CN103142523B - Dropping pills containing etoposide - Google Patents
Dropping pills containing etoposide Download PDFInfo
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- CN103142523B CN103142523B CN201310092505.0A CN201310092505A CN103142523B CN 103142523 B CN103142523 B CN 103142523B CN 201310092505 A CN201310092505 A CN 201310092505A CN 103142523 B CN103142523 B CN 103142523B
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- China
- Prior art keywords
- etoposide
- drop pill
- clathrate
- cyclodextrin
- weight
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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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 40
- 229960005420 etoposide Drugs 0.000 title claims abstract description 40
- 239000006187 pill Substances 0.000 title claims abstract description 30
- 239000012530 fluid Substances 0.000 claims description 12
- 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 12
- 239000000203 mixture Substances 0.000 claims description 11
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 10
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 10
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 10
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 10
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 10
- 229940093429 polyethylene glycol 6000 Drugs 0.000 claims description 10
- 229940057995 liquid paraffin Drugs 0.000 claims description 9
- 229960000502 poloxamer Drugs 0.000 claims description 9
- 229920001983 poloxamer Polymers 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 8
- 239000003814 drug Substances 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- 230000000694 effects Effects 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
- 239000012982 microporous membrane Substances 0.000 description 2
- -1 polyoxyethylene monostearate Polymers 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007962 solid dispersion Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 229940008099 dimethicone Drugs 0.000 description 1
- 239000004205 dimethyl polysiloxane Substances 0.000 description 1
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- TZBAVQKIEKDGFH-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound [Cl-].C1=CC=C2SC(C(=O)NCC[NH+](CC)CC)=CC2=C1 TZBAVQKIEKDGFH-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical class 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 1
- 239000003600 podophyllotoxin derivative Substances 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to dropping pills, and in particular to dropping pills containing etoposide clathrate compounds.
Description
Technical field
The application relates to a kind of drop pill, particularly, is the drop pill that comprises etoposide clathrate.
Background technology
Drop pill has the following feature: 1, equipment simple, easy to operate, be beneficial to labor protection, process cycle is short, productivity ratio is high; 2, process conditions are easy to control, steady quality, and dosage is accurate, and heated time is short, and the volatile medicine of oxidizable and tool is dissolved in after substrate, can increase its stability; 3, to hold liquid drug amount large for substrate, therefore can make liquid drug solidify; 4, the drop pill of preparing with solid dispersion technology has the feature rapid, bioavailability is high that absorbs.
Clathrate has the following advantages: cover bad stink, reduce zest; Increase drug dissolution and bioavailability; Improve medicine stability.
Etoposide (etoposide) is a semi-synthetic podophyllotoxin derivative, has broad-spectrum anti-tumor activity, clinical acute leukemia, carcinoma of testis and the small cell lung cancer of being used for the treatment of.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.
Summary of the invention
The present invention, in order to solve existing etoposide preparations poor stability, shortcoming that bioavailability is low, has invented etoposide clathrate drop pill.
The application is first prepared into clathrate by etoposide, and then is prepared into drop pill, enclose and drop pill technology are united two into one, and the advantage of performance two aspects.
Etoposide clathrate comprises active component and enclose material, and active component is etoposide, and enclose material is alpha-cyclodextrin, beta-schardinger dextrin-, hydroxyl beta-schardinger dextrin-, one or more of hydroxypropylβ-cyclodextrin.The part by weight of active component and enclose material is 3:1-1:3.
The preparation method of etoposide clathrate comprises:
(1) in water or aquiferous ethanol medium, by a certain percentage, by etoposide and alpha-cyclodextrin, beta-schardinger dextrin-, hydroxyl beta-schardinger dextrin-, one or more reactions of hydroxypropylβ-cyclodextrin, gained solution, through extremely clarification of filtering with microporous membrane, is isolated to clathrate from mixture; Or
(2) with solid form, by etoposide and alpha-cyclodextrin, beta-schardinger dextrin-, hydroxyl beta-schardinger dextrin-, one or more reactions of hydroxypropylβ-cyclodextrin; Or
(3) etoposide and alpha-cyclodextrin, beta-schardinger dextrin-, hydroxyl beta-schardinger dextrin-, high energy milling is carried out in one or more reactions of hydroxypropylβ-cyclodextrin.
The above-mentioned etoposide clathrate preparing is crossed to 100-200 mesh sieve, be mixed into solid dispersion system with substrate and stabilizing agent, at 70 ± 5 ℃, splash into the condensed fluid of 0-20 ℃, adsorption condensing liquid, drop pill drying, to obtain final product.
The substrate of indication of the present invention comprises one or both the mixture such as polyethylene glycol 6000, Macrogol 4000, polyoxyethylene monostearate, sodium stearate, glycerin gelatine, poloxamer, stearic acid.
Applicant is surprised to find that, when substrate is selected the compositions of polyethylene glycol 6000 and poloxamer, and the part by weight of the two is while being 65:35, and the drop pill making becomes ball, roundness best.
The stabilizing agent of indication of the present invention comprises that phosphatic PH buffering is right, as sodium hydrogen phosphate and sodium dihydrogen phosphate; Dipotassium hydrogen phosphate and potassium dihydrogen phosphate.
The condensed fluid of indication of the present invention comprises condensed fluid dimethicone, liquid paraffin, Oleum Camelliae, vegetable oil etc.
Metering of the present invention is weight.
Embodiment 1
The prescription of drop pill is (by weight):
Etoposide clathrate (etoposide: hydroxypropylβ-cyclodextrin is 1:3) 4g
Compositions (part by weight of the two the is 65:35) 7.9g of polyethylene glycol 6000+poloxamer
Dipotassium hydrogen phosphate and potassium dihydrogen phosphate 0.1g
Condensed fluid is liquid paraffin.
Preparation method:
1. prepare by the following method etoposide clathrate:
(1) in water or aquiferous ethanol medium, in proportion, 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 100-200 mesh sieve; By even to polyethylene glycol 6000, poloxamer, dipotassium hydrogen phosphate and potassium dihydrogen phosphate ground and mixed, heating and melting on water-soluble, and mix; Etoposide clathrate is added in the fused mass of polyethylene glycol 6000, poloxamer, dipotassium hydrogen phosphate and potassium dihydrogen phosphate, mix, in impouring material fluid bath, keep 65-75 ℃ of temperature 10 minutes, above-mentioned medicinal liquid is splashed in the liquid paraffin of 0-20 ℃ and form drop pill, absorb condensed fluid, dry drop pill, packing.
Embodiment 2
The prescription of drop pill is (by weight):
Etoposide clathrate (etoposide: hydroxypropylβ-cyclodextrin is 1:3) 4g
Polyethylene glycol 6000 7.9g
Dipotassium hydrogen phosphate and potassium dihydrogen phosphate 0.1g
Condensed fluid is liquid paraffin.
Preparation method is the same.
Embodiment 3
The prescription of drop pill is (by weight):
Etoposide clathrate (etoposide: hydroxypropylβ-cyclodextrin is 1:3) 4g
Poloxamer 7.9g
Dipotassium hydrogen phosphate and potassium dihydrogen phosphate 0.1g
Condensed fluid is liquid paraffin.
Preparation method is the same.
Embodiment 4
The prescription of drop pill is (by weight):
Etoposide clathrate (etoposide: hydroxypropylβ-cyclodextrin is 1:3) 4g
Polyoxyethylene monostearate 7.9g
Dipotassium hydrogen phosphate and potassium dihydrogen phosphate 0.1g
Condensed fluid is liquid paraffin.
Preparation method is the same.
Matched group 1
The prescription of drop pill is (by weight):
Etoposide 4g
Polyethylene glycol 6000 7.9g
Dipotassium hydrogen phosphate and potassium dihydrogen phosphate 0.1g
Condensed fluid is liquid paraffin.
Preparation method is the same.
Matched group 2
The prescription of drop pill is (by weight):
Etoposide 4g
Poloxamer 7.9g
Dipotassium hydrogen phosphate and potassium dihydrogen phosphate 0.1g
Condensed fluid is liquid paraffin.
Preparation method is the same.
Etoposide clathrate drop pill experimental result
The method of pressing Chinese Pharmacopoeia (2000 editions) detects smooth rounding rate and the dissolve scattered time limit of drop pill, the results are shown in Table 1.
Table 1
| Group | Smooth rounding rate (%) | Dissolve scattered time limit (min) |
| Embodiment 1 | 97.52 | 2.8 |
| Embodiment 2 | 96.11 | 3.0 |
| Embodiment 3 | 95.42 | 2.8 |
| Embodiment 4 | 92.26 | 3.0 |
| Matched group 1 | 82.37 | 5.3 |
| Matched group 2 | 78.95 | 6.1 |
Result shows, etoposide clathrate drop pill provided by the invention meets the regulation of Chinese Pharmacopoeia (2000 editions) about drop pill.And according to polyethylene glycol 6000: poloxamer part by weight is that clathrate drop pill prepared by 65:35 has more excellent effect with respect to drop pill and the non-clathrate drop pill of non-this special ratios.
Claims (1)
1. an etoposide drop pill, is characterized in that: the prescription of drop pill is by weight:
Etoposide clathrate 4g
The compositions 7.9g of polyethylene glycol 6000+poloxamer
Dipotassium hydrogen phosphate and potassium dihydrogen phosphate 0.1g
Condensed fluid is liquid paraffin, wherein etoposide in etoposide clathrate: hydroxypropylβ-cyclodextrin weight ratio is 1: 3, and in the compositions of polyethylene glycol 6000+poloxamer, the part by weight of the two is 65: 35.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310092505.0A CN103142523B (en) | 2013-03-21 | 2013-03-21 | Dropping pills containing etoposide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310092505.0A CN103142523B (en) | 2013-03-21 | 2013-03-21 | Dropping pills containing etoposide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103142523A CN103142523A (en) | 2013-06-12 |
| CN103142523B true CN103142523B (en) | 2014-06-25 |
Family
ID=48541039
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310092505.0A Active CN103142523B (en) | 2013-03-21 | 2013-03-21 | Dropping pills containing etoposide |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103142523B (en) |
-
2013
- 2013-03-21 CN CN201310092505.0A patent/CN103142523B/en active Active
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》.2011,第31卷(第11期),第2103页右栏第3行至第5行，第2104页第2.4栏和第3.1栏. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103142523A (en) | 2013-06-12 |
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| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information |
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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| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 266103 3601 Tuen Jie Road, Qingdao economic and Technological Development Zone, Shandong Patentee after: CP 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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| CP01 | Change in the name or title of a patent holder | ||
| CP03 | Change of name, title or address |
Address after: No.3601 Tuanjie Road, Qingdao Economic and Technological Development Zone, Shandong Province 266426 Patentee after: Qingdao Guoxin Pharmaceutical Co.,Ltd. Country or region after: China Address before: No. 3601 Tuanjie Road, Qingdao Economic and Technological Development Zone, Shandong Province Patentee before: CP PHARMACEUTICAL (QINGDAO) Co.,Ltd. Country or region before: China |
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