WO2021213522A1 - 一种具有示踪功能的药物制剂及其输送系统 - Google Patents

一种具有示踪功能的药物制剂及其输送系统 Download PDF

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WO2021213522A1
WO2021213522A1 PCT/CN2021/089529 CN2021089529W WO2021213522A1 WO 2021213522 A1 WO2021213522 A1 WO 2021213522A1 CN 2021089529 W CN2021089529 W CN 2021089529W WO 2021213522 A1 WO2021213522 A1 WO 2021213522A1
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drug
liquid
catheter
agent
medicine
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PCT/CN2021/089529
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English (en)
French (fr)
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董永华
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苏州医本生命科技有限公司
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Publication of WO2021213522A1 publication Critical patent/WO2021213522A1/zh
Priority to US18/049,264 priority Critical patent/US20230089830A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/48—Diagnostic techniques
    • A61B6/481—Diagnostic techniques involving the use of contrast agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/02—Detecting, measuring or recording pulse, heart rate, blood pressure or blood flow; Combined pulse/heart-rate/blood pressure determination; Evaluating a cardiovascular condition not otherwise provided for, e.g. using combinations of techniques provided for in this group with electrocardiography or electroauscultation; Heart catheters for measuring blood pressure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/02—Detecting, measuring or recording pulse, heart rate, blood pressure or blood flow; Combined pulse/heart-rate/blood pressure determination; Evaluating a cardiovascular condition not otherwise provided for, e.g. using combinations of techniques provided for in this group with electrocardiography or electroauscultation; Heart catheters for measuring blood pressure
    • A61B5/02028—Determining haemodynamic parameters not otherwise provided for, e.g. cardiac contractility or left ventricular ejection fraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/48—Diagnostic techniques
    • A61B8/481—Diagnostic techniques involving the use of contrast agent, e.g. microbubbles introduced into the bloodstream
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
    • A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
    • A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
    • A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
    • A61K49/226—Solutes, emulsions, suspensions, dispersions, semi-solid forms, e.g. hydrogels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/007—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests for contrast media
    • 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
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/1407—Infusion of two or more substances
    • A61M5/1409—Infusion of two or more substances in series, e.g. first substance passing through container holding second substance, e.g. reconstitution systems
    • 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
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/142—Pressure infusion, e.g. using pumps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/02—Arrangements for diagnosis sequentially in different planes; Stereoscopic radiation diagnosis
    • A61B6/03—Computed tomography [CT]
    • A61B6/032—Transmission computed tomography [CT]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/50—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment specially adapted for specific body parts; specially adapted for specific clinical applications
    • A61B6/504—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment specially adapted for specific body parts; specially adapted for specific clinical applications for diagnosis of blood vessels, e.g. by angiography
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/06—Measuring blood flow
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/08—Detecting organic movements or changes, e.g. tumours, cysts, swellings
    • A61B8/0891—Detecting organic movements or changes, e.g. tumours, cysts, swellings for diagnosis of blood vessels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/48—Diagnostic techniques
    • A61B8/488—Diagnostic techniques involving Doppler signals

Definitions

  • the invention relates to a pharmaceutical preparation with a tracing function, and also relates to a delivery system of the pharmaceutical preparation, and belongs to the technical field of medical devices.
  • gaseous contrast agents such as carbon dioxide need to be injected with a relatively large amount of gas to empty the blood in the blood vessel to produce low-density contrast, thereby displaying the image of the blood vessel.
  • carbon dioxide can be quickly absorbed by human blood, it can still cause tissue hypoxia and ischemia to a certain extent. Therefore, clinically, carbon dioxide angiography can only be performed in the arteries below the diaphragm, and carbon dioxide angiography cannot be performed in the heart and brain, or organs that are sensitive to ischemia or hypoxia.
  • the primary technical problem to be solved by the present invention is to propose a pharmaceutical preparation with a tracer function.
  • Another technical problem to be solved by the present invention is to provide a delivery system for the above-mentioned pharmaceutical preparations.
  • a pharmaceutical preparation with a tracer function comprising a catheter and a tube head containing a tracer drug, wherein:
  • the catheter is provided with a liquid or gaseous first medicine and a second medicine, and the first medicine and the second medicine are each divided into multiple sections and arranged in series in the catheter at intervals; the first medicine and the One of the second drugs is a tracer drug that can be developed in medical imaging equipment in the human body; the first drug and the second drug are immiscible, poorly soluble, or slightly soluble, and meet the acceptable standards in the art Treatment compatibility requirements.
  • the first drug is a contrast agent
  • the second drug is a gaseous isolating agent
  • the first medicine or the second medicine in liquid form is located at both ends of the catheter.
  • the catheter is further provided with a gaseous or liquid multi-section third medicine, and the third medicine is arranged between the first medicine and the second medicine,
  • the third drug is not miscible with the first drug and the second drug, and the third drug meets the compatibility requirements acceptable in the art; the third drug meets the compatibility requirements with the second drug.
  • the first drug is a tracer drug, which is a liquid contrast agent, and is located at both ends of the catheter;
  • the second drug is a gaseous release agent, and both sides of each segment of the second drug are the first drug;
  • the third drug is an embolic agent or a perfusion agent, and each section of the third drug is on both sides of the second drug;
  • the arrangement of the first medicine, the third medicine, the second medicine, and the third medicine is repeated as a unit from the end of the catheter until the other end of the catheter is the first medicine.
  • the first drug is an anhydrous iodine contrast agent
  • the second drug is carbon dioxide
  • the third drug is alcohol
  • an aerobic contrast agent including a catheter and a tube head.
  • the catheter is provided with oxygen and a liquid contrast agent, and the oxygen and the contrast agent are each divided into multiple segments. Are arranged in series at intervals in the catheter,
  • the oxygen and liquid contrast agent are immiscible, poorly soluble or slightly soluble, and meet the requirements of acceptable therapeutic compatibility in the art.
  • an aerobic embolic agent including a catheter and a tube head, the catheter is provided with oxygen, a liquid contrast agent, and a liquid embolic agent, the oxygen, the contrast agent, and The embolic agent is divided into multiple segments, and the contrast agent and the embolic agent are arranged in series in the catheter at intervals through the oxygen,
  • the oxygen, liquid contrast agent and liquid embolic agent are immiscible, poorly soluble or slightly soluble, and meet the requirements of acceptable therapeutic compatibility in the art.
  • an aerobic perfusion agent including a catheter and a tube head.
  • the catheter is provided with oxygen, a liquid contrast agent, and a liquid perfusion agent.
  • the oxygen, the contrast agent, and the The perfusion agent is divided into multiple segments, and the contrast agent and the embolic agent are arranged in series in the catheter at intervals through the oxygen,
  • the oxygen, liquid contrast agent and liquid perfusion agent are not mutually soluble, insoluble or slightly soluble, and meet the requirements of acceptable therapeutic compatibility in the art.
  • a delivery system of a pharmaceutical preparation with a tracer function which includes a syringe pump, a catheter, a sheath socket and a puncture needle connected in sequence, wherein the catheter is the aforementioned catheter.
  • the pharmaceutical preparations with tracing function provided by the embodiments of the present invention include aerobic contrast agents, aerobic embolic agents and aerobic perfusion agents. Through a one-time simple operation, they can be applied to a variety of contrast techniques without reducing the concentration of embolic agents. Under the circumstances, a clear contrast can be realized, saving the dosage of the medicine while maintaining a high concentration of the medicine. Moreover, injecting oxygen together with drugs during interventional surgery can increase cell activity, thereby improving drug efficacy, and achieve inhibitory effects on tumor cells; it can also improve the flexibility of drug compatibility and achieve accurate hemodynamic analysis.
  • Figure 1 is a schematic diagram of a gas-liquid preparation delivery system provided by an embodiment of the present invention
  • FIG. 2 is a schematic diagram of the structure of the gas-liquid preparation in the first embodiment of the present invention.
  • FIG. 3 is a schematic diagram of the structure of the gas-liquid preparation in the second embodiment of the present invention.
  • 4A is a diagram showing the effect of gas-liquid preparation under X-ray display in the first embodiment of the present invention.
  • Fig. 4B is a display effect diagram of the gas-liquid preparation of Fig. 4A under X-rays
  • Fig. 4C is a display effect diagram of the gas-liquid preparation of Fig. 4A under X-rays
  • FIG. 5 is a schematic diagram of the structure of the gas-liquid preparation in the fifth embodiment of the present invention.
  • Fig. 6A is a diagram showing the fitting of the head end joint of the gas-liquid preparation pipe and the tail end joint of the pipe in the fifth embodiment of the present invention.
  • 6B is a schematic diagram of the state of the catheter in the fifth embodiment of the present invention.
  • Figure 7A is an X-ray photograph of a PE tube when the tube voltage is 49.90kV;
  • Figure 7B is an X-ray photograph of the PE tube when the tube voltage is 80.90kV;
  • Figure 7C is an X-ray photograph of the PE tube when the tube voltage is 89.80kV;
  • Figure 8A is a continuous exposure acquisition diagram when an iodine-sodium chloride mixed solution is injected into the No. 10-1 PE tube;
  • Figure 8B is a continuous exposure and acquisition diagram of the No. 10-2 PE tube with the simulated catheter advancing under the condition of adding the abdominal phantom;
  • FIG. 9A is a diagram of the left renal artery embolization of experimental rabbit 1, and the removal of bilateral kidneys for general observation;
  • Figure 9B is an observation diagram of the general condition of the embolized kidney (ie, left kidney) specimen after soaking in formalin solution for 12 hours;
  • Figure 9C is an observation view of the coronal section of the left kidney
  • Fig. 10A is a diagram showing the general observation of both kidneys after embolization of both kidneys of experimental rabbit 2;
  • Figure 10B is an observation view of a gross specimen of the left kidney after being soaked in formalin for 12 hours;
  • Figure 10C is an observation view of the coronal section of the left kidney
  • Figure 10D is an observation view of a gross specimen of the right kidney after being soaked in formalin for 12 hours;
  • Figure 11A shows that edema and degeneration can be observed in left renal tubular epithelial cells
  • Figure 11B shows the fragmentation of elastic fibers in a few arterial walls in the left kidney
  • Figure 12A is a diagram showing the cortical infarct area in the right kidney
  • Figure 12B is a diagram of edema and degeneration of the left renal tubular epithelial cells
  • Figure 13A is a sample picture of a gas-liquid tandem embolic agent provided by an embodiment of the present invention, which includes about 6 microliters of carbon dioxide and about 15 microliters of 75% alcohol;
  • 13B is a sample picture of a gas-liquid tandem embolic agent provided by an embodiment of the present invention, which includes about 60 microliters of carbon dioxide and about 15 microliters of 75% alcohol;
  • 14A is a sample picture of a gas-liquid tandem embolic agent provided by an embodiment of the present invention, which includes about 10 microliters of carbon dioxide and about 15 microliters of lipiodol;
  • 14B is a sample picture of a gas-liquid tandem embolic agent provided by an embodiment of the present invention, which includes about 70 microliters of carbon dioxide and about 15 microliters of lipiodol;
  • Figures 15A to 15G are respectively various contrast images obtained in the animal experiment of the present invention.
  • gas-liquid preparations described in the embodiments of the present invention include preparations formed alternately by gas and liquid, as well as preparations formed alternately by a first liquid and a second liquid (the two are not compatible).
  • gas-liquid preparation only includes preparations formed by alternating gas and liquid; otherwise, “gas-liquid preparation” includes the foregoing two situations.
  • the drug preparation delivery system includes a syringe pump 100, a catheter 200, a sheath base 400 and a vascular sheath 500.
  • the syringe pump 100 is connected to the tail end (the end close to the syringe pump) of the catheter 200, and the other end (the distal end, the end close to the patient) of the catheter 200 is connected to the vascular sheath 500 through the sheath socket 400.
  • One end of the vascular sheath 500 is inserted into an arterial blood vessel (not shown) or human tissue (for example, tumor tissue).
  • Syringe pump 100 can be selected according to the needs of interventional surgery. Conventional models can be selected, such as the Perfusor Space micro-injection pump from Germany, or the dual-channel micro-injection pump (WZS-50F6) produced by Zhejiang Smith Medical Instrument Co., Ltd., which can achieve a variety of Multi-rate bolus injection. A person of ordinary skill in the art can understand that instead of using the syringe pump 100, it is also possible to push the injection by hand.
  • the catheter 200 and the sheath base 400 are connected by a Luer connector.
  • the Luer connector complies with the Chinese standard GB/T 1962.2-2001 or the international standard ISO 594-2-1998. Syringe, needle and other medical devices are 6% (Luer) conical connectors. Part 2: The provisions of the locking connector. Quick connection of available medical equipment.
  • the sheath base 400 meets the requirements of industry standards YY0450.1-2003 and YY0258.2-2004, and is connected to the side branch 300.
  • the catheter 200 includes a tube body 1 and a tube head 2 (ie, a Luer connector).
  • the tube body 1 is a slender tubular structure, and the two ends are closed by the tube head 2.
  • the tube body 1 is made of materials such as plastic, resin or glass, preferably high-performance polyolefin thermoplastic elastomer (TPE), such as the new MT-12051 TPE material produced by Polymax TPE.
  • TPE high-performance polyolefin thermoplastic elastomer
  • the normal average lumen diameter of arterial vessels is: elastic arteries about 15 mm; muscular arteries about 6 mm, arterioles about 37 microns, and capillaries about 9 microns.
  • the outer diameter and inner diameter of the gas-liquid preparation catheter provided by the embodiments of the present invention have various specifications, and the inner diameter range includes but is not limited to 0.2-15mm, preferably 0.5-8mm. The selection of a suitable specification can realize that the outer diameter of the catheter can be less than or Equal to the inner diameter of arteries. When the outer diameter of the catheter becomes smaller, the inner diameter becomes smaller correspondingly, and the flow resistance of the gas or liquid in the tube body 1 becomes larger.
  • the small inner diameter makes it difficult for the gas or liquid to flow when no pressure is applied to the gas or liquid in the tube body 1, so even if there is external vibration, the gas or liquid will not move relative to each other (will not mix with each other).
  • Suspension especially suitable for liquid-liquid preparations such as first liquid-second liquid-first liquid-second liquid, which use liquid as a release agent.
  • Larger inner diameters, such as 2mm and above, are suitable for gas as a liquid separator.
  • the pharmaceutical preparations provided by the embodiments of the present invention can also be used for the treatment of hemangiomas, liver cancer, brain tumors, etc., and therefore are not limited to arteries.
  • the pipe head 2 includes a male head 2A and a female head 2B, which are respectively located at two ends of the pipe body 1 and are used for sealing/sealing the liquid or gas in the pipe body 1.
  • Tube head 2 is a standard Luer connector. Because one end of the pipe body is a male head 2A, and the other end is a female head 2B, the two pipe bodies 1 can be connected to the male head of one of the pipes 1 with the female head of the other to realize the connection of multiple pipes 1 Connect, so as to achieve an increase in the amount of medicine (that is, the medicine in the multiple tubes 1 can be continuously supplied).
  • the tube body 1 can be easily connected to various conventional syringes or other medical devices through the Luer connector, so that the Gaseous or liquid medicines can be injected into humans or animals through conventional syringes and the like.
  • the male and female Luer connectors at both ends of the catheter 200 can be connected to realize the function of increasing the sealing of the catheter during storage and transportation, and also reduce the packaging volume of the catheter.
  • the medicine in the tube body 1 exists in the form of gas or liquid (including suspension).
  • the medicines in the tube 1 may include different kinds of medicines, for example, embolic agents, perfusion agents, chemical ablative agents, anesthetics, and the like.
  • the medicine in the tube 1 has a variety of combinations, such as liquid (contrast agent)-gas spacer (oxygen)-liquid (contrast agent)-gas spacer (oxygen) staggered or spaced form (see Figure 2) ; It can also be a staggered or spaced form of the first liquid (contrast agent)-the second liquid (embolization agent)-the first liquid (contrast agent)-the second liquid (embolization agent); it can also be the first liquid (contrast Agent)-gas spacer (oxygen)-second liquid (embolizer)-gas spacer (oxygen)-first liquid (contrast agent)-gas spacer (oxygen)-second liquid (embolizer) staggered or Interval form (see Figure 3). In other words, it can be in the form of liquid-gas interleaving, or in the form of liquid-liquid interleaving.
  • the liquid for example, contrast agent
  • the liquid is arranged on the two ends (head and tail) of the tube body 1, so that on the one hand, it is convenient to see the liquid (contrast agent) at both ends during the contrast imaging, thereby positioning the entire tube
  • the first embodiment of the present invention is an aerobic contrast agent.
  • the total capacity of the tube body 1 is 10 mL, and the length is 1 meter.
  • the capacity of the tube body 1 is determined by the amount of drugs used in the interventional operation and the speed of medication, and can be set to 400mm, 600mm, 800mm in length and corresponding inner diameters of different specifications. If the volume required for interventional surgery exceeds the total volume of one tube (for example, 10 mL), multiple gas-liquid preparations can be connected (connect the male and female luer connectors of two adjacent gas-liquid preparations) Just connect).
  • the tube body 1 contains two kinds of medicines: a contrast agent (the first medicine 11) and a spacer (the second medicine 12), which are used for angiography of interventional therapy.
  • the first medicine 11 is a liquid contrast agent ioverol
  • the second medicine 12 is a gaseous spacer oxygen.
  • Oxygen 12 separates each section of contrast medium 11 (ie, a staggered form of liquid-gas-liquid-gas), and the total amount of gas in the catheter 1 cannot be greater than 0.8mL to avoid human discomfort.
  • the amount of gas in each section cannot More than 0.1mL to avoid embolism.
  • the compatibility of drugs in the catheter needs to consider the reasonable design of physics, chemistry, and curative effect, and meet the regulations of pharmacy, especially the contraindications of physics and chemistry.
  • a first liquid and a second liquid in the catheter the two liquids may precipitate out due to the change in solubility. Therefore, such a liquid uses a release agent (such as a gas) to avoid turbidity or precipitation caused by the mixing of the two.
  • carbon dioxide is used as a spacer, it will change the pH value of the adjacent liquid, which may cause some strongly alkaline drug liquids to precipitate and precipitate due to the change in pH value, so this drug liquid needs to be used
  • Oxygen is used as a release agent, or a contrast agent is used as a release agent.
  • the first drug and the second drug are divided into multiple segments, each segment of the first drug is the same length, L1; each segment of the second drug is the same length, L2.
  • L1 the same length
  • L2 the same length
  • the segment length L1 of the first drug (contrast agent) the segment length L2 of the second drug (isolating agent).
  • L1 L2 (that is, the lengths of the first medicine and the second medicine are equal)
  • L is the length of the catheter 1
  • the number of segments of the first drug (contrast agent) is 2N*L/(2N+1)
  • the number of segments of the second drug is N*L/(2N+1).
  • each segment length L1 or L2 needs to consider 1) the dosage control of each segment of the drug; 2) the control of the total amount of each drug in the entire tube body 1.
  • the dosage of the drug in each segment is controlled by the fluidity of the drug in the tube 1. If the fluidity is low, the amount of medicine in each section is small, that is, the length of each section is short; if the flow is high, the amount of medicine in each section is large.
  • the total control of each drug in the tube 1 is affected by the safe dosage for human use, which is well known to doctors.
  • the segment length L2 of each segment of the second drug, the release agent, and the oxygen is smaller than the segment length L1 of each segment of the first drug contrast agent.
  • the length of the oxygen segment is too long, it will cause the flow of the contrast agent (there is a situation where it cannot be pushed); on the other hand, the air bubbles formed after the oxygen enters the blood cannot be too large, otherwise human discomfort may occur. That is, the first drug (contrast agent) and the second drug (isolating agent) are immiscible, poorly soluble or slightly soluble, and meet the requirements of acceptable therapeutic compatibility in the art.
  • the tube body 1 When performing angiography, the tube body 1 is pressurized by the syringe pump 100 (which can also be injected manually instead of the syringe pump), so that the first drug (contrast agent) 11 at the head end of the tube body 1 first enters the blood vessel; located in the tube body 1.
  • the first drug (contrast agent) 11 at the tail end enters the blood vessel last. Since the first drug at the head end and the first drug at the tail end are both contrast agents, they can be imaged under X-rays, so that the position of the head liquid 120 and the position of the tail liquid 121 can be seen on the image picture.
  • the first medicine 11A is a liquid contrast agent (ioverol) and is located at both ends of the catheter 200;
  • the second medicine 12A is a gaseous isolating agent (carbon dioxide ), and each segment of the first drug is located on both sides of a segment of the second drug.
  • the third medicine 13 is an embolic agent or a perfusion agent (75% alcohol in this embodiment), and each section of the third medicine 13 is located between two sections of the second medicine 12A.
  • the drugs are arranged in series from the catheter head in the order of liquid contrast agent (ioverol)-gaseous spacer (carbon dioxide)-embolic agent or perfusion agent (alcohol)-gaseous spacer (carbon dioxide), in the above arrangement It is a unit that is repeatedly arranged in the catheter, and liquid contrast agent is added to the tail of the catheter as the final medicine.
  • the first drug (contrast agent), the second drug (isolating agent) and the third drug (embolizer or perfusion agent) are immiscible, poorly soluble or slightly soluble, and meet the requirements of acceptable therapeutic compatibility in the art.
  • L1, L2, and L3 can also be changed according to the dose of the drug, and they are not necessarily equal. It is assumed that the three are equal, which is only a simplified description for the convenience of understanding, but does not constitute any limitation to the present invention.
  • the gas-liquid preparation of the second embodiment of the present invention can reduce the amount of contrast agent and embolic agent, because the embolic agent does not need to fill the entire target vessel (assuming the amount required for filling is the V target vessel ), Only the amount of N*V target vessel /(4N+1) is needed to fill the target vessel together with the contrast agent and the spacer.
  • the second embodiment of the present invention can trace the position of the embolic agent under X-rays, which is mainly realized by liquid contrast agent and carbon dioxide contrast agent. Because carbon dioxide blocks the mixing of the liquid contrast agent and the embolic agent, the relative concentration of the embolic agent is not affected by the contrast agent (the embolic agent is not in contact with the blood and will not be diluted by the blood), and the best embolic performance of the embolic agent is realized. At the same time, the pharmaceutical preparation of the present embodiment also prolongs the contact time of the embolic agent and the target blood vessel.
  • the embolic agent (the third medicine 13) is located between the two second medicines (gas spacers), and the gas gap makes the flow rate of the embolic agent become even higher compared to the injection of the embolic agent (without gas) in conventional interventional therapy. Slow, so the contact time of the embolic agent and the cells in the blood vessel is quite long. Moreover, the osmotic pressure of the internal tissues of the tumor is high, and the embolic agent does not have blood dilution but maintains a high concentration (the osmotic pressure is higher than that of conventional preparations), so it is easy to penetrate into the tumor microvessels and spread, causing the tumor cells to degenerate and die.
  • the second embodiment of the present invention can also be suitable for photoacoustic radiography (B-ultrasound) and X-ray radiography (CT), and can also conveniently perform hemodynamic monitoring.
  • B-ultrasound photoacoustic radiography
  • CT X-ray radiography
  • carbon dioxide is a gas that is not physiologically hazardous, and its solubility in the blood is 2.3 times that of oxygen, it is not easy to form air clots.
  • Carbon dioxide is also a gaseous negative contrast agent, which can be used for angiography. After carbon dioxide enters the blood, it is soluble in the blood and is excreted from the lungs when it reaches the pulmonary circulation. Therefore, this is a contrast agent that does not increase the burden of circulation and does not cause allergic reactions.
  • carbon dioxide is not easy to store, clinical preparation of a carbon dioxide machine is required for angiography.
  • This embodiment is an aerobic embolic agent, including the first medicine 11 is a liquid contrast agent (ioverol), and is located at both ends of the catheter; the second medicine 12 is a gaseous isolating agent (oxygen), and the first Each segment of the drug is located on both sides of the segment of the second drug; the third drug is an embolic agent, such as 75% alcohol or iodized oil, arterial chemoembolization agent, radiotherapy embolization agent, microsphere suspension, etc. Since the structure of the pharmaceutical preparation is similar to that of the second embodiment, it will not be repeated here.
  • the aerobic embolic agent in this embodiment includes a catheter and a tube head. The catheter is provided with oxygen, a liquid contrast agent, and a liquid embolic agent.
  • the oxygen, the contrast agent, and the embolic agent are each divided into multiple segments. And the contrast agent and the embolic agent are arranged in series in the catheter at intervals through the oxygen.
  • the oxygen, the contrast agent and the embolic agent are immiscible, poorly soluble or slightly soluble, and meet the requirements of acceptable therapeutic compatibility in the art.
  • This embodiment is an aerobic perfusion agent, including the first medicine 11 is a liquid contrast agent (ioverol), and is located at both ends of the catheter; the second medicine 12 is a gaseous isolating agent (oxygen), and the first Each segment of the drug is located on both sides of the segment of the second drug; the third drug is an infusion agent, such as infusion drugs used in TAI, TAE, TACE, chemotherapeutic drugs for arterial infusion, etc., radioactive particle suspension, microsphere mixture Suspension etc.
  • the aerobic perfusion agent of this embodiment includes a catheter and a tube head.
  • the catheter is provided with oxygen, a liquid contrast agent, and a liquid perfusion agent.
  • the oxygen, the contrast agent, and the perfusion agent are each divided into multiple segments, And the contrast agent and the embolic agent are arranged in series in the catheter at intervals through the oxygen.
  • the oxygen, the contrast agent, and the perfusion agent are immiscible, poorly soluble or slightly soluble, and meet the requirements of acceptable therapeutic compatibility in the art.
  • the release agent used in the present invention can be not only oxygen or carbon dioxide, but also human-safe gases such as super oxygen (O 3 ).
  • the contrast agents used in the present invention include X-ray contrast agents, which can be ionic or non-ionic contrast agents; also include MRI contrast agents, which can be macromolecular paramagnetic imaging agents, nanostructured imaging agents; Including ultrasound imaging agents, such as liquid fluorocarbon nanoemulsion.
  • the first drug is an embolic agent (75% alcohol)
  • the second drug is a gaseous isolating agent (carbon dioxide).
  • the drugs at both ends of the catheter 200 are liquid embolic agents.
  • the catheter is repeatedly arranged in a loop with alcohol-embolizer as a unit from the head, and alcohol is added to the tail of the catheter 200.
  • the ratio of the length of the first drug (75% alcohol) grain to the length of the second drug (carbon dioxide) is 1.
  • the length of the alcohol grain can be appropriately extended, for example The length ratio of alcohol and carbon dioxide can be 2:1.
  • the catheter has a total length of 100 cm and an inner diameter of 2.0 mm.
  • the ratio of tube length to inner diameter is also particularly important. Because the gap between gaseous medicine and liquid medicine is built into the catheter, if the total length of the catheter is too short, the amount of medicine is limited. If the inner diameter is increased in order to increase the amount of medicine, especially the embolic agent is volatile In the case of liquid medicine, it will increase the loss of medicine during transportation and storage. If the length of the catheter is too long and the inner diameter is too small, the resistance to pushing the medicine will increase. If the inner diameter is too large, the volume of the catheter and the amount of medicine will increase, resulting in loss and waste of medicine. The optimal catheter length and inner diameter ratio can achieve more convenient and effective surgical medication under the condition of acceptable drug damage.
  • the catheter 200 is pre-installed with fillers and stored for later use. That is, in the pharmaceutical factory, the drug solution is injected into the catheter 200, the tube heads 2 are sealed, and then stored, transported, etc., when the operation is performed, the doctor opens one or two of the tube heads 2 and connects to the operation On the instrument, the filler in the catheter 200 is injected into the organism.
  • this mode is called: pre-installed mode.
  • the proximal end of the catheter 200 is directly connected to the bolus injection device, and the distal end is connected to the needle. That is, during the operation, while injecting into the catheter 200, it is connected to the needle through the distal end of the tube 2 to allow the liquid or gas in the catheter 200 to enter the living body.
  • this mode is called: pre-installed mode.
  • the first embodiment of the gas-liquid preparation provided by the embodiment of the present invention is suitable for both X-ray contrast and ultrasound contrast, and both can obtain clear contrast images.
  • the current ultrasound contrast agent is a thin and soft bubble with a high-density inert gas (not easily soluble in water or blood) with a thin and soft outer membrane.
  • the diameter is generally about 2-5um. It has a long stable time and good vibration and echo characteristics. For example, Optison and so on. This is because the bubble-containing liquid has strong scattering characteristics for ultrasonic waves.
  • bubble-containing liquid as an ultrasound contrast agent and injected into human blood vessels can enhance the ultrasound Doppler signal of blood flow and improve the clarity and clarity of ultrasound images. Resolution.
  • the first embodiment of the present invention combines a gas-liquid contrast agent and utilizes the immiscibility of the two to form a medicine arranged in series at intervals, and high-quality contrast images can be obtained under CT or ultrasound.
  • the embolic agent, the liquid tracer and the carbon dioxide are pre-filled into the catheter in the set sequence, and the luer connector is used to seal the catheter.
  • Contrast agents, embolic agents, and perfusion agents can be input at the same time in one operation (other drugs are also available, because it only needs to be compatible in the catheter and tolerated by the human body, and multiple drugs can be placed in the catheter at intervals); also solved The problem that carbon dioxide cannot be stored in the clinic and the carbon dioxide manufacturing equipment must be used during the operation, so that the operation does not need to be equipped with a carbon dioxide manufacturing machine.
  • the catheter containing the tracer drug can be used directly.
  • the Luer connector can realize the interconnection of multiple catheters, and the drug dose is not Restrictions, it is possible to input multiple types and large doses of drugs at one time.
  • the second drug 12 oxygen immediately enters the blood vessel. Because oxygen can be oxygenated with red blood cells, it can be partially absorbed, as long as the injection volume is not more than 0.02mL/kg (because it is generally believed that air greater than 0.02mL/kg enters the blood vessel and will make people feel uncomfortable, but more than 2mL/kg If the air enters the blood vessels, it will die suddenly).
  • the injection volume of the conventional dosage form of contrast agent is approximately 2mL/kg, and the injection volume per injection is approximately 8mL.
  • the first drug (contrast agent) only needs about 4 mL of contrast agent. This is because, in the prior art, 8 mL of contrast agent needs to be delivered to fill the target blood vessel, while the catheter filled with gas-liquid preparations of the first embodiment of the present invention only needs to deliver about 4 mL of contrast agent, plus 4 mL of oxygen. Can fill the target blood vessel. It can be seen that the use of the present invention can save the amount of medicine. It should be noted that the data in the present invention is only used as an example to facilitate understanding, and does not constitute any limitation to the present invention.
  • hypoxic environment of tumor cells When oxygen is used as the gas barrier in the present invention, it can change the hypoxic state of tumors and kill tumor cells. Winners of the 2019 Nobel Prize in Physiology or Medicine, three scientists discovered the mechanism of hypoxia-inducible factors (HIF) and biological oxygen sensing pathways. Studies have found that tumor cells induce hypoxia through various mechanisms, create a chronic hypoxic environment, activate the hypoxia-inducible factor HIF signaling pathway, accelerate tumor growth, increase tumor invasiveness, and promote tumor metastasis.
  • HIF hypoxia-inducible factors
  • oxygen can be delivered into tumor tissues, which can destroy the hypoxic environment of tumor cells, and act synergistically with radiotherapy and chemotherapeutic drugs, thereby improving the curative effect of cancer treatment.
  • the second embodiment of the present invention is a cyclic combination of liquid contrast agent-gaseous release agent-embolic agent-gaseous release agent, and the gaseous release agent uses carbon dioxide that has both isolation and tracing effects.
  • Oxygen is given at the same time for radiography or treatment to improve the comfort of radiography or treatment.
  • the use of the contrast agent in the present invention can deliver oxygen to human tissues at the same time as the contrast, thereby improving the comfort of the patient.
  • the drugs in the same catheter provided by the embodiments of the present invention can be separated by a suitable spacer, so as to ensure that the drugs adjacent to both sides of the spacer can be injected into the body at the same time (need to meet the compatibility requirements in terms of curative effect).
  • the present invention reduces the physical or chemical compatibility requirements of the medicament on the premise of meeting the requirements of the therapeutic compatibility.
  • the gas-liquid preparation provided by the embodiments of the present invention contains oxygen, and oxygen bubbles can be used to measure hemodynamic indicators; it is also possible to monitor the movement trajectory of the contrast agent section by section to measure hemodynamic indicators. This is because the flow speed, direction, quantity, etc. of the chain bubble or liquid section can be directly monitored.
  • the propulsion pressure can be detected. The advancing pressure is related to factors such as blood viscosity, vascular embolization status, contrast agent/embolization agent concentration and other factors. Combined with the data of the contrast image, more accurate vascular embolization data can be obtained through hemodynamic analysis and calculation, thereby improving the treatment effect. Meet the current development requirements of medical big data technology.
  • the angiography image shows that the blood vessels are chain-shaped, in which the first medicine 120 is a liquid contrast agent, which is displayed in black; the second medicine 121 is oxygen, which is displayed Light-colored bubbles.
  • the experimental image shown in Figure 5 shows that the experimental image shown in Figure 5.
  • the gas-liquid preparation provided by the embodiment of the present invention can be injected as a contrast agent at one time, and then the B-ultrasound and CT examinations are performed successively, and there is no need to inject the contrast agent separately before the B-ultrasound and the CT examination. Whether it is to reduce the amount of the contrast agent or to reduce the painful feeling of the patient, the present invention has an improvement compared with the conventional contrast agent.
  • the inventor conducted the following experiments to observe the physical properties and development effects of the gas-liquid tandem embolic agent provided in the embodiments of the present invention.
  • Carbon dioxide-alcohol gas-liquid tandem embolic agent 10 polyethylene transparent tubes (polyethylene tubes, hereinafter referred to as PE tubes) pre-filled with carbon dioxide-alcohol gas-liquid embolization agents, each tube is 100cm in length and 2.0mm in inner diameter , Both ends of the connector are standard Luer male and female connectors, which can be directly connected to the matching pipe connector.
  • the pre-filled content in the PE pipe is 75% alcohol solution and carbon dioxide, and the micro-flow pump valve is controlled by a computer for interval
  • the unit length of each section of gas and liquid column in the tube can be controlled between 3mm and 15mm according to the needs.
  • the preparation of this batch of 10 tubes will try to control the length of each section within 10mm, and make it as relatively uniform as possible .
  • DSA Digital subtraction angiography system
  • the camera rack can fix up to 14 PE pipes at the same time.
  • the fixing plate at the upper end of the rack is designed with 14 grooves.
  • the PE pipe is embedded in the groove, and the PE pipe joint is clamped at one end of the groove, and then the PE pipe is straightened.
  • One joint is stuck on the groove of another movable plate with adjustable position.
  • This movable plate is designed with 14 grooves, which correspond to the grooves on the top of the shelf one by one.
  • the round holes at both ends of the movable plate pass through the threads on both sides of the camera frame.
  • the metal column can adjust the position of the movable plate as a whole. When the PE pipes to be photographed are all straightened, tighten the two screws on the metal column located on the upper and lower movable plates to ensure that all the PE pipes remain straight during the shooting.
  • the PE tube After the PE tube is pre-filled, take a real-time photo of the sample and observe; after the PE tube is delivered by commercial express, the PE tube will be inspected and recorded.
  • the digital image stitching method is adopted for photography, the projection distance is 180cm, and the middle point of the tube is taken as the axis, and the exposure is divided into upper, middle and lower sections.
  • the center line of the middle section is perpendicular to the midpoint of the detector, and the upper and lower sections of photography are respectively tilted
  • the tube angle is realized, three images are obtained after three exposures, and the images are sent to the image post-processing workstation for seamless stitching.
  • Preparation before DSA imaging In order to simulate the angiographic subtraction process during DSA subtraction photography, take the 10-1 PE tube and fix it on the rectangular wooden board with medical tape; take the 10-2 PE tube The tube is straightened and fixed on the rectangular cardboard, and then fixed to the long axis of the human abdomen simulation model.
  • Preparation of aner's iodine-sodium chloride mixed solution take about 20ml of sodium chloride injection into a flask, and then pour a little aner's iodine type III skin disinfectant into the flask for staining, so that the solution looks yellow-brown.
  • Gas and liquid unit length measurement measure the length of the contents in 9 of the PE pipes (the 10-10 pipes are not included in the statistics due to the damage of the joints during the experiment). Define each section of the gas column/liquid column in the PE tube as a unit of gas column/liquid column, and perform digital X-ray photography on the PE tube at full 1 week and full 2 weeks after it arrives in the laboratory, using the built-in line of the PACS system Measuring tool to measure and record the unit length of each gas column and liquid column formed by carbon dioxide and alcohol in the PE pipe. The unit is mm, and the value is kept to two decimal places; all gas/liquid column units in each pipe The sum of the lengths is the total length of the gas/liquid column in the pipe.
  • the catheter provided by the 10 basic invention embodiments is selected.
  • the tube body is transparent, and the gas column and liquid column that can be distinguished by the naked eye are filled in the space between the tubes.
  • the unit length of the gas and liquid columns is relatively uniform.
  • FIG. 6A it is a fitting diagram of the head end joint of the gas-liquid preparation pipe and the tail end joint of the pipe in the embodiment of the present invention.
  • FIG. 6B it is a state diagram of the catheter of the pre-inflated liquid medicine in the embodiment of the present invention, and it can be seen that the unit length of gas and liquid is relatively uniform.
  • the No. 10-2 tube is advanced by manually pulling the simulated catheter, and the image is obtained by continuous exposure acquisition under the state of DSA subtraction.
  • the image of the overall movement of the PE tube can be observed and basically Recognize the image composed of carbon dioxide and alcohol solution in the PE tube, as shown in Figure 8B; when the PE tube is injected with an iodine-sodium chloride mixed solution, the image obtained by continuous exposure under the state of DSA subtraction can be observed.
  • the content is briefly pushed forward in the process, but the separation between the gas column and the liquid column is not clear.
  • X-ray photography of 10 catheters of pre-inflated-liquid tandem embolic agent can clearly distinguish the different components of gas and liquid.
  • the carbon dioxide gas component shows a low density
  • the anhydrous alcohol solution shows a relatively high density.
  • the density difference between the two can clearly show the gas-liquid interval of the reagent in the tube, and obtain a more satisfactory X-ray photograph.
  • Digital X-ray stitching photography is mainly used clinically for the photography of the spine and bones and joints, and its purpose is to obtain a complete image of anatomical structure.
  • X-ray photography adopted the method of tube tilt angle, and obtained ideal stitched images.
  • DSA digital subtraction angiography
  • the reasons for the changes in the gas and liquid composition of the gas-liquid pre-filled PE pipe may be as follows: 1. Part of the carbon dioxide is soluble in the alcohol solution at room temperature. The carbon dioxide can react with water to form carbonic acid, and the carbonic acid produced is also unstable. It can be re-decomposed into water and carbon dioxide, and the chemical reaction between the two is reversible, so the carbon dioxide gas in the tube cannot maintain an absolutely stable state; 2.
  • the closure screw of the PE tube at both ends of the pre-filled-liquid tandem embolic agent The tightness of the cap is designed for ordinary liquids, and may not be able to completely seal gas and volatile liquids; 3.
  • the stretching and curling of the reagent tube during the experiment will also cause the position of the gas and liquid units to change. However, the above changes do not affect the effect of tracing and embolization.
  • experimental rabbit 1 2 male healthy ordinary New Zealand rabbits, named experimental rabbit 1 and experimental rabbit 2, according to the order of the experiment, weighing 2.0kg (experimental rabbit 1) and 2.1kg (experimental rabbit 2) respectively.
  • donorgxinhua Experimental Animal Farm (license number: SCXK (Guangdong) 2019-0023). Regularly reared in a single cage for 2 to 3 days to adapt to the environment.
  • 1% sodium pentobarbital injection 1g sodium pentobarbital powder is dissolved in 100ml of normal saline to prepare a 1% sodium pentobarbital solution
  • Iodixanol (320mgI/ml): American GE company, trade name Weishi Parker
  • KMP catheter HNB5.0-38-40-P-NS-KMP, American Cook Company
  • DSA Digital subtraction angiography system
  • the length of the liquid column in the tube is measured on the obtained X-ray pictures.
  • the measurement method is the same as above.
  • the linear measurement tool built in the PACS system is also used.
  • the total length of the liquid column in each tube is the total length of the liquid column in the tube.
  • the inner diameter of the PE tube is known. It is 2.0mm, and the liquid volume in each PE pipe is estimated using the cylindrical volume formula.
  • the silk thread above the puncture point ligates the carotid artery to prevent bleeding.
  • 5 ml of 0.1% heparin saline through the catheter sheath to prevent thrombus formation in the catheter sheath.
  • the KMP catheter was introduced to the abdominal aorta through the guide wire, and the contrast agent iodixanol was pushed by hand for contrast.
  • the inferior branch of the left renal artery is selected as the target branch for embolization, and the micro-guide wire guides the microcatheter into the target branch.
  • 1ml of iodixanol is slowly injected to confirm that the microcatheter is in the target branch, and then in the microtubule.
  • the end of the PE tube is connected with No. 4-5 PE tube (CO 2 + C 2 H 6 O), and the back end of the PE tube is connected to a syringe for manual injection of 2.5 ml of iodixanol. Slowly push out all the carbon dioxide+absolute alcohol in the PE tube.
  • the target branch was rechecked with iodixanol, which showed that the peripheral branches of the target branch were reduced.
  • 2ml of 1% pentobarbital sodium was added to maintain the sedation of the experimental rabbits.
  • the microcatheter was introduced into the main trunk of the right renal artery for angiography, which showed that the diameter of the main trunk of the right renal artery became narrower. Therefore, no embolization test was performed on the right renal artery.
  • experimental rabbit 2 Take experimental rabbit 2; target artery: left renal artery.
  • the experimental procedure was the same as before: the experimental rabbits were anesthetized, disinfected, exposed and punctured the right carotid artery, and the KMP catheter was introduced to the abdominal aorta for angiography.
  • the microcatheter enters the main trunk of the left renal artery, and under fluoroscopy monitoring, 1ml of iodixanol is injected first, and the end of the microtubule is connected to the gas-liquid tandem embolization agent No.
  • the back end of the embolic agent tube is connected to a syringe to push iodixanol 4ml. Then use the same method to inject the same composition of gas-liquid tandem embolization agent No. 4-4 tube (CO 2 +75% C 2 H 6 O+Na 2 CO 3 ), the target artery is also the left renal artery, the back end of the embolization agent tube Connect the syringe and push the contrast agent about 3ml.
  • target artery right renal artery.
  • the microcatheter enters the main trunk of the right renal artery.
  • 1ml iodixanol is injected first, and the back end of the microtube is connected to the gas-liquid tandem embolization agent No. 4-1 PE tube (CO 2 +75% C 2 H 6 O ), the back end of the PE tube is connected to a syringe to inject 3ml of iodixanol, and observe the development of the gas-liquid tandem embolization agent with iodixanol as the reference during the bolus injection.
  • the microcatheter After the embolization of the left and right renal arteries of experimental rabbit 2 was completed, the microcatheter was guided into the main trunk of the left renal artery for reexamination with iodixanol, and the distal branches of the left renal artery were not visualized. After 5 minutes, the microcatheter was placed in the abdominal aorta for angiographic re-examination. It was observed that the right renal artery and most of its branches were still visible.
  • Both experimental rabbit 1 and experimental rabbit 2 were killed immediately after the embolization was completed.
  • the experimental rabbits were dissected and bilateral kidneys were taken out to observe the appearance changes, and then the embolized kidney specimens were put into 10% formalin solution for internal fixation 12
  • the kidney specimens were taken out the next day, and cut along the coronal and cross-sections from the kidney hilum.
  • the kidney specimens were divided into four parts.
  • the kidney specimens on each side were divided into upper ventral, upper dorsal, lower ventral and lower back Later, the specimens were embedded in paraffin, and they were stained with conventional HE and elastic fiber, and observed under an optical microscope to record the pathological changes that occurred.
  • kidney on the embolized side ie the left kidney
  • the unembolized kidney ie, the right kidney
  • the surface of the kidney It was still smooth, and the ischemic area, the middle and lower part of the left kidney, showed large, dark yellow changes (Figure 9A).
  • the size of the embolized kidney ie, the left kidney was basically the same as before, with a long diameter of about 3.4 and a transverse diameter of about 2.1cm;
  • the middle and lower ischemic areas showed gray-yellow changes (Figure 9B, 9C).
  • both kidneys are swollen, the left kidney is about 2.8cm in length and 1.8cm in transverse diameter; the right kidney is about 2.9cm in length and 1.9cm in transverse diameter; the surface of both kidneys is still smooth, and there are scattered patches on both kidneys. Spot-like dark yellow ischemic area ( Figure 10A).
  • HE staining 1Several small focal renal cortical infarcts can be seen on the upper dorsal side of the right kidney, renal tubular cells are edema and degeneration, the brush border of proximal convoluted tubule epithelial cells disappears, lightly stained particles appear in the cell cytoplasm, and the cells show granular degeneration; The glomerular cell nucleus in the infarcted area was fragmented and dissolved, showing changes after cell necrosis; no clear pathological changes were seen in the renal interstitium ( Figure 12A). 2There was edema and degeneration of renal tubular epithelial cells in the left kidney; no clear pathological changes were seen in the glomeruli and renal interstitium ( Figure 12B).
  • This experiment is the first attempt to use carbon dioxide as a contrast agent, and to carry three alcohol-based chemical embolization agents into the renal artery. Preliminary observations are made of the effects of anhydrous alcohol, 75% alcohol + sodium carbonate, and 75% alcohol on the renal artery and renal tissues. Pathological changes.
  • renal tubular epithelial cell degeneration and edema It is manifested as renal tubular epithelial cell degeneration and edema; small arterial wall edema is considered to be related to anhydrous alcohol injury, while the change of elastic fiber in the arterial wall is not a common phenomenon under the microscope, and it has not been determined whether it is the effect of anhydrous alcohol. The consequence may be degeneration of the blood vessel wall of the experimental rabbit.
  • 75% alcohol was injected into the renal artery, and specimens were taken for pathological observation immediately after embolization. According to the observation results, 75% alcohol injected through the renal artery caused renal tubular epithelial degeneration and small artery wall edema. , Even one of the kidneys had focal infarct changes, and its pathological changes were similar to those caused by absolute alcohol. 75% alcohol is used for disinfection, and its mechanism includes (1) causing hypertonic dehydration of bacterial cells. Alcohol molecules can act on the peptide chain links of protein molecules, resulting in protein denaturation and precipitation. This effect is even greater at 70% content. Significant; (2) 60%-85% alcohol is easier to penetrate into the bacteria, causing the bacterial cells to destroy and dissolve;
  • alcohol inhibits the normal metabolism by inhibiting the bacterial enzyme system, especially oxidase and dehydrogenase, thereby inhibiting the growth of bacteria.
  • sodium carbonate was innovatively added to a 75% alcohol solution.
  • the purpose is to use sodium carbonate to react with water in the solution to generate carbonate, so that the embolic agent contains alkaline components and achieve acid-base balance embolization.
  • this experiment uses healthy rabbits as the test object, and the preliminary results obtained are similar to pure 75% alcohol and anhydrous alcohol.
  • the three vascular interventional tracing pharmaceutical preparations in the experimental formula can all cause the degeneration and necrosis of renal tubular cells, leading to edema of the small arterial wall.
  • Carbon dioxide contrast agent 2 pcs
  • the tube is made of Teflon, with an inner diameter of 2mm, an outer diameter of 2.4mm, and a length of 1000mm;
  • This gas-liquid preparation uses a contrast agent diluted to 75%, which can be clearly displayed under fluoroscopy.
  • the left renal artery was injected with carbon dioxide-saline-contrast agent, and 30 microliters of carbon dioxide entered the blood vessel. After 3 minutes, the gas was basically absorbed by ultrasound, and the blood flow was normal.
  • embolization of the left renal artery take a radiograph and inject the new embolic agent.
  • the scale of the syringe is 1.5ml.
  • the scale of the syringe is 0.8ml.
  • a total of 0.7ml of embolic agent enters the target blood vessel. Among them, it contains about 350 microliters of 75% alcohol and about 240 microliters of carbon dioxide.
  • the image under DSA is clear, and 5 minutes after injection, the contrast injection shows that the entire kidney is basically embolized.
  • the syringe scale is 2.0ml when the embolic agent starts to enter the blood vessel, and the syringe scale is 1.2ml when blood reflux is found, and a total of 0.8ml embolic agent enters the target blood vessel. It contains about 300 microliters of 75% alcohol and about 300 microliters of carbon dioxide. The image under DSA is clear. The injection of contrast agent 5 minutes after injection will embolize the end of renal blood vessels more thoroughly, and a small amount of alcohol will enter the distal vein.
  • Carbon dioxide-saline-contrast agent was injected into the hepatic artery, and continuous bubbles appeared in the portal vein after 2.5 minutes.
  • embolic agent into the hepatic artery until the blood refluxes and inject 1.2ml of embolic agent, which contains about 500 microliters of 75% alcohol and about 600 microliters of carbon dioxide. The injection is carried out for 5 minutes, and the embolization is observed by injecting the contrast agent, showing hepatic artery embolism. completely.
  • embolic agent into the carotid artery until the blood refluxes and inject 1.2ml embolic agent, which contains about 500 microliters of 75% alcohol and about 600 microliters of carbon dioxide. Contrast agent was injected for 5 minutes to observe the embolism, showing that the carotid artery embolization was complete.
  • the left renal artery was injected with carbon dioxide-normal saline, 22 microliters of carbon dioxide entered the blood vessel, 2 minutes later, the gas was basically absorbed by ultrasound, and the blood flow was normal.
  • gas-liquid embolization agent into the carotid artery, using catheter 5.
  • the injected gas-liquid embolization agent contains about 400 microliters of 75% alcohol and about 600 microliters of carbon dioxide. Observed by DSA, some alcohol and carbon dioxide entered the distal internal jugular vein.

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Abstract

一种具有示踪功能的药物制剂及输送系统，药物制剂包括液态或气态的第一药物(11，11A，120)和第二药物(12，12A，121)，第一药物(11，11A，120)和第二药物(12，12A，121)各自分为多段在导管(200)内间隔串联设置；第一药物(11，11A，120)和第二药物(12，12A，121)中的一个为在人体内可在医学影像设备显影的示踪药物；第一药物(11，11A，120)和第二药物(12，12A，121)之间不互溶且满足配伍要求。药物制剂可以包括有氧造影剂、有氧栓塞剂和有氧灌注剂，通过一次性简便操作，可以适用于多种造影技术，节约药物用量的同时保持药物高浓度；在介入手术中与药物一同注入氧气，可以增加细胞活性从而提高药效，实现对肿瘤细胞的抑制作用；还可以提高药物配伍灵活性，实现精准的血流动力学分析。

Description

一种具有示踪功能的药物制剂及其输送系统 技术领域
本发明涉及一种具有示踪功能的药物制剂，同时还涉及该药物制剂的输送系统，属于医疗器械技术领域。
背景技术
在介入手术临床操作时，为了实现栓塞剂的可监视性，医生常常将非离子型碘对比剂与无水酒精混合，例如碘佛醇、碘克沙醇等。这种做法稀释了无水酒精的浓度，导致栓塞效果不理想。另外，对于液态造影剂，还存在另一个问题：在临床操作中，需要先输入造影剂，然后清洗，再输入栓塞剂。输入造影剂时，造影剂需要充满导管；输入栓塞剂时，栓塞剂或栓塞剂溶液需要充满导管，因此造影剂和栓塞剂的使用量均比较大，不仅操作繁复，还容易给人体带来过大的代谢负担。
另外，有的医生在某些情况下使用气态造影剂。但是，二氧化碳等气态造影剂需要注射较大量的气体，以排空血管内的血液而产生低密度对比，从而显示血管影像。虽然二氧化碳可以较快被人体血液吸收，但是在一定程度上还是会造成组织缺氧、缺血。因此，临床上只能在横膈肌以下区域的动脉内做二氧化碳动脉造影，不能在心脑部位、对缺血或缺氧敏感的脏器进行二氧化碳动脉造影。
如何解决上述现有技术存在的问题，仍然是本领域技术人员研究的热点。
发明内容
本发明所要解决的首要技术问题在于提出一种具有示踪功能的药物制剂。
本发明所要解决的另一技术问题在于提出一种上述药物制剂的输送系统。
为实现上述目的，本发明采用下述的技术方案：
根据本发明实施例的第一方面，提供一种具有示踪功能的药物制剂，所述药物制剂包括盛装有示踪药物的导管和管头，其中：
所述导管内设置有液态或气态的第一药物和第二药物，所述第一药物和所述第二药物各自分为多段在所述导管内间隔串联设置；所述第一药物和所述第二药物中的一个为在人体内可在医学影像设备显影的示踪药物；所述第一药物和所述第二药物之间不互溶、难溶或微溶，并且满足本领域可接受的治疗配伍要求。
其中较优地，所述第一药物为造影剂；并且所述第二药物为气态隔离剂。
其中较优地，位于所述导管的两端的是液态的第一药物或第二药物。
其中较优地，所述导管内还设置有气态或液态的多段第三药物，所述第三药物设置在所述第一药物和所述第二药物之间，
所述第三药物与所述第一药物和所述第二药物均不互溶，所述第三药物符合本领域可接受的配伍要求；所述第三药物与所述第二药物符合配伍要求。
其中较优地，所述第一药物为示踪药物为液态造影剂，并且位于所述导管的两端；
所述第二药物是气态隔离剂，并且所述第二药物的每一段的两侧均为所述第一药物；
所述第三药物是栓塞剂或灌注剂，并且所述第三药物的每一段的两侧均为所述第二药物；
所述导管内从端部起以所述第一药物、第三药物、第二药物、第三药物的排列方式作为一个单元进行重复排列直至所述导管另一端为所述第一药物为止。
其中较优地，所述第一药物是无水碘造影剂，所述第二药物是二氧化碳，所述第三药物是酒精。
根据本发明实施例的第二方面，提供一种有氧造影剂，包括导管和管头，所述导管内设置有氧气和液态的造影剂，所述氧气和所述造影剂各自分为多段且在所述导管内间隔串联设置，
所述氧气和液态的造影剂不互溶、难溶或微溶，且满足本领域可接受的治疗配伍要求。
根据本发明实施例的第三方面，提供一种有氧栓塞剂，包括导管 和管头，所述导管内设置有氧气、液态的造影剂和液体栓塞剂，所述氧气、所述造影剂及所述栓塞剂各自分为多段，并且所述造影剂及所述栓塞剂通过所述氧气在所述导管内间隔串联设置，
所述氧气、液态的造影剂和液体栓塞剂不互溶、难溶或微溶，且满足本领域可接受的治疗配伍要求。
根据本发明实施例的第四方面，提供一种有氧灌注剂，包括导管和管头，所述导管内设置有氧气、液态的造影剂和液体灌注剂，所述氧气、所述造影剂及所述灌注剂各自分为多段，并且所述造影剂及所述栓塞剂通过所述氧气在所述导管内间隔串联设置，
所述氧气、液态的造影剂和液体灌注剂不互溶、难溶或微溶，且满足本领域可接受的治疗配伍要求。
根据本发明实施例的第五方面，提供一种具有示踪功能的药物制剂的输送系统，包括依次连接的注射泵、导管、鞘管座以及穿刺针，其中所述导管是前述导管。
本发明实施例提供的具有示踪功能的药物制剂，包括有氧造影剂、有氧栓塞剂和有氧灌注剂，通过一次性简便操作，即可以适用于多种造影技术，不降低栓塞剂浓度情况下实现清晰造影，节约药物用量同时保持药物高浓度。而且，在介入手术中与药物一同注入氧气，可以增加细胞活性从而提高药效，实现对肿瘤细胞的抑制作用；还可以提高药物配伍灵活性，实现精准的血流动力学分析。
附图说明
图1为本发明实施例提供的气液制剂输送系统的示意图；
图2为本发明的第一实施例中，气液制剂的结构示意图；
图3为本发明的第二实施例中，气液制剂的结构示意图；
图4A为本发明的第一实施例中，气液制剂的X射线下显示效果图；
图4B为图4A的气液制剂在X射线下的显示效果图；
图4C为图4A的气液制剂在X射线下的显示效果图；
图5为本发明的第五实施例中，气液制剂的结构示意图；
图6A为本发明的第五实施例中，气液制剂导管头端接头与导管尾端接头相适配图；
图6B为本发明的第五实施例中，导管状态的示意图；
图7A为管电压49.90kV时，PE管的X射线拍摄图片；
图7B为管电压80.90kV时，PE管的X射线拍摄图片；
图7C为管电压89.80kV时，PE管的X射线拍摄图片；
图8A为向10-1号PE管内推注安尔碘-氯化钠混合溶液时进行连续曝光采集图；
图8B为在加入腹部体模的条件下，模拟导管前进对10-2号PE管进行连续曝光采集图；
图9A为对实验兔1进行左肾动脉栓塞后，取出双侧肾脏进行大体观察图；
图9B为福尔马林溶液浸泡12小时后，栓塞肾(即左肾)标本大体情况观察图；
图9C为左肾冠状切面观察图；
图10A为对实验兔2进行双肾动脉栓塞后，取出双肾进行大体观察图；
图10B为福尔马林浸泡12小时后，左肾大体标本观察图；
图10C为左肾冠状切面观察图；
图10D为福尔马林浸泡12小时后，右肾大体标本观察图；
图11A为左肾肾小管上皮细胞可观察到水肿变性现象；
图11B为左肾可观察到极个别动脉管壁弹力纤维断裂现象；
图12A为右肾出现皮质梗死区图示；
图12B为左肾肾小管上皮细胞出现水肿变性图；
图13A为本发明实施例提供的气-液串联栓塞剂的样品图片，其中包括二氧化碳约6微升，75％酒精约15微升；
图13B为本发明实施例提供的气-液串联栓塞剂的样品图片，其中包括二氧化碳约60微升，75％酒精约15微升；
图14A为本发明实施例提供的气-液串联栓塞剂的样品图片，其中包括二氧化碳约10微升，碘油约15微升；
图14B为本发明实施例提供的气-液串联栓塞剂的样品图片，其中包括二氧化碳约70微升，碘油约15微升；
图15A～图15G分别为本发明的动物实验中，所得到的各种造影 图像。
具体实施方式
下面结合附图和具体实施例对本发明的技术内容进行详细具体的说明。
本发明实施例所述的“气液制剂”，包括气体和液体交替形成的制剂，也包括第一液体和第二液体(两者不相溶)交替形成的制剂。为了简便描述，在特别强调是气体-液体-气体的结构时“气液制剂”仅包括气体和液体的交替形成的制剂，否则“气液制剂”包含前述两种情况。
如图1和图2所示，本发明实施例提供的药物制剂输送系统包括注射泵100、导管200、鞘管座400以及血管鞘500。注射泵100与导管200的尾端(靠近注射泵的一端)连接，导管200的另一端(远端，靠近患者的一端)通过鞘管座400连接血管鞘500。血管鞘500的一端插入动脉血管(未图示)或人体组织(例如肿瘤组织)内。
注射泵100,可以根据介入手术的需要，选择常规型号，例如德国贝朗微量注射泵Perfusor Space，或者浙江史密斯医学仪器有限公司生产的双道微量注射泵(WZS-50F6型)，可以实现多种速率多种容量的推注。本技术领域普通技术人员可以理解,不用注射泵100,改用手推注射也是可以的。
导管200与鞘管座400通过鲁尔接头连接。鲁尔接头符合中国标准GB/T 1962.2-2001或者国际标准ISO 594-2-1998注射器、针头及其他医疗器械为6％(鲁尔)的锥形接头第2部分:锁紧接头的规定,用可用医疗器械的快速连接。
鞘管座400符合行业标准YY0450.1-2003以及YY0258.2-2004的要求，其连接侧支管300。
导管200包括管体1和管头2(即，鲁尔接头)。管体1是细长的管状结构，两端被管头2封闭。管体1由塑料、树脂或玻璃等材料制成，优选高性能聚烯烃热塑弹性体(TPE)，例如普力马热塑性弹性体(Polymax TPE)公司生产的MT-12051型TPE新材料。
动脉血管的正常平均管腔直径为：弹性动脉约15毫米；肌肉动脉约6毫米，小动脉约37微米，毛细血管约9微米。本发明实施例提供的气液制剂的导管的外径和内径有多种规格，内径范围包括但不限于 0.2～15mm，优选为0.5～8mm，选用合适的规格可以实现导管的外径可以小于或等于动脉血管的内径。当导管外径变小，内径相应变小，管体1内的气体或液体的流动阻力就变大。小的内径,在对管体1内气体或液体没有施加压力的情况下，会使气体或液体不易流动，因此即使有外部施加的震动，气体或液体也不会有相对移动(不会彼此混悬),尤其适用于第一液体-第二液体-第一液体-第二液体这样以液体作为隔离剂的液液制剂。较大的内径，例如2mm及以上内径的情况下，则适合以气体作为液体的隔离剂。但是，本发明实施例提供的药物制剂也可以用于血管瘤、肝癌、脑瘤等的治疗，因此并不限于动脉。
管头2包括公头2A和母头2B，分别位于管体1的两端，用于封闭/密封管体1内的液体或气体。管头2是标准鲁尔接头。因为管体一端为公头2A，且另一端为母头2B，所以两根管体1可以通过将其中一根的公头与另一根的母头对接，由此实现多根管体1的连接，从而实现药量的增加(即，多根管体1中的药物可以实现连续供药)。此外，因为采用标准的鲁尔接头(国标GB/T 1962.2-2001)，所以管体1可以方便地通过鲁尔接头，连接到各类常规注射器或其他医疗器械上，以使管体1内的气态或液态药物可以通过常规注射器等输入到人体或动物体内。在使用前，储存运输阶段，可将导管200两端的公母鲁尔接头相连，实现储存运输过程中增加导管密封性的功能，还可以缩小导管包装体积。
管体1内的药物以气体或液体(含混悬液)的形式存在。管体1内的药物可以包括不同种类的药，例如，栓塞剂、灌注剂、化学消融剂显影剂、麻醉剂等。
管体1内的药物有多种组合形态，例如是液体(造影剂)－气体间隔剂(氧气)－液体(造影剂)－气体间隔剂(氧气)的交错或间隔的形式(参见图2)；也可以是第一液体(造影剂)－第二液体(栓塞剂)－第一液体(造影剂)－第二液体(栓塞剂)的交错或间隔的形式；也可以是第一液体(造影剂)－气体间隔剂(氧气)－第二液体(栓塞剂)－气体间隔剂(氧气)－第一液体(造影剂)－气体间隔剂(氧气)－第二液体(栓塞剂)的交错或间隔形式(参见图3)。换言之，可以是液气交错的形式，也可以是液液交错的形式。
优选的是，将液体(例如造影剂)设置在管体1的两端(头部及尾部)，这样一方面方便造影成像中能够看到两端的液体(造影剂)成像，从而定位出整个管体1内的气液制剂的位置；另一方面也可以提高气密性，防止气体泄漏。
<第一实施例>
本发明第一实施例是有氧造影剂。在本发明的第一实施例中，管体1的总容量是10mL，长度为1米。管体1的容量由介入手术的药物用量和用药速度决定,可以设置为400mm、600mm、800mm的不同规格的长度及对应内径。如果介入手术时需要的容量超过一根管体的总容量(例如，10mL)，则可以将多根气液制剂连起来(将相邻两根气液制剂的公鲁尔接头与母鲁尔接头连接就行)。管体1内部容纳的是2种药物：造影剂(第一药物11)和隔离剂(第二药物12)，用于介入治疗的血管造影。如图2所示，第一药物11是液态的造影剂碘佛醇；第二药物12是气态的隔离剂氧气。氧气12将各段造影剂11间隔开(即，液体－气体－液体－气体的交错形式)，而且导管1内的气体的总量不能大于0.8mL以避免造成人体不适，每一段气体的量不能大于0.1mL以避免造成栓塞。导管内的药物配伍需要考虑物理、化学、疗效方面的合理设计，符合药剂学的规定，尤其是物理和化学方面的配伍禁忌。例如，在导管内有第一液体和第二液体时，两种液体可能因为溶解度的改变而析出沉淀。因此，这样的液体就用隔离剂(例如气体)来避免两者混合导致的混浊或沉淀。再例如，如果用二氧化碳作隔离剂，那么会改变与之相邻的液体的PH值，就可能造成一些强碱性的药物液体因PH值的改变而析出沉淀，所以这种药物液体就需要用氧气做隔离剂，或者用造影剂作隔离剂。
第一药物和第二药物均分为多段，第一药物的每一段等长，为L1；第二药物的每一段等长，为L2。本领域普通技术人员也可以理解，每一段不等长也是可以的，并不限制为均分的情况。第一药物(造影剂)的段长L1≥第二药物(隔离剂)的段长L2。在此假设L1＝L2(即，第一药物和第二药物各段长度相等),则管体1的长度L1＝L2＝L/(2N+1)，其中L为导管1的长度，而且，第一药物(造影剂)的段数为2N*L/(2N+1)，第二药物的段数为N*L/(2N+1)。
各段长度L1或L2的设计，需要考虑1)每一段药物量的用量控制；2)整个管体1内的每一种药物的总量的控制。每一段药物量的用量控制，受药物在管体1内的流动性的影响。如果流动性低，则每一段的药物量就小，即每一段药物的长度短；如果流程性高，则每一段的药物量就大。管体1内的每一种药物的总量控制，受人用安全剂量的影响，这是医生所熟知的。
在本实施例中，第二药物，隔离剂，氧气的每一段的段长L2小于第一药物造影剂的每一段的段长L1。一方面因为氧气的段长过长，会导致造影剂的流动(出现推不动的情况)；另一方面因为氧气进入血液后形成气泡不能过大，否则可能出现人体不适。即，第一药物(造影剂)与第二药物(隔离剂)之间不互溶、难溶或微溶，且满足本领域可接受的治疗配伍要求。
在进行血管造影时，通过注射泵100(也可以手工注入，代替注射泵)对管体1加压，使得位于管体1头端的第一药物(造影剂)11首先进入血管；位于管体1尾端的第一药物(造影剂)11最后进入血管。由于头端第一药物和尾端第一药物均为造影剂,所以在X射线下均能成像，使得影像图片上可以看到头端液体120的位置以及尾端液体121的位置。
<第二实施例>
如图3所示，本发明第二实施例中，第一药物11A是液态造影剂(碘佛醇)，并且位于所述导管200的两端；所述第二药物12A是气态隔离剂(二氧化碳)，并且所述第一药物的每一段均位于第二药物的一段的两侧。第三药物13是栓塞剂或灌注剂(本实施例中为75％酒精)，并且第三药物13的每一段均位于两段所述第二药物12A之间。在导管200中，从导管头部起药物串联排列顺序为液态造影剂(碘佛醇)-气态间隔剂(二氧化碳)-栓塞剂或灌注剂(酒精)-气态间隔剂(二氧化碳)，以上述排列为一个单元在导管内重复排列，所述导管尾部增加液态造影剂作为最终药物。第一药物(造影剂)、第二药物(隔离剂)及第三药物(栓塞剂或灌注剂)之间不互溶、难溶或微溶，且满足本领域可接受的治疗配伍要求。
图3中，导管1中的三种药物的体积比(长度比)是：碘佛醇N +1：二氧化碳2N：75％酒精N，其中L1＝L2＝L3＝L/(4N+1)，L为导管1的长度,L1、L2、L3分别是每段第一药物的长度、每段第二药物的长度和每段第三药物的长度。本技术领域的普通技术人员可以理解，L1、L2、L3也可以根据药物剂量而改变，并不一定相等。在此假设三者相等，只是为方便理解做的简化描述，但不构成对本发明的任何限制。
与第一实施例的类似，本发明的第二实施例的气液制剂可以减少造影剂和栓塞剂的用量，因为栓塞剂不需要充满整个靶血管(假设充满需要的用量为V 靶血管)，只需要N*V 靶血管/(4N+1)的用量就可以与造影剂和隔离剂的共同充满靶血管。
而且，本发明的第二实施例可以在X射线下示踪栓塞剂位置，主要通过液态造影剂及二氧化碳造影剂实现。由于二氧化碳阻隔了液态造影剂和栓塞剂的混合，使栓塞剂相对浓度不受造影剂影响(栓塞剂与血液不接触，不会被血液稀释)，实现栓塞剂最佳的栓塞性能。同时本实施药物制剂还延长了栓塞剂与靶血管的接触时间。这是因为栓塞剂(第三药物13)位于两第二药物(气态隔离剂)之间，气体间隔使得栓塞剂的流速，与常规介入治疗中注入栓塞剂(没有气体)相比，变得更慢了，所以栓塞剂与血管中的细胞接触时间相当变长。而且，肿瘤内部组织渗透压高，栓塞剂没有血液稀释而保持高浓度(渗透压较常规制剂的更高)，因此容易渗透到肿瘤微血管并扩散，使肿瘤细胞变性坏死。
本发明的第二实施例也可以适于光声造影(B超)也适于X射线造影(CT)，还能方便地进行血流动力监测。
因为第二药物二氧化碳是没有生理危害性的气体，在血液中的溶解度为氧气的2.3倍，所以不易形成气栓。二氧化碳同时还是一种气态阴性对比剂，可用于血管造影，二氧化碳进入血液后，可溶于血液，并在到达肺循环的时候从肺里排出。因此，这是一种不增加循环负担，不会出现过敏反应的对比剂。但由于二氧化碳不便于保存，在血管造影时需要二氧化碳机临床制备，在临床中如果将二氧化碳充入栓塞剂中可实现微泡结构，但微泡结构示踪性不好均匀度无法控制且易消灭，上述问题给临床广泛应用带来了一定限制。但是正因为二氧化碳的水 溶性强但不溶于碘液，可以与无水碘造影剂配伍,同时二氧化碳与酒精不互溶，可以起到很好的隔绝造影剂与栓塞剂的作用，且不影响二者药性，提高药物配伍灵活性。
<第三实施例>
本实施例为有氧栓塞剂，包括第一药物11是液态造影剂(碘佛醇)，并且位于所述导管的两端；第二药物12是气态隔离剂(氧气)，并且所述第一药物的每一段均位于第二药物的一段的两侧；第三药物是栓塞剂，例如75％酒精或碘化油，动脉化疗栓塞剂、放疗栓塞剂、微球混悬液等。因该药物制剂的结构与第二实施例的结构类似，在此不赘述。本实施例中的有氧栓塞剂，包括导管和管头，所述导管内设置有氧气、液态的造影剂和液体栓塞剂，所述氧气、所述造影剂及所述栓塞剂各自分为多段，并且所述造影剂及所述栓塞剂通过所述氧气在所述导管内间隔串联设置。所述氧气、所述造影剂及所述栓塞剂之间不互溶、难溶或微溶，且满足本领域可接受的治疗配伍要求。
<第四实施例>
本实施例为有氧灌注剂，包括第一药物11是液态造影剂(碘佛醇)，并且位于所述导管的两端；第二药物12是气态隔离剂(氧气)，并且所述第一药物的每一段均位于第二药物的一段的两侧；第三药物是灌注剂，例如TAI、TAE、TACE中使用的灌注药物、动脉灌注用化疗药物等、放射粒子混悬液、微球混悬液等。
本实施例的有氧灌注剂，包括导管和管头，所述导管内设置有氧气、液态的造影剂和液体灌注剂，所述氧气、所述造影剂及所述灌注剂各自分为多段，并且所述造影剂及所述栓塞剂通过所述氧气在所述导管内间隔串联设置。所述氧气、所述造影剂及所述灌注剂之间不互溶、难溶或微溶，且满足本领域可接受的治疗配伍要求。
因该药物制剂的结构与第二实施例的结构类似，在此不赘述。
以上结合不同实施例介绍了本发明的技术方案及技术优势。在本发明中使用的隔离剂，不仅可以是氧气或者二氧化碳，还可以是超氧(O 3)等人体安全的气体。本发明所使用的造影剂，包括X射线造影剂，可以是离子型造影剂，也可以是非离子型造影剂；也包括MRI造影剂，可以是大分子顺磁性显影剂，纳米结构显影剂；还包括超声显 影剂，例如液态氟碳纳米乳剂。
<第五实施例>
在本发明的第五实施例中，第一药物为栓塞剂(75％酒精)，第二药物为气态隔离剂(二氧化碳)，为了防止气体流失，导管200两端药物为液体栓塞剂，本实施例中导管从头部起以酒精-栓塞剂为一个单元重复循环排列，在导管200尾部增设酒精。本实施例中第一药物(75％酒精)药柱长度和第二药物(二氧化碳)长度比为1，由于酒精具有一定挥发性，为了保证酒精的栓塞效果，酒精药柱长度可适当延长，例如酒精和二氧化碳的长度比可为2:1。在本实施例中导管总长为100cm，内径2.0mm。管长和内径的比例也尤为重要，由于气态药物和液态药物间隔内置于导管内，如果导管总长过短，药物盛装量有限，如果为了提高药物盛装量提高内径，尤其是栓塞剂为可挥发性液态药物的情况下，会增加药物在运输和储存过程中的损耗。如导管长度过长，内径过小，推药阻力会加大，如果内径过大，也会增加导管体积及药物用量，造成药物的损失和浪费。最佳的导管长度和内径比可实现在可接受药损的情况下，手术用药更为便捷有效。
<第六实施例>
如前述第五实施例中，导管200预装有填充物，存储备用。即，在制药厂内将药液推注到导管200内，将管头2均封闭，然后进行储存、运输等，到手术时，由医生打开管头2中的一个或两个，连接到手术器械上，才将导管200内的填充物推注到生物体内。以下将此模式称为：预装模式。在本实施例中，导管200的近端与推注设备直接连接，远端与针头连接。即，在手术过程中一边推注到导管200内，一边就通过远端的管头2连接到针头，使导管200内的液体或气体进入生物体内。以下将此模式称为：现装模式。
参考图13A～图14B，以下提供部分实验数据，是基于现装模式得到的实验数据。但是，本领域普通技术人员可以理解，预装模式下也可以得到相同的实验数据。
Figure PCTCN2021089529-appb-000001
利用本发明实施例提供的不同配伍的气液药物制剂,可以分别获得以下技术效果。
一.适用于多种造影技术。本发明实施例提供的气液制剂的第一实施例，既适用X射线造影，也适于超声造影，均能获得清晰的造影图像。目前的超声造影剂为包裹高密度惰性气体(不易溶于水或血液)为主的外膜薄而柔软的气泡，直径一般在2～5um左右，稳定时间长，振动及回波特性好，例如Optison等。这是因为，含气泡的液体对超声波有强散射的特性,将含气泡的液体作为超声造影剂，注射到人体血管中，可以增强血流的超声多普勒信号并提高超声图像的清晰度和分辨率。因此，做CT时，碘佛醇这样的液态造影剂成像出来的图像，比气态造影剂成像出来的图像更清晰；但是做B超时，气态造影剂的图像，比液态造影剂的图像更清晰。本发明的第一实施例将气液造影剂结合，利用二者的不互溶性，制成串联间隔设置的药剂，在CT或 超声下均可获得优质的造影图像。
二.操作简便。本发明实施例通过将栓塞剂、液态示踪剂和二氧化碳按设置顺序预充进导管，并利用鲁尔接头封闭导管。既可以实现一次操作就同时输入造影剂、栓塞剂、灌注剂(也还可以有其它药物，因为只需要满足在导管内配伍且人体耐受，导管内可以间隔设置多种药物)；也解决了临床中二氧化碳无法储存，必须在手术中使用二氧化碳制造设备的问题，使手术无需配备二氧化碳制造机，盛装有示踪药物的导管可直接使用，鲁尔接头可实现多导管互接，药物剂量不受限制，可以一次性输入多种类、大剂量药物。
三.节约药物用量。如图5所示，当头端第一药物11进入血管后，紧接着进入血管的是第二药物12氧气。由于氧气能够与血红细胞进行氧合，因此可以被部分吸收，只要注入量不大于0.02mL/kg(因为通常认为大于0.02mL/kg的空气进入血管，会让人感觉不适，而大于2mL/kg的空气进入血管，就会猝死)。以冠状动脉介入治疗为例，常规剂型的造影剂的注入量大致为2mL/kg，一次注入量为大约8mL。如果采用本发明第一实施例的气液制剂，假设L1＝L2，则第一药物(造影剂)只需要约4mL造影剂。这是因为，现有技术中需要输送8mL造影剂才能充满靶血管，而本发明第一实施例的装满气液制剂的导管只需输送大约4mL的造影剂，再加上4mL的氧气，就能充满靶血管。可见，采用本发明可以节约药物用量。需要说明的是，本发明中的数据，只是用作示例以方便理解，并不构成对本发明的任何限制。
四.增加细胞活性从而提高药效。正因为氧气会增加血管内皮细胞的活性，增加内皮细胞对栓塞剂或其他在气液制剂中的治疗药剂的吸收能力，所以，在注入药物的同时注入间隔气体氧气，可以提高药效。
五.改变肿瘤细胞的缺氧环境。在以氧气为本发明中的气体隔离剂时，可以改变肿瘤的缺氧状态，杀灭肿瘤细胞。2019年诺贝尔生理学或医学奖获得者,三位科学家发现了低氧诱导因子HIF(Hypoxia-inducible factors)以及生物氧气感知通路的机理。研究发现肿瘤细胞通过各种机制诱导缺氧，制造慢性缺氧环境，激活低氧诱导因子HIF信号通路，加速肿瘤的生长，提高肿瘤的侵袭性，促使肿 瘤发生转移。利用本发明实施例提供的气液药物制剂，将氧气送入肿瘤组织内，可以破坏肿瘤细胞的缺氧环境，与放疗、化疗药物协同作用，从而提高癌症治疗的疗效。
六.保持药物浓度。氧气或者二氧化碳等气体隔离剂进入血管后，会挤压血液，使得隔离剂后方的药物，即造影剂(也就是位于导管头端的造影剂之外的造影剂)、栓塞剂或者灌注剂等药物进入血管时，不会与血液接触，也就不会稀释在血液中，也不会出现层流现象，因此可以保持药物的高浓度(与注入时浓度相同)。例如，本发明的第二实施例为液态造影剂-气态隔离剂-栓塞剂-气态隔离剂循环组合，气态隔离剂使用的是既有隔离效果，又有示踪效果的二氧化碳。在血管介入栓塞手术中，液态造影剂和二氧化碳的配合有效的增强了示踪效果，二氧化碳将液态示踪剂和栓塞剂隔离，实现了精准且清晰的示踪栓塞剂的同时还保证了栓塞剂的浓度不受血液影响，实现有效栓塞。
七.造影或者治疗同时输氧，提高造影或者治疗的舒适度。采用本发明中的造影剂，可以在造影的同时给人体组织输送氧气，提高患者的舒适度。
八.提高药物配伍灵活性。如前述，本发明实施例提供的同一导管内的药物，可以利用适合的隔离剂来进行分隔，从而保证隔离剂两侧相邻的药物可以同时注入体内(需要满足疗效方面的配伍要求)。这样，原本不能配伍在一起的药物，因为有隔离剂，而且被相对固定在隔离剂之间，所以不能配伍在一起的药物不会在一起发生物理或化学变化。因此，在满足疗效配伍方面的要求的前提下，本发明降低了药剂在物理或化学方面的配伍要求。
九.便于精准的血流动力学分析。正是基于图5所示的图像效果，可以用于血流动力学分析。本发明实施例提供的气液制剂中包含氧气，可以利用氧气气泡来测量血流动力学指标；也可以监测一段一段的造影剂的运动轨迹来测量血流动力学指标。这是因为链式的气泡或液体段的流动速度、方向、数量等是可以直接监测到的。而且，利用注射泵100推注时，能检测到推进压力。推进压力与血液粘稠度、血管栓塞状态、造影剂/栓塞剂的浓度等因素相关，结合造影图像的数据，可以通过血流动力学分析计算得到更准确的血管栓塞数据，从而提高治 疗效果，满足当前医疗大数据技术的发展要求。
参见图4所示的示意图，采用本发明实施例提供的气液制剂，血管造影图像显示血管为链状，其中第一药物120是液态造影剂，显示为黑色；第二药物121为氧气，显示为浅色的气泡。如图5所示的实验图像所示。
临床上可以一次性注入本发明实施例提供的气液制剂作为造影剂，然后就先后进行B超检查和CT检查，不需要在B超检查和CT检查前分别注入造影剂。无论是减少造影剂用量，还是减少患者的痛苦感受,本发明较常规的造影剂均有改善。
为了验证本发明的技术效果，发明人进行以下实验，对本发明实施例提供的气-液串联栓塞剂的物理特性及显影效果进行观察。
一、实验材料：
二氧化碳-酒精气-液串联栓塞剂：10根预充了二氧化碳-酒精气-液串联栓塞剂的聚乙烯透明管(polyethylene管，以下简称PE管)，每根导管长度为100cm，内径为2.0mm，两端接头为标准鲁尔公母接头，能同与之相适配的导管接头直接相连，PE管内的预充内容物为75％酒精溶液和二氧化碳，利用计算机控制微流泵阀门进行间隔预充，管内每一段气、液柱单位长度可根据需求控制在3mm～15mm之间，本批次10根管的制备将每一段长度尽量控制在10mm以内，并且尽可能使其做到相对均匀。按10-1、10-2……10-10顺序对10根PE管进行编号。
二、实验试剂及设备：
(一)试剂
1.广东怡翔制药有限公司生产的氯化钠注射液(250ml：2.25g)
2.上海利康消毒高科技有限公司生产的安尔碘Ⅲ型皮肤消毒液
(二)实验设备：
1.X射线摄影系统：德国Siemens YISO DR数字化X射线摄影系统
2.数字减影血管成像系统(DSA)：德国Siemens Axiom Artis dTA悬吊式数字平板血管造影系统
3.X射线摄影用仿真人体模型
4.自制可调节长度的导管X射线摄影架。
该摄影架最多可同时固定14根PE管，架子上端的固定板设计了14个凹槽，把PE管嵌入凹槽，利用PE管的接头卡在凹槽一端，再把PE管拉直，另一接头卡在另一块可调节位置的活动板的凹槽上，这块活动板设计了14个凹槽，与架子顶端的凹槽一一对应，活动板两端的圆孔通过摄影架两边的螺纹金属柱可整体调节活动板的位置，当被拍摄的PE管全部伸直后，收紧金属柱上位于活动板上下的两颗螺钉，保证全部PE管在摄影过程中维持在伸直状态。
三、实验方法：
(一)气-液串联栓塞剂的大体观察
PE管预充完毕，拍摄样品的即时照片，并进行观察；PE管经过商业快递后，再对PE管进行检查和观察记录。
(二)气-液串联栓塞剂的体外数字化X射线摄影
1.PE管的固定方法
将10根含二氧化碳-酒精的PE管的头端和尾端分别固定于摄影架上方和下方的凹槽，移动下方活动板，找到使PE管达到最大拉伸状态的位置，活动板两端螺钉固定好位置，将摄影架立于探测器前方，准备对10根栓塞剂管进行整体拍摄。
2.摄影方法：
采用数字图像拼接方法进行摄影，投照距离为180cm，以管的中点为轴线，分上、中、下三段进行曝光，中段摄影中心线垂直探测器中点，上、下段摄影分别通过倾斜球管角度实现，在进行三次曝光后得到三幅图像，将图像发至图像后处理工作站进行无缝拼接。
3.摄影参数：分别采用三组不同的管电压(kV)(49.90kV；80.90kV；89.80kV)进行拍摄，管电流由系统根据管电压自行调整(相应地分别为772mA；916mA；909mA)。
(三)气-液串联栓塞剂体外DSA成像：透视和减影摄影采集
1.DSA成像前准备：为便于在DSA减影摄影采集时模拟血管造影减影过程，取10-1号PE管，用医用胶带将其伸直固定于长方形木板上；取10-2号PE管，将其伸直后固定于长方形硬纸板上，再与人体腹部仿真模型成长轴固定。
安尔碘-氯化钠混合溶液的制备：取氯化钠注射液约20ml于烧瓶内，随后向内倒入少许安尔碘Ⅲ型皮肤消毒液染色，使溶液外观呈黄褐色。
2.DSA成像：
①固定好10-1号PE管的木板于DSA检查床，透视下静态观察10-1号PE管内气体和液体的显影情况。
②固定DSA检查床；助手匀速向头侧牵拉固定10-1号PE管的木板，使PE管在透视期间进行移动，以此模拟气-液串联栓塞剂在导管内移动的效果，观察其在透视下显影的效果；随后重复这一过程，启动DSA曝光摄影进行连续减影采集。
③用5毫升注射器，抽吸安尔碘-氯化钠混合溶液5ml，并把注射器接上10-1号PE管接头，手动推注安尔碘-氯化钠混合溶液，利用混合溶液推动PE管内的二氧化碳-酒精，将其全部排出管外，模拟栓塞剂从PE管内被推注到管外的过程，观察到黄褐色的安尔碘-氯化钠混合溶液充满PE管即为注射终点，读取此时注射器的刻度，约2ml；推注过程中10-1号PE管固定木板保持在DSA床上静止，DSA床亦固定不动，并进行约5秒的曝光采集，得到动态减影图像，观察栓塞剂管的动态显影情况。
④以人体腹部仿真体模为基础，用10-2号PE管重复进行上述操作，观察二氧化碳-酒精在人体厚度条件中DSA透视和减影采集效果。
(四)观察二氧化碳-酒精预充PE管中气-液态外观的变化
1.储存条件与时间：10根PE管在到达实验室后被封装于聚丙烯(PP，polypropylene)材质保鲜盒中，并处于常温干燥的环境中，为了观察不同时间点管内气-液态物质在此环境中的变化，随机选取两个时间点：到达实验室满1周时(记录为时间点1)、到达实验室满2周时(记录为时间点2)，通过观察记录这两个时间点内管内容物的长度变化来侧面反应其整体变化。
2.气、液单位长度测量：对其中9根PE管内的内容物长度进行测量(其中10-10号管因实验过程中接头发生损坏未纳入统计)。将PE管内每一段气柱/液柱定义为一个气柱/液柱单位，分别于PE管到达实验室后满1周及满2周时对其进行数字化X射线摄影，利用PACS 系统内置的直线测量工具，对PE管内的二氧化碳和酒精所形成的每一个气柱及液柱单位长度进行测量和记录，单位为mm，数值保留到小数点后两位；将每根管中全部气/液柱单位长度相加即为管内气/液柱总长度。
3.统计学处理及数据分析：
采用SPSS 16.0统计学软件进行统计分析，所有计量资料以`x±S形式表示。对于计量资料用Shapiro-Wilk法进行正态性检验。两组独立样本均数比较，若符合正态分布，采用t检验，若不符合正态分布，则采取秩和检验；两组配对样本均数比较，若符合正态分布，采用t检验，若不符合正态分布，则采取符号秩和检验；多组定量资料的比较，若每组资料服从正态分布并且方差齐性，则采取方差分析处理，若既不服从正态分布又不满足方差齐性，则采用Welch’s anova检验。取P＜0.05为差异具有统计学意义。
四、实验结果
(一)气-液串联栓塞剂的大体观察结果
选用10根本发明实施例提供的导管，管体透明，管内间隔填充肉眼可分辨的气体柱及液体柱，气、液柱单位长度相对均匀。如图6A所示，为本发明实施例中气液制剂导管头端接头与导管尾端接头相适配图。如图6B所示，为本发明实施例中预充气液药物的导管状态图，可见气、液单位长度相对均匀。
(二)气-液串联栓塞剂体外数字化X射线摄影结果
气-液串联栓塞剂设置三种不同管电压条件(49.90kV；80.90kV；89.80kV)进行数字化X射线拍摄，均能够较为明确地显示PE管中气柱和液柱的排列，对图像的窗宽及窗位进行适当调节，均能满足实验观察的需要，照片中显示管内密度较高的为液体成分(75％酒精溶液)，密度较低的为气体成分(二氧化碳)。
如图7B所示，使用默认管电压80.90kV时，图像灰白，对比度显示尚可，较图7A略差；如图7C所示，当管电压再升高达到89.80kV时，图像灰白程度进一步加重，对比度显示情况较前更差；适当降低管电压到49.90kV时，能够清晰显示PE管内气柱、液柱的排布，图像对比度清晰，如图7A所示。
(三)气-液串联栓塞剂体外DSA成像结果
1.固定DSA检查床；助手匀速向头侧牵拉固定10-1PE管的木板，透视下仅能观察PE管的外形，但无法明确观察其运动情况，亦无法分辨管内气-液成分；进行DSA连续曝光采集的减影图像，可以较为清楚地显示PE管及其内的气液柱间隔特征，表现为明暗相间，明亮(白色)为75％酒精溶液，灰暗(灰黑色)为二氧化碳，并且能够观察其运动情况。气液柱长短间隔肉眼观察呈不均匀排列。
2.向PE管推注安尔碘-氯化钠混合溶液时，透视条件下依然仅能观察PE管的外形，不能明确观察PE管内容物的运动情况及气-液成分；如图8A所示，进行DSA减影状态下连续曝光采集，可清楚显示PE管外形及其内气-液柱间隔特征，亦可以清楚显示PE管内的二氧化碳和酒精溶液往前推进的影像。
3.在加入腹部体模的条件下，10-2号管通过手动牵拉模拟导管前进，并进行DSA减影状态下连续曝光采集获得图像，PE管整体运动的影像能够进行观察，并且能够基本分辨PE管内二氧化碳和酒精溶液间隔组成的影像，如图8B所示；向PE管内推注安尔碘-氯化钠混合溶液时进行DSA减影状态下连续曝光采集获得的影像，可观察PE管内容物被短暂推行前移的过程，但气柱和液柱的间隔则分辨欠清晰。
四、二氧化碳-酒精预充PE管中气-液态的变化观察结果
(一)9根PE管分别在到达实验室满1周时及满2周时进行各管之间气柱及液柱单位长度比较
结果：1.在到达实验室满1周时9根PE管间液柱单位长度进行比较，差异有统计学意义(P＝0.00)2.在到达实验室满1周时9根PE管间气柱单位长度进行比较，差异有统计学意义(P＝0.00)3.在到达实验室满2周时9根PE管间液柱单位长度进行比较，差异有统计学意义(P＝0.00)4.在到达实验室满2周时9根PE管间气柱单位长度进行比较，差异有统计学意义(P＝0.00)。
(二)9根PE管每根管分别在到达实验室满1周时及到达实验室满2周时各管内的气柱单位长度与液柱单位长度比较。
结果：1.管10-1、10-2、10-7、10-8在两个时间点，以及管10-5在到达实验室满2周时，管内气柱单位长度与液柱单位长度比较的差异具有统计学意义(P＜0.05)，且均反应液柱单位长度大于气柱单位长度；2.管10-3、10-4、10-6、10-10，以及管10-5在到达实验室满1周时，管内气柱单位长度与液柱单位长度比较的差异不具有统计学意义(P＞ 0.05)。
(三)9根PE管在到达实验室满1周时与到达实验室满2周时气柱/液柱单位长度的比较
结果：1.在到达实验室满1周时与到达实验室满2周时9根PE管中液柱单位长度比较，差异无统计学意义(P＝0.338)2.在到达实验室满1周时与到达实验室满2周时9根PE管中气柱单位长度比较，差异无统计学意义(P＝0.055)。
(四)9根PE管分别在到达实验室满1周时及满2周时进行管内气柱及液柱总长度比较
结果：1.在9根PE管到达实验室满1周时，对9根管的气柱与液柱总长度比较的差异具有统计学意义(P＝0.041)，管内的液柱总长度大于管内的气柱总长度；2.在9根PE管到达实验室满2周时，对9根管的气柱与液柱总长度比较的差异具有统计学意义(P＝0.039)，管内的液柱总长度大于管内的气柱总长度。
(五)9根PE管在到达实验室满1周时与到达实验室满2周时管内气柱及液柱总长度的比较
结果：1.对比9根PE管在到达实验室满1周时与到达实验室满2周时管内气柱总长度，差异无统计学意义(P＝0.632)；2.对比9根PE管在到达实验室满1周时与到达实验室满2周时管内液柱总长度，差异无统计学意义(P＝0.072)。
管内气、液柱单位长度的比较见表1，管内气、液柱总长度的比较见表1。
表1 管内气柱单位长度与液柱单位长度比较(单位：mm)
Figure PCTCN2021089529-appb-000002
Figure PCTCN2021089529-appb-000003
表2 管内气柱总长度与液柱总长度比较(单位：mm)
Figure PCTCN2021089529-appb-000004
五、结果分析
(一)气-液串联气-液预充PE管的体外数字化X射线摄影
对预充气-液串联栓塞剂的10根导管进行X射线摄影，可较为明确的分辨其中的气、液不同成分，二氧化碳气体成分显示低密度，而无水酒精溶液则显示相对稍高密度，依据两者的密度差从而可以较为清楚地显示管中试剂的气液间隔，得到较为满意的X射线拍摄图片。本实验由于PE管的长度较长，因此需要利用数字化X射线摄影拼接技术得到一张完整的覆盖管全程的拍摄图片。数字化X射线拼接摄影在临床上主要用于脊柱和骨关节的摄影，其目的是为了得到完整的解剖结构图像。本实验X射线摄影采用了球管倾斜角度的摄影方式，得到了理想的拼接图像。
(二)气-液串联栓塞剂体外数字化透视和减影采集观察
本实验利用数字减影血管造影系统(DSA)设备分别使用透视和减影曝光采集两种成像方式对气-液预充PE管进行了观察。PE管固定在木板上整体移动模拟栓塞剂运动进行减影采集的图像，分辨效果明显优于透视，由于实际上PE管内的预充二氧化碳和酒精等没有发生变动，故模拟DSA采集到的图像能清晰辨别PE管内气和液的不同成分，模拟的动态减影影像对气体和液体的显示也比较清楚。
(三)气-液串联栓塞剂经过运输和存储后气、液成分发生的变化
对9根气-液预充PE管在运输后、短时间内不同储存时间点进行观察，得出运输后储存1周和2周后各管之间分别进行气体单位长度及液体单位长度的比较，结果均显示有统计学差异，故认为9根气-液预充PE管内容物的气体及液体单位长度在两个时间点均具有差别。提示PE管内的气液柱长度发生了变化，即气液出现混合的现象。
单独比较9根气-液预充PE管运输后储存1周后液柱单位长度改变，显示差异无统计学意义；独立比较PE管内气体单位长度，同样显示差异 亦无统计学意义，表明运输后储存一周后，PE管内预充的液体量和气体量没有减少；其中酒精挥发量可忽略。对每一根气-液预充PE管在运输后储存满1周和满2周时对其内部的气体及液体单位长度进行比较，结果有1根在存储满2周时出现具有统计学意义的差异；4根差异均无统计学意义，4根差异具有统计学意义；后者又显示为液柱总长度均大于气柱总长度，考虑部分管内气体成分减少。
接到快递送达的9根气-液预充PE管后，它们在原封装袋内，再储存在PP材质保鲜盒内，并放置在20°干燥环境中。气-液预充PE管中气、液成分发生变化的原因可能有以下几点：1.部分二氧化碳在常温下溶于酒精溶液，二氧化碳可以与水发生反应生成碳酸，而生成的碳酸也不稳定从而能够重新分解为水和二氧化碳，两者之间的化学反应为可逆性，因此管中的二氧化碳气体无法维持绝对稳定状态；2.预充气-液串联栓塞剂的PE管两端接头的封闭螺帽的密封性是针对普通液体设计的，可能无法完全密封气体和易挥发的液体；3.实验过程中试剂管的拉伸和卷曲也会造成气、液单元的位置变动。但上述变化并不影响示踪及栓塞效果。
下面介绍本发明所述药物制剂的动物实验的情况。
实验目的：
采用不同配方的气-液串联栓塞剂对实验兔进行肾动脉栓塞实验，观察本发明实施例提供的药物制剂在活体介入手术过程中的可操作性，并通过病理学观察了解各气-液串联栓塞剂的栓塞效果。
一、实验动物：
2只雄性健康普通级新西兰兔，按实验先后顺序分别命名为实验兔1、实验兔2，体重分别为2.0kg(实验兔1)、2.1kg(实验兔2)，由广州市花都区花东信华实验动物养殖场提供(许可证号：SCXK(粤)2019-0023)。单笼常规饲养2～3日适应环境。
二、主要试剂、器材与设备
(一)试剂：
1.气-液串联栓塞剂5种，预充成分和编号见下表3：
表3 气-液串联栓塞剂PE管及预充物
Figure PCTCN2021089529-appb-000005
Figure PCTCN2021089529-appb-000006
2.速眠新II号注射液(2ml:0.2g)：敦化市圣达动物药品有限公司
3. 1％戊巴比妥钠注射液：将1g戊巴比妥钠粉末溶于100ml生理盐水中配置成1％戊巴比妥钠溶液
4.碘克沙醇(320mgI/ml)：美国GE公司，商品名威视派克
5.肝素钠注射液(2ml:12500U)：成都市海通药业有限公司
6.利多卡因(5ml:0.1g)：上海朝晖药业有限公司
(二)器材:
6F桡动脉穿刺套装(AVANTI)：504-616Z，美国强生公司
5F KMP导管：HNB5.0-38-40-P-NS-KMP，美国库克公司
2.7F微导管(Progreat)：MC-PE27131，日本泰尔茂公司
(三)设备：
1.数字减影血管成像系统(DSA)：德国Siemens Axiom Artis dTA悬吊式数字平板血管造影系统
2.自制可调节长度的导管X射线摄影架
三、实验方法
(一)气-液串联栓塞剂的数字化X射线摄影及PE管内液体容积估算
在开展动物栓塞实验前，对本次实验所使用的所有试剂管进行数字化X射线摄影。将栓塞剂管固定于自制导管X射线摄影架，拍摄方法仍采用数字图像拼接方法(详见上述实验)。
对得到的X射线拍摄图片进行管内液柱长度的测量，测量方法同上，同样利用PACS系统内置的直线测量工具，每根管内液柱长度累加即为管内液柱总长度，已知PE管内径为2.0mm，利用圆柱体积公式估算出各PE管内液体容积。
V＝πr 2h
(二)经右颈动脉入路行肾动脉栓塞
1.CO 2+C 2H 6O实验性栓塞
取实验兔1，经兔左后肢肌注速眠新II号0.2ml及经左侧耳缘静脉注射1％戊巴比妥钠2.5ml进行复合麻醉。麻醉成功后，兔足-头位仰卧于DSA检查床，四肢固定于自制实验板上，右侧颈部备皮、消毒、铺巾。沿气管右缘找到右侧颈动脉搏动处，切开皮肤，逐层分离皮下组织，暴露右颈总动脉。在右颈总动脉下方引入2条丝线，分别固定在动脉穿刺点的上下方；局部喷洒少量1％利多卡因浸润，助手轻轻提起两侧丝线固定右颈总动脉，使用21G桡动脉穿刺套针穿刺动脉前壁，穿刺成功退出针芯引入导丝，透视确认导丝在动脉行程内后，退出穿刺针外鞘，沿导丝引入6F导管鞘，用穿刺点下方的丝线结扎固定导管鞘，穿刺点上方的丝线结扎颈动脉防止出血。通过导管鞘旁路注射0.1％肝素盐水5ml防止导管鞘形成血栓。经导丝引入KMP导管至腹主动脉，手推对比剂碘克沙醇进行造影。
选定左肾动脉中下极分支作为栓塞的靶分支，微导丝引导微导管进入靶分支，在透视监视下先缓慢推注1ml碘克沙醇确认微导管在靶分支内，再在微管尾端接上4-5号PE管(CO 2+C 2H 6O)，PE管后端接注射器手动推注碘克沙醇2.5ml。缓慢地全部推出PE管内的二氧化碳+无水酒精，5分钟后复查以碘克沙醇复查靶分支造影，显示靶分支的末梢分支减少。实验过程追加1％戊巴比妥钠2ml维持实验兔镇静。将微导管引入右肾动脉主干进行造影，显示右肾动脉主干管径痉挛变细，因此未对右肾动脉进行栓塞试验。
2.CO 2+75％C 2H 6O+Na 2CO 3实验性栓塞
取实验兔2；靶动脉：左肾动脉。实验步骤同前：实验兔麻醉、消毒、暴露和穿刺右侧颈动脉、引入KMP导管至腹主动脉造影。微导管进入左肾动脉主干，在透视监视下先推注1ml碘克沙醇，在微管尾端接气-液串联栓塞剂4-3号管(CO 2+75％C 2H 6O+Na 2CO 3)，栓塞剂管后端接注射器手推碘克沙醇4ml。随后用相同方法注射相同成分的气-液串联栓塞剂4-4号管(CO 2+75％C 2H 6O+Na 2CO 3)，靶动脉同样为左肾动脉，栓塞剂管后端接注射器手推对比剂约3ml。
3.CO 2+75％C 2H 6O实验性栓塞
继续使用实验兔2；靶动脉：右肾动脉。微导管进入右肾动脉主干， 在透视监视下先推注1ml碘克沙醇，将微管后端接气-液串联栓塞剂4-1号PE管(CO 2+75％C 2H 6O)，PE管后端接注射器推注碘克沙醇3ml，推注时观察气-液串联栓塞剂在以碘克沙醇为参照的情况下的显影情况。随后直接用3ml碘克沙醇推注相同成分的气-液串联栓塞剂4-2号管(CO 2+75％C 2H 6O)，靶动脉同样为右肾动脉。右肾动脉栓塞后立即复查DSA，可观察到右肾动脉远端分支显影均消失。
实验兔2左右肾动脉栓塞完成后，引导微导管进入左肾动脉主干以碘克沙醇复查造影，左肾动脉远端分支均亦未见显影。相隔5分钟后将微导管置于腹主动脉进行造影复查，观察到右肾动脉及大部分分支尚可见显影。
(四)病理学检查：
实验兔1和实验兔2均在栓塞术完成后即刻处死，对实验兔进行解剖并取出双侧肾脏，观察其外观变化，随后将栓塞侧肾脏标本放入10％福尔马林溶液内固定12小时，并于次日取出双肾标本，从肾门分别沿冠状面及横断面进行切割，共分割为四部分，将每侧肾标本分为上腹侧、上背侧、下腹侧和下背侧，随后将标本进行石蜡包埋，并对其进行常规HE染色，以及弹力纤维染色，并于光学显微镜下观察，记录发生的病理学改变。
实验结果
一.PE管内液体容积估算结果
各PE管内液体成分容积估算结果见表4。
表4 PE管内液体容积估算
出厂编号 管内液柱总长度(cm) 管内液体容积估算值(ml)
4-1 59.13 1.86
4-2 78.76 2.47
4-3 75.37 2.37
4-4 77.32 2.43
4-5 77.08 2.43
二.病理观察结果
(一)外部观察表现：
1.实验兔1：
栓塞后即刻观察：栓塞侧肾脏(即左肾)肿胀，长径约3.4cm，横径约2.2cm；未栓塞侧肾脏(即右肾)长径约3.1cm，横径约2.1cm；肾脏 表面尚光滑，缺血区即左肾中下份呈大片状暗黄色改变(图9A)。
浸泡福尔马林12小时后取出标本观察：栓塞侧肾脏(即左肾)体积基本同前，长径约3.4，横径约2.1cm；栓塞侧肾脏(即左肾)皮髓质分界清晰，中下份缺血区呈灰黄色改变(图9B、9C)。
2.实验兔2：
栓塞后即刻观察：双肾肿胀，左肾长径约2.8cm，横径约1.8cm；右肾长径约2.9cm，横径约1.9cm；双肾表面尚光滑，双肾可见散在斑片、斑点状暗黄色缺血区(图10A)。
浸泡福尔马林12小时后取出标本观察：双肾体积较前增大，左肾长径约3.1cm，横径约2.0cm；右肾长径约3.3cm，横径约2.2cm；双肾皮髓质分界尚清，双肾呈不均匀灰黄色缺血改变(图10B、10C、10D)。
(二)镜下表现：
1.实验兔1：
HE染色：左肾上背侧可观察到肾小管上皮细胞水肿变性，小动脉管壁水肿；肾小球及肾间质未见明确病理改变(图11A)。
弹力纤维染色：左肾上背侧可观察到极个别动脉管壁弹力纤维断裂(图11B)。
2.实验兔2：
HE染色：①右肾上背侧可见几个小灶性肾皮质梗死区，肾小管细胞水肿变性，近曲小管上皮细胞刷状缘消失，细胞胞浆内出现淡染颗粒，细胞呈颗粒变性改变；梗死区肾小球细胞核碎裂、溶解，呈现细胞坏死后改变；肾间质未见明确病理改变(图12A)。②左肾可见部分出现肾小管上皮细胞出现水肿变性；肾小球及肾间质未见明确病理改变(图12B)。
三、三种不同示踪药物制剂对肾脏的病理作用讨论
本实验首次尝试使用二氧化碳为对比剂，分别携带三种以酒精为基础的化学栓塞剂进入肾动脉，初步观察无水酒精、75％酒精+碳酸钠、75％酒精对肾动脉和肾组织产生的病理改变。
(一)无水酒精
本实验中兔1的左肾在使用二氧化碳+无水酒精进行肾动脉注射即刻，肉眼即可观察到大面积的缺血改变，但镜下未发现相应的肾皮质细胞坏死，与病理科医生讨论后，推测无水酒精注射后到标本获取和固定的时间较短，肾缺血区细胞尚未发生坏死改变；而肾小管对缺血更为敏 感，故镜下的病理改变主要集中在肾小管，表现为肾小管上皮细胞变性水肿；小动脉管壁水肿考虑与无水酒精损伤有关，而动脉管壁部分弹力纤维断裂的改变在镜下不是普遍现象，目前尚未能确定是否为无水酒精作用的后果，或为实验兔血管壁退行性变。
(二)75％酒精
本实验中尝试以75％酒精对肾动脉进行注射，并于栓塞后即刻取标本进行病理学观察，根据观察结果，75％酒精经肾动脉注射后引起了肾小管上皮变性，以及小动脉壁水肿，甚至其中一个肾出现了灶性梗死改变，其病理学改变与无水酒精所致的病理改变相似。75％酒精用作消毒，其机理包括(1)引起细菌细胞的高渗脱水，酒精分子能够作用于蛋白质分子的肽链环节，导致蛋白质发生变性沉淀，这种作用在70％的含量时更为显著；(2)60％～85％的酒精比较容易渗透到菌体内，使细菌细胞破坏溶解；
(3)对微生物酶系统具有破坏作用：酒精通过抑制细菌酶系统，特别是氧化酶和脱氢酶等，阻碍正常代谢从而抑制细菌生长。
(三)75％酒精混合碳酸钠
本实验在75％酒精溶液中创新性加入碳酸钠，目的是希望利用碳酸钠与溶液中水反应生成碳酸根，使栓塞剂中含有碱性成分，实现酸碱平衡的栓塞。但本实验使用健康兔作为试验的对象，初步得到的结果与单纯75％酒精及无水酒精相仿。
综上所述，实验配方中的三种血管介入示踪药物制剂，均可致肾小管细胞变性、坏死，导致小动脉壁水肿。
<第二实验>
实验目的：
2.1观察该配比气液栓塞剂在透视下的可见度，是否可以清晰观察到气液流的流动方向，停滞或返流。
2.2观察该配比气液栓塞剂注射到血管内对局部血流产生的影响：如，血流缓慢、血流停滞或中断，
栓塞后局部血管的DSA和超声的影像数据。
2.3根据实验结果寻找最佳的气液栓塞剂配比和栓塞剂用量。
三、实验过程观察
3.1选择实验兔左侧肾动脉，用生理盐水推注二氧化碳造影剂，使用B超动态监测气柱通过动脉-实质的运行情况，观察记录以下信息：
(1)血流速度变化。
(2)二氧化碳吸收情况。
(3)血流基本恢复时间。
3.2依情况对左右侧肾脏交替注射。
3.3待二氧化碳完全吸收，超选左侧肾动脉进行栓塞前造影，然后进行酒精栓塞剂注射，手动缓慢推注行DSA观察，气液栓塞剂进入目标血管，流动逐步缓慢直至停止或有少量返流，观察该过程在透视下的清晰程度，并记录推注到目标血管的栓塞剂量。
3.4栓塞注射完成后即刻造影观察，并进行5分钟后，15分钟后，30分钟后造影观察目标血管及其分支栓塞结果。
3.5对右侧肾脏和肝脏依次进行酒精栓塞观察，进一步收集数据。
3.6对颈总动脉和颈外动脉先后进行酒精栓塞观察。
3.7栓塞实验完成后对实验兔肾脏和肝脏进行标本制作，以作病理分析。
五：实验过程
5.1于2020年08月04日进行第一次新型栓塞剂动物实验
5.1.1气液栓塞剂样品明细：
二氧化碳造影剂，2支；
导管，材质为特氟龙，内径2mm，外径2.4mm，长度1000mm；
填充物，如下表所示
Figure PCTCN2021089529-appb-000007
5.2.2本次气液制剂使用稀释至75％的造影剂，在透视下可清晰显示。
5.2.3左肾动脉注射二氧化碳-盐水-造影剂，30微升二氧化碳进入血管，3分钟后超声观察气体基本吸收，血流正常。
5.2.4左肾动脉栓塞前先造影，推注新型栓塞剂，栓塞剂开始进入血管时注射器刻度为1.5ml，发现血液返流时注射器刻度为0.8ml，总计0.7ml栓塞剂进入目标血管中，其中含75％酒精约350微升，二氧化碳约240微升，DSA下观察图像清晰，注射后5分钟造影注入，显示整个肾脏基本栓塞。
5.2.5右肾动脉栓塞前造影，推注新型栓塞剂，栓塞剂开始进入血管时注射器刻度为2.0ml，发现血液返流时注射器刻度为1.2ml，总计 0.8ml栓塞剂进入目标血管中，其中含75％酒精约300微升，二氧化碳约300微升，DSA下观察图像清晰，注射后5分钟造影剂注入，对肾脏血管末梢栓塞更为彻底，少量酒精进入远端静脉。
5.2.6肝动脉注射二氧化碳-盐水-造影剂，2.5分钟后门静脉出现连续气泡。
5.2.7肝动脉注射栓塞剂，直至血液返流注射栓塞剂1.2ml，其中含75％酒精约500微升，二氧化碳约600微升，注射5分钟进行造影剂注入观察栓塞情况，显示肝动脉栓塞完全。
5.2.8颈动脉注射栓塞剂，直至血液返流注射栓塞剂1.2ml，其中含75％酒精约500微升，二氧化碳约600微升。注射5分钟进行造影剂注入观察栓塞情况，显示颈动脉栓塞完全。
5.2.9此次实验总结：
5.2.9.1气液栓塞剂注入肝动脉，门静脉出现连续气泡，此现象需要再进一步实验进行寻找原因。
5.2.9.2肝脏、肾脏及颈外动脉栓塞后未进行即时、5分钟及10分钟的造影观察，未进行排除栓塞的具体原因
5.3于2020年08月20日进行第三次新型栓塞剂动物实验
5.3.1气液栓塞剂样品明细：
Figure PCTCN2021089529-appb-000008
5.3.2左肾，右肾，肝脏行B超观察基础情况。
5.3.3左肾动脉注射二氧化碳-生理盐水，22微升二氧化碳进入血管， 2分钟后超声观察气体基本吸收，血流正常。
5.3.4左肾动脉，使用导管1，栓塞前造影，推注栓塞剂，栓塞剂开始进入血管直至血液返流时注射器刻度分别为1.7ml，1.5ml，共计0.2ml栓塞剂进入目标血管，其中含75％酒精约160微升，气液清晰度理想。观察可见左肾上极栓塞而下极未栓塞，初步判断可能性为：微导管内的生理盐水-气体随血流先行进入左肾下极，形成一定阻碍使得后面推注的酒精基本进入左肾上极。
5.3.4.1左肾栓塞后即刻的造影图像见图15A，超声显示血流基本消失(图15B)。
5.3.4.2左肾栓塞后5分钟的造影图像见15C。
5.4对肝动脉推注气液栓塞剂，使用导管2-4，至血液返流时观察注射栓塞剂4.2ml，其中含有75％酒精约1100微升。
5.4.1肝脏栓塞前造影见图15D。
5.4.2肝脏栓塞后5分钟造影见图15E。
5.5对颈动脉推注气液栓塞剂，使用导管5，在注射的气液栓塞剂中含75％酒精约400微升，二氧化碳约600微升。通过DSA观察，有部分酒精和二氧化碳进入远端颈内静脉中。
5.5.1颈内动脉栓塞前造影见图15F。
5.5.2颈内动脉栓塞后即刻造影见图15G，显示颈内动脉栓塞完全。
需要强调的是，在上述说明中只是为了使描述更清楚，才区分各个实施例，以及各个实验数据。本领域普通技术人员可以理解，各个实施例中的导管内的填充物配方、各种规格的导管、手术现场在导管中注入常温溶解度低于1％的液态或气态的填充物的方式或者是通过仓储运输之后的导管(导管内已预装了溶解度低于1％的液态或气态的填充物)的方式等，可以组合成新的技术方案，并不限于上述实施例中的组合方案。
上面对本发明所提供的具有示踪功能的药物制剂及其输送系统进行了详细的说明。对本领域的一般技术人员而言，在不背离本发明实质内容的前提下对它所做的任何显而易见的改动，都将构成对本发明专利权的侵犯，将承担相应的法律责任。

Claims (12)

  1. 一种具有示踪功能的药物制剂，包括用于盛装示踪药物的导管和管头，其特征在于：
    所述导管内设置有液态或气态的第一药物和第二药物，所述第一药物和所述第二药物各自分为多段在所述导管内间隔串联设置；
    所述第一药物和所述第二药物中的一个为在人体内可在医学影像设备显影的示踪药物；
    所述第一药物和所述第二药物之间不互溶、难溶或微溶，且满足本领域可接受的治疗配伍要求。
  2. 如权利要求1所述的药物制剂，其特征在于：
    所述第一药物为造影剂，所述第二药物为气态隔离剂。
  3. 如权利要求1所述的药物制剂，其特征在于：
    位于所述导管的两端的是液态的第一药物或第二药物。
  4. 如权利要求1所述的药物制剂，其特征在于：
    所述导管内还设置有气态或液态的多段第三药物，
    所述第三药物设置在所述第一药物和所述第二药物之间；
    所述第三药物与所述第一药物和所述第二药物均不互溶，所述第三药物符合本领域可接受的配伍要求；所述第三药物与所述第二药物符合配伍要求。
  5. 如权利要求4所述的药物制剂，其特征在于：
    所述第一药物为示踪药物为液态造影剂，并且位于所述导管的两端；
    所述第二药物是气态隔离剂，并且所述第二药物的每一段的两侧均为所述第一药物；
    所述第三药物是栓塞剂或灌注剂，并且所述第三药物的每一段的两侧均为所述第二药物；
    所述导管内从端部起以所述第一药物、第三药物、第二药物、第三药物的排列方式作为一个单元进行重复排列直至所述导管另一端为所述第一药物为止。
  6. 如权利要求5所述的药物制剂，其特征在于：
    所述第一药物是无水碘造影剂，所述第二药物是二氧化碳，所述第三药物是酒精。
  7. 一种有氧造影剂，其特征在于包括导管和管头，所述导管内设置有氧气和液态的造影剂，所述氧气和所述造影剂各自分为多段且在所述导管内间隔串联设置；
    所述氧气和液态的造影剂不互溶、难溶或微溶，并且满足本领域可接受的治疗配伍要求。
  8. 一种有氧栓塞剂，其特征在于包括导管和管头，所述导管内设置有氧气、液态的造影剂和液体栓塞剂，所述氧气、所述造影剂及所述栓塞剂各自分为多段，并且所述造影剂及所述栓塞剂通过所述氧气在所述导管内间隔串联设置；
    所述氧气、液态的造影剂和液体栓塞剂不互溶、难溶或微溶，并且满足本领域可接受的治疗配伍要求。
  9. 一种有氧灌注剂，其特征在于包括导管和管头，所述导管内设置有氧气、液态的造影剂和液体灌注剂，所述氧气、所述造影剂及所述灌注剂各自分为多段，并且所述造影剂及所述栓塞剂通过所述氧气在所述导管内间隔串联设置；
    所述氧气、液态的造影剂和液体灌注剂不互溶、难溶或微溶，并且满足本领域可接受的治疗配伍要求。
  10. 一种具有示踪功能的药物制剂的输送系统，包括依次连接的注射泵、导管、鞘管座以及穿刺针，其特征在于：
    所述导管是权利要求1～11中任意一项所述的导管。
  11. 如权利要求10所述的输送系统，其特征在于：
    所述导管通过鲁尔接头与所述注射泵和所述鞘管座连接。
  12. 如权利要求10或11所述的输送系统，其特征在于：
    所述导管的内径大于或等于所述导管鞘的内径。
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