JP5206616B2 - Composition for gastrointestinal imaging in CT colonography - Google Patents

Description

  The present invention relates to a composition for gastrointestinal imaging and a kit or package for gastrointestinal imaging in CT colonography.

Large intestine examination (CT colonography) by computed tomography (CT) is an examination method that is becoming common with the development of helical CT and multi-row detector CT. In order to successfully draw a 3D image of the large intestine using a multi-row detector CT such as MDCT (Multi detector-row CT), it is necessary to eliminate the intestinal contents in the intestinal preparation, and the presence of feces and liquid residues Is greatly involved in the ability to visualize lesions. However, when an oral intestinal cleanser is used to reduce residual stool, there is a problem that liquid residue increases.

  For this reason, it is preferable to perform a colonoscopy prior to MDCT to aspirate the liquid residue. Colonoscopy is a method of inspecting the colon lumen visually through a scope by inserting a flexible tube, called a coronoscope, and a flexible tube integrated with an endoscope. In colonoscopy, a doctor operates a tube to detect a lesion such as a tumor in the colon lumen.Some patients have an uncomfortable tube inserted in their body and have a long examination time. There is a case that complains about pain, and good evaluation is not always obtained from the viewpoint of patient acceptability (compliance).

  On the other hand, in the above-mentioned Patent Document 1, for example, when a barium sulfate aqueous suspension is used as a contrast agent, based on the knowledge that the gastrointestinal motility promoter improves the contrast ability of the X-ray contrast agent for gastrointestinal examination, Use is suggested.

  Further, although a simple method has been proposed as a pretreatment method for CT, there remains a problem as a pretreatment method for precise examination in that the imaging ability is sacrificed.

JP 2002-53496 A

  Thus, the object of the present invention is to enable visualization of residual water of the intestinal lavage fluid or liquid residue of intestinal fluid that often appears in the colon cavity after intestinal lavage in examinations such as colon cancer by CT colonography. An object of the present invention is to provide a composition for gastrointestinal tract imaging and a liquid for oral administration, which reduce the burden on the stomach and have high visualization ability.

  The present inventors have successfully solved the problem of liquid residue when using an oral intestinal irrigant in the pretreatment of CT colonography, and as a result of various investigations on a composition for gastrointestinal imaging with excellent imaging ability, The present invention has been completed.

  That is, the present invention includes the following aspects.

(1) Gastrointestinal imaging composition containing an iodine compound, comprising a colloid osmotic pressure adjusting agent and / or a crystalline osmotic pressure adjusting agent, and a composition for CT colonographic gastrointestinal imaging .

  (2) The colloid osmotic pressure adjusting agent is at least one selected from the group consisting of polyethylene glycol, polydextrose, dextran, dextrin, hydroxyethyl starch, gum arabic, pullulan, pectin, albumin and carboxymethylcellulose. The composition for gastrointestinal imaging according to (1) above.

  (3) The composition for gastrointestinal tract imaging according to (1) or (2) above, wherein the crystalline osmotic pressure adjusting agent is an electrolyte or an electrolyte and a saccharide.

  (4) The above (3), wherein the saccharide is at least one saccharide selected from the group consisting of sorbitol, xylitol, erythritol, mannitol, trehalose, lactitol, lactulose, maltitol, palatinose, raffinose and glycerin. The composition for gastrointestinal tract imaging as described.

  (5) A liquid preparation for oral administration in gastrointestinal imaging containing an iodine compound, wherein the iodine content is 15 to 90 mg / mL.

(6) Polyethylene glycol, polydextrose, dextran, dextrin, hydroxyethyl starch containing an electrolyte such that Na ⁺ is 30 to 150 mEq / L, K ⁺ is 3 to 20 mEq / L, and Cl ⁻ is 20 to 70 mEq / L. At least one colloid osmotic pressure regulator selected from the group consisting of gum arabic, pullulan, pectin, albumin and carboxymethylcellulose and / or sorbitol, xylitol, erythritol, mannitol, trehalose, lactitol, lactulose, maltitol, palatinose, The liquid for oral administration according to the above (5), which contains at least one saccharide selected from the group consisting of raffinose and glycerin.

  (7) Both (a) an aqueous solution containing an iodine compound and (b) an aqueous solution or solid agent containing a colloid osmotic pressure regulator and / or a crystalline osmotic pressure regulator are filled together or in separate containers. CT colonography digestive tract imaging kit or package characterized by being sealed.

  (8) Between the first storage chamber filled with an aqueous solution containing an iodine compound, the second storage chamber filled with a solid agent containing a colloid osmotic pressure adjusting agent and / or a crystalline osmotic pressure adjusting agent, and both chambers A gastrointestinal tract imaging kit or package comprising a multi-chamber container comprising a releasable isolating means disposed in the chamber and a port member communicating with one chamber.

  According to the present invention, in the examination of colon cancer or the like by CT colonography, it is possible to visualize the residual water of the intestinal lavage fluid or the liquid residue storage of the intestinal fluid that often appears in the colon cavity after intestinal lavage. A composition for gastrointestinal imaging and a liquid for oral administration can be easily provided with reduced burden and high visualization ability.

An air image in CT colonography is shown (Experimental example 1). An iodinated contrast image in CT colonography is shown (Experimental Example 1). A composite image of an air image and a contrast image in CT colonography is shown (Experiment 1).

Hereinafter, the present invention will be described in detail.
Examples of the iodo (iodine) compound used in the composition for gastrointestinal imaging or the liquid for oral administration of the present invention include organic iodo compounds such as triiodobenzenes having iodine bonded to the 2, 4 and 6 positions of the benzene ring. be able to. Specific compounds include amidotrizoic acid (chemical name 3,5-diacetamino-2,4,6-triiodobenzoic acid), sodium amidotrizoate meglumine, amidotrizoic acid meglumine, sodium iotaramate, meglumine iotaramate, iotroxic acid Examples include meglumine, iotrolane, ioxagric acid, ioxirane, iopamidol, iopromide, iohexol, ioversol, and iomeprol.

  Each iodo compound may exhibit side effects such as anaphylaxis-like reaction, and can be appropriately selected depending on the patient background such as allergic constitution.

  The use of sodium amidotrizoate meglumine is particularly preferred for patients with a low risk of side effects such as allergic constitution from the standpoint of pharmaceutical stability and cost.

  Sodium amidotrizoate meglumine can be prepared as an aqueous solution containing 1 to 70 g of amidotrizoic acid, 5 to 700 mg of sodium hydroxide and 1 to 20 g of meglumine in 100 mL, and should be blended with other ingredients such as a colloid osmotic pressure regulator. Is preferred. More preferably, a solution prepared as an aqueous solution containing 55 to 65 g of amidotrizoic acid, 600 to 650 mg of sodium hydroxide and 14 to 18 g of meglumine in 100 mL is preferable.

  Examples of the colloid osmotic pressure adjusting agent of the gastrointestinal contrast medium of the present invention include polyethylene glycol, polydextrose, dextran, dextrin, hydroxyethyl starch, gum arabic, pullulan, pectin, carboxymethyl cellulose and the like. Among these, a polymer selected from polydextrose, dextran, hydroxyethyl starch, gum arabic, pullulan and pectin is particularly preferable from the viewpoint of pharmaceutical stability and the like.

  As the crystalline osmotic pressure adjusting agent, an electrolyte or a mixture of an electrolyte and a saccharide is used. As a preferable composition for gastrointestinal imaging in CT colonography, particularly screening examination, a mixture of an electrolyte and a saccharide can be mentioned because it is excellent in patient acceptability including formulation stability and ease of administration. .

The electrolyte refers to a substance that is dissociated into ions in the solution, and includes Na ⁺ , K ⁺ , Ca ⁺⁺ , Mg ⁺⁺ , Cl ⁻ , HCO ₃ ⁻ , SO ₄ ⁻⁻ , HPO ₄ ⁻⁻ , an organic acid group, An organic base etc. can be mentioned. More specifically, examples include the same compounds as those used in intravenously administered electrolyte infusions and the like. Sodium ion sources include sodium chloride, sodium acetate, sodium citrate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium sulfate, sodium lactate, etc., and potassium ion sources include potassium chloride, potassium acetate, citric acid Potassium, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium sulfate, potassium lactate, etc., calcium ion sources include calcium chloride, calcium gluconate, calcium pantothenate, calcium lactate, calcium acetate, calcium glycerophosphate, Magnesium sulfate, magnesium chloride, magnesium acetate, magnesium citrate, etc. as magnesium ion sources, and sodium dihydrogen phosphate, disodium hydrogen phosphate, glyceroline as phosphate ion sources Examples of sodium ion include sodium chloride, potassium chloride, calcium chloride, and magnesium chloride as the chloride ion source, and sodium bicarbonate as the bicarbonate ion source. These compounds are in the form of hydrates. It may be.

The saccharide mixed with the electrolyte includes sugar alcohol in addition to sugar. Specific examples include sorbitol, xylitol, erythritol, mannitol, trehalose, lactitol, lactose, maltitol, palatinose, raffinose, glycerin and the like. Among these, xylitol, sorbitol, lactulose, lactitol and raffinose are particularly preferable for reasons such as formulation stability and patient acceptability including ease of administration.

  The above-mentioned colloid osmotic pressure adjusting agent and / or crystalline osmotic pressure adjusting agent, which is an active ingredient of the composition for gastrointestinal tract imaging of the present invention, minimizes fluctuations in serum electrolyte balance and osmotic pressure in vivo. It is an important ingredient. As the osmotic pressure adjusting agent, the colloid osmotic pressure adjusting agent and the crystalline osmotic pressure adjusting agent are used alone or in combination. The amount is adjusted depending on the time until the CT colonography examination after intestinal lavage and the contents of the meal on the day before the patient's examination, etc. For the above reasons, it is dissolved in water and has an osmotic pressure of 200 to 500 mOsm / L. It is preferable to use as. More preferably, the type and amount of each component should be selected so that the isotonic pressure range of 320 to 360 mOsm / L or an osmotic pressure range close to isotonicity can be adjusted.

  In the composition for gastrointestinal imaging of the present invention, it is preferable to adjust the iodine content that affects the gastrointestinal imaging ability to 15 mg / mL or more in order to depict the residual water of the intestinal lavage fluid and the liquid residue storage of the intestinal fluid, More preferably, it is adjusted to 18-80 mg / mL. In particular, a liquid preparation of 350 to 450 mL with an iodine content adjusted to 18 to 19 mg / mL is preferable because it can clearly depict the liquid residue storage part of the intestinal irrigation solution and reduce the burden of the patient on the contrast medium.

The usage-amount of a colloid osmotic pressure regulator is 2-40 grams, for example in a 400 mL liquid formulation, Preferably it is 10-30 grams. In order to balance the electrolytic mass absorbed from the intestinal tract and the electrolytic mass secreted into the intestinal tract and maintain the serum electrolyte balance, when the gastrointestinal contrast composition is dissolved in water, Na ⁺ : 30 to 150 mEq / L, It is preferable to add an electrolyte such that K ⁺ : 3 to 20 mEq / L, Cl ⁻ : 20 to 70 mEq / L, and HCO ₃ ⁻ : 10 to 50 mEq / L. In order to suppress the absorption of moisture and electrolytes in the intestinal tract of the gastrointestinal contrast solution dissolved in water, it is preferable to add hardly absorbable ions such as magnesium ions and sulfate ions. In the case of magnesium ions, when the composition for gastrointestinal imaging is dissolved in water, it is preferably adjusted to 40 to 120 mEq / L. In the case of sulfate ions, when the composition for digestive tract imaging is dissolved in water, it is preferably adjusted to 40 to 120 mEq / L. When the saccharide is used as the crystalline osmotic pressure adjusting agent, the amount used is 2 to 40 grams, preferably 5 to 10 grams, in a 400 mL solution. As a preferable formulation, a mixture of a colloid osmotic pressure adjusting agent and an electrolyte, or a mixture of an electrolyte and a saccharide as a crystalline osmotic pressure adjusting agent can be exemplified.

  Also, iodine compounds are very bitter. Therefore, it is preferable to apply taste-masking or flavoring means to the composition for gastrointestinal tract imaging of the present invention. For example, a liquid preparation can be easily taken by adding a sweetener such as saccharin sodium and a citrus flavor.

  The colloid osmotic pressure adjusting agent and / or the crystalline crystalline osmotic pressure adjusting agent contained as an active ingredient in the composition for gastrointestinal tract imaging of the present invention, after adjusting the particle diameter so that each component can be mixed, It is preferable to fill an airtight container, seal and wrap it, and place it in circulation. And it is suitable for the purpose of use to adjust the internal volume so that one package can be taken as, for example, a 400 mL liquid preparation. In particular, for easy use and convenience of use, it is preferable to adjust the internal volume so that all of the iodine compound and other components are dissolved in 350 to 450 mL in one package.

In addition, before administering the composition for gastrointestinal tract imaging of the present invention, the intestinal contents are eliminated by pretreatment with an oral intestinal irrigant. As a specific example of the oral intestinal irrigant, a combination of polyethylene glycol and an electrolyte is used. (For example, “NIFLEC” (trade name) relating to the invention disclosed in JP-A-1-125319, manufactured by Ajinomoto Pharma Co., Ltd.).

Hereinafter, the present invention will be described in more detail with reference to test examples.
Example 1: Gastrointestinal imaging composition (liquid preparation)
2.93 g of sodium chloride, 1.49 g of potassium chloride, 3.37 g of sodium bicarbonate, 11.37 g of anhydrous sodium sulfate, 118 g of polyethylene glycol, 59.74 g of amidotrizoic acid, 629 mg of sodium hydroxide, 15,92 g of meglumine, calcium diedetate 10 mg of sodium, 200 mg of saccharin sodium, and orange flavor were dissolved in water to make 2 L.

Example 2: Gastrointestinal contrast medium preparation kit 2.93 g of sodium chloride, 1.49 g of potassium chloride, 3.37 g of sodium hydrogen carbonate, 11.37 g of anhydrous sodium sulfate and 118 g of polyethylene glycol are mixed to obtain a mixed powder. .

  On the other hand, 59.74 g of amidotrizoic acid, 629 mg of sodium hydroxide, 15,92 g of meglumine, 10 mg of calcium disodium edetate, 200 mg of saccharin sodium, and orange flavor are dissolved in water to prepare 100 mL of sodium amidotrizoate meglumine solution.

  27.43 g of the mixed powder is filled in an oxygen and carbon dioxide hardly permeable plastic container body having an internal volume capable of accommodating 400 mL of an aqueous solution, and 20 mL of the sodium amidotrizoate meglumine solution is placed in a small chamber provided in the cap part of the container body. And sealed with a breakable film. This multi-chamber plastic container separately contains the powder component and the liquid component for gastrointestinal tract imaging of the present invention, and is provided with a filling port capable of filling water. At the time of use, after filling a predetermined amount of water from the filling port and dissolving the powder component, the cap film is pressed to break the sealing film filled with sodium amidotrizoate meglumine solution and dissolve the sodium amidotrizoate meglumine solution and powder component The liquid is configured to be mixed in the container.

Example 3: Gastrointestinal imaging composition (liquid formulation in a container)
75.6 g of magnesium citrate, 2.93 g of sodium chloride, 1.49 g of potassium chloride, 3.37 g of sodium bicarbonate, 11.37 g of anhydrous sodium sulfate, 59.74 g of amidotrizoic acid, 629 mg of sodium hydroxide, 15,92 g of meglumine, edet Disodium 10 mg calcium disodium, 200 mg saccharin sodium, and orange flavor were dissolved in water to 2 L. This solution was filled and sealed in a plastic container having an inner volume of 450 mL and hardly permeable to oxygen and carbon dioxide, and sterilized by heating.

Test Example 1: MDCT imaging For preoperative cases of colorectal cancer without ileus symptoms, 137.16 g of oral intestinal cleanser (trade name “NIFREC” manufactured by Ajinomoto Pharma Co., Ltd.) was dissolved in water to 2 L, of which 1620 mL was orally After administration and elimination of intestinal contents, 400 mL of the liquid preparation of Example 1 was orally administered. MDCT imaging was performed when the excretory fluid became transparent. MDCT is "Aquilion M8"
(Manufactured by Toshiba), the imaging conditions are detector configuration 8 × 2 mm, helical pitch 7.0-13.0, tube voltage 120 kV, tube current is 250-300 mA, 0.5 sec / Rot depending on the abdominal thickness. It was. The image processing workstation uses “ZIOM900” (manufactured by zio Software) to perform three-dimensional image processing by the Volume Rendering method. Both iodine contrast images (FIG. 2) were constructed, and both image data were synthesized (FIG. 3).

Imaging Results By using the preparation for gastrointestinal tract imaging of the present invention, it becomes possible to depict the intestinal tract that is missing due to liquid residue in the conventional pretreatment, and colon cancer and diverticula that cannot be observed with the air image shown in FIG. It can be observed in FIG. 3, which is a composite image of this and the iodine contrast image shown in FIG. In addition, it is useful as preoperative information that the intestinal tract can be drawn throughout the large intestine.

  As described above, the composition for gastrointestinal tract imaging of the present invention can construct a liquid residue in the large intestine as an iodinated contrast image, and is easily mixed and diluted when reaching the liquid residue scattered in the intestine due to the characteristics of the composition. In addition, it provides an appropriate increase in X-ray absorption. As a result, the large intestine portion containing the liquid residue that could not be drawn due to submergence in the past can be drawn by synthesizing with the air image, and the inspection accuracy can be improved.

Test Example 2: Comparison of test accuracy due to difference in iodine compound content MDCT imaging was performed in the same manner as in Test Example 1 except that 100 mL of water was added to 400 mL of the liquid preparation for gastrointestinal imaging of Example 1 and a total amount of 500 mL was orally administered. I did it. Both the air image and the iodine contrast image were constructed from the imaging data, and both image data were synthesized. The degree of visualization of lesions was evaluated and compared according to the contrast criteria shown in Table 1 below for each of the four cases of this test example and test example 1. The evaluation of each example is shown in Table 2 below.

In the case of using the liquid preparation for gastrointestinal tract imaging of Example 1 (Test Example 1), all the cases showed the lesions very clearly, but in Test Example 2, the lesions could be pointed out clinically, but their synthesis The resolution of the image tended to decrease. This is different from the liquid preparation for contrast imaging in Example 1 (iodine content of 18.5 mg / mL) and the preparation of Test Example 2 (iodine content of 14.8 mg / mL) in that the iodine content is clinically different. In order to perform MDCT imaging that can withstand the examination, it can be said that a composition capable of preparing a liquid preparation for gastrointestinal contrast prepared at 15 mg / mL at least equal to or higher than the iodine content of this example is preferable.

Claims (9)

  Oral administration of an iodo compound-containing composition for gastrointestinal imaging containing an osmotic pressure adjusting agent selected from the group consisting of a colloid osmotic pressure adjusting agent that is polyethylene glycol and a crystalline osmotic pressure adjusting agent that includes magnesium citrate that is an electrolyte. An image processing method in CT colonography after intestinal tract cleaning for performing MDCT imaging, wherein an air image and an iodine contrast image are constructed by MDCT imaging, and both image data are synthesized.   2. The image processing method according to claim 1, wherein the osmotic pressure adjusting agent includes a colloid osmotic pressure adjusting agent which is polyethylene glycol and a crystalline osmotic pressure adjusting agent which is an electrolyte or an electrolyte and a saccharide.   The image processing method according to claim 2, wherein the saccharide is at least one saccharide selected from the group consisting of sorbitol, xylitol, erythritol, mannitol, trehalose, lactitol, lactulose, maltitol, palatinose, raffinose, and glycerin.   The image processing method according to claim 1 or 2, wherein the iodine content of the composition for gastrointestinal imaging is 15 to 90 mg / mL. The composition for gastrointestinal tract imaging comprises an electrolyte such that Na ⁺ is 30 to 150 mEq / L, K ⁺ is 3 to 20 mEq / L, and Cl ⁻ is 20 to 70 mEq / L. The image processing method according to item.   Intestinal lavage characterized by constructing an iodo-contrast image using an iodo compound-containing composition for gastrointestinal imaging containing a colloid osmotic pressure regulator that is polyethylene glycol and an electrolyte or a crystalline osmotic pressure regulator that is an electrolyte and a saccharide A method for constructing an iodine contrast image in later CT colonography.   The method for constructing an iodine contrast image in CT colonography according to claim 6, wherein a liquid residue of a digestive tract cleaning agent present in the large intestine is constructed as an iodine contrast image. An iodo compound-containing composition for gastrointestinal tract imaging comprising a colloid osmotic pressure adjusting agent that is polyethylene glycol and a crystalline osmotic pressure adjusting agent that is an electrolyte or an electrolyte and a saccharide in the image processing method according to any one of claims 1 to 5. Use of things. Use of an iodine compound-containing composition for gastrointestinal tract imaging comprising a colloid osmotic pressure adjusting agent that is polyethylene glycol and a crystalline osmotic pressure adjusting agent that is an electrolyte or an electrolyte and a saccharide in the method for constructing an iodinated contrast image according to claim 6 or 7. .

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