Microcrystal patch formula containing polysulfonic acid mucopolysaccharide and application of microcrystal patch formula

Abstract

The invention belongs to the technical field of biological medicine, and particularly relates to a formula and application of a microcrystal patch containing polysulfonic acid mucopolysaccharide. The microcrystal patch disclosed by the invention is prepared from the following components in percentage by mass: 96 to 97 percent of purified water, 0.6 percent of polyvinyl alcohol, 1 to 2 percent of sodium hyaluronate with the molecular weight of 50,000 to 10,000, 0.6 to 1 percent of sodium hyaluronate with the molecular weight of 400,000 to 800,000 and 1 to 2 percent of polysulfonic acid mucopolysaccharide. The result of the embodiment shows that the patch with weak mechanical property is adaptive to the part with weak cuticle and sensitive skin, and the patch with strong mechanical property is adaptive to the part with thick cuticle. Through the physical permeation promotion effect of microcrystals, polysulfonic acid mucopolysaccharide can be efficiently carried to penetrate through a skin barrier to directly reach a target part, and the medicine utilization rate is remarkably increased; the formula is simple in components, the skin irritation risk is reduced from the source, and the production cost is reduced.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to a microcrystalline patch formulation containing polysulfated mucopolysaccharide and its application. Background Technology

[0002] Polysulfated mucopolysaccharides are glycosaminoglycans naturally found in animal and plant tissues, possessing anti-inflammatory, antithrombotic, and wound-healing pharmacological activities. Currently, their clinical application mainly relies on cream formulations for improving varicose veins, postoperative hematomas, and superficial phlebitis. However, this formulation has significant limitations: firstly, due to the skin barrier, the transdermal efficiency is low, making it difficult to achieve effective concentrations at the lesion site; secondly, the cream's sticky texture makes it prone to being rubbed off by clothing or sweat, affecting the persistence of therapeutic effects; and thirdly, some patients may experience skin irritation or allergic reactions after long-term use.

[0003] In the field of scar repair, there are existing topical medications, but they suffer from insufficient penetration, resulting in weak effects and almost no improvement for old scars (>6 months). Injectable medications and laser treatments have significant side effects, and long-term use may lead to symptoms such as skin atrophy, telangiectasia, and hypopigmentation, and the recurrence rate is high.

[0004] Microdermal transdermal technology, as a novel delivery system, has been proven to penetrate the stratum corneum through micron-sized needle-like structures, improving drug bioavailability and offering advantages such as ease of use, good adhesion, and waterproofing. However, this technology has not yet been applied to the delivery of polysulfated mucopolysaccharides, and its application in the skincare and cosmetic field remains a gap.

[0005] Therefore, there is an urgent need for a microcrystalline patch based on polysulfated mucopolysaccharide to overcome the shortcomings of traditional dosage forms, achieve efficient transdermal drug delivery, and provide a better solution for scar fading and acne relief. Summary of the Invention

[0006] The purpose of this invention is to provide a microcrystalline patch containing polysulfated mucopolysaccharide. The patch provided by this invention relies on the physical penetration-enhancing effect of microcrystals to efficiently carry polysulfated mucopolysaccharide through the skin barrier, significantly improve drug utilization, and achieve the technical effect of low composition and high efficacy in fading scars.

[0007] To achieve the above objectives, the present invention provides the following technical solution: The present invention provides a microcrystalline patch, which is composed of microcrystalline units and an adhesive tape base layer; the microcrystalline unit includes a protrusion and a base connecting the base layer; the protrusion of the microcrystalline unit includes polysulfonic acid mucopolysaccharide, and the polysulfonic acid mucopolysaccharide accounts for 1-2%.

[0008] Preferably, the protruding portion of the microcrystalline unit further includes the following raw materials: polyvinyl alcohol, sodium hyaluronate, and purified water.

[0009] Preferably, the raw material composition ratio of the acne-removing microcrystalline patch, calculated by weight, is as follows: purified water accounts for 96-97%, polyvinyl alcohol accounts for 0.6%, sodium hyaluronate accounts for 1.6%-3%, and polysulfated mucopolysaccharide accounts for 1-2%.

[0010] Preferably, the sodium hyaluronate comprises sodium hyaluronate with a molecular weight of 0.5-10,000 and sodium hyaluronate with a molecular weight of 400,000-800,000, wherein the sodium hyaluronate with a molecular weight of 0.5-10,000 accounts for 1-2% and the sodium hyaluronate with a molecular weight of 400,000-800,000 accounts for 0.6-1%.

[0011] The present invention also provides a method for preparing the microcrystalline patch as described above, the method comprising the following steps: (1) Add polyvinyl alcohol to a beaker of purified water, heat in a water bath, and cool to obtain a polyvinyl alcohol solution; (2) Add sodium hyaluronate and polysulfated mucopolysaccharide to a beaker of purified water and stir to dissolve; (3) Mix the cooled polyvinyl alcohol solution from step (1) with the solution from step (2) after stirring and dissolving to obtain a mixture, and let it stand. (4) The solution after step (3) is left to stand is poured, dried and die-cut on the selected mold, and medical-grade backing tape is attached to form a microcrystalline patch.

[0012] Preferably, the water bath heating temperature in step (1) is 70-85 ℃; the water bath heating time is 2 h.

[0013] Preferably, the drying in step (4) is carried out in a forced-air drying oven; the drying temperature is 23-27 ℃; the drying environment humidity is 30-40 % RH; and the drying time is 10 h.

[0014] The present invention also provides the use of the microcrystalline patch as described above in the preparation of products for fading scars or preventing scar formation.

[0015] Compared with the prior art, the beneficial effects of the present invention are as follows: 1) The polysulfated mucopolysaccharide microcrystalline patch of the present invention has a simplified formula and fewer components, avoiding the risk of skin irritation caused by the addition of a large number of excipients such as emulsifiers and preservatives in traditional cream formulations; at the same time, relying on the physical penetration-enhancing effect of microcrystals, it can efficiently carry polysulfated mucopolysaccharides to penetrate the skin barrier, significantly improving drug utilization, and achieving the technical effect of low components and high efficacy in fading scars.

[0016] 2) This invention shapes the ingredients into micro-protrusions, which can loosen the skin's stratum corneum barrier and facilitate the delivery of active ingredients to the deeper layers of the skin. When the microcrystals come into contact with the skin, under the influence of body temperature and the skin's microenvironment, the micro-protrusions gradually dissolve, releasing the active ingredients at specific points, thereby improving the delivery efficiency of the active ingredients and thus enhancing the therapeutic effect.

[0017] 3) This invention is based on the regulatory effect of sodium hyaluronate molecular weight on the mechanical properties of patches. By precisely adjusting the compounding ratio of sodium hyaluronate with different molecular weights, a series of microcrystalline patches with gradient mechanical properties are obtained. Addressing the differences in the physiological characteristics of skin in different parts of the body, these gradient mechanical properties allow for precise adaptation: patches with weaker mechanical properties are gentler and can effectively avoid mechanical stimulation to areas with thin stratum corneum and high sensitivity, ensuring medication safety; patches with stronger mechanical properties have better skin adhesion and penetration enhancement capabilities, and can be adapted to areas with thicker stratum corneum, ensuring that the microcrystalline structure fully exerts its physical penetration-enhancing effect and improves the transdermal efficiency of active ingredients.

[0018] 4) This invention innovatively simplifies the preparation process by reducing the number of components in the formula, which not only reduces the difficulty of operation and quality control costs in the production process, but also reduces the batch differences of products caused by multi-component reactions and improves production stability.

[0019] 5) This invention uses a room temperature drying forming process, which is different from the heating drying method of the existing technology. This process preserves the anti-inflammatory and repair-promoting activities of polysulfated mucopolysaccharides to the maximum extent, ensuring that the product maintains its high efficacy during storage and use. Attached Figure Description

[0020] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0021] Figure 1 This is a schematic diagram of a microcrystalline patch.

[0022] Figure 2 This is a schematic diagram of the Shore hardness curve of the microcrystalline patch prepared in Example 1.

[0023] Figure 3 This is a schematic diagram of the Shore hardness curve of the microcrystalline patch prepared in Example 2.

[0024] Figure 4 This is a schematic diagram of the Shore hardness curve of the microcrystalline patch prepared in Example 3.

[0025] Figure 5 This is a schematic diagram illustrating the solubility of the microcrystalline patch prepared in Example 3.

[0026] Figure 6 This is a comparison chart of the scar repair process after intervention with the microcrystalline patch prepared in Example 3. Detailed Implementation

[0027] The present invention provides a microcrystalline patch, which is composed of microcrystalline units and an adhesive tape base layer; the microcrystalline unit includes a protrusion and a base connecting the base layer; the protrusion of the microcrystalline unit includes polysulfonic acid mucopolysaccharide, and the polysulfonic acid mucopolysaccharide accounts for 1-2%.

[0028] Preferably, the protruding portion of the microcrystalline unit further includes the following raw materials: polyvinyl alcohol, sodium hyaluronate, and purified water.

[0029] Preferably, the raw material composition ratio of the acne-removing microcrystalline patch, calculated by weight, is as follows: purified water accounts for 96-97%, polyvinyl alcohol accounts for 0.6%, sodium hyaluronate accounts for 1.6%-3%, and polysulfated mucopolysaccharide accounts for 1-2%.

[0030] Preferably, the sodium hyaluronate comprises sodium hyaluronate with a molecular weight of 0.5-10,000 and sodium hyaluronate with a molecular weight of 400,000-800,000, wherein the sodium hyaluronate with a molecular weight of 0.5-10,000 accounts for 1-2%; the sodium hyaluronate with a molecular weight of 400,000-800,000 accounts for 0.6-1%; and the polysulfated mucopolysaccharide accounts for 1%.

[0031] The present invention also provides a method for preparing the microcrystalline patch as described above, the method comprising the following steps: (1) Add polyvinyl alcohol to a beaker of purified water, heat in a water bath, and cool to obtain a polyvinyl alcohol solution; (2) Add sodium hyaluronate and polysulfated mucopolysaccharide to a beaker of purified water and stir to dissolve; (3) Mix the cooled polyvinyl alcohol solution from step (1) with the solution from step (2) after stirring and dissolving to obtain a mixture, and let it stand. (4) The solution after step (3) is left to stand is poured, dried and die-cut on the selected mold, and medical-grade backing tape is attached to form a microcrystalline patch.

[0032] Preferably, the water bath heating temperature in step (1) is 70-85 ℃; the water bath heating time is 2 h.

[0033] The preferred temperature for water bath heating is 80℃.

[0034] Preferably, the drying in step (4) is carried out in a forced-air drying oven; the drying temperature is 23-27 ℃; the drying environment humidity is 30-40 % RH; and the drying time is 10 h.

[0035] The drying temperature is preferably 25°C, and the drying environment is preferably 30%RH.

[0036] The present invention also provides the use of the microcrystalline patch as described above in the preparation of products for fading scars or preventing scar formation.

[0037] To further illustrate the present invention, the technical solutions provided by the present invention will be described in detail below with reference to the accompanying drawings and embodiments, but these should not be construed as limiting the scope of protection of the present invention.

[0038] Unless otherwise specified, the production processes, experimental methods, or testing methods involved in the embodiments of this invention are all conventional methods in the prior art, and their names and / or abbreviations are all conventional names in the field, which are very clear and distinct in the relevant application areas. Those skilled in the art can understand the conventional process steps based on the names and apply the corresponding equipment, and implement them according to conventional conditions or the conditions recommended by the manufacturer.

[0039] The various instruments, equipment, raw materials or reagents used in the embodiments of this invention are not subject to any special restrictions on their source. They are all conventional products that can be purchased through regular commercial channels and can be prepared according to conventional methods known to those skilled in the art.

[0040] Example 1 This invention provides a microcrystalline patch containing polysulfated mucopolysaccharide, specifically comprising the following components by weight: purified water accounting for 96.4%, polyvinyl alcohol accounting for 0.6%, sodium hyaluronate with a molecular weight of 0.5-10,000 accounting for 1%, sodium hyaluronate with a molecular weight of 400,000-800,000 accounting for 1%, and polysulfated mucopolysaccharide accounting for 1%.

[0041] The preparation method is as follows: 1. Add polyvinyl alcohol to a beaker containing purified water according to the weight parts, heat in an 80°C water bath, and cool to room temperature after it is completely dissolved. 2. Add sodium hyaluronate and polysulfated mucopolysaccharide to a beaker containing purified water according to the weight proportions, stir and dissolve at room temperature for later use; 3. Mix the cooled polyvinyl alcohol solution with the solution from step 2 and stir to ensure complete dispersion; 4. After the air bubbles have completely disappeared, pour the solution into the selected mold. 6. After pouring, transfer the mold to a forced-air drying oven for drying, controlling the oven temperature at 25℃ and the ambient humidity at 30%RH; 7. After it is completely dry, perform a film cutting process and attach the backing tape to obtain the final product.

[0042] Example 2 This invention provides a microcrystalline patch containing polysulfated mucopolysaccharide, specifically comprising the following substances in parts by weight: The composition of the product is as follows: purified water accounts for 96.15%, polyvinyl alcohol accounts for 0.6%, sodium hyaluronate with a molecular weight of 0.5-10,000 accounts for 1.5%, sodium hyaluronate with a molecular weight of 400,000-800,000 accounts for 0.75%, and polysulfated mucopolysaccharide accounts for 1%.

[0043] The preparation method is the same as in Example 1.

[0044] Example 3 This invention provides a microcrystalline patch containing polysulfated mucopolysaccharide, specifically comprising the following substances in parts by weight: The composition of the product is as follows: purified water accounts for 96.8%, polyvinyl alcohol accounts for 0.6%, sodium hyaluronate with a molecular weight of 0.5-10,000 accounts for 2%, sodium hyaluronate with a molecular weight of 400,000-800,000 accounts for 0.6%, and polysulfated mucopolysaccharide accounts for 1%.

[0045] The preparation method is the same as in Example 1.

[0046] Example 4 Morphological Characterization The microcrystalline patch prepared in Example 1 was placed flat on a stage, and the morphology of the microneedles was observed using a microscope. Figure 1 As shown in the figure. The results show that the prepared microcrystals have smooth surfaces, neat arrays, and intact needle shapes.

[0047] Example 5 Mechanical Property Testing Microcrystalline patches prepared in Examples 1-3 were used as test samples to conduct mechanical property tests to verify the influence of different preparation processes on the mechanical properties of the products.

[0048] Record the curves of the samples in each embodiment as the instrument presses down, such as... Figure 2-4 As shown. Substituting the slopes of each curve into the Shore hardness standard calculation formula, the Shore hardness value of the patch in Example 1 is calculated to be 27; the Shore hardness value of the patch in Example 2 is 32; and the Shore hardness value of the patch prepared in Example 3 is 43.

[0049] The comparison of the hardness values ​​above shows that the higher the proportion of low molecular weight sodium hyaluronate in the patch, the higher the hardness of the patch.

[0050] Example 6: Solubility Test The microcrystalline patch prepared in Example 3 was subjected to a skin adhesion and dissolution performance test. The specific steps are as follows: Healthy volunteers (excluding those with skin diseases or allergies) were selected. Microcrystalline patches were applied to clean skin areas on the inner forearm of the volunteers. The dissolution process of the microcrystalline structure of the patches was observed and recorded in real time using a microscope. The resulting microscope images are shown below. Figure 5 As shown.

[0051] Depend on Figure 5 As shown, after 0.5 hours of application to the skin, signs of dissolution appeared on the surface of the microcrystals; after 1 hour of application, about 50% of the microcrystal structure had completely dissolved; after 1-2 hours and 3 hours of continuous observation, all the protruding parts of the microcrystals had completely dissolved, and there were no obvious redness, swelling, stinging or other discomfort reactions on the skin surface after dissolution, indicating that the microcrystal patch has ideal in-situ skin dissolution performance and can meet the application requirements of transdermal delivery.

[0052] Example 7 The microcrystalline patches prepared in Example 3 were tested for scar repair effects. The specific steps are as follows: Two volunteers were selected, excluding those with skin diseases, allergies, or contraindications related to scar repair. They used the microcrystalline patch prepared in Example 3 once a day, removing it after 3 hours of application, for 15 consecutive days. The scar area was photographed and recorded on the 5th, 10th, and 15th days.

[0053] Volunteer 1 had a postoperative scar near the navel and began using the microcrystalline patch prepared according to this invention six months after surgery; Volunteer 2 had a scar on the ankle caused by a bump, accompanied by pigmentation accumulation. Relevant test photos are shown below. Figure 6 As shown.

[0054] Depend on Figure 6 It was found that after 15 days of continuous use, the scars of both volunteers showed significant improvement: the postoperative scar area of ​​Volunteer 1 was significantly reduced, and the raised parts became smoother; the pigmentation of the bump scar of Volunteer 2 was significantly lightened, the small amount of hyperplasia tended to be flattened, and the difference from the surrounding normal skin was significantly reduced. At the same time, during the entire use process, neither volunteer experienced any discomfort such as redness, swelling, stinging, or itching at the application site.

[0055] This indicates that the microcrystalline patch not only has ideal in-situ skin dissolution properties, but also excellent scar repair effects and skin compatibility, which can meet the application requirements of transdermal delivery products for scar repair.

[0056] Example 8 The microcrystalline patches prepared in Example 3 were compared with commercially available polysulfated mucopolysaccharide creams. The specific steps are as follows: 8.1 Preparation of simulated skin: A self-made PVA hydrogel membrane was used as the simulated skin. The specific operation was as follows: a 15% PVA1799 solution was prepared, the solution was spread on a glass plate, and then frozen at -18℃ for 24 hours, and then thawed at 4℃. This cycle was repeated three times to obtain a PVA hydrogel membrane with a thickness of about 2 mm. The PVA hydrogel membrane was cut into 30 mm × 30 mm squares for later use. 8.2 Pretreatment of simulated skin samples: Gently wipe away the surface water on the front side of the PVA hydrogel with absorbent paper; press the polysulfated mucopolysaccharide microcrystal patch onto the front side of a simulated skin sample after wiping away the water. Apply an equal amount of the drug, polysulfated mucopolysaccharide cream (purchased externally), to the front side of another simulated skin after wiping off the liquid. Prepare four pieces of each of the two drug-loaded simulated skins and place them in a sealed container. Take one piece out after 0.5, 1, 2, and 4 hours for drug testing.

[0057] 8.3 Simulated intradermal drug detection: 8.3.1 Use a cotton swab dipped in water to wipe away the ointment from the front of the simulated skin where the ointment was applied (repeat 3 times), and set aside. Remove the microcrystals from the simulated skin with the drug-loaded microcrystals pressed on, and then use a cotton swab dipped in water to clean the surface of the medicated skin to wipe away any possible drug residue (repeat 3 times). 8.3.2 The simulated skin was placed in 5 ml of water and ultrasonically extracted 3 times, repeated three times, to extract polysulfated mucopolysaccharides; 8.3.3 Combine the three aqueous solutions from the extraction of polysulfated mucopolysaccharides and place them in a graduated test tube; place the graduated test tube on a rotary evaporator and concentrate it to 3 ml at room temperature for later use; 8.3.4 Thin-layer chromatography colorimetric determination of polysulfated mucopolysaccharide content ratio. A semi-quantitative thin-layer chromatography colorimetric method was used to determine the ratio of polysulfated mucopolysaccharide content in simulated skin. Extracts were spotted onto silica gel thin-layers using standard glass capillary spotting tubes. Microcrystalline extract was spotted once, and cream extract was spotted once. After drying the spots, colorimetric analysis was performed under a 254 nm UV lamp. The color intensity of the cream extract spots was weaker than that of the microcrystalline extract spots. The spotting, drying, and colorimetric analysis were repeated at the cream extract spot locations until the color intensity of the cream extract spots matched that of the microcrystalline extract spots. The results are shown in Table 1.

[0058] Table 1. Time and frequency of sampling

[0059] 3.5 Experimental Results: Thin-layer chromatography (TLC) showed that the number of spotting times for the cream extract was approximately several times the dilution factor compared to the microcrystalline extract. This indicates that, under the same administration conditions, the polysulfated mucopolysaccharide microcrystalline formulation has a better drug delivery effect than the cream.

[0060] This embodiment verifies the transdermal advantages of polysulfated mucopolysaccharide-loaded microcrystals using a simulated skin model. It can significantly improve the transdermal penetration efficiency of drugs and increase the amount of drug residue in the skin, providing experimental basis for the optimization of polysulfated mucopolysaccharide transdermal drug delivery formulations.

[0061] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A microdermal patch, characterized by, The microcrystal patch is composed of microcrystal units and an adhesive tape base layer; the microcrystal units include a raised portion and a base portion connected to the base layer; the raised portion of the microcrystal units includes polysulfated mucopolysaccharide, and the polysulfated mucopolysaccharide accounts for 1-2%.

2. The microdermal patch of claim 1, wherein, The raised portion of the microcrystal units further includes the following raw materials: polyvinyl alcohol, sodium hyaluronate, and purified water.

3. The microdermal patch according to any one of claims 1-2, wherein, The raw material composition of the acne-removing microcrystal patch accounts for, by weight: 96-97% of purified water, 0.6% of polyvinyl alcohol, 1.6-3% of sodium hyaluronate, and 1-2% of polysulfated mucopolysaccharide.

4. The microdermal patch of claim 2, wherein the microdermal patch is characterized by, The sodium hyaluronate includes sodium hyaluronate with a molecular weight of 0.5-10,000 and sodium hyaluronate with a molecular weight of 40-800,000, and the sodium hyaluronate with a molecular weight of 0.5-10,000 accounts for 1-2%; the sodium hyaluronate with a molecular weight of 40-800,000 accounts for 0.6-1%.

5. A method of preparing the microcrystal patch according to any one of claims 1 to 4, characterized in that, The preparation method includes the following steps: (1) adding polyvinyl alcohol into a beaker of purified water, heating in a water bath, and cooling to obtain a polyvinyl alcohol solution; (2) adding sodium hyaluronate and polysulfated mucopolysaccharide into a beaker of purified water, and stirring and dissolving; (3) mixing and stirring the cooled polyvinyl alcohol solution of step (1) and the stirred and dissolved solution of step (2) to obtain a mixed solution, and standing; (4) pouring, drying, and die cutting the standing solution of step (3) on a selected mold, attaching a medical-grade backing tape, and forming a microcrystal patch.

6. The method of claim 5, wherein, The temperature of the water bath heating of step (1) is 70-85 ℃, and the time of the water bath heating is 2 h.

7. The method of claim 5, wherein, The drying of step (4) is performed in a forced air oven, the temperature of the drying is 23-27 ℃, the humidity of the drying environment is 30-40% RH, and the drying time is 10 h.

8. Use of the microcrystal patch of any one of claims 1-4 in the preparation of a product for lightening scars or preventing scar formation.

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