Streptoproteinase compound preparation with mucus removing and defoaming functions and preparation process of streptoproteinase compound preparation

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a streptavidin compound preparation with mucus removing and defoaming functions and a preparation process thereof. The preparation consists of streptavidin, sodium bicarbonate, dimeticone, silicon dioxide, polysorbate 80 and a filler / adhesive. The preparation method comprises the following steps: stirring dimeticone and silicon dioxide at 145-155 DEG C to react for 7-8 hours to form a compound through a step-by-step granulation process, performing wet granulation, mixing active ingredients at low temperature, and finally performing dry granulation and sub-packaging. The method is characterized in that 1) streptavidin and dimeticone synergistically decompose mucin and break bubbles, and double-view interference is synchronously eliminated; the pH value in the stomach is maintained to be 7-10 through sodium bicarbonate, the enzyme activity is guaranteed, step-by-step granulation avoids high-temperature damage to the enzyme structure, and 5-minute rapid disintegration is achieved through the 80-mesh sieve granule control technology. The preoperative process is simplified, the drug synergism is improved, and the preparation is suitable for gastroscopy and other scenes.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a pronase compound preparation with mucus-removing and foaming-removing functions and a preparation process thereof. Background Art

[0002] Gastroscopy is the gold standard for diagnosing upper gastrointestinal diseases, and the clarity of its field of view directly impacts lesion detection. However, the gastric environment is plagued by two major interfering factors: the mucus layer and foam. Healthy adults secrete approximately 1.5-2.5 liters of gastric mucus daily. Mucin is the primary component of mucin, which forms a gel layer up to 500 μm thick covering the gastric mucosa. This scatters the endoscopic light source, making it difficult to identify small lesions. Clinical studies have shown that mucus interference can increase the missed diagnosis rate of early gastric cancer by 17%-23%.

[0003] To improve visual field quality, existing technologies use two separate types of preparations: 1. Defoaming agents: Simethicone powder, a typical example, breaks up foam by reducing the surface tension of bubbles. However, dimethicone has no effect on mucus protein and cannot resolve the mucus coating problem. When foam and mucus coexist in the stomach, defoaming alone can only improve visual clarity by approximately 35%.

[0004] 2. Mucolytics: Pronase specifically hydrolyzes mucin peptide bonds, but its activity depends on an alkaline environment of pH 7-10. The pH of the gastric acid environment is only 1.5-3.5, and direct oral administration of pronase results in over 90% loss of enzyme activity. Existing solutions require the use of sodium bicarbonate to neutralize gastric acid. For example, clinically used pronase granules require patients to dissolve two bags of pronase and sodium bicarbonate simultaneously before taking.

[0005] This bag-based drug delivery model has significant drawbacks: The procedure is cumbersome: Before gastroscopy, two bags of medication must be opened, poured into a container, and shaken with water to dissolve, leading to poor patient compliance. The error rate in emergency or elderly patients is as high as 28%. Inaccurate dosage: Packaging in separate bags can easily result in missing a bag, leading to pH adjustment failure or insufficient enzyme activity; Delayed onset of effect: The dissolution process takes 3-5 minutes, and delaying medication will shorten the drug's effect time in the stomach.

[0006] Furthermore, existing preparations have a single function: dimethicone preparations only eliminate foaming, and pronase preparations only remove mucus. Gastroscopy requires the sequential administration of two medications, which not only prolongs preparation time but also leads to asynchronous effects due to the interval between dosing. Statistics show that when dual preparations are used, 12%-15% of cases still require intraoperative flushing due to residual mucus, extending the examination time by an average of 6.2 minutes. Therefore, developing a single-dose preparation that combines mucus removal and defoaming functions and is easy to take is a key requirement for improving the efficiency of gastroscopy diagnosis. Summary of the Invention

[0007] The present invention aims to provide a pronase compound preparation with mucus-removing and foaming-removing functions and a preparation process thereof.

[0008] In order to achieve the above objectives, the following technical solutions are provided: A pronase compound preparation with mucus-removing and foaming-removing functions, comprising the following components based on the total weight of the compound preparation: Pronase: 180-220 mg; Sodium bicarbonate: 180-220 mg; Simethicone: 270-330 mg; Silicon dioxide: 22.5-27.5 mg; Polysorbate 80: 45-55 mg; Filler: 3577-4372 mg, the filler is selected from lactose, glucose, sucrose, mannitol, starch, dextrin or powdered sugar; Binder: 225-275 mg, the binder is selected from hydroxypropyl cellulose, polyvinyl pyrrolidone, starch slurry, syrup, ethanol, isopropyl alcohol or polyethylene glycol.

[0009] Furthermore, based on the total weight of the compound preparation, it is composed of the following ingredients: Pronase: 200 mg; Sodium bicarbonate: 200 mg; Simethicone: 300 mg; Silicon dioxide: 25 mg; Polysorbate 80: 50mg; Lactose: 3975mg; Hydroxypropyl cellulose: 250 mg.

[0010] A preparation process of a pronase compound preparation with mucus-removing and foaming-removing functions comprises the following steps: (1) reacting dimethicone with silicon dioxide at 145-155° C. with stirring for 7-8 hours, and cooling to room temperature to obtain a composite; (2) uniformly mixing the complex obtained in step (1) with polysorbate 80 to form a mixture A; (3) Mixing mixture A with a filler and a binder, wet granulating the mixture, and drying the mixture to obtain granules B; (4) Passing Granule B through an 80-mesh sieve, adding pronase and sodium bicarbonate, mixing well, and granulating; (5) Repackaging: 5g per bag.

[0011] Furthermore, the filler in step (3) is lactose.

[0012] Furthermore, the binder in step (3) is hydroxypropyl cellulose.

[0013] Furthermore, the wetting agent used in the wet granulation in step (3) is water or ethanol.

[0014] Furthermore, the mixing in step (4) adopts a three-dimensional motion mixer, and the mixing time is 15 to 30 minutes.

[0015] Furthermore, the granulation in step (4) is dry granulation.

[0016] The beneficial effects of the present invention are: 1. Dual-action synergistic clearance mechanism. Pronase specifically hydrolyzes the disulfide bonds (EC3.4.24.28) of mucus glycoproteins, and combined with simethicone to disrupt the phospholipid bilayer of the gastric membrane, achieving spatiotemporal synergy in mucus dissolution and defoaming. Experiments have shown that this complex system can reduce the thickness of the gastric mucus layer from 2.1 mm to 0.3 mm (optical coherence tomography) and reduce gastric bubble density by 94% (laser Doppler velocimetry), effectively eliminating the source of double vision interference during gastroscopy.

[0017] 2. Precise regulation of enzyme activity. Sodium bicarbonate rapidly neutralizes gastric acid in the stomach (raising the pH from 1.5 to 7.8), creating a microenvironment with a pH of 7-10, which keeps the serine residues in the active center of pronase activated. DSC thermal analysis showed that the enzyme's thermal denaturation temperature increased from 58°C to 72°C under this pH condition, and testing at a constant temperature of 37°C extended its half-life to 12 hours.

[0018] 3. Optimized clinical operation procedures. A single 5g bag (with a filling tolerance of ±0.05g) allows for direct oral administration without dissolution, reducing the number of steps required by traditional split-dosage products by 70%. Simulated clinical trials showed that medical staff's operation time was reduced from 12 minutes to 3 minutes, and the error rate decreased by 83%.

[0019] 4. Spatiotemporal drug release. The step-by-step granulation process enables simultaneous release of pronase particles ≤180μm and sodium bicarbonate particles ≤150μm in the stomach. Dissolution curves show a time difference of less than 1.2 minutes between the two peak releases (USP paddle method, 50 rpm). This synchronized release ensures complete mucolytic and antifoaming effects within 15 minutes, a 40% reduction in duration compared to commercially available products.

[0020] 5. Low-temperature protection of enzyme structure. Pronase is added at 40°C in the following steps to avoid protein denaturation caused by traditional high-temperature granulation (>80°C). This process maintains 98.7% of the enzyme's secondary structure, a 22 percentage point improvement compared to higher-temperature processes.

[0021] Optimized dissolution kinetics. Granulation through an 80-mesh sieve (particle size D50 = 175 μm) resulted in a particle surface area of ​​1.1 m² / g (BET method), shortening the intragastric disintegration time to 5 minutes (USP dissolution apparatus). HPLC analysis showed a 5-minute dissolution rate of 92.3%, a 35 percentage point improvement over conventional processes. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 This is a process flow chart for the synthesis of compound preparations.

[0023] Figure 2 This is an SEM image of the composite preparation, showing the complete encapsulation of silicon dioxide by dimethicone.

[0024] Figure 3 Schematic diagram of the particle flowability repose angle test. The repose angle is 28°. DETAILED DESCRIPTION

[0025] The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention; it is obvious that the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention. Example 1

[0026] 1. Raw material formula Pronase: 200 mg (activity ≥40 U / mg, purity 95.2% as determined by HPLC, in compliance with GB / T23527-2009).

[0027] Sodium bicarbonate: 200 mg (pharmaceutical grade, heavy metal content <10 ppm as determined by ICP-MS, purity 99.7%).

[0028] Dimethicone: 300 mg (viscosity 500 mPa·s, measured by rotational viscometer, in accordance with USP41 standard).

[0029] Silicon dioxide: 25 mg (specific surface area 305 m² / g, determined by BET method, pharmaceutical grade, in accordance with GB25576-2010).

[0030] Polysorbate 80: 50 mg (HLB value 14.9, structure verified by infrared spectroscopy, in compliance with GB25551-2010).

[0031] Lactose: 3975mg (anhydrous lactose, crystal form confirmed by X-ray diffraction, in compliance with GB25595-2010).

[0032] Hydroxypropyl cellulose: 250 mg (viscosity 4050 mPa·s, measured by falling ball viscometer, in accordance with JP17 standard).

[0033] 2. Preparation process Complex synthesis Reaction conditions: Temperature: 150°C (precisely controlled by PID controller, fluctuation ±0.5°C).

[0034] Stirring rate: 40 rpm (using a digital stirrer, torque 0.2 N·m).

[0035] Reaction time: 7.5 hours (reaction progress was monitored by online infrared spectroscopy).

[0036] Steps: (1) Add dimethyl silicone oil and silicon dioxide to a 500 mL stainless steel reactor.

[0037] (2) High-purity nitrogen (99.999%) was introduced for replacement three times to maintain the oxygen content less than 0.05%.

[0038] (3) Raise the temperature to 150°C and stir the reaction at constant temperature.

[0039] (4) After the reaction is completed, DSC detection is used to confirm that the dimethyl silicone oil completely encapsulates the silica.

[0040] Emulsification mixing Mixing parameters: Temperature: 25°C (controlled by a constant temperature water bath).

[0041] Rotation speed: 40 rpm (using magnetic stirrer, rotation speed error ±1 rpm).

[0042] Time: 15 minutes (accurately controlled by a timer).

[0043] Steps: (1) Add the complex and polysorbate 80 into a 100 mL beaker.

[0044] (2) Stir magnetically until a uniform emulsion is formed (monitor the dispersion using a laser particle size analyzer).

[0045] Wet granulation Granulation parameters: Adhesive: Deionized water (resistivity ≥ 18 MΩ·cm).

[0046] Screen mesh: 24 mesh (wire diameter 0.45mm, in line with GB / T6003.1-2012).

[0047] Drying conditions: 60°C x 2 hours (fluidized bed drying, inlet air velocity 1.2 m / s).

[0048] Steps: (1) Add lactose and hydroxypropyl cellulose into the granulator.

[0049] (2) Spray pure water into the soft material (monitor the soft material status through the torque sensor).

[0050] (3) After sieving and granulating, the product was dried in a fluidized bed to a moisture content of 2.8% (detected by an infrared moisture meter).

[0051] Active ingredient blend Mixing parameters: Equipment: SYH-200 three-dimensional motion mixer (volume 200L, in line with GMP standards).

[0052] Speed: 25rpm (precisely controlled by frequency converter).

[0053] Time: 25 minutes (determined by verification of mixing uniformity).

[0054] Steps: (1) The dried granules were passed through an 80-mesh sieve (wire diameter 0.18 mm).

[0055] (2) Add pronase and sodium bicarbonate.

[0056] (3) Verification of mixing uniformity: The pronase content was determined by HPLC, with RSD = 2.1%.

[0057] Dry granulation Rolling parameters: Pressure: 6kN (controlled by hydraulic system, pressure error ±0.1kN).

[0058] Roller speed: 8rpm (frequency control, speed error ±0.5rpm).

[0059] Screen mesh number: 30 mesh (wire diameter 0.3mm).

[0060] Operation steps: ( Figure 1 ) 1. The mixed granules are rolled into sheets by a twin-screw extruder (model: FL-100).

[0061] 2. Crusher (model: PSJ-60) crushes the particles and sieves them into whole particles.

[0062] Repackaging Packaging conditions: Aluminum plastic bag: PA / PE composite film (thickness 80μm, oxygen permeability 0.08cm 3 / (m2 ·day))).

[0063] Packing capacity: 5g / bag (electronic weighing, error ±0.05g).

[0064] Structural characteristics Composite morphology: SEM shows that silica is completely wrapped by dimethicone ( Figure 2 ), particle size distribution D50=2.3μm (measured by laser particle size analyzer).

[0065] Particle flowability: Angle of repose 28° ( Figure 3 ) (determined by fixed funnel method, in compliance with GB / T11986-2008).

[0066] Bulk density: 0.65 g / cm³ (determined by measuring cylinder method, three parallel experiments, RSD=1.2%). Example 2

[0067] Recipe Adjustment Mannitol: 3980mg (pharmaceutical grade, melting point 166°C as determined by DSC, in compliance with GB25581-2010).

[0068] Polyvinylpyrrolidone: 260 mg (PVPK30, intrinsic viscosity 27 mL / g, in accordance with GB29210-2012).

[0069] The rest is the same as in Example 1.

[0070] Process adjustment Adhesive solution: 10% PVP ethanol solution (ethanol concentration 95%, in accordance with GB31640-2016).

[0071] Granulation parameters: Screen mesh number: 20 mesh (wire diameter 0.6mm).

[0072] Drying temperature: 55°C x 3 hours (oven drying).

[0073] The rest is the same as in Example 1.

[0074] Performance data: Granule hardness: 35N (measured by tablet hardness tester).

[0075] Friability: 0.8% (measured by Roche friability tester).

[0076] Example 3 Recipe Adjustment Lecithin: 52 mg (pharmaceutical grade, phosphatidylcholine content 68% as determined by thin-layer chromatography, in compliance with GB28401-2012). The remainder is the same as in Example 1.

[0077] Process adjustment Emulsification steps: Temperature: 60°C (constant temperature water bath).

[0078] Dissolution time: 10 minutes (magnetic stirring).

[0079] The rest is the same as in Example 1.

[0080] Performance data: Emulsion particle size: D50=0.8μm (measured by laser particle size analyzer).

[0081] Zeta potential: -25mV (measured by nanoparticle size analyzer).

[0082] Comparative Example 1 Technical feature deviation: Pronase and sodium bicarbonate directly participate in the synthesis of the complex. Others are the same as in Example 1.

[0083] Performance degradation: Residual enzyme activity: 8% (HPLC method, Agilent 1260 system, C18 column, mobile phase acetonitrile-water = 30:70).

[0084] Defoaming time in the stomach: 15 minutes (simulated gastric fluid test, pH 1.2, temperature 37°C).

[0085] Comparative Example 2 Technical feature deviation: dimethicone (325 mg) was used directly. Other procedures were the same as in Example 1.

[0086] Performance degradation: Foam removal rate: 41% (GB / T13354-1992 standard, measured at a constant temperature of 25°C).

[0087] Mucus clearance rate: 35% (determined by ultraviolet spectrophotometry using a porcine gastric mucus model).

[0088] Comparative Example 3 Deviation from technical characteristics: Sodium bicarbonate dosage 100 mg.

[0089] Performance degradation: Intragastric pH: 4.2 (BravopH telemetry capsule, simulating the human gastric environment).

[0090] Residual enzyme activity rate: 52% (inactivation due to failure to reach the optimal pH 7-10).

[0091] Standardization of test methods 1. Enzyme activity detection: Instrument: Agilent 1260 Infinity HPLC system.

[0092] Chromatographic column: ZORBAX SB-C18 (4.6×250 mm, 5 μm).

[0093] Mobile phase: acetonitrile-water (30:70, containing 0.1% TFA).

[0094] Detection wavelength: 214nm.

[0095] 2. Foam removal rate determination: Method: GB / T13354-1992.

[0096] Instrument: Foam tester (model: QBZY-1).

[0097] Conditions: 25°C, 5% sodium dodecyl sulfate solution.

[0098] 3. Gastric pH telemetry: Instrument: Bravo pH Monitoring System (Medtronic).

[0099] Subjects: 6 healthy volunteers.

[0100] Measurement time: 0-60 minutes after taking the medicine.

[0101] Table 1: Key performance comparison

[0102] The above description is merely a preferred embodiment of the present invention; however, the scope of protection of the present invention is not limited thereto. Any person skilled in the art who, within the technical scope disclosed by the present invention, makes equivalent substitutions or modifications based on the technical solutions and improved concepts of the present invention shall be covered by the scope of protection of the present invention.

Claims

1. A compound preparation of pronase with mucus-removing and foam-removing functions, characterized in that: Based on the total weight of the compound preparation, the following ingredients composition: Pronase: 180-220 mg; Sodium bicarbonate: 180-220 mg; Simethicone: 270-330 mg; Silicon dioxide: 22.5-27.5 mg; Polysorbate 80: 45-55 mg; Filler: 3577-4372 mg, the filler is selected from lactose, glucose, sucrose, mannitol, starch, dextrin or powdered sugar; Binder: 225-275 mg, the binder is selected from hydroxypropyl cellulose, polyvinyl pyrrolidone, starch slurry, syrup, ethanol, isopropyl alcohol or polyethylene glycol.

2. The pronase compound preparation with mucus-removing and foam-removing functions according to claim 1, characterized in that: Based on the total weight of the compound preparation, the following ingredients composition: Pronase: 200 mg; Sodium bicarbonate: 200 mg; Simethicone: 300 mg; Silicon dioxide: 25 mg; Polysorbate 80: 50mg; Lactose: 3975mg; Hydroxypropyl cellulose: 250 mg.

3. A process for preparing the compound preparation of pronase with mucus-removing and defoaming function according to claim 1 or 2, characterized in that: The following steps are involved: (1) reacting dimethicone with silicon dioxide at 145-155° C. with stirring for 7-8 hours, and cooling to room temperature to obtain a composite; (2) uniformly mixing the complex obtained in step (1) with polysorbate 80 to form a mixture A; (3) Mixing mixture A with a filler and a binder, wet granulating the mixture, and drying the mixture to obtain granules B; (4) Passing Granule B through an 80-mesh sieve, adding pronase and sodium bicarbonate, mixing well, and granulating; (5) Repackaging: 5g per bag.

4. The process for preparing the compound pronase preparation with mucus-removing and foam-removing functions according to claim 3, wherein: The filler in step (3) is lactose.

5. The process of the pronase compound preparation with mucus-removing and foam-removing functions according to claim 3, characterized in that: The binder in step (3) is hydroxypropyl cellulose.

6. The process for preparing the compound pronase preparation with mucus-removing and foam-removing functions according to claim 3, characterized in that: The wetting agent used in the wet granulation in step (3) is water or ethanol.

7. The process for preparing the compound preparation of pronase with mucus-removing and foam-removing functions according to claim 3, characterized in that: The mixing in step (4) is carried out using a three-dimensional motion mixer, and the mixing time is 15 to 30 minutes.

8. The process for producing the compound pronase preparation with mucus-removing and foam-removing functions according to claim 3, characterized in that: The granulation in step (4) is dry granulation.

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