CN100415242C - Drop pills of vepeside and preparation process thereof - Google Patents
Drop pills of vepeside and preparation process thereof Download PDFInfo
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- CN100415242C CN100415242C CNB2005100748422A CN200510074842A CN100415242C CN 100415242 C CN100415242 C CN 100415242C CN B2005100748422 A CNB2005100748422 A CN B2005100748422A CN 200510074842 A CN200510074842 A CN 200510074842A CN 100415242 C CN100415242 C CN 100415242C
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Abstract
The present invention relates to an etoposide drop pill preparation and a preparation process thereof. The etoposide drop pill preparation is composed of etoposide and auxiliary ingredients comprising medicinal adjuvant, etc. The present invention has a preparation method that the etoposide is added to the dissolved medicinal adjuvant to be stirred uniformly and dripped into a pill. After being condensed in a condensing agent, the pill is dried to prepare the etoposide drop pill preparation. The etoposide drop pill preparation has the advantages of short dissolving time, rapid buccal absorption, high oral taking bioavailability and low toxic side effect.
Description
Technical field
The present invention relates to a kind of drop pills of vepeside agent and preparation method thereof, belong to technical field of medicine.
Technical background
Etoposide (Etoposide) claims etoposide, etoposide again, and etoposide is the semi-synthetic derivant of table Rhizoma Dysosmae Versipellis, i.e. 4 '-demethyl epipodophyllotoxin 9-(4,6-O-methylene-β-D-pyranglucoside).It is present clinical a kind of important cancer therapy drug commonly used, it is to pulmonary carcinoma, leukemia, carcinoma of testis, Kaposi's sarcoma, Ewing's tumor, gestation embryo cell cancer, Hokdkin disease, large celllymphoma, neuroblastoma and child's striped muscle have significant curative effect, also can unite with other medicines and use treatment ovarian cancer, gastric cancer and hepatocarcinoma.Especially small cell lung cancer and carcinoma of testis have been gone through to treat in the U.S..Be the cell toxicity medicament of period specific, mainly act on the cell cycle S phase, make cell can not carry out mitosis.Its mechanism of action is main and suppress topoisomerase H α, and it is relevant to cause dna double chain or strand to destroy.This product and teniposide (VM-26) have crossing drug resistant.
Being used for clinical etoposide at present only has two kinds of dosage forms, i.e. injection and oral soft capsule agent, and wherein injection uses inconvenience, and cost is also very high; Because the dissolubility extreme difference of etoposide in water causes the oral soft capsule preparation bioavailability of prior art low, only is 25%-74%.Therefore, keep medicine antineoplastic effective blood drug concentration, number of times is taken in the dosage or the increase that certainly will need to increase oral soft capsule, and then causes the increase of toxic and side effects.Slow (control) release formulation of enteric that etoposide enteric slow (control) is released solid dispersed formulation and preparation method thereof (application number 02153962.6) needs expensive pharmaceutic adjuvant, and some adjuvant does not still have homemade at present, is difficult to satisfy domestic clinical demand.
The patent of relevant etoposide has: (1) Etoposide preparation (application number 90104175.0) has been protected and has been comprised etoposide, the plain ether derivant of polyvinylpyrrolidone and water soluble fiber, and etoposide is approximately 10-20% (w/w) in the preparation total amount.These patent related products are exactly the etoposide soft capsule of present China listing.This patent and the application's content is irrelevant.(2) etoposide enteric slow (control) is released the etoposide enteric slow (control) that solid dispersed formulation and preparation method thereof (application number 02153962.6) application is and is released the solid dispersion medicine compositions, and what its dosage form application was protected is tablet and hard capsule.(3) other patent: etoposide-2-dimethylamino compound hydrochloride dihydrate crystallization and preparation method thereof (application number 89108575.0), the freeze-dried preparation of etoposide-2-dimethylamino compound (application number 91100373.8), crystalline etoposide 4 '-phosphate ester diethyl alcoholates (application number 92111350.1), etoposide-2-dimethylamino compound hydrochloride dihydrate crystallization and preparation method thereof (application number 92112450.3), the method (application number 93106360.4) for preparing glucoside podophyllum ethyldene phosphate ester and its intermediate, the intermediate (CN 97112747.6) of preparation glucoside podophyllum ethyldene phosphate ester, the new technique for synthesizing of antineoplastic medicine-etoposide (application number 90102873.8), the preparation method of Etoposide phosphate and etoposide (application number 94118214.2,97123032.3,97123033.1,97123031.5), synthesis process of antineoplastic drug etoposide (application number 00119609.X), above-mentioned patent are all irrelevant with the invention of present patent application.
Summary of the invention
The object of the present invention is to provide a kind of etoposide oral administration dripping pill and preparation method thereof, to increase clinical pharmaceutical dosage form, overcome the low shortcoming of soft capsule dissolution bad student thing availability, and the performance drop pill absorbs the dosage form advantage fast, that bioavailability is high, reach the raising bioavailability, bring into play quick-acting therapeutical effect, reduce toxic and side effects.Buccal is the vascularity that utilizes the oral cavity abundant, make medicine be absorbed into blood rapidly, reach the required blood drug level of antitumor, most medicines are swallowed and are entered in the body in the time of buccal, because the poorly water-soluble of etoposide, general preparation is difficult to improve bioavailability of medicament and dispersive property, and this is the low inherence basis of its bioavailability.Medicinal adjuvant in the drop pill has good peptizaiton, can make medicine reach nanometer and micron-sized dispersion, reduces the chance of intermolecular collision, reaches the purpose that improves bioavailability.Another object of the present invention provides the preparation method of ring drop pills of vepeside.
The specific embodiment
For achieving the above object, the present invention is implemented by following technical proposals.
1, the resulting drop pill of the present invention comprises following composition
Medicine of the present invention is the drop pill of being made by following component;
Pharmaceutical formulation:
Etoposide 5%～40% (W/W)
Medicinal adjuvant 60%～95% (W/W)
In drop pills of vepeside, the amount of etoposide is 5%～40% (W/W) of drop pill gross weight; Preferred 10%～40% (W/W); Medicinal adjuvant is formed for one or more pharmaceutic adjuvants, accounts for 60%～95% (W/W) of drop pill gross weight.
Medicinal adjuvant drop pill substrate, surfactant (contain or do not contain), cosolvent (contain or do not contain).Drop pill substrate is meant one or more the compositions in the Polyethylene Glycol (PEG), Myrj 45, sodium stearate, glycerin gelatine, stearic acid, glyceryl monostearate, hydrogenated vegetable oil, insect wax of molecular weight 〉=1500.The compositions of preferred Polyethylene Glycol-4000, Polyethylene Glycol-6000 and different proportion thereof.The best is the compositions of PEG-4000 and PEG-6000.Wherein yet can not contain or contain other does not influence drop pill substrate on a small quantity and returns other solid-state adjuvants at normal temperatures, as surfactant poloxamer, dodecyl sodium sulfate, CMS-Na and tween 80 etc., and preferred tween 80 and CMS-Na; These adjuvants help dispersion, stripping, uniformity and the stability of medicine.Also can use or not use some cosolvents, as ethanol, propylene glycol, glycerol, liquid macrogol, preferred alcohol.
2, the resulting drop pill of the present invention prepares by following method
The present invention adopts following preparation method: take by weighing medicinal adjuvant by formula ratio, wherein can also add other pharmaceutic adjuvants such as the tween 80 that help the drop pill Chinese medicine to discharge, CMS-Na etc., heat fused, the etoposide that adds formula ratio, fully stir and make its complete fusion, be uniformly dispersed, make fused solution; Perhaps take by weighing etoposide, add an amount of cosolvent, after the slight fever dissolving, be added in the medicinal adjuvant fused solution of formula ratio, mix, volatilize cosolvent, after being uniformly dispersed, make fused solution by formula ratio; Fused solution is put in the surge drum of drop pill machine, insulation splashes in condensed fluid proper temperature under with certain speed of dripping, and is condensed into ball, and the collection drop pill is removed coolant, and drying can obtain the finished product of medicine.It is simple that this preparation method has technology, adjuvant cheapness, the production characteristics that wait easy to control the quality.
The quality standard of raw material etoposide meets the requirement of China national drug standard in the prescription of medicine of the present invention.
In the preparation method of medicine of the present invention, liquid Paraffin, methyl-silicone oil, vegetable oil, kerosene all can be used as condensed fluid, are preferably liquid Paraffin, methyl-silicone oil.During as condensed fluid, the drop pill roundness is better with liquid Paraffin or methyl-silicone oil, size evenly, smooth surface, solid colour.The results are shown in Table 1.
The different condensing droplet system results of table 1
| Condensed fluid | Liquid Paraffin | Methyl-silicone oil | Vegetable oil | Kerosene |
| The drop pill mouldability | Formability is good | Formability is good | Formability is poor | Formability is good |
| The drop pill shape | Spheroidal | Spheroidal | Lamellar | Oblate spheroid |
| With the principal agent dissolubility | Do not dissolve | Do not dissolve | Do not dissolve | Do not dissolve |
In the preparation method of medicine of the present invention, these two kinds of methods of fusion method and solvent-fusion method all can be used as the method for making drop pill, but the preferred molten method.
With the uniformity of dosage units is index, proves that the uniformity of dosage units of fusion method and solvent-fusion method all meets the pharmacopeia regulation.But the operation of solvent-fusion method is more numerous and diverse, is difficult for determining in the fused solution whether emptying of ethanol, the difficult control of commercial production; From appearance luster, the drop pill color that fusion method and solvent-fusion method are made all is off-white color, and size is even, smooth surface, solid colour.Take all factors into consideration the preferred molten method.
In the preparation method of medicine of the present invention, the holding temperature of fused solution is 60 ℃～110 ℃, is preferably 70 ℃～95 ℃, and the best is 75～90 ℃.
In making the process of etoposide-PEG fused solution, need constantly to stir, make it become homogeneous phase, can contain air in certain amount in the fused solution this moment, should exclude air in drop pill production, otherwise will influence the roundness of drop pill.Therefore, after fused solution makes, must insulation place a period of time, the air in the fused solution is got rid of totally fully.Etoposide-PEG fused solution is incubated 20,25,30 minutes respectively under 80 ℃, drips the system drop pill then respectively, whether the surface of observing drop pill has plaque, to determine best temperature retention time.Found that, there is a small amount of very little plaque on the drop pill surface that is incubated 20,25 minutes molten melt drop system, show that being incubated 20,25 minutes bubbles does not catch up with only fully: be incubated the drop pill smooth surface of 30 minutes molten melt drop system, no plaque shows fused solution Ex-all fully after 30 minutes.
Therefore, in the preparation method of medicine of the present invention, the temperature retention time of fused solution is at least 20 minutes, is preferably at least 30 minutes.
Fused solution has a little hangover when water dropper drips, and when moving, fused solution then may bring the sub-fraction air into again in air, if the condensed fluid upper temp is too low, then hangover has little time withdrawal, air has little time to discharge fused solution and promptly solidifies, influences shaped degree of drop pill and surface flatness.Condensed fluid lower floor temperature is too high, and the fused solution condensation is incomplete, and drop pill can also influence the drop pill roundness in condensate line bottom adhesion.Through overtesting, upper strata condensed fluid height should be controlled at about 20cm to well, and following layer height is good with 30cm, and under this height, the drop pill condensation is complete, good moldability, adhesion.
Therefore, in the preparation method of medicine of the present invention, the temperature on condensed fluid top is 10～45 ℃, 15～35 ℃ of preferred temperature, 20～30 ℃ of optimum temperatures; The temperature of condensed fluid bottom is-10～10 ℃: preferred temperature-5～5 ℃, optimum temperature-3～3 ℃.Top condensed fluid height is preferably 10～35cm, preferred heights 15～30cm, optimum height 20cm; Bottom condensed fluid height is preferably 20～40cm, preferred heights 25～35cm, optimum height 30cm.
The present invention investigates dripping factors such as speed, a distance.In the preparation method of medicine of the present invention, drip apart from being 2～8cm, dripping speed is 10～100 droplets/minute; Be preferably and drip apart from 2～5cm, dripping speed is 30～70 droplets/minute.
Can find out the advantage of drop pill of the present invention from table 2.General about 6 minutes of drop pill dissolve scattered time limit of the present invention, (＞30min) molten loosing rapidly shortened the time that entering performance drug effect in the body than soft capsule.
Table 2 etoposide soft capsule and drop pills of vepeside dissolve scattered time limit of the present invention are relatively
| Sample number into spectrum | 1 | 2 | 3 | 4 | 5 | 6 |
| Lastet capsule (etoposide soft capsule) min | 45 | 48 | 43 | 50 | 51 | 43 |
| Drop pills of vepeside lot number 040818min | 6.5 | 6.1 | 6.7 | 5.5 | 6.3 | 6.2 |
Etoposide is indissoluble in water.For solid PEG etoposide is melted into wherein at normal temperatures, make it to be molecularity or nanometer distributions in drop pill, the molecular weight of PEG is bigger, lattice is made up of the parallel spiral chain of two row, when condensing after the fusion, the Polyethylene Glycol lattice produces all damagedly in the double-helical space, and damaged its character that changes of this lattice is as dissolubility, dissolution rate, absorbability and hygroscopicity etc.Etoposide belongs to micromolecule, can insert in the PEG molecule, thereby increase the dissolution rate and the infiltration rate of etoposide medicine, and the dissolubility of etoposide in water increased greatly.Therefore, the present invention makes drop pill with etoposide, take the back its to melt diffusing property better than soft capsule; And make drop pill, can swallow, can be dispersed with very soon under one's belt and be beneficial to gastrointestinal absorption.Can containing, more help the absorption of this product by the liposoluble passage of oral mucosa, directly enter blood circulation, onset in 3 minutes arrives tumor focus fast, and effect more is better than common oral preparation.
In addition, drop pills of vepeside of the present invention also has following advantage: little, the taking convenience of volume is easy to be accepted by the patient; The drop pill production process is few, and the cycle is short, the automaticity height, and the production efficiency height, cost is low, is easy to industrialization; The drop pill working condition is easy to control, and the ball method of double differences is different little, and content is more accurate, and quality is guaranteed; The bioavailability height of most critical, toxic and side effects is little; This dosage form is one of dosage form of country's recommendation at present.
3, the route of administration of the resulting drop pills of vepeside of the present invention
The route of administration of drop pills of vepeside is meant in various treatment for cancer to be used buccal and or swallows.According to the disease that gives object, body weight and the state of an illness, give dosage usually in the scope in 0.005-1 gram/sky.
The following examples are used to further specify the present invention, but they are not to attempt in office where face limits the scope of the invention.
Embodiment 1
Prescription (specification: the 10mg/ ball)
Etoposide 10g
Macrogol 4000 30g
Make 1000 altogether
Preparation method:
Weight proportion by each component is weighed, and Macrogol 4000 heating is made it fusion, adds the etoposide fine powder, and constantly stirring makes whole fusions, puts in the reservoir of drop pill machine, and 80 ℃ of insulations 30 minutes are stand-by.Adjust and drip apart from being 3cm, at the uniform velocity splash in the liquid paraffin condensed fluid that contains methyl-silicone oil with 50 droplets/minute the speed of dripping, the temperature of condensed fluid top 20cm is 20 ± 2 ℃, and the temperature of bottom 30cm is 0 ± 1 ℃.Collect drop pill, remove the condensing agent on drop pill surface, drying is selected ball, gets product.
Molten diffusing timing: six batch samples that go out with above-mentioned prescription and explained hereafter are carried out molten diffusing timing, measurement result such as following table according to appendix X11A the 3rd method of Chinese Pharmacopoeia version in 2000.
The molten diffusing timing result of table 36 batch samples (minute)
| Lot number | 040816-1 | 040816-2 | 040817-1 | 040817-2 | 040818-1 | 04081 8-2 |
| The 1st ball | 6.0 | 5.5 | 5.5 | 5.2 | 6.5 | 5.8 |
| The 2nd ball | 5.5 | 6.2 | 5.9 | 6.5 | 6.7 | 6.5 |
| The 3rd ball | 6.0 | 6.5 | 5.5 | 6.2 | 6.5 | 5.7 |
| The 4th ball | 6.5 | 6.1 | 6.4 | 4.5 | 6 | 6.5 |
| The 5th ball | 6.1 | 5.5 | 5.5 | 6.3 | 6.5 | 6.1 |
| The 6th ball | 5.5 | 5.6 | 6.1 | 6.5 | 6.2 | 5.5 |
The result shows that prepared drop pills of vepeside all has the molten faster diffusing time.
Embodiment 2
Prescription (specification: the 10mg/ ball)
Etoposide 10g
Polyethylene glycol 6000 30g
Tween 80 0.25g
Make 1000 altogether
Preparation method:
Weight proportion by each component is weighed, and polyethylene glycol 6000 heating is made it fusion, adds etoposide fine powder and tween 80, and constantly stirring makes whole fusions, puts in the reservoir of drop pill machine, and 86 ℃ of insulations 30 minutes are stand-by.Adjust and drip apart from being 4cm, at the uniform velocity splash in the liquid paraffin condensed fluid with 60 droplets/minute the speed of dripping, the temperature of condensed fluid top 20cm is 23 ± 3 ℃, and the temperature of bottom 30cm is 5 ± 1 ℃.Collect drop pill, remove the condensing agent on drop pill surface, drying is selected ball, gets product.
Embodiment 3
Prescription (specification: the 10mg/ ball)
Etoposide 10g
Polyethylene glycol 6000: Macrogol 4000 (1: 5) 30g
Make 1000 altogether
Preparation method:
Weight proportion by each component is weighed, and the heating of Macrogol 4000 and polyethylene glycol 6000 is made it fusion, adds the etoposide fine powder, and constantly stirring makes whole fusions, puts in the reservoir of drop pill machine, and 80 ℃ of insulations 30 minutes are stand-by.Adjust and drip apart from being 3cm, at the uniform velocity splash in the liquid paraffin condensed fluid with 60 droplets/minute the speed of dripping, the temperature of condensed fluid top 20cm is 21 ± 2 ℃, and the temperature of bottom 30cm is 0 ± 1 ℃.Collect drop pill, remove the condensing agent on drop pill surface, drying is selected ball, gets product.
Embodiment 4
Prescription (specification: the 5mg/ ball)
Etoposide 5g
Polyethylene glycol 6000: Macrogol 4000 (1: 4) 30g
Make 1000 altogether
Preparation method:
Weight proportion by each component is weighed, and the heating of Macrogol 4000 and polyethylene glycol 6000 is made it fusion, adds the etoposide fine powder, and constantly stirring makes whole fusions, puts in the reservoir of drop pill machine, and 90 ℃ of insulations 30 minutes are stand-by.Adjust and drip apart from being 3cm, at the uniform velocity splash in the liquid paraffin condensed fluid with 40 droplets/minute the speed of dripping, the temperature of condensed fluid top 20cm is 21 ± 2 ℃, and the temperature of bottom 30cm is 0 ± 1 ℃.Collect drop pill, remove the condensing agent on drop pill surface, drying is selected ball, gets product.
Embodiment 5
Prescription (specification: the 8mg/ ball)
Etoposide 8g
Polyethylene glycol 6000: Macrogol 4000 (2: 1) 32g
Make 1000 altogether
Preparation method:
Weight proportion by each component is weighed, and the heating of Macrogol 4000 and polyethylene glycol 6000 is made it fusion, adds the etoposide fine powder, and constantly stirring makes whole fusions, puts in the reservoir of drop pill machine, and 95 ℃ of insulations 30 minutes are stand-by.Adjust and drip apart from being 3cm, at the uniform velocity splash in the liquid paraffin condensed fluid with 60 droplets/minute the speed of dripping, the temperature of condensed fluid top 20cm is 21 ± 2 ℃, and the temperature of bottom 30cm is 0 ± 1 ℃.Collect drop pill, remove the condensing agent on drop pill surface, drying is selected ball, gets product.
Embodiment 6
Prescription (specification: the 5mg/ ball)
Etoposide 5g
Macrogol 4000 20g
Make 1000 altogether
Preparation method:
Weight proportion by each component is weighed, and Macrogol 4000 heating is made it fusion, second glycosides fine powder when adding foot, and constantly stirring makes whole fusions, puts in the reservoir of drop pill machine, and 85 ℃ of insulations 30 minutes are stand-by.Adjust and drip apart from being 3cm, at the uniform velocity splash in the methyl-silicone oil condensed fluid with 60 droplets/minute the speed of dripping, the temperature on condensed fluid top is 20 ± 2 ℃, and the temperature of bottom is 0 ± 1 ℃.Collect drop pill, remove the condensing agent on drop pill surface, drying is selected ball, gets product.
Embodiment 7
Prescription (specification: the 10mg/ ball)
Etoposide 10g
Macrogol 4000 30g
Stearic acid 2g
Make 1000 altogether
Preparation method:
Weight proportion by each component is weighed, and the heating of Macrogol 4000 and stearic acid is made it fusion, adds the etoposide fine powder, and constantly stirring makes whole fusions, puts in the reservoir of drop pill machine, and 80 ℃ of insulations 30 minutes are stand-by.Adjust and drip apart from being 3cm, at the uniform velocity splash in the methyl-silicone oil condensed fluid with 55 droplets/minute the speed of dripping, the temperature on condensed fluid top is 20 ± 2 ℃, and the temperature of bottom is 0 ± 1 ℃.Collect drop pill, remove the condensing agent on drop pill surface, drying is selected ball, gets product.
Embodiment 8
Prescription (specification: the 10mg/ ball)
Etoposide 10g
Macrogol 4000 40g
Carboxymethyl starch sodium 0.5g
Make 1000 altogether
Preparation method:
Etoposide adds an amount of dehydrated alcohol, after slight fever makes dissolving, is added on fused Macrogol 4000 and CMS-Na, constantly stirs, and volatilizes ethanol, put in the reservoir of drop pill machine, 85 ℃ the insulation 30 minutes stand-by.Adjust and drip apart from being 4cm, at the uniform velocity splash in the liquid Paraffin condensed fluid with 50 droplets/minute the speed of dripping, the temperature on condensed fluid top is 20 ± 2 ℃, and the temperature of bottom is 0 ± 1 ℃.Collect drop pill, remove the condensing agent on drop pill surface, drying is selected ball, gets product.
Embodiment 9
Prescription (specification: the 15mg/ ball)
Etoposide 15g
Polyethylene glycol 6000: Macrogol 4000 (1: 20) 35g
Glyceryl monostearate 0.5g
Make 1000 altogether
Preparation method:
Weight proportion by each component is weighed, and the heating of Polyethylene Glycol and glyceryl monostearate is made it fusion, adds the etoposide fine powder, and constantly stirring makes whole fusions, puts in the reservoir of drop pill machine, and 80 ℃ of insulations 30 minutes are stand-by.Adjust and drip apart from being 4cm, at the uniform velocity splash in the kerosene condensed fluid with 60 droplets/minute the speed of dripping, the temperature on condensed fluid top is 20 ± 2 ℃, and the temperature of bottom is 0 ± 1 ℃.Collect drop pill, remove the condensing agent on drop pill surface, drying is selected ball, gets product.
Embodiment 10
Prescription (specification: the 20mg/ ball)
Etoposide 20g
Polyethylene glycol 6000: Macrogol 4000 (1: 10) 40g
Make 1000 altogether
Preparation method:
Weight proportion by each component is weighed, and Polyethylene Glycol heating is made it fusion, adds the etoposide fine powder, and constantly stirring makes whole fusions, puts in the reservoir of drop pill machine, and 85 ℃ of insulations 30 minutes are stand-by.Adjust and drip apart from being 4cm, at the uniform velocity splash in the liquid paraffin condensed fluid with 50 droplets/minute the speed of dripping, the temperature on condensed fluid top is 20 ± 2 ℃, and the temperature of bottom is 0 ± 1 ℃.Collect drop pill, remove the condensing agent on drop pill surface, drying is selected ball, gets product.
Embodiment 11
Prescription (specification: the 10mg/ ball)
Etoposide 10g
Polyethylene glycol 6000: Macrogol 4000 (1: 1) 25g
Make 1000 altogether
Preparation method:
Weight proportion by each component is weighed, and Polyethylene Glycol heating is made it fusion, adds the etoposide fine powder, and constantly stirring makes whole fusions, puts in the reservoir of drop pill machine, and 95 ℃ of insulations 30 minutes are stand-by.Adjust and drip apart from being 5cm, at the uniform velocity splash in the liquid paraffin condensed fluid with 30 droplets/minute the speed of dripping, the temperature on condensed fluid top is 20 ± 2 ℃, and the temperature of bottom is 0 ± 1 ℃.Collect drop pill, remove the condensing agent on drop pill surface, drying is selected ball, gets product.
Embodiment 12
The body giving drugs into nose of drop pills of vepeside is for dynamic test and bioavailability
This test utilizes etoposide
3H label Radioactive tracer techniques are studied the pharmacokinetics feature of two kinds of preparation dogs of drop pills of vepeside of the present invention and etoposide soft capsule (Japan produce) after oral.The result shows that the present invention is at the pharmacokinetic parameter AUC and the C of identical dosage group drop pills of vepeside
MaxNumerical value is greater than soft capsule, the T of drop pill
PeaK and t
1/2kaBe starkly lower than soft capsule.The absorptance soft capsule of drop pills of vepeside of the present invention is fast, and the general 45～65min in advance of peak time in the blood show that drop pills of vepeside of the present invention has the characteristics of fast Absorption than soft capsule, and bioavailability has improved about 25%.
Experimental technique
Get 1.0 mci's
3Grind well dry back in H-etoposide (50% alcoholic solution) the adding 8.0g etoposide content and move into grinding 20min in the KL-50 ball mill.Take by weighing the 50mg powder and make soft capsule and drop pill, standby.
Experiment grouping and sample collection: experiment divides drop pill and two kinds of dosage forms of soft capsule, respectively establish three dosage groups (10,20 and 40mg/kg, 6 animals of every experimental group.10,20,40,60,90,120,150,180,240,300,360 and 480 min get the about 2ml of blood from the vein of dog after the administration, the citric acid anticoagulant, and it is standby that the centrifugal 15-20min of 5000rpm gets blood plasma.
Sample treatment and result calculate: conventional treatment and assay method according to pharmacokinetics carry out.
Conclusion: pharmacokinetic parameter: utilize pharmacokinetics software (3P
97) process of fitting treatment tries to achieve pharmacokinetic parameter separately, the AUC of oral absorption process, C
Max, T
PeakAnd t
1/2kaEtc. parameter.
Embodiment 13
Prescription (specification: the 20mg/ ball)
Etoposide 20g
Macrogol 4000 25g
Make 1000 altogether
Preparation method:
Weight proportion by each component is weighed, and Polyethylene Glycol heating is made it fusion, adds the etoposide fine powder, and constantly stirring makes whole fusions, puts in the reservoir of drop pill machine, and 85 ℃ of insulations 30 minutes are stand-by.Adjust and drip apart from being 4cm, at the uniform velocity splash in the liquid paraffin condensed fluid with 50 droplets/minute the speed of dripping, the temperature on condensed fluid top is 20 ± 2 ℃, and the temperature of bottom is 0 ± 1 ℃.Collect drop pill, remove the condensing agent on drop pill surface, drying is selected ball, gets product.
Embodiment 14
Prescription (specification: the 25mg/ ball)
Etoposide 25g
Macrogol 4000 25g
Make 1000 altogether
Preparation method:
Weight proportion by each component is weighed, and Polyethylene Glycol heating is made it fusion, adds the etoposide fine powder, and constantly stirring makes whole fusions, puts in the reservoir of drop pill machine, and 80 ℃ of insulations 30 minutes are stand-by.Adjust and drip apart from being 3cm, at the uniform velocity splash in the liquid paraffin condensed fluid with 60 droplets/minute the speed of dripping, the temperature on condensed fluid top is 20 ± 2 ℃, and the temperature of bottom is 0 ± 1 ℃.Collect drop pill, remove the condensing agent on drop pill surface, drying is selected ball, gets product.
Embodiment 15
Prescription (specification: the 15mg/ ball)
Etoposide 15g
Macrogol 4000 22g
Glycerin gelatine 1g
Insect wax 0.2g
Make 1000 altogether
Preparation method:
Weight proportion by each component is weighed, and Polyethylene Glycol, glycerin gelatine, insect wax heating are made it fusion, adds the etoposide fine powder, and constantly stirring makes whole fusions, puts in the reservoir of drop pill machine, and 85 ℃ of insulations 30 minutes are stand-by.Adjust and drip apart from being 4cm, at the uniform velocity splash in the liquid paraffin condensed fluid with 50 droplets/minute the speed of dripping, the temperature on condensed fluid top is 20 ± 2 ℃, and the temperature of bottom is 0 ± 1 ℃.Collect drop pill, remove the condensing agent on drop pill surface, drying is selected ball, gets product.
Embodiment 16
Prescription (specification: the 10mg/ ball)
Etoposide 10g
Macrogol 4000 25g
Glycerin gelatine 1g
Hydrogenated vegetable oil 0.5g
Poloxamer 0.3g
Make 1000 altogether
Preparation method:
Weight proportion by each component is weighed, and Polyethylene Glycol, glycerin gelatine, hydrogenated vegetable oil, poloxamer heating are made it fusion, adds the etoposide fine powder, and constantly stirring makes whole fusions, puts in the reservoir of drop pill machine, and 90 ℃ of insulations 30 minutes are stand-by.Adjust and drip apart from being 5cm, at the uniform velocity splash in the liquid paraffin condensed fluid with 30 droplets/minute the speed of dripping, the temperature on condensed fluid top is 20 ± 2 ℃, and the temperature of bottom is 0 ± 1 ℃.Collect drop pill, remove the condensing agent on drop pill surface, drying is selected ball, gets product.
Claims (1)
1. drop pills of vepeside, it is characterized in that this drop pill made by the etoposide of 10g and the Macrogol 4000 of 30g, make 1000 drop pill altogether, the preparation method of this drop pill is: each component is weighed according to described weight, the Macrogol 4000 heating is made it fusion, add the etoposide fine powder, constantly stirring makes whole fusions, place the reservoir of drop pill machine, 80 ℃ the insulation 30 minutes stand-by; Adjust and drip apart from being 3cm, at the uniform velocity splash in the liquid paraffin condensed fluid that contains methyl-silicone oil with 50 droplets/minute the speed of dripping, the temperature of condensed fluid top 20cm is 20 ± 2 ℃, and the temperature of bottom 30cm is 0 ± 1 ℃; Collect drop pill, remove the condensing agent on drop pill surface, drying is selected ball, gets product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100748422A CN100415242C (en) | 2005-06-07 | 2005-06-07 | Drop pills of vepeside and preparation process thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100748422A CN100415242C (en) | 2005-06-07 | 2005-06-07 | Drop pills of vepeside and preparation process thereof |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1478481A (en) * | 2002-12-06 | 2004-03-03 | 重庆华邦制药股份有限公司 | Etoposide enteric slow (controlled) release solid dispersing preparation and its preparation method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1478481A (en) * | 2002-12-06 | 2004-03-03 | 重庆华邦制药股份有限公司 | Etoposide enteric slow (controlled) release solid dispersing preparation and its preparation method |
Non-Patent Citations (6)
| Title |
|---|
| 新型依托泊甙胶囊的研制及释放度研究. 要芬梅等.中国药房，第10卷第3期. 1999 |
| 新型依托泊甙胶囊的研制及释放度研究. 要芬梅等.中国药房，第10卷第3期. 1999 * |
| 药剂学. 屠锡德，802，815-820，人民卫生出版社. 2004 |
| 药剂学. 屠锡德，802，815-820，人民卫生出版社. 2004 * |
| 葛根素滴丸的制剂研究及评价. 严冬.成都中医药大学.博士学位论文. 2003 |
| 葛根素滴丸的制剂研究及评价. 严冬.成都中医药大学.博士学位论文. 2003 * |
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