CN100400113C - Preparation method of metal support surface micro blind hole drug-loaded layer - Google Patents
Preparation method of metal support surface micro blind hole drug-loaded layer Download PDFInfo
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- CN100400113C CN100400113C CNB2006101094228A CN200610109422A CN100400113C CN 100400113 C CN100400113 C CN 100400113C CN B2006101094228 A CNB2006101094228 A CN B2006101094228A CN 200610109422 A CN200610109422 A CN 200610109422A CN 100400113 C CN100400113 C CN 100400113C
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- metal rack
- support surface
- blind hole
- deionized water
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Abstract
The invention discloses a preparing method of metal rack surface micro-blind hole drug-carrying layer, which comprises the following steps: a. heating NaOH solution at 100 deg.c to dispose metal rack surface, removing impurity and oxide film, cleaning through deionized water, drying, b. preparing 0.01-1.00mol/L etching liquid through analytical pure acid under normal temperature, marking the etching liquid, c. immersing the metal rack in the etching liquid under normal temperature for 8-20h, cleaning through deionized water, drying, d. allocating certain density of organic solution through organic solvent and metal rack carrier under normal temperature, e. placing metal rack with micro-blind hole on the surface in the organic solution under normal temperature, shocking through microwave for 15 min, drying.
Description
Affiliated field
The present invention relates to the manufacture method of the manufacture method of micro blind hole drug-loaded layer, particularly metal support surface micro blind hole drug-loaded layer.The present invention is the innovative design on existing clinical medicine use metal rack basis, and we propose to make Microvia at metal support surface, make its carrier as medicine, thereby overcome the harmful effect that metal rack implants and produced.Metal rack is a biomaterial medical and that comply with the national standard requirements, as surgical implant rustless steel, cochrome, Nitinol etc.Can be applicable to make all netted supports of implant into body tube chamber inner cylinder, as angiocarpy bracket, cerebrovascular support, peripheral blood vessel support, splenic artery support, esophagus urethra rack etc.
Background technology
It is the narrow effective method for treatment of cardiovascular that the metal current support is got involved urethroptasty, and it is obvious that it has curative effect, and acute occlusion rate is low, advantages such as wide accommodation; But because the implantation of metal rack causes vascular endothelial injury and inflammatory reaction easily, make the new intima hyperplasia and form new scar tissue, cause restenosis; Relevant report and clinical practice confirm that the restenosis rate that metal rack is implanted in back a year can reach about 30%.For reducing the restenosis rate after metal rack is implanted, researchers have been developed medication coat slow release (or eluting) support, both drug stent through extremely hard and bitter effort; The drug stent coating method of having put on market mainly adopts macromolecular compound as carrier layer, and its advantage is that the positioning and slow release effect of medicine is reduced to below 10% restenosis; Implant back nine months following up a case by regular visits to and show that the restenosis rate that has can be lower than 4%; But new problem has occurred, and the macromolecular compound carrier layer makes in the blood vessel of human body has increased the metabolic material of a kind of new needs again.
Drug stent is to cover one deck macromolecule medicine carrying material on the backbone metal surface, because both elastic modelling quantity differ greatly, so between the two adhesion is difficult to the maintenance original state after support and twice retrospective deformation of the common experience of macromolecule drug-loaded layer; Again because Framework construction is that beam column and bridge muscle are spaced, so pressure is held and expanded north change process each point tension force must be inconsistent, thereby medicine-carrying polymer layer and metal rack interface are taken off and are occurred in varying degrees between the two, inflow blood flow in ground when being taken off fragment and not waiting causes the patient acute, subacute stent thrombosis and far-end of limb thrombosis to occur.
Summary of the invention
The present invention seeks to provides a kind of manufacture method of metal support surface micro blind hole drug-loaded layer at existing technological deficiency.Make Microvia at metal support surface, make its carrier, thereby overcome the shortcoming of ubi supra as medicine, again can target positioning and slow release medicine.
The present invention adopts electrochemical method, and metal support surface is handled.Utilize existing medical implant metal rack and corrosive liquid to interact; Make metal support surface form even relatively, a lot of Microvias of average pore size about 0.8-2.5 μ m.Increased the surface area of metal rack like this, when medicament-carried,, made that also medicine is relatively stable, be evenly dispersed in rack surface as the hiding-place of medicine; And in vivo in the blood vessel slowly, orientation discharges medicine, thereby plays due effect.
Correlational study of the present invention confirms, at a certain temperature, the medical stainless steel metal rack is immersed in the hydrochloric acid solution of concentration between 0.01-1.00mol/L, just can form even, a plurality of Microvias at rack surface behind the storing certain hour.First principles analysis according to redox reaction: when hydrochloric acid solution was 1.00mol/L, its standard electrode EMF was 0.0000V; Cr under acid condition
+ 2/ Cr, Cr
+ 3/ Cr
+ 2, Fe
+ 2/ Fe, Ni
+ 2The standard electrode EMF of/Ni is respectively :-0.91V ,-0.41V ,-0.44V ,-0.25V.Therefrom as can be seen, redox reaction, Fe, Cr then take place earlier in Cr metal and HCl
+ 2With the HCl effect; Last Ni again with the HCl effect.Its relevant reaction equation is as follows:
Cr+2HCl → CrCl
2(blueness)+H
2↑
4CrCl
2+ 4HCl+O
2→ 4CrCl
3(green)+2H
2O
Fe+2HCl → FeCl
2(green)+H
2↑
Ni+2HCl → NiCl
2(green)+H
2↑
According to above-mentioned analysis, metal rack such as surgical implant mainly contain transition active metal elements such as Fe, Cr, Ni with biomaterials such as rustless steel, cochrome, Nitinols, and the reaction expression with corrosive liquid is under certain condition:
M+2H
+＝M
2++H
2↑
M: be metallic atom; M
2+For having the metal ion of two positive charges; The metal ion that dissociates is out removed by cleaning.
The manufacture method of metal support surface micro blind hole drug-loaded layer may further comprise the steps:
A, with the heating about 100 ℃ NaOH solution metal support surface is handled, remove existing impurity and oxide-film, use the deionized water cleaning, drying then;
B, at normal temperatures accurately prepares the 0.01-1.00mol/L corrosive liquid with analytically pure acid, and corrosive liquid is demarcated;
C, at normal temperatures with the above-mentioned metal rack of having handled, is immersed in about 8h-20h in the corrosive liquid of having demarcated, takes out back washed with de-ionized water, drying;
D, at normal temperatures with the medicine that volatile organic solvent and metal rack carried, prepares certain density organic solution;
E, at normal temperatures forms the metal rack of Microvia with the surface, put into be dissolved with medicament-carried organic solution, through microwave concussion 15min, take out after drying.
The invention is characterized in the key property that does not change metal rack, used corrosive liquid is non-oxidizing HCl, H
2SO
4Deng solution, and strict control concentration, the temperature of reaction and the time of effect, make metal support surface micro blind hole size, how much controlled, both can reach the purpose of a certain amount of medicine of carrying.
At the Microvia of metal support surface made, its average pore size is about 0.8-2.5 μ m; At antitumor drug such as paclitaxel, the rapamycin etc. of clinical use, its bulk of molecule is between the hundreds of nanometer; So the micropore of metal support surface can load a certain amount of medicine fully; The existence of metal support surface micro blind hole has correspondingly increased the surface area and the medicine carrying space of metal rack, makes the relative firm attachment of medicine in metal support surface; Simultaneously because the distribution of Microvia is again more uniform, so medicine also can scatter and play the effect of target positioning and slow release medicine very equably.
The specific embodiment
Example 1, with metal rack n piece, put in the NaOH solution of 100ml 2.00mol/L, be heated to 100 ℃, take out behind the 30min with deionized water clean, dry.Be immersed in then in the hydrochloric acid solution of 50ml 1.00mol/L, place 8h, clean, dry after taking out with deionized water; Put it at last be dissolved with in the medicament-carried organic solution, through microwave concussion 15min, take out after drying.
Example 2, with metal rack n piece, put in the NaOH solution of 100ml 2.00mol/L, be heated to 100 ℃, take out behind the 30min with deionized water clean, dry.Be immersed in then in the hydrochloric acid solution of 50ml 0.50mol/L, place 16h, clean, dry after taking out with deionized water; Put it at last be dissolved with in the medicament-carried organic solution, through microwave concussion 15min, take out after drying.
Example 3, with n piece of metal rack, handle the back through aqueous slkali and interact with corrosive liquid, make metal support surface form even relatively, a lot of Microvias of average pore size about 0.8-2.5 μ m; Put it into the CHCl that is dissolved with paclitaxel or rapamycin medicine then
3Or other volatile organic solvent, concentration is in the solution of 5mg/ml, through microwave concussion 15min, takes out after drying.
Claims (4)
1. the manufacture method of metal support surface micro blind hole drug-loaded layer may further comprise the steps:
A, metal support surface is handled, removed existing impurity and oxide-film, take out behind the 30min, use the deionized water cleaning, drying with the 100ml, the 2.00mol/L NaOH solution that are heated to 100 ℃;
B, at normal temperatures accurately prepares the 0.01-1.00mol/L corrosive liquid with analytically pure acid, and corrosive liquid is demarcated;
C, at normal temperatures with the above-mentioned metal rack of having handled, is immersed in 8h-20h in the corrosive liquid of having demarcated concentration, takes out the back and uses washed with de-ionized water, and drying obtains even, a plurality of Microvias and the average pore size metal rack at 0.8-2.5 μ m;
D, at normal temperatures, with the medicine that volatile organic solvent and metal rack carried, compound concentration is the organic solution of 5mg/ml;
E, at normal temperatures forms the metal rack of Microvia with the surface, put into be dissolved with medicament-carried organic solution, through microwave concussion 15min, take out after drying.
2. according to the manufacture method of the described metal support surface micro blind hole drug-loaded layer of claim 1, may further comprise the steps:
A, metal rack is put in the 100ml 2.00mol/L NaOH solution that is heated to 100 ℃, is taken out behind the 30min, with deionized water clean, dry;
B, cleaning and dried metal rack are immersed in the corrosive liquid of 50ml, 0.50mol/L, place 16h, and be clean, dry with deionized water after taking out.
3. according to the manufacture method of the described metal support surface micro blind hole drug-loaded layer of claim 1, may further comprise the steps:
A, metal rack is put in the 100ml 2.00mol/L NaOH solution that is heated to 100 ℃, is taken out behind the 30min, with deionized water clean, dry;
B, cleaning and dried metal rack are immersed in the corrosive liquid of 50ml, 1.00mol/L, place 8h, and be clean, dry with deionized water after taking out; Carrying out medicine then loads.
4. according to the manufacture method of the described metal support surface micro blind hole drug-loaded layer of claim 1, may further comprise the steps:
A, at normal temperatures is dissolved in CHCl with paclitaxel or rapamycin medicine
3, concentration is in the solution of 5mg/ml;
B, the surface is formed the metal rack of Microvia, put into above-mentioned solution,, take out after drying through microwave concussion 15min.
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| CN100400113C true CN100400113C (en) | 2008-07-09 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101199873B (en) * | 2006-12-14 | 2013-06-19 | 乐普（北京）医疗器械股份有限公司 | Medicament elution instrument nanometer class colon washer machineole drug releasing structure and preparing method thereof |
| CN101313873B (en) * | 2007-05-31 | 2011-03-23 | 乐普（北京）医疗器械股份有限公司 | Biology polypeptide medicament blood vessel bracket and preparation method thereof |
| CN101883592A (en) * | 2007-10-10 | 2010-11-10 | Miv治疗有限公司 | Calcium phosphate coated stents comprising cobalt chromium alloy |
| WO2010048757A1 (en) * | 2008-10-31 | 2010-05-06 | Dong Heyan | Method for preparation of rack with micro-blind holes on the surface carrying gene material |
| CN108404228A (en) * | 2018-03-14 | 2018-08-17 | 广东工业大学 | A kind of preparation method of stainless steel nano drug-carrying holder and slow-releasing agent |
| CN111249601A (en) * | 2018-11-30 | 2020-06-09 | 上海微创医疗器械（集团）有限公司 | Porous balloon and preparation method thereof |
| CN115317675B (en) * | 2022-08-23 | 2024-02-27 | 苏州中天医疗器械科技有限公司 | Drug eluting stent and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050055080A1 (en) * | 2003-09-05 | 2005-03-10 | Naim Istephanous | Modulated stents and methods of making the stents |
| CN1725988A (en) * | 2002-11-13 | 2006-01-25 | 斯特根有限公司 | Medical apparatus and manufacture method thereof with porous layer |
-
2006
- 2006-08-14 CN CNB2006101094228A patent/CN100400113C/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1725988A (en) * | 2002-11-13 | 2006-01-25 | 斯特根有限公司 | Medical apparatus and manufacture method thereof with porous layer |
| US20050055080A1 (en) * | 2003-09-05 | 2005-03-10 | Naim Istephanous | Modulated stents and methods of making the stents |
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Assignee: Liaoning Biomedical Materials R&D Center Co., Ltd. Assignor: Dong Heyan|Yinyi Biological Materical Research and Development Co., Ltd., Dalian Contract fulfillment period: 2008.12.1 to 2016.11.30 contract change Contract record no.: 2008210000087 Denomination of invention: Preparation method of metal support surface micro blind hole drug-loaded layer Granted publication date: 20080709 License type: Exclusive license Record date: 2008.12.9 |
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Effective date of registration: 20100122 Address after: Guangming Street Jinzhou District of Dalian City, Liaoning Province, Han Road 811. Zip code: 116100 Patentee after: Liaoning Biomedical Materials R&D Center Co., Ltd. Address before: 150-5, No. 54, Shahekou Road, Dalian District, Liaoning, 116021 Co-patentee before: Yinyi Biological Materical Research and Development Co., Ltd., Dalian Patentee before: Dong ho Yan |
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Address after: Guangming Street Jinzhou District of Dalian City, Liaoning Province, Han Road No. 8-11 116100 Patentee after: LIAONING YINYI BIOTECHNOLOGY CO., LTD. Address before: Guangming Street Jinzhou District of Dalian City, Liaoning Province, Han Road No. 8-11 116100 Patentee before: Liaoning Biomedical Materials R&D Center Co., Ltd. |