Patent Application
20240131311
The present application relates to the technical field of medical devices, in particular, to a drug-loaded medical device and a preparation method thereof.
In recent years, a variety of interventional or implantable medical devices containing drug coating have been developed for various mechanisms of vascular restenosis. The drug-coated balloons and the drug eluting stents both essentially stem from the concept of catheter-based devices for local drug delivery. They achieve the inhibition of intimal hyperplasia by carrying drugs, albeit differing in the method of drug delivery and the duration of local drug action. The drug-coated balloons have attracted more and more attention due to the concept of “intervention without implantation”. Numerous clinical trials have already demonstrated satisfactory efficacy and safety of the drug-coated balloons in various conditions such as coronary artery stenosis, small vessel diseases, and bifurcation lesions. The drug-coated balloons are uniformly coated with anti-proliferative drugs, and after delivery to the lesion site, the drugs are released within a short expansion time (30 s to 60 s), inhibiting the proliferation of vascular smooth muscle cells.
Recently, it has been found that the drug formulation used in implantable or interventional drug-loaded medical devices plays a crucial role in drug transfer and retention. It has been discovered that drugs in crystalline form have better transfer and retention performances compared to drugs in amorphous form. The crystalline drugs have higher drug concentrations in tissue over an extended period, and the effective drug concentrations can be maintained for more than 28 days, which is particularly important for inhibiting restenosis. However, it is challenging to obtain crystalline macrolide structures using traditional methods such as ultrasound spraying or drop coating. These methods often result in a drug in an amorphous state. Even though the crystallization is promoted by the method such as adjusting the supersaturation of macrolide drugs, the resulting crystalline particles often exhibit rhombic or spheroidal morphologies. The crystalline drugs with these rounded morphologies have weak interactions with the vascular wall, leading to unsatisfactory drug transfer performance. Consequently, the preparation of elongated rod-shaped crystalline particles with sharp morphologies for macrolide drugs is highly challenging.
The present application relates to a drug-loaded medical device, including a medical device body and at least one drug coating, the drug coating is attached to at least one side of a surface of the medical device body.
A main component of the drug coating includes a macrolide drug. The drug coating includes elongated prismatic crystals each with at least three lateral edges, and/or the drug coating includes crystal clusters of the elongated prismatic crystals each with at least three lateral edges. An aspect ratio of each elongated prismatic crystal is in a range from 1:1 to 40:1.
In some embodiments, the elongated prismatic crystal includes at least two adjacent lateral surfaces with an included angle smaller than 90 degrees.
In some embodiments, the macrolide drug includes at least one of rapamycin, zotarolimus, everolimus, temsirolimus, biolimus, 7-O-desmethylrapamycin, temsirolimus, ridaforolimus, 40-O-(2-hydroxyethyl)-rapamycin, 32-deoxo rapamycin, biolimus A9, ABT-578, SDZ RAD, or SAR943.
The present application also relates to a preparation method of a drug-loaded medical device, the main component of which includes the macrolide drug as defined above, the method including:
1) dispersing macrolide drug crystal powder in a solvent, adding rigid microspheres, agitating, and filtering out the rigid microspheres to obtain a suspension;
2) taking a medical device body including a solid-phase surface, applying the suspension onto the surface of the medical device body, and drying the surface to obtain a medical device intermediate; and
3) applying a supersaturated solution of the macrolide drug onto the surface of the medical device intermediate and drying the surface.
In order to more clearly describe the technical solutions in the embodiments of the present application or the conventional art, the drawings to be used in the description of the embodiments or the conventional art will be described briefly. Apparently, the drawings described below are merely for some embodiments of the present application. For ordinary skilled persons in the art, other drawings can also be obtained based on the following drawings without creative work.
Reference will now be made in detail to embodiments of the present application, one or more examples of which are described below. Each example is provided by way of illustration, not limitation of the present application. It will be apparent to those skilled in the art that various modifications and variations can be made in the present application without departing from the scope or spirit of the present application. For example, features illustrated or described as part of one embodiment can be used in another embodiment to yield a further embodiment.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs. The terms used herein in the specification of the present application are only for the purpose of describing specific embodiments, and are not intended to limit the present application. As used herein, the term “and/or” includes any and all combinations of one or more of the associated listed items.
The medical device mentioned in present application refers to any drug carrier used in a medical process, and is not limited to the definition of medical device in the medical industry.
The present application relates to a drug-loaded medical device, including a medical device body and at least one drug coating. The medical device includes a solid-phase surface, and the drug coating is attached to a side of the solid-phase surface. The drug coating includes elongated prismatic crystals each with at least three lateral edges, and/or the drug coating includes crystal clusters of the elongated prismatic crystals each with at least three lateral edges.
The crystals can be in at least two forms in the drug coating, one is elongated prisms, and the other is cluster aggregates or “crystal clusters”. The crystal cluster includes a plurality of elongated prisms. The elongated prism includes at least three lateral edges. The cross-section of the elongated prism can be triangular or quadrangular, such as rhomboidal.
The drug coating that includes the elongated prisms and/or crystal clusters has one or more of the following features:
In some embodiments, an aspect ratio of at least one elongated prismatic crystal in the drug coating is in a range from 1:1 to 40:1, such as 2:1, 3:1, 4.1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 25:1, 30:1, 35:1.
In some embodiments, the aspect ratio of at least one elongated prismatic crystal in the drug coating is in a range from 2:1 to 20:1.
In some embodiments, an included angle between adjacent lateral surfaces of the elongated prism in the drug coating is smaller than 90 degrees, such as 80 degrees, 70 degrees, 60 degrees, 50 degrees, 40 degrees, 30 degrees, 20 degrees, 10 degrees, in some embodiments smaller than 60 degrees, in some embodiments smaller than 40 degrees, in some embodiments smaller than 35 degrees, and in some embodiments between 20 degrees and 35 degrees.
In some embodiments, the elongated prismatic crystals and/or crystal clusters account for more than 90% by mass, such as more than 98% by mass, of the drug coating on the surface of the medical device body.
In some embodiments, an included angle between the lateral edges of the elongated prismatic crystal and the surface of the medical device body is in a range from 0° to 90°, for example 30° to 70°.
In some embodiments, the loss rate of the drug coating attached to the surface of the medical device body is less than or equal to 24%. The loss rate described in the present application refers to the loss rate of the drug during delivery of the drug-loaded medical device through a vascular model. The smaller the loss rate, the higher the utilization rate of the drug, giving the surgeon more operating time, and the surgeon's operation does not have to be restricted by the drug loss rate of the medical device, and does not need to be completed in a very short time.
In some embodiments, the loss rate of the drug coating attached to the surface of the medical device body is less than or equal to 20%.
In some embodiments, the loss rate of the drug coating attached to the surface of the medical device body is less than or equal to 15%.
In some embodiments, the thickness of the drug coating on the surface of the medical device body is in a range from 1 μm to 50 μm, such as 5 μm, 10 μm, 15 μm, 20 μm, 25 μm, 30 m, 35 μm, 40 μm, 45 μm.
In some embodiments, the medical device body is a drug-coated balloon, a drug eluting stent, a medical patch, or a sheath for an introducer, etc.
In some embodiments, the macrolide drug is selected from the group consisting of a rapamycin drug, erythromycin, peplomycin, spiramycin, tilmicosin, azithromycin, clarithromycin (Biaxin), dirithromycin, roxithromycin, carbomycin A, josamycin, kitasamycin, oleandomycin, spiramycin, troleandomycin, tylosin, tacrolimus, telithromycin, cethromycin, and combinations thereof.
In some embodiments, the rapamycin drug is selected from the group consisting of rapamycin, zotarolimus, everolimus, temsirolimus, biolimus, 7-O-desmethylrapamycin, temsirolimus (CCI-779), ridaforolimus (or deforolimus), 40-O-(2-hydroxyethyl)-rapamycin (SDZ RAD), 32-deoxo rapamycin (SAR943), biolimus A9, ABT-578, SDZ RAD, SAR943, and combinations thereof.
In some embodiments, the macrolide drug accounts for 50% or above of the total mass of drug, such as 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or 100%.
In some embodiments, at least one elongated prism in the drug coating includes 4, 5, 6, 7, 8, 9, 10 or more lateral edges.
In some embodiments, the drug coating further includes at least one of a) to c) as follows:
In some embodiments, the main component of the drug delivery carrier layer includes at least one of calcium chloride, urea, polyvinylpyrrolidone, polyvinyl alcohol, collagen, gelatin, polysaccharide, stearic acid, iopromide, iopamidol, iohexol, ioversol, citric acid, glucan, polysorbate, sorbitol, chitosan, poloxamer, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, sodium hyaluronate, sodium alginate, ammonium shellacate, n-butyryl tri-n-hexyl citrate (BTHC), shellac, or PEG.
In some embodiments, the antioxidant is selected from the group consisting of dibutyl hydroxytoluene, butylated hydroxyanisole, ascorbic acid, palmitate, tocopherol, probucol, vitamin E, polyethylene glycol succinate, and combinations thereof.
In some embodiments, the drug coating also includes an organic crystallization nucleating agent, selected from the group consisting of a salt of an organic acid, a dibenzylidene sorbitol derivative, a diamide, a hydrazide, and combinations thereof.
In some embodiments, the at least one active drug other than the macrolide drug is at least one of paclitaxel, a paclitaxel derivative, cilostazol, ticlopidine, a phosphodiesterase inhibitor, nafronyl, pentoxifylline, rivaroxaban, apixaban, dabigatran etexilate, tirofiban, a thrombin inhibitor, a factor Xa inhibitor, a vitamin K inhibitor, a cyclooxygenase inhibitor, an ADP receptor antagonist or inhibitor, a platelet glycoprotein IIb/IIIa receptor antagonist, dexamethasone, prednisolone, corticosterone, budesonide, a natriuretic peptide, an estrogen, sulfasalazine, aminosalicylic acid, acemetacin, aescin, aminopterin, antimycin, arsenic trioxide, aristolochic acid, aspirin, berberine, bilobol, endostatin, angiostatin, angiopeptin, an monoclonal antibody that can block the proliferation of smooth muscle cells, levofloxacin, hydroxycamptothecin, vinblastine, vincristine, doxorubicin, 5-fluorouracil, cisplatin, a bisphosphonate, a selective estrogen receptor modulator, strontium ranelate, actinomycin D, cyclosporine A, cyclosporine C, brefeldin A, relaxin, a guanylate activating enzyme regulator, nitroxyl prodrug CXL-1020, a nitrate drug, sodium nitroprusside, nitroglycerin, a thymidine kinase inhibitor antibiotic, nesiritide, a calcium channel blocker such as diltiazem, verapamil, nicardipine, platelet vasodilator-stimulated phosphoprotein, vasodilator-stimulated phosphoprotein, papaverine, adenosine, magnesium sulfate, xantinol nicotinate, or nicorandil.
In some embodiments, the paclitaxel derivative includes one or more of docetaxel, nab-paclitaxel, or nap-paclitaxel.
The present application further relates to a preparation method of a drug-loaded medical device. The method includes following steps:
1) Prepare macrolide drug crystal powder and disperse it in a solvent, add rigid microspheres, agitate, and filter out the rigid microspheres to obtain a suspension.
2) Take a medical device body including a solid-phase surface, apply the suspension onto the surface of the medical device body, and dry the surface to obtain a medical device intermediate.
3) Apply a supersaturated solution of the macrolide drug onto the surface of the medical device intermediate and dry the surface.
In some embodiments, the suspension includes crystalline microparticles of the macrolide drug with a particle size in a range from 100 nm to 1000 nm.
In some embodiments, the particle size of the crystalline microparticles can be 200 nm, 300 nm, 400 nm, 500 nm, 600 nm, 700 nm, 800 nm, 900 nm, and further can be 200 nm to 500 nm.
In some embodiments, the purity of the macrolide drug in the crystalline microparticles is equal to or greater than 80%, and can be 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or 100%.
In some embodiments, the concentration of the supersaturated solution is in a range from 1 mg/mL to 100 mg/mL, and can be 2 mg/mL, 3 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL, 8 mg/mL, 9 mg/mL, 10 mg/mL, 11 mg/mL, 12 mg/mL, 13 mg/mL, 14 mg/mL, 15 mg/mL, 16 mg/mL, 17 mg/mL, 18 mg/mL, 19 mg/mL, 20 mg/mL, 30 mg/mL, 40 mg/mL, 50 mg/mL, 60 mg/mL, 70 mg/mL, 80 mg/mL, 90 mg/mL; for example, 5 mg/mL to 70 mg/mL, 10 mg/mL to 50 mg/mL, or 20 mg/mL to 40 mg/mL.
In some embodiments, the concentration of the macrolide drug in the solvent is in a range from 4 mg/10 mL to 10 mg/10 mL, and the mass of the rigid microspheres is in a range from 1 g to 4 g, the mixture is agitated on a vortex mixer for 8 min to 12 min, and the agitating speed is 2000 rpm to 3000 rpm.
In some embodiments, the solvent is an alkane, and can be at least one of n-heptane, octane, n-hexane, pentane, or cyclohexane.
In some embodiments, the rigid microspheres are made of a material including at least one of zirconium oxide, silicon nitride, hard stainless steel, hard tungsten carbide, sintered corundum, or agate. In some embodiments, the particle size of the rigid microspheres is 800 to 1200 times of the particle size of the crystalline microparticles, such as 900, 1000, or 1100 times. In some embodiments, the particle size of the rigid microspheres is in a range from 0.1 mm to 0.8 mm, such as in a range from 0.2 mm to 0.5 mm.
In some embodiments, in step 2), a drug delivery carrier layer is disposed on the solid-phase surface of the medical device body; in some embodiments, the drug delivery carrier layer is the drug delivery carrier layer as defined above.
The drug delivery carrier layer is coated on the surface of the implantable or interventional medical device, so that not only the subsequent coating of the supersaturated solution of the macrolide drug can be more uniform, but also the bioavailability of the drug can be improved. The drug delivery carrier layer plays the role of a stent and can increase contact between the drug coating and blood vessel wall, promoting the drug transfer. In some embodiments, step 2) further includes a step of spraying a solution of an organic crystallization nucleating agent onto the surface of the intermediate and drying it. The organic nucleating agent is selected from the group consisting of a salt of an organic acid, a dibenzylidene sorbitol derivative, a diamide, a hydrazide, and combinations thereof.
In some embodiments, the supersaturated solution of the macrolide drug further includes an antioxidant and/or at least one active drug other than the macrolide drug.
In some embodiments, the antioxidant is a pharmaceutical antioxidant as defined above; the antioxidant is dibutylhydroxytoluene as an example, which can modulate the crystallization behavior of macrolides.
In some embodiments, the at least one active drug other than the macrolide drug is at least one other active drug other than the macrolide drug as defined above.
In some embodiments, the method for coating is at least one of micropipetting, dip coating, brushing, or spraying (such as spraying with an ultrasonic piezoelectric nozzle).
The one or more embodiments of the present application successfully prepare elongated prismatic active drug crystalline particles with high aspect ratio, sharp edges and corners, which can effectively improve the adhesion performance of the drug on the medical device, allowing prolonged delivery time of the medical device, and increase the transfer speed of the drug to a blood vessel wall, and prolong drug concentration in tissue. The embodiments of the present application will be described in detail below in combination with examples.
In the following examples, the balloon catheter has a diameter of 3.0 mm and a length of 20 mm.
1 g of rapamycin raw material was dispersed in 50 mL of n-heptane, added with a stir bar, stirred overnight with a stirring speed of 300 rpm at room temperature under protection against light, and then filtered to obtain a filter cake. The filter cake was vacuum dried to obtain crystalline rapamycin, whose crystallinity was measured using infrared spectroscopy or powder X-ray diffraction, resulting that the crystallinity is above 90%.
7 mg of the above crystalline rapamycin was put in a brown bottle, added with 10 mL of n-heptane to disperse the rapamycin, and then added with 2.5 g of zirconia beads (Φ0.2-0.3 mm). The bottle was sealed and agitated on a vortex mixer for 10 minutes at a speed of 2500 rpm. After the agitation, the mixture was ultrasonicated in a water bath for 3 minutes, and filtered with a 40 μm nylon filter to remove the zirconia beads and obtain the filtrate. 20 μL of the filtrate was drawn by a micro syringe and evenly coated onto a surface of a balloon, and air dried for 2 hours under protection against light.
125 mg of rapamycin and 15 mg of dibutylhydroxytoluene were dissolved in a mixed solution of 3 mL of acetone and 2 mL of ethanol, and then added with 3 mL of purified water to form a supersaturated solution of rapamycin.
The prepared rapamycin supersaturated solution was uniformly sprayed by ultrasonic spray onto the surface of the balloon prepared in the previous step at a drug concentration of 3 μg/mm2. The rotation speed of the balloon was 200 rpm, the moving speed of the ultrasonic spray nozzle was 0.2 mm/s, and the solution ejection speed was 0.8 μL/s. After air dried for 24 hours, the balloon surface was sterilized with ethylene oxide, and the morphology thereof was observed under a scanning electron microscope (SEM).
1 g of everolimus raw material was dispersed in 50 mL of n-heptane, added with a stir bar, stirred overnight with a stirring speed of 300 rpm at room temperature under protection against light, and then filtered to obtain a filter cake. The filter cake was vacuum dried to obtain crystalline everolimus, whose crystallinity was measured using infrared spectroscopy or powder X-ray diffraction, resulting that the crystallinity is above 90%.
7 mg of the above crystalline everolimus was put in a brown bottle, added with 10 mL of n-heptane to disperse the everolimus, and then added with 2.5 g of zirconia beads (ΦD0.2-0.3 mm). The bottle was sealed and agitated on a vortex mixer for 10 minutes at a speed of 2500 rpm. After the agitation, the mixture was ultrasonicated in a water bath for 3 minutes, and filtered with a 40 μm nylon filter to remove the zirconia beads and obtain the filtrate. 20 μL of the filtrate was drawn by a micro syringe and evenly coated onto a surface of a balloon, and air dried for 2 hours under protection against light.
125 mg of everolimus, 25 mg of paclitaxel, and 15 mg of dibutylhydroxytoluene were dissolved in a mixed solution of 3 mL of acetone and 2 mL of ethanol, and then added with 3 mL of purified water to form a supersaturated solution of everolimus.
The prepared everolimus supersaturated solution was uniformly sprayed by ultrasonic spray onto the surface of the balloon prepared in the previous step at a drug concentration of 3 μg/mm2. The rotation speed of the balloon was 200 rpm, the moving speed of the ultrasonic spray nozzle was 0.2 mm/s, and the solution ejection speed was 0.8 μL/s. After air dried for 24 hours, the balloon surface was sterilized with ethylene oxide, and the morphology thereof was observed under a scanning electron microscope (SEM). In the SEM photo, not only elongated prisms but also paclitaxel crystals on the surface of the elongated prisms can be observed.
1 g of rapamycin raw material was dispersed in 50 mL of n-heptane, added with a stir bar, stirred overnight with a stirring speed of 300 rpm at room temperature under protection against light, and then filtered to obtain a filter cake. The filter cake was vacuum dried at 50° C. to obtain crystalline rapamycin, whose crystallinity was measured using infrared spectroscopy or powder X-ray diffraction, resulting that the crystallinity is above 90%.
A balloon catheter (with a diameter of 3.0 mm and a length of 20 mm) was provided, and 20 μL of a methanol-water solution of calcium chloride (50 mg/mL, methanol:water=1:1, v:v) was first sprayed onto the surface of the balloon catheter. 7 mg of the above crystalline rapamycin was put in a brown bottle, added with 10 mL of n-heptane to disperse the rapamycin, and then added with 2.5 g of zirconia beads (Φ0.1-0.8 mm). The bottle was sealed and agitated on a vortex mixer for 10 minutes at a speed of 2500 rpm. After the agitation, the mixture was ultrasonicated in a water bath for 3 minutes, and filtered with a 40 μm nylon filter to remove the zirconia beads and obtain the filtrate. 20 μL of the filtrate was drawn by a micro syringe and evenly coated onto the surface of the balloon, and air dried for 2 hours under protection against light.
125 mg of rapamycin and 15 mg of dibutylhydroxytoluene were dissolved in a mixed solution of 3 mL of acetone and 2 mL of ethanol, and then added with 3 mL of purified water to form a supersaturated solution of rapamycin.
The prepared rapamycin supersaturated solution was uniformly sprayed by ultrasonic spray onto the surface of the balloon prepared in the previous step at a drug concentration of 3 μg/mm2. The rotation speed of the balloon was 200 rpm, the moving speed of the ultrasonic spray nozzle was 0.2 mm/s, and the solution ejection speed was 0.8 μL/s. After air dried for 24 hours, the balloon surface was sterilized with ethylene oxide, and the morphology thereof was observed under a scanning electron microscope (SEM).
Effects of supersaturated solutions of rapamycin at different concentrations on the morphology.
1 g of rapamycin raw material was dispersed in 50 mL of n-heptane, added with a stir bar, stirred overnight with a stirring speed of 300 rpm at room temperature under protection against light, and then filtered to obtain a filter cake. The filter cake was vacuum dried to obtain crystalline rapamycin, whose crystallinity was measured using infrared spectroscopy or powder X-ray diffraction, resulting that the crystallinity is above 90%.
7 mg of the above crystalline rapamycin was put in a brown bottle, added with 10 mL of n-heptane to disperse the rapamycin, and then added with 2.5 g of zirconia beads (D0.2-0.3 mm). The bottle was sealed and agitated on a vortex mixer for 10 minutes at a speed of 2500 rpm. After the agitation, the mixture was ultrasonicated in a water bath for 3 minutes, and filtered with a 40 μm nylon filter to remove the zirconia beads and obtain the filtrate. 20 μL of the filtrate was drawn by a micro syringe and evenly coated onto a surface of a balloon, and air dried for 2 hours under protection against light.
360 mg of rapamycin and 30 mg of dibutylhydroxytoluene were dissolved in a mixed solution of 3 mL of acetone and 2 mL of ethanol, and then added with 1 mL of purified water to form a supersaturated solution of rapamycin (60 mg/mL).
The prepared rapamycin supersaturated solution was uniformly sprayed by ultrasonic spray onto the surface of the balloon prepared in the previous step at a drug concentration of 3 μg/mm2. The rotation speed of the balloon was 200 rpm, the moving speed of the ultrasonic spray nozzle was 0.2 mm/s, and the solution ejection speed was 0.8 μL/s. After air dried for 24 hours, the balloon surface was sterilized with ethylene oxide, and the morphology thereof was observed under a scanning electron microscope (SEM).
1 g of rapamycin raw material was dispersed in 50 mL of n-heptane, added with a stir bar, stirred overnight with a stirring speed of 300 rpm at room temperature under protection against light, and then filtered to obtain a filter cake. The filter cake was vacuum dried to obtain crystalline rapamycin, whose crystallinity was measured using infrared spectroscopy or powder X-ray diffraction, resulting that the crystallinity is above 90%.
7 mg of the above crystalline rapamycin was put in a brown bottle, added with 10 mL of n-heptane to disperse rapamycin, and then added with 2.5 g of zirconia beads (D0.2-0.3 mm). The bottle was sealed and agitated on a vortex mixer for 10 minutes at a speed of 2500 rpm. After the agitation, the mixture was ultrasonicated in a water bath for 3 minutes, and filtered with a 40 μm nylon filter to remove the zirconia beads and obtain the filtrate. 20 μL of the filtrate was drawn by a micro syringe and evenly coated onto a surface of a balloon, and air dried for 2 hours under protection against light.
40 mg of rapamycin and 15 mg of dibutylhydroxytoluene were dissolved in a mixed solution of 3 mL of acetone and 2 mL of ethanol, and then added with 3 mL of purified water to form a supersaturated solution of rapamycin.
The prepared rapamycin supersaturated solution was uniformly sprayed by ultrasonic spray onto the surface of the balloon prepared in the previous step at a drug concentration of 3 μg/mm2. The rotation speed of the balloon was 200 rpm, the moving speed of the ultrasonic spray nozzle was 0.2 mm/s, and the solution ejection speed was 0.8 μL/s. After air dried for 24 hours, the balloon surface was sterilized with ethylene oxide, and the morphology thereof was observed under a scanning electron microscope (SEM).
7 mg of clarithromycin was put in a brown bottle, added with 10 mL of n-heptane to disperse the clarithromycin, and then added with 2.5 g of zirconia beads (Φ00.2-0.3 mm). The bottle was sealed and agitated on a vortex mixer for 10 minutes at a speed of 2500 rpm. After the agitation, the mixture was ultrasonicated in a water bath for 3 minutes, and filtered with a 40 μm nylon filter to remove the zirconia beads and obtain the filtrate. 20 μL of the filtrate was drawn by a micro syringe and evenly coated onto a surface of a balloon, and air dried for 2 hours under protection against light.
80 mg of clarithromycin and 15 mg of dibutylhydroxytoluene were dissolved in a mixed solution of 3 mL of acetone and 2 mL of ethanol, and then added with 3 mL of purified water to form a supersaturated solution of clarithromycin.
The prepared clarithromycin supersaturated solution was uniformly sprayed by ultrasonic spray onto the surface of the balloon prepared in the previous step at a drug concentration of 3 μg/mm2. The rotation speed of the balloon was 200 rpm, the moving speed of the ultrasonic spraying nozzle was 0.2 mm/s, and the solution ejection speed was 0.8 μL/s. After air dried for 24 hours, the balloon surface was sterilized with ethylene oxide, and the morphology thereof was observed under a scanning electron microscope (SEM).
1 g of rapamycin raw material was dispersed in 50 mL of n-heptane, added with a stir bar, stirred overnight with a stirring speed of 300 rpm at room temperature under protection against light, and then filtered to obtain a filter cake. The filter cake was vacuum dried to obtain crystalline rapamycin, whose crystallinity was measured using infrared spectroscopy or powder X-ray diffraction, resulting that the crystallinity is above 90%.
7 mg of the above crystalline rapamycin was put in a brown bottle, added with 10 mL of n-heptane to disperse the rapamycin, and then added with 2.5 g of zirconia beads (Φ0.2-0.3 mm). The bottle was sealed and agitated on a vortex mixer for 10 minutes at a speed of 2500 rpm. After the agitation, the mixture was ultrasonicated in a water bath for 3 minutes, and filtered with a 40 μm nylon filter to remove the zirconia beads and obtain the filtrate. 20 μL of the filtrate was drawn by a micro syringe and evenly coated onto a surface of a balloon, and air dried for 2 hours under protection against light.
160 mg of rapamycin and 15 mg of dibutylhydroxytoluene were dissolved in a mixed solution of 3 mL of acetone and 2 mL of ethanol, and then added with 3 mL of purified water to form a supersaturated solution of rapamycin.
The prepared rapamycin supersaturated solution was uniformly sprayed by ultrasonic spray onto the surface of the balloon prepared in the previous step at a drug concentration of 3 μg/mm2. The rotation speed of the balloon was 200 rpm, the moving speed of the ultrasonic spray nozzle was 0.2 mm/s, and the solution ejection speed was 0.8 μL/s. After air dried for 24 hours, the balloon surface was sterilized with ethylene oxide, and the morphology thereof was observed under a scanning electron microscope (SEM).
1 g of rapamycin raw material was dispersed in 50 mL of n-heptane, added with a stir bar, stirred overnight with a stirring speed of 300 rpm at room temperature under protection against light, and then filtered to obtain a filter cake. The filter cake was vacuum dried at 50° C. to obtain crystalline rapamycin, whose crystallinity was measured using infrared spectroscopy or powder X-ray diffraction, resulting that the crystallinity is above 90%.
A balloon catheter (with a diameter of 3.0 mm and a length of 20 mm) was provided, and 20 μL of butylated hydroxytoluene (dissolved in n-heptane, 50 mg/mL) solution was first sprayed onto the surface of the balloon catheter. 7 mg of the above crystalline rapamycin was put in a brown bottle, added with 10 mL of n-heptane to disperse the rapamycin, and then added with 2.5 g of zirconia beads (Φ0.1-0.8 mm). The bottle was sealed and agitated on a vortex mixer for 10 minutes at a speed of 2500 rpm. After the agitation, the mixture was ultrasonicated in a water bath for 3 minutes, and filtered with a 40 μm nylon filter to remove the zirconia beads and obtain the filtrate. 20 μL of the filtrate was drawn by a micro syringe and evenly coated onto the surface of the balloon, and air dried for 2 hours under protection against light.
125 mg of rapamycin and 15 mg of dibutylhydroxytoluene were dissolved in a mixed solution of 3 mL of acetone and 2 mL of ethanol, and then added with 3 mL of purified water to form a supersaturated solution of rapamycin. The prepared rapamycin supersaturated solution was uniformly sprayed by ultrasonic spray onto the surface of the balloon prepared in the previous step at a drug concentration of 3 μg/mm2. The rotation speed of the balloon was 200 rpm, the moving speed of the ultrasonic spray nozzle was 0.2 mm/s, and the solution ejection speed was 0.8 μL/s. After air dried for 24 hours, the balloon surface was sterilized with ethylene oxide, and the morphology thereof was observed under a scanning electron microscope (SEM).
1 g of rapamycin raw material was dispersed in 50 mL of n-heptane, added with a stir bar, stirred overnight with a stirring speed of 300 rpm at room temperature under protection against light, and then filtered to obtain a filter cake. The filter cake was vacuum dried at 50° C. to obtain crystalline rapamycin, whose crystallinity was measured using infrared spectroscopy or powder X-ray diffraction, resulting that the crystallinity is above 90%.
A balloon catheter (with a diameter of 3.0 mm and a length of 20 mm) was provided. 7 mg of the above crystalline rapamycin was put in a brown bottle, added with 10 mL of n-heptane to disperse the rapamycin, and then added with 2.5 g of zirconia beads (Φ0.1-0.8 mm). The bottle was sealed and agitated on a vortex mixer for 10 minutes at a speed of 2500 rpm. After the agitation, the mixture was ultrasonicated in a water bath for 3 minutes, and filtered with a 40 μm nylon filter to remove the zirconia beads and obtain the filtrate. 20 μL of the filtrate was drawn by a micro syringe and evenly coated onto a surface of the balloon, and air dried for 2 hours under protection against light.
125 mg of rapamycin, 25 mg of paclitaxel, and 15 mg of dibutylhydroxytoluene were dissolved in a mixed solution of 3 mL of acetone and 2 mL of ethanol, and then added with 3 mL of purified water to form a supersaturated solution of rapamycin. The prepared supersaturated solution was uniformly sprayed by ultrasonic spray onto the surface of the balloon prepared in the previous step at a drug concentration of 3 μg/mm2. The rotation speed of the balloon was 200 rpm, the moving speed of the ultrasonic spray nozzle was 0.2 mm/s, and the solution ejection speed was 0.8 IL/s. After air dried for 24 hours, the balloon surface was sterilized with ethylene oxide, and the morphology thereof was observed under a scanning electron microscope (SEM).
1 g of rapamycin raw material was dispersed in 50 mL of n-heptane, added with a stir bar, stirred overnight with a stirring speed of 300 rpm at room temperature under protection against light, and then filtered to obtain a filter cake. The filter cake was vacuum dried at 50° C. to obtain crystalline rapamycin, whose crystallinity was measured using infrared spectroscopy or powder X-ray diffraction, resulting that the crystallinity is above 90%.
A metal stent (with a diameter of 3.0 mm and a length of 18 mm) was provided. 7 mg of the above crystalline rapamycin was put in a brown bottle, added with 10 mL of n-heptane to disperse the rapamycin, and then added with 2.5 g of zirconia beads (Φ0.1-0.8 mm). The bottle was sealed and agitated on a vortex mixer for 10 minutes at a speed of 2500 rpm. After the agitation, the mixture was ultrasonicated in a water bath for 3 minutes, and filtered with a 40 μm nylon filter to remove the zirconia beads and obtain the filtrate. 20 μL of the filtrate was drawn by a micro syringe and evenly coated onto a surface of the stent, and air dried for 2 hours under protection against light.
125 mg of rapamycin and 15 mg of dibutylhydroxytoluene were dissolved in a mixed solution of 3 mL of acetone and 2 mL of ethanol, and then added with 3 mL of purified water to form a supersaturated solution of rapamycin. The prepared supersaturated solution was uniformly sprayed by ultrasonic spray onto the surface of the metal stent prepared in the previous step to form a drug content of 100 μg. The rotation speed of the stent was 200 rpm, the moving speed of the ultrasonic spray nozzle was 0.2 mm/s, and the solution ejection speed was 0.8 μL/s. After air dried for 24 hours, the stent surface was sterilized with ethylene oxide, and the morphology thereof was observed under a scanning electron microscope (SEM).
1 g of rapamycin raw material was dispersed in 50 mL of n-heptane, added with a stir bar, stirred overnight with a stirring speed of 300 rpm at room temperature under protection against light, and then filtered to obtain a filter cake. The filter cake was vacuum dried at 50° C. to obtain crystalline rapamycin, whose crystallinity was measured using infrared spectroscopy or powder X-ray diffraction, resulting that the crystallinity is above 90%.
A balloon catheter (with a diameter of 3.0 mm and a length of 20 mm) was provided. 2 mg of the above crystalline rapamycin was put in a brown bottle, added with 10 mL of n-heptane to disperse the rapamycin, and then added with 2.5 g of zirconia beads (Φ0.1-0.8 mm). The bottle was sealed and agitated on a vortex mixer for 10 minutes at a speed of 2500 rpm. After the agitation, the mixture was ultrasonicated in a water bath for 3 minutes, and filtered with a 40 μm nylon filter to remove the zirconia beads and obtain the filtrate. 20 μL of the filtrate was drawn by a micro syringe and evenly coated onto a surface of the balloon, and air dried for 2 hours under protection against light.
125 mg of rapamycin and 15 mg of dibutylhydroxytoluene were dissolved in a mixed solution of 3 mL of acetone and 2 mL of ethanol, and then added with 3 mL of purified water to form a supersaturated solution of rapamycin. The prepared supersaturated solution was uniformly sprayed by ultrasonic spray onto the surface of the balloon prepared in the previous step at a drug concentration of 3 μg/mm2. The rotation speed of the balloon was 200 rpm, the moving speed of the ultrasonic spray nozzle was 0.2 mm/s, and the solution ejection speed was 0.4 μL/s. After air dried for 24 hours, the balloon surface was sterilized with ethylene oxide, and the morphology thereof was observed under a scanning electron microscope (SEM).
1 g of rapamycin raw material was dispersed in 50 mL of n-heptane, added with a stir bar, stirred overnight with a stirring speed of 300 rpm at room temperature under protection against light, and then filtered to obtain a filter cake. The filter cake was vacuum dried at 50° C. to obtain crystalline rapamycin, whose crystallinity was measured using infrared spectroscopy or powder X-ray diffraction, resulting that the crystallinity is above 90%.
A balloon catheter (with a diameter of 3.0 mm and a length of 20 mm) was provided. 2 mg of the above crystalline rapamycin was put in a brown bottle, added with 10 mL of n-heptane to disperse rapamycin, and then added with 2.5 g of zirconia beads (Φ0.1-0.8 mm). The bottle was sealed and agitated on a vortex mixer for 10 minutes at a speed of 2500 rpm. After the agitation, the mixture was ultrasonicated in a water bath for 3 minutes, and filtered with a 40 μm nylon filter to remove the zirconia beads and obtain the filtrate. 20 μL of the filtrate was drawn by a micro syringe and evenly coated onto a surface of the balloon, and air dried for 2 hours under protection against light. Then, 20 μL of sodium benzoate water solution (15 mg/ml) was evenly sprayed onto the surface of the balloon, and air dried for 5 hours under protection against light.
125 mg of rapamycin and 15 mg of dibutylhydroxytoluene were dissolved in a mixed solution of 3 mL of acetone and 2 mL of ethanol, and then added with 3 mL of purified water to form a supersaturated solution of rapamycin. The prepared supersaturated solution was uniformly sprayed by ultrasonic spray onto the surface of the balloon prepared in the previous step at a drug concentration of 3 μg/mm2. The rotation speed of the balloon was 200 rpm, and the moving speed of the ultrasonic spray nozzle was 0.2 mm/s, and the solution ejection speed was 0.4 μL/s. After air dried for 24 hours, the balloon surface was sterilized with ethylene oxide, and the morphology thereof was observed under a scanning electron microscope (SEM).
7 mg of paclitaxel was put in a brown bottle, added with 10 mL of n-heptane to disperse the paclitaxel, then added with 2.5 g of zirconia beads (Φ0.2-0.3 mm). The bottle was sealed and agitated on a vortex mixer for 10 minutes at a speed of 2500 rpm. After the agitation, the mixture was ultrasonicated in a water bath for 3 minutes, and filtered with a 40 μm nylon filter to remove the zirconia beads and obtain the filtrate. 20 μL of the filtrate was drawn by a micro syringe and evenly coated onto a surface of a balloon, and air dried for 2 hours under protection against light.
125 mg of paclitaxel and 15 mg of dibutylhydroxytoluene were dissolved in a mixed solution of 3 mL of acetone and 2 mL of ethanol, and then added with 3 mL of purified water to form a supersaturated solution of paclitaxel.
The prepared paclitaxel supersaturated solution was uniformly sprayed by ultrasonic spray onto the surface of the balloon prepared in the previous step at a drug concentration of 3 μg/mm2. The rotation speed of the balloon was 200 rpm, the moving speed of the ultrasonic spray nozzle was 0.2 mm/s, and the solution ejection speed was 0.8 μL/s. After air dried for 24 hours, the balloon surface was sterilized with ethylene oxide, and the morphology thereof was observed under a scanning electron microscope (SEM).
125 mg of rapamycin was dissolved in a mixed solution of 3 mL of acetone and 2 mL of ethanol, and then added with 3 mL of purified water to form a supersaturated solution of rapamycin.
The prepared rapamycin supersaturated solution was uniformly sprayed by ultrasonic spray onto a surface of a balloon at a drug concentration of 3 μg/mm2. The rotation speed of the balloon was 200 rpm, the moving speed of the ultrasonic spray nozzle was 0.2 mm/s, and the solution ejection speed was 0.8 μL/s. After air dried for 24 hours, the balloon surface was sterilized with ethylene oxide, and the morphology thereof was observed under a scanning electron microscope (SEM).
Test Methods and Results
1. Test for Retention Time on Tissue
A group of healthy pigs weighting between 35 kg to 40 kg were selected and administered with aspirin at a dose of 100 mg/day and with clopidogrel at a dose of 75 mg/day for 3 days before operation. The drug balloon or drug stent prepared in the above examples were delivered to a target blood vessel segment, selected from blood vessel segments in the left circumflex (LCX) artery, left anterior descending (LAD) artery, and right coronary artery (RCA) of the coronary arteries of the pigs, dilated for 1 minute with a dilation ratio (ratio of balloon dilation diameter to blood vessel diameter) of 1.1 to 1.2, followed by a 60-second dilation period. Subsequently, the balloon or stent was deflated and withdrawn from the body. The sampling time points were set as 30 minutes, 7 days, and 28 days after the implantation, with 3 pigs used for each time point in the experiment. Postoperatively, the pigs were administered with the anticoagulant drug, clopidogrel (75 mg/d) and aspirin (100 mg/d). The pigs were sacrificed according to the designated time points, and tissue samples were collected for analysis of drug concentrations using high-performance liquid chromatography-mass spectrometry (HPLC-MS). The drug residues on the balloon surface after the experiment were measured using high-performance liquid chromatography (HPLC).
2. Firmness Test
A heart and vascular model was prepared (according to ASTM F2394-07). The drug balloon prepared in the above example was introduced into a guiding catheter along a guide wire and finally delivered to the edge of the heart model. The delivery time was controlled to be 2 minutes, and then, the balloon without dilation was withdrawn out and the residual amount of drug on the balloon was measured. The firmness was measured by the delivery loss rate of drug during the delivery to the heart and vascular model (delivery loss %=1−residual drug amount on the balloon/nominal drug amount, %). The lower the delivery loss rate, the better the coating firmness.
3. Measurement of Aspect Ratio of Drug Crystalline Particles
The drug crystalline particle carrier device prepared in each example were examined using a scanning electron microscope (SEM) to capture images of the drug coating. Then, the length and width of the drug crystalline particles were measured by using Image J software. The aspect ratio which was equal to length/width was calculated.
16 ± 3.2
22 ± 4.9
312 ± 23.1
291 ± 88.9
278 ± 54.2
23 ± 6.1
387 ± 41.3
83 ± 22.6
280 ± 66.1
14 ± 7.9
As shown in
It can be seen from Table 3 that the drug balloons prepared in Examples 1 to 12 exhibit excellent coating firmness, with delivery losses less than or equal to 24%. In contrast, the delivery losses of Comparative Examples 1 and 2 are more than 30%, the firmness is poor, making the drug easy to loss during delivery. The drug balloons prepared in Examples 1 to 12 of the present application have excellent firmness and can be used in complex lesions. This is likely due to that the technical solution in the present application abandons the hydrophilic excipients commonly used in traditional coated balloons. Furthermore, the prismatic morphology of the drug crystals results in greater contact force with the device substrate, significantly reducing drug loss in delivery.
The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the technical features are described in the embodiments. However, as long as there is no contradiction in the combination of these technical features, the combinations should be considered as in the scope of the present application.
The above-described embodiments are only several implementations of the present application, and the descriptions are relatively specific and detailed, but they should not be construed as limiting the scope of the present application. It should be understood by those of ordinary skill in the art that various modifications and improvements can be made without departing from the concept of the present application, and all fall within the protection scope of the present application. Therefore, the patent protection of the present application shall be defined by the appended claims, the description and drawings may be used to illustrate the content of the claim.
| Number | Date | Country | Kind |
|---|---|---|---|
| 202110195532.5 | Feb 2021 | CN | national |
This application is an U.S. national phase application under 35 U.S.C. § 371 based upon international patent application No. PCT/CN2022/073345 filed on Jan. 24, 2022, which itself claims priority to Chinese patent application No. 202110195532.5, titled “DRUG-LOADED MEDICAL INSTRUMENT AND PREPARATION METHOD THEREFOR”, filed on Feb. 22, 2021, in the China National Intellectual Property Administration, the content of which is hereby incorporated by reference in its entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2022/073345 | 1/24/2022 | WO |
