Injectable compositions and related methods

Abstract

This paper describes injectable compositions and methods of use. The injectable compositions may comprise at least one biocompatible material selected from polyethylene glycol (PEG), alginates, methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, chitosan, carboxymethyl chitosan, laponite, gelatin, xanthan gum, or combinations thereof, and a biocompatible salt solution. The composition may be formulated to separate tissue layers by forming a gel within the submucosal tissue. The viscosity of the composition may decrease by at least 50% within 24 hours at 37°C.

Description

Technical Field

[0001] Various aspects of the present disclosure generally relate to compositions and related methods useful for medical treatment. In particular, for example, an injectable composition for separating tissue layers during endoscopic surgery.

Background Art

[0002] Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) aimed at removing lesions usually separate the gastrointestinal (GI) tract mucosal layer (and lesions) from the GI tract muscular layer and use a lifting agent to reduce the risk of GI tract perforation. Physiological saline is generally used as the lifting agent, but since this is rapidly absorbed in the body, multiple reinjections are usually required for long-term medical treatment.

Summary of the Invention

[0003] The present disclosure includes compositions and methods useful for separating tissue layers, for example, during endoscopic surgery. According to some aspects of the present disclosure, the composition may include at least one biocompatible material selected from polyethylene glycol (PEG), alginate, methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, chitosan, carboxymethylchitosan, laponite, gelatin, xanthan gum, or a combination thereof, and a biocompatible salt solution. The composition is formulated to separate tissue layers by forming a gel within the submucosal tissue, and the viscosity of the composition decreases by at least 50% within 24 hours at 37°C.

[0004] In some embodiments, the composition may contain about 0.125% w / v to about 3% w / v of PEG. In some examples, the molecular weight of PEG may be in the range of about 400 Da to 8000 Da. In some examples, the molecular weight of PEG may be in the range of about 1000 Da to 4000 Da. In some examples, the composition may contain about 1% w / v to about 2% w / v of PEG. In some examples, the molecular weight of PEG may be about 3350 Da. In some examples, the biocompatible salt may contain sodium chloride of physiological saline, the physiological saline having a concentration of about 0.7% w / v to about 1.2% w / v. In some examples, the composition may contain about 0.01% w / v to about 0.6% w / v of alginate. In some examples, the composition may contain about 0.1% w / v to about 0.4% w / v of methylcellulose. In some examples, the composition may contain about 0.1% w / v to about 0.6% w / v of hydroxypropyl methylcellulose. In some examples, the composition may contain approximately 0.1% w / v to approximately 0.4% w / v of chitosan.

[0005] In some embodiments, the composition may be contained in a syringe. In some examples, the syringe may include a 23 gauge (0.6 mm outer diameter) needle, and the injection force of the composition through the needle may be less than 60 N.

[0006] This disclosure includes, for example, methods for treating a subject. In some examples, the method may include injecting the composition into the submucosal tissue of the subject. In some examples, the composition can provide a lifting force of at least 6 mm for at least 90 minutes after injection.

[0007] This disclosure includes, for example, a composition comprising a polyethylene glycol (PEG) polymer having a molecular weight in the range of about 400 Da to about 8000 Da in an amount of about 0.125% w / v to about 3% w / v, and a biocompatible salt solution, wherein the composition is formulated to separate tissue layers by forming a gel in the submucosal tissue.

[0008] According to some embodiments, the viscosity of the composition can decrease by at least 50% within 24 hours at 37°C. In some examples, the PEG polymer may have a molecular weight of about 3500 Da.

[0009] This disclosure includes a method for treating a subject, for example, by injecting a composition into the submucosal tissue of the subject, the composition may comprise about 0.125% w / v to about 3% w / v of polyethylene glycol (PEG) polymer and a biocompatible salt solution, the composition can separate tissue layers by forming a gel within the submucosal tissue, and the PEG polymer may have a molecular weight in the range of about 400 Da to about 8000 Da. In some examples, the composition may provide a lifting force of at least 8 mm for at least 60 minutes after injection. [Brief explanation of the drawing]

[0010] The accompanying drawings, incorporated into this application and constituting part of this application, illustrate aspects of this disclosure and, together with the specification, explain the principles of this disclosure. [Figure 1] As explained in Example 1, the injection force is shown according to the syringe plunger distance. [Figure 2] As explained in Example 2, the height of tissue lift over time is shown. [Figure 3] As explained in Example 3, it exhibits a change in viscosity over time. [Figure 4A] Figures 4A to 4C show the tissue elevation height over time and corresponding photographs, as explained in Example 5. [Figure 4B] Same as above. [Figure 4C] Same as above. [Figure 5A] Figures 5A and 5B show the normalized tissue lift height over time and corresponding photographs, as described in Example 6. [Figure 5B] Same as above. [Figure 6A] Figures 6A and 6B show the normalized tissue lift height over time and corresponding photographs, as described in Example 7. [Figure 6B] Same as above. [Figure 7A] Figures 7A and 7B show the injection force data described in Example 8. [Figure 7B] Same as above. [Modes for carrying out the invention]

[0011] Detailed explanation The general description above and the detailed description below are for illustrative and illustrative purposes only and do not limit the claimed features.

[0012] As used herein, the terms “include,” “contain,” or other variations thereof are intended to be non-exclusive. That is, a process, method, composition, article, or apparatus that includes a list of elements may include not only those elements but also other elements not expressly listed, or other elements that may be associated with such a process, method, composition, article, or apparatus. The term “exemplary” is used in the sense of “example,” not “ideal.”

[0013] As used herein, the singular forms “one,” “this,” and “the foregoing” also include the plural form unless otherwise indicated by the context. The term “about” means approximately the same as the number or value being referenced. As used herein, the term “about” should be understood to include ±5% of the specified quantity or value. All ranges are understood to include the endpoints. For example, a quantity in the range from 0.1g to 10g includes 0.1g, 10g, and all values ​​in between.

[0014] This disclosure includes injectable compositions formulated to form a gel for separating tissue layers during medical procedures, such as endoscopic surgery. The compositions can be injected into the submucosa of the GI duct to lift and / or elevate the GI duct mucosa and / or lesion from the GI duct muscularis layer, for example, during EMR or ESD. These compositions can reduce the risk of tissue perforation of the GI duct. These compositions may be biodegradable. The compositions herein can be delivered to the target by an appropriate medical device, such as a catheter inserted through an endoscope.

[0015] The compositions herein may offer a variety of properties and / or characteristics, including, among other things, a decrease in viscosity under shear strain (shear thinning). Such properties allow the compositions to be injected and delivered to a target site via appropriate medical devices, such as single / multi-lumen catheters including endoscopes, and syringes, among other devices useful for medical procedures. The compositions herein can form gels in separate layers of the target site and / or tissue. The compositions herein can separate tissue over a long period of time, reducing and / or eliminating the need for multiple injections during medical procedures such as EMR and ESD. The compositions herein may be biocompatible.

[0016] The composition herein may comprise one or more biocompatible materials and physiological saline. For example, one or more biocompatible materials may include polyethylene glycol (PEG), alginates, carboxymethylcellulose, chitosan (e.g., carboxymethyl chitosan), methylcellulose, hydroxypropyl methylcellulose, laponite, gelatin, xanthan gum, and combinations thereof. The biocompatible material may also comprise a mixture of nanosilicates, gelatin, and tantalum, for example, a mixture of gelatin and nanoclay.

[0017] In the case of polymers such as PEG that may have different molecular weights depending on the amount of overlap or cross-linking, or that may encompass a range of molecular weights, the biocompatible material can be selected to have a molecular weight suitable for the desired properties of the composition. For example, in materials with a high degree of polymerization and cross-linking, the degradation time can be longer compared to materials with less polymerization and cross-linking. Further, for example, the molecular weight of the biocompatible material can affect other properties of the composition, such as viscosity and shear strength.

[0018] According to some aspects of the present disclosure, the biocompatible material can include PEG having a molecular weight in the range of, among other possibilities, from about 400 Da (g / mol) to about 8000 Da, such as from about 400 Da to about 600 Da, from about 900 Da to about 1000 Da, from about 1450 Da to about 1540 Da, from about 2000 Da to about 3000 Da, from about 3350 Da to about 4000 Da, or from about 4600 Da to about 8000 Da. In some examples, the biocompatible material includes hydroxypropyl methylcellulose having a molecular weight in the range of less than 50,000 Da, such as from about 10,000 Da to 50,000 Da. In some examples, the biocompatible material includes hydroxypropyl methylcellulose having a molecular weight in the range of 50,000 Da or more, such as from about 50,000 Da to 60,000 Da. In some examples, the biocompatible material includes chitosan having a molecular weight in the range of less than 100,000 Da, such as from about 25,000 Da to 100,000 Da.

[0019] According to some aspects of the present disclosure, the composition can include from about 0.01% w / v to about 30% w / v of the biocompatible material, such as from about 5% w / v to about 15% w / v, from about 2% w / v to about 7% w / v, from about 12% w / v to about 20% w / v, from about 8% w / v to about 16% w / v, from about 4% w / v to about 10% w / v, from about 0.1% w / v to about 8% w / v, from about 0.125% w / v to about 3.0% w / v, from about 1.0% w / v to about 2.0% w / v, from about 0.01% w / v to about 0.6% w / v, from about 0.1% w / v to about 0.6% w / v, or from about 0.1% w / v to about 0.4% w / v.

[0020] In some examples, the composition comprises from about 0.125% w / v to about 20.0% w / v PEG, such as from about 0.0125% w / v to about 3% w / v PEG, or from about 1.0% w / v to about 2.0% w / v PEG. In some examples, the composition comprises at least 12.5% w / v PEG, such as PEG in the range of about 12.5% w / v to about 20% w / v. In some examples, the composition comprises from about 0.01% w / v to about 0.6% w / v alginate, such as about 0.0625% w / v, about 0.125% w / v, about 0.25% w / v, or about 0.5% w / v. In some examples, the composition comprises from about 0.1% w / v to about 0.6% w / v hydroxypropylmethylcellulose, such as about 0.125% w / v, about 0.25% w / v, or about 0.5% w / v. In some examples, the composition comprises from about 0.1% w / v to about 0.4% w / v methylcellulose, such as about 0.125% w / v or about 0.25% w / v. In some examples, the composition comprises from about 0.1% w / v to about 0.6% w / v chitosan, such as about 0.25% w / v or about 0.5% w / v.

[0021] The composition may comprise a biocompatible and / or physiological saline solution, such as sodium chloride saline. In some examples, the composition may comprise a saline solution having a concentration in the range of about 0.7% w / v to about 1.2% w / v, such as about 0.9% w / v.

[0022] As described above, the composition herein can be delivered to a target site of a subject via a suitable medical device. For example, the composition herein can be filled into a syringe attached to a hypodermic needle and injected into the submucosal tissue. The composition herein can separate tissue layers by forming a gel within the submucosal tissue. The composition may have shear strength properties that facilitate injection. For example, when passing through a 23-gauge (outer diameter 0.6 mm) needle, the composition may exhibit an injection force of less than 60 N, such as in the range of about 20 N to 60 N, or in the range of about 20 N to about 50 N. In some examples, the composition herein may exhibit an injection force of less than 50 N, such as in the range of about 30 N to 50 N, when passing through a 23-gauge needle.

[0023] The compositions herein may provide appropriate separation of tissue layers and / or distance between tissue layers during a medical procedure. In some examples, the distance between tissue layers provided by the composition at the time of injection may be at least 6 mm, for example, in the range of 6 mm to 15 mm. For example, the distance between tissue layers may be at least 8 mm, at least 10 mm, or at least 12 mm. The distance between tissue layers is maintained for at least 30 minutes, for example, 30 minutes to about 2 hours, or about 90 minutes. In some examples herein, the distance between tissue layers maintained by the composition may be at least 8 mm for at least 60 minutes. In some examples, the distance between tissue layers maintained by the composition may be at least 10 mm for at least 30 minutes. In some examples, the distance between tissue layers maintained by the composition may be at least 12 mm during the initial injection.

[0024] The viscosity of the composition here may decrease over time at 37°C, for example, during decomposition or bioabsorption. For example, the viscosity may decrease by at least 50% within 24 hours at 37°C after injection. In some cases, the viscosity may decrease by at least 70% within 72 hours at 37°C after injection.

[0025] Examples The following examples are intended to illustrate aspects of the Disclosure, but are not inherently limiting. It is understood that the Disclosure includes additional embodiments that are not inconsistent with the foregoing description and the following examples. The Disclosure is not limited to the examples further described below and includes additional conditions without departing from the scope of the Disclosure.

[0026] Example 1 A test was conducted to evaluate the injection strength of a PEG-containing composition compared to physiological saline (NERL® blood bank saline). PEG3350 (Sigma Aldrich) was dissolved at a 2% w / v concentration in 0.9% w / v physiological saline. To improve visibility, one drop of FD&C Blue 1 was used per 20 mL of solution. Sterile solutions were prepared by bottle-top vacuum filtration through a 0.2 μm aPES filter membrane.

[0027] The injection force was measured for two samples of each solution. Each sample was filled into a glass syringe fitted with a 23-gauge (0.6 mm outer diameter) needle. The solution was injected at 0.4 mL / second, and the injection force was measured as the syringe plunger traveled a distance of 30 mm. Figure 1 shows the injection force (N) as a function of syringe plunger distance (mm). The PEG3350 solution showed an injection force of less than 60 N at its maximum.

[0028] Example 2 The tissue-lifting ability of the composition in Example 1 was evaluated in an in vitro model. 2 cc of PEG3350 solution was injected into the submucosa of porcine colon tissue using a 10 mL syringe and a 23 gauge (0.6 mm outer diameter) needle. The tissue height was measured every 30 minutes. Figure 2 shows the tissue lift height (mm) over time (minutes). With the PEG3350 solution, the height was approximately 12 mm (0 min) after the initial injection, but decreased to approximately 11 mm at 30 mins, approximately 9 mm at 60 mins, and approximately 6 mm at 90 mins. A clearly different behavior was observed with physiological saline, where the height decreased rapidly.

[0029] Example 3 The degradation of the PEG3350 solutions in Examples 1 and 2 was investigated to evaluate how the material behaves in the body after injection. Viscosity changes were monitored over time at 37°C. As shown in Figure 3, the viscosity decreased by approximately 70% in 24 hours.

[0030] Example 4 Various compositions (A-S) were prepared according to Tables 1-7 below. Comparative compositions (T-V) were prepared according to Tables 8 and 9. Compositions A-Q and T-V were prepared with 0.9% physiological saline solution. Compositions R and S were prepared with water. The injection force tested as described in Example 2 is also noted. Compositions A-S showed injection forces within the target specifications, while compositions T-V showed injection forces outside the desired range.

[0031] [Table 1]

[0032] [Table 2]

[0033] [Table 3]

[0034] [Table 4]

[0035] [Table 5]

[0036] [Table 6]

[0037] [Table 7]

[0038] [Table 8]

[0039] [Table 9]

[0040] Example 5 Compositions were prepared using PEG4000 2% w / v (2), carboxymethylcellulose (CMC) 2% w / v (3), physiological saline 0.9% w / v (4), alginate 2% w / v (5), and chitosan 2% w / v (6), and their ability to lift tissue in an in vitro model was evaluated. Porcine colon tissue was thawed overnight. 2 cc of each composition was injected into the submucosa of the sigmoid colon and descending colon using a 10 mL Luer lock syringe and a 25 gauge (0.5 mm outer diameter) needle. Tissue height was measured every 30 minutes with a ruler. Figure 4A shows the tissue lift height (mm) over time (minutes). Figure 4B is a photograph of porcine colon tissue at various sites after initial injection of the composition, and Figure 4C is a photograph of the porcine colon 60 to 90 minutes after injection.

[0041] Example 6 Compositions were prepared using 1% w / v alginate (non-sterile), 2% w / v PEG4000 (non-sterile), 1% w / v alginate (sterile), 2% w / v PEG4000 (sterile), and 0.9% w / v physiological saline, and their ability to lift tissue in an in vitro model was evaluated. FD&C Blue1 was used with each composition to improve visibility. 2 cc of each composition was injected into the submucosa of sow tissue using a 10 mL syringe and a 25 gauge (0.5 mm outer diameter) needle. Figure 5A shows the normalized tissue height (mm) over time (minutes), and Figure 5B is a photograph of pig colon tissue after injection of the composition at various locations within the tissue. In Figure 5B, sample 2 corresponds to PEG4000 2% w / v (sterile), sample 3 to alginate 1% w / v (non-sterile), sample 9 to physiological saline 0.9% w / v, and sample 10 to alginate 1% w / v (sterile).

[0042] Example 7 To evaluate the tissue-lifting ability in an in vitro model, compositions were prepared using 8.910% w / v laponite / 1.080% w / v gelatin (non-sterile) and 0.9% w / v physiological saline. 0.5 mL or 1 mL of the sample was injected into the submucosa of porcine colon tissue. Figure 6A shows the normalized tissue height (mm) over time (minutes), and Figure 6B is a photograph of porcine colon tissue after injection of the composition at various locations within the tissue. In Figure 6B, sample 11 corresponds to the injection of 1 mL of 8.910% w / v laponite / 1.080% w / v gelatin (non-sterile), and sample 12 corresponds to the injection of 0.5 mL of 8.910% w / v laponite / 1.080% w / v gelatin (non-sterile).

[0043] Example 8 As described above in Example 4, the injection force was measured for various compositions prepared using laponite 8.910% w / v / gelatin 1.080% w / v, chitosan 2% w / v, alginate 2% w / v (non-sterile), carboxymethylcellulose (CMC) 2% w / v, glycerol, alginate 1% w / v (non-sterile), alginate 1% w / v (sterile), PEG4000 2% w / v (sterile), PEG4000 2% w / v (non-sterile), and physiological saline 0.9% w / v. Figure 7A shows the maximum injection force (N) and overall injection force (N) for each composition. Figure 7B also shows the average force (N) depending on the syringe plunger distance (mm). The composition prepared with laponite 8.910% w / v / gelatin 1.080% w / v was observed to have the highest maximum force.

[0044] It will be apparent to those skilled in the art that various modifications and changes can be made to the disclosed devices and methods without departing from the scope of this disclosure. Other aspects of this disclosure will be apparent to those skilled in the art from the examination of this specification and the practice of the features disclosed herein. This specification and the examples are intended to be for illustrative purposes only, and the true scope and spirit of this disclosure are set forth by the following claims.

Claims

1. An injectable composition, At least one biocompatible material selected from polyethylene glycol (PEG), alginate, methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, chitosan, carboxymethyl chitosan, laponite, gelatin, xanthan gum, or a combination thereof, and Biocompatible salt solution Includes, The composition is formulated to separate tissue layers by forming a gel within the submucosal tissue. The viscosity of the composition decreases by at least 50% within 24 hours at 37°C.

2. The composition according to claim 1, comprising approximately 0.125% w / v to approximately 3% w / v of PEG.

3. The composition according to claim 1 or 2, wherein the molecular weight of the PEG is in the range of approximately 400 Da to 8000 Da.

4. The composition according to any one of claims 1 to 3, wherein the molecular weight of the PEG is in the range of approximately 1000 Da to 4000 Da.

5. The composition according to any one of claims 1 to 4, comprising approximately 1% w / v to approximately 2% w / v of PEG.

6. A composition according to any one of claims 1 to 5, comprising approximately 2% w / v PEG.

7. The composition according to any one of claims 1 to 6, wherein the molecular weight of the PEG is approximately 3350 Da.

8. The composition according to any one of claims 1 to 7, comprising physiological saline having a concentration of approximately 0.7% w / v to approximately 1.2% w / v.

9. A composition according to any one of claims 1 to 8, comprising approximately 0.01% w / v to approximately 0.6% w / v of alginate.

10. A composition according to any one of claims 1 to 9, comprising approximately 0.1% w / v to approximately 0.4% w / v methylcellulose.

11. A composition according to any one of claims 1 to 10, comprising approximately 0.1% w / v to approximately 0.6% w / v hydroxypropyl methylcellulose.

12. A composition according to any one of claims 1 to 11, comprising approximately 0.1% w / v to approximately 0.4% w / v of chitosan.

13. A delivery device, such as a syringe, comprising the composition described in any one of claims 1 to 12.

14. The delivery device according to claim 13, wherein the syringe includes a 23 gauge (0.6 mm outer diameter) needle, and the composition has an injection force of less than 60 N through the needle.

15. Use of the composition according to any one of claims 1 to 14 for separating the submucosal layers of the target tissue.

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