CN108057168B - Preparation method of medicine balloon - Google Patents
Preparation method of medicine balloon Download PDFInfo
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- CN108057168B CN108057168B CN201711092572.7A CN201711092572A CN108057168B CN 108057168 B CN108057168 B CN 108057168B CN 201711092572 A CN201711092572 A CN 201711092572A CN 108057168 B CN108057168 B CN 108057168B
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- balloon
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- saccule
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
- A61M31/002—Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time
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- 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
- A61L31/08—Materials for coatings
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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
- 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
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- 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
- A61L31/16—Biologically active materials, e.g. therapeutic substances
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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Abstract
The invention discloses a preparation method of a medicine balloon, wherein a medicine transferring layer used by the medicine balloon adopts a layered coating method and is coated on a bottom layer, namely a middle layer. The drug-loaded catalyst is superimposed on the substrate during the coating process and is not mixed with the substrate. The drug balloon promotes the drug to be transferred to the vessel wall from the surface of the balloon in a short time to the maximum extent. The drug coating is a process of quick release, quick absorption and slow elimination at the target blood vessel part, namely the peripheral blood vessel drug balloon dilatation catheter can play the role of effective drugs and has good clinical application prospect.
Description
Technical Field
The invention relates to a preparation method of a medicine balloon.
Background
The global burden of Peripheral Artery Disease (PAD) is increasing, with 1.64 million people suffering from peripheral artery disease in 2000, and increasing to 2.02 million cases in 2010 with nearly a quarter (23.5%) increase in prevalence. As the population ages, the incidence of peripheral arterial disease increases dramatically with age; the number of patients with peripheral artery disease will continue to increase in the next few years.
Peripheral Artery Disease (PAD) of the lower extremities is an important manifestation of systemic atherosclerosis. The disease is caused by one or more arteriosclerotic lesions (restricting or blocking blood flow to the lower limb) of the arteries of the lower limb.
Arterial occlusion of the lower extremities causes several clinical manifestations, ranging from asymptomatic to Intermittent Claudication (IC), which eventually leads to severe lower extremity ischemia (CLI), with a severe drop in arterial blood flow that endangers the lower extremities.
Approximately 30% to 50% of PAD patients will progress in the course of the disease from intermittent claudication to severe lower limb ischemia. The prognosis of severe lower limb ischemia is poor, and the death rate is high. Within 1 year after the onset of severe lower limb ischemia, 25% of patients will die, and another 30% require large amputations. Patients with diabetes, smoking, lipid profile disorders, hypertension, or renal failure are at higher risk for developing peripheral artery disease. High mortality is caused by co-existing cardiovascular disease.
Therefore, the treatment of peripheral artery disease aims at the protection of limbs, alleviation of symptoms, improvement of functional status and prevention of cardiovascular events (acute myocardial infarction [ MI ], stroke and vascular death). Treatment of peripheral artery disease includes risk factor relief (smoking cessation, exercise therapy, etc.), drug treatment, and ultimately lower limb revascularization.
Surgery has long been recognized as the gold standard for revascularization therapy. However, with the introduction of new devices, intravascular treatment is now considered as the first line treatment for claudication patients and patients with severe lower limb ischemia.
The drug balloon is coated with a drug (such as paclitaxel) on the surface of the balloon, wherein paclitaxel is an antiproliferative drug capable of specifically binding and stabilizing microtubules. By preventing microtubule depolymerization, paclitaxel can inhibit smooth muscle cell and fibroblast proliferation and migration as well as extracellular matrix secretion. These effects can inhibit the proliferation of the intima of the blood vessel, thereby inhibiting the restenosis of the blood vessel.
When peripheral blood vessel operation is carried out, particularly in the process of balloon dilatation, the medicine (such as paclitaxel) on the surface of the medicine elution balloon catheter can be extruded into the narrow blood vessel wall, so that enough medicine is dissolved and permeates into the blood vessel wall, intimal cell hyperplasia caused by tearing of the blood vessel and the media membrane with pathological changes due to balloon dilatation is inhibited, the purpose of resisting the hyperplasia of the blood vessel and the media membrane is achieved, and the patency rate of target blood vessels at the late stage of operation is improved.
Disclosure of Invention
The invention aims to provide a preparation method of a medicine balloon.
The technical scheme adopted by the invention is as follows:
a preparation method of a drug balloon comprises the following steps:
1) taking several drops of bottom layer solutionThe liquid is uniformly coated on the surface of the balloon, so that the concentration of the substance on the bottom layer of the surface of the balloon is 0.5-5 mu g/mm2Blow-drying the bottom layer solution, and airing at room temperature for at least 30min to obtain the balloon coated with the bottom layer;
2) taking a plurality of drops of the middle layer solution to be uniformly coated on the surface of the saccule coated with the bottom layer obtained in the previous step, and enabling the concentration of the middle layer substance on the surface of the saccule coated with the bottom layer to be 4-30 mu g/mm2Drying the middle layer solution by blowing, and airing at room temperature for at least 30min to obtain the balloon coated with the middle layer;
3) dropping a medicine solution with a proper concentration on the surface of the balloon coated with the middle layer, rotating the balloon while dropping, uniformly coating the medicine on the balloon, drying the medicine by blowing, drying the medicine for 20-50 min at room temperature, and drying the medicine to obtain a medicine balloon;
the bottom layer material is at least one selected from polyethylene oxide, polyvinyl acetate and polyvinylpyrrolidone;
the middle layer material is at least one selected from acetate, benzoate, maleate, succinate, ascorbate, citrate, tartrate, lactate, oxalate, aspartate, nicotinate, gluconate, glutamate, vanillic acid salt, lactobionic acid salt, polyethylene glycol, tromethamine, xylitol, sorbitol, mannitol and amino alcohol.
Further, in the step 1), the concentration of the bottom layer solution is 1 mg/ml-50 mg/ml.
Further, in the step 2), the concentration of the middle layer solution is 10 mg/ml-1000 mg/ml.
Further, in the step 1) and the step 2), the specific drying operation is as follows: and blowing the bottom layer solution or the middle layer solution by using wind at the temperature of 22-28 ℃ within 80-110 s.
Further, in the step 1) and the step 2), the saccule is rotated back and forth in the blow-drying process.
Further, in the step 3), the concentration of the medicine solution is 8.0 mg/ml-11.5 mg/ml
Further, in step 3), the drug solution is coated twice, and the balloon is rotated while dripping during the coating process.
Further, in step 3), the specific operation of drying is as follows: and blowing with cold air at room temperature for 10-60s during the first coating, blowing with hot air at a fan middle gear during the second coating, keeping the object away from the fan for 45-60 cm, blowing with cold air at room temperature, rotating the balloon, and drying uniformly.
Further, the material of the balloon is selected from one of polyethylene, Pebax, nylon elastomer, PET and polyurethane.
Further, the drug is selected from one or more of paclitaxel, everolimus, tacrolimus, phosphorylcholine, CD34 antibody and derivatives thereof.
A drug balloon, the preparation method of which is the method of any one of the above.
The invention has the beneficial effects that:
(1) in the medicine balloon prepared by the method, the connecting force between the coating and the surface of the balloon is enhanced, the coating fastness is enhanced, and the middle layer cannot fall off and cannot peel off visually.
(2) The drug transferring layer used by the drug balloon is coated on the bottom layer, namely the middle layer, by a layered coating method. The drug-loaded catalyst is superimposed on the substrate during the coating process and is not mixed with the substrate. The drug balloon promotes the drug to be transferred to the vessel wall from the surface of the balloon in a short time (1-10 minutes) to the maximum extent.
(3) The method of the invention does not need to carry out surface treatment on the saccule, and realizes the purpose of protecting the characteristics of the saccule.
(4) The method of the invention can be used for accurately placing the medicine in the middle layer of the medicine coating layer by a universal and accurate titration method. The accurate medicine coating has the advantages of effectively controlling the medicine loading capacity and achieving good clinical curative effect.
(5) After the drug balloon enters the pig artery for expansion, the drug coating on the balloon can be quickly released and absorbed by the target blood vessel, the absorption peak value can be reached at 0 moment, and the drug content of the target blood vessel part is far higher than the lowest effective dose of 47ng/g (0.047 mu g/g) after 28 days; the result shows that the drug coating is a process of quick release, quick absorption and slow elimination at the target blood vessel part, namely the peripheral blood vessel drug balloon dilatation catheter can play the role of effective drugs.
Drawings
FIG. 1 is a graph of paclitaxel drug-time profile in vivo in swine after balloon dilatation of the drug of the present invention;
fig. 2 is a graph of paclitaxel concentration-time curve of target blood vessel in pig body with the drug balloon dilatation catheter of the invention.
Detailed Description
A preparation method of a drug balloon comprises the following steps:
1) a plurality of drops of bottom layer solution are uniformly coated on the surface of the balloon, so that the concentration of the bottom layer substance on the surface of the balloon is 0.5-5 mu g/mm2Blow-drying the bottom layer solution, and airing at room temperature for at least 30min to obtain the balloon coated with the bottom layer;
2) taking a plurality of drops of the middle layer solution to be uniformly coated on the surface of the saccule coated with the bottom layer obtained in the previous step, and enabling the concentration of the middle layer substance on the surface of the saccule coated with the bottom layer to be 4-30 mu g/mm2Drying the middle layer solution by blowing, and airing at room temperature for at least 20min to obtain the balloon coated with the middle layer;
3) dropping a medicine solution with a proper concentration on the surface of the balloon coated with the middle layer, rotating the balloon while dropping, uniformly coating the medicine on the balloon, drying the medicine by blowing, drying the medicine for 20-50 min at room temperature, and drying the medicine to obtain a medicine balloon;
the bottom layer material is at least one selected from polyethylene oxide, polyvinyl acetate and polyvinylpyrrolidone;
the middle layer material is at least one selected from acetate, benzoate, maleate, succinate, ascorbate, citrate, tartrate, lactate, oxalate, aspartate, nicotinate, gluconate, glutamate, vanillic acid salt, lactobionic acid salt, polyethylene glycol, tromethamine, xylitol, sorbitol, mannitol and amino alcohol.
Preferably, in the step 1), the concentration of the bottom layer solution is 1mg/ml to 50 mg/ml.
Preferably, in the step 1) and the step 2), the drying specifically comprises the following steps: and blowing the bottom layer solution or the middle layer solution by using wind at the temperature of 22-28 ℃ within 80-110 s.
Preferably, in the step 1) and the step 2), the balloon is rotated back and forth in the blow-drying process.
Preferably, in the step 2), the concentration of the middle layer solution is 10mg/ml to 1000 mg/ml.
Preferably, in the step 3), the concentration of the medicine solution is 8.0 mg/ml-11.5 mg/ml.
Preferably, in step 3), the drug solution is coated twice, and the balloon is rotated while dropping during the coating process.
Preferably, in the step 3), the specific operation of blow-drying is as follows: and blowing with cold air at room temperature for 10-60s during the first coating, blowing with hot air of a fan during the second coating, keeping away objects from the fan for 45-60 cm, blowing with cold air at room temperature, rotating the balloon, and drying uniformly.
More preferably, in the step 3), the medicine solution is coated twice, half of the medicine solution is firstly dripped on the surface of the saccule coated with the middle layer for the first time, the saccule is rotated while dripping, so that the medicine is uniformly coated on the saccule, and meanwhile, cold air is blown for 10-60s at room temperature; opening a fan middle gear and hot air; taking the other half amount of the medicine solution for the second time, keeping the saccule away from the fan for about 45-60 cm, rotating the saccule while dripping to enable the medicine to be uniformly covered on the saccule, blowing hot air for 10-60s, then closing the hot air, opening cold air, and rotating the saccule to enable the medicine to be uniformly dried.
Preferably, the temperature of the hot air is 35-50 ℃.
Preferably, in the step 3), the drying temperature is 35-38 ℃, and the drying time is at least 24 h.
Preferably, the material of the balloon is selected from one of polyethylene, Pebax, nylon elastomer, PET and polyurethane.
Preferably, the drug is selected from one or more of paclitaxel, everolimus, tacrolimus, phosphorylcholine, CD34 antibody and derivatives thereof.
A drug balloon, the preparation method of which is the method of any one of the above.
The present invention will be further described with reference to the following examples.
Example 1
1. Balloon treatment
The polyethylene balloon used for coating was first subjected to the following treatments: trimming → inflating → sealing → washing → drying → weighing.
2. Coating the bottom layer
2.1 priming: taking a proper amount of bottom layer solution (namely polyethylene oxide solution) with the concentration of 20.1mg/ml, pouring the bottom layer solution into a special glass vessel, dipping two drops of the bottom layer solution by a coating brush each time, and uniformly coating the bottom layer solution on the surface of the balloon to ensure that the concentration of the bottom layer substance on the surface of the balloon is 3 mu g/mm2. And (5) turning on a fan (at a low wind speed without heating), wherein the distance is about 45-60 cm. Coating the saccule back and forth by using a coating brush, wherein the bottom layer solution is completely dried through about 90s, and the environmental temperature needs to be controlled between 22 and 25 ℃.
2.2 weighing the balloon after coating the bottom layer: airing the saccule coated with the bottom layer for at least 30min at room temperature, weighing, and recording data;
3. coating the middle layer
3.1 coat middle layer: taking appropriate amount of middle layer solution (i.e. xylitol solution) with concentration of 375mg/ml, pouring into special glassware, dipping two drops of middle layer solution with coating brush each time, coating on the balloon to make the concentration of middle layer substance on the surface of the balloon coated with the bottom layer be 15 μ g/mm2. And (5) turning on a fan (at a low wind speed without heating), wherein the distance is about 45-60 cm. The saccule is rotated back and forth for about 80-110 s, and the middle layer is lightly coated with a coating brush for several times before being completely dried, so that the surface of the coating is uniform. The environmental temperature needs to be controlled to be 22-28 ℃ during coating.
3.2 weighing the balloon coated with the middle layer: airing the balloon coated with the middle layer for at least 30min at room temperature, weighing, and recording data;
4. coating with a drug-loaded layer
4.1 coating a medicine layer: the saccule coated with the middle layer solution is flatly placed on a special glass small disc, and a proper amount of prepared paclitaxel solution (the concentration of paclitaxel is between 8.0mg/ml and 11.5 mg/ml) is sucked by a pipette.
Taking and using
(because the dosage of each specification of the saccule is different, a simplified calculation formula is written out), and the content of the paclitaxel on the saccule is ensured to be 3 mug/mm2. Turning on a fan (low-grade, cold air), dripping half amount of medicinal solution on the surface of the balloon coated with the middle layer, rotating the balloon while dripping, uniformly covering the medicinal solution on the balloon, and blowing for 10-60S; and opening a fan (middle grade, hot air (35-50 ℃)) to take the other half amount of the medicine solution, keeping the saccule away from the fan by about 45-60 cm, and rotating the saccule while dripping to enable the medicine to be uniformly coated on the saccule. When the medicinal solution is quick-dried, the hot air is closed, the cold air is opened, and the saccule is moved to be uniformly dried. Air-drying at room temperature for 20-50 min, and oven-drying at 35-38 deg.C for at least 24 hr to obtain medicinal balloon
4.2 weigh balloon weight after drug loading: airing the coated balloon at room temperature for 20-50 min, drying in an oven at 35-38 ℃ for at least 24h to obtain a medicinal balloon, weighing, and recording data;
5. balloon storage: storing under conditions of drying, shading and the like.
Example 2 a method of making a drug balloon,
1) several drops of bottom layer solution (25mg/ml) are uniformly coated on the surface of the balloon (the balloon material is polyethylene), so that the concentration of the bottom layer substance on the surface of the balloon is 1.32 mu g/mm2Blowing the bottom layer solution by wind within 110s at 28 ℃ (rotating the saccule back and forth in the blowing process), and airing at room temperature for at least 30min to obtain the saccule coated with the bottom layer;
2) several drops of the middle layer solution (100mg/ml) were uniformly coated on the surface of the balloon coated with the bottom layer obtained in the above step so that the concentration of the middle layer substance on the surface of the balloon coated with the bottom layer was 4.82. mu.g/mm2Blowing the middle layer solution by using wind within 80s (rotating the saccule back and forth in the blowing process), drying the saccule at room temperature for at least 30min, drying the saccule for 2.5h at 45 ℃, and drying the saccule at room temperature for at least 30min to obtain the saccule coated with the middle layer;
3) dropping paclitaxel medicine solution on the surface of the balloon coated with the middle layer, turning on a fan (low-grade, cold air), dropping half amount of medicine solution on the surface of the balloon coated with the middle layer, rotating the balloon while dropping, uniformly covering the medicine on the balloon, and blowing for 10-60S; and opening a fan (middle grade, hot air (35-50 ℃)) to take the other half amount of the medicine solution, keeping the saccule away from the fan by about 45-60 cm, and rotating the saccule while dripping to enable the medicine to be uniformly coated on the saccule. When the medicinal solution is quick-dried, the hot air is closed, the cold air is opened, and the saccule is moved to be uniformly dried. Air drying at room temperature for 50min, and oven drying at 35 deg.C for at least 24h to obtain medicinal balloon.
Example 3 a method of making a drug balloon,
1) several drops of bottom layer solution (30mg/ml) are uniformly coated on the surface of the balloon (the balloon material is Pebax) to ensure that the concentration of the bottom layer substance on the surface of the balloon is 2 mu g/mm2Blowing the bottom layer solution by using wind within 100s at 25 ℃ (rotating the saccule back and forth in the blow-drying process), and airing at room temperature for at least 30min to obtain the saccule coated with the bottom layer;
2) several drops of the middle layer solution (400mg/ml) were uniformly coated on the surface of the balloon coated with the bottom layer obtained in the above step so that the concentration of the middle layer substance on the surface of the balloon coated with the bottom layer was 8.26. mu.g/mm2Blowing the middle layer solution by wind within 110s (rotating the saccule back and forth in the blowing process), drying at room temperature for at least 30min, drying at 55 ℃ for 2.5h, and drying at room temperature for at least 30min to obtain the saccule coated with the middle layer;
3) dropping paclitaxel medicine solution on the surface of the balloon coated with the middle layer, turning on a fan (low-grade, cold air), dropping half amount of medicine solution on the surface of the balloon coated with the middle layer, rotating the balloon while dropping, uniformly covering the medicine on the balloon, and blowing for 10-60S; and opening a fan (middle grade, hot air (35-50 ℃)) to take the other half amount of the medicine solution, keeping the saccule away from the fan by about 45-60 cm, and rotating the saccule while dripping to enable the medicine to be uniformly coated on the saccule. When the medicinal solution is quick-dried, the hot air is closed, the cold air is opened, and the saccule is moved to be uniformly dried. Air drying at room temperature for 20min, and oven drying at 35 deg.C for at least 24h to obtain medicinal balloon.
Example 4 a method of making a drug balloon,
1) several drops of bottom layer solution (50mg/ml) are uniformly coated on the surface of the balloon (the balloon material is nylon) so that the concentration of the bottom layer substance on the surface of the balloon is 2.07 mu g/mm2Blowing the bottom layer solution by wind at 22-28 ℃ within 80s (blow drying)Rotating the saccule back and forth in the process), and airing at room temperature for at least 30min to obtain the saccule coated with the bottom layer;
2) several drops of the middle layer solution (10mg/ml) were uniformly coated on the surface of the balloon coated with the bottom layer obtained in the above step so that the concentration of the middle layer substance on the surface of the balloon coated with the bottom layer was 4.85. mu.g/mm2Blowing the middle layer solution by wind within 110s (rotating the saccule back and forth in the blowing process), drying the saccule at room temperature for at least 30min, drying the saccule at 45 ℃ for 1.5h, and drying the saccule at room temperature for at least 30min to obtain the saccule coated with the middle layer;
3) dropping paclitaxel medicine solution on the surface of the balloon coated with the middle layer, turning on a fan (low-grade, cold air), dropping half amount of medicine solution on the surface of the balloon coated with the middle layer, rotating the balloon while dropping, uniformly covering the medicine on the balloon, and blowing for 10-60S; and opening a fan (middle grade, hot air (35-50 ℃)) to take the other half amount of the medicine solution, keeping the saccule away from the fan by about 45-60 cm, and rotating the saccule while dripping to enable the medicine to be uniformly coated on the saccule. When the medicinal solution is quick-dried, the hot air is closed, the cold air is opened, and the saccule is moved to be uniformly dried. Air drying at room temperature for 200min, and oven drying at 35 deg.C for at least 24h to obtain medicinal balloon.
Example 5 a method of making a drug balloon,
1) several drops of bottom layer solution (50mg/ml) are uniformly coated on the surface of the saccule (the saccule material is nylon elastomer) to ensure that the concentration of the bottom layer substance on the surface of the saccule is 2.09 mu g/mm2Blowing the bottom layer solution by using wind at 22 ℃ within 80s (rotating the saccule back and forth in the blowing process), and airing at room temperature for at least 30min to obtain the saccule coated with the bottom layer;
2) several drops of the middle layer solution (10mg/ml) were uniformly coated on the surface of the balloon coated with the bottom layer obtained in the above step so that the concentration of the middle layer substance on the surface of the balloon coated with the bottom layer was 7.56. mu.g/mm2Blowing the middle layer solution by using wind within 80s (rotating the saccule back and forth in the blowing process), drying the saccule at room temperature for at least 30min, drying the saccule for 2.5h at 55 ℃, and drying the saccule at room temperature for at least 30min to obtain the saccule coated with the middle layer;
3) dropping paclitaxel medicine solution on the surface of the balloon coated with the middle layer, turning on a fan (low-grade, cold air), dropping half amount of medicine solution on the surface of the balloon coated with the middle layer, rotating the balloon while dropping, uniformly covering the medicine on the balloon, and blowing for 10-60S; and opening a fan (middle grade, hot air (35-50 ℃)) to take the other half amount of the medicine solution, keeping the saccule away from the fan by about 45-60 cm, and rotating the saccule while dripping to enable the medicine to be uniformly coated on the saccule. When the medicinal solution is quick-dried, the hot air is closed, the cold air is opened, and the saccule is moved to be uniformly dried. Air drying at room temperature for 50min, and oven drying at 35 deg.C for at least 24h to obtain medicinal balloon.
Example 6 a method of making a drug balloon,
1) several drops of bottom layer solution (1mg/ml) are uniformly coated on the surface of the saccule (the saccule material is PET), so that the concentration of the bottom layer substance on the surface of the saccule is 1.04 mu g/mm2Blowing the bottom layer solution by wind within 110s at 28 ℃ (rotating the saccule back and forth in the blowing process), and airing at room temperature for at least 30min to obtain the saccule coated with the bottom layer;
2) several drops of the middle layer solution (1000mg/ml) were uniformly coated on the surface of the balloon coated with the bottom layer obtained in the above step so that the concentration of the middle layer substance on the surface of the balloon coated with the bottom layer was 8.92. mu.g/mm2Blowing the middle layer solution by using wind within 80s (rotating the saccule back and forth in the blowing process), drying the saccule at room temperature for at least 30min, drying the saccule for 1.5h at 55 ℃, and drying the saccule at room temperature for at least 30min to obtain the saccule coated with the middle layer;
3) dropping everolimus drug solution on the surface of the balloon coated with the middle layer, turning on a fan (low-grade and cold air), dropping half amount of drug solution on the surface of the balloon coated with the middle layer, rotating the balloon while dropping, enabling the drug to be uniformly coated on the balloon, and blowing for 10-60 seconds; and opening a fan (middle grade, hot air (35-50 ℃)) to take the other half amount of the medicine solution, keeping the saccule away from the fan by about 45-60 cm, and rotating the saccule while dripping to enable the medicine to be uniformly coated on the saccule. When the medicinal solution is quick-dried, the hot air is closed, the cold air is opened, and the saccule is moved to be uniformly dried. Air drying at room temperature for 20min, and oven drying at 35 deg.C for at least 24h to obtain medicinal balloon.
Example 7 a method of making a drug balloon,
1) several drops of bottom layer solution (40mg/ml) are uniformly coated on the surface of the balloon (the balloon material is polyurethane), so that the concentration of the bottom layer substance on the surface of the balloon is 1.17 mu g/mm2Blowing the bottom layer solution by wind within 110s at 26 ℃ (rotating the saccule back and forth in the blowing process), and airing at room temperature for at least 30min to obtain the saccule coated with the bottom layer;
2) several drops of the middle layer solution (500mg/ml) were uniformly coated on the surface of the balloon coated with the bottom layer obtained in the above step so that the concentration of the middle layer substance on the surface of the balloon coated with the bottom layer was 6.79. mu.g/mm2Blowing the middle layer solution by wind within 90s (rotating the saccule back and forth in the blowing process), drying at room temperature for at least 30min, drying at 55 ℃ for 2.5h, and drying at room temperature for at least 30min to obtain the saccule coated with the middle layer;
3) dropping the tacrolimus drug solution on the surface of the balloon coated with the middle layer, turning on a fan (low-grade and cold air), dropping half of the drug solution on the surface of the balloon coated with the middle layer, rotating the balloon while dropping, enabling the drug to be uniformly coated on the balloon, and blowing for 10-60 seconds; and opening a fan (middle grade, hot air (35-50 ℃)) to take the other half amount of the medicine solution, keeping the saccule away from the fan by about 45-60 cm, and rotating the saccule while dripping to enable the medicine to be uniformly coated on the saccule. When the medicinal solution is quick-dried, the hot air is closed, the cold air is opened, and the saccule is moved to be uniformly dried. Air drying at room temperature for 40min, and oven drying at 38 deg.C for at least 24h to obtain medicinal balloon.
Example 8 a method of making a drug balloon,
1) several drops of bottom layer solution (30mg/ml) are uniformly coated on the surface of the balloon (the balloon material is polyethylene), so that the concentration of the bottom layer substance on the surface of the balloon is 0.89 mu g/mm2Drying the bottom layer solution by using wind within 80-110 s at 22-28 ℃ (rotating the saccule back and forth in the drying process), and airing at room temperature for at least 30min to obtain the saccule coated with the bottom layer;
2) several drops of the middle layer solution (600mg/ml) were uniformly coated on the surface of the balloon coated with the bottom layer obtained in the above step so that the concentration of the middle layer substance on the surface of the balloon coated with the bottom layer was 8.23. mu.g/mm2Blowing the middle layer solution by wind within 110s (rotating the saccule back and forth in the blowing process), drying at room temperature for at least 30min, drying at 55 ℃ for 2.5h, and drying at room temperature for at least 30min to obtain the saccule coated with the middle layer;
3) dripping the phosphorylcholine medicinal solution on the surface of the balloon coated with the middle layer, turning on a fan (low-grade and cold air), dripping half of the medicinal solution on the surface of the balloon coated with the middle layer, rotating the balloon while dripping, uniformly coating the medicinal solution on the balloon, and blowing for 10-60 seconds; and opening a fan (middle grade, hot air (35-50 ℃)) to take the other half amount of the medicine solution, keeping the saccule away from the fan by about 45-60 cm, and rotating the saccule while dripping to enable the medicine to be uniformly coated on the saccule. When the medicinal solution is quick-dried, the hot air is closed, the cold air is opened, and the saccule is moved to be uniformly dried. Air drying at room temperature for 50min, and oven drying at 35 deg.C for at least 24h to obtain medicinal balloon.
Example 9 a method of making a drug balloon,
1) several drops of bottom layer solution (45mg/ml) are uniformly coated on the surface of the balloon (the balloon material is polyurethane), so that the concentration of the bottom layer substance on the surface of the balloon is 0.77 mu g/mm2Blowing the bottom layer solution by using wind at 27 ℃ within 80s (rotating the saccule back and forth in the blow-drying process), and airing at room temperature for at least 30min to obtain the saccule coated with the bottom layer;
2) several drops of the middle layer solution (700mg/ml) were uniformly coated on the surface of the balloon coated with the bottom layer obtained in the above step so that the concentration of the middle layer substance on the surface of the balloon coated with the bottom layer was 5.53. mu.g/mm2Blowing the middle layer solution by using wind within 80s (rotating the saccule back and forth in the blowing process), drying the saccule at room temperature for at least 30min, drying the saccule for 1.5h at 45 ℃, and drying the saccule at room temperature for at least 30min to obtain the saccule coated with the middle layer;
3) dripping the CD34 antibody medicine solution on the surface of the saccule coated with the middle layer, turning on a fan (low grade, cold air), firstly, dripping half amount of the medicine solution on the surface of the saccule coated with the middle layer, rotating the saccule while dripping, enabling the medicine to be uniformly coated on the saccule, and blowing for 10-60S; and opening a fan (middle grade, hot air (35-50 ℃)) to take the other half amount of the medicine solution, keeping the saccule away from the fan by about 45-60 cm, and rotating the saccule while dripping to enable the medicine to be uniformly coated on the saccule. When the medicinal solution is quick-dried, the hot air is closed, the cold air is opened, and the saccule is moved to be uniformly dried. Air drying at room temperature for 20min, and oven drying at 35 deg.C for at least 24h to obtain medicinal balloon.
The drug balloons prepared in the examples were further tested for their effectiveness.
First, bottom, middle and drug layer data detection
Table 1 below lists the bottom, middle and drug layer data for drug balloons prepared by the method of the invention.
Table 1 drug balloon coating data analysis
Second, drug release effect detection
The method comprises the following steps: the medicine balloon prepared by the invention is used in animal experiments of pigs, and 2 minutes after the femoral artery of the pigs is dilated by the medicine balloon, the medicine content on the balloon is detected, and the medicine content in a target blood vessel is detected.
As a result: the results of the drug content on the balloon are shown in table 2, and it can be seen that most of the drug carried by the coating is released (70%) and a small amount of the drug is remained in the coating after the balloon is expanded.
TABLE 2 drug content before and after balloon dilatation of the drug of the invention
Third, the drug releasing effect of the drug balloon in animal body
(1) After the femoral artery of the pig is dilated by the drug balloon, the detection result of the drug content in the plasma of the pig is shown in figure 1, and it can be seen that the drug content in the plasma reaches the highest peak immediately after being released and then is reduced. After 24 hours, the drug had substantially disappeared from the plasma.
(2) The detection result of the drug content in the target blood vessel after the femoral artery of the pig is dilated by the drug balloon is shown in figure 2. Immediately after balloon expansion, the drug content in the target vessel reached 1.5 mg/g. Although the drug content in the target vascular site was much reduced after 28 days, it was also much higher than the minimum effective dose of 47ng/g (0.047. mu.g/g).
(3) After the drug balloon provided by the invention is used for dilating the porcine blood vessel, the drug content in each tissue is shown in table 3. From the data, it can be seen that the vast majority of the drug is translocated into the vessel wall. The drug content in blood and other tissues, such as the liver, is low.
TABLE 3 drug content of drug balloon of the invention in various tissues after animal body expansion
The following conclusions can be drawn by using the medicine balloon catheter in the pig body for the test:
1) the total AUClast value of paclitaxel in blood vessel is 167264263.0ng hr/g, AUClast value in liver tissue is 63351ng hr/g, and total distribution amount in target blood vessel is far higher than that in liver tissue, and shows main distribution;
2) the drug content reaches the peak value of 1.4 multiplied by 10 when the target blood vessel part is at 0h6ng/g(1.4×103μ g/g) and a content of 1.16X 10 at 7 days5ng/g (116. mu.g/g). The content is gradually reduced and still remains 1.28 × 10 at 28 days4ng/g(12.8μg/g)。
3) After the peripheral blood vessel drug balloon dilatation catheter enters a pig artery for dilatation, the paclitaxel content in blood reaches a peak value when T is 0.083h, and after 28 days, paclitaxel cannot be detected in the blood, namely the paclitaxel in the blood can be basically eliminated after 28 days.
4) After the peripheral blood vessel drug balloon dilatation catheter enters the pig artery for dilatation, the drug coating on the balloon can be quickly released and absorbed by the target blood vessel, the absorption peak value can be reached at 0 moment, and the drug content of the target blood vessel part is far higher than the lowest effective dose of 47ng/g (0.047 mu g/g) after 28 days; the result shows that the drug coating is a process of quick release, quick absorption and slow elimination at the target blood vessel part, namely the peripheral blood vessel drug balloon dilatation catheter can play the role of effective drugs.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (11)
1. The preparation method of the medicine balloon is characterized by comprising the following steps:
1) a plurality of drops of bottom layer solution are uniformly coated on the surface of the balloon, so that the concentration of the bottom layer substance on the surface of the balloon is 0.5-5 mu g/mm2Blow-drying the bottom layer solution, and airing at room temperature for at least 30min to obtain the balloon coated with the bottom layer;
2) taking a plurality of drops of the middle layer solution to be uniformly coated on the surface of the saccule coated with the bottom layer obtained in the previous step, and enabling the concentration of the middle layer substance on the surface of the saccule coated with the bottom layer to be 4-30 mu g/mm2Drying the middle layer solution by blowing, and airing at room temperature for at least 20min to obtain the balloon coated with the middle layer;
3) dropping a medicine solution with a proper concentration on the surface of the balloon coated with the middle layer, rotating the balloon while dropping, uniformly coating the medicine on the balloon, drying the medicine by blowing, drying the medicine for 20-50 min at room temperature, and drying the medicine to obtain a medicine balloon;
the bottom layer material is at least one selected from polyethylene oxide, polyvinyl acetate and polyvinylpyrrolidone;
the middle layer material is at least one of acetate, benzoate, maleate, succinate, ascorbate, citrate, tartrate, lactate, oxalate, aspartate, nicotinate, gluconate, glutamate, vanillic acid salt, lactobionic acid salt, tromethamine, xylitol, sorbitol, mannitol and amino alcohol;
the concentration of the medicine solution is 8.0 mg/ml-11.5 mg/ml.
2. The method as claimed in claim 1, wherein in step 1), the concentration of the bottom layer solution is 1mg/ml to 50 mg/ml.
3. The method as claimed in claim 1, wherein in step 1) and step 2), the drying operation is as follows: and blowing the bottom layer solution or the middle layer solution by using wind at the temperature of 22-28 ℃ within 80-110 s.
4. The method of claim 1, wherein the balloon is rotated back and forth during blow-drying in step 1) and step 2).
5. The method of claim 1, wherein in step 3), the drug solution is coated twice and the balloon is rotated while dripping during coating.
6. The method according to claim 1 or 5, wherein in the step 3), the drying specifically comprises: and blowing with cold air at room temperature for 10-60s during the first coating, blowing with hot air at a fan middle gear during the second coating, keeping the object away from the fan for 45-60 cm, blowing with cold air at room temperature, rotating the balloon, and drying uniformly.
7. The method of claim 1, wherein the material of the balloon is selected from one of polyethylene, nylon, PET, polyurethane.
8. The method of claim 1, wherein the material of the balloon is selected from nylon elastomers.
9. The method of claim 1, wherein the balloon material is selected from Pebax.
10. The method according to any one of claims 1 or 7 to 9, wherein the drug is selected from one or more of paclitaxel, everolimus, tacrolimus, phosphorylcholine, CD34 antibodies and derivatives thereof.
11. A drug balloon, the method for preparing the same being as in any one of claims 1 to 10.
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| CN201711092572.7A CN108057168B (en) | 2017-11-08 | 2017-11-08 | Preparation method of medicine balloon |
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| CN201711092572.7A CN108057168B (en) | 2017-11-08 | 2017-11-08 | Preparation method of medicine balloon |
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| CN108057168A CN108057168A (en) | 2018-05-22 |
| CN108057168B true CN108057168B (en) | 2021-06-29 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP3259267B2 (en) * | 1993-12-28 | 2002-02-25 | ニプロ株式会社 | Chemical injection device |
| CN104623740B (en) * | 2013-11-15 | 2018-02-16 | 微创心脉医疗科技（上海）有限公司 | A kind of medicinal balloon and preparation method thereof |
| CN104511084A (en) * | 2014-12-30 | 2015-04-15 | 深圳市信立泰生物医疗工程有限公司 | Balloon catheter |
| GB201512030D0 (en) * | 2015-07-09 | 2015-08-19 | Jmedtech Pte Ltd | Composition |
| CN204932563U (en) * | 2015-09-22 | 2016-01-06 | 傅国胜 | A kind of dabbling drug sacculus |
| CN108883257B (en) * | 2016-03-23 | 2021-05-28 | 泰尔茂株式会社 | Balloon catheter and method of manufacture and treatment thereof |
| US10695542B2 (en) * | 2016-04-04 | 2020-06-30 | Medtronic Vascular, Inc. | Drug coated balloon |
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