Summary of the invention
The object of the present invention is to provide a kind of new pharmaceutical preparation and preparation method thereof, this invention preparation is mainly by Herba Schizonepetae, Herba Menthae, and Radix Saposhnikoviae, Radix Bupleuri, Folium Perillae, Radix Puerariae, Radix Platycodonis, Semen Armeniacae Amarum, the Radix Angelicae Dahuricae, Herba Corydalis Bungeanae, Rhizoma Phragmitis is prepared from.Herba Schizonepetae has the diffusing wind that induces sweat in the side, the effect of rash, Radix Platycodonis and Semen Armeniacae Amarum can lung qi dispersing in we cough-relieving, eliminate the phlegm, when the cough that the treatment flu causes, no matter be the cough that causes of wind and cold or the cough due to the wind heat, all have good therapeutic effect.Radix Bupleuri have induce sweat bring down a fever, function such as dispersing the stagnated live-QI to relieve the stagnation of QI, ascending spleen-QI.In we mainly with its antipyretic function of inducing sweat., be afraid of cold adstante febre tightly unable at the body that the treatment flu causes uses Radix Bupleuri can receive remarkable result.Other flavour of a drug Folium Perillae heat radiation of inducing sweat in the side, relieving QI stagnancy in the stomach; The Radix Saposhnikoviae inducing diaphoresis to dispel wind wins and wets, relieving convulsion; Radix Puerariae is separated famine and is brought down a fever, and promotes the production of body fluid; The diffusing wind dehumidifying of the Radix Angelicae Dahuricae, understand things pain-stopping; The Herba Corydalis Bungeanae heat-clearing and toxic substances removing, the removing heat from blood detumescence; The Rhizoma Phragmitis clearing away heat and promoting production of body fluid, relieving restlessness.All medicines are the effect of long memorial wind, dissipating cold, the heat clearing away of inducing sweat altogether.It is easy to carry that preparation of the present invention--chewable tablet has kept the good efficacy and the conventional tablet of granule, stable in properties, the simple characteristic of preparation technology; Also have following advantage: need not disintegrating procedue, the medicine stripping is rapid, absorbs soon the bioavailability height; Taking convenience need not with mixing in water for oral taking or takes, and especially is fit to old man, child and the patient of difficulty that swallows; Simultaneously said preparation is the Sugarless type preparation, is applicable to that also vast diabetics takes.
The present invention constitutes like this:
A kind of chewable tablets for treating cold and clearing heat is calculated by weight, and it is mainly by 500~1000 parts of Herba Schizonepetaes, 150~300 parts of Herba Menthaes, 250~500 parts of Radix Saposhnikoviaes, 250~500 parts of Radix Bupleuri, 150~300 parts of Folium Perillaes, 250~500 parts of Radix Puerariaes, 150~300 parts of Radix Platycodoniss, 200~400 parts of Semen Armeniacae Amarums, 150~300 parts of the Radixs Angelicae Dahuricae, 500~1000 parts of Herba Corydalis Bungeanaes, 500~700 parts of Rhizoma Phragmitiss and suitable adjuvant are prepared from.Described adjuvant is meant filler, sweeting agent, volatile oil inclusion complex.Sweeting agent is selected from one or more in stevioside, betanin, the Aspartane, and filler is selected from one or more in lactose, mannitol, the xylitol.The volatile oil inclusion complex is meant doubly its cyclodextrin inclusion complex.
Chewable tablets for treating cold and clearing heat is preparation like this: above ten simply, gets Herba Schizonepetae, Herba Menthae, Folium Perillae mixing back extraction volatile oil, and the aqueous solution after distillation device is in addition collected, and medicinal residues are continued to employ; Volatile oil betacyclodextrin inclusion (volatile oil-betacyclodextrin-water=1~3: 4~10: 50~100,40~80 ℃ were stirred 0.5~3 hour), cold preservation is spent the night, and filters, and inclusion complex low temperature (30~50 ℃) drying is ground into fine powder.Eight flavors such as medicinal residues and all the other Radix Saposhnikoviaes add 10~14 times of water gagings and decoct secondary, each 0.5~3 hour, collecting decoction, filter, filtrate and above-mentioned aqueous solution merge, and being concentrated into relative density is the thick paste of 1.25-1.30 (60 ℃), drying is ground into fine powder and above-mentioned volatile oil inclusion complex fine powder and mixes, it is an amount of to add sweeting agent and filler, mixing is granulated drying, tabletting, promptly.
Specifically, chewable tablet is preparation like this: it is mainly made by weight by following raw material: 750 parts of Herba Schizonepetaes, 225 parts of Herba Menthaes, 375 parts of Radix Saposhnikoviaes, 375 parts of Radix Bupleuri, 225 parts of Folium Perillaes, 375 parts of Radix Puerariaes, 225 parts of Radix Platycodoniss, 300 parts of Semen Armeniacae Amarums, 225 parts of the Radixs Angelicae Dahuricae, 750 parts of Herba Corydalis Bungeanaes, 600 parts of Rhizoma Phragmitiss.More than ten simply, get Herba Schizonepetae, Herba Menthae, Folium Perillae and add 10 times of water gagings after mixing, soaked 2 hours, steam distillation 6 hours extracts volatile oil, the device collection in addition of the aqueous solution after the distillation, medicinal residues are continued to employ; Volatile oil betacyclodextrin inclusion (volatile oil-betacyclodextrin-water=1: 6: 80,60 ℃ were stirred 1 hour), cold preservation is spent the night, and filters, and inclusion complex low temperature (40 ℃) drying is ground into fine powder.Eight flavors such as medicinal residues and all the other Radix Saposhnikoviaes add 12 times of amounts of water and decoct secondary, each 1.5 hours, collecting decoction, filter, filtrate and above-mentioned aqueous solution merge, and being concentrated into relative density is the thick paste of 1.25-1.30 (60 ℃), drying under reduced pressure is ground into fine powder and above-mentioned volatile oil inclusion complex fine powder and mixes, it is an amount of to add 37.5 parts of aspartames and mannitol, mixing is granulated drying, compacting is in blocks, promptly.
At prior art, former dosage form prescription rationally, determined curative effect and super quality and competitive price, be the good medicine of treatment flu.But drawbacks such as the need hot water dissolving carries inconvenience when taking, and mouthfeel is bad; Chewable tablet of the present invention, volume is little, and is portable; Taking convenience need not with mixing in water for oral taking or takes, for the patient of fetch water inconvenience and dysphagia provides a great convenience condition; Can directly act on respiratory tract, absorb rapidly, curative effect is better, has greatly improved bioavailability; Delicious taste has improved the especially compliance of children taking of patient; Be the Sugarless type preparation simultaneously, be applicable to that also vast diabetics takes; Meet the modern requirement of Chinese medicine preparation.
The inventor finds in development process, the kind of disintegrating agent, consumption, and the concentration of wetting agent has considerable influence to it, and for this reason, the applicant has carried out a series of experiments, and is rationally feasible with proof technology of the present invention.
Experimental example 1: extraction process examination
1.1 volatile oil extraction process
Take by weighing Herba Schizonepetae 200g, Herba Menthae 60g, Folium Perillae 60g for a, get 3 parts altogether, investigate whether medical material soaks, amount of water and carry the oil time.Different time writes down oil pump capacity, till no longer increasing basically to oil mass.The results are shown in Table 1, table 2.
Table 1 volatile oil extracts to be investigated
Processing method | Amount of water | 2 hours (ml) | 4 hours (ml) | 6 hours (ml) | 8 hours (ml) |
Do not soak 2 hours soaked overnight | 10 times 10 times 10 times | 1.15 1.29 1.32 | 1.24 1.48 1.49 | 1.35 1.50 1.51 | 1.35 1.50 1.51 |
As shown in Table 1, immersion has certain influence to the extraction effect of volatile oil, and soak 2 hours suitable with the effect of soaked overnight, 4 hours volatile oil of medicinal material extract extracts fully substantially, the increase of minute quantity was only arranged to 6 hours, oil mass no longer increases after 8 hours, so determine the volatile oil extraction conditions is: carry oily medical material and soaked bag 2 hours, extraction time is to be advisable in 6 hours.
Investigate the influence of amount of water to the volatile oil extracted amount, result of the test sees Table 2.
Table 2 is proposed the investigation that oil adds the water multiple
Amount of water | 2 hours (ml) | 4 hours (ml) | 6 hours (ml) |
8 times 10 times 12 times | 1.15 1.24 1.25 | 1.44 1.51 1.52 | 1.45 1.51 1.52 |
As shown in Table 2, adding 8~12 times of water gagings all can extract oil to some extent, but experiment is found, because of the loose bubble of medical material quality, it is bad that 8 times of water gagings extract the volatile oil effects, and 10 times of amount volatile oil extracted amounts are more or less the same with 12 times of amount extractions, consider save time, the energy, factor such as reduce cost determines that preferable condition is: add 10 times of amounts of water.
Comprehensive above-mentioned result of the test, the extraction process of Herba Schizonepetae, Herba Menthae, Folium Perillae volatile oil is: add 10 times of water gagings and soaked vapor distillation 6 hours 2 hours.
1.2 volatile oil beta-CD inclusion complex Study on Preparation
Volatile oil adopts β-CD inclusion technology to make volatile oil beta-CD inclusion complex, have high stability, low volatility, low irritant and advantages such as comfortable taste, taking convenience.Can reduce the loss of volatile oil, cover its bad smell, guarantee curative effect.Adopt L9 (34) orthogonal table design experiment, carry out the preferred of inclusion condition.
Volatile oil: Herba Schizonepetae, Herba Menthae, Folium Perillae mix the back and adopt water vapour distillation volatile oil, and the relative density of volatile oil is 0.950.
The mensuration of the betacyclodextrin inclusion complex recovery rate of volatile oil: it is a certain amount of that precision takes by weighing β-CD, adds 10 times of distilled water, and heating in water bath makes dissolving, reduce to set point of temperature again, under stirring condition, volatile oil-ethanol liquid (1: 2) is slowly joined in β-CD aqueous solution, continue to stir inclusion, cooling, put refrigerator and cooled and hide 24h, filter, inclusion complex is used a small amount of distilled water and absolute ethanol washing respectively, 40 ℃ of dryings promptly get volatile oil-β-CD inclusion complex.Press the factor level of table 3 and the L of table 4
9(3
4) condition of orthogonal table experimentizes, 9 volatile oil inclusion complexes, calculate the inclusion complex recovery rate.Its computing formula is respectively:
With volatile oil betacyclodextrin inclusion complex recovery rate is index, carries out variance analysis.The results are shown in Table 5.
Table 3 volatile oil beta-CD inclusion complex preparation technology factor level table
Level | Oil: β-CD (ml:g) | Amount of water (ml) | The inclusion temperature (℃) | Mixing time (h) |
1 2 | 1∶8 1∶7 | 80 70 | 80 60 | 1.5 1.0 |
Table 4 orthogonal experiment data table
Sequence number | A | B | C | D | The yield of volatile oil (%) |
1 2 3 4 5 6 7 8 9 K
1 K
2 K
3 - k
1 - k
2 - k
3 S
j | 1 1 1 2 2 2 3 3 2 134 195 232 44.67 65.00 77.34 1632.67 | 1 2 3 1 2 3 1 2 3 194 185 182 64.67 61.67 60.67 26.00 | 1 2 3 2 3 1 3 1 2 186 190 185 62.00 63.34 61.67 4.67 | 1 2 3 3 1 2 2 3 1 176 193 192 58.67 64.33 64.00 60.67 | 43 47 44 70 60 65 81 78 73 CT=34969 |
Table 5 analysis of variance table
Annotate: F
1-0.05(1,3)=10.13 F
1-0.01(1,3)=34.12; " Δ " merging is as the test error quadratic sum.
As shown in Table 5, the A factor has the influence of utmost point significance to the result, selects A
3B, D factor have the significance influence, select B
1D
2The C factor does not have obvious influence, takes all factors into consideration, and selects C
2Be advisable.So optimum condition is: A
3B
1C
2, that is: get the β-CD of 6 times of amounts of volatile oil, be dissolved in the water of 80 times of amounts of volatile oil, inclusion under 60 ℃ condition stirred 1 hour.
1.3 extraction process by water examination
Take by weighing medical material Radix Saposhnikoviae 37.5g, Radix Bupleuri 37.5g, Radix Puerariae 37.5g, Radix Platycodonis 22.5g, Semen Armeniacae Amarum 30g, Radix Angelicae Dahuricae 22.5g, Herba Corydalis Bungeanae 75g, Rhizoma Phragmitis 60g for a, totally 3 parts, add 10 times, 12 times, 14 times water gagings respectively, by formulation and technology extract, concentrate, dry, get 3 parts of dry extracts, (an appendix VI of Chinese Pharmacopoeia version in 2000 D) measures according to high performance liquid chromatography, the results are shown in Table 6.
Table 6 amount of water preference data table
Sample number | Inventory (g) | Add the water multiple | Paste volume (g) | Puerarin total amount (mg) |
1 2 3 | 322.5 322.5 322.5 | 10 12 14 | 22.4 26.4 28.7 | 200.704 204.072 205.779 |
The result shows that amount of water has certain influence to extraction effect, and 12 times of extractions with 14 times of amount of water are complete substantially, so take all factors into consideration from practical factors such as energy consumptions, determines to add 12 times of amounts that water volume is a medical material.
Experimental example 2: concentrate and drying process research
2.1, concentrate: adopt vacuum concentration, condition is: vacuum 0.06Kpa, 60 ℃ of temperature.Being concentrated into relative density is the thick extractum of 1.25-1.30 (50 ℃ of surveys).
2.2, drying: adopt drying under reduced pressure, condition is: 60 ℃ of temperature; Vacuum-0.1Kpa, dry 8 hours.
2.3, the dried cream powder yield investigates test:
Recipe quantity by text takes by weighing medicine respectively, totally 3 parts, by the extraction process of working out under the method for making item extract, make with extra care, concentrate, dry.Flour extraction sees Table 7.
The test of table 7 dried cream powder yield
Lot number | Crude drug amount (g) | Dried cream must be measured (g) | Dried cream yield (%) | Average paste-forming rate (%) |
030528 030603 030611 | 4425 4425 4425 | 711.10 765.47 723.82 | 16.10 17.30 16.36 | 16.59 |
As shown in Table 10: the average yield of dried cream powder is 16.59%, and tentative paste-forming rate must not be lower than 13.0%.
Experimental example 3: preparations shaping Journal of Sex Research
3.1, the selection of adjuvant type
(1) selection of filler
According to data, chewable tablet generally selects water soluble adjuvants such as mannitol, sorbitol, sucrose, xylitol as filler.Because of this product is no sugar chawing tablet, can not use sucrose, so be filler with mannitol, lactose, xylitol respectively, carry out pressure testing, preferred result sees Table 8.
The screening of table 8 filler kind
Principal agent (g) | Mannitol (g) | Lactose (g) | Xylitol (g) | Compressibility | Mouthfeel |
75 75 75 | 75 - - | - 75 - | - - 75 | Not so good carefully | Good generally good |
According to The above results, with mannitol, lactose, xylitol is that filler can both satisfy the preparation requirement substantially, but be that filler then certain draws moistly because of it has with the xylitol, cause sticking and flower sheet, though and be that the filler compressibility is good with the lactose, but cost is higher, and mouthfeel is slightly poor, and mannitol itself has sweet taste, draws moist little, compressibility is good, mouthfeel is good, so determine with mannitol as best filler.
(2) selection of sweeting agent
Sweeting agent commonly used has: stevioside, betanin, aspartame (Aspartrame), glycyrrhizin and saccharin sodium etc.Because betanin is alkalescence, probably influential to composition, glycyrrhizin is the class adrenocortical hormones, and taking for a long time probably influences human electrolyte's metabolism; Glucide is a synthetic sweetener, and the stevioside mouthfeel is bad, is sweeting agent so select aspartame for use.
3.2, the selection of supplementary product consumption
(1) mannitol calculates according to prescription extract amount, and the each dose of medicated powder is about 0.75g.Design sheet respectively heavily for 1.0g, 1.5g, 1.8g, carry out pressure testing, the result is as follows:
The preferred result table of table 9 mannitol consumption
Tested number | Sheet is heavy | Principal agent amount (g) | Mannitol amount (g) | Result of the test |
1 2 3 | 1.0 1.5 1.8 | 0.75 0.75 0.75 | 0.25 0.75 1.05 | Granule is met thermal softening, the good characters of can't granulating, and the good good characters of compressibility, compressibility is good |
Above result shows, because of medicated powder have certain draw moist, the granule moisture absorption is serious at least for the mannitol consumption, can't make the 1.0g sheet, and the compressibility of 1.5g sheet and 1.8g sheet is all better, considers from the cost angle, determines that sheet heavily is 1.5g, the consumption of mannitol adds to full dose and gets final product then according to the actual amount of each batch medicated powder.
(2) aspartame is got the granule three equal parts that do not add sweeting agent by above-mentioned prepared, the aspartame that adds finished product preparation 2.0%, 2.5%, 3.0% amount respectively, 2.0% amount mouthfeel bitter, the sweet taste of 3.0% amount is heavier, 2.5% the amount more moderate, so select the aspartame of 2.5% amount that adds finished product preparation for use, count 37.5 parts by weight.
3.3, the selection of wetting agent
Take by weighing medical material by recipe quantity, extract, obtain water and promote powder and medical material powder according to above-mentioned definite extracting method.Because of medicated powder is water extract, granulate with water that then viscosity is bigger, can't granulate, thus select ethanol as wetting agent, and investigate the granulating efficiency of different concentration ethanol.With being divided into 5 parts behind the two abundant mix homogeneously, carry out the comparison of Different concentrations of alcohol granulating efficiency.Because of the large percentage of mixed powder Chinese drugs powder, viscosity is relatively poor, so select the ethanol of concentration range 70-95% to test (23 ℃ of room temperatures; Relative humidity 50%), its result is as follows:
The preferred result table of table 10 wetting agent
Sequence number | Concentration of alcohol (%) | Granulating efficiency |
1 2 3 4 5 | 70 80 85 90 95 | Made soft material is slightly hard, easily clumps together; The thicker made soft material of granule is harder; The made soft material soft durometer of grain forming weak effect is moderate; The better made soft material soft durometer of grain forming effect is moderate; The effective made soft material of grain forming is loose; Not molding of granule |
Table 10 shows, determines that wetting agent is 85~90% ethanol, and consumption is approximately 1/3 of medicated powder.
Experimental example 4: preparation stabilization Journal of Sex Research
In order to investigate the stability of moulding process, we place 40 ℃, relative humidity with the chewable tablet of polyethylene bottle packing is 75% climatic chamber, places 1 month, takes out, and measures the appearance character of its test front and back, the results are shown in Table 11.
Comparing result before and after table 11 accelerated test
Sample | Outward appearance | Mouthfeel | Tablet weight variation |
After testing before the test | Sepia tablet sepia tablet | Good | Qualified |
The result shows: this medicine has no significant change at aspects such as appearance color, physical behaviors before and after the accelerated test, illustrates that this medicine is basicly stable, and moulding process is reasonable.
Concrete embodiment
Embodiment 1: Herba Schizonepetae 750g, Herba Menthae 225g, Radix Saposhnikoviae 375g, Radix Bupleuri 375, Folium Perillae 225g, Radix Puerariae 375g, Radix Platycodonis 225g, Semen Armeniacae Amarum 300g, Radix Angelicae Dahuricae 225g, Herba Corydalis Bungeanae 750g, Rhizoma Phragmitis 600g
More than ten simply, get Herba Schizonepetae, Herba Menthae, Folium Perillae and add 10 times of water gagings after mixing, soaked 2 hours, steam distillation 6 hours extracts volatile oil, the device collection in addition of the aqueous solution after the distillation, medicinal residues are continued to employ; Volatile oil betacyclodextrin inclusion (volatile oil-betacyclodextrin-water=1: 6: 80,60 ℃ were stirred 1 hour), cold preservation is spent the night, and filters, and inclusion complex low temperature (40 ℃) drying is ground into fine powder.Eight flavors such as medicinal residues and all the other Radix Saposhnikoviaes add 12 times of amounts of water and decoct secondary, each 1.5 hours, collecting decoction, filter, filtrate and above-mentioned aqueous solution merge, and being concentrated into relative density is the thick paste of 1.25-1.30 (60 ℃), drying under reduced pressure is ground into fine powder and above-mentioned volatile oil inclusion complex fine powder and mixes, it is an amount of to add aspartame 37.5g and mannitol, mixing is used 85% alcohol granulation, drying, tabletting, promptly.
Embodiment 2: Herba Schizonepetae 750g, Herba Menthae 225g, Radix Saposhnikoviae 375g, Radix Bupleuri 375, Folium Perillae 225g, Radix Puerariae 375g, Radix Platycodonis 225g, Semen Armeniacae Amarum 300g, Radix Angelicae Dahuricae 225g, Herba Corydalis Bungeanae 750g, Rhizoma Phragmitis 600g
More than ten simply, get Herba Schizonepetae, Herba Menthae, Folium Perillae and add 8 times of water gagings after mixing, soaked 4 hours, steam distillation 4 hours extracts volatile oil, the device collection in addition of the aqueous solution after the distillation, medicinal residues are continued to employ; Volatile oil betacyclodextrin inclusion (volatile oil-betacyclodextrin-water=2: 7: 90,50 ℃ were stirred 1.5 hours), cold preservation is spent the night, and filters, and inclusion complex low temperature (30 ℃) drying is ground into fine powder; Eight flavors such as medicinal residues and all the other Radix Saposhnikoviaes add 10 times of water gagings and decoct secondary, each 3 hours, collecting decoction, filter, filtrate and above-mentioned aqueous solution merge, and being concentrated into relative density is the thick paste of 1.25-1.30 (60 ℃), drying is ground into fine powder and above-mentioned volatile oil inclusion complex fine powder and mixes, it is an amount of to add stevioside 12g, saccharin sodium 15g and xylitol, mixing is used 90% alcohol granulation, drying, tabletting, promptly.
Embodiment 3: Herba Schizonepetae 750g, Herba Menthae 225g, Radix Saposhnikoviae 375g, Radix Bupleuri 375, Folium Perillae 225g, Radix Puerariae 375g, Radix Platycodonis 225g, Semen Armeniacae Amarum 300g, Radix Angelicae Dahuricae 225g, Herba Corydalis Bungeanae 750g, Rhizoma Phragmitis 600g
More than ten simply, get Herba Schizonepetae, Herba Menthae, Folium Perillae and add 8 times of water gagings after mixing, soaked 2 hours, steam distillation 6 hours extracts volatile oil, the device collection in addition of the aqueous solution after the distillation, medicinal residues are continued to employ; Volatile oil betacyclodextrin inclusion (volatile oil-betacyclodextrin-water=3: 10: 100,40 ℃ were stirred 3 hours), cold preservation is spent the night, and filters, and inclusion complex low temperature (50 ℃) drying is ground into fine powder; Eight flavors such as medicinal residues and all the other Radix Saposhnikoviaes add 12 times of water gagings and decoct secondary, each 3 hours, collecting decoction, filter, filtrate and above-mentioned aqueous solution merge, and being concentrated into relative density is the thick paste of 1.25-1.30 (60 ℃), drying is ground into fine powder and above-mentioned volatile oil inclusion complex fine powder and mixes, add betanin 2.5g, aspartame 37.5g, glycyrrhizin 7.5g and lactose, xylitol is an amount of, mixing is used 90% alcohol granulation, drying, tabletting, promptly.
Embodiment 4: Herba Schizonepetae 750g, Herba Menthae 225g, Radix Saposhnikoviae 375g, Radix Bupleuri 375, Folium Perillae 225g, Radix Puerariae 375g, Radix Platycodonis 225g, Semen Armeniacae Amarum 300g, Radix Angelicae Dahuricae 225g, Herba Corydalis Bungeanae 750g, Rhizoma Phragmitis 600g
More than ten simply, get Herba Schizonepetae, Herba Menthae, Folium Perillae and add 12 times of water gagings after mixing, soaked overnight, steam distillation 8 hours extracts volatile oil, the aqueous solution after distillation device is in addition collected, medicinal residues are continued to employ; Eight flavors such as medicinal residues and all the other Radix Saposhnikoviaes add 14 times of water gagings and decoct secondary, each 2 hours, collecting decoction, filter, filtrate and above-mentioned aqueous solution merge, and being concentrated into relative density is the thick paste of 1.25-1.30 (60 ℃), drying is ground into fine powder and above-mentioned volatile oil inclusion complex fine powder and mixes, it is an amount of to add aspartame 42.5g and lactose, mixing is used 85% alcohol granulation, drying, tabletting, promptly.