DRUG-LOADED IMPLANTED MEDICAL DEVICE AND PREPARATION METHOD THEREFOR

Abstract

A drug-loaded implanted medical device and a preparation method therefor. The drug-loaded implanted medical device comprises a device body and grooves (2) distributed on the surface of the device body, and at least one of the grooves (2) is loaded with a solid drug (11); the solid drug (11) is a crystal or has a form in which a crystal coexists with an amorphous body. The preparation method is implemented by loading the solid drug (11) into at least one of the grooves (2) by means of solution crystallization.

Claims

1. A drug-loaded implantable medical device, comprising a body and grooves distributed on a surface of the body, at least one of the grooves having a solid drug loaded therein, the solid drug being a crystal or having a form in which a crystal and an amorphous body coexist.

2. The drug-loaded implantable medical device according to claim 1, wherein the solid drug is one or more selected from the group consisting of paclitaxel, sirolimus and sirolimus derivatives.

3. The drug-loaded implantable medical device according to claim 1, wherein the grooves each have a depth of from 5 μm to 100 μm.

4. The drug-loaded implantable medical device according to claim 1, wherein the grooves each have an opening area of from 200 μm.sup.2 to 75,000 μm.sup.2.

5. A preparation method of a drug-loaded implantable medical device according to claim 1, wherein the solid drug is loaded in the at least one of the grooves using a solution crystallization process.

6. The method according to claim 5, wherein the solution crystallization process is performed by obtaining a drug solution through dissolution of an active drug in a mixed solvent, disposing the drug solution into the at least one of the grooves, and after volatilization or evaporation of the mixed solvent, obtaining an implantable medical device in which the solid drug is entirely or partially crystallized in the at least one of the grooves.

7. The method according to claim 6, wherein the mixed solvent comprises a solvent A and a solvent B, the solvent A selected from acetone, isopropanol, methanol or ethanol, preferably selected from isopropanol or ethanol, the solvent B selected from n-heptane, acetonitrile, n-propyl acetate or ethyl acetate, preferably selected from n-heptane or n-propyl acetate.

8. The method according to claim 7, wherein a volume ratio of the solvent A to solvent B is from 2:1 to 1:99.

9. The method according to claim 6, wherein the active drug is present in the drug solution at a mass percentage of from 0.1% to 20%.

10. The method according to claim 6, wherein the drug solution is subjected to two or more processes of spraying and solvent volatilization or evaporation, so as to be loaded in the grooves in batches.

11. The method according to claim 10, wherein the spraying is conducted at an ambient temperature of from 20° C. to 40° C.

12. The method according to claim 10, wherein the drug solution is sprayed for 2-25 times per groove, each spray providing an amount of from 300 pL to 600 pL of the drug solution.

13. The drug-loaded implantable medical device according to claim 3, wherein the grooves each have a depth of from 15 μm to 75 μm.

14. The drug-loaded implantable medical device according to claim 4, wherein the grooves each have an opening area of from 2,000 μm.sup.2 to 15,000 μm.sup.2.

15. The drug-loaded implantable medical device according to claim 4, wherein the grooves each have an opening area of from 4,000 μm.sup.2 to 8,000 μm.sup.2.

16. The method according to claim 9, wherein the active drug is present in the drug solution at a mass percentage of from 2% to 10%.

17. The method according to claim 11, wherein the spraying is conducted at an ambient temperature of from 25° C. to 30° C.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0021] FIG. 1 is a structural schematic of a stent of the prior art.

[0022] FIG. 2 schematically illustrates a drug-loading groove of the stent surface of FIG. 1 and a solid drug loaded therein.

[0023] FIG. 3 is an electron micrograph of the drug-loaded stent of Embodiment 1.

[0024] FIG. 4 is an electron micrograph of a solid drug in a drug-loading groove of Embodiment 1.

DETAILED DESCRIPTION

[0025] For ease of understanding, the provided drug-loaded implantable medical device will be described below combining with specific embodiments. It is to be understood that these embodiments are provided merely for illustration of present application rather than limiting the scope thereof in any sense.

[0026] For ease of explanation, the technical solution of present application implemented using merely one specific stent is described below and reference can be made for implementations of other types of drug-loaded implantable medical devices.

[0027] The medical device involved in the present application may be either an implantable device or a device for extracorporeal use. It can be either used temporarily in a short term or permanently implanted for a long term. In some embodiment, suitable devices are those typically used to provide medical therapy and/or diagnostics for heart rhythm disorders, heart failures, valve diseases, vascular diseases, diabetes, neurological diseases and disorders, orthopedics, neurosurgery, oncology, ophthalmology, and ENT surgeries. The medical devices involved in present application may include, but are not limited to, stent, stent graft, anastomotic connector, synthetic patch, lead, electrode, needle, guide wire, catheter, sensor, surgical instruments, angioplasty balloon, wound drainage tube, shunt, pipe, infusion sleeve, intraurethral cannula, pellet, implant, blood oxygenator, pump, vascular graft, vascular access port, heart valve, annuloplasty ring, suture, surgical clip, surgical nail, pacemaker, implantable defibrillator, neurostimulator, orthopedic devices, cerebrospinal fluid shunt, implantable drug pump, spinal cage, artificial intervertebral disc, replacement devices for nucleus pulposus, ear canal, intraocular lens and any tubing used in an interventional surgery.

[0028] As shown in FIG. 1, the stent is made of cobalt-chromium alloy and constructed from a plurality of main support rings 1, 8 and connecting rods 4, 6 connecting the rings together. Each main support ring consists of a plurality of wavy elements. Each wavy element consists of arc-shaped reinforcing sections 9, straight sections 10 composed of struts and intermediate sections (e.g., 3, 5, 7) connecting the reinforcing sections 9 and straight sections 10. The external surface of each straight section is provided with a groove 2 that can load a drug. In the wavy elements of the main support rings, each straight section 10 has a width of 96 μm, and each reinforcing section 9 has a width of 91 μm. In addition, the intermediate section smoothly links the straight section 10 with the reinforcing section 9, and the stent body has a thickness of 100 μm.

[0029] The laser cutting technique is used to form a groove 2 with a substantially rectangular opening. The groove 2 has a depth of from 5 μm to 100 μm, preferably from 15 μm to 75 μm, such as 30 μm, and the groove opening has an area of from 200 μm.sup.2 to 75,000 μm.sup.2, preferably from 2,000 μm.sup.2 to 15,000 μm.sup.2, more preferably from 4,000 μm.sup.2 to 8,000 μm.sup.2. The groove 2 has been processed for use. It is to be noted that the openings of the grooves 2 may be square, elliptic, circular or irregular. Distributions of the grooves 2 on the stent body may be regular or random, may be continuous or discontinuous, may be across the entire surface of the stent body or just present in some portions, may have a uniform density or a region-dependent density.

[0030] In general, a solid drug may be loaded in the grooves 2 using the following approach.

[0031] A drug solution obtained by dissolving the active drug in mixed solvent is filtered and accurately sprayed into the grooves of the stent body. After volatilization or evaporation of the mixed solvent and drying, a drug stent in which the solid drug is entirely or partially crystallized in each groove is obtained.

[0032] FIG. 2 shows that a solid drug 11 is loaded in a groove 2 formed on the surface of a metal stent strut.

[0033] Optionally, the drug solution obtained by dissolving the active drug in the mixed solvents may be subjected to two or more processes of spraying and solvent volatilization or evaporation, so as to be disposed in grooves in batches. In this way, a drug-loaded stent with different drug-loading amounts in different grooves or a drug-loaded stent satisfying a specific desired drug release profile can be obtained.

[0034] The setup and crystallization will be described in greater detail in following embodiments.

Embodiment 1

[0035] A drug solution containing 5% by weight of sirolimus was obtained by placing sirolimus in 10 ml of a methanol/n-propyl acetate (v/v=1:70) mixture at 40° C. for 1 h and then filtering the solution. The obtained drug solution is accurately sprayed into grooves 2 of a stent body at a controlled amount of 500 pL per groove 2. The stent body was then placed at 20° C. for natural volatilization or evaporation of the solvents. After natural volatilization or evaporation of the solvents, the spray process was repeated until each groove 2 had been treated for a total of 5 times. After that, irradiating sterilization was performed to the stent body, so as to result in a carrier-free drug stent. As shown in the electron micrographs of FIGS. 3 and 4, the crystalline solid drug was present in the carrier-free drug stent.

Embodiment 2

[0036] A drug solution containing 1% by weight of sirolimus was obtained by placing sirolimus in 10 ml of an ethanol/n-propyl acetate (v/v=1:2) mixture at 40° C. for 1 h and then filtering the solution. The obtained drug solution is accurately sprayed into grooves 2 of a stent body at a controlled amount of 500 pL per groove 2. The stent body was then placed at 20° C. for natural volatilization or evaporation of the solvents. After natural volatilization or evaporation of the solvents, the spray process was repeated until each groove 2 had been treated for a total of 25 times. After that, irradiating sterilization was performed to the stent, so as to result in a carrier-free drug stent.

Embodiment 3

[0037] A drug solution containing 1% by weight of sirolimus was obtained by placing sirolimus in 10 ml of an acetone/n-heptane (v/v=1:5) mixture at 35° C. for 1 h and then filtering the solution. The obtained drug solution is accurately sprayed into grooves 2 of a stent body at a controlled amount of 500 pL per groove 2. The stent body was then placed at 25° C. for natural volatilization or evaporation of the solvents. After natural volatilization or evaporation of the solvents, the spray process was repeated until each groove 2 had been treated for a total of 25 times. After that, irradiating sterilization was performed to the stent, so as to result in a carrier-free drug stent.

Embodiment 4

[0038] A drug solution containing 1% by weight of sirolimus was obtained by placing sirolimus in 10 ml of an isopropanol/n-heptane (v/v=1:1) mixture at 35° C. for 1 h and then filtering the solution. The obtained drug solution is accurately sprayed into grooves 2 of a stent body at a controlled amount of 500 pL per groove 2. The stent body was then placed at 25° C. for natural volatilization or evaporation of the solvents. After natural volatilization or evaporation of the solvents, the spray process was repeated until each groove 2 had been treated for a total of 25 times. After that, irradiating sterilization was performed to the stent, so as to result in a carrier-free drug stent.

Embodiment 5

[0039] A drug solution containing 1% by weight of paclitaxel was obtained by placing paclitaxel in 10 ml of a acetone/ethyl acetate (v/v=1:2) mixture at 35° C. for 2 h and then filtering the solution. The obtained drug solution is accurately sprayed into grooves 2 of a stent body at a controlled amount of 600 pL per groove 2. The stent body was then placed at 25° C. for natural volatilization or evaporation of the solvents. After natural volatilization or evaporation of the solvents, the spray process was repeated until each groove 2 had been treated for a total of 2 times. After that, irradiating sterilization was performed to the stent, so as to result in a carrier-free drug stent.

Embodiment 6

[0040] A drug solution containing 6% by weight of paclitaxel was obtained by placing paclitaxel in 10 ml of a acetone/acetonitrile (v/v=2:1) mixture at 35° C. for 2 h and then filtering the solution. The obtained drug solution is accurately sprayed into grooves 2 of a stent body at a controlled amount of 300 pL per groove 2. The stent body was then placed at 20° C. for natural volatilization or evaporation of the solvents. After natural volatilization or evaporation of the solvents, the spray process was repeated until each groove 2 had been treated for a total of 2 times. After that, irradiating sterilization was performed to the stent, so as to result in a carrier-free drug stent.

Embodiment 7

[0041] A drug solution containing 3% by weight of paclitaxel was obtained by placing paclitaxel in 10 ml of an isopropanol/n-propyl acetate (v/v=1:80) mixture at 35° C. for 2 h and then filtering the solution. The obtained drug solution is accurately sprayed into grooves 2 of a stent body at a controlled amount of 300 pL per groove 2. The stent body was then placed at 20° C. for natural volatilization or evaporation of the solvents. After natural volatilization or evaporation of the solvents, the spray process was repeated until each groove 2 had been treated for a total of 2 times. After that, irradiating sterilization was performed to the stent, so as to result in a carrier-free drug stent.

Embodiment 8

[0042] A drug solution containing 10% by weight of paclitaxel was obtained by placing zotarolimus in 10 ml of an isopropanol/n-propyl acetate (v/v=1:1) mixture at 30° C. for 0.5 h and then filtering the solution. The obtained drug solution is accurately sprayed into grooves 2 of a stent body at a controlled amount of 300 pL per groove 2. The stent body was then placed at 20° C. for natural volatilization or evaporation of the solvents. After natural volatilization or evaporation of the solvents, the spray process was repeated until each groove 2 had been treated for a total of 9 times. After that, irradiating sterilization was performed to the stent, so as to result in a carrier-free drug stent.

Embodiment 9

[0043] A drug solution containing 10% by weight of paclitaxel was obtained by placing zotarolimus in 10 ml of an isopropanol/n-propyl acetate (v/v=2:1) mixture at 30° C. for 0.5 h and then filtering the solution. The obtained drug solution is accurately sprayed into grooves 2 of a stent body at a controlled amount of 300 pL per groove 2. The stent body was then placed at 20° C. for natural volatilization or evaporation of the solvents. After natural volatilization or evaporation of the solvents, the spray process was repeated until each groove 2 had been treated for a total of 9 times. After that, irradiating sterilization was performed to the stent, so as to result in a carrier-free drug stent.

Embodiment 10

[0044] A drug solution containing 10% by weight of paclitaxel was obtained by placing zotarolimus in 10 ml of an isopropanol/n-propyl acetate (v/v=2:1) mixture at 20° C. for 0.5 h and then filtering the solution. The obtained drug solution is accurately sprayed into grooves 2 of a stent body at a controlled amount of 300 pL per groove 2. The stent body was then placed at 20° C. for natural volatilization or evaporation of the solvents. After natural volatilization or evaporation of the solvents, the spray process was repeated until each groove 2 had been treated for a total of 9 times. After that, irradiating sterilization was performed to the stent, so as to result in a carrier-free drug stent.

Embodiment 11

[0045] A drug solution containing 20% by weight of paclitaxel was obtained by placing zotarolimus in 10 ml of an isopropanol/n-propyl acetate (v/v=1:10) mixture at 20° C. for 0.5 h and then filtering the solution. The obtained drug solution is accurately sprayed into grooves 2 of a stent body at a controlled amount of 350 pL per groove 2. The stent body was then placed at 20° C. for natural volatilization or evaporation of the solvents. After natural volatilization or evaporation of the solvents, the spray process was repeated until each groove 2 had been treated for a total of 4 times. After that, irradiating sterilization was performed to the stent, so as to result in a carrier-free drug stent.

Embodiment 12

[0046] A drug solution containing 20% by weight of paclitaxel was obtained by placing zotarolimus in 10 ml of an isopropanol/n-propyl acetate (v/v=1:50) mixture at 25° C. for 0.5 h and then filtering the solution. The obtained drug solution is accurately sprayed into grooves 2 of a stent body at a controlled amount of 350 pL per groove 2. The stent body was then placed at 20° C. for natural volatilization or evaporation of the solvents. After natural volatilization or evaporation of the solvents, the spray process was repeated until each groove 2 had been treated for a total of 4 times. After that, irradiating sterilization was performed to the stent, so as to result in a carrier-free drug stent.

Embodiment 13

[0047] A drug solution containing 10% by weight of paclitaxel was obtained by placing zotarolimus in 10 ml of an isopropanol/n-propyl acetate (v/v=1:99) mixture at 30° C. for 0.5 h and then filtering the solution. The obtained drug solution is accurately sprayed into grooves 2 of a stent body at a controlled amount of 400 pL per groove 2. The stent body was then placed at 20° C. for natural volatilization or evaporation of the solvents. After natural volatilization or evaporation of the solvents, the spray process was repeated until each groove 2 had been treated for a total of 7 times. After that, irradiating sterilization was performed to the stent, so as to result in a carrier-free drug stent.

Comparative Experiments

[0048] Comparative Example: a stent with a polymer coating is prepared in accordance with the method disclosed in CN 101879102 A.

[0049] Drug release experiments in vitro are performed for comparison between the carrier-free drug-loaded stents prepared in accordance with the above Embodiments and the drug-loaded stent of Comparative Example.

[0050] In vitro release was performed:

[0051] using the small cup method provided in the Chinese Pharmacopoeia with a 5% aqueous solution of sodium dodecyl sulfate (SDS) as a release medium at a temperature of 37° C. and a speed of 100 rpm. The results of samples taken respectively at 1 h, 8 h, 24 h, 3 d, 7 d, 14 d are shown in Table 1.

TABLE-US-00001 TABLE 1 Time 1 h 8 h 24 h 3 d 7 d 14 d Control Compartive 19.6% 38.5% 45.5% 62.4% 79.2% 93.9% Group Example Experimental Embodiment 1 25.5% 45.1% 53.8% 70.7% 85.5% 97.1% Group Embodiment 2 22.2% 40.4% 47.3% 66.0% 81.9% 94.0% Embodiment 3 23.4% 40.9% 48.1% 63.4% 75.6% 90.1% Embodiment 4 18.8% 39.8% 48.0% 65.1% 82.1% 98.9% Embodiment 5 13.9% 31.9% 40.5% 57.3% 74.1% 95.5% Embodiment 6 15.5% 33.4% 41.6% 55.2% 76.6% 96.7% Embodiment 7 16.1% 34.3% 40.7% 55.9% 72.9% 96.1% Embodiment 8 21.4% 35.7% 44.0% 58.7% 83.6% 98.8% Embodiment 9 22.8% 42.4% 49.7% 65.1% 84.6% 99.2% Embodiment 10 19.4% 39.0% 46.8% 61.1% 80.6% 95.3% Embodiment 11 12.8% 31.1% 38.9% 52.9% 67.9% 86.1% Embodiment 12 20.2% 40.1% 47.9% 64.0% 79.9% 95.5% Embodiment 13 18.6% 36.0% 45.1% 65.0% 83.1% 99.1%

[0052] As can be seen from the results in Table 1, the technical solution of present application can completely replace conventional drug carriers with crystallization to achieve drug loading and sustained release. Moreover, compared to the solution of using drug carriers, present application is able to fully solve the problem of clinical inflammatory response caused by the drug carrier and thus eliminate the consequent risks of the delayed vascular endothelialization and late vessel restenosis.

[0053] It is to be noted that the above embodiments are presented merely for the purpose of illustrating the present application and are not intended to limit it in any sense. Although the present application has been described in detail with reference to the foregoing embodiments, those of ordinary skilled in the art will appreciate that modifications can be made for the technical solutions provided in above embodiments or equivalent replacements can be made for part or all of the technical features. Such modifications or equivalent replacements do not depart the essence of the technical solutions from the scope of the various embodiments of the application.