Drug-loaded polymer-based itraconazole solution and application thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a drug-loaded polymer-based itraconazole solution and application thereof. The preparation method of the drug-loaded polymer-based itraconazole solution comprises the following steps: (1) mixing itraconazole and a polymer according to a mass ratio of 1: 10-1: 20, and adding the mixture into an organic solvent; (2) stirring at 25-60 DEG C for 4-6 hours until a uniform and transparent drug-loaded polymer solution is formed; and (3) removing the organic solvent through reduced pressure distillation or freeze drying to obtain the drug-loaded polymer-based itraconazole solution. According to the polymer-based itraconazole solution preparation provided by the invention, itraconazole is loaded into a specific polymer matrix to form a uniform and stable solution system, so that the solubility of itraconazole can be remarkably improved. And the used polymer material has excellent biocompatibility and safety.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to a drug-loaded polymer-based itraconazole solution and its application. Background Art

[0002] In recent years, with the rapid development of pharmaceutical science and materials science, the drug delivery system (DDS) has become one of the important means for treating various diseases. Traditional pharmaceutical preparations have problems such as low bioavailability, poor targeting, and significant side effects, while the polymer-based drug delivery system has gradually become a research hotspot due to its unique properties.

[0003] Itraconazole is a broad-spectrum antifungal drug widely used in the treatment of superficial and deep fungal infections, including dermatophytosis, candidiasis, and aspergillosis, etc. Existing itraconazole preparations have problems such as poor solubility, low absorption efficiency, and large toxic and side effects. However, itraconazole faces many challenges in clinical applications: 1. Poor solubility: Itraconazole belongs to BCS class II drugs and has low water solubility, which limits its absorption and distribution in the body. 2. Low bioavailability: Due to poor solubility, the absorption efficiency of itraconazole after oral administration is low, resulting in the need for higher doses to achieve therapeutic effects. 3. Toxic and side effects: High-dose use may cause hepatotoxicity, gastrointestinal discomfort, and other adverse reactions. Therefore, it is particularly important to develop a new dosage form that can improve the solubility of itraconazole, improve its bioavailability, and reduce toxic and side effects.

[0004] The polymer-based drug delivery system is a new drug delivery technology that loads drug molecules into a specific polymer matrix. This system combines drugs with polymers through physical or chemical methods to achieve controlled release and efficient delivery of drugs. Compared with traditional preparations, the polymer-based drug delivery system has the following advantages: solubilization: Some polymers can significantly improve the solubility of poorly soluble drugs by forming micelles or nanoparticles, etc. Sustained-release / controlled-release function: The polymer-based drug delivery system can regulate the drug release rate, prolong the drug action time, and reduce the dosing frequency. Targeting: By modifying the polymer surface, selective delivery of drugs to specific tissues or cells can be achieved. Enhanced stability: Polymer encapsulation can protect drugs from the influence of the external environment (such as pH changes, enzyme degradation, etc.) and improve drug stability.

[0005] Although a variety of itraconazole preparations have been developed, these preparations still have some deficiencies: Traditional solution: Usually, a large amount of cosolvents (such as ethanol or polyethylene glycol) need to be added to improve solubility, but this may lead to increased irritation or decreased patient tolerance. Solid dispersion: Although it can improve solubility and bioavailability, the preparation process is complex and costly. Liposome preparation: Although it has good targeting and sustained-release properties, the preparation process is cumbersome and difficult for large-scale production. Nanoparticle preparation: Although it can effectively improve the solubility and stability of drugs, the safety issues of carrier materials have not been completely solved. In addition, the drug delivery systems for itraconazole in the prior art mostly focus on single functions (such as solubilization or sustained release), and it is difficult to meet multiple clinical needs simultaneously.

[0006] Therefore, there is an urgent need for a drug-loaded polymer-based itraconazole solution and its application. Summary of the Invention

[0007] The object of the present invention is to provide a drug-loaded polymer-based itraconazole solution and its application.

[0008] To achieve the above object, the present invention provides the following technical solutions: A drug-loaded polymer-based itraconazole solution, characterized in that the preparation method of the drug-loaded polymer-based itraconazole solution comprises the following steps: (1) Mix itraconazole and the polymer in a mass ratio of 1:10 to 1:20, and add them to an organic solvent; (2) Stir at 25 - 60 °C for 4 - 6 hours until a homogeneous and transparent drug-loaded polymer solution is formed; (3) Remove the organic solvent by vacuum distillation or freeze-drying to obtain the drug-loaded polymer-based itraconazole solution.

[0009] Further, the polymer is a composition of modified polyvinyl alcohol and modified poly(lactic-co-glycolic acid) copolymer, and the mass ratio of the two is 1:1 to 1:3, and the total mass of the polymer accounts for 10 - 20 wt% of the solution system.

[0010] Further, the preparation method of the modified polyvinyl alcohol comprises the following steps: (1) Dissolve polyvinyl alcohol in deionized water to prepare a PVA solution with a concentration of 5 - 10 wt%; (2) Add the crosslinking agent glutaraldehyde to the PVA solution, and control the mass ratio of the crosslinking agent to PVA to be 1:30 to 1:50; (3) Stir and react at 40 - 50 °C for 4 - 6 h, wash, and remove the unreacted crosslinking agent glutaraldehyde to obtain the modified polyvinyl alcohol.

[0011] Further, the preparation method of the modified poly(lactic-co-glycolic acid) copolymer comprises the following steps: (1) Dissolve 5 g to 20 g of poly(lactic-co-glycolic acid) in 80 ml to 95 ml of tetrahydrofuran to prepare a solution. (2) Add 0.5 g to 0.7 g of carbodiimide and react at room temperature for 4 - 6 h. (3) After the reaction is completed, remove the unreacted reagents by rotary evaporation to obtain the modified poly(lactic-co-glycolic acid).

[0012] The modified PVA of the present invention is cross-linked to further enhance its mechanical strength and chemical stability. In the drug delivery system, it can effectively prevent the aggregation of drug particles and maintain the uniformity of the solution. PLGA is a biodegradable biomedical polymer material with good drug loading capacity and sustained release performance. The modified PLGA optimizes its degradation rate and drug release behavior by adjusting the molecular weight and surface modification. The combination of the modified PVA and the modified PLGA forms a "double-layer structure": This double-layer structure can significantly improve the overall stability of the solution and reduce the influence of the external environment on the drug. The combination of the modified PVA and the modified PLGA not only retains the advantages of both, but also further enhances the biocompatibility through synergistic effects. The hydrophilic outer shell of PVA reduces the local irritation that PLGA may cause, while the core structure of PLGA ensures the safe delivery of the drug.

[0013] Further, the organic solvent is selected from at least one of dichloromethane, ethyl acetate, and acetone, and the volume ratio of the organic solvent to the total mass of itraconazole and the polymer is 30:1 to 50:1 ml / g.

[0014] Further, in step (b), the stirring speed is 300 - 1000 rpm, and a segmented temperature control process is adopted: stir at 25 - 35 °C for 30 - 60 minutes in the first stage and stir at 40 - 50 °C for 1 - 2 hours in the second stage.

[0015] Further, when performing vacuum distillation in step (c), the pressure is controlled at -0.08 to -0.1 MPa and the temperature is 30 - 40 °C.

[0016] Further, 0.1 - 1 wt% of a surfactant is also added in step (1).

[0017] Further, the surfactant is a mixture of poloxamer 188, Tween-80, and sodium dodecyl sulfate with a weight ratio of 1:(1.2 - 1.4):(0.4 - 0.6).

[0018] Surfactants of different types and concentrations in the present invention can have a significant impact on the stability of the solution: selecting the appropriate type of surfactant and its ratio is the key. The synergistic effect between the surfactant in the present invention and the modified PVA and modified PLGA, and the combined action of the surfactant and PVA form a denser protective layer, further improving the long-term stability of the solution. The surfactant can regulate the interfacial properties of the solution, making it easier for cells to come into contact with the solution and obtain drugs, thereby providing a better growth environment for the cells. The presence of the surfactant can control the release rate of the drug from the PLGA matrix, achieving a more precise controlled release effect.

[0019] The present invention provides the application of the described itraconazole solution based on a drug-loaded polymer in the medical field.

[0020] Compared with the prior art, the advantages and beneficial effects of the present invention are as follows: 1. The present invention proposes an itraconazole solution preparation based on a polymer. By loading itraconazole into a specific polymer matrix, a homogeneous and stable solution system is formed, which can significantly improve the solubility of itraconazole. The polymer materials used should have excellent biocompatibility and safety to ensure that they do not cause immune rejection or other adverse reactions in the body. By optimizing the polymer structure and preparation process, this solution can not only achieve the rapid release of itraconazole, but also be designed into a sustained-release or targeted delivery system as needed.

[0021] 2. The itraconazole solution based on a drug-loaded polymer of the present invention has broad application prospects in multiple fields: it can be used to treat various superficial and deep fungal infections, especially suitable for patients who do not respond well to traditional preparations. By adjusting the solution concentration and viscosity, it can be developed into forms such as sprays, gels or ointments for local treatment of the skin or mucosal sites. When combined with antibiotics or other antifungal drugs, the curative effect can be improved and the risk of drug resistance can be reduced.

[0022] 3. PVA is a water-soluble polymer material with good film-forming property and hydrophilicity. After modification, PVA is cross-linked to further enhance its mechanical strength and chemical stability. In the drug delivery system, it can effectively prevent the aggregation of drug particles and maintain the uniformity of the solution. PLGA is a biodegradable biomedical polymer material with good drug loading capacity and sustained-release performance. After modification, PLGA optimizes its degradation rate and drug release behavior by adjusting the molecular weight and surface modification. The combination of modified PVA and modified PLGA forms a "double-layer structure": This double-layer structure can significantly improve the overall stability of the solution and reduce the influence of the external environment on the drug. The combination of modified PVA and modified PLGA not only retains the advantages of both, but also further enhances the biocompatibility through synergistic effects. The hydrophilic outer shell of PVA reduces the local irritation that PLGA may cause, while the core structure of PLGA ensures the safe delivery of the drug.

[0023] 4. Surfactants are a class of compounds that can reduce the surface tension of liquids and mainly play the following roles in the drug delivery system: Surfactants can form a protective layer on the surface of drug particles to prevent particle aggregation or precipitation, thereby improving the physical stability of the solution. Surfactants can improve the dispersibility of drug particles in the solution and make them evenly distributed. Surfactants can enhance the wettability of the solution to biological tissues and promote the absorption and utilization of drugs. Different types and concentrations of surfactants in the present invention will have a significant impact on the stability of the solution: Selecting the appropriate type of surfactant and its ratio is the key. The synergistic effect between the surfactants of the present invention and modified PVA and modified PLGA, and the surfactants and PVA act together to form a denser protective layer, further improving the long-term stability of the solution. Surfactants can adjust the interfacial properties of the solution, making it easier for cells to contact the solution and obtain drugs, thus providing a better growth environment for cells. The presence of surfactants can regulate the release rate of drugs from the PLGA matrix to achieve a more precise controlled release effect.

[0024] By simultaneously using modified PVA and modified PLGA, and surfactants with specific ratios, the stability and biocompatibility of the drug-loaded polymer-based itraconazole solution have been significantly improved. Detailed implementation mode

[0025] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0026] Example 1 This embodiment provides a drug-loaded polymer-based itraconazole solution. The preparation method of the drug-loaded polymer-based itraconazole solution comprises the following steps: (1) Mix itraconazole and the polymer at a mass ratio of 1:10, and add them into an organic solvent; (2) Stir at 60 °C for 4 hours until a uniform and transparent drug-loaded polymer solution is formed; (3) Remove the organic solvent by vacuum distillation or freeze-drying to obtain the drug-loaded polymer-based itraconazole solution.

[0027] The polymer is a composition of modified polyvinyl alcohol and modified poly(lactic-co-glycolic acid) copolymer, and the mass ratio of the two is 1:3, and the total mass of the polymer accounts for 10 wt% of the solution system.

[0028] The preparation method of the modified polyvinyl alcohol comprises the following steps: (1) Dissolve polyvinyl alcohol in deionized water to prepare a PVA solution with a concentration of 10 wt%; (2) Add crosslinking agent glutaraldehyde to the PVA solution, and control the mass ratio of the crosslinking agent to PVA to be 1:30; (3) Stir and react at 50 °C for 4 h, wash to remove the unreacted crosslinking agent glutaraldehyde, and obtain the modified polyvinyl alcohol.

[0029] The preparation method of the modified poly(lactic-co-glycolic acid) copolymer comprises the following steps: (1) Dissolve 20 g of poly(lactic-co-glycolic acid) copolymer in 80 ml of tetrahydrofuran to prepare a solution; (2) Add 0.7 g of carbodiimide and react at room temperature for 4 h; (3) After the reaction is completed, remove the unreacted reagents by rotary evaporation to obtain the modified poly(lactic-co-glycolic acid) copolymer.

[0030] The organic solvent is selected from dichloromethane, and the volume ratio of the organic solvent to the total mass of itraconazole and the polymer is 50:1 ml / g.

[0031] In step (b), the stirring speed is 300 rpm, and a segmented temperature control process is adopted: stir at 35 °C for 30 minutes in the first stage and stir at 50 °C for 1 hour in the second stage.

[0032] In step (c), when vacuum distillation is adopted, the pressure is controlled at -0.1 MPa and the temperature is 30 °C.

[0033] In step (1), 1 wt% of a surfactant is further added.

[0034] The surfactant is a mixture of poloxamer 188, Tween-80 and sodium dodecyl sulfate with a weight ratio of 1:1.2:0.6.

[0035] Example 2 This example provides a drug-loaded polymer-based itraconazole solution. The preparation method of the drug-loaded polymer-based itraconazole solution includes the following steps:

[0036] (1) Mix itraconazole and the polymer in a mass ratio of 1:20, and add them to an organic solvent; (2) Stir at 25 °C for 6 hours until a homogeneous and transparent drug-loaded polymer solution is formed; (3) Remove the organic solvent by vacuum distillation or freeze-drying to obtain the drug-loaded polymer-based itraconazole solution.

[0037] The polymer is a composition of modified polyvinyl alcohol and modified poly(lactic-co-glycolic acid) copolymer, with a mass ratio of 1:1 between the two, and the total mass of the polymer accounts for 20 wt% of the solution system.

[0038] The preparation method of the modified polyvinyl alcohol includes the following steps: (1) Dissolve polyvinyl alcohol in deionized water to prepare a 5 wt% PVA solution; (2) Add the crosslinking agent glutaraldehyde to the PVA solution, and control the mass ratio of the crosslinking agent to PVA to be 1:50; (3) Stir and react at 40 °C for 6 h, wash to remove the unreacted crosslinking agent glutaraldehyde, and obtain the modified polyvinyl alcohol.

[0039] The preparation method of the modified poly(lactic-co-glycolic acid) copolymer includes the following steps: (1) Dissolve 10 g of poly(lactic-co-glycolic acid) copolymer in 95 ml of tetrahydrofuran to prepare a solution; (2) Add 0.5 g of carbodiimide and react at room temperature for 6 h; (3) After the reaction is completed, remove the unreacted reagents by rotary evaporation to obtain the modified poly(lactic-co-glycolic acid) copolymer.

[0040] The organic solvent is selected from dichloromethane, and the volume ratio of the organic solvent to the total mass of itraconazole and the polymer is 30:1 ml / g.

[0041] In step (b), the stirring speed is 1000 rpm, and a segmented temperature control process is adopted: the first stage is to stir at 25 °C for 60 minutes, and the second stage is to stir at 40 °C for 2 hours.

[0042] In step (c), when vacuum distillation is used, the pressure is controlled at -0.08 MPa and the temperature is 40 °C.

[0043] In step (1), 1 wt% of a surfactant is also added.

[0044] The surfactant is a mixture of poloxamer 188, tween 80 and sodium dodecyl sulfate at a weight ratio of 1:1.4:0.4.

[0045] Comparative Example 1 The difference between this comparative example and Example 1 is that the polymer is modified polyvinyl alcohol.

[0046] Comparative Example 2 The difference between this comparative example and Example 1 is that the polymer is modified poly(lactic-co-glycolic acid).

[0047] Comparative Example 3 The difference between this comparative example and Example 1 is that modified polyvinyl alcohol is replaced by polyvinyl alcohol.

[0048] Comparative Example 4 The difference between this comparative example and Example 1 is that modified poly(lactic-co-glycolic acid) is replaced by poly(lactic-co-glycolic acid).

[0049] Comparative Example 5 The difference between this comparative example and Example 1 is that the polymer is a composition of modified polyvinyl alcohol and modified poly(lactic-co-glycolic acid) with a mass ratio of 1:0.2.

[0050] Comparative Example 6 The difference between this comparative example and Example 1 is that the surfactant is a mixture of poloxamer 188, tween-80 and sodium dodecyl sulfate at a weight ratio of 1:1:1.

[0051] Performance Test 1. Stability test: The drug-loaded polymer-based itraconazole solution was placed at room temperature for 6 months, and precipitation or stratification was observed

[0052] 2. The effect of the drug-loaded polymer-based itraconazole solution on the viability of mammalian cells (L929 fibroblasts) was detected by the MTT method.

[0053] L929 fibroblasts were selected, inoculated into 96-well plates, and cultured until the logarithmic growth phase. The drug-loaded solution (volume fraction 1%) was added, and a blank control group (containing only the medium) was set up.

[0054] After culturing for 48 hours, the cell viability was detected by the MTT method.

[0055] According to ISO 10993-5 standard: Cell viability ≥ 70%: non-toxic.

[0056] [[ID=5W2]]Cell viability between 50%-70%: slightly toxic.

[0057] Cell viability < 50%: significantly toxic.

[0058] Table 1 Performance Test Results

[0059] As can be seen from Table 1, the itraconazole solution based on the drug-loaded polymer of the present invention has high stability and good biocompatibility.

[0060] In Comparative Example 1, only modified polyvinyl alcohol is used as the polymer. In Comparative Example 2, only modified poly(lactic-co-glycolic acid) is used as the polymer. It can be seen that the stability of the itraconazole solution based on the drug-loaded polymer decreases and the biocompatibility deteriorates. It shows that only when these two polymers act synergistically can the stability of the solution be improved and a better living environment for cells be provided.

[0061] In Comparative Example 3, the modified polyvinyl alcohol is not modified. In Comparative Example 4, the modified poly(lactic-co-glycolic acid) is not modified. It can be seen that the stability of the itraconazole solution based on the drug-loaded polymer decreases and the biocompatibility deteriorates. It shows that only after these two polymers are modified to produce a better synergistic effect can the stability of the solution be improved and a better living environment for cells be provided.

[0062] In Comparative Example 5, the polymer is a composition of modified polyvinyl alcohol and modified poly(lactic-co-glycolic acid) with different mass ratios. It can be seen that the stability of the itraconazole solution based on the drug-loaded polymer decreases and the biocompatibility deteriorates slightly.

[0063] In Comparative Example 6, the surfactant is a mixture of poloxamer 188, Tween-80 and sodium dodecyl sulfate with a weight ratio of 1:1:1. It can be seen that the stability of the itraconazole solution based on the drug-loaded polymer decreases and the biocompatibility deteriorates. It shows that the ratio of the surfactant has a significant impact on the stability of the solution and will simultaneously cooperate with the components in the solution to provide a better environment for cells.

[0064] By simultaneously using modified PVA and modified PLGA, and a surfactant with a specific ratio, the stability and biocompatibility of the itraconazole solution based on the drug-loaded polymer have been significantly improved.

[0065] The above is the preferred embodiment of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A drug-loaded polymer-based itraconazole solution, characterized in that, The preparation method of the itraconazole solution based on drug-loaded polymer comprises the following steps: (1) Mix itraconazole and polymer according to the mass ratio of 1:10 - 1:20, and add them into an organic solvent; (2) Stir at 25 - 60 °C for 4 - 6 hours until a uniform and transparent drug-loaded polymer solution is formed; (3) Remove the organic solvent by vacuum distillation or freeze-drying to obtain the itraconazole solution based on drug-loaded polymer.

2. The drug-loaded polymer-based itraconazole solution according to claim 1, wherein The polymer is a composition of modified polyvinyl alcohol and modified poly(lactic-co-glycolic acid) copolymer, and the mass ratio of the two is 1:1 - 1:3, and the total mass of the polymer accounts for 10 - 20 wt% of the solution system.

3. The drug-loaded polymer-based itraconazole solution according to claim 2, characterized in that, The preparation method of the modified polyvinyl alcohol comprises the following steps: (1) Dissolve polyvinyl alcohol in deionized water to prepare a PVA solution with a concentration of 5 - 10 wt%; (2) Add cross-linking agent glutaraldehyde to the PVA solution, and control the mass ratio of the cross-linking agent to PVA to be 1:30 - 1:50; (3) Stir and react at 40 - 50 °C for 4 - 6 h, wash to remove the unreacted cross-linking agent glutaraldehyde to obtain the modified polyvinyl alcohol.

4. The drug-loaded polymer-based itraconazole solution according to claim 2, characterized in that, The preparation method of the modified poly(lactic-co-glycolic acid) copolymer comprises the following steps: (1) Dissolve 5 g - 20 g of poly(lactic-co-glycolic acid) copolymer in 80 ml - 95 ml of tetrahydrofuran to prepare a solution; (2) Add 0.5 g - 0.7 g of carbodiimide and react at room temperature for 4 - 6 h; (3) After the reaction is completed, remove the unreacted reagents by rotary evaporation to obtain the modified poly(lactic-co-glycolic acid) copolymer.

5. The drug-loaded polymer-based itraconazole solution according to claim 2, wherein The organic solvent is selected from at least one of dichloromethane, ethyl acetate, and acetone, and the volume ratio of the organic solvent to the total mass of itraconazole and polymer is 30:1 - 50:1 ml / g.

6. The drug-loaded polymer-based itraconazole solution according to claim 1, characterized in that, In step (b), the stirring speed is 300 - 1000 rpm, and a segmented temperature control process is adopted: stir at 25 - 35 °C for 30 - 60 minutes in the first stage, and stir at 40 - 50 °C for 1 - 2 hours in the second stage.

7. The drug-loaded polymer-based itraconazole solution according to claim 1, characterized in that, In step (c), when vacuum distillation is adopted, the pressure is controlled at -0.08 to -0.1 MPa and the temperature is 30 - 40 °C.

8. The drug-loaded polymer-based itraconazole solution according to claim 1, wherein In step (1), 0.1 - 1 wt% of surfactant is further added.

9. The drug-loaded polymer-based itraconazole solution according to claim 8, characterized in that, The surfactant is a mixture of poloxamer 188, Tween-80, and sodium dodecyl sulfate with a weight ratio of 1:(1.2 - 1.4):(0.4 - 0.6).

10. Application of the itraconazole solution based on drug-loaded polymer according to any one of claims 1 - 9 in the medical field.

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