CN103110639A - Preparation method of capsule containing tegafur, gimeracil and potassium oxonate - Google Patents
Preparation method of capsule containing tegafur, gimeracil and potassium oxonate Download PDFInfo
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- CN103110639A CN103110639A CN2013100307320A CN201310030732A CN103110639A CN 103110639 A CN103110639 A CN 103110639A CN 2013100307320 A CN2013100307320 A CN 2013100307320A CN 201310030732 A CN201310030732 A CN 201310030732A CN 103110639 A CN103110639 A CN 103110639A
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- ftorafur
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Abstract
The invention relates to a preparation method of a capsule containing tegafur, gimeracil and potassium oxonate. The preparation method is characterized in that gimeracil is added in a form of micronized solid. The preparation method related by the invention overcomes bad water solubility of gimeracil by utilizing a micronized technology, thus the improvement of medicament dissolution is facilitated.
Description
Technical field
The invention belongs to pharmaceutical technology, be specifically related to a kind of preparation method that contains the capsule of ftorafur, gimeracil and oteracil potassium.
Background technology
Ftorafur is the cell cycle specific antineoplastic agent, and primary treatment digestive tract tumor as gastric cancer, colon and rectum carcinoma and cancer of pancreas, also can be used for treating breast carcinoma, lung bronchogenic carcinoma and hepatocarcinoma etc.Ftorafur is the derivant of fluorouracil (5-FU), has good bioavailability, its oral rear 5-FU that first is converted into, be converted into again 5-fluorouracil Deoxydization nucleotide (5-FUMP), the latter can suppress thymidylate synthase, thereby disturb the biosynthesis of DNA, the performance anti-tumor activity.
Yet the 5-FU that ftorafur produces is extremely unstable in vivo, easily by the dihydropyrimidine dehydrogenase in normal structure and tumor (DPD) fast degradation (reaching more than 85%) and inactivation.Gimeracil is a kind of effective DPD antagonist, makes the blood drug level of 5-FU be in for a long time higher level by suppressing DPD, thereby obtains the curative effect similar with the 5-FU Intravenous Infusion.
The oteracil potassium oral administration is distributed widely in gastrointestinal tract after absorbing, and optionally suppresses orotate phosphoribosyl-transferase, blocking-up 5-FU phosphorylation, thus alleviate the gastrointestinal tract toxicity when not affecting the 5-FU anti-tumor activity.
By ftorafur, gimeracil and three kinds of compositions of oteracil potassium according to the mol ratio ratio of 1: 0.4: 1 form for lucky capsule difficult to understand, claim again S-1, Industrial Co., Ltd succeeds in developing by Japanese roc, and go on the market in Japan first in March, 1999, nowadays approved is used for the treatment of kinds of tumors, comprises late gastric cancer, tumor of head and neck, advanced colorectal cancer, nonsmall-cell lung cancer, metastatic breast cancer, transitivity cancer of pancreas and cancer of biliary duct.
The water solublity of above-mentioned three kinds of active component is all poor, we find in the preparation process, gimeracil wherein is due to soluble,very slightly in water, and material density is less, static is large, if adopt traditional formulation and technology, its dissolution is difficult to reach requirement, causes the interior absorption process of body to delay, and affects the treatment.
Patent CN101574326A discloses a kind of preparation method that contains the capsule of ftorafur, CDHP and Oteracil Potassium, this invention has improved the stability of medicine by the preparation micropill, but added a large amount of surfactants in order to improve dissolution and bioavailability, therefore may produce larger zest to gastrointestinal tract.
Patent CN102302499A discloses a kind of capsule that contains ftorafur, gimeracil and oteracil potassium, although it has reduced the consumption of Surfactant SDS in preparation process, but still may have GI irritation, and may affect the physiologically active of preparation.
Micronization is material to be prepared into the process of micron order or following powder body with advanced person's physics or chemical means, has been widely used at present the fields such as food, medicine, cosmetics, and micronization can improve dissolubility and the bioavailability of medicine effectively.
Summary of the invention
The object of the present invention is to provide a kind of preparation method that contains the capsule of ftorafur, gimeracil and oteracil potassium, gimeracil wherein adds with the micronizing solid form.
Gimeracil micropowder in capsule described in the present invention is with gimeracil and appropriate filler mix homogeneously, then carries out that micronization obtains.
In the present invention, the particle diameter of gimeracil micropowder is 0.1-100 μ m, and micropowder obtains by the physics method of micronization.
Capsule provided by the invention is comprised of other adjuvants of ftorafur, gimeracil, oteracil potassium and residue.
Other adjuvants of residue in the capsule that contains ftorafur, gimeracil and oteracil potassium provided by the invention comprise filler, disintegrating agent, binding agent and lubricant.
Filler in capsule provided by the invention is selected from microcrystalline Cellulose, pregelatinized Starch, lactose, mannitol; Disintegrating agent is selected from microcrystalline Cellulose, pregelatinized Starch, polyvinylpolypyrrolidone; Binding agent is selected from polyvidone, hypromellose, sodium carboxymethyl cellulose; Lubricant is selected from magnesium stearate, Pulvis Talci, micropowder silica gel.
The preparation method that contains the capsule of ftorafur, gimeracil and oteracil potassium provided by the invention, its advantage is:
1, can significantly improve the dissolution of medicine, thereby improve bioavailability.
2, do not contain surfactant, can reduce medicine to the gastrointestinal zest.
3, preparation technology is simple, is fit to suitability for industrialized production.
Description of drawings
Fig. 1 is the stripping curve of ftorafur in the capsule of embodiment 1-3;
Fig. 2 is the stripping curve of gimeracil in the capsule of embodiment 1-3;
Fig. 3 is the stripping curve of oteracil potassium in the capsule of embodiment 1-3.
The specific embodiment
In order to understand better the present invention, by the following examples the preparation method of capsule of the present invention is described further, but protection scope of the present invention do not limited.
Embodiment 1
(in 1000) composed as follows write out a prescription:
Preparation technology:
(1) ftorafur, oteracil potassium, gimeracil are crossed respectively 100 mesh sieves, and 80 mesh sieves are crossed respectively in microcrystalline Cellulose, pregelatinized Starch, and magnesium stearate is crossed 120 mesh sieves, and is standby;
(2) take gimeracil and the pregelatinized Starch mix homogeneously of recipe quantity, carry out the air-flow micronization, get gimeracil-pregelatinized Starch mixture micropowder;
(3) take ftorafur, oteracil potassium, the microcrystalline Cellulose of recipe quantity, with said mixture micropowder mixing, add 2%PVP
K30Alcoholic solution soft material processed, 26 mesh sieves are granulated, 60 ℃ of dryings 3 hours, 24 mesh sieve granulate;
(4) get above-mentioned granule, add the magnesium stearate of recipe quantity, mixing is filled No. 2 hard capsules and is got final product.
Embodiment 2
(in 1000) composed as follows write out a prescription:
Preparation technology:
(1) ftorafur, oteracil potassium, gimeracil are crossed respectively 100 mesh sieves, and 80 mesh sieves are crossed respectively in lactose, microcrystalline Cellulose, pregelatinized Starch, and magnesium stearate is crossed 120 mesh sieves, and is standby;
(2) take gimeracil and the lactose mix homogeneously of recipe quantity, take out after ball milling 1h in the Place grinding machine, get gimeracil-milk-sugar mixture micropowder;
(3) take ftorafur, oteracil potassium, microcrystalline Cellulose, the pregelatinized Starch of recipe quantity, with said mixture micropowder mixing, add 5%PVP
K30Alcoholic solution soft material processed, 26 mesh sieves are granulated, 60 ℃ of dryings 2 hours, 24 mesh sieve granulate;
(4) get above-mentioned granule, add the magnesium stearate of recipe quantity, mixing is filled No. 2 hard capsules and is got final product.
Embodiment 3
(in 1000) composed as follows write out a prescription:
Preparation technology:
(1) ftorafur, oteracil potassium, gimeracil are crossed respectively 100 mesh sieves, and 80 mesh sieves are crossed respectively in microcrystalline Cellulose, pregelatinized Starch, and magnesium stearate is crossed 120 mesh sieves, and is standby;
(2) take gimeracil and the 40g pregelatinized Starch mix homogeneously of recipe quantity, carry out the air-flow micronization, get gimeracil-pregelatinized Starch mixture micropowder;
(3) take ftorafur, oteracil potassium, the microcrystalline Cellulose of recipe quantity, with said mixture micropowder and remaining pregelatinized Starch mixing, add 4% hypromellose aqueous solution soft material processed, 26 mesh sieves are granulated, 60 ℃ of dryings 3 hours, 24 mesh sieve granulate;
(4) get above-mentioned granule, add the Pulvis Talci of recipe quantity, mixing is filled No. 2 hard capsules and is got final product.
The Dissolution Rate Testing of embodiment 4 capsules
Get each 6 of the prepared capsules of above-described embodiment 1-3, according to dissolution method (two appendix X C the second methods of Chinese Pharmacopoeia version in 2010), take water 900ml as solvent, rotating speed is per minute 50 to turn, temperature 37+0.5 ℃, operation in accordance with the law in the time of 5,10,15,30,45 minutes, is drawn dissolution fluid 10ml respectively, replenish simultaneously the water of equivalent, dissolution fluid is measured according to high performance liquid chromatography with 0.45 μ m filtering with microporous membrane, calculates stripping quantity.The dissolution of each active component in capsule (ftorafur, gimeracil, oteracil potassium) the results are shown in Table 1.
The dissolution (%, n=6) of each active component in the obtained capsule of table 1 embodiment 1-3
By as seen from Table 1, the dissolution of embodiments of the invention each active component in the time of 15 minutes has all surpassed the limit (80%) of regulation, and the dissolution of gimeracil in the time of 15 minutes shows that all over 90% the capsule that contains ftorafur, gimeracil and oteracil potassium according to method preparation of the present invention has good dissolution.
The stripping curve of the ftorafur in the obtained capsule of above-described embodiment 1-3, gimeracil, oteracil potassium is seen respectively Fig. 1, Fig. 2 and Fig. 3.
Claims (7)
1. a preparation method that contains the capsule of ftorafur, gimeracil and oteracil potassium, is characterized in that, gimeracil wherein adds with the micronizing solid form.
2. capsule according to claim 1, is characterized in that, gimeracil micropowder wherein is with gimeracil and appropriate filler mix homogeneously, then carries out micronization.
3. according to claim 1-2 described capsules, is characterized in that, the particle diameter of described gimeracil micropowder is 0.1-100 μ m.
4. according to claim 1-3 described capsules, is characterized in that, described gimeracil micropowder obtains by the physics method of micronization.
5. according to claim 1-4 described capsules, is characterized in that, is comprised of other adjuvants of ftorafur, gimeracil, oteracil potassium and residue.
6. capsule according to claim 5, is characterized in that, other adjuvants of described residue comprise filler, disintegrating agent, binding agent and lubricant.
7. capsule according to claim 6, is characterized in that, described filler is selected from microcrystalline Cellulose, pregelatinized Starch, lactose, mannitol; Disintegrating agent is selected from microcrystalline Cellulose, pregelatinized Starch, polyvinylpolypyrrolidone; Binding agent is selected from polyvidone, hypromellose, sodium carboxymethyl cellulose; Lubricant is selected from magnesium stearate, Pulvis Talci, micropowder silica gel.
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| CN2013100307320A CN103110639A (en) | 2013-01-28 | 2013-01-28 | Preparation method of capsule containing tegafur, gimeracil and potassium oxonate |
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| CN2013100307320A CN103110639A (en) | 2013-01-28 | 2013-01-28 | Preparation method of capsule containing tegafur, gimeracil and potassium oxonate |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102614183A (en) * | 2012-03-05 | 2012-08-01 | 齐鲁制药(海南)有限公司 | Oral preparation containing tegafur, gimeracil and oteracil potassium |
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- 2013-01-28 CN CN2013100307320A patent/CN103110639A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102614183A (en) * | 2012-03-05 | 2012-08-01 | 齐鲁制药(海南)有限公司 | Oral preparation containing tegafur, gimeracil and oteracil potassium |
Non-Patent Citations (1)
| Title |
|---|
| 周建平主编: "《药剂学》", 31 March 2007, 东南大学出版社, article "增加药物溶出度的方法", pages: 206-207 * |
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Application publication date: 20130522 |