A self-adhesive drug-loaded hydrogel medical strip with a double-layer Janus structure and its preparation method

Abstract

The present invention relates to the field of medical biomaterials, and discloses a self-adhesive drug-loaded hydrogel medical strip with a double-layer Janus structure and a preparation method thereof. The method includes: preparing an upper matrix solution with polyethylene glycol diacrylate, lithium saponite nanoclay, a first ultraviolet light initiator, and water; preparing a lower matrix solution with sodium alginate, acrylamide, methacrylated gelatin, a second ultraviolet light initiator, and water; synchronously extruding the upper and lower matrix solutions to a coagulation bath by using a flat needle with a double-layer flow channel; and sequentially curing by ultraviolet light and blue light irradiation to obtain the self-adhesive drug-loaded hydrogel medical strip with a double-layer Janus structure. The present invention adopts a synchronous extrusion process, can be continuously produced, the formed strip can be directly wound and stored, reduces packaging requirements, increases the utilization rate of storage space, and reduces production costs. Its lower-layer hydrogel is used for drug loading and water retention, and the upper-layer polymer provides mechanical strength and sufficient stability. The upper and lower layers cooperate with each other to improve the overall performance.

Description

Technical Field

[0001] The present invention relates to the field of medical biomaterials, and specifically relates to a self-adhesive drug-loaded hydrogel medical strip with a double-layer Janus structure and a preparation method thereof. Background Art

[0002] In the fields of tissue engineering and biomedical materials, hydrogel materials are widely used in wound repair, drug delivery, etc. due to their good biocompatibility and biomimetic modulus. However, there are many inevitable problems in the application of traditional hydrogel materials in wound repair:

[0003] 1. Hydrogels of single components are difficult to simultaneously possess mechanical strength and biocompatibility: for example, methacrylated gelatin has excellent biocompatibility but low mechanical strength;

[0004] 2. It is difficult to scale up: existing preparation methods for multi-layer structures include layer-by-layer coating or secondary processing, which are cumbersome and have poor performance;

[0005] 3. Storage problems: single-layer drug-loaded hydrogels are prone to dehydration and failure, and are difficult to store.

[0006] These problems not only limit the medical prospects of hydrogels, but also greatly increase the production cost of hydrogel patches, seriously hindering their commercial applications. Summary of the Invention

[0007] In view of the above technical problems, the present invention provides a self-adhesive drug-loaded hydrogel medical strip with a double-layer Janus structure and a preparation method thereof, so as to solve the problems of difficult preparation and poor performance of existing double-layer hydrogel medical patches or dressings.

[0008] To achieve the above object, the present invention provides a preparation method for a self-adhesive drug-loaded hydrogel medical strip with a double-layer Janus structure, including the following steps:

[0009] (1) Prepare the upper matrix solution

[0010] Polyethylene glycol diacrylate, lithium saponite nanoclay, and a first ultraviolet light initiator are added to water and mixed evenly to obtain the upper matrix solution;

[0011] (2) Prepare the lower matrix solution

[0012] Sodium alginate, acrylamide, methacrylated gelatin, and a second ultraviolet light initiator are added to water and mixed evenly to obtain the lower matrix solution;

[0013] (3) Synchronous extrusion

[0014] The upper matrix solution and the lower matrix solution prepared in steps (1) and (2) are simultaneously extruded into a coagulation bath using a flat needle with a double-layer flow channel to form a double-layer structural material including an upper matrix material and a lower matrix material, where the upper matrix solution and the lower matrix solution respectively correspond to the upper flow channel and the lower flow channel of the flat needle;

[0015] In the present invention, by adjusting the influence of the laminar flow caused by viscosity on the flow rate, the upper and lower matrix solutions can be uniformly extruded, satisfying that the square root of the ratio of the heights of the upper and lower flow channels of the flat needle is proportional to the ratio of the viscosities of the upper and lower matrix solutions, satisfying , and are the heights of the upper and lower flow channels respectively, and are the viscosities of the upper and lower matrix solutions respectively. The coefficient f takes a value of 0.9 to 1.1, and the best value is when f is 1;

[0016] (4) Stepwise crosslinking

[0017] The double-layer structural material passing through the coagulation bath in step (3) is first irradiated with a first ultraviolet light source to cure the upper matrix material, and then irradiated with a second ultraviolet light source to cure the lower matrix material, finally obtaining a self-adhesive drug-loaded hydrogel medical strip with a double-layer Janus structure. Among them, the wavelength of the first ultraviolet light source is less than that of the second ultraviolet light source, and preferably the difference in their wavelengths is at least 20 nm.

[0018] In the present invention, a flat needle with a double-layer flow channel is used to simultaneously extrude the upper / lower matrix solutions. The key lies in adjusting the influence of the laminar flow caused by viscosity on the flow rate, so that the upper / lower matrix solutions can be uniformly and continuously extruded. In a preferred embodiment, the viscosity of the upper matrix solution is , the viscosity of the lower matrix solution is , the height of the upper flow channel is 0.45 mm, and the height of the lower flow channel is 0.30 mm.

[0019] For the self-adhesive drug-loaded hydrogel medical strip with a double-layer Janus structure of the present invention, its upper structure is formed into a dense structure by ultraviolet crosslinking of the upper matrix solution, which is used to provide mechanical support and waterproof performance. The lower structure is formed into a porous network by ionic crosslinking of polymers containing amino, hydroxyl, carboxyl, and carbonyl groups in the lower matrix solution, which is used to load drugs and has adhesiveness at the same time; the raw materials in the upper and lower layers can achieve a synchronous crosslinking process under ultraviolet light, so that covalent crosslinking can occur between the gel in the lower layer and the polymer in the upper layer, thus realizing the construction of a stable interface.

[0020] As a further preferred technical solution of the present invention, the first ultraviolet light initiator is Irgacure 2959; and / or, the second ultraviolet light initiator is lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP).

[0021] As a further preferred technical solution of the present invention, in the upper matrix solution, the content of polyethylene glycol diacrylate is 10-30 wt.%, the content of lithium saponite nanoclay is 1-5 wt.%, and the content of the first ultraviolet light initiator is 0.5-3 wt.%. For example, the content of polyethylene glycol diacrylate can be typical but non-limiting mass percentage contents such as 10 wt.%, 15 wt.%, 20 wt.%, 25 wt.%, etc., the content of lithium saponite nanoclay can be typical but non-limiting mass percentage contents such as 1 wt.%, 2 wt.%, 3 wt.%, 4 wt.%, 5 wt.%, etc., and the content of the first ultraviolet light initiator can be typical but non-limiting mass percentage contents such as 0.5 wt.%, 1 wt.%, 1.5 wt.%, 2 wt.%, 2.5 wt.%, 3 wt.%, etc.

[0022] As a further preferred technical solution of the present invention, in the lower matrix solution, the content of sodium alginate is 0.5-3 wt.%, the content of acrylamide is 1-10 wt.%, the content of methacrylated gelatin is 1-10 wt.%, and the content of the second ultraviolet light initiator is 0.5-2 wt.%. For example, the content of sodium alginate can be typical but non-limiting mass percentage contents such as 0.5 wt.%, 1 wt.%, 1.5 wt.%, 2 wt.%, 2.5 wt.%, 3 wt.%, etc., the content of acrylamide can be typical but non-limiting mass percentage contents such as 1 wt.%, 2 wt.%, 3 wt.%, 4 wt.%, 5 wt.%, 6 wt.%, 7 wt.%, 8 wt.%, 9 wt.%, etc., the content of methacrylated gelatin can be typical but non-limiting mass percentage contents such as 1 wt.%, 2 wt.%, 3 wt.%, 4 wt.%, 5 wt.%, 6 wt.%, 7 wt.%, 8 wt.%, 9 wt.%, etc., and the content of the second ultraviolet light initiator can be typical but non-limiting mass percentage contents such as 0.5 wt.%, 1 wt.%, 1.5 wt.%, 2 wt.%, etc.

[0023] As a further preferred technical solution of the present invention, the coagulation bath is a CaCl2 solution with a concentration of 1-5 wt.%, for example, typical but non-limiting mass percentage concentrations such as 1 wt.%, 1.5 wt.%, 2 wt.%, 3 wt.%, 4 wt.%.

[0024] As a further preferred technical solution of the present invention, in the step of stepwise crosslinking, curing is carried out in two stages according to different types of initiators, specifically: in the first stage, the upper matrix material is cured by irradiating with a first ultraviolet light source with a wavelength of 365 nm and an intensity of 5-15 mW / cm² for 10-30 seconds; in the second stage, the lower matrix material is cured by irradiating with a second ultraviolet light source with a wavelength of 405 nm and an intensity of 5-10 mW / cm² for 1-3 minutes.

[0025] According to another aspect of the present invention, the present invention also provides a self-adhesive drug-loaded hydrogel medical strip with a double-layer janus structure, which is prepared by the above method. It should be noted here that: the self-adhesive drug-loaded hydrogel medical strip of the present invention has a drug-loading function, and can be specifically realized by referring to the existing conventional methods for drug-loaded hydrogels, for example: doping drug components into the lower matrix solution during the preparation of the strip, or applying drug components on the surface of the lower structure formed by the lower matrix solution during the use of the strip. The drug components can be selected as antibacterial and anti-inflammatory drug components according to different treatment purposes for wounds, which belongs to conventional technology and will not be exemplified here.

[0026] Compared with the prior art, the present invention can achieve the following beneficial effects:

[0027] (1) One-piece molding: Synchronous extrusion and stepwise crosslinking greatly shorten the preparation cycle, eliminating the cumbersome steps of multi-layer coating or secondary reaction required for multi-layer structures in traditional methods.

[0028] (2) Performance synergy: The hydrogel of the lower structure is used for drug loading and water retention, and the polymer of the upper structure provides mechanical strength and sufficient stability. The upper and lower layers cooperate with each other to improve the overall performance.

[0029] (3) Scalability: The synchronous extrusion process is adopted, which can be continuously produced. The formed strips can be directly wound and stored, reducing packaging requirements, increasing the utilization rate of storage space, reducing production costs, and thus facilitating industrial mass production. Specific Embodiments

[0030] The following will detail the specific embodiments of the present invention. It should be understood that the specific embodiments described here are only for explaining and illustrating the present invention, and are not used to limit the present invention.

[0031] Unless otherwise defined, the technical terms used in the following embodiments have the same meaning as commonly understood by those skilled in the field to which the present invention belongs. The test reagents used in the following embodiments are all conventional biochemical reagents unless otherwise specified; the experimental methods are all conventional methods unless otherwise specified.

[0032] Example 1: One-piece molded double-layer structure hydrogel strip

[0033] (1) Prepare the upper matrix solution

[0034] Using water as the solvent, the dosages of the remaining components are as follows laponite nanoclay and photoinitiator are mixed to prepare an upper matrix solution with a viscosity of .

[0035] (2)Prepare the lower matrix solution

[0036] Using water as the solvent, the dosages of the remaining components are mixed according to 1.25 wt.% sodium alginate, 5 wt.% acrylamide, 5 wt.% methacrylated gelatin, and 1 wt.% initiator LAP to prepare a lower matrix solution with a viscosity of .

[0037] (3)Coextrusion

[0038] Design a flat needle with a double-layer channel structure in which the upper channel and the lower channel are parallel and superimposed. Among them: the widths of the upper and lower channels are the same, both are 10 mm; the height of the upper channel is 0.45 mm, and the height of the lower channel is 0.3 mm; the upper matrix solution and the lower matrix solution prepared in steps (1) and (2) are coextruded into a coagulation bath (2 wt.% CaCl2 solution) through the flat needle, where the upper matrix solution corresponds to the upper channel and the lower matrix solution corresponds to the lower channel. The flow rates of the upper and lower matrix solutions are 150 mL / h and 100 mL / h respectively. When the upper and lower matrix solutions are extruded through the flat needle, a laminar flow phenomenon appears, so that the upper and lower matrix solutions can be evenly and continuously extruded into the coagulation bath and form a double-layer structural material including the upper matrix material and the lower matrix material. The heights of the upper and lower channels correspond to the thicknesses of the upper and lower matrix materials.

[0039] (4)Stepwise crosslinking

[0040] For the double-layer structural material extruded into the coagulation bath in step (3), the lower matrix material forms an initial gel structure through ionic crosslinking in the coagulation bath, and then undergoes stepwise curing to form a stable double-layer structure with covalent bonds. Specifically: in the first stage, irradiate with 365 nm and 10 mW / cm² for 30 seconds; in the second stage, irradiate with 405 nm and 8 mW / cm² for 2 minutes to finally obtain a double-layer janus-structured hydrogel medical strip.

[0041] The performance of the hydrogel medical strip prepared in Example 1 was measured as follows

[0042] Adhesion strength: 2.8 N / cm; Tensile strength of the upper layer: 1.23 MPa, Water absorption rate: 984%; Tensile strength of the lower layer: 0.34 MPa; Overall tensile strength: 0.86 MPa.

[0043] Comparative Example 1: Layer-by-layer coating to form a double-layer hydrogel strip

[0044] First, prepare the upper and lower matrix solutions using the same steps (1) and (2) as in Example 1; then, coat the lower matrix solution on a pre-prepared template with the same width and thickness as the lower flow channel in Example 1, and fix it by irradiating with blue light at 405 nm and 8 mW / cm²; after the lower matrix solution is completely cured, coat the upper solution on the cured lower template with the same width and thickness as the upper flow channel in Example 1, and fix it by irradiating with ultraviolet light at 365 nm and 10 mW / cm².

[0045] Compare the preparation cycle (excluding the preparation cycle of the upper and lower matrix solutions) of the two methods in Example 1 and Comparative Example 1 with the interfacial strength of the final product (preset length is 10 cm). The results are shown in Table 1.

[0046] Table 1

[0047]

[0048] Since the present invention uses the synchronous extrusion method, the upper and lower matrix solutions can be continuously extruded into the coagulation bath to form a stable double-layer structure. Combined with light fixation, continuous production can be achieved. When preparing double-layer hydrogel strips in large quantities, compared with layer-by-layer coating to form double-layer hydrogel strips, the cycle is short and the operation is convenient, thus having obvious advantages.

[0049] Comparative Example 2: Forming a single-layer hydrogel strip

[0050] Prepare the lower matrix solution using the same step (2) as in Example 1, then extrude the lower matrix solution into the coagulation bath (2 wt.% CaCl2 solution) through the lower flow channel of the flat needle in Example 1 at a flow rate of 100 mL / h, and then irradiate with light at 405 nm and 8 mW / cm² for 2 minutes to obtain a single-layer hydrogel strip.

[0051] Record the change in water retention rate within 7 days after the preparation of the double-layer hydrogel strip in Example 1 and the single-layer hydrogel strip in Comparative Example 2. The results are shown in Table 2.

[0052] Table 2

[0053]

[0054] As can be seen from Table 2, the single-layer hydrogel is prone to dehydration and failure and difficult to store, while the double-layer hydrogel has a longer water retention effect. This is because the single-layer hydrogel is directly exposed to the environment, significantly accelerating the water evaporation rate. Secondly, in the double-layer structure, the upper layer is formed by ultraviolet cross-linking of polyethylene glycol diacrylate (PEGDA) and lithium soapstone nanoclay to form a dense network structure. This dense network structure serves as a physical barrier, effectively reducing the evaporation of the water stored in the inner layer. The double-layer Janus structure realizes the optimization of high water absorption and excellent water retention performance through the multi-functional design of the dense upper layer and the highly water-absorbent lower layer.

[0055] To further prove the beneficial technical effects of the present invention, based on the preparation method of Example 1 below, only by changing the height ratio of the upper and lower flow channels (the rest of the operations are the same as those in Example 1), that is, fixing the height of the lower flow channel at 0.3 mm and adjusting the height of the upper flow channel to verify the influence of the height ratio of different upper and lower flow channels on the uniformity of the extruded solution (the viscosity of the upper solution is 264 ± 5 mPa·s, and the viscosity of the lower solution is 120 ± 5 mPa·s), the experimental data and results are shown in Table 3.

[0056] Table 3

[0057]

[0058] As can be seen from the data in Table 3, when the height ratio is 1.5, the matching with the viscosity of the matrix solution is the best, the interfacial strength reaches 1.7 N / cm, and the prepared double-layer structure is uniform (that is, the upper and lower layer interfaces are obvious); when the height ratio of the upper and lower flow channels deviates from 1.5 times, too large or too small, the flow rate will be unbalanced, resulting in interfacial defects.

[0059] The present invention adjusts the height of the flow channels so that the height ratio of the upper and lower flow channels of the flat needle is proportional to the square root of the viscosity ratio of the upper and lower matrix solutions, so as to adjust the influence of the laminar flow caused by the viscosity on the flow rate, enabling the upper and lower layers to be extruded evenly, and then forming a double-layer structure, making it possible to continuously and integrally form a double-layer structure strip, improving the efficiency.

[0060] Although the specific implementation manners of the present invention are described above, those skilled in the art should understand that these are only examples, and various changes or modifications can be made to this implementation manner without departing from the principles and essence of the present invention. The protection scope of the present invention is only defined by the appended claims.

Claims

1. A preparation method of a self-adhesive drug-loaded hydrogel medical strip with a double-layer Janus structure, characterized in that, It includes the following steps: (1) Prepare the upper matrix solution Polyethylene glycol diacrylate, laponite nanoclay and the first ultraviolet initiator are added to water and mixed evenly to obtain the upper matrix solution; (2) Prepare the lower matrix solution Sodium alginate, acrylamide, methacrylated gelatin and the second ultraviolet initiator are added to water and mixed evenly to obtain the lower matrix solution; (3) Synchronous extrusion The upper matrix solution and the lower matrix solution prepared in steps (1) and (2) are synchronously extruded into a coagulation bath through a flat needle with a double-layer flow channel to form a double-layer structural material including an upper matrix material and a lower matrix material. The upper matrix solution and the lower matrix solution respectively correspond to the upper flow channel and the lower flow channel of the flat needle; The ratio of the heights of the upper and lower channels of the flat needle is proportional to the square root of the ratio of the viscosities of the upper and lower matrix solutions, satisfying the formula: = f , where and are the heights of the upper and lower channels respectively, and are the viscosities of the upper and lower matrix solutions respectively, and the coefficient f takes a value of 0.9 to 1.1; (4) Step-by-step crosslinking The double-layer structural material passing through the coagulation bath in step (3) is first irradiated by a first ultraviolet light source to cure the upper matrix material, and then irradiated by a second ultraviolet light source to cure the lower matrix material, and finally a double-layer Janus structure self-adhesive drug-loaded hydrogel medical strip is obtained; Among them, the wavelength of the first ultraviolet light source is less than the wavelength of the second ultraviolet light source.

2. The preparation method of the self-adhesive drug-loaded hydrogel medical strip with a double-layer Janus structure according to claim 1, characterized in that The first ultraviolet initiator is Irgacure 2959; and / or, the second ultraviolet initiator is lithium phenyl-2,4,6-trimethylbenzoylphosphinate.

3. The preparation method of the self-adhesive drug-loaded hydrogel medical strip with a double-layer Janus structure according to claim 1, characterized in that, In the upper matrix solution, the content of polyethylene glycol diacrylate is 10-30 wt.%, the content of laponite nanoclay is 1-5 wt.%, and the content of the first ultraviolet initiator is 0.5-3 wt.%.

4. The preparation method of the self - adhesive drug - loaded hydrogel medical strip with a double - layer Janus structure according to claim 1, wherein, In the lower matrix solution, the content of sodium alginate is 0.5-3 wt.%, the content of acrylamide is 1-10 wt.%, the content of methacrylated gelatin is 1-10 wt.%, and the content of the second ultraviolet initiator is 0.5-2 wt.%.

5. The preparation method of the self-adhesive drug-loaded hydrogel medical strip with a double-layer Janus structure according to claim 1, characterized in that, The coagulation bath is a 1-5 wt.% concentration of CaCl2 solution.

6. The preparation method of the self-adhesive drug-loaded hydrogel medical strip with a double-layer Janus structure according to claim 1, characterized in that, In the step of step-by-step crosslinking, curing is carried out in two stages according to different types of initiators. Specifically: in the first stage, the upper matrix material is cured by irradiating with a first ultraviolet light source with a wavelength of 365 nm and an intensity of 5-15 mW / cm² for 10-30 seconds; in the second stage, the lower matrix material is cured by irradiating with a second ultraviolet light source with a wavelength of 405 nm and an intensity of 5-10 mW / cm² for 1-3 minutes.

7. A self-adhesive drug-loaded hydrogel medical strip with a double-layer Janus structure, characterized in that, It is prepared by the method according to any one of claims 1-6.

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