CN103142545A - Enteric capsule of etoposide - Google Patents
Enteric capsule of etoposide Download PDFInfo
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- CN103142545A CN103142545A CN2013100925012A CN201310092501A CN103142545A CN 103142545 A CN103142545 A CN 103142545A CN 2013100925012 A CN2013100925012 A CN 2013100925012A CN 201310092501 A CN201310092501 A CN 201310092501A CN 103142545 A CN103142545 A CN 103142545A
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- etoposide
- clathrate
- enteric coated
- coated capsule
- cyclodextrin
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Abstract
The invention relates to an enteric capsule of etoposide. The etoposide is prepared into an inclusion compound, and then the inclusion compound is prepared into the enteric capsule.
Description
Technical field
The application relates to a kind of enteric coated capsule, particularly, is etoposide clathrate enteric coated capsule.
Background technology
Etoposide (etoposide) is the carbohydrate metabolism product of podophyllotoxin (podophyllotoxin), belongs to the 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 reaches and be decomposed into the non-activity product in acid medium is 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 relatively poor at the gastrointestinal tract dissolution, and bioavailability is not high.CN101259100A discloses a kind of etoposide preparations, wherein etoposide is prepared into phosphatide complexes, and then is prepared into the multiple dosage forms such as tablet, capsule.Yet this preparation cost is high, bioavailability is low, can not be advantageously applied to clinical.
Summary of the invention
The present invention has invented etoposide clathrate enteric coated capsule in order to solve the existing low shortcoming of etoposide preparations bioavailability.
Clathrate has the following advantages: cover bad stink, reduce zest; Increase drug dissolution and bioavailability; Improve medicine stability.
The applicant finds, now etoposide is prepared into clathrate, then is prepared into enteric coated capsule in conjunction with specific adjuvant, has advantages of that stability is high, disintegration rate is fast and bioavailability is high.
The application provides a kind of enteric coated capsule of etoposide, comprising:
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 disintegration rate, stability, dissolutions 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 enteric coated capsule.Wherein said diluent is the compositions of lactose and microcrystalline Cellulose, both part by weight is 7.3:2.5, lubricant is the compositions of polyvinylpolypyrrolidone and magnesium stearate, both part by weight is 1.5:5.5, enteric coating material is the compositions of HP-55 and CAP, and both part by weight is 1:5.Experimental results show that, be not that the conventional adjuvant of any pharmacy all is fit to preparation etoposide clathrate enteric coated capsule, select the effect of etoposide clathrate enteric coated capsule at aspects such as dissolution velocity, stability, dissolutions that this specific adjuvant prepares to be better than the etoposide clathrate enteric coated capsule 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 enteric coated capsule is (by weight):
The preparation method of capsule: 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 get final product the granule that the makes hungry area softgel shell of packing into.
Embodiment 1 prescription
Etoposide clathrate: etoposide: hydroxypropylβ-cyclodextrin is 1:2
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 get final product the granule that the makes hungry area softgel shell of packing into.
Embodiment 2 prescriptions
Etoposide clathrate: etoposide: hydroxypropylβ-cyclodextrin is 1:2
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
Preparation method is the same.
The comparative example 2
Etoposide clathrate: etoposide: hydroxypropylβ-cyclodextrin is 1:2
Preparation method is the same.
The comparative example 3
Etoposide clathrate: etoposide: hydroxypropylβ-cyclodextrin is 1:2
Preparation method is the same.
The comparative example 4
Etoposide clathrate: etoposide: hydroxypropylβ-cyclodextrin is 1:2
Preparation method is the same.
The comparative example 5
Etoposide clathrate: etoposide: hydroxypropylβ-cyclodextrin is 1:2
Preparation method is the same.
The comparative example 6
Etoposide clathrate: etoposide: hydroxypropylβ-cyclodextrin is 1:2
Preparation method is the same.
The impact of different enteric coating materials on the etoposide enteric coated capsule
Test method: the etoposide enteric coated capsule that different enteric coating materials prepare is measured dissolution rate respectively in simulated gastric fluid environment and simulation intestinal environment.The results are shown in Table 1.
Prescription:
Etoposide clathrate: etoposide: hydroxypropylβ-cyclodextrin is 1:2
Table 1
Can be found out by table 1 data, only have and adopt the compositions of HP-55 and CAP almost insoluble in the simulated gastric fluid environment as group 1 enteric coated capsule (being embodiment 1) of enteric coating material, almost all strippings in the simulation intestinal environment; And the enteric coated capsule that other enteric coating materials prepare dissolution rate in the simulated gastric fluid environment is larger, can not make capsule safety stomach and to intestinal disintegrate again.Therefore, what the application's enteric coated capsule adopted is specific enteric coating adjuvant, and the enteric coating adjuvant of other types is not suitable for being prepared into etoposide clathrate enteric coated capsule.
Etoposide enteric coated capsule stability test
To embodiment 1,2 and outward appearance, dissolution, content and the dissolution time of the enteric coated capsule 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 2.
(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 2.
(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 2.
Hot and humid and the high light stability inferior of each embodiment enteric coated capsule of table 2.
the diluent type of selecting in comparative example 1 does not change, but part by weight in the compositions of lactose and microcrystalline Cellulose both changes, the lubricant type of selecting in comparative example 2 does not change, but part by weight in the compositions of polyvinylpolypyrrolidone and magnesium stearate both changes, in comparative example 3, diluent changes to starch, comparative example's 4 lubricants change to single polyvinylpolypyrrolidone, in comparative example 5, lubricant changes to Pulvis Talci, in comparative example 6, diluent changes to lactose, lubricant changes to micropowder silica gel.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 enteric coated capsule for preparing (comparative example 1-6) is with respect to all significantly reductions of embodiment 1,2.
Claims (5)
1. enteric coated capsule, wherein active component is etoposide.
2. enteric coated capsule as claimed in claim 1, wherein etoposide is clathrate, and the enclose material is hydroxypropylβ-cyclodextrin, and the part by weight of etoposide and enclose material is 3:1-1:3.
3. enteric coated capsule as claimed in claim 2, comprising:
4. enteric coated capsule as claimed in claim 3, wherein said diluent is the compositions of lactose and microcrystalline Cellulose, both part by weight is 7.3:2.5, lubricant is the compositions of polyvinylpolypyrrolidone and magnesium stearate, both part by weight is 1.5:5.5, enteric coating material is the compositions of HP-55 and CAP, and both part by weight is 1:5.
5. enteric coated capsule as claimed in claim 4, wherein etoposide in the etoposide clathrate: hydroxypropylβ-cyclodextrin is 1:2,
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310092501.2A CN103142545B (en) | 2013-03-21 | 2013-03-21 | Enteric capsule of etoposide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310092501.2A CN103142545B (en) | 2013-03-21 | 2013-03-21 | Enteric capsule of etoposide |
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| Publication Number | Publication Date |
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| CN103142545A true CN103142545A (en) | 2013-06-12 |
| CN103142545B CN103142545B (en) | 2014-05-21 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201310092501.2A Active CN103142545B (en) | 2013-03-21 | 2013-03-21 | Enteric capsule of etoposide |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110934843A (en) * | 2019-12-11 | 2020-03-31 | 正大制药（青岛）有限公司 | Frovatriptan succinate tablet and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003095498A1 (en) * | 2002-05-10 | 2003-11-20 | Yunqing Liu | Complex of organic medicines and beta-cyclodextrin derivatives and its preparing process |
| 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 |
-
2013
- 2013-03-21 CN CN201310092501.2A patent/CN103142545B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003095498A1 (en) * | 2002-05-10 | 2003-11-20 | Yunqing Liu | Complex of organic medicines and beta-cyclodextrin derivatives and its preparing process |
| 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 (1)
| Title |
|---|
| 孙鹤文等: "中等取代度的羟丙基-β-环糊精对依托泊苷的包埋特性分析", 《药物分析杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110934843A (en) * | 2019-12-11 | 2020-03-31 | 正大制药（青岛）有限公司 | Frovatriptan succinate tablet and preparation method thereof |
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| Publication number | Publication date |
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| CN103142545B (en) | 2014-05-21 |
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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. |
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