Patent Publication Number: US-2022226066-A1

Title: Formulation for Gastrointestinal Marking

Description:
CROSS-REFERENCE TO RELATED APPLICATION(S) 
     This application claims the benefit of U.S. Provisional Application No. 63/140,072, filed on Jan. 21, 2021, and U.S. Provisional Application No. 63/286,311, filed on Dec. 6, 2021, the contents of which are hereby incorporated by reference in their entirety for all purposes. 
    
    
     TECHNICAL FIELD 
     This disclosure relates to gastrointestinal endoscopy. 
     BACKGROUND 
     Tattooing may be used in gastrointestinal endoscopic procedures to visually mark tissue, including lesions for endoscopic resection and resection sites for later examination. Tattooing generally includes injection of an ink formulation, which includes carbon black, into gastrointestinal tissue, such as the submucosa. Conventional ink formulations are, however, subject to migration of the carbon black. 
     SUMMARY 
     Disclosed herein are implementations of an ink formulation tattooing gastrointestinal tissue and for tattooing gastrointestinal tissue. 
     In implementation, an ink formulation for gastrointestinal tattooing includes water, carbon black, and hyaluronic acid. 
     The hyaluronic acid may have a molecular weight of 80 kDa, 100 kDa, or more. The hyaluronic acid may be of between 0.2 and 5 times, such as between 0.5 and 2 times, the mass of the carbon black. The hyaluronic acid may be of 0.1% to 2% by mass, such as 0.2% to 0.6% by mass. The water may be of 70%, 75% or more by mass, such as approximately 79.5% by mass. The carbon black may be of 0.1% to 2% by mass, or 0.1% to 1% by mass, such as approximately 0.3% by mass. The ink formulation may further include glycerol, polysorbate (e.g., sorbitan mono-9-octadecenoate poly(oxy-1,2-ethanediyl), also known as polysorbate 80 or by the trade name of Tween 80), and benzyl alcohol. The glycerol may be of 10% to 20% by mass, such as approximately 18% by mass. The polysorbate may be of 0.5% to 1.5% by mass, such as approximately 0.8% by mass. The benzyl alcohol may be of 0.5% to 1.5% by mass, such as approximately 1% by mass. The ink formulation may be sterilized. The ink formulation may not include a dye. 
     In an implementation, a syringe includes the ink formulation as described above. 
     In an implementation, a method is provided for tattooing gastrointestinal tissue, which includes injecting the ink formulation as described above. 
     In an implementation, a radiopaque ink formulation is provided for gastrointestinal imaging, which includes water, carbon black, hyaluronic acid, and a radiopaque formulation. 
     In an implementation, A method of marking a gastrointestinal site includes providing a first volume of a first formulation in a first syringe and providing a second volume of a second formulation in a second syringe. The method further includes coupling the first syringe and the second syringe with an injection needle via a stopcock, directing a portion of the first volume into the injection needle, and inserting the injection needle into a target site. The method also includes directing a portion of the second volume into the injection needle, and directing another portion of the first volume into the injection needle. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The disclosure is best understood from the following detailed description when read in conjunction with the accompanying drawings. It is emphasized that, according to common practice, the various features of the drawings are not to-scale. On the contrary, the dimensions of the various features are arbitrarily expanded or reduced for clarity. 
         FIG. 1  is picture illustrating migration of a conventional ink formulation and a preferred ink formulation 30 days after injection thereof. 
         FIG. 2  is an x-ray image of another preferred ink formulation after injection thereof. 
         FIG. 3  is a picture of a device to mix and deliver the preferred ink formulations, according to one embodiment. 
         FIG. 4  is a picture of another device to mix and deliver the preferred ink formulations, according to another embodiment. 
         FIG. 5  is a picture of another device to mix and deliver the preferred ink formulations, according to another embodiment. 
         FIG. 6  is a block diagram of a method of mixing and delivering the preferred ink formulations. 
     
    
    
     DETAILED DESCRIPTION 
     Disclosed herein are embodiments of various formulations for marking tissue in gastrointestinal endoscopic procedures, which may be less susceptible to migration than conventional ink formulations and may also be visible under x-ray. The formulations can include one or more of an ink formulation, a radiopaque ink formulation, and a radiopaque formulation. 
     As described in further detail below, the formulations generally includes water and hyaluronic acid, and may further include one or more additional materials, such as ink, radiopaque materials, glycerol, benzyl alcohol, and polysorbate. The formulations may be a suspension that includes the water and hyaluronic acid, and which may further include the one or more additional materials. 
     The ink formulation may, for example, be provided in volumes of five cubic centimeters (cc), ten cc, or fifteen cc in a syringe. For example, it may be advantageous to include ten cc syringes of the ink formulation to provide additional volume of the ink formulation over the five cc syringe for priming needles and related equipment for administering the ink formulation. 
     The ink formulation includes the water in a concentration of greater than 70% by mass, such as greater than 75% by mass (e.g., 75% to 90% by mass, for example, 75% to 85%, such as approximately 79.5% or approximately 84%). For example, a 10 cc syringe or other container of the ink formulation may include greater than 7.5 grams of water (e.g., 7.5 to 9.0 grams, for example, 7.5 to 8.5 grams, such as approximately 7.95 grams or approximately 8.4 grams). 
     The ink formulation includes the ink, which may, for example, include carbon black. The ink formulation includes the carbon black in a concentration of 0.005% to 2% by mass (e.g., 0.01% to 1%, such as approximately 0.3% or approximately 1%). 
     The ink formulation may include the visual marking materials that consist essentially of the carbon black. For example, the ink formulation may not include other ingredients used as visual markers in gastrointestinal endoscopy, such as dyes (e.g., indigo carmine (i.e., 5,5′-indigodisulfonic acid sodium salt) or methylene blue (i.e., methylthioninium chloride)). 
     The ink formulation includes the hyaluronic acid and, in particular, includes hyaluronic acid having a molecular weight of approximately 80 kDa or greater, for example, preferably 80 kDa to 1,000 kDa (e.g., 80 kDa to 200 kDa, such as approximately 100 kDa). 
     Without being held to a particular theory, it is believed that hyaluronic acid of such molecular weight may help prevent or hinder migration of the visual marker (i.e., the ink or carbon black) over time, as discussed in further detail below with respect to  FIG. 1 . Hyaluronic acid of lower and higher molecular weight may still prevent or hinder migration of the ink, albeit possibly with lesser effectiveness. Hyaluronic acid of such molecular weight may also have anti-inflammatory effect, while hyaluronic acid of lower molecular weight may cause inflammation. 
     Preventing or otherwise hindering migration of the ink (e.g., the carbon black) provides a benefit of maintaining the location of the visual marker for later reference, for example, to support procedures and/or diagnoses to be performed at a later time and/or by another care provider. For example, the visual marker may be a reference for later-performed endoluminal procedures, such as endoscopic submucosal dissection, or open procedures. 
     Furthermore, preventing or otherwise hindering migration of the ink with the hyaluronic acid and/or the anti-inflammatory effect of the hyaluronic acid may provide other benefits of preventing or otherwise hindering inflammation, fibrosis, and/or granuloma formation that might otherwise occur with the presence and/or spread of ink without the hyaluronic acid. 
     The ink formulation may further include the hyaluronic acid in a concentration of 0.1% to 2% by mass, such as 0.2% to 1% (e.g., 0.2% to 0.6%, such as approximately 0.4%). 
     Instead or additionally, the quantity or concentration of the hyaluronic acid may be expressed in terms of relative concentration, quantity, or mass of the ink (i.e., the carbon black). For example, the ink formulation may include the hyaluronic acid at 0.2 to 5 times (e.g., 0.4 to 2 times, such as approximately 0.4 times or approximately 1.3 times) the concentration or mass of the ink (i.e., the carbon black). 
     As referenced above, the ink formulation may include other ingredients, which may include one or more bulking agents, and/or benzyl alcohol. 
     The ink formulation may also include one or more bulking agents. The one or more bulking agents may, for example, include glycerol, polysorbate, collagen, and/or methylcellulose. The ink formulation may include the one or more bulking agents, if provided, in a total concentration of 10% to 30% by mass (e.g., 10% to 25%, such as approximately 19%). In embodiments in which the one or more bulking agents include glycerol, the ink formulation may include the glycerol in a concentration of 10% to 25% (e.g., 10% to 20%, such as approximately 18%). In embodiments in which the one or more bulking agents include polysorbate, the ink formulation may include the polysorbate in a concentration of 0.2% to 2% (e.g., 0.5% to 1.5%, such as approximately 0.8%). 
     In embodiments in which the one or more bulking agents include both glycerol and collagen, the ink formulation may include the glycerol in a concentration of 1% to 10% (e.g., 2% to 5%, such as approximately 3%) and the collagen in a concentration of 5% to 20% by mass (e.g., 10% to 15%, such as approximately 12%). 
     The ink formulation may also include benzyl alcohol. The ink formulation may include the benzyl alcohol in a concentration of 0.2% to 2% by mass (e.g., 0.5% to 1.5%, such as approximately 1%). 
     The ink formulation may include methocellulose and/or simethicone instead of or in addition to those various other ingredients described above. 
     As referenced above, the ink formulation may be a suspension. For example, the ink formulation may be prepared by mixing the ingredients with a centrifuge, which include the water, the ink, and the hyaluronic acid, and may further include one or more of the additional ingredients if provided (e.g., glycerol, polysorbate, collagen, and/or benzyl alcohol). 
     Furthermore, the ink formulation is sterilized. For example, after mixing the ingredients with the centrifuge to form a pre-sterilization ink formulation, the pre-sterilization ink formulation may be sterilized according to a sterilization process. The sterilization process may include subjecting the pre-sterilization ink formulation to heat and/or pressure for an extended duration to form the ink formulation (e.g., the sterilized ink formulation). For example, the sterilization process may include inserting the pre-sterilization ink formulation into an autoclave and heated to between 100 degrees Celsius and 130 degrees Celsius (e.g., between 110 degrees Celsius and 120 degrees Celsius) for a duration of between 10 minutes and 30 minutes (e.g., approximately 20 minutes), or other sufficient temperate and time duration to sterilize the pre-sterilization ink formulation to form the ink formulation (i.e., the sterilized ink formulation). 
     It should be noted that the sterilization process may alter the concentrations and/or properties of the materials of the pre-sterilization ink formulation. For example, the sterilization process may reduce the concentration of the water of the pre-sterilization ink formulation (e.g., causing evaporation thereof), thus requiring the pre-sterilization ink formulation to include a higher concentration of water than desired for the final concentration of water in the sterilized ink formulation. Furthermore, the sterilization process may change the molecular weight of the hyaluronic acid, for example, reducing the molecular weight of the hyaluronic acid, thus requiring that the pre-sterilization ink formulation include hyaluronic acid of a higher molecular weight that desired for the final molecular weight of the hyaluronic acid in the sterilized ink formulation. 
     In a first preferred example, the ink formulation includes by mass 84% water, 1% carbon black, 0.4% hyaluronic acid having a molecular weight of 100 kDa, 3% glycerol, and 11.6% collagen. 
     In a second preferred example, the ink formulation includes by mass 79.5% water, 0.3% carbon black, 0.4% hyaluronic acid, 18% glycerol, 0.8% polysorbate, and 1% benzyl alcohol. The hyaluronic acid has a molecular weight of approximately 100 kDa, which was provided in the pre-sterilization ink formulation with a molecular weight of approximately 1,000 kDa. 
     Referring to  FIG. 1 , testing was performed in which a conventional ink formulation  102  and the second preferred ink formulation  104  were both injected to tattoo (i.e., provide markers) in a colon  100  of a subject. As shown in  FIG. 1 , 30 days after injection, the conventional ink formulation  102  (outlined in dash-dash lines) migrated significantly to several times its original size (e.g., more than twenty times the visible area), while the second preferred ink formulation  104  (outlines in dash-dot lines) migrated substantially less (e.g., less than five times the original visible area). 
     The conventional ink formulation included by mass greater than 76% water, 10% to 20% glycerol, 0.5% to 1.5% polysorbate, 0.5% to 1.5% benzyl alcohol, and 0.01% to 1% carbon black. The second preferred ink formulation is as described above. 
     The radiopaque ink formulation can include the ink formulation as described above and can also include a radiopaque formulation. Accordingly, the radiopaque ink formulation can be viewed with a visible light camera (e.g., a camera inserted into the target site) and under x-ray imaging (e.g., still x-ray images and/or live x-ray images). 
     The radiopaque formulation may, for example, be provided in volumes of one cc, two ccs, or three ccs in a syringe. For example, it may be advantageous to include three cc syringes of the radiopaque formulation to provide additional volume of the radiopaque formulation over smaller syringes marking multiple locations without changing the syringe being used. 
     The radiopaque formulation can include any biocompatible material that is visible under x-ray. For example, the radiopaque formulation can include one or more biocompatible metals such as titanium (Ti), tantalum (Ta), stainless steel, platinum (Pt), gold (Au), silver (Ag), and any other biocompatible metal. The radiopaque formulation can also include one or more biocompatible polymers such as poly-ether-ether-ketone (PEEK), polycarbonate, etc., where the biocompatible polymers further include radiopaque material such as barium sulfate or one or more of the biocompatible metals above. 
     The radiopaque formulation can be provided as a powder that includes a group of individual grains of the radiopaque formulation. In some embodiments, a size (e.g., a diameter for grains that are spherical, or the longest measurement for grains that are not spherical) of the individual grains of the radiopaque formulation are between ten and two-hundred micrometers (e.g., between twenty and one-hundred-eighty micrometers, such as between forty and one-hundred-fifty micrometers). 
     The radiopaque formulation can also include, for example, hyaluronic acid having a molecular weight of approximately 80 kDa or greater, for example, preferably 80 kDa to 1,000 kDa (e.g., 80 kDa to 200 kDa, such as approximately 100 kDa). 
     The radiopaque formulation can be mixed, for example, with the ink formulation (e.g., to create a radiopaque ink formulation) prior to being injected into a target site. The radiopaque formulation can be mixed by hand, in a centrifuge (as described above), or by any other known method. In some embodiments, the radiopaque formulation and the ink formulation can be mixed as they are being injected into the target site. The radiopaque formulation and the ink formulation can also be injected into the target site separately. Devices and methods used to inject the radiopaque ink formulation into a target site are further described with reference to  FIGS. 3-6 . 
     The radiopaque formulation can also be sterilized in the same manner described above with respect to the ink formulation. 
     With reference to  FIG. 2 , an x-ray image  200  of the radiopaque ink formulation after injection thereof in a colon  202  is shown. The x-ray image  200  was taken twenty-eight days after the radiopaque ink formulation was injected in the colon  202 . The radiopaque ink formulation was injected at four locations in the colon  202  (e.g., a location  230 , a location  232 , a location  234 , and a location  236 ). As shown, twenty-eight days after injection each of the locations  230 - 236  is distinct from each other, allowing for accurate targeting of each of the locations  230 - 236  under x-ray guidance. 
     In some embodiments, the radiopaque formulation is provided without other components or constituents. Accordingly, when using only the radiopaque formulation, the radiopaque formulation can be viewed under x-ray imaging (e.g., still x-ray images and/or live x-ray images) but not with a visible light camera. 
     In some instances, the constituents of the formulations disclosed herein may not remain mixed homogeneously after manufacturing, sterilization, shipping, and any other handling involved. Therefore, it may be necessary to ensure the constituents are properly mixed prior to injection into a target site. 
       FIG. 3  is a picture of a device  300  to mix and deliver the formulations, according to one embodiment. The device  300  is shown as a double-barreled syringe and includes a first barrel  340 , a second barrel  342 , a plunger  344 , and a tip  350 . Each component of the device  300  is generally manufactured from a polymer that does not react with the components held within it. Examples of materials from which the device  300  can be manufactured include polyethylene and polycarbonate. 
     The first barrel  340  and the second barrel  342  are generally cylindrical and tubular in shape, but any other suitable geometric configurations can be used. The first barrel  340  and the second barrel  342  are separate and distinct and are configured to store components to be mixed. For example, the first barrel  340  can store the ink formulation and the second barrel  342  can store the radiopaque formulation. 
     The plunger  344  includes a first arm  346  partially disposed within the first barrel  340  and a second arm  348  partially disposed within the second barrel  342 . Each of the first arm  346  and the second arm  348  may include a sealing component (e.g., an o-ring, a gasket, etc.) to seal against an inner wall of the first barrel  340  and the second barrel  342 , respectively. As the plunger  344  is pressed toward the first barrel  340  and the second barrel  342 , the sealing components interact with the inner walls to drive the components stored within the device  300  toward the tip  350 . 
     The tip  350  is shown covered in  FIG. 2 , however the tip  350  includes a mixing component (not shown) configured to mix the contents of the first barrel  340  with the contents of the second barrel  342  as each of the contents flow through the mixing component. In some embodiments, the mixing component can be a helical mixer that forces the contents to flow through the tip in a helical manner to promote mixing. The mixing component can also include a tortuous path of switchbacks through which the contents must flow to exit the tip. 
     A needle can also be coupled with the tip  350  such that the contents flow through the needle to be injected into the target site. 
       FIG. 4  is a picture of another device  400  to mix and deliver the formulations, according to another embodiment. The device  400  is shown to include a first syringe  450 , a second syringe  452 , and a stopcock  454 . The first syringe  450  and the second syringe  452  are the same size (e.g., both can hold volumes of five cc, ten cc, fifteen cc, etc.). As shown, the first syringe  450  is empty with the plunger fully depressed, and the second syringe  452  includes any one of the formulations disclosed herein. 
     To mix the constituents of the formulation to create a homogeneous mix or an approximately homogeneous mix, the first syringe  450  and the second syringe  452  are each coupled with the stopcock  454 , and the stopcock is positioned to allow flow between the first syringe  450  and the second syringe  452 . Mixing is accomplished by fully depressing the plunger of the syringe in which the constituents are stored to direct the constituents to the empty syringe, thereby filling the empty syringe. In the example configuration shown in  FIG. 4 , the plunger of the second syringe  452  is depressed and the contents of the second syringe (e.g.  452  are directed through the stopcock  454  and into the first syringe  450 , causing the plunger of the first syringe to move to receive the contents. This process can be repeated as needed, thereby moving the contents back and forth between the first syringe  450  and the second syringe  452  until a desirable mix is achieved. After achieving the desirable mix of the formulation, the syringe containing the formulation (e.g., either the first syringe  450  or the second syringe  452 ) is removed from the stopcock  454 . A needle can be coupled with a tip of the syringe, inserted at the target site, and the formulation can be delivered to the target site by depressing the plunger. 
       FIG. 5  is a picture of another device  500  to mix and deliver the formulations, according to another embodiment. The device  500  is shown to include a first syringe  550 , a second syringe  552 , and the stopcock  454 . The first syringe  450  and the second syringe  452  are different sizes. For example, the first syringe  550  may be configured to hold a volume of one cc, two ccs, or three ccs. The second syringe  552  may be configured to hold a volume of five ccs, ten ccs, or fifteen ccs. The volumes disclosed are examples, and the syringes can be configured to hold different volumes as long as the first syringe  550  is configured to hold a lower volume than the second syringe  552 . 
     As shown, the first syringe  550  includes the radiopaque formulation, and the second syringe  552  includes the ink formulation. In some embodiments, the second syringe  552  includes all of the constituents of the ink formulation without the ink (e.g., water, hyaluronic acid, and/or bulking agents), referred to herein as the “non-ink formulation”. The non-ink formulation can be mixed and sterilized as described above with respect to the ink formulation. The formulation in the second syringe  552  may be mixed using the technique described with reference to  FIG. 4 . In some embodiments, the first syringe  550  and the second syringe  552  can be coupled via the stopcock  454  and the contents of first syringe  550  and the second syringe  552  can be mixed using a technique similar to that described with reference to  FIG. 4  prior to injecting into the target site. Additionally, the device  500  can be used to inject the contents of the first syringe  550  and the second syringe  552  into the target site without first mixing the contents together. This injection method is further described with reference to  FIG. 6 . 
       FIG. 6  is a block diagram of a method  600  of mixing and delivering the formulations. As shown, at operation  662  constituents are mixed. For example, constituents of the ink formulation may be mixed according to the technique described with reference to  FIG. 4 . In other embodiments, the constituents can be mixed by hand (e.g., hand shaken, etc.) or with any other kind of mixer (e.g., vibration mixer, etc.). 
     At operation  664 , a first amount of the ink formulation can be directed through a delivery device. For example, and with reference to  FIG. 5 , the first syringe  550  and the second syringe  552  can be coupled with the stopcock  454 , and an injection needle (not shown) can also be coupled with the stopcock  454 . The stopcock  454  can be adjusted to allow flow from the second syringe  552  to the needle, and the plunger of the second syringe  552  can be depressed until the ink formulation exits the tip of the injection needle, thereby priming the injection needle. 
     At operation  666 , the target location is accessed. For example, the location to be marked is observed using a visible light camera, x-ray imaging, or both. The injection needle (while still coupled with the stopcock  454 , the first syringe  550 , and the second syringe  552 ) is inserted to the target location until the tip of the injection needle reaches the target location. The position of the tip of the injection needle can be confirmed via the visible light camera, x-ray imaging, or both. 
     At operation  668 , the radiopaque formulation is directed through the device  500 . For example, the stopcock  454  is adjusted to allow flow between the first syringe  550  and the injection needle. The plunger of the first syringe  550  can then be depressed to direct the radiopaque formulation through the device  500 . In some embodiments, the plunger of the first syringe  550  is fully depressed to direct all of the radiopaque formulation through the device  500 . In some embodiments, the plunger of the first syringe  550  is depressed only a portion of the length of the first syringe  550  to deliver only a portion of the radiopaque formulation through the device  500 . 
     At operation  670 , a second amount of the ink formulation is directed through the device  500 . Based on the size of the injection needle, the radiopaque formulation may or may not reach the target location at operation  668 . For example, the injection needle may be sized such that it can accommodate a volume of approximately one cc and the volume of radiopaque formulation injected may be less than one cc. To ensure that the entire volume of radiopaque formulation reaches the target site, a second amount of the ink formulation is directed through the device  500 . 
     For example, the stopcock  454  is adjusted to allow flow between the second syringe  552  and the injection needle. The plunger of the second syringe  552  is then depressed to direct the second amount of the ink formulation through the device  500 . In some embodiments, the second amount of the ink formulation is approximately the same amount as the first amount of the ink formulation. The second amount of the ink formulation can also be greater than or less than the first amount of the ink formulation as long as the second amount of the ink formulation directs the entire amount of the radiopaque formulation into the target site. 
     The method  600  is described above with the second syringe  552  including the ink formulation such that, after injection, the mark can be viewed with both a visible light camera and under x-ray. The second syringe  552  can also include the non-ink formulation such that the mark can be viewed only under x-ray. 
     The term “approximately,” as used herein, includes a range of +/− 20% of the indicated value. 
     While the disclosure has been described in connection with certain embodiments, it is to be understood that the disclosure is not to be limited to the disclosed embodiments but, on the contrary, is intended to cover various modifications and equivalent arrangements included within the scope of the appended claims, which scope is to be accorded the broadest interpretation so as to encompass all such modifications and equivalent structures as is permitted under the law.