A preparation method of a composite carrier for drug solubilization

Abstract

The invention discloses a preparation method of a composite carrier for drug solubilization, using liquidambar formosana, poloxamer, and terpineol as the composite carrier. The mass ratio of liquidambar formosana to poloxamer is 1:1 to 6, the mass ratio of liquidambar formosana to terpineol is 1:1 to 6, and the mass ratio of the poorly soluble drug is 10% - 40% of the total mass of the system. Taking silymarin as the model drug, a solid dispersion prepared by the hot-melt method with liquidambar formosana, poloxamer, and terpineol as the composite carrier has a cumulative dissolution rate of 91.8% in 40 minutes in simulated gastric juice and intestinal juice, and its saturated solubility is increased by 42 times.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to a preparation method of a composite carrier for drug solubilization. Background Art

[0002] Poorly water-soluble drugs have low solubility in water, which affects the absorption and distribution of drugs in the body, making it difficult for drugs to reach the minimum concentration required for treatment, difficult to be absorbed by the body, and having low bioavailability, thus limiting their clinical applications. At the same time, due to the low drug content of poorly water-soluble drugs in aqueous solvents, it is difficult to achieve diversification of their dosage forms. Currently, 40% of the drugs on the market and 80 - 90% of the drugs under research are poorly water-soluble drugs. Therefore, the change in the solubility of such drugs has a crucial impact on their absorption. Currently, there are many methods for improving the solubility of poorly soluble drugs, such as nanocrystals, solid lipid nanoparticles, liposome dispersions, cyclodextrin inclusion complexes, solid dispersions, nano-suspensions, etc.

[0003] The above-mentioned drug solubilization systems and the poorly water-soluble drug carriers used in the technologies still have limitations in aspects such as the solubility improvement of poorly water-soluble drugs in water, the stability of the solubilization system, and antibacterial properties, and are still restricted in the preparation of poorly water-soluble drug preparations. For example, nanocrystals have poor thermal stability, which can cause an increase in particle size and a decrease in solubility; liposomes have a low drug loading capacity and poor carrier stability, and their structure is easily damaged under external influences; solid dispersions are prone to aging and have poor stability; when preparing cyclodextrin inclusion complexes, natural cyclodextrins have low solubility in both water and organic solvents, have limitations on the size of the molecules that can be included, and show certain nephrotoxicity. Compared with the currently common drug solubilization systems, the present invention has a wide range of applicability to poorly soluble drugs. The prepared solubilization system in a colloidal state significantly improves the saturated solubility and dissolution rate of drugs, and the system is stable and has antibacterial properties, overcoming the defect of easy aging of traditional solubilization systems to a certain extent.

[0004] Chinese medicinal material Liquidambar formosana Hance resin is a natural resin, mainly containing ambrutic acid, ambrutol acid, ambrudiol acid, Liquidambar formosana ursolic acid, liquidambaric acid, liquidambaridiol acid, and Liquidambar formosana novic acid. Wu Weixi found through experimental analysis that there are various chemical components such as volatile oils, organic acids, saponins, cardiac glycosides, steroids, alkaloids, and coumarins in Liquidambar formosana Hance resin. The most abundant of them are pentacyclic triterpenoid compounds, which have the skeletal structures of oleanane, ursane, and lupane respectively. Among them, the lipophilic structure of the pentacyclic triterpenic acids contained in Liquidambar formosana Hance resin enables it to have the property of dissolving lipophilic drugs. Liquidambar formosana Hance resin also contains carboxyl groups that can form a supramolecular emulsification system with poloxamer through hydrogen bond structures. At the same time, Liquidambar formosana Hance resin has good antibacterial activity, is non-toxic, and can be developed and applied in related pharmaceutical and food products.

[0005] Poloxamer is the nonproprietary name for polyoxyethylene polyoxypropylene copolymer. The product produced by BASF in Germany has the trade name Pluronic. Among them, the polyoxyethylene chain has relatively hydrophilic properties, and the polyoxypropylene chain has relatively lipophilic properties. Therefore, poloxamer is a nonionic polymer surfactant and is mainly used as an emulsifier and solubilizer in pharmaceutical preparations. Due to the characteristics of poloxamer itself, the polymer tends to spontaneously aggregate in polar media, increasing the solubility of drugs and preventing their precipitation by generating micelle-like structures that can carry hydrophobic drugs. Poloxamer belongs to a type of polyether. Polyethers have very low toxicity and are commonly used as pharmaceutical excipients and emulsifiers; they are often used in oral, nasal sprays, eyes, ear drops, and shampoos.

[0006] 4-Terpineol is the main component of tea tree oil, accounting for 35% - 40%, and is also its main active ingredient. 4-Terpineol is a monocyclic monoterpene alcohol with a spicy, woody, earthy, and lily aroma and is one of the useful daily chemical fragrances. And terpineol has the function of a natural preservative and is often used as an additive ingredient in food flavors and appetite enhancers. At the same time, terpineol also has anti-allergic and local astringent effects, has good antibacterial activity, is non-toxic, and can be developed and applied in related pharmaceutical and food products. When it is applied to the preparation of a solubilization system for poorly soluble drugs, it can also effectively improve the taste of oral pharmaceutical preparations. Summary of the Invention

[0007] The object of the present invention is to provide a method for preparing a composite carrier for drug solubilization, obtaining a poorly soluble drug solubilization system in a colloidal state with a wide range of applications. This composite carrier can inhibit the crystallization of the active pharmaceutical ingredient, enabling the active pharmaceutical ingredient to be distributed in the carrier in an amorphous state.

[0008] To this end, the present invention uses the hot melt method, with styrax, poloxamer, and styrax as the solubilization system of the composite carrier. The specific technical solution is as follows:

[0009] The solubilization system of the poorly soluble drug with styrax, poloxamer, and styrax as the composite carrier, calculated by mass percentage, consists of the following effective components: composed of the compounding of styrax, poloxamer, and terpineol. The mass ratio of styrax to poloxamer is 1:1 - 6, and the mass ratio of styrax to terpineol is 1:1 - 6. The mass ratio of the poorly soluble drug is 10% - 40% of the total mass of the system.

[0010] Preferably, for the solubilization system of the poorly soluble drug, calculated by mass percentage, the optimal ratio of the composite carrier of this solubilization system is poloxamer:styrax:terpineol = 1:1:1.

[0011] The present invention also adopts the following technical solution: Through a hot-melt method, liquidambar formosana, poloxamer, and terpineol are subjected to strong stirring for 0.5 - 2 h in an oil bath at 20 - 85 °C to obtain a homogeneous and stable hot melt; then insoluble drugs are added, and stirring is continued strongly for 10 - 30 min to obtain a homogeneous system, followed by cooling to obtain a solubilization system.

[0012] Application of the above drug solubilization system in solubilizing insoluble drugs, wherein the insoluble drug is selected from any one of silymarin, quercetin, baicalin, baicalein, daidzein, etc.

[0013] Compared with the prior art, the beneficial effects of the present invention are mainly reflected in that: Terpineol and liquidambar formosana respectively form hydrogen bonds with poloxamer to form a supramolecular emulsion system. One end of this composite carrier is a hydrophilic structure and the other end is a lipophilic structure, which can effectively improve the solubility of insoluble drugs in water. Moreover, terpineol has the function of a natural preservative, is often used as an additive component of food flavors and appetite enhancers, has good antibacterial activity, is non-toxic, can be developed and applied in related pharmaceutical and food products, and when used in the preparation of an insoluble drug solubilization system, can also effectively improve the taste of pharmaceutical preparations. The oral pharmaceutical preparation prepared on the basis of this carrier is safe and non-toxic, can significantly increase the wettability of insoluble drugs, increase the solubility in water, inhibit the crystallization of insoluble drugs, and improve the bioavailability of drugs. Specific embodiments

[0014] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto: It should be understood that these embodiments are the preferred implementation schemes of the present invention and are only used for specific illustration. Based on the above description and these embodiments, those skilled in the art can determine the necessary features of the present invention, and various changes and modifications can be made to the present invention without departing from the purpose and technical scope of the present invention to adapt it to various uses and conditions.

[0015] "r·min -1 " represents "rotational speed"; "nm" represents "nanometer"; "min" represents the time unit "minute"; "°C" represents "degree Celsius"; "mg / L" represents "concentration unit".

[0016] Example 1

[0017] Select 0.3 g of poloxamer polymer, 0.3 g of liquidambar formosana, and 0.3 g of terpineol. Through a hot-melt method, poloxamer, liquidambar formosana, and terpineol are subjected to an oil bath at 75 °C and stirred strongly for 1.5 h to obtain a homogeneous and stable hot melt. Then 15% of the total mass of the system of silymarin is added, and stirring is continued strongly for 30 min to obtain a homogeneous system, followed by cooling to obtain a solubilization system in a colloidal state.

[0018] Set the temperature of the intelligent dissolution tester to 37 ± 0.5 °C and the rotation speed to 100 r / min. Add 900 ml of distilled water that has been degassed by ultrasound to the dissolution cup. Weigh precisely 1 g of the solubilization system of silymarin and put it into the dissolution cup. Start the rotation and timing. At 5 min, 10 min, 20 min, 40 min, and 60 min respectively, use a syringe to extract 10 ml of the dissolution solution. Immediately after taking it out, add isothermal distilled water to make up 900 ml. After sampling, continue to rotate the stirring rod until the solubilization system in water is completely disintegrated, stop the rotation, and record the complete disintegration time of the above solubilization system in distilled water. Filter the sample solutions at each time period through a 0.45 μm microporous filter membrane, take the filtrate to measure the absorbance and calculate the cumulative dissolution rate of the sample, and draw the dissolution curve. The dissolution results are shown in Table 1 and Appendix Figure 1 。

[0019] Weigh an excessive amount of the above silymarin solubilization system respectively into 250 ml beakers, add 100 ml of distilled water for dissolution, stir strongly for 56 hours to saturate the dissolution solution, take the upper suspension, centrifuge it in a centrifuge for 10 min, take the supernatant to measure its absorbance, and determine its saturated solubility in water by the standard curve method. The dissolution results are shown in Table 1.

[0020] Comparative Example 1

[0021] Select 0.45 g of poloxamer polymer and 0.45 g of liquidambar formosana. By the hot melt method, heat the poloxamer and liquidambar formosana in an oil bath at 75 °C and stir strongly for 1.5 h to obtain a homogeneous and stable hot melt. Then add 15% of silymarin based on the total mass of the system, stir strongly for 30 min to obtain a homogeneous system, and cool to obtain a solubilization system in a colloidal state.

[0022] Take 1 g of the obtained solubilization system. For the silymarin / poloxamer / liquidambar formosana solubilization system, except for the different masses of each component, the detection method of the dissolution results is carried out according to Example 1 for detection. The dissolution results are shown in Table 1 and Appendix Figure 1 。

[0023] Comparative Example 2

[0024] Select 0.9 g of poloxamer polymer. By the hot melt method, heat the poloxamer in an oil bath at 75 °C and stir strongly for 1.5 h to obtain a hot melt. Then add 15% of silymarin based on the total mass of the system, stir strongly for 30 min to obtain a homogeneous system, and cool to obtain a solubilization system in a colloidal state.

[0025] Take 1 g of the obtained solubilization system. For the silymarin / poloxamer solubilization system, except for the different masses of each component, the detection method of the dissolution results is carried out according to Example 1 for detection. The dissolution results are shown in Table 1 and Appendix Figure 1 。

[0026] The results of Example 1 and Comparative Examples 1 - 2 are shown in Table 1:

[0027] Table 1 Dissolution Results of Example 1 and Comparative Examples 1-2

[0028] Brief Description of the Drawings

[0029] Figure 1 It is the cumulative dissolution curve graph of Example 1 and Comparative Examples 1-2

[0030] Examples 2-25

[0031] Optimal ratio selection of the composite carrier of the drug solubilization system: Select poloxamer high molecular polymer, and prepare the silymarin solubilization system with poloxamer, liquidambar formosana, and terpineol according to a certain mass ratio. The preparation method is the same as that of Example 1, and a solubilization system in a colloidal state is obtained.

[0032] Except for the different masses of each component in the above solubilization system, the dissolution result detection method is the same as that of Example 1 for detection. The dissolution results are shown in Table 2.

[0033] The experimental components and dissolution results are shown in Table 2 below:

[0034] Table 2

[0035]

[0036]

[0037] Regarding the results obtained from the above examples as shown in the table, the results show that compared with Comparative Example 1 (a drug solubilization system with poloxamer and liquidambar formosana as the composite carrier) and Comparative Example 2 (a drug solubilization system with poloxamer as the single carrier), the drug solubilization system with poloxamer - liquidambar formosana resin - terpineol as the composite carrier has a faster dissolution rate, a faster disintegration speed, and a greatly increased saturation solubility. Compared with the saturation solubility of the silymarin raw material drug of 0.05 mg / ml. When the preferred ratio of the composite carrier is poloxamer∶liquidambar formosana resin∶terpineol = 1∶1∶1, the saturation solubility of the silymarin solubilization system containing terpineol reaches 2.1 mg / ml, which is 42 times that of the raw material drug. The preferred ratio of the composite carrier of this solubilization system is poloxamer∶liquidambar formosana resin∶terpineol = 1∶1∶1.

[0038] Example 26

[0039] Select 0.3 g of poloxamer high molecular polymer, 0.3 g of liquidambar formosana, and 0.3 g of terpineol. By the hot melt method, poloxamer, liquidambar formosana, and terpineol are oil-bathed at 75°C and stirred strongly for 1.5 h to obtain a homogeneous and stable hot melt. Then, 15% of quercetin based on the total mass of the system is added and stirred strongly for 30 min to obtain a homogeneous system, and then cooled to obtain a solubilization system in a colloidal state.

[0040] Take 1 g of the obtained solubilization system, and the dissolution result detection method is carried out according to Example 1. The dissolution results are shown in Table 3. The saturated solubility of the solubilization system reaches 0.1 mg / m, and the saturated solubility of the API is 0.0006 mg / ml, which is 167 times that of the API.

[0041] Example 27

[0042] Select 0.3 g of poloxamer polymer, 0.3 g of liquidambar formosana, and 0.3 g of terpineol. By the hot-melt method, poloxamer, liquidambar formosana, and terpineol are oil-bathed at 75 °C and vigorously stirred for 1.5 h to obtain a homogeneous and stable hot melt. Then, 15% of the total mass of the system of baicalin is added and vigorously stirred for 30 min to obtain a homogeneous system, which is cooled to obtain a solubilization system in a colloidal state.

[0043] Take 1 g of the obtained solubilization system, and the dissolution result detection method is carried out according to Example 1. The dissolution results are shown in Table 3. The saturated solubility of the solubilization system reaches 23.5 mg / ml, and the saturated solubility of the API is 0.18 mg / ml, which is 130 times that of the API.

[0044] Example 28

[0045] Select 0.3 g of poloxamer polymer, 0.3 g of liquidambar formosana, and 0.3 g of terpineol. By the hot-melt method, poloxamer, liquidambar formosana, and terpineol are oil-bathed at 75 °C and vigorously stirred for 1.5 h to obtain a homogeneous and stable hot melt. Then, 15% of the total mass of the system of baicalein is added and vigorously stirred for 30 min to obtain a homogeneous system, which is cooled to obtain a solubilization system in a colloidal state.

[0046] Take 1 g of the obtained solubilization system, and the dissolution result detection method is carried out according to Example 1. The dissolution results are shown in Table 3. The saturated solubility of the solubilization system reaches 17.4 mg / ml, and the saturated solubility of the API is 0.09 mg / ml, which is 193 times that of the API.

[0047] Example 29

[0048] Select 0.3 g of poloxamer polymer, 0.3 g of liquidambar formosana, and 0.3 g of terpineol. By the hot-melt method, poloxamer, liquidambar formosana, and terpineol are oil-bathed at 75 °C and vigorously stirred for 1.5 h to obtain a homogeneous and stable hot melt. Then, 15% of the total mass of the system of daidzein is added and vigorously stirred for 30 min to obtain a homogeneous system, which is cooled to obtain a solubilization system in a colloidal state.

[0049] Take 1 g of the obtained solubilization system, and the dissolution result detection method is carried out according to Example 1. The dissolution results are shown in Table 3. The saturated solubility of the solubilization system reaches 67.8 mg / ml, and the saturated solubility of the API is 1.5 mg / ml, which is 45 times that of the API.

[0050] The results of Examples 26 to 29 are shown in Table 3:

[0051] Table 3

[0052]

[0053]

Claims

1. A preparation method of a drug solubilization system applied to the solubilization of silymarin, characterized in that, The preparation method is as follows: By means of a hot-melt method, liquidambar formosana, poloxamer, and terpineol with a mass ratio of 1:1:1 are strongly stirred in an oil bath at 75°C for 1.5 h to obtain a homogeneous and stable hot melt; then 15% of silymarin based on the total mass of the system is added, and stirring is continued strongly for 30 min to obtain a homogeneous system, which is cooled to obtain a solubilization system; the solubilization system is in a colloidal state.

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