A dual-color indicator-based intestinal stricture detection device and its preparation method

Abstract

This invention discloses a dual-color indicator-based intestinal stricture detection device and its preparation method. The intestinal stricture detection device includes a small intestinal indicator, a colonic indicator, and a protective outer membrane. The small intestinal indicator is configured to release a first indicator after being in the small intestinal environment for more than a predetermined disintegration time. The first indicator is configured to be absorbed by the small intestine to give the produced urine a first color. The colonic indicator is connected to the small intestinal indicator and is configured to release a second indicator in the colonic environment. The second indicator is configured to be absorbed by the colon to give the produced urine a second color. The protective outer membrane covers the small intestinal and colonic indicator and is configured to be insoluble in the gastric environment but soluble in the small intestinal environment. By judging the color and production sequence of the urine, the retention status of the intestinal stricture detection device can be determined. The device is biodegradable and does not rely on external equipment for detection, making the detection process convenient and safe.

Description

Technical Field

[0001] This invention belongs to the field of capsule endoscopy technology, specifically, it relates to a dual-color indicator-based intestinal stenosis detection device and its preparation method. Background Technology

[0002] In the diagnosis and treatment of gastrointestinal diseases, capsule endoscopy (CE) has become a widely accepted clinical examination method due to its advantages such as being non-invasive, painless, anesthesia-free, well-tolerated, and without the risk of cross-infection. However, capsule retention (i.e., a capsule remaining in the digestive tract for more than two weeks without being expelled) remains the most significant and serious complication of CE examination. The incidence of capsule retention in the general population is approximately 0.73%-1.4%, while the risk is significantly increased to 21% in patients with intestinal strictures (such as Crohn's disease, intestinal obstruction, NSAID-induced bowel disease, intestinal tumors, and postoperative adhesions). Once a capsule becomes retained, it may become the core of a foreign body in the intestinal lumen, causing fecal impaction or worsening existing strictures. Approximately 15% of capsule retention cases will further induce acute intestinal obstruction. Managing such cases often requires drug, endoscopic, or surgical intervention, which not only increases patient suffering and medical risks but also adds to their financial burden.

[0003] Currently, international clinical guidelines recommend using exploration capsules to assess bowel accessibility before surgery to mitigate the risk of capsule retention. The only commercially available exploration capsule product is Medtronic's PillCam. TM The Patency Capsule consists of a capsule body and a radio frequency detector, both covered by a medical polymer film. The capsule body is identical in shape and size to a capsule endoscope, primarily made of biodegradable lactose. The capsule body internally encapsulates an RFID tag and barium sulfate that can be visualized under X-rays, but does not contain lenses or other complex electronic components. If the patency capsule remains in the patient's body for more than a specified time (usually 30 hours) and it is difficult to confirm its arrival at the colon via abdominal X-ray, intestinal stricture is diagnosed, and a CE examination is not recommended. In this case, the capsule body gradually degrades under the influence of digestive fluids, while the non-degradable components (such as the RFID tag) are reduced in size after being folded and wrapped by the medical polymer film, allowing them to pass through the stricture and be expelled from the body.

[0004] Several domestic companies have successfully developed similar products to PillCam. TMPatency Capsules' RFID-guided capsules, with structures, materials, and principles largely consistent with foreign products, have achieved domestic substitution and reduced costs. The latest research focuses on material substitution, process optimization, and signal system upgrades. Patent CN116919322A uses food-grade pigment (betalain) instead of non-degradable RFID tags and barium, indicating capsule disintegration through red urine. While this technology achieves device-free reading and complete component degradation, reducing patient examination costs and radiation exposure risks, it still has a fundamental flaw: the release of betalain is interpreted as intestinal stricture, failing to recognize retention caused by slow colonic transit (accounting for approximately 67% of cases not expelled). These patients, who could safely undergo CE examination, are misdiagnosed with intestinal stricture, missing a diagnostic opportunity.

[0005] In summary, existing exploration capsule technology has the following drawbacks:

[0006] (1) Inability to accurately locate the retention site: When traditional exploration capsules (containing barium) are retained, an abdominal X-ray / CT scan is required to confirm whether they have reached the colon. However, due to the overlap of information in the abdominal soft tissue, abdominal X-ray examination is sometimes difficult to accurately determine the retention location. Although abdominal CT can help improve the accuracy of the judgment, it is not recommended considering factors such as the patient's radiation dose and cost. The new exploration capsules, which use a single colored indicator, magnetic control element, etc. instead of RFID tags / barium, rely solely on the retention time as the basis for judging intestinal stenosis, ignoring the retention caused by slow colonic transit (accounting for about 67%). Such patients could safely undergo CE examination, but are misjudged as unsuitable, missing the opportunity for diagnosis. (2) Non-degradable components bring secondary risks: Traditional exploration capsules contain components made of non-degradable materials (such as medical polymer shells, RFID tags, etc.). Once retained, they themselves become foreign objects that need to be removed, posing a risk of secondary intervention. (3) Reliance on large equipment: The interpretation of results from traditional exploration capsules requires the use of X-rays, CT scans or dedicated RFID scanners, which is a complex process and difficult to apply to primary healthcare or home screening scenarios. Summary of the Invention

[0007] (a) The technical problem to be solved by the present invention

[0008] How to provide a device for detecting intestinal stenosis that can achieve precise positioning and indication, has higher safety, and is more convenient to use?

[0009] (II) The technical solution adopted in this invention

[0010] A dual-color indicator-based intestinal stenosis detection device, the intestinal stenosis detection device comprising:

[0011] Small intestinal indicator, the small intestinal indicator being configured to release a first indicator after the duration of being in the small intestinal environment exceeds a predetermined disintegration time, the first indicator being configured to be absorbed by the small intestine to give the resulting urine a first color;

[0012] A colon indicator, connected to the small intestine indicator, is configured to release a second indicator in the colonic environment, the second indicator being configured to be absorbed by the colon to give the produced urine a second color;

[0013] A protective outer membrane covering the small intestinal indicator and the colonic indicator, the protective outer membrane being configured to be insoluble in the gastric environment and soluble in the small intestinal environment.

[0014] Optionally, the small intestine indicator includes a time-delayed disintegration shell and a first indicator, the first indicator being sealed inside the time-delayed disintegration shell, the time-delayed disintegration shell being configured to disintegrate after being in the small intestine environment for a period exceeding a predetermined disintegration time.

[0015] Optionally, the small intestine indicator further includes a plug, the time-delayed disintegration shell has a chamber, the plug is sealed at the opening of the chamber, the first indicator is contained in the chamber, and the plug is configured to disintegrate after being in the small intestine environment for a period exceeding a predetermined disintegration time.

[0016] Optionally, the material of the first indicator includes one of betalain, dragon fruit powder, and riboflavin.

[0017] Optionally, the predetermined disintegration time ranges from 30 hours to 80 hours.

[0018] Optionally, the colonic indicator includes a controlled-release membrane and a second indicator, the controlled-release membrane coating the second indicator, the controlled-release membrane being configured to be insoluble in the small intestinal environment and soluble in the colonic environment.

[0019] Optionally, the second indicator includes one of methylene blue, triamterene, amitriptyline, and cimetidine.

[0020] Optionally, the controlled-release membrane is made of an enzyme-triggered material and a pH-dependent material, wherein the enzyme-triggered material is configured to be insoluble in the small intestinal flora environment and soluble in the colonic flora environment, and the pH-dependent material is configured to be insoluble in the small intestinal pH environment and soluble in the colonic pH environment.

[0021] Optionally, the small intestine indicator portion and the colon indicator portion are bonded together with an adhesive.

[0022] This application also discloses a method for preparing the above-mentioned intestinal stenosis detection device based on dual-color indication.

[0023] (III) Beneficial Effects

[0024] This invention discloses a dual-color indicator-based intestinal stenosis detection device and its preparation method, which, compared with existing methods, has the following technical advantages:

[0025] The dual-color intestinal stenosis detection device releases different indicators when small bowel stenosis and colonic functional retention occur, resulting in different urine colors. By judging the urine color and the order in which different colors of urine are produced, the retention status of the intestinal stenosis detection device in the digestive tract can be determined, further determining whether a CE examination can be performed. The intestinal stenosis detection device is biodegradable, and even if it is retained, it will not pose a secondary risk. Moreover, it does not rely on external equipment for detection, making the detection process convenient and safe. Attached Figure Description

[0026] Figure 1 This is a schematic diagram of a dual-color indicator-based intestinal stenosis detection device according to one or more embodiments.

[0027] Figure 2 This is a schematic diagram of the small intestine indicator section of a dual-color indicator-based intestinal stenosis detection device according to one or more embodiments.

[0028] Figure 3 This is a schematic diagram of the colon indicator section of a dual-color intestinal stenosis detection device according to one or more embodiments.

[0029] Figure 4 This is a flowchart illustrating the interpretation of detection results using a dual-color indicator-based intestinal stenosis detection device according to one or more embodiments. Detailed Implementation

[0030] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0031] Before describing the various embodiments of this application in detail, the technical concept of this application is first briefly described: Existing exploration capsule products typically contain non-degradable components, posing secondary risks due to retention, making it impossible to accurately locate the retention site, and requiring external large equipment for detection, which is cumbersome and has limited applicability. Therefore, the intestinal stenosis detection device based on dual-color indication provided by this application has the key improvement of including a small intestine indicator and a colon indicator. The small intestine indicator releases a first indicator when it remains in the small intestine environment for more than a predetermined disintegration time. The colon indicator begins to disintegrate and release a second indicator upon reaching the colon. The absorption of the two indicators results in different urine colors. By judging the urine color and the order in which the different colors are produced, the retention status of the intestinal stenosis detection device in the digestive tract can be determined, further determining whether a CE inspection can be performed. This intestinal stenosis detection device is entirely degradable, and even if it remains, it will not pose secondary risks. Furthermore, it does not require external equipment for detection, making the detection process convenient and safe. The specific principle of the intestinal stenosis detection device based on dual-color indication of this application will be described below with reference to more embodiments.

[0032] Specifically, such as Figure 1 , Figure 2 and Figure 3 As shown, the dual-color intestinal stricture detection device includes a small intestine indicator 10, a colon indicator 20, and a protective outer membrane 30. The small intestine indicator 10 is configured to release a first indicator 11 after being in the small intestine environment for more than a predetermined disintegration time. The first indicator 11 is configured to be absorbed by the small intestine to give the resulting urine a first color. The colon indicator 20 is connected to the small intestine indicator 10 and is configured to be insoluble in the small intestine environment but soluble in the colon environment, releasing a second indicator 21. The second indicator 21 is configured to be absorbed by the colon to give the resulting urine a second color. The protective outer membrane 30 covers the small intestine indicator 10 and the colon indicator 20. The protective outer membrane 30 is configured to be insoluble in the gastric environment but soluble in the small intestine, protecting the device from complete passage through the stomach. The size and shape of the intestinal stricture detection device are consistent with those of a standard capsule endoscope. The first color and the second color are two clearly distinguishable colors.

[0033] In one or more embodiments, the small intestine indicator 10 includes a time-delayed disintegration shell 12 and a first indicator 11. The first indicator 11 is sealed inside the time-delayed disintegration shell 12, which is configured to disintegrate after being in the small intestine environment for a predetermined period of time. The first indicator 11 is exposed to digestive juices and dissolves rapidly, producing a noticeable change in urine color after absorption in the small intestine. The small intestine indicator 10 also includes a stopper 13. The time-delayed disintegration shell 12 has a chamber 12a, and the stopper 13 is sealed at the opening of the chamber 12a. The first indicator 11 is contained in the chamber 12a, and the stopper 13 is configured to disintegrate after being in the small intestine environment for a predetermined period of time. The chamber 12a is an open structure to facilitate loading the first indicator 11, and then sealing the chamber 12a with the stopper 13. The first indicator 11 is in granular form.

[0034] In one or more embodiments, the colon indicator 20 includes a controlled-release membrane 22 and a second indicator 21, the controlled-release membrane 22 covering the second indicator 21, and the controlled-release membrane 22 being configured to be insoluble in the small intestinal environment and soluble in the colonic environment. The second indicator 21 is hemispherical in shape to facilitate coating by the controlled-release membrane 22 and to facilitate connection between the colon indicator 20 and the small intestinal indicator 10. Exemplarily, the small intestinal indicator 10 and the colon indicator 20 are bonded together using an adhesive.

[0035] For example, the predetermined disintegration time for the small intestine indicator 10 ranges from 30 to 80 hours, while the colon indicator 20 requires one to two hours to dissolve in the colonic environment. When this intestinal stricture detection device is applied, three possible outcomes are possible:

[0036] First, if the entire intestinal stricture detection device is successfully expelled within the predetermined time frame, it indicates that there is no stricture in the small intestine, the intestine is patent, and the intestinal stricture detection device has a short residence time in the intestine, insufficient to disintegrate or dissolve. Second, if only the second color of urine appears, it indicates that the small intestine indicator 10 passed through the small intestine smoothly within the predetermined time frame, and the colon indicator dissolved first in the colonic environment. This result indicates that there is no stricture in the small intestine. Third, if only the first color of urine appears, it indicates that the small intestine indicator 10 did not pass through the small intestine smoothly within the predetermined time frame and disintegrated, and the first indicator was absorbed. This situation indicates that there is stricture in the small intestine. The first two results indicate that the small intestine is patent and CE examination can be performed; the third situation indicates that the small intestine is not patent and CE examination is not suitable.

[0037] Among these factors, the color change of urine and the sequence of these changes are crucial for determining the location of retention in the digestive tract by the intestinal stricture detection device. Therefore, the material selection for each component is critical to ensure that different components disintegrate in their respective digestive tract segments. The material selection for each component is described below.

[0038] For the time-delayed disintegration shell 12 of the small intestine indicator section 10, since it remains in the small intestine environment for 30 to 80 hours before disintegrating, far exceeding the normal small intestine transit time (3-4 hours), the time-delayed disintegration shell 12 is required to possess strong hydrophobicity and a certain mechanical strength. In one or more embodiments, the time-delayed disintegration shell 12 is prepared using a hydrophobic framework plus a small amount of disintegrant to achieve controllable disintegration time. Preferably, the material of the time-delayed disintegration shell 12 includes a core inhibitor, an auxiliary inhibitor, a filler, a flow aid, a disintegrant, and a lubricant, with a thickness of 2-4 mm. The specific details of each component are as follows:

[0039] Core inhibitor: Hydrogenated vegetable oil (such as hydrogenated corn oil, hydrogenated castor oil, hydrogenated soybean oil, hydrogenated palm oil, etc.) is selected as the hydrophobic framework, with a dosage of 30%-50% w / w and a melting point of 58℃-70℃. After micronization, it forms a dense hydrophobic network and achieves ultra-long disintegration of 30-80 hours through the dissolution mechanism.

[0040] Auxiliary inhibitors: Long-chain fatty acid monoglycerides (such as glyceryl monostearate, glyceryl monopalmitate, glyceryl monobehenate, etc.) are selected, with an amount of 5%-10% w / w, to fill the pores and synergistically enhance hydrophobicity.

[0041] Filler: Compressible pharmaceutical excipients (excluding hygroscopic sugar fillers) are selected, including but not limited to microcrystalline cellulose, pregelatinized starch, silicified microcrystalline cellulose, etc., at a dosage of 20%-40% w / w, to provide basic compressibility, and must be completely encapsulated by hydrophobic materials.

[0042] Flow aid: Colloidal silica is selected, with a dosage of 0.1%-0.5% w / w, to improve the flowability of the above hydrophobic powder, ensure stable tablet weight difference, and guarantee smooth tableting.

[0043] Disintegrants: The types of disintegrants that can be used include, but are not limited to, crospovidone (PVPP), low-substituted hydroxypropyl cellulose (L-HPC), and crospovidone carboxymethyl cellulose sodium (CCNa), etc. The dosage is 0-5% w / w. They absorb water and swell, breaking the skeleton from the inside to ensure final disintegration.

[0044] Lubricant: The types of lubricants that can be used include, but are not limited to, magnesium stearate, sodium stearate fumarate, glyceryl behenate, etc., at 0.5%-1% w / w.

[0045] Preparation method of time-delayed disintegration shell 12: Add the micronized raw materials (excluding lubricant) to a V-type mixer according to the mass ratio, and mix for 20-30 minutes to ensure that the hydrophobic excipients are fully coated on the surface of the hydrophilic particles. Add the lubricant and mix for another 3-5 minutes (over-mixing the lubricant will excessively enhance the hydrophobicity). Add the uniformly mixed raw materials to a custom mold and press the time-delayed disintegration shell using a single-punch / rotary tablet press.

[0046] For the first indicator 11 in granular form, it should rapidly disintegrate upon exposure to digestive fluids and cause a noticeable color change in urine after absorption in the small intestine. Therefore, while ensuring proper granulation, it is necessary to create as many water absorption channels and swelling forces as possible within the granules. This embodiment preferably uses dry granulation to ensure the stability of the indicator, while providing excellent granule flowability, high production efficiency, and good process control. The first indicator 11 comprises indicator X, filler, disintegrant, pore-forming agent, flow aid, and lubricant. The specific details of each component are as follows:

[0047] Indicator X: A highly safe indicator (food-grade pigment) is selected, requiring that it be absorbed through the small intestine and produce an easily distinguishable color change in urine. To avoid individual differences leading to urine that is too light in color and difficult to identify, a safety redundancy can be provided. Preferably, betalain is extremely safe and can be absorbed through the small intestine to produce purplish-red urine. In other embodiments, indicator X can be dragon fruit powder, producing reddish-purple urine; indicator X can also be riboflavin, producing bright yellow urine.

[0048] Filler: Compressible pharmaceutical excipients are selected, including but not limited to microcrystalline cellulose, pregelatinized starch, silicified microcrystalline cellulose, etc., at a dosage of 40%-60% w / w, providing good compressibility and its own hygroscopicity, and serving as the "skeleton" of the granules.

[0049] Disintegrants: Selecting a suitable disintegrant is key to achieving rapid particle disintegration. Suitable disintegrants include, but are not limited to, crospovidone (PVPP), low-substituted hydroxypropyl cellulose (L-HPC), and crospovidone carboxymethyl cellulose (CCNa), used at a dosage of 0-5% w / w. These disintegrants can bind to other particles under pressure and absorb water and swell upon contact with water, thus causing the particles to "burst" and ensuring rapid disintegration upon exposure to digestive fluids.

[0050] Pore-forming agent: Water-soluble sugar alcohols or sugars are selected, including but not limited to mannitol, sucrose, lactose, glucose, polyethylene glycol, etc. These can construct water-soluble microchannels, allowing digestive fluids to slowly penetrate into the matrix. Mannitol is preferred, used at 20%-40% w / w.

[0051] Flow aid: Colloidal silica, dosage 0.5%-1% w / w, improves the flowability of powder mixtures and ensures uniform feeding.

[0052] Lubricant: Types of disintegrants that can be used include, but are not limited to, magnesium stearate, sodium stearate fumarate, and glyceryl behenate, at 0.5%-1% w / w. Compared to magnesium stearate, sodium stearate fumarate has better hydrophilicity and less impact on disintegration, making it the preferred choice when rapid disintegration is required.

[0053] Preparation method: Pass all powdered raw materials (except external lubricant) through an 80-100 mesh sieve to ensure uniform particle size. Premix indicator X with an equal amount of filler using the "equal incremental method" until the color is uniform. Add the premix and all remaining raw materials (except lubricant) to a V-type mixer and mix for 15-20 minutes. Use a dry granulator to press out "barely formed" flakes (i.e., able to form continuous, easy-to-handle flakes, but easily crumbled by hand). Sizing the pressed, fragile flakes through a vibrating sieve to obtain particles with uniform size, mostly between 16-40 mesh. Transfer the sized particles to a mixing tank, add sieved sodium stearate, and mix at low speed for 3-5 minutes.

[0054] The stopper 13 primarily serves as a physical seal, facilitating the subsequent bonding of the two parts. The stopper 13 uses the same formula and preparation method as the time-delayed disintegration shell 12. The uniformly mixed raw materials are added to a custom mold and pressed out using a single-punch / rotary tablet press.

[0055] The second indicator 21 of the colonic indicator 20 comprises indicator Y, filler, disintegrant, pore-forming agent, flow aid, and lubricant. The specific details of each component are as follows:

[0056] Indicator Y: A food-grade pigment or pharmaceutical dye with high safety profile should be selected, requiring that it be absorbed through the colon and produce a noticeable color change in urine (indicators X and Y should produce easily distinguishable urine color changes). To avoid individual differences leading to urine that is too light to be easily identified, a safety redundancy can be provided. Methylene blue is preferred for indicator Y because it is one of the few known substances that can be effectively absorbed by the colon and produce a noticeable color change in urine, and it has a history of pharmaceutical approval. Its safety is well-supported by data, and its indicator effect is obvious. In other embodiments, indicator Y may also be triamterene, amitriptyline, cimetidine, etc., which may also produce blue-green urine.

[0057] Filler: Compressible pharmaceutical excipients (including but not limited to microcrystalline cellulose, pregelatinized starch, silicified microcrystalline cellulose, etc.) or pH-sensitive matrix materials (including but not limited to Eudragit® FS30D, Eudragit® S100, etc., with a solubility threshold pH ≥ 7.0, capable of responding to the pH environment in the colon). Used at 40%-60% w / w, providing good compressibility and serving as the "skeleton" of the tablet core.

[0058] Disintegrants: Disintegrants that can be used include, but are not limited to, crospovidone (PVPP), low-substituted hydroxypropyl cellulose (L-HPC), and sodium crospovidone carboxymethyl cellulose (CCNa), at a dosage of 0-5% w / w. They can bind to other particles under pressure and absorb water and swell upon contact with water, thereby causing the tablet core to disintegrate rapidly.

[0059] Pore-forming agent: Water-soluble sugar alcohols or sugars are selected, including but not limited to mannitol, sucrose, lactose, glucose, polyethylene glycol, etc. These can construct water-soluble microchannels, allowing digestive fluids to slowly penetrate into the matrix. Mannitol is preferred, used at 20%-40% w / w.

[0060] Flow aid: Colloidal silica, dosage 0.5%-1% w / w, improves the flowability of powder mixtures and ensures uniform feeding.

[0061] Lubricant: Types of disintegrants that can be used include, but are not limited to, magnesium stearate, sodium stearate fumarate, and glyceryl behenate, at 0.5%-1% w / w. Sodium stearate fumarate is preferred because it has better hydrophilicity and less impact on disintegration, making it the first choice when rapid disintegration is required.

[0062] Preparation method: Pass all powder raw materials (except external lubricant) through an 80-100 mesh sieve to ensure uniform particle size. Premix the indicator and a portion of the filler using an "equal incremental method" until the color is uniform. Then, add the remaining raw materials (except external lubricant) to a V-type mixer and mix for 15-20 minutes. Add the lubricant and continue mixing for 3-5 minutes. Pack the uniformly mixed material into a custom mold. Use a single-punch / rotary tablet press to compress the powder into small-sized, low-hardness tablets for the second indicator.

[0063] For example, the controlled-release membrane is designed to specifically respond to the colonic environment; it is insoluble in the upper digestive tract (small intestine) but specifically dissolves in the colon. It can be made using at least one of pH-dependent materials and enzyme-triggered materials. The pH-dependent strategy utilizes the pH gradient changes in the digestive tract and is currently the most mature and widely used colon-targeting strategy. Enzyme-triggered technology relies on specific enzymes (such as azoreductases, glycosidases, and polysaccharide-degrading enzymes) produced by the colonic flora to achieve precise release, and is currently the most targeted and specific colonic controlled-release technology. Preferably, employing a dual pH-dependent / enzyme-triggered response mechanism can significantly improve the accuracy and reliability of the colonic response, ensuring the precise release of indicator Y in the colon.

[0064] Currently, the most widely used pH-dependent coating materials are acrylic resin polymers, including the Eudragit series (such as FS30D and L100-55) and the Eudraguard series. These materials have precise pH solubility thresholds, allowing for drug dissolution and release under specific pH conditions. The main challenge of pH-dependent systems lies in the instability of the pH environment under pathological conditions. Enzyme-triggered materials must meet two criteria: non-degradation in the upper gastrointestinal tract and efficient enzymatic hydrolysis by colonic flora. Natural polysaccharides have become core materials for enzyme-triggered systems due to their good biodegradability and colonic enzyme specificity. Currently, the most widely used include guar gum, pectin, chitosan, and β-cyclodextrin.

[0065] Preparation method: Disperse the enzyme-triggered material, pH-dependent material, and plasticizer (10%-20% of the total polymer) in an 80% ethanol / water solution and stir magnetically until completely dissolved. Sieve (100 mesh) to remove any impurities or undispersed particles. The coating solution should be continuously stirred slowly to prevent precipitation. Place the hemispherical second indicator 21 into a high-efficiency coating pan; the target coating weight gain is 5%-8%.

[0066] For example, the adhesive plays a crucial role in connecting the small intestinal indicator and the colon indicator, and must maintain its structural integrity for 30-80 hours to withstand gastrointestinal motility. The adhesive is not degraded in the digestive tract and is excreted intact with feces. The adhesive does not interfere with the independent dissolution / release mechanisms of the two parts. Suitable adhesives include, but are not limited to, ethyl cellulose, shellac, corn gluten, and polylactic-co-glycolic acid copolymers. Ethyl cellulose is preferred as the adhesive.

[0067] Preparation method: Slowly add ethyl cellulose (2%-5% w / v) to a measured amount of anhydrous ethanol (10%-20% by dry weight of triethyl citrate can be added as a plasticizer to increase the toughness of the adhesive layer). Place on a magnetic stirrer and stir continuously (the temperature can be slightly heated to 40℃-45℃ to accelerate dissolution) until a clear, particle-free, homogeneous solution is formed. Cool to room temperature, seal and store for later use to prevent ethanol evaporation. Fix the small intestine indicator part in a flat base or mold groove, ensuring that the bonding surface is facing upwards and stable. Using a micro-dispensing machine or a fine-tipped brush, draw a small amount of ethyl cellulose solution and accurately and evenly apply it to the bonding surface of the small intestine. Immediately align the bonding surface of the colon indicator part with the small intestine part coated with adhesive and gently press them together. Apply slight but constant pressure for about 30-60 seconds to ensure close contact between the two parts and remove excess air bubbles and a small amount of adhesive. Transfer the pre-bonded composite to a ventilated area and cure at room temperature for at least 2-4 hours. After ethanol evaporates, it forms a tough film. Ethyl cellulose is degradable in the intestines and does not interfere with overall degradation.

[0068] For example, the protective outer membrane 30 wraps around the outer side of the device body, which is formed by bonding the small intestinal indicator portion and the colonic indicator portion. It is a crucial barrier ensuring the device passes intact through the acidic environment of the stomach and dissolves rapidly in the upper small intestine. Its performance directly affects whether the device can be precisely triggered in the target intestinal segment. Suitable materials include, but are not limited to, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and polyacrylic acid resin (Eudragit® L / S series). Polyacrylic acid resin II is preferably used as the material for the protective outer membrane 30.

[0069] Preparation method: Disperse the coating material (5%-10% w / v) in 95% ethanol and stir until completely dissolved. Add the plasticizer triethyl citrate (1%-2% w / v, equivalent to 20% of the polymer weight) and stir until homogeneous. Under high-speed shear, add the anti-sticking agent talc (1.25%-5% w / v, equivalent to 25%-50% of the polymer weight) and continue stirring to form a homogeneous suspension. To reduce sedimentation, it is best to use ultrafine talc (1000 mesh). Use a high-efficiency coating pan for coating, with a target weight gain of 3%-5%.

[0070] In one specific embodiment, the material composition of each component of the intestinal stenosis detection device is as follows.

[0071] The first indicator 11 consists of: betaine powder (10% w / w), microcrystalline cellulose (60% w / w), crospovidone (8% w / w), mannitol (20% w / w), colloidal silica (1%) and sodium stearate fumarate (1%).

[0072] Composition of time-delayed disintegration shell 12 and stopper 13: hydrogenated corn oil (50% w / w), glyceryl monostearate (10% w / w), microcrystalline cellulose (35% w / w), colloidal silica (1% w / w), crospovidone (3% w / w), magnesium stearate (1% w / w).

[0073] The second indicator 21 of the colon indicator 20 consists of: methylene blue (10% w / w), polyacrylic acid resin III (50% w / w), microcrystalline cellulose (30% w / w), crospovidone (8% w / w), colloidal silica (1%) and sodium stearate fumarate (1%).

[0074] The controlled-release membrane 22 is composed of: corn gluten (2% w / w), low-esterified pectin (2% w / w), polyacrylic acid resin III (6% w / w), triethyl citrate (1%), and 80% aqueous ethanol solution.

[0075] Adhesive composition: ethyl cellulose (5% w / v), triethyl citrate (1%), ethanol.

[0076] The protective outer membrane 30 is composed of: polyacrylic acid resin II (10% w / v), triethyl citrate (1%), and 95% ethanol solution.

[0077] After preparation, the intestinal stenosis detection device was subjected to the following tests: (1) in vitro simulated gastrointestinal transit test of the complete device (stomach → small intestine → colon). (2) small intestinal indicator disintegration time limit test. (3) colon indicator release behavior test under pH / enzyme dual triggering. (4) in vivo animal (experimental pig) verification experiment to confirm the correspondence between urine color change and intestinal location.

[0078] like Figure 4 As shown, the detection procedure for the intestinal stenosis detection device includes: the subject swallows the intestinal stenosis detection device, and urination is observed and recorded. The following three results may occur:

[0079] Result 1: The device was completely expelled within 30 hours → bowel function was unobstructed, suitable for CE examination.

[0080] Result 2: The presence of only or first blue-green urine indicates unobstructed bowel function, making it suitable for CE examination.

[0081] Result 3: The presence of only or first purple-red urine indicates small intestinal stenosis, making CE examination unsuitable.

[0082] The intestinal stenosis detection device based on dual-color indication provided in this embodiment (hereinafter referred to as this solution) has the following technical effects.

[0083] 1. Precisely locate the stuck area: a leap from time-series judgment to location diagnosis.

[0084] Traditional capsule endoscopy relies solely on retention time (>30 hours) as the criterion for diagnosing intestinal stricture, which is essentially an indirect and coarse inference based on time. This new approach introduces a dual-color indicator system, enabling direct and proactive diagnosis of the retention site. The dual-color indicator-based intestinal stricture detection device responds specifically to different digestive tract environments: at small intestinal strictures, a first indicator is released due to prolonged retention; a second indicator is only triggered under specific pH and microbial enzyme conditions in the colon. Subjects can accurately distinguish between true small intestinal stricture and functional colonic retention based on the sequence of urine color changes, minimizing the misdiagnosis rate caused by slow colonic transit, significantly improving the accuracy and reliability of pre-capsule endoscopy assessment, and expanding the applicable population for capsule endoscopy.

[0085] 2. Proactive degradation safety guarantee: turning the risk of retention into nothingness.

[0086] Existing exploration capsules contain non-degradable components (such as RFID tags and medical-grade polymer plastic shells). After the capsule body degrades, these components form new foreign bodies, which, if lodged, must be removed endoscopically or surgically, increasing patient suffering and financial burden. This solution completely eliminates this risk from the design stage. The entire device is made from fully biodegradable pharmaceutical excipients. Even if lodging occurs, the device will automatically disintegrate into small, safe particles within a preset time window (30-80 hours). This "active degradation" characteristic avoids secondary medical interventions caused by device lodging, greatly improving the safety and acceptability for subjects and addressing a core concern for clinical promotion.

[0087] 3. Ease of operation and universality: Empowering new screening models at the grassroots level and at home.

[0088] This solution revolutionizes the complex process of traditional methods that rely on large imaging equipment (X-ray, CT) or dedicated RFID scanners for result interpretation. Its result interpretation method is extremely simple and intuitive—patients only need to observe changes in urine color to make their own judgment. This "equipment-free" interpretation method brings revolutionary advantages: it greatly reduces medical costs and reliance on professional personnel, enabling bowel patency screening to be smoothly carried out in community hospitals, primary care clinics, and even patients' homes. It provides a powerful technological tool for establishing a tiered medical system and promoting the widespread adoption of early screening for digestive tract diseases, and is particularly suitable for large-scale population screening and long-term follow-up.

[0089] 4. Gastrointestinal friendliness: Improves subject comfort and safety.

[0090] Existing exploratory capsules use barium (contrast agent) and iron (which produces black stool) as indicators, which may irritate the gastrointestinal tract and increase the burden on patients with digestive diseases. This protocol recommends using food-grade pigments / pharmaceutical dyes as indicators, preferably a combination of betaine and methylene blue. The former is a food-grade dye, and the latter is the active ingredient of the approved pre-colonoscopy oral dye (Leverlan® Methylene Blue Enteric-coated Sustained-Release Tablets), which has an extremely high safety record and minimal irritation to the gastrointestinal mucosa. Furthermore, while previous exploratory capsules often used anhydrous lactose as the main material, this protocol uses an alternative material, avoiding the risk of increased abdominal discomfort in lactose-intolerant individuals after using the device. This choice reduces potential discomfort for subjects during the examination, improves tolerability and overall experience, reflecting a patient-centered design philosophy.

[0091] 5. Zero radiation risk: Ensuring the safety of screening sensitive populations.

[0092] Traditional imaging-based tracking methods inevitably expose subjects to ionizing radiation. This protocol offers a purely biochemical diagnostic method that completely avoids any form of radiation exposure. Therefore, this protocol is also suitable for radiation-sensitive populations (such as children, women of childbearing age, and pregnant women), and is a safe and reliable method for screening bowel openness with irreplaceable clinical value.

[0093] The specific embodiments of the present invention have been described in detail above. Although some embodiments have been shown and described, those skilled in the art should understand that modifications and improvements can be made to these embodiments without departing from the principles and spirit of the present invention as defined by the claims and their equivalents, and such modifications and improvements should also be within the protection scope of the present invention.

Claims

1. A dual-color indicator-based intestinal stenosis detection device, characterized in that, The intestinal stricture detection device includes: Small intestinal indicator, the small intestinal indicator being configured to release a first indicator after being in a small intestinal environment for a period exceeding a predetermined disintegration time, the first indicator being configured to be absorbed by the small intestine to give the resulting urine a first color, the small intestinal indicator including a time-delayed disintegration shell and a first indicator, the first indicator being sealed inside the time-delayed disintegration shell, the time-delayed disintegration shell being configured to disintegrate after being in a small intestinal environment for a period exceeding a predetermined disintegration time; A colon indicator unit connected to a small intestine indicator unit, the colon indicator unit being configured to release a second indicator in a colonic environment, the second indicator being configured to be absorbed by the colon to give the produced urine a second color, the colon indicator unit including a controlled-release membrane and a second indicator, the controlled-release membrane coating the second indicator, the controlled-release membrane being configured to be insoluble in a small intestinal environment and soluble in a colonic environment; A protective outer membrane covering the small intestinal indicator and the colonic indicator, the protective outer membrane being configured to be insoluble in the gastric environment and soluble in the small intestinal environment.

2. The intestinal stenosis detection device based on dual-color indication according to claim 1, characterized in that, The small intestine indicator also includes a plug, the time-delayed disintegration shell has a chamber, the plug is sealed at the opening of the chamber, the first indicator is contained in the chamber, and the plug is configured to disintegrate after being in the small intestine environment for a period exceeding a predetermined disintegration time.

3. The intestinal stenosis detection device based on dual-color indication according to claim 1, characterized in that, The first indicator is made from one of the following materials: betalain, dragon fruit powder, or riboflavin.

4. The intestinal stenosis detection device based on dual-color indication according to claim 1, characterized in that, The predetermined disintegration time ranges from 30 hours to 80 hours.

5. The intestinal stenosis detection device based on dual-color indication according to claim 1, characterized in that, The second indicator includes one of methylene blue, triamterene, amitriptyline, and cimetidine.

6. The intestinal stenosis detection device based on dual-color indication according to claim 1, characterized in that, The controlled-release membrane is made of an enzyme-triggered material and a pH-dependent material. The enzyme-triggered material is configured to be insoluble in the small intestinal flora environment and soluble in the colonic flora environment. The pH-dependent material is configured to be insoluble in the small intestinal pH environment and soluble in the colonic pH environment.

7. The intestinal stenosis detection device based on dual-color indication according to claim 1, characterized in that, The small intestinal indicator portion and the colon indicator portion are bonded together with an adhesive.

8. A method for preparing the intestinal stenosis detection device based on dual-color indication as described in any one of claims 1 to 7.

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