CN113633617A - Solid dispersion and solid dosage form containing Reidesciclovir and preparation method thereof - Google Patents
Solid dispersion and solid dosage form containing Reidesciclovir and preparation method thereof Download PDFInfo
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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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
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
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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
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- 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
Abstract
The invention provides a solid dispersion containing Reidesciclovir and a solid dosage form containing the solid dispersion, belonging to the technical field of pharmaceutical preparations. The invention also provides a preparation method of the solid dispersion and the solid dosage form. The solid dosage form containing the Reidesciclovir is prepared by firstly adopting a hot-melt extrusion technology to prepare a solid dispersion containing the Reidesciclovir and the copovidone, then preparing the solid dispersion with a filler, a disintegrant, a glidant and a lubricant into a mixture, and finally preparing the mixture into a solid dosage form, such as a tablet. The solid preparation of the Ruidexiwei provided by the invention improves the dissolution rate and bioavailability of the medicine in the oral solid preparation, and has larger clinical application value; in addition, the solid preparation of the RudeSewei prepared by the invention has stable and controllable quality and is convenient for industrial production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a solid dispersion containing Redexilvir, a preparation method of the solid dispersion, a solid dosage form containing the solid dispersion, and a preparation method of the solid dosage form.
Background
Reddesivir Remdesivir is a broad-spectrum antiviral drug developed by Jilide corporation of the U.S. pharmaceutical industry and originally designed to treat Ebola virus, and early cell experiments and animal experiments show that it can produce good antiviral activity against SARS coronavirus and MERS coronavirus by inhibiting RNA polymerase. In 11 months in 2018, in order to respond to the Ebola epidemic situation, Congo (gold) initiates a clinical control test under the initiative of world health organization, and tests the curative effects of 4 new medicines such as Remdesivir, MAb114, REGN-EB3 and Zmapp. The competition only takes 9 months to win or lose. Since the leading advantages of the REGN-EB3 and the mAb-114 are very obvious, the committee decides to finish the test in advance in 8 months in 2019, and the two drugs are popularized in a large range. Reidesciclovir has thus early withdrawn the battle against Ebola. However, during this time, girlidide has not stopped studying the role of redciclovir in other areas, including coronaviruses, for which "re-emerging" the vodka was buried.
It is worth mentioning that the prototype drug for Reidesciclovir GS-5734 is GS-441524, which is an FDA approved veterinary drug that has been recommended for the treatment of feline infectious peritonitis, which is rare but fatal and is caused by feline coronavirus. Reidesvir is currently considered to be one of the most potential drugs for achieving the most potential inhibition of new coronavirus, and for treating new coronavirus pneumonia (COVID-19). The year 2020 is that the day is 7/5,gillendoco announced that the national institute of health and labor (MHLW) of Japan has passed through a special approval route
(injection Ruidexiwei) as a therapeutic agent for SARS-CoV-2 infection; the 10-month 8-day girlidd science promulgated injection reed-ciclovir phase three clinical data from a phase 3 biorandom double-blind placebo-controlled study conducted by the american National Institute for Allergy and Infectious Disease (NIAID), covering about 1060 hospitalized patients worldwide. The data show that hospitalized patients receiving injection of reiciclovir recovered five days faster on average, while patients with severe disease recovered seven days faster, with these severe disease patients accounting for 85% of the total study. The American Food and Drug Administration (FDA) approved Reid West injection in Jilide science for treating patients in New crown hospitals at 22/10/2020, becoming the first approved new crown treatment drug in the United states.
Rudexilvir is a nucleoside analogue with broad-spectrum antiviral activity, can inhibit RNA-dependent RNA-polymerases (RdRp), has an active ingredient GS-5734 which is a phosphoramidate precursor of 1' -cyano adenosine analogue, and is metabolized in cells to generate an active triphosphate form-NTP. Ridciclovir, a monophosphate prodrug, can significantly increase the potency of the parent nucleoside by delivering the monophosphate into the cell and effectively bypassing the rate-limiting first phosphorylation step. The phenol and amino acid ester in the structure mask the negative charge of the monophosphate group, so that the monophosphate group can conveniently and passively permeate into cells. Intracellular esterases (such as carboxyesterase-1 and cathepsin a) decompose esters into carboxyl structures, then continue to decompose into nucleoside monophosphates, and finally are phosphorylated into nucleoside triphosphates to exert antiviral effects.
Chemical name of Reidesciclovir: (2S) -2- ((S) - ((((2R, 3S,4R,5R) -5- (4-Aminopyrrolo [2, 1-f)][1,2,4]Triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methoxyphenoxyphosphoryl) amino) propionic acid 2-ethylbutyl ester of the formula C27H35N6O8P, molecular weight 602.58. The structural formula is shown as the following formula I:
the LogP of the Reidesciclovir is 2.2, the pKa is 3.1, and the solubility in an aqueous medium is poor. The currently clinically used preparation of the Reidesciclovir is a freeze-dried powder injection or an injection with the specification of 100mg, needs intravenous infusion administration, has quick response and is suitable for critically ill patients with serious illness. FDA suggested that possible side effects of reed-solomon include: elevated liver enzyme levels and allergic reactions including changes in blood pressure and heart rate, hypoxemia, fever, shortness of breath, asthma, swelling (e.g., lips, periocular, subcutaneous), rash, nausea, sweating, or trembling. For mild and moderate patients, the development of a Rudexiwei oral administration form which is convenient to take, increases the medication compliance of the patients and has high oral bioavailability is urgently needed.
Currently, the clinically used injection Rudexiwei has the following defects: 1. systemic or local infection is easy to generate due to improper treatment; 2. the medicine is excessive or the drip is too fast, so that adverse reactions are easy to generate, and even the life is threatened; 3. continuous over-infusion, which is prone to overload or electrolyte imbalance; 4. the increase of iatrogenic diseases.
The Reidesciclovir is a low-solubility medicament, and the solubility of the medicament has great influence on the in-vivo bioavailability. Therefore, the key point of the invention is to improve the dissolution rate and bioavailability of the compound in the research of pharmaceutical preparations. Methods commonly used for improving the solubility of poorly soluble drugs include micronization technology, cyclodextrin inclusion technology, and the like.
The micronization treatment of the raw materials of the product can cause raw material loss and easily generate agglomeration. The saturated solubility of the Reidesvir in different cyclodextrin concentrations is examined, and the finding shows that the required sulfobutyl beta cyclodextrin precise amount is 1.3g when 100mg of Reidesvir is dissolved, the cyclodextrin essence is sticky, and the oral tablet prepared by the cyclodextrin essence is not easy to form.
Therefore, a Rudexiwei oral tablet with strong formula process operability, simple preparation process and high dissolution rate is urgently needed at present.
Disclosure of Invention
The invention provides a solid dosage form containing the Redexilvir, which has high drug dissolution, stable quality and good bioavailability. The solid preparation of the invention has simple preparation process and strong operability, does not use organic solvent and is convenient for industrial scale-up production.
The invention adopts Hot-Melt Extrusion technology (HME), also called Melt Extrusion technology (Melt Extrusion technology), and firstly prepares a solid dispersion containing the Redcisvir, then prepares the prepared solid dispersion with a filler, a disintegrant, a glidant and a lubricant into a total mixture, and finally prepares the total mixture into a tablet. Compared with the common tablet, the tablet obtained by the invention greatly improves the bioavailability of the active ingredient of the Rudexilvir and has higher clinical application value.
The invention provides a solid dispersion containing Reideciclovir, which comprises an active ingredient Reideciclovir and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier is copovidone, and the weight ratio of the Reideciclovir to the copovidone is 1:1-1: 4.
In some embodiments of the invention, the copovidone is copovidone VA64, and the weight ratio of redciclovir to copovidone VA64 is from 1:2 to 1: 3.
The invention also provides a preparation method of the solid dispersion containing the Reidesciclovir, which comprises the following steps:
(1) uniformly mixing the Reidesciclovir and the copovidone in a ratio of 1:1-1:4 to prepare a physical mixture;
(2) setting the extrusion temperature of a double-screw hot-melting extruder to be 140-220 ℃, starting a screw when the preset temperature is reached, adding the physical mixture obtained in the step (1) into the extruder, extruding a solid substance through the screw, and cooling;
(3) and (3) crushing the solid obtained in the step (2), and sieving the crushed solid with a 60-100-mesh sieve to obtain the solid dispersion containing the Redexilvir.
In the above preparation method of the present invention, in some embodiments, the ridciclovir and copovidone VA64 are uniformly mixed in a ratio of 1:2 to 1:3 in step (1).
The present invention also provides a solid dosage form containing redexivir, comprising a solid dispersion as described in any one of the above, and a filler, a disintegrant, a glidant and a lubricant.
In some embodiments, the solid dosage form containing redexivir of the present invention comprises the following components in percentage by weight:
in some embodiments, the solid dosage form containing redexivir of the present invention comprises the following components in percentage by weight:
in some embodiments, the solid dosage form containing redexivir of the present invention comprises the following components in percentage by weight:
the filler is selected from one or more of mannitol, lactose and microcrystalline cellulose.
The disintegrant is selected from one or more of croscarmellose sodium, crospovidone, and carboxymethyl starch sodium.
The glidant is selected from silicon dioxide.
The lubricant is selected from one or more of magnesium stearate, stearic acid, hydrogenated vegetable oil, glyceryl behenate and sodium stearyl fumarate.
In at least one embodiment, the filler is mannitol or a combination of mannitol and microcrystalline cellulose, the disintegrant is croscarmellose sodium, the glidant is silicon dioxide, and the lubricant is magnesium stearate.
Specifically, the invention provides a solid dosage form containing Reidevir, which comprises the following components in percentage by weight:
one embodiment of a solid dosage form containing redexivir provided by the invention is as follows: comprises the following components in percentage by weight:
one embodiment of a solid dosage form containing redexivir provided by the invention is as follows: comprises the following components in percentage by weight:
the invention also provides a preparation method of a solid dosage form containing the Redexilvir, which comprises the following steps:
(1) uniformly mixing the Reidesciclovir and the copovidone in a ratio of 1:1-1:4 to prepare a physical mixture;
(2) setting the extrusion temperature of a double-screw hot-melting extruder to be 140-220 ℃, starting a screw when the preset temperature is reached, adding the physical mixture obtained in the step (1) into the extruder, extruding a solid substance through the screw, and cooling;
(3) crushing the solid obtained in the step (2), and sieving the crushed solid with a 60-100-mesh sieve to obtain a solid dispersion containing the Redexilvir;
(4) uniformly mixing the solid dispersion obtained in the step (3) with a filling agent, a disintegrating agent, a glidant and a lubricant to obtain a total mixture;
(5) and (4) tabletting the total mixture obtained in the step (4) to prepare tablets.
In at least one embodiment of the above preparation method of the present invention, in step (1), the ridciclovir and copovidone VA64 are uniformly mixed in a ratio of 1:2 to 1: 3.
In the above preparation method of the present invention, in some embodiments, the filler is selected from one or a combination of mannitol, lactose and microcrystalline cellulose; the disintegrant is selected from one or more of croscarmellose sodium, crospovidone, and carboxymethyl starch sodium; the glidant is selected from silicon dioxide; the lubricant is selected from one or more of magnesium stearate, stearic acid, hydrogenated vegetable oil, glyceryl behenate and sodium stearyl fumarate.
Compared with the prior art, the invention has the following advantages:
(1) the solid preparation of the Rudexiwei preparation prepared by the hot-melt extrusion technology is an oral preparation, and is convenient for patients to take.
(2) The solid preparation of the Rudesiwei prepared by the hot-melt extrusion technology increases the medication compliance of patients with mild and moderate degrees, and can avoid the risk possibly brought by the overdose of the injection medication.
(3) The solid preparation of the Rudexiwei tablet prepared by the hot-melt extrusion technology has higher dissolution rate and higher bioavailability after in vivo absorption than the common tablet. Animal experiments prove that: the solid dosage form of the ridciclovir prepared by hot-melt extrusion technology (example 1) of the invention is 3.5 times of the oral bioavailability of the general ridciclovir tablet (comparative example 1) in Beagle dogs.
(4) The preparation method adopts a hot-melt extrusion technology to prepare the solid dispersion of the RudeSewei, realizes no dust, continuous operation and good reproducibility through melting, screw shearing and extrusion, has the advantages of uniform dispersion of active ingredients in a carrier material, simple preparation process, no solvent residue, convenient operation, no introduction of other impurities in the whole process, suitability for industrial mass production, stable and reliable quality of the obtained product and better clinical application value.
Drawings
FIG. 1 is a graph showing the dissolution profiles of examples 1-2 and comparative example 1 in purified water + 0.2% SDS dissolution medium.
Detailed Description
The invention is further illustrated by the following examples. It should be understood that: the embodiments of the present invention are given for illustration only, and not for limitation of the present invention, and the simple modifications of the present invention based on the technical solutions of the present invention are within the protection scope of the present invention.
Example 1
The preparation method comprises the following steps:
(1) uniformly mixing the Reidesciclovir and the copovidone VA64 according to the formula amount to prepare a physical mixture;
(2) setting the extrusion temperature of the double-screw hot-melt extruder at 140-220 ℃, starting the screw after the preset temperature is reached, controlling the rotation speed of the screw to be 20-400 rpm, adding the physical mixture in the step (1) into the extruder, extruding a solid substance through the screw, and cooling;
(3) crushing the solid obtained in the step (2), and sieving the crushed solid with a 60-mesh sieve to obtain a solid dispersion with uniform particle size distribution;
(4) uniformly mixing the solid dispersion obtained in the step (3) with a filling agent, a disintegrating agent, a flow aid and a lubricant according to the prescription amount to obtain a total mixture;
(5) and (4) tabletting the total mixture obtained in the step (4) to prepare tablets, controlling the average weight difference to be +/-3%, and tabletting the hardness to be 8-18 kg.
Example 2
The preparation method comprises the following steps: same as in example 1.
Comparative example 1 Reidesciclovir general oral tablet
The preparation method comprises the following steps:
(1) uniformly mixing the Reidesciclovir and the mannitol according to the weight percentage;
(2) adding crospovidone, and uniformly mixing with the mixture obtained in the step (1);
(3) sieving magnesium stearate with a 40-mesh sieve, and mixing with the mixture obtained in the step (2) uniformly;
(4) tabletting the mixture obtained in the step (3), controlling the average weight difference to be +/-3%, and controlling the tabletting hardness to be 4kg-12 kg.
Quality evaluation test of examples 1-2 and comparative example 1
1. In vitro dissolution test
The in vitro dissolution curve of the oral solid preparation of the Rudexiluwei is measured by the following experimental method: the paddle method is adopted, the rotating speed is 50 revolutions per minute, and 900ml of dissolution medium is adopted. The elution profiles of the products obtained in examples 1-2 and comparative example 1 in purified water + 0.2% SDS were determined, respectively. Taking appropriate amount of eluate at 5min, 10min, 20min, 30min, 45min, and 60min respectively, filtering, and taking the filtrate as sample solution; in addition, a proper amount of a RudeSeivir reference substance (prepared according to the prior art) is precisely weighed, and is diluted into a solution with the concentration of about 0.1mg/ml by using a dissolution medium after being dissolved by adding methanol, so as to be used as a reference substance solution. According to high performance liquid chromatography (high performance liquid chromatography 0512 of the four ministry of Japan medicine 2015), octadecyl silica gel bonded silica gel is used as a filling agent, 20mmol/L ammonium acetate (pH value is adjusted to 4.6 by glacial acetic acid) -methanol (42:58) is used as a mobile phase, the detection wavelength is 245nm, the column temperature is 50 ℃, and the flow rate is 1.0 ml/min. Precisely measuring 5 mul of reference solution and sample solution, respectively injecting into a liquid phase chromatograph, recording chromatogram, and calculating dissolution rate according to external standard method and peak area, and the results are shown in Table 1.
The in vitro dissolution curves of the ridciclovir tablets obtained in examples 1-2 of the present invention and comparative example 1 are shown in fig. 1.
Table 1 in vitro cumulative dissolution (%) "of the ruidexiwei tablets of examples 1 to 2 and comparative example 1 in purified water + 0.2% SDS medium
And (4) conclusion: from the above data, it is clear that the release rate of the ridciclovir tablets of examples 1-2 is significantly faster and higher than that of the ridciclovir tablets of comparative example 1 in purified water + 0.2% SDS. Therefore, compared with the common tablet, the oral solid preparation of the ridiflower prepared by adopting the hot-melt extrusion technology improves the in vitro dissolution rate.
2. Stability survey
In this study, the effect factor test was performed after the reed-seivir tablets of examples 1-2 were packaged in oral high-density polyethylene bottles (45 ml), and the effects on the content, dissolution rate and related substances were examined after the tablets were left at high temperatures of 40 ℃ and 60 ℃ for 5 days, and the results are shown in table 2:
table 2 stability results of the reed-seivir tablets of examples 1-2 under accelerated conditions
As a result: the reed-seivir tablets in the embodiments 1-2 have small content change, no obvious change in related substances and dissolution rate under the test conditions of influence factors of high temperature of 40 ℃ and 60 ℃, and all indexes meet the requirements of quality standards, which indicates that the product is stable under the high temperature condition.
3. Bioavailability of
To study the bioavailability of oral solid dosage forms of ridciclovir, the ridciclovir tablets of example 1 and comparative example 1 were administered to 6 Beagle dogs (6 Beagle dogs tested were numbered P11, P12, P13, P14, P15, P16, respectively) at a dose of 100 mg/dog using a single dose parallel dosing design, plasma samples were collected and tested for their concentration of ridciclovir and the major metabolite, ridciclovir nucleoside (DHG), pharmaceutical time curves were plotted and pharmacokinetic parameters were calculated. Redexilvir is a prodrug that is rapidly absorbed into the bloodConverting into DHG, so that the calculation of the pharmacokinetic parameters of the experiment is calculated according to the concentration of the DHG; AUC obtained after administration of the Reidesvir tablets of example 1 and comparative example 1lastAfter dose normalization of the parameters, the relative bioavailability was calculated. The pharmacokinetic parameters of Beagle dogs after administration of the reed-seivir tablets of example 1 and comparative example 1 are listed in table 3 below:
TABLE 3 pharmacokinetic parameters of the major metabolite of Reidesvir, Reidesvir nucleoside (DHG)
And (4) conclusion: after 100 mg/dog of the Beagle dog is respectively dosed with a common Redexilvir tablet (comparative example 1) and a tablet prepared by a hot-melt extrusion process (example 1), the dose is 8.61-15.34 mg/kg after the dosing is converted, the measurable prototype drug concentration point after the dosing is less, and DHG is the measured main component. The bioavailability of the RedeSiwei tablet prepared by the hot-melt extrusion process is 3.5 times that of the common tablet calculated by the exposure amount of DHG.
Claims (10)
1. A solid dispersion containing redciclovir comprises an active ingredient, namely the redciclovir, and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier is copovidone, and the weight ratio of the redciclovir to the copovidone is 1:1-1: 4.
2. The solid dispersion of claim 1, wherein the copovidone is copovidone VA64, the weight ratio of ridciclovir to copovidone VA64 being from 1:2 to 1: 3.
3. A method for preparing a solid dispersion containing redexivir, comprising the steps of:
(1) uniformly mixing the Reidesciclovir and the copovidone in a ratio of 1:1-1:4 to prepare a physical mixture;
(2) setting the extrusion temperature of a double-screw hot-melt extruder to be 140-220 ℃, starting a screw when the preset temperature is reached, adding the physical mixture obtained in the step (1) into the extruder, extruding a solid substance through the screw, and cooling;
(3) crushing the solid obtained in the step (2), and sieving the crushed solid with a 60-100-mesh sieve to obtain a solid dispersion containing the Redexilvir;
preferably, in the step (1), the Reideciclovir and the copovidone VA64 are mixed uniformly in a ratio of 1:2-1: 3.
4. A solid dosage form containing redexivir, comprising the solid dispersion of any one of claims 1-3, and a filler, a disintegrant, a glidant, and a lubricant.
5. The solid dosage form of claim 4, comprising the following components in weight percent:
preferably, the composition comprises the following components in percentage by weight:
more preferably, the composition comprises the following components in percentage by weight:
6. the solid dosage form according to claim 4, wherein the filler is selected from one or a combination of mannitol, lactose, microcrystalline cellulose; the disintegrant is selected from one or more of croscarmellose sodium, crospovidone and carboxymethyl starch sodium; the glidant is selected from silicon dioxide; the lubricant is selected from one or more of magnesium stearate, stearic acid, hydrogenated vegetable oil, glyceryl behenate and sodium stearyl fumarate;
preferably, wherein the filler is mannitol or a combination of mannitol and microcrystalline cellulose, the disintegrant is croscarmellose sodium, the glidant is silicon dioxide, and the lubricant is magnesium stearate.
7. A solid dosage form containing Redexilvir comprises the following components in percentage by weight:
8. the solid dosage form of claim 7, comprising the following components in weight percent:
or
9. A process for the preparation of a solid dosage form containing redexivir, comprising the steps of:
(1) uniformly mixing the Reidesciclovir and the copovidone in a ratio of 1:1-1:4 to prepare a physical mixture;
(2) setting the extrusion temperature of a double-screw hot-melt extruder to be 140-220 ℃, starting a screw when the preset temperature is reached, adding the physical mixture obtained in the step (1) into the extruder, extruding a solid substance through the screw, and cooling;
(3) crushing the solid obtained in the step (2), and sieving the crushed solid with a 60-100-mesh sieve to obtain a solid dispersion containing the Redexilvir;
(4) uniformly mixing the solid dispersion obtained in the step (3) with a filling agent, a disintegrating agent, a glidant and a lubricant to obtain a total mixture;
(5) tabletting the total mixture obtained in the step (4) to prepare tablets,
preferably, the Rudexilvir and the copovidone VA64 in the step (1) are uniformly mixed in a ratio of 1:2-1: 3.
10. The method for preparing a solid dosage form according to claim 9, wherein the filler is selected from one or a combination of mannitol, lactose and microcrystalline cellulose; the disintegrant is selected from one or more of croscarmellose sodium, crospovidone, and carboxymethyl starch sodium; the glidant is selected from silicon dioxide; the lubricant is selected from one or more of magnesium stearate, stearic acid, hydrogenated vegetable oil, glyceryl behenate and sodium stearyl fumarate.
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| US11377456B2 (en) | 2020-06-11 | 2022-07-05 | Apotex Inc. | Crystalline form of Remdesivir |
| WO2023108942A1 (en) * | 2021-12-13 | 2023-06-22 | 苏州旺山旺水生物医药有限公司 | Pharmaceutical composition of oral deuterated nucleoside or pharmaceutically acceptable salt thereof, preparation method therefor and application thereof |
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| CN108348526A (en) * | 2015-09-16 | 2018-07-31 | 吉利德科学公司 | The method for treating Arenaviridae and coronaviridae virus infection |
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| 方亮: "《药剂学》", 31 March 2016 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11377456B2 (en) | 2020-06-11 | 2022-07-05 | Apotex Inc. | Crystalline form of Remdesivir |
| WO2023108942A1 (en) * | 2021-12-13 | 2023-06-22 | 苏州旺山旺水生物医药有限公司 | Pharmaceutical composition of oral deuterated nucleoside or pharmaceutically acceptable salt thereof, preparation method therefor and application thereof |
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| CN116549396A (en) | 2023-08-08 |
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