Disclosure of Invention
Aiming at the defects and actual demands of the prior art, the invention provides the drug coating for the drug coating balloon, and the preparation method and the application thereof, which can ensure that the drug coating is not damaged in the transmission process and can be rapidly released at the lesion part.
In order to achieve the above purpose, the invention adopts the following technical scheme:
in a first aspect, the present invention provides a drug coating for a drug coated balloon, the drug coating comprising a release layer and a protective layer, the release layer comprising a drug, an amphiphilic carrier and a release modifier, the protective layer comprising a hydrophobic compound, the release modifier comprising any one or a combination of at least two of povidone K12, glucose, fructose, galactose, trehalose, urea, monobasic potassium phosphate, monobasic sodium phosphate, sodium chloride, potassium chloride or a water soluble vitamin.
In the invention, a drug coating formula is designed, the amphiphilic carrier can enhance the binding force of the release layer and the protective layer, the protective layer is prevented from falling off, the release regulator can accelerate the dissolution process, and the drug is released in the balloon expansion stage by utilizing the synergistic cooperation of the amphiphilic carrier and the release regulator, so that the low transmission loss and the quick release are realized.
Preferably, the drug comprises any one or a combination of at least two of macrolide immunosuppressants, paclitaxel, cyclosporine, gingerol, losartan, daidzein, docetaxel, dexamethasone, methotrexate, dextran, mitomycin, heparin sodium, doxorubicin hydrochloride, hirudin, argatroban, dipyridamole, prostacyclin analogues, nitroglycerin, nitroprusside, suramin, endostatin, serotonin blockers, steroids, or oligopeptides.
Preferably, the amphiphilic carrier comprises any one or a combination of at least two of phospholipids, glycolipids, cholesterol, poloxamers or amphiphilic polymers.
Preferably, the amphiphilic polymer comprises any one or a combination of at least two of polyethylene glycol-polyamino acid block copolymer, ethylene glycol-deoxycholic acid polymer, polyethylene glycol-chitosan polymer, chitosan-deoxycholic acid polymer, cholesterol-polyethyleneimine polymer or polysaccharide-fatty acid polymer.
Preferably, the hydrophobic compound comprises any one or a combination of at least two of hydrogenated phospholipids, fully synthetic phospholipids, benzoic acid, stearic acid, fat-soluble vitamins or cholesterol esters.
Preferably, the mass ratio of the drug, the amphiphilic carrier and the release regulator in the raw materials of the release layer is 1 (10-20): (5-60), including but not limited to 1:15:55, 1:12:8, 1:19:30, 1:10:10, 1:13:59, 1:16:15, 1:17:40 or 1:18:50;
preferably, the thickness of the release layer is 1-3.5 μm, including but not limited to 1.2 μm, 1.5 μm, 2 μm, 2.5 μm, 3 μm, 3.2 μm or 3.4 μm.
Preferably, the thickness of the protective layer is 0-1 μm, but not 0 μm.
In a second aspect, the present invention provides a method of preparing a drug coating for a drug coated balloon according to the first aspect, the method comprising:
mixing the drug, the amphiphilic carrier and the release modifier with a first solvent to obtain a release layer component; mixing the hydrophobic compound with a second solvent to obtain a protective layer component; spraying the release layer component on the solid surface to form a release layer, and spraying the protective layer component on the release layer to form a protective layer to obtain the drug coating.
Preferably, the concentration of the hydrophobic compound in the protective layer component is 0.02-0.1 g/mL, including but not limited to 0.03 g/mL, 0.04 g/mL, 0.05 g/mL, 0.06 g/mL, 0.08 g/mL or 0.09 g/mL.
The preparation process of the drug coating is simple and is convenient for mass production.
Preferably, the first solvent and the second solvent are each independently selected from any one or a combination of at least two of water, dichloromethane, chloroform, methanol, ethanol or acetone.
In a third aspect, the present invention provides the use of a drug coating for a drug coated balloon as described in the first aspect for the preparation of a drug coated balloon.
In a fourth aspect, the present invention provides a drug-coated balloon comprising a balloon body and a drug-coated balloon of the first aspect coated on the outer surface of the balloon body, the release layer being located between the outer surface of the balloon and the protective layer.
In a fifth aspect, the present invention provides a method of preparing a drug-coated balloon according to the first aspect, the method comprising:
mixing the drug, the amphiphilic carrier and the release modifier with a first solvent to obtain a release layer component; mixing the hydrophobic compound with a second solvent to obtain a protective layer component; spraying the release layer component on the outer surface of the balloon to form a release layer, folding the balloon after the release layer is prepared, and spraying the protective layer component after the balloon is folded to form a protective layer, thereby obtaining the drug coating balloon.
Preferably, the first solvent and the second solvent are each independently selected from any one or a combination of at least two of water, dichloromethane, chloroform, methanol, ethanol or acetone.
Compared with the prior art, the invention has the following technical effects:
in the invention, a drug coating formula is designed, the amphiphilic carrier can enhance the binding force of the release layer and the protective layer, the protective layer is prevented from falling off, the release regulator can accelerate the dissolution process, and the drug is released in the balloon expansion stage by utilizing the synergistic cooperation of the amphiphilic carrier and the release regulator, so that the low transmission loss and the quick release are realized.
Detailed Description
The technical means adopted by the invention and the effects thereof are further described below with reference to the examples and the attached drawings. It is to be understood that the specific embodiments described herein are merely illustrative of the invention and are not limiting thereof.
The specific techniques or conditions are not identified in the examples and are described in the literature in this field or are carried out in accordance with the product specifications. The reagents or equipment used were conventional products available for purchase through regular channels, with no manufacturer noted.
Example 1
This example produced a drug coated balloon (schematic structure shown in fig. 1).
S1, preparing a release layer solution: dissolving 0.23g of cholesterol, 0.2g of poloxamer and 0.02g of rapamycin in 25 mL chloroform to form a mixed solution, dropwise adding the mixed solution into 20mL water, fully stirring and evaporating to remove chloroform, and finally adding 0.1g of povidone K12 and 0.03g of trehalose and fully stirring to form a release layer solution.
S2, preparing a protective layer solution: 0.3g of stearic acid was dissolved in 15mL ethanol to form a protective layer solution.
S3, spraying a release layer solution on the bare balloon, wherein the carrier is high-purity nitrogen, the spraying pressure is 0.08Mpa, the flow is 0.1 mL/min, and the thermal curing is carried out for 2 min at 50 ℃ once for 15 times.
S4, folding and shaping the balloon after the release layer is prepared, wherein the folding temperature is 50 ℃, and the shaping temperature is 55 ℃.
S5, taking out the shaped saccule sheath, spraying a protective layer solution, wherein the carrier is high-purity nitrogen, the pressure is 0.05 Mpa, and the flow is 0.05 mL/min.
S6, drying the sprayed saccule, packaging and sterilizing after inspection.
Example 2
The present example prepares a drug coated balloon.
S1, preparing a release layer solution: dissolving 0.34 g soybean lecithin, 0.038 g cholesterol and 0.014 g everolimus in 20mL ethanol to form a mixed solution, dropwise adding the mixed solution into 20mL water, fully stirring and evaporating to remove ethanol, and finally adding 0.12 g urea and 0.05g glucose and fully stirring to form a release layer solution.
S2, preparing a protective layer solution: 0.11. 0.11 g hydrogenated soybean phospholipid and 0.03. 0.03g vitamin E were dissolved in 10. 10 mL ethanol to form a protective layer solution.
S3, spraying a release layer solution on the bare balloon, wherein the carrier is high-purity nitrogen, the spraying pressure is 0.04 MPa, and the flow is 0.08 mL/min. Each spray was heat cured at 50 ℃ for 2 min for a total of 10 times.
S4, folding and shaping the balloon after the release layer is prepared, wherein the folding temperature is 50 ℃, and the shaping temperature is 55 ℃.
S5, taking out the shaped saccule sheath, spraying protective layer solution, wherein the carrier is high-purity nitrogen, the pressure is 0.04 MPa, and the flow is 0.02 mL/min.
S6, drying the sprayed saccule, packaging and sterilizing after inspection.
Example 3
The present example prepares a drug coated balloon.
S1, preparing a release layer solution: 0.2. 0.2g propyl chitosan (molecular weight 30000), 0.16. 0.16 g glycolipid and 0.02. 0.02g paclitaxel were dissolved in 18mL ethanol to form a mixed solution. The mixture was added dropwise to 18mL water and the ethanol was removed by evaporation with sufficient agitation. Finally, 0.05g sodium chloride, 0.05g fructose and 0.02g vitamin B are added and fully stirred to form a release layer solution.
S2, preparing a protective layer solution: 0.16 g cholesterol acetate, 0.01 g vitamin E was dissolved in 15mL hot ethanol to form a protective layer solution.
S3, spraying a release layer solution on the bare balloon, wherein the carrier is high-purity nitrogen, the spraying pressure is 0.04 MPa, and the flow is 0.06 mL/min. Each spray was heat cured at 50 ℃ for 2 min for a total of 10 times.
S4, folding and shaping the balloon after the release layer is prepared, wherein the folding temperature is 50 ℃, and the shaping temperature is 55 ℃.
S5, taking out the shaped saccule sheath, spraying protective layer solution, wherein the carrier is high-purity nitrogen, the pressure is 0.04 MPa, and the flow is 0.02 mL/min.
S6, drying the sprayed saccule, packaging and sterilizing after inspection.
Example 4
The present example prepares a drug coated balloon.
S1, preparing a release layer solution: 1.55. 1.55 g polyethylene glycol-chitosan copolymer (Sigma-Aldrich, 40% -70% PEGylation, molecular weight 1000), 0.005. 0.005 g daidzein, 0.065g dextran, and 0.04g paclitaxel were dissolved in 20mL methanol-acetone solution to form a mixed solution. The mixture was added dropwise to 15mL of water and methanol and acetone were removed by evaporation with sufficient stirring. Finally, 1.60g of urea and 0.6. 0.6 g of sodium dihydrogen phosphate are added and stirred well to form a release layer solution.
S2, preparing a protective layer solution: 0.38 g benzoic acid, 0.55 g vitamin E was dissolved in 15mL hot ethanol to form a protective layer solution.
S3, spraying a release layer solution on the bare balloon, wherein the carrier is high-purity nitrogen, the spraying pressure is 0.06 MPa, and the flow is 0.01 mL/min. Each spray was heat-cured at 55℃for 2 min for a total of 13 times.
S4, folding and shaping the balloon after the release layer is prepared, wherein the folding temperature is 50 ℃, and the shaping temperature is 55 ℃.
S5, taking out the shaped saccule sheath, spraying protective layer solution, wherein the carrier is high-purity nitrogen, the pressure is 0.04 MPa, and the flow is 0.02 mL/min.
Example 5
The present example prepares a drug coated balloon.
S1, preparing a release layer solution: 1.35 g polyethylene glycol-lysine block copolymer (Thermo Fisher, molecular weight 10000), 0.033g docetaxel, 0.045 g zotarolimus were dissolved in 20mL chloroform solution to form a mixed solution. The mixture was added dropwise to 22 mL water and methanol and acetone were removed by evaporation with sufficient agitation. Finally, 1.14g of glucose and 1.2g of povidone K12 are added and stirred well to form a release layer solution.
S2, preparing a protective layer solution: dipalmitoyl phosphatidylcholine 0.56g was dissolved in 10 mL chloroform to form a protective layer solution.
S3, spraying a release layer solution on the bare balloon, wherein the carrier is high-purity nitrogen, the spraying pressure is 0.06 Mpa, and the flow is 0.01 mL/min. Each spray was heat-cured at 55℃for 2 min for a total of 13 times.
S4, folding and shaping the balloon after the release layer is prepared, wherein the folding temperature is 50 ℃, and the shaping temperature is 55 ℃.
S5, taking out the shaped saccule sheath, spraying protective layer solution, wherein the carrier is high-purity nitrogen, the pressure is 0.04 MPa, and the flow is 0.02 mL/min.
Comparative example 1
The drug coated balloon was prepared in this comparative example.
The only difference compared to example 1 is that povidone K12 and trehalose are not added to the release layer spray solution and that povidone K12 and trehalose lacking in comparative example 1 are added in a proportion of 0.13g to poloxamer and cholesterol. Namely 0.26g of poloxamer and 0.3g of cholesterol, otherwise the same as in example 1.
Test case
This test example tests the effect of the drug coated balloons prepared in the examples and comparative examples.
Test scheme: fig. 2 is an experimental diagram of the M2 section of the drug balloon dilation catheter from a guide wire to a middle cerebral artery, fig. 3 is an experimental diagram of the drug balloon dilation catheter from a femoral artery to an intracranial artery, and the elution amounts of the drug under three simulated use conditions are tested by using a human body blood vessel model, wherein the specific operation process is as follows:
1. simulating only transmission processes
Selecting a whole body artery model, simulating blood by using PBS (phosphate buffered saline) eluent, pumping the eluent to simulate blood circulation by using a peristaltic pump, firstly placing a guide wire, ascending along a femoral artery to a target blood vessel, then, moving a medicine balloon dilation catheter along the guide wire to the target blood vessel, stopping pumping and discharging the eluent, respectively testing the medicine content in the eluent and the medicine content on the balloon, and calculating the elution quantity;
2. simulating only the expansion process
Selecting an intracranial artery model, simulating blood by using PBS (phosphate buffer solution), pumping eluent by a peristaltic pump to simulate blood circulation, firstly, not starting the peristaltic pump, placing a guide wire, ascending along a carotid artery to a target blood vessel, then, moving a drug balloon dilation catheter along the guide wire to the target blood vessel, starting the peristaltic pump after the drug balloon dilation catheter reaches the target blood vessel, immediately dilating the balloon 30s after the eluent is filled in the model, finishing the detection of the residual drug quantity on the eluent and the balloon by withdrawing the balloon, and calculating the elution quantity;
3. full process simulation
Selecting a whole body artery model, simulating blood by using PBS (phosphate buffered saline) eluent, pumping the eluent to simulate blood circulation by using a peristaltic pump, firstly placing a guide wire, ascending along a femoral artery to a target blood vessel, then moving a medicine balloon dilation catheter to the target blood vessel along the guide wire, expanding the balloon 30s after reaching, stopping pumping, discharging the eluent, respectively testing the medicine content in the eluent and the medicine content on the balloon, and calculating the elution quantity.
The drug content was tested by high performance liquid chromatography under the test conditions shown in table 1.
TABLE 1
The drugs in the examples and comparative examples were changed to rapamycin of equal mass, and a balloon of 3.0X10. 20 mm gauge was used, and the remaining conditions were unchanged, and the results are shown in Table 2.
TABLE 2
In order to realize low transmission loss and quick release simultaneously, the elution amount in the transmission process is required to be as low as possible, and the elution amount in the expansion process is as high as possible, as can be seen from the results of table 2, compared with comparative example 1, the drug coated balloon prepared in the embodiment of the invention realizes low transmission loss and quick release simultaneously, the elution efficiency of the drug can be greatly reduced without adding a release regulator, and further compared with the release regulator, the embodiment 2 has low transmission loss and higher elution rate of the target blood vessel, which indicates that the invention controls the specific release layer and the protective layer components to cooperate, and can further reduce the transmission loss and improve the release efficiency in the expansion process simultaneously.
In summary, the drug coating formula is designed, the amphiphilic carrier can enhance the binding force between the release layer and the protective layer, the protective layer is prevented from falling off, the release regulator can accelerate the dissolution process, and the drug is released in the balloon expansion stage by the synergistic cooperation of the amphiphilic carrier and the release regulator, so that low transmission loss and quick release are realized.
The applicant states that the detailed method of the present invention is illustrated by the above examples, but the present invention is not limited to the detailed method described above, i.e. it does not mean that the present invention must be practiced in dependence upon the detailed method described above. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.