A preparation method of a general-purpose capsule with reduced harmful impurities and improved overall stability

Abstract

The application discloses a preparation method of a general-purpose capsule with reduced harmful impurities and improved overall stability, and belongs to the technical field of traditional Chinese medicine preparations. S1, formula amount of picrorhiza scrophulariiflora, coptis, catechu and fragrant ink are mixed and crushed into fine powder to form a mixture one, sugar powder is added into the mixture one and stirred and mixed uniformly to form a mixture two; borneol and artificial musk are mixed and finely ground to form a mixture three; S2, bovine bile is boiled for 10-30 min, filtered, and a filtrate is obtained; S3, a stabilizing agent is added into the filtrate, and the amount of the stabilizing agent is adjusted to pH 7.2-7.8; S4, formula amount of bear bile powder and ox gall are added into the filtrate adjusted in S3 to form a mixture four; S5, the mixture two is added into the mixture four to form a mixture five, and an ethanol aqueous solution is further added, and the mixture is granulated, dried, and screened by a granulator to obtain intermediate granules; S6, the mixture three and the intermediate granules are uniformly mixed, packaged, and filled into capsules to obtain the general-purpose capsule. The general-purpose capsule has reduced harmful impurities and improved overall stability.

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine preparations, and in particular to a method for preparing Wanying Capsules that reduces harmful impurities and improves overall stability. Background Technology

[0002] Wanying Capsules are made from Coptis chinensis, Coptis chinensis, catechu, cinnamon, ox bile, bezoar, bear bile powder, borneol, and artificial musk. They have the effects of clearing heat, detoxifying, and calming the nerves. They are used for oral ulcers, swollen gums and throat, high fever in children, and irritability caused by internal accumulation of pathogenic toxins.

[0003] CN115463175A discloses a method for preparing a universal capsule, comprising the following steps: S1, pulverizing Coptis chinensis, catechu, and cinnamon into fine powder, then adding bezoar and mixing well to obtain a fine powder composition; S2, dissolving bear bile powder in water to obtain a bear bile powder aqueous solution, concentrating the bezoar, filtering, and obtaining bezoar paste; S3, mixing the bezoar paste with the bear bile powder aqueous solution, adding it to the fine powder composition, mixing and stirring to form uniformly sized particles; S4, grinding the cooling composition, mixing it with the particles obtained in step 3, and filling it into capsules to obtain the product.

[0004] Although CN115463175A has good heat-clearing and detoxifying effects, the purpose of concentrating bovine bile in CN115463175A is twofold: firstly, to inactivate the drug, and secondly, to remove excess water. However, the concentration in CN115463175A under reduced pressure at 50℃~90℃ (preferably 60℃~70℃) to a specific gravity of 1.2g / mL leads to the following shortcomings:

[0005] (1) The inactivation temperature is low and the pressure is reduced, resulting in incomplete inactivation. Some viruses, such as swine fever virus, are not completely inactivated (see CN116785460A Example 1).

[0006] (2) The concentration time is relatively long. It takes at least 2 hours to concentrate the ox bile to a specific gravity of 1.2 g / mL in a vacuum concentration tank. The long time means that the effective substances in the ox bile will be transformed or evaporated under the heat environment for a long time, thereby reducing the efficacy and resulting in higher levels of harmful components such as free bilirubin.

[0007] (3) The lack of system stabilization measures leads to decreased stability after long-term storage, with a decrease in effective components such as bilirubin and an increase in harmful components such as free bilirubin.

[0008] The above background information is provided to facilitate understanding of the present invention and is not intended to be publicly known technology disclosed to the general public prior to the application of this invention. Summary of the Invention

[0009] To address the aforementioned deficiencies, this invention provides a method for preparing a universal capsule that reduces harmful impurities and improves overall stability, aiming to improve at least one of the problems mentioned in the background art.

[0010] The technical solution is: a method for preparing a universal capsule that reduces harmful impurities and improves overall stability, comprising the following steps:

[0011] S1. Mix and grind the prescribed amounts of Coptis chinensis, Coptis chinensis, catechu, and cinnamon into a fine powder to form mixture one. Add powdered sugar to mixture one and stir well to form mixture two. Mix and grind borneol and artificial musk into a fine powder to form mixture three.

[0012] S2, Boil the ox bile for 10 to 30 minutes, filter, and obtain the filtrate;

[0013] S3, Add a pH adjuster to the filtrate, the amount of which is enough to adjust the pH of the filtrate to 7.2~7.8;

[0014] S4, add the prescribed amount of bear bile powder and bezoar to the filtrate adjusted in S3 to form mixture four;

[0015] S5, add mixture 2 to mixture 4 to form mixture 5, then add ethanol aqueous solution, and granulate, dry, sizing and sieve through a granulator to obtain intermediate granules;

[0016] S6. Mix the mixture with the intermediate particles, divide into portions, fill into capsules, and make Wanying Capsules.

[0017] The formula for Wanying Capsules is as follows:

[0018] Coptis chinensis 50-65 parts by weight, Picrorhiza scrophulariiflora 50-65 parts by weight, Catechu 50-65 parts by weight, Scented ink 105-125 parts by weight, Bear bile powder 10.2-12 parts by weight, Calculus bovis 2-3.5 parts by weight, Ox bile 80-98 parts by weight, Borneol 3-4 parts by weight, Artificial musk 2-3.5 parts by weight;

[0019] The mass fraction is one of grams, kilograms, thousand kilograms, or ten thousand kilograms.

[0020] Furthermore, in S1, the particle size of mixture one is 160μm~175μm; the amount of sugar powder added is 550 parts by weight~650 parts by weight; borneol and artificial musk are mixed, ground, and sieved through a 50-70 mesh sieve.

[0021] Furthermore, in S2, boiling is performed at atmospheric pressure.

[0022] Furthermore, in S4, the bezoar is cultured in vitro with a particle size of 160μm~175μm.

[0023] Furthermore, in the ethanol-water solution in S5, the amount of ethanol is 150 to 200 parts by weight, and the amount of purified water is the amount that minimizes the water activity of the system while ensuring molding.

[0024] Furthermore, in S5, the drying temperature is 50℃~60℃, granulation is performed by installing a 10-mesh stainless steel screen on a gyratory pellet mill, and sieving is performed by installing 10-mesh and 80-mesh stainless steel screens on a gyratory pellet mill.

[0025] Furthermore, in S3, the regulating stabilizer is an organic base.

[0026] Furthermore, the organic base is one of L-arginine hydrochloride, L-arginine, or L-lysine.

[0027] Furthermore, in S3, the regulating stabilizer is an inorganic base.

[0028] Furthermore, the inorganic base is sodium bicarbonate.

[0029] Compared with the prior art, the principles and beneficial effects of the present invention are as follows:

[0030] Because bilirubin has clear pharmacological activities (antioxidant, anti-inflammatory, etc.), it is an effective ingredient in Wan Ying Capsules. The raw materials of Wan Ying Capsules, such as ox bile, bezoar, and bear bile powder, all contain bilirubin.

[0031] However, free bilirubin (indirect bilirubin) in the blood can detach from albumin and penetrate the blood-brain barrier that protects the brain. Once in the brain, free bilirubin can deposit and interfere with the energy metabolism and function of nerve cells, leading to kernicterus and causing irreversible brain damage (manifested as intellectual disability, motor disorders, hearing loss, etc.). Therefore, free bilirubin is a clear neurotoxin.

[0032] Non-free bilirubin (direct bilirubin) cannot freely penetrate cell membranes and the blood-brain barrier. It is excreted by hepatocytes into tiny bile ducts and becomes one of the main pigment components of bile. When bile enters the intestines, non-free bilirubin is converted into urobilinogen and stercobilin by intestinal bacteria. Most of it is excreted with feces (making feces yellow), and a small portion is reabsorbed.

[0033] Therefore, the detection of both bilirubin and free bilirubin is indispensable in the quality testing of Wanying Capsules.

[0034] The inventors of this invention discovered that by replacing the concentration of ox bile in the existing technology with boiling, adding bear bile powder before boiling, adding a regulator and stabilizer to the ox bile after boiling, adding bezoar to the ox bile, and then adding a mixture of Coptis chinensis, Coptis chinensis, catechu, and sesame oil to the ox bile and mixing them thoroughly, a protective system is formed for the Wan Ying capsules during preparation and storage. This not only improves the efficacy of the Wan Ying capsules and reduces harmful impurities in the finished Wan Ying capsules, but also forms a stable protective system for the Wan Ying capsules, improving their overall stability.

[0035] The inventors of this invention have also discovered that L-arginine hydrochloride is particularly suitable as a regulating stabilizer for Wan Ying capsules. Detailed Implementation

[0036] As used in this article:

[0037] "Prepared from" is synonymous with "comprising". The terms "comprising", "including", "having", "containing", or any other variations thereof as used herein are intended to cover non-exclusive inclusion. For example, a composition, step, method, article, or apparatus that includes the listed elements is not necessarily limited to those elements, but may include other elements not expressly listed or elements inherent to such composition, step, method, article, or apparatus.

[0038] When a quantity, concentration, or other value or parameter is expressed as a range, a preferred range, or a range defined by a series of upper and lower preferred values, this should be understood as specifically disclosing all ranges formed by any pair of any upper or preferred value with any lower or preferred value, regardless of whether the range is disclosed individually. For example, when the range “1–5” is disclosed, the described range should be interpreted as including ranges “1–4”, “1–3”, “1–2”, “1–2 and 4–5”, “1–3 and 5”, etc. When numerical ranges are described herein, unless otherwise stated, the range is intended to include its endpoints and all integers and fractions within that range.

[0039] The technical solution of the present invention will be clearly and completely described below with reference to embodiments and comparative examples. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0040] Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be construed as limiting the scope of this application. Unless otherwise specified in the embodiments and comparative examples, specific conditions were applied under conventional conditions or conditions recommended by the manufacturer. Materials or instruments used without a specified manufacturer are all commercially available products. All materials used in the following embodiments and comparative examples were purchased from the same batch.

[0041] In these embodiments, unless otherwise specified, the portions and percentages are all by weight.

[0042] "Parts by mass" refers to the basic unit of measurement that expresses the mass ratio of multiple components. One part can represent any unit mass, such as 1g or 2.689g. If we say that component A has "a" parts by mass and component B has "b" parts by mass, it means the ratio of the mass of component A to the mass of component B is a:b. Alternatively, it can mean that the mass of component A is aK and the mass of component B is bK (K is any number representing a multiplier). It is important to understand that, unlike the number of parts by mass, the sum of the mass parts of all components is not limited to 100 parts.

[0043] "And / or" is used to indicate that one or both of the described situations may occur, for example, A and / or B includes (A and B) and (A or B).

[0044] In the following examples and comparative examples, the specification of Wanying Capsules is 0.3g / capsule.

[0045] Example 1

[0046] The formula for Wanying Capsules is as follows: 54 parts by weight of Coptis chinensis, 54 parts by weight of Picrorhiza scrophulariiflora, 54 parts by weight of catechu, 108 parts by weight of cinnamon ink, 10.8 parts by weight of bear bile powder, 2.7 parts by weight of in vitro cultured bezoar, 87 parts by weight of ox bile, 3.3 parts by weight of borneol, and 2.7 parts by weight of artificial musk.

[0047] A method for preparing a panacea capsule that reduces harmful impurities and improves overall stability includes the following steps:

[0048] S1. Mix and grind Coptis chinensis, Coptis chinensis, catechu and cinnamon into fine powder to form mixture one, with a particle size of 175μm; add 607.5 parts by weight of sugar powder to mixture one, stir and mix well to form mixture two; mix and grind borneol and artificial musk into fine powder, and then sieve through a 60-mesh sieve to form mixture three.

[0049] S2, Boil the ox bile for 30 minutes, filter, and obtain the filtrate.

[0050] This step is carried out in a vacuum concentrator, but it is done at atmospheric pressure.

[0051] In this step, within 30 minutes, the time for the ox bile to go from room temperature to boiling is 15 minutes.

[0052] S3, add L-arginine hydrochloride to the filtrate as a regulating stabilizer. The amount of L-arginine hydrochloride added is enough to adjust the pH of the filtrate to 7.5.

[0053] S4. Add bear bile powder and in vitro cultured bezoar to the filtrate adjusted in S3, stir and mix well to form mixture four, wherein the particle size of the in vitro cultured bezoar is 175μm.

[0054] S5. Add mixture 2 to mixture 4, mix well to form mixture 5, then add ethanol aqueous solution, stir, and process into granules using a granulator, dry, granulate, and sieve to obtain intermediate granules.

[0055] In this step, the drying temperature is 55℃. Granulation is performed using a gyratory pellet mill with a 10-mesh stainless steel screen, and sieving is performed using a gyratory pellet mill with 10-mesh and 80-mesh stainless steel screens.

[0056] In the ethanol-water solution, the amount of ethanol is 181 parts by weight, and the amount of purified water is just enough to ensure the formation while minimizing the water activity of the system.

[0057] S6. Mix the mixture with the intermediate particles, divide the mixture into portions, fill the portions into capsules, and make 1000 capsules of Wanying.

[0058] Example 2

[0059] Compared with Example 1, the difference is that in S3, L-arginine is used instead of L-arginine hydrochloride in Example 1.

[0060] Example 3

[0061] The difference compared to Example 2 is that in S3, pH=7.2.

[0062] Example 4

[0063] The difference compared to Example 2 is that in S3, pH=7.8.

[0064] Example 5

[0065] The difference from Example 2 is that in S3, L-arginine in Example 2 is replaced with L-lysine.

[0066] Example 6

[0067] The difference from Example 2 is that in S3, sodium bicarbonate is used instead of L-arginine in Example 2.

[0068] Comparative Example 1

[0069] Compared with Example 2, the difference is that S3 is omitted, that is, S4 is directly entered after S2, the filtrate is not adjusted and stabilized, and no adjustment and stabilizer is added.

[0070] Comparative Example 2 (using CN115463175A process)

[0071] In this comparative example, the formulation is the same as that of Example 1, except that no regulator or stabilizer is added, and the other excipients and their amounts are also the same. All processes are carried out in the same equipment.

[0072] A method for preparing a universal capsule includes the following steps:

[0073] S1. Mix and grind Coptis chinensis, Coptis chinensis, catechu, and cinnamon into a fine powder to form Mixture 1. The particle size of Mixture 1 is 175μm. Add cultured bezoar with a particle size of 175μm to Mixture 1 to form Mixture 2. Add 607.5 parts by weight of sugar powder to Mixture 2 and stir to form Mixture 3. Mix and grind borneol and artificial musk into a fine powder, and then sieve through a 60-mesh sieve to form Mixture 4.

[0074] S2, concentrate and filter ox bile to obtain a bile paste with a specific gravity of 1.2 g / mL; dissolve bear bile powder in boiling water (purified water) to obtain a bear bile powder aqueous solution, the amount of boiling water being 0.35 times the weight of the bear bile powder; mix the bile paste with the bear bile powder aqueous solution to form bile-bear paste.

[0075] Concentration is carried out in a vacuum concentration tank at a temperature of 65°C and a vacuum level of -0.06 MPa.

[0076] S3. Add mixture three to the bear bile extract, mix well to form mixture five, then add an ethanol aqueous solution, stir, and process into granules using a granulator, then dry, granulate, and sieve to obtain intermediate granules.

[0077] In this step, the drying temperature is 55℃. Granulation is performed using a gyratory pellet mill with a 10-mesh stainless steel screen, and sieving is performed using a gyratory pellet mill with 10-mesh and 80-mesh stainless steel screens.

[0078] In the ethanol-water solution, the amount of ethanol is 181 parts by weight, and the amount of purified water is just enough to ensure the formation while minimizing the water activity of the system.

[0079] S4. Mix the mixture with the intermediate particles, divide the mixture into portions, fill the portions into capsules, and make 1000 capsules of Wanying.

[0080] Wanying capsules were prepared using Examples 1-6 and Comparative Examples 1-2. Bilirubin and free bilirubin were tested, and the results are shown in Table 1 below.

[0081] Accelerated stability tests were conducted on the Wanying capsules prepared in Examples 1-6 and Comparative Examples 1-2 (3 months and 12 months, respectively). The test conditions were: temperature 40℃±2℃ and relative humidity 75%±5%. The bilirubin and free bilirubin of the Wanying capsules after the accelerated test were detected, and the results are shown in Table 1 below.

[0082] Table 1 Test Results

[0083] In Table 1, each test result is the average of 10 samples, and each sample is one Wanying capsule (weight 0.3g).

[0084] From Table 1, we can see that:

[0085] (1) Compared with Comparative Example 2, when only the vacuum concentration of Comparative Example 1 was replaced with boiling, although the total bilirubin in the freshly prepared product increased slightly, the free bilirubin also increased accordingly.

[0086] (2) Compared with Comparative Examples 1 and 2, Examples 1-6 show that after the addition of a regulator and stabilizer, the added regulator and stabilizer stabilizes the formulation system during the preparation process. Not only does the total bilirubin in the freshly prepared product increase, but the free bilirubin also decreases. Among the regulators and stabilizers, L-arginine hydrochloride is superior to L-arginine, L-arginine is superior to L-lysine, and L-lysine is superior to sodium bicarbonate.

[0087] (3) Compared with Comparative Examples 1 and 2, in Examples 1-6, under accelerated conditions, the stabilizing effect of the stabilizer was more prominent as the acceleration time progressed. The free bilirubin of L-arginine hydrochloride did not increase significantly, and the bilirubin content decreased by only 0.02 mg. In contrast, the free bilirubin content of Comparative Example 2 increased by 0.7 μg (reaching 2.85 μg), the free bilirubin content of Comparative Example 1 increased by 0.9 μg (reaching 3.5 μg), the bilirubin content of Comparative Example 2 decreased by 0.08 mg, and the bilirubin content of Comparative Example 1 decreased by 0.09 mg.

[0088] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

[0089] Furthermore, those skilled in the art will understand that although some embodiments herein include certain features included in other embodiments but not others, combinations of features from different embodiments are intended to be within the scope of this application and form different embodiments. The information disclosed in this background section is intended only to enhance the understanding of the general background of this application and should not be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

Claims

1. A method for preparing a general-purpose capsule having reduced harmful impurities and improved overall stability, characterized by, It comprises the following steps: S1, mix the formula amount of Swertia mussotii Franch, Coptis chinensis Franch, Acacia catechu, and Borneol to form a mixture one, add sugar powder to the mixture one, stir to form a mixture two; mix Borneol and artificial musk to form a mixture three; the amount of sugar powder added is 550 parts by weight to 650 parts by weight; S2, boil the bovine bile for 20 min to 35 min, filter to obtain a filtrate; S3, add a stabilizing agent to the filtrate, and the amount of the stabilizing agent added is to adjust the pH of the filtrate to 7.2 to 7.8, and the stabilizing agent is an organic base or an inorganic base; S4, add the formula amount of bear bile powder and ox gall to the filtrate after S3 adjustment to form a mixture four; S5, add the mixture two to the mixture four to form a mixture five, and then add an ethanol aqueous solution to form intermediate particles by a granulator, drying, and screening; S6, mix the mixture three with the intermediate particles, and then package and encapsulate to form the Wanying capsule; The formula of the Wanying capsule is as follows: Coptis chinensis Franch 50 parts by mass to 65 parts by mass, Swertia mussotii Franch 50 parts by mass to 65 parts by mass, Acacia catechu 50 parts by mass to 65 parts by mass, Borneol 105 parts by mass to 125 parts by mass, bear bile powder 10.2 parts by mass to 12 parts by mass, ox gall 2 parts by mass to 3.5 parts by mass, bovine bile 80 parts by mass to 98 parts by mass, Borneol 3 parts by mass to 4 parts by mass, and artificial musk 2 parts by mass to 3.5 parts by mass; The parts by mass are one of grams, kilograms, kilogram, or ten kilograms.

2. The method of claim 1, wherein the method is characterized by: In S1, the particle size of the mixture one is 160 μm to 175 μm; and the Borneol and the artificial musk are mixed and finely ground to pass through a 50 mesh to 70 mesh sieve.

3. The method of claim 1, wherein the method is characterized by: In S2, the boiling is operated at normal pressure.

4. The method for preparing a general-purpose capsule having reduced harmful impurities and improved overall stability according to claim 1, characterized by, In S4, the ox gall is an in vitro cultured ox gall, and the particle size is 160 μm to 175 μm.

5. The method of claim 1, wherein the method is characterized by: In S5, the ethanol aqueous solution contains 150 parts by weight to 200 parts by weight of ethanol, and the amount of purified water is an amount that ensures molding while minimizing the water activity of the system.

6. The method of claim 1, wherein the method is characterized by: In S5, the whole granulation is performed by a swinging granulator equipped with a 10 mesh stainless steel screen, and the screening is performed by a swinging granulator equipped with a 10 mesh and an 80 mesh stainless steel screen.

7. The method of claim 1, wherein the method is characterized by: The organic base is one of L-arginine hydrochloride, L-arginine, or L-lysine.

8. The method of claim 1, wherein the method is characterized by: The inorganic base is sodium bicarbonate.

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