CN107041873B - Preparation method of sofosbuvir coated tablet - Google Patents
Preparation method of sofosbuvir coated tablet Download PDFInfo
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- CN107041873B CN107041873B CN201710086054.8A CN201710086054A CN107041873B CN 107041873 B CN107041873 B CN 107041873B CN 201710086054 A CN201710086054 A CN 201710086054A CN 107041873 B CN107041873 B CN 107041873B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
- A61K9/2036—Silicones; Polysiloxanes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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Abstract
The invention relates to the field of medicinal preparations, in particular to a sofosbuvir coated tablet containing a simethicone auxiliary material. The tablet has good stability, and the dissolution is not influenced by the coating temperature.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a preparation method of a fast-dissolving sofosbuvir coated tablet.
Background
Hepatitis C Virus (HCV) is one of the major pathogens causing chronic hepatitis, primarily transmitted through the blood. According to the statistics of the world health organization, the infection rate of HCV is about 3% globally, and about 1.8 million people are infected with HCV. HCV viral infection can lead to chronic inflammatory necrosis and fibrosis of the liver, and some patients can develop cirrhosis and even hepatocellular carcinoma.
The standard treatment scheme of HCV infection is that interferon α or PEG-IFN α is combined with ribavirin, but the drug adverse reaction of the treatment scheme is large, the treatment effect is poor, the treatment scheme treats patients infected by HCV of gene type 2 and 3, the persistent virological response (SVR) is 80%, but the SVR of a person infected by HCV of gene type 1 is only about 50%, Sofosbuvir is a nucleoside inhibitor of the first HCV specific NS5B polymerase worldwide.
CN104622836A discloses that the dissolution of the drug product is significantly reduced when preparing coated tablets containing sofosbuvir of form 1. The reason is that the temperature of the tablet is kept at 46 +/-5 ℃ in the conventional coating process, and in a coating system of an aqueous solution, the crystal form 1 is easy to form hard plate-shaped curing glue, so that the disintegration of the tablet is slowed, and the dissolution rate of the medicine is obviously reduced. To ensure rapid dissolution of the drug, CN104622836A uses a composite coating material containing ethylcellulose and hypromellose to reduce the coating temperature to 28 ℃ -38 ℃. However, the composite coating material is not applied in large-scale commercialization, needs to be specially customized and has higher cost.
Therefore, the invention aims to provide the crystal form 1 sofosbuvir coated tablet which can be quickly dissolved and is suitable for industrial production.
Disclosure of Invention
The invention provides a rapidly-dissolved crystal form 1 sofosbuvir coated tablet and a preparation method thereof, and is suitable for industrial mass production.
The crystal form 1 sofosbuvir coated tablet contains simethicone auxiliary materials. Through a large number of research experiments, the invention surprisingly discovers that the dissolving-out of the crystal form 1 sofosbuvir coated tablet can not be influenced by the coating temperature by adopting the dimeticone. The tablet of the invention can use the conventional coating materials which are well-established and commercialized, and is particularly suitable for industrial production.
The invention also provides a preparation method of the crystal form 1 sofosbuvir coated tablet, which comprises the following steps:
1) mixing sofosbuvir, simethicone and pharmaceutically acceptable auxiliary materials, and performing dry granulation;
2) mixing the obtained granules with pharmaceutically acceptable adjuvants, and tabletting;
3) preheating the tablet core in a high-efficiency coating machine, controlling the temperature of the tablet bed to be 40-55 ℃, uniformly spraying the coating liquid on the surface of the tablet core, and fully drying to obtain the sofosbuvir coated tablet.
Preferably, the pharmaceutically acceptable auxiliary material in step 1) comprises one or a combination of microcrystalline cellulose, mannitol, croscarmellose sodium, colloidal silicon dioxide and stearic acid.
Preferably, the pharmaceutically acceptable auxiliary material in step 2) comprises one or a combination of croscarmellose sodium, colloidal silicon dioxide and magnesium stearate.
Preferably, the invention also provides a preparation method of the crystal form 1 sofosbuvir coated tablet, which comprises the following steps:
1) mixing sofosbuvir, simethicone, microcrystalline cellulose, mannitol, croscarmellose sodium, colloidal silicon dioxide and stearic acid, and performing dry granulation;
2) mixing the obtained granule with croscarmellose sodium, colloidal silicon dioxide and magnesium stearate, and tabletting;
3) preheating the tablet core obtained by tabletting in a high-efficiency coating machine, controlling the temperature of the tablet core to be 40-55 ℃, uniformly spraying the coating liquid on the surface of the tablet core, and fully drying to obtain the sofosbuvir coated tablet.
Preferably, the dimethicone content is from 3 to 10%, more preferably from 3 to 8% by weight of the tablet.
Preferably, the content of the sofosbuvir crystal form 6 is 10-50% of the tablet weight, and further preferably 30-35%.
Preferably, the preparation method also comprises pretreatment of the raw material of the sofosbuvir, namely treatment of micro powder of the raw material of the sofosbuvir, wherein the particle size d (90) is preferably less than or equal to 100 um. Sofosbuvir exists in form 1.
Preferably, the weight gain of the coating is 1.0-5.0%.
Preferably, the coating material comprises one or a combination of polyethylene glycol (PEG), Hypromellose (HPMC) or polyvinyl alcohol (PVA), and the coating may further comprise antisticking agent, opacifier, plasticizer, lake, etc. Preferably, the coating material may optionally be a commercial coating material, such as opadry film coating powder. Preferably, in the granulating step, the granulating extrusion pressure is controlled to be 10-20 kg.
Preferably, in the tabletting step, the weight range of the tablets is controlled within +/-5%.
Preferably, the solvent for coating comprises an organic solvent or an aqueous solution of an organic solvent, wherein the organic solvent is selected from ethanol or acetone, more preferably, the organic solvent is selected from ethanol.
The invention also provides a sofosbuvir tablet pharmaceutical composition, which comprises a core part and an external part, and comprises the following components in percentage by weight:
a core part:
the external part is as follows:
1-5% of croscarmellose sodium
0.1-2% of colloidal silicon dioxide
0.1 to 3 percent of magnesium stearate
Drawings
Fig. 1 is a powder X-ray diffraction pattern of a sample of form 1.
Detailed Description
The invention is further illustrated by the following specific examples, which are not intended to be limiting.
Example 1
The preparation method of the sofosbuvir crystal form 1 is the same as CN 102858790A. The obtained crystal form sample was subjected to powder X-ray diffraction analysis, and the results are shown in fig. 1. The analysis result shows that the characteristic spectrogram of the prepared crystal form sample is consistent with the spectrogram of the Sofosbuvir crystal form 1 reported in the literature, and the XRPD 2 theta reflections are about 5.0, 7.3, 9.4 and 18.1.
Example 2:
the dissolution rate of the crystal form 1 sofosbuvir tablets is obtained by adopting the following detection method:
according to a dissolution determination method (second method of appendix XC of second part of Chinese pharmacopoeia 2010 edition), 900ml of phosphate buffer solution (250 ml of 0.2mol/L potassium dihydrogen phosphate solution is taken, 118ml of 0.2mol/L sodium hydroxide solution is added, diluted to 1000ml by water and shaken evenly) with pH of 6.8 is taken as a dissolution medium, 75 revolutions per minute is carried out, the medium temperature is 37.0 ℃, the operation is carried out according to the method, 10ml of solution is taken and filtered after 15 minutes; taking the subsequent filtrate to prepare a solution containing about 20 mu g of sofosbuvir per ml, taking the solution as a test solution, and respectively measuring the absorbance at the wavelength of 260nm by a spectrophotometry (appendix IV A of the second part of Chinese pharmacopoeia 2010 edition); taking another appropriate amount of the sofosbuvir reference substance, precisely weighing, adding phosphate buffer solution with pH6.8 to dissolve to prepare solution containing about 20 mu g of the sofosbuvir per 1ml, and taking the solution as the reference substance solution. The dissolution amount of each tablet is calculated according to an external standard method.
Example 3:
the particle size of sofosbuvir is as follows: d90 ═ 80 μm.
The preparation method comprises the following steps:
1) and (3) granulating: uniformly mixing the raw and auxiliary materials of sofosbuvir, simethicone, microcrystalline cellulose, mannitol, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate according to the prescription amount of the core part, and performing dry granulation and finishing;
2) total mixing: mixing the obtained granule with adjuvant such as croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate;
3) tabletting: regulating tablet weight, pressure of the main machine and tabletting to obtain plain tablets.
4) Coating: the plain tablets were added to a coating pan for coating, and the tablet bed temperature was controlled at about 45 ℃.
Dissolution test results show that the dissolution rate of the coated tablet prepared by the method in 15 minutes is 96%.
Example 4:
the particle size of sofosbuvir is as follows: d90 ═ 60 μm.
The sofosbuvir tablets were prepared by the same preparation method as in example 2, with the bed temperature controlled at about 55 ℃.
Dissolution test results show that the 15-minute dissolution rate of the coated tablet prepared by the method is 99%.
Example 5:
after the samples of examples 3 and 4 are accelerated for 6 months at 40 ℃, the content of the samples is higher than 99 percent through HPLC detection, and good stability is shown.
Comparative example 1:
the particle size of sofosbuvir is as follows: d90 ═ 80 μm.
The preparation method comprises the following steps:
1) and (3) granulating: uniformly mixing the raw and auxiliary materials of sofosbuvir, microcrystalline cellulose, mannitol, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate according to the prescription amount of the core part, and performing dry granulation and size stabilization;
2) total mixing: mixing the obtained granule with adjuvant such as croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, and dimethyl silicon;
3) tabletting: regulating tablet weight, pressure of the main machine and tabletting to obtain plain tablets.
4) Coating: the plain tablets were added to a coating pan for coating, and the tablet bed temperature was controlled at about 45 ℃.
Dissolution test results show that the 15-minute dissolution rate of the coated tablet prepared by the method is lower than 90%. Thus, simethicone must be added during granulation and only during compression will adversely affect tablet dissolution.
Comparative example 2:
the particle size of sofosbuvir is as follows: d90 ═ 80 μm.
The preparation method of example 3 was used to prepare sofosbuvir tablets.
Dissolution test results show that 15-minute dissolution rates of the plain tablets and the coated tablets prepared by the method are 99% and 87%, respectively. Therefore, the dissolution rate of the coated tablet is remarkably reduced without using the simethicone auxiliary material, so that the active ingredients cannot be rapidly dissolved.
Claims (8)
1. A preparation method of a sofosbuvir crystal form 1 coated tablet comprises the following steps:
1) mixing the sofosbuvir crystal form 1, the dimeticone and pharmaceutically acceptable auxiliary materials, and performing dry granulation; the grain diameter of the sofosbuvir crystal form 1 is not more than 100um (d (90); the content of the dimethyl silicone oil is 3-10% of the weight of the tablet; the auxiliary materials comprise microcrystalline cellulose, mannitol and croscarmellose sodium;
2) mixing the obtained granules with pharmaceutically acceptable adjuvants, and tabletting; the auxiliary material comprises croscarmellose sodium;
3) preheating the tablet core in a high-efficiency coating machine, controlling the temperature of the tablet bed to be 40-55 ℃, uniformly spraying the coating liquid on the surface of the tablet core, and fully drying to obtain the sofosbuvir coated tablet.
2. The method according to claim 1, wherein the simethicone is contained in an amount of 3 to 8% by weight of the tablet.
3. The method for preparing the compound of claim 1, wherein the pharmaceutically acceptable auxiliary materials in step 1) comprise one or a combination of microcrystalline cellulose, mannitol, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate.
4. The preparation method according to claim 1, wherein the pharmaceutically acceptable auxiliary material in step 2) comprises one or a combination of croscarmellose sodium, colloidal silicon dioxide and magnesium stearate.
5. The preparation method according to claim 1, wherein the content of the sofosbuvir crystal form 1 is 10-50% of the tablet weight.
6. The method of claim 1, wherein the weight of the coating is increased by 1.0-5.0%.
7. A sofosbuvir coated tablet prepared according to the process of any one of claims 1-6.
8. Use of the sofosbuvir coated tablet of claim 7 in the preparation of a medicament for the treatment of hepatitis c.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710086054.8A CN107041873B (en) | 2017-02-17 | 2017-02-17 | Preparation method of sofosbuvir coated tablet |
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| CN201710086054.8A CN107041873B (en) | 2017-02-17 | 2017-02-17 | Preparation method of sofosbuvir coated tablet |
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| CN107041873A CN107041873A (en) | 2017-08-15 |
| CN107041873B true CN107041873B (en) | 2020-02-28 |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104039319A (en) * | 2011-11-29 | 2014-09-10 | 吉利德法莫赛特有限责任公司 | Compositions and methods for treating hepatitis c virus |
| CN104622836A (en) * | 2014-12-23 | 2015-05-20 | 浙江华海药业股份有限公司 | Sofosbuvircoated tablet and preparation method thereof |
| CN104840964A (en) * | 2015-05-07 | 2015-08-19 | 南京正大天晴制药有限公司 | Stable sofosbuvir drug combination and preparation method thereof |
| CN104906062A (en) * | 2015-06-30 | 2015-09-16 | 浙江天顺生物科技有限公司 | Sofosbuvir tablet and preparation method thereof |
| CN105380922A (en) * | 2015-12-18 | 2016-03-09 | 北京华禧联合科技发展有限公司 | Sofosbuvir film-coated tablets and preparation method thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HUE047777T2 (en) * | 2013-01-31 | 2020-05-28 | Gilead Pharmasset Llc | Combination formulation of two antiviral compounds |
| EP3113762A1 (en) * | 2014-03-05 | 2017-01-11 | Galenicum Health S.L. | Stable pharmaceutical compositions of sofosbuvir |
| CA2984421C (en) * | 2015-05-01 | 2024-04-09 | Cocrystal Pharma, Inc. | Nucleoside analogs for treatment of the flaviviridae family of viruses and cancer |
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2017
- 2017-02-17 CN CN201710086054.8A patent/CN107041873B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104039319A (en) * | 2011-11-29 | 2014-09-10 | 吉利德法莫赛特有限责任公司 | Compositions and methods for treating hepatitis c virus |
| CN104622836A (en) * | 2014-12-23 | 2015-05-20 | 浙江华海药业股份有限公司 | Sofosbuvircoated tablet and preparation method thereof |
| CN104840964A (en) * | 2015-05-07 | 2015-08-19 | 南京正大天晴制药有限公司 | Stable sofosbuvir drug combination and preparation method thereof |
| CN104906062A (en) * | 2015-06-30 | 2015-09-16 | 浙江天顺生物科技有限公司 | Sofosbuvir tablet and preparation method thereof |
| CN105380922A (en) * | 2015-12-18 | 2016-03-09 | 北京华禧联合科技发展有限公司 | Sofosbuvir film-coated tablets and preparation method thereof |
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