CN101095735B - Preparation method of Chinese traditional medicine soft capsules for relieving cough - Google Patents
Preparation method of Chinese traditional medicine soft capsules for relieving cough Download PDFInfo
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Abstract
The invention relates to a Chinese pharmaceutical soft capsule for relieving cough and process for preparation, which is prepared from Chinese parasol tree root 300g, Chinese ephedra 250g, oldenlandia 150g, saxifrage 150g, loquat leaves 150g, mulberry bark 100g, soybean oil 1.2 times by weight of the medicament content, the soft capsule also includes a rubber skin consisting of gelatin, glycerin, water and titanium dioxide by a ratio of 100 : 45 : 100 :2, and is prepared through enclosing the medicaments into closed soft rubber shell.
Description
The application's name that to be the applicant submit on October 26th, 2005 is called: " a kind of cough relief traditional Chinese medicine preparation and preparation method thereof ", application number are: the dividing an application of the application for a patent for invention of 200510200647X.
Technical field:
The present invention relates to Chinese medicinal soft capsule agent of a kind of cough-relieving and preparation method thereof, belong to technical field of Chinese medicine.
Background technology:
Present various antitussive is a lot, but great majority are Western medicine, easily have side effects when taking.And the effect of Chinese medicine cough-relieving is not ideal, and takes inconvenience, and this brings many troubles to the patient, and for reaching the purpose of treatment, a large amount of research has been done by many inventors and medicine enterprise, and the product of some treatments also is provided; Be called " capsule against cough and preparation technology thereof " and develop as ZL 02134145.1, name for treating this type of disease, but the hygroscopicity of the product of discovery preparation is strong in the research that continues, and makes that the capsule hygroscopicity is stronger, storage for a long time is perishable, unstable product quality.And the dosage form kind is abundant inadequately, is suitable for crowd's narrow range, and bioavailability, the medicine stability of conventional dosage forms are undesirable, and the problem that especially bioavailability of effective ingredient is not high is badly in need of solving; In view of such circumstances, improve dosage changing form and just become the thing that people are badly in need of solving.
Summary of the invention:
The objective of the invention is to: Chinese medicine preparation of a kind of cough-relieving and preparation method thereof is provided; The present invention is directed to prior art, the preparation that provides increases medicine stability, absorbs soon, improves the high effect of bioavailability, and it is extensive to be suitable for the crowd, patient's taking convenience; Also can cover the adverse drug abnormal smells from the patient, to address the above problem.
The present invention constitutes like this: calculate by weight, it is with Radix firmianae 300g, Herba Ephedrae 250g, Herba Hedyotidis Diffusae 150g, Herba Saxifragae 150g, Folium Eriobotryae 150g, Cortex Mori 100g, adds appropriate amount of auxiliary materials again and makes.
Described preparation comprises granule, dispersible tablet, pellet, soft capsule, drop pill, tablet, oral liquid.
Preparation method of the present invention: get Herba Ephedrae and be ground into fine powder, cross 60 mesh sieves,
60After the Co radiation sterilization, standby; All the other five tastes add 8 times of water gagings and decoct 2 times, and each 2 hours, filter, being concentrated into relative density is 1.28 (40 ℃), drying is pulverized, and crosses 60 mesh sieves, with above-mentioned Herba Ephedrae fine powder mixing, adds adjuvant then and makes different preparations respectively.
The granule of described preparation prepares like this: it is an amount of to add 2.5% aspartame and dextrin, mixes, and makes granule, drying, promptly.
The dispersible tablet of described preparation prepares like this: get PPVP5g and lemon yellow mixing, get 3/5PPVP3g and cream powder mix homogeneously; K30 anhydrous alcohol solution with 1.5% is made binding agent, 40 order system material, granulate, and the mixed powder of surplus 2/5PPVP2g of Retained and lemon yellow mixing is added in the granule that makes, tabletting, promptly.
The pellet of described preparation prepares like this: add appropriate amount of starch, and with 60% ethanol and 2% soybean oil system soft material, the soft material of making micropill mechanism ball, wet feed pushed the 0.8mm sieve aperture, and the wet grain of strip cuts off round as a ball, 50～60 ℃ of drying and mouldings, cross 16～20 mesh sieves, select ball, promptly.
The soft capsule of described preparation prepares like this: press medication amount: substrate amount=1: 1.2 adding soybean oil, mixing; The prescription of rubber is a gelatin: glycerol: water: titanium dioxide=100: 45: 100: 2, batchingization adhesive tape part is: weigh batching, in the inputization glue jar, merceration is warming up to 65 ± 5 ℃ gradually after 30 minutes, stirred 4 hours and simultaneously evacuation remove bubble, treat evenly back blowing of sizing material, incapsulate after the filtration in the sizing material bucket of machine; The debugging pellet press, 65 ℃ of gelatin box controls, mould rotating speed 2.0 is rolled in 45 ℃ of sprinkler body temperature controls, rubber thickness 0.8mm, 20～24 ℃ of room temperature controls, relative humidity＜50% pelleting; The dry typing drying of rolling that adopts combined with two steps of pallet, dry 3 hours of the typing of rolling, and 24 ℃ of baking temperatures, dry relative humidity answers＜40%, and drying time is at 24～36 hours, promptly.
The drop pill of described preparation prepares like this: get extract powder 200g, PEG4000 200g and polyoxyethylene monostearate Arlacel-40 10g, mix homogeneously, fuse in the water-bath, stir evenly, drip and in dimethicone, to become ball, drip apart from 5cm drip footpath 2.5nm/2nm, mix 80 ℃ of ointment temperature, liquid coolant height 70cm, promptly.
The tablet of described preparation prepares like this: adds microcrystalline Cellulose 40g, uses 80% alcohol granulation, and drying, granulate adds magnesium stearate 1g, mixing, tabletting, coating, promptly.
The oral liquid of described preparation prepares like this: clear paste 300ml stirs evenly with sucrose 1000g, sodium benzoate 0.5g, filters, and adds water to ormal weight, promptly.
Among the we, Radix firmianae, Herba Ephedrae, Herba Hedyotidis Diffusae, Herba Saxifragae, Folium Eriobotryae, Cortex Mori compatibility, nourishing the lung to arrest cough, resolving phlegm and relieving asthma.Be applicable to the cough with asthma that flu causes, acute bronchitis etc.
Compared with prior art, micropill disintegrative of the present invention is good, and the bioavailability height is particularly suitable for the middle-aged and elderly people patient and takes; Medicine tablet formulation provided by the invention, the mode of taking is more, can swallow, buccal, and it is convenient to use more than capsule, this medicine is met water and can rapid disintegrate be formed homodisperse aqueous solution in 3 minutes simultaneously, has solved the not high problem of effective ingredient bioavailability; Soft capsule of the present invention is that drug blockage is formed in soft gel coat, has solved medicine and has met damp and hot problem of unstable; Can also cover poor taste, abnormal smells from the patient, play the effect that increases stability, improves bioavailability; Drop pill of the present invention absorbs soon the bioavailability height.
The present invention finds in the process of development granule, granule enters in the body with solution state, compare with oral solid formulation, reduced disintegrating procedue in the body, help the absorption of this product, shortened onset time greatly, but also there is certain problem in this product granule, is exactly that hygroscopicity is strong, mouthfeel is bitter.The present invention drafts by correctives and preferred supplementary product kind and solves this two problems.Because consider among the crowd of being suitable for and have diabetics, draw up and be equipped with sugar-free granule, with high-potency sweetener as correctives, whole supplementary product consumption is reduced significantly, simultaneously, also need under the situation that does not increase supplementary product consumption, there be the strong excessively problem of former medicated powder hygroscopicity in the solution raw material medicated powder by the kind and the technological parameter of strict screening adjuvant.
The present invention finds in the process of development capsule, and pharmacopeia regulation dispersible tablet must disintegrate fully in 3 minutes in 19 ℃～21 ℃ water, and suspension ability, bioavailability, dispersed homogeneous degree etc. are also had higher requirement.And the paste-forming rate of extract of the present invention is very high, viscosity is excessive, hygroscopicity is strong excessively, make must write out a prescription to moulding process in the kind of various adjuvants and consumption select to require very strict, deviation is arranged slightly, will cause product defective.The micropill diameter is similar to particle properties less than 2.5mm, the bioavailability height.
When development product of the present invention, maximum difficulty is exactly that the extractum hygroscopicity is strong and mobile poor, and poor plasticity is difficult to molding and molten diffusing slower.Soft capsule disintegrate in gastrointestinal is fast, and after softgel shell broke, medicine disperseed rapidly, so the drug release stripping is fast, produce effects is rapid, the bioavailability height; Semi-transparent soft capsule and better packaging material can protect medicine not to be subjected to the effect of dampness and airborne oxygen, light, thereby improve the stability of labile element; So the stability of soft capsule itself and moulding process directly influence the stability of product, be the technology of ten minutes crux.
In the process of development drop pill, find, substrate polyethylene glycols commonly used is that esterification forms, it is the surface-active water-soluble base of a kind of tool, dissolubility to insoluble drug is not good, the present invention adds Arlacel-40 change polyethylene glycols itself and does not have lipophilic structure and surface-active property, help the absorption of medicine, if but the consumption of Arlacel-40 is too high, and can cause the hygroscopicity of product to strengthen.
Experimental example 1: Study on Forming
(1) granule Study on Forming
In development process, the greatest problem that discovery the present invention makes granule is exactly that hygroscopicity is strong, mouthfeel is bitter.Because consider the crowd of being suitable for, the sugar-free granule fully of drawing up is so supplementary product consumption is just fewer, and that this product contains the former powder hygroscopicity of extractum is very strong, supplementary product consumption can not be too much situation under, strictness screening and control that must be by adjuvant and process conditions just can address these problems.
Supplementary product kind and consumption thereof are investigated
(1) correctives is selected
Sweetleaf agent function comparison sheet
Kind sucrose aspartame cyclamate
180～300 times 50 times of sugarinesses 1 (standard of comparison)
Flavor matter has the metalloid flavor carefully
80 times of costs of price 1 (standard of comparison) are low
The unrestricted consumption limit of consumption
(but diabetes are avoided usefulness) generally is no more than 0.1%
Safety is better carefully
Through relatively comprehensive, selected aspartame is made the correctives of this product, and required using through the mouthfeel debugging gets.Screening experiment: get four parts of extract powders, portion does not add any adjuvant, and three parts add 2%, 2.5%, 3% aspartame mixing respectively in addition, adds an amount of boiled water and takes after mixing it with water, and tastes its flavor through many people, judges the quality of mouthfeel, and it the results are shown in Table.
The aspartame scale
Tested number 1234
Addition does not add 2% and adds 2.5% adding 3%
Adjuvant aspartame aspartame aspartame
Mouthfeel is moderate sweet excessively than the sweet slightly bitterness sugariness that still has of bitterness
The result shows, adds 2.5% aspartame, and mouthfeel is moderate.
(2) wettability test is got two parts of extract powders, a dextrin that adds, and mixing is put respectively in the flat weighing bottle of having weighed, and accurate the title, decide, and measures its hygroscopic capacity under 25 ℃ of temperature, 75% property of relative humidity, the results are shown in Table.
(2) dispersible tablet Study on Forming
Dispersible tablet meet water rapidly disintegrate form the water dispersion tablet of uniform sticky suspension, it is poor to have solved former dosage form disintegrative, stripping is shortcoming slowly, and the dispersible tablet that the present invention makes is disintegrate fully in 3 minutes in 19 ℃～21 ℃ water, and suspension ability is good, bioavailability is high, dispersed homogeneous degree.
(1) adjuvant screening
(2) check disintegration
Adopting changes the basket method, and lift disintegration tester, tablet are got the situation of 6 observations by screen cloth.The then well more pleasant bulk absorption of disintegrative of percent of pass height.
The result shows, gets PPVP5g and lemon yellow mixing, get 3/5 with the extract powder mix homogeneously, K30 anhydrous alcohol solution with 1.5% is made binding agent, 40 order system material, granulate, and the mixed powder of surplus 2/5PPVP2g of Retained and lemon yellow mixing is added in the granule that makes, tabletting, the dispersible tablet product that obtains is easy to disintegrate.
(3) pellet Study on Forming
The micropill diameter is less than 2.5mm, and class is in particle properties, the bioavailability height, and the present invention is when development product micropill of the present invention, and maximum difficulty is exactly that hygroscopicity is strong and mobile poor, and poor plasticity is difficult to molding.The micropill manufacturing technology and the adjuvant that adopt screening to obtain make product be easy to disintegrate, and the bioavailability height is well-behaved.
(1) supplementary product kind and consumption are selected
Wettability test is got two parts of extract powders, a starch that adds, and mixing is put respectively in the flat weighing bottle of having weighed, and accurate the title, decide, and is to measure its hygroscopic capacity under 75% condition at 25 ℃ of temperature, relative humidity, the results are shown in Table.
The result shows that it is rationally feasible to adopt starch to make adjuvant.
(2) system soft material
Get extractum fine powder and starch, soybean oil and ethanol and make soft material with wet granulation process in right amount, make it to reach and hold agglomeratingly, that pinches can loose, standby.Research emphasis concentration of alcohol and soybean oil consumption influence pill, and experimental result sees Table.
Concentration of alcohol is investigated
| Tested number | Concentration of alcohol | System soft material situation |
| 1 | 70％ | Soft material easily bonds |
| 2 | 60％ | Soft material is moderate |
| 3 | 50％ | Soft material viscosity is not enough |
The soybean oil consumption is investigated
| Tested number | The soybean oil consumption | The pill situation |
| 1 | 60% ethanol, 1% soybean oil | Soft material viscosity is not enough, can't pill |
| 2 | 60% ethanol, 2% soybean oil | Soft material is moderate, is fit to pill |
| 3 | 60% ethanol, 3% soybean oil | Soft material easily bonds, the pill difficulty |
The result as seen, it is more satisfactory to adopt 60% ethanol, 2% soybean oil to be that adhesive is granulated, otherwise is difficult to molding.
(3) pill
The soft material that makes is with micropill mechanism ball, and wet feed pushed the 0.8mm sieve aperture, and the wet grain of strip cuts off round as a ball, and 50～60 ℃ of drying and mouldings are crossed 16～20 mesh sieves and selected ball.
(4) soft capsule Study on Forming
Soft capsule disintegrate in gastrointestinal is fast, and after softgel shell broke, medicine disperseed rapidly, so the drug release stripping is fast, produce effects is rapid, the biological utilisation height; Semi-transparent soft capsule can protect medicine not to be subjected to the effect of oxygen, light in dampness and the air with packaging material preferably, thereby improves the stability of labile element; So capsular stability and moulding process are very crucial technology.
(1) supplementary product kind and consumption are selected
1. disperse medium (or claiming substrate) is selected
At fill material and substrate energy mix homogeneously, and under the prerequisite of unobstructed defeated material of energy and pelleting, reduce substrates quantity as far as possible.By test of many times, determine medication amount (g): substrate amount (g)=be advisable at 1: 1.2, experimental result sees Table.
| Medication amount (g): substrate amount (g) | 1∶1 | 1∶1.2 | 1∶1.5 |
| Quality of liquid medicine | Viscosity is big, mobile poor | Viscosity is big, flowability is all good | Differences in viscosity, mobile big |
2. capsule shells prescription screening
According to the form below proportion scale batching, put into the 500ml bottle,suction, 65 ℃ of water-baths are dissolved, automatic stirringization glue, the while evacuation, about vacuum 0.095Mpa, insulation was placed 1 hour behind the operator hour, filtered glue, get a part of glue and measure viscosity and other performance, part glue evenly is paved into skim (smear below earlier one deck liquid paraffin) on iron plate, be positioned over to observe the rubber performance next day and judge again, with the investigation result of each index by good to poorly using " +++" successively, " ++ ", "+", "-" expression the results are shown in Table.
Rubber batching The selection result
| Batching (gelatin: glycerol: unit water): g | Viscosity (Mpas) | Flexibility | Elasticity | Toughness | Characteristics | Overall merit |
| 1.100∶35∶100 | 3.62 | - | -- | + | Crisp, hard | Difference |
| 2.100∶45∶100 | 3.32 | + | ++ | +++ | Tough, good film-forming property | Fine |
| 3.100∶55∶100 | 3.59 | + | ++ | + | Good springiness | Generally |
| 4.100∶45∶80 | 3.72 | ++ | ++ | + | Good springiness, viscosity is big | Fine |
| 5.100∶45∶120 | 3.11 | +++ | + | -- | Too soft | Difference |
Through above screening, overall merit is considered the characteristics of fill material, selects prescription 2, i.e. gelatin 100g: glycerol 45g: water 100g.
3. opacifier is selected
The transparent adhesive tape softgel shell easily causes instability, so need to add a certain amount of opacifier.Select titanium dioxide (titanium dioxide) to make opacifier through investigation and can reach effective shaded effect, and steady quality, not with rubber cement and implant generation chemical change.Its consumption is through investigating with gelatin: glycerol: water: titanium dioxide=100g: 45g: 100g: 2g is advisable, and little to the rubber quality influence, the results are shown in Table.
The opacifier consumption is selected
| Usage ratio (g of unit) gelatin: glycerol: water: titanium dioxide | The rubber transparency | Rubber cement viscosity (Mpas) | Overall merit |
| 100∶45∶100∶0.5 | Translucent | 3.01 | Consumption is not enough |
| 100∶45∶100∶1 | Translucent | 3.10 | Consumption is not enough |
| 100∶45∶100∶2 | Translucent | 3.36 | Good |
| 100∶45∶100∶3 | Translucent | 3.52 | Viscosity is bigger |
(2) molding technological condition is investigated
1. the extractum grinding particle size is investigated
Extractum is pulverized, crossed 60 orders, 80 orders, 100 orders, 120 mesh sieves respectively, press extractum: substrate=adding in 1: 1.2 is even through the colloid mill mill, observes the mixing situation, and fruiting period sees Table.
The extractum grinding particle size is investigated
| Granularity (order) | 60 | 80 | 100 | 120 |
| The mixing situation | Can not mixing, high speed centrifugation (10000/min) 30min layering | The energy mixing, high speed centrifugation (10000/min) 30min layering | The energy mixing, 30min is not stratified for high speed centrifugation (10000/min) | The energy mixing, 30min is not stratified for high speed centrifugation (10000/min) |
As seen from the above table, extractum was pulverized 80 mesh sieves, and just therefore the energy mixing, selects extractum to pulverize 80 mesh sieves.
2. fill material mixes
Laboratory is got extractum and was pulverized 80 mesh sieves, presses extractum: substrate=add soybean oil at 1: 1.2, use the colloid mill mixing, and evacuation removes bubble, and is standby.
3. batchingization glue is investigated
By aforementioned preferred prescription is gelatin: glycerol: water: titanium dioxide=100g: 45g: 100g: the 2g weigh batching, and with different temperatures glue.The results are shown in Table.
Changing the glue temperature investigates
| Temperature (℃) | Change the glue time (H) | The rubber quality |
| 50 | 6 | Good |
| 60 | 5 | Good |
| Temperature (℃) | Change the glue time (H) | The rubber quality |
| 70 | 5 | Good |
| 80 | 5 | Harder |
| 90 | 4 | Rubber has bubble, and is hard |
By last table prompting, it is the most suitable with 60～70 ℃ to change the glue temperature.So batchingization adhesive tape part is: weigh batching, in the inputization glue jar.Merceration was warming up to 65 ± 5 ℃ in 30 minutes gradually, stir 5 when turbid and simultaneously evacuation remove bubble, treat evenly back blowing of sizing material, incapsulate after the filtration in the sizing material bucket of machine.
4. pelleting: the sizing material bucket and the spice bucket of room temperature of insulation are delivered to the capsule machine top, be connected, debug pellet press with machine, 65 ℃ of gelatin box temperature controls, mould rotating speed 2.0 is rolled in 45 ℃ of sprinkler body temperature controls, rubber thickness 0.8mm, 20～24 ℃ of indoor temperatures, relative humidity＜50%.Treat that it is to survey loading amount once every half an hour in the pelleting process that ball content loading amount is regulated in pellet press debugging back.
5. dry
Typing is dry: in being sent to rotating cage, rotating cage is blown a cold wind over while rotating through the soft capsule of pellet press extrusions, rotates the drying about 2 of finalizing the design when turbid.
Tray dried: the soft gelatin capsule of cold air drying is contained in clean rustless steel charging tray splendid attire in rotating cage, moves to about 22 ℃ of temperature, when airing 30 is turbid in the hothouse of relative humidity below 50%, and constantly stirs.Survey capsule moisture and be dry suiting below 10%.
Dry lime light: drying adopts rolling to finalize the design and combines with two steps of tray dried, and rolling typing drying is advisable when investigation is turbid with two, and overlong time is then rough; Baking temperature is advisable about investigating with 22 ℃, and it is long that it's low drying time is past temperature, though increase in temperature can shorten drying time, easily produces Testudinis to capsule surface and splits; Dry relative humidity should be lower than 50% through investigating, otherwise is difficult for dry; Got final product below 10% with control moisture drying time about 24～36 hours.
(5) drop pill moulding process
(1) screening of substrate
The fusion situation of substrate and principal agent relatively
| The prescription number | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
| Medication amount (g) | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
| Macrogol 4000 (g) | 30 | 20 | 20 | 20 | 10 | 10 | ----- | ----- |
| Polyethylene glycol 6000 (g) | ----- | ----- | ----- | 20 | 30 | 35 | 40 | 45 |
| Arlacel-40 | ----- | ----- | 10 | 10 | ----- | ----- | 10 | ----- |
| The prescription number | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
| The fusion situation | Principal agent can merge with substrate, but that system does not have is mobile | Principal agent can merge with substrate, but system is better mobile | Principal agent can merge with substrate, but the system flowability is fine | Principal agent can merge with substrate, but the system flowability is fine | Principal agent can merge relatively poor with substrate | Principal agent can merge with substrate, but that system does not have is mobile | Principal agent can merge with substrate, but the system flowability is relatively poor | Principal agent can merge with substrate, but system is better mobile |
| The drop pill outward appearance | ----- | Roundness is poor, hangover | Smooth, roundness is good | Smooth, roundness is good | ----- | Roundness is poor, hangover | ----- | Roundness is poor slightly, and hangover is arranged slightly |
| Drop pill hardness | ----- | Hardness is little | Hardness is better | Hardness is better | ----- | Hardness is better | Hardness is better | |
| The ball method of double differences is different | ----- | 20％ | 8.0％ | 12.5％ | ----- | 20％ | 20％ | |
| Dissolve scattered time limit min) | ----- | 7～8 | 4～5 | 9～10 | ----- | 6～8 | 6～8 |
The result shows, the drop pill stripping that composite interstitial substance makes is very fast, because the esterification of polyethylene glycols substrate forms, be the surface-active water-soluble base of a kind of tool (fusing point is 46～51 ℃), Arlacel-40 has changed polyethylene glycols itself and has not had lipophilic structure and surface-active character, improve the dissolubility of insoluble drug, help the absorption of medicine show.
(3) drip apart from, drip the selection of speed, temperature
Drip distance, drip selection fast, temperature: external diameter was fixed as 4.1,6.1mm in the interior external diameter of drip was fixing.Evaluation index: the heavy qualification rate of ball is by 2000 editions weight differential requirements of the Pharmacopoeia of the People's Republic of China: meet ± 7.5% within.
| Group | Temperature (℃) | Drip apart from (cm) | Liquid coolant height (cm) | The heavy qualification rate (%) of ball |
| 1 | 90 | 4 | 50 | 78.3 |
| 2 | 90 | 5 | 60 | 86.4 |
| 3 | 90 | 8 | 70 | 82.0 |
| 4 | 80 | 4 | 60 | 91.3 |
| 5 | 80 | 5 | 70 | 95.2 |
| 6 | 80 | 8 | 50 | 90.0 |
| 7 | 70 | 4 | 70 | 91.7 |
| 8 | 70 | 5 | 50 | 89.1 |
| 9 | 70 | 8 | 60 | 85.2 |
The result shows, the optimum condition of preparation drop pill of the present invention: drip to become ball in dimethicone, drip apart from 5cm, drip footpath 2.5mm/2mm mixes 80 ℃ of ointment temperature, liquid coolant height 70cm.
(6) bioavailability relatively
The SD rat, body weight 250～280g, male and female half and half, fasting overnight (can't help water), next day, gastric infusion was 3.8/Kg to medicament.15min after the administration before the electron donating group medicine, 30min, 50min, 80min, 2h, 3h, 4h, and 8h heart blood sampling, each blood sample point is with 6 rats.Blood sample is put the anticoagulant heparin pipe, 3000r/min, and centrifugal 5min, separated plasma is put 30 ℃ and is saved to analysis.High performance liquid chromatogram liquid chromatography instrument is by the M510 pump, the U6K injector, and M490 variable-wavelenght detector and 810 chromatographic data treating stations are formed (WATER, the U.S.).Analytical column is μ Bondpaka (0.45mm * 25cm); Mobile phase is that 0.01mol/L potassium dihydrogen phosphate-methanol (92: 8) is mobile phase, and detecting wavelength is that ephedrine hydrochloride extracts in the 210nm. blood, adds 5mlCHCL
3,, interior mark 50 μ L, test tube do 30 ° tiltedly in horizontal direction jolting device, and 15min is extracted in jolting, centrifugal (3000r/min) 10min, aqueous phase discarded, the accurate 4ml organic facies of drawing is in a clean tube, at 37 ℃ of water-baths, N
2Dry up under the air-flow, residue dissolves the sample introduction analytical attack again with 200 μ L mobile phases.
Rat plasma ephedrine hydrochloride concentration change (N=6)
The result shows that the bioavailability of product of the present invention is greater than capsule.
(7) antiinflammatory action (influence of xylol induced mice auricle edema)
Experimental technique: face with preceding that dispersible tablet of the present invention, micropill, soft capsule are mixed with the 0.10g/ml suspension with 0.5% hydroxy methocel (CMC-Na) is standby, animal is used healthy Kunming mouse, body weight 20 grams.Mice is divided into 7 groups (matched group normal saline) at random, irritate the long-pending 20ml/kg of being of body of stomach, in two weeks of continuous irrigation stomach, once a day, the last administration is only used microsyringe 0.05ml/ after 30 minutes, dimethylbenzene is applied to mouse right ear, put to death mice after 15 minutes, cut two ears, dash with the 8mm diameter steel and lay round auricle in left and right sides auricle same area respectively along the auricle baseline, the torsion Libra claims two ear weight in wet bases, with two auricle weight differences as the swelling level index.Inhibitory rate of intumesce equals the difference of average swelling degree of matched group and the average swelling degree of administration group and takes advantage of 100% again divided by the average swelling degree of matched group.
| Group | Dosage (g/Kg) | Animal (only) | Average swelling degree (mg) | Suppression ratio (%) |
| Matched group | 20ml/Kg | 8 | 23.31±2.43 | |
| The hydrocortisone group | 0.04 | 8 | 7.03±2.31 | 70.21 |
| The KEPING JIAONANG group | 2.0 | 8 | 16.23±1.31 | 30.13 |
| Dispersible tablet group of the present invention | 2.0 | 8 | 14.34±4.51 | 32.12 |
| Micropill group of the present invention | 2.0 | 8 | 13.48±2.31 | 33.12 |
| Soft capsule group of the present invention | 2.0 | 8 | 13.25±2.38 | 33.25 |
Fruiting period shows that preparation of the present invention has good antiinflammatory action, is better than KEPING JIAONANG.
The stability of Oral test
3 batches of this product, under room temperature, placed 1 year, respectively 0 month, 3 months, 6 months, 9 months, 12 months, carry out character, ph value and limit test of microbe, investigate character, the variation of ph value, microbial check result and show that every index has no significant change.
The micropill stability test
3 batches of this product were placed under room temperature 1 year, respectively 0 month, 3 months, 6 months, 9 months, 12 months, carry out character, limit test of microbe, investigate character, the microbial check result shows that every index has no significant change.
Concrete embodiment:
Embodiments of the invention 1: Radix firmianae 300g, Herba Ephedrae 250g, Herba Hedyotidis Diffusae 150g, Herba Saxifragae 150g, Folium Eriobotryae 150g, Cortex Mori 100g, get Herba Ephedrae 250g and be ground into fine powder, cross 60 mesh sieves (flour extraction 90%),
60After the Co radiation sterilization, standby.All the other five tastes add 8 times of water gagings and decoct 2 times, and each 2 hours, filter, being concentrated into relative density is 1.28 (40 ℃), drying is pulverized, and crosses 60 mesh sieves (yield is about 15%), with above-mentioned Herba Ephedrae fine powder mixing; It is an amount of to add 2.5% aspartame and dextrin, mixes, and makes granule, and drying promptly gets granule.
Embodiments of the invention 2: Radix firmianae 300g, Herba Ephedrae 250g, Herba Hedyotidis Diffusae 150g, Herba Saxifragae 150g, Folium Eriobotryae 150g, Cortex Mori 100g, get Herba Ephedrae 250g and be ground into fine powder, cross 60 mesh sieves (flour extraction 90%),
60After the Co radiation sterilization, standby.All the other five tastes add 8 times of water gagings and decoct 2 times, and each 2 hours, filter, being concentrated into relative density is 1.28 (40 ℃), drying is pulverized, and crosses 60 mesh sieves (yield is about 15%), with above-mentioned Herba Ephedrae fine powder mixing; Get PPVP5g and lemon yellow mixing, get 3/5PPVP3g and cream powder mix homogeneously.K30 anhydrous alcohol solution with 1.5% is made binding agent, 40 order system material, granulate, and the mixed powder of surplus 2/5PPVP2g of Retained and lemon yellow mixing is added in the granule that makes, and tabletting promptly gets dispersible tablet.
Embodiments of the invention 3: Radix firmianae 300g, Herba Ephedrae 250g, Herba Hedyotidis Diffusae 150g, Herba Saxifragae 150g, Folium Eriobotryae 150g, Cortex Mori 100g, get Herba Ephedrae 250g and be ground into fine powder, cross 60 mesh sieves (flour extraction 90%),
60After the Co radiation sterilization, standby.All the other five tastes add 8 times of water gagings and decoct 2 times, and each 2 hours, filter, being concentrated into relative density is 1.28 (40 ℃), drying is pulverized, and crosses 60 mesh sieves (yield is about 15%), with above-mentioned Herba Ephedrae fine powder mixing; Add appropriate amount of starch, with 60% ethanol and 2% soybean oil system soft material, the soft material of making is with micropill mechanism ball, and wet feed pushed the 0.8mm sieve aperture, and the wet grain cut-out of strip is round as a ball, 50～60 ℃ of drying and mouldings, 16～20 mesh sieves, select ball, promptly get pellet.
Embodiments of the invention 4: Radix firmianae 300g, Herba Ephedrae 250g, Herba Hedyotidis Diffusae 150g, Herba Saxifragae 150g, Folium Eriobotryae 150g, Cortex Mori 100g, get Herba Ephedrae 250g and be ground into fine powder, cross 60 mesh sieves (flour extraction 90%),
60After the Co radiation sterilization, standby.All the other five tastes add 8 times of water gagings and decoct 2 times, and each 2 hours, filter, being concentrated into relative density is 1.28 (40 ℃), drying is pulverized, and crosses 60 mesh sieves (yield is about 15%), with above-mentioned Herba Ephedrae fine powder mixing, press medication amount: substrate amount=1: 1.2 adding soybean oil, mixing; The prescription of rubber is a gelatin: glycerol: water: titanium dioxide=100g: 45g: 100g: 2g, batchingization adhesive tape part is: weigh batching, in the inputization glue jar, merceration is warming up to 65 ± 5 ℃ gradually after 30 minutes, stirred 4 hours and simultaneously evacuation remove bubble, treat evenly back blowing of sizing material, incapsulate after the filtration in the sizing material bucket of machine; The debugging pellet press, 65 ℃ of gelatin box controls, mould rotating speed 2.0 is rolled in 45 ℃ of sprinkler body temperature controls, rubber thickness 0.8mm, 20～24 ℃ of room temperature controls, relative humidity＜50% pelleting; The dry typing drying of rolling that adopts combined with two steps of pallet, dry 3 hours of the typing of rolling, and 24 ℃ of baking temperatures, dry relative humidity answers＜40%, and promptly got soft capsule at 24～36 hours drying time.
Embodiments of the invention 5: Radix firmianae 300g, Herba Ephedrae 250g, Herba Hedyotidis Diffusae 150g, Herba Saxifragae 150g, Folium Eriobotryae 150g, Cortex Mori 100g, get Herba Ephedrae 250g and be ground into fine powder, cross 60 mesh sieves (flour extraction 90%),
60After the Co radiation sterilization, standby.All the other five tastes add 8 times of water gagings and decoct 2 times, and each 2 hours, filter, being concentrated into relative density is 1.28 (40 ℃), drying is pulverized, and crosses 60 mesh sieves (yield is about 15%), with above-mentioned Herba Ephedrae fine powder mixing; Get extract powder 200g, two parts of PEG4000200g and polyoxyethylene monostearate Arlacel-40 10g, mix homogeneously fuses in the water-bath, stir evenly, drip and in dimethicone, to become ball, drip apart from 5cm drip footpath 2.5nm/2nm, mix 80 ℃ of ointment temperature, liquid coolant height 70cm promptly gets drop pill.
Embodiments of the invention 6: Radix firmianae 300g, Herba Ephedrae 250g, Herba Hedyotidis Diffusae 150g, Herba Saxifragae 150g, Folium Eriobotryae 150g, Cortex Mori 100g, get Herba Ephedrae 250g and be ground into fine powder, cross 60 mesh sieves (flour extraction 90%),
60After the Co radiation sterilization, standby.All the other five tastes add 8 times of water gagings and decoct 2 times, and each 2 hours, filter, being concentrated into relative density is 1.28 (40 ℃), drying is pulverized, and crosses 60 mesh sieves (yield is about 15%), with above-mentioned Herba Ephedrae fine powder mixing; Add microcrystalline Cellulose 40g, use 80% alcohol granulation, drying, granulate adds magnesium stearate 1g, mixing, tabletting, coating promptly gets tablet.
Embodiments of the invention 7: Radix firmianae 300g, Herba Ephedrae 250g, Herba Hedyotidis Diffusae 150g, Herba Saxifragae 150g, Folium Eriobotryae 150g, Cortex Mori 100g, get Herba Ephedrae 250g and be ground into fine powder, cross 60 mesh sieves (flour extraction 90%),
60After the Co radiation sterilization, standby.All the other five tastes add 8 times of water gagings and decoct 2 times, and each 2 hours, filter, being concentrated into relative density is 1.28 (40 ℃), drying is pulverized, and crosses 60 mesh sieves (yield is about 15%), with above-mentioned Herba Ephedrae fine powder mixing; Clear paste 300ml stirs evenly with sucrose 1000g, sodium benzoate 0.5g, filters, and adds water to ormal weight, promptly gets oral liquid.
Claims (1)
1. the preparation method of the Chinese medicinal soft capsule agent of a cough-relieving, it comprises Radix firmianae 300g, Herba Ephedrae 250g, Herba Hedyotidis Diffusae 150g, Herba Saxifragae 150g, Folium Eriobotryae 150g, Cortex Mori 100g, it is characterized in that: get Herba Ephedrae and be ground into fine powder, cross 60 mesh sieves,
60After the Co radiation sterilization, standby; All the other five tastes add 8 times of water gagings decoctions 2 times, and each 2 hours, filter, relative density is 1.28 when being concentrated into 40 ℃, drying is pulverized, and crosses 60 mesh sieves, with above-mentioned Herba Ephedrae fine powder mixing, then by medication amount: substrate amount=1: 1.2 adding soybean oil, mixing; The prescription of rubber is a gelatin: glycerol: water: titanium dioxide=100: 45: 100: 2, batchingization adhesive tape part is: weigh batching, in the inputization glue jar, merceration is warming up to 65 ± 5 ℃ gradually after 30 minutes, stirred 4 hours and simultaneously evacuation remove bubble, treat evenly back blowing of sizing material, incapsulate after the filtration in the sizing material bucket of machine; The debugging pellet press, 65 ℃ of gelatin box controls, mould rotating speed 2.0 is rolled in 45 ℃ of sprinkler body temperature controls, rubber thickness 0.8mm, 20～24 ℃ of room temperature controls, relative humidity＜50% pelleting; The dry typing drying of rolling that adopts combined with two steps of pallet, dry 3 hours of the typing of rolling, and 24 ℃ of baking temperatures, dry relative humidity＜40%, drying time is at 24～36 hours, promptly.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1413708A (en) * | 2002-11-19 | 2003-04-30 | 贵州柏强制药有限公司 | Capsule for releiving cough and its preparation technology |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1413708A (en) * | 2002-11-19 | 2003-04-30 | 贵州柏强制药有限公司 | Capsule for releiving cough and its preparation technology |
Non-Patent Citations (4)
| Title |
|---|
| 国家药品监督管理局.国家中成药标准汇编-内科-肺系-咳平胶囊.国家药品监督管理局,2002,497. * |
| 时军, 程怡.辅料在软胶囊剂型中的应用.中医药学刊21 9.2003,21(9),1429-1430. * |
| 马旭, 刘建平, 翁麟骧 , 李立民.软胶囊崩解迟缓现象影响因素研究.中国药科大学学报34 5.2003,34(5),414-418. * |
| 马旭, 刘建平, 翁麟骧, 李立民.软胶囊崩解迟缓现象影响因素研究.中国药科大学学报34 5.2003,34(5),414-418. * |
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