Traditional Chinese medicine external preparation for preventing picc-related venous thrombosis and preparation method thereof

Abstract

The invention discloses a traditional Chinese medicine external preparation for preventing picc-related venous thrombosis and a preparation method of the traditional Chinese medicine external preparation, and relates to the technical field of traditional Chinese medicine external preparations. The carrier system comprises a mesoporous silica core, a shear force-body temperature double-response hydrogel middle layer and a pH-responsive gradient cross-linked calcium alginate shell. According to the present invention, with the triple targeting strategy and the multi-signal response carrier system, the precise enrichment and the dynamic release according to the pathological stage of the drug at the thrombus good-onset site can be achieved, and the problems of insufficient targeting and mismatching of the drug release time sequence of the traditional preparation can be solved; the modified traditional Chinese medicine components have the effects of repairing the glycocalyx layer, inhibiting inflammation and specifically resisting thrombus, and the limitation of a traditional extraction process is broken through; the intelligent response matrix is combined with the photo-thermal regulation and transdermal optimization technology, so that the medicine permeation and the skin safety are balanced; according to the preparation process of the carrier, through precise regulation and directional modification, the targeted recognition and controlled release performance is remarkably enhanced, and a new safe and efficient prevention strategy is provided for clinic.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of external use of traditional Chinese medicine, in particular to a traditional Chinese medicine external preparation for preventing picc-related venous thrombosis and a preparation method thereof. BACKGROUND

[0002] The peripherally inserted central catheter (PICC) is widely used in the fields of tumor chemotherapy, parenteral nutrition, etc. due to its long-term indwelling advantage, but the PICC-related venous thrombosis (CRT) has a high incidence, and its pathological mechanism involves the "Virchow triad" of vascular endothelial injury, hemodynamic changes and high blood coagulation state. The current clinical prevention methods mainly include: ① systemic anticoagulant drugs, which have bleeding risks and individual differences; ② catheter surface modification, which is limited in biocompatibility and long-term effect; ③ traditional Chinese medicine external preparations, such as gel or cream (Chuanxiong) mainly containing blood-activating and stasis-removing components, which play an anti-coagulation and anti-inflammatory role through transdermal absorption, but the existing technology still has the following fundamental defects:

[0003] I. Technical bottleneck of traditional Chinese medicine external preparation:

[0004] 1. Limitation of mechanism: sustained drug release mode based on "passive defense":

[0005] The existing Chinese medicine external preparation follows the linear logic of "drug penetration-local concentration maintenance", through ethanol extraction, transdermal enhancer or using cream base to prolong skin retention time. However, this mode has inherent contradictions: sustained high concentration of drugs can easily cause skin allergy, and reducing the dose cannot meet the prevention needs during the high incidence period of thrombosis. The core problem is that "preventing thrombosis" is simply equated with "maintaining drug concentration", ignoring the dynamic pathological process of thrombosis and the possibility of early warning intervention.

[0006] 2. Lack of targeting: unable to precisely act on the thrombosis site at the catheter-vascular interface:

[0007] PICC thrombosis often occurs at the catheter tip and the blood vessel valve, while the existing external preparation relies on skin penetration and then distributes in the blood circulation, and the concentration of drugs reaching the lesion site is significantly attenuated. More importantly, the damage of the catheter surface biofilm and the vascular endothelial glycocalyx layer is the core inducement of thrombosis, but the existing technology has never involved specific intervention of the lesion microenvironment, resulting in "low drug arrival rate-unclear action target" double efficiency loss.

[0008] II. Lack of existing technology in the understanding of pathological mechanism:

[0009] 1. Ignoring the early inflammatory signal transduction of thrombosis:

[0010] Studies have shown that after PICC catheterization, the vascular endothelial cells release inflammatory factors due to mechanical stimulation, initiating platelet activation and coagulation cascade. However, existing traditional Chinese medicine preparations only focus on fibrin deposition in the later stage of thrombosis and do not use inflammatory markers as intervention targets. For example, although related patents mention "anti-inflammatory effects", they do not clearly link inflammatory factors to drug release, and still belong to non-specific intervention.

[0011] 2. Lack of response mechanism for dynamic pathological process:

[0012] Thrombosis is a sequential process of vascular endothelial injury, platelet adhesion and fibrin deposition. The existing technology uses a "single component + constant release" mode, which cannot match the pathological needs at different stages. Excessive release of blood-activating and stasis-removing components in the early stage of thrombosis may interfere with endothelial repair, while insufficient release in the later stage of thrombosis cannot inhibit fibrin crosslinking. This mismatch in intervention is essentially due to the lack of a drug release regulation mechanism synchronized with the pathological process.

[0013] Therefore, a traditional Chinese medicine external preparation for preventing PICC-related venous thrombosis and a preparation method thereof are provided to overcome the above problems. SUMMARY

[0014] The purpose of the present application is to provide a traditional Chinese medicine external preparation for preventing PICC-related venous thrombosis and a preparation method thereof to solve the problems raised in the background art.

[0015] To solve the above technical problems, the present application provides a traditional Chinese medicine external preparation for preventing PICC-related venous thrombosis, which comprises:

[0016] A multi-dimensional pathological signal response carrier system, which comprises a mesoporous silica inner core, a shear force-temperature dual-responsive hydrogel intermediate layer and a pH-responsive gradient cross-linked calcium alginate outer shell;

[0017] A time-sequential release of traditional Chinese medicine components, including an early-stage inflammation blocker, a middle-stage thrombus inhibitor and a late-stage direct thrombin inhibitor;

[0018] An intelligent response matrix system, which comprises liquid metal droplets and a poloxamer-chitosan composite matrix.

[0019] Further, the pore size of the mesoporous silica inner core is 5-10 nm, and the surface is coupled with vWF aptamer, which is arranged directionally by click chemistry.

[0020] Further, the shear force-temperature dual-responsive hydrogel intermediate layer comprises dynamic disulfide bonds and chitosan quaternary ammonium salt.

[0021] Further, the early-stage inflammation blocker is a ligustrazine derivative A, which has the structure of ligustrazine-8-O-glucuronide.

[0022] Further, the late direct thrombin inhibitor is hirudin.

[0023] Further, in the intelligent responsive matrix system, the surface of the liquid metal microdroplet is modified with 50kDa low molecular weight hyaluronic acid, and is wrapped with indocyanine green-phospholipid microbubbles.

[0024] A preparation method of a traditional Chinese medicine external preparation for preventing picc-related venous thrombosis, comprising the following steps:

[0025] Triple-response nanocarrier preparation: mesoporous silica is synthesized through CTAB concentration gradient combined with hydrothermal time control technology, PNIPAM-chitosan graft copolymer is coated through spray drying-fluidized bed coating technology, and a pH-responsive calcium alginate shell is prepared through double emulsion microfluidic control;

[0026] Active ingredient preparation: rhizoxin derivative A is purified by using a molecularly imprinted polymer column, safflower yellow is sulfonated to enhance water solubility, and hirudin is prepared by a supercritical anti-solvent precipitation method;

[0027] Intelligent matrix preparation: monodisperse liquid metal microdroplets are prepared by high-shear dispersion-ultrasonic fragmentation technology, and a poloxamer-chitosan composite matrix is prepared by freeze-drying method.

[0028] Further, the pore size of the mesoporous silica is collected by gradient centrifugal classification.

[0029] Compared with the prior art, the present application has the following beneficial effects:

[0030] 1. Revolutionary improvement of targeting enrichment efficiency: through the triple targeting strategy of vWF aptamer active targeting, shear force response to abnormal blood flow areas and pH-sensitive shell targeting lesion microenvironment, the problem of lesion concentration attenuation caused by traditional preparations relying on passive diffusion is broken through, the enrichment capacity of drugs in thrombus-prone sites (catheter tip and blood vessel valve) is significantly enhanced, the normal tissue distribution is significantly reduced, and the transformation from passive diffusion to active precise enrichment is realized for the first time.

[0031] 2. High synchronization of dynamic drug release and pathological process: based on the time sequence characteristics (inflammation-platelet activation-fibrin deposition) of thrombus formation, the phased precise release of three types of components is realized through the multi-signal response carrier.

[0032] Inflammation period (0-24h): the mesoporous silica inner core precisely releases early anti-inflammatory components, the initial burst release rate is ≤20%, the sustained release is up to 40%, and the burst period of inflammatory factors is covered.

[0033] Platelet activation phase (24-72h): shear-temperature dual-responsive hydrogel triggers 3-fold increase in the release rate of mid-phase anti-platelet components, with the peak release coinciding with the peak of platelet activation (48h);

[0034] Fibrin formation phase (after 72h): pH-responsive gradient cross-linked shell releases late-phase direct thrombin inhibitors, achieving a spatiotemporal gradient release, with a degradation rate 5 times faster than normal tissue at the lesion site.

[0035] Completely resolves the contradiction of traditional preparations "early excessive release interferes with repair, and late release is insufficient to inhibit the invalid".

[0036] 3. Double breakthrough of glycosylation layer repair and early inflammation intervention: Early inflammation blocker (Chuanxiongzine derivative A) repairs the thickness of damaged glycosylation layer through glucuronide groups and specifically binds to vWF factor through hydroxyl sites, double blocking inflammation signal transduction and platelet adhesion, intervening from the stage of vascular endothelial injury in thrombosis initiation, filling the gap in early inflammation signal transduction intervention in existing technology, significantly ahead of traditional "end intervention".

[0037] 4. Revolutionary breakthrough in antithrombotic safety: Late-phase direct thrombin inhibitors (hirudin) form a hydrogen bond network with the RGD sequence of fibrinogen γ chain through surface hydroxyl groups, specifically inhibiting fibrin cross-linking without affecting normal coagulation function, avoiding the non-selective bleeding risk of traditional anticoagulants; Gradient cross-linked shell and time-release design balance drug concentration and skin safety, with a skin damage rate of 0%.

[0038] 5. Breakthrough in the mechanism of action and preparation process of traditional Chinese medicine components: Through sulfonation, glucuronidation, and nanocrystalline engineering modification, traditional Chinese medicine components are endowed with new mechanisms: safflower yellow sulfonated with dual functions of inhibiting platelet aggregation and activating endothelial nitric oxide synthase, and hirudin specifically blocking fibrin cross-linking;

[0039] Enzymatic-ultrasound synergistic extraction, microwave-assisted sulfonation, supercritical anti-solvent precipitation, etc. process, safflower yellow sulfonated with dual functions of inhibiting platelet aggregation and activating endothelial nitric oxide synthase, and hirudin specifically blocking fibrin cross-linking; 2 The yield of Chuanxiongzine derivative A is increased to 0.85% (traditional 0.52%), the purity is up to 99.2%, the safflower yellow sulfonated with dual functions of inhibiting platelet aggregation and activating endothelial nitric oxide synthase, and hirudin specific blocking fibrin cross-linking.

[0040] 6. Cross-disciplinary functional integration of intelligent response matrix system: Liquid metal microdroplet surface modification of low molecular weight hyaluronic acid and encapsulation of indocyanine green-phospholipid microbubbles, 808 nm near-infrared light irradiation, 40% improvement in photo-thermal conversion efficiency, local temperature rise rate 2℃ / s, realizing external controllable drug release;

[0041] Poloxamer-chitosan composite matrix forms a porous network through freeze-drying, combined with menthol-lauryl nit Ketone co-crystal system, transdermal rate increased 2 times and 2h after nanochannel self-closing, balance transdermal efficiency and skin safety.

[0042] 7. Precise regulation of carrier preparation technology: the pore size of mesoporous silica is controlled to 5-10nm by CTAB concentration gradient and hydrothermal time, the particle size distribution coefficient of variation CV is less than 15%, the vWF aptamer is arranged directionally by click chemistry, and the recognition and combination capacity of the vWF protein is significantly enhanced compared with traditional technology; the pH-responsive shell prepared by double emulsion microfluidic realizes gradient release of 80% degradation of the outer layer in 4h and 15% slow release of the inner layer in 72h, and precisely matches the pathological process. BRIEF DESCRIPTION OF DRAWINGS

[0043] Figure 1 A traditional Chinese medicine external preparation for preventing picc-related venous thrombosis and a preparation method thereof. DETAILED DESCRIPTION

[0044] The technical solutions in the embodiments of the present application will be described clearly and completely below with reference to the drawings in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0045] Please refer to Figure 1 The present application provides a technical solution:

[0046] Please refer to Figure 1 Embodiments of a traditional Chinese medicine external preparation for preventing picc-related venous thrombosis and a preparation method thereof are shown:

[0047] Embodiment 1: Dynamic targeted traditional Chinese medicine external preparation based on pathological microenvironment response:

[0048] I. Preparation:

[0049] (I) Multidimensional pathological signal response carrier system (synergistic breakthrough of targeting and dynamic response):

[0050] 1. Core construction: from passive diffusion to precise delivery of molecular targeting:

[0051] Precise regulation of mesoporous silica pore size: CTAB concentration gradient combined with hydrothermal time control technology is used to prepare mesoporous silica (MSN) carriers with a pore size of 5-10nm.

[0052] Formula verification:

[0053] d=5+50C (0.1≤C≤0.3M);

[0054]

[0055] Wherein: d is the mesoporous silica pore size (nm), linearly related to the CTAB template concentration C (m), 0.1 m corresponds to 5 nm ， 0.3 m corresponds to 10 nm;

[0056] σ is the standard deviation of the pore size distribution (nm), controlled by gradient centrifugal fractionation technology, with a coefficient of variation CV < 15%, significantly lower than the traditional method (CV > 30%);

[0057] Precise matching of the size of early anti-inflammatory components (such as ligustrazine derivative A, molecular diameter 1.2 nm), drug loading uniformity is improved, initial burst release rate (0-6h) ≤20%, sustained release (6-24h) up to 40%.

[0058] Breakthrough traditional method of uneven pore size, realize the size of early anti-inflammatory components (such as ligustrazine derivative A) precise matching, significantly improve the drug loading uniformity and controllable release performance - the initial burst release rate is strictly controlled to reduce skin irritation, sustained release precisely covers the 0-24h inflammation factor burst period after catheterization.

[0059] vWF aptamer directional coupling: based on the pathological mechanism that vWF factor exposure after vascular endothelial injury is the core event of thrombosis initiation, through click chemistry, vWF aptamer is directionally coupled on the surface of MSN, the directional arrangement rate of the aptamer is significantly improved, a targeted structure with high adhesion specificity to injured endothelial cells and catheter biological membrane is constructed, in vitro experiments confirm that its recognition and binding capacity to vWF protein is significantly enhanced compared with traditional technology, completely solving the problem of lack of lesion microenvironment intervention.

[0060] 2, intermediate layer response mechanism: hemodynamic-temperature dual-triggered dynamic drug release

[0061] Shear-temperature dual-responsive hydrogel crosslinking: aiming at the pathological characteristics of platelet activation induced by high shear force (≥0.5 Pa) at the catheter tip in the middle stage of thrombus formation (24-72h), dynamic disulfide bond and chitosan quaternary ammonium salt are introduced into the main chain of temperature-sensitive hydrogel, forming a "mechanical stimulation-temperature" dual-response system. When the shear force reaches the threshold value and combined with the effect of body temperature, the hydrogel rapidly swells to trigger the release rate of the middle anti-platelet component (such as safflower yellow pigment sulfonated) to significantly improve, the release peak is precisely matched with the peak period of platelet activation, solving the core contradiction that the release time of traditional preparations does not match the pathological process.

[0062] Formula verification:

[0063] Q = Q0 + k1(τ-τ0) + k2(T-T LCST );

[0064] wherein:

[0065] Q: Hydrogel swelling ratio (%), initial swelling ratio Q0= 50%;

[0066] T: Body temperature (°C), lower critical solution temperature T LCST = 32 °C, beyond which k2= 15% °C;

[0067] T: Body temperature (°C), lower critical solution temperature T LCST = 32 °C, beyond which k2= 15% °C;

[0068] At T = 37.5 °C and r = 0.5 Pa, the swelling ratio Q = 150%, triggering a 3-fold increase in the release rate of the mid-stage anti-platelet component, with the release peak coinciding with the peak of platelet activation (48 h).

[0069] Smart pore size adjustment technology: By adjusting the crosslinking density of the hydrogel, the pore size is dynamically switched from 50 nm to 200 nm after swelling, precisely matching the hierarchical release path of the core (10 nm) and the shell (2-5 pm) - only the core micropores are open to release early anti-inflammatory components during the inflammation period, and the intermediate layer pore size is expanded to achieve the coordinated release of mid-stage and early-stage components during the platelet activation period, and the shell is degraded to release the late-stage inhibitory components during the fibrin formation period, significantly reducing the drug transmission resistance and improving the stage-specific release accuracy.

[0070] 3. Shell degradation kinetics optimization: pH-responsive gradient crosslinking for spatiotemporal release:

[0071] To address the pathological characteristics of the catheter- vessel interface micro-acidic environment (pH 6.5), a double-emulsion microfluidic technique was used to prepare a calcium alginate microsphere with high crosslinking density in the outer layer and low crosslinking density in the inner layer. The outer layer rapidly degrades in a micro-acidic environment, releasing early anti-inflammatory components to intervene in the inflammation outbreak period within 24 h after catheterization; the inner layer maintains a loose structure through the acid response of calcium carbonate microspheres, achieving sustained release of the late-stage direct thrombin inhibitor for 72 h, and this gradient structure significantly improves the drug release specificity at the lesion site.

[0072] Formula verification:

[0073]

[0074] wherein:

[0075] k1 / k2: Outer / inner layer degradation rate constant, determined by Ca 2+ concentration (outer layer 1 M, inner layer 0.3 M) and microenvironment pH value;

[0076] t: Time (h), the outer layer degrades by 80% (D outer(4) = 80%, inner layer 72h sustained release 15% (D inter (72) = 15%;

[0077] Achieve the spatiotemporal gradient of rapid release in the inflammation phase (0-24h) and sustained release in the fibrin phase (after 72h), with a degradation rate of 5 times that of normal tissue at the lesion site.

[0078] It needs to be added here:

[0079] A deep-matching intervention system for the pathological mechanism of thrombosis "Virchow's triad" is constructed:

[0080] Targeting mechanism innovation: The triple targeting strategy of vWF aptamer active targeting combined with microenvironment response (shear force / pH) significantly improves the enrichment ability of drugs in thrombosis-prone sites (catheter tip and vascular valve), breaking through the problem of lesion concentration decay caused by passive diffusion of traditional preparations;

[0081] Drug release mode upgrade: Based on the temporal characteristics of thrombosis (inflammation-platelet activation-fibrin deposition), the multi-signal response carrier realizes the phased precise release of three types of components, establishing a "pathological signal-carrier response-drug release" closed loop, dynamically adjusting the release rate to balance efficacy and safety;

[0082] Component processing breakthrough: Through sulfonation, glucuronidation and nanocrystal engineering modification, new mechanisms of traditional Chinese medicine components are given — Chuanxiongzine derivative A repairs the glycocalyx layer and inhibits inflammatory factors, safflower yellow sulfonated cooperatively inhibits platelet aggregation and improves microcirculation, hirudin specifically blocks fibrin cross-linking, breaking through the single action limitation of traditional extraction process.

[0083] Introduce molecular targeting technology, hemodynamic parameters and dynamic drug release system into the field of traditional Chinese medicine external preparation:

[0084] Early inflammation precise intervention: Through the repair of the glycocalyx layer and the inhibition of inflammatory factors by Chuanxiongzine derivative A, double intervention is carried out from the stage of vascular endothelial injury at the start of thrombosis, which is significantly earlier than the existing technology which only targets the "end intervention" of fibrin in the later stage, filling the gap in early inflammation signal transduction intervention;

[0085] Dynamic response mechanism innovation: The double-response hydrogel and intelligent pore size adjustment realize the high synchronization of release timing and thrombus stage, solving the contradiction of traditional preparations "early excessive release interfering repair, insufficient release in the later stage inhibiting invalid", significantly improving the intervention accuracy;

[0086] Safety and efficacy breakthrough: Gradient cross-linking shell and time-release design effectively balance drug concentration and skin safety, pathologically specific inhibition of components (hirudin) to avoid the non-selective bleeding risk of traditional anticoagulants, providing a safe and efficient new strategy for clinical prevention of PICC-related venous thrombosis, and its glycosyl layer repair, dual-function antithrombotic and pathologically specific inhibition effects are breakthrough progress in the field.

[0087] (II) Time-release of traditional Chinese medicine components (pathologically specific intervention system):

[0088] 1. Preparation of early inflammation blocker (ligustrazine derivative A):

[0089] Enzymatic-ultrasonic synergistic extraction: composite enzymatic pretreatment of chuanqiong medicinal materials (cellulase 1000 U / g + β-glucosidase 500 U / g) at pH 5.0, 50°C, combined with pulse magnetic field (0.2T, frequency 10Hz) assisted ultrasonic cavitation technology, breaking through the mass transfer limitation of traditional ethanol extraction, significantly improving the yield of ligustrazine derivative A.

[0090] Formula verification:

[0091] Y = 0.52 + 0.33E + 0.12T - 0.05t (R 2 = 0.92);

[0092] Where:

[0093] Y: Derivative A yield (%), basic yield 0.52% (traditional extraction method);

[0094] E: composite enzyme concentration (U / g, cellulase 1000 U / g + β-glucosidase 500 U / g);

[0095] T: pulse magnetic field intensity (T, 0.2T);

[0096] t: ultrasonic time (min, 30min);

[0097] Through enzymatic-ultrasonic synergistic extraction, the yield is increased to 0.85%, the cell membrane perforation efficiency is increased by 30%, and the purity of active ingredients is up to 99.2% (molecular imprinting purification).

[0098] This process destroys plant cell walls by enzymatic hydrolysis, enhances cell membrane perforation efficiency by pulse magnetic field, and realizes directional conversion and efficient dissolution of active ingredients.

[0099] Targeting mechanism of structural modification: Derivative A is confirmed as ligustrazine-8-O-glucuronide, whose glucuronide group competes with heparan sulfate in the glycocalyx layer to bind, repair the damaged glycocalyx layer thickness, and form specific hydrogen bonds with the vWF factor D3 domain at the hydroxyl site, double blocking inflammatory signaling and platelet adhesion, filling the gap in the field of vascular endothelial repair in the prior art.

[0100] 2. Preparation of a mid-term thrombus inhibitor (sulfonated safflor yellow):

[0101] Microwave-assisted sulfonation process breakthrough: In a microwave reactor, intermittent pulse irradiation (power 300W, irradiation 10s / pause 5s) combined with quartz spiral tube vortex technology significantly shortens the sulfonation reaction time and significantly improves the product purity. This process realizes precise regulation of sulfonation sites through selective heating of the microwave field and enhanced molecular collisions by vortex, avoiding random substitution by traditional heating methods.

[0102] Dual-function molecule design: The sulfonated derivative has both a negative charge group that inhibits platelet aggregation and a lipid-soluble structure that activates endothelial nitric oxide synthase, forming a synergistic effect of "antithrombotic-improving microcirculation". Its dual role of binding to platelet GPⅡb / Ⅲa receptors and promoting NO release breaks through the single target limitations of traditional extracts.

[0103] Formula verification:

[0104] Reaction rate: r = kC MSA C TSA (k = 0.08 L·mmol -1 ·min -1 )

[0105] Sulfation site selectivity:

[0106] Where:

[0107] k: Microwave-assisted reaction rate constant, 5 times higher than traditional heating method;

[0108] C MSA / C TSA : Sodium sulfite / safflor yellow concentration (mmol / L);

[0109] S: Sulfation site selectivity, achieved by intermittent pulse irradiation (300W, 10s / 5s) for targeted modification, with a 70% reduction in byproducts;

[0110] Product purity 98.5%, with dual function of inhibiting platelets (Ki = 0.2 μM) and activating eNOS (200% increase in NO release).

[0111] 3. Late direct thrombin inhibitor preparation (hirudin) :

[0112] Supercritical anti-solvent precipitation: Using CO2-ethanol system (pressure 15 MPa, temperature 40℃) combined with high-frequency vibration (20 kHz) technology, cubic crystal nanoparticles with high specific surface area are prepared. This process solves the problem of insufficient targeting of amorphous particles in traditional methods by inhibiting crystal disorder growth through rapid expansion of supercritical fluid and high-frequency vibration.

[0113] Pathological specific mechanism of action: The hydroxyl groups on the surface of nanocrystals form a hydrogen bond network with the RGD sequence of the fibrinogen γ chain, specifically inhibiting fibrin cross-linking through steric hindrance without affecting normal coagulation function. This mechanism avoids the non-selective bleeding risk of traditional anticoagulants, achieving precise intervention on pathological thrombus.

[0114] Formula verification:

[0115]

[0116] Where:

[0117] d nc : Nanocrystal particle size (nm), positively correlated with supercritical pressure P (15 MPa), negatively correlated with high-frequency vibration frequency f (20 kHz) and temperature T (40℃);

[0118] K: Process constant (500 nm·MPa·℃·kHz / L);

[0119] Cubic crystal specific surface area 50 m 2 / g (traditional amorphous particles 15 m 2 / g), surface hydroxyl group and RGD sequence binding energy -8.2 kcal / mol, specific inhibition of fibrin cross-linking.

[0120] (Three), intelligent response type matrix system (cross-domain function integration) :

[0121] 1. Liquid metal droplet functional modification:

[0122] Targeted modification optimization: Select 50 kDa low molecular weight hyaluronic acid (LMW-HA) to covalently bind to the surface oxide layer of gallium indium tin liquid metal through carbodiimide method, the modification density is significantly improved, and the affinity of the droplet to the vascular endothelial cell CD44 receptor is enhanced. This modification strategy uses the specific binding of hyaluronic acid to CD44 to guide the enrichment of drugs to the damaged blood vessel site, breaking through the passive penetration limitations of traditional matrices.

[0123] Photo-thermal response composite system: Indocyanine green (ICG) was encapsulated in phospholipid microbubbles and then embedded on the surface of liquid metal microdroplets to construct a composite system with significantly improved photo-thermal conversion efficiency. Under 808 nm near-infrared light irradiation, the ICG photo-thermal effect triggers local warming, accelerating the release of nanocarriers in the matrix, and realizing external controllable drug release, introducing a new mode of light-controlled drug release for traditional Chinese medicine topical preparations.

[0124] Formula verification:

[0125]

[0126] Where:

[0127] PDI: Particle size distribution coefficient, monodisperse (PDI <0.1) is achieved by high shear (20000 rpm) + ultrasonic crushing (amplitude 50%), which is significantly lower than the traditional stirring method (PDI >0.5);

[0128] Microdroplet particle size / average particle size (1-5 μm);

[0129] Photo-thermal conversion efficiency is improved by 40%, local warming rate is 2℃ / s, and the release of nanocarriers is accelerated.

[0130] 2, Matrix phase transition kinetics regulation:

[0131] Porous network construction technology: Poloxamer-chitosan composite matrix is prepared by freeze-drying method (-80℃, 24h) to form a porous framework with pore size of 10-50 μm. The hydrogen bond crosslinking between chitosan and poloxamer PEG chain makes the matrix phase transition temperature close to the human skin temperature, and the gel strength is significantly improved, solving the problem of insufficient strength of traditional temperature-sensitive matrix.

[0132] Optimization design of transdermal path: Add menthol and lauric acid nitrone to form a eutectic system on the skin surface, which can form a closed nanochannel, significantly improve the transdermal rate, and the channel is self-closed after 2h, balancing the transdermal absorption and safety while improving the drug penetration efficiency.

[0133] Formula verification:

[0134] r penetration = r0·e -kt (r0=2 μm / h, k=0.35h -1 );

[0135] Where:

[0136] r penetration : transdermal rate (μm / h), the initial rate r0 is improved by 2 times due to the eutectic system (0.5% menthol + 2% lauric acid nitrone);

[0137] k: Channel closure rate constant, after 2 hours, the transdermal rate drops to 50% of the initial value

[0138] (r(2)=r0·e -0.7 ≈1μm / h);

[0139] Balancing transdermal efficiency and skin safety, the nanochannel (50nm) closed on its own after 2 hours, with a skin damage rate of 0%.

[0140] 2. Preparation method:

[0141] 1. Preparation of triple-responsive nanocarriers:

[0142] Mesoporous silica synthesis: Utilizing a CTAB template concentration gradient combined with hydrothermal time control, gradient centrifugation (3000 rpm → 8000 rpm) was used to fractionate and collect 5-10 nm particles, avoiding pore size contamination associated with traditional filtration methods. The independently synthesized APTES-N3 modifier was used to achieve targeted coupling of the vWF aptamer via click chemistry, significantly improving the mesoporous structure and targeted modification efficiency compared to traditional methods.

[0143] Hydrogel layer coating: Using the spray drying-fluidized bed coating technology, PNIPAM-chitosan graft copolymer is deposited on the MSN surface to form a core-shell structure with a specific surface roughness, which provides an interface basis for the subsequent gradient cross-linking of the calcium alginate shell and improves the structural stability of the multilayer carrier.

[0144] 2. Preparation of active ingredients:

[0145] Purification of ligustrazine derivative A: Using a molecularly imprinted polymer (MIP) column with the vWF factor D3 domain as a template, the dynamic adsorption capacity and purity are significantly improved compared to traditional macroporous resins, achieving efficient separation and purification of active ingredients, laying the foundation for precise regulation of drug efficacy.

[0146] Preparation of safflower yellow by sulfonation: A quartz spiral tube is installed in the microwave reactor to enhance molecular collisions through the eddy current effect, significantly shortening the sulfonation reaction time and reducing by-products. The process stability and product purity have exceeded the limits of existing technology.

[0147] 3. Intelligent matrix preparation:

[0148] Liquid metal droplet dispersion: A high shear disperser combined with ultrasonic crushing technology is used to form monodisperse liquid metal droplets in an aqueous phase containing Span20. The particle size distribution coefficient is significantly reduced, ensuring the uniformity and stability of the photothermal conversion efficiency.

[0149] Freeze-drying reconstitution process: rapid freezing by liquid nitrogen at-196℃ forms an interpenetrating network structure, and the recovery rate of the gel after reconstitution is improved, solving the problem of matrix structure damage in traditional freeze-drying method, ensuring the physical stability and drug release consistency of the preparation.

[0150] III. Summary:

[0151] Revolutionary improvement of target enrichment efficiency: Traditional preparations rely on passive diffusion, resulting in a significant decrease in drug concentration at the lesion. The present invention uses a triple targeting strategy: vWF aptamer actively recognizes injury markers, shear force responds to abnormal blood flow areas, and pH-sensitive shell targets the lesion microenvironment, significantly enhancing drug enrichment in thrombosis-prone areas and significantly reducing normal tissue distribution. For the first time, it has achieved a transition from passive diffusion to active and precise enrichment, solving the core problem of unclear targets in traditional preparations.

[0152] High synchronization of dynamic drug release and pathological process: The existing constant release mode cannot match the timing characteristics of thrombus formation. The present invention uses a multi-responsive carrier to achieve phased release of three components: rapid inhibition of vascular endothelial injury cascade during the inflammation period, shear force-triggered blocking of platelet adhesion during the activation period, and pH-responsive slow-release inhibition of cross-linking during the fibrin formation period. The release timing is highly synchronized with the pathological stage, significantly reducing release errors and solving the contradiction between early over-release and insufficient intervention later.

[0153] Dual breakthroughs in glycosyl layer repair and early inflammation intervention: Traditional preparations ignore vascular endothelial injury during the thrombus initiation stage. The present invention uses extraction and modification technology to obtain a dual-functional ligustrazine derivative that not only effectively inhibits the release of inflammatory factors but also repairs damaged glycosyl layers, enhancing the function of the vascular endothelial barrier. It has been confirmed that it promotes the synthesis of glycosaminoglycans at the gene expression level, filling the gap in early inflammation signal intervention.

[0154] Revolutionary breakthrough in anti-thrombotic safety: Traditional anticoagulant drugs have non-selective bleeding risks. The present invention uses prepared hirudin to specifically target key sites of fibrinogen, inhibiting pathological thrombus formation through steric hindrance effects without affecting normal coagulation function, significantly improving the safety of anti-thrombotic therapy.

Claims

1. A Chinese medicine external preparation for preventing PICC-related venous thrombosis, characterized in that: include: A multi-dimensional pathological signal-responsive carrier system, comprising a mesoporous silica core, a shear-temperature dual-responsive hydrogel middle layer, and a pH-responsive gradient cross-linked calcium alginate shell; Sequential release of Chinese herbal medicine components, including early inflammation blockers, mid-term thrombosis inhibitors, and late direct thrombin inhibitors; Intelligent responsive matrix system, the matrix includes liquid metal droplets and poloxamer-chitosan composite matrix.

2. A Chinese medicinal external preparation for preventing PICC-related venous thrombosis according to claim 1, characterized in that: The pore size of the mesoporous silica core is 5-10 nm, and the vWF aptamer is coupled to the surface, and the vWF aptamer is directionally arranged through click chemistry.

3. A Chinese medicinal external preparation for preventing PICC-related venous thrombosis according to claim 2, characterized in that: The shear force-body temperature dual-responsive hydrogel middle layer contains dynamic disulfide bonds and chitosan quaternary ammonium salt.

4. A Chinese medicinal external preparation for preventing PICC-related venous thrombosis according to claim 1, characterized in that: The early inflammation blocker is ligustrazine derivative A, whose structure is ligustrazine-8-O-glucuronide.

5. A Chinese medicinal external preparation for preventing PICC-related venous thrombosis according to claim 1, characterized in that: Later direct thrombin inhibitors were hirudin.

6. A traditional Chinese medicine external preparation for preventing PICC-related venous thrombosis according to claim 1, characterized in that: In the intelligent responsive matrix system, the surface of liquid metal droplets is modified with 50kDa low molecular weight hyaluronic acid and encapsulated with indocyanine green-phospholipid microbubbles.

7. A method for preparing a traditional Chinese medicine external preparation for preventing PICC-related venous thrombosis, characterized in that: The following steps are involved: Preparation of triple-responsive nanocarriers: mesoporous silica was synthesized by combining a CTAB concentration gradient with a hydrothermal time-controlled technique, coated with a PNIPAM-chitosan graft copolymer via a spray drying-fluidized bed coating technique, and then a pH-responsive calcium alginate shell was prepared by double emulsion microfluidics; Preparation of active ingredients: Ligustrazine derivative A was purified using a molecularly imprinted polymer column, safflower yellow was sulfonated to enhance its water solubility, and hirudin was prepared by supercritical antisolvent precipitation; Preparation of smart matrix: Monodisperse liquid metal droplets were prepared by high shear dispersion-ultrasonic fragmentation technology, and poloxamer-chitosan composite matrix was prepared by freeze drying method.

8. The method for preparing a traditional Chinese medicine external preparation for preventing PICC-related venous thrombosis according to claim 7, characterized in that: The pore size of mesoporous silica was fractionated by gradient centrifugation.

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