CN100459982C - Dispersible tablet of doxifluridine - Google Patents
Dispersible tablet of doxifluridine Download PDFInfo
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- CN100459982C CN100459982C CNB200410090727XA CN200410090727A CN100459982C CN 100459982 C CN100459982 C CN 100459982C CN B200410090727X A CNB200410090727X A CN B200410090727XA CN 200410090727 A CN200410090727 A CN 200410090727A CN 100459982 C CN100459982 C CN 100459982C
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- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 title claims abstract description 58
- 229950005454 doxifluridine Drugs 0.000 title claims abstract description 58
- 239000007919 dispersible tablet Substances 0.000 title claims abstract description 30
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Abstract
The present invention provides a dispersible tablet dosage form of doxifluridine, which is characterized by its speedy decentralization and dissolution when being in vitro. Through clinical applications, it is found that compared to common doxifluridine capsules, the clinical curative effect is considerably improved, at the same time the adverse reaction is remarkably reduced and unexpected effects are acquired. In accordance with the present invention, for extensive cancer patients executing chemotherapy by adopting doxifluridine, the pains of chemotherapy are considerably alleviated, the neoplastic chemotherapy effect is improved, and said medicine has prodigious clinical use values; 5-FU is a specific anti-metabolizing medicine during the S period, and the unexpected effects obtained in accordance with the present invention are of good enlightening significance for researching pharmacodynamics features and mechanism of action of doxifluridine. In addition, it is convenient for aged and children to take the medicine in accordance with the present invention, with stable formulation, fast absorption, high bioavailability and few adverse reaction, which can be used as medicine for treating breast carcinoma, cancer of stomach, carcinoma of colon, restocarcinoma, nasopharyngeal carcinoma and the like.
Description
Technical field
The invention belongs to pharmaceutical preparations technology.
Background technology
Cancer is the serious disease that threatens the human life, has 1/3 people tumor to occur approximately in their life different phase in developed country, and wherein about 1/4 people dies from tumor, and pulmonary carcinoma is the first cause of the death.What China's sickness rate was the highest is gastric cancer, secondly is pulmonary carcinoma, intestinal cancer and breast carcinoma etc.The generation of cancer and death have the gesture that is on the rise, and have become first cause of the death in some area.Therefore the research of antitumor drug more and more draws attention.China has classified cancer research as one of 38 key scientific and technological projects.
Doxifluridine claims doxifluridine, 5-DFUR again, is the precursor substance of 5-FU (5-fluorouracil).It is synthetic the seventies in eighties of last century by Luo Shi (Roche) company U.S. branch company, and trade name fortulon (Furtulon) at first puts goods on the market the nineties in Japan.In the past fluoridize the pyrimidine serial medicine after oral, mainly through the liver drug enzyme enzymolysis or be hydrolyzed into 5-FU naturally and bring into play therapeutical effect.Different therewith, fortulon is by showing that at tumor tissues highly active pyrimidine-nucleoside phosphorylase (PyNPase) changes into 5-FU, and therefore, it has the certain selectivity antitumous effect.
The doxifluridine capsule is by productions such as Shanghai Roche Group company limited, Hengrui Medicine Co., Ltd., Jiangsu Prov., and specification is 200mg.One daily amount, 800～1200mg divides and takes for 3～4 times, in one after each meal.And can suitably increase and decrease according to age, symptom.6～8 weeks were a course of treatment.
We are by having done the clinical practice of doxifluridine after a large amount of investigation, find that dosage form such as only conventional tablet on the present market can not satisfy the demand of extensive patients far away, especially take the serious cancer patient of difficulty, take the patient of gastrointestinal absorption function reduction behind the antitumor drug for a long time for those, the conventional tablet of doxifluridine is not ideal clinical application mode.Common doxifluridine tablet both inconvenient patient take, and bioavailability is also low, and GI irritation is big, causes the compliance of tumor patient medication behind the long-term prescription to descend, and this has fettered the performance of doxifluridine anti-tumor activity to a great extent.
Doxifluridine has certain selectivity to tumor tissues, compares with 5-FU, and this has reduced the untoward reaction of its blood system and digestive system to a certain extent.It is higher that a kind of curative effect is sought in exploitation, and the doxifluridine pharmaceutical dosage form that untoward reaction is littler for vast tumor patient alleviates the misery of chemotherapy, is the target of pharmaceutical manufacturer struggle for many years.But because some specific physicochemical properties of doxifluridine, development difficulty is bigger, only has some common capsules and tablet to use for the patient now.
Summary of the invention
The invention provides a kind of doxifluridine tablet formulation.The advantage of doxifluridine tablet formulation of the present invention is further to improve the principal agent dissolubility, promptly meet water and can form even viscosity suspension rapidly, can be dispersed into granule in the rapid disintegrate of gastrointestinal tract, the medicine distribution area is increased, absorption point increases, avoid the conventional capsule agent at gastrointestinal tract local drug concentration height, shortcomings such as stimulating gastrointestinal mucosa, alleviated feel sick, digestive system untoward reaction such as vomiting, inappetence, improved patient's compliance, have taking convenience, absorb characteristics such as fast, bioavailability height, and make things convenient for the patient to take.And the ordinary preparation of doxifluridine, as capsule, its specification is the 200mg/ grain, because of disintegrate and the slow abundant absorption that influences medicine of medicine stripping, the patient of old man, child and dysphagia takes often and has any problem.
Technical scheme
Doxifluridine dosage form of the present invention is a tablet formulation, and principal agent composition doxifluridine amount is optimized for 20～1200mg, more is optimized for 80～400mg, and optimum turns to 200mg.
Disintegrating agent is the tablet formulation disintegrating agent commonly used of preparation tablet formulation, and disintegrant content is optimized for 1～80% among the present invention, more is optimized for 10～30%.Optimization principles: guaranteeing that the consumption of disintegrating agent is few under the fast prerequisite of the rapid stripping of disintegrate of the present invention.
Through a large amount of experimentatioies repeatedly, determined the final technology preparation of doxifluridine dispersible tablet, and confirmed that in animal experiment the present invention has above-mentioned advantage really.In test, we have selected multiple medicinal disintegrating agent with disintegration properties to compare, surprised discovery, and not all disintegrating agent that can be used for dispersible tablet can both be applied to the present invention.The technical barrier that the present invention solves, also be technical characterictic is the selection to disintegrating agent, finally selected disintegrating agent and be in the disintegrating agents such as starch, pregelatinized Starch, carboxymethyl starch sodium, hydroxypropyl cellulose, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, hydroxypropyl starch, carboxymethylcellulose calcium, sodium alginate, hydroxy acid cellulose, sodium carboxymethyl cellulose, methacrylic acid, divinylbenzene copolyesters, IRP-88, guar gum, Herba Xanthii glue, glucosan, carboxymethylcellulose calcium one or more.
In research process, investigated the preparation technology of doxifluridine dispersible tablet, determined that its preparation technology is doxifluridine, the disintegrating agent mix homogeneously of recipe quantity, granulate and dry back adding recipe quantity lubricant mixing tabletting or directly in above-mentioned mixed powder, add recipe quantity lubricant mixing tabletting, promptly.
Description of drawings:
Fig. 1: the external stripping curve of prescription A: Fig. 2: the external stripping curve of prescription B: Fig. 3: the external stripping curve of prescription C: Fig. 4: the external stripping curve of prescription D: Fig. 5: the external stripping curve of prescription E: Fig. 6: the external stripping curve of prescription F: Fig. 7: the external stripping curve of prescription G: Fig. 8: the external stripping curve of prescription H:
The specific embodiment
Embodiment (recipe quantity is 1000):
Eight kinds of concrete prescriptions:
Prescription A:
Doxifluridine 20g
Hydroxypropyl cellulose (disintegrating agent) 96g
Magnesium stearate (lubricant) 1.5g
Micropowder silica gel (fluidizer) 2.5g
Preparation technology: principal agent is crossed 100 mesh sieves, and disintegrating agent is crossed 80 mesh sieves, takes by weighing principal agent, the disintegrating agent mix homogeneously of recipe quantity, adds the lubricant of recipe quantity, mixing, and tabletting, promptly.Dispersible tablet is limited to 1.0min when disperseing.
Prescription B:
Doxifluridine 60g
Hydroxypropyl cellulose (disintegrating agent) 108g
10% starch slurry (binding agent) 100g
Magnesium stearate (lubricant) 2g
Preparation technology: principal agent is crossed 100 mesh sieves, and disintegrating agent is crossed 80 mesh sieves, takes by weighing principal agent, the disintegrating agent mix homogeneously of recipe quantity, adds binding agent and granulates in right amount, and dry back adds recipe quantity lubricant mixing, and tabletting promptly.Dispersible tablet is limited to 1.2min when disperseing.
Prescription C:
Doxifluridine 80g
Microcrystalline Cellulose (disintegrating agent) 122
Preparation technology: principal agent is crossed 100 mesh sieves, and disintegrating agent is crossed 80 mesh sieves, takes by weighing principal agent, the disintegrating agent mix homogeneously of recipe quantity, adds dehydrated alcohol and granulates in right amount, and dry back tabletting promptly.Dispersible tablet is limited to 0.6min when disperseing.
Prescription D:
Doxifluridine 200g
Crospolyvinylpyrrolidone (disintegrating agent) 30g
Microcrystalline Cellulose (fluidizer) 60g
5%PVP
K30Ethanol solution (binding agent) 140g
Magnesium stearate (lubricant) 3g
Preparation technology is with prescription B.Dispersible tablet is limited to 0.8min when disperseing.
Prescription E:
Doxifluridine 300g
Hydroxypropyl cellulose (disintegrating agent) 40g
Crospolyvinylpyrrolidone (disintegrating agent) 40g
10% starch slurry (binding agent) 160g
Magnesium stearate (lubricant) 4g
Preparation technology is with prescription B.Dispersible tablet is limited to 0.7min when disperseing.
Prescription F:
Doxifluridine 400g
Carboxymethyl starch sodium (disintegrating agent) 15g
Crospolyvinylpyrrolidone (disintegrating agent) 15g
Microcrystalline Cellulose (filler) 140g
10% starch slurry (binding agent) 240g
Magnesium stearate (lubricant) 6g
Preparation technology is with prescription B.Dispersible tablet is limited to 1.5min when disperseing.
Prescription G:
Doxifluridine 800g
Carboxymethyl starch sodium (disintegrating agent) 30g
Hydroxypropyl cellulose (disintegrating agent) 50g
5%PVP
K30Aqueous solution (binding agent) 300g
Magnesium stearate (lubricant) 8g
Preparation technology is with prescription B.Dispersible tablet is limited to 1.4min when disperseing.
Prescription H:
Doxifluridine 1200g
Crospolyvinylpyrrolidone (disintegrating agent) 14g
Microcrystalline Cellulose (filler) 160g
4%PVP
K30Aqueous solution (binding agent) 400g
Magnesium stearate (lubricant) 10g
Preparation technology is with prescription B.Dispersible tablet is limited to 2.5min when disperseing.
Doxifluridine dispersible tablet dispersing uniformity and dissolution in vitro inspection
1, doxifluridine dispersible tablet dispersing uniformity is checked
The doxifluridine dispersible tablet (A～H), its dispersing uniformity experimental technique is as follows for prescription: get 2 of this product, put jolting in the 100ml water, and in 20 ℃ ± 1 ℃ water, all disintegrates and sieve in 3 minutes by No. 2.See table explanation 1～8 for details.
2, the mensuration of doxifluridine dispersible tablet dissolution in vitro
The doxifluridine dispersible tablet (prescription A～H), its dissolution in vitro experimental technique is as follows: get this product according to dissolution method (two appendix X of Chinese Pharmacopoeia version in 2000 C, first method) device, with water 900ml is solvent, and rotating speed is that per minute 100 changes, operation in accordance with the law, in the time of 30 minutes, get solution 10ml, filter, get subsequent filtrate 5ml and place the 100ml measuring bottle, be diluted with water to scale, as need testing solution.According to spectrophotography (two appendix IV of Chinese Pharmacopoeia version in 2000 A), measure trap at 269nm wavelength place; In addition precision takes by weighing that to put the doxifluridine reference substance of constant weight through 105 ℃ of dryings an amount of, with water dissolution and quantitatively dilution make the solution that contains 10 μ g among every 1ml, measure trap with method, calculate every stripping quantity, limit is 80% of a labelled amount, should be up to specification.See description of drawings 1～8 for details.
Table 1: the cumulative in vitro dissolution of prescription A
Table 2: the cumulative in vitro dissolution of prescription B
Table 3: the cumulative in vitro dissolution of prescription C
Table 4: the cumulative in vitro dissolution of prescription D
Table 5: the cumulative in vitro dissolution of prescription E
Table 6: the cumulative in vitro dissolution of prescription F
Table 7: the cumulative in vitro dissolution of prescription G
Table 8: the cumulative in vitro dissolution of prescription H
The clinical verification of doxifluridine dispersible tablet and doxifluridine capsule for treating malignant tumor
Case is selected
The gastric cancer and the PATIENTS WITH LARGE BOWEL that 161 examples are had can not performing the operation of pathology or cytology's confirmation or recurrence after operation, be divided into doxifluridine dispersible tablet group and doxifluridine capsule matched group at random according to the gross tumor volume size, every group of each 80 example, estimate that life cycle is more than 1 year, the scoring of muscle power situation is more than 70 minutes, and hemogram, hepatic and renal function and cardiac function are all normal before the treatment.
Administrated method
Doxifluridine dispersible tablet group (late 10:00) and play back (6:00 early) morning and take doxifluridine dispersible tablet 600mg, 8 weeks of continuous use respectively before the sleeping of every day; Matched group is before the sleeping of every day (late 10:00) and play back (6:00 early) morning and take doxifluridine capsule 600mg, 8 weeks of continuous use respectively also.Two groups of slow this body weight take the circumstances into consideration to reduce to 500mg/ time the following person of 50kg.
The judgement of curative effect and untoward reaction
Press the standard of WHO, curative effect is divided into alleviates (CR) fully, and part is alleviated (PR), stable (NC), progress (PD); Untoward reaction is divided into 0～IV degree.
Result of the test
1. clinical efficacy
When 8 weeks of medication finished, the remission rate of dispersible tablet group was 39.5%, and the remission rate of Capsules group is 21.3%, carries out X 2 test, and two groups have significant difference (P＜0.01), and concrete the results are shown in Table 1.
Table 1 doxifluridine dispersible tablet and doxifluridine capsule compare the curative effect of gastric cancer and colorectal cancer
2. untoward reaction
The untoward reaction of doxifluridine dispersible tablet group is lighter, mostly is I, II degree greatly, and the hematology does not see III, the toxicity of IV degree, leukopenia 18.8%, thrombocytopenia 5.3%.Non-haematics toxicity mainly is to feel sick, vomit (10.5%), diarrhoea (9.8%), I degree liver function injury (10.3%), slight alopecia (6.8%); Because untoward reaction is slighter, does not have the patient because of not tolerating drug withdrawal, the compliance of medication is fine.The untoward reaction of Capsules group also mostly is I, II degree greatly, and the hematology has the toxicity of 3 example generation III, IV degree, leukopenia 34.7%, thrombocytopenia 12.1%.Non-haematics toxicity mainly is to feel sick, vomit (39.8%), diarrhoea (17.3%), I degree liver function injury (18.5%), slight alopecia (15.6%); 8 routine patients are arranged because of not tolerating drug withdrawal, the compliance of medication is compared with the dispersible tablet group and is significantly descended.More than each index carry out X 2 test, the dispersible tablet group of doxifluridine and capsule group all have significant difference (P＜0.05).
By above clinical test results, can draw as drawing a conclusion: the tablet formulation of doxifluridine and common capsule compare, and clinical efficacy significantly strengthens, and untoward reaction significantly descends, and has obtained beyond thought effect.Disperse and the fast characteristics of stripping according to dispersible tablet drug, can't release above-mentioned conclusion (of pressure testing).
The beyond thought result that the present invention is obtained carries out the cancer patient of chemotherapy for vast use doxifluridine, has alleviated the misery of chemotherapy greatly, has improved the chemotherapy effect to tumor, has very big value for clinical application; 5-FU is a specific antimetabolite of S phase, and the obtained beyond thought effect of the present invention has good inspired significance for the research doxifluridine pharmacodynamics characteristics and the mechanism of action.
Claims (2)
1. the medicinal application dosage form of a doxifluridine, it is characterized in that it is a dispersible tablet, contain active component doxifluridine and disintegrating agent, described disintegrating agent is one or more in carboxymethyl starch sodium, hydroxypropyl cellulose, microcrystalline Cellulose and the crospolyvinylpyrrolidone, and the content of disintegrating agent is 1～80%.
2. the medicinal application dosage form of doxifluridine as claimed in claim 1, the amount that it is characterized in that doxifluridine contained in the described dispersible tablet is 20～1200mg.
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| Application Number | Priority Date | Filing Date | Title |
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| CNB200410090727XA CN100459982C (en) | 2004-08-30 | 2004-11-10 | Dispersible tablet of doxifluridine |
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| CN200410057362 | 2004-08-30 | ||
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| CNB200410090727XA CN100459982C (en) | 2004-08-30 | 2004-11-10 | Dispersible tablet of doxifluridine |
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| GB0915877D0 (en) * | 2009-09-10 | 2009-10-14 | E Therapeutics Plc | Cancer cell apoptosis |
| CN105343029B (en) * | 2015-12-08 | 2018-10-12 | 上海朝晖药业有限公司 | A kind of doxifluridine capsule and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5116600A (en) * | 1989-01-05 | 1992-05-26 | Otsuka Pharmaceutical Co., Ltd. | Composition and method for inhibiting inflammation caused by non-parenteral administration of 5-fluorouracil type compounds |
| US20030104062A1 (en) * | 2000-02-04 | 2003-06-05 | Depomed, Inc. | Shell-and-core dosage form approaching zero-order drug release |
| US6682759B2 (en) * | 2002-02-01 | 2004-01-27 | Depomed, Inc. | Manufacture of oral dosage forms delivering both immediate-release and sustained-release drugs |
-
2004
- 2004-11-10 CN CNB200410090727XA patent/CN100459982C/en not_active Expired - Lifetime
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5116600A (en) * | 1989-01-05 | 1992-05-26 | Otsuka Pharmaceutical Co., Ltd. | Composition and method for inhibiting inflammation caused by non-parenteral administration of 5-fluorouracil type compounds |
| US20030104062A1 (en) * | 2000-02-04 | 2003-06-05 | Depomed, Inc. | Shell-and-core dosage form approaching zero-order drug release |
| US6682759B2 (en) * | 2002-02-01 | 2004-01-27 | Depomed, Inc. | Manufacture of oral dosage forms delivering both immediate-release and sustained-release drugs |
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