Solid micro-needle patch device for rapid compression hemostasis and preparation method of solid micro-needle patch device
Patent Information
- Application Number
- CN202411049433.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-08-01
- Publication Date
- 2024-12-10
Smart Images
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Abstract
Description
Technical Field
[0001] The present invention belongs to the field of biomedical materials, in particular to the field of A61K9 / 00, and more specifically to a solid microneedle patch device for rapid compression hemostasis and a preparation method thereof. Background Art
[0002] Radial artery access and femoral artery access are the main surgical routes for clinical interventional surgery. Compression is usually required for more than 6 hours after radial artery access surgery, and for more than 12 hours after femoral artery access surgery. Currently, the use of physical devices to compress and stop bleeding is the main intervention method after clinical surgery.
[0003] Due to the long compression time, the affected limb is immobilized for a long time, the distal reflux of the compression site is not smooth, and swelling and pain often occur at the distal end of the pressure, which is difficult for patients to tolerate; too long compression time can easily lead to skin ulcer infection and blister formation, especially in elderly patients with loose skin; in addition, long-term compression can easily lead to radial nerve damage and increase the incidence of radial artery occlusion; insufficient compression time or too little pressure will affect the hemostatic effect, easily lead to hematoma at the puncture site, and form serious vascular complications; therefore, after completing interventional examinations or interventional treatments, patients usually need to stay in the hospital for at least 24 hours, which greatly increases the economic cost of medical and health care.
[0004] In addition, after surgical anesthesia or arterial blood gas collection, compression of the punctured artery is often required to stop bleeding, which usually requires manual compression for 10-15 minutes, is time-consuming and labor-intensive, and the compression effect is often poor, which can easily lead to hematoma at the puncture site.
[0005] The mechanical compression devices currently used in clinical practice, such as the prior art CN109276290A, cannot effectively solve the above problems, resulting in great pain for patients after puncture, especially for elderly patients with loose skin, many complications of hemostasis compression, long hospitalization observation time, and high medical costs. Therefore, clinical attempts have been made to combine dressings and drugs with hemostatic functions with physical compression in an attempt to speed up the hemostasis time and improve the hemostasis effect, but the clinical effect is not good.
[0006] The skin of human limbs is mainly composed of epidermis, dermis, subcutaneous tissue and blood vessels. Among them, the epidermis is the outermost layer of skin tissue, with a thickness of about 2000μm, and is composed of stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum and stratum basale. The stratum corneum is lipophilic, with a thickness of about 10-40μm, and is a key rate-limiting barrier that affects the effect of hemostatic dressings or hemostatic drugs. How to effectively penetrate the stratum corneum restriction barrier to achieve hemostatic and antibacterial effects is a technical problem that urgently needs to be solved in this field. Summary of the invention
[0007] Nowadays, radial artery access and femoral artery access in clinical surgery require compression for at least 6 hours to stop bleeding after surgery. However, if the compression time is too long and the compression force is too strong, it is easy to cause skin rupture and infection at the compression site of the patient. In severe cases, it may lead to vascular complications and increase the patient's pain. Therefore, it is necessary to improve the compression hemostasis device in clinical practice. To this end, the first aspect of the present invention provides a solid microneedle patch device for rapid compression hemostasis; the solid microneedle patch device includes a compression device with a solid microneedle patch, or a tape, bandage, non-woven fabric, hydrocolloid, or hydrogel with a solid microneedle patch, the device contacts the skin for compression through a pressure surface, and a solid microneedle patch is adhered to the pressure surface; the compression device with a solid microneedle patch includes a screw-type compression device with an additional microneedle patch or an airbag compression device with an additional microneedle patch.
[0008] The second aspect of the present invention provides a method for preparing a solid microneedle patch device for rapid compression hemostasis, comprising the following steps: attaching the non-pressure surface of the solid microneedle patch to a compression device or adhesive tape, bandage, non-woven fabric, hydrocolloid, or hydrogel.
[0009] Preferably, the method for preparing the solid microneedle patch comprises the following steps:
[0010] The hemostatic dressing and auxiliary materials are dissolved in a solvent, and a mixed hemostatic component solution is prepared by heating and ultrasound. The hemostatic component solution is then cast on a mold using a micromolding method so that the solution completely fills the holes in the mold cavity. The mold is then vacuumed for 3 minutes, and the process is repeated 3 times. The mixed solution is supplemented to form a backing substrate, which is then dried in a dryer at 25°C for 24 hours.
[0011] Preferably, the solid microneedle contains a dressing with a hemostatic effect, and the dressing with a hemostatic effect includes, but is not limited to, one or more of chitosan, carboxymethyl chitosan, dextran, hyaluronic acid, alginate, gelatin, cellulose, collagen, zeolite, kaolin, and montmorillonite.
[0012] Preferably, the carboxymethyl chitosan has a degree of deacetylation greater than 70% and a weight average molecular weight greater than 1 million Daltons.
[0013] Further preferably, the degree of deacetylation of the carboxymethyl chitosan is greater than 90%, and the weight average molecular weight is greater than 2 million Daltons; as an implementable case, the carboxymethyl chitosan can be purchased from Shanghai Aladdin, brand: C304739.
[0014] Preferably, the solvent includes: one of distilled water, isopropanol, glycerol, butanediol, carbon tetrachloride, and methanol.
[0015] Further preferably, the solvent comprises distilled water.
[0016] Preferably, the mass concentration of the hemostatic dressing component solution is 5-15%.
[0017] Preferably, the material of the mold includes: polydimethylsiloxane and / or polymethyl methacrylate.
[0018] More preferably, the material of the mold is polydimethylsiloxane.
[0019] Beneficial Effects
[0020] (1) The present invention proposes for the first time to combine microneedle technology with compression hemostasis, and the prepared solid microneedle patch can achieve rapid hemostasis.
[0021] (2) In the present invention, carboxymethyl chitosan is preferably used as the hemostatic dressing component in the solid microneedle patch, which can effectively stop bleeding and has a certain antibacterial effect. In addition, carboxymethyl chitosan has good biocompatibility and biodegradability, and the hemostatic microneedle patch is safe and reliable to use.
[0022] (3) Carboxymethyl chitosan can effectively stop bleeding and inhibit bacteria. In the present invention, carboxymethyl chitosan with a deacetylation degree greater than 70% and a weight-average molecular weight greater than 1 million Daltons is preferred, which can effectively reduce the theoretical breakage rate of the hemostatic microneedle patch and ensure that the microneedles can effectively puncture the stratum corneum of the skin and quickly stop bleeding. If the deacetylation degree and the weight-average molecular weight are small, the yield strength of the microneedle material after vacuum drying is relatively small, and the puncture performance of the microneedle will be negatively affected.
[0023] (4) In the present invention, polydimethylsiloxane is preferably used as the material of the mold. Polydimethylsiloxane has a low surface free energy of about 21.6 dyn / cm, is chemically stable, and does not adhere to the carboxymethyl chitosan material. It is also soft, easily deformable, and has good elasticity, thereby ensuring the stability of the hemostatic microneedle patch needle body.
[0024] (5) Currently, more than 90% of clinical hemostatic dressings or clinical hemostatic drugs are highly hydrophilic but weakly lipophilic, and cannot effectively penetrate the stratum corneum rate-limiting barrier. Therefore, the present invention selects the carboxymethyl chitosan microneedle puncture form, which can effectively penetrate the stratum corneum rate-limiting barrier, quickly stop bleeding and inhibit bacteria.
[0025] (6) Currently, mechanical compression devices are mainly used in medicine to stop bleeding, and the hemostasis time is relatively short. The solid microneedle patch provided by the present invention can be used together with a hemostatic compressor, which not only has excellent hemostatic effect, but also can significantly reduce the incidence of bleeding and hematoma, effectively shorten the hemostasis time, and accelerate the patient's recovery.
[0026] (7) The mass concentration of the hemostatic auxiliary material in the hemostatic component solution is limited to 5-15% in the present invention. If the mass concentration is too low, the stiffness of the hemostatic microneedle patch will be poor and effective transdermal hemostasis will not be achieved. BRIEF DESCRIPTION OF THE DRAWINGS
[0027] Figure 1 Schematic diagram of the preparation process of the solid microneedle patch in Example 1.
[0028] Figure 2 The schematic diagram of the structure of the solid microneedle patch in Example 1; wherein 1 is substrate, 2 is needle body.
[0029] Figure 3 This is a physical picture of the appearance of the solid microneedle patch in Example 1.
[0030] Figure 4 This is a scanning electron microscope image of the solid microneedle in Example 1, with a scale of 500 μm.
[0031] Figure 5 This is a test diagram of the mechanical properties of the solid microneedle in Example 1.
[0032] Figure 6 This is a real picture of the microneedle transdermal performance test in Example 1.
[0033] Figure 7 This is a fluorescence image of the microneedle transdermal performance test in Example 1.
[0034] Figure 8 This is a diagram of the dissolved residues of microneedles in agarose in Example 1.
[0035] Fig. 9 This is a diagram showing the dissolution of the microneedle body in Example 1 at different times.
[0036] Fig.10 This is a graph showing the hemostasis data of the solid microneedle patch in Example 1. DETAILED DESCRIPTION
[0037] Example 1
[0038] In a first aspect, the present example provides a solid microneedle patch device, which is a screw-type compression device with an additional microneedle patch, and compresses the skin through a pressure surface, wherein the solid microneedle patch is adhered to the pressure surface.
[0039] The second aspect of this example provides a method for preparing a solid microneedle patch device: the non-pressure surface of the solid microneedle patch is attached to a screw-type compression device.
[0040] The preparation process of the solid microneedle patch is as follows Figure 1 As shown:
[0041] The hemostatic component carboxymethyl chitosan and the auxiliary materials polyvinyl pyrrolidone and polyvinyl alcohol are dissolved in distilled water to prepare a mixed aqueous solution of 5% carboxymethyl chitosan, 20% polyvinyl pyrrolidone and 6% polyvinyl alcohol by mass concentration, and heated and ultrasonically formed a uniform mixed solution. Then, the carboxymethyl chitosan aqueous solution is cast on a polydimethylsiloxane mold by a double-mold method so that the solution completely fills the holes in the mold cavity. Then, vacuum is applied for 3 minutes, and the process is repeated 3 times. The mixed solution is supplemented to form a backing substrate, which is then placed in a dryer and dried at 25°C for 24 hours to obtain a hemostatic microneedle patch.
[0042] The carboxymethyl chitosan has a deacetylation degree greater than 90% and a weight average molecular weight of 2.4 million Daltons and is purchased from Shanghai Aladdin.
[0043] Figure 1 Schematic diagram of the preparation process of the solid microneedle patch in Example 1.
[0044] Figure 2 Schematic diagram of the structure of the hemostatic microneedle patch in Example 1; wherein 1 is substrate, 2 is microneedle.
[0045] Figure 3 This is a schematic diagram of the appearance of the hemostatic microneedle patch in Example 1.
[0046] Performance Testing
[0047] Test 1: Microscopic morphology test
[0048] In order to observe the condition of the hemostatic microneedle patch needle body in Example 1, the spatial distribution of the microneedles, the array and the height of the microneedles; the dried microneedle sample was directly adhered to the conductive glue, and then gold spraying test was performed: the Oxford Quorum SC7620 sputtering coater was used to spray gold for 45 seconds, and the gold spraying current was 10mA; then the sample morphology test was taken using a TESCAN MIRA LMS scanning electron microscope, and the acceleration voltage was 3kV when the morphology was taken. The results are shown in Figure 1. Figure 4 The prepared microneedle patch is composed of 49 (7×7) needles on a bottom plate, with a height of 1000±10 μm, a base width of 900±10 μm, and a center space of 573±5 μm between adjacent needles. The needle body presents a conical shape, uniform size, and sharp tip.
[0049] Test 2: Mechanical properties test
[0050] The microneedle was compressed by a precision probe to obtain the stress-strain curve. The sample was subjected to compression test using a P / 20Rmm cylindrical probe. The specific method parameters were as follows: test speed 0.1mm / s (sample size: thickness 2000mm, surface area 100mm 2)Test method: Use constant compression rate mode to perform vertical compression test on the microneedle. The theoretical breaking force of the microneedle can be measured from the force-displacement curve of Jiangsu Jicui Precision Nanoindenter, and compared with the penetration force required for the skin, to determine whether the microneedle can penetrate the skin. When the yield force of the microneedle is less than the skin puncture force, the microneedle will break before penetrating the skin and will not be able to pierce the skin. Therefore, the skin puncture force should be measured and compared with the yield force of the microneedle to predict the puncture effectiveness of the microneedle. See the yield stress change diagram corresponding to the test in Example 1 for details. Figure 5 .
[0051] It can be seen that the single needle yield force in Example 1 is much greater than the minimum force of 58 mN required to penetrate the skin, indicating that the solid microneedle can penetrate the skin.
[0052] Test 3: Transdermal performance test
[0053] The microneedle material was fluorescently labeled with FITC (fluorescein isothiocyanate), and then the microneedle penetration depth was observed using a CLSM confocal microscope. A microneedle patch containing FITC was prepared. The hemostatic microneedle patch was inserted into the skin of a miniature pig and removed after 60 seconds. Figure 6 The results show that the microneedle body dissolved and a clear microneedle array was left on the pig skin surface. CLSM was used to observe the green fluorescence signal of FITC. Figure 7 Green fluorescence signals can be clearly observed in the image. Obviously, the solid microneedles can pierce the stratum corneum.
[0054] Test 4: Microneedle dissolution test
[0055] The dissolution of the microneedles was further evaluated. In order to facilitate the observation of the dissolution of the microneedles, methylene blue dye was added to the microneedles. The prepared microneedles containing methylene blue were inserted into 3% agarose, and the dissolution of the microneedles was observed every 30 seconds. Figure 8 As shown in the figure, after 30 seconds, the microneedle patch was pulled out, leaving obvious blue dye on the agar and showing a clear microneedle array shape. Further observation of the dissolution of the microneedle body at different times showed the following results: Fig. 9 As shown in the figure, compared with 0s, the microneedle tip was obviously dissolved after 30s, and the microneedle body was almost completely dissolved after 60s. This shows that the microneedle has good dissolution performance.
[0056] Test 5: Hemostasis effect test
[0057] The hemostatic microneedle patch is placed in contact with the skin wound and completely covers it. A screw-type compressor is used to adjust the contact surface pressure by screwing. With the help of the rigidity of the microneedles, the microneedles penetrate the stratum corneum of the skin. With the help of the rapid disintegration and metabolism of the microneedle components in the epidermal tissue fluid and on the skin surface, a sterile covering layer of the wound is formed under physical pressure. The microneedle material can cover and block the wound, and release it to the superficial tissue under the epidermis. With the help of physical pressure, the activated clotting time (ACT value) around the bleeding point is quickly reduced to achieve a rapid hemostasis effect. Fig.10 As shown: Using the hemostatic microneedle patch provided in Example 1 of the present invention in combination with a screw-type compressor can significantly reduce the hemostasis time after arterial puncture compared to using only a screw-type compressor under the same pressure, and after adding the hemostatic microneedle patch, the amount of bleeding and hematoma are further alleviated, and at the same time, the activated clotting time (ACT) is significantly reduced after 15 minutes of compression around the bleeding point.
Claims
1. A solid microneedle patch device for rapid compression hemostasis, characterized in that: The solid microneedle patch device includes a compression device with a solid microneedle patch, or an adhesive tape, bandage, non-woven fabric, hydrocolloid, or hydrogel with a solid microneedle patch; the solid microneedle patch contacts and compresses the skin through a pressure surface, and the pressure surface is adhered with solid microneedles made of a dressing.
2. A method for preparing the hemostatic microneedle patch device according to claim 1, characterized in that: The following steps are involved: The solid microneedle patch is obtained by attaching the non-pressure surface of the solid microneedle patch to a compression device or adhesive tape, bandage, non-woven fabric, hydrocolloid, or hydrogel.
3. The method for preparing the hemostatic microneedle patch device according to claim 2, characterized in that: The preparation method of the solid microneedle patch comprises the following steps: The hemostatic dressing and auxiliary materials were dissolved in a solvent, and a mixed hemostatic component solution was prepared by heating and ultrasound. The hemostatic component solution was then cast on the mold by micromolding so that the solution completely filled the holes in the mold cavity. The mold was then vacuumed for 3 minutes, and the process was repeated 3 times. The mixed hemostatic component solution was added to form a backing substrate, which was then dried in a dryer at 25°C for 24 hours to obtain a solid microneedle patch.
4. The method for preparing a solid microneedle patch according to claim 3, characterized in that: The solid microneedle contains a hemostatic dressing with a hemostatic effect, and the hemostatic dressing with a hemostatic effect includes, but is not limited to, one or more of chitosan, carboxymethyl chitosan, dextran, hyaluronic acid, alginate, gelatin, cellulose, collagen, zeolite, kaolin, and montmorillonite.
5. The method for preparing the hemostatic microneedle patch according to claim 4, characterized in that: The mass concentration of the hemostatic dressing in the hemostatic component solution is 5-15%.
6. The method for preparing the hemostatic microneedle patch according to claim 5, characterized in that: The solvent includes: one or more of distilled water, isopropanol, glycerol, butanediol, carbon tetrachloride and methanol.
7. The method for preparing the hemostatic microneedle patch according to claim 6, characterized in that: The material of the mold includes polydimethylsiloxane and / or polymethyl methacrylate.