CN109330977B

CN109330977B - Lipid substance-coated drug-loaded nanofiber and preparation method thereof

Info

Publication number: CN109330977B
Application number: CN201811130464.9A
Authority: CN
Inventors: 余灯广; 万熙; 海涛; 罗敏艺; 冯张宾; 王珂
Original assignee: University of Shanghai for Science and Technology
Current assignee: University of Shanghai for Science and Technology
Priority date: 2018-09-27
Filing date: 2018-09-27
Publication date: 2022-05-13
Anticipated expiration: 2038-09-27
Also published as: CN109330977A

Abstract

The invention provides a lipid substance-coated drug-loaded nanofiber and a preparation method thereof. The lipid substance-coated drug-loaded nanofiber is characterized by comprising a core layer and a sheath layer coated outside the core layer, wherein the core layer is the drug-loaded nanofiber, and the raw materials for preparing the sheath layer contain the lipid substance and do not contain drugs. The method has the advantages of simple preparation process, single-step effectiveness, clear structure, small diameter, good linearity, uniform diameter distribution, smooth fiber surface, no bad phenomena of string beads, particles or silk grains mixing and the like of the prepared electrospun drug-carrying nano-fibers wrapped by lipid substance thin layers, and capability of providing good zero-order controlled release effect of the drug. Meanwhile, the method is based on the improved coaxial electrospinning technology, has a simple process and single-step effectiveness, and is suitable for industrial expanded production.

Description

Lipid substance-coated drug-loaded nanofiber and preparation method thereof

Technical Field

The invention belongs to the field of materials science, and relates to an electrospinning drug-loaded nanofiber with lipid substance thin layer coating.

Background

The medicinal sustained-release material is always the hot research and development object of biological medicine materials due to the advantages of 'safe, effective and convenient' administration. However, over the past half century, the most common method has been to disperse the drug in a carrier material, which regulates the slow release of the drug through its physicochemical properties. The most common carrier materials are polymers, including natural and synthetic polymers. On the other hand, lecithin is also often used as a sustained or controlled release carrier material for drugs due to its high biocompatibility. In the development of various delivery systems, both polymers and lecithin have their own relative advantages. In recent years, therefore, some studies have been eager to combine a polymer and lecithin together in order to obtain a better drug delivery effect. In these delivery systems, the majority are both heterogeneous systems, i.e. the lecithin-polymer and the drug components are homogeneously mixed together, and these systems are mainly present in the form of particles, especially nanoparticles (K. Hadinoto, A. Sundaresan, W.S. how, Lipid-polymer nanoparticles a new genetic delivery form: a review, Eur.J. Pharm. Biopharm.85(2013) 427-443).

Today's nanotechnology development increasingly emphasizes the supportive role of nanostructures in imparting nanocunctionality to materials. Among the various complex nanostructures, the core-sheath structure is currently the most widely used structural feature (N.Kamaly, B.Yameen, J.Wu, O.C.Farokhzad, Degradable controlled-release polymers and polymeric nanoparticles: mechanisms of controlling drug release, chem.Rev.116(2016) 2602-. If the position structure characteristics of lecithin and polymer materials can be further regulated and controlled on the spatial distribution of the nano material to form certain core-sheath structure characteristics, a functional nano product which is better than a common lecithin-polymer blended mixed material can be obtained. Wherein the coaxial electrostatic spinning technology can effectively prepare functional nano materials with various core-sheath structural characteristics in a single step.

The high-voltage electrostatic spinning technology is a top-down nano-manufacturing technology, and is characterized by that it utilizes the external electric field force to overcome the surface tension and cohesive force of liquid drop at the tip of spray head to form jet flow, under the combined action of electrostatic repulsion force, coulomb force and surface tension the atomized liquid jet flow is high-frequency bent, drawn and split, and drawn by tens of millions of times within tens of milliseconds, and the solvent is volatilized or the melt is cooled to obtain nano-grade fibre at receiving end. The technology has the advantages of simple process, convenient operation and control, wide material selection range and strong controllability, and can prepare the nanofiber with microstructure characteristics through the design of the spray head, so the technology is considered as a method which most probably realizes the industrial production of the continuous nanofiber, and the functional nanofiber prepared by applying the technology has good prospect.

With the development of nanotechnology, the preparation and application of materials with complex nano-structure characteristics are increasingly relied on, and accordingly, the multi-fluid high-voltage electrostatic spinning technology and the prepared nano-fibers with complex structure characteristics also become popular fields for competitive research and development in various countries, in particular to the coaxial electrospinning technology and the corresponding core-sheath structure nano-fibers. In conventional coaxial electrospinning, the sheath fluid must have good electrospinning fiber-forming properties, and since such polymers are very rare, the nanostructure preparation capability of conventional coaxial electrospinning techniques is greatly limited. In recent years, Yu et al have successfully developed an improved coaxial electrospinning technique (Deng-Guang Yu, Jiano-Jiano Li, Gareth R.Williams, and Min zhao. Electrospun amorphous solid dispersions of porous water-soluble drugs: A new view. journal of Controlled Release,2018, Doi:10.1016/j. concurel.2018.08.016), in which the sheath fluid may be devoid of fiberizing properties. Because there are infinite fluids (such as various small molecule solutions, emulsions, suspensions, polymer dilute solutions, etc.) without fiber-forming properties, the capability of the electrospinning technology in the preparation of core-sheath structure functional nanomaterials is greatly expanded.

Disclosure of Invention

The invention aims to provide a drug-loaded nanofiber and a preparation method thereof, wherein the nanofiber has good biocompatibility, can effectively overcome the initial burst effect of a drug, and is beneficial to the long-term slow controlled release of the drug.

In order to achieve the aim, the invention provides a lipid substance-coated drug-loaded nanofiber, which is characterized by comprising a core layer and a sheath layer coated outside the core layer; the core layer is a drug-loaded nanofiber; the raw material for preparing the sheath layer contains lipid substances and does not contain drugs.

The lipid material can be selected from various oils and lipids, preferably at least one of edible and medicinal lipid materials such as beeswax, stearin, soybean lecithin, egg yolk lecithin and cholesterol.

The raw materials of the drug-loaded nanofiber comprise a polymer and a drug, the polymer is various pharmaceutical polymer auxiliary materials with electrospinning fiber forming performance, and at least one of cellulose and derivatives thereof, chitosan, edible protein, epsilon-polycaprolactone, polylactic acid and the like is preferably selected.

The invention also provides a preparation method of the lipid substance-coated drug-loaded nanofiber, which is characterized by comprising the steps of dissolving the lipid substance in a solvent to obtain a sheath spinning solution; dissolving a drug and a polymer in a solvent to obtain a core spinning solution; and carrying out coaxial electrostatic spinning to prepare the lipid substance-coated drug-loaded nanofiber.

The invention finds that the improved coaxial electrospinning technology can be applied to prepare the electrospinning drug-carrying nanofiber with lipid substance thin layer coating on the basis of interdisciplinary multidisciplinary of materials, medical application, nano structure and electrohydrodynamic technology. The improved coaxial electrospinning process is an improved coaxial electrospinning process with an inner core fluid having electrospinning fiber forming performance and an outer sheath fluid having no spinnability. The invention adopts an improved coaxial electrospinning process, uses lipid substances without electrospinning fiber forming performance as sheath liquid, uses a mixed solution of polymer with fiber forming performance and medicament as core liquid, and implements the electrospinning process together. Preparing the nanofiber with the core-sheath structure by ultra-fast stretching and drying in the electrospinning process, wherein the surface of the nanofiber is a thin layer of lipid substance, and the lipid substance does not contain a medicament; the inner core of the fiber is a composite of the drug and the polymer. Because the lipid thin layer changes the surface enrichment phenomenon of the drug, and simultaneously because of the hydrophobic effect of the lipid substance, the slow controlled release performance of the drug from the polymer can be improved, and a good controlled release effect of the drug can be obtained.

The nano fiber is formed by mixing lipid substances and drug-loaded polymer fibers, and the lipid substances are wrapped on the surface of the drug-loaded nano fiber in a thin layer mode to form a core-sheath structure characteristic. The nano-fiber can effectively eliminate the initial explosive release effect of the common medicament-carrying nano-fiber, and obtain better medicament sustained and controlled release performance. The fiber has the characteristics of no drug on the surface and good biocompatibility.

Compared with the prior art, the invention has the beneficial effects that:

the nanofiber of the invention is characterized in that: 1) the lipid thin layer is wrapped without drugs, so that the surface of the fiber is free of drugs; 2) the lipid substance has good biocompatibility; 3) at human body temperature, lipid substances are easy to disperse; 4) the initial burst effect of the medicine can be effectively overcome; 4) is favorable for the slow controlled release of the medicine for a long time. The method has the advantages of simple preparation process, single-step effectiveness, clear structure, small diameter, good linearity, uniform diameter distribution, smooth fiber surface, no bad phenomena of string beads, particles or silk grains mixing and the like of the prepared electrospun drug-carrying nano-fibers wrapped by lipid substance thin layers, and capability of providing good zero-order controlled release effect of the drug. Meanwhile, the method is based on the improved coaxial electrospinning technology, has a simple process and single-step effectiveness, and is suitable for industrial expanded production.

Drawings

FIG. 1 is a schematic cross-sectional structure diagram of a lipid substance coated drug-loaded nanofiber;

FIG. 2 is a schematic diagram of modified coaxial electrospinning.

FIG. 3 scanning electron microscopy of electrospun drug-loaded nanofibers with thin layer encapsulation of lipid material (500 ×).

FIG. 4 Transmission Electron microscopy (200,000X) of electrospun drug-loaded nanofibers with thin layer coating of lipid material.

Figure 5 in vitro drug controlled release profile of electrospun drug loaded nanofibers: a-common electro-spinning drug-loaded nano-fiber; b-the thin layer of electrospun beeswax of the invention encapsulates the ibuprofen/ethylcellulose nanofibers.

Detailed Description

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the teaching of the present invention, and such equivalents may fall within the scope of the present invention as defined in the appended claims.

Example 1: construction of improved coaxial electrospinning device

According to the literature (Xufang, Xuying, wide residual light, preparation of drug zero-order controlled release nano-fiber by circular coaxial electrospinning of polymer dilute solution, proceedings of Shanghai university of physical engineering, 2015,37(2):165-168.), an improved coaxial electrospinning device is built, and comprises two axial-flow injection pumps, a coaxial spinning head, a fiber receiving plate, a high-voltage electrostatic power supply and two axial-flow injection pumps, wherein one of the two axial-flow injection pumps is provided with a core liquid injector, and the injector can be directly connected with the coaxial spinning head. The other is provided with a sheath liquid injector, sheath liquid is conveyed to the coaxial spinning head through a high-elasticity silicone tube, a high-voltage electrostatic power supply is connected with the coaxial spinning head through crocodile pliers, and a fiber receiving flat plate is grounded.

Example 2: preparation of spinning solution and implementation of improved coaxial electrospinning

5.0g of beeswax was dissolved in 100 ml of a mixed solvent of N, N-dimethylacetamide (DMAc) and ethanol (30: 70 by volume) at room temperature to prepare a pale yellow solution as a sheath spinning solution.

5.0g ibuprofen and 20.0g ethylcellulose (viscosity range 8-12mPa.s) were dissolved together in 100 ml ethanol to form a clear solution as core spinnable solution.

Common single-fluid electrospinning process and improved coaxial electrospinning process are carried out under the following process conditions to prepare common electrospun drug-loaded nanofiber and beeswax thin-layer coated ibuprofen/ethyl cellulose nanofiber. The improved coaxial electrospinning process adopts the improved coaxial electrospinning device in the embodiment 1.

Thin layer of beeswax encapsulating ibuprofen/ethylcellulose nanofibers: the flow rate of the core liquid is 2.0mL/h, the flow rate of the sheath liquid is 0.5mL/h, the distance between the receiving plate and the spinneret orifice is 15cm, and the voltage is 12 kV. The ambient temperature is (23 + -1) deg.C, the ambient humidity is 62 + -4%, and the electrospinning process is shown in FIG. 2.

As shown in fig. 1, the obtained beeswax thin layer coated ibuprofen/ethylcellulose nanofiber comprises a core layer and a sheath layer coated outside the core layer, the core layer is a drug-loaded nanofiber and consists of a polymer fiber-forming base material 3 and a drug 2, and the sheath layer contains beeswax 3 and no drug.

Common electrospun drug-loaded nanofibers: the flow rate of the core liquid is 2.0mL/h, the flow rate of the sheath liquid is 0mL/h, the distance between the receiving plate and the spinneret orifice is 15cm, and the voltage is 12 kV. The ambient temperature is (23 +/-1) DEG C, and the ambient humidity is 62 +/-4%.

Example 3: characterization of morphology and structure of electrospun drug-loaded nanofiber with lipid substance thin layer coating

The fiber prepared in example 2 was observed after carbon spraying on the surface thereof using a field scanning electron microscope (FESEM), and the result is shown in fig. 3 under a condition of 500 times magnification. The prepared fiber has good linearity and uniform size, does not have the phenomena of spindle or silk particle mixing and the like, and reflects that the prepared beeswax thin layer coated ibuprofen/ethyl cellulose nanofiber has good morphological characteristics.

The prepared fiber was further subjected to internal structure using a Transmission Electron Microscope (TEM), and the result is shown in fig. 4 under a magnification of 200,000 times. The fiber core sheath has obvious structural characteristics, a thin drug-free beeswax layer is wrapped outside the fiber core sheath, and the gray level of the thin drug-free beeswax layer is smaller than that of the drug-polymer composite layer of the core.

Example 4: in-vitro drug controlled release performance analysis of electrospun drug-loaded nanofiber with lipid substance thin layer coating

According to a second method for measuring release degree in appendix XD of Chinese pharmacopoeia 2015 edition, an RCZ-8A intelligent dissolution experimental instrument is adopted to carry out in-vitro dissolution test on the obtained beeswax thin layer coated ibuprofen/ethyl cellulose nano-fiber. The rotation speed is controlled to be 50rpm, the temperature is 37 +/-0.1 ℃, 900mL of phosphate buffer solution with pH6.8 is taken as a dissolution medium, and the in-vitro sustained and controlled release performance of the medicament is examined. Sampling 5mL according to preset time to obtain a dissolution liquid sample, and immediately supplementing isothermal fresh medium with the same volume. After the sample is properly diluted, ultraviolet measurement is carried out at a lambda of 260nm by using an ultraviolet-visible spectrophotometer, and the cumulative dissolution percentage of the ibuprofen medicament is calculated and repeated for 6 times. The in vitro dissolution and release result of the drug is shown in fig. 5, and compared with the single ibuprofen/ethyl cellulose nanofiber, the beeswax thin layer coated ibuprofen/ethyl cellulose nanofiber has better drug slow release performance, which is specifically shown in that the initial burst effect of the drug is basically eliminated, the drug release rate is more gradual, and the drug release time is longer. The reason for this is that the thin layer of beeswax on the outside eliminates the phenomenon of enrichment on the fiber surface of the drug, and at the same time, due to the hydrophobic effect of beeswax, the diffusion process of the drug from the polymer base material to the dissolution liquid is delayed.

Example 5: electrospun soybean lecithin-coated paracetamol/ethyl cellulose nanofiber

Referring to example 2, 5.0g of soybean lecithin was dissolved in 100 ml of methylene chloride at room temperature to prepare a pale brown solution as a sheath spinning solution. 5.0g of paracetamol and 20.0g of ethylcellulose were dissolved together in 100 ml of ethanol to form a clear solution as a core spinnable solution. An improved coaxial electrostatic spinning process is implemented under the following process conditions to prepare the paracetamol/ethyl cellulose nano-fiber coated by the electro-spun soybean lecithin: the flow rate of the core liquid is 1.0mL/h, the flow rate of the sheath liquid is 0.2mL/h, the distance between the receiving plate and the spinneret orifice is 20cm, and the voltage is 15 kV. The obtained soybean lecithin-coated paracetamol/ethyl cellulose nanofiber comprises a core layer and a sheath layer coated outside the core layer; the core layer is a drug-loaded nanofiber, and the preparation raw material of the sheath layer contains lipid substance soybean lecithin and does not contain drugs.

Example 6: ferulic acid/epsilon-polycaprolactone nanofiber coated by electrospun beeswax

Referring to example 2, 5.0g of beeswax was dissolved in 100 ml of a mixed solvent of N, N-dimethylacetamide (DMAc) and ethanol (30: 70 by volume) at room temperature to prepare a pale yellow solution as a sheath spinning solution. 5.0g of ferulic acid and 10.0g of epsilon-polycaprolactone were dissolved together in 100 ml of chloroform to form a clear solution which served as the core spinnable solution. An improved coaxial electrostatic spinning process is implemented under the following process conditions to prepare the ferulic acid/epsilon-polycaprolactone nanofiber wrapped by the electro-spun beeswax: the flow rate of the core liquid is 2.0mL/h, the flow rate of the sheath liquid is 0.5mL/h, the distance between the receiving plate and the spinneret orifice is 15cm, and the voltage is 8 kV. The ferulic acid/epsilon-polycaprolactone nanofiber wrapped by the beeswax comprises a core layer and a sheath layer wrapped outside the core layer; the core layer is a drug-loaded nanofiber, and the raw materials for preparing the sheath layer contain lipid substance beeswax and no drug.

Claims

1. A drug-loaded nanofiber wrapped by lipid substances is characterized by comprising a core layer and a sheath layer wrapped outside the core layer; the core layer is a drug-loaded nanofiber; the raw material for preparing the sheath layer contains lipid substances and does not contain drugs;

the lipid substance is beeswax;

the raw materials of the drug-loaded nanofiber comprise polymers and drugs, wherein the polymers are various pharmaceutical polymer auxiliary materials with electrospinning fiber forming performance;

the lipid substance-coated drug-loaded nanofiber is prepared by adopting a coaxial electrostatic spinning process.

2. The lipid material coated drug-loaded nanofiber according to claim 1, wherein the polymer is at least one of cellulose and its derivatives, chitosan, edible protein, epsilon-polycaprolactone and polylactic acid.

3. The method for preparing lipid substance coated drug-loaded nanofiber as claimed in any of claims 1-2, which comprises dissolving lipid substance in solvent as sheath spinning solution; dissolving a drug and a polymer in a solvent to obtain a core spinning solution; and carrying out coaxial electrostatic spinning to prepare the lipid substance-coated drug-loaded nanofiber.