A pH response charge reversal type acne-removing microneedle patch

Abstract

The present application relates to the technical field of medical devices, in particular to a pH-responsive charge-reversal type acne-removing microneedle patch, the matrix of the acne-removing microneedle patch is composed of carboxymethylated chitosan, active ingredients and pure water; the carboxymethylated chitosan is single-substitution-degree carboxymethylated chitosan or a mixture of two carboxymethylated chitosans with different substitution degrees. In particular, the present application adopts two carboxymethylated chitosans with different substitution degrees for blending as the matrix, by changing the blending ratio, the apparent isoelectric point, drug release rate and mechanical properties of the whole system can be continuously and finely adjusted, so as to overcome the contradiction that single-substitution-degree carboxymethylated chitosan is difficult to balance rapid response, rapid release and sufficient mechanical strength, and realize the synergistic optimization and customization of performance.

Description

Technical Field

[0001] This invention relates to the field of medical device technology, specifically to a pH-responsive charge-reversing microneedle patch for acne treatment. Background Technology

[0002] Acne, a common inflammatory skin disease, is closely related to the proliferation of Propionibacterium acnes in the pilosebaceous unit. Traditional topical preparations are limited by the barrier function of the stratum corneum, resulting in low drug penetration efficiency and difficulty in achieving effective concentrations at the lesion site. Although microneedling technology can break through the stratum corneum barrier, most existing products lack the ability to actively respond to the specific pathological microenvironment of acne, such as elevated pH levels, resulting in untargeted drug release that may cause skin irritation or incomplete treatment.

[0003] Carboxymethylated chitosan is a highly water-soluble chitosan derivative with advantages such as good biocompatibility and biodegradability. However, how to precisely design the molecular structure of carboxymethylated chitosan to not only serve as a drug carrier but also actively respond to the elevated pH value at acne inflammation sites for intelligent targeted delivery remains an unsolved technical problem. Furthermore, materials with a single degree of substitution often present irreconcilable contradictions in terms of solubility, mechanical strength, and pH response sensitivity. Summary of the Invention

[0004] The purpose of this invention is to provide a pH-responsive charge reversal microneedle patch for acne treatment. The core matrix material of this microneedle patch is specially designed to intelligently identify and respond to changes in the microenvironment of acne-inflamed areas, rapidly responding through surface charge reversal, thereby significantly improving treatment efficacy and reducing side effects.

[0005] To achieve the above objectives, the present invention adopts the following technical solution: A pH-responsive charge-reversal acne-removing microneedle patch, wherein the matrix of the acne-removing microneedle patch comprises carboxymethylated chitosan, active ingredients, and purified water.

[0006] Preferably, the carboxymethylated chitosan is a carboxymethylated chitosan with a single degree of substitution or a mixture of two carboxymethylated chitosans with different degrees of substitution.

[0007] Furthermore, the degree of carboxymethyl substitution of the single-degree-of-substitution carboxymethylated chitosan is controlled between 0.3 and 1.0, and the apparent isoelectric point of the single-degree-of-substitution carboxymethylated chitosan is between 4.5 and 6.5.

[0008] Furthermore, the mixture of the two carboxymethylated chitosans with different degrees of substitution includes a first type of carboxymethylated chitosan and a second type of carboxymethylated chitosan.

[0009] Preferably, the mass ratio of the first type of carboxymethylated chitosan to the second type of carboxymethylated chitosan is 1:9 to 9:1, and more preferably, the mass ratio is 3:7 to 7:3.

[0010] Preferably, the first type of carboxymethylated chitosan has a higher degree of substitution, ranging from 0.6 to 1.2; the second type of carboxymethylated chitosan has a lower degree of substitution, ranging from 0.2 to 0.6. By adjusting the mixing ratio of the first type of carboxymethylated chitosan and the second type of carboxymethylated chitosan, the apparent isoelectric point of the matrix based on the mixture of the two types of carboxymethylated chitosan with different degrees of substitution is precisely controlled to be 4.5 to 6.5.

[0011] More preferably, the degree of carboxymethyl substitution of the final material system, whether as a single component or in blends, is concentrated between 0.35 and 0.8, and the apparent isoelectric point is concentrated between 5.0 and 6.0.

[0012] Preferably, the raw material for preparing the carboxymethylated chitosan is chitosan with a degree of deacetylation of not less than 85%, in order to ensure the performance stability and reactivity of the product.

[0013] Preferably, the active ingredient includes at least a component capable of inhibiting or killing Propionibacterium acnes, and may further include a component with anti-inflammatory or skin barrier repair functions.

[0014] Preferably, the acne-removing microneedle patch adopts an integrated molding process. The solution is prepared by adding carboxymethylated chitosan to pure water, then adding active ingredients and stirring evenly. The solution is then added to a microneedle mold, centrifuged, dried and cured, and then peeled off to obtain an acne-removing microneedle patch containing a microneedle array and a backing layer.

[0015] Compared with the prior art, the present invention has the following outstanding advantages: First, this invention achieves truly intelligent active targeting. The material designed in this invention has a nearly neutral surface charge in the slightly acidic environment of healthy skin (pH approximately 5.4–5.8), and its molecular chains are tightly contracted, resulting in an extremely stable microneedle morphology that prevents premature drug release. However, in the slightly alkaline environment (pH > 6.5) where acne inflammation occurs, its surface rapidly transforms into a negatively charged state. Because the polymer chains are densely covered with negative charges, and the surface of Propionibacterium acnes also carries a negative charge, the strong electrostatic repulsion between the same charges causes the polymer network to rapidly expand, allowing for targeted and rapid drug release at the lesion site, greatly improving the precision and efficiency of treatment.

[0016] Secondly, the challenge of balancing material properties was solved through a blending strategy. Blending two materials with different degrees of substitution is an innovative design. This is not merely physical mixing, but the creation of a precisely controllable composite material system. By changing the blending ratio, the apparent isoelectric point, drug release rate, and mechanical properties of the entire system can be continuously and precisely adjusted. This overcomes the contradiction that a single material cannot simultaneously achieve rapid response, rapid release, and sufficient mechanical strength, thus realizing synergistic optimization and customization of performance. The molecular chain of single-substituted carboxymethyl chitosan has a relatively uniform distribution of functional groups. However, when two carboxymethyl chitosans with different degrees of substitution are blended, the low-substituted carboxymethyl chitosan contains a large number of amino and hydroxyl groups, while the high-substituted carboxymethyl chitosan contains a large number of carboxyl groups. This difference in functional groups results in stronger intermolecular and electrostatic interactions in the blended matrix, thereby enhancing the matrix strength. At the same time, in the inflammatory microenvironment of acne with pH > 6.5, the high-substituted region preferentially swells and dissociates, rapidly building hydration channels within the matrix and promoting the overall disintegration of the matrix from the inside out. This enables the explosive and targeted release of active ingredients at the lesion site.

[0017] Secondly, the product has a simple and reliable structure. The integrated homogeneous matrix design avoids complex multi-layer structures, simplifies the manufacturing process, improves product consistency and stability, and ensures the uniform distribution of active ingredients in the microneedles.

[0018] Finally, this technology platform is highly scalable. This intelligent matrix system can serve as a universal platform for delivering active ingredients, combining with drugs or active ingredients with different mechanisms of action, thus laying a solid technological foundation for the development of a series of precision acne treatment products. Detailed Implementation

[0019] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0020] Example 1: A pH-responsive charge-reversal acne-removing microneedle patch 10 g of chitosan raw material with a degree of deacetylation of 90% was dissolved in a 2% acetic acid solution. Isopropanol was added to the system as a dispersion medium under stirring, followed by slow dropwise addition of a 20% sodium hydroxide solution for alkalization. The reaction system temperature was controlled at 60℃. Chloroacetic acid was slowly added to the system at a molar ratio of chloroacetic acid to chitosan sugar residues of 0.8:1 to initiate the carboxymethylation reaction, which was continued for 4 hours. After the reaction was complete, the product was precipitated using ethanol. After thorough washing and drying, a white powdery carboxymethylated chitosan sample was obtained, designated CMCS-1, with a degree of carboxymethyl substitution of 0.65. This product is readily soluble in water, forming a clear, homogeneous, and viscous aqueous solution.

[0021] Example 2: A pH-responsive charge-reversal acne-removing microneedle patch Following the method of Example 1, by changing the molar ratio of chloroacetic acid to chitosan sugar residues at ratios of 0.68:1 and 1.0:1 respectively, while keeping other conditions constant, two other carboxymethylated chitosan samples were prepared, designated CMCS-2 and CMCS-3. Both were completely soluble in water to form homogeneous solutions. The degree of substitution of CMCS-2 was determined to be 0.55, and that of CMCS-3 was 0.8.

[0022] Example 3: A pH-responsive charge-reversal acne-removing microneedle patch Following the method of Example 1, by changing the molar ratio of chloroacetic acid to chitosan sugar residues at ratios of 0.42:1 and 0.6:1 respectively, while keeping other conditions constant, two other carboxymethylated chitosan samples were prepared, designated CMCS-4 and CMCS-5. Both were completely soluble in water to form a homogeneous solution. The degree of substitution of CMCS-4 was determined to be 0.35, and that of CMCS-5 was 0.5.

[0023] Example 4: A pH-responsive charge-reversal acne-removing microneedle patch The CMCS-1 obtained in Example 1 was prepared into an aqueous solution with a concentration of 8% by weight / volume. Azelaic acid (1% by weight of CMCS-1) was added to this solution as an antibacterial agent, and dipotassium glycyrrhizate (0.5% by weight) as an anti-inflammatory agent. The solution was stirred until homogeneous, forming a clear, homogeneous microneedle molding solution with a certain degree of viscoelasticity. The molding process was performed using a template method: the molding solution was precisely injected into a polydimethylsiloxane negative mold with a regular inverted pyramid microporous array needle height of 500 micrometers and a bottom width of 300 micrometers. The mold was placed in a centrifuge and centrifuged at 3000 rpm for 5 minutes to ensure that the molding solution completely filled each microneedle cavity and eliminated internal air bubbles. The mold was then transferred to room temperature and allowed to dry horizontally for 24 hours. After the moisture had completely evaporated and the matrix had solidified, the patch was carefully peeled off from the mold to obtain an integrated acne-removing microneedle patch with a complete structure, sharp needles, and a single CMCS matrix.

[0024] The degree of substitution of CMCS-1 as the matrix is ​​0.65, the apparent isoelectric point is 5.4, the potential is close to zero at pH 5.5, and the potential drops significantly to -15mV at pH 7.0, showing clear charge reversal characteristics; the solubility is 22g / L, the dry compressive strength of the acne-removing microneedle patch prepared in Example 4 is 0.42MPa, the antibacterial rate of Propionibacterium acnes is 85.4%, the drug release rate is 42.3% after 1 hour and 81.3% after 4 hours under inflamed skin conditions.

[0025] Example 5: A pH-responsive charge-reversal acne-removing microneedle patch CMCS-2 (degree of substitution 0.55) and CMCS-3 (degree of substitution 0.8) prepared in Example 2 were weighed separately at a mass ratio of 5:5 and thoroughly mixed to obtain a homogeneous powder. The powder was then added to pure water and stirred until completely dissolved to prepare an aqueous solution of the blend with a total concentration of 8% by weight / volume. This solution was also clear and homogeneous. Azelaic acid and dipotassium glycyrrhizate, the same active ingredients as in Example 4, were added to this solution and stirred until homogeneous to obtain a microneedle molding solution. The microneedle was molded using the same template method centrifugal casting and drying demolding process as in Example 4, ultimately yielding an acne-removing microneedle patch based on the CMCS-2 and CMCS-3 blend.

[0026] The apparent isoelectric point of the blended matrix is ​​5.4, the solubility is 23 g / L, the zeta potential at pH 7.0 is -15 mV, the dry compressive strength of the acne microneedle patch prepared in Example 5 is 0.48 MPa, the antibacterial rate of Propionibacterium acnes is 91.1%, the drug release rate is 63.7% after 1 hour and 84.2% after 4 hours under inflamed skin conditions.

[0027] Example 6: A pH-responsive charge-reversal acne-removing microneedle patch The CMCS-5 with a degree of substitution of 0.5 obtained in Example 3 was fully dissolved in water to prepare an aqueous solution of the blend with a total concentration of 8% by weight / volume. This solution was also clear and homogeneous. Azelaic acid and dipotassium glycyrrhizate, the same types and proportions of active ingredients as in Example 4, were added to this solution and stirred evenly to obtain a microneedle blend molding solution. The microneedle was molded using the same template method centrifugal casting and drying demolding process as in Example 4 to finally obtain an acne treatment microneedle patch with CMCS-5 as the matrix.

[0028] The matrix has an apparent isoelectric point of 5.8, a solubility of 17 g / L, and a Zeta potential of -12.7 mV at pH 7.0. The acne-removing microneedle patch prepared in Example 6 has a dry compressive strength of 0.47 MPa, an antibacterial rate of 86.2% against Propionibacterium acnes, and a drug release rate of 44.5% after 1 hour and 82.1% after 4 hours under inflamed skin conditions.

[0029] Example 7: A pH-responsive charge-reversal acne-removing microneedle patch CMCS-1 with a degree of substitution of 0.65 obtained in Example 1 and CMCS-4 with a degree of substitution of 0.35 obtained in Example 3 were weighed separately at a mass ratio of 7:3 and thoroughly mixed to obtain a homogeneous powder. The mixed powder was then added to pure water and stirred until completely dissolved to prepare an aqueous solution of the blend with a total concentration of 8% by weight / volume. This solution was also clear and homogeneous. Azelaic acid and dipotassium glycyrrhizate, the same types and proportions of active ingredients as in Example 4, were added to this solution and stirred evenly to obtain a microneedle molding solution of the blend. The microneedle was molded using the same template method centrifugal casting and drying demolding process as in Example 4 to finally obtain an acne-removing microneedle patch with the CMCS-1 and CMCS-4 blend as the matrix.

[0030] The apparent isoelectric point of the blended matrix is ​​5.8, the solubility is 18 g / L, the zeta potential at pH 7.0 is -12.7 mV, the dry compressive strength of the acne microneedle patch prepared in Example 7 is 0.55 MPa, the antibacterial rate of Propionibacterium acnes is 92.4%, the drug release rate is 65.2% after 1 hour and 85.2% after 4 hours under inflamed skin conditions.

[0031] Comparative Example 1 In contrast, ordinary chitosan without carboxymethylation modification and with a degree of deacetylation of 90% was used to prepare microneedle patches according to the same formulation and process as in Example 4. Since ordinary chitosan is only soluble in acidic aqueous solutions, its molding solution needs to be prepared with dilute acetic acid, and the shrinkage and deformation of the needles are more obvious after drying due to the evaporation of acetic acid.

[0032] It can be seen that acne-removing microneedle patches prepared using carboxymethyl chitosan with a single degree of substitution or two different degrees of substitution can both achieve pH-responsive drug release. In particular, using two different degrees of substitution carboxymethyl chitosan as the matrix not only results in higher strength of the microneedle patch, but also a higher rate of targeting Propionibacterium acnes and better drug release.

[0033] Note: The method for detecting the antibacterial rate of Propionibacterium acnes is as follows: the microneedle patch is added to PBS buffer to dilute the Propionibacterium acnes to a concentration of 10. 5 The experimental group was prepared in liquid culture medium containing CFU / mL microneedle patches; the control group was prepared in liquid culture medium without active ingredients. The samples were transferred to an anaerobic incubator and incubated at 37℃ for 24 h. After mixing, 100 μL of the sample was serially diluted 10-fold and spread onto anaerobic agar plates. The plates were then incubated anaerobically at 37℃ for another 72 h. Colonies were counted and the average inhibition rate was calculated. Inhibition rate (%) = [(number of viable bacteria in the control group - number of viable bacteria in the experimental group) / number of viable bacteria in the control group] × 100%.

[0034] Unless otherwise specified, all proportions and percentages mentioned in this invention are mass proportions and mass percentages; all raw materials are commercially available.

[0035] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely preferred examples and are not intended to limit the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of the present invention is defined by the appended claims and their equivalents.

Claims

1. A pH-responsive charge-reversal acne-removing microneedle patch, characterized in that, The matrix of the acne-removing microneedle patch includes carboxymethylated chitosan, active ingredients, and purified water; The carboxymethylated chitosan is a carboxymethylated chitosan with a single degree of substitution or a mixture of two carboxymethylated chitosans with different degrees of substitution.

2. The pH-responsive charge-reversal acne-removing microneedle patch according to claim 1, characterized in that, The degree of carboxymethyl substitution of the monosubstituted carboxymethyl chitosan is controlled between 0.3 and 1.0, and the apparent isoelectric point of the monosubstituted carboxymethyl chitosan matrix is ​​between 4.5 and 6.

5.

3. The pH-responsive charge-reversal acne-removing microneedle patch according to claim 1, characterized in that, The mixture of two carboxymethylated chitosans with different degrees of substitution includes a first type of carboxymethylated chitosan and a second type of carboxymethylated chitosan.

4. The pH-responsive charge-reversal acne-removing microneedle patch according to claim 3, characterized in that, The mass ratio of the first type of carboxymethylated chitosan to the second type of carboxymethylated chitosan is 1:9 to 9:

1.

5. The pH-responsive charge-reversal acne-removing microneedle patch according to claim 3, characterized in that, The degree of substitution of the first type of carboxymethylated chitosan is 0.6 to 1.

2.

6. The pH-responsive charge-reversal acne-removing microneedle patch according to claim 3, characterized in that, The degree of substitution of the second type of carboxymethylated chitosan is 0.2 to 0.

6.

7. The pH-responsive charge-reversal acne-removing microneedle patch according to claim 4, characterized in that: The first type of carboxymethylated chitosan and the second type of carboxymethylated chitosan were accurately weighed in proportion, thoroughly mixed in solid form, and then dissolved in pure water. By adjusting the mass ratio of the two, the apparent isoelectric point was continuously and precisely controlled, so that the apparent isoelectric point of the mixed matrix was precisely controlled between 4.5 and 6.

5.

8. The pH-responsive charge-reversal acne-removing microneedle patch according to claim 1, characterized in that, The raw material for preparing carboxymethylated chitosan is chitosan with a degree of deacetylation of not less than 85% to ensure the performance stability and reactivity of the product.

9. The pH-responsive charge-reversal acne-removing microneedle patch according to claim 1, characterized in that, The active ingredient includes at least components capable of inhibiting or killing Propionibacterium acnes, and may further include components with anti-inflammatory or skin barrier repair functions.

10. The pH-responsive charge-reversal acne-removing microneedle patch according to claim 1, characterized in that, The acne-removing microneedle patch adopts an integrated molding process. The solution is prepared by adding carboxymethyl chitosan to pure water, then adding active ingredients and stirring evenly to form a matrix. The matrix is ​​then added to a microneedle mold, centrifuged, dried and cured, and then peeled off to obtain an acne-removing microneedle patch containing a microneedle array and a backing layer.