Chikang oral dissolving powder as well as preparation method and application thereof

Abstract

The invention provides Tongkang oral dissolving powder as well as a preparation method and application thereof. The Tongkang oral dissolving powder is prepared from the following raw materials in parts by weight: 250-350 parts of astragalus membranaceus, 150-250 parts of bighead atractylodes rhizome, 50-150 parts of divaricate saposhnikovia root, 250-360 parts of oyster, 15-35 parts of pericarpium citri reticulatae and 270-400 parts of Chinese yam. Through proper raw material and auxiliary material selection, a preparation method and parameter design, the children's health oral dissolving powder solves the problems that children's health tablets and granules are difficult to take, the pharmacokinetic performance is poor and the like, and an effective means is provided for further expanding the application of children's health Chinese patent medicines.

Description

TECHNICAL FIELD

[0001] The application belongs to the field of traditional Chinese medicine and the field of pharmaceuticals, and specifically provides a Tongkang oral dissolving powder, a preparation method and application thereof. BACKGROUND

[0002] As a traditional Chinese medicine for enhancing immunity and improving digestive function of children, Tongkang tablets and Tongkang granules are popular in the market. Tongkang tablets are chewable tablets, and it is difficult for young children to chew. The granules have problems such as slow release of insoluble components, and volatile oil is easy to distribute unevenly in solid preparations. SUMMARY

[0003] To solve the above problems:

[0004] On the one hand, the application provides a Tongkang oral dissolving powder, which is prepared from raw materials including the following raw medicinal materials by weight: 250-350 of Astragalus, 150-250 of Atractylodes, 50-150 of Ledebouriella, 250-360 of Ostrea, 15-35 of Citrus, and 270-400 of Dioscorea.

[0005] Further, the Tongkang oral dissolving powder is prepared from raw materials including the following raw medicinal materials by weight: 280-340 of Astragalus, 200-230 of Atractylodes, 80-120 of Ledebouriella, 300-340 of Ostrea, 20-30 of Citrus, and 300-350 of Dioscorea.

[0006] Further, the Tongkang oral dissolving powder is prepared from raw materials including the following raw medicinal materials by weight: 322 of Astragalus, 214 of Atractylodes, 108 of Ledebouriella, 322 of Ostrea, 26 of Citrus, and 322 of Dioscorea.

[0007] Further, the Tongkang oral dissolving powder is prepared from raw materials including the following raw medicinal materials by weight: 2-9 of stevioside, 350-550 of mannitol, 10-35 of cross-linked sodium carboxymethyl cellulose, 2-10 of citric acid, and 1-20 of micro-powder silica gel.

[0008] Further, the Tongkang oral dissolving powder is prepared from raw materials including the following raw medicinal materials by weight: 3-7 of stevioside, 400-500 of mannitol, 15-25 of cross-linked sodium carboxymethyl cellulose, 4-8 of citric acid, and 8-12 of micro-powder silica gel.

[0009] Further, the Tongkang oral dissolving powder is prepared from raw materials including the following raw medicinal materials by weight: 6 of stevioside, 450 of mannitol, 20 of cross-linked sodium carboxymethyl cellulose, 6 of citric acid, and 10 of micro-powder silica gel.

[0010] Further, the auxiliary materials of the Tongkang oral dissolving powder further include vanillin and orange flavoring.

[0011] Further, the preparation method of the Tongkang oral dissolving powder includes:

[0012] (1) Dry and crush the Dioscorea opposita Thunb and Pericarpium Citri Reticulatae;

[0013] (2) Extract the aromatic oil from the Saposhnikovia divaricata and Atractylodes macrocephala Koidz;

[0014] (3) Water extract the residues of the Saposhnikovia divaricata and Atractylodes macrocephala Koidz after the extraction of the aromatic oil in step (2) to obtain extract 1;

[0015] (4) Water extract the Astragalus membranaceus and Ostrea to obtain extract 2;

[0016] (5) Combine the extract 1 and the extract 2 and concentrate to obtain a clear paste;

[0017] (6) Configure the clear paste into a clear paste solution;

[0018] (7) Use steviol glycoside, mannitol, croscarmellose sodium, Pericarpium Citri Reticulatae powder, and Dioscorea opposita Thunb powder for flow layer spray granulation;

[0019] (8) Dry and crush to obtain dry compression powder;

[0020] (9) Mix the aromatic oil into an aromatic milk, and spray the aromatic milk into the dry compression powder;

[0021] (10) Add micronized silica gel to the mixture.

[0022] On the other hand, the application provides a preparation method of the Tongkang oral dissolving powder

[0023] (1) Dry and crush the Dioscorea opposita Thunb and Pericarpium Citri Reticulatae;

[0024] (2) Extract the aromatic oil from the Saposhnikovia divaricata and Atractylodes macrocephala Koidz;

[0025] (3) Water extract the residues of the Saposhnikovia divaricata and Atractylodes macrocephala Koidz after the extraction of the aromatic oil in step (2) to obtain extract 1;

[0026] (4) Water extract the Astragalus membranaceus and Ostrea to obtain extract 2;

[0027] (5) Combine the extract 1 and the extract 2 and concentrate to obtain a clear paste;

[0028] (6) Configure the clear paste into a clear paste solution;

[0029] (7) Use steviol glycoside, mannitol, croscarmellose sodium, Pericarpium Citri Reticulatae powder, and Dioscorea opposita Thunb powder for flow layer spray granulation;

[0030] (8) Dry and crush to obtain dry compression powder;

[0031] (9) Mix the aromatic oil into an aromatic milk, and spray the aromatic milk into the dry compression powder;

[0032] (10) Add micronized silica gel to the mixture.

[0033] Further, in step (3), 8-15 times of water of the residue quality is added, and extracted for 1-2 times, and decocted for 1-3 hours; preferably, 10 times of water of the residue quality is added, and extracted for 1 time, and decocted for 1.5 hours.

[0034] Further, in step (4), 8-15 times of water of the total medicinal material quality is added respectively, and extracted for 2 times, and decocted for 1-3 hours each time; preferably, 10 times of water of the total medicinal material quality is added in the first time, and decocted for 2 hours, and 8 times of water of the total medicinal material quality is added in the second time, and decocted for 1.5 hours.

[0035] Further, in step (5), the concentration is to the relative density of 1.11-1.25; preferably, the concentration is to the relative density of 1.2-1.22.

[0036] Further, in step (7), the feeding rate in the flow layer spray granulation is 1.2-2.2 ml / min, the atomization pressure of the clear paste solution is 0.2-0.6 bar, and the granulation temperature is greater than or equal to 70℃; preferably, the feeding rate is 1.7 ml / min, the atomization pressure is 0.2 bar, and the air inlet temperature is 70℃.

[0037] Further, in step (8), the oil pressure in the dry pressing is 160-200 bar.

[0038] Further, in step (9), the aromatic oil and orange essence are mixed with 50-500 mL of 95% ethanol to form an aromatic mixed emulsion, and the same amount is added into the dry pressed powder in an increasing manner.

[0039] In another aspect, the present application also claims to protect the fingerprint spectrum construction method of the above Tongkang oral dissolving powder, and the method comprises:

[0040] About 2 g of the clear paste is accurately weighed and placed in a 50 ml conical flask with a plug, 20 ml of methanol is accurately added, and extracted by heating reflux for 60 min, cooled, the weight is re-weighed, the lost weight is made up with methanol, shaken uniformly, filtered with a 0.45 μm microporous filter membrane, and the filtrate is taken as the product sample solution. 10 μl of the sample solution is accurately taken and determined by HPLC.

[0041] Further, the conditions for HPLC chromatographic determination are as follows:

[0042] The chromatographic column is Kromasil 100-5 C18 (250 mm x 4.6 mm, 5 μm); the mobile phase system is acetonitrile-0.1% formic acid aqueous solution; the mobile phase A is acetonitrile, the mobile phase B is 0.1% formic acid, gradient elution (Table 26), the flow rate is 1 ml / min, the column temperature is 25℃, the detection wavelength is 260 nm, the detector is an ultraviolet detector DAD-3000, and the injection amount is 10 μl.

[0043] In another aspect, the present application provides use of the above-mentioned Tongkang oral dissolving powder in the preparation of a medicine for improving immunity.

[0044] In another aspect, the present application provides use of the above-mentioned Tongkang oral dissolving powder in the preparation of a medicine for treating repeated respiratory tract infections in children.

[0045] In another aspect, the present application provides use of the above-mentioned Tongkang oral dissolving powder in the preparation of a medicine for treating body weakness, excessive sweating, fatigue and / or loss of appetite.

[0046] The medicinal materials can be cleaned according to the condition of the medicinal materials and production requirements.

[0047] The time, temperature, filtration, extraction times, and concentration degree in the water extraction method of medicinal materials can be routinely adjusted by those skilled in the art as needed. BRIEF DESCRIPTION OF DRAWINGS

[0048] Figure 1 HPLC fingerprint of the clear paste and main chromatographic peaks thereof.

[0049] Figure 2 Chromatographic overlay for precision investigation.

[0050] Figure 3 Chromatographic overlay for repeatability investigation.

[0051] Figure 4 HPLC fingerprint overlay of 10 batches of clear paste (batch number: 180610, 181201, 190401, 190402, 190403, 190501, 190502, 190503, 190504, 190505). DETAILED DESCRIPTION

[0052] Example 1: Treatment and extraction method of basic medicinal materials

[0053] Sorting of Chinese medicinal materials (except for Chinese herbal pieces):

[0054] According to the ingredient list of medicinal materials and raw materials, check the name, batch number (or factory number), and quantity of the Chinese medicinal materials. Pour the medicinal materials onto the sorting table, and pick out the moldy parts and impurities. Weigh the sorted medicinal materials, label them, and wait for use.

[0055] Cleaning (except for Chinese herbal pieces):

[0056] Put the sorted yam and dried tangerine peel into a drum washing machine (water flow 500 / h, feeding speed 400 kg / h) or a washing pool, and clean them with flowing water.

[0057] Drying:

[0058] After cleaning, dry in a low-temperature vacuum drying oven or a hot air circulation oven. Set the vacuum degree to -0.075 to -0.094 MPa and the temperature to 75 to 85°C for 14 to 18 hours in a low-temperature vacuum drying oven; dry in a hot air circulation oven at 80 to 85°C for 18 to 20 hours. Moisture content ≤ 8.5%.

[0059] Coarsely crushed (except Chinese herbal medicine pieces):

[0060] The Atractylodes macrocephala was crushed into pieces ≤ 2 cm using a WF high-efficiency coarse crusher, and the Astragalus and Saposhnikovia divaricata were cut into pieces ≤ 10 cm using a variable frequency speed slicing and segmenting machine. The coarsely crushed herbs were weighed, labeled, and set aside.

[0061] Crushing:

[0062] Chinese yam and dried tangerine peel were pulverized separately in a WFJ-15 airflow mill to a particle size ≥ 200 mesh. The pulverized herbs were weighed and labeled. The herbal powder was stored in a clean, sealed plastic bag.

[0063] Extracting essential oils:

[0064] According to the ingredient list for raw materials and auxiliary materials, verify the name, batch number (or factory entry number), and quantity of the Chinese medicinal materials. Place the herbs Saposhnikovia divaricata and Atractylodes macrocephala into the multi-functional extraction tank. Open the CIP, add drinking water, and open the agitator and drain valve to rinse for 1-2 minutes. After rinsing, add 6 times the total amount of medicinal materials in water and soak for 1.5 hours. Then, distill at 95-100°C for 5 hours or longer. Collect the aromatic oil according to the volatile oil collector operating procedures.

[0065] decoction:

[0066] Add 10 times the amount of water to the residue of Saposhnikovia divaricata and Atractylodes macrocephala, heat and extract once, decoct for 1.5 hours, stir at a speed of 30-60 rpm, decoct at a temperature of 95-100°C, and pass the medicinal liquid through a 100-mesh sieve.

[0067] For the Astragalus and Oyster, open the CIP, add drinking water, and open the agitator and drain valve to rinse for 1-3 minutes. After rinsing, heat and decoct twice: first, add 10 times the total amount of medicinal material in water and boil for 2 hours; then, add 8 times the total amount of medicinal material in water and boil for 1.5 hours. Keep the agitator at 30-60 rpm and the boiling temperature at 95-100°C. Pass the solution through a 100-mesh sieve.

[0068] concentrate:

[0069] The two kinds of extract liquid are extracted into vacuum concentration equipment, and concentrated under the conditions of vacuum degree -0.06 to -0.1 Mpa and temperature 50 to 60℃ to clear paste with relative density of 1.25 to 1.35 (measured at 50℃) as measured by specific gravity. The clear paste is transferred to a mixing barrel, mixed, and boiled to 100℃ for 30 minutes. The clear paste is loaded into a clean clear paste barrel with a label under sealed conditions.

[0070] Basic method for preparation of the formulation of Example 2

[0071] Flow layer spray granulation:

[0072] The density of the spray body solution is 1.11 to 1.25 (measured at 50℃), and the moisture of the spray granulation is 0.5 to 6.5%.

[0073] Vanillin solution preparation:

[0074] 0.8g of vanillin is dissolved in about 1.0kg of hot purified water.

[0075] Citric acid solution preparation:

[0076] 6g of citric acid is dissolved in about 1.0kg of hot purified water.

[0077] Clear paste solution preparation:

[0078] The clear paste, the dissolved vanillin solution, and the citric acid solution are mixed in a mixing barrel and heated to 60 to 85℃.

[0079] Granulation:

[0080] The stevioside, mannitol, croscarmellose sodium, dried tangerine peel powder, and dried yam powder are poured into a trolley according to the production prescription amount, the trolley is pushed into a flow layer spray granulation dryer, the equipment is started, and spray granulation and drying are performed. The spray frequency is 8 to 30 HZ, the inlet air temperature is 70 to 80℃, the material temperature is 35 to 50℃, the outlet air temperature is 45 to 75℃, the slurry addition temperature is 60 to 85℃, the fan frequency is 30 to 50 HZ, and the feeding speed is:

[0081] 1.2 to 2.2ml / min; atomization pressure: 0.2 to 0.6bar; bag shaking interval: 25.0S, bag shaking time: 16.0S, and bag shaking frequency: 1.5S. After the clear paste adsorption is completed, the moisture is detected, if the moisture is greater than 6%, the drying is continued, the moisture detection is performed once about 10min, the drying time is less than or equal to 30min, and the moisture is less than or equal to 4%, and the drying is ended.

[0082] Dry compression:

[0083] The purpose of this step is to improve the uniformity of the powder, reduce stratification, and ensure uniform content. The conditions that need to be protected for this step are as follows: set the screw feeding rotation speed to 30-50 rpm, the compression roller rotation speed to 8-15 rpm, the compression roller gap to 0.4-0.6 mm, the oil pressure to 160-200 bar, the crushing rotation speed to 80-120 rpm, the granulating rotation speed to 80-120 rpm, the granulating mesh to Ф1.2 mm, and the water cooling to ≤20℃.

[0084] Crushing:

[0085] Place the dry-pressed granules in an air jet mill and pass them all through a 120-mesh sieve to obtain dry-pressed powder.

[0086] Add the fragrance mixed emulsion:

[0087] Method for preparing the fragrance mixed emulsion:

[0088] Mix the fragrance oil extracted from the prescribed amount of medicinal materials with 1.6 mL of orange essence and 50-500 mL of 95% ethanol to form the fragrance mixed emulsion.

[0089] Take 500-5000 g of the dry-pressed powder described above, slowly spray it into the fragrance mixed emulsion at a ratio of 20:1, and mix it evenly. At the same time, continuously stir it (such as magnetic stirring or paddle stirring) for 5 minutes to prevent local concentration from forming lumps. Then, add an equal amount of dry-pressed powder incrementally and mix it evenly. The purpose of incrementally adding an equal amount of fragrance mixed emulsion is to ensure uniform dispersion of ingredients and improve the consistency of drug efficacy, enhance the stability of the preparation, prevent loss of ingredients, and improve the physical properties of the preparation for clinical application.

[0090] Total mixing:

[0091] Add the micronized silica gel to the mixed powder described above and mix for 20 minutes.

[0092] Equipment and raw materials used in the preparation process of Example 3

[0093] Instrument equipment:

[0094] XS205 DualRange ten-millionth analytical balance (Mettler-Toledo Instruments (Shanghai) Co., Ltd.);

[0095] HH-6 constant temperature water bath (Guangzhou Kangheng Instrument Co., Ltd.);

[0096] MJ33 rapid moisture meter (Mettler-Toledo Instruments (Shanghai) Co., Ltd.);

[0097] STREA-1 fluidized bed (Switzerland NIRO-AEROMATIC Co., Ltd.);

[0098] YC-FBDG-8 fluidized bed granulator (YENCHEN, Taiwan, China);

[0099] Reagents and consumables:

[0100] The main raw materials are shown in Table 1.

[0101] Table 1 Main raw materials

[0102]

[0103] Example 4 Main prescription auxiliary material screening (orthogonal experiment L9 (3 4 ))

[0104] The factors and levels for screening excipients of the main prescription are shown in Table 2, and the key indicator analysis results are shown in Table 3.

[0105] Table 2 Factors and levels of screening of main prescription excipients

[0106] Factor Level 1 Level 2 Level 3 Mannitol (A) 40％ 45％ 50％ CMC-Na (B) 2％ 4％ 6％ Silica (C) 0.5％ 1％ 1.5％

[0107] Table 3 Analysis of key indicators results

[0108]

[0109] The best prescription based on comprehensive score

[0110] Prescription combination: A2B1C2 (45% mannitol + 2% CMC-Na + 1% silicon dioxide). Basis: Comprehensive score 92 points (full score 100), significantly better than other combinations (second best S5 = 88 points). Detailed indicators are shown in Table 4.

[0111] Table 4 Effect of the optimal prescription

[0112] Index Observed value Standard Angle of repose 34° ≤40° Bulk density 0.361 g / mL ≥ 0.35 g / mL Dissolution time 23s ≤30s Hygroscopicity 3.5％ ≤5％ Content uniformity RSD 2.1% ≤5％

[0113] Example 5 Stevioside concentration screening

[0114] The sensory evaluation method is carried out according to the following steps:

[0115] (1) Evaluation team: 10 adults with normal taste who abstained from spicy food 24 hours before the test;

[0116] (2) Sample preparation: Steviol glycosides of various concentrations were prepared according to the basic formula A2B1C2 and dissolved in 20 ml of pure water;

[0117] (3) Scoring rules:

[0118] -Sensory acceptance: 0 points (vomiting) → 10 points (desire to drink again)

[0119] - Bitterness intensity: 0 points (none) → 5 points (sustained bitterness ≥ 1 minute)

[0120] (4) Data processing: Discard 2 highest / lowest scores, take average of remaining 8 ± standard deviation

[0121] Results

[0122] As shown in Table 5, the 0.6% group had the highest sensory acceptance (8.8 ± 0.4), the lowest bitterness intensity (0.3 ± 0.1), and the least impact on powder properties (θ = 34.8° ≤ 35°; H = 3.9% ≤ 5%).

[0123] Table 5: Screening results of steviol glycoside concentration:

[0124]

[0125] Example 6: Final formulation and performance verification

[0126] The composition and performance of the final formulation are shown in Tables 6 and 7.

[0127] Table 6: Composition of final formulation

[0128] Ingredient Proportion Traditional Chinese medicine extract 51.4％ Mannitol 45％ Cross-linked sodium carboxymethyl cellulose 2％ Silica 1％ Stevioside 0.6％

[0129] Table 7: Key performance indicators of final formulation

[0130] Index Optimization result Standard Whether it meets Angle of repose 34.8° ≤40° √ Bulk density 0.358 g / mL ≥ 0.35 g / mL √ Dissolution time 24s ≤30s √ Hygroscopicity (72 h) 3.9％ ≤5％ √ Content uniformity RSD 2.3% ≤5％ √ Sensory acceptance 8.8 / 10 ≥7.5 √

[0131] Accelerated stability (40°C / 75% RH, 1 month).

[0132] Hygroscopicity: 4.1% (still within the standard).

[0133] Dissolution time: 26 s (not significantly prolonged).

[0134] Flowability: θ = 35.2°.

[0135] Conclusion:

[0136] Optimal formulation: 45% mannitol + 2% CMC-Na + 1% silicon dioxide + 0.6% steviol glycosides, all key indicators meet the standards, and the sensory acceptance is excellent (8.8 / 10).

[0137] Continuous stability: 1) Long-term monitoring of hygroscopicity (25°C / 60% RH, 12 months), 2) optimization of packaging: use of aluminum-plastic composite film bags (moisture permeability ≤0.5 g / m 2 ·day)

[0138] Example 7: Screening of clear paste relative density

[0139] The fluidized bed process parameters were set as follows: feed rate 2.2 ml / min, atomization pressure 0.4 bar, and inlet air temperature 60°C. The relative density (room temperature) of the clear paste was adjusted to 1.05, 1.11, 1.15, 1.20, 1.25, and 1.28, respectively. The air flow was adjusted to make the material in a boiling state, and the granulation effect was observed. The results are shown in Table 8.

[0140] Table 8 Screening results of the relative density of the clear paste

[0141]

[0142] The results show that when the relative density of the clear paste is 1.05 (room temperature), the granules are too wet and cannot be continuously sprayed. When the relative density of the clear paste is between 1.11 and 1.25 (room temperature), the granulation is smooth, and the granules are uniform in size and color. When the relative density of the clear paste is greater than or equal to 1.28, the nozzle is easily blocked. The thinner the clear paste, the longer the working time. To improve efficiency, the clear paste with a relative density of 1.20 (room temperature) is selected for granulation.

[0143] Example 8 Screening of the fluidized bed spray granulation process

[0144] Single factor screening of the feed rate of the fluidized bed spray granulation equipment:

[0145] The relative density of the clear paste was fixed at 1.20 (room temperature), the inlet air temperature was 80°C, and the atomization pressure was 0.4 bar. The feed rate was adjusted to 1.2 ml / min, 2.2 ml / min, 3.2 ml / min, and 4.2 ml / min, respectively. The air flow was adjusted to make the material in a boiling state, and the granulation effect was observed. The results are shown in Table 9.

[0146] Table 9 Screening results of the feed rate

[0147]

[0148] The results show that when the feed rate is greater than 3.2 ml / min, the material is too wet, and if not dried in time, it is easy to cause the granules to stick together, resulting in larger granules. Wet granules are easily adhered to the nozzle, causing blockage. According to the actual granulation situation, the feed rate of 1.2-2.2 ml / min is selected for further optimization.

[0149] Single factor screening of the atomization pressure of the fluidized bed spray granulation equipment:

[0150] The relative density of the clear paste was fixed at 1.22 (room temperature), the feed rate was 2.2 ml / min, and the inlet air temperature was 60°C. The atomization pressure was adjusted to 0.2 bar, 0.4 bar, and 0.6 bar, respectively. The air flow was adjusted to make the material in a boiling state, and the granulation effect was observed. The results are shown in Table 10.

[0151] Table 10 Screening results of the atomization pressure

[0152]

[0153] The results show that the atomization pressure of the clear paste is between 0.2-0.6 bar, and the atomization state is good. When the atomization pressure is greater than 0.6 bar, the formed mist droplets are too fine, and it is difficult to granulate.

[0154] Single factor screening of fluidized bed inlet air temperature:

[0155] The relative density of the fixed clear paste is 1.22 (room temperature), the feeding rate is 2.2 ml / min, the atomization pressure is 0.4 bar, the inlet air temperature is adjusted to 60°C, 70°C and 80°C, the air volume is adjusted to make the material in a boiling state, and the granulation condition is observed. The results are shown in Table 11.

[0156] Table 11 Screening results of inlet air temperature

[0157]

[0158] The results show that when the temperature is low, the particle humidity is large, which leads to wall sticking and is not easy to dry. When the temperature is greater than 70°C, loose and dry particles can be prepared, which is beneficial to dry compression.

[0159] Optimization of fluidized bed spray process parameters by orthogonal test:

[0160] Determination of molding rate:

[0161] The prepared particles are weighed and passed through 20 mesh and 80 mesh sieves in turn. The particles that can pass through the 20 mesh sieve but cannot pass through the 80 mesh sieve are collected as qualified particles. The molding rate is calculated according to the following formula.

[0162]

[0163] Determination of moisture content:

[0164] Determined by moisture rapid tester.

[0165] Orthogonal test results and analysis:

[0166] Based on the above single factor test results, the relative density of the clear paste is selected as 1.22 (room temperature), the feeding speed (A), the atomization pressure (B) and the inlet air temperature (C) are selected as the observation factors, and three levels are set respectively. The molding rate and moisture content of the prepared particles are determined in turn, and two indexes are evaluated respectively. Orthogonal design table L9(34) is used for experiment. The factor level and experimental results are shown in Table 12 and Table 13, and the variance analysis results of two indexes are shown in Table 14 and Table 15.

[0167] Table 12 Factor level table

[0168]

[0169] Table 13 Orthogonal test results

[0170]

[0171] Table 14 Analysis of variance of forming rate

[0172]

[0173] Note: F 0.05 (2,2) = 19.00

[0174] Table 15 Analysis of variance of moisture

[0175]

[0176] Note: F 0.05 (2,2) = 19.00

[0177] From the results of intuitive analysis and analysis of variance, in terms of forming rate as an index, the influence degree of each factor on the experimental results is A (feed rate) > B (atomization pressure) > C (inlet air temperature), wherein A (feed rate) and B (atomization pressure) have significant difference; in terms of moisture as an index, each factor has no significant influence on the experimental results, and it can be known from the combination of the two that the best flow layer spray process condition is A2B1C2, i.e. when the relative density of the clear paste is 1.22 (at room temperature), the feed rate is 1.7 ml / min, the atomization pressure is 0.2 bar, and the inlet air temperature is 70°C.

[0178] Example 9 Screening of dry compression and crushing parameters

[0179] The purpose of crushing after dry compression is to make the flowability of the crushed powder better; in the packaging process, the loading amount is stable, and the dosage form is more accurate. The index for measuring the flowability of the powder is the angle of repose, and the lower the angle, the better the flowability, and vice versa, the worse the flowability.

[0180] The flowability of the powder is determined by the compactness of the particles, and the dry compression equipment mainly compresses the particles to be compact, and the parameter that determines whether the particles are compact is the oil pressure. Therefore, the oil pressure parameter is screened

[0181] Table 16 Screening results of atomization pressure

[0182]

[0183]

[0184] The results in Table 16 show that the flowability of the powder is good when the dry compression oil pressure is between 160-200 bar, the hardness is insufficient after dry compression when the oil pressure is less than 160 bar, and the flowability of the powder is not good, and the flowability of the powder is good when the oil pressure is greater than or equal to 160 bar.

[0185] Example 10 Pilot test and pilot test

[0186] Pilot prescription:

[0187]

[0188] Pilot process verification:

[0189] Three batches of products should be prepared according to the above preferred process conditions, and 160 g of powder should be prepared. The results in Table 17 show that the process is stable and feasible, and the moisture content of the prepared product is (6.07 ± 0.58) %, which meets the requirements of the Pharmacopoeia, and the solubility test is qualified.

[0190] Table 17 Process verification results

[0191]

[0192] Pilot process verification and commercial batch production:

[0193] First, three batches of pilot tests were performed, and the results in Table 18 show that the decoction pieces were extracted and concentrated, and the dry extract yield was 37.6%, and the pilot product yield was 75.5% to 80%. The process parameters of the three batches of tests were stable, and the process was reasonable and feasible. Subsequently, commercial batch production (50,000 bags / batch) was performed, and the batch numbers were: 200401, 200402, and 200403. The process parameters were stable and feasible, and the samples were used for subsequent research.

[0194] Table 18 Tongkang pilot test data of three batches

[0195] Example 11 Dissolution characteristics and pharmacodynamic advantages of Tongkang oral dissolving powder and granules

[0196] In vitro dissolution / disintegration experiment:

[0197] The methods and results are shown in Tables 19 and 20.

[0198] Table 19 In vitro dissolution and disintegration test methods

[0199]

[0200]

[0201] Table 20 Disintegration / dissolution time

[0202] Dosage form Complete disintegration / dissolution time (seconds) Difference Tongkang oral dispersion 8.5±1.2 - Tongkang granules 128.6±15.3 ↑ 15 times

[0203] Conclusion:

[0204] The disintegration rate of Tongkang oral dissolving powder in the oral environment is significantly faster than the dissolution rate of granules in water (p < 0.001), which meets the technical requirements of "no need for water and instant melting upon entry".

[0205] Pharmacodynamic advantage demonstration: from dissolution speed to onset speed:

[0206] PK study (animal model) design: beagle dogs (n = 6) were given drugs in a cross-over manner.

[0207] Group A: Tongkang oral dissolving powder (direct oral administration)

[0208] Group B: Tongkang granules (gavaged after complete dissolution)

[0209] Detection index: blood concentration (HPLC-MS / MS)

[0210] Intensive sampling points: 5, 10, 15, 20, 30, 45, 60, 120 min

[0211] Table 21 Blood concentration and related index detection results

[0212]

[0213] As shown in the results of Table 21, the peak time (Tmax) of Tongkang oral dissolving powder was significantly shortened, proving that rapid disintegration translates into earlier absorption, while the bioavailability (AUC) is not lost.

[0214] Example 12 Technical advantage of oral dissolving powder and equivalent incremental process verification research report

[0215] This study verified that, under the same prescription and extraction process:

[0216] Tongkang oral dissolving powder has a significant advantage in dissolution speed and bioavailability (T 50 68% shorter, C max 42% higher) compared to granules.

[0217] Adding aromatic mixed cream to the equivalent incremental method can improve the uniformity of volatile oil distribution (RSD ≤ 2.1%) and stability (retention rate of 91.5% for 6 months).

[0218] The experimental scheme is shown in Tables 22 and 23.

[0219] Table 22 Oral dissolving powder advantage experiment drugs

[0220] Group Prescription source Process details Tongkang oral dispersion (02) Same as Tongkang granules (01) prescription micronized (D 90 ≤ 80 μm) Tongkang granules (01) Same extract Wet granulation (particle size 500-1000 μm) Fragrant mixed milk Atractylone Equal amount incremental method vs direct mixing

[0221] Dissolution experiment: paddle method (200 ml simulated gastric fluid, 50 rpm), HPLC determination of astragaloside A dissolution curve.

[0222] Table 23 Equivalent incremental process verification parameters

[0223] Test item Method Determination standard Uniformity GC-MS (10-point sampling) RSD ≤ 3% Stability Accelerated test (40℃ / RH 75%) 6-month retention rate ≥ 90%

[0224] The dissolution and pharmacokinetic parameters of the orally dissolving powder and granules are shown in Table 24.

[0225] Table 24 Comparison of dissolution and pharmacokinetic parameters (mean ± SD)

[0226]

[0227] Conclusion: The orally dissolving powder achieves rapid release and enhanced efficacy by bypassing the disintegration step and micronization. The orally dissolving powder significantly improves the dissolution rate (T 50 ↓68%) and bioavailability (Cmax↑42%) compared to the granules.

[0228] The results of the uniformity and stability tests of the volatile oil are shown in Table 25.

[0229] Table 25 Uniformity and stability of volatile oil

[0230] Fingerprint spectrum research report of intermediate product Tongkangqing paste in Example 13

[0231] This study establishes the fingerprint spectrum of the paste, conducts methodology investigation and similarity evaluation.

[0232] Detection method

[0233] Take about 2 g of the paste, accurately weigh it, and place it in a 50 ml conical flask with a stopper. Accurately add 20 ml of methanol, and use heating reflux extraction for 60 min. Let it cool, re-weigh it, make up the weight loss with methanol, shake it well, filter it with a 0.45 μm microporous filter membrane, and take the filtrate as the product sample solution. Accurately take 10 μl of the sample solution, and determine it by HPLC.

[0234] Chromatographic column: Kromasil 100-5 C18 (250 mm x 4.6 mm, 5 μm); mobile phase system: acetonitrile-0.1% formic acid aqueous solution; mobile phase A is acetonitrile, mobile phase B is 0.1% formic acid, gradient elution (Table 26), flow rate is 1 ml / min, column temperature is 25°C, detection wavelength is 260 nm, detector: ultraviolet detector DAD-3000, injection volume: 10 μl.

[0235] Table 26 Elution program of mobile phase

[0236]

[0237] Systematic investigation

[0238] (1) Precision investigation

[0239] Take about 2 g of the paste (batch number: 190401), accurately weigh it, and prepare the sample solution according to the preparation method of the sample solution. Continuously inject 6 times, analyze it by HPLC, and obtain the HPLC fingerprint spectrum of the paste.Figure 1 The relative retention time and relative peak area of each of the 11 common chromatographic peaks in the HPLC fingerprint of each sample were calculated, and the average value (Mean) and relative standard deviation (RSD%) were obtained. The results showed that the RSD of the relative retention time of each chromatographic peak was less than 1.0%, and the RSD of the relative peak area was less than 3.0%, indicating that the method had good precision. Figure 2 Table 27, Table 28).

[0240] Table 27 Precision test results of HPLC fingerprint of clear paste (relative retention time)

[0241]

[0242] Table 28 Precision test results of HPLC fingerprint of clear paste (relative peak area)

[0243]

[0244] (2) Repeatability test

[0245] About 2 g of clear paste (batch number: 190401) was accurately weighed, and 6 test sample solutions were prepared in parallel according to the preparation method of test sample solution. The HPLC fingerprint of clear paste was obtained by injecting the test sample solutions. Figure 3 The relative retention time and relative peak area of each of the 11 common chromatographic peaks in the HPLC fingerprint of each sample were calculated, and the average value (Mean) and relative standard deviation (RSD%) were obtained. The results showed that the RSD of the relative retention time and relative peak area of each chromatographic peak was less than 1.0%, indicating that the method had good repeatability.

[0246] Table 29 Repeatability test results of HPLC fingerprint of clear paste (relative retention time)

[0247]

[0248]

[0249] Table 30 Repeatability test results of HPLC fingerprint of clear paste (relative peak area)

[0250]

[0251] (3) Stability test

[0252] Take about 2 g of the clear paste (batch number: 190401), accurately weigh, prepare 1 sample according to the preparation method of the test sample solution, and determine at 8 different time points of 0, 2, 4, 8, 12, 16, 24 and 48 hours to obtain the HPLC fingerprint of the test sample solution. Figure 4 )Take peak No. 8 as the reference peak, calculate the relative retention time and relative peak area of 11 common chromatographic peaks in the HPLC fingerprint of the sample within 5-60 min, and calculate the corresponding average value (Mean) and relative standard deviation (RSD%). The results show that the RSD of the relative retention time of each chromatographic peak is less than 1.0%, and the RSD of the relative peak area is less than 3.0%, indicating that the method has good stability.

[0253] Table 31 Stability test results of the HPLC fingerprint of the clear paste (relative retention time)

[0254]

[0255] Table 31 Stability test results of the HPLC fingerprint of the clear paste (relative peak area)

[0256]

[0257] Fingerprint and similarity evaluation of the clear paste

[0258] Using the fingerprint determination method, the fingerprints of 10 batches of clear paste were determined, which were substituted into the "Traditional Chinese Medicine Chromatographic Fingerprint Similarity Evaluation System 2004A Edition" to generate the control fingerprint (see Figure 4 ), and the similarity of the chromatogram of 5-60 min was calculated, and the results are shown in Table 32.

[0259] Table 32 Similarity evaluation table of 10 batches of clear paste 5-60 min fingerprint

[0260]

[0261] The results show that the similarity of the fingerprints of 10 batches of clear paste and the control fingerprint reaches 0.9 or more.

[0262] Example 14 Report on screening study of oral dispersant auxiliary material combination

[0263] The existing children's dispersant is in a dilemma:

[0264] Adding disintegrant (CCMC-Na) to accelerate dispersion → moisture absorption increases dramatically → storage period caking deterioration reduces disintegrant to ensure stability → slow dispersion → children refuse to take

[0265] The present application first found that 1% silicon dioxide + 2% cross-linked sodium carboxymethyl cellulose in the mannitol system produces a synergistic anti-humidity effect.

[0266] Table 33 Dissolution-moisture absorption synergy experiment and results

[0267] Group Dissolution time (s) Accelerated test hygroscopicity (40℃ / RH 75%) Bioavailability (AUC0-12) Control group 1 45±3.2 12.5%↑ (clumping in the first month) 78.3±5.2 Control group 2 ＞60 8.7％ 82.1±4.1 The present application 28±1.8 4.2 (3-month flow freely) 95.6±3.7

[0268] Conclusion:

[0269] Dissolution rate is 1 time faster than conventional combination (p<0.01)

[0270] Moisture absorption rate is reduced by more than 50% (1 / 3 of control group 1)

[0271] Bioavailability is significantly improved (↑17.2%, p<0.001)

[0272] Table 34 Comparison of experimental results

[0273]

[0274] Table 35 Comparison of experimental data

[0275]

[0276] Conclusion:

[0277] (1) Cross-linked sodium carboxymethyl cellulose lacks technical inspiration in the application of powders (literature only for tablets);

[0278] (2) The local moisture control effect of silicon dioxide offsets its moisture absorption defects, which is an unexpected discovery;

[0279] (3) The combination of the three makes the bioavailability breakthrough to >95% (conventional powder <80%).

Claims

1. A Tongkang orally disintegrating powder, characterized in that: The Tongkang oral dispersant is prepared from the following raw materials in parts by weight: 250-350 parts of astragalus, 150-250 parts of atractylodes, 50-150 parts of siler, 250-360 parts of oyster, 15-35 parts of dried tangerine peel, and 270-400 parts of yam.

2. The Tongkangkourongsan according to claim 1 is prepared from raw materials comprising the following raw materials in parts by weight: 280-340 grams of astragalus, 200-230 grams of atractylodes, 80-120 grams of siler, 300-340 grams of oyster, 20-30 grams of dried tangerine peel, and 300-350 grams of yam.

3. The Tongkang oral dispersant according to claim 1 is prepared from raw materials comprising the following raw materials in parts by weight: 322 parts of Astragalus, 214 parts of Atractylodes, 108 parts of Saposhnikovia, 322 parts of Oyster, 26 parts of Tangerine Peel, and 322 parts of Chinese Yam.

4. The Tongkang oral dispersible powder according to any one of claims 1 to 3, which is prepared from raw materials including the following excipients in parts by weight: 2-9 parts of steviol glycosides, 350-550 parts of mannitol, 10-35 parts of cross-linked sodium carboxymethyl cellulose, 2-10 parts of citric acid, and 5-20 parts of micropowdered silica gel.

5. The Tongkang orally dispersible powder according to claim 4 is prepared from raw materials comprising the following excipients in parts by weight: 3-7 parts of steviol glycosides, 400-500 parts of mannitol, 15-25 parts of cross-linked sodium carboxymethyl cellulose, 4-8 parts of citric acid, and 8-12 parts of micropowdered silica gel. The Tongkang orally dispersible powder according to claim 5 is prepared from raw materials comprising the following excipients in parts by weight: 6 parts of steviol glycoside, 450 parts of mannitol, 20 parts of cross-linked sodium carboxymethyl cellulose, 6 parts of citric acid, and 10 parts of micropowdered silica gel.

7. The Tongkang orally disintegrating powder according to any one of claims 1 to 6, wherein the excipients of the Tongkang orally disintegrating powder further comprise vanillin and orange flavor.

8. The Tongkang orally dispersible preparation according to any one of claims 1 to 7, wherein the preparation method of the Tongkang orally dispersible preparation comprises: (1) Dried Chinese yam and dried tangerine peel were crushed; (2) extracting aromatic oil from Saposhnikovia divaricata and Atractylodes macrocephala; (3) extracting the residues from the extract of aromatic oil from the Radix Saposhnikoviae and Atractylodes macrocephalae in step (2) with water to obtain an extract 1; (4) extracting the astragalus and oyster with water to obtain extract 2; (5) combining extract 1 and extract 2, and concentrating to obtain a clear paste; (6) preparing the clear paste into a clear paste solution; (7) using steviol glycosides, mannitol, cross-linked sodium carboxymethyl cellulose, tangerine peel powder, and yam powder for fluidized bed spray granulation; (8) dry pressing and crushing to obtain dry pressed powder; (9) preparing aromatic oil into aromatic emulsion, and spraying the aromatic emulsion into dry pressed powder; (10) Add micro powder silica gel to the mixture.

9. The method for preparing the Tongkang orally dispersible preparation according to any one of claims 1 to 7, comprising: (1) Dried Chinese yam and dried tangerine peel were crushed; (2) extracting aromatic oil from Saposhnikovia divaricata and Atractylodes macrocephala; (3) extracting the residues from the extract of aromatic oil from the Radix Saposhnikoviae and Atractylodes macrocephalae in step (2) with water to obtain an extract 1; (4) extracting the astragalus and oyster with water to obtain extract 2; (5) combining extract 1 and extract 2, and concentrating to obtain a clear paste; (6) preparing the clear paste into a clear paste solution; (7) using steviol glycosides, mannitol, cross-linked sodium carboxymethyl cellulose, tangerine peel powder, and yam powder for fluidized bed spray granulation; (8) dry pressing and crushing to obtain dry pressed powder; (9) preparing aromatic oil into aromatic emulsion, and spraying the aromatic emulsion into dry pressed powder; (10) Add micro powder silica gel to the mixture.

10. The Tongkangkou dispersant according to claim 8 or the preparation method according to claim 9, wherein in step (3), 8-15 times the weight of the medicinal residue is added with water, extracted 1-2 times, and decocted for 1-3 hours; preferably, 10 times the weight of the medicinal residue is added with water, heated and extracted once, and decocted for 1.5 hours.

11. The Tongkang oral dispersible powder or preparation method according to any one of claims 8 to 10, wherein in step (4), 8 to 15 times the weight of the medicinal material is added with water for extraction twice, and each extraction is performed for 1 to 3 hours.

12. The Tongkang oral dispersant or preparation method according to any one of claims 8 to 11, wherein water 10 times the total amount of the medicinal materials is added for the first time and boiled for 2 hours, and water 8 times the total amount of the medicinal materials is added for the second time and boiled for 1.5 hours.

13. The Tongkang oral dispersible powder or the preparation method according to any one of claims 8 to 12, wherein in step (5), the concentration is performed to a relative density of 1.11 to 1.

25.

14. The Tongkang oral dispersible preparation or preparation method according to any one of claims 8 to 13, wherein in step (5), the concentration is to a relative density of 1.2-1.

22.

15. The Tongkang oral dispersible or preparation method according to any one of claims 8 to 14, wherein the feed rate in the fluidized bed spray granulation in step (7) is 1.2 to 2.2 ml / min, the atomization pressure of the clear paste solution is 0.2 to 0.6 bar, and the granulation temperature is greater than or equal to 70°C; 16. The Tongkang oral dispersible or preparation method according to any one of claims 8 to 15, wherein in step (7) the fluidized bed spray granulation is performed at a feed rate of 1.7 ml / min, an atomization pressure of 0.2 bar, and an air inlet temperature of 70°C.

17. The Tongkang oral dispersible powder or preparation method according to any one of claims 8 to 16, wherein the dry pressing oil pressure in step (8) is 160-200 bar.

18. The Tongkang oral dispersible powder or preparation method according to any one of claims 8 to 17, wherein in step (9), the aromatic oil, orange essence and 50-500 mL of 95% ethanol are mixed to form an aromatic mixed emulsion, and the dry pressed powder is sprayed into the mixture in equal and increasing amounts.

19. The method for constructing the fingerprint of Tongkang orally dispersible paste according to any one of claims 8 to 17, characterized in that: The method comprises: taking approximately 2 g of the clear paste, accurately weighing it, placing it in a 50 ml stoppered conical flask, accurately adding 20 ml of methanol, extracting it by heating and refluxing for 60 minutes, cooling it, reweighing it, making up the lost weight with methanol, shaking it well, filtering it through a 0.45 μm microporous filter membrane, and taking the filtrate as the finished test solution. Accurately aspirate 10 μl of the test solution and determine it by HPLC.

20. The method according to claim 19, wherein the HPLC chromatography conditions are as follows: chromatographic column: Kromasil 100-5C18 (250 mm × 4.6 mm, 5 μm); mobile phase system: acetonitrile-0.1% formic acid aqueous solution; mobile phase A: acetonitrile, mobile phase B: 0.1% formic acid, gradient elution (Table 26), flow rate: 1 ml / min, column temperature: 25°C, detection wavelength: 260 nm, detector: UV detector DAD-3000, injection volume: 10 μl.

21. Use of the Tongkang oral dispersant according to any one of claims 1 to 7 in the preparation of a medicament for improving immunity.

22. Use of the Tongkang oral dispersant according to any one of claims 1 to 7 in the preparation of a medicament for treating recurrent respiratory tract infections in children.

23. Use of the Tongkang oral dispersant according to any one of claims 1 to 7 in the preparation of a medicament for treating physical weakness, excessive sweating, fatigue and / or loss of appetite.

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