CN114351287A

CN114351287A - Preparation method of composite drug-loaded fiber based on micro-spinning

Info

Publication number: CN114351287A
Application number: CN202210067004.6A
Authority: CN
Inventors: 陈宇岳; 方瑛; 林红; 张德锁
Original assignee: Suzhou University
Current assignee: Suzhou University
Priority date: 2022-01-20
Filing date: 2022-01-20
Publication date: 2022-04-15
Anticipated expiration: 2042-01-20
Also published as: CN114351287B

Abstract

The invention discloses a preparation method of a composite drug-loaded fiber based on micro-spinning, which comprises the following steps: a1, taking polyvinylpyrrolidone and sodium alginate, respectively adding water, stirring and heating to obtain polyvinylpyrrolidone solution and sodium alginate solution; a2, mixing a polyvinylpyrrolidone solution and a sodium alginate solution, and adding acetaminophen to form a mixed spinning solution; a3, preparing continuous composite drug-loaded fibers by taking mixed spinning solution as a core layer and calcium chloride solution as sheath flow laminar flow in a coaxial microfluid spinning mode. The composite drug-loaded fibers with uniform arrangement and uniform diameter are prepared by combining a microfluid spinning technology and an ionic crosslinking curing method, so that the drug-loaded rate of the composite drug-loaded fibers is improved, and the drug slow-release effect of the composite drug-loaded fibers is realized.

Description

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

Technical Field

The invention relates to a composite drug-loaded fiber, in particular to a preparation method of the composite drug-loaded fiber based on micro-spinning.

Background

In a sustained and controlled drug release system, a carrier material is one of the important components. Carrier materials can affect the release rate of the drug, and different drug release kinetics are possible with different carrier materials for loading the drug. Generally, suitable carrier materials have the basic characteristics of good biocompatibility, no toxicity or harm to human, easy release of the drug, stable drug effect and the like.

Commonly used carrier materials include biodegradable or non-biodegradable polymer materials, as well as natural polymer materials. Common carrier materials include polylactic acid, polylactic acid-glycolic acid copolymer, polyvinylpyrrolidone, chitosan, sodium alginate and the like. The polyvinylpyrrolidone is an artificially synthesized water-soluble flexible long-chain nonionic polymer compound, has excellent solubility and biocompatibility, has excellent physiological inertia, cannot participate in metabolism of a human body, and is non-toxic and harmless. In recent decades, more and more researchers have increased their research and PVP has become more and more widely used.

The traditional method for preparing the drug-releasing fiber comprises dry spinning, wet spinning, electrostatic spinning and the like. In the prior art, a two-step desolvation method is used for preparing gelatin nano-particles (GNP) containing Bovine Serum Albumin (BSA), then a PCL fiber is prepared by using a dry spinning method, and GNP particles are loaded on the fiber, so that a system capable of carrying and releasing protein drugs is created. In the prior art, the improved wet spinning technology is utilized to prepare the polyacrylonitrile PAN fiber loaded with tamoxifen citrate TAM. In the prior art, a drug-loaded nano-composite fiber which takes a glycerin monostearate thin layer as a shell layer and takes berberine hydrochloride and ethyl cellulose as a core layer is prepared by using coaxial electrostatic spinning. However, these spinning methods have some limitations, and dry spinning requires high temperature and requires that the carrier material and the drug are not easily degraded, which may destroy the activity of the drug; the coagulation bath required by wet spinning is generally toxic liquid, has harm to the body, needs to be removed at a later stage, and can damage the activity of drug molecules; electrostatic spinning generally requires high voltage to spin, and the solvent required for preparing the spinning solution is sometimes toxic liquid and harmful to human body.

There is therefore a need for a process for preparing fibers which is simpler to operate, which alleviates the disadvantages of the conventional preparation processes and which retains the advantages of the drug delivery systems.

Disclosure of Invention

The invention overcomes the defects of the prior art and provides a preparation method of the composite drug-loaded fiber based on micro-spinning. In order to achieve the purpose, the invention adopts the technical scheme that: 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;

a2, mixing a polyvinylpyrrolidone solution and a sodium alginate solution, and adding acetaminophen to form a mixed spinning solution;

a3, preparing continuous composite drug-loaded fibers by a microfluid spinning mode.

In a preferred embodiment of the invention, the mixed spinning solution is used as a core layer, the calcium chloride solution is used as a sheath flow laminar flow, the mixed spinning solution and the calcium chloride solution are coaxially sprayed out of fibers at different flow rates, and the fibers are continuously and rotatably drawn to form continuous fibers under the action of the rotary traction force of a collecting device; the composite drug-loaded fiber is prepared and formed by setting the translation rate and the cycle number of the collecting device.

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

In a preferred embodiment of the present invention, the concentration of the polyvinylpyrrolidone solution is 15 to 21 wt%, the concentration of the sodium alginate solution is 1 to 2 wt%, and the ratio of the polyvinylpyrrolidone solution to the sodium alginate solution is in a range from 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 solution in an amount of 0 to 30 wt% based on the total solute.

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

A composite drug-loaded fiber is prepared by adopting the preparation method based on the micro-spinning composite drug-loaded fiber, and is characterized in that: the composite drug-loaded fiber is core-shell fiber, polyvinylpyrrolidone, sodium alginate and acetaminophen are uniformly dispersed in the composite drug-loaded fiber in an amorphous state, and hydrogen bonds are formed between the composite drug-loaded fibers.

In a preferred embodiment of the 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 invention, when the concentrations of the polyvinylpyrrolidone solution and the acetaminophen are respectively in the range of 5-21 wt% and 0-30 wt%, the cumulative release percentage of the acetaminophen of the composite drug-loaded fiber is positively correlated with the concentrations of the polyvinylpyrrolidone solution and the acetaminophen.

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

(1) the invention takes polyvinylpyrrolidone as a carrier of acetaminophen, combines a microfluid spinning technology and an ionic crosslinking solidification method, and prepares the composite drug-loaded fiber with neat arrangement and uniform diameter, thereby improving the drug-loaded rate of the composite drug-loaded fiber and realizing the drug slow-release effect of the composite drug-loaded fiber.

(2) In the composite drug-loaded fiber prepared by the invention, the polyvinylpyrrolidone, the sodium alginate and the acetaminophen are combined in a physical form, hydrogen bonding effects are realized among fiber components, the acetaminophen is uniformly dispersed in the composite fiber in an amorphous state, the polyvinylpyrrolidone and the sodium alginate can effectively inhibit crystallization and precipitation of the acetaminophen, and the drug-loaded amount and the sustained-release effect of the composite drug-loaded fiber are further improved.

(3) The invention obtains the diameter, interval and uniformity of the composite drug-loaded fiber with larger drug-loading rate by adjusting the concentrations of different polyvinylpyrrolidone and sodium alginate, adjusting the ratio between the polyvinylpyrrolidone and the sodium alginate, and adjusting the output rate of the mixed spinning solution in the microfluid spinning and the rotation rate and translation rate of the collecting device, thereby obtaining the larger cumulative release percentage of the acetaminophen.

When the rotation speed of the collecting device is 50r/min, the translation speed of the collecting device is 4mm/min, the circular translation is carried out once, the flow rate of the core layer solution is 28mL/h, the flow rate of the sheath flow layer solution is 14mL/h, the weight percent of polyvinylpyrrolidone solution and 2 weight percent of sodium alginate solution are calculated according to the ratio of 1: 2 as a core layer solution and 0.1mol/L calcium chloride solution as a sheath flow layer solution, the fibers can be continuously prepared by coaxial microfluid spinning, microfibers with the length of 9.42 meters can be produced within one minute, and the production rate reaches 15.7 cm/s.

(4) The composite drug-loaded fiber prepared by micro-spinning has a large specific surface area, pores in the fiber can be used for storing drugs, the fiber can well encapsulate the drugs after solidification, brownian motion of the drugs is limited, the probability of mutual collision between drug molecules is reduced, formation of drug crystal nuclei is avoided to a certain extent, and the drug-loaded capacity and the sustained-release effect of the composite drug-loaded fiber are ensured.

The composite drug-loaded fiber prepared by micro-flow spinning does not need high temperature, does not cause decomposition or damage activity to carrier materials or drugs, does not need high-voltage spinning, and does not generate toxic liquid in the process of preparing spinning solution.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below, it is obvious that the drawings in the following description are only some embodiments described in the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts;

FIG. 1 is a flow chart of the preparation of a composite drug-loaded fiber based on micro-spinning according to the present invention;

FIG. 2 is an SEM image of PVP/SA/AAP composite fibers of different PVP solution concentrations according to a first embodiment of the invention;

FIG. 3 is an SEM image of PVP/SA/AAP composite fiber cross-sections at different PVP solution concentrations for example one of the present invention;

FIG. 4 is an SEM image of PVP/SA/AAP composite fibers of different AAP mass fractions of example two of the present invention;

FIG. 5 is a schematic diagram of a PVP/SA/AAP composite fiber according to a third embodiment of the present invention;

FIG. 6 is a chart of the infrared spectra of PVP, SA, AAP and AAP mass fractions of 0 wt%, 10 wt%, 20 wt% and 30 wt% for PVP/SA/AAP composite fibers of example four of the present invention;

FIG. 7 is an XRD plot of AAP, PVP, SA, PVP/SA composite fiber membrane and PVP/SA/AAP composite fiber membrane of example four of the present invention;

FIG. 8 is a mechanical analysis graph of PVP/SA/AAP composite fibers of example four of the present invention;

fig. 9 is a standard curve and standard curve equation for AAP of example five of the present invention in phosphate buffered solution at pH 7.4;

FIG. 10 is a graph of the in vitro release of AAP from example five of the present invention in PVP/SA/AAP composite fibers.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

As shown in fig. 1, a preparation flow chart of a composite drug-loaded fiber based on micro-spinning provided by the invention is shown. The preparation method of the composite drug-loaded fiber based on micro-spinning comprises the following steps:

a3, preparing continuous composite drug-loaded fibers by a microfluid spinning mode. Example one

Since the microfluid spinning is carried out at normal temperature and normal pressure, the spinning solution is not subjected to other external forces except the thrust of an injection pump in the whole continuous spinning process, so that the concentration of the solution is important for spinning in order to ensure the normal running of the spinning process. In order to ensure that the fiber is only swelled and insoluble in the drug release process, the ion crosslinking method is adopted to quickly solidify the fiber, and it is also important to find the proper concentrations of sodium alginate and calcium chloride. Therefore, this example is to verify the effect of different spinning solution concentrations on the formation of PVP/SA/AAP composite drug-loaded fibers.

The PVP solution and the SA solution have certain viscosities, and the solution viscosities also rise as the concentration rises. The spinning solution flow channel is narrow, so that when the solution concentration is too high, the viscosity is too high, the blockage phenomenon is easy to occur, but when the solution concentration is too low, the fiber is not easy to form, and the end breakage is easy to occur.

In order to carry out spinning experiments and ensure that fibers can not break during spinning, 5 wt%, 10 wt% and 15 wt% PVP solutions and 1 wt% and 2 wt% SA solutions are respectively prepared, and the weight ratio of the PVP solution to the SA solution is 1: 1 and 1: 2 to obtain mixed spinning solutions with different concentrations, and experimental design samples are shown in table 1. In this example, the concentration of the calcium chloride solution was selected to be 0.1 mol/L.

Table 1 experimental design samples

It was found by the above experiments that a 15 wt% PVP solution was mixed with a2 wt% SA solution in the following ratio 1: 2 as a core layer solution and 0.1mol/L calcium chloride solution as a sheath flow layer solution, and can continuously prepare fibers through coaxial microfluid spinning, and the fibers basically do not break.

When it is determined that a 15 wt% PVP solution and a2 wt% SA solution are mixed in a mass ratio of 1: 2, continuously preparing 18 wt% and 21 wt% of PVP solution after successfully preparing the composite fiber, keeping the same SA solution and mixing ratio, preparing the composite fiber by using the same coaxial microfluid spinning process parameters, and exploring the influence of the change of the concentration of the PVP solution on the fiber morphology and the influence of the PVP solution on drug release when used as a drug slow release system in the later period. The topography of the surface of the PVP/SA/AAP composite fibers at different PVP solution concentrations is shown in fig. 2, where SEM images of the PVP/SA/AAP composite fibers are shown in fig. 2a, 2b and 2c as PVP/SA/AAP composite fiber concentrations of 15 wt%, 18 wt% and 21 wt%, respectively.

From FIG. 2, it can be seen that the fiber is smoother and more mellow with the increase of PVP content, and the diameter is about 30-50 μm. Also, as the content of PVP increases, the diameter of the fiber becomes thinner. The diameters of PVP/SA/AAP composite fibers at PVP solution concentrations of 15 wt%, 18 wt% and 21 wt% were 44 μm, 39 μm and 34 μm, respectively.

The reason is that the relative content of sodium alginate is reduced along with the increase of PVP content, the shrinkage speed of gel fiber is reduced in the drying process, shrinkage gaps are reduced, the surface of the fiber becomes smoother, and meanwhile, the relative content of sodium alginate is reduced, so that the acting force between water molecules of a sodium alginate solvent is reduced, the solvent of the fiber is more fully volatilized in the drying process, and the diameter of the fiber is reduced.

The internal structure of PVP/SA/AAP composite fibers of different PVP solution concentrations is shown in FIG. 3, wherein the SEM images of the cross-section of the PVP/SA/AAP composite fibers of 15 wt%, 18 wt% and 21 wt% PVP solution concentrations are shown in FIGS. 3(a-c), 3(d-f) and 3(g-i), respectively.

From fig. 3a, fig. 3d and fig. 3g, it can be obtained that there is no obvious cavity defect inside the PVP/SA/AAP composite fiber, which indicates that PVP, SA and AAP have good compatibility and can be uniformly mixed.

From FIG. 3b, the shell-like structure of the PVP/SA/AAP composite fiber is obtained, because SA and Ca2 are present in the microchannel when the spinning solution of the core layer meets the calcium chloride solution of the sheath flow layer₊Is greater than the cure rate of PVP, a portion of the SA rapidly forms a gel on the outer surface of the fiber before the PVP component, and the fiber surface has a gel shell layer which facilitates encapsulation of the drug.

From fig. 3e and fig. 3h, the gel shell of the composite fiber becomes thinner and thinner as the concentration of the PVP solution increases, and Ca2 can be separated because the relative content of SA decreases as the content of PVP increases₊The content of the gel layer formed by combination is also reduced, so that the gel shell layer on the surface of the fiber becomes thinner along with the increase of the concentration of the PVP solution. From fig. 3c, 3f and 3i, it can be seen that there is a tiny pore structure inside the composite fiber, which facilitates the loading and release of the drug, and the pore size inside the fiber is more as the concentration of the PVP solution increases.

Example two

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. Fixing the conductive adhesive on an electric microscope stage, then adhering a plurality of PVP/SA/AAP composite fibers prepared above on the conductive adhesive, spraying gold for 90s, and observing the surface topography characteristics of the fibers by adopting an R-8100 cold field scanning electron microscope. The test conditions were a voltage of 3kV and a voltage of 10 mA. And (3) brittle-breaking the composite fiber by using liquid nitrogen, and observing the section morphology characteristics of the fiber by adopting the same test method and test conditions.

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

From fig. 4, the PVP/SA/AAP composite fibers with different AAP mass fractions still have smooth and continuous surfaces and no obvious block or crystalline substances are precipitated, which indicates that the acetaminophen is uniformly dispersed in the composite fibers. The diameter of the fiber changes slightly with the increase of the AAP mass fraction, which indicates that the addition of the model drug has little influence on the fiber diameter.

EXAMPLE III

In the preparation method, the microfluid spinning process parameters have certain influence on fiber forming. Therefore, this example was conducted to investigate the effect of the microfluid spinning process parameters on fiber formation.

The microfluid spinning machine mainly comprises a microfluid injection pump and a fiber receiving platform. The first part of the microfluidic injection pump is used for controlling the output speed and the output quantity of the spinning solution, and mainly comprises: a double-channel injection pump, an injector, a polytetrafluoroethylene tube and a coaxial needle. The second part of the fiber receiving platform is used for receiving fibers and mainly comprises a roller receiver, a rotating motor, a circulating stepping translation platform, a heater and a control panel. Wherein the two-channel injection pump can respectively and independently control the two injectors, different propelling speeds are set, and all parts of the microfluid spinning device are connected with a connector by polytetrafluoroethylene tubes.

The roller receiver on the microfluid spinning machine generates traction force through continuous rotation, so that the spinning solution can be stretched into a fiber shape on one hand, and the fiber solidified through ionic crosslinking can be received on the other hand, so that the traction force is provided, and the fiber becomes more ordered. The rotational speed of the drum receiver is determined by the rotational speed of the rotating motor, which affects the diameter of the fiber.

When the rotating speed is too low, the receiver can not draw out fibers from the needle rapidly, the fibers cannot be formed, and when the rotating speed is too high, the traction force provided by the receiver is too large, the fibers can be broken, and the number of broken fibers is large. In order to obtain the fiber membranes which are orderly arranged and have uniform diameters, the later-stage drug release experiment is facilitated, the receiver circularly moves at a certain translation speed, and the fiber membranes which are orderly and uniformly spaced can be collected on the roller. The speed of translation and the number of cycles of the receiver directly affect the size of the inter-fiber spacing and the density of the fiber film.

The output speed of the spinning solution is controlled by the propelling speed of the injection pump, and the fibers which are well formed and uniformly distributed can be obtained only by finding the proper flow rates of the core layer solution and the sheath flow layer solution.

Thus, the microfluid spinning machine of this embodiment affects the diameter, spacing and uniformity of the fibers by the output rate of the mixed spin fluid determined by the syringe pump, the rotational speed of the motor on the fiber receiving platform, and the cyclic step translation rate. In the embodiment, the composite fiber membrane which is orderly arranged, uniform in diameter and adjustable in size can be obtained through the optimized setting of the three process parameters. The experimental protocol of table 2 was designed according to the three process parameters described above.

TABLE 2 Experimental protocols

As can be seen from Table 2, when the rotational speed of the drum receiver was 50r/min, the translation speed of the receiver was 4mm/min, the cyclic translation was performed once, the flow rate of the core layer solution was 28mL/h, and the flow rate of the sheath layer solution was 14mL/h, well-formed fibers could be obtained, and fibers could be continuously prepared.

The experimental protocol of this example was combined with the experimental method of the first example, when the rotational speed of the drum receiver was 50r/min, the translation speed of the receiver was 4mm/min, the cyclic translation was performed once, the flow rate of the core layer solution was 28mL/h, the flow rate of the sheath flow layer solution was 14mL/h, and the ratio of 15 wt% PVP solution to 2 wt% SA solution was determined according to a 1: 2 as a core layer solution and 0.1mol/L calcium chloride solution as a sheath flow layer solution, the fibers can be continuously prepared by coaxial microfluid spinning, microfibers with the length of 9.42 meters can be produced within one minute, and the production rate reaches 15.7 cm/s.

Meanwhile, after AAP accounting for 10 wt%, 20 wt% and 30 wt% of the total solute is added into the core layer spinning solution, the fiber can still be continuously prepared. Fig. 5 is a diagram of a fiber object obtained by optimizing the experimental scheme according to the first embodiment and the second embodiment, and it can be seen that the fiber formation is good, and a fiber array and a fiber membrane can be further prepared.

Example four

In the embodiment, the PVP/SA/AAP composite drug-loaded fiber prepared in the above embodiment is subjected to morphology characterization.

(1) PVP/SA/AAP composite fiber Fourier Infrared Spectroscopy (FITR) test

FIG. 6 is an infrared spectrum of PVP/SA/AAP composite fibers having mass fractions of PVP, SA, AAP, and AAP of 0 wt%, 10 wt%, 20 wt%, and 30 wt%.

FIG. 6a shows that the PVP sample appeared at 3446cm^-1、2956cm^-1、1661cm^-1And 1290cm^-1The absorption peaks at (B) correspond to stretching vibrations of-CH, -CH-CH2, -C ═ O and-CN, 1423cm^-1Corresponds to deformation vibration of-CH of the circulating CH2 group in PVP. As shown in FIG. 6b, the SA sample appeared at 3423cm^-1、2925cm^-1、1606cm^-1、1405cm^-1And 1025cm^-1The absorption peaks at (a) correspond to stretching vibrations of-OH, -CH, -COO, -C ═ O and-C-O-C-groups, respectively. FIG. 6c shows that the AAP sample appears at 3320cm^-1、1650cm^-1The absorption peaks at (b) correspond to stretching vibration of-OH and-C ═ O on the amide bond, respectively.

Fig. 6(e-g) shows that the infrared spectra of PVP/SA/AAP composite fibers with different drug loadings all show characteristic absorption peaks of PVP, SA and AAP, and no new characteristic absorption peak appears, which indicates that the model drugs AAP, PVP and SA are physically blended, and the physicochemical properties of the drugs are not changed, and the drug action is not affected.At the same time, with the increase of the AAP content, 1650cm^-1the-C ═ O characteristic absorption peak intensity on the amido bond is gradually weakened, and hydrogen bonds are probably generated among the acetaminophen, the PVP and the SA.

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

If the drug is crystallized, the stability, bioavailability and therapeutic effect of the drug are affected, so that the crystallization of the drug is prevented when a drug sustained-release system is prepared. The process of drug crystallization in a polymer matrix is largely divided into two stages, the first stage being nucleation and the second stage being nucleation. In the first stage, the drugs collide with each other by random "brownian motion" to form "dimers", and then these "dimers" collide with each other to form nuclei. As more and more "dimers" of the drug come together, the nucleation phase is entered. It takes a certain time for the drug to crystallize and then to precipitate from the polymer.

The prepared PVP/SA/AAP composite fiber membrane carrying the medicine is stored at room temperature for 3 months, the distribution state of AAP in the PVP/SA/AAP composite fiber membrane, AAP and PVP and SA in the polymer matrix are detected by X-ray diffraction after 3 months, and figure 7 is an XRD curve chart of the AAP, the PVP, the SA, the PVP/SA composite fiber membrane and the PVP/SA/AAP composite fiber membrane.

As can be seen from fig. 7a, acetaminophen (AAP) prodrug exhibits typical characteristic diffraction peaks at 12.04 °, 13.76 °, 15.4 °, 16.66 °, 18.12 °, 20.3 °, 23.38 °, 24.32 °, 26.5 °, 29 °, 22 °, and 32.44 °.

However, in fig. 7e, it can be seen that no characteristic diffraction peak of AAP drug is observed in the PVP/SA/AAP composite fiber membrane carrying drugs, and only characteristic diffraction peaks of PVP and SA in the polymer matrix are observed, which indicates that AAP is distributed in the drug-carrying composite fiber in an amorphous state, and also indicates that the PVP/SA composite fiber can effectively inhibit crystallization of AAP. The fiber prepared by micro-spinning has a large specific surface area, pores in the fiber can be used for storing the medicine, the fiber can well encapsulate the medicine after being solidified, the Brownian motion of the medicine is limited, the probability of mutual collision among medicine molecules is reduced, and the formation of medicine crystal nuclei is avoided to a certain extent. And in infrared spectroscopic analysis, hydrogen bonds can be formed between the obtained AAP and PVP and SA, so that the crystallization of the medicament is further inhibited.

(3) Mechanical property test of PVP/SA/AAP composite fiber

This example performed mechanical property analysis on the PVP/SA/AAP composite fiber prepared as described above, as shown in fig. 8. Preparing samples of the fibers according to the gauge length of 200mm, testing the breaking strength of the composite fibers by using an Instron5967 material testing machine, testing each sample for 30 times, and taking an average value as a test result when the nerve pulling speed is 20 mm/min.

Wherein FIG. 8a is a bar graph of breaking strength for PVP/SA/AAP composite fibers having PVP mass fractions of 15 wt%, 18 wt% and 21 wt%, respectively; FIG. 8b is a stress-strain plot of composite fibers of different PVP mass fractions; FIG. 8c is a bar graph of the breaking strength of PVP/SA/AAP composite fibers with different drug loading; figure 8d is a stress-strain plot of PSA fibers at different drug loadings.

From FIG. 8a, it can be obtained that the breaking strength of PVP/SA/AAP composite fiber with 15 wt%, 18 wt% and 21 wt% PVP mass fraction is 39.14 + -5.31 MPa, 44.48 + -5.5 MPa and 59.08 + -5.31 MPa respectively. With the increase of the content of PVP, the breaking strength of the composite fiber is increased, because with the increase of the content of PVP, hydrogen bonds between PVP and SA are increased on one hand, and hydrogen bonds in PVP molecules are increased on the other hand, so that the breaking strength of the composite fiber is improved.

The PVP/SA/AAP composite fiber obtained from FIG. 8b is a flexible fiber, and the elongation at break of the fiber is basically over 20%, and the elongation at break of the fiber is slightly increased along with the increase of the content of PVP.

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

It can be seen from fig. 8d that, with the addition of small drug molecules, the slippage of macromolecular chains in the fiber is increased, and the elongation at break of the composite fiber is slightly increased, but after the AAP content is increased, the elongation at break of the composite fiber is slightly decreased due to the increase of intermolecular forces among fiber components.

EXAMPLE five

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

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

Weighing a PVP/SA/AAP composite fiber membrane, placing the PVP/SA/AAP composite fiber membrane in a PBS buffer solution, mixing the PVP/SA/AAP composite fiber membrane in 2h, 4h, 6h, 8h, 10h, 12h, 24h, 26h, 28h, 30h, 32h, 34h, 36h, 48h, 50h, 52h, 54h, 56h, 58h, 60h and 72h respectively, then diluting, measuring the ultraviolet absorbance of the PVP/SA/AAP composite fiber membrane at 245nm, adding an equal amount of the PBS buffer solution into a slow release system, keeping the solution capacity constant, and taking three parallel samples of each drug-loaded fiber.

The AAP content was calculated according to the standard curve equation for AAP, and the cumulative percent AAP release was calculated according to the following formula and the in vitro release curve of PVP/SA/AAP conjugate fiber was plotted. The formula is as follows:

wherein Q is the cumulative percent of AAP released, v is the volume of the sustained release solution PBS, v is_dVolume of PBS after dilution, c_iThe concentration (mug/mL) of the drug in the release solution during the ith sampling is shown, A is the mass (mug) of the AAP contained in the composite drug-loaded fiber, and n is the sampling frequency.

FIG. 10 is a graph of AAP release in vitro from PVP/SA/AAP composite fibers. As can be seen from FIG. 10a, as the PVP content was increased, the cumulative percent release of the PVP/SA/AAP composite fiber also increased. The reason is that the gel shell layer of the fiber is thinned with the increase of the content of the PVP, the obstruction of the release of the model drug AAP from the fiber is reduced, and the PVP is a water-soluble high polymer, the probability of degrading the PVP/SA/AAP composite fiber framework is increased along with the thinning of the fiber shell layer, the release path of the AAP is increased, and the cumulative release percentage of the AAP is increased. And with the increase of the content of PVP, the diameter of the fiber is thinned, the specific surface area of the fiber is increased, the drug loading rate on the surface of the fiber is increased, the drug in the fiber is more easily dispersed into the PBS buffer solution, and the cumulative release rate of the drug is increased. Meanwhile, the three PVP/SA/AAP composite fibers are released in the first 12 hours and approximate to linear release, and the release rate after 12 hours is slow and approximate to uniform release. This is because when the AAP on the surface layer of the fiber is released, the remaining AAP can only diffuse from the inside to the outside of the fiber and then be released, and the release rate is slowed down.

FIGS. 10b, 10c, and 10d are release profiles for different drug loadings of PVP/SA/AAP composite fibers with 15 wt% PVP, 18 wt% PVP, and 21 wt% PVP content, respectively.

As can be seen from the figure, as the drug loading increased, the cumulative percent release of the fibers also increased. The 15 wt% PVP, 18 wt% PVP and 21 wt% PVP contents were obtained from tables 3, 4 and 5, the cumulative release percentages at the first 12h for PVP/SA/AAP composite fibres having an AAP content of 10 wt% were 45.74%, 59.86% and 70.43%, respectively. The cumulative percent release of PVP/SA/AAP composite fibers having an AAP content of 20 wt% was 54.57%, 72.69% and 78.12%. The cumulative release percentage of the PSA composite fiber having an AAP content of 30 wt% was 61.11%, 80%, and 89.72%. This is because the more the content of AAP is, the more the drug is dispersed on the surface of the fiber and is released more easily in the first 12 hours. The cumulative release percentage of PVP/SA/AAP composite fiber with an AAP content of 10 wt% after 72h was 63.54%, 71.85% and 79.13%; the cumulative percent release of PVP/SA/AAP composite fiber with an AAP content of 20 wt% was 70.56%, 81.92% and 86.96%; the cumulative percent release of PVP/SA/AAP composite fibers having an AAP content of 30 wt% was 80.85%, 89.99% and 97.35%. This is because AAP has poor water solubility and the drug embedded in the fiber is not easily released, so that the release rate is slowed, and hydrogen bonds are formed between AAP and PVP, thereby inhibiting crystallization of AAP. When the content of AAP is increased, the hydrogen bonds generated reach a saturated amount due to the constant content of PVP, so that excessive AAP can be crystallized and separated on the surface of the fiber and dissolved in PBS under the washing of PBS phosphate buffer solution, and the cumulative drug release percentage of the drug is increased.

TABLE 315 wt% PVP cumulative release rate of AAP in PVP/SA/AAP composite fibers

TABLE 418 wt% PVP cumulative release rate of AAP in PVP/SA/AAP composite fibers

TABLE 521 wt% PVP cumulative release rate of AAP in PVP/SA/AAP composite fibers

In order to explore the drug release mechanism of the PVP/SA/AAP composite fiber, a drug release curve chart of the PVP/SA/AAP composite fiber is fitted through 5 drug release kinetic models, and a suitable model is evaluated according to a correlation coefficient R2. Zero order release means that the drug release rate does not change over time, i.e. the release rate of the drug remains constant over the release period.

First order release means that the release rate is proportional to the drug concentration per unit time. It is generally accepted that zero order release is the desired controlled release profile for extravascular administration and that first order release is the basal release profile. The matrix type drug sustained-release system is generally divided into a monolithic matrix system, a swelling matrix system and an erosion matrix system. The Weibull model indicates that the release rate of a drug is directly proportional to the diffusion coefficient, and the release mechanism is generally diffusion or matrix erosion. The Higuchi model is generally applicable to a monolithic framework system, which means that a drug diffuses through a polymer molecular network and pores in the framework system, and the polymer degradation rate is generally far less than the diffusion rate of the drug.

The Ritger-Peppas model is generally applicable to swelling type skeleton systems, and the drug release mechanism is judged according to the slope of a fitting curve. When the slope is less than or equal to 0.43, the release mechanism of the drug is Fickian diffusion; when 0.43< slope <0.89, the release mechanism of the drug is non Fickian diffusion; when the slope is 0.89, the release mechanism of the drug is degradation of the matrix.

Tables 6, 7 and 8 are fits of the drug release kinetic models of the PVP/SA/AAP composite fiber release profiles with PVP contents of 15 wt%, 18 wt% and 21 wt%, respectively. The drug release kinetics models of the PVP/SA/AAP composite fiber release profiles with 15 wt%, 18 wt% and 21 wt% PVP content, evaluated according to the correlation coefficient R2, are in good agreement with the Weibull model and the Ritger-Peppas model. The drug release model of the PVP/SA/AAP composite fiber with 15 wt% of PVP content is more consistent with the Ritger-Peppas model, the slope of the fitting equation is 0.20322 and is less than 0.43, and the drug release mechanism of the PVP/SA/AAP composite fiber with 15 wt% of PVP content is closer to Fickian diffusion. The release models of the PVP/SA/AAP composite fiber with 18 wt% and 21 wt% PVP contents are more consistent with the Weibull model, which shows that the release mechanism of the PVP/SA/AAP composite fiber is mainly the diffusion and skeleton erosion of the drug. Comprehensively shows that the drug is released from the PVP/SA/AAP composite fiber and mainly undergoes two stages, the first stage is that the fiber framework is swelled, the drug outside the fiber is diffused out through Fickian, and the release rate of the drug is faster; the second stage is degradation of the fibrous skeleton, diffusion of the drug from the inside of the fiber, and a slow release rate of the drug.

TABLE 6 PVP/SA/AAP composite fiber with 15 wt% PVP release profile pharmacokinetic model fitting

TABLE 7 PVP/SA/AAP composite fiber with 18 wt% PVP release profile pharmacokinetic model fitting

TABLE 8 PVP/SA/AAP composite fiber with 21 wt% PVP release profile pharmacokinetic model fitting

In light of the foregoing description of the preferred embodiment of the present invention, it is to be understood that various changes and modifications may be made by one skilled in the art without departing from the spirit and scope of the invention. The technical scope of the present invention is not limited to the content of the specification, and must be determined according to the scope of the claims.

Claims

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

2. The preparation method of the micro-spinning-based composite drug-loaded fiber according to claim 1, characterized in that: the mixed spinning solution is used as a core layer, the calcium chloride solution is used as a sheath flow laminar flow, the mixed spinning solution and the calcium chloride solution are coaxially sprayed out of fibers at different flow rates, and the fibers are continuously and rotatably drawn to form continuous fibers under the action of the rotary traction force of a collecting device; the composite drug-loaded fiber is prepared and formed by setting the translation rate and the cycle number of the collecting device.

3. The preparation method of the micro-spinning-based composite drug-loaded fiber according to claim 1, characterized in that: the concentration of the polyvinylpyrrolidone solution is 5-15 wt%, the concentration of the sodium alginate solution is 1-2 wt%, and the polyvinylpyrrolidone solution and the sodium alginate solution are mixed according to the ratio of 1: 1-2.

4. The preparation method of the micro-spinning-based composite drug-loaded fiber according to claim 1, characterized in that: the concentration of the polyvinylpyrrolidone solution is 15-21 wt%, the concentration of the sodium alginate solution is 1-2 wt%, and the polyvinylpyrrolidone solution and the sodium alginate solution are mixed according to the ratio of 1: 1-2.

5. The preparation method of the micro-spinning-based composite drug-loaded fiber according to claim 2, characterized in that: the concentration of the calcium chloride solution is 0.1-0.2 mol/L.

6. The preparation method of the micro-spinning-based composite drug-loaded fiber according to claim 1, characterized in that: and adding the acetaminophen accounting for 0-30 wt% of the total solute into the mixed spinning solution.

7. The preparation method of the micro-spinning-based composite drug-loaded fiber according to claim 2, characterized in that: the rotation speed of the collecting device is 30-50 r/min, the translation speed of the collecting device is 3-5 mm/min, the circular translation is performed once, the flow rate of the core layer solution is 16-28 mL/h, and the flow rate of the sheath flow layer solution is 8-14 mL/h.

8. The composite drug-loaded fiber is prepared by the preparation method based on the micro-spinning composite drug-loaded fiber according to any one of claims 1 to 7, and is characterized in that:

the composite drug-loaded fiber is core-shell fiber, polyvinylpyrrolidone, sodium alginate and acetaminophen are uniformly dispersed in the composite drug-loaded fiber in an amorphous state, and hydrogen bonds are formed between the composite drug-loaded fibers.

9. The composite drug-loaded fiber of claim 8, wherein: the breaking strength of the composite drug-loaded fiber is positively correlated with the concentrations of the polyvinylpyrrolidone and the acetaminophen.

10. The composite drug-loaded fiber of claim 8, wherein: when the concentrations of the polyvinylpyrrolidone solution and the acetaminophen are respectively in the ranges of 5-21 wt% and 0-30 wt%, the accumulative release percentage of the acetaminophen of the composite drug-loaded fiber is positively correlated with the concentrations of the polyvinylpyrrolidone solution and the acetaminophen.