WO2016037413A1 - 一种药物涂层组合物、其制备方法及利用其制成的植入或介入医疗器械 - Google Patents

一种药物涂层组合物、其制备方法及利用其制成的植入或介入医疗器械 Download PDF

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WO2016037413A1
WO2016037413A1 PCT/CN2014/091205 CN2014091205W WO2016037413A1 WO 2016037413 A1 WO2016037413 A1 WO 2016037413A1 CN 2014091205 W CN2014091205 W CN 2014091205W WO 2016037413 A1 WO2016037413 A1 WO 2016037413A1
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component
drug
solution
coating composition
paclitaxel
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PCT/CN2014/091205
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English (en)
French (fr)
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赵中
薛冠华
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浙江归创医疗器械有限公司
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Priority claimed from CN201410456663.4A external-priority patent/CN104174074B/zh
Application filed by 浙江归创医疗器械有限公司 filed Critical 浙江归创医疗器械有限公司
Publication of WO2016037413A1 publication Critical patent/WO2016037413A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials

Definitions

  • the invention belongs to the technical field of medical instruments, and in particular relates to a drug coating composition, a preparation method thereof and an implanted or interventional medical device made thereof.
  • Both drug-coated balloons and drug-eluting stents are essentially derived from the concept of a catheter-based topical drug delivery device that inhibits intimal hyperplasia by carrying drugs, but only the way the drug is carried and the time of action of the local drug Traditionally, the maintenance of local vascular drug action is the basis for its anti-proliferative effect. However, with the development of in vitro cells, animal experiments and human studies, it has been found that this is not the case. Initially, people were able to carry out a short-term contact with the vessel wall through a contrast agent to investigate the possibility of this method to inhibit restenosis.
  • peripheral lower limb vascular stents After years of development, drug stents have achieved very good results in coronary vascular disease, but there are certain limitations in the application of peripheral lower limb vascular stents. This is mainly due to the fact that, unlike coronary vessels, the arteries in the legs are long and straight, not the site of continuous movement. When the vascular occlusion is cleared, the probability of restenosis of the peripheral lower extremity vessels is much higher than that of the coronary vessels.
  • the advantage of a drug-eluting balloon is that it can accommodate blood vessels with a wide range of diameters. Since there is no metal residue in the body, there is no possibility of fragmentation, tissue proliferation or even clogging of the blood vessels.
  • the main foreign peripheral drug balloon companies are as follows:
  • B Braun's Sequent Please balloon system is paclitaxel, which uses iopromide as a carrier and is dissolved in water by iopromide. Sexually achieves a rapid release of paclitaxel.
  • the Dior I generation balloon system uses nanoporous technology to directly bind paclitaxel to the balloon surface, releasing the drug from the pores by pressure and into the vascular tissue.
  • the amount of absorption in the vascular tissue after pore adsorption is small, so Dior II changed the process, using shellac as a carrier. After the shellac swelled in the blood, it reached the lesion position and could be quickly squeezed.
  • the release of the drug, from the public data shows that the drug absorption of the diseased part of the modified process has been greatly improved.
  • the release curve of the drug is different under different formula conditions.
  • the drug needs to be released quickly, while releasing the particle size as much as possible while minimizing losses during delivery.
  • the drug balloon is a cardiovascular interventional material, it limits the choice of materials.
  • the existing drug balloon and preparation techniques mainly include the following:
  • Polyvinylpyrrolidone iodine usually contains a high content of elemental iodine (brown or deep red, 9-12%, dry weight ratio of PVP). It is usually used as a bactericidal, sterilizing and antiseptic agent for spectroscopy. Elemental iodine will gradually release into the environment. The proportion of patients who cause irritation and allergies will also increase.
  • the Sequent please drug balloon of the German company B. Braun uses paclitaxel as a functional drug and iopromide as a carrier material (US Pat. No. 8,439,986 B2; US8389043B2; US8257305B2; US7750041B2).
  • the rapid release of paclitaxel is achieved by the fast dissolution rate of iopromide in water.
  • This is the representative of the first generation of drug-eluting balloons, which has a large market in the market.
  • the coatings of such balloons have poor affinity, the coating strength is not good, and they are seriously lost in the middle of reaching the release site. After release, a large amount of paclitaxel drug insoluble matter is generated, which easily blocks blood vessels.
  • In.Pact a product of the American company Medtronic/Invatec, uses urea as a drug carrier (US Patent No. US20110295200A1; US20100233228A1).
  • Urea also does not increase the affinity between paclitaxel and the balloon surface.
  • their dissolution rates in water vary greatly, resulting in the formation of larger drug particles and increased clogging of blood vessels or blood vessels.
  • the Passeo-18 Lux of the German company Biotronik uses n-Butyryl tri-n-hexyl-citrate.
  • the fat of this adjuvant The solubility is higher than that of urea, and the phase separation from paclitaxel is better, but after all, it is a small molecule adjuvant.
  • the coating formula has poor affinity with the balloon, and the coating peels off seriously, and it is seriously lost in the future when it reaches the release site.
  • Lutonix Moxy's formula (US Patent US8425459B2; US8414526B2; US8241249B2) uses a surfactant, paclitaxel has a good coating uniformity on the surface of the balloon, and adhesion to the balloon is good, but due to the use of surfactants, the ball The surface of the capsule absorbs water significantly and the drug coating is easy to fall off. In addition, the drug is too uniform and does not release well after entering the vessel wall. Poor efficacy.
  • the balloon coating of the German company Aachen-Resonance and the American company COOK Medical uses pure paclitaxel, which relies on the crystallization of the drug itself to form a single coating. It enters the vessel wall under the mechanical pressure generated when the balloon expands, and has a certain sustained release period. However, since there is no carrier, the adhesion is not good, and the balloon folding is not a small loss. There are many opportunities to form large particles. Security is questioned.
  • German company Eurocor Freeway US Patent US20120143132A1; US20100076542A1; European Patent EP2125060B1;
  • EP2421572A2; EP2243501A1 uses shellac, has good adhesion, and the coating is transparent and uniform.
  • the disadvantage is that the shellac is very brittle, and the stability of the entire drug coating is not good after being combined with the water-insoluble paclitaxel.
  • shellac is a natural product, impurities are still inevitable after purification. The risks of biocompatibility and heat sources increase a lot.
  • drug-eluting balloons are a new and effective method for the treatment of blood vessels and other internal organs in the medical field, which is widely recognized by doctors in clinical use.
  • the products currently on the market and being developed have certain curative effects, and there are also disadvantages of different degrees.
  • the present invention is directed to a pharmaceutical coating composition suitable for application to an implanted or interventional medical device for use in implanting or intervening medical devices such as drug coated balloons and drug eluting stents. (DES) and other immersed in blood or distilled water to quickly disintegrate, while not forming large drug crystal particles, to avoid thrombosis and vascular occlusion.
  • DES drug coated balloons and drug eluting stents.
  • the invention also provides a method of preparing the pharmaceutical coating composition.
  • the present invention also provides an implanted or interventional medical device made using the drug coating composition, the implanted or interventional medical device comprising a drug eluting balloon, a drug eluting stent, and the like.
  • a pharmaceutical coating composition suitable for application to the surface of an implanted or interventional medical device comprising the following components:
  • the first component is a hydrophilic polymer
  • the second component is a drug for treating revascularization of the inner wall of blood vessels
  • the third component is an inorganic substance selected from the group consisting of one or more of an inorganic elemental substance, a water-soluble inorganic salt or an amphiphilic small molecule compound;
  • the weight ratio of the hydrophilic polymer to the drug for treating the revascularization of the blood vessel wall is 0.3-3:1, and the third component accounts for the total weight of the first component, the second component, and the third component. 0.005-5.0%;
  • the fourth component is a solvent system, and the solvent system includes a solvent that dissolves each of the first component, the second component, and the third component.
  • the treatment site of the implanted or interventional medical device includes: blood vessels and other conduits of the human body like the trachea, esophagus, urethra, vagina and fallopian tubes.
  • the hydrophilic polymer and the drug for treating the re-proliferation of the inner wall of the blood vessel that is, the weight ratio of the first component to the second component are 1.8-2.2:1, and the third component accounts for the first component and the second component. 0.005-2.0% of the total weight of the component and the third component.
  • the hydrophilic polymer is selected from the group consisting of polyvinylpyrrolidone (PVP), polyvinylpyrrolidone containing a coupled iodine, polyvinyl alcohol (PVA), polyethylene oxide (PEO) or polyethylene glycol ( PEG);
  • the drug for treating revascularization of the inner wall of the blood vessel is selected from the group consisting of paclitaxel or a derivative thereof, rapamycin or a derivative thereof, and an anticoagulant
  • the inorganic element is selected from the group consisting of iodine, bromine or nicotinamide
  • the inorganic inorganic salt is selected from the group consisting of sodium iodide, calcium iodide, sodium chloride or calcium chloride, and the amphiphilic small molecule compound is vitamin E-TPGS.
  • polyvinylpyrrolidone PVP
  • polyvinylpyrrolidone containing a combination of iodine PVA
  • polyethylene oxide PEO
  • PEG polyethylene glycol
  • the derivative of paclitaxel comprises the derivative of paclitaxel comprising docetaxel;
  • the rapamycin derivative comprises everolimus, Zotraromus, worship Biolimus; anticoagulants include cilostazol, heparin.
  • the implanted or interventional medical device comprises: coronary vascular stent, coronary vascular balloon, peripheral vascular stent, peripheral vascular balloon, intracranial vascular stent, intracranial vascular balloon, urethral stent, urethral bulb Capsule, esophageal stent or esophageal balloon.
  • the solvent in which the first component is dissolved is selected from one or two or more of water, ethanol, methanol or tetrahydrofuran; and the solvent in which the second component is dissolved is ethanol.
  • the solvent in which the third component is dissolved is one or a combination of two or more of water, ethanol or methanol.
  • the first component is obtained by dissolving the first component with ethanol, and the third component and the appropriate amount of water are added to the first component solution to be sufficiently mixed to obtain a third component solution, and the second component is ethanol.
  • the second component solution is obtained, and the volume ratio between the second component solution, the third component solution, and the water is 1-2:1-2:0.1-1.
  • the volume ratio between the second component solution, the third component solution, and the water is preferably from 1:1-2:0.25 to 0.28.
  • a method for preparing the pharmaceutical coating composition comprising the steps of: a, preparing a third component solution: thoroughly mixing the first component with a solvent, and arranging the first component at a concentration of 0.1-1 g/ml
  • the solution is stored at a temperature of 40-50 ° C to completely dissolve the first component, and then the third component is thoroughly mixed with the first component solution to obtain a third component solution, so that the third component solution is
  • the concentration of the three components is 0.001-0.1 g/ml
  • the preparation of the second component solution the second component is thoroughly mixed with the solvent, and the second component solution having a concentration of 0.05-0.5 g/ml is disposed, and Incubating at a temperature of 40-50 ° C until the second component is completely dissolved; c.
  • Formulation of the drug coating composition adding the third component solution and water to the second component solution, the second component
  • the volume ratio between the solution, the third component solution and the water is 1-2:1-2:0.1-1, sealed, and uniformly stirred to obtain a drug coating composition for coating on the surface of the implanted or interventional medical device. .
  • the method for preparing the above pharmaceutical coating composition comprises the following method: a, preparing an iodine solution: thoroughly mixing polyvinylpyrrolidone (PVP) with ethanol, and disposing a polyvinylpyrrolidone at a concentration of 0.1-0.3 g/ml.
  • PVP polyvinylpyrrolidone
  • paclitaxel ethanol solution Formulation: mixing paclitaxel with ethanol, dissolving a solution of paclitaxel in a concentration of 0.1-0.3 g/ml, and incubating at a temperature of 40-50 ° C until paclitaxel is completely dissolved;
  • preparation of the drug coating composition The iodine solution and distilled water were added to the paclitaxel ethanol solution, and the volume ratio between the paclitaxel ethanol solution, the iodine solution and the water was 1:1-2:0.25-0.28, sealed, and uniformly stirred to obtain a drug coating composition.
  • the preparation method of the above pharmaceutical coating composition comprises the following method: a. Preparation of a sodium iodide solution: thoroughly mixing polyvinylpyrrolidone (PVP) with ethanol, and arranging a concentration of 0.1-0.3 g/ml. A solution of vinylpyrrolidone (PVP) in ethanol and stored at 40-50 ° C to dissolve all PVP and then to PVP ethanol NaI is added to the solution and mixed thoroughly to obtain sodium iodide solution, so that the concentration of NaI in the sodium iodide solution is 0.05-0.5 g/ml; b. Preparation of paclitaxel ethanol solution: the paclitaxel and ethanol are thoroughly mixed, and the concentration is 0.1-0.3.
  • PVP polyvinylpyrrolidone
  • paclitaxel ethanol solution g/ml paclitaxel ethanol solution and incubated at 40-50 ° C until paclitaxel is completely dissolved; c, preparation of the drug coating composition: adding the sodium iodide solution and distilled water to the paclitaxel ethanol solution, paclitaxel The volume ratio between the ethanol solution, the sodium iodide solution and the water is 1:1 to 2:0.25 to 0.28, sealed, and uniformly stirred to obtain a drug coating composition.
  • the preparation method of the above pharmaceutical coating composition comprises the following method: a. Preparation of a nicotinamide solution: thoroughly mixing polyvinylpyrrolidone (PVP) with ethanol, and disposing a polyethylene having a concentration of 0.1-0.3 g/ml.
  • PVP polyvinylpyrrolidone
  • PVP Pyrrolidone
  • paclitaxel ethanol solution preparation paclitaxel and ethanol are thoroughly mixed, a concentration of 0.1-0.3g / ml paclitaxel ethanol solution, and kept at 40-50 ° C temperature until paclitaxel completely dissolved
  • drugs Formulation of the coating composition adding the nicotinamide solution and distilled water to the paclitaxel ethanol solution, the volume ratio between the paclitaxel ethanol solution, the nicotinamide solution and the water is 1:1-2:0.25-0.28, The film was sealed and stirred uniformly to obtain a drug coating composition.
  • the method for preparing the above pharmaceutical coating composition comprises the following method: a. Preparation of a nicotinamide calcium chloride solution: thoroughly mixing polyvinylpyrrolidone (PVP) with ethanol at a concentration of 0.1-0.3 g/ml. Polyvinylpyrrolidone (PVP) ethanol solution, and stored at 40-50 ° C to dissolve all PVP, and then add nicotinamide and calcium chloride to the PVP ethanol solution and mix well to obtain nicotinamide calcium chloride solution, so that the smoke
  • the concentration of nicotinamide in the amide calcium chloride solution is 0.01-0.05 g/ml, and the concentration of calcium chloride is 0.002-0.01 g/ml; b.
  • Preparation of paclitaxel ethanol solution the paclitaxel and ethanol are thoroughly mixed, and the concentration is 0.1-0.3. g/ml paclitaxel ethanol solution, and incubated at 40-50 ° C until paclitaxel is completely dissolved; c, preparation of the drug coating composition: adding the nicotinamide calcium chloride solution and distilled water to the paclitaxel ethanol solution The volume ratio of the paclitaxel ethanol solution, the nicotinamide calcium chloride solution and the water is 1:1 to 2:0.25 to 0.28, and the mixture is uniformly stirred to obtain a drug coating composition.
  • the preparation method of the above pharmaceutical coating composition comprises the following method: a, BHT solution preparation: polyvinylpyrrolidone (PVP) and ethanol are thoroughly mixed, and the concentration of polyvinylpyrrolidone is 0.1-0.3 g/ml.
  • BHT solution preparation polyvinylpyrrolidone (PVP) and ethanol are thoroughly mixed, and the concentration of polyvinylpyrrolidone is 0.1-0.3 g/ml.
  • paclitaxel ethanol solution (PVP) ethanol solution, and stored at 40-50 ° C to dissolve all PVP, and then add BHT to PVP ethanol solution and mix well to obtain BHT solution, the concentration is 0.00025-0.01g / ml;
  • paclitaxel ethanol solution Formulation thoroughly mix paclitaxel with ethanol, and configure a solution of paclitaxel in a concentration of 0.1-0.3 g/ml, and Incubating at a temperature of 40-50 ° C until paclitaxel is completely dissolved; c.
  • Formulation of the drug coating composition adding the BHT solution and distilled water, the paclitaxel ethanol solution, the BHT solution and the water between the paclitaxel ethanol solution
  • the volume ratio is from 1:1 to 2:0.25 to 0.28, sealed, and uniformly stirred to obtain a drug coating composition.
  • the drug paclitaxel may be replaced by paclitaxel or a derivative thereof, rapamycin or a derivative thereof, an anticoagulant, or the like, when the drug is rapa
  • the preparation method and concentration control of the rapamycin ethanol solution are the same as the paclitaxel ethanol solution.
  • the solvent of the system is mainly methanol, so that the solubility of rapamycin is better.
  • An implant or interventional medical device prepared using the drug coating composition by immersing a drug-coated implant or interventional medical device semi-finished product in the drug coating composition of the present invention Take it out after 5 to 60 seconds; dry at room temperature, fold, and sterilize to obtain the product.
  • the implanted or interventional medical device prepared by the pharmaceutical coating composition has a surface coating density of 0.5-10 ⁇ g/mm 2 and a net drug content of 0.2-8 ⁇ g/mm on the surface of the drug eluting device. 2 .
  • the present invention employs a water soluble high polymer such as polyvinylpyrrolidone as a carrier for a drug coating.
  • a water soluble high polymer such as polyvinylpyrrolidone
  • the drug coating quickly disintegrates (within 60-120 seconds) after contact with the blood vessel, allowing the drug in the coating to completely enter the vessel wall.
  • polyvinylpyrrolidone is an amphiphilic compound (having affinity for both polar and non-polar solvents and compounds), it does not form phase separation with paclitaxel.
  • the drug coating is very uniform and the adhesion to the surface of the balloon is also very good.
  • the coating disintegrates to form coarse particles which are insoluble in water which can be seen by the naked eye. It may block blood vessels.
  • Another key ingredient of the present invention is an inorganic additive having special effects such as iodine, calcium iodide, sodium iodide, calcium chloride or other water-soluble small molecules such as niacinamide.
  • These water-soluble salts or inorganic elements are present in the drug coating, which block the drug (like paclitaxel and rapamycin) and have high hydrophilicity.
  • Polymer such as polyvinylpyrrolidone). After forming a uniform, good adhesion balloon coating, it is immersed in water or blood to adjust the particle size of the drug.
  • a third key point of the invention is the formulation of the solvent, which does not have similar solubility to the drug (paclitaxel or rapamycin) and the polymer. Therefore, the effect of the composite solvent will be much better, such as ethanol, methanol, acetone, Water, tetrahydrofuran, etc. dissolve the drug, the polymer, and then mix the two solutions to form a homogeneous coating solution.
  • the preferred solvent of the first component is ethanol, water, or a mixed system of two;
  • the preferred solvent of the second component is ethanol, acetone, tetrahydrofuran, or a mixture of two of them.
  • the preferred solvent for the third component is ethanol, methanol, or a mixture of both.
  • the formulation and coating process of the present invention have a certain range of application, for example, several inorganic salts and neutral small molecules can adjust the uniformity of the coating, the affinity, and the rate of disintegration in water (blood). And the drug coating residue, as well as the formation of drug crystal particles.
  • the finally formed drug balloon coating is uniform, has good affinity with the balloon, and the coating peels off when folded, and rapidly disintegrates after being immersed in blood or distilled water.
  • a short period of time less than 1 minute
  • most of the drug coating will leave the surface of the balloon without forming large drug crystal particles, avoiding thrombosis and vascular occlusion.
  • Example 1A Preparation method of inorganic salt-containing drug balloon
  • PVP polyvinylpyrrolidone
  • Paclitaxel Ethanol Solution Weigh about 0.15 g of paclitaxel, add 25 ml glass vial; add 1 ml of ethanol to the glass vial; incubate in an oven at 45 ° C until paclitaxel is completely dissolved.
  • Preparing a sodium iodide solution adding about 0.4 g of NaI to a 25 ml sample vial; pipetting 8 ml of PVP ethanol solution into a sample vial;
  • Formulation of the drug coating composition Add about 1-2 ml of sodium iodide solution and a small amount (0.262 ml) of distilled water to the paclitaxel ethanol solution, seal, and mix well.
  • Balloon application The balloon is immersed in the above-mentioned drug coating composition (solution); it is kept for 5 to 60 seconds, and then taken out; dried at room temperature for 6 hours; folded, sterilized, and packaged.
  • Drug release rate and particle size test The balloon prepared by the above method was inflated to 2 atmospheres, then placed in a 20 ml 0.1 M phosphate buffer bottle, allowed to stand for 1 minute, then the balloon was removed, dried, and weighed. . At the same time, the residual of the drug coating on the balloon surface and the appearance of the drug crystal in the buffer bottle were observed. The test results are shown in Table 1. Results: More than 80% of the drug coating was smoothly released into the buffer, while no large particles were observed in the buffer bottle (no particles larger than 10 microns in diameter).
  • Example 1B Preparation method of inorganic salt-containing drug balloon
  • PVP polyvinylpyrrolidone
  • Preparation of paclitaxel methanol solution Weigh about 0.15 g of paclitaxel, add 25 ml glass bottle; add 1 ml of methanol to the glass bottle; incubate in an oven at 45 ° C until paclitaxel is completely dissolved.
  • Preparing a sodium iodide solution adding about 0.4 g of NaI to a 25 ml sample vial; pipetting 8 ml of PVP methanol solution into a sample vial;
  • Formulation of the drug coating composition Add about 1-2 ml of sodium iodide solution and a small amount (0.262 ml) of distilled water to the paclitaxel methanol solution, seal, and stir well.
  • Balloon application The balloon is immersed in the above-mentioned drug coating composition; it is kept for 5 to 60 seconds, then taken out; dried at room temperature for 6 hours; folded, sterilized, and packaged.
  • Drug release rate and particle size test The balloon prepared by the above method was inflated to 2 atmospheres, then placed in a 20 ml 0.1 M phosphate buffer bottle, allowed to stand for 1 minute, then the balloon was removed, dried, and weighed. . At the same time, the residual of the drug coating on the surface of the balloon and the state of the drug crystal in the buffer bottle were observed. The test results are shown in Table 2. RESULTS: More than 72% of the drug coating was smoothly released into the buffer, while no large particles were observed in the buffer bottle (no particles larger than 10 microns in diameter, the same below).
  • PVP ethanol solution 4 g PVP (Povidone K30) was weighed in a 0.0001 g precision balance and added to a 25 ml sample vial; 20 ml of ethanol was pipetted into the sample vial. Tighten the stopper, shake it, and store in a 45 ° C oven until all PVP is dissolved.
  • Paclitaxel Ethanol Solution Weigh about 0.15 g of paclitaxel, add 25 ml glass vial; add 1 ml of ethanol to the glass vial; incubate in an oven at 45 ° C until paclitaxel is completely dissolved.
  • Formulating a nicotinamide solution adding about 0.2 g of niacinamide to a 25 ml sample vial; pipetting 8 ml of a PVP ethanol solution into a sample vial;
  • Formulation of the drug coating composition About 1-2 ml of a nicotinamide solution and a small amount (0.262 ml) of distilled water were added to the paclitaxel ethanol solution, sealed, and stirred uniformly.
  • Balloon application The balloon is immersed in the above-mentioned drug coating composition; it is kept for 5 to 60 seconds, then taken out; dried at room temperature for 6 hours; folded, sterilized, and packaged.
  • Drug release rate and particle size test The balloon prepared by the above method was inflated to 2 atmospheres, then placed in a 20 ml 0.1 M phosphate buffer bottle, allowed to stand for 1 minute, then the balloon was removed, dried, and weighed. . At the same time, the residual of the drug coating on the balloon surface and the state of the drug crystal in the buffer bottle were observed. The test results are shown in Table 3. Results: More than 73% of the drug coating was smoothly released into the buffer, while a very small amount of large particles (particles larger than 10 microns in diameter) were observed in the buffer bottle.
  • Example 3 Preparation method of drug balloon containing two small molecule adjuvants:
  • PVP ethanol solution 4 g PVP (Povidone K30) was weighed in a 0.0001 g precision balance and added to a 25 ml sample vial; 20 ml of ethanol was pipetted into the sample vial. Tighten the stopper, shake it, and store in a 45 ° C oven until all PVP is dissolved.
  • Paclitaxel Ethanol Solution Weigh about 0.15 g of paclitaxel, add 25 ml glass vial; add 1 ml of ethanol to the glass vial; incubate in an oven at 45 ° C until paclitaxel is completely dissolved.
  • Formulating a nicotinamide calcium chloride solution adding about 0.1 g of nicotinamide and about 0.02 g of calcium chloride to a 25 ml sample vial; pipetting 8 ml of a PVP ethanol solution into a sample vial;
  • Formulation of the drug coating composition About 1-2 ml of a nicotinamide calcium chloride solution and a small amount (0.262 ml) of distilled water are added to the paclitaxel ethanol solution, sealed, and stirred uniformly.
  • Balloon application The balloon is immersed in the above-mentioned drug coating composition; it is kept for 5 to 60 seconds, then taken out; dried at room temperature for 6 hours; folded, sterilized, and packaged.
  • Drug release rate and particle size test The balloon prepared by the above method was inflated to 2 atmospheres, then placed in a 20 ml 0.1 M phosphate buffer bottle, allowed to stand for 1 minute, then the balloon was removed, dried, and weighed. . At the same time, the residual of the drug coating on the surface of the balloon and the state of the drug crystal in the buffer bottle were observed. The test results are shown in Table 4. Results: More than 76% of the drug coating was smoothly released into the buffer, while a certain amount of large particles (particles above 10 microns in diameter) were observed in the buffer bottle.
  • PVP ethanol solution 4 g PVP (Povidone K30) was weighed in a 0.0001 g precision balance and added to a 25 ml sample vial; 20 ml of ethanol was pipetted into the sample vial. Tighten the stopper, shake it, and store in a 45 ° C oven until all PVP is dissolved.
  • Paclitaxel Ethanol Solution Weigh about 0.15 g of paclitaxel, add 25 ml glass vial; add 1 ml of ethanol to the glass vial; incubate in an oven at 45 ° C until paclitaxel is completely dissolved.
  • Preparing an ethanol solution of iodine adding about 0.008 g of iodine to a 25 ml sample vial; pipetting 8 ml of PVP ethanol solution into a sample vial;
  • Formulation of the drug coating composition About 1 ml of the elemental iodine solution and a small amount (0.262 ml) of distilled water were added to the paclitaxel ethanol solution, and the mixture was uniformly stirred.
  • Balloon application The balloon is immersed in the above-mentioned drug coating composition; it is kept for 5 to 60 seconds, then taken out; dried at room temperature for 6 hours; folded, sterilized, and packaged.
  • Drug release rate and particle size test The balloon prepared by the above method was inflated to 2 atmospheres, then placed in a 20 ml 0.1 M phosphate buffer bottle, allowed to stand for 1 minute, then the balloon was removed, dried, and weighed. . At the same time, the residual of the drug coating on the surface of the balloon and the state of the drug crystal in the buffer bottle were observed. The test results are shown in Table 5. Results: More than 90% of the drug coating was smoothly released into the buffer, while no large particle drug (particles above 10 microns in diameter) was observed in the buffer bottle.
  • PVP ethanol solution 4 g PVP (Povidone K30) was weighed in a 0.0001 g precision balance and added to a 25 ml sample vial; 20 ml of ethanol was pipetted into the sample vial. Tighten the stopper, shake it, and store in a 45 ° C oven until all PVP is dissolved.
  • paclitaxel (PTX) ethanol solution weigh about 0.30 g of paclitaxel, add 25 ml glass bottle; 1 ml of ethanol was added to the glass bottle; the oven was incubated at 45 ° C until the paclitaxel was completely dissolved.
  • Preparing an ethanol solution of iodine adding about 0.008 g of iodine to a 25 ml sample vial; pipetting 8 ml of PVP ethanol solution into a sample vial;
  • Formulation of the drug coating composition About 1 ml of the elemental iodine solution and a small amount (0.262 ml) of distilled water were added to the paclitaxel ethanol solution, and the mixture was uniformly stirred.
  • Balloon application The balloon is immersed in the above-mentioned drug coating composition; it is kept for 5 to 60 seconds, then taken out; dried at room temperature for 6 hours; folded, sterilized, and packaged.
  • Drug release rate and particle size test The balloon prepared by the above method was inflated to 2 atmospheres, then placed in a 20 ml 0.1 M phosphate buffer bottle, allowed to stand for 1 minute, then the balloon was removed, dried, and weighed. . At the same time, the residual of the drug coating on the surface of the balloon and the appearance of the drug crystal in the buffer bottle were observed. The test results are shown in Table 6. Results: More than 90% of the drug coating was smoothly released into the buffer, while no large particle drug (particles above 10 microns in diameter) was observed in the buffer bottle.
  • PVP ethanol solution 4 g PVP (Povidone K30) was weighed in a 0.0001 g precision balance and added to a 25 ml sample vial; 20 ml of ethanol was pipetted into the sample vial. Tighten the stopper, shake it, and store in a 45 ° C oven until all PVP is dissolved.
  • Paclitaxel Ethanol Solution Weigh about 0.15 g of paclitaxel, add 25 ml glass vial; add 1 ml of ethanol to the glass vial; incubate in an oven at 45 ° C until paclitaxel is completely dissolved.
  • Preparing an ethanol solution of vitamin E-TPGS adding about 0.002 g of vitamin E-TPGS to a 25 ml sample vial; pipetting 8 ml of PVP ethanol solution into a sample vial;
  • Formulation of the drug coating composition About 1-2 ml of the vitamin E-TPGS solution and a small amount (0.262 ml) of distilled water were added to the paclitaxel ethanol solution, sealed, and stirred uniformly.
  • Balloon application The balloon is immersed in the above-mentioned drug coating composition; it is kept for 5 to 60 seconds, then taken out; dried at room temperature for 6 hours; folded, sterilized, and packaged.
  • Drug release rate and particle size test The balloon prepared by the above method was inflated to 2 atmospheres, then placed in a 20 ml 0.1 M phosphate buffer bottle, allowed to stand for 1 minute, then the balloon was removed, dried, and weighed. . At the same time, the residual of the drug coating on the surface of the balloon and the state of the drug crystal in the buffer bottle were observed. The test results are shown in Table 7. RESULTS: More than 75% of the drug coating was smoothly released into the buffer, while a certain amount of large granular drug crystals (particles above 10 microns in diameter) were observed in the buffer bottle.
  • PVP ethanol solution 4 g PVP (Povidone K30) was weighed in a 0.0001 g precision balance and added to a 25 ml sample vial; 20 ml of ethanol was pipetted into the sample vial. Tighten the stopper, shake it, and store in a 45 ° C oven until all PVP is dissolved.
  • paclitaxel acetone solution weigh about 0.15g paclitaxel, add 25ml glass bottle; add in glass bottle 1 ml of acetone was added; the oven was incubated at 45 ° C until paclitaxel was completely dissolved.
  • Preparing an ethanol solution of vitamin E-TPGS adding about 0.002 g of vitamin E-TPGS to a 25 ml sample vial; pipetting 8 ml of PVP ethanol solution into a sample vial;
  • Formulation of the drug coating composition About 1-2 ml of the vitamin E-TPGS solution and a small amount (0.262 ml) of distilled water were added to the paclitaxel acetone solution, sealed, and stirred uniformly.
  • Balloon application The balloon is immersed in the above-mentioned drug coating composition; it is kept for 5 to 60 seconds, then taken out; dried at room temperature for 6 hours; folded, sterilized, and packaged.
  • Drug release rate and particle size test The balloon prepared by the above method was inflated to 2 atmospheres, then placed in a 20 ml 0.1 M phosphate buffer bottle, allowed to stand for 1 minute, then the balloon was removed, dried, and weighed. . At the same time, the residual of the drug coating on the surface of the balloon and the state of the drug crystal in the buffer bottle were observed. The test results are shown in Table 8. Results: More than 60% of the drug coating was smoothly released into the buffer, while a certain amount of large granular drug crystals (particles above 10 microns in diameter) were observed in the buffer bottle.
  • PVP ethanol solution 4 g PVP (Povidone K30) was weighed in a 0.0001 g precision balance and added to a 25 ml sample vial; 20 ml of ethanol was pipetted into the sample vial. Tighten the stopper, shake it, and store in a 45 ° C oven until all PVP is dissolved.
  • paclitaxel tetrahydrofuran solution About 0.15 g of paclitaxel was weighed and added to a 25 ml glass vial; 1 ml of tetrahydrofuran was added to the glass vial; the oven was incubated at 45 ° C until the paclitaxel was completely dissolved.
  • Preparing an ethanol solution of vitamin E-TPGS adding about 0.002 g of vitamin E-TPGS to a 25 ml sample vial; pipetting 8 ml of PVP ethanol solution into a sample vial;
  • Formulation of the drug coating composition About 1-2 ml of the vitamin E-TPGS solution and a small amount (0.262 ml) of distilled water were added to the paclitaxel tetrahydrofuran solution, sealed, and stirred uniformly.
  • Balloon application The balloon is immersed in the above-mentioned drug coating composition; it is kept for 5 to 60 seconds, then taken out; dried at room temperature for 6 hours; folded, sterilized, and packaged.
  • Drug release rate and particle size test The balloon prepared by the above method was inflated to 2 atmospheres, then placed in a 20 ml 0.1 M phosphate buffer bottle, allowed to stand for 1 minute, then the balloon was removed, dried, and weighed. . At the same time, the residual of the drug coating on the surface of the balloon and the state of the drug crystal in the buffer bottle were observed. The test results are shown in Table 9. Results: More than 80% of the drug coating was smoothly released into the buffer, while a certain amount of large granular drug crystals (particles above 10 microns in diameter) were observed in the buffer bottle.
  • PVP ethanol solution 4 g PVP (Povidone K30) was weighed in a 0.0001 g precision balance and added to a 25 ml sample vial; 20 ml of ethanol was pipetted into the sample vial. Tighten the stopper, shake it, and store in a 45 ° C oven until all PVP is dissolved.
  • Paclitaxel Ethanol Solution Weigh about 0.15 g of paclitaxel, add 25 ml glass vial; add 1 ml of ethanol to the glass vial; incubate in an oven at 45 ° C until paclitaxel is completely dissolved.
  • Formulating an ethanol solution of BHT adding about 0.002 g of BHT to a 25 ml sample vial; pipetting 8 ml of a PVP ethanol solution into a sample vial;
  • Formulation of the drug coating composition About 1-2 ml of the vitamin E-TPGS solution and a small amount (0.262 ml) of distilled water were added to the paclitaxel ethanol solution, sealed, and stirred uniformly.
  • Balloon application The balloon is immersed in the above-mentioned drug coating composition; it is kept for 5 to 60 seconds, then taken out; dried at room temperature for 6 hours; folded, sterilized, and packaged.
  • Drug release rate and particle size test The balloon prepared by the above method was inflated to 2 atmospheres, then placed in a 20 ml 0.1 M phosphate buffer bottle, allowed to stand for 1 minute, then the balloon was removed, dried, and weighed. . At the same time, the residual of the drug coating on the balloon surface and the state of the drug crystal in the buffer bottle were observed. The test results are shown in Table 10. Results: More than 80% of the drug coating was smoothly released into the buffer, while a very small amount of large granular drug crystals were observed in the buffer bottle.
  • PVP ethanol solution 4 g PVP (Povidone K30) was weighed in a 0.0001 g precision balance and added to a 25 ml sample vial; 20 ml of ethanol was pipetted into the sample vial. Tighten the stopper, shake it, and store in a 45 ° C oven until all PVP is dissolved.
  • rapamycin ethanol solution weigh about 0.15g rapamycin, add 25ml glass bottle; in glass bottle 1 ml of ethanol was added; the oven was incubated at 45 ° C until the rapamycin was completely dissolved.
  • Formulating an ethanol solution of BHT adding about 0.002 g of BHT to a 25 ml sample vial; pipetting 8 ml of a PVP ethanol solution into a sample vial;
  • Formulation of the drug coating composition About 1-2 ml of the vitamin E-TPGS solution and a small amount (0.262 ml) of distilled water were added to the rapamycin ethanol solution, sealed, and stirred uniformly.
  • Balloon application The balloon is immersed in the above-mentioned drug coating composition; it is kept for 5 to 60 seconds, then taken out; dried at room temperature for 6 hours; folded, sterilized, and packaged.
  • Drug release rate and particle size test The balloon prepared by the above method was inflated to 2 atmospheres, then placed in a 20 ml 0.1 M phosphate buffer bottle, allowed to stand for 1 minute, then the balloon was removed, dried, and weighed. . At the same time, the residual of the drug coating on the balloon surface and the state of the drug crystal in the buffer bottle were observed. The test results are shown in Table 11. RESULTS: 58% of the drug coating was smoothly released into the buffer, while a very small amount of large granular drug crystals were observed in the buffer bottle.
  • the concentration of the first component solution, PVP ethanol solution is 0.2 g/ml, wherein 0.2 g/ml is the optimum concentration, and the concentration is the same from the overall process point of view.
  • the resulting drug coating density is related and can be appropriately increased or decreased according to the proportional relationship to adjust the density of the coating.

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Abstract

一种药物涂层组合物、其制备方法及利用其制成的植入或介入医疗器械，所述药物涂层组合物包括如下组分：第一组分为亲水性高聚物；第二组分为治疗血管内壁再增生的药物；第三组分为无机物，所述无机物选自无机单质、水溶性无机盐或两亲性小分子化合物中的一种或两种以上的组合物；第四组分为溶剂体系，溶剂体系包括将第一组分、第二组分和第三组分各自溶解的溶剂。所述药物涂层组合物制成的药物球囊涂层，与球囊的亲和性好，折叠时涂层脱落小，浸入血液或蒸馏水中后会快速崩解，同时不形成大的药物晶体颗粒，避免血栓形成和血管堵塞的情况。

Description

一种药物涂层组合物、其制备方法及利用其制成的植入或介入医疗器械 技术领域
本发明属于医疗器械技术领域，特别涉及一种药物涂层组合物、其制备方法及利用其制成的植入或介入医疗器械。
背景技术
药物涂层球囊和药物洗脱支架(DES)本质上都源于以导管为基础的局部药物输送装置这一概念，通过携带药物抑制内膜增生，只是携带药物的方式以及局部药物作用时间不同；传统上认为，局部血管药物作用的维持是发挥其抗增生作用的基础，然而随着离体细胞、动物实验以及人体研究的开展，人们发现事实并非如此。最初人们通过造影剂携带药物使之与血管壁短暂接触，来探讨这种方法抑制再狭窄的可能性，研究发现，将加入亲脂性紫杉醇的造影剂——优维显与培养的血管平滑肌细胞进行共孵育，即使短暂的3min培养即可完全抑制血管平滑肌增生，并且时间可达2周；培养15min后，脂溶性紫杉醇进入局部动脉壁的剂量可达肝素的20倍。随后的动物实验也发现，术中使用加入紫杉醇的优维显以及紫杉醇包被球囊(扩张1min)，即可使得血管壁中紫杉醇的浓度达到抗细胞增殖的浓度(即使超过90％的药物进入血流)，从而显著降低再狭窄的发生，这种效果甚至好于DES，这可能是由于支架本身的struts即可造成血管损伤反应，而球囊表面的光滑既避免了操作本身带来的损伤，又保证了药物平稳均匀释放和接触。药物涂层球囊的出现正是基于两个理论：(1)脂溶性的紫杉醇或西罗莫司能迅速被血管组织摄取，抗增殖药物的持续释放对抑制再狭窄的炎性反应进程来说并非必要；(2)药物短期暴露即可明显阻断早期的增生启动因子。
药物支架经过多年的发展，在冠脉血管疾病中已经获得了非常好的效果，但是在外周下肢血管支架中的应用存在了一定的局限。这主要是由于，不同于冠脉血管，腿部的动脉血管长且直，不是持续运动的部位。当血管堵塞疏通后，外周下肢血管的再狭窄机率比冠脉血管高很多。药物洗脱球囊的优势在于它能够适应直径范围很大的血管，由于没有金属在体内的残留，也就不存在支架可能存在的破碎，组织增生甚至是堵塞血管的风险。在欧洲，介入手术中采用DEB治疗外周下肢血管堵塞在国外的临床中已经被证明是一种很有效的手段，欧洲已经有数家公司有产品上市但是尚未进入中国市场，国内的厂家正处于研发阶段，暂时也没有相关产品上市。国内市场销售的仅有不载药的外周 球囊导管，相关企业主要有：强生医疗，乐普医疗，波士顿科技，库克，巴德国际等。药物涂层球囊导管在远期疗效相对于未载药球囊导管存在着极大的优势。
国外主要的外周药物球囊公司如下表：
Figure PCTCN2014091205-appb-000001
药物球囊制备的关键在于药物的涂层，不同公司的产品有着不同的设计理念，如B Braun公司的Sequent Please球囊系统的药物是紫杉醇，采用碘普罗胺为载体，通过碘普罗胺的水溶性来达到紫杉醇的快速释放。Dior I代球囊系统使用纳米多孔的技术直接将紫杉醇结合于球囊表面，通过加压将药物从孔隙中释放出来，进入血管组织。在临床效果来看，孔隙吸附后再血管组织中的吸收量较小，因此Dior II更改了工艺，采用虫胶为载体，虫胶在血液中吸水膨胀后，到达病变位置，挤压后能快速释放药物，从公开数据显示，更改后工艺的病变部位药物吸收量得到了很大的提高。
药物涂层的技术难点在于：
1.配方的选择，不同的配方条件下，药物的释放曲线不一样。对于药物球囊来说，需要药物可以快速释放，释放的同时尽量减少释放颗粒的大小，同时在输送过程中能尽量减少损失。而且由于药物球囊属于心血管介入性材料，就更加限制了材料的选择。
2.涂覆工艺的选择，选择好配方后，需要合适的工艺将载药溶液涂覆到球囊表面， 这种涂覆的工艺会直接影响到药物在球囊表面的分布均一性，药物在球囊表面的形态，最终会影响到药物的释放，药物释放的颗粒，因此即使有了成熟的配方在没有合适的涂覆工艺的情况下，也无法得到期望的药物涂层。
3.折叠工艺的选择，在球囊的涂层干燥完全之后，需要将球囊进行折叠，此时，要考虑将来的药物球囊可以在血管中顺利通过，通过过程中药物不会大量损失，涂层不能在传输过程中大片脱落，折叠不能影响到药物的释放曲线。有时用三折，有时用五折。
现有的药物球囊和制备技术主要有以下几种：
美国公司CVIngenuity的配方(美国专利US8491925B2、US8257722B2、US8128951B2、US8114429B2)采用聚乙烯吡咯酮碘(polynylpyrrol idone或PVP-I)为辅剂，得到的药物涂层效果不错，涂层均匀，见水后释放速度快，也不会形成大的紫杉醇药物晶体。但这种配方的缺点是聚乙烯吡咯酮碘是通过化学合成(美国专利2,739,922，欧洲专利EP 19790100966)而得到的聚乙烯吡咯酮和碘的稳定配位化合物(stable complex，见http：//en.wikipedia.org/wiki/Povidone-iodine)。聚乙烯吡咯酮碘通常含有很高含量的元素状的碘(棕色或深红色，9-12％，PVP的干重比例)。它通常是用作光谱的杀菌，消毒防腐的药剂。元素态的碘会逐渐释放的环境中去。这样造成刺激和过敏的病人比例也会提高。
德国公司B.Braun的Sequent please载药球囊以紫杉醇为功能药物，碘普罗胺为载体材料(美国专利US8439868B2；US8389043B2；US8257305B2；US7750041B2)。通过碘普罗胺在水中溶解速率快的特点，达到紫杉醇的快速释放。这是第一代药物洗脱球囊的代表，在市场上占有不小的市场。但在广泛的使用中，发行这类球囊的涂层亲和性很差，涂层强度不好，在到达释放地点前途中丢失严重。释放后大块的紫杉醇药物不溶物产生，容易堵塞血管。
美国公司美敦力(Medtronic/Invatec)的产品In.Pact用了尿素为药物载体(美国专利US20110295200A1；US20100233228A1)。但由于尿素和紫杉醇，性质差异很大，在同一种溶剂中的溶解度和结晶特点不一样，所以涂层分相明显，均一性不理想。尿素也不会增加紫杉醇与球囊表面之间的亲和性。另外它们在水中溶解速度差异很大，造成较大药物颗粒的形成，增加血栓或血管的堵塞。与此类似，德国公司Biotronik的Passeo-18Lux用的是丁酰柠檬酸三正己酯(n-Butyryl tri-n-hexyl-citrate)。这个辅剂的脂 溶性比尿素高一点，与紫杉醇的相分离好一点，但毕竟是小分子辅剂，涂层配方与球囊的亲和性差，涂层剥离严重，在到达释放地点前途中丢失严重。
Lutonix Moxy的配方(美国专利US8425459B2；US8414526B2；US8241249B2)用了表面活性剂，紫杉醇在球囊表面的涂层均匀性不错，与球囊的粘合性也不错，但由于表面活性剂的使用，球囊表面吸收水分明显，药物涂层容易脱落。另外药物太均匀，进入血管壁后不能很好地缓释。药效欠佳。
德国公司Aachen-Resonance和美国公司COOK Medical的球囊涂层采用纯紫杉醇，依靠药物自身的结晶来形成单一涂层。在球囊扩展时产生的机械压力下进入血管壁，有一定的缓释期。但由于没有载体，粘合性不好，球囊折叠是损失不小。形成大颗粒的机会很多。安全性受到质疑。
德国公司Eurocor Freeway(美国专利US20120143132A1；US20100076542A1；欧洲专利EP2125060B1；
EP2421572A2；EP2243501A1)使用了虫胶，粘合性好，涂层透明，均匀。但缺点是虫胶很脆，与不溶于水的紫杉醇结合后，整个药物涂层的稳定性不好。同时由于虫胶是天然产物，经过纯化后杂质仍然难免。生物相容性和热源的危险增加不少。
综上所述，药物洗脱球囊是介入医疗界的一个新的有效的治疗血管和其他体内官腔的方法，在临床使用得到了医生的普遍认可。现在市场上销售和正在研发的产品都有一定疗效，也都存在不同程度上的缺点。
发明内容
本发明旨在提供一种适用于涂在植入或介入医疗器械表面的药物涂层组合物，该药物涂层组合物使用后可使植入或介入医疗器械如药物涂层球囊和药物洗脱支架(DES)等浸入血液或蒸馏水中快速崩解，同时不会形成大的药物晶体颗粒，避免血栓形成和血管堵塞的情况。
本发明还提供一种所述药物涂层组合物的制备方法。
本发明还提供一种利用所述药物涂层组合物的制成的植入或介入医疗器械，所述的植入或介入医疗器械包括药物洗脱球囊、药物洗脱支架等。
本发明解决其技术问题所采用的技术方案是：
一种适用于涂在植入或介入医疗器械表面的药物涂层组合物，包括如下组分：
第一组分为亲水性高聚物；
第二组分为治疗血管内壁再增生的药物；
第三组分为无机物，选自无机单质、水溶性无机盐或两亲性小分子化合物中的一种或两种以上的组合物；
各组分中，亲水性高聚物与治疗血管内壁再增生的药物的重量比为0.3-3∶1，第三组分占第一组分、第二组分和第三组分总重量的0.005-5.0％；
第四组分为溶剂体系，溶剂体系包括将第一组分、第二组分和第三组分各自溶解的溶剂。该植入或介入医疗器械的治疗部位包括：血管和人体其他管道像气管，食道，尿道，阴道和输卵管。
进一步的，亲水性高聚物与治疗血管内壁再增生的药物，即第一组分与第二组分的重量比为1.8-2.2∶1，第三组分占第一组分、第二组分和第三组分总重量的0.005-2.0％。
作为优选，所述的亲水性高聚物选自聚乙烯吡咯酮(PVP)，含有耦合碘的聚乙烯吡咯酮，聚乙烯醇(PVA)，聚氧化乙烯(PEO)或聚乙二醇(PEG)；所述的治疗血管内壁再增生的药物选自紫杉醇或其衍生物、雷帕霉素或其衍生物、抗血凝药；所述的无机单质选自碘，溴或烟酰胺；水溶性无机盐选自碘化钠，碘化钙，氯化钠或氯化钙，两亲性小分子化合物为维生素E-TPGS。这里需要指出的是，由于聚乙烯吡咯酮(PVP)，含有耦合碘的聚乙烯吡咯酮，聚乙烯醇(PVA)，聚氧化乙烯(PEO)或聚乙二醇(PEG)这几种高聚物在水或乙醇，甲醇中的溶解度基本相同，因此可以互相替换，在使用过程中，使得最终得到的药物涂层亲水性好，崩解速度快；而无机盐在整个组分中把药物隔开，因此不会形成大颗粒药物晶体。
作为优选，所述紫杉醇的衍生物包括所述紫杉醇的衍生物包括多西紫杉醇(docetaxel)；雷帕霉素衍生物包括依维莫司(everolimus)，若他咯里莫司(Zotarolimus)，拜尔里莫司(Biolimus)；抗血凝药包括西洛他唑(Cilostazol)，肝素(heparin)。
作为优选，所述的植入或介入医疗器械包括：冠脉血管支架，冠脉血管球囊、外周血管支架、外周血管球囊、颅内血管支架、颅内血管球囊、尿道支架，尿道球囊、食道支架或食道球囊。
作为优选，所述的溶剂体系中，将第一组分溶解的溶剂选自水，乙醇，甲醇或四氢呋喃中的一种或两种以上的组合物；将第二组分溶解的溶剂为乙醇，甲醇，四氢呋喃或 丙酮中的一种或两种以上的组合物；将第三组分溶解的溶剂为水，乙醇或甲醇中的一种或两种以上的组合物。第一组分和第二个组分在不同溶剂中的溶解和混合过程是非常重要的。不同溶剂会优先地溶解不用的组分，像药或高聚物，还有无机组分等，以得到均匀牢固的涂层。
作为优选，用乙醇将第一组分溶解后得到第一组分溶液，向第一组分溶液中加入第三组分和适量水充分混合得到第三组分溶液，用乙醇将第二组分溶解后得到第二组分溶液，第二组分溶液、第三组分溶液和水三者之间的体积比为1-2∶1-2∶0.1-1。进一步的，第二组分溶液、第三组分溶液和水三者之间的体积比为优选为1∶1-2∶0.25-0.28。
一种所述药物涂层组合物的制备方法，包括如下步骤：a、第三组分溶液的配制：将第一组分与溶剂充分混合，配置浓度为0.1-1g/ml的第一组分溶液，并于40-50℃温度下保存使第一组分全部溶解，再向第一组分溶液中加入第三组分充分混合，得到第三组分溶液，使第三组分溶液中第三组分的浓度为0.001-0.1g/ml；b、第二组分溶液的配制：将第二组分与溶剂充分混合，配置浓度为0.05-0.5g/ml的第二组分溶液，并在40-50℃温度下保温直到第二组分完全溶解；c、药物涂层组合物的配制：在所述第二组分溶液中加入所述第三组分溶液和水，第二组分溶液、第三组分溶液和水三者之间的体积比为1-2∶1-2∶0.1-1，封口，搅拌均匀，得到用于涂在植入或介入医疗器械表面的药物涂层组合物。
进一步的，上述药物涂层组合物的制备方法包括如下一种方法，a、碘溶液的配制：将聚乙烯吡咯烷酮(PVP)与乙醇充分混合，配置浓度为0.1-0.3g/ml的聚乙烯吡咯烷酮(PVP)乙醇溶液，并于40-50℃温度下保存使PVP全部溶解，再向PVP乙醇溶液中加入I充分混合，得到碘溶液，浓度为0.001-0.01g/ml；b、紫杉醇乙醇溶液的配制：将紫杉醇与乙醇充分混合，配置浓度为0.1-0.3g/ml的紫杉醇乙醇溶液，并在40-50℃温度下保温直到紫杉醇完全溶解；c、药物涂层组合物的配制：在所述紫杉醇乙醇溶液中加入所述碘溶液和蒸馏水，紫杉醇乙醇溶液、碘溶液和水三者之间的体积比为1∶1-2∶0.25-0.28，封口，搅拌均匀，得到药物涂层组合物。
进一步的，上述药物涂层组合物的制备方法包括如下一种方法，a、碘化钠溶液的配制：将聚乙烯吡咯烷酮(PVP)与乙醇充分混合，配置浓度为0.1-0.3g/ml的聚乙烯吡咯烷酮(PVP)乙醇溶液，并于40-50℃温度下保存使PVP全部溶解，再向PVP乙醇 溶液中加入NaI充分混合，得到碘化钠溶液，使碘化钠溶液中NaI浓度为0.05-0.5g/ml；b、紫杉醇乙醇溶液的配制：将紫杉醇与乙醇充分混合，配置浓度为0.1-0.3g/ml的紫杉醇乙醇溶液，并在40-50℃温度下保温直到紫杉醇完全溶解；c、药物涂层组合物的配制：在所述紫杉醇乙醇溶液中加入所述碘化钠溶液和蒸馏水，紫杉醇乙醇溶液、碘化钠溶液和水三者之间的体积比为1∶1-2∶0.25-0.28，封口，搅拌均匀，得到药物涂层组合物。
进一步的，上述药物涂层组合物的制备方法包括如下一种方法，a、烟酰胺溶液的配制：将聚乙烯吡咯烷酮(PVP)与乙醇充分混合，配置浓度为0.1-0.3g/ml的聚乙烯吡咯烷酮(PVP)乙醇溶液，并于40-50℃温度下保存使PVP全部溶解，再向PVP乙醇溶液中加入烟酰胺充分混合，得到烟酰胺溶液，使烟酰胺溶液中烟酰胺浓度为0.02-0.2g/ml；b、紫杉醇乙醇溶液的配制：将紫杉醇与乙醇充分混合，配置浓度为0.1-0.3g/ml的紫杉醇乙醇溶液，并在40-50℃温度下保温直到紫杉醇完全溶解；c、药物涂层组合物的配制：在所述紫杉醇乙醇溶液中加入所述烟酰胺溶液和蒸馏水，紫杉醇乙醇溶液、烟酰胺溶液和水三者之间的体积比为1∶1-2∶0.25-0.28，封口，搅拌均匀，得到药物涂层组合物。
进一步的，上述药物涂层组合物的制备方法包括如下一种方法，a、烟酰胺氯化钙溶液的配制：将聚乙烯吡咯烷酮(PVP)与乙醇充分混合，配置浓度为0.1-0.3g/ml的聚乙烯吡咯烷酮(PVP)乙醇溶液，并于40-50℃温度下保存使PVP全部溶解，再向PVP乙醇溶液中加入烟酰胺和氯化钙充分混合，得到烟酰胺氯化钙溶液，使烟酰胺氯化钙溶液中烟酰胺浓度为0.01-0.05g/ml、氯化钙浓度为0.002-0.01g/ml；b、紫杉醇乙醇溶液的配制：将紫杉醇与乙醇充分混合，配置浓度为0.1-0.3g/ml的紫杉醇乙醇溶液，并在40-50℃温度下保温直到紫杉醇完全溶解；c、药物涂层组合物的配制：在所述紫杉醇乙醇溶液中加入所述烟酰胺氯化钙溶液和蒸馏水，紫杉醇乙醇溶液、烟酰胺氯化钙溶液和水三者之间的体积比为1∶1-2∶0.25-0.28，封口，搅拌均匀，得到药物涂层组合物。
进一步的，上述药物涂层组合物的制备方法包括如下一种方法，a、BHT溶液的配制：将聚乙烯吡咯烷酮(PVP)与乙醇充分混合，配置浓度为0.1-0.3g/ml的聚乙烯吡咯烷酮(PVP)乙醇溶液，并于40-50℃温度下保存使PVP全部溶解，再向PVP乙醇溶液中加入BHT充分混合，得到BHT溶液，浓度为0.00025-0.01g/ml；b、紫杉醇乙醇溶液的配制：将紫杉醇与乙醇充分混合，配置浓度为0.1-0.3g/ml的紫杉醇乙醇溶液，并 在40-50℃温度下保温直到紫杉醇完全溶解；c、药物涂层组合物的配制：在所述紫杉醇乙醇溶液中加入所述BHT溶液和蒸馏水，紫杉醇乙醇溶液、BHT溶液和水三者之间的体积比为1∶1-2∶0.25-0.28，封口，搅拌均匀，得到药物涂层组合物。
上述提供的各种优选的药物涂层组合物的制备方法中，采用的药物紫杉醇可由紫杉醇或其衍生物、雷帕霉素或其衍生物、抗血凝药等药物替换，当药物为雷帕霉素时，雷帕霉素乙醇溶液的配制方法和浓度控制同紫杉醇乙醇溶液。进一步的，当药物为雷帕霉素时，体系溶剂以甲醇为主可以使雷帕霉素的溶解性较好。
一种利用所述药物涂层组合物制备的植入或介入医疗器械，其过程是：将未经过药物涂覆的植入或介入医疗器械半成品浸没于本发明所述的药物涂层组合物中，保持5-60秒钟后取出；室温下干燥，折叠，灭菌，得到产品。
作为优选，所述药物涂层组合物制备的植入或介入医疗器械，其表面涂层的密度为0.5-10μg/mm2，药物净含量在药物洗脱器械表面的密度为0.2-8μg/mm2。
具体来讲，本发明采用水溶性高聚物如聚乙烯吡咯酮作为药物涂层的载体。由于有像聚乙烯吡咯酮这样的亲水性高聚物，药物涂层在接触血管后会迅速崩解(在60-120秒内)，让涂层中的药物完全进入血管壁。同时由于聚乙烯吡咯酮是两亲化合物(对极性和非极性溶剂和化合物都有亲和力)，所以跟紫杉醇不会形成相分离。在使用了这类高聚物后，药物涂层非常均匀，与球囊表面的粘合也非常好。但是浸入水中，涂层崩解，形成肉眼能看到的不溶于水的粗大颗粒。可能会堵塞血管。
本发明的另一个关键成分是有特殊功效的无机类的添加剂，如碘，碘化钙，碘化钠，氯化钙或其他水溶性的小分子，如烟酰胺等。这些水溶性的盐类或无机元素(不是与高聚物稳定偶合或配位的碘离子等)存在与药物涂层中，隔断了药物(像紫杉醇和雷帕霉素)与亲水性的高聚物(如聚乙烯吡咯酮)。再形成了均匀，粘合性好的球囊涂层后，浸入水或血液后，起到调节药物颗粒度的作用。经试验证明，比例合适的配方和涂层，在球囊涂层浸入水中后，达到了快速崩解和药物颗粒度小(肉眼目测是乳液状，而不是大颗粒)。这些无机小分子添加剂的比例非常关键，用量过高，会影响涂层成薄性能(太脆或太粘)，过低，又不能起到形成微小药物颗粒的作用。
本发明的第三个关键点是溶剂的配方，单纯的溶剂不会有对药物(紫杉醇或雷帕霉素)和高聚物有相似的溶解性。所以复合溶剂效果会好不少，比如乙醇，甲醇，丙酮， 水，四氢呋喃等分别溶解药物，高聚物，然后混合两个溶液，形成均相涂液。在本发明用到的溶剂体系，第一组分的优选溶剂是乙醇、水，或者是两种的混合体系；第二组分的优选溶剂是乙醇、丙酮、四氢呋喃，或者是其中两种的混合体系；第三组分的优选溶剂是乙醇、甲醇，或者是两种的混合体系。
本发明的配方和涂层工艺有一定的适用范围，比如好几种无机盐和中性的小分子都能够起到调节涂层均匀性，亲和性，和水中(血液)中崩解的速度和药物涂层残留，还有药物晶体颗粒的形成。
通过本发明的配方和涂层工艺，最后形成的药物球囊涂层，均匀，与球囊的亲和性好，折叠时涂层脱落小，浸入血液或蒸馏水中后会快速崩解，在很短时间内(短于1分钟)大部分的药物涂层都会脱离球囊表面，同时不形成大的药物晶体颗粒，避免血栓形成和血管堵塞的情况。
具体实施方式
下面通过具体实施例，对本发明的技术方案作进一步的具体说明。应当理解，本发明的实施并不局限于下面的实施例，对本发明所做的任何形式上的变通和/或改变都将落入本发明保护范围。
在本发明中，若非特指，所有的份、百分比均为重量单位，所采用的设备和原料等均可从市场购得或是本领域常用的。下述实施例中的方法，如无特别说明，均为本领域的常规方法。
实施例1A：含无机盐药物球囊的制备方法
聚乙烯吡咯烷酮(PVP)乙醇溶液的配置：用0.0001g精度的天平称量4g PVP(Povidone K30)，加入25ml样品瓶中，用移液枪吸取20ml的乙醇加入到样品瓶中。旋紧瓶塞，振荡搅拌后，放到45℃烘箱保存直至PVP全部溶解。
紫杉醇乙醇溶液的配制：称量约0.15g紫杉醇，加入25ml玻璃瓶；在玻璃瓶中加入1ml的乙醇；在45℃烘箱保温直到紫杉醇完全溶解。
配制碘化钠溶液：把约0.4gNaI加入25ml样品瓶中；用移液枪吸取PVP乙醇溶液8ml加入到样品瓶中；
配制药物涂层组合物：在紫杉醇乙醇溶液中加入约1-2ml的碘化钠溶液和少量(0.262ml)的蒸馏水，封口，搅拌均匀。
球囊涂药：将球囊浸没于上述的药物涂层组合物(溶液)中；保持5-60秒钟，后取出；在室温干燥6小时；折叠，灭菌，包装。
药物释放速度和颗粒度试验：把上述方法制得的球囊充气到2个大气压，然后放到20ml的0.1M的磷酸盐缓冲液瓶中，静止1分钟，然后取出球囊，干燥，称重。同时观察球囊表面药物涂层的残留情况和缓冲液瓶中的药物晶体的状念，试验结果见表1。结果：超过80％的药物涂层顺利地释放到缓冲液中，同时缓冲液瓶没有观察到大颗粒(无直径10微米以上的颗粒)。
表1
Figure PCTCN2014091205-appb-000002
实施例1B：含无机盐药物球囊的制备方法
聚乙烯吡咯烷酮(PVP)甲醇溶液的配置：用0.0001g精度的天平称量4g PVP(Povidone K30)，加入25ml样品瓶中，用移液枪吸取20ml的甲醇加入到样品瓶中。旋紧瓶塞，振荡搅拌后，放到45℃烘箱保存直至PVP全部溶解。
紫杉醇甲醇溶液的配制：称量约0.15g紫杉醇，加入25ml玻璃瓶；在玻璃瓶中加入1ml的甲醇；在45℃烘箱保温直到紫杉醇完全溶解。
配制碘化钠溶液：把约0.4g NaI加入25ml样品瓶中；用移液枪吸取PVP甲醇溶液8ml加入到样品瓶中；
配制药物涂层组合物：在紫杉醇甲醇溶液中加入约1-2ml的碘化钠溶液和少量(0.262ml)的蒸馏水，封口，搅拌均匀。
球囊涂药：将球囊浸没于上述的药物涂层组合物中；保持5-60秒钟，后取出；在室温干燥6小时；折叠，灭菌，包装。
药物释放速度和颗粒度试验：把上述方法制得的球囊充气到2个大气压，然后放到20ml的0.1M的磷酸盐缓冲液瓶中，静止1分钟，然后取出球囊，干燥，称重。同时观察球囊表面药物涂层的残留情况和缓冲液瓶中的药物晶体的状态，试验结果见表2。结果：超过72％的药物涂层顺利地释放到缓冲液中，同时缓冲液瓶没有观察到大颗粒(无直径10微米以上的颗粒，下同)。
表2
Figure PCTCN2014091205-appb-000003
实施例2：含小分子辅剂的药物球囊制备方法：
PVP乙醇溶液的配置：用0.0001g精度的天平称量4g PVP(Povidone K30)，加入25ml样品瓶中；用移液枪吸取20ml的乙醇加入到样品瓶中。旋紧瓶塞，振荡搅拌后，放到45℃烘箱保存直至PVP全部溶解。
紫杉醇乙醇溶液的配制：称量约0.15g紫杉醇，加入25ml玻璃瓶；在玻璃瓶中加入1ml的乙醇；在45℃烘箱保温直到紫杉醇完全溶解。
配制烟酰胺溶液：把约0.2g烟酰胺加入25ml样品瓶中；用移液枪吸取PVP乙醇溶液8ml加入到样品瓶中；
配制药物涂层组合物：在紫杉醇乙醇溶液中加入约1-2ml的烟酰胺溶液和少量(0.262ml)的蒸馏水，封口，搅拌均匀。
球囊涂药：将球囊浸没于上述的药物涂层组合物中；保持5-60秒钟，后取出；在室温干燥6小时；折叠，灭菌，包装。
药物释放速度和颗粒度试验：把上述方法制得的球囊充气到2个大气压，然后放到20ml的0.1M的磷酸盐缓冲液瓶中，静止1分钟，然后取出球囊，干燥，称重。同时观察球囊表面药物涂层的残留情况和缓冲液瓶中的药物晶体的状态，试验结果见表3。结果：超过73％的药物涂层顺利地释放到缓冲液中，同时缓冲液瓶观察到极少量的大颗粒(直径10微米以上的颗粒)。
表3
Figure PCTCN2014091205-appb-000004
实施例3：含两种小分子辅剂的药物球囊制备方法：
PVP乙醇溶液的配置：用0.0001g精度的天平称量4g PVP(Povidone K30)，加入25ml样品瓶中；用移液枪吸取20ml的乙醇加入到样品瓶中。旋紧瓶塞，振荡搅拌后，放到45℃烘箱保存直至PVP全部溶解。
紫杉醇乙醇溶液的配制：称量约0.15g紫杉醇，加入25ml玻璃瓶；在玻璃瓶中加入1ml的乙醇；在45℃烘箱保温直到紫杉醇完全溶解。
配制烟酰胺氯化钙溶液：把约0.1g烟酰胺和约0.02g氯化钙加入25ml样品瓶中；用移液枪吸取PVP乙醇溶液8ml加入到样品瓶中；
配制药物涂层组合物：在紫杉醇乙醇溶液中加入约1-2ml的烟酰胺氯化钙溶液和少量(0.262ml)的蒸馏水，封口，搅拌均匀。
球囊涂药：将球囊浸没于上述的药物涂层组合物中；保持5-60秒钟，后取出；在室温干燥6小时；折叠，灭菌，包装。
药物释放速度和颗粒度试验：把上述方法制得的球囊充气到2个大气压，然后放到20ml的0.1M的磷酸盐缓冲液瓶中，静止1分钟，然后取出球囊，干燥，称重。同时观察球囊表面药物涂层的残留情况和缓冲液瓶中的药物晶体的状念，试验结果见表4。结果：超过76％的药物涂层顺利地释放到缓冲液中，同时缓冲液瓶观察到一定量的大颗粒(直径10微米以上的颗粒)。
表4
Figure PCTCN2014091205-appb-000005
实施例4A：含无机单质碘的药物球囊制备方法1(PTX∶PVP∶I＝1.0∶1.33∶0.007，克/克/克)：
PVP乙醇溶液的配置：用0.0001g精度的天平称量4g PVP(Povidone K30)，加入25ml样品瓶中；用移液枪吸取20ml的乙醇加入到样品瓶中。旋紧瓶塞，振荡搅拌后，放到45℃烘箱保存直至PVP全部溶解。
紫杉醇乙醇溶液的配制：称量约0.15g紫杉醇，加入25ml玻璃瓶；在玻璃瓶中加入1ml的乙醇；在45℃烘箱保温直到紫杉醇完全溶解。
配制碘的乙醇溶液：把约0.008g碘加入25ml样品瓶中；用移液枪吸取PVP乙醇溶液8ml加入到样品瓶中；
配制药物涂层组合物：在紫杉醇乙醇溶液中加入约1ml的元素态碘溶液和少量(0.262ml)的蒸馏水，封口，搅拌均匀。
球囊涂药：将球囊浸没于上述的药物涂层组合物中；保持5-60秒钟，后取出；在室温干燥6小时；折叠，灭菌，包装。
药物释放速度和颗粒度试验：把上述方法制得的球囊充气到2个大气压，然后放到20ml的0.1M的磷酸盐缓冲液瓶中，静止1分钟，然后取出球囊，干燥，称重。同时观察球囊表面药物涂层的残留情况和缓冲液瓶中的药物晶体的状态，试验结果见表5。结果：超过90％的药物涂层顺利地释放到缓冲液中，同时缓冲液瓶没有观察到大颗粒药物(直径10微米以上的颗粒)。
表5
Figure PCTCN2014091205-appb-000006
实施例4B：含无机单质碘的药物球囊制备方法2(PTX∶PVP∶I＝1.5∶1∶0.005，克/克/克)
PVP乙醇溶液的配置：用0.0001g精度的天平称量4g PVP(Povidone K30)，加入25ml样品瓶中；用移液枪吸取20ml的乙醇加入到样品瓶中。旋紧瓶塞，振荡搅拌后，放到45℃烘箱保存直至PVP全部溶解。
紫杉醇(PTX)乙醇溶液的配制：称量约0.30g紫杉醇，加入25ml玻璃瓶；在玻 璃瓶中加入1ml的乙醇；在45℃烘箱保温直到紫杉醇完全溶解。
配制碘的乙醇溶液：把约0.008g碘加入25ml样品瓶中；用移液枪吸取PVP乙醇溶液8ml加入到样品瓶中；
配制药物涂层组合物：在紫杉醇乙醇溶液中加入约1ml的元素态碘溶液和少量(0.262ml)的蒸馏水，封口，搅拌均匀。
球囊涂药：将球囊浸没于上述的药物涂层组合物中；保持5-60秒钟，后取出；在室温干燥6小时；折叠，灭菌，包装。
药物释放速度和颗粒度试验：把上述方法制得的球囊充气到2个大气压，然后放到20ml的0.1M的磷酸盐缓冲液瓶中，静止1分钟，然后取出球囊，干燥，称重。同时观察球囊表面药物涂层的残留情况和缓冲液瓶中的药物晶体的状念，试验结果见表6。结果：超过90％的药物涂层顺利地释放到缓冲液中，同时缓冲液瓶没有观察到大颗粒药物(直径10微米以上的颗粒)。
表6
Figure PCTCN2014091205-appb-000007
实施例5A含小分子辅剂维生素E-TPGS的药物球囊制备方法：
PVP乙醇溶液的配置：用0.0001g精度的天平称量4g PVP(Povidone K30)，加入25ml样品瓶中；用移液枪吸取20ml的乙醇加入到样品瓶中。旋紧瓶塞，振荡搅拌后，放到45℃烘箱保存直至PVP全部溶解。
紫杉醇乙醇溶液的配制：称量约0.15g紫杉醇，加入25ml玻璃瓶；在玻璃瓶中加入1ml的乙醇；在45℃烘箱保温直到紫杉醇完全溶解。
配制维生素E-TPGS的乙醇溶液：把约0.002g维生素E-TPGS加入25ml样品瓶中；用移液枪吸取PVP乙醇溶液8ml加入到样品瓶中；
配制药物涂层组合物：在紫杉醇乙醇溶液中加入约1-2ml的维生素E-TPGS溶液和少量(0.262ml)的蒸馏水，封口，搅拌均匀。
球囊涂药：将球囊浸没于上述的药物涂层组合物中；保持5-60秒钟，后取出；在室温干燥6小时；折叠，灭菌，包装。
药物释放速度和颗粒度试验：把上述方法制得的球囊充气到2个大气压，然后放到20ml的0.1M的磷酸盐缓冲液瓶中，静止1分钟，然后取出球囊，干燥，称重。同时观察球囊表面药物涂层的残留情况和缓冲液瓶中的药物晶体的状态，试验结果见表7。结果：超过75％的药物涂层顺利地释放到缓冲液中，同时缓冲液瓶观察到一定数量的大颗粒药物晶体(直径10微米以上的颗粒)。
表7
Figure PCTCN2014091205-appb-000008
实施例5B含小分子辅剂维生素E-TPGS的药物球囊制备方法：
PVP乙醇溶液的配置：用0.0001g精度的天平称量4g PVP(Povidone K30)，加入25ml样品瓶中；用移液枪吸取20ml的乙醇加入到样品瓶中。旋紧瓶塞，振荡搅拌后，放到45℃烘箱保存直至PVP全部溶解。
紫杉醇丙酮溶液的配制：称量约0.15g紫杉醇，加入25ml玻璃瓶；在玻璃瓶中加 入1ml的丙酮；在45℃烘箱保温直到紫杉醇完全溶解。
配制维生素E-TPGS的乙醇溶液：把约0.002g维生素E-TPGS加入25ml样品瓶中；用移液枪吸取PVP乙醇溶液8ml加入到样品瓶中；
配制药物涂层组合物：在紫杉醇丙酮溶液中加入约1-2ml的维生素E-TPGS溶液和少量(0.262ml)的蒸馏水，封口，搅拌均匀。
球囊涂药：将球囊浸没于上述的药物涂层组合物中；保持5-60秒钟，后取出；在室温干燥6小时；折叠，灭菌，包装。
药物释放速度和颗粒度试验：把上述方法制得的球囊充气到2个大气压，然后放到20ml的0.1M的磷酸盐缓冲液瓶中，静止1分钟，然后取出球囊，干燥，称重。同时观察球囊表面药物涂层的残留情况和缓冲液瓶中的药物晶体的状态，试验结果见表8。结果：超过60％的药物涂层顺利地释放到缓冲液中，同时缓冲液瓶观察到一定数量的大颗粒药物晶体(直径10微米以上的颗粒)。
表8
Figure PCTCN2014091205-appb-000009
实施例5C含小分子辅剂维生素E-TPGS的药物球囊制备方法：
PVP乙醇溶液的配置：用0.0001g精度的天平称量4g PVP(Povidone K30)，加入25ml样品瓶中；用移液枪吸取20ml的乙醇加入到样品瓶中。旋紧瓶塞，振荡搅拌后，放到45℃烘箱保存直至PVP全部溶解。
紫杉醇四氢呋喃溶液的配制：称量约0.15g紫杉醇，加入25ml玻璃瓶；在玻璃瓶中加入1ml的四氢呋喃；在45℃烘箱保温直到紫杉醇完全溶解。
配制维生素E-TPGS的乙醇溶液：把约0.002g维生素E-TPGS加入25ml样品瓶中；用移液枪吸取PVP乙醇溶液8ml加入到样品瓶中；
配制药物涂层组合物：在紫杉醇四氢呋喃溶液中加入约1-2ml的维生素E-TPGS溶液和少量(0.262ml)的蒸馏水，封口，搅拌均匀。
球囊涂药：将球囊浸没于上述的药物涂层组合物中；保持5-60秒钟，后取出；在室温干燥6小时；折叠，灭菌，包装。
药物释放速度和颗粒度试验：把上述方法制得的球囊充气到2个大气压，然后放到20ml的0.1M的磷酸盐缓冲液瓶中，静止1分钟，然后取出球囊，干燥，称重。同时观察球囊表面药物涂层的残留情况和缓冲液瓶中的药物晶体的状态，试验结果见表9。结果：超过80％的药物涂层顺利地释放到缓冲液中，同时缓冲液瓶观察到一定数量的大颗粒药物晶体(直径10微米以上的颗粒)。
表9
Figure PCTCN2014091205-appb-000010
实施例6A含小分子抗氧化剂2，6-二叔丁基对甲酚(3，5-di-tert-butyl-4-hydroxytoluene，BHT)的药物球囊制备方法：
PVP乙醇溶液的配置：用0.0001g精度的天平称量4g PVP(Povidone K30)，加入25ml样品瓶中；用移液枪吸取20ml的乙醇加入到样品瓶中。旋紧瓶塞，振荡搅拌后，放到45℃烘箱保存直至PVP全部溶解。
紫杉醇乙醇溶液的配制：称量约0.15g紫杉醇，加入25ml玻璃瓶；在玻璃瓶中加入1ml的乙醇；在45℃烘箱保温直到紫杉醇完全溶解。
配制BHT的乙醇溶液：把约0.002g BHT加入25ml样品瓶中；用移液枪吸取PVP乙醇溶液8ml加入到样品瓶中；
配制药物涂层组合物：在紫杉醇乙醇溶液中加入约1-2ml的维生素E-TPGS溶液和少量(0.262ml)的蒸馏水，封口，搅拌均匀。
球囊涂药：将球囊浸没于上述的药物涂层组合物中；保持5-60秒钟，后取出；在室温干燥6小时；折叠，灭菌，包装。
药物释放速度和颗粒度试验：把上述方法制得的球囊充气到2个大气压，然后放到20ml的0.1M的磷酸盐缓冲液瓶中，静止1分钟，然后取出球囊，干燥，称重。同时观察球囊表面药物涂层的残留情况和缓冲液瓶中的药物晶体的状态，试验结果见表10。结果：超过80％的药物涂层顺利地释放到缓冲液中，同时缓冲液瓶观察到极少量的大颗粒药物晶体。
表10
Figure PCTCN2014091205-appb-000011
实施例6B含小分子抗氧化剂2，6-二叔丁基对甲酚(3，5-di-tert-butyl-4-hydroxytoluene，BHT)的药物球囊制备方法：
PVP乙醇溶液的配置：用0.0001g精度的天平称量4g PVP(Povidone K30)，加入25ml样品瓶中；用移液枪吸取20ml的乙醇加入到样品瓶中。旋紧瓶塞，振荡搅拌后，放到45℃烘箱保存直至PVP全部溶解。
雷帕霉素乙醇溶液的配制：称量约0.15g雷帕霉素，加入25ml玻璃瓶；在玻璃瓶 中加入1ml的乙醇；在45℃烘箱保温直到雷帕霉素完全溶解。
配制BHT的乙醇溶液：把约0.002g BHT加入25ml样品瓶中；用移液枪吸取PVP乙醇溶液8ml加入到样品瓶中；
配制药物涂层组合物：在雷帕霉素乙醇溶液中加入约1-2ml的维生素E-TPGS溶液和少量(0.262ml)的蒸馏水，封口，搅拌均匀。
球囊涂药：将球囊浸没于上述的药物涂层组合物中；保持5-60秒钟，后取出；在室温干燥6小时；折叠，灭菌，包装。
药物释放速度和颗粒度试验：把上述方法制得的球囊充气到2个大气压，然后放到20ml的0.1M的磷酸盐缓冲液瓶中，静止1分钟，然后取出球囊，干燥，称重。同时观察球囊表面药物涂层的残留情况和缓冲液瓶中的药物晶体的状态，试验结果见表11。结果：58％的药物涂层顺利地释放到缓冲液中，同时缓冲液瓶观察到极少量的大颗粒药物晶体。
表11
Figure PCTCN2014091205-appb-000012
本发明的以上各实施例中，采用的第一组分溶液——PVP乙醇溶液浓度均为0.2g/ml，这里的0.2g/ml为最佳浓度，从整体工艺角度来看，其浓度与最终得到的药物涂层密度有关，可以根据比例关系适当增加或降低，从而调节涂层的密度。
以上所述的实施例只是本发明的一些较佳的方案，并非对本发明作任何形式上的限制，在不超出权利要求所记载的技术方案的前提下还有其它的变体及改型。

Claims (10)

  1. 一种适用于涂在植入或介入医疗器械表面的药物涂层组合物，其特征在于包括如下组分：
    第一组分为亲水性高聚物；
    第二组分为治疗血管内壁再增生的药物；
    第三组分为无机物，选自无机单质、水溶性无机盐或两亲性小分子化合物中的一种或两种以上的组合物；
    各组分中，亲水性高聚物与治疗血管内壁再增生的药物的重量比为0.3-3∶1，第三组分占第一组分、第二组分和第三组分总重量的0.005-5.0％；
    第四组分为溶剂体系，溶剂体系包括将第一组分、第二组分和第三组分各自溶解的溶剂。
  2. 根据权利要求1所述的药物涂层组合物，其特征在于：所述的亲水性高聚物选自聚乙烯吡咯酮(PVP)，含有耦合碘的聚乙烯吡咯酮，聚乙烯醇(PVA)，聚氧化乙烯(PEO)或聚乙二醇(PEG)；所述的治疗血管内壁再增生的药物选自紫杉醇或其衍生物、雷帕霉素或其衍生物、抗血凝药；所述的无机单质选自碘，溴或烟酰胺；水溶性无机盐选自碘化钠，碘化钙，氯化钠或氯化钙，两亲性小分子化合物为维生素E-TPGS。
  3. 根据权利要求1所述的药物涂层组合物，其特征在于：所述紫杉醇的衍生物包括多西紫杉醇(docetaxel)；雷帕霉素衍生物包括依维莫司(everolimus)，若他咯里莫司(Zotarolimus)，拜尔里莫司(Biolimus)；抗血凝药包括西洛他唑(Cilostazol)，肝素(heparin)。
  4. 根据权利要求1所述的药物涂层组合物，其特征在于：所述的植入或介 入医疗器械包括：冠脉血管支架，冠脉血管球囊、外周血管支架、外周血管球囊、颅内血管支架、颅内血管球囊、尿道支架，尿道球囊、食道支架或食道球囊。
  5. 根据权利要求1所述的药物涂层组合物，其特征在于：所述的溶剂体系中，将第一组分溶解的溶剂选自水，乙醇，甲醇或四氢呋喃中的一种或两种以上的组合物；将第二组分溶解的溶剂为乙醇，甲醇，四氢呋喃或丙酮中的一种或两种以上的组合物；将第三组分溶解的溶剂为水，乙醇或甲醇中的一种或两种以上的组合物。
  6. 根据权利要求5所述的药物涂层组合物，其特征在于：用乙醇将第一组分溶解后得到第一组分溶液，向第一组分溶液中加入第三组分和适量水充分混合得到第三组分溶液，用乙醇将第二组分溶解后得到第二组分溶液，第二组分溶液、第三组分溶液和水三者之间的体积比为1-2∶1-2∶0.1-1。
  7. 一种所述药物涂层组合物的制备方法，其特征在于包括如下步骤：
    a、第三组分溶液的配制：将第一组分与溶剂充分混合，配置浓度为0.1-1g/ml的第一组分溶液，并于40-50℃温度下保存使第一组分全部溶解，再向第一组分溶液中加入第三组分充分混合，得到第三组分溶液，使第三组分溶液中第三组分的浓度为0.001-0.1g/ml；
    b、第二组分溶液的配制：将第二组分与溶剂充分混合，配置浓度为0.05-0.5g/ml的第二组分溶液，并在40-50℃温度下保温直到第二组分完全溶解；
    c、药物涂层组合物的配制：在所述第二组分溶液中加入所述第三组分溶液 和水，第二组分溶液、第三组分溶液和水三者之间的体积比为1-2∶1-2∶0.1-1，封口，搅拌均匀，得到用于涂在植入或介入医疗器械表面的药物涂层组合物。
  8. 根据权利要求7所述的药物涂层组合物的制备方法，其特征在于包括如下步骤：
    a、碘溶液的配制：将聚乙烯吡咯烷酮(PVP)与乙醇充分混合，配置浓度为0.1-0.3g/ml的聚乙烯吡咯烷酮(PVP)乙醇溶液，并于40-50℃温度下保存使PVP全部溶解，再向PVP乙醇溶液中加入I充分混合，得到碘溶液，浓度为0.001-0.01g/ml；
    b、紫杉醇乙醇溶液的配制：将紫杉醇与乙醇充分混合，配置浓度为0.1-0.3g/ml的紫杉醇乙醇溶液，并在40-50℃温度下保温直到紫杉醇完全溶解；
    c、药物涂层组合物的配制：在所述紫杉醇乙醇溶液中加入所述碘溶液和蒸馏水，紫杉醇乙醇溶液、碘溶液和水三者之间的体积比为1∶1-2∶0.25-0.28，封口，搅拌均匀，得到药物涂层组合物。
  9. 一种利用所述药物涂层组合物制备的植入或介入医疗器械，其特征在于：将未经过药物涂覆的植入或介入医疗器械半成品浸没于权利要求1或7所述的药物涂层组合物中，保持5-60秒钟后取出；室温下干燥，折叠，灭菌，得到产品。
  10. 根据权利要求9所述的植入或介入医疗器械，其特征在于：其表面涂 层的密度为0.5-10μg/mm2，药物净含量在药物洗脱器械表面的密度为0.2-8μg/mm2。
PCT/CN2014/091205 2014-09-09 2014-11-14 一种药物涂层组合物、其制备方法及利用其制成的植入或介入医疗器械 WO2016037413A1 (zh)

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