Intravascular long-lasting oil phase drug solution and liquid infusion balloon delivery

Abstract

The application discloses an oil-phase drug solution for intravascular long-term retention, which comprises an oil-phase solvent and a therapeutic drug; the oil-phase solvent is selected from one or more than two of fatty acids and phospholipids. The application also provides application of the oil-phase drug solution for intravascular long-term retention in a liquid infusion balloon, and the liquid infusion balloon is used for treating vascular diseases. The liquid infusion balloon is delivered to a vascular lesion site, the liquid infusion balloon is inflated, and the oil-phase drug solution is squeezed out, so that the oil-phase drug solution can be retained in the blood vessel for a long time and dissolve cholesterol crystals in the blood vessel, thereby removing atherosclerotic plaques. The application can solve the problems of low drug coating delivery efficiency, great damage to blood vessels, difficult long-term treatment and the like of the current balloon, and the problems of short drug retention and short activity maintenance time of the existing liquid infusion balloon.

Description

Technical Field

[0001] This invention relates to the field of medical device technology, specifically to a long-lasting intravascular oil-phase drug solution and its delivery method based on a liquid perfusion balloon. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Cardiovascular disease is the leading cause of death and death worldwide, and percutaneous coronary angioplasty (PTCA) is currently a crucial treatment for cardiovascular diseases. The development of PTCA has gone through several stages. Initially, it involved using only a bare balloon to dilate the narrowed area to restore blood supply. However, this method was prone to acute occlusion after dilation, resulting in a high rate of re-stenosis. To address this issue, bare-metal stents (BMS) were developed to provide long-term mechanical support to the blood vessel and prevent vascular rebound. However, vascular damage caused during stent implantation can induce intimal hyperplasia, leading to restenosis. Furthermore, drug-eluting stents (DES) reduced the restenosis rate by introducing anti-proliferative drugs; however, due to the long-term retention of the stent implant, serious side effects such as late-stage thrombosis still occur.

[0004] Therefore, drug-coated balloons (DCBs) were developed that can efficiently release drugs to inhibit intimal hyperplasia without leaving permanent devices in the patient's body, ushering in a new era of "invasive, implant-free" treatment. The drug coating in a DCB mainly consists of a hydrophobic antiproliferative drug and an excipient: the drug is crystallized by the excipient and deposited on the surface of the balloon; when the balloon expands at the lesion site, the drug crystals are pierced into the blood vessel surface under pressure, thereby achieving rapid drug transfer.

[0005] The existing DCB has certain defects: (1) During intravascular delivery, a large amount of drug is detached due to mechanical flushing of the blood, resulting in a drug delivery efficiency of less than 10%, and the detached drug particles may cause thrombosis in the blood vessels; (2) The drug enters the blood vessels by puncture, which causes greater damage to the blood vessel wall. At the same time, the long-term contact between the vascular endothelium and the drug leads to delayed repair and increases the risk of late thrombosis; (3) The excipients in the current regimen have potential immunogenicity and have the risk of causing long-term chronic inflammation; (4) The currently commonly used rapamycin drug has poor lipophilicity and is difficult to maintain an effective concentration in the tissue for a long time, making it difficult to achieve long-term treatment.

[0006] Fluid-perfused balloons are currently available. Fluid-perfused balloons include single-layer balloons and multi-layer balloons. Among them, the double-layer balloon is a common type of multi-layer balloon. The two layers are an inner layer and an outer layer, with a gap between them to be filled with drug-containing liquid. When in use, the inner layer can be inflated to make the entire balloon expand and fit against the blood vessel wall. Further inflation allows the drug-containing liquid between the inner and outer layers to seep out or flow out from the surface of the outer layer. For example, patent specification CN115300767A discloses a double-layer self-infusing balloon, comprising a double-layer balloon, including an inflatable balloon and a drug-filled balloon disposed outside the inflatable balloon. The inner cavity of the drug-filled balloon communicates with a drug reservoir ring disposed proximally to the double-layer balloon. The drug reservoir ring is used to transfer the drug delivered from the proximal end. The outer surface of the drug-filled balloon is provided with dialysis holes for drug release. By adopting the double-layer balloon design, the inflation and drug infusion of the balloon can be separated independently. By placing the drug-filled balloon on the outer layer of the inflatable balloon and communicating the inner cavity of the drug-filled balloon with the drug reservoir ring proximally to the double-layer balloon, the drug can be infused into the inner cavity of the drug-filled balloon through the drug reservoir ring in the form of drug infusion, and the drug can be released through the dialysis holes on the outer surface of the drug-filled balloon, so that the drug can act directly on the lesion site.

[0007] However, currently, liquid perfusion balloons infuse aqueous solutions, making it very difficult to retain and maintain the activity of the drug. Summary of the Invention

[0008] To address the aforementioned technical problems and shortcomings in the field, this invention provides a long-lasting intravascular oil-phase drug solution and its delivery method based on a liquid-perfusion balloon, thereby solving the problems of low drug delivery efficiency, significant vascular damage, and difficulty in long-term treatment caused by current balloon-based drug coatings, as well as the short drug retention and activity maintenance time of existing liquid-perfusion balloon deliveries.

[0009] The specific technical solution is as follows:

[0010] In a first aspect, the present invention provides an oil-phase drug solution that can be retained in blood vessels for a long time, comprising an oil-phase solvent and a therapeutic drug;

[0011] The oil phase solvent is selected from one or more of fatty acids and phospholipids.

[0012] The selection of the oil phase solvent in this invention mainly considers the following factors:

[0013] 1. The oil phase solvent is immiscible with water, thus isolating it from body fluids after it is delivered into the bloodstream, thereby achieving sustained drug release.

[0014] 2. As an in vivo therapeutic drug formulation, the solvent needs to have good biocompatibility to avoid further damage to vascular tissue.

[0015] 3. Ideally, the oil phase solvent should also have anti-inflammatory capabilities, so as to synergistically work with the drug to achieve long-term regulation of chronic inflammation in blood vessels.

[0016] The oil phase solvent is preferably one or more of oleic acid, isoleic acid, linoleic acid, conjugated linoleic acid, linolenic acid, dihomo-γ-linolenic acid, caprylic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, ethyl oleate, lecithin, phosphatidylglycerol, dilauroyl phosphatidylcholine, 1-palmitoyl-2-oleoyl phosphatidylcholine, and lysophosphatidylcholine, and is further preferably one or more of linoleic acid, linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, dilauroyl phosphatidylcholine, and lecithin.

[0017] The therapeutic drugs include, but are not limited to, one or more of the following: rapamycin, octyl 4-itaconate, paclitaxel, indomethacin, colchicine, quercetin, dexamethasone, aspirin, 5-fluorouracil, monoclonal antibody drugs, DNA / RNA drugs, and inhibitors.

[0018] The oil-phase drug solution that is retained in the blood vessels for a long time, based on the total mass of the oil-phase solvent and the therapeutic drug as 100%, may have a mass percentage of 0.1% to 10%, and may further be 1% to 5%.

[0019] Secondly, the present invention provides the application of the long-lasting intravascular oil-phase drug solution described in the first aspect in a liquid perfusion balloon. The liquid perfusion balloon can be a single-layer balloon, a multi-layer balloon (e.g., a double-layer balloon), etc.

[0020] The liquid-perfusion balloon can be used to inject the oil-phase drug solution.

[0021] Preferably, the surface of the liquid infusion balloon has a microporous structure. Further, the pore size of the microporous structure is preferably 10-200 μm, such as 20 μm, 30 μm, 50 μm, 70 μm, 80 μm, etc., and more preferably 50-100 μm. The present invention selects this pore size mainly for two considerations: (1) Due to the long alkyl chain structure, the viscosity of the oil phase solution is greater than that of the aqueous phase solution, resulting in a larger surface tension that needs to be overcome when it is squeezed out in the microporous structure. Therefore, a larger pore size is required to achieve injection; (2) When the micropore size is too large, the surface tension that needs to be overcome when the liquid is squeezed out decreases significantly, causing the balloon to lose its pressure-holding ability and liquid leakage to occur at a lower pressure, making it impossible to dilate the narrowed part of the blood vessel.

[0022] The liquid perfusion balloon can be used for the treatment of vascular diseases. Specifically, the liquid perfusion balloon can be delivered to the lesion site in the blood vessel. The interior of the liquid perfusion balloon can be inflated to squeeze the oil-phase drug solution into the blood vessel. The oil-phase drug solution can remain in the blood vessel for a long time and dissolve cholesterol crystals in the blood vessel, thereby clearing atherosclerotic plaques.

[0023] In some applications, the liquid-infused balloon is a single-layer balloon.

[0024] In some applications, the liquid perfusion balloon has a two-layer structure with an inner and an outer layer, and a gap between the inner and outer layers. The long-acting oil-phase drug solution that remains in the blood vessel fills the gap. The inner layer of the liquid perfusion balloon can be inflated to expand the liquid perfusion balloon and squeeze out the long-acting oil-phase drug solution that remains in the blood vessel.

[0025] The outer surface of the liquid perfusion balloon can be provided with micropores, permeation pores, etc., to allow the oil phase drug solution to flow out and permeate.

[0026] Thirdly, the present invention provides a liquid perfusion balloon containing the long-acting intravascular oil-phase drug solution described in the first aspect. The long-acting intravascular oil-phase drug solution can be pre-infused into the liquid perfusion balloon, or it can be infused into the liquid perfusion balloon during its use within the blood vessel, or a combination of both methods can be used.

[0027] The liquid-perfusion balloon can be used to inject the oil-phase drug solution.

[0028] Preferably, the surface of the liquid infusion balloon has a microporous structure. Further, the pore size of the microporous structure is preferably 10-200 μm, such as 20 μm, 30 μm, 50 μm, 70 μm, 80 μm, etc., and more preferably 50-100 μm. The present invention selects this pore size mainly for two considerations: (1) Due to the long alkyl chain structure, the viscosity of the oil phase solution is greater than that of the aqueous phase solution, resulting in a larger surface tension that needs to be overcome when it is squeezed out in the microporous structure. Therefore, a larger pore size is required to achieve injection; (2) When the micropore size is too large, the surface tension that needs to be overcome when the liquid is squeezed out decreases significantly, causing the balloon to lose its pressure-holding ability and liquid leakage to occur at a lower pressure, making it impossible to dilate the narrowed part of the blood vessel.

[0029] In some embodiments, the liquid-infused balloon is a single-layer balloon.

[0030] In some embodiments, the liquid perfusion balloon has a two-layer structure of an inner layer and an outer layer, with a gap between the inner and outer layers. The long-acting oil-phase drug solution retained in the blood vessel fills the gap. The inner layer of the liquid perfusion balloon can be inflated to expand the liquid perfusion balloon and squeeze out the long-acting oil-phase drug solution retained in the blood vessel.

[0031] The outer surface of the liquid perfusion balloon can be provided with micropores, permeation pores, etc., to allow the oil phase drug solution to flow out and permeate.

[0032] A delivery method for a liquid-infused balloon based on the third aspect includes:

[0033] Delivering a fluid-perfusion balloon to the lesion site within the blood vessel;

[0034] Inflation causes the internal balloon to expand, allowing it to conform to the blood vessel wall;

[0035] The oil-phase drug solution is infused into the cavity of a single-layer balloon or the cavity between two-layer balloons. Pressure is applied to force the fluid out of the micropores and / or permeable pores on the surface of the balloon and directly into the blood vessel.

[0036] Compared with the prior art, the beneficial effects of this invention are as follows:

[0037] 1) The drug is delivered in the form of a homogeneous oil phase solution, which can remain stable during delivery; the balloon is injected after reaching the lesion site, and there is no loss of drug during the entire delivery process.

[0038] 2) Drug delivery via liquid injection avoids mechanical damage to the vascular endothelium caused by drug crystal penetration, and the injected drug penetrates deep into the tissue, thus enabling the vascular endothelial homeostasis to recover rapidly after treatment.

[0039] 3) Oil-phase solvents such as linolenic acid are endogenous fatty acids in the human body, which have anti-inflammatory effects and can reduce inflammation in lesions.

[0040] 4) Oil phase solvents can avoid direct contact between drugs and body fluids, enabling long-term retention and sustained release of drugs at the lesion site. Attached Figure Description

[0041] Figure 1 The graph shows the amount of drug retained in the blood vessels of Example 1 and Comparative Example 1 after 3 days, 1 week and 4 weeks of delivery.

[0042] Figure 2 The graph shows the residual cholesterol levels in the blood vessels of Example 1 and Comparative Example 1 in an atherosclerosis model after 3 days, 1 week, and 4 weeks of delivery.

[0043] Figure 3 These are vascular slices of Example 1 and Comparative Example 2 after intravascular drug delivery. Detailed Implementation

[0044] Terminology explanation: "In the blood vessel" refers to the blood vessel wall, especially the intima and media layers, which are 10 to 500 micrometers thick.

[0045] The present invention will be further described below with reference to the accompanying drawings and specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention.

[0046] Unless otherwise specified, the operating methods in the following examples are generally performed under conventional conditions or as recommended by the manufacturer.

[0047] The bilayer balloons used in the following examples are liquid perfusion balloons with an inner and outer layer structure. There is a gap between the inner and outer layers for filling with drug solution. The outer layer surface has micropores. When in use, the inner layer of the liquid perfusion balloon can be inflated to expand the liquid perfusion balloon and squeeze out the filled drug solution.

[0048] The migration and action process of the oil-phase drug solution of the present invention are illustrated as follows: squeezed to the outside of the balloon → released to the vascular lumen wall → rapidly and efficiently penetrated into the vascular wall tissue (especially at the location of plaque) for a long time → acted on the target site to dissolve cholesterol crystals.

[0049] Example 1:

[0050] The antiproliferative drug rapamycin was dissolved in the oily solvent linolenic acid to obtain an oil-phase drug solution with a concentration of 10 mg / mL. The fluid perfusion balloon used was a double-layered balloon with a surface pore size of 50 μm. The fluid perfusion balloon was delivered into the blood vessel and pressurized to 8 atm to ensure close contact with the vessel wall. The oil-phase drug solution was then infused into the gap between the two layers of the balloon, and the pressure was increased to 10 atm. The drug was expelled from the micropores on the surface of the balloon into the blood vessel, with a delivery volume of 100 μL.

[0051] Theoretical calculations show that the drug delivery rate via the balloon can reach 10 μg / mm. 2 This is higher than the drug loading capacity of existing drug-coated balloons (2~3 μg / mm). 2 After the blood vessels were removed from the balloon and homogenized, the drug delivery was tested using HPLC. The drug delivery efficiency was found to be as high as 60%, which is much higher than the 10% drug delivery efficiency of traditional drug-coated balloons.

[0052] Comparative Example 1:

[0053] The antiproliferative drug rapamycin was dissolved in butyric acid to obtain a drug solution with a concentration of 10 mg / mL. The fluid perfusion balloon used was a double-layered balloon with a surface pore size of 50 μm. The fluid perfusion balloon was delivered into the blood vessel, and the balloon was inflated to a pressure of 8 atm to ensure close contact with the vessel wall. The drug solution was then infused into the gap between the two layers of the balloon, and the pressure was increased to 10 atm. The drug was expelled from the micropores on the surface of the balloon into the blood vessel, with a delivery volume of 100 μL.

[0054] Blood vessels were removed after 3 days, 1 week, and 4 weeks of delivery in Example 1 and Comparative Example 1. After homogenization, the drug retention was tested using HPLC, and the results are as follows: Figure 1 As shown, when using linolenic acid, a solvent that is immiscible with water, more than 50% of the drug remains in the bloodstream after 4 weeks of drug delivery, achieving long-acting sustained release. However, when using butyric acid, a more hydrophilic solvent, approximately 40% of the drug is lost one day after delivery, about 80% after one week, and almost no drug remains after 4 weeks.

[0055] In an atherosclerosis model, blood vessels from the control group, Example 1, and Comparative Example 1 were harvested after 3 days, 1 week, and 4 weeks of passage. After homogenization, the cholesterol content in the blood vessels was measured using HPLC. The results are as follows: Figure 2 As shown, when linolenic acid, which can effectively dissolve cholesterol, was used, more than 80% of the cholesterol was cleared after 4 weeks of drug delivery. However, when butyric acid, which cannot effectively dissolve cholesterol, was used as a solvent, the cholesterol clearance rate was still less than 30% after 4 weeks.

[0056] Comparative Example 2:

[0057] The antiproliferative drug rapamycin was dissolved in linolenic acid to obtain a drug solution with a concentration of 10 mg / mL. The fluid perfusion balloon used was a double-layered balloon with a surface pore size of 5 μm. The fluid perfusion balloon was delivered into the blood vessel, and the balloon was inflated to a pressure of 8 atm to ensure it adhered tightly to the vessel wall. The drug solution was then infused into the gap between the two layers of the balloon, and the pressure was increased to 10 atm.

[0058] In Example 1 and Comparative Example 2, frozen section analysis was performed after delivery using Nile Red as a model drug. The results are as follows: Figure 3 As shown in Example 1, the drug is mainly distributed 10-100 μm below the vascular endothelium, enabling in situ treatment of smooth muscle and inflammatory cells. In contrast, the drug in Comparative Example 2 failed to be delivered into the blood vessels, demonstrating the influence of the pore size of the fluid-perfusion balloon surface on its fluid perfusion capacity.

[0059] Example 2:

[0060] Octyl 4-itaconate was dissolved in the oily solvent docosahexaenoic acid (DHA) to obtain an oil-phase drug solution with a concentration of 20 mg / mL. The liquid perfusion balloon used was a double-layered balloon with a surface pore size of 30 μm. The liquid perfusion balloon was delivered into the blood vessel and pressurized to 10 atm to ensure close contact with the vessel wall. The oil-phase drug solution was then infused into the gap between the two layers of the balloon, and the pressure was increased to 12 atm. The drug was expelled from the micropores on the surface of the balloon into the blood vessel, with a delivery volume of 50 μL.

[0061] An evaluation using an atherosclerosis model revealed that, after 4 weeks of administration, 42% of the drug 4-itaconic octyl ester remained in the blood vessels, and the cholesterol clearance rate in the blood vessels reached 75%.

[0062] Example 3:

[0063] Dexamethasone was dissolved in the oily solvent eicosapentaenoic acid (EPA) to obtain an oil-phase drug solution with a concentration of 5 mg / mL. The liquid perfusion balloon used was a single-layer balloon with a surface pore size of 80 μm. The liquid perfusion balloon was delivered into the blood vessel, and the oil-phase liquid was directly injected into the balloon. The pressure was increased to 10 atm, and the drug was extruded from the micropores on the surface of the liquid perfusion balloon and directly entered the blood vessel. The drug delivery volume was 100 μL.

[0064] An evaluation using an atherosclerosis model revealed that, after 4 weeks of administration, 45% of the dexamethasone remained in the blood vessels, and 80% of the cholesterol was cleared from the blood vessels.

[0065] Example 4:

[0066] Quercetin was dissolved in the oily solvent dilauroyl phosphatidylcholine to obtain an oil-phase drug solution with a concentration of 20 mg / mL. The fluid perfusion balloon used was a single-layer balloon with a surface pore size of 20 μm. The fluid perfusion balloon was delivered into the blood vessel, and the oil-phase liquid was directly injected into the balloon. The pressure was increased to 10 atm, and the drug was extruded from the micropores on the surface of the fluid perfusion balloon and directly entered the blood vessel. The drug delivery volume was 50 μL.

[0067] An evaluation using an atherosclerosis model revealed that, after 4 weeks of administration, quercetin retention in blood vessels was 38%, and cholesterol clearance in blood vessels reached 77%.

[0068] Example 5:

[0069] miR-22 was dissolved in the oily solvent lecithin to obtain an oil-phase drug solution with a concentration of 10 nmol / mL. The liquid perfusion balloon used was a double-layered balloon with a surface pore size of 70 μm. The liquid perfusion balloon was delivered into the blood vessel and pressurized to 8 atm to ensure close contact with the vessel wall. The oil-phase drug solution was then infused into the gap between the two layers of the balloon, and the pressure was increased to 10 atm. The drug was expelled from the micropores on the surface of the balloon into the blood vessel, with a delivery volume of 100 μL.

[0070] An evaluation using an atherosclerosis model revealed that, after 4 weeks of administration, 25% of the miR-22 remained in the blood vessels, and 73% of the cholesterol was cleared from the blood vessels.

[0071] Furthermore, it should be understood that after reading the above description of the present invention, those skilled in the art can make various alterations or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. Use of an intravascular long-retention oil phase drug solution in the manufacture of a liquid infused balloon, characterized in that, The intravascular long-acting retained oil-phase drug solution is composed of an oil-phase solvent and a therapeutic drug, and the mass percentage of the therapeutic drug in the total mass of the oil-phase solvent and the therapeutic drug is 0.1%-10%; The intravascular long-acting retained oil-phase drug solution is composed of linolenic acid and rapamycin, or composed of docosahexaenoic acid and 4-octyl icotinic acid, or composed of eicosapentaenoic acid and dexamethasone, or composed of dilaurylphosphatidylcholine and quercetin, or composed of lecithin and miR-22; The surface of the liquid perfusion balloon has a microporous structure, and the pore size of the microporous structure is 10-200 μm; The liquid perfusion balloon is used for treating vascular diseases, is delivered to a vascular lesion site, is inflated, and extrudes the oil-phase drug solution in the balloon to the vascular wall, so that the oil-phase drug solution can be long-acting retained in the blood vessel and dissolve cholesterol crystals in the blood vessel to remove atherosclerotic plaques.

2. Use according to claim 1, characterized in that, The mass percentage of the therapeutic drug in the total mass of the oil-phase solvent and the therapeutic drug is 1%-5%.

3. Use according to claim 1, characterized in that, The liquid perfusion balloon is a single-layer balloon; or The liquid perfusion balloon has a two-layer structure of an inner layer and an outer layer, and a gap is left between the inner layer and the outer layer, the intravascular long-acting retained oil-phase drug solution is filled in the gap, and the inner layer of the liquid perfusion balloon is inflatable to expand the liquid perfusion balloon and extrude the intravascular long-acting retained oil-phase drug solution. The mass percentage of the therapeutic drug in the total mass of the oil-phase solvent and the therapeutic drug is 1%-5%. The liquid perfusion balloon is a single-layer balloon; or The liquid perfusion balloon has a two-layer structure of an inner layer and an outer layer, and a gap is left between the inner layer and the outer layer, the intravascular long-acting retained oil-phase drug solution is filled in the gap, and the inner layer of the liquid perfusion balloon is inflatable to expand the liquid perfusion balloon and extrude the intravascular long-acting retained oil-phase drug solution.

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