Summary of the invention
Existing etoposide preparations need be taken medicine three times general every day, and the course for the treatment of is long, and the patient is difficult to adhere to for a long time.Simultaneously, because the blood concentration fluctuation is large, and the blood peak concentration is too high, some side effect relevant with peak concentration often occur.
The present invention takes inconvenience, shortcoming that bioavailability is low in order to solve existing etoposide preparations, invented etoposide clathrate slow-releasing granules, reduce medicining times, absorption rate slows down, extend biological half-life, blood drug level is controlled in the effective blood drug concentration scope, thereby reduces side effect, improve patient's compliance.
Clathrate has the following advantages: cover bad stink, reduce zest; Increase drug dissolution and bioavailability; Improve medicine stability.
The applicant finds, existing etoposide is prepared into clathrate, then is prepared into sustained-release granular formulation in conjunction with specific adjuvant, have advantages of that stability is high, had good sustained release effect and bioavailability high.
The application provides a kind of sustained-release granular formulation of etoposide, comprising:
Etoposide clathrate 20-50 part
Excipient 15-50 part
Disintegrating agent 20-30 part
Correctives 1-5 part
Polymethacrylates 7-25 part
Ethyl cellulose 5-15 part
The etoposide clathrate comprises active component and enclose material, and active component is etoposide, and the enclose material is hydroxypropylβ-cyclodextrin.The part by weight of active component and enclose material is 3:1-1:3, preferred 1:2.Experiment showed, alpha-cyclodextrin, beta-schardinger dextrin-, the clathrate that the etoposide clathrate that the hydroxyl beta-schardinger dextrin-prepares prepares inferior to hydroxypropylβ-cyclodextrin in aspect effects such as dissolution velocity, stability, inclusion rates far away.
The impact of different enclose materials on the etoposide clathrate
The enclose material |
Dissolution velocity (min) |
Stability |
Inclusion rate |
Alpha-cyclodextrin |
12 |
Generally |
80% |
Beta-schardinger dextrin- |
14 |
Generally |
82% |
The hydroxyl beta-schardinger dextrin- |
12 |
Generally |
78% |
Hydroxypropylβ-cyclodextrin |
5 |
Good |
93% |
Test method is with reference to the method for two regulations of 2010 editions Chinese Pharmacopoeias.
In this application, select specific adjuvant to prepare etoposide clathrate sustained-release granular formulation.Wherein said excipient is the compositions of lactose and sucrose, and both part by weight is 7.2:3.5, and disintegrating agent is the compositions of polyvinylpolypyrrolidone and cross-linking sodium carboxymethyl cellulose, and both part by weight is 2.7:6.5, and correctives is selected from saccharin sodium or aspartame.Experimental results show that, be not that the conventional adjuvant of any pharmacy all is fit to preparation etoposide clathrate granule, select the effect of etoposide clathrate granule at aspects such as dissolution velocity, stability, dissolutions that this specific adjuvant prepares to be better than the etoposide clathrate granule that other adjuvants prepare far away.
The preparation method of etoposide clathrate comprises:
(1) in water or aquiferous ethanol medium, by a certain percentage, with etoposide and hydroxypropylβ-cyclodextrin reaction, gained solution through extremely clarification of filtering with microporous membrane, is isolated clathrate from mixture; Or
(2) with solid form, with etoposide and hydroxypropylβ-cyclodextrin reaction; Or
(3) high energy milling is carried out in the reaction of etoposide and hydroxypropylβ-cyclodextrin.
Metering of the present invention is weight.
Preferably, the prescription of sustained-release granular formulation is (by weight):
25 parts of etoposide clathrates
(both part by weight is 20 parts to the compositions of lactose and sucrose
7.2:3.5)
20 parts of the groups of polyvinylpolypyrrolidone and cross-linking sodium carboxymethyl cellulose
Compound (both part by weight is 2.7:6.5)
2 parts of saccharin sodium or aspartames
11 parts of polymethacrylates
6 parts of ethyl celluloses
Embodiment 1 prescription
Etoposide clathrate: etoposide: hydroxypropylβ-cyclodextrin is 1:2
25 parts of etoposide clathrates
(both part by weight is 20 parts to the compositions of lactose and sucrose
7.2:3.5)
20 parts of the groups of polyvinylpolypyrrolidone and cross-linking sodium carboxymethyl cellulose
Compound (both part by weight is 2.7:6.5)
2 parts of saccharin sodium
11 parts of polymethacrylates
6 parts of ethyl celluloses
Preparation method:
1. prepare by the following method the etoposide clathrate:
(1) in water or aquiferous ethanol medium, by a certain percentage, with etoposide and hydroxypropylβ-cyclodextrin reaction, gained solution through extremely clarification of filtering with microporous membrane, is isolated clathrate from mixture; Or
(2) with solid form, with etoposide and hydroxypropylβ-cyclodextrin reaction; Or
(3) high energy milling is carried out in the reaction of etoposide and hydroxypropylβ-cyclodextrin.
2. the etoposide clathrate was pulverized 100 mesh sieves, all the other adjuvants were pulverized 80 mesh sieves; Accurately take the supplementary material of recipe quantity, mix homogeneously adds suitable quantity of water mixture furnishing paste is granulated on granulator, 18 mesh sieve granulate, and 60 ℃ of dryings namely get granule.
Embodiment 2 prescriptions
Etoposide clathrate: etoposide: hydroxypropylβ-cyclodextrin is 1:2
25 parts of etoposide clathrates
(both part by weight is 20 parts to the compositions of lactose and sucrose
7.2:3.5)
15 parts of the groups of polyvinylpolypyrrolidone and cross-linking sodium carboxymethyl cellulose
Compound (both part by weight is 2.7:6.5)
2 parts of aspartames
11 parts of polymethacrylates
6 parts of ethyl celluloses
Preparation method is the same.
Embodiment 3
The described etoposide of embodiment 1 and hydroxypropylβ-cyclodextrin fully are ground in 50% ethanol form even mastic, after vacuum drying white powder, in the water of this powder solubility property more not the etoposide of enclose improved 12 times.
The comparative example 1
Etoposide clathrate: etoposide: hydroxypropylβ-cyclodextrin is 1:2
25 parts of etoposide clathrates
(both part by weight is 20 parts to the compositions of lactose and sucrose
1:1)
20 parts of the groups of polyvinylpolypyrrolidone and cross-linking sodium carboxymethyl cellulose
Compound (both part by weight is 2.7:6.5)
2 parts of aspartames
11 parts of polymethacrylates
6 parts of ethyl celluloses
Preparation method is the same.
The comparative example 2
Etoposide clathrate: etoposide: hydroxypropylβ-cyclodextrin is 1:2
25 parts of etoposide clathrates
(both part by weight is 20 parts to the compositions of lactose and sucrose
7.2:3.5)
20 parts of the groups of polyvinylpolypyrrolidone and cross-linking sodium carboxymethyl cellulose
Compound (both part by weight is 1:1)
2 parts of aspartames
11 parts of polymethacrylates
6 parts of ethyl celluloses
Preparation method is the same.
The comparative example 3
Etoposide clathrate: etoposide: hydroxypropylβ-cyclodextrin is 1:2
25 parts of etoposide clathrates
20 parts of starch
20 parts of the groups of polyvinylpolypyrrolidone and cross-linking sodium carboxymethyl cellulose
Compound (both part by weight is 2.7:6.5)
2 parts of aspartames
11 parts of polymethacrylates
6 parts of ethyl celluloses
Preparation method is the same.
The comparative example 4
Etoposide clathrate: etoposide: hydroxypropylβ-cyclodextrin is 1:2
25 parts of etoposide clathrates
(both part by weight is 20 parts to the compositions of lactose and sucrose
7.2:3.5)
20 parts of polyvinylpolypyrrolidone
2 parts of saccharin sodium
11 parts of polymethacrylates
6 parts of ethyl celluloses
Preparation method is the same.
The comparative example 5
Etoposide clathrate: etoposide: hydroxypropylβ-cyclodextrin is 1:2
25 parts of etoposide clathrates
(both part by weight is 20 parts to the compositions of lactose and sucrose
7.2:3.5)
20 parts of microcrystalline Cellulose
2 parts of aspartames
11 parts of polymethacrylates
6 parts of ethyl celluloses
Preparation method is the same.
The comparative example 6
Etoposide clathrate: etoposide: hydroxypropylβ-cyclodextrin is 1:2
25 parts of etoposide clathrates
20 parts of lactose
20 parts of microcrystalline Cellulose
2 parts of aspartames
Preparation method is the same.
The impact of different slow-release materials on etoposide clathrate granule
Prescription:
Etoposide clathrate: etoposide: hydroxypropylβ-cyclodextrin is 1:2
25 parts of etoposide clathrates
(both part by weight is 20 parts to the compositions of lactose and sucrose
7.2:3.5)
20 parts of the groups of polyvinylpolypyrrolidone and cross-linking sodium carboxymethyl cellulose
Compound (both part by weight is 2.7:6.5)
2 parts of saccharin sodium
11 parts of slow-release material A
6 parts of slow-release material B
Table 1
Test method: according to dissolution method (2010 editions two appendix XC the second methods of Chinese Pharmacopoeia), with 0.01mol/L hydrochloric acid solution 900ml as dissolution medium, rotating speed is 50 rev/mins, and operation is in accordance with the law measured granule at the stripping quantity of 1h, 6h and 12h according to ultraviolet visible spectrophotometry.
Can be found out to only have the combination of polymethacrylates and ethyl cellulose just can obtain desirable slow release effect as slow-release material by table 1 result; No matter other slow-release materials are compositions or single a kind of slow-release material of two kinds of slow-release materials, and slow release effect is all undesirable, and the extracorporeal releasing speed of group 2,5,6,7 is too slow, and the extracorporeal releasing speed of group 3,4,8 is too fast.
Etoposide slow-release granule dispersing uniformity and Their Dissolution Test in vitro
The Dissolution Rate Testing result shows: according to dissolution method (2010 editions two appendix XC the second methods of Chinese Pharmacopoeia), with 0.01mol/L hydrochloric acid solution 900ml as dissolution medium, rotating speed is 50 rev/mins, operation in accordance with the law, measure granule at the stripping quantity of 1h, 6h and 12h according to ultraviolet visible spectrophotometry, result is that the stripping of embodiment 1,2 sustained-release granular formulations is slow, even.The results are shown in following table 2.
Table 2 stripping percentage rate
Experimental data by table 1 and table 2 can find out, adopted the dissolution in vitro of the etoposide slow-release granule (embodiment 1 and embodiment 2) that specific adjuvant prepares optimum.
Etoposide slow-release granule stability test
To embodiment 1,2 and outward appearance, the content of the sustained-release granular formulation of comparative example 1-6 carried out factors influencing.
(1) hot test: get embodiment 1,2 and comparative example 1-6 sample be tiled in right amount in culture dish, the calorstat that is placed in 60 ℃ was placed 10 days, during this 0th, 5,10 day, taking sample determination respectively, measurement result sees Table 3.
(2) high wet test: sample thief is tiled in culture dish in right amount, placed under the condition of 25 ℃ of relative humidity RH90% ± 5% 10 days, and during this 0th, 5,10 day, taking sample determination respectively, measurement result sees Table 3.
(3) strong illumination test, sample thief is tiled in culture dish in right amount, is placed in the light cupboard the condition illumination of 4500Lx ± 500Lx 10 days, and during this 0th, 5,10 day, taking sample determination respectively, measurement result sees Table 3.
Hot and humid and the high light stability inferior of each embodiment sustained-release granular formulation of table 3.
the excipient type of selecting in comparative example 1 does not change, but part by weight in the compositions of lactose and sucrose both changes, the disintegrating agent type of selecting in comparative example 2 does not change, but part by weight in the compositions of polyvinylpolypyrrolidone and cross-linking sodium carboxymethyl cellulose both changes, in comparative example 3, excipient changes to starch, comparative example's 4 disintegrating agents change to single polyvinylpolypyrrolidone, in comparative example 5, disintegrating agent changes to microcrystalline Cellulose, in comparative example 6, excipient changes to lactose, disintegrating agent changes to microcrystalline Cellulose, without slow-release material.Experimental data by table 2 can be found out, in the identical situation of each composition consumption, no matter be that change has occured the adjuvant type, or the adjuvant type not have to change but has changed the usage ratio of component, and the stability of the etoposide slow-release granule for preparing (comparative example 1-6) is with respect to all significantly reductions of embodiment 1,2.