquid microemulsion system according to claim 1, characterized in that, The ionic liquid accounts for 10%-50% of the ionic liquid microemulsion system by weight.

7. The ionic liquid microemulsion system according to claim 1, characterized in that, The oil phase is selected from one of isopropyl myristate, glyceryl stearate, glyceryl caprylate, medium-chain triglycerides, and squalane.

8. The ionic liquid microemulsion system according to claim 1, characterized in that, The surfactant is a nonionic surfactant.

9. A method for preparing the ionic liquid microemulsion system according to any one of claims 1-8, characterized in that, The preparation method includes the following steps: The target drug is dissolved in an ionic liquid to obtain a mixed liquid; The oil phase and surfactant were dissolved in water and subjected to ultrasonic homogenization to obtain a microemulsion. Under continuous stirring, the mixed liquid is added to the microemulsion to obtain the ionic liquid microemulsion system.

10. The use of the ionic liquid microemulsion system according to any one of claims 1-8 in the preparation of a transdermal drug delivery carrier.

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