Dosoxromilc and glycyrrhizin dipotassium compound oral disintegrating tablet and preparation method thereof

Abstract

The application discloses a compound doxofylline and glycyrrhizin disodium oral disintegrating tablet and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The oral disintegrating tablet comprises doxofylline 30-40%, glycyrrhizin disodium 3-5%, a filling agent 60-65%, a flavoring agent 0.9-1.5% and a lubricant 0.4-0.6% by mass percentage. The preparation method is prepared by adopting a powder direct compression method. The oral disintegrating tablet has a synergistic therapeutic effect of bronchodilator and hormone-like anti-inflammatory effect. The glycyrrhizin disodium as an active ingredient from liquorice has a side effect far less than that of hormones, and in the case of improving the therapeutic effect, the adverse reaction is reduced. After being prepared into the oral disintegrating tablet, the oral disintegrating tablet has the advantages of easy carrying, convenient taking, rapid effect, obvious bioavailability better than that of common tablets, low mucosal irritation to the gastrointestinal tract and the like, and provides a high-compliance drug delivery mode for clinical treatment.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a compound oral disintegrating tablet of doxophylline and dipotassium glycyrrhizinate and its preparation method. Background Technology

[0002] Asthma ranks among the most prevalent respiratory diseases in the Chinese population, and its incidence and mortality rate from acute exacerbations are showing an increasing trend year by year. Doxofylline, a widely used bronchodilator in clinical practice, has demonstrated strong bronchodilatory activity against various types of asthma, and its role in the treatment of asthma is becoming increasingly prominent.

[0003] Doxofylline (DFL) is a bronchodilator used to treat asthma and chronic obstructive pulmonary disease (COPD). It relaxes bronchial smooth muscle, helping to dilate airways and improve respiratory function. However, doxofylline primarily acts as a bronchodilator, with relatively weak anti-inflammatory and immunomodulatory effects. Clinically, it is often combined with glucocorticoids to enhance airway anti-inflammation and control airway hyperresponsiveness. The combination of these two drugs can achieve a synergistic effect of spasmodic and anti-inflammatory effects, helping to quickly relieve acute asthma symptoms and reducing the risk of adverse reactions from high-dose use of a single drug. Glycyrrhizic acid (GL) is the main active ingredient in licorice root. Studies have shown that glycyrrhizic acid can promote the expression of secretory components in airway models, and its effect is similar to that of glucocorticoids, but the molecular mechanism is different, therefore there are no obvious adverse reactions associated with hormones. Glycyrrhizate salts are a class of water-soluble derivatives obtained by salting glycyrrhizic acid. Dipotassium glycyrrhizate is a representative example and has high application value. Studies have shown that the combined use of doxophylline and glycyrrhizic acid can achieve complementary antispasmodic, anti-inflammatory, and antioxidant mechanisms, while reducing gastrointestinal irritation. This improves formulation compliance and further enhances therapeutic safety and overall efficacy. Adding glycyrrhizic acid to the prescription can also mask the bitterness of doxophylline to some extent and improve the palatability of the formulation.

[0004] However, currently, the most common commercially available formulations in China are tablets, leading to poor medication adherence in children and patients with dysphagia, and a lack of clinically applicable dosage forms. Oral formulations are usually the first-line choice, commonly including suspensions, solutions, tablets, and capsules. However, oral solutions suffer from poor stability, are not easy to carry, and have inaccurate dosing characteristics, affecting patient compliance and making them unsuitable for patients with dysphagia. Therefore, there is an urgent clinical need for an ideal oral drug delivery system for pediatric patients and those with dysphagia to treat asthma, and orally disintegrating tablets, with their advantage of rapid disintegration without water, can be considered the first-line dosage form. This invention designs a dosage form that combines dipotassium glycyrrhizate and doxophylline to create an orally disintegrating tablet, which not only improves drug bioavailability and enhances the patient's treatment experience but also enables faster and more precise therapeutic effects in clinical practice, potentially providing better treatment options for patients with respiratory diseases. Summary of the Invention

[0005] The purpose of this invention is to provide a compound orally disintegrating tablet containing doxophylline and dipotassium glycyrrhizate. This tablet is composed of doxophylline, dipotassium glycyrrhizate, a filler, a flavoring agent, and a lubricant. It achieves a synergistic therapeutic effect of bronchodilator and steroid-like anti-inflammatory agent. Furthermore, the dipotassium glycyrrhizate, as an active ingredient derived from licorice, has significantly fewer side effects than steroids. This invention improves therapeutic efficacy, reduces adverse reactions, enhances patient compliance, and addresses the swallowing difficulties associated with existing formulations.

[0006] To achieve the above objectives, the present invention employs the following technical means: A compound oral disintegrating tablet containing doxophylline and dipotassium glycyrrhizate comprises, by weight percentage: 30%~40% doxophylline, 3%~5% dipotassium glycyrrhizate, 60%~65% filler, 0.9%~1.5% flavoring agent, and 0.4%~0.6% lubricant; preferably, 33.33% doxophylline, 4% dipotassium glycyrrhizate, 63.05% filler, 1.2% flavoring agent, and 0.5% lubricant.

[0007] The filler is filler 1 or filler 2; wherein, filler 1 comprises D-mannitol, crystalline cellulose, low-substituted hydroxypropyl methylcellulose, light anhydrous silica, crosslinked polyvinylpyrrolidone, and POVACOAT (polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer); filler 2 comprises D-... Mannitol, crospovidone, polyvinyl acetate, and a polyvinyl acetate dispersion. Filler 1 is preferred.

[0008] The flavoring agent is a mixture of samaran and menthol. Preferably, the mass percentages of samaran and menthol are 0.4% and 0.8%, respectively.

[0009] The lubricant is selected from sodium stearate, stearic acid, and magnesium stearate. Preferably, the lubricant is sodium stearate with a mass fraction of 0.5%.

[0010] The preparation method of the doxophylline dipotassium glycyrrhizate compound orally disintegrating tablets adopts the direct powder compression technology, and specifically includes the following steps: (1) Weigh a certain amount of doxorubicin and dipotassium glycyrrhizate, mix them evenly, and sieve them; (2) Weigh a certain amount of filler and mix it evenly with the powder obtained in step (1); (3) Weigh a certain amount of flavoring agent and sieve it. Mix it evenly with the powder obtained in step (2) using the equal incremental method. (4) Weigh a certain amount of lubricant and sieve it. Mix it evenly with the powder obtained in step (3) using the equal incremental method. Compress the evenly mixed powder on a tablet press with a compression force of 80 MPa to 240 MPa to obtain the dipotassium dipotassium disodium glycyrrhizate oral disintegrating tablets.

[0011] This invention screened the types and ratios of fillers, flavoring agents, and lubricants through single-factor experiments to determine the optimal formulation for doxophylline dipotassium glycyrrhizate compound orally disintegrating tablets. All quality indicators of the finished product meet the specifications for orally disintegrating tablets, exhibiting excellent drug dissolution rate and rapid onset of action. High temperature and humidity influence tests showed that the physicochemical properties and drug content of the formulation remained stable under aluminum-plastic packaging, demonstrating good storage reliability.

[0012] The beneficial effects of this invention are as follows: 1) The doxophylline dipotassium glycyrrhizinate compound orally disintegrating tablets of the present invention have stable quality and meet the pharmacopoeia requirements. A reliable in vitro detection method has been established. It has the advantages of rapid release and in vivo bioavailability comparable to the reference preparation.

[0013] 2) The doxophylline dipotassium glycyrrhizinate compound oral disintegrating tablets of the present invention can effectively improve the symptoms of asthma model mice and reduce lung damage, providing a scientific basis for industrial production, quality control and clinical application. At the same time, it provides a better formulation option for the clinical treatment of asthma, and has important experimental value and clinical significance.

[0014] 3) The doxophylline dipotassium glycyrrhizate compound orally disintegrating tablets of the present invention have a hardness of 30 N~40 N and a disintegration time of 25 s~30 s when the tableting force is 160 MPa. The friability and content uniformity both meet the standards for orally disintegrating tablets. Attached Figure Description

[0015] Figure 1 The dissolution curves of the orally disintegrating tablets prepared in Example 4 are shown; (A) doxophylline; (B) dipotassium glycyrrhizate.

[0016] Figure 2 The average plasma concentration-time curves of doxophylline in Example 4, Comparative Example 1, and commercially available ordinary tablets are shown.

[0017] Figure 3 This is the blood concentration-time curve of glycyrrhetinic acid in Example 4.

[0018] Figure 4 Methods for drug administration and model establishment in mice.

[0019] Figure 5 The statistical results of the lung index score of mice (n=8).

[0020] Figure 6 The levels of inflammatory factors in mouse serum (n=8) are: (A) IgE, (B) IL-4, (C) IL-5, (D) IL-13.

[0021] Figure 7HE staining results of mouse lung tissue (200×); (A) Blank control group, (B) Model group, (C) Commercially available formulation group, (D) Comparative example 1, (E) Example 4. Detailed Implementation

[0022] The preferred embodiments of the present invention will now be described in detail with reference to specific examples. It should be understood that the following examples are given for illustrative purposes only and are not intended to limit the scope of the invention. Those skilled in the art can make various modifications and substitutions to the present invention without departing from its spirit and essence.

[0023] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0024] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0025] Example 1 A tablet containing filler 1 has the following formulation: Doxofylline: 100 mg (33.33 w / w%) Dipotassium glycyrrhizate: 12 mg (4 w / w%) Filler 1: 188 mg (62.67 w / w%), composed of the following components (by weight percentage): D-mannitol 68%, crystalline cellulose 16%, low-substituted hydroxypropyl methylcellulose 5%, light anhydrous silica 1%, crospovidone 6%, POVACOAT (polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer) 4%.

[0026] A method for preparing a tablet containing filler 1, the specific operation steps are as follows: (1) Weigh out the prescribed amount of theophylline and dipotassium glycyrrhizate, mix them evenly, and pass them through a 100-mesh sieve; (2) Weigh the prescribed amount of filler 1 and mix it evenly with the powder from step (1). Compress the mixed powder into tablets using a single-punch tablet press.

[0027] Example 2 A tablet containing filler 2 has the following formulation: Doxofylline: 100 mg (33.33 w / w%) Dipotassium glycyrrhizate: 12 mg (4 w / w%) Filler 2: 188 mg (62.67 w / w%), composed of the following components (by weight percentage): D Mannitol 90%, crospovidone 5%, polyvinyl acetate 4.5%, povidone 0.5%.

[0028] A method for preparing a tablet containing filler 2, the specific operation steps are as follows: (1) Weigh out the prescribed amount of theophylline and dipotassium glycyrrhizate, mix them evenly, and pass them through a 100-mesh sieve; (2) Weigh the prescribed amount of filler 2 and mix it evenly with the powder from step (1). Compress the mixed powder into tablets using a single-punch tablet press.

[0029] Example 3 Comparison of fillers in Example 1 and Example 2: Tablets were pressed using a tablet press at pressures of 80 MPa, 160 MPa, and 240 MPa, respectively. Thickness t (m) and tablet diameter D (m) were measured with vernier calipers, and hardness F (N) was measured with a hardness tester. Each experiment was performed in triplicate. The tensile strength T = 2F / ΠDt (N / m) was calculated. 2 Plotting pressure P on the x-axis and tensile strength T on the y-axis, the slope k value can be used to evaluate the compressibility of the auxiliary material.

[0030]

[0031]

[0032] Tablets prepared using filler 1 have a smaller Hausner ratio and Carr's index, and better compressibility. Within the selected compression force range, filler 1 has higher tensile strength than filler 2, indicating that filler 1 provides better formability.

[0033] Example 4 A compound oral disintegrating tablet (GL-DFL ODT) containing doxophylline and dipotassium glycyrrhizinate has the following formulation: Doxofylline: 100 mg (33.33 w / w%) Dipotassium glycyrrhizate: 12 mg (4 w / w%) Filler 1 (same as Example 1): 189 mg (63.05 w / w%) Sodium fumarate: 1.5 mg (0.5 w / w%) Semamate: 1.2 mg (0.4 w / w%) Menthol: 2.4 mg (0.8 w / w%) A method for preparing a compound oral disintegrating tablet containing doxophylline and dipotassium glycyrrhizate, the specific steps of which are as follows: (1) Weigh out the prescribed amount of theophylline and dipotassium glycyrrhizate, mix them evenly, and pass them through a 100-mesh sieve; (2) Weigh out the prescribed amount of filler 1 and mix it evenly with the powder obtained in step (1); (3) Weigh out the prescribed amount of flavoring agents semathymide and menthol, grind them through a 200-mesh sieve, and mix them evenly with the powder obtained in step (2) using the equal incremental method; (4) Weigh out the prescribed amount of lubricant sodium stearate fumarate and pass it through a 200-mesh sieve. Mix it evenly with the powder obtained in step (3) using the equal incremental method. Compress the mixed powder on a single punch tablet press with a tableting force of 160 MPa to obtain the dipotassium dipotassium disodium glycyrrhizate oral disintegrating tablets.

[0034] Example 5 Quality evaluation of a compound oral disintegrating tablet containing doxophylline and dipotassium glycyrrhizate: 5.1 Appearance The doxophylline dipotassium glycyrrhizinate compound orally disintegrating tablets (GL-DFL ODT) prepared in Example 4 are white, uncoated, round tablets with a smooth surface without scratches, no visible foreign matter, and suitable hardness and abrasion resistance.

[0035] 5.2 Tableting force results When the hardness is low, the prepared orally disintegrating tablets exhibit easy wear and powdering at the edges, and are highly brittle. While tablets with a hardness above 30 N have a complete and glossy appearance and meet the hardness requirements, disintegration times exceeding 30 seconds occur when the hardness is above 40 N. Choosing a compression force of 160 MPa yields orally disintegrating tablets with a hardness between 30 N and 40 N and a disintegration time of less than 30 seconds.

[0036]

[0037] 5.3 Hardness Results Six orally disintegrating tablets prepared in Example 4 were randomly selected, and their hardness was measured using a tablet hardness tester. A hardness of 30 N or higher was required to meet the quality requirements. All three batches of samples had hardness within the range of 30 N to 40 N, indicating suitable hardness and abrasion resistance, and thus met the specifications.

[0038]

[0039] 5.4 Friability Results The friability tester was used for determination. Test conditions: rotation speed 25 r / min, 100 rotations. Procedure: Take 6 g of the orally disintegrating tablets prepared in Example 4. After gently blowing away the powder on the tablet surface with a bulb syringe, accurately weigh the total weight of the tablets. Then place all the tablets into the tester, rotate for 4 minutes, gently remove them, and gently blow away any scattered powder with a bulb syringe again. Accurately weigh the total weight and calculate the weight loss after the test. The result should not exceed 1% of the original total weight, and no broken tablets should appear. If the weight loss exceeds the 1% limit, the test should be repeated twice more to obtain the average weight loss of the three tests. Again, no broken tablets should appear, and the average weight loss should not exceed the 1% limit. The three batches of samples showed a weight loss of no more than 1%, and no broken or pulverized tablets were found. The friability test met the pharmacopoeia standards.

[0040]

[0041] 5.5 Disintegration Time Results The disintegration time was tested using a disintegration apparatus. Following the method outlined in Chapter 0921 of the 2020 edition of the Pharmacopoeia of the People's Republic of China (Part IV), a disintegration apparatus was used. Approximately 900 mL of purified water was placed in the disintegration apparatus cup at a temperature of 37±0.5℃. A stainless steel tube was fixed to a support and immersed in the disintegration apparatus cup. The lowest point of the stainless steel screen was adjusted to 15 mm below the water surface. Six tablets were gently dropped into the screen for testing, and the disintegration time of each tablet was measured and averaged. All three batches of samples completely disintegrated and passed through the disintegration apparatus screen within 30 seconds, indicating that the disintegration time of the orally disintegrating tablets prepared in Example 4 met the requirements.

[0042]

[0043] 5.6 Content Uniformity Results Ten orally disintegrating tablets were randomly selected from each batch prepared in Example 4. The tablet weights were accurately measured, and the samples were crushed and placed in a 100 mL volumetric flask. The flask was then diluted to volume with 2% acetic acid-methanol (20:80) and shaken well. The solution was filtered, and 1 mL of the filtrate was accurately transferred to a 100 mL volumetric flask, diluted to volume, and shaken well to prepare the test solution. The average content of the 10 orally disintegrating tablets was calculated. The absolute value A and standard deviation S of the difference between the labeled amount and the mean. A + 2.2S ≤ L (L = 15) for the three batches of samples indicates that the content uniformity of Example 4 meets the pharmacopoeia standard.

[0044]

[0045] Example 6 In vitro dissolution evaluation: Following the dissolution determination method in the 2020 edition of the Chinese Pharmacopoeia, water was used as the dissolution medium (900 mL), the rotation speed was 50 r / min, and the temperature was 37℃. The dissolution test was conducted using the paddle method, with samples taken at 1 min, 2 min, 3 min, 4 min, 5 min, 10 min, and 15 min. An equal volume of buffer solution was added to the dissolution medium, and the samples were immediately filtered through a 0.45 μm microporous membrane after sampling. The orally disintegrating tablets prepared in Example 4 exhibited the unique advantage of rapid disintegration and dissolution. The dissolution curve determination results of Example 4 are shown below. Figure 1 As shown, the dissolution rate of doxophylline and dipotassium glycyrrhizate in water reaches over 80% within 5 minutes, which can meet the clinical need for rapid onset of action.

[0046] Example 7 Influencing Factors Experiment: Forty orally disintegrating tablets prepared in Example 4 were packaged in aluminum-plastic packaging. External conditions were set at 60℃±2℃ and RH 75%±5%. Samples were taken at 0, 5, and 10 days for testing. Hardness, thickness, hygroscopicity, disintegration time, and active pharmaceutical ingredient content were investigated.

[0047]

[0048] As shown in Table 8, the stability test results indicate that the formulation exhibits good stability after being placed in aluminum-plastic packaging at 60℃ / RH75% for 10 days.

[0049] Comparative Example 1 A doxophylline orally disintegrating tablet (DFL ODT) has the following formulation: Doxofylline: 100 mg (33.33 w / w%) Filler 1 (same as Example 1): 195 mg (64.97 w / w%) Sodium fumarate: 1.5 mg (0.5 w / w%) Semamate: 1.2 mg (0.4 w / w%) Menthol: 2.4 mg (0.8 w / w%) A method for preparing doxofylline orally disintegrating tablets, the specific steps of which are as follows: (1) Weigh the prescribed amount of doxofylline and pass it through a 100-mesh sieve; (2) Weigh out the prescribed amount of filler 1 and mix it evenly with the powder from step (1); (3) Weigh out the prescribed amount of flavoring agents semathymide and menthol, grind them through a 200-mesh sieve, and mix them evenly with the powder from step (2) using the equal incremental method; (4) Weigh out the prescribed amount of lubricant sodium stearate fumarate and pass it through a 200-mesh sieve. Mix it evenly with the powder from step (2) using the equal incremental method. Compress the mixed powder on a single punch tablet press with a compression force of 160 MPa to obtain the theophylline orally disintegrating tablets.

[0050] Example 8 Bioavailability study of a compound oral disintegrating tablet containing doxophylline and dipotassium glycyrrhizate: 8.1 Chromatographic conditions 1. Pre-column: ZORBAX Eclipse XDB-C18 (4×2.0 mm) 2. Column: ZORBAX Eclipse XDB-C18 (4.6×30 mm, 3.5 μm) 3. Injection volume: 5 μL 4. Column temperature measurement: 40℃ 5. Flow rate: 0.25 mL / min 8.2 Pharmacokinetic Administration Methods Six healthy Japanese white rabbits (3 kg ± 0.5 kg) were fasted overnight before administration. The study followed a three-phase, three-sequence crossover design, with a one-week buffer period between each phase. The dosage was doxophylline 100 mg / rabbit and dipotassium glycyrrhizate 12 mg / rabbit.

[0051] Before administration, rabbits were randomly assigned to three groups: commercially available regular tablets, doxophylline orally disintegrating tablets, and doxophylline dipotassium glycyrrhizate orally disintegrating tablets.

[0052] Oral administration method: Administer 1 / 2 tablet of commercially available doxophylline (containing 100 mg of doxophylline) orally. Use a mouth opener to open the rabbit's mouth, place the tablet in the pharynx, and give an appropriate amount of water to promote swallowing and prevent the tablet from sticking to the throat.

[0053] Orally disintegrating tablet administration method: Place the rabbit in a restraint device and open its mouth with a mouth opener. Then, place the orally disintegrating tablet in the mouth, moisten it with an appropriate amount of water, and apply gentle tension to restrain the mouth to ensure complete disintegration of the tablet and prevent chewing.

[0054] 8.3 Pharmacokinetic parameters The test formulation and the reference formulation were orally administered to white rabbits at equivalent doses (100 mg / rabbit). The relative bioavailability of the test formulation relative to the reference formulation was 103.99%; the C0.05 of both formulations was... max AUC (0-t) and T maxStatistical comparisons showed no significant differences (P>0.05). The relative bioavailability of doxophylline orally disintegrating tablets, doxophylline dipotassium glycyrrhizate orally disintegrating tablets, and the reference formulation were 100.3%, 100%, and 103%, respectively, indicating that the bioavailability of Example 4, Comparative Example 1, and the reference formulation was extremely similar, achieving in vivo absorption effects comparable to commercially available formulations. The pharmacokinetic parameters of Example 4 and Comparative Example 1 are shown in Tables 9 and 10 below, and the results of the mean plasma concentration-time curves are as follows. Figure 2 and Figure 3 As shown. By Figure 2 It can be seen that, statistically, there were no statistically significant differences in the peak concentration, time to peak concentration, and area under the curve of doxophylline in Example 4 and Comparative Example 1 compared with the reference formulation. Figure 3 It is known that dipotassium glycyrrhizate is difficult to absorb directly after oral administration and needs to be metabolized into glycyrrhetinic acid by intestinal flora before it can enter the blood circulation. This results in a significant lag in the blood concentration of glycyrrhetinic acid in Example 4, making it difficult to detect significant blood concentration at early time points.

[0055]

[0056]

[0057] Example 9 Pharmacodynamic study of a compound oral disintegrating tablet containing doxophylline and dipotassium glycyrrhizate: 9.1 Establishment of an asthma mouse model Forty female BALB / c mice were randomly divided into five groups: a blank control group, an asthma model group, a commercially available formulation group, a doxophylline orally disintegrating tablet group (Comparative Example 1), and a doxophylline dipotassium glycyrrhizate compound orally disintegrating tablet group (Example 4). After one week of acclimatization, mice were sensitized by intraperitoneal injection of 0.2 mL of 0.1% ovalbumin (OVA) suspension on days 0, 7, and 14. From day 21, mice were placed in a self-made closed nebulizer and challenged with 2% OVA solution via nebulization for 30 minutes daily for 7 consecutive days. The blank control group received an equal volume of physiological saline during the same period, and underwent intraperitoneal injection and nebulization using the same method.

[0058] Treatment was administered via gavage. The dosage for the commercially available formulation and the doxophylline orally disintegrating tablets group was 750 mg / kg. The dosage for the doxophylline dipotassium glycyrrhizinate orally disintegrating tablets group was calculated based on 750 mg / kg of doxophylline and 75 mg / kg of dipotassium glycyrrhizinate, administered 30 minutes before each nebulization. All drugs were prepared as a suspension using 0.5% sodium carboxymethyl cellulose. The mouse administration and modeling methods are as follows. Figure 4 As shown.

[0059] 9.2 Lung Index Score in Mice Lung Index = Right Lung Mass (mg) / Body Mass (g) The statistical results of the mouse lung index are shown in Table 11 below. Figure 5 As shown, compared with the blank control group, the lung index of mice in the model control group was significantly increased (P<0.0001). After treatment, the lung index of mice in the drug-treated group and the commercially available formulation treatment group was significantly decreased (P<0.0001).

[0060]

[0061] 9.3 Serum inflammatory factor levels in mice Blood was collected from the orbital rim, centrifuged at 10,000 r / min for 15 min, and the supernatant was collected for analysis and stored at -80℃ for later use. Plasma IgE, IL-4, IL-5, and IL-13 levels in each group of mice were calculated according to the kit instructions. The results of serum inflammatory factor levels in mice are shown in Tables 12 and 13. Figure 6 As shown, the serum levels of IgE, IL-4, IL-5, and IL-13 in the model control group were higher than those in the blank control group; the serum levels of IgE, IL-4, IL-5, and IL-13 in the commercially available formulation treatment group, the doxophylline orally disintegrating tablet treatment group, and the doxophylline dipotassium glycyrrhizinate orally disintegrating tablet treatment group were lower than those in the model control group. This indicates that all treatment groups can inhibit the expression of inflammatory factors in the serum of asthmatic mice, with the doxophylline dipotassium glycyrrhizinate orally disintegrating tablet group showing a stronger inhibitory effect on the IL-4 inflammatory factor.

[0062]

[0063]

[0064] 9.4 HE staining of lung tissue Three mice were randomly selected from each group. After sacrifice, lung tissue was rapidly separated and thoroughly rinsed with pre-cooled physiological saline to remove residual bloodstains and impurities from the lung tissue surface. A portion of the right lung tissue was placed in 4% paraformaldehyde fixative and fixed at room temperature for 24 hours. Subsequently, it underwent gradient dehydration and clearing processes, and was routinely embedded in paraffin to prepare lung tissue blocks. Serial sections were prepared along the sagittal plane, with a section thickness controlled at approximately 4 μm. Hematoxylin-eosin (HE) staining was then performed. The pathological morphology and structural changes of the lung tissue in each group were observed using an optical microscope. Pathological images were simultaneously acquired and analyzed. The degree of lung tissue damage was comprehensively assessed based on the HE staining results, with a focus on observing the peri-airway inflammatory cell infiltration, alveolar septal thickening, bronchoconstriction, and typical pathological manifestations such as interstitial congestion and edema. The HE staining results of the lung tissue are shown below. Figure 7As shown, after the corresponding drug intervention, the pathological damage of the lung tissue in mice in each drug administration group was alleviated to varying degrees. The lung tissue structure was significantly more regular than that of the model group, the number of inflammatory cells infiltrating the airway and lung interstitium was significantly reduced, and the overall pathological morphology was significantly improved compared with the model group. Among them, the alveolar morphology of the doxophylline dipotassium glycyrrhizinate oral disintegrating tablet group in Example 4 was more regular and orderly, the lung interstitial congestion was significantly improved, only a small number of inflammatory cells were present in the lung tissue, and the inflammatory infiltration phenomenon was significantly improved.

Claims

1. A compound oral disintegrating tablet containing doxophylline and dipotassium glycyrrhizate, characterized in that... By weight percentage, it includes: 30%~40% doxophylline, 3%~5% dipotassium glycyrrhizate, 60%~65% filler, 0.9%~1.5% flavoring agent, and 0.4%~0.6% lubricant.

2. The doxophylline-glycyrrhizic acid dipotassium compound orally disintegrating tablets according to claim 1, characterized in that, The orally disintegrating tablets comprise, by weight percentage: 33.33% doxophylline, 4% dipotassium glycyrrhizate, 63.05% filler, 1.2% flavoring agent, and 0.5% lubricant.

3. The orally disintegrating tablets of doxophylline and dipotassium glycyrrhizate according to claim 1, characterized in that, The filler is filler 1 or filler 2; wherein, the composition of filler 1 includes D-mannitol, crystalline cellulose, low-substituted hydroxypropyl methylcellulose, light anhydrous silica, cross-linked polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer; the composition of filler 2 includes D-mannitol, cross-linked polyvinyl alcohol, polyvinyl acetate and polyvinyl alcohol dispersion.

4. The orally disintegrating compound tablets containing doxophylline and dipotassium glycyrrhizate according to claim 1, characterized in that, The flavoring agent includes sematriol and menthol; wherein the mass percentages of sematriol and menthol are 0.4% and 0.8%, respectively.

5. The orally disintegrating compound tablets of doxophylline and dipotassium glycyrrhizate according to claim 1, characterized in that, The lubricant is selected from one of magnesium stearate, stearic acid, and sodium stearate fumarate.

6. A method for preparing the orally disintegrating compound tablets of doxophylline and dipotassium glycyrrhizate according to any one of claims 1-5, characterized in that, Includes the following steps: (1) Weigh out the theophylline and dipotassium glycyrrhizate, mix them evenly, and sieve them; (2) Weigh the filler and mix it evenly with the powder obtained in step (1); (3) Weigh the flavoring agent and sieve it. Mix it evenly with the powder obtained in step (2) using the equal incremental method. (4) Weigh the lubricant and sieve it. Mix it with the powder obtained in step (3) using the equal incremental method. Compress the mixed powder on a tablet press to obtain the dipotassium dipotassium glycyrrhizate compound oral disintegrating tablets.

7. The preparation method of the doxophylline dipotassium glycyrrhizate compound orally disintegrating tablets according to claim 6, characterized in that, In step (4), the tableting force is 80 MPa to 240 MPa.

8. The preparation method of the doxophylline dipotassium glycyrrhizate compound orally disintegrating tablets according to claim 6, characterized in that, When the tableting force is 160 MPa, the resulting orally disintegrating tablets have a hardness of 30 N~40 N, a disintegration time of 25 s~30 s, and both the friability and content uniformity meet the standards for orally disintegrating tablets.

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