CN102988320A - Capecitabine dispersible tablet and preparation method thereof - Google Patents

Abstract

The invention discloses a capacitabine dispersible tablet and a preparation method thereof. The formula of the dispersible tablet is as follows: the proportion of a main drug of capacitabine ranges from 70%-80%; the proportion of an adhesive of polyvinylpyrrolidone K30 ranges from 3%-7%; the proportion of a disintegrating agent of cross-linked sodium carboxymethyl cellulose ranges from 3%-7%; and the proportion of a filling agent of microcrystalline cellulose ranges from 10%-20%.

Description

A kind of capecitabine dispersible tablet and preparation method thereof

Technical field

The present invention relates to a kind of field of pharmaceutical preparations, particularly a kind of safe, stable capecitabine dispersible tablet and preparation method thereof.

Background technology

Capecitabine (English name Capecitabine) is first oral fluorinated pyrimidine carbamate series antineoplastic medicament, its chemical name is 5 '-deoxidation-5-fluoro-N[(amoxy) carbonyl]-born of the same parents' (pyrimidine nuclear) glycosides.Chemical structural formula:

After capecitabine is applicable to Dukes'C phase, primary tumo(u)r radical correction, be suitable for accepting separately single medicine auxiliary treatment of the colorectal cancer patients for the treatment of of 5-FU class medicine.The disease free survival phase (DFS) of its treatment is not second to 5-fluorouracil and formyl tetrahydrofolic acid scheme for combining (5-FU/LV).Capecitabine list medicine or all can not prolong Overall survival (OS) with the other drug combined chemotherapy, but existing test data shows that capecitabine can improve the disease free survival phase than 5-FU/LV in Combination chemotherapy.

Concrete indication is as follows:

Colorectal cancer: when the first-selected alone 5-FU class Drug therapy of metastatic colorectal cancer patients, capecitabine can be used as First-line chemotherapy.When capecitabine and other drug combined chemotherapy, be better than the single medicine chemotherapy of 5-FU/LV life cycle.There is no at present advantage life cycle of proof capecitabine list medicine chemotherapy.Relevant capecitabine replaces safety and the also further research of advantage life cycle of 5-FU/LV in combined chemotherapy.

The breast carcinoma combined chemotherapy: capecitabine can be united the metastatic breast cancer that is used for the treatment of the failure of anthracycline-containing pharmaceutical admixtures chemotherapy with docetaxel.

The single medicine chemotherapy of breast carcinoma: capecitabine also can be used for the treatment of separately to paclitaxel and the equal drug resistance of anthracycline-containing medicine chemotherapy regimen or to taxol resistance with can not re-use the metastatic breast cancer patient of anthracene nucleus medicament treatment (for example having accepted accumulated dose 400mg/m2 amycin or amycin congener).Drug resistance is defined as during the treatment disease and continues progress (have or alleviate without initial), or finishes recurrence in 6 months after the adjuvant chemotherapy that contains anthracene nucleus medicament.

Gastric cancer: capecitabine is applicable to the first-line treatment of inoperable late period or metastatic gastric carcinoma.

Get permission listing in the U.S. in April, 1998, goes on the market in states such as Switzerland successively subsequently.Begin to register clinical trial in China in November, 1999, carry out clinical trial by 5 national antitumor drug clinical experimental study centers on the ground such as Beijing, Shanghai, Guangzhou, and go on the market with trade name " xeloda ".

The capecitabine sheet that goes on the market at present, sheet is heavy larger, and is conventional tablet, takes difficulty for severe patient in the cancer, and hard to bear being subjected to is in order to enlarge the medication crowd, convenient clinical use.The inventor wishes that it is prepared into the dispersion sheet uses.Dispersible tablet means in water the rapidly homodisperse tablet of disintegrate.With respect to solid preparations such as conventional tablet, capsules, dispersible tablet has taking convenience, disintegrate is rapid, absorption is fast and the bioavailability high.It has simple, the taking convenience of preparation, can reduce medicine untoward reaction, improve the advantage such as drug bioavailability.

But in the process of preparation dispersible tablet, the inventor finds, the result who uses different prescriptions and different process conditions to obtain varies, particularly in the requirement that is difficult to reach pharmacopeia aspect stability and the dissolution, the inventor screens the composition and engineering of dispersible tablet for this reason, finally obtains a kind of dispersible tablet prescription and preparation method of efficient stable.

Summary of the invention

The invention provides a kind of capecitabine dispersible tablet, its prescription is composed as follows:

Its accounting example scope of principal agent capecitabine is 70% ~ 80% (w/w);

Its accounting example scope of polyvinyl pyrrolidone K30 is 3% ~ 7% (w/w);

Its accounting example scope of disintegrating agent cross-linking sodium carboxymethyl cellulose is 3% ~ 7% (w/w);

Its accounting example scope of filler microcrystalline Cellulose is 10% ~ 20% (w/w)

Preferred capecitabine dispersible tablet, its prescription is composed as follows:

Its accounting example scope of principal agent capecitabine is 75% (w/w);

Its accounting example scope of polyvinyl pyrrolidone K30 is 5% (w/w);

Its accounting example scope of disintegrating agent cross-linking sodium carboxymethyl cellulose is 5% (w/w);

Its accounting example scope of filler microcrystalline Cellulose is 15% (w/w);

On the other hand, the present invention also provides the preparation method of capecitabine dispersible tablet of the present invention, comprises the steps:

(a) it is for subsequent use to take by weighing respectively capecitabine (cross 120 orders), cross-linking sodium carboxymethyl cellulose, the microcrystalline Cellulose of recipe quantity;

(b) it is for subsequent use that PVP K30 is prepared into concentration of aqueous solution 5% (w/w);

(c) respectively capecitabine, cross-linking sodium carboxymethyl cellulose, microcrystalline Cellulose are put into three-dimensional motion mixer, mix homogeneously;

(d) 5% PVP K30 aqueous solution adds in the above mixed material, granulation, dry, granulate.

(e) tabletting

The present invention investigates the use of the used disintegrating agent cross-linking sodium carboxymethyl cellulose of capecitabine dispersible tablet, polyvinyl pyrrolidone K30, filler microcrystalline Cellulose.With the capecitabine dispersible tablet of different binding agents, disintegrating agent, the preparation of filler ratio by the character to product, dissolution and capecitabine degradation rate are evaluation index, preferred solubilizing agent ratio is prepared the preparation that can reach the pharmacopeia requirement, thereby is finished the present invention.

Composition and engineering method of the present invention obtains through screening, adopts single factor design method commonly used in the pharmacy, major auxiliary burden kind and consumption in the dispersible tablet is investigated, and contrasted with the original prescription product.Take the dissolution of the capecitabine dispersible tablet of different polyvinyl pyrrolidone K30, disintegrating agent cross-linking sodium carboxymethyl cellulose, the preparation of filler microcrystalline Cellulose ratio as investigating index, the result of screening is preferred adhesive PVP K30, disintegrating agent cross-linking sodium carboxymethyl cellulose, filler microcrystalline Cellulose and the ratio consumption between them.

Screening process is as follows:

According to dispersible tablet instant capacity characteristic, carry out following screening with reference to pertinent literature and dispersible tablet supplementary product kind commonly used and consumption:

Table 5-1 capecitabine dispersible tablet prescription forms

Conclusion: should be fit to industrialization production requirements by prescription by above verification experimental verification.

The screening of process optimization is as follows:

1, the different meshes raw material process is optimized

Capecitabine raw material slightly soluble in water is soluble in methanol, ethanol, acetonitrile.

The different meshes raw material on the product dissolution to affect the result as follows

Conclusion: when preparation research, crude drug was pulverized 120 mesh sieves, in order to reach and the former similar dissolution of medicine that grinds.Thereby reach good bioavailability and bioequivalence.

2, the screening of baking temperature

This product technical process is wet granulation, carries out following optimization for different drying modes

Conclusion: the checking baking temperature is at 50 ℃, and dry 6 hours the most suitable.

The capecitabine dispersible tablet of technical solution of the present invention preparation is compared with existing commercially available capecitabine flake products, can strengthen bioavailability, is compared with existing technology, and has improved stability, dissolution.

Below further specify beneficial effect of the present invention by test data:

The test of test example 1 sterilization stability

Capecitabine dispersible tablet to embodiment 1, embodiment 2 and comparative example 1 preparation is estimated, and investigates preparation character, dissolution and capecitabine degradation rate.The results are shown in Table 1.

The stability of the different prescription of table 1 capecitabine dispersible tablet

Detect index	Embodiment 1	Embodiment 2	Comparative example 1
				Character	The white ovals matrix	The white ovals matrix	The white ovals matrix
Dissolution	98%	98%	88%
				Degradation rate	0.6%	0.6%	1.4%

By as seen from Table 1, the sample of the more commercially available formula preparation of capecitabine dispersible tablet of the present invention's preparation can strengthen bioavailability, the various easily characteristics of the mode of taking.

The test of test example 2 storage-stables

The capecitabine dispersible tablet of embodiment 1, embodiment 2 and comparative example 1 preparation was at room temperature preserved 24 months, take content, total impurities as investigating index, carried out long-time stability and investigate test.The results are shown in Table 2.

The different prescription of table 2 capecitabine dispersible tablet is long-time stability under the holding conditions at room temperature

Minute	Embodiment 1	Embodiment 2	Comparative example 1
				0 month	0.61%	0.65%	0.81%
March	0.70%	0.70%	0.95%
				June	0.80%	0.81%	1.10%
JIUYUE	0.92%	0.90%	1.25%
				December	0.99%	0.98%	1.34%
18 months	1.05%	1.10%	1.46%
				24 months	1.22%	1.22%	1..52%
36 months	1.48%	1.47%	2.20%
				36 months content of drug	98.1%	98.9%	97.8%

By as seen from Table 2, the sample of the more commercially available formula preparation of capecitabine dispersible tablet of the present invention's preparation can at room temperature be preserved 36 months, and product quality still meets the national drug standards.

What wherein comparative example 1 adopted is the preparation method of conventional tablet, and prescription derives from this product description of company of Roche Group.Method is as follows:

500g capecitabine, 80.35g lactose, 19.2g cross-linking sodium carboxymethyl cellulose are added in the three-dimensional motion mixer, fully mix homogeneously; The material of mix homogeneously is put into efficient wet granulator, for subsequent use; Hypromellose (w/v) soft material processed of adding 3% is crossed 20 eye mesh screens, drying, granulate, adding 32g MCC mix homogeneously, tabletting.

The invention effect

The quality of high capecitabine dispersible tablet can be provided by the present invention as mentioned above.The present invention can strengthen bioavailability, and it is various to take mode, satisfies more administration crowd.

In sum, the invention provides a kind of new capecitabine dispersible tablet prescription and preparation method, production process is simple, has distinct creativeness and practicality, in clinical use good application prospect will be arranged.

The specific embodiment

The present invention will be described in more detail by the following examples, but the present invention is not limited to this.

Embodiment 1

75% capecitabine was pulverized 120 mesh sieves, microcrystalline Cellulose 10% (w/w), cross-linking sodium carboxymethyl cellulose 15% (w/w) be added in the three-dimensional motion mixer, fully mix homogeneously; The material of mix homogeneously is put into efficient wet granulator, for subsequent use; Add 5% PVP K30 soft material processed, cross 20 eye mesh screens, baking temperature is at 50 ℃, drying 6 hours, granulate, mix homogeneously, tabletting and get final product.

Embodiment 2

80% capecitabine was pulverized 120 mesh sieves, microcrystalline Cellulose 7.5% (w/w), cross-linking sodium carboxymethyl cellulose 7.5% (w/w) be added in the three-dimensional motion mixer, fully mix homogeneously; The material of mix homogeneously is put into efficient wet granulator, for subsequent use; Add 5% PVP K30 soft material processed, cross 20 eye mesh screens, baking temperature is at 50 ℃, drying 6 hours, granulate, mix homogeneously, tabletting and get final product.

Embodiment 3

Capecitabine 75%, microcrystalline Cellulose 15% (w/w), cross-linking sodium carboxymethyl cellulose 7.5% (w/w) are added in the three-dimensional motion mixer, fully mix homogeneously; The material of mix homogeneously is put into efficient wet granulator, for subsequent use; Add 2.5% PVP K30 soft material processed, mistake 20 eye mesh screens, drying, granulate, mix homogeneously, tabletting and get final product.

Embodiment 4

Capecitabine 80%, microcrystalline Cellulose 8% (w/w), cross-linking sodium carboxymethyl cellulose 10% (w/w) are added in the three-dimensional motion mixer, fully mix homogeneously; The material of mix homogeneously is put into efficient wet granulator, for subsequent use; Add 2% PVP K30 soft material processed, mistake 20 eye mesh screens, drying, granulate, mix homogeneously, tabletting and get final product.

Embodiment 5

Capecitabine 75%, microcrystalline Cellulose 10% (w/w), cross-linking sodium carboxymethyl cellulose 4% (w/w) are added in the three-dimensional motion mixer, fully mix homogeneously; The material of mix homogeneously is put into efficient wet granulator, for subsequent use; Add 6% PVP K30 soft material processed, mistake 20 eye mesh screens, drying, granulate, mix homogeneously, tabletting and get final product.

Claims (3)

1. capecitabine dispersible tablet is characterized in that it is composed as follows:

Its accounting example scope of principal agent capecitabine is 70% ~ 80%;

Its accounting example scope of polyvinyl pyrrolidone K30 is 3% ~ 7%;

Its accounting example scope of disintegrating agent cross-linking sodium carboxymethyl cellulose is 3% ~ 7%;

Its accounting example scope of filler microcrystalline Cellulose is 10% ~ 20%;

Its preparation method is as follows:

(a) take by weighing respectively capecitabine, cross-linking sodium carboxymethyl cellulose, the microcrystalline Cellulose of recipe quantity, mix homogeneously is put into efficient wet granulator, and is for subsequent use;

(b) the PVP K30 aqueous solution is added in the material that mixes the preparation soft material;

(c) efficient wet granulator is granulated, and granule order number is 20 orders;

(d) boiling drier, drying;

(e) granulate, granule order several 18;

(f) high-efficiency rotating tablet machine, tabletting.

2. capecitabine dispersible tablet according to claim 1 is characterized in that it is composed as follows:

Its accounting example scope of principal agent capecitabine is 75%;

Its accounting example scope of polyvinyl pyrrolidone K30 is 5%;

Its accounting example scope of disintegrating agent cross-linking sodium carboxymethyl cellulose is 5%;

Its accounting example scope of filler microcrystalline Cellulose is 15%;

Its preparation method is as follows:

(a) take by weighing respectively capecitabine, cross-linking sodium carboxymethyl cellulose, the microcrystalline Cellulose of recipe quantity, mix homogeneously is put into efficient wet granulator, and is for subsequent use;

(b) the PVP K30 aqueous solution is added in the material that mixes the preparation soft material;

(c) efficient wet granulator is granulated, and granule order number is 20 orders;

(d) boiling drier, drying;

(e) granulate, several 18 orders of granule order;

(f) high-efficiency rotating tablet machine, tabletting.

3. the preparation method of the described capecitabine dispersible tablet of claim 1 is characterized in that step is as follows:

Its prescription is composed as follows:

Its accounting example scope of principal agent capecitabine is 70% ~ 80%;

Its accounting example scope of polyvinyl pyrrolidone K30 is 3% ~ 7%;

Its accounting example scope of disintegrating agent cross-linking sodium carboxymethyl cellulose is 3% ~ 7%;

Its accounting example scope of filler microcrystalline Cellulose is 10% ~ 20%;

Its preparation method is as follows:

(a) take by weighing respectively capecitabine, cross-linking sodium carboxymethyl cellulose, the microcrystalline Cellulose of recipe quantity, mix homogeneously is put into efficient wet granulator, and is for subsequent use;

(b) the PVP K30 aqueous solution is added in the material that mixes the preparation soft material;

(c) efficient wet granulator is granulated, and granule order number is 20 orders;

(d) boiling drier, drying;

(e) granulate, granule order several 18;

(f) high-efficiency rotating tablet machine, tabletting.