Preparation method of pseudo-ginseng and dragon's blood capsules

Abstract

The invention belongs to the technical field of traditional Chinese medicine preparations, and particularly relates to a preparation method of pseudo-ginseng and dragon's blood capsules. The technical problem to be solved by the invention is to provide a method capable of effectively improving dissolution of effective components in the pseudo-ginseng and dragon's blood capsule. The method comprises the following steps: a, adding water into a dispersing agent, and uniformly grinding to obtain dispersion liquid; b, dissolving the dragon's blood in an ethanol solution, filtering to obtain dragon's blood liquid, uniformly mixing the dragon's blood liquid and the dispersion liquid, filtering, grinding, drying, sieving, and obtaining a granular material; and c, adding panax notoginseng saponins and pharmaceutically acceptable auxiliary materials into the dispersion, granulating, drying, granulating, totally mixing, and filling to obtain the panax notoginseng and dragon's blood capsule. The radix notoginseng and dragon's blood capsules prepared by the method are high in dissolution rate, meanwhile, the process steps are simplified, beta-cyclodextrin does not need to be subjected to clathration and vacuum concentration, and the production cost is saved.

Description

[0001] This application is a divisional application of application number 202111677064.1, application date 2021.12.31, and invention name "Method for preparing Panax notoginseng Longxuejie capsules". Technical Field

[0002] The invention belongs to the technical field of traditional Chinese medicine preparations, and particularly relates to a preparation method of a Sanqi Longxuejie capsule. Background Art

[0003] Dragon's blood is a resin extracted from the oily wood of the lily family plant Dracaena scabra. It mainly contains volatile oils, flavonoids, phenols, cardiac glycosides, polysaccharides and other ingredients, and has the effects of promoting blood circulation and dispersing blood stasis, relieving pain and stopping bleeding, and healing sores and promoting tissue regeneration. Panax notoginseng total saponins have anti-myocardial ischemia, anti-shock, anti-arrhythmia effects and inhibiting the proliferation of vascular smooth muscle cells, and can treat coronary heart disease, hypertension, hyperlipidemia, etc. The existing technology uses dragon's blood and Panax notoginseng total saponins as main ingredients to prepare preparations for the treatment of cardiovascular and cerebrovascular diseases.

[0004] Due to the poor water solubility of dragon's blood, the oral dosage is large, which seriously affects its efficacy and bioavailability. Cyclodextrin inclusion drug is a new drug preparation technology developed in recent years. Cyclodextrin inclusion can improve the water solubility of drugs, increase stability, and improve bioavailability. Adding ethanol to prepare cyclodextrin inclusion complexes of poorly soluble drugs is currently the most commonly used method.

[0005] Patent document CN1483432A discloses a dragon's blood inclusion compound, which uses an ethanol solution of dragon's blood mixed with an aqueous solution of β-cyclodextrin to prepare the inclusion compound. Under the condition of adding an aqueous solution of an organic solvent, since cyclodextrin can also include an organic solvent with a certain hydrophobicity, the organic solvent will be included together with the drug to form a ternary inclusion compound of drug-organic solvent-cyclodextrin, and the possibility of forming a binary inclusion compound of drug-cyclodextrin is small, resulting in less dissolution of the active ingredients in the dragon's blood in the finished product. Summary of the invention

[0006] The object of the present invention is to overcome the above-mentioned defects and provide a method that can effectively improve the dissolution of effective ingredients in Sanqi Longxuejie Capsules, especially to improve the solubility of dragon's blood A, dragon's blood B and notoginseng total saponins (ginsenoside Rg1, ginsenoside Rb1 and notoginsenoside R1) in Sanqi Longxuejie Capsules.

[0007] The present invention provides a method for preparing Sanqi Longxuejie capsule, comprising the following steps:

[0008] a. Add water to the dispersant and grind evenly to obtain a dispersion;

[0009] b. dissolving dragon's blood in an ethanol solution, filtering to obtain dragon's blood liquid, uniformly mixing the dragon's blood liquid and the dispersion, filtering, grinding, drying, and sieving to obtain a dispersion;

[0010] c. Adding Panax notoginseng total saponins and pharmaceutically acceptable excipients to the dispersion for granulation, drying, granulation, total mixing and filling to obtain Panax notoginseng dragon blood capsules.

[0011] Wherein, in the preparation method of the above-mentioned Panax notoginseng Longxuejie Capsule, in step a, the dispersant is at least one of porous starch or sodium polyacrylate.

[0012] Preferably, the dispersant is porous starch and sodium polyacrylate; wherein the mass ratio of porous starch to sodium polyacrylate is 1:1.

[0013] Furthermore, in step a, the amount of water added is 2 to 4 times the mass of the dispersant.

[0014] Preferably, the amount of water added is 3 times the mass of the dispersant.

[0015] Wherein, in the preparation method of the above-mentioned Panax notoginseng dragon's blood capsule, in step b, when preparing the dragon's blood solution, the mass ratio of the dispersant to the dragon's blood is 3 to 4:1.

[0016] Preferably, the mass ratio of the dispersant to dragon's blood is 4:1.

[0017] Furthermore, in step b, the mass concentration of the ethanol solution is 95%; the amount of ethanol solution added is 8 times the mass of Dragon's Blood.

[0018] Furthermore, in step b, after dissolving dragon's blood in ethanol solution, the solution is filtered using an 80-mesh filter.

[0019] Among them, in the preparation method of the above-mentioned Panax notoginseng Longxuejie Capsule, in step c, Panax notoginseng total saponins, silicon dioxide, talcum powder and ethanol solution with a mass concentration of 95% are added to the dispersion for wet granulation, and the stirring speed during the granulation process is 100-150r / min; the granulation speed is 1000-1500r / min.

[0020] Furthermore, in step c, the drying temperature is 60-70° C. and the particles are dried until the moisture content is less than 5%.

[0021] Furthermore, in step c, the mesh size of the sieve used for granulation is 16 meshes.

[0022] Furthermore, in step c, the rotation speed during the total mixing process is 15 r / min; and the total mixing time is 15 min.

[0023] The beneficial effects of the present invention are:

[0024] The present invention uses at least one of porous starch or sodium polyacrylate as a dispersant and adopts solid dispersion technology to prepare Sanqi Longxuejie capsule, so that an adsorption layer is formed on the surface of drug solid particles, the charge on the surface of the solid particles is increased, and the reaction force between particles forming steric hindrance is increased, thereby improving the solubility of five effective components (Loire's blood A, Loire's blood B, ginsenoside Rg1, ginsenoside Rb1 and Sanqi saponin R1) in Sanqi Longxuejie capsule, so that the effective components can be fully dissolved, the efficacy of the drug is fully exerted, and the bioavailability of the effective components of the drug is improved. Compared with the prior art, the present invention does not need to include β-cyclodextrin, reduce pressure and concentrate, etc., simplifies the process steps, effectively improves the dissolution of Sanqi Longxuejie capsule, and greatly saves production costs and improves production efficiency. DETAILED DESCRIPTION

[0025] Specifically, the present invention provides a method for preparing Sanqi Longxuejie capsule, comprising the following steps:

[0026] a. Add water to the dispersant and grind evenly to obtain a dispersion;

[0027] b. dissolving dragon's blood in an ethanol solution, filtering to obtain dragon's blood liquid, uniformly mixing the dragon's blood liquid and the dispersion, filtering, grinding, drying, and sieving to obtain a dispersion;

[0028] c. Adding Panax notoginseng total saponins and pharmaceutically acceptable excipients to the dispersion for granulation, drying, granulation, total mixing and filling to obtain Panax notoginseng dragon blood capsules.

[0029] The inventor of the present application creatively uses at least one of porous starch or sodium polyacrylate as a dispersant to form an adsorption layer on the surface of solid particles, increase the charge on the surface of the solid particles, and enhance the reaction force between particles that forms steric hindrance, thereby improving the solubility of the active ingredients in the drug and allowing the active ingredients in the Sanqi Longxuejie Capsule to be fully dissolved.

[0030] The present invention will be further described in detail below with reference to specific embodiments.

[0031] The raw materials used in the present invention can all be obtained commercially.

[0032] Example 1

[0033] Accurately weigh 500 g of porous starch, add water 3 times the mass of the porous starch, grind evenly to obtain a dispersion; weigh 125 g of dragon's blood, dissolve it in 8 times the mass of 95% ethanol solution, filter it with an 80-mesh filter to obtain dragon's blood liquid; mix the dragon's blood liquid and the dispersion evenly, grind, dry, and sieve to obtain a dispersion.

[0034] Add 312.5g of Panax notoginseng total saponins, 46.875g of talc and 46.875g of silicon dioxide to the obtained dispersion and add them into a wet preparation machine, add an appropriate amount of ethanol solution with a mass concentration of 95%, stir and granulate, and the stirring speed during the granulation process is 130r / min; the granulation speed is 1200r / min, and the granulated particles are dried at 65°C until the moisture content is less than 5%; the dried particles are sized using a 16-mesh sieve and then mixed, and the rotation speed during the mixing process is 15r / min; the total mixing time is 15min, and then filled to obtain Panax notoginseng Longxuejie Capsules.

[0035] Example 2

[0036] Accurately weigh 500 g of sodium polyacrylate, add 3 times the mass of water of the sodium polyacrylate, grind evenly to obtain a dispersion; weigh 165 g of dragon's blood and dissolve it in 8 times the mass of 95% ethanol solution, filter with an 80-mesh filter to obtain dragon's blood liquid; mix the dragon's blood liquid and the dispersion evenly, grind, dry, and sieve to obtain a dispersion.

[0037] Add 412.5g of Panax notoginseng total saponins, 61.875g of talc and 61.875g of silicon dioxide to the obtained dispersion and add them into a wet preparation machine, add an appropriate amount of ethanol solution with a mass concentration of 95%, stir and granulate, and the stirring speed during the granulation process is 150r / min; the granulation speed is 1500r / min, and the granulated particles are dried at 60°C until the moisture content is less than 5%; the dried particles are sized using a 16-mesh sieve and then mixed, and the rotation speed during the mixing process is 15r / min; the total mixing time is 15min, and then filled to obtain Panax notoginseng Longxuejie Capsules.

[0038] Example 3

[0039] Accurately weigh 250 g of sodium polyacrylate and 250 g of porous starch, add 4 times the mass of water, grind evenly to obtain a dispersion; weigh 125 g of dragon's blood, dissolve it in 8 times the mass of 95% ethanol solution, filter it with an 80-mesh filter to obtain dragon's blood liquid; mix the dragon's blood liquid and the dispersion evenly, grind, dry, and sieve to obtain a dispersion.

[0040] Add 312.5g of Panax notoginseng total saponins, 46.875g of talc and 46.875g of silicon dioxide to the obtained dispersion and add them into a wet preparation machine, add an appropriate amount of ethanol solution with a mass concentration of 95%, stir and granulate, and the stirring speed during the granulation process is 120r / min; the granulation speed is 1300r / min, and the granulated particles are dried at 70°C until the moisture content is less than 5%; the dried particles are sized using a 16-mesh sieve and then mixed, and the rotation speed during the mixing process is 15r / min; the total mixing time is 15min, and then filled to obtain Panax notoginseng Longxuejie Capsules.

[0041] Comparative Example 1

[0042] The dragon's blood inclusion compound comprises 22% dragon's blood and 78% beta-cyclodextrin by weight percentage. 8 times the amount of 95% ethanol solution is added to 125g dragon's blood, stirred and dissolved, and filtered through 80 meshes to obtain dragon's blood liquid. 443g beta-dextrin is accurately measured and 12.5 times the weight of water is added to dissolve to obtain beta-cyclodextrin liquid. The two solutions are mixed and stirred, filtered, and the filtrate is concentrated and dried under reduced pressure, and crushed together with the filter residue to a particle size of 10-50μm to obtain the inclusion compound.

[0043] Add 312.5 g of Panax notoginseng total saponins, 46.875 g of talc and 46.875 g of silicon dioxide to the obtained dispersion and add them into a wet preparation machine, add an appropriate amount of 95% ethanol solution and stir to granulate, dry, granulate, mix and fill according to Example 1 to obtain Panax notoginseng Longxuejie Capsules.

[0044] Comparative Example 2

[0045] Weigh 125g of dragon's blood and dissolve it in 8 times the mass concentration of 95% ethanol solution to obtain dragon's blood liquid; weigh 500g of polyvinyl pyrrolidone and add 3 times the mass of water to dissolve it to obtain polyvinyl pyrrolidone solution, mix the two liquids, filter, grind into particles, dry, and sieve to obtain a dispersion.

[0046] Add 312.5 g of Panax notoginseng total saponins, 46.875 g of talc and 46.875 g of silicon dioxide to the obtained dispersion and add them into a wet preparation machine, add an appropriate amount of 95% ethanol solution and stir to granulate, dry, granulate, mix and fill according to Example 1 to obtain Panax notoginseng Longxuejie Capsules.

[0047] Experimental Example 1 Determination of the content of active ingredients in Sanqi Longxuejie capsules

[0048] The Sanqi Longxuejie capsules prepared in Examples 1 to 3 and Comparative Examples 1 to 2 were determined according to the high performance liquid chromatography method (General Rule 0512) of the Chinese Pharmacopoeia 2020 Edition Part I for the determination of dragon's blood A (C 17 H 18 O4) and dragon's blood B (C 18 H 20 O5), Panax notoginseng saponins (ginsenoside Rg1 (C 42 H 72 O 14 )、ginsenoside Rb1(C 54 H 92 O 23 ) and notoginsenoside R1(C 47 H 80 O 18)) content, specifically as follows:

[0049] Determination of the content of lordreyadin A and lordreyadin B:

[0050] Chromatographic conditions and system suitability test: octadecylsilane bonded silica gel is used as filler; acetonitrile-0.4% phosphoric acid solution (37:63) is used as mobile phase; detection wavelength is 275nm. The theoretical plate number calculated based on the peak of lordreyadin B should not be less than 10,000.

[0051] Preparation of reference solution: Take appropriate amount of Loureirin A reference substance and Loureirin B reference substance, weigh accurately, add methanol to make a mixed solution containing 25ug of Loureirin A and 15ug of Loureirin B per 1mL.

[0052] Preparation of test solution: Take the contents of this product under the item of filling volume difference, grind it finely, take 0.2g, accurately weigh it, put it in a 50mL volumetric flask, add appropriate amount of ethanol, ultrasonically treat it (power 250W, frequency 50kHz) for 20 minutes, cool it, add ethanol to the scale, shake it well, filter it, and take the filtrate to obtain it.

[0053] Determination method: Accurately pipette 10uL of reference solution and test solution respectively, inject into liquid chromatograph, and determine.

[0054] Qualification standard: Each capsule of this product contains dragon's blood and dragon's blood A (C 17 H 18 O4) and dragon's blood B (C 18 H 20 O5) shall not be less than 3.10 mg.

[0055] Determination of total saponin content of Panax notoginseng

[0056] Chromatographic conditions and system suitability test: octadecylsilane bonded silica gel is used as filler; acetonitrile is used as mobile phase A, water is used as mobile phase B, and gradient elution is performed according to the provisions in Table 1; the detection wavelength is 203 nm. The theoretical plate number calculated based on the ginsenoside Rg1 peak should be no less than 6000.

[0057] Table 1 Mobile phase gradient for determination of total saponin content of Panax notoginseng

[0058] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0～20 20 80 20～45 20→46 80→54 45～55 46→55 54→45 55～60 55 45

[0059] Preparation of reference solution: Take appropriate amount of ginsenoside Rg1 reference substance, ginsenoside Rb1 reference substance and notoginsenoside R1 reference substance, weigh them accurately, add methanol to make a mixed solution containing ginsenoside Rg10.5 mg, ginsenoside Rb10.3 mg and notoginsenoside R10.15 mg per 1 mL.

[0060] Preparation of test solution: Take the contents of this product under the item of filling amount difference, grind it finely, take 0.75g, weigh it accurately, put it in a stoppered conical flask, add 25mL of water accurately, stopper it, weigh it, shake it for 60 minutes, weigh it again, make up the lost weight with water, shake it well, filter it, and take the filtrate to obtain it.

[0061] Determination method: Accurately pipette 10uL of reference solution and test solution respectively, inject into liquid chromatograph, and determine.

[0062] Qualification standard: Each capsule of this product contains ginsenoside Rg1(C 42 H 72 O 14 )>Ginsenoside Rb1(C 54 H 92 O 23 )、Notoginsenoside R1(C 47 H 80 O 18 ) and ginsenoside Re(C 48 H 82 O 18 The total amount of ) shall not be less than 11.0 mg. The determination results are shown in Table 2.

[0063] Table 2 Results of determination of effective ingredient content in finished products of Examples and Comparative Examples

[0064]

[0065] Experimental Example 2 Determination of the dissolution rate of the active ingredients in Sanqi Longxuejie capsules

[0066] Take this product and use the second method of dissolution of Part IV of the Chinese Pharmacopoeia 2020 Edition for determination. Take 6 capsules of Sanqi Longxuejie Capsules for determination in each of the examples and comparative examples. Use 0.3% polysorbate 80 phosphate buffer (pH 6.8) (1.7g potassium dihydrogen phosphate, 1.775g anhydrous disodium hydrogen phosphate, 3.0g polysorbate 80, add water to dissolve in 1000mL) as the dissolution medium, the speed is 100 rpm, operate according to the law, and take the solution at 10min, 15min, 30min, and 45min of dissolution, respectively. Take an appropriate amount of liquid, filter it with a 0.45 micron microporous filter membrane (water system, diameter 13mm), discard 2mL of the initial filtrate, take the subsequent filtrate and determine it according to the method of dragon's blood A, dragon's blood B, ginsenoside Rg1, ginsenoside Rb1 and notoginsenoside R1 under the content determination item, and inject 20uL at most. Take an appropriate amount of dragon's blood A, dragon's blood B, ginsenoside Rg1, ginsenoside Rb1 and notoginsenoside R1 reference substances, accurately weigh them, dissolve them in methanol and quantitatively dilute them to make a solution containing about 2 micrograms per 1mL, and determine it in the same way, with an injection volume of 10uL. Calculate the solubility of dragon's blood A, dragon's blood B, ginsenoside Rg1, ginsenoside Rb1 and notoginsenoside R1 per grain by the external standard method. The results are shown in Tables 3 to 7.

[0067] Table 3 Dissolution test results of the finished products of the embodiments and comparative examples (in terms of Loreerain A)

[0068]

[0069] Table 4 Dissolution test results of the finished products of the embodiments and comparative examples (in terms of Loreerain B)

[0070]

[0071]

[0072] Table 5 Dissolution test results of the finished products of the embodiments and comparative examples (in terms of ginsenoside Rg1)

[0073]

[0074] Table 6 Dissolution test results of the finished products of the embodiments and comparative examples (in terms of ginsenoside Rb1)

[0075]

[0076] Table 7 Dissolution test results of the finished products of the embodiments and comparative examples (in terms of notoginsenoside R1)

[0077]

[0078] In summary, the active ingredient of Sanqi Longxuejie Capsule prepared by the method of the present invention is dragon's blood A (C 17H 18 O4), dragon's blood element B (C 18 H 20 O5), Panax notoginseng saponins (ginsenoside Rg1 (C 42 H 72 O 14 )、ginsenoside Rb1(C 54 H 92 O 23 ) and notoginsenoside R1(C 47 H 80 O 18 )) can be fully dissolved, and the method of the present invention reduces the number of steps, does not require inclusion of β-cyclodextrin, and does not require reduced pressure concentration, thereby greatly saving production costs.

Claims

1. A method for preparing Sanqi Longxuejie capsule, characterized in that: The steps include: a. Add water to the dispersant and grind evenly to obtain a dispersion; the dispersant is porous starch and sodium polyacrylate in a mass ratio of 1:1; b. Dissolve dragon's blood in ethanol solution, filter to obtain dragon's blood liquid, mix the dragon's blood liquid and the dispersion evenly, filter, grind, dry, and sieve to obtain a dispersion; the mass ratio of dragon's blood to dispersant is 1:4; c. Adding Panax notoginseng total saponins and pharmaceutically acceptable excipients to the dispersion for granulation, drying, granulation, total mixing and filling to obtain Panax notoginseng dragon blood capsules.

2. The method for preparing the Sanqi Longxuejie capsule according to claim 1, characterized in that: In step a, the amount of water added is 2 to 4 times the mass of the dispersant.

3. The method for preparing the Sanqi Longxuejie capsule according to claim 2, characterized in that: In step a, the amount of water added is 3 times the mass of the dispersant.

4. The method for preparing the Sanqi Longxuejie capsule according to claim 1, characterized in that: In step b, the mass concentration of the ethanol solution is 95%; the amount of the ethanol solution added is 8 times the mass of Dragon's Blood.

5. The method for preparing the Sanqi Longxuejie capsule according to claim 1, characterized in that: In step b, after dissolving dragon's blood in an ethanol solution, the solution is filtered using an 80-mesh filter.

6. The method for preparing the Sanqi Longxuejie capsule according to claim 1, characterized in that: In step c, notoginseng total saponins, silicon dioxide, talcum powder and 95% ethanol solution are added to the dispersion for wet granulation. The stirring speed during the granulation process is 100-150 r / min; the granulation speed is 1000-1500 r / min.

7. The method for preparing the Sanqi Longxuejie capsule according to claim 1, characterized in that: In step c, the drying temperature is 60-70° C. and the particles are dried until the moisture content is less than 5%.

8. The method for preparing the Sanqi Longxuejie capsule according to claim 1, characterized in that: In step c, the mesh size of the sieve used for granulation is 16 meshes.

9. The method for preparing Sanqi Longxuejie Capsule according to claim 1, characterized in that: In step c, the rotation speed during the total mixing process is 15 r / min; the total mixing time is 15 min.

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