CN100382790C - Compound yew drop pills and its preparation method - Google Patents
Compound yew drop pills and its preparation method Download PDFInfo
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- CN100382790C CN100382790C CNB2005100979709A CN200510097970A CN100382790C CN 100382790 C CN100382790 C CN 100382790C CN B2005100979709 A CNB2005100979709 A CN B2005100979709A CN 200510097970 A CN200510097970 A CN 200510097970A CN 100382790 C CN100382790 C CN 100382790C
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Abstract
The present invention discloses a medication oral drug preparation which is used for adjunctive therapy of middle and late stages lung cancer chemotherapy caused by qi asthenia phlegm stasis. The present invention aims to replenish the insufficiency of the existing oral drug preparation for adjunctive therapy of lung cancer chemotherapy. A compound yew dripping pill which can satisfy the quality index of relevant dripping pill preparation prescribed in the country drug standard and simultaneously has the advantages high biologic utilization rate, fast release of medicine, fast apparent rate, convenience for taking, low cost and no pollution in the manufacture is provided. The compound yew dripping pill of the present invention uses extracts of more than three traditional Chinese medicines of yew, red ginseng, licorice, etc. as raw materials which are together prepared with medicine carrier which serves as a matrix.
Description
Technical field
The present invention relates to a kind of eliminating evil eliminating stagnation function that has, the pharmaceutical composition that is used for the auxiliary treatment of the medium and advanced lung cancer chemotherapy due to the qi-asthenia phlegm stasis of blood is a kind of oral drug preparation that feedstock production forms with the extract that contains pharmaceutically active ingredient in 3 flavors such as Ramulus et folium taxi cuspidatae, Radix Ginseng Rubra, Radix Glycyrrhizae particularly.
Background technology
The compound taxol capsule that is prepared from according to the preparation method that provides among the national drug standards WS-10935 (ZD-0935)-2002, it is a kind of eliminating evil eliminating stagnation function that has, the oral capsule that is used for the auxiliary treatment of the medium and advanced lung cancer chemotherapy due to the qi-asthenia phlegm stasis of blood, through clinical verification for many years, determined curative effect is the common drug that clinical and family is used for the treatment of above-mentioned disease.
Below be prescription and technology and the brief description that provides among the drug standard WS-10935 (ZD-0935)-2002:
Prescription: bark of Ramulus et folium taxi cuspidatae 50000g, Radix Ginseng Rubra 166g, Radix Glycyrrhizae 500g, silica 1 33g, make 1000.
Method for making: above three flavor medical materials, bark of Ramulus et folium taxi cuspidatae is pulverized, cross 20 mesh sieves, according to the method under fluid extract and the extractum item (appendix 1O of Chinese Pharmacopoeia version in 2000), make solvent with 95% ethanol, flood after 48 hours, percolation slowly, the collection liquid of filtering, 40 ℃ of decompression recycling ethanols add water and dichloromethane to doing, fully mix, leave standstill after 4 hours and tell and collect dichloromethane solution, water liquid reuse dichloromethane extraction 3 times merges each time dichloromethane solution, filter, the reclaim under reduced pressure dichloromethane is to doing, and residue adds kieselguhr and mixes thoroughly with the dissolving of ethyl acetate-methanol (3: 1) mixed solution, removal of solvent under reduced pressure, pack in the percolation bucket, use the normal hexane percolation earlier, continue and use the dichloromethane percolation, collect the dichloromethane percolate, the reclaim under reduced pressure dichloromethane is to doing, and residue dissolves with ethyl acetate, according to column chromatography (an appendix VI of Chinese Pharmacopoeia version in 2000 C), with silica gel is absorbent, normal hexane-acetone (75: 25) is eluant, and eluting is collected the eluent that contains paclitaxel, decompression and solvent recovery is to doing: Radix Glycyrrhizae, red ginseng powder is broken into coarse powder, according to the method under fluid extract and the extractum item (appendix 10 of Chinese Pharmacopoeia version in 2000), make solvent with 70% ethanol, flood after 48 hours, percolation slowly, collect percolate, reclaim ethanol, be condensed into thick paste, mix with the above-mentioned paclitaxel extractum that contains, add silicon dioxide, fully mixing is made wetting agent with 95% ethanol, make granule, dry below 60 ℃, incapsulate, promptly.
Function cures mainly: eliminating evil eliminating stagnation.The auxiliary treatment that is used for the medium and advanced lung cancer chemotherapy due to the qi-asthenia phlegm stasis of blood.
According to another bibliographical information: compound taxol capsule (original name Ramulus et folium taxi cuspidatae capsule) is a compound Chinese medicinal preparation, and its main active is paclitaxel, Ba Kating-III, RO, Rb1, Rg1 and triterpenoid saponin etc.Active anticancer is the strongest, and the microtubule of mechanism of action and target site united state promotes the microtubule assembling, suppresses its depolymerization, thereby suppress the Spindle function cell mitogen is stagnated.Found that up to now paclitaxel can induce the apoptosis of kinds of tumors, comprised ovarian cancer, lymphoma, leukemia, pulmonary carcinoma, gastrointestinal cancer and breast carcinoma etc., RESEARCH ON CELL-BIOLOGY finds that the taxol induced cell mitogen is stagnated the G2-M phase that betides.Report paclitaxels such as Bhalla can make the bc1-2MRNA downward modulation.The bc1-2 phosphorylation of taxol induced is only and causes more major reason of tumor death.This research prompting compound taxol capsule is to pulmonary carcinoma effective percentage (CR+PR) 41.1%, colorectal cancer 22.2%, gastric cancer 50.0%, oral cancer 100.0% (Tan Yongzhong, Li Jing, Li Zhongyou is among Xiao, Shu Qi, Chen Xuyuan. the clinical observation of compound taxol capsule for treating advanced malignant tumor. the 525th page of Chongqing medical science the 31st the 6th phase of volume of June in 2002).
Owing to reasons such as technologies of preparing, the oral formulations of most drug, especially the oral formulations of Chinese medicine, exist all after taking that dissolve scattered time limit is long, dissolution is low, absorption is relatively poor, problem such as liver sausage first pass effect and bioavailability are lower, thereby influence the performance of drug effect, also directly affect therapeutic effect.In addition, conventional peroral dosage form is as tablet, capsule, granule (electuary) etc., in preparation process because the technology of granulation is arranged, therefore can produce bigger dust pollution, can staff's health be worked the mischief to a certain extent, also can cause certain pollution simultaneously to environment.Moreover, the complex manufacturing of conventional oral formulations, production cost is higher, thereby patient's drug cost is also improved thereupon, is unfavorable for improving the ability of seeking medical advice of extensive patients, also is unfavorable for improving the general health level of society.
The drop pill that adopts solid dispersion technology to be prepared from has thoroughly changed the existing defective of conventional oral formulations from the frame mode of medicine.Owing to make the active component of medicine and substrate fusion be one and form liquid in advance, make active constituents of medicine fully dissolve and be dispersed in uniformly in the chemical lattice of substrate fused solution, thereby make the effective surface area of drug molecule (group) increase greatly, improved the contact area of active constituents of medicine dissolving back with gastrointestinal tract mucosa; Owing to the ease of solubility of substrate, make drop pill after taking, can dissolve rapidly, and absorbed simultaneously, played high speed, good effect efficiently by gastrointestinal tract mucosa.In addition because the medicament contg height of drop pill, volume is little, dissolution velocity is fast, dissolving back mouthfeel is good, also can adopt the mode of sublingual administration, can make effective ingredient directly absorb and enter blood circulation by the Sublingual mucosa, avoid the first pass effect of conventional oral formulations effectively, also avoid some drugs gastrointestinal tract to be produced the side effect that stimulates without gastrointestinal tract and liver.
Yet, because the preparation technology of drop pill is still not really ripe, its relevant device does not yet reach standardized degree, when utilizing the prior art for preparing drop pill, product quality is subjected to the physicochemical property of medicine, the kind of substrate and with the ratio of medicament mixed, factor affecting such as condensing agent and temperature thereof, the rounding rate, the quality index of the relevant dropping pill formulation of defined differs bigger in indexs such as the ball method of double differences is different and the national drug standards, such product is in use having a strong impact on the accuracy of dosage, also make the qualification rate of product reduce aborning, increased production cost, thereby also indirect increase patient's drug cost, thereby make its practicality also decrease.
Summary of the invention
Purpose of the present invention, be to replenish the existing deficiency that is used for the oral drug preparation of lung cancer chemotherapy auxiliary treatment, a kind of quality index that can satisfy the relevant dropping pill formulation of defined in the national drug standards is provided, also possesses simultaneously the bioavailability height, release fast, quick produce effects, taking convenience, cheap, and free of contamination aborning compound yew drop pills.Compound yew drop pills involved in the present invention with the extract that contains Ramulus et folium taxi cuspidatae, Radix Ginseng Rubra, Radix Glycyrrhizae etc. 3 flavor Chinese medicines and be raw material, is prepared from the pharmaceutically suitable carrier as substrate.Be prepared by the following technical solutions, can obtain compound yew drop pills involved in the present invention:
[preparation method]
1. raw material: the extract that contains pharmaceutically active ingredient in 3 flavors such as Ramulus et folium taxi cuspidatae, Radix Ginseng Rubra, Radix Glycyrrhizae;
2. substrate: polyethylene glycols, sorbitol anhydride class, polyoxyethylene sorbitol acid anhydride class, polyoxyethylene stearate 40 esters, beta cyclodextrin, poloxamer, carboxymethyl starch sodium, sodium lauryl sulphate, stearic acid, sodium stearate, glycerin gelatine, Lac, the mixture of one or more in above-mentioned pharmaceutically suitable carrier;
3. proportioning: with g or kg is unit, drug extract: substrate=1: 1～1: 9;
More practical proportion: drug extract: substrate=1: 1～1: 5;
4. according to the given ratio of prescription, accurately take by weighing drug extract and substrate, be placed on heating while stirring in the heating container, standby until the fused solution that obtains containing drug extract and substrate and/or emulsion and/or suspension;
5. adopt homemade or general drop pill machine, TZDW-1 type drop pill machine as Changzheng Tianmin High Science ﹠ Technology Co., Ltd., Beijing's production, adjust the temperature control system of drop pill machine, make the water dropper temperature heating of drop pill machine and remain on 50 ℃～90 ℃, the temperature cooling of condensing agent also remains on 40 ℃～-5 ℃;
6. when treating in dropping-pill machine head and the condensation column that the temperature of condensing agent reaches desired state of temperature respectively, above-mentioned medicinal liquid is placed in the water dropper jar of drop pill machine, splash in the condensing agent, cooling is shunk and is shaped, promptly.
Annotate: described condensing agent is any one or the two or more mixture in liquid paraffin, methyl-silicone oil, the vegetable oil.
[attached: the preparation of drug extract]
With g or kg is unit, get 300 parts of bark of Ramulus et folium taxi cuspidatae, 1 part of Radix Ginseng Rubra, Radix Glycyrrhizae 3, more than three the flavor medical materials, bark of Ramulus et folium taxi cuspidatae is pulverized, cross 20 mesh sieves, according to the method under Chinese Pharmacopoeia version appendix IO fluid extract in 2000 and the extractum item, make solvent with 95% ethanol, flood after 48 hours slowly percolation, the collection liquid of filtering, 40 ℃ of decompression recycling ethanols add water and dichloromethane to doing, fully mix, leave standstill after 4 hours and tell and collect dichloromethane solution, water liquid reuse dichloromethane extraction 3 times merges each time dichloromethane solution, filter, the reclaim under reduced pressure dichloromethane is to doing, and residue adds kieselguhr and mixes thoroughly with the mixed solution dissolving of 3: 1 ethyl acetate and methanol, removal of solvent under reduced pressure, pack in the percolation bucket, use the normal hexane percolation earlier, continue and use the dichloromethane percolation, collect the dichloromethane percolate, the reclaim under reduced pressure dichloromethane is to doing, and residue dissolves with ethyl acetate, according to an appendix VIC of Chinese Pharmacopoeia version in 2000 column chromatography, with silica gel is absorbent, 3: 1 normal hexane and acetone are mixed into eluant, and eluting is collected the eluent that contains paclitaxel, decompression and solvent recovery becomes extractum to doing; Radix Glycyrrhizae, red ginseng powder are broken into coarse powder, according to the method under Chinese Pharmacopoeia appendix 10 fluid extracts of version in 2000 and the extractum item, make solvent with 70% ethanol, flood after 48 hours slowly percolation, collect percolate, reclaim ethanol, be condensed into thick paste, mix and make evenly with the above-mentioned paclitaxel extractum that contains, promptly; Or, be ground into dry powder, promptly dry below 60 ℃.
[beneficial effect]
The compound taxol capsule that is prepared from according to the preparation method that provides among the national drug standards WS-10935 (ZD-0935)-2002, it is a kind of eliminating evil eliminating stagnation function that has, the oral capsule that is used for the auxiliary treatment of the medium and advanced lung cancer chemotherapy due to the qi-asthenia phlegm stasis of blood, through clinical verification for many years, determined curative effect is the common drug that clinical and family is used for the treatment of above-mentioned disease.
Owing to reasons such as technologies of preparing, the oral formulations of most drug, especially the oral formulations of Chinese medicine, exist all after taking that dissolve scattered time limit is long, dissolution is low, absorption is relatively poor, problem such as liver sausage first pass effect and bioavailability are lower, thereby influence the performance of drug effect, also directly affect therapeutic effect.In addition, conventional peroral dosage form is as tablet, capsule, granule (electuary) etc., in preparation process because the technology of granulation is arranged, therefore can produce bigger dust pollution, can staff's health be worked the mischief to a certain extent, also can cause certain pollution simultaneously to environment.Moreover, the complex manufacturing of conventional oral formulations, production cost is higher, thereby patient's drug cost is also improved thereupon, is unfavorable for improving the ability of seeking medical advice of extensive patients, also is unfavorable for improving the general health level of society.
The drop pill that adopts solid dispersion technology to be prepared from has thoroughly changed the existing defective of conventional oral formulations from the frame mode of medicine.Yet, because the preparation technology of drop pill is still not really ripe, its relevant device does not yet reach standardized degree, when utilizing the prior art for preparing drop pill, product quality is subjected to the physicochemical property of medicine, the kind of substrate and with the ratio of medicament mixed, factor affecting such as condensing agent and temperature thereof, the rounding rate, the quality index of the relevant dropping pill formulation of defined differs bigger in indexs such as the ball method of double differences is different and the national drug standards, such product is in use having a strong impact on the accuracy of dosage, also make the qualification rate of product reduce aborning, increased production cost, thereby also indirect increase patient's drug cost, thereby make its practicality also decrease.
Compound yew drop pills involved in the present invention is compared with the compound taxol capsule has following beneficial effect:
1. compound yew drop pills involved in the present invention, scope, proportioning and the process conditions of used adjuvant have been determined by a large amount of tests, and select the equipment of function admirable for use, make technology of preparing disclosed in this invention more be useful for industrial production requirement, the yield rate height, accurate measurement, production cost is lower.
2. compound yew drop pills involved in the present invention, utilize surfactant to be substrate, the extract of pharmaceutically active ingredient is made solid dispersion in containing 3 flavors such as Ramulus et folium taxi cuspidatae, Radix Ginseng Rubra, Radix Glycyrrhizae, making medicine be molecule, colloid or microcrystalline state is scattered in the substrate, the total surface area of medicine increases, and substrate is hydrophilic, contact promptly with saliva and to dissolve rapidly, and absorb by oral mucosa, can make medicine molten microgranule or the solution of loosing into rapidly, thereby make the dissolving of medicine and absorb to accelerate, thereby improved bioavailability, bring into play efficient, quick-acting effects etc.; Simultaneously, compound yew drop pills involved in the present invention is not influenced by feed, and all can containing take ante cibum after meal, also can not produce any residual harmful substance at gastric, thereby make medication safer.
3. compound yew drop pills involved in the present invention mixes medicine material mutually with molten matrix, splashes in the not miscible condensed fluid and makes.Therefore, the stability of drug height, not facile hydrolysis, oxidation, and the operation be under liquid state, to carry out, no dust pollution is not subject to the influence of crystal formation, thereby has guaranteed the quality of medicine, has increased stability.
4. production technology, the equipment of preparation drop pill are simple, easy to operate, the automaticity height, and labor intensity is low, the production efficiency height.Workshop does not have dust simultaneously, helps labor protection and environmental protection yet.
5. the production cost of preparation drop pill is usually with about 50% of other oral formulations of kind, and compares with oral liquid, and the dosage of drop pill is accurate, thereby makes the patient take metering control easily.
The specific embodiment
Now with several groups of specific embodiments, be described further with regard to the preparation method of compound yew drop pills of the present invention.
[selection of prescription]
1. raw material: make the extract dry powder that contains pharmaceutically active ingredient in 3 flavors such as Ramulus et folium taxi cuspidatae, Radix Ginseng Rubra, Radix Glycyrrhizae in advance according to [appendix], standby;
2. single-matrix: be selected from Polyethylene Glycol
1000, Polyethylene Glycol
4000, Polyethylene Glycol
6000, Polyethylene Glycol
10000, Polyethylene Glycol
20000, a kind of in the carrier such as span 40, polyoxyethylene stearate 40 esters, poloxamer, sodium lauryl sulphate, stearic acid, sodium stearate, glycerin gelatine, Lac;
3. composite substrate: with g or kg is unit, by weight, selects carriers such as Polyethylene Glycol, polyoxyethylene stearate 40 esters, carboxymethyl starch sodium, beta cyclodextrin, tween to carry out composite test;
3.1 the combination of two kinds of different substrates: with g or kg is unit, by weight, gets 1 part polyoxyethylene stearate 40 esters or beta cyclodextrin or carboxymethyl starch sodium or tween, makes up with 1～10 part Polyethylene Glycol, and Polyethylene Glycol wherein is meant Polyethylene Glycol
1000～Polyethylene Glycol
20000In any one or two or more mixture;
3.2 the combination of three kinds of different substrates: with g or kg is unit, by weight, get 1 part polyoxyethylene stearate 40 esters and 0.5～5 part carboxymethyl starch sodium (or beta cyclodextrin or tween) and 1～10 part Polyethylene Glycol and make up, Polyethylene Glycol wherein is meant Polyethylene Glycol
1000～Polyethylene Glycol
20000In any one or two or more mixture;
3.3 the combination of four kinds of different substrates: with g or kg is unit, by weight, get 1 part polyoxyethylene stearate 40 esters and 0.5～5 part carboxymethyl starch sodium (or beta cyclodextrin) and make up with 0.5～5 part tween and 1～10 part Polyethylene Glycol, Polyethylene Glycol wherein is a Polyethylene Glycol
1000～Polyethylene Glycol
20000In one or more mixture;
The proportioning of drug extract and substrate (with g or kg is unit, by weight):
Drug extract: substrate=1: 1～1: 9;
5. the process according to [preparation method] 4～7 is prepared, and can obtain the compound yew drop pills of different size.
Test the test of a single-matrix
Cooperating prepared compound yew drop pills in qualitative difference with different substrates in order to observe the drug extract thing, is unit with g or kg, according to 1: 1,1: 3,1: 9 ratio, with drug extract respectively with Polyethylene Glycol
1000, Polyethylene Glycol
4000, Polyethylene Glycol
6000, Polyethylene Glycol
10000, Polyethylene Glycol
20000, matrix phases such as span 40, polyoxyethylene stearate 40 esters, poloxamer, sodium lauryl sulphate, stearic acid, sodium stearate, glycerin gelatine, Lac cooperate, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 3 groups of drug extracts and different substrates, and obtain 3 groups of different experimental results and see Table 1～table 3.
Test the composite test of 2 two kinds of different substrates
Cooperate prepared compound yew drop pills in qualitative difference in order to observe drug extract with two kinds of different substrates, with g or kg is unit, get 1 part polyoxyethylene stearate 40 esters (S40 ester) or beta cyclodextrin or carboxymethyl starch sodium or tween, respectively with 1 part, 5 parts, 10 parts Polyethylene Glycol makes up, again with drug extract and composite substrate respectively with 1: 1,1: 3,1: 9 ratio matches, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 3 groups of drug extracts and various combination substrate, and obtain 3 groups of different experimental results and see Table 4～table 6.
Test the composite test of three or three kinds of different substrates
Cooperate prepared compound yew drop pills in qualitative difference in order to observe drug extract with three kinds of different substrates, with g or kg is unit, get 1 part polyoxyethylene stearate 40 esters (S40 ester) respectively with 0.5 part, 3 parts, 5 parts beta cyclodextrin (or carboxymethyl starch sodium or tween), and 1 part, 5 parts, 10 parts Polyethylene Glycol makes up, again with drug extract and composite substrate respectively with 1: 1,1: 3,1: 9 ratio matches, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 3 groups of drug extracts and various combination substrate, and obtain 3 groups of different experimental results and see Table 7～table 9.
Test the composite test of four or four kinds of different substrates
Cooperate prepared Anshen Bunao drip ball in qualitative difference in order to observe drug extract with four kinds of different substrates, with g or kg is unit, get 1 part polyoxyethylene stearate 40 esters (S40 ester) respectively with 0.5 part, 3 parts, 5 parts beta cyclodextrin (or carboxymethyl starch sodium), and 0.5 part, 3 parts, 5 parts tween, and 1 part, 5 parts, 10 parts Polyethylene Glycol makes up, again with drug extract and composite substrate respectively with 1: 1,1: 3,1: 9 ratio matches, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 3 groups of drug extracts and various combination substrate, and obtain 3 groups of different experimental results and see Table 10～table 12.
The group practices of table 1 drug extract and single-matrix
(drug extract: substrate=1: 1)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyethylene Glycol 1000 | 50.0 | 67 | ＜30 | ＞10 | + |
| Polyethylene Glycol 4000 | 50.0 | 79 | ＜30 | ＞10 | ++ |
| Polyethylene Glycol 6000 | 50.0 | 80 | ＜30 | ＞10 | ++ |
| Polyethylene Glycol 10000 | 50.0 | 81 | ＜30 | ＞10 | ++ |
| Polyethylene Glycol 20000 | 50.0 | 81 | ＜30 | ＞10 | ++ |
| Span 40 | 50.0 | 63 | ＜30 | ＞10 | ++ |
| Polyoxyethylene stearate 40 esters | 50.0 | 79 | ＜30 | ＞10 | ++ |
| Poloxamer | 50.0 | 82 | ＜30 | ＞10 | ++ |
| Sodium lauryl sulphate | 50.0 | 63 | ＞30 | ＞10 | ++ |
| Stearic acid | 50.0 | 63 | ＞30 | ＞10 | +++ |
| Sodium stearate | 50.0 | 61 | ＞30 | ＞10 | +++ |
| Glycerin gelatine | 50.0 | 60 | ＞30 | ＞10 | ++ |
| Lac | 50.0 | 60 | ＞30 | ＞10 | + |
The group practices of table 2 drug extract and single-matrix
(drug extract: substrate=1: 3)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyethylene Glycol 1000 | 25.0 | 78 | ＜30 | ＞10 | ++ |
| Polyethylene Glycol 4000 | 25.0 | 88 | ＜30 | ＜10 | +++ |
| Polyethylene Glycol 6000 | 25.0 | 88 | ＜30 | ＜10 | +++ |
| Polyethylene Glycol 10000 | 25.0 | 86 | ＜30 | ＜10 | +++ |
| Polyethylene Glycol 20000 | 25.0 | 86 | ＜30 | ＜10 | +++ |
| Span 40 | 25.0 | 66 | ＜30 | ＞10 | +++ |
| Polyoxyethylene stearate 40 esters | 25.0 | 84 | ＜30 | ＞10 | ++ |
| Poloxamer | 25.0 | 86 | ＜30 | ＜10 | +++ |
| Sodium lauryl sulphate | 25.0 | 73 | ＞30 | ＞10 | ++ |
| Stearic acid | 25.0 | 73 | ＞30 | ＞10 | +++ |
| Sodium stearate | 25.0 | 75 | ＞30 | ＞10 | +++ |
| Glycerin gelatine | 25.0 | 71 | ＞30 | ＞10 | ++ |
| Lac | 25.0 | 71 | ＞30 | ＞10 | ++ |
The group practices of table 3 drug extract and single-matrix
(drug extract: substrate=1: 10)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyethylene Glycol 1000 | 10.0 | 84 | ＜30 | ＞10 | ++ |
| Polyethylene Glycol 4000 | 10.0 | 89 | ＜30 | ＜10 | +++ |
| Polyethylene Glycol 6000 | 10.0 | 90 | ＜30 | ＜10 | +++ |
| Polyethylene Glycol 10000 | 10.0 | 88 | ＜30 | ＜10 | +++ |
| Polyethylene Glycol 20000 | 10.0 | 86 | ＜30 | ＜10 | +++ |
| Span 40 | 10.0 | 66 | ＜30 | ＞10 | +++ |
| Polyoxyethylene stearate 40 esters | 10.0 | 84 | ＜30 | ＞10 | ++ |
| Poloxamer | 10.0 | 87 | ＜30 | ＜10 | +++ |
| Sodium lauryl sulphate | 10.0 | 73 | ＞30 | ＞10 | +++ |
| Stearic acid | 10.0 | 74 | ＞30 | ＞10 | +++ |
| Sodium stearate | 10.0 | 73 | ＞30 | ＞10 | +++ |
| Glycerin gelatine | 10.0 | 73 | ＞30 | ＞10 | +++ |
| Lac | 10.0 | 72 | ＞30 | ＞10 | ++ |
The group practices of table 4 drug extract and two kinds of substrate
(drug extract: substrate=1: 1)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| S40 ester: Polyethylene Glycol=1: 1 | 50.0 | 88 | ＜30 | ＜10 | +++ |
| S40 ester: Polyethylene Glycol=1: 5 | 50.0 | 89 | ＜30 | ＜10 | +++ |
| S40 ester: Polyethylene Glycol=1: 10 | 50.0 | 89 | ＜30 | ＜10 | +++ |
| Beta cyclodextrin: Polyethylene Glycol=1: 1 | 50.0 | 82 | ＜30 | ＞10 | ++ |
| Beta cyclodextrin: Polyethylene Glycol=1: 5 | 50.0 | 82 | ＜30 | ＞10 | ++ |
| Beta cyclodextrin: Polyethylene Glycol=1: 10 | 50.0 | 85 | ＜30 | ＞10 | ++ |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 1 | 50.0 | 84 | ＜30 | ＞10 | ++ |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 5 | 50.0 | 86 | ＜30 | ＜10 | +++ |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 10 | 50.0 | 87 | ＜30 | ＜10 | +++ |
| Tween: Polyethylene Glycol=1: 1 | 50.0 | 79 | ＜30 | ＞10 | ++ |
| Tween: Polyethylene Glycol=1: 5 | 50.0 | 83 | ＜30 | ＞10 | ++ |
| Tween: Polyethylene Glycol=1: 10 | 50.0 | 84 | ＜30 | ＞10 | ++ |
The group practices of table 5 drug extract and two kinds of substrate
(drug extract: substrate=1: 3)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| S40 ester: Polyethylene Glycol=1: 1 | 25.0 | 88 | ＜30 | ＜10 | +++ |
| S40 ester: Polyethylene Glycol=1: 5 | 25.0 | 89 | ＜30 | ＜10 | +++ |
| S40 ester: Polyethylene Glycol=1: 10 | 25.0 | 88 | ＜30 | ＜10 | +++ |
| Beta cyclodextrin: Polyethylene Glycol=1: 1 | 25.0 | 84 | ＜30 | ＞10 | ++ |
| Beta cyclodextrin: Polyethylene Glycol=1: 5 | 25.0 | 85 | ＜30 | ＞10 | ++ |
| Beta cyclodextrin: Polyethylene Glycol=1: 10 | 25.0 | 85 | ＜30 | ＞10 | +++ |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 1 | 25.0 | 84 | ＜30 | ＞10 | ++ |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 5 | 25.0 | 85 | ＜30 | ＜10 | +++ |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 10 | 25.0 | 86 | ＜30 | ＜10 | +++ |
| Tween: Polyethylene Glycol=1: 1 | 25.0 | 78 | ＜30 | ＞10 | ++ |
| Tween: Polyethylene Glycol=1: 5 | 25.0 | 80 | ＜30 | ＞10 | ++ |
| Tween: Polyethylene Glycol=1: 10 | 25.0 | 80 | ＜30 | ＞10 | ++ |
The group practices of table 6 drug extract and two kinds of substrate
(drug extract: substrate=1: 9)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| S40 ester: Polyethylene Glycol=1: 1 | 10.0 | 89 | ＜30 | ＜10 | +++ |
| S40 ester: Polyethylene Glycol=1: 5 | 10.0 | 90 | ＜30 | ＜10 | +++ |
| S40 ester: Polyethylene Glycol=1: 10 | 10.0 | 91 | ＜30 | ＜10 | +++ |
| Beta cyclodextrin: Polyethylene Glycol=1: 1 | 10.0 | 87 | ＜30 | ＜10 | ++ |
| Beta cyclodextrin: Polyethylene Glycol=1: 5 | 10.0 | 89 | ＜30 | ＜10 | ++ |
| Beta cyclodextrin: Polyethylene Glycol=1: 10 | 10.0 | 89 | ＜30 | ＜10 | ++ |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 1 | 10.0 | 85 | ＜30 | ＞10 | ++ |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 5 | 10.0 | 86 | ＜30 | ＜10 | +++ |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 10 | 10.0 | 88 | ＜30 | ＜10 | +++ |
| Tween: Polyethylene Glycol=1: 1 | 10.0 | 79 | ＜30 | ＞10 | ++ |
| Tween: Polyethylene Glycol=1: 5 | 10.0 | 83 | ＜30 | ＞10 | ++ |
| Tween: Polyethylene Glycol=1: 10 | 10.0 | 82 | ＜30 | ＞10 | ++ |
The group practices of table 7 drug extract and three kinds of substrate
(drug extract: substrate=1: 1)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| S40 ester: beta cyclodextrin: Polyethylene Glycol=1: 0.5: 1 | 50.0 | 85 | ＜30 | ＞10 | +++ |
| S40 ester: beta cyclodextrin: Polyethylene Glycol=1: 3: 5 | 50.0 | 87 | ＜30 | ＜10 | +++ |
| S40 ester: beta cyclodextrin: Polyethylene Glycol=1: 5: 10 | 50.0 | 87 | ＜30 | ＜10 | +++ |
| S40 ester: carboxymethyl starch sodium: Polyethylene Glycol=1: 0.5: 1 | 50.0 | 88 | ＞30 | ＜10 | +++ |
| S40 ester: carboxymethyl starch sodium: Polyethylene Glycol=1: 3: 5 | 50.0 | 89 | ＞30 | ＜10 | +++ |
| S40 ester: carboxymethyl starch sodium: Polyethylene Glycol=1: 5: 10 | 50.0 | 90 | ＞30 | ＜10 | +++ |
| S40 ester: tween: Polyethylene Glycol=1: 0.5: 1 | 50.0 | 82 | ＜30 | ＞10 | ++ |
| S40 ester: tween: Polyethylene Glycol=1: 3: 5 | 50.0 | 83 | ＜30 | ＞10 | ++ |
| S40 ester: tween: Polyethylene Glycol=1: 5: 10 | 50.0 | 85 | ＜30 | ＞10 | ++ |
The group practices of table 8 drug extract and three kinds of substrate
(drug extract: substrate=1: 3)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| S40 ester: beta cyclodextrin: Polyethylene Glycol=1: 0.5: 1 | 25.0 | 87 | ＜30 | ＜10 | +++ |
| S40 ester: beta cyclodextrin: Polyethylene Glycol=1: 3: 5 | 25.0 | 89 | ＜30 | ＜10 | +++ |
| S40 ester: beta cyclodextrin: Polyethylene Glycol=1: 5: 10 | 25.0 | 90 | ＜30 | ＜10 | +++ |
| S40 ester: carboxymethyl starch sodium: Polyethylene Glycol=1: 0.5: 1 | 25.0 | 84 | ＜30 | ＞10 | +++ |
| S40 ester: carboxymethyl starch sodium: Polyethylene Glycol=1: 3: 5 | 25.0 | 88 | ＞30 | ＜10 | +++ |
| S40 ester: carboxymethyl starch sodium: Polyethylene Glycol=1: 5: 10 | 25.0 | 89 | ＞30 | ＜10 | +++ |
| S40 ester: tween: Polyethylene Glycol=1: 0.5: 1 | 25.0 | 85 | ＜30 | ＞10 | +++ |
| S40 ester: tween: Polyethylene Glycol=1: 3: 5 | 25.0 | 88 | ＜30 | ＜10 | +++ |
| S40 ester: tween: Polyethylene Glycol=1: 5: 10 | 25.0 | 88 | ＜30 | ＜10 | +++ |
The group practices of table 9 drug extract and three kinds of substrate
(drug extract: substrate=1: 9)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| S40 ester: beta cyclodextrin: Polyethylene Glycol=1: 0.5: 1 | 10.0 | 88 | ＜30 | ＜10 | ++ |
| S40 ester: beta cyclodextrin: Polyethylene Glycol=1: 3: 5 | 10.0 | 90 | ＜30 | ＜10 | +++ |
| S40 ester: beta cyclodextrin: Polyethylene Glycol=1: 5: 10 | 10.0 | 91 | ＜30 | ＜10 | +++ |
| S40 ester: carboxymethyl starch sodium: Polyethylene Glycol=1: 0.5: 1 | 10.0 | 87 | ＜30 | ＜10 | +++ |
| S40 ester: carboxymethyl starch sodium: Polyethylene Glycol=1: 3: 5 | 10.0 | 88 | ＞30 | ＜10 | +++ |
| S40 ester: carboxymethyl starch sodium: Polyethylene Glycol=1: 5: 10 | 10.0 | 90 | ＞30 | ＜10 | +++ |
| S40 ester: tween: Polyethylene Glycol=1: 0.5: 1 | 10.0 | 86 | ＜30 | ＜10 | +++ |
| S40 ester: tween: Polyethylene Glycol=1: 3: 5 | 10.0 | 86 | ＜30 | ＜10 | +++ |
| S40 ester: tween: Polyethylene Glycol=1: 5: 10 | 10.0 | 88 | ＜30 | ＜10 | +++ |
The group practices of table 10 drug extract and four kinds of substrate
(drug extract: substrate=1: 1)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| S40 ester: beta cyclodextrin: tween: Polyethylene Glycol=1: 0.5: 0.5: 1 | 50.0 | 83 | ＜30 | ＞10 | ++ |
| S40 ester: beta cyclodextrin: tween: Polyethylene Glycol=1: 3: 3: 5 | 50.0 | 85 | ＜30 | ＞10 | ++ |
| S40 ester: beta cyclodextrin: tween: Polyethylene Glycol=1: 5: 5: 10 | 50.0 | 85 | ＜30 | ＞10 | +++ |
| S40 ester: carboxymethyl starch sodium: tween: Polyethylene Glycol=1: 0.5: 0.5: 1 | 50.0 | 82 | ＞30 | ＞10 | ++ |
| S40 ester: carboxymethyl starch sodium: tween: Polyethylene Glycol=1: 3: 3: 5 | 50.0 | 84 | ＞30 | ＞10 | ++ |
| S40 ester: carboxymethyl starch sodium: tween: Polyethylene Glycol=1: 5: 5: 10 | 50.0 | 83 | ＞30 | ＞10 | ++ |
The group practices of table 11 drug extract and four kinds of substrate
(drug extract: substrate=1: 3)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| S40 ester: beta cyclodextrin: tween: Polyethylene Glycol=1: 0.5: 0.5: 1 | 25.0 | 84 | ＜30 | ＞10 | ++ |
| S40 ester: beta cyclodextrin: tween: Polyethylene Glycol=1: 3: 3: 5 | 25.0 | 85 | ＜30 | ＜10 | +++ |
| S40 ester: beta cyclodextrin: tween: Polyethylene Glycol=1: 5: 5: 10 | 25.0 | 86 | ＜30 | ＜10 | +++ |
| S40 ester: carboxymethyl starch sodium: tween: Polyethylene Glycol=1: 0.5: 0.5: 1 | 25.0 | 86 | ＞30 | ＜10 | ++ |
| S40 ester: carboxymethyl starch sodium: tween: Polyethylene Glycol=1: 3: 3: 5 | 25.0 | 86 | ＞30 | ＜10 | +++ |
| S40 ester: carboxymethyl starch sodium: tween: Polyethylene Glycol=1: 5: 5: 10 | 25.0 | 88 | ＞30 | ＜10 | +++ |
The group practices of table 12 drug extract and four kinds of substrate
(drug extract: substrate=1: 9)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| S40 ester: beta cyclodextrin: tween: Polyethylene Glycol=1: 0.5: 0.5: 1 | 10.0 | 87 | ＜30 | ＜10 | ++ |
| S40 ester: beta cyclodextrin: tween: Polyethylene Glycol=1: 3: 3: 5 | 10.0 | 88 | ＜30 | ＜10 | +++ |
| S40 ester: beta cyclodextrin: tween: Polyethylene Glycol=1: 5: 5: 10 | 10.0 | 89 | ＜30 | ＜10 | +++ |
| S40 ester: carboxymethyl starch sodium: tween: Polyethylene Glycol=1: 0.5: 0.5: 1 | 10.0 | 87 | ＞30 | ＜10 | ++ |
| S40 ester: carboxymethyl starch sodium: tween: Polyethylene Glycol=1: 3: 3: 5 | 10.0 | 87 | ＞30 | ＜10 | +++ |
| S40 ester: carboxymethyl starch sodium: tween: Polyethylene Glycol=1: 5: 5: 10 | 10.0 | 88 | ＞30 | ＜10 | +++ |
1. can be seen by the result in the table: when the ratio of drug extract and substrate was 1: 1, its rounding rate, the ball method of double differences was different and index such as hardness is all undesirable, and dissolve scattered time limit influenced not obvious.
2. when the ratio of drug extract and substrate is 1: 3, the rounding rate, the ball method of double differences is different and index such as hardness slightly all begins to enter preferable state.
3. when the ratio of drug extract and substrate is 1: 9, the rounding rate, the ball method of double differences is different and hardness etc. improves not obvious.
4. the general effect of composite interstitial substance is better than single-matrix.
5. the hardness method for expressing in the subordinate list adopts drop pill is placed on the glass plate, press...withes one's finger it, observes its metamorphosis."+" expression flicking promptly is out of shape, " ++ " expression distortion of firmly pressing, and " +++" expression is indeformable by it.
Claims (4)
1. pharmaceutical composition compound yew drop pills that is used for medium and advanced lung cancer chemotherapy auxiliary treatment, with the extract that contains pharmaceutically active ingredient in Ramulus et folium taxi cuspidatae, Radix Ginseng Rubra, Radix Glycyrrhizae 3 flavors is raw material, be prepared from pharmaceutically suitable carrier, it is characterized in that as substrate:
(1) preparation of drug extract: with g or kg is unit, get 300 parts of bark of Ramulus et folium taxi cuspidatae, 1 part of Radix Ginseng Rubra, 3 parts in Radix Glycyrrhizae, more than three the flavor medical materials, bark of Ramulus et folium taxi cuspidatae is pulverized, cross 20 mesh sieves, according to the method under Chinese Pharmacopoeia version appendix IO fluid extract in 2000 and the extractum item, make solvent with 95% ethanol, flood after 48 hours slowly percolation, the collection liquid of filtering, 40 ℃ of decompression recycling ethanols add water and dichloromethane to doing, fully mix, leave standstill after 4 hours and tell and collect dichloromethane solution, water liquid reuse dichloromethane extraction 3 times merges each time dichloromethane solution, filter, the reclaim under reduced pressure dichloromethane is to doing, and residue adds kieselguhr and mixes thoroughly with the mixed solution dissolving of 3: 1 ethyl acetate and methanol, removal of solvent under reduced pressure, pack in the percolation bucket, use the normal hexane percolation earlier, continue and use the dichloromethane percolation, collect the dichloromethane percolate, the reclaim under reduced pressure dichloromethane is to doing, and residue dissolves with ethyl acetate, according to an appendix VIC of Chinese Pharmacopoeia version in 2000 column chromatography, with silica gel is absorbent, 3: 1 n-hexane and acetone are mixed into eluant, and eluting is collected the eluent that contains paclitaxel, decompression and solvent recovery becomes extractum to doing; Radix Glycyrrhizae, red ginseng powder are broken into coarse powder, according to the method under Chinese Pharmacopoeia appendix 10 fluid extracts of version in 2000 and the extractum item, make solvent with 70% ethanol, flood after 48 hours slowly percolation, collect percolate, reclaim ethanol, be condensed into thick paste, mix and make evenly with the above-mentioned paclitaxel extractum that contains, promptly; Or, be ground into dry powder, promptly dry below 60 ℃;
(2) described substrate is polyoxyethylene stearate 40 esters or carboxymethyl starch sodium or beta cyclodextrin or tween and Polyethylene Glycol, and its mixed proportion is 1: 1～1: 10; The mixed proportion of drug extract and substrate is 1: 1～1: 5, and wherein Polyethylene Glycol is selected from any one or the two or more mixture in cetomacrogol 1000～Macrogol 2000 0;
(3) according to aforementioned proportion, accurately take by weighing described extract and substrate, be placed in the heating container heating while stirring, standby until the fused solution that obtains containing described extract and substrate or emulsion or suspension;
(4) temperature control system of adjustment drop pill machine makes the water dropper heating of drop pill machine and maintains the temperature at 50 ℃～90 ℃, and the condensing agent cooling also maintains the temperature at 40 ℃～-5 ℃;
When (5) treating that dropping-pill machine head and condensing agent reach described state of temperature respectively, above-mentioned medicinal liquid is placed in the water dropper jar of drop pill machine, splash in the condensing agent, cooling is shunk and is shaped, promptly.
2. compound yew drop pills as claimed in claim 1 is characterized in that: described substrate is the mixture of polyoxyethylene stearate 40 esters and beta cyclodextrin or carboxymethyl starch sodium or tween and Polyethylene Glycol, and its mixed proportion is 1: 0.5: 1～1: 5: 10.
3. compound yew drop pills as claimed in claim 1, it is characterized in that: described substrate is the mixture of polyoxyethylene stearate 40 esters and beta cyclodextrin or carboxymethyl starch sodium and tween and Polyethylene Glycol, and its mixed proportion is 1: 0.5: 0.5: 1～1: 5: 5: 10.
4. compound yew drop pills as claimed in claim 1 is characterized in that: described condensing agent is methyl-silicone oil or liquid paraffin or vegetable oil.
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| CN100459976C (en) * | 2007-02-15 | 2009-02-11 | 黄成安 | Compound paclitaxel preparation containing phospholipid dispersant and its preparation method |
| CN102935097A (en) * | 2011-12-19 | 2013-02-20 | 徐英奎 | Taxus compound traditional Chinese medicine having anticancer effect and preparation method thereof |
| CN103099843A (en) * | 2012-12-17 | 2013-05-15 | 潘凌烊 | Health-care product capsule for treating cancers and preparation method thereof |
| CN106994170A (en) * | 2016-01-26 | 2017-08-01 | 天津禾盛医药技术开发有限公司 | A kind of Chinese medicine dripping pills of auxiliary treatment lung cancer |
| CN107441151A (en) * | 2017-09-01 | 2017-12-08 | 重庆赛诺生物药业股份有限公司 | A kind of Chinese medicine preparation for treating breast cancer and preparation method thereof |
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| CN1462617A (en) * | 2003-05-21 | 2003-12-24 | 刘智 | Alkaloid oral applied drop pills possessing anticarcinogenesis and its preparation method |
| CN1660029A (en) * | 2004-08-10 | 2005-08-31 | 北京正大绿洲医药科技有限公司 | New technique for preparing drop pills and special dripper device |
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| CN1462617A (en) * | 2003-05-21 | 2003-12-24 | 刘智 | Alkaloid oral applied drop pills possessing anticarcinogenesis and its preparation method |
| CN1660029A (en) * | 2004-08-10 | 2005-08-31 | 北京正大绿洲医药科技有限公司 | New technique for preparing drop pills and special dripper device |
Non-Patent Citations (1)
| Title |
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| 国家中成药标准汇编中成药地方标准上升国家标准部分. 国家药品监督管理局，357-358，国家药品监督管理局. 2002 * |
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