Composition for submucosal injection, reagent combination, and applications thereof

Abstract

Described herein is a composition for submucosal injection comprises a biocompatible modified starch and a pharmaceutically acceptable carrier for injection. The biocompatible modified starch is in an amount ranging from 0.2 wt % to 50 wt % of the total weight of composition. The biocompatible modified starch is selected from one or more of the group consisting of: etherified starches, esterified starches, cross-linked starches, pre-gelatinized starches, graft starches and composite modified starches, which has a molecular weight ranging from 3,000 to 2,000,000 daltons, a water absorbency capability of at least twice of its own weight, and a particle size from 500 nm to 1000 μm. The viscosity of the composition ranges from 9 mPa.Math.s to 150,000 mPa.Math.s at 25° C. The present disclosure also provides a combination reagent for submucosal injection, comprising the above-mentioned biocompatible modified starch and the pharmaceutically acceptable carrier for injection.

Claims

1. A method for lifting up a first tissue layer from a second tissue layer comprising delivering a submucosal injection of a composition into the first tissue layer further comprising: acquiring the composition, wherein the composition comprises a biocompatible modified starch in an amount ranging from 0.2 wt % to 50 wt % of a total weight of composition, which has a molecular weight from 3,000 to 2,000,000 daltons, a water absorbency capability of at least twice of its own weight, and a particle size from 500 nm to 1000 μm, wherein the biocompatible modified starch is selected from one or more of the group consisting of etherified starches comprise a carboxymethyl starch and a salt thereof, esterified starches, cross-linked starches, pre-gelatinized starches, graft starches, and composite modified starches; and a pharmaceutically acceptable carrier for injection, wherein the viscosity of the composition ranges from 9 mPa.Math.s to 150,000 mPa.Math.s at 25° C.

2. The method of claim 1, wherein the pharmaceutically acceptable carrier for injection is selected from one or more of the group consisting of: physiological saline, balanced salt solution, glucose solution, sterile pyrogen-free water, and glycerin.

3. The method of claim 2, wherein: the the cross-linked starches comprise a cross-linked carboxymethyl starch and a salt thereof; the pre-gelatinized starches comprise a pre-gelatinized hydroxypropyl starch diphosphate; the graft starches comprise a propylene ester-carboxymethyl starch grafted copolymer and acrylic acid-carboxymethyl starch grafted copolymer; the composite modified starches comprise a pre-gelatinized hydroxypropyl starch diphosphate.

4. The method of claim 3, wherein the biocompatible modified starch is in an amount ranging from 0.2 wt % to 20 wt %, or 0.5 wt % to 10 wt %, or 0.5 wt % to 5 wt %, or 1 wt % to 5 wt %, or 0.5 wt % to 1.5 wt %, or 2 wt % to 6 wt % of the total weight of composition.

5. The method of claim 4, wherein the viscosity of the composition ranges from 9 mPa.Math.s to 100,000 mPa.Math.s, or 9 mPa.Math.s to 10,000 mPa.Math.s, or 9 mPa.Math.s to 5,000 mPa.Math.s, or 9 mPa.Math.s to 1,000 mPa.Math.s at 25° C.

6. The method of claim 3, wherein the biocompatible modified starch has a molecular weight ranging from 3,000 to 200,000 daltons, or 5,000 to 100,000 daltons, or 5,000 to 50,000 daltons.

7. The method of claim 3, wherein the biocompatible modified starch has a water absorbency capability from 2 to 100 times, or 5 to 75 times, or 5 to 50 times, or 2 to 10 times, or 2 to 5 times of its own weight.

8. The composition of claim 3, wherein the biocompatible modified starch has a particle size ranging from 1 μm to 500 μm, or 1 μm to 1000 μm, or 10 μm to 1000 μm.

9. The method of claim 1, wherein the biocompatible modified starch is degradable by amylases.

10. The method of claim 1, wherein at least one of the first tissue layer or the second tissue layer comprises digestive tract mucosa, respiratory mucosa, genital tract mucosa or urinary tract mucosa and wherein: the digestive tract mucosa comprises an esophageal mucosa or a gastrointestinal mucosa; the respiratory mucosa comprises a nasal mucosa, a laryngeal mucosa, an oral mucosa, a tracheal mucosa or a bronchial mucosa; the urinary tract mucosa comprises a urethral mucosa or a bladder mucosa; and the genital tract mucosa comprises a vaginal mucosa or a uterine mucosa.

11. The method of claim 1, wherein the biocompatible modified starch is a carboxymethyl starch sodium in an amount ranging from 1 wt % to 25 wt % of the total weight of composition, and the pharmaceutically acceptable carrier for injection is physiological saline.

12. The method of claim 1, wherein the biocompatible modified starch is a hydroxypropyl starch diphosphate in an amount ranging from 0.5 wt % to 25 wt % of the total weight of composition, and the pharmaceutically acceptable carrier for injection is physiological saline.

13. The method of claim 1, wherein the biocompatible modified starch is a cross-linked carboxymethyl starch sodium in an amount ranging from 0.5 wt % to 20 wt % of the total weight of composition, and the pharmaceutically acceptable carrier for injection is physiological saline.

14. The method of claim 1, wherein: the esterified starches comprise a carboxymethyl starch and a salt thereof; the cross-linked starches comprise a cross-linked carboxymethyl starch and a salt thereof; the pre-gelatinized starches comprise a pre-gelatinized hydroxypropyl starch diphosphate; the graft starches comprise a propylene ester-carboxymethyl starch grafted copolymer and an acrylic acid-carboxymethyl starch grafted copolymer; the composite modified starches comprise a pre-gelatinized hydroxypropyl starch diphosphate.

15. The method of claim 1, wherein the biocompatible modified starch is in an amount ranging from 0.2 wt % to 20 wt %, or 0.5 wt % to 10 wt %, or 0.5 wt % to 5 wt %, or 1 wt % to 5 wt %, or 0.5 wt % to 1.5 wt %, or 2 wt % to 6 wt % of the total weight of composition.

16. The method of claim 1, wherein the viscosity of the composition ranges from 9 mPa.Math.s to 100,000 mPa.Math.s, or 9 mPa.Math.s to 10,000 mPa.Math.s, or 9 mPa.Math.s to 5,000 mPa.Math.s, or 9 mPa.Math.s to 1,000 mPa.Math.s at 25° C.

17. The method of claim 1, wherein the biocompatible modified starch has a molecular weight ranging from 3,000 to 200,000 daltons, or 5,000 to 100,000 daltons, or 5,000 to 50,000 daltons.

18. The method of claim 1, wherein the biocompatible modified starch has a water absorbency capability from 2 to 100 times, or 5 to 75 times, or 5 to 50 times, or 2 to 10 times, or 2 to 5 times of its own weight.

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

20. The method of claim 1, wherein the biocompatible modified starch is a carboxymethyl starch sodium in an amount ranging from 1 wt % to 25 wt % of the total weight of composition, and the pharmaceutically acceptable carrier for injection is physiological saline.

21. The method of claim 1, wherein the biocompatible modified starch is a hydroxypropyl starch diphosphate in an amount ranging from 0.5 wt % to 25 wt % of the total weight of composition, and the pharmaceutically acceptable carrier for injection is physiological saline.

22. The method of claim 1, wherein the biocompatible modified starch is a cross-linked carboxymethyl starch sodium in an amount ranging from 0.5 wt % to 20 wt % of the total weight of composition, and the pharmaceutically acceptable carrier for injection is physiological saline.

23. A submucosal injection composition comprising: a biocompatible modified starch and a pharmaceutically acceptable carrier for injection, wherein the pharmaceutically acceptable carrier for injection is physiological saline, wherein, the biocompatible modified starch is a carboxymethyl starch sodium, which has a molecular weight ranging from 3,000 to 2,000,000 daltons, a water absorbency capability of at least twice of its own weight, and a particle size from 500 nm to 1000 μm, wherein the biocompatible modified starch is degradable by amylases, and wherein the biocompatible modified starch, in an amount ranging from 1 wt % to 25 wt % of a total weight of the composition, is mixed with the pharmaceutically acceptable carrier to form a viscous composition with a viscosity ranging from 9 mPa.Math.s to 150,000 mPa.Math.s at 25° C.

24. The composition of claim 23, wherein the biocompatible modified starch is in an amount ranging from 1 wt % to 5 wt % or 2 wt % to 6 wt % of the total weight.

25. The composition of claim 23, wherein the viscosity of the formed viscous composition ranges from 9 mPa.Math.s to 100,000 mPa.Math.s, or 9 mPa.Math.s to 10,000 mPa.Math.s, or 9 mPa.Math.s to 5,000 mPa.Math.s, or 9 mPa.Math.s to 1,000 mPa.Math.s at 25° C.

26. The composition of claim 23, wherein the biocompatible modified starch has a molecular weight ranging from 3,000 to 200,000 daltons, or 5,000 to 100,000 daltons, or 5,000 to 50,000 daltons.

27. The composition of claim 23, wherein the biocompatible modified starch has a water absorbency capability ranging from 2 to 100 times, or 5 to 75 times, or 5 to 50 times, or 2 to 10 times, or 2 to 5 times of its own weight.

28. The composition of claim 23, wherein the biocompatible modified starch has a particle size ranging from 1 μm to 500 μm, or 1 μm to 1000 μm, or 10 μm to 1000 μm.

29. A submucosal injection composition comprising: a biocompatible modified starch and a pharmaceutically acceptable carrier for injection, wherein the pharmaceutically acceptable carrier for injection is physiological saline, wherein, the biocompatible modified starch is a hydroxypropyl starch diphosphate, which has a molecular weight ranging from 3,000 to 2,000,000 daltons, a water absorbency capability of at least twice of its own weight, and a particle size from 500 nm to 1000 wherein the biocompatible modified starch is degradable by amylases, and wherein the biocompatible modified starch, in an amount ranging from 0.5 wt % to 25 wt % of a total weight of the composition, is mixed with the pharmaceutically acceptable carrier to form a viscous composition with a viscosity ranging from 9 mPa.Math.s to 150,000 mPa.Math.s at 25° C.

30. The composition of claim 29, wherein the biocompatible modified starch is in an amount ranging from 0.5 wt % to 10 wt %, or 0.5 wt % to 5 wt %, or 1 wt % to 5 wt %, or 0.5 wt % to 1.5 wt %, or 2 wt % to 6 wt % of the total weight.

31. The composition of claim 29, wherein the viscosity of the formed viscous composition ranges from 9 mPa.Math.s to 100,000 mPa.Math.s, or 9 mPa.Math.s to 10,000 mPa.Math.s, or 9 mPa.Math.s to 5,000 mPa.Math.s, or 9 mPa.Math.s to 1,000 mPa.Math.s at 25° C.

32. The composition of claim 29, wherein the biocompatible modified starch has a molecular weight ranging from 3,000 to 200,000 daltons, or 5,000 to 100,000 daltons, or 5,000 to 50,000 daltons.

33. The composition of claim 29, wherein the biocompatible modified starch has a water absorbency capability ranging from 2 to 100 times, or 5 to 75 times, or 5 to 50 times, or 2 to 10 times, or 2 to 5 times of its own weight.

34. The composition of claim 29, wherein the biocompatible modified starch has a particle size ranging from 1 μm to 500 μm, or 1 μm to 1000 μm, or 10 μm to 1000 μm.

35. A submucosal injection composition comprising: a biocompatible modified starch and a pharmaceutically acceptable carrier for injection, wherein the pharmaceutically acceptable carrier for injection is physiological saline, wherein, the biocompatible modified starch is a cross-linked carboxymethyl starch sodium, which has a molecular weight ranging from 3,000 to 2,000,000 daltons, a water absorbency capability of at least twice of its own weight, and a particle size from 500 nm to 1000 μm, wherein the biocompatible modified starch is degradable by amylases, and wherein the biocompatible modified starch, in an amount ranging from 0.5 wt % to 20 wt % of a total weight of the composition, is mixed with the pharmaceutically acceptable carrier to form a viscous composition with a viscosity ranging from 9 mPa.Math.s to 150,000 mPa.Math.s at 25° C.

36. The composition of claim 35, wherein the biocompatible modified starch is in an amount ranging from 0.5 wt % to 10 wt %, or 0.5 wt % to 5 wt %, or 1 wt % to 5 wt %, or 0.5 wt % to 1.5 wt %, or 2 wt % to 6 wt % of the total weight.

37. The composition of claim 35, wherein the viscosity of the formed viscous composition ranges from 9 mPa.Math.s to 100,000 mPa.Math.s, or 9 mPa.Math.s to 10,000 mPa.Math.s, or 9 mPa.Math.s to 5,000 mPa.Math.s, or 9 mPa.Math.s to 1,000 mPa.Math.s at 25° C.

38. The composition of claim 35, wherein the biocompatible modified starch has a molecular weight ranging from 3,000 to 200,000 daltons, or 5,000 to 100,000 daltons, or 5,000 to 50,000 daltons.

39. The composition of claim 35, wherein the biocompatible modified starch has a water absorbency capability ranging from 2 to 100 times, or 5 to 75 times, or 5 to 50 times, or 2 to 10 times, or 2 to 5 times of its own weight.

40. The composition of claim 35, wherein the biocompatible modified starch has a particle size ranging from 1 μm to 500 μm, or 1 μm to 1000 μm, or 10 μm to 1000 μm.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a structural schematic diagram of the apparatus for delivering the composition for submucosal injection as described herein.

DETAILED DESCRIPTION OF THE INVENTION

(2) Definition

(3) 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 degraded and/or absorbed by organisms and tissues. Since the composition for submucosal injection as described herein is used for submucosal injection, that is, it is directly injected into the mucosa tissues, the biocompatibility especially refers to the absorbability and non-allergenicity of the materials in full compliance with biosafety principles.

(4) The term “water absorbency capability” as used herein refers to the ratio between the mass or volume of water absorbed by unit mass or volume of the water absorbent and the volume or mass of the water absorbent.

(5) The term “mucosa” as used herein refers to a layer of mucosal tissues within the organs such as the digestive tract (including mouth, stomach, intestines, etc.), respiratory tract, genital tract and urinary tract. The mucosal tissues have blood vessels and nerves distributed therein and can secrete mucus. The mucosa as described herein comprises digestive tract mucosa, respiratory tract mucosa, genital tract mucosa or urinary tract mucosa and so on.

(6) The term “pharmaceutically acceptable carrier for injection” 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 for injection” 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.

(7) For the operator who operates the apparatus for delivering the composition for submucosal injection as described herein, the “proximal end” used herein refers to the portion that is close to the operator.

(8) For the operator who operates the apparatus for delivering the composition for submucosal injection as described herein, the “distal end” used herein refers to the portion that is far away from the operator.

(9) U.S. Patent Application No. US20110208158A1 describes use of carboxymethyl cellulose (CMC) for submucosal injection. Carboxymethyl cellulose is a species of cellulose materials, which is significantly distinct from the modified starches used in the present invention in molecular structure and has a completely different metabolic pathway in the body from that of the modified starches used in the present invention. Starches can be degraded by amylases and amylases in the human body, while cellulose is gradually degraded by the phagocytosis of phagocytic cells in the human body. Therefore, the modified starch materials exhibit reduced local stimulation to human mucosal tissues, and can be rapidly metabolized within several hours or several days, while the cellulose materials take several weeks or even months to be completely absorbed by human tissues. That is to say, cellulose materials may cause local tissue proliferation and interfere tissue healing. Thus, the modified starch materials for submucosal injection as described herein are significantly superior to the cellulose materials.

(10) Respective aspects of the present invention will be described in greater detail by reference to the following specific examples. Such examples merely intend to illustrate the present invention but not to limit the scope and the spirit of the present invention.

EXAMPLE 1

Composition for Submucosal Injection

(11) This example illustrated compositions #4 to #16 for submucosal injection prepared by dispersing three exemplary biocompatible modified starches #1 to #3 as listed in Table 1 into physiological saline at various weight percentages at room temperature. Table 1 listed the physicochemical parameters of the three exemplary biocompatible modified starches used in this example. Table 2 listed the weight percentages of the biocompatible modified starches in the compositions #4 to #16 for submucosal injection and the viscosities of the compositions.

(12) TABLE-US-00001 TABLE 1 Particle Molecular Water Size Weight Absorbency *Viscosity No. (μm) (daltons) Capability (mPa .Math. s) #1 10-1000  3,000-2,000,000 23 34-3000 carboxymethyl *the viscosity starch of 2% sodium aqueous solution measured at 37° C. #2 10-1000 15,000-2,000,000 17.5 500-5000 pre-gelatinized *the viscosity hydroxypropyl of 6.67% starch aqueous diphosphate solution measured at 37° C. #3 10-1000  5,000-2,000,000 23.5 10,000- cross-linked 100,000 carboxymethyl * the viscosity starch of 2% sodium aqueous solution measured at 37° C.

(13) TABLE-US-00002 TABLE 2 Viscosity* No. Components and Formulation (mPa .Math. s)  #4 sample #1 + physiological saline: 103 the concentration of sample #1 in physiological saline was 5 wt %  #5 sample #1 + physiological saline: 57 the concentration of sample #1 in physiological saline was 4 wt %  #6 sample #1 + physiological saline: 33 the concentration of sample #1 in physiological saline was 3 wt %  #7 sample #1 + physiological saline: 20 the concentration of sample #1 in physiological saline was 2 wt %  #8 sample #1 + physiological saline: 18 the concentration of sample #1 in physiological saline was 1 wt %  #9 sample #2 + physiological saline: 9 the concentration of sample #2 in physiological saline was 2 wt % #10 sample #2 + physiological saline: 12 the concentration of sample #2 in physiological saline was 3 wt % #11 sample #2 + physiological saline: 28 the concentration of sample #2 in physiological saline was 4 wt % #12 sample #2 + physiological saline: 113 the concentration of sample #2 in physiological saline was 5 wt % #13 sample #2 + physiological saline: 150 the concentration of sample #2 in physiological saline was 6 wt % #14 sample #3 + physiological saline: 12 the concentration of sample #3 in physiological saline was 0.5 wt % #15 sample #3 + physiological saline: 136 the concentration of sample #3 in physiological saline was 1 wt % 150 #16 sample #3 + physiological saline: the concentration of sample #3 in physiological saline was 1.5 wt % *The viscosity was measured at 25° C. by using a sc4-31 rotor at a rotation speed of 200 rpm.

(14) In this example, the changes in the heights of the droplets formed by the above-mentioned compositions #4 to #16 with time were measured by a filter paper test as described below.

(15) The filter paper test included following steps: placing a filter paper on a horizontal substrate, dropping 0.2 ml of each composition onto the filter paper with a plastic dropper, and recording the changes in the heights of the formed droplets with time. Control samples were commercially available hyaluronic acid (HA), hydroxyethyl starch (plasma substitutes, HES), and physiological saline.

(16) The changes in the heights of the formed droplets with time as measured by the filter paper test were shown in Table 3 below.

(17) TABLE-US-00003 TABLE 3 Height of the Height of droplet at the droplet Decline No. the beginning after 5 minutes Rate  #4 5.5 mm 4.5 mm 18.2%  #5 3.5 mm 3.0 mm 14.3%  #6 2.0 mm 1.5 mm 25.0%  #7 2.0 mm 1.5 mm 25.0%  #8 1.5 mm 1.0 mm 33.3%  #9 0.3 mm 0.2 mm  3.3% #10 0.5 mm 0.5 mm   0% #11 1.5 mm 1.2 mm  2.0% #12 2.2 mm 2.0 mm  9.1% #13 2.5 mm 2.4 mm  4.0% #14 0.5 mm 0.4 mm   20% #15 3.0 mm 2.8 mm  6.7% #16 4.5 mm 3.8 mm 15.6% *Commercially Available 2.5 mm 0.5 mm 80.0% HA Injection Commercially Available 1.0 mm 0  100% HES Plasma Substitutes Commercially Available 0 0 — Physiological Saline *The viscosity of the commercially available HA injection was 198 mPa .Math. s, which was measured at 25° C. by using a sc4-31 rotor at a rotation speed of 200 rpm.

(18) According to the results as listed in Table 3, after the compositions for submucosal injection comprising the biocompatible modified starches and the pharmaceutically acceptable diluent (for example, physiological saline), as described herein, were added dropwise to the filter paper and absorbed by the filter paper, the heights of the droplets formed by the compositions #4 to #16 on the filter paper were much higher than those formed by commercially available HA injection, HES plasma substitutes and physiological saline. And the decline rates of the droplets formed by the compositions #4 to #16 on the filter paper were much lower than those formed by the commercially available HA injection, HES plasma substitutes and the physiological saline.

(19) The filter paper used in the filter paper test had a porous structure, which can simulate the reticular connective tissue of the submucosa. The results of the filter paper test demonstrated that: 1) In the compositions for submucosal injection as described herein, the biocompatible modified starches were swollen in the pharmaceutically acceptable diluent rather than being dissolved, such that the swollen modified starches play a role in forming a submucosal cushion with certain height and strength. 2) Commercially available HA injection formed a droplet with a height of 2.5 mm at the beginning. However, after 5 minutes, the droplet sharply drops to 0.5 mm, indicating that the commercially available HA injection cannot effectively form a submucosal cushion with certain height and strength. Therefore, if the HA injection was used during surgery, it is not capable of forming a submucosal cushion with certain height and strength. 3) Both commercially available saline and HES plasma substitutes diffused along the gap of the filter paper. This is one of the reasons why doctors need to repeatedly perform injection during surgery.

(20) Next, the changes in the heights of the cushions formed by the above-mentioned compositions #4 to #16 with time after submucosal injection under gastric mucosa were tested. The specific steps for test included: cutting a porcine stomach into samples with a size of about 5×5 cm and placing it on a horizontal substrate, and injecting the above compositions #4 to #16 into submucosa using an injection needle at an injection volume of 1 ml. The changes in the heights of the submucosal cushions formed after injection with time were observed and recorded. Control samples were commercially available hyaluronic acid (HA), hydroxyethyl starch (plasma substitutes, HES), and physiological saline. The test results were listed in Table 4 as below.

(21) TABLE-US-00004 TABLE 4 Height of the Height of the cushions at the cushions after 30 Decline No. beginning minutes Rate  #4 8.0 mm 8.0 mm 0  #5 7.5 mm 7.5 mm 0  #6 6.5 mm 6.5 mm 0  #7 5.0 mm 5.0 mm 0  #8 4.5 mm 4.5 mm 0  #9 4.0 mm 4.0 mm 0 #10 4.5 mm 4.5 mm 0 #11 5.0 mm 5.0 mm 0 #12 7.5 mm 7.5 mm 0 #13 8.0 mm 8.0 mm 0 #14 4.0 mm 4.0 mm 0 #15 7.5 mm 7.5 mm 0 #16 8.0 mm 8.0 mm 0 commercially available 5.0 mm 3.0 mm 40.0% HA injection commercially available 7.0 mm 4.0 mm 42.9% HES plasma substitutes commercially available 5.0 mm 2.0 mm 60.0% physiological saline

(22) According to the results as listed in Table 4, the heights of the submucosal cushions formed by the compositions #4 to #16 can last for 30 minutes, while the heights of the submucosal cushions formed by the commercially available HA injection, HES plasma substitutes and physiological saline significantly dropped within 30 minutes after injection.

(23) From the above test results for the compositions #4 to #16, the compositions were able to form a fully bulged submucosal cushions after submucosal injection, and the submucosal cushions can last sufficient time period for surgeries. Therefore, the submucosal cushions formed by the compositions for submucosal injection as described herein were beneficial for separating the lesion mucosa from the muscle layer by doctors, facilitating resection of mucosa, reducing the damage to the submucosal tissue, avoiding complications such as perforation, and inhibiting bleeding due to resection of mucosal tissue. The compositions for submucosal injection comprised biocompatible modified starches, which were swollen in an aqueous solution rather than being dissolved. Therefore, the compositions were significantly superior to other materials that were dissolved in an aqueous solution. After the compositions for submucosal injection comprising the biocompatible modified starches were injected into submucosa, free water molecules contained therein can rapidly diffuse to the surrounding tissues as free water molecules were smaller, while it was difficult for the swollen modified starch molecules to overcome the resistance to diffuse to the surrounding tissues as the swollen modified starch molecules were larger. Therefore, the height of the submucosal cushion can last sufficient time for surgery operation. If a material that was soluble in water (for example, a soluble modified starch) was used, the aqueous solution of such material upon injecting into submucosa easily diffused to the surrounding tissues along the connective tissue between the submucosa and the muscle layer due to formation of homogeneous system with water. Therefore, the height of the submucosal cushion formed by the material that was soluble in water cannot last sufficient time for surgery operation. The compositions for submucosal injection as described herein exhibited improved safety for use in vivo due to utilization of biocompatible modified starches and thus the risk of irritation of local tissues caused by use of other materials was reduced. In addition, the residual biocompatible modified starches after surgery can be rapidly degraded by amylases and/or amylases in the human body within several minutes or hours without affecting tissue healing.

EXAMPLE 2

Apparatus for Delivering the Composition for Submucosal Injection

(24) As shown in FIG. 1, this example illustrated a delivery apparatus as described herein, comprising: a hollow housing 1 with a hollow portion 5 for receiving an injection agent to be delivered, and a proximal end 6a and a distal end 6b, a plunger 2 and a plunger rod 3 coupled to the plunger, and a plunger drive mechanism 4. The plunger 2 was disposed in the hollow portion 5. The plunger rod 3 is configured to drive the plunger 2 to reciprocate in the hollow portion 5, such that the composition for submucosal injection can be delivered out of the distal end 6b from the hollow portion 5. The plunger drive mechanism had a first arm 7a and a second arm 7b pivotally coupled to each other, wherein the first arm 7a and the second arm 7b had a proximal end 7a′ or 7b′ and a distal end 7a ″ or 7b ″. The distal end 7a ″ of the first arm was coupled to the proximal end 6a of the housing, and the distal end 7b ″ of the second arm was coupled to the proximal end of the plunger rod. When the first arm 7a and the second arm 7b were pivoted to force the proximal end 7a′ of the first arm and the proximal end 7b′ of the second arm to move in a direction of facing each other, the second arm 7b forced the plunger rod 3 to drive the plunger 2 to move to the distal end 6b in the hollow portion 5. The first arm 7a was coupled to the second arm 7b by a resilient spring 11, such that the proximal ends of the first and second arms rotated in a direction of facing each other to force the plunger rod to drive the plunger to move in the hollow portion, followed by returning of the first arm and the second arm to an initial position. The plunger rod was also provided with a thread scale corresponding to the amount of formulation delivered. A catheter 10 with a needle 9 was coupled to the distal end of the hollow housing for injecting the composition for submucosal injection into the submucosa.

(25) When using the conventional injection device and the infusion apparatus, doctors needed to operate the syringe with both hands, and thus operation was performed by multiple people at the same time with inconvenience. The delivery apparatus as described herein can be operated by one hand, and was capable of delivering a composition for submucosal injection having conveying resistance as listed in Table 5. From Table 5, the delivery apparatus as described herein can deliver the composition for submucosal injection having a viscosity that is not less than 10 mPa.Math.s at 25° C. The plunger rod of the delivery apparatus as described herein was provided with a thread scale corresponding to the amount of the composition for submucosal injection delivered, so that accurate volume delivered by each bolus injection can be calculated according to the inner diameter of the syringe. Therefore, over-operation of the conventional injection device due to too high resistance can be avoided to accurately control injection dosage.

(26) TABLE-US-00005 TABLE 5 No. Conveying Resistance (N)  #4 175  #5 150  #6 80  #7 30  #8 20  #9 26 #10 33 #11 62 #12 112 #13 200 #14 35 #15 150 #16 200 Commercially Available 88 HA Injection Commercially Available 24 HES Plasma Substitutes Commercially Available 10 Physiological Saline

EXAMPLE 3

Use of the Composition for Submucosal Injection as Described Herein During Resection of the Lesion Mucosa

(27) This example illustrated injection of a composition for submucosal injection comprising carboxymethyl starch sodium and physiological saline into the gastric mucosa of Bama miniature pigs and the effects thereof. 1. Composition for submucosal injection: sample #6, (3 wt % carboxymethyl starch sodium+physiological saline); 2. Animal: Bama miniature pigs, weight: 40 kg; 3. Test method: Bama miniature pigs were placed on an operation table in the supine position with general anesthesia, and then the limbs were fixed. 2 ml injection was submucosally injected directly into anterior wall of the stomach by virtue of Olympus gastroscope, and the control group accepted the same volume of physiological saline. Next, submucosal dissection was performed by incising mucosa with electrosurgical knife under gastroscope. 4. Dosage: 2 ml per injection point; 5. Administration Route: injection under gastroscope; 6. Observation Target: height and strength of submucosal cushion, and formation of submucosal edema. 7. Results: (i) Height and Strength of Submucosal Cushion

(28) The height of the submucosal cushion formed by the sample #6 was above 4 mm lasting for 30 minutes during surgery, and its strength completely satisfied the surgical needs. However, the strength of submucosal cushion formed by physiological saline as control group was very low and cannot meet surgical needs. Therefore, multiple injections were needed during the operation. (ii) Submucosal Edema No edema was observed in the experimental group of injection of sample #6. The submucosal connective tissue exhibited a clear texture and can be easily peeled off by electrosurgical knife. Significant edema was observed in control group of injection of physiological saline, and thus peeling of submucosal connective tissue by electrosurgical knife was hindered.

(29) According to the same method, the composition #11 (4 wt % hydroxypropyl starch diphosphate+physiological saline) and the composition #14 (0.5 wt % cross-linked carboxymethyl starch sodium+physiological saline) were injected into the gastric submucosa of Bama miniature pigs, and the effects were observed.

(30) Results: (i) Height and Strength of Submucosal Cushion The heights of the submucosal cushions formed by the compositions #11 and #14 were over 4 mm during the 30-minute surgery, and the strength thereof completely satisfied surgical needs. In contrast, the strength of submucosal cushion formed by physiological saline as control group was very low and cannot meet surgical needs, and thus multiple injections were needed during the operation. (ii) Submucosal Edema No edema was observed in the experimental groups of injection of samples #11 and #14. The submucosal connective tissue exhibited a clear texture and can be easily peeled off by electrosurgical knife. Significant edema was observed in control group of injection of physiological saline, and thus peeling of submucosal connective tissue by electrosurgical knife was hindered.

(31) The present disclosure is described in greater detail with reference to the specific examples. These examples are merely illustrative, but not intended to limit the scope of the present invention. One having the ordinary skill in the art would understand that various modifications, changes or substitutions may be made without departing from the spirit and scope thereof. Thus, the equivalent variations according to the present invention come within the scope of the present invention.