CN1586534A - Nao'an oral disintegration tablet and its preparing method - Google Patents
Nao'an oral disintegration tablet and its preparing method Download PDFInfo
- Publication number
- CN1586534A CN1586534A CN 200410062501 CN200410062501A CN1586534A CN 1586534 A CN1586534 A CN 1586534A CN 200410062501 CN200410062501 CN 200410062501 CN 200410062501 A CN200410062501 A CN 200410062501A CN 1586534 A CN1586534 A CN 1586534A
- Authority
- CN
- China
- Prior art keywords
- oral cavity
- ethanol
- disintegration tablet
- cavity disintegration
- disintegrating agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 55
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 51
- 238000002360 preparation method Methods 0.000 claims abstract description 35
- 235000019414 erythritol Nutrition 0.000 claims abstract description 33
- 239000004386 Erythritol Substances 0.000 claims abstract description 28
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 claims abstract description 28
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 claims abstract description 28
- 229940009714 erythritol Drugs 0.000 claims abstract description 28
- 239000000284 extract Substances 0.000 claims abstract description 24
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- 235000008434 ginseng Nutrition 0.000 claims abstract description 20
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 claims abstract description 19
- 229920002101 Chitin Polymers 0.000 claims abstract description 12
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 5
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims abstract description 5
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- 125000002057 carboxymethyl group Chemical class [H]OC(=O)C([H])([H])[*] 0.000 claims description 17
- 239000000706 filtrate Substances 0.000 claims description 17
- 239000011734 sodium Substances 0.000 claims description 15
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 14
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
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Landscapes
- Medicinal Preparation (AREA)
Abstract
The Nao'an oral disintegrated tablet consists of supercritical Chuanxiong rhizome extract, cyclodextrin clathrate of borneol, alcohol extract of Chuanxiong rhizome residue, angelica, ginseng and safflower, and medicinal supplementary material. The preparation process is also disclosed. One kind of composite disintegrating agent is also disclosed, which consists of erythritol in 30-70 wt% and chitin or available common disintegrating agent. Compared with available technology, the present invention has high effective component content, shorter disintegration time, more powerful pharmacological effect and higher stability.
Description
Technical field
The invention belongs to technical field of Chinese medicines, be specifically related to a kind of brain peace oral cavity disintegration tablet and preparation method thereof.
Technical background
With Rhizoma Chuanxiong, Radix Angelicae Sinensis, Flos Carthami, Radix Ginseng, Borneolum Syntheticum is that the preparation of crude drug has brain peace sheet (ZYB2072003031), brain peace granule (ZYB2072002196), NAOAN JIAONANG (WS3-178 (Z-030)-97 (Z)).Application number is 99112911 patent documentation employing ginseng crude drug pulverizing, Rhizoma Chuanxiong, Radix Angelicae Sinensis medical material 75%-95% ethanol extraction, water extract-alcohol precipitation extract, and Flos Carthami water hot dipping precipitate with ethanol extract and the blended method of Borneolum Syntheticum are prepared into capsule.The medicine of this prepared is used as medicine with fine powder, and bioavailability is low; The effect of water extract-alcohol precipitation removal impurity is limited, thereby dose is big; The supercritical fluid extraction that the patent documentation of application number 02110979 adopts 80%-95% ethanol to make entrainer obtains the effective ingredient in Rhizoma Chuanxiong, Radix Angelicae Sinensis, the Flos Carthami, and Radix Ginseng 65% ethanol extraction and the blended method of Borneolum Syntheticum are prepared into XINXING NAOAN JIAONANG.Modern pharmacological research shows, main effective ingredient ferulic acid in the Radix Angelicae Sinensis has antioxidation and free radical effect, and effectively anticoagulant and thrombosis are used for the treatment of the blood vessel embolism vasculitis, acute cerebral thrombosis and migraine and atherosclerosis [Wan Riyi, etc.Effective ingredient separates and assay in Chinese medicine angelica and the preparation thereof.Strait Pharmaceutical Journal, 2002,14 (3): 1]; Ferulic acid is an organic acid, with supercritical fluid extraction is very difficult it is extracted [Li Weimin, etc.The modernization of Chinese medicine and supercritical liquid extraction technique.Chinese Medicine science and technology publishing house, 2002,122]; Flos Carthami is a drug for invigorating blood circulation and eliminating stasis, main effective site that water miscible flavone compound Carthamus yellow that wherein contains and S-A Hydroxysafflor yellow A are the Flos Carthami function of promoting blood circulation to disperse blood clots and effective ingredient [the gold ring, etc.Macroporous resin column chromatography prepares Carthamus yellow and S-A Hydroxysafflor yellow A.Chinese herbal medicine, 35 (1): 25], these compositions almost can not extract with supercritical fluid extraction.This shows that it is extremely unreasonable and unscientific utilizing supercritical liquid extraction technique to extract the bigger material of polarity.Drop pill is in clinical practice, and bioavailability and disintegration rate all are not so good as oral cavity disintegration tablet.
In patent retrieval, find no any report that closes brain peace oral cavity disintegration tablet.
Oral cavity disintegration tablet is a kind of new pharmaceutical preparation, and it can absorb through hypoglossis mucous membrane, directly enters blood, has avoided first pass effect effectively, so taking dose is little, and safety is good, and effect rapidly.Though be oral formulations, can reach the effect of ejection preparation.Therefore just progressively become the focus that pharmaceutical manufacturer and research and development field are paid close attention to.This dosage form mainly is to select suitable fast disintegrant, by the existing certain rigidity of its tablet of making, certain sedimentation is arranged again.Can not need the water assisting deglutition when taking, can rapid disintegrate become fine grained in the oral cavity, only several swallowing acts can be finished drug administration process.Its more common solid orally ingestible absorbs fast, bioavailability height, and taking convenience.
The preparation oral cavity disintegration tablet will be considered the problem of following critical aspects: 1, the advantage of oral cavity disintegration tablet just is rapid disintegrate, and it is fast to discharge medicine, reaches rapid-action effect, seeks suitable disintegrants, to guarantee oral cavity disintegration tablet disintegrate rapidly in the oral cavity; 2, seek relatively inexpensive pharmaceutic adjuvant, to reduce production cost; 3, only need the just disintegrate fully of water of minute quantity owing to disintegrating tablet, therefore must consider stability, prolongation shelf life and the shelf-life of humidity environment oral cavity disintegration tablet higher relatively in the process of storage, significant to medical manufacturing enterprise.
Disintegrating agent is commonly used in the oral cavity disintegration tablet adjuvant have low-substituted hydroxypropyl cellulose (L-HPC), cross-linking sodium carboxymethyl cellulose (CCNa), crospolyvinylpyrrolidone (PVPP), crosslinked carboxymethylstach sodium (CCMS-Na) etc. [He Jianchang, etc.New oral solid quick releasing formulation-oral cavity quick disintegrating slice.The pharmacy practice magazine, 2000,18 (3): 151].These adjuvants are all water insoluble, but a common characteristic is all arranged, and have hygroscopicity [pharmaceutical preparation portion of Shanghai Institute of Pharmaceutical Industry, Pharmaceutical National Engineering Research Center exactly.Pharmaceutic adjuvant application technology (second edition), Chinese Medicine science and technology publishing house, 2002,73～75].In the higher environment of humidity, oral cavity disintegration tablet is the moisture absorption especially easily, and cracked trend is arranged.So relatively harsher to environment requirement in production, storage and transportation with the oral cavity disintegration tablet that these adjuvants are made, must adopt special packing, seal cover, desiccant bag etc., all can produce considerable influence to production cost.And above-mentioned disintegrating agent all is synthetic through chemical process, and price is higher, for the more relatively oral cavity disintegration tablet of adjuvant content, can cause production cost to increase, and and then can increase patient's financial burden.Therefore, seek disintegrating agent functional, that price is suitable, make that the disintegration time of oral cavity disintegration tablet is shorter, price is more cheap, stability better becomes one of key problem in technology of exploitation oral cavity disintegration tablet.
Application number is 99802175 patent application bibliographical information, and during as disintegrating agent, the hardness of making oral cavity disintegration tablet is identical with disintegration time at the erythritol that uses separately equivalent or low-substituted hydroxypropyl cellulose (L-HPC).The erythritol sweet taste is pure, after eating nice and cool mouthfeel characteristic is arranged, and also can make correctives and use, and reduces the weight of oral cavity disintegration tablet.Erythritol can not influence normal carbohydrate metabolism, is fit to diabetes patient; And be sweet taste material low in calories, be suitable for obese patients, simultaneously caries prevention is also had positive role.
Chitin is the relatively low natural pharmaceutic adjuvant of a kind of price, and it has another name called chitin, chitin, is a kind of biological polysaccharide polymer material, extensively is present in the carapace in the unicellular lower eukaryote.This material can be degraded by lyase, has excellent biological compatibility, avirulence, chemical property quite stable.
Summary of the invention
The objective of the invention is in order to overcome the deficiency that above-mentioned prior art exists, provide a kind of taking convenience, rapid-action to indication, reach the peak early, curative effect obviously, the brain peace orally disintegrating tablet preparation of preparation stabilization.
According to raw medicinal material contained effective ingredient and physicochemical property thereof, the present invention adopts the fat-soluble effective ingredient in the high supercritical fluid extraction equipment extraction Rhizoma Chuanxiong medical material of extraction efficiency, and carries out enclose with cyclodextrin, further consolidates its stability; The acidic ethanol extraction concentrated solution and the Radix Ginseng of Rhizoma Chuanxiong medicinal residues, Radix Angelicae Sinensis medical material, flos carthami ethanol extraction concentrated solution is crossed the macroporous adsorbent resin remove impurity, obtains effective site; With cyclodextrin clathrate, effective site and pharmaceutic adjuvant combination, be prepared into oral cavity disintegration tablet.The brain peace oral cavity disintegration tablet that utilizes above-mentioned preparation method to obtain is rich in active component, and impurity content is low, and active constituent content wherein significantly increases, and drug effect also is greatly improved.
In the selection course that disintegrating agent uses in oral cavity disintegration tablet, we discover that erythritol and disintegrating agent commonly used at present mix by a certain percentage, form a kind of compound disintegrating agent and have more performance, the oral cavity disintegration tablet made from it compares with the simple oral cavity disintegration tablet that uses erythritol or disintegrating agent commonly used at present to make, the disintegration time of oral cavity disintegration tablet was shortened, and because erythritol has very little hygroscopicity, the stability of the feasible oral cavity disintegration tablet of making significantly improves.In the compound disintegrating agent, erythritol is in the amount ranges of 30%-70%, and along with the increase of content, the disintegration time of oral cavity disintegration tablet shortens, and stability strengthens.
We find that in experiment chitin disintegrating agent effect with commonly used at present aspect the disintegrate effect is suitable, even are better than disintegrating agent commonly used.
We have studied compound disintegrating agent in experiment, select the mixture of use erythritol and chitin, disintegrating agent commonly used, are based on many-sided consideration.When making disintegrating agent with single erythritol, though erythritol has very little hygroscopicity, the tablet stability of making is good, and the swelling degree after the single erythritol suction is less, influences the disintegrating property of oral cavity disintegration tablet, and disintegration time is prolonged.Add a certain amount of disintegrating agent commonly used, utilize rapid expansible character after their moisture absorptions, neither influence the stability of oral cavity disintegration tablet, also kept the characteristic of its rapid disintegrate, reached reasonable effect.
The present invention is achieved through the following technical solutions:
One, process recipes
(1) the raw medicinal material weight proportion is: 0.01 part of Rhizoma Chuanxiong 8-13 part, Radix Angelicae Sinensis 5-10 part, Flos Carthami 3-8 part, Radix Ginseng 0.8-1.2 part, Borneolum Syntheticum;
(2) raw medicinal material optimum weight proportioning is: 10 parts of Rhizoma Chuanxiongs, 8 parts of Radix Angelicae Sinensis, 5 parts on Flos Carthami, 1 part of Radix Ginseng, 0.01 part of Borneolum Syntheticum;
(3) get the Rhizoma Chuanxiong medical material, pulverize, cross 20 mesh sieves, through supercritical extraction, extracting pressure is 10-50Mpa, at 20-70 ℃ of cycling extraction 1-4 hour, obtains supercritical extract; Medicinal residues are standby; Supercritical extract and Borneolum Syntheticum are dissolved with small amount of ethanol, slowly add in β-CD or HP-β-CD aqueous solution, 50 ℃ were stirred 3 hours, continued under the room temperature to stir 5 hours, filtered, and obtained clathrate;
(4) with Rhizoma Chuanxiong medicinal residues, Radix Angelicae Sinensis medical material with twice of the pH value 1-6 acidic ethanol extraction of 60%-85%; Be equivalent to medical material weight 6-10 solvent doubly each the adding; Extracted 2 hours for the first time, extracted 1 hour for the second time; Merge ethanol extract, filter, filtrate is concentrated into does not have the alcohol flavor; With Radix Ginseng, flos carthami with twice of the ethanol extraction of 50%-85%; Be equivalent to medical material weight 6-10 solvent doubly each the adding; Extracted 2-3 hour for the first time, extracted 1-2 hour for the second time; Merge ethanol extract, filter, filtrate is concentrated into does not have the alcohol flavor; Merge concentrated solution, last macroporous adsorbent resin, the washing of doubly measuring earlier with 3-6, reuse 30%-80% ethanol elution is collected ethanol elution; Be condensed into extractum, drying obtains ethanol extraction;
(5) preparation prescription proportioning of the present invention is: clathrate 2-20 weight portion, extract 2-10 weight portion, disintegrating agent 10-30 weight portion, filler 30-60 weight portion, correctives 1-6 weight portion, lubricant 0.1-3 weight portion;
(6) clathrate, extract are mixed with pharmaceutic adjuvant, granulation, drying, granulate, tabletting, check, packing obtain oral cavity disintegration tablet.
Utilize the volatile ingredient in the supercritical fluid extraction Rhizoma Chuanxiong medical material, temperature is low, the time is short, extraction is complete, has kept original character of effective ingredient to greatest extent; Use cyclodextrin inclusion compound, and be equipped with the compound disintegrating agent that contains erythritol, further increase its stability; Ethanol extraction, the technology of macroporous adsorbent resin remove impurity has been removed impurity effectively, and effective site has been played enrichment, content of effective is significantly improved, in conjunction with novel compound recipe disintegrating agent, make preparation of the present invention to reach therapeutic effect sooner again, drug effect is greatly improved.
Two, the research of compound disintegrating agent
1. the disintegrating agent performance is investigated experiment
Experimental raw: erythritol, chitin, low-substituted hydroxypropyl methylcellulose, carboxymethyl starch sodium, crosslinked carboxymethyl fecula sodium, insoluble crospolyvinylpyrrolidone, buy by market.
Experimental technique:
(1) solubility experiment: the saturated aqueous solution at 37 ℃ of preparation samples, utilize membrane filter to filter, obtain filtrate, the filtrate of predetermined of accurately weighing is utilized the freeze-drying drying, thereby is obtained the content of water, calculate water-soluble on the water content basis that obtains thus again, the results are shown in Table 1.
(2) viscosity experiment: the saturated aqueous solutions at 37 ℃ of different disintegrating agents of preparation, utilize membrane filter to filter, obtain filtrate, utilize viscometer to obtain filtrate 37 ℃ viscosity, the results are shown in Table 1.
(3) measurement of wettability: precision takes by weighing above-mentioned disintegrating agent, dry weighs fully, is put into 1 week under 25 ℃ and 75% the damp condition, takes by weighing weight, and the calculating wettability the results are shown in Table 1.
(4) volume increases percent: the volume of moisture absorption fore-and-aft survey disintegrating agent, calculate the percent of the volume increase of disintegrating agent, and see Table 1.
Table 1 disintegrating agent performance is investigated relatively
Dissolubility W/V viscosity mpa.s wettability volume increases
Disintegrating agent
(37℃) (37℃) (％) (％)
Erythritol 45 3.5 0.03 0.02
Chitin--11.29 16.57
Low-substituted hydroxypropyl methylcellulose--14.09 20.36
Carboxymethyl starch sodium--21.07 22.89
Crosslinked carboxymethyl fecula sodium--22.18 28.14
Insoluble crospolyvinylpyrrolidone--22.64 27.62
Conclusion: the characteristics of investigating experiment and oral cavity disintegration tablet by above-mentioned performance, we can analyze, erythritol has very big advantage as disintegrating agent in wettability, but because its moisture pick-up properties is very little, volume increase degree is also very little, therefore, in disintegrating procedue volumetric expansion slow, can not reach the requirement of the rapid disintegrate of oral cavity disintegration tablet; Erythritol is again good correctives simultaneously, not only can be used as disintegrating agent but also can be used as correctives if choose suitable weight, can significantly reduce consumption, the operation in the formulation preparation process and the cost of preparation of pharmaceutic adjuvant; Other disintegrating agent hygroscopicity is too big, causes the Orally disintegrating tablet stability very poor; By analyzing, erythritol is carried out mixing of proper proportion with other disintegrating agent, the compound disintegrating agent as oral cavity disintegration tablet has good advantages.
2. the selection of compound disintegrating agent
Experimental raw: choose crosslinked carboxymethyl fecula sodium and carry out different proportion with erythritol and mix, mixed proportion is respectively erythritol: crosslinked carboxymethyl fecula sodium=1: 9 or 2: 8 or 3: 7 or 4: 6 or 5: 5 or 6: 4 or 7: 3 or 8: 2 or 9: 1, totally 9 groups, be respectively experimental group 1-9, with experimental group 1-9 and same filler (in microcrystalline Cellulose, the nano micro crystal cellulose a kind of) and lubricant (in magnesium stearate, Pulvis Talci, the Stepanol MG a kind of), carry out tabletting; Change above-mentioned disintegrating agent into chitin,, be experimental group 10, carry out tabletting with same filler, mix lubricant with weight; Change above-mentioned disintegrating agent into weight crosslinked carboxymethyl fecula sodium, with same filler, mix lubricant, experimental group 11 carries out tabletting.
Experimental technique:
(1) hardness of mensuration tablet: utilize the tablet hardness tester to measure the hardness of tablet, the results are shown in Table 2.
(2) stability experiment: tablet is put into 12 weeks under 25 ℃ and 75% the damp condition, observes the tablet spoilage, the results are shown in Table 2.
(3) disintegrate experiment: according to " the disintegration of tablet method of testing of stipulating in the Chinese pharmacopoeia utilizes the disintegrate tester to measure, and the results are shown in Table 2.
(4) disintegrate test in the oral cavity, disintegration time, grittiness, taste to three health adults have tested experimental group the results are shown in Table 2.
The selection of table 2 experimental group disintegrating agent
The hardness spoilage disintegration time Orally disintegrating time
Experimental group grittiness taste
(kg) (％) (s) (s)
1 4.1 22.1 42.1 51.2 have bad
2 3.9 21.6 43.6 52.9 have generally
3 2.1 9.3. 26.3 32.9 are seldom good
4 2.2 8.6 25.2 28.3 is seldom good
5 2.2 8.1 26.1 26.7 is seldom good
6 2.1 8.6 26.9 27.4 is seldom good
7 2.0 9.3 26.8 27.3 is seldom good
8 1.9 9.6 35.9 38.6 is seldom good
9 1.8 10.2 35.6 39.1 is seldom good
10 4.6 33.9 54.1 62.9 have much very poor
11 4.8 36.5 55.6 62.8 have much very poor
Change above-mentioned chitin, crosslinked carboxymethyl fecula sodium into low-substituted hydroxypropyl methylcellulose, crosslinked carboxymethyl fecula sodium, crosslinked insoluble polyvinylpyrrolidone, experimentize, the result of experimental result and table 2 is close.
Experimental result shows, erythritol is mixed with into the mixing disintegrating agent with other disintegrating agent, has good effect, simultaneously because erythritol has sweet taste, so can reduce or replace correctives to use, by experiment erythritol: the suitable ratio of other disintegrating agent be 3-7: 7-3.
3. preparation disintegration time mensuration
In order to prove absolutely that the employed compound disintegrating agent of brain peace oral cavity disintegration tablet of the present invention has disintegrate characteristics rapidly than single disintegrating agent, we have carried out following experiment: disintegrating agent is selected in the design by table 3 for use, make into oral cavity disintegration tablet with effective ingredient at identical pressure lower sheeting, place the beaker of the 10ml that fills 37 ℃ of water of 5ml, stir with 30 rev/mins speed, measure the disintegration of the oral cavity disintegration tablet that contains different disintegrating agents.
Table 3 preparation disintegration time mensuration
Disintegrating agent
Disintegration
The experiment consumption
Form (s)
(g∶g)
1 chitin-30.1
2 erythritols: chitin 3: 7 17.4
3 low-substituted hydroxypropyl methylcellulose-27.5
4 erythritols: low-substituted hydroxypropyl methylcellulose 4: 6 16.7
5 carboxymethyl starch sodium-38.2
6 erythritols: carboxymethyl starch sodium 5: 5 15.1
7 crosslinked carboxymethyl fecula sodium-40.3
8 erythritols: crosslinked carboxymethyl fecula sodium 6: 4 14.5
9 insoluble crospolyvinylpyrrolidone-33.3
10 erythritols: insoluble crospolyvinylpyrrolidone 7: 3 13.3
The result: the oral cavity disintegration tablet that uses compound disintegrating agent is in 13.3-17.4 all disintegrates and by No. 2 sieves in second; The oral cavity disintegration tablet that uses single disintegrating agent is in 27.5-40.3 all disintegrates and by No. 2 sieves in second.Illustrate that compound disintegrating agent of the present invention has disintegrate characteristics rapidly really.
Three, assay analysis
Content of ferulic acid in the high effective liquid chromatography for measuring brain peace preparation
1. instrument and reagent high performance liquid chromatograph comprise LC-10ATvp type solvent delivery pump, SPD-10ATvp type UV, visible light detector (day island proper Tianjin company); N2000 chromatographic work station (Zhejiang University's intelligent information Graduate School of Engineering); KQ3200 type ultrasonic washing instrument (Kunshan Ultrasonic Instruments Co., Ltd.), TGL-16G high speed tabletop centrifuge (Anting Scientific Instrument Factory, Shanghai).Chromatographically pure methanol (Beijing chemical reagents corporation); Water is tri-distilled water (self-control); Other reagent is analytical pure.NAOAN JIAONANG (Yadong, TongYuan city, Jilin pharmaceutical factory); XINXING NAOAN JIAONANG, brain peace oral cavity disintegration tablet (Qianluchun Science and Technology Co., Ltd., Beijing's laboratory provides); Ferulic acid reference substance (Nat'l Pharmaceutical ﹠ Biological Products Control Institute).
2. chromatographic column tested in chromatographic condition and system suitability: the C of Di Ma company
18Post (5 μ m, 150mm * 4.6mm, I.D); Mobile phase: methanol-2% acetic acid (35: 65); Flow velocity: 1.0ml/min; Detect wavelength 313nm; Number of theoretical plate should be not less than 3000 by ferulic acid peak compute.
3. reference substance mixed solution preparation precision takes by weighing the about 3mg of ferulic acid reference substance, puts in the 100mL measuring bottle, and adding methanol ultrasonicly makes dissolving, adds methanol again to scale, shakes up, promptly.
4. the ferulic acid reference substance solution of variable concentrations is prepared in the standard curve preparation respectively, and sample introduction is measured under the said determination condition.The result shows, ferulic acid sample size and peak area in 0.0775 μ g～0.620 μ g scope are the good linear relation, and linear equation is Y=909.8X-16498, r=0.9995.
5. 10 of test samples are got in the preparation of need testing solution, and accurate the title decided porphyrize, get 0.5g, the accurate title, decide, and puts in the tool plug conical flask, the accurate methanol 10ml that adds claims to decide weight, supersound process 1 hour, put coldly, claim again to decide weight, supply the weight that subtracts mistake with methanol, shake up, get supernatant liquid filtering, get subsequent filtrate, promptly.
6. accurate each the 10 μ l of need testing solution that draw of algoscopy inject chromatograph of liquid, measure peak area, calculate content with standard curve.The results are shown in Table 4.
Ferulaic acid content relatively in the table 4 brain peace preparation
Ferulic acid
Group (mg)
NAOAN JIAONANG 0.24
XINXING NAOAN JIAONANG 5.08
Brain peace oral cavity disintegration tablet 7.12
*Represent one time dose
Annotate: the each dose of brain peace oral cavity disintegration tablet of the present invention is 4,2 times on the one.
Conclusion: above assay description of test, the effective ingredient content of ferulic acid in the brain peace oral cavity disintegration tablet of the present invention increases, and brain of the present invention peace oral cavity disintegration tablet bioavailability is higher, proves absolutely that preparation technology of the present invention has practical significance.
Four, pharmacology embodiment
1. brain peace preparation is to the influence of rat thrombus in vivo formation
Rat is divided into 4 groups at random, 10 every group, is respectively normal saline matched group, NAOAN JIAONANG group, XINXING NAOAN JIAONANG, brain peace oral cavity disintegration tablet group.With each treated animal administration (the normal saline group gives isopyknic normal saline), every day 1 time, successive administration 7d, 1h after the last administration, rat is used 10% chloral hydrate, press 0.3g/kg body weight anesthesia back and fix, separate left common carotid artery, on the thrombosis instrument with 2mA galvanism blood vessel 7min after, the record thrombus formation time.The results are shown in Table 5.
The influence that table 5 pair rat thrombus in vivo forms (X ± SD)
Group Mus number (only) thrombus formation time (min)
Matched group 10 632.34 ± 47.18
NAOAN JIAONANG group 10 773.47 ± 79.54
*
XINXING NAOAN JIAONANG group 10 806.28 ± 98.47
*
Brain peace oral cavity disintegration tablet group 10 887.68 ± 107.47
*
Annotate: compare with matched group:
*P＜0.05:
*P＜0.01
Brain peace oral cavity disintegration tablet and NAOAN JIAONANG, XINXING NAOAN JIAONANG can both the prolong rats thrombus in vivo formation, and the pharmacological action of brain peace oral cavity disintegration tablet is better than NAOAN JIAONANG, XINXING NAOAN JIAONANG.
2. brain peace preparation is to the thrombotic influence of rats in vitro
Rat is divided into 4 groups at random, 10 every group, is respectively normal saline matched group, NAOAN JIAONANG group, XINXING NAOAN JIAONANG, brain peace oral cavity disintegration tablet group.With each treated animal administration (the normal saline group gives isopyknic normal saline), every day 1 time, successive administration 7d, 1h after the last administration fixes rat anesthesia, from abdominal aortic blood 1.8ml, at once put into silica gel tube, and put it in the extracorporeal thrombosis forming device of 37 ℃ of constant temperature, rotate 15min after, removal of thromboses is measured its length, weight in wet base and dry weight.The results are shown in Table 6.
The thrombotic influence of table 6 pair rats in vitro (X ± SD)
Thrombosis length wet weight of thrombus thrombosis dry weight
Group (l/cm) is (m/g) (m/g)
Matched group 6.43 ± 1.25 0.292 ± 0.078 0.153 ± 0.040
NAOAN JIAONANG group 5.08 ± 0.88
*0.258 ± 0.062
*0.112 ± 0.042
*
XINXING NAOAN JIAONANG group 4.95 ± 0.74
*0.235 ± 0.046
*0.106 ± 0.037
*
Brain peace oral cavity disintegration tablet group 4.57 ± 1.02
*0.214 ± 0.068
*0.089 ± 0.036
*
Annotate: compare with matched group:
*P＜0.05;
*P＜0.01
Brain peace oral cavity disintegration tablet and NAOAN JIAONANG, XINXING NAOAN JIAONANG can both obviously shorten external thrombus and form length, reduce the weight in wet base and the dry weight of thrombosis, and the pharmacological action of brain peace oral cavity disintegration tablet is better than NAOAN JIAONANG, XINXING NAOAN JIAONANG.
3. brain is pacified the preparation antiplatelet aggregative activity
Rat is divided into 4 groups at random, 10 every group, is respectively normal saline matched group, NAOAN JIAONANG group, XINXING NAOAN JIAONANG, brain peace oral cavity disintegration tablet group.With each treated animal administration (the normal saline group gives isopyknic normal saline), every day 1 time, successive administration 7d, 1h after the last administration, from abdominal aortic blood, anticoagulant adopts 3.28% sodium citrate after the Animal Anesthesia, with blood with 1: 9 mixed.With anticoagulated whole blood 1500rmin under 20 ℃ of conditions
-1Centrifugal 5min, and the acquisition platelet rich plasma (platelet-richplasma, PRP).After leaving and taking quantitative PRP, will remain PRP once more with 3000rmin
-1Centrifugal 10min, and acquisition own control platelet poor plasma (platelet-poorplasma, PPP).Regulate PRP concentration with PPP, make each PRP concentration identical.In 37 ℃ constant temperature hole after the preheating, (final concentration is 3 μ molL to add ADP with PRP
-1) cause and write down maximum agglutination rate by platelet aggregation.The results are shown in Table 7.
Table 7 brain peace preparation antiplatelet aggregative activity (X ± SD)
Group Mus number (only) maximum agglutination rate (η/%)
Matched group 10 89.12 ± 9.37
NAOAN JIAONANG group 10 68.26 ± 20.58
*
XINXING NAOAN JIAONANG group 10 62.58 ± 16.14
*
Brain peace oral cavity disintegration tablet group 10 50.27 ± 18.56
*
Annotate: compare with matched group:
*P＜0.05;
*P＜0.01;
Brain peace oral cavity disintegration tablet and NAOAN JIAONANG, XINXING NAOAN JIAONANG be anticoagulant obviously, and the pharmacological action of brain peace oral cavity disintegration tablet is better than NAOAN JIAONANG, XINXING NAOAN JIAONANG.
Above pharmacological evaluation proves, pacifies oral cavity disintegration tablet with the brain of new technology preparation and has better therapeutic effect.
Five, preparation embodiment
Embodiment 1
(1) raw medicinal material is: Rhizoma Chuanxiong 800g, Radix Angelicae Sinensis 700g, Flos Carthami 700g, Radix Ginseng 110g, Borneolum Syntheticum 1g;
(2) get the Rhizoma Chuanxiong medical material, pulverize, cross 20 mesh sieves, through supercritical extraction, extracting pressure is 15Mpa, 300 ℃ of cycling extractions 2 hours, obtains supercritical extract 12g; Medicinal residues are standby; Supercritical extract and Borneolum Syntheticum are dissolved with small amount of ethanol, slowly add in β-CD aqueous solution, 50 ℃ were stirred 3 hours, continued under the room temperature to stir 5 hours, filtered, and obtained clathrate 30g;
(3) be twice of 1.2 hydrochloric acid acidic ethanol extraction with Rhizoma Chuanxiong medicinal residues, Radix Angelicae Sinensis medical material with 85% pH value; Each solvent that is equivalent to 8 times of medical material weight that adds; Extracted 2 hours for the first time, extracted 1 hour for the second time; Merge ethanol extract, filter, filtrate is concentrated into does not have the alcohol flavor; With Radix Ginseng, flos carthami with twice of 50% ethanol extraction; Each solvent that is equivalent to 9 times of medical material weight that adds; Extracted 2 hours for the first time, extracted 2 hours for the second time; Merge ethanol extract, filter, filtrate is concentrated into does not have the alcohol flavor; Merge concentrated solution, last macroporous adsorbent resin, with the washing of 6 times of amounts, reuse 35% ethanol elution is collected ethanol elution earlier; Be condensed into extractum, drying obtains ethanol extraction 92g;
(4) preparation prescription is:
Clathrate 30g
Extract 92g
Nano micro crystal cellulose 520g
Erythritol 40g
Chitin 112g
Magnesium stearate 5g
(5) clathrate, ethanol extraction are mixed with pharmaceutic adjuvant, granulation, drying, granulate, tabletting, check, packing obtain 2000 of oral cavity disintegration tablets.
Embodiment 2
(1) raw medicinal material is: Rhizoma Chuanxiong 1000g, Radix Angelicae Sinensis 800g, Flos Carthami 500g, Radix Ginseng 100g, Borneolum Syntheticum 1g;
(2) get the Rhizoma Chuanxiong medical material, pulverize, cross 20 mesh sieves, through supercritical extraction, extracting pressure is 35Mpa, 60 ℃ of cycling extractions 3 hours, obtains supercritical extract 33g; Medicinal residues are standby; Supercritical extract and Borneolum Syntheticum are dissolved with small amount of ethanol, slowly add in HP-β-CD aqueous solution, 50 ℃ were stirred 3 hours, continued under the room temperature to stir 5 hours, filtered, and obtained clathrate 172g;
(3) be twice of 2.5 phosphoric acid acidic ethanol extraction with Rhizoma Chuanxiong medicinal residues, Radix Angelicae Sinensis medical material with 75% pH value; Each solvent that is equivalent to 10 times of medical material weight that adds; Extracted 2 hours for the first time, extracted 1 hour for the second time; Merge ethanol extract, filter, filtrate is concentrated into does not have the alcohol flavor; With Radix Ginseng, flos carthami with twice of 65% ethanol extraction; Each solvent that is equivalent to 8 times of medical material weight that adds; Extracted 1 hour for the first time, extracted 2 hours for the second time; Merge ethanol extract, filter, filtrate is concentrated into does not have the alcohol flavor; Merge concentrated solution, last macroporous adsorbent resin, with the washing of 4 times of amounts, reuse 50% ethanol elution is collected ethanol elution earlier; Be condensed into extractum, drying obtains ethanol extraction 27g;
(4) preparation prescription is:
Clathrate 172g
Extract 27g
Microcrystalline Cellulose 380g
Erythritol 80g
Carboxymethyl starch sodium 120g
Pulvis Talci 21g
(5) clathrate, ethanol extraction are mixed with pharmaceutic adjuvant, granulation, drying, granulate, tabletting, check, packing obtain 2000 of oral cavity disintegration tablets.
Embodiment 3
(1) raw medicinal material is: Rhizoma Chuanxiong 900g, Radix Angelicae Sinensis 700g, Flos Carthami 700g, Radix Ginseng 100g, Borneolum Syntheticum 1g;
(2) get the Rhizoma Chuanxiong medical material, pulverize, cross 20 mesh sieves, through supercritical extraction, extracting pressure is 45Mpa, 500 ℃ of cycling extractions 2 hours, obtains supercritical extract 21g; Medicinal residues are standby; Supercritical extract and Borneolum Syntheticum are dissolved with small amount of ethanol, slowly add in β-CD aqueous solution, 50 ℃ were stirred 3 hours, continued under the room temperature to stir 5 hours, filtered, and obtained clathrate 104g;
(3) be twice of 4.2 hydrochloric acid acidic ethanol extraction with Rhizoma Chuanxiong medicinal residues, Radix Angelicae Sinensis medical material with 70% pH value; Each solvent that is equivalent to 6 times of medical material weight that adds; Extracted 2 hours for the first time, extracted 1 hour for the second time; Merge ethanol extract, filter, filtrate is concentrated into does not have the alcohol flavor; With Radix Ginseng, flos carthami with twice of 70% ethanol extraction; Each solvent that is equivalent to 10 times of medical material weight that adds; Extracted 3 hours for the first time, extracted 3 hours for the second time; Merge ethanol extract, filter, filtrate is concentrated into does not have the alcohol flavor; Merge concentrated solution, last macroporous adsorbent resin, with the washing of 5 times of amounts, reuse 65% ethanol elution is collected ethanol elution earlier; Be condensed into extractum, drying obtains ethanol extraction 72g;
(4) preparation prescription is:
Clathrate 104g
Extract 72g
Nano micro crystal cellulose 390g
Erythritol 50g
Crosslinked carboxymethyl fecula sodium 130g
Stevioside 40g
Stepanol MG 14g
(5) clathrate, ethanol extraction are mixed with pharmaceutic adjuvant, granulation, drying, granulate, tabletting, check, packing obtain 2000 of oral cavity disintegration tablets.
Embodiment 4
(1) raw medicinal material is: Rhizoma Chuanxiong 1300g, Radix Angelicae Sinensis 500g, Flos Carthami 800g, Radix Ginseng 80g, Borneolum Syntheticum 1g;
(2) get the Rhizoma Chuanxiong medical material, pulverize, cross 20 mesh sieves, through supercritical extraction, extracting pressure is 27Mpa, 40 ℃ of cycling extractions 4 hours, obtains supercritical extract 16g; Medicinal residues are standby; Supercritical extract and Borneolum Syntheticum are dissolved with small amount of ethanol, slowly add in HP-β-CD aqueous solution, 50 ℃ were stirred 3 hours, continued under the room temperature to stir 5 hours, filtered, and obtained clathrate 84g;
(3) be twice of 6.0 phosphoric acid acidic ethanol extraction with Rhizoma Chuanxiong medicinal residues, Radix Angelicae Sinensis medical material with 60% pH value; Each solvent that is equivalent to 8 times of medical material weight that adds; Extracted 2 hours for the first time, extracted 1 hour for the second time; Merge ethanol extract, filter, filtrate is concentrated into does not have the alcohol flavor; With Radix Ginseng, flos carthami with twice of 85% ethanol extraction; Each solvent that is equivalent to 6 times of medical material weight that adds; Extracted 2 hours for the first time, extracted 1 hour for the second time; Merge ethanol extract, filter, filtrate is concentrated into does not have the alcohol flavor; Merge concentrated solution, last macroporous adsorbent resin, with the washing of 3 times of amounts, reuse 80% ethanol elution is collected ethanol elution earlier; Be condensed into extractum, drying obtains ethanol extraction 77g;
(4) preparation prescription is:
Clathrate 84g
Extract 77g
Microcrystalline Cellulose 480g
Erythritol 50g
Crospolyvinylpyrrolidone 80g
Stevioside 16g
Magnesium stearate 10g
(5) clathrate, ethanol extraction are mixed with pharmaceutic adjuvant, granulation, drying, granulate, tabletting, check, packing obtain 2000 of oral cavity disintegration tablets.
Claims (9)
1. a brain is pacified oral cavity disintegration tablet, it is characterized in that it is by the supercritical extract of Rhizoma Chuanxiong and the cyclodextrin clathrate 2-20 weight portion of Borneolum Syntheticum, the ethanol extraction 2-10 weight portion of the acidic ethanol extraction thing of Rhizoma Chuanxiong medicinal residues, Radix Angelicae Sinensis and Radix Ginseng, Flos Carthami and pharmaceutic adjuvant are formed; Its feature also is disintegrating agent 10-30 weight portion in the pharmaceutic adjuvant, filler 30-60 weight portion, correctives 1-6 weight portion, lubricant 0.1-3 weight portion.
2. disintegrating agent according to claim 1 is by erythritol and a kind of compound disintegrating agent of forming that is selected from chitin, low-substituted hydroxypropyl methylcellulose, carboxymethyl starch sodium, crosslinked carboxymethyl fecula sodium, the insoluble crospolyvinylpyrrolidone, and the weight percentage of its mesoerythrit is 30%-70% not.
3. oral cavity disintegration tablet according to claim 1, its preparation method may further comprise the steps:
(1) the raw medicinal material weight proportion is: 0.01 part of Rhizoma Chuanxiong 8-13 part, Radix Angelicae Sinensis 5-10 part, Flos Carthami 3-8 part, Radix Ginseng 0.8-1.2 part, Borneolum Syntheticum;
(2) get the Rhizoma Chuanxiong medical material, pulverize, cross 20 mesh sieves, through supercritical extraction, extracting pressure is 10-50Mpa, at 20-70 ℃ of cycling extraction 1-4 hour, obtains supercritical extract; Medicinal residues are standby; Supercritical extract and Borneolum Syntheticum are dissolved with small amount of ethanol, slowly add in β-CD or HP-β-CD aqueous solution, 50 ℃ were stirred 3 hours, continued under the room temperature to stir 5 hours, filtered, and obtained clathrate;
(3) with Rhizoma Chuanxiong medicinal residues, Radix Angelicae Sinensis medical material with twice of the pH value 1-6 acidic ethanol extraction of 60%-85%; Be equivalent to medical material weight 6-10 solvent doubly each the adding; Extracted 2 hours for the first time, extracted 1 hour for the second time; Merge ethanol extract, filter, filtrate is concentrated into does not have the alcohol flavor; With Radix Ginseng, flos carthami with twice of the ethanol extraction of 50%-85%; Be equivalent to medical material weight 6-10 solvent doubly each the adding; Extracted 2-3 hour for the first time, extracted 1-2 hour for the second time; Merge ethanol extract, filter, filtrate is concentrated into does not have the alcohol flavor; Merge concentrated solution, last macroporous adsorbent resin, the washing of doubly measuring earlier with 3-6, reuse 30%-80% ethanol elution is collected ethanol elution; Be condensed into extractum, drying obtains ethanol extraction;
(4) clathrate, extract are mixed with pharmaceutic adjuvant, granulation, drying, granulate, tabletting, check, packing obtain oral cavity disintegration tablet.
4. be a kind of in microcrystalline Cellulose or the nano micro crystal cellulose according to claim 1 or 3 described filleies.
5. be a kind of in mannitol or the stevioside according to claim 1 or 3 described correctivess.
6. be a kind of in magnesium stearate or Pulvis Talci or the Stepanol MG according to claim 1 or 3 described lubricants.
7. oral cavity disintegration tablet according to claim 3, wherein the raw medicinal material weight proportion is: 10 parts of Rhizoma Chuanxiongs, 8 parts of Radix Angelicae Sinensis, 5 parts on Flos Carthami, 1 part of Radix Ginseng, 0.01 part of Borneolum Syntheticum.
8. acidic ethanol according to claim 3, wherein being used for the alcoholic acid acid of acidify is a kind of of hydrochloric acid or phosphoric acid, the pH value of acidic ethanol is 3-5.
9. oral cavity disintegration tablet according to claim 3, wherein macroporous adsorbent resin is nonpolar macroporous adsorption resin or low pole macroporous adsorbent resin.
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| CN 200410062501 CN1586534A (en) | 2004-06-30 | 2004-06-30 | Nao'an oral disintegration tablet and its preparing method |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US12151876B2 (en) | 2012-06-18 | 2024-11-26 | K-Fee System Gmbh | Methods of making and using a portion capsule |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US12151876B2 (en) | 2012-06-18 | 2024-11-26 | K-Fee System Gmbh | Methods of making and using a portion capsule |
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