CN107115571B - Slow release material for self-degradation cardiovascular stent coating - Google Patents
Slow release material for self-degradation cardiovascular stent coating Download PDFInfo
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- 230000007281 self degradation Effects 0.000 title abstract description 5
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/08—Materials for coatings
- A61L31/10—Macromolecular materials
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/148—Materials at least partially resorbable by the body
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/16—Biologically active materials, e.g. therapeutic substances
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2420/00—Materials or methods for coatings medical devices
- A61L2420/06—Coatings containing a mixture of two or more compounds
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- Epidemiology (AREA)
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- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
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Abstract
The scheme relates to a slow release material for a self-degradation cardiovascular stent coating, which comprises the following components: the degradable polymer at least comprises poly D, L-lactide molecular chains; wherein the number average molecular weight of the poly D, L-lactide molecular chain is 8000-; p of the poly-D, L-lactide molecular chainrThe value is > 0.91. The self-degradation slow release material for the cardiovascular stent coating can wrap medicines, slowly degrade and release the medicines at the parts to be treated, accurately apply the medicines to the parts to be treated in blood vessels in a certain period, realize the combined use of multiple treatment means under a single puncture operation by means of the functions of the stent, effectively improve the treatment efficiency and reduce the operation pain and treatment cost of patients.
Description
Technical Field
The invention relates to a cardiovascular stent coating material, in particular to a slow release material for a self-degradable cardiovascular stent coating.
Background
The cardiovascular stent operation is a new technology for improving myocardial blood supply insufficiency and cardiac artery obstruction caused by coronary heart disease. Stents are typically delivered to the site where placement is desired by a puncture procedure. However, the trend in future medicine is multifunctionalization and intellectualization, which is costly for patients if a single operation is just to put one cardiovascular stent. If the treatment of a long-term or various diseases can be completed in one operation, the pain and the medical cost of a patient can be reduced, and the utilization rate of medical resources is improved. From the prior art, the function of the stent is single, and the development and utilization degree of the surface coating of the stent is shallow.
Disclosure of Invention
Aiming at the technical problems in the prior art, the purpose of the scheme is to provide a slow-release material for a self-degradable cardiovascular stent coating, which can wrap a medicament, slowly degrade in a blood vessel and release the medicament, and can accurately apply the medicament to a part to be treated in the blood vessel in a certain period.
In order to achieve the purpose, the scheme is achieved through the following technical scheme:
a slow release material for a self-degradable cardiovascular stent coating comprises:
the degradable polymer at least comprises poly D, L-lactide molecular chains;
wherein the number average molecular weight of the poly D, L-lactide molecular chain is 8000-;
p of the poly-D, L-lactide molecular chainrThe value is > 0.91.
Preferably, the sustained-release material, wherein the number average molecular weight of the poly D, L-lactide molecular chain is 10000-15000 g/mol.
Preferably, the sustained-release material, wherein the number average molecular weight of the poly D, L-lactide molecular chain is 12000-13000 g/mol.
Preferably, the sustained-release material is one in which P of the poly D, L-lactide molecular chainrThe value is > 0.94.
Preferably, the sustained-release material is one in which P of the poly D, L-lactide molecular chainrThe value was > 0.97.
Preferably, the sustained-release material, wherein the degradable polymer further comprises a poly β -butyrolactone molecular chain.
Preferably, the sustained-release material, wherein the mass ratio of the poly β -butyrolactone molecular chain to the poly D, L-lactide molecular chain is 1-1.5: 10.
Preferably, the sustained-release material, wherein the number average molecular weight of the poly β -butyrolactone molecular chain is 8000-.
Use of a sustained release material as described in any one of the preceding claims in the coating of a cardiovascular stent.
The invention has the beneficial effects that: the self-degradation slow release material for the cardiovascular stent coating can wrap medicines, slowly degrade and release the medicines at the parts to be treated, accurately apply the medicines to the parts to be treated in blood vessels in a certain period, realize the combined use of multiple treatment means under a single puncture operation by means of the functions of the stent, effectively improve the treatment efficiency and reduce the operation pain and treatment cost of patients.
Drawings
FIG. 1 is a graph showing the degradation profile in blood of examples 1 to 3 of the present invention.
Fig. 2 is a graph showing the sustained release profile of examples 1 to 3 of the present application in blood.
Fig. 3 is a graph of the degradation profile in blood for examples 1 and 6 of the present case.
Fig. 4 is a graph showing the sustained release in blood of examples 1 and 6 of the present application.
Detailed Description
The present invention is further described in detail below with reference to the attached drawings so that those skilled in the art can implement the invention by referring to the description text.
The monomer molecular center of Lactide (LA) contains 2 chiral centers, and industrially, single optically active monomer D-lactide, L-lactide or D, L-lactide (rac-LA, i.e., racemic lactide) mixed with one or both of them can be obtained. Polylactide of different microstructures can be obtained by ring-opening polymerization of the above monomers. The microstructure herein includes the stereoregularity of the polymeric chains in addition to the conventional molecular weight and molecular weight distribution. With P in the ring-opening polymerisation of lactiderValues represent the selectivity of the racemic (isotactic) structure. According to literature reports (k.a.m.thakur, r.t.kean and e.s.hall, anal.chem.,1997,69,4303), they can be calculated by measuring the homonuclear decoupled nuclear magnetic hydrogen spectrum of the polymer, as follows: 2-3mg of polymer is taken and proper amount of CDCl is added3Dissolving, measuring hydrogen spectrum in Bruker AC 400MHz NMR nuclear magnetic resonance instrument, and performing homonuclear decoupling on methyl proton during sampling. According to the formula: pr＝1-{{([mmm]+[mrm]+[rmm])-([rmr]+[mmr])}/{([mmm]+[mrm]+[rmm])+([rmr]+[mmr])}}＝1-{{([iii]+[isi]+[sii])-([sis]+[iis])}/{{([iii]+[isi]+[sii])+([sis]+[iis]) And (4) calculating. The ring-opening polymerization reaction of lactide is as follows:
there are a variety of catalysts that catalyze the ring-opening polymerization of lactide monomers, these catalysts are typically metal complexes, with the central metal typically being a transition metal or a rare earth metal. Wherein the metal complex isBody structure pair PrThe value was most affected, followed by the polymerization solvent and polymerization temperature, P obtained with Tetrahydrofuran (THF)rMost preferably, toluene and DME are used twice; p obtained by polymerization at ordinary temperature (20 ℃ C.) or belowrPreferably, the higher the temperature, PrThe lower the value.
Example 1
A sustained release material comprising: the degradable polymer at least comprises poly D, L-lactide molecular chains, and the polymerization process is as follows: adding D, L-lactide into a polymerization bottle with a dehydrated deoxygenation stirrer in a glove box, adding tetrahydrofuran by using a syringe, stirring for 5min at room temperature, adding a tetrahydrofuran solution of a catalyst by using the syringe, polymerizing for 0.5h at room temperature, stopping reaction by using alcohol containing 5% hydrochloric acid, precipitating the polymer by using industrial alcohol, and drying in vacuum to constant weight to obtain polylactide. GPC measured number average molecular weight (M)n) Is 0.81X 104Molecular weight distribution (M)w/Mn) Is 1.11, PrThe value is 0.98.
The structural formula of the catalyst is as follows:
wherein, the central metal M can be one of zirconium, nickel, iron, yttrium, ytterbium or europium. Example 1 ytterbium was chosen as the central metal; r can be selected from methyl or tert-butyl, and R is selected to be tert-butyl in example 1.
The ligand synthesis method comprises the following steps: 50.0g of 2, 4-di-tert-butylphenol is added into a 250mL round-bottom flask, about 150mL of methanol is added, magnetic stirring is carried out until the phenol is completely dissolved, then 37% formaldehyde aqueous solution (25mL) and N, N-dimethylethylenediamine (18mL) are added in sequence according to the proportion, the oil bath temperature is controlled at 70 ℃, the reaction is carried out for 24 hours, a large amount of white turbidity appears in the reaction system, and TLC monitors that the raw materials are basically disappeared. Suction filtration to obtain white solid, washing with cold methanol for several times, and vacuum drying.
The catalyst synthesis method comprises the following steps: the THF solution of the ligand was added to an equivalent of Yb [ N (SiMe)3)2]2(THF)2The THF solution is changed into a reddish brown transparent solution, the reaction is stirred at room temperature for about 12 hours, the THF solvent is pumped out by a vacuum pump under reduced pressure, a small amount of n-hexane is added, the n-hexane is removed under reduced pressure, so that high-boiling point silamine is taken away, and the operation is repeated for three times. Adding THF/toluene mixed solvent, heating for extraction, centrifuging to remove a little impurity, transferring the clear liquid into a crystallization bottle, placing in a refrigerator for crystallization, and separating out red blocky crystals after several days to obtain the catalyst.
There are many catalysts that can be used to prepare high selectivity poly-D, L-lactide, and this example only lists one of the preparation methods, but is not limited to this method.
Example 2
The same conditions as in example 1 were used except that the THF solvent used in the polymerization was replaced with DME (ethylene glycol dimethyl ether). GPC measured number average molecular weight (M)n) Is 0.93X 104Molecular weight distribution (M)w/Mn) Is 1.16, PrThe value is 0.91.
Example 3
The catalyst was changed to:
otherwise, the conditions were the same as in example 1. GPC measured number average molecular weight (M)n) Is 1.04X 104Molecular weight distribution (M)w/Mn) Is 1.12, PrThe value is 0.96.
Example 4
The degradation rate of the sustained-release material in human blood is researched: 2g of each of the poly D, L-lactides having a thickness of 0.2mm prepared in examples 1 to 3 was immersed in 10mL of human blood (blood type O) in a nitrogen glove box, taken out every 10 days, dried and weighed, and the results are shown in FIG. 1. As can be seen from FIG. 1, poly D, L-lactide was able to maintain substantially linear degradation over the first 30 days, degradation gradually deviated from linear over 30-60 days, exhibited a tendency to slow down, and P of poly D, L-lactiderThe lower the value, the more difficult it is to degrade, and the later the degradation rate is uncontrollable, which will be a pharmaceutically designed band for the coatingThe difficulty. When P is presentrValues less than 0.90 substantially lose the utility value.
Experiments also find that the slow release material is not sensitive to blood type, and the degradation effect of the slow release material in blood of type A, B or AB is consistent with the result in blood of type O in the embodiment 1, so that the results of other blood types are not repeated in the scheme.
Example 5
The slow release performance of the slow release material in human blood is researched: respectively dissolving and uniformly mixing 2g of poly D, L-lactide prepared in the above examples 1-3 and 0.5g of FITC-containing fluorophore molecules in THF, and then draining the solvent to obtain a flaky solid with the thickness of 0.2 mm; the sample was immersed in 10mL of human blood (blood type O) in a nitrogen glove box, and the intensity of fluorescence generated by excitation was measured every 10 days for the molecules containing FITC fluorophore in the blood, whereby the content of the molecules containing FITC fluorophore was obtained, and the results are shown in fig. 2. As can be seen from FIG. 2, the sustained-release material maintains substantially linear release of the fluorescent molecules at the early stage, but the release rate becomes slow at the later stage. P of poly D, L-lactiderThe lower the value, the greater the decrease in the release rate at a later stage, and even the release tends to stop (example 2). Such late stage non-linear release properties would result in uncontrolled application of the coating and if the amount of drug released from the coating does not reach a threshold value, the coating would fail to develop a therapeutic effect at a later stage.
In order to improve the linearity of the slow release material in medium and long term slow release, another polyester is introduced to dilute the proportion of oxygen in a polymer so as to regulate the slow release performance of the slow release material in the later period, so that the medium and long term slow release base material can be developed.
β -butyrolactone (β -BBL) belongs to lactone, can open ring and polymerize, and can use catalyst with lactide, because the mechanism of ring-opening polymerization of lactone by catalyst is basically the same, it provides possibility for copolymerization of β -butyrolactone with D, L-lactide, and the reaction formula of β -butyrolactone polymerization is as follows:
example 6
β -butyrolactone monomer was mixed with the D, L-lactide monomer in a mass ratio of 10: 1 of D, L-lactide monomer to β -butyrolactone monomer, the remaining conditions were the same as those in example 1n) Is 1.20X 104Molecular weight distribution (M)w/Mn) Is 1.19, PrPoly β -butyrolactone chain: GPC measured number average molecular weight (M)n) Is 1.57X 104Molecular weight distribution (M)w/Mn) Is 1.23.
The mass ratio of the D, L-lactide monomer to the β -butyrolactone monomer is preferably controlled to 10: 1-1.5, and if the amount of the β -butyrolactone monomer is too large, the degradation performance of the sustained-release material in blood is affected.
Example 7
Research on the degradation rate of the sustained-release material in human blood comprises the steps of soaking 2g of the polymer with the thickness of 0.2mm prepared in the example 1 and the example 6 in 10mL of human blood (O-type blood) in a nitrogen glove box, taking out the polymer every 10 days, drying and weighing, and obtaining the result shown in figure 3. from figure 3, after the poly β -butyrolactone molecular chain is introduced, the degradation rate of the whole sustained-release material is linearly degraded in a design period of 60 days.
Example 6 is a random copolymer, and the present inventors have found that the linear degradation effect of example 6 can be obtained even when a block copolymer is used. Therefore, the arrangement of the two molecular chains has little influence on degradation and slow release, and the degradation results of other copolymers are not repeated in the scheme.
Example 8
The slow release performance of the slow release material in human blood is researched, wherein 2g of the polymer prepared in the embodiment 1 and the embodiment 6 and 0.5g of FITC-containing fluorescent group molecules are respectively dissolved and uniformly mixed in THF, then the solvent is drained to prepare a solid with the thickness of 0.2mm, the solid is soaked in 10mL of human blood (O type blood) in a nitrogen glove box, the intensity of fluorescence generated by excitation of the FITC-containing fluorescent group molecules in the blood is measured every 10 days to obtain the content of the FITC-containing fluorescent group molecules, and the result is shown in figure 4. from figure 4, after the poly β -butyrolactone molecular chain is introduced, the release rate of the whole slow release material is linearly degraded in a design period of 60 days, the quantitative design of a drug administration scheme is facilitated, the dosage and the drug administration period are controllable, and a new solution is provided for the continuous interventional drug administration treatment of postoperative patients.
While embodiments of the invention have been described above, it is not limited to the applications set forth in the description and the embodiments, which are fully applicable in various fields of endeavor to which the invention pertains, and further modifications may readily be made by those skilled in the art, it being understood that the invention is not limited to the details shown and described herein without departing from the general concept defined by the appended claims and their equivalents.
Claims (9)
1. A slow release material for a self-degradable cardiovascular stent coating is characterized by comprising the following components:
the degradable polymer at least comprises poly D, L-lactide molecular chains;
wherein the number average molecular weight of the poly D, L-lactide molecular chain is 8000-;
p of the poly-D, L-lactide molecular chainrThe value is > 0.91.
2. The sustained-release material according to claim 1, wherein the number average molecular weight of the poly D, L-lactide molecular chain is 10000-15000 g/mol.
3. The sustained-release material according to claim 2, wherein the number-average molecular weight of the poly D, L-lactide molecular chain is 12000-13000 g/mol.
4. The sustained-release material according to claim 1, wherein the poly D, L-lactide molecular chain has P as a constituentrThe value is > 0.94.
5. The sustained-release material of claim 4, wherein the poly D, L-lactide is present in the polymerP of ester molecular chainrThe value was > 0.97.
6. The sustained-release material of claim 1, wherein the degradable polymer further comprises a poly β -butyrolactone molecular chain.
7. The sustained-release material according to claim 6, wherein the mass ratio of the poly β -butyrolactone molecular chain to the poly D, L-lactide molecular chain is 1-1.5: 10.
8. The sustained-release material according to claim 6, wherein the number-average molecular weight of the poly β -butyrolactone molecular chain is 8000-20000 g/mol.
9. Use of a sustained release material according to any one of claims 1 to 8 in the coating of a cardiovascular stent.
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