A capsule of potentilla discolor bunge and a preparation method thereof

Abstract

This invention discloses the contents of a Tibetan Artemisia capillaris capsule, which is prepared from the following raw and excipient materials in weight percentages: 55%–59% filler, 3%–6% flow aid, and the remainder being Tibetan Artemisia capillaris extract; the Tibetan Artemisia capillaris extract is an alcoholic extract of Tibetan Artemisia capillaris. The Tibetan Artemisia capillaris granules of this invention not only meet the quality requirements of the pharmacopoeia but also have low cost, making them suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, and specifically relates to a Tibetan Artemisia capillaris capsule. Background Technology

[0002] Tibetan Artemisia capillaris is the dried whole herb of Swertia mussotii Franch., a plant belonging to the Gentianaceae family. It mainly contains flavonoids, sine, iridoids and their glycosides, triterpenes, and alkaloids, and has the effects of clearing heat and detoxifying, clearing the liver and promoting bile secretion, removing dampness and relieving jaundice, and strengthening the stomach. It holds an important place in both traditional Chinese and Tibetan medicine, and is used to treat jaundice-type hepatitis, cirrhosis, ascites, cholecystitis, biliary syndrome, bile reflux gastritis, indigestion, acute bacillary dysentery, acute jaundice-type hepatitis, acute conjunctivitis, acute pharyngitis, and burns.

[0003] Because the decoction of Artemisia capillaris is extremely bitter, patients find it difficult to accept. Currently, it has been made into modern preparations such as granules and capsules for clinical use. However, due to the high viscosity and poor flowability of Artemisia capillaris extract, the choice of excipients will affect the stability of the capsules, thus affecting the quality of the drug and hindering its clinical application. Summary of the Invention

[0004] To solve the above-mentioned technical problems, the present invention provides the contents of a Tibetan Artemisia capillaris capsule, the other components of which are prepared from the following raw and excipient materials in weight percentage:

[0005] The composition consists of 55%–59% filler, 3%–6% flow aid, and the remainder is Artemisia capillaris extract.

[0006] The extract of Artemisia capillaris is an alcoholic extract of Artemisia capillaris.

[0007] Furthermore, it is prepared from the following raw and auxiliary materials by weight percentage:

[0008] The composition includes 58.2% filler, 3% flow aid, and 38.8% Artemisia capillaris extract.

[0009] Furthermore, the filler is mannitol.

[0010] Furthermore, the flow aid is magnesium stearate and / or silicon dioxide.

[0011] Furthermore, the flow aid is magnesium stearate and silicon dioxide in a mass ratio of 1:2 to 5.

[0012] Furthermore, the flow aid is magnesium stearate and silicon dioxide in a mass ratio of 1:2.

[0013] Furthermore, the silicon dioxide is colloidal silicon dioxide.

[0014] Furthermore, the extract of Artemisia capillaris is obtained by reflux extraction of Artemisia capillaris with 75% ethanol, and the extract is then purified by removing the ethanol and residue.

[0015] The present invention also provides a Tibetan Artemisia capillaris capsule, which is a capsule made by filling the aforementioned contents into a capsule shell.

[0016] The present invention also provides a method for preparing the aforementioned Artemisia capillaris capsules, which includes the following steps:

[0017] Weigh the raw and auxiliary materials according to the aforementioned ratio, mix them well, and fill them into the capsule shells to obtain the final product.

[0018] The present invention relates to a capsule formulation of Artemisia capillaris, which is a mixture of specific types and amounts of excipients. The contents have a small angle of repose, good flowability, and high bulk density and tap density. When filled into a capsule shell, the resulting capsules meet the requirements of the pharmacopoeia and are low in cost, making them suitable for large-scale industrial production.

[0019] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions, or alterations can be made without departing from the basic technical concept of the present invention.

[0020] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description

[0021] Figure 1 HPLC chromatograms of reference (A), test (B), and negative control (C) solutions; 1. Swertiamain 2. Gentipicrin 3. Swertiain Detailed Implementation

[0022] Example 1: Preparation of Artemisia capillaris capsules

[0023] formula:

[0024] raw materials type Proportion raw materials Artemisia capillaris extract 38.8％ filler Mannitol 58.2％ Flow aid magnesium stearate 1％ Flow aid colloidal silica 2％

[0025] Preparation method:

[0026] 1) Preparation of Tibetan Artemisia capillaris extract: Take Tibetan Artemisia capillaris, crush it, add 6 times the amount of 75% ethanol and reflux for 2 hours, extract a total of 3 times, remove ethanol and residue from the extract to obtain the extract;

[0027] 2) Weigh the raw and auxiliary materials according to the ratio, mix them well, and fill them into the capsule shells to obtain the final product.

[0028] Example 2: Preparation of Artemisia capillaris capsules

[0029] formula:

[0030] raw materials type Proportion raw materials Artemisia capillaris extract 39％ filler Mannitol 58％ Flow aid magnesium stearate 1％ Flow aid colloidal silica 2％

[0031] Preparation method: Same as in Example 1

[0032] Example 3: Preparation of Artemisia capillaris capsules

[0033] formula:

[0034] raw materials type Proportion raw materials Artemisia capillaris extract 38％ filler Mannitol 59％ Flow aid magnesium stearate 1％ Flow aid colloidal silica 2％

[0035] Preparation method: Same as in Example 1

[0036] Example 4: Preparation of Artemisia capillaris capsules

[0037] formula:

[0038] raw materials type Proportion raw materials Artemisia capillaris extract 39％ filler Mannitol 55％ Flow aid magnesium stearate 1％ Flow aid colloidal silica 5％

[0039] Preparation method: Same as in Example 1

[0040] Example 5: Preparation of Artemisia capillaris capsules

[0041] formula:

[0042] raw materials type Proportion raw materials Artemisia capillaris extract 40％ filler Mannitol 56％ Flow aid magnesium stearate 1％ Flow aid colloidal silica 3％

[0043] Preparation method: Same as in Example 1

[0044] The following experimental examples illustrate the beneficial effects of the present invention.

[0045] Experimental Example 1: Study on the excipient formulation of Artemisia capillaris capsules

[0046] 1. Prescription optimization

[0047] Based on preliminary experiments, it was determined that the active pharmaceutical ingredient (API) had good water solubility but poor flowability. Therefore, mannitol and microcrystalline cellulose were initially selected as fillers, and magnesium stearate and colloidal silica were selected as flow aids for direct filling. This process is simple and has a high drug loading capacity.

[0048] 1.1 Reagents and Equipment

[0049] Table 1 Experimental drugs and reagents

[0050]

[0051] Table 2 Experimental Instruments and Equipment

[0052]

[0053] 1.2 Experimental Methods

[0054] Sample preparation: The active pharmaceutical ingredient (API) Artemisia capillaris extract, along with excipients, fillers, and flow aids (mannitol, colloidal silica, and magnesium stearate), were weighed according to the formulation design and mixed for 30 minutes before being filled into containers. Samples were taken for performance testing. The API was prepared as follows: Artemisia capillaris was pulverized and refluxed with 6 times the volume of 75% ethanol for 2 hours, for a total of 3 extractions. Ethanol and impurities were removed from the extract to obtain the final product.

[0055] 1.2.1 Liquidity

[0056] The sample is flowed vertically through a glass funnel onto a glass plate. The end of the funnel is 3 cm vertically away from the glass plate. The flowing powder forms a cone on the glass plate. The angle between the surface of the cone and the horizontal plane is measured, which is the angle of repose of the sample.

[0057] 1.2.2 Bulk density and tapped density

[0058] 1.2.2.1 Bulk Density

[0059] According to "0993 Determination of Bulk Density and Tap Density" in the Chinese Pharmacopoeia (2020 Edition), this method is used to determine the packing density of drug or excipient powders in a loose state. A loose state refers to the state formed when a powder sample is poured into a container without compressive force. Bulk density can be determined by measuring the volume of a certain mass of sieved powder sample in a graduated cylinder (Method 1). Take approximately 100g of the powder sample to be tested (if necessary, pass it through a 1.0mm sieve to fully disperse any lumps formed during storage), accurately weigh it, and slowly pour it into a glass graduated cylinder. Carefully scrape the top, avoiding compaction of the powder. Record the apparent volume V1 at the nearest graduation. Take three portions of the same batch of sample, perform parallel measurements, record the readings, and use the average value as the result.

[0060] Bulk density is calculated using the formula loose density ρa=M / V1, where ρa is the bulk density by fixed mass method (g / mL), M is the mass of the powder sample (g), and V1 is the volume of the drug powder (mL).

[0061] 1.2.2.2 Tap density

[0062] According to "0993 Determination of Bulk Density and Tapped Density" in the Chinese Pharmacopoeia (2020 Edition), tapped density is determined by measuring the tapped volume of a fixed mass sample. The measuring apparatus includes a graduated cylinder and a tapping device (tapping frequency of 250 ± 15 times per minute, amplitude of 3 mm ± 0.2 mm). The graduated cylinder, filled with loose powder, is fixed on a holder and tapped 10, 500, and 1250 times, recording the corresponding volumes V10, V500, and V1250, accurate to the smallest graduation. If the difference between V500 and V1250 is less than 2 mL, V1250 is taken as the tapped volume; if the difference is greater than 2 mL, the number of taps is increased until the difference between two consecutive recorded volumes is less than 2 mL. If feasible, the lowest possible number of taps should be selected. Three samples from the same batch are measured in parallel, and the readings are recorded; the average value is taken as the result.

[0063] The tap density is calculated using the formula ρb=m / V2, where ρb is the tap density (g / mL), m is the mass of the powder sample (g), and V2 is the tap volume of the sample (mL).

[0064] 1.2.3 Content Determination

[0065] Chromatographic conditions: Column: ACE EXCEL C18-PFP (250mm×4.6mm, 5μm); Mobile phase: methanol: 0.1% formic acid water = 25:75 (v:v); Flow rate: 1.0mL / min; UV detection wavelength: 254nm; Injection volume: 10μL; Column temperature: 30℃.

[0066] Preparation of reference solution: Accurately weigh 10 mg of swertiamarin reference standard, 10 mg of gentiopicrin reference standard, and 10 mg of swertiamarin reference standard, and dilute to 10 mL in a volumetric flask with methanol.

[0067] Preparation of the test solution: Take 1 g of the contents from the volume difference section, accurately weigh it, place it in a stoppered conical flask, accurately add 50 mL of methanol, weigh it, sonicate (52 kHz, 180 W) for 30 min, cool it, weigh it again, make up the weight loss with methanol, shake well, filter it, and take the filtrate to obtain the test solution.

[0068] Preparation of negative control solution: Prepare negative samples lacking gentiopicroside raw material according to the prescription ratio and process, and prepare negative control solution according to the test solution preparation method.

[0069] 1.2.3.1 Specificity test: Accurately pipette the reference solution, test solution, and negative control solution, and determine according to the method, recording the chromatogram. See [link to chromatogram]. Figure 1The results showed that the test solution had a peak with the same retention time at the corresponding position as the reference solution, indicating that the negative control solution did not interfere with the determination and had good specificity.

[0070] 1.2.3.2 Linearity Examination: Take the above-mentioned swertiamarin, gentiopicrin, and swertiamarin reference stock solutions. Accurately pipette an appropriate amount of the reference solution into a 5 mL volumetric flask, and dilute to volume with methanol to prepare the following reference solutions sequentially: swertiamarin at concentrations of 0.5 mg / mL, 0.2 mg / mL, 0.125 mg / mL, 0.025 mg / mL, 0.01275 mg / mL, and 0.00625 mg / mL; gentiopicrin at concentrations of 2 mg / mL, 0.6 mg / mL, 0.4 mg / mL, 0.04 mg / mL, 0.004 mg / mL, and 0.001 mg / mL; and swertiamarin at concentrations of 1.0 mg / mL, 0.2 mg / mL, 0.1 mg / mL, 0.05 mg / mL, 0.025 mg / mL, and 0.01275 mg / mL. Inject 10 μL of each of the prepared reference solutions into the liquid chromatograph and determine their peak areas. Plot the standard curve and obtain the linear regression equation in Table 3.

[0071] Table 3 Linear Regression Equations

[0072]

[0073] 1.2.3.3 Precision: 10 μL of the above reference solution was accurately pipetted and injected repeatedly 6 times. The peak area was measured. The RSDs of swertiamarin, gentiopicrin, and swertiamarin were 0.27%, 0.20%, and 0.13%, respectively.

[0074] 1.2.3.4 Stability: Accurately pipette 10 μL of the same test solution and inject it at 0, 2, 4, 6, 8, 10, 12, and 24 h, respectively, and measure the peak area. The RSDs of swertiamarin, gentiopicrin, and swertiamarin were 1.08%, 0.95%, and 2.07%, respectively, indicating that the solution was basically stable within 24 h.

[0075] 1.2.3.5 Repeatability: Accurately weigh 6 portions of the test sample, process the sample according to the test sample preparation method in section 1.5, and determine the peak area of ​​the relevant components according to the above chromatographic conditions. The results show that the RSDs of swertiamarin, gentiopicrin, and swertiamarin are 0.70%, 0.84%, and 0.82%, respectively.

[0076] 1.2.3.6 Recovery Test: Accurately weigh three portions of the capsule contents powder, and perform six parallel groups. Add gentiopicrin, swertiamarin, and swertiamarin standards at ratios of 1:0.8, 1:1, and 1:1.2, respectively. Prepare the test solution according to the method for preparing the test solution, determine the content under the assay conditions, and calculate the recovery rate of each component. This indicates that the sample extraction and preparation methods are accurate.

[0077] 1.2.4 Dissolution Test

[0078] Take one capsule and accurately weigh it. Use 900 mL of 0.1 mol / L hydrochloric acid solution as the dissolution medium. Perform parallel tests on six samples for each medium. Use a rotating drum at 100 r / min, following the basket method described in the 2020 edition of the Chinese Pharmacopoeia. Take 5 mL samples at 5, 10, 15, 30, 45, and 60 min, filter them through a 0.45 μm microporous membrane, and collect the filtrate as the test solution. Measure the peak area of ​​each test solution under the above chromatographic conditions and calculate the dissolution rate.

[0079] 2. Experimental Results

[0080] 2.1 Formulation Design and Results of Excipients and Fillers

[0081] Samples of the contents of Tibetan Artemisia capillaris capsules were prepared according to four different prescription designs. The dissolution amount and angle of repose of the four groups of samples were measured at 60 min. The results are shown in Tables 7 and 8.

[0082] Table 7 Dissolution rate at 60 min under different formulations

[0083]

[0084] Table 8 Angle of repose under different prescriptions

[0085]

[0086] The results showed that when the ratio of active pharmaceutical ingredient (API) to excipient / filler was 2:8 and 4:6, the dissolution rate and angle of repose did not change significantly. Therefore, the ratio of API to excipient was relatively optimal at 4:6.

[0087] 2.2 Formulation Design and Results of Excipients and Gliding Agents

[0088] Samples of the contents of Tibetan Artemisia capillaris capsules were prepared according to three different formulations of gliding agents. The effects of adding different gliding agents were investigated, and the angle of repose of the three groups of samples was measured. The results are shown in Table 9.

[0089] Table 9 Angle of repose under different prescriptions

[0090]

[0091] The results showed that the angle of repose was smaller when silica and magnesium stearate were added, while the angle of repose was significantly reduced after the addition of mannitol. Therefore, silica and magnesium stearate were chosen as the gliding agents.

[0092] 2.3 Final prescription design and results

[0093] Based on the results of the three formulation designs of the aforementioned gliding agent, the effects of different filler compositions on dissolution, bulk density, tap density, etc. were determined, and the results are shown in Tables 10-12.

[0094] Table 10 Dissolution under different formulation conditions

[0095]

[0096] Table 11 Bulk density and tap density under different formulation conditions

[0097]

[0098] Table 12 Determination of main components under different formulation conditions

[0099]

[0100]

[0101] The results showed that more than 90% of the different fillers could be dissolved within 10 minutes. However, when mannitol was added, the angle of repose was small, the fluidity was good, and the bulk density and tap density were large. Therefore, mannitol was chosen as the filler.

[0102] 3. Summary

[0103] Through formulation design and optimization, the final selected excipients were mannitol XL, colloidal silica, and magnesium stearate, with proportions of 58.2%, 2%, and 1%, respectively.

[0104] The final formula for Tibetan Artemisia capillaris capsules is as follows:

[0105] raw materials type Proportion raw materials Artemisia capillaris extract 38.8％ filler Mannitol 58.2％ Flow aid magnesium stearate 1％ Flow aid colloidal silica 2％

[0106] In summary, the Artemisia capillaris capsule of the present invention, with contents formed by mixing specific types and amounts of excipients, has a small angle of repose, good flowability, and high bulk density and tap density. When filled into the capsule shell, the resulting capsule meets the requirements of the pharmacopoeia and is low in cost, making it suitable for actual large-scale industrial production.

Claims

1. The contents of a Tibetan Artemisia capillaris capsule, characterized in that: It is made from the following raw and auxiliary materials by weight percentage: Mannitol 58.2%, magnesium stearate 1%, colloidal silica 2%, Artemisia capillaris extract 38.8%; The Tibetan Artemisia capillaris extract is obtained by reflux extraction of Tibetan Artemisia capillaris with 75% ethanol, and the extract is then purified by removing ethanol and residue.

2. A capsule formulation of Artemisia capillaris, characterized in that: It is a capsule made by filling the contents of claim 1 into a capsule shell.

3. A method for preparing the Artemisia capillaris capsules of claim 2, characterized in that: It includes the following steps: Weigh the raw and auxiliary materials according to the aforementioned ratio, mix them well, and fill them into the capsule shells to obtain the final product.

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