WO2018019055A1 - 用于动脉血管病变扩张载药球囊的复配药物及载药球囊 - Google Patents

用于动脉血管病变扩张载药球囊的复配药物及载药球囊 Download PDF

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WO2018019055A1
WO2018019055A1 PCT/CN2017/089228 CN2017089228W WO2018019055A1 WO 2018019055 A1 WO2018019055 A1 WO 2018019055A1 CN 2017089228 W CN2017089228 W CN 2017089228W WO 2018019055 A1 WO2018019055 A1 WO 2018019055A1
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drug
balloon
solvent
loaded
compound
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PCT/CN2017/089228
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English (en)
French (fr)
Inventor
张庭超
陈忠
符伟国
岳嘉宁
李阳
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杭州唯强医疗科技有限公司
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Publication of WO2018019055A1 publication Critical patent/WO2018019055A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/422—Anti-atherosclerotic agents
    • 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
    • A61M2210/00—Anatomical parts of the body
    • A61M2210/12—Blood circulatory system

Definitions

  • the present invention belongs to the technical field of medicine, and relates to a compound medicine and a drug-loaded balloon, and particularly relates to a compound medicine and a drug-loading balloon for expanding an arterial vascular lesion and expanding a drug-loaded balloon.
  • Arterial vascular disease (occlusion, calcification, stenosis, etc.) is one of the main causes of death in patients with vascular disease.
  • the main treatments for this disease are: 1. Surgery bridges the diseased blood vessels; 2. Vascular interventional stent Angioplasty, implantation of a stent at the diseased vessel; 3. Vascular interventional balloon angioplasty, using an expandable balloon catheter, balloon expansion of the diseased vessel, allowing the diseased vessel to restore the original lumen diameter.
  • the second and third methods are more and more popular among doctors and patients because of their small trauma, rapid recovery, and remarkable curative effect.
  • the second method of implanting the stent although providing a better solution for the treatment of atherosclerosis and intravascular stenosis, greatly improved the treatment efficiency, but there are intravascular and in-stent restenosis, small The therapeutic effects of blood vessels, bifurcated vessels, and in situ lesions are not satisfactory. As the number of patients receiving per-therapy has increased year by year, the absolute number of patients with stent restenosis is quite large.
  • the third method of dilating sputum due to the high use pressure, can cause the vessel wall of the lesion to rupture and be squeezed into the surrounding tissue.
  • the wall of the blood vessel treated in this way usually shows an increase in thickness within a few weeks or months, similar to the formation of a scar.
  • these blood vessels will soon be narrowed again (restenosis). Therefore, restenosis is a serious medical problem and causes increased medical costs and patient suffering.
  • a drug-expanding balloon catheter has recently been proposed, and an anti-proliferative drug is coated on the surface of the balloon catheter, and the balloon is instantaneously expanded, so that the drug is rapidly transferred to the blood vessel wall and adhered to the blood vessel wall.
  • the drug transferred by this method is difficult to maintain biological effects and effects on the blood vessel wall for a long time. The reason is that the adhesion between the drug coating and the surface of the balloon is small.
  • the drug Before the drug is placed in the lesion, it will be washed away by the delivery catheter, the wall of the blood vessel, and the blood flowing at a high speed, which will cause a large loss of the drug;
  • the proliferative drug is insoluble in water, the drug is slow by the tissue cells, and the bioavailability of the drug is low.
  • the drug-coated particles on the balloon catheter tend to agglomerate and agglomerate, which may cause blood vessel embolism after falling off.
  • the second method of implanting the stent although providing a better solution for the treatment of atherosclerosis and intravascular stenosis, greatly improved the treatment efficiency, but there are intravascular and in-stent restenosis, small The therapeutic effects of blood vessels, bifurcated vessels, and in situ lesions are not satisfactory. As the number of patients receiving per-therapy has increased year by year, the absolute number of patients with stent restenosis is quite large.
  • the third method of dilating sputum due to the high use pressure, can cause the vessel wall of the lesion to rupture and be squeezed and displaced into the surrounding tissue.
  • the wall of the blood vessel treated in this way usually shows an increase in thickness within a few weeks or months, similar to the formation of a scar.
  • these blood vessels will soon be narrowed again (restenosis). Therefore, restenosis is a serious medical problem and causes increased medical costs and patient suffering.
  • the drug Before the drug is placed in the lesion, it will be washed away by the delivery catheter, the wall of the blood vessel, and the blood flowing at a high speed, which will cause a large loss of the drug;
  • the proliferative drug is insoluble in water, the drug is slow by the tissue cells, and the bioavailability of the drug is low.
  • the drug-coated particles on the balloon catheter tend to agglomerate and agglomerate, which may cause blood vessel embolism after falling off.
  • the technical problem to be solved by the present invention is to provide a compound medicine for the above defects of the prior art.
  • the compound drug is released quickly, prevents the active drug component from agglomerating, uniformly adheres to the surface of the balloon, and is not easy to form a blood vessel embolism.
  • a further technical problem to be solved by the present invention is to provide a drug-loaded balloon in which the binding force of the active drug to the surface of the balloon is balanced, so that the drug is efficiently delivered to the target site and the release and absorption of the drug can be accelerated.
  • a compound drug for an arterial vasculopathy dilatation drug-loaded balloon comprising a raw material: a lipophilic active drug for treating arterial vascular disease, a drug compounding agent, a solvent, wherein the active drug and the drug compounding agent The mass ratio is 1.2-4.8; the mass ratio of the total mass of the active drug and the drug compounding agent to the solvent is 8-20; the drug compounding agent is a hydrophilic surfactant; the solvent is water-miscible A non-polar solvent or a mixed solution of a non-polar solvent and water.
  • the mass ratio of the active drug to the drug compounding agent is 1.5 to 4.8.
  • the mass-to-volume ratio of the total mass of the active drug and the drug compounding agent to the solvent is 10-15 (g/1) .
  • the active drug is paclitaxel, rapamycin, paclitaxel derivative or rapamycin derivative.
  • the drug compounding agent is one or more of glucosamine, acetamide, sorbitol, PEG100, and the like. .
  • the grape amine is N-methyl-D-glucose methylamine, N-methyl-D-glucose Amine or octanoyl-N-methylglucamine.
  • the solvent is at least one of methanol, ethanol, acetone, ethyl acetate, DMSO, DMF; or the solvent A mixed solution of at least one of methanol, ethanol, acetone, ethyl acetate, DMSO, and DMF mixed with water.
  • the solvent is at least one of methanol, ethanol, DMSO, or the solvent is methanol, ethanol, DMSO At least one Mixed solution after mixing with water.
  • a drug-loaded balloon comprising a balloon with a flap structure, a drug coating attached to a surface of the balloon, the drug coating comprising an active drug and a drug compounding agent; the active drug is used for treating an arterial blood vessel a lipophilic active drug of the lesion; the pharmaceutical compound is a hydrophilic surfactant.
  • the drug compounding agent encapsulates or separates the active drug particles.
  • the active drug is a lipophilic drug which has a therapeutic effect on arterial vascular disease
  • the drug compounding agent is a hydrophilic surfactant.
  • the choice of lipophilic drugs is to avoid the problem that the hydrophilic drug is soluble in water and has a large loss in transport.
  • the lipophilic drug since the lipophilic drug has poor adhesion to the surface of the balloon and is not easily dispersed by mutual agglomeration, it is necessary to use a drug complex.
  • the agent acts as a surfactant to adjust the balance of the binding force between the lipophilic active drug and the balloon surface, and accelerates the release and absorption of the drug, and the hydrophilic lipophilic substance of the drug compounding agent first It will combine with the lipophilic active drug (rapamycin or paclitaxel, etc.) to prevent the drug coating from agglomerating due to the aggregation of the lipophilic active drug molecules, and the surface tension of the balloon surface material is reduced, resulting in lipophilicity.
  • the lipophilic active drug rapamycin or paclitaxel, etc.
  • the active drug uniformly adheres to the surface of the balloon; at the same time, the drug compounding agent acts as a physical spacer between the crystal particles of the lipophilic active drug, increases the specific surface area of the lipophilic active drug particle, and increases the solubility in the cell gap. , thereby facilitating the infiltration during contact with the blood, promoting the insertion of the drug into the target site of the balloon catheter. Is more quickly released, accelerating drug reaches the lipid bilayer membrane targeting diseased tissue; thus accelerating drug diffusion into the tissue and greatly facilitate the absorption of lipophilic active drug is target lesion tissue cells.
  • the active drug can be delivered to the targeted diseased tissue area quickly or directly during or after the clinical procedure, and the homolyzed balloon catheter should rapidly release the active drug in an effective and efficient manner at the desired target site, It can quickly penetrate into the targeted tissue and adhere to the blood vessel wall to exert long-term effects to treat arterial vascular diseases.
  • Another important role of using a drug compounding agent is to reduce the risk of vascular embolization. Since the active drug tends to agglomerate on the surface of the balloon, it is washed away and enters the blood vessel, which may cause a problem of blood vessel embolism. Using a pharmaceutical compounding agent, the drug compounding agent acts as a physical space between the lipophilic active drug crystal particles The effect of the septum reduces the agglomeration of active drugs and reduces the risk of vascular embolism.
  • the drug-loaded balloon of the present invention is for delivering an active drug to a target site of a blood vessel or a lumen, and a drug coating is applied to the outer surface of the balloon catheter. Due to the use of active drugs and drug compounding agents, the drug coating is rubbed against the catheter sheath and washed by high-speed blood, which is not easy to fall off and causes a large loss.
  • the drug compounding agent accelerates the release rate of the active drug from the balloon, so that the active drug is released in a very short period of time and rapidly penetrates into the tissue at the diseased site, thereby enhancing the active drug in the vascular system or other body lumens.
  • the absorption rate in the diseased tissue can solve the rapid loss of the drug to the target lesion after the loss of the drug in the clinical use and the expansion of the balloon.
  • FIG. 1 is a schematic view showing the state of a compound drug on a surface of a balloon according to an embodiment of the present invention
  • 2a-2c are diagrams showing the morphology of the drug-loaded drug capsules of the present invention under 500-fold, 1000-fold, and 2000-fold electron microscopes;
  • FIGS. 3a-3c are views showing the morphology of a conventional drug-loaded drug-loaded balloon under a 500-fold, 1000-fold, and 2000-fold electron microscope;
  • 4a-4d are respectively a pre-expansion angiogram of a drug-loaded balloon, a balloon dilatation angiogram, an immediate angiogram after balloon dilation, and a 28-day follow-up angiogram;
  • FIGS. 5a-5d are respectively a contrast-enhancing angiogram of a drug-loaded balloon, a balloon dilatation angiogram, an immediate angiogram after balloon dilation, and a 28-day follow-up angiogram;
  • FIG. 6 is a cross-sectional view of a drug-loaded balloon of the present invention.
  • a compound drug for an arterial vasculopathy dilatation drug-loaded balloon comprising a raw material: a lipophilic active drug for treating arterial vascular disease, a drug compounding agent, a solvent, wherein the active drug and the drug compounding agent
  • the mass ratio is 1.2-4.8; because the compound drug is repeatedly coated or soaked on the balloon, the active drug is
  • the mass ratio of the drug compounding agent is very broad, and the present invention is applicable in the range of 1.2 to 4.8.
  • the mass ratio of the active drug to the drug compounding agent is from 1.5 to 4.8.
  • the mass-to-volume ratio of the total mass of the active drug and the drug compounding agent to the solvent is 8-20 (g/1); preferably, the mass-to-volume ratio of the total mass of the active drug and the drug compounding agent to the solvent is 10 -15 (g/1).
  • the pharmaceutical compounding agent is a hydrophilic surfactant; preferably, the pharmaceutical compounding agent is one or more of a glucosamine substance, acetamide, sorbitol, PEG100 and the like. Most preferably, the glucosamine is N-methyl-D-glucosylamine, N-methyl-D-glucosamine or octanoyl-N-methylglucamine.
  • the above-mentioned drug compounding agent has the same effect, and can be optionally substituted in the following examples.
  • the solvent is a water-miscible non-polar solvent or a mixed solution of a non-polar solvent and water.
  • the solvent is at least one of methanol, ethanol, acetone, ethyl acetate, DMSO (dimethyl sulfoxide), DMF (dimethylformamide); or the solvent is methanol, ethanol, acetone, acetic acid A mixed solution of at least one of ethyl ester, DMS 0, and DMF mixed with water.
  • the solvent is at least one of methanol, ethanol, and DMSO, or the solvent is a mixed solution of at least one of methanol, ethanol, and DMSO mixed with water.
  • the above solvents have the same functions, and can be arbitrarily replaced in the following examples.
  • the compound drug of the present invention is for the treatment of arterial vascular disease, and the drug also has a corresponding change as the therapeutic technique continues to develop, but the present invention is applicable to a lipophilic active drug for treating arterial vascular disease.
  • the active drug is paclitaxel, rapamycin or taxol.
  • the above-mentioned compound drug is made into a drug-loaded balloon as shown in FIG. 6 by soaking, spraying, or the like, and the drug-loaded balloon includes a balloon 100 having a flap structure.
  • the surface of the balloon 100 is pleated, that is, the surface of the balloon 100 is folded to obtain a flap structure balloon, and the flap has a star-shaped structure in cross section, which is easy to wind up.
  • the number of flaps can be set according to actual needs. It can be folded 2-6 petals; more preferably 3 petals, 6 petals.
  • a drug coating layer 200 is attached to the surface of the balloon 100.
  • the drug coating layer 200 includes an active drug and a drug compounding agent. The crystal formed by the active drug and the drug compounding agent adheres to the surface of the balloon 100.
  • the active drug is used for treatment. a lipophilic active drug for arterial vascular disease; the drug compounding agent is a hydrophilic surfactant.
  • the drug compounding agent encapsulates or spaces the active drug particles, thereby preventing the drug coating from agglomerating due to aggregation of the lipophilic active drug molecules,
  • the same drug compounding agent reduces the surface tension of the balloon surface material, making the lipophilic active drug and the balloon surface Uniform adhesion; reduces active drug agglomeration and reduces the risk of vascular embolism.
  • a drug-loaded balloon is used to deliver an active drug to a target site of a blood vessel or a lumen, to treat a stenosis in a blood vessel or lumen, to prevent intimal or epithelial hyperplasia;
  • a blood vessel refers to a coronary artery, a peripheral artery or a brain Arterial vessels; lumens refer to the esophagus, airways, intestines, biliary tract, urinary tract, prostate or cerebral access.
  • Embodiment 1 A compound drug for an arterial vasculopathy dilatation drug-loaded balloon, comprising a raw material:
  • paclitaxel 20mg PEG100, dissolved in a mixed solvent of 4.25ml of acetone and 2ml of water to prepare a mixed solution; a peripheral balloon catheter (diameter 6.0mm, length 60mm) balloon portion was soaked into the mixed solution, and taken out, dry. After 10 times of repeated soaking, the drug-loaded balloon was obtained after drying, and the drug density in the drug coating was 3.86 g/mm as determined by HPLC.
  • the material of the balloon catheter is one or more of nylon, nylon elastomer, PU, Pebax. PET or polyethylene.
  • Example 2 A compound drug for an arterial vasculopathy dilatation drug-loaded balloon, including raw materials:
  • paclitaxel 50 mg
  • a mixed solvent 6 ml of acetone and 1 ml of water
  • a peripheral balloon catheter (diameter 6.0 mm, length 60 mm)
  • the capsule was partially soaked in the mixed solution, taken out, and dried. After 10 times of repeated soaking, the drug-loaded balloon was obtained after drying, and the drug density in the drug coating was 3.17 g/mm 2 as detected by HPL C.
  • Example 3 a compound drug for an arterial vasculopathy dilatation drug-loaded balloon, including raw materials:
  • rapamycin 20 mg of N-methyl-D-glucosamine, dissolved in 6.7 ml of methanol solution; Peripheral balloon catheter (diameter 6.0 mm, length 60 mm) The balloon was partially soaked in the mixed solution, taken out, and dried. After repeated soaking for 12 times, the drug-loaded balloon was obtained after drying, and the drug density in the drug coating was determined by HPLC to be 4.78 g/mm 2 .
  • Example 4 a compound drug for an arterial vasculopathy dilatation drug-loaded balloon, including raw materials:
  • Example 5 a compound drug for an arterial vasculopathy dilatation drug-loaded balloon, including raw materials:
  • paclitaxel and 16.7 mg of acetamide were dissolved in 2.8 ml of ethyl acetate; the solution was applied dropwise to the surface of a balloon catheter (diameter 6.0 mm, length 60 mm) and dried. After repeated application by repeated dripping, the drug-loaded balloon was obtained, and the drug density in the drug coating was 1.78 g/mm.
  • Example 6 a compound drug for an arterial vasculopathy dilatation drug-loaded balloon, including raw materials:
  • Example 7 a compound drug for an arterial vasculopathy dilatation drug-loaded balloon, including raw materials:
  • paclitaxel 50 mg was dissolved in a mixed solution of 4.25 ml of acetone and 2 ml of water; the solution was applied dropwise to the surface of a balloon of a peripheral balloon catheter (diameter 6.0 mm, length 60 mm), and dried. After repeated application by repeated dripping, the coating drug density was 5.2 g/mm 2 as determined by HPLC.
  • FIG. 1 it is a schematic diagram of the state of the compound drug on the surface of the balloon, the active drug is granular, the drug compounding agent and the solvent are liquid, and the active drug is wrapped to serve as a spacer for the lipophilic drug crystal particles. Increase the specific surface area of the drug particles.
  • the drug composition of the present invention is made into a drug-loaded balloon, and a drug coating layer is formed on the surface of the balloon under the electron microscope of 500 times, 1000 times, and 2000 times, respectively.
  • the existing therapeutic drug paclitaxel is used as a drug-loaded balloon, and the drug coating on the surface of the balloon is formed by a 500-fold, 1000-fold, 2000-fold electron microscope.
  • the crystal form of the drug coating formed is in the form of a rod or a needle, and the particle size is moderate (about 20 ⁇ m), and the distribution is uniform, and the most important combination between the particles is Loose, not reunited.
  • paclitaxel is used alone in the therapeutic drug, and the crystal form is crystallized after coating with the balloon, and the particle size difference is large and the agglomeration is obvious.
  • the target vessel of an artificial blood vessel is subjected to a mass loss simulation test in a simulated use system for delivery, and the amount of the drug is lost before the balloon is expanded and expanded, that is, during the balloon catheter insertion and movement to the target site.
  • HPLC test conditions are: Shimadzu LC-20A High Performance Liquid Chromatograph, Column: Aglilent ZOBAX SB-C18
  • the vascular model system was simulated in vitro to test the level of drug-loaded balloon particle shedding.
  • Subject Healthy pig, about 3 months old, weighing 30 ⁇ 35kg.
  • Example 4 and Comparative Example 1 were respectively made into drug-loaded balloons, and the drug-loaded balloon catheter was puncture from the carotid artery.
  • the drug-loaded balloon catheter was delivered to the left and right iliac/femoral arteries, and the balloon was pressurized to about 6 atm, and expanded for 3 minutes.
  • the drug-loaded balloon catheter was withdrawn and the puncture was sutured.
  • DSA angiography was performed to observe the occlusion of the target vessel and downstream vessels.
  • FIGS. 4a-4d are a pre-ball expansion angiogram of a drug-loaded balloon, a balloon dilatation angiogram, an immediate angiogram after balloon dilation, and a 28-day follow-up. Contrast image; Figure 5a-5d is the balloon 1 pre-expansion angiogram, balloon dilatation ⁇ angiogram, balloon angiogram immediately after expansion, 28 days Visit the angiogram.
  • Example 4 The drug-loaded balloon catheter prepared in Example 4 was completed before and after expansion of the femoral artery in pigs, and 28 days follow-up DS
  • a angiography showed that the blood vessels in the target vessel and the downstream vessels were smooth, and no complications such as stenosis, dissection, and occlusion were observed.
  • the drug-loaded balloon catheter prepared in Comparative Example 1 was angiographically displayed immediately before dilation of the femoral artery in the pig and after completion of dilation. Everything is normal, blood circulation is smooth.
  • follow-up DSA angiography after 28 days showed that the target vessel segment was completely occluded and blood flow could not pass normally. It can be seen that the drug-loaded balloon catheter prepared by the invention can greatly reduce the incidence of vascular occlusion.
  • the compound drug of the present invention can be transported to a target site of a blood vessel or a lumen through a balloon catheter, and the drug coating covers the outer surface of the balloon catheter, and the drug coating contains an activity.
  • the drug and drug compounding agent, the drug compounding agent accelerates the release rate of the active drug from the balloon, and the drug is released in a very short period of time and rapidly penetrates into the tissue at the diseased site, thereby improving the drug in the vascular system or
  • the absorption rate in the diseased tissues of other body lumens can solve the rapid loss of the drug to the target lesion after the loss of the drug in the clinical use and the expansion of the balloon.
  • the compounding drug of the present invention can very effectively solve the agglomeration problem caused by the crystal form, size and drug crystal agglomeration of the lipophilic drug.
  • the effect of achieving good inhibition of diseased vessel restenosis is greatly reduced, and the incidence of vascular embolization is greatly reduced.

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Abstract

一种用于动脉血管病变扩张载药球囊的复配药物及载药球囊。复配药物包括原料：用于治疗动脉血管病变的亲脂性活性药物、药物复配剂、溶剂，活性药物与药物复配剂质量比为1.2-4.8，活性药物和药物复配剂的总质量与溶剂的质量体积比为8-20(g/l)，药物复配剂为亲水性表面活性剂，溶剂为与水互溶的非极性溶剂、或者是与水互溶的非极性溶剂与水的混合溶液。载药球囊包括折瓣结构的球囊，球囊表面附着有药物涂层，药物涂层包括活性药物和药物复配剂。

Description

用于动脉血管病变扩张载药球囊的复配药物及载药球囊 技术领域
[0001] 本发明属于医药技术领域， 涉及一种复配药物及载药球囊， 尤其涉及一种用于 动脉血管病变扩张载药球囊的复配药物及载药球囊。
背景技术
[0002] 动脉血管病变 （闭塞， 钙化， 狭窄等） 是血管疾病患者发生死亡的主要原因之 一， 目前针对该疾病主要治疗方式是： 1、 外科手术对病变血管进行桥接； 2、 血管介入支架成形术， 在病变血管处植入支架； 3、 血管介入球囊成形术， 使用 可膨胀球囊导管， 对病变血管进行球囊扩张， 使得病变血管恢复原始管腔直径 。 其中， 第二和第三方法因其创伤小， 恢复快， 疗效显著， 目前越来越受医生 和患者欢迎。
[0003] 采用第二种方法植入支架， 虽然对于解决动脉粥样硬化和血管内狭窄提供了比 较好的解决方案， 使治疗效率大为提高， 但存在血管内和支架内再狭窄， 对小 血管、 分叉血管及原位病变等的治疗效果不理想等缺点， 由于接受 per冶疗的患 者数量逐年上升， 发生支架再狭窄的患者的绝对数量相当大。
[0004] 采用第三种方法扩张吋， 因使用压力很高， 可导致病变的血管壁发生破裂， 并 且被挤压移位至周围组织中。 用此方法处理的血管壁通常在几周或几个月内就 出现厚度增加的情况， 类似于形成疤痕。 结果， 由于动脉硬化的进展， 这些血 管不久将再次狭窄 （再狭窄） 。 因此， 再狭窄是一个严重的医学难题并造成医 疗费用升高以及患者痛苦。
[0005] 目前针对再狭窄而采用的方法包括： 单纯球囊的再次扩张、 定向斑块旋切术、 旋磨术、 血管内放射治疗及重复支架植入等， 现有的裸球囊和药物支架都存在 一定的局限性， 裸球囊的再狭窄率偏高， 而药物支架对于小血管和分叉血管的 治疗效果也不佳， 二者均未能显示其理想的有效性或安全性。
[0006] 针对上述疑难问题， 新近提出采用药物扩张球囊导管， 将抗增生性药物涂覆在 球囊导管表面， 球囊瞬间扩张， 使得药物快速转移至血管壁并粘附在血管壁上 ， 以使得药物发挥长期药效作用。 但是， 这种方法转移的药物在血管壁上难以 长吋间地、 持久地保持生物学效应和药效。 原因是药物涂层与球囊表面之间的 粘结力较小， 药物置入病变处前会受到输送导管、 血管壁的摩擦以及高速流动 的血液冲走， 从而会导致药物大量损失； 由于抗增生药物在水中不溶的， 药物 被组织细胞慢， 药物生物可利用度低。 另外， 球囊导管上的药物涂层颗粒易团 聚而结块， 脱落后易造成血管栓塞。
技术问题
[0007] 采用第二种方法植入支架， 虽然对于解决动脉粥样硬化和血管内狭窄提供了比 较好的解决方案， 使治疗效率大为提高， 但存在血管内和支架内再狭窄， 对小 血管、 分叉血管及原位病变等的治疗效果不理想等缺点， 由于接受 per冶疗的患 者数量逐年上升， 发生支架再狭窄的患者的绝对数量相当大。
[0008] 采用第三种方法扩张吋， 因使用压力很高， 可导致病变的血管壁发生破裂， 并 且被挤压移位至周围组织中。 用此方法处理的血管壁通常在几周或几个月内就 出现厚度增加的情况， 类似于形成疤痕。 结果， 由于动脉硬化的进展， 这些血 管不久将再次狭窄 （再狭窄） 。 因此， 再狭窄是一个严重的医学难题并造成医 疗费用升高以及患者痛苦。
[0009] 目前针对再狭窄而采用的方法包括： 单纯球囊的再次扩张、 定向斑块旋切术、 旋磨术、 血管内放射治疗及重复支架植入等， 现有的裸球囊和药物支架都存在 一定的局限性， 裸球囊的再狭窄率偏高， 而药物支架对于小血管和分叉血管的 治疗效果也不佳， 二者均未能显示其理想的有效性或安全性。
[0010] 针对上述疑难问题， 新近提出采用药物扩张球囊导管， 将抗增生性药物涂覆在 球囊导管表面， 球囊瞬间扩张， 使得药物快速转移至血管壁并粘附在血管壁上 ， 以使得药物发挥长期药效作用。 但是， 这种方法转移的药物在血管壁上难以 长吋间地、 持久地保持生物学效应和药效。 原因是药物涂层与球囊表面之间的 粘结力较小， 药物置入病变处前会受到输送导管、 血管壁的摩擦以及高速流动 的血液冲走， 从而会导致药物大量损失； 由于抗增生药物在水中不溶的， 药物 被组织细胞慢， 药物生物可利用度低。 另外， 球囊导管上的药物涂层颗粒易团 聚而结块， 脱落后易造成血管栓塞。 问题的解决方案
技术解决方案
[0011] 本发明要解决的技术问题在于， 针对现有技术的上述缺陷， 提供一种复配药物
， 复配药物释放速度快、 防止活性药物组分团聚、 与球囊表面均匀粘附、 不易 形成血管栓塞。
[0012] 本发明进一步要解决的技术问题在于， 提供一种活性药物与球囊表面的粘结力 平衡， 使得药物有效输送到目标位置且可加快药物的释放和吸收的载药球囊。
[0013] 本发明解决其技术问题所采用的技术方案是：
[0014] 一种用于动脉血管病变扩张载药球囊的复配药物， 包括原料： 用于治疗动脉血 管病变的亲脂性活性药物、 药物复配剂、 溶剂， 其中活性药物与药物复配剂质 量比为 1.2- 4.8; 活性药物和药物复配剂的总质量与溶剂的质量体积比为 8-20; 所 述药物复配剂为亲水性表面活性剂； 所述溶剂为与水互溶的非极性溶剂、 或者 是非极性溶剂与水的混合溶液。
[0015] 所述的用于动脉血管病变扩张载药球囊的复配药物中， 优选所述活性药物与药 物复配剂质量比为 1.5-4.8。
[0016] 所述的用于动脉血管病变扩张载药球囊的复配药物中， 优选所述活性药物和药 物复配剂的总质量与溶剂的质量体积比为 10-15 (g/1) 。
[0017] 所述的用于动脉血管病变扩张载药球囊的复配药物中， 优选所述活性药物为紫 杉醇、 雷帕霉素、 紫杉醇衍生物或雷帕霉素衍生物。
[0018] 所述的用于动脉血管病变扩张载药球囊的复配药物中， 优选所述药物复配剂为 葡萄胺类物质、 乙酰胺、 山梨醇、 PEG100等中的一种或几种。
[0019] 所述的用于动脉血管病变扩张载药球囊的复配药物中， 优选所述葡萄胺类物质 为 N-甲基 -D-葡萄糖甲胺、 N-甲基 -D-葡萄糖乙胺或辛酰基 -N-甲基葡萄糖胺。
[0020] 所述的用于动脉血管病变扩张载药球囊的复配药物中， 优选所述溶剂为甲醇、 乙醇、 丙酮、 乙酸乙酯、 DMSO、 DMF中的至少一种； 或者所述溶剂为甲醇、 乙醇、 丙酮、 乙酸乙酯、 DMSO、 DMF中的至少一种与水混合后的混合溶液。
[0021] 所述的用于动脉血管病变扩张载药球囊的复配药物中， 优选所述溶剂为甲醇、 乙醇、 DMSO中的至少一种， 或者所述溶剂为甲醇、 乙醇、 DMSO中的至少一种 与水混合后的混合溶液。
[0022] 一种载药球囊， 包括折瓣结构的球囊， 在球囊表面附着有药物涂层， 药物涂层 包括活性药物和药物复配剂； 所述活性药物为用于治疗动脉血管病变的亲脂性 活性药物； 所述药物复配剂为亲水性表面活性剂。
[0023] 所述的载药球囊中， 优选所述药物涂层中， 药物复配剂包裹或间隔活性药物颗 粒。
发明的有益效果
有益效果
[0024] 本发明复配药物中， 活性药物是对动脉血管病变有治疗作用的亲脂性药物， 药 物复配剂是亲水性表面活性剂。 其中， 选择亲脂性药物是避免亲水性药物溶于 水、 输送中损失大的问题， 但是由于亲脂性药物与球囊表面的粘结力较差、 相 互团聚不易分散， 还需配合使用药物复配剂， 药物复配剂的作用是作为表面活 性剂调节亲脂性活性药物与球囊表面的粘结力平衡， 同吋加快药物的释放和吸 收， 而且药物复配剂的亲水亲脂物质首先会与亲脂性活性药物 （雷帕霉素或紫 杉醇等） 结合， 防止了亲脂性活性药物分子相互聚集而导致的药物涂层结块， 同吋降低了球囊表面材料的表面张力， 使得亲脂性活性药物与球囊表面均匀地 粘附； 同吋， 药物复配剂在亲脂性活性药物晶体颗粒间起到物理间隔的作用， 增加了亲脂性活性药物颗粒的比表面积， 增加细胞间隙中的溶解度， 从而有利 于在与血液接触过程中的浸润作用， 促进药物在球囊导管置入靶位点的过程中 更为快速地释放， 加速药物到达靶向病变组织细胞膜的脂双层； 从而加速药物 向组织中的扩散并且大大促进了亲脂性活性药物被靶血管病变组织细胞的吸收 。 最终， 可以使得在临床过程中或之后将活性药物快速直接地被输送到靶向病 变组织区域， 同吋球囊导管应当在所需的靶位置以有效且高效的方式快速地释 放活性药物， 使之可以快速地渗入到靶向组织， 并粘附在血管壁上， 长期发挥 药效， 以治疗动脉血管疾病。
[0025] 使用药物复配剂另外一个重要作用是减少血管栓塞的风险， 由于活性药物在球 囊表面易团聚结块， 输送中被冲刷掉落后进入血管， 会造成血管栓塞的问题， 本发明采用药物复配剂， 药物复配剂在亲脂性活性药物晶体颗粒间起到物理间 隔的作用， 减少了活性药物团聚， 减少了血管栓塞的风险。
[0026] 本发明的载药球囊， 用于将活性药物输送到血管或管腔的靶位点， 药物涂层覆 盖在球囊导管的外表面上。 由于采用了活性药物和药物复配剂， 使得药物涂层 在与导管鞘的摩擦以及被高速流动的血液冲刷吋， 不易脱落而导致大量的损失
。 药物复配剂加快了活性药物从球囊上的释放速度， 使得活性药物在非常短的 吋期内释放并快速渗透进入患病部位处的组织， 从而提高活性药物在血管系统 或其他身体管腔的患病组织中的吸收率， 可以解决在临床使用输送过程中的药 物量损失和球囊扩张之后药物向靶病变部位的快速转载。
对附图的简要说明
附图说明
[0027] 下面将结合附图及实施例对本发明作进一步说明， 附图中：
[0028] 图 1是本发明实施例的复配药物在球囊表面状态示意图；
[0029] 图 2a-2c是本发明复配药物制成载药球囊分别在 500倍、 1000倍、 2000倍电镜下 的形态图；
[0030] 图 3a-3c是现有治疗药物制成载药球囊分别在 500倍、 1000倍、 2000倍电镜下的 形态图；
[0031] 图 4a-4d分别为本发明实施例 4制成载药球囊的球囊扩张前造影图、 球囊扩张吋 造影图、 球囊扩张后即刻造影图、 28天随访造影图；
[0032] 图 5a-5d分别为对比例 1药物制成载药球囊的球囊扩张前造影图、 球囊扩张吋造 影图、 球囊扩张后即刻造影图、 28天随访造影图；
[0033] 图 6是本发明载药球囊剖视图。
实施该发明的最佳实施例
本发明的最佳实施方式
[0034] 为了对本发明的技术特征、 目的和效果有更加清楚的理解， 现对照附图详细说 明本发明的具体实施方式。
[0035] 一种用于动脉血管病变扩张载药球囊的复配药物， 包括原料： 用于治疗动脉血 管病变的亲脂性活性药物、 药物复配剂、 溶剂， 其中活性药物与药物复配剂质 量比为 1.2- 4.8 ; 由于复配药物在球囊上进行反复涂覆或浸泡， 则对活性药物与 药物复配剂质量比要求非常宽泛， 在 1.2- 4.8范围内都适用本发明。 优选所述活 性药物与药物复配剂质量比为 1.5-4.8。
[0036] 活性药物和药物复配剂的总质量与溶剂的质量体积比为 8-20 (g/1) ； 优选所述 活性药物和药物复配剂的总质量与溶剂的质量体积比为 10-15 (g/1) 。
[0037] 所述药物复配剂为亲水性表面活性剂； 优选所述药物复配剂为葡萄胺类物质、 乙酰胺、 山梨醇、 PEG100等中的一种或几种。 最优选所述葡萄胺类物质为 N-甲 基 -D-葡萄糖甲胺、 N-甲基 -D-葡萄糖乙胺或辛酰基 -N-甲基葡萄糖胺。 上述药物 复配剂所起的作用相同， 在下面的实施例中， 可以任意替换。
[0038] 所述溶剂为与水互溶的非极性溶剂、 或者是非极性溶剂与水的混合溶液。 优选 所述溶剂为甲醇、 乙醇、 丙酮、 乙酸乙酯、 DMSO (二甲基亚砜） 、 DMF (二甲 基甲酰胺)中的至少一种； 或者所述溶剂为甲醇、 乙醇、 丙酮、 乙酸乙酯、 DMS 0、 DMF中的至少一种与水混合后的混合溶液。 最优选所述溶剂为甲醇、 乙醇、 DMSO中的至少一种， 或者所述溶剂为甲醇、 乙醇、 DMSO中的至少一种与水混 合后的混合溶液。 上述溶剂所起的作用相同， 在下面的实施例中， 可以任意替 换。
[0039] 本发明的复配药物是用于治疗动脉血管病变的， 随着治疗技术的不断发展， 药 物也有相应变化， 但是只要用于治疗动脉血管病变的亲脂性活性药物都适用本 发明。 优选所述活性药物为紫杉醇、 雷帕霉素或紫杉酚。
[0040] 将上述复配药物通过浸泡、 喷涂等制成如图 6所示的载药球囊， 载药球囊包括 折瓣结构的球囊 100。 对球囊 100表面进行褶皱处理， 即对球囊 100表面进行折瓣 得到折瓣结构球囊， 折瓣使得球囊 100横截面为星形结构， 易于收卷。 折瓣数量 可以根据实际需要设定。 可以折 2-6瓣； 更优选 3瓣、 6瓣。 在球囊 100表面附着有 药物涂层 200， 药物涂层 200包括活性药物和药物复配剂， 活性药物和药物复配 剂形成的晶体附着在球囊 100表面； 所述活性药物为用于治疗动脉血管病变的亲 脂性活性药物； 所述药物复配剂为亲水性表面活性剂。
[0041] 所述的载药球囊中， 优选所述药物涂层 200中， 药物复配剂包裹或间隔活性药 物颗粒， 从而防止亲脂性活性药物分子相互聚集而导致的药物涂层结块， 同吋 药物复配剂降低了球囊表面材料的表面张力， 使得亲脂性活性药物与球囊表面 均匀地粘附； 降低活性药物团聚， 减少了血管栓塞的风险。
[0042] 载药球囊用于将活性药物输送到血管或管腔的靶位点， 治疗血管或管腔内的狭 窄、 防止内膜或上皮增生； 血管指冠状动脉血管、 外周动脉血管或脑动脉血管 ； 管腔指食道、 气道、 肠道、 胆道、 泌尿道、 前列腺或脑通道。
[0043] 以下采用具体实施例， 详述本发明的技术方案：
[0044] 实施例 1、 一种用于动脉血管病变扩张载药球囊的复配药物， 包括原料：
[0045] 亲脂性活性药物 紫杉醇 30mg
[0046] 药物复配剂 PEG100 20mg
[0047] 溶剂 丙酮 4.25ml、 水 2ml。
[0048] 将 30mg紫杉醇、 20mgPEG100， 溶解于 4.25ml丙酮和 2ml水的混合溶剂中制备 成混合溶液； 将外周球囊导管 （直径 6.0mm， 长 60mm) 球囊部分浸泡至混合溶 液中， 取出， 干燥。 经 10次反复浸泡， 干燥后得载药球囊， 于 HPLC检测得到药 物涂层中的药物密度为 3.86 g/mm
[0049] 球囊导管的材料为尼龙、 尼龙弹性体、 PU、 Pebax. PET或聚乙烯中的一种或 几种。
[0050] 实施例 2、 一种用于动脉血管病变扩张载药球囊的复配药物， 包括原料：
[0051] 亲脂性活性药物 紫杉醇 50mg
[0052] 药物复配剂 N-甲基 -D-葡萄糖乙胺 10.42mg
[0053] 溶剂 丙酮 6ml、 水 lml。
[0054] 将 50mg紫杉醇、 10.42mg N-甲基 -D-葡萄糖乙胺， 溶解于 6ml丙酮和 lml水的混 合溶剂中制备成混合溶液； 将外周球囊导管 （直径 6.0mm， 长 60mm) 球囊部分 浸泡至混合溶液中， 取出， 干燥。 经 10次反复浸泡， 干燥后得载药球囊， 于 HPL C检测得到药物涂层中的药物密度为 3.17 g/mm 2。
[0055] 实施例 3、 一种用于动脉血管病变扩张载药球囊的复配药物， 包括原料：
[0056] 亲脂性活性药物 雷帕霉素 60mg
[0057] 药物复配剂 N-甲基 -D-葡萄糖乙胺 20mg
[0058] 溶剂 甲醇 6.7ml。
[0059] 将 60mg雷帕霉素、 20mg N-甲基 -D-葡萄糖乙胺， 溶解于 6.7ml甲醇溶液中； 将 外周球囊导管 （直径 6.0mm， 长 60mm) 球囊部分浸泡至混合溶液中， 取出， 干 燥。 经 12次反复浸泡， 干燥后得载药球囊， 于 HPLC检测得到药物涂层中的药物 密度为 4.78 g/mm 2。
[0060] 实施例 4、 一种用于动脉血管病变扩张载药球囊的复配药物， 包括原料：
[0061] 亲脂性活性药物 雷帕霉素 20mg
[0062] 药物复配剂 N-甲基 -D-葡萄糖甲胺 8.8mg、 山梨醇 8mg
[0063] 溶剂 乙醇 2.4ml和水 lml。
[0064] 将 20mg雷帕霉素、 8.7mg N-甲基 -D-葡萄糖甲胺和 8mg山梨醇， 溶解于 2.4ml乙 醇和 lml水的混合溶液中； 将混合溶液喷涂施加于外周球囊导管 （直径 6.0mm， 长 60mm) 球囊表面上， 干燥。 经多次反复的喷涂， 干燥后得载药球囊， 于 HPL C检测得到药物涂层中的药物密度为 2.95 g/mm 2。
[0065] 实施例 5、 一种用于动脉血管病变扩张载药球囊的复配药物， 包括原料：
[0066] 亲脂性活性药物 紫杉醇 25mg
[0067] 药物复配剂 乙酰胺 16.7mg
[0068] 溶剂 乙酸乙酯 2.8ml。
[0069] 将 25mg紫杉醇、 16.7mg乙酰胺， 溶解于 2.8ml乙酸乙酯中； 将溶液滴涂于外周 球囊导管 （直径 6.0mm， 长 60mm) 球囊表面上， 干燥。 经多次反复滴涂后干燥 得载药球囊， 于 HPLC检测得到药物涂层中的药物密度为 1.78 g/mm
[0070] 实施例 6、 一种用于动脉血管病变扩张载药球囊的复配药物， 包括原料：
[0071] 亲脂性活性药物 紫杉酚 25mg
[0072] 药物复配剂 辛酰基 -N-甲基葡萄糖胺 20mg
[0073] 溶剂 DMF2.25ml。
[0074] 实施例 7、 一种用于动脉血管病变扩张载药球囊的复配药物， 包括原料：
[0075] 亲脂性活性药物 雷帕霉素 25mg
[0076] 药物复配剂 乙酰胺 16.7mg
[0077] 溶剂 DMSO 2.8ml。
[0078] 对比例 1
[0079] 将 24mg紫杉醇、 28mg碘普罗胺， 溶解于 7ml乙醇溶液中； 将溶液滴涂于外周球 囊导管 （直径 6.0mm， 长 60mm) 球囊表面上， 干燥。 经多次反复滴涂， 干燥施 后， 于 HPLC检测得到涂层药物密度为 3.64 g/mm 2。
[0080] 对比例 2
[0081] 将 50mg紫杉醇溶解于 4.25ml丙酮和 2ml水的混合溶液中； 将溶液滴涂于外周球 囊导管 （直径 6.0mm， 长 60mm) 球囊表面上， 干燥。 经多次反复滴涂， 干燥施 后， 于 HPLC检测得到涂层药物密度为 5.2 g/mm 2。
[0082] 形态观察
[0083] 如图 1所示， 是复配药物在球囊表面状态示意图， 活性药物为颗粒状， 药物复 配剂和溶剂为液体， 将活性药物包裹， 起到了亲脂性药物晶体颗粒的间隔作用 ， 增加药物颗粒比表面积。
[0084] 如图 2a-2c所示， 是本发明药物复配剂制成载药球囊， 在球囊表面形成药物涂层 分别在 500倍、 1000倍、 2000倍电镜下的形态图。 如图 3a-3c所示， 是现有治疗药 物紫杉醇制成载药球囊， 在球囊表面形成药物涂层分别在 500倍、 1000倍、 2000 倍电镜下的形态图。 从图中看， 本发明复配药物制成载药球囊后， 形成的药物 涂层的晶型成棒状或针状， 颗粒大小适中 （约 20μηι) ， 分布均匀， 最重要地颗 粒间结合较松散， 不团聚。 而现有技术中治疗药物单独使用紫杉醇， 在涂覆在 球囊后结晶的晶型混乱、 粒径差异大、 团聚明显。
[0085] 输送过程损失模拟测试
[0086] 用人工血管的靶血管在模拟使用系统进行输送过程要无量损失模拟测试， 测试 在球囊扩张膨胀之前， 即球囊导管插入并且移动到靶位点的过程中的药物量损 失。
[0087] 分别将实施例 1~5的复配药物和对比例 1~2制备的药物制成载药球囊， 将载药球 囊导管插入体外模拟血管模型中。 在模拟血管设备系统中输送以及在漂浮吋间 1
20秒， 不扩张， 然后取出球囊导管。 利用 HPLC分析球囊导管上残余的药物， 计 算输送过程药物量损失。 HPLC测试条件为： 日本岛津 LC-20A高效液相色谱仪， 色谱柱： Aglilent ZOBAX SB-C18
4.6x250mm, 5um， 流动相： 甲醇:乙腈:水 = 230:360:410， 柱温： 30°C， 紫外检 测器， 检测波长 227nm， 流速： 1.0 ml/min。 [0088] HPLC测定结果如表 1所示：
[0089] 表 1输送过程损失模拟测试结果
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Figure imgf000011_0001
[0090] 表 1结果表明： 与对比例 1相比， 本发明的球囊导管在移动到治疗性介入位点的 过程中的药物量损失要明显少得多。 且与只使用活性药物而无药物复配剂的对 比例 2相比效果更明显。 说明本发明的药物涂层与球囊导管之间的粘结力较大， 载药球囊在到达靶病变部位吋剩余在球囊表面上药量更多， 更有利于药物高效 释放。
[0091] 体内药物释放测试
[0092] 在兔子体内腹主动脉行载药球囊扩张术进行药物释放测试。
[0093] 新西兰白兔， 约 6个月大， 体重约 3kg。 分别将实施例 1~5的复配药物和对比例 1 ~2制备的药物制成载药球囊， 将载药球囊导管从股动脉穿刺口位置， 输送至腹 主动脉后对球囊充至约 6atm。 扩张吋间 60~120秒， 保持血液流冲刷 10分钟， 然 后将球囊导管卸压并回撤取出， 收集靶血管组织。 通过组织提取和 HPLC， 测试 靶血管组织中的药物含量以及球囊上保留的残余药量， 测试条件同上， 结果如 表 2所示。
[0094] 表 2体外模拟测试结果
[]
Figure imgf000012_0001
[0095] 由表 2可知： 与对比例 1相比， 本发明的载药球囊导管兔子体内腹主动脉血管扩 张后， 药物快速转移至血管壁的量明显要多。 且与只使用活性药物而无任何药 物复配剂的对比例 2相比差异更明显。 说明本发明具有快速药物的释放特性， 以 及高效药物转移能力。
[0096] 微粒试验
[0097] 在体外模拟血管模型系统， 对载药球囊微粒脱落水平进行测试。
[0098] 分别将实施例 1~5的复配药物和对比例 1~2制备的药物制成载药球囊， 将载药球 囊导管插入体外模拟血管模型中。 在模拟血管设备系统中输送至靶向血管部位
， 保持输送吋间 120秒， 然后对球囊导管充压至 6atm， 扩张吋间 60~120秒， 卸压 ， 然后取出球囊导管。 靶血管末端收集载药球囊冲刷下来的颗粒。 然后于微粒 检测仪上检测所脱落颗粒的尺寸大小， 粒径分布以及数量。 结果如表 3所示。
[0099] 表 3.微粒脱落统计
Figure imgf000013_0001
[0100] 由表 3可知： 与对比例 1相比， 本发明药物制成的载药球囊导管在体外模拟系统 扩张后， 微粒脱落在各粒径数量分布上明显要少。 且与只使用活性药物而无任 何药物复配剂的对比例 2相比效果更明显。 说明本发明在球囊上的药物具有更少 的微粒脱落， 脱落的微粒粒径更小。 进一步说明本发明药物临床使用中具有更 安全的性能。
[0101] 动物实验
[0102] 在猪体内髂 /动脉过度扩张载药球囊， 28天后评估球扩段血管， 下游血管闭塞
， 以及下游组织缺血坏死等现象。
[0103] 实验对象： 健康猪， 约 3个月大， 30~35kg重。
[0104] 实验步骤： 以实施例 4和对比例 1为例， 分别将实施例 4的复配药物和对比例 1制 备的药物制成载药球囊， 将载药球囊导管从颈动脉穿刺口位置， 在 DSA造影设 备的帮助下， 将载药球囊导管输送至左右髂 /股动脉后对球囊充压至约 6atm， 扩 张 3分钟后。 撤出载药球囊导管， 缝合穿刺口。 28天后随访， 用 DSA造影， 观察 靶血管和下游血管闭塞情况。
[0105] 如图 4a-4d为本发明实施例 4的复配药物制成载药球囊的球囊扩张前造影图、 球 囊扩张吋造影图、 球囊扩张后即刻造影图、 28天随访造影图； 如图 5a-5d为对比 例 1的球囊扩张前造影图、 球囊扩张吋造影图、 球囊扩张后即刻造影图、 28天随 访造影图。
[0106] 实施例 4制备的载药球囊导管在猪体内股动脉完成扩张前后， 以及 28天随访 DS
A造影显示， 靶血管以及下游血管血流通畅， 未见狭窄、 夹层、 闭塞等并发症； 对比例 1制备的载药球囊导管在猪体内股动脉扩张前， 以及完成扩张后即刻动脉 造影显示一切正常， 血流通畅。 但在 28天后随访 DSA造影显示， 靶血管段已完 全闭塞， 血流已无法正常通过。 可见本发明制备的载药球囊导管可大大降低了 血管闭塞的发生率。
[0107] 从上述实验可以看出： 本发明复配药物可以通过球囊导管输送到血管或管腔的 靶位点， 药物涂层覆盖在球囊导管的外表面上， 药物涂层中含有活性药物和药 物复配剂， 药物复配剂加快了活性药物从球囊上的释放速度， 药物在非常短的 吋期内释放并快速渗透进入患病部位处的组织， 从而提高药物在血管系统或其 他身体管腔的患病组织中的吸收率， 可以解决在临床使用输送过程中的药物量 损失和球囊扩张之后药物向靶病变部位的快速转载。
[0108] 另外可以看出： 本发明复配药物可非常有效地解决亲脂药物晶形、 尺寸大小以 及药物晶体团聚导致的结块问题。 在获得良好的抑制病变血管再狭窄的效果同 吋， 大大减少了血管栓塞发生的几率。

Claims
权利要求书
一种用于动脉血管病变扩张载药球囊的复配药物， 其特征在于， 包括 原料： 用于治疗动脉血管病变的亲脂性活性药物、 药物复配剂、 溶剂 ， 其中活性药物与药物复配剂质量比为 1.2-
4.8; 活性药物和药物复配 剂的总质量与溶剂的质量体积比为 8-20 (g/1) ； 所述药物复配剂为亲 水性表面活性剂； 所述溶剂为与水互溶的非极性溶剂、 或者是非极性 溶剂与水的混合溶液。
根据权利要求 1所述的用于动脉血管病变扩张载药球囊的复配药物， 其特征在于， 所述活性药物与药物复配剂质量比为 1.5-4.8。
根据权利要求 1所述的用于动脉血管病变扩张载药球囊的复配药物， 其特征在于， 所述活性药物和药物复配剂的总质量与溶剂的质量体积 比为 10-15 (g/1) 。
根据权利要求 1-3任意一项所述的用于动脉血管病变扩张载药球囊的 复配药物， 其特征在于， 所述活性药物为紫杉醇、 雷帕霉素或紫杉酚
[权利要求 5] 根据权利要求 1-3任意一项所述的用于动脉血管病变扩张载药球囊的 复配药物， 其特征在于， 所述药物复配剂为葡萄胺类物质、 乙酰胺、 山梨醇、 PEG100等中的一种或几种。
[权利要求 6] 根据权利要求 5所述的用于动脉血管病变扩张载药球囊的复配药物， 其特征在于， 所述葡萄胺类物质为 N-甲基 -D-葡萄糖甲胺、 N-甲基 -D- 葡萄糖乙胺或辛酰基 -N-甲基葡萄糖胺。
[权利要求 7] 根据权利要求 1-3任意一项所述的用于动脉血管病变扩张载药球囊的 复配药物， 其特征在于， 所述溶剂为甲醇、 乙醇、 丙酮、 乙酸乙酯、 DMSO、 DMF中的至少一种； 或者所述溶剂为甲醇、 乙醇、 丙酮、 乙 酸乙酯、 DMSO、 DMF中的至少一种与水混合后的混合溶液。
[权利要求 8] 根据权利要求 7所述的用于动脉血管病变扩张载药球囊的复配药物， 其特征在于， 所述溶剂为甲醇、 乙醇、 DMSO中的至少一种， 或者所 述溶剂为甲醇、 乙醇、 DMSO中的至少一种与水混合后的混合溶液。
[权利要求 9] 一种载药球囊， 其特征在于， 包括折瓣结构的球囊， 在球囊表面附着 有药物涂层， 药物涂层包括活性药物和药物复配剂； 所述活性药物为 用于治疗动脉血管病变的亲脂性活性药物； 所述药物复配剂为亲水性 表面活性剂。
[权利要求 10] 根据权利要求 9所述的载药球囊， 其特征在于， 所述药物涂层中， 药 物复配剂包裹或间隔活性药物颗粒。
PCT/CN2017/089228 2016-07-27 2017-06-20 用于动脉血管病变扩张载药球囊的复配药物及载药球囊 WO2018019055A1 (zh)

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