WO2017054433A1

WO2017054433A1 - Elastic modulus adjustable polyurethane composition, scaffold composite and preparation method thereof

Info

Publication number: WO2017054433A1
Application number: PCT/CN2016/078430
Authority: WO
Inventors: 张文芳; 薛波新
Original assignee: 圆容生物医药无锡有限公司
Priority date: 2015-09-30
Filing date: 2016-04-05
Publication date: 2017-04-06

Abstract

Disclosed are an elastic modulus adjustable polyurethane composition, a scaffold composite and a preparation method thereof. The properties of the PU, such as the PU's elasticity, modulus, strength, elastic modulus, abrasion resistance, lubricity, hydrophilic-hydrophobic property and so on, can be varied in a large range by adjusting the proportions of the composition and the molecular weight of each component, and the PU can be used to prepare a variety of medical products for interventional implantation into the human body needing different degrees of softness and hardness and being biocompatible, in particular comprising an implantable device, an implantable artificial organ, a contact artificial organ, a scaffold, an organ auxiliary device, etc.

Description

Polyurethane composition with adjustable elastic modulus, stent composite and preparation method thereof

Technical field

The present invention relates to a composition having a polyurethane (PU) having an elastic modulus adjustable. By adjusting the ratio of the compositions A and B and the molecular weight of each component, the properties of the PU can be varied over a wide range, such as PU. Elasticity, modulus, strength, modulus of elasticity, wear resistance, lubricity, hydrophobicity, etc. are applied to biocompatible compatible implants for various medical products, which belong to the field of biodegradable biomaterials. .

Background of the invention

Polyurethane (PU) is a generic term for polyurethanes and is a general term for macromolecular compounds containing a carbamate (-NHC00-) group in the main chain. It is formed by the addition of an organic diisocyanate or a polyisocyanate with a dihydroxy or polyhydroxy compound. As shown in the typical PU chemical structure, the polymer backbone is composed of a soft segment (soft segment) having a glass transition temperature lower than room temperature and a rigid segment (hard segment) having a glass transition temperature higher than room temperature. Generally, it is synthesized by using a polyether or a polyester diol to form a soft segment of the polymer. The segment has a low glass transition temperature and a low polarity, and constitutes a continuous phase of the material, imparting PU elasticity and controlling the PU. Low temperature resistance, solvent resistance and weather resistance; and the segment formed by the reaction of diisocyanate and chain extender is a hard segment, and the hard segment chain generally formed has a high glass transition temperature, strong polarity, and -CO present in the hard segment. The -NH-functional group forms a large number of hydrogen bonds between the molecular chains, has strong interaction force, exists in a crystalline state, and controls properties such as PU strength and heat resistance. The difference in polarity between the hard and soft segments of the PU and the crystallization of the hard segment itself lead to their thermodynamic incompatibility and the tendency to spontaneously separate, so the hard segments tend to clump together to form microdomains, dispersed in soft In the continuous phase formed by the segments, a microphase separation structure is formed. The advantage of this material is that it can be designed in a wide range by designing different soft and hard segments of structure, length and distribution, relative proportions, and changing the relative molecular mass. Change the properties of PU, such as PU elasticity, modulus, strength, modulus of elasticity, abrasion resistance, lubricity, hydrophilicity, biocompatibility, and biostability.

Medical PU has good elasticity, tensile strength and elongation at break, good wear resistance and flexural resistance, easy molding, large controllable range, good tissue compatibility and blood compatibility. Excellent performance, such as sex, is widely used in medical materials. Biodegradable polymers provide mechanical support when used in vivo and serve as a platform for biological tissue regeneration or repair. It degrades after a period of time, depending on biodegradability. The type of polymer and the tissue environment. Thus, biodegradable polymers are particularly useful in orthopedic applications as well as in tissue engineering products and therapies. Therefore, it is desirable for researchers in the field to prepare polyurethanes which are suitable for use in different tissue environments and which have an adjustable degradation time and can be tailored according to the properties of the products.

The degradable stent comprises a polymer material scaffold and a degradable metal scaffold, wherein the degradable polymer material comprises: PLLA, PLA, PGA, PDO and PCL, wherein PLLA has good rigidity, flexibility, stability and heat resistance. It has been successfully applied to the coating materials of metal stents and self-prepared into stents; the degradable metal stent materials are magnesium alloys and iron alloy materials, among which magnesium alloy materials have gradually become the mainstream of degradable stent research with its excellent processing properties. Due to the alkaline environment and hydrogen generated by the degradation process of magnesium alloy materials, a large number of uses are limited; since the tissues and organs of different parts such as blood vessels, trachea and urethra have different performance requirements for tissue engineering biomaterials, a series of different mechanical properties are obtained. Biomaterials such as degradation properties and processability are essential. Due to the mechanical properties of a single material and the acidity and alkali environment caused by degradation, the problem of aseptic inflammation in the body is solved. For this reason, a suitable composite polymer material is sought. Better stent design process, composite stent has better clinical application value.

After years of research, we have successfully completed the mass production of degradable polycaprolactone polyurethane materials, making it possible to use degradable polycaprolactone polyurethanes for product development. many Literature studies have reported that polycaprolactone polyurethane materials have good mechanical properties, biocompatibility, blood compatibility and easy processing. They are used in drug delivery vehicles, medical surgical materials, tissue engineering stents, etc. It is a very promising biodegradable medical material and is an excellent composite scaffold component.

Magnesium is an essential element of human metabolism. It is second only to potassium, sodium and calcium in the human body. It accounts for about half of all magnesium in the body. Studies have shown that magnesium is a cofactor for many enzymes and has a stable DNA and RNA structure; in vivo, magnesium is maintained between 0.7 and 1.05 mmol/L through the kidneys and intestines; magnesium can stimulate new bone growth with good histocompatibility . The main disadvantage of magnesium is its low corrosion resistance. In the physiological environment of pH (7.4-7.6), magnesium has a strong reduction effect, which loses the mechanical integrity before the tissue is fully healed, and produces hydrogen which cannot be absorbed by the body in time. The early application of magnesium-based materials in the human body to produce a large amount of gas causes magnesium to be unapplied to the human body. Therefore, it is very realistic to prepare a magnesium-based alloy that can be controlled to degrade, so that the hydrogen generated during the degradation of magnesium is metabolized by the tissue fluid. Significance, a variety of magnesium alloy materials with different degradation and processing properties have also become a research hotspot.

Degradable stents can be used in a variety of vessels in the body, including natural body passages or body lumens, but also artificial body openings and body lumens, such as bypass or ileostomy. Examples include: coronary vascular stents, intracranial vascular stents, peripheral vascular stents, splenic artery stents, intraoperative stents, heart valve stents, biliary stents, esophageal stents, intestinal stents, pancreatic duct stents, urethral stents, and tracheal stents. The ureteral stent is the most mature in the research and application of clinical vascular stents. It has been reported in the literature that polylactic acid is used as a drug-coated vascular stent. It is also useful to prepare vascular stents by using PLLA materials through 3D printing or engraving. The ureteral stent and the urethral stent with controlled degradation time were prepared by PLGA. The common intraurethral stents were spiral stent, polyurethane stent, bioabsorbable stent, metal mesh stent and heat sensitive stent. Due to the following five conditions after metal stent implantation: a. postoperative blood clot obstruction; b. original chronic urine Patients with retention, long-term catheterization before surgery, bladder detrusor fibrosis; c. prostatic urethra proximal is not covered by stent; d. granulation tissue or epithelial hyperplasia, causing stent stenosis; e. prostate tissue continues to increase Large, more than the ends of the stent, plugged stents, etc., bioresorbable stent: a degradable stent made of pressurized polylactic acid, tissue reaction is light, can be completely absorbed within 12-14 months, in the urethra The short-term effect of stenting for benign prostatic hyperplasia is better, but its final effect remains to be seen, but it is still an effective method for patients with benign prostatic hyperplasia who are not suitable for transurethral resection of the prostate.

The urethral stent is divided into a permanent stent and a temporary stent according to the patient's condition. The temporary stent supports the urinary tract rather than the urethral wall. It is divided into a metal stent and an absorbable biodegradable stent. It has been developed in recent years. A temporary stent consisting of a polymeric glycolic acid polymer (PGA) or a lactic acid polymer (PLA) with good histocompatibility, low inflammatory response, low infection rate, no crystallization on the surface, no need to remove or Replacement and other features.

A large number of clinical reports indicate that the short-term efficacy of stent therapy is definite, but its therapeutic effect has declined over time, and there are still some problems to be solved:

(1) Prostatic hyperplasia is a benign progressive disease that increases with age and may extend beyond the range supported by the stent as it continues to increase;

(2) There are different degrees of granulation tissue and epithelial hyperplasia in the frame after stent implantation;

(3) How to better grasp the indications and contraindications, select the appropriate size of the stent and put it in the right position.

It has been found through research that the double-balloon degradable urethral magnesium alloy peritoneal stent designed by the invention not only can well place the stent in a suitable position, but also can achieve a good supporting effect, and the results of animal experiments in vivo show that Due to the dissolution of the coating, the tissue has no adverse reactions such as granuloma, and has very practical clinical application value.

The research on the preparation of scaffolds and coated stents by using degradable polycaprolactone polyurethane has not been reported, and related products have not been listed.

Summary of the invention

The present application adjusts the softness and hardness of the product by adjusting the ratio of the two structures of polyurethane, and can be used for preparing medical sanitary materials and dressings, such as various soft tissue brackets, suture materials, and adhesives; The acid triisocyanate reacts to form a network cross-linked structure. The test results show that the elastic modulus of the resulting material can be higher than 500 MPa and the elongation at break is greater than 50%, which can be used to prepare polyurethane products with higher elastic modulus, such as blood vessels. Stents, fracture fixation implants and other orthopedic applications such as spinal cages have a very broad clinical value.

The present invention provides a polyurethane composition having an adjustable elastic modulus, which is composed of polymers I and II having the following formulas A and B, respectively, and the weight ratio of the polymer I to the polymer II is in the range of I. :II=(0.01-1):(1-0.1),

Wherein, by changing the weight ratio of the polymer I and the polymer II and their respective molecular weights, the elastic modulus of the polyurethane composition can be adjusted in the range of 50 MPa to 1000 MPa, and the range can be adjusted within the range of 10% to 1000%. The elongation at break of the polyurethane composition,

Molecular formula A:

a is an integer in the range of 5-50, and b is an integer in the range of 5-50.

Molecular formula B:

x is an integer in the range of 5 to 50, and y is an integer in the range of 5 to 50.

In one embodiment, wherein the weight ratio of the polymer I to the polymer II is I: II = (0.01 - 0.5): 1, wherein a in the formula A is an integer in the range of 10-20, and b is 10- An integer in the range of 25, where x is an integer in the range of 10-20, y is an integer in the range of 10 to 25, and the elastic modulus can be adjusted in the range of 100 MPa to 500 MPa, the elongation at break The adjustable range is from 100% to 700%.

The present invention also provides a polyurethane composition comprising a polymer III having the formula C, or a polymer IV having the formula D,

Molecular formula C:

n is an integer in the range 1-25, and R is -CH ₂ - or -COOC ₄ H ₉ -,

Formula D:

R ¹ is

h is an integer in the range 1-20, and k is an integer in the range 1-25.

In one embodiment, the polyurethane composition has a modulus of elasticity greater than 400 MPa and an elongation at break in the range of 30% to 300%.

The present invention further provides a method of preparing a polyurethane composition comprising further reacting a polyurethane with lysine triisocyanate after completion of its synthesis reaction to form a network-like crosslinked structure, the modulus of elasticity of the polyurethane composition Above 400 MPa, the elongation at break is in the range of 30% to 300%.

In one embodiment, the synthesis reaction of the polyurethane is selected from the following methods:

(1) using ε-caprolactone in different ratios (ranging from 6:1 to 1:1) and PEG-synthesized linear polycaprolactone diol having a molecular weight in the range of from 200 to 2000, and the product thereof and diisocyanate Reaction, using a glycol as a chain extender, stannous octoate (0.01-0.1 wt% of total mass) as a catalyst, the reaction to obtain the polyurethane;

(2) using a polylactic acid having a molecular weight in the range of 200-2000, such as PLA, PGA, PLGA, and a glycol to synthesize a linear lactic acid-glycolic acid copolyol, reacting the product with a different diisocyanate, stannous octoate (total amount 0.01-0.1 wt%) as a catalyst, the reaction gives the polyurethane; or

(3) using a different polymer diol as a soft chain, reacting it with LDI and BDO, stannous octoate (0.01-0.1 wt% of the total amount) as a catalyst, and reacting to obtain the polyurethane,

Wherein the diisocyanate is selected from the group consisting of: 1,6-hexamethylene diisocyanate, isophorone diisocyanate, lysine methyl ester diisocyanate, cis-cyclohexane diisocyanate, anti Formula - cyclohexane diisocyanate, 1,4-butane diisocyanate, 1,2-ethane diisocyanate, 1,3-propane diisocyanate, 4,4'-methylene-bis(cyclohexyl isocyanate), One or two of 2,4,4-trimethyl 1,6-hexane diisocyanate;

Wherein the chain extender glycol is selected from the group consisting of ethylene glycol, diethylene glycol, tetraethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,6-hexanediol, 1,7-g One or two of a diol, 1,8-octanediol, 1,9-nonanediol, and 1,10-decanediol;

Wherein the polymer diol comprises poly-(4-hydroxybutyrate) diol (P4HB diol), poly-(3-hydroxybutyrate) diol (P3HB diol), polypropylene glycol and any copolymerization thereof , including PLGA diol, P(LA/CL) diol and P(3HB/4HB) diol, polyether polyol such as poly(tetrahydrofuran), polycarbonate polyol such as poly(hexamethylene carbonate) One or two of the alcohols.

In one embodiment, wherein the reaction of the polyurethane with lysine triisocyanate is selected from one of the following:

(1) The polyurethane obtained in the above method and L-lysine triisocyanate are reacted in a twin-screw extruder having a moisture content of less than 10 ppm for 20 minutes, and stirred and polymerized to obtain a high modulus of elasticity. Polyurethane composition;

(2) The polyurethane obtained in the above method is poured into a kneader or a kneader in an environment having a moisture content of less than 10 ppm, directly added with L-lysine triisocyanate, and stirred at room temperature for half an hour to obtain high a modulus of elasticity of the polyurethane composition;

(3) The polyurethane obtained in the above method is added to an anhydrous organic solvent (tetrahydrofuran, dichloromethane or chloroform) to form a viscous solution, and L-lysine is directly added in an environment having a moisture content of less than 10 ppm. a triisocyanate, the reaction system is stirred or shaken, and the organic solvent is vacuum-dried after half an hour of normal temperature reaction to obtain the polyurethane composition having a high modulus of elasticity; or

(4) The polyurethane obtained in the above method is directly added to L-lysine triisocyanate in an environment having a moisture content of less than 10 ppm, and the reaction system is stirred or shaken and mixed at room temperature. After half an hour of reaction, the organic solvent was vacuum dried to obtain the polyurethane composition having a high modulus of elasticity.

The present invention also provides a polyurethane composition prepared by the above method.

The invention also provides the use of the polyurethane composition in the preparation of a medical implant material selected from the group consisting of an implant device, an implantable artificial organ, a contact artificial organ, a stent, an interventional catheter, and an organ. assisting equipments.

The present invention further provides a degradable stent composite comprising a polyurethane composition and a degradable metal material, the weight ratio of the polyurethane composition to the degradable metal material being in the range of 0.1-99%:1%-99.9% Inside.

The degradable stent composite may include a stent formed of the degradable metal material, the coating formed of the polyurethane composition, and preferably the polyurethane composition and the The weight ratio of the degraded metal material is in the range of from 5 to 90%: 10% to 95%.

The polyurethane can be a polyurethane composition.

Preferably, the polyurethane is selected from the group consisting of polylactic acid type polyurethane, polycaprolactone type polyurethane, and one or both of two degradable polyurethane derivatives (silicone, polyamino acid modification, polysaccharide modification), preferably Poly(ε-caprolactone) diol (PCL) is a soft segment, polyurethane with L-lysine diisocyanate (LDI) and chain extender 1,4-butanediol (BDO) as hard segment (PU) )material.

In one embodiment, the degradable stent composite further comprises other polymeric materials selected from the group consisting of polylactic acid, polycaprolactone, polydioxanone, and copolymers thereof (PPDO, PLA-PDO), polydioxanone (PPDO), polytrimethylene carbonate, polylactic acid-trimethylene carbonate copolymer, polycaprolactone-trimethylene carbonate copolymer, polyhydroxyl At least one of acetic acid and polylactic acid-glycolic acid copolymer, the biodegradable polymer material has a viscosity average molecular weight of 500 to 1,000,000.

Preferably, in the degradable stent composite, the metal material comprises iron having a purity greater than 99.0%, a magnesium-iron alloy having a purity greater than 99.0% magnesium, and a weight percentage of 1:0.01-10, One or two combinations of a magnesium-zinc alloy having a weight percentage of 1:0.01-1, a magnesium-calcium alloy having a weight percentage of 1:0.01-1, and a weight ratio of 1:0.01-0.1 magnesium-aluminum alloy, preferably Magnesium-iron alloy (weight ratio is preferably 1:0.01-0.1), magnesium-zinc alloy (weight ratio is preferably 1:0.01-0.1), for example: Mg-Nd-Zn-Zr, Mg-Zn-Mn, Mg-Zn-Mn- Se-Cu alloy, Zn content of 3.5 wt%, Mn content of 0.5-1.0 wt%, Se content of 0.4-1.0 wt%, Cu content of 0.2-0.5 wt%, Mg balance; magnesium-calcium alloy (% by weight Preferably, it is 1:0.01-0.1), for example: Mg-Zn-Ca-Fe, magnesium-aluminum alloy (weight ratio is preferably 1:0.01-0.1, for example: aluminum (Al): 2.0 to 3.0 wt.%, zinc (Zn) ): 0.5 to 1.0 wt.%, manganese (Mn), and Mg balance.

The present invention also provides a method of preparing the above-described degradable stent composite, comprising the steps of:

(1) preparing, engraving, etching or cutting the degradable metal material into a desired pattern;

(2) Dissolving the polyurethane composition of the present invention in an organic solvent (selected from decane, tetrahydrofuran, isoamyl acetate, hexane, dichloromethane, chloroform, cyclohexanone, dimethylformamide, and heptane) In one or both of them, a coating material is prepared (material concentration: 5-50%);

(3) The coating material prepared in (2) is repeatedly dip-coated or uniformly sprayed on the surface of the metal stent prepared in (1) to form a composite stent with a coating having a thickness in the range of 0.001 to 1 mm. Internally, it is preferably 0.01 to 0.5 mm.

In one embodiment, the method of degradable stent composites can include the following steps:

(1) The degradable metal material is prepared, engraved, etched or cut into a desired pattern or strip shape, and the diameter of the pattern is 0.01-3 mm;

(2) The polyurethane composition according to claim 1-4 or 8 and polylactic acid are mixed and dissolved in an organic solvent in a weight ratio of 1:0.1 to 10, and are formed into a film having a thickness of 0.01- 3mm, preferably 0.1-1mm;

(3) The film prepared by (2) is wound on the surface of the metal stent prepared in (1), and is prepared. Covered stent

(4) The coated stent prepared in (3) is polished to a degradable stent composite by dip coating or spraying a hydrophilic coating.

In another embodiment, the method of degradable scaffold complex comprises one of the following methods:

(1) Mix magnesium alloy powder (powder diameter range: 10nm-1mm) with degradable medical polyurethane material solution (organic solvent dissolved and configured into a viscous solution of 20-90% concentration), and print through 3D printer A stent having a diameter and a wall thickness is required, and the dry organic solvent is evaporated by hot air to obtain the degradable stent composite;

(2) The 3D printer is provided with two feeding devices, one feeding device is added with magnesium alloy powder (the powder diameter ranges from 10 nm to 1 mm), and the other feeding device is added with a degradable medical polyurethane material solution (configured with organic solvent The concentration is 20-90%), the two substances are mixed in proportion during the feeding process, and the stent of the set size and shape is printed, and the dry organic solvent is evaporated by hot air to obtain the degradable stent composite;

(3) The 3D printer is equipped with two feeding devices. Magnesium alloy powder (powder diameter range: 10nm-1mm) is added to one feeding device, and degradable medical polyurethane material and polylactic acid are added to the other feeding device in proportion (1:0.1). -10) The mixture is dissolved in an organic solvent and is disposed in an organic solvent to a concentration of 20-90%. The two materials are mixed in proportion during the feeding process to print a stent of a set size and shape, and the hot air is dried and evaporated to dry organic a solvent to obtain the degradable stent complex;

(4) The 3D printer is equipped with two feeding devices. Magnesium alloy powder is added to one feeding device (the powder diameter ranges from 10 nm to 1 mm). The high temperature melting prints out the bracket as needed, and the passivation treatment is used for standby; another feeding device can be added. The degraded medical polyurethane material and the polylactic acid are mixed and dissolved in an organic solvent in a ratio (1:0.1-10), and are disposed in a concentration of 20-90% with an organic solvent, and the coating film is printed on the stent, and the hot air is dried and evaporated. Organic solvent, the resulting Degradable stent complex.

In one embodiment, the degradable stent composite of the present invention or the degradable stent composite prepared by the method of the present invention has a structure, composition and shape suitable for blood vessels, veins, esophagus, biliary tract, trachea, bronchi, small intestine , large intestine, urethra, ureter or other segments close to the tubular passage, for example, as a vascular stent, tracheal stent, bronchial stent, urethral stent, esophageal stent, biliary stent, ureteral stent (double J tube), ureteral stricture stent, A stent for the small intestine, a stent for the large intestine, a laryngeal implant, a bypass catheter, or an ileostomy.

The degradable stent composite of the present invention may further comprise a contrast agent selected from the group consisting of zirconium dioxide, barium sulfate and iodine.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings used in the description of the embodiments will be briefly described below. It is obvious that the drawings in the following description are only some embodiments of the present invention. Other drawings can also be obtained from those skilled in the art based on these drawings without paying any creative effort.

Figure 1 is a schematic view of a magnesium alloy stent;

Figure 2 is a schematic view of a coated stent;

Figure 3 is a schematic view of a stent graft;

Figure 4 is a schematic view of the urethral stent placed on the double balloon;

Figure 5 is a schematic view of the urethral stent;

Figure 6 is a plan view showing the deployment of the ureteral stent.

DESCRIPTION OF REFERENCE NUMERALS: 1. Positioning balloon inflation catheter connector, 2. Positioning balloon inflation catheter, 3. Balloon inflation catheter coating tube, 4. Column balloon, 5. Spherical positioning balloon, 6. Column balloon Inflatable catheter connector, 7, cylindrical balloon inflation catheter, 8, degradable urethral stent.

Mode for carrying out the invention

The present invention will be clearly and completely described in the following embodiments of the present invention. It is obvious that the described embodiments are a part of the embodiments of the present invention, and not all of them. Embodiments; it should be noted that the embodiments in the present application and the features in the embodiments may be combined with each other without conflict. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative efforts are within the scope of the present invention.

In order to obtain a biomaterial suitable for in vivo use, the present invention discloses an elastic modulus tunable polyurethane composition and its use in a medical implant material, the polyurethane composition having an elastic modulus adjustable at 50-1000 MPa, fracture The composition has an elongation of 10% to 1000% and is composed of the following formulas A and B, and the composition has a weight percentage of A:B = 0.01 - 1: 1-0.1.

Molecular formula A:

The range of a is 5-50, and the range of b is 5-50.

Molecular formula B:

x ranges from 5 to 50, and y ranges from 5 to 50.

Preferably, the composition formulas A and B are by weight in the range of A:B = 0.01 to 0.5:1.

Molecular formula A:

Preferably, a ranges from 10 to 20 and b ranges from 10 to 25.

Molecular formula B:

Preferably, x ranges from 10 to 20 and y ranges from 10 to 25.

The obtained product has an elastic modulus of 100-500 MPa and an elongation at break of 100% to 700%.

The polymer prepared by the invention can increase lysine triisocyanate in the late stage of the reaction to form an ultrahigh elastic polyurethane polymer having a modulus of elasticity of 400 MPa and an elongation at break of 30% to 300%, and the following molecular formula is formed:

Molecular formula C:

n ranges from 1 to 25, and R is -CH ₂ - or -COOC ₄ H ₉ -.

Formula D:

R ¹ is

The range of h is 1-20, and the range of k is 1-25.

A highly elastic modulus degradable polyurethane is prepared by using lysine triisocyanate, and a final product obtained by the disclosed polyurethane synthesis reaction is added with lysine triisocyanate to form a network crosslinked structure to form an ultrahigh elastic polyurethane. The composition specifically includes the following polyurethane synthesis reaction:

(1) Synthesizing linear polycaprolactone diols using different ratios of ε-caprolactone and PEG of different molecular weights (molecular weight 200-2000), reacting the products with different diisocyanates, using different diols as A chain extender, stannous octoate (0.01-0.1 wt% of the total amount) is used as a catalyst to obtain a final product.

(2) using a specific molecular weight (molecular weight range 200-2000) polymer such as PLA, PGA, PLGA or a monomer of LA or GA and different diols to synthesize linear lactic acid-glycolic acid copolyol, the products are different The diisocyanate is reacted, and stannous octoate (0.01-0.1 wt% of the total amount) is used as a catalyst to obtain a final product.

(3) using different polymer diols as soft chains, reacting them with LDI and BDO, stannous octoate (0.01-0.1 wt% of the total amount) as a catalyst, and the reaction is finally produced. Things.

Wherein the diisocyanate is selected from the group consisting of: 1,6-hexamethylene diisocyanate, isophorone diisocyanate, lysine methyl ester diisocyanate, cis-cyclohexane diisocyanate, trans-cyclohexane diisocyanate, 1,4-butane diisocyanate, 1,2-ethane diisocyanate, 1,3-propane diisocyanate, 4,4'-methylene-bis(cyclohexyl isocyanate), 2,4,4-trimethyl One or two of 1,6-hexane diisocyanate;

Wherein the chain extender glycol is selected from the group consisting of ethylene glycol, diethylene glycol, tetraethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,6-hexanediol, 1,7-heptanediol One or two of 1,8-octanediol, 1,9-nonanediol, and 1,10-decanediol.

Wherein the polymer diol is selected from the group consisting of poly-(4-hydroxybutyrate) diol (P4HB diol), poly-(3-hydroxybutyrate) diol (P3HB diol), polypropylene glycol, and any copolymer thereof Including PLGA diol, P(LA/CL) diol, and P(3HB/4HB) diol. One or both of a polyether polyol such as poly(tetrahydrofuran), a polycarbonate polyol such as poly(hexamethylene carbonate) glycol.

L-lysine triisocyanate is added to the obtained product of the above method to carry out capping to prepare a polyurethane having a high elastic modulus, and the preparation method is as follows:

One of the methods: the final product obtained by the method according to claim 4 is reacted in a twin-screw extruder extruder for 20 minutes in an environment having a moisture content of less than 10 ppm, and the mixture is stirred and extruded to obtain a polyurethane having a high elastic modulus. fiber;

Method 2: The final product obtained by the method according to claim 4 is poured into a kneader or a kneader in an environment having a moisture content of less than 10 ppm, and directly added with L-lysine triisocyanate, and stirred at room temperature for half an hour. That is;

Method 3: After the reaction is completed according to the method of claim 4, an anhydrous organic solvent is added to prepare a viscous solution, and L-lysine triisocyanate is directly added in an environment having a moisture content of less than 10 ppm, and the reaction system is stirred or shaken. Mixed, normal temperature reaction after half an hour An organic solvent is selected by vacuum extraction, wherein the organic solvent is selected from the group consisting of toluene, p-xylene, decane, isoamyl acetate, hexane, benzene, dichloromethane, chloroform, 1, 4-cyclohexanone, ketone, One or two of dimethylformamide, heptane, dimethylcarbamate, tetrahydrofuran, petroleum ether, dimethyl sulfoxide, ethylene terephthalate, preferably tetrahydrofuran, dichloromethane, trichloro One or a combination of methane and 1,4 cyclohexanone;

Method 4: After the reaction is completed according to the method of claim 4, L-lysine triisocyanate is directly added in an environment having a moisture content of less than 10 ppm, and the reaction system is stirred or shaken, and the organic solvent is vacuum-dried after half an hour of normal temperature reaction. That is.

The elastic modulus adjustable polyurethane composition of the invention and the application thereof in medical implant materials, the specific applications include: implanted devices, implantable artificial organs, contact artificial organs, stents, interventional catheters, and organ assist devices, Specifically, it includes bone plate, bone nail, bone needle, bone rod, spinal internal fixation equipment, ligation wire, polypigment, bone wax, bone repair material, brain aneurysm clip, silver clip, vascular anastomosis clip (device), plastic material , cardiac or tissue repair materials, intraocular filling materials, birth control rings, nerve patches; implantable artificial organs include: artificial esophagus, artificial blood vessels, artificial vertebral bodies, artificial joints, artificial urethra, artificial valves, artificial kidneys, meaning Milk, artificial skull, artificial jaw, artificial heart, artificial tendon, cochlear implant, artificial anal closure; touch artificial organs include: artificial throat, artificial skin, artificial cornea; stent blood vessels specifically include: stent, prostate stent, biliary tract Stent, esophageal stent and ureteral stent; organ assisting device specifically includes: implantable hearing aid, artificial liver support device; Ring and blood processing equipment: pump, blood storage blood filter, micro-plug filter, blood filter, water filter (ultrafiltration), bubble remover, pump tube, blood circuit; hemodialysis device, hemodiafiltration device, Hemofiltration device, blood purification line, dialysis blood circuit, blood plastic pump tube, arteriovenous puncturing device, multi-layer flat dialyzer, hollow fiber dialyzer, hollow fiber filter, adsorber, plasma separator, blood detoxification (perfusion perfusion), blood purification extracorporeal circulation blood (pipe), intraoperative autologous blood returning machine; interventional equipment: intravascular Catheter: intravascular contrast catheter, balloon dilatation catheter, central venous catheter, trocar peripheral catheter, micro floating catheter, arteriovenous pressure catheter; guide wire and sheath, including: hard wire, soft wire, kidney Arterial guide wire, micro-guide wire, push guide wire, super-sliding guide wire, arterial sheath, venous vascular sheath, micro-puncture vascular sheath; embolization equipment, specifically including: filter, spring embolus, embolization microsphere, platinum micro-emboli, Occluder, IV (IV), central vein (CV), vascular access, lung heat buffer balloon, angiography, angioplasty balloon, urology, special catheter, pacemaker wire insulation, artificial blood vessel, heart Valve, cardiac assist device, left ventricular assist device, intra-aortic balloon counterpulsation, total artificial heart, artificial kidney, hemodialysis, artificial lung, blood oxygen exchanger, blood perfusion, blood filtration, blood washing, artificial pancreas, breast Fillings, wound dressings, facial reconstruction materials, surgical adhesives, drug controlled release, artificial tubing, for enhancing the flow and excretion of body fluids, birth control pills, penile prostheses, etc. Test bed need, the developer may be added during the manufacturing process: zirconium dioxide, non-ionic contrast agent and a pure barium sulfate powder of one.

The route of polyurethane synthesis and its commonly used cyanate ester scheme are as follows:

method one:

Using a specific ratio of ε-caprolactone and PEG to synthesize linear polycaprolactone diol, react it with LDI and BDO, stannous octoate (0.01-0.1wt% of the total amount) as a catalyst, and add different PEG increases its soft segment ratio to give the final product, such as Examples 1-12.

Method Two:

Different ratios of ε-caprolactone and PEG of different molecular weights are used to synthesize linear polycaprolactone diol, and the product is reacted with different diisocyanates, using different diols as chain extenders, stannous octoate (total A quantity of 0.01 to 0.1% by weight) is used as a catalyst. The reaction gives the final product, such as Examples 13-33.

Method three:

A specific ratio of ε-caprolactone and PEG is used to synthesize linear polycaprolactone diol, which is reacted with LDI and BDO, stannous octoate (0.01-0.1 wt% of the total amount) as a catalyst, and finally L- Lysine triisocyanate acts as a blocking agent to give the final product, such as Examples 34-41.

Method four:

Different ε-caprolactone and PEG are used to synthesize linear polycaprolactone diol as a soft chain, which is reacted with IPDI, HDI, LDI and various diols, stannous octoate (0.01-0.1 total amount) The wt%) as a catalyst, the reaction gives the final product, such as Examples 42-51.

Method five:

The linear lactic acid-glycolic acid copolyol is synthesized using a specific molecular weight (molecular weight range 200-2000) of PLA, PGA, PLGA and different diols, and the product is reacted with different diisocyanates, stannous octoate (total 0.01 -0.1 wt%) as a catalyst, the reaction gives the final product, such as Examples 52-56.

The invention also discloses a degradable stent composition, the stent supporting material is a degradable metal material, and the coating or coating material is a degradable medical polyurethane material, and the weight percentage of the two is 1-99%: 1%-99 More preferably, the weight percentage is 5-90%: 10%-95%, wherein the degradable medical polyurethane material is selected from the group consisting of polylactic acid type polyurethane, polycaprolactone type polyurethane, and two degradable polyurethane derivatives (silicone, poly One or two of amino acid modification, polysaccharide modification, wherein the polyisocyanate selected for the hard segment is preferably non-toxic and free of benzene rings, such as hexamethylene diisocyanate (HDI), isophorone diisocyanate (IPDI), L-lysine diisocyanate (LDI), L-lysine triisocyanate, etc., preferably poly(ε-caprolactone) glycol (PCL) as a soft segment, L-lysine The acid diisocyanate (LDI) and the chain extender 1,4-butanediol (BDO) are hard segment PU materials.

Degradable polycaprolactone type polyurethane with LDI as a hard segment has more advantages:

(1) The degradation product is an amino acid-lysine in the human body;

(2) The degradation product does not lower the pH of nearby tissues and therefore does not cause inflammation;

(3) the surface is easy to connect with biological reagents;

(4) The surface and cell interface are friendly, and the non-biological specific effect is small.

The degradable stent composition disclosed in the present invention, wherein the selected polyurethane may be a composition formed by the following structural formula, changing the proportion and molecular weight of the composition, and the elastic modulus thereof may be adjusted at 50-1000 MPa, and the elongation at break is 10 Adjusted in the range of % to 1000%, the polyurethane composition is composed of the following formulas A and B, and the weight percentage thereof ranges from A:B=0.01 to 1:1 to 0.1, preferably A:B=0.01 to 1:0.5-1. .

Molecular formula A:

The range of a is 5-50, and the range of b is 5-50.

Molecular formula B:

The range of x is 5-50, and the range of y is 5-50.

The degradable stent composition disclosed in the invention, wherein the selected polyurethane can synthesize linear polycaprolactone diol with different ratios of ε-caprolactone and PEG of different molecular weight (molecular weight 200-2000), and the products thereof are different The diisocyanate reaction uses a different diol as a chain extender, and stannous octoate (0.03 wt% of the total amount) is used as a catalyst to obtain a final product.

The degradable stent composition disclosed in the invention, wherein the selected polyurethane can also use PLA, PGA, PLGA and different glycols with specific molecular weight (molecular weight range 200-2000). A linear lactic acid-glycolic acid copolyol is reacted with a different diisocyanate, and stannous octoate (0.03 wt% of the total amount) is used as a catalyst to obtain a final product.

The degradable stent composition disclosed in the invention, wherein the selected polyurethane can also be the above polycaprolactone type polyurethane linear molecule and the polylactic acid type polyurethane linear molecule, and the lysine triisocyanate is added to form a network crosslinked structure. Forming an ultra-high elastic polyurethane composition, specifically comprising the following polyurethane synthesis reaction:

Method 3: After the reaction is completed according to the method of claim 4, an anhydrous organic solvent is added to prepare a viscous solution, and L-lysine triisocyanate is directly added in an environment having a moisture content of less than 10 ppm, and the reaction system is stirred or shaken. Mixed, normal temperature reaction after half an hour An organic solvent is selected by vacuum extraction, wherein the organic solvent is selected from the group consisting of toluene, p-xylene, decane, isoamyl acetate, hexane, benzene, dichloromethane, chloroform, 1, 4-cyclohexanone, ketone, One or two of dimethylformamide, heptane, dimethylcarbamate, tetrahydrofuran, petroleum ether, dimethyl sulfoxide, ethylene terephthalate, preferably tetrahydrofuran, dichloromethane, trichloro One or a combination of methane and 1,4 cyclohexanone.

The degradable stent composition disclosed by the invention can add other polymer materials according to the soft and hard need of the stent peritoneum, such as polylactic acid, polycaprolactone, polydioxanone and its copolymer (PPDO, PLA-PDO) polydioxanone (PPDO), polytrimethylene carbonate, polylactic acid-trimethylene carbonate copolymer, polycaprolactone-trimethylene carbonate copolymer, polyglycolic acid , polylactic acid-glycolic acid copolymer, polyetheretherketone, polyvinylpyrrolidone and/or polyethylene glycol, polyvalerolactone, poly-ε-decalactone, polylactide, polyglycolide, polylactide Copolymer with polyglycolide, poly-ε-caprolactone, polyhydroxybutyric acid, polyhydroxybutyrate, polyhydroxyvalerate, polyhydroxybutyrate-co-valerate, poly(1, 4-dioxane-2,3-dione), poly(1,3-dioxan-2-one), polydioxanone, polyanhydride (such as polyshun) Butenic anhydride), polyhydroxymethacrylate, fibrin, polycyanoacrylate, polycaprolactone dimethacrylate, poly-β-maleic acid, polycaprolactone butyl acrylate ,Come Multi-block polymer of oligo-caprolactone diol and oligodioxanone diol, polyethylene glycol and polybutylene terephthalate), polypivalolactone, polyglycolic acid trimethyl Carbonate, polycaprolactone-glycolide, poly(γ-ethyl glutamate), poly(DTH-iminocarbonate), poly(DTE-co-DT-carbonate), poly (double Phenol A-iminocarbonate), polyorthoester, polyglycolic acid trimethyl carbonate, trimethyl carbonate, polyiminocarbonate, poly(N-vinyl)-pyrrolidone, polyvinyl alcohol, poly Ester amide, ethanolated polyester, polyphosphate, polyphosphazene, poly[p-carboxyphenoxy)propane], polyhydroxyvaleric acid, polyanhydride, polyethylene oxide-propylene oxide, flexible polyurethane, in the main chain Polyurethanes, polyether esters (such as polyethylene oxide), polyolefin oxalic acid a biodegradable ester, a polyorthoester, and a copolymer thereof, carrageenan, fibrinogen, starch, collagen, protein-containing polymer, polyamino acid, synthetic polyamino acid, zein, The polymer material has a viscosity average molecular weight of 500 to 1,000,000, preferably a polylactic acid material, and more preferably PLGA (LA:GA ratio is 1-3:1) according to the degradation of the stent, for example, the ratio of LA:GA is 75: 25; 65: 35 and 50: 50, etc., the polymer viscosity average molecular weight is 50,000-500,000, preferably the polymer viscosity average molecular weight is 50,000-150,000, in order to improve the flexibility of the product, a non-toxic plasticizer may also be added. Tributyl citrate (TBC), acetyl tributyl citrate (ATBC), trioctyl trimellitate, tris(810) trimellitate, triglyceride trimellitate, pyromellitic acid IV Octyl ester, diethylene glycol dibenzoate, diethylene glycol dibenzoate, dipropylene glycol dibenzoate, dioctyl terephthalate, dioctyl terephthalate, sebacate One or more of ester and epoxidized soybean oil.

The degradable metal material disclosed by the invention has the components of iron, copper, zinc, cobalt, manganese, chromium, selenium, iodine, nickel, fluorine, molybdenum, vanadium, tin, silicon, germanium, boron, antimony, arsenic, silver, A combination of one or more elements, the weight percentage of the magnesium alloy material is: 0-2.0% of iron, 0-2.0% of copper, 0-2.0% of zinc, 0-2.0% of cobalt, 0-2.0% of manganese, chromium 0-2.0%, selenium 0-2.0%, iodine 0-2.0%, nickel 0-2.0%, fluorine 0-2.0%, molybdenum 0-2.0%, vanadium 0-2.0%, tin 0-2.0%, silicon 0- 2.0%, 锶0-2.0%, boron 0-2.0%, 铷0-2.0%, silver 0.1-4%; including: high-purity iron (purity greater than 99.0%), high-purity magnesium (purity greater than 99.0%), magnesium-iron alloy (% by weight) 1:0.01-10), magnesium-zinc alloy (weight ratio 1:0.01-1), magnesium-calcium alloy (weight ratio 1:0.01-1), magnesium-aluminum alloy (weight ratio 1:0.01- One or two combinations of 0.1). Among them, magnesium iron alloy (weight ratio is preferably 1:0.01-0.1), magnesium-zinc alloy (weight ratio is preferably 1:0.01-0.1), such as: Mg-Nd-Zn-Zr, Mg-Zn-Mn, Mg-Zn-Mn -Se-Cu alloy, Zn content of 3.5 wt%, Mn content of 0.5-1.0 wt%, Se content of 0.4-1.0 wt%, Cu content of 0.2-0.5 wt%, Mg balance; magnesium-calcium alloy (weight The percentage is preferably 1:0.01-0.1), For example: Mg-Zn-Ca-Fe, magnesium aluminum alloy (weight ratio is preferably 1:0.01-0.1, such as: aluminum (Al): 2.0-3.0 wt.%, zinc (Zn): 0.5-1.0 wt.% , manganese (Mn), Mg balance.

The coated stent disclosed in the present invention is prepared as follows:

(1) Preparing, engraving, etching or cutting the degradable metal material into a desired pattern (various shapes as shown in Figure 1);

(2) Dissolving polymer A: a degradable medical polyurethane material in an organic solvent to prepare a coating material (material concentration: 5-50%, specifically dissolving the polyurethane in a tetrahydrofuran solution to prepare a 10-30% solution);

(3) preparing the metal stent prepared in (1) by (2) repeated dip coating, spraying or electrospinning on the surface of the stent, at least partially coating a pillar forming a grid or a grid to form a coated composite stent. The thickness of the coated material is preferably between 0.01 and 3 mm, preferably between 0.01 and 0.5 mm.

The peritoneal stent disclosed in the present invention is prepared as follows:

(1) Preparing, engraving, etching or cutting the degradable metal material into a desired pattern or strip shape (various shapes as shown in Fig. 1);

(2) Dissolving polymer A: degradable medical polyurethane material and polymer B: polylactic acid (PLGA, LA:GA ratio of 65:35, viscosity average molecular weight of 80,000-100,000) in an organic solvent in a 1:2 mixture a film formed to have a thickness of 0.01 to 3 mm, preferably 0.1 to 1 mm;

(3) The metal stent prepared in (1) is wound on the surface of the metal material by the film prepared in (2) to form a film stent;

(4) The composite material prepared in (3) is dried, polished and polished by dip coating or spraying a hydrophilic coating (such as chitosan, hyaluronic acid, collagen, cellulose, etc.). Membrane support.

The stent disclosed in the invention is prepared by 3D printing technology:

(1) One of the preparation methods: magnesium alloy powder (powder diameter range: 10 nm - 1 mm, excellent 1um-100um) is mixed with a degradable medical polyurethane material solution (organic dissolved and dissolved, configured as a viscous solution of 20-90% concentration, preferably a 30-50% concentration of tetrahydrofuran or chloroform solution), and passed through 3D. The printer prints a bracket that requires a diameter and a wall thickness, and the hot air is dried to evaporate the dry organic solvent;

(2) Preparation method 2: 3D printer is equipped with two feeding devices, one feeding device is added with magnesium alloy powder (the powder diameter ranges from 10 nm to 1 mm, preferably 1 um to 100 um), and another feeding device is added with degradable medical polyurethane. a material solution (configured in an organic solvent to a concentration of 20-90%, preferably 30-50% concentration in tetrahydrofuran or chloroform), and the two materials are mixed in proportion during the feeding process to print the set size and shape. The support, hot air drying volatile organic solvent is obtained.

(3) Preparation method 3: 3D printer is provided with two feeding devices, one feeding device is added with magnesium alloy powder (the powder diameter ranges from 10 nm to 1 mm, preferably 1 um to 100 um), and another feeding device is added with degradable medical polyurethane. The material and the polylactic acid are mixed and dissolved in an organic solvent in a ratio (1:0.1-10), and are disposed in an organic solvent to a concentration of 20-90%, preferably 30-50% concentration of tetrahydrofuran or chloroform solution, two kinds. The material is mixed in proportion during the feeding process, and the stent of the set size and shape is printed, and the hot air is dried to evaporate the dry organic solvent.

(4) Preparation method 4: The 3D printer is provided with two feeding devices, and a magnesium alloy powder is added to a feeding device (the powder diameter ranges from 10 nm to 1 mm, preferably 1 um to 100 um), and the high temperature melting prints the stent as needed, and is passivated. The treatment is reserved; another defeeding device is added with a degradable medical polyurethane material and polylactic acid in a ratio (1:0.1-10) mixed and dissolved in an organic solvent, and is disposed in an organic solvent to a percentage concentration of 20-90% on the stent. The coating film is printed, and the hot air is dried to evaporate the dry organic solvent.

Among them, the magnesium alloy powder (the diameter of the powder is in the range of 10 nm to 1 mm, preferably 1 um to 100 um) can be passivated according to the various methods disclosed in accordance with the requirements of the degradation time of the stent. A corrosion-resistant, non-toxic conversion film.

The organic solvent of the present invention is selected from the group consisting of toluene, p-xylene, decane, isoamyl acetate, hexane, benzene, dichloromethane, chloroform, cyclohexanone, ketone, dimethylformamide, One or two of heptane, dimethylcarbamate, tetrahydrofuran, petroleum ether, dimethyl sulfoxide, ethylene terephthalate, preferably tetrahydrofuran, decane, isoamyl acetate, hexane, two One or two of methyl chloride, chloroform, cyclohexanone, dimethylformamide, and heptane.

The double balloon design of the delivery urethral stent, as shown in Figure 1, the design principle of the urethral stent: usually the diameter of the urethral stent is 4-7mm, the length is 3-5cm, and the stent is processed into a pattern that can be expanded and supported, and installed on the ball. The manner of the capsule can be squeezed on the balloon by the tension of the stent tube itself, or it can be crimped and adhered to the balloon, installed in place with the expansion of the balloon, placed in the prostatic urethra, and the urethra The distal end of the stent is 3-5 mm from the urethral sphincter, so that the urethral stent can both expand the urethra without damaging the sphincter. The polymer material used for preparation of the balloon and the stent comprises a contrast agent, specifically one selected from the group consisting of zirconium dioxide, barium sulfate and iodine, wherein the material used for the balloon is added such as polyvinyl chloride or dry glue. Adding developer barium sulfate to rubber, silicone rubber and natural latex, adding commonly used iodine preparations for contrast imaging in preparation of urethral stents, such as diatrizoate, iodine, diazonic acid, iodine Phenylhexaol, iopromide and iupamidol.

The balloon design of the delivery vessel stent is consistent with commercially available products.

The organic solvent of the present invention is selected from the group consisting of toluene, p-xylene, decane, isoamyl acetate, hexane, benzene, dichloromethane, chloroform, cyclohexanone, ketone, dimethylformamide, One or two of heptane, dimethylcarbamate, tetrahydrofuran, petroleum ether, dimethyl sulfoxide, ethylene terephthalate, preferably tetrahydrofuran, chloroform, toluene, p-xylene, acetic acid One of amyl ester or hexane.

The stent of the present invention comprises a contrast agent, specifically selected from the group consisting of zirconium dioxide, barium sulfate and iodine One of the preparations must be added in an amount of 1 to 20%, preferably 2 to 10% by weight based on the polymer material.

When preparing the vascular stent, the anticoagulant component is cross-linked by the cross-linking agent such as glutaraldehyde on the surface of the treated bare stent, and the blood coagulation component can select hirudin, heparan sulfate and its derivative. For example, complete desulfurization and N-reacetylated heparin desulfurization and N-reacetylated heparin are prepared as anticoagulant coatings that do not activate blood coagulation.

When it is necessary to prepare a stent with a long degradation time, a corrosion-resistant non-toxic conversion membrane can be formed on the surface of the degradable magnesium alloy, and a phosphate conversion membrane method, a phytic acid conversion membrane, a rare earth salt conversion membrane method, and an organic conversion coating film are commonly used. The method, or fluorination treatment on the surface of the bare stent, is specifically to polish the untreated biodegradable magnesium alloy stent, and soak for 12 to 96 hours in a mass percentage of 20-40% hydrofluoric acid.

The degradable stent composition of the present invention is characterized in that commercially available or already disclosed polypeptides, proteins and active ingredients, including anti-proliferation, anti-migration, anti-angiogenesis, anti-drug, can be added to the polyurethane material according to clinical needs. Physiologically active drugs for inflammation, anti-inflammatory, cytostatic, cytotoxic or antithrombotic effects, such as sirolimus, everolimus, pimecrolimus, melanin, ifosfamide, tromethamine, Chlorambucil, bendamustine, somatostatin, tacrolimus, roxithromycin, daunorubicin, ascomycin, bafilomycin, ramustine, cyclophosphamide, Estrostatin, dacarbazine, erythromycin, medimycin, spectabilin, concanavalin, clarithromycin, oleandomycin, vinblastine, vincristine, vindesine , vinorelbine, etoposide, teniposide, nimustine, carmustine, busulfan, procarbazine, troxulfan, temozolomide, thiotepa, doxorubicin, arou Star, epirubicin, mitoxantrone, idarubicin, bleomycin, mitochondrial C, dactinomycin, methotrexate, fludarabine, fludarabine-5'-dihydrophosphate, cladribine, guanidine, thioguanine, cytarabine, fluorouracil, gemcitabine, card Peitabin, docetaxel, carboplatin, cisplatin, oxaliplatin, rosuvastatin, atorvastatin, pravastatin, pitavastatin, doxorubicin, cerivastatin, sim Rutastatin, lovastatin, fluvastatin, ampicillin, irinotecan, topotecan, hydroxyurea, miltefosin, pentastatin, aldesleukin, retinoic acid, asparaginase, culture Gappaase, anastrozole, exemestane, letrozole, formestane, aminoglutethimide, bromocreatine, bromocriptine, wild ergot, ergoline, ergoline, ergoline Alkali, ergotoxin, ergoline, ergot, ergometrine, ergotamine, ergot, ergotin, ergoline, ergocriptine, ergoline, ergometrine, Erlenonitrile, ergoacetone, ergosterol, lysergic acid, doxorubicin, azithromycin, spiramycin, sifaxan, 8-α-ergoline, dimethylergoline, ergot, 1-ene Propyl ergoacetate, 1-allyl terezone, lysergic acid amide, lysergic acid diethylamine, iso-lysergic acid, iso-ergotamide, iso-lysergic acid diethylamine, mesal ergot, thalidomide, 5-isoquinolinesulfonyl) homopiperazine, cyclosporine, smooth muscle cell proliferation inhibitor 2ω, ergobenzyl ester, methyl ergometrine, dimethyl Ergometrine, pergolide, propyl ergoside and terguride, celecoxib, epothilone A and B, mitoxantrone, azathioprine, mycophenolate mofetil, antisense c-myc, anti B-myc, betulinic acid, camptothecin, wood paphos, melanocyte promoting hormone, active protein C, interleukin 1-β-inhibitor, β-lapaquinone, podophyllotoxin, birch , 2-hydroxyindole, morazin, peginterferon alfa-2b, digstatin, filgrastim, dacarbazine, basiliximab, dac beads Monoclonal antibody, selectin, cholesterol ester transporter inhibitor, cadherin, cytokine inhibitor, cyclooxygenase-2 inhibitor, thymosin alpha-1, fumaric acid, and its ester, calcipotriol , carbamazeol, laphol, nuclear factor kB, angiostatin, ciprofloxacin, fluoxetine, monoclonal antibody that inhibits muscle cell proliferation, bovine basic fibroblast growth factor antagonist, probucol , prostaglandin, 1,11-dimethoxycoumarin-6-one, 1-hydroxy-11-methoxycoumarin-6-one, tocolide, colchicine, nitric oxide Body, it Moxifene, phosphoestrol, medroxyprogesterone, estradiol cyclopentanoate, estradiol benzoate, tranilast, verapamil, staurosporine, beta-estradiol, alpha-female Glycol, estriol, estrone, ethinyl estradiol, Tyrosine kinase inhibitors, cyclosporine A, paclitaxel and its derivatives, synthetic and triethylene macrocyclic oligomers obtained from natural sources and derivatives thereof, monobutyrazole, acetaminophen, Diclofenac, lornazol, dapsone, o-carbamoyl-phenoxy-acetic acid, lidocaine, ketoprofen, mefenamic acid, oncostatin, avastin, hydroxychloroquine, auranofin , sodium thiosuccinate, oxacillin, celecoxib, β-sitosterol, adenosylmethionine, marticaine, polyethylene glycol monododecyl ether, vanillyl amide, left menthol , benzocaine, aescin, elibutin, colchicine, cytochalasin AE, indanocine, nocodazole, piroxicam, meloxicam, chloroquine phosphate, penicillium Amine, S100 protein, subtilisin, vitreous binding protein receptor antagonist, azelastine, sulfhydryl cyclase stimulating agent, metalloproteinase 1 and 2 tissue inhibitors, free nucleic acids, nucleic acids incorporating viral transmitters, Deoxyribonucleic acid and ribonucleic acid fragments, plasminogen activator inhibitor 1, plasminogen activator inhibition Agent 2, antisense oligonucleotide, vascular endothelial growth factor inhibitor, insulin-like growth factor 1, active agent from antibiotic group, penicillin, antithrombotic agent, desulfurization and N-reacetylated heparin, tissue fiber Lysozyme activator, GpIIb/IIIa platelet membrane receptor, factor Xa inhibitor antibody, heparin, hirudin, r- hirudin, D-phenylalanine-valine-arginine-chloromethanone (D -phenylalanyl-L-prolyl-L-arginine chloromethyl ketone), acetylcholinesterase inhibitor, thiolase inhibitor, prostacyclin, taprostine, interferon alpha, beta and gamma, histamine antagonist, serotonin Stagnation agents, inhibitors of apoptosis, modulators of apoptosis, protamine, sodium salt of 2-methylthiazolidine-2,4-dicarboxylic acid, prourokinase, streptokinase, warfarin, and urokinase, Vasodilators, platelet-derived growth factor antagonists, clopidogrel bromide, nifedipine, tocopherol, vitamins B1, B2, B6 and B12, folic acid, morpholine, tea polyphenols, epicatechin gallate Ester, gallocatechin gallate, leflunomide, anarubic acid , Etanercept, procainamide, retinoic acid, quinidine, Disopyramide Disopyramide, flecainide, propafenone, sotalol, amine Iodophenone, natural or synthetically obtained steroids, inonotc alginate, marziprin A, sulfasalazine, etoricin, triamcinolone, epimethicillin, velvet mushroom, manzanin, Renal sputum, hydrocortisone acetate, betamethasone, dexamethasone, non-steroidal anti-inflammatory substances, antifungal agents, antiprotozoal agents, natural terpenoids, 4,7-oxycyclocarbanic acid, dryland chrysanthemum萜B1, B2, B3 and B7, saponin, scorpion scorpion A, B and C, anti-cyanin C, Bruceain N and P, iso-deoxygen bilirubin, white flower Valeric lactone A and B, glyceryl theophylline A, B, C and D, fragrant tea A and B, chlorinated nitidine, 12-β-hydroxypregnane-3,20-dione,栲利素素 B, scented scented tea, scented scented tea, scented scented tea, A and B, yew A and B, ralonilid), triptolide, ursolic acid , Glycerate A, Iso-Germanic acid, Phytosterol, Guanqiu A, Magnesium, Podoside, Aristolochic Acid, Aminoguanidine, Hydroxylamine, Pulsatilla , original white-headed vegetarian, small Scopolamine, chlorhexidine chloride, poisonous sucrose toxin, xylophylline, eucalyptus isoflavone A, turmeric, dihydrophylloline, ginkgo phenol, ginkgo phenol, ginkgo acid, etc., and salts and hydrates of the above active agents , solvates, enantiomers, racemic compounds, enantiomeric mixtures, diastereomeric mixtures, and mixtures thereof.

The design concept and the embodiments of the present invention are described below in conjunction with the specific embodiments, but those skilled in the art should understand that these are merely exemplary embodiments and are not intended to limit the scope of the invention.

Synthesis Example of Polymer Materials with Different Degrees of Softness and Hardness

Note: The raw materials used in this example were pretreated to a moisture content of less than 10 ppm for use.

Example 1

Weigh 9.0g ε-caprolactone, 3.0g PEG-600, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen Cycle 3 times, and seal the vacuum reaction bottle under vacuum condition, put The reaction was carried out in an oil bath at 140 ° C for 24 h to obtain a linear polymer. Weigh 2g of L-lysine diisocyanate and 0.6g of BDO, then add 0.5g of PEG-200 into a vacuum reaction bottle, vacuum and seal the bottle mouth, and put it into a 70 ° C oil bath for 4h to get the final product.

Example 2

Weigh 9.0g ε-caprolactone, 3.0g PEG-600, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Weigh 2gL-lysine diisocyanate and 0.68g BDO, add 0.5g of PEG-400 into the vacuum reaction bottle, vacuum and seal the bottle mouth, and put it into the oil bath of 70 °C for 4h to get the final product.

Example 3

Weigh 9.0g ε-caprolactone, 3.0g PEG-600, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Weigh 2g of L-lysine diisocyanate and 0.7g of BDO, then add 0.5g of PEG-600 into a vacuum reaction bottle, vacuum and seal the bottle mouth, and put it into a 70 ° C oil bath for 4h to get the final product.

Example 4

Weigh 9.0g ε-caprolactone, 3.0g PEG-600, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Weigh 2g of L-lysine diisocyanate and 0.9g of BDO, then add 0.5g of PEG-1000 into a vacuum reaction bottle, vacuum and seal the bottle mouth, and put it into the oil bath of 70 °C for 4h to get the final product.

Example 5

Weigh 9.0g ε-caprolactone, 3.0g PEG-600, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Weigh 2g of L-lysine diisocyanate and 0.6g of BDO, then add 0.5g of PEG-1500 into a vacuum reaction bottle, vacuum and seal the bottle mouth, and put it into the oil bath of 70 °C for 4h to get the final product.

Example 6

Weigh 9.0g ε-caprolactone, 3.0g PEG-600, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Weigh 2g of L-lysine diisocyanate and 1.0g of BDO, then add 0.5g of PEG-2000 into a vacuum reaction bottle, vacuum and seal the bottle mouth, and put it into the oil bath of 70 °C for 4h to get the final product.

Example 7

Weigh 8.0g ε-caprolactone, 4.0g PEG-400, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Weigh 2g of L-lysine diisocyanate and 0.6g of BDO, then add 0.5g of PEG-200 into a vacuum reaction bottle, vacuum and seal the bottle mouth, and put it into a 70 ° C oil bath for 4h to get the final product.

Example 8

Weigh 8.0g ε-caprolactone, 4.0g PEG-400, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Weigh 2gL-lysine dimer Cyanate ester and 0.6 g of BDO were added to a vacuum reaction flask by adding 0.5 g of PEG-400, vacuumed and sealed, and placed in an oil bath at 70 ° C for 4 hours to obtain a final product.

Example 9

Weigh 8.0g ε-caprolactone, 4.0g PEG-400, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Weigh 2gL-lysine diisocyanate and 0.6g BDO, then add 0.5g of PEG-600 into the vacuum reaction bottle, vacuum and seal the bottle mouth, and put it into the oil bath at 70 °C for 4h to get the final product.

Example 10

Weigh 8.0g ε-caprolactone, 4.0g PEG-400, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Weigh 2g of L-lysine diisocyanate and 0.6g of BDO, then add 0.5g of PEG-1000 into a vacuum reaction bottle, vacuum and seal the bottle mouth, and put it into a 70 ° C oil bath for 4h to get the final product.

Example 11

Weigh 8.00g ε-caprolactone, 4.00g PEG-400, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Weigh 2g of L-lysine diisocyanate and 0.6g of BDO, then add 0.5g of PEG-1500 into a vacuum reaction bottle, vacuum and seal the bottle mouth, and put it into the oil bath of 70 °C for 4h to get the final product.

Example 12

Weigh 8.0g ε-caprolactone, 4.0g PEG-400, stannous octoate (total 0.03wt%) as a catalyst, added to the vacuum reaction flask, and then added a magnetic stirrer, vacuum / nitrogen-filled 3 times, and sealed the vacuum reaction bottle under vacuum conditions, into the oil bath at 140 ° C The reaction was carried out for 24 h to obtain a linear polymer. Weigh 2g of L-lysine diisocyanate and 0.8g of BDO, then add 0.5g of PEG-2000 into a vacuum reaction bottle, vacuum and seal the bottle mouth, and put it into a 70 ° C oil bath for 4h to get the final product.

Example 13

Weigh 6.0g ε-caprolactone, 6.0g PEG-600, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Further, 2 g of L-lysine diisocyanate and 0.7 g of 1,6-hexanediol were weighed, placed in a vacuum reaction flask, evacuated and sealed, and placed in an oil bath at 70 ° C for 4 hours to obtain a final product.

Example 14

Weigh 6.0g ε-caprolactone, 6.0g PEG-400, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Then weighed 2.5 g of isophorone diisocyanate and 0.5 g of 1,6-hexanediol, placed in a vacuum reaction flask, vacuumed and sealed the bottle mouth, and placed in an oil bath at 70 ° C for 4 h to obtain the final product. .

Example 15

Weigh 6.0g ε-caprolactone, 6.0g PEG-200, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Weigh 2 g of L-lysine diisocyanate and 2.6 g of 1,3-propanediol, put them into a vacuum reaction flask, evacuate and seal the mouth of the bottle. The reaction was carried out in an oil bath at 70 ° C for 4 h to obtain a final product.

Example 16

Weigh 9.0g ε-caprolactone, 3.0g PEG-1000, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Further, 3 g of 1,3-propane diisocyanate and 2.5 g of 1,3-propanediol were weighed, placed in a vacuum reaction flask, vacuumed and sealed, and placed in an oil bath at 70 ° C for 4 hours to obtain a final product.

Example 17

Weigh 9.0g ε-caprolactone, 3.0g PEG-600, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Further, cis-cyclohexane diisocyanate and 0.5 g of ethylene glycol were weighed, placed in a vacuum reaction flask, vacuumed and sealed, and placed in an oil bath at 70 ° C for 4 hours to obtain a final product.

Example 18

Weigh 8.0g ε-caprolactone, 4.0g PEG-600, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Further, 3 g of L-lysine diisocyanate and 0.3 g of ethylene glycol were weighed, placed in a vacuum reaction flask, vacuumed and sealed, and placed in an oil bath at 70 ° C for 4 hours to obtain a final product.

Example 19

Weigh 8.0g ε-caprolactone, 4.0g PEG-400, stannous octoate (0.03wt% of the total amount) as a catalyst, add it to the vacuum reaction bottle, and add a magnetic stirrer. The vacuum/nitrogen gas was circulated for 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Further, 5 g of 1,4-butane diisocyanate and 2.6 g of BDO were weighed, placed in a vacuum reaction flask, vacuumed and sealed, and placed in an oil bath at 70 ° C for 4 hours to obtain a final product.

Example 20

Weigh 8.0g ε-caprolactone, 4.0g PEG-200, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Further, 3 g of L-lysine diisocyanate and 1.5 g of BDO were weighed, placed in a vacuum reaction flask, evacuated and sealed, and placed in an oil bath at 70 ° C for 4 hours to obtain a final product.

Example 21

Weigh 8.0g ε-caprolactone, 4.0g PEG-200, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Further, 4 g of L-lysine diisocyanate and 0.9 g of BDO were weighed, placed in a vacuum reaction flask, evacuated and sealed, and placed in an oil bath at 70 ° C for 4 hours to obtain a final product.

Example 22

Weigh 8.0g ε-caprolactone, 5.0g PEG-200, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Further, 5 g of L-lysine diisocyanate and 1.5 g of tetraethylene glycol were weighed, placed in a vacuum reaction flask, vacuumed and sealed, and placed in an oil bath at 70 ° C for 4 hours to obtain a final product.

Example 23

Weigh 8.0g ε-caprolactone, 3.0g PEG-200, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Then, 3 g of HDI and 1.0 g of tetraethylene glycol were weighed, placed in a vacuum reaction flask, vacuumed and sealed, and placed in an oil bath at 70 ° C for 4 hours to obtain a final product.

Example 24

Weigh 12.0g ε-caprolactone, 4.0g PEG-1000, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Further, 3 g of L-lysine diisocyanate and 0.6 g of BDO were weighed, placed in a vacuum reaction flask, vacuumed and sealed, and placed in an oil bath at 70 ° C for 4 hours to obtain a final product.

Example 25

Weigh 18.0g ε-caprolactone, 4.0g PEG-1000, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Further, 4 g of L-lysine diisocyanate and 0.8 g of diethylene glycol were weighed, placed in a vacuum reaction flask, vacuumed and sealed, and placed in an oil bath at 70 ° C for 4 hours to obtain a final product.

Example 26

Weigh 20.00g ε-caprolactone, 4.0g PEG-1000, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen Cycle 3 times, and seal the vacuum reaction bottle under vacuum condition, put The reaction was carried out in an oil bath at 140 ° C for 24 h to obtain a linear polymer. Further, 5 g of L-lysine diisocyanate and 0.6 g of BDO were weighed, placed in a vacuum reaction flask, vacuumed and sealed, and placed in an oil bath at 70 ° C for 4 hours to obtain a final product.

Example 27

Weigh 15.00g ε-caprolactone, 10.00g PEG-1000, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Further, 5 g of L-lysine diisocyanate and 1.2 g of diethylene glycol were weighed, placed in a vacuum reaction flask, vacuumed and sealed, and placed in an oil bath at 70 ° C for 4 hours to obtain a final product.

Example 28

Weigh 6.00g ε-caprolactone, 4.00g PEG-600, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Further, 3 g of L-lysine diisocyanate and 1.6 g of 1,8-octanediol were weighed, placed in a vacuum reaction flask, vacuumed and sealed, and placed in an oil bath at 70 ° C for 4 hours to obtain a final product.

Example 29

Weigh 6.00g ε-caprolactone, 5.00g PEG-600, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Further, 4 g of L-lysine diisocyanate and 1.0 g of 1,8-octanediol were weighed, placed in a vacuum reaction flask, evacuated and sealed, and placed in an oil bath at 70 ° C for 4 hours to obtain a final product.

Example 20

Weigh 6.00g ε-caprolactone, 6.00g PEG-600, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Further, 5 g of L-lysine diisocyanate and 0.6 g of BDO were weighed, placed in a vacuum reaction flask, vacuumed and sealed, and placed in an oil bath at 70 ° C for 4 hours to obtain a final product.

Example 31

Weigh 6.00g ε-caprolactone, 6.00g PEG-600, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Further, 6 g of L-lysine diisocyanate and 0.6 g of BDO were weighed, placed in a vacuum reaction flask, vacuumed and sealed, and placed in an oil bath at 70 ° C for 4 hours to obtain a final product.

Example 32

Weigh 6.00g ε-caprolactone, 6.00g PEG-400, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Further, 3 g of L-lysine diisocyanate and 0.6 g of BDO were weighed, placed in a vacuum reaction flask, vacuumed and sealed, and placed in an oil bath at 70 ° C for 4 hours to obtain a final product.

Example 33

Weigh 6.00g ε-caprolactone, 6.00g PEG-400, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Weigh 4gL-lysine dimer Cyanate ester and 0.6 g of BDO were placed in a vacuum reaction flask, vacuumed and sealed, and placed in an oil bath at 70 ° C for 4 h to obtain the final product.

Example 34

Weigh 6.00g ε-caprolactone, 6.00g PEG-400, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Weigh 5g of L-lysine diisocyanate and 1.0g of tetraethylene glycol, put it into a vacuum reaction bottle, vacuum and seal the bottle mouth, and put it into the oil bath of 70 °C for 4h to obtain the final product, in the moisture content. In an environment of less than 10 ppm, it is poured into a kneader or a kneader, and 2.0 g of L-lysine triisocyanate is directly added and stirred sufficiently, and the reaction is carried out at room temperature for half an hour.

Example 35

Weigh 6.00g ε-caprolactone, 6.00g PEG-400, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Further, 6 g of L-lysine diisocyanate and 0.6 g of BDO were weighed, placed in a vacuum reaction flask, vacuumed and sealed, and placed in an oil bath at 70 ° C for 4 hours to obtain a final product.

Example 36

Weigh 10g of poly-(4-hydroxybutyrate) diol, stannous octoate (0.03wt% of total) as a catalyst, add a magnetic stirrer, weigh 3g of L-lysine diisocyanate and 0.6g of BDO Put into a vacuum reaction bottle, vacuum/nitrogen cycle for 3 times, vacuum and seal the bottle mouth, put it into the oil bath at 70 °C for 4h, take the vacuum reaction bottle and cool it to room temperature, the moisture content is less than 10ppm. Under the environment, 0.6 g of L-lysine triisocyanate was added for blocking, and the mixture was stirred at room temperature for 30 minutes to obtain a final product.

Example 37

Weigh 10 g of poly-(3-hydroxybutyrate) diol, stannous octoate (0.03 wt% of total) as a catalyst, and add a magnetic stirrer to weigh 3 g of L-lysine diisocyanate and 0.6 g of BDO. Put into a vacuum reaction bottle, vacuum/nitrogen cycle for 3 times, vacuum and seal the bottle mouth, put it into the oil bath at 70 °C for 4h, take the vacuum reaction bottle and cool it to room temperature, the moisture content is less than 10ppm. Under the environment, 0.6 g of L-lysine triisocyanate was added for blocking, and the mixture was stirred at room temperature for 30 minutes to obtain a final product.

Example 38

Weigh 10g of PLGA diol, stannous octoate (0.03wt% of total) as a catalyst, add a magnetic stirrer, weigh 3g of L-lysine diisocyanate and 0.6g of BDO, put it into vacuum reaction bottle, vacuum / After filling with nitrogen for 3 times, vacuum and seal the bottle mouth, put it in a 70 ° C oil bath for 4 h, in the environment with water content less than 10 ppm, add the reaction product to the mixer, add 0.6g L-lysine three The isocyanate was capped and stirred at room temperature for 30 min to give the final product.

Example 39

Weigh 10g of P (LA / CL) diol, stannous octoate (0.03wt% of total) as a catalyst, add a magnetic stirrer, weigh 3g of L-lysine diisocyanate and 0.6g of BDO, put into vacuum reaction In the bottle, vacuum or nitrogen-filled cycle 3 times to vacuum and seal the bottle mouth, put it into the oil bath at 70 °C for 4h, take the vacuum reaction bottle out and cool to room temperature, add 0.6 in the environment of moisture content less than 10ppm The gL-lysine triisocyanate was capped and stirred at room temperature for 30 min to give the final product.

Example 40

Weigh 10g of poly(tetrahydrofuran) diol, stannous octoate (0.03wt% of total) as a catalyst, add a magnetic stirrer, weigh 3g of L-lysine diisocyanate and 0.6g of BDO, and put it into the vacuum reaction bottle. Medium, vacuuming/nitrogen filling cycle 3 times vacuuming and sealing the bottle The solution was placed in an oil bath at 70 ° C for 4 h, and the vacuum reaction flask was taken out and cooled to room temperature. After the moisture content was less than 10 ppm, 0.6 g of L-lysine triisocyanate was added for blocking, and the mixture was stirred at room temperature for 30 minutes to obtain a final solution. product.

Example 41

Weigh 10 g of poly(hexamethylene carbonate) diol, stannous octoate (0.03 wt% of the total amount) as a catalyst, and then add a magnetic stirrer to weigh 3 g of L-lysine diisocyanate and 0.6 g of BDO. Put into a vacuum reaction flask, evacuate and vacuum nitrogen for 3 times, vacuum and seal the bottle mouth, put it into the oil bath at 70 °C for 4h, take the vacuum reaction bottle out and cool to room temperature, in the environment with moisture content less than 10ppm Next, 1.6 g of L-lysine triisocyanate was added for blocking, and the mixture was stirred at room temperature for 30 minutes to obtain a final product.

Example 42

Weigh 6.00g ε-caprolactone, 3.00g PEG-600, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. 3 g of IPDI and 0.6 g of BDO were weighed, placed in a vacuum reaction flask, vacuumed and sealed, and placed in an oil bath at 70 ° C for 4 h to obtain the final product.

Example 43

Weigh 12.0g ε-caprolactone, 3.0g PEG-1000, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. 3 g of LDI and 0.6 g of BDO were weighed, placed in a vacuum reaction flask, vacuumed and sealed, and placed in an oil bath at 70 ° C for 4 h to obtain the final product.

Example 44

Weigh 8.0g ε-caprolactone, 3.0g PEG-600, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Then weighed 2.7HDI and 0.6g BDO, placed in a vacuum reaction flask, vacuumed and sealed the bottle mouth, and placed in an oil bath at 70 ° C for 4 h to obtain the final product.

Example 45

Weigh 6.0g ε-caprolactone, 3.0g PEG-600, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Further weighed 2.4 g of IPDI, 0.6 g of HDI and 0.6 g of BDO, placed in a vacuum reaction flask, vacuumed and sealed the mouth of the bottle, and placed in an oil bath at 70 ° C for 4 h to obtain the final product.

Example 46

Weigh 6.0g ε-caprolactone, 3.0g PEG-600, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Further weighed 2.1 g of IPDI, 0.9 g of HDI and 0.6 g of BDO, placed in a vacuum reaction flask, vacuumed and sealed the mouth of the bottle, and placed in an oil bath at 70 ° C for 4 h to obtain the final product.

Example 47

Weigh 6.0g ε-caprolactone, 3.0g PEG-600, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Weigh 1.8g LDI, 1.2 g of HDI and 0.6 g of BDO were placed in a vacuum reaction flask, evacuated and sealed, and placed in an oil bath at 70 ° C for 4 h to obtain the final product.

Example 48

Weigh 6.0g ε-caprolactone, 3.0g PEG-600, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. 1.5 g of IPDI, 1.5 g of HDI and 0.6 g of BDO were weighed, placed in a vacuum reaction flask, vacuumed and sealed, and placed in an oil bath at 70 ° C for 4 h to obtain the final product.

Example 49

Weigh 6.0g ε-caprolactone, 3.0g PEG-600, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Further, 3.0 g of HDI and 0.8 g of 1,6-hexanediol were weighed, placed in a vacuum reaction flask, vacuumed and sealed, and placed in an oil bath at 70 ° C for 4 hours to obtain a final product.

Example 50

Weigh 6.0g ε-caprolactone, 3.0g PEG-600, stannous octoate octoate (0.02wt% of total) as a catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / Nitrogen gas was cycled 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Further, 3.0 g of LDI and 0.9 g of 1,7-heptanediol were weighed, placed in a vacuum reaction flask, vacuumed and sealed, and placed in an oil bath at 70 ° C for 4 hours to obtain a final product.

Example 51

Weigh 6.0g ε-caprolactone, 3.0g PEG-600, stannous octoate (total 0.03wt%) as a catalyst, added to the vacuum reaction flask, and then added a magnetic stirrer, vacuum / nitrogen-filled 3 times, and sealed the vacuum reaction bottle under vacuum conditions, into the oil bath at 140 ° C The reaction was carried out for 24 h to obtain a linear polymer. Then, 3.0 g of LDI and 1.0 g of 1,8-octanediol were weighed, placed in a vacuum reaction flask, vacuumed and sealed, and placed in an oil bath at 70 ° C for 4 hours to obtain a final product.

Example 52

Glycolic acid (4g), L-lactic acid (12g) and BDO (1.1g) were weighed into a vacuum reaction flask, dried at 80 ° C under high vacuum, and stopped at 150 ° C for 48 h. HDI (2 g) and octanoic acid were added. Tin (0.02% by weight of total) was reacted in an oil bath at 70 ° C for 6 h to obtain the final product. The vacuum reaction flask was taken out and cooled to room temperature, and 0.6 g of L-lysine triisocyanate was added for blocking, shaking or stirring at room temperature. The final product was obtained in 30 min.

Example 53

Glycolic acid (8g), DL-lactic acid (12g) and BDO (1.5g) were weighed into a vacuum reaction flask, dried at 80 ° C under high vacuum, and stopped at 170 ° C for 24 h. The reaction was stopped and IPDI (2 g) and octanoic acid were added. Tin (0.02 wt% of the total amount) was reacted in an oil bath at 70 ° C for 4 h to obtain a final product. The vacuum reaction flask was taken out and cooled to room temperature, and 1.0 g of L-lysine triisocyanate was added for blocking, and the mixture was repeatedly passed through a kneading machine. The mixture was stirred for 30 min to obtain the final product.

Example 54

Glycolic acid (4g), DL-lactic acid (12g) and 1,6-hexanediol (1.8g) were weighed into a vacuum reaction flask, dried at 80 ° C under high vacuum, and reacted at 150 ° C for 24 h, then stopped, and added IPDI. (2g) and stannous octoate (0.02wt% of total amount) were reacted in an oil bath at 70 ° C for 6 h, the vacuum reaction flask was taken out and cooled to room temperature, and the material was dissolved by adding 20 ml of tetrahydrofuran, and 1.0 g of L-lysine was added. The isocyanate was capped and stirred for 30 min to give the final product. The final product is obtained.

Example 55

12 g of PLGA (LA:GA=2:1) and 1,6-hexanediol (1.8 g) were weighed into a vacuum reaction flask, dried at 80 ° C under high vacuum, and reacted at 150 ° C for 24 h, then stopped, and added IPDI ( 2g) and stannous octoate (0.02% by weight of total) were reacted in an oil bath at 70 ° C for 6 h to obtain the final product. The vacuum reaction flask was taken out and cooled to room temperature, and 1.0 g of L-lysine triisocyanate was added for blocking. The mixture was stirred and kneaded by a kneading machine for 30 minutes to obtain a final product.

Example 56

Glycolic acid (8g), L-lactic acid (12g) and BDO (0.8g) were weighed into a vacuum reaction flask, dried at 80 ° C under high vacuum, and reacted at 150 ° C for 24 h, then stopped, and added LDI (2.8 g) and octanoic acid. Stannous (0.02 wt% of the total amount) was reacted in an oil bath at 70 ° C for 6 h, the vacuum reaction flask was taken out and cooled to room temperature, the material was dissolved by adding 20 ml of tetrahydrofuran, and 1.6 g of L-lysine triisocyanate was added for blocking. Stir for 30 min to give the final product. The final product is obtained.

Example 57

Weigh 6 parts of 9.00g ε-caprolactone, 3.00g PEG-600, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / The gas was circulated for 3 times, and the feed port was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Weigh 2g of L-lysine diisocyanate and 0.6g of BDO, add 0.05mol of PEG-200, PEG400, PEG1000, PEG1500, PEG2000 to the vacuum reaction bottle, vacuum and seal the feed port, and put the oil at 70 °C. The reaction was carried out in a bath for 4 h to give the final product.

Table 1

Example 58

At the same time, 3 samples were prepared, and glycolic acid (4g), DL-lactic acid (12g) and 1,6-hexanediol (1.8g) were weighed into a vacuum reaction flask, dried at 80 ° C under high vacuum, and reacted at 150 ° C for 24 h. After the reaction was stopped, LDI (2 g) and stannous octoate (0.02 wt% of total) were added and reacted in an oil bath at 70 ° C for 6 h to obtain a final product. The vacuum reaction flask was taken out and cooled to room temperature, and the moisture content was less than 10 ppm. In the kneading machine, 0.5 g, 1.0 g, and 2.0 g of L-lysine triisocyanate were separately added for blocking, and the final product was obtained by repeated kneading for 60 minutes. The test results were as follows:

Table 2

L-赖氨酸三异氰酸酯L-lysine triisocyanate	0.5g0.5g	1.0g1.0g	2.0g2.0g
弹性模量Elastic Modulus	300MPa300MPa	380MP380MP	550MP550MP
断裂伸长率Elongation at break	200％200%	120％120%	70％70%

Example 59 Degradation Experimental Study

According to the product of each component in Example 57, the mixture was mixed in a high-vacuum mixer to prepare a fiber having a diameter of 0.3-0.35 mm, and the physiological saline solution at 37 ° C was changed every day to observe the degradation and determine the elongation of the fiber. The rate is once a week, and the experimental results are as follows:

table 3

The experimental results show that with the prolongation of degradation time, the material degrades and the elongation at break decreases, which provides a reference for the preparation of various products.

Degradable stent composite embodiment:

Degradable Scaffold Complex Examples of magnesium alloy compositions selected in Examples 1-9 are as follows:

Table 4

Magnesium metal stent materials can also be selected from high purity magnesium or high purity iron depending on the degradation time.

Degradable stent complex Example 1: vascular stent graft

The preparation process is as follows:

(1) Prepare, engrave, etch or cut the degradable metal material (the composition ratio of the alloy composition according to 9 in the list) into the desired pattern or slat shape (as shown in Figure 1). The diameter of the bracket is 1mm and long. 2cm;

(2) The stent prepared in (1) was polished, soaked in a mass percentage of 30% hydrofluoric acid for 24 hours, taken out, washed with 75% ethanol, and dried.

(3) Dissolving polymer A: degradable medical polyurethane material (viscosity average molecular weight 10,000, breaking strength 35 MPa, elongation at break 350%) in chloroform solvent and 0.2-0.3 on tetrafluoroethylene sheet Mm thick film;

(4) The film prepared by (3) is wound on the surface of the metal stent metal material prepared in (1) to form a film stent (as shown in FIG. 5);

(5) Drying, polishing, and polishing the composite material prepared in (4) by dip coating or spraying a hydrophilic coating (such as an aqueous solution made of chitosan, hyaluronic acid, collagen, cellulose, etc.) As a stent graft.

Degradable stent complex Example 2: Double balloon urethral stent graft

The double balloon urethral stent shown in Fig. 1 is made of silica gel material. The stent is pressed or adhered to the columnar balloon, and after being placed in the urethra, the balloon is injected into the balloon, and the columnar balloon expands the stent and supports The urethra area.

The peritoneal urethral stent is prepared as follows:

(1) Prepare, engrave, etch or cut the degradable metal material (the alloy composition ratio is selected according to 9 in the list) into the desired pattern or slat shape (various shapes as shown in Figure 6). The frame is 3mm in diameter and 2cm in length;

(2) Dissolving polymer A: a degradable medical polyurethane material and a polymer B: PLGA (wherein a ratio of LA:GA of 70:30 and a viscosity average molecular weight of 80,000) in a 1:2 mixture to dissolve in a dichloromethane solvent. Laying a film of 0.2-0.3 mm thick on a tetrafluoroethylene sheet;

(3) winding the film prepared in (2) on the surface of the metal stent metal material prepared in (1) to form a film stent (as shown in FIG. 3);

(4) Drying, polishing, and polishing the composite material prepared in (3) by dip coating or spraying a hydrophilic coating (such as an aqueous solution made of chitosan, hyaluronic acid, collagen, cellulose, etc.) As a stent graft.

Degradable Scaffold Complex Example 3: A polycaprolactone type polyurethane synthesis scheme is exemplified as follows:

plan 1:

Weigh 9.00g ε-caprolactone, 3.00g PEG-600, stannous octoate as catalyst, add to the test tube, add a magnetic stirrer, vacuum/nitrogen cycle for 3 times, and under vacuum conditions The tube was sealed and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. 2 g of L-lysine diisocyanate and 0.8 g of BDO were weighed, placed in a test tube, evacuated and the tube was sealed. The reaction was carried out in an oil bath at 70 ° C for 4 h to obtain a final product.

Scenario 2:

Weigh 6.00g ε-caprolactone, 6.00g PEG-200, stannous octoate as catalyst, add to the test tube, add a magnetic stirrer, vacuum/nitrogen cycle for 3 times, and under vacuum conditions The tube was sealed and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. 2 g of L-lysine diisocyanate and 0.6 g of BDO were weighed, placed in a test tube, evacuated and the tube was sealed. The reaction was carried out in an oil bath at 70 ° C for 4 h to obtain a final product.

Option 3:

Weigh 8.00g ε-caprolactone, 4.00g PEG-1000, stannous octoate as catalyst The agent is added to the test tube, and then a magnetic stirrer is added, vacuumed/nitrogenated for 3 times, and the test tube mouth is sealed under vacuum condition, and placed in an oil bath at 140 ° C for 24 hours to obtain linear polymerization. Things. Further weigh 3 g of L-lysine diisocyanate and 0.7 g of BDO, put them into a test tube, evacuate and seal the tube. The reaction was carried out in an oil bath at 70 ° C for 4 h to obtain a final product.

Option 4

Weigh 9.0g ε-caprolactone, 3.0g PEG-600, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Weigh 2g of L-lysine diisocyanate and 0.6g of BDO, then add 0.5g of PEG-200 into a vacuum reaction bottle, vacuum and seal the bottle mouth, and put it into a 70 ° C oil bath for 4h to get the final product.

Option 5

Option 6

Option 7

Option 8

Option 9

Option 10

Weigh 8.0g ε-caprolactone, 4.0g PEG-400, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen Cycle 3 times, and seal the vacuum reaction bottle under vacuum condition, put The reaction was carried out in an oil bath at 140 ° C for 24 h to obtain a linear polymer. Weigh 2g of L-lysine diisocyanate and 0.6g of BDO, then add 0.5g of PEG-400 into a vacuum reaction bottle, vacuum and seal the bottle mouth, and put it into the oil bath of 70 °C for 4h to get the final product.

Option 11

Option 12

Weigh 9.00g ε-caprolactone, 4.00g PEG-400, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Weigh 2g of L-lysine diisocyanate and 0.6g of BDO, then add 0.5g of PEG-1500 into a vacuum reaction bottle, vacuum and seal the bottle mouth, and put it into the oil bath of 70 °C for 4h to get the final product.

Option 13

Option 14

Option 15

Option 16

Option 17

Weigh 10g of poly(hexamethylene carbonate) diol, stannous octoate (0.03wt% of total) as a catalyst, add a magnetic stirrer, and weigh 3g of L-lysine diisocyanate and 0.6gBDO, placed in a vacuum reaction bottle, vacuumed / nitrogen-filled cycle 3 times vacuum and sealed the bottle mouth, placed in a 70 ° C oil bath for 4h, the vacuum reaction bottle was taken out to cool to room temperature, the moisture content is less than In a 10 ppm environment, 1.6 g of L-lysine triisocyanate was added for blocking, and the mixture was stirred at room temperature for 30 minutes to obtain a final product.

Option 18

Weigh 6.0g ε-caprolactone, 3.0g PEG-600, stannous octoate (0.03wt% of total) as catalyst, add to the vacuum reaction bottle, add a magnetic stirrer, vacuum / nitrogen The mixture was circulated 3 times, and the vacuum reaction bottle mouth was sealed under vacuum, and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Weigh 2.4g IPDI, 0.6gHDI and 0.6g BDO, put it into the vacuum reaction bottle, vacuum and seal the bottle mouth, and put it into the oil bath at 70 °C.

Option 19

Option 20

Glycolic acid (4g), L-lactic acid (12g) and BDO (1.1g) were weighed into a vacuum reaction flask, dried at 80 ° C under high vacuum, and stopped at 150 ° C for 48 h. HDI (2 g) and octanoic acid were added. Tin (0.02 wt% of the total amount) was reacted in an oil bath at 70 ° C for 6 h to obtain a final product, which was capped by adding 0.6 g of L-lysine triisocyanate under vacuum, and shaken at room temperature or stirred for 30 min to obtain a final product.

Option 21

Glycolic acid (4g), DL-lactic acid (12g) and 1,6-hexanediol (1.8g) were weighed into a vacuum reaction flask, dried at 80 ° C under high vacuum, and reacted at 150 ° C for 24 h, then stopped, and added IPDI. (2g) and stannous octoate (0.02% by weight of total) were reacted in an oil bath at 70 ° C for 6 h to obtain a final product. The vacuum reaction flask was taken out and cooled to room temperature, and 1.0 g of L-lysine triisocyanate was added for sealing. At the end, the kneading machine was repeatedly kneaded and stirred for 30 minutes to obtain a final product.

Option 22

Degradable stent complex Example 4: ureteral stent

The preparation process is as follows:

(1) Degradable metal materials (the alloy composition ratio is selected according to 1 in the list or 99% magnesium content, 1% Mn content)

Magnesium-manganese alloy) is drawn into a tube with an outer diameter of 1 mm, a wall thickness of 0.2 mm and a length of 40 cm, and is engraved into a desired pattern (the schematic diagram after the tube is unfolded is shown in Fig. 6);

(2) Dissolving polymer A: a degradable medical polyurethane material and a polymer B: PLGA (wherein a ratio of LA:GA of 60:40 and a viscosity average molecular weight of 100,000) in a 1:1 mixture in a solvent of dichloromethane. Laying a film of 0.2-0.3 mm thick on a tetrafluoroethylene sheet;

(3) winding the film prepared in (2) on the surface of the metal stent metal material prepared in (1) to form a film stent;

(4) Drying, polishing, and polishing the composite material prepared in (3) by dip coating or spraying a hydrophilic coating (such as an aqueous solution made of chitosan, hyaluronic acid, collagen, cellulose, etc.) A stent graft is made.

Degradable stent composite Example 5: Preparation of gradient-degradable ureteral stents by 3D printing

A 3D printer with two feeding devices is selected, a magnesium alloy powder (powder particle size of 30-80 um) is added to one feeding device, and a polymer material (degradable medical polyurethane material and polylactic acid are added in proportion to another feeding device) 1:1), chloroform is set to a concentration of 30% solution), ureteral stent length (15-40cm, evenly divided into 8 segments), magnesium alloy powder: polymer material weight ratio from (1:11) : 8) It is divided into 8 parts of gradient printing, and the bracket of the set size and shape is printed, and the hot air is dried to evaporate the dry organic solvent.

The printed bracket can be surface treated by dip coating or spraying according to product requirements.

Degradable stent composite Example 6: Preparation of vascular stents using 3D printing technology

A 3D printer with two feeding devices is selected, and a magnesium alloy powder (powder particle size of 30-80 um) is added to a feeding device, and the stent is printed at a high temperature and melted as needed, and passivation is used for standby, and another feeding device is used. Adding polymer materials (degradable medical polyurethane material and polylactic acid in proportion (1:3), using chloroform to form a 50% solution), printing the coating film, and drying the volatile organic solvent by hot air Got it.

Degradable stent complex Example 7: Degradation of double balloon urethral stent Beagle implant

The double balloon urethral stent prepared in Examples 1 and 2 was sterilized with ethylene oxide. Six Beagle dogs weighing about 12KG were selected and placed in the urethra of the dogs for observation, 3 in each group. The degree of swelling of the urethra, serological and histological sections were observed regularly after operation. The experimental results showed that the stent in Example 1 began to degrade after 2 weeks, and the degradation was complete at 6 weeks. The stent in Example 2 began to degrade at 4 weeks, completely degraded at 8 weeks, and the inflammatory reaction of the urethra was light, and the tissue compatibility was good. , has a very good supporting role.

The above embodiments are only used to illustrate the technical solutions of the present invention, and are not limited thereto; The present invention has been described in detail in the foregoing embodiments, and those of ordinary skill in the art will understand that the technical solutions described in the foregoing embodiments may be modified or equivalently substituted for some of the technical features; Or, instead, the essence of the corresponding technical solutions is not deviated from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

A polyurethane composition having an adjustable elastic modulus, the polyurethane composition being composed of polymers I and II having the following formulas A and B, respectively, and the weight ratio of the polymer I to the polymer II is in the range of I: II = ( 0.01-1): (1-0.1),

Wherein, by changing the weight ratio of the polymer I and the polymer II and their respective molecular weights, the elastic modulus of the polyurethane composition can be adjusted in the range of 50 MPa to 1000 MPa, and the range can be adjusted within the range of 10% to 1000%. The elongation at break of the polyurethane composition,

Molecular formula A:

a is an integer in the range of 5-50, and b is an integer in the range of 5-50.

Molecular formula B:

x is an integer in the range of 5 to 50, and y is an integer in the range of 5 to 50.
The polyurethane composition according to claim 1, wherein said polymer I and polymer II have a weight ratio of I: II = (0.01 - 0.5): 1, wherein a in the formula A is an integer in the range of 10-20 , b is an integer in the range of 10-25, x in the formula B is an integer in the range of 10-20, y is an integer in the range of 10-25, and the elastic modulus can be adjusted in the range of 100 MPa to 500 MPa, The elongation at break can be adjusted from 100% to 700%.
A polyurethane composition comprising a polymer III having the formula C, or a polymer IV having the formula D,

Molecular formula C:

n is an integer in the range 0-25, and R is -CH 2 - or -COOC 4 H 9 -,

Formula D:

R 1 is

h is an integer in the range 0-20, and k is an integer in the range 0-25.
The polyurethane composition according to claim 3, wherein the polyurethane composition has a modulus of elasticity higher than 400 MPa and an elongation at break in the range of 30% to 300%.
A method of preparing a polyurethane composition comprising the polyamine of claim 1 or 2 The ester composition is further reacted with lysine triisocyanate after the end of its synthesis reaction to form a network crosslinked structure having an elastic modulus of more than 400 MPa and an elongation at break of 30% to 300%. Within the scope, wherein the synthesis reaction of the polyurethane is selected from the following steps:

(1) reacting a product with a diisocyanate using ε-caprolactone in a weight or volume ratio ranging from 6:1 to 1:1 and a PEG-synthesized linear polycaprolactone diol having a molecular weight in the range of from 200 to 2000 Using a glycol as a chain extender, stannous octoate (0.01-0.1 wt% of total mass) as a catalyst, reacting to obtain the polyurethane;

(2) using a polylactic acid having a molecular weight in the range of 200-2000, such as PLA, PGA, PLGA, and a glycol to synthesize a linear lactic acid-glycolic acid copolyol, reacting the product with a different diisocyanate, stannous octoate (total amount 0.01-0.1 wt%) as a catalyst, the reaction gives the polyurethane; or

(3) using a different polymer diol as a soft chain, reacting it with LDI and BDO, stannous octoate (0.01-0.1 wt% of the total amount) as a catalyst, and reacting to obtain the polyurethane,

Wherein the diisocyanate is selected from the group consisting of: 1,6-hexamethylene diisocyanate, isophorone diisocyanate, lysine methyl ester diisocyanate, cis-cyclohexane diisocyanate, trans-cyclohexane Diisocyanate, 1,4-butane diisocyanate, 1,2-ethane diisocyanate, 1,3-propane diisocyanate, 4,4'-methylene-bis(cyclohexyl isocyanate), 2,4,4 One or two of trimethyl 1,6-hexane diisocyanate;

Wherein the chain extender glycol is selected from the group consisting of ethylene glycol, diethylene glycol, tetraethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,6-hexanediol, 1,7-g One or two of a diol, 1,8-octanediol, 1,9-nonanediol, and 1,10-decanediol;

Wherein the polymer diol comprises poly-(4-hydroxybutyrate) diol (P4HB diol), poly-(3-hydroxybutyrate) diol (P3HB diol), polypropylene glycol and any copolymerization thereof , including PLGA diol, P(LA/CL) diol and P(3HB/4HB) diol, polyether polyol such as poly (four Hydrogenfuran), one or both of polycarbonate polyols such as poly(hexamethylene carbonate) glycol.
The method of claim 5 wherein the reaction of said polyurethane with lysine triisocyanate is selected from one of the following:

(1) The polyurethane obtained in claim 5, and L-lysine triisocyanate are reacted in a twin-screw extruder having a moisture content of less than 10 ppm for 20 minutes, and stirred and polymerized and extruded to obtain a high modulus of elasticity. The polyurethane composition;

(2) The polyurethane obtained in claim 5 is poured into a kneader or a kneader in an environment having a moisture content of less than 10 ppm, directly added with L-lysine triisocyanate, and stirred at room temperature for half an hour to obtain a high modulus of elasticity of the polyurethane composition;

(3) The polyurethane obtained in claim 5 is added to an anhydrous organic solvent (tetrahydrofuran, dichloromethane or chloroform) to form a viscous solution, and L-lysine is directly added in an environment having a moisture content of less than 10 ppm. Acid triisocyanate, the reaction system is stirred or shaken, and reacted at room temperature for half an hour, and then vacuum-dried the organic solvent to obtain the polyurethane composition having a high modulus of elasticity; or

(4) The polyurethane obtained in claim 5 is directly added with L-lysine triisocyanate in an environment having a moisture content of less than 10 ppm, and the reaction system is stirred or shaken and mixed, and the organic solvent is vacuum-dried after half an hour of normal temperature reaction. The polyurethane composition having a high modulus of elasticity.
A polyurethane composition prepared by the method of any of claims 5-6.
The use of the polyurethane composition according to any one of claims 1 to 4, in the preparation of a medical implant material selected from the group consisting of an implant device, an implantable artificial organ, a contact artificial organ , stents, interventional catheters, and organ assist devices.
A degradable stent composite comprising a polyurethane composition and a degradable metal material, the weight ratio of the polyurethane composition to the degradable metal material being in the range of from 0.1 to 99%: 1% to 99.9%.
A degradable stent composite according to claim 9, comprising a stent formed of said degradable metal material, said stent formed of said polyurethane composition, and preferably said polyurethane combination The weight ratio of the substance to the degradable metal material is in the range of from 5 to 90%: 10% to 95%.
The degradable stent composite according to claim 9 or 10, wherein the polyurethane is the polyurethane composition according to any one of claims 1-4 or 7.
The degradable stent composite according to claim 9 or 10, wherein the polyurethane is selected from the group consisting of polylactic acid type polyurethane, polycaprolactone type polyurethane, and two degradable polyurethane derivatives (silicone, polyamino acid modification, polysaccharide One or two of the modified), preferably a poly(ε-caprolactone) diol (PCL) as a soft segment, L-lysine diisocyanate (LDI) and a chain extender 1,4- Butylene glycol (BDO) is a hard segment polyurethane (PU) material.
The degradable stent composite according to any one of claims 9 to 12, further comprising another polymer material selected from the group consisting of polylactic acid, polycaprolactone, polydioxanone, and Copolymer (PPDO, PLA-PDO), polydioxanone (PPDO), polytrimethylene carbonate, polylactic acid-trimethylene carbonate copolymer, polycaprolactone-trimethylene carbonate At least one of an ester copolymer, a polyglycolic acid, and a polylactic acid-glycolic acid copolymer, the biodegradable polymer material having a viscosity average molecular weight of 500 to 1,000,000.
The degradable stent composite according to any one of claims 9 to 13, wherein the metal material comprises iron having a purity of more than 99.0%, a purity of more than 99.0% magnesium, and a magnesium iron alloy having a weight percentage of 1:0.01-10. a magnesium-zinc-based alloy having a weight percentage of 1:0.01-1, a magnesium-calcium alloy having a weight percentage of 1:0.01-1, and a combination of one or two of a weight ratio of 1:0.01-0.1 magnesium-aluminum alloy. Preferably, the magnesium iron alloy (weight ratio is preferably 1:0.01-0.1), the magnesium-zinc alloy (weight ratio is preferably 1:0.01-0.1), for example: Mg-Nd-Zn-Zr, Mg-Zn-Mn, Mg-Zn-Mn -Se-Cu alloy, Zn content of 3.5 wt%, Mn content of 0.5-1.0 wt%, Se content of 0.4-1.0 wt%, Cu content of 0.2-0.5 wt%, Mg balance; Magnesium-calcium-based alloy (weight ratio is preferably 1:0.01-0.1), for example: Mg-Zn-Ca-Fe, magnesium-aluminum alloy (weight ratio is preferably 1:0.01-0.1, for example: aluminum (Al): 2.0 to 3.0 Wt.%, zinc (Zn): 0.5 to 1.0 wt.%, manganese (Mn), Mg balance.
A method of preparing a degradable stent composite according to any of claims 9-14, comprising the steps of:

(1) preparing, engraving, etching or cutting the degradable metal material into a desired pattern or strip shape, preferably having a diameter of 0.01 to 3 mm;

(2) The polyurethane composition according to Claims 1-4 or 7 is dissolved in an organic solvent (selected from decane, tetrahydrofuran, isoamyl acetate, hexane, dichloromethane, chloroform, cyclohexanone, In one or both of dimethylformamide and heptane, a coating material is prepared (the concentration of the polyurethane composition in the coating is 5-50%);

(3) The coating material prepared in (2) is repeatedly dip-coated or uniformly sprayed on the surface of the metal stent prepared in (1) to form a composite stent with a coating having a thickness in the range of 0.001 to 1 mm. Internally, it is preferably 0.01 to 0.5 mm.
A method of preparing a degradable stent composite according to any of claims 9-14, comprising the steps of:

(1) The degradable metal material is prepared, engraved, etched or cut into a desired pattern or strip shape, and the diameter of the pattern is 0.01-3 mm;

(2) The polyurethane composition according to claim 1-4 or 7 and polylactic acid are mixed and dissolved in an organic solvent in a ratio of 1:0.1 to 10 by weight, and are formed into a film having a thickness of 0.01 to 3 mm. Preferably 0.1-1 mm;

(3) winding the film prepared by (2) on the surface of the metal stent prepared in (1) to form a film stent;

(4) The coated stent prepared in (3) is polished and polished into the degradable stent composite by dip coating or spraying a hydrophilic coating.
A method of preparing a degradable stent composite according to any one of claims 9-14, comprising one of the following methods:

(1) a solution of a magnesium alloy powder (a powder diameter ranging from 10 nm to 1 mm) and a polyurethane composition according to any one of claims 1 to 4 or 7 (the organic polyurethane solvent is used to dissolve the polyurethane composition and It is formulated into a viscous solution of 20-90% concentration) and uniformly mixed, and a stent having a diameter and a wall thickness is printed by a 3D printer, and the dry organic solvent is dried by hot air to obtain the degradable stent composite;

(2) Adding two feeding devices to the 3D printer, adding a magnesium alloy powder (a powder diameter ranging from 10 nm to 1 mm) to one feeding device, and adding one of the feeding devices according to any one of claims 1-4 or 7 a solution of the polyurethane composition (20-90% by weight with an organic solvent), the two materials are mixed in proportion during the feeding process, and the stent of the set size and shape is printed, and the hot air is dried to dry the organic solvent. Obtaining the degradable scaffold complex;

(3) The 3D printer is provided with two feeding devices, one feeding device is added with magnesium alloy powder (the powder diameter ranges from 10 nm to 1 mm), and the other feeding device is added in proportion (1:0.1-10) as claimed in claim 1 The polyurethane composition according to any one of 4 or 7 and the polylactic acid, which are mixed and dissolved in an organic solvent, and are formulated with an organic solvent to have a concentration of 20-90%, and the two substances are mixed in proportion during the feeding process. Then, the stent of the set size and shape is printed, and the dry organic solvent is evaporated by hot air to obtain the degradable stent composite;

(4) The 3D printer is equipped with two feeding devices. Magnesium alloy powder is added to one feeding device (the powder diameter ranges from 10 nm to 1 mm). The high temperature melting prints out the bracket as needed, and the passivation treatment is used for standby; another feeding device is proportional. (1:0.1-10) The polyurethane composition according to any one of claims 1 to 4 or 7 and polylactic acid are added, and then mixed and dissolved in an organic solvent, and the organic solvent is formulated to have a percentage concentration of 20-90%, a coating film is printed on the stent, and the dry organic solvent is evaporated by hot air to obtain the degradable stent composite.
Degradable stent composite according to any one of claims 9-14 or as claimed The degradable stent composite prepared by the method of any one of 15-17, wherein the structure, composition and shape are suitable for blood vessels, veins, esophagus, biliary tract, trachea, bronchus, small intestine, large intestine, urethra, ureter Or other fragments close to the tubular passage, for example, as a vascular stent, a tracheal stent, a bronchial stent, a urethral stent, an esophageal stent, a biliary stent, a ureteral stent (double J tube), a ureteral stricture stent, a stent for the small intestine, A stent for the large intestine, a laryngeal implant, a bypass catheter, or an ileostomy.
The degradable stent composite of claim 18, further comprising a contrast agent selected from the group consisting of zirconium dioxide, barium sulfate, and iodine.