CN110604726B

CN110604726B - Sofosbuvir composition and application thereof

Info

Publication number: CN110604726B
Application number: CN201910656347.4A
Authority: CN
Inventors: 高海丽; 谭鑫强; 宿亮; 袁秀菊; 王洪锋; 龙世玉; 陈涛; 王玲兰; 王新军; 罗隽; 秦杰峰; 吴正勇; 文琛; 徐彬滨
Original assignee: Hunan Qianjin Xiangjiang Pharmaceutical Co ltd; Qianjin Pharmaceutical Co ltd
Current assignee: Hunan Qianjin Xiangjiang Pharmaceutical Co ltd; Qianjin Pharmaceutical Co ltd
Priority date: 2019-07-19
Filing date: 2019-07-19
Publication date: 2022-06-07
Anticipated expiration: 2039-07-19
Also published as: CN110604726A

Abstract

The invention discloses a sofosbuvir composition and application thereof. The content of the sofosbuvir composition consists of the following components in percentage by mass: 88-95% of sofosbuvir, 4-10% of a disintegrating agent and 0.1-5% of a flow aid; the preparation method of the sofosbuvir composition content comprises the following steps: sieving Sofosbuvir, mixing with a disintegrating agent and a flow aid, and then rolling and crushing by using a dry-method granulator, and finishing granules to obtain the Sofosbuvir tablet; wherein, the granulating conditions are as follows: the pressure is 40-80 kg/cm²The distance between the pressing wheels is 1-3 mm, the extrusion speed is 10-20 rpm, the rotating speed of the feeding screw is 5-20 rpm, and the aperture of the granulating screen is 0.6-2.0 mm. The Sofosbuvir composition prepared by the invention is easy to swallow, has few impurity types and small amount (the maximum single impurity is controlled below 0.01 percent, and the total impurity is controlled below 0.025 percent), has the dissolution rate equivalent to that of the original ground tablet under the condition of four dissolution media, can be quickly dissolved to about 98 percent by 0.1M hydrochloric acid solution for 15min, and has good stability.

Description

Sofosbuvir composition and application thereof

Technical Field

The invention relates to the technical field of medicinal preparations, in particular to a sofosbuvir composition and application thereof.

Background

Viral hepatitis C, abbreviated as hepatitis C and hepatitis C, is a viral hepatitis caused by Hepatitis C Virus (HCV) and is mainly transmitted by blood transfusion, acupuncture, drug absorption and other ways. According to the world health organization, the global infection rate of HCV is about 3%, and it is estimated that about 1.8 million people are infected with HCV and nearly 400 million people are infected with hepatitis c every year. Hepatitis c is known by the world health organization as a "virus timed bomb" and 35 million people die each year. It is understood that 2015 viral hepatitis alone results in the death of 134 million people, and at least 7100 million are chronic hepatitis c patients. Hepatitis c can lead to chronic inflammatory necrosis and fibrosis of the liver, and some patients may develop cirrhosis and even hepatocellular carcinoma (HCC). The mortality rate associated with HCV infection (death from liver failure and hepatocellular carcinoma) will continue to increase over the next 20 years, posing significant health and life risks to the patient and becoming a serious social and public health problem.

The birth of the hepatitis C solid oral medicine, Sofosbuvir (also translated as Sofosbuvir, the English name Sofosbuvir, the trade name Sovaldi), which is the nasal progenitor, rescues hepatitis C patients who can only be treated with interferon and suffer from great side effects. Sofosbuvir (Sofosbuvir, 400mg, tablet) was developed by Gilidide (Gilead) and is a once daily oral nucleoside analogue polymerase inhibitor capable of blocking a specific protein required for hepatitis C virus replication and is used in the treatment of adult chronic Hepatitis C Virus (HCV) infection. On 6 th 12 th 2013, sofosbuvir is approved by the Food and Drug Administration (FDA) to be marketed in the united states, on 6 th 1 st 2014, approved by the european drug administration (EMEA) to be marketed in countries of the european union, on 26 th 3 rd 2015, to be marketed in japan officially, and has not been marketed in china to date. Sofosbuvir, which is used as the basic part of an antiviral treatment regimen for the treatment of chronic Hepatitis C Virus (HCV) infection, is the first effective and safe drug for the treatment of HCV infection without the concomitant use of interferon, can be used in combination with ribavirin for the treatment of adult patients with chronic hepatitis c types 2 and 3, and can also be used in combination with polyethylene glycol interferon (PEG-IFN) and ribavirin as a first-line drug for adult patients with chronic hepatitis c types 1 and 4. Sofosbuvir marketing was based on data support from 6 phase III studies (NEUTRINO, FISSION, POSITRON, FUSION, VALENCE, PHOTON-1). 1947 clinical trials involving subjects were evaluated in HCV-infected patients who had not previously received treatment (initial treatment) or who had no effect on previous treatment (had a history of treatment), and also included patients with combined HCV and HIV infection. The results of all clinical trials show that one treatment regimen comprising sofosbuvir is effective against multiple types of hepatitis c virus. In addition, sofosbuvir is also effective in subjects who cannot tolerate or adopt interferon-based treatment regimens and in liver cancer subjects awaiting liver transplantation, providing unmet medical needs for these patient populations.

However, the original prescription has complex composition, the weight of a commercially available tablet with the specification of 400mg reaches 1245mg, the appearance is large by 20mm multiplied by 9mm, the tablet is not easy to swallow, the medication compliance and the compliance are not good, and the tablet is difficult to take especially for people with uncomfortable throat. The medicament in the market is single in form, limited in clinical medication selection, more in impurity types in finished product stability investigation, basically coated tablets at present, and the problems of defects, material adhesion to rollers, high cost and the like existing in the process of dry granulation in the prior art are solved. For example, both patents 201510955793.7 and 201710086196.4 provide a sofosbuvir coated tablet, which is prepared by optimized compounding of auxiliary materials, so that the dissolution rate and stability of the coated tablet are improved; however, the problem of using more auxiliary materials exists, more dosage needs to be taken if the corresponding effect is achieved; meanwhile, the preparation process comprises the steps of granulation, tabletting, coating and the like, and is relatively complex.

Therefore, there is a need to develop a new formulation of sofosbuvir that is easy to swallow, high in dissolution rate, less in impurities and good in stability.

Disclosure of Invention

The invention aims to overcome the defects of low dissolution rate, more impurities, poor stability and difficult swallowing of a sofosbuvir product in the prior art, and provides a sofosbuvir composition which is easy to swallow, high in dissolution rate, less in impurities and good in stability.

Another object of the present invention is to provide the use of the above sofosbuvir composition in a medicament for treating chronic hepatitis c.

The above purpose of the invention is realized by the following scheme:

the content of the sofosbuvir composition consists of the following components in percentage by mass:

88-95% of sofosbuvir, 4-10% of a disintegrating agent and 0.1-5% of a flow aid;

the preparation method of the contents of the sofosbuvir composition is as follows:

s1: sieving the sofosbuvir for later use;

s2: mixing sofosbuvir, a disintegrating agent and a flow aid, then rolling and grinding by using a dry-method granulator, and finishing granules to obtain the sofosbuvir composition; wherein the pressure is 40-80 kg/cm²The distance between the pinch rollers is 1-3 mm, and the extrusion speed is 10-20 rpmThe rotating speed of the feeding screw is 5-20 rpm, and the aperture of the granulating screen is 0.6-2.0 mm.

The invention adopts a dry-method granulator to carry out the working procedures of rolling, crushing, granule finishing and the like by adjusting the formula; by controlling the pressure, the extrusion speed, the pressing wheel spacing, the rotating speed of a feeding screw and the mesh size and the mesh number of the granulating screen in dry granulation, the prepared sofosbuvir composition is easy to swallow, the impurity types are few, the amount is small (the maximum single impurity is controlled below 0.01 percent, the total impurity is controlled below 0.025 percent), the dissolution rate under the four dissolution medium conditions is equivalent to that of the original grinding tablet, the 0.1M hydrochloric acid solution can be quickly dissolved out to about 98 percent within 15min, the stability is good, related substances have no obvious change (the content is increased from 0.017 to 0.051) in stability test investigation of 6 months, and the dissolution rate is superior to that of the original grinding tablet (related substances of the original grinding tablet are increased and are increased from 0.026 to 0.097%). The ratio of the fine powder of the Sofosbuvir particles is less than 20 percent, the bulk density is 0.65-0.95 g/ml, and the angle of repose is 34-42 degrees.

Meanwhile, the invention solves the technical defect that the production efficiency is reduced due to the poor flowability of the material and the disassembly and cleaning of a card machine caused by the adhesion of a roller in the original dry granulation process, the whole production process is smooth, the process is simple and stable, and the uniform, high-quality, safe and effective Sofosbuvir composition can be produced and is used for treating the clinical chronic Hepatitis C (HCV).

Therefore, preferably, the content of the sofosbuvir composition consists of the following components in percentage by mass:

88-93% of sofosbuvir, 5-9% of a disintegrating agent and 2.0-3.0% of a glidant.

Preferably, the disintegrating agent is one or more of dry starch, croscarmellose sodium, sodium carboxymethyl starch and cross-linked polyvinylpyrrolidone. These disintegrating agents have good water absorbability and expansibility, and are strong in disintegrability and free from incompatibility or resistance with active ingredients. More preferably, the disintegrant is croscarmellose sodium.

Preferably, the glidant is one or more of silicon dioxide, hydrogenated vegetable oil or polyethylene glycol. The glidant is beneficial to improving the material transfer of the mixture of the bulk drug with poor fluidity and other components, can well solve the problem that the material adheres to a roller in the dry granulation process, and has stable property, no toxic or side effect and no influence on the exertion of the drug effect. More preferably, the glidant is silicon dioxide.

More preferably, the content of the sofosbuvir composition is composed of the following components in percentage by mass:

88.9 percent of sofosbuvir, 8.1 percent of croscarmellose sodium and 3.0 percent of silicon dioxide.

Preferably, in S1, the mesh number of the sieve is 30-50 meshes; more preferably, the mesh number of the screen is 40 meshes.

Preferably, in S2, the pressure is 50-70 kg/cm²The interval between the press wheels is 1.5-2.5 mm, the extrusion speed is 12-16 rpm, the rotating speed of the feeding screw is 10-15 rpm, and the aperture of the granulating screen is 1.2 mm.

Preferably, in S2, the mixing is performed for 5-25 min by using a mixer. Further, the mixing time is 10-20 min.

Preferably, the composition is a capsule, granule or tablet; more preferably, the composition is a capsule. The invention greatly reduces the tablet weight of the preparation, and prepares the giant tablet with the volume of 1245mg into the capsule which is easy to swallow and has the filling amount of only 450mg by adjusting the formula.

In addition, the invention changes the current situation that the medicament is single in form and limited in clinical medication selection in the current market, can provide flexibility of clinical medication selection for patients, particularly patients with discomfort in throat and dysphagia and medical care personnel, diversifies the Sofosbuvir dosage form, can well meet the clinical medication requirement, and has the advantages of convenient taking, good compliance and dependence and good clinical significance.

Compared with the prior art, the invention has the following beneficial effects:

the invention adopts a dry-method granulator to carry out the working procedures of rolling, crushing, granule finishing and the like by adjusting the formula; the prepared sofosbuvir composition is easy to swallow by controlling the pressure, the extrusion speed, the pressure wheel spacing, the feeding screw rotating speed and the mesh size and the mesh number of granulation in dry granulation, the impurity types are few, the amount is small (the maximum single impurity is controlled below 0.01 percent, the total impurity is controlled below 0.025 percent), the dissolution rate under four dissolution medium conditions is equivalent to that of the original grinding tablet, the 0.1M hydrochloric acid solution can be rapidly dissolved out to about 98 percent in 15min, the stability is good, related substances have no obvious change (increased from 0.017 to 0.051) in stability test investigation of 6 months, the dissolution rate is superior to that of the original grinding tablet (related substances of the original grinding tablet are increased and increased from 0.026 to 0.097 percent), the fine powder proportion of the sofosbuvir composition particles is less than 20 percent, the bulk density is 0.65-0.95 g/ml, and the repose angle is 34-42 degrees.

Meanwhile, the invention solves the process defect problems that the flowability of the material is poor in the original dry granulation process, and the production efficiency is reduced due to the disassembly and cleaning of the card machine caused by the adhesion of the roller.

The invention greatly simplifies the formulation composition of the original research, further reduces the dosage of unit dose with the same specification, reduces the types and the dosage of auxiliary materials in the formulation composition, thereby reducing impurities generated by the interaction between the medicines, improving the dissolution rate of the medicines, having good stability, simplifying the preparation process, removing the procedures of tabletting and coating and reducing the cost. The preparation process is simple and stable, can produce the uniform, high-quality, safe and effective sofosbuvir composition, and can be applied to the treatment of chronic Hepatitis C (HCV).

Drawings

FIG. 1 is a graph showing the dissolution curves of three samples prepared in example 8 of the present invention and the original product commercially available in 0.1M hydrochloric acid;

FIG. 2 is a graph showing the dissolution curves in water of three batches of samples prepared in example 8 of the present invention and the original product commercially available from the original research;

FIG. 3 is a graph showing the dissolution curves of three samples prepared in example 8 of the present invention and the original product commercially available in phosphate buffer at pH 4.5;

FIG. 4 shows the dissolution curves of the three samples prepared in example 8 of the present invention and the original product commercially available from the original grinder in phosphate buffer at pH 6.8.

Detailed Description

The present invention will be further described with reference to the following specific examples and drawings, which are not intended to limit the invention in any manner. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.

Unless otherwise indicated, reagents and materials used in the present invention are commercially available.

Example 1

The embodiment provides a sofosbuvir hard capsule which is prepared from a raw material medicament and an auxiliary material, wherein the raw material medicament is an original ground crystal sofosbuvir, the auxiliary material comprises croscarmellose sodium and silicon dioxide, and the content of each component is calculated according to 50 granules and is shown in the table below. Table 1 formulation of sofosbuvir hard capsules provided in example 1

The preparation method of the sofosbuvir hard capsule content granules adopted in the embodiment comprises the following steps:

1) sieving the bulk drug sofosbuvir with a 40-mesh sieve for later use;

2) weighing the bulk drugs, the auxiliary materials, the disintegrating agent and the glidant in the formula amount, and mixing for 15min in a mixer; then rolling and crushing by adopting a dry-method granulator under the pressure of 60kg/cm²The extrusion speed is 15rpm, the pinch roller interval is 2mm, the rotating speed of a feeding screw is 15rpm, the aperture of a granulating screen is 1.2mm, the granulation is carried out, the phenomenon that materials are adhered to rollers is avoided, and the particle formability is good;

3) detecting the content of the particles prepared in the step 2), determining the filling amount according to the content, adjusting a measuring disc,

filling the capsules with gelatin hollow capsules, and packaging to obtain capsules.

Example 2

The difference between the hard sofosbuvir capsule prepared in the embodiment and the embodiment 1 is that the content of each component of the hard sofosbuvir capsule prepared in the embodiment is as follows according to 50 granules:

table 2 formulation of sofosbuvir hard capsules provided in example 2

Example 3

The embodiment provides a sofosbuvir hard capsule which is prepared from a raw material medicament and an auxiliary material, wherein the raw material medicament is an original ground crystal sofosbuvir, the auxiliary material comprises croscarmellose sodium and silicon dioxide, and the content of each component is calculated according to 50 granules and is shown in the table below.

Table 3 formulation of sofosbuvir hard capsules provided in example 3

1) sieving the bulk drug sofosbuvir with a 30-mesh sieve for later use;

2) weighing the bulk drugs, the auxiliary materials, the disintegrating agent and the glidant in the formula amount, and mixing for 5min in a mixer; then rolling and crushing by adopting a dry type granulator under the pressure of 40kg/cm²The extrusion speed is 10rpm, the pinch roller interval is 1mm, the rotating speed of a feeding screw is 5rpm, the aperture of a granulating screen is 0.6mm, the granulation is carried out, the phenomenon that materials are adhered to rollers is avoided, and the particle formability is good;

3) detecting the content of the granules prepared in the step 2), determining the filling amount according to the content, adjusting a metering disc, filling the granules with gelatin hollow capsules, and packaging to obtain capsules.

Example 4

Table 4 formulation of sofosbuvir hard capsules provided in example 4

1) sieving the bulk drug sofosbuvir with a 50-mesh sieve for later use; (ii) a

2) Weighing the bulk drugs, the auxiliary materials, the disintegrating agent and the flow aid according to the prescription amount, and mixing in a mixer for 20 min; then rolling and grinding with dry granulator under 80kg/cm²The extrusion speed is 10rpm, the pinch roller interval is 3mm, the rotating speed of a feeding screw is 10rpm, the aperture of a granulating screen is 1.6mm, the granulating is carried out, the phenomenon that materials are adhered to rollers is avoided, and the particle formability is good;

Example 5

Table 5 formulation of sofosbuvir hard capsules provided in example 5

1) sieving the bulk drug sofosbuvir with a 45-mesh sieve for later use;

2) weighing the bulk drugs with the prescription amount, and mixing the bulk drugs with the auxiliary materials, namely the disintegrating agent and the glidant in a mixer for 20 min; then rolling and crushing by adopting a dry type granulator under the pressure of 70kg/cm²The extrusion speed is 20rpm, the pinch roller interval is 2mm, the rotating speed of a feeding screw is 20rpm, the aperture of a granulating screen is 1.2mm, the granulation is carried out, and no material appearsThe roller sticking phenomenon is avoided, and the particle formability is good;

Example 6 Performance test of Sofosbuvir particles of examples 1 to 5

The performance of the sofosbuvir granules (materials before filling capsules) prepared in examples 1 to 5 was tested, and the results of the test of the granulation process and the granule performance are shown in the following table.

Table 6 performance test of sofosbuvir particles prepared in examples 1 to 5

	Material sticking condition	Angle of repose (°)	Bulk density (g/ml)	Fluidity of the resin
					Example 1	Is free of	39.0	0.80	Is preferably used
Example 2	Is free of	39.2	0.82	Is better
					Example 3	Is free of	42.0	0.95	Good taste
Example 4	Is free of	34.8	0.65	Good taste
					Example 5	Is free of	36.7	0.76	Good taste

From the test results in table 6, the performance test results of the sofosbuvir granules prepared in examples 1 to 5 were good, and no material was adhered, but the flowability of examples 1 and 2 was better than that of the other examples.

Example 7 dissolution test of Sofosbuvir granules of examples 1 to 5

The sofosbuvir hard capsules prepared in examples 1 to 5 were subjected to an examination of their dissolution curves in four media, 0.1M hydrochloric acid solution, ph6.8 phosphate buffer, ph4.5 acetate buffer, and water, respectively, and compared with the dissolution curve of the commercially available stock tablets.

Dissolution conditions:

volume of dissolution medium: 900mL

The method comprises the following steps: second part of the Chinese pharmacopoeia 2010 edition attached XC second method (Paddle method)

Rotating speed: 75rpm

Sampling points are as follows: 5. 10, 15, 20, 30, 45 and 60min, taking 10mL of the dissolved liquid, filtering by 0.45 mu m

Filtering with membrane, and simultaneously adding equal amount of isothermal medium.

A determination method, namely an ultraviolet spectrophotometer method.

The dissolution rate detection data of the sofosbuvir hard capsules prepared in the examples 1-5 are shown in the table below.

Table 7 dissolution test of sofosbuvir hard capsules prepared in examples 1 to 5

Table 8 content measurement of sofosbuvir hard capsules prepared in examples 1 to 5

	Content (%)	Maximum single impurity (%)	Total impurities (%)
				Example 1	99.6	0.010	0.019
Example 2	99.9	0.007	0.017
				Example 3	98.9	0.010	0.025
Example 4	99.7	0.009	0.021
				Example 5	98.6	0.008	0.023
Commercially available product	98.5	0.015	0.026

From the test results in table 7, the dissolution rates of the sofosbuvir hard capsules prepared in examples 1-5 in four dissolution media are equivalent to those of the original product sold in the market, and the sofosbuvir hard capsules can be rapidly dissolved to about 98% in 0.1M hydrochloric acid solution for 15 min; from the test results in table 8, the content of sofosbuvir hard capsules prepared in examples 1 to 5 and related substances are better than those of the original product on the market, and the maximum single impurity of example 2 is minimum (0.007%), and the total impurity is minimum (0.017%).

Example 8

This example, referring to example 2, differs from example 2 in the size of the batch size, and this example prepares three batches (140701, 140702, 140703) of a trial 2.3 million batches of sofosbuvir hard capsules in parallel, all following the dry granulation process of example 2. The corresponding detection is carried out, and the control range and the detection result of the key process parameters are as follows:

TABLE 9 control ranges and test results for key process parameters provided in this example

Example 9: EXAMPLE 8 sample testing

Example 8 sample dissolution Curve examination

The dissolution curves of 140701, 140702 and 140703 in example 8 in four media of 0.1M hydrochloric acid solution, pH6.8 phosphate buffer solution, pH4.5 acetate buffer solution and water were examined and compared with the dissolution curve of the original tablet, the dissolution test method in example 7 was the same as the dissolution test method, and the test data are as follows:

TABLE 10140701.140702.140703 dissolution test data for three batches of sofosbuvir hard capsules and commercially available tablets

And (4) conclusion: according to the test data shown in Table 10, 140701, 140702 and 140703 in example 8 were dissolved in four media, i.e., 0.1M hydrochloric acid solution, pH6.8 phosphate buffer solution, pH4.5 acetate buffer solution and water, respectively, and the dissolution curves are shown in FIGS. 1 to 4. FIGS. 1 to 4 show the dissolution curves of the self-preparation of the present invention and the commercially available products in 0.1M hydrochloric acid, water, pH4.5 phosphate buffer and pH6.8 phosphate buffer, respectively; as can be seen from the attached figures in the specification, the dissolution curves of the self-prepared product prepared by the invention and the commercially available original ground product in 4 media are consistent.

B: example 8 substance examination

The related substance detection method comprises the following steps: taking a proper amount of the content (about 20mg equivalent to sofosbuvir), putting the content into a 20ml measuring flask, adding methanol, ultrasonically dissolving, diluting to a scale, shaking uniformly, filtering, and taking the subsequent filtrate as a test solution; an appropriate amount was precisely measured and diluted with methanol to make 1ug of solution per 1ml as a control solution. The detection is carried out according to a high performance liquid chromatography test, and the data of specific related substances are shown in the following table.

TABLE 11140701.140702.140703 content of three batches of Sofosbuvir hard capsules and commercially available tablets and related substance test data (area normalization statistics)

And (4) conclusion: in example 8, the number of the 140701, 140702 and 140703 samples is only two, the number of the 140701, 140702 and 140703 samples is less than 6, and the maximum single impurity and the total impurity are lower than those of the original ground commercial product, in example 8, the maximum single impurity of 140701, 140702 and 140703 samples is 0.010, the maximum single impurity of the original ground commercial product is 0.020, the maximum total impurity of 140701, 140702 and 140703 samples in example 8 is 0.020, the maximum total impurity of the original ground commercial product is 0.026, and in example 8, the safety of 140701, 140702 and 140703 samples is better.

C stability test results

Three batches of sofosbuvir hard capsules (batch numbers 140701, 140702, 140703) from example 8 were compared to the commercial stock ground tablets for influencing, accelerating and long-term stability, respectively, under the following conditions and results:

TABLE 12 results of conventional stability studies

EXAMPLE 10 Effect of granulation pressure on product

Referring to example 2, the difference from example 2 is that the effect of the granulation pressure on the product was examined using the granulation pressure in step 2) of the process for preparing the contents of sofosbuvir hard capsule as a single factor variable.

The results show that when the granulation pressure is less than 40kg/cm²In the case of the extrusion, the resulting extruded sheet has poor moldability, is brittle, contains a large amount of fine powder, has a non-uniform particle size, and has poor flowability, and is not suitable for the next step. When the pressure for granulating is more than 80kg/cm²In the case of the extrusion, the resulting extruded sheet has good moldability, but is discolored, slightly hard, coarse in particle size and non-uniform in particle size, and is not suitable for the next step.

For example, when the pressure for granulating is 30kg/cm²When the material is adhered, loose and fragile, the fine powder is more than 30 percent, the angle of repose is 43.4 degrees, and the fluidity is poor. When the pressure of the granulation is 90kg/cm²When the material is light yellow, the particles are coarse, the particle sizes are not uniform, the angle of repose of the product is 33.7 degrees, and the flowability is poor.

EXAMPLE 11 Effect of the pinch roller spacing of granulation on the product

Referring to example 2, the difference from example 2 is that the effect of the pinch roller spacing on the product is examined using the pinch roller spacing for granulation in step 2) of the process for preparing the contents granules of sofosbuvir hard capsules as a single factor variable.

The results show that when the pinch roller spacing is greater than 3, the resulting extruded sheet has larger particles and less uniform particles, which are not suitable for the next step. If the interval between the granulating pressing wheels is 4, the material has coarse particles, nonuniform sizes, a repose angle of 42.5 degrees and poor flowability.

EXAMPLE 12 Effect of feed screw speed for pelletization on product

Referring to example 2, the difference from example 2 was that the influence of the feed screw rotation speed on the product was examined using the feed screw rotation speed for granulation in step 2) of the process for preparing the contents granules of sofosbuvir hard capsules as a single factor variable.

The results show that when the feed screw rotation rate is more than 20, the resulting extruded sheet is slightly inferior in moldability, brittle, much fine powder and poor in flowability. If the rotation speed of the feeding screw is more than 25rpm, the angle of repose of the product is 33.8 degrees, the material is adhered, loose and fragile, the fine powder is more than 30 percent, and the flowability is poor.

EXAMPLE 13 Effect of mesh size of granulation on product

Referring to example 2, the difference from example 2 is that the influence of the mesh size on the product is examined by using the mesh size of the granules prepared in step 2) of the preparation process of the contents granule of sofosbuvir hard capsule as a single factor variable.

The results show that when the mesh size is larger than 2mm, the capsule particles are larger, the degree of compression is smaller and the particles are less uniform. For example, when the mesh size of the sieve is 2.2mm, the obtained capsule particles are larger, the compression degree is slightly smaller than that before granulation, the improvement of the compression degree of the particles with the mesh size of 1.2mm is not obvious in example 2, and the particles are slightly less uniform.

Comparative example 1

This comparative example refers to example 2, and differs from example 2 in that the contents of sofosbuvir hard capsules are prepared as follows:

1) sieving the bulk drug sofosbuvir with a 40-mesh sieve for later use;

2) weighing the bulk drugs, the auxiliary materials, the disintegrating agent and the glidant in the formula amount, and mixing for 15min in a mixer; preparing soft material with purified water, sieving with mesh size of 1.2mm, granulating, drying in oven at 60 deg.C until water content is less than 3%, and sieving with 20 mesh sieve;

Compared with example 2, the maximum filling amount of the granules prepared by the wet granulation process provided by the comparative example is about 301 mg/granule, and the theoretical filling amount and the specified Sofosbuvir 400 mg/granule cannot be reached.

In conclusion, the Sofosbuvir hard capsule preparation prepared by the invention has simple and stable prescription composition and preparation process, can produce uniform, high-quality, safe and effective Sofosbuvir capsules with the specification of 400mg and the loading capacity of 450mg, is used for treating chronic Hepatitis C (HCV), and has good clinical significance and market value.

While the present invention has been described in terms of specific process equipment and process steps illustrated in the above examples, it will be apparent to those of ordinary skill in the art that it is not intended to limit the invention to the above examples, but rather to illustrate the principles of the invention, it is to be understood that the invention is susceptible to various changes and modifications without departing from the spirit and scope of the invention as defined by the appended claims.

Claims

1. The sofosbuvir composition is characterized in that the content of the sofosbuvir composition consists of the following components in percentage by mass: 88-95% of sofosbuvir, 4-10% of a disintegrating agent and 0.1-5% of a flow aid;

s1: sieving the sofosbuvir for later use;

s2: mixing sofosbuvir, a disintegrating agent and a flow aid, then rolling and grinding by using a dry-method granulator, and finishing granules to obtain the sofosbuvir composition;

wherein the pressure is 40-80 kg/cm2, the pinch roller interval is 1-3 mm, the extrusion speed is 10-20 rpm, the rotating speed of a feeding screw is 5-20 rpm, and the aperture of a granulating screen is 0.6-2.0 mm;

the disintegrant is one or more of dry starch, croscarmellose sodium, sodium carboxymethyl starch and crospolyvinylpyrrolidone, and the glidant is one or more of silicon dioxide, hydrogenated vegetable oil or polyethylene glycol.

2. The sofosbuvir composition according to claim 1, wherein the contents of the sofosbuvir composition consist of the following components in mass percent: 88-93% of sofosbuvir, 5-9% of a disintegrating agent and 2.0-4.0% of a glidant.

3. The sofosbuvir composition according to claim 2, wherein the disintegrant is croscarmellose sodium and the glidant is silicon dioxide.

4. The sofosbuvir composition according to claim 3, wherein the contents of the sofosbuvir composition consist of the following components in percentage by mass: 88.9 percent of sofosbuvir, 8.1 percent of croscarmellose sodium and 3.0 percent of silicon dioxide.

5. The sofosbuvir composition as claimed in claim 1, wherein the mesh number of the sieve in S1 is 30 to 50 mesh.

6. The sofosbuvir composition as claimed in claim 1, wherein the pressure in S2 is 50-70 kg/cm2, the pinch roller spacing is 1.5-2.5 mm, the extrusion speed is 12-16 rpm, the rotation speed of a feeding screw is 10-15 rpm, and the aperture of a granulating screen is 1.2 mm.

7. The sofosbuvir composition according to claim 1, wherein in S2, the mixing is performed by mixing in a mixer for 5-25 min.

8. The sofosbuvir composition according to claim 1, wherein the composition is a capsule, a granule or a tablet.

9. Use of the sofosbuvir composition as claimed in any of claims 1 to 8 in the manufacture of a medicament for the treatment of chronic hepatitis c.