Implant rod for hypertension and preparation method thereof

Abstract

The invention relates to a hypertension implant rod and a preparation method thereof, and relates to the technical field of hypertension implant rods, the hypertension implant rod comprises a quick release layer, a slow release layer and a long-acting regulation and control layer from outside to inside, the quick release layer comprises, by mass, 60-70% of bacterial cellulose (BC), 15-25% of polydopamine (PDA), 3-8% of ciprofloxacin, 3-8% of protamine and 4-6% of indapamide, the slow release layer comprises, by mass, 20-30% of a long-acting regulation and control layer, and the long-acting regulation and control layer comprises, by mass, 20-30% of a slow release layer and 20-30% of a long-acting regulation and control layer. The sustained release layer is prepared from 55 to 65 percent of polylactic acid-glycolic acid copolymer, 20 to 30 percent of cross-linked gelatin, 8 to 12 percent of lacidipine and 4 to 6 percent of spirolactone, and the long-acting regulation and control layer is prepared from 65 to 75 percent of L-polylactic acid, 20 to 30 percent of beta-glycine crystal, 3 to 5 percent of silk fibroin (SF), 0.5 to 1.0 percent of calcitonin gene related peptide CGRP and 0.1 to 0.3 percent of neuropeptide Y. The hypertension implant rod can be matched with various treatment cycles through gradient degradation, realizes'on-demand treatment ', is high in biocompatibility, is suitable for subcutaneous implantation, and is convenient and safe to operate.

Description

Technical Field

[0001] This invention relates to the field of implantation technology, specifically to a hypertension implantation stick and a method for preparing a hypertension implantation stick. Background Technology

[0002] The subcutaneous implantation therapy for hypertension involves using specialized instruments to implant medical-grade foreign proteins into acupoints on the human body. The foreign proteins exert a lasting and gentle physiological, physical, and biochemical effect on the acupoints and meridians, thereby achieving the goal of treating hypertension.

[0003] Currently, implant sticks used in implantation procedures typically employ catgut or other absorbable medical sutures. Catgut is obtained from the fibrous tissue layer beneath the mucosa of sheep intestines or the serosa connective tissue layer of bovine intestines. Through mechanical separation and cleaning of the animal intestines, a thin strip primarily composed of collagen (a polypeptide) is obtained. This strip is then treated with a weak cross-linking agent (such as formaldehyde, alum, or chromium salts), and then one to five strips are combined, stretched, and twisted. To improve the suture's performance and appearance, the twisted catgut suture needs to be polished and subsequently soaked in a suitable liquid to increase its flexibility. The main medical mechanism of the most widely used common medical catgut suture is to replace the physical stimulation of acupuncture, but the therapy is relatively simple and lacks other extended therapeutic effects. To address these issues, the main preparation method involves soaking medical catgut in different medications to form a drug-releasing system using the catgut as a carrier. During use, the carried drug is slowly released to achieve a therapeutic effect.

[0004] Chinese invention patent application CN109248198A discloses an acupoint implant stick for treating hypertension, which is obtained by soaking catgut in a medicinal solution. The medicinal solution is made from the following components in parts by weight: 10 parts of red anise root / red anise root bark, 10-30 parts of paulownia leaves, 5-12 parts of achyranthes bidentata, 3-15 parts of rhubarb, 0.6-3 parts of Panax notoginseng, and 30-100 parts of medical alcohol. The medicinal solution is obtained by grinding red anise root / red anise root bark, paulownia leaves, achyranthes bidentata, rhubarb, and Panax notoginseng into granules or powder, mixing them according to the above-mentioned parts by weight, adding medical alcohol, soaking, and then filtering. The acupoint implant stick is made by soaking medical catgut in the above medicinal solution for 5-10 days, then removing and drying it, soaking it again for 5-10 days, removing it, drying it, and sterilizing it.

[0005] The acupoint implant stick of this invention has good therapeutic effects and a high cure rate. Its preparation process is simple and suitable for industrial production. However, catgut contains processing residues such as animal proteins (e.g., collagen) and chromium salts, which can easily trigger local rejection reactions, manifesting as redness, swelling, induration, or even ulceration. It also has high immunogenicity, posing a significant risk to patients with allergies, and its absorption rate is greatly affected by individual differences (age, nutritional status), leading to unstable efficacy. With the development of the industry, those skilled in the art have also developed a series of new implant stick materials.

[0006] Chinese invention patent application CN1748802A discloses the application of a biodegradable suture material in acupoint implantation. The suture material is a surgical suture made of polymeric synthetic materials such as polyglycolic acid (PGA), glycolide and lactide copolymer (PGLA), dioxane-1, glycosyl ketone polymer (PDS), gluconic acid polymer (Glycomer), Glycolide / epsiloncaprolactone, and (Poliglecaprone 25).

[0007] This application of biodegradable synthetic sutures to replace traditional catgut sutures for acupoint implantation therapy offers advantages such as minimal tissue reaction, stable absorption, controllable stimulation intensity and suture absorption time based on clinical treatment needs, and complete suture absorption. While the aforementioned novel polymeric materials (such as PGLA) reduce immunogenicity, the local accumulation of degradation products (such as lactic acid and glycolic acid) affects the tissue microenvironment. For example, the acidic environment generated by PGLA degradation may trigger a mild inflammatory response. Furthermore, in addition to biocompatibility issues, implantation rods also suffer from a mismatch between degradation rate and treatment cycle, and asynchronous material degradation and drug release, requiring further research. Summary of the Invention

[0008] To address the aforementioned issues, this invention provides a hypertension implant stick and its preparation method. The hypertension implant stick of this invention undergoes gradient degradation, can be matched with multiple treatment cycles, achieves "on-demand treatment," has high biocompatibility, is suitable for subcutaneous implantation, and is convenient and safe to operate.

[0009] In a first aspect, the present invention provides a hypertension implantation stick, which comprises, from the outside to the inside, an immediate-release layer, a sustained-release layer, and a long-acting regulating layer. By mass fraction, the immediate-release layer comprises 60-70% bacterial cellulose (BC), 15-25% polydopamine (PDA), 3-8% ciprofloxacin, 3-8% protamine sulfate, and 4-6% indapamide; the sustained-release layer comprises 55-65% polylactic-co-glycolic acid copolymer (PLGA), 20-30% cross-linked gelatin, 8-11% lacidipine, and 4-6% spironolactone; and the long-acting regulating layer comprises 65-75% L-polylactic acid, 20-30% β-glycine crystals, 3-5% silk fibroin (SF), and 0.5-1.0% calcitonin gene-related peptide (CGRP).

[0010] In the above technical solution, the bacterial cellulose (BC) nanofiber network provides mechanical support in the immediate-release layer, and its porous structure allows for drug diffusion. Human lysozyme progressively hydrolyzes β-1,4 glycosidic bonds, achieving complete degradation within 3-6 months without acidic products. In an inflammatory microenvironment (pH < 6.5), polydopamine (PDA) transforms from a quinone structure to a phenolic structure, significantly increasing porosity and accelerating drug release. It adheres to tissue in situ via catechol groups, reducing the risk of translocation. Ciprofloxacin inhibits DNA gyrase, and protamine disrupts the bacterial membrane potential; ciprofloxacin and protamine synergistically fight bacteria. Protamine neutralizes heparin, preventing bleeding at the implantation site. Indapamide rapidly diffuses through the pores of bacterial cellulose / polydopamine, reaching peak concentration in 30 minutes, and inhibits Na+ in the distal convoluted tubule. + -Cl⁻ cotransporter increases 24-hour urinary sodium excretion. The immediate-release layer can release indapamide within 0-72 hours, and the pH-sensitive hydrogel rapidly releases indapamide, taking effect in 30 minutes, lowering systolic blood pressure and resolving acute blood pressure fluctuations.

[0011] In the sustained-release layer, polylactic acid-glycolic acid copolymer (PLGA) is used for degradation regulation, encapsulating lipid-soluble drugs through hydrophobic interactions to achieve sustained drug release and avoid burst release. Cross-linked gelatin amino groups neutralize the lactic acid produced by the degradation of the PLAGA, maintaining a local pH > 6.8. Lacidipine and spironolactone synergistically lower blood pressure; lacidipine blocks L-type calcium channels, reducing vascular smooth muscle tone, while spironolactone competitively inhibits aldosterone receptors, reducing sodium retention. The sustained-release layer allows for slow release over 1-24 months, and PLGA and cross-linked gelatin provide sustained release of lacidipine and spironolactone, maintaining stable blood pressure.

[0012] In the long-acting regulatory layer, β-glycine aligns with polylactic acid (PLA), generating voltage during vascular pulsation, activating voltage-gated calcium channels, and inducing vasodilation. The PLA crystalline region provides a long-term degradation cycle, matching the needs of long-term treatment. Silk fibroin is released in a controlled manner: the β-sheet conformation (FTIR detection of the 1635 cm⁻¹ peak) forms hydrophobic microdomains, and the release rate of CGRP / neuropeptide Y is positively correlated with the piezoelectric signal intensity (r=0.89). The calcitonin gene-related peptide CGRP can activate the vascular endothelial AC-cAMP pathway, increasing NO release. The long-acting regulatory layer can achieve long-term release over 24-36 months; piezoelectricity can trigger CGRP release, targeting and regulating vascular function.

[0013] Optionally, the preparation steps of the polylactic acid-glycolic acid copolymer are as follows: lactic acid and glycolic acid are mixed in a molar ratio of 7-8:2-3, pre-condensed at 155-165℃ for 1-3 hours, heated to 170-180℃, reacted under vacuum of <100 Pa for 58-60 hours, discharged under nitrogen protection, pulverized and sieved to obtain the polylactic acid-glycolic acid copolymer.

[0014] In the above technical solution, by adjusting the ratio of lactic acid to glycolic acid, the complete degradation of the implanted rod within 3-6 months under the skin is precisely controlled. Pre-polymerization ensures that lactic acid and glycolic acid fully copolymerize to form oligomers, avoiding the formation of homopolymers and preventing molecular chain breakage at high temperatures later. The vacuum stage removes the byproduct water.

[0015] Optionally, the preparation steps of the cross-linked gelatin are as follows: Deionized water is heated to 45-55℃, gelatin powder is slowly added, and magnetic stirring is performed at 400-600 rpm until completely dissolved to obtain a transparent solution with a mass-volume percentage concentration of 8-12% w / v. 1% w / v glutaraldehyde solution is added to the transparent solution, and the volume ratio of the transparent solution to the glutaraldehyde solution is 10:1. The solution is magnetically stirred at a constant temperature of 20-30℃ and 100-300 rpm. The cross-linked gelatin gel is poured into -20℃ ethanol for rapid cooling and solidification, and then pulverized and sieved to obtain the cross-linked gelatin.

[0016] In the above technical solution, the use of glutaraldehyde in cross-linked gelatin can form 10-50 μm channels, improving the drug diffusion coefficient. The concentration of glutaraldehyde solution is 1% w / v. If the concentration is >2%, it will lead to excessive cross-linking and reduce the swelling rate; if it is <0.5%, it will lead to insufficient cross-linking.

[0017] Optionally, the long-acting regulatory layer further includes 0.1-0.3% neuropeptide Y.

[0018] In the above technical solution, neuropeptide Y can block Y1 receptors, reduce sympathetic nerve excitability, and target and regulate neurovascular function with calcitonin gene-related peptide CGRP, thus synergistically lowering blood pressure.

[0019] Secondly, the present invention provides a method for preparing a hypertension implant stick, the method comprising the following steps: Preparation of the long-acting regulatory layer: Calcitonin gene-related peptide CGRP was dissolved in a 5% w / v SF aqueous solution and ultrasonically treated at 100W for 25-35s to form a peptide emulsion. Polylactic acid (PLLA) and β-glycine crystals were dispersed in a 7:3 molar ratio of chloroform and acetone to form a 12% w / v injection PLLA / β-glycine solution. The peptide emulsion with a flow rate of 0.8 mL / h was used as the inner layer, and the PLLA / β-glycine solution with a flow rate of 2.0 mL / h was used as the outer layer. Coaxial spinning was performed under the conditions of 16-20 kV voltage, 14-16 cm receiving distance, and 20-30℃ temperature. Then, the mixture was heat-cured by hot air treatment at 75-85℃ for 8-12 min, followed by rapid cooling in a water bath at 3-5℃ to obtain the long-acting regulatory layer. Preparation of the sustained-release layer: PLGA, lacidipine, and spironolactone were dissolved in dichloromethane to form an oil phase, with a molar ratio of PLGA to dichloromethane of 1:8-9. Crushed cross-linked gelatin was dispersed in deionized water to form an inner aqueous phase, and a 2% polyvinyl alcohol solution was used as an outer aqueous phase. Double emulsion droplets were obtained using a W / O / W emulsion method. After evaporation at room temperature for 4-5 hours, microspheres were obtained. The microspheres were dispersed in PBS buffer at pH 7-7.5 and mixed with a long-acting control layer and shaken for 1.5-2.5 hours. The mass ratio of the microspheres to the long-acting control layer was 1-2:1, forming composite fibers. Helical structure shaping: The composite fiber is immersed in PBS buffer containing 0.1% trypsin at pH 7-7.5 for 1.5-2.5 h, then wound around a titanium wire mandrel with a diameter of 0.3 mm, a tension of 0.5 N is applied, and the mandrel is removed after 8-12 min. The fiber is then treated in a vacuum oven at 55-65℃ for 3-5 h to obtain the helical fiber. Preparation of the immediate-release layer: The spiral fibers were immersed in 1-3 mg / mL dopamine-Tris buffer solution at pH 8-9 and shaken at room temperature for 10-14 hours to form polydopamine on the surface. After rinsing, the fibers were alternately immersed in ciprofloxacin solution, protamine solution, and indapamide solution for 2-3 cycles, each for 8-12 minutes, to form coated fibers. The bacterial cellulose was then used to coat the coated fibers, and the fibers were hot-pressed at 0.4-0.6 MPa and 45-55℃ for 8-12 minutes. The fibers were then treated with hydrogen peroxide vapor at 40-50℃ for 40-50 minutes to obtain the hypertension implant stick.

[0020] In the above technical solutions, coaxial spinning can constrain the directional growth of β-glycine in the PLLA shell, thereby increasing the piezoelectric constant; thermosetting can eliminate internal stress, stabilize the crystal structure, and improve the crystallinity of PLLA; and rapid freezing can stabilize the orientation structure and stabilize the piezoelectric properties.

[0021] The W / O / W emulsion method was used to enable PLGA to self-assemble and encapsulate drugs at the oil-water interface. The microspheres were mixed and vibrated with the long-acting regulation layer, and the long-acting regulation layer was uniformly coated by electrostatic attraction.

[0022] Enzymatic hydrolysis of gelatin can weaken the interface, reduce the elastic modulus, and the tension causes the PLLA molecular chains to form a β-sheet conformation, giving it superelasticity.

[0023] Dopamine undergoes oxidative polymerization to form polydopamine, which forms covalent bonds with fibrous amino groups through quinone groups. BC nanofibers can penetrate into the pores of polydopamine to form a pore size gradient filter, thereby inhibiting drug burst release.

[0024] Optionally, the preparation step of the long-acting regulatory layer further includes dissolving CGRP and neuropeptide Y in a 5% w / v SF aqueous solution and sonicating at 100 W for 25-35 s to form a peptide emulsion.

[0025] Thirdly, this invention provides a hypertension implant stick and a method for preparing the same, and the application of the resulting hypertension implant stick in the treatment of hypertension. In summary, the present invention has at least one of the following beneficial technical effects: 1. The rapid-release layer in the hypertension implant stick of the present invention can release indapamide within 0-72 hours. The pH-sensitive hydrogel rapidly releases indapamide, which takes effect in 30 minutes, reduces systolic blood pressure, and resolves acute blood pressure fluctuations.

[0026] 2. The sustained-release layer of the hypertension implant stick of the present invention can slowly release over 1-24 months. The polylactic acid-glycolic acid copolymer and cross-linked gelatin can continuously release lacidipine and spironolactone to maintain blood pressure homeostasis.

[0027] 3. The long-acting regulatory layer of the hypertension implant stick of the present invention can release long-acting effects within 24-36 months. Piezoelectricity can trigger the release of CGRP and neuropeptide Y, which can target and regulate vascular and nerve functions. Detailed Implementation

[0028] The present invention will be further described in detail below with reference to the embodiments.

[0029] All materials used in the following examples are available for purchase on the market.

[0030] Example 1: This example discloses a hypertension implantation rod and its preparation method.

[0031] The hypertension implant stick comprises, from the outside to the inside, an immediate-release layer, a sustained-release layer, and a long-acting regulating layer. By mass fraction, the immediate-release layer comprises 60% bacterial cellulose (BC), 25% polydopamine (PDA), 8% ciprofloxacin, 3% protamine sulfate, and 4% indapamide; the sustained-release layer comprises 55% polylactic-co-glycolic acid copolymer, 30% cross-linked gelatin, 11% lacidipine, and 4-6% spironolactone; and the long-acting regulating layer comprises 65% L-polylactic acid, 30% β-glycine crystals, 4.5% silk fibroin (SF), and 0.5% calcitonin gene-related peptide (CGRP).

[0032] The preparation method of the hypertension implant stick includes the following steps: S1. Preparation of the long-acting regulatory layer: Calcitonin gene-related peptide CGRP was dissolved in a 5% w / v SF aqueous solution and ultrasonically treated at 100 W for 30s to form a peptide emulsion. L-polylactic acid and β-glycine crystals were dispersed in a 7:3 molar ratio of chloroform and acetone to form a 12% w / v injection PLLA / β-glycine solution. The peptide emulsion with a flow rate of 0.8 mL / h was used as the inner layer, and the PLLA / β-glycine solution with a flow rate of 2.0 mL / h was used as the outer layer. Coaxial spinning was performed under the conditions of 18kV voltage, 14-16cm receiving distance, and 25℃ temperature. Then, the mixture was heat-cured by hot air treatment at 80℃ for 10min, followed by rapid cooling in a 4℃ water bath to obtain the long-acting regulatory layer. S2. Preparation of the sustained-release layer: S21. Preparation of polylactic acid-glycolic acid copolymer: Lactic acid and glycolic acid are mixed in a molar ratio of 7:3, pre-polymerized at 160°C for 2 hours, heated to 175°C, reacted under vacuum of <100 Pa for 60 hours, discharged under nitrogen protection, pulverized and sieved to obtain the polylactic acid-glycolic acid copolymer. S22. Preparation of cross-linked gelatin: Deionized water was heated to 50°C, gelatin powder was slowly added, and the mixture was magnetically stirred at 500 rpm until completely dissolved to obtain a transparent solution with a mass-volume percentage concentration of 10% w / v. 1% w / v glutaraldehyde solution was added to the transparent solution, with a volume ratio of 10:1 between the transparent solution and the glutaraldehyde solution. The mixture was magnetically stirred at a constant temperature of 25°C and 200 rpm. The cross-linked gelatin gel was poured into -20°C ethanol for rapid cooling and solidification, and then pulverized and sieved to obtain the cross-linked gelatin. S23. PLGA, lacidipine, and spironolactone are dissolved in dichloromethane to form an oil phase, wherein the molar ratio of PLGA to dichloromethane is 1:9. Crushed cross-linked gelatin is dispersed in deionized water to form an inner aqueous phase, and a 2% polyvinyl alcohol solution is used as an outer aqueous phase. Double emulsion droplets are obtained by W / O / W emulsion method. After evaporation at room temperature for 4 hours, microspheres are obtained. The microspheres are dispersed in PBS buffer at pH 7-7.5 and mixed with a long-acting control layer and shaken for 2 hours. The mass ratio of microspheres to long-acting control layer is 1.5:1 to form composite fibers. S3. Helical structure shaping: The composite fiber was immersed in PBS buffer containing 0.1% trypsin at pH 7-7.5 for 2 hours, then wound around a titanium wire mandrel with a diameter of 0.3 mm, applied a tension of 0.5 N, maintained for 10 minutes, and then the titanium wire mandrel was removed and treated in a vacuum oven at 60°C for 4 hours to obtain the helical fiber. S4. Preparation of the immediate-release layer: The spiral fiber was immersed in a 2 mg / mL pH 8-9 dopamine-Tris buffer solution and shaken at room temperature for 12 h to form polydopamine on the surface. After rinsing, it was alternately immersed in ciprofloxacin solution, protamine solution, and indapamide solution for 3 cycles, each for 10 min to form a coated fiber. Then, the bacterial cellulose was used to coat the coated fiber, and it was hot-pressed at 0.5 MPa and 50 °C for 10 min. Then, it was treated with hydrogen peroxide vapor at 45 °C for 45 min to obtain the hypertension implant stick.

[0033] Example 2: This example discloses a hypertension implantation rod and its preparation method.

[0034] The hypertension implant stick comprises, from the outside to the inside, an immediate-release layer, a sustained-release layer, and a long-acting regulating layer. By mass fraction, the immediate-release layer comprises 70% bacterial cellulose (BC), 15% polydopamine (PDA), 3% ciprofloxacin, 6% protamine sulfate, and 6% indapamide; the sustained-release layer comprises 65% polylactic-co-glycolic acid copolymer, 20% cross-linked gelatin, 9% lacidipine, and 6% spironolactone; and the long-acting regulating layer comprises 75% L-polylactic acid, 21% β-glycine crystals, 3% silk fibroin (SF), and 1.0% calcitonin gene-related peptide (CGRP).

[0035] The preparation method is the same as in Example 1.

[0036] Example 3: This example discloses a hypertension implantation rod and its preparation method.

[0037] The hypertension implant stick comprises, from the outside to the inside, an immediate-release layer, a sustained-release layer, and a long-acting regulating layer. By mass fraction, the immediate-release layer comprises 65% bacterial cellulose (BC), 20% polydopamine (PDA), 5% ciprofloxacin, 5% protamine sulfate, and 5% indapamide; the sustained-release layer comprises 60% polylactic-co-glycolic acid copolymer, 25% cross-linked gelatin, 10% lacidipine, and 5% spironolactone; and the long-acting regulating layer comprises 70% L-polylactic acid, 25% β-glycine crystals, 4.2% silk fibroin (SF), and 0.8% calcitonin gene-related peptide (CGRP).

[0038] The preparation method is the same as in Example 1.

[0039] Example 4: This example discloses a method for preparing a hypertension implant stick.

[0040] The hypertension implant stick comprises, from the outside to the inside, an immediate-release layer, a sustained-release layer, and a long-acting regulating layer. By mass fraction, the immediate-release layer comprises 65% bacterial cellulose (BC), 20% polydopamine (PDA), 5% ciprofloxacin, 5% protamine sulfate, and 5% indapamide; the sustained-release layer comprises 60% polylactic-co-glycolic acid copolymer, 25% cross-linked gelatin, 10% lacidipine, and 5% spironolactone; and the long-acting regulating layer comprises 70% L-polylactic acid, 25% β-glycine crystals, 4% silk fibroin (SF), 0.8% calcitonin gene-related peptide (CGRP), and 0.2% neuropeptide Y.

[0041] The preparation method of the hypertension implant stick includes the following steps: S1. Preparation of the long-acting regulatory layer: Calcitonin gene-related peptide CGRP and neuropeptide Y were dissolved in a 5% w / v SF aqueous solution and ultrasonicated at 100 W for 30 s to form a peptide emulsion. Polylactic acid (PLLA) and β-glycine crystals were dispersed in a 7:3 molar ratio of chloroform and acetone to form a 12% w / v injection PLLA / β-glycine solution. The peptide emulsion with a flow rate of 0.8 mL / h was used as the inner layer, and the PLLA / β-glycine solution with a flow rate of 2.0 mL / h was used as the outer layer. Coaxial spinning was performed under the conditions of 18 kV voltage, 14-16 cm receiving distance, and 25℃ temperature. Then, the mixture was heat-cured by hot air treatment at 80℃ for 10 min, followed by rapid cooling in a 4℃ water bath to obtain the long-acting regulatory layer. S2. Preparation of the sustained-release layer: S21. Preparation of polylactic acid-glycolic acid copolymer: Lactic acid and glycolic acid are mixed in a molar ratio of 7:3, pre-polymerized at 160°C for 2 hours, heated to 175°C, reacted under vacuum of <100 Pa for 60 hours, discharged under nitrogen protection, pulverized and sieved to obtain the polylactic acid-glycolic acid copolymer. S22. Preparation of cross-linked gelatin: Deionized water was heated to 50°C, gelatin powder was slowly added, and the mixture was magnetically stirred at 500 rpm until completely dissolved to obtain a transparent solution with a mass-volume percentage concentration of 10% w / v. 1% w / v glutaraldehyde solution was added to the transparent solution, with a volume ratio of 10:1 between the transparent solution and the glutaraldehyde solution. The mixture was magnetically stirred at a constant temperature of 25°C and 200 rpm. The cross-linked gelatin gel was poured into -20°C ethanol for rapid cooling and solidification, and then pulverized and sieved to obtain the cross-linked gelatin. S23. PLGA, lacidipine, and spironolactone are dissolved in dichloromethane to form an oil phase, wherein the molar ratio of PLGA to dichloromethane is 1:9. Crushed cross-linked gelatin is dispersed in deionized water to form an inner aqueous phase, and a 2% polyvinyl alcohol solution is used as an outer aqueous phase. Double emulsion droplets are obtained by W / O / W emulsion method. After evaporation at room temperature for 4 hours, microspheres are obtained. The microspheres are dispersed in PBS buffer at pH 7-7.5 and mixed with a long-acting control layer and shaken for 2 hours. The mass ratio of microspheres to long-acting control layer is 1.5:1 to form composite fibers. S3. Helical structure shaping: The composite fiber was immersed in PBS buffer containing 0.1% trypsin at pH 7-7.5 for 2 hours, then wound around a titanium wire mandrel with a diameter of 0.3 mm, applied a tension of 0.5 N, maintained for 10 minutes, and then the titanium wire mandrel was removed and treated in a vacuum oven at 60°C for 4 hours to obtain the helical fiber. S4. Preparation of the immediate-release layer: The spiral fiber was immersed in a 2 mg / mL pH 8-9 dopamine-Tris buffer solution and shaken at room temperature for 12 h to form polydopamine on the surface. After rinsing, it was alternately immersed in ciprofloxacin solution, protamine solution, and indapamide solution for 3 cycles, each for 10 min to form a coated fiber. Then, the bacterial cellulose was used to coat the coated fiber, and it was hot-pressed at 0.5 MPa and 50 °C for 10 min. Then, it was treated with hydrogen peroxide vapor at 45 °C for 45 min to obtain the hypertension implant stick.

[0042] Test 1: Mechanical properties of the hypertension implant rods prepared in Examples 1-4 were tested. The tensile strength and maximum force elongation were tested according to GB / T228.1-2010 Metallic Materials - Tensile Testing - Part 1: Test Method at Room Temperature. The results are shown in Table 1.

[0043] Table 1 Example performance Tensile strength (MPa) Maximum elongation at force (%) Example 1 234.5 15.31 Example 2 236.7 15.36 Example 3 243.2 15.57 Example 4 245.4 15.61 As can be seen from the data in Table 1, the hypertension implant stick of this application has excellent tensile strength and maximum force elongation. In particular, the hypertension implant stick obtained in Example 4 has a tensile strength of 245.4 MPa and a maximum force elongation of 15.61%.

[0044] Test 2: Twenty-five spontaneously hypertensive male rats aged 16-20 weeks with systolic blood pressure >180 mmHg, diastolic blood pressure ≥110 mmHg, heart rate 350-450 bpm, and body weight 250±20 g were selected. These rats were divided into 5 groups of 5 rats each. Hypertensive implant sticks were implanted subcutaneously into acupoints. All antihypertensive medications were discontinued the day before treatment, and blood pressure was measured and recorded on the morning of treatment. The specific subcutaneous implantation method was as follows: The lower border of the biceps brachii muscle on one upper limb was selected as the main acupoint. After routine disinfection, local anesthesia with 1% lidocaine was performed. The hypertensive implant sticks prepared in Examples 1-4 and the blank control implant stick (implanted without medication) were implanted subcutaneously into the biceps brachii muscle of the upper limb using a special instrument. After implantation, a band-aid was applied, and local pressure was applied for 15-20 minutes to prevent bleeding and infection. The band-aid was removed after 48 hours. Blood pressure was measured in each group at 24 hours, 4 weeks, 12 weeks and 24 weeks after implantation. Skin and subcutaneous tissue samples were taken from the implantation site 28 days after implantation for H&E staining inflammation test. The test results are shown in Tables 2 and 3.

[0045] Table 2

[0046] Table 3

[0047] As shown in Tables 2 and 3, when the hypertension implant sticks prepared in Examples 1-4 of this application were subcutaneously implanted into rats, the pH-sensitive hydrogel in the rapid-release layer rapidly released indapamide within 24 hours after implantation, inhibiting renal tubular Na+. + Reabsorption reduces blood volume. Vascular pulsation activates the β-glycine / PLLA piezoelectric layer, instantly releasing CGRP analogs to dilate blood vessels. From 4 to 12 weeks after implantation, the system enters a stable phase, where polylactic-co-glycolic acid copolymer and cross-linked gelatin in the sustained-release layer continuously release lacidipine and spironolactone, inhibiting vasoconstriction and sodium retention. NPY inhibitors are gradually released, reducing sympathetic nerve activity. After 24 weeks, the system enters a decline phase; material degradation leads to a decrease in drug release rate, and blood pressure slowly recovers.

[0048] The hypertension implant stick of the present invention can be matched with multiple treatment cycles through gradient degradation, realizing "on-demand treatment", with high biocompatibility, suitable for subcutaneous implantation, and convenient and safe operation.

[0049] The above are all preferred embodiments of the present invention and are not intended to limit the scope of protection of the present invention. Therefore, all equivalent changes made in accordance with the structure, shape and principle of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A hypertension implant rod, characterized in that, The high blood pressure implant rod comprises, from outside to inside, a fast-release layer, a slow-release layer and a long-acting regulation layer, and the fast-release layer comprises, by mass fraction, 60-70% bacterial cellulose (BC), 15-25% polydopamine (PDA), 3-8% ciprofloxacin, 3-8% protamine, 4-6% indapamide, the slow-release layer comprises 55-65% polylactic acid-glycolic acid copolymer, 20-30% cross-linked gelatin, 8-11% lercanidipine and 4-6% spironolactone, and the long-acting regulation layer comprises 65-75% levorotatory polylactic acid, 20-30% β-glycine crystal, 3-5% silk fibroin (SF) and 0.5-1.0% calcitonin gene-related peptide (CGRP).

2. The implantable bar for hypertension according to claim 1, wherein The polylactic acid-glycolic acid copolymer is prepared by the following steps: mixing lactic acid and glycolic acid at a molar ratio of 7-8:2-3, pre-polymerizing at 155-165 ℃ for 1-3 h, increasing the temperature to 170-180 ℃, reacting under a vacuum degree of <100 Pa for 58-60 h, discharging under nitrogen protection, crushing and sieving to obtain the polylactic acid-glycolic acid copolymer.

3. A hypertension implant rod according to claim 1 or 2, characterised in that The cross-linked gelatin is prepared by the following steps: heating deionized water to 45-55 ℃, slowly adding gelatin powder, magnetically stirring at 400-600 rpm until completely dissolved to obtain a transparent solution with a mass / volume percentage concentration of 8-12% w / v, adding 1% w / v glutaraldehyde solution to the transparent solution, the volume ratio of the transparent solution to the glutaraldehyde solution being 10:1, constant-temperature magnetic stirring at 20-30 ℃ and 100-300 rpm, pouring the cross-linked gelatin gel into -20 ℃ ethanol for rapid cooling and solidification, crushing and sieving to obtain the cross-linked gelatin.

4. The implantable bar for hypertension according to claim 1, wherein The long-acting regulation layer further comprises 0.1-0.3% neuropeptide Y.

5. A method of manufacturing a hypertension implant rod according to any one of claims 1-4, c h a r a c t e r i s e d in that The preparation method of the high blood pressure implant rod comprises the following steps: Preparation of the long-acting regulation layer: dissolving calcitonin gene-related peptide (CGRP) in a 5% w / v SF aqueous solution, ultrasonically treating at 100 W for 25-35 s to form a peptide emulsion, dispersing levorotatory polylactic acid and β-glycine crystal in a mixed solvent of chloroform and acetone at a molar ratio of 7:3 to form a 12% w / v injection PLLA / β-glycine solution, using the peptide emulsion as the inner layer at a flow rate of 0.8 mL / h and the PLLA / β-glycine solution as the outer layer at a flow rate of 2.0 mL / h, performing coaxial spinning under the conditions of an electric voltage of 16-20 kV, a receiving distance of 14-16 cm and a temperature of 20-30 ℃, then performing heat curing by hot air treatment at a temperature of 75-85 ℃ for 8-12 min, and then rapidly cooling in a water bath at 3-5 ℃ to obtain the long-acting regulation layer; Preparation of the sustained release layer: PLGA, lercanidipine, and spironolactone were dissolved in dichloromethane to form an oil phase, the molar ratio of PLGA to dichloromethane was 1:8-9, the crushed cross-linked gelatin was dispersed in deionized water to form an inner water phase, and 2% polyvinyl alcohol solution was used as an outer water phase, a double emulsion droplet was obtained by W / O / W emulsion method, and microspheres were obtained after volatilization at room temperature for 4-5 h, the microspheres were dispersed in PBS buffer solution with pH 7-7.5, mixed and shaken with the long-acting control layer for 1.5-2.5 h, the mass ratio of the microspheres to the long-acting control layer was 1-2:1, and a composite fiber was formed; Shaping of the spiral structure: the composite fiber was immersed in PBS buffer solution containing 0.1% trypsin with pH 7-7.5 for 1.5-2.5 h, then wound on a titanium wire mandrel with a diameter of 0.3 mm, a tension of 0.5 N was applied, the titanium wire mandrel was removed after maintaining for 8-12 min, and the spiral fiber was obtained by vacuum oven treatment at 55-65℃ for 3-5 h; Preparation of the immediate release layer: the spiral fiber was immersed in 1-3 mg / mL dopamine-Tris buffer solution with pH 8-9, and the surface was formed with polydopamine after oscillation at room temperature for 10-14 h, the spiral fiber was taken out and washed, and then was immersed in ciprofloxacin solution, protamine solution, and indapamide solution alternately for 2-3 cycles, each cycle was 8-12 min to form a coated fiber, then the bacterial cellulose was wrapped around the coated fiber, and the high blood pressure implant rod was obtained by hot pressing at 0.4-0.6 MPa and 45-55℃ for 8-12 min, and then treating in hydrogen peroxide steam at 40-50℃ for 40-50 min.

6. A method for preparing a hypertension implant stick according to claim 5, characterized in that, The preparation steps of the long-acting control layer further include dissolving CGRP and neuropeptide Y in 5% w / v SF aqueous solution, and ultrasonic treatment at 100 W for 25-35 s to form a peptide emulsion.

7. Use of a high blood pressure implant rod in the treatment of high blood pressure, characterized in that The high blood pressure implant rod is prepared by using the high blood pressure implant rod according to any one of claims 1-4, or the preparation method of the high blood pressure implant rod according to any one of claims 5-6.

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