Chitosan / pullulan microfiber carrier and preparation method thereof, sustained-release drug and preparation method thereof, and pharmaceutical composition

Abstract

The present invention discloses a chitosan / pululan microfiber carrier and a preparation method thereof, wherein the fiber carrier comprises a core layer and a shell layer formed outside the core layer, wherein the core layer is a blend of chitosan and pullulan, and the shell layer is formed by cross-linking at least chitosan and sodium tripolyphosphate on the surface of the core layer. The present invention provides a sustained-release drug and a composition thereof having good loading performance and sustained-release performance, and has simple, efficient and controllable processing performance and good application efficiency.

Description

Technical Field

[0001] The present invention relates to a sustained-release drug carrier technology, in particular to a chitosan / pullulan microfiber carrier and a preparation method thereof, a sustained-release drug and a preparation method thereof, and a drug composition. Background Art

[0002] The drug sustained-release system is a new drug delivery system proposed by Smith Kline in 1952. It combines different types of drugs with polymer carriers by physical adsorption or chemical adsorption, and then releases the drugs through dissolution, diffusion and erosion. By designing the polymer carrier, the drug is slowly released in the human body for a long time to maximize the efficacy of the drug, thereby effectively treating the disease. However, the traditional drug delivery method will cause a large fluctuation in drug concentration. The drug concentration will be very high at the beginning, and it may even exceed the upper limit that the human body can accept, causing side effects to the human body. After a large amount of drug is released, the subsequent release rate will gradually decrease, so that the drug content in the body will be lower than the effective dose, causing the drug to lose its therapeutic effect. Therefore, the traditional drug delivery method cannot achieve the purpose of sustained drug release. Although the method of administering drugs in small amounts and multiple times can control the drug concentration in the patient's body to a certain extent, the operation is too cumbersome. In contrast, after the introduction of the drug sustained-release system, the drug can be released from the carrier at a constant rate within a certain period of time, so that the drug concentration in the human body fluids is maintained within the effective range with small fluctuations, thereby preventing large differences in drug concentration, ensuring that the patient's disease is treated, and effectively weakening the toxic and side effects of the drug; and the drug sustained-release system can design different carriers according to the characteristics of the drug, so as to achieve effective loading of the drug dose, reduce the harm of the drug to the human body, reduce the number of medications, and thus alleviate the pain caused to the patient by continuous medication; it can also achieve slow and precise release of the drug according to the conditions under which the drug takes effect, so as to achieve the purpose of drug treatment, prolong the duration of drug treatment, and ensure the stability of drug treatment, thereby reducing the consumption of manpower, material resources and financial resources.

[0003] Acetaminophen (AAP) is a common anti-inflammatory drug that can be used to treat colds, fever, joint pain, neuralgia, migraine and other mild and moderate pains. However, excessive use can cause serious liver damage and is easily overused in daily life. Therefore, how to improve the duration of its effective concentration is the main research direction at present.

[0004] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention and should not be regarded as an acknowledgment or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art. Summary of the invention

[0005] The object of the present invention is to provide a chitosan / pullulan microfiber carrier and a preparation method thereof, a sustained-release drug and a preparation method thereof, and a pharmaceutical composition, which have good long-term effectiveness and molding processing performance, and are useful for maintaining the blood peak value of acetaminophen (AAP) sustained-release drugs within a suitable range in a long-term manner.

[0006] To achieve the above objectives, an embodiment of the present invention provides a chitosan / pullulan microfiber carrier, comprising a core layer and a shell layer formed on the outside of the core layer, wherein the core layer is a blend of chitosan and pullulan, and the shell layer is formed by cross-linking at least chitosan and sodium tripolyphosphate (TPP) on the surface of the core layer.

[0007] In one or more embodiments of the present invention, the mass ratio of chitosan (CS) to pullulan (Pul) in the blend of the core layer is (1-3): 1. The best mechanical properties of the core layer appear when CS / Pul is 2:1.

[0008] In one or more embodiments of the present invention, the mass ratio of chitosan to TPP is (3-9): (75-125).

[0009] In one or more embodiments of the present invention, the diameter of the microfibers is 29 μm to 40 μm.

[0010] In one or more embodiments of the present invention, the preparation method of the chitosan / pululan microfiber carrier comprises the following steps: preparing a core layer spinning solution and a shell layer spinning solution, wherein the core layer spinning solution is a mixed solution of chitosan and pullulan, and the shell layer spinning solution is a sodium tripolyphosphate solution; microfluidic spinning is performed using a coaxial syringe, wherein the coaxial syringe has an inner flow channel and an outer flow channel formed on the outer side of the inner flow channel; during microfluidic spinning, the core layer spinning solution is transported to the inner flow channel, and the shell layer spinning solution is transported to the outer flow channel.

[0011] In one or more embodiments of the present invention, the mixed solution of chitosan and pullulan is obtained by mixing at least 2-3wt.% chitosan solution and 3-15wt.% pullulan solution. Preferably, the mixed solution of chitosan and pullulan is obtained by mixing at least 2-3wt.% chitosan acetic acid solution and 3-15wt.% pullulan aqueous solution.

[0012] In one or more embodiments of the present invention, the mixed solution of chitosan and pullulan is obtained by mixing a chitosan solution and a pullulan solution at a mass ratio of at least (1-4):1.

[0013] In one or more embodiments of the present invention, the concentration of the sodium tripolyphosphate solution is 2-10 wt.%.

[0014] In one or more embodiments of the present invention, during microfluidic spinning, the flow rate ratio of the core layer spinning solution to the shell layer spinning solution is (8-10):(25-30).

[0015] In one or more embodiments of the present invention, when the CS / Pul mass ratio is 1:1 and the TPP concentration is 2 wt %, the chitosan / pululan microfiber carrier has the best swelling performance, and the swelling rate reaches 227%.

[0016] In one or more embodiments of the present invention, the sustained-release drug comprises the chitosan / pululan microfiber carrier as described above and a drug component formed on the carrier, wherein the drug component is selected from acetaminophen, ibuprofen, tea polyphenols, diclofenac, doxorubicin, berberine sulfate, and tetracycline. Preferably, the drug component is loaded on the core layer.

[0017] In one or more embodiments of the present invention, the content of the drug component in the sustained-release drug is 4-10 wt %.

[0018] In one or more embodiments of the present invention, the method for preparing a sustained-release drug comprises the following steps: preparing a core layer spinning solution and a shell layer spinning solution, wherein the core layer spinning solution is a mixed solution of chitosan, pullulan and drug components, and the shell layer spinning solution is a sodium tripolyphosphate solution; microfluidic spinning is performed using a coaxial syringe, wherein the coaxial syringe has an inner flow channel and an outer flow channel formed outside the inner flow channel; during microfluidic spinning, the core layer spinning solution is transported to the inner flow channel, and the shell layer spinning solution is transported to the outer flow channel.

[0019] In one or more embodiments of the present invention, the pharmaceutical composition includes the above-mentioned sustained-release drug. In this case, in addition to an appropriate amount of the above-mentioned sustained-release drug, the pharmaceutical composition may also selectively add tablet excipients such as dextrin and liquid excipients such as saline depending on the dosage form.

[0020] Compared with the prior art, the chitosan / pullulan microfiber carrier and its preparation method, the sustained-release drug and its preparation method, and the pharmaceutical composition according to the embodiments of the present invention have good carrier formability, good production and processability, strong drug loading capacity, and good long-acting sustained-release performance. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 is a schematic diagram of the preparation process of a chitosan / pullulan microfiber carrier according to one embodiment of the present invention;

[0022] Figure 2 are SEM images of chitosan / pululan microfiber carriers with different CS / Pul mass ratios (TPP concentration is 2 wt %) according to one embodiment of the present invention: (a) 1:1; (b) 2:1; (c) 3:1;

[0023] Figure 3 are microscopic images of chitosan / pululan microfiber carriers with different CS / Pul mass ratios (TPP concentration is 2 wt %) according to one embodiment of the present invention: (a) 1:1; (b) 2:1; (c) 3:1;

[0024] Figure 4 are SEM images of chitosan / pululan microfiber carriers with different TPP concentrations (CS / Pul mass ratio is 1:1) according to one embodiment of the present invention: (a) 2 wt% (b) 6 wt% (c) 10 wt%;

[0025] Figure 5 are microscopic images of chitosan / pululan microfiber carriers with different TPP concentrations (CS / Pul mass ratio is 1:1) according to one embodiment of the present invention: (a) 2 wt% (b) 6 wt% (c) 10 wt%;

[0026] Figure 6 The infrared spectra of CS, Pul and CP composite fibers according to one embodiment of the present invention are as follows: (a) CS; (b) Pul; (c) chitosan / pullulan microfiber carrier;

[0027] Figure 7 is an XRD pattern of CS and Pul according to one embodiment of the present invention;

[0028] Figure 8 1 is an XRD diagram of chitosan / pululan microfiber carriers with different spinning solution components according to one embodiment of the present invention: (ac) when CS / Pul is 1:1, the TPP concentrations are 2wt%, 6wt%, and 10wt% respectively; (df) when CS / Pul is 2:1, the TPP concentrations are 2wt%, 6wt%, and 10wt% respectively; (gi) when CS / Pul is 3:1, the TPP concentrations are 2wt%, 6wt%, and 10wt% respectively;

[0029] Fig. 9 1 is a mechanical analysis diagram of a chitosan / pululan microfiber carrier according to an embodiment of the present invention: (a) breaking strength; (b) breaking elongation;

[0030] Fig.10 : are the swelling curves of chitosan / pululan microfiber carriers with different TPP concentrations within 4 hours according to one embodiment of the present invention: (a) 2 wt%; (b) 6 wt%; (c) 10 wt%;

[0031] Fig.11 1 is the swelling curve of chitosan / pululan microfiber carriers with different CS / Pul mass ratios within 4 hours according to one embodiment of the present invention: (a) 1:1; (b) 2:1; (c) 3:1;

[0032] Fig.12 is the standard curve of acetaminophen in phosphate buffer solution (pH = 7.4);

[0033] Fig.13 are SEM images of CPA (4 wt % AAP) composite fibers with different TPP concentrations according to one embodiment of the present invention: (a) 2 wt %, (b) 6 wt %, (c) 10 wt %;

[0034] Fig.14 are microscope images of CPA (4 wt % AAP) composite fibers with different TPP concentrations according to one embodiment of the present invention: (a) 2 wt %, (b) 6 wt %, (c) 10 wt %;

[0035] Fig.15 are SEM images of CPA (2 wt % TPP) composite fibers with different AAP contents according to one embodiment of the present invention: (a) 4 wt %, (b) 7 wt %, (c) 10 wt %;

[0036] Fig.16 are microscope images of CPA (2 wt % TPP) composite fibers with different AAP contents according to one embodiment of the present invention: (a) 4 wt %, (b) 7 wt %, (c) 10 wt %;

[0037] Fig.17 is an infrared spectra of CPA composite fibers according to an embodiment of the present invention: (a) CS, (b) Pul, (c) AAP, (d) CPA composite fibers;

[0038] Fig.18 1 is an XRD diagram of AAP, CP composite fiber, and CPA composite fiber according to one embodiment of the present invention: (a) AAP, (b) CP composite fiber, (c) CPA composite fiber;

[0039] Fig.19 The thermogravimetric analysis (TGA) and microentropy thermogravimetric analysis (DTG) of CS, Pul, CPA composite fibers according to one embodiment of the present invention: (a) thermogravimetric analysis graph (TGA); (b) microentropy thermogravimetric analysis graph (DTG);

[0040] Fig. 20 : are in vitro drug release curves of CPA composite fibers with different AAP contents according to one embodiment of the present invention: (a) 4 wt%, (b) 7 wt%, (c) 10 wt%;

[0041] Fig.211 and 2 are in vitro drug release curves of CPA composite fibers prepared with different TPP concentrations according to one embodiment of the present invention: (a) 2 wt%, (b) 6 wt%, and (c) 10 wt%. DETAILED DESCRIPTION

[0042] The specific implementation modes of the present invention are described in detail below in conjunction with the accompanying drawings, but it should be understood that the protection scope of the present invention is not limited by the specific implementation modes.

[0043] Unless explicitly stated otherwise, throughout the specification and claims, the term “comprise” or variations such as “include” or “comprising”, etc., will be understood to include the stated elements or components but not to exclude other elements or components.

[0044] The preparation of the chitosan / pululan microfiber carrier of the present invention mainly includes: Figure 1 As shown: First, weigh a certain mass of chitosan (CS) powder and dissolve it in 2wt% acetic acid solution, stir it with a magnetic stirrer until it is a clear solution, and then stand and degas to obtain a CS solution of appropriate concentration. Secondly, take a certain mass of pullulan (Pul) powder and dissolve it in deionized water, stir it until it is completely dissolved, stand and degas to obtain a Pul solution of appropriate concentration. Then, mix the CS solution and the Pul solution in a certain proportion, stir it at room temperature until the solution is transparent and bubble-free, and use it as the core spinning solution. Finally, weigh a certain mass of sodium tripolyphosphate (TPP) powder and dissolve it in deionized water to obtain a TPP solution of a certain concentration. At room temperature and pressure, use a 10mL syringe to inhale a certain amount of core spinning solution, and then use a 20mL syringe to inhale a certain amount of shell spinning solution TPP solution, install the two syringes on the syringe pump, and connect the syringe, coaxial needle and receiving device through a silicone hose. The flow rates of the spinning liquid and curing liquid are adjusted through the control panel, and the rotation speed of the drum receiver is set so that a single fiber can be wound around the drum under the action of the drawing force. Then the number of cycle times and the translation rate are set so that the fibers are wound on the drum in an orderly manner to obtain a neatly arranged CP composite fiber membrane.

[0045] Example 1

[0046] The chitosan / pululan microfiber carrier of this embodiment is prepared as follows: 3wt% CS acetic acid solution and 15wt% Pul deionized water solution are blended in a mass ratio of 1:1 to obtain a core layer spinning solution, and 2wt% TPP deionized water solution is used as a shell layer spinning solution. The microfluidic spinning machine parameters are set as follows: the rotation rate of the drum receiving device is 25r / min, the translation speed is 1mm / min, the core layer spinning solution flow rate is 8mL / h, and the shell layer spinning solution flow rate is 25mL / h. CP fibers are prepared, the fibers are well formed, and a uniformly arranged fiber membrane can be formed.

[0047] Example 2

[0048] The chitosan / pululan microfiber carrier of this embodiment is prepared as follows: 3wt% CS acetic acid solution and 15wt% Pul deionized water solution are blended in a mass ratio of 2:1 to obtain a core layer spinning solution, and 2wt% TPP deionized water solution is used as a shell layer spinning solution. The microfluidic spinning machine parameters are set as follows: the rotation rate of the drum receiving device is 25r / min, the translation speed is 1mm / min, the core layer spinning solution flow rate is 8mL / h, and the shell layer spinning solution flow rate is 25mL / h. CP fibers are prepared, the fibers are well formed, and a uniformly arranged fiber membrane can be formed.

[0049] Example 3

[0050] The chitosan / pululan microfiber carrier of this embodiment is prepared as follows: 3wt% CS acetic acid solution and 15wt% Pul deionized water solution are blended in a mass ratio of 3:1 to obtain a core layer spinning solution, and 2wt% TPP deionized water solution is used as a shell layer spinning solution. The microfluidic spinning machine parameters are set as follows: the rotation rate of the drum receiving device is 25r / min, the translation speed is 1mm / min, the core layer spinning solution flow rate is 8mL / h, and the shell layer spinning solution flow rate is 25mL / h. CP fibers are prepared, the fibers are well formed, and a uniformly arranged fiber membrane can be formed.

[0051] Example 4

[0052] The chitosan / pululan microfiber carrier of this embodiment is prepared as follows: 2wt% CS acetic acid solution and 3wt% Pul deionized water solution are blended in a mass ratio of 1:1 to obtain a core layer spinning solution, and 10wt% TPP deionized water solution is used as a shell layer spinning solution. The microfluidic spinning machine parameters are set as follows: the rotation rate of the drum receiving device is 25r / min, the translation speed is 1mm / min, the core layer spinning solution flow rate is 10mL / h, and the shell layer spinning solution flow rate is 30mL / h. CP fibers are prepared, the fibers are well formed, and a uniformly arranged fiber membrane can be formed.

[0053] Example 5

[0054] The chitosan / pululan microfiber carrier of this embodiment is prepared as follows: 2wt% CS acetic acid solution and 10wt% Pul deionized water solution are blended in a mass ratio of 1:1 to obtain a core layer spinning solution, and 10wt% TPP deionized water solution is used as a shell layer spinning solution. The microfluidic spinning machine parameters are set as follows: the rotation rate of the drum receiving device is 25r / min, the translation speed is 1mm / min, the core layer spinning solution flow rate is 10mL / h, and the shell layer spinning solution flow rate is 30mL / h. CP fibers are prepared, the fibers are well formed, and a uniformly arranged fiber membrane can be formed.

[0055] Example 6

[0056] The chitosan / pululan microfiber carrier of this embodiment is prepared as follows: 2.5wt% CS acetic acid solution and 8wt% Pul deionized water solution are blended in a mass ratio of 1:1 to obtain a core layer spinning solution, and 10wt% TPP deionized water solution is used as a shell layer spinning solution. The microfluidic spinning machine parameters are set as follows: the rotation rate of the drum receiving device is 25r / min, the translation speed is 1mm / min, the core layer spinning solution flow rate is 10mL / h, and the shell layer spinning solution flow rate is 30mL / h. CP fibers are prepared, the fibers are well formed, and a uniformly arranged fiber membrane can be formed.

[0057] Example 7

[0058] The chitosan / pululan microfiber carrier of this embodiment is prepared as follows: 2.5wt% CS acetic acid solution and 12wt% Pul deionized water solution are blended in a mass ratio of 1.5:1 to obtain a core layer spinning solution, 4wt% TPP deionized water solution is used as a shell layer spinning solution, and the microfluidic spinning machine parameters are set as follows: the rotation rate of the drum receiving device is 40r / min, the translation speed is 4mm / min, the core layer spinning solution flow rate is 9mL / h, and the shell layer spinning solution flow rate is 26mL / h. CP fibers are prepared, the fibers are well formed, and a uniformly arranged fiber membrane can be formed.

[0059] Example 8

[0060] The chitosan / pululan microfiber carrier of this embodiment is prepared as follows: 2.2wt% CS acetic acid solution and 8wt% Pul deionized water solution are blended in a mass ratio of 2.5:1 to obtain a core layer spinning solution, and 8wt% TPP deionized water solution is used as a shell layer spinning solution. The microfluidic spinning machine parameters are set as follows: the rotation rate of the drum receiving device is 30r / min, the translation speed is 3mm / min, the core layer spinning solution flow rate is 8.5mL / h, and the shell layer spinning solution flow rate is 28mL / h. CP fibers are prepared, the fibers are well formed, and a uniformly arranged fiber membrane can be formed.

[0061] Example 9

[0062] The chitosan / pululan microfiber carrier of this embodiment is prepared as follows: 2.7wt% CS acetic acid solution and 6wt% Pul deionized water solution are blended in a mass ratio of 3:1 to obtain a core layer spinning solution, 7.5wt% TPP deionized water solution is used as the shell layer spinning solution, and the microfluidic spinning machine parameters are set as follows: the rotation rate of the drum receiving device is 45r / min, the translation speed is 2mm / min, the core layer spinning solution flow rate is 9.5mL / h, and the shell layer spinning solution flow rate is 29mL / h. CP fibers are prepared, the fibers are well formed, and a uniformly arranged fiber membrane can be formed.

[0063] The only difference between Examples 11-19 and Examples 1-9 is that the core spinning solution is also added with 4wt% of the drug component (ibuprofen can be selected), 4wt% of the drug component (ibuprofen can be selected), 4wt% of the drug component (ibuprofen can be selected), 40wt% of the drug component (tea polyphenols can be selected), 40wt% of the drug component (tea polyphenols can be selected), 40wt% of the drug component (tea polyphenols can be selected), 5wt% of the drug component (adriamycin can be selected), 3wt% of the drug component (diclofenac can be selected), and 8wt% of the drug component (tetracycline can be selected). Including but not limited to the above-mentioned embodiments of SPA, the drug component can be selected from AAP, ibuprofen, tea polyphenols, diclofenac, adriamycin, berberine sulfate, tetracycline, etc., and their combination forms are not exemplified one by one here.

[0064] The performance of some samples of the embodiments of the present invention are tested and compared below, and the specific scheme is selected from different situations included in the following combination: The preparation of the chitosan / pululan microfiber carrier of this embodiment is as follows: a 3wt% CS acetic acid solution and a 15wt% Pul deionized water solution are blended in a mass ratio of 1:1, 2:1 or 3:1 to obtain a core spinning solution, and a deionized water solution of TPP with a concentration of 2wt%, 6wt% or 10wt% is selected as the shell spinning solution. The parameters of the microfluidic spinning machine are set as follows: the rotation rate of the drum receiving device is 25r / min, the translation speed is 1mm / min, the core layer spinning solution flow rate is 8mL / h, and the shell layer spinning solution flow rate is 25mL / h. CP fibers are prepared, the fibers are well formed, and a uniformly arranged fiber membrane can be formed.

[0065] Effect of Spinning Solution Components on Fiber Forming

[0066] In the microfluidic spinning process, the spinning solution is not only driven by the microfluidic pump, but its own fluid mechanics properties are also crucial, mainly because the spinning channel will be reduced to the micron level during the microfluidic spinning process, and its fluid mechanics properties cannot be ignored in the microscopic environment. Therefore, the concentration and composition of the spinning solution have a great influence on the fiber forming. At the same time, the crosslinking agent concentration is also very important for the fiber forming by using the principle of ion crosslinking to solidify the fiber.

[0067] Since the CS solution itself has a certain viscosity, and its fluidity decreases with the increase of solution concentration, the chitosan trial spinning concentrations of 2wt% and 3wt% with relatively good fluidity are selected. Since pullulan is easily soluble in water and has good fluidity, considering the influence of the main components of the fiber on the fiber forming, four different concentrations of Pul solutions of 3wt%, 10wt%, 12wt%, and 15wt% are prepared. CS solution and Pul solution are blended in a mass ratio of 1:1, 2:1, 3:1, and 4:1 to obtain a spinning solution as the core spinning solution for coaxial spinning. At the same time, 2wt% and 10wt% TPP solutions are selected as shell spinning solutions for spinning. The design is taken as an example for comparison with the scheme shown in Table 1:

[0068] Table 1 Experimental scheme and spinning results of microfluidic spinning solution components

[0069]

[0070]

[0071] Through comparison, it was found that when 3wt% CS solution and 15wt% Pul solution were blended as spinning solution in a mass ratio of 1:1, 2:1, 3:1, and 4:1, they could be spun with 10wt% TPP solution, and the fiber would basically not break. However, after reducing the concentration of TPP solution (2wt% TPP solution), when 3wt% CS solution and 15wt% Pul solution were blended as spinning solution in a mass ratio of 4:1, the fiber formation was poor. Therefore, the CS / Pul mass ratio was selected as 1:1, 2:1, and 3:1, and the TPP concentration was 2wt%, 6wt%, and 10wt% for subsequent comparison verification.

[0072] Effect of spinning process parameters on fiber forming

[0073] The fiber receiving device of microfluid spinning mainly relies on drum receiving and stepping translation. Using a coaxial needle, the outer phase solution covers the inner solution at the needle tip, and the ion cross-linking reaction quickly forms the fiber. Then, the drafting force is provided by the rotating motor to stretch the fiber from the needle tip and wind it on the drum. The stepping motor continuously moves horizontally to form a fiber membrane with uniform vertical arrangement. The rotation rate of the rotating motor will affect the fiber forming. When the rotation speed is too fast, the drafting force provided is large, and the fiber is easily broken, resulting in many broken ends and discontinuity. When the rotation speed is low, the drafting force is small, and the fiber will not be wound in time and beading will occur, resulting in poor forming. The stepping motor cooperates with the rotating motor to continuously translate, which is conducive to the formation of uniformly arranged fiber membranes. However, the stepping will generate a force perpendicular to the drafting force on the fiber. When this force is too large, it will also cause the fiber to break easily. The flow rate of the spinning solution is set by a microfluidic pump. If the flow rate is too slow, droplet-like solids will form at the needle tip due to rapid cross-linking to block the needle. The flow rate of the solidified liquid is slow, and the fiber is difficult to cross-link and form. Therefore, it is necessary to find a suitable process parameter to obtain well-formed and evenly arranged fibers. After comprehensive evaluation, the comparison is made with the example shown in Table 2.

[0074] Table 2 Control scheme and spinning results of microfluidic spinning process

[0075]

[0076]

[0077] By comparison, it is found that when the rotation rate of the drum receiving device is 25r / min, the translation speed is 1mm / min, the core solution flow rate is 8mL / h, and the shell solution flow rate is 25mL / h, the fiber is well formed and a uniformly arranged fiber membrane can be formed. After comparison, it is found that the above parameters can be used for blending at a mass ratio of 1:1, 2:1, and 3:1 to obtain spinning solution and 2wt%, 6wt%, and 10wt% shell spinning solution.

[0078] Effect of Spinning Solution Components on Fiber Morphology

[0079] By comparing the spinning solution components, it was determined that 3wt% CS solution and 15wt% Pul solution were mixed in a mass ratio of 1:1, 2:1, and 3:1 as the core layer spinning solution, and the TPP concentration of the shell layer spinning solution was set to 2wt%, 6wt% and 10wt%. CP composite fibers were prepared under the same microfluidic spinning parameters (rotation rate of the drum receiving device was 25r / min, translation speed was 1mm / min, core layer spinning solution flow rate was 8mL / h, and shell solution flow rate was 25mL / h) to explore the influence of spinning solution components on fiber morphology.

[0080] (1) Effect of CS / Pul mass ratio on fiber morphology

[0081] Figure 2 The following are the surface morphology photos of CP fibers prepared with different CS / Pul mass ratios. It can be seen from the figure that the prepared CP fibers are well formed, and as the chitosan content in the spinning solution increases, the fiber surface gradually becomes smooth. When the chitosan content is low, there are longitudinal stripes on the fiber surface. This is mainly because when the chitosan content is low, the chitosan and sodium tripolyphosphate are not cross-linked tightly enough, the internal void volume increases, and it shrinks during the drying process to form grooves.

[0082] Figure 3 The optical microscope images of CP fibers with CS / Pul mass ratios of 1:1, 2:1, and 3:1. The diameters of CP fibers with CS / Pul mass ratios of 1:1, 2:1, and 3:1 were 34.4±5.17μm, 34.92±4.45μm, and 36.15±6.17μm, respectively. The diameter of CP fibers changed slightly with the change of CS / Pul ratio, but the overall diameter change was within the error range, indicating that the change of CS / Pul ratio had little effect on the fiber diameter.

[0083] (2) Effect of TPP concentration on fiber morphology

[0084] Figure 4 and Figure 5 SEM images and optical microscope photos of CP fibers with a CS / Pul mass ratio of 1:1 and TPP concentrations of 2wt%, 6wt%, and 10wt%, respectively. Figure 4 It can be seen that CP fibers with different cross-linking agent concentrations are well formed, and with the increase of TPP concentration, the number of fine grooves on the fiber surface increases. This may be because when the chitosan content is relatively low, the increase in TPP concentration intensifies the cross-linking reaction, and there are no large gaps inside the fiber, resulting in the formation of more fine grooves during the drying process.

[0085] Figure 5 The diameters of CP fibers with TPP concentrations of 2wt%, 6wt%, and 10wt% were 32.44±3.59μm, 34.4±5.17μm, and 35.68±3.12μm, respectively. The diameter of CP fibers increased slightly with the increase of TPP concentration. This may be because the increase of TPP concentration caused a more complete reaction between chitosan and TPP, which changed the internal structure of the fiber and strengthened the interaction with water molecules. It was difficult for water molecules to evaporate completely, which made the fiber diameter thicker.

[0086] Infrared Spectrum Analysis of CP Composite Fiber

[0087] In order to further determine the molecular structure inside the fiber, the CP fiber was characterized by Fourier infrared spectroscopy. The spinning solution composition of the CP composite fiber selected here is: CS / Pul mass ratio 1:1, TPP concentration 2wt%.

[0088] like Figure 6 Shown are the infrared spectra of CS powder, Pul powder, and CP composite fiber, respectively. Curve a in the figure is the infrared spectrum of CS. The broad peak at 3319cm-1 corresponds to the stretching vibration of chitosan OH and NH, the peak at 1650cm-1 corresponds to the stretching vibration of chitosan C=O, and the peak at 1072cm-1 corresponds to the stretching vibration of CO. Curve b in the figure is the infrared spectrum of pullulan. The sharp peak at 3626cm-1 corresponds to the stretching vibration of OH, the broad peak at 3290cm-1 corresponds to the stretching vibration of OH, the peak at 1650cm-1 corresponds to the -OCO- group, the vibration peak at 1208cm-1 is CH, the peak at 1072cm-1 is the stretching vibration of CH, and the absorption peaks at 959cm-1, 872cm-1, and 703cm-1 are α-(1,6) glycosidic bond, α-pyranose ring, and α-(1,4) glycosidic bond, respectively. Figure 5 As shown in the middle curve c, in the infrared spectrum of CP composite microfibers, the absorption peaks of 1123cm-1 and 872cm-1 are significantly enhanced, mainly because chitosan and TPP are successfully cross-linked, and -P=O and -POC are introduced. Finally, the infrared spectrum test shows that chitosan and TPP are successfully cross-linked, and only physically blended with pullulan.

[0089] X-ray diffraction analysis of CP composite fibers

[0090] X-ray diffraction analysis is mainly used to determine the internal structure of the material. The width and height of the peaks in the spectrum are used to determine the size of the grains inside the material, and to make certain judgments on the solution permeability of the material. Because the drug release carrier should have a certain solution permeability, X-ray diffraction is used to characterize the prepared CP composite fiber.

[0091] Figure 7 The XRD curves of pullulan and chitosan are shown in Figure 1. As can be seen from the figure, pullulan powder has a broad peak at 2θ of 18°, which indicates that pullulan has a typical amorphous structure and is an amorphous powder with disordered internal molecular arrangement. Chitosan powder has a diffraction peak at 2θ of 20°, which is a characteristic peak of chitosan.

[0092] Figure 8Figure 2 is the XRD diagram of CP composite fiber under different spinning solution components. From Figure ac, it can be found that at 2wt% TPP concentration, when the mass ratio of CS solution to Pul solution is 1:1, the composite fiber has only one broad peak, and the peak value is slightly lower than that of chitosan and pullulan, indicating that there is interaction between chitosan and pullulan polysaccharide. Figure 8 It can be seen from df that when the TPP concentration increases, the number of peaks increases, and the peak intensity also increases to a certain extent, indicating that the number of larger crystals inside the composite fiber increases, which may be related to the degree of cross-linking between chitosan and sodium tripolyphosphate. Figure 8 As can be seen in a, d, and g, the relative content of chitosan increases, and the degree of reaction between chitosan and the cross-linking agent is different, forming peaks of different intensities, indicating that there are cross-linked chitosans with different crystalline structures inside the fiber.

[0093] Analysis of mechanical properties of CP composite fibers

[0094] Fig. 9 The bar graph of the breaking strength and elongation at break of CP composite fibers. It can be clearly seen from the bar graph that with the increase of TPP concentration, the breaking strength of CP composite fibers gradually increases while the breaking elongation gradually decreases. This may be because the TPP concentration increases, the degree of cross-linking reaction increases during the fiber curing process, the internal crystal structure of the fiber changes, and the breaking strength increases. With the increase of the relative content of chitosan, when the cross-linking agent concentration is 2wt%, the breaking strength is not much different. When the cross-linking agent concentration is 6wt% and 10wt%, the breaking strength first increases and then decreases. With the increase of chitosan content, the elongation at break first increases and then decreases. This may be related to the number of amino groups in the fiber. The increase of chitosan content and the increase of amino groups strengthen the hydrogen bonds between molecules and improve the mechanical properties. The best mechanical properties appear when CS / Pul is 2:1, indicating that at this ratio, the amino groups of chitosan and the carboxyl groups of pullulan can form favorable intermolecular hydrogen bonds. When the chitosan content is further increased, chitosan forms intramolecular hydrogen bonds instead of intermolecular hydrogen bonds, which reduces the mechanical properties.

[0095] Swelling properties of CP composite fiber membrane

[0096] The swelling performance examines the water absorption performance of the fiber membrane. If the fiber membrane has good water absorption performance, on the one hand, it can be used in wound dressings to absorb tissue fluid well, keep the wound clean, and reduce infection. On the other hand, it is based on the drug release system. Since one of the mechanisms of drug release is the swelling mechanism, the fiber membrane has good swelling performance, which is conducive to the release of drugs.

[0097] At room temperature, the swelling rate of the CP composite fiber membrane prepared at different TPP concentrations in deionized water changes with time. Fig.10 As shown in the figure, it can be seen that with the increase of time, the swelling of the CP fiber membrane first increases and then tends to stabilize. Almost all CP fiber membranes reach swelling equilibrium in two hours. The CP composite fiber membrane prepared with a TPP concentration of 2wt% and a CS / Pul mass ratio of 1:1 has the best swelling performance, with a swelling rate of 227%; while the CP composite fiber membrane prepared with a TPP concentration of 10wt% and a CS / Pul mass ratio of 3:1 has the lowest swelling rate, which is only 73%.

[0098] Fig.11 The following is a curve showing the change of swelling rate of CP composite fiber membranes with different CS / Pul mass ratios in deionized water over time at room temperature. It can be seen from the figure that when the CS / Pul mass ratio is the same, the TPP concentration has a greater effect on the swelling properties of the CP composite fiber membrane. It can be seen that as the cross-linking agent concentration and the CS / Pul mass ratio increase successively, the swelling rate of the CP fiber membrane decreases successively. This is mainly because as the chitosan content and the cross-linking agent concentration change, the content of the crystalline area inside the CP fiber changes, and it becomes increasingly difficult for water molecules to penetrate, causing the swelling rate to change.

[0099] Through the above examples, we can know that:

[0100] (1) 3 wt% CS solution and 15 wt% Pul solution were blended in a mass ratio of 1:1, 2:1 or 3:1 to obtain a core layer spinning solution, and 2 wt%, 6 wt% or 10 wt% TPP solution was used as a shell layer spinning solution. The parameters of the microfluidic spinning machine were set as follows: the rotation rate of the roller receiving device was 25 r / min, the translation speed was 1 mm / min, the core layer spinning solution flow rate was 8 mL / h, and the shell layer spinning solution flow rate was 25 mL / h. CP fibers were prepared, and the fibers were well formed and could form a uniformly arranged fiber membrane.

[0101] (2) Morphological structure observations show that the CS / Pul mass ratio has little effect on the fiber diameter. The diameters of CP fibers with CS / Pul mass ratios of 1:1, 2:1, and 3:1 are 34.4±5.17μm, 34.92±4.45μm, and 36.15±6.17μm, respectively. The diameters of CP fibers with TPP concentrations of 2wt%, 6wt%, and 10wt% are 32.44±3.59μm, 34.4±5.17μm, and 35.68±3.12μm, respectively. The fiber diameter increases slightly with the increase of TPP concentration. CP fibers spun under different CS / Pul mass ratios or different TPP concentrations are well formed and have no beaded structure.

[0102] (3) The Fourier transform infrared spectroscopy (FITR) of CP fibers showed that chitosan and TPP were successfully cross-linked, and only physically blended with pullulan. XRD results showed that there was interaction between chitosan and pullulan, and as the TPP concentration increased, the number of larger crystals inside the composite fibers increased, generating composite fibers with different crystalline structures.

[0103] (4) Mechanical properties results show that the breaking strength of CP fiber increases with the increase of TPP concentration, and the breaking elongation gradually decreases. With the increase of chitosan content, when the TPP concentration is 2wt%, the breaking strength is not much different. When the TPP concentration is 6wt% and 10wt%, the breaking strength increases first and then decreases, and the breaking elongation also shows a trend of increasing first and then decreasing with the increase of chitosan content.

[0104] (5) Swelling performance results show that the CP fiber membrane reaches swelling equilibrium in two hours. The swelling rate of the CP fiber membrane decreases with increasing TPP concentration or CS / Pul mass ratio. The CP fiber membrane with a CS / Pul mass ratio of 1:1 and a TPP concentration of 2wt% has the best swelling performance, with a swelling rate of 227%.

[0105] Further verification of drug loading performance:

[0106] The preparation of the sustained-release drug of the present invention, i.e., the drug-loaded chitosan / pullulan microfiber carrier, can be to take a certain mass of chitosan (CS) powder and add it to a 2wt% acetic acid solution, stir it with a magnetic stirrer until there are no particles, and place it until there are no bubbles, so as to obtain a CS solution of appropriate concentration. Secondly, take a certain mass of pullulan (Pul) powder and add it to deionized water, stir it until it is completely dissolved, stop stirring, place it until there are no bubbles, and then prepare a Pul solution of appropriate concentration. Finally, the CS solution and the Pul solution are mixed in a ratio of 1:1, stirred with a magnetic stirrer until the mixture is uniform, and then placed until there are no bubbles, and then weigh a certain weight of acetaminophen (AAP) and add it to the mixed solution, stir it in a 37°C water bath until there are no particles, and obtain a CS / Pul / AAP mixed solution as a core layer spinning solution, and control the amount of AAP added in the core layer spinning solution to account for 4wt%, 7wt%, and 10wt% of the total solute. Finally, a certain amount of sodium tripolyphosphate (TPP) solid powder is dissolved in deionized water to obtain a TPP solution of appropriate concentration as the shell spinning solution. At room temperature and pressure, a certain amount of core spinning solution is sucked in with a 10mL syringe, and a certain amount of shell spinning solution TPP solution is sucked in with a 20mL syringe. The two syringes are installed on the injection pump, and the syringes, coaxial needles and receiving devices are connected through silicone hoses. The flow rate of the spinning solution and the curing solution is adjusted through the control panel, and the speed of the drum receiver is set so that a single fiber can be wound around the drum under the action of the drawing force, and then the number of cycles and the translation rate are set so that the fibers are wound in an orderly manner on the drum to obtain a neatly arranged CPA composite fiber membrane.

[0107] Drug release performance of CPA composite fiber

[0108] (1) Calibration of acetaminophen (AAP) standard curve

[0109] An appropriate amount of acetaminophen was weighed and dissolved in a phosphate buffer solution (pH=7.4). The prepared acetaminophen solution was scanned using an ultraviolet spectrophotometer with a model number of UV-5800. The scanning wavelength range was 200-600 nm. It was found that the maximum absorption wavelength of acetaminophen in the phosphate buffer solution was 243 nm. Therefore, the absorbance of the acetaminophen solution was measured at 243 nm to draw a standard curve.

[0110] Weigh 5 mg of acetaminophen and dissolve it in 10 ml of phosphate buffer (pH=7.4), transfer it into a 50 ml volumetric flask to make up the volume, and obtain a stock solution. Then use a pipette to draw 0.1 ml, 0.2 ml, 1 ml, 2 ml, and 4 ml of the stock solution into a 10 ml volumetric flask to make up the volume, use a UV-5800 ultraviolet spectrophotometer to measure the standard solution of known concentration, obtain the absorbance of the drug at different concentrations, draw a standard curve of acetaminophen, and calculate the linear correlation coefficient.

[0111] Fig.12 The standard curve of acetaminophen in phosphate buffer solution (pH = 7.4) is obtained by linear fitting: y = 0.06875x + 0.03859 (R 2 =0.99799). Therefore, within the concentration range of 1 μg / mL-40 μg / mL, there is a good linear relationship between the concentration of AAP and its ultraviolet absorbance at 243 nm.

[0112] (2) Determination of AAP release from CPA composite fibers in vitro

[0113] A constant temperature oscillating water bath was used to simulate the temperature of human body fluids, different oscillation rates were used to simulate the fluctuation of human body fluids, and a phosphate buffer solution with pH = 7.4 was used to simulate human body fluids. The drug-loaded fibers were placed in this environment to simulate in vitro drug release. The specific operations are as follows:

[0114] Weigh 20 mg of CPA composite fiber, put it into a dialysis bag, and then put it into a centrifuge tube containing 30 mL of phosphate buffer. After sealing, put it into a constant temperature shaking water bath and shake it. The temperature was set to 37°C and the shaking rate was 30 r / min.

[0115] Then, 3 mL of drug release solution was taken at 10 min, 20 min, 30 min, 40 min, 50 min, 60 min, 70 min, 80 min, 90 min, 105 min, 120 min and 150 min, and its absorbance at 243 nm was measured. Then, 3 mL of blank phosphate buffer was added to the centrifuge tube, and the solution volume was kept constant. The in vitro drug release experiment of each composite fiber was repeated three times. Finally, the concentration of AAP was calculated according to the standard curve equation of AAP, and then the cumulative release percentage of AAP was calculated to draw the corresponding drug release curve.

[0116] Percentage of drug released

[0117] Q n is the percentage of drug release from the first to the nth sampling

[0118] A is the total amount of drug in the fiber

[0119] C n is the drug concentration in the release medium at the nth sampling

[0120] C i is the drug concentration in the release medium at the i-th sampling

[0121] Spinnable properties of drug-loaded CPA composite fibers

[0122] The microfluidic spinning conditions are: the rotation rate of the drum receiving device is 25r / min, the translation speed is 1mm / min, the core layer solution flow rate is 8mL / h, and the sheath layer solution flow rate is 25mL / h. CPA composite fibers were successfully prepared. At the same time, the addition of drugs has no effect on the molding of the fibers. At different cross-linking agent concentrations, the fibers can still be well formed. Therefore, the prepared CPA composite fibers were further characterized by SEM and optical microscopy to confirm the influence of TPP concentration and AAP content on fiber morphology.

[0123] (1) Effect of TPP concentration on the morphology of CPA composite fibers

[0124] Fig.13 The SEM images of CPA fibers with TPP concentrations of 2wt%, 6wt%, and 10wt% are shown in Figure 1. As can be seen from the figure, CPA fibers with different TPP concentrations are well formed, and with the increase of TPP concentration, the fiber surface gradually becomes smooth and round.

[0125] Fig.14 The optical microscope images of CPA fibers with AAP content of 4wt%, TPP concentration of 2wt%, 6wt%, and 10wt% respectively, the diameters of CPA fibers with TPP concentration of 2wt%, 6wt%, and 10wt% are 32.63±2.53μm, 31.39±3.08μm, and 37.8±5.39μm respectively. When the TPP concentration is 10wt%, the fiber diameter changes greatly and the fiber becomes thicker. This may be because when the cross-linking agent concentration is high, chitosan reacts more fully with TPP, the internal structure of the fiber changes, the interaction with water molecules is strengthened, and the water molecules are difficult to completely volatilize, making the fiber diameter thicker.

[0126] (2) Effect of AAP content on CPA fiber morphology

[0127] Fig.15The following are SEM images of CPA fibers with a TPP concentration of 2wt% and AAP contents of 4wt%, 7wt%, and 10wt%. As can be seen from the figure, CPA fibers with different AAP contents are well formed, with smooth surfaces and no obvious agglomeration or crystal precipitation, indicating that acetaminophen is well loaded into the fibers, and with the increase of AAP content, the fibers gradually become rounded and the surface grooves decrease.

[0128] Fig.16 The optical microscope images of CPA fibers with a TPP concentration of 2wt% and AAP contents of 4wt%, 7wt%, and 10wt% respectively. The diameters of CPA fibers with AAP contents of 4wt%, 7wt%, and 10wt% were 33.04±3.98μm, 32.7±4.11μm, and 32.63±2.53μm, respectively. The diameter of CPA fibers changed slightly with the change of crosslinker concentration, but the overall diameter change was within the error range, indicating that the change in the content of the model drug AAP had little effect on the fiber diameter.

[0129] Infrared Spectrum Analysis of CPA Composite Fiber

[0130] Fig.17 The infrared spectra of CS powder, Pul powder, AAP powder and CPA composite fiber are shown in Figure 1. As shown in curve a, the infrared spectrum of chitosan is at 3304cm -1 The broad peak at 1421 cm -1 The characteristic peak at 1021cm belongs to the bending vibration of CH2. -1 The peak at 3356 cm is the stretching vibration of CO. Curve b corresponds to the infrared spectrum of pullulan. -1 The broad peaks at 1549, 1199 cm-1 correspond to the stretching vibration of OH. -1 The vibration peak of CH is at 1070cm -1 The stretching vibration of CH is at 872 cm -1 The absorption peak at 3326 cm is that of the α-pyranose ring. Curve c is the infrared spectrum of acetaminophen. -1 、1650cm -1 、1560cm -1 The characteristic peak at 1432 cm corresponds to the stretching vibration of -OH, -C=O and C=C skeleton on the amide bond. -1 The characteristic peak at corresponds to the ring breathing vibration peak. Curve d is the infrared spectrum of CPA drug-loaded fiber. The characteristic absorption peaks of CS, Pul and AAP were found in the infrared spectrum of CPA drug-loaded fiber, and no new absorption peaks were found, indicating that AAP, CS and Pul are aggregated in the form of physical blending, which has no effect on the physical and chemical properties of the drug.

[0131] XRD analysis of CPA composite fibers

[0132] When studying the drug release kinetics of the prepared drug-loaded microfibers, the physical state of the drug in the polymer carrier is also an important parameter, which may vary from molecular dispersion (amorphous) to a clear crystalline structure. Therefore, XRD analysis was performed on the prepared drug-loaded microfibers to characterize the dispersion state of the drug in the microfibers.

[0133] Fig.18 The XRD curves of AAP, CP composite fibers and CPA composite fibers. Curve a in the figure is the XRD curve of acetaminophen, which has typical characteristic diffraction peaks at 12.11°, 13.76°, 15.57°, 16.62°, 18.2°, 20.39°, 23.47°, 24.39°, 26.39°, and 32.51°. The CP composite fiber has only one large broad peak, indicating that its interior is an amorphous structure. Compared with curve a, the spectrum of the CPA composite fiber is almost a straight line, with very small peaks at 14.07°, 18.21°, 22.21°, and 25.86°, indicating that AAP crystals are still present in the CPA composite fiber, but the strength is relatively reduced. Thermogravimetric (TG) analysis of CPA composite fibers

[0134] Thermogravimetric analysis technology is used to study the thermal stability and thermal degradation kinetics of polymer materials. The thermal stability of drug carriers prepared from different materials also varies.

[0135] from Fig.19 As can be seen in Figure a, CS shows two stages of weight loss, at 30-100°C and 200-350°C, respectively. The weight loss in the first stage is mainly due to the evaporation of water in the chitosan sample, and the second stage is mainly caused by the decomposition of CS itself, including the dehydration and degradation of the chitosan ring and the cleavage of some groups on the molecular chain. Fig.19 The weight loss of Pul in a is also divided into two stages, at 30-100°C and 250-350°C respectively. The first stage is the evaporation of the residual water in Pul, and the second stage is a process of rapid weight loss, which is caused by the degradation of the main chain of the pullulan polysaccharide molecule. Fig.19 The thermogravimetric analysis curve of CPA in a shows that CPA composite fiber also has two weight loss intervals. The first interval is 30-250℃, which is mainly due to the evaporation of residual water in the sample and the cleavage of amino groups on chitosan. The second interval is 250-350℃, which is mainly due to the degradation of chitosan main chain macromolecules and the degradation of pullulan main chain covalent bonds. Fig.19It can be seen from the DTG curve in Figure b that the thermal stability of CPA fiber is lower than that of CS and Pul. This is mainly because the chitosan molecular segments are rearranged during the cross-linking reaction, and its internal structure changes, resulting in a decrease in thermal stability.

[0136] Study on the in vitro release of drugs from CPA composite fiber membrane

[0137] Fig. 20 The in vitro drug release curve of CPA composite fibers with different AAP contents is shown in the figure. It can be seen that the cumulative drug release of CPA composite fibers prepared under the spinning component with a crosslinking agent TPP concentration of 10wt% and an AAP content of 10wt% within 150min is the highest at 59.16%. Fig. 20 In ac: It can be seen that with the increase of TPP concentration, the percentage of drug release of AAP from CPA fiber is gradually decreasing. This may be because when the relative content of chitosan in CPA composite fiber is the same, the TPP concentration increases, the degree of cross-linking increases, and the internal structure of the fiber is compact, which makes drug release more difficult and reduces the percentage of drug release. With the increase of AAP content in CPA fiber, the percentage of drug release is also gradually increasing.

[0138] Fig.21 In vitro drug release curves of CPA composite fibers prepared at different TPP concentrations. Fig.21 It can be seen that when TPP concentration is low, the drug release percentage when AAP content is 10wt% and 7wt% is significantly higher than 4wt%. This may be because the TPP concentration is low, the drug content is high, the cross-linking is not tight, water molecules are easy to penetrate, and the drug release is easy to release, making the drug release percentage relatively high. With the increase of cross-linking agent concentration, the drug release percentage is still high when the drug content is high. At the same time, it can be seen that the drug release process in the first 30 minutes is close to a straight line, and the subsequent release process is slower and slower, mainly because the early release is mainly a burst release on the fiber surface, and the later release is the diffusion release of the drug inside the fiber from the inside to the outside, and the release rate slows down.

[0139] Effect of drug release mechanism in CPA composite fiber membrane

[0140] The main factor affecting drug release is the structure of the carrier, so the drug release kinetic model was fitted for the CPA composite fibers prepared at different TPP concentrations. However, the drug sustained release process is complex, and one mechanism model is usually difficult to explain. This study selected the ideal zero-order release model, first-order release model, Weibull, Higuchi, Ritger-Peppas, and Hixson-Crowell models to fit the drug release mechanism of CPA fibers, and found that the drug release process of CPA fibers, the results are shown in Tables 3 to 5.

[0141] Table 3 Drug release kinetic model fitting of the drug release curve of CPA composite fibers with 2wt% TPP

[0142]

[0143] Table 4 Drug release kinetic model fitting of the drug release curve of 6wt% TPP CPA composite fiber

[0144]

[0145] Table 5 Drug release kinetic model fitting of the drug release curve of CPA composite fibers with 10wt% TPP

[0146]

[0147] Tables 3-5 are the drug release kinetic model fitting of the drug release curves of CPA composite fibers with TPP concentrations of 2wt%, 6wt%, and 10wt%. 2 To judge the degree of agreement, the drug release curves of CPA composite fibers with TPP concentrations of 2wt%, 6wt%, and 10wt% are more consistent with the drug release kinetic model, the Korsemeyer-Peppas model, and the Higuchi model. Further comparison found that the drug release curves of CPA composite fibers with TPP concentrations of 2wt%, 6wt%, and 10wt% are more consistent with the drug release kinetic model, the Korsemeyer-Peppas model, and the slopes of their fitting equations are 0.40595, 0.44931, and 0.45204, respectively. The slopes of the fitting equations with TPP concentrations of 2wt% and 6wt% are both less than 0.45, indicating that their drug release mechanism is closer to Fick's diffusion. The slope of the fitting equation with TPP of 10wt% is slightly greater than 0.45, indicating that the mechanism of drug release is non-Fick's diffusion. The drug release kinetic model of the drug release curve of CPA composite fiber with crosslinker concentration of 2wt%, 6wt%, and 10wt% is also consistent with the Higuchi model, indicating that part of the drug is released from the hydrophobic part of the fiber. In summary, there are two main ways for drug release from CPA composite fibers. The first is fiber skeleton swelling, the hydrophilic part of the fiber quickly dissolves, and the drug diffuses out through the Fick mechanism. The second is fiber skeleton degradation, the drug diffuses out from the hydrophobic part inside the fiber, and the drug release gradually slows down.

[0148] By characterizing the morphology and structure of CPA composite fibers, the release behavior and release mechanism of drugs in PBS buffer with a pH value of 7.4, the following conclusions were drawn:

[0149] (1) 3 wt% CS solution and 15 wt% Pul solution were mixed in a mass ratio of 1:1, and then 4 wt%, 7 wt%, and 10 wt% of the model drug AAP were added to the mixed solution to obtain the core layer spinning solution and 2 wt%, 6 wt%, and 10 wt% of TPP solution were used as the shell layer spinning solution. The rotation rate of the drum receiving device was set to 25 r / min, the translation speed was 1 mm / min, the core layer spinning solution flow rate was 8 mL / h, and the shell layer spinning solution flow rate was 25 mL / h. CPA composite fibers were successfully prepared, the fibers were well formed, and a uniformly arranged fiber membrane could be formed.

[0150] (2) Microscope observation showed that the change of the content of the model drug AAP had no significant effect on the fiber diameter. The diameters of the CPA composite fibers with AAP contents of 4wt%, 7wt%, and 10wt% were 33.04±3.98μm, 32.7±4.11μm, and 32.63±2.53μm, respectively. The diameters of the CPA composite fibers with TPP concentrations of 2wt%, 6wt%, and 10wt% were 32.63±2.53μm, 31.39±3.08μm, and 37.8±5.39μm, respectively. When the TPP concentration was 10wt%, the fiber diameter changed greatly and the fiber became thicker. The SEM images showed that the CPA composite fibers with different AAP contents were well formed, with no lumps or crystals attached to the fiber surface, indicating that AAP was well loaded into the fiber, and with the increase of AAP content, the fiber gradually became rounded and the surface grooves decreased.

[0151] (3) Through the analysis of the internal structure of CPA composite fibers, it was found that the model drug AAP was physically blended with CS and Pul, and some drugs existed in the fiber in a crystalline form. The thermal stability of CPA composite fibers was lower than that of CS and Pul, mainly because the chitosan molecular segments were rearranged during the cross-linking reaction, and its internal structure changed, resulting in reduced thermal stability.

[0152] (4) The drug release percentage of CPA composite fibers decreased with the increase of crosslinking agent concentration, and increased with the increase of model drug AAP content. The cumulative drug release rate of CPA composite fibers within 150 min can reach 59.16%.

[0153] (5) The drug release kinetic model of the drug release curve of CPA composite fibers is consistent with the Korsemeyer-Peppas model and the Higuchi model, indicating that there are two main mechanisms for drug release: the first is the swelling mechanism, and the second is the degradation mechanism, in which the drug is released from the hydrophobic part inside the fiber.

[0154] The foregoing description of specific exemplary embodiments of the present invention is for the purpose of illustration and demonstration. These descriptions are not intended to limit the present invention to the precise form disclosed, and it is clear that many changes and variations can be made based on the above teachings. The purpose of selecting and describing the exemplary embodiments is to explain the specific principles of the present invention and its practical application, so that those skilled in the art can realize and utilize various different exemplary embodiments of the present invention and various different selections and changes. The scope of the present invention is intended to be limited by the claims and their equivalents.

Claims

1. A sustained-release drug, comprising a chitosan / pululan microfiber carrier and a drug component formed on the carrier, wherein the drug component is selected from acetaminophen, ibuprofen, tea polyphenols, diclofenac, doxorubicin, berberine sulfate, and tetracycline; the chitosan / pululan microfiber carrier comprises a core layer and a shell layer formed outside the core layer, the core layer is a blend of chitosan and pullulan, the shell layer is formed by cross-linking chitosan and sodium tripolyphosphate on the surface of the core layer, the mass ratio of chitosan to pullulan in the blend of the core layer is (1-3):1, and the mass ratio of chitosan to TPP is (3-9):(75-125); a method for preparing the chitosan / pululan microfiber carrier comprises the following steps: preparing a core layer spinning solution and a shell layer spinning solution, wherein the core layer spinning solution is a mixed solution of chitosan and pullulan, and the shell layer spinning solution is a sodium tripolyphosphate solution; The microfluidic spinning is performed by using a coaxial syringe, wherein the coaxial syringe has an inner flow channel and an outer flow channel formed outside the inner flow channel; During microfluidic spinning, the core layer spinning solution is transported to the inner flow channel, and the shell layer spinning solution is transported to the outer flow channel; The mixed solution of chitosan and pullulan is obtained by mixing 3wt.% chitosan solution and 15wt.% pullulan solution. The mixed solution of chitosan and pullulan is obtained by mixing chitosan solution and pullulan solution in a mass ratio of (1-3):

1. The concentration of the sodium tripolyphosphate solution is 2-10wt.%.

2. The method for preparing the sustained-release drug according to claim 1, comprising the following steps: Prepare a core layer spinning solution and a shell layer spinning solution, wherein the core layer spinning solution is a mixed solution of chitosan, pullulan and an appropriate amount of drug components, and the shell layer spinning solution is a sodium tripolyphosphate solution; The microfluidic spinning is performed by using a coaxial syringe, wherein the coaxial syringe has an inner flow channel and an outer flow channel formed outside the inner flow channel; During microfluidic spinning, the core layer spinning solution is transported to the inner flow channel, and the shell layer spinning solution is transported to the outer flow channel.

3. A pharmaceutical composition comprising the sustained-release drug according to claim 1.

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