CN114984252A - Application of poloxamer in-vivo ultrasonic coupling agent and ultrasonic coupling agent - Google Patents
Application of poloxamer in-vivo ultrasonic coupling agent and ultrasonic coupling agent Download PDFInfo
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Images
Classifications
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
- A61B8/12—Diagnosis using ultrasonic, sonic or infrasonic waves in body cavities or body tracts, e.g. by using catheters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
- A61B8/42—Details of probe positioning or probe attachment to the patient
- A61B8/4272—Details of probe positioning or probe attachment to the patient involving the acoustic interface between the transducer and the tissue
- A61B8/4281—Details of probe positioning or probe attachment to the patient involving the acoustic interface between the transducer and the tissue characterised by sound-transmitting media or devices for coupling the transducer to the tissue
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B2503/00—Evaluating a particular growth phase or type of persons or animals
- A61B2503/40—Animals
Abstract
The invention discloses an application of poloxamer in an in-vivo ultrasonic couplant and the ultrasonic couplant, wherein the in-vivo ultrasonic couplant is temperature sensitive gel, the ultrasonic couplant is in a liquid state below the gel transition temperature of the ultrasonic couplant, and the ultrasonic couplant is in a gel state above the gel transition temperature of the ultrasonic couplant and has acoustic characteristic impedance matched with human tissues. The ultrasonic coupling agent has the following advantages: the gel has the property of temperature control and gelling, is liquid at relatively low temperature, can be rapidly gelled at body temperature when being injected into a lesion part in a body, and has the basic performance requirements of a common ultrasonic coupling agent, less ultrasonic energy loss and high ultrasonic image definition; the medicament has no toxicity, can be applied in vivo, has good biocompatibility, can be smoothly and naturally discharged through the body lumen, and can not block the body natural lumens such as esophagus, gastrointestinal tract, pancreatic bile duct, urethra, ureter and the like; has acid and alkali resistance.
Description
Technical Field
The invention belongs to the technical field of medicines, relates to an auxiliary preparation for medical examination, and particularly relates to an application of poloxamer in an in-vivo ultrasonic coupling agent and the ultrasonic coupling agent.
Background
The ultrasonic examination is a noninvasive imaging examination method widely used in clinic, and can observe the pathological tissue forms of subcutaneous tissues and internal organs. However, most of the ultrasonic examinations are performed on the body surface, and for some small organs or small tissue lesions in the body, a method of performing an examination by feeding an ultrasonic probe through a natural lumen of the human body, such as vaginal B-ultrasound, Endoscopic Ultrasound (EUS), and the like, has been developed in recent years. The endoscope ultrasonic examination operation can clearly display five-layer structures on the wall of the digestive tract by leading the ultrasonic probe into the ultrasonic probe through an endoscope biopsy channel or carrying the ultrasonic probe at the tip of the endoscope for examination, and has high diagnostic value on the lesion of the wall of the digestive tract and the lesion of adjacent organs around the digestive tract. The ultrasonic probe is positioned at the front end of the endoscope, and can simultaneously carry out electronic endoscope and ultrasonic examination, and in the ultrasonic endoscope examination, a medium is required to fill the space in the probe and the tube cavity, so that diagnosis can be finished. Currently, the most common medium is degassed water. However, water storage is difficult due to the high mobility of water and the stimulation of gastrointestinal motility, especially in the esophagus and duodenum lumen. At this time, in order to complete the examination, the digestive lumen needs to be continuously filled with water. The operation and the ultrasonic endoscope diagnosis are greatly influenced, and simultaneously, complications such as abdominal distension, abdominal pain and the like and even the risk of aspiration are likely to occur due to rapid and large-amount water injection. The traditional ultrasonic couplant clinically used at present is mainly used for body surface ultrasonic examination, is in a gel state, and is inconvenient to deliver into a body through a long and narrow pipeline in an injection mode due to the viscous texture. No special coupling agent for EUS approved by the national drug administration exists in China. Therefore, the development of an injectable, safe and reliable couplant special for in vivo ultrasound is urgently needed in clinic.
Disclosure of Invention
In view of the above, an object of the present invention is to provide an application of poloxamer in an ultrasonic couplant in vivo.
The technical scheme is as follows:
the application of poloxamer or its derivatives in the preparation of in vivo ultrasonic couplant is characterized in that the in vivo ultrasonic couplant is temperature sensitive gel, the ultrasonic couplant is in liquid state below the gel transition temperature of the in vivo ultrasonic couplant, and the ultrasonic couplant is in gel state above the gel transition temperature of the in vivo ultrasonic couplant, and has acoustic characteristic impedance matched with human tissues.
In one embodiment, the ultrasound coupling agent has a gel transition temperature of either between 10 ℃ and 37 ℃, or between 15 ℃ and 37 ℃, or between 20 ℃ and 37 ℃, or between 25 ℃ and 37 ℃, or between 30 ℃ and 37 ℃, or between 35 ℃ and 37 ℃.
The second purpose of the invention is to provide a temperature-sensitive ultrasonic couplant. The technical scheme is as follows:
an in vivo ultrasound coupling agent is characterized by comprising poloxamer or a derivative thereof and a pharmaceutically acceptable solvent, wherein the poloxamer or the derivative thereof is dissolved in the solvent to form the ultrasound coupling agent;
the ultrasonic couplant is temperature-sensitive gel, the gel transition temperature of the ultrasonic couplant is between 10 ℃ and 37 ℃, the ultrasonic couplant is in a liquid state below the gel transition temperature, and the ultrasonic couplant is in a gel state above the gel transition temperature;
the poloxamer derivative is selected from one or more of products modified by sulfhydrylation, carboxylation, amination, etherification, carboxymethylation or hydroxypropylation.
In one embodiment, the gel transition temperature of the ultrasonic couplant is between 25 ℃ and 37 ℃.
In one embodiment, the gel transition temperature is between 35 ℃ and 37 ℃.
In one embodiment, the poloxamer or derivative thereof has a molecular weight of 12600-14600 daltons.
In one embodiment, the upper solvent is any one of deionized water, physiological saline, balanced salt solution, glucose solution, or sterile pyrogen-free water.
In one embodiment, the viscosity of the ultrasonic coupling agent is 100-1000Pa & s in a liquid state; the viscosity of the ultrasonic couplant is 10,000-80,000 Pa.s in a gel state.
In one embodiment, the poloxamer is present in an amount of 10% to 30% by weight.
It is a further object of the present invention to provide a couplant delivery assembly. The technical scheme is as follows:
the couplant conveying assembly is characterized by comprising a packaging container, wherein the ultrasonic couplant is contained in the packaging container; preferably, the packaging container is a squeeze-type container or a piston-type container with a liquid outlet, so as to allow the ultrasonic coupling agent to be discharged from the liquid outlet when the packaging container is pressed or the piston is pushed.
Preferably, the liquid outlet of the packaging container is connected with a conduit.
Drawings
FIG. 1 is a plot of viscosity versus temperature for several different examples of aqueous poloxamer solution samples;
FIG. 2 is a graph of the time for which samples of the aqueous poloxamer solution of example 12 form gels at different pH;
FIG. 3 is an ultrasonic imaging experiment operation scene diagram of the ultrasonic coupling agent used for a piglet esophageal lesion model and an endoscope picture of the ultrasonic coupling agent injected into an esophagus;
FIG. 4 is an EUS image of a normal esophagus of a small fragrant pig using the ultrasonic coupling agent of the present invention;
FIG. 5 is an EUS image of the ultrasonic couplant used under a piglet esophageal lesion model;
fig. 6 is an EUS image of a control group of the present invention, which was continuously perfused with normal saline in the esophagus and used in a small-scented pig esophageal lesion model.
Detailed Description
The present invention will be further described with reference to the following examples and the accompanying drawings.
Definition of terms
The term "biocompatibility" as used herein refers to a property of living body tissues in response to an inactive material, and generally refers to compatibility between the material and a host, and the evaluation of biocompatibility mainly follows the principle of biosafety, i.e., the elimination of destructive properties of the biological material on human tissues and organs, such as sensitization, cytotoxicity and carcinogenicity, and further, depending on the site of use, if it is directly applied to tissues and organs in the human body, the material is required to be degradable and/or absorbable by body tissues. The biocompatible ultrasonic couplant for the endoscope can be used for ultrasonic endoscopy in the body cavity of a human body, so that the biocompatible material in the invention has no cytotoxicity, carcinogenicity and sensibility, and completely conforms to the principle of biosafety.
The term "pharmaceutically acceptable solvent" as used herein means a solvent which does not cause any toxic or adverse side effects upon application to the human body and which is compatible with the active ingredient in which it is dissolved and/or suspended and/or complexed and/or mixed.
The chemical name of poloxamer is polyoxyethylene polyoxypropylene ether block copolymer, and the molecular formula is HO (C) 2 H 4 O)m·(C 3 H 6 O) n.H, is a pharmaceutical compound approved by the FDA in the United states, has excellent biocompatibility and safety, and can be absorbed/degraded in vivo.
The various aspects of the present invention will be described in detail with reference to specific examples, which are provided for illustration only and are not intended to limit the scope and spirit of the present invention.
Temperature-controlled colloid-forming ultrasonic coupling agent
Poloxamer aqueous solutions have long been known for their temperature sensitive properties, and some gel-type drugs have been developed by taking advantage of their temperature sensitive properties. In order to study the gel forming performance of poloxamer water-based solutions with different molecular weights and different concentrations, poloxamer with different commercial grades is purchased. Weighing a certain amount of poloxamer, and respectively dissolving the poloxamer in deionized water to prepare solutions with the mass concentration of 10-30%. Wherein the poloxamer raw materials are listed in examples 1-17 in Table 1 respectively, and the trade name and molecular weight of the poloxamer raw materials are given in Table 1. The gel forming property and the viscosity of the product at the temperature of 0-45 ℃ are tested by a rheometer. Table 1 lists the physical and chemical parameters for gel forming properties of the solutions prepared in examples 1-17.
TABLE 1 composition and gelling Properties of Poloxamer solutions of different molecular weights, concentrations
As can be seen from Table 1, poloxamer F68, which is a 10% to 30% by weight aqueous solution, did not form a gel between 0 and 45 deg.C within the test range.
As can be seen from Table 1 and FIG. 1, for the samples of examples 10-18, i.e., the poloxamer F127 aqueous solution with the concentration of 10% -30%, when the mass concentration of the solution reaches 15%, gel can be formed at 31.2-35 ℃, and the viscosity of the gel is 1.37 × 10 4 Pa · s. The gel transition was very rapid and the gel formed within 10 seconds after the gel transition temperature was reached. And as the concentration increases, the gel transition temperature gradually decreases, and the gel viscosity gradually increases.
The gelation property of poloxamer F108 aqueous solution is similar to that of poloxamer F127 aqueous solution, when the concentration mass reaches 17.5%, the gelation temperature is 38 deg.C, and the gel viscosity is 1.70 × 10 4 Pa.s, the gel transition temperature gradually decreases with the increase of the concentration, the gelling temperature of the 30 percent aqueous solution is 18 ℃, and the viscosity of the formed gel is 6.01 multiplied by 10 4 Pa·s。
According to the research result of the gel forming performance, the samples capable of forming gel at 0-45 ℃ are preliminarily considered to have the potential of being used as temperature-sensitive ultrasonic couplants. Based on this, samples of examples 12 to 14 and 21 to 24 were taken, and acoustic performance tests were performed according to the method specified in the industry standard (YY0299-2016) for medical ultrasonic couplants, and the results are shown in table 2.
TABLE 2 comparison of acoustic parameters in the gel state of some samples with standards
As can be seen from Table 2, the sound velocity of the gel formed by the samples with different concentrations is 1520-1620 m/s, the slope of the sound attenuation coefficient is less than or equal to 0.1 dB/(cm-MHz), and the sound characteristic impedance is 1.5 multiplied by 10 6 ～1.7×10 6 Pa · s/m. Therefore, the gel formed by the samples has good impedance matching with the acoustic characteristic of the tissues in the human body cavity, has small acoustic attenuation, and is suitable for being used as a couplant for ultrasonic endoscopy.
Within the allowable gelling concentration range, the gel transition temperature can be changed by changing the concentration of the solution, and the ultrasonic couplant disclosed by the invention has good temperature control property.
In the preparation of the ultrasonic coupling agent, besides deionized water, physiological saline, balanced salt solution, glucose solution or sterile pyrogen-free water can be used as a solvent.
In addition, because the temperature sensitivity of the poloxamer solution is derived from the fact that molecules of the poloxamer solution have hydrophilic and hydrophobic segments at the same time, and the strength of intermolecular hydrogen bond acting force is changed under different temperature conditions, when the ultrasonic coupling agent is prepared, besides monomeric poloxamer, poloxamer modified by sulfhydrylation, carboxylation, amination, etherization, carboxymethylation, hydroxypropylation and the like can be used, as long as the gel forming performance of the poloxamer derivative solution is not influenced by the modified substitution.
When the ultrasonic couplant is prepared, a pharmaceutically allowable amount of functional auxiliary agents can be added into the solution, such as one or more of pH regulator, lubricant, humectant, dye, antibacterial agent, filler, therapeutic agent, preservative, disinfectant, stabilizer and defoaming agent.
pH stability of ultrasound coupling agent
A sample of example 12 was taken and a small amount of stain was added to form a pale blue gel at 37 ℃. The pale blue gels were placed in equal volumes of solutions at pH 1, 4, 7 and 10, respectively, and observed for gelling stability over time. As shown in FIG. 2, the sample can stably exist for 120min at different pH values, which shows that the ultrasonic couplant of the invention has good stability at different pH values. Considering that the pH range distribution in the natural cavity of the human body is wide, for example, in the digestive tract, the stomach is in a strong acid environment, and the small intestine is in a weak alkaline environment, so the pH stability requirement of the ultrasonic couplant is high. The sample of this example fully meets the in vivo ultrasound couplant use requirements.
Sterilization of ultrasonic coupling agent
The gel-forming sample is contained in a container and is sterilized by using a conventional sterilization mode, such as radiation, ozone, ethylene oxide or moist heat, and the like, without influencing the gel-forming performance and acoustic performance parameters, thereby indicating that the conventional sterilization mode is feasible.
Ultrasonic couplant delivery assembly
In order to facilitate clinical use, the ultrasonic couplant can be packaged by a medical elastic polymer tube or an injector, and a liquid outlet of the tube or the injector is plugged. When the ultrasonic couplant is used, the liquid outlet is opened and is connected to a liquid feeding channel of the endoscope, and the liquid ultrasonic couplant is injected into an internal cavity of a human body or an animal body. In order to facilitate the use, the catheter can be also configured, the catheter is connected with the liquid outlet, and the ultrasonic coupling agent is injected into the cavity of the human body or the animal body through the catheter.
Animal experiment by ultrasonic endoscopy
The gel-forming sample is used for Bama miniature pig endoscope ultrasonic examination, and the ultrasonic coupling effect is inspected.
Experimental materials: the samples of examples 11-14, 22-25 were used as ultrasonic couplants;
experimental animals: bama miniature pig, weight 25 kg;
the test method comprises the following steps: the whole numb back of the Bama miniature pig lies on the side of the operating table, and the four limbs are fixed. The esophagus lesion model is constructed by entering the esophagus from the mouth by means of an electronic gastroscope or a double-channel gastroscope and directly injecting 2ml of normal saline under the mucosa of the pig esophagus to enable the mucosa to bulge. Then, any ultrasonic couplant of the invention is applied to the mucosa swelling section of the esophagus through a conveying catheter through a working channel of a gastroscope, the dosage is within 20ml, a control group is continuously perfused with normal saline, the dosage is 100 plus 200ml, the probe is detected by an ultrasonic probe (12-20MHz) of an olympus or Fuji endoscope, and the definition of an ultrasonic image is recorded and compared.
Fig. 3 illustrates an experimental operation scene of the ultrasound coupling agent of example 12 used for a small fragrant pig esophageal lesion model and an endoscopic picture of the ultrasound coupling agent injected into the esophageal tract. It can be seen that this ultrasound coupling agent is easily injected into the esophagus and forms a gel soon after entering the esophagus.
As shown in figure 4, the endoscope ultrasonic image of the normal esophagus of the small fragrant pig can be seen, a clearer esophageal wall ultrasonic image can be obtained, and noise is less.
An endoscopic ultrasound image of the small fragrant pig esophageal lesion model is shown in fig. 5, wherein a darker area in the esophageal wall, namely a part indicated in a yellow dotted line in the right graph, can be clearly distinguished, and is an occupying model formed by injecting physiological saline in the esophageal wall. In contrast, the esophagus was continuously perfused with saline, and as shown in fig. 6, the darker area in the esophageal wall, i.e., the portion indicated by the yellow dashed line in the right-hand figure, is a space occupying model formed by injecting saline into the esophageal wall, and the space occupying border is slightly inferior to that shown in fig. 5.
The results of endoscopic ultrasonic animal experiments show that the ultrasonic coupling agent has good injectability, can gradually increase the temperature after entering the animal body cavity to form gel, and shows good ultrasonic coupling effect.
It will be readily understood by those skilled in the art that the intracorporeal ultrasound coupling agents can be used for endoscopic ultrasound imaging of the respiratory tract, urinary system, reproductive system, etc., in addition to ultrasound imaging of the digestive tract.
The ideal coupling agent is in a liquid state at room temperature (25 ℃) before entering a patient body, the injection resistance is similar to water, and once entering the human body, the liquid components are quickly gelatinized in the environment of 35-37 ℃ of the human body. Considering the EUS inspection time, the couplant needs to maintain the gel state for 30 minutes or more. Meanwhile, as the coupling agent enters the body cavity, all the coupling agents also have the following characteristics: safe and nontoxic, has good biocompatibility, and can be applied to natural cavities and tracts of human bodies and minimally invasive surgery.
In many of the examples given herein, some of the samples of the examples have a gel transition temperature that is lower than the body temperature of a human, e.g., between 10 ℃ and 25 ℃, and may be in a gel state at room temperature. Before use, the sample can be kept at 4 ℃ for a period of time to maintain the liquid state, and is taken out and injected quickly when in use, and the sample gradually heats up in the process of entering the cavity of the human body or the animal body, and can quickly form gel to meet the requirement of ultrasonic examination, so the ultrasonic couplant has potential application. However, it is easier to use an ultrasonic couplant with a gel transition temperature of 25 ℃ to 37 ℃, more preferably an ultrasonic couplant with a gel transition temperature of 30 ℃ to 37 ℃.
The invention has the beneficial effects that:
the poloxamer solution as the ultrasonic couplant for in vivo use has the following advantages:
(1) after the gel is formed, the gel has the basic performance requirements of the common ultrasonic coupling agent, the ultrasonic energy loss is less, and the ultrasonic image definition is high;
(2) the gel has the property of temperature control and gelling, is liquid at relatively low temperature, and can rapidly gel at body temperature when being injected into a lesion part in a body;
(3) non-toxic, capable of in vivo application, good biocompatibility, absorbable (can be fully absorbed/degraded in the human body);
(4) can not block the esophagus, the gastrointestinal tract, the pancreatic bile duct, the urethra, the ureter and other natural body cavities;
(5) the endoscope is convenient to use, is liquid when the temperature is lower than the body temperature, and can be easily injected into a cavity in a body through an endoscope working channel (such as a biopsy forceps channel);
(6) the ultrasonic probe and the endoscope are not corroded or damaged;
(7) has acid and alkali resistance;
(8) the flushing is easy, and the working channel of the endoscope can not be blocked;
(9) the sterilization is easy to realize, and the aseptic requirement is met;
(10) the price is reasonable and easy to obtain.
Finally, it should be noted that the above-mentioned description is only a preferred embodiment of the present invention, and that those skilled in the art can make various similar representations without departing from the spirit and scope of the present invention.
Claims (10)
1. The application of poloxamer or its derivatives in the preparation of in vivo ultrasonic couplant is characterized in that the in vivo ultrasonic couplant is temperature sensitive gel, the ultrasonic couplant is in liquid state below the gel transition temperature of the in vivo ultrasonic couplant, and the ultrasonic couplant is in gel state above the gel transition temperature of the in vivo ultrasonic couplant, and has acoustic characteristic impedance matched with human tissues.
2. Use according to claim 1, characterized in that: the gel transition temperature of the ultrasonic couplant is between 10 ℃ and 37 ℃, or between 15 ℃ and 37 ℃, or between 20 ℃ and 37 ℃, or between 25 ℃ and 37 ℃, or between 30 ℃ and 37 ℃, or between 35 ℃ and 37 ℃.
3. An in vivo ultrasound couplant, comprising: the ultrasonic couplant comprises poloxamer or a derivative thereof and a pharmaceutically acceptable solvent, wherein the poloxamer or the derivative thereof is dissolved in the solvent to form the ultrasonic couplant;
the ultrasonic couplant is temperature-sensitive gel, the gel transition temperature of the ultrasonic couplant is between 10 ℃ and 37 ℃, the ultrasonic couplant is in a liquid state below the gel transition temperature, and the ultrasonic couplant is in a gel state above the gel transition temperature;
the poloxamer derivative is selected from one or more of products modified by sulfhydrylation, carboxylation, amination, etherification, carboxymethylation or hydroxypropylation.
4. The intrabody ultrasound couplant of claim 3, wherein: the gel transition temperature of the ultrasonic couplant is between 25 ℃ and 37 ℃.
5. The intrabody ultrasound couplant of claim 3, wherein: the gel transition temperature is between 35 ℃ and 37 ℃.
6. The intrabody ultrasound couplant of claim 3, wherein: the molecular weight of the poloxamer or the derivative thereof is 12600-14600 dalton.
7. The intrabody ultrasound couplant of claim 3, wherein: the solvent is any one of deionized water, normal saline, balanced salt solution, glucose solution or sterile pyrogen-free water.
8. The intrabody ultrasound couplant of claim 3, wherein: when the liquid ultrasonic coupling agent is in a liquid state, the viscosity of the ultrasonic coupling agent is 100-1000Pa & s; the viscosity of the ultrasonic couplant is 10,000-80,000 Pa.s in the gel state.
9. The intrabody ultrasound couplant of claim 3, wherein: the weight percentage of the poloxamer is 10% -30%.
10. A couplant delivery assembly, comprising: the ultrasonic couplant packaging container comprises a packaging container, wherein the ultrasonic couplant is contained in the packaging container, and preferably, the packaging container is a squeezing deformation type container or a piston push-injection type container with a liquid outlet, so that the ultrasonic couplant is allowed to be discharged from the liquid outlet when the packaging container is pressed or a piston is pushed.
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