A continuous flow process for the preparation of chitosan hollow microspheres

Abstract

This invention discloses a continuous flow method for preparing chitosan hollow microspheres. The invention utilizes ultrasonic microreactor technology combined with emulsion crosslinking to successfully prepare chitosan hollow microspheres. The hollow chitosan microspheres provided by this invention are suitable for encapsulating various drugs, with a precisely tunable particle size within the range of 200 nm to 1.5 μm. They exhibit excellent biocompatibility and biodegradability, and a high drug loading capacity. The preparation process is a continuous synthesis process, resulting in highly uniform particle size and morphology of the product. The preparation process is safe, efficient, and easily scaled up.

Description

Technical Field

[0001] This invention relates to the field of carrier technology, and in particular to a continuous flow preparation method for chitosan hollow microspheres. Background Technology

[0002] Hollow microspheres, due to their unique structure and properties, have wide applications in various fields such as drug delivery, environmental remediation, and thermal insulation materials. Chitosan, with its excellent biocompatibility, is a superior drug carrier material, and its use as the wall material for hollow microspheres shows great potential in drug delivery. Although various methods for preparing hollow microspheres exist, reports on chitosan hollow microspheres are still relatively few, especially regarding nanoscale hollow chitosan microspheres, which have yet to be studied. Summary of the Invention

[0003] The purpose of this invention is to overcome the shortcomings and deficiencies of the prior art and provide a continuous flow preparation method for chitosan hollow microspheres.

[0004] Another object of the present invention is to provide chitosan hollow microspheres.

[0005] Another object of the present invention is to provide applications of the above-mentioned chitosan hollow microspheres.

[0006] The objective of this invention is achieved through the following technical solution: A continuous flow preparation method for chitosan hollow microspheres includes the following steps: 1) Preparation of chitosan solution: Chitosan is dissolved in acetic acid solution to obtain chitosan solution; 2) Preparation of the oil phase: An emulsifier is added to liquid paraffin to obtain the oil phase; 3) Mix the chitosan solution from step 1) with the oil phase from step 2), and first shear and stir the mixture in a high-speed homogenizer to obtain a pre-emulsion; 4) Pass the pre-emulsion obtained in step 3) into an ultrasonic microreactor for emulsification to obtain an emulsion; 5) A crosslinking agent is introduced into the emulsion obtained in step 4), and a suspension is obtained after stirring; 6) The suspension obtained in step 5) is washed with petroleum ether and ethanol in sequence and then dried with hot air to obtain hollow chitosan microspheres.

[0007] Further, the concentration of the chitosan solution in step 1) is 0.5 wt% to 2.5 wt%, preferably 2 wt%. Further, the concentration of the acetic acid solution in step 1) is 1 wt% to 3 wt%, preferably 2 wt%.

[0008] Further, the emulsifier mentioned in step 2) is at least one of nonionic emulsifiers, ionic surfactants, natural emulsifiers, and polymeric emulsifiers, preferably Tween 80.

[0009] Further, the mass fraction of the emulsifier mentioned in step 2) is 5% to 15%, preferably 10%.

[0010] Further, the volume ratio of the chitosan solution to the oil phase in step 3) is 1:3 to 1:8, preferably 1:3.

[0011] Furthermore, the parameters of the high-speed homogenizer mentioned in step 3) are 3500±500 rpm.

[0012] Furthermore, the mixing time described in step 3) is 3 ± 1 min.

[0013] Furthermore, the ultrasonic microreactor described in step 4) is set with a flow rate of 6±1 mL / min and a power of 120±20 W.

[0014] Furthermore, the emulsification time described in step 4) is 90±5 s.

[0015] Further, the crosslinking agent mentioned in step 5) is at least one of aldehydes, carboxyl groups, sodium tripolyphosphate, and citric acid, preferably glutaraldehyde.

[0016] Further, the mass fraction of the crosslinking agent mentioned in step 5) is 50% to 300%, preferably 150%.

[0017] Furthermore, the stirring time described in step 5) is 6 ± 1 h.

[0018] A type of chitosan hollow microsphere is obtained by the above preparation method.

[0019] The above-mentioned chitosan hollow microspheres are used in the preparation of drug carriers / drug delivery systems.

[0020] This invention utilizes ultrasonic microreactor (USMR) technology combined with emulsification crosslinking to successfully prepare chitosan hollow microspheres, the particle size of which can be precisely controlled within the range of 200 nm to 1.5 μm.

[0021] The present invention has the following advantages and effects compared with the prior art: The hollow chitosan microspheres provided by this invention are suitable for encapsulating various drugs. The particle size is precisely adjustable within the range of 200 nm to 1.5 μm, exhibiting excellent biocompatibility and biodegradability, and a high capacity for drug loading. The preparation process is a continuous synthesis process, resulting in highly uniform particle size and morphology of the product. The preparation process is safe, efficient, and easily scaled up. Attached Figure Description

[0022] Figure 1 This is a flowchart of the continuous flow preparation method of chitosan hollow microspheres of the present invention; Figure 2 This is a diagram of the apparatus for the continuous flow preparation method of chitosan hollow microspheres according to the present invention; Figure 3 This is a scanning electron microscope image (scale bar: 5 μm) of the chitosan hollow microspheres of the present invention. Figure 4 This is a scanning electron microscope image (scale bar: 20 μm) of the chitosan hollow microspheres of the present invention. Figure 5 This is a scanning electron microscope image (scale bar is 3 μm) of the chitosan hollow microspheres of the present invention. Detailed Implementation

[0023] To make the technical problem to be solved, the technical solution, and the beneficial effects of the present invention clearer, the present invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the present invention and are not intended to limit the present invention.

[0024] The terminology used in the embodiments of this invention is for the purpose of describing particular embodiments only and is not intended to limit the invention. The singular forms “a,” “the,” and “the” as used in the embodiments of this invention and the appended claims are also intended to include the plural forms unless the context clearly indicates otherwise.

[0025] In the following examples, room temperature refers to 15–30°C.

[0026] Unless otherwise specified, all percentages in the following examples are by mass percentages.

[0027] The ultrasonic microreactors in the following examples are products sold by Moge Microfluidics Technology (Shantou) Co., Ltd.

[0028] Example 1 1) Preparation of chitosan solution: (Aqueous phase) Chitosan is dissolved in 2% acetic acid solution at room temperature to obtain a chitosan solution with a mass concentration of 2%; 2) Preparation of the oil phase: Add 10% by mass of emulsifier Tween 80 to liquid paraffin; 3) Mix the chitosan solution from step 1) with the oil phase from step 2) at a volume ratio of 1:3, and then shear and stir the mixture in a high-speed homogenizer (3500 rpm) for 3 min to obtain a pre-emulsion. 4) Pass the pre-emulsion obtained in step 3) into an ultrasonic microreactor for emulsification for 90 s to obtain an emulsion; the ultrasonic microreactor is set with a flow rate of 6 mL / min and a power of 120 W. 5) Pass 150% of the crosslinking agent glutaraldehyde into the obtained emulsion and stir for 6 hours to obtain a suspension; 6) The obtained suspension was washed with petroleum ether and ethanol in sequence and then dried with hot air to obtain hollow chitosan microspheres.

[0029] Figure 3 , Figure 4 , Figure 5 This is a scanning electron microscope (SEM) image of the chitosan nanogel microsphere carrier prepared in this embodiment. As can be seen from the image, the obtained chitosan nanogel microspheres have a relatively uniform particle size distribution, and the particle size can be precisely controlled within the range of 200 nm to 1.5 μm by adjusting the power and residence time of the ultrasonic microreactor. Figure 5 The ruptured chitosan microspheres were captured and observed to be a single shell. Combined with the cross-linking characteristics of glutaraldehyde in the emulsion droplets, the chitosan microspheres generated by this method are hollow microspheres.

[0030] Example 2 1) Preparation of chitosan solution: (Aqueous phase) Chitosan is dissolved in 2% acetic acid solution at room temperature to obtain a chitosan solution with a mass concentration of 0.5%; 2) Preparation of the oil phase: Add 5% by mass of Tween 80 emulsifier to liquid paraffin; 3) Mix the chitosan solution from step 1) with the oil phase from step 2) at a volume ratio of 1:8, and then shear and stir the mixture in a high-speed homogenizer (3500 rpm) for 3 min to obtain a pre-emulsion. 4) Pass the pre-emulsion obtained in step 3) into an ultrasonic microreactor for emulsification for 90 s to obtain an emulsion; the ultrasonic microreactor is set with a flow rate of 6 mL / min and a power of 120 W. 5) Pass 300% of the crosslinking agent glutaraldehyde into the obtained emulsion and stir for 6 h to obtain a suspension; 6) The obtained suspension was washed with petroleum ether and ethanol in sequence and then dried with hot air to obtain hollow chitosan microspheres.

[0031] Example 3 1) Preparation of chitosan solution: (Aqueous phase) Chitosan is dissolved in 2% acetic acid solution at room temperature to obtain a chitosan solution with a mass concentration of 2.5%; 2) Preparation of the oil phase: Add 15% by mass of emulsifier to the liquid paraffin; 3) Mix the chitosan solution from step 1) with the oil phase from step 2) at a volume ratio of 1:5, and then shear and stir the mixture in a high-speed homogenizer (3500 rpm) for 3 min to obtain a pre-emulsion. 4) Pass the pre-emulsion obtained in step 3) into an ultrasonic microreactor for emulsification for 90 s to obtain an emulsion; the ultrasonic microreactor is set with a flow rate of 6 mL / min and a power of 120 W. 5) Pass 50% of the crosslinking agent glutaraldehyde into the obtained emulsion and stir for 6 h to obtain a suspension; 6) The obtained suspension was washed with petroleum ether and ethanol in sequence and then dried with hot air to obtain hollow chitosan microspheres.

[0032] Example 4 1) Preparation of chitosan solution: (Aqueous phase) Chitosan is dissolved in 2% acetic acid solution at room temperature to obtain a chitosan solution with a mass concentration of 1.5%; 2) Preparation of the oil phase: Add 10% by mass of emulsifier to the liquid paraffin; 3) Mix the chitosan solution from step 1) with the oil phase from step 2) at a volume ratio of 1:6, and then shear and stir the mixture in a high-speed homogenizer (3500 rpm) for 3 min to obtain a pre-emulsion. 4) Pass the pre-emulsion obtained in step 3) into an ultrasonic microreactor for emulsification for 90 s to obtain an emulsion; the ultrasonic microreactor is set with a flow rate of 6 mL / min and a power of 120 W. 5) Pass 100% crosslinking agent glutaraldehyde into the obtained emulsion and stir for 6 h to obtain a suspension; 6) The obtained suspension was washed with petroleum ether and ethanol in sequence and then dried with hot air to obtain hollow chitosan microspheres.

[0033] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A continuous flow process for the preparation of chitosan hollow microspheres, characterized in that: Includes the following steps: 1) Preparation of chitosan solution: Chitosan is dissolved in acetic acid solution to obtain chitosan solution; 2) Preparation of the oil phase: An emulsifier is added to liquid paraffin to obtain the oil phase; 3) Mix the chitosan solution from step 1) with the oil phase from step 2), and first shear and stir the mixture in a high-speed homogenizer to obtain a pre-emulsion; 4) Pass the pre-emulsion obtained in step 3) into an ultrasonic microreactor for emulsification to obtain an emulsion; 5) A crosslinking agent is introduced into the emulsion obtained in step 4), and a suspension is obtained after stirring; 6) The suspension obtained in step 5) is washed with petroleum ether and ethanol in sequence and then dried with hot air to obtain hollow chitosan microspheres.

2. The continuous flow preparation method of chitosan hollow microspheres according to claim 1, characterized in that: The concentration of the chitosan solution mentioned in step 1) is 0.5 wt% to 2.5 wt%. The concentration of the acetic acid solution mentioned in step 1) is 1 wt% to 3 wt%.

3. The continuous flow preparation method of chitosan hollow microspheres according to claim 1, characterized in that: The emulsifier mentioned in step 2) is at least one of the following: nonionic emulsifier, ionic surfactant, natural emulsifier, and polymer emulsifier; The mass fraction of the emulsifier mentioned in step 2) is 5% to 15%.

4. The continuous flow preparation method of chitosan hollow microspheres according to claim 1, characterized in that: The volume ratio of the chitosan solution to the oil phase in step 3) is 1:3 to 1:

8.

5. The continuous flow preparation method of chitosan hollow microspheres according to claim 1, characterized in that: The crosslinking agent mentioned in step 5) is at least one of aldehydes, carboxyl groups, sodium tripolyphosphate, and citric acid; The mass fraction of the crosslinking agent mentioned in step 5) is 50% to 300%.

6. The continuous flow preparation method of chitosan hollow microspheres according to any one of claims 1-5, characterized in that: The concentration of the chitosan solution mentioned in step 1) is 2 wt%; The concentration of the acetic acid solution mentioned in step 1) is 2 wt%; The emulsifier mentioned in step 2) is Tween 80; The mass fraction of the emulsifier mentioned in step 2) is 10%; The volume ratio of the chitosan solution to the oil phase in step 3) is 1:3; The crosslinking agent mentioned in step 5) is glutaraldehyde; The mass fraction of the crosslinking agent mentioned in step 5) is 150%.

7. The continuous flow preparation method of chitosan hollow microspheres according to any one of claims 1-5, characterized in that: The parameters of the high-speed homogenizer mentioned in step 3) are 3500±500 rpm; The mixing time described in step 3) is 3 ± 1 min; The stirring time described in step 5) is 6 ± 1 h.

8. The continuous flow preparation method of chitosan hollow microspheres according to any one of claims 1-5, characterized in that: The ultrasonic microreactor described in step 4) is set with a flow rate of 6±1 mL / min and a power of 120±20 W. The emulsification time described in step 4) is 90 ± 5 s.

9. Chitosan hollow microspheres characterized in that: It is obtained by the preparation method described in any one of claims 1-8.

10. Use of the chitosan hollow microspheres as described in claim 9 for the preparation of a drug carrier / drug delivery system.

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