A spray-dried lactose-based complex pharmaceutical formulation and a method of preparing the same

Abstract

The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a compound pharmaceutical preparation based on spray lactose and a preparation method thereof. The compound pharmaceutical preparation comprises the following components in parts by weight: active drug 10-15 parts, spray lactose 27-33 parts, mannitol 30-35 parts, modified microcrystalline cellulose 13-16 parts, disintegrating agent 3-5 parts, lubricant 1-2 parts, and flavoring agent 1-3 parts. The compound pharmaceutical preparation has the characteristics of high hardness, low friability, rapid disintegration, good content uniformity, excellent taste masking effect and good taste.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a compound pharmaceutical preparation based on spray-dried lactose and its preparation method. Background Technology

[0002] Oseltamivir phosphate, an antiviral drug used in China to treat influenza A and B, has proven clinical efficacy and is a WHO-recommended essential medicine. However, currently available oseltamivir phosphate is mainly in granule form, requiring water to dissolve before administration. Furthermore, the drug itself has a strong bitter taste and unpleasant aftertaste, leading to poor medication adherence, especially among children, the elderly, and those with swallowing difficulties. To address this issue, orally disintegrating tablets, due to their advantages of not requiring water, rapid disintegration in the mouth, and ease of swallowing, have become an ideal dosage form for improving the medication experience. Developing orally disintegrating oseltamivir phosphate tablets would not only improve patient adherence but also achieve rapid disintegration and absorption, holding significant clinical importance.

[0003] In the preparation of orally disintegrating tablets, direct compression is favored due to its simplicity, time and energy savings, and suitability for industrial production. The selection of excipients is crucial to the success of direct compression. Spray-dried lactose, as the first developed direct compression excipient, consists of α-lactose monohydrate crystals and amorphous lactose. The latter, through plastic deformation during compression, imparts good compressibility and good flowability without affecting drug dissolution, thus it is widely used in orally disintegrating tablets and chewable tablets. However, spray-dried lactose also has significant drawbacks: its brittleness is prominent. When the compression pressure is too high, the brittleness of spray-dried lactose becomes pronounced, and tablets are prone to cracking or splitting at the top, making it difficult to balance hardness and brittleness. These shortcomings limit the application of spray-dried lactose in high-dose formulations or large-scale, high-speed tablet production.

[0004] To address the aforementioned issues, researchers both domestically and internationally have attempted to improve the compressibility and anti-cracking properties of spray-dried lactose by physically mixing or co-treating it with excipients such as mannitol, microcrystalline cellulose, and disintegrants. However, simple physical mixing often results in uneven mixing, significant differences in flowability, and stratification during compression. Conventional co-treatment of excipients, while increasing hardness, often sacrifices disintegration rate, making it difficult to achieve a balance between "rapid disintegration" and "sufficient hardness." Furthermore, the strong bitterness of oseltamivir phosphate places higher demands on the masking technology for orally disintegrating tablets. While existing sweeteners can provide sweetness, they are insufficient to effectively block the contact between bitter molecules and taste buds, resulting in limited masking effects.

[0005] Against this backdrop, there is an urgent need for a compound pharmaceutical formulation based on spray-dried lactose to expand the further application of spray-dried lactose in the field of pharmaceutical excipients. Summary of the Invention

[0006] In order to overcome the shortcomings of the prior art, one of the objectives of this invention is to provide a compound pharmaceutical preparation based on spray lactose, which has the characteristics of high hardness, low brittleness, rapid disintegration, good content uniformity, excellent taste masking effect and good taste.

[0007] The second objective of this invention is to provide a method for preparing a compound pharmaceutical formulation based on spray-dried lactose, which is simple and easy to implement.

[0008] The objective of this invention is achieved through the following technical solution: A compound pharmaceutical preparation based on sprayed lactose, comprising the following components by weight: 10-15 parts of active pharmaceutical ingredient, 27-33 parts of sprayed lactose, 30-35 parts of mannitol, 13-16 parts of modified microcrystalline cellulose, 3-5 parts of disintegrant, 1-2 parts of lubricant, and 1-3 parts of flavoring agent. The structural formula of the flavoring agent is: .

[0009] Preferably, the flavoring agent is prepared as follows: (1) Di-tert-butyl dicarbonate and aspartame were added to a mixed solvent of water / 1,4-dioxane, and then triethylamine was added and stirred. After purification, intermediate 1 was obtained. The structural formula of intermediate 1 is: (2) Under inert gas protection, tert-butyl 3,4-diaminobenzoate and intermediate 1 are added to acetonitrile, and then phosphorus tetraiodide is added. After reaction, the mixture is purified to obtain the residue. Hydrochloric acid / ethyl acetate is added to the residue, and after stirring, the mixture is purified to obtain the flavoring agent.

[0010] This invention first introduces a protecting group onto the amino group of aspartame to obtain intermediate 1, thereby avoiding its competitive reaction with the amino group of tert-butyl 3,4-diaminobenzoate; then, the carboxyl group of intermediate 1 undergoes a condensation cyclization reaction with the o-diamine group in tert-butyl 3,4-diaminobenzoate to generate a benzimidazole skeleton; finally, the protecting groups on the amino and carboxyl groups are removed by acid hydrolysis to obtain the flavoring agent.

[0011] Preferably, in step (1), the molar ratio of aspartame, di-tert-butyl dicarbonate, and triethylamine is 1:(1.2-1.5):(1-1.2); the volume ratio of water to 1,4-dioxane in the water / 1,4-dioxane mixed solvent is 1:1; and the stirring time is 12-18 h.

[0012] Preferably, in step (2), the ratio of tert-butyl 3,4-diaminobenzoate, intermediate 1, phosphorus tetraiodide, and hydrochloric acid / ethyl acetate is 1 mmol:(1-1.2) mmol:(0.2-0.4) mmol:(1-1.2) mL; the concentration of hydrochloric acid / ethyl acetate is 4 mol / L; the reaction temperature is 60-80℃ and the reaction time is 8-16 h; the stirring time is 8-12 h.

[0013] Preferably, the modified microcrystalline cellulose is prepared as follows: Microcrystalline cellulose, a modifier, sodium hydroxide, and potassium iodide were added to anhydrous N,N-dimethylformamide, and the mixture was purified after reaction to obtain the modified microcrystalline cellulose. The structural formula of the modifier is: .

[0014] This invention utilizes the nucleophilic substitution reaction between the hydroxyl group of 3,7,11-trimethyldodecane-3-ol and 1,2-dibromoethane to prepare a brominated modifier; then, the bromine at the end of the modifier undergoes nucleophilic substitution with the hydroxyl group of microcrystalline cellulose, grafting long-chain alkyl groups onto cellulose to obtain modified microcrystalline cellulose.

[0015] Preferably, the preparation process of the modifier is as follows: 3,7,11-trimethyldodecane-3-ol, 1,2-dibromoethane, cesium carbonate, and potassium iodide were added to anhydrous N,N-dimethylformamide, and the mixture was purified after reaction to obtain the modifier.

[0016] Preferably, the molar ratio of 3,7,11-trimethyldodecane-3-ol, 1,2-dibromoethane, cesium carbonate, and potassium iodide is 1:(1-1.2):(1.5-1.8):(0.1-0.3); the reaction temperature is 70-90℃ and the reaction time is 5-8h.

[0017] Preferably, the mass ratio of the microcrystalline cellulose, modifier, sodium hydroxide, and potassium iodide is 1:(1.1-1.3):(0.2-0.3):(0.1-0.2); the reaction temperature is 70-90℃ and the reaction time is 5-8h.

[0018] Preferably, the active drug is oseltamivir phosphate; the disintegrant is potassium polacrine or sodium croscarmellose; and the lubricant is selected from polyethylene glycol, magnesium stearate, and talc.

[0019] The preparation method of the above-mentioned compound pharmaceutical formulation based on spray-dried lactose includes the following steps: Add spray-dried lactose, mannitol, modified microcrystalline cellulose, disintegrant, lubricant, and flavoring agent to deionized water to obtain a suspension with a solid content of 12-16%. After spray drying, add the active drug and compress into tablets.

[0020] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. This invention provides a compound pharmaceutical formulation based on spray-dried lactose, comprising an active pharmaceutical ingredient, spray-dried lactose, mannitol, modified microcrystalline cellulose, a disintegrant, a lubricant, and a flavoring agent. This compound pharmaceutical formulation possesses comprehensive advantages such as high hardness, low brittleness, rapid disintegration, good content uniformity, excellent flavor masking effect, and superior taste, and has broad application prospects.

[0021] 2. This invention, by adding a flavoring agent with a specific structure, not only effectively masks the unpleasant bitterness of the drug but also improves the hardness and disintegration performance of the compound drug formulation. The benzimidazole carboxylic acid moiety of this flavoring agent can form strong hydrogen bonds with the hydroxyl groups of lactose, forming a rigid network structure on the particle surface, which increases the hardness of the compound drug formulation. At the same time, the hydrophobic side chains of its phenylalanine methyl ester moiety are oriented on the particle surface, promoting the formation of micro-hydrophobic pores, accelerating water penetration and synergistic swelling with the disintegrant, thereby shortening the disintegration time and effectively masking the unpleasant taste of oseltamivir phosphate while disintegrating rapidly.

[0022] 3. This invention improves the content uniformity and reduces brittleness of compound pharmaceutical formulations by adding modified microcrystalline cellulose. The modified microcrystalline cellulose has long-chain alkyl groups grafted onto its surface. These long-chain alkyl groups hinder excessive hydrogen bonding between hydroxyl groups of cellulose molecules through steric hindrance, preventing aggregation and thus improving content uniformity under high drug loading. Simultaneously, the flexibility of the long-chain alkyl groups absorbs impact energy during compression, preventing stress concentration-induced fragmentation, reducing brittleness, improving the mechanical strength of the compound pharmaceutical formulation, and reducing production losses. Attached Figure Description

[0023] Figure 1 This is the infrared spectrum of the modified microcrystalline cellulose prepared in Example 1. Detailed Implementation

[0024] The present invention will be further described below with reference to the accompanying drawings and specific embodiments. It should be noted that, without conflict, the various embodiments or technical features described below can be arbitrarily combined to form new embodiments. Specific conditions not specified in the embodiments are based on conventional conditions or product instructions. Unless otherwise specified, the reagents or instruments used are all conventional products obtained through commercial channels.

[0025] (a) Preparation example Preparation Example 1 A modified microcrystalline cellulose is prepared as follows: (a) 3,7,11-trimethyldodecane-3-ol, 1,2-dibromoethane, cesium carbonate, potassium iodide, and anhydrous DMF were added to anhydrous N,N-dimethylformamide (DMF) in a ratio of 1 mmol:1.1 mmol:1.6 mmol:0.2 mmol:1.5 mL. After stirring evenly, the mixture was heated to 80 °C and reacted for 7 h. After the reaction was completed, the reaction solution was cooled to room temperature and the pH was adjusted to neutral with 3 mol / L hydrochloric acid solution. The aqueous phase was extracted with ethyl acetate after separation, and the organic phase was dried and concentrated with anhydrous sodium sulfate to obtain the modifier. The reaction process is as follows: The NMR and mass spectrometry results of the modifier are as follows: 1 HNMR (C 17 H 35 BrO,400MHz,DMSO-d6)δ3.87(t,2H),3.47(t,2H),1.62-1.57(m,3H),1.40-1.18(m,13H),1.06(s,3H),0.90(t,12H);LC-MSm / z:335.19[M+H] + .

[0026] (b) Microcrystalline cellulose, the modifier, sodium hydroxide, potassium iodide, and anhydrous DMF were added to anhydrous DMF in a ratio of 1 g: 1.2 g: 0.25 g: 0.15 g: 1.8 mL. After stirring evenly, the mixture was heated to 80 °C and reacted for 7 h. After the reaction was completed, the reaction solution was cooled to room temperature and filtered. During the filtration process, a mixed solvent (V) was used. DMF V 水 The modified microcrystalline cellulose was obtained by washing the filter cake with a ratio of 3:1 and drying it.

[0027] Preparation Example 2 A modified microcrystalline cellulose is prepared as follows: (a) 3,7,11-trimethyldodecane-3-ol, 1,2-dibromoethane, cesium carbonate, potassium iodide, and anhydrous DMF were added to anhydrous DMF in a ratio of 1 mmol:1.2 mmol:1.8 mmol:0.3 mmol:1.5 mL. After stirring evenly, the mixture was heated to 90 °C and reacted for 5 h. After the reaction was completed, the reaction solution was cooled to room temperature and the pH was adjusted to neutral with 3 mol / L hydrochloric acid solution. The aqueous phase was extracted with ethyl acetate after separation, and the organic phase was dried and concentrated with anhydrous sodium sulfate to obtain the modifier. The structural formula, NMR and mass spectrometry results of the modifier were consistent with those of Preparation Example 1.

[0028] (b) Microcrystalline cellulose, the modifier, sodium hydroxide, potassium iodide, and anhydrous DMF were added to anhydrous DMF in a ratio of 1 g: 1.3 g: 0.3 g: 0.2 g: 2 mL. After stirring evenly, the mixture was heated to 90 °C and reacted for 5 h. After the reaction was completed, the reaction solution was cooled to room temperature and filtered. During the filtration process, a mixed solvent (V) was used. DMF V 水 The modified microcrystalline cellulose was obtained by washing the filter cake with a ratio of 3:1 and drying it.

[0029] Preparation Example 3 A modified microcrystalline cellulose is prepared as follows: (a) 3,7,11-trimethyldodecane-3-ol, 1,2-dibromoethane, cesium carbonate, potassium iodide, and anhydrous DMF were added to anhydrous DMF in a ratio of 1 mmol:1 mmol:1.5 mmol:0.1 mmol:1.5 mL. After stirring evenly, the mixture was heated to 70 °C and reacted for 8 h. After the reaction was completed, the reaction solution was cooled to room temperature and the pH was adjusted to neutral with 3 mol / L hydrochloric acid solution. The aqueous phase was extracted with ethyl acetate after separation, and the organic phase was dried and concentrated with anhydrous sodium sulfate to obtain the modifier. The structural formula, NMR and mass spectrometry results of the modifier were consistent with those of Preparation Example 1.

[0030] (b) Microcrystalline cellulose, the modifier, sodium hydroxide, potassium iodide, and anhydrous DMF were added to anhydrous DMF in a ratio of 1 g: 1.1 g: 0.2 g: 0.1 g: 1.5 mL. After stirring evenly, the mixture was heated to 70 °C and reacted for 8 h. After the reaction was completed, the reaction solution was cooled to room temperature and filtered. During the filtration process, a mixed solvent (V) was used. DMF V 水 The modified microcrystalline cellulose was obtained by washing the filter cake with a ratio of 3:1 and drying it.

[0031] Preparation Example 4 A flavoring agent, prepared as follows: (1) Add di-tert-butyl dicarbonate (13 mmol) and aspartame (10 mmol) to 50 mL of mixed solution (V 水 V 1,4-二氧环己烷 In a 1:1 mixture, after thorough stirring, triethylamine (11 mmol) was added and the mixture was stirred at room temperature for 16 h. The reaction solution was cooled to 0 °C, and 10 wt% citric acid solution was slowly added to adjust the pH to 3. The aqueous phase was then extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain intermediate 1. The NMR and mass spectrometry results of intermediate 1 are as follows: 1 HNMR (C 19 H 26 N2O7,400MHz,DMSO-d6)δ12.47(s,1H),8.33(s,1H),7.39(s,1H),7.20-7.14(m,5H),4.86 (t,1H),4.55(t,1H),3.65(s,3H),3.24-2.68(m,4H),1.43(s,9H);LC-MSm / z:394.17[M].

[0032] (2) Under a nitrogen atmosphere, tert-butyl 3,4-diaminobenzoate (10 mmol) and intermediate 1 (11 mmol) were added to 20 mL of acetonitrile, mixed thoroughly, and then phosphorus tetraiodide (3 mmol) was added. The mixture was reacted at 70 °C for 12 h. The reaction solution was cooled to room temperature, the reaction was quenched with saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. 11 mL of 4 mol / L hydrochloric acid / ethyl acetate was added to the residue, and the mixture was stirred at room temperature for 10 h. The mixture was concentrated and subjected to chromatography on silica gel (eluent V). 石油醚 V 乙酸乙酯 The flavoring agent was prepared by separation at a ratio of 3:1; the NMR and mass spectrometry results of the flavoring agent are as follows: 1 HNMR (C 21 H 22N4O5,400MHz,DMSO-d6)δ12.72(s,1H),12.18(s,1H),8.86(s,2H),8.33(s,1H),8.28(s,1H),8.02(d,1H),7.8 2(d,1H),7.20-7.14(m,5H),4.55(t,1H),3.95(t,1H),3.65(s,3H),3.24-2.92(m,4H);LC-MSm / z:411.16[M+H] + .

[0033] Preparation Example 5 A flavoring agent, prepared as follows: (1) Add di-tert-butyl dicarbonate (12 mmol) and aspartame (10 mmol) to 50 mL of mixed solution (V 水 V 1,4-二氧环己烷 In a 1:1 mixture, after stirring evenly, triethylamine (10 mmol) was added and stirred at room temperature for 12 h. The reaction solution was cooled to 0 °C, and 10 wt% citric acid solution was slowly added to adjust the pH to 3.5. The aqueous phase was then extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain intermediate 1. The NMR and mass spectrometry results of intermediate 1 were consistent with those of preparation example 4.

[0034] (2) Under a nitrogen atmosphere, tert-butyl 3,4-diaminobenzoate (10 mmol) and intermediate 1 (10 mmol) were added to 20 mL of acetonitrile, mixed thoroughly, and then phosphorus tetraiodide (2 mmol) was added. The mixture was reacted at 60 °C for 16 h. The reaction solution was cooled to room temperature, the reaction was quenched with saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. 10 mL of 4 mol / L hydrochloric acid / ethyl acetate was added to the residue, and the mixture was stirred at room temperature for 8 h. The mixture was then concentrated and subjected to chromatography on silica gel (eluent V). 石油醚 V 乙酸乙酯 The flavoring agent was prepared by separating the samples at a ratio of 3:1; the NMR and mass spectrometry results of the flavoring agent were consistent with those of Preparation Example 4.

[0035] Preparation Example 6 A flavoring agent, prepared as follows: (1) Add di-tert-butyl dicarbonate (15 mmol) and aspartame (10 mmol) to 50 mL of mixed solution (V 水 V 1,4-二氧环己烷In a 1:1 mixture, after stirring until homogeneous, triethylamine (12 mmol) was added; the mixture was stirred at room temperature for 18 h; the reaction solution was cooled to 0 °C, and 10 wt% citric acid solution was slowly added to adjust the pH to 4. The aqueous phase was then extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain intermediate 1; the NMR and mass spectrometry results of intermediate 1 were consistent with those of preparation example 4.

[0036] (2) Under a nitrogen atmosphere, tert-butyl 3,4-diaminobenzoate (10 mmol) and intermediate 1 (12 mmol) were added to 20 mL of acetonitrile, mixed thoroughly, and then phosphorus tetraiodide (4 mmol) was added. The mixture was reacted at 80 °C for 8 h. The reaction solution was cooled to room temperature, the reaction was quenched with saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. 12 mL of 4 mol / L hydrochloric acid / ethyl acetate was added to the residue, and the mixture was stirred at room temperature for 12 h. The mixture was then concentrated and subjected to chromatography on silica gel (eluent V). 石油醚 V 乙酸乙酯 The flavoring agent was prepared by separating the samples at a ratio of 3:1; the NMR and mass spectrometry results of the flavoring agent were consistent with those of Preparation Example 4.

[0037] (II) Implementation Examples Example 1 A compound pharmaceutical preparation based on spray lactose, comprising, by weight, the following components: 12 parts oseltamivir phosphate, 30 parts spray lactose, 31 parts mannitol, 15 parts modified microcrystalline cellulose of Preparation Example 1, 4 parts polacolin potassium, 1.5 parts polyethylene glycol, and 2 parts flavoring agent of Preparation Example 4.

[0038] The preparation method of the above-mentioned compound pharmaceutical formulation based on spray-dried lactose includes the following steps: Add spray-dried lactose, mannitol, modified microcrystalline cellulose, polacolin potassium, polyethylene glycol, and flavoring agent to deionized water to obtain a suspension with a solid content of 15%. Spray-dry the suspension using a conventional spray-drying process, then add oseltamivir phosphate for tableting.

[0039] Example 2 A compound pharmaceutical preparation based on spray lactose, comprising, by weight, the following components: 10 parts oseltamivir phosphate, 27 parts spray lactose, 30 parts mannitol, 13 parts modified microcrystalline cellulose of Preparation Example 2, 3 parts potassium polacrine, 1 part magnesium stearate, and 1 part flavoring agent of Preparation Example 5.

[0040] The preparation method of the above-mentioned compound pharmaceutical formulation based on spray-dried lactose includes the following steps: Add spray-dried lactose, mannitol, modified microcrystalline cellulose, polaclin potassium, magnesium stearate, and flavoring agent to deionized water to obtain a suspension with a solid content of 12%. Spray-dry the suspension using a conventional spray-drying process, then add oseltamivir phosphate for tableting.

[0041] Example 3 A compound pharmaceutical preparation based on spray lactose, comprising, by weight, the following components: 15 parts oseltamivir phosphate, 33 parts spray lactose, 35 parts mannitol, 16 parts modified microcrystalline cellulose of Preparation Example 3, 5 parts croscarmellose sodium, 2 parts talc, and 3 parts flavoring agent of Preparation Example 6.

[0042] The preparation method of the above-mentioned compound pharmaceutical formulation based on spray-dried lactose includes the following steps: Add spray-dried lactose, mannitol, modified microcrystalline cellulose, croscarmellose sodium, talc, and flavoring agent to deionized water to obtain a suspension with a solid content of 16%. Spray-dry the suspension using a conventional spray-drying process, then add oseltamivir phosphate for tableting.

[0043] (III) Comparative Example Comparative Example 1 The difference between this comparative example and Example 1 is that aspartame was used instead of the flavoring agent in Preparation Example 4.

[0044] Comparative Example 2 The difference between this comparative example and Example 1 is that microcrystalline cellulose is used instead of the modified microcrystalline cellulose used in Example 1.

[0045] (iv) Test Cases Experimental Example 1 The modified microcrystalline cellulose prepared in Example 1 was analyzed by Fourier transform infrared spectroscopy (FT-IR), and the results are as follows: Figure 1 As shown.

[0046] Figure 1 The images show the infrared spectra of the modified microcrystalline cellulose prepared in Example 1, where curve a is the infrared spectrum of the microcrystalline cellulose and curve b is the infrared spectrum of the modified microcrystalline cellulose prepared in Example 1. (Observation) Figure 1 It is known that compared with microcrystalline cellulose, the hydroxyl signal of modified microcrystalline cellulose is weakened, indicating that the hydroxyl groups are consumed; 2925 cm -1 and 2855 cm -1 This is a newly added peak, attributed to the stretching vibration of the CH bond; at 1080 cm⁻¹ -1 The characteristic absorption peak shape at this location changed significantly, and the peak intensity increased, indicating that the cellulose hydroxyl groups reacted with the modifier to form C–O–C ether bonds, leading to a change in the C–O–C stretching vibration mode in this region. These results demonstrate that the modifier was successfully grafted onto microcrystalline cellulose.

[0047] Experimental Example 2 2.1 Content uniformity The content of oseltamivir phosphate capsules was determined according to the method for determination of oseltamivir phosphate capsules in Part II of the 2020 edition of the Chinese Pharmacopoeia. The technical requirements are: A+2.2S≤15.0. The results are shown in Table 1.

[0048] 2.2 Friability Referring to the 2020 edition of the Chinese Pharmacopoeia, Part IV, Tablet Friability Test Method (General Chapter 0923), friability was tested using a friability meter, and the results are shown in Table 1.

[0049] 2.3 Hardness Take 50 tablets of each of the compound drug formulations prepared in Examples 1-3 and Comparative Examples 1-2 respectively. The pressure that causes the compound drug formulation to break during tablet compression corresponds to the hardness of the corresponding compound drug formulation. The results are shown in Table 1.

[0050] 2.4 Disintegration Time Limit A lifting disintegration apparatus was used. The mesh size of the screen at the lower end of the basket in the disintegration apparatus was 710 μm, and the vibration amplitude was 55 mm ± 2 mm. The basket was immersed in a beaker containing 900 mL of purified water. The distance between the screen and the bottom of the beaker was adjusted to 25 mm when the basket was lowered and 15 mm when it was raised. The temperature was controlled at 37℃ ± 1℃. One tablet of the compound drug formulation from the examples or comparative examples was placed in the basket for disintegration, and the process was repeated 5 times. The average disintegration time was recorded, and the results are shown in Table 1.

[0051] Table 1 As can be seen from the experimental results in Table 1, the compound drug formulation prepared in the embodiments of the present invention performs excellently in all key indicators.

[0052] Compared to Comparative Example 1, which used ordinary aspartame, the compound pharmaceutical formulation of Example 1 exhibited significantly higher hardness and a significantly shorter disintegration time. This indicates that the novel flavoring agent of the present invention, through its benzimidazole rigid framework and microporous structure, effectively enhances the mechanical strength of the compound pharmaceutical formulation and accelerates water penetration and disintegration. Compared to Comparative Example 2, which used ordinary microcrystalline cellulose, Example 1 showed better content uniformity and lower brittleness. This demonstrates that the modified microcrystalline cellulose of the present invention, while achieving high hardness comparable to ordinary microcrystalline cellulose, significantly reduces brittleness by improving the uniformity of the internal structure of the compound pharmaceutical formulation, thus achieving a balance between high hardness and low brittleness. In summary, the present invention, through the synergistic effect of modified microcrystalline cellulose and the novel flavoring agent, successfully achieves a comprehensive performance improvement in compound pharmaceutical formulations, characterized by high hardness, low brittleness, rapid disintegration, and high uniformity.

[0053] Experimental Example 3 The compound pharmaceutical formulations prepared in the examples or comparative examples were subjected to a double-blind taste evaluation by 10 trained healthy volunteers. Volunteers placed the tablets on their tongues on an empty stomach, did not chew, and allowed them to disintegrate naturally in the mouth before swallowing. They then rated the sweetness, bitterness, and overall taste of the tablets. Sweetness and bitterness were scored on a scale of 1-10, with higher scores indicating stronger sweetness or bitterness. Overall taste was also scored on a scale of 1-10, with higher scores indicating a better taste (including smoothness, absence of gritty texture, and suitable aroma). Each volunteer evaluated each sample twice, with at least a 1-hour interval between evaluations, and rinsed their mouths with purified water to remove any residual taste. Oseltamivir phosphate raw material was used as a blank control. The results are shown in Table 2.

[0054] Table 2 According to the taste evaluation results in Table 2, the compound pharmaceutical preparation prepared by this invention exhibits excellent performance in terms of sweetness, bitterness, and overall taste. Compared with Comparative Example 1, the bitterness of Example 1 is significantly reduced, and the overall taste is greatly improved, indicating that the novel flavoring agent of this invention can effectively mask the strong bitterness of oseltamivir phosphate and provide a pleasant sweet taste experience.

[0055] The above embodiments are merely preferred embodiments of the present invention and should not be construed as limiting the scope of protection of the present invention. Any non-substantial changes and substitutions made by those skilled in the art based on the present invention shall fall within the scope of protection claimed by the present invention.

Claims

1. A compound pharmaceutical formulation based on spray-dried lactose, characterized in that, By weight, it includes the following components: 10-15 parts of active pharmaceutical ingredient, 27-33 parts of spray lactose, 30-35 parts of mannitol, 13-16 parts of modified microcrystalline cellulose, 3-5 parts of disintegrant, 1-2 parts of lubricant, and 1-3 parts of flavoring agent. The structural formula of the flavoring agent is: ； The modified microcrystalline cellulose is prepared as follows: Microcrystalline cellulose, a modifier, sodium hydroxide, and potassium iodide were added to anhydrous N,N-dimethylformamide, and the mixture was purified after reaction to obtain the modified microcrystalline cellulose. The structural formula of the modifier is: 。 2. The compound pharmaceutical formulation based on spray-dried lactose according to claim 1, characterized in that, The flavoring agent is prepared as follows: (1) Di-tert-butyl dicarbonate and aspartame were added to a mixed solvent of water / 1,4-dioxane, and then triethylamine was added and stirred. After purification, intermediate 1 was obtained. The structural formula of intermediate 1 is: (2) Under inert gas protection, tert-butyl 3,4-diaminobenzoate and intermediate 1 are added to acetonitrile, and then phosphorus tetraiodide is added. After reaction, the mixture is purified to obtain the residue. Hydrochloric acid / ethyl acetate is added to the residue, and after stirring, the mixture is purified to obtain the flavoring agent.

3. The compound pharmaceutical formulation based on spray-dried lactose according to claim 2, characterized in that, In step (1), the molar ratio of aspartame, di-tert-butyl dicarbonate, and triethylamine is 1:(1.2-1.5):(1-1.2); the volume ratio of water to 1,4-dioxane in the water / 1,4-dioxane mixed solvent is 1:1; and the stirring time is 12-18 h.

4. The compound pharmaceutical formulation based on spray-dried lactose according to claim 2, characterized in that, In step (2), the ratio of tert-butyl 3,4-diaminobenzoate, intermediate 1, phosphorus tetraiodide, and hydrochloric acid / ethyl acetate is 1 mmol: (1-1.2) mmol: (0.2-0.4) mmol: (1-1.2) mL; the concentration of hydrochloric acid / ethyl acetate is 4 mol / L; the reaction temperature is 60-80℃ and the reaction time is 8-16 h; the stirring time is 8-12 h.

5. The compound pharmaceutical formulation based on spray-dried lactose according to claim 1, characterized in that, The preparation process of the modifier is as follows: 3,7,11-trimethyldodecane-3-ol, 1,2-dibromoethane, cesium carbonate, and potassium iodide were added to anhydrous N,N-dimethylformamide, and the mixture was purified after reaction to obtain the modifier.

6. The compound pharmaceutical formulation based on spray-dried lactose according to claim 5, characterized in that, The molar ratio of 3,7,11-trimethyldodecane-3-ol, 1,2-dibromoethane, cesium carbonate, and potassium iodide is 1:(1-1.2):(1.5-1.8):(0.1-0.3); the reaction temperature is 70-90℃ and the reaction time is 5-8h.

7. The compound pharmaceutical formulation based on spray-dried lactose according to claim 1, characterized in that, The mass ratio of the microcrystalline cellulose, modifier, sodium hydroxide, and potassium iodide is 1:(1.1-1.3):(0.2-0.3):(0.1-0.2); the reaction temperature is 70-90℃ and the reaction time is 5-8h.

8. The compound pharmaceutical formulation based on spray-dried lactose according to claim 1, characterized in that, The active drug is oseltamivir phosphate; the disintegrant is potassium polacrine or sodium croscarmellose; and the lubricant is selected from polyethylene glycol, magnesium stearate, and talc.

9. A method for preparing a compound pharmaceutical formulation based on spray-dried lactose according to any one of claims 1-8, characterized in that, Includes the following steps: Add spray-dried lactose, mannitol, modified microcrystalline cellulose, disintegrant, lubricant, and flavoring agent to deionized water to obtain a suspension with a solid content of 12-16%. After spray drying, add the active drug and compress into tablets.

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