CN116616969A - Drug delivery device and preparation method - Google Patents
Drug delivery device and preparation method Download PDFInfo
- Publication number
- CN116616969A CN116616969A CN202310628537.1A CN202310628537A CN116616969A CN 116616969 A CN116616969 A CN 116616969A CN 202310628537 A CN202310628537 A CN 202310628537A CN 116616969 A CN116616969 A CN 116616969A
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- Prior art keywords
- drug
- alcohol
- acid
- delivery device
- phase change
- Prior art date
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- 238000002360 preparation method Methods 0.000 title abstract description 11
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- 230000008093 supporting effect Effects 0.000 claims abstract description 30
- 239000012782 phase change material Substances 0.000 claims description 50
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Classifications
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- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
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- A—HUMAN NECESSITIES
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- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/848—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents having means for fixation to the vessel wall, e.g. barbs
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- A—HUMAN NECESSITIES
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- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/95—Instruments specially adapted for placement or removal of stents or stent-grafts
- A61F2/958—Inflatable balloons for placing stents or stent-grafts
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/10—Balloon catheters
- A61M25/1002—Balloon catheters characterised by balloon shape
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/10—Balloon catheters
- A61M25/104—Balloon catheters used for angioplasty
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
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- A—HUMAN NECESSITIES
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- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/95—Instruments specially adapted for placement or removal of stents or stent-grafts
- A61F2/958—Inflatable balloons for placing stents or stent-grafts
- A61F2002/9583—Means for holding the stent on the balloon, e.g. using protrusions, adhesives or an outer sleeve
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/10—Balloon catheters
- A61M2025/1043—Balloon catheters with special features or adapted for special applications
- A61M2025/105—Balloon catheters with special features or adapted for special applications having a balloon suitable for drug delivery, e.g. by using holes for delivery, drug coating or membranes
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- A—HUMAN NECESSITIES
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- A61M25/00—Catheters; Hollow probes
- A61M25/10—Balloon catheters
- A61M2025/1043—Balloon catheters with special features or adapted for special applications
- A61M2025/1075—Balloon catheters with special features or adapted for special applications having a balloon composed of several layers, e.g. by coating or embedding
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- A61M25/10—Balloon catheters
- A61M2025/1043—Balloon catheters with special features or adapted for special applications
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Landscapes
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- Medicinal Chemistry (AREA)
- Media Introduction/Drainage Providing Device (AREA)
Abstract
The application discloses a drug delivery device and a preparation method, wherein the drug is arranged on a drug microneedle, the drug microneedle is arranged into a detachable structure, the drug microneedle can be embedded into a blood vessel wall under the action of the expansion of a balloon body for continuous drug administration, the novel design of the drug delivery device can fundamentally solve the defect of the drug balloon, can greatly reduce the drug loss in the delivery process, can reduce the generation of particles, has a blood vessel supporting effect, can avoid the disastrous effect caused by acute vascular occlusion, and can fix nearby drug microneedles together by arranging a supporting ring, so that the drug microneedle is not easy to separate, the supporting ring is annular and can support blood vessels, and the acute vascular occlusion is prevented.
Description
[ field of technology ]
The application relates to the technical field of vascular disease treatment, in particular to the technical field of drug delivery devices.
[ background Art ]
Atherosclerosis (AS) is a major cause of coronary heart disease, cerebral infarction, peripheral arterial vascular disease, for example, intracranial atherosclerosis disease (ICAD) is a major cause of ischemic stroke, accounting for about 17-35% of asian ischemic cerebrovascular events, peripheral Arterial Disease (PAD) is a global health burden affecting 20% of the population over 80 years old, and in recent years, the incidence of cardiovascular and cerebrovascular disease in China rises year by year with a tendency to younger, bringing heavy health and economic burden to people and society.
Percutaneous angioplasty and percutaneous intravascular stent angioplasty are an innovative technique for treating intravascular stenosis, and greatly improve the therapeutic effect of patients suffering from atherosclerosis. However, the drug stent still faces the risks of restenosis in the stent, late thrombus of the stent and the like at present, and the drug stent has still not ideal therapeutic effects on tortuous intracranial blood vessels, lower limb blood vessels and the like due to the rigid metal structure, easy fracture and the like.
In order to solve the defects of the drug stent, a drug balloon which is inserted into the non-implanted drug balloon is invented and used for treating atherosclerosis diseases. The medicine saccule is formed by coating antiproliferation medicine on the saccule surface based on saccule forming operation, and is delivered to the target lesion position through saccule catheter, and the antiproliferation medicine is transferred to the blood vessel wall after the saccule is expanded, so that the proliferation of blood vessel smooth muscle is permanently inhibited, the stenosis of blood vessel is reduced, and the treatment effect is achieved. However, current drug balloons still face the following problems: 1) The drug coating is poorly robust and is largely lost during delivery. Studies have shown that about 80% of the drug in current drug balloons on the market is lost during delivery (J Am Coll Cardiol intv.2020,13 (24) 2840-2849.); the medicine is lost after a large amount of medicine is fallen before reaching the lesion position, so that the medicine is difficult to deliver and transfer effective medicine for the tortuosity lesion and the diffuse long lesion, and the treatment effect is poor; 2) The drug coating generates a large amount of particles in the conveying and expanding processes, the size of the particles falling off is more than 300 mu m, vascular embolism and 'slow blood flow' and 'no reflow' phenomena are easily caused, the 'slow blood flow' and 'no reflow' phenomena are related to poor clinical effects, the intracranial arterial embolic stroke with thinner blood vessels is easily caused, the amputation rate of lower limb arteries is increased, and the treatment effect is seriously influenced; 3) The saccule is hard, the friction resistance of the drug coating is large, and for tortuous vessels, the drug saccule is difficult to convey to a lesion position, so that treatment failure is caused; 4) Compared with a drug stent, the drug balloon lacks supporting force on blood vessels, can cause disastrous consequences for the occurrence of acute vascular occlusion, seriously influences clinical treatment effects, and is also a main defect of the drug balloon; the above problems limit the clinical effects of the drug balloon.
The existing preparation method of the drug coating comprises the steps of dripping, dip coating, ultrasonic spraying, gas auxiliary spraying and the like, and the drug particles in the drug coating are adhered to each other to form a sheet-shaped or film-shaped drug particle aggregate. Even if the individual drug particles are small in size, they may fall off in aggregate during delivery or expansion, and the size of the fall off is extremely large, which necessarily results in embolization of the distal blood vessel. Referring to the prior art, the present application mainly aims at optimizing a drug coating or a delivery device so as to reduce drug loss and particle shedding in the delivery process, and the vascular supporting effect of a drug balloon cannot be fundamentally solved or given. Therefore, if the drug balloon which can reduce the loss in the conveying process, reduce the falling of particles and simultaneously has the function of supporting blood vessels can be designed and prepared, the defect of the drug balloon can be fundamentally overcome, and the treatment field and the clinical effect of the drug balloon are expected to be further expanded.
The application aims to provide a drug delivery device which can greatly reduce drug loss in the delivery process, reduce generation of particles, have a vascular supporting effect and avoid disastrous effects caused by acute vascular occlusion.
[ application ]
The application aims to solve the problems in the prior art, and provides a drug delivery device and a preparation method thereof, which can greatly reduce the drug loss in the delivery process, reduce the generation of particles and avoid the disastrous consequences caused by acute vascular occlusion.
In order to achieve the above object, the present application provides a drug delivery device, comprising a balloon body and a drug coating layer provided on the surface of the balloon body, wherein the drug coating layer comprises a phase change material soluble layer provided on the surface of the balloon body and a plurality of drug microneedles fixed on the phase change material soluble layer, the drug microneedles are provided with drugs, and the drug microneedles are provided with tips capable of penetrating into blood vessel walls;
the phase change material soluble layer is normally in a solid state, and is converted from the solid state to a liquid state when the phase change material soluble layer is above a phase change temperature.
Preferably, the drug coating further comprises a plurality of supporting rings fixed on the phase change material soluble layer, and at least part of the drug microneedles are fixedly arranged on the outer walls of the supporting rings.
Preferably, the supporting ring is made of degradable materials, and the degradable materials for preparing the supporting ring are any one or a combination of more than one of polylactic acid, polyglycolic acid, polylactic acid-glycollic acid copolymer, polybutylene succinate, polyhydroxyalkanoate, polycaprolactone, polyethylene adipate, polyhydroxybutyrate valerate copolymer, polypropylene carbonate, polydioxanone, polydiolate, cellulose, chitosan, starch, sodium alginate and gelatin.
Preferably, the support ring has a complete degradation time of greater than 1 month.
Preferably, the support ring has a complete degradation time of greater than 6 months.
Preferably, the support ring has a complete degradation time of greater than 1 year.
Preferably, the drug microneedle is composed of active drugs and auxiliary materials, wherein the active drugs are at least one of rapamycin, rapamycin derivatives, dexamethasone, taxol, docetaxel, probucol, colchicine, heparin, warfarin sodium, vitamin K antagonists, aspirin, prostaglandin, salvianolic acid, nitrate drugs, lysine-piprolin, dipyridamole, ampicillin, cephalosporin, sulfadiazine, streptomycin sulfate, cefoxitin, nalidixic acid, pipecolic acid, daunorubicin, doxorubicin, carboplatin and macrolides; the auxiliary materials are one or more of lactylamine salt, citric acid, resveratrol, polybutylmethacrylate, stearamide, isooctyl palmitate, linoleic acid, linolenic acid, glycerol monooleate, iohexol, iopromide, urea, sorbitol, polysorbate, trihexyphenyl citrate, phospholipid, luo Paiqin matrix, cholesterol, vitamin E polyethylene glycol succinate, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, polybutylene succinate, polyhydroxyalkanoate, polycaprolactone, polyethylene adipate, polyhydroxybutyrate valerate copolymer, polyvinylpyrrolidone, polyvinyl alcohol, poloxamer and tween.
Preferably, a curable resin layer is further included between the phase change material soluble layer and the balloon body, and the curable resin is excited under ultraviolet light or blue light.
Preferably, the phase change material dissolvable layer is composed of one or more of fatty acid phase change materials or a combination of fatty acid phase change materials and one or more fatty alcohols.
Preferably, the fatty acid phase change material comprises stearic acid, lauric acid, capric acid, myristic acid and palmitic acid; the fatty alcohol is aliphatic alcohol with 8-34 carbon atoms chain, including decyl alcohol, n-undecyl alcohol, lauryl alcohol, tridecyl alcohol, tetradecyl alcohol, pentadecyl alcohol, hexadecyl alcohol, heptadecyl alcohol, octadecyl alcohol, nonadecyl alcohol, eicosyl alcohol, heneicosyl alcohol, docosyl alcohol, tetracosyl alcohol, hexacosyl alcohol, octacosyl alcohol, triacontyl alcohol and tetracosyl alcohol.
Another object of the present application is to propose a method of manufacturing a drug delivery device comprising the steps of:
step a, preparing a female die, namely preparing a female die matched with the saccule body, wherein a plurality of microneedle dies matched with the drug microneedles are arranged in the female die, and the tips of the microneedle dies face to the direction far away from the center of the female die;
step b, preparing a microneedle, pouring the prepared drug solution into a prepared female die, vacuumizing for 1-4min at normal temperature to completely fill the die, sucking off redundant solvent, and vacuum drying at 25-35 ℃ to completely solidify the solvent to obtain a drug coating;
step d, preparing a soluble layer of the phase-change material, selecting one or more fatty acid phase-change materials or pouring the fatty acid phase-change materials and one or more fatty alcohol solutions on a mold, vacuumizing for 1-4min at normal temperature to completely fill the mold and sucking out redundant solvents; vacuum drying at 25-35 deg.c to solidify the solvent completely to obtain soluble phase change material layer;
and f, wrapping the prepared mould containing the drug coating on the surface of the balloon, and obtaining the drug delivery device after curing, packaging and ethylene oxide sterilization.
Preferably, the step a further comprises arranging a plurality of ring molds corresponding to the supporting rings in the female mold, wherein the ring molds are in a groove corresponding to the supporting rings and are communicated with the non-tips of the corresponding microneedle molds;
and a step c is further included between the step b and the step d, wherein a supporting ring is prepared, one or a combination of polylactic acid, polyglycolic acid, a polylactic acid-glycollic acid copolymer, polybutylene succinate, polyhydroxyalkanoate, polycaprolactone, polyethylene glycol adipate, polyhydroxybutyrate valerate copolymer, polypropylene carbonate, polydioxanone, sodium alginate, cellulose, chitosan, starch, sodium alginate and gelatin is poured on the inner ring mold part of the female mold, vacuum pumping is performed for 1-4min at normal temperature to completely fill the mold and absorb redundant solvent, and then vacuum drying is performed at 30 ℃ to completely remove the solvent and solidify.
Preferably, the step d and the step f further include a step e of preparing a curable resin layer, continuously dripping the curable resin on the mold prepared in the step d, vacuumizing for 1-4min at normal temperature to completely fill the mold, and curing for 0.5-2min under blue light to prepare the curable resin layer.
Preferably, the female mold is prepared in step a by polydimethylsiloxane.
The drug delivery device and the preparation method have the beneficial effects that: according to the application, the medicine is arranged on the medicine micro-needle and is in a detachable structure, the medicine micro-needle can be embedded into the vascular wall under the action of the expansion of the balloon body for continuous administration, the defect of the medicine balloon can be fundamentally overcome by the novel design of the medicine conveying device, the medicine loss in the conveying process can be greatly reduced, the generation of particles can be reduced, the blood vessel supporting effect is realized, the disastrous effect caused by acute vascular occlusion can be avoided, the nearby medicine micro-needles can be fixed together by the supporting ring, the medicine micro-needle is not easy to separate, the supporting ring is annular, the blood vessel can be supported, and the acute vascular occlusion is prevented.
The features and advantages of the present application will be described in detail by way of example with reference to the accompanying drawings.
[ description of the drawings ]
Fig. 1 is a schematic perspective view of a drug delivery device according to the present application.
Fig. 2 is a schematic view of the structure of a drug microneedle and a support ring of a drug delivery device of the present application within a vessel wall.
In the figure: 1-sacculus body, 2-medicine coating, 21-phase change material soluble layer, 22-support ring, 23-medicine micropins, 3-vascular wall.
[ detailed description ] of the application
The present application will be further described in detail with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present application more apparent. It should be understood that the detailed description and specific examples, while indicating the application, are intended for purposes of illustration only and are not intended to limit the scope of the application. In addition, in the following description, descriptions of well-known structures and techniques are omitted so as not to unnecessarily obscure the present application.
In the description of the present application, it will be understood that when an element is referred to as being "fixed" or "disposed" on another element, it can be directly on the other element or be indirectly on the other element. When an element is referred to as being "connected to" another element, it can be directly connected to the other element or be indirectly connected to the other element.
In the description of the present application, it should be noted that the terms "center", "length", "width", "thickness", "upper", "lower", "front", "rear", "left", "right", "vertical", "horizontal", "top", "bottom", "inner", "outer", and the like indicate orientations or positional relationships based on the orientations or positional relationships shown in the drawings, or orientations or positional relationships in which the inventive product is conventionally placed in use, are merely for convenience in describing the present application and simplifying the description, and do not indicate or imply that the apparatus or element to be referred to must have a specific orientation, be configured and operated in a specific orientation, and therefore should not be construed as limiting the present application. Furthermore, the terms "first," "second," "third," and the like are used merely to distinguish between descriptions and should not be construed as indicating or implying relative importance. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include one or more such feature. In the description of the present application, the meaning of "a plurality" is two or more, unless explicitly defined otherwise. The meaning of "a number" is one or more than one unless specifically defined otherwise.
In the description of the present application, it should also be noted that, unless explicitly specified and limited otherwise, the terms "disposed," "mounted," "connected," and "connected" are to be construed broadly, and may be, for example, fixedly connected, detachably connected, or integrally connected; can be mechanically or electrically connected; can be directly connected or indirectly connected through an intermediate medium, and can be communication between two elements. The specific meaning of the above terms in the present application will be understood in specific cases by those of ordinary skill in the art.
Embodiment one:
referring to fig. 1 and 2, the present embodiment discloses a drug delivery device, which includes a balloon body 1 and a drug coating 2 disposed on the surface of the balloon body 1, wherein the drug coating 2 includes a phase change material soluble layer 21 disposed on the surface of the balloon body 1 and a plurality of drug microneedles 23 fixed on the phase change material soluble layer 21, the drug microneedles 23 have a drug thereon, and the drug microneedles 23 have tips capable of penetrating into a blood vessel wall; the drug microneedles 23 are divergently distributed on the phase change material-dissolvable layer 21; the phase change material soluble layer 21 is normally in a solid state, and changes from a solid state to a liquid state when the phase change material soluble layer 21 is above a phase change temperature. In the use process of the drug delivery device, the balloon body 1 is in a contracted state when the drug delivery device is delivered, when the drug delivery device is delivered to a lesion of a blood vessel, the balloon body 1 is expanded, the drug microneedles 23 penetrate and are embedded into the wall 3 of the blood vessel, then laser optical fibers are led into the inner shaft of the catheter and then led into the balloon body 1, near infrared light (NIR) is slowly emitted to heat and melt the phase change material soluble layer 21, so that the drug microneedles 23 are separated from the surface of the balloon body 1, the drug microneedles 23 are embedded in the wall 3 of the blood vessel, and the drug is continuously and slowly released to inhibit the proliferation of the blood vessel; according to the application, the medicine is arranged on the medicine micro needle 23, and the medicine micro needle 23 is arranged into a detachable structure, so that the medicine micro needle 23 can be embedded into the vascular wall under the action of the expansion of the balloon body 1 for continuous administration, the defect of the medicine balloon can be fundamentally overcome by the novel design of the medicine conveying device, the medicine loss in the conveying process can be greatly reduced, the generation of particles can be reduced, the vascular supporting effect is realized, and the disastrous effect caused by acute vascular occlusion can be avoided.
Preferably, the drug microneedle 23 is composed of active drugs and auxiliary materials, wherein the active drugs are at least one of rapamycin, rapamycin derivatives, dexamethasone, taxol, docetaxel, probucol, colchicine, heparin, warfarin sodium, vitamin K antagonists, aspirin, prostaglandin, salvianolic acid, nitrate drugs, lisinopilin, dipyridamole, ampicillin, cephalosporin, sulfadiazine, streptomycin sulfate, cefoxitin, nalidixic acid, pipecolic acid, daunorubicin, doxorubicin, carboplatin and macrolides; the auxiliary materials are one or more of lactylamine salt, citric acid, resveratrol, polybutylmethacrylate, stearamide, isooctyl palmitate, linoleic acid, linolenic acid, glycerol monooleate, iohexol, iopromide, urea, sorbitol, polysorbate, trihexyphenyl citrate, phospholipid, luo Paiqin matrix, cholesterol, vitamin E polyethylene glycol succinate, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, polybutylene succinate, polyhydroxyalkanoate, polycaprolactone, polyethylene adipate, polyhydroxybutyrate valerate copolymer, polyvinylpyrrolidone, polyvinyl alcohol, poloxamer and tween. Those skilled in the art will choose according to the actual therapeutic needs and circumstances of use.
Preferably, the phase change material dissolvable layer 21 is composed of one or more of fatty acid-based phase change materials or a combination of fatty acid-based phase change materials and one or more fatty alcohols; the fatty acid phase change material comprises stearic acid, lauric acid, capric acid, myristic acid and palmitic acid; the fatty alcohol is aliphatic alcohol with 8-34 carbon atoms chain, including decyl alcohol, n-undecyl alcohol, lauryl alcohol, tridecyl alcohol, tetradecyl alcohol, pentadecyl alcohol, hexadecyl alcohol, heptadecyl alcohol, octadecyl alcohol, nonadecyl alcohol, eicosyl alcohol, heneicosyl alcohol, docosyl alcohol, tetracosyl alcohol, hexacosyl alcohol, octacosyl alcohol, triacontyl alcohol and tetracosyl alcohol. Those skilled in the art can choose according to the actual therapeutic requirements and the environment of use, and only need to ensure that the phase-change material soluble layer 21 is solid in normal state and is transformed from solid to liquid above the phase-change temperature.
Embodiment two:
referring to fig. 1 and 2, in the first embodiment, the drug coating 2 further includes a support ring 22 fixed on the phase-change material soluble layer 21, a part of the drug microneedles 23 are fixedly arranged on the outer wall of the support ring 22, and another part of the drug microneedles 23 are fixed on the phase-change material soluble layer 21. When the phase change material soluble layer 21 is dissolved, the drug micro-needles 23 on the support ring 22 can be anchored on the blood vessel wall, so that the drug micro-needles 23 and the support ring 22 are fixed, displacement is prevented, the drug micro-needles 23 arranged on the support ring 22 are not easy to separate, and the support ring 22 is annular, can support blood vessels, and prevent acute vascular occlusion.
Preferably, three support rings 22 are provided on the phase change material dissolvable layer 21 in this embodiment. The drug microneedles 23 which are not fixed on the support rings 22 are arranged between the three support rings 22 and can effectively protect the discrete drug microneedles 23 through the support rings 22. In alternative embodiments, a suitable number of support rings 22 may be provided, depending on the actual requirements.
Preferably, the supporting ring 22 is made of a degradable material, and the degradable material of which the supporting ring 22 is made is any one or a combination of several of polylactic acid, polyglycolic acid, polylactic acid-glycollic acid copolymer, polybutylene succinate, polyhydroxyalkanoate, polycaprolactone, polyethylene adipate, polyhydroxybutyrate valerate copolymer, polypropylene carbonate, polydioxanone, poly citric acid glycol ester, cellulose, chitosan, starch, sodium alginate and gelatin. Those skilled in the art will choose according to the actual therapeutic needs and circumstances of use.
Preferably, the support ring 22 has a thickness of 50 to 500 μm and a thickness of 50 to 200. Mu.m. In another alternative embodiment, the support ring 22 is more preferably 60-120 μm thick.
Embodiment III:
preferably, on the basis of the second embodiment, a curable resin layer is further included between the phase change material soluble layer 21 and the balloon body 1, and the curable resin is excited under ultraviolet light or blue light. The curable resin layer can enhance the adhesion between the balloon body 1 and the phase change material soluble layer 21.
Preferably, the drug microneedle 23 microneedle protrusions may be conical and/or prismatic.
Preferably, the support ring 22 may be formed as a complete ring or a broken ring.
Preferably, the drug microneedles 23 are randomly distributed on the surface of the balloon. In another alternative embodiment, the drug coating 2 is configured to be symmetrically distributed along the balloon center.
Preferably, the support ring 22 has a complete degradation time of greater than 1 month. In another alternative embodiment, the support ring 22 more preferably has a complete degradation time of greater than 6 months, and in yet another alternative embodiment, the support ring 22 has an optimal complete degradation time of greater than 1 year.
Preferably, the length of the drug microneedle 23 is 50 μm to 2000 μm. In another alternative embodiment, the support ring 22 is preferably 100-1000 μm in length; in another alternative embodiment, the support ring 22 is more preferably 200-800 μm in length;
preferably, the bottom diameter of the drug microneedle 23 is 10 μm to 1500 μm. In another alternative embodiment, the support ring 22 preferably has a diameter of 100-800 μm; in another alternative embodiment, the support ring 22 is more preferably 200-500 μm in diameter.
Embodiment four:
the embodiment provides a method for preparing the drug delivery device, which comprises the following steps:
step a, preparing a female die, namely preparing the female die through polydimethylsiloxane, arranging a plurality of microneedle moulds matched with drug microneedles 23 in the female die, enabling the tips of the microneedle moulds to face away from the center of the female die, arranging three ring moulds corresponding to the support rings 22 on the female die, wherein the ring mould structure is a groove corresponding to the support rings 22 and communicated with the non-tips of the corresponding microneedle moulds, and the ring mould structure is arranged on the opposite sides of the tips of the microneedle moulds;
step b, preparing a microneedle, and preparing a drug solution, wherein the drug solution specifically comprises the steps of dissolving rapamycin, lecithin and polylactic acid-glycolic acid copolymer (PLGA) in ethanol together, wherein the concentration is 30mg/ml, 10mg/ml and 20mg/m respectively; injecting the prepared drug solution into a microneedle mould in a prepared female mould, vacuumizing for 2min at normal temperature to completely fill the mould and suck redundant solvent, and then vacuum drying at 30 ℃ to completely solidify the solvent, wherein the microneedle preparation is completed;
step c, preparing a supporting ring, namely dissolving polylactic acid-glycolic acid copolymer (PLGA) in ethanol with the concentration of 20mg/ml, pouring the solution into a ring mold part, and vacuumizing for 2min at normal temperature to completely fill the mold and absorb redundant solvent; vacuum drying at 30 ℃ is then performed to completely remove the solvent and cure;
step d, preparing a phase-change material soluble layer, dissolving lauric acid in ethanol with the concentration of 20mg/ml, pouring the solution on a die, vacuumizing for 2min at normal temperature to completely fill the die and sucking out redundant solvent;
vacuum drying at 30deg.C to completely solidify the solvent to obtain drug coating;
step e, preparing a curable resin layer, continuously dripping the curable resin (208-CTH-F) on the die prepared in the step d, vacuumizing for 2min at normal temperature to completely fill the die, and curing for 1min under blue light to prepare the curable resin layer;
and f, wrapping the prepared mold containing the curable resin layer and the drug coating on the surface of the balloon, curing for 2min under blue light, packaging, and sterilizing by ethylene oxide to obtain the drug delivery device.
Fifth embodiment:
the embodiment provides another preparation method of the drug delivery device, which comprises the following steps:
step a, preparing a female die, namely preparing the female die through polydimethylsiloxane, arranging a plurality of microneedle moulds matched with drug microneedles 23 in the female die, enabling the tips of the microneedle moulds to face away from the center of the female die, arranging three ring moulds corresponding to the support rings 22 on the female die, wherein the ring mould structure is a groove corresponding to the support rings 22 and communicated with the non-tips of the corresponding microneedle moulds, and the ring mould structure is arranged on the opposite sides of the tips of the microneedle moulds;
step b, preparing a microneedle, wherein the drug solution specifically comprises the steps of dissolving paclitaxel, lecithin and polylactic acid-glycolic acid copolymer (PLGA) into ethanol together, wherein the concentration is 30mg/ml, 10mg/ml and 20mg/m respectively; pouring the prepared medicinal solution into the prepared female mold, vacuumizing at normal temperature for 2min to completely fill the mold and suck excessive solvent, and then vacuum drying at 30deg.C to completely solidify the solvent, wherein the preparation of the microneedle is completed;
step c, preparing a supporting ring, namely dissolving polylactic acid-glycolic acid copolymer (PLGA) in ethanol with the concentration of 20mg/ml, pouring the solution into a ring mold part, and vacuumizing for 2min at normal temperature to completely fill the mold and absorb redundant solvent; vacuum drying at 30 ℃ is then performed to completely remove the solvent and cure;
step d, preparing a phase-change material soluble layer, dissolving lauric acid in ethanol with the concentration of 20mg/ml, pouring the solution on a die, vacuumizing for 2min at normal temperature to completely fill the die and sucking out redundant solvent; vacuum drying at 30deg.C to completely solidify the solvent to obtain drug coating;
step e, continuously dripping the curable resin (208-CTH-F) on the die prepared in the step d, vacuumizing for 2min at normal temperature to completely fill the die, and curing for 1min under blue light to prepare a curable resin layer;
and f, wrapping the prepared mold containing the curable resin layer and the drug coating on the surface of the balloon, curing for 2min under blue light, packaging, and sterilizing by ethylene oxide to obtain the drug delivery device.
Example six:
the embodiment provides another preparation method of the drug delivery device, which comprises the following steps:
step a, preparing a female die, namely preparing the female die through polydimethylsiloxane, arranging a plurality of microneedle moulds matched with drug microneedles 23 in the female die, enabling the tips of the microneedle moulds to face away from the center of the female die, arranging three ring moulds corresponding to the support rings 22 on the female die, wherein the ring mould structure is a groove corresponding to the support rings 22 and communicated with the non-tips of the corresponding microneedle moulds, and the ring mould structure is arranged on the opposite sides of the tips of the microneedle moulds;
step b, preparing a microneedle, wherein the drug solution specifically comprises the steps of dissolving rapamycin, lecithin and chitosan together in ethanol, wherein the concentration is 30mg/ml, 10mg/ml and 20mg/m respectively; pouring the prepared medicinal solution into the prepared female mold, vacuumizing at normal temperature for 2min to completely fill the mold and suck excessive solvent, and then vacuum drying at 30deg.C to completely solidify the solvent, wherein the preparation of the microneedle is completed;
step c, preparing a supporting ring, namely dissolving polylactic acid-glycolic acid copolymer (PLGA) in ethanol with the concentration of 20mg/ml, pouring the solution into a ring mold part, and vacuumizing for 2min at normal temperature to completely fill the mold and absorb redundant solvent; vacuum drying at 30 ℃ is then performed to completely remove the solvent and cure;
step d, preparing a phase-change material soluble layer, dissolving lauric acid in ethanol with the concentration of 20mg/ml, pouring the solution on a die, vacuumizing for 2min at normal temperature to completely fill the die and sucking out redundant solvent; vacuum drying at 30deg.C to completely solidify the solvent to obtain drug coating;
step e, preparing a curable resin layer, continuously dripping the curable resin (208-CTH-F) on the die prepared in the step d, vacuumizing for 2min at normal temperature to completely fill the die, and curing for 1min under blue light to prepare the curable resin layer;
and f, wrapping the prepared mold containing the curable resin layer and the drug coating on the surface of the balloon, curing for 2min under blue light, packaging, and sterilizing by ethylene oxide to obtain the drug delivery device.
Fastness testing
Simulating actual operation flow, passing the drug delivery devices prepared in the fourth, fifth and sixth embodiments through an in vitro simulation model (the fluidity is PBS), testing the residual drug content on the delivered product by using High Performance Liquid Chromatography (HPLC), and calculating the coating firmness of the product by using the following formula:
the following table was obtained:
| fastness degree | |
| Example IV | 99.8％ |
| Example five | 99.3％ |
| Example six | 99.7％ |
The firmness of the fourth, fifth and sixth embodiments is up to 99.3% -99.8%, namely, the medicine in the simulated conveying process is basically free from loss; the drug delivery device prepared by the application can greatly reduce the drug delivery loss through the drug coating integrally formed by the die, and avoid the toxic and side effects caused by the drug falling off in the delivery process;
insoluble particle testing
The actual surgical procedure was simulated, the drug delivery devices of examples and comparative examples were passed through an in vitro simulation model (flow is PBS), and when delivered to the target site, the balloon was inflated to nominal pressure, held for 1min, then the balloon was withdrawn, and the fluid flowing from the collection system was used to measure the size and number of insoluble particles shed during delivery and inflation using a particle analyzer. The following table was obtained:
from insoluble particle test data, insoluble particles which are more than or equal to 25 mu m and more than or equal to 100 mu m in the fourth, fifth and sixth embodiments are not detected, and the number of the fallen particles is very small, so that the medicine conveying device prepared by the application can reduce medicine falling in the conveying and expanding processes, and the embolism of blood vessels caused by overlarge particle size is avoided.
Drug transfer test
In-vitro simulated drug transfer, the drug delivery device of each embodiment described above was passed through an in-vitro simulated model and reached the isolated porcine arterial vessel segment, kept at a constant temperature of 37 ℃, then expanded for 1min at nominal pressure, and then depressurized to remove the drug balloon. The transferred drug amount was then measured by gas chromatography-mass spectrometry (GC-MS) while the drug balloon surface residual drug amount was tested using HPLC. The following table was obtained:
| drug transfer rate | Balloon surface drug residue% | |
| Example IV | 98.2％ | 1.6％ |
| Example five | 98.5％ | 0.8％ |
| Example six | 97.6％ | 2.1％ |
From the above table, it can be seen that, in the fourth, fifth and sixth embodiments, more than 97.6% of the drug is transferred to the vessel wall, which indicates that the drug microneedle and the soluble phase change material layer configured in the drug delivery device prepared by the present application can transfer the drug to the vessel wall with high efficiency, the drug microneedle can be inserted and retained in the vessel wall in a releasable manner, the drug can be firmly retained in the vessel wall, and the slow release time of the drug can be prolonged.
The working process of the application comprises the following steps:
in the working process of the drug delivery device, the balloon body 1 is in a contracted state when the drug delivery device is delivered to a lesion of a blood vessel, the balloon body 1 is expanded, the drug micro-needles 23 penetrate and are embedded into the blood vessel wall 3, then laser optical fibers are led into an inner shaft of the catheter and then led into the balloon body 1, near infrared light (NIR) is slowly emitted to heat and melt the phase-change material soluble layer 21, so that the drug micro-needles 23 are separated from the surface of the balloon body 1, the drug micro-needles 23 are embedded in the blood vessel wall 3, the support ring 22 is anchored on the blood vessel wall through the drug micro-needles 23 connected with the drug micro-needles 23, so that the drug micro-needles 23 and the support ring 22 are fixed, displacement is prevented, the drug micro-needles 23 arranged on the support ring 22 are not easy to separate, the support ring 22 is annular, the blood vessel can be supported, acute blood vessel occlusion is prevented, and continuous slow release of the drug on the drug micro-needles 23 is used for inhibiting proliferation of the blood vessel.
Standard parts used in the document of the application can be purchased from the market, the specific connection modes of all parts adopt conventional means such as mature bolts, rivets and welding in the prior art, the electric sliding rail sliding seat, the air cylinder, the welding machine, the electric telescopic rod and the internal parts of the controller adopt conventional models in the prior art, the internal structure of the electric sliding rail sliding seat, the air cylinder, the welding machine, the electric telescopic rod and the controller belong to the prior art structure, a worker can finish normal operation of the electric sliding rail sliding seat, the electric telescopic rod and the controller according to the manual of the prior art, and the circuit connection adopts the conventional connection modes in the prior art, so that the specific description is not made.
It should be noted that, although the foregoing embodiments have been described herein, the scope of the present application is not limited thereby. Therefore, based on the innovative concepts of the present application, alterations and modifications to the embodiments described herein, or equivalent structures or equivalent flow transformations made by the present description and drawings, apply the above technical solutions directly or indirectly to other relevant technical fields, all of which are included in the scope of protection of the present patent.
Claims (10)
1. Drug delivery device, including sacculus body (1) and locate drug coating (2) on sacculus body (1) surface, its characterized in that: the drug coating (2) comprises a phase change material soluble layer (21) arranged on the surface of the balloon body (1) and a plurality of drug microneedles (23) fixed on the phase change material soluble layer (21), wherein the drug microneedles (23) are provided with drugs, and the drug microneedles (23) are provided with tips capable of penetrating into the vascular wall;
the phase change material soluble layer (21) is normally in a solid state, and the phase change material soluble layer (21) is converted from a solid state to a liquid state when the phase change temperature is higher than the phase change temperature.
2. A drug delivery device as in claim 1, wherein: the drug coating (2) further comprises a plurality of supporting rings (22) fixed on the phase change material soluble layer (21), and at least part of the drug microneedles (23) are fixedly arranged on the outer wall of the supporting rings (22).
3. A drug delivery device as in claim 2, wherein: the supporting ring (22) is made of degradable materials, and the degradable materials for preparing the supporting ring (22) are any one or more of polylactic acid, polyglycolic acid, polylactic acid-glycollic acid copolymer, polybutylene succinate, polyhydroxyalkanoate, polycaprolactone, polyethylene adipate, polyhydroxybutyrate valerate copolymer, polypropylene carbonate, polydioxanone, cellulose, chitosan, starch, sodium alginate and gelatin.
4. A drug delivery device according to claim 3, wherein: the support ring (22) has a complete degradation time of greater than 1 month.
5. A drug delivery device as in claim 1, wherein: the drug microneedle (23) consists of active drugs and auxiliary materials, wherein the active drugs are at least one of rapamycin, rapamycin derivatives, dexamethasone, taxol, docetaxel, probucol, colchicine, heparin, warfarin sodium, vitamin K antagonists, aspirin, prostaglandin, salvianolic acid, nitrate drugs, lysine-picoline, dipyridamole, ampicillin, cephalosporin, sulfadiazine, streptomycin sulfate, cefoxitin, nalidixic acid, pipecolic acid, daunorubicin, doxorubicin, carboplatin and macrolides; the auxiliary materials are one or more of lactylamine salt, citric acid, resveratrol, polybutylmethacrylate, stearamide, isooctyl palmitate, linoleic acid, linolenic acid, glycerol monooleate, iohexol, iopromide, urea, sorbitol, polysorbate, trihexyphenyl citrate, phospholipid, luo Paiqin matrix, cholesterol, vitamin E polyethylene glycol succinate, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, polybutylene succinate, polyhydroxyalkanoate, polycaprolactone, polyethylene adipate, polyhydroxybutyrate valerate copolymer, polyvinylpyrrolidone, polyvinyl alcohol, poloxamer and tween.
6. A drug delivery device as in claim 1, wherein: the phase change material soluble layer (21) and the balloon body (1) also comprise a curable resin layer, and the curable resin is excited under ultraviolet light or blue light.
7. A drug delivery device as in claim 1, wherein: the phase change material soluble layer (21) consists of one or more of fatty acid phase change materials or is formed by compounding the fatty acid phase change materials with one or more fatty alcohols; the fatty acid phase change material comprises stearic acid, lauric acid, capric acid, myristic acid and palmitic acid; the fatty alcohol is aliphatic alcohol with 8-34 carbon atoms chain, including decyl alcohol, n-undecyl alcohol, lauryl alcohol, tridecyl alcohol, tetradecyl alcohol, pentadecyl alcohol, hexadecyl alcohol, heptadecyl alcohol, octadecyl alcohol, nonadecyl alcohol, eicosyl alcohol, heneicosyl alcohol, docosyl alcohol, tetracosyl alcohol, hexacosyl alcohol, octacosyl alcohol, triacontyl alcohol and tetracosyl alcohol.
8. A method of manufacturing a drug delivery device, comprising the steps of:
step a, preparing a female die, namely preparing a female die matched with the saccule body (1), wherein a plurality of microneedle dies matched with the drug microneedles (23) are arranged in the female die, and the tips of the microneedle dies face the direction far away from the center of the female die;
step b, preparing a microneedle, pouring the prepared drug solution into a prepared female die, vacuumizing for 1-4min at normal temperature to completely fill the die, sucking off redundant solvent, and vacuum drying at 25-35 ℃ to completely solidify the solvent to obtain a drug coating (2);
step d, preparing a soluble layer of the phase-change material, selecting one or more fatty acid phase-change materials or pouring the fatty acid phase-change materials and one or more fatty alcohol solutions on a mold, vacuumizing for 1-4min at normal temperature to completely fill the mold and sucking out redundant solvents; vacuum drying at 25-35 deg.c to solidify the solvent completely to obtain soluble phase change material layer;
and f, wrapping the prepared mould containing the drug coating on the surface of the balloon, and obtaining the drug delivery device after curing, packaging and ethylene oxide sterilization.
9. A drug delivery device as in claim 8, wherein: the step a further comprises arranging a plurality of ring molds corresponding to the supporting rings (22) in the female mold, wherein the ring molds are in a groove corresponding to the supporting rings (22) and are communicated with the non-tips of the corresponding microneedle molds;
and a step c is further included between the step b and the step d, wherein a supporting ring is prepared, one or a combination of polylactic acid, polyglycolic acid, a polylactic acid-glycollic acid copolymer, polybutylene succinate, polyhydroxyalkanoate, polycaprolactone, polyethylene glycol adipate, polyhydroxybutyrate valerate copolymer, polypropylene carbonate, polydioxanone, sodium alginate, cellulose, chitosan, starch, sodium alginate and gelatin is poured on the inner ring mold part of the female mold, vacuum pumping is performed for 1-4min at normal temperature to completely fill the mold and absorb redundant solvent, and then vacuum drying is performed at 30 ℃ to completely remove the solvent and solidify.
10. A drug delivery device as in claim 8, wherein: and d, preparing a curable resin layer, continuously dripping the curable resin on the die prepared in the step d, vacuumizing for 1-4min at normal temperature to completely fill the die, and curing for 0.5-2min under blue light to prepare the curable resin layer.
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