CN108295359B

CN108295359B - Drug-loaded device and preparation method thereof

Info

Publication number: CN108295359B
Application number: CN201611262098.3A
Authority: CN
Inventors: 卢金华; 谢琦宗; 符伟国; 岳嘉宁
Original assignee: Lifetech Scientific Shenzhen Co Ltd
Current assignee: Lifetech Scientific Shenzhen Co Ltd; Zhongshan Hospital Fudan University
Priority date: 2016-12-30
Filing date: 2016-12-30
Publication date: 2021-05-07
Anticipated expiration: 2036-12-30
Also published as: CN108295359A; WO2018121352A1

Abstract

The invention discloses a medicine carrying device and a preparation method thereof. The medicine carrying device comprises a device body and a medicine coating layer arranged on the surface of the device body. The medicine carrying device has a contraction state and an expansion state, and the outer diameter of the medicine carrying device in the contraction state is smaller than that of the medicine carrying device in the expansion state. The protective sleeve is sleeved outside the medicine carrying instrument. The protective sleeve is made of a high polymer material, and can swell in an organic solvent. The protective sleeve is firstly swelled to a larger inner diameter in a solvent, then sleeved on the surface of a medicine carrying instrument, and then shrunk to an original size along with the volatilization of an organic solvent, so that the protective sleeve is tightly wrapped outside the medicine carrying instrument. Therefore, the invention can reduce the friction force between the inner wall of the protective sleeve and the drug coating of the drug-carrying instrument, avoid damaging the drug coating or the instrument body, constrain the drug-carrying instrument to a smaller outline outer diameter and improve the passability of the drug-carrying instrument in a curved human body lumen or a narrow pathological change part.

Description

Drug-loaded device and preparation method thereof

Technical Field

The invention belongs to the field of medical instruments, and relates to a medicine carrying instrument and a preparation method thereof.

Background

Compared with the traditional open surgery treatment, the intracavity interventional therapy has the advantages of small wound, quick recovery, low complication rate, high curative effect and the like, and gradually becomes the preferred mode for vascular surgeons to treat vascular lesions.

A Drug Eluting Balloon (DEB) belongs to one of the intracavity interventional therapy methods, and the principle is as follows: the active drug is coated on the surface of the expandable balloon, and the expandable balloon is conveyed to the diseased part of a human body and then is pressurized and expanded, so that the active drug is released to the vessel wall and plays the drug effect. During production of DEBs, the drug-coated expandable balloon flap needs to be wrapped around and then sleeved into the protective sleeve.

A Drug Eluting Stent (DES) also belongs to a minimally invasive surgery treatment method, and the principle is that a Drug coating is coated on the surface of a bare Stent, the DES is conveyed to a human lesion part and expanded, and the Drug is slowly released from the coating to continuously exert the Drug effect. DES typically requires a conventional inflatable balloon to assist in expansion after reaching the lesion. Therefore, during the production of DES, it is necessary to crimp the DES outside the folded and wrapped expandable balloon and then to nest the crimped expandable balloon and DES together in a protective sleeve.

For the medicine-carrying instrument, the protective sleeve has the function of protecting the medicine coating, and the medicine coating can be prevented from being damaged in the production and transportation processes. Meanwhile, the protective sleeve can restrict the medicine carrying instrument to a smaller outer diameter size, so that the medicine carrying instrument can smoothly pass through tortuous human blood vessels.

In the actual production process, in order to reduce the overall dimension of the drug-carrying device, a protective sleeve with a smaller inner diameter is selected to be sleeved outside the drug-carrying device and tightly bound the drug-carrying device. However, in the process of sleeving the protective sleeve to the outside of the drug-carrying device, friction between the drug coating on the surface of the drug-carrying device and the inner wall of the protective sleeve can damage the drug coating and also damage the device body. For example, causing the expandable balloon to buckle and damage the expandable balloon body, thereby reducing the effectiveness of the DEB; or the DES and the expandable balloon are relatively displaced, so that the positioning and expansion of the DES at a lesion site are influenced, and the safety of the DES is reduced.

And the protective sleeve with larger inner diameter can increase the contour size of the medicine carrying instrument and reduce the trafficability of the medicine carrying instrument in a human body lumen. Moreover, the protective sleeve with the larger inner diameter has lower constraint force on the drug-loading device, so that the constraint force on the flap of the DEB is weaker, and when the DEB is placed into a human body, the wound flap is flushed and dispersed by high-speed blood flow, and a large amount of drug which is originally covered by the flap is lost; or cause the DES, which was originally crimped onto the expandable balloon, to fall off or expand before reaching the lesion site, causing injury to the patient.

Disclosure of Invention

Based on this, there is a need for a drug delivery device with a suitably dimensioned protective sleeve that not only constrains the drug delivery device to a smaller outer profile, but also avoids friction between the protective sleeve and the drug coating from damaging the drug coating or the device body.

The invention provides a medicine carrying device which comprises a device body and a medicine coating layer arranged on the surface of the device body. The drug delivery device has a contracted state and an expanded state. The outer diameter of the drug carrying device in the contraction state is smaller than that of the drug carrying device in the expansion state. The protective sleeve is sleeved outside the medicine carrying instrument. The protective sleeve is made of high polymer materials. The protective sleeve may swell in organic solvents.

In one embodiment, the ratio of the inner diameter of the protective sleeve after swelling to the inner diameter of the protective sleeve before swelling is (1.1-2): 1. the present invention defines the ratio of the inner diameter of the protective sleeve after the swelling to the inner diameter of the protective sleeve before the swelling as the degree of swelling of the inner diameter of the protective sleeve. The swelling degree range is (1.1-2): 1, the protective sleeve can be smoothly sleeved on the surface of the instrument body after swelling; and the time required for the protective sleeve to return to the inner diameter before swelling and tightly bind the instrument body after being sleeved on the surface of the instrument body can be reduced.

In one embodiment, the polymer material is at least one selected from the group consisting of silicone, polyolefin, polyurethane, and polyurethane-modified polymer.

In one embodiment, the organic solvent is selected from at least one of methanol, ethanol, acetone, chloroform, tetrahydrofuran, dimethylsulfoxide, or liquid organic alkane having a carbon number ranging from 5 to 16.

In one embodiment, the drug coating includes an active drug. The active drug is at least one selected from anti-intimal hyperplasia drugs, anticoagulant drugs, anti-platelet adhesion drugs, anti-infective drugs, antibacterial drugs, anti-inflammatory drugs, anti-allergy drugs or anti-tumor drugs.

In one embodiment, the anti-intimal hyperplasia drug is selected from at least one of everolimus, rapamycin, paclitaxel, docetaxel, paclitaxel derivatives, probucol, or colchicine. The anticoagulant drug is at least one of heparin, warfarin sodium or vitamin K antagonist. The anti-platelet adhesion medicine is at least one of aspirin, prostaglandin, salvianolic acid, nitrate medicine, lysine and dipyridamole. The anti-infective drug is at least one of ampicillin, cefamycin, sulfadiazine or streptomycin sulfate. The antibacterial drug is at least one of chitosan and derivatives thereof, cefoxitin, nalidixic acid or pipemidic acid. The anti-tumor drug is at least one of daunorubicin, adriamycin, carboplatin or macrolides.

In one embodiment, the active agent is selected from at least one of rapamycin, a rapamycin derivative, paclitaxel, or a paclitaxel derivative.

In one embodiment, the drug coating further comprises a carrier. The carrier is selected from at least one of polar group-containing small molecular organic matters or high molecular polymers. The polar group includes-OH, -SO₃H、-NH₂-NHR or-COOH.

In one embodiment, the small organic molecule is selected from at least one of sodium ferulate, L-phenylalanine, benzoate, methionine, proline, lysine, leucine, hydroxypropyl- β -cyclodextrin, sorbitol, L-valine, nicotinamide, acetamide, meglumine, L-isoleucine, glucose, maltose, tween 80, mannitol, lecithin, tryptophan, L-threonine, salicylic acid, sodium p-aminosalicylate, sodium heparin, or vitamin C.

In one embodiment, the high molecular polymer is selected from at least one of polyethylene glycol, polylysine, sodium hyaluronate, poloxamer, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene oxide, polyacrylate, polyacrylamide, polylactic acid, polyglycolic acid, polycaprolactone, polyglycolide, glycolide-lactide copolymer, polydioxanone, polyhydroxyalkanoate, polytrimethylene carbonate, polyurethane, or polyether urethane.

In one embodiment, the protective sleeve has an axial length before swelling that is greater than or equal to the axial length of the drug-impregnated device in the collapsed state. The inner diameter of the protective sleeve before swelling is smaller than or equal to the outer diameter of the drug-carrying device in the contracted state.

In one embodiment, at least one groove is arranged between the proximal end and the distal end of the tube body of the protection tube along the axial direction of the protection tube, and the proximal end and/or the distal end of the groove is/are provided with a notch.

In one embodiment, the length of the cut-out along the axial direction of the protection sleeve ranges from 5 mm to 15 mm.

In one embodiment, the pre-loaded device is an interventional or implantable device. The interventional instrument comprises a drug balloon catheter, a radiography catheter, a central venous catheter, a pressure measuring catheter, a catheter or a disposable interventional therapy instrument probe. The implantable device includes a drug eluting stent, bone screw, or bone plate.

The invention also provides a manufacturing method of the medicine carrying instrument with the protective sleeve, which comprises the following steps:

applying the drug coating to the surface of the device body to obtain the drug-loaded device; placing the protective sleeve in the organic solvent to swell the protective sleeve to obtain a swelled protective sleeve; and sleeving the swollen protective sleeve outside the drug-carrying instrument and drying to obtain the drug-carrying instrument.

In one embodiment, the preparation method further comprises the step of removing residual organic solvent on the surface of the swollen protective sleeve before the step of sleeving the swollen protective sleeve on the outside of the drug-loaded device and drying.

In one embodiment, at least one groove is formed between the proximal end and the distal end of the protective sleeve in the axial direction of the protective sleeve, and the manufacturing method further includes a step of forming a cut at the proximal end and/or the distal end of the groove after the step of removing the remaining organic solvent on the surface of the swollen protective sleeve.

In one embodiment, the swelling time ranges from 5 minutes to 24 hours.

In one embodiment, the drying comprises air drying at normal temperature, air drying, vacuum drying, freeze drying, or heat drying at 30 ℃ to 60 ℃.

Compared with the prior art, the invention at least has the following beneficial effects:

(1) in the medicine carrying instrument provided by the invention, the protective sleeve is made of a high polymer material which can be swelled by a solvent. In the process of arranging the protective sleeve on the outer part of the medicine carrying instrument, the inner diameter of the protective sleeve is enlarged through solvent swelling, so that the friction between the protective sleeve and the medicine carrying instrument is reduced, and the medicine coating or the instrument body of the medicine carrying instrument is prevented from being damaged.

(2) According to the medicine carrying instrument provided by the invention, after the medicine carrying instrument is sleeved with the protective sleeve, the protective sleeve gradually shrinks along with the gradual volatilization of the solvent in the protective sleeve and finally recovers to the initial inner diameter, so that the purpose of tightly restraining the medicine carrying instrument is achieved.

(3) The drug-carrying instrument provided by the invention is bound to a smaller outline outer diameter by the protective sleeve, and is favorable for the permeability of the drug-carrying instrument in a bent tube cavity or a narrow pathological change part in a human body.

Drawings

Fig. 1 is a schematic structural view of a drug eluting balloon catheter provided in the first embodiment, which includes a drug eluting balloon body and a protective sleeve;

FIG. 2a is a cross-sectional view of the protective casing of FIG. 1 taken along line A-A;

fig. 2b is a cross-sectional view of another embodiment of the protective sleeve of fig. 1 taken along line a-a;

fig. 3 is a schematic structural view of a drug eluting stent provided in example four.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

In order to more clearly describe the structure of balloon catheters and vascular stents, the terms "proximal" and "distal" are defined herein as terms commonly used in the interventional medical field. Specifically, in the field of interventional medicine, "distal" refers to the end that is distal from the operator during a surgical procedure, and "proximal" refers to the end that is proximal to the operator during the surgical procedure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

Example one

Referring to fig. 1, a drug eluting balloon catheter 100 according to an embodiment includes a drug eluting balloon catheter body 10 and a protective sleeve 20. The drug eluting balloon catheter body 10 comprises a balloon catheter 11 and a drug coating 12. The balloon catheter 11 includes a catheter 111 having opposite proximal and distal ends and an inflatable balloon 112 (not inflated) disposed at the distal end of the catheter 111. The outer surface of the expandable balloon 112 has a drug coating 12. When the inflatable balloon 112 is not inflated, the inflatable balloon 112 has three flaps (not shown) wrapped around. The proximal developing ring 113 and the distal developing ring 114 are disposed on the outer surface of the catheter 111 near the proximal end and near the distal end, respectively.

The protective sleeve 20 is made of a polymer material. The protective sleeve 20 is sleeved outside the inflatable balloon 112 and limits the deployment of the three wrapped flaps of the inflatable balloon 112. The protective sleeve 20 is made of a silicone material. The silica gel material can swell in a solvent. Thus, the protective sleeve 20 is swollen in a solvent and then wrapped around the exterior of the expandable balloon 112. The ratio of the inner diameter of the protection sleeve 20 after swelling to the inner diameter of the protection sleeve 20 before swelling is (1.1-2): 1. the ratio of the inner diameter of the protection sleeve 20 after swelling to the inner diameter of the protection sleeve 20 before swelling is defined as the degree of swelling of the inner diameter of the protection sleeve 20. The swelling degree range is (1.1-2): 1, the protection sleeve 20 can be smoothly sleeved on the surface of the expandable balloon 112 after swelling; and may reduce the time required for the protective sleeve 20 to return to the pre-swelling inner diameter and tightly restrain the inflatable balloon 112 after being fitted over the surface of the inflatable balloon 112. Specifically, in the present embodiment, the ratio of the inner diameter of the protection sleeve 20 after swelling to the inner diameter of the protection sleeve 20 before swelling is 1.3.

The protection sleeve 20 has an axial length before swelling that is greater than or equal to the axial length of the inflated expandable balloon 112, which facilitates complete encapsulation of the expandable balloon 112 and protection of the drug coating 12 after the protection sleeve 20 has been swollen and returned to its axial length before swelling. The protective sleeve 20 has an inner diameter before swelling that is less than or equal to the outer diameter of the inflated expandable balloon 112, facilitating tight binding of the expandable balloon 112 to a smaller profile outer diameter after the protective sleeve 20 has been swollen and returned to its outer diameter before swelling. Preferably, in this embodiment, the protective sleeve 20 has an axial length before it is swelled that is greater than the axial length of the inflated inflatable balloon 112. The protective sleeve 20 has an inner diameter before swelling that is approximately equal to the outer diameter of the inflated expandable balloon 112.

At least one groove is formed between the proximal end and the distal end of the protective sleeve 20 along the axial direction of the protective sleeve 20. The shape of the groove in a cross section perpendicular to the axial direction of the protection sleeve 20 may be V-shaped (see fig. 2a), C-shaped (see fig. 2b), or other shapes. At least one of the proximal and distal ends of the recess has a notch. The length of the cutout in the axial direction of the protection sleeve 20 ranges from 5 mm to 15 mm. Preferably, in this embodiment, a first groove (not shown) and a second groove (not shown) are disposed along the axial direction of the protection sleeve 20 between the proximal end and the distal end of the protection sleeve 20. The first and second grooves are symmetrically disposed about the central axis of the protective sleeve 20. The proximal end of the first recess has a first cut 21. The proximal end of the second groove has a second cut (not shown). The length of the first cutout 21 in the axial direction of the protection sleeve 20 and the length of the second cutout in the axial direction of the protection sleeve 20 are both 10 mm.

The preparation method of the drug eluting balloon catheter 100 provided in this embodiment is as follows:

the first step is as follows: paclitaxel is used as the anti-tissue proliferation active drug, and is dissolved in ethanol after being mixed with a sodium benzoate carrier to prepare a drug coating solution. The PTA balloon catheter with a balloon gauge of 4.0 mm x 40 mm was subjected to plasma pretreatment. The drug coating solution was sprayed onto the expandable balloon surface of the PTA balloon catheter. And (5) drying at normal temperature. And then the expandable balloon is folded into three wings by a balloon flap folding machine and wound to obtain the drug eluting balloon catheter body 10.

The second step is that: two grooves are carved between the near end and the far end of the tube body of the silicone tube with the original inner diameter of 0.043 inch and the original length of 70 mm along the axial direction of the silicone tube, and the two grooves are symmetrically arranged around the central axis of the silicone tube. Then, the silicone tube was placed in an ethanol solvent to swell for 60 minutes, and the swelling degree of the inner diameter of the silicone tube was measured to be 1.3. And taking out the swelled silicone tube. And drying the residual ethanol solvent on the inner surface and the outer surface of the silica gel tube at normal temperature. The proximal end of each groove was cut with a blade along the axial direction of the silicone tube by an incision having an axial length of about 10 mm to obtain a protective sleeve 20 made of silicone material.

The third step: the expandable balloon 112 of the drug eluting balloon catheter body 10 with the wound flap obtained in the first step is inserted into the protective sleeve 20 obtained in the second step through the incision obtained in the second step, and then dried for 2 hours at normal temperature until the protective sleeve 20 shrinks to the original size (i.e., the inner diameter is 0.043 inch and the length is 70 mm), and then packaged and sterilized to obtain the drug eluting balloon catheter 100 of the present embodiment.

The drug eluting balloon catheter 100 of the present embodiment may be used in conjunction with an external balloon dilation pressure pump for conventional balloon dilation as long as the protective sleeve 20 is torn away from the surface of the inflatable balloon 112 along the incision of the groove by the operator.

It is understood that, in the preparation method provided in this example, the order of the first step and the second step may be interchanged. That is, the protective sleeve 20 is first manufactured, the drug eluting balloon catheter body 10 is then manufactured, the expandable balloon 112 of the drug eluting balloon catheter body 10 is then inserted into the protective sleeve 20, and then the protective sleeve 20 is dried, packaged and sterilized, thereby achieving the purpose of the present invention.

It is understood that, in the preparation method provided in this embodiment, the second step includes a step of drying the ethanol solvent remaining on the inner and outer surfaces of the silica gel tube at normal temperature, and in other embodiments, this step may not be included. That is, in other embodiments, after the swollen silicone tube is removed, the proximal end of the groove of the silicone tube may be directly cut by a blade to form a cut having an axial length of about 10 mm along the axial direction of the silicone tube, and the protective sleeve 20 of silicone material may also be obtained. The expandable balloon 112 of the drug eluting balloon catheter body 10 with the folded and wound flap obtained in the first step is then inserted into the protective sleeve 20 through the incision, and then dried, packaged and sterilized to achieve the object of the present invention.

It will be appreciated that to avoid affecting the effectiveness of the drug eluting balloon catheter 100, this embodiment provides a method of making the expandable balloon 112 with the drug coating 12 within the non-notched body portion of the protective sleeve 20.

Example two

The structure of the drug eluting balloon catheter provided in this example is substantially the same as the structure of the drug eluting balloon catheter provided in the first example. The difference is that in this embodiment, the number of flaps of the inflatable balloon is four. Three grooves are arranged between the near end of the tube body and the far end of the tube body of the protective sleeve along the axial direction of the protective sleeve. The distal end of each groove has a notch. The length of the incision in the axial direction of the protective sleeve was 5 mm. And the material of the protective sleeve is different from that of the protective sleeve of the first embodiment.

The preparation method of the drug eluting balloon catheter provided in this example is as follows:

the first step is as follows: rapamycin is used as an anti-tissue proliferation active drug, and is mixed with a sodium benzoate carrier and a polyethylene glycol carrier and then dissolved in methanol to prepare a drug coating solution. The PTA balloon catheter with the balloon specification of 5.0 mm x 60 mm is subjected to plasma pretreatment. The drug coating solution was sprayed onto the expandable balloon surface of the PTA balloon catheter. And (5) drying at normal temperature. And then the expandable balloon is folded into four wings by a balloon flap folding machine and wound to obtain the drug eluting balloon catheter body.

The second step is that: three grooves are carved between the near end and the far end of the pipe body of the polyethylene pipe with the original inner diameter of 0.049 inch and the original length of 90 mm along the axial direction of the polyethylene pipe, and the three grooves are symmetrically arranged around the central shaft of the polyethylene pipe. The polyethylene pipe was then swollen in n-heptane solvent for 24 hours, and the inner diameter swelling degree of the polyethylene pipe was measured to be 2. The swollen polyethylene tube was removed. And drying the residual n-heptane solvent on the inner surface and the outer surface of the polyethylene pipe at normal temperature. The distal end of each groove was cut with a blade along the axial direction of the polyethylene tube by an axial length of about 5 mm to obtain a protective sleeve made of polyethylene material.

The third step: the expandable balloon of the drug eluting balloon catheter body after the flap winding obtained in the first step is inserted into the protective sleeve obtained in the second step through the incision of the second step, and the expandable balloon is ensured to be positioned in the tube body part of the protective sleeve without the incision. Air-dried at 30 ℃ for 24 hours until the protective sleeve shrunk to its original dimensions (i.e., 0.049 inch inner diameter and 90 mm length). And packaging and sterilizing to obtain the drug eluting balloon catheter of the embodiment.

EXAMPLE III

The structure of the drug eluting balloon catheter provided in this example is substantially the same as the structure of the drug eluting balloon catheter provided in the first example. The difference is that in this embodiment, the number of flaps of the inflatable balloon is six. A groove is arranged between the near end of the tube body and the far end of the tube body of the protective sleeve along the axial direction of the protective sleeve. The proximal and distal ends of the groove have cutouts. The length of the cut in the axial direction of the protective sleeve was 15 mm. And the material of the protective sleeve is different from that of the protective sleeve of the first embodiment.

the first step is as follows: paclitaxel is used as an anti-tissue-proliferation active drug, and is dissolved in acetone after being mixed with a polyethylene glycol carrier to prepare a drug coating solution. The PTA balloon catheter with the balloon specification of 6.0 mm x 80 mm is subjected to plasma pretreatment. The drug coating solution was brushed onto the expandable balloon surface of the PTA balloon catheter. And (5) drying at normal temperature. And folding the expandable balloon into six wings by a balloon flap folding machine and winding to obtain the drug eluting balloon catheter body.

The second step is that: a groove is carved between the near end and the far end of the tube body of the polyurethane tube with the original inner diameter of 0.053 inch and the original length of 110 mm along the axial direction of the silicone tube. Then, the polyurethane tube was placed in a tetrahydrofuran solvent to swell for 5 minutes, and the degree of swelling of the inner diameter of the polyurethane tube was measured to be 1.1. The swollen polyurethane tube was removed. And drying the tetrahydrofuran solvent remained on the inner surface and the outer surface of the polyurethane tube at normal temperature. And cutting the proximal end and the distal end of the groove by a blade along the axial direction of the polyurethane tube to form a cut with the axial length of about 15 mm to obtain the protective sleeve made of the polyurethane material.

The third step: the expandable balloon of the drug eluting balloon catheter body after the flap winding obtained in the first step is inserted into the protective sleeve obtained in the second step through the incision of the second step, and the expandable balloon is ensured to be positioned in the tube body part of the protective sleeve without the incision. And then vacuum-dried at 45 c for 5min until the protective sleeve shrinks to the original size (i.e., inner diameter of 0.053 inch and length of 110 mm), packaged, and sterilized to obtain the drug-eluting balloon catheter with a protective sleeve of this example.

Example four

Referring to fig. 3, the fourth embodiment of the drug eluting stent 300 includes a drug eluting stent body 30 and a protecting sleeve 40. The drug eluting stent body 30 has a contracted state and an expanded state. The outer diameter of the drug eluting stent body 30 in the contracted state is smaller than the outer diameter of the drug eluting stent body 30 in the expanded state. Drug eluting stent body 30 is crimped outside of expandable balloon 50 (not inflated) by a crimping machine or other tooling fixture. When the inflatable balloon 50 is not inflated with pressure, the inflatable balloon 50 has three flaps (not shown) wrapped around. The protective sleeve 40 closely fits over the exterior of the drug eluting stent body 30 and limits the coiled flap deployment of the expandable balloon 50.

The drug eluting stent body 30 comprises a bare stent 31 and a drug coating 32 arranged on the outer surface of the bare stent 31.

The protective sleeve 40 is made of a silicone material. The silica gel material can swell in a solvent. Therefore, the protective sleeve 40 is tightly wrapped outside the drug eluting stent body 30 after swelling in a solvent. The axial length of the protective sleeve 40 before swelling is greater than or equal to the axial length of the drug eluting stent body 30 in the contracted state, facilitating the protective sleeve 40 to completely wrap the drug eluting stent body 30 in the contracted state. The protective sleeve 40 has an inner diameter before swelling that is less than or equal to the outer diameter of the drug eluting stent body 30 in the collapsed state, facilitating the protective sleeve 40 to tightly bind the drug eluting stent body 30 in the collapsed state to a smaller profile outer diameter. Preferably, in this embodiment, the axial length of the protection sleeve 40 is greater than the axial length of the drug eluting stent body 30 in the collapsed state. The protective sleeve 40 has an inner diameter before swelling equal to the outer diameter of the drug eluting stent body 30 in the contracted state.

At least one groove is formed between the proximal end and the distal end of the protective sleeve 40 along the axial direction of the protective sleeve 40, and at least one of the proximal end and the distal end of the groove has a cut. The length of the cutout in the axial direction of the protection sleeve 40 ranges from 5 mm to 15 mm. Preferably, in this embodiment, a first groove (not shown) and a second groove (not shown) are disposed along the axial direction of the protection sleeve 40 between the proximal end and the distal end of the protection sleeve 40. The first and second grooves are axially symmetrical about the central axis of the protective sleeve 40. The proximal end of the first recess has a first notch 41. The proximal end of the second groove 42 has a second cutout (not shown). The length of the first cutout 41 in the axial direction of the protection sleeve 40 and the length of the second cutout in the axial direction of the protection sleeve 40 are both 10 mm.

The preparation method of the drug eluting stent 300 provided in this example is as follows:

the first step is as follows: rapamycin is used as an anti-tissue proliferation active drug, and is mixed with a polylactic acid carrier and then dissolved in tetrahydrofuran to prepare a drug coating solution. The drug coating solution was applied dropwise to the surface of an iron-based alloy stent of 4.0 mm × 38 mm in specification, and air-dried at 30 ℃ to constant weight, to obtain a drug-eluting stent body 30. The balloon catheter with a balloon gauge of 4.0 mm x 40 mm was then plasma pretreated. And then the expandable balloon of the balloon catheter is folded into three wings by a balloon flap machine and wound. The drug eluting stent body 30 is crimped outside the expandable balloon 50 using a crimping machine.

The second step is that: two grooves are carved between the near end and the far end of the tube body of the silicone tube with the original inner diameter of 0.044 inch and the original length of 70 mm along the axial direction of the silicone tube, and the two grooves are symmetrically arranged around the central axis of the silicone tube. Then, the silicone tube was placed in an ethanol solvent to swell for 60 minutes, and the swelling degree of the inner diameter of the silicone tube was measured to be 1.4. And taking out the swelled silicone tube. And drying the residual ethanol solvent on the inner surface and the outer surface of the silica gel tube at normal temperature. The proximal end of each groove was cut with a blade along the axial direction of the silicone tube by an incision having an axial length of about 10 mm to obtain a protective sleeve 40 made of silicone material.

The third step: the drug eluting stent body 30 crimped on the surface of the expandable balloon 50 obtained in the first step is inserted into the protective sleeve 40 obtained in the second step through the incision of the second step, and the drug eluting stent body 30 is secured in the body portion of the protective sleeve having no incision. Air-dried at 60 c for 1 hour until the protective sleeve 40 shrunk to its original dimensions (i.e., 0.044 inch inner diameter and 70 mm length). Packaging and sterilizing to obtain the drug-eluting stent 300 of the present embodiment.

The present embodiment provides a drug eluting stent 300 that, in use, allows for a normal stenting procedure as long as the protective sleeve 40 is torn open along the incision of the groove and removed from the surface of the drug eluting stent body 30.

EXAMPLE five

The structure of the drug eluting stent provided in this example is substantially the same as that provided in example four. The difference is that in this example, the material of the bare stent of the drug eluting stent is different from the material of the bare stent of the drug eluting stent provided in example four. A groove is arranged between the near end of the tube body and the far end of the tube body of the protective sleeve along the axial direction of the protective sleeve. The distal end of the groove has a notch. The length of the cut in the axial direction of the protective sleeve was 15 mm. And the material of the protective sleeve is different from that of the protective sleeve of the fourth embodiment.

The preparation method of the drug eluting stent provided in this example is as follows:

the first step is as follows: everolimus is used as an anti-tissue proliferation active drug, and is mixed with a polycaprolactone carrier and then dissolved in ethanol to prepare a drug coating solution. Dripping the drug coating solution on the surface of a pure iron stent with the specification of 5.0 mm multiplied by 58 mm, and drying by air blast at 30 ℃ to constant weight to obtain a drug eluting stent body. The plasma pretreatment was performed on a balloon catheter with a balloon gauge of 5.0 mm x 60 mm. And then the expandable balloon of the balloon catheter is folded into three wings by a balloon flap machine and wound. The drug eluting stent body is crimped outside the expandable balloon by a crimping machine.

The second step is that: a groove was cut in the axial direction of a polyethylene tube between the proximal end and the distal end of the tube body of the polyethylene tube having an original inner diameter of 0.049 inch and an original length of 70 mm. The polyethylene tube was then placed in an acetone solvent to swell for 30 minutes, and the degree of swelling of the inner diameter of the polyethylene tube was measured to be 1.1. The swollen polyethylene tube was removed. And drying the acetone solvent remained on the inner surface and the outer surface of the polyethylene pipe at normal temperature. The distal end of the groove was cut with a blade along the axial direction of the polyethylene tube by an incision having an axial length of about 15 mm to obtain a protective sleeve made of polyethylene material.

The third step: the drug-eluting stent body crimped outside the expandable balloon obtained in the first step is inserted into the protective sleeve obtained in the second step through the incision of the second step, and is secured in the tube portion of the protective sleeve having no incision. And then allowed to air dry at ambient temperature for 24 hours until the protective sleeve shrinks to its original dimensions (i.e., 0.049 inch inner diameter and 70 mm length). And packaging and sterilizing to obtain the drug eluting stent of the embodiment.

EXAMPLE six

The structure of the drug eluting stent provided in this example is substantially the same as that provided in example four. The difference is that in this embodiment, three grooves are provided between the proximal end and the distal end of the protective sleeve along the axial direction of the protective sleeve. The proximal and distal ends of the groove have cutouts. The length of the incision in the axial direction of the protective sleeve was 5 mm. And the material of the protective sleeve is different from that of the protective sleeve of the fourth embodiment.

the first step is as follows: paclitaxel is used as an anti-tissue-proliferation active drug, and is mixed with a nicotinamide carrier and then dissolved in acetone to prepare a drug coating solution. And brushing the drug coating solution on the surface of a pure iron stent with the specification of 6.0 mm multiplied by 78 mm, and drying by blowing air at 30 ℃ to constant weight to obtain a drug eluting stent body. The plasma pretreatment was performed on a balloon catheter with a balloon gauge of 6.0 mm x 80 mm. And then the expandable balloon of the balloon catheter is folded into three wings by a balloon flap machine and wound. The drug eluting stent body is crimped outside the expandable balloon by a crimping machine.

The second step is that: two grooves are carved between the near end and the far end of the tube body of the polyurethane tube with the original inner diameter of 0.053 inch and the original length of 110 mm along the axial direction of the polyurethane tube, and the two grooves are symmetrically arranged around the central shaft of the polyurethane tube. Then, the polyurethane tube was swollen in a chloroform solvent for 30 minutes, and the degree of swelling of the inner diameter of the polyurethane tube was measured to be 1.6. The swollen polyurethane tube was removed. And drying the residual chloroform solvent on the inner surface and the outer surface of the polyurethane tube at normal temperature. And cutting the proximal end and the distal end of each groove by a blade along the axial direction of the silicone tube to form a cut with the axial length of about 10 mm to obtain the protective sleeve made of the polyurethane material.

The third step: the drug-eluting stent body crimped outside the expandable balloon obtained in the first step is inserted into the protective sleeve obtained in the second step through the incision of the second step, and is secured in the tube portion of the protective sleeve having no incision. And then heated at 60 c for 12 hours until the protective sleeve shrinks to the original dimensions (i.e., inner diameter of 0.053 inches and length of 110 mm). And packaging and sterilizing to obtain the drug eluting stent of the embodiment.

Comparative example 1

The structure of the drug eluting balloon catheter of comparative example one is substantially the same as that provided in example one. The difference is that the material of the protective sleeve of comparative example one is different from the material of the protective sleeve of example one.

The preparation method of the drug eluting balloon catheter of comparative example i was as follows:

the first step is as follows: paclitaxel is used as the anti-tissue proliferation active drug, and is dissolved in ethanol after being mixed with a sodium benzoate carrier to prepare a drug coating solution. The PTA balloon catheter with a balloon gauge of 4.0 mm x 40 mm was subjected to plasma pretreatment. The drug coating solution was sprayed onto the expandable balloon surface of the PTA balloon catheter. And (5) drying at normal temperature. And then the expandable balloon is folded into three wings by a balloon flap folding machine and wound to obtain the drug eluting balloon catheter body.

The second step is that: when the expandable balloon of the drug-eluting balloon catheter body obtained in the first step was inserted into a polytetrafluoroethylene tube having an inner diameter of 0.043 inch and a length of 70 mm, it was found that the proximal end of the expandable balloon was wrinkled and could not be used normally.

The third step: the drug eluting balloon catheter body was fabricated according to the same procedure as in the first step, and the expandable balloon of the drug eluting balloon catheter body was inserted into a polytetrafluoroethylene tube having an inner diameter of 0.044 inch and a length of 70 mm, and packaged and sterilized to obtain the drug eluting balloon catheter of comparative example one.

Comparative example No. two

The structure of the drug eluting balloon catheter of the comparative example two was substantially the same as that provided in the example one. The difference is that the material of the protective sleeve of comparative example two is different from the material of the protective sleeve of example one.

The preparation method of the drug eluting balloon catheter of comparative example two was as follows:

The second step is that: inserting the expandable balloon of the drug eluting balloon catheter body obtained in the first step into a catheter body with an original inner diameter of 2 mm, a length of 140 mm and a heat shrinkage ratio of 2: 1 in the polyolefin heat shrinkable tube.

The third step: and heating the drug eluting balloon catheter with the polyolefin heat-shrinkable tube at 125 ℃ for 90 seconds to heat and shrink the polyolefin heat-shrinkable tube, packaging and sterilizing to obtain the drug eluting balloon catheter of the comparative example II.

Comparative example No. three

The structure of the drug eluting stent of comparative example three is substantially the same as that provided in example four. The difference is that the material of the protective sleeve of comparative example three is different from the material of the protective sleeve of example four, and the protective sleeve of comparative example three does not have axially disposed grooves.

The preparation method of the drug-eluting stent of comparative example three was as follows:

the first step is as follows: rapamycin is used as an anti-tissue proliferation active drug, and is mixed with a polylactic acid carrier and then dissolved in tetrahydrofuran to prepare a drug coating solution. Dripping the drug coating solution on the surface of an iron-based alloy stent with the specification of 4.0 mm multiplied by 38 mm, and blowing and drying at 30 ℃ until the weight is constant to obtain a drug eluting stent body. The balloon catheter with a balloon gauge of 4.0 mm x 40 mm was then plasma pretreated. And then the expandable balloon of the balloon catheter is folded into three wings by a balloon flap machine and wound. The drug eluting stent body is crimped outside the expandable balloon by a crimping machine.

The second step is that: the drug-eluting stent body crimped outside the expandable balloon obtained in the first step was inserted into a polytetrafluoroethylene tube having an original inner diameter of 0.044 inch and a length of 70 mm, and axial displacement was found to occur between the drug-eluting stent body and the expandable balloon, and the distance of the axial displacement was measured to be about 8 mm.

The third step: the drug-eluting stent body crimped outside the expandable balloon was fabricated according to the same procedure as in the first step, and the drug-eluting stent body crimped outside the expandable balloon was inserted into a polytetrafluoroethylene tube having an inner diameter of 0.045 inch and a length of 70 mm, packaged and sterilized to obtain the drug-eluting stent of comparative example three.

Expandable balloon body inspection

The appearance and diameter of the expandable balloon of the drug eluting balloon catheter provided in example one and the expandable balloon of the drug eluting balloon catheter of comparative example two were measured, respectively. The specific method comprises the following steps: the protective sleeve on the surface of the expandable balloon of the drug eluting balloon catheter provided in example one and the protective sleeve on the surface of the expandable balloon of the drug eluting balloon catheter of comparative example two were removed, respectively, the drug coating on the surface of the expandable balloon was gently wiped off with a dust-free cloth that had been wetted with purified water, and the expandable balloon was expanded to a nominal pressure (the nominal pressure is the expansion pressure required to reach the nominal diameter of the balloon catheter on the package) using a contrast agent solution (e.g., iopamidol solution, iohexol solution, iopromide solution, iomeprol solution, iopentol solution, ioversol solution, iotrolan solution, or iodixanol solution) stained with crystal violet. The expanded expandable balloon was placed under a 3D microscope to observe the appearance, and the actual diameter of the expandable balloon was measured under 20 x magnification and compared to the nominal diameter of the expandable balloon (nominal diameter is the diameter nominal for the balloon catheter package). The results of the actual diameter test of the expandable balloon at nominal pressure are shown in table 2.

TABLE 2 actual diameter test results for expandable balloon at nominal pressure

Table 1 the results show that: example one provides a drug eluting balloon catheter with an actual balloon diameter of 4002.2 μm at nominal pressure, which is substantially the same as the nominal diameter of a PTA balloon catheter with a balloon gauge of 4.0 mm x 40 mm. The actual diameter of the expandable balloon of the drug eluting balloon catheter of comparative example two was 3267.5 μm, which is well below the nominal diameter of the PTA balloon catheter with a balloon gauge of 4.0 mm x 40 mm.

3D microscopic observation shows that the effective area of the expandable balloon of the drug eluting balloon catheter provided in the first example is in a regular cylindrical shape in the inflated state. The expandable balloon of the drug eluting balloon catheter of comparative example two was significantly deformed in each section of the expandable balloon in the inflated state.

The above results indicate that, in the drug eluting balloon catheter provided in the first embodiment, the protective sleeve is wrapped outside the expandable balloon after swelling, which neither damages the expandable balloon body of the drug eluting balloon catheter nor affects the filling expansion of the expandable balloon after being placed in a human body.

Total drug amount test comparison

The total drug amount of the drug eluting balloon catheter refers to the total content of active drugs in the drug coating loaded on the surface of the expandable balloon of the drug eluting balloon catheter. The stability of the method of making a drug eluting balloon catheter is generally evaluated by the distribution of the total drug content of a plurality of drug eluting balloon catheters.

Three groups of 5 drug-eluting balloon catheter samples (hereinafter abbreviated as DEB samples) were prepared according to the preparation methods of example one, comparative example one, and comparative example two, respectively. During the preparation, the drug coating solutions applied to the surfaces of the expandable balloons of the three sets of DEB samples were identical. The total drug amount of the three groups of DEB samples were then examined separately to evaluate the effect of protective sleeves made of different materials on the stability of the preparation process.

The specific detection method comprises the following steps: three sets of DEB samples were soaked in methanol just completely submerged in the DEB samples, after removing the protective sleeves. Sonication dissolved the drug coating in methanol. And analyzing the concentration of the paclitaxel in the methanol by using high performance liquid chromatography (HPLC for short), and calculating the total dosage of the paclitaxel of each DEB sample according to the volume of the methanol. Total amount of paclitaxel-paclitaxel concentration in methanol x volume of methanol.

The HPLC detection conditions are as follows: hippocastane model LC-20A high performance liquid chromatograph. A chromatographic column: zobax SB-C18 column (4.6X 250 mm, 5 μm) from Agilent, USA. Column temperature: at 30 ℃. Mobile phase: methanol: acetonitrile: water 230:360: 410. Flow rate: 1.0 mL/min. An ultraviolet detector. Detection wavelength: 227 nm. The results of the total drug testing of the three groups of DEB samples are shown in table 1.

TABLE 1 Total drug dose test results for DEB samples

As can be seen from Table 1:

(1) the average total drug amount of the 5 samples prepared by the preparation method of example one was 1073.42, which is significantly higher than the average total drug amount of the 5 samples prepared by the preparation methods of comparative example one and comparative example two.

(2) The standard deviation of the total drug amount of the 5 samples prepared by the preparation method of example one was 24.97, which is significantly lower than the standard deviation of the total drug amount of the 5 samples prepared by the preparation methods of comparative example one and comparative example two.

The results show that the DEB sample prepared by the preparation method provided by the invention has higher total drug dosage because the protective sleeve is wrapped outside the expandable balloon after swelling, and the loss of the drug coating when the expandable balloon of the DEB sample is inserted into the protective sleeve in the production process is effectively reduced. Meanwhile, the preparation method of the drug eluting balloon provided by the invention has high stability, and the total dosage difference between different DEB samples is small, so that the preparation method is more suitable for industrialization.

In vitro simulated delivery process dosage loss test

The drug eluting balloon catheter provided in example one and the drug eluting balloon catheter of comparative example one were subjected to in vitro simulation tests for drug loss during delivery. The drug loss in the delivery process of the drug eluting balloon catheter refers to the drug loss amount in the period from the time when the expandable balloon of the drug eluting balloon catheter is placed into the guide catheter to the time when the expandable balloon is gradually pushed to the target blood vessel of the lesion part until the expandable balloon is filled. The ratio of the drug loss in the delivery process to the initial drug on the surface of the expandable balloon is the drug loss rate in the delivery process. Since the protective sleeve needs to be removed before the expandable balloon is placed in the guiding catheter, the flaps, which are already tightly wound, begin to gradually expand outward. During the process that the expandable balloon is pushed to the target lesion site, the high-speed scouring of blood flow can accelerate the unfolding process of each flap, so that the medicine coating in the area originally covered by the flap is directly washed by the blood flow to fall off. Therefore, the protective sleeve with the smaller inner diameter has stronger constraint effect on the flaps of the expandable balloon, the unfolding speed of the flaps is slower after the protective sleeve is removed, the flaps which maintain the winding state have longer protection time on the drug coating covered under the flaps, and the drug loss rate in the delivery process is lower.

The isolated pig coronary artery blood vessel is used for simulating a target blood vessel of a human coronary artery system, and an in-vitro simulation test of the drug loss in the delivery process is carried out in an in-vitro simulation blood vessel model. The loss of the delivery process of the drug eluting balloon catheter was examined. The specific method comprises the following steps: the protective sleeves on the drug eluting balloon catheters prepared in the first embodiment and the first embodiment are respectively torn off, and then the drug eluting balloon catheters are respectively inserted into an in-vitro simulated blood vessel model and are conveyed to a target blood vessel along a simulated blood vessel path and stay. Timing is started when the drug eluting balloon catheter is inserted into the in-vitro simulated blood vessel model, and the drug eluting balloon catheter is taken out after 90 seconds. The residual drug amount on the surface of the expandable balloon was analyzed by HPLC, and the drug loss rate during the delivery process was calculated according to the following formula:

the drug loss rate during the delivery process is (initial drug quantity on the surface of the expandable balloon-residual drug quantity on the surface of the expandable balloon)/initial drug quantity on the surface of the expandable balloon x 100%.

The HPLC detection conditions are as follows: hippocastane model LC-20A high performance liquid chromatograph. A chromatographic column: a column (4.6X 250 mm, 5 μm) of ZoBAX SB-C18, Agilent, USA. Column temperature: at 30 ℃. Mobile phase: methanol: acetonitrile: water 230:360: 410. Flow rate: 1.0 mL/min. An ultraviolet detector. Detection wavelength: 227 nm. The results of the in vitro simulated delivery drug loss test are shown in table 3.

TABLE 3 in vitro simulated delivery Process dosage loss test results

Table 3 the data shows: the drug-eluting balloon catheter provided in the first example has a significantly smaller drug loss rate during the delivery process than the drug-eluting balloon catheter of the first comparative example. In the drug eluting balloon catheter provided in the first embodiment, the protective sleeve wrapped outside the expandable balloon after swelling can effectively reduce the drug loss of the drug eluting balloon catheter during the delivery process.

Drug eluting stent profile size testing

The contour dimension of the drug eluting stent refers to the overall contour outer diameter of the drug eluting stent body and the expandable balloon after the drug eluting stent body is pressed and held outside the expandable balloon. The contour dimension of the drug eluting stent is determined by the tight pressing and holding degree of the drug eluting stent body and the expandable balloon. The contour size of the drug eluting stent is small, which is beneficial to the drug eluting stent to smoothly pass through the bending complex blood vessel and the stenotic lesion part. Meanwhile, the pressing and the holding between the drug eluting stent body and the expandable balloon are tight. Therefore, there is less risk of relative displacement between the drug eluting stent body and the expandable balloon, and less risk of the drug eluting stent body falling off the surface of the expandable balloon.

Two groups of 5 drug-eluting stent samples (hereinafter referred to as DES samples) were prepared according to the preparation methods of example four and comparative example three, respectively. In the preparation process, the drug coating solutions applied to the surfaces of the iron-based alloy stents of the two sets of DES samples were identical. The two sets of DES samples were then tested for profile size separately. The test results are shown in table 4:

table 4 contour dimension test results for drug eluting stents

As can be seen from Table 4: the DES samples provided in example four had smaller profile dimensions and the profile dimension data for the 5 DES samples were more concentrated than the DES samples of comparative example three. In the DES sample provided in example four, the protective sleeve wrapped around the outside of the DES after swelling allows the DES sample to have a smaller outer diameter, sufficiently protect the coating and reduce the overall size of the drug stent, leaving no space for outward expansion of the drug eluting stent body and the expandable balloon. In contrast, in the third comparative example, only the protective sleeve with a larger inner diameter can be used to avoid the drug coating from being damaged by friction with the inner wall of the protective sleeve or avoid the displacement between the drug eluting stent body and the expandable balloon, so that the profile size of the DES sample is larger. Therefore, the bonding force between the drug-eluting stent body and the expandable balloon of the comparative example four is poor, increasing the risk of the drug-eluting stent body falling off from the outside of the expandable balloon.

In summary, in the drug-carrying device provided by the invention, the protective sleeve is made of a polymer material which can be swelled by a solvent. In the process of sleeving the protective sleeve to the outside of the medicine carrying instrument, the protective sleeve made of the high polymer material is swelled in a solvent to increase the inner diameter of the protective sleeve, so that the medicine carrying instrument can be inserted into the protective sleeve without friction, and the medicine coating or the instrument body of the medicine carrying instrument is prevented from being damaged. And then the solvent is volatilized, so that the protective sleeve is contracted to the initial inner diameter under the action of external factors without mechanical force, a heat source and the like, and the drug-loaded instrument is bound to the smaller outline outer diameter, thereby being beneficial to the smooth passing of the drug-loaded instrument through a bent tube cavity or a narrow pathological change part in a human body.

In addition, the at least one groove is formed between the near end and the far end of the protective sleeve body along the axial direction of the protective sleeve, so that an operator can tear off the protective sleeve directly before use. Therefore, when the medicine carrying instrument is separated from the protective sleeve, the friction force between the inner surface of the protective sleeve and the outer surface of the medicine carrying instrument is prevented from damaging the medicine coating or the instrument body.

The drug eluting balloon catheter provided by the invention can be used for restraining the expandable balloon of the drug eluting balloon catheter to a smaller external profile through the protective sleeve, and can also be used for avoiding the damage of the drug coating or the expandable balloon body caused by the friction force between the protective sleeve and the drug coating. The expandable balloon can be tightly bound to a smaller size by the protective sleeve without heating, and the drug in the drug coating cannot be degraded by heating or the expandable balloon body cannot be deformed by heating. And after the protective sleeve is removed from the outside of the expandable balloon, a plurality of flaps of the expandable balloon can be continuously and tightly wound, so that the drug loss caused by high-speed flushing of blood flow in the conveying process is reduced.

The drug eluting stent provided by the invention not only can be used for binding the drug eluting stent body to a smaller external profile through the protective sleeve, but also can be used for avoiding the displacement between the drug coating or between the drug eluting stent body and the expandable balloon caused by the friction force between the protective sleeve and the drug coating. The drug eluting stent body and the expandable balloon can be tightly bound to a smaller size by the protective sleeve without heating, and the drug in the drug coating can not be degraded by heating or the drug eluting stent body and the expandable balloon can not be deformed by heating.

It can be understood that the technical scheme provided by the invention is only schematically described by the drug eluting balloon catheter and the drug eluting stent, and the technical scheme provided by the invention can also be used for other interventional medical devices or implantable medical devices. The interventional instrument comprises a contrast catheter, a central venous catheter, a pressure measuring catheter, a catheter or a disposable interventional therapy instrument probe. The implantable device includes a bone screw or plate. The purpose of the invention can be achieved by only adopting a high polymer material which can be swelled by a solvent to manufacture the protective sleeve, firstly swelling the protective sleeve in the solvent, then sleeving the protective sleeve outside the interventional medical instrument or the implantable medical instrument, and then volatilizing the solvent.

It can also be understood that the technical solution provided by the present invention is described schematically above only with a drug delivery device, and the technical solution provided by the present invention can also be used for other non-drug delivery devices. When the technical scheme provided by the invention is applied to other non-drug-carrying instruments, the protective sleeve still has the technical effect of protecting the instrument body from being damaged, the non-drug-carrying instruments can be tightly bound to a smaller outline outer diameter, and the passability of the non-drug-carrying instruments in a bent lumen part or a narrow part of a human body is improved.

The embodiments of the present invention have been described above with reference to the accompanying drawings, but the present invention is not limited to the above-described specific embodiments. The particular embodiments described above are illustrative only and not limiting. Those skilled in the art, having the benefit of this disclosure, may effect numerous modifications thereto without departing from the scope and spirit of the invention as set forth in the claims that follow.

Claims

1. Medicine carrying instrument, include protective case, apparatus body and locate the medicine coating on apparatus body surface, medicine carrying instrument has contraction status and expansion state, medicine carrying instrument is in external diameter during contraction status is comparatively medicine carrying instrument is in external diameter during expansion state is little, protective case locates the outside of medicine carrying instrument, a serial communication port, protective case is made by macromolecular material, protective case can take place the swelling in organic solvent, the protective sheath is located again through the cover after swelling in organic solvent medicine carrying instrument's outside.

2. The drug delivery device of claim 1, wherein the ratio of the inner diameter of the protective sleeve after swelling to the inner diameter of the protective sleeve before swelling ranges from (1.1-2): 1.

3. the drug delivery device of claim 1, wherein the polymeric material is selected from at least one of silicone, polyolefin, polyurethane, and polyurethane modified polymers.

4. The drug delivery device of claim 1, wherein the organic solvent is selected from at least one of methanol, ethanol, acetone, chloroform, tetrahydrofuran, dimethyl sulfoxide, or a liquid organic alkane having a number of carbon atoms in the range of 5 to 16.

5. The drug-loaded device of claim 1, wherein the drug coating comprises an active drug selected from at least one of an anti-intimal hyperplasia drug, an anticoagulant drug, an anti-platelet adhesion drug, an anti-infective drug, an antibacterial drug, an anti-inflammatory drug, an anti-allergic drug, or an anti-neoplastic drug.

6. The pre-loaded device of claim 5, wherein the active drug is selected from at least one of rapamycin, a rapamycin derivative, paclitaxel, or a paclitaxel derivative.

7. The pre-drug delivery device of claim 1, wherein the protective sleeve has an axial length before swelling that is greater than or equal to the axial length of the pre-drug delivery device in the collapsed state, and wherein the protective sleeve has an inner diameter before swelling that is less than or equal to the outer diameter of the pre-drug delivery device in the collapsed state.

8. The drug delivery device of claim 1, wherein at least one groove is provided between the proximal end and the distal end of the tube body of the protective sleeve along the axial direction of the protective sleeve, and the groove has a cut at the proximal end and/or the distal end.

9. The pre-loaded device of claim 8, wherein the incision has a length in the axial direction of the protective sleeve in the range of 5 mm to 15 mm.

10. The pre-loaded device of claim 1, wherein the pre-loaded device is an interventional or implantable device comprising a drug balloon catheter, a contrast catheter, a central venous catheter, a manometry catheter, a catheter or a disposable interventional instrument probe, the implantable device comprising a drug eluting stent, a bone nail or a bone plate.

11. The method of making a medicated device of claim 1, comprising the steps of:

applying the drug coating to the surface of the device body to obtain the drug-loaded device; placing the protective sleeve in the organic solvent to swell the protective sleeve to obtain a swelled protective sleeve; and sleeving the swollen protective sleeve outside the medicine-carrying instrument and drying.

12. The method of manufacturing of claim 11, wherein the protective sleeve has an axial length before swelling that is greater than or equal to the axial length of the drug-loaded device in the collapsed state, and the protective sleeve has an inner diameter before swelling that is less than or equal to the outer diameter of the drug-loaded device in the collapsed state.

13. The method of manufacturing of claim 11, further comprising removing residual organic solvent from the surface of the swollen protective sleeve before placing the swollen protective sleeve over the exterior of the drug-loaded device and drying.

14. The method of claim 11, wherein at least one groove is provided between the proximal end and the distal end of the body of the protective sleeve in the axial direction of the protective sleeve, and wherein after removing the residual organic solvent on the surface of the swollen protective sleeve, the method further comprises forming a cut at the proximal end and/or the distal end of the groove.

15. The method of claim 11, wherein the swelling time is in a range of 5 minutes to 24 hours.

16. The method of claim 11, wherein the drying comprises air drying at room temperature, air drying, vacuum drying, freeze drying, or heat drying at 30 ℃ to 60 ℃.