CN103142545B - Enteric capsule of etoposide - Google Patents
Enteric capsule of etoposide Download PDFInfo
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- CN103142545B CN103142545B CN201310092501.2A CN201310092501A CN103142545B CN 103142545 B CN103142545 B CN 103142545B CN 201310092501 A CN201310092501 A CN 201310092501A CN 103142545 B CN103142545 B CN 103142545B
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- etoposide
- clathrate
- cyclodextrin
- hydroxypropylβ
- enteric coated
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- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 title claims abstract description 62
- 229960005420 etoposide Drugs 0.000 title claims abstract description 62
- 239000002775 capsule Substances 0.000 title claims abstract description 29
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 16
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 6
- 239000008101 lactose Substances 0.000 claims description 4
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 claims description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 3
- 235000019359 magnesium stearate Nutrition 0.000 claims description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 3
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 abstract 2
- 230000000052 comparative effect Effects 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 13
- 239000002671 adjuvant Substances 0.000 description 11
- 238000004090 dissolution Methods 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- 239000002702 enteric coating Substances 0.000 description 7
- 238000009505 enteric coating Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000000314 lubricant Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 2
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 2
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000010316 high energy milling Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000012982 microporous membrane Substances 0.000 description 2
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 2
- 229960001237 podophyllotoxin Drugs 0.000 description 2
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000004088 simulation Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000023852 carbohydrate metabolic process Effects 0.000 description 1
- 235000021256 carbohydrate metabolism Nutrition 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 239000013521 mastic Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
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- Medicinal Preparation (AREA)
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 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, and then is 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
The present invention, in order to solve the low shortcoming of existing etoposide preparations bioavailability, has invented etoposide clathrate enteric coated capsule.
Clathrate has the following advantages: cover bad stink, reduce zest; Increase drug dissolution and bioavailability; Improve medicine stability.
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:
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 disintegration rate, stability, dissolutions 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 enteric coated capsule.Wherein said diluent is the compositions of lactose and microcrystalline Cellulose, the two part by weight is 7.3:2.5, lubricant is the compositions of polyvinylpolypyrrolidone and magnesium stearate, the two part by weight is 1.5:5.5, enteric coating material is the compositions of HP-55 and CAP, and the two part by weight is 1:5.Experimental results show that, be not that the conventional adjuvant of any pharmacy is all applicable to preparing etoposide clathrate enteric coated capsule, select the etoposide clathrate enteric coated capsule that this specific adjuvant prepares to be better than in the effect of the aspects such as dissolution velocity, stability, dissolution 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, 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 enteric coated capsule is (by weight):
The preparation method of capsule: 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 ℃ are dry, pack the granule making into hungry area softgel shell.
Embodiment 1 writes out a prescription
Etoposide clathrate: etoposide: hydroxypropylβ-cyclodextrin is 1:2
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 ℃ are dry, pack the granule making into hungry area softgel shell.
Embodiment 2 writes out a prescription
Etoposide clathrate: etoposide: hydroxypropylβ-cyclodextrin is 1:2
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
Preparation method is the same.
Comparative example 2
Etoposide clathrate: etoposide: hydroxypropylβ-cyclodextrin is 1:2
Preparation method is the same.
Comparative example 3
Etoposide clathrate: etoposide: hydroxypropylβ-cyclodextrin is 1:2
Preparation method is the same.
Comparative example 4
Etoposide clathrate: etoposide: hydroxypropylβ-cyclodextrin is 1:2
Preparation method is the same.
Comparative example 5
Etoposide clathrate: etoposide: hydroxypropylβ-cyclodextrin is 1:2
Preparation method is the same.
Comparative example 6
Etoposide clathrate: etoposide: hydroxypropylβ-cyclodextrin is 1:2
Preparation method is the same.
The impact of different enteric coating materials on etoposide enteric coated capsule
Test method: the etoposide enteric coated capsule that different enteric coating materials are prepared 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 simulated gastric fluid environment as group 1 enteric coated capsule (being embodiment 1) of enteric coating material, almost all strippings in simulation intestinal environment; And the enteric coated capsule that other enteric coating materials prepare dissolution rate in 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
Outward appearance, dissolution, content and the dissolution time of the enteric coated capsule 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 ℃ is placed 10 days, during this 0th, 5,10 days, taking sample determination respectively, measurement result is in table 2.
(2) high wet test: sample thief is laid in culture dish is in right amount placed 10 days under the condition of 25 ℃ of relative humidity RH90% ± 5%, and during this 0th, 5,10 days, taking sample determination respectively, measurement result is in table 2.
(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 2.
Hot and humid and the high light stability inferior of the each embodiment enteric coated capsule of table 2.
The diluent type of selecting in comparative example 1 does not change, but in the compositions of lactose and microcrystalline Cellulose, the part by weight of the two changes, the lubricant type of selecting in comparative example 2 does not change, but in the compositions of polyvinylpolypyrrolidone and magnesium stearate, the part by weight of the two 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 occurred adjuvant type, or adjuvant type does not change but has changed the usage ratio of component, and the stability of the etoposide enteric coated capsule preparing (comparative example 1-6) all significantly reduces with respect to embodiment 1,2.
Claims (1)
1. an etoposide enteric coated capsule, is characterized in that: comprise following weight portion composition:
The two part by weight of described lactose and microcrystalline Cellulose is 7.3:2.5, the two part by weight of described polyvinylpolypyrrolidone and magnesium stearate is 1.5:5.5, the two part by weight of described HP-55 and CAP is 1:5, wherein etoposide in etoposide clathrate: hydroxypropylβ-cyclodextrin weight ratio 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 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103142545A CN103142545A (en) | 2013-06-12 |
| CN103142545B true CN103142545B (en) | 2014-05-21 |
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|---|---|---|---|
| CN201310092501.2A Active CN103142545B (en) | 2013-03-21 | 2013-03-21 | Enteric capsule of etoposide |
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| CN110934843A (en) * | 2019-12-11 | 2020-03-31 | 正大制药（青岛）有限公司 | A kind of furotriptan succinate tablet and preparation method thereof |
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 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1232539C (en) * | 2002-05-10 | 2005-12-21 | 刘云清 | Match of organic medicine and beta-cyclodextrin derivative and its preparing process |
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Patent 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 |
Non-Patent Citations (2)
| Title |
|---|
| 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;孙鹤文等;《药物分析杂志》;20111231;第31卷(第11期);第2103-2107页 * |
| 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》.2011,第31卷(第11期),第2103-2107页. |
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