CN114159400A - Favipiravir core-wrapped tablet - Google Patents
Favipiravir core-wrapped tablet Download PDFInfo
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- CN114159400A CN114159400A CN202111383310.2A CN202111383310A CN114159400A CN 114159400 A CN114159400 A CN 114159400A CN 202111383310 A CN202111383310 A CN 202111383310A CN 114159400 A CN114159400 A CN 114159400A
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- favipiravir
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- ZCGNOVWYSGBHAU-UHFFFAOYSA-N favipiravir Chemical group NC(=O)C1=NC(F)=CNC1=O ZCGNOVWYSGBHAU-UHFFFAOYSA-N 0.000 title claims abstract description 105
- 229950008454 favipiravir Drugs 0.000 title claims abstract description 97
- 239000003826 tablet Substances 0.000 claims abstract description 73
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
-
- 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
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Virology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Communicable Diseases (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
The invention discloses a composition of a Favipiravir core-spun tablet and a preparation method thereof. The preparation can be quickly released to achieve the purpose of quick effect after being orally taken, and then the sustained-release tablet core can be stably released, so that the effective antiviral concentration of the medicine in vivo is maintained, the acting time of the medicine in vivo is prolonged, the total administration dosage is reduced, the problems of unstable blood concentration, obvious peak valley phenomenon, high adverse reaction incidence and poor patient administration compliance of the existing preparation of the Favipiravir are solved, and the preparation type is more reasonable than the existing preparation on the market.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a composition of a Favipiravir core-spun tablet and a preparation method thereof.
Background
The chemical name of the Favipiravir (favipiravir) is 6-fluoro-3-oxo-hydroxypyrazine-2-formamide, which is a virus RNA polymerase inhibitor, and the Favipiravir is converted into Favipiravir nucleoside triphosphate in vivo after being taken orally, has a structure similar to purine, competes with purine virus RNA polymerase, inhibits the synthesis of virus RNA, and thus plays a role in resisting viruses. The Favipiravir is an influenza treatment drug developed by Nippon Fushan chemical company, a Favipiravir common tablet with the specification of 200mg in 3 months in 2014 is marketed in Japan, and a Favipiravir common tablet which is produced by Hai Zhen Yao industry authorized by an Avigan manufacturer and is a Favipiravir common tablet is marketed in China at present, has the specification of 200mg, is suitable for treating various influenza including H1N1, H5N1 and H7N9, and is mainly used for treating novel or reoccurrent influenza for adults. The usage and dosage of the Favilavir tablet are as follows: the dose was 1600mg twice daily for the first day, and 600mg twice daily from the next day to the fifth day.
The existing common Favipiravir tablets have the defects that the dosage is too high after single administration (the dosage is up to 1600 mg/time after first day administration), the blood concentration in vivo is obvious in peak valley, the adverse reaction rate is high, the Avigan specification clearly indicates that the adverse reaction rate is 19.96 percent, the adverse reaction rate comprises serious adverse reactions such as shock, anaphylactic reaction, pneumonia, fulminant pneumonia, liver dysfunction, epidermal necrosis syndrome, acute kidney injury, leukopenia, thrombocytopenia, nervous system symptoms, hemorrhagic colitis and the like, and the administration safety and the compliance of patients are low.
Aiming at the defects of the prior art, the invention aims to provide a composition of a Favipiravir core-spun tablet and a preparation method thereof. The Lavipiravir core-coated tablet provided by the invention provides a more scientific, reasonable, safe and effective administration mode than the existing Lavipiravir marketed preparation, the Lavipiravir core-coated tablet combines two drug release mechanisms of quick release and slow release, the quick release peripheral layer after oral administration quickly releases the drug, the antiviral effect is quickly exerted, then the slow release tablet core stably releases the drug, the blood concentration is more stable, the fluctuation of the peak valley is small, and the incidence rate of adverse reaction can be effectively reduced; the sustained-release tablet core can effectively prolong the antiviral action time of the medicine in vivo, has lasting treatment effect, can also obviously reduce the total administration dosage, improves the medication safety and the medication compliance of patients, and achieves better treatment effect compared with the common preparation.
Disclosure of Invention
The invention aims to provide a composition of a Favipiravir core-coated tablet and a preparation method thereof, aiming at the problems of overhigh single-dose administration, obvious peak and valley phenomena of blood concentration in vivo, higher adverse reaction incidence rate and lower medicine taking safety and compliance of patients of the existing common Favipiravir tablets on the market, and the combination of two quick-release mechanisms and slow-release mechanisms, the rapid-effect and stable medicine release can be realized, the fluctuation of the peak and valley phenomena of the blood concentration is small, the adverse reaction incidence rate is effectively reduced, the total dosage of the medicine is reduced, the safety and the compliance of the patients are improved, and more reasonable preparation types and administration modes are provided compared with the existing preparation, so that the better treatment effect is achieved.
The invention provides a Favipiravir core-spun tablet which is characterized by consisting of an inner layer Favipiravir sustained-release tablet core and an outer layer Favipiravir quick-release outer peripheral layer.
The Favipiravir core-spun tablet is characterized in that the weight ratio of the Favipiravir sustained-release tablet core to the Favipiravir quick-release peripheral layer is as follows:
favipiravir sustained release tablet core: 28% -48%;
favipiravir quick-release peripheral layer: 52 to 72 percent.
The Favipiravir sustained-release tablet core is characterized in that the composition of the sustained-release tablet core comprises Favipiravir, a framework material, a filling agent, an adhesive and a lubricant.
The Favipiravir sustained-release tablet core is characterized in that the weight ratio of the Favipiravir, the framework material, the filling agent, the adhesive and the lubricant in the sustained-release tablet core is as follows:
favipiravir: 47.0 to 88.5 percent,
Framework material: 10.0 to 30.0 percent,
Filling agent: 1.0 to 10.0 percent,
Adhesive: 0.4 to 5.0 percent,
Lubricant: 0.1 to 5.0 percent.
Preferably, the weight proportions of the favipiravir, the framework material, the filler, the adhesive and the lubricant in the favipiravir sustained-release tablet core are as follows:
favipiravir: 58.5 to 88.5 percent,
Framework material: 10.0 to 30.0 percent,
Filling agent: 1.0 to 5.0 percent,
Adhesive: 0.4 to 4.4 percent,
Lubricant: 0.1 to 2.1 percent.
The Favipiravir sustained-release tablet core is characterized in that the particle size of the Favipiravir contained in the tablet core is 90-230 microns.
In the favipiravir sustained-release tablet core, the framework material is selected from one or more of methylcellulose, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, croscarmellose sodium, hydrogenated castor oil, sodium alginate and agar, and preferably the hydroxypropyl methylcellulose and the sodium carboxymethylcellulose are selected.
In the favipiravir sustained-release tablet core, the filler is selected from one or more of lactose, mannitol, sorbitol, sucrose, starch, dextrin, cyclodextrin, calcium phosphate, calcium hydrophosphate and microcrystalline cellulose, and preferably microcrystalline cellulose.
In the favipiravir sustained-release tablet core, the adhesive is selected from one or more of pregelatinized starch, arabic gum, methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone, and is preferably hydroxypropyl methylcellulose.
In the fapiroviru sustained-release tablet core, the lubricant is selected from one or more of talcum powder, superfine silica gel powder and sodium stearyl fumarate, and preferably, the sodium stearyl fumarate.
The Favipiravir immediate-release peripheral layer is characterized by comprising the Favipiravir, a filler, a disintegrating agent, a binder and a lubricant.
The fast-release favipiravir peripheral layer is characterized in that the fast-release favipiravir peripheral layer comprises the following components in parts by weight:
favipiravir: 5.0 to 96.5 percent,
Filling agent: 2.0 to 35 percent,
Disintegrating agent: 1.0 to 45 percent,
Adhesive: 0.4 to 10 percent,
Lubricant: 0.1 to 5 percent.
Preferably, the weight ratio of the components of the favipiravir, the filler, the disintegrating agent, the adhesive and the lubricant in the fast-release peripheral layer of the favipiravir is as follows:
favipiravir: 28.0 to 96.5 percent,
Filling agent: 2.0 to 30.0 percent,
Disintegrating agent: 1.0 to 34.0 percent,
Adhesive: 0.4 to 5.0 percent,
Lubricant: 0.1 to 3.0 percent.
The fast-release outer peripheral layer of the Favipiravir is characterized in that the particle size of the Favipiravir contained in the fast-release outer peripheral layer is 60-120 mu m.
In the fapiroviri quick-release peripheral layer, the filler is selected from one or more of lactose, mannitol, sorbitol, sucrose, starch, dextrin, cyclodextrin, calcium phosphate, calcium hydrogen phosphate and microcrystalline cellulose, and is preferably microcrystalline cellulose.
In the fast-release peripheral layer of fapiroviru, the disintegrating agent is selected from one or more of sodium carboxymethyl starch, hydroxypropyl starch, calcium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, calcium ammonium alginate and superfine silica gel powder, and preferably, the cross-linked sodium carboxymethyl cellulose, the cross-linked polyvinylpyrrolidone and the superfine silica gel powder are selected.
In the fapiroviru quick-release peripheral layer, the adhesive is selected from one or more of pregelatinized starch, acacia, methyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone, and is preferably polyvinylpyrrolidone.
In the fast-release peripheral layer of the Favipiravir, the lubricant is selected from one or more of talcum powder, superfine silica gel powder and sodium stearyl fumarate, and the sodium stearyl fumarate is preferred.
The invention provides a preparation method of a Favipiravir core-spun tablet, which is characterized by comprising the following steps:
1) mixing and pressing Favipiravir, a framework material, a filling agent, a bonding agent and a lubricating agent into the Favipiravir sustained-release tablet core according to the weight proportion of each component in the Favipiravir sustained-release tablet core;
2) mixing the Favipiravir, the filler, the disintegrant, the adhesive, the lubricant and the like according to the weight ratio of the components in the Favipiravir quick-release peripheral layer, and tabletting the mixture with the coating slow-release tablet core to obtain the Favipiravir core-spun tablet.
As a preferable scheme of the preparation method, the preparation method of the Favipiravir core-spun tablet is characterized by comprising the following steps:
1) dissolving a bonding agent in water or an organic solvent according to the weight ratio of the components in the sustained-release tablet core, firstly uniformly mixing Favipiravir and a part of framework materials, gradually adding a bonding agent solution into the mixture of the Favipiravir and the part of the framework materials to prepare uniform wet granules, uniformly mixing the dried granules with a filling agent and the other part of the framework materials, uniformly mixing the dried granules with a lubricating agent, and finally pressing to obtain the Favipiravir sustained-release tablet core;
2) dissolving an adhesive in water or an organic solvent according to the weight ratio of the components in the quick-release peripheral layer, firstly uniformly mixing Favipiravir, a filler and a disintegrating agent, gradually adding the adhesive solution into the mixture of Favipiravir, the filler and the disintegrating agent to prepare uniform wet granules, adding a lubricant into the granules obtained after drying, uniformly mixing, and tabletting with the sustained-release tablet core obtained in the step 1) to obtain the Favipiravir core-coated tablet.
Compared with the prior art, the Favipiravir core-spun tablet provided by the invention has the advantages that two drug release mechanisms of quick release and slow release are combined, the quick-release peripheral layer of the core-spun tablet is quickly released after oral administration, the antiviral effect can be quickly exerted, the drug is slowly released by the slow-release core tablet inside, the effective antiviral action time of the drug in the body of the drug is prolonged, the administration dose is reduced, the administration times are reduced, the peak valley phenomenon is avoided, the adverse reaction incidence is reduced, and a more scientific, reasonable, safe and effective administration mode and preparation type are provided compared with the existing Favipiravir commercial preparation.
Drawings
In order to facilitate understanding of the technical solutions of the present invention in the prior art, the drawings used in the prior art are briefly described below.
Fig. 1 is a schematic diagram of a fapirovir core-spun tablet according to an embodiment of the present invention, which is a description of the fapirovir core-spun tablet of the present invention and can be implemented in many different forms, without limiting the scope of the present invention.
Fig. 2 is a graph comparing the administration time curves of the self-prepared viravir core-spun tablets and the commercially available viravir tablets in the embodiment of the invention.
Detailed Description
For ease of understanding, the present invention will now be described more fully hereinafter with reference to the accompanying examples, but which are not intended to be limiting of the invention, which may be embodied in many different forms.
Example 1 preparation of core-coated Favipiravir tablets 1
Recipe 1 (single dose, unit mg):
the preparation process comprises the following steps:
1) preparation of a favipiravir sustained-release tablet core: weighing formula dose method pirlavir and sodium carboxymethylcellulose, uniformly mixing, gradually adding a hydroxypropyl methylcellulose E5 aqueous solution for granulation, drying, adding hydroxypropyl methylcellulose K100M, uniformly mixing with microcrystalline cellulose, adding sodium stearyl fumarate, uniformly mixing, and pressing into a shallow concave tablet core with the diameter of 8.5mm and the hardness of 60-80N.
2) Preparing a fast-release outer peripheral layer of favipiravir: weighing formula amount method pirlavir, microcrystalline cellulose, micropowder silica gel, croscarmellose sodium and crospolyvinylpyrrolidone, uniformly mixing, gradually adding polyvinylpyrrolidone K30 aqueous solution for granulating, drying, adding sodium stearyl fumarate, uniformly mixing, tabletting the mixed powder and the sustained release tablet core obtained in step 1) by adopting a ZPW-26 rotary core-wrapping machine to obtain the pirlavir core-wrapping tablet with the diameter of 11.0 mm.
Example 2 preparation of core-spun flapware 2
Recipe 2 (single dose, unit mg):
the preparation process comprises the following steps:
1) preparation of a favipiravir sustained-release tablet core: weighing formula dose method pirlavir and sodium carboxymethylcellulose, uniformly mixing, gradually adding a hydroxypropyl methylcellulose E5 aqueous solution for granulation, drying, adding hydroxypropyl methylcellulose K15M and microcrystalline cellulose, uniformly mixing, adding sodium stearyl fumarate, uniformly mixing, and pressing into a shallow concave tablet core with the diameter of 8.5mm and the hardness of 60-80N.
2) Preparing a fast-release outer peripheral layer of favipiravir: weighing formula amount method pirlavir, microcrystalline cellulose, micropowder silica gel, croscarmellose sodium and crospolyvinylpyrrolidone, uniformly mixing, gradually adding polyvinylpyrrolidone K30 aqueous solution for granulating, drying, adding sodium stearyl fumarate, uniformly mixing, tabletting the mixed powder and the sustained release tablet core obtained in step 1) by adopting a ZPW-26 rotary core-wrapping machine to obtain the pirlavir core-wrapping tablet with the diameter of 11.0 mm.
Example 3 preparation of Favipiravir core tablets 3
Prescription 3 (single dose, unit mg):
the preparation process comprises the following steps:
1) preparation of a favipiravir sustained-release tablet core: weighing formula dose method pirlavir and sodium carboxymethylcellulose, uniformly mixing, gradually adding a hydroxypropyl methylcellulose E5 aqueous solution for granulation, drying, adding hydroxypropyl methylcellulose K4M and microcrystalline cellulose, uniformly mixing, adding sodium stearyl fumarate, uniformly mixing, and pressing into a shallow concave tablet core with the diameter of 8.5mm and the hardness of 60-80N.
2) Preparing a fast-release outer peripheral layer of favipiravir: weighing formula amount method pirlavir, microcrystalline cellulose, micropowder silica gel, croscarmellose sodium and crospolyvinylpyrrolidone, uniformly mixing, gradually adding polyvinylpyrrolidone K30 aqueous solution for granulating, drying, adding sodium stearyl fumarate, uniformly mixing, tabletting the mixed powder and the sustained release tablet core obtained in step 1) by adopting a ZPW-26 rotary core-wrapping machine to obtain the pirlavir core-wrapping tablet with the diameter of 11.0 mm.
Example 4 preparation of Favipiravir core tablets 4
Recipe 4 (single dose, unit mg):
the preparation process comprises the following steps:
1) preparation of a favipiravir sustained-release tablet core: weighing formula dose method pirlavir and sodium carboxymethylcellulose, uniformly mixing, gradually adding a hydroxypropyl methylcellulose E5 aqueous solution for granulation, drying, adding hydroxypropyl methylcellulose K4M and microcrystalline cellulose, uniformly mixing, adding sodium stearyl fumarate, uniformly mixing, and pressing into a shallow concave tablet core with the diameter of 8.5mm and the hardness of 60-80N.
2) Preparing a fast-release outer peripheral layer of favipiravir: weighing formula-dose method piravir, microcrystalline cellulose, micropowder silica gel and crosslinked polyvinylpyrrolidone, uniformly mixing, gradually adding polyvinylpyrrolidone K30 aqueous solution for granulation, drying, adding sodium stearyl fumarate, uniformly mixing, and tabletting the mixed powder and the sustained-release tablet core obtained in step 1) by adopting a ZPW-26 rotary core-wrapping machine to obtain the piravir core-wrapping tablet with the diameter of 11.0 mm.
Example 5 preparation of Favipiravir core tablets 5
Recipe 5 (single dose, unit mg):
the preparation process comprises the following steps:
1) preparation of a favipiravir sustained-release tablet core: weighing formula dose method pirlavir and sodium carboxymethylcellulose, uniformly mixing, gradually adding a hydroxypropyl methylcellulose E5 aqueous solution for granulation, drying, adding hydroxypropyl methylcellulose K4M and microcrystalline cellulose, uniformly mixing, adding sodium stearyl fumarate, uniformly mixing, and pressing into a shallow concave tablet core with the diameter of 8.5mm and the hardness of 60-80N.
2) Preparing a fast-release outer peripheral layer of favipiravir: weighing formula-amount Laevir, microcrystalline cellulose, micropowder silica gel, pregelatinized starch and crosslinked polyvinylpyrrolidone, uniformly mixing, gradually adding polyvinylpyrrolidone K30 aqueous solution for granulating, drying, adding sodium stearyl fumarate, uniformly mixing, tabletting the mixed powder and the sustained-release tablet core obtained in step 1) by adopting a ZPW-26 rotary core-wrapping machine to obtain the Laevir core-wrapping tablet with the diameter of 11.0 mm.
Example 6 preparation of Favipiravir core tablets 6
Prescription 6 (single dose, unit mg):
the preparation process comprises the following steps:
1) preparation of a favipiravir sustained-release tablet core: weighing formula dose method pirlavir and sodium carboxymethylcellulose, uniformly mixing, gradually adding a hydroxypropyl methylcellulose E5 aqueous solution for granulation, drying, adding hydroxypropyl methylcellulose K4M and microcrystalline cellulose, uniformly mixing, adding sodium stearyl fumarate, uniformly mixing, and pressing into a shallow concave tablet core with the diameter of 8.5mm and the hardness of 60-80N.
2) Preparing a fast-release outer peripheral layer of favipiravir: weighing formula-amount Laevir, microcrystalline cellulose, micropowder silica gel, sodium carboxymethyl starch and crosslinked polyvinylpyrrolidone, uniformly mixing, gradually adding polyvinylpyrrolidone K30 aqueous solution for granulation, drying, adding sodium stearyl fumarate, uniformly mixing, tabletting the mixed powder and the sustained-release tablet core obtained in step 1) by adopting a ZPW-26 rotary core-wrapping machine, and thus obtaining the Laevir core-wrapping tablet with the diameter of 11.0 mm.
Example 7 in vitro dissolution cumulative Release Curve determination
The piravir core-coated tablets prepared by the self-preparation method of the embodiments 1 to 6 and the commercially available faviravir tablets are taken, and 5ml of purified water is sampled at the rotating speed of 50r/min and the temperature of 15min, 30min, 1h, 3h, 5h and 8h respectively according to a release degree measuring method (second method of 2020 edition in Chinese pharmacopoeia). The wavelength was 321nm as determined by UV method, and the control concentration was about 8. mu.g/ml.
Table 1: EXAMPLES 1-6 in vitro dissolution cumulative Release Profile times from preparations and commercially available products
| Sample (I) | 15min | 30min | 1h | 3h | 5h | 10h | 15h | 20h |
| Example 1 | 56％ | 59％ | 61％ | 70％ | 81％ | 96％ | 99％ | 100％ |
| Example 2 | 56％ | 60％ | 66％ | 76％ | 87％ | 98％ | 100％ | 100％ |
| Example 3 | 57％ | 62％ | 68％ | 81％ | 92％ | 99％ | 100％ | 100％ |
| Example 4 | 37％ | 46％ | 65％ | 81％ | 90％ | 99％ | 100％ | 100％ |
| Example 5 | 49％ | 58％ | 68％ | 81％ | 91％ | 99％ | 100％ | 100％ |
| Example 6 | 52％ | 55％ | 66％ | 81％ | 90％ | 99％ | 100％ | 100％ |
| Commercially available product | 96％ | 99％ | 100％ | -- | -- | -- | -- | -- |
According to the dissolution curve results of the above examples 1-6, the drug in the peripheral quick release layer is quickly released, and the effective antiviral blood concentration in vivo can be quickly achieved; the sustained-release tablet core takes hydroxypropyl methylcellulose and sodium carboxymethylcellulose as framework materials, the surface of the sustained-release tablet core is hydrated to form a gel layer when meeting water, the drug on the surface is quickly dissolved, and the gel layer is thickened to delay the release of the drug, so that the Favipiravir can maintain safe and effective antiviral blood concentration in vivo for a long time.
Example 8 in vivo pharmacokinetic testing in animals
In the invention, 12 Beagle dogs are used as test animals, and a double-preparation double-cycle cross experimental design is adopted to perform in vivo pharmacokinetic experimental study on the Favipiravir core-spun tablets (example 3) and the Favila tablets which are commercially available. The single administration dose of the self-prepared Pilatavir core-spun tablet group is 350mg multiplied by 2 tablets, and the single administration dose of the commercially available Favelavir tablet group is 200mg multiplied by 4 tablets. Plasma was collected at time points of 5 minutes (+ -1 minute), 15 minutes (+ -1 minute), 30 minutes (+ -2 minutes), 1 hour (+ -2 minutes), 2 hours (+ -5 minutes), 4 hours (+ -5 minutes), 6 hours (+ -10 minutes), 8 hours (+ -15 minutes), 12 hours (+ -15 minutes), 18 hours (+ -15 minutes), and 24 hours (+ -30 minutes) before administration, after administration, respectively, and the faviravir concentration therein was determined. Fasting is carried out for 12h before administration, water is not forbidden, and food is recovered for 4h after administration. The average plasma concentration of the Favipiravir proves that compared with the Favipiravir tablets sold in the market, the self-made Favipiravir core-spun tablets effectively modify the in-vivo release of the medicament, obviously prolong the time of safe and effective anti-virus blood concentration of the Favipiravir in the body, reduce the total administration dosage, simultaneously maintain the bioavailability equivalent to that of the products sold in the market, and have no obvious adverse reaction in the test process of animals with the self-made Favipiravir core-spun tablets. The results of the pharmacokinetic parameters of the self-prepared piravir core-spun tablets and the commercially available piravir tablets are shown in the following table.
Table 2: comparison of pharmacokinetic parameters for a self-prepared Pilaravir core tablet (example 3) and a commercially available Vilaravir tablet
| Sample name | Cmax(ng·mL-1) | AUC(ng·h·mL-1) | Tmax(h) |
| Example 3 | 51.2 | 536 | 1.0±0.5 |
| Commercially available product | 65.6 | 520 | 0.5±0.5 |
The results of the pharmacokinetic experiment in animals show that: compared with the commercially available faviravir tablets, the self-made pinavir tablet has the advantages that the peak-valley phenomenon is obviously improved, the drug release is more stable, the effective antiviral action time in vivo is obviously prolonged, the area under the drug time curves of the two tablets is basically consistent, meanwhile, the blood concentration of the self-made pinavir tablet after being taken can reach the peak within about 1h, the effect is quick, and the treatment advantage of the quick-release and slow-release dual drug release mechanism is fully embodied.
Claims (4)
1. A Favipiravir core-spun tablet is characterized in that the core-spun tablet consists of an inner layer Favipiravir sustained-release tablet core and an outer layer Favipiravir quick-release outer peripheral layer, wherein the sustained-release tablet core accounts for 28% -48% of the total weight of the tablet, the quick-release outer peripheral layer accounts for 52% -72% of the total weight of the tablet, and the weight ratio of the components is as follows:
a sustained release tablet core:
47.0 to 88.5 percent of Favipiravir,
10.0 to 30.0 percent of framework material,
1.0 to 10.0 percent of filling agent,
0.4 to 5.0 percent of adhesive,
0.1 to 5.0 percent of lubricant;
quick release outer peripheral layer:
5.0 to 96.5 percent of Favipiravir,
2.0 to 35 percent of filling agent,
1.0 to 45 percent of disintegrating agent,
0.4 to 10 percent of adhesive,
0.1 to 5 percent of lubricant.
2. The favipiravir core-spun tablet of claim 1, wherein: the skeleton material in the sustained-release tablet core is selected from one or more of methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, sodium carboxymethylcellulose, croscarmellose sodium, hydrogenated castor oil, sodium alginate and agar; the filler is selected from one or more of lactose, mannitol, sorbitol, sucrose, starch, dextrin, cyclodextrin, calcium phosphate, calcium hydrogen phosphate, and microcrystalline cellulose; the adhesive is one or more selected from pregelatinized starch, acacia, methylcellulose, ethyl cellulose, hypromellose, sodium carboxymethylcellulose, and polyvinylpyrrolidone; the lubricant is selected from one or more of talcum powder, superfine silica gel powder and sodium stearyl fumarate, and the filler in the quick-release peripheral layer is selected from one or more of lactose, mannitol, sorbitol, sucrose, starch, dextrin, cyclodextrin, calcium phosphate, calcium hydrogen phosphate and microcrystalline cellulose; the disintegrating agent is selected from one or more of sodium carboxymethyl starch, hydroxypropyl starch, calcium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, ammonium calcium alginate, and silica gel micropowder; the adhesive is one or more selected from pregelatinized starch, acacia, methylcellulose, ethyl cellulose, hypromellose, sodium carboxymethylcellulose, and polyvinylpyrrolidone; the lubricant is selected from one or more of pulvis Talci, silica gel micropowder, and sodium stearyl fumarate.
3. The fapirovir core-spun tablet of claim 2, characterized in that the skeleton material in the sustained release tablet core is selected from hypromellose and sodium carboxymethylcellulose, the filler is selected from microcrystalline cellulose, the binder is selected from hypromellose, and the lubricant is selected from sodium stearyl fumarate; the filler in the quick-release outer peripheral layer is selected from microcrystalline cellulose, the disintegrating agent is selected from croscarmellose sodium, crospolyvinylpyrrolidone and superfine silica gel powder, the adhesive is selected from polyvinylpyrrolidone, and the lubricant is selected from sodium stearyl fumarate.
4. The Favipiravir core-spun tablet according to any one of claims 1 to 3, characterized in that the preparation method comprises the following steps:
1) dissolving a bonding agent in water or an organic solvent according to the weight ratio of the components in the sustained-release tablet core, firstly uniformly mixing Favipiravir and a part of framework materials, gradually adding a bonding agent solution into the mixture of the Favipiravir and the part of the framework materials to prepare uniform wet granules, uniformly mixing the dried granules with a filling agent and the other part of the framework materials, uniformly mixing the dried granules with a lubricating agent, and finally pressing to obtain the Favipiravir sustained-release tablet core;
2) dissolving an adhesive in water or an organic solvent according to the weight ratio of the components in the quick-release peripheral layer, firstly uniformly mixing Favipiravir, a filler and a disintegrating agent, gradually adding the adhesive solution into the mixture of Favipiravir, the filler and the disintegrating agent to prepare uniform wet granules, adding a lubricant into the granules obtained after drying, uniformly mixing, and tabletting with the sustained-release tablet core obtained in the step 1) to obtain the Favipiravir core-coated tablet.
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