Composite medicine coating for treating pulmonary arterial hypertension

Abstract

The invention discloses a composite medicine coating for treating pulmonary arterial hypertension, and belongs to the technical field of medical instruments. The coating is composed of an inert protective layer and a composite drug coating, the inert protective layer is a polyamino acid polymer, responds to pH change and is rapidly disintegrated only in the pH environment of a target site, and the loss of the composite drug coating in the delivery process is reduced; the composite drug coating is a composite component containing two or more gene regulatory factors and / or drugs, achieves a synergistic effect through a signal path, cells and a gene level, more efficiently regulates pulmonary artery endothelial cell dysfunction and smooth muscle cell injury, and has precise targeting and irreplaceability.

Description

Technical Field

[0001] This invention belongs to the field of medical device technology, specifically relating to a composite drug coating for treating pulmonary hypertension. Background Technology

[0002] Pulmonary hypertension (PH) is a cardiopulmonary vascular disease that easily leads to chronic cor pulmonale and right heart failure, with a 3-year survival rate of less than 60%. PH is characterized by persistent vasoconstriction caused by pulmonary artery resistance and pulmonary artery occlusive remodeling. Its main pathophysiological features are pulmonary artery endothelial cell dysfunction leading to inflammation, endothelial-mesenchymal transition, smooth muscle cell damage, altered cell metabolism, and enhanced vascular cell proliferation, resulting in luminal narrowing and increased resistance. Currently, treatment methods for PH are broadly classified into three categories: drug control, heart-lung transplantation, and interventional therapy. Drug therapy mainly involves endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclin analogs. While these drugs can relieve symptoms and improve the condition, they have drawbacks such as side effects, significant individual variability, inability to cure the disease, and complex combination therapy. Furthermore, they cannot completely cure the condition, and drug therapy may not achieve ideal results for severely ill patients. Some targeted drugs are also expensive, placing a heavy financial burden on patients with long-term use. While surgeries such as heart and lung transplantation can treat pulmonary hypertension at its root, the surgeries themselves are high-risk, donors are scarce, and the patient's condition often becomes uncontrollable during the waiting period. Interventional therapy can precisely treat the target lesion, is relatively safe, minimally invasive, and allows for rapid recovery. However, currently, there is no composite drug-coated balloon dilatation catheter used clinically to treat pulmonary hypertension. Traditional balloon atrial septostomy is generally used, creating a small hole in the atrial septum to divert blood from the right atrium to the left atrium, reducing the load on the right heart and improving the patient's symptoms. Furthermore, current interventional device drug coatings face challenges in the treatment of pulmonary hypertension: a) significant drug loss during delivery; b) existing sustained-release coatings release slowly and incompletely at the lesion site; and c) single drugs are insufficient to address the complex pathological network of pulmonary hypertension.

[0003] Therefore, how to reduce drug loss during delivery, increase the release rate of the coating at the lesion site, and adapt to the complex pathological network of pulmonary hypertension has become an important issue that urgently needs to be addressed. Summary of the Invention

[0004] Therefore, the purpose of this invention is to provide a composite drug coating for treating pulmonary hypertension. The coating consists of an inert protective layer and a composite drug coating. The inert protective layer is a polyamino acid polymer that responds to pH changes and rapidly disintegrates only in the pH environment of the target site, reducing the loss of the composite drug coating during delivery. The composite drug coating is a composite component containing two or more gene regulatory factors and / or drugs, which exert synergistic effects through signaling pathways, cells, and genes, more efficiently regulating pulmonary artery endothelial cell dysfunction and smooth muscle cell damage, exhibiting precise targeting and irreplaceability.

[0005] To achieve the above objectives, the present invention provides the following technical solution: In a first aspect, the present invention provides a composite drug coating for treating pulmonary hypertension, wherein the outermost layer is an inert protective layer and the inner layer is a composite drug coating, the composite drug coating comprising gene regulatory factor components and / or drug components.

[0006] Among them, the gene regulatory factors act on BMPR2, SOX17, miRNAs, BMP9, ALK1, Endoglin, SMAD9, BMPR1B, TBX4, CAV1, and KCNK3.

[0007] Among them, the composite drug coating targets the core pathological mechanisms of pulmonary hypertension, such as abnormal BMPR2 signaling pathway, disordered pulmonary vascular endothelial-smooth muscle cell interaction, and inflammation-mediated vascular remodeling, complementing the precise targeting and irreplaceable nature of the gene drug coating.

[0008] Among them, the composite drug coating uses a synergistic combination of multiple genes and / or drugs to improve the adaptability to pathological mechanisms.

[0009] Among them, the composite drug coating used to treat pulmonary hypertension remains intact under normal physiological conditions, has a high degree of matching with the pathological environment, and the local pathological environment has a lower pH than the normal site. The inert protective layer only disintegrates rapidly in the acidic environment of the target site.

[0010] Based on the above technical solution, the inert protective layer is further composed of a polyamino acid polymer, which includes polyleucine, polyaspartic acid, polylysine, polythreonine, polycysteine, or polyglutamic acid.

[0011] The polyamino acid polymer is a non-drug-loaded physical coating that rapidly releases the drug from the inner drug coating only in response to pH changes.

[0012] Based on the above technical solution, the composite drug coating further includes one or more of amlodipine, nifedipine, eprostol, treprostol, bosentan, ambrisentan, macitentan, milrinone, amrinone, sildenafil, tadalafil, furosemide, torasemide, and riociguat.

[0013] Based on the above technical solution, the gene regulatory factor component further includes at least two of the following: tacrolimus, cytokinin, Treg cell lyophilized powder, miR-21, miR-22, miR-29a, miR-126, nuclear factor-κB inhibitor, and antisense oligonucleotide.

[0014] Based on the above technical solution, the drug component further comprises one or more of the following: calcium channel blockers, prostacyclin derivatives, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, diuretics, and guanylate cyclase agonists.

[0015] Based on the above technical solution, the composite drug coating is further divided into layers, with each layer separately carrying the gene regulatory factor component and the drug component.

[0016] Based on the above technical solution, further, the gene regulatory factor component and the drug component are mixed and loaded onto the composite drug coating.

[0017] Based on the above technical solution, further, the content of the gene regulatory factor component is not less than 30% of the content of the composite drug coating, and the content of the drug component is not less than 10% of the content of the composite drug coating.

[0018] The content of the gene regulatory factor component is not less than 30% of the content of the composite drug coating, and the content of the drug component is not less than 10% of the content of the composite drug coating. This represents the minimum effective threshold required to achieve the shift from symptomatic treatment to etiological treatment.

[0019] Based on the above technical solution, the composite drug coating and the inert protective layer are prepared by coating them sequentially.

[0020] The sequential coating design avoids potential interactions between the drug and the protective layer material (such as charge attraction and hydrogen bonding), ensuring that after the protective layer disintegrates, the drug can be released instantly in its 100% active form, without any residue or sustained-release effect. This approach decouples the protective and therapeutic functions physically and chemically.

[0021] The preparation process involves selecting two or more different active pharmaceutical ingredients or drug coating solutions, and applying the mixture of active pharmaceutical ingredients or drug coatings to the surface of devices such as stents, balloons, and catheters by one or more of the following methods: dip coating, spraying, plating, deposition, pad printing, printing, and smearing.

[0022] Secondly, the present invention provides the application of the above-mentioned composite drug coating for treating pulmonary hypertension in a medical device, wherein the drug coating content on the medical device ranges from 0.1 to 20.0 mg.

[0023] Among them, a composite drug coating for treating pulmonary hypertension is applied to the surface of a medical device for the treatment of pulmonary hypertension. The stability of the active drug coating at physiological pH is achieved through an inert protective layer, ensuring "zero loss."

[0024] The polyamino acid polymers of this invention are high molecular weight compounds polymerized from amino acid monomers, exhibiting good biocompatibility, biodegradability, and pH sensitivity. The polylysine of this invention is a polyamino acid polymerized from lysine monomers. Its side chain contains amino groups, which carry a positive charge under physiological conditions. This change in charge makes it pH sensitive, and by utilizing this pH sensitivity, it is released in the acidic environment of pulmonary hypertension lesions, thereby exerting a therapeutic effect. Simultaneously, its positive charge may also facilitate interaction with negatively charged cell surfaces, promoting the uptake of gene regulators or drugs by cells.

[0025] The polyaspartic acid of this invention is a biodegradable polyamino acid. It contains a large number of carboxyl groups, which dissociate to varying degrees at different pH values, making polyaspartic acid sensitive to pH changes. In an alkaline environment, the carboxyl groups dissociate, the polymer becomes negatively charged, and its hydrophilicity increases; in an acidic environment, the carboxyl groups are protonated, and the hydrophilicity decreases. This characteristic allows polyaspartic acid to regulate drug release based on the pH difference at the lesion site in composite drug coating applications. In the treatment of pulmonary hypertension, the pH difference between the lesion site and normal tissue can be utilized to achieve precise drug release at the pulmonary artery lesion site, improving the therapeutic effect, while its biodegradability ensures that it does not remain in the body for a long time.

[0026] The BMPR2 of this invention serves as a target for the treatment of pulmonary hypertension. Its mechanism involves point mutations and domain abnormalities in the BMPR2 kinase domain, which can significantly inhibit receptor function, preventing the formation of the heterodimer complex or causing it to lose kinase activity and blocking downstream signaling pathways. This leads to excessive cell proliferation and inhibited apoptosis, resulting in vascular remodeling and the development of pulmonary hypertension. For example, the absence of BMPR2 increases the expression of ARRB2 and CTNNB1 through the TGF-G signaling pathway, jointly activating cell proliferation-related genes, increasing the inflammatory response of vascular endothelial cells, and promoting adverse vascular remodeling.

[0027] The mechanism by which SOX17 of the present invention serves as a target for the treatment of pulmonary hypertension is as follows: enhancer mutations in the binding regions of the two transcription factors HOXA5 and ROR-α upstream of the SOX17 gene lead to downregulation of SOX17 gene expression, which may in turn lead to pulmonary artery endothelial cell dysfunction and pulmonary hypertension.

[0028] The miRNA gene factors of this invention serve as therapeutic targets for pulmonary hypertension. At the gene level, their mechanism involves changes in the expression of various miRNAs, which are closely related to the TGF-β and BMPR2 signaling pathways. For example, miR-21, miR-29a, miR-145, miR-126, and miR-155 play important regulatory roles in pulmonary hypertension. By regulating the expression of these miRNAs, the transcription of a series of cell proliferation-related genes is promoted, which can affect the TGF-β and BMPR2 signaling pathways, leading to pulmonary artery media smooth muscle proliferation and pulmonary vascular remodeling, thereby influencing the pathological process of pulmonary hypertension.

[0029] The nuclear factor-κB inhibitor of this invention serves as a target for the treatment of pulmonary hypertension. Its mechanism in the signaling pathway is as follows: In patients with pulmonary hypertension, various factors such as hypoxia and oxidative stress can activate nuclear factor-κB. Activated nuclear factor-κB translocates into the cell nucleus and binds to the promoter regions of related genes, initiating the transcription of a series of inflammatory factors, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). The release of these inflammatory factors triggers an inflammatory response in the lungs, leading to endothelial cell damage and inflammatory cell infiltration, further exacerbating the inflammatory state of the blood vessel wall and promoting the development of pulmonary hypertension. Furthermore, at the gene level, its mechanism involves the regulation of the proliferation of pulmonary artery smooth muscle cells and endothelial cells. It can regulate the expression of cell cycle-related proteins and promote cell proliferation. Excessive activation of nuclear factor-κB leads to abnormal proliferation of pulmonary artery smooth muscle cells, thickening of the blood vessel wall, and narrowing of the lumen, thus worsening pulmonary hypertension.

[0030] The synergistic effect of BMPR2 and miRNAs (such as miR-21) can enhance BMP signaling and inhibit pulmonary vascular remodeling and endothelial cell proliferation. miR-21 may enhance BMP signaling by inhibiting molecules that resist BMP signaling, while BMPR2 gene therapy directly restores the function of BMP receptors.

[0031] The synergistic effect of SOX17 and miRNAs (such as miR-29a) can regulate endothelial cell function, reducing inflammation and abnormal proliferation. Upregulation of SOX17 may inhibit endothelial cell proliferation by affecting the HGF / c-Met signaling pathway, while miR-29a may alleviate inflammation and fibrosis by inhibiting pro-fibrotic signaling.

[0032] The combined use of BMPR2, SOX17, and multiple miRNAs can inhibit pulmonary vascular remodeling through multiple pathways. The synergistic effect of BMPR2 and SOX17 can restore the normal structure and function of pulmonary vessels, while miRNAs inhibit the pathological remodeling process by regulating related signaling pathways.

[0033] Compared with the prior art, the present invention has the following beneficial effects: 1. The coating of this invention consists of an inert protective layer and a composite drug coating. The inert protective layer is a polyamino acid polymer that responds to pH changes and rapidly disintegrates only in the pH environment of the target site, reducing the loss of the composite drug coating during delivery. The composite drug coating is a composite component containing two or more gene regulatory factors and / or drugs, which exert synergistic effects through signaling pathways, cells, and genes, and more efficiently regulate pulmonary artery endothelial cell dysfunction and smooth muscle cell damage, exhibiting precise targeting and irreplaceability.

[0034] 2. This invention prepares a composite drug coating based on the pathological mechanism of pulmonary hypertension, applying a multi-component composite drug coating to the surface of a medical device. The outermost layer of the device surface is an inert protective layer, and the inner layer is one or more layers of the composite drug coating. The inert protective layer is independent of the drug coating, only responding to pH changes to function as a physical barrier, and does not undergo a bonding reaction with the composite drug coating, allowing the drug to be more firmly encapsulated on the device surface; it also prevents the drug coating from detaching during device delivery, improving drug utilization; upon reaching the target lesion under acidic conditions, the inert protective layer rapidly decomposes, exposing the composite drug coating and allowing the drug to release and exert its effect. The composite drug coating employs a synergistic combination of multiple genes and / or drugs, which adhere to the pulmonary artery wall upon exposure. Multiple components exert synergistic effects at the signaling pathway, cellular, and gene levels, jointly restoring pulmonary artery endothelial cell function and inhibiting smooth muscle cell damage through multiple mechanisms, avoiding the limiting effects of single drugs, improving the adaptability to the pathological mechanism, and thus comprehensively improving the clinical symptoms and quality of life of patients with pulmonary hypertension. This method not only targets known causes and pathophysiological mechanisms but also takes into account the complexity and diversity of the disease, providing new ideas and directions for the treatment of pulmonary hypertension. Secondly, dilating the stenotic lesion using medical devices such as balloons and stents can provide physical support to the narrowed area, improving treatment efficacy. Attached Figure Description

[0035] To more clearly illustrate the embodiments of the present invention, the accompanying drawings involved in the embodiments will be briefly described below.

[0036] Figure 1 It is a drug coating composed of two-component drugs with a mixed coating method; Figure 2 It is a drug coating composed of two-component drugs with a layered coating method; In the figure: 1. Inert protective layer; 2. Hybrid two-component composite drug coating; 3. Layered two-component composite drug coating. Detailed Implementation

[0037] This invention discloses a composite drug coating for treating pulmonary hypertension. The coating consists of an inert protective layer and a composite drug coating. The outermost layer is an inert protective layer, which is a polyamino acid polymer. The inner layer is a composite drug coating, which is a compound containing two or more gene regulatory factors and / or drugs. The inert protective layer is a non-drug-loaded physical coating used to prevent the drug coating from detaching during device delivery, thereby improving drug utilization. The composite drug coating exerts a synergistic effect through signaling pathways, cellular and gene-level pathways, more efficiently regulating pulmonary artery endothelial cell dysfunction and smooth muscle cell damage. This invention differs from traditional drug coatings. The composite drug coating targets the core pathological mechanism of pulmonary hypertension, complementing the precise targeting and irreplaceable nature of gene-based drug coatings. A pH-responsive inert protective layer is used, allowing for rapid decomposition upon reaching the target lesion in an acidic environment, exposing the composite drug coating and releasing the drug to exert its effect. This invention achieves "zero-loss" delivery and "instantaneous complete release" of composite drugs targeting the complex pathological mechanism of pulmonary hypertension during interventional delivery.

[0038] This invention provides a composite drug coating applied to the surface of an interventional medical device. The outermost layer of the device surface is an inert protective layer independent of the drug coating. This is a non-drug-loaded physical coating that does not undergo a bonding reaction with the composite drug coating. The inert protective layer only responds to pH changes and rapidly disintegrates in the pH environment of the target site, protecting the drug coating from detachment during delivery and reducing drug delivery loss. The composite drug coating exhibits high adaptability to pathological mechanisms, with synergistic effects from multiple genes and / or drugs, avoiding the limited effects of single drugs. It enhances the effects of resisting pulmonary artery smooth muscle cell damage, regulating pulmonary artery endothelial cell function, and inhibiting gene mutations in pulmonary artery endothelial cells and smooth muscle cells. The composite drug coating targets the core pathological mechanisms of pulmonary hypertension, complementing the precise targeting and irreplaceable nature of gene-based drug coatings.

[0039] The composite drug coating has two or more effects, namely, resisting pulmonary artery smooth muscle cell damage, regulating pulmonary artery endothelial cell function, and inhibiting gene mutations in pulmonary artery endothelial cells and smooth muscle cells.

[0040] The composite drug coating exerts a three-layer synergistic effect. Preferably, the first layer involves gene repair: such as BMPR2 gene supplements and miR-126 mimics. miR-126 stabilizes the vascular endothelium and synergizes with upstream BMPR2 to promote pathway recovery at the post-transcriptional level. Preferably, the second layer involves signaling pathway regulation: such as tacrolimus (upregulating BMPR2) and antisense oligonucleotides (inhibiting NF-κB), simultaneously repairing pro-repair signals and inhibiting pro-inflammatory signals. Preferably, the third layer involves cellular function regulation: such as anti-inflammatory Treg cell secretions and prostacyclin analogs that relax blood vessels and inhibit proliferation, regulating both the immune microenvironment and vascular tone.

[0041] The inert protective layer has a high degree of compatibility with the pathological environment. The pH of the local pathological environment is lower than that of the normal site, and the inert protective layer can only dissolve in the acidic environment of the target site.

[0042] Polyamino acid polymers serve as drug-free physical coatings, independent of the drug coating itself. They respond only to pH changes, disintegrating under acidic conditions to expose the composite drug coating, enabling rapid release of the inner composite drug coating. This also prevents drug coating detachment during device delivery, improving drug utilization. The dissolution / disintegration pH thresholds of the polyamino acids (such as polylysine and polyaspartic acid) are carefully designed, for example, by adjusting the degree of polymerization and side chain modifications (such as the degree of acylation) to fine-tune their pH sensitivity, making them stable at normal vascular blood pH (~7.4) and rapidly responding to the acidic microenvironment of disease (pH < 7.1). "Instantaneous complete release" is achieved through the rapid and complete disintegration of the protective layer in the acidic microenvironment of the disease. The pH-responsive material is an independent, drug-free, purely physical barrier. Its sole function is "on / off." Once "on" (disintegrated), the inner drug can immediately and completely contact the diseased tissue; the release kinetics are determined by the drug coating itself, not by the protective layer material. This is a more direct and precise trigger-release strategy.

[0043] The present invention will be described in detail below with reference to the embodiments. However, the implementation of the present invention is not limited thereto. Obviously, the embodiments described below are only some embodiments of the present invention. For those skilled in the art, other similar embodiments can be obtained without creative effort and all fall within the protection scope of the present invention. Example

[0044] Preparation method of composite drug coating: Weigh 5.00 mg of tacrolimus raw material and 5.00 mg of Treg cell lyophilized powder and dissolve them in 15 mL of ethanol. Apply the solution to the surface of the balloon using a spraying method to form a coating with a content of 2.00 mg. Dry at room temperature and sterilize to obtain a drug-coated balloon A. Weigh 5.00 mg of tacrolimus raw material and dissolve it in 15 mL of ethanol. Prepare a balloon B with a drug coating content of 2.00 mg using the same method. Weigh 5.00 mg of Treg cell lyophilized powder and dissolve it in 15 mL of ethanol. Prepare a balloon C with a drug coating content of 2.00 mg using the same method. Dissolve the drug in the three groups of drug-coated balloons in 10 mL of physiological saline to prepare the drug coating solution. Prepare a bare balloon D as a blank control group. In vitro cell experiments were conducted using human small pulmonary artery smooth muscle cells, which were divided into a model group (D) and drug-coated groups (A, B, and C). All four groups were cultured in a hypoxic incubator to establish the model. After 24 hours, the model group (D) was given 0.5% sterile saline, while the drug-coated groups (A, B, and C) were given 0.5% drug coating solution. After drug administration, both groups were placed in a normoxic incubator for another 2 hours. Subsequently, the BMPR2 concentration was measured. The results showed that compared with the model group, drug coating group A increased the intracellular BMPR2 concentration by 68%, drug coating group B increased the intracellular BMPR2 concentration by 29%, and drug coating group C increased the intracellular BMPR2 concentration by 36%. The results indicate that the drug coating with the combination of the two components can increase the expression of BMPR2 through a dual-channel synergistic effect.

[0045] Tacrolimus is a calcineurin inhibitor with immunomodulatory and anti-inflammatory activities. It has been shown to upregulate BMPR2 expression and repair endothelial dysfunction. Tacrolimus operates through a dual mechanism of action as a calcineurin inhibitor, also binding to FKBP12 (a BMP signaling inhibitor). Tacrolimus releases FKBP12 from ALK1 (a type I receptor activator-like kinase), ALK2, and ALK3, thereby upregulating BMPR2 expression.

[0046] Treg cells are a subset of T cells that control the body's autoimmune response. Treg cells interact directly or indirectly with other immune cells by secreting cytokines and chemokines, such as IL-10 and BMPR2, thereby suppressing the inflammatory response of pulmonary hypertension.

[0047] This innovative treatment strategy regulates BMPR2 expression through a dual-channel mechanism, increasing the number of receptors on the cell surface and restoring their normal signal transduction function. On the other hand, it can also indirectly enhance BMPR2 activity by inhibiting molecules or pathways that negatively regulate BMPR2 expression. This dual-action mechanism ensures comprehensive activation of the BMPR2 signaling pathway, contributing to the restoration of normal pulmonary artery structure and function. Simultaneously, Treg cells play a role, targeting and inhibiting the release of pro-inflammatory cytokines, reducing inflammatory cell infiltration, and regulating excessive immune system responses. Through this pathway, they can significantly reduce systemic and local inflammatory responses in patients with pulmonary hypertension, alleviate vascular wall damage and fibrosis, create favorable conditions for pulmonary artery decompression and recovery, and rapidly and effectively relieve patient symptoms, improving quality of life. Example

[0048] Preparation method of composite drug-coated stent: Immerse the stent in a 25% miR-22 gene protein saline solution for 3-15 min, and apply the drug-coated stent to the stent surface using a dip-coating method. After removal, dry for 10-30 min, and then immerse in the solution again. Repeat this process 13 times to form a coating with a content of 1.20 mg. Then, weigh 5.00 mg of miR-22 gene protein, dissolve it in 10 mL of saline solution, and apply it to the stent surface using a spray-coating method to form a coating with a content of 2.00 mg. Dry at room temperature to obtain a drug-coated stent A. Immerse the stent in a 25% miR-22 gene protein saline solution for 3-15 min, and apply the drug-coated stent to the stent surface using a dip-coating method. After removal, dry for 10-30 min, and then immerse in the solution again. Repeat this process 21 times to form a coating with a content of 2.00 mg. Dry at room temperature to obtain a drug-coated stent B. 5.00 mg of carboxin was dissolved in 10 mL of physiological saline and sprayed onto the surface of the scaffold to form a coating with a concentration of 2.00 mg. The coating was then dried at room temperature to obtain a drug-coated scaffold C. The drugs from the three drug-coated scaffolds were dissolved in 10 mL of physiological saline to prepare the drug coating solutions. A bare scaffold D was also prepared as a blank control group. In vitro cell experiments were conducted using human small pulmonary artery smooth muscle cells, which were divided into a model group (D) and drug-coated groups (A, B, and C). All four groups were cultured in a hypoxic incubator to establish the model. After 24 hours, the model group (D) was given 0.8% sterile saline, while the drug-coated groups (A, B, and C) were given 0.8% drug coating solution. After drug administration, both groups were cultured in a normoxic incubator for another 2 hours. Subsequently, the concentration of MYCBP in groups A and B was measured, and the concentration of BMPR2 in groups A and C was measured. The results showed that compared with the model group, drug coating group A increased the intracellular BMPR2 concentration by 58% and reduced MYCBP expression by 43%; drug coating group B reduced MYCBP expression by 32%; and drug coating group C increased the intracellular BMPR2 concentration by 19%. The results indicate that the drug coatings with the two components complement each other and exhibit a synergistic effect.

[0049] As an endogenous non-coding RNA, miR-22's precise release at the target lesion site specifically inhibits the translation of MYCBP. MYCBP, a key regulator of the c-Myc signaling pathway, directly suppresses abnormal activation of this pathway through downregulation. The c-Myc pathway plays a central role in the proliferation and gene transcription of pulmonary artery smooth muscle cells, and its overactivation is a significant factor in the development of pulmonary hypertension. Therefore, by reducing MYCBP translation, miR-22 effectively blocks abnormal signal transduction in the c-Myc pathway, thereby inhibiting excessive proliferation of pulmonary artery smooth muscle cells and reducing abnormal gene transcription activity, laying an important foundation for alleviating pulmonary artery pressure.

[0050] Meanwhile, silage proteins, as key components of the cell wall cell, a unique cellular structure, play a crucial role in maintaining the structural stability of the cell wall cell through release and redistribution at the target lesion site. They also participate in regulating various cellular functions, including cell proliferation and differentiation. In the pathological process of pulmonary hypertension, pulmonary artery smooth muscle cells are severely damaged, and BMPR2 expression is often significantly decreased, leading to an imbalance in vascular repair and proliferation regulation. The release of silage proteins, through a series of complex molecular mechanisms, upregulates BMPR2 expression levels in membrane tissue and the cell wall cell, promoting the repair of damaged pulmonary artery smooth muscle cells while inhibiting abnormal cell proliferation. This process not only helps alleviate pulmonary artery stenosis and hypertension but also promotes healthy remodeling of the vascular wall.

[0051] Therefore, the synergistic effect of miR-22 and cytokinin at the target lesion site constitutes a multi-layered and precise treatment strategy. These two mechanisms complement and promote each other, working together to address the pathological process of pulmonary hypertension, effectively relieving pulmonary artery pressure and improving patients' clinical symptoms and prognosis. This innovative treatment method opens up new avenues for the treatment of pulmonary hypertension and provides valuable insights and inspiration for the treatment of other related diseases. Example

[0052] Preparation method of inert protective layer: Weigh 5.00 mg of polylysine and dissolve it in 20 mL of deionized water. Slowly add sodium hydroxide solution to adjust the pH value to between 6.9 and 7.1. Then, uniformly coat the solution onto the surface of the instrument with the composite drug coating that has been left to dry for 24 hours. Place the instrument in an oven at 37°C to allow the solvent to evaporate and dry. The resulting polylysine coating is the inert protective layer. Example

[0053] Validating the effect of the pH responsiveness of the inert protective layer on drug loss and release: Weigh 5.00 mg of riociguat and 10 mL of 50% miR-126 gene protein saline solution, mix thoroughly, and apply the mixture to the surface of the balloon using a spray method to form a coating with a content of 2.00 mg. Dry at room temperature to obtain one drug-coated balloon A. Prepare 10 balloons for later use. Repeat the above operation, then take the inert protective layer from Example 3 and coat it onto the surface of the device with the composite drug coating that has been dried for 24 hours. Place the device in an oven at 37°C to allow the solvent to evaporate and dry, forming a drug-coated balloon B with a polylysine inert protective layer. Prepare 10 balloons for later use. Weigh 5.00 mg of riociguat, 2.50 mg of polylysine, and 10 mL of 50% miR-126 gene protein saline solution, mix them thoroughly, slowly add sodium hydroxide solution to adjust the pH to between 6.9 and 7.1, and apply the mixture to the surface of the balloon by spraying to form a coating with a content of 2.00 mg. Dry at room temperature to obtain a drug-coated balloon C. Prepare 10 balloons for later use.

[0054] Balloons with different drug coatings were used in simulated delivery within isolated blood vessels modeled as pulmonary hypertension (the vascular environment was completely identical to that of living human blood vessels; normal blood vessels had a pH of 7.35-7.45, while lesion sites had a pH of 6.9-7.1). Upon reaching the target lesion site, the balloons were immediately withdrawn. The residual amount of drug coating on the balloon surface was measured and compared with the initial concentration to calculate the drug loss rate during delivery. Alternatively, balloons with different drug coatings were used in simulated delivery, expansion, and withdrawal within isolated blood vessels modeled as pulmonary hypertension (the vascular environment was completely identical to that of living human blood vessels; normal blood vessels had a pH of 7.35-7.45, while lesion sites had a pH of 6.9-7.1). Upon reaching the target lesion site, the balloons were immediately expanded and held for 30 seconds before being withdrawn. The residual amount of drug coating on the balloon surface was measured and compared with the initial concentration to calculate the drug release rate. Balloons with different drug coatings were placed in phosphate buffer solution (pH 7.35-7.45) for 24 hours, and then in phosphate buffer solution (pH 6.9-7.1) for 1 minute. The integrity of the coating appearance was observed. The test results are shown in Table 1.

[0055] Table 1.

[0056] Sample Name loss rate Release rate Appearance in an environment with pH 7.35-7.45 Appearance in an environment with pH 6.9-7.1 Drug Coating A 43.8%±4.1% 46.1%±3.9% Obvious detachment and dissolution Obvious detachment and dissolution Drug coating B 2.9%±1.1% 98.8%±2.4% Complete without peeling or dissolution Completely dissolved Drug coating C 35.1%±5.1% 52.6%±6.7% Obvious detachment and dissolution Obvious detachment and dissolution Based on the comparison of test results, the design of polylysine as an independent inert protective layer reduces the risk of drug burst release in non-target lesion areas and can reduce the release and detachment of the composite drug coating during intravascular delivery. Simultaneously, upon reaching the target lesion area, the inert protective layer rapidly disintegrates, significantly increasing the release rate of the composite drug coating. This demonstrates the superiority of the "decoupling design" of this invention.

[0057] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A composite drug coating for treating pulmonary hypertension, characterized in that, The outermost layer is an inert protective layer, and the inner layer is a composite drug coating, which contains gene regulatory factor components and / or drug components.

2. The composite drug coating for treating pulmonary hypertension according to claim 1, characterized in that, The inert protective layer is composed of polyamino acid polymers, including polyleucine, polyaspartic acid, polylysine, polythreonine, polycysteine, or polyglutamic acid.

3. The composite drug coating for treating pulmonary hypertension according to claim 1, characterized in that, The composite drug coating also contains one or more of the following: amlodipine, nifedipine, eprostol, treprostol, bosentan, ambrisentan, macitentan, milrinone, amrinone, sildenafil, tadalafil, furosemide, torasemide, and riociguat.

4. The composite drug coating for treating pulmonary hypertension according to claim 1, characterized in that, The gene regulatory factor components include at least two of the following: tacrolimus, cytokinin, Treg cell lyophilized powder, miR-21, miR-22, miR-29a, miR-126, nuclear factor-κB inhibitor, and antisense oligonucleotides.

5. A composite drug coating for treating pulmonary hypertension according to claim 1, characterized in that, The drug components include one or more of the following: calcium channel blockers, prostacyclin derivatives, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, diuretics, and guanylate cyclase agonists.

6. The composite drug coating for treating pulmonary hypertension according to claim 1, characterized in that, The composite drug coating is layered, with each layer separately loading the gene regulatory factor component and the drug component.

7. A composite drug coating for treating pulmonary hypertension according to claim 1, characterized in that, The gene regulatory factor component and the drug component are mixed and loaded onto the composite drug coating.

8. A composite drug coating for treating pulmonary hypertension according to claim 1, characterized in that, The content of the gene regulatory factor component is not less than 30% of the content of the composite drug coating, and the content of the drug component is not less than 10% of the content of the composite drug coating.

9. A composite drug coating for treating pulmonary hypertension according to claim 1, characterized in that, The composite drug coating and the inert protective layer are prepared by coating them sequentially.

10. The application of a composite drug coating for treating pulmonary hypertension as described in any one of claims 1 to 9 in a medical device, characterized in that, The drug coating content on the medical device ranges from 0.1 to 20.0 mg.

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