CN111714260B - Bracket and application thereof - Google Patents
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- CN111714260B CN111714260B CN202010694668.6A CN202010694668A CN111714260B CN 111714260 B CN111714260 B CN 111714260B CN 202010694668 A CN202010694668 A CN 202010694668A CN 111714260 B CN111714260 B CN 111714260B
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Classifications
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- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
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- 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
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- 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
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- A61M27/00—Drainage appliance for wounds or the like, i.e. wound drains, implanted drains
- A61M27/002—Implant devices for drainage of body fluids from one part of the body to another
- A61M27/008—Implant devices for drainage of body fluids from one part of the body to another pre-shaped, for use in the urethral or ureteral tract
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- A—HUMAN NECESSITIES
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- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2240/00—Manufacturing or designing of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
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- A—HUMAN NECESSITIES
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- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
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- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a stent and application thereof, wherein the stent is used for a urinary system pipeline and comprises a stent matrix and a drug arranged on the stent matrix; when the stent is implanted into the urinary system pipeline, the stent matrix plays roles of supporting and draining the urinary system pipeline, the drug is used for preventing or reducing the occurrence of restenosis of the urinary system pipeline, and the stent has a low-dosage high-efficiency treatment effect, a longer drug release period and better slow release capacity. In addition, the bracket of the invention can realize targeting effect, effectively avoid the condition that the liver is metabolized at first when orally taking medicine, and greatly reduce the side effect of the medicine on the whole body because the dosage is about 10% of the dosage of oral administration or injection mode.
Description
Technical Field
The invention belongs to the field of medical instruments, and relates to a bracket and application thereof.
Background
Urinary tract stenosis (e.g. ureteral stenosis, urethral stricture) is a common disease of the urinary system, and besides congenital stenosis, inflammation and injury are main causes of the urinary tract stenosis, such as ureteroscopy, holmium and thulium laser lithotripsy, various pelvic surgery, ureteral infection, urethral lumen infection and the like.
At present, the clinic treatment modes of the urinary system pipeline stenosis include repeated operation modes such as dilatation, incision, anastomosis, dragging-in, substitution and the like, and after operation, a patient needs to be implanted with a bracket for supporting and draining. The existing brackets on the market only do physical support and drainage function, do not play a role in repairing or treating injury, but can stimulate the organism to trigger inflammation after being implanted, so that scar tissues are formed at the injury part, and the restenosis of the urinary system pipeline is caused. For restenosis of urinary system, other complications are easily caused if the operation is repeated, which not only brings great pain to the body and spirit of the patient, but also increases the economic burden.
Therefore, it is highly desirable to provide a stent that can prevent or reduce restenosis in urinary tract vessels.
Disclosure of Invention
The invention aims to provide a stent and application thereof, wherein the stent can play a role in supporting and draining a urinary system pipeline, can prevent or reduce the occurrence of restenosis of the urinary system pipeline, has a low-dosage high-efficiency treatment effect, has a longer drug release period and better slow release capability.
To achieve the purpose, the invention adopts the following technical scheme:
it is an object of the present invention to provide a stent for a urinary system tract, the stent comprising a stent matrix and a drug disposed on the stent matrix. When the stent is implanted into the urinary system pipeline, the stent matrix plays a role in supporting and draining the urinary system pipeline, and the drug is used for preventing or reducing the occurrence of restenosis of the urinary system pipeline.
In one embodiment, the urinary tract is a ureter and/or a urethra and, correspondingly, the stent is a ureter stent and/or a urethra stent. Specifically, the stent implanted in the urinary system pipeline can be a ureteral stent, a urethral stent or a combination of the ureteral stent and the urethral stent, and the stent can be adjusted according to actual needs by a person skilled in the art. The ureteral stent is arranged in the ureter, so that on one hand, the ureter can be supported and drained, and on the other hand, the occurrence of restenosis of the ureter can be prevented or reduced; the urethral stent is placed in the urethra, so that on one hand, the urethral stent can play a role in supporting and draining the urethra, and on the other hand, the urethral stent can prevent or reduce the occurrence of urethral restenosis.
In one embodiment, one or more ureteral stents are implanted in the ureter, and the skilled artisan can adjust the specific number of implants according to actual needs; similarly, one or more of the urethral stents are implanted in the urethra, and one skilled in the art can adjust the specific number of implants as desired.
In one specific embodiment, the ureteral stent can be a single J tube, a double J tube or a straight tube, and the ureteral stent can be selected by a person skilled in the art according to actual needs.
In one specific embodiment, the urethral stent can be a single-cavity catheter, a double-cavity catheter or a three-cavity catheter; the urethral stent can be balloon-equipped or non-balloon-equipped; and the selection and adjustment can be carried out by the person skilled in the art according to actual needs.
In one embodiment, the individual stents have a drug loading of 30 μg to 200mg, e.g., 30 μg, 50 μg, 100 μg, 500 μg, 800 μg, 1mg, 10mg, 50mg, 100mg, 150mg, 200mg, etc.
In one embodiment, a single said stent releases a drug amount of 5 μg-2mg per day, e.g. 5 μg, 10 μg, 50 μg, 100 μg, 300 μg, 500 μg, 800 μg, 1mg, 1.2mg, 1.5mg, 1.8mg, 2mg, etc.
In one embodiment, the period of drug release for a single stent is 5-90 days, e.g., 5 days, 10 days, 20 days, 30 days, 40 days, 50 days, 60 days, 70 days, 80 days, 90 days, etc.
The single stent can be a single ureteral stent or a single urethral stent.
The single stent releases 5 mug-2 mg of drug per day, and the total drug carrying amount of the single stent is in the range of 30 mug-200 mg, so that the drug released per day and the total drug amount reach the threshold value of action, thereby effective treatment can be carried out, and meanwhile, the drug released per day and the total drug amount are controlled within safe amounts, so that the drug amount is small but the treatment efficiency is high. In addition, the single stent releases 5 mug-2 mg of medicine every day and continuously releases for 5-90 days, and the release speed is stable and the release is uniform.
In one embodiment, the drug of a single stent does not release or releases less than 1mg (e.g., 5 μg, 10 μg, 50 μg, 100 μg, 300 μg, 500 μg, 800 μg, 1mg, etc.) 1h-7 days (e.g., 1h, 6h, 12h, 18h, 1 day, 2 days, 3 days, 4 days, 45 days, 6 days, 7 days, etc.) after the stent is implanted.
The single drug of the stent is not released or the release amount is lower than 1mg in 1h-7 days after the stent is implanted, so as to avoid the action of a large amount of drugs in the early stage, reduce the defense and repair functions of the organism, and further lead to infection diffusion and delay wound healing.
In one embodiment, the drug comprises a glucocorticoid-containing drug. In early inflammation, glucocorticoid can stabilize intracellular lysosome membrane, protect mitochondria, relieve exudation, edema, telangiectasia, leukocyte infiltration and phagocytosis, thereby improving red, swelling, heat, pain, etc.; in the later stage of inflammation, the glucocorticoid can inhibit proliferation of capillary blood vessels and fibroblasts, inhibit synthesis of collagen and mucopolysaccharide and proliferation of granulation tissues, thereby preventing adhesion and scar formation, and further preventing or reducing occurrence of restenosis of urinary system pipelines.
It should be noted that glucocorticoids are not beneficial for wound healing, and as mentioned above, the drug of the stent alone is not released or is released less than 1mg 1h-7 days after the completion of the implantation of the stent, so that there is sufficient time for the release of the drug containing glucocorticoids after wound healing.
In one embodiment, the glucocorticoid-containing drug comprises any one or a combination of at least two of clobetasol, ambroxide, triamcinolone acetonide, tranilast, budesonide, mometasone furoate, dexamethasone, betamethasone, fluorometsone, fluorometholone, hydrocortisone, rimexolone, dexamethasone, cortolone, prednisolone, triamcinolone, rofluminide, ciclesonide, prednisone, cortisone, or triamcinolone.
In one embodiment, given that urinary system infections are common complications after stent implantation, the medicament further comprises an anti-infective medicament comprising any one or a combination of at least two of beta lactams, macrolides, quinolones, aminoglycosides, antiviral or antifungal agents.
In one specific embodiment, the material of the bracket matrix is degradable material and/or non-degradable material.
In one embodiment, the stent matrix is a degradable material.
In one embodiment, the degradable material comprises any one or a combination of at least two of polylactide, polylactide-glycolide, polyglycolide/polylactic acid copolymer, polyethylene glycol, polycaprolactone, poly-n-ester, polyglycolic acid, polybutylene succinate, caprolactone-lactide copolymer, or polyhydroxyalkanoate.
In one embodiment, the stent matrix is a non-degradable material.
In one embodiment, the non-degradable material comprises any one or a combination of at least two of rubber, silicone rubber, polyester, polyvinyl chloride, polyurethane, or metal (e.g., nickel titanium alloy).
In one embodiment, the scaffold matrix has a hardness of 60-99A, such as 60A, 65A, 70A, 75A, 80A, 85A, 90A, 95A, 99A, etc.; the support matrix with the hardness can ensure that the support matrix has a good supporting effect on the urinary system pipeline, if the hardness of the support matrix is too low, the support matrix is easy to squeeze and deform, and the support matrix is difficult to support the urinary system pipeline, so that the treatment effect is affected, and if the hardness of the support matrix is too high, the support matrix is not easy to convey and the urinary system pipeline is possibly damaged.
According to one aspect of the invention, the drug is dispersed within the interior of the stent matrix to form a matrix stent.
In one embodiment, the drug may be dispersed throughout the interior of the stent matrix to provide an overall therapeutic effect; the medicament can also be dispersed in a specific position of the stent matrix so as to carry out targeted local treatment according to the damage condition.
In one embodiment, the drug may be uniformly dispersed throughout the interior of the stent matrix to provide an overall therapeutic effect; the drug may also be unevenly dispersed throughout the interior of the stent matrix, more severely damaged sites may be dispersed, and less lightly damaged sites may be dispersed.
In one embodiment, the particle size of the drug is 800-12500 mesh, such as 800 mesh, 1000 mesh, 2000 mesh, 3000 mesh, 4000 mesh, 5000 mesh, 6000 mesh, 7000 mesh, 8000 mesh, 9000 mesh, 10000 mesh, 12500 mesh; controlling the release rate of the medicine by controlling the mesh number of the medicine, thereby controlling the medicine effect and the release period; when the mesh number of the medicine is too low, the particle size of the medicine is larger, and the medicine is difficult to dissolve out from the inside of the stent matrix, so that the treatment effect is affected; when the mesh number of the drug is too high, the particle size of the drug is small, and the drug is easily dissolved out from the inside of the stent, which may cause an excessive blood concentration, thereby possibly causing other side reactions.
In one embodiment, when the material of the stent matrix is silicone rubber, the stent comprises 45-90% (e.g., 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, etc.) of silicone rubber, 5-50% (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, etc.) of drug, 0.1-3% (e.g., 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, etc.) of cross-linking agent, and 0.1-3% (e.g., 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, etc.) of catalyst by mass; by controlling the addition amount of each substance in the bracket, each substance is mutually matched to control the release rate of the medicine, thereby controlling the medicine effect and the release period.
In one embodiment, the cross-linking agent comprises hydrogen containing silicone oil and/or hydrogen containing siloxane.
In one embodiment, the catalyst comprises any one or a combination of at least two of platinum, a platinum complex, a ruthenium complex, or a rhodium complex.
In one embodiment, the silicone rubber has a crosslink density of 1000 to 8000g/mol, such as 1500g/mol、2000g/mol、2500g/mol、3000g/mol、3500g/mol、4000g/mol、4500g/mol、5000g/mol、5500g/mol、6000g/mol、6500g/mol、7000g/mol、7500g/mol or 8000g/mol, etc.
The crosslinking density of the silicone rubber refers to the number of effective network chains contained in the unit volume of the silicone rubber, and can characterize the crosslinking degree of the silicone rubber. During the test, it was found that under the same conditions, the greater the crosslinking density of the silicone rubber, the smaller the drug release. When the medicine is dispersed in the silicone rubber, the release rate of the medicine is controlled by controlling the crosslinking density of the silicone rubber, so as to achieve a better treatment effect. However, the crosslinking density of the silicone rubber affects the properties of the silicone rubber such as elastic modulus, breaking strength, and elongation at break. According to the test, the cross-linking density of the silicone rubber has the optimal elasticity and slow release effect in the range.
In one embodiment, the method for preparing the stent comprises the following steps: mixing the silicon rubber, the medicine, the cross-linking agent and the catalyst, and vulcanizing and cross-linking to obtain the bracket.
In one embodiment, when the scaffold matrix is a degradable material, the scaffold comprises 49-95% (e.g., 49%, 52%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, etc.) by mass of the degradable material, 4-50% (e.g., 4%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, etc.) of the drug, and optionally 1-20% (e.g., 1%, 3%, 5%, 8%, 10%, 12%, 15%, 18%, 20%, etc.) of the water-soluble polymer.
As urine flows out, the degradable material degrades under the action of the optional water-soluble polymer, i.e., the stent matrix degrades under the action of the optional water-soluble polymer. As the stent matrix degrades, the drug dispersed within the stent matrix is released. The degradation rate of the stent matrix can be controlled by controlling the addition amount of the optional water-soluble polymer and the outflow amount of urine, so that the slow release of the drug can be controlled, and the better slow release and treatment effects can be achieved. It is obtained through experiments that when 1-20% of water-soluble polymer is added, the drug release rate is better.
In one embodiment, the water-soluble polymer comprises any one or a combination of at least two of chitosan, gelatin, acacia, hyaluronic acid, cellulose and derivatives thereof, polyacrylamide, polyacrylic acid, polyvinylpyrrolidone, polyvinyl acid, polymaleic anhydride, polyquaternium or starch.
In one embodiment, the method for preparing the stent comprises the following steps: and mixing the degradable material, the drug and the optional water-soluble polymer under the melting condition, and extruding and molding to obtain the stent. The method is to match the melting points of the degradable material and the drug to prevent the deactivation of the drug when the temperature is too high.
In one embodiment, the method for preparing the stent comprises the following steps: and mixing the degradable material, the drug and the optional water-soluble polymer in a solvent, removing the solvent, and heating and shaping to obtain the stent.
In the matrix stent, since the drug is dispersed in the inside of the stent matrix, the stent matrix is required to be made of a material capable of releasing the drug, and the material may be polyester in addition to the silicone rubber and the degradable material. The matrix stent has a relatively long drug release period and can be applied to cases requiring long-term stent implantation.
According to another aspect of the present invention, the drug is dispersed on the outer surface of the stent matrix, a drug coating is formed on the outer surface of the stent matrix, and the stent is a coated stent.
In one embodiment, the drug coating and the stent matrix are connected together through crosslinking, wherein the crosslinking comprises chemical crosslinking and physical crosslinking, the chemical crosslinking comprises polycondensation crosslinking or polyaddition crosslinking, the physical crosslinking comprises any one of photo-crosslinking, thermal crosslinking, radiation crosslinking or natural crosslinking, the specific crosslinking mode is not particularly limited, and the person skilled in the art can adjust according to actual needs.
In one embodiment, the drug coating is disposed in a coated or encapsulated manner on the outer surface of the stent matrix.
In one embodiment, the coating means comprises any one of dipping, spinning, spraying or brushing, preferably spraying.
In one embodiment, the drug coating may be disposed on the entire outer surface of the stent matrix, or may be disposed locally on the outer surface of the stent matrix, and may be adjusted as desired by those skilled in the art.
In one embodiment, the thickness of the drug coating is 0.01-1mm, such as 0.01mm, 0.05mm, 0.1mm, 0.3mm, 0.5mm, 0.7mm, 1mm, etc.
In one specific embodiment, the support base includes opposite ends, one of which is an inlet end for introducing urine and the other of which is an outlet end for introducing urine. The thickness of the drug coating of the leading-in end is larger than that of the drug coating of the leading-out end.
In one specific embodiment, the inlet end of the ureteral stent is a near-kidney end, and the outlet end of the ureteral stent is a near-bladder end.
In one specific embodiment, the inlet end of the urethral stent is a near-bladder end, and the outlet end of the urethral stent is a near-urethral orifice end.
Considering that 1-2L of urine is generated in the urinary system in normal condition every day, the urine flows out from top to bottom along the ureter and urethra, and the thickness of the drug coating at the inlet end is larger than that at the outlet end, so that the drug concentration difference caused by urine flushing can be compensated. The thickness of the drug coating can be changed in a linear mode, a curve mode or a gradient mode from the lead-in end to the lead-out end, and the thickness change rule of the drug coating is not particularly limited as long as the fact that the thickness of the drug coating of the lead-in end is larger than that of the drug coating of the lead-out end is met.
In one embodiment, the method for preparing the stent comprises the following steps: the preparation method comprises the steps of adding (dissolving) 40-98% (for example, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98% and the like) of biodegradable polymer materials and 2-60% (for example, 2%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60% and the like) of drugs into a solvent, uniformly mixing to obtain a mixed solution, coating the mixed solution on the outer surface of a stent matrix, and volatilizing the solvent to form a drug coating to obtain the stent. When in use, the medicine can be released along with the degradation of the biodegradable polymer material. The stent matrix can be prepared in advance by extrusion molding, braiding molding and other methods, and the stent matrix is not limited in material and can be combined with a biodegradable polymer material serving as a drug-carrying base material.
In one embodiment, the biodegradable polymeric material is any one or a combination of at least two of gelatin, starch, hyaluronic acid, cellulose, chitosan, polylactic acid, polyglycolic acid, polycaprolactone, polylactide-caprolactone, or polylactic acid-caprolactone.
In one embodiment, the solvent may be any one or a combination of at least two of water, methylene chloride, chloroform, acetone, isopropanol, ethanol, tetrahydrofuran, hexafluoroisopropanol, hexafluoroacetone, dimethyl sulfoxide, acetonitrile, diethyl ether, ethyl acetate, n-hexane, pyridine, toluene, benzene, dimethylformamide, n-heptane, methanol, ethylamine, lactic acid, petroleum ether, glycerol, octanoic acid, n-hexanol, or cyclohexane.
In one embodiment, the mixed solution is atomized into particles using an atomizing device and then coated on the outer surface of the stent matrix.
In one embodiment, the microparticles are coated on the outer surface of the stent matrix in a wet or semi-dry state.
In one embodiment, the particles have a particle size of 50nm to 500 μm (e.g., 50nm、100nm、300nm、500nm、800nm、1μm、5μm、10μm、50μm、100μm、150μm、200μm、250μm、300μm、350μm、400μm、450μm、500μm, etc.), preferably 500nm to 200 μm.
In one embodiment, the method of preparing the stent further comprises pre-treating the outer surface of the stent matrix prior to the coating.
In one embodiment, the treatment mode comprises any one or a combination of at least two of plasma treatment, swelling treatment, sand blasting treatment, frosting treatment, dermatoglyph treatment, electrostatic treatment or wetting treatment.
In one specific embodiment, the mixed solution further comprises a polymer with a long degradation period or non-degradation, wherein the mass percentage of the polymer with the long degradation period or non-degradation is 0.5% -10% (e.g. 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, etc.), at this time, the mass percentage of the biodegradable polymer material is 40% -95%, and the mass percentage of the drug is 2% -50%. In this way, the release rate of the drug can be reduced.
In one embodiment, the polymer with a long degradation period is any one or a combination of at least two of polylactic acid, polyacetol, a blend containing polyglycolic acid, polyglycolic acid copolymer or polyvinyl alcohol.
In one embodiment, the non-degradable polymer is any one or a combination of at least two of polyvinylpyrrolidone, parylene, silicone oil, silicone gel, silicone rubber, or polyethylene glycol.
In one embodiment, the method for preparing the stent comprises the following steps: the method comprises the steps of uniformly mixing 24-80% (e.g. 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, etc.) of silicone rubber, 18-70% (e.g. 20%, 30%, 40%, 50%, 60%, 70%, etc.), a micronized drug, 0.1-3% (e.g. 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, etc.), and 0.1-3% (e.g. 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, etc.) of a cross-linking agent by mass percent and a catalyst to obtain a mixed material, and then curing and combining the mixed material and a stent matrix to obtain the stent. The stent matrix can be prepared in advance by extrusion molding, braiding molding and the like.
In one embodiment, the method for preparing the stent comprises the following steps: uniformly mixing 24-80% by mass of silicon rubber, 18-70% by mass of micronized drug, 0.1-3% by mass of cross-linking agent and 0.1-3% by mass of catalyst to obtain a mixed material, solidifying the mixed material to obtain a drug film (namely a drug coating on the outer surface of a stent matrix after the preparation of the stent is completed), and then combining the drug film and the stent matrix together by a secondary solidification or gluing mode to obtain the stent. The material of the stent matrix is not limited, and the stent matrix can be glued or secondarily solidified with the silicone rubber medical film. The stent matrix can be prepared in advance by extrusion molding, braiding molding and the like.
The secondary curing is suitable for the stent matrix made of the silicone rubber, and the drug film and the stent matrix which are not cured completely are subjected to pressurization and/or heating for secondary vulcanization, so that the stent matrix and the drug film are combined completely. The method does not need to add new materials, and the two materials are combined more firmly and have stable performance.
The adhesive is suitable for bracket matrixes made of all materials, and the selected adhesive can be any one or a combination of at least two of silicone rubber, UV (ultraviolet) adhesive, resin adhesive, hot melt adhesive, pressure-sensitive adhesive, latex and the like, and is preferably silicone rubber.
The thickness of the drug film can influence the concentration gradient of the drug, and the drug film with different thickness can cause the drug to form different exudation degrees in the release process, so that the drug has different release rates. When the thickness of the medicinal film is 0.01-1mm, the medicinal film has better medicinal effect and longer release period.
In both embodiments, the cross-linking agent comprises a hydrogen containing silicone oil and/or a hydrogen containing siloxane.
In both embodiments, the catalyst comprises any one or a combination of at least two of platinum, a platinum complex, a ruthenium complex, or a rhodium complex.
In both embodiments, the micronized drug has a particle size of 800-12500 mesh, such as 800 mesh, 1000 mesh, 2000 mesh, 3000 mesh, 4000 mesh, 5000 mesh, 6000 mesh, 7000 mesh, 8000 mesh, 9000 mesh, 12500 mesh, etc.; the drug release rate is controlled by controlling the mesh number of the drugs, so that the drug effect and the release period are controlled. The relationship between the mesh number of the drug and the release rate of the drug is as described above, and will not be described here.
In both embodiments, the silicone rubber has a crosslink density of 1000 to 8000g/mol, such as 1500g/mol、2000g/mol、2500g/mol、3000g/mol、3500g/mol、4000g/mol、4500g/mol、5000g/mol、5500g/mol、6000g/mol、6500g/mol、7000g/mol、7500g/mol or 8000g/mol, etc. The release rate of the drug is controlled by controlling the crosslinking density of the silicone rubber in the drug coating, thereby controlling the drug effect and the release period. The relationship between the crosslinking density of the silicone rubber and the release rate of the drug is as described above, and will not be described here.
On the basis of any one of the two aspects, a controlled release layer and/or a hydrophilic coating layer is/are further arranged on the outer surface of the stent matrix or the outer surface of the drug coating layer.
The controlled release layer can control the release rate of the drug, thereby controlling the drug effect and the release period.
The stent can generate certain friction with the tube wall of the urinary system pipeline in the process of being implanted into the urinary system pipeline, thereby causing patients to feel pain to a certain extent. In order to reduce the friction force in the implantation process, a layer of hydrophilic coating can be arranged on the outer surface of the stent matrix or the outer surface of the drug coating, and when the hydrophilic coating is contacted with water or water-containing tissues, water drops form a smaller contact angle on the surface of the hydrophilic coating, so that the water drops have a larger spreading area, and a layer of super-lubricated surface water film is formed, thereby reducing the friction force in the process of implanting the stent into a urinary system pipeline.
In one embodiment, the controlled release layer has a thickness of 0.01 to 1mm, such as 0.01mm, 0.05mm, 0.1mm, 0.2mm, 0.3mm, 0.4mm, 0.5mm, 0.6mm, 0.7mm, 0.8mm, 0.9mm, 1mm, and the like.
In one embodiment, the material of the controlled release layer is silicone rubber.
In one embodiment, the silicone rubber has a crosslink density of 1000 to 8000g/mol, such as 1000g/mol、1500g/mol、2000g/mol、2500g/mol、3000g/mol、3500g/mol、4000g/mol、4500g/mol、5000g/mol、5500g/mol、6000g/mol、8000g/mol, etc.
In one embodiment, the silicone rubber and stent matrix or drug coating are bonded together by glue.
In one embodiment, the silicone rubber and stent matrix or drug coating are cured together in a semi-solid state.
When the material of the controlled release layer is silicon rubber, the release rate of the medicine is controlled by controlling the crosslinking density of the controlled release layer, so that the medicine effect and the release period are controlled. The relationship between the crosslinking density of the silicone rubber and the release rate of the drug is as described above, and will not be described here.
In one embodiment, the hydrophilic coating has a thickness of 0.01 to 0.5mm, such as 0.01mm, 0.12mm, 0.15mm, 0.17mm, 0.2mm, 0.22mm, 0.25mm, 0.27mm, 0.3mm, 0.5mm, and the like.
In one specific embodiment, the material of the hydrophilic coating is any one or a combination of at least two of polyethylene oxide, polyacrylic acid, polyacrylamide, polyvinyl alcohol, polyvinylpyrrolidone, polyisocyanate, sodium hyaluronate or maleic acid. In this way, the hydrophilic coating does not chemically react with the drug to modify or inactivate the drug.
In one specific embodiment, the thickness of the hydrophilic coating is 0.01-0.5mm, so that the hydrophilic coating can be uniformly and fully contacted with water to form an ultra-smooth surface water film on one hand and can be rapidly spread on the other hand, and the release rate of the medicine can be further controlled through the arrangement of the hydrophilic coating, so that the medicine effect and the release period are controlled.
In one embodiment, the stent comprises both a controlled release layer disposed on the outer surface of the stent matrix or the outer surface of the drug coating and a hydrophilic coating disposed on the outer surface of the controlled release layer.
The drug coating and/or the controlled release layer and/or the hydrophilic coating are/is arranged, so that the diameter of the finally obtained stent is 0.1-1mm larger than that of a conventional stent in the market, the adherence of the stent can be increased, namely, the stent can be tightly combined with the wall of a urinary system pipeline, the wall has certain elasticity, and repeated experiments prove that the implantation of the urethral stent cannot be influenced by the expansion within 1mm, and the discomfort caused by the expansion of the wall cannot be additionally increased. The stent is tightly combined with the wall of the urinary system pipeline, which is favorable for the absorption of the medicine by the mucous layer of the wall.
In addition, for coated stents, by providing a controlled release layer and/or a hydrophilic coating, the drug coating can be prevented from falling off due to friction during implantation.
It is a second object of the present invention to provide a use of a stent according to one of the objects for the preparation of a drug delivery system.
In one embodiment, the stent is used for supporting, draining and preventing or reducing the occurrence of restenosis of the urinary tract; further, for ureters and/or urethra.
Compared with the prior art, the invention has the following beneficial effects:
The stent is used for the urinary system pipeline and comprises a stent matrix and a drug arranged on the stent matrix, when the stent is implanted into the urinary system pipeline, the stent matrix plays a role in supporting and draining the urinary system pipeline, the drug is used for preventing or reducing the occurrence of restenosis of the urinary system pipeline, and the stent has a low dosage and high-efficiency treatment effect, a longer drug release period and a better slow release capability. In addition, the bracket of the invention can realize targeting effect, effectively avoid the condition that the liver is metabolized at first when orally taking medicine, and greatly reduce the side effect of the medicine on the whole body because the dosage is about 10% of the dosage of oral administration or injection mode.
Detailed Description
The technical scheme of the invention is further described by the following specific embodiments. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.
Example 1
The embodiment provides a bracket, which comprises a bracket matrix and medicines containing glucocorticoid, wherein the medicines containing glucocorticoid are mometasone furoate, the average particle size is 5000 meshes, the bracket matrix is made of silicone rubber, and the crosslinking density of the silicone rubber is 5000g/mol.
The embodiment provides a method for preparing a bracket, which comprises the following steps: mixing 10 parts by weight of medicine (mometasone furoate) and 30 parts by weight of silicone rubber (HTV medical silicone rubber, molecular weight of 20-100 ten thousand), 1.2 parts by weight of cross-linking agent (hydroxy silicone oil) and 1.2 parts by weight of catalyst (platinum) on a rubber mixing mill until the mixture is uniform, vulcanizing and cross-linking, and extruding the mixture on an extruder to form the bracket.
The physical properties of the stent of this example were tested according to the test method of standard GB/T531, and it is known that: the hardness of the stent matrix was 80A.
The support force of the stent was tested using a radial support load cell, compressing a 10% force value of 106N.
According to the content of the drug components in the sample, the drug dissolution test instrument is used for carrying out drug dissolution on the sample in a simulated urine solution at 37 ℃, and the amount of the dissolved drug is tested by High Performance Liquid Chromatography (HPLC), so that the maximum amount of the drug dissolution is 200 mug/d in the first 7 days, the total amount of the drug release is 1055 mug in the first 7 days, and the average release degree is 80 mug/d in 30 days.
The ureteral stent with 8F specification is prepared by adopting the method, and animal experiments are carried out on the ureteral stent:
establishing an animal model of a ureter scar mechanism, taking 10 female New Zealand rabbits (each rabbit has 2 ureters), establishing a damage model in the ureters by using holmium laser, and after debridement, performing radiography measurement on the diameter D1 of a stenosis section and the diameter D2 of a normal ureter at the far end of the stenosis section, wherein the method comprises the following steps of The ureteral stenosis degree was calculated.
Animals were divided into an experimental group and a control group, 5 experimental groups were implanted with homemade ureteral stents (8F gauge, mometasone furoate with average daily release of 80 μg over 30 days), and a control group was implanted with a commercial ureteral stent of conventional 8F gauge without drug. Tube drawing was performed after 1 month, scar conditions and stenosis degree were measured and observed, and the observation results were shown in table 1 after 1 month of follow-up.
TABLE 1
As can be seen from Table 1, the experimental stent and the control stent are randomly implanted, the urethral stricture degree is measured by adopting radiography, when the urethral stricture degree is pulled out after one month of implantation, the stricture degree of the experimental group is 12.94+/-2.02%, the stricture degree of the control group is 21.8+/-11.8%, and P is 0.043 <0.05, and the difference is obvious; after tube drawing for 1 month, the stenosis degree of the experimental group is 7.00+/-4.57%, the stenosis degree of the control group is 22.1+/-19.1%, and P is 0.035 <0.05, and the significant difference exists.
Dissected 1 month after tube drawing, tissue sections were taken, analyzed using Image-Pro Plus 6.0 software, 8 sites were selected for each section, and the depth of tissue damage was measured. The injury depth of the experimental group is 1554+/-115 mu m, the injury depth of the control group is 1777+/-139 mu m, and P is 0.001 <0.05, so that the difference is obvious.
Tissue sections were taken, stained and the percentage of collagen fiber area was measured using Image-pro plus 6.0 analysis software, with the percentage of collagen fiber area of the experimental group being 51.78+ -5.96% and the percentage of collagen fiber area of the control group being 69.96 + -3.88%. P is 0.000 < 0.05, with significant differences.
Animal experiments prove that the treatment effect of the experimental group is better than that of the control group.
The urethral stent is prepared by adopting the method, and animal experiments are carried out on the urethral stent:
The change in the expression levels of PCNA, bcl-2 in the tissue of the sections was detected by immunohistochemical SP method.
The sample is selected from a normal urethra section and a urethra scar section, and the scar section is 1cm long after the tube drawing of the experimental group and the control group is carried out for 1 month.
After slicing and cutting, the slices are fixed by formaldehyde solution with the volume fraction of 10%, paraffin is embedded, and the slices are continuously sliced with the thickness of 1 mm.
The sections are dewaxed conventionally, endogenous peroxidase is eliminated by hydrogen peroxide with the volume fraction of 3%, normal sheep serum is blocked after antigen is repaired, primary antibody and secondary antibody are added in sequence, DAB color development, hematoxylin counterstain and sealing slice observation are carried out.
The cells with brown yellow particles in the nucleus were PCNA positive expression cells, and the cells with yellow or brown yellow particles in the cytoplasm were bcl-2 positive expression cells, as shown in Table 2.
TABLE 2
As can be seen from Table 2, a large number of PCNA and bcl-2 positive expressing cells were seen in scar tissue, with significant differences (P < 0.05) compared to normal urethra. After the test group and the control group are drawn for 1 month, the urethral stricture rate of the test group is obviously different from that of the control group, and the urethral stricture rate of the test group is obviously smaller than that of the control group; and the control group can see a large number of PCNA and bcl-2 positive expression cells, which are significantly different from the experimental group.
Animal experiments prove that the treatment effect of the experimental group is better than that of the control group.
Comparative example 1
The difference from example 1 is only that the particle size of the drug was 500 mesh, and the remaining composition and preparation method were the same as example 1.
The physical properties of the scaffolds of this comparative example were tested according to the test method of example 1, and it was found that: the hardness of the stent matrix was 78A.
The support force of the stent was tested using a radial support load cell, compressing a 10% force value of 108N.
According to the content of the medicine components in the sample calculated by weight, the medicine is dissolved in the simulated urine solution at 37 ℃ by using a medicine dissolution tester, and the amount of the dissolved medicine is tested by HPLC, so that the maximum amount of the medicine dissolved in the first 7 days is 60 mug/d within 30 days, the medicine is gradually and smoothly slowed down later, and the average release degree is 12 mug/d within 30 days.
As is clear from the comparison between example 1 and comparative example 1, the lower the number of drug particles, the larger the drug particle size and the lower the drug release amount.
Comparative example 2
The difference from example 1 was only that the particle diameter of the drug was 15000 mesh, and the remaining composition and preparation method were the same as example 1.
The physical properties of the scaffolds of this comparative example were tested according to the test method of example 1, and it was found that: the hardness of the stent matrix was 82A.
The support force of the stent was tested using a radial support load cell, compressing a 10% force value of 105N.
According to the content of the drug ingredients in the sample, the drug dissolution test instrument is used for carrying out drug dissolution on the sample in a simulated urine solution at 37 ℃, and the HPLC test is used for measuring the quantity of the drug dissolved, so that the maximum quantity of the drug dissolved in the first 7 days is 479 mug/d within 30 days, the drug dissolved in the first 7 days gradually and smoothly gradually and slowly approaches the sample, and the average release degree within 30 days is 213 mug/d.
As is clear from the comparison between example 1 and comparative example 2, the higher the number of drug particles, the smaller the drug particle size and the higher the drug release amount.
Comparative example 3
The only difference from example 1 is that the cross-linking density of the silicone rubber is 2000g/mol, and the remaining composition and preparation method are the same as in example 1.
The physical properties of the scaffolds of this comparative example were tested according to the test method of example 1, and it was found that: the hardness of the stent matrix was 60A.
The support force of the stent was tested using a radial support load cell, compressing a 10% force value of 83N.
According to the content of the drug ingredients in the sample, the drug dissolution test instrument is used for carrying out drug dissolution on the sample in a simulated urine solution at 37 ℃, and the HPLC test is used for measuring the quantity of the drug dissolved, so that the maximum quantity of the drug dissolved in the first 7 days is 305 mug/d within 30 days, the drug dissolved in the first 7 days gradually and smoothly gradually and slowly approaches the last 7 days, and the average release degree within 30 days is 118 mug/d.
As is evident from the comparison of example 1 and comparative example 3, a low crosslink density increases the drug release amount and decreases the hardness of the stent matrix.
Comparative example 4
The difference from example 1 was only that the crosslinking density of the silicone rubber was 10000g/mol, and the remaining composition and the production method were the same as those of example 1.
The physical properties of the scaffolds of this comparative example were tested according to the test method of example 1, and it was found that: the hardness of the stent matrix was 92A.
The support force of the stent was tested using a radial support load cell, compressing a 10% force value of 136N.
According to the content of the medicine components in the sample calculated by weight, the medicine is dissolved in the simulated urine solution at 37 ℃ by using a medicine dissolution tester, and the amount of the dissolved medicine is tested by HPLC, so that the maximum amount of the medicine dissolved in the first 7 days is 72 mug/d within 30 days, the medicine is gradually and smoothly slowed down later, and the average release degree within 30 days is 11 mug/d.
As is evident from the comparison of example 1 and comparative example 4, the high crosslinking density reduces the drug release amount and increases the hardness of the stent matrix.
Example 2
The embodiment provides a stent, which comprises a stent matrix and a drug containing glucocorticoid dispersed in the stent matrix, wherein the stent matrix is made of caprolactone-lactide copolymer, and the drug containing glucocorticoid is budesonide.
The embodiment provides a method for preparing a bracket, which comprises the following steps: 20 parts by weight of a degradable material (caprolactone-lactide copolymer) and 1.5 parts by weight of a drug containing glucocorticoid (budesonide) are dissolved in 50ml of acetone, then 2 parts by weight of a water-soluble polymer (cellulose, which is firstly dissolved in 5ml of water and then added into an acetone solution) are added and mixed, the solvent is removed, and the stent is obtained by heating and shaping.
The support force of the stent was tested using a radial support load cell, compressing a 10% force value of 92N.
Calculating the content of the medicine components in the sample according to the weight, performing medicine dissolution and degradation experiments on the sample in a simulated urine solution at 37 ℃ by using a medicine dissolution tester, and testing the medicine dissolution amount by using HPLC, wherein the average release degree is 73 mug/d within 30 days; taking out the bracket to test radial supporting force in 7 days, wherein the compression force value of 10% is 51N, and the mass loss is 12%; the stent was removed for 30 days to test radial support force, compression by 10% force value 13N, mass loss 82%.
Example 3
The embodiment provides a bracket, which comprises a bracket matrix and medicines containing glucocorticoid, wherein the medicines containing glucocorticoid are dispersed in the bracket matrix, the bracket matrix is made of polyglycolic acid, and the medicines containing glucocorticoid are mometasone furoate.
The embodiment provides a method for preparing a bracket, which comprises the following steps: uniformly mixing 80 parts by weight of degradable material (polyglycolic acid), 5 parts by weight of medicine containing glucocorticoid (mometasone furoate) and 10 parts by weight of water-soluble polymer (chitosan) under a melting condition (140 ℃), and extruding and shaping to obtain the stent.
The support force of the stent was tested using a radial support load cell, compressing a 10% force value of 103N.
Calculating the content of the medicine components in the sample according to the weight, performing medicine dissolution and degradation experiments on the sample in a simulated urine solution at 37 ℃ by using a medicine dissolution tester, and testing the quantity of the dissolved medicine by using HPLC, wherein the average release degree is 61 mug/d within 30 days; taking out the bracket to test radial supporting force in 7 days, wherein the compression force value of 10% is 58N, and the mass loss is 20%; the stent was removed for 30 days to test radial support force, compression by 10% force value of 9N and mass loss of 88%.
Example 4
The embodiment provides a stent, which comprises a stent matrix and a drug coating containing glucocorticoid drug coated on the outer surface of the stent matrix, wherein the stent is made of polyurethane, and the thickness of the drug coating containing glucocorticoid drug is 0.2mm.
The embodiment provides a method for preparing a bracket, which comprises the following steps:
(1) Mixing 2 parts by weight of biodegradable high polymer material (polycaprolactone), 0.2 part by weight of polymer (polylactic acid) with long degradation period and 0.1 part by weight of glucocorticoid-containing drug (mometasone furoate) in 50mL of acetone to obtain mixed solution;
(2) Melting and extruding polyurethane to obtain a bracket matrix;
(3) And (3) treating the stent matrix obtained in the step (2) with plasma for 30 seconds, atomizing the mixed solution obtained in the step (1) into particles with the particle size of 50nm-500 mu m by using tooling equipment, uniformly spraying the particles on the outer surface of the treated stent matrix, adopting air blowing semi-drying in the spraying process, and drying in a drying box at the temperature of 40 ℃ after the spraying is finished to completely volatilize the solvent to obtain the stent.
The support force of the stent was tested using a radial support load cell, compressing a 10% force value of 113N.
According to the content of the drug components in the sample, a drug dissolution test is carried out on the sample in a simulated urine solution at 37 ℃ by using a drug dissolution tester, the amount of the drug dissolved is tested by HPLC, the maximum amount of the drug dissolved in the first 7 days is 273 mug/d within 30 days, the total release amount in the first 7 days is 1396 mug, and the average release degree within 30 days is 92 mug/d.
The ureteral stent with 8F specification is prepared by the method, and animal experiments similar to those of the example 1 are carried out, wherein 2 female New Zealand rabbits are taken, and when the ureteral stent is pulled out after being implanted for one month, the average stenosis rate of an experimental group is 11.54+/-1.58%, the stenosis degree of a control group is 21.8+/-11.8%, and P is 0.024 <0.05, so that the ureteral stent has obvious difference; after tube drawing for 1 month, the stenosis degree of the experimental group is 6.09+/-3.54%, the stenosis degree of the control group is 22.1+/-19.1%, and P is 0.029 <0.05, and the significant difference exists.
Dissected 1 month after tube drawing, tissue sections were taken, analyzed using Image-Pro Plus 6.0 software, 8 sites were selected for each section, and the depth of tissue damage was measured. The injury depth of the experimental group is 1470+/-173 mu m, the injury depth of the control group is 1777+/-139 mu m, and P is 0.034 <0.05, and the significant difference exists.
Tissue sections were taken, stained and the percentage of collagen fiber area was measured using Image-pro plus 6.0 analysis software, with the percentage of collagen fiber area of the experimental group being 46.75±2.59% and the percentage of collagen fiber area of the control group being 69.96 ±3.88%. P is 0.000 < 0.05, with significant differences.
Animal experiments prove that the treatment effect of the experimental group is better than that of the control group.
Example 5
The embodiment provides a stent, which comprises a stent matrix and a drug coating of a drug containing glucocorticoid, wherein the drug coating is coated on the outer surface of the stent matrix, the stent is made of silicon rubber, and the thickness of the drug coating of the drug containing glucocorticoid is 0.3mm.
The embodiment provides a method for preparing a bracket, which comprises the following steps:
(1) Uniformly mixing 30 parts by weight of silicone rubber (RTV-2), 10 parts by weight of a micronized drug (dexamethasone with a particle size of 3000 meshes) containing glucocorticoid, 0.6 part by weight of a cross-linking agent (hydroxy silicone oil) and 0.6 part by weight of a catalyst (platinum) to obtain a mixed material;
(2) Shaping 60 parts by weight of silicon rubber (RTV-2) through extrusion processing to obtain a bracket matrix;
(3) And (3) placing the mixed material obtained in the step (1) and the bracket matrix obtained in the step (2) in a mold, and curing (the curing temperature is 100 ℃, the curing pressure is 13MPa, and the curing time is 10 min) to obtain the bracket.
The physical properties of the scaffolds of this example were tested according to the test method of example 1, as follows: the hardness of the stent matrix was 86A.
According to the content of the drug components in the sample, the drug dissolution test instrument is used for carrying out drug dissolution on the sample in a simulated urine solution at 37 ℃, and the content of the drug dissolved by HPLC is tested, so that the maximum content of the drug dissolved in the first 7 days is 118 mug/d within 30 days, and the average release degree within 30 days is 76 mug/d.
Example 6
The embodiment provides a stent, which comprises a stent matrix and a drug coating of a drug containing glucocorticoid, wherein the drug coating is coated on the outer surface of the stent matrix, the stent is made of nickel-titanium alloy wires, and the thickness of the drug coating of the drug containing glucocorticoid is 0.1mm.
The embodiment provides a method for preparing a bracket, which comprises the following steps:
(1) Mixing 25 parts by weight of heat-vulcanized double-component silicon rubber A (dakangning), 6 parts by weight of micronized drug (dexamethasone with the particle size of 6000 meshes) containing glucocorticoid and 1.5 parts by weight of catalyst (model 5000PPM, derived eucalyptus globulus) uniformly; uniformly mixing 25 parts by weight of heat-vulcanized two-component silicone rubber B (daokannin), 6 parts by weight of micronized drug (dexamethasone with a particle size of 6000 meshes) containing glucocorticoid and 1.5 parts by weight of cross-linking agent (model PMX-0930, source daokannin); mixing the mixed medicine-containing A/B uniformly in equal amount, and placing into a mold for curing (the curing temperature is 106 ℃, the curing pressure is 13MPa, and the curing time is 20 min) to obtain a medicine film;
(2) Braiding and shaping nickel-titanium alloy wires to obtain a bracket matrix;
(3) And (3) sticking the medicinal film obtained in the step (1) and the stent matrix obtained in the step (2) together by adopting silicone rubber (Wake E41) to obtain the stent.
The support force of the stent was tested using a radial support load cell, compressing a 10% force value of 73N.
According to the content of the drug components in the sample, a drug dissolution tester is used for carrying out drug dissolution on the sample in a simulated urine solution at 37 ℃, and the amount of the drug dissolved is tested by HPLC, so that the maximum amount of the drug dissolved in the first 7 days is 296 mug/d and the average release degree is 97 mug/d within 30 days.
Example 7
The difference from example 1 is that the outer surface of the stent further comprises a controlled release layer, the controlled release layer is made of silicone rubber, the crosslinking density of the silicone rubber is 1000g/mol, and the thickness of the controlled release layer is 0.02mm.
The embodiment also provides a preparation method of the bracket, which comprises the following steps:
(1) After evenly mixing the silicon rubber, extruding the silicon rubber into a tube shape to obtain a sleeve controlled release layer with the thickness of 0.02 mm;
(2) And (3) splitting the silicon rubber sleeve controlled release layer obtained in the step (1) along the axis, coating the glue, sleeving the glue on the bracket prepared in the embodiment 1, and heating and fixing for 5min to obtain the bracket in the embodiment.
The support force of the stent was tested using a radial support load cell, compressing a 10% force value of 112N.
According to the content of the drug components in the sample, the drug dissolution test instrument is used for carrying out drug dissolution on the sample in a simulated urine solution at 37 ℃, and the HPLC test is used for measuring the quantity of the drug dissolved, so that the maximum quantity of the drug dissolved in the first 7 days is 89 mug/d within 30 days, the total quantity of the drug released in the first 7 days is 796 mug, and the average release degree within 30 days is 71 mug/d.
Example 8
The difference from example 1 is that the outer surface of the stent further comprises a controlled release layer, the controlled release layer is made of silicone rubber, the crosslinking density of the silicone rubber is 6000g/mol, and the thickness of the controlled release layer is 0.2mm.
The embodiment also provides a preparation method of the bracket, which comprises the following steps:
(1) After evenly mixing the silicon rubber, extruding the silicon rubber into a tube shape to obtain a sleeve controlled release layer with the thickness of 0.2 mm;
(2) And (3) splitting the silicon rubber sleeve controlled release layer obtained in the step (1) along the axis, coating the glue, sleeving the glue on the bracket prepared in the embodiment 1, and heating and fixing for 5min to obtain the bracket in the embodiment.
The support force of the stent was tested using a radial support load cell, compressing a 10% force value of 128N.
According to the content of the drug components in the sample, the drug dissolution test instrument is used for carrying out drug dissolution on the sample in a simulated urine solution at 37 ℃, and the HPLC test is used for measuring the quantity of the drug dissolved, so that the maximum quantity of the drug dissolved in the first 7 days is 16 mug/d within 30 days, the total quantity of the drug released in the first 7 days is 166 mug, and the average release degree within 30 days is 65 mug/d.
Example 9
The difference from example 1 is that the outer surface of the stent is also provided with a hydrophilic coating, the hydrophilic coating is made of polyvinylpyrrolidone and has a thickness of 0.03mm.
The embodiment also provides a preparation method of the bracket, which comprises the following steps:
(1) And (3) spraying the polyvinylpyrrolidone mixed solution on the outer surface of the stent obtained in the example 1, and performing ultraviolet crosslinking and curing to obtain the stent in the example.
The physical properties of the scaffolds of this example were tested according to the test method of example 1, as follows: the hardness of the scaffold was 80A.
The support force of the stent was tested using a radial support load cell, compressing a 10% force value of 108N.
According to the content of the drug components in the sample, the drug dissolution test instrument is used for carrying out drug dissolution on the sample in a simulated urine solution at 37 ℃, and the HPLC test is used for measuring the quantity of the drug dissolved, so that the maximum quantity of the drug dissolved in the first 7 days is 5 mug/d within 30 days, the total quantity of the drug released in the first 7 days is 37 mug, and the average release degree within 30 days is 53 mug/d.
Animal experiments of ureteral stents were performed according to the method of example 1, the stent of example 1 and the stent of this example were randomly implanted, and after 1 month of tube drawing, the urethral stricture was measured by radiography, the stricture of example 1 group was 12.94±2.02%, the stricture of this example group was 9.84±2.70%, and P was 0.01 < 0.05, with significant differences; after 1 month of tube drawing, the example 1 group had a stenosis degree of 7.00.+ -. 4.57%, the example group had a stenosis degree of 2.64.+ -. 2.54%, and P was 0.019 < 0.05, with a significant difference.
Dissected 1 month after tube drawing, tissue sections were taken, analyzed using Image-Pro Plus 6.0 software, 8 sites were selected for each section, and the depth of tissue damage was measured. The injury depth of the example 1 group is 1554+/-115 mu m, the injury depth of the example group is 1316+/-134 mu m, and P is 0.001 < 0.05, which has obvious difference.
Tissue sections were taken, stained and the percentage of collagen fiber area was measured using Image-pro plus 6.0 analysis software, with the percentage of collagen fiber area for example 1 group being 51.78+ -5.96% and for example group being 40.69 + -5.43%. P is 0.000 < 0.05, with significant differences.
Animal experiments prove that the treatment effect of the embodiment group is better than that of the embodiment 1 group.
Example 10
The difference from example 4 is that the outer surface of the drug coating is also provided with a hydrophilic coating, the hydrophilic coating is made of maleic acid and has a thickness of 0.02mm.
The embodiment also provides a preparation method of the bracket, which comprises the following steps:
(1) And spraying the maleic acid mixed solution on the outer surface of the drug coating of the stent obtained in the embodiment 4, and performing ultraviolet crosslinking and curing to obtain the stent in the embodiment.
The support force of the stent was tested using a radial support load cell, compressing a 10% force value of 119N.
According to the content of the drug components in the sample, the drug dissolution test instrument is used for carrying out drug dissolution on the sample in a simulated urine solution at 37 ℃, and the HPLC test is used for measuring the quantity of the drug dissolved, so that the maximum quantity of the drug dissolved in the first 7 days is 3 mug/d within 30 days, the total quantity of the drug released in the first 7 days is 41 mug, and the average release degree within 30 days is 62 mug/d.
The ureteral stent with 8F specification is prepared by the method, and animal experiments similar to those of the example 1 are carried out, wherein 2 female New Zealand rabbits are taken, and when the ureteral stent is pulled out after being implanted for one month, the average stenosis rate of an experimental group is 11.06+/-1.06%, the stenosis degree of a control group is 21.8+/-11.8%, and P is 0.019 < 0.05, so that the ureteral stent has obvious difference; after tube drawing for 1 month, the stenosis degree of the experimental group is 5.79+/-3.09%, the stenosis degree of the control group is 22.1+/-19.1%, and P is 0.026 < 0.05, and the significant difference exists.
Dissected 1 month after tube drawing, tissue sections were taken, analyzed using Image-Pro Plus 6.0 software, 8 sites were selected for each section, and the depth of tissue damage was measured. The injury depth of the experimental group is 1291+/-122 mu m, the injury depth of the control group is 1777+/-139 mu m, and P is 0.002 <0.05, and the difference is obvious.
Tissue sections were taken, stained and the percentage of collagen fiber area was measured using Image-pro plus 6.0 analysis software, with the percentage of collagen fiber area of the experimental group being 47.99 + -5.73% and the percentage of collagen fiber area of the control group being 69.96 + -3.88%. P is 0.002 < 0.05, with significant differences.
Animal experiments prove that the treatment effect of the experimental group is better than that of the control group.
The applicant declares that the above is only a specific embodiment of the present invention, but the scope of the present invention is not limited thereto, and it should be apparent to those skilled in the art that any changes or substitutions that are easily conceivable within the technical scope of the present invention disclosed by the present invention fall within the scope of the present invention and the disclosure.
Claims (35)
1. A stent for a urinary system pipeline, which is characterized by comprising a stent matrix and a drug arranged on the stent matrix, wherein the drug is a drug containing glucocorticoid;
the stent comprises a ureteral stent and/or a urethral stent; the hardness of the bracket matrix is 60-99A;
The bracket matrix is made of degradable materials or non-degradable materials;
when the material of the bracket matrix is a non-degradable material, the material of the bracket matrix is silicon rubber, and the bracket comprises 45-90% of silicon rubber, 5-50% of medicine, 0.1-3% of cross-linking agent and 0.1-3% of catalyst by mass percent;
The crosslinking density of the silicone rubber is 1000-8000 g/mol;
When the material of the bracket matrix is degradable material, the bracket comprises 49-95% of degradable material, 4-50% of medicine and 1-20% of water-soluble polymer by mass percent;
The drug carrying amount of the single stent is 30 mug-200 mg;
a single said stent releases 5 μg-2 mg doses per day;
The drug is dispersed in the stent matrix or on the outer surface of the stent matrix, and a drug coating is formed on the outer surface of the stent matrix;
The stent matrix comprises opposite two ends, wherein one end is a leading-in end and used for leading in urine, the other end is a leading-out end and used for leading out urine, and the thickness of a drug coating of the leading-in end is larger than that of a drug coating of the leading-out end;
the particle size of the medicine in the bracket matrix is 800-12500 meshes;
the thickness of the drug coating is 0.01-1 mm;
the outer surface of the stent matrix or the outer surface of the drug coating is also provided with a controlled release layer and a hydrophilic coating, the controlled release layer is arranged on the outer surface of the stent matrix or the outer surface of the drug coating, and the hydrophilic coating is arranged on the outer surface of the controlled release layer;
The thickness of the controlled release layer is 0.01-1 mm;
The material of the controlled release layer is silicon rubber;
The crosslinking density of the silicone rubber is 1000-8000 g/mol;
The thickness of the hydrophilic coating is 0.01-0.5 mm;
the hydrophilic coating is made of any one or a combination of at least two of polyethylene oxide, polyacrylic acid, polyacrylamide, polyvinyl alcohol, polyvinylpyrrolidone, polyisocyanate, sodium hyaluronate and maleic acid.
2. A stent for a urinary system pipeline, which is characterized by comprising a stent matrix and a drug arranged on the stent matrix, wherein the drug is a drug containing glucocorticoid;
The stent comprises a ureteral stent and/or a urethral stent;
the hardness of the bracket matrix is 60-99A;
The bracket matrix is made of degradable materials or non-degradable materials;
when the material of the bracket matrix is a non-degradable material, the material of the bracket matrix is silicon rubber, and the bracket comprises 45-90% of silicon rubber, 5-50% of medicine, 0.1-3% of cross-linking agent and 0.1-3% of catalyst by mass percent;
The crosslinking density of the silicone rubber is 1000-8000 g/mol;
When the material of the bracket matrix is degradable material, the bracket comprises 49-95% of degradable material, 4-50% of medicine and 1-20% of water-soluble polymer by mass percent;
a single said stent releases 5 μg-2 mg doses per day;
the release period of the drug of the single stent is 5-90 days;
The drug is dispersed in the stent matrix or on the outer surface of the stent matrix, and a drug coating is formed on the outer surface of the stent matrix;
The stent matrix comprises opposite two ends, wherein one end is a leading-in end and used for leading in urine, the other end is a leading-out end and used for leading out urine, and the thickness of a drug coating of the leading-in end is larger than that of a drug coating of the leading-out end;
the particle size of the medicine in the bracket matrix is 800-12500 meshes;
the thickness of the drug coating is 0.01-1 mm;
the outer surface of the stent matrix or the outer surface of the drug coating is also provided with a controlled release layer and a hydrophilic coating, the controlled release layer is arranged on the outer surface of the stent matrix or the outer surface of the drug coating, and the hydrophilic coating is arranged on the outer surface of the controlled release layer;
The thickness of the controlled release layer is 0.01-1 mm;
The material of the controlled release layer is silicon rubber;
The crosslinking density of the silicone rubber is 1000-8000 g/mol;
The thickness of the hydrophilic coating is 0.01-0.5 mm;
the hydrophilic coating is made of any one or a combination of at least two of polyethylene oxide, polyacrylic acid, polyacrylamide, polyvinyl alcohol, polyvinylpyrrolidone, polyisocyanate, sodium hyaluronate and maleic acid.
3. A stent for a urinary system pipeline, which is characterized by comprising a stent matrix and a drug arranged on the stent matrix, wherein the drug is a drug containing glucocorticoid;
The stent comprises a ureteral stent and/or a urethral stent;
the hardness of the bracket matrix is 60-99A;
The bracket matrix is made of degradable materials or non-degradable materials;
when the material of the bracket matrix is a non-degradable material, the material of the bracket matrix is silicon rubber, and the bracket comprises 45-90% of silicon rubber, 5-50% of medicine, 0.1-3% of cross-linking agent and 0.1-3% of catalyst by mass percent;
The crosslinking density of the silicone rubber is 1000-8000 g/mol;
When the material of the bracket matrix is degradable material, the bracket comprises 49-95% of degradable material, 4-50% of medicine and 1-20% of water-soluble polymer by mass percent;
The drug of the single stent is not released or the release amount is lower than 1 mg in 1 h-7 days after the stent is implanted;
The drug is dispersed in the stent matrix or on the outer surface of the stent matrix, and a drug coating is formed on the outer surface of the stent matrix;
The stent matrix comprises opposite two ends, wherein one end is a leading-in end and used for leading in urine, the other end is a leading-out end and used for leading out urine, and the thickness of a drug coating of the leading-in end is larger than that of a drug coating of the leading-out end;
the particle size of the medicine in the bracket matrix is 800-12500 meshes;
the thickness of the drug coating is 0.01-1 mm;
the outer surface of the stent matrix or the outer surface of the drug coating is also provided with a controlled release layer and a hydrophilic coating, the controlled release layer is arranged on the outer surface of the stent matrix or the outer surface of the drug coating, and the hydrophilic coating is arranged on the outer surface of the controlled release layer;
The thickness of the controlled release layer is 0.01-1 mm;
The material of the controlled release layer is silicon rubber;
The crosslinking density of the silicone rubber is 1000-8000 g/mol;
The thickness of the hydrophilic coating is 0.01-0.5 mm;
the hydrophilic coating is made of any one or a combination of at least two of polyethylene oxide, polyacrylic acid, polyacrylamide, polyvinyl alcohol, polyvinylpyrrolidone, polyisocyanate, sodium hyaluronate and maleic acid.
4. The stent of any one of claims 1-3, wherein the ureteral stent comprises any one of a single J-tube, a double J-tube, or a straight tube.
5. A stent according to any one of claims 1-3, wherein the urethral stent comprises any one of a single lumen urinary catheter, a double lumen urinary catheter or a triple lumen urinary catheter.
6. A stent according to any one of claims 1 to 3 wherein the urethral stent comprises a balled urethral stent or a ballless urethral stent.
7. A scaffold according to any one of claims 1 to 3, wherein the glucocorticoid-containing drug comprises any one or a combination of at least two of clobetasol, ambetanide, triamcinolone acetonide, tranilast, budesonide, mometasone furoate, dexamethasone, betamethasone, dexamethasone, fluorometholone, hydrocortisone base, rimexolone, dexamethasone, cortolone, prednisolide, triamcinolone, rofluminide, ciclesonide, prednisone, cortisone or triamcinolone.
8. A stent according to any one of claims 1 to 3 wherein the drug further comprises an anti-infective drug comprising any one or a combination of at least two of beta lactams, macrolides, quinolones, aminoglycosides, antiviral or antifungal.
9. A scaffold according to any of claims 1-3, wherein the degradable material comprises any one or a combination of at least two of polylactide, polylactide-glycolide, polyglycolide/polylactic acid copolymer, polyethylene glycol, polycaprolactone, poly-n-ester, polyglycolic acid, polybutylene succinate, caprolactone-lactide copolymer, or polyhydroxyalkanoate.
10. A scaffold according to any of claims 1 to 3, wherein the cross-linking agent comprises hydrogen containing silicone oil and/or hydrogen containing siloxane.
11. A scaffold according to any of claims 1 to 3, wherein the catalyst comprises any one or a combination of at least two of platinum, a platinum complex, a ruthenium complex or a rhodium complex.
12. A scaffold according to any one of claims 1 to 3, wherein when the scaffold matrix is of a non-degradable material, the scaffold is prepared by a process comprising: mixing the silicon rubber, the medicine, the cross-linking agent and the catalyst, and vulcanizing and cross-linking to obtain the bracket.
13. A scaffold according to any of claims 1to 3, wherein the water soluble polymer comprises any one or a combination of at least two of chitosan, gelatin, acacia, hyaluronic acid, cellulose and derivatives thereof, polyacrylamide, polyacrylic acid, polyvinylpyrrolidone, polyvinyl acid, polymaleic anhydride, polyquaternium or starch.
14. A scaffold according to any one of claims 1 to 3, wherein when the scaffold matrix is of a degradable material, the scaffold is prepared by a process comprising: and mixing the degradable material, the drug and the water-soluble polymer under the melting condition, and extruding and molding to obtain the stent.
15. A scaffold according to any one of claims 1 to 3, wherein when the scaffold matrix is of a degradable material, the scaffold is prepared by a process comprising: and mixing the degradable material, the medicine and the water-soluble polymer in a solvent, removing the solvent, and heating and shaping to obtain the stent.
16. A stent according to any one of claims 1 to 3, wherein the drug coating is provided in a coated or encapsulated manner on the outer surface of the stent matrix.
17. The stent of claim 16, wherein the coating comprises any one of dipping, spinning, spraying, or brushing.
18. The stent of claim 17 wherein the coating is by spraying.
19. A scaffold according to any one of claims 1 to 3, wherein when the scaffold matrix is of a degradable material, the scaffold is prepared by a process comprising: dissolving 40-98% by mass of biodegradable polymer material and 2-60% by mass of drug in a solvent to obtain a mixed solution; and coating the mixed solution on the outer surface of the stent matrix to form the stent.
20. The stent of claim 19 wherein the mixed liquor is atomized into particles using an atomizing device and then coated onto the outer surface of the stent matrix.
21. The stent of claim 20 wherein the microparticles are coated on the outer surface of the stent matrix in a wet or semi-dry state.
22. The stent of claim 20, wherein the microparticles have a particle size of 50 nm-500 μm.
23. The stent of claim 22, wherein the microparticles have a particle size of 500 nm-200 μm.
24. The scaffold of claim 19, wherein the biodegradable polymeric material comprises any one or a combination of at least two of gelatin, starch, hyaluronic acid, cellulose, chitosan, polylactic acid, polyglycolic acid, polycaprolactone, polylactide-caprolactone, or polylactic acid-caprolactone.
25. The stent of claim 19, wherein the mixed solution further comprises a polymer with a long degradation period or non-degradable polymer, the mass percentage of the polymer with a long degradation period or non-degradable polymer is 0.5-10%, the mass percentage of the biodegradable polymer material is 40-95%, and the mass percentage of the drug is 2-50%.
26. The stent of claim 25, wherein the long-period polymer comprises any one or a combination of at least two of polylactic acid, polyglycolic acid, a blend comprising polyglycolic acid, a polyglycolic acid copolymer, or polyvinyl alcohol.
27. The stent of claim 25, wherein the non-degradable polymer comprises any one or a combination of at least two of polyvinylpyrrolidone, parylene, silicone oil, silicone gel, silicone rubber, or polyethylene glycol.
28. The stent of claim 19, wherein the method of preparing the stent further comprises pre-treating the outer surface of the stent matrix prior to the coating.
29. The stent of claim 28, wherein the treatment comprises any one or a combination of at least two of plasma treatment, swelling treatment, grit blasting treatment, sanding treatment, dermatoglyph treatment, electrostatic treatment, or wetting treatment.
30. A scaffold according to any one of claims 1 to 3, wherein when the scaffold matrix is of a non-degradable material, the scaffold is prepared by a process comprising: mixing 24-80% by mass of silicon rubber, 18-70% by mass of micronized drug, 0.1-3% by mass of cross-linking agent and 0.1-3% by mass of catalyst to obtain a mixed material, and then solidifying and combining the mixed material and a bracket matrix to obtain the bracket.
31. A scaffold according to any one of claims 1 to 3, wherein when the scaffold matrix is of a non-degradable material, the scaffold is prepared by a process comprising: mixing 24-80% by mass of silicon rubber, 18-70% by mass of micronized drug, 0.1-3% by mass of cross-linking agent and 0.1-3% by mass of catalyst to obtain a mixed material, curing the mixed material to obtain a medicinal membrane, and combining the medicinal membrane and a bracket matrix together by a secondary curing or gluing mode to obtain the bracket.
32. The stent of claim 31, wherein the micronized drug has a particle size of 800-12500 mesh.
33. The stent of claim 31, wherein the cross-linking agent comprises hydrogen containing silicone oil and/or hydrogen containing siloxane.
34. The stent of claim 31, wherein the catalyst comprises any one or a combination of at least two of platinum, a platinum complex, a ruthenium complex, or a rhodium complex.
35. Use of a scaffold according to any of claims 1-34 in the manufacture of a drug delivery system.
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| WO2017054433A1 (en) * | 2015-09-30 | 2017-04-06 | 圆容生物医药无锡有限公司 | Elastic modulus adjustable polyurethane composition, scaffold composite and preparation method thereof |
| CN105251059A (en) * | 2015-11-16 | 2016-01-20 | 北京航空航天大学 | Degradable repair stent used for urethra and ureter and preparation methods |
| CN106473847A (en) * | 2016-11-22 | 2017-03-08 | 曹庆杰 | The dilatancy local urinary tract intracavity stent system of degradable |
| CN109925537A (en) * | 2018-04-19 | 2019-06-25 | 易浦润（上海）生物技术有限公司 | A kind of elastic membrane, preparation method and application |
| CN109288832A (en) * | 2018-10-31 | 2019-02-01 | 浦易（上海）生物技术有限公司 | A kind of medication coat composition and its preparation method and application for ureter bracket |
| CN110882422A (en) * | 2019-12-31 | 2020-03-17 | 浦易（上海）生物技术有限公司 | Airway stent and application thereof |
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| CN111714260A (en) | 2020-09-29 |
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