CN106667936B - Sofosbuvir tablet and preparation method thereof - Google Patents
Sofosbuvir tablet and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a sofosbuvir tablet and a preparation method thereof. The sofosbuvir tablet comprises a tablet core and a film coating layer, wherein the tablet core is prepared from an active ingredient and a pharmaceutically acceptable auxiliary material through a wet granulation process, the active ingredient is a sofosbuvir crystal form 6, and the auxiliary material comprises a filling agent, a disintegrating agent, an adhesive and a lubricant; in the tablet core, the following components are contained in percentage by mass: 625-70% of Sofosbuvir crystal form, 20-65% of filler, 1-10% of disintegrant, 0.5-3% of lubricant and 0.25-5% of adhesive. The preparation method of the Sofosbuvir tablet provided by the invention is simpler and more convenient, is suitable for large-scale production and the current situation of pharmaceutical equipment in China, does not cause the crystal form change of the active ingredient Sofosbuvir during the preparation process, does not cause the conditions of material hardening and difficult granulation, and is stable in quality, simple in process, high in yield, good in stability and suitable for industrial batch production.
Description
Technical Field
The invention relates to a sofosbuvir tablet and a preparation method thereof, belonging to the technical field of pharmaceutical preparations.
Background
Hepatitis c is a systemic infectious disease caused by Hepatitis C Virus (HCV) and mainly caused by liver damage, and its acute infection symptoms are not obvious and chronic. Chronic hepatitis c patients have a very low self-healing rate, with about 10.0% to 20.0% of HCV-infected patients developing cirrhosis within 20 years of infection, and about 5.0% to 7.0% of cases eventually dying from cirrhosis or liver cancer. Hepatitis C has become an important cause of end-stage liver diseases in countries such as Europe, America and Japan, and has high recurrence rate, especially chronic patients have higher recurrence rate, thus bringing heavy economic burden to patients, families and society.
Sofosbuvir (also known as Sofosbuvir, the british name Sofosbuvir, trade name Sovaldi) is a new drug developed by gilide corporation for treating chronic hepatitis c, and is approved by the U.S. Food and Drug Administration (FDA) to be marketed in the united states at 12 and 6 days in 2013, and is approved by the european drug administration (EMEA) to be marketed in countries of the european union at 1 and 16 days in 2014, and is not marketed in china until now. The medicine is the first medicine which can safely and effectively treat certain types of hepatitis C without combining interferon. Clinical trials demonstrated that the overall sustained virological response rate (SVR) of this drug in combination with peginterferon and ribavirin was as high as 90% for type 1 and 4 hepatitis c; aiming at type 2 hepatitis C, the SVR of the medicine and ribavirin is 89-95 percent; aiming at type 3 hepatitis C, the SVR of the medicine and ribavirin is 61-63%. Sofosbuvir has been incorporated into the american association for liver disease research (AASLD) guidelines for the treatment of hepatitis c. The Sofosbuvir is successfully marketed, can eliminate the requirement on the traditional injection medicine Interferon (IFN) when being used for treating the specific genotype chronic hepatitis C, reduces the adverse reaction of patients and improves the compliance of the patients, and is widely considered as a breakthrough treatment medicine for the chronic hepatitis C.
Sofosbuvir (Sofosbuvir) is a nucleoside analogue (NS5B) polymerase inhibitor, does not need to use interferon for HCV infection of certain genotypes, can reduce side effects, and has good curative effect. The preparation is a film coated tablet developed by Jilidd science company, has the trade name of Sovaldi, and is clinically used for treating chronic hepatitis C. Sofosbuvir is a white or off-white crystal, slightly soluble in water. Belongs to BCS III according to a biological pharmacy classification system. The dissolution rate of the Sovaldi tablet in water, hydrochloric acid medium with pH1.0, acetate buffer solution with pH4.5 and phosphate buffer solution with pH6.8 (75 r/min) is more than 85% in 15 minutes.
Patent CN104039319A discloses a composition and method for the treatment of HCV wherein the active ingredient is sofosbuvir. Patents CN104039319A, CN104546783A, CN104622836A, CN104906062A, CN104840964A, and the like all disclose methods for preparing sofosbuvir tablets, but the preparation of the sofosbuvir tablets all adopt a dry granulation method, and the method needs to use a dry granulator, has high requirements on equipment, is complex in preparation process, low in granule yield, needs to repeatedly roll in the granulation process, consumes long time, substantially increases production cost, and is not beneficial to improving labor efficiency.
We want to find a simpler and more convenient preparation method suitable for large-scale production and the current state of pharmaceutical equipment in China to obtain the Sofosbuvir tablets with stable quality. Through research, the inventor surprisingly finds that the crystal form 6 of the raw material sofosbuvir prepared into the tablet by adopting the traditional wet granulation method does not cause the crystal form of the active ingredient sofosbuvir to change, the content and related substances do not obviously change, and the situations of material hardening and difficult granulation do not exist in the preparation process.
Disclosure of Invention
In order to solve the technical problems, the invention provides the sofosbuvir tablets and the preparation method thereof, the method is simpler and more convenient, the preparation method is suitable for large-scale production and the current situation of pharmaceutical equipment in China, the crystal form change of an active ingredient sofosbuvir is not caused in the preparation process, the situations of material hardening and difficult granulation do not exist, and the finally obtained tablets have stable quality, simple process, high yield and good stability and are suitable for industrial batch production.
The technical scheme adopted by the invention is as follows:
the invention provides a Sofosbuvir tablet, which comprises a tablet core and a film coating layer, wherein the tablet core is prepared from an active ingredient and a pharmaceutically acceptable auxiliary material through a wet granulation process, the active ingredient is a Sofosbuvir crystal form 6, and the auxiliary material comprises a filling agent, a disintegrating agent, an adhesive and a lubricant; in the tablet core, the following components are contained in percentage by mass: 625-70% of Sofosbuvir crystal form, 20-65% of filler, 1-10% of disintegrant, 0.5-3% of lubricant and 0.25-5% of adhesive;
the filler is one or a combination of more of microcrystalline cellulose, pregelatinized starch, mannitol, starch and dextrin;
the disintegrating agent is one or a combination of more of croscarmellose sodium, crospovidone, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose;
the lubricant is one or a combination of magnesium stearate, stearic acid, superfine silica gel powder and talcum powder;
the adhesive is one or a combination of starch slurry, hydroxypropyl methylcellulose and povidone.
Further, the preferable filler is one or a combination of more of microcrystalline cellulose, pregelatinized starch and mannitol, and the further preferable filler is one or a combination of microcrystalline cellulose and pregelatinized starch.
Further, the preferable disintegrating agent is one or a combination of more of croscarmellose sodium, crospovidone and sodium carboxymethyl starch, and the more preferable filler is croscarmellose sodium.
Further, the preferred lubricant is one or a combination of two of magnesium stearate and aerosil, and the further preferred lubricant is magnesium stearate.
Further, the preferred binder is one or a combination of two of hydroxypropyl methylcellulose and povidone, and the further preferred binder is povidone.
The invention also provides a preparation method of the sofosbuvir tablet, which comprises the following steps:
preprocessing raw material medicines: continuously sieving or micronizing the sofosbuvir crystal form 6 to ensure that the grain diameter of the sofosbuvir crystal form 6 is more than 60 meshes;
adhesive solution preparation: preparing an adhesive solution by using water or ethanol water;
mixing raw materials and auxiliary materials: weighing sofosbuvir and a filler according to the formula ratio, and uniformly mixing in a high-shear mixing granulator;
granulating: setting granulation parameters, adding a binder solution for granulation, drying to enable the moisture content of the material to be less than or equal to 3.5%, and finishing granules;
mixing the materials: putting the finished particles and the lubricant into a main mixer to be uniformly mixed;
sixthly, tabletting: placing the granules in a high-speed rotary tablet press, controlling tablet weight and host machine pressure, and tabletting;
and (c) coating: placing the qualified tablet core in a high-efficiency coating machine, and coating a film coating to ensure that the weight of the film coating is 2-4% of the weight of the tablet core to obtain the Sofosbuvir tablet;
wherein, the disintegrating agent is added in the third step and mixed with the sofosbuvir and the filling agent or added in the fifth step and mixed with the finished granules and the lubricating agent or added in the third step, and the rest is added in the fifth step.
Further, in the step I, the particle size of the preferred Sofosbuvir crystal form 6 is more than or equal to 80 meshes.
Furthermore, in the second step, the adhesive is preferably prepared into a solution by water, and the prepared mass concentration is 2-10%.
And further, in the step III, a screen with 16-40 meshes is adopted for whole granules.
Furthermore, in the step of sixthly, the content difference of the components in the tablet core is controlled within +/-3.5 percent, and the hardness of the tablet core is controlled to be 120N-200N.
The tablets of the invention are ordinary film-coated tablets, using a gastric-soluble coating material conventional in the pharmaceutical field, such as the Opadry II gastric-soluble film-coated premix produced by Shanghai Kalopanan. The solvent used for preparing the coating solution is water or an aqueous ethanol solution, and more preferably, the solvent used is water.
Compared with the prior art, the invention has the beneficial effects that:
(1) according to the invention, by optimizing the formula and the process, the Sofosbuvir tablets are not hardened and difficult to granulate in the preparation process; the content and related substances are not obviously changed in the preparation process, the crystal form and raw materials of sofosbuvir in the finished product sofosbuvir film-coated tablet are consistent and unchanged, and are crystal form 6, which shows that the active ingredient sofosbuvir crystal form 6 is suitable for being prepared into tablets by a wet granulation method;
(2) the Sofosbuvir tablets prepared by the method have stable quality, simple and mature production process and high yield, accord with the current situation of most preparation factory equipment in China, can greatly improve the production efficiency and reduce the production cost, and are suitable for industrial batch production.
Drawings
Figure 1 is an XRPD pattern of crystalline form 6 of sofosbuvir feedstock used in an embodiment;
FIG. 2 is an XRPD pattern of the particles after total mixing;
FIG. 3 is an XRPD pattern for a Sofosbuvir tablet core;
FIG. 4 is an XRPD pattern for Sofosbuvir film coated tablets;
figure 5 is a particle size distribution diagram of a micronized starting material of sofosbuvir.
Detailed Description
For a further understanding of the present invention, reference will now be made in detail to the following examples, which are intended to be illustrative, but not limiting, of the invention.
Example 1
Product recipe (1000 tablets):
the preparation process comprises the following steps:
preprocessing raw material medicines: sieving the Sofosbuvir raw material by 80 meshes for later use;
adhesive solution preparation: preparing 2% solution of polyvidone K90 with water;
mixing raw materials and auxiliary materials: taking Sofosbuvir, microcrystalline cellulose, mannitol and croscarmellose sodium according to the formula ratio, and uniformly mixing in a high-shear mixing granulator (stirring paddle: 120rpm, 10 min);
granulating: adding 2% polyvidone K90 solution, granulating (spraying time: 4 min; stirring speed: 150 rpm; shearing speed 1200rpm), drying (60 deg.C, controlling water content of the material to be less than or equal to 3.5%), and grading to 40 mesh;
mixing the materials: putting the finished particles and the micro silica gel powder with the formula amount into a total mixer to be uniformly mixed (the rotating speed is 15rpm and is 2 min);
sixthly, tabletting: placing the granules in a high-speed rotary tablet press, controlling the tablet weight and the host machine pressure (tablet weight: 0.58 g-0.62 g, hardness: 130N-160N), and tabletting;
and (c) coating: placing the qualified tablet core in a high-efficiency coating machine, preparing a gastric-soluble coating premix (Opadry II film coating premix produced by Shanghai Carlekang) solution with the solid content of 12% by using a 75% ethanol water solution (volume percentage), spraying a coating solution, coating a film, and increasing the weight of the coating by 2-4%.
Example 2
Product recipe (1000 tablets):
the preparation process comprises the following steps:
preprocessing raw material medicines: sieving the Sofosbuvir raw material by 80 meshes for later use;
adhesive solution preparation: preparing 5% solution of polyvidone K30 with water;
mixing raw materials and auxiliary materials: taking Sofosbuvir, microcrystalline cellulose, pregelatinized starch and crospovidone according to the formula ratio, and uniformly mixing in a high-shear mixing granulator (stirring paddle: 120rpm, 10 min);
granulating: adding 5% polyvidone K30 solution, granulating (spraying time: 4 min; stirring speed: 150 rpm; shearing speed 1200rpm), drying (60 deg.C, controlling water content of the material to be less than or equal to 3.5%), and grading to 20 mesh;
mixing the materials: putting the finished particles and the micro silica gel powder with the formula amount into a total mixer to be uniformly mixed (the rotating speed is 15rpm and is 2 min);
sixthly, tabletting: placing the granules in a high-speed rotary tablet press, controlling the tablet weight and the host machine pressure (tablet weight: 0.58 g-0.62 g, hardness: 130N-160N), and tabletting;
and (c) coating: placing the qualified tablet core in a high-efficiency coating machine, preparing a gastric-soluble coating premix (Opadry II film coating premix produced by Shanghai Carlekang) solution with the solid content of 12% by using 50% ethanol water solution (volume percentage), spraying coating solution, coating a film, and increasing the weight of the coating by 2-4%.
Example 3
Product recipe (1000 tablets):
the preparation process comprises the following steps:
preprocessing raw material medicines: sieving the Sofosbuvir raw material by 80 meshes for later use;
adhesive solution preparation: preparing povidone K30 into 8% solution with water for later use;
mixing raw materials and auxiliary materials: taking Sofosbuvir, microcrystalline cellulose, pregelatinized starch, mannitol and 1/2 sodium croscarmellose according to the formula amount, and uniformly mixing in a high-shear mixing granulator (stirring paddle: 120rpm, 10 min);
granulating: adding 5% polyvidone K30 solution, granulating (spraying time: 4 min; stirring speed: 150 rpm; shearing speed 1200rpm), drying (60 deg.C, controlling water content of the material to be less than or equal to 3.5%), and grading to 20 mesh;
mixing the materials: putting the finished granules, magnesium stearate with the formula amount and croscarmellose sodium with the formula amount of 1/2 into a total mixer, and uniformly mixing (rotating speed: 15rpm, 2 min);
sixthly, tabletting: placing the granules in a high-speed rotary tablet press, controlling the tablet weight and the host machine pressure (tablet weight: 0.58 g-0.62 g, hardness: 130N-160N), and tabletting;
and eighty percent of coating: and (2) placing the qualified tablet core in a high-efficiency coating machine, preparing a gastric-soluble coating premix (Opadry II film coating premix produced by Shanghai Carlekang) solution with the solid content of 12% by using water, spraying the solution into a coating solution, and coating the film, wherein the weight of the coating is increased by 2-4%.
The sofosbuvir raw material (form 6) used in example 3 (fig. 1), the granules after the total mixing (fig. 2), the tablet core obtained by tabletting (fig. 3) and the film-coated tablet obtained by coating (fig. 4) were subjected to X-ray powder diffraction tests (XRPD), respectively, and from the characteristic XRPD2 θ -reflection of these XRPD patterns, the crystalline form of the raw material sofosbuvir was not changed during the preparation process. The conventional wet granulation method can be used for preparing the tablet of the raw material sofosbuvir crystal form 6.
Example 4
Product recipe (1000 tablets):
the preparation process comprises the following steps:
preprocessing raw material medicines: micronizing Sofosbuvir raw material (D90: 3.147um) (figure 5) for use;
adhesive solution preparation: preparing povidone K30 into 8% solution with water for later use;
mixing raw materials and auxiliary materials: taking Sofosbuvir, microcrystalline cellulose, pregelatinized starch, mannitol and 1/2 sodium croscarmellose according to the formula amount, and uniformly mixing in a high-shear mixing granulator (stirring paddle: 120rpm, 10 min);
granulating: adding 5% polyvidone K30 solution, granulating (spraying time: 4 min; stirring speed: 150 rpm; shearing speed 1200rpm), drying (60 deg.C, controlling water content of the material to be less than or equal to 3.5%), and grading to 20 mesh;
mixing the materials: putting the finished granules, magnesium stearate with the formula amount and croscarmellose sodium with the formula amount of 1/2 into a total mixer, and uniformly mixing (rotating speed: 15rpm, 2 min);
sixthly, tabletting: placing the granules in a high-speed rotary tablet press, controlling the tablet weight and the host machine pressure (tablet weight: 0.58 g-0.62 g, hardness: 130N-160N), and tabletting;
ninthly, coating: and (2) placing the qualified tablet core in a high-efficiency coating machine, preparing a gastric-soluble coating premix (Opadry II film coating premix produced by Shanghai Carlekang) solution with the solid content of 12% by using water, spraying the solution into a coating solution, and coating the film, wherein the weight of the coating is increased by 2-4%.
Example 5
Product recipe (1000 tablets):
the preparation process comprises the following steps:
preprocessing raw material medicines: sieving the Sofosbuvir raw material by a 40-mesh sieve for later use;
adhesive solution preparation: preparing povidone K30 into 8% solution with water for later use;
mixing raw materials and auxiliary materials: taking Sofosbuvir, microcrystalline cellulose, pregelatinized starch, mannitol and 1/2 sodium croscarmellose according to the formula amount, and uniformly mixing in a high-shear mixing granulator (stirring paddle: 120rpm, 10 min);
granulating: adding 5% polyvidone K30 solution, granulating (spraying time: 4 min; stirring speed: 150 rpm; shearing speed 1200rpm), drying (60 deg.C, controlling water content of the material to be less than or equal to 3.5%), and grading to 20 mesh;
mixing the materials: putting the finished granules, magnesium stearate with the formula amount and croscarmellose sodium with the formula amount of 1/2 into a total mixer, and uniformly mixing (rotating speed: 15rpm, 2 min);
sixthly, tabletting: placing the granules in a high-speed rotary tablet press, controlling the tablet weight and the host machine pressure (tablet weight: 0.58 g-0.62 g, hardness: 130N-160N), and tabletting;
coating r: and (2) placing the qualified tablet core in a high-efficiency coating machine, preparing a gastric-soluble coating premix (Opadry II film coating premix produced by Shanghai Carlekang) solution with the solid content of 12% by using water, spraying the solution into a coating solution, and coating the film, wherein the weight of the coating is increased by 2-4%.
Example 6
Product recipe (1000 tablets):
the preparation process comprises the following steps:
preprocessing raw material medicines: sieving the Sofosbuvir raw material by a 60-mesh sieve for later use;
adhesive solution preparation: preparing povidone K30 into 8% solution with water for later use;
mixing raw materials and auxiliary materials: taking Sofosbuvir, microcrystalline cellulose, pregelatinized starch, mannitol and 1/2 sodium croscarmellose according to the formula amount, and uniformly mixing in a high-shear mixing granulator (stirring paddle: 120rpm, 10 min);
granulating: adding 5% polyvidone K30 solution, granulating (spraying time: 4 min; stirring speed: 150 rpm; shearing speed 1200rpm), drying (60 deg.C, controlling water content of the material to be less than or equal to 3.5%), and grading to 20 mesh;
mixing the materials: putting the finished granules, magnesium stearate with the formula amount and croscarmellose sodium with the formula amount of 1/2 into a total mixer, and uniformly mixing (rotating speed: 15rpm, 2 min);
sixthly, tabletting: placing the granules in a high-speed rotary tablet press, controlling the tablet weight and the host machine pressure (tablet weight: 0.58 g-0.62 g, hardness: 130N-160N), and tabletting;
coating: and (2) placing the qualified tablet core in a high-efficiency coating machine, preparing a gastric-soluble coating premix (Opadry II film coating premix produced by Shanghai Carlekang) solution with the solid content of 12% by using water, spraying the solution into a coating solution, and coating the film, wherein the weight of the coating is increased by 2-4%.
Example 7
Product recipe (1000 tablets):
the preparation process comprises the following steps:
preprocessing raw material medicines: sieving the Sofosbuvir raw material by 80 meshes for later use;
adhesive solution preparation: preparing 5% solution of hydroxypropyl methylcellulose with water for later use;
mixing raw materials and auxiliary materials: taking Sofosbuvir, microcrystalline cellulose, starch, dextrin and low-substituted hydroxypropyl cellulose according to the formula amount, and uniformly mixing in a high-shear mixing granulator (stirring paddle: 120rpm, 10 min);
granulating: adding 5% hydroxypropyl methylcellulose solution, granulating (spraying time: 4 min; stirring speed: 150 rpm; shearing speed 1200rpm), drying (60 deg.C, controlling water content of the material to be less than or equal to 3.5%), and grading to 16 mesh;
mixing the materials: putting the finished granules, stearic acid, talcum powder and sodium carboxymethyl starch in a formula ratio into a total mixer, and uniformly mixing (rotating speed: 15rpm, 2 min);
sixthly, tabletting: placing the granules in a high-speed rotary tablet press, controlling the tablet weight and the host machine pressure (tablet weight: 0.58 g-0.62 g, hardness: 130N-160N), and tabletting;
and (c) coating: and (2) placing the qualified tablet core in a high-efficiency coating machine, preparing a gastric-soluble coating premix (Opadry II film coating premix produced by Shanghai Carlekang) solution with the solid content of 12% by using water, spraying the solution into a coating solution, and coating the film, wherein the weight of the coating is increased by 2-4%.
Example 8
Product recipe (1000 tablets):
the preparation process comprises the following steps:
preprocessing raw material medicines: sieving the Sofosbuvir raw material by 80 meshes for later use;
adhesive solution preparation: preparing starch into 10% starch slurry solution with boiling water;
mixing raw materials and auxiliary materials: taking Sofosbuvir, microcrystalline cellulose, pregelatinized starch and crospovidone according to the formula ratio, and uniformly mixing in a high-shear mixing granulator (stirring paddle: 120rpm, 10 min);
granulating: adding 10% starch slurry solution, granulating (spraying time: 4 min; stirring speed: 150 rpm; shearing speed 1200rpm), drying (60 deg.C, controlling water content of material to be less than or equal to 3.5%), and grading to 20 mesh;
mixing the materials: putting the finished particles and the micro silica gel powder with the formula amount into a total mixer to be uniformly mixed (the rotating speed is 15rpm and is 2 min);
sixthly, tabletting: placing the granules in a high-speed rotary tablet press, controlling the tablet weight and the host machine pressure (tablet weight: 0.58 g-0.62 g, hardness: 130N-160N), and tabletting;
and (c) coating: and (3) placing the qualified tablet core in a high-efficiency coating machine, spraying a gastric-soluble coating premix (Opadry II film coating premix produced by Shanghai Carlekang) solution with the solid content of 12%, coating a film, and increasing the weight of the coating by 2-4%.
Example 9
Product recipe (1000 tablets):
the preparation process comprises the following steps:
preprocessing raw material medicines: sieving the Sofosbuvir raw material by 80 meshes for later use;
adhesive solution preparation: preparing 5% solution of polyvidone K90 with ethanol;
mixing raw materials and auxiliary materials: taking Sofosbuvir, microcrystalline cellulose, pregelatinized starch and croscarmellose sodium according to the formula ratio, and uniformly mixing in a high-shear mixing granulator (stirring paddle: 120rpm, 10 min);
③ granulating: adding 5% polyvidone K90 alcohol solution, granulating (spraying time: 4 min; stirring speed: 150 rpm; shearing speed 1200rpm), drying (60 deg.C, controlling water content of the material to be less than or equal to 3.5%), and grading to 24 mesh;
fourthly, total mixing: putting the finished granules and the magnesium stearate with the formula amount into a total mixer, and uniformly mixing (rotating speed: 15rpm, 2 min);
tabletting: placing the granules in a high-speed rotary tablet press, controlling the tablet weight and the host machine pressure (tablet weight: 0.58 g-0.62 g, hardness: 130N-160N), and tabletting;
sixthly, coating: and (2) placing the qualified tablet core in a high-efficiency coating machine, preparing a gastric-soluble coating premix (Opadry II film coating premix produced by Shanghai Carlekang) solution with the solid content of 12% by using water, spraying the solution into a coating solution, and coating the film, wherein the weight of the coating is increased by 2-4%.
Example 10
The dissolution curves of the sofosbuvir tablets of examples 1 to 9 of the present invention were measured by the second paddle method of the dissolution and release determination method of 0931 in the four-part general rules of the chinese pharmacopoeia 2015 edition, and the results are shown in the following table. Wherein, the dissolution medium is 900ml of phosphate buffer solution with pH6.8, the rotating speed is 75r/min, the determination is carried out by adopting an ultraviolet spectrophotometry, the determination wavelength of the Sofosbuvir is 260nm, the sampling time is as follows: 5min, 10min, 15min, 30min, 45min, and compared with the "Sovaldi" preparation (the dissolution method refers to Sofosbuvir dissolution method published by FDA), the results are shown in the following table:
TABLE 1
The dissolution rates of the home-made Sofosbuvir tablets and the Sovaldi preparation are both faster, and the dissolution rate is more than 85% in 15 min. The dissolution test results of the sofosbuvir in the examples 4, 5, 6 and 7 show that the dissolution rates of the micronized sofosbuvir tablets and the sofosbuvir tablets passing through 60-mesh sieves and 80-mesh sieves are not obviously changed; the dissolution of the Sofosbuvir tablets passing through a 40-mesh sieve in 5 minutes and 10 minutes is obviously slower than that of other Sofosbuvir tablets with controlled particle size. Therefore, the related requirements can be met by controlling the raw material sofosbuvir to pass through a 60-mesh sieve, preferably a 80-mesh sieve to prepare the sofosbuvir tablet.
Example 11
The samples of examples 1 to 9 were taken and left to stand at high temperature (60 ℃), light (5000lx), high humidity (92.5% RH), respectively, for 5 days and 10 days, respectively, and the contents and related substances were measured and compared with the results of day 0, and the results are shown in the following table:
chromatographic conditions are as follows: c18 alkyl bonded silica gel column; mobile phase A: 0.05% phosphoric acid aqueous solution, mobile phase B: acetonitrile; flow rate: 1.5 ml/min; column temperature: 30 ℃; wavelength 260nm, injection volume: 20 ul; gradient elution.
The home-made sample is placed for 10 days at high temperature (60 ℃), illumination (5000lx) and high humidity (92.5% RH), the content and related substances are not obviously changed, and the active ingredient sofosbuvir crystal form 6 is suitable for being prepared into tablets by a wet granulation method.
Example 12
The samples of examples 1-9 were placed at 40 ℃ and 75% humidity for 6 months, and the content and related substances were measured and compared with the initial samples, and the results are shown in the following table:
after the samples of the embodiments 1-9 are placed for 6 months under the conditions of 40 ℃ and 75% humidity, the content and related substances are basically unchanged, and the related requirements are met. The sample quality of the invention is stable, and the prescription and the process are suitable for larger-scale production.
Claims (9)
1. A sofosbuvir tablet comprises a tablet core and a film coating layer, wherein the tablet core is prepared from an active ingredient and pharmaceutically acceptable auxiliary materials through a wet granulation process, the active ingredient is a sofosbuvir crystal form 6, and the auxiliary materials comprise a filling agent, a disintegrating agent, an adhesive and a lubricating agent; in the tablet core, the following components are contained in percentage by mass: 625-70% of Sofosbuvir crystal form, 20-65% of filler, 1-10% of disintegrant, 0.5-3% of lubricant and 0.25-5% of adhesive;
the filler is one or a combination of more of microcrystalline cellulose, pregelatinized starch, mannitol, starch and dextrin;
the disintegrating agent is one or a combination of more of croscarmellose sodium, crospovidone, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose;
the lubricant is one or a combination of magnesium stearate, stearic acid, superfine silica gel powder and talcum powder;
the adhesive is one or a combination of more of starch slurry, hydroxypropyl methylcellulose and povidone;
the wet granulation process comprises the following steps:
preprocessing raw material medicines: sieving or micronizing the sofosbuvir crystal form 6 to ensure that the grain diameter of the sofosbuvir crystal form 6 can pass through a sieve of more than 60 meshes;
adhesive solution preparation: preparing an adhesive solution by using water or ethanol water;
mixing raw materials and auxiliary materials: weighing sofosbuvir and a filler according to the formula ratio, and uniformly mixing in a high-shear mixing granulator;
granulating: setting granulation parameters, adding a binder solution for granulation, drying to enable the moisture content of the material to be less than or equal to 3.5%, and finishing granules;
mixing the materials: placing the granules and the lubricant into a main mixer to be uniformly mixed;
sixthly, tabletting: placing the granules in a high-speed rotary tablet press, controlling tablet weight and host machine pressure, and tabletting;
and (c) coating: placing the qualified tablet core in a high-efficiency coating machine, and coating a film coating to ensure that the weight of the film coating is 2-4% of the weight of the tablet core to obtain the Sofosbuvir tablet;
wherein, the disintegrating agent is added in the third step to be mixed with the sofosbuvir and the filling agent or is added in the fifth step to be mixed with the granules after the granules are sized and the lubricating agent or is added in the third step partially, and the rest is added in the fifth step.
2. The sofosbuvir tablet as claimed in claim 1, wherein: the filler is one or more of microcrystalline cellulose, pregelatinized starch, and mannitol.
3. The sofosbuvir tablet as claimed in claim 1, wherein: the disintegrant is one or more of croscarmellose sodium, crospovidone, and sodium carboxymethyl starch.
4. The sofosbuvir tablet as claimed in claim 1, wherein: the lubricant is one or two of magnesium stearate and aerosil.
5. The sofosbuvir tablet as claimed in claim 1, wherein: the binder is one or the combination of two of hydroxypropyl methylcellulose and povidone.
6. The sofosbuvir tablet as claimed in claim 1, wherein: the filler is one or more of microcrystalline cellulose, pregelatinized starch and mannitol;
the disintegrant is one or more of croscarmellose sodium, crospovidone, and sodium carboxymethyl starch;
the lubricant is one or the combination of magnesium stearate and aerosil;
the binder is one or the combination of two of hydroxypropyl methylcellulose and povidone.
7. The sofosbuvir tablet as claimed in claim 1, wherein: in the step of the wet granulation process, the particle size of the sofosbuvir crystal form 6 is sieved by a sieve of 80 meshes.
8. The sofosbuvir tablet as claimed in claim 1, wherein: in the second step of the wet granulation process, the adhesive is prepared into a solution with water, and the prepared mass concentration is 2-10%.
9. The sofosbuvir tablet as claimed in claim 1, wherein: in the step (iv) of the wet granulation process, a sieve with 16-40 meshes is adopted for whole granules.
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| CN110693887B (en) * | 2019-05-17 | 2022-06-17 | 歌礼药业（浙江）有限公司 | Tablet containing Sofosbuvir and Lavidavir and preparation method thereof |
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