CN1311853C - Quick release Yuquan micropill - Google Patents
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- CN1311853C CN1311853C CNB2005100515418A CN200510051541A CN1311853C CN 1311853 C CN1311853 C CN 1311853C CN B2005100515418 A CNB2005100515418 A CN B2005100515418A CN 200510051541 A CN200510051541 A CN 200510051541A CN 1311853 C CN1311853 C CN 1311853C
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Abstract
The present invention relates to a quick release Yuquan micro pill for treating diabetes and a preparation method thereof. The preparation method of the quick release Yuquan micro pill for treating diabetes comprises the following steps: the heating reflux extracting process of kudzuvine root and Chinese magnolivine fruit is carried out by ethanol; residue after extraction is mixed into 4 kinds of medicine of snakegourd root, ophiopogon root, radix glycyrrhiza and rehmanniae, a boiling process is carried out by adding water, and then filtration is carried out; water and ethanol extracting liquid becomes the liquid with the solid amount of about 16% (W/W) by reducing pressure and concentrating, and a dry extract can be obtained by the atomized drying process of the obtained extracting liquid; the powder of the dry extract and microcrystalline cellulose are put into a fluidized bed granulating coating machine according to the ratio by weight of 68 to 40:32 to 60 (W/W) of the powder of the dry extract to the microcrystalline cellulose, a granulating process is carried out by top spraying 5% polyvinyl pyrrolidone (W/V) or side spraying 10% polyvinyl pyrrolidone water solution (W/V), and granules become circular by rolling; the micro pills of 30 to 60 meshes are collected, and a coating process is carried out. The quick release Yuquan micro pill has the advantages of significant treating effect which is better than that of the original dose form Yuquan pill, high effect taking speed, small use dose, complete medicine absorption and high biologic utilization degree.
Description
Invention field
The present invention relates to a kind of Chinese medicine preparation for the treatment of diabetes, promptly the Chinese medicine pellet preparation particularly, the present invention relates to a kind of quick release Yuquan micropill for the treatment of diabetes and preparation method thereof.
Background technology
Diabetes are department of endocrinology commonly encountered diseases, frequently-occurring disease, also claim adult's morbidity type diabetes, how to fall ill after 35～40 years old, account for diabetics more than 90%, and ascendant trend is gradually arranged in recent years.Clinical is outstanding feature with the hyperglycemia, and prolonged illness can cause the infringement of a plurality of systems of whole body.Have refractory more, the relapse rate height, take medicine all the life, characteristics such as complication is many, case fatality rate height.
Also there is toxic and side effects simultaneously in blood sugar lowering Western medicine commonly used because of its effect limitation does not have the comprehensive therapy effect.If take the blood sugar lowering Western medicine for a long time, cause causing that than big accumulating of toxic and side effects the patient produces drug resistance and dependency, in the course of time, improved the incidence rate of a disease such as diabetic nephropathy, retinopathy, neuropathy, diabetic foot again.And have clear and definite blood sugar lowering, the Chinese medicine of insulin sensitivity enhancing (especially compound preparation) except that being difficult for producing the drug resistance through the modern pharmacological research proof, also have lighter toxicity, the advantage of side effect.
YUQUAN WAN is loose by clear leaf sky scholar " plant good fortune hall public-selected good recipe " Yuquan and is changed agent and form, and is a classics recipe, has replenishing YIN and removing heat, the effect of promoting the production of body fluid to quench thirst.Clinically be used for light, medium-sized type 2 diabetes mellitus patient determined curative effect, effectively drink polyphagia, polyuria, asthenia, symptoms such as emaciated physique more than the diabetes-alleviating.Shortcomings such as but it exists bioavailability low, and drug absorption is incomplete, and dosage is big and outward appearance thick, big, black.The inventor concentrates on studies to the preparation of YUQUAN WAN, carries out the dosage form process modification on the basis of tradition name side YUQUAN WAN, by Orthogonal Experiment and Design, filters out the preparation technology of optimization, has finished the present invention thus.
Summary of the invention
The purpose of this invention is to provide a kind of quick release Yuquan micropill for the treatment of diabetes and preparation method thereof.
The objective of the invention is to realize by following technical proposal:
Quick release Yuquan micropill of the present invention is by following method preparation, wherein:
Prescription:
Radix Puerariae 5-25 weight portion Fructus Schisandrae Chinensis 5-25 weight portion
Radix Glycyrrhizae 1-10 weight portion Radix Trichosanthis 5-25 weight portion
Radix Rehmanniae 5-25 parts by weight 5-25 Radix Ophiopogonis weight portion
Method for making:
Radix Puerariae, Fructus Schisandrae Chinensis, Radix Glycyrrhizae, Radix Trichosanthis 4 flavor medicated powder are broken into coarse powder, and Radix Rehmanniae is cut into small pieces, and Radix Ophiopogonis, tuber was standby; Radix Puerariae, add in the Fructus Schisandrae Chinensis be equivalent to 4～8 times of weight of crude drug amount 60～95%, preferred 70～90% ethanol (V/V) heating and refluxing extraction 1～3 time, each 1～3 hour, filter merging filtrate; After Radix Puerariae and Fructus Schisandrae Chinensis filtering residue are flung to ethanol, incorporate in Radix Trichosanthis, Radix Ophiopogonis, Radix Glycyrrhizae, the Radix Rehmanniae 4 flavor medicines, add 6 6～10 times of decoctings of distinguishing the flavor of crude drug amount weight that are equivalent to write out a prescription and boil 1～3 time, each 1～2 hour, filter collecting decoction; Being evaporated to solid content is 15～17%, preferred 16% (W/W); With gained extracting solution spray drying, inlet temperature is set at 170～180 ℃, and outlet temperature is set at 80～90 ℃, obtains dry extract; According to the dry extract powder: the microcrystalline Cellulose weight ratio is that the ratio of 68～40: 30～60 (W/W) drops in the fluidized bed prilling coating machine, is sprayed or side spray grain by the top as binding agent with 5～10% polyvinylpyrrolidones or 3～6% hypromellose aqueous solutions (W/V).
Optimized technical scheme of the present invention is:
Prescription:
Radix Puerariae 15 weight portion Fructus Schisandrae Chinensis 15 weight portions
Radix Glycyrrhizae 5 weight portion Radix Trichosanthis 15 weight portions
Radix Rehmanniae 15 weight portion weight portions Radix Ophiopogonis 15
Method for making:
Radix Puerariae, Fructus Schisandrae Chinensis, Radix Glycyrrhizae, Radix Trichosanthis 4 flavor medicated powder are broken into coarse powder, and Radix Rehmanniae is cut into small pieces, and Radix Ophiopogonis, tuber was standby; Radix Puerariae adds 80% ethanol (V/V) heating and refluxing extraction 2 times be equivalent to 8 times of weight of crude drug amount in the Fructus Schisandrae Chinensis, each 2 hours, filter merging filtrate; After Radix Puerariae and Fructus Schisandrae Chinensis filtering residue are flung to ethanol, incorporate in Radix Trichosanthis, Radix Ophiopogonis, Radix Glycyrrhizae, the Radix Rehmanniae 4 flavor medicines, add the 68 times of decoctings of distinguishing the flavor of crude drug amount weight that are equivalent to write out a prescription and boil 2 times, each 2 hours, filter collecting decoction; Being evaporated to solid content is 15～17%, preferred 16% (W/W); With gained extracting solution spray drying, inlet temperature is set at 170～180 ℃, and outlet temperature is set at 80～90 ℃, obtains dry extract; According to the dry extract powder: the microcrystalline Cellulose weight ratio is that the ratio of 40: 60 (W/W) drops in the fluidized bed prilling coating machine, is granulated by top spray 5% polyvinylpyrrolidone aqueous solution (W/V), collects 30～60 order granules.
The quick release Yuquan micropill curative effect height that the present invention prepares, using dosage is little, drug absorption is complete, bioavailability is high, taking convenience, be convenient to storage and custody.
The prepared quick release Yuquan micropill preparation of the present invention can be used for the treatment of the ripe Sheng card of the deficiency of YIN of diabetes, is equivalent to the type 2 diabetes mellitus of doctor trained in Western medicine, and disease is seen polydipsia, polyphagia, polyuria, asthenia, emaciated physique etc.
Further specify the present invention below by embodiment.It should be understood that embodiments of the invention are to be used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.In addition, in the present invention, (v/v) expression volume by volume concentration or volume ratio; (w/w) expression weight ratio concentration or weight ratio; (w/v) expression bulking value specific concentration or w/v, its corresponding unit is (grams per milliliter).
Embodiment 1: Yuquan micropill dry extract Study on extraction
1.1 the process conditions research that Radix Puerariae, Fructus Schisandrae Chinensis, Radix Glycyrrhizae, Radix Trichosanthis, Radix Rehmanniae, Radix Ophiopogonis extract:
Because the effective ingredient puerarin of Radix Puerariae in the prescription, first element, second element dissolubility in ethanol in the Fructus Schisandrae Chinensis are bigger, and the polysaccharide in Radix Ophiopogonis, Radix Trichosanthis, the Radix Rehmanniae, the glycyrrhizic acid in the Radix Glycyrrhizae all are water miscible.In order to maximally utilise the active ingredient of the medicine of respectively distinguishing the flavor of, we consider that the former two extracts with the alcohol of high concentration, and remaining decocting has designed eight technologies.Specific as follows:
Technology one: the whole decoctings of Six-element medicine, 10 times of amounts for the first time, 1 hour; 8 times of amounts for the second time, 1 hour.
Technology two: whole 30% alcohol extractions (V/V), 10 times of amounts for the first time, 1 hour; 8 times of amounts for the second time, 1 hour.
Technology three: whole 60% alcohol extractions (V/V), 8 times of amounts for the first time, 1 hour; 6 times of amounts for the second time, 1 hour.
Technology four: whole 95% alcohol extractions (V/V), 8 times of amounts for the first time, 1 hour; 6 times of amounts for the second time, 1 hour.
Technology five: Radix Puerariae, Fructus Schisandrae Chinensis 80% alcohol extraction (V/V), twice, 1 hour/time, 8 times of amounts for the first time, 6 times of amounts for the second time, medicinal residues discard; Radix Rehmanniae, Radix Ophiopogonis, Radix Glycyrrhizae, Radix Trichosanthis decocting, twice, 1 hour/time.
Technology six: Radix Puerariae, Fructus Schisandrae Chinensis 80% alcohol extraction (V/V), twice, 1 hour/time, for the first time 8 times of amounts, 6 times of amounts for the second time; Medicinal residues are incorporated all the other four Chinese medicine decoctings into, 10 times of amounts for the first time, 1 hour; 8 times of amounts for the second time, 1 hour.
Technology seven: Radix Puerariae, Fructus Schisandrae Chinensis, alcohol extraction Radix Ophiopogonis 80% (V/V), twice, 1 hour/time, for the first time 8 times of amounts, 6 times of amounts for the second time; Medicine is looked into and is integrated with Radix Rehmanniae, Radix Glycyrrhizae, Radix Trichosanthis decocting, and 2 times, 1 hour/time, for the first time 10 times of amounts, 8 times of amounts for the second time.
Technology eight: Radix Ophiopogonis, Radix Trichosanthis water decoction-alcohol sedimentation, decocting: 10 times of amounts for the first time, 1 hour, 8 times of amounts for the second time, 1 hour, merge extractive liquid, also was concentrated into 1: 1 (W/V), adding 95% ethanol (V/V) makes solution concentration reach 80% (V/V), standing over night then, polysaccharide is separated out, and filters back solution and discards; Radix Glycyrrhizae, Radix Rehmanniae decocting, 10 times of amounts for the first time, hour, 8 times of amounts for the second time, 1 hour; Radix Puerariae, Fructus Schisandrae Chinensis 80% alcohol extraction (V/V), 8 times of amounts for the first time, 1 hour, 6 times of amounts for the second time, 1 hour, be condensed into after medicinal liquid merges extractum and with the polysaccharide mixing that obtains.
The extracting solution reclaim under reduced pressure of each worker's generation, vacuum drying.Gained extractum amount sees Table 1:
The different extraction process dry extract of table 1. yield
| Technology number | Extractum weight (g) | Yield of extract (%, (W/W) |
| 1 2 3 4 5 6 7 8 | 89.0399 59.5959 59.8118 25.3948 67.1641 77.5895 76.688 40.5648 | 55.65 37.25 37.38 15.87 41.98 48.49 47.93 25.35 |
To its active component scoring, gained the results are shown in Table 2:
Each activity index composition comprehensive grading in table 2. different process
| Technology number | Puerarin (mg) | Deoxyschizandrin (mg) | Schisandrin B (mg) | Glycyrrhizic acid (mg) | Total polysaccharides (mg) | Total score |
| 1 2 3 4 5 6 7 8 | 579 661 651 578 736 768 778 363 | 2.303 15.233 28.256 27.369 19.118 13.934 2.903 25.226 | 6.718 40.751 89.507 86.908 64.700 46.495 8.603 86.894 | 0.0603 0.1691 0.2050 0.2133 0.1302 0.1148 0.1118 0.1508 | 12.85 2.59 1.20 0.11 4.52 5.46 6.23 2.85 | 63.255 57.962 62.603 55.671 68.297 69.030 65.324 44.965 |
Standards of grading *: regulation puerarin, deoxyschizandrin, second element, glycyrrhizic acid, total polysaccharides full marks were respectively 50 minutes, 7 minutes, 7 minutes, 6 minutes and 30 minutes.The high-load of puerarin is 730.5mg, is designated as 50 fens, and other value is designated as A/730.5 * 50; First element, the high-load of second element are respectively 42.07mg and 77.97mg, and they are designated as 7 fens respectively, and other value then is designated as B/42.17 * 7 and B/77.97 * 7; The high-load of glycyrrhizic acid is 202mg, is designated as 6 fens, and then other value is designated as C/202 * 6 respectively; The high-load of total polysaccharides is 13.29mg, is designated as 30 fens, and then other value is designated as D/13.29 * 30 respectively.Always keep the score and be A/730.5 * 50+B/42.17 * 7+B/77.97 * 7+C/202 * 6+D/13.29 * 30.
For asking optimised process, cooperate technical study.Yuquan micropill extract to eight kinds of different process preparations has carried out pharmacodynamics test, has observed its influence to epinephrine and alloxan mice hyperglycemia model blood glucose, and the result is as follows:
1. to the influence of epinephrine induced hyperglycemia mice blood sugar content
According to " Chinese biochemical drug magazine ", 2002,23 (3), the 112-114 page or leaf: the method for describing in " the alpha-glucosaccharase enzyme preparation is to the hypoglycemic activity of mice in the Fructus Schisandrae Chinensis ", get 120 of normal mouses, be divided into 12 groups, normal control group and model control group Huan stomach normal saline, all the other the 10 groups medicines (6g/kg) that extract to different process respectively, 0.1ml/10g, continuous 8 days.Fasting is 3 hours after the last administration, and except that normal group, all the other are respectively organized the abdominal cavity and annotate epinephrine 100ug/kg.After 30 minutes, get blood respectively and adopt glucose GOD-PAP method to measure blood glucose value, the results are shown in Table 3:
The influence of table 3. pair epinephrine induced hyperglycemia mice blood sugar content
| Group | Dosage (g/kg) | Number of animals (only) | Blood glucose value (mmol/L) |
| No. 8 technology groups of No. 7 technology groups of No. 6 technology groups of No. 5 technology groups of No. 4 technology groups of No. 3 technology groups of No. 2 technology groups of No. 1 technology group of Normal group model control group | 6 6 6 6 6 6 6 6 | 10 10 10 10 10 10 10 10 10 10 | 8.69±0.76 11.91±2.77 9.62±1.14 ** 10.26±1.35 10.48±0.88 9.8±1.21 * 10.44±1.3 9.25±0.86 ** 10.23±1.29 12.78±2.13 |
"
*" represent to compare P＜0.05 with model control group, "
*" represent to compare P＜0.01 (following each table together) with model control group
2. to the influence of alloxan diabetes mouse's blood sugar content
According to " Chinese biochemical drug magazine ", 2002,23 (3), 112-114 page or leaf: the method for describing in " the alpha-glucosaccharase enzyme preparation is to the hypoglycemic activity of mice in the Fructus Schisandrae Chinensis ", the alloxan diabetes mice is by normal mouse lumbar injection alloxan (200mg/kg), survey fasting glucose after 72 hours, choose blood glucose value the above person of 11.0mmol/L.The difference of each treated animal average blood sugar is not more than 0.5mmol/L during grouping.Get 110 of alloxan diabetes mices, be divided into 11 groups at random, be respectively the administration group of model group and 10 kinds of different process, different process administration group is respectively with the 6g/kg dosed administration, 0.1ml/10g model group is given isometric normal saline, continuous 7 days, fasting is 3 hours after the last administration, gets blood and adopts glucose GOD-PAP method to measure blood glucose value.The results are shown in Table 4:
The influence of table 4. pair alloxan diabetes mouse's blood sugar content
| Group | Dosage (g/kg) | Number of animals (only) | Blood glucose value (mmol/L) |
| Normal control group model matched group | 10 10 | 8.69±0.76 11.91±2.77 |
| No. 8 technology groups of No. 7 technology groups of No. 6 technology groups of No. 5 technology groups of No. 4 technology groups of No. 3 technology groups of No. 2 technology groups of No. 1 technology group | 6 6 6 6 6 6 6 6 | 10 10 10 10 10 10 10 10 | 9.62±1.14 ** 10.26±1.35 10.48±0.88 9.8±1.21 * 10.44±1.3 9.25±0.86 * 10.23±1.29 12.78±2.13 |
Comprehensive two result of the tests think that the 1st, 4 and No. 6 technology is preferable to the blood sugar decreasing effect of diabetic mice, all can select.In conjunction with activity index composition comprehensive grading result, technology 6 comprehensive gradings are the highest, are optimum selection, i.e. Radix Puerariae, Fructus Schisandrae Chinensis 80% alcohol extraction (V/V), twice, 1 hour/time, for the first time 8 times of amounts, 6 times of amounts for the second time; Medicinal residues are incorporated all the other four Chinese medicine decoctings into, 10 times of amounts for the first time, 1 hour; 8 times of amounts for the second time, 1 hour.
1.2 the alcohol extraction process of Yuquan micropill is preferred:
Adopt orthogonal experiment method to determine Radix Puerariae, Fructus Schisandrae Chinensis alcohol extraction optimum process condition, select concentration of alcohol, alcohol adding amount, extraction time and 4 factors of extraction time as the investigation factor, 3 levels of each factor selection are investigated, as following table:
Table 5. factor level table
| Level | Factor | |||
| Concentration of alcohol A (%) | Alcohol adding amount B (doubly) | Extraction time (hour) | Extraction time D (inferior) | |
| 1 2 3 | 70 80 90 | 4 6 8 | 1 2 3 | 1 2 3 |
Take by weighing Radix Puerariae, each 15g of Fructus Schisandrae Chinensis 30g altogether according to the prescription ratio, claim 9 parts, experimentize analysis result such as table 6 according to orthogonal experiment scheme table:
Table 6. positive quadraturing design test analysis result
| Sequence number | Concentration of alcohol A (%) | Extraction time (hour) | Extracted amount (doubly) | Extraction time (inferior) | Puerarin content (mg) | First cellulose content (mg) | Second cellulose content (mg) | Comprehensive grading |
| 1 2 3 | 70 70 70 | 1 2 3 | 4 6 8 | 1 2 3 | 251.31 366.92 336.34 | 12.324 22.57 24.628 | 32.5875 51.24 47.6185 | 60.44 93.32 88.99 |
| 4 5 6 7 8 9 | 80 80 80 90 90 90 | 1 2 3 1 2 3 | 6 8 4 8 4 6 | 3 1 2 2 3 1 | 393.88 315.19 317.68 335.07 356.54 282.81 | 19.746 17.501 17.8932 20.9364 20.9300 10.1145 | 45.2228 49.063 49.9278 53.5236 53.6536 34.9305 | 92.89 80.51 81.53 88.00 91.31 64.32 | ||||
| K 1 K 2 K 3 K 1 2 K 2 2 K 2 2 R | 242.75 254.93 243.63 58927.5625 64989.3649 59355.5769 4.06 | 241.33 265.14 234.84 58240.1689 70299.2196 55149.8256 10.1 | 233.28 250.53 257.5 54419.5584 62765.2809 66306.2500 8.07 | 205.27 262.85 273.19 42135.7729 69090.1225 74632.7761 22.64 | ||||||||
Standards of grading *: standards of grading: the plain full marks of regulation puerarin and deoxyschizandrin, second respectively are 60 minutes, 20 minutes, 20 minutes, and the high-load of puerarin is 393.88mg, is designated as 60 fens, and other value is kept the score and is M/393.88 * 60; The high-load of first element, second element is respectively 24.628mg and 53.6536mg, and their divide and are designated as 20 fens, and other is kept the score respectively and is N/24.628 * 20 and N/53.6538 * 20, always keeps the score to be M/393.88 * 60+N/24.628 * 20+N/53.6538 * 20.The results of analysis of variance sees Table 7:
Table 7. The results of analysis of variance
| The source | Sum of sguares of deviation from mean | Degree of freedom | Variance | The F value | Significance |
| A B C D | 30.76 169.68 103.64 892.83 | 2 2 2 2 | 15.38 84.84 51.82 446.415 | 1 5.52 3.37 29.03 | P＞0.1 0.01＜P＜0.05 0.05＜P＜0.1 P＜0.01 |
F
0.1(2，8)=3.1 F
0.05(2，8)=4.46 F
0.01(2，8)＝8.65
By The above results is carried out variance analysis, the result as seen, D factor (extraction time) and B factor (extraction time) have the significance influence to the result, A, C two factors do not have the significance influence to the result.Optimum combination should be A
2B
2C
3D
3Make comparisons with the data of extracting three gained extracting twice, extracts twice data and account for and extract three times more than 90% of data, thus can think that twice composition of extraction extracts fully substantially, so selection D
2Do not have the significance difference owing to extract multiple, so select 8 times of amounts to extract, be C according to routine
2
According to The results of analysis of variance, actual in conjunction with producing, in line with the low principle of cost, determined the alcohol extraction process optimum condition: extract twice with 80% ethanol (V/V), the first time 8 times of amounts, 2 hours; 8 times of amounts for the second time, 2 hours.Get Radix Puerariae 30g, Fructus Schisandrae Chinensis 30g, carry out confirmatory experiment according to the optimum process condition of determining.Then wherein active constituent content is as shown in table 8 below.
Table 8. alcohol extraction process demonstration test
| Puerarin content (mg) | First cellulose content (mg) | Second cellulose content (mg) | Total score |
| 370.29 | 19.4928 | 55.4873 | 97.42 |
Confirmatory experiment shows: the technology that optimizes is rationally feasible.
1.3 the extraction process by water of Yuquan micropill is preferred:
Adopt orthogonal experiment method to determine best extraction process by water condition, select amount of water, decocting time, 3 factors of decoction number of times as the investigation factor, each factor selects 3 levels to investigate, and is as shown in table 9:
Table 9. factor level table
| Level | Factor | ||
| Amount of water (doubly) | Decocting time (hour) | Decoct number of times (inferior) | |
| 1 2 3 | 6 8 10 | 1 15 2 | 1 2 3 |
Take by weighing Radix Ophiopogonis, Radix Trichosanthis, each 270g of Radix Rehmanniae, Radix Glycyrrhizae 90g, totally nine parts in the prescription ratio.Every part adds after Radix Puerariae, the Fructus Schisandrae Chinensis alcohol extraction medicinal residues in addition and carries out water by the orthogonal design condition and carry, and the results are shown in Table 10:
Table 10. orthonormal design of experiments analysis result
| Sequence number | Concentration of alcohol A (%) | Extraction time (hour) | Extracted amount (doubly) | Extraction time (inferior) | Puerarin content (mg) | First cellulose content (mg) | Second cellulose content (mg) | Comprehensive grading |
| 1 2 3 4 5 6 7 8 | 70 70 70 80 80 80 90 90 | 1 2 3 1 2 3 1 2 | 4 6 8 6 8 4 8 4 | 1 2 3 3 1 2 2 3 | 251.31 366.92 336.34 393.88 315.19 317.68 335.07 356.54 | 12.324 22.57 24.628 19.746 17.501 17.8932 20.9364 20.9300 | 32.5875 51.24 47.6185 45.2228 49.063 49.9278 53.5236 53.6536 | 60.44 93.32 88.99 92.89 80.51 81.53 88.00 91.31 |
| 9 | 90 | 3 | 6 | 1 | 282.81 | 10.1145 | 34.9305 | 64.32 | ||
| K 1 K 2 K 3 K 1 2 K 2 2 K 2 2 R | 242.75 254.93 243.63 58927.5625 64989.3649 59355.5769 4.06 | 241.33 265.14 234.84 58240.1689 70299.2196 55149.8256 10.1 | 233.28 250.53 257.5 54419.5584 62765.2809 66306.2500 8.07 | 205.27 262.85 273.19 42135.7729 69090.1225 74632.776 1 22.64 | ||||||
Standards of grading
*: same with the standards of grading of table 2.
Variance analysis sees the following form 11:
Table 11. The results of analysis of variance
| The source | Sum of sguares of deviation from mean | Degree of freedom | Variance | The F value | Significance |
| A B C | 6.12 19.08 99.82 | 2 2 2 | 3.06 9.54 49.91 | 1 3.12 16.31 | P＞0.1 P＞0.1 P＜0.01 |
F
0.1(2，8)＝3.1 F
0.05(2，8)＝4.46 F
0.01(2，8)＝8.65
In conjunction with pharmacodynamics test, observed of the influence of different orthogonal design technology to element on the kidney and alloxan mice hyperglycemia model blood glucose, the result is as follows:
1. to the influence of epinephrine induced hyperglycemia mice blood sugar content
According to " Chinese biological magazine ", 2002,23 (3), the 112-114 page or leaf: method of describing in " the alpha-glucosidase agent is to the hypoglycemic activity of mice in the Fructus Schisandrae Chinensis ", measure blood glucose value with reference to " among the embodiment 1.1 1. in method ", the results are shown in Table 12:
The influence of table 12. pair epinephrine induced hyperglycemia mice blood sugar content
| Group | Dosage (g/kg) | Number of animals (only) | Blood glucose value (mmol/L) |
| No. 6 technology groups of No. 5 technology groups of No. 4 technology groups of No. 3 technology groups of No. 2 technology groups of No. 1 technology group of Normal group model control group | 6 6 6 6 6 6 | 10 10 10 10 10 10 10 10 | 8.39±1.05 13.43±2.49 11.19±2.28 ** 11.97±1.76 14.68±2.69 13.58±1.58 10.87±2.12 ** 96.1±1.62 ** |
| The former No. 6 technology group # of No. 9 technology groups of No. 8 T skills of No. 7 technology groups group | 6 6 6 6 | 10 10 10 10 | 11.62±2.16 * 14.26±2.03 11.26±1.25 * 11.49±1.60 * |
Among under 1 of #: the embodiment 1.1 " technology 6 ", down with.
2. to the influence of alloxan diabetes mouse's blood sugar content
According to " Chinese biochemical drug magazine ", 2002,23 (3), 112-114 page or leaf: the method for describing in " the alpha-glucosaccharase enzyme preparation is to the hypoglycemic activity of mice in the Fructus Schisandrae Chinensis ", measure blood glucose value with reference to " among the embodiment 1.2 2. method ", the results are shown in Table 13:
The influence of table 13. pair alloxan diabetes mouse's blood sugar content
| Group | Dosage (g/kg) | Number of animals (only) | Blood glucose value (mmol/L) |
| The former No. 6 technology group # of No. 9 technology groups of No. 8 technology groups of No. 7 technology groups of No. 6 technology groups of No. 5 technology groups of No. 4 technology groups of No. 3 technology groups of No. 2 technology groups of No. 1 technology group of model control group | 6 6 6 6 6 6 6 6 6 6 | 10 10 10 10 10 10 10 10 10 10 10 | 15.33±1.51 13.17±2.99 14.27±2.81 14.12±2.46 14.42±2.66 13.57±3.05 12.90±2.05 * 11.42±1.91 ** 13.62±3.26 14.59±1.51 13.75±2.66 |
From above two result of the tests as seen, 1st, 5,6,7, No. 9 technology and former No. 6 technology group administration group medicines are to the hypoglycemic activity of epinephrine induced mice hyperglycemia obviously (P＜0.05 or 0.01), and 6th, No. 7 technology and former No. 6 technology medicines are to alloxan diabetes mouse's blood sugar content blood sugar decreasing effect significantly (P＜0.05 or 0.01), comprehensive two result of the tests, think that the blood sugar decreasing effect of the 6th, No. 7 technology diabetic mice is preferable, all can select.
By table 10, table 11 analysis-by-synthesis, the A factor does not have significance, and A
2With A
3Numerical value considers that from energy-conservation angle the A factor is got A substantially near no significant difference
2Get final product; The B factor does not have significance yet, and on data, B
2With B
3Also no significant difference is basic identical, for guaranteeing may to get B fully according to exhausting
3The C factor has significance, but extraction ratio accounts for more than 93% of extraction for the third time for the second time, considers from saving cost and industrial aspect, selects C
2So optimum process condition is A
2B
2C
2Promptly 8 times of water gagings extract, and extract twice, each two hours.On drug effect, technology 6 and 7 all can be selected, but analyzes theoretically, and technology 6 is only extracted 1 time, is can't extract completely; Technology 7 is extracted 3 times, and it is also higher to extract multiple, and energy consumption is bigger, and the cycle is long.In conjunction with chemical index component analysis and pharmacodynamics, can think A
2B
2C
2It is optimum selection.Because it has reflected that not only the result that the activity index component content is measured has also taken into account technology 6 and technology 7 simultaneously, has promptly respected the result of pharmacodynamics.
In sum, orthogonal experiment determines that the good technology of water extraction is: 8 times of water gagings, each 2 hours, twice totally through active component comprehensive grading, variance analysis and pharmacodynamic experiment.
Demonstration test: by the optimised process of above-mentioned selection, i.e. Radix Puerariae, each 30g of Fructus Schisandrae Chinensis, i.e. two recipe quantities are with 80% ethanol (V/V) extraction, 8 times of amounts, each 2 hours, twice totally; After medicinal residues volatilize ethanol, incorporate Radix Glycyrrhizae 10g into, Radix Trichosanthis, Radix Rehmanniae, Radix Ophiopogonis each 30g, water is carried in the lump, 8 times of amounts, each 2 hours, twice totally.Carry out confirmatory experiment, record its active component content such as table 14:
Table 14. confirmatory experiment (n=3)
| Puerarin content | The first cellulose content | The second cellulose content | Glycyrrhizic acid content | Polyoses content |
| 756.65 | 51.80 | 82.14 | 127.42 | 9.15 |
Annotate: unit is milligram, is total to the contained total amount of the corresponding extractum of 160g crude drug by two recipe quantities.
By measured data as can be seen, content all is higher than the data of orthogonal test basically, can think optimum process condition.
The preparation method of experimental example 2. Yuquan micropills
Get each 17 kilograms of the Radix Puerariaes that are ground into coarse powder, Fructus Schisandrae Chinensis, Radix Trichosanthis, 17 kilograms of strippings and slicings of Radix Rehmanniae, be ground into 5.7 kilograms in the Radix Glycyrrhizae of coarse powder, Radix Ophiopogonis, tuber was 17 kilograms, determined that by final technology drops into extraction pot with Radix Puerariae, Fructus Schisandrae Chinensis, adds 8 times of amounts of 80% ethanol (V/V) (272L), heating and refluxing extraction two hours, after emitting extracting solution, add isodose 80% ethanol (V/V) again, heating and refluxing extraction two hours.After medicinal residues volatilize ethanol, other medical material is dropped in the lump, add 8 times of amounts of water 725.6L respectively, extracted twice totally two hours.
Merge ethanol extract and aqueous extract, decompression is concentrated into solid content and is about 16% (W/W).With gained extracting solution spray drying, inlet temperature is set at 180 ℃, and outlet temperature is set at 90 ℃.Finally obtain 29.95 kilograms in medicated powder, water content is 4.2%, and the rate of extract is 33.02% (W/W).According to the dry extract powder: microcrystalline Cellulose is the ratio of 55～40: 45～60 (W/W), with 5% polyvinylpyrrolidone aqueous solution or 3%HPMC aqueous solution (W/V) is binding agent, 67～71 ℃ of inlet temperature, 40 ℃ of sheet bed tempertaures, atomizing pressure 3bar, spray of fluid bed top or side spray pelletize, round as a ball; Use (W/V) moistureproof coating liquid coating of 18%OPADRYII (85G64874) (Shanghai Colorcon Coating Technology Co., Ltd's production), 45～50 ℃ of fluidized-bed temperatures, atomizing pressure 0.8～1kg/cm
2The micropill that this method is equipped with is 20～80 orders, and preferred 30～60 orders are smooth, the spherical piller of rounding.
Experimental example 3. preparation Yuquan micropills
Get each 17 kilograms of the Radix Puerariaes that are ground into coarse powder, Fructus Schisandrae Chinensis, Radix Trichosanthis, 17 kilograms of strippings and slicings of Radix Rehmanniae, be ground into 5.7 kilograms of the glycosides grass of coarse powder, Radix Ophiopogonis, tuber was 17 kilograms, determined that by final technology drops into extraction pot with Radix Puerariae, Fructus Schisandrae Chinensis, adds 8 times of amounts of 80% ethanol (V/V) (272L), heating and refluxing extraction two hours, after emitting extracting solution, go into isodose 80% ethanol (V/V) again, heating and refluxing extraction two hours.After medicinal residues volatilize ethanol, other medical material is dropped in the lump, add 8 times of amounts of water 725.6L respectively, extracted twice totally two hours.
Merge ethanol extract and aqueous extract, decompression is concentrated into solid content and is about 16% (W/W).With gained extracting solution spray drying, inlet temperature is set at 180 ℃, and outlet temperature is set at 90 ℃.Finally obtain 30.63 kilograms in medicated powder, water content is 45%, and the rate of extract is 33.77% (W/W).According to the dry extract powder: the ratio of microcrystalline Cellulose 40: 60 (W/W) is a binding agent with 5% polyvidon aqueous solution (W/V), 67～71 ℃ of inlet temperature, and 40 ℃ of sheet bed tempertaures, atomizing pressure 3bar, the spray pelletize of fluid bed top, round as a ball; Use (W/V) moistureproof coating liquid coating of 18%OPADRYII (85G64874) (Shanghai Colorcon Coating Technology Co., Ltd's production), 45～50 ℃ of fluidized-bed temperatures, atomizing pressure 0.8～1kg/cm
2The micropill of this method preparation is 30～60 orders, and is smooth, the spherical piller of rounding.
Experimental example 4. preparation Yuquan micropills
Get each 0.45 kilogram of the Radix Puerariae that is ground into coarse powder, Fructus Schisandrae Chinensis, Radix Trichosanthis, 0.45 kilogram of stripping and slicing of Radix Rehmanniae, be ground into 0.15 kilogram in the Radix Glycyrrhizae of coarse powder, Radix Ophiopogonis, tuber was 0.45 kilogram, determined that by final technology drops into extraction pot with Radix Puerariae, Fructus Schisandrae Chinensis, adds 8 times of amounts of 80% ethanol (V/V), heating and refluxing extraction two hours, after emitting extracting solution, go into isodose 80% ethanol (V/V) again, heating and refluxing extraction two hours.After medicinal residues volatilize ethanol, other medical material is dropped in the lump, add 8 times of amounts of water respectively, extracted twice totally two hours.
Merge ethanol extract and aqueous extract, decompression is concentrated into solid content and is about 16% (W/W).With gained extracting solution spray drying, inlet temperature is set at 180 ℃, and outlet temperature is set at 90 ℃.Finally obtain 0.816 kilogram in medicated powder, water content is 4.1%, and the rate of extract is 34.00% (W/W).According to the dry extract powder: microcrystalline Cellulose is the ratio of 68: 32 (W/W), is bonding profit with 10% polyvidon aqueous solution (W/V), 67～71 ℃ of inlet temperature, and 40 ℃ of sheet bed tempertaures, atomizing pressure 3bar, fluid bed side spray pelletize, round as a ball; Use (W/V) moistureproof coating liquid coating of 18%OPADRYII (85G64874) (Shanghai Colorcon Coating Technology Co., Ltd's production), 35～40 ℃ of fluidized-bed temperatures, atomizing pressure 0.8～1kg/cm
2The micropill of this method preparation is 30～60 orders, and is smooth, the spherical piller of rounding.
Experimental example 5 preparation Yuquan micropills
Get each 10 kilograms of the Radix Puerariaes that are ground into coarse powder, Fructus Schisandrae Chinensis, Radix Trichosanthis, 8 kilograms of strippings and slicings of Radix Rehmanniae, be ground into 3 kilograms in the Radix Glycyrrhizae of coarse powder, Radix Ophiopogonis, tuber was 8 kilograms, determined that by final technology drops into extraction pot with Radix Puerariae, Fructus Schisandrae Chinensis, adds 6 times of amounts of 90% ethanol (V/V), heating and refluxing extraction 3 hours, after emitting extracting solution, add isodose 90% ethanol (V/V) again, heating and refluxing extraction 2 hours.After medicinal residues volatilize ethanol, other medical material is dropped in the lump, add 10 times of amounts of water respectively, extracted totally 3 times 1 hour.
Merge ethanol extract and aqueous extract, decompression is concentrated into solid content and is about 17% (W/W).With gained extracting solution spray drying, inlet temperature is set at 175 ℃, and outlet temperature is set at 85 ℃.Finally obtain 15.72 kilograms in dry extract medicated powder, water content is 43%, and the rate of extract is 32.08% (W/W).According to the dry extract powder: microcrystalline Cellulose is the ratio of 50: 50 (W/W), is binding agent with 6% hydroxypropyl methylcellulose aqueous solution (W/V), 70 ℃ of inlet temperature, and 42 ℃ of sheet bed tempertaures, atomizing pressure 3bar, fluidized bed prilling is round as a ball; Use (W/V) moistureproof coating liquid coating of 18%OPADRYII (85G64874) (going up the production of every Ka Lekang packaging technique company limited), 42～48 ℃ of fluidized-bed temperatures, atomizing pressure 1kg/cm
2The micropill of this method preparation is 30～60 orders, and is smooth, the spherical piller of rounding.
Experimental example 6. preparation Yuquan micropills
Get each 1 kilogram of the Radix Puerariae that is ground into coarse powder, Fructus Schisandrae Chinensis, Radix Trichosanthis Radix Rehmanniae, 1 kilogram of stripping and slicing of Radix Rehmanniae, be ground into 0.2 kilogram in the Radix Glycyrrhizae of coarse powder, Radix Ophiopogonis, tuber was 1 kilogram, determined that by final technology drops into extraction pot with Radix Puerariae, Fructus Schisandrae Chinensis, adds 6 times of amounts of 90% ethanol (V/V), heating and refluxing extraction 3 hours, after emitting extracting solution, add isodose 90% ethanol (V/V) again, heating and refluxing extraction 2 hours.After medicinal residues volatilize ethanol, other medical material is dropped in the lump, add 10 times of amounts of water respectively, when extracting 1, totally 3 times.
Merge ethanol extract and aqueous extract, decompression is concentrated into solid content and is about 17% (W/W).With gained extracting solution spray drying, inlet temperature is set at 175 ℃, and outlet temperature is set at 85 ℃.Finally obtain 1.64 kilograms in dry extract medicated powder, water content is that 4.0% the rate of extract is 31.63% (W/W).According to the dry extract powder: microcrystalline Cellulose is the ratio of 50: 50 (w/w), is binding agent with 7.5% polyvinylpyrrolidone aqueous solution (W/V), 70 ℃ of inlet temperature, and 39 ℃ of sheet bed tempertaures, atomizing pressure 3bar, fluid bed side spray pelletize, round as a ball; Use (W/V) moistureproof coating liquid coating of 18%OPADRYII (85G64874) (Shanghai Colorcon Coating Technology Co., Ltd's production), 42～45 ℃ of fluidized-bed temperatures, atomizing pressure 21kg/cm
2The micropill of this method preparation is 30～60 orders, and is smooth, the spherical piller of rounding.
Experimental example 7. preparation Yuquan micropills
Get each 2 kilograms of the Radix Puerariaes that are ground into coarse powder, Fructus Schisandrae Chinensis, Radix Trichosanthis, 2 kilograms of strippings and slicings of Radix Rehmanniae, be ground into 0.8 kilogram in the Radix Glycyrrhizae of coarse powder, Radix Ophiopogonis, tuber was 2 kilograms, determined that by final technology drops into extraction pot with Radix Puerariae, Fructus Schisandrae Chinensis, adds 6 times of amounts of 90% ethanol (V/V), heating and refluxing extraction 3 hours, after emitting extracting solution, add isodose 90% ethanol (V/V) again, heating and refluxing extraction 2 hours.After medicinal residues volatilize ethanol, other medical material is dropped in the lump, add 10 times of amounts of water respectively, extracted totally 3 times 1 hour.
Merge ethanol extract and aqueous extract, decompression is concentrated into solid content and is about 15% (W/W).With gained extracting solution spray drying, inlet temperature is set at 175 ℃, and outlet temperature is set at 85 ℃.Finally obtain 3.51 kilograms in dry extract medicated powder, water content is 3.9%, and the rate of extract is 32.46% (W/W).According to the dry extract powder: microcrystalline Cellulose is the ratio of 60: 40 (w/w), is binding agent with 9% polyvinylpyrrolidone aqueous solution (W/V), 70 ℃ of inlet temperature, and 42 ℃ of sheet bed tempertaures, atomizing pressure 3bar, fluid bed side spray pelletize, round as a ball; Use (W/V) moistureproof coating liquid coating of 18%OPADRYII (85G64874) (Shanghai Colorcon Coating Technology Co., Ltd's production), 39～44 ℃ of fluidized-bed temperatures, atomizing pressure 1kg/cm
2This method preparation little bears ball and be 30～60 orders, and be smooth, the spherical piller of rounding.
The Yuquan micropill main pharmacodynamics experiment that embodiment 8. embodiment 3 prepare:
Medicine and reagent are as follows:
Yuquan micropill, according to the preparation of embodiment 3 methods, Shanghai Institute of Pharmaceutical Industry provides, lot number: 040309,
Face with before adding an amount of distilled water and be made into suitable concn, be i.e. 1g/ml.
Alloxan (Alloxan), U.S. Fluka company produces, lot number: 445307/131603091
YUQUAN WAN, the 0.15g/ ball, Jin Ding pharmaceutcal corporation, Ltd in Chengdu produces, lot number: 020725.
JIANGZHILING PIAN, the 25mg/ sheet, Junan, Shandong Province pharmaceutical factory produces, lot number: 020607.
The adrenalin hydrochloride injection, 1mg/ml, the good Pharmaceutical of Wuhan promise Group Plc, lot number: 011001
Capsulae Duoxikang, Yuwang Pharmaceutical Co., Ltd., Shandong Prov.'s product, lot number 011021 is made Emulsion during experiment.
Tolbutamide, the Changjiang river, Jiangsu pharmaceutcal corporation, Ltd product, lot number 0202217.
The glucose detection test kit, the Mai Ke of Sichuan Province Science and Technology Ltd. produces, lot number: 1103041
Concrete experiment is as follows:
8.1 the influence of epinephrine induced hyperglycemia mice blood sugar content
According to " Chinese biochemical drug magazine ", 2002,23 (3), the 112-114 page or leaf: the method for describing in " the alpha-glucosidase agent is to the hypoglycemic activity of mice in the Fructus Schisandrae Chinensis ", get 70 of normal mouses and be divided into 7 groups at random, 10 every group, normal control and model control group are irritated stomach with the volume normal saline, all the other respectively organize dosed administration as shown in Table 15, once a day, and continuous 11 days.Fasting is 3 hours after the last administration, and except that the normal group matched group, all the other respectively organize lumbar injection epinephrine 100ug/kg.Broken end is got blood respectively after injecting back 30 minutes, adopts glucose GOD-PAP method to survey the pyridine blood sugar content.The results are shown in Table 15:
The influence of table 15. pair epinephrine induced hyperglycemia mice blood sugar content
| Group | Dosage (g/kg) | Number of animals (only) | Blood glucose value (mmol/L) |
| Normal group model control group Yuquan micropill group Yuquan micropill group Yuquan micropill group diabetes pill group diaformin tablet group | - - 3.58 5.37 8.05 12.0 0.1 | 10 10 10 10 10 10 10 | 7.70±1.22 12.17±1.57 ▲▲ 10.72±1.20 * 9.95±1.49 ** 9.25±1.81 ** 10.14±1.79 ** 8.70±1.37 ** |
"
*" represent to compare P＜0.05 with model control group, "
*" represent to compare P＜0.01 with model control group, "
▲" represent to compare P＜0.05 with the normal control group, "
▲ ▲" expression and normal control group P＜0.01 relatively, below each table with.
The result shows that model control group mouse blood sugar value is significantly higher than the normal control group, and the modeling success is described; Yuquan micropill is little, in, heavy dose of administration group medicine hypoglycemic activity is obvious, compare difference with model control group significance (P＜0.05 or 0.01) is arranged, middle dosage group hypoglycemic activity is compared hypoglycemic activity with the former dosage form group of YUQUAN WAN and slightly is better than the former dosage form group of YUQUAN WAN, but there was no significant difference.
8.2 influence to the alloxan diabetes rats blood sugar content
Get normal rat, press 200mg/kg dosage lumbar injection alloxan, cut the tail blood sampling after 72 hours and survey fasting glucose, choose blood glucose value and be animal pattern the above person of 11.1mmol/L.Get 60 of alloxan diabetes Mus, be divided into 6 groups at random, the difference of each treated animal average blood sugar value is not more than 0.5mmol/L during grouping.Show the dosage gastric infusion by table 16, the 1ml/100g body weight, model group is given isometric normal saline, and once a day, continuous 14 days, fasting was 12 hours after the not inferior administration, and heart extracting blood adopts glucose GOD-PAP method to measure blood glucose value.The results are shown in Table 16:
The influence of table 16. pair alloxan diabetes mouse's blood sugar content
| Group | Dosage (g/kg) | Blood glucose value (mmol/L) |
| Model contrast Yuquan micropill Yuquan micropill Yuquan micropill YUQUAN WAN JIANGZHILING PIAN | 1.61 3.22 6.44 7.2 0.1 | 16.18±2.78 13.15±2.68 ** 13.30±2.68 ** 12.50±2.13U 13.43±2.16 ** 11.98±1.77 ** |
The result shows that each administration group blood sugar decreasing effect is remarkable, compares significant difference (P＜0.01) with model group, and Yuquan micropill administration group is compared there was no significant difference with former dosage form.
8.3 glucose is caused the influence that rat blood sugar raises
Get 70 of normal rats, be divided into 7 groups at random, 10 every group.Press the gastric infusion of dosage shown in the table 17, normal control group and glucose model group give isometric normal saline, 1ml/100g, once a day, continuous 14 days.Fasting 10 hours after time administration, except that the normal control group, all the other animal lumbar injection glucose solution 2g/kg, respectively at the injection back after 30,60 and 120 minutes the socket of the eye vein get blood, adopt glucose GOD-PAP method to measure blood glucose value.The results are shown in Table 17:
The influence of table 17. pair glucose hyperglycemic rat blood sugar content
| Group | Dosage (g/kg) | Injection back different time blood glucose value (mmol/L) | |||
| 0 minute | 30 minutes | 60 minutes | 120 minutes | ||
| Normal control model contrast Yuquan micropill Yuquan micropill Yuquan micropill YUQUAN WAN JIANGZHILING PIAN | - - 3.58 5.37 8.05 12.0 0.1 | 6.40±1.76 6.53±1.27 6.20±1.57 6.41±1.48 6.38±1.98 6.61±1.22 6.78±0.99 | 6.46±1.67 9.89±1.84 ▲▲7.84±1.46 **7.59±1.65 **7.62±1.42 **8.16±1.30 *7.69±1.39 ** | 6.49±1.39 8.93±1.00 ▲▲7.19±1.13 **7.10±1.44 **7.01±1.16 **7.75±1.31 *6.96±1.21 ** | 6.44±1.20 7.75±1.19 ▲6.50±1.06 *6.49±1.44 *6.31±1.36 *6.79±1.32 6.38±0.91 * |
From table 17 result as seen, the rat hyperglycemia that Yuquan micropill causes exogenous glucose has tangible blood sugar lowering effect, effect is better than former dosage form group, but there was no significant difference, comparatively obvious effect in the 120th minute, each administration group of Yuquan micropill is compared difference with model group have significance (P＜0.05), and former dosage form group is compared then there was no significant difference with model group.
8.4 influence to normal rat blood sugar value
Get 60 of normal rats, be divided into 6 groups at random, 10 every group.Press the administration of the stomach of dosage canister shown in the table 18, the normal control group gives isometric normal saline, 1ml/100g, once a day, continuous 10 days.Fasting is 3 hours after the not inferior administration, and heart extracting blood adopts glucose GOD-PAP method to measure blood glucose value.The results are shown in Table 18:
The influence of table 18. pair normal rat blood sugar value
| Group | Dosage (g/kg) | Blood glucose value (mmol/L) |
| Normal control Yuquan micropill Yuquan micropill Yuquan micropill YUQUAN WAN | - 2.15 4.30 8.59 9.6 | 7.12±1.18 5.61±0.40 ▲▲ 5.97±0.66 ▲▲ 5.40±0.74 ▲▲ 6.14±1.02 ▲ |
| Tolbutamide | 0.6 | 5.34±0.57 |
Table 18 result shows that each dosage group of Yuquan micropill all obviously reduces the effect (P＜0.01) of normal rat blood glucose, and blood sugar reducing function has been compared potentiation with the former dosage form of YUQUAN WAN but too late positive control drug.
8.5 influence to mice serum triglyceride and total cholesterol level
Get 60 of mices, male and female half and half are divided into 6 groups at random by body weight: blank group, Max EPA, three dosage groups of Yuquan micropill and YUQUAN WAN group.Successive administration 10 days, fasting is 10 hours after the last administration, and eye socket is got blood and is surveyed triglyceride (TG) and serum total cholesterol (TC) content in the serum.The results are shown in Table 19:
The influence of table 19. pair mice serum lipid content
| Group | Dosage (g/kg) | TC(mmol/L) | TG(mmol/L) |
| Normal control Yuquan micropill Yuquan micropill Yuquan micropill YUQUAN WAN Max EPA | - 2.15 4.30 8.59 9.6 0.45 | 1.71±0.23 2.64±0.28 2.62±0.32 2.60±0.32 2.61±0.25 2.25±0.24 | 0.97±0.15 1.11±0.10 1.08±0.17 1.01±0.12 1.02±0.14 0.85±0.10 |
Table 19 result shows that each dosage group of Yuquan micropill and YUQUAN WAN group all do not have obvious influence to normal mice serum TG and TC, and Max EPA has obvious reduction effect to it.
8.6 the influence of the hyperlipemia in mice serum lipids that egg yolk is caused
Get 70 of male mices, be divided into 7 groups at random by body weight: normal control group, model control group, Max EPA group, three dosage groups of Yuquan micropill and YUQUAN WAN group, gastric infusion is 10 days continuously, and two matched groups all give every Mus 0.5ml distilled water.After the last administration except that the normal control group, the equal lumbar injection 70% egg bacterial emulsion 0.5ml of all the other every Mus.Fasting is got blood in eye socket after 16 hours and is surveyed TC and TG.The results are shown in Table 20:
The influence of the hyperlipemia in mice serum lipids that table 20. pair egg yolk causes
| Group | Dosage (g/kg) | TC(mmol/L) | TG(mmol/L) |
| Normal control model contrast Yuquan micropill Yuquan micropill Yuquan micropill diabetes pill vs Duo-xi-kang | - - 2.15 4.30 8.59 9.6 0.45 | 1.75±0.21 7.03±0.51 ** 5.08±0.20 * 5.33±0.27 * 5.37±0.26 * 5.32±0.40 * 5.97±0.37 * | 1.16±0.18 2.41±0.27 ** 1.68±0.23 * 1.70±0.23 * 1.71±0.22 * 1.74±0.21 * 1.75±0.22 * |
Table 20 result shows that each dosage group of Yuquan micropill and YUQUAN WAN group all have obvious reduction effect to hyperlipemia in mice TC and the TG that egg yolk is caused, its effect is suitable with Max EPA.
The comprehensive table of going up can draw: Yuquan micropill can obviously reduce the blood sugar level of adrenal gland's disposition hyperglycemia mice, reduce the blood sugar content of alloxan diabetes rat, reduce the effect of normal rat blood glucose, the glucose carbohydrate tolerance of normal rat is improved significantly and compares Yuquan micropill with the former dosage form of dosage YUQUAN WAN strong hypoglycemic activity trend is arranged; Normal mice serum TG and TC all there is not obvious influence; Hyperlipemia in mice TC and TG that egg yolk is caused all have obvious reduction effect.
The long term toxicity test of the Yuquan micropill that embodiment 9. embodiment 3 prepare:
Respectively with corresponding to 36g (crude drug)/kg (body weight), 18g (crude drug)/kg (body weight), the dosage of the Yuquan micropill of the embodiment 3 of 9g (crude drug)/kg (body weight) is irritated gastric infusion to rat, matched group gives the equal-volume distilled water, continuous 26 weeks, observe general situation every day, jede Woche is measured body weight 1 time.After 13 weeks of administration, put to death 12 (male 6 female 6) animals for every group and carry out pathology, hematological examination, blood biochemistry checking.After 26 weeks of administration, put to death 18 (male 9 female 9) animals once more for every group and carry out pathology, hematological examination, blood biochemistry checking.Continue to observe for 3 weeks after the drug withdrawal of residue animal, carry out hematology, pathology and blood biochemistry checking once more.The result: activities in rats is normal, does not occur obviously unusual or dead; Hematological examination, blood biochemical are learned results such as inspection, routine urianlysis, pathological examination and shown: the Yuquan micropill successive administration is after 13 weeks and after 26 weeks of administration, and administration group blood glucose value (GLU) all obviously reduces (P＜0.01); After 26 weeks of administration, heavy dose of group spleen index increases obviously (P＜0.05); After drug withdrawal continue to observe for 3 weeks, each treated animal hematology, blood biochemical were learned and are checked, pathological examination index and matched group be than there are no significant difference (P＞0.05).The pathological examination result shows: the interstitial lung inflammation all sees matched group and administration group, and it may be relevant with raising condition such as environment.The visible liver kitchen range of minority rat cell infiltration, kidney skin medullary substance and pulpa lienis matter have hyperemia also to be present in matched group and administration group simultaneously, and no significant difference.All pathological examination results show, do not find the pathological change relevant with drug toxicity.
In sum, rat gavages 26 weeks of Yuquan micropill continuously, does not see the irreversible toxic reaction relevant with medicine.
The Yuquan micropill acute toxicity test of embodiment 10. embodiment 3:
The Yuquan micropill of embodiment 3 is 192g (crude drug)/kg to the maximum dosage-feeding of mice, presses weighing machine, and its dosage is equivalent to 320 times of the clinical consumption per day of people (60kg meter), illustrates that Yuquan micropill is safer in this dosage.
The Yuquan micropill of embodiment 11. embodiment 3 and former YUQUAN WAN dissolution test result compare:
Press Chinese Pharmacopoeia (two appendix XC of version in 2000) the dissolution method three therapeutic methods of traditional Chinese medicine, 150ml water is medium, 100rpm measures the content of stripping composition, and the dissolution that calculates the Yuquan micropill of embodiment 3 and commercially available YUQUAN WAN (production of Sichuan Jiuzhitang Jinding Pharmaceutical Co., Ltd., Chengdu) each time is also compared.Situation sees Table 21,22.
Table 21. Yuquan micropill and the stripping of YUQUAN WAN puerarin are relatively
| Time (minute) | Yuquan micropill puerarin dissolution (%) | YUQUAN WAN puerarin dissolution (%) |
| 2 5 8 12 15 20 25 30 40 50 60 90 120 180 240 300 360 480 1230 | 97.99 101.01 100.84 101.68 100.34 99.83 97.82 97.82 99.66 99.50 101.85 100.84 101.51 98.66 100.17 101.34 99.16 98.32 101.68 | 1.83 3.28 4.34 5.52 6.35 8.02 9.61 11.62 15.70 21.19 25.91 39.49 52.98 69.62 81.00 88.99 90.29 94.26 100 |
The glycyrrhizic acid stripping relatively in table 22. Yuquan micropill and the YUQUAN WAN
| Time (minute) | Yuquan micropill glycyrrhizic acid dissolution (%) | YUQUAN WAN glycyrrhizic acid dissolution (%) |
| 2 5 | 97.07 103.90 | 5.73 6.52 |
| 8 12 15 20 25 30 40 50 60 90 120 180 240 300 360 480 1230 | 106.82 105.85 101.95 101.95 100.49 100.49 97.76 97.56 99.02 100.98 99.51 99.51 97.56 98.05 99.02 98.54 94.63 | 7.91 8.70 8.70 10.28 11.66 13.44 21.15 25.49 30.83 46.25 61.46 76.68 90.91 95.45 99.60 102.77 97.83 |
Above-mentioned data as can be seen, puerarin and glycyrrhizic acid all promptly discharged in 2～5 minutes fully in the Yuquan micropill, and the puerarin in the YUQUAN WAN discharges (94.26%) as yet fully in 480 minutes, 360 minutes sides of glycyrrhizic acid discharge fully.The result shows: the release in vitro Yuquan micropill obviously is better than YUQUAN WAN.
In sum, the quick release Yuquan micropill by the present invention's preparation has than former dosage form pressure spring ball good effect, the advantage fast, that using dosage is little, drug absorption is complete, bioavailability is high of proving effective.This scientific formulation is reasonable, wherein Radix Rehmanniae YIN nourishing and the production of body fluid promoting heat clearing away, kind kidney nourishing water.Fructus Schisandrae Chinensis reinforces the kidney and astringes the lung, and the reducing urination that promotes the production of body fluid does not make water liquid become under being eager.The Radix Puerariae expelling pathogenic factors from muscles for reducing heat that promotes the production of body fluid; The Radix Trichosanthis promoting the production of body fluid to quench thirst, clearing heat and moistening dryness; Radix Ophiopogonis nourishing YIN and moistening the lung, reinforcing stomach reg fluid.The Radix Glycyrrhizae eliminating fire and detoxication, QI invigorating and in, coordinating the actions of various ingredients in a prescription.Six medicines match, and are core with the replenishing YIN and removing heat, and it is then thirsty from ending to promote the production of body fluid.Can be used for the treatment that diabetes belongs to the scorching card of the deficiency of YIN, be equivalent to the type 2 diabetes mellitus of doctor trained in Western medicine.Can effectively treat and drink polyphagia, polyuria, asthenia, clinical symptoms such as emaciated physique more than the diabetes.
Claims (10)
1. quick release Yuquan micropill for the treatment of diabetes is characterized in that being made by following method:
Wherein raw material is:
Radix Puerariae 5-25 weight portion Fructus Schisandrae Chinensis 5-25 weight portion
Radix Glycyrrhizae 1-10 weight portion Radix Trichosanthis 5-25 weight portion
Radix Rehmanniae 5-25 weight portion 5-25 Radix Ophiopogonis weight portion
Method for making:
Radix Puerariae, Fructus Schisandrae Chinensis, Radix Glycyrrhizae, Radix Trichosanthis 4 flavor medicated powder are broken into coarse powder, and Radix Rehmanniae is cut into small pieces, and Radix Ophiopogonis, tuber was standby; Radix Puerariae adds 60～95% ethanol (V/V) heating and refluxing extraction 1～3 time be equivalent to 4～8 times of weight of crude drug amount in the Fructus Schisandrae Chinensis, each 1～3 hour, filter merging filtrate; After Radix Puerariae and Fructus Schisandrae Chinensis filtering residue are flung to ethanol, incorporate in Radix Trichosanthis, Radix Ophiopogonis, Radix Glycyrrhizae, the Radix Rehmanniae 4 flavor medicines, add 6～10 times of decoctings that are equivalent to 6 flavor crude drug amount weight and boil 1～3 time, each 1～2 hour, filter collecting decoction; Being evaporated to solid content is 15～17% (W/W); With gained extracting solution spray drying, obtain dry extract; According to the dry extract powder: the microcrystalline Cellulose weight ratio is that the ratio of 68～40: 32～60 (W/w) drops in the fluidized bed prilling coating machine, with 5～10% polyvinylpyrrolidone aqueous solutions or 3～6% hydroxypropyl methylcellulose aqueous solutions (W/V) is binding agent, adopt side spray or top spray grain, round as a ball, coating.
2. according to the quick release Yuquan micropill of claim 1, in the wherein said method for making, Radix Puerariae adds 70～90% ethanol (V/V) heating and refluxing extraction that is equivalent to 4～8 times of weight of crude drug amount in the Fructus Schisandrae Chinensis.
3. according to the quick release Yuquan micropill of claim 2, wherein raw material is:
Radix Puerariae 15 weight portion Fructus Schisandrae Chinensis 15 weight portions
Radix Glycyrrhizae 5 weight portion Radix Trichosanthis 15 weight portions
Radix Rehmanniae 15 weight portion weight portions Radix Ophiopogonis 15.
4. according to the quick release Yuquan micropill of one of claim 1-3, in the wherein said method for making, Radix Puerariae, Fructus Schisandrae Chinensis, Radix Glycyrrhizae, Radix Trichosanthis 4 flavor medicated powder are broken into coarse powder, Radix Rehmanniae is cut into small pieces, and Radix Ophiopogonis, tuber was standby; Radix Puerariae adds 80% ethanol (V/V) heating and refluxing extraction 2 times be equivalent to 8 times of weight of crude drug amount in the Fructus Schisandrae Chinensis, each 2 hours, filter merging filtrate; After Radix Puerariae and Fructus Schisandrae Chinensis filtering residue are flung to ethanol, incorporate in Radix Trichosanthis, Radix Ophiopogonis, Radix Glycyrrhizae, the Radix Rehmanniae 4 flavor medicines, add 8 times of decoctings that are equivalent to 6 flavor crude drug amount weight and boil 2 times, each 2 hours, filter collecting decoction; Being evaporated to solid content is 16% (W/W); With gained extracting solution spray drying, inlet temperature is set at 170～180 ℃, and outlet temperature is set at 80～90 ℃, obtains dry extract.
5. according to the quick release Yuquan micropill of claim 4, in the wherein said method for making, according to the dry extract powder: the microcrystalline Cellulose weight ratio is that the ratio of 40: 60 (W/W) drops in the fluidized bed prilling coating machine.
6. according to the quick release Yuquan micropill of claim 4, in the wherein said method for making, according to the dry extract powder: the microcrystalline Cellulose weight ratio is that the ratio of 68: 32 (W/W) drops in the fluidized bed prilling coating machine.
7. according to the quick release Yuquan micropill of claim 5, in the wherein said method for making, granulate, use 18%OPADRYII (W/V) moistureproof coating liquid coating by top spray 5% polyvinylpyrrolidone aqueous solution (W/).
8. according to the quick release Yuquan micropill of claim 6, in the wherein said method for making, spray 10% polyvinylpyrrolidine water distribution solution (W/V) by side and granulate, use 18%OPADRYII (W/V) moistureproof coating liquid coating.
9. according to the quick release Yuquan micropill of claim 7 or 8, in the wherein said method for making, 40～50 ℃ of pelletize stream temperatures, atomizing pressure 0.8～1kg/cm
2
10. according to the quick release Yuquan micropill of claim 9, the micropill of wherein said method for making preparation is the spherical piller of the sliding rounding of 30～60 sight.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100515418A CN1311853C (en) | 2005-03-04 | 2005-03-04 | Quick release Yuquan micropill |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100515418A CN1311853C (en) | 2005-03-04 | 2005-03-04 | Quick release Yuquan micropill |
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| CN1682935A CN1682935A (en) | 2005-10-19 |
| CN1311853C true CN1311853C (en) | 2007-04-25 |
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| CNB2005100515418A Active CN1311853C (en) | 2005-03-04 | 2005-03-04 | Quick release Yuquan micropill |
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| CN103784716A (en) * | 2012-10-31 | 2014-05-14 | 成都九芝堂金鼎药业有限公司 | Traditional Chinese medicine composition for treating type-2 diabetes and its preparation method and use |
| CN103623211B (en) * | 2013-11-29 | 2016-05-18 | 成都九芝堂金鼎药业有限公司 | A kind of medicine pill preparation method who treats diabetes |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1381233A (en) * | 2001-04-17 | 2002-11-27 | 刘文江 | Solid disperser of quick-releasing vitamine A acid |
| CN1569068A (en) * | 2003-07-22 | 2005-01-26 | 周美华 | Preparation method of |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1381233A (en) * | 2001-04-17 | 2002-11-27 | 刘文江 | Solid disperser of quick-releasing vitamine A acid |
| CN1569068A (en) * | 2003-07-22 | 2005-01-26 | 周美华 | Preparation method of |
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| CN1682935A (en) | 2005-10-19 |
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