CN114351287B - Preparation method of composite drug-loaded fiber based on micro-fluid spinning - Google Patents

Abstract

The invention discloses a preparation method of composite drug-loaded fiber based on micro-flow spinning, which includes the following steps: A1. Take polyvinylpyrrolidone and sodium alginate, add water respectively, stir and heat to obtain polyvinylpyrrolidone solution and sodium alginate solution; A2. Mix polyvinylpyrrolidone solution and sodium alginate solution, and then add acetaminophen to form a mixed spinning solution; A3. Use the mixed spinning solution as the core layer and the calcium chloride solution as the sheath flow laminar flow. Continuous composite drug-loaded fibers were prepared by coaxial microfluidic spinning. Combining microfluidic spinning technology and ion cross-linking curing method, composite drug-loaded fibers with neat arrangement and uniform diameter are produced, which increases the drug-loading capacity of the composite drug-loaded fibers and achieves the sustained drug release effect of the composite drug-loaded fibers.

Description

Preparation method of composite drug-loaded fiber based on micro-flow spinning

Technical field

The invention relates to a composite drug-loaded fiber, and in particular to a preparation method of a micro-flow spinning composite drug-loaded fiber.

Background technique

In drug sustained and controlled release systems, carrier materials are one of the most important components. Carrier materials will affect the release rate of drugs. Using different carrier materials to load drugs may have different drug release kinetics. Generally speaking, a suitable carrier material must have basic characteristics such as good biocompatibility, non-toxic and harmless to humans, easy release of drugs and stable drug efficacy.

Commonly used carrier materials include biodegradable or non-biodegradable polymer materials and natural polymer materials. Common carrier materials include polylactic acid, polylactic acid-glycolic acid copolymer, polyvinylpyrrolidone, chitosan, sodium alginate, etc. Among them, polyvinylpyrrolidone is a synthetic water-soluble flexible long-chain non-ionic polymer compound with excellent solubility and biocompatibility. It also has excellent physiological inertness and will not participate in the metabolism of the human body. toxic free and safe. In recent decades, more and more researchers have increased their research on it, and the application range of PVP has become wider and wider.

Traditional methods for preparing drug-releasing fibers include dry spinning, wet spinning and electrospinning. In the existing technology, a two-step desolvation method is used to prepare gelatin nanoparticles GNP containing bovine serum albumin BSA, and then dry spinning is used to prepare PCL fiber, and the GNP particles are loaded on the fiber, creating a method that can carry and release Protein drug systems. The existing technology uses improved wet spinning technology to prepare polyacrylonitrile PAN fibers loaded with tamoxifen citrate TAM. In the prior art, drug-loaded nanocomposite fibers containing a thin layer of glyceryl monostearate as the shell layer and berberine hydrochloride and ethyl cellulose as the core layer were also prepared by using coaxial electrospinning. However, these spinning methods have some limitations. Dry spinning requires high temperatures and the carrier materials and drugs must not be easily degraded, which may destroy the activity of the drugs. The coagulation bath required for wet spinning is generally a toxic liquid, which is harmful to It is harmful to the body and needs to be removed later, and it may also destroy the activity of drug molecules; electrospinning generally requires high voltage to spin, and the solvents required to configure the spinning solution sometimes use toxic liquids, which are harmful to the body. harmful.

Therefore, there is a need to propose a fiber preparation method that is simpler to operate, can alleviate the shortcomings of traditional preparation methods, and can retain the advantages of a drug sustained release system.

Contents of the invention

The present invention overcomes the shortcomings of the prior art and provides a preparation method for composite drug-loaded fibers based on micro-flow spinning. In order to achieve the above object, the technical solution adopted by the present invention is: a preparation method of composite drug-loaded fiber based on micro-flow spinning, which is characterized by including the following steps:

A1. Take polyvinylpyrrolidone and sodium alginate, add water respectively, stir and heat to obtain polyvinylpyrrolidone solution and sodium alginate solution;

A2. Mix polyvinylpyrrolidone solution and sodium alginate solution, and then add acetaminophen to form a mixed spinning solution;

A3. Prepare continuous composite drug-loaded fibers through microfluidic spinning.

In a preferred embodiment of the present invention, the mixed spinning liquid is used as the core layer, and the calcium chloride solution is used as the sheath flow laminar flow. The mixed spinning liquid and calcium chloride solution are coaxially ejected into the fiber at different flow rates. Under the action of the rotational traction force of the collection device, continuous fibers are drawn out by continuous rotation; by setting the translation rate and number of cycles of the collection device, composite drug-loaded fibers are prepared and formed.

In a preferred embodiment of the present invention, the concentration of the polyvinylpyrrolidone solution is 5-15wt%, the concentration of the sodium alginate solution is 1-2wt%, the polyvinylpyrrolidone solution and the sodium alginate solution Mix according to the ratio of 1:1~2.

In a preferred embodiment of the present invention, the concentration of the polyvinylpyrrolidone solution is 15-21wt%, the concentration of the sodium alginate solution is 1-2wt%, the polyvinylpyrrolidone solution and the sodium alginate solution Mix according to the ratio of 1:1~2.

In a preferred embodiment of the present invention, the concentration of the calcium chloride solution is 0.1-0.2 mol/L.

In a preferred embodiment of the present invention, the acetaminophen is added to the mixed spinning liquid with a mass fraction of 0 to 30 wt% of the total solute.

In a preferred embodiment of the present invention, the rotation speed of the collection device is 30 to 50 r/min, the translation speed of the collection device is 3 to 5 mm/min, and the translation speed is once in a cycle, and the flow rate of the core layer solution is 16 to 28 mL/min. h, the flow rate of the sheath layer solution is 8 to 14 mL/h.

A composite drug-loaded fiber made by any of the above-mentioned preparation methods of composite drug-loaded fiber based on micro-flow spinning, characterized in that: the composite drug-loaded fiber is core-shell fiber, polyvinylpyrrolidone, alginic acid Sodium and acetaminophen are evenly dispersed in the composite drug-loaded fiber in an amorphous state, and there are hydrogen bonds between the composite drug-loaded fibers.

In a preferred embodiment of the present invention, the breaking strength of the composite drug-loaded fiber is positively correlated with the concentrations of the polyvinylpyrrolidone and the acetaminophen.

In a preferred embodiment of the present invention, when the concentrations of polyvinylpyrrolidone solution and acetaminophen are in the range of 5 to 21 wt% and 0 to 30 wt% respectively, the cumulative release percentage of acetaminophen of the composite drug-loaded fiber is consistent with the desired There is a positive correlation between the concentration of polyvinylpyrrolidone solution and acetaminophen.

The present invention solves the defects existing in the background technology and has the following beneficial effects:

(1) The present invention uses polyvinylpyrrolidone as the carrier of acetaminophen, combines microfluid spinning technology and ion cross-linking curing method to produce composite drug-loaded fibers with neat arrangement and uniform diameter, which improves the loading capacity of the composite drug-loaded fibers. dosage to achieve the drug sustained release effect of the composite drug-loaded fiber.

(2) In the composite drug-loaded fiber prepared by the present invention, polyvinylpyrrolidone, sodium alginate and acetaminophen are physically combined, there are hydrogen bonds between fiber components, and acetaminophen is evenly dispersed in an amorphous state In the composite fiber, polyvinylpyrrolidone and sodium alginate can effectively inhibit the crystallization of acetaminophen, further improving the drug loading capacity and sustained release effect of the composite drug-loaded fiber.

(3) The present invention adjusts the concentrations of different polyvinylpyrrolidone and sodium alginate, adjusts the ratio between polyvinylpyrrolidone and sodium alginate, adjusts the output rate of the mixed spinning solution in microfluidic spinning, and adjusts the rotation of the collection device. The velocity and translation rate are used to obtain the diameter, spacing and uniformity of the composite drug-loaded fiber with a larger drug load, thereby obtaining a larger cumulative release percentage of acetaminophen.

In the present invention, when the rotation speed of the collection device is 50 r/min, the translation speed of the collection device is 4 mm/min, and the circulation translation is once, the flow rate of the core layer solution is 28 mL/h, and the flow rate of the sheath flow layer solution is 14 mL/h, 15wt% The polyvinylpyrrolidone solution and 2wt% sodium alginate solution were mixed in a ratio of 1:2 to prepare the spinning solution as the core layer solution and the 0.1mol/L calcium chloride solution as the sheath layer solution. Fluid spinning continuously prepares fibers and can produce 9.42 meters of microfibers in one minute, with a productivity of 15.7cm/s.

(4) The composite drug-loaded fiber prepared by micro-flow spinning in the present invention has a relatively large specific surface area. At the same time, there are pores inside the fiber to store drugs. After solidification, the fiber can encapsulate the drug well and limit the Brownian motion of the drug. , reduces the probability of collision between drug molecules, avoids the formation of drug crystal nuclei to a certain extent, and ensures the drug-loading capacity and sustained-release effect of the composite drug-loaded fiber.

The composite drug-loaded fiber prepared by micro-flow spinning in the present invention does not require the use of high temperatures, will not cause decomposition or deactivation of carrier materials or drugs, does not require high-voltage spinning, and does not produce toxic liquids during the process of preparing the spinning solution.

Description of the drawings

In order to explain the embodiments of the present invention or the technical solutions in the prior art more clearly, the drawings needed to be used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings in the following description are only These are some embodiments recorded in the present invention. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without exerting creative efforts;

Figure 1 is a flow chart for the preparation of a micro-spun composite drug-loaded fiber of the present invention;

Figure 2 is an SEM image of PVP/SA/AAP composite fibers with different PVP solution concentrations in Example 1 of the present invention;

Figure 3 is an SEM image of the cross-section of the PVP/SA/AAP composite fiber with different PVP solution concentrations in Example 1 of the present invention;

Figure 4 is an SEM image of PVP/SA/AAP composite fibers with different AAP mass fractions in Example 2 of the present invention;

Figure 5 is a physical diagram of the PVP/SA/AAP composite fiber according to Embodiment 3 of the present invention;

Figure 6 is an infrared spectrum of PVP/SA/AAP composite fibers with PVP, SA, AAP and AAP mass fractions of 0wt%, 10wt%, 20wt% and 30wt% in Example 4 of the present invention;

Figure 7 is the XRD curve diagram of AAP, PVP, SA, PVP/SA composite fiber membrane and PVP/SA/AAP composite fiber membrane in Example 4 of the present invention;

Figure 8 is a mechanical analysis diagram of the PVP/SA/AAP composite fiber in Example 4 of the present invention;

Figure 9 is the standard curve and standard curve equation of AAP in phosphate buffer solution of pH=7.4 according to Example 5 of the present invention;

Figure 10 is an in vitro release curve diagram of AAP in PVP/SA/AAP composite fiber according to Example 5 of the present invention.

Detailed ways

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only some of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts fall within the scope of protection of the present invention.

As shown in Figure 1, there is shown a flow chart for the preparation of a micro-spun composite drug-loaded fiber provided by the present invention. The preparation method of composite drug-loaded fiber based on micro-flow spinning includes the following steps:

A1. Take polyvinylpyrrolidone and sodium alginate, add water respectively, stir and heat to obtain polyvinylpyrrolidone solution and sodium alginate solution;

A2. Mix polyvinylpyrrolidone solution and sodium alginate solution, and then add acetaminophen to form a mixed spinning solution;

A3. Prepare continuous composite drug-loaded fibers through microfluidic spinning. Embodiment 1

Since microfluidic spinning is carried out at normal temperature and pressure, the spinning solution is not subjected to other external forces except the thrust of the syringe pump during the entire continuous spinning process. Therefore, in order to ensure the normal progress of the spinning process, the solution The concentration is important for spinning. In order to ensure that the fiber only swells but does not dissolve during the drug release process, the ionic cross-linking method is used to quickly solidify the fiber. It is also important to find the appropriate concentrations of sodium alginate and calcium chloride. Therefore, this example is to verify the influence of different spinning solution concentrations on the shaping of PVP/SA/AAP composite drug-loaded fibers.

PVP solution and SA solution themselves have a certain viscosity, and as the concentration increases, the viscosity of the solution will also increase. Since the flow channel of the spinning solution is relatively narrow, when the solution concentration is too high, the viscosity will be too high, which will easily cause clogging. However, when the solution concentration is too low, the fiber will not be easy to form and breakage will easily occur.

In order to carry out the spinning experiment and ensure that the fiber will not break during the spinning process, 5wt%, 10wt% and 15wt% PVP solutions, as well as 1wt% and 2wt% SA solutions were prepared respectively, and the ratio was 1:1. Mixed with a mass ratio of 1:2 to obtain mixed spinning solutions of different concentrations. The experimental design samples are shown in Table 1. Among them, the concentration of the calcium chloride solution in this embodiment is selected to be 0.1 mol/L.

Table 1 Experimental design samples

Through the above experiments, it was found that the spinning solution prepared by mixing 15wt% PVP solution and 2wt% SA solution in a ratio of 1:2 was used as the core layer solution and the 0.1mol/L calcium chloride solution was used as the sheath layer solution. axial microfluidic spinning continuously prepares fibers, and fibers are basically not broken.

After it was determined that 15wt% PVP solution and 2wt% SA solution were mixed in a mass ratio of 1:2, and the composite fiber could be successfully prepared, 18wt% and 21wt% PVP solutions were continued, keeping the same SA solution and Mixing ratio, use the same coaxial microfluidic spinning process parameters to prepare composite fibers, and explore the impact of changes in PVP solution concentration on fiber morphology and the impact on drug release when used as a drug sustained release system. The surface morphology of PVP/SA/AAP composite fibers with different PVP solution concentrations is shown in Figure 2, where Figures 2a, 2b and 2c show PVP/SA/AAP with 15wt%, 18wt% and 21wt% PVP solution concentrations respectively. SEM image of composite fiber.

From Figure 2, it can be seen that as the PVP content increases, the fibers become smoother and rounder, with a diameter of about 30 to 50 μm. Moreover, as the PVP content increases, the diameter of the fiber becomes thinner. The diameters of PVP/SA/AAP composite fibers with PVP solution concentrations of 15wt%, 18wt% and 21wt% are 44μm, 39μm and 34μm respectively.

The reason is that as the PVP content increases, the relative content of sodium alginate decreases. During the drying process, the shrinkage speed of the gel fiber slows down, the shrinkage gaps decrease, the fiber surface becomes smoother, and the relative content of sodium alginate decreases. , reducing the interaction between water molecules of the sodium alginate solvent, allowing the solvent to evaporate more fully during the drying process of the fiber, and the fiber diameter becomes thinner.

The internal structure of PVP/SA/AAP composite fibers with different PVP solution concentrations is shown in Figure 3, where Figures 3(a-c), 3(d-f), and 3(g-i) show the PVP solution concentrations of 15wt%, 18wt%, and 21wt% respectively. SEM image of the cross-section of PVP/SA/AAP composite fiber.

From Figure 3a, Figure 3d and Figure 3g, it can be seen that there are no obvious cavity defects inside the PVP/SA/AAP composite fiber, indicating that PVP, SA and AAP have good compatibility and can be mixed evenly.

From Figure 3b, a shell-like structure appears on the outside of the PVP/SA/AAP composite fiber. This is because when the spinning solution in the core layer meets the calcium chloride solution in the sheath flow layer in the microchannel, SA and Ca2 ₊ The cross-linking rate is greater than the curing speed of PVP, so part of the SA quickly forms a gel on the outer surface of the fiber before the PVP component, and the fiber surface has a gel shell, which is beneficial to the encapsulation of drugs.

At the same time, it can be seen from Figure 3e and Figure 3h that as the concentration of PVP solution increases, the gel shell of the composite fiber becomes thinner and thinner. As the PVP content increases, the relative content of SA decreases and can be separated from Ca2 ₊ The content of the combined gel layer is also reduced, so the gel shell on the fiber surface becomes thinner as the concentration of the PVP solution increases. It can be seen from Figures 3c, 3f and 3i that there is a tiny pore structure inside the composite fiber, which is beneficial to the loading and release of drugs, and as the concentration of the PVP solution increases, the more pores there are inside the fiber.

Embodiment 2

This example explores the effect of different AAP mass fractions on the morphology of composite fibers. SEM images of drug-loaded PVP/SA/AAP composite fibers with different AAP mass fractions. Fix the conductive glue on the electron microscope stage, then take several PVP/SA/AAP composite fibers prepared above and stick them on the conductive glue, spray gold for 90 seconds, and use R-8100 cold field scanning electron microscope to observe the surface morphology characteristics of the fibers. The test conditions are voltage 3kV and voltage 10mA. Use liquid nitrogen brittle fracture composite fiber and use the same testing method and testing conditions to observe the cross-sectional morphological characteristics of the fiber.

As shown in Figure 4, Figures 4a, 4b, 4c and 4d show SEM images of PVP/SA/AAP composite fibers with AAP mass fractions of 0wt%, 10wt%, 20wt% and 30wt% respectively.

From Figure 4, the surface of PVP/SA/AAP composite fibers with different AAP mass fractions is still relatively smooth and continuous, with no obvious block or crystalline material precipitating, indicating that acetaminophen is evenly dispersed in the composite fiber. As the mass fraction of AAP increases, the diameter of the fiber changes slightly, indicating that the addition of the model drug has little effect on the fiber diameter.

Embodiment 3

In the above preparation method, the microfluidic spinning process parameters have a certain impact on fiber forming. Therefore, this example is to explore the influence of microfluidic spinning process parameters on fiber forming.

The microfluidic spinning machine mainly consists of two parts: a microfluidic syringe pump and a fiber receiving platform. The first part of the microfluidic syringe pump is used to control the output speed and volume of the spinning solution. It mainly includes: dual-channel syringe pump, syringe, polytetrafluoroethylene tube and coaxial needle. The second part of the fiber receiving platform is used to receive fibers, and mainly includes a roller receiver, a rotating motor, a cyclic stepping translation platform, a heater and a control panel. The dual-channel syringe pump can independently control the two syringes and set different propulsion speeds. The components of the microfluidic spinning device are connected with polytetrafluoroethylene tubes and connectors.

The drum receiver on the microfluidic spinning machine generates traction through continuous rotation. On the one hand, it can stretch the spinning liquid into fiber shape, and on the other hand, it can receive the fibers solidified by ion cross-linking, providing traction and making the fibers become more Orderly. The rotation speed of the drum receiver is determined by the rotation rate of the rotating motor, so the rotation rate of the rotating motor will affect the diameter of the fiber.

When the rotation speed is too low, the receiver cannot quickly pull out the fiber from the needle, and the fiber cannot be formed. When the rotation speed is too high, the traction force provided by the receiver is too large, the fiber will be pulled off, and there will be more broken wires. In order to obtain neatly arranged fiber membranes with uniform diameters, which will facilitate later drug release experiments, the receiver is allowed to move cyclically at a certain translation speed, and orderly and evenly spaced fiber membranes can be collected on the drum. The translation speed and number of cycles of the receiver directly affect the spacing between fibers and the density of the fiber membrane.

The output speed of the spinning solution is controlled by the propulsion speed of the syringe pump. It is necessary to find the appropriate flow rate of the core layer solution and the sheath layer solution to obtain well-formed and evenly arranged fibers.

Therefore, in this embodiment, the microfluidic spinning machine affects the diameter, spacing and uniformity of the fibers through the output rate of the mixed spinning liquid determined by the syringe pump, the rotation rate of the motor on the fiber receiving platform, and the cycle step translation rate. In this embodiment, a composite fiber membrane with neat arrangement, uniform diameter and adjustable size can be obtained by optimizing the settings of the above three process parameters. In this embodiment, the experimental plan shown in Table 2 is designed based on the above three process parameters.

Table 2 Experimental plan

It can be obtained from Table 2 that when the rotation speed of the drum receiver is 50r/min, the translation speed of the receiver is 4mm/min, and the cycle is translated once, the flow rate of the core layer solution is 28mL/h, and the flow rate of the sheath layer solution is 14mL/h. When, well-formed fibers can be obtained, and fibers can be produced continuously.

Through the experimental plan of this embodiment combined with the experimental method of the above-mentioned Example 1, it is obtained that when the rotation speed of the drum receiver is 50 r/min, the translation speed of the receiver is 4 mm/min, and the cyclic translation is performed once, the flow rate of the core layer solution is 28 mL/min. h, the flow rate of the sheath layer solution is 14mL/h, the spinning solution prepared by mixing 15wt% PVP solution and 2wt% SA solution in a ratio of 1:2 is used as the core layer solution and 0.1mol/L calcium chloride solution As a sheath layer solution, fibers can be continuously prepared through coaxial microfluidic spinning, and 9.42-meter-long microfibers can be produced in one minute with a productivity of 15.7cm/s.

At the same time, after adding AAP with a mass fraction of 10wt%, 20wt% and 30wt% of the total solute in the core layer spinning liquid, fibers can still be continuously produced. Figure 5 is a physical picture of the fiber obtained after optimizing the experimental plan according to Example 1 and Example 2. It can be seen from the figure that the fiber is well formed, and fiber arrays and fiber membranes can be further prepared.

Embodiment 4

In this example, the morphology of the PVP/SA/AAP composite drug-loaded fiber prepared in the above example was characterized.

(1) PVP/SA/AAP composite fiber Fourier transform infrared spectroscopy (FITR) test

Figure 6 is the infrared spectrum of PVP/SA/AAP composite fibers with mass fractions of PVP, SA, AAP and AAP of 0wt%, 10wt%, 20wt% and 30wt%.

As shown in Figure 6a, the absorption peaks of the PVP sample appearing at 3446cm ^-1 , 2956cm ^-1 , 1661cm ^-1 and 1290cm ^-1 respectively correspond to the stretching vibrations of -CH, -CH-CH2, -C=O and -CN. The absorption peak at 1423 cm ^-1 corresponds to the deformation vibration of -CH of the cyclic CH2 group in PVP. As shown in Figure 6b, the absorption peaks of the SA sample appearing at 3423cm ^-1 , 2925cm ^-1 , 1606cm ^-1 , 1405cm ^-1 and 1025cm ^-1 correspond to -OH, -CH, -COO, -C=O and - respectively. Stretching vibration of COC-group. As shown in Figure 6c, the absorption peaks of the AAP sample at 3320 cm ^-1 and 1650 cm ^-1 correspond to the stretching vibration of -OH and -C=O on the amide bond, respectively.

As shown in Figure 6(eg), the infrared spectra of PVP/SA/AAP composite fibers with different drug loadings all show the characteristic absorption peaks of PVP, SA and AAP, and no new characteristic absorption peaks appear, indicating that the model drug AAP and PVP , SA are combined in the form of physical blending, which will not change the physical and chemical properties of the drug and will not affect the function of the drug. At the same time, as the AAP content increases, the intensity of the -C=O characteristic absorption peak on the amide bond at 1650 cm ^-1 gradually weakens, which may be due to hydrogen bonds between acetaminophen, PVP, and SA.

(2) X-ray diffraction (XRD) test of PVP/SA/AAP composite fiber

If the drug crystallizes, it will affect the stability, bioavailability and efficacy of the drug. Therefore, when preparing a drug sustained-release system, it is necessary to prevent drug crystallization. The process of drug crystallization in polymer matrix is mainly divided into two stages, the first stage is nucleation, and the second stage is crystal nucleation growth. In the first stage, drugs collide with each other through irregular "Brownian motion" to form "dimers", and then these "dimers" collide with each other to form crystal nuclei. As more and more "dimers" of the drug gather together, the crystal nucleus growth stage is entered. So it takes time for the drug to crystallize and then separate out of the polymer.

The prepared drug-loaded PVP/SA/AAP composite fiber membrane was stored at room temperature for 3 months. After 3 months, X-ray diffraction was used to determine the distribution state of AAP, AAP, and polymer in the PVP/SA/AAP composite fiber membrane. PVP and SA in the matrix were detected. Figure 7 shows the XRD curves of AAP, PVP, SA, PVP/SA composite fiber membrane and PVP/SA/AAP composite fiber membrane.

It can be seen from Figure 7a that the original drug of acetaminophen (AAP) is at 12.04°, 13.76°, 15.4°, 16.66°, 18.12°, 20.3°, 23.38°, 24.32°, 26.5°, 29, 22° and 32.44°. Typical characteristic diffraction peaks appear.

However, as shown in Figure 7e, no characteristic diffraction peak of AAP original drug was observed in the drug-loaded PVP/SA/AAP composite fiber membrane. Only the characteristic diffraction peaks of PVP and SA in the polymer matrix were observed, indicating that AAP is in an amorphous form. The state is distributed in the drug-loaded composite fiber, which also shows that the PVP/SA composite fiber can effectively inhibit the crystallization of AAP. This is because the fibers prepared by micro-flow spinning have a relatively large specific surface area, and there are also pores inside the fibers to store drugs. After solidification, the fibers can encapsulate the drugs very well, and also limit the Brownian motion of the drugs, reducing the intermittency between drug molecules. The probability of collision with each other avoids the formation of drug crystal nuclei to a certain extent. Moreover, through infrared spectrum analysis, it was found that hydrogen bonds will be formed between AAP, PVP, and SA, further inhibiting the crystallization of the drug.

(3) Mechanical property testing of PVP/SA/AAP composite fibers

In this example, the mechanical properties of the PVP/SA/AAP composite fiber prepared above were analyzed, as shown in Figure 8. The fiber samples were prepared with a pitch length of 200 mm, and the breaking strength of the composite fiber was tested using an Instron5967 material testing machine. Each sample was tested 30 times, and the pulling speed was 20 mm/min. The average value was taken as the test result.

Figure 8a is a histogram of breaking strength of PVP/SA/AAP composite fibers with PVP mass fractions of 15wt%, 18wt% and 21wt% respectively; Figure 8b is a stress-strain curve of composite fibers with different PVP mass fractions; Figure 8c is The breaking strength histogram of PVP/SA/AAP composite fibers with different drug loading contents; Figure 8d is the stress-strain curve of PSA fibers with different drug loading contents.

From Figure 8a, it can be seen that the breaking strengths of PVP/SA/AAP composite fibers with PVP mass fractions of 15wt%, 18wt% and 21wt% are 39.14±5.31MPa, 44.48±5.5MPa and 59.08±5.31MPa respectively. As the PVP content increases, the breaking strength of the composite fiber increases. The reason is that as the PVP content increases, on the one hand, the hydrogen bonds between PVP and SA are increased, and on the other hand, the intramolecular hydrogen bonds of PVP are increased, thereby improving the Breaking strength of composite fibers.

It can be seen from Figure 8b that the PVP/SA/AAP composite fiber is a flexible fiber, and its elongation at break is basically above 20%. As the PVP content increases, the elongation at break of the fiber also increases slightly.

It can be seen from Figure 8c that with the increase of model drug, the breaking strength of the fiber also increases slightly. The breaking strength of the drug-loaded composite fiber with mass fractions of 0, 10wt%, 20wt% and 30wt% AAP is 37.27±4.17MPa respectively. , 39.14±5.31MPa, 39.45±5.4MPa and 43.06±5.21MPa. This is because as the AAP content increases, the uniform distribution of AAP small molecules in the fiber will increase the intermolecular force between fiber components, thereby increasing the breaking strength of the composite fiber.

It can be seen from Figure 8d that with the addition of small drug molecules, the slippage of macromolecular chains in the fiber will increase, and the elongation at break of the composite fiber will increase slightly. However, as the AAP content continues to increase, due to the fiber components The intermolecular force increases, and the elongation at break of the composite fiber decreases slightly.

Embodiment 5

This example measures the in vitro release of AAP in the PVP/SA/AAP composite fiber prepared in the above example.

Figure 9 is the standard curve and standard curve equation of AAP in buffer solution. The standard curve shows that the AAP concentration is in the range of 0.5μg/mL-50μg/mL, and the absorbance and concentration show a good linear relationship.

Weigh the PVP/SA/AAP composite fiber membrane and mix it in PBS buffer solution at 2h, 4h, 6h, 8h, 10h, 12h, 24h, 26h, 28h, 30h, 32h, 34h, 36h, 48h, 50h, respectively. 52h, 54h, 56h, 58h, 60h and 72h, and then dilute it, measure its UV absorbance at 245nm, and add an equal amount of PBS buffer solution to the sustained-release system to keep the solution volume constant. Each drug-loaded fiber is used as Three parallel samples.

Calculate the AAP content according to the standard curve equation of AAP, calculate the cumulative release percentage of AAP according to the following formula, and draw the in vitro release curve of the PVP/SA/AAP composite fiber. The formula is: Among them, Q is the cumulative release percentage of AAP, v is the volume of sustained-release solution PBS, v _d is the volume of diluted PBS, c _i is the drug concentration (μg/mL) in the release solution during the i-th sample exchange, and A is the composite load. The mass of AAP contained in medicinal fiber (μg), n is the number of sampling times.

Figure 10 is the in vitro release curve of AAP in PVP/SA/AAP composite fiber. It can be seen from Figure 10a that as the PVP content increases, the cumulative release percentage of the PVP/SA/AAP composite fiber also increases. The reason is that as the PVP content increases, the gel shell of the fiber becomes thinner, and the hindrance to the release of the model drug AAP from the fiber is reduced. Moreover, PVP is a water-soluble polymer, and along with the thinning of the fiber shell, The probability of degradation of the PVP/SA/AAP composite fiber skeleton will increase, which increases the release pathway of AAP and increases the cumulative release percentage of AAP. And as the PVP content increases, the diameter of the fiber will become thinner, the specific surface area of the fiber will increase, the drug loading capacity on the fiber surface will also increase, and the drugs in the fiber will be more easily dispersed into the PBS buffer solution. The cumulative release rate will also increase. At the same time, it can be obtained that the release rate of the three PVP/SA/AAP composite fibers is approximately linear in the first 12 hours, and the release rate after 12 hours is slower, approximately uniform release. This is because after the AAP on the surface of the fiber is released, the remaining AAP can only diffuse from the inside of the fiber to the outside and then be released, and the release rate will slow down.

Figures 10b, 10c and 10d are the release curves of PVP/SA/AAP composite fibers with different drug loading contents of 15wt% PVP, 18wt% PVP and 21wt% PVP respectively.

It can be seen from the figure that as the drug loading increases, the cumulative release percentage of fiber also increases. From Table 3, Table 4 and Table 5, the cumulative release percentages of PVP/SA/AAP composite fiber with 15wt% PVP, 18wt% PVP and 21wt% PVP in the first 12 hours were 45.74% and 59.86 respectively. % and 70.43%. The cumulative release percentages of PVP/SA/AAP composite fibers with an AAP content of 20wt% were 54.57%, 72.69% and 78.12%. The cumulative release percentages of PSA composite fibers with an AAP content of 30wt% were 61.11%, 80% and 89.72%. This is because the greater the content of AAP, the more drugs are dispersed on the surface of the fiber and the easier it is to be released within the first 12 hours. After 72 hours, the cumulative release percentages of PVP/SA/AAP composite fibers with 10wt% AAP content were 63.54%, 71.85% and 79.13%; the cumulative release percentages of PVP/SA/AAP composite fibers with 20wt% AAP content were 70.56%, 81.92%. and 86.96%; the cumulative release percentages of the PVP/SA/AAP composite fiber with an AAP content of 30wt% are 80.85%, 89.99% and 97.35%. This is because the water solubility of AAP is not good, and the drug embedded in the fiber is not easily released, so the drug release rate will slow down, and hydrogen bonds will be formed between AAP and PVP, inhibiting the crystallization of AAP. When the AAP content increases, because the PVP content is constant, the hydrogen bonds generated will reach a saturation level, so that excess AAP will crystallize and precipitate on the surface of the fiber. Under the washing of PBS phosphate buffer, it will be dissolved in PBS and the drug will be released. The cumulative drug release percentage increases.

Table 3 Cumulative release rate of AAP in PVP/SA/AAP composite fiber with 15wt% PVP

Table 4 Cumulative release rate of AAP in PVP/SA/AAP composite fiber with 18wt% PVP

Table 5 Cumulative release rate of AAP in PVP/SA/AAP composite fiber with 21wt% PVP

In order to explore the drug release mechanism of PVP/SA/AAP composite fiber, five drug release kinetic models were used to fit the drug release curve of PVP/SA/AAP composite fiber, and the suitable model was evaluated based on the correlation coefficient R2. Zero-order release means that the drug release rate does not change with time, that is, the drug release rate remains constant during the release cycle.

First-order release means that the release rate per unit time is proportional to the drug concentration. It is generally believed that zero-order release for extravascular administration is the ideal controlled release mode, and first-order release is the basic release mode. Matrix type drug sustained and controlled release systems are generally divided into monolithic matrix systems, swelling matrix systems and dissolution matrix systems. The Weibull model means that the release rate of a drug is proportional to the diffusion coefficient, and the drug release mechanism is generally diffusion or matrix dissolution. The Higuchi model is generally applicable to the entire framework system, which means that the drug diffuses through the polymer molecular network and pores in the framework system. Generally, the polymer degradation rate is much smaller than the diffusion rate of the drug.

The Ritger-Peppas model is generally suitable for swelling matrix systems, and the drug release mechanism is judged based on the slope of the fitting curve. When the slope ≤ 0.43, the drug release mechanism is Fickian diffusion; when 0.43 < slope < 0.89, the drug release mechanism is non-Fickian diffusion; when the slope = 0.89, the drug release mechanism is matrix degradation.

Table 6, Table 7 and Table 8 are the fitting of the drug release kinetic model of the drug release curve of PVP/SA/AAP composite fiber with PVP content of 15wt%, 18wt% and 21wt% respectively. According to the evaluation of the correlation coefficient R2, the drug release kinetic model of the PVP/SA/AAP composite fiber drug release curve with PVP content of 15wt%, 18wt% and 21wt% is consistent with the Weibull model and the Ritger-Peppas model. The drug release model of PVP/SA/AAP composite fiber with 15wt% PVP content is more consistent with the Ritger-Peppas model. The slope of the fitting equation is 0.20322, which is less than 0.43, indicating that the drug release model of PVP/SA/AAP composite fiber with 15wt% PVP content is more consistent with the Ritger-Peppas model. The drug mechanism is closer to Fickian diffusion. The drug release models of PVP/SA/AAP composite fibers with 18wt% and 21wt% PVP contents are more consistent with the Weibull model, indicating that the drug release mechanism of PVP/SA/AAP composite fibers is mainly drug diffusion and matrix dissolution. Comprehensive description: The release of drugs from PVP/SA/AAP composite fibers mainly goes through two stages. The first stage is that the fiber skeleton swells, and the drugs outside the fiber diffuse out through Fickian, and the drug release rate is faster; the second stage The fiber skeleton is degraded, the drugs inside the fiber diffuse out, and the drug release rate slows down.

Table 6 Drug release kinetic model fitting of drug release curve of PVP/SA/AAP composite fiber containing 15wt% PVP

Table 7 Drug release kinetic model fitting of drug release curve of PVP/SA/AAP composite fiber containing 18wt% PVP

Table 8 Drug release kinetic model fitting of drug release curve of PVP/SA/AAP composite fiber containing 21wt% PVP

The above is based on the ideal embodiment of the present invention. Through the above description, relevant personnel can make various changes and modifications without departing from the scope of the technical idea of the present invention. The technical scope of the present invention is not limited to the content in the description, and must be determined based on the scope of the claims.

Claims (4)

1. The preparation method of the composite drug-loaded fiber based on micro-spinning is characterized by comprising the following steps:

a1, taking polyvinylpyrrolidone and sodium alginate, respectively adding water, stirring and heating to obtain polyvinylpyrrolidone solution and sodium alginate solution; the concentration of the polyvinylpyrrolidone solution is 15-21 wt%, the concentration of the sodium alginate solution is 2wt%, and the polyvinylpyrrolidone solution and the sodium alginate solution are mixed according to the following weight ratio of 1:2, mixing in proportion;

a2, mixing a polyvinylpyrrolidone solution and a sodium alginate solution, and then adding acetaminophen to form a mixed spinning solution; adding 0-30wt% of acetaminophen into the mixed spinning solution, wherein the acetaminophen accounts for 0-30wt% of the total solute, but the acetaminophen is not included;

a3, taking the mixed spinning solution as a core layer, taking 0.1mol/L calcium chloride solution as a sheath flow laminar flow, coaxially spraying out fibers from the mixed spinning solution and the calcium chloride solution at different flow rates in a microfluid spinning mode, and continuously rotationally drafting out continuous fibers under the action of rotational traction force of a collecting device; preparing and forming continuous composite medicine carrying fibers by setting the translation rate and the circulation times of the collecting device;

the rotation speed of the collecting device is 50r/min, the translation speed of the collecting device is 4mm/min, the circulating translation is carried out once, the flow rate of the core layer solution is 28mL/h, and the flow rate of the sheath flow layer solution is 14mL/h.

2. A composite drug-loaded fiber prepared by the preparation method based on micro-fluid spinning of the composite drug-loaded fiber in claim 1, which is characterized in that:

the composite medicine carrying fiber is core-shell fiber, polyvinylpyrrolidone, sodium alginate and acetaminophen are uniformly dispersed in the composite medicine carrying fiber in an amorphous state, and hydrogen bonding is performed among the composite medicine carrying fibers.

3. A composite drug-loaded fiber as defined in claim 2, wherein: the breaking strength of the composite drug-carrying fiber is positively correlated with the concentration of the polyvinylpyrrolidone and the concentration of the acetaminophen.

4. A composite drug-loaded fiber as defined in claim 2, wherein: when the concentrations of the polyvinylpyrrolidone solution and the acetaminophen are respectively in the range of 15-21 wt% and 0-30 wt%, and the concentration of the acetaminophen is not included in the range of 0wt%; the cumulative percent acetaminophen release of the composite drug-loaded fibers is positively correlated to the concentration of the polyvinylpyrrolidone solution and acetaminophen.