Drug-loaded oil gel bead and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a drug-loaded oil gel bead and a preparation method thereof. The preparation method of the drug-loaded oil gel beads comprises the following steps: (1) dispersing cellulose nanofibers in water to obtain a water phase; (2) dissolving the medicine in a dispersing agent to form an oil phase; and (3) finally dispersing the water phase in the step (1) into the oil phase in the step (2) to form liquid drops, and freeze-drying to obtain the product. According to the invention, the cellulose nanofiber aqueous dispersion and the drug-containing oil dispersion are simply mixed and replaced, so that the oil gel bead with a stable structure and high drug loading capacity can be obtained, and the oil gel bead has a good industrial application prospect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a drug-loaded oleogel bead and its preparation method. Background Technology

[0002] Oil gels are semi-solid materials formed by structuring liquid oils in a three-dimensional network using gelling agents. Cellulose nanofibers can lock oil molecules within their self-formed three-dimensional nanonetwork, thus transforming liquid oil into a solid or semi-solid state. Cellulose nanofibers (CNFs) are fibrous materials extracted from natural cellulose, with diameters in the nanoscale and lengths reaching the micrometer scale. They combine the renewable, biodegradable, and biocompatible properties of natural cellulose with the advantages of high specific surface area and high strength of nanomaterials.

[0003] Currently, the preparation of oleogels using CNF generally requires prior chemical modification, followed by preparation via emulsion template method or solvent exchange method.

[0004] The solvent exchange method involves first modifying the CNF surface to introduce carboxyl / hydroxyl groups to improve water solubility; then, a modified CNF aqueous dispersion with a solid content of 1-3% is physically / chemically cross-linked to form a hydrogel; finally, it is dehydrated using a solvent gradient such as methanol and then immersed in the oil phase to complete the displacement and obtain an oleogel (Reference: Roman, C., García-Morales, M., Eugenio, ME, et al. Asustainable methanol-based solvent exchange method to produce nanocellulose-based ecofriendly lubricants[J]. Journal of Cleaner Production, 2021, 319:128673.1-128673.10.). The emulsion template method involves first modifying CNF with hydrophobicity through chemical grafting (e.g., long-chain alkyl groups) or physical adsorption to stabilize the oil-water interface; then mixing the modified CNF with the oil / water phase and preparing a Pickering emulsion by high-speed shearing or ultrasonication; finally removing the aqueous phase by vacuum distillation or freeze-drying to allow it to self-assemble into an oleogel (Reference: Zou Y., Tian Y., Zhao B., et al. Effects of cellulose diameter on the formation and rheological properties of edible walnut oleogels structured by cellulose nanofiber[J]. Food Hydrocolloids, 2024, 154: 1.1-1.11).

[0005] Chinese invention patent publication number CN120754308A discloses a multifunctional oleogel wound dressing and its preparation method. The raw material of the multifunctional oleogel wound dressing includes oleogel. The preparation method of oleogel includes the following steps: preheating oil and adding the antisolvent β-sitosterol and candelilla wax to mix and obtain a mixture; adding curcumin to the mixture, mixing and cooling to obtain the oleogel. This invention uses the antisolvent β-sitosterol and candelilla wax to prepare a curcumin lipid carrier (mixture) with good stability and spreadability. The prepared oleogel has the ability to promote the healing of chronic diabetic wounds. However, this invention does not utilize cellulose nanofibers to prepare the oleogel, and the performance of the oleogel is poor.

[0006] In summary, the preparation of oleogels using CNF currently requires chemical modification of its molecular structure. Furthermore, both solvent displacement and emulsion template methods are complex and produce poor oleogel performance. There are currently no reports on the preparation of oleogels using natural CNF. Summary of the Invention

[0007] This invention addresses the problems existing in the prior art by providing a drug-loaded oleogel bead and its preparation method.

[0008] To achieve the above objectives, the technical solution adopted by the present invention is as follows: A method for preparing drug-loaded oleogel beads includes the following steps: (1) First, disperse cellulose nanofibers in water to obtain an aqueous phase; (2) The drug is then dispersed in a dispersant to form an oil phase; (3) Finally, the aqueous phase from step (1) is dispersed into the oil phase from step (2) to form droplets, which are then freeze-dried and separated to obtain drug-loaded oil gel beads.

[0009] Preferably, the solid content of cellulose nanofibers in the aqueous phase in step (1) is 1-5%.

[0010] More preferably, the solid content of the cellulose nanofibers in the aqueous phase is 2-4%.

[0011] Preferably, the drug in step (2) includes one or more of water-soluble drugs, low-melting-point fat-soluble drugs, and high-melting-point fat-soluble drugs.

[0012] Preferably, the water-soluble drug includes one or more of B vitamins and vitamin C.

[0013] Preferably, the low-melting-point fat-soluble drug includes one or more of vitamin E, vitamin E acetate, vitamin D3, vitamin A, fish oil, and algal oil.

[0014] Preferably, the high-melting-point fat-soluble drug includes one or more of paclitaxel, β-carotene, and astaxanthin.

[0015] Preferably, when the drug is a water-soluble drug or a high-melting-point fat-soluble drug, it is dispersed in a dispersant by grinding, and the drug content in the oil phase is 1-30%. More preferably, the drug content in the oil phase is 20-30%.

[0016] Preferably, when the drug is a low-melting-point fat-soluble drug, it is dispersed in a dispersant by stirring, and the drug content in the oil phase is 1-100%. More preferably, the drug content in the oil phase is 5-20%.

[0017] Preferably, the dispersant in step (2) includes one or more of sunflower seed oil, coconut oil, cocoa butter, and vitamin E acetate.

[0018] Preferably, the oil phase in step (2) contains 0.5-5 wt% Span 80.

[0019] More preferably, the oil phase in step (2) contains 0.5-2 wt% Span 80.

[0020] Preferably, the dispersion method in step (3) includes droplet method, shear dispersion method or membrane emulsification method.

[0021] The droplet method involves slowly dripping a dispersed phase into an incompatible continuous phase in the form of droplets using devices such as needles or syringes. The droplets then solidify physically or cross-link chemically within the continuous phase to form dispersed particles.

[0022] The shear dispersion method uses the strong shear force generated by equipment such as high-speed stirrers and homogenizers to tear the dispersed phase into tiny droplets in the continuous phase, and then fixes the droplets into dispersed particles through a solidification reaction.

[0023] Membrane emulsification involves passing a dispersed phase through the micropores of an SPG membrane with uniform pore size under pressure, forming uniformly sized droplets on the continuous phase side, which are then solidified to obtain dispersed particles.

[0024] Preferably, the mass ratio of the aqueous phase to the oil phase in step (3) is 1-100:100.

[0025] More preferably, the mass ratio of the aqueous phase to the oil phase in step (3) is 10-30:100.

[0026] Preferably, the freeze-drying conditions in step (3) are: pre-cooling at -85℃ to -10℃ for 2-12 hours, and then freeze-drying at -50℃ to -80℃ and 5-150 Pa for 24-48 hours.

[0027] More preferably, the freeze-drying conditions in step (3) are: pre-cooling at -85℃ to -50℃ for 2-5 hours, and then freeze-drying at -50℃ to -60℃ and 5-20 Pa for 24-48 hours.

[0028] The beneficial effects of this invention are as follows: (1) This invention obtains an oleogel bead with better structural stability and higher drug loading by simply mixing cellulose nanofibers with a drug-containing oil dispersion, which has good prospects for industrial application.

[0029] (2) By setting a specific freeze-drying method, the present invention significantly improves the physicochemical properties of oleogel beads, making them more structurally stable and with a higher drug loading capacity. Attached Figure Description

[0030] Figure 1 Electron micrograph of the vitamin E acetate oleogel beads prepared in Example 1.

[0031] Figure 2 The image shows an electron microscope image of the folic acid oleogel beads prepared in Example 2. Detailed Implementation

[0032] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection claimed by the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, and such changes should also fall within the scope of protection claimed by the present invention.

[0033] The present invention will be further described below by way of specific embodiments. Unless otherwise specified, all instruments, devices, equipment, reagents, products, etc., used in the embodiments of the present invention are obtained through conventional commercial means.

[0034] Cellulose nanofibers were purchased from Hangzhou Zhiyou Technology Co., Ltd., item number ZYHH-CNF03.

[0035] Example 1 A method for preparing vitamin E acetate oleogel beads using cellulose nanofibers, comprising the following steps: (1) First, fully disperse the cellulose nanofibers in water to form an aqueous phase with a solid content of 3%.

[0036] (2) Then, the low-melting-point fat-soluble drug vitamin E acetate is fully dispersed at 30°C, and then Span 80 with a final concentration of 0.5 wt% is added to form an oil phase with a drug content of 100%.

[0037] (3) Finally, 10g of the aqueous phase from step (1) was evenly dripped into 50g of the oil phase from step (2) through a 24G syringe to form uniformly dispersed droplets. The droplets were pre-cooled in a refrigerator at -85℃ for 2 hours, and then freeze-dried in a freeze dryer at a cold trap temperature of -55℃ and a vacuum of 5pa for 24 hours. The droplets were filtered to obtain vitamin E acetate oleogel beads with a drug loading of 97.96±0.06% (the drug loading test method is referenced in: Wang, Ling, You, De-Shuang, Guo, Dan-yan, et al. Preparation and Properties of Sodiµm Carboxymethyl Cellulose Microspheres by Dropping Method[J].ACS OMEGA,2025,10(5):4754-4762).

[0038] The scanning electron microscope image of the vitamin E acetate oleogel beads prepared in this embodiment is shown below. Figure 1 As shown.

[0039] Example 2 A method for preparing folic acid oleogel beads using cellulose nanofibers, comprising the following steps: (1) First, fully disperse the cellulose nanofibers in water to form an aqueous phase with a solid content of 2%; (2) Then, sunflower seed oil and water-soluble drug folic acid were put into a Pailer PHN Labstar 0.3E grinder at a ratio of 1mL:0.3g and ground and mixed (grinder speed 1500r / min, zircon bead diameter 1.2mm). After grinding for 5min, Span 80 with a final concentration of 2 wt% was added to obtain an oil phase with a drug content of 30%.

[0040] (3) Take 10g of oil phase and 10g of water phase, and shear emulsify at 10000rpm for 5min to obtain emulsion. Finally, put the emulsion into a refrigerator at -85℃ for 5h, and then freeze dry it in a freeze dryer at -55℃ and 20pa vacuum for 48h. Filter to obtain folic acid oleogel beads with a drug loading of 11.19±0.03% (the drug loading test method is referenced from: Omer, RO, Abdelatti, NO, Khalid, AE, et al. Development and Validation of Direct UV-Spectrophotometric Methods for the Analysis of Folic Acid in Bulkand Dosage Form[J]. Journal of Applied Spectroscopy,2024,91(5):1141-1148).

[0041] The scanning electron microscope image of the folic acid oleogel beads prepared in this embodiment is shown below. Figure 2 As shown.

[0042] Example 3 A method for preparing paclitaxel oleogel beads using cellulose nanofibers, comprising the following steps: (1) First, fully disperse the cellulose nanofibers in water to form an aqueous phase with a solid content of 5%; (2) Coconut oil and the high-melting-point fat-soluble drug paclitaxel were put into a Pailer PHNLabstar 0.3E grinder at a ratio of 1mL:0.01g and ground and mixed (grinder speed 1500r / min, zircon bead diameter 1.2mm). After grinding for 5min, Span 80 with a final concentration of 5 wt% was added to obtain an oil phase with a drug content of 1%.

[0043] (3) Take 100g of oil phase and 1g of water phase, pass them through an SPG membrane with a pore size of 10 micrometers to obtain an emulsion, and finally put the emulsion into a refrigerator at -10℃ for 12h to pre-cool, and then put it into a freeze dryer with a cold trap temperature of -80℃ and a vacuum degree of 150pa for 24h to freeze dry. Filter to obtain paclitaxel oleogel beads with a drug loading of 0.824±0.034% (the test method for drug loading is referenced in: Zhuang, Xuechen, Pang, Jiamin, Qiu, Dan, et al. Preparation, characterisation and evaluation of loading paclitaxel into debranched corn starch[J]. IndustrialCrops and Products,2025,229:120969).

[0044] Comparative Example 1 Compared with Example 1, the only difference is that the cellulose nanofibers are replaced with carboxymethyl cellulose (CAS No.: 9000-11-7).

[0045] The final filtration yielded vitamin E acetate oleogel beads with a drug loading of 75.26±1.45%.

[0046] Comparative Example 2 Compared with Example 1, the only difference is that an aqueous phase with a solid content of 10% is formed in step (1).

[0047] The final filtration yielded vitamin E acetate oleogel beads with a drug loading of 82.73±0.86%.

[0048] Comparative Example 3 Compared with Example 2, the only difference is that an aqueous phase is not prepared, as follows: A method for preparing folic acid oleogel beads using cellulose nanofibers, comprising the following steps: (1) First, sunflower seed oil and water-soluble drug folic acid were put into a Pailer PHN Labstar 0.3E grinder at a ratio of 1mL:0.3g and ground and mixed (grinder speed 1500r / min, zircon bead diameter 1.2mm). After grinding for 5min, Span 80 with a final concentration of 2 wt% was added to obtain an oil phase with a drug content of 30%.

[0049] (2) Take 10g of oil phase and 10g of cellulose nanofibers, and shear emulsify them at 10000rpm for 5min to obtain an emulsion. Finally, put the emulsion into a refrigerator at -85℃ for 5h, and then freeze-dry it in a freeze dryer at -55℃ and 20pa vacuum for 48h. Filter to obtain folic acid oleogel beads with a drug loading of 8.78±0.34%.

[0050] Comparative Example 4 Compared with Example 2, the only difference is that pre-cooling is not performed in step (3), as follows: A method for preparing folic acid oleogel beads using cellulose nanofibers, comprising the following steps: (1) First, fully disperse the cellulose nanofibers in water to form an aqueous phase with a solid content of 2%; (2) Then, sunflower seed oil and water-soluble drug folic acid were put into a Pailer PHN Labstar 0.3E grinder at a ratio of 1mL:0.3g and ground and mixed (grinder speed 1500r / min, zircon bead diameter 1.2mm). After grinding for 5min, Span 80 with a final concentration of 2 wt% was added to obtain an oil phase with a drug content of 30%.

[0051] (3) Take 10g of oil phase and 10g of water phase, and shear emulsify at 10000rpm for 5min to obtain emulsion. Finally, put the emulsion into a freeze dryer with a cold trap temperature of -55℃ and a vacuum degree of 20pa for 48h, and filter to obtain folic acid oleogel beads with a drug loading of 6.54±0.45%.

[0052] Comparative Example 5 Compared with Example 2, the only difference is that the freezing conditions in step (3) are different, as follows: A method for preparing folic acid oleogel beads using cellulose nanofibers, comprising the following steps: (1) First, fully disperse the cellulose nanofibers in water to form an aqueous phase with a solid content of 2%; (2) Then, sunflower seed oil and water-soluble drug folic acid were put into a Pailer PHN Labstar 0.3E grinder at a ratio of 1mL:0.3g and ground and mixed (grinder speed 1500r / min, zircon bead diameter 1.2mm). After grinding for 5min, Span 80 with a final concentration of 2 wt% was added to obtain an oil phase with a drug content of 30%.

[0053] (3) Take 10g of oil phase and 10g of water phase, and shear emulsify at 10000rpm for 5min to obtain emulsion. Finally, put the emulsion into a refrigerator at 0℃ for 12h to pre-cool, and then put it into a freeze dryer with a cold trap temperature of -85℃ and a vacuum degree of 20pa for 48h to freeze dry. Filter to obtain folic acid oleogel beads with a drug loading of 5.73±1.67%.

[0054] Test Example 1: Average Particle Size and Oil Holding Capacity (OBC) Test 1. Average particle size test method: The morphology of the samples was observed and photographed by scanning electron microscope (SEM, Phenom Pro scanning electron microscope, Phenom, Netherlands). The obtained SEM images of each sample were imported into Nano measurer1.2 software for particle size measurement.

[0055] 2. Oil Holding Capacity (OBC) Test: Weigh approximately 1.0g of the prepared oleogel beads, carefully wipe off the surface oil with absorbent paper, weigh them, and record the mass as m1. Place the weight in a 50mL centrifuge tube, cap it, and centrifuge. Set the centrifuge speed to 10000rpm and the time to 10min. After centrifugation, remove the oleogel beads, carefully wipe off the surface oil with absorbent paper, weigh them, and record the mass as m2. Calculate the oil holding capacity using the following formula:

[0056] In the formula, m 1 represents the mass of the oleogel beads before centrifugation, in grams; m 2 represents the mass of the oleogel beads after centrifugation, in grams; w The percentage represents the drug loading. A higher oil retention rate indicates a more stable oleogel bead structure.

[0057] The test results for average particle size and oil holding capacity are shown in Table 1.

[0058] Table 1. Test results of average particle size and oil holding capacity

[0059] Test Example 2: Dissolution Rate Test Weigh 30 mg of oleogel beads and place them in 30 mL of 50% (v / v) ethanol aqueous solution. After dissolving at 20°C, 25°C, and 30°C for 0.5 h and 1 h, respectively, test the dissolved drug content (test method is consistent with the corresponding examples and comparative examples), and calculate the dissolution rate (the ratio of dissolved drug amount to drug loading). The lower the dissolution rate, the better the drug loading effect of the oleogel beads. The formula for calculating the dissolution rate is as follows:

[0060] In the formula, Q Dissolution rate, % Ct The concentration of the drug in the solution at time t is expressed in mg / mL. V 0 represents the total volume of the solution, in mL; m The mass of the oleogel beads added is measured in mg. L wt% represents the drug loading of the oleogel beads.

[0061] The dissolution rate and drug loading results are shown in Table 2.

[0062] Table 2 Dissolution rate and drug loading results

[0063] Test Example 3: Texture Analyzer Test A single sample was taken and its texture parameters were tested using a Bollerfeld CTX texture analyzer with a TPA dual-cycle method at a speed of 1 mm / s. The test data are shown in Table 3.

[0064] Table 3 TPA Test Data

[0065] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing drug-loaded oleogel beads, characterized in that, Includes the following steps: (1) First, disperse cellulose nanofibers in water to obtain an aqueous phase; (2) The drug is then dispersed in a dispersant to form an oil phase; (3) Finally, the aqueous phase from step (1) is dispersed into the oil phase from step (2) to form droplets, which are then freeze-dried and separated to obtain drug-loaded oleogel beads.

2. The preparation method according to claim 1, characterized in that, The solid content of cellulose nanofibers in the aqueous phase in step (1) is 1-5%.

3. The preparation method according to claim 1, characterized in that, The drug mentioned in step (2) includes one or more of water-soluble drugs, low-melting-point fat-soluble drugs, and high-melting-point fat-soluble drugs.

4. The preparation method according to claim 3, characterized in that, The water-soluble drug includes one or more of B vitamins and vitamin C; the low-melting-point fat-soluble drug includes one or more of vitamin E, vitamin E acetate, vitamin D3, vitamin A, fish oil, and algal oil; the high-melting-point fat-soluble drug includes one or more of paclitaxel, β-carotene, and astaxanthin.

5. The preparation method according to claim 3, characterized in that, When the drug is a water-soluble drug or a high-melting-point fat-soluble drug, the drug is dispersed in a dispersant by grinding, and the content of the drug in the oil phase is 1-30%.

6. The preparation method according to claim 3, characterized in that, When the drug is a low-melting-point fat-soluble drug, the drug is dispersed in the dispersant by stirring, and the content of the drug in the oil phase is 1-100%.

7. The preparation method according to claim 1, characterized in that, In step (2), the dispersant includes one or more of sunflower seed oil, coconut oil, cocoa butter, and vitamin E acetate; the oil phase contains 0.5-5 wt% Span 80.

8. The preparation method according to claim 1, characterized in that, The dispersion method described in step (3) includes dropleting, shear dispersion or membrane emulsification.

9. The preparation method according to claim 1, characterized in that, In step (3), the mass ratio of the aqueous phase to the oil phase is 1-100:100; the freeze-drying conditions are: pre-cooling at -85℃~-10℃ for 2-12h, and then freeze-drying at -50~-80℃ and 5-150pa for 24-48h.

10. A drug-loaded oleogel bead prepared by the preparation method according to any one of claims 1-9.

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