A Jinfeng Pills for treating infertility and its preparation method

Abstract

The present invention belongs to the technical field of pharmaceutical preparation, and particularly relates to a Jinfeng Pills for treating infertility and its preparation method. The preparation method of the Jinfeng Pills intermediate is involved, including the following steps: ginseng, cinnamon, motherwort, Glossy Privet Fruit and processed Polygonum multiflorum Thunb. are pulverized, sieved and mixed to obtain medicinal powder; the particle size range D90 of the medicinal powder is 130 μm - 145 μm, D50 is 50 μm - 80 μm, and D10 is 20 μm - 30 μm. In the preparation method of the Jinfeng Pills in this application, the medicinal flavors that are used as powder in the medicine are pulverized by a specific pulverization process, the mixing uniformity is easy to meet the standard, the mixing process takes a short time, the mixing uniformity is excellent, and at the same time the powder has good fluidity.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug preparation, and particularly relates to a Jinfeng Pills for treating infertility and its preparation method. Background Art

[0002] In traditional Chinese medicine, infertility is closely related to the kidney. According to "Medical Compendium of Chinese and Western Medicine", "Both men and women's fertility depends on the kidney's strength. When the kidney is prosperous, it can naturally conceive a fetus." The kidney is the foundation of the congenital and the root of the vital energy. "The essence of the five zang-organs lies in the kidney." The kidney is in charge of storing essence, reproduction, and is the prime mover of life. Insufficient kidney yang, decline of the fire of the gate of vitality, the thoroughfare and conception vessels are not warmed, the uterine vessels are not nourished, and sperm cannot be captured to form pregnancy, so it leads to infertility due to cold uterus. Therefore, the treatment of this disease should start from tonifying the kidney and assisting yang, tonifying qi and nourishing blood, promoting blood circulation and regulating menstruation, promoting ovulation, and regulating endocrine. During menstruation, promoting blood circulation and regulating menstruation should be supplemented.

[0003] The formula of Jinfeng Pills is reasonable, with specific drugs and remarkable effects. Curculiginis Rhizoma and Epimedii Folium are taken from the meaning of "Erxian Decoction" and combined with Cinnamomi Cortex and Cornu Cervi Pantotrichum to warm and tonify the kidney yang; Polygonati Multiflori Radix Praeparata and Ligustri Lucidi Fructus nourish the kidney and yin to "seek yang from yin"; Ginseng invigorates the spleen and replenishes qi, nourishes the acquired to support the congenital to strengthen the gate of vitality; Leonuri Herba promotes blood circulation and regulates menstruation; Colla Corii Asini nourishes yin and blood. All the drugs are used together, and the medicinal power reaches directly to the lower energizer, warming the meridians and dispelling cold, warming the uterus and capturing sperm, promoting pregnancy and nourishing the fetus. Pharmacological studies show that it has the effects of promoting follicle development, regulating the H-P-O axis, sedation, analgesia, regulating the central nervous system, enhancing immunity, nourishing blood, anti-aging, promoting ovulation, exciting the uterus, increasing libido, and improving microcirculation.

[0004] Chinese Patent Application CN103272162A discloses a traditional Chinese medicine composition for treating infertility and its preparation method. Through the promoting qi and activating blood circulation effects of Leonuri Herba, Codonopsis Pilosula, Epimedii Folium, Angelicae Sinensis Radix, Rehmanniae Radix Praeparata, Citri Reticulatae Pericarpium, Linderae Radix, Astragali Radix, Chuanxiong Rhizoma, Atractylodis Macrocephalae Rhizoma Praeparata, Cyperi Rhizoma Rotundum, Poria, Aucklandiae Radix, Perillae Folium, Colla Corii Asini, Amomi Fructus Villosi, Scutellariae Radix, Succinum, Glycyrrhizae Radix et Rhizoma, Aquilariae Lignum Resinatum, Cyathulae Radix, Lycii Fructus, qi and blood are harmonized in women, and essence is replenished, diuresis is promoted, kidney yang is tonified, and the kidney is nourished in men. Infertility is treated by both infertile couples taking it together. Chinese Patent Application CN108619441A discloses a pharmaceutical composition for treating infertility, its preparation method and uses. Through Lycii Fructus, Cuscuta Chinensis Lam., Ginseng, Cinnamomi Cortex, Alpiniae Oxyphyllae Fructus, Longan Arillus, Rubi Fructus, Epimedii Folium, Curculiginis Rhizoma, Morindae Officinalis Radix, it tonifies the middle energizer and promotes diuresis, tonifies yin and supports yang to tonify the kidney and replenish essence, fill the essence qi, and improve the congenital deficiency of kidney essence to treat infertility. Chinese Patent Application CN103989803A discloses a traditional Chinese medicine for treating infertility. Eucommiae Cortex, Cinnamomi Cortex, Astragali Radix, Cuscuta Chinensis Lam., Ginseng, Magnoliae Officinalis Cortex, Asari Herba, Rehmanniae Radix Praeparata, Glycyrrhizae Radix et Rhizoma are used to strengthen the root and vital energy, strengthen the healthy qi and eliminate pathogenic factors, promote qi to raise yang, nourish yin and blood, replenish essence and marrow, invigorate the spleen and benefit the lung, prevent miscarriage and stop diarrhea, promote blood circulation and dredge the meridians to promote conception.

[0005] As a classic traditional Chinese medicine for warming the kidney and promoting yang, Jinfeng Pills can treat infertility. During the processing of Jinfeng Pills, the medicinal flavors that are used as powders need to optimize the pulverization process. Using different pulverization process parameters, the achieved effects are significantly different. After mixing with a mixer, the particle size distribution of the obtained medicinal powder is measured, and the mixing uniformity and fluidity are used as evaluation indicators to select the appropriate particle size distribution of the Jinfeng Pills powder. Summary of the Invention

[0006] In view of the problems existing in the prior art, the present invention provides a Jinfeng Pills for treating infertility and its preparation method. By optimizing and improving the pulverization process of the medicinal flavors that are used as powders in Jinfeng Pills, a powder drug with an appropriate particle size distribution range is obtained, thereby greatly improving the mixing uniformity of the effective active ingredients of the drug, and at the same time improving the fluidity of the powder, providing a basis for the quality uniformity of the subsequent Jinfeng Pills finished products and ensuring the stability of its clinical efficacy.

[0007] The present invention is realized through the following technical solutions:

[0008] A preparation method of an intermediate of Jinfeng Pills for treating infertility, comprising the following steps:

[0009] Ginseng, cinnamon, motherwort, glossy privet fruit, and processed fleece-flower root are pulverized, sieved, and mixed to obtain a medicinal powder; the particle size range of the medicinal powder is D90 of 130 μm - 145 μm, D50 of 50 μm - 80 μm, and D10 of 20 μm - 30 μm.

[0010] Preferably, the pulverization is carried out 1 - 2 times and sieved through a 80 - 120 mesh sieve.

[0011] Further preferably, the pulverization is carried out 2 times, the first time through an 80 - 100 mesh sieve, and the second time through a 100 - 120 mesh sieve.

[0012] Still further preferably, the pulverization is carried out 2 times, the first time through an 80 mesh sieve, and the second time through a 100 mesh sieve.

[0013] Still further preferably, the pulverization is carried out 2 times, the first time through a 100 mesh sieve, and the second time through a 120 mesh sieve.

[0014] Further preferably, the pulverization is carried out 1 time and sieved through a 100 mesh sieve.

[0015] Preferably, before mixing, it is sieved through an 80 - 90 mesh sieve, the rotation speed of the mixing is 10 - 12 rpm, and the mixing time is 20 - 60 min.

[0016] The present invention also relates to a preparation method of Jinfeng Pills for treating infertility, comprising the following steps:

[0017] (1) Decoct epimedium, curculigo rhizome and pilose antler with water, combine the decoction liquids, filter, and concentrate to obtain a clear extract;

[0018] (2) Stew donkey-hide gelatin with water until melted, mix it with the clear extract and the Jinfeng Pills intermediate prepared by the above preparation method, dry, pulverize, make pills by rolling with honey and water, and dry to obtain the said Jinfeng Pills.

[0019] Preferably, in step (1), the number of decoction times is 1 - 3 times, add 6 - 8 times the amount of water each time, the decoction time each time is 2 - 3 h, and after filtration, concentrate to a relative density of 1.20 - 1.22 measured at 70 °C.

[0020] The present invention also relates to Jinfeng Pills prepared by the above preparation method. By weight, the raw materials of the Jinfeng Pills include: 2 - 2.8 parts of epimedium, 1.2 - 2 parts of pilose antler, 1.6 - 2.4 parts of curculigo rhizome, 4 - 4.8 parts of cinnamon, 5.6 - 6.4 parts of ginseng, 1.2 - 2 parts of donkey-hide gelatin, 5.6 - 6.4 parts of processed fleece-flower root, 7.6 - 8.4 parts of glossy privet fruit, and 7.6 - 8.4 parts of motherwort.

[0021] Preferably, by weight, the raw materials of the Jinfeng Pills include: 2.4 parts of epimedium, 1.6 parts of pilose antler, 2 parts of curculigo rhizome, 4.4 parts of cinnamon, 6 parts of ginseng, 1.6 parts of donkey-hide gelatin, 6 parts of processed fleece-flower root, 8 parts of glossy privet fruit, and 8 parts of motherwort.

[0022] Ginseng, epimedium, pilose antler, curculigo rhizome, cinnamon, donkey-hide gelatin, processed fleece-flower root, glossy privet fruit and motherwort, the original plant sources, medicinal parts, nature, flavor, meridian tropism, efficacy, etc. of the above medicinal materials all conform to the corresponding regulations in Part I of the Chinese Pharmacopoeia 2020 Edition.

[0023] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0024] (1) In the preparation method of Jinfeng Pills in this application, the medicinal flavors that are used as powders are pulverized by a specific pulverization process, the mixing uniformity is easy to meet the standard, the mixing process takes a short time, the mixing uniformity is excellent, and at the same time, the powder fluidity is good;

[0025] (2) The medicinal powder prepared by the pulverization process conditions in this application can fully meet the quality requirements of the production process of Jinfeng Pills, thereby ensuring the uniformity of the quality of each batch of produced Jinfeng Pills and the stability of the clinical efficacy of Jinfeng Pills. Description of the Drawings

[0026] Figure 1 It is the chromatogram of the reference substance solution of ginsenoside Rb1 for the determination of the content of ginsenoside Rb1 in the determination of mixing uniformity;

[0027] Figure 2 It is the chromatogram of the sample solution of Sample 1 - 1 taken at 30 minutes for the determination of the content of ginsenoside Rb1 in the determination of mixing uniformity;

[0028] Figure 3 is Figure 2 an enlarged view;

[0029] Figure 4 is the chromatogram of the reference substance solution for the determination of the content of 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside in the determination of mixing uniformity;

[0030] Figure 5 is the chromatogram of the sample solution of 1-1 taken at 30 minutes for the determination of the content of 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside in the determination of mixing uniformity;

[0031] Figure 6 is the chromatogram of the cinnamaldehyde reference substance solution for the determination of cinnamaldehyde content in the determination of mixing uniformity;

[0032] Figure 7 is the chromatogram of the sample solution of 1-1 taken at 30 minutes for the determination of cinnamaldehyde content in the determination of mixing uniformity;

[0033] The peaks not fully shown in the attached drawings do not affect the understanding of the technical solution of the present application by those skilled in the art. Detailed implementation manners

[0034] The present invention will be further described in detail below in conjunction with specific embodiments. The following embodiments are not used to limit the present invention, but are only used to illustrate the present invention. The experimental methods used in the following embodiments, unless otherwise specified, and the experimental methods without specific conditions noted in the embodiments are usually carried out under conventional conditions. The materials, reagents, etc. used in the following embodiments, unless otherwise specified, can be obtained from commercial channels.

[0035] Embodiment 1

[0036] A Jinfeng Pills for treating infertility, calculated by weight parts, the raw materials are: 6 parts of ginseng, 4.4 parts of cinnamon, 8 parts of motherwort, 8 parts of glossy privet fruit, 6 parts of processed fleece-flower root, 2.4 parts of epimedium, 2.0 parts of curculigo rhizome, 1.6 parts of pilose antler and 1.6 parts of donkey-hide gelatin.

[0037] The preparation method of the above-mentioned Jinfeng Pills is as follows:

[0038] (1) Take ginseng, cinnamon, motherwort, glossy privet fruit, and processed fleeceflower root respectively, and crush them twice with a turbo mill. The blower speed is adjusted to 45 Hz, and the feeder speed is adjusted to 15 Hz. The built-in sieve of the mill is 80 mesh for the first time and 100 mesh for the second time. After the sound of the mill shows an idling sound for 2 minutes, stop crushing. Pass the crushed medicinal powders through an 80-mesh sieve with a high-efficiency sieve powder machine respectively, collect the sieved medicinal powders, and mix the above 6 kinds of medicinal powders with a three-dimensional motion high-efficiency mixer respectively. The rotation speed of the mixer is 10 revolutions per minute, and mix for 60 minutes to obtain Medicinal Powder 1. After detection, the particle size D90 of Medicinal Powder 1 is 145.257 μm, D50 is 77.269 μm, and D10 is 28.225 μm;

[0039] (2) Take epimedium, curculigo rhizome, and pilose antler, decoct them twice with water. Use 8 times the amount of water for the first time and 6 times the amount of water for the second time, and decoct each time for 2 hours. Combine the decoction liquids, filter, and concentrate to obtain a clear paste with a relative density of 1.21 (measured at 70 °C);

[0040] (3) Add donkey-hide gelatin to the steaming pot, add 5 times the mass of water of the donkey-hide gelatin and soak for 30 minutes. After heating until completely dissolved, mix it with the above clear paste and Medicinal Powder 1, dry, crush, make pills by rolling with honey and adding water, dry, and coat and polish to obtain the described Jinfeng Pills.

[0041] Example 2

[0042] A kind of Jinfeng Pills for treating infertility, the raw materials are the same as those in Example 1. The difference in the preparation method from Example 1 is that in step (1), it is crushed once with a turbo mill, and the built-in sieve of the mill is 100 mesh, and the rest of the steps are the same as those in Example 1 to obtain Medicinal Powder 2. After detection, the particle size D90 of Medicinal Powder 2 is 141.251 μm, D50 is 62.915 μm, and D10 is 25.592 μm.

[0043] Example 3

[0044] A kind of Jinfeng Pills for treating infertility, the raw materials are the same as those in Example 1. The difference in the preparation method from Example 1 is that in step (1), it is crushed twice with a turbo mill, the built-in sieve of the mill is 100 mesh for the first time and 120 mesh for the second time, and the rest of the steps are the same as those in Example 1 to obtain Medicinal Powder 3. After detection, the particle size D90 of Medicinal Powder 3 is 130.162 μm, D50 is 52.379 μm, and D10 is 20.363 μm.

[0045] Example 4

[0046] A kind of Jinfeng Pills for treating infertility, calculated by weight, the raw materials are: 5.6 parts of ginseng, 4.0 parts of cinnamon, 7.6 parts of motherwort, 7.6 parts of glossy privet fruit, 5.6 parts of processed fleeceflower root, 2.0 parts of epimedium, 1.6 parts of curculigo rhizome, 1.2 parts of pilose antler, and 1.2 parts of donkey-hide gelatin.

[0047] The preparation method of the above-mentioned Jinfeng Pills is as follows:

[0048] (1) Take ginseng, cinnamon, motherwort, glossy privet fruit and processed fleece-flower root respectively, and crush them once with a turbo mill. The speed of the blower is adjusted to 40 Hz, and the speed of the feeder is adjusted to 8 Hz. The built-in sieve of the mill is 100 meshes. After the sound of the mill shows an idling sound for 2 minutes, stop crushing. Pass the crushed medicinal powder through a 90-mesh sieve with a high-efficiency sieve powder machine respectively, collect the sieved medicinal powder, and mix the above 6 kinds of medicinal powders with a three-dimensional motion high-efficiency mixer respectively. The rotation speed of the mixer is 10 revolutions per minute, and mix for 40 minutes to obtain medicinal powder 4. After detection, the particle size D90 of medicinal powder 4 is 142.685 μm, D50 is 63.528 μm, and D10 is 26.432 μm.

[0049] (2) Take epimedium, curculigo rhizome and pilose antler, decoct them twice with water. Use 7 times the amount of water for the first time and 7 times the amount of water for the second time, and decoct each time for 2.5 hours. Combine the decoction liquids, filter, and concentrate to obtain a clear paste with a relative density of 1.20 measured at 70 °C.

[0050] (3) Add donkey-hide gelatin to the steaming pot, add 5 times the mass of water of donkey-hide gelatin and soak for 30 minutes. Heat until completely dissolved, then mix with the above clear paste and medicinal powder 4, dry, crush, make pills by rolling with honey and water, dry, coat and polish to obtain the Jinfeng Pills.

[0051] Example 5

[0052] A kind of Jinfeng Pills for treating infertility, calculated by weight, the raw materials are: 6.4 parts of ginseng, 4.8 parts of cinnamon, 8.4 parts of motherwort, 8.4 parts of glossy privet fruit, 6.4 parts of processed fleece-flower root, 2.8 parts of epimedium, 2.4 parts of curculigo rhizome, 2.0 parts of pilose antler and 2.0 parts of donkey-hide gelatin.

[0053] The preparation method of the above-mentioned Jinfeng Pills is as follows:

[0054] (1) Take ginseng, cinnamon, motherwort, glossy privet fruit and processed fleece-flower root respectively, and crush them twice with a turbo mill. The speed of the blower is adjusted to 50 Hz, and the speed of the feeder is adjusted to 25 Hz. The built-in sieve of the mill is 100 meshes for the first time and 120 meshes for the second time. After the sound of the mill shows an idling sound for 2 minutes, stop crushing. Pass the crushed medicinal powder through a 90-mesh sieve with a high-efficiency sieve powder machine respectively, collect the sieved medicinal powder, and mix the above 6 kinds of medicinal powders with a three-dimensional motion high-efficiency mixer respectively. The rotation speed of the mixer is 12 revolutions per minute, and mix for 20 minutes to obtain medicinal powder 5. After detection, the particle size D90 of medicinal powder 5 is 130.975 μm, D50 is 52.996 μm, and D10 is 21.085 μm;

[0055] (2) Take Epimedii Folium, Curculiginis Rhizoma, and Cornu Cervi Pantotrichum, decoct them twice with water. Use 6 times the amount of water for the first decoction and 8 times the amount of water for the second decoction, each decocting for 3 hours. Combine the decoction liquids, filter, and concentrate to obtain a clear extract with a relative density of 1.22 measured at 70°C.

[0056] (3) Add Colla Corii Asini to the steaming pot, add 5 times the mass of water as that of Colla Corii Asini to soak for 30 minutes. Heat until completely dissolved, then mix with the above-mentioned clear extract and Medicinal Powder 5, dry, pulverize, make pills by rolling with honey and adding water, dry, coat, and polish to obtain the said Jinfeng Pills.

[0057] Comparative Example 1

[0058] The difference from Example 1 is only that in step (1), it is pulverized once with a turbo mill, and the built-in sieve of the mill is 80 mesh; the remaining steps are the same as those in Example 1 to obtain Medicinal Powder 6. After testing, the particle size D90 of Medicinal Powder 6 is 151.193 μm, D50 is 86.149 μm, and D10 is 37.152 μm.

[0059] Comparative Example 2

[0060] The difference from Example 1 is only that in step (1), it is pulverized once with a turbo mill, and the built-in sieve of the mill is 120 mesh; the remaining steps are the same as those in Example 1 to obtain Medicinal Powder 7. After testing, the particle size D90 of Medicinal Powder 7 is 107.418 μm, D50 is 35.152 μm, and D10 is 12.281 μm.

[0061] Comparative Example 3

[0062] The difference from Example 1 is only that in step (1), it is pulverized once with a turbo mill, and the built-in sieve of the mill is 150 mesh; the remaining steps are the same as those in Example 1 to obtain Medicinal Powder 8. After testing, the particle size D90 of Medicinal Powder 8 is 82.524 μm, D50 is 28.428 μm, and D10 is 9.525 μm.

[0063] The differences between Examples 1 - 3 and Comparative Examples 1 - 3 are shown in Table 1.

[0064] Table 1 Mesh number of the sieve of the mill and number of pulverization times

[0065]

[0066]

[0067] Effect test

[0068] In Examples 1-3 and Comparative Examples 1-3, in step (1), the six kinds of medicinal powders were respectively mixed using a three-dimensional motion high-efficiency mixer. The rotation speed of the mixer was 10 revolutions per minute. Sampling was carried out for the determination of mixing uniformity at 10 minutes, 20 minutes, 30 minutes, 45 minutes, and 60 minutes after starting the mixer, and sampling was carried out for the determination of particle size distribution and powder flowability after 60 minutes of mixing.

[0069] Test Example 1 Determination of mixing uniformity

[0070] 1. Sampling method for determination of mixing uniformity

[0071] After stopping at each sampling time point, open the upper cover of the three-dimensional motion mixer, and use a GTD-D type fixed-point metering sampling probe to sample at three layers: the upper layer, the middle layer, and the discharge port in the three-dimensional motion mixer.

[0072] At the upper layer, sample at 4 points near the mixer wall in the front, back, left, and right along the cross and at the cross center point, a total of 5 points. The corresponding sample numbers for each sampling point are sample 1-1, sample 1-2, sample 1-3, sample 2-1, sample 2-2, sample 2-3, sample 3-1, sample 3-2, sample 3-3, sample 4-1, sample 4-2, sample 4-3, sample 5-1, sample 5-2, sample 5-3.

[0073] At the middle layer, sample at 4 sampling points near the inner wall of the mixer in the front, back, left, and right along the cross and at the cross center point, a total of 5 points. The corresponding sample numbers for each sampling point are sample 6-1, sample 6-2, sample 6-3, sample 7-1, sample 7-2, sample 7-3, sample 8-1, sample 8-2, sample 8-3, sample 9-1, sample 9-2, sample 9-3, sample 10-1, sample 10-2, sample 10-3.

[0074] At the discharge port, sample at the center point, and the corresponding sample numbers are sample 11-1, sample 11-2, sample 11-3.

[0075] Quantitatively take 2 g from each sampling point for detecting the content of ginsenoside Rb1, a characteristic component of ginseng, and take a total of three samples. Quantitatively take 1 g from each sampling point for determining the content of 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside, a characteristic component of Polygonum multiflorum Thunb. preparata, and take a total of three samples. Take 4 g from each sampling point for determining the content of cinnamaldehyde, a characteristic component of cinnamon, and take a total of three samples. Send the samples for the determination of content uniformity.

[0076] 2. Sampling method for determination of particle size distribution

[0077] After mixing, use a GTD-D type fixed-point metering and sampling probe to take 20 g of samples from each of the sampling points in the upper layer, middle layer, and discharge port, a total of 220 g of samples, according to the above-mentioned sampling method for measuring mixing uniformity. Place them together in a 500-ml stoppered sample bottle, tightly cap the bottle, invert it up and down 50 times to mix thoroughly. Use a sampling spoon to take one spoonful of sample from 4 sampling points near the bottle wall in the front, back, left, and right directions along the cross direction in the upper layer and 1 sampling point at the center of the bottle, place it in the sample bottle, invert it up and down thoroughly 50 times to mix evenly, and then send the sample for particle size distribution measurement.

[0078] 3. Determination of mixing uniformity

[0079] 3.1 Determination method for the content of ginsenoside Rb1, a characteristic component of ginseng

[0080] Refer to the content determination method in the drug registration standard of Jinfeng Pills. The specific test method is as follows.

[0081] (1) Preparation of reference substance solution: Weigh accurately 10 mg of ginsenoside Rb1 reference substance, place it in a 100-ml volumetric flask, dissolve it with methanol and dilute to the mark, shake well. Pipette accurately 5 ml of the above solution into a 10-ml volumetric flask, dilute it to the mark with methanol, and shake well to obtain a solution containing 0.07 mg per 1 ml.

[0082] (2) Preparation of test solution: Weigh accurately 2 g of the sample, add 50 ml of methanol, ultrasonically treat for 20 minutes, let it cool, centrifuge at 3000 revolutions per minute for 10 minutes, take the supernatant. Ultrasonically extract the residue once again in the same way, combine the supernatants. Wash the residue with 30 ml of methanol, centrifuge, and incorporate the washing liquid into the supernatant. Concentrate it under reduced pressure to dryness. Dissolve the residue with an appropriate amount of methanol, transfer it to a 10-ml volumetric flask, add methanol to the mark, shake well, filter through a 0.45-μm microporous membrane, and take the filtrate, which is the test solution.

[0083] (3) Chromatographic conditions and system suitability: Use octadecylsilane chemically bonded silica gel as the filler (the pressure resistance should not be less than 3500 psi). Use acetonitrile as mobile phase A and water as mobile phase B, and perform gradient elution according to the regulations in Table 2: flow rate 1.6 ml / min; column temperature 35 °C; detection wavelength 203 nm. Calculate the number of theoretical plates based on the ginsenoside Rb1 peak.

[0084] Table 2 Elution program

[0085]

[0086] (4) Determination method: Pipette accurately 10 μl of the reference substance solution and the test solution respectively, inject them into the liquid chromatograph for determination, record the chromatogram. The chromatograms of the reference substance solution and the test solution (sampling 1-1 sample at 30 minutes) are respectively Figure 1 、 Figure 2 andFigure 3 as shown

[0087] According to the "Technical Guidelines for the Study of Mixing Uniformity and In-Process Dosage Unit Uniformity of Oral Solid Preparations of Chemical Drugs (Trial)", one sample is tested at each sampling point, and the RSD value of the content of ginsenoside Rb1 at 11 sampling points is calculated to evaluate the mixing uniformity of each powder. When the content RSD is greater than 5%, the remaining 2 samples at each sampling point need to be tested, and the content RSD is calculated for all the tested samples.

[0088] The determination results are shown in Table 3-8.

[0089] 3.2 Determination method for the content of 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside, a characteristic component of processed Polygonum multiflorum

[0090] Referring to the method for the determination of stilbene glycoside in processed Polygonum multiflorum in Part I of the Chinese Pharmacopoeia (2020 Edition), the specific test method is as follows.

[0091] (1) Chromatographic conditions and system suitability test: Use octadecylsilane chemically bonded silica gel as the filler; use acetonitrile-water (25:75) as the mobile phase; the detection wavelength is 320 nm. The number of theoretical plates calculated based on the peak of 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside should be not less than 2000.

[0092] (2) Preparation of reference substance solution: Take an appropriate amount of 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside reference substance, accurately weigh it, and dissolve it in dilute ethanol to make a solution containing 0.2 mg per 1 ml, that is, obtain.

[0093] (3) Preparation of test solution: Take about 1 g of the powder of this product, accurately weigh it, place it in a stoppered conical flask, accurately add 25 ml of dilute ethanol, weigh it, heat under reflux for 30 minutes, cool, weigh it again, make up the lost weight with dilute ethanol, shake well, let it stand, filter the supernatant, and take the continuous filtrate, that is, obtain.

[0094] (4) Determination method: Accurately pipette 10 μl of the reference substance solution and the test solution respectively, inject them into the liquid chromatograph for determination, that is, obtain. The chromatograms of the reference substance and the test sample (sampling 1-1 sample at 30 minutes) are respectively Figure 4 and Figure 5 as shown

[0095] According to the Technical Guidelines for the Study of Mixing Uniformity and Unit Uniformity of Controlled Dosages of Chemical Oral Solid Preparations (Trial), one sample is tested at each sampling point, and the RSD values ​​of the 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside content at 11 sampling points are calculated to judge the mixing uniformity of each drug powder. When the content RSD is greater than 5%, the remaining 2 samples at each sampling point need to be tested, and the content RSD is calculated for all tested samples.

[0096] The measurement results are shown in Table 3-8.

[0097] 3.3 Determination of cinnamaldehyde content, a characteristic component of cinnamon

[0098] Referring to the cinnamon content determination method in Part I of the 2020 edition of the Chinese Pharmacopoeia, the specific test method is as follows.

[0099] (1) Chromatographic conditions and system suitability test: Octadecylsilane bonded silica gel is used as filler; acetonitrile-water (35:75) is used as mobile phase; detection wavelength is 290 nm. The theoretical plate number calculated based on the cinnamaldehyde peak should be no less than 3000.

[0100] (2) Preparation of reference solution: Take an appropriate amount of cinnamaldehyde reference substance, weigh it accurately, and add methanol to make a solution containing 10 μg per 1 ml.

[0101] (3) Preparation of test solution: Take about 4g of the powder of this product, weigh it accurately, place it in a stoppered conical bottle, accurately add 25ml of methanol, weigh it, ultrasonically treat it (power 350W, frequency 35kHz) for 10 minutes, leave it overnight, ultrasonically treat it once in the same way, weigh it again, make up the lost weight with methanol, shake it well, and filter it. Accurately measure 1ml of the filtrate, place it in a 25ml volumetric bottle, add methanol to the scale, shake it well, and obtain it.

[0102] (4) Determination method: Accurately pipette 10 μl of reference solution and test solution respectively, inject into liquid chromatograph, and determine. The chromatograms of reference solution and test solution (1-1 sample taken every 30 minutes) are: Figure 6 and Figure 7 shown.

[0103] According to the Technical Guidelines for the Study of Mixing Uniformity and Unit Uniformity of Controlled Dosages of Chemical Oral Solid Preparations (Trial), one sample is tested at each sampling point, and the RSD values ​​of the cinnamaldehyde content at 11 sampling points are calculated to judge the mixing uniformity of each drug powder. When the content RSD is greater than 5%, the remaining 2 samples at each sampling point need to be tested, and the content RSD is calculated for all tested samples.

[0104] 4. Particle size distribution determination

[0105] Using the Topsizer Omek laser particle size analyzer, the measurement was carried out by the dry method. The dispersion medium was air, the background sampling time was 12 seconds, and the sample sampling time was 12 seconds. The particle size distributions of the 6 kinds of medicinal powders in Examples 1-3 and Comparative Examples 1-3 were detected respectively, and the D90, D50, and D10 particle size ranges of each sample were measured. The results are shown in Table 9.

[0106] 5. Measurement of powder flowability

[0107] The remaining samples of the 6 kinds of medicinal powders in Examples 1-3 and Comparative Examples 1-3 after taking out the samples for measuring the particle size distribution were used to measure the powder flowability. The measurement method was in accordance with the "Guidelines for the Measurement of Powder Flowability" issued by the National Pharmacopoeia Commission. The angle of repose of the 6 kinds of medicinal powders was measured by the funnel method, and the results are shown in Table 9.

[0108] Table 3 Measurement results of the mixing uniformity of 11 sampling points of Medicinal Powder 1 in Example 1 at different mixing times

[0109]

[0110]

[0111] Table 4 Measurement results of the mixing uniformity of 11 sampling points of Medicinal Powder 2 in Example 2 at different mixing times

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[0113] Table 5 Measurement results of the mixing uniformity of 11 sampling points of Medicinal Powder 3 in Example 3 at different mixing times

[0114]

[0115] Table 6 Measurement results of the mixing uniformity of 11 sampling points of Medicinal Powder 6 in Comparative Example 1 at different mixing times

[0116]

[0117]

[0118] Table 7 Measurement results of the mixing uniformity of 11 sampling points of Medicinal Powder 7 in Comparative Example 2 at different mixing times

[0119]

[0120]

[0121] Table 8 Measurement results of the mixing uniformity of 11 sampling points of Medicinal Powder 8 in Comparative Example 3 at different mixing times

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[0123]

[0124]

[0125] Table 9 Summary of the determination results of the mixing uniformity, particle size distribution and flowability angle of repose for the mixing tests of Medicinal Powder 1-3 and Medicinal Powder 6-8

[0126]

[0127]

[0128] Analysis of test results

[0129] Material mixing is a key process in the production process of oral solid preparations. The purpose of this process is to make the mixed materials fully and evenly mixed to ensure that each unit dose of the material contains an equal amount of active substances, thus ensuring the uniformity of the finished product content.

[0130] Mixing uniformity is a general index to evaluate whether the material mixing process meets the requirements. In the "Technical Guidelines for the Study of Mixing Uniformity and In-process Dosage Unit Uniformity of Chemical Oral Solid Preparations (Trial)", there are clear regulations on the acceptance criteria for the mixing uniformity of materials for oral solid preparations. It is stipulated that at least 10 sampling points should be selected. When the relative standard deviation RSD of the content of the detected components at each sampling point ≤ 5%, the mixing uniformity meets the regulations; when RSD > 5%, the mixing uniformity is unacceptable.

[0131] Judging from the test results in Table 9, as the internal sieve of the pulverizer becomes finer, the pulverization particle size of each medicinal flavor of Jinfeng Pills pulverized into medicine becomes smaller. In the mixing process, the coarser the particle size of the Jinfeng Pills medicinal powder, the less favorable it is for mixing. Comparing Medicinal Powder 6 with Medicinal Powder 1, Medicinal Powder 2, and Medicinal Powder 3, although the mixing uniformity compliance time is 20 minutes for all of them, when the mixing time is extended, the mixing uniformity of Medicinal Powder 6 cannot be improved more significantly, while the finer Medicinal Powder 1, Medicinal Powder 2, and Medicinal Powder 3 can be mixed more evenly, and the content deviation of the three index components at each sampling point is smaller.

[0132] The test results show that the Jinfeng Pills medicinal powder being too fine is also not favorable for mixing. For example, the particle sizes of Medicinal Powder 7 and Medicinal Powder 8 are smaller than those of Medicinal Powder 1, Medicinal Powder 2, and Medicinal Powder 3, especially the D50 is much smaller, indicating that the proportion of extremely fine powder in Medicinal Powder 7 and Medicinal Powder 8 is more. Due to the powder being too fine, it has strong hygroscopicity and greater adhesiveness, resulting in poor powder fluidity, which can be seen from the determination results of the angle of repose. The angles of repose of Medicinal Powder 7 and Medicinal Powder 8 are greater than 40°, belonging to powders with poor fluidity. Therefore, it is instead not easy for the two to be mixed evenly. Medicinal Powder 7 needs 30 minutes of mixing to meet the mixing uniformity standard, and the content deviation of the three index components at each sampling point is relatively large. For Medicinal Powder 8, after 60 minutes of mixing, the RSD value of the mixing uniformity is slightly lower than 5%, indicating that the Jinfeng Pills medicinal powder being too fine is not conducive to uniform mixing.

[0133] In terms of mixing uniformity, both powder 7 and powder 8 are unacceptable comminution schemes.

[0134] In terms of the angle of repose of the powder, the smaller the comminution particle size of each medicinal flavor of Jinfeng Pills comminuted for use in medicine, the larger the angle of repose of the powder, and the worse the fluidity of the powder. When the particle size distribution of the powder is D90 = 107.418 μm, D50 = 35.152 μm, and D10 = 12.281 μm, that is, the tested powder 7, the angle of repose is as high as 41.39°, and the fluidity is poor. The particle size distribution range of powder 8 is even smaller, and the angle of repose is close to 50°, belonging to a powder with very poor fluidity. Obviously, neither of them is suitable for the subsequent preparation process of Jinfeng Pills.

[0135] Among the 6 tested powders, powders 1, 2, and 3 have a short mixing uniformity compliance time, a small angle of repose of the powder, and excellent fluidity, and are the optimal comminution schemes for each medicinal flavor of Jinfeng Pills comminuted for use in medicine.

[0136] Therefore, comprehensively speaking, among the 6 powders, the particle size distributions of powders 1, 2, and 3 are the best, the mixing uniformity compliance time is moderate, and the powder fluidity is good.

[0137] To ensure that the mixing uniformity of the Jinfeng Pills powder mixing process is easily compliant, the mixing process takes a short time, the mixing uniformity is excellent, and at the same time the powder fluidity is good, it is necessary to stipulate the appropriate particle size range of the powder to formulate the comminution process.

[0138] In the embodiment of the present invention, the particle size distribution range of the Jinfeng Pills powder is D90 = 130 μm - 145 μm, D50 = 50 μm - 80 μm, D10 = 20 μm - 30 μm, and the comminution process is to use a turbo mill equipped with a 100-mesh sieve for comminution once, or install an 80-mesh sieve for the first time and a 100-mesh sieve for the second time for comminution twice, or install a 100-mesh sieve for the first time and a 120-mesh sieve for the second time for comminution twice. The powder prepared by comminution according to such process conditions can fully meet the quality requirements of the Jinfeng Pills production process, thereby ensuring the uniformity of the quality of each batch of Jinfeng Pills finished products and ensuring the stability of the clinical efficacy of Jinfeng Pills.

[0139] The above detailed description is a specific description of one feasible embodiment of the present invention. This embodiment is not intended to limit the patent scope of the present invention. Any equivalent implementation or modification without departing from the present invention shall be included within the scope of the technical solution of the present invention.

Claims

1. A method for preparing Jinfeng Pills for treating infertility, characterized in that: The following steps are involved: (1) boiling epimedium, curculigo and pilose antler with water, combining the decoctions, filtering and concentrating to obtain a clear paste; (2) stewing the donkey-hide gelatin with water, mixing it with the qinggao and the intermediate of Jinfeng Pills, drying, crushing, and making pills with refined honey and water, and drying to obtain the Jinfeng Pills; The preparation method of the Jinfeng Pill intermediate comprises the following steps: Ginseng, cinnamon bark, motherwort, Ligustrum lucidum and processed Polygonum multiflorum are crushed, sieved and mixed to obtain a powder; the particle size range of the powder is D90 of 130 μm-145 μm, D50 of 50 μm-80 μm, and D10 of 20 μm-30 μm; the powder is the intermediate of Jinfeng Pills; The crushing is performed twice, the first time through an 80-mesh sieve, and the second time through a 100-mesh sieve; the mixing speed is 10-12 rpm, and the mixing time is 20-60 min; The raw materials of the Jinfeng Pills are as follows: 2-2.8 parts of epimedium, 1.2-2 parts of pilose antler, 1.6-2.4 parts of curculigo, 4-4.8 parts of cinnamon, 5.6-6.4 parts of ginseng, 1.2-2 parts of donkey-hide gelatin, 5.6-6.4 parts of processed Polygonum multiflorum, 7.6-8.4 parts of Ligustrum lucidum and 7.6-8.4 parts of Leonurus japonicus.

2. A method for preparing Jinfeng Pills for treating infertility, characterized in that: The following steps are involved: (1) boiling epimedium, curculigo and pilose antler with water, combining the decoctions, filtering and concentrating to obtain a clear paste; (2) stewing the donkey-hide gelatin with water, mixing it with the qinggao and the intermediate of Jinfeng Pills, drying, crushing, and making pills with refined honey and water, and drying to obtain the Jinfeng Pills; The preparation method of the Jinfeng Pill intermediate comprises the following steps: Ginseng, cinnamon bark, motherwort, Ligustrum lucidum and processed Polygonum multiflorum are crushed, sieved and mixed to obtain a powder; the particle size range of the powder is D90 of 130 μm-145 μm, D50 of 50 μm-80 μm, and D10 of 20 μm-30 μm; the powder is the intermediate of Jinfeng Pills; The crushing is performed twice, the first time through a 100-mesh screen, and the second time through a 120-mesh screen; the mixing speed is 10-12 rpm, and the mixing time is 20-60 min; The raw materials of the Jinfeng Pills are as follows: 2-2.8 parts of epimedium, 1.2-2 parts of pilose antler, 1.6-2.4 parts of curculigo, 4-4.8 parts of cinnamon, 5.6-6.4 parts of ginseng, 1.2-2 parts of donkey-hide gelatin, 5.6-6.4 parts of processed Polygonum multiflorum, 7.6-8.4 parts of Ligustrum lucidum and 7.6-8.4 parts of Leonurus japonicus.

3. A method for preparing Jinfeng Pills for treating infertility, characterized in that: The following steps are involved: (1) boiling epimedium, curculigo and pilose antler with water, combining the decoctions, filtering and concentrating to obtain a clear paste; (2) stewing the donkey-hide gelatin with water, mixing it with the qinggao and the intermediate of Jinfeng Pills, drying, crushing, and making pills with refined honey and water, and drying to obtain the Jinfeng Pills; The preparation method of the Jinfeng Pill intermediate comprises the following steps: Ginseng, cinnamon bark, motherwort, Ligustrum lucidum and processed Polygonum multiflorum are crushed, sieved and mixed to obtain a powder; the particle size range of the powder is D90 of 130 μm-145 μm, D50 of 50 μm-80 μm, and D10 of 20 μm-30 μm; the powder is the intermediate of Jinfeng Pills; The crushing is performed by crushing once and passing through a 100-mesh screen; the mixing speed is 10-12 rpm, and the mixing time is 20-60 min; The raw materials of the Jinfeng Pills are as follows: 2-2.8 parts of epimedium, 1.2-2 parts of pilose antler, 1.6-2.4 parts of curculigo, 4-4.8 parts of cinnamon, 5.6-6.4 parts of ginseng, 1.2-2 parts of donkey-hide gelatin, 5.6-6.4 parts of processed Polygonum multiflorum, 7.6-8.4 parts of Ligustrum lucidum and 7.6-8.4 parts of Leonurus japonicus.

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