CN114351287B - Preparation method of composite drug-loaded fiber based on micro-fluid spinning - Google Patents
Preparation method of composite drug-loaded fiber based on micro-fluid spinning Download PDFInfo
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Abstract
The invention discloses a preparation method of a composite drug-loaded fiber based on micro-fluid 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 then adding acetaminophen to form a mixed spinning solution; a3, preparing continuous composite drug-carrying fibers by taking the mixed spinning solution as a core layer, taking the calcium chloride solution as a sheath flow laminar flow and adopting a coaxial microfluid spinning mode. The composite drug-carrying fiber with uniform diameter is prepared by combining a microfluid spinning technology and an ion crosslinking curing method, so that the drug-carrying capacity of the composite drug-carrying fiber is improved, and the drug slow-release effect of the composite drug-carrying fiber is realized.
Description
Technical Field
The invention relates to a composite medicine carrying fiber, in particular to a preparation method of a composite medicine carrying fiber based on micro-fluid spinning.
Background
In the sustained and controlled release systems of drugs, carrier materials are one of the important components. The carrier material affects the release rate of the drug and different drug release kinetics are possible with different carrier materials for loading the drug. Generally, a proper carrier material has the basic characteristics of good biocompatibility, no toxicity or harm to human, easy release of medicine, stable drug effect and the like.
Commonly used carrier materials include biodegradable or non-biodegradable polymeric materials, as well as natural polymeric materials. Common carrier materials are 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 high molecular compound, has excellent solubility and biocompatibility, and simultaneously has excellent physiological inertia, does not participate in metabolism of a human body, and is nontoxic and harmless. In recent decades, more and more researchers have increased their research, and PVP has been used in a wider range of applications.
The traditional method for preparing the drug release 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 dry spinning method is used for preparing PCL fibers, and GNP particles are loaded on the fibers, so that a protein drug system capable of being carried and released is created. The prior art utilizes an improved wet spinning technology to prepare polyacrylonitrile PAN fibers loaded with tamoxifen citrate TAM. In the prior art, the drug-loaded nano composite fiber with the glyceryl monostearate thin layer as a shell layer and the berberine hydrochloride and ethyl cellulose as core layers 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 be not easily degraded, possibly damaging the activity of the drug; the coagulating bath required by wet spinning is generally toxic liquid, which is harmful to human body and needs to be removed later, and the activity of drug molecules can be destroyed; electrospinning generally requires high voltages to spin, and the solvents required to prepare the dope are sometimes toxic liquids, which are harmful to the body.
There is therefore a need to propose a process for the preparation of fibres which is simpler to operate, which can alleviate the drawbacks of the traditional preparation processes and which can preserve the advantages of the drug delivery system.
Disclosure of Invention
The invention overcomes the defects of the prior art and provides a preparation method of a composite drug-carrying fiber based on micro-fluid spinning. In order to achieve the above purpose, the invention adopts the following technical scheme: 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 then adding acetaminophen to form a mixed spinning solution;
a3, preparing the continuous composite drug-carrying fiber by a micro-fluid spinning mode.
In a preferred embodiment of the invention, the mixed spinning solution is taken as a core layer, the calcium chloride solution is taken as a sheath flow laminar flow, the mixed spinning solution and the calcium chloride solution are coaxially sprayed out of the fiber at different flow rates, and the fiber is continuously rotated and drawn out to form continuous fiber under the action of the rotation traction force of the collecting device; and preparing and forming the composite drug-carrying fiber by setting the translation rate and the circulation times of the collecting device.
In a preferred embodiment of the present invention, 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 according to the following weight ratio of 1:1 to 2.
In a preferred embodiment of the present invention, 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 according to the following weight ratio 1:1 to 2.
In a preferred embodiment of the present invention, the concentration of the calcium chloride solution is 0.1 to 0.2mol/L.
In a preferred embodiment of the present invention, the acetaminophen is added to the mixed spinning solution in an amount of 0-30 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 circulating 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.
The composite medicine carrying fiber is prepared by adopting the preparation method based on the micro-fluid spinning composite medicine carrying fiber, and 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.
In a preferred embodiment of the present invention, the breaking strength of the composite drug-loaded fiber is positively correlated with the concentration of the polyvinylpyrrolidone and the acetaminophen.
In a preferred embodiment of the present invention, the cumulative percentage of acetaminophen released from the composite drug-loaded fiber is positively correlated with the concentrations of polyvinylpyrrolidone solution and acetaminophen when the concentrations of polyvinylpyrrolidone solution and acetaminophen are in the range of 5-21 wt% and 0-30 wt%, respectively.
The invention solves the defects existing in the background technology, and has the following beneficial effects:
(1) The invention uses polyvinylpyrrolidone as the carrier of acetaminophen, combines the micro-fluid spinning technology and the ion crosslinking curing method to prepare the composite drug-carrying fiber which is orderly arranged and uniform in diameter, improves the drug-carrying capacity of the composite drug-carrying fiber and realizes the drug slow-release effect of the composite drug-carrying fiber.
(2) The polyvinylpyrrolidone, sodium alginate and acetaminophen in the composite drug-carrying fiber prepared by the invention are combined in a physical form, the fiber components have hydrogen bond effect, and the acetaminophen is uniformly dispersed in the composite fiber in an amorphous state, so that the polyvinylpyrrolidone and the sodium alginate can effectively inhibit the crystallization precipitation of the acetaminophen, and the drug-carrying capacity and the sustained release effect of the composite drug-carrying fiber are further improved.
(3) According to the invention, the diameters, intervals and uniformity of the composite drug-carrying fibers with larger drug-carrying capacity are obtained by adjusting the concentrations of different polyvinylpyrrolidone and sodium alginate, adjusting the proportion between polyvinylpyrrolidone and sodium alginate, adjusting the output rate of the mixed spinning solution in micro-fluid spinning and the rotation rate and the translation rate of the collecting device, so that the larger cumulative release percentage of acetaminophen is obtained.
According to the invention, when 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, the flow rate of the sheath flow layer solution is 14mL/h, and the weight percent of polyvinylpyrrolidone solution and the weight percent of sodium alginate solution are 1:2 as core layer solution and 0.1mol/L calcium chloride solution as sheath flow layer solution, can continuously prepare fiber through coaxial micro-fluid spinning, can produce micro-fiber with the length of 9.42 m in one minute, and has the productivity of 15.7cm/s.
(4) The composite medicine carrying fiber prepared by utilizing the micro-fluid spinning has larger specific surface area, and meanwhile, the inside of the fiber is also provided with pores for storing medicines, so that the fiber can well encapsulate medicines after solidification, the Brownian movement of the medicines is also limited, the probability of mutual collision among medicine molecules is reduced, the formation of medicine crystal nucleus is avoided to a certain extent, and the medicine carrying capacity and the sustained-release effect of the composite medicine carrying fiber are ensured.
The composite medicine carrying fiber prepared by utilizing the micro-fluid spinning does not need to use high temperature, does not decompose or destroy activity on a carrier material or medicine, does not need to use 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 that are required to be used in the embodiments or the description of the prior art will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments described in the present invention, and other drawings can be obtained according to these drawings without inventive effort for a person skilled in the art;
FIG. 1 is a flow chart of a 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 example one of the present invention at various PVP solution concentrations;
FIG. 3 is an SEM image of a cross-section of PVP/SA/AAP composite fiber of example one of the invention at various PVP solution concentrations;
FIG. 4 is an SEM image of PVP/SA/AAP composite fibers of example two of the invention with different AAP mass fractions;
FIG. 5 is a physical drawing of PVP/SA/AAP composite fiber according to the third embodiment of the invention;
FIG. 6 is an infrared spectrum of PVP/SA/AAP composite fibers with mass fractions of 0wt%, 10wt%, 20wt% and 30wt% for PVP, SA, AAP and AAP of example four of the present invention;
FIG. 7 is an XRD plot of AAP, PVP, SA, PVP/SA composite fiber membranes and PVP/SA/AAP composite fiber membranes of example four of the invention;
FIG. 8 is a graph of mechanical analysis of PVP/SA/AAP composite fibers according to 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 saline at ph=7.4;
fig. 10 is an in vitro release profile of AAP in PVP/SA/AAP composite fiber according to example five of the invention.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
As shown in fig. 1, a preparation flow chart of the composite drug-loaded fiber based on micro-fluid spinning is shown. The preparation method of the composite drug-loaded fiber based on micro-fluid spinning 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 then adding acetaminophen to form a mixed spinning solution;
a3, preparing the continuous composite drug-carrying fiber by a micro-fluid spinning mode. Example 1
Since the micro-fluid spinning is carried out at normal temperature and normal pressure, the spinning solution is not subjected to other external forces except the thrust of the injection pump in the whole continuous spinning process, so that the concentration of the solution is important to spinning in order to ensure the normal running of the spinning process. In order to ensure that the fiber only swells and is not dissolved in the drug release process, the ionic crosslinking method is adopted to rapidly solidify the fiber, and the proper concentration of sodium alginate and calcium chloride is also important to be found. Therefore, in order to verify the molding influence of different spinning solution concentrations on PVP/SA/AAP composite drug-carrying fibers, the embodiment is provided.
The PVP solution and the SA solution have certain viscosity, and the viscosity of the solution can be increased along with the increase of the concentration. Because the spinning flow channel is relatively thin and narrow, when the concentration of the solution is too high, the viscosity is too high, so that the blocking phenomenon is very easy to occur, but when the concentration of the solution is too low, the fiber is not easy to form, and the breakage of the head is easy to occur.
To enable spinning experiments, ensure that the fiber does not break during spinning, 5wt%, 10wt% and 15wt% PVP solutions, and 1wt% and 2wt% SA solutions were respectively provided, and according to 1:1 and 1:2 to obtain mixed spinning solutions with different concentrations, and experimental design samples are shown in table 1. Wherein, the concentration of the calcium chloride solution in the embodiment is selected to be 0.1mol/L.
Table 1 experimental design samples
It was found by the above experiments that a 15wt% PVP solution was mixed with a 2wt% SA solution according to 1:2 as core layer solution and 0.1mol/L calcium chloride solution as sheath flow layer solution, and can continuously prepare fiber through coaxial microfluid spinning without breaking the fiber.
When 15wt% PVP solution and 2wt% SA solution were determined in mass ratio 1:2, after successfully preparing the composite fiber, continuously preparing 18wt% and 21wt% PVP solution, keeping the same SA solution and mixing proportion, preparing the composite fiber by using the same coaxial microfluid spinning process parameters, and exploring the influence of the change of PVP solution concentration on the fiber morphology and the influence of the change of PVP solution concentration on the drug release when the composite fiber is used as a drug slow-release system in the later period. The morphology of the PVP/SA/AAP composite fiber surface at different PVP solution concentrations is shown in FIG. 2, where SEM images of PVP/SA/AAP composite fibers at 15wt%,18wt% and 21wt% PVP solution concentrations are shown in FIGS. 2a, 2b and 2c, respectively.
From FIG. 2, it was found that the fibers were smoother and more round with increasing PVP content, and had diameters of about 30 to 50. Mu.m. And the diameter of the fiber becomes finer as the PVP content increases. The PVP/SA/AAP conjugate fibers at concentrations of 15wt%,18wt% and 21wt% PVP solution were 44 μm, 39 μm and 34 μm, respectively.
The reason is that along with the increase of PVP content, the relative content of sodium alginate reduces, and the shrinkage speed of gel fiber slows down in the drying process, and the shrinkage space reduces, and the fiber surface becomes smoother, and the reduction of sodium alginate relative content has reduced the effort between sodium alginate solvent hydrone simultaneously, lets the fiber in the drying process solvent volatilize more abundant, and the fiber diameter becomes thin.
The internal structure of PVP/SA/AAP composite fibers at different PVP solution concentrations is shown in FIG. 3, wherein FIGS. 3 (a-c), 3 (d-f), 3 (g-i) show SEM images of sections of PVP/SA/AAP composite fibers at 15wt%,18wt% and 21wt% PVP solution concentrations, respectively.
From fig. 3a, 3d and 3g, no obvious cavity defect inside the PVP/SA/AAP composite fiber can be obtained, which indicates that PVP, SA and AAP have good compatibility and can be uniformly mixed.
From fig. 3b, the outer appearance of the PVP/SA/AAP composite fiber is obtained as a shell-like structure,this is because SA and Ca2 are present in the micro-channel when the spinning solution of the core layer meets the calcium chloride solution of the sheath flow layer + The rate of cross-linking of (a) is greater than the rate of solidification of PVP, so that a portion of the SA rapidly forms a gel on the outer surface of the fiber prior to the PVP component, and the fiber surface has a gel shell layer, which facilitates encapsulation of the drug.
Meanwhile, as the concentration of PVP solution increases, the gel shell layer of the composite fiber is thinner and thinner, and the relative content of SA is reduced with the increase of PVP content, so that the composite fiber can be separated from Ca2 + The content of the bound gel layer also decreases, so the gel shell layer on the fiber surface becomes thinner as the concentration of PVP solution increases. From fig. 3c, 3f and 3i it can be seen that the composite fiber has a micro pore size structure inside, which facilitates loading and release of the drug, and that the more pore size inside the fiber as the PVP solution concentration increases.
Example two
The present example explores the effect of different AAP mass fractions on the morphology of the composite fibers. SEM images of drug loaded PVP/SA/AAP composite fibers with different AAP mass fractions. Fixing conductive adhesive on an electronic microscope table, then taking a plurality of PVP/SA/AAP composite fibers prepared by the method to be adhered on the conductive adhesive, spraying metal for 90s, and observing the surface morphology features of the fibers by adopting an R-8100 cold field scanning electron microscope. The test condition is a voltage of 3kV and a voltage of 10mA. And (3) brittle fracture of the composite fiber by liquid nitrogen, and observing the cross-sectional morphology characteristics of the fiber by adopting the same test method and test conditions.
As shown in fig. 4, in which fig. 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 fig. 4, the surface of PVP/SA/AAP composite fibers of different AAP mass fractions remained relatively smooth and continuous, without significant massive or crystalline material precipitation, indicating a uniform dispersion of acetaminophen in the composite fibers. As the AAP mass fraction increases, the fiber diameter slightly changes, indicating that the addition of model drug has little effect on fiber diameter.
Example III
In the preparation method, the micro-fluid spinning process parameters have a certain influence on fiber forming. Therefore, this example was designed to investigate the effect of microfluidic spinning process parameters on fiber formation.
The microfluidic spinning machine mainly comprises two parts of a microfluidic injection pump and a fiber receiving platform. The first part of microfluidic injection pump is used for controlling the output speed and output quantity of the spinning solution and mainly comprises: a dual channel syringe pump, a syringe, a polytetrafluoroethylene tube and a coaxial needle. The second part of fiber receiving platform is used for receiving the fibers and mainly comprises a roller receiver, a rotary motor, a circulating stepping translation platform, a heater and a control panel. Wherein the two-channel injection pump can respectively and independently control two injectors, different propelling speeds are set, and all parts of the micro-fluid spinning device are connected by a polytetrafluoroethylene tube and a connector.
The roller receiver on the micro-fluid spinning machine can generate traction force through continuous rotation, so that on one hand, the spinning solution can be stretched into fiber shape, on the other hand, the fiber solidified through ionic crosslinking can be received, and the traction force is provided, so that the fiber becomes more ordered. The rotational speed of the drum receiver is determined by the rotational speed of the rotating motor, so the rotational speed of the rotating motor affects the diameter of the fibers.
When the rotating speed is too low, the receiver cannot rapidly draft out the fibers from the needle head, the fibers cannot be molded, 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 relatively large. In order to obtain the fiber membranes which are orderly arranged and uniform in diameter, the device is beneficial to later drug release experiments, and the receiver can circularly move at a certain translation speed, so that the orderly and uniformly spaced fiber membranes can be collected on the roller. The translational speed and number of cycles of the receiver directly affect the size of the inter-fiber spacing and the density of the fiber membranes.
The output speed of the spinning solution is controlled by the advancing speed of the injection pump, and proper flow rates of the core layer solution and the sheath flow layer solution are needed to be found, so that the fiber with good molding and uniform arrangement can be obtained.
Thus, the micro-fluid spinning machine in this embodiment influences the diameter, spacing, and uniformity of the fibers by the output rate of the mixed dope, the rotation rate of the motor on the fiber receiving platform, and the cyclic step-by-step translation rate determined by the syringe pump. According to 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 protocol
As shown in Table 2, when the rotation speed of the drum receiver was 50r/min, the translation speed of the receiver was 4mm/min, the circulation 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, a fiber having good formation was obtained, and the fiber was continuously produced.
The experimental scheme of this embodiment is obtained by combining the experimental method of the first embodiment, when the rotation speed of the roller receiver is 50r/min, the translation speed of the receiver is 4mm/min, the cyclic translation is performed once, the flow rate of the core layer solution is 28mL/h, the flow rate of the sheath layer solution is 14mL/h, and the ratio of 15wt% PVP solution to 2wt% SA solution is 1:2 as core layer solution and 0.1mol/L calcium chloride solution as sheath flow layer solution, can continuously prepare fiber through coaxial micro-fluid spinning, can produce micro-fiber with the length of 9.42 m in one minute, and has the productivity of 15.7cm/s.
Meanwhile, after the AAP accounting for 10wt percent, 20wt percent and 30wt percent of the total solute is added into the core layer spinning solution, the fiber can still be continuously prepared. Fig. 5 is a graphic representation of fibers obtained after optimizing the experimental protocol according to example one and example two, from which it can be seen that the fibers are well formed and that the fiber arrays and fiber membranes can be further prepared.
Example IV
The PVP/SA/AAP composite drug-loaded fiber prepared in the 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 and PVP/SA/AAP composite fibers with mass fractions of 0wt%, 10wt%, 20wt% and 30 wt%.
FIG. 6a shows PVP sample at 3446cm -1 、2956cm -1 、1661cm -1 And 1290cm -1 The absorption peaks at which correspond to the stretching vibrations of-CH, -CH2, -c=o and-CN, 1423cm, respectively -1 Corresponds to the deformation vibration of-CH of the circulating CH2 group in PVP. As shown in FIG. 6b, SA samples appear at 3423cm -1 、2925cm -1 、1606cm -1 、1405cm -1 And 1025cm -1 The absorption peaks at the positions correspond to-OH, -CH, -COO-stretching vibration of c=o and-C-O-C-groups. FIG. 6c shows AAP sample appearance at 3320cm -1 、1650cm -1 The absorption peaks at these correspond to the stretching vibrations of-OH and-c=o on the amide bond, respectively.
As shown in fig. 6 (e-g), the infrared spectra of PVP/SA/AAP composite fibers with different drug loading amounts show characteristic absorption peaks of PVP, SA and AAP, and no new characteristic absorption peak appears, which indicates that the model drug AAP and PVP are combined in a physical blending mode, so that the physicochemical properties of the drug are not changed, and the drug action is not influenced. At the same time, 1650cm with increasing AAP content -1 The characteristic absorption peak intensity of-C=O on the amide bond gradually weakens, and the characteristic absorption peak intensity is probably that hydrogen bonds are generated among acetaminophen, PVP and SA.
(2) PVP/SA/AAP composite fiber X-ray diffraction (XRD) test
If the crystallization of the medicine affects the stability, bioavailability and curative effect of the medicine, the medicine is prevented from crystallizing when preparing a medicine slow-release system. The crystallization process of the drug in the polymer matrix is mainly divided into two stages, the first stage being nucleation and the second stage being nucleation growth. In the first phase, the drugs collide with each other by random "brownian motion" to form "dimers", which then collide with each other to form nuclei. As more and more "dimers" of the drug aggregate, the nucleation phase is entered. It takes a certain time for the drug to crystallize and then precipitate from the polymer.
The prepared drug-loaded PVP/SA/AAP composite fiber membrane was stored at room temperature for 3 months, and the distribution state of AAP in the PVP/SA/AAP composite fiber membrane was detected by X-ray diffraction after 3 months, and PVP and SA in the AAP and polymer matrices were detected, and the XRD graphs of the AAP, PVP, SA, PVP/SA composite fiber membrane and PVP/SA/AAP composite fiber membrane were shown in FIG. 7.
As can be seen from fig. 7a, acetaminophen (AAP) as a crude drug exhibited 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, no characteristic diffraction peak of the AAP active ingredient was observed in the drug-loaded PVP/SA/AAP composite fiber membrane, and only characteristic diffraction peaks of PVP and SA in the polymer matrix were observed, indicating that AAP was distributed in the drug-loaded composite fiber in an amorphous state, and also indicating that the PVP/SA composite fiber can effectively inhibit crystallization of AAP. The fiber prepared by micro-fluid spinning has larger specific surface area, and meanwhile, pores are formed in the fiber to store the medicine, so that the medicine can be well encapsulated after the fiber is solidified, the Brownian movement of the medicine is also limited, the probability of collision among medicine molecules is reduced, and the formation of medicine crystal nucleus is avoided to a certain extent. In addition, through infrared spectrum analysis, hydrogen bonds are formed between AAP and PVP and SA, so that crystallization of the medicine is further inhibited.
(3) Mechanical property test of PVP/SA/AAP composite fiber
In this example, mechanical properties of the PVP/SA/AAP composite fiber prepared as described above were analyzed, as shown in FIG. 8. The fiber is prepared according to the gauge length of 200mm, the breaking strength of the composite fiber is tested by using an Instron5967 material tester, each sample is tested for 30 times, and the drawing speed is 20mm/min, and the average value is taken as a test result.
Wherein FIG. 8a is a bar graph of breaking strength of PVP/SA/AAP composite fibers having PVP mass fractions of 15wt%,18wt% and 21wt%, respectively; FIG. 8b is a graph of stress-strain curves for composite fibers of different PVP mass fractions; FIG. 8c is a bar graph of breaking strength of PVP/SA/AAP composite fibers with varying drug loading; fig. 8d is a stress-strain plot of PSA fibers of different drug loading.
From FIG. 8a, breaking strength of PVP/SA/AAP composite fibers with PVP mass fractions of 15wt%,18wt% and 21wt% were 39.14.+ -. 5.31MPa, 44.48.+ -. 5.5MPa and 59.08.+ -. 5.31MPa, respectively, were obtained. As the PVP content increases, the breaking strength of the composite fiber increases, because as the PVP content increases, on the one hand, the hydrogen bond between PVP and SA increases, and on the other hand, the intramolecular hydrogen bond of PVP increases, thereby improving the breaking strength of the composite fiber.
The PVP/SA/AAP composite fiber obtained from FIG. 8b is a flexible fiber, the elongation at break of which is substantially 20% or more, and the elongation at break of the fiber increases slightly with increasing PVP content.
As shown in fig. 8c, the breaking strength of the fiber slightly increases with the increase of the model drug, and the breaking strengths of the drug-loaded composite fiber of AAP with mass fractions of 0, 10wt%, 20wt% and 30wt% are 37.27 ±4.17MPa, 39.14 ±5.31MPa, 39.45 ±5.4MPa and 43.06 ±5.21MPa, respectively. This is because as the AAP content increases, even distribution of AAP small molecules in the fiber increases intermolecular forces between fiber components, thereby improving the breaking strength of the composite fiber.
As can be seen from fig. 8d, with the addition of small molecules of the drug, the slippage of the 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 continuously increased, the elongation at break of the composite fiber is slightly reduced due to the increase of intermolecular forces between fiber components.
Example five
This example measures the in vitro release of AAP from PVP/SA/AAP composite fibers prepared in the previous examples.
Fig. 9 is a standard curve and standard curve equation for AAP in buffer solution. The standard curve shows that AAP concentration is in the range of 0.5 μg/mL-50 μg/mL, and the absorbance and concentration show good linear relationship.
PVP/SA/AAP composite fiber membranes are weighed and placed into PBS buffer solution to be mixed, and the solution capacity is kept constant at the positions of 2h, 4h, 6h, 8h, 10h, 12h, 24h, 26h, 28h, 30h, 32h, 34h, 36h, 48h, 50h, 52h, 54h, 56h, 58h, 60h and 72h respectively, then the solution is diluted, the ultraviolet absorbance at 245nm is measured, and the same amount of PBS buffer solution is added into a slow release system, so that three parallel samples are made for each drug carrying fiber.
The AAP content was calculated according to the standard curve equation of AAP, and the cumulative AAP release percentage was calculated according to the following formula, and the in vitro release curve of PVP/SA/AAP composite fiber was plotted. The formula is:wherein Q is AAP cumulative release percentage, v is the volume of slow-release solution PBS, v d For the volume of PBS after dilution c i Drug concentration (μg/mL) in the released liquid at the time of sampling for the ith exchange, A is AAP mass (μg) contained in the composite drug-carrying fiber, and n is the number of times of sampling.
Figure 10 is a graph of in vitro release of AAP in PVP/SA/AAP composite fibers. As can be seen from fig. 10a, as the PVP content increases, the cumulative percent release of the PVP/SA/AAP composite fiber also increases. The reason is that the gel shell layer of the fiber is thinned along with the increase of the PVP content, the release of the model drug AAP from the fiber is hindered to be reduced, the PVP is a water-soluble high polymer, the probability of degradation of the PVP/SA/AAP composite fiber skeleton 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 as PVP content increases, the diameter of the fiber becomes thinner, the specific surface area of the fiber increases, the drug loading capacity on the surface of the fiber also increases, the drug in the fiber can be more easily dispersed into PBS buffer solution, and the accumulated release rate of the drug also increases. Meanwhile, three PVP/SA/AAP composite fibers can be obtained, wherein the release of the three PVP/SA/AAP composite fibers is approximately linear in the first 12 hours, and the release rate after 12 hours is slow and approximately uniform. This is because after the AAP on the surface layer of the fiber is released, the remaining AAP can be diffused from the inside to the outside of the fiber and then released again, and the release rate is slowed down.
Figures 10b, 10c and 10d are release profiles of different drug loading of PVP/SA/AAP composite fibers with 15wt% PVP,18wt% PVP and 21wt% PVP content, respectively.
As can be seen, as the drug loading increases, the cumulative percent release of the fibers increases. 15wt% PVP,18wt% PVP and 21wt% PVP were obtained from tables 3, 4 and 5, and the cumulative percent release for the PVP/SA/AAP composite fibers with an AAP content of 10wt% was 45.74%, 59.86% and 70.43%, respectively, over the first 12 hours. 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 percent release of PSA composite fibers with AAP content of 30 wt.% was 61.11%,80% and 89.72%. This is because the more AAP content, the more drug is dispersed on the surface of the fiber and is more easily released within the first 12 hours. PVP/SA/AAP composite fiber cumulative release percentage after 72 hours with AAP content of 10wt% was 63.54%,71.85% and 79.13%; PVP/SA/AAP composite fiber with AAP content of 20wt% has cumulative release percentage of 70.56%,81.92% and 86.96%; PVP/SA/AAP composite fiber release cumulative release percentage with AAP content of 30wt% was 80.85%, 89.99% and 97.35%. The AAP has poor water solubility, so that the medicine embedded in the fiber is not easy to release, the medicine release rate is slowed down, and hydrogen bonds are generated between the AAP and PVP, so that the crystallization of the AAP is inhibited. When the AAP content is increased, the hydrogen bond generated can reach a saturation amount due to the fact that the PVP content is certain, so that excessive AAP can be crystallized and separated out on the surface of the fiber, and the AAP is dissolved in PBS under the flushing of PBS phosphate buffer solution, so that the accumulated drug release percentage of the drug is increased.
TABLE 3 cumulative AAP Release Rate in PVP/SA/AAP Complex fibers with 15wt% PVP
TABLE 4 cumulative AAP Release Rate in PVP/SA/AAP Complex fibers with 18wt% PVP
TABLE 5 cumulative AAP Release Rate in PVP/SA/AAP Complex fibers with 21wt% PVP
In order to explore the drug release mechanism of PVP/SA/AAP composite fiber, a drug release curve graph of 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.
Primary release means that the release rate per unit time is proportional to the drug concentration. The zero order release of extravascular administration is generally considered to be the ideal controlled release mode, with the primary release being the basic release mode. The sustained and controlled drug release systems of the framework type are generally classified into monolithic framework systems, swelling-type framework systems and erosion-type framework systems. The Weibull model refers to that the release rate of a drug is directly proportional to the diffusion coefficient, and the mechanism of drug release is generally diffusion or skeleton erosion. The Higuchi model is generally applicable to monolithic framework systems, meaning that the drug diffuses through the polymer molecular network and pore channels in the framework system, and generally the polymer degradation rate is much less than the diffusion rate of the drug.
The Ritger-Peppas model is generally applicable to swelling matrix systems, and determines the mechanism of drug release based on the slope of a fitted curve. When the slope is less than or equal to 0.43, the release mechanism of the medicine is Fickian diffusion; when 0.43< slope <0.89, the release mechanism of the drug is non-Fickian diffusion; when slope=0.89, the release mechanism of the drug is matrix degradation.
Tables 6, 7 and 8 are the fit of the drug release kinetics models of PVP/SA/AAP composite fiber release profiles with PVP content of 15wt%,18wt% and 21wt%, respectively. According to the evaluation of a correlation coefficient R2, a drug release kinetic model of PVP/SA/AAP composite fiber drug release curves with PVP content of 15wt%,18wt% and 21wt% is matched with a Weibull model and a Ritger-Peppas model. The drug release model of the PVP/SA/AAP composite fiber with 15wt% PVP content is more consistent with the Ritger-Peppas model, the slope of a fitting equation is 0.20322 and is smaller than 0.43, and the drug release mechanism of the PVP/SA/AAP composite fiber with 15wt% PVP content is closer to Fickian diffusion. The drug release model of PVP/SA/AAP composite fiber with 18wt% and 21wt% PVP content is more identical with the Weibull model, which shows that the drug release mechanism of PVP/SA/AAP composite fiber is mainly diffusion and skeleton erosion of the drug. Comprehensively showing that the drug is released from PVP/SA/AAP composite fiber to mainly undergo two stages, wherein the first stage is that the fiber skeleton swells, the drug outside the fiber is diffused out through Fickian, and the release rate of the drug is higher; the second stage is the degradation of the fibrous skeleton, the diffusion of the drug out of the interior of the fiber, and the slow release rate of the drug.
TABLE 6 model fitting of drug release kinetics of PVP/SA/AAP Complex fiber drug release curves with 15wt% PVP
TABLE 7 model fitting of drug release kinetics of PVP/SA/AAP Complex fiber drug release curves with 18wt% PVP
TABLE 8 model fitting of drug release kinetics of PVP/SA/AAP Complex fiber drug release curves containing 21wt% PVP
The above-described preferred embodiments according to the present invention are intended to suggest that, from the above description, various changes and modifications can be made by the person skilled in the art 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 description, but must be determined according to the scope of 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.
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