BIOCOMPATIBLE ULTRASONIC COUPLING AGENT FOR ENDOSCOPE AND USE THEREOF

Abstract

Disclosed herein is a biocompatible ultrasonic coupling agent for endoscopes, comprising a biocompatible modified starch and a pharmaceutically acceptable carrier, or comprising an ingredient selected from the group consisting of cellulose, polyvinylpyrrolidone, polyoxyethylene, sodium alginate, glucan, hyaluronic acid, chitosan, light sensitive glue, ultrasonic sensitive glue, pH sensitive glue, gelatin and carbomer, and a pharmaceutically acceptable carrier; wherein the ultrasonic coupling agent produces an acoustic characteristic impedance matching the acoustic characteristic impedance of the human tissues during use for endoscopic ultrasound examination. Disclosed herein is also a kit for endoscopic ultrasound examination, comprising the said biocompatible ultrasonic coupling agent.

Claims

1. (canceled)

2. (canceled)

3. (canceled)

4. (canceled)

5. (canceled)

6. (canceled)

7. (canceled)

8. (canceled)

9. (canceled)

10. A method of using an ultrasonic coupling agent during an endoscopic ultrasound examination, comprising: acquiring the ultrasonic coupling agent wherein the ultrasonic coupling agent comprises a biocompatible modified starch, wherein the biocompatible modified starch comprises at least one of pre-gelatinized starches, acid-modified starches, composite modified starches, esterified starches, etherified starches, cross-linked starches, or graft starches and wherein the biocompatible modified starch has a molecular weight from 3,000 to 2,000,000 Dalton, has a water absorbency capability from 2 to 100 times of its own weight, and has a particle size ranging from 1 to 1000 μm; and applying the ultrasonic coupling agent proximate human tissue during the endoscopic ultrasound examination, wherein the biocompatible modified starch is adapted to produces an acoustic characteristic impedance matching an acoustic characteristic impedance of the human tissues.

11. The method of claim 10, wherein the biocompatible modified starch has a molecular weight in a range of 3,000 to 200,000 Dalton, or in a range of 3,000 to 100,000 Dalton, or in a range of 3,000 to 50,000 Dalton.

12. The method of claim 10, wherein the biocompatible modified starch has a water absorbency capability in a range of 5 to 75 times, in a range of 5 to 50 times, in a range of 2 to 10 times, or in a range of 2 to 5 times of its own weight.

13. The method of claim 10, wherein the biocompatible modified starch has a particle size ranging 1 to 500 μm, or in a range of 10 to 1000 μm.

14. The method of claim 10, wherein: the etherified starches comprise at least one of a carboxymethyl starch and a salt thereof, an oxidized starch or a hydroxyethyl starch; the esterified starches comprise carboxymethyl starch and a salt thereof; the cross-linked starches comprise cross-linked carboxymethyl starch and a salt thereof, the pre-gelatinized starches comprise a pre-gelatinized hydroxypropyl starch diphosphate; the graft starches comprise propylene ester-carboxymethyl starch grafted copolymer and acrylic acid-carboxymethyl starch grafted copolymer; and the composite modified starches comprise pre-gelatinized hydroxypropyl starch diphosphate.

15. The use-method of claim 10, wherein the acoustic characteristic impedance is in a range of 1.5×10.sup.6 to 1.7×10.sup.6 Pa.Math.s/m.

16. A biocompatible ultrasonic coupling agent adapted to be used in an endoscopic procedure, comprising: a composition selected from the group consisting of cellulose, polyvinylpyrrolidone, polyoxyethylene, sodium alginate, glucan, hyaluronic acid, chitosan, light sensitive glue, ultrasonic sensitive glue, pH sensitive glue, gelatin and carbomer; and a pharmaceutically acceptable carrier, wherein the ultrasonic coupling agent is adapted to produces an acoustic characteristic impedance matching an acoustic characteristic impedance of the human tissue during the endoscopic procedure.

17. The biocompatible ultrasonic coupling agent of claim 16, wherein the composition is selected from the group consisting of cellulose, polyvinylpyrrolidone, polyoxyethylene, sodium alginate, glucan, hyaluronic acid, chitosan, light sensitive glue, ultrasonic sensitive glue, pH sensitive glue, gelatin and carbomer and wherein the composition is in an amount from 0.1% to 10%, or 0.1% to 9%, or 0.1% to 8%, or 0.1% to 7%, or 0.1% to 6%, or 0.1% to 5%, or 0.1% to 4%, or 0.1% to 3%, or 0.1% to 2%, or 0.1% to 1%, or 0.1% to 0.5%, or 0.1% to 0.2% of a total weight of the ultrasonic coupling agent.

18. The biocompatible ultrasonic coupling agent of claim 16, wherein the ultrasonic coupling agent is adapted to produces an acoustic characteristic impedance from 1.5×10.sup.6 to 1.7×10.sup.6 Pa.Math.s/m.

19. (canceled)

20. (canceled)

21. (canceled)

22. (canceled)

23. The method of claim 10, wherein the biocompatible modified starch is degradable by an amylase and/or a saccharidase.

24. The method of claim 10, wherein the biocompatible modified starch is in an amount of 0.1% to 10%, or 0.1% to 9%, or 0.1% to 8%, or 0.1% to 7%, or 0.1% to 6%, or 0.1% to 5%, or 0.1% to 4%, or 0.1% to 3%, or 0.1% to 2%, or 0.1% to 1%, or 0.1% to 0.5%, or 0.1% to 0.2% of a total weight of the ultrasonic coupling agent.

25. The method of claim 10, wherein the ultrasonic coupling agent comprises a pharmaceutically acceptable carrier and wherein the pharmaceutically acceptable carrier is selected from the group consisting of normal saline, balanced salt solution, glucose solution, sterile pyrogen-free water and glycerine.

26. The method of claim 10, wherein the biocompatible modified starch has a water absorbency capability in a range of 5 to 75 times, in a range of 5 to 50 times, in a range of 2 to 10 times, or in a range of 2 to 5 times of its own weight.

27. The method of claim 10, wherein the biocompatible modified starch has a particle size ranging from 1 to 500 μm or 10 to 1000 μm.

28. A biocompatible ultrasonic coupling agent adapted to be used in an endoscopic procedure, comprising: a biocompatible modified starch, wherein the biocompatible modified starch comprises at least one of pre-gelatinized starches, acid-modified starches, composite modified starches, esterified starches, etherified starches, cross-linked starches, or graft starches and wherein the biocompatible modified starch has a molecular weight from 3,000 to 2,000,000 Dalton, has a water absorbency capability from 2 to 100 times of its own weight, and has a particle size ranging from 1 to 1000 μm; and a pharmaceutically acceptable carrier, wherein the ultrasonic coupling agent is adapted to produce an acoustic characteristic impedance matching an acoustic characteristic impedance of human tissue during the endoscopic procedure.

29. The biocompatible ultrasonic coupling agent of claim 28, wherein the biocompatible modified starch has a molecular weight in a range of 3,000 to 200,000 Dalton, or in a range of 3,000 to 100,000 Dalton, or in a range of 3,000 to 50,000 Dalton.

30. The biocompatible ultrasonic coupling agent of claim 28, wherein the biocompatible modified starch has a water absorbency capability in a range of 5 to 75 times, in a range of 5 to 50 times, in a range of 2 to 10 times, or in a range of 2 to 5 times of its own weight.

31. The biocompatible ultrasonic coupling agent of claim 28, wherein the acoustic characteristic impedance is in a range of 1.5×10.sup.6 to 1.7×10.sup.6 Pa.Math.s/m.

32. The biocompatible ultrasonic coupling agent of claim 28, wherein the biocompatible modified starch is degradable by an amylase and/or a saccharidase.

33. The biocompatible ultrasonic coupling agent of claim 28, wherein the biocompatible modified starch is in an amount of 0.1% to 10%, or 0.1% to 9%, or 0.1% to 8%, or 0.1% to 7%, or 0.1% to 6%, or 0.1% to 5%, or 0.1% to 4%, or 0.1% to 3%, or 0.1% to 2%, or 0.1% to 1%, or 0.1% to 0.5%, or 0.1% to 0.2% of a total weight of the ultrasonic coupling agent.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0065] FIGS. 1A to 1K are ultrasound images obtained by using the ultrasonic coupling agent as provided herein and the control sample.

[0066] FIG. 2 is a schematic diagram to illustrate the use of the kit for endoscopic ultrasound examination according to one embodiment as described herein.

[0067] FIG. 3 is a schematic diagram to illustrate the use of the kit for endoscopic ultrasound examination according to one embodiment as described herein.

[0068] FIG. 4 is a schematic diagram to illustrate the use of the kit for endoscopic ultrasound examination according to one embodiment as described herein.

[0069] FIG. 5 is a schematic diagram to illustrate the use of the kit for endoscopic ultrasound examination according to one embodiment as described herein.

DETAILED DESCRIPTION OF THE INVENTION

[0070] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be any limitation of the invention. As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.

Definition

[0071] The term “biocompatibility” or “biocompatible” as used herein refers to ability of tissues in a living body to perform an appropriate response to an inactive material. Generally, it refers to the compatibility of the materials with the host. Evaluation on biocompatibility mainly follows biosafety principles, i.e., elimination of injurious effect of biological materials on human tissues and organs, such as allergenicity, cytotoxicity and carcinogenicity. In addition, according to the sites on which the biological materials are to be applied, after the biological materials are directly used on the tissues and organs in the human body, they are required to be degradable and/or absorbable by organisms and tissues. Since the biocompatible ultrasonic coupling agent as described herein can be used for endoscopic ultrasound examination in human cavities, the biocompatibility as used herein especially refers to the absorbability and non-allergenicity of the materials in full compliance with biosafety principles.

[0072] The term “absorbable/degradable or degraded” as used herein means that a substance can be gradually destroyed in the organism (chemical hydrolysis, enzymatic hydrolysis, or phagocytic action, etc.), including morphological and structural destruction and performance changes, and the resultant products after degradation can be absorbed and metabolized by the organism, or can be self-decomposed. During absorbency or degradation, no by-products harmful to the human body is produced.

[0073] The term “water absorbency capability” as used herein refers to the ratio of the mass or volume of water absorbed by unit mass or volume of the water absorbent to the volume or mass of the water absorbent.

[0074] The term “pharmaceutically acceptable carrier” as used herein means that the carrier does not produce any toxic or adverse side effects after applying to a human, and is compatible with the active ingredients dissolved and/or suspended and/or complexed and/or mixed therein. The term “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, isotonic agents, excipients, and the like, which are known to those of ordinary skill in the art, and combinations thereof.

[0075] For the operator who operates the device for delivering the ultrasonic coupling agent as described herein, the “proximal end” used herein refers to the portion that is closest to the operator.

[0076] For the operator who operates the device for delivering the ultrasonic coupling agent as described herein, the “distal end” used herein refers to the portion that is farthest away from the operator.

[0077] The ultrasonic coupling agent for endoscopes as provided herein has the following advantages: [0078] 1) It meets the basic performance requirements for the common ultrasonic coupling agent, with reduced loss of ultrasonic energy and high ultrasonic image definition. [0079] 2) It has bioadhersivity, and thus can be adhered to the mucosa of the cavities and organs for a period time that is sufficient to perform endoscopic ultrasound examination and treatment, and it is able to stretch the wrinkles of the natural cavity of the human body. [0080] 3) It is non-toxic, and can be used in vivo, with good biocompatibility and absorbency (can be fully absorbed/degraded in the human body). [0081] 4) It will not block the gastrointestinal tract, pancreaticobiliary duct, urethra, ureter and other natural human cavities. [0082] 5) It can be easily injected into the organ cavities in the body through the working channel of the endoscope (such as the biopsy clamp channel). [0083] 6) It does not corrode or damage the ultrasound probe and endoscope. [0084] 7) It has acid and alkali resistance. [0085] 8) It can be easily cleaned without blocking the working channel of the endoscope. [0086] 9) It can be easily sterilized to meet sterile requirements. [0087] 10) It has reasonable cost and can be easily obtained.

[0088] The aspects of the present invention will be described in greater detail by referring to the working examples as below. The working examples are illustrative without making limitation to the scope and the spirit of the present invention.

Example 1. Biocompatible Ultrasonic Coupling Agent for Endoscopes

[0089] Table 1 lists the starting materials #1 to #10, which are dispersed into normal saline (NS) at varied amounts to prepare ultrasonic coupling agent samples #11 to #20. The chemical and physical parameters of the starting materials #1 to #10 are listed in Table 1. The amounts of the starting materials and NS that are used to prepare the ultrasonic coupling agent samples #11 to #20 and the performance parameters of the resultant ultrasonic coupling agent samples #11 to #20 are listed in Table 2.

TABLE-US-00001 TABLE 1 Molecular Particle Water Viscosity No. Starting Material Weight Size Absorbancy (mPa .Math. s) #1 Polyoxyethylene .sup. 100,000-10,000,000 0.5~2000 μm 21 30-1000 in 1% (PEO) aqueous at 37° C. #2 Polyvinylpyrrolidone   8,000-1,500,000 5~1000 μm 9 50-1000 in 5% (PVP) aqueous at 37° C. #3 hydroxyethylcellulose 30,000-500,000 10~1000 μm 20 5-60,000 in 2% (HEC) aqueous at 20° C. #4 carboxymethylcellulose 5,000-20,000 100~1000 μm 29 1000-50000 in 1% (CMC) aqueous at 37° C. #5 Arabic gum  200,000-1,000,000 5~1000 μm 10 50-1000 in 1% aqueous at 37° C. #6 tragacanth  100,000-1,000,000 100~1500 μm 15 400-600 in 1% aqueous at 25° C. #7 Carbomer 1,000,000-5,000,000  10~1000 μm 19 1000-50,000 in 0.5% aqueous at 37° C. #8 sodium alginate 30,000-250,000 100~1500 μm 23 1000-50000 in 1% aqueous at 37° C. #9 hydroxyethyl starch 100,000-300,000  10~1000 μm 4 1-100 in 1% (HES) aqueous at 37° C. #10 glucan   5,000-2,000,000 10~1000 μm 5 1-100 in 2% aqueous at 37° C.

TABLE-US-00002 TABLE 2 acoustic slope of sound sound characteristic attenuation velocity impedance coefficient (35° C.) (35° C.) (35° C.) Viscosity Adhesion No. Formula Appearance pH m/s Pa .Math. s/m dB/(cm .Math. MHz) (mPa .Math. s) (gf) Standard Colorless or light- 5.5~8.0 1520~1620 1.5 × 10.sup.6~1.7 × 10.sup.6 ≤0.05 / / Requirements colored transparent gel, no or only a few bubbles, no insoluble foreign matter #11 Sample #1 + NS, Good 8.0 1520~1620 1.5 × 10.sup.6~1.7 × 10.sup.6 ≤0.05 783 16.0 with 1 wt % sample #1 #12 Sample #2 + NS, Good 6.2 1520~1620 1.5 × 10.sup.6~1.7 × 10.sup.6 ≤0.05 350 10.6 with 5 wt % sample #2 #13 Sample #3 + NS, Good 6.5 1520~1620 1.5 × 10.sup.6~1.7 × 10.sup.6 ≤0.05 29645 19.8 with 1 wt % sample #3 #14 Sample #4 + NS, Good 7.8 1520~1620 1.5 × 10.sup.6~1.7 × 10.sup.6 ≤0.05 23680 19.5 with 0.5 wt % sample #4 #15 Sample #5 + NS, Good 7.0 1520~1620 1.5 × 10.sup.6~1.7 × 10.sup.6 ≤0.05 296 6.3 with 2 wt % sample #5 #16 Sample #6 + NS, Good 5.5 1520~1620 1.5 × 10.sup.6~1.7 × 10.sup.6 ≤0.05 514 11.2 with 1 wt % sample #6 #17 Sample #7 + NS, Good 8.0 1520~1620 1.5 × 10.sup.6~1.7 × 10.sup.6 ≤0.05 25440 20.5 with 0.2 wt % sample #7 #18 Sample #8 + NS, Good 6.4 1520~1620 1.5 × 10.sup.6~1.7 × 10.sup.6 ≤0.05 21835 19.8 with 0.5 wt % sample #8 #19 Sample #9 + NS, Good 7.0 1520~1620 1.5 × 10.sup.6~1.7 × 10.sup.6 ≤0.05 43 4.2 with 6 wt % sample #9 #20 Sample #10 + NS, Good 7.0 1520~1620 1.5 × 10.sup.6~1.7 × 10.sup.6 ≤0.05 165 6.4 with 5 wt % sample #10

[0090] The performance parameters listed in Table 2 were measured according to the methods specified in the industry standard for medical ultrasonic coupling agents (YY0299). From Table 2, it can be seen that the ultrasonic coupling agent of the present invention can achieve a sound velocity from 1520 to 1620 m/s, with the slope of the sound attenuation coefficient ≤0.05 dB/(cm.Math.MHz), and an acoustic characteristic impedance ranging from 1.5×10.sup.6 to 1.7×10.sup.6 Pa.Math.s/m. It can be seen that the ultrasonic coupling agent of the present invention produces an acoustic characteristic impedance that perfectly matches the acoustic characteristic impedance of the tissues in human cavities, and has low sound attenuation, suitable for use as a coupling agent for endoscopic ultrasound examination.

[0091] The above samples #11 to #20 are placed in a 50 mL centrifuge tube. A gauze with an area of 1.5×1.5 cm is dipped into each sample. Then the ultrasonic probe is inserted into each sample and the image detected by the ultrasonic probe is recorded. The control sample is normal saline. FIGS. 1A to 1K show the images detected by the ultrasonic probe in the samples #11 to #20, in which FIG. 1K is the result from the control sample.

[0092] From FIGS. 1A to 1K, it can be seen that the images returned by the ultrasonic coupling agent of the present invention have high definition and less white noise. Therefore, the ultrasonic coupling agent of the present invention is suitable for use as a coupling agent for endoscopic ultrasound examination.

Example 2. Use of the Biocompatible Ultrasonic Coupling Agent in In Vivo Examination

[0093] FIG. 2 is a schematic diagram to illustrate the use of the kit for endoscopic ultrasound examination according to one embodiment as described herein. As shown in FIG. 2, the ultrasonic coupling agent prepared according to Example 1 is directly delivered to the surface 9 of the gastric mucosa that is to be examined by the endoscope, through the working channel (such as water channel or channel for biopsy clamp) of the endoscope, via the delivery tube 2 connected to the distal of the delivery device 1 according to the present invention. Then the ultrasound probe 4 of the endoscope directly contacts the ultrasonic coupling agent 10, to perform ultrasonic detection and examination on the tissues and organs.

[0094] FIG. 3 is a schematic diagram to illustrate the use of the kit for endoscopic ultrasound examination according to one embodiment as described herein. As shown in FIG. 3, the ultrasonic coupling agent prepared according to Example 1 is directly delivered to lesion site in the stomach which is to be examined by the endoscope along the outer wall of the endoscope (with the delivery tube 2 fixed along the outer wall of the endoscope by a fastener 5), through the delivery tube 2 connected to the distal of the delivery device 1 according to the present invention. Then the ultrasound probe 4 of the endoscope directly contacts the ultrasonic coupling agent 10, to perform ultrasonic detection and examination on the tissues and organs.

[0095] FIG. 4 is a schematic diagram to illustrate the use of the kit for endoscopic ultrasound examination according to one embodiment as described herein. As shown in FIG. 4, the ultrasonic coupling agent prepared according to Example 1 is delivered to a balloon 6 connected to the distal of the endoscope along the outer wall of the endoscope (with the delivery tube 2 fixed along the outer wall of the endoscope by a fastener 5), through the delivery tube 2 connected to the distal of the delivery device 1 according to the present invention, and then the balloon 6 filled with the ultrasonic coupling agent 10 is attached to the lesion site 7 in the stomach which is to be examined. Next, the ultrasound probe 4 of the endoscope performs ultrasonic detection and examination on the tissues and organs through the balloon.

[0096] FIG. 5 is a schematic diagram to illustrate the use of the kit for endoscopic ultrasound examination according to one embodiment as described herein. As shown in FIG. 5, the ultrasonic coupling agent prepared according to Example 1 is directly delivered to lesion site in the intestine which is to be examined by the endoscope along the outer wall of the endoscope (with the delivery tube 2 fixed along the outer wall of the endoscope by a fastener 5), through the delivery tube 2 connected to the distal of the delivery device 1 according to the present invention. Then the ultrasound probe 4 of the endoscope directly contacts the ultrasonic coupling agent 10, to perform ultrasonic detection and examination on the tissues and organs.

Example 3. Effect of the Biocompatible Ultrasonic Coupling Agent in Endoscopic Ultrasound Examination In Vivo

[0097] This example illustrates the effect of the ultrasonic coupling agent samples #11 to #20 prepared according to Example 1 in gastroscopy ultrasound examination on Bama miniature pig.

[0098] 1. Ultrasonic coupling agent: samples #11 to #20 prepared according to Example 1

[0099] 2. Animals: Bama miniature pig, with body weight of 40 kg

[0100] 3. Experimental method: After general anesthesia, the Bama miniature pig lied on its back on the operating table with its limbs fixed. The Olympus GIF-XQ240 electronic gastroscope was used to enter from the mouth. 2 ml of normal saline was submucosally injected into the pig's esophagus to form submucosal bulges. Then the biocompatible ultrasonic coupling agents prepared according to Example 1 were applied on the bulging section through the working channel of the gastroscope via the delivery tube by using the delivery device. The control group was continuously perfused with NS. The P2615-M Fuji endoscopic ultrasound probe was used to perform detection. The ultrasonic images and the definition thereof were recorded and compared.

Example 4. Effect of the Biocompatible Ultrasonic Coupling Agent in Endoscopic Ultrasound Examination In Vivo

[0101] This example illustrates the effect of the ultrasonic coupling agent samples #11 to #20 prepared according to Example 1 in gastroscopy ultrasound examination on Bama miniature pig.

[0102] 1. Ultrasonic coupling agent: samples #11 to #20 prepared according to Example 1

[0103] 2. Animals: Bama miniature pig, with body weight of 40 kg

[0104] 3. Experimental method: After general anesthesia, the Bama miniature pig lied on its back on the operating table with its limbs fixed. The Olympus ultrasonic endoscope was used to enter from the mouth. 2 ml of normal saline was submucosally injected into the anterior wall of the upper third of the pig's stomach to form submucosal bulges. Then the biocompatible ultrasonic coupling agents prepared according to Example 1 were applied on the bulging section through the working channel of the gastroscope via the delivery tube by using the delivery device. The control group was continuously perfused with NS. The ultrasound probe was used to perform detection. The ultrasonic images and the definition thereof were recorded and compared.