Pharmaceutical composition for forming enhanced in-situ intravascular stent, drug carrying device and treatment system

Abstract

The invention discloses a pharmaceutical composition for forming an enhanced in-situ intravascular stent, a drug loading device and a treatment system, the pharmaceutical composition comprises a photoactive cross-linking agent used for inducing protein molecules in primary tissues to be cross-linked by light excitation; the auxiliary cross-linking agent comprises a plurality of binding sites and a flexible chain connected with the plurality of binding sites, and the auxiliary cross-linking agent is used for bridging and cross-linking with protein molecules in the primary tissue. Compared with the prior art, the pharmaceutical composition provided by the invention can form a more compact fiber structure on a blood vessel after light activation, so that the effect of angiogenesis is effectively improved.

Description

Technical Field

[0001] The present application relates to the field of medical device technology, and in particular to a drug composition, a drug-carrying device and a treatment system for forming an enhanced in-situ vascular stent. Background Art

[0002] Angioplasty balloons can be used to open calcified lesions in the arterial wall and are one of the main ways to revascularize arterial stenosis. However, when blood vessels are dilated, they can cause damage to the vascular wall, thereby inducing thrombosis and the release of growth factors, which will lead to restenosis or subsequent reclosure of dilated blood vessels. At present, the above problems are mainly solved by implanting vascular stents in blood vessels. Existing vascular stents are mainly divided into two categories. One is made of biocompatible metals, but may cause thrombosis and immunogenicity, and this permanent stent may interfere with subsequent treatment, leading to corrosion perforation and potential aneurysms; the other is biodegradable stents, which solve the problem of permanent existence of metal stents, but the acid products of degradation can cause severe inflammatory reactions, and at the same time cause atrophy and degeneration of the muscle elastic elements of the arterial wall, causing arterial dilatation. In order to reduce the restenosis rate after stent implantation in diseased blood vessels, drug-eluting stents are widely used. Although drug-eluting stents can inhibit the proliferation of vascular smooth muscle cells and prevent restenosis of blood vessels, they also hinder the long-term recovery of the endothelial cell layer, thereby causing thrombosis of the vascular wall.

[0003] At present, the emerging treatment method is natural vascular stent, that is, balloon dilatation catheter with photosensitive compounds or drugs. Unlike traditional drug balloons, the balloon part of this type of balloon dilatation catheter can scatter visible light, so that the photosensitive compound is excited, thereby inducing the rapid combination of collagen and elastin in the blood vessel wall, forming a stent in situ, and achieving blood vessel healing and repair. However, in this treatment plan, the photosensitive compound can only induce the cross-linking of adjacent collagen and elastin in the blood vessel wall, and the in situ stent fiber structure is loose, which affects the effect of angioplasty. Summary of the invention

[0004] In view of the problems of the prior art, the present application provides a drug composition, a drug-carrying device and a treatment system for forming an enhanced in situ vascular stent, which are applied to treat vascular stenosis and can enhance the effect of angioplasty.

[0005] The present application provides a pharmaceutical composition for forming an enhanced in situ vascular stent, comprising:

[0006] Photoactive crosslinkers are used to induce crosslinking of protein molecules in native tissues under light excitation;

[0007] The auxiliary cross-linking agent comprises a plurality of binding sites and a flexible chain connecting the plurality of binding sites, and the auxiliary cross-linking agent is used for bridging and cross-linking with protein molecules in native tissues.

[0008] The present application also provides a pharmaceutical composition for forming an enhanced in situ vascular stent, comprising a photoactive cross-linking agent and an auxiliary cross-linking agent, wherein the mass ratio of the photoactive cross-linking agent to the auxiliary cross-linking agent is 0.5 to 3:1.

[0009] The present application also provides a pharmaceutical composition for forming an enhanced in situ vascular stent, comprising a photoactive crosslinker and an auxiliary crosslinker, wherein the auxiliary crosslinker is a polypeptide, and the mass ratio of the photoactive crosslinker to the auxiliary crosslinker is 0.5 to 3:1.

[0010] Optionally, the mass ratio of the photoactive cross-linking agent to the auxiliary cross-linking agent is 0.5 to 2:1.

[0011] Optionally, the mass ratio of the photoactive cross-linking agent to the auxiliary cross-linking agent is 1 to 2:1.

[0012] Optionally, the photoactive crosslinker is selected from at least one of naphthylimide derivatives, rose bengal, riboflavin phosphate, indoline, hemicyanine derivatives, cyanines, squarylium cyanine, boron-dipyrromethene, porphyrin derivatives, porphine derivatives, phthalocyanine derivatives, anthraquinone derivatives or conjugated polymers.

[0013] Optionally, the naphthalene imide derivative is selected from at least one of 1,8-naphthalene imide, 4-substituted-1,8-naphthalene imide, and a naphthalene imide dimer.

[0014] Optionally, the riboflavin phosphate is riboflavin sodium phosphate.

[0015] Optionally, the auxiliary cross-linking agent includes a plurality of binding sites and a flexible chain connecting the plurality of binding sites, and the flexible chain is at least one of polyethers, linear polysaccharides, polypeptides, and polyethylene imine.

[0016] Optionally, the auxiliary cross-linking agent has a molecular weight of 1,000 to 10,000.

[0017] Optionally, the binding site is provided by at least one of an amino acid, a polypeptide, or a hyperbranched polypeptide.

[0018] Optionally, the binding site is an amino acid or a terminal amino acid of a polypeptide.

[0019] Optionally, the amino acid is at least one of tyrosine, tryptophan, histidine, lysine, arginine, methionine, and cysteine.

[0020] Optionally, the polypeptide is selected from at least one of tyrosine, tryptophan, histidine, lysine, arginine, methionine, and cysteine ​​bonded together by peptide bonds.

[0021] Optionally, the polypeptide is a hyperbranched polypeptide, and the hyperbranched polypeptide is a multi-generation peptide dendrimer selected from at least one of tyrosine, tryptophan, histidine, lysine, arginine, methionine, and cysteine.

[0022] Optionally, the pharmaceutical composition further comprises a pharmaceutical agent, such as a pharmaceutical agent for inhibiting endothelial cell proliferation.

[0023] Optionally, the drug agent is selected from at least one of rapamycin, sirolimus, everolimus, zotarolimus, 42-(dimethylphosphinate) rapamycin (deforolimus), deforolimus, biolimus, umirolimus, and tacrolimus.

[0024] Optionally, the drug agent is selected from at least one of paclitaxel, protaxel, and docetaxel.

[0025] Optionally, the mass ratio of the photoactive cross-linking agent to the drug agent is 0.2 to 2:1.

[0026] Optionally, the mass ratio of the photoactive cross-linking agent to the drug agent is 0.4-1.5:1.

[0027] Optionally, the mass ratio of the photoactive cross-linking agent to the drug agent is 0.5 to 1:1.

[0028] Optionally, the pharmaceutical composition further comprises a carrier for loading the pharmaceutical agent.

[0029] Optionally, the carrier is at least two of polyethylene glycol, polyvinyl alcohol (PVA), polyethylene oxide (PEO), polysorbate, polyvinyl pyrrolidone, magnesium stearate, urea, tri-n-hexyl butyryl citrate, iopromide, ethyl cellulose, methylparaben, ethylparaben, acetyl tributyl citrate, glyceryl stearate, diethyl pyrocarbonate (DEPC), distearyl phosphatidylethanolamine-polyethylene glycol (DSPE-mPEG), cholesterol, phospholipids, polylactide (PLA), polyglycolide (PGA), polylactic acid-glycolic acid copolymer (PLGA), polyorthoester, polyanhydride, polyamino acid, polyhydroxybutyric acid, polyacetal, polycyanoacrylate, polycaprolactone, polydioxanone, polyalkylene alkylate, polyalkyl carbonate, gelatin, collagen, fibric acid, alginate, chitin, chitosan, dextran, hyaluronic acid, shellac, and pectin.

[0030] Optionally, the mass ratio of the drug agent to the carrier is 1 to 10:1.

[0031] Optionally, the mass ratio of the drug agent to the carrier is 2 to 8:1.

[0032] Optionally, the mass ratio of the drug agent to the carrier is 4 to 6:1.

[0033] The present application also provides a pharmaceutical composition for forming an enhanced in situ vascular stent, which comprises the following raw materials in parts by weight:

[0034]

[0035] Optionally, the pharmaceutical composition comprises the following raw materials by weight:

[0036]

[0037] Optionally, the pharmaceutical composition comprises the following raw materials by weight:

[0038]

[0039] The present application also provides a drug-carrying device, comprising an interventional instrument and a drug composition loaded on the interventional instrument, wherein the drug composition comprises a photoactive cross-linking agent and an auxiliary cross-linking agent.

[0040] Optionally, the interventional device is a balloon catheter, and the balloon catheter comprises:

[0041] The balloon body has a relatively inflated state and a deflated state suitable for interventional delivery;

[0042] A catheter having a distal end and a proximal end opposite to each other, wherein the distal end is in communication with the balloon body and is used for delivering a fluid into the balloon body;

[0043] The light-guiding element has a light source input end and a light-emitting end, wherein the light-emitting end is located in the balloon body.

[0044] Optionally, the balloon catheter further comprises:

[0045] The inner tube has the balloon body located outside the inner tube, the distal end of the inner tube is fixed to the balloon body, and the inner tube also extends toward the proximal end through the interior of the catheter.

[0046] Optionally, the distal end of the light-guiding element is fixed to the outer wall of the inner tube, or to the inner wall of the balloon, or to the inside of the inner tube.

[0047] Optionally, the light guiding element is an optical fiber.

[0048] The present application also provides a treatment system, comprising:

[0049] A drug-carrying device, comprising an interventional device and a drug composition loaded on the interventional device, wherein the drug composition comprises a photoactive cross-linking agent and an auxiliary cross-linking agent;

[0050] A light source is used to apply light energy to the photoactive cross-linking agent.

[0051] Optionally, the light source can output a light beam with a wavelength of 300 to 500 nm.

[0052] The present application also provides a method for preparing a drug-carrying device, comprising the following steps:

[0053] Provide interventional devices;

[0054] A drug coating is formed on the surface of the interventional device, and the raw materials of the drug coating include a photoactive cross-linking agent and an auxiliary cross-linking agent.

[0055] Optionally, the interventional device includes a balloon body, the balloon body has a contracted state suitable for interventional delivery and a relatively inflated state, and forming a drug coating on the surface of the interventional device includes:

[0056] The photoactive cross-linking agent, the auxiliary cross-linking agent and the first dispersant are prepared into a first drug solution, and the first drug solution is used to form a first drug solution coating on the surface of the interventional device.

[0057] Optionally, forming a drug coating on the surface of the interventional device further comprises:

[0058] The drug agent, the carrier and the second dispersant are prepared into a second drug solution, and the second drug solution is used to form a second drug solution coating on the surface of the interventional device.

[0059] Optionally, the first dispersant is selected from at least one of water, methanol, ethanol, formic acid, acetic acid, acetonitrile, isopropanol, acetone, ethyl acetate, n-hexane, cyclohexane, dichloromethane, methyl acetate, butyl acetate, carbon tetrachloride, butanone, n-hexane, n-pentane, and n-heptane.

[0060] Optionally, the first liquid medicine is prepared in the following order: the auxiliary cross-linking agent is mixed with the first dispersant, and then the photoactive cross-linking agent is mixed in.

[0061] Optionally, the auxiliary cross-linking agent and the first dispersant need to be mixed evenly before adding the photoactive cross-linking agent and mixing evenly.

[0062] Optionally, the second dispersant is selected from at least one of water, methanol, ethanol, formic acid, acetic acid, acetonitrile, isopropanol, acetone, ethyl acetate, n-hexane, cyclohexane, dichloromethane, methyl acetate, butyl acetate, carbon tetrachloride, butanone, n-hexane, n-pentane, and n-heptane.

[0063] Optionally, the second drug solution is prepared in the order of mixing the carrier with the second dispersant and then mixing in the drug agent.

[0064] Optionally, the carrier and the second dispersant need to be mixed evenly before adding the drug agent for mixing. Optionally, the first drug liquid coating and the second drug liquid coating are formed on the surface of the interventional device in any order.

[0065] Optionally, the first drug liquid coating is first formed on the surface of the interventional instrument to obtain a preform, and then the second drug liquid coating is formed on the surface of the preform.

[0066] Optionally, when the first drug liquid coating and the second drug liquid coating are formed, the balloon is in an inflated state.

[0067] Optionally, forming the first liquid coating includes applying the first liquid and drying it.

[0068] Optionally, the coating method is spray coating or dipping coating.

[0069] Optionally, the coating amount of the first liquid medicine is 1-10 μg / mm2 calculated as the photoactive crosslinking agent per square millimeter of the interventional device surface area. 2 .

[0070] Optionally, forming the second liquid coating includes applying the second liquid and drying it. Optionally, after drying, the thickness of the second liquid coating is 5 to 20 μm.

[0071] Optionally, the coating amount of the second drug solution is calculated as 1-10 μg / mm per square millimeter of the interventional device surface area. 2 .

[0072] Optionally, the first dispersant is water, and the coating amount of the first liquid medicine is calculated as 1 to 8 μg / mm per square millimeter of the surface area of ​​the interventional device based on the photoactive crosslinking agent. 2 .

[0073] Optionally, the coating amount of the first liquid medicine is 2-5 μg / mm2 calculated as the photoactive crosslinking agent per square millimeter of the interventional device surface area. 2 .

[0074] Optionally, the second dispersant is n-heptane, and the coating amount of the second drug solution is calculated as 1 to 8 μg / mm per square millimeter of the interventional device surface area. 2 .

[0075] Optionally, the coating amount of the second drug solution is calculated as 2-5 μg / mm per square millimeter of the interventional device surface area. 2 .

[0076] Optionally, the drug-coated balloon is evacuated and folded into petals to put the balloon in a contracted state.

[0077] Optionally, the evacuated and petal-folded balloon body is heat-set to keep the balloon body in a contracted state.

[0078] Optionally, heat setting is performed at 45 to 52° C. for 5 to 15 minutes.

[0079] The present application also provides a balloon catheter system, comprising:

[0080] The interventional device comprises a balloon body, wherein the balloon body has a contracted state suitable for interventional delivery and a relatively inflated state, and the balloon wall of the balloon body has a porous structure;

[0081] A supply device, used for supplying fluid into the balloon body, wherein the fluid contains a photoactive cross-linking agent and an auxiliary cross-linking agent;

[0082] A light source is used to apply light energy to the photoactive cross-linking agent and the auxiliary cross-linking agent.

[0083] Optionally, the pore size of the pore structure is 3 to 16 μm; and the number of pores on the surface of the balloon is 100 to 1000.

[0084] Optionally, the supply device includes a medicine storage bottle for storing fluid, the fluid includes a solvent, and the photoactive cross-linking agent and the auxiliary cross-linking agent are dispersed in the same solvent.

[0085] Optionally, the solvent is divided into a first solvent and a second solvent, the photoactive crosslinking agent and the first solvent are formulated into a first fluid, and the auxiliary crosslinking agent and the second solvent are formulated into a second fluid;

[0086] The supply device comprises:

[0087] A first medicine storage bottle, used for storing a first fluid;

[0088] A second medicine storage bottle, used for storing a second fluid;

[0089] A fluid valve is used to control the supply of the first fluid or the second fluid to the balloon body.

[0090] Optionally, the fluid valve has a first state allowing a first fluid to pass through and a second state allowing a second fluid to pass through, and the fluid valve enters the second state after completing the first state.

[0091] Optionally, when supplying the first fluid or the second fluid, the first fluid is first supplied to the balloon body in sequence, and then light is irradiated; and then the second fluid is supplied to the balloon body.

[0092] Optionally, the illumination is maintained from the start of supplying the first fluid until the supply of the second fluid is completed and ends after a second delay.

[0093] Optionally, the illumination includes:

[0094] The first illumination, from the start of supplying the first fluid to the end after the first fluid is supplied and after a first delay;

[0095] The second illumination starts from the beginning of supplying the second fluid and ends after the second fluid is supplied and a second delay has elapsed.

[0096] Optionally, the intensity of the illumination is 5 to 500 mW / cm 2 , the illumination time is 1 to 30 minutes.

[0097] The present application also provides a balloon catheter system, comprising:

[0098] The interventional device comprises a balloon body, wherein the balloon body has a contracted state suitable for interventional delivery and a relatively inflated state, and the balloon wall of the balloon body has a porous structure;

[0099] A supply device, used for supplying fluid into the balloon, wherein the fluid contains a photoactive cross-linking agent, an auxiliary cross-linking agent, and a drug agent;

[0100] A light source is used to apply light energy to the photoactive cross-linking agent and the auxiliary cross-linking agent.

[0101] Optionally, the drug agent is at least one of rapamycin, sirolimus, everolimus, zotarolimus, 42-(dimethylphosphinate) rapamycin (deforolimus), deforolimus, biolimus, umirolimus, tacrolimus, paclitaxel, protaxel, and docetaxel.

[0102] The present application also provides a balloon catheter system, comprising:

[0103] An interventional device comprises a balloon body, wherein the balloon body has a contracted state suitable for interventional delivery and a relatively inflated state, the balloon wall of the balloon body has a porous structure, and the outer wall of the balloon body is loaded with a coating containing a photoactive crosslinking agent;

[0104] A supply device, used for supplying the auxiliary cross-linking agent into the balloon body in a fluid manner;

[0105] A light source is used to apply light energy to the photoactive cross-linking agent and the auxiliary cross-linking agent.

[0106] Compared with the prior art, the present application provides a pharmaceutical composition for forming an enhanced in situ vascular stent. After adding an auxiliary cross-linking agent, it is equivalent to building a "bridge" between non-adjacent proteins. After light activation, non-adjacent proteins can also be cross-linked. The natural vascular stent formed in this way has denser fibers, greatly improving the effect of angioplasty. BRIEF DESCRIPTION OF THE DRAWINGS

[0107] Figure 1 This is a schematic diagram of the structure of a treatment system in one embodiment of the present application;

[0108] Figure 2 This is a schematic diagram of the structure of the balloon body and the drug coating in one embodiment of the present application;

[0109] Figure 3 is a schematic structural diagram of a treatment system in another embodiment;

[0110] Figure 4 Figure 1 is a diagram of the pore structure of the balloon;

[0111] Figure 5 This is an EVG staining image of a vascular lesion segment before treatment in an embodiment;

[0112] Figure 6 This is the EVG staining image after applying a photoactive cross-linking agent to the vascular lesion segment;

[0113] Figure 7 EVG staining images after applying photoactive cross-linking agents and auxiliary cross-linking agents to the vascular lesion segment;

[0114] Figure 8 This is the EVG staining diagram of Application Example 1 of this application;

[0115] Fig. 9 This is the EVG staining diagram of Application Example 2 of this application;

[0116] Fig.10 This is the EVG staining diagram of Application Example 3 of this application;

[0117] Fig.11 This is the EVG staining diagram of Application Example 4 of this application;

[0118] Fig.12 This is the EVG staining diagram of Application Example 5 of this application;

[0119] Fig.13 This is the EVG staining diagram of Example 1 used in this application.

[0120] The reference numerals in the figures are described as follows:

[0121] 100, drug-carrying device; 110, balloon body; 120, catheter; 130, light-guiding element; 140, inner tube; 150, pore structure;

[0122] 200. Drug coating;

[0123] 300, light source;

[0124] 400, blood vessel wall;

[0125] 500. Supply device. DETAILED DESCRIPTION

[0126] The following will be combined with the drawings in the embodiments of the present application to clearly and completely describe the technical solutions in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of this application.

[0127] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this application belongs. The terms used herein in the specification of this application are only for the purpose of describing specific embodiments and are not intended to limit this application. The term "and / or" used herein includes any and all combinations of one or more of the related listed items.

[0128] An embodiment of the present application provides a pharmaceutical composition for forming an enhanced in situ vascular stent, comprising:

[0129] Photoactive crosslinkers are used to induce crosslinking of protein molecules in native tissues under light excitation;

[0130] The auxiliary cross-linking agent comprises a plurality of binding sites and a flexible chain connecting the plurality of binding sites, and the auxiliary cross-linking agent is used for bridging and cross-linking with protein molecules in native tissues.

[0131] Another embodiment of the present application provides a pharmaceutical composition for forming an enhanced in situ vascular stent, comprising a photoactive crosslinker and an auxiliary crosslinker, wherein the mass ratio of the photoactive crosslinker to the auxiliary crosslinker is 0.5 to 3:1, for example 0.5 to 2:1, and for example 1 to 2:1.

[0132] The photoactive cross-linking agent in the pharmaceutical composition can promote the cross-linking of collagen or other proteins on the blood vessel wall after being activated by light, forming a natural vascular stent and reducing the inflammatory response caused by implanting the stent.

[0133] The auxiliary cross-linking agent in the pharmaceutical composition is equivalent to building a "bridge" between non-adjacent proteins. Under the light excitation conditions of the photoactivator, the amino group or polypeptide contained in the auxiliary cross-linking agent is used to cross-link with the collagen in the blood vessel wall. The original photoactivator can only promote the cross-linking of adjacent collagen / elastin through light activation, regardless of whether it participates in the cross-linking reaction itself. After adding the auxiliary cross-linking agent, the chain length can form covalent cross-links between proteins that are farther apart, increase the cross-linking of collagen in the blood vessel wall, form a natural vascular stent, and make the fibers of the blood vessel wall denser, greatly improving the effect of angioplasty.

[0134] Under light excitation, the photoactivator is activated to generate a transient singlet excited state, and generates a triplet excited state intermediate by molecular intersystem crossing. The triplet excited state intermediate undergoes intramolecular charge transfer and enters a long-lived intramolecular charge transfer state. The photoactivator in the triplet excited state converts free oxygen into reactive oxygen free radicals through photoelectron transfer. Reactive oxygen promotes the cross-linking reaction of oxidizable amino acid residues (such as tyrosine, tryptophan, histidine, methionine, and cysteine) of proteins in the vascular wall. The photoactivator generates reactive oxygen after light activation to promote the cross-linking of adjacent collagen or other proteins in the vascular wall. After adding an auxiliary cross-linking agent, the amino acid groups connected at both ends of the flexible chain, such as amino groups, can also undergo condensation reactions with amino acid residues on the vascular wall, such as carboxyl groups and N-hydroxysuccinimide, under light activation, thereby promoting the cross-linking of proteins, which is equivalent to building a "bridge" between non-adjacent proteins. After light activation, non-adjacent proteins can also undergo cross-linking. In this way, the natural vascular stent formed in situ has denser fibers, greatly improving the effect of angioplasty.

[0135] It can enhance the cross-linking of natural structural proteins (collagen / elastin) in the ECM of the vascular wall to form a natural vascular remodeling stent. It can not only avoid thrombosis and immunogenicity caused by implanted stents, but also solve the inflammation caused by biodegradable stents, effectively inhibit elastic retraction, and prevent the occurrence of restenosis of blood vessels after surgery.

[0136] The photoactive crosslinking agent can be at least one of naphthalimide derivatives, rose bengal, riboflavin phosphate, indoline, hemicyanine derivatives, cyanines, squarylium cyanine, boron-dipyrromethene, porphyrin derivatives, porphine derivatives, phthalocyanine derivatives, anthraquinone derivatives or conjugated polymers.

[0137] The naphthalene imide derivative may be at least one of 1,8-naphthalene imide, 4-substituted-1,8-naphthalene imide and naphthalene imide dimer. The riboflavin phosphate may be riboflavin sodium phosphate.

[0138] In one embodiment, the auxiliary crosslinking agent includes a plurality of binding sites and a flexible chain connecting the plurality of binding sites, wherein the flexible chain is at least one of polyethers, linear polysaccharides, and polyethyleneimine. The molecular weight of the auxiliary crosslinking agent is 1000 to 20000, such as 2000 to 10000, and another example is 4000 to 8000.

[0139] The polyether may be polyethylene glycol, and the linear polysaccharide may be carboxymethyl cellulose. The molecular weight of polyethylene glycol is 1000 to 10000, for example, 2000 to 8000. The molecular weight of carboxymethyl cellulose is 5000 to 10000, for example, 6000 to 8000, and another example is 6400. The molecular weight of polyethylene imine is 2000 to 8000, for example, 5000 to 6000.

[0140] The binding site is provided by at least one of an amino acid, a polypeptide, or a hyperbranched polypeptide. Specifically, the binding site is the terminal amino acid of an amino acid or a polypeptide, for example, the binding site is at least one of tyrosine, tryptophan, histidine, lysine, arginine, methionine, and cysteine. The polypeptide is a polypeptide formed by binding at least one of tyrosine, tryptophan, histidine, lysine, arginine, methionine, and cysteine ​​through a peptide bond. The polypeptide can also be a hyperbranched polypeptide, for example, a multi-generation peptide dendrimer of at least one of tyrosine, tryptophan, histidine, lysine, arginine, methionine, and cysteine, which can provide more binding sites.

[0141] In one embodiment, the pharmaceutical composition for forming an enhanced in situ vascular stent includes a photoactive crosslinker and an auxiliary crosslinker, the mass ratio of the photoactive crosslinker to the auxiliary crosslinker is 0.5 to 3:1, wherein the auxiliary crosslinker is a polypeptide. The polypeptide can be a polypeptide formed by peptide bonds of at least one of tyrosine, tryptophan, histidine, lysine, arginine, methionine, and cysteine, such as a copolymer of lysine and tryptophan or polylysine. The polypeptide can also be a hyperbranched polypeptide, such as a multi-generation peptide dendrimer of at least one of tyrosine, tryptophan, histidine, lysine, arginine, methionine, and cysteine.

[0142] In practical application, suitable photoactive crosslinkers and auxiliary crosslinkers can be selected from multiple perspectives, such as biocompatibility and crosslinking effect. In one embodiment, the photoactive crosslinker is riboflavin phosphate, and the auxiliary crosslinker is at least one of lysine-PEG-lysine, tyrosine-PEG-tyrosine, polylysine, lysine-tryptophan copolymer acid, glycine-carboxymethyl cellulose-glycine, tryptophan-carboxymethyl cellulose-tryptophan, phenylalanine and tyrosine-modified polyethyleneimine. Regarding the preparation of the auxiliary crosslinker, the PEG end group obtained by polymerization of ethylene oxide or ethylene glycol is a hydroxyl group with low reactivity, which can only react with other groups under more intense conditions and easily destroy the modified object. Therefore, it is often necessary to activate it first in practical application. PEG can be activated by esterification, cyanuric chloride method, etc. to obtain polyethylene glycol with double terminal amino groups.

[0143] For example, in one embodiment, the preparation method of double-terminated amino polyethylene glycol NH2-PEG-NH2 is:

[0144] (1) PEG4000 (20 g, 5 mmol) was dissolved in CH2Cl2 (100 mL), and a solution of TsCl (3.81 g, 20 mmol) in pyridine (76 mL) was added. The mixture was mixed thoroughly and reacted at room temperature for 24 h. The mixture was extracted with 3 mol / L HCl (470 mL). Sodium bicarbonate (5 g) was added to the organic layer and stirred vigorously. The mixture was filtered and the filtrate was evaporated to dryness to obtain a crude white powder of PEG2 p-toluenesulfonate.

[0145] (2) The crude PEG2 p-toluenesulfonate was dissolved in THF (8.7 mL) at 40° C. under stirring, and the solution was added dropwise into vigorously stirred ether (435 mL). The precipitate was filtered and dried in vacuo to obtain the pure PEG2 p-toluenesulfonate.

[0146] (3) Place the mixture together with 25% to 28% aqueous ammonia (160 mL) in a 250 mL pressure-resistant container, react at 140°C for 6 h, then cool to room temperature and extract with CH2Cl2 (160 mL). Add 1 mol / L aqueous NaOH solution (140 mL) to the organic layer (about 140 mL, containing PEG2 ammonium p-toluenesulfonate), stir for 2 h and let stand. Separate the organic layer, wash with water until neutral, and evaporate to dryness to obtain NH2-PEG4000-NH2.

[0147] (4) The same method can be used to prepare bisamino polyethylene glycol with different molecular weights.

[0148] The pharmaceutical composition also includes a pharmaceutical agent, such as a pharmaceutical agent for inhibiting endothelial cell proliferation. The mass ratio of the photoactive crosslinking agent to the pharmaceutical agent is 0.2 to 2:1, such as 0.4 to 1.5:1, and for example 0.5 to 1:1.

[0149] Specifically, the drug agent can be at least one of rapamycin, sirolimus, everolimus, zotarolimus, 42-(dimethylphosphinate) rapamycin (deforolimus), deforolimus, biolimus, umirolimus, and tacrolimus, which has the effect of inhibiting cell growth. The drug agent can also be at least one of paclitaxel, protaxel, and docetaxel, which has an anti-proliferative effect.

[0150] The pharmaceutical composition also includes a carrier for loading the pharmaceutical agent. The mass ratio of the pharmaceutical agent to the carrier is 1 to 10:1, for example, 2 to 8:1, and for example, 4 to 6:1.

[0151] Specifically, the carrier is at least two of a second polyethylene glycol, polyvinyl alcohol (PVA), polyethylene oxide (PEO), polysorbate, polyvinyl pyrrolidone, magnesium stearate, urea, tri-n-hexyl butyryl citrate, iopromide, ethyl cellulose, methylparaben, ethylparaben, acetyl tributyl citrate, glyceryl stearate, diethyl pyrocarbonate (DEPC), distearoyl phosphatidylethanolamine-polyethylene glycol (DSPE-mPEG), cholesterol, phospholipids, polylactide (PLA), polyglycolide (PGA), polylactic acid-glycolic acid copolymer (PLGA), polyorthoesters, polyanhydrides, polyamino acids, polyhydroxybutyric acid, polyacetals, polycyanoacrylates, polycaprolactones, polydioxanone, polyalkylene alkylates, polyalkyl carbonates, gelatin, collagen, fibric acid, alginic acid, chitin, chitosan, dextran, hyaluronic acid, shellac, and pectin.

[0152] One embodiment provides a pharmaceutical composition for forming an enhanced in situ vascular stent, comprising the following raw materials in parts by weight:

[0153]

[0154] For example, the pharmaceutical composition includes the following raw materials by weight:

[0155]

[0156] For another example, the pharmaceutical composition includes the following raw materials in parts by weight:

[0157]

[0158] See also Figure 1 , 2 The present application also provides a drug-carrying device 100, comprising an interventional device and a drug composition loaded on the interventional device, wherein the drug composition comprises a photoactive cross-linking agent and an auxiliary cross-linking agent.

[0159] The interventional device is a balloon catheter 120, which includes a balloon body 110, a catheter 120 and a light guide element 130; the balloon body 110 has a relatively inflated state and a contracted state suitable for interventional delivery; the catheter 120 has a relatively distal end and a proximal end, and the distal end is connected to the balloon body 110, and fluid can be delivered into the balloon body 110 to inflate the balloon body 110; the light guide element 130 has a light source 300 input end and a light emitting end, wherein the light emitting end is in the balloon body 110. The catheter 120 element can be an optical fiber.

[0160] In one embodiment, the balloon catheter 120 further includes an inner tube 140, the balloon body 110 is located outside the inner tube 140, the distal end of the inner tube 140 is fixedly connected to the balloon body 110, and the inner tube 140 extends toward the proximal end through the interior of the catheter 120. Accordingly, the distal end of the light guide element 130 is fixed to the outer wall of the inner tube 140, or to the inner wall of the balloon body 110, or to the interior of the inner tube 140.

[0161] The material of the inner tube 140 can be block polyetheramide resin (PEBAX), nylon or thermoplastic polyurethane elastomer rubber (TPU), and the color is colorless and transparent, which is conducive to the light transmission of the luminous guidewire.

[0162] An embodiment of the present application provides a method for preparing a drug carrying device 100, comprising:

[0163] Provide interventional devices;

[0164] A drug coating 200 is formed on the surface of the interventional device, and the raw materials of the drug coating 200 include a photoactive crosslinking agent and an auxiliary crosslinking agent. The types and amounts of the photoactive crosslinking agent and the auxiliary crosslinking agent can refer to the types and amounts mentioned above.

[0165] The interventional device includes a balloon body 110, and the balloon body 110 has a contracted state suitable for interventional delivery and a relatively inflated state. The drug coating 200 formed on the surface of the interventional device includes a first drug liquid coating and a second drug liquid coating.

[0166] The first liquid medicine is coated on the surface of the balloon body 110 in the inflated state and dried, and the first dispersant is removed to obtain a preform, wherein the first liquid medicine comprises a photoactive crosslinking agent, an auxiliary crosslinking agent and a first dispersant. The first dispersant is mainly used to disperse the photoactive crosslinking agent and the auxiliary crosslinking agent uniformly for easy coating, and the first dispersant is selected from at least one of water, methanol, ethanol, formic acid, acetic acid, acetonitrile, isopropanol, acetone, ethyl acetate, n-hexane, cyclohexane, dichloromethane, methyl acetate, butyl acetate, carbon tetrachloride, butanone, n-hexane, n-pentane and n-heptane.

[0167] The preparation method of the first liquid medicine is that after the auxiliary cross-linking agent and the first dispersant are evenly mixed, the photoactive cross-linking agent is added and evenly dispersed. When the mixture is evenly mixed, ultrasonic vibration is used to promote the even dispersion.

[0168] The second drug liquid is coated on the surface of the preform and dried, and the second dispersant is removed to obtain the drug-carrying device 100 . The second drug liquid includes a drug reagent, a carrier and a second dispersant.

[0169] The second dispersant is mainly used to disperse the carrier and the drug agent evenly for easy coating. The second dispersant is selected from at least one of water, methanol, ethanol, formic acid, acetic acid, acetonitrile, isopropanol, acetone, ethyl acetate, n-hexane, cyclohexane, dichloromethane, methyl acetate, butyl acetate, carbon tetrachloride, butanone, n-hexane, n-pentane, and n-heptane.

[0170] The second liquid medicine is prepared by mixing the carrier and the second dispersant uniformly, then adding the drug reagent and mixing uniformly. When the mixture is uniform, ultrasonic vibration is used to promote uniform dispersion. The coating method can be spray coating or dipping coating.

[0171] The first liquid coating amount is calculated as 1-10 μg / mm2 of the surface area of ​​the interventional device based on the photoactive crosslinking agent. 2 The coating amount of the second drug solution is calculated as 1 to 10 μg / mm 2 The first dispersant is water, and the coating amount of the first liquid is 1 to 8 μg / mm calculated based on the photoactive crosslinking agent. 2 , for example 2 to 5 μg / mm 2 .

[0172] The second dispersant is n-heptane, and the coating amount of the second drug solution is 1-8 μg / mm2 based on the surface area of ​​the interventional device. 2 , for example 2 to 5 μg / mm 2 .

[0173] The first liquid medicine is coated on the surface of the balloon body 110 and dried to form a first liquid medicine coating. After drying, the thickness of the first liquid medicine coating is 5 to 20 μm. On the formed first liquid medicine coating, the second liquid medicine is coated and dried. After drying, the thickness of the second liquid medicine coating is 5 to 20 μm. Of course, the first liquid medicine coating can also be formed on the balloon body 110 first, and then the second liquid medicine coating is formed. The balloon body 110 with the drug coating 200 is evacuated and folded into petals and then heat-set to keep the balloon body 110 in a contracted state. The heat setting method is 45 to 52°C for 5 to 15 minutes, preferably at 50°C for 10 minutes.

[0174] An embodiment of the present application provides a therapeutic system, including a drug carrying device 100 and a light source 300. The drug carrying device 100 includes an interventional device and a drug composition loaded on the interventional device, and the drug composition includes a photoactive cross-linking agent and an auxiliary cross-linking agent; the light source 300 is used to apply light energy to the photoactive cross-linking agent, and the light source 300 can output a light beam with a wavelength of 300 to 700 nm.

[0175] In this embodiment, the drug composition can be delivered to a specified location in a blood vessel by using a coating and an interventional device. Specifically, the balloon 110 can be used as a carrier to administer the drug composition. The inflated balloon 110 contacts the blood vessel wall 400 for administration. The types and amounts of the photoactive cross-linking agent and the auxiliary cross-linking agent can refer to the above-mentioned types and amounts.

[0176] See also Figure 8 In the embodiment shown, the photoactive cross-linking agent is riboflavin sodium phosphate, the auxiliary cross-linking agent is glycine-carboxymethyl cellulose-glycine, the light source 300 can output a light beam with a wavelength of 450nm, and the time for applying light to the blood vessel is 3 minutes, which can repair the breakage of elastic fibers and collagen fibers in the blood vessel and form a fiber-dense micro-scaffold in situ in the blood vessel.

[0177] See also Figure 3 , 4 An embodiment of the present application provides a balloon catheter system, including an interventional instrument, a supply device and a light source; the interventional instrument includes a balloon body 110, the balloon body 110 has a contracted state suitable for interventional delivery and a relatively inflated state, and the balloon body 110 has a pore structure 150 on its wall; the supply device 500 is used to supply fluid into the balloon body, and the fluid contains a photoactive cross-linking agent and an auxiliary cross-linking agent; the light source 300 is used to apply light energy to the photoactive cross-linking agent and the auxiliary cross-linking agent.

[0178] The supply device further comprises an infusion pump for driving the fluid to be supplied into the balloon body.

[0179] The fluid can keep the balloon in an inflated state and be output to the surrounding environment of the balloon body through the pore structure 150. The pore size of the pore structure 150 can be 3-16 μm, for example 3-8 μm, and for example 5 μm. The number of pores on the surface of the balloon body is 100-1000, for example 400-800, and for example 650.

[0180] In one embodiment, the supply device includes a medicine storage bottle for storing a fluid, the fluid includes a photoactive crosslinker, an auxiliary crosslinker and a solvent, and the photoactive crosslinker and the auxiliary crosslinker are dispersed in the same solvent. The solvent is water, and the pH can be adjusted to form a buffer according to actual application. The concentration of the photoactive crosslinker in the fluid is 0.2-60 mg / mL, for example, 0.5-1.2 mg / mL; the concentration of the auxiliary crosslinker is 0.1-30 mg / mL, for example, 0.5-10 mg / L.

[0181] In another embodiment, the solvent is divided into a first solvent and a second solvent, the photoactive crosslinker and the first solvent are formulated into a first fluid, and the auxiliary crosslinker and the second solvent are formulated into a second fluid. The supply device includes a first medicine storage bottle, a second medicine storage bottle, and a fluid valve, wherein the first medicine storage bottle is used to store the first fluid, the second medicine storage bottle is used to store the second fluid, and the fluid valve is used to control the supply of the first fluid or the second fluid to the balloon body.

[0182] Wherein, the first solvent and the second solvent are both water, and the pH can be adjusted to form a buffer according to actual application. The concentration of the photoactive crosslinker in the first fluid is 0.2-60 mg / mL, such as 0.5-1.2 mg / mL; the concentration of the auxiliary crosslinker in the second fluid is 0.1-30 mg / mL, such as 0.5-10 mg / L.

[0183] The fluid valve has a first state for allowing a first fluid to pass through and a second state for allowing a second fluid to pass through, and the fluid valve enters the second state after completing the first state.

[0184] When supplying the first fluid or the second fluid, the first fluid is first supplied to the balloon body in sequence, and then light is irradiated; and then the second fluid is supplied to the balloon body.

[0185] There are many ways of illumination according to actual application requirements. For example, in one embodiment, illumination includes:

[0186] The first illumination, from the start of supplying the first fluid to the end after the first fluid is supplied and after a first delay;

[0187] The second illumination starts from the beginning of supplying the second fluid and ends after the second fluid is supplied and a second delay has elapsed.

[0188] The intensity of the first and second illumination is 5-500 mW / cm 2 The first delay time is 1 to 3 minutes; the second delay time is 1 to 3 minutes.

[0189] In another embodiment, the illumination is maintained from the start of supplying the first fluid until the supply of the second fluid is completed and ends after a second delay.

[0190] In one embodiment, the balloon catheter system includes an interventional instrument, a supply device and a light source; the interventional instrument includes a balloon body 110, the balloon body 110 has a contracted state and a relatively inflated state suitable for interventional delivery, and the balloon body 110 has a pore structure 150 on its wall; the supply device 500 is used to supply fluid into the balloon body, the fluid containing a photoactive cross-linking agent, an auxiliary cross-linking agent and a drug agent; the light source is used to apply light energy to the photoactive cross-linking agent and the auxiliary cross-linking agent.

[0191] The drug agent is at least one of rapamycin, sirolimus, everolimus, zotarolimus, 42-(dimethylphosphinate) rapamycin (deforolimus), deforolimus, biolimus, umirolimus, tacrolimus, paclitaxel, protaxel, and docetaxel.

[0192] See also Figure 5 The local tissue diagram of the vascular lesion segment before treatment is shown. Figure 5 It can be seen that there are multiple breaks between the blue-black elastic fibers and between the pink collagen fibers, and the break lengths are 6.41μm, 17.6μm, 22.2μm, 38.3μm, and 38.7μm, respectively, indicating that the fibers have short breaks and long breaks. Take two groups of vascular lesion segments with roughly the same breakage conditions, and use the treatment system in this embodiment to treat the vascular lesion segments. The fluid used in one group is a solution prepared by a photoactive cross-linking agent and a solvent, and the fluid used in the other group is a solution prepared by a photoactive cross-linking agent, an auxiliary cross-linking agent, and a solvent. During the treatment process, light-induced cross-linking is performed. Among them, the solvent is water, and the other parameters are the same. After the treatment, the morphology of the elastic fibers and collagen fibers of each group of vascular tissue sections after EVG staining is observed under a microscope.

[0193] Results Figure 6 , 7 . Figure 6 This is a picture of vascular tissue after treatment with a photoactive cross-linking agent. It can be seen that the short breaks of elastic fibers and collagen fibers in the tissue are much reduced, for example, 6.41μm, and are effectively repaired, but the long breaks are basically not reduced, for example, 22.2μm, 38.3μm, and 38.7μm, and are not effectively repaired. Figure 7 This is a diagram of vascular tissue after treatment with a photoactive crosslinker and an auxiliary crosslinker. It can be seen that the short and long breaks of elastic fibers and collagen fibers in the tissue are effectively repaired and reconnected to form a dense fiber structure. This experiment shows that the auxiliary crosslinker can build a "bridge" between non-adjacent proteins. After light activation, non-adjacent proteins can also be cross-linked, making the natural vascular stent formed in situ have denser fibers, greatly improving the effect of angioplasty.

[0194] Considering the cross-linking repair effect, the fluids used include a first fluid and a second fluid. When treating a blood vessel, the first fluid is applied to a designated location of the blood vessel through the treatment system and irradiated with light. After the application of the first fluid, the irradiation is continued for 1 to 3 minutes, for example, 3 minutes. Then, the second fluid is applied to the designated location of the blood vessel and irradiated with light. After the application of the second fluid, the irradiation is continued for 1 to 3 minutes, for example, 3 minutes. Since the application of the first fluid, the irradiation is always maintained, and the intensity of the irradiation is 5 to 500 mW / cm 2 , for example 500mW / cm 2 .

[0195] An embodiment of the present application provides a balloon catheter system, including an interventional instrument, a supply device and a light source, wherein the interventional instrument includes a balloon body, the balloon body has a contracted state suitable for interventional delivery and a relatively inflated state, the balloon body's wall has a porous structure, and the outer wall of the balloon body is loaded with a coating containing a photoactive crosslinker; the supply device is used to supply an auxiliary crosslinker into the balloon body in a fluid manner; the light source is used to apply light energy to the photoactive crosslinker and the auxiliary crosslinker.

[0196] The photoactive crosslinking agent on the balloon can be released by perfusing physiological saline or fluid containing an auxiliary crosslinking agent into the balloon. Considering the crosslinking repair effect, the balloon of this embodiment is delivered to the designated position of the blood vessel, and physiological saline is perfused into the balloon to expand the compressed balloon. The balloon pressure is maintained at 6atm, the photoactive crosslinking agent in the coating is released, and light is applied; after 1 to 3 minutes of light exposure, a fluid containing an auxiliary crosslinking agent is perfused into the balloon, and light is maintained during the perfusion, and light is continued for 1 to 3 minutes after the fluid perfusion is completed. The intensity of light exposure is 5 to 500mW / cm 2 , for example 500mW / cm 2 The photoactivator of the pharmaceutical composition of the present application generates active oxygen that can promote the cross-linking of the auxiliary cross-linking agent and the protein in the blood vessel wall 400, forming an in situ vascular stent during balloon expansion. This in situ vascular stent will form denser fibers due to the presence of the auxiliary cross-linking agent, reduce the damage to the blood vessel caused by balloon expansion, and effectively prevent the occurrence of restenosis of the blood vessel.

[0197] Preparation Example 1 Preparation of Lysine-PEG-Lysine:

[0198] (1) 3.0 g of lysine and 40 mL of THF were added to a reaction flask and stirred for 10 min to form a suspension. 1.58 g of triphosgene was dissolved in 20 mL of THF and then added to the suspension (50° C.). The reactant immediately turned into a gel and could not be stirred by a magnet. After 20 min, the gel slowly dissolved again and the magnet began to stir. After 40 min, it turned into a light yellow transparent liquid. After continuing the reaction for 30 min, excess air was discharged and 180 mL of n-hexane was added. The mixture was allowed to stand for 24 h to allow complete crystallization. A white solid was obtained by suction filtration. The solid was then recrystallized using a mixed solvent of THF:hexane (v:v=1:3) and dried under vacuum at room temperature to obtain lysine anhydride.

[0199] (2) 1.2 g of lysine anhydride was dissolved in 12 mL of DMF, and then 0.6 g of NH2-PEG-NH2 was dissolved in 12 mL of DMF and added thereto. Dry nitrogen was introduced and stirred. The mixture was reacted at 40° C. for 72 h. The solvent was evaporated under reduced pressure and then dissolved in CH2Cl2. The mixture was then precipitated with excess anhydrous ether, filtered, and dried under vacuum at room temperature to obtain lysine-PEG-lysine.

[0200] Preparation Example 2 Tyrosine-PEG-Tyrosine

[0201] (1) Add 3.0 g of tyrosine and 40 mL of THF to a reaction flask and stir for 10 min to form a suspension. Dissolve 1.58 g of triphosgene in 20 mL of THF and add the mixture to the suspension (50° C.). The reaction product immediately turns into a gel and cannot be stirred by a magnet. After 20 min, the gel slowly dissolves and the magnet begins to stir. After 40 min, the gel turns into a light yellow transparent liquid. Continue to react for 30 min, expel excess air, add 180 mL of n-hexane, and allow to stand for 24 h to allow complete crystallization. Filter to obtain a white solid, which is then recrystallized using a mixed solvent of THF:hexane (v:v=1:3) and dried under vacuum at room temperature to obtain tyrosine anhydride.

[0202] (2) 1.2 g of tyrosine anhydride was dissolved in 12 mL of DMF, and then 0.6 g of NH2-PEG-NH2 was dissolved in 12 mL of DMF and added thereto. Dry nitrogen was introduced and stirred. The mixture was reacted at 40° C. for 72 h. The solvent was evaporated under reduced pressure and then dissolved in CH2Cl2. The mixture was then precipitated with excess anhydrous ether, filtered, and dried under vacuum at room temperature to obtain tyrosine-PEG-tyrosine.

[0203] Preparation Example 3 Polylysine

[0204] (1) 42.0 g of L-lysine, triphosgene and tetrahydrofuran were added to a dry three-necked flask, stirred at 50° C. for 1.5 h until the solution became clear, then the heating was stopped and the solution was cooled naturally to room temperature. The solution was filtered by sedimentation with cold hexane, the obtained powder was dissolved in ethyl acetate, the organic layer was extracted with cold water, then dried and filtered with anhydrous magnesium sulfate, the filtrate was spin-dried and vacuum dried, and recrystallized with a mixed solvent of tetrahydrofuran and n-hexane to finally obtain a white solid powder lysine anhydride monomer.

[0205] (2) Dissolve 10g of lysine anhydride monomer in anhydrous DMF, then add 5mL of 10mg / mL propylamine solution dissolved in anhydrous DMF. After stirring the solution at room temperature for 72h, dialyze the reaction mixture with a dialysis bag (500D), and freeze-dry the solution in the dialysis bag to obtain a white powder. Dissolve 7.5g of the white powder in 75mL of trifluoroacetic acid, then add 30m 33% hydrogen bromide acetic acid solution and react at room temperature for 3 hours. Then precipitate with anhydrous ether, and then add a small amount of water to the precipitate and rotary evaporate to dry. Dissolve the obtained solid in water, neutralize with sodium hydroxide to pH=9, dialyze with a dialysis bag, and freeze-dry the solution in the dialysis bag to obtain polylysine.

[0206] Preparation Example 4 Synthesis of Lysine-Tryptophan Copolymer

[0207] 1.316 g of L-lysine and 0.204 g of tryptophan were completely dissolved in 5 mL of distilled water, and deoxygenated by nitrogen bubbling for 30 min. The solution was heated in an oil bath at 180°C for 6 hours. After cooling, it was dissolved in 10 mL of ethanol and precipitated in 100 mL of ethyl acetate to obtain a light yellow insoluble substance, which was dissolved in deionized water and then rotary evaporated, and then placed in a freeze dryer for freeze drying to finally obtain a light yellow solid lysine-tryptophan copolymer.

[0208] Preparation Example 5 Glycine-Carboxymethylcellulose-Glycine

[0209] (1) Dissolve 1 g of carboxymethyl cellulose (CMC) in 100 mL of ultrapure water and stir overnight. Add 0.614 g of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride sodium salt (EDC-HCl) and glycine Gly or tryptophan Trp to the solution. Stir continuously at room temperature for 24 hours at pH 5. During this period, the pH value of the solution is kept constant with 0.1 M NaOH or 0.1 M HCl. Then dialyze with a 6000 g / mol MW dialysis membrane in 2 M NaCl solution for 1 day, ultrapure water for 3 days, freeze for 2 days (-37°C), and store at 25°C and 10 -3 The mixture was freeze-dried at 100 mbar for 2 days.

[0210] (2) The reaction mixture obtained in the above step was precipitated in anhydrous ethanol (125 mL). The filter cake was filtered and washed three times with anhydrous ethanol. The product was collected and dialyzed in 2M NaCl solution for 1 day using a 6000 g / mol MW dialysis membrane, dialyzed in ultrapure water for 3 days, frozen for 2 days (-37°C), and stored at -25°C and 10 -3 The mixture was freeze-dried for 2 days under mbar conditions to obtain glycine-carboxymethylcellulose-glycine (Gly-CMC-Gly) or L-tryptophan-carboxymethylcellulose-L-tryptophan (Trp-CMC-Trp).

[0211] Preparation Example 6 Synthesis of Tryptophan-Carboxymethyl Cellulose-Tryptophan

[0212] (1) Dissolve 1 g of carboxymethyl cellulose (CMC) in 100 mL of ultrapure water and stir overnight. Add 0.614 g of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride sodium salt (EDC-HCl) and tryptophan Trp to the solution. Stir continuously at room temperature for 24 hours at pH 5. During this period, the pH value of the solution is kept constant with 0.1 M NaOH or 0.1 M HCl. Then dialyze with a 6000 g / mol MW dialysis membrane in 2 M NaCl solution for 1 day, dialyze in ultrapure water for 3 days, freeze for 2 days (-37°C), and store at 25°C and 10 -3 The mixture was freeze-dried at 100 mbar for 2 days.

[0213] (2) The reaction mixture obtained in the above step was precipitated in anhydrous ethanol (125 mL). The filter cake was filtered and washed three times with anhydrous ethanol. The product was collected and dialyzed in 2M NaCl solution for 1 day using a 6000 g / mol MW dialysis membrane, dialyzed in ultrapure water for 3 days, frozen for 2 days (-37°C), and stored at -25°C and 10 -3 Tryptophan-carboxymethyl cellulose-tryptophan (Trp-CMC-Trp) was obtained by freeze-drying for 2 days under mbar conditions.

[0214] Preparation Example 7 Synthesis of Phenylalanine and Tyrosine Modified Polyethyleneimine

[0215] 0.15 mol phenylalanine and 0.15 mol tyrosine were weighed and dissolved in 15 mL MES buffer, 0.6 mg EDCI / NHS was added as a catalyst, and the reaction was catalyzed at 25 ° C for 6 h. Subsequently, 0.0625 mol polyethyleneimine (molecular weight of 5000) was dissolved in 12 mL N, N-dimethylformamide together with the catalyzed phenylalanine and tyrosine to obtain a mixed solution, and 0.5 mL triethylamine was added to the mixed solution as a catalyst, and then stirred at 25 ° C for 48 h for substitution reaction. After the reaction was completed, the reaction system was transferred into a dialysis bag with a molecular weight cutoff of 1000 and dialyzed in double distilled water for 3 days. The dialyzed solution was filtered using a 0.45 μm filter membrane, and the filtered solution was freeze-dried using a freeze dryer to obtain a white powder product, namely, polyethyleneimine modified with phenylalanine and tyrosine.

[0216] Example 1

[0217] (1) Prepare the first liquid medicine:

[0218] 32 mg of the lysine-PEG-lysine prepared in Preparation Example 1 was fully mixed with 2 mL of water to prepare a carrier solution; 32 mg of riboflavin sodium phosphate was added to the carrier solution and subjected to ultrasonic oscillation to prepare a first drug solution.

[0219] (2) Preparation of the second liquid:

[0220] 40 mg of phospholipid and 5 mg of cholesterol were dissolved in 5 mL of n-heptane, and after ultrasonic dissolution, 50 mg of rapamycin was weighed into the above solution, and vortexed and ultrasonically dispersed to prepare the second drug solution.

[0221] (3) Preparation of drug-loaded balloons:

[0222] First, spray the first liquid on the surface of the balloon (inflated state) and dry it. The spraying amount is 3 μg / mm based on riboflavin sodium phosphate. 2 , the thickness of the first liquid coating formed is 14 μm;

[0223] The second liquid was sprayed on the first liquid coating and dried. The spraying amount was 2 μg / mm2 based on rapamycin. 2 , the thickness of the second liquid coating formed is 10 μm;

[0224] The balloon was evacuated and folded into petals, and then heat-set at 50°C for 10 min to obtain a drug-loaded balloon.

[0225] Example 2

[0226] (1) Prepare the first liquid medicine:

[0227] 32 mg of the lysine-PEG-lysine prepared in Preparation Example 1 was fully mixed with 2 mL of water to prepare a carrier solution; 32 mg of tetrachlorofluorescein was added to the carrier solution and subjected to ultrasonic oscillation to prepare a first drug solution.

[0228] (2) Preparation of the second liquid:

[0229] 40 mg of phospholipid and 5 mg of cholesterol were dissolved in 5 mL of n-heptane, and after ultrasonic dissolution, 50 mg of rapamycin was weighed into the above solution, and vortexed and ultrasonically dispersed to prepare the second drug solution.

[0230] (3) Preparation of drug-loaded balloons:

[0231] First, spray the first liquid on the surface of the balloon (inflated state) and dry it. The spraying amount is 3 μg / mm based on tetrachlorotetraiodine fluorescein. 2 , the thickness of the first liquid coating formed is 14 μm;

[0232] The second liquid was sprayed on the first liquid coating and dried. The spraying amount was 2 μg / mm2 based on rapamycin. 2 , the thickness of the second liquid coating formed is 10 μm;

[0233] The balloon was evacuated and folded into petals, and then heat-set at 50°C for 10 min to obtain a drug-loaded balloon.

[0234] Example 3

[0235] (1) Prepare the first liquid medicine:

[0236] 32 mg of the tyrosine-PEG-tyrosine prepared in Preparation Example 2 was fully mixed with 2 mL of water to prepare a carrier solution; 32 mg of riboflavin sodium phosphate was added to the carrier solution and subjected to ultrasonic oscillation to prepare a first drug solution.

[0237] (2) Preparation of the second liquid:

[0238] 40 mg of phospholipid and 5 mg of cholesterol were dissolved in 5 mL of n-heptane, and after ultrasonic dissolution, 50 mg of rapamycin was weighed into the above solution, and vortexed and ultrasonically dispersed to prepare the second drug solution.

[0239] (3) Preparation of drug-loaded balloons:

[0240] First, spray the first liquid on the surface of the balloon (inflated state) and dry it. The spraying amount is 3 μg / mm based on riboflavin sodium phosphate. 2 , the thickness of the first liquid coating formed is 14 μm;

[0241] The second liquid was sprayed on the first liquid coating and dried. The spraying amount was 2 μg / mm2 based on rapamycin. 2The thickness of the second chemical liquid coating formed is 10 μm.

[0242] The balloon was evacuated and folded into petals, and then heat-set at 50°C for 10 min to obtain a drug-loaded balloon.

[0243] Example 4

[0244] (1) Prepare the first liquid medicine:

[0245] 32 mg of the polylysine prepared in Preparation Example 3 was fully mixed with 2 mL of water to prepare a carrier solution; 32 mg of riboflavin sodium phosphate was added to the carrier solution and subjected to ultrasonic oscillation to prepare a first drug solution.

[0246] (2) Preparation of the second liquid:

[0247] 40 mg of phospholipid and 5 mg of cholesterol were dissolved in 5 mL of n-heptane, and after ultrasonic dissolution, 50 mg of rapamycin was weighed into the above solution, and vortexed and ultrasonically dispersed to prepare the second drug solution.

[0248] (3) Preparation of drug-loaded balloons:

[0249] First, spray the first liquid on the surface of the balloon (inflated state) and dry it. The spraying amount is 3 μg / mm based on riboflavin sodium phosphate. 2 , the thickness of the first liquid coating formed is 14 μm;

[0250] The second liquid was sprayed on the first liquid coating and dried. The spraying amount was 2 μg / mm2 based on rapamycin. 2 , the thickness of the second liquid coating formed is 10 μm;

[0251] The balloon was evacuated and folded into petals, and then heat-set at 50°C for 10 min to obtain a drug-loaded balloon.

[0252] Example 5

[0253] (1) Prepare the first liquid medicine:

[0254] 32 mg of the lysine-tryptophan copolymer prepared in Preparation Example 4 was fully mixed with 2 mL of water to prepare a carrier solution; 32 mg of riboflavin sodium phosphate was added to the carrier solution and subjected to ultrasonic oscillation to prepare a first drug solution.

[0255] (2) Preparation of the second liquid:

[0256] 40 mg of phospholipid and 5 mg of cholesterol were dissolved in 5 mL of n-heptane, and after ultrasonic dissolution, 50 mg of rapamycin was weighed into the above solution, and vortexed and ultrasonically dispersed to prepare the second drug solution;

[0257] (3) Preparation of drug-loaded balloons:

[0258] First, spray the first liquid on the surface of the balloon (inflated state) and dry it. The spraying amount is 3 μg / mm based on riboflavin sodium phosphate. 2 , the thickness of the first liquid coating formed is 14 μm;

[0259] The second liquid was sprayed on the first liquid coating and dried. The spraying amount was 2 μg / mm2 based on rapamycin. 2 The thickness of the second chemical liquid coating formed is 10 μm.

[0260] (4) The balloon is evacuated and folded into petals, and then heat-set at 50°C for 10 min to obtain a drug-loaded balloon.

[0261] Example 6

[0262] (1) Prepare the first liquid medicine:

[0263] 32 mg of the glycine-carboxymethyl cellulose-glycine prepared in Preparation Example 5 was fully mixed with 2 mL of water to prepare a carrier solution; 32 mg of riboflavin sodium phosphate was added to the carrier solution and subjected to ultrasonic oscillation to prepare a first drug solution.

[0264] (2) Preparation of the second liquid:

[0265] 40 mg of phospholipid and 5 mg of cholesterol were dissolved in 5 mL of n-heptane, and after ultrasonic dissolution, 50 mg of rapamycin was weighed into the above solution, and vortexed and ultrasonically dispersed to prepare the second drug solution;

[0266] (3) Preparation of drug-loaded balloons:

[0267] First, spray the first liquid on the surface of the balloon (inflated state) and dry it. The spraying amount is 3 μg / mm based on riboflavin sodium phosphate. 2 , the thickness of the first liquid coating formed is 14 μm;

[0268] The second liquid was sprayed on the first liquid coating and dried. The spraying amount was 2 μg / mm2 based on rapamycin. 2 , the thickness of the second liquid coating formed is 10 μm;

[0269] The balloon was evacuated and folded into petals, and then heat-set at 50°C for 10 min to obtain a drug-loaded balloon.

[0270] Example 7

[0271] (1) Prepare the first liquid medicine:

[0272] 32 mg of the tryptophan-carboxymethyl cellulose-tryptophan prepared in Preparation Example 6 was fully mixed with 2 mL of water to prepare a carrier solution; 32 mg of riboflavin sodium phosphate was added to the carrier solution and subjected to ultrasonic oscillation to prepare a first drug solution.

[0273] (2) Preparation of the second liquid:

[0274] 40 mg of phospholipid and 5 mg of cholesterol were dissolved in 5 mL of n-heptane, and after ultrasonic dissolution, 50 mg of rapamycin was weighed into the above solution, and vortexed and ultrasonically dispersed to prepare the second drug solution;

[0275] (3) Preparation of drug-loaded balloons:

[0276] First, spray the first liquid on the surface of the balloon (inflated state) and dry it. The spraying amount is 3 μg / mm based on riboflavin sodium phosphate. 2 , the thickness of the first liquid coating formed is 14 μm;

[0277] The second liquid was sprayed on the first liquid coating and dried. The spraying amount was 2 μg / mm2 based on rapamycin. 2 , the thickness of the second liquid coating formed is 10 μm;

[0278] The balloon was evacuated and folded into petals, and then heat-set at 50°C for 10 min to obtain a drug-loaded balloon.

[0279] Example 8

[0280] (1) Prepare the first liquid medicine:

[0281] 32 mg of the phenylalanine- and tyrosine-modified polyethyleneimine prepared in Preparation Example 7 was fully mixed with 2 mL of water to prepare a carrier solution; 32 mg of riboflavin sodium phosphate was added to the carrier solution and subjected to ultrasonic oscillation to prepare a first drug solution.

[0282] (2) Preparation of the second liquid:

[0283] 40 mg of phospholipid and 5 mg of cholesterol were dissolved in 5 mL of n-heptane, and after ultrasonic dissolution, 50 mg of rapamycin was weighed into the above solution, and vortexed and ultrasonically dispersed to prepare the second drug solution;

[0284] (3) Preparation of drug-loaded balloons:

[0285] First, spray the first liquid on the surface of the balloon (inflated state) and dry it. The spraying amount is 3 μg / mm based on riboflavin sodium phosphate. 2 , the thickness of the first liquid coating formed is 14 μm;

[0286] The second liquid was sprayed on the first liquid coating and dried. The spraying amount was 2 μg / mm2 based on rapamycin. 2 , the thickness of the second liquid coating formed is 10 μm;

[0287] The balloon was evacuated and folded into petals, and then heat-set at 50°C for 10 min to obtain a drug-loaded balloon.

[0288] Example 9

[0289] Preparation of the first fluid: riboflavin sodium phosphate was added into water and ultrasonically vibrated to prepare a riboflavin solution with a concentration of 0.5 mg / mL as the first fluid;

[0290] Preparation of the second fluid: Lysine-PEG-lysine was added to water and subjected to ultrasonic oscillation to prepare a mixed solution with a concentration of 16 mg / mL as the second fluid. Balloon: With a pore structure, the pore diameter is 5 μm, and the number of pores is 650.

[0291] Example 10

[0292] (1) Preparation of drug-loaded balloons:

[0293] 32 mg of riboflavin sodium phosphate was added to polyethylene glycol and ultrasonically oscillated to prepare a first drug solution; 40 mg of phospholipids and 5 mg of cholesterol were dissolved in 5 mL of n-heptane and ultrasonically dissolved, and 50 mg of rapamycin was weighed into the above solution and vortexed and ultrasonically dispersed to prepare a second drug solution;

[0294] The balloon has a porous structure (pore size 5 μm, number of pores 650). First, the first liquid is sprayed on the surface of the balloon (inflated state) and dried. The spraying amount is 3 μg / mm based on riboflavin sodium phosphate. 2 The thickness of the first liquid coating formed is 14 μm; the second liquid is sprayed on the first liquid coating and dried, and the spraying amount is 2 μg / mm based on rapamycin. 2 The thickness of the second drug liquid coating formed is 10 μm; the balloon body is vacuumed and folded into petals, and the drug-loaded balloon is obtained after heat setting at 50° C. for 10 minutes.

[0295] (2) Fluid preparation: Lysine-PEG-lysine was added to water and subjected to ultrasonic oscillation to prepare a mixed solution with a concentration of 16 mg / mL as the fluid.

[0296] Comparative Example 1

[0297] (1) Prepare the first liquid medicine:

[0298] 32 mg of polyethylene glycol and 2 mL of water were fully mixed to prepare a carrier solution; 32 mg of riboflavin sodium phosphate was added to the carrier solution and subjected to ultrasonic oscillation to prepare a first drug solution.

[0299] (2) Preparation of the second liquid:

[0300] 40 mg of phospholipid and 5 mg of cholesterol were dissolved in 5 mL of n-heptane, and after ultrasonic dissolution, 50 mg of rapamycin was weighed into the above solution, and vortexed and ultrasonically dispersed to prepare the second drug solution.

[0301] (3) Preparation of drug-loaded balloons:

[0302] First, spray the first liquid on the surface of the balloon (inflated state) and dry it. The spraying amount is 3 μg / mm based on riboflavin sodium phosphate. 2 , the thickness of the first liquid coating formed is 14 μm;

[0303] The second liquid was sprayed on the first liquid coating and dried. The spraying amount was 2 μg / mm2 based on rapamycin. 2 The thickness of the second chemical liquid coating formed is 10 μm.

[0304] (4) The balloon is evacuated and folded into petals, and then heat-set at 50°C for 10 min to obtain a drug-loaded balloon.

[0305] Application Example 1

[0306] The effectiveness of the drug balloon was studied using a porcine peripheral artery model. In the porcine peripheral artery model, the balloon of Example 1 was pushed into the blood vessel, and the compressed balloon was expanded by perfusing fluid at a pressure of 6 atm. Then, while maintaining the pressure of the balloon, the light-guiding element emitted light of 450 nm wavelength, and the light curing time was 3 minutes. After illumination, the balloon was withdrawn from the blood vessel. The morphology of elastic fibers and collagen fibers of each sample tissue section after EVG staining was observed under a microscope, see Figure 8 .

[0307] Application Example 2

[0308] The effectiveness of the drug balloon was studied using a porcine peripheral artery model. In the porcine peripheral artery model, the balloon of Example 4 was pushed into the blood vessel, and the compressed balloon was expanded by perfusing fluid at a pressure of 6 atm. Then, while maintaining the pressure of the balloon, the light-guiding element emitted light of 450 nm wavelength, and the light curing time was 3 minutes. After illumination, the balloon was withdrawn from the blood vessel. The morphology of elastic fibers and collagen fibers of each sample tissue section after EVG staining was observed under a microscope, see Fig. 9 .

[0309] Application Example 3

[0310] The effectiveness of the drug balloon was studied using a porcine peripheral artery model. In the porcine peripheral artery model, the balloon of Example 6 was pushed into the blood vessel, and the compressed balloon was expanded by perfusing fluid at a pressure of 6 atm. Then, while maintaining the pressure of the balloon, the light-guiding element emitted light of 450 nm wavelength, and the light curing time was 3 minutes. After illumination, the balloon was withdrawn from the blood vessel. The morphology of elastic fibers and collagen fibers of each sample tissue section after EVG staining was observed under a microscope, see Fig.10 .

[0311] Application Example 4

[0312] In a porcine peripheral artery model, the drug-loaded balloon of Example 9 was pushed into the blood vessel, and the compressed balloon was expanded by perfusing the first fluid at a pressure of 6 atm, and then the light-guiding element emitted light of 450 nm wavelength while maintaining the pressure of the balloon, and the light-curing time was 3 minutes; then the second fluid was perfused at a pressure of 6 atm, and then the light-guiding element emitted light of 450 nm wavelength while maintaining the pressure of the balloon, and the light-curing time was 3 minutes, and the balloon was withdrawn from the blood vessel after illumination. The morphology of elastic fibers and collagen fibers of each sample tissue section after EVG staining was observed under a microscope, see Fig.11 .

[0313] Application Example 5

[0314] In a porcine peripheral artery model, the balloon of Example 10 was pushed into the blood vessel, and the compressed balloon was expanded by perfusing physiological saline at a pressure of 6 atm. Then, while maintaining the pressure of the balloon, the light-guiding element emitted light of 450 nm wavelength. After the light curing time was 3 minutes, the fluid was perfused at a pressure of 6 atm. Then, while maintaining the pressure of the balloon, the light irradiation was continued for 3 minutes. After the light irradiation, the balloon was withdrawn from the blood vessel. The morphology of elastic fibers and collagen fibers of each sample tissue section after EVG staining was observed under a microscope, see Fig.12 .

[0315] Application Comparative Example 1

[0316] The effectiveness of the drug balloon was studied using a porcine peripheral artery model. In the porcine peripheral artery model, the balloon of Comparative Example 1 was pushed into the blood vessel, and the compressed balloon was expanded by perfusing fluid at a pressure of 6 atm. Then, while maintaining the pressure of the balloon, the light-guiding element emitted light of 450 nm wavelength, and the light curing time was 3 minutes. After illumination, the balloon was withdrawn from the blood vessel. The morphology of elastic fibers and collagen fibers of each sample tissue section after EVG staining was observed under a microscope, see Fig.13 .

[0317] Application results see Figures 8 to 13 It can be seen that the blue-black elastic fibers and pink collagen fibers in Application Examples 1, 2, 3, 4, and 5 are more uniform and dense than those in Comparative Example 1, indicating that the addition of an auxiliary cross-linking agent can effectively protect blood vessels from tearing during dilation, and tissue damage is more minor.

[0318] The above-mentioned embodiments only express several implementation methods of the present application, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for a person of ordinary skill in the art, several variations and improvements can be made without departing from the concept of the present application, and these all belong to the protection scope of the present application. Therefore, the protection scope of the present application shall be subject to the attached claims.

Claims

1. A pharmaceutical composition for forming an enhanced in situ vascular stent, characterized in that: include: Photoactive crosslinkers are used to induce crosslinking of protein molecules in native tissues under light excitation; The auxiliary cross-linking agent comprises a plurality of binding sites and a flexible chain connecting the plurality of binding sites, and the auxiliary cross-linking agent is used for bridging and cross-linking with protein molecules in native tissues.

2. A pharmaceutical composition for forming an enhanced in situ vascular stent, characterized in that: The invention comprises a photoactive crosslinking agent and an auxiliary crosslinking agent, wherein the mass ratio of the photoactive crosslinking agent to the auxiliary crosslinking agent is 0.5 to 3:

1.

3. A pharmaceutical composition for forming an enhanced in situ vascular stent, characterized in that: The invention comprises a photoactive cross-linking agent and an auxiliary cross-linking agent, wherein the auxiliary cross-linking agent is a polypeptide, and the mass ratio of the photoactive cross-linking agent to the auxiliary cross-linking agent is 0.5-3:

1.

4. The pharmaceutical composition according to claim 2, characterized in that The photoactive crosslinking agent is selected from at least one of naphthylimide derivatives, rose bengal, riboflavin phosphate, indoline, hemicyanine derivatives, cyanines, squarylium cyanine, boron-dipyrromethene, porphyrin derivatives, porphine derivatives, phthalocyanine derivatives, anthraquinone derivatives or conjugated polymers; The auxiliary cross-linking agent comprises a plurality of binding sites and a flexible chain connecting the plurality of binding sites, wherein the flexible chain is at least one of polyethers, linear polysaccharides, and polyethyleneimine; The binding site is provided by at least one of amino acids, polypeptides, and hyperbranched polypeptides.

5. The pharmaceutical composition according to claim 4, characterized in that The pharmaceutical composition also includes a pharmaceutical agent; The pharmaceutical agent is selected from at least one of rapamycin, sirolimus, everolimus, zotarolimus, 42-(dimethylphosphinate) rapamycin, rufolimus, biolimus, umimios, and tacrolimus; The mass ratio of the photoactive cross-linking agent to the drug agent is 0.2 to 2:

1.

6. The pharmaceutical composition according to claim 5, characterized in that The pharmaceutical composition also includes a carrier for loading the pharmaceutical agent; The mass ratio of the drug agent to the carrier is 1 to 10:

1.

7. A pharmaceutical composition for forming an enhanced in situ vascular stent, characterized in that: By weight, it includes the following raw materials: Auxiliary cross-linking agent 100; Photoactive crosslinker 50-300; Drug reagents 10-150; Carrier 10~150.

8. A drug carrying device, characterized in that: The invention comprises an interventional device and a drug composition loaded on the interventional device, wherein the drug composition comprises a photoactive cross-linking agent and an auxiliary cross-linking agent.

9. The method for preparing the drug carrying device according to claim 8, characterized in that: The following steps are involved: Provide interventional devices; A drug coating is formed on the surface of the interventional device, and the raw materials of the drug coating include a photoactive cross-linking agent and an auxiliary cross-linking agent.

10. A treatment system, characterized in that: include: A drug-carrying device, comprising an interventional device and a drug composition loaded on the interventional device, wherein the drug composition comprises a photoactive cross-linking agent and an auxiliary cross-linking agent; A light source is used to apply light energy to the photoactive cross-linking agent.

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