Drug delivery device

Abstract

The invention relates to the technical field of medical equipment, in particular to a drug delivery device. The invention provides a drug delivery device. The drug delivery device comprises an outer tube, an inner tube and a balloon, wherein the inner tube and the balloon are arranged in the outer tube; a pipe cavity is formed between the outer pipe and the inner pipe; the outer tube and the inner tube penetrate through the whole balloon in the axial direction, a plurality of holes are formed in the portion, in the balloon, of the outer tube in the axial direction, a plurality of micropores are formed in the surface of the balloon, and the micropores penetrate through the wall of the balloon. The technical problem that in the prior art, the far-end liquid outlet amount is small is solved.

Description

[Technical field]

[0001] The present invention relates to the technical field of medical equipment, and in particular to a drug delivery device. [Background technology]

[0002] Atherosclerosis (AS) is the main cause of coronary heart disease, cerebral infarction, and peripheral arterial vascular disease. For example, intracranial atherosclerotic disease (ICAD) is the main cause of ischemic stroke, accounting for about 17-35% of ischemic cerebrovascular events in Asians. Peripheral arterial disease (PAD) is a global health burden that affects 20% of the population over 80 years old, and has a trend of becoming younger, bringing heavy health and economic burdens to people and society.

[0003] Percutaneous angioplasty and percutaneous endovascular stenting are innovative technologies for the treatment of vascular stenosis, which have greatly improved the treatment effect of patients with atherosclerotic diseases. However, drug-eluting stents are still facing risks such as in-stent restenosis and late stent thrombosis. In addition, due to their rigid metal structure and easy fracture, drug-eluting stents are still not ideal for the treatment of tortuous intracranial blood vessels and lower limb blood vessels.

[0004] In order to solve the drawbacks of drug-eluting stents, people invented the "intervention without implantation" drug balloon, which is used to treat atherosclerotic diseases. Drug balloon is based on balloon angioplasty, with anti-proliferative drugs coated on the balloon surface, which are delivered to the target lesion site through a balloon catheter. After the balloon is expanded, the anti-proliferative drugs are transferred to the blood vessel wall, thereby permanently inhibiting the proliferation of vascular smooth muscle, reducing vascular stenosis, and achieving the therapeutic effect. However, the current drug balloon still faces the following problems: 1) The drug coating has poor firmness, and a large amount of drug is lost during the delivery process. Existing studies have shown that 80% of the drugs in drug-eluting balloons currently on the market are lost during the delivery process (JAm Coll Cardiol Intv. 2020, 13 (24) 2840–2849.); a large amount of drugs have fallen off and lost before reaching the lesion site. For tortuous lesions and diffuse long lesions, it is difficult to deliver and transfer an effective amount of drugs, resulting in poor treatment effects; 2) The drug coating produces a large number of particles during the delivery and expansion process, and the size of the shed particles is as high as 300 μm or more, which can easily cause vascular embolism and "slow blood flow" and "no reflow" phenomena. "Slow blood flow" and "no reflow" phenomena are related to poor clinical effects, and can easily cause embolic stroke in intracranial arteries with thinner blood vessels, and increase the amputation rate of lower limb arteries, seriously affecting the treatment effect; 3) The balloon is relatively hard, and the friction resistance of the drug coating is large. For tortuous blood vessels, it is difficult for the drug balloon to be delivered to the lesion site, resulting in treatment failure;

[0005] In addition, atherosclerotic diseases are often accompanied by severe calcification lesions, especially infrapopliteal artery lesions, with the proportion of medial calcification lesions as high as 72%. Severe calcification lesions hinder the transfer of drugs on drug-coated balloons and retention in the vascular wall. The drugs are quickly washed away by the blood flow, thus affecting the anti-proliferative efficacy of the drugs.

[0006] The Chinese utility model patent with announcement number CN215386905U discloses a shock wave assisted drug infusion balloon catheter and medical equipment, which includes: an outer tube; a balloon connected to one end of the outer tube, and a liquid outlet hole is arranged on the side wall of the balloon; an inner tube is inserted into the outer tube and the balloon in sequence, and the inner tube passes through the balloon; the gap between the inner tube and the outer tube forms a drug delivery channel; a shock wave generator is located in the balloon and is arranged on the outer wall of the inner tube. The shock wave assisted drug infusion balloon catheter has a plurality of liquid outlet holes on the surface of the balloon, and a drug delivery channel is formed through the gap between the inner tube and the outer tube, so that the external drug can reach the balloon with the help of the drug delivery channel, and then enter the blood vessel through the infusion hole on the surface of the balloon. The patent infuses through the gap between the inner tube and the outer tube. Since the balloon is long, the amount of liquid discharged at the distal end will be relatively reduced or even no liquid will be discharged through this method, affecting the distal treatment. [Summary of the invention]

[0007] The purpose of the present invention is to overcome the above-mentioned deficiencies of the prior art and to provide a drug delivery device, which aims to solve the technical problem of low distal liquid output in the prior art.

[0008] To achieve the above-mentioned purpose, the present invention proposes a drug delivery device, comprising an outer tube, an inner tube arranged in the outer tube and a balloon; a lumen is provided between the outer tube and the inner tube; the outer tube and the inner tube both axially penetrate the entire balloon, the outer tube is axially provided with a plurality of holes in the part inside the balloon, a plurality of micropores are provided on the surface of the balloon, and the micropores penetrate the wall of the balloon.

[0009] Preferably, the opening of the hole is larger than the opening of the micropore, and the aperture ratio of the hole to the micropore is 1-120.

[0010] Preferably, the holes are evenly distributed on the outer tube within the balloon.

[0011] Preferably, the holes are asymmetrically distributed on the outer tube in the balloon, and the number of holes in the middle position of the holes is greater than that at the distal end and the proximal end.

[0012] Preferably, the pore size is 1um-1000um, and the pore size of the micropore is 1um-100um.

[0013] Preferably, a filter membrane is provided on the hole, and the pore size of the filter membrane is smaller than the pore size of the micropore.

[0014] Preferably, the micropore density at the distal end of the balloon is greater than the micropore density at the proximal end of the balloon and / or the micropore diameter at the distal end of the balloon is greater than the micropore diameter at the proximal end of the balloon.

[0015] Preferably, the ratio of the micropore density at the distal end of the balloon to the micropore density at the proximal end of the balloon is 1-10; the ratio of the micropore diameter at the distal end of the balloon to the micropore diameter at the proximal end of the balloon is 1-8.

[0016] Preferably, it further comprises a tube seat, on which a first interface and a second interface are provided, wherein the second interface is connected to the tube cavity for conveying liquid medicine; and the first interface is connected to the inner tube.

[0017] Preferably, the drug solution is an active drug dissolved or dispersed in a dispersant, and the dispersant can be selected from a mixture of any one or more of purified water, physiological saline, and contrast agent; the active drug can be a pure drug or nano drug particles formed with other ingredients, and the other ingredients include micelles, liposomes, nanocrystals, dendritic molecular carriers, polymer nanoparticles or one or more; the active drug is rapamycin or its derivatives, ABT-578, zotarolimus, everolimus, umefloxacin, temsirolimus, tacrolimus, pimecrolimus, nitric oxide synthase, C3 exoenzyme, RhoA inhibitor, tubulusin, A3 agonist, C One or more of B2 agonists, 17-AAG, Hsp90 antagonists, tyrosine phosphorylation inhibitors, cathepsin S inhibitors, paclitaxel or its derivatives, taxol, docetaxel, corticosteroids, glucocorticoids, dexamethasone, ceramide, dimethylsphingosine, ether-linked diglycerides, ether-linked phosphatidic acid, dihydrosphingosine, estrogen, tacrolimus, tacrolimus analogs, actinomycin D, prostaglandins, vitamin A, probucol, batimastat, statins, trapidil, mitomycin C and cytochalasin B, cytotoxic substances, ethanol, chemotherapeutic agents, sclerosing agents, gene therapy agents, anti-angiogenic agents, and antibodies.

[0018] Compared with the prior art, the drug delivery device provided by the present invention has the following beneficial effects:

[0019] 1. By passing both the inner tube and the outer tube through the balloon, and opening a hole in the outer tube, the liquid is discharged through the lumen. Since the lumen infusion diameter is small, it is easy to generate a large infusion pressure, which is easier to fill the entire lumen, and then enter the balloon from the hole, so that the liquid medicine entering the balloon has a wider distribution range. Compared with the prior art method of directly injecting liquid medicine into the balloon, it avoids the situation that when there are many micropores, it is easy to cause a small amount of liquid medicine to be discharged from the distal end or even no liquid, resulting in poor treatment effect.

[0020] 2. Since the diameter of the hole is larger than that of the micropore, the speed of the drug solution entering the balloon from the lumen is relatively fast, which will increase the pressure inside the balloon. The pressure of the drug solution in the balloon entering the lesion from the micropore becomes greater, and then through high-pressure perfusion, it is easier for the drug solution to break through the calcification and plaque obstacles at the lesion, and efficiently transfer the drug to the blood vessel wall or the inner wall of the cavity.

[0021] 3. The liquid concentration at different locations can be better controlled by adjusting the location and quantity of holes and micropores, as well as the density at different locations, so as to better meet the actual needs of different dosages at different locations.

[0022] The features and advantages of the present invention will be described in detail through embodiments in conjunction with the accompanying drawings.

Brief Description of the Drawings

[0023] Figure 1 It is a schematic structural diagram of a drug delivery device according to the first embodiment of the present invention.

[0024] Figure 2 It is a schematic diagram of the structure of the drug delivery device with different micropore distribution densities according to the second embodiment of the present invention.

[0025] Figure 3 It is a schematic diagram of the structure in which a filter membrane is added to the hole of the drug delivery device of Example 3.

[0026] Figure 4 It is a structural schematic diagram of the distribution positions of the holes in the drug delivery device of the fourth embodiment.

[0027] In the figure: 1, first interface; 2, second interface; 3, tube seat; 4, outer tube; 5, inner tube; 6, tube cavity; 7, balloon; 8, micropore; 10, hole. [Specific implementation method]

[0028] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below through the accompanying drawings and embodiments. However, it should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the scope of the present invention. In addition, in the following description, the description of known structures and technologies is omitted to avoid unnecessary confusion of the concept of the present invention.

[0029] In the description of the present invention, it should be noted that when an element is referred to as being "fixed to" or "disposed on" another element, it may be directly on the other element or indirectly on the other element. When an element is referred to as being "connected to" another element, it may be directly connected to the other element or indirectly connected to the other element.

[0030] In the description of the present invention, it should be noted that the terms "center", "length", "width", "thickness", "up", "down", "front", "back", "left", "right", "vertical", "horizontal", "top", "bottom", "inside", "outside" and the like indicate positions or positional relationships based on the positions or positional relationships shown in the accompanying drawings, or the positions or positional relationships in which the invention product is usually placed when in use, and are only for the convenience of describing the present invention and simplifying the description, rather than indicating or implying that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and therefore cannot be understood as limiting the present invention. In addition, the terms "first", "second", "third" and the like are only used to distinguish descriptions, and cannot be understood as indicating or implying relative importance. Thus, the features defined as "first" and "second" may explicitly or implicitly include one or more of the features. In the description of the present invention, "multiple" means two or more, unless otherwise clearly and specifically defined. "Several" means one or more, unless otherwise clearly and specifically defined.

[0031] In the description of the present invention, it is also necessary to explain that, unless otherwise clearly specified and limited, the terms "set", "install", "connect", and "connect" should be understood in a broad sense, for example, it can be a fixed connection, a detachable connection, or an integral connection; it can be a mechanical connection or an electrical connection; it can be a direct connection, or it can be indirectly connected through an intermediate medium, or it can be the internal communication of two elements. For ordinary technicians in this field, the specific meanings of the above terms in the present invention can be understood according to specific circumstances.

[0032] Embodiments of the present disclosure are now described in detail with reference to the accompanying drawings. As used herein, the term "clinician" refers to a doctor, surgeon, nurse, or any other care provider, and may include auxiliary personnel. The term "proximal end" will refer to the portion of the device or its components that is closer to the clinician, and the term "distal end" will refer to the portion of the device or its components that is farther away from the clinician.

[0033] Embodiment 1:

[0034] See also Figure 1The embodiment of the present invention provides a drug delivery device, comprising an outer tube 4, an inner tube 5 disposed inside the outer tube 4, and a balloon 7. A lumen 6 is provided between the outer tube 4 and the inner tube 5. The outer tube 4 and the inner tube 5 both penetrate the entire balloon 7 axially, the outer tube 4 is provided with a plurality of holes 10 axially in the portion inside the balloon 7, and a plurality of micropores 8 are provided on the surface of the balloon 7, and the micropores 8 penetrate the wall of the balloon 7.

[0035] Specifically, the liquid medicine is transported along the lumen 6 and enters the balloon 7 along the hole 10. Since the infusion diameter of the lumen 6 is small, it is easy to generate a large infusion pressure, which is easy to fill the entire lumen 6 and then enter the balloon 7 from the hole 10, so that the liquid medicine entering the balloon 7 has a wider distribution range. If the liquid is directly injected into the balloon 7, the amount of liquid medicine in the distal balloon will be small or even zero, affecting the treatment effect.

[0036] Peripheral lesions, especially below-knee lesions, are long, and the longest vascular lesions can reach more than 200 mm. Currently, perfusion balloons are mostly designed based on the anatomical structure of coronary vessels, and the balloon length is short, usually not exceeding 30 mm. For long lesions, when the balloon length is too long, the perfusion liquid flows from the proximal end of the catheter to the distal end of the catheter, resulting in uneven liquid discharge from the micropores on the balloon surface, and it is very easy for the micropores at the distal end of the balloon to not discharge liquid. The product of the present invention can better treat lesions in blood vessels without causing the distal end to not discharge liquid.

[0037] In an optional embodiment, the liquid medicine is an active drug dissolved or dispersed in a dispersant, and the dispersant can be selected from a mixture of any one or more of purified water, physiological saline, and contrast agent. The active drug can be a pure drug or nano drug particles formed with other ingredients, and the nano drug particles include micelles, liposomes, nanocrystals, dendritic molecular carriers, polymer nanoparticles, etc. The active drug is rapamycin or its derivatives, ABT-578, zotarolimus, everolimus, biolimusA9, deforolimus (also known as rapamycin-42 (dimethyl hypophosphite) (ridaforolimus)), temsirolimus, tacrolimus, pimcrolimus, nitric oxide synthase, C3 exoenzyme, RhoA inhibitor, tubulusin, A3 agonist, CB2 agonist, 17-AAG, Hsp90 antagonist, tyrosine phosphorylation inhibitor (tyrphostins), cathepsin S inhibitor, paclitaxel or its derivatives One or more of a biologic, paclitaxel, docetaxel, corticosteroids, glucocorticoids, dexamethasone, ceramide, dimethylsphingosine, ether-linked diglycerides, ether-linked phosphatidic acid, sphinganines, estrogens, taxol, taxol analogs, actinomycin D, prostaglandins, vitamin A, probucol, batimastat, statins, trapidil, mitomycin C and cytochalasin B, cytotoxic substances, ethanol, chemotherapeutic agents, sclerosing agents, gene therapy agents, antiangiogenic agents, antibodies, or any other agent considered to be effective in the treatment of tumors.

[0038] The target tissue of the drug delivery device of the present invention is positioned in a body cavity. The body cavity can be a vascular cavity or a lesion area of ​​a non-vascular cavity such as an artery, vein, tear duct, airway, prostate, nostril, sinus, ear canal, bile duct, urethra, etc. of a patient. The drug delivery device of the present invention is also applicable to cancers at other body cavities, and delivers therapeutic agents from the outside of the tumor to the tumor. For example, it has clinical applications in the treatment of oral, nasal, pharyngeal, lung, esophageal, stomach, intestine, colon, pancreas, rectum, cervix, uterus and prostate cancer.

[0039] Referring to Fig. 1, in an optional embodiment, a tube base 3 is further included, and a first interface 1 and a second interface 2 are provided on the tube base 3. The second interface 2 is connected to the tube cavity 6 for conveying liquid medicine, and the liquid medicine enters the tube cavity 6 through the second interface 2. The first interface 1 is connected to the inner tube 5, and the guide wire enters the inner tube 5 from the first interface 1 to guide the balloon 7 into the vascular cavity or non-vascular cavity of the patient's artery, vein, lacrimal duct, airway, nasal esophagus, bile duct, urethra and other lesions.

[0040] See also Figure 1 In an optional embodiment, the opening of the hole 10 is larger than the opening of the micropore 8, and the aperture ratio of the hole 10 to the micropore 8 is 1-120. The aperture of the hole 10 is 1um-1000um, and the aperture of the micropore 8 is 1um-100um.

[0041] Furthermore, the pore 10 preferably has a diameter of 100 μm-800 μm.

[0042] Hole 10 has a larger liquid outflow, so that the pressure of the balloon 7 becomes larger when the drug is discharged from the micropore 8, and the drug can be ejected from the micropore 8. The drug is evenly transferred to the lesion site to avoid toxicity caused by excessive local drug concentration in the lesion or insufficient treatment caused by geographical loss of the lesion. The microporous perfusion balloon is a common PTCA balloon with micropores on the surface. The anti-proliferative drug solution is transferred to the blood vessel wall by pressurization. The high-pressure injection can break through the obstacles of plaques and partial calcified lesions at the lesion site. Compared with the drug-coated balloon, the drug transfer efficiency is improved, and there is no drug delivery loss and the generation of drug particles, which reduces distal vascular embolism and systemic toxicity.

[0043] Embodiment 2:

[0044] On the basis of the first embodiment, the uniformity of the liquid outflow from the micropores can be further improved by adjusting the distribution of the micropores 8 on the surface of the balloon 7, so that the drug can evenly cover the lesion, avoiding toxicity caused by excessive drug concentration in the lesion or insufficient treatment caused by geographical loss of the lesion. Although the pressure change of the lumen 6 is small, the liquid outflow from the holes 10 at various locations will still change after the length becomes longer. By changing the density and / or pore size of the micropores 8, the liquid outflow from various locations can be made more uniform.

[0045] See also Figure 2 In an optional embodiment, the density of the micropores 8 at the distal end of the balloon 7 is greater than the density of the micropores 8 at the proximal end of the balloon 7 and / or the pore size of the micropores 8 at the distal end of the balloon 7 is greater than the pore size of the micropores 8 at the proximal end of the balloon 7. The liquid output is relatively large in places with high density or large pore size, which can make up for the disadvantage of small amount of medicine in the balloon 7 at the distal end.

[0046] See also Figure 2In an optional embodiment, the ratio of the density of the micropores 8 at the distal end of the balloon 7 to the density of the micropores 8 at the proximal end of the balloon 7 is 1-10. The ratio of the pore size of the micropores 8 at the distal end of the balloon 7 to the pore size of the micropores 8 at the proximal end of the balloon 7 is 1-8.

[0047] Embodiment three:

[0048] In the first and second embodiments, the larger particles (dust or drug crystals) in the lumen 6 enter the balloon 7 and then enter the blood vessel or cavity, causing embolism of the blood vessel or cavity. This problem can be solved by:

[0049] See also Figure 3 In an optional embodiment, a filter membrane is provided on the hole 10, the pore size of the filter membrane is smaller than the pore size of the micropore 8, and the filter membrane blocks large particles.

[0050] Embodiment 4:

[0051] Known or expected plaque structures, for example, some vascular plaque lesions are thicker in the middle than near the end and the distal end. Based on Examples 1-3, a balloon 7 can be manufactured that sprays liquid more forcefully and / or in a larger amount near the middle. The specific structure is as follows:

[0052] See also Figure 4 In an optional embodiment, the holes 10 are asymmetrically distributed on the outer tube 4 in the balloon 7, and the number of holes in the middle of the holes 10 is greater than that in the distal and proximal ends. It can be predicted that the liquid injection flow rate and / or flow velocity of the micropores 8 in the middle of the balloon 7 is larger, which can better treat the middle position of the plaque lesion.

[0053] For some plaque lesions that are relatively uniform, it is also necessary to ensure that the amount of drug is uniform everywhere. Figure 1 In an optional embodiment, the holes 10 are evenly distributed on the outer tube 4 in the balloon 7. Preferably, there are three holes 10, one at the distal end, one at the proximal end, and one at the middle position. Since the inner diameter of the lumen 6 is small, the pressure difference at each location is small, and the liquid medicine coming out is relatively uniform. Thus, the holes 10 can make the liquid medicine entering each location of the balloon 7 sprayed more evenly.

[0054] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A drug delivery device, comprising an outer tube (4), an inner tube (5) arranged inside the outer tube (4) and a balloon (7); a lumen (6) is provided between the outer tube (4) and the inner tube (5); characterized in that: The outer tube (4) and the inner tube (5) both penetrate the entire balloon (7) in the axial direction; a plurality of holes (10) are axially provided on the portion of the outer tube (4) inside the balloon (7); a plurality of micropores (8) are provided on the surface of the balloon (7); and the micropores (8) penetrate the wall of the balloon (7).

2. A drug delivery device according to claim 1, characterized in that: The opening of the hole (10) is larger than the opening of the micropore (8), and the aperture ratio of the hole (10) to the micropore (8) is 1-120.

3. A drug delivery device according to claim 1, characterized in that: The holes (10) are evenly distributed on the outer tube (4) inside the balloon (7).

4. A drug delivery device according to claim 1, characterized in that: The holes (10) are asymmetrically distributed on the outer tube (4) inside the balloon (7), and the number of holes at the middle position of the holes (10) is greater than that at the distal end and the proximal end.

5. A drug delivery device according to claim 1, characterized in that: The pore (10) has a diameter of 1 um to 1000 um, and the micropore (8) has a diameter of 1 um to 100 um.

6. A drug delivery device according to claim 1, characterized in that: A filter membrane is provided on the hole (10), and the pore size of the filter membrane is smaller than the pore size of the micropore (8).

7. A drug delivery device according to claim 1, characterized in that: The density of the micropores (8) at the distal end of the balloon (7) is greater than the density of the micropores (8) at the proximal end of the balloon (7) and / or the pore size of the micropores (8) at the distal end of the balloon (7) is greater than the pore size of the micropores (8) at the proximal end of the balloon (7).

8. A drug delivery device according to claim 7, characterized in that: The ratio of the density of the micropores (8) at the distal end of the balloon (7) to the density of the micropores (8) at the proximal end of the balloon (7) is 1-10; the ratio of the pore size of the micropores (8) at the distal end of the balloon (7) to the pore size of the micropores (8) at the proximal end of the balloon (7) is 1-8.

9. A drug delivery device according to claim 1, characterized in that: It also comprises a tube seat (3), on which a first interface (1) and a second interface (2) are provided, wherein the second interface (2) is connected to the tube cavity (6) for conveying liquid medicine; and the first interface (1) is connected to the inner tube (5).

10. A drug delivery device according to claim 9, characterized in that: The drug solution is an active drug dissolved or dispersed in a dispersant, and the dispersant can be selected from a mixture of any one or more of purified water, physiological saline, and contrast agent; the active drug can be a pure drug or nano drug particles formed with other ingredients, and the nano drug particles include micelles, liposomes, nanocrystals, dendritic molecular carriers, and polymer nanoparticles; the active drug is rapamycin or its derivatives, ABT-578, zotarolimus, everolimus, umefloxacin, dafosfolimus, temsirolimus, tacrolimus, pimecrolimus, nitric oxide synthase, C3 exoenzyme, RhoA inhibitor, tubulusin, A3 agonist, CB2 agonist , 17-AAG, Hsp90 antagonists, tyrosine phosphorylation inhibitors, cathepsin S inhibitors, paclitaxel or its derivatives, taxol, docetaxel, corticosteroids, glucocorticoids, dexamethasone, ceramide, dimethylsphingosine, ether-linked diglycerides, ether-linked phosphatidic acid, dihydrosphingosine, estrogen, tacrolimus, tacrolimus analogs, actinomycin D, prostaglandins, vitamin A, probucol, batimastat, statins, trapidil, mitomycin C and cytochalasin B, cytotoxic substances, ethanol, chemotherapeutic agents, sclerosing agents, gene therapy agents, anti-angiogenic agents, antibodies, one or more.

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