CN100435755C - Bracket for eluting medication - Google Patents
Bracket for eluting medication Download PDFInfo
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- CN100435755C CN100435755C CNB2004100531793A CN200410053179A CN100435755C CN 100435755 C CN100435755 C CN 100435755C CN B2004100531793 A CNB2004100531793 A CN B2004100531793A CN 200410053179 A CN200410053179 A CN 200410053179A CN 100435755 C CN100435755 C CN 100435755C
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- mytrolimus
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Abstract
The present invention relates to a bracket for medicine eluting, which is composed of a bracket performing the function of supporting and a coating layer for loading medicine covered on the surface of the bracket. The present invention is characterized in that the coating layer for loading medicine is composed of 0.5 to 99.5% of polymer and 0.5 to 99.5% of active component according to the weight percentage, wherein the active component is Mytrolimus (CCI-779); the material of the coating layer is styrene-isobutylene-cinnamic tri-block copolymer of which the styrene content is 35 to 55 wt%; the bracket can be used in angiocarpy; due to the adoption of the proper active component and a proper carrier, the present invention has an obvious therapeutic effect. A test result shows that after the bracket is implanted for 28 days, intima of blood vessels almost has no proliferation, and no stenosis occurs after the blood vessels are damaged; the styrene-isobutylene-cinnamic tri-block copolymer has a favorable biocompatibility, and the bracket of the mytrolimus coating layer has a favorable effect on inhibiting the hyperplasia of the intima after the blood vessels are damaged; the bracket can effectively inhibit the occurrence of restenosis.
Description
Technical field
This patent relates to a class medical apparatus and instruments, is specifically related to a kind of bracket for eluting medicament that prevents that the postangioplasty tunica intima from excessively thickening.
Technical background
The arteries support is that cardiovascular and peripheral blood vessel block the main means that pathological changes is carried out interventional therapy, from Sigwart in 1986 etc. since human body is placed the first routine coronary stent, this The Application of Technology spreading speed is very fast, at present accounted for more than 80% of this disease treatment, and rapidly to other blood vessels and cavity expansion.
But the disadvantage of this technology is the generation of restenosis behind the support simultaneously, and incidence rate is 20% to 30% at present.Restenosis is the inaccessible once more of postangioplasty lesion vessels, is the key constraints of long-term vessel open, the health of serious threat postoperative patient.
The support postoperative restenosis is mainly caused by the blood vessel wall intimal thickening.Blood vessel causes the endotheliocyte and the smooth muscle cell damage of blood vessel wall after the support expansion, can cause thrombosis and inflammatory reaction.Follow the release of hematoblastic cell growth factor, as PDGF, EGF etc., the propagation of stimulated vascular smooth muscle cell and migration.The smooth muscle cell that is activated is synthetic phenotype by shrinking phenotypic transformation, and in impaired back 3 days, 20% to 40% middle film smooth muscle cell enters cell generation cycle.New synthetic cell migration is secreted a large amount of extracellular matrixs to the smooth muscle theca interna.Simultaneously, inflammatory cell can be attacked damage location, the more deep layer of intravasation wall.The endotheliocyte of dysfunction is also contributed to some extent to the propagation and the migration of smooth muscle cell.Endothelium up to damaged part grows up to again, and intimal proliferation just slows down gradually, yet extracellular matrix increases and further causes intimal thickening.This multiple bioprocess acts on the generation of the restenosis that has caused the postoperative blood vessel simultaneously.
Many pharmaceutical preparatioies empirical tests have the effect that suppresses vascular restenosis.Yet patient's whole body is taken antiproliferative medicine and is not produced remarkable result in lesion.And whole body take reach the treatment valid density some medicines, may surpass it to the toxigenous Cmin of human body.
The generation of utilization bracket for eluting medicament prevention of restenosis has obtained tangible curative effect.Bracket for eluting medicament generally is made of support and its surperficial drug-carried coat.Use the support carrying medicaments, can obtain medicine and discharge, thereby effectively suppress the generation of vascular restenosis at local organization concentration height under the very low situation of systemic concentrations in the part of lesion.As the patent of applicant in first to file, application number: 02146905.9.
Discover that at present the derivant of Mytrolimus (CCI-779) and other Rapamycin can suppress mTOR (Rapamycin target protein) kinase activity, thereby play the effect that suppresses cell proliferation.
After factors stimulated growth, 4E-BP1 and S6K kinases generation phosphorylation in the people, Mus coronary artery smooth muscle cell and be activated (Hidalgo M, Rowinsky EK, et al.Oncogene2000; 19:6680).4E-BP1 and S6K kinases are G1 phase important protein very in the S phase process in the cell cycle.Discharge after the 4E-BP1 phosphorylation by its eIF-4E that detains, the translation that eIF-4E and eIF-4G, 4B, 4A form mRNA starts the factor, together opens the albumen that promotes cell proliferation with regulatory factor such as cyclin D1 and synthesizes.Can further make ribosome be in the state of activation that to translate synthetic proteins behind the S6K tyrosine phosphorylation.Correspondingly, cyclin B1, cyclin D1, cyclin E, Cdk1, Cdk2, the PCNA protein level of representing cell to enter proliferating cycle raise, thereby stimulated vascular smooth muscle cell enters the multiplicative stage.
Rapamycin can realize its anti-proliferative effect by suppressing 4E-BP1 and the kinase whose phosphorylation of S6K; Mytrolimus can also raise by the protein level that suppresses cell generation cycle, stop cell enter the S phase (Shile H, et al.Current Opinion in Pharmacology 2003,3:371-377).The Rapamycin-FKBP-12 complex can suppress the Rb phosphorylation, and unphosphorylated Rb can detain transcription factor E2F, thereby stops albumen synthetic.For example, Rapamycin shows in experiment can suppress the smooth muscle cell growth that VEGF causes, suppresses (YuY, the Sato JD.J Cell Physiol 1999 of increasing of cyclin D1 and P21 simultaneously; 178:235.Vinals F, Chambard JC, Pouyssegur J, et al.JBC 1999; 274:26776); In zoopery, Rapamycin causes the serious forfeiture of Cor Sus domestica adventitia tremulous pulse to serotonin and the slight reactive diastole ability of losing Kallidin I, show vasodilation function generation obstacle (the Jeanmart H that it can make the NO mediation, Malo O, Carrier M, et al.JHeart Lung Transplant 2002:21:990) etc.
Mytrolimus is the solubility esterification derivative of Raparmycin, can produce the biological action of similar Rapamycin.
Pharmaceutical carrier, as the important component part of bracket for eluting medicament, require to have do not produce noxious substance, character such as not broken in the support process of expansion, sticking connection sacculus.US006545097 has introduced a kind of styrene-isobutene .-cinnamic triblock copolymer, this polymer is stable in vivo, do not produce any noxious substance, and can be by changing the ratio of styrene and isobutene., the viscosity of telomerized polymer and tensile strength.
CN02146905.9 has introduced the method that strengthens adhesion between drug-loaded layer and support, promptly can have a bottom between drug-loaded layer and support, and to improve the adhesion of drug-loaded layer and support, bottom is made up of one or more polymer.
But, the open at present technology of reporting, all do not mention how Mytrolimus (CCI-779) being used for bracket for eluting medicament with styrene-isobutene .-cinnamic triblock copolymer, especially do not mention the styrene-isobutene .-cinnamic triblock copolymer that adopts which kind of type, therefore how Mytrolimus (CCI-779) is used for bracket for eluting medicament with styrene-isobutene .-cinnamic triblock copolymer, to satisfy the needs of clinical treatment, be people the problem very be concerned about.
Summary of the invention
The technical issues that need to address of the present invention are to disclose a kind of to be active component with Mytrolimus (CCI-779), to be the bracket for eluting medicament of coating material with styrene-isobutene .-cinnamic triblock copolymer, to satisfy the needs of clinical treatment.
Bracket for eluting medicament of the present invention is made of passive support and the drug-carried coat that covers rack surface, it is characterized in that wherein drug-carried coat is that the polymer of 0.5-99.5% and the active component of 0.5-99.5% are formed by percentage by weight;
Described active component is the derivant of a kind of rapamycin (Rapamycin), Mytrolimus (CCI-779).Mytrolimus promptly has biological action under low concentration, easily by vascular tissue diffusion, and the double effects with anti-hypertrophy and anti-inflammatory, and allow normally endothelialization again.This pharmaceutical preparation, the polymer support that can sneak into Biostatic is coated on rack surface by the method for dip-coating or spraying, be placed on the vascular lesion position with support, the slow release that realization continues from rack surface, not only limited the hypertrophy of local smooth muscle cell but also reduced outgrowth promoting factors such as inflammatory reaction, thereby can strengthen restriction restenosis.
The inventor finds that coating material is the key technology factor of bracket for eluting medicament equally.Styrene-isobutene. of the present invention-cinnamic triblock copolymer can satisfy the each side specification requirement of the described support of invention.Mytrolimus is the solubility esterification derivative of Rapamycin, and bioavailability obviously improves, but this compounds chemical stability under polarity condition is poor slightly.The coating material that the present invention selects for use, belong to non-polar material, not only biocompatibility is good, also very stable in vivo, do not produce any catabolite, do not make medicine lose due curative effect thereby can in bracket coating, not produce the environment that quickens the Mytrolimus decomposition, help medicine and discharge according to the design needs are stable.
In addition, the mechanical performance of coating material affects the clinical safety of support, mainly comprises viscosity, hardness and tensile strength etc.:
Viscosity is too strong, coating easily and induction system stick together, may produce two kinds of bad results, the one,, induction system can be returned and be removed, but coating returns in the process of removing in induction system and tear, and causes acute, subacute stent thrombosis; The 2nd,, induction system can not be returned and be removed, and need induction system be taken out with surgical operation, has increased patient's the misery and the burden of operative doctor.
The hardness level of coating material is directly relevant with the tensile strength of coating material.Hardness is too little, and the tensile strength of coating material is low, can not bear the effect of mechanical force in the balloon expandable process, causes coating damage easily, brings potential safety hazard to clinical practice.
The tensile strength of coating material is too big, the mechanical performance of support will be subjected to the influence of coating layer thickness, in the case, the name pressure of support will change, and also can produce the adherent problem such as bad of support, in addition, tensile strength is big, can reduce the elongation at break of material, thereby make coating crackle behind balloon expandable, occur, can cause challenge to clinical safety equally.
Through a large amount of test of inventor, the coating material that the inventor selects for use is:
Styrene-content is at styrene-isobutene .-cinnamic triblock copolymer of 35～55wt%.This polymer can pass through the mechanical performance of the ratio telomerized polymer of change styrene and isobutene..
For styrene-isobutene .-styrene triblock copolymer, the hardness of material, tensile strength are directly proportional with styrene-content; The elongation at break and the styrene-content of material are inversely proportional to.Just, along with the increase of styrene block proportion, the hardness of coating material increases, and elongation at break reduces, and toughness is poor more.When styrene-content was lower than 35wt%, the viscosity of coating material was big, hardness is little, tensile strength is low, the needs of holding capacity in the time of can not satisfying the support expansion, and coating is torn easily.And styrene-content is when being higher than 55wt%, though material hardness can meet the demands, the elongation at break of coating is low, expansion that can limit bracket or crackle occurs after the support expansion.In the selected styrene and isobutene. proportion of patent, the influence that can avoid coating material to cause to stent safety because of the problems referred to above.
In order to improve the adhesion of drug-loaded layer and support, can between drug-carried coat and support, can have a bottom.
Drug-carried coat thickness is the 0.1-100 micron;
Underlayer thickness is 0.1～10 micron.
Support of the present invention can adopt conventional method to make, as the method for 02146905.9 patent disclosure.
Described support can be used for cardiovascular, owing to adopted suitable active component and carrier, therefore has very notable therapeutic effect, and result of the test shows: support was implanted after 28 days, and tunica intima does not almost have no narrow generation after hypertrophy, the vascular injury; Styrene-isobutene .-cinnamic triblock copolymer has excellent biological compatibility, and the Mytrolimus coating bracket has good effect to suppressing intimal hyperplasia after artery injury, can effectively suppress restenosis and take place.
Description of drawings
Fig. 1 various dose Mytrolimus is to the inhibitory action of the inductive human body large artery trunks of PDGF smooth muscle cell proliferation.
Fig. 2 variable concentrations Mytrolimus is to the inhibitory action of the inductive mice smooth muscle cell proliferation of PDGF.
Fig. 3 variable concentrations Mytrolimus is to the toxic action of human endothelial cells.
Fig. 4 is through the styrene-isobutene .-cinnamic triblock copolymer coating bracket (styrene-content 30wt%) of balloon expandable.
Fig. 5 is through the styrene-isobutene .-cinnamic triblock copolymer coating bracket (styrene-content 35wt%) of balloon expandable.
Fig. 6 is through the styrene-isobutene .-cinnamic triblock copolymer coating bracket (styrene-content 50wt%) of balloon expandable.
Fig. 7 is through the styrene-isobutene .-cinnamic triblock copolymer coating bracket (styrene-content 55wt%) of balloon expandable.
Fig. 8 is through the styrene-isobutene .-cinnamic triblock copolymer coating bracket (styrene-content 65wt%) of balloon expandable.
The support that Fig. 9 does not contain medicine was implanted in the porcine coronary after 28 days, the damaged blood vessels tissue slice.
The support that figure l0 contains medicine (Mytrolimus) was implanted in the porcine coronary after 28 days, the damaged blood vessels tissue slice.
The specific embodiment
Human body large artery trunks smooth muscle cell was cultivated 3 days in containing the smooth muscle cell basic culture solution (SmGM) of PDGF, and the Mytrolimus that observes various dose is to PDGF inducing cell inhibition of proliferation effect (Fig. 1).MTS absorption value (approximately being 1.5) when not adding medicine with adding 20ng/ml PDGF inducing cell propagation in the culture fluid under the similarity condition compares, and the result shows among the figure, the IC of Mytrolimus
50Value approximately is 500ng/ml.The mice smooth muscle cell was cultivated 48 hours in the DMEM culture fluid that adds 0.25%FBS and PDGF, and the Mytrolimus that observes various dose is to PDGF inducing cell inhibition of proliferation effect (Fig. 2).The result shows among the figure, the IC of Mytrolimus
50Value approximately is 0.3micro M, and the IC of Rapamycin
50Value approximately is 1micro M.Compare, Mytrolimus is suppressing to have similar effect aspect the inductive smooth muscle cell proliferation of PDGF to Rapamycin.
Embodiment 2
The mice smooth muscle cell that the serum culture fluid is cultivated, the Mytrolimus of adding 20%FBS and 100nM 24 hours.At each cell cycle stages of cell number, G0/G1 phase cell accounts for 80% with cells were tested by flow cytometry, and S phase cell accounts for 7%, and G2/M phase cell accounts for 13%.(G0/G1 phase cell accounts for 58% with only add the splitted result of 20%FBS activated cell in culture fluid, S phase cell accounts for 22%, G2/M phase cell accounts for 17.5%) compare, Mytrolimus can make the inductive smooth muscle cell circulation of serum stop at the G0/G1 phase, suppress the growth and the division of cell, thereby suppress the neointima propagation of damaged blood vessels.
Embodiment 3
Mytrolimus carries out external with the Boyden case of improveing the influence of smooth muscle cell migration.The medicine of variable concentrations joins in the smooth muscle cell culture fluid, cultivates and after 48 hours transfer behavior is estimated.Think have PDGF to induce and when not having drug effect the mobility of cell be 100%, estimate the inhibitory action (table 1) of Mytrolimus to human body large artery trunks and mice smooth muscle cell migration.The result shows, its IC
50Value approximately is 2ng/ml, and Mytrolimus is suppressing to have similar effect aspect the smooth muscle cell migration to Rapamycin.
Table 1 various dose Mytrolimus is to the inhibitory action of smooth muscle cell migration
Embodiment 4
Mytrolimus is joined in the culture fluid of human endothelial cells, cultivate after 3 days and estimate the cytotoxicity (Fig. 3) that it produces human endothelial cells with the LDH analytic process.The result shows that Mytrolimus is similar to the influence of human endothelial cells to Rapamycin, CC
50Value approximately is respectively 10microM and 2microM.Mytrolimus and Rapamycin have similar influence to the process of endothelialization again of damaged blood vessels.
Embodiment 5
The support bottom layer treatment
Get 0.2g ethylene-vinyl alcohol copolymer and 0.1g polybutyl methacrylate, add 10mlDMAc, under 80 ℃ of conditions, be uniformly dispersed, be sprayed at coronary artery bracket and (be not limited to arteria coronaria, also carotid artery, renal artery, entocranial artery etc.) surface, will prop up and be placed in 80 ℃ of vacuum drying ovens, solidified 2 hours, the DMAC that the pure water flush away is residual, dry back is stand-by.
Embodiment 6
Styrene-isobutene .-cinnamic triblock copolymer with 0.2g, at room temperature join in the 10ml oxolane and be mixed with homogeneous solution, it is mixed evenly to add 0.1g Mytrolimus again, is sprayed at support or has the rack surface of bottom, will prop up to be placed in the vacuum drying oven and dry.Fig. 4 is respectively that styrene-content is respectively 30,35,50,55 to Fig. 8, and during 65wt%, the gross weight that obtains drug-carried coat is at 750ug, and coating layer thickness is 10 the photo of support behind balloon expandable.
Presentation of results among the figure influence of styrene-isobutene. ratio to coating performance.When styrene-content hanged down, polymeric adhesive was big, intensity is low, and easy and sacculus adhesion causes coating to tear in the balloon expandable process; When styrene-content was high, the polymer fracture percentage elongation reduced, and tangible cracking phenomena appears in expansion back coating, and these all bring certain potential safety hazard to stent applications.And styrene-content is when selected scope, as 35,50, and 55wt%, the mechanical performance of coating can satisfy the requirement of support through balloon expandable.To shown in Figure 8, after the support expansion, the even and complete nothing of coating is damaged as Fig. 5.
Embodiment 7
To do carrier with above-mentioned polymer, the arteria coronaria coating bracket that is loaded with 180ug Mytrolimus is implanted in the health pig coronary artery, estimates its inhibition effect to intimal hyperplasia after artery injury, and contrasts with the polymer coating support that does not contain medicine.
Fig. 9 and Figure 10 are that two kinds of supports are implanted the vascular tissue section photo after 28 days, and Fig. 9 is the section of polymer coating support implantable intravascular; Figure 10 is the section of coating stent of medicine implantable intravascular.
Among the figure, left side figure is the matched group blood vessel, and right figure is the blood vessel of implanting after 28 days.
By Fig. 9 and Figure 10 as seen, the tunica intima of implanting the Mytrolimus coating bracket does not almost have no narrow generation after hypertrophy, the vascular injury; There is certain hypertrophy in the matched group blood vessel wall.The zoopery presentation of results, styrene-isobutene .-cinnamic triblock copolymer has excellent biological compatibility, and the Mytrolimus coating bracket has good effect to suppressing intimal hyperplasia after artery injury, can effectively suppress restenosis and take place.
Embodiment 8
Among the embodiment 5, the 10ml mixed solution of the finely dispersed styrene-isobutene. of room temperature-cinnamic triblock copolymer and Mytrolimus is sprayed at the intracranial stent surface, will prop up to be placed in the vacuum drying oven and dry.
Claims (8)
1. a bracket for eluting medicament is made of passive support and the drug-carried coat that covers rack surface, it is characterized in that wherein drug-carried coat is that the polymer of 0.5-99.5% and the active component of 0.5-99.5% are formed by percentage by weight;
Described active component is Mytrolimus (CCI-779);
Said polymer is that styrene-content is styrene-isobutene .-cinnamic triblock copolymer of 35～55wt%.
2. bracket for eluting medicament according to claim 1 is characterized in that, adds the anticoagulation preparation in drug-carried coat.
3. bracket for eluting medicament according to claim 2 is characterized in that the anticoagulation preparation is selected from Cilostazol, thiophene chloropyridine, a kind of in the Clopidogrel Hydrogensulfate.
4. bracket for eluting medicament according to claim 3 is characterized in that, the anticoagulation preparation is 5%～20% in the gross weight of drug-carried coat.
5. according to each described bracket for eluting medicament of claim 1～4, it is characterized in that between drug-carried coat and support, having a bottom.
6. bracket for eluting medicament according to claim 5 is characterized in that, primer is selected from a kind of in ethylene-vinyl alcohol copolymer, vinyl-vinyl acetate copolymer or styrene-isobutene. block copolymer.
7. bracket for eluting medicament according to claim 6 is characterized in that, underlayer thickness is 0.1～10 micron.
8. bracket for eluting medicament according to claim 1 is characterized in that, drug-carried coat thickness is the 0.1-100 micron.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100531793A CN100435755C (en) | 2004-07-27 | 2004-07-27 | Bracket for eluting medication |
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| CNB2004100531793A CN100435755C (en) | 2004-07-27 | 2004-07-27 | Bracket for eluting medication |
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| CN100435755C true CN100435755C (en) | 2008-11-26 |
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102274550B (en) | 2010-06-13 | 2014-11-26 | 上海微创医疗器械（集团）有限公司 | Interventional medical device |
| CA3035774A1 (en) * | 2016-09-22 | 2018-03-29 | Mercator Medsystems, Inc. | Treatment of restenosis using temsirolimus |
| EP3629774A4 (en) | 2017-05-26 | 2021-03-03 | Mercator Medsystems, Inc. | Combination therapy for treatment of restenosis |
| EP3765122A4 (en) | 2018-03-14 | 2021-12-15 | Mercator Medsystems, Inc. | Medical instrument and medical method for localized drug delivery |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1436076A (en) * | 2000-06-16 | 2003-08-13 | 惠氏公司 | Method of treating cardiovascular disease |
| US20040039441A1 (en) * | 2002-05-20 | 2004-02-26 | Rowland Stephen Maxwell | Drug eluting implantable medical device |
| US20040063805A1 (en) * | 2002-09-19 | 2004-04-01 | Pacetti Stephen D. | Coatings for implantable medical devices and methods for fabrication thereof |
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2004
- 2004-07-27 CN CNB2004100531793A patent/CN100435755C/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1436076A (en) * | 2000-06-16 | 2003-08-13 | 惠氏公司 | Method of treating cardiovascular disease |
| US20040039441A1 (en) * | 2002-05-20 | 2004-02-26 | Rowland Stephen Maxwell | Drug eluting implantable medical device |
| US20040063805A1 (en) * | 2002-09-19 | 2004-04-01 | Pacetti Stephen D. | Coatings for implantable medical devices and methods for fabrication thereof |
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Address after: 201203, 501, Newton Road, Zhangjiang hi tech park, Shanghai, Pudong Patentee after: Shanghai MicroPort Medical Equipment (Group) Co., Ltd. Address before: 201203, 501, Newton Road, Zhangjiang hi tech park, Shanghai, Pudong Patentee before: Weichuang Medical Equipment (Shanghai) Co., Ltd. |