CN114748432B - Preparation process of traditional Chinese medicine compound granules - Google Patents
Preparation process of traditional Chinese medicine compound granules Download PDFInfo
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- CN114748432B CN114748432B CN202210512562.9A CN202210512562A CN114748432B CN 114748432 B CN114748432 B CN 114748432B CN 202210512562 A CN202210512562 A CN 202210512562A CN 114748432 B CN114748432 B CN 114748432B
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Abstract
The invention discloses a preparation process of traditional Chinese medicine compound granules, which comprises the following steps: (1) Decocting radix Isatidis, fructus Gardeniae and flos Lonicerae in water, filtering decoction, and mixing filtrates to obtain three mixed extractive solutions; (2) Grinding cornu Bubali and Concha Margaritifera respectively, decocting respectively, filtering, mixing filtrates, and clathrating with cyclodextrin to obtain mixed hydrolysate; (3) Concentrating the three mixed extract liquid and the mixed hydrolysate to obtain five mixed extractum; (4) Dispersing cholic acid and hyodeoxycholic acid by mannitol to obtain mixed cholic acid dispersed powder or granule; (5) Dispersing baicalin with mannitol to obtain baicalin dispersed powder or granule; (6) And finally, uniformly mixing the five mixed extractum, the mixed cholic acid and the baicalin solid dispersion, adding auxiliary materials, drying, and granulating to obtain the finished product. The novel process can mask peculiar smell and bitter taste, improves the medication compliance of patients, and improves the quality and stability of qingkailing granules.
Description
Technical Field
The invention belongs to the technical field of traditional Chinese medicine particles, and in particular relates to a preparation process of traditional Chinese medicine compound particles.
Background
The traditional Chinese herbal medicines are prepared into traditional Chinese medicine formulations such as pills, powder, ointment, pellets and the like, but the defects of large dosage, unstable quality, poor preservability and the like have greatly restricted the development of the traditional Chinese medicines. The extraction and separation of the effective components in the extracted Chinese herbal medicines are the key points of improving the curative effect of the Chinese herbal medicines, reducing adverse reactions and improving the internal quality of the preparation. The Chinese medicinal granule is oral solid preparation prepared by extracting the medicinal materials with water or other solvents by proper method, and concentrating. It is a new formulation developed by applying the modern preparation technology on the basis of powder. The traditional Chinese medicine granule is a preparation prepared by extracting Chinese herbal medicines, and according to the properties of medicinal material components, a modern natural medicine extraction method is comprehensively utilized, so that various effective components of the traditional Chinese medicine can be effectively extracted, and meanwhile, ineffective excessive impurities are removed, so that the clinical curative effect is more reliable, and side effects and adverse reactions are reduced. Meanwhile, the quality is controllable by using modern pharmaceutical equipment and pharmaceutical technology, and the standardized batch production can be realized, so that the trouble of temporary decoction is avoided. Meanwhile, the volume is reduced, the concentration is high, the dosage is small, and the administration, the carrying and the storage are convenient.
The chemical components of the raw medicinal materials of the traditional Chinese medicine have diversity and complexity, a plurality of medicinal materials have unique bitter taste, and in the processes of processing, compatibility, decoction, preparation and the like, the components are subjected to hydrolysis, polymerization, oxidation, reduction and other reactions to generate new substances, and the bitter mechanisms of the substances are different. The effective components extracted from the Chinese herbal medicines generally have peculiar smell and bitter taste of the Chinese herbal medicines. These conditions all lead to complex, intense and durable bitter taste of most traditional Chinese medicine preparations, which significantly reduces the medication compliance of patients (especially for chronic patients who need to take medicine for a long time, children patients who are sensitive to taste and patients with special psychological mental diseases), and has great influence on the clinical application of the traditional Chinese medicine preparations. It is necessary to investigate taste masking methods suitable for Chinese medicinal preparations. The traditional Chinese medicine preparation mostly adopts traditional methods of processing, adding auxiliary materials, adding guiding drugs and the like to achieve the purpose of flavoring. The taste masking of the current drugs is mainly based on the following principles (1) adding substances to influence the perception of bad taste by taste buds, such as adding flavoring agents (sweeteners, fragrances, etc.), taste blockers or taste paralyzers, etc.; (2) reducing direct contact of the drug with the taste buds by formulation means, such as coating, clathration, solid dispersion, ion exchange, etc.; (3) the modification of the molecular structure of the medicine, such as preparation of prodrug, enzyme treatment, etc., can effectively mask the bad smell of the effective components of the Chinese herbal medicine.
The solubility of the effective components of the Chinese herbal medicine is poor in water, and the preparation is required to be increased in solubility so that the clarity, uniformity and the like of the preparation meet the quality standard requirements, and the effective components are better absorbed in the body.
Qingkailing granule mainly comprises heat-clearing and fire-purging antidote such as cholic acid, concha Margaritifera, hyodesoxycholic acid, fructus Gardeniae, cornu Bubali, radix Isatidis, baicalin, flos Lonicerae, etc., and is a heat-clearing agent with effects of clearing heat, removing toxic substances, and tranquilizing. Mainly treats the symptoms of high fever, dysphoria, sore throat, deep red tongue, yellow coating and rapid pulse caused by exogenous wind-heat toxin and internal excessive fire toxin; the symptoms of upper respiratory tract infection, viral cold, acute suppurative tonsillitis, acute pharyngitis, acute tracheitis, high fever and the like belong to the symptoms. Qingkailing granule is the mature technology and quality standard at present, and the product quality is stable, but the potential for further improvement still exists.
Disclosure of Invention
The invention aims to: in order to overcome the defects of the prior art, the invention provides a preparation process of the traditional Chinese medicine compound granule, which adopts a new process, can mask peculiar smell and bitter taste of traditional Chinese medicines such as baicalin, cholic acid, hyodeoxycholic acid and the like in qingkailing, improves the medication compliance of patients, improves the clarity of the qingkailing granule dissolved in water, has more stable contents of active ingredients such as cholic acid, geniposide, baicalin and total nitrogen, and has remarkably smaller content reduction during storage. Thereby improving the quality and stability of qingkailing granule.
The technical scheme is as follows: in order to achieve the aim of the invention, the invention adopts the following technical scheme:
a preparation process of a traditional Chinese medicine compound granule mainly comprises cholic acid, mother-of-pearl, hyodeoxycholic acid, gardenia, cornu bubali, radix isatidis, baicalin and honeysuckle, and comprises the following steps:
(1) Decocting radix Isatidis, fructus Gardeniae and flos Lonicerae in water, filtering decoction, and mixing filtrates to obtain three mixed extractive solutions;
(2) Decocting cornu Bubali and Concha Margaritifera respectively, filtering, mixing the two filtrates, and clathrating with cyclodextrin to obtain mixed hydrolysate;
(3) Dispersing cholic acid and hyodeoxycholic acid by mannitol to obtain mixed cholic acid dispersed powder or granule;
(4) Dispersing baicalin with mannitol to obtain baicalin dispersed powder or granule;
(5) Uniformly mixing the three mixed extract liquid and the mixed hydrolysate, and concentrating to obtain a five mixed extract;
(6) And finally, uniformly mixing the five mixed extractum with mixed cholic acid and baicalin dispersed powder or particles, adding auxiliary materials, drying and granulating to obtain the finished product.
Preferably, the traditional Chinese medicine compound granule is mainly prepared from the following raw materials in parts by weight:
13+ -1 parts of cholic acid, 200+ -5 parts of mother-of-pearl, 15+ -1 parts of hyodeoxycholic acid, 100+ -3 parts of gardenia, 100+ -3 parts of cornu bubali, 800+ -20 parts of radix isatidis, 20+ -1 parts of baicalin and 240+ -5 parts of honeysuckle.
Preferably, the traditional Chinese medicine compound granule is mainly prepared from the following raw materials in parts by weight:
13 parts of cholic acid, 200 parts of mother-of-pearl, 15 parts of hyodeoxycholic acid, 100 parts of gardenia,
100 parts of cornu bubali, 800 parts of radix isatidis, 20 parts of baicalin and 240 parts of honeysuckle.
Preferably, in the step (1), the radix isatidis, the gardenia and the honeysuckle are mixed, decocted and extracted for 2-3 times by adding water, each time for 0.5-1h, the extracting solutions are combined, concentrated to the clear paste with the relative density of 1.22-1.28 at 80 ℃, and filtered, thus obtaining the triple mixed extracting solution.
In the step (2), cornu bubali is ground into powder, added into alkaline solution, decocted for 6-8 hours and filtered when the powder is hot; adding Concha Margaritifera into acidic solution, decocting for 6-8 hr, filtering while it is hot, cooling the filtrate, mixing with cornu Bubali filtrate, concentrating, precipitating with ethanol, refrigerating, filtering, concentrating again, and clathrating with beta-cyclodextrin by ultrasonic method to obtain mixed hydrolysate.
Further preferably, the alkaline solution is selected from barium hydroxide solution; the acidic solution is selected from sulfuric acid solution; the method for clathrating the beta-cyclodextrin by utilizing the ultrasonic method comprises the following steps of:
calculating the dosage of the beta cyclodextrin according to the dosage of the buffalo horn raw material, wherein the buffalo horn is: beta cyclodextrin weight ratio = 100: 100-400, charging, setting the temperature at 50-70 ℃, ultrasonic power at 200-400W, and time at 40-50min, and refrigerating overnight.
Preferably, in step (3), cholic acid and hyodeoxycholic acid are dispersed by solvent-melting method, cholic acid: mannitol weight ratio=13:30-150.
Further preferably, the method for dispersing cholic acid and hyodeoxycholic acid by the solvent-melting method comprises the steps of:
firstly, heating mannitol of a carrier to enable the carrier to be completely melted, and dissolving cholic acid and hyodeoxycholic acid with prescribed amounts by alcohol to obtain mixed cholate liquid; slowly adding the mixed cholic acid solution into the carrier, stirring to completely melt, rapidly placing in cold water bath, vigorously stirring to completely solidify, drying to obtain eutectic, pulverizing, and sieving to obtain mixed cholic acid solid dispersion particles.
Preferably, in the step (4), baicalin is dispersed by a solvent-melting method, and the baicalin: mannitol weight ratio = 20: 20-60 parts; further preferably, the method for dispersing baicalin by using a solvent-melting method comprises the following steps:
preparing baicalin into baicalin solution, heating carrier mannitol to completely melt, slowly adding baicalin solution into molten mannitol under stirring, rapidly stirring, and continuously heating and stirring for 1.5-2.5 hr until the mixture is uniform and stable; drying, pulverizing, and sieving to obtain baicalin solid dispersion granule.
Preferably, in step (6), the auxiliary material comprises one or more of sweetener and flavoring agent; wherein the sweetener comprises sucrose, glucose, saccharin sodium, sodium cyclamate, stevioside, aspartame, sucralose, etc.; the flavoring agent comprises menthol, apple essence, cinnamon essence, banana essence, orange oil essence, cinnamaldehyde, ethyl acetate, etc. .
According to the invention, the solid dispersion technology is adopted to disperse the insoluble components of baicalin, cholic acid and hyodeoxycholic acid which generate bitter taste in qingkailing granules in mannitol to form coprecipitate, so that the bitter taste of the qingkailing granules can be covered, and the solubility of the qingkailing granules is increased, thereby improving the bioavailability; meanwhile, the beta-cyclodextrin is adopted to have a cup-shaped annular oligosaccharide, a large number of hydroxyl groups exist outside the molecule, the hydrophilicity is good, the inner cavity is hydrophobic, under the action of Van der Waals force, the beta-cyclodextrin can fully or partially wrap guest medicine molecules into main molecules with a cavity structure, so that the medicine molecules are prevented from directly contacting taste buds, various amino acids generated by the odor and bitter buffalo horn hydrolysis in qingkailing granules are prevented, the beta-cyclodextrin is used for wrapping the medicine molecules in the inner cavity, the medicine molecules are prevented from directly contacting the taste buds, the solubility of the medicines in water is increased, and the prepared qingkailing granules are clear and transparent when being dissolved in water. Finally, the amino acid generated by the hydrolysis of baicalin, cholic acid, hyodesoxycholic acid and buffalo horn in qingkailing granule is coated by solid dispersion technology and beta-cyclodextrin, which avoids the direct contact of the medicine with the outside and increases the stability of the medicine preparation. In addition, the cholic acid, the hyodeoxycholic acid and the baicalin are prepared into solid dispersion, so that compared with the conventional cyclodextrin inclusion, the odor masking effect can be remarkably improved, the odor is greatly reduced, and meanwhile, the preparation stability can be remarkably improved.
The beneficial effects are that: compared with the prior art, the invention improves the prior art, mainly carries out solid dispersion technical treatment and beta cyclodextrin inclusion on the medicine which generates peculiar smell and bitter taste, avoids the direct contact of medicine molecules with taste buds, improves the compliance of the medicine, simultaneously increases the solubility of the medicines in water, and ensures that the prepared qingkailing granule is clear and transparent when dissolved in water. Finally, baicalin, cholic acid and hyodeoxycholic acid in qingkailing granules are dispersed in mannitol to prepare solid dispersion, so that the taste masking effect and stability of the preparation can be remarkably improved. Therefore, the invention has simple process, can further improve the taste, improve the compliance of particles, and further improve the stability, thereby improving the quality of the preparation.
Detailed Description
Examples the present invention will be described in further detail. It should be noted that modifications (e.g., changes in raw material types, amounts, etc.) may be made by those skilled in the art without departing from the principles of the present invention, and such modifications should also be considered as being within the scope of the present invention.
Example 1
Prescription:
12 parts of cholic acid, 200 parts of mother-of-pearl, 15 parts of hyodeoxycholic acid, 100 parts of gardenia,
100 parts of cornu bubali, 800 parts of radix isatidis, 20 parts of baicalin and 240 parts of honeysuckle.
The preparation process comprises the following steps:
(1) Mixing radix Isatidis, fructus Gardeniae and flos Lonicerae, decocting in water for 1 hr each time, mixing extractive solutions, concentrating to fluid extract with relative density of 1.22-1.28 at 80deg.C, and filtering to obtain three-mixed extractive solution.
(2) Grinding cornu Bubali, adding into 4mol/L barium hydroxide solution, decocting for 7 hr, and filtering while hot; adding Concha Margaritifera into 4mol/L sulfuric acid solution, decocting for 7 hr, filtering while it is hot, cooling the filtrate, mixing with cornu Bubali filtrate, filtering, concentrating the filtrate to 2 times of the raw materials, cooling, adding ethanol to make ethanol content reach 60%, stirring, standing for 24 hr, filtering, recovering ethanol from the filtrate, regulating pH to 7 with 20% sodium hydroxide solution, refrigerating, filtering, concentrating the filtrate to relative density of 1.36-1.40 (60deg.C), and mixing with cornu Bubali: mother of pearl: beta cyclodextrin weight ratio = 100:200:100. putting the materials into a reaction tank according to the proportion, setting the temperature at 50 ℃, and the ultrasonic power at 200W for 50min, refrigerating overnight to obtain the mixed hydrolysate, and clathrating the mixed hydrolysate with beta-cyclodextrin by using an ultrasonic method.
(3) Cholic acid: hyodeoxycholic acid: mannitol weight ratio = 13:15:30; firstly, heating mannitol of a carrier to enable the carrier to be completely melted, and dissolving cholic acid and hyodeoxycholic acid with prescribed amounts by using ethanol to obtain mixed cholate liquid; slowly adding the mixed bile acid liquid into a carrier, stirring to completely melt, rapidly placing in a cold water bath at 0-5 ℃ to vigorously stir to completely solidify, placing in a drying box, drying at 50 ℃ for 3 hours to obtain a eutectic, crushing, and sieving with a 80-mesh sieve to obtain the mixed bile acid solid dispersion.
(4) The preparation method comprises the following steps of: mannitol weight ratio = 20:20. adding baicalin into a small amount of water solution, and adjusting pH to 8 with sodium hydroxide solution to dissolve the baicalin; heating carrier mannitol to completely melt, slowly adding baicalin solution into the melt system under stirring, rapidly stirring, and continuously heating and stirring for 2 hr until the mixture is uniform and stable; drying in a constant temperature drying oven at 50deg.C for 2 hr, pulverizing, and sieving with 80 mesh sieve to obtain baicalin solid dispersion.
(5) Mixing the above three mixed extractive solutions with the mixed hydrolysate, and concentrating to obtain QINGKAILING granule five mixed extract.
(6) The qingkailing granule five-mixed extract is uniformly mixed with sucralose, orange oil essence, mixed cholic acid and baicalin solid dispersion, dried and made into granules, thus obtaining the qingkailing granule five-mixed extract.
Example 2
Prescription:
13 parts of cholic acid, 200 parts of mother-of-pearl, 15 parts of hyodeoxycholic acid, 100 parts of gardenia,
100 parts of cornu bubali, 800 parts of radix isatidis, 20 parts of baicalin and 240 parts of honeysuckle.
The preparation process comprises the following steps:
(1) Mixing radix Isatidis, fructus Gardeniae and flos Lonicerae, decocting in water for 1 hr each time, mixing extractive solutions, concentrating to fluid extract with relative density of 1.22-1.28 at 80deg.C, and filtering to obtain three-mixed extractive solution.
(2) Grinding cornu Bubali, adding into 4mol/L barium hydroxide solution, decocting for 7 hr, and filtering while hot; adding Concha Margaritifera into 4mol/L sulfuric acid solution, decocting for 7 hr, filtering while it is hot, cooling the filtrate, mixing with cornu Bubali filtrate, filtering, concentrating the filtrate to 3 times of the raw materials, cooling with ethanol to 60%, stirring, standing for 24 hr, filtering, recovering ethanol from the filtrate, regulating pH to 7 with 20% sodium hydroxide solution, refrigerating, filtering, concentrating the filtrate to relative density of 1.36-1.40 (60deg.C), and mixing with cornu Bubali according to cornu Bubali: mother of pearl: beta cyclodextrin weight ratio = 100:200:400. putting the materials into a reaction tank according to the proportion, setting the temperature to 70 ℃, and carrying out ultrasonic power to 400W for 40min, refrigerating overnight to obtain the beta-cyclodextrin clathrate by using an ultrasonic method, thus obtaining the mixed hydrolysate.
(3) Cholic acid: hyodeoxycholic acid: mannitol weight ratio = 13:15:150; firstly, heating mannitol of a carrier to enable the carrier to be completely melted, and dissolving cholic acid and hyodeoxycholic acid with prescribed amounts by using ethanol to obtain mixed cholate liquid; slowly adding the mixed bile acid liquid into a carrier, stirring to completely melt, rapidly placing in a cold water bath at 0-5 ℃ to vigorously stir to completely solidify, placing in a drying box, drying at 50 ℃ for 3 hours to obtain a eutectic, crushing, and sieving with a 80-mesh sieve to obtain the mixed bile acid solid dispersion.
(4) The preparation method comprises the following steps of: mannitol weight ratio = 20:60. adding baicalin into a small amount of water solution, and adjusting pH to 8 with sodium hydroxide solution to dissolve the baicalin; heating carrier mannitol to completely melt, slowly adding baicalin solution into the melt system under stirring, rapidly stirring, and continuously heating and stirring for 2 hr until the mixture is uniform and stable; drying in a constant temperature drying oven at 50deg.C for 2 hr, pulverizing, and sieving with 80 mesh sieve to obtain baicalin solid dispersion. .
(5) Mixing the above three mixed extractive solutions with the mixed hydrolysate, and concentrating to obtain QINGKAILING granule five mixed extract.
(6) Mixing the qingkailing granule five-mixed extract with aspartame, menthol, apple essence, mixed cholic acid and baicalin solid dispersion, drying, and granulating.
Example 3
Prescription:
13 parts of cholic acid, 200 parts of mother-of-pearl, 15 parts of hyodeoxycholic acid, 100 parts of gardenia,
100 parts of cornu bubali, 800 parts of radix isatidis, 20 parts of baicalin and 240 parts of honeysuckle.
The preparation process comprises the following steps:
(1) Mixing radix Isatidis, fructus Gardeniae and flos Lonicerae, decocting in water for 1 hr each time, mixing extractive solutions, concentrating to fluid extract with relative density of 1.22-1.28 at 80deg.C, and filtering to obtain three-mixed extractive solution.
(2) Grinding cornu Bubali, adding into 4mol/L barium hydroxide solution, decocting for 7 hr, and filtering while hot; adding Concha Margaritifera into 4mol/L sulfuric acid solution, decocting for 7 hr, filtering while it is hot, cooling the filtrate, mixing with cornu Bubali filtrate, filtering, concentrating the filtrate to 2 times of the raw materials, cooling, adding ethanol to 60%, stirring, standing for 24 hr, filtering, recovering ethanol from the filtrate, regulating pH to 7 with 20% sodium hydroxide solution, refrigerating, filtering, concentrating the filtrate to relative density of 1.36-1.40 (60deg.C), and mixing with cornu Bubali according to the ratio of cornu Bubali: mother of pearl: beta cyclodextrin weight ratio = 100:200:250. putting the materials into a reaction tank according to the proportion, setting the temperature to be 60 ℃, and the ultrasonic power to be 300W for 45min, refrigerating overnight to obtain the beta-cyclodextrin clathrate by using an ultrasonic method, thus obtaining the mixed hydrolysate.
(3) Cholic acid: hyodeoxycholic acid: mannitol weight ratio = 13:15:90; firstly, heating mannitol of a carrier to enable the carrier to be completely melted, and dissolving cholic acid and hyodeoxycholic acid with prescribed amounts by using ethanol to obtain mixed cholate liquid; slowly adding the mixed bile acid liquid into a carrier, stirring to completely melt, rapidly placing in a cold water bath at 0-5 ℃ to vigorously stir to completely solidify, placing in a drying box, drying at 50 ℃ for 3 hours to obtain a eutectic, crushing, and sieving with a 80-mesh sieve to obtain the mixed bile acid solid dispersion.
(4) The preparation method comprises the following steps of: mannitol weight ratio = 20:40. adding baicalin into a small amount of water solution, and adjusting pH to 8 with sodium hydroxide solution to dissolve the baicalin; heating carrier mannitol to completely melt, slowly adding baicalin solution into the melt system under stirring, rapidly stirring, and continuously heating and stirring for 2 hr until the mixture is uniform and stable; drying in a constant temperature drying oven at 50deg.C for 2 hr, pulverizing, and sieving with 80 mesh sieve to obtain baicalin solid dispersion.
(5) Mixing the above three mixed extractive solutions with the mixed hydrolysate, and concentrating to obtain QINGKAILING granule five mixed extract.
(6) Mixing the qingkailing granule five-mixed extract with sucrose powder, mixed cholic acid and baicalin solid dispersion, drying, and granulating.
Comparative example 1
Prescription:
13 parts of cholic acid, 200 parts of mother-of-pearl, 15 parts of hyodeoxycholic acid, 100 parts of gardenia,
100 parts of cornu bubali, 800 parts of radix isatidis, 20 parts of baicalin and 240 parts of honeysuckle.
The preparation process comprises the following steps:
(1) Mixing radix Isatidis, fructus Gardeniae and flos Lonicerae, decocting in water for 1 hr each time, mixing extractive solutions, concentrating to fluid extract with relative density of 1.22-1.28 at 80deg.C, and filtering to obtain three-mixed extractive solution.
(2) Grinding cornu Bubali, adding into 4mol/L barium hydroxide solution, decocting for 7 hr, and filtering while hot; adding Concha Margaritifera into 4mol/L sulfuric acid solution, decocting for 7 hr, filtering, cooling the filtrate, mixing with cornu Bubali filtrate, filtering, concentrating the filtrate to 2 times of the amount of the raw materials, cooling with ethanol to 60%, stirring, standing for 24 hr, filtering, recovering ethanol from the filtrate, regulating pH to 7 with 20% sodium hydroxide solution, refrigerating, filtering, concentrating the filtrate to relative density of 1.36-1.40 (60deg.C), and mixing the hydrolyzed solution;
(3) Firstly, preparing the beta-cyclodextrin and water into a saturated aqueous solution, then adding cholic acid and hyodeoxycholic acid which are dissolved in a prescription amount and are adjusted to have a pH value of 8-9 by using a 40% sodium hydroxide solution, stirring for 0.5 hours at the temperature of 80 ℃, and then refrigerating at the temperature of 0-5 ℃ to obtain mixed cholate liquid;
(4) The preparation method comprises the following steps of: beta cyclodextrin weight ratio = 20:30. grinding beta-cyclodextrin and 3 times of water, adding baicalin, grinding into paste, vacuum filtering, and drying to obtain baicalin clathrate;
(5) Uniformly mixing the three mixed solutions with the mixed hydrolysate and the mixed bile acid solution, and concentrating to obtain qingkailing granule seven mixed extract;
(6) And finally, uniformly mixing the qingkailing granule seven mixed extract with sucrose powder and baicalin inclusion compound, drying, and granulating to obtain the qingkailing granule seven mixed extract.
Comparative example 2
Prescription:
13 parts of cholic acid, 200 parts of mother-of-pearl, 15 parts of hyodeoxycholic acid, 100 parts of gardenia,
100 parts of cornu bubali, 800 parts of radix isatidis, 20 parts of baicalin and 240 parts of honeysuckle.
The preparation process comprises the following steps:
(1) Mixing radix Isatidis, fructus Gardeniae and flos Lonicerae, decocting in water for 1 hr each time, mixing extractive solutions, concentrating to fluid extract with relative density of 1.22-1.28 at 80deg.C, and filtering to obtain three-mixed extractive solution.
(2) Grinding cornu Bubali, adding into 4mol/L barium hydroxide solution, decocting for 7 hr, and filtering while hot; adding Concha Margaritifera into 4mol/L sulfuric acid solution, decocting for 7 hr, filtering while it is hot, cooling the filtrate, mixing with cornu Bubali filtrate, filtering, concentrating the filtrate to 2 times of the raw materials, cooling, adding ethanol to make ethanol content reach 60%, stirring, standing for 24 hr, filtering, recovering ethanol from the filtrate, regulating pH to 7 with 20% sodium hydroxide solution, refrigerating, filtering, concentrating the filtrate to relative density of 1.36-1.40 (60deg.C), and mixing with cornu Bubali: mother of pearl: beta cyclodextrin weight ratio = 100:200:250. putting the materials into a reaction tank according to the proportion, setting the temperature to be 60 ℃, and the ultrasonic power to be 300W for 45min, refrigerating overnight to obtain the mixed hydrolysate, and clathrating the mixed hydrolysate with beta-cyclodextrin by using an ultrasonic method;
(3) Firstly, preparing the beta-cyclodextrin and water into a saturated aqueous solution, then adding cholic acid and hyodeoxycholic acid which are dissolved in a prescription amount and are adjusted to have a pH value of 8-9 by using a 40% sodium hydroxide solution, stirring for 0.5 hours at the temperature of 80 ℃, and then refrigerating at the temperature of 0-5 ℃ to obtain mixed cholate liquid;
(4) Uniformly mixing the three mixed solutions with the mixed hydrolysate and the mixed bile acid solution, and concentrating to obtain qingkailing granule seven mixed extract;
(5) Finally, the qingkailing granule seven mixed extract is evenly mixed with sucrose powder and baicalin, dried and made into granules, thus obtaining the qingkailing granule seven mixed extract.
Comparative example 3
Prescription:
13 parts of cholic acid, 200 parts of mother-of-pearl, 15 parts of hyodeoxycholic acid, 100 parts of gardenia,
100 parts of cornu bubali, 800 parts of radix isatidis, 20 parts of baicalin and 240 parts of honeysuckle.
The preparation process comprises the following steps:
(1) Decocting three materials including radix Isatidis, fructus Gardeniae and flos Lonicerae with water twice for 1 hr each time, filtering, mixing filtrates, concentrating to obtain fluid extract with relative density of 1.22-1.28 at 80deg.C, and filtering to obtain three mixed extractive solutions;
(2) Grinding cornu Bubali, adding into 4mol/L barium hydroxide solution, decocting for 7 hr, and filtering while hot; adding Concha Margaritifera into 4mol/L sulfuric acid solution, decocting for 7 hr, filtering while it is hot, cooling the filtrate, mixing with cornu Bubali filtrate, filtering, concentrating the filtrate to 2 times of the raw materials, cooling, adding ethanol to make ethanol content reach 60%, stirring, standing for 24 hr, filtering, recovering ethanol from the filtrate, regulating pH to 7 with 20% sodium hydroxide solution, refrigerating, filtering, concentrating the filtrate to relative density of 1.36-1.40 (60deg.C), and mixing with cornu Bubali: mother of pearl: beta cyclodextrin weight ratio = 100:200:250. putting the materials into a reaction tank according to the proportion, setting the temperature to be 60 ℃, and the ultrasonic power to be 300W for 45min, refrigerating overnight to obtain the mixed hydrolysate, and clathrating the mixed hydrolysate with beta-cyclodextrin by using an ultrasonic method;
(3) Firstly, preparing the beta-cyclodextrin and water into a saturated aqueous solution, then adding cholic acid and hyodeoxycholic acid which are dissolved in a prescription amount and are adjusted to have a pH value of 8-9 by using a 40% sodium hydroxide solution, stirring for 0.5 hours at the temperature of 80 ℃, and then refrigerating at the temperature of 0-5 ℃ to obtain mixed cholate liquid;
(4) The preparation method comprises the following steps of: beta cyclodextrin weight ratio = 20:30. grinding beta-cyclodextrin and 3 times of water, adding baicalin, grinding into paste, vacuum filtering, and drying to obtain baicalin clathrate;
(5) Mixing the above three mixed extractive solutions with the mixed hydrolysate, mixed bile acid solution and baicalin clathrate, and concentrating to obtain QINGKAILING granule seventh mixed extract;
(6) And finally, uniformly mixing the qingkailing granule seven mixed extract with sucrose powder, drying, and granulating to obtain the qingkailing granule seven mixed extract.
Experimental example particle stability investigation
1. Method for measuring component in particles
1. Baicalin is measured by high performance liquid chromatography.
The chromatographic condition and system applicability test uses octadecylsilane chemically bonded silica as filler; methanol-water-glacial acetic acid (45:55:1) is taken as a mobile phase; the detection wavelength was 274nm. The theoretical plate number should be not less than 3000 calculated according to baicalin peak.
Preparation of control solution baicalin control, precisely weighing, and adding 50% methanol to obtain solution containing 0.1mg per 1 ml.
The preparation of the sample solution comprises taking the sample under different loading amounts, mixing, grinding, taking about 1.5g, precisely weighing, placing in a 100ml measuring flask, adding 50% methanol 80ml, ultrasonic treating (power 180W, frequency 40 kHz) for 15 min, cooling, adding 50% methanol to scale, shaking, filtering, and collecting the filtrate.
Precisely sucking 5 μl of each of the reference solution and the sample solution by the assay method, and injecting into a liquid chromatograph for assay.
Each bag of the product contains baicalin (C) 21 H 18 O 11 ) 18.2 to 21.8mg.
2. Cholic acid high performance liquid chromatography.
The chromatographic condition and system applicability test uses octadecylsilane chemically bonded silica as filler; methanol-1% acetic acid solution (75:25) is used as mobile phase; detected with an evaporative light scattering detector. The theoretical plate number is not lower than 8000 calculated according to cholic acid peak.
Preparing reference solution, precisely weighing appropriate amount of cholic acid reference, and adding methanol to obtain solution containing 0.2mg per 1 ml.
The preparation of the sample solution comprises the steps of taking the sample under different loading amounts, uniformly mixing, taking a proper amount, grinding, taking about 2g, precisely weighing, placing in a 50ml measuring flask, precisely adding 25ml of water, shaking to dissolve, adding 20ml of methanol, performing ultrasonic treatment (power is 180W and frequency is 40 kHz) for 30 minutes, cooling, adding methanol to a scale, shaking uniformly, filtering, and taking the subsequent filtrate.
The measuring method precisely absorbs 10 mu l and 20 mu l of reference substance solution and 20 mu l of test substance solution, and the method comprises the steps of injecting the reference substance solution and the 20 mu l of test substance solution into a liquid chromatograph, measuring, and calculating by using a two-point external standard method logarithmic equation.
Each bag of the product contains cholic acid (C) 24 H 40 O 5 ) 10.6 to 15.4mg.
3. The fructus Gardeniae is measured by high performance liquid chromatography.
The chromatographic condition and system applicability test uses octadecylsilane chemically bonded silica as filler; acetonitrile-water (11:89) as mobile phase; the detection wavelength was 238nm. The theoretical plate number should be not less than 3000 calculated by gardenoside peak.
Preparation of reference solution A proper amount of gardenoside reference is taken, precisely weighed, and 50% methanol is added to prepare a solution containing 30 mug per 1 ml.
The preparation of the sample solution comprises taking the sample under different loading amounts, mixing, grinding, taking about 0.8g, precisely weighing, placing into a conical flask with a plug, precisely adding 25ml of 50% methanol, sealing, weighing, ultrasonic treating (power 180W, frequency 40 kHz) for 20 min, cooling, weighing again, supplementing the lost weight with 50% methanol, shaking, filtering, and collecting the filtrate.
The measurement method precisely absorbs 10 mu l of each of the reference substance solution and the test substance solution, and the solution is injected into a liquid chromatograph for measurement, thus obtaining the product.
Each bag of the product contains gardenoside (C) 17 H 24 O 10 ) And not less than 1.2mg.
4. Total nitrogen determination
Mixing the above materials under different loading amounts, grinding, collecting 0.3g, precisely weighing, and measuring by nitrogen measurement method.
The total nitrogen (N) content of each bag of the product is 11.2-14.8 mg.
2. Acceleration test
1. Method of
3 parallel test samples (100 bags per batch, 3 g/bag) were taken for each group of particles, and placed at 40 ℃ ± 2 ℃ for 6 months at 75% ± 5% relative temperature, and the true temperature and humidity were monitored. During the test period, the samples are respectively sampled 1 time at the end of the 0 th month, the 1 st month, the 2 nd month, the 3 rd month and the 6 th month, and the detection is carried out according to the stability important investigation project. The method for measuring the content of each component is as described in the first item.
2. Results
Each time point is 3 batches of samples, 10 bags of samples are sampled for detection, and the average value of the measurement results is calculated, so that the following results are obtained:
as can be obtained from the above table, example 3 is a novel preparation process of the present invention, and comparative example 1 is that only baicalin is included by beta cyclodextrin in the mixed hydrolysate of cornu bubali and mother-of-pearl and baicalin; comparative example 2 is that only the mixed hydrolysate of buffalo horn and mother-of-pearl was included with beta cyclodextrin in the mixed hydrolysate of buffalo horn and mother-of-pearl and baicalin; comparative example 3 is that the mixed hydrolysate of cornu Bubali and Concha Margaritifera and baicalin are both coated with betacyclodextrin. From the results, at 0 month, the solubility and the clarity and the content of the effective components of the four groups are not obviously different, and all meet the quality standard, but the smell of the comparative example 1 is fishy, and the protein, the polypeptide and the amino acid generated by the hydrolysis and the hydrolysis of buffalo horn do not have cyclodextrin inclusion; comparative example 2, having a bitter taste due to the bitter taste of baicalin; the granule prepared in comparative example 3 has a good taste masking effect, but has slight fishy bitter taste, while the granule prepared in example 3 of the invention has moderate taste and completely eliminates the fishy bitter taste. At the end of 6 months, the granules of comparative examples 1, 2 and 3 had significantly poorer solubility and clarity, and the content of baicalin as an active ingredient was significantly reduced, as compared with the granules at 0 month. The qingkailing granule prepared by the novel process of the embodiment 3 has moderate taste, and has no obvious difference with the granule prepared by the novel process of the embodiment of the invention in the end of 6 months in terms of solubility and clarity and content of active ingredients.
3. Long-term test
1. Method of
3 batches of parallel experimental samples (100 bags per batch, 3 g/bag) are taken from each group of particles, the particles are placed for 24 months under the conditions of 30+/-2 ℃ and 65+/-5% of relative humidity, 1 time is taken every 3, 6 or 12 months, and the particles are taken for 0, 3, 6, 9, 12, 18 and 24 months respectively, and the projects are inspected and detected according to the stability emphasis. The method for measuring the content of each component is as described in the first item.
2. Results
Each time point is 3 batches of samples, 10 bags of samples are sampled for detection, and the average value of the measurement results is calculated, so that the following results are obtained:
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as can be obtained from the above table, example 3 is a novel preparation process of the present invention, and comparative example 1 is that only baicalin is included by beta cyclodextrin in the mixed hydrolysate of cornu bubali and mother-of-pearl and baicalin; comparative example 2 is that only the mixed hydrolysate of buffalo horn and mother-of-pearl was included with beta cyclodextrin in the mixed hydrolysate of buffalo horn and mother-of-pearl and baicalin; comparative example 3 is that the mixed hydrolysate of cornu Bubali and Concha Margaritifera and baicalin are both coated with betacyclodextrin. From the results, at 0 month, the solubility and the clarity and the content of the effective components of the four groups are not obviously different, and all meet the quality standard, but the smell of the comparative example 1 is fishy, and the protein, the polypeptide and the amino acid generated by the hydrolysis of buffalo horn are not included by cyclodextrin; comparative example 2, having a bitter taste due to the bitter taste of baicalin; the granule prepared in comparative example 3 has a good taste masking effect, but has slight fishy bitter taste, while the granule prepared in example 3 of the invention has moderate taste and completely eliminates the fishy bitter taste. Starting from the end of 12 months, the granules of comparative examples 1, 2 and 3 gradually become less soluble and the active ingredient content gradually decreases. By the end of 24 months, the granules of comparative examples 1, 2 and 3 had significantly poorer solubility and clarity and significantly lower active ingredient content than at 0 month. The qingkailing granule prepared by the novel process of the embodiment 3 has no obvious difference with the granule prepared by the novel process of the embodiment at the end of 24 months in terms of solubility and clarity and content of active ingredients.
Claims (6)
1. The preparation process of the traditional Chinese medicine compound granule is characterized by comprising the following steps of:
(1) Decocting radix Isatidis, fructus Gardeniae and flos Lonicerae in water, filtering decoction, and mixing filtrates to obtain three mixed extractive solutions;
(2) Decocting cornu Bubali and Concha Margaritifera respectively, filtering, mixing the two filtrates, and clathrating with cyclodextrin to obtain mixed hydrolysate;
(3) Dispersing cholic acid and hyodeoxycholic acid by mannitol to obtain mixed cholic acid dispersed powder or granule;
(4) Dispersing baicalin with mannitol to obtain baicalin dispersed powder or granule;
(5) Uniformly mixing the three mixed extract and the mixed hydrolysate, and concentrating to obtain a five mixed extract;
(6) Finally, mixing the five mixed extractum with mixed cholic acid and baicalin dispersed powder or granules, adding auxiliary materials, drying and granulating to obtain the finished product;
in the step (3), cholic acid and hyodeoxycholic acid are dispersed by a solvent-melting method, and cholic acid: mannitol weight ratio = 13: 30-150;
the method for dispersing cholic acid and hyodeoxycholic acid by using the solvent-melting method comprises the following steps:
firstly, heating mannitol of a carrier to enable the carrier to be completely melted, and dissolving cholic acid and hyodeoxycholic acid with prescribed amounts by alcohol to obtain mixed cholate liquid; slowly adding the mixed cholic acid solution into the carrier, stirring to completely melt, rapidly placing in a cold water bath, vigorously stirring to completely solidify, drying to obtain eutectic, pulverizing, and sieving to obtain mixed cholic acid dispersion particles;
in the step (4), baicalin is dispersed by a solvent-melting method, and the baicalin is dispersed by a solvent-melting method: mannitol weight ratio = 20: 20-60 parts; the method for dispersing baicalin by adopting a solvent melting method comprises the following steps of:
preparing baicalin into baicalin solution, heating carrier mannitol to completely melt, slowly adding the baicalin solution into molten mannitol while stirring, rapidly stirring, and continuously heating and stirring for 1.5-2.5h until the mixture is uniform and stable; drying, pulverizing, and sieving to obtain baicalin dispersible granule;
in the traditional Chinese medicine compound granule, the weight parts of cholic acid, mother-of-pearl, hyodeoxycholic acid, gardenia, cornu bubali, radix isatidis, baicalin and honeysuckle are as follows:
13+ -1 parts of cholic acid, 200+ -5 parts of mother-of-pearl, 15+ -1 parts of hyodeoxycholic acid, 100+ -3 parts of gardenia,
100+ -3 parts of cornu bubali, 800+ -20 parts of radix isatidis, 20+ -1 parts of baicalin and 240+ -5 parts of honeysuckle.
2. The preparation process of the traditional Chinese medicine compound granule according to claim 1, wherein the traditional Chinese medicine compound granule comprises the following components in parts by weight:
13 parts of cholic acid, 200 parts of mother-of-pearl, 15 parts of hyodeoxycholic acid, 100 parts of gardenia,
100 parts of cornu bubali, 800 parts of radix isatidis, 20 parts of baicalin and 240 parts of honeysuckle.
3. The preparation process of the traditional Chinese medicine compound granule according to claim 1, wherein in the step (1), the radix isatidis, the gardenia and the honeysuckle are mixed, decocted and extracted for 2-3 times by adding water for 0.5-1h each time, the extracting solutions are combined, concentrated to clear paste with the relative density of 1.22-1.28 at 80 ℃, and filtered, thus obtaining the three-mixed extracting solution.
4. The process for preparing the compound Chinese medicinal particles according to claim 1, wherein in the step (2), cornu bubali is ground into powder, added into alkaline solution, decocted for 6-8 h and filtered when the powder is hot; adding Concha Margaritifera into acidic solution, decocting for 6-8 hr, filtering while it is hot, cooling the filtrate, mixing with cornu Bubali filtrate, concentrating, precipitating with ethanol, refrigerating, filtering, concentrating again, and clathrating with beta-cyclodextrin by ultrasonic method to obtain mixed hydrolysate.
5. The process for preparing the compound Chinese medicinal particles according to claim 4, wherein the alkaline solution is selected from barium hydroxide solution; the acidic solution is selected from sulfuric acid solution; the method for clathrating the beta-cyclodextrin by utilizing the ultrasonic method comprises the following steps of:
calculating the dosage of the beta cyclodextrin according to the dosage of the buffalo horn raw material, wherein the buffalo horn is: beta cyclodextrin weight ratio = 100: 100-400, feeding, setting the temperature to be 50-70 ℃, and the ultrasonic power to be 200-400W for 40-50min, and refrigerating overnight to obtain the product.
6. The process for preparing compound Chinese medicinal particles according to claim 1, wherein in the step (6), the auxiliary materials comprise one or more of sweetener and aromatic; wherein the sweetener comprises sucrose, glucose, saccharin sodium, sodium cyclamate, stevioside, aspartame or sucralose; the flavoring agent comprises menthol, apple essence, cinnamon essence, banana essence, orange oil essence, cinnamaldehyde or ethyl acetate.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1247078A (en) * | 1999-04-12 | 2000-03-15 | 中外合资哈尔滨一洲制药有限公司 | Process for preparing medical particles Qingkailing by wrapping chololic acid and animal extract with cyclodextrin |
| CN1861131A (en) * | 2005-05-13 | 2006-11-15 | 康国忠 | Qingkailing dixinwan pill prepn. and its prepn. method |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1247078A (en) * | 1999-04-12 | 2000-03-15 | 中外合资哈尔滨一洲制药有限公司 | Process for preparing medical particles Qingkailing by wrapping chololic acid and animal extract with cyclodextrin |
| CN1861131A (en) * | 2005-05-13 | 2006-11-15 | 康国忠 | Qingkailing dixinwan pill prepn. and its prepn. method |
Non-Patent Citations (1)
| Title |
|---|
| 奉建芳主编."中药制剂半成品的固体分散技术".《现代中药制剂设计》.中国医药科技出版社,2020,(第1版),282-284页. * |
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