CN105380922A - Sofosbuvir film-coated tablets and preparation method thereof - Google Patents
Sofosbuvir film-coated tablets and preparation method thereof Download PDFInfo
- Publication number
- CN105380922A CN105380922A CN201510955793.7A CN201510955793A CN105380922A CN 105380922 A CN105380922 A CN 105380922A CN 201510955793 A CN201510955793 A CN 201510955793A CN 105380922 A CN105380922 A CN 105380922A
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- CN
- China
- Prior art keywords
- suo feibuwei
- film coating
- coating tablet
- film
- tablet
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- 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
-
- 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
-
- 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
- A61K9/282—Organic compounds, e.g. fats
Abstract
The invention provides sofosbuvir film-coated tablets and a preparation method thereof. The sofosbuvir film-coated tablets comprise tablet cores prepared from sofosbuvir and at least one auxiliary material accepted in pharmacy and film coating layers. The sofosbuvir film-coated tablets are characterized in that the tablet cores are prepared through a fluidized bed one-step granulating technology, a film forming material of the film coating layers is prepared from propylene glycol and hydroxypropyl methylcellulose, and the mass ratio of the propylene glycol to the hydroxypropyl methylcellulose is 1:1-1:5. The sofosbuvir film-coated tablets prepared through the method have the rapid dissolving characteristic and the good stability.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to Suo Feibuwei film coating tablet of a kind of stable and Fast Stripping and preparation method thereof.
Background technology
Suo Feibuwei (is translated into again rope fluorine cloth Wei, English name Sofosbuvir, trade name Sovaldi) exploitation of Shi Ji Leadd B.V is used for the treatment of the new drug of chronic hepatitis c, in December 6 Nikkei U.S. food Drug Administration (FDA) approval in 2013 in U.S.'s listing, Nikkei Europe drug administration January 16 in 2014 (EMEA), approval was gone on the market in EU countries.This medicine is first without the need to combining the medicine of interferon with regard to some type hepatitis C of the safe and effective treatment of energy.Clinical trial confirms for 1 and 4 type hepatitis C, and the overall continued viral response rate (SVR) of this medication combined Peg-IFN alpha-2b and ribavirin is up to 90%; For 2 type hepatitis C, the SVR of this medication combined ribavirin is 89%-95%; For 3 type hepatitis C, the SVR of this medication combined ribavirin is 61%-63%.Suo Feibuwei has been included into hepatopathy EASD of the U.S. (AASLD) hepatitis C treatment guidelines.
Hepatitis C, referred to as hepatitis C, hepatitis C, that one infects by hepatitis C virus (HCV) viral hepatitis caused, main through propagation such as blood transfusion, acupuncture, drug abuse, add up according to World Health Organization (WHO), the infection rate of whole world HCV is about 3%, estimates that about 1.8 hundred million people have infected HCV, annual new hepatitis C case about 3.5 ten thousand example.Hepatitis C is global prevalence, and can cause the necrosis of liver chronic inflammatory disease and fibrosis, some patients can develop into liver cirrhosis even hepatocarcinoma (HCC).Continuation increases by mortality rate (death that liver failure and hepatocarcinoma cause) relevant to HCV infection in following 20 years, very harmful to the health and lives of patient, has become serious society and public health problem.The successful listing of Suo Feibuwei, when treating for specific gene type chronic hepatitis C, the demand to conventional injection interfering effects of drug element (IFN) can be eliminated, reduce the untoward reaction of patient and improve the compliance of patient, being widely regarded as the breakthrough medicine of chronic hepatitis c.
Suo Feibuwei (English name: Sofosbuvir; Molecular formula: C22H29FN3O9P; Molecular weight: 529.45) chemistry is by name: (S)-2-(((S)-(((2R; 3R; 4R; 5R)-5-(2; 4-dioxo-3,4-dihydro-pyrimidin-1 (2H)-Ji)-4-fluoro-3-hydroxy-4-methyl oxolane-2-base) (phenoxy group) phosphoryl) amino) isopropyl propionate.Suo Feibuwei external appearance characteristic is white to off-white powder, and room temperature condition and pH are in the scope of 1.5-8.0, dissolubility >=2.0mg/ml, and in water, dissolubility is slightly soluble.
Its chemical constitution is as follows:
CN102858790A discloses 6 kinds of crystal formations (form 1 ~ form 6) and amorphous.The different crystal forms of Suo Feibuwei has different X-RPD TuPu method peaks, and this patent is pointed out, form 1, form 2 and form 3 are nonsolvated forms respectively, and 1:1 deuterated methanol solvate and 1:1 chloroform compound, form 6 is solid water-free form.Form 4 and form 5 are converted into form 1 after filtration, and form 2, form 3 are converted into form 1 through being separated.Form 1 is stable in hermetic container, and under unlimited system, the form 1 easily moisture absorption, can transfer form 6 to after certain approach.Form 1 can transfer form 6 to by least two kinds of modes.Mutual between the polymorphism of compound and polymorphic transforms safety and the effectiveness that can affect medicine significantly, therefore must go to report the crystal formation temperature of compound in formulation products.
CN102459299A discloses Suo Feibuwei and preparation method, and comprises the purposes that hepatitis C virus is infected in treatment.
Two kinds of tablets that it is active fraction preparation that WO2013082003 discloses with Suo Feibuwei form 1.Tablet A is coated tablet, and tablet B adds in label to add color lake but the tablet of non-coating.The present inventor studies discovery, its packaging technique (tablet temperature remains on 46 ± 5 DEG C, the coated systems of aqueous solution) in preparation technology disclosed in WO2013082003, form 1 very easily forms plate-like solidification glue, affect disintegration of tablet, dissolution rate in vitro obviously reduces.
Therefore, the object of this invention is to provide a kind of stable, can the Suo Feibuwei film coating tablet of Fast Stripping.
Summary of the invention
The invention provides stable and can the Suo Feibuwei film coating tablet and preparation method thereof of Fast Stripping.Innovative significance is to provide the preparation method of Fast Stripping type Suo Feibuwei film coating tablet containing stable form and applicable industrialized great production.
According to the present invention, Suo Feibuwei effective dose is 400mg.
Published patent form, form 1 or amorphous phase can be applicable to being developed to pharmaceutical preparation to other crystalline forms.And form 1 can change into amorphous under given conditions.The microstructure of amorphous substance is the unordered set of molecule or principle, and amorphous compound may have the quick absorption promoting medicine, increases the advantages such as the bioavailability of medicine, but also may have the shortcoming of less stable.
According to the present invention, Suo Feibuwei adds with unbodied form.
Particle diameter (ParticleSize) size is the physical attribute of compound, under equal quality condition, the granule surface area that under usual conditions, particle diameter is little is greater than the surface area of the large granule of particle diameter, and the granule that meaning particle diameter is little is more with the contact surface of dissolution medium, is more conducive to substance dissolves.Suo Feibuwei is slightly water-soluble compound, therefore, can increase surface area within the specific limits, thus improve dissolubility by reducing particle diameter.
According to the present invention, Suo Feibuwei adds with micronized form, its mean diameter D50≤100um; Preferential D50≤85um.
According to the present invention, the ratio (W/W) of described active component Suo Feibuwei shared by oral solid pharmaceutical formulation is 30%-60%; Preferably 45%-50%.
According to the present invention, described Suo Feibuwei film coating tablet, is made up of, as filler, disintegrating agent, fluidizer, lubricant Suo Feibuwei and one or more pharmaceutically acceptable adjuvants.
According to the present invention, the label of described tablet is composed as follows: Suo Feibuwei (30%-60%), filler (20%-50%), disintegrating agent (2%-8%), fluidizer (0.5%-1%), lubricant (0.5%-2.5%).
According to the present invention, the Suo Feibuwei of described amorphous form, in pelletization, by the effect of moisture and temperature, affects grain forming, causes caking, reduce yield, reduce stripping.Therefore, the effect of moisture and temperature need be eliminated.
According to the present invention, the Suo Feibuwei of described amorphous form, in aqueous solution coating specially good effect, by the effect of moisture and temperature, easily forms plate-like solid, reduces stripping.Therefore, the effect of moisture and temperature need be eliminated.
Accompanying drawing explanation
Fig. 1 is preparation technology's flow chart of Suo Feibuwei film coating tablet described in the invention process case.
Detailed description of the invention
The present invention is more explained detailedly further by following case study on implementation, but following case study on implementation is not to limit the scope of the invention.
The formula of the pharmaceutical composition of the invention process case is composed as follows:
Embodiment 1 (1000 amounts)
A preparation method for Suo Feibuwei thin membrane coated tablet, comprises following step:
(1) Suo Feibuwei crude drug is carried out micronization, obtain micronization crude drug (D50=103um, D90=172um, D10=34um), for subsequent use;
(2) take the Suo Feibuwei of formula ratio, microcrystalline Cellulose PH102, mannitol, cross-linking sodium carboxymethyl cellulose, polyethylene glycol 6000, and be placed in high shear mixing granulator mix homogeneously;
(3) material of mix homogeneously in high shear mixing granulator is transferred in fluid bed, the PVP K30 solution configured is sprayed in fluid bed and granulates.Temperature of charge is 40 DEG C, and air-introduced machine frequency is 35HZ, and atomizing pressure is 0.2MPa.
(4) by the granule that makes through 80 mesh sieve granulate, add microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, micropowder silica gel, magnesium stearate mixing after granulate, tabletting, obtains plain sheet;
(5) by the coating powder containing propylene glycol and hypromellose (1:3) with 95% ethanol be configured to the solid content of 8% (w/w).The plain sheet obtained in step (4) is carried out coating in coating pan, and coated tablet bed tempertaure is 30 ~ 40 DEG C.Coating weight gain 1%-3%, to obtain final product.
Accompanying drawing 1 is shown in technological process.
Plain sheet prepared by said method and the testing result of coated tablet as follows:
| Project | Element sheet | Thin membrane coated tablet |
| Disintegration | 45 seconds | 51 seconds |
| Dissolution (15min) | 98％ | 97％ |
| Maximum list is mixed | 0.05％ | 0.05％ |
| Total assorted | 0.23％ | 0.23％ |
Embodiment 2
Suo Feibuwei crude drug particle diameter in case study on implementation is adjusted to D50=68um, D90=115um, D10=17um, and 60 mesh sieve granulate after granulating, other operations prepare plain sheet with the preparation method of case study on implementation 1.
Coating steps is carried out as follows: by the coating powder containing propylene glycol and hypromellose (1:1) with 75% ethanol be configured to the solid content of 8% (w/w).The plain sheet obtained in step (4) is carried out coating in coating pan, and coated tablet bed tempertaure is 30 ~ 35 DEG C.Coating weight gain 1%-3%, to obtain final product.
Testing result is as follows:
| Project | Element sheet | Thin membrane coated tablet |
| Disintegration | 35 | 44 |
| Dissolution (15min) | 98％ | 98％ |
| Maximum list is mixed | 0.03％ | 0.03％ |
| Total assorted | 0.16％ | 0.15％ |
Embodiment 3
Preparation process is with case study on implementation 1, Suo Feibuwei crude drug particle size distribution: D50=34um, D90=93um, D10=7um.
Coating steps is carried out as follows: by the coating powder containing propylene glycol and hypromellose (1:5) with 85% ethanol water be configured to the solid content of 8% (w/w).The plain sheet obtained in step (4) is carried out coating in coating pan, and coated tablet bed tempertaure is 30 ~ 35 DEG C.Coating weight gain 1%-3%, to obtain final product.
Testing result is as follows:
| Project | Element sheet | Thin membrane coated tablet |
| Disintegration | 43 seconds | 53 seconds |
| Dissolution (15min) | 98％ | 97％ |
| Maximum list is mixed | 0.03％ | 0.03％ |
| Total assorted | 0.17％ | 0.17％ |
Although the present invention with better case study on implementation openly as above; but it is not for limiting the present invention; any those skilled in the art without departing from the spirit and scope of the present invention; the Method and Technology content of above-mentioned announcement can be utilized to make possible variation and amendment to technical solution of the present invention; therefore; every content not departing from technical solution of the present invention; the any simple modification done above case study on implementation according to technical spirit of the present invention, equivalent variations and modification, all belong to the protection domain of technical solution of the present invention.
Claims (10)
1. Yi Zhong Suo Feibuwei film coating tablet, containing active component Suo Feibuwei and at least one pharmaceutically label made of acceptable adjuvant, and based calcium, it is characterized in that described label is prepared by fluidized bed granulation method, the filmogen of based calcium is hypromellose and propylene glycol, and wherein the mass ratio of propylene glycol and hypromellose is 1:1 ~ 1:5.
2. Suo Feibuwei film coating tablet as claimed in claim 1, is characterized in that the mass ratio of propylene glycol and hypromellose is 1:2 ~ 1:5.
3. Suo Feibuwei film coating tablet as claimed in claim 1, is characterized in that the mass ratio of propylene glycol and hypromellose is 1:3.
4. Suo Feibuwei film coating tablet as claimed in claim 1, is characterized in that described active component Suo Feibuwei is micronized, mean diameter D50≤85um.
5. Suo Feibuwei film coating tablet as claimed in claim 1, is characterized in that active component Suo Feibuwei is with amorphous existence.
6. the Suo Feibuwei film coating tablet as described in as arbitrary in claim 1 to 5, is characterized in that carrying out one-step palletizing by fluid bed, comprises the steps:
1) crude drug pretreatment: by Suo Feibuwei micronization;
2) binder solution preparation: take recipe quantity PVPk30, be dissolved in ethanol water;
3) mix: take the Suo Feibuwei of formula ratio, microcrystalline Cellulose PH102, mannitol, cross-linking sodium carboxymethyl cellulose, polyethylene glycol 6000, and be placed in high shear mixing granulator mix homogeneously;
4) granulate: the material of mix homogeneously in high shear mixing granulator is transferred in fluid bed, material steadiness parameter, inlet temperature are set; The PVP K30 solution configured is sprayed in fluid bed, granulates;
5) granulate: oscillating granulator granulate, obtains target particles.
7. Suo Feibuwei film coating tablet as claimed in claim 6, the preparation of its fluid bed is characterised in that: step 2) described in the volume percent content of ethanol water be 70%-95%; Step 4) described in temperature of charge be 40 DEG C; Step 5) described in granulate be employing 60 ~ 80 mesh sieve granulate.
8. prepare a method for Suo Feibuwei film coating tablet as claimed in claim 1, comprise the steps:
1) coating solution configuration: the film coating agent that is filmogen containing hypromellose and propylene glycol being dissolved or dispersed in concentration is must coating solution in the ethanol water of 75% ~ 95%;
2) film coating: label is preheating in high-efficiency coating machine, control strip bed tempertaure is 30 DEG C ~ 40 DEG C, and coating solution even spraying is also fully dry to sheet wicking surface, obtains Suo Feibuwei film coating tablet.
9. the method for Suo Feibuwei film coating tablet as claimed in claim 8, is characterized in that the concentration of ethanol water is 85% ~ 95%.
10. the method for Suo Feibuwei film coating tablet as claimed in claim 8, is characterized in that sheet bed tempertaure is 30 DEG C ~ 35 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510955793.7A CN105380922A (en) | 2015-12-18 | 2015-12-18 | Sofosbuvir film-coated tablets and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510955793.7A CN105380922A (en) | 2015-12-18 | 2015-12-18 | Sofosbuvir film-coated tablets and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105380922A true CN105380922A (en) | 2016-03-09 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510955793.7A Pending CN105380922A (en) | 2015-12-18 | 2015-12-18 | Sofosbuvir film-coated tablets and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107041873A (en) * | 2017-02-17 | 2017-08-15 | 杭州青玥医药科技有限公司 | The preparation method of rope fluorine cloth Wei coated tablet |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104546783A (en) * | 2014-12-12 | 2015-04-29 | 安徽一灵药业有限公司 | Sofosbuvir film coating tablet preparation and preparation method thereof |
| 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 |
| WO2015132321A1 (en) * | 2014-03-05 | 2015-09-11 | Galenicum Health S.L. | Stable pharmaceutical compositions of sofosbuvir |
| 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 |
-
2015
- 2015-12-18 CN CN201510955793.7A patent/CN105380922A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2015132321A1 (en) * | 2014-03-05 | 2015-09-11 | Galenicum Health S.L. | Stable pharmaceutical compositions of sofosbuvir |
| CN104546783A (en) * | 2014-12-12 | 2015-04-29 | 安徽一灵药业有限公司 | Sofosbuvir film coating tablet preparation and preparation method thereof |
| 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 |
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| 谢敏，等: "《制药设备运行与维护》", 28 February 2015, 广东高等教育出版社 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107041873A (en) * | 2017-02-17 | 2017-08-15 | 杭州青玥医药科技有限公司 | The preparation method of rope fluorine cloth Wei coated tablet |
| CN107041873B (en) * | 2017-02-17 | 2020-02-28 | 杭州青玥医药科技有限公司 | Preparation method of sofosbuvir coated tablet |
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