CN110584851A

CN110584851A - Ultrasonic controlled-release grooved degradable microsphere drug-loaded stent and preparation method thereof

Info

Publication number: CN110584851A
Application number: CN201910895565.3A
Authority: CN
Inventors: 张海军; 葛均波; 侯文博
Original assignee: Shandong Branden Medical Devices Co Ltd
Current assignee: Shandong Branden Medical Devices Co Ltd
Priority date: 2019-09-21
Filing date: 2019-09-21
Publication date: 2019-12-20

Abstract

The invention discloses an ultrasonic controlled-release grooved degradable microsphere drug-loaded stent and a preparation method thereof, belonging to the field of medical drug-loaded vascular stents. The outer surface of the stent is provided with the drug coating, and the design of the groove on the outer surface increases the drug carrying capacity of the stent. The coating comprises degradable drug-loaded microspheres and a hydrophilic adhesive, drug loss caused by blood scouring in the compression, expansion and delivery processes of the self-expanding stent can be reduced by loading drugs on the microspheres and the grooves, and abrasion of a drug layer is reduced when the self-expanding stent is compressed and released. After the stent reaches a lesion part, in vitro ultrasonic intervention is carried out, the medicine-carrying microspheres are broken to release the medicine, and the unbroken microspheres degrade to release the medicine slowly. The invention improves the drug-loading rate of the stent, reduces the drug loss in stent processing and operation, prolongs the release time of the drug, controls the release rate and improves the safety and the effectiveness of stent products.

Description

Ultrasonic controlled-release grooved degradable microsphere drug-loaded stent and preparation method thereof

Technical Field

The invention belongs to the field of medical drug-loaded vascular stents in the field of medical instruments, and particularly relates to an ultrasonic controlled-release grooved degradable microsphere drug-loaded stent and a preparation method thereof.

Background

The drug eluting stent carries drugs through the polymer coated on the surface of the stent, and after the stent is implanted into a vascular lesion part, the drugs are released from the polymer coating to the wall of a cardiovascular vessel in an eluting mode to play pharmacological actions, such as inhibiting mitosis of cells and preventing restenosis of the vessel. In 2000, the first generation of the drug eluting stent, Cypher, was successfully used clinically for the first time. Over a decade, with the continuous efforts of scientists, drug eluting stents have undergone several generations of development and the therapeutic effect is becoming more perfect, however, at present, drug-loaded stents still face the following problems: (1) the bioavailability of the drug carried by the stent is low (2) the drug loss caused by blood scouring in the process of compressing, expanding and delivering the ball-expanding stent and the abrasion of the drug layer in the process of compressing and releasing the self-expanding stent. (3) Uncontrolled drug release (4) post-stent implantation restenosis and thrombotic events.

Patent CN200410096617 introduces a blood vessel stent with non-penetrating grooves or blind holes, which can be punched on the stent to increase the drug-carrying area, and partially avoid the drug loss caused by stent compression, stent expansion and blood flushing in the implantation process.

Patent CN200780050848 introduces an asymmetric drug controlled-release coating coronary stent, the drug stent coating is multilayer, and the drug concentration increases from outside to inside.

Patent CN201010200449 introduces a stent with drug temperature-sensitive controlled release function, which can utilize temperature to adjust the release rate of drug in the stent.

Patent CN201010222964 introduces a drug-loaded stent in a human body lumen and a preparation method thereof, wherein a plurality of holes are uniformly distributed on the peripheral surface of the stent, and the drug-loaded stent realizes targeted release of the drug, thereby increasing the controlled release capacity and the effective utilization rate of the drug.

Patent CN201110162705 introduces a bioabsorbable polymer stent matrix, a preparation method and an application thereof, wherein an incisional stent using an absorbable polymer as a stent main body material has a smaller outer diameter, can be better transmitted in a blood vessel, and can more easily pass through a narrow lesion area.

Patent CN201110235823 discloses a medicine carrying stent with ultrasonic intelligent controlled release, which can control the drug release rate and release time of the stent by ultrasonic technology.

Patent CN201110386167 discloses an embedded type graded drug release three-dimensional stent and a preparation method thereof, the patent wraps a stent inner layer-shaped embryo with high porosity through a stent outer layer-shaped embryo with low porosity to form an embedded type double-layer structure stent, the types of drug carried by the inner layer and the outer layer of the stent are different, and the degradation rate of the stent can be used for regulating and controlling the drug release rate.

Patent CN201510825145 discloses an antithrombotic intravascular stent and a preparation method and application thereof, wherein a nondegradable alumina hydrogel coating is coated on the surface of the stent, an antithrombotic drug is carried, the enrichment of the drug prevents the formation of thrombus, and the problem of vascular restenosis and even reous caused by matrix degradation is avoided.

CN201610285689 describes a stent and a drug delivery device, which can realize the recycling of the stent.

Patent CN201810959780 introduces a drug-carrying stent for improving blood circulation, wherein a through hole is formed in the side wall of the stent, blood can pass through the through hole on the surface of the stent, so that the shearing force is reduced, and the blood flow condition near the stent is improved.

However, these patents do not fully address the above-mentioned problems. The invention provides a solution for improving the human body utilization rate of stent drugs, reducing drug loss caused by blood scouring in the compression, expansion and delivery processes of a spherical expansion stent, reducing the abrasion of a drug layer in the compression and release processes of a self-expanding stent, regulating and controlling drug release and reducing restenosis and thrombosis events after stent implantation by using a mode of loading degradable drug-loaded microspheres in grooves and ultrasonically responding to controlled release.

Disclosure of Invention

In order to solve the problems, the invention provides an ultrasonic controlled-release grooved degradable microsphere drug-loaded stent and a preparation method thereof. The stent coating is composed of ultrasonic response microspheres and a hydrophilic adhesive, and the degradable ultrasonic response microspheres can respond to ultrasonic with specific frequency, pulse and period, so that the aims of quick release, slow release or selective release are fulfilled.

The raw materials of the stent comprise zinc alloy, stainless steel, nickel-titanium alloy and cobalt-chromium alloy. The hydrophilic adhesive comprises PEG, iopromide, urea and shellac.

The shape of the groove comprises one or more of a strip shape, a square shape, a ring shape, a corrugated shape, a round hole shape, a triangular shape and a star shape.

The width of the groove is 0.020mm-0.20mm, and is further optimized to be 0.03mm-0.10 mm.

The depth of the groove is 0.003mm-0.10mm, and is further optimized to be 0.005mm-0.08 mm.

The length of the groove is 0.020mm-2.5mm, and is further optimized to be 0.1mm-1.5 mm.

The arrangement mode of the grooves is one of single-row arrangement, two-row flat arrangement and multi-row array arrangement.

The drug of the drug-loaded microsphere comprises the following anti-thrombotic drugs: aspirin, clopidogrel, heparin, urokinase, drugs to prevent inflammatory reactions: kaempferol, amlexanox, drugs that prevent smooth muscle proliferation: glucocorticoids, betamethasone, desmethasone, prednisolone, paclitaxel, rapamycin, drugs that promote endothelial cell proliferation: the growth factors such as ECGF, ECGs, bFGF, VEGF and the like, and the material of the microsphere comprises PLA, PLGA and PCL.

The mass ratio of the drug to the drug-loaded polymer in the stent coating is 1: 100-1: 30, further optimizing, 1: 10-3: 10, the particle size of the microsphere is 0.1-10 um, further optimization, 3-8 um, the microsphere responds to ultrasound, and can be induced by ultrasound with specific frequency, intensity and mode to achieve the purposes of burst release, slow release and selective release.

Various carried medicines are wrapped in the microspheres, the medicine carrying microspheres are fixed on the outer surface of the notch groove support and inside the groove through a hydrophilic adhesive, the microspheres have ultrasonic response characteristics, the microspheres break under ultrasonic induction of certain strength, frequency, time and pulse, the medicines are released, the microspheres can be induced to perform burst release according to different conditions of patients, and the microspheres with slow release or different particle sizes break and are released at different time periods to perform targeted treatment.

The groove on the outer surface of the bracket not only improves the drug-loading capacity of the bracket, but also reduces the loss of the drug during blood washing. The efficiency of drug delivery is improved.

A preparation method of an ultrasonic controlled-release grooved degradable microsphere drug-loaded stent comprises the following steps:

1) and (3) carrying out laser engraving on the support by using a femtosecond laser cutting machine, wherein the laser wavelength is 1064nm, the light spot is 0.003mm-0.05mm, and the laser power is 50W-100W.

2) And (3) carrying out support laser grooving by using a femtosecond laser cutting machine: grooving by using a laser beam with the wavelength of 1064nm, the light spot of 0.003mm-0.05mm and the power of 50W-100W, or grooving the bracket by using an electrochemical etching method: coating a corrosion-resistant material on the surface of the bracket, removing the corrosion-resistant material of the part to be grooved by using laser, connecting the treated bracket with a power supply anode, and placing the bracket in corrosive liquid for electrochemical corrosion grooving.

3) And after the grooving of the bracket is finished, spraying the medicine, wherein the spraying method comprises soaking, micro-jetting, liquid medicine spraying and ultrasonic spraying.

4) And (5) drying in vacuum.

5) The stent is compressed.

The invention provides a method for preparing an ultrasonic response degradable microsphere, which comprises the following steps:

1) the drug-loaded microsphere is composed of a degradable polymer and a drug wrapped in the drug-loaded microsphere, the material of the drug-loaded microsphere has good biocompatibility, and the physical structure design of the microsphere has responsiveness to ultrasound.

2) The particle size of the microspheres is 0.1-10 um, preferably 5um, so as to prevent embolism.

3) After the preparation of the microspheres is finished, the microspheres are dispersed into a water-soluble dispersing agent with a specific formula to prepare a drug-loaded coating material, the drug-loaded coating material is fixed on the surface of the stent by a dipping or spraying method, after the drug-loaded coating material is dried under a certain condition, liquid components of the dispersing agent are volatilized, and the rest components are used as an adhesive to fix the microspheres on the surface of the stent to prepare the drug-loaded stent.

In summary, the innovation of the invention is as follows:

1) the medicine carrying microspheres are sprayed for carrying medicine after the support is grooved, so that the medicine content of the medicine carrying support is increased, the grooved medicine carrying support prevents blood of the ball expanding support from scouring to cause medicine loss, and the self-expanding support releases, abrades and falls off, so that the medicine utilization rate is improved.

2) The ultrasonic response controllable release mode microspheres increase the capability of the stent to deal with different diseases and realize the controllable release of the drugs.

3) The unbroken microspheres are slowly released with degradation of the microspheres themselves under ultrasonic intervention.

4) The medicine concentration and action time of the pathological change part are controlled by controlling the strength, time, position, wall thickness and quantity of the induction mode, so that the safety, effectiveness and controllability of treatment are ensured.

Description of the drawings:

fig. 1 is a flow chart of a preparation process of notch medicine carrying of an ultrasonic controlled release groove medicine carrying stent.

Fig. 2 is a schematic diagram of ultrasound-induced drug release at a cardiac site.

Fig. 3 is a schematic view of the application of the stent at the peripheral part.

1, after 3 grooves are formed on the surface of a bare stent formed by 2 stent pipes, 4 drug coatings on the surface of the stent are soaked and adhered on the surface of a 5-ultrasound controlled-release groove drug-loaded stent 6, the stent groove is enlarged, 7-drug-loaded microcapsule outer membrane 8, 9 grooves of a 9-drug-loaded stent 10, drug-loaded microcapsules 11 are broken under the ultrasound stimulation of a microcapsule 12 ultrasound release source 13, the periphery of the microcapsule 12 is provided with grooves and drug-loaded stent 14, and the

1. Detailed description of the preferred embodiments

The invention will be described in more detail below with reference to the drawings, but the scope of the invention is not limited thereto.

FIG. 1 is a flow chart of a preparation process of grooving and drug loading for an ultrasonic controlled-release grooved drug-loaded stent, which comprises the steps of firstly cutting 1 a stent tube by a laser cutting machine, forming 2 a molded naked stent surface pattern on the cut stent, then grooving the surface of the stent by the laser cutting machine or an electrochemical etching method, forming 3 grooves in the form of the grooved stent surface on the grooved stent, soaking the grooved stent in a solution containing a hydrophilic adhesive and drug-loaded microspheres, carrying out step 4 of soaking and adhering the stent with a drug coating, taking out the soaked stent, and volatilizing a solvent to complete the preparation process of grooving and drug loading for the ultrasonic controlled-release grooved drug-loaded stent. The surface of the finished product ultrasonic controlled-release groove medicine-carrying stent is in a surface form of a finished product of a 5-ultrasonic controlled-release medicine-carrying grooved stent, the groove part of the stent is amplified, and the amplification condition of 6 stent grooves is obtained: the groove of the bracket is square, and the inner cloth is adhered with drug-carrying microspheres. The amplified drug-loaded microspheres are drug-loaded microspheres with 8 drug components wrapped by 7 drug-loaded microsphere outer membranes, wherein the microsphere outer membranes are made of degradable high-molecular polymers with ultrasonic response characteristics.

Fig. 2 is a schematic diagram of drug release induced by ultrasound at a heart part, wherein an ultrasound release source 12 releases ultrasound to stimulate a 9-grooved drug-carrying stent implanted at the heart part, and a 10-carrying microcapsule in a groove of the grooved drug-carrying stent is broken in response to the ultrasound to become a 11-ultrasonic-stimulated drug-carrying microcapsule, so that drug components in the drug-carrying microcapsule are released.

Fig. 3 is a schematic diagram of the application of the stent at the peripheral part, wherein an ultrasonic probe 14 is tightly contacted with the skin surface of the implanted part of the drug-carrying stent with the peripheral grooves 13 to release ultrasonic waves to stimulate the microcapsules in the grooves of the drug-carrying stent with the peripheral grooves 13 to break and release drugs.

Preparation of a scaffold

The raw materials of the stent comprise zinc alloy, stainless steel, cobalt-chromium alloy and the like to manufacture a balloon expandable stent, nickel-titanium alloy to manufacture a self-expandable stent with a shape memory function, and a laser engraving machine is used for engraving the stent by adopting a light beam with the wavelength of 1064nm, the light spot of 0.003mm-0.05mm and the laser power of 50W-100W.

Two-support notch groove

The support has two grooving modes, namely laser grooving and electrochemical corrosion grooving.

The laser grooving mode is as follows: grooving by using a laser cutting machine, wherein the laser cutting machine adopts a light beam with the wavelength of 1064nm, the light spot of 0.003mm-0.05mm and the laser power of 50W-100W.

The chemical etching grooving mode is as follows: coating a corrosion-resistant material on the surface of the bracket, removing the corrosion-resistant material of the part to be grooved by using laser, connecting the treated bracket with a power supply anode, and placing the bracket in corrosive liquid for electrochemical corrosion grooving.

Preparation of three-drug-loaded microsphere

A certain film material: PLA, PLGA, PCL and different types of drugs are dissolved in dichloromethane as oil phase. Polyvinyl alcohol (PVA) water solution with a certain concentration is used as a water phase, the two-phase mixed solution is led into a rapid membrane emulsification device, under the pressurization of nitrogen, the two-phase mixed solution rapidly passes through membrane pores with the pore diameter of 0.1-10 um for many times, the solution is mechanically stirred to volatilize an organic solvent, and is centrifugally washed for 5 times repeatedly, and freeze-dried to prepare a finished microsphere product.

Coating of four stent drug coatings

Soaking the grooved support in the medicinal coating material at room temperature for 5-60 min; or coating the above medicinal materials to 1mm²The area of the bracket is 0.1ug-50ug of the dosage of the effective medicine, and the effective medicine is sprayed on the inner surface and the outer surface of the bracket; controlling the temperature to be 10-80 ℃, and drying for 30min in vacuum; the stent is compressed.

Example 1

The support is carved by zinc-copper alloy pipe laser, and a hole-shaped groove is carved on the inner surface and the outer surface of the support by an electrochemical corrosion method. Preparing paclitaxel poly PLGA microspheres with the drug content of 1 percent respectively, preparing PEG (polyethylene glycol) with the concentration of 8mg/ml at room temperature as an adhesive, adding the adhesive into the microspheres, coating the microspheres by using a dipping method, dipping for 5min, vacuum drying, stent compression, packaging and ethylene oxide sterilization.

Example 2

The support is laser engraved and the elongated grooves are engraved using 316L stainless steel tubing. Rapamycin PLGA microspheres with the drug content of 3% are prepared.

Preparing 5mg/ml shellac at room temperature as adhesive, adding microsphere, and spraying to obtain 1mm shellac powder²Spraying the dosage of 2ug of effective medicine in the area of the stent, vacuum drying, compressing the stent, packaging, and sterilizing with ethylene oxide.

Example 3

The nickel-titanium alloy tube is used for laser engraving the stent, and corrugated grooves are engraved on the inner surface and the outer surface of the stent by an electrochemical corrosion method. Preparing bFGF microspheres with the medicine content of 0.5 percent respectively.

Preparing 8mg/ml PEG as adhesive at room temperature, adding 4 kinds of microspheres, soaking for 20min by soaking method, vacuum drying, and sterilizing with ethylene oxide.

Example 4

And utilizing the cobalt-chromium alloy pipe to laser engrave the support and engrave the annular groove. Urokinase microspheres with drug contents of 3% were prepared.

Preparing 5mg/ml iopromide as adhesive at room temperature, adding microsphere, and spraying to obtain a coating with thickness of 1mm²Spraying the dosage of the effective medicine with the area of 10ug of the stent, vacuum drying, compressing the stent, packaging and sterilizing by ethylene oxide.

Effect verification 1

Experimental groups: and 6 stainless steel drug-loaded stents with 316L grooves with the same specification and model are manufactured, wherein the stents are carved by the tube laser and the elongated grooves are carved. Preparing paclitaxel poly PLGA microspheres with the drug content of 3%, preparing 5mg/ml of shellac at room temperature as adhesive, adding the shellac into the microspheres, and spraying to obtain the stent with the drug content of 2ug/mm²Spraying the effective dosage of the medicine, and vacuum drying.

Control group: 6 stainless steel drug-loaded stents of 316L are manufactured, and the specification and the model are the same as those of an experimental group. Wherein the tube is laser engraved. Preparing paclitaxel poly PLGA microspheres with the drug content of 3%, preparing 5mg/ml shellac as adhesive at room temperature, adding the shellac into the microspheres with the same dosage as the experimental group, and spraying to obtain 1mm microspheres²The area of the bracket is 2ug of dosage spraying of effective medicine, and the bracket is dried in vacuum.

Taking 3 supports of the experimental group and the control group respectively, and detecting the drug content by using high performance liquid chromatography.

And (3) taking the rest of the stents of the experimental group and the control group for stent compression and expansion, simulating blood flow scouring operation by using normal saline for 30s, and detecting the drug content of the stent by using liquid chromatography.

The detection results are as follows:

table 1 effect verification 1 test results

It can be seen from the data that stent notching reduced the drug loss caused by stent compression, stenting, and blood washout.

Effect verification 2

Experimental groups: and 6 nickel-titanium alloy groove drug-loaded stents with the same specification and model are manufactured, wherein the stents are carved by the tube laser and the corrugated grooves are carved. And (3) preparing the rapamycin PLGA microspheres with the medicine content of 3%. Preparing 5mg/ml PEG as adhesive at room temperature, adding microsphere, and spraying to obtain stent with drug content of 3 ug/mm²Spraying the effective dosage of the medicine, and vacuum drying.

Respectively putting the brackets into containers filled with simulated body fluid with pH 7.2, wherein 5ml of simulated body fluid solvent is in each container, detecting the rapamycin content in the simulated body fluid after soaking for 20min, carrying out ultrasonic treatment on 3 simulated extraction liquid containers for 3min, and carrying out ultrasonic treatment on the other 3 simulated extraction liquid containers without carrying out ultrasonic treatment, and detecting the rapamycin content in the simulated body fluid after soaking for 20 min.

Table 2 effect verification 2 test results

From the above table, it can be known that the drug-loaded stent is basically consistent in drug release conditions after being soaked for 20min, and after part of the stent is subjected to ultrasound for 3min, the stent is soaked for 20min, so that the stent after ultrasound releases more drugs compared with the stent without ultrasound, and the ultrasound-released degradable drug-loaded microspheres can react to ultrasound induction to achieve the purpose of ultrasound controlled release.

Claims

1. The utility model provides an supersound controlled release notch groove degradable microballon medicine carrying support and preparation method thereof, includes the support body, support medicine coating, its characterized in that, the support by have good biocompatibility the material make, the surface has the recess that distributes evenly, support surface and recess inside coating have the medicine coating of supersound response characteristic, can adopt the mode of ultrasonic intervention, make the degradable medicine carrying microballon in the coating break, the medicine release, the microballon medicine slow release that does not break completely, the microballon that does not break releases the medicine along with microballon self degradation release medicine.

2. The ultrasound controlled-release grooved degradable microsphere drug-loaded stent and the preparation method thereof as claimed in claim 1, wherein the good biocompatibility material of the stent includes but is not limited to zinc alloy, stainless steel, nickel titanium alloy, cobalt chromium alloy.

3. The ultrasound controlled-release grooved degradable microsphere drug-loaded stent and the preparation method thereof as claimed in claim 1, wherein the shape of the stent grooves includes but is not limited to one or more of strip shape, square shape, ring shape, corrugated shape, round hole shape, triangular shape and star shape, the width of the grooves is 0.020mm-0.20mm, the depth of the grooves is 0.003mm-0.05mm, the length of the grooves is 0.020mm-1.5mm, and the arrangement mode of the grooves is one of single row arrangement, two-row flat arrangement or multi-row array arrangement.

4. The ultrasonic controlled-release grooved degradable microsphere drug-loaded stent and the preparation method thereof as claimed in claim 1, wherein the drug coating is composed of two parts: hydrophilic adhesive and ultrasonic response degradable drug-loaded microspheres.

5. The scaffold hydrophilic adhesive according to claim 4, wherein the hydrophilic adhesive comprises one or more of PEG, iopromide, urea and shellac.

6. The stent degradable drug-loaded microsphere of claim 4, wherein the drugs include but are not limited to anti-thrombotic drugs: aspirin, clopidogrel, heparin, urokinase, drugs to prevent inflammatory reactions: kaempferol, amlexanox, drugs that prevent smooth muscle proliferation: glucocorticoids, betamethasone, desmethasone, prednisolone, paclitaxel, rapamycin, drugs that promote endothelial cell proliferation: ECGF, ECGs, bFGF, VEGF.

7. The stent degradable drug-loaded microsphere of claim 4, wherein the raw material of the degradable microsphere comprises polylactic acid (PLA), lactic-co-glycolic acid (PLGA) and Polycaprolactone (PCL), and the mass ratio of the coating microsphere drug to the drug-loaded polymer is 1: 100-1: 30, the particle size of the microsphere is 0.1-10 um, and the microsphere responds to ultrasound and can be induced by ultrasound with specific frequency, intensity and period to achieve the purposes of burst release, slow release and selective release.

8. The ultrasonic controlled-release grooved degradable microsphere drug-loaded stent and the preparation method thereof according to claim 1 are characterized in that the preparation method comprises the following steps: the method comprises the following steps of utilizing a femtosecond laser cutting machine to carry out laser engraving on the support, carrying out support grooving or utilizing an electrochemical etching method to carry out support grooving, spraying medicine, drying in vacuum and compressing the support.

9. The laser cutting machine according to claim 8, wherein the laser engraving is performed by using a light beam with a wavelength of 1064nm, a light spot of 0.003mm-0.05mm and a power of 50W-100W.

10. An electrochemical etching method according to claim 8, characterized in that the surface of the stent is coated with corrosion-resistant material, the corrosion-resistant material of the portion to be grooved is removed by laser, the treated stent is connected with a power supply anode, and is placed in an etching solution for electrochemical etching grooving.

11. The drug spraying method of claim 8 comprising: soaking, micro-jetting, liquid medicine spraying and ultrasonic spraying.