CN1244321C - Gastric 5-fluorouracil double slow release tablet of float and stay type for curing gastric cancer - Google Patents
Gastric 5-fluorouracil double slow release tablet of float and stay type for curing gastric cancer Download PDFInfo
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- CN1244321C CN1244321C CNB031477607A CN03147760A CN1244321C CN 1244321 C CN1244321 C CN 1244321C CN B031477607 A CNB031477607 A CN B031477607A CN 03147760 A CN03147760 A CN 03147760A CN 1244321 C CN1244321 C CN 1244321C
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Abstract
The present invention relates to a double slow-release tablet of a float and stay type for treating gastric cancer, which is composed of a medicine carrying layer and a float layer, wherein the medicine carrying layer comprises 5-fluorouracil, hydrophilic macromolecular gelatin materials and medicine-release regulating materials, and the float layer comprises the hydrophilic macromolecular gelatin materials, foaming agents and auxiliary floating materials. After the double float and slow-release tablet contacts gastric juice, density is quickly reduced because of volume expansion, and accordingly, the double float and slow-release tablet can float on the gastric juice, and the released medicines can maintain high medicine concentration for a long time in the entogastric part. The present invention generates damaging effects on the tissues of the gastric cancer to obtain the effects of treating the gastric cancer. The present invention is characterized in that the medicine release performance and the float performance of the double float tablet can be freely regulated.
Description
Technical field
The present invention relates to a kind of oral slow-releasing preparation at the stomach treating malignant tumor, the characteristics of said preparation are that it can rise rapidly after oral and float, and swim in all the time on the gastric juice, the drug slow of drug-loaded layer discharges lastingly, thereby tumor stomach is produced persistent lethal effect.Therefore, the prepared preparation of the present invention late gastric cancer patient of treatment that can be used for to undergo surgery.
Background technology
Gastric cancer is a kind of common malignant disease, is the main diseases therefore of causing death in the global range, and brings very big difficulty to clinical treatment.Because the gastric cancer onset is concealment, the patients with gastric cancer major part of present domestic clinical definite all belongs to progressive stage, and the Patients with Gastric Cancer of early discovery is less than 50%.The treatment effect of advanced gastric carcinoma is unsatisfactory, domestic document announcement, 5 years survival rates of advanced gastric carcinoma only about 15%, and foreign data also only has 5～40%.Treatment at present is as follows in the method that treatment gastric cancer adopts often:
Surgical radical treatment: effective Therapeutic Method of gastric cancer is still based on the radical-ability surgical operation at present, and behind the early gastric cancer radical excision, survival rate can reach more than 90% in 5 years.But at present great majority belong to middles and advanced stage in China's patients with gastric cancer of going to a doctor, and cell transfer makes the 50% patient excision that can't undergo surgery, and for such patient, 5 years survival rates of postoperative also have only 20%～30%.
Intravenous drip chemotherapy: use low dose of persistent instillation 5-fluorouracil treatment gastric cancer, obtained preferably curative effect and caused extensive concern.Treated 35 routine gastric cancer in 240 hours with the 5-fluorouracil persistent instillation, persistent instillation group effective percentage is 51.4%, and conventional intravenous drip group effective percentage only is 25.0%.But, continue intravenous drip and compare with conventional intravenous drip 5-fluorouracil, bigger to the digestive tract mucosa injury.
Interventional therapy: but for the patients with advanced gastric cancer of radical resection, before the surgery art, postoperative can implement tremulous pulse and get involved chemotherapy; To patients with advanced gastric cancer that can not radical resection, also can select corresponding interventional therapy.Owing to be local application, systemic drug concentration obviously lowers than intravenous chemotherapy, and incidence of vomiting is very low.Perfusion thromboembolism posterior tuberosity body ischemia makes microcirculation form obstacle, and along with the prolongation of time, the toxic action of chemotherapeutics makes the oncocyte necrosis.
Compare with systemic chemotherapy, interventional therapy can make the lesion tissue local concentration improve really, and still, chemotherapeutics unavoidably enters other organ-tissue with blood flow, not only causes the waste of medicine, also other histoorgan is caused certain harm.In addition, because chemotherapeutics is to pass through intravenously administrable, medicine all can produce certain effect to each organ of whole body, toxicity is bigger, if the medicine of treatment gastric cancer can be located release under one's belt, then can reduce the toxic and side effects of medicine greatly, but because the influence of physiologic factor such as gastric peristalsis and diet, medicine is short stay under one's belt only.Therefore, needs are a kind of can be at the new oral targeted drug preparation of stomach site-specific delivery of drugs, and this treatment to gastric cancer has crucial meaning.
Description of the invention
The objective of the invention is to provide a kind of side effect low and have 5-fluorouracil floating in stomach retention sustained-release sheet of targeting characteristics and preparation method thereof.
The present invention also aims to provide a kind of double-deck gastric floating slow-release preparation of being formed by drug-loaded layer and floating layer, it is characterized in that said drug-loaded layer regulates material by 5-fluorouracil, hydrophilic macromolecule gel rubber material, drug release and forms, form by hydrophilic macromolecule gel rubber material, foaming agent, expanding material and auxiliary floating material for said floating layer.
In the present invention, the gross weight of drug-loaded layer is between 150～250mg, and the gross weight of floating layer is between 150～250mg, and preferred weight is 200mg, and the content of 5-fluorouracil is between 50～120mg in the drug-loaded layer.
In the present invention, used hydrophilic high molecular material can be selected from high viscosity hydroxypropyl emthylcellulose, sodium alginate or their mixture in the drug-loaded layer, and it is optional from polyvinylpyrrolidone, Polyethylene Glycol, microcrystalline Cellulose, low-viscosity hydroxypropylmethylc,llulose or their mixture that drug release is regulated material; The hydrophilic macromolecule gel rubber material of said floating layer can be selected from the high viscosity hydroxypropyl emthylcellulose, foaming agent can be selected from sodium bicarbonate, swollen magnesium carbonate or their mixture, expanding material is card pool nurse 934, and auxiliary floating material can be selected from magnesium stearate, starch or and derivant or their mixture.
In the present invention, as the viscosity of the high viscosity hydroxypropyl emthylcellulose of drug-loaded layer hydrophilic high mol gel between 4000～100000 centipoises, said polyvinylpyrrolidone is PVP K29～32, said Polyethylene Glycol can be selected from PEG4000, PEG6000 or its mixture, and said low-viscosity hydroxypropylmethylc,llulose is HPMC E15 LV; The viscosity of said hydroxypropyl emthylcellulose as floating layer hydrophilic high mol gel is between 4000～100000 centipoises.
In one embodiment of the invention, the ratio of hydrophilic macromolecule gel rubber material and foaming agent is 1: 0.1 to 1: 1.0 in the floating layer, and the ratio of hydrophilic macromolecule gel rubber material and auxiliary floating material is 1: 2.5 to 1: 3.5.
Tablet of the present invention is to be prepared with method commonly used in the prior art, for example, drug-loaded layer and floating layer can be pulverized 80～00 mesh sieves with used raw material and used part or all of adjuvant respectively, mix homogeneously, adopt wet granulation technique or in method granulation technique or two kinds of granulation techniques that method of granulating combines, mixture to raw material and various adjuvants is granulated, and fills it into successively then in the punch die, with diameter 8～12mm mould tabletting.The hardness of the prepared tablet of the present invention is generally between about 30～100N.
The detection method of tablet of the present invention relevant dissolution in according to Pharmacopoeia of the People's Republic of China version appendix in 2000 is measured for the release medium carries out external medicine stripping with the simulated gastric fluid, all can satisfy following release rule: release 10～35% in 1 hour, release 30～45% in 2 hours, release 40～60% in 3 hours, release 50～75% in 5 hours, and release was more than 90% in 6 hours.In the example of the present invention all floating tablets the external flotation time all greater than 6 hours.
The double-deck floating slow-release tablet of the present invention preparation is met the foaming agent that gastric juice can aerogenesis because floating layer contains, and therefore, and can expand after gastric juice contacts, and makes the density of whole double-layer tablet be lower than density of medium, can swim in above the gastric juice.The macromolecular material of floating layer with can form gel after gastric juice contacts, the prevention bubble breaks, and therefore, can produce persistent buoyancy.The hydrophilic macromolecule gel rubber material of drug-loaded layer contacts the back and forms gel with water, the mode that combines by corrosion and diffusion with other material is controlled the release of medicine.Therefore, contained medicine can slowly continue to discharge in flotation process, keeps a constant relatively drug level in the gastric part.
Come the present invention is further detailed with following embodiment, but these embodiment can not produce any restriction to the present invention.
Description of drawings
Fig. 1 has represented the floating and release mechanism of the double-deck floating Entogastric lingering slow releasing tablet of 5-fluorouracil of the present invention.
Embodiment
Example 1: with the 5-fluorouracil is model drug, the component of drug-loaded layer: 1 part of 5 fluorouracil, 0.1 part of HPMC K15MCR, 0.3 part of HPMC E15LV, 0.3 part of PEG-4000,0.01 part of PVPK29～32,2 part starch or derivatives thereof, 0.1 part of microcrystalline Cellulose mix, the granule for preparing drug-loaded layer by wet granulation technology: the component of floating layer: 1 part of HPMCK100MCR, 0.4 part of sodium bicarbonate, 3 parts of starch or derivatives thereofs mix, wet granulation, then, in this granule, add 0.3 part of card pool nurse and 0.2 part of magnesium stearate again, mix.In 1: 1～1: 1.5 ratio was in the punch die of 11mm to diameter with drug-loaded layer and the particles filled of floating layer respectively successively, tabletting.
Example 2: with the 5-fluorouracil is model drug, and drug-loaded layer comprises: 1 part of 5-fluorouracil and 0.2 part of HPMC K15MCR, 0.3 part of HPMC E15LV, 0.1 part of PEG-4000,2 parts of starch or derivatives thereofs prepare the granule of drug-loaded layer by wet granulation technology; The composition of floating layer and preparation method are in the punch die of 11mm to diameter with drug-loaded layer and the particles filled of floating layer with example 1 respectively in 1: 1～1: 1.5 ratio successively, tabletting.
Example 3: with the 5-fluorouracil is model drug, drug-loaded layer: 1 part of 5-fluorouracil mixes with 0.15 part of HPMC K15MCR, 0.2 part of HPMC E15LV, 0.2 part of PEG-4000,0.3 part of PVPK29～32,2 part starch or derivatives thereof, 0.15 part of microcrystalline Cellulose, prepares the granule of drug-loaded layer by wet granulation technology; The composition of floating layer and preparation method are in the punch die of 11mm to diameter with drug-loaded layer and the particles filled of floating layer with example 1 respectively in 1: 1～1: 1.5 ratio successively, tabletting.
Example 4: with the 5-fluorouracil is model drug, with drug-loaded layer: 1 part of 5-fluorouracil mixes with 0.2 part of HPMC K15MCR, 0.3 part of HPMC E15LV, 0.1 part of PEG-4000,0.3 part of PVPK29～32,2 part starch or derivatives thereof, 0.1 part of microcrystalline Cellulose, prepares the granule of drug-loaded layer by wet granulation technology; The composition of floating layer and preparation method are in the punch die of 11mm to diameter with drug-loaded layer and the particles filled of floating layer with example 1 respectively in 1: 1～1: 1.5 ratio successively, tabletting.
Example 5: with the 5-fluorouracil is model drug, drug-loaded layer is: 1 part of 5-fluorouracil and 0.24 part of HPMC K15MCR, 0.3 part of HPMC E15LV, 0.15 part of PEG-4000,0.15 part of PVP K29～32,1.8 part starch or derivatives thereof, 0.3 microcrystalline Cellulose prepare the granule of drug-loaded layer by wet granulation technology; The composition of floating layer and preparation method are in the punch die of 11mm to diameter with drug-loaded layer and the particles filled of floating layer with example 1 respectively in 1: 1～1: 1.5 ratio successively, tabletting.
Claims (10)
1. the double-deck floating in stomach retention sustained-release of 5-fluorouracil sheet is characterized in that it is made up of two-layer, and wherein one deck is a drug-loaded layer, and another layer be floating layer.
2. slow releasing tablet as claimed in claim 1, wherein said drug-loaded layer are regulated material by 5-fluorouracil, hydrophilic macromolecule gel rubber material, drug release and are formed; Said floating layer is made up of hydrophilic macromolecule gel rubber material, foaming agent, expanding material and auxiliary floating material.
3. slow releasing tablet as claimed in claim 2, wherein the hydrophilic macromolecule gel rubber material of said drug-loaded layer is selected from high viscosity hydroxypropyl emthylcellulose, sodium alginate or their mixture, and drug release is regulated material and is selected from polyvinylpyrrolidone, Polyethylene Glycol, microcrystalline Cellulose, low-viscosity hydroxypropylmethylc,llulose or their mixture; The hydrophilic macromolecule gel rubber material of said floating layer is selected from the high viscosity hydroxypropyl emthylcellulose, foaming agent is selected from sodium bicarbonate, magnesium carbonate or their mixture, expanding material is card pool nurse 934, and auxiliary floating material is selected from magnesium stearate or starch and derivant or their mixture.
4. slow releasing tablet as claimed in claim 2 is characterized in that the ratio of hydrophilic macromolecule gel rubber material and foaming agent is 1: 0.1 to 1: 1.0 in the floating layer, and the ratio of hydrophilic macromolecule gel rubber material and auxiliary floating material is 1: 2.5 to 1: 3.5.
5. slow releasing tablet as claimed in claim 3, the viscosity of wherein said high viscosity hydroxypropyl emthylcellulose as drug-loaded layer hydrophilic high mol gel is between 4000～100000 centipoises, said polyvinylpyrrolidone is PVP K29～32, said Polyethylene Glycol is selected from PEG4000, PEG6000 or its mixture, and said low-viscosity hydroxypropylmethylc,llulose is HPMCE15LV; The viscosity of said high viscosity hydroxypropyl emthylcellulose as floating layer hydrophilic high mol gel is between 4000～100000 centipoises.
6. as any described slow releasing tablet of claim in front, the gross weight that it is characterized in that drug-loaded layer is between 150～250mg, and the weight of floating layer is between 150～250mg.
7. slow releasing tablet as claimed in claim 5, the weight that is characterised in that 5-fluorouracil in the drug-loaded layer is between 50～120mg.
8. slow releasing tablet as claimed in claim 5 is characterized in that the weight of floating layer is 200mg.
9. slow releasing tablet as claimed in claim 5, the detection method that it is characterized in that its relevant dissolution in according to Pharmacopoeia of the People's Republic of China version appendix in 2000, measure for the release medium carries out external medicine stripping with the simulated gastric fluid, all can satisfy following release rule: release 10～35% in 1 hour, release 30～45% in 2 hours, release 40～60% in 3 hours, and release 50～75% in 5 hours, and release was more than 90% in 6 hours.In the example of the present invention all floating tablets the external flotation time all greater than 6 hours.
10. one kind prepares 1 method as any described slow releasing tablet of claim in front, it is characterized in that respectively raw material that drug-loaded layer and floating layer is used and used part or all of adjuvant pulverized 80～100 mesh sieves, mix homogeneously, adopt wet granulation technique or dry granulation technology or two kinds of granulation techniques that method of granulating combines, respectively the mixture of raw material and various adjuvants is granulated, particles filled in punch die with drug-loaded layer and floating layer successively then is with diameter 8～12mm mould tabletting.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031477607A CN1244321C (en) | 2003-06-26 | 2003-06-26 | Gastric 5-fluorouracil double slow release tablet of float and stay type for curing gastric cancer |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031477607A CN1244321C (en) | 2003-06-26 | 2003-06-26 | Gastric 5-fluorouracil double slow release tablet of float and stay type for curing gastric cancer |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1565427A CN1565427A (en) | 2005-01-19 |
| CN1244321C true CN1244321C (en) | 2006-03-08 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNB031477607A Expired - Lifetime CN1244321C (en) | 2003-06-26 | 2003-06-26 | Gastric 5-fluorouracil double slow release tablet of float and stay type for curing gastric cancer |
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| CN (1) | CN1244321C (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102076215A (en) * | 2008-06-30 | 2011-05-25 | 托卡根公司 | Formulations of 5-fluorocytosine and uses thereof |
| CN101721417B (en) * | 2009-12-21 | 2014-04-09 | 深圳海王药业有限公司 | Entogastric lingering floating slow-release tablet for treating malignant tumor of gastrointestinal tract |
| CN109276572B (en) * | 2018-11-16 | 2020-10-27 | 浙江省人民医院 | Application of loganin and 5-fluorouracil in combination in treatment of gastric cancer |
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- 2003-06-26 CN CNB031477607A patent/CN1244321C/en not_active Expired - Lifetime
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Free format text: FORMER OWNER: WEI ZHENPING Effective date: 20150210 Owner name: JILIN PEPTIDE VALLEY BIOLOGICAL ENGINEERING CO., L Free format text: FORMER OWNER: LI YONG Effective date: 20150210 |
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Effective date of registration: 20150210 Address after: 134500 Fusong Jilin industrial concentration area Patentee after: JILIN PEPTIDE VALLEY BIOENGINEERING Co.,Ltd. Address before: 100083 No. 38, Haidian District, Beijing, Xueyuan Road Patentee before: Li Yong Patentee before: Wei Zhenping |
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Granted publication date: 20060308 |