Hypotensive material for subcutaneous implantation and preparation method thereof

Abstract

The invention discloses an antihypertensive material for subcutaneous implantation and a preparation method of the antihypertensive material, and belongs to the technical field of biomedical materials. The antihypertensive material comprises a carrier material and a drug mixture loaded on the carrier material according to a mass ratio of (10-15): (5-8), and the carrier material comprises the following raw materials: polylactic acid-glycolic acid copolymer, citric acid-chitosan ester, genipin and a silicon dioxide active material. The silicon dioxide active material is obtained by compounding mesoporous silicon dioxide nanoparticles and a collagen coating on the surface of the mesoporous silicon dioxide nanoparticles. According to the antihypertensive material disclosed by the invention, a degradable skeleton is provided by the polylactic acid-glycolic acid copolymer, citric acid-chitosan ester is used as a toughening agent and an antibacterial material, genipin is used as a cross-linking agent, and a mesoporous structure of a silicon dioxide active material is used for loading a medicine; the problems that an existing subcutaneous implant material is high in burst release rate, poor in mechanical property, insufficient in biocompatibility and the like are solved.

Description

Technical Field

[0001] This application belongs to the technical field of biomedical materials, and specifically relates to an antihypertensive material for subcutaneous implantation and a preparation method thereof. Background Art

[0002] Subcutaneous implant materials contain the original drug powder in rod-shaped capsules made of high-molecular compounds. This enables the drug to avoid the first-pass effect during liver metabolism and directly enter the blood circulation system through the absorption of subcutaneous tissue, thereby improving the bioavailability of the drug. Due to its characteristics such as targeted drug delivery, low dose, relatively constant release rate, and stable blood drug concentration, it is a better treatment approach for chronic and lifelong diseases that require small doses and long-term drug administration. Hypertension is the main inducer of global cardiovascular and cerebrovascular diseases, and patients need to take drugs for a long time to control blood pressure. However, traditional oral or injection drug delivery methods have problems such as poor compliance and large fluctuations in blood drug concentration, which easily lead to unstable blood pressure control and an increased risk of complications.

[0003] Currently, most subcutaneous implant materials for hypertension rely on carrier degradation to control release. However, the current carriers are all single polymer carriers, such as polylactic acid (PLA) and poly(lactic-co-glycolic acid) (PLGA). These materials have problems such as poor toughness, high drug burst release rate, and mismatch between degradation rate and drug release. Therefore, there is an urgent need to prepare a new type of subcutaneous implant material that can achieve long-term and stable controlled release. Summary of the Invention

[0004] To solve the problems in the prior art, the purpose of this application is to provide an antihypertensive material for subcutaneous implantation and a preparation method thereof, which can simultaneously take into account mechanical properties, drug sustained-release performance, and long-term degradation function.

[0005] To achieve the above object, this application provides an antihypertensive material for subcutaneous implantation, including a carrier material and a drug mixture loaded on the carrier material with a mass ratio of (10 - 15):(5 - 8);

[0006] Among them, the carrier material includes the following raw materials: poly(lactic-co-glycolic acid), citric acid-chitosan ester, genipin, and silica active material;

[0007] Among them, the silica active material is obtained by compounding mesoporous silica nanoparticles with a collagen coating on their surface.

[0008] Furthermore, the drug mixture includes the following components in parts by weight:

[0009] 15 - 25 parts of amlodipine, 8 - 12 parts of losartan potassium, 1 - 3 parts of folic acid, and 20 - 30 parts of hydroxypropyl-β-cyclodextrin.

[0010] Further, the carrier material comprises the following raw materials in parts by weight:

[0011] 80 to 120 parts of poly (lactic-co-glycolic acid), 15 to 20 parts of citric acid-chitosan ester, 0.1 to 1 part of genipin, and 1 to 5 parts of silica active material.

[0012] Further, the silica active material is prepared by the following method:

[0013] Disperse mesoporous silica nanoparticles in type I collagen solution and perform ultrasonic treatment, then collect the precipitate after stirring and centrifugation;

[0014] Wash the precipitate and then freeze-dry it to obtain the silica active material.

[0015] Further, the pore diameter of the mesoporous silica nanoparticles is 5 nm to 10 nm, and the specific surface area is 800 m 2 / g to 1000 m 2 / g; the concentration of the type I collagen solution is 0.5 mg / mL to 2 mg / mL.

[0016] To achieve the above object, the present application also provides a preparation method of a blood pressure lowering material, comprising the following steps:

[0017] Prepare 30 wt% to 40 wt% of the poly (lactic-co-glycolic acid) in the raw materials into a poly (lactic-co-glycolic acid) enhanced film;

[0018] Dissolve 50 wt% to 60 wt% of the poly (lactic-co-glycolic acid) in the raw materials and the citric acid-chitosan ester in an organic solvent, and stir evenly to obtain a first solution;

[0019] Add a drug mixture to the first solution, perform ultrasonic dispersion and static defoaming to obtain a second solution, and then obtain a nanofiber membrane by electrospinning the second solution;

[0020] Disperse the silica active material in the organic solution of the remaining poly (lactic-co-glycolic acid) in the raw materials to obtain a third solution;

[0021] Stack the poly (lactic-co-glycolic acid) enhanced film and the nanofiber membrane, and then cast the third solution to obtain a multilayer material;

[0022] Immerse the multilayer material in a genipin solution for crosslinking reaction, and then wash and dry it to obtain the blood pressure lowering material.

[0023] Further, in the step of obtaining the nanofiber membrane by electrospinning the second solution, the parameters of electrospinning include: a 27G needle, a flow rate of 1.0 mL / h to 1.2 mL / h, a receiver rotation speed of 800 rpm to 1000 rpm, and an electrospinning time of 5 h to 10 h.

[0024] Further, the poly(lactic-co-glycolic acid) reinforced membrane is a composite material of nanofibrous poly(lactic-co-glycolic acid) copolymer and bulk poly(lactic-co-glycolic acid) copolymer, and the composite material is prepared by the following method:

[0025] Prepare nanofibers of poly(lactic-co-glycolic acid) copolymer by electrospinning;

[0026] Stack and hot-press the nanofibers and bulk poly(lactic-co-glycolic acid) copolymer to obtain the poly(lactic-co-glycolic acid) reinforced membrane.

[0027] Further, the temperature of hot pressing is 70°C to 90°C, the pressure of hot pressing is 3 MPa to 8 MPa, and the time of hot pressing is 8 min to 12 min.

[0028] Further, the temperature of the cross-linking reaction is 35°C to 40°C, and the time of the cross-linking reaction is 5 h to 10 h.

[0029] In summary, the present application has the following advantages:

[0030] The antihypertensive material provided by the present application realizes the effects of initial low burst release and later linear release after in vivo implantation through the synergistic effect of the degradation performance of PLGA and the mesoporous diffusion of the silica active material; the overall elongation at break and fatigue resistance of the material are improved through the toughening effect of citric acid-chitosan ester, and the degradation rate is synchronized with the drug release through the genipin cross-linking network. The two effects synergistically optimize the mechanical properties and degradation time effect, and greatly extend the degradation period; the collagen coating on the surface of the mesoporous silica nanomaterial can reduce the foreign body reaction and promote the adhesion of fibroblasts, and the carrier material selected in the present application has good biocompatibility, which can reduce the inflammatory reaction after subcutaneous implantation. Figure 1 It is a schematic flow chart of the preparation method of the antihypertensive material for subcutaneous implantation provided by the embodiment of the present application. Detailed embodiments

[0031] The principles and features of the present application will be described below in conjunction with embodiments. The examples cited are only used to explain the present application and are not intended to limit the scope of the present application. It should be understood that every intermediate value between the upper and lower limits of the scope is also specifically disclosed. Each intermediate value within any stated value or stated range, as well as each smaller range between any other stated value or intermediate value within the stated range, is also included in the present application. The upper and lower limits of these smaller ranges may be independently included or excluded from the range. For those conditions not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. For reagents or instruments whose manufacturers are not specified, they are all conventional products that can be obtained through commercial purchase.

[0032] In a first aspect, the present application provides an antihypertensive material for subcutaneous implantation, comprising a carrier material and a drug mixture loaded on the carrier material in a mass ratio of (10 - 15):(5 - 8); wherein, the carrier material comprises the following raw materials: poly(lactic-co-glycolic acid) (PLGA), citric acid-chitosan ester (CCE), genipin and silica active material; the silica active material is obtained by compounding mesoporous silica nanoparticles with a collagen coating on its surface.

[0033] The antihypertensive material provided by the present application is a sustained-release material for subcutaneous implantation, which is used to slowly release drugs in the body to maintain a stable blood drug concentration, thereby effectively controlling blood pressure. The carrier material of the present application has biodegradable properties. As the internal drugs are continuously released, the carrier is also slowly degraded and absorbed in the in-vivo environment. When the drug release is complete, the carrier will also disintegrate and be absorbed by the matrix, and there is no need for a second surgery to remove it. The present application solves the pain points of existing subcutaneous implantation materials, such as high burst release rate, poor mechanical properties, and insufficient biocompatibility, through material functionalization modification, structural innovation, and process coordination, providing a long-acting and safe treatment tool for hypertensive patients.

[0034] Specifically, the present application has carried out functionalization modification on the material: ① PLGA is used as the matrix material, and the molecular weight is controlled between 80,000 Da and 150,000 Da, providing a biodegradable polymer backbone to gradually release drugs through hydrolysis, thereby controlling the degradation rate. ② CCE is used as a toughening agent and antibacterial material, forming a hydrogen bond network through hydroxyl groups and PLGA ester groups, improving the toughness of the material and inhibiting crack propagation. ③ Genipin is used as a cross-linking agent, reacting with the amino and carboxyl groups of PLGA and CCE to form a three-dimensional cross-linking network, which can enhance the network stability, regulate the swelling rate of the cross-linking network, and delay degradation. ④ The mesoporous structure of the silica active material can effectively load drugs, and the collagen coating on its surface can inhibit drug burst release and promote cell adhesion.

[0035] In summary, the antihypertensive material provided by the present application has at least the following advantages:

[0036] 1) Long-term antihypertensive effect: By slowly releasing the drug, the antihypertensive effect can be maintained for a long time, reducing the frequency of drug administration for patients.

[0037] 2) Reducing side effects: Compared with oral drugs, subcutaneous implantation reduces the irritation of the drug to the gastrointestinal tract and systemic side effects.

[0038] 3) Improving patient compliance: There is no need for frequent drug administration, improving the quality of life and treatment compliance of patients.

[0039] In this application, the mass ratio of the carrier material to the drug mixture is (10 - 15):(5 - 8), which can ensure that the drug mixture is fully encapsulated in the carrier material, while avoiding an increase in the burst release rate due to an overdose of the drug. And the content of the carrier material can make the PLGA matrix and CCE form a continuous phase, thereby improving the tensile strength of the carrier material. When the drug is overloaded, it will cause the pores of the nanofiber membrane to be blocked, thereby increasing the burst release rate and reducing the toughness of the material; when the drug loading rate is insufficient, it will lead to insufficient drug loading, and the implant material needs to be replaced multiple times, losing the meaning of long-acting controlled release. Therefore, it is necessary to strictly control the drug loading amount according to the proportional relationship provided in this application.

[0040] In some alternative embodiments of this application, the drug mixture includes the following components in parts by weight:

[0041] Amlodipine 15 - 25 parts, losartan potassium 8 - 12 parts, folic acid 1 - 3 parts, and hydroxypropyl-β-cyclodextrin (HP-β-CD) 20 - 30 parts.

[0042] In the above scheme, amlodipine mainly serves as a long-acting calcium channel blocker and is used to reduce peripheral resistance in the drugs of this application; losartan potassium mainly serves as an angiotensin receptor antagonist, and in this application, it synergistically reduces peripheral resistance and renin-angiotensin activity with amlodipine through different mechanisms to achieve the purpose of multi-target blood pressure control; folic acid can reduce the level of homocysteine, mainly for the treatment of H-type hypertension, can reduce the risk of stroke, and at the same time folic acid also helps to reduce the cardiovascular risk of hypertensive patients. Hydroxypropyl-β-cyclodextrin encapsulates the lipophilic drug (amlodipine) through its hydrophobic cavity, which can improve the solubility and stability of the drug and is beneficial to the slow release of the drug.

[0043] In this application, the parts by weight of the drug combination amlodipine can be 15 parts, 16 parts, 17 parts, 18 parts, 19 parts, 20 parts, 21 parts, 22 parts, 23 parts, 24 parts, 25 parts, and so on; the parts by weight of losartan potassium can be 8 parts, 9 parts, 9.5 parts, 10 parts, 10.5 parts, 11 parts, 12 parts, and so on; the parts by weight of folic acid can be 1 part, 1.2 parts, 1.5 parts, 1.8 parts, 2.0 parts, 2.4 parts, 2.8 parts, 3 parts, and so on; the parts by weight of HP-β-CD can be 20 parts, 21 parts, 24 parts, 25 parts, 27 parts, 28 parts, 30 parts, and so on. In this application, the content of amlodipine should not be too high, otherwise it will lead to too high local drug concentration and cause the risk of hypotension. The content of losartan potassium should not be too low, otherwise it will lead to insufficient ARB (Angiotensin Receptor Blocker) effect and cannot effectively inhibit angiotensin II, resulting in blood pressure fluctuations. The content of HP-β-CD should not be lower than the proportional relationship in this application, otherwise it will lead to uneven drug dispersion and too high drug burst release rate; the content of HP-β-CD should not be too high to avoid too slow drug release rate due to the decrease in material porosity and unable to reduce blood pressure in time.

[0044] In some alternative embodiments of the present application, the carrier material comprises the following raw materials in parts by weight:

[0045] 80 parts to 120 parts of poly(lactic-co-glycolic acid), 15 parts to 20 parts of citric acid-chitosan ester, 0.1 part to 1 part of genipin, and 1 part to 5 parts of silica active material.

[0046] In the above solution, the content of the PLGA matrix within the proportional range can ensure the structural stability of the material; the content of CCE should not be too low, otherwise it will reduce the toughening effect and elongation at break of the material, and the content of CCE should not be too high, otherwise the excessive hydroxyl groups will compete with the PLGA ester groups for crosslinking, resulting in a decrease in crosslinking density and a reduction in material rigidity. Too low content of genipin will also reduce the crosslinking density, resulting in easy swelling and deformation of the material, and too high content of genipin will lead to over-crosslinking, increasing the brittleness of the material, and the residual genipin will cause cytotoxicity and further trigger an inflammatory response. The silica active material can extend the drug release period through the pore size confinement effect. When its content is too high, it may cause mesopore blockage and affect the drug release rate.

[0047] In some alternative embodiments of the present application, the silica active material is prepared by the following method: Dispersing mesoporous silica nanoparticles (MSNs) in type I collagen solution and performing ultrasonic treatment, then collecting the precipitate after stirring and centrifugation;

[0048] Washing the precipitate and freeze-drying to obtain the silica active material.

[0049] In the above solution, the prepared silica active material has a core-shell structure. The core layer retains the original mesoporous structure of mesoporous silica for drug loading and slow release. The shell layer is a uniform nanoscale coating, which is a collagen coating formed by type I collagen covering the surface of mesoporous silica. Among them, the RGD sequence (Arg-Gly-Asp) of collagen can promote cell adhesion and reduce the foreign body reaction. And the collagen coating of this application does not completely block the pores of MSNs, and still allows drug molecules (such as amlodipine, molecular weight ≈ 408 Da) to be released by diffusion, reducing the burst release rate, and thus improving the slow release stability performance.

[0050] It is worth mentioning that the type I collagen solution in this application is not only used to construct the core-shell structure, but also has a synergistic effect with other components. For example, the amino group of collagen forms a hydrogen bond with the ester group (-COOR) of PLGA to enhance the interfacial binding force. The rigid core of mesoporous silica and the flexible chain of PLGA form a "sea-island structure" to improve the mechanical properties of the material, including tensile strength and elongation at break. At the same time, the carboxyl group (-COOH) of collagen forms a hydrogen bond network with the hydroxyl group (-OH) of CCE. The genipin crosslinking agent reacts with both collagen and CCE at the same time to form a three-dimensional interpenetrating network. Under the synergistic effect, the crosslinking density is increased, which not only improves the fracture toughness, but also delays the hydrolysis of PLGA, and thus extends the degradation period. At the same time, the collagen coating encapsulates lipophilic drugs (such as amlodipine) through hydrophobic interaction to reduce burst release; folic acid is adsorbed on the surface of collagen through hydrogen bond to achieve dual-drug synergistic controlled release.

[0051] As a further improvement of this application, the pore diameter of the mesoporous silica nanoparticles is 5 nm to 10 nm, and the specific surface area is 800 m 2 / g to 1000 m 2 / g; the concentration of the type I collagen solution is 0.5 mg / mL to 2 mg / mL, and the proportional relationship between the mesoporous silica nanoparticles and the type I collagen solution is 1 g (mesoporous silica nanoparticles): 5 mL to 20 mL (type I collagen solution).

[0052] In the above solution, the pore diameter of the mesoporous silica nanoparticles can match the molecular size of amlodipine in the drug, improve the drug loading effect, and avoid the hindrance of drug diffusion due to too small pore diameter, resulting in too slow drug release rate and untimely drug action. The high specific surface area of the mesoporous silica nanoparticles can provide sufficient adsorption sites to reduce the probability of drug burst release. The concentration range of the collagen solution can ensure uniform coating of collagen and promote cell adhesion. If the concentration of the collagen solution is higher than 2 mg / mL, it will cause the coating to be too thick and block the mesopores, thereby reducing the drug loading capacity.

[0053] As a further improvement of the present application, the ultrasonic treatment time in the preparation process of the silica active material is 25min to 40min, the ultrasonic treatment power is 200W to 300W, the stirring speed is 180rpm to 300rpm, the stirring time is 10h to 12h, the centrifugal speed is 8000rpm to 10000rpm, and the centrifugal time is 10min to 20min.

[0054] The present application uses ultrasonic cavitation to break the agglomeration of silica active materials and ensure dispersibility, and ultrasonic energy can also enhance the electrostatic bonding between collagen and the surface of mesoporous silica. Ultrasonic treatment for 25min to 40min can balance the dispersion effect and material integrity, avoid the collapse of the mesoporous structure of mesoporous silica due to excessive ultrasound, and avoid uneven dispersion of silica active materials due to insufficient ultrasound time. The stirring speed and time will directly affect the performance of the continuous coating formed by collagen on the surface of mesoporous silica. For example, when the speed is too fast, the shear force will tear the collagen fibers and reduce the biological activity. When the speed is low, it will cause uneven collagen deposition and no coating coverage in the local area, which will lead to an increase in the drug burst rate in the local area. The parameters of the centrifugal step in the present application can ensure the complete removal of free collagen and ensure the purity of the silica active material. At the same time, the centrifugal time is controlled to be less than 20min to avoid the formation of hard agglomerations due to excessive compression of mesoporous silica, and further avoid the increase of the particle size of mesoporous silica after redispersion.

[0055] like Figure 1 As shown, in a second aspect, based on a general inventive concept, the present application also provides a method for preparing a hypotensive material for subcutaneous implantation, comprising the following steps:

[0056] S10, preparing a polylactic acid-glycolic acid reinforced film from 30 wt % to 40 wt % of the polylactic acid-glycolic acid copolymer in the raw material;

[0057] S20, dissolving 50 wt % to 60 wt % of the polylactic acid-glycolic acid copolymer and citric acid-chitosan ester in the raw material in an organic solvent, and stirring to obtain a first solution;

[0058] S30, adding a drug mixture to the first solution, dispersing by ultrasonication and standing to degas, obtaining a second solution, and then treating the second solution by electrostatic spinning to obtain a nanofiber membrane;

[0059] S40, dispersing the silicon dioxide active material in the organic solution of the remaining amount of polylactic acid-glycolic acid copolymer in the raw material to obtain a third solution;

[0060] S50, stacking the polylactic acid-glycolic acid reinforced membrane and the nanofiber membrane in a mold, then casting the third solution, and curing to obtain a multilayer material;

[0061] S60. Immerse the multi-layer material in genipin solution for cross-linking reaction, and then wash and dry to obtain the blood pressure lowering material.

[0062] In the preparation method of this application, a multi-layer blood pressure lowering material is obtained through chemical modification and structural design. The base layer is a PLGA reinforcing film, which provides mechanical support for the entire multi-layer structure; the middle is a nanofiber layer, which can load the drug mixture and silica reinforcing material, and at the same time control the sustained release rate of the blood pressure lowering material; the outer layer is a dense PLGA film (prepared by casting a film from the third solution), which can inhibit the initial burst release of the drug through the formed cross-linking network. In addition, this application uses silica active material as a structure regulating material, which can significantly improve the coordination with PLGA, CCE toughening agent and genipin cross-linking agent, realizing the optimization of mechanical properties (such as the improvement of tensile strength and elongation at break) and the enhancement of drug controlled release (reducing the burst release rate and making the release period match the degradation rate). Finally, cross-linking with genipin can strengthen the interfacial bonding, thereby forming a stable network and extending the drug release period, enabling the blood pressure lowering material to act effectively in the body for a long time.

[0063] In the multi-layer structure of this application, the nanofiber layer has a high specific surface area, which can increase the drug loading capacity, while CCE plays a role in toughening and inhibiting crack propagation, and genipin plays a role in strengthening the interface and reducing the swelling rate in the cross-linking network. The drug is uniformly dispersed in PLGA / CCE fibers and released through a dual mechanism of diffusion and degradation, achieving a controllable release rate; the collagen layer on the surface plays a role in inhibiting burst release and promoting cell adhesion, achieving a stable release effect; at the same time, the mesoporous channels of the silica active material also play a role in extending the release period. The three work together to regulate the release rate and period of the drug to achieve the purpose of stable sustained release.

[0064] The poly(lactic-co-glycolic acid) copolymer in the raw materials of this application is divided into three parts in this application. One part is used to prepare the first solution (wherein, the poly(lactic-co-glycolic acid) copolymer used in the first solution accounts for 50wt% - 60wt% of the total mass of the poly(lactic-co-glycolic acid) copolymer, and the concentration of the poly(lactic-co-glycolic acid) copolymer in the first solution is set to 5% - 10%, w / v). The second part is used to prepare the poly(lactic-co-glycolic acid) reinforced film (wherein, the poly(lactic-co-glycolic acid) copolymer used in the poly(lactic-co-glycolic acid) reinforced film accounts for 30wt% - 40wt% of the total mass of the poly(lactic-co-glycolic acid) copolymer). The third part is used to prepare the third solution (wherein, the poly(lactic-co-glycolic acid) copolymer used in the third solution is the balance, and the concentration of the poly(lactic-co-glycolic acid) copolymer in the third solution is set to 10% - 20%, w / v). The high proportion of PLGA content in the first solution can ensure fiber continuity and drug loading capacity, and at the same time synergistically toughen with CEE. In the poly(lactic-co-glycolic acid) reinforced film, the nanofibrous poly(lactic-co-glycolic acid) copolymer and the massive poly(lactic-co-glycolic acid) copolymer are in an equal proportion relationship, and a "rigid-flexible" composite structure is formed by hot pressing, which can provide mechanical support and improve compressive and tensile strength. In the third solution, the low proportion of PLGA content can penetrate the fiber gaps, enhance the interfacial bonding, and avoid too high a swelling rate.

[0065] In some alternative embodiments of this application, in the step of obtaining a nanofiber membrane by electrospinning the second solution, the parameters of electrospinning include: a voltage of 20 kV, a 27G needle, a flow rate of 1.0 mL / h - 1.2 mL / h, a receiver rotation speed of 800 rpm - 1000 rpm, and an electrospinning time of 5 h - 10 h. In this application, the parameters of electrospinning can generate a fiber material with a diameter of 200 nm - 500 nm, and the drug loading capacity can be improved through the high specific surface area of the fiber material; at the same time, the rotation speed of the receiver can induce fiber orientation, thereby improving the tensile strength.

[0066] In some alternative embodiments of this application, the poly(lactic-co-glycolic acid) reinforced film is a composite material of a nanofibrous poly(lactic-co-glycolic acid) copolymer and a massive poly(lactic-co-glycolic acid) copolymer, and the composite material is prepared by the following method:

[0067] Prepare nanofibers of poly(lactic-co-glycolic acid) copolymer by electrospinning;

[0068] Stack and hot press the nanofibers and the massive poly(lactic-co-glycolic acid) copolymer to obtain the poly(lactic-co-glycolic acid) reinforced film.

[0069] In the above scheme, the fiber orientation of the poly(lactic-co-glycolic acid) reinforced film improves the longitudinal tensile degree and toughness, and the fiber arrangement forms a directional channel, which can achieve drug gradient release and reduce the initial release amount.

[0070] As an embodiment of the present application, the nanofibrous poly(lactic-co-glycolic acid) is prepared by the following method: 1) Dissolve the poly(lactic-co-glycolic acid) particles in hexafluoroisopropanol (HFIP) to obtain a poly(lactic-co-glycolic acid) solution with a concentration of 10% - 12% (w / v), avoiding the formation of beaded fibers due to too low concentration and also avoiding too high solution viscosity and difficult electrospinning due to too high concentration. 2) Perform electrospinning on the poly(lactic-co-glycolic acid) solution. The specific parameters include: using a 27G stainless steel needle, controlling the injection flow rate to be 0.8 mL / h - 1.0 mL / h, the voltage to be 20 kV, the receiving distance to be 15 cm - 18 cm, the rotation speed to be 1000 rpm - 1200 rpm, and the electrospinning time to be 8 h - 10 h. The fiber diameter of the obtained nanofibrous poly(lactic-co-glycolic acid) is 190 nm - 290 nm.

[0071] As a specific embodiment of the present application, the bulk poly(lactic-co-glycolic acid) is prepared by a conventional method. Specifically:

[0072] Dissolve the PLGA particles in HFIP to obtain a solution with a concentration of 10% (w / v);

[0073] Pour the solution into a mold and control the thickness with a scraper (target 50 μm - 100 μm);

[0074] Volatilize the solvent in a fume hood at 25°C for 12 h, dry it at 40°C and a vacuum of -0.1 MPa for 24 h, and cut it into blocks (10 mm * 50 mm).

[0075] In some alternative embodiments of the present application, the hot pressing temperature is 70°C - 90°C, the hot pressing pressure is 3 MPa - 8 MPa, and the hot pressing time is 8 min - 12 min.

[0076] In the present application, the hot pressing temperature is close to the glass transition temperature of PLGA, which can promote the entanglement of molecular chains between layers, thereby enhancing the interfacial bonding strength. Avoiding thermal degradation of PLGA caused by too high temperature, which may lead to a decrease in molecular weight and embrittlement of the material. The balance of hot pressing pressure can ensure the denseness between layers, avoiding too high porosity resulting in burst release of drugs, and avoiding too high pressure leading to a decrease in the interfacial peel strength, thereby reducing the risk of delamination after implantation in the body.

[0077] In some alternative embodiments of the present application, the crosslinking reaction temperature is 35°C - 40°C, and the crosslinking reaction time is 5 h - 10 h.

[0078] In this application, a temperature of 35°C to 40°C can activate the reaction between genipin crosslinking agent and amino groups, thereby increasing the crosslinking density. The time interval can ensure sufficient crosslinking, thereby reducing the material swelling rate and preventing problems such as low crosslinking density, high burst release rate, and excessive material swelling rate caused by insufficient crosslinking time.

[0079] In some specific application scenarios of this application, the antihypertensive material can be precisely processed into a cylindrical implant product that meets clinical requirements, usually made using conventional molds. For example:

[0080] (1) Select stainless steel or polytetrafluoroethylene (PTFE) for the mold, polish the inner wall to a mirror surface to avoid material adhesion. The inner diameter of the mold is 2 mm and the length is 20 mm. Spray a release agent inside the mold and dry it at 80°C for 30 min.

[0081] (2) Cut the obtained antihypertensive material (fiber crosslinked film) into strips, wind and form it with a winding machine, and evenly coat the PLGA solution as an adhesive between layers.

[0082] (3) Place the wound cylinder into the mold, place it in a hot press and process it at 80°C and 5 MPa for 10 min to melt and bond the PLGA solution between layers. Then cool it to 25°C with water and slowly release the pressure to obtain a cylindrical preliminary product (the preliminary product can also be immersed in genipin solution again for crosslinking and strengthening).

[0083] (4) Sterilize the preliminary product with ethylene oxide at 55°C and 60% humidity for 4 h, and ventilate and analyze for 48 h until the residue is <10 ppm.

[0084] In the following examples, PLGA was purchased from Shenzhen Jusheng Biotechnology Co., Ltd., LA:GA = 75:25, and the molecular weight was 100,000 Da; genipin was purchased from Chengdu Kangbang Biotechnology Co., Ltd.; HP-β-CD was purchased from Shanghai Ruichu Biotechnology Co., Ltd. CCE was synthesized by a conventional method. Specifically:

[0085] ① Dissolve chitosan (1 g) in 1 vol% acetic acid solution (100 mL), stir until completely dissolved (about 2 - 4 h), and adjust the pH to 4.5 - 5.0 to obtain a chitosan solution;

[0086] ② Dissolve citric acid (2 g) in deionized water (50 mL), add 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC, 0.5 g) and N-hydroxysuccinimide (NHS, 0.3 g), and stir at room temperature for 30 min;

[0087] ③ Slowly add the solution obtained in step ② to the chitosan solution and react in a 60°C water bath for 8 h;

[0088] ④ After the reaction is completed, the mixture is dialyzed (molecular weight cut-off 3.5 kDa) for 3 days to remove unreacted citric acid and the catalyst, and then freeze-dried to obtain a white sponge-like CCE product.

[0089] The above technical solutions of the present application will be described in detail below in conjunction with specific embodiments.

[0090] Example 1

[0091] This example provides an antihypertensive material for subcutaneous implantation, including a carrier material and a drug mixture loaded on the carrier material with a mass ratio of 15:8;

[0092] Among them, the drug mixture includes the following components in parts by weight:

[0093] 20 parts of amlodipine, 10 parts of losartan potassium, 3 parts of folic acid, and 25 parts of hydroxypropyl-β-cyclodextrin.

[0094] The carrier material includes the following raw materials in parts by weight:

[0095] 100 parts of poly(lactic-co-glycolic acid), 15 parts of citric acid-chitosan ester, 1 part of genipin, and 2 parts of silica active material.

[0096] This example also provides a preparation method of the above antihypertensive material for subcutaneous implantation, including the following steps:

[0097] S1. Preparation of silica active material

[0098] Disperse 1 g of mesoporous silica nanoparticles with a pore size of 5 nm and a specific surface area of 1000 m 2 / g in 5 mL of type I collagen solution (pH = 4.0, 1 mg / mL) and ultrasonically treat it at 300 W for 30 min, then collect the precipitate after stirring and centrifugation; the stirring speed is 300 rpm, the stirring time is 10 h, the centrifugation speed is 8000 rpm, and the centrifugation time is 15 min;

[0099] Wash the precipitate 3 times with deionized water and then freeze-dry to obtain the silica active material.

[0100] S2. Preparation of poly(lactic-co-glycolic acid) reinforced membrane

[0101] Dissolve poly(lactic-co-glycolic acid) particles (15 parts of raw materials) in hexafluoroisopropanol (HFIP, 1.5 L) to obtain a poly(lactic-co-glycolic acid) solution with a concentration of 10% (w / v). Electrospinning is performed on the poly(lactic-co-glycolic acid) solution to obtain poly(lactic-co-glycolic acid) nanofibers;

[0102] The parameters of electrospinning include: using a 27G stainless steel needle, controlling the injection flow rate at 0.8 mL / h, the voltage at 20 kV, the receiving distance at 15 cm, the rotation speed at 1000 rpm, and the spinning time at 8 h.

[0103] The nanofibers and bulk poly(lactic-co-glycolic acid) (15 parts of raw materials) were laminated and hot-pressed at a mass ratio of 1:1 to obtain a poly(lactic-co-glycolic acid) reinforced membrane; the hot-pressing temperature was 80 °C, the hot-pressing pressure was 5 MPa, and the hot-pressing time was 10 min.

[0104] S3. Dissolve a part of poly(lactic-co-glycolic acid) (60 parts of raw materials) and citric acid-chitosan ester in hexafluoroisopropanol, and stir at 500 rpm for 6 h until completely dissolved to obtain the first solution (the concentration of poly(lactic-co-glycolic acid) is 6%, w / v);

[0105] S4. Add a drug mixture to the first solution, disperse it by ultrasonic wave (40 kHz, 30 min), and then let it stand for 4 h to remove bubbles to obtain the second solution;

[0106] S5. Electrospin the second solution to obtain a nanofiber membrane;

[0107] 27G needle, receiving distance 18 cm, voltage 18 kV, flow rate 1.0 mL / h, receiver rotation speed 1000 rpm, and electrospinning time 8 h.

[0108] S6. Disperse the silica active material in a poly(lactic-co-glycolic acid) solution (10 parts of raw materials) to obtain the third solution (the concentration of poly(lactic-co-glycolic acid) is 10%, w / v);

[0109] S7. Stack the poly(lactic-co-glycolic acid) reinforced membrane and the nanofiber membrane in a mold in sequence, and cast the third solution in this mold to form a film (using the drop coating method, the dropping speed is 1 mL / min, controlling the film thickness to be 100 μm, and naturally drying for 24 hours at room temperature of 25 °C and relative humidity of 50%. The following examples are all processed by the same film casting method), to obtain a multilayer material;

[0110] S8. Immerse the multilayer material in a 0.5 wt% genipin solution (pH = 7.4, PBS buffer solution, the same below) for cross-linking reaction, then rinse with PBS and freeze-dry to obtain a hypotensive material. The temperature of the cross-linking reaction is 35 °C, and the time of the cross-linking reaction is 6 h.

[0111] Example 2

[0112] This example provides a hypotensive material for subcutaneous implantation, including a carrier material and a drug mixture loaded on the carrier material with a mass ratio of 10:5;

[0113] Among them, the drug mixture includes the following components in parts by weight:

[0114] 25 parts of amlodipine, 8 parts of losartan potassium, 1 part of folic acid, and 20 parts of hydroxypropyl-β-cyclodextrin.

[0115] Among them, the carrier material includes the following raw materials in parts by weight:

[0116] 100 parts of poly(lactic-co-glycolic acid), 20 parts of citric acid-chitosan ester, 0.8 part of genipin, and 1 part of silica active material.

[0117] This embodiment also provides a preparation method of the above antihypertensive material for subcutaneous implantation, including the following steps:

[0118] S1. Prepare the silica active material

[0119] Disperse 1 g of mesoporous silica nanoparticles with a pore size of 5 nm and a specific surface area of 800 m 2 / g in 20 mL of type I collagen solution (pH = 4.0, 0.5 mg / mL) and perform ultrasonic treatment at 300 W for 25 min. Then, after stirring and centrifugation, collect the precipitate; the stirring speed is 180 rpm, the stirring time is 12 h, the centrifugation speed is 8000 rpm, and the centrifugation time is 20 min;

[0120] Wash the precipitate 3 times with deionized water and then freeze-dry to obtain the silica active material.

[0121] S2. Prepare the poly(lactic-co-glycolic acid) reinforced membrane

[0122] Dissolve poly(lactic-co-glycolic acid) copolymer particles (20 parts of raw materials) in hexafluoroisopropanol (HFIP) to obtain a poly(lactic-co-glycolic acid) copolymer solution with a concentration of 10% (w / v). Perform electrospinning on the poly(lactic-co-glycolic acid) copolymer solution to obtain poly(lactic-co-glycolic acid) copolymer nanofibers;

[0123] The parameters of electrospinning include: using a 27G stainless steel needle, controlling the injection flow rate to be 1.0 mL / h, the voltage to be 20 kV, the receiving distance to be 18 cm, the rotation speed to be 1200 rpm, and the electrospinning time to be 8 h.

[0124] Stack and hot-press the nanofibers and bulk poly(lactic-co-glycolic acid) copolymer (20 parts of raw materials) at a mass ratio of 1:1 to obtain the poly(lactic-co-glycolic acid) reinforced membrane; the hot-pressing temperature is 70 °C, the hot-pressing pressure is 8 MPa, and the hot-pressing time is 8 min.

[0125] S3. Dissolve the poly (lactic-co-glycolic acid) (50 parts of raw materials) and citric acid-chitosan ester in hexafluoroisopropanol, and stir at 500 rpm for 6 h until completely dissolved to obtain the first solution (the concentration of poly (lactic-co-glycolic acid) is 5%, w / v).

[0126] S4. Add the drug mixture to the first solution, disperse it by ultrasonic wave (40 kHz, 30 min), and let it stand for 4 h to remove bubbles to obtain the second solution.

[0127] S5. Electrospin the second solution to obtain a nanofiber membrane.

[0128] Among them, the parameters of electrospinning include: 27G needle, receiving distance of 18 cm, voltage of 18 kV, flow rate of 1.0 mL / h, receiver rotation speed of 800 rpm, and electrospinning time of 10 h.

[0129] S6. Disperse the silica active material in the poly (lactic-co-glycolic acid) solution (10 parts of raw materials) to obtain the third solution (the concentration of poly (lactic-co-glycolic acid) is 10%, w / v).

[0130] S7. Stack the poly (lactic-co-glycolic acid) reinforced membrane and the nanofiber membrane in the mold in turn, and cast the third solution in the mold to form a film to obtain a multi-layer material.

[0131] S8. Immerse the multi-layer material in a 0.5 wt% genipin solution (pH = 7.4) for cross-linking reaction, then rinse it with PBS and freeze-dry it to obtain the antihypertensive material. The temperature of the cross-linking reaction is 35 °C, and the time of the cross-linking reaction is 6 h.

[0132] Example 3

[0133] This example provides an antihypertensive material for subcutaneous implantation, including a carrier material and a drug mixture loaded on the carrier material with a mass ratio of 12:7.

[0134] Among them, the drug mixture includes the following components in parts by weight:

[0135] 15 parts of amlodipine, 10 parts of losartan potassium, 2 parts of folic acid, and 28 parts of hydroxypropyl-β-cyclodextrin.

[0136] The carrier material includes the following raw materials in parts by weight:

[0137] 100 parts of poly (lactic-co-glycolic acid), 15 parts of citric acid-chitosan ester, 0.1 part of genipin, and 1.8 parts of silica active material.

[0138] This example also provides a preparation method of the above antihypertensive material for subcutaneous implantation, including the following steps:

[0139] S1. Preparation of silica active material

[0140] Disperse mesoporous silica nanoparticles with a pore diameter of 10 nm and a specific surface area of 1000 m 2 / g in a type I collagen solution (pH = 4.0, 12 mL) at a concentration of 1 mg / mL, and ultrasonically treat it for 25 min at 300 W. Then, collect the precipitate after stirring and centrifugation; the stirring speed is 250 rpm, the stirring time is 10 h, the centrifugation speed is 8000 rpm, and the centrifugation time is 15 min;

[0141] Wash the precipitate 3 times with deionized water and then freeze-dry it to obtain the silica active material.

[0142] S2. Preparation of poly(lactic-co-glycolic acid) reinforced membrane

[0143] Dissolve poly(lactic-co-glycolic acid) copolymer particles (15 parts of raw materials) in hexafluoroisopropanol (HFIP) to obtain a poly(lactic-co-glycolic acid) copolymer solution with a concentration of 10% (w / v). Electrospinning is carried out on the poly(lactic-co-glycolic acid) copolymer solution to obtain poly(lactic-co-glycolic acid) copolymer nanofibers;

[0144] The parameters of electrospinning include: using a 27G stainless steel needle, controlling the injection flow rate to be 0.8 mL / h, the voltage to be 20 kV, the receiving distance to be 15 cm, the rotation speed to be 1200 rpm, and the electrospinning time to be 8 h.

[0145] Stack and hot-press the nanofibers and bulk poly(lactic-co-glycolic acid) copolymer (15 parts of raw materials) at a mass ratio of 1:1 to obtain the poly(lactic-co-glycolic acid) reinforced membrane; the hot-pressing temperature is 90 °C, the hot-pressing pressure is 3 MPa, and the hot-pressing time is 8 min.

[0146] S3. Dissolve poly(lactic-co-glycolic acid) copolymer (60 parts of raw materials) and citric acid-chitosan ester in hexafluoroisopropanol, and stir at 500 rpm for 6 h until completely dissolved to obtain the first solution (the concentration of poly(lactic-co-glycolic acid) copolymer is 6%, w / v);

[0147] S4. Add a drug mixture to the first solution, ultrasonically disperse it (40 kHz, 30 min) and let it stand for 4 h to defoam to obtain the second solution;

[0148] S5. Electrospin the second solution to obtain a nanofiber membrane;

[0149] 27G needle, receiving distance 18 cm, voltage 18 kV, flow rate 1.0 mL / h, receiver rotation speed 1000 rpm, and electrospinning time 5 h.

[0150] S6. Disperse the silica active material in a poly(lactic-co-glycolic acid) copolymer solution (10 parts of raw materials) to obtain a third solution (the concentration of poly(lactic-co-glycolic acid) copolymer is 10%, w / v);

[0151] S7. Stack the poly(lactic-co-glycolic acid) reinforced film and the nanofiber membrane in a mold in sequence, and cast the third solution into a film in this mold to obtain a multi-layer material;

[0152] S8. Immerse the multi-layer material in a 0.5 wt% genipin solution (pH = 7.4) for cross-linking reaction, then rinse with PBS and freeze-dry to obtain a blood pressure lowering material. The temperature of the cross-linking reaction is 35 °C, and the time of the cross-linking reaction is 6 h.

[0153] Example 4

[0154] This example provides a blood pressure lowering material for subcutaneous implantation, which includes a carrier material and a drug combination loaded on the carrier material with a mass ratio of 15:5;

[0155] Among them, the drug combination includes the following components in parts by weight:

[0156] 18 parts of amlodipine, 9 parts of losartan potassium, 1.5 parts of folic acid, and 28 parts of hydroxypropyl-β-cyclodextrin.

[0157] The carrier material includes the following raw materials in parts by weight:

[0158] 100 parts of poly(lactic-co-glycolic acid) copolymer, 18 parts of citric acid-chitosan ester, 0.75 part of genipin, and 2.5 parts of silica active material.

[0159] This example also provides a preparation method of the above-mentioned blood pressure lowering material for subcutaneous implantation, which includes the following steps:

[0160] S1. Prepare the silica active material

[0161] Disperse 1 g of mesoporous silica nanoparticles with a pore size of 8 nm and a specific surface area of 1000 m 2 / g in a 1 mg / mL type I collagen solution (pH = 4.0, 15 mL), perform ultrasonic treatment at 300 W for 25 min, then collect the precipitate after stirring and centrifugation; the stirring speed is 180 rpm, the stirring time is 10 h, the centrifugation speed is 8000 rpm, and the centrifugation time is 20 min;

[0162] Wash the precipitate 3 times with deionized water and then freeze-dry to obtain the silica active material.

[0163] S2. Prepare the poly(lactic-co-glycolic acid) reinforced film

[0164] Dissolve poly(lactic-co-glycolic acid) copolymer particles (15 parts of raw materials) in hexafluoroisopropanol (HFIP) to obtain a poly(lactic-co-glycolic acid) copolymer solution with a concentration of 10% (w / v). Electrospinning is carried out on the poly(lactic-co-glycolic acid) copolymer solution to obtain nanofibers of poly(lactic-co-glycolic acid);

[0165] The parameters of electrospinning include: using a 27G stainless steel needle, controlling the injection flow rate at 0.8 mL / h, the voltage at 20 kV, the receiving distance at 15 cm, the rotation speed at 1000 rpm, and the spinning time at 8 h.

[0166] Stack and hot-press the nanofibers and bulk poly(lactic-co-glycolic acid) copolymer (15 parts of raw materials) at a mass ratio of 1:1 to obtain a poly(lactic-co-glycolic acid) reinforced membrane; the hot-pressing temperature is 85 °C, the hot-pressing pressure is 6 MPa, and the hot-pressing time is 10 min.

[0167] S3. Dissolve poly(lactic-co-glycolic acid) copolymer (60 parts of raw materials) and citric acid-chitosan ester in hexafluoroisopropanol, and stir at 500 rpm for 6 h until completely dissolved to obtain a first solution (the concentration of poly(lactic-co-glycolic acid) copolymer is 6%, w / v);

[0168] S4. Add a drug mixture to the first solution, ultrasonically disperse (40 kHz, 30 min) and let it stand for defoaming for 4 h to obtain a second solution;

[0169] S5. Electrospin the second solution to obtain a nanofiber membrane;

[0170] 27G needle, receiving distance 18 cm, voltage 18 kV, flow rate 1.0 mL / h, receiver rotation speed 800 rpm, and electrospinning time 6 h.

[0171] S6. Disperse the silica active material in a poly(lactic-co-glycolic acid) copolymer solution (10 parts of raw materials) to obtain a third solution (the concentration of poly(lactic-co-glycolic acid) copolymer is 10%, w / v);

[0172] S7. Stack the poly(lactic-co-glycolic acid) reinforced membrane and the nanofiber membrane in a mold in sequence, and cast the third solution in the mold to form a film to obtain a multi-layer material;

[0173] S8. Immerse the multi-layer material in a 0.5 wt% genipin solution (pH = 7.4) for cross-linking reaction, then rinse with PBS and freeze-dry to obtain a blood pressure lowering material. The temperature of the cross-linking reaction is 35 °C, and the time of the cross-linking reaction is 6 h.

[0174] Example 5

[0175] This embodiment provides an antihypertensive material for subcutaneous implantation, which includes a carrier material and a drug mixture loaded on the carrier material with a mass ratio of 10:7;

[0176] Among them, the drug mixture includes the following components in parts by weight:

[0177] 15 parts of amlodipine, 8 parts of losartan potassium, 1 part of folic acid, and 22 parts of hydroxypropyl-β-cyclodextrin.

[0178] The carrier material includes the following raw materials in parts by weight:

[0179] 100 parts of poly (lactic-co-glycolic acid), 18 parts of citric acid-chitosan ester, 1 part of genipin, and 4.5 parts of silica active material.

[0180] This embodiment also provides a preparation method of the above antihypertensive material for subcutaneous implantation, including the following steps:

[0181] S1. Prepare the silica active material

[0182] Disperse 1 g of mesoporous silica nanoparticles with a pore size of 5 nm and a specific surface area of 1000 m 2 / g in 15 mL of type I collagen solution (pH = 4.0, 1 mg / mL), and perform ultrasonic treatment at 300 W for 25 min. Then, collect the precipitate after stirring and centrifugation; the stirring speed is 180 rpm, the stirring time is 10 h, the centrifugation speed is 8000 rpm, and the centrifugation time is 10 min;

[0183] Wash the precipitate 3 times with deionized water and then freeze-dry to obtain the silica active material.

[0184] S2. Prepare the poly (lactic-co-glycolic acid) reinforced membrane

[0185] Dissolve poly (lactic-co-glycolic acid) copolymer particles (15 parts of raw materials) in hexafluoroisopropanol (HFIP) to obtain a poly (lactic-co-glycolic acid) copolymer solution with a concentration of 10% (w / v). Electrospinning is performed on the poly (lactic-co-glycolic acid) copolymer solution to obtain poly (lactic-co-glycolic acid) nanofibers;

[0186] The parameters of electrospinning include: using a 27G stainless steel needle, controlling the injection flow rate to be 0.8 mL / h, the voltage to be 20 kV, the receiving distance to be 15 cm, the rotation speed to be 1000 rpm, and the spinning time to be 8 h.

[0187] Stack and hot-press the nanofibers and massive poly (lactic-co-glycolic acid) copolymer (15 parts of raw materials) at a mass ratio of 1:1 to obtain the poly (lactic-co-glycolic acid) reinforced membrane; the hot-pressing temperature is 80 °C, the hot-pressing pressure is 5 MPa, and the hot-pressing time is 12 min.

[0188] S3. Dissolve poly (lactic - co - glycolic acid) (50 parts of raw materials) and citric acid - chitosan ester in hexafluoroisopropanol, and stir at 500 rpm for 6 h until completely dissolved to obtain the first solution (the concentration of poly (lactic - co - glycolic acid) is 5%, w / v);

[0189] S4. Add the drug mixture to the first solution, disperse it by ultrasonic wave (40 kHz, 30 min), and let it stand for 4 h to remove bubbles to obtain the second solution;

[0190] S5. Electrospun the second solution to obtain a nanofiber membrane;

[0191] 27G needle, receiving distance of 18 cm, voltage of 18 kV, flow rate of 1.2 mL / h, receiver rotation speed of 1000 rpm, and electrospinning time of 5 h.

[0192] S6. Disperse the silica active material in the poly (lactic - co - glycolic acid) solution (20 parts of raw materials) to obtain the third solution (the concentration of poly (lactic - co - glycolic acid) is 20%, w / v);

[0193] S7. Stack the poly (lactic - co - glycolic acid) reinforced membrane and the nanofiber membrane in a mold in turn, and cast the third solution into a film in the mold to obtain a multilayer material;

[0194] S8. Immerse the multilayer material in 0.5 wt% genipin solution (pH = 7.4) for cross - linking reaction, then rinse it with PBS and freeze - dry to obtain the antihypertensive material. The temperature of the cross - linking reaction is 35 °C, and the time of the cross - linking reaction is 6 h.

[0195] Experimental Example 1

[0196] Take 50 spontaneously hypertensive rats (SHR), divide them into 5 groups evenly, with 10 rats in each group. All rats are male, and the rat age is 9 - 10 weeks.

[0197] Test method: When the male SHR is in a conscious state, first place the rat in a rat bag and keep the temperature at 35 °C constant. Use the Softron BP - 98A type intelligent non - invasive blood pressure meter for rats to measure the systolic blood pressure (SBP) and diastolic blood pressure (DBP) of the rat's tail artery by the method of cuffing the tail. Take the data measured before implantation as the blood pressure before drug administration. The antihypertensive materials prepared by subcutaneous implantation in Examples 1 - 5 are made into implanted drugs with a length of 20 mm and a diameter of 2 ± 0.05 mm through a mold, and are respectively implanted subcutaneously in the upper abdomen of the rats. Measure the blood pressure after drug administration at time points of 3 d, 7 d, 14 d, 28 d, and 56 d. The results are shown in Table 1 and Table 2.

[0198] Table 1 Systolic Blood Pressure

[0199]

[0200] Table 2 Diastolic blood pressure

[0201]

[0202] In Table 1-2, * indicates p < 0.05 compared with before drug administration, and ** indicates p < 0.01.

[0203] Experimental Example 2 - Typical Case

[0204] The subcutaneous implantable antihypertensive material prepared in Example 1 was made into an implantable drug with a length of 20 mm and a diameter of 2 mm through a mold, and was subcutaneously implanted at the Qingling acupoint of patients with essential hypertension in the internal medicine department of the New Chang'an International Maternity Hospital. Each time, 3 implants were made. The implantation method was as follows: after local infiltration anesthesia, they were arranged and implanted subcutaneously. After successful implantation, the patients stopped taking oral antihypertensive drugs within 48 hours, and their blood pressure was monitored daily. The data are shown in Table 3.

[0205] Table 3 Comparison table of blood pressure monitoring values before and after subcutaneous implantation of essential hypertension

[0206]

[0207]

[0208] Although the specific implementation modes of the present application have been described in detail, it should not be construed as a limitation on the protection scope of the present application. Within the scope described in the claims, various modifications and deformations that can be made by those skilled in the art without creative efforts still fall within the protection scope of the present application.

Claims

1. A hypotensive material for subcutaneous implantation, characterized in that, It includes a carrier material with a mass ratio of (10 - 15):(5 - 8) and a drug mixture loaded on the carrier material; Among them, the carrier material includes the following raw materials: poly(lactic - co - glycolic acid), citric acid - chitosan ester, genipin, and silica active material; Among them, the silica active material is obtained by compounding mesoporous silica nanoparticles with a collagen coating on its surface.

2. The antihypertensive material for subcutaneous implantation according to claim 1, characterized in that, The drug mixture includes the following components by weight: 15 parts - 25 parts of amlodipine, 8 parts - 12 parts of losartan potassium, 1 part - 3 parts of folic acid, and 20 parts - 30 parts of hydroxypropyl - β - cyclodextrin.

3. The antihypertensive material for subcutaneous implantation according to claim 1, wherein The carrier material includes the following raw materials by weight: 80 parts - 120 parts of poly(lactic - co - glycolic acid), 15 parts - 20 parts of citric acid - chitosan ester, 0.1 part - 1 part of genipin, and 1 part - 5 parts of silica active material.

4. The antihypertensive material for subcutaneous implantation according to claim 1, wherein The silica active material is prepared by the following method: Disperse mesoporous silica nanoparticles in a type I collagen solution and perform ultrasonic treatment, then collect the precipitate after stirring and centrifugation; Wash the precipitate and freeze - dry it to obtain the silica active material.

5. The antihypertensive material for subcutaneous implantation according to claim 4, characterized in that, The pore diameter of the mesoporous silica nanoparticles is 5 nm to 10 nm, and the specific surface area is 800 m 2 / g to 1000 m 2 / g; The concentration of the type I collagen solution is 0.5mg / mL - 2mg / mL.

6. A preparation method of the blood pressure reducing material according to any one of claims 1 to 5, characterized in that, It includes the following steps: Prepare 30wt% - 40wt% of the poly(lactic - co - glycolic acid) in the raw materials into a poly(lactic - co - glycolic acid) enhanced film; Dissolve 50wt% - 60wt% of the poly(lactic - co - glycolic acid) and the citric acid - chitosan ester in an organic solvent, stir evenly to obtain a first solution; Add the drug mixture to the first solution, perform ultrasonic dispersion and static defoaming to obtain a second solution, and then obtain a nanofiber membrane by electrospinning the second solution; Disperse the silica active material in the organic solution of the remaining poly(lactic - co - glycolic acid) to obtain a third solution; Stack the poly(lactic - co - glycolic acid) enhanced film and the nanofiber membrane, and then cast the third solution to obtain a multi - layer material; Immerse the multi - layer material in a genipin solution for cross - linking reaction, and then wash and dry it to obtain a blood - pressure - lowering material.

7. The preparation method according to claim 6, characterized in that, In the step of obtaining the nanofiber membrane by electrospinning the second solution, the parameters of the electrospinning include: a 27G needle, a flow rate of 1.0mL / h - 1.2mL / h, a receiver rotation speed of 800rpm - 1000rpm, and an electrospinning time of 5h - 10h.

8. The preparation method according to claim 6, characterized in that, The poly(lactic - co - glycolic acid) enhanced film is a composite material of nanofibrous poly(lactic - co - glycolic acid) and bulk poly(lactic - co - glycolic acid), and the composite material is prepared by the following method: Prepare nanofibers of poly(lactic - co - glycolic acid) by electrospinning; Stack and hot - press the nanofibers and the bulk poly(lactic - co - glycolic acid) to obtain the poly(lactic - co - glycolic acid) enhanced film.

9. The preparation method according to claim 8, characterized in that, The temperature of the hot - pressing is 70°C - 90°C, the pressure of the hot - pressing is 3MPa - 8MPa, and the time of the hot - pressing is 8min - 12min.

10. The preparation method according to claim 6, characterized in that, The temperature of the crosslinking reaction is 35°C to 40°C, and the time of the crosslinking reaction is 5 h to 10 h.

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