Insoluble active compound transdermal drug delivery preparation and preparation method thereof

Abstract

The invention relates to the technical field of transdermal drug delivery, and discloses a transdermal drug delivery preparation of an indissolvable active compound and a preparation method of the transdermal drug delivery preparation. The preparation method comprises the following steps: respectively preparing the eutectic solvent and the polyelectrolyte aggregate; and blending the eutectic solvent and the polyelectrolyte aggregate, and then adding a drug for mixing to obtain the transdermal drug delivery preparation of the indissolvable active compound, or blending the eutectic solvent and the medicine, and then adding the polyelectrolyte aggregate for mixing to obtain the transdermal drug delivery preparation of the indissolvable active compound. According to the application, an innovative indissolvable active compound transdermal drug delivery preparation is constructed by taking a deep-eutectic solvent and polyelectrolyte aggregate composite system as a core, and the composition and the structure of the composite system and the interaction between the drug and the skin are optimized, so that efficient solubilization, synergistic infiltration promotion and stable slow release of the drug are realized; the preparation has good biocompatibility and safety, can solve many problems in transdermal administration of indissolvable active compounds, and improves the action effect and clinical application value of the drug.

Description

Technical Field

[0001] The present application relates to the technical field of transdermal drug delivery, and mainly to a transdermal drug delivery preparation of a poorly soluble active compound and a preparation method thereof. Background Art

[0002] The main barrier for drugs to enter the body through the skin is the stratum corneum, and other layers can generally be ignored. However, when the drug is highly lipid-soluble, it passes through the stratum corneum at a faster rate. The active epidermis has more water-soluble substances, and lipid-soluble drugs are difficult to penetrate. At this time, the barrier effect of the active epidermis on drugs cannot be ignored. Poorly soluble active compounds occupy an important position in drug research and development, but their low solubility and low permeability severely limit their application in transdermal administration.

[0003] Traditional transdermal drug delivery preparations mainly rely on common drug solvents and excipients to try to solve the solubility and permeability problems of drugs. For example, some conventional organic solvents such as ethanol and propylene glycol can increase the solubility of poorly soluble drugs to a certain extent, but they have the disadvantages of strong volatility, large skin irritation and adverse effects on drug stability. Moreover, these organic solvents often cannot fundamentally and effectively improve the ability of drugs to penetrate the main barrier of the stratum corneum of the skin, resulting in the transdermal penetration efficiency of drugs being still very low, making it impossible for most drugs to reach effective therapeutic concentrations, greatly limiting their clinical application effects and scope. As a commonly used drug carrier, liposomes have certain targeting and drug encapsulation capabilities, and can improve the distribution of drugs in the body, but they are limited in improving the solubility of poorly soluble drugs, and their preparation process is relatively complicated, costly, and poor in stability. During storage and use, liposome aggregation, fusion and drug leakage are prone to occur, thereby affecting the efficacy and safety of drugs. In addition, microemulsion preparations are also a technology that attempts to be used for transdermal delivery of poorly soluble drugs. However, the formation of microemulsions requires a precise ratio of surfactant, co-surfactant and oil phase, and phase separation may occur after long-term storage, resulting in uneven drug distribution, affecting the sustained release and penetration of drugs. At the same time, some components in microemulsions may cause adverse reactions such as skin allergies, limiting their wide clinical application.

[0004] It can be seen that in the existing technology, whether it is a single solvent system or a traditional drug carrier system, neither of them can fully solve the two key problems of low solubility and difficulty in penetration during the transdermal administration of poorly soluble active compounds. It is also difficult to ensure good biocompatibility and safety while ensuring efficient drug delivery. An innovative transdermal drug delivery technology and preparation with excellent comprehensive performance is urgently needed to meet clinical needs and promote the progress of drug research and development. Therefore, the existing technology still needs to be improved and developed. Summary of the invention

[0005] In view of the above-mentioned deficiencies in the prior art, the purpose of the present application is to provide a poorly soluble active compound transdermal administration preparation and a preparation method thereof, aiming to solve the problems of low solubility and difficulty in penetration in the existing transdermal administration of poorly soluble active compounds.

[0006] The technical solution of this application is as follows: In a first aspect, the present application provides a method for preparing a transdermal preparation of a poorly soluble active compound, which comprises the following steps: preparing a deep eutectic solvent and polyelectrolyte coacervate respectively; The low eutectic solvent and the polyelectrolyte coacervate are blended, and then the drug is added and mixed to obtain the transdermal administration preparation of the poorly soluble active compound; Alternatively, the low eutectic solvent and the drug are mixed, and then the polyelectrolyte coacervate is added and mixed to obtain the transdermal administration preparation of the poorly soluble active compound.

[0007] This application uses an innovative low eutectic solvent / polyelectrolyte coacervate composite system to utilize various interactions such as hydrogen bonds and electrostatics between its molecules to achieve efficient solubilization of poorly soluble drugs, ensure that the drug exists in a dissolved state, and provide sufficient drug concentration for subsequent transdermal penetration. By regulating the lipid fluidity of the stratum corneum of the skin and the charge interaction with the skin surface, the drug is synergistically promoted to penetrate the stratum corneum and enter the active epidermis and dermis, significantly improving the transdermal penetration rate and cumulative penetration of the drug, thereby enhancing the bioavailability of the drug and improving the therapeutic effect.

[0008] Furthermore, the mass ratio of the low eutectic solvent to the polyelectrolyte coacervate is 1:1000-50:100.

[0009] Furthermore, the polyelectrolyte aggregates include one or more of biological polysaccharide-based polyelectrolyte aggregates, biological molecule polyelectrolyte aggregates, and synthetic polymer polyelectrolyte aggregates.

[0010] Furthermore, the method for preparing the polyelectrolyte coacervate comprises the following steps: preparing a positively charged solution and a negatively charged solution respectively; The positively charged solution and the negatively charged solution are mixed and allowed to stand for more than 2 hours; The positive charge solution is prepared by dissolving a positive charge material in water, wherein the mass concentration of the positive charge material in the positive charge solution is 0.5%-8%. The negative charge solution is prepared by dissolving a negative charge material in water, wherein the mass concentration of the negative charge material in the negative charge solution is 0.5%-8%.

[0011] Furthermore, the mass ratio of the positively charged material to the negatively charged material in the polyelectrolyte coagulation body is 15:1-1:20.

[0012] Furthermore, the positively charged material is one or more of chitosan, chitosan oligosaccharide, polyethyleneimine, polylysine, carboxymethyl chitosan, chitosan quaternary ammonium salt, polyvinylpyrrolidone quaternary ammonium salt, polyguanidine compound, polyarginine, and cationic starch; The negatively charged material is one or more of polyacrylic acid, gum arabic, sodium alginate, polymethacrylic acid, polyaspartic acid, sodium hyaluronate, sodium carboxymethyl cellulose, pectate, carrageenan, and sodium polyphosphate.

[0013] Further, the deep eutectic solvent includes one or both of a hydrophilic deep eutectic solvent and an amphiphilic deep eutectic solvent; The preparation method of the deep eutectic solvent comprises the following steps: Stirring and mixing the hydrogen bond acceptor and the hydrogen bond donor to obtain a mixture, and then heating and stirring to react until the mixture is homogeneous and transparent; The molar ratio of the hydrogen bond acceptor to the hydrogen bond donor is 4:1-1:5; The heating temperature is 70-90°C.

[0014] Furthermore, the hydrogen bond acceptor is one or more of betaine and choline chloride; The hydrogen bond donor is one or more of urea, glycerol, xylitol, α-hydroxy acid, amino acid, and diethyl L-tartrate.

[0015] Furthermore, the mass proportion of the drug in the transdermal administration preparation of the poorly soluble active compound is 0.5-5%; The drug is one or more of ibuprofen, salicylic acid, naproxen, piroxicam, carbamazepine, digoxin, griseofulvin, lovastatin, nifedipine, gemfibrozil, paclitaxel, docetaxel, cabazitaxel, itraconazole, voriconazole, posaconazole, doxorubicin, daunorubicin, and etoposide.

[0016] In a second aspect, the present application further provides a poorly soluble active compound transdermal preparation, wherein the preparation is prepared by the method for preparing the poorly soluble active compound transdermal preparation as described in the first aspect.

[0017] Beneficial effects: (1) Significantly improve the solubility of poorly soluble active compounds: Overcoming the problem of limited solubility of traditional solvents and carriers for poorly soluble drugs, the poorly soluble active compounds are stably dispersed in molecular or ionic state through the unique intermolecular interactions of the low eutectic solvent / polyelectrolyte condensate composite system, such as hydrogen bonding and electrostatic effects, which greatly improves the solubility of the drug and ensures that a sufficient amount of the drug can enter the skin to exert its efficacy, rather than being deposited in solid form on the skin surface and unable to be absorbed and utilized.

[0018] (2) Effectively enhance the transdermal penetration of drugs: To solve the problem that existing technologies make it difficult for drugs to penetrate the stratum corneum, the main barrier of the skin, by using low eutectic solvents to regulate the lipid fluidity of the stratum corneum of the skin. At the same time, with the help of the synergistic effect of the interaction between polyelectrolyte aggregates and the surface charge of the skin, the drug is promoted to pass smoothly through the stratum corneum into the active epidermis and dermis, thereby increasing the transdermal penetration rate and cumulative penetration of the drug, thereby significantly improving the bioavailability of the drug, achieving an effective therapeutic effect, and avoiding treatment failure due to insufficient drug penetration or the need for a more invasive drug administration method.

[0019] (3) Ensure good biocompatibility and safety: In view of the defects in biocompatibility and safety of existing technologies, such as high irritation of organic solvents, poor stability of liposomes, and easy allergic reaction of microemulsions, low eutectic solvents and polyelectrolyte raw materials with good biocompatibility are selected, and toxic and harmful organic solvents and additives are avoided in the preparation process of the preparation. This ensures that the transdermal preparations have no obvious irritation to the skin during long-term use, and will not cause allergic reactions and inflammatory reactions. This ensures the safety and comfort of patients' medication and improves patients' compliance. It is especially suitable for the long-term transdermal treatment needs of chronic diseases.

[0020] (4) Achieve stable sustained release of drugs: To make up for the deficiency of traditional preparations in effectively controlling the drug release rate, the sustained release system formed by the low eutectic solvent / polyelectrolyte coacervate composite system and the drug can be released slowly and continuously in the skin, maintain a stable drug concentration, avoid large fluctuations in drug concentration, reduce the frequency of drug administration, further improve the therapeutic effect of the drug, and at the same time reduce the toxic and side effects of the drug, providing a more optimized solution for clinical medication. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 The present invention is a flow chart for the preparation of transdermal preparations for poorly soluble active compounds. DETAILED DESCRIPTION

[0022] The present application provides a transdermal preparation of a poorly soluble active compound and a preparation method thereof. To make the purpose, technical scheme and effect of the present application clearer and more specific, the present application is further described in detail below. It should be understood that the specific embodiments described herein are only used to explain the present application and are not used to limit the present application.

[0023] Existing technologies such as conventional organic solvents, liposomes and microemulsions can improve drug solubility to a certain extent, but the degree of solubilization of poorly soluble active compounds is limited and cannot meet clinical needs. In addition, traditional transdermal drug delivery preparations have difficulty breaking through the barrier of the skin's stratum corneum, resulting in low drug penetration efficiency.

[0024] For this problem, refer to Figure 1 The present application provides a method for preparing a transdermal preparation of a poorly soluble active compound, which comprises the following steps: S1, preparing a deep eutectic solvent and a polyelectrolyte coacervate respectively; S2a, blending the low eutectic solvent and the polyelectrolyte coacervate, and then adding the drug to mix, to obtain a transdermal administration preparation of a poorly soluble active compound; S2b, or blending the low eutectic solvent and the drug, and then adding the polyelectrolyte coacervate to mix, to obtain the transdermal administration preparation of the poorly soluble active compound.

[0025] This application uses an innovative low eutectic solvent / polyelectrolyte coacervate composite system to utilize various interactions such as hydrogen bonds and electrostatics between its molecules to achieve efficient solubilization of poorly soluble drugs, ensure that the drug exists in a dissolved state, and provide sufficient drug concentration for subsequent transdermal penetration. By regulating the lipid fluidity of the stratum corneum of the skin and the charge interaction with the skin surface, the drug is synergistically promoted to penetrate the stratum corneum and enter the active epidermis and dermis, significantly improving the transdermal penetration rate and cumulative penetration of the drug, thereby enhancing the bioavailability of the drug and improving the therapeutic effect.

[0026] Further, in step S1, the deep eutectic solvent includes one or a combination of a hydrophilic deep eutectic solvent and an amphiphilic deep eutectic solvent.

[0027] Furthermore, the step of preparing the deep eutectic solvent comprises: The hydrogen bond acceptor and the hydrogen bond donor are stirred and mixed to obtain a mixture, and then heated and stirred to react until the mixture is uniform and transparent.

[0028] The molar ratio of the hydrogen bond acceptor to the hydrogen bond donor is 4:1-1:5; the heating temperature is 70-90°C, and the reaction time can also be controlled within 2.5-4 hours to ensure that the reaction is complete. In the present application, the solid raw materials of the hydrogen bond acceptor and the hydrogen bond donor will form a liquid mixture after mixing and heating, and at the same time, a uniform and transparent low eutectic solvent is formed after the reaction.

[0029] Furthermore, the hydrogen bond acceptor is one or more of betaine and choline chloride; the hydrogen bond donor is one or more of urea, glycerol, xylitol, α-hydroxy acid, amino acid, and diethyl L-tartrate.

[0030] Furthermore, in step S1, the polyelectrolyte aggregates include one or a combination of two or more of biological polysaccharide-based polyelectrolyte aggregates, biological molecule polyelectrolyte aggregates and synthetic polymer polyelectrolyte aggregates.

[0031] Furthermore, the polyelectrolyte coacervate is a biopolysaccharide-based polyelectrolyte coacervate, and the steps of preparing the polyelectrolyte coacervate include: preparing a positively charged solution and a negatively charged solution respectively; The positively charged solution and the negatively charged solution were mixed and allowed to stand for more than 2 hours; Among them, the positively charged solution is prepared by dissolving the positively charged material in water, and the mass concentration of the positively charged material in the positively charged solution is 0.5%-8%. The negatively charged solution is prepared by dissolving the negatively charged material in water, and the mass concentration of the negatively charged material in the negatively charged solution is 0.5%-8%.

[0032] In the present application, in order to utilize the characteristics of the low eutectic solvent and the polyelectrolyte coacervate, the two need to be prepared separately and then mixed, and the polyelectrolyte coacervate can be formed after standing due to the electrostatic interaction between the positively charged material and the negatively charged material. The prepared polyelectrolyte coacervate has liquid-like properties and can be uniformly mixed with the low eutectic solvent by maintaining a certain fluidity.

[0033] Furthermore, the mass ratio of the positively charged material to the negatively charged material in the prepared polyelectrolyte coacervate is 15:1-1:20.

[0034] Furthermore, the positively charged material is one or more of chitosan, chitosan oligosaccharide, polyethyleneimine, polylysine, carboxymethyl chitosan, chitosan quaternary ammonium salt, polyvinylpyrrolidone quaternary ammonium salt, polyguanidine compounds, polyarginine, and cationic starch; the negatively charged material is one or more of polyacrylic acid, gum arabic, sodium alginate, polymethacrylic acid, polyaspartic acid, sodium hyaluronate, sodium carboxymethyl cellulose, pectinate, carrageenan, and sodium polyphosphate.

[0035] Specifically, existing organic solvents have problems such as high irritation and toxicity, liposomes have poor stability and are complex and costly to prepare, and microemulsions are prone to phase separation and allergic reactions. This application selects low eutectic solvents and polyelectrolyte raw materials with good biocompatibility, avoids the use of harmful solvents and additives, ensures that the preparation has no obvious irritation to the skin and no allergic reactions during long-term use, ensures the safety of patients' medication, and improves patients' compliance.

[0036] Furthermore, in step S2a or S2b, the mass proportion of the drug in the poorly soluble active compound transdermal administration preparation is 0.5-5%. The low eutectic solvent / polyelectrolyte coacervate composite system prepared in the present application has good solubility for the drug, and further increasing the dosage of the drug is likely to cause waste.

[0037] Furthermore, the drugs selected in the present application are generally poorly soluble active compounds with low solubility in water. Through the setting of the present application, the problem that traditional preparations of such poorly soluble compounds are difficult to exert their efficacy through the skin is effectively solved. The drugs can specifically be one or more of ibuprofen, salicylic acid, naproxen, piroxicam, carbamazepine, digoxin, griseofulvin, lovastatin, nifedipine, gemfibrozil, paclitaxel, docetaxel, cabazitaxel, itraconazole, voriconazole, posaconazole, doxorubicin, daunorubicin, etoposide, etc.

[0038] Further, in step S2a or S2b, the mass ratio of the low eutectic solvent and the polyelectrolyte coacervate is 1:1000-50:100. In the present application, the low eutectic solvent has good solubility and affinity for the drug, and the polyelectrolyte coacervate can provide a specific microenvironment and spatial structure, and the synergistic effect of the two can better overcome the poor solubility of the drug and improve the dissolution effect and stability of the drug. By controlling the appropriate ratio range, the hydrogen bonds and electrostatic interactions between the low eutectic solvent and the polyelectrolyte coacervate can be optimized to form a more ideal intermolecular interaction. These interactions can effectively disperse the poorly soluble active compounds in a molecular or ionic state, so that the drug molecules are better combined with the solvent and the coacervate, thereby improving the solubility of the drug. At the same time, the presence of the drug in a molecular or ionic state can enable more drug molecules to pass through barriers such as the stratum corneum of the skin and enter the skin to exert their efficacy, rather than being deposited on the skin surface in a solid form and unable to be absorbed and utilized, thereby improving the bioavailability of the drug.

[0039] More specifically, the ratio of the low eutectic solvent and the polyelectrolyte coacervate will affect the rheological properties of the composite system, such as viscosity, elasticity, etc. Within this ratio range, the rheological properties of the system can be adjusted to make it more suitable for the preparation and application of the drug. For example, for some drug preparations that need to be applied or injected, the composite system can be controlled to have appropriate viscosity and elasticity, which is convenient for operation and use. Moreover, the appropriate ratio can enable the low eutectic solvent and the polyelectrolyte coacervate to form a stable composite system to avoid phase separation. Phase separation may lead to uneven distribution of drugs, affecting the efficacy and safety of the drugs. By controlling the ratio, it is possible to ensure that the composite system remains in a stable state during storage and use, ensuring the uniformity and consistency of the drugs. By controlling the ratio, it is also possible to achieve slow or rapid release of drugs to meet the therapeutic needs of different drugs.

[0040] The present application utilizes the unique intermolecular interactions of the low eutectic solvent / polyelectrolyte condensate composite system, such as hydrogen bonding and electrostatic effects, to stably disperse the poorly soluble drugs in a molecular or ionic state, thereby greatly improving the drug solubility and ensuring that a sufficient amount of the drug can enter the skin to exert its efficacy, rather than being deposited in solid form on the skin surface and unable to be absorbed and utilized. This can overcome the problem of limited solubility of traditional solvents and carriers for poorly soluble drugs.

[0041] The present application also provides a poorly soluble active compound transdermal drug delivery preparation, wherein the preparation is prepared by the preparation method of the poorly soluble active compound transdermal drug delivery preparation as described above. The present application is based on the overall design of a transdermal drug delivery preparation of a low eutectic solvent / polyelectrolyte coacervate composite system, and the low eutectic solvent and the polyelectrolyte coacervate are composited to simultaneously solve the solubilization and penetration problems of the poorly soluble active compound transdermal drug delivery process, especially solubilization with the help of the low eutectic solvent, and penetration of the poorly soluble drug in the stratum corneum and the active epidermis with the help of the low eutectic solvent and the polyelectrolyte coacervate, respectively.

[0042] The transdermal preparations for poorly soluble active compounds provided in the present application can also be designed into different dosage forms according to needs, including gels, creams, patches, etc. Specifically, the overall viscosity of the dosage form can be increased by increasing the amount of polyelectrolyte coacervate, and the molecular weight of the polyelectrolyte coacervate raw materials can also be regulated to adjust its rheological properties.

[0043] Specifically, most existing preparations cannot achieve stable and sustained release of drugs in the skin, which can easily cause fluctuations in drug concentration, affect efficacy and may increase toxic side effects. The present application provides a transdermal delivery technology for poorly soluble active compounds based on a low eutectic solvent / polyelectrolyte coacervate composite system, which utilizes the disturbance of the stratum corneum by the low eutectic solvent and the "infiltration" of the active epidermis by the coacervate to synergistically achieve deep delivery of poorly soluble active compounds; by means of hydrogen bond interactions between the low eutectic solvent and the poorly soluble active compounds, the solubilization of the poorly soluble active compounds is achieved, and the problem of coacervate loading on the poorly soluble active compounds is solved. The composite system constructed by the present application forms a sustained-release system with the drug, which can control the slow release of the drug in the skin, maintain a stable drug concentration, reduce the number of dosing times, optimize the treatment plan, and at the same time reduce the potential risks caused by excessive peak drug concentrations, thereby improving the safety and effectiveness of drug treatment.

[0044] The invention is further described below by means of specific examples.

[0045] Example 1 Betaine was selected as a hydrogen bond acceptor and urea as a hydrogen bond donor. The mixture was weighed in a molar ratio of 1:2 and placed in a round-bottom flask with a magnetic stirrer to obtain a mixture. The mixture was stirred in an oil bath at 85°C for 3 hours until a uniform and transparent low eutectic solvent was formed, which was recorded as DES1. A positively charged solution of chitosan with a mass concentration of 2% and a negatively charged solution of polyacrylic acid with a mass concentration of 2% were prepared respectively. The positively charged solution and the negatively charged solution were mixed in a mass ratio of chitosan to polyacrylic acid of 1:2, and then allowed to stand for more than 2 hours to form a polyelectrolyte coacervate, which was recorded as PEC1. DES1 and PEC1 were blended in a mass ratio of 3:97 to construct a low eutectic solvent / polyelectrolyte coacervate composite solubilization and penetration enhancement system, and then 2% of the ibuprofen drug by mass in the preparation was added and mixed to obtain the poorly soluble active compound transdermal administration preparation of Example 1. Compared with water, the solubility of ibuprofen in the composite system increases by 134 times, the penetration enhancement ratio increases by nearly 20 times, and the effective drug release time is more than 24 hours.

[0046] Example 2 Betaine was selected as a hydrogen bond acceptor and glycerol as a hydrogen bond donor. The mixture was weighed in a molar ratio of 2:3, placed in a round-bottom flask with a magnetic stirrer, and mixed to obtain a mixture. The mixture was stirred and reacted in an oil bath at 90°C for 2.5 hours until a uniform and transparent low eutectic solvent was formed, which was recorded as DES2. A positively charged solution of chitosan with a mass concentration of 2% and a negatively charged solution of gum arabic with a mass concentration of 2% were prepared respectively. The positively charged solution and the negatively charged solution were mixed in a mass ratio of chitosan to gum arabic of 1:3, and then allowed to stand for more than 2 hours to form a polyelectrolyte coacervate, which was recorded as PEC2. DES2 and PEC2 were blended in a mass ratio of 5:95 to construct a low eutectic solvent / polyelectrolyte coacervate composite solubilization and penetration enhancement system, and salicylic acid drug accounting for 5% by mass in the preparation was added and mixed to obtain the poorly soluble active compound transdermal administration preparation of Example 2. Compared with water, the solubility of salicylic acid in the composite system increases by 195 times, the penetration enhancement rate increases by nearly 4 times, and the effective drug release time is more than 24 hours.

[0047] Example 3 Choline chloride was selected as a hydrogen bond acceptor and xylitol as a hydrogen bond donor. They were weighed in a molar ratio of 3:2, placed in a round-bottom flask with a magnetic stirrer, mixed to obtain a mixture, and stirred in an oil bath at 75°C for 4 hours until a uniform and transparent low eutectic solvent was formed, which was recorded as DES3; a positively charged solution with a mass concentration of 1% of chitosan oligosaccharide and a negatively charged solution with a mass concentration of 2% of sodium alginate were prepared respectively, and the positively charged solution and the negatively charged solution were mixed in a mass ratio of chitosan oligosaccharide to sodium alginate of 1:3, and then allowed to stand for more than 2 hours to form a polyelectrolyte coacervate, which was recorded as PEC3; DES3 and PEC3 were blended in a mass ratio of 5:95 to construct a low eutectic solvent / polyelectrolyte coacervate composite solubilization and penetration enhancement system, and then salicylic acid drug accounting for 5% by mass in the preparation was added and mixed to obtain the poorly soluble active compound transdermal administration preparation of Example 3. Compared with water, the solubility of salicylic acid in the composite system increases by 125 times, the penetration enhancement ratio increases by nearly 5 times, and the effective drug release time is more than 24 hours.

[0048] Example 4 Betaine was selected as a hydrogen bond acceptor and glycerol as a hydrogen bond donor. After weighing at a molar ratio of 2:3, the mixture was placed in a round-bottom flask with a magnetic stirrer, and the mixture was mixed to obtain a mixture. The mixture was stirred and reacted in an oil bath at 90°C for 2.5 hours until a uniform and transparent low eutectic solvent was formed, which was recorded as DES4; a positively charged solution with a mass concentration of 1% of chitosan and a negatively charged solution with a mass concentration of 2% of gum arabic were respectively prepared, and the positively charged solution and the negatively charged solution were mixed at a mass ratio of chitosan to gum arabic of 1:3, and then allowed to stand for more than 2 hours to form a polyelectrolyte coacervate, which was recorded as PEC4; DES4 and PEC4 were blended at a mass ratio of 50:50 to construct a low eutectic solvent / polyelectrolyte coacervate composite solubilization and penetration enhancement system, and then salicylic acid drugs accounting for 5% of the mass in the preparation were added and mixed to obtain the poorly soluble active compound transdermal administration preparation of Example 4. Salicylic acid can be effectively dissolved in the composite system, but the overall dosage form is biased, the viscosity is low, and the penetration enhancement ratio is increased by nearly 2 times.

[0049] Comparative Example 1 Betaine was selected as a hydrogen bond acceptor and urea as a hydrogen bond donor. After being weighed in a molar ratio of 1:2, the mixture was placed in a round-bottom flask with a magnetic stirrer, and mixed to obtain a mixture. The mixture was stirred and reacted in an oil bath at 85°C for 3 hours until a uniform and transparent low eutectic solvent was formed, which was recorded as DES5. A positively charged solution of chitosan with a mass concentration of 2% and a negatively charged solution of polyacrylic acid with a mass concentration of 2% were respectively prepared and directly added to DES5, wherein corresponding amounts of the positively charged solution and the negatively charged solution were added in a mass ratio of chitosan to polyacrylic acid of 1:2, and the total mass of the positively charged solution and the negatively charged solution was recorded as M5. The mixed mass ratio of DES5 and M5 was 5:95, and then 2% of the ibuprofen drug by mass in the preparation was added and mixed to obtain the preparation of Comparative Example 1. The composite system finally formed can effectively dissolve the ibuprofen drug, but cannot form a good dosage form, and cannot achieve effective penetration promotion.

[0050] Comparative Example 2 Betaine was selected as a hydrogen bond acceptor and cyclodextrin as a hydrogen bond donor. After being weighed in a molar ratio of 1:2, they were placed in a round-bottom flask with a magnetic stirrer, mixed to obtain a mixture, and stirred in an oil bath at 85°C for 3 hours until a uniform and transparent low eutectic solvent was formed, which was recorded as DES6; a positively charged solution of chitosan with a mass concentration of 2% and a negatively charged solution of sodium alginate with a mass concentration of 2% were respectively prepared and directly added to DES6, wherein corresponding amounts of the positively charged solution and the negatively charged solution were added according to a mass ratio of chitosan to polyacrylic acid of 1:2, and the total mass of the positively charged solution and the negatively charged solution was recorded as M6, and the mixed mass ratio of DES6 and M6 was 5:95, and then 2% of the ibuprofen drug by mass in the preparation was added and mixed, and then acetic acid fumigation was performed to form a gel to obtain the preparation of Comparative Example 2, and the gel composite system finally formed can effectively dissolve the ibuprofen drug, but cannot achieve effective penetration promotion.

[0051] It should be understood that the application of the present application is not limited to the above examples. For ordinary technicians in this field, improvements or changes can be made according to the above description, and all these improvements and changes should fall within the scope of protection of the present application.

Claims

1. A method for preparing a transdermal preparation of a poorly soluble active compound, characterized in that: The following steps are involved: preparing a deep eutectic solvent and polyelectrolyte coacervate respectively; The low eutectic solvent and the polyelectrolyte coacervate are blended, and then the drug is added and mixed to obtain the transdermal administration preparation of the poorly soluble active compound; Alternatively, the low eutectic solvent and the drug are mixed, and then the polyelectrolyte coacervate is added and mixed to obtain the transdermal administration preparation of the poorly soluble active compound.

2. The method for preparing the transdermal preparation of a poorly soluble active compound according to claim 1, characterized in that: The mass ratio of the low eutectic solvent to the polyelectrolyte coacervate is 1:1000-50:

100.

3. The method for preparing the transdermal preparation of a poorly soluble active compound according to claim 1, characterized in that: The polyelectrolyte aggregates include one or more of biological polysaccharide-based polyelectrolyte aggregates, biological molecular polyelectrolyte aggregates, and synthetic polymer polyelectrolyte aggregates.

4. The method for preparing the transdermal preparation of a poorly soluble active compound according to claim 3, characterized in that: The preparation method of the polyelectrolyte coacervate comprises the following steps: preparing a positively charged solution and a negatively charged solution respectively; The positively charged solution and the negatively charged solution are mixed and allowed to stand for more than 2 hours; The positive charge solution is prepared by dissolving a positive charge material in water, wherein the mass concentration of the positive charge material in the positive charge solution is 0.5%-8%. The negative charge solution is prepared by dissolving a negative charge material in water, wherein the mass concentration of the negative charge material in the negative charge solution is 0.5%-8%.

5. The method for preparing the transdermal preparation of a poorly soluble active compound according to claim 4, characterized in that: The mass ratio of the positive charge material to the negative charge material in the polyelectrolyte coacervate is 15:1-1:

20.

6. The method for preparing the transdermal preparation of a poorly soluble active compound according to claim 4, characterized in that: The positively charged material is one or more of chitosan, chitosan oligosaccharide, polyethyleneimine, polylysine, carboxymethyl chitosan, chitosan quaternary ammonium salt, polyvinylpyrrolidone quaternary ammonium salt, polyguanidine compound, polyarginine, and cationic starch; The negatively charged material is one or more of polyacrylic acid, gum arabic, sodium alginate, polymethacrylic acid, polyaspartic acid, sodium hyaluronate, sodium carboxymethyl cellulose, pectate, carrageenan, and sodium polyphosphate.

7. The method for preparing a transdermal preparation of a poorly soluble active compound according to claim 1, characterized in that: The deep eutectic solvent includes one or both of a hydrophilic deep eutectic solvent and an amphiphilic deep eutectic solvent; The preparation method of the deep eutectic solvent comprises the following steps: Stirring and mixing the hydrogen bond acceptor and the hydrogen bond donor to obtain a mixture, and then heating and stirring to react until the mixture is homogeneous and transparent; The molar ratio of the hydrogen bond acceptor to the hydrogen bond donor is 4:1-1:5; The heating temperature is 70-90°C.

8. The method for preparing the transdermal preparation of a poorly soluble active compound according to claim 7, characterized in that: The hydrogen bond acceptor is one or more of betaine and choline chloride; The hydrogen bond donor is one or more of urea, glycerol, xylitol, α-hydroxy acid, amino acid, and diethyl L-tartrate.

9. The method for preparing a transdermal preparation of a poorly soluble active compound according to claim 1, characterized in that: The mass proportion of the drug in the transdermal administration preparation of the poorly soluble active compound is 0.5-5%; The drug is one or more of ibuprofen, salicylic acid, naproxen, piroxicam, carbamazepine, digoxin, griseofulvin, lovastatin, nifedipine, gemfibrozil, paclitaxel, docetaxel, cabazitaxel, itraconazole, voriconazole, posaconazole, doxorubicin, daunorubicin, and etoposide.

10. A transdermal preparation for a poorly soluble active compound, characterized in that: The preparation method is prepared by the method for preparing the transdermal preparation of the poorly soluble active compound according to any one of claims 1 to 9.

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