CN106310392B - Coating solution, recoverable vena cava filter and preparation method thereof - Google Patents
Coating solution, recoverable vena cava filter and preparation method thereof Download PDFInfo
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- CN106310392B CN106310392B CN201510400716.5A CN201510400716A CN106310392B CN 106310392 B CN106310392 B CN 106310392B CN 201510400716 A CN201510400716 A CN 201510400716A CN 106310392 B CN106310392 B CN 106310392B
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Abstract
The invention discloses a coating solution, a preparation method of a recyclable vena cava filter and the recyclable vena cava filter prepared by the preparation method. The surface of the recoverable vena cava filter is coated with an anti-intimal proliferation substance and an anticoagulant anti-thrombus substance which can degrade organic polymer materials; wherein the anti-intimal proliferation substance mainly acts to inhibit intimal proliferation of the inferior vena cava, thereby reducing adhesion between the wall of the vena cava and the filter; moreover, the main function of the anticoagulant and antithrombotic substance is to play a strong anticoagulation role and inhibit the generation and multiplication of thrombus in the filter.
Description
Technical Field
The invention relates to the field of medical instruments, in particular to a thrombus filtering device in vena cava, and more particularly relates to a coating solution, a preparation method of a recyclable vena cava filter and the manufactured recyclable vena cava filter.
Background
1. Venous thromboembolism
Venous Thromboembolism (VTE) including Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) is a common clinical disease with high morbidity and mortality in recent years. VTE incidence is higher than myocardial infarction and stroke in the united states, mortality is higher than breast cancer and aids, and is considered the second most lost workday following upper respiratory tract infection, with enormous financial and energy losses to society.
2. Vena cava filter
Anticoagulation has been the gold standard for VTE therapy with the goal of preventing thrombosis, preventing PE, and restoring patency of embolic veins. When a patient has anticoagulation contraindication or bleeding complications and has to stop anticoagulation, the falling thrombus can be effectively intercepted by implanting the Vena cava filter (Vena cava filter VCF) to prevent the occurrence of lethal pulmonary embolism. The only function of the vena cava filter is to prevent fatal pulmonary embolism by trapping free thrombus.
3. Recoverable vena cava filter
Permanent vena cava filters have been used clinically for over 40 years and once implanted in humans cannot be removed. Although permanent vena cava filters reduce the incidence of pulmonary embolism, they also present long-term complications such as inferior vena cava thrombosis, VTE recurrence, venous reflux disorder, and the like. With the development of technology, various semipermanent filters have appeared in succession, so that the implantation indications of the filters are gradually enlarged, and the most widely used ones are the recyclable vena cava filters.
In 2003, the recyclable vena cava filter was used clinically, and when the risk factor of PE persists, there is a large thrombus in the filter or the recycling fails, the recyclable vena cava filter can be left in the body as a permanent filter, and if the risk factor does not exist, the recyclable vena cava filter can be taken out after the PE is in a dangerous period.
In 2006, the recoverable vena cava filter accounted for 50% of the total filter usage. However, after the large-scale clinical application, people gradually find that the removable filter is not perfect, and reports of complications such as displacement, perforation, filter fracture, infection and the like are increasing.
The FDA in the U.S. at 8 months in 2010 and the labor province in the heaven of 10 months in 2010 send out warnings in succession, the use of the filter is required to be standardized, and the filter is recycled as soon as possible after the vena cava filter can be recycled, so that the filter is prevented from being placed in a human body for a long time. So the filter should be removed as early as clinically acceptable when the high risk factor for pulmonary embolism is removed.
According to the report of doctor Smouse about G ü nth Tulip, the reasons why the recoverable vena cava filter cannot be normally recovered are two, namely that the filter intercepts thrombus or thrombus formation in the filter, and that the vena cava filter is adhered to the wall of the inferior vena cava.
Patent document No. CN101843531A (hereinafter referred to as document 1) discloses a drug-coated thrombus filter, which comprises: thrombus filters, drug carriers and drugs; the thrombus filter is positioned on the innermost layer, the drug carrier is coated on the surface of the thrombus filter, and the drug is loaded in the drug carrier. The document 1 provides a drug-coated thrombus filter which uses a thrombus filter as a framework and is coated with a drug carrier material containing a thrombolytic anticoagulant drug on the surface thereof to form a drug-coated layer, and which can effectively prevent local thrombus blockage, inferior vena cava blockage and complications thereof.
In the document 1, the surface of the filter is coated with a thrombolytic anticoagulant, thereby solving the problem that the filter blocks thrombus or thrombus in the filter is difficult to remove or cannot be taken out of the recoverable vena cava filter.
However, document 1 does not solve the problem of adhesion of the vena cava filter to the wall of the inferior vena cava; the recyclable vena cava filter is still not removable.
The adhesion problem of the vena cava filter and the wall of the inferior vena cava is mainly caused by the hyperplasia of the intima of the blood vessel, and the adhesion problem is as follows:
in clinical practice it has been found that adhesion of the filter to the vena cava is usually around 2 weeks after filter implantation, the longer the time, the heavier the adhesion. Intimal hyperplasia of the blood vessel caused by the supporting part of the filter appears after 2 weeks; about 4 weeks later, the intimal hyperplasia of the blood vessel covers the filter and the supporting part of the blood vessel, and the adhesion of the filter and the vessel wall is obvious. So the existing expert consensus is: if the vena cava filter is not recovered for more than 4 weeks, it is typically left in the body as a permanent filter.
Disclosure of Invention
It is an object of the present invention to overcome or alleviate at least some of the above disadvantages and to provide a coating solution for application to the surface of a recyclable vena cava filter, comprising:
polycaprolactone/chloroform solution (polycaprolactone solution in chloroform);
anticoagulant antithrombotic substance and anti-intimal proliferation substance dissolved in the polycaprolactone/chloroform solution,
the mass percentage of the anticoagulant antithrombotic substance to the mass of the polycaprolactone in the polycaprolactone/chloroform solution is A, wherein A is more than 0 and less than or equal to 100 percent,
the percentage B of the mass of the anti-intimal proliferation substance to the mass of the polycaprolactone in the polycaprolactone/chloroform solution is that B is more than 0 and less than or equal to 100 percent.
In a preferred embodiment, the anticoagulant antithrombotic substance is at least one of heparin, hirudin, and urokinase.
Similarly, the anti-intimal proliferation substance is at least one of rapamicins, taxanes and mitomycins.
In addition, the mass to volume ratio of the polycaprolactone/chloroform solution was 20%, i.e. 20g of polycaprolactone was dissolved per 100ml of chloroform.
Further, the mass percentage of the anticoagulant and antithrombotic substance to the mass of the polycaprolactone in the polycaprolactone/chloroform solution is 10 percent; the percentage of the mass of the anti-intimal proliferation substance to the mass of the polycaprolactone in the polycaprolactone/chloroform solution was 10%.
Or the mass percentage of the anticoagulant antithrombotic substance to the mass of the polycaprolactone in the polycaprolactone/chloroform solution is 20 percent; the percentage of the mass of the anti-intimal proliferation substance to the mass of the polycaprolactone in the polycaprolactone/chloroform solution is 20%.
The present invention further provides a method for preparing a recyclable vena cava filter having anticoagulant and anti-intimal proliferation effects using the above coating solution, comprising preparing the filter in advance, and then further comprising:
step (1) of subjecting any one of the above-described preferred coating solutions to ultrasonic treatment;
step (2), uniformly coating the coating solution subjected to ultrasonic treatment in the step (1) on the surface of a filter prepared in advance to form a substance coating;
and (3) drying the filter after the step (2).
Preferably, in step (3),
firstly, the filter on which the substance coating layer is formed is placed at room temperature and naturally dried for 12 hours;
the filter after the natural drying was placed at room temperature and vacuum-dried in a vacuum oven for 12 hours.
Of course, the present invention provides a recyclable vena cava filter produced by the above-described method of manufacturing a recyclable vena cava filter.
Preferably, the prepared filter is a stainless steel filter, a cobalt-chromium alloy filter, a nickel-titanium alloy filter or a polymer material filter.
Drawings
These and other aspects of the present invention will now be described in more detail, with reference to the appended drawings showing a currently preferred embodiment of the invention. Wherein:
FIG. 1 is a cross-sectional view of a retrievable vena cava filter according to this embodiment;
FIG. 2 is a graph showing the release of heparin in this example;
FIG. 3 is a graph showing the release profile of rapamycin according to this example;
FIG. 4 is a scanning electron microscope image showing the coating solubility of various substances on the surface of the filter according to this example.
Detailed Description
The present invention is further illustrated by the following figures and specific examples, which are to be understood as illustrative only and not as limiting the scope of the invention, which is to be given the full breadth of the appended claims and any and all equivalent modifications thereof which may occur to those skilled in the art upon reading the present specification.
The technical key point of the embodiment is that the recyclable vena cava filter is coated with an anti-intima proliferation substance and an anti-coagulation and anti-thrombosis substance which are combined with a degradable organic high polymer material in a dip-coating manner; wherein the anti-intimal proliferation substance mainly acts to inhibit intimal proliferation of the inferior vena cava, thereby reducing adhesion between the wall of the vena cava and the filter; moreover, the anticoagulant and antithrombotic substance mainly plays a role in inhibiting the generation and multiplication of thrombus and playing a strong anticoagulant role.
Therefore, in the window period of thrombus formation, the two substances are continuously released on the surface of the filter to play an ideal role in resisting adhesion and preventing thrombus formation, so that the taking time of the recyclable vena cava filter is prolonged, the taking difficulty of the recyclable vena cava filter is reduced, the recycling success rate of the recyclable vena cava filter is improved, and the surgical risk is reduced.
Specifically, this example dissolves the anticoagulation antithrombotic substance and the anti-intimal proliferation substance in the polycaprolactone/chloroform solution as a coating solution to coat the surface of the recoverable vena cava filter.
The coating solution applied to the surface of the recoverable vena cava filter comprises: polycaprolactone/chloroform solution with mass volume ratio of 20%; and the anticoagulant antithrombotic substance and the anti-intimal proliferation substance are dissolved in the polycaprolactone/chloroform solution, and the mass of the anticoagulant antithrombotic substance and the anti-intimal proliferation substance is 1 to 20 percent of that of the polycaprolactone in the polycaprolactone/chloroform solution.
For the explanation of the above mass relationship: the mass-to-volume ratio is a common measurement unit in the field of medicinal chemistry, namely 20g of polycaprolactone is dissolved in 100ml of chloroform solution; meanwhile, the mass of the anticoagulant antithrombotic substance and the anti-intimal proliferation substance is 1 to 20 percent of that of 20g of polycaprolactone, namely 0.2 to 4 g.
Further, the anticoagulant and antithrombotic substance of the present embodiment may be one of heparin, hirudin and urokinase, or any combination thereof. In consideration of the fact that the clinical systemic intravenous administration of heparin can effectively inhibit the generation and the multiplication of thrombus and play a strong anticoagulation role, the heparin is used on the filter, and the local sustained release of the heparin can effectively reduce or inhibit the formation of thrombus in the filter, so the anticoagulation antithrombotic substances mentioned in the following embodiment are all replaced by the heparin.
Furthermore, the anti-intimal proliferation substance may be one of rapamicin, paclitaxel and mitomycin, or any combination thereof. Because rapamycin has the advantages of high efficiency, long half-life period (60h), long action time and the like, the anticoagulant and antithrombotic substances mentioned in the embodiment are replaced by rapamycin.
After selection of the material type and completion of the material proportioning, this example prepared a recoverable vena cava filter in the following manner.
Preparing 20% (mass volume ratio) Polycaprolactone (PCL)/chloroform solution;
adding 20% of rapamycin and 20% of heparin sodium into a Polycaprolactone (PCL)/chloroform solution according to the mass of the PCL to prepare a coating solution coated on the surface of the recoverable vena cava filter.
Carrying out ultrasonic treatment on the coating solution row for 10 min;
the coating solution after the ultrasonic treatment is coated on the surface of the recyclable vena cava filter by a dip coating method to form a substance coating on the surface of the filter.
And (3) placing the recyclable vena cava filter with the substance coating in a room temperature environment for 12h for natural drying, and then placing the recyclable vena cava filter in a vacuum drying oven for further room temperature drying for 12 h.
As shown in FIG. 1, a recyclable vena cava filter having a substance coating 2 coated on the surface of a filter 1 can be obtained by the above-described steps; for the recovered vena cava filter produced, this example makes the following feasibility test.
(1) Testing the compression and post-release anti-stripping capabilities of the recoverable vena cava filter:
weighing the prepared recyclable vena cava filter, putting the recyclable vena cava filter into a catheter, putting the recyclable vena cava filter into the catheter for 10 times, weighing the recyclable vena cava filter, and observing the coating on the surface of the recyclable vena cava filter by a scanning electron microscope before and after contraction. The mass of the coating before and after the measurement by a 5-position balance is 0.46052 g and 0.46065g respectively, and the total mass of the coating is not obviously changed. The results of the anti-stripping test show that the coating at the filter strip portion is no longer flat, strip ridges appear, and the nodes remain flat.
(2) In vitro substance release profile test, etc.; release content test (30 days):
placing the hollow tubular sample in a 1ml syringe, adding 1ml of buffer solution with the pH of 7.4, releasing in a shaking table at 37 ℃, sampling according to a preset time point, taking out 1ml of release solution each time, extracting rapamycin three times by using 1ml of chloroform, removing the chloroform by using a rotary evaporator, dissolving in acetonitrile, and measuring the content at the position of 278nm ultraviolet; the content of heparin in the aqueous solution is still determined by 631nm ultraviolet by a toluidine blue method, and the heparin is frozen at the temperature of-20 ℃ without sampling and detection. In actual tests, as rapamycin is released along with degradation of PCL, the rate is slower, and heparin has larger release amount due to poor compatibility with PCL coating, and particularly, the release curves can be referred to fig. 2 and 3.
(3) Animal experiments;
in the experiment, 50-60 kg of 12 adult sheep of the same variety with similar average age are adopted and are adaptively fed in advance.
Experiment design:
3 sheep were used as control intervention group (CI), 3 as control laparotomy group (CL), implanted with normal filter; 3 as an experimental intervention group (EI), 3 as an experimental abdominal opening group (EL), respectively implanting drug-coated filters, respectively taking out 1 sheep per group in 10,20 and 30 days after implanting the filters, performing vena cava radiography after anesthesia, knowing the patency degree of inferior vena cava and whether thrombus is formed in the filters, then performing direct operation of the CL group and the EL group to open the abdomen and take out the inferior vena cava segment blood vessel with the filters, and measuring the degree of the filters covered by the hyperplasia intima; taking out pathological sections of the intima, performing hematoxylin-eosin (HE) staining and PCNA immunohistochemical examination, measuring the thickness of the neointima, and grasping the intimal hyperplasia condition; CI and experimental EI groups were performed with interventional filter removal procedures to determine how easy filter removal was at different time points.
The results of the above tests are summarized in this example as follows:
① tests on the anti-stripping ability of the coating after compression and release show that there is no significant loss of the coating before and after compression and release of the filter, specification
② test on release pattern of in vitro substance shows that the release of heparin reaches more than 50% on day 1, while rapamycin is hardly released in the first few days and is released in large amount in 20-30 days.
③ results of animal experiments HE and PCNA show that the recoverable vena cava filter with the drug coating can effectively inhibit hyperplasia of vein endothelium and reduce the wrapping of the filter by endothelium in 10-20 days compared with the filter without the drug coating, thereby reducing the recovery difficulty of the filter and having certain anticoagulation and antithrombotic effects.
In addition, regarding the selected concentrations of the anticoagulant and anti-thrombus substance and the anti-intimal proliferation substance, the present example also performed a related experiment, that is, the mass of the anticoagulant and anti-thrombus substance and the anti-intimal proliferation substance is 1% -20% of the mass of polycaprolactone.
As shown in fig. 4, the sem results show that: when the mass of the anticoagulant antithrombotic substance and the anti-intimal proliferation substance is about 1 percent and 5 percent of that of the polycaprolactone, the filter cannot be covered by the anticoagulant antithrombotic substance and the anti-intimal proliferation substance;
when the masses of the anticoagulant antithrombotic substance and the anti-intimal proliferation substance are both 10% of that of polycaprolactone, the anticoagulant antithrombotic substance and the anti-intimal proliferation substance can cover the filter, but the surface holes are more;
when the masses of the anticoagulant antithrombotic substance and the intima proliferation substance are both 20 percent of the mass of polycaprolactone, the anticoagulant antithrombotic substance and the intima proliferation substance can be finished
The filter is covered completely, and the surface of the filter is smooth.
In conclusion, the anticoagulant antithrombotic substance and the anti-intimal proliferation substance accounting for 20% of the mass of the polycaprolactone can ensure the complete coverage of the anticoagulant antithrombotic substance and the anti-intimal proliferation substance on the surface of the filter.
The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above embodiments, and all technical solutions belonging to the idea of the present invention belong to the protection scope of the present invention. It should be noted that modifications and embellishments within the scope of the invention may occur to those skilled in the art without departing from the principle of the invention, and are considered to be within the scope of the invention.
Claims (5)
1. A coating solution for application to the surface of a retrievable vena cava filter, comprising:
the polycaprolactone/chloroform solution is 20% in mass volume ratio, namely 20g of polycaprolactone is dissolved in 100ml of chloroform solution;
anticoagulant antithrombotic substance and anti-intimal proliferation substance dissolved in the polycaprolactone/chloroform solution,
the percentage of the mass of the anticoagulant antithrombotic substance to the mass of the polycaprolactone in the polycaprolactone/chloroform solution is A, wherein 10 percent < A is less than or equal to 20 percent,
the percentage of the mass of the anti-intimal proliferation substance to the mass of the polycaprolactone in the polycaprolactone/chloroform solution is B, wherein B is more than 10% and less than or equal to 20%;
the anticoagulant antithrombotic substance is heparin;
the anti-intimal proliferation substance is at least one of rapapsidases, taxol and mitogen.
2. A method of preparing a recyclable vena cava filter having anticoagulant and anti-intimal proliferation effects, comprising preparing the filter in advance, comprising:
a step (1) of subjecting the coating solution of claim 1 to ultrasonic treatment;
step (2), uniformly coating the coating solution subjected to ultrasonic treatment in the step (1) on the surface of a filter prepared in advance to form a substance coating;
and (3) drying the filter after the step (2).
3. The method for preparing a recoverable vena cava filter according to claim 2, wherein in step (3), first, the filter on which the substance coating is formed is left to dry naturally for 12 hours at room temperature; the filter after the natural drying was placed at room temperature and vacuum-dried in a vacuum oven for 12 hours.
4. A recyclable vena cava filter, characterized by being produced by the method of claim 2 or 3.
5. The recyclable vena cava filter according to claim 4, wherein the filter is selected from a stainless steel filter, a cobalt-chromium alloy filter, a nickel-titanium alloy filter, or a polymer material filter.
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| CN201510400716.5A CN106310392B (en) | 2015-07-09 | 2015-07-09 | Coating solution, recoverable vena cava filter and preparation method thereof |
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| CN201510400716.5A CN106310392B (en) | 2015-07-09 | 2015-07-09 | Coating solution, recoverable vena cava filter and preparation method thereof |
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| CN106310392B true CN106310392B (en) | 2020-02-11 |
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Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6447530B1 (en) * | 1996-11-27 | 2002-09-10 | Scimed Life Systems, Inc. | Atraumatic anchoring and disengagement mechanism for permanent implant device |
| CN101843531A (en) * | 2010-05-25 | 2010-09-29 | 天健医疗科技(苏州)有限公司 | Medicament coated thrombus filter |
| CN102973339A (en) * | 2011-09-05 | 2013-03-20 | 上海市第十人民医院 | Cardia stent with drug coating |
| CN103027763A (en) * | 2012-11-16 | 2013-04-10 | 北京泰杰伟业科技有限公司 | Vena cava filter coated with macromolecular coating and preparation method for macromolecular coating |
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