CN102872483B - Poly-(Epsilon-caprolactone) drug eluting stent modification method - Google Patents
Poly-(Epsilon-caprolactone) drug eluting stent modification method Download PDFInfo
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- CN102872483B CN102872483B CN201210355642.4A CN201210355642A CN102872483B CN 102872483 B CN102872483 B CN 102872483B CN 201210355642 A CN201210355642 A CN 201210355642A CN 102872483 B CN102872483 B CN 102872483B
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- caprolactone
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- eluting medicament
- chitosan
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Abstract
The invention relates to a poly-(Epsilon-caprolactone) drug eluting stent modification method adopting chitosan. The method comprises the step of melt blending or coating or both. A modified poly-(Epsilon-caprolactone) drug eluting stent is superior in both drug release (particularly early stages of drug release) and degradation to a conventional poly-(Epsilon-caprolactone) drug eluting stent.
Description
Technical field
The present invention relates to a kind of method of modifying of poly-(6-caprolactone) bracket for eluting medicament, specifically, relates to a kind of method adopting poly-(6-caprolactone) bracket for eluting medicament of poly-(6-caprolactone) modification of chitosan graft.
Background technology
Coronary heart disease is as a kind of common cardiovascular disease, underwent coronary interventional procedure (PCI) is the therapeutic modality of current main flow, it grows up based on the percutaneous tranluminal coronary angioplasty (PTCA) of carrying out at Gruentzig in 1977, mainly have passed through simple balloon dilatation, level in patients after coronary artery stenting and bracket for eluting medicament three developmental stage.But the brachymedial phase restenosis incidence rate that balloon dilatation and traditional bare metal stent cause because of vessel wall elasticity retraction and vascellum endometrial hyperplasia after implanting, up to more than 50%, seriously constrains the development of PCI.
In order to suppress and prevent PCI postoperative restenosis, bracket for eluting medicament suppresses by utilizing the breeding hypertrophy of medicine to vascular smooth muscle covering rack surface Polymer-supported, thus realizes the treatment of vascular restenosis.From the Cypher support of Cordis company in 2002 research and development since the listing of Europe, bracket for eluting medicament obtains a wide range of applications in PCI treatment, it effectively can reduce in-stent restenosis and again get involved problem, brachymedial phase restenosis problem obtains and effectively suppresses, but research finds that bracket for eluting medicament, compared to balloon dilatation and conventional metals bare bracket, late period (> 1 year) stent thrombosis problem more easily occurs.In addition, commercialization support is substantially based on metal material at present, and histocompatibility issues caused in digestion of metallic ion and Remained mass is the subject matter that metal rack platform exists.Although by improving metal composition (such as introducing the element such as nickel, titanium) or carrying out finishing (such as plated surface oxide layer, attachment inorganic protective layer etc.) effectively to solve the problem to it; but because the biological non-biodegradable of matrix itself; after in support, medicine is released; remaining metal rack is still present in human body, causes neointimal hyperplasia as a kind of foreign body implant is as easy as rolling off a log thus causes in-stent restenosis problem.
Polyester material is an important component part in Biodegradable material, as polylactic acid (PLA), polyglycolic acid (PGA) and poly-(6-caprolactone) (PCL) etc., be widely used in biomedical sector.Poly-(6-caprolactone) Food and Drug Administration (FDA) approval, can use as biomedical material, in Europe, PCL is used as nail clinically; It is clinical that the left ethisterone long-acting implantation agent Capronor that PCL makes completes the II phase in the U.S..In addition, research shows that the degradation cycle compared to PLA and PGA, PCL is longer, and degradation time is in vivo generally 2-4, and along with the increase of molecular weight, soak time is in vivo also longer.Initial number average molecular weight be 50,000 PCL need the time of 3 years could be degradable in body, therefore can be effective as mechanical support point before neovascularization.Secondly, because it is degraded and molecular structure slowly, the inflammatory effector of PCL is also little compared with the above two.But the existing bracket for eluting medicament be made up of PCL remains deficiency in the degraded of drug release (particularly medicine early stage release) and bracket for eluting medicament, still has room for improvement.
Summary of the invention
The present inventor finds through extensive and deep research: adopt existing poly-(6-caprolactone) bracket for eluting medicament of poly-(6-caprolactone) modification of chitosan graft, and poly-(6-caprolactone) bracket for eluting medicament of modification of gained performance in the degraded of drug release (particularly medicine release in early stage) and bracket for eluting medicament is all better than existing poly-(6-caprolactone) bracket for eluting medicament.
The object of the invention is, provide a kind of method of modifying of poly-(6-caprolactone) bracket for eluting medicament, the key step of described method of modifying is:
Poly-(6-caprolactone), poly-(6-caprolactone) of chitosan graft and medicine will be comprised through melt-processed molding, obtain object (modification gathers (6-caprolactone) bracket for eluting medicament);
Or,
First poly-(6-caprolactone) and medicine will be comprised through melt-processed molding, obtain bracket for eluting medicament A, then by poly-(6-caprolactone) fusion coating of chitosan graft on the surface of obtained bracket for eluting medicament A, obtain object (modification gathers (6-caprolactone) bracket for eluting medicament);
Or,
First poly-(6-caprolactone), poly-(6-caprolactone) of chitosan graft and medicine will be comprised through melt-processed molding, obtain bracket for eluting medicament B, then by poly-(6-caprolactone) fusion coating of chitosan graft on the surface of obtained bracket for eluting medicament B, obtain object (modification gathers (6-caprolactone) bracket for eluting medicament);
Wherein, the acetyl degree distribution of chitosan used is 81% ~ 100%, and its viscosity-average molecular weight is 1.03 × 10
5~ 10.35 × 10
5, poly-(6-caprolactone) of chitosan graft used is 1 with the mass ratio (total amount) of poly-(6-caprolactone) used: (1 ~ 10).
Accompanying drawing explanation
The cross section of the configuration of surface of Fig. 1 bracket for eluting medicament I (being prepared by embodiment 1) and section surface sweeping Electronic Speculum figure,
Wherein, the cross section surface sweeping Electronic Speculum figure of the configuration of surface of (a)-bracket for eluting medicament I,
The section surface sweeping Electronic Speculum figure of the configuration of surface of (b)-bracket for eluting medicament I.
The drug release patterns figure of Fig. 2 bracket for eluting medicament I ~ IV (being prepared by embodiment 1 ~ 4) and bracket for eluting medicament 1 ~ 2 (being prepared by comparative example 1 ~ 2).
Detailed description of the invention
In the present invention's preferred technical scheme, in poly-(6-caprolactone) of chitosan graft used, chitosan repetitive grafting 6 ~ 30 (6-caprolactone) repetitives, its structural representation formula is as follows:
Wherein, R
1~ R
4independently be selected from: H or
a kind of in (repetitive of poly-(6-caprolactone), curve mark is grafting end), and R
1~ R
4be asynchronously H.
Preferred technical scheme is: chitosan repetitive grafting 6 ~ 20 (6-caprolactone) repetitives.
Best technical scheme is: chitosan repetitive grafting 9 ~ 18 (6-caprolactone) repetitives.
In another preferred technical scheme of the present invention, poly-(6-caprolactone) of chitosan graft used is 1 with the mass ratio (total amount) of poly-(6-caprolactone) used: (1 ~ 4).
In a further preferred technical solution of the present invention, in the gross weight of described bracket for eluting medicament above for 100%, its Chinese medicine accounts for 0.1wt% ~ 10wt% (being more preferably 1wt% ~ 5wt%).
Wherein, described medicine can be that paclitaxel is or/and aspirin.
In sum, the method for poly-(6-caprolactone) bracket for eluting medicament of modification provided by the invention, comprises the following steps:
Poly-(6-caprolactone) melt blending of poly-(6-caprolactone) and chitosan graft will be comprised, add paclitaxel again or/and aspirin (the feed molar ratio row of each material are identical as mentioned before) and appropriate amount of drug go up acceptable auxiliary agent (as Polyethylene Glycol and/or glycerol etc.) stir after in ascending pipe mould, the pressure recession applying certain hour removes, and obtains object after cooling.
Or,
First poly-(6-caprolactone) and paclitaxel will be comprised or/and aspirin and the upper acceptable auxiliary agent (as Polyethylene Glycol and/or glycerol etc.) of appropriate amount of drug are through melt-processed molding, obtain bracket for eluting medicament Aa, then by poly-(6-caprolactone) fusion coating of chitosan graft on the surface of obtained bracket for eluting medicament Aa, obtain object;
Wherein, the feed ratio of each material is identical as mentioned before.
First poly-(6-caprolactone), poly-(6-caprolactone) of chitosan graft and paclitaxel will be comprised or/and aspirin and appropriate amount of drug go up acceptable auxiliary agent (as Polyethylene Glycol and/or glycerol etc.) through melt-processed molding, obtain bracket for eluting medicament Bb, then by poly-(6-caprolactone) fusion coating of chitosan graft on the surface of obtained bracket for eluting medicament Bb, obtain object;
Wherein, the feed ratio of each material is identical as mentioned before.
In the present invention, poly-(6-caprolactone) used and chitosan are commercially available product, and poly-(6-caprolactone) of chitosan graft prepares by document (Carbohydrate Polymers 2010 (80) 498-503).
Compared with prior art, tool of the present invention has the following advantages:
(1) chitosan and polycaprolactone material all have good biocompatibility, and can be degraded to micromolecule and got rid of by kidney organ.The hydrophobicity of pure polycaprolactone support is comparatively strong, and drug release is slow, improves the hydrophilicity of pure support, realize the Stable Release of medicine after introducing graft polymers.
(2) preparation technology is relatively simple, and mould is simple and easy to system and material source enriches.
Be further elaborated the present invention below by embodiment, its object is only better to understand content of the present invention.Should be understood that protection scope of the present invention is not limited by the cases cited.
In the examples below that, poly-(6-caprolactone) used is provided by upper seamount Jilin Chemical work company limited, and chitosan used is provided by ZHEJIANG AOXING BIOTECHNOLOGY CO., LTD.
Embodiment 1
Being averaged mole is 80; on poly-(6-caprolactone) of 000 and each chitosan unit, grafting 9 poly-(6-caprolactone) is as the matrix material of support; both mass ratioes are 3: 1; it is blended and be heated to 150 DEG C; add and inject mould after paclitaxel stirs (internal diameter of mould is 1mm; external diameter is 2mm); withdraw from after applying 1 minute at 150 DEG C by 5MPa power; cool the rear demoulding or immerse the demoulding in dehydrated alcohol, obtaining bracket for eluting medicament I.
Embodiment 2
Being averaged mole is 80; on poly-(6-caprolactone) of 000 and each chitosan unit, grafting 16 poly-(6-caprolactone) is as the matrix material of support; both mass ratioes are 4: 1; its blend is heated to 150 DEG C; add and inject above-mentioned mould after paclitaxel and aspirin stir (internal diameter of mould is 1mm; external diameter is 2mm); withdraw from after applying 1 minute at 150 DEG C by 5MPa power; cool the rear demoulding or immerse the demoulding in dehydrated alcohol, obtaining bracket for eluting medicament II.
Embodiment 3
First being averaged mole is 80, poly-(6-caprolactone) of 000 is as matrix material of support, this polymer is heated to 80 DEG C, add and inject mould after paclitaxel stirs (internal diameter of mould is 1mm, external diameter is 2mm), withdraw from after applying 1 minute at 100 DEG C by 5MPa power, cool the rear demoulding or immerse the demoulding in dehydrated alcohol, obtaining bracket for eluting medicament Aa-1;
Then; the polymer of grafting 18 on each chitosan unit poly-(6-caprolactone) is heated to 150 DEG C of meltings; and be coated on bracket for eluting medicament Aa-1 and (coating of surface uniform densification can be formed in the mould of external diameter 2mm); cooling and demolding or immerse the demoulding in dehydrated alcohol (poly-(6-caprolactone) is 4: 1 with the mass ratio of chitosan graft poly-(6-caprolactone)), obtains bracket for eluting medicament III.
Embodiment 4
Being averaged mole is 80, on poly-(6-caprolactone) of 000 and each chitosan unit, grafting 9 poly-(6-caprolactone) is as the matrix material of support, both mass ratioes are 3: 1, add paclitaxel stir after blended and inject mould after being heated to 120 DEG C (internal diameter of mould is 1mm, external diameter is 2mm), withdraw from after applying 1 minute by 5MPa power, cool the rear demoulding or immerse the demoulding in dehydrated alcohol, obtaining support Bb-1;
Then; the polymer of grafting 9 on each chitosan unit poly-(6-caprolactone) is heated to 150 DEG C of meltings; and be coated on support Bb-1 and (coating of surface uniform densification can be formed in the mould of external diameter 2mm); cooling and demolding or immerse the demoulding in dehydrated alcohol (total poly-(6-caprolactone) is 10: 1 with the mass ratio of chitosan graft poly-(6-caprolactone)), obtains bracket for eluting medicament IV.
Comparative example 1
Being averaged mole is 80; poly-(6-caprolactone) of 000 is as matrix material of support; be heated to 80 DEG C; add and inject mould after paclitaxel stirs (internal diameter of mould is 1mm; external diameter is 2mm); withdraw from after applying 1 minute at 100 DEG C by 5MPa power, cool the rear demoulding or immerse the demoulding in dehydrated alcohol, obtaining bracket for eluting medicament 1.
Comparative example 2
Being averaged mole is 80; poly-(6-caprolactone) of 000 is as matrix material of support; by it to 100 DEG C; add and inject above-mentioned mould after paclitaxel and aspirin stir (internal diameter of mould is 1mm; external diameter is 2mm); withdraw from after applying 1 minute at 150 DEG C by 5MPa power, cool the rear demoulding or immerse the demoulding in dehydrated alcohol, obtaining bracket for eluting medicament 2.
At identical conditions, the medicine-releasing performance of testing drug FirebirdTM I ~ IV and bracket for eluting medicament 1 ~ 2, it the results are shown in Figure 2.
As shown in Figure 2, drug release (particularly medicine release in the early stage) performance of bracket for eluting medicament I ~ IV is obviously better than bracket for eluting medicament 1 ~ 2.
Claims (10)
1. the method for poly-(6-caprolactone) bracket for eluting medicament of modification, it is characterized in that, the key step of described method is:
First will comprise poly-(6-caprolactone) and medicine through melt-processed molding, obtain bracket for eluting medicament A, then by poly-(6-caprolactone) fusion coating of chitosan graft on the surface of obtained bracket for eluting medicament A, obtain object;
Or,
First poly-(6-caprolactone), poly-(6-caprolactone) of chitosan graft and medicine will be comprised through melt-processed molding, obtain bracket for eluting medicament B, then by poly-(6-caprolactone) fusion coating of chitosan graft on the surface of obtained bracket for eluting medicament B, obtain object;
Wherein, the acetyl degree distribution of chitosan used is 81% ~ 100%, and its viscosity-average molecular weight is 1.03 × 10
5~ 10.35 × 10
5, poly-(6-caprolactone) of chitosan graft used is 1 with the mass ratio of poly-(6-caprolactone) used: (1 ~ 10).
2. the method for claim 1, is characterized in that, wherein in poly-(6-caprolactone) of chitosan graft used, and chitosan repetitive grafting 6 ~ 30 6-caprolactone repetitives.
3. method as claimed in claim 2, is characterized in that, wherein in poly-(6-caprolactone) of chitosan graft used, and chitosan repetitive grafting 6 ~ 20 6-caprolactone repetitives.
4. method as claimed in claim 3, is characterized in that, wherein in poly-(6-caprolactone) of chitosan graft used, and chitosan repetitive grafting 9 ~ 18 6-caprolactone repetitives.
5. the method as described in claim 1 or 4, is characterized in that, wherein poly-(6-caprolactone) of chitosan graft used is 1 with the mass ratio of poly-(6-caprolactone) used: (1 ~ 4).
6. the method for claim 1, is characterized in that, wherein in the gross weight of described bracket for eluting medicament for 100%, medicine accounts for 0.1wt% ~ 10wt%.
7. method as claimed in claim 6, is characterized in that, wherein in the gross weight of described bracket for eluting medicament for 100%, medicine accounts for 1wt% ~ 5wt%.
8. method as claimed in claims 6 or 7, it is characterized in that, wherein said medicine is that paclitaxel is or/and aspirin.
9. method as claimed in claim 5, is characterized in that, wherein in the gross weight of described bracket for eluting medicament for 100%, medicine accounts for 1wt% ~ 5wt%.
10. method as claimed in claim 9, it is characterized in that, wherein said medicine is that paclitaxel is or/and aspirin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210355642.4A CN102872483B (en) | 2012-09-19 | 2012-09-19 | Poly-(Epsilon-caprolactone) drug eluting stent modification method |
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|---|---|---|---|
| CN201210355642.4A CN102872483B (en) | 2012-09-19 | 2012-09-19 | Poly-(Epsilon-caprolactone) drug eluting stent modification method |
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| CN102872483A CN102872483A (en) | 2013-01-16 |
| CN102872483B true CN102872483B (en) | 2015-02-18 |
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