Defoaming agent adaptive to digestive tract environment, preparation method and application

Abstract

The invention discloses a defoaming agent adaptive to a digestive tract environment, and a preparation method and application thereof, and relates to the technical field of digestive tract examination assistance. The defoaming agent comprises simethicone, hyaluronidase, bromelain and sodium bicarbonate, and the preparation form is a capsule in which a quick-release drug-loading unit and an enteric drug-loading unit are mixed. The preparation method comprises the following steps: preparing the quick-release drug-loading unit, preparing the enteric drug-loading unit, and mixing and encapsulating. The defoaming agent is orally taken 25-35 minutes before gastroscopy, a closed loop of gastric acid neutralization, thick mucus degradation and foam removal effects can be formed, the problem of poor defoaming caused by mucus wrapping foam is solved, the field of view in the stomach is optimized, and the accuracy of stomach disease diagnosis is guaranteed.

Description

Technical Field

[0001] This invention relates to the field of defoaming agents used in gastrointestinal examinations, specifically to an defoaming agent adapted to the gastrointestinal environment, its preparation method, and its application. Background Technology

[0002] Gastroscopy is a crucial tool for diagnosing gastric diseases such as atrophic gastritis and Helicobacter pylori infection, and its accuracy highly depends on a clear view of the stomach. However, in these pathological conditions, the gastric mucosa secretes a large amount of thick mucus. This mucus is highly viscous, has poor fluidity, and easily combines with gas in the stomach to form a stable mucus-foam complex, especially accumulating in the folds of the gastric antrum. This complex directly obstructs the endoscope lens and the lesion area, severely interfering with observation.

[0003] Simethicone is currently commonly used in clinical practice as a pre-endoscopic defoaming agent, which defoams by reducing the surface tension of the foam. However, because the foam core is encapsulated by thick mucus, simethicone cannot penetrate the mucus barrier to reach the foam core. It can only act on a small amount of free foam on the surface, resulting in poor defoaming effect. The clearance rate of the mucus-foam complex is far from meeting clinical needs.

[0004] Looking further, existing solutions only focus on the single aspect of defoaming. If hyaluronidase, bromelain, or other enzymes are used to degrade thick mucus, the acidic environment of the stomach (pH 1-pH 3) will rapidly denature and inactivate these enzymes. Without addressing the mucus issue, defoaming agents will struggle to overcome the complex barrier, resulting in a situation where mucus remains and defoaming is ineffective, leading to poor visibility. Clinical data shows that with current solutions, the foam residue rate in the gastric antral folds exceeds 15%, and when enzymes are used concurrently, the enzyme activity retention rate is only 60%, easily leading to missed diagnoses of early lesions.

[0005] In summary, the current lack of an integrated solution that synergistically addresses gastric acid neutralization, thick mucus degradation, and efficient foam removal fails to meet clinical needs for clear endoscopic visualization, necessitating innovative technologies to improve the accuracy of gastric disease diagnosis. Summary of the Invention

[0006] In view of the technical problems existing in the prior art, the present invention aims to provide an antifoaming agent adapted to the digestive tract environment, its preparation method and application.

[0007] One of the objectives of this invention is to provide an antifoaming agent adapted to the digestive tract environment, comprising the following raw materials: simethicone, hyaluronidase, bromelain, and sodium bicarbonate.

[0008] Preferably, the mass ratio of sodium bicarbonate to simethicone is (4-6):1.

[0009] Preferably, the ratio of active units of hyaluronidase to bromelain is 5:1 to 7:1.

[0010] Preferably, the mass-activity ratio of simethicone to bromelain is (7-9) mg:1U.

[0011] Preferably, the defoamer is formulated as a capsule, wherein the capsule contains a mixture of an immediate-release drug delivery unit and an enteric-coated drug delivery unit; The immediate-release drug delivery unit uses sodium bicarbonate as the active ingredient, and the enteric-coated drug delivery unit uses simethicone, hyaluronidase, and bromelain as active ingredients.

[0012] Preferably, the immediate-release drug delivery unit further includes a first pharmaceutical excipient, which includes a filler and a binder; The filler is one or both of pharmaceutical-grade microcrystalline cellulose and pharmaceutical-grade lactose; The adhesive is a 5%-8% pharmaceutical-grade hydroxypropyl methylcellulose aqueous solution; The total amount of the first pharmaceutical excipient is 10%-20% of the total weight of the immediate-release drug delivery unit.

[0013] Preferably, the enteric-coated drug delivery unit further includes a second pharmaceutical excipient, which includes a pellet matrix excipient and a coating auxiliary excipient; The excipient for the skeleton of the vegetarian pill is a mixture of pharmaceutical-grade pregelatinized starch and pharmaceutical-grade polyethylene glycol 400; The weight ratio of the mixture of pharmaceutical-grade pregelatinized starch and pharmaceutical-grade polyethylene glycol 400 is 3:1-5:1; The coating auxiliary materials are pharmaceutical grade diethyl phthalate and pharmaceutical grade talc. The pharmaceutical-grade diethyl phthalate accounts for 10%-15% of the weight of the acrylic resin coating material; the pharmaceutical-grade talc accounts for 5%-8% of the weight of the acrylic resin coating material.

[0014] A second objective of this invention is to provide a method for preparing an antifoaming agent adapted to the digestive tract environment, comprising: S1: Prepare an immediate-release drug delivery unit by mixing sodium bicarbonate with the first pharmaceutical excipient to prepare an immediate-release drug delivery unit; S2: Prepare enteric-coated drug delivery unit by mixing simethicone, hyaluronidase, bromelain and a second pharmaceutical excipient to form a pellet, and then coating the pellet. S3: Mixing and encapsulation: The immediate-release drug-carrying unit obtained in S1 is mixed with the enteric-coated drug-carrying unit obtained in S2 and then filled into a regular capsule shell to obtain the defoaming agent.

[0015] Preferably, the coating material used in the coating process of S2 is acrylic resin, and the enteric drug delivery unit is dissolved in an environment with pH > 6 after coating.

[0016] The third objective of this invention is to provide an application of an antifoaming agent adapted to the digestive tract environment, wherein the antifoaming agent is used to optimize the intragastric field of view before gastroscopy; the method of administration is oral administration 25-35 minutes before gastroscopy.

[0017] Beneficial effects of this invention: This invention utilizes a combination of raw materials including simethicone, hyaluronidase, bromelain, and sodium bicarbonate to achieve highly efficient clearance of thick mucus-foam complexes in the stomach at the microscopic level. Sodium bicarbonate creates an optimal environment for enzyme activity. It precisely neutralizes gastric acid at pH 1-3, maintaining a stable pH of 6-7 within the stomach. This range perfectly matches the optimal activity range of hyaluronidase and bromelain, preventing the secondary structure hydrogen bond breakage of both enzymes due to acidity. This ensures complete exposure of the enzyme's active sites, providing the basis for mucus degradation.

[0018] The two enzymes work synergistically to dismantle the three-dimensional structure of thick mucus. Hyaluronidase first catalyzes the breakage of β-1,4 glycosidic bonds of hyaluronic acid in thick mucus, destroying the mucus polysaccharide backbone and transforming the gel-like mucus into a loose flocculent state. Bromelain then acts on the peptide bonds between aromatic amino acid residues of mucin, breaking it down into small molecular fragments and completely dismantling the mucus protein network. This causes the mucus that originally encapsulated the foam to lose its physical barrier function, and the foam core is completely exposed.

[0019] After the degradation of exposed foam slime, simethicone can be dispersed into 1-5μm droplets, uniformly covering the exposed foam gas-liquid interface, reducing the interfacial tension from 35-40mN / m to 15-20mN / m, breaking the surface tension balance of the foam, causing the foam film to thin and rupture rapidly, thus achieving complete foam removal.

[0020] In summary, this invention forms a complete closed-loop mechanism involving gastric acid neutralization, dual enzyme activity activation, mucus disintegration, foam exposure, and simethicone defoaming. It addresses the technical problem of poor defoaming effect caused by thick mucus encapsulating foam in the stomach at the microscopic level, providing a clear intragastric field of view for gastroscopy and ensuring the accuracy of gastric disease diagnosis. Detailed Implementation

[0021] According to a first aspect of the present invention, an antifoaming agent adapted to the digestive tract environment is provided, comprising the following raw materials: simethicone, hyaluronidase, bromelain, and sodium bicarbonate.

[0022] In this invention, simethicone, hyaluronidase, bromelain, and sodium bicarbonate are selected as defoaming agent raw materials. The core is to address the technical pain point that simethicone cannot reach the foam core due to the thick mucus in the stomach encapsulating the foam, resulting in poor defoaming effect. The invention constructs a complete action chain of environmental optimization, mucus degradation, and precise defoaming, with each of the four raw materials playing its own role and being irreplaceable.

[0023] Sodium bicarbonate was chosen to provide the necessary pH environment for the activity of both enzymes, addressing the issue of enzyme inactivation under acidic conditions in the stomach. The pH of the stomach in an empty state is 1-3, while the optimal activity pH for hyaluronidase and bromelain is 6-7. An acidic environment causes secondary structural changes in the protein molecules of both enzymes, masking or destroying their active sites and directly resulting in the loss of their mucus-degrading ability. Sodium bicarbonate can react quantitatively with hydrochloric acid in the stomach, stabilizing the stomach pH to 6-7 by neutralizing the acid. The generated carbon dioxide is expelled as a mild gas, without disturbing the local gastric environment. This process provides the prerequisite for enzyme activation and is fundamental to subsequent mucus degradation. Replacing it with other weak bases would either result in insufficient neutralization efficiency or lead to an excessive increase in stomach pH. Therefore, sodium bicarbonate is the optimal environmental optimization material.

[0024] Thick gastric mucus is often produced due to atrophic gastritis or Helicobacter pylori infection. This thick mucus is a three-dimensional gel structure composed of a polysaccharide backbone and a protein network, which cannot be completely destroyed by a single enzyme. Hyaluronidase specifically catalyzes the breakage of β-1,4 glycosidic bonds in hyaluronic acid molecules, degrading high-molecular-weight hyaluronic acid into oligosaccharides, directly disrupting the polysaccharide backbone of the mucus and causing the gel-like mucus to initially loosen into a flocculent state. Bromelain specifically hydrolyzes the peptide bonds between aromatic amino acid residues such as tyrosine and phenylalanine in mucin, breaking down mucin into small peptides and free amino acids, completely disintegrating the protein network of the mucus. Only through the synergistic action of these two enzymes can the thick mucus be transformed from a tight gel into small molecular fragments that can be expelled with gastric peristalsis, fully exposing the encapsulated foam core. If only a single enzyme is used, it cannot destroy the protein network composed of mucin, and the mucus will still encapsulate the foam in a loose gel form, failing to expose the foam.

[0025] The stability of foam depends on the surface tension balance at the gas-liquid interface. The interfacial tension of gastric foam is approximately 35-40 mN / m, and simethicone is the only ingredient that can precisely reduce the surface tension of foam in this scenario. Its molecular structure contains polydimethylsiloxane chains that can quickly adsorb onto the gas-liquid interface of the foam, reducing the interfacial tension to 15-20 mN / m, directly disrupting the surface tension balance of the foam and causing the foam film to rapidly thin and rupture. If other defoamers are used instead, they either cannot stably adsorb onto the foam interface due to excessive hydrophilicity, or they will non-specifically bind to the gastric mucosa. Therefore, simethicone is the core raw material for precise defoaming after mucus degradation, and it needs to function after the mucus has been degraded by two enzymes to avoid being encapsulated by thick mucus and becoming ineffective.

[0026] In summary, the selection of these four raw materials forms an inseparable technical system encompassing sodium bicarbonate for pH adjustment, dual-enzyme degradation of the slime, and simethicone for defoaming; none of them can be omitted. Without sodium bicarbonate, the dual enzymes are inactivated and cannot degrade the slime; without the dual enzymes, the simethicone is encapsulated by the slime and cannot defoam; without simethicone, the foam cannot be removed even after the slime is degraded. Ultimately, these materials work together to solve the problem of poor defoaming effect in existing technologies.

[0027] In a preferred embodiment of the present invention, the mass ratio of sodium bicarbonate to simethicone is (4-6):1.

[0028] In this invention, this ratio ensures that sodium bicarbonate accurately neutralizes gastric acid, maintaining the pH value stably within the optimal activity range of the two enzymes (6-7). Under fasting conditions, the typical parameters of gastric acid are a volume of 10-15 mL, a concentration of 0.1 mol / L, and a pH of 1-3. Based on the chemical reaction equation NaHCO3 + HCl = NaCl + H2O + CO2, neutralizing 10-15 mL of 0.1 mol / L hydrochloric acid requires 0.84-1.26 g of sodium bicarbonate. Based on clinical validation of its defoaming effect and safety, the typical single-dose dosage of simethicone in this invention is 350-450 mg. When the mass ratio of sodium bicarbonate to simethicone is 4:1, the dosage of sodium bicarbonate is 1.4-1.8 g; when the ratio is 6:1, the dosage of sodium bicarbonate is 2.1-2.7 g. This dosage range fully covers the 0.84-1.26g required to neutralize 10-15mL of gastric acid, with a small margin reserved to accommodate individual differences in gastric acid secretion. It ensures that the gastric pH is stably adjusted to 6-7, which is exactly the optimal activity range of hyaluronidase and bromelain. This prevents the enzyme proteins from undergoing secondary structure hydrogen bond breakage due to acidity or conformational distortion due to excessive alkalinity, ensuring complete exposure of the active sites of both enzymes.

[0029] When the ratio is less than 4:1, the amount of sodium bicarbonate used is insufficient, failing to effectively neutralize gastric acid, directly leading to the inactivation of both enzymes and the failure of mucus degradation. If the ratio is <4:1, taking 400mg of simethicone as an example, the amount of sodium bicarbonate used is only 1.2g, which can only neutralize about 14mL of 0.1mol / L hydrochloric acid, close to the lower limit of gastric acid in the stomach. If the individual has a large amount of gastric acid secretion, such as a gastric acid volume of more than 15mL, the pH value in the stomach after neutralization can only rise to 4-5, far below the optimal pH of the two enzymes (6-7). At this time, the activity of hyaluronidase will decrease by more than 50% due to the low pH value, and bromelain will be almost completely inactivated. The two enzymes cannot degrade the polysaccharide backbone and protein network of thick mucus, and the mucus still surrounds the foam core in a gel-like state. Even if simethicone is released, it cannot contact the foam, resulting in poor defoaming effect and failing to solve the core technical problem.

[0030] When the ratio is higher than 6:1, excessive sodium bicarbonate can cause a double problem: excessively high pH, ​​leading to inactivation of both enzymes and abnormal gastric pressure. If the ratio is greater than 6:1, such as 7:1, taking 400mg of simethicone as an example, the amount of sodium bicarbonate used reaches 2.8g. After neutralizing 10-15mL of gastric acid, 1.54-1.96g of sodium bicarbonate remains, which will continue to react with the small amount of hydrochloric acid secreted by the gastric mucosa, causing the gastric pH to rise to 8-9. On the one hand, excessive alkalinity will disrupt the protein conformation of the two enzymes: at a pH of 8, the activity of hyaluronidase is only 30% of its optimal value, and bromelain is completely inactivated due to deprotonation of the peptide bond catalytic site, thus failing to degrade mucus. On the other hand, the carbon dioxide generated by the reaction of excessive sodium bicarbonate will cause a sudden increase in gastric pressure, causing abdominal distension, belching, and even gastric gas to interfere with the endoscopic field of view, thus affecting the diagnostic effect.

[0031] The products of the reaction between sodium bicarbonate and gastric acid are sodium chloride, water, and carbon dioxide. The final concentration of sodium chloride in the stomach is about 0.5%-0.8%, which is close to the concentration of physiological saline. This will not change the osmotic pressure of the gastric fluid and can prevent the aggregation of simethicone droplets due to osmotic pressure differences. Carbon dioxide is expelled with gastric peristalsis in the form of mild bubbles and will not form stable foam, so it will not affect the simethicone's ability to remove target foam.

[0032] Therefore, the mass ratio of (4-6):1 is the only optimal range that balances gastric acid neutralization efficiency, dual enzyme activity assurance, simethicone defoaming effect, and patient tolerance. It can ensure the synergistic effect of each raw material and form a complete technical closed loop of neutralization, enzymatic hydrolysis, and defoaming.

[0033] In a preferred embodiment of the present invention, the ratio of active units of hyaluronidase to bromelain is 5:1-7:1.

[0034] In this invention, the core of this ratio is matching the compositional characteristics of thick gastric mucus with the requirements for dual-enzyme degradation. Clinical studies show that in the thick gastric mucus of patients with atrophic gastritis and Helicobacter pylori infection, the mass ratio of the polysaccharide backbone hyaluronic acid to the protein network mucin is approximately 5:1-7:1, and 1U of hyaluronidase and 1U of bromelain corresponds precisely to the degradation efficiency of 1μg of hyaluronic acid and 1μg of mucin, respectively. At this ratio, the dual-enzyme degradation can completely cover the two core components in the mucus, without leaving any excess substrate or interrupting degradation due to insufficient enzymes, thus laying the foundation for the complete disintegration of the mucus.

[0035] When the ratio is less than 5:1, hyaluronidase activity is insufficient, failing to rapidly break down the polysaccharide backbone. The intact hyaluronic acid chains encapsulate the mucin, preventing bromelain from accessing the peptide bond substrate. For example, at a 4:1 ratio, 4U of hyaluronidase at 37℃ degrades only 20μg of hyaluronic acid in 10 minutes, exposing only 5μg of mucin. The remaining mucin remains encapsulated, resulting in a loose polysaccharide-protein complex in the final mucus, with a foam core exposure rate of less than 70%, directly impacting the defoaming effect of simethicone.

[0036] When the ratio is higher than 7:1, excessive hyaluronidase leads to asynchronous degradation. The polysaccharide backbone is completely destroyed within 5 minutes, while the degradation of mucin by bromelain is slow. Undegraded mucin will aggregate due to loss of support, forming new mucin-foam complexes and wasting enzyme raw materials. Only when the ratio is 5:1-7:1, the two enzymes degrade synchronously, converting the mucus into small molecular fragments within 10 minutes, and the foam core exposure rate reaches 100%, meeting the subsequent defoaming requirements.

[0037] In a preferred embodiment of the present invention, the mass-activity ratio of simethicone to bromelain is (7-9) mg:1U.

[0038] In this invention, the ratio is derived by precisely matching the mucus degradation efficiency of bromelain with the defoaming ability of simethicone. The core is to ensure that all the foam released after the bromelain degrades the mucus can be completely covered and destroyed by simethicone, while avoiding defects caused by insufficient or excessive dosage.

[0039] From the perspective of the matching between degradation and defoaming, 1U of bromelain can degrade approximately 0.8mg of gastric mucoprotein within 10 minutes, releasing 0.5-1mL of foam in this process. Meanwhile, 7-9mg of simethicone can disperse into 1-5μm droplets in the stomach. These molecules can uniformly cover the gas-liquid interface of this volume of foam through Brownian motion, reducing the interfacial tension from 35-40mN / m to 15-20mN / m, precisely breaking the foam's stability and achieving complete defoaming. If the ratio is lower than 7mg:1U, the number of simethicone droplets is insufficient to completely cover the foam interface, leaving some foam residue because the interfacial tension has not decreased to the critical value, resulting in a defoaming rate of less than 80%.

[0040] From the perspective of avoiding excessive side effects, if the ratio is higher than 9mg:1U, simethicone will exceed the gastric dispersion threshold. Excess simethicone droplets will aggregate, which will not only fail to contact the foam, but may also adhere to the gastric mucosa surface to form a transparent film, interfering with the observation of mucosal details by gastroscopy. At the same time, excessive raw materials will increase the cost of formulation, and there is no additional defoaming benefit, which does not meet the principle of technical economy.

[0041] In a preferred embodiment of the present invention, the defoamer is formulated as a capsule, wherein the capsule contains a fast-release drug delivery unit and an enteric-coated drug delivery unit. The immediate-release drug delivery unit uses sodium bicarbonate as the active ingredient, and the enteric-coated drug delivery unit uses simethicone, hyaluronidase, and bromelain as active ingredients.

[0042] In this invention, the core of the formulation design is to precisely match the action sequence from gastric acid neutralization, mucus degradation to foam removal. By functional partitioning of the immediate release and enteric-coated drug delivery units, conflicts in raw material characteristics such as the inactivation of dual enzymes upon contact with acid and the premature encapsulation of simethicone by mucus are resolved, ensuring that each component functions in the stomach according to the preset logic.

[0043] From the perspective of sodium bicarbonate's functional requirements, it needs to be preferentially released and rapidly neutralize gastric acid. Therefore, it is formulated as an immediate-release drug delivery unit: the immediate-release drug delivery unit is uncoated, and the capsule shell can directly contact gastric juice after disintegration in the stomach, releasing ≥90% of sodium bicarbonate within 10 minutes, rapidly reacting with hydrochloric acid in the stomach to adjust the pH to 6-7. This process must precede the release of the dual enzymes and simethicone; otherwise, the dual enzymes will immediately undergo protein conformational denaturation upon entering the acidic environment, their active sites will be masked, and they will lose their ability to degrade mucus. If sodium bicarbonate is mixed with the dual enzymes and simethicone to form ordinary pellets, although sodium bicarbonate can neutralize gastric acid, the dual enzymes will be continuously exposed to an incompletely regulated acidic environment during the neutralization process, and the activity retention rate can only reach 60%, which cannot meet the requirements for efficient mucus degradation.

[0044] Considering the functional requirements of the dual enzymes and simethicone, they need to be released after being neutralized by gastric acid. Therefore, they are formulated into an enteric-coated drug delivery unit. The enteric-coated drug delivery unit is coated with acrylic resin and dissolves only in an environment with a pH > 6. After the immediate-release drug delivery unit has completed the neutralization of gastric acid, the enteric coating gradually ruptures, releasing the dual enzymes and simethicone. On the one hand, the dual enzymes are fully activated in a neutral environment and can synergistically degrade thick mucus; on the other hand, the mucus has already been degraded when the simethicone is released, so it will not be encapsulated by the mucus and can directly contact the foam core. If enteric coating is not used, the dual enzymes and simethicone will be released simultaneously with sodium bicarbonate. The dual enzymes will be inactivated due to the lack of neutralization of gastric acid, and the simethicone will also be masked by undegraded mucus, reducing the defoaming effect by more than 70%.

[0045] From the perspective of overall capsule compatibility, mixed encapsulation allows for precise control of the dosage ratio and release synergy of the two types of pellets. The capsule shell rapidly disintegrates within 5 minutes in the stomach without interfering with pellet release; the immediate-release drug delivery unit and the enteric-coated drug delivery unit are mixed and encapsulated at a preset weight ratio, ensuring that the neutralization amount of sodium bicarbonate, the degradation amount of the two enzymes, and the defoaming amount of simethicone in each capsule are perfectly matched. If other dosage forms such as tablets or granules are used, the mixed ingredients in tablets cannot achieve the functional zoning of the two types of pellets, and the pellets in granules are prone to stratification, making it impossible to precisely control the dosage ratio. Both of these would disrupt the closed loop of neutralization, degradation, and defoaming, leading to the failure of the overall effect.

[0046] In a preferred embodiment of the present invention, the immediate-release drug delivery unit further includes a first pharmaceutical excipient, which includes a filler and a binder; The filler is one or both of pharmaceutical-grade microcrystalline cellulose and pharmaceutical-grade lactose; The adhesive is a 5%-8% pharmaceutical-grade hydroxypropyl methylcellulose aqueous solution; The total amount of the first pharmaceutical excipient is 10%-20% of the total weight of the immediate-release drug delivery unit.

[0047] In this invention, the core of the excipient selection and dosage design is to solve the problem of poor formability of sodium bicarbonate powder itself while ensuring the rapid release of sodium bicarbonate by the immediate-release drug delivery unit, and at the same time avoid the excipient from interfering with the gastric acid neutralization efficiency, so as to fully match the functional requirements of prioritizing the neutralization of gastric acid and constructing an enzyme activity environment.

[0048] From the perspective of filler selection, pharmaceutical-grade microcrystalline cellulose or lactose is the only excipient that can balance both pelleting properties and rapid release. Sodium bicarbonate, being a fine powder, has poor flowability and no binding properties, making it prone to loosening and breakage when directly pelleted. Microcrystalline cellulose, on the other hand, possesses excellent flowability and plasticity, allowing it to mix evenly with sodium bicarbonate powder, filling the voids within the pellets and forming a stable framework. Furthermore, it rapidly swells and disintegrates in gastric juice without hindering the release of sodium bicarbonate. Lactose, with its high water solubility, dissolves without producing sticky residue, further accelerating the dispersion of sodium bicarbonate in gastric juice. If other fillers are used instead, either the slow swelling rate will delay the release of sodium bicarbonate, or residual sticky substances will coat the sodium bicarbonate particles, leading to a decrease in neutralization efficiency of more than 30%.

[0049] From the perspective of binder selection and concentration control, a 5%-8% pharmaceutical-grade hydroxypropyl methylcellulose aqueous solution can precisely balance adhesive force and rapid release. After dissolving in water, hydroxypropyl methylcellulose forms a low-viscosity colloid that can bind sodium bicarbonate and filler powder into uniform pellets with an extremely thin adhesive layer, less than 5 μm in thickness. When the concentration is below 5%, the adhesive force is insufficient, and the pellets are easily broken during production, transfer, or storage, resulting in uneven dosage. When the concentration is above 8%, the adhesive layer thickens to more than 10 μm, forming a slowly dissolving gel film on the surface of the pellets. This extends the sodium bicarbonate release time from 10 minutes to more than 15 minutes, missing the window of opportunity for preferential neutralization of gastric acid and failing to promptly create a neutral environment for the dual enzymes.

[0050] Based on the control logic of 10%-20% of the total amount of the first pharmaceutical excipient, this range can achieve the optimal balance between molding stability and active ingredient content. When the amount is less than 10%, the excipient cannot fully coat the sodium bicarbonate powder, and the pellets are prone to surface roughness, internal voids, and insufficient mechanical strength after molding, with a breakage rate of over 20% during transportation. When the amount is more than 20%, it will dilute the unit content of sodium bicarbonate, resulting in a decrease in the proportion of sodium bicarbonate in a single pellet. The total weight of the pellets needs to be increased to meet the neutralization requirements, which not only increases the capsule volume but also slightly delays the initial release rate of sodium bicarbonate due to the excessively high proportion of excipients. Only 10%-20% of the amount can ensure that the compressive strength of the pellets reaches 8-10N, while the proportion of sodium bicarbonate exceeds 80%, and more than 90% can be released within 10 minutes, accurately achieving the goal of neutralizing gastric acid.

[0051] In a preferred embodiment of the present invention, the enteric-coated drug-carrying unit further includes a second pharmaceutical excipient, which includes a pellet matrix excipient and a coating auxiliary excipient. The excipient for the skeleton of the vegetarian pill is a mixture of pharmaceutical-grade pregelatinized starch and pharmaceutical-grade polyethylene glycol 400; The weight ratio of the mixture of pharmaceutical-grade pregelatinized starch and pharmaceutical-grade polyethylene glycol 400 is 3:1-5:1; The coating auxiliary materials are pharmaceutical grade diethyl phthalate and pharmaceutical grade talc. The pharmaceutical-grade diethyl phthalate accounts for 10%-15% of the weight of the acrylic resin coating material; the pharmaceutical-grade talc accounts for 5%-8% of the weight of the acrylic resin coating material.

[0052] In this invention, the excipients for the pellet skeleton are pharmaceutical-grade pregelatinized starch and polyethylene glycol 400 (3:1-5:1), the core of which is to resolve the conflicting characteristics and release requirements of the active ingredients. Pregelatinized starch gives the pellet good formability, preventing breakage, and it swells and disintegrates within 3 minutes in a neutral environment without hindering ingredient release; polyethylene glycol 400 can disperse simethicone into 1-3μm droplets and also protect the activity of both enzymes. The 3:1-5:1 ratio balances forming and release. Below 3:1, the pellet is resistant to pressure difference and prone to moisture absorption and denaturation; above 5:1, the skeleton disintegrates slowly, missing the mucus degradation window. At this ratio, the pellet achieves the required strength, has low moisture absorption, and an ingredient release rate exceeding 98%.

[0053] In the coating excipients, diethyl phthalate enhances the flexibility of the coating film, preventing the acrylic resin from cracking and allowing gastric acid to seep in. At this ratio, the film is crack-free and dissolves within 2 minutes when the pH is >6. Talc prevents pellet adhesion during coating, ensuring a uniform film layer. Below 5%, the adhesion rate is high, resulting in a thin film and acid leakage; above 8%, the film is rough with pinholes, ensuring that the two enzymes are not inactivated in the stomach. In summary, these two types of excipients, from the perspectives of skeletal support and coating protection, achieve acid-insoluble, rapid-release of the enteric-coated drug delivery unit, matching the action sequence of first neutralization and then degradation.

[0054] According to a second aspect of the present invention, a method for preparing an antifoaming agent adapted to the digestive tract environment is provided, comprising: S1: Prepare an immediate-release drug delivery unit by mixing sodium bicarbonate with the first pharmaceutical excipient to prepare an immediate-release drug delivery unit; S2: Prepare enteric-coated drug delivery unit by mixing simethicone, hyaluronidase, bromelain and a second pharmaceutical excipient to form a pellet, and then coating the pellet. S3: Mixing and encapsulation: The immediate-release drug-carrying unit obtained in S1 is mixed with the enteric-coated drug-carrying unit obtained in S2 and then filled into a regular capsule shell to obtain the defoaming agent.

[0055] In this invention, the core of the preparation process is to ensure that the functional characteristics of the immediate-release drug delivery unit and the enteric drug delivery unit are not destroyed through functional partitioning and precise combination, and to fully match the action sequence of gastric acid neutralization, mucus degradation and foam removal, while ensuring the activity and dosage accuracy of each component.

[0056] The rapid-release drug delivery unit is prepared because sodium bicarbonate needs to be preferentially released and rapidly neutralized to stomach acid. Mixing it separately with the first pharmaceutical excipient for pelleting avoids premature contact with the enteric-coated drug delivery unit components. If mixed for pelleting, although sodium bicarbonate can neutralize stomach acid, the two enzymes will be exposed to trace amounts of acidic substances from the excipient or environment during preparation, leading to decreased activity. Furthermore, pelleting separately allows for the regulation of pellet disintegration rate through the excipient, ensuring that the neutralization reaction begins immediately upon entering the stomach, thus creating a suitable pH environment for the subsequent release of the components.

[0057] The preparation of enteric-coated drug-loaded units aims to address the stability and release sequence issues of the dual enzymes and simethicone. First, these three components are mixed with a second pharmaceutical excipient to form pellets. The synergistic effect of pregelatinized starch and polyethylene glycol 400 achieves micro-dispersion of simethicone and protection of the dual enzyme activity. Subsequent coating treatment precisely controls the release environment, ensuring dissolution only at pH > 6. This prevents the pellets from being destroyed by the acidic environment in the stomach, ensuring that the dual enzymes and simethicone are released only after neutralization by gastric acid, preventing premature inactivation or encapsulation by mucus.

[0058] Mixed encapsulation is used to precisely control the dosage ratio and synergistic release of the two types of pellets. Independently prepared immediate-release drug delivery units and enteric-coated drug delivery units are mixed in a preset weight ratio and encapsulated in ordinary capsules. This ensures that the amount of sodium bicarbonate neutralization, the amount of degradation by the two enzymes, and the amount of simethicone defoaming in each capsule are perfectly matched. At the same time, the rapid disintegration of the ordinary capsule shell does not interfere with the release logic of the pellets. If other combination methods are used, it will increase the complexity of patient administration and cannot guarantee that the two types of pellets enter the stomach at the same time, thus disrupting the closed-loop sequence of neutralization followed by degradation.

[0059] In a preferred embodiment of the present invention, the coating material used in the coating process of S2 is acrylic resin, and the enteric drug delivery unit is dissolved in an environment with pH > 6 after coating.

[0060] In this invention, pharmaceutical-grade acrylic resin exhibits strictly pH-dependent solubility. In the acidic environment of the stomach (pH 1-3) during an empty stomach, the resin molecular chains are tightly coiled and cannot be dissolved by gastric juice, forming a dense protective film to prevent gastric acid from penetrating the capsule and avoiding conformational denaturation of the two enzymes due to acidic conditions. When sodium bicarbonate rapidly neutralizes the gastric acid, and the gastric pH rises to the neutral / weakly alkaline range of 6-7, the carboxyl groups on the resin molecular chains dissociate, the molecular structure expands, and it is rapidly dissolved by gastric juice, ensuring the timely release of the two enzymes and simethicone. If other enteric-coated materials are used instead, either the dissolution pH threshold is too low, causing premature release of components before complete neutralization of gastric acid, leading to inactivation of the two enzymes; or the dissolution rate is too slow, missing the optimal window for mucus degradation and disrupting the sequential closed loop of neutralization followed by degradation.

[0061] From a process and safety perspective, acrylic resin possesses the core advantages of pharmaceutical-grade excipients. On one hand, it exhibits excellent film-forming properties and high mechanical strength, forming a uniform film layer during coating that is less prone to cracking due to collisions during production and transportation, thus preventing gastric acid leakage. On the other hand, it can be safely degraded and metabolized in vivo, leaving no residual risk and meeting the safety requirements for oral formulations. Furthermore, the dissolution pH of this material perfectly matches the target pH (6-7) after sodium bicarbonate neutralizes gastric acid, enabling release triggered once gastric acid neutralization is achieved. This ensures that the dual enzymes degrade mucus in their optimal activity environment, and that simethicone comes into contact with foam after mucus degradation, ultimately guaranteeing the defoaming effect.

[0062] The third objective of this invention is to provide an application of the defoaming agent adapted to the digestive tract environment as described above, characterized in that the defoaming agent is applied to optimize the intragastric field of view before gastroscopy; the method of administration is oral administration 25-35 minutes before gastroscopy.

[0063] Example Based on the raw material ratio range of claims 1-7, five examples and three comparative examples were set up to verify the effectiveness of the technical solution of the present invention. All examples and comparative examples adopted capsule form with immediate-release drug delivery unit and enteric-coated drug delivery unit.

[0064] (1) Common settings of auxiliary materials The first pharmaceutical excipient uses pharmaceutical-grade microcrystalline cellulose or lactose as filler and 5%-8% concentration of pharmaceutical-grade hydroxypropyl methylcellulose aqueous solution as binder. The total amount used accounts for 10%-20% of the total weight of the immediate-release drug-loaded unit, which meets the molding stability requirements and does not affect the release of sodium bicarbonate.

[0065] The second pharmaceutical excipient, the pellet matrix, is a mixture of pharmaceutical-grade pregelatinized starch and polyethylene glycol 400 in a weight ratio of 3:1-5:1, ensuring the dispersion of simethicone and the activity of both enzymes. The coating excipients are pharmaceutical-grade diethyl phthalate and pharmaceutical-grade talc. Pharmaceutical-grade diethyl phthalate accounts for 10%-15% of the acrylic resin coating material to enhance the flexibility of the coating film. Pharmaceutical-grade talc accounts for 5%-8% of the acrylic resin to prevent coating adhesion. After coating, it is ensured that the enteric drug delivery unit is completely dissolved within 2 minutes in an environment with pH > 6.

[0066] 1.1 Raw material ratio Table 1. Raw material and excipient ratios for Examples 1-5 and Comparative Examples 1-3

[0067] 1.2 Preparation method Preparation of the immediate-release drug-loaded unit: Mix sodium bicarbonate with the first pharmaceutical excipient according to the dosage in Table 1, stir at 300 r / min for 5 min to form a soft material, extrude and spheroidize, extrusion speed 60 r / min, spheroidization speed 800 r / min, dry at 40℃ until moisture content <3%, and sieve into 1.0~1.5 mm pellets.

[0068] Preparation of enteric-coated drug-loaded unit: Mix simethicone oil, dual enzyme dosage and second pharmaceutical excipient according to Table 1 to prepare soft material, extrude and roll into 1.0~1.2mm pellets; coat with acrylic resin coating solution containing diethyl phthalate and talc, rotate the coating pan at 40 r / min and introduce air at 60℃, until the pellets increase in weight by 15%, and cure at 40℃ for 4h.

[0069] Mixed encapsulation: The immediate-release drug delivery unit and the enteric-coated drug delivery unit are mixed at a weight ratio of 1:1 and filled into capsule shells, with each capsule weighing 0.8~1.0g.

[0070] 1.3 Performance Testing Table 2 Test Indicators and Methods

[0071] Table 3 Performance test results of Examples 1-5 and Comparative Examples 1-3

[0072] All five examples met the requirements of clearance rate ≥90%, activity retention rate ≥90%, residue rate ≤5%, and score ≥4 points. Example 3 showed the strongest synergistic effect in neutralization, degradation, and defoaming, resulting in the best effect. Comparative Example 1 lacked sodium bicarbonate, and due to the absence of gastric acid neutralization, both enzymes were inactivated, resulting in a clearance rate of only 57.8%; Comparative Example 2 deviated from the mass ratio due to insufficient sodium bicarbonate, leading to incomplete neutralization; Comparative Example 3 deviated from the activity ratio due to insufficient hyaluronidase, resulting in incomplete mucus degradation. All of these examples demonstrate the necessity of the core parameter range.

Claims

1. An antifoaming agent adapted to the digestive tract environment, characterized in that, It includes the following ingredients: simethicone, hyaluronidase, bromelain, and sodium bicarbonate.

2. The defoamer adapted to the digestive tract environment as described in claim 1, characterized in that, The mass ratio of sodium bicarbonate to simethicone is (4-6):

1.

3. The defoamer adapted to the digestive tract environment as described in claim 1, characterized in that, The ratio of the activity units of hyaluronidase to bromelain is 5:1 to 7:

1.

4. The defoamer adapted to the digestive tract environment as described in claim 1, characterized in that, The mass-activity ratio of simethicone to bromelain is (7-9) mg:1U.

5. The defoamer adapted to the digestive tract environment as described in claim 1, characterized in that, The defoaming agent is formulated in the form of capsules, and the capsules contain a mixture of an immediate-release drug delivery unit and an enteric-coated drug delivery unit. The immediate-release drug delivery unit uses sodium bicarbonate as the active ingredient, and the enteric-coated drug delivery unit uses simethicone, hyaluronidase, and bromelain as active ingredients.

6. The defoamer adapted to the digestive tract environment as described in claim 5, characterized in that, The immediate-release drug delivery unit further includes a first pharmaceutical excipient, which includes a filler and a binder; The filler is one or both of pharmaceutical-grade microcrystalline cellulose and pharmaceutical-grade lactose; The adhesive is a 5%-8% pharmaceutical-grade hydroxypropyl methylcellulose aqueous solution; The total amount of the first pharmaceutical excipient is 10%-20% of the total weight of the immediate-release drug delivery unit.

7. The defoamer adapted to the digestive tract environment as described in claim 5, characterized in that, The enteric-coated drug delivery unit further includes a second pharmaceutical excipient, which includes a pellet matrix excipient and a coating auxiliary excipient. The excipient for the skeleton of the vegetarian pill is a mixture of pharmaceutical-grade pregelatinized starch and pharmaceutical-grade polyethylene glycol 400; The weight ratio of the mixture of pharmaceutical-grade pregelatinized starch and pharmaceutical-grade polyethylene glycol 400 is 3:1-5:1; The coating auxiliary materials are pharmaceutical grade diethyl phthalate and pharmaceutical grade talc. The pharmaceutical-grade diethyl phthalate accounts for 10%-15% of the weight of the acrylic resin coating material; the pharmaceutical-grade talc accounts for 5%-8% of the weight of the acrylic resin coating material.

8. The method for preparing an antifoaming agent adapted to the digestive tract environment as described in any one of claims 1 to 7, characterized in that, include: S1: Prepare an immediate-release drug delivery unit by mixing sodium bicarbonate with the first pharmaceutical excipient to prepare an immediate-release drug delivery unit; S2: Prepare enteric-coated drug delivery unit by mixing simethicone, hyaluronidase, bromelain and a second pharmaceutical excipient to form a pellet, and then coating the pellet. S3: Mixing and encapsulation: The immediate-release drug-carrying unit obtained in S1 is mixed with the enteric-coated drug-carrying unit obtained in S2 and then filled into a regular capsule shell to obtain the defoaming agent.

9. The method for preparing the defoamer adapted to the digestive tract environment as described in claim 8, characterized in that, The coating material used in the coating process of S2 is acrylic resin, and the enteric drug delivery unit is dissolved in an environment with pH > 6 after coating.

10. The application of the defoamer adapted to the digestive tract environment as described in any one of claims 1 to 7, characterized in that, The defoaming agent is used to optimize the intragastric field of view before gastroscopy; the administration method is oral administration 25-35 minutes before gastroscopy.

Images