Electrospun carrier materials for oral mucosal drug delivery and methods of making

Abstract

The application discloses an electrospun carrier material for oral mucosa administration and a preparation method thereof. The carrier material is prepared by electrospinning polyvinyl alcohol as a spinning forming material and blending the polyvinyl alcohol with dopamine modified gelatin. The material is composed of micro-nano fibers and has a large specific surface area. When the carrier material is attached to a target, in a wet oral environment, water will infiltrate into the gaps of the fibers through capillary force. After the fibers absorb water, the fibers swell, the fiber spacing becomes smaller, and the upper layer of the film will spontaneously spread on the target due to the action of gravity. When the material is in a fully wet state, within a certain strain range, the storage modulus of the film material is greater than the loss modulus, the fiber film is transformed into a gel state, the hydroxyl groups of polyvinyl alcohol and the carboxyl groups on the molecular chains of gelatin in the material are bonded with water molecules to form hydrogen bonds, the film material will spread, and the drug will be slowly released from the reticular structure. The carrier material also has good mechanical properties, meets the needs of daily oral movement, and maintains the integrity of the base material.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials technology, specifically relating to electrospun carrier materials for oral mucosal drug delivery, and a method for preparing such materials. Background Technology

[0002] The treatment of oral diseases is severely limited by existing dosage forms. Due to the limited retention of drugs on the mucosa, these dosage forms suffer from drawbacks such as short contact time, poor site specificity, and sensitivity to mechanical stimulation. Oral films prepared using electrospinning technology, in addition to increasing drug loading capacity due to their large specific surface area, can effectively enhance drug solubility and permeability. The moist environment of the oral mucosa requires the matrix to have high wet adhesion properties. Depending on the properties of different substrates, adhesion mechanisms in a moist environment include surface tension, dehydration, diffusion, electrostatic interaction, and chemisorption. Currently, dopamine, a derivative of dopamine, is often used for surface modification of various materials due to its excellent adhesion properties. However, matrix systems are mostly prepared by coating or as hydrogels. Coated films often fail to balance mechanical properties and flexibility, while hydrogels often require exogenous or endogenous stimulation to achieve controlled drug release. A suitable drug delivery system is required to provide sustained drug release, directly targeting the disease or lesion site, especially under conditions where adhesion is difficult due to the moist environment of the oral cavity and the flexibility of the mucosal tissue surface. There is currently no effective commercial drug delivery system that can fully meet this clinical need. Summary of the Invention

[0003] The purpose of this invention is to provide an electrospun carrier material for oral mucosal drug delivery, which solves the problem that oral mucosal drug delivery materials tend to clump together at the target site and cannot spread spontaneously due to the moist environment of the oral cavity and the flexibility of the mucosal tissue surface.

[0004] Another object of the present invention is to provide a method for preparing an electrospun carrier material for oral mucosal drug delivery.

[0005] The first technical solution adopted in this invention is an electrospun carrier material for oral mucosal drug delivery, which uses polyvinyl alcohol as the spinning material, and blends it with dopamine-modified gelatin in a mass ratio of 1:1 to 1:3 and then prepares a fiber membrane by electrospinning. The fiber membrane is also loaded with an antibacterial agent when it is prepared by electrospinning.

[0006] The second technical solution adopted in this invention is a method for preparing an electrospun carrier material for oral mucosal drug delivery, the specific operation steps of which are as follows:

[0007] Step 1: Prepare dopamine-modified gelatin;

[0008] Step 2: Prepare polyvinyl alcohol / dopamine modified gelatin electrospun fiber membrane;

[0009] Step 3: Immerse the gelatin-based electrospun fiber membrane prepared above in an antibacterial agent solution with a mass concentration of 10-100 mg / mL for 0.5-12 h to obtain a gelatin-based electrospun fiber membrane loaded with antibacterial agent.

[0010] The invention is further characterized in that,

[0011] Step 1 is as follows:

[0012] The purified gelatin was prepared into a gelatin aqueous solution with a mass fraction of 2-5% w / v. Then, it was stirred and mixed with dopamine and a biological cross-linking agent. After reacting for 12-24 hours, it was dialyzed with deionized water and freeze-dried to obtain gelatin-dopamine lyophilized product. The mass ratio of gelatin to dopamine was 1:0.1-0.5, and the mass ratio of gelatin to biological cross-linking agent was 1:0.01-0.05.

[0013] Step 2 is as follows:

[0014] The gelatin-dopamine lyophilized product prepared in step 1 was dissolved in mixed solution A to prepare a gelatin-dopamine solution with a mass fraction of 10-20%. This solution was then mixed with a polyvinyl alcohol aqueous solution with a mass fraction of 10-20% at a mass ratio of 1:1-3 and stirred until homogeneous to obtain an electrospinning solution. The electrospinning solution was added to an electrospinning device, the operating parameters of the electrospinning device were set, and electrospinning was performed to obtain a polyvinyl alcohol / dopamine modified gelatin electrospinned fiber membrane.

[0015] Mixed solution A includes acetic acid, ethanol and water, wherein the volume ratio of acetic acid, ethanol and water is 20-80:10-70:10-70.

[0016] The operating parameters of the electrospinning device are as follows: voltage 10–25 kV, feed speed 0.5–1 mL / h, receiving distance 5–10 cm, and working time 30–360 min.

[0017] The polyvinyl alcohol / dopamine modified gelatin electrospun fiber membrane obtained in step 2 has a fiber range of 300 nm to 3 μm.

[0018] Biocrosslinking agents include, but are not limited to, genipin and citric acid.

[0019] Antibacterial agents include aminoglycosides, such as amikacin.

[0020] The synthesis principle of key steps in this invention:

[0021] This invention utilizes electrospinning technology to impart a micro / nanofiber structure to polyvinyl alcohol and dopamine-modified gelatin. Because this carrier material is composed of micro / nanofibers, it possesses a large specific surface area. When this carrier material is applied to the target area, in the moist environment of the oral cavity, water will seep into the gaps between the fibers through capillary forces. The fibers absorb water and swell, reducing the inter-fiber spacing. The upper layer of the membrane will spontaneously spread at the target area due to gravity. Polyvinyl alcohol and dopamine-modified gelatin are hydrophilic materials with a water contact angle of less than 90°, allowing for complete wetting. When the carrier material is in a fully wetted state, it primarily undergoes elastic deformation within a certain strain range, exhibiting a solid state with a storage modulus greater than its loss modulus, demonstrating hydrogel characteristics. The hydroxyl groups in polyvinyl alcohol and the carboxyl groups on the gelatin molecular chains bond with water molecules to form hydrogen bonds, thereby achieving membrane spreading. Dopamine endows this carrier material with excellent wet adhesion properties. Furthermore, by immobilizing the antibacterial agent in situ, when the agent is fully wetted, the storage modulus of the membrane exceeds the loss modulus within a certain strain range, completing the transition from the fibrous membrane to the gel state. The drug is slowly released from the network structure, achieving sustained release of the antibacterial agent. The prepared electrospun fiber membrane exhibits self-spreading properties, wet adhesion properties, and sustained drug release properties in a simulated oral wet environment (phosphate buffer), making it a high-performance oral mucosal drug delivery system.

[0022] The beneficial effects of this invention are:

[0023] This invention provides an electrospun carrier material for oral mucosal drug delivery that combines self-spreading properties, wet adhesion properties, and sustained drug release properties in a simulated moist oral environment (phosphate buffer). This material serves as a novel drug delivery system with widely available raw materials and a simple preparation process. This invention utilizes electrospinning technology to impart a micro / nanofiber structure to polyvinyl alcohol and dopamine-modified gelatin. Because this carrier material is composed of micro / nanofibers, it has a large specific surface area. When this carrier material is applied to the target site, in the moist oral environment, water will wet into the gaps between the fibers through capillary action. The fibers absorb water and swell, reducing the inter-fiber spacing. The upper layer of the membrane will spontaneously spread at the target site due to gravity. When it is fully wetted, within a certain strain range, the storage modulus of the membrane exceeds the loss modulus, completing the transition from the fiber membrane to the gel state. The hydroxyl groups of polyvinyl alcohol and the carboxyl groups on the gelatin molecular chains bond with water molecules to form hydrogen bonds, causing the membrane to spread and the drug to be slowly released from the network structure. The presence of catechol in the system allows the substrate to adhere to wet tissue. This carrier material also possesses excellent mechanical properties, meeting the needs of daily oral movements and maintaining the integrity of the substrate. Attached Figure Description

[0024] Figure 1 This is the structural formula of the dopamine-modified gelatin product prepared in Example 2 of the present invention;

[0025] Figure 2 This is the nuclear magnetic resonance spectrum of the dopamine-modified gelatin prepared in Example 2 of this invention;

[0026] Figure 3 This is the infrared spectrum of the dopamine-modified gelatin prepared in Example 2 of this invention;

[0027] Figure 4 This is a SEM image of the electrospinning of the polyvinyl alcohol / dopamine modified gelatin product prepared in Example 2 of this invention.

[0028] Figure 5 This is a graph showing the rheological test results of polyvinyl alcohol / dopamine modified gelatin fiber membrane under wet conditions.

[0029] Figure 6 This is the drug release curve of amikacin immobilized in situ using the electrospun fiber membrane of the present invention.

[0030] Figure 7 This is a diagram showing the mechanical properties of the membrane material of the present invention.

[0031] Figure 8 This is a comparison chart of the spreading performance of the membrane material of this invention with other membrane materials in water. Detailed Implementation

[0032] The electrospun carrier material for oral mucosal drug delivery provided by the present invention uses polyvinyl alcohol as the spinning material. It is mixed with dopamine-modified gelatin at a mass ratio of 1:1 to 1:3 and then electrospun to prepare a fiber membrane. The fiber membrane is also loaded with an antibacterial agent during the preparation of the fiber membrane by electrospinning.

[0033] The present invention will be further described below with reference to specific embodiments.

[0034] Example 1

[0035] Step 1: Preparation of dopamine-modified gelatin: A 2% w / v gelatin aqueous solution was prepared from purified gelatin, then mixed with dopamine and a bio-crosslinking agent. After reacting for 12 hours, the mixture was dialyzed with deionized water and freeze-dried for later use. The mass ratio of gelatin to dopamine was 1:0.1, and the mass ratio of gelatin to the bio-crosslinking agent was 1:0.01.

[0036] Step 2: Preparation of polyvinyl alcohol / dopamine modified gelatin electrospun fiber membrane: Dissolve the lyophilized gelatin-dopamine in acetic acid-ethanol-water (80:10:10). v:v:vA 10% (w / v) gelatin-dopamine solution was prepared in a solution and mixed with a 10% (w / v) polyvinyl alcohol aqueous solution at a mass ratio of 1:1 (g:g) and stirred until homogeneous to obtain an electrospinning solution. The electrospinning solution was added to an electrospinning apparatus, and the operating parameters were set as follows: voltage 10 kV, feed speed 0.5 mL / h, receiving distance 5 cm, and working time 30 min. Electrospinning was then performed to obtain polyvinyl alcohol / dopamine modified gelatin electrospun fiber membranes with fiber diameters ranging from 300 nm to 3 μm.

[0037] Step 3: Immerse the gelatin-based electrospun fiber membrane prepared above in an antibacterial agent solution with a mass concentration of 10 mg / mL for 0.5 h to obtain a gelatin-based electrospun fiber membrane loaded with antibacterial agent.

[0038] Example 2:

[0039] Step 1: Preparation of dopamine-modified gelatin: A 2.5% w / v gelatin aqueous solution was prepared from purified gelatin. This solution was then mixed with dopamine and a bio-crosslinking agent, and allowed to react for 24 hours. Afterward, the mixture was dialyzed with deionized water and freeze-dried for later use. The mass ratio of gelatin to dopamine was 1:0.125, and the mass ratio of gelatin to the bio-crosslinking agent was 1:0.03.

[0040] Step 2: Preparation of polyvinyl alcohol / dopamine modified gelatin electrospun fiber membrane: Dissolve the lyophilized gelatin-dopamine in acetic acid-ethanol-water (60:20:20). v:v:v A 10% (w / v) gelatin-dopamine solution was prepared in a solution and mixed with a 20% (w / v) polyvinyl alcohol aqueous solution at a mass ratio of 1:3 (g:g) and stirred until homogeneous to obtain an electrospinning solution. The electrospinning solution was added to an electrospinning apparatus, and the operating parameters were set as follows: voltage 25 kV, feed speed 1 mL / h, receiving distance 10 cm, and working time 360 ​​min. Electrospinning was then performed to obtain polyvinyl alcohol / dopamine modified gelatin electrospun fiber membranes with fiber diameters ranging from 300 nm to 3 μm.

[0041] Step 3: Immerse the gelatin-based electrospun fiber membrane prepared above in an antibacterial agent solution with a mass concentration of 50 mg / mL for 12 h to obtain a gelatin-based electrospun fiber membrane loaded with antibacterial agent.

[0042] like Figure 1 The structural formula of the prepared dopamine-modified gelatin product is shown, which demonstrates that the dopamine-modified gelatin is grafted onto the gelatin chain via a bio-crosslinking agent.

[0043] like Figure 2The prepared dopamine-modified gelatin's 1H NMR spectrum, for pure gelatin, contains three characteristic peaks in its infrared spectrum. These peaks are due to the CO stretching vibration of the amide I bond appearing at 1648 cm⁻¹. -1 At this point, the NH bending vibration of the amide II bond is at 1513 cm⁻¹. -1 The 1266 cm⁻¹ region was observed, and the CN stretching vibration of the amide III bond resulted in this. -1 The peak value is generated at 3288.6 cm⁻¹, and for polyvinyl alcohol, this is 3288.6 cm⁻¹. -1 The peak value is attributed to the -OH vibration, and the C=C stretching vibration of the terminal vinyl group is at 839.9 cm⁻¹. -1 The characteristic peaks of polyvinyl alcohol (PVA) appeared at 30-30 cm⁻¹ in the polyvinyl alcohol composite film, confirming the complete mixing of PVA and dopamine-modified gelatin. In the dopamine-modified gelatin fibrous film, the characteristic peaks of PVA were observed at 30-30 cm⁻¹. -1 The broadband at this point represents the stretching vibration of catechol-OH, which proves the success of dopamine grafting.

[0044] like Figure 3 The infrared spectrum of the prepared dopamine-modified gelatin is shown. The peak at 6.7 ppm corresponds to the aromatic ring of dopamine, and the peak at 2.75 ppm corresponds to the methylene group near the phenyl group in dopamine. These peaks are not observed in the spectrum of pure gelatin. This result confirms the successful preparation of dopamine-modified gelatin.

[0045] like Figure 4 The SEM characterization results of the membrane material of the present invention show that the membrane material has a fibrous structure.

[0046] like Figure 5 The figure shown is a diagram of the rheological test results of the membrane material of the present invention under a wet environment. It can be found that within a certain strain range, the material mainly undergoes elastic deformation and is in a solid state. Its storage modulus is greater than its loss modulus, which demonstrates the characteristics of a hydrogel.

[0047] like Figure 6 The drug release curve of the membrane material of the present invention shown in the figure indicates that amikacin fixed on the membrane is continuously released after 24 hours.

[0048] like Figure 7 The mechanical properties of the membrane material of the present invention are shown in the figure. As can be seen from the figure, the maximum tensile strength of the membrane material of the present invention can reach 5 MPa, which meets the requirement that the membrane material is not easily detached after being adhered to the inside of the oral cavity.

[0049] like Figure 8As shown, comparing the spreading performance of the membrane material of the present invention with that of other membrane materials in water reveals that the membrane material of the present invention can spread spontaneously in water, while commercially available compound chlorhexidine dexamethasone membranes shrink after absorbing water, and hydrophilic electrospun membranes such as the polyvinyl alcohol and gelatin materials used in the present invention, gelatin electrospun fiber membranes dissolve upon contact with water, and polyvinyl alcohol electrospun fiber membranes shrink after absorbing water.

[0050] Example 3

[0051] Step 1: Preparation of dopamine-modified gelatin: A 5% w / v gelatin aqueous solution was prepared from purified gelatin, then mixed with dopamine and a bio-crosslinking agent. After reacting for 24 hours, the mixture was dialyzed with deionized water and freeze-dried for later use. The mass ratio of gelatin to dopamine was 1:0.5, and the mass ratio of gelatin to the bio-crosslinking agent was 1:0.05.

[0052] Step 2: Preparation of polyvinyl alcohol / dopamine modified gelatin electrospun fiber membrane: Dissolve the lyophilized gelatin-dopamine in acetic acid-ethanol-water (20:70:10). v:v:v A 15% (w / v) gelatin-dopamine solution was prepared in a solution and mixed with a 15% (w / v) polyvinyl alcohol aqueous solution at a mass ratio of 1:2 (g:g) and stirred until homogeneous to obtain an electrospinning solution. The electrospinning solution was added to an electrospinning apparatus, and the operating parameters were set as follows: voltage 15 kV, feed speed 0.8 mL / h, receiving distance 8 cm, and working time 200 min. Electrospinning was then performed to obtain polyvinyl alcohol / dopamine modified gelatin electrospun fiber membranes with fiber diameters ranging from 300 nm to 3 μm.

[0053] Step 3: Immerse the gelatin-based electrospun fiber membrane prepared above in an antibacterial agent solution with a mass concentration of 100 mg / mL for 6 h to obtain a gelatin-based electrospun fiber membrane loaded with antibacterial agent.

[0054] Example 4

[0055] Step 1: Preparation of dopamine-modified gelatin: A 5% w / v gelatin aqueous solution was prepared from purified gelatin, then mixed with dopamine and a bio-crosslinking agent. After reacting for 24 hours, the mixture was dialyzed with deionized water and freeze-dried for later use. The mass ratio of gelatin to dopamine was 1:0.5, and the mass ratio of gelatin to the bio-crosslinking agent was 1:0.05.

[0056] Step 2: Preparation of polyvinyl alcohol / dopamine modified gelatin electrospun fiber membrane: Dissolve the lyophilized gelatin-dopamine in acetic acid-ethanol-water (20:10:70). v:v:vA 20% (w / v) gelatin-dopamine solution was prepared in a solution and mixed with a 20% (w / v) polyvinyl alcohol aqueous solution at a mass ratio of 1:3 (g:g) and stirred until homogeneous to obtain an electrospinning solution. The electrospinning solution was added to an electrospinning apparatus, and the operating parameters were set as follows: voltage 25 kV, feed speed 1 mL / h, receiving distance 10 cm, and working time 360 ​​min. Electrospinning was then performed to obtain a polyvinyl alcohol / dopamine modified gelatin electrospun fiber membrane with a fiber diameter ranging from 300 nm to 3 μm.

[0057] Step 3: Immerse the gelatin-based electrospun fiber membrane prepared above in an antibacterial agent solution with a mass concentration of 50 mg / mL for 6 h to obtain a gelatin-based electrospun fiber membrane loaded with antibacterial agent.

[0058] This invention utilizes electrospinning technology to impart a micro / nanofiber structure to polyvinyl alcohol and dopamine-modified gelatin. Because this carrier material is composed of micro / nanofibers, it possesses a large specific surface area. When this carrier material is applied to the target area, in the moist environment of the oral cavity, water will seep into the gaps between the fibers through capillary forces. The fibers absorb water and swell, reducing the inter-fiber spacing. The membrane layer will spontaneously spread at the target area due to gravity. When it is fully wetted, within a certain strain range, the storage modulus of the membrane material exceeds the loss modulus, completing the transition from the fiber membrane to the gel state. The hydroxyl groups of polyvinyl alcohol and the carboxyl groups on the gelatin molecular chains form hydrogen bonds with water molecules, causing the membrane to spread and the drug to be slowly released from the network structure. The presence of catechol in the system allows the substrate to adhere to moist tissue. This carrier material also possesses good mechanical properties, meeting the needs of daily oral movements and maintaining the integrity of the substrate.

[0059] This invention utilizes electrospinning to prepare polyvinyl alcohol / dopamine modified gelatin fiber membranes, which can achieve sustained drug release by immobilizing antibacterial agents. The fiber membrane exhibits self-spreading properties, wet adhesion, and sustained drug release in a simulated oral wet environment (phosphate buffer, pH 7.2), making it a suitable oral mucosal drug delivery material.

Claims

1. An electrospun carrier material for oral mucosal drug delivery, characterized in that, The carrier material is a fiber membrane prepared by electrospinning polyvinyl alcohol (PVA) as the spinning material, by blending PVA with dopamine-modified gelatin; the fiber membrane is also loaded with an antibacterial agent during electrospinning; the specific steps for preparing the electrospun carrier material for oral mucosal drug delivery are as follows: Step 1, prepare dopamine-modified gelatin, as follows: The purified gelatin was prepared into a gelatin aqueous solution with a mass-volume percentage of 2-5% w / v. This solution was then mixed with dopamine and a biocrosslinking agent, and allowed to react for 12-24 hours. After dialysis with deionized water, the mixture was freeze-dried to obtain a gelatin-dopamine lyophilized product. The mass ratio of gelatin to dopamine was 1:0.1-0.5, and the mass ratio of gelatin to the biocrosslinking agent was 1:0.01-0.

05. The biocrosslinking agent included genipin. Step 2, preparing polyvinyl alcohol / dopamine modified gelatin electrospun fiber membrane; details are as follows: The gelatin-dopamine lyophilized product prepared in step 1 is dissolved in mixed solution A to prepare a gelatin-dopamine solution with a mass fraction of 10-20%. This solution is then mixed with a polyvinyl alcohol aqueous solution with a mass fraction of 10-20% at a mass ratio of 1:1-3 and stirred until homogeneous to obtain an electrospinning solution. The electrospinning solution is then added to an electrospinning device, the operating parameters of the electrospinning device are set, and electrospinning is performed to obtain a polyvinyl alcohol / dopamine modified gelatin electrospinned fiber membrane. The mixed solution A comprises acetic acid, ethanol and water, wherein the volume ratio of acetic acid, ethanol and water is 20-80:10-70:10-70; Step 3: Immerse the polyvinyl alcohol / dopamine modified gelatin electrospun fiber membrane prepared above in an antibacterial agent solution with a mass concentration of 10-100 mg / mL for 0.5-12 h to obtain a polyvinyl alcohol / dopamine modified gelatin electrospun fiber membrane loaded with antibacterial agent.

2. The method for preparing the electrospun carrier material for oral mucosal drug delivery as described in claim 1, characterized in that, The specific steps are as follows: Step 1, prepare dopamine-modified gelatin, as follows: The purified gelatin was prepared into a gelatin aqueous solution with a mass-volume percentage of 2-5% w / v. This solution was then mixed with dopamine and a biocrosslinking agent, and allowed to react for 12-24 hours. After dialysis with deionized water, the mixture was freeze-dried to obtain a gelatin-dopamine lyophilized product. The mass ratio of gelatin to dopamine was 1:0.1-0.5, and the mass ratio of gelatin to the biocrosslinking agent was 1:0.01-0.

05. The biocrosslinking agent included genipin. Step 2, preparing polyvinyl alcohol / dopamine modified gelatin electrospun fiber membrane; details are as follows: The gelatin-dopamine lyophilized product prepared in step 1 is dissolved in mixed solution A to prepare a gelatin-dopamine solution with a mass fraction of 10-20%. This solution is then mixed with a polyvinyl alcohol aqueous solution with a mass fraction of 10-20% at a mass ratio of 1:1-3 and stirred until homogeneous to obtain an electrospinning solution. The electrospinning solution is then added to an electrospinning device, the operating parameters of the electrospinning device are set, and electrospinning is performed to obtain a polyvinyl alcohol / dopamine modified gelatin electrospinned fiber membrane. The mixed solution A comprises acetic acid, ethanol and water, wherein the volume ratio of acetic acid, ethanol and water is 20-80:10-70:10-70; Step 3: Immerse the polyvinyl alcohol / dopamine modified gelatin electrospun fiber membrane prepared above in an antibacterial agent solution with a mass concentration of 10-100 mg / mL for 0.5-12 h to obtain a polyvinyl alcohol / dopamine modified gelatin electrospun fiber membrane loaded with antibacterial agent.

3. The method for preparing the electrospun carrier material for oral mucosal drug delivery according to claim 2, characterized in that, The operating parameters of the electrospinning device are as follows: voltage 10–25 kV, feed speed 0.5–1 mL / h, receiving distance 5–10 cm, and operating time 30–360 min.

4. The method for preparing the electrospun carrier material for oral mucosal drug delivery according to claim 2, characterized in that, The polyvinyl alcohol / dopamine modified gelatin electrospun fiber membrane obtained in step 2 has a fiber range of 300 nm to 3 μm.

5. The method for preparing the electrospun carrier material for oral mucosal drug delivery according to claim 2, characterized in that, The antibacterial agent includes amikacin.

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