CN103142500B - Sustained-release particle of etoposide - Google Patents
Sustained-release particle of etoposide Download PDFInfo
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- CN103142500B CN103142500B CN201310092527.7A CN201310092527A CN103142500B CN 103142500 B CN103142500 B CN 103142500B CN 201310092527 A CN201310092527 A CN 201310092527A CN 103142500 B CN103142500 B CN 103142500B
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- etoposide
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- clathrate
- slow
- cyclodextrin
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Abstract
The invention relates to a sustained-release particle of etoposide. The etoposide is prepared into an inclusion compound, and then the inclusion compound is prepared into the sustained-release particle.
Description
Technical field
The application relates to a kind of sustained-release granular formulation, particularly, is etoposide clathrate slow-releasing granules.
Background technology
Etoposide (etoposide) is the carbohydrate metabolism product of podophyllotoxin (podophyllotoxin), belongs to cell cycle specific antitumor drug, is mainly used in treating small cell lung cancer, lymphatic cancer etc.But the absolute bioavailability of etoposide oral formulations only has 25%～75%.The poorly water-soluble of etoposide and to be decomposed into non-activity product in acid medium be the main cause that causes its oral formulations bioavailability low.
Etoposide mainly contains the dosage forms such as tablet, capsule, injection at present for clinical, and these dosage forms are poor at gastrointestinal tract dissolution, and bioavailability is not high.CN101259100A discloses a kind of etoposide preparations, wherein etoposide is prepared into phosphatide complexes, is then being prepared into the multiple dosage form such as tablet, capsule.But this preparation cost is high, bioavailability is low, can not be advantageously applied to clinical.
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 patient is difficult to adhere to for a long time.Meanwhile, because blood concentration fluctuation is large, and blood peak concentration is too high, often occurs the side effect that some are relevant with peak concentration.
The present invention takes inconvenience, shortcoming that bioavailability is low in order to solve existing etoposide preparations, invent etoposide clathrate slow-releasing granules, reduce medicining times, absorption rate slows down, extend biological half-life, blood drug level is controlled within the scope of effective blood drug concentration, 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.
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
Etoposide clathrate comprises active component and enclose material, and active component is etoposide, and enclose material is hydroxypropylβ-cyclodextrin.The part by weight of active component and enclose material is 3:1-1:3, preferably 1:2.Experiment showed, alpha-cyclodextrin, beta-schardinger dextrin-, the clathrate that the etoposide clathrate that 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 etoposide clathrate
| Enclose material | Dissolution velocity (min) | Stability | Inclusion rate |
| Alpha-cyclodextrin | 12 | Generally | 80% |
| Beta-schardinger dextrin- | 14 | Generally | 82% |
| 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 the two part by weight is 7.2:3.5, and disintegrating agent is the compositions of polyvinylpolypyrrolidone and cross-linking sodium carboxymethyl cellulose, and the two 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 is all applicable to preparing etoposide clathrate granule, select the etoposide clathrate granule that this specific adjuvant prepares to be better than in the effect of the aspects such as dissolution velocity, stability, dissolution 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, etoposide is reacted with hydroxypropylβ-cyclodextrin, gained solution, through extremely clarification of filtering with microporous membrane, is isolated to clathrate from mixture; Or
(2), with solid form, etoposide is reacted with hydroxypropylβ-cyclodextrin; Or
(3) etoposide reacts with hydroxypropylβ-cyclodextrin and carries out high energy milling.
Metering of the present invention is weight.
Preferably, the prescription of sustained-release granular formulation is (by weight):
25 parts of etoposide clathrates
(the two 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 (the two 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 writes out a prescription
Etoposide clathrate: etoposide: hydroxypropylβ-cyclodextrin is 1:2
25 parts of etoposide clathrates
(the two 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 (the two 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 etoposide clathrate:
(1) in water or aquiferous ethanol medium, by a certain percentage, etoposide is reacted with hydroxypropylβ-cyclodextrin, gained solution, through extremely clarification of filtering with microporous membrane, is isolated to clathrate from mixture; Or
(2), with solid form, etoposide is reacted with hydroxypropylβ-cyclodextrin; Or
(3) etoposide reacts with hydroxypropylβ-cyclodextrin and carries out high energy milling.
2. etoposide clathrate was pulverized to 100 mesh sieves, all the other adjuvants were pulverized to 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 DEG C are dry, obtain granule.
Embodiment 2 writes out a prescription
Etoposide clathrate: etoposide: hydroxypropylβ-cyclodextrin is 1:2
25 parts of etoposide clathrates
(the two 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 (the two 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
Etoposide described in embodiment 1 and hydroxypropylβ-cyclodextrin are fully ground to and form even mastic in 50% ethanol, after vacuum drying white powder, in the water of this powder solubility property more not the etoposide of enclose improved 12 times.
Comparative example 1
Etoposide clathrate: etoposide: hydroxypropylβ-cyclodextrin is 1:2
25 parts of etoposide clathrates
(the two 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 (the two 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.
Comparative example 2
Etoposide clathrate: etoposide: hydroxypropylβ-cyclodextrin is 1:2
25 parts of etoposide clathrates
(the two 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 (the two part by weight is 1:1)
2 parts of aspartames
11 parts of polymethacrylates
6 parts of ethyl celluloses
Preparation method is the same.
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 (the two 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.
Comparative example 4
Etoposide clathrate: etoposide: hydroxypropylβ-cyclodextrin is 1:2
25 parts of etoposide clathrates
(the two 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.
Comparative example 5
Etoposide clathrate: etoposide: hydroxypropylβ-cyclodextrin is 1:2
25 parts of etoposide clathrates
(the two 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.
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
(the two 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 (the two 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 annex XC the second methods of Chinese Pharmacopoeia), using 0.01mol/L hydrochloric acid solution 900ml as dissolution medium, rotating speed is 50 revs/min, and operation is in accordance with the law measured the stripping quantity of granule at 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, be 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
Dissolution Rate Testing result shows: according to dissolution method (2010 editions two annex XC the second methods of Chinese Pharmacopoeia), using 0.01mol/L hydrochloric acid solution 900ml as dissolution medium, rotating speed is 50 revs/min, operation in accordance with the law, measure the stripping quantity of granule at 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 optimum of the etoposide slow-release granule (embodiment 1 and embodiment 2) that specific adjuvant prepares.
Etoposide slow-release granule stability test
Outward appearance, the content of the sustained-release granular formulation to embodiment 1,2 and comparative example 1-6 have carried out factors influencing.
(1) hot test: get embodiment 1,2 and comparative example 1-6 sample is laid in culture dish in right amount, the calorstat that is placed in 60 DEG C is placed 10 days, during this 0th, 5,10 days, taking sample determination respectively, measurement result is in table 3.
(2) high wet test: sample thief is laid in culture dish is in right amount placed 10 days under the condition of 25 DEG C of relative humidity RH90% ± 5%, and during this 0th, 5,10 days, taking sample determination respectively, measurement result is in table 3.
(3) strong illumination test, sample thief is laid in culture dish in right amount, is placed in light cupboard the condition illumination of 4500Lx ± 500Lx 10 days, and during this 0th, 5,10 days, taking sample determination respectively, measurement result is in table 3.
Hot and humid and the high light stability inferior of the each embodiment sustained-release granular formulation of table 3.
The excipient type of selecting in comparative example 1 does not change, but in the compositions of lactose and sucrose, the part by weight of the two changes, the disintegrating agent type of selecting in comparative example 2 does not change, but in the compositions of polyvinylpolypyrrolidone and cross-linking sodium carboxymethyl cellulose, the part by weight of the two 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 occurred adjuvant type, or adjuvant type does not change but has changed the usage ratio of component, and the stability of the etoposide slow-release granule preparing (comparative example 1-6) all significantly reduces with respect to embodiment 1,2.
Claims (2)
1. a slow-releasing granules, is characterized in that: the component that comprises following weight portion:
Described excipient is the compositions of lactose and sucrose, the two part by weight is 7.2:3.5, described disintegrating agent is the compositions of polyvinylpolypyrrolidone and cross-linking sodium carboxymethyl cellulose, the two part by weight is 2.7:6.5, correctives is selected from saccharin sodium or aspartame, wherein etoposide in etoposide clathrate: hydroxypropylβ-cyclodextrin is 1:2.
2. slow-releasing granules as claimed in claim 1, is characterized in that: the component that comprises following weight portion:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310092527.7A CN103142500B (en) | 2013-03-21 | 2013-03-21 | Sustained-release particle of etoposide |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310092527.7A CN103142500B (en) | 2013-03-21 | 2013-03-21 | Sustained-release particle of etoposide |
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| CN103142500B true CN103142500B (en) | 2014-07-02 |
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| CN104173295B (en) * | 2014-09-10 | 2016-08-31 | 李淑兰 | Lincomycin slow-releasing granules |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101422478A (en) * | 2008-11-14 | 2009-05-06 | 李铁军 | Etoposide slow-release drop-pills and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101422478A (en) * | 2008-11-14 | 2009-05-06 | 李铁军 | Etoposide slow-release drop-pills and preparation method thereof |
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Address after: 266103 Qingdao economic and Technological Development Zone, unity Road, No. 3601, Shandong Applicant after: Qingdao Zhengda Haier Pharmaceutical Co., Ltd. Address before: 266103 Haier Road, Shandong, Qingdao, No. 1 Applicant before: Qingdao Zhengda Haier Pharmaceutical Co., Ltd. |
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Address after: 266103 3601 Tuen Jie Road, Qingdao economic and Technological Development Zone, Shandong Patentee after: Zhengda Pharmaceutical (Qingdao) Co., Ltd. Address before: 266103 3601 Tuen Jie Road, Qingdao economic and Technological Development Zone, Shandong Patentee before: Qingdao Zhengda Haier Pharmaceutical Co., Ltd. |