CN1268324C - Chinese medicinal soft capsule and preparing process thereof - Google Patents
Chinese medicinal soft capsule and preparing process thereof Download PDFInfo
- Publication number
- CN1268324C CN1268324C CNB2004100374097A CN200410037409A CN1268324C CN 1268324 C CN1268324 C CN 1268324C CN B2004100374097 A CNB2004100374097 A CN B2004100374097A CN 200410037409 A CN200410037409 A CN 200410037409A CN 1268324 C CN1268324 C CN 1268324C
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- Prior art keywords
- ethanol
- soft capsule
- weight portion
- mesh sieves
- behind
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- 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.)
- Expired - Lifetime
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
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Abstract
The present invention discloses a Chinese medicine soft capsule preparation for inhibiting tumor growth and a preparation method thereof. Crude drugs, such as turmeric root-tuber, hairyvein agrimonia herb and bud, bitter orange, nux vomica powder, etc. are processed by the techniques of ethanol back flow, spray-drying, etc. so as to prepare the soft capsule of the present invention; compared with the original oral administration preparation, the soft capsule of the present invention can effectively enhance the biological availability, can reduce the content of strychnine in the soft capsule and the everyday dose of the soft capsule, and can economically and safely perform the functions of activating blood circulation to dissipate blood stasis, alleviating pain to disperse knots, inhibiting tumor growth, strengthening vital qi to eliminate pathogenic factor and enhancing immunity of organisms.
Description
Technical field
The present invention relates to a kind of soft capsule preparation and preparation method thereof, particularly relate to pure Chinese medicinal soft capsule preparation of a kind of blood circulation promoting and blood stasis dispelling, pain-relieving powder for treating joint, heat-clearing and toxic substances removing, strengthening vital QI to eliminate pathogenic factors, inhibition tumor growth, human body immunity improving power and preparation method thereof, belong to medical technical field.
Background technology
Clinically for tumor treatment as a rule based on the method for operation, chemotherapy and operation combined chemotherapy, treatment meanss such as radiotherapy, enhancing human body immunity power are auxilliary.But above-mentioned Therapeutic Method all has bigger untoward reaction usually, and as the gastrointestinal reaction, passive protective physical fitness descends or the like behind alopecia, leukopenia, postoperative or the radiation exposure.PINGXIAO JIA0NANG is the pharmaceutical preparation with strengthening vital QI to eliminate pathogenic factors, enhancing human body immunity power, inhibition tumor growth of being made by pure Chinese medicines such as Radix Curcumae, Herba Agrimoniae, Fructus Aurantii, Semen Strychni Pulveratums.Verify by clinical the use widely, prove that its antitumor curative effect is definite, can effectively improve patient's immune level (cellular immunization, humoral immunization) and with chemotherapeutics treatment, radiotherapy and use, effect with attenuation synergistic, can alleviate clinical symptoms, stablize the state of an illness, reduce relapse rate, on the basis of improving life quality, the effect that effectively prolongs life cycle.But existing clinically oral formulations is tablet and hard capsule, and it is poor to exist oral absorption, and bioavailability is low, and easily the moisture absorption is not easy to carry, and the diversity of tabletting or filling is bigger aborning, is subjected to many shortcomings such as secondary pollution easily.In addition, the more important thing is each dose patient's every day big (can reach 24 every day at most).Because contain Semen Strychni Pulveratum in the prescription, and Semen Strychni is a kind of therapeutic dose and the more approaching toxic medicament of toxic dose, have another name called bitter reality, vomiting nut, Semen Strychni, be the seed of loganiaceae plant Semen Strychni.Cold in nature, bitter in the mouth is poisonous.Return liver, spleen channel.Effect mass dissipating and swelling eliminating, removing obstruction in the collateral to relieve pain, tradition are used for rheumatoid arthritis stubborn, paralysis and numbness, cellulitis carbuncle and painful swelling, traumatic injury etc.Say Semen Strychni " open meridians, the merit that reaches the joint thoroughly outclass its medicine " in " Records of Tradition Chinese and Western Medicine in Combination ".Semen Strychni clinical practice nearly one thousand years do not wane, and illustrate that it has significant effect, are " severe and lingering illness has been apt in the violent agent of poison ".Successive dynasties have been experienced from " nontoxic " to " poisonous " process to " big poison " to the toxic understanding of Semen Strychni.Modern pharmacological research shows that Semen Strychni contains brucine (strychnine), strychnine (Bu Lusheng), γ-colubrine and β-colubrine, vomicine, novacine, loganin etc.Main alkaloid is strychnine and strychnine.The reflection function of the at first excited spinal cord of therapeutic dose, respiratory center and vasomotor center in next excited oblongata, and can improve the sensorial function of cerebral cortex.Toxic dose can suppress respiratory center.Strychnine can also strengthen the effect that stops cholinesterase to destroy acetylcholine, and enterokinesia is strengthened, and causes stomachache, diarrhoea.Neural intramuscular all capable of blocking passes when strychnine and strychnine maximal dose, presents curariform action mask.Semen Strychni also can directly damage renal cells, causes acute renal failure, uremia.Oral strychnine 1 time can be poisoned for 5～10 milligrams, and 30 milligrams can cause death and die; Clothes Semen Strychni crude drug 7 grams can cause death and die.Latent period of poisoning is 30～180 minutes.Therefore " the medical toxicant management method " of Ministry of Public Health issue stipulates that clearly this class medicine of similar strychnine should strict control and management.Contain strychnine in every of the PINGXIAO JIA0NANG and can reach 0.35mg at most, according to taking 24 of every days, then the strychnine consumption can reach 8.4mg/ day, with maximum dose 10mg on the one of strychnine very near (strychnine maximum dose on the one is 10mg in the kind of poisonous substances (Ministry of Public Health is defended No. 27 file of medicine (89) " about carrying out the notice of " medical toxicant management method " ")).Therefore, if can effectively improve bioavailability, reduce the content of strychnine in the preparation and dose every day of preparation, just can be more economically, the effect of the flat oral preparation for eliminating blood circulation promoting and blood stasis dispelling of performance of safety, pain-relieving powder for treating joint, inhibition tumor growth, strengthening vital QI to eliminate pathogenic factors, human body immunity improving power.
In addition,, can reduce each dose so on the one hand, also can increase bioavailability on the other hand, better be absorbed by human body if can make with extra care extraction by the other side's Chinese medicine.
Summary of the invention
The purpose of this invention is to provide a kind of pure Chinese medicinal soft capsule preparation; Second purpose of the present invention provides a kind of bioavailability height, safe refining pure Chinese medicinal soft capsule preparation; The 3rd purpose of the present invention provides a kind of preparation method of Chinese medicinal soft capsule preparation; Another object of the present invention provides a kind of preparation method that can make with extra care the Chinese medicinal soft capsule preparation that extracts to crude drug.
For achieving the above object, the present invention has adopted following technical scheme:
Radix Curcumae 50～58 weight portions; Herba Agrimoniae 50～58 weight portions; Fructus Aurantii 85～95 weight portions; Oletum Trogopterori 40～50 weight portions; Alumen 50～58 weight portions; Sal Nitri 50～58 weight portions; Resina Toxicodendri 15～20 weight portions; Semen Strychni Pulveratum 15～30 weight portions.
More than eight the flavor medicines adopt following preparation method can make soft capsule preparation of the present invention.Concrete process program is as follows:
Process program:
1. extract:
(1) with Radix Curcumae, Fructus Aurantii two flavor pulverizing medicinal materials become coarse powder, cross 24 orders～50 mesh sieves; Oletum Trogopterori, Alumen, Sal Nitri, Resina Toxicodendri four Chinese medicine material is ground into fine powder, crosses 100 orders～120 mesh sieves; Use the 60-80% ethanol percolation, merge behind the diacolation liquid recycling ethanol;
(2) the last medicinal residues of percolation are with Herba Agrimoniae decocting three times, and collecting decoction filters, and concentrates; Add ethanol and staticly settle, the collecting precipitation thing is dissolved in water;
(3) percolate spherical tank decompression recycling ethanol is crossed the macropore resin bed respectively after merging and pure hypostasis filter with 400 order filter clothes behind the percolate recovery ethanol and is analysed post, with ethanol and distilled water eluting; Obtain refining extract after the concentrated back of merging eluent is spray-dried;
2. add in the above-mentioned refining extract and cross 80～120 mesh sieves through the Semen Strychni Pulveratum mix homogeneously of superfine grinding, under stirring, join solvent gradually, heating makes it to remain on 40～80 ℃ and stir and to make it dissolving, the dissolving back adds adjuvants such as wetting agent, suspending agent and stabilizing agent, fully stirring makes it be mixed into uniform suspension, again suspension crossed pelleting behind colloid mill, the degassing evacuation, finalized the design, select ball, wash ball, drying, promptly.
Technical solution of the present invention can also for:
Radix Curcumae 54 weight portion Herba Agrimoniaes 55 weight portion Fructus Aurantiis 80 weight portion Oletum Trogopteroris 45 weight portions
Alumen 58 weight portion Sal Nitri 54 weight portion Resina Toxicodendri 20 weight portion Semen Strychni Pulveratums 20 weight portions
Radix Curcumae, Fructus Aurantii two flavor pulverizing medicinal materials are become coarse powder, cross 24 mesh sieves; Oletum Trogopterori, Alumen, Sal Nitri, Resina Toxicodendri four Chinese medicine material are ground into fine powder, cross 100 mesh sieves; With 8 times of amount 70% ethanol, flood after 24 hours, promptly get percolate with 5ml/min speed percolation, merge standby behind the diacolation liquid recycling ethanol;
The last medicinal residues of percolation add 8 times of water with Herba Agrimoniae, and decocting three times decocted 2 hours at every turn, and collecting decoction filters, and concentrates; Add ethanol and adjust to that to contain the alcohol amount be 80%, staticly settled 24 hours at 4 ℃～8 ℃, the collecting precipitation thing is dissolved in water;
Percolate spherical tank decompression recycling ethanol is crossed the macropore resin bed respectively after merging and pure hypostasis filter with 400 order filter clothes behind the percolate recovery ethanol and is analysed post, with ethanol and distilled water eluting; Obtain refining extract after the concentrated back of merging eluent is spray-dried;
Add in the above-mentioned refining extract and cross 120 mesh sieves through the Semen Strychni Pulveratum mix homogeneously of superfine grinding, under stirring, join in the PEG400 gradually, heating makes it to remain on 60 ℃ and stir and to make it dissolving, the abundant stirring made it be mixed into uniform suspension after the dissolving back added adjuvant wetting agent, suspending agent and stabilizing agent, again suspension crossed pelleting behind colloid mill, the degassing evacuation, finalized the design, select ball, wash ball, drying, promptly.
The described solvent of above-mentioned preparation method can be any one or any several mixture in vegetable oil, PEG400, PGE, isopropyl alcohol, glycerol, tween 80, the water etc.; Adjuvant such as stabilizing agent, suspending agent can be any one or a few the mixture in glycerol, water, soybean lecithin, Cera Flava, aluminum monostearate, ethyl cellulose, the solid polyethylene glycol etc.
Through investigating, test Semen Strychni pharmacokinetic parameter in vivo and analyzing and learn, Semen Strychni Pulveratum is used as medicine after superfine grinding is impalpable powder, can accelerate, strengthen its absorption in vivo, also can accelerate simultaneously its removing in vivo, reduce accumulating in vivo.Therefore,, the consumption of Semen Strychni be can reduce, same even better therapeutic reached being used as medicine after the Semen Strychni Pulveratum superfine grinding, and littler to the toxic and side effects of body.In addition, the extractum of eight flavor medicines is pulverized the back to be dissolved as solvent dispersion with vegetable oil, simultaneously can add surfactant or other absorption enhancers, oil phase was because of the effect of surfactant after medicine entered in the body, can spontaneous formation Emulsion, drug powder distributes between oil/water is biphase on the one hand, relies on the huge surface area of little oil droplet to be distributed in rapidly and uniformly in the gastrointestinal tract, increases effective absorbing area; The chyle of Xing Chenging can enter blood through lymphsystem on the other hand, has avoided the influence of first pass effect, so bioavailability of medicament can be greatly improved.
Adopt decoction and alcohol sedimentation technique to extract among the present invention simultaneously, the more abundant reservation, effectively pressed down the cancer medicinal ingredient in the Herba Agrimoniae, therefore can improve the antitumor action of soft capsule preparation of the present invention greatly, and can remove impurity, make effective ingredient of the present invention more definite, improve the curative effect of product of the present invention.
Following experimental example is used to further specify the present invention:
Experimental example 1 soft capsule preparation preparation technology project study of the present invention
The principal agent Herba Agrimoniae has certain antineoplastic action according to its decocting liquid of modern pharmacological research in the prescription.Herba Agrimoniae mainly contains agrimophol (agrimophol), agrimonolide (agrimonolide), and contain galuteolin (luteoloside), Herba Agrimoniae first, second, third element (agrimonin A, B, C), (agrimol A～E), other contains tannin, sterol, Saponin and volatile oil to match agrimophol A～E.The present invention test shows that therefore effect that its water extract-alcohol precipitation extract suppresses tumor obviously greater than n-butanol extract, consider in the extraction process design that extracting Herba Agrimoniae with decoction and alcohol sedimentation technique effectively presses down the cancer medicinal ingredient.
Making with extra care of extract considers to use the macroporous resin chromatographic column to remove impurity such as tannin, starch, phytoprotein.
1. percolation extraction conditions screening
Use orthogonal experiment, investigate factors such as solvent consumption, percolation speed, grinding particle size,, select with experimental establishment research as follows about factor level to the influence of percolation extraction effect:
(1) factor level is selected to learn according to long-term practice, the performance that Chinese medicine leaches the preparation curative effect depends primarily on extraction, and the percolation effect is subjected to the factors such as solvent concentration, dip time, solvent consumption, percolation speed, grinding particle size and the influence of factor varying level.Need dipping a period of time as percolation is last, dip time is defined as 24 hours according to knowhow, so percolation extracts when investigating, and chooses concentration of alcohol, solvent consumption, percolation speed, grinding particle size as factor, the varying level of high spot reviews factor is to the influence of percolation extraction effect.Take all factors into consideration in conjunction with aspects such as production cost, the energy.
(2) index determines that selecting the extractum recovery rate is evaluation index, and its reason and assay method are as follows:
The extractum recovery rate: extractum is the material base of solid preparation performance curative effect, and its recovery rate height directly influences preparation process, is reasonable, effective control device so be chosen as the extraction index.
Assay method: merge extractive liquid,, filter, be adjusted to 1000ml, therefrom get 100ml again, in the dry evaporating dish of having weighed of impouring, water-bath is concentrated into dried, moves into 105 ℃ of oven dryings 3 hours to constant weight, taking-up, put in the exsiccator and cool off after 30 minutes, taking-up is weighed, and calculates.
(3) orthogonal test learns that according to test arrangement and result and The results of analysis of variance best percolation process program is a Radix Curcumae, and Fructus Aurantii two flavor pulverizing medicinal materials become coarse powder, cross 24 mesh sieves; Oletum Trogopterori, Alumen, Sal Nitri, Resina Toxicodendri four Chinese medicine material is ground into fine powder, crosses 100 mesh sieves; With 8 times of amount 70% ethanol, flood after 24 hours, promptly get percolate with 5ml/min speed percolation.
(4) repeated confirmatory experiment carries out repeated confirmatory experiment by above extraction process condition, extracting as a result by visible this optimum organization condition of the result of repeated confirmatory experiment, the extractum yield fluctuates less, all meet the orthogonal test optimum level, as seen this extraction process condition is reasonable, feasible and stable.
2. water extract-alcohol precipitation extraction conditions screening
Use orthogonal experiment, investigate of the influence of factors such as amount of water, decocting time, number of times, alcohol precipitation concentration, precipitate with ethanol time and number of times, select with experimental establishment research as follows about factor level to the water extract-alcohol precipitation extraction effect:
(1) factor level is selected to learn according to long-term practice, the performance that Chinese medicine leaches the preparation curative effect depends primarily on extraction, and extraction effect is subjected to the factors such as amount of water, decocting time, number of times, alcohol precipitation concentration, precipitate with ethanol time and number of times and the influence of factor varying level.So water extract-alcohol precipitation extracts when investigating, and chooses factors such as amount of water, decocting time, number of times, alcohol precipitation concentration, precipitate with ethanol time and number of times, the varying level of high spot reviews factor is to the influence of extraction effect.Take all factors into consideration in conjunction with aspects such as production cost, the energy.
(2) index determines that selecting the extractum recovery rate is evaluation index, and its reason and assay method are as follows:
The extractum recovery rate: extractum is the material base of solid preparation performance curative effect, and its recovery rate height directly influences preparation process, is reasonable, effective control device so be chosen as the extraction index.
Assay method: merge extractive liquid,, filter, be adjusted to 1000ml, therefrom get 100ml again, in the dry evaporating dish of having weighed of impouring, water-bath is concentrated into dried, moves into 105 ℃ of oven dryings 3 hours to constant weight, taking-up, put in the exsiccator and cool off after 30 minutes, taking-up is weighed, and calculates.
(3) orthogonal test learns that best water extract-alcohol precipitation extraction process scheme is that the last medicinal residues of percolation add 8 times of decoctings three times with Herba Agrimoniae, each 2 hours according to test arrangement and result and The results of analysis of variance.Add ethanol and adjust to that to contain the alcohol amount be 80%, 4 ℃～8 ℃ precipitations once, the sedimentation time is 24 hours.
(4) repeated confirmatory experiment carries out repeated confirmatory experiment by above extraction process condition, extracting as a result by visible this optimum organization condition of the result of repeated confirmatory experiment, the extractum yield fluctuates less, all meet the orthogonal test optimum level, as seen this extraction process condition is reasonable, feasible and stable.
3. content is prepared and Study on Forming
(1) specification determines
We investigate the extract powder recovery rate of 3 batches of medical materials, the results are shown in Table 1
Table 1 extract powder recovery rate
| Lot number | Extract powder recovery rate (%) | The average recovery rate of extract powder (%) |
| 030301 | 25.2 | |
| 030302 | 25.6 | 25.5 |
| 030303 | 25.7 |
Be about 25.5% through this technology of test of many times extract powder recovery rate.Making things convenient for the aspect to consider from soft capsule practical condition and taking, the 0.5g extract powder is made 2 soft capsules, is 1: 1 o'clock according to a large amount of evidence extract powders with solvent and adjuvant ratio, and soft capsule content flowability and stability are all relatively good; So soft capsule specification of the present invention is every heavy 0.5g.
(2) prescription determines
The soft capsule preparation technical study is mainly investigated problems such as the mobile and stability, disintegration of the selection of adjuvant and consumption, content.Research contents is as follows:
We select soybean oil, PEG400 respectively for use is substrate, by different proportion extract powder is suspended in wherein, content flowability, stability, disintegration to be index investigation said preparation prescription.The results are shown in Table 2.
Table 2 soft capsule prescription screening of the present invention table
| Prescription | R1 | R2 | R3 | R4 | R5 | R6 | |
| Extract powder (g) | 100 | 100 | 100 | 100 | 100 | 100 | |
| Adjuvant | Soybean oil (g) | 100 | 150 | 200 | |||
| PEG400 (g) | 200 | 150 | 100 | ||||
| Investigate index | The content flowability | Relatively poor | Relatively poor | Better | Better | Better | Better |
| Stability | Can not suspendible | Precipitation is arranged | Precipitation is arranged | A little precipitation | Relatively poor | Better | |
| Disintegration (minute) | 25.3 | 15.5 | 23.5 | 14.6 | 22.1 | 12.9 |
Annotate: above prescription is and earlier extract powder is added in the adjuvant (soybean oil or PEG400), and low speed stirs diffusing, and then the speed of speedup to 400 rev/min stirred 1.5 hours gradually, suspendible evenly back is crossed colloid mill, be pressed into soft capsule, clean drying with 95% ethanol.
The content flowability is judged the content flowability according to knowhow.
After stability leaves standstill 48 hours with the content for preparing, get the sample determination (liquid is divided into upper, middle and lower-ranking) of different liquid layers, measure strychnine content wherein, to investigate the stability of content.
Be medium disintegration with the simulated gastric fluid, under 37 ± 1 ℃ of conditions, according to an appendix VIIA of Chinese Pharmacopoeia version in 2000 inspection technique disintegration, measures in accordance with the law.
Conclusion:, think the better and requirement up to specification of prescription R6 to be suitable for big production through integrated survey to content flowability, stability and soft capsule disintegration; So select the R6 prescription for use.
(3) preparation of rubber solution
The elasticity size of soft capsule shell depends on the weight ratio between dry gelatin in the softgel shell, plasticizer (often being glycerol, sorbitol or both mixture) and the water three.Through investigate finding that relatively relatively the weight ratio of Shi Heing is dried plasticizer: dry gelatin=0.4～0.6: 1.0, and the ratio of water and gelatin is about 1: 1.2.The consistency and elasticity of the softgel shell under this ratio is all proper.Determine that through comparative test three's proper ratio is a gelatin: water: glycerol=1: 0.9: 0.5.
Gelatin, water, glycerol are put into container according to the above ratio, be heated to about 80 ℃, add an amount of screening agent (as food coloring), correctives (as sucrose, xylitol), antiseptic (as methyl parahydroxybenzoate, propyl p-hydroxybenzoate etc.) stirring again, make fully and dissolve, be incubated 1～2 hour, leave standstill, make the foam come-up, defoam, filter, 60 ℃ of insulations promptly get rubber solution.
Experimental example 2: the pharmacokinetics comparative study of thick Semen Strychni Pulveratum and ultra-fine Semen Strychni Pulveratum
Get 200 of mices, divide 20 groups at random, each 10 groups of thick Semen Strychni Pulveratum and ultra-fine Semen Strychni Pulveratum test group compare test and investigate thick Semen Strychni Pulveratum and ultra-fine Semen Strychni Pulveratum absorption process different in vivo.Each organizes mice respectively with the disposable administration of single dose.After the administration, serve as to detect index, be determined at the blood drug level of strychnine in the different intervals point mouse blood with the HPLC method with strychnine in the Semen Strychni.The result shows that the Semen Strychni absorption in vivo meets one compartment open model, and the main pharmacokinetic parameters of thick Semen Strychni Pulveratum is: T
Max=0.34h, C
Max=2.36 μ g.mL
-1, AUC 32.59 μ gmL
-1H
-1, CL 2 79 μ gmL
-1H
-1The main pharmacokinetic parameters of ultra-fine Semen Strychni Pulveratum is: T
Max=0.36h, C
Max=4.53ngmL
-1, AUC 9.76 μ gmL
-1, CL 926ngmL
-1H
-1
Above-mentioned thick Semen Strychni Pulveratum and thin Semen Strychni Pulveratum storage and time relationship in animal body sees Table 3 and table 4.
The body storage and the time relationship of the thick Semen Strychni Pulveratum of table 3
| Group | Blanking time/h | Number of animals | Death toll | Mortality rate/% | Body storage/mgkg-1 |
| 1 | 0.25 | 10 | 9 | 0.90 | 159.66 |
| 2 | 0.5 | 10 | 8 | 0.80 | 131.36 |
| 3 | 1 | 10 | 9 | 0.90 | 157.23 |
| 4 | 2 | 10 | 7 | 0.70 | 123.52 |
| 5 | 3 | 10 | 7 | 0.70 | 123.52 |
| 6 | 4 | 10 | 6 | 0.60 | 107.63 |
| 7 | 6 | 10 | 4 | 0.40 | 77.94 |
| 8 | 8 | 10 | 3 | 0.30 | 64.72 |
| 9 | 12 | 10 | 2 | 0.20 | 51.25 |
| 10 | 14 | 10 | 1 | 0.10 | 28.79 |
The body storage and the time relation of the ultra-fine Semen Strychni Pulveratum of table 4
| Group | Blanking time/h | Number of animals | Death toll | Mortality rate/% | Body storage/mgkg-1 |
| 1 | 0.25 | 10 | 10 | 1.00 | 182.47 |
| 2 | 0.5 | 10 | 9 | 0.90 | 151.33 |
| 3 | 1 | 10 | 9 | 0.95 | 179.25 |
| 4 | 2 | 10 | 8 | 0.80 | 118.69 |
| 5 | 3 | 10 | 5 | 0.50 | 68.51 |
| 6 | 4 | 10 | 6 | 0.60 | 79.82 |
| 7 | 6 | 10 | 3 | 0.30 | 31.58 |
| 8 | 8 | 10 | 2 | 0.20 | 23.27 |
| 9 | 12 | 10 | 1 | 0.10 | 11.47 |
| 10 | 14 | 10 | 0 | 0.00 | 9.82 |
Result of the test shows that its absorption in vivo can be accelerated, be strengthened to Semen Strychni after superfine grinding, and its oral back toxic action also has increase to a certain degree simultaneously; But Semen Strychni can quicken its elimination in vivo again through superfine grinding on the other hand, reduces its accumulating in vivo.Semen Strychni Pulveratum decrement after superfine grinding can be used as medicine clinically can reach and the same curative effect of former dosage coarse powder, and can excrete faster, reduces noxious substance accumulating in vivo.
Experimental example 3: the comparison (bioequivalence test) of the capsule of soft capsule preparation of the present invention and same recipe aspect bioavailability
Get 10 of the beagle dogs of growing up, divide 2 groups at random, each 1 group of soft capsule dosage form of the present invention and capsule formulation test group compare test and investigate soft capsule dosage form of the present invention and capsule formulation absorption process different in vivo.Each organizes the beagle dog respectively with 10 times of disposable administrations of clinical using dosage (soft capsule 0.25g grain of the present invention * 20, capsule 0.21g grain * 40) after the administration, with strychnine in the preparation serves as to detect index, is determined at the blood drug level of strychnine in the different time points beagle dog blood with the HPLC method.Area (AUC under blood drug level-time graph
0-t) calculate blood peak concentration of drug (C with trapezoidal method
Max) and peak time (T
Max) directly obtain by test data, adopt two-one sided test, the AUC of soft capsule dosage form of the present invention and capsule formulation is carried out evaluation of bioequivalence, eliminate half-life (T
1/2) adopt the 3P87 medicine to calculate for process simulation.
Two kinds of drug form dynamic metabolism parameters relatively see Table 5 and 6.
The pharmacokinetic parameter of table 5 soft capsule dosage form of the present invention
| Numbering | Maximum plasma concentration (C MAX)μg/ml | Reach blood peak concentration of drug time (T MAX)H | Half-life (T 1/2) H | Area under curve (AUC 0-t1/2) μg/ml*H |
| 1 | 5.36 | 0.34 | 3.29 | 12.261 |
| 2 | 5.28 | 0.36 | 3.18 | 11.167 |
| 3 | 5.68 | 0.34 | 3.23 | 12.311 |
| 4 | 5.25 | 0.38 | 3.21 | 11.143 |
| 5 | 5.72 | 0.36 | 3.24 | 12.355 |
The pharmacokinetic parameter of table 6 capsule formulation
| Numbering | Maximum plasma concentration (C MAX)μ g/mI | Reach blood peak concentration of drug time (T MAX)H | Half-life (T 1/2) H | Area under curve (AUC 0-t1/2) μg/ml*H |
| 1 | 4.89 | 0.46 | 6.35 | 21.602 |
| 2 | 4.75 | 0.42 | 6.12 | 20.306 |
| 3 | 5.04 | 0.50 | 6.38 | 21.697 |
| 4 | 4.92 | 0.42 | 6.22 | 21.402 |
| 5 | 5.14 | 0.48 | 6.18 | 21.973 |
The result shows: soft capsule preparation of the present invention is compared tangible absorption of capsule preparations and is speeded (time that arrives peak concentration shortens), and maximum plasma concentration increases (peak concentration increase), and half-life while shortens, and the toxic component of medicine is difficult for accumulating in vivo.
Experimental example 4: flat elimination capsule antitumor action
Mice is divided into 4 groups at random, i.e. normal control group, lotus tumor model group, normal medicine feed group and lotus tumor medicine feed group.Every group of mice pressed the 20g/kg administration, every day 1 time, continuous 10 days.Normal control group and lotus tumor model group gavage isopyknic normal saline simultaneously.Every treated animal is all put to death the next day of drug withdrawal, gets spleen and does the active detection of spleen IL-2.The result shows that lotus tumor medicine feed group IL-2 activity illustrates that apparently higher than lotus tumor model group flat elimination capsule can obviously strengthen tumor mice IL-2 activity.Normal medicine feed group and normal control group no significant difference illustrate that flat elimination capsule is to the active nothing influence of normal body IL-2.
Experimental example 5: set upright and Detoxication:
Flat elimination capsule can obviously strengthen high temperature resistant, cold-resistant, the hypoxia-bearing capability of lotus S180 solid tumor mice, strengthens cellular immunization and the humoral immunity level of lotus mice, and strengthens the activity of tumor necrosis factor, illustrates that flat elimination capsule has centralizing function.Flat elimination capsule can resist bone marrow depression, granulocytopenia and the hepar damnification of mice after cyclophosphamide and the radiation treatment, illustrates that flat elimination capsule has protective effect to chemotherapy and radiocurable untoward reaction.
Embodiment preparation of soft capsule method of the present invention
1, extract:
(1) Radix Curcumae 50g, Fructus Aurantii 85g two flavor pulverizing medicinal materials become coarse powder, cross 24 mesh sieves; Oletum Trogopterori 45g, Alumen 58g, Sal Nitri 54g, Resina Toxicodendri 20g four Chinese medicine material is ground into fine powder, crosses 100 mesh sieves; With 8 times of amount 70% ethanol, flood after 24 hours, promptly get percolate with 5ml/min speed percolation, merge standby behind the diacolation liquid recycling ethanol;
(2) last medicinal residues behind the percolation are added 8 times of water with Herba Agrimoniae 55g, decoct three times, decocted 2 hours at every turn.Collecting decoction filters, and concentrates; In concentrated solution, add ethanol and adjust to that to contain the alcohol amount be 80%, staticly settled 24 hours, filter that to collect filter cake standby at 4 ℃～8 ℃;
(3) percolate spherical tank decompression recycling ethanol is crossed the macropore resin bed respectively after merging and pure hypostasis filter with 400 order filter clothes behind the percolate recovery ethanol and is analysed post, with ethanol and distilled water eluting; Obtain refining extract after the concentrated back of merging eluent is spray-dried.
2, adding is crossed 120 mesh sieves through the Semen Strychni Pulveratum 20g of superfine grinding mix homogeneously in the above-mentioned refining extract, under stirring, join in the PEG400 gradually, heating makes it to remain on 60 ℃ and stir and to make it dissolving, fully stirring makes it be mixed into uniform suspension, again suspension crossed pelleting behind colloid mill, the degassing evacuation, finalized the design, select ball, wash ball, drying, promptly get 1000 of flat elimination capsules.
Claims (3)
1, a kind of Chinese medicinal soft capsule preparation is characterized in that it being to be prepared from by following method:
Radix Curcumae 50～58 weight portion Herba Agrimoniaes 50～58 weight portion Fructus Aurantiis 85～95 weight portions
Oletum Trogopterori 40～50 weight portion Alumens 50～58 weight portion Sal Nitri 50～58 weight portions
Resina Toxicodendri 15～20 weight portion Semen Strychni Pulveratums 15～30 weight portions
Radix Curcumae, Fructus Aurantii two flavor pulverizing medicinal materials are become coarse powder, cross 24 orders～50 mesh sieves; Oletum Trogopterori, Alumen, Sal Nitri, Resina Toxicodendri four Chinese medicine material are ground into fine powder, cross 100 orders～120 mesh sieves; With 60～80% ethanol percolations, merge behind the diacolation liquid recycling ethanol;
The last medicinal residues of percolation are with Herba Agrimoniae decocting three times, and collecting decoction filters, and concentrates; Add ethanol and staticly settle, the collecting precipitation thing is dissolved in water, and gets pure hypostasis solution;
Cross the macropore resin bed respectively after merging and pure hypostasis aqueous solution filter with 400 order filter clothes behind the percolate recovery ethanol and analyse post, with ethanol and distilled water eluting; Obtain refining extract after the concentrated back of merging eluent is spray-dried;
Add in the above-mentioned refining extract and cross 80～120 mesh sieves through the Semen Strychni Pulveratum mix homogeneously of superfine grinding, under stirring, join in the solvent gradually, heating makes it to remain on 40～80 ℃ and stir and to make it dissolving, the dissolving back adds wetting agent, suspending agent and stabilizing agent, fully stirs to make it be mixed into uniform suspension; Again suspension crossed pelleting behind colloid mill, the degassing evacuation, finalized the design, select ball, wash ball, drying, promptly.
2, a kind of according to claim 1 Chinese medicinal soft capsule preparation is characterized in that it being to be prepared from by following method:
Radix Curcumae 50g Herba Agrimoniae 55g Fructus Aurantii 85g Oletum Trogopterori 45g
Alumen 58g Sal Nitri 54g Resina Toxicodendri 20g Semen Strychni Pulveratum 20g
Radix Curcumae, Fructus Aurantii two flavor pulverizing medicinal materials become coarse powder, cross 24 mesh sieves; Oletum Trogopterori, Alumen, Sal Nitri, Resina Toxicodendri four Chinese medicine material are ground into fine powder, cross 100 mesh sieves; With 8 times of amount 70% ethanol, flood after 24 hours, promptly get percolate with 5ml/min speed percolation, merge standby behind the diacolation liquid recycling ethanol;
Last medicinal residues add 8 times of water with Herba Agrimoniae behind the percolation, decoct three times, decoct 2 hours at every turn, and collecting decoction filters, and concentrates; In concentrated solution, add ethanol and adjust to that to contain the alcohol amount be 80%, staticly settled 24 hours, filter collecting precipitation thing filter cake, be dissolved in water at 4 ℃～8 ℃, pure hypostasis solution;
Percolate spherical tank decompression recycling ethanol is crossed the macropore resin bed respectively after merging and pure hypostasis solution filter with 400 order filter clothes behind the percolate recovery ethanol and is analysed post, with ethanol and distilled water eluting; Obtain refining extract after the concentrated back of merging eluent is spray-dried;
Add in the above-mentioned refining extract and cross 120 mesh sieves through the Semen Strychni Pulveratum 20g of superfine grinding mix homogeneously, under stirring, join in the PEG400 gradually, heating makes it to remain on 60 ℃ and stir and to make it dissolving, the abundant stirring made it be mixed into uniform suspension after the dissolving back added adjuvant wetting agent, suspending agent and stabilizing agent, again suspension crossed pelleting behind colloid mill, the degassing evacuation, finalized the design, select ball, wash ball, drying, promptly get 1000 of flat elimination capsules.
3, a kind of Chinese medicinal soft capsule preparation is characterized in that it being to be prepared from by following method:
Radix Curcumae 54 weight portion Herba Agrimoniaes 55 weight portion Fructus Aurantiis 80 weight portion Oletum Trogopteroris 45 weight portions
Alumen 58 weight portion Sal Nitri 54 weight portion Resina Toxicodendri 20 weight portion Semen Strychni Pulveratums 20 weight portions
Radix Curcumae, Fructus Aurantii two flavor pulverizing medicinal materials are become coarse powder, cross 24 mesh sieves; Oletum Trogopterori, Alumen, Sal Nitri, Resina Toxicodendri four Chinese medicine material are ground into fine powder, cross 100 mesh sieves; With 8 times of amount 70% ethanol, flood after 24 hours, promptly get percolate with 5ml/min speed percolation, merge standby behind the diacolation liquid recycling ethanol;
The last medicinal residues of percolation add 8 times of water with Herba Agrimoniae, and decocting three times decocted 2 hours at every turn, and collecting decoction filters, and concentrates; Add ethanol and adjust to that to contain the alcohol amount be 80%, staticly settled 24 hours at 4 ℃～8 ℃, the collecting precipitation thing is dissolved in water;
Percolate spherical tank decompression recycling ethanol is crossed the macropore resin bed respectively after merging and pure hypostasis filter with 400 order filter clothes behind the percolate recovery ethanol and is analysed post, with ethanol and distilled water eluting; Obtain refining extract after the concentrated back of merging eluent is spray-dried;
Add in the above-mentioned refining extract and cross 120 mesh sieves through the Semen Strychni Pulveratum mix homogeneously of superfine grinding, under stirring, join in the PEG400 gradually, heating makes it to remain on 60 ℃ and stir and to make it dissolving, the abundant stirring made it be mixed into uniform suspension after the dissolving back added adjuvant wetting agent, suspending agent and stabilizing agent, again suspension crossed pelleting behind colloid mill, the degassing evacuation, finalized the design, select ball, wash ball, drying, promptly.
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2004100374097A CN1268324C (en) | 2004-04-30 | 2004-04-30 | Chinese medicinal soft capsule and preparing process thereof |
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| CNB2004100374097A CN1268324C (en) | 2004-04-30 | 2004-04-30 | Chinese medicinal soft capsule and preparing process thereof |
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| CN1268324C true CN1268324C (en) | 2006-08-09 |
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| CN101284120A (en) * | 2008-05-29 | 2008-10-15 | 宁夏金太阳药业有限公司 | Process for preparing Pingxiao preparation |
| CN102499960B (en) * | 2011-11-29 | 2014-06-18 | 上海景峰制药有限公司 | Method for improving uniformity of strychnine in nux vomica powder of bone and tendon pill capsules |
| CN103566281B (en) * | 2012-07-27 | 2016-12-21 | 西安正大制药有限公司 | A kind of Traditional Chinese medicine composition with anti-tumor effect and preparation method |
| CN103566282B (en) * | 2012-07-27 | 2017-05-31 | 西安正大制药有限公司 | A kind of Traditional Chinese medicine composition with anti-tumor effect and preparation method |
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