Self-adhesive drug carrier thermosensitive hydrogel dressing and preparation method thereof

Abstract

The application discloses a kind of self-adhesive drug carrier temperature-sensitive hydrogel dressings, it includes temperature-sensitive matrix and imine polymer.The present application poloxamer F127 is used as temperature-sensitive matrix, and imine polymer formed by chitooligosaccharide and dopamine is used as self-adhesion component and also is the bacteriostatic oxygen molecule controlled-release system of buffer-controlled carrier, forms unique buffer-controlled release oxygen system, and a kind of composite hydrogel dressings with self-adhesion, self-healing, antibacterial, controlled release and other multiple specific functions is constructed, can be used for daily disinfection, wound healing, scar repair, the treatment of diabetic foot skin ulcer, acne and acne and the treatment of herpes skin damage;The product of the present application has good antibacterial property, water solubility, biological safety, biocompatibility, can be injected or processed into shape, can be used for rapid hemostasis, can partially replace suture, fast close wound.

Description

Technical Field

[0001] This invention relates to the field of medical materials technology. More specifically, this invention relates to a self-adhesive drug carrier thermosensitive hydrogel dressing and its preparation method. Background Technology

[0002] Bacterial infectious diseases account for one-third of global deaths. Skin tissue is an important barrier for the body to resist external environmental infections. Therefore, preventing skin tissue from bacterial infection and accelerating the healing of damaged skin tissue wounds are very urgent tasks in clinical medical work. At present, antibiotic-based therapy is the most common method of treating infections. However, the overuse of antibiotics can lead to increased bacterial resistance and even the emergence of superbugs. Medical dressings are biomedical materials used to treat sores, wounds, and other skin lesions. They are widely used in daily life. During skin trauma reconstruction or recovery, medical dressings can temporarily function as part of the skin barrier, providing a favorable microenvironment for wound healing. Medical dressings play important roles such as providing a physical barrier, controlling wound secretions and odor, controlling wound infection, stopping bleeding, reducing or eliminating scar formation, and accelerating wound healing. Hydrogel medical dressings are a new type of wound dressing developed in recent years. They are mainly composed of a gel-like substance with a three-dimensional network structure formed by the water absorption and swelling of a high-molecular polymer. Their water content can reach 96%, maintaining a moist environment on the wound surface. Hydrogels are widely used in the medical industry, such as in hydrogel dressings, drug delivery systems (DDS), and implants. Hydrogel dressings can create a local moist environment, activate the body's own enzymes to liquefy inactive tissue, accelerate the decomposition of necrotic tissue, and play a role in debridement. They are widely used in venous ulcers and ischemic arterial ulcers, while also providing occlusive protection to prevent the invasion of external bacteria. Market research indicates that the global wound dressing market was worth approximately US$13.7 billion in 2022, with high-end dressings accounting for 54.47%. With the aging global population and the increasing demands for personal hygiene and the growth of the medical care market, the dressing market is projected to reach US$20 billion by 2030.

[0003] Hydrogel dressings, with their high water content and structure similar to the extracellular matrix, offer adjustable properties and can be widely used as a novel type of biomedical dressing. Currently, hydrogel dressings on the domestic and international markets include sodium polyacrylate, polyvinyl alcohol, carbomer, hydroxyethyl cellulose, chitosan, hyaluronic acid, and sodium alginate. However, ordinary hydrogel dressings often provide excessively tight coverage of wounds, resulting in poor breathability. During application, ordinary hydrogel dressings are unsuitable for wounds with significant exudate and may soak the surrounding skin, failing to prevent bacterial infection. Most often, a second dressing is required, leading to significant limitations in the application of ordinary hydrogel dressings. Summary of the Invention

[0004] One object of the present invention is to solve at least the above-mentioned problems and to provide at least the advantages that will be described later.

[0005] Another objective of this invention is to provide a self-adhesive drug carrier thermosensitive hydrogel dressing, which is a composite hydrogel dressing with multiple specific functions such as self-adhesion, self-healing, antibacterial, and controlled release, and can effectively solve the limitations of ordinary hydrogel dressings.

[0006] To achieve these objectives and other advantages according to the invention, a self-adhesive drug carrier thermosensitive hydrogel dressing is provided, comprising a thermosensitive matrix and an imine polymer having a structure as shown in general formula (1):

[0007]

[0008] Preferably, in the self-adhesive drug carrier thermosensitive hydrogel dressing, the imine polymer has a structural formula as shown in formula (2), formula (3), or formula (4):

[0009]

[0010] Preferably, the self-adhesive drug carrier thermosensitive hydrogel dressing is prepared by the following steps: dissolving equimolar amounts of chitosan oligosaccharide and dopamine in a solvent, adding an equimolar amount of a dialdehyde compound to the chitosan oligosaccharide at room temperature, stirring and reacting for 2 hours, and removing the solvent by vacuum distillation to obtain the imine polymer.

[0011] Preferably, in the self-adhesive drug carrier thermosensitive hydrogel dressing, the solvent is ethanol with a volume fraction of 98%.

[0012] Preferably, in the self-adhesive drug carrier thermosensitive hydrogel dressing, the dialdehyde compound is malondialdehyde, butanedialdehyde, or glutaraldehyde, corresponding to the imine compound shown in formula (2), formula (3), or formula (4).

[0013] Preferably, the self-adhesive drug carrier thermosensitive hydrogel dressing has a thermosensitive matrix of saprolol F127.

[0014] Preferably, the self-adhesive drug carrier thermosensitive hydrogel dressing comprises 12-25% by mass of a thermosensitive matrix and 0.5-4% by mass of an imine polymer.

[0015] The present invention also provides a method for preparing a self-adhesive drug carrier thermosensitive hydrogel dressing, which includes the following steps: dissolving a thermosensitive matrix in a 3% (v / v) aqueous solution of chlorine dioxide, stirring evenly, adding an imine polymer, and stirring at 60°C for 1 hour to obtain the thermosensitive matrix: imine polymer: chlorine dioxide aqueous solution = 0.17g: 0.03g: 1ml.

[0016] Preferably, in the method for preparing the self-adhesive drug carrier thermosensitive hydrogel dressing, the thermosensitive matrix is ​​saprolol F127, and the imine polymer has a structural formula as shown in formula (2), formula (3), or formula (4):

[0017]

[0018] The present invention has at least the following beneficial effects:

[0019] 1. This invention uses poloxamer F127 as a temperature-sensitive matrix and an imine polymer formed by chitosan oligosaccharide and dopamine as a self-adhesive component and a controlled-release carrier to form a unique controlled-release oxygen system. This results in a composite hydrogel dressing with multiple specific functions, including self-adhesion, self-healing, antibacterial properties, and controlled release. It can be used for daily disinfection, wound healing, scar repair, treatment of diabetic foot ulcers, acne, pimples, and herpes skin lesions. The product of this invention has good antibacterial properties, water solubility, biocompatibility, and can be injected or processed into various shapes. It can be used for rapid hemostasis, partially replacing sutures, and quickly closing wounds.

[0020] 2. The hydrogel in the hydrogel dressing of the present invention has a sustainable oxygen release effect. The continuous release of oxygen enhances the survival and migration of keratinocytes and dermal fibroblasts, promotes the expression of angiogenic growth factors and angiogenesis in diabetic wounds, reduces the expression of pro-inflammatory cytokines, and further enhances the thermally responsive and tough adhesive hydrogel. Combining high extensibility, toughness, tissue adhesion, and macrophage response, it has mechanical activity and immunomodulatory effects. The hydrogel dressing of the present invention can strongly adhere to the skin and actively contract the wound in response to skin temperature exposure to accelerate wound healing. Research results show that the product of the present invention provides continuous oxygenation, promotes the formation of blood vessels, granulation tissues, etc. at the wound site, and promotes wound healing.

[0021] Other advantages, objectives and features of the present invention will become apparent in part from the following description, and in part from those skilled in the art through study and practice of the invention. Attached Figure Description

[0022] Figure 1 This is the proton NMR spectrum of the imine polymer 1 in Example 1 of the present invention;

[0023] Figure 2 This is the carbon NMR spectrum of imine polymer 1 in Example 1 of the present invention;

[0024] Figure 3 This is the proton NMR spectrum of the imine polymer 2 in Example 2 of the present invention;

[0025] Figure 4 This is the carbon NMR spectrum of the imine polymer 2 in Example 2 of the present invention;

[0026] Figure 5 This is the proton NMR spectrum of the imine polymer 3 in Example 3 of the present invention;

[0027] Figure 6 This is the carbon NMR spectrum of the imine polymer 3 in Example 3 of the present invention. Detailed Implementation

[0028] The present invention will now be described in further detail with reference to the accompanying drawings and embodiments, so that those skilled in the art can implement it based on the description.

[0029] It should be understood that terms such as “having,” “comprising,” and “including” as used herein do not exclude the presence or addition of one or more other elements or combinations thereof.

[0030] It should be noted that, unless otherwise specified, the experimental methods described in the following implementation plan are all conventional methods, and the reagents and materials described are all commercially available unless otherwise specified.

[0031] In the description of this invention, the terms "lateral", "longitudinal", "up", "down", "front", "rear", "left", "right", "vertical", "horizontal", "top", "bottom", "inner", and "outer" indicate the orientation or positional relationship based on the orientation or positional relationship shown in the accompanying drawings. They are used only for the convenience of describing this invention and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation. Therefore, they should not be construed as limitations on this invention.

[0032] This invention provides a self-adhesive drug carrier thermosensitive hydrogel dressing, comprising a thermosensitive matrix and an imine polymer, wherein the imine polymer has a structure as shown in general formula (1) (where n is a natural number, n = 0, 1, 2, 3, 4...):

[0033]

[0034] In another technical solution, the self-adhesive drug carrier thermosensitive hydrogel dressing has an imine polymer having a structural formula as shown in formula (2), formula (3), or formula (4):

[0035]

[0036] In another technical solution, the self-adhesive drug carrier thermosensitive hydrogel dressing, the preparation method of the imine polymer includes the following steps: dissolving equimolar amounts of chitosan oligosaccharide and dopamine in a solvent, adding an equimolar amount of a dialdehyde compound to the chitosan oligosaccharide at room temperature, stirring and reacting for 2 hours, and removing the solvent by vacuum distillation to obtain the imine polymer. In this invention, chitosan oligosaccharide with a degree of polymerization of 10 is selected.

[0037] In another technical solution, the solvent in the self-adhesive drug carrier thermosensitive hydrogel dressing is ethanol with a volume fraction of 98%.

[0038] In another technical solution, the self-adhesive drug carrier thermosensitive hydrogel dressing uses malondialdehyde, butanedialdehyde, or glutaraldehyde as the dialdehyde compound, which corresponds to the imine compound shown in formula (2), formula (3), or formula (4).

[0039] In another technical solution, the self-adhesive drug carrier thermosensitive hydrogel dressing uses saprolol F127 as the thermosensitive matrix.

[0040] In another technical solution, the self-adhesive drug carrier thermosensitive hydrogel dressing comprises 12-25% by mass of a thermosensitive matrix and 0.5-4% by mass of an imine polymer. The hydrogel dressing of the present invention is an aqueous solution mixture comprising 12-25% (by mass) of a thermosensitive matrix (poloxam F127), 0.5-4% (by mass) of an imine polymer, and 2-5% (by volume) of stable chlorine dioxide.

[0041] The present invention also provides a method for preparing a self-adhesive drug carrier thermosensitive hydrogel dressing, which includes the following steps: dissolving a thermosensitive matrix in a 3% (v / v) aqueous solution of chlorine dioxide, stirring evenly, adding an imine polymer, and stirring at 60°C for 1 hour to obtain the thermosensitive matrix: imine polymer: chlorine dioxide aqueous solution = 0.17g: 0.03g: 1ml.

[0042] The hydrogel prepared by this invention is a liquid, wherein saprolol F127 is gel-like at body temperature, and the imine polymer has viscosity, forming a self-adhesive gel. In use, the hydrogel dressing of this invention can be directly sprayed onto the wound to form a gel film attached to the wound.

[0043] In another technical solution, the method for preparing the self-adhesive drug carrier thermosensitive hydrogel dressing includes a thermosensitive matrix of saprolol F127 and an imine polymer having a structural formula as shown in formula (2), formula (3), or formula (4):

[0044]

[0045] <Example 1>

[0046] Synthesis of imine polymer 1

[0047] Take 0.1 mol each of chitosan oligosaccharide and dopamine, dissolve them in 100 ml of 98% ethanol, add 0.1 mol of malondialdehyde at room temperature, stir and react for 2 h, remove ethanol by vacuum distillation, and obtain a light brown imine polymer product CS-DA-Mal (yield of 75%), which is imine polymer 1, with the structural formula shown in formula (2).

[0048] Imine polymer 1 (C 180 H 242 N 20 O 51 Molecular Weight: 3502.01; Exact Mass: 3499.70; m / z: 3501.70; Elemental Analysis: C, 61.69; H, 6.91; N, 8.05.

[0049] The proton NMR spectrum of imine polymer 1 is shown below. Figure 1 As shown; 1 H NMR(CDCl3):7.51(2H,br,CH),6.52(2H,m,CH),6.41(1H,m,CH),5.01(2H,m,OH),3.61(2H,m,CH2),3.51(1H,m,CH),3.38 (2H,m,CH2),2.61(2H,d,CH2),2.01(4H,m,CH2),1.71(2H,m,CH),1.41(5H,m,CH,CH2),1.11(1H,m,CH),0.92(1H,m,CH);

[0050] The carbon NMR spectrum of imine polymer 1 is shown below. Figure 2 As shown; 13 C NMR(CDCl3):32.1,35.6,37.8,61.4,62.2,65.3,73.0,73.6,80.2,97.5,114.8,117.2,121.8,133.5,144.5,147.2,163.7;

[0051]

[0052] <Example 2>

[0053] Synthesis of imine polymer 2

[0054] Take 0.1 mol each of chitosan oligosaccharide and dopamine, dissolve them in 100 ml of 98% ethanol, add 0.1 mol of succinal aldehyde at room temperature, stir and react for 2 h, remove ethanol by vacuum distillation, and obtain a light brown imine polymer product CS-DA-Sua (yield of 81%), which is imine polymer 2, with the structural formula shown in formula (3).

[0055] Imine polymer 2 (C 190 H 262 N 20 O 51 Molecular Weight: 3642.28; Exact Mass: 3639.85; m / z: 3641.86; Elemental Analysis: C, 62.61; H, 7.23; N, 7.71.

[0056] The proton NMR spectrum of imine polymer 2 is shown below. Figure 3 As shown; 1 H NMR(CDCl3):7.52(1H,br,OH),7.50(1H,br,CH),6.51(2H,m,CH),6.42(1H,m,CH),5.02(2H,m,OH),3.62(2H,m,CH2),3.5 1(1H,m,CH),3.37(2H,m,CH2),2.62(2H,d,CH2),2.01(4H,m,CH2),1.70(2H,m,CH),1.41(5H,m,CH,CH2),1.11(1H,m,CH);

[0057] The carbon NMR spectrum of imine polymer 2 is shown below. Figure 4 As shown; 13 C NMR(CDCl3):25.1,25.4,32.1,35.6,37.8,61.7,62.5,65.3,73.0,73.6,80.2,114.8,117.2,121.8,133.5,144.5,147.2,163.7;

[0058]

[0059] <Example 3>

[0060] Synthesis of imine polymer 3

[0061] Take 0.1 mol each of chitosan oligosaccharide and dopamine, dissolve them in 100 ml of 98% ethanol, add 0.1 mol of glutaraldehyde at room temperature, stir and react for 2 h, remove ethanol by vacuum distillation, and obtain a light brown imine polymer product CS-DA-Glu (yield 78%), which is imine polymer 3, with the structural formula shown in formula (4).

[0062] Imine polymer 3 (C 200 H 282 N 20 O 51 Molecular Weight: 3782.55; Exact Mass: 3780.01; m / z: 3782.02; Elemental Analysis: C, 63.58; H, 7.53; N, 7.39; The proton NMR spectrum of imine polymer 3 is shown below. Figure 5 As shown; 1 H NMR(CDCl3):7.51(2H,br,CH),6.52(2H,m,CH),6.43(1H,m,CH),5.01(2H,m,OH),3.62(2H,m,CH2),3.51(1H,m,CH),3.37(2H,m,CH2),3.01 (1H,m,CH),2.61(2H,d,CH2),2.01(4H,m,CH2),1.71(2H,m,CH2),1.41(5H,m,CH,CH2),1.31(2H,m,CH2),1.10(1H,m,CH),0.91(1H,m,CH);

[0063] The carbon NMR spectrum of imine polymer 3 is shown below. Figure 6 As shown; 13 C NMR(CDCl3):22.7,28.8,29.1,32.1,35.6,37.8,61.7,62.5,65.3,73.0,73.6,80.2,114.8,117.2,121.8,133.5,144.5,147.5,163.7;

[0064]

[0065] <Example 4>

[0066] A method for preparing hydrogel for self-adhesive drug carrier thermosensitive hydrogel dressing includes the following steps: dissolving 17g of saprologne F127 in 100ml of a 3% (v / v) stable chlorine dioxide aqueous solution, stirring evenly, adding 3g of chitosan to the aqueous solution, and stirring at 60℃ for 1h to obtain hydrogel one.

[0067] <Example 5>

[0068] A method for preparing hydrogel for self-adhesive drug carrier thermosensitive hydrogel dressing includes the following steps: dissolving 17g of saprologne F127 in 100ml of a 3% (v / v) stable chlorine dioxide aqueous solution, stirring evenly, adding 3g of dopamine to the aqueous solution, and stirring at 60℃ for 1h to obtain hydrogel II.

[0069] <Example 6>

[0070] A method for preparing hydrogel for self-adhesive drug carrier thermosensitive hydrogel dressing includes the following steps: dissolving 17g of saprologne F127 in 100ml of stable chlorine dioxide aqueous solution with a volume fraction of 3%, stirring evenly, adding 3g of dopamine and 3g of chitosan oligosaccharide to the aqueous solution, and stirring at 60℃ for 1h to obtain hydrogel three.

[0071] <Example 7>

[0072] A method for preparing hydrogel for self-adhesive drug carrier thermosensitive hydrogel dressing includes the following steps: dissolving 17g of saprologne F127 in 100ml of a 3% (v / v) stable chlorine dioxide aqueous solution, stirring until homogeneous, adding 3g of imine polymer 1 to the aqueous solution, and stirring at 60℃ for 1h to obtain hydrogel four.

[0073] <Example 8>

[0074] A method for preparing hydrogel for self-adhesive drug carrier thermosensitive hydrogel dressing includes the following steps: dissolving 17g of saponom F127 in 100ml of a 3% volume fraction stable chlorine dioxide aqueous solution, stirring evenly, adding 3g of imine polymer 2 to the aqueous solution, and stirring at 60℃ for 1h to obtain hydrogel five.

[0075] <Example 9>

[0076] A method for preparing hydrogel for self-adhesive drug carrier thermosensitive hydrogel dressing includes the following steps: dissolving 17g of saprologne F127 in 100ml of a 3% volume fraction stable chlorine dioxide aqueous solution, stirring evenly, adding 3g of imine polymer 3 to the aqueous solution, and stirring at 60℃ for 1h to obtain hydrogel six.

[0077] <Experimental Example 1>

[0078] Wound healing test

[0079] Thirty Wistar rats (approximately 160g, six weeks old) were used. The rats were anesthetized by intraperitoneal injection of 5% trichloroacetaldehyde. The hair on their backs was clipped, and the skin was disinfected by wiping with 75% alcohol. A 1cm × 1cm circular wound was made on the midline of the rat's back, 4cm from the midline behind the ear, using a 1cm diameter skin biopsy instrument. The excision reached the fascia. A dressing was applied to the wound on the rat's back twice daily.

[0080] The wound was observed on days 0, 2, 4, 6, and 8. Each time, the wound was cleaned, photographed, and the hydrogel dressing was changed. The wound area was measured using Imagel software, and the wound healing rate was calculated.

[0081] The formula for calculating the degree of healing is as follows:

[0082] Wound healing percentage % = [(wound area on day n - initial wound area) / initial wound area] × 100%;

[0083] The experiment was divided into the following eight groups:

[0084] Control group: Take sterile water;

[0085] Control group: Wounds were treated with commercially available wound gel dressings; (Baumann's Moisturizing Gel Dressing was selected as the commercially available wound gel dressing).

[0086] Experimental group 1: Hydrogel 1 prepared in Example 4;

[0087] Experimental Group 2: Hydrogel II prepared in Example 5;

[0088] Experimental group 3: Hydrogel III prepared in Example 6;

[0089] Experimental group 4: Hydrogel IV prepared in Example 7;

[0090] Experimental group 5: Hydrogel 5 prepared in Example 8;

[0091] Experimental group 6: Hydrogel VI prepared in Example 9;

[0092] The healing rate (%) at different time points for each group was statistically analyzed, and the results are shown in Table 1.

[0093] Table 1

[0094]

[0095] During the experiment, the hydrogels in experimental groups 1-6 were liquids, which were sprayed directly onto the wounds and adhered well to form gels with moderate viscosity. The results showed that the wound healing rate of experimental groups 4-6 exceeded 98% on day 8, an improvement of approximately 15% compared to the control group. This demonstrates that the self-adhesive thermosensitive hydrogels prepared using three imine polymers in this invention have a synergistic promoting effect on wound healing in mice, significantly accelerating wound healing.

[0096] The self-adhesive, temperature-sensitive hydrogel composition of this invention not only exhibits good water solubility and high viscosity, but also demonstrates a synergistic effect of its multiple components on wound healing in mice. This formulation can be applied to skincare products, pharmaceuticals, and other fields to enhance the skin's self-repair capabilities and promote wound healing.

[0097] The number of devices and processing scale described herein are for the purpose of simplifying the description of the invention. Applications, modifications, and variations of the invention will be readily apparent to those skilled in the art.

[0098] Although embodiments of the present invention have been disclosed above, they are not limited to the applications listed in the specification and embodiments. They can be applied to various fields suitable for the present invention. For those skilled in the art, other modifications can be easily made. Therefore, without departing from the general concept defined by the claims and their equivalents, the present invention is not limited to the specific details and illustrations shown and described herein.

Claims

1. A self-adhesive drug carrier thermosensitive hydrogel dressing, characterized in that, The preparation method includes the following steps: dissolving the thermosensitive matrix in a 3% (v / v) aqueous solution of chlorine dioxide, stirring until homogeneous, adding the imine polymer, and then heating at a temperature of 60°C. o Stirring at C for 1 hour yields the product; the temperature-sensitive matrix is ​​poloxamer F127, and the imine polymer has the structural formula shown in formula (2), formula (3) or formula (4): 。 2. The self-adhesive, medicated carrier, temperature-sensitive hydrogel dressing of claim 1, wherein, The imine polymer is prepared by the following method: equimolar amounts of chitosan oligosaccharide and dopamine are dissolved in a solvent, an equimolar amount of dialdehyde compound is added, the mixture is stirred at room temperature for 1 to 4 hours, and the solvent is removed to obtain the polymer.

3. The self-adhesive drug carrier thermosensitive hydrogel dressing of claim 2, wherein, The dialdehyde compound is malondialdehyde, succinaldehyde, or glutaraldehyde.

4. The self-adhesive drug carrier temperature-sensitive hydrogel dressing of claim 1, wherein, The thermosensitive matrix has a mass fraction of 12% to 25% in the dressing, and the imine polymer has a mass fraction of 0.5% to 4% in the dressing.

5. A method for preparing a self-adhesive drug carrier thermosensitive hydrogel dressing as described in any one of claims 1 to 4, characterized in that, Includes the following steps: Poloxamer F127 was dissolved in a 3% (v / v) aqueous solution of chlorine dioxide and stirred until homogeneous. Then, an imine polymer having the structure shown in formula (2), (3) or (4) was added and stirred at 60°C for 1 hour to obtain the product.

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