Six-ingredient rehmannia pill and preparation process thereof

Abstract

The invention discloses a Liuwei Dihuang pill and a preparation process thereof. The Liuwei Dihuang pill comprises the following components in percentage by mass: 20-30% of prepared rehmannia root, 10-20% of dogwood, 10-20% of Chinese yam, 8-12% of rhizoma alismatis, 8-12% of moutan bark, 10-20% of poria cocos, 2-8% of an inorganic compound additive and 5-15% of an adhesive. The inorganic compound additive is composed of 1-3% of nanoscale calcium phosphate and 2-4% of nanoscale silicon dioxide; the preparation process comprises the following steps: S1, pretreating raw materials, cleaning, drying, and carrying out superfine grinding; s2, preparing an inorganic compound additive; s3, mixing and dispersing; s4, pelleting and forming; according to the preparation process provided by the invention, the uniformity and the stability of the Liuwei Dihuang pill can be remarkably improved, inorganic components and organic components are combined more tightly, and the medicine absorption efficiency and the bioavailability are improved, so that the clinical curative effect is improved.

Description

Technical Field

[0001] The invention relates to the technical field of modern Chinese medicine preparations, in particular to a Liuwei Dihuang Pill and a preparation process thereof. Background Art

[0002] Liuwei Dihuang Pills is a classic Chinese medicine prescription. Its traditional preparation process uses medicinal materials such as Rehmannia root, Cornus officinalis, and Chinese yam as the core, supplemented by inorganic mineral medicinal ingredients such as gypsum and cinnabar. It has the effect of nourishing yin and tonifying the kidney.

[0003] However, the traditional technology has the following technical defects in long-term application:

[0004] In traditional processes, mineral drugs such as gypsum and cinnabar are mostly used directly in their natural form, and their physical and chemical properties are easily affected by environmental humidity and temperature fluctuations. During long-term storage, inorganic components are prone to deliquescence, crystallization or agglomeration, resulting in decreased drug uniformity and loss of active ingredients, which in turn affects the stability of drug efficacy. In traditional pill preparation processes, inorganic and organic components are mainly combined through physical mixing, with a loose structure and difficulty in forming a stable composite system. After oral administration, the pills disintegrate slowly in the body, and the dissolution rate of inorganic components is inconsistent with the release of organic active ingredients, resulting in low drug absorption efficiency and insufficient bioavailability, affecting clinical efficacy. Summary of the invention

[0005] The object of the present invention is to provide a Liuwei Dihuang Pill and a preparation process thereof to solve the problems raised in the above-mentioned background technology.

[0006] To achieve the above object, the present invention provides the following technical scheme: a preparation process of Liuwei Dihuang Pills, the preparation process formula comprising the following components by mass percentage: 20-30% of Rehmannia glutinosa, 10-20% of Cornus officinalis, 10-20% of Dioscorea opposita, 8-12% of Alisma orientalis, 8-12% of Paeonia suffruticosa, 10-20% of Poria cocos, 2-8% of inorganic compound additives, and 5-15% of adhesive; the inorganic compound additives are composed of 1-3% of nano-scale calcium phosphate and 2-4% of nano-scale silicon dioxide;

[0007] The preparation process comprises the following steps:

[0008] S1: Wash and dry Rehmannia root, Cornus officinalis, Dioscorea opposita, Rhizoma Alismatis, Cortex Moutan and Poria cocos respectively, and then ultrafine grind into fine powder with a particle size of no more than 50 μm, and mix the obtained fine powders evenly according to the proportion;

[0009] S2: mixing nano-scale calcium phosphate and nano-scale silicon dioxide in proportion, surface-modifying with a silane coupling agent, dispersing in an ethanol solution to form a suspension, and then spray-drying the suspension to obtain modified inorganic composite particles;

[0010] S3: adding the modified inorganic composite particles to the fine powder obtained in step S1, and mixing for 10-15 minutes using a high-speed shear mixer to ensure uniform dispersion;

[0011] S4: heating the binder to 40-55° C., adding the binder to the mixture obtained in step S3, stirring the mixture for 20-30 min using a vacuum mixer to form a soft material, and forming the soft material into pills using a centrifugal pill making machine;

[0012] S5: drying the pills with microwaves, with a microwave power of 500-800 W and a drying time of 1-2 h, and controlling the moisture content of the pills to be no more than 5%;

[0013] S6: Polishing the dried pills using a food-grade polishing agent to obtain the Liuwei Dihuang Pills.

[0014] Preferably, the silane coupling agent is γ-aminopropyltriethoxysilane, and the modification amount is 0.5-1.5% of the total mass of the inorganic compound.

[0015] Preferably, the adhesive is refined honey with a water content of no more than 18% and a viscosity of 3000-5000 mPa·s.

[0016] Preferably, the ultrafine grinding adopts a liquid nitrogen low-temperature grinding process, and the grinding temperature is controlled at -20°C to -40°C.

[0017] Preferably, the silane coupling agent modification process is carried out in an ethanol solution, the ethanol concentration is 75%-95%, and the modification reaction time is 1-3 hours.

[0018] Preferably, the nanoscale calcium phosphate is an amorphous structure with a specific surface area of ​​≥100m 2 / g, and the surface hydroxyl density is 3-5OH / nm 2 .

[0019] Preferably, the pore size of the nano-silicon dioxide is 2-10 nm and the pore volume is 0.8-1.5 cm 3 / g, and the surface is loaded with calcium citrate dispersant, and the loading amount of the calcium citrate dispersant is 0.1%-0.5%.

[0020] Preferably, the pill making speed is 100-200 r / min, and the pill making time is 5-10 min.

[0021] Preferably, the food-grade polishing agent is corn starch, the polishing time is 5-10 min, and the polishing speed is 50-100 r / min.

[0022] Preferably, the interface bonding strength between the inorganic compound additive and the fine powder in the composite particles is not less than 5 MPa, and the interface bonding strength is measured by nanoindentation method.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] 1. The present invention uses an ultrafine grinding process to pulverize the medicinal materials to a particle size of 40 μm, making it easier to mix the medicinal ingredients evenly and improving the uniformity of the medicinal ingredients. Nano-scale calcium phosphate and nano-scale silicon dioxide are used as inorganic compound additives, and the surface is modified by a silane coupling agent to enhance the combination of inorganic particles and medicinal powder, thereby improving the stability of the entire pill.

[0025] 2. The present invention helps to adjust the drug release rate by adding modified inorganic composite particles, so that the dissolution rate of inorganic components and the release of organic active ingredients are more coordinated, thereby improving the absorption efficiency of drugs in the body. By controlling the pill making speed and time, the disintegration characteristics and drug release behavior of the pills can be further optimized.

[0026] 3. The present invention uses modified inorganic composite particles, which have better physical and chemical stability and are not easily affected by environmental humidity and temperature fluctuations, thereby reducing deliquescence, crystallization or agglomeration. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 The present invention is a flow chart of the preparation process of Liuwei Dihuang Pills. DETAILED DESCRIPTION

[0028] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0029] See also Figure 1 , the present invention provides a technical solution:

[0030] Embodiment 1:

[0031] A preparation process of Liuwei Dihuang Pills, the preparation process formula comprises the following components by mass percentage: 25% of Radix Rehmanniae Preparata, 15% of Fructus Corni, 15% of Rhizoma Dioscoreae, 10% of Rhizoma Alismatis, 10% of Cortex Moutan, 15% of Poria, 5% of inorganic compound additive, and 10% of adhesive; the inorganic compound additive consists of 2% of nano-scale calcium phosphate and 3% of nano-scale silicon dioxide; the silane coupling agent adopts gamma-aminopropyl triethoxysilane, and the modification amount is 1% of the total mass of the inorganic compound; the adhesive adopts refined honey, and the water content is 15% and the viscosity is 4000mPa·s.

[0032] The preparation process comprises the following steps:

[0033] S1: Wash and dry Rehmannia root, Cornus officinalis, Chinese yam, Rhizoma Alismatis, Cortex Moutan and Poria respectively, dry at 40°C to a moisture content of no more than 8%, and grind to fine powder with a particle size of 40 μm. The ultrafine grinding adopts liquid nitrogen low-temperature grinding process, and the grinding temperature is controlled at -30°C. The obtained fine powders are mixed uniformly according to the above ratio;

[0034] S2: Mix nano-scale calcium phosphate and nano-scale silicon dioxide in the above ratio, and after surface modification with a silane coupling agent, disperse them in an ethanol solution to form a suspension. The silane coupling agent modification process is carried out in an ethanol solution with an ethanol concentration of 95% and a modification reaction time of 2 hours. The suspension is then spray dried with an inlet temperature of 160°C and an outlet temperature of 80°C to obtain modified inorganic composite particles. The nano-scale calcium phosphate has an amorphous structure and a specific surface area of ​​115 m 2 / g, and the surface hydroxyl density is 4.2OH / nm 2 ; The pore size of nano-silica is 5nm and the pore volume is 1.2cm 3 / g, and the surface is loaded with calcium citrate dispersant, and the loading amount of calcium citrate dispersant is 0.3%;

[0035] S3: adding the modified inorganic composite particles to the fine powder obtained in step S1, and mixing for 12 minutes using a high-speed shear mixer to ensure uniform dispersion;

[0036] S4: heating the binder to 50° C., adding the binder to the mixture obtained in step S3, stirring the mixture for 25 minutes using a vacuum mixer to form a soft material, and then forming the soft material into pills using a centrifugal pill making machine at a pill making speed of 150 r / min for 8 minutes;

[0037] S5: drying the pills with microwaves at a microwave power of 650 W and a drying time of 1.5 h, and controlling the moisture content of the pills to be no greater than 5%;

[0038] S6: Polishing the dried pills with a food-grade polishing agent, wherein the food-grade polishing agent is corn starch, the polishing time is 8 minutes, and the polishing speed is 80 r / min to obtain the Liuwei Dihuang Pills.

[0039] Embodiment 2:

[0040] A preparation process of Liuwei Dihuang Pills, the preparation process formula comprises the following components by mass percentage: 25% of Radix Rehmanniae Preparata, 15% of Fructus Corni, 15% of Dioscorea Opposita, 10% of Rhizoma Alismatis, 10% of Cortex Moutan, 15% of Poria, 8% of inorganic compound additive, and 6% of adhesive; the inorganic compound additive consists of 3% of nano-scale calcium phosphate and 5% of nano-scale silicon dioxide; the silane coupling agent adopts gamma-aminopropyl triethoxysilane, and the modification amount is 1.5% of the total mass of the inorganic compound; the adhesive adopts refined honey, and the water content is 15% and the viscosity is 4000mPa·s.

[0041] The preparation process comprises the following steps:

[0042] S1: Wash and dry Rehmannia root, Cornus officinalis, Chinese yam, Rhizoma Alismatis, Cortex Moutan and Poria respectively, dry at 40°C to a moisture content of no more than 8%, and grind to fine powder with a particle size of 40 μm. The ultrafine grinding adopts liquid nitrogen low-temperature grinding process, and the grinding temperature is controlled at -30°C. The obtained fine powders are mixed uniformly according to the above ratio;

[0043] S2: Mix nano-scale calcium phosphate and nano-scale silicon dioxide in the above ratio, and after surface modification with a silane coupling agent, disperse them in an ethanol solution to form a suspension. The silane coupling agent modification process is carried out in an ethanol solution with an ethanol concentration of 95% and a modification reaction time of 3 hours. The suspension is then spray dried with an inlet temperature of 160°C and an outlet temperature of 80°C to obtain modified inorganic composite particles. The nano-scale calcium phosphate has an amorphous structure and a specific surface area of ​​115 m 2 / g, and the surface hydroxyl density is 4.2OH / nm 2 ; The pore size of nano-silica is 5nm and the pore volume is 1.2cm 3 / g, and the surface is loaded with calcium citrate dispersant, and the loading amount of calcium citrate dispersant is 0.3%;

[0044] S3: adding the modified inorganic composite particles to the fine powder obtained in step S1, and mixing for 12 minutes using a high-speed shear mixer to ensure uniform dispersion;

[0045] S4: heating the binder to 50° C., adding the binder to the mixture obtained in step S3, stirring the mixture for 25 minutes using a vacuum mixer to form a soft material, and then forming the soft material into pills using a centrifugal pill making machine at a pill making speed of 150 r / min for 8 minutes;

[0046] S5: drying the pills with microwaves, with a microwave power of 800 W and a drying time of 2 h, and controlling the moisture content of the pills to be no more than 5%;

[0047] S6: Polishing the dried pills with a food-grade polishing agent, wherein the food-grade polishing agent is corn starch, the polishing time is 8 minutes, and the polishing speed is 80 r / min to obtain the Liuwei Dihuang Pills.

[0048] Embodiment three:

[0049] A preparation process of Liuwei Dihuang Pills, the preparation process formula comprises the following components by mass percentage: 25% of Radix Rehmanniae Preparata, 15% of Fructus Corni, 15% of Rhizoma Dioscoreae, 10% of Rhizoma Alismatis, 10% of Cortex Moutan, 15% of Poria, 2% of inorganic compound additive, and 15% of adhesive; the inorganic compound additive consists of 1% of nano-scale calcium phosphate and 1% of nano-scale silicon dioxide; the silane coupling agent adopts gamma-aminopropyl triethoxysilane, and the modification amount is 0.8% of the total mass of the inorganic compound; the adhesive adopts refined honey, and the water content is 15% and the viscosity is 4000mPa·s.

[0050] The preparation process comprises the following steps:

[0051] S1: Wash and dry Rehmannia root, Cornus officinalis, Chinese yam, Alisma orientalis, Paeonia suffruticosa root and Poria cocos respectively, dry at 40°C until the moisture content is no more than 8%, and grind to fine powder with a particle size of 40 μm. The ultrafine grinding adopts liquid nitrogen low-temperature grinding process, and the grinding temperature is controlled at -20°C. The obtained fine powder is mixed evenly according to the above ratio;

[0052] S2: Mix nano-scale calcium phosphate and nano-scale silicon dioxide in the above ratio, and after surface modification with a silane coupling agent, disperse them in an ethanol solution to form a suspension. The silane coupling agent modification process is carried out in an ethanol solution with an ethanol concentration of 95% and a modification reaction time of 3 hours. The suspension is then spray dried with an inlet temperature of 160°C and an outlet temperature of 80°C to obtain modified inorganic composite particles. The nano-scale calcium phosphate has an amorphous structure and a specific surface area of ​​115 m 2 / g, and the surface hydroxyl density is 4.2OH / nm 2 ; The pore size of nano-silica is 5nm and the pore volume is 1.2cm 3 / g, and the surface is loaded with calcium citrate dispersant, and the loading amount of calcium citrate dispersant is 0.3%;

[0053] S3: adding the modified inorganic composite particles to the fine powder obtained in step S1, and mixing for 12 minutes using a high-speed shear mixer to ensure uniform dispersion;

[0054] S4: heating the binder to 50° C., adding the binder to the mixture obtained in step S3, stirring the mixture for 25 min using a vacuum mixer to form a soft material, and then forming the soft material into pills using a centrifugal pill making machine at a pill making speed of 100 r / min for 8 min;

[0055] S5: drying the pills with microwaves, with a microwave power of 800 W and a drying time of 2 h, and controlling the moisture content of the pills to be no more than 5%;

[0056] S6: Polishing the dried pills with a food-grade polishing agent, wherein the food-grade polishing agent is corn starch, the polishing time is 5 minutes, and the polishing speed is 80 r / min to obtain the Liuwei Dihuang Pills.

[0057] By comparing Examples 1, 2 and 3, it can be seen that Example 1 has the best balance, with significant improvements in stability, efficacy and cost, with an inorganic content of 5%, a modification of 1% and a drying of 600W for the best comprehensive performance; Example 2 is the stability limit of a high-load inorganic system, with an inorganic content of 8%, a modification of 1.5% and a drying of 800W for maximum inorganic function; Example 3 is the humidity adaptability and economy under low inorganic content, with an inorganic content of 2%, a modification of 0.8% and a drying of 500W for anti-deliquescent and low cost.

[0058] The present invention uses an ultrafine grinding process to pulverize medicinal materials to a particle size of 40 μm, so that the medicinal material components are easier to mix evenly, and the uniformity of the medicinal components is improved. Nano-scale calcium phosphate and nano-scale silicon dioxide are used as inorganic compound additives, and surface modification is performed by a silane coupling agent to enhance the combination of inorganic particles and medicinal material fine powder, thereby improving the stability of the entire pill; the addition of modified inorganic composite particles helps to adjust the drug release rate, so that the dissolution rate of inorganic components and the release of organic active components are more coordinated, thereby improving the absorption efficiency of the drug in the body, and by controlling the pill making speed and time of the pills, the disintegration characteristics and drug release behavior of the pills can be further optimized; the modified inorganic composite particles are used, and these particles have better physical and chemical stability, are not easily affected by environmental humidity and temperature fluctuations, thereby reducing deliquescence, crystallization or agglomeration phenomena;

[0059] In summary, the preparation process provided by the present invention can significantly improve the uniformity and stability of Liuwei Dihuang Pills, the combination of inorganic components and organic components is closer, and the drug absorption efficiency and bioavailability are improved, thereby improving the clinical efficacy.

[0060] Experiment 1: Stability test (accelerated test)

[0061] Detection indicators Example 1 Results Traditional process results (control) Test Standards 6-month caking rate 0％ 35％ Chinese Pharmacopoeia 2020 Loganin retention rate 97.2％ 68.5％ HPLC method (acetonitrile-water) Paeonol retention rate 96.8％ 72.1％ HPLC method (methanol) Changes in water content 4.8％→5.1％ 5.0％→8.9％ Rapid Moisture Tester

[0062] Experiment 2: Dissolution and bioavailability

[0063] Test items Example 1 Data Traditional process data Test conditions Calcium ion dissolution (12h) 92%(pH 6.8) 48％ Paddle method (50rpm) Paeonol Release T50 1.2h 3.5h Dissolution curve fitting Rat AUC (0-24h) 1520 μg·h / mL 720 μg·h / mL LC-MS / MS method

[0064] The dissolution rate is as high as over 90%, indicating that the inorganic components can be effectively released and work synergistically with the organic components. Experiment 3: Interface bonding strength and microstructure

[0065] Detection indicators Example 1 Results Traditional craft results Detection Methods Interface bonding strength 5.8MPa 1.2MPa Nanoindenter Particle dispersion uniformity 2.7％ 12.5％ SEM-EDS surface scanning

[0066] The Si-O-Ca chemical bond constructed by modifying the silane coupling agent can increase the inorganic-organic interface bonding strength to more than 5MPa.

[0067] Experiment 4: Safety Verification (Heavy Metal Residues)

[0068]

[0069]

[0070] Appendix: Experimental method reference standards

[0071] HPLC detection: Loganin: chromatographic column Agilent ZORBAX SB-C18 (4.6×250mm, 5μm), mobile phase acetonitrile-water (15:85).

[0072] Disintegration time determination: According to the disintegration time test method of "Chinese Pharmacopoeia" 0921, the medium is pure water, and the temperature is 37±1℃.

[0073] Nanoindentation test: Instrument: Bruker TI 950, load 10 mN, loading rate 0.5 mN / s.

[0074] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A preparation process of Liuwei Dihuang Pills, characterized in that: The preparation process formula comprises the following components by mass percentage: 20-30% of Radix Rehmanniae Preparata, 10-20% of Fructus Corni, 10-20% of Rhizoma Dioscoreae, 8-12% of Rhizoma Alismatis, 8-12% of Cortex Moutan, 10-20% of Poria, 2-8% of inorganic compound additive, and 5-15% of adhesive; the inorganic compound additive is composed of 1-3% of nano-scale calcium phosphate and 2-4% of nano-scale silicon dioxide; The preparation process comprises the following steps: S1: Wash and dry Rehmannia root, Cornus officinalis, Dioscorea opposita, Rhizoma Alismatis, Cortex Moutan and Poria cocos respectively, and then ultrafine grind into fine powder with a particle size of no more than 50 μm, and mix the obtained fine powders evenly according to the proportion; S2: mixing nano-scale calcium phosphate and nano-scale silicon dioxide in proportion, surface-modifying with a silane coupling agent, dispersing in an ethanol solution to form a suspension, and then spray-drying the suspension to obtain modified inorganic composite particles; S3: adding the modified inorganic composite particles to the fine powder obtained in step S1, and mixing for 10-15 minutes using a high-speed shear mixer to ensure uniform dispersion; S4: heating the binder to 40-55° C., adding the binder to the mixture obtained in step S3, stirring the mixture for 20-30 min using a vacuum mixer to form a soft material, and forming the soft material into pills using a centrifugal pill making machine; S5: drying the pills with microwaves, with a microwave power of 500-800 W and a drying time of 1-2 h, and controlling the moisture content of the pills to be no more than 5%; S6: Polishing the dried pills using a food-grade polishing agent to obtain the Liuwei Dihuang Pills.

2. The preparation process of Liuwei Dihuang Pills according to claim 1, characterized in that: The silane coupling agent adopts gamma-aminopropyltriethoxysilane, and the modification amount is 0.5-1.5% of the total mass of the inorganic compound.

3. The preparation process of Liuwei Dihuang Pills according to claim 1, characterized in that: The adhesive is made of refined honey, the moisture content of which is no more than 18% and the viscosity is 3000-5000 mPa·s.

4. The preparation process of Liuwei Dihuang Pills according to claim 1, characterized in that: The ultrafine grinding adopts a liquid nitrogen low-temperature grinding process, and the grinding temperature is controlled at -20°C to -40°C.

5. The preparation process of Liuwei Dihuang Pills according to claim 1, characterized in that: The silane coupling agent modification process is carried out in an ethanol solution, the ethanol concentration is 75%-95%, and the modification reaction time is 1-3 hours.

6. The preparation process of Liuwei Dihuang Pills according to claim 1, characterized in that: The nanoscale calcium phosphate has an amorphous structure and a specific surface area of ​​≥100m 2 / g, and the surface hydroxyl density is 3-5OH / nm 2 .

7. The preparation process of Liuwei Dihuang Pills according to claim 1, characterized in that: The pore size of the nano-scale silica is 2-10 nm, and the pore volume is 0.8-1.5 cm 3 / g, and the surface is loaded with calcium citrate dispersant, and the loading amount of the calcium citrate dispersant is 0.1%-0.5%.

8. The preparation process of Liuwei Dihuang Pills according to claim 1, characterized in that: The pill making speed of the pills is 100-200 r / min, and the pill making time is 5-10 min.

9. The preparation process of Liuwei Dihuang Pills according to claim 1, characterized in that: The food-grade polishing agent is corn starch, the polishing time is 5-10 minutes, and the polishing speed is 50-100 r / min.

10. The preparation process of Liuwei Dihuang Pills according to claim 1, characterized in that: The interface bonding strength between the inorganic compound additive and the fine powder in the composite particles is not less than 5 MPa, and the interface bonding strength is measured by nanoindentation method.

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