CN103816159A - Tegafur gimeracil oteracil potassium capsule and preparation method thereof - Google Patents
Tegafur gimeracil oteracil potassium capsule and preparation method thereof Download PDFInfo
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- CN103816159A CN103816159A CN201410105459.8A CN201410105459A CN103816159A CN 103816159 A CN103816159 A CN 103816159A CN 201410105459 A CN201410105459 A CN 201410105459A CN 103816159 A CN103816159 A CN 103816159A
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Abstract
The invention discloses a tegafur gimeracil oteracil potassium capsule and a preparation method thereof. The tegafur gimeracil oteracil potassium capsule comprises the following components: tegafur, potassiumoxonate, gimeracil, poloxamer and a lubricating agent. The capsule can be rapidly dissolved, and the preparation method of the capsule is simple to operate and suitable for industrial production.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of for lucky capsule difficult to understand and preparation method thereof.
Background technology
Ftorafur (FT, FT207) is one of miazines anticarcinogen, and it is the prodrug of 5-fluorouracil (5-FU), and most solid tumors are had to inhibitory action.Competent biosynthesis of disturbing blocking dna, RHA and protein in vivo, thus its antitumaous effect produced.Prove by medical basic research and clinical observation, ftorafur toxic and side effects is little, and chemotherapeutic index is higher, on immunosuppressive action and also less on the impact about immune internal organs, be can be clinically the safe drugs of use continuously.After this product is oral, through gastrointestinal absorption, within 1-3 hour, blood level reaches summit.Last longer than intravenously administrable, therefore can bring into play its good therapeutic effect.Be mainly used in gastric cancer, cancer of bile ducts, rectal cancer, colon cancer, cancer of pancreas, hepatocarcinoma, breast carcinoma, pulmonary carcinoma and incidence cancer.In addition, to preventing that recurrence after operation, transfer from having certain curative effect.The topmost untoward reaction of ftorafur is symptom of digestive tract, bone marrow depression and neurotoxicity etc.This product is Fluorouracil derivative, in vitro without antitumor action, mainly changes fluorouracil into and works through liver in vivo.Its effect is identical with fluorouracil, chemotherapeutic index is fluorouracil 2 times.
Gimeracil (CDHP) and oteracil potassium (OXO) use and there is no obvious active anticancer separately respectively, and they combine use with ftorafur be in order to improve curative effect and to reduce toxicity.The effect of CDHP is the anticancer therapeutic for improving FT, when FT is oral enter in body after, first under the catalysis of liver P450 activating enzymes, be transformed into 5-FU, afterwards except 10% left and right enters intestinal and produce phosphorylation under orotic acid ribose transferring enzyme (ORTC) catalysis, the 5-FU of all the other 90% left and right is under the catalysis of liver dihydropyrimidine dehydrogenase (DPD), and the approach that follows 5-FU is transformed into triphosphoric acid floxuridine (FUTP) and two activated product performance antitumaous effects of a phosphoric acid doxifluridine (FdUMP).So DPD is the main rate-limiting enzyme of 5-FU degraded, DPD activity is depended in the maintenance of its blood plasma 5-FU level.CDHP is the reversible inhibitor of DPD.Through comparing, the effect that CDHP suppresses DPD activity is 180 times of uracil, thereby can effectively suppress the degraded of 5-FU.Experiment showed, as CDHP: when FT coordinates with 0.4: 1 (M), can make 5-FU effect level in tumor tissues keep more than 12 hours, can not make again the toxicity of intestinal increase.The Main Function of oteracil potassium is the activity that suppresses the ORTC of small intestine.In the metabolic process of ftorafur, there is the 5-FU of 10% left and right to enter intestinal tissue, under the catalysis of orotic acid ribose transferring enzyme, produce phosphorylation, this process is considered to produce the main cause of intestinal toxic and side effects.The another one outstanding feature of OXO be oral enter in body after, the overwhelming majority is distributed in small intestinal cell surface, enters blood circulation, tumor tissues and other normal structures while only having few part.Therefore, OXO mainly suppresses the effect of 5-FU phosphorylation in small intestine, can in tumor tissues, not affect the activity of 5-FU.In the time that OXO: FT (M) is 1: 1, can keep higher tumor killing effect, reduction intestinal toxicity that again can be by a relatively large margin.
Ftorafur is slightly molten in water, and gimeracil is soluble,very slightly in water, and oteracil potassium is slightly soluble in water, but clinical requirement medicine Fast Stripping, onset rapidly, this just requires to adopt suitable prescription and technique to improve medicine in preparation production.
CN101574326B the present invention relates to a kind of capsule preparations containing ftorafur, gimeracil and oteracil potassium and preparation method thereof, it is characterized in that this capsule preparations contains ftorafur micropill, gimeracil micropill and oteracil potassium micropill.But prepare pellet preparations, technique is comparatively complicated, large production difficulty is large, and three kinds of piller particle diameters, density are all variant, capsule charge process, and content uniformity is difficult to guarantee.
CN102614183A the present invention relates to a kind of oral formulations that contains ftorafur, gimeracil and oteracil potassium, the active component that contains following granularity: ftorafur≤180 μ m, gimeracil≤150 μ m, oteracil potassium≤150 μ m, further preferred, particle diameter≤20 μ the m of described ftorafur, particle diameter≤3 μ the m of gimeracil, the particle diameter≤3 μ m of oteracil potassium.Although do not contain surfactant in preparation, added disintegrating agent.Due to the easy moisture absorption of disintegrating agent, and cause the degraded of medicine, micronization technology simultaneously, dust is large, is unfavorable for labor protection.
CN102302499A discloses a kind of capsule preparations containing ftorafur, gimeracil and oteracil potassium, and this invention has improved for lucky dissolution difficult to understand, for guaranteeing Fast Stripping, add surfactant, consumption reaches 0.9-5mg/ grain, has increased GI irritation, reduces patient's compliance.
CN101574326A discloses a kind of for lucky capsule preparations difficult to understand and preparation method thereof, this invention has improved for lucky stability difficult to understand, but the dissolution of medicine does not improve, for guaranteeing Fast Stripping, added a large amount of surfactants, minimum amount reaches 10mg/ grain, larger to GI irritation, adopt coating of pellets technology, Workshop Production complex process simultaneously.
CN103211820A preparation method for lucky capsule difficult to understand, inventor is dissolved in ftorafur in methanol, gimeracil is dissolved in hydrochloric acid solution, oteracil potassium is dissolved in sodium hydroxide solution, then after three kinds of solution being mixed rapidly, add fast microcrystalline Cellulose and stir, slow cooling to 4 ℃ left and right, obtains being attached to the nano-grade medicine on microcrystalline Cellulose simultaneously; Dry medicine-containing particle; In dry granule, add lubricant, mix homogeneously, incapsulates.Utilize acid-base neutralization and nanocrystal technology to prepare nano-grade medicine, to improve dissolution.But used a large amount of solvents, and industrialization difficulty.
Summary of the invention
In view of the deficiencies in the prior art, it is a kind of for lucky capsule preparations difficult to understand and preparation method thereof that the present invention intends providing, described rapid for lucky capsule preparations stripping difficult to understand, this preparation method suitability for industrialized production simple to operate, applicable.
The present invention is achieved through the following technical solutions:
A kind of for lucky capsule difficult to understand, comprise following component: ftorafur, oteracil potassium, gimeracil, poloxamer, lubricant.
Wherein, the weight ratio of gimeracil and poloxamer is preferably 1:2-4.
Described capsule can also comprise Methyl flamprop, and the weight ratio of gimeracil and Methyl flamprop is 1:2-4.
Described lubricant is one or more in magnesium stearate, sodium stearyl fumarate, Pulvis Talci, preferably sodium stearyl fumarate.
The described preparation method for lucky capsule difficult to understand, comprises the steps: poloxamer heating and melting, adds gimeracil, be stirred to dissolve, take this solution as binding agent, on ftorafur, the mixed powder of oteracil potassium, granulate, dry, add lubricant, after mix homogeneously, be filled into capsule.In mixed powder pelletization, also can add Methyl flamprop.
In this invention, the creationary poloxamer that utilizes of inventor, as solubilizing agent, is dissolved in gimeracil in the fused solution of poloxamer, then on oteracil potassium and the mixed powder of ftorafur, granulate, not only reduced supplementary product kind, and drug-eluting is rapid, production process is smooth.
Compared with prior art, the present invention has following beneficial effect:
(1) substantially without dust, be conducive to labor protection;
(2) drug-eluting is rapid, 5min stripping completely;
(3) surfactant-free and disintegrating agent, ensures drug safety.
The specific embodiment
It will be appreciated that; for those skilled in the art; in enforcement of the present invention, clearly and can be easy to make and not deviate from other embodiment and the modification of scope and the aim of the invention described above, be all included in protection scope of the present invention.Therefore the scope that, should not be construed as claims is limited in following examples.
Embodiment 1
Preparation technology:
50 ℃ of heating and meltings of poloxamer, gimeracil joins in this fused solution, then on oteracil potassium and the mixed powder of ftorafur, granulates, finally mix homogeneously with magnesium stearate, capsule charge.
Embodiment 2
Preparation technology:
50 ℃ of heating and meltings of poloxamer, gimeracil joins in this fused solution, then on oteracil potassium and the mixed powder of ftorafur, granulates, finally mix homogeneously with sodium stearyl fumarate, capsule charge.
Embodiment 3
Preparation technology:
50 ℃ of heating and meltings of poloxamer, gimeracil joins in this fused solution, then on oteracil potassium and the mixed powder of ftorafur, granulates, finally mix homogeneously with sodium stearyl fumarate, capsule charge.
Embodiment 4
Preparation technology:
50 ℃ of heating and meltings of poloxamer, gimeracil joins in this fused solution, then on the mixed powder of oteracil potassium, Methyl flamprop and ftorafur, granulates, finally mix homogeneously with sodium stearyl fumarate, capsule charge.
Embodiment 5
Preparation technology:
50 ℃ of heating and meltings of poloxamer, gimeracil joins in this fused solution, then on the mixed powder of oteracil potassium, Methyl flamprop and ftorafur, granulates, finally mix homogeneously with sodium stearyl fumarate, capsule charge.
Comparative example 1
Preparation technology:
Recipe quantity takes ftorafur, gimeracil, oteracil potassium, is added to the water, and stirs, add in ball mill, grind 120min, suspension is sprayed in the fluid bed that adds sucrose dry, the dry thing of spraying is mixed homogeneously with magnesium stearate, filling and get final product on capsule filler.
Comparative example 2
Preparation technology:
Recipe quantity takes ftorafur, gimeracil, oteracil potassium, adds in ball mill, grinds 120min, obtains mixture, mixture is mixed homogeneously with sucrose, the magnesium stearate of mistake 100 mesh sieves, and filling and get final product on capsule filler.
Comparative example 3
Preparation technology:
Recipe quantity takes ftorafur, gimeracil, oteracil potassium, comminution by gas stream respectively, D90<3 μ m.Then with cross the sucrose of 100 mesh sieves, mix homogeneously, adds water appropriate, granulates, dry, dry granule is mixed homogeneously with magnesium stearate, filling and get final product on capsule filler.
Comparative example 4
Preparation technology:
Take lactose, add in the water of recipe quantity, stir, dissolve; Recipe quantity takes ftorafur, gimeracil, oteracil potassium, adds in lactose aqueous solution, stirs, and adds in ball mill, grinds 120min, grind size measurement result, D90<130nm.It is dry that suspension is sprayed, will spray to be dried thing and to mix homogeneously with magnesium stearate, and filling and get final product on capsule filler.
Comparative example 5
Preparation technology:
Recipe quantity takes poloxamer, gimeracil, oteracil potassium, ftorafur mix homogeneously, adds pure water appropriate, granulates, and is dried and finally mixs homogeneously with sodium stearyl fumarate, capsule charge.
Comparative example 6
Preparation technology:
50 ℃ of heating and meltings of polyoxyl stearate, gimeracil joins in this fused solution, then on oteracil potassium and the mixed powder of ftorafur, granulates, finally mix homogeneously with sodium stearyl fumarate, capsule charge.
Checking embodiment
Adopt dissolution method (two appendix XC first methods of Chinese Pharmacopoeia version in 2010), take aqueous solution as dissolution medium, rotating speed is 50 revs/min, temperature is 37 ± 0.5 ℃ of operations in accordance with the law, in the time of 15 minutes, and draw solution 10ml, membrane filtration by solution with 0.22 μ m, adopt the dissolution of high effective liquid chromatography for measuring for gimeracil in lucky capsule difficult to understand, limit is labelled amount 85%, and stripping the results are shown in following table.
Table dissolution determination result
| Embodiment | 5min dissolution (%) | 15min dissolution (%) |
| Embodiment 1 | 99.9 | 99.9 |
| Embodiment 2 | 99.2 | 100.1 |
| Embodiment 3 | 98.8 | 98.9 |
| Embodiment 4 | 99.8 | 100.1 |
| Embodiment 5 | 99.9 | 100.0 |
| Comparative example 1 | 54.2 | 87.2 |
| Comparative example 2 | 48.9 | 86.5 |
| Comparative example 3 | 50.6 | 87.1 |
| Comparative example 4 | 56.6 | 90.2 |
| Comparative example 5 | 46.3 | 83.2 |
| Comparative example 6 | 52.1 | 87.8 |
It can be seen from the table, embodiment of the present invention 1-5, stripping is rapid, the basic stripping completely of 5min; Comparative example 1, and the dry rear medicine that grinds, sprays has gathering, therefore stripping is poor; Comparative example 2, and raw material adopts dry grinding, and medicine is easily assembled, and mix with sucrose is common after grinding, and are difficult to be dispersed in sucrose surface, and stripping is poor; Comparative example 3, and flow of feed gas is mixed with sucrose after pulverizing, wet granulation, and after granulating, drug particles can become again greatly, and therefore stripping is poor; Comparative example 4, replace sucrose with lactose, but lactose dissolution velocity in water is fast not as sucrose, and osmotic pressure is relevant not as sucrose height, therefore causes stripping result not as embodiment; Comparative example 5, do not prepare poloxamer, gimeracil dispersion, therefore stripping is poor; Comparative example 6, use solubilizing agent polyoxyl stearate instead, and solubilizing effect is bad.
Above result, has further verified superiority of the present invention.
Claims (9)
1. for a lucky capsule difficult to understand, it is characterized in that, comprise following component: ftorafur, oteracil potassium, gimeracil, poloxamer, lubricant.
2. according to claim 1 for lucky capsule difficult to understand, it is characterized in that, the weight ratio of gimeracil and poloxamer is 1:2-4.
3. according to claim 1 for lucky capsule difficult to understand, it is characterized in that, described capsule can also comprise Methyl flamprop.
4. according to claim 3 for lucky capsule difficult to understand, it is characterized in that, the weight ratio of gimeracil and Methyl flamprop is 1:2-4.
5. according to claim 1 for lucky capsule difficult to understand, it is characterized in that, lubricant is magnesium stearate, sodium stearyl fumarate, Pulvis Talci.
6. according to claim 1 for lucky capsule difficult to understand, it is characterized in that, lubricant is sodium stearyl fumarate.
7. the preparation method for lucky capsule difficult to understand according to claim 1, it is characterized in that comprising the steps: poloxamer heating and melting, add gimeracil, be stirred to dissolve, take this solution as binding agent, on ftorafur, the mixed powder of oteracil potassium, granulate, dry, add lubricant, after mix homogeneously, be filled into capsule.
8. the preparation method for lucky capsule difficult to understand according to claim 3, it is characterized in that comprising the steps: poloxamer heating and melting, add gimeracil, be stirred to dissolve, take this solution as binding agent, on ftorafur, Methyl flamprop, the mixed powder of oteracil potassium, granulate, dry, add lubricant, after mix homogeneously, be filled into capsule.
9. the preparation method for lucky capsule difficult to understand, it is characterized in that comprising the steps: poloxamer heating and melting, add gimeracil, be stirred to dissolve, take this solution as binding agent, on ftorafur, the mixed powder of oteracil potassium, granulate, dry, add lubricant, after mix homogeneously, be filled into capsule.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410105459.8A CN103816159B (en) | 2014-03-20 | 2014-03-20 | A kind of for lucky capsule difficult to understand and preparation method thereof |
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| CN201410105459.8A CN103816159B (en) | 2014-03-20 | 2014-03-20 | A kind of for lucky capsule difficult to understand and preparation method thereof |
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| CN103816159A true CN103816159A (en) | 2014-05-28 |
| CN103816159B CN103816159B (en) | 2016-04-13 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106420759A (en) * | 2016-11-03 | 2017-02-22 | 江苏恒瑞医药股份有限公司 | Preparation method of tegafur gimeracil oteracil potassium composition |
| CN106581001A (en) * | 2016-11-03 | 2017-04-26 | 江苏恒瑞医药股份有限公司 | Preparation method of tegafur gimeracil and oteracil potassium composition |
| CN107865871A (en) * | 2016-09-23 | 2018-04-03 | 江苏恒瑞医药股份有限公司 | A kind of tegafur, gimeracil and oteracil potassium composition and preparation method thereof |
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| CN102302499A (en) * | 2011-07-12 | 2012-01-04 | 山东新时代药业有限公司 | Capsule preparation containing tegafur, gimeracil and potassium oxonate |
| CN102309492A (en) * | 2010-07-02 | 2012-01-11 | 天津金耀集团有限公司 | Tegafur, gimeracil and oteracil potassium compound injecta |
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2014
- 2014-03-20 CN CN201410105459.8A patent/CN103816159B/en active Active
Patent Citations (3)
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| CN101843621A (en) * | 2009-12-30 | 2010-09-29 | 山东新时代药业有限公司 | TS-1 granules and preparation method thereof |
| CN102309492A (en) * | 2010-07-02 | 2012-01-11 | 天津金耀集团有限公司 | Tegafur, gimeracil and oteracil potassium compound injecta |
| CN102302499A (en) * | 2011-07-12 | 2012-01-04 | 山东新时代药业有限公司 | Capsule preparation containing tegafur, gimeracil and potassium oxonate |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107865871A (en) * | 2016-09-23 | 2018-04-03 | 江苏恒瑞医药股份有限公司 | A kind of tegafur, gimeracil and oteracil potassium composition and preparation method thereof |
| CN107865871B (en) * | 2016-09-23 | 2021-09-03 | 江苏恒瑞医药股份有限公司 | Tegiloi composition and preparation method thereof |
| CN106420759A (en) * | 2016-11-03 | 2017-02-22 | 江苏恒瑞医药股份有限公司 | Preparation method of tegafur gimeracil oteracil potassium composition |
| CN106581001A (en) * | 2016-11-03 | 2017-04-26 | 江苏恒瑞医药股份有限公司 | Preparation method of tegafur gimeracil and oteracil potassium composition |
| CN106581001B (en) * | 2016-11-03 | 2018-12-21 | 江苏恒瑞医药股份有限公司 | A kind of preparation method of tegafur, gimeracil and oteracil potassium composition |
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| CN103816159B (en) | 2016-04-13 |
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