CN110755388B - Preparation process of blackberry lily granules - Google Patents
Preparation process of blackberry lily granules Download PDFInfo
- Publication number
- CN110755388B CN110755388B CN201911234342.9A CN201911234342A CN110755388B CN 110755388 B CN110755388 B CN 110755388B CN 201911234342 A CN201911234342 A CN 201911234342A CN 110755388 B CN110755388 B CN 110755388B
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Abstract
The invention provides a preparation process of belamcanda chinensis granules, which comprises a main drug and at least two auxiliary drugs, and is characterized by comprising the following steps: s1 extraction process route screening procedure, S2 main drug extraction process condition screening procedure and S3 adjuvant extraction process condition screening procedure; the process adopts modern Chinese medicine production and analysis detection technology, carries out scientific and systematic research on the aspects of extraction, preparation and pilot plant test of the variety, and develops the variety into a modern Chinese medicine preparation which is safe and effective, has stable quality and is convenient to use.
Description
Technical Field
The invention relates to the field of traditional Chinese medicine preparations, in particular to a preparation process of blackberrylily rhizome granules.
Background
The existing traditional Chinese medicine preparation is usually formulated according to experience or the guidance of the traditional prescription. The formulation scheme often has the problems of low accuracy, incapability of forming a systematic traditional Chinese medicine granular preparation process, and lack of safety, effectiveness and quality stability.
Disclosure of Invention
The invention aims to overcome the defects, and carries out preclinical research on new traditional Chinese medicines according to the requirements of the national drug registration management method under the guidance of the traditional Chinese medicine theory. The modern Chinese medicine production and analysis detection technology is adopted, scientific and systematic research is carried out on the aspects of extraction, preparation and pilot plant test of the variety, and the variety is developed into a safe and effective modern Chinese medicine preparation with stable quality and convenient use.
The invention provides a preparation process of belamcanda chinensis granules, which comprises a main drug and at least two auxiliary drugs, and is characterized by comprising the following steps: s1 extraction process route screening procedure, S2 main drug extraction process condition screening procedure and S3 adjuvant extraction process condition screening procedure;
wherein, the screening process of the S1 extraction process route comprises the following process steps:
s1-1, determining active ingredients according to the characteristics of the target medicine;
s1-2, determining the content detection method of the active ingredients related to S1-1;
s1-3, determining two or more extraction process routes;
s1-4, carrying out experiments by adopting different extraction process routes of S1-3;
s1-5, adopting the detection method of S1-2 to detect the content of each active component in the experimental results of each route of S1-4;
s1-6, determining the optimal extraction process route according to the detection result of S1-5;
when the optimal extraction process route comprises a scheme of respectively extracting the main medicines and the auxiliary medicines;
aiming at the extraction scheme of the main drugs, the screening process of the extraction process conditions of the main drugs of S2 comprises the following process steps:
s2-1, determining two or more main drug extraction process conditions based on the optimal extraction process route obtained in S1-6;
s2-2, carrying out experiments by adopting different extraction process conditions of the main drugs of S2-1;
s2-3, adopting the detection method of S1-2 to detect the content of each active component in the experimental result of each process condition of S2-2;
s2-4, determining the optimal extraction process conditions of the main drugs according to the detection result and the paste yield result of S2-3;
aiming at the extraction scheme of the adjuvant, the screening process of the extraction process conditions of the S3 adjuvant comprises the following process steps:
s3-1, determining two or more than two adjuvant extraction process conditions based on the optimal extraction process route obtained in S1-6;
s3-2, carrying out experiments by adopting different extraction process conditions of the main drugs of S3-1;
s3-3, adopting the detection method of S1-2 to detect the content of each active component in the experimental result of each process condition of S3-2;
s3-4, calculating according to the detection result and the paste yield result of S3-3 by using a formula of the score di ═ Yi/Ymax, and scoring the content of each active ingredient and the paste yield under each process condition;
s3-5, obtaining comprehensive scores of all process conditions according to preset weights of all active ingredients and cream yield;
s3-6, obtaining the best adjuvant extraction process conditions according to the comprehensive scoring result of S3-5.
Furthermore, the preparation process of the blackberry lily granules provided by the invention is characterized by comprising the following steps: the screening process of the extraction process conditions of the adjuvant drug of S3 further comprises a checking process;
the checking procedure is to carry out orthogonal analysis on the detection result of S3-3 and the paste yield result;
according to the result of orthogonal analysis, determining the significance sequence of each specific condition in the process conditions of the extraction of the adjuvant;
and judging the optimal auxiliary drug extraction checking process conditions according to the significance sequence.
Furthermore, the preparation process of the blackberry lily granules provided by the invention is characterized by comprising the following steps: when the optimal adjuvant extraction checking process condition is different from the optimal adjuvant extraction process condition, sequentially performing the following steps:
step 1, adopting optimal adjuvant extraction and checking process conditions and optimal adjuvant extraction process conditions to respectively carry out experiments;
step 2, detecting the content of each active ingredient in the experimental result of each process condition of S3-2 by adopting the detection method of S1-2;
and 3, judging the final optimal adjuvant extraction process conditions according to the detection result and the ointment yield result of the S3-3.
Furthermore, the preparation process of the blackberry lily granules provided by the invention is characterized by comprising the following steps: also comprises preparation auxiliary materials;
the preparation auxiliary materials comprise a main auxiliary material and at least one auxiliary material;
also comprises a step of screening the preparation materials of S4;
the screening process of the S4 preparation materials comprises the following process steps:
s4-1, mixing the main auxiliary materials and various auxiliary materials according to a set proportion, and respectively carrying out performance tests;
s4-2, obtaining a formula scheme of the auxiliary materials of the target preparation according to the performance test result.
Furthermore, the preparation process of the blackberry lily granules provided by the invention is characterized by comprising the following steps: the extraction process route comprises a separation and alcohol precipitation process, a separation and alcohol-free precipitation process, a combined extraction and alcohol precipitation process and a combined extraction and alcohol-free precipitation process;
the factors for determining the extraction process conditions of the main drugs are selected from at least one of solvent addition, extraction time and extraction times;
the factor for determining the extraction process condition of the adjuvant is selected from at least one of solvent addition amount, extraction time and extraction frequency.
Furthermore, the preparation process of the blackberry lily granules provided by the invention is characterized by comprising the following steps: the main drug is ephedra;
the adjuvant comprises semen Armeniacae amarum, Bombyx Batryticatus, rhizoma Belamcandae, radix Scutellariae, radix Peucedani, herba Rorippae, periostracum Cicadae, and radix Stemonae;
the above active ingredients are baicalin, tectoridin, irigenin, ephedrine hydrochloride, baicalein, and wogonin;
the element for determining the extraction process condition of the main drug is extraction time;
the factors for determining the process conditions of the extraction of the adjuvant are the addition amount of a solvent, the extraction time and the extraction times.
Furthermore, the preparation process of the blackberry lily granules provided by the invention is characterized by comprising the following steps: the method for detecting the content of the active ingredients comprises the following steps:
chromatographic conditions are as follows: acetonitrile is used as a mobile phase A, 0.1 percent phosphoric acid is used as a mobile phase B, and the elution is carried out according to the gradient with the flow rate of 0.8ml/min, the column temperature of 25 ℃ and the chromatographic column Waters symmetry C184.6mm multiplied by 150mm5 mu m;
wherein the detection wavelength of baicalin, irigenin, tectoridin, baicalein and wogonin is 274nm, and the detection wavelength of ephedrine hydrochloride is 210 nm.
Furthermore, the preparation process of the blackberry lily granules provided by the invention is characterized by comprising the following steps: when the optimal process route obtained by the screening process of the S1 extraction process route is a separate extraction and alcohol precipitation process or a combined extraction and alcohol precipitation process;
the method also comprises a screening process of alcohol precipitation process conditions, and comprises the following steps;
step 1, carrying out experiments by adopting different alcohol precipitation process conditions;
step 2, detecting the content of each active ingredient in the experimental result of each process condition in the step 1 by adopting a detection method of S1-2;
and 3, obtaining the optimal alcohol precipitation process condition according to the detection result and the yield result of the step 2.
Furthermore, the preparation process of the blackberry lily granules provided by the invention is characterized by comprising the following steps: the optimal extraction process of the blackberry lily granules comprises the following steps:
A1. soaking herba Ephedrae in water for 1 hr, decocting twice (0.5 hr for the first time and 0.5 hr for the second time), adding 10 times of water each time, mixing decoctions under hot filtration condition, and concentrating under reduced pressure to relative density of about 1.16;
A2. adding 10 times of water into the ephedra herb residues and the rest eight medicines, extracting for three times, each time for 0.5 hour, combining the decoctions under the hot filtering condition, filtering, and concentrating the filtrate until the relative density is 1.08-1.10;
A3. adding 3 times of 95% ethanol, settling for 24 hr, collecting supernatant, recovering ethanol, concentrating under reduced pressure to relative density of about 1.16, and vacuum drying to obtain extract.
Furthermore, the preparation process of the blackberry lily granules provided by the invention is characterized by comprising the following steps: the optimal prescription of the blackberrylily rhizome preparation forming process comprises the following steps: 1g of dry extract powder, 0.65g of dextrin, 0.65g of mannitol and 0.018g of steviosin.
Effects and effects of the invention
The invention analyzes the relationship between the prescription composition and each medicinal component in the compound on the basis of clinical application according to the technical guidance principle of the extraction and purification process of traditional Chinese medicines and natural medicines, and researches the process route on the basis of the research of the physicochemical properties and the pharmacological action of the components contained in each medicinal component. Orthogonal design is adopted, and the extraction process is investigated by taking the addition amount of a solvent, the extraction time, the extraction times and the like as investigation factors. And further examine various processes such as alcohol precipitation. Combining the action characteristics of the medicinal components, the granules are adopted as preparations for research when developing new medicaments.
Drawings
Fig. 1, the preparation process flow of belamcanda chinensis granules.
Detailed Description
1. Extraction Process route screening research
Screening 6 active ingredients including baicalin, baicalein, wogonin, tectoridin, irigenin and ephedrine by using Chinese medicinal serum medicinal chemistry research mode. In the screening work of the extraction process route, the extraction amount of six components, namely baicalin, baicalein, wogonin, belamcandin, irisfloretin and ephedrine is selected as an evaluation index, and 4 processes are carried out: (1) a separate extraction and alcohol precipitation process, (2) a separate extraction and alcohol precipitation-free process, (3) a combined extraction and alcohol precipitation process, and (4) a combined extraction and alcohol precipitation-free process are investigated, and a more scientific and reasonable extraction process route is determined.
1.1 method of analyzing active ingredient
The method for measuring the content of baicalin, belamcandin, irisflorentin, ephedrine hydrochloride, baicalein and wogonin comprises the following steps:
chromatographic conditions are as follows: acetonitrile is used as a mobile phase A, 0.1% phosphoric acid is used as a mobile phase B, gradient elution is carried out according to the following table, the flow rate is 0.8ml/min, the column temperature is 25 ℃, the chromatographic column Waters symmetry C184.6mm multiplied by 150mm5 mu m, the detection wavelength of baicalin, sub-wild tectorigenin, tectoridin, baicalein and wogonin is 274nm, and the detection wavelength of ephedrine hydrochloride is 210 nm.
Preparing a test solution: precisely weighing about 0.5g of extract, placing in a conical flask with a plug, precisely adding 25ml of methanol, weighing, ultrasonically treating for 30 min, cooling, weighing, adding methanol to make up for the lost weight, shaking, filtering, and collecting the filtrate.
Preparation of a standard solution: taking appropriate amount of each standard reference substance, precisely weighing, and adding methanol-water (8:2) mixed solution to obtain solution containing 0.1mg per 1 ml.
1.2 preparation by extraction
On the basis of earlier research, the effective component transfer rate of the blackberry lily mixture is taken as an index, and the extraction process route is screened:
(1) a fractional extraction and alcohol precipitation process: taking 27g of ephedra medicinal material, adding water for soaking for 1 hour, decocting twice, wherein the first time is 0.5 hour, the second time is 1.5 hours, adding 10 times of water for each time, combining decoctions (filtering while hot), and concentrating under reduced pressure until the relative density is about 1.16 (the measured density p is m/V, 80-85 ℃).
And adding water into the ephedra herb residues and the rest eight medicines, decocting for two times, namely 10 times of water is added for the first time, decocting for 1.5 hours, 8 times of water is added for the second time, decocting for 40 minutes, combining decoctions (filtering while hot), filtering, and concentrating the filtrate until the relative density is 1.08-1.10(80-85 ℃).
Adding 2 times of ethanol (95% ethanol) for settling for 24 hours, taking supernate, recovering ethanol, and concentrating under reduced pressure until the relative density is about 1.16(80-85 ℃). The sample was concentrated and dried under vacuum.
(2) The fractional extraction alcohol precipitation-free process comprises the following steps: taking 27g of ephedra medicinal material, adding water for soaking for 1 hour, decocting twice, wherein the first time is 0.5 hour, the second time is 1.5 hours, adding 10 times of water for each time, combining decoctions (filtering while hot), and concentrating under reduced pressure until the relative density is about 1.16 (the measured density p is m/V, 80-85 ℃). The sample was concentrated and dried under vacuum.
And (3) decocting the residues of the ephedra herb and the rest eight medicines with water twice, wherein 10 times of water is added for the first time and is decocted for 1.5 hours, 8 times of water is added for the second time and is decocted for 40 minutes, the decoction liquid is combined (filtered while the decoction liquid is hot), the filtration is carried out, the filtrate is concentrated until the relative density is 1.08-1.10(80-85 ℃), and the two filtrates are combined. The sample was concentrated and dried under vacuum.
(3) A combined extraction and alcohol precipitation process: and adding water into the ephedra herb residues and the rest eight medicines, decocting twice, adding 10 times of water for the first time, decocting for 1.5 hours, adding 8 times of water for the second time, decocting for 40 minutes, combining the decoctions (filtering while hot), filtering, concentrating the filtrate until the relative density is 1.08-1.10(80-85 ℃), adding 2 times of ethanol (95% ethanol), settling for 24 hours, taking the supernatant, recovering the ethanol, and concentrating under reduced pressure until the relative density is about 1.16(80-85 ℃).
(4) The combined extraction process has no alcohol precipitation process: all the medicinal materials are decocted for two times by adding 10 times of water for the first time, and decocted for 1.5 hours, and 8 times of water for the second time, and decocted for 40 minutes, the decoction liquids are combined (filtered while hot), filtered, and concentrated to the relative density of 1.08-1.10(80-85 ℃), and the two filtrates are combined. The sample was concentrated and dried under vacuum.
1.3 results of the experiment
The extract preparation was carried out according to four processes, the results of cream yield and active ingredient content are shown in table 1:
TABLE 1 summary of cream yield and content of samples from different extraction processes
Through comparative experiments, the following results are found: the content of ephedrine in the single extract of herba Ephedrae is increased obviously compared with the combined decoction process, and the single decoction of herba Ephedrae can increase the content of ephedrine in the extract. Compared with the processes before and after the alcohol precipitation process, the single ephedra decoction process is still reserved on the process route. The alcohol precipitation process can reduce the paste yield of the extract, and the subsequent experiments adopt a single herba ephedrae extraction process, a mixed extraction process of the rest medicines and an alcohol precipitation process of the rest medicines.
2 optimization of extraction Process
2.1 study of Ephedra sinica Stapf extraction Process
2.1.1 examination of the amount of Water absorbed
The water immersion and the water absorption times of the ephedra are considered to determine the water absorption condition of the medicinal materials. The method comprises the following specific operations: taking 50g of ephedra medicinal material, adding 500ml (500g) of water, observing the immersion condition of the medicinal material, and measuring the water absorption capacity of the medicinal material after 2 hours.
2.1.2 extraction Process investigation.
In the original process, the ephedra is extracted for 2 times, wherein the first time is 0.5 hour, the second time is 1.5 hours, and 10 times of water is added. The method is characterized in that the influence of different extraction time on the extraction rate and the ephedrine extraction amount is examined on the basis of the original formula preparation, and the method comprises three extraction processes: the process is as follows: extracting for 2 times, wherein the first time is 0.5 hour, the second time is 1.5 hours, and 10 times of water is added; the process II comprises the following steps: extracting for 2 times, the first time is 0.5 hour, and the second time is 1 hour, and adding 10 times of water. And (3) process III: extracting for 2 times, the first time is 0.5 hour, the second time is 0.5 hour, and 10 times of water is added.
And extracting, concentrating and drying the sample according to the conditions, and calculating the yield. And detecting the content of ephedrine.
2.1.3 results of the experiment:
(1) examination of the amount of water absorbed
TABLE 2 examination result of water absorption times of herba Ephedrae
(2) Investigation of extraction Process
TABLE 3 examination of the extraction process of Ephedra
Through the investigation experiment of the water absorption times of medicinal materials, the water absorption times of the ephedra medicinal materials are about 2.5 times. Different ephedra extraction process researches find that the yield of the second extraction is 0.5 hour, 1 hour and 1.5 hour and the content difference of ephedrine hydrochloride is not obvious, so that the ephedra extraction process is confirmed as follows: herba Ephedrae is extracted with 10 times of water for 2 times, the first time for 0.5 hr, and the second time for 0.5 hr.
2.2 investigation of the extraction Process of the remaining drugs
2.2.1 Experimental design
The experiment adopts an L93(4) orthogonal design, takes the addition amount of a solvent, the extraction time and the extraction times as investigation factors, takes total flavone, baicalin, irisflorentin and belamcanda chinensis glycoside as investigation indexes, takes the addition amount of the solvent, the extraction time and the extraction times as investigation factors, and screens the best residual medicine extraction process, which is shown in Table 4.
TABLE 4 extraction factor of the rest herbs-horizon table
| Level of factor | Extraction time (h) | Solvent amount (crude drug multiple) | Number of times of extraction |
| 1 | 0.5 | 6 | 1 |
| 2 | 1 | 8 | 2 |
| 3 | 1.5 | 10 | 3 |
2.2.2 Experimental methods
Extracting preparation prescription amount of 134.4g, and repeating each process for 2 times; (8.1 g of almond, 16.2g of blackberrylily rhizome (smashed), 8.1g of ephedra herb, 21g of baical skullcap root, 16.2g of whiteflower hogfennel root, 32.4g of rorippa rorifolia, 8.1g of cicada slough (smashed) and 16.2g of sessile stemona root (roasted)). The test was performed according to the protocol of the orthogonal test, the extracts were filtered separately, concentrated under reduced pressure, and the concentrate was dried under reduced pressure and vacuum to give 9 parts of extract. The optimal water extraction process is obtained by respectively calculating the extract yield of 9 parts of extract and each index in the extract and carrying out orthogonal analysis.
TABLE 5 Experimental arrangement chart
2.2.3 results of the experiment
2.2.3.1 extraction of experimental results
According to the orthogonality test Table L93 4) Investigating the influence of the water consumption, the decoction time and the decoction times on the decoction effect, wherein the main influence factors on the decoction process are the following, comprehensively analyzing according to the content of effective components in the extract and the yield of the extract, and setting the weight ratio as follows: shooting device18% of dry glycoside, 18% of baicalin, 18% of baicalein, 18% of irisfloretin, 18% of wogonin and 10% of dry paste. The scoring criteria were di ═ Yi/Ymax.
TABLE 6 results of orthogonal experiments
TABLE 7 composite scoring results
The individual scores are calculated from di Yi/Ymax (rounded values in the table for the sake of illustration), and the actual composite score is obtained as the individual score by its weight.
2.2.3.2 results of orthogonal analysis
The corresponding experimental data were analyzed according to the L9(34) orthogonal table, see the following Table.
TABLE 8 visual analysis results
TABLE 9 analysis of variance results
And (3) comprehensive analysis results: the significance is that C (extraction times) is more than A (extraction time) and more than B (solvent times); the optimal process conditions for visual analysis are as follows: a2B3C3 (to K in visual analysis)2Maximum amount), adding 10 times of solvent, and extracting for 3 times each for 1 h.
2.2.4 verification of extraction process of the rest medicines
The optimal extraction process obtained from the orthogonal experiment is as follows: adding 10 times of water, extracting for three times, each time for 1 hr.
The highest composite score group among all experimental group data was group 3: the extraction process comprises adding 10 times of water, extracting for three times, each time for 0.5 hr.
In order to further optimize the experimental conditions, two experimental conditions were subjected to process validation, each set of conditions was set with 2 parallel experiments: experiment a: adding 10 times of water, extracting for three times, each time for 0.5 hr. Experiment b: adding 10 times of water, extracting for three times, each time for 1 hr. And extracting, concentrating and drying the sample according to the conditions, and calculating the yield. And detecting the content of baicalein, baicalin, wogonin, irigenin and tectoridin in the extract. Extraction preparation prescription amount 134.4 g: (almond 8.1g, batryticated silkworm (breaking), blackberry lily 8.1g, Chinese ephedra 8.1g, baikal skullcap root 21g, peucedanum root 16.2g, rorippa rorifolia 32.4g, cicada shell (breaking), stemona root 16.2g)
Table 10 verifies the results of the experiment
Through verification and comparison experiments, the experiments a and b have no significant difference in the comparison of the extraction yield and the content of each effective component, and the extraction cost problem is considered, and the extract process of the process is determined as follows: adding 10 times of water, extracting for three times, each time for 0.5 hr.
2.3 investigation of alcohol precipitation technique of the remaining drugs
Extraction and preparation: 625g of (37.5 g of almond, 75g of (smashed) stiff silkworm, 37.5g of blackberrylily rhizome, 37.5g of ephedra herb, 100g of baical skullcap root, 75g of whiteflower hogfennel root, 150g of rorippa rorifolia, 37.5g of (smashed) cicada slough and 75g of (fried) sessile stemona root) are added with 10 times of water for extraction for three times, and each time is 0.5 hour. Combining the decoctions (filtering while the decoctions are hot), filtering, and concentrating the filtrate to a relative density of 1.08-1.10(80-85 ℃). The concentrated solution is divided into 4 parts.
2.3.1 alcohol precipitation experiment
4 experiments are designed according to the times of different ethanol, and the experiments are as follows:
experiment 1: adding 1 time of ethanol (95% ethanol) into the concentrated solution, settling for 24 hours, taking the supernatant, recovering the ethanol, and concentrating under reduced pressure until the relative density is about 1.16(80-85 ℃).
Experiment 2: adding 2 times of ethanol (95% ethanol) into the concentrated solution, settling for 24 hours, taking the supernatant, recovering the ethanol, and concentrating under reduced pressure until the relative density is about 1.16(80-85 ℃).
Experiment 3: adding 3 times of ethanol (95% ethanol) into the concentrated solution, settling for 24 hours, taking the supernatant, recovering the ethanol, and concentrating under reduced pressure until the relative density is about 1.16(80-85 ℃).
Experiment 4: adding 4 times of ethanol (95% ethanol) into the concentrated solution, settling for 24 hours, taking the supernatant, recovering the ethanol, and concentrating under reduced pressure until the relative density is about 1.16(80-85 ℃).
And extracting, concentrating and drying the sample according to the conditions, and calculating the yield. And detecting the content of baicalein, baicalin, wogonin, irigenin and tectoridin.
2.3.2 results of the experiment
TABLE 11 investigation of different alcohol precipitation concentrations
According to the measurement results of different alcohol precipitation concentrations on the extract yield and the content of the effective components, considering the transfer rate and the efficiency of the effective components, the alcohol precipitation times are determined to be 3 times of that of ethanol for alcohol precipitation.
2.4 extraction Process
The extraction process of the blackberry lily particles determined according to the bench test is as follows: taking 27g of ephedra medicinal material, adding water for soaking for 1 hour, decocting twice, wherein the first time is 0.5 hour, the second time is 0.5 hour, adding 10 times of water for each time, combining decoctions (filtering while hot), and concentrating under reduced pressure until the relative density is about 1.16 (the measured density p is m/V, 80-85 ℃).
Adding 10 times of water into the ephedra herb residues and the rest eight medicines, extracting for three times, each time for 0.5 hour, combining decoction liquids (filtering while hot), filtering, and concentrating the filtrate to the relative density of 1.08-1.10(80-85 ℃). Adding 3 times of ethanol (95% ethanol), settling for 24 hr, collecting supernatant, recovering ethanol, concentrating under reduced pressure to relative density of 1.16(80-85 deg.C), and vacuum drying to obtain extract. The specific process is shown in figure 1.
3 formulation Process investigation
3.1 dosage form selection
The composition is prepared from clinical experience, and the original formulation is a mixture. According to the characteristics of the ingredients of the medicine and the characteristics of the medicine taken by children, the granules are adopted when developing new medicines, so that the medicine is convenient for patients to take and carry, the product has stable properties, and is easy for mass production and convenient for storage and transportation.
3.2 formulation adjuvant selection
According to the previous extraction experiment, the extract rate of the blackberry lily extract is determined to be about 17%, and the conversion relation between crude drugs and the extract is 5.8g crude drugs/g extract. Converting the usage amount of the blackberry lily mixture into an extract: the extract is 3.24g per day for children under one year of age, and 1.08g per day for children under one year of age, calculated 3 times per day. The extract is 6.48g per day for children over one year, and 2.16g per day according to 3 times daily administration. The proportion of the raw medicine to the auxiliary materials is 1: 1.3, screening auxiliary materials and researching preparations according to the proportion. In the aspect of auxiliary material selection, glucose powder, lactose, soluble starch, dextrin and mannitol are mainly selected as auxiliary materials for preparation investigation.
3.3 investigation of the amount of raw and auxiliary materials
3.3.1 preliminary screening of auxiliary materials
Mixing the extract powder with adjuvants (1: 1.3), sieving with 40 mesh sieve, and placing in 30 deg.C oven for 48 hr. NaCl was periodically placed in a glass desiccator having a saturated solution of sodium chloride (NaCl) at the bottom until a supersaturated solution of NaCl was formed, at which time the relative humidity in the desiccator was 75%. Putting the medicinal powder with the thickness of about 2mm at the bottom of a flat weighing bottle with constant weight, accurately weighing, placing in the dryer, weighing after 48h, making 2 groups, and calculating the average value.
TABLE 12 sample hygroscopicity test table
The moisture absorption investigation result shows that the dry extract powder has strong dilutability, and the lactose and the mannitol in the auxiliary materials have better effect of reducing the moisture absorption of the extract.
3.3.2 formability examination
Screening auxiliary materials according to the requirements of the paste yield of the extraction process and the dosage of the prescription, wherein the dosage of the extract powder and the auxiliary materials is 1: 1.3 taking sucrose powder, lactose, soluble starch, dextrin and mannitol as auxiliary materials, taking 40g of extract powder, 5 parts of extract powder, taking a specified amount according to the table 1, uniformly mixing the extract powder with the auxiliary materials (1: 1.3), using a proper amount of 70% ethanol as a wetting agent to prepare a soft material, granulating by using a 14-mesh sieve, finishing by using a 16-mesh sieve, drying at the temperature of below 60 ℃ to constant weight, and measuring the forming rate, the angle of repose and the solubility.
(1) Examination of particle flowability
Angle of repose measurement: adopt fixed funnel method, be about to 3 funnels series connection and be fixed in the suitable height department on the coordinate paper of horizontal placement, make the distance of funnel lower shed apart from the coordinate paper be H, carefully pour the sample into topmost funnel along the funnel wall in, until the cone point of the funnel powder of bottommost touches the funnel mouth, measure the diameter R of cone bottom by the coordinate paper this moment, calculate the angle of repose.
(2) Particle solubility investigation
Referring to the test method for soluble particles in the pharmacopoeia of 2015 edition, test article I0g (1 bag of single-dose package of traditional Chinese medicine) was taken, 200ml of hot water was added, stirred for 5 minutes, and immediately observed that the soluble particles should be completely dissolved or slightly turbid.
TABLE 13 investigation of properties of granules
| Numbering | Compounding ratio of auxiliary materials | Molding ratio (%) | Angle of repose | Solubility in water |
| 1 | Extract +1.3 glucose | 84.02 | 29.74 | The particles are totally dissolved and are relatively turbid |
| 2 | Extract +1.3 lactose | 85.81 | 33.69 | The particles are totally dissolved and are relatively turbid |
| 3 | Extract +1.3 soluble starch | 75.74 | 31.61 | The particles are not completely dissolved |
| 4 | Extract +1.3 dextrin | 82.96 | 29.74 | The particles are totally dissolved and are relatively turbid |
| 5 | Extract +1.3 mannitol | 85.71 | 31.61 | The particles are totally dissolved and are relatively turbid |
3.3.3 auxiliary Material mixing Process investigation
On the basis of a single auxiliary material preparation, the solubility, the forming rate and the fluidity are comprehensively considered, the performances of auxiliary materials with different proportions in the aspects of hygroscopicity, the solubility and the fluidity are further considered, and finally the auxiliary material formula is formed by taking dextrin and mannitol as final auxiliary materials, wherein the proportion of the two auxiliary materials is 1: 1.
TABLE 14 particle Performance test Table (Mixed excipients)
3.4 identification of flavours
The granular extract powder is bitter and astringent and difficult to swallow, is suitable for children, and is added with a certain amount of flavoring agent for improving the compliance and compliance of the patients to the medicine. Stevia rebaudianum is selected as the leaf correcting agent in the test because of pure sweet taste, long residual time, delicious aftertaste and the quality which is closest to that of cane sugar, can be used as the sweet taste improving agent in medicines and foods, can not be absorbed by human bodies after being taken, can not generate heat, and is non-toxic and safe and reliable to use.
The steviosin with different parts is added into the materials, and people with different tastes are tested, so that the taste is modified when the steviosin is added to 0.2-0.6% bitter or slightly bitter and added to 0.8%.
3.3 preparation Molding Process Studies
Prescription: 1g of dry extract powder, 0.65g of dextrin, 0.65g of mannitol and 0.018g of steviosin.
The granulation mode is as follows: wet granulation
The granule prepared by the formula has good shape, good fluidity and reliable molding process. The obtained product has good solubility and moldability, and meets the regulations of the general rules of granule preparations. According to the prescription, the crude drug amount of the composition taken by a child in one year is 18.75g each time, the cream yield is 17%, the daily extract amount is 3.18g, and the daily granule amount is 7.5 g. The granule is taken 3 times a day clinically, and 2.5g of the granule is taken each time.
4 pilot study
The purpose of the pilot test study is to judge the portability of the process parameters and whether the adjustment is needed and the direction of the adjustment according to whether the test result is within the allowable limit after the process scale is enlarged on the basis of the optimized process parameters obtained by the pilot test study. In the pilot plant production, the amount of extraction solvent and the extraction time can be directly used for pilot plant amplification without being adjusted by changing the equipment scale. The difference between the pilot plant process and the pilot plant process is mainly shown in that factors which are not needed to be considered in the pilot plant process need to be considered in the pilot plant process and even in the large-scale production process, and the influence and the acceptable influence degree which are possibly brought by the factors are evaluated, including: the extraction efficiency is reduced due to the possible uneven heat transfer after the scale-up of the extraction equipment. The loss of drug during the pilot scale process, evaluated the cumulative effect of more or less loss during drug transfer between each process step of drug preparation, can be reduced to negligible by careful handling during pilot scale. There is also a need to focus on the variation of some non-productive process factors after scale-up. For example, the feeding time, the time for adding the solvent, the temperature rise time, the discharging time and the like which are not needed to be considered in the pilot plant but are needed to be considered after the production scale is enlarged.
4.1 Pilot plant test Process for extraction
The optimized extraction process determined by preliminary small-scale research is as follows: taking 27g of ephedra medicinal material, adding water for soaking for 1 hour, decocting twice, adding 10 times of water for each time, decocting for 0.5 hour, combining the decoctions (filtering while hot), and concentrating under reduced pressure until the relative density is about 1.16 (the measured density rho is m/V, 80-85 ℃).
Mixing the residue with the rest eight materials, extracting with 10 times of water for three times (each time for 0.5 hr), mixing decoctions (hot filtering), filtering, and concentrating the filtrate to relative density of 1.08-1.10(80-85 deg.C). Adding 3 times of ethanol (95% ethanol), settling for 24 hr, collecting supernatant, recovering ethanol, concentrating under reduced pressure to relative density of about 1.16(80-85 deg.C), and vacuum drying to obtain extract.
Three pilot studies of extraction process were performed at 5000 bags (2.5 g/bag). The extraction prescription amounts are as follows:
2025g of almond (broken) 2025g, 4050g of stiff silkworm (broken), 2025g of ephedra (fried), 2025g of blackberry lily, 5250g of scutellaria baicalensis, 4050g of whiteflower hogfennel root, 8100g of rorippa indica, 2025g of cicada slough (broken) and 4050g of radix stemonae (fried), and 31.6Kg of crude drugs.
4.2 medicinal material information:
TABLE 15 examination table of pilot plant drugs
4.3 Pilot sample yield:
table 16 shows the condition of the paste tested
4.4 transfer Rate of Pilot test samples
TABLE 17 tables of effective ingredient transfer
As can be seen from the test, the paste yield is 16.78% on average, which is equivalent to the small test process, and the test result is ideal. The transfer rate of effective components of the three batches of extracts is more than 50%.
4.2 Pilot plant test Process for formulations
According to the process and the prescription determined by small test granulation test research and the extract yield conditions of three batches of pilot-scale extraction, three batches of pilot-scale granulation prescriptions are designed, dextrin, mannitol and stevioside are used as auxiliary materials, a one-step granulation process is adopted, 3 batches of pilot-scale granulation tests are carried out, the prepared granules are packaged into composite aluminum-plastic bags, 2.5g of each bag is packaged, and the test results are shown in table 6.
TABLE 18 three batches of one-step granulation test recipe
Note that the pilot scale-up for the one-step granulation test is currently only scaled up from 800g to 5000g per batch of the pilot plant to 5 times the prescription amount, subject to the batch capacity limitations of the fluidized bed plant (only two fluidized bed plants with batch capacities of 5kg and 60 kg). However, considering the characteristics of stable control of the process and parameters of the fluidized bed granulation process and good repeatability, the fluidized bed granulation process and the prescription determined in the granulation process can be expected to be feasible for continuously enlarging the scale.
4.3 Pilot sample testing
TABLE 19 results of three pilot plant tests
The results of three batches of pilot granulation test show that the fluidized bed one-step granulation process is stable, the granule quality is qualified and controllable, the fine granules are few, and the granule yield is higher.
5 Forming Process
On the basis of small and pilot test researches, the forming process of the mixture of the blackberry lily is formed.
5.1 prescription
150g of almond, 300g of stiff silkworm, 150g of ephedra (fried), 150g of blackberry lily, 400g of baical skullcap root, 300g of whiteflower hogfennel root, 600g of Indian rorippa herb, 150g of cicada slough and 300g of sessile stemona root (fried).
5.2 preparation of
The 9 medicines are prepared by taking ephedra medicinal materials, adding water for soaking for 1 hour, decocting twice, adding 10 times of water for each time, decocting for 0.5 hour, combining the decoctions (filtering while hot), concentrating under reduced pressure until the relative density is about 1.16 (the measured density p is m/V, 80-85 ℃),
decocting the residues of the ephedra herb and the other eight medicines by adding water for three times, adding 10 times of water for the first time, adding 8 times of water for the second time and the third time, each time for 30 minutes, combining the decoctions (filtering while hot), filtering, and concentrating the filtrate to the relative density of 1.08-1.10(80-85 ℃). Adding 3 times of ethanol (95% ethanol) for settling for 24 hours, taking supernate, recovering ethanol, and concentrating under reduced pressure until the relative density is about 1.16(80-85 ℃). Adding herba Ephedrae concentrated solution, vacuum drying, pulverizing, adding mannitol 140g, maltodextrin, and aspartame 8g, granulating to 1000g, and packaging.
Claims (2)
1. A preparation process of belamcanda chinensis granules is characterized by comprising the following steps:
the extraction process of the blackberry lily granules comprises the following steps:
A1. soaking herba Ephedrae in water for 1 hr, decocting twice (0.5 hr for the first time and 0.5 hr for the second time), adding 10 times of water each time, mixing decoctions under hot filtration condition, and concentrating under reduced pressure to relative density of 1.16;
A2. adding 10 times of water into the ephedra herb residues and the rest eight medicines, extracting for three times, mixing the decoction under the hot filtering condition after 0.5 hour each time, filtering, concentrating the filtrate until the relative density is 1.08-1.10, adding 3 times of 95% ethanol, settling for 24 hours, taking the supernatant, recovering the ethanol, and concentrating under reduced pressure until the relative density is about 1.16;
A3. adding herba Ephedrae concentrated solution into A2 concentrated solution, and vacuum drying to obtain extract;
the other eight ingredients are almond, stiff silkworm, blackberry lily, scutellaria, whiteflower hogfennel root, rorippa rorifolia, cicada slough and stemona.
2. The process of claim 1, wherein the process comprises the steps of:
the prescription of the belamcanda chinensis granule preparation forming process is as follows: 1g of dry extract powder, 0.65g of dextrin, 0.65g of mannitol and 0.018g of steviosin.
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