WO2021168930A1 - Tablet of remdesivir and preparation method therefor - Google Patents

Abstract

A tablet of Remdesivir and a preparation method therefor. The tablet comprises a tablet core and a film coating layer. The tablet core comprises the following components in mass fractions: 50-65% of Remdesivir, 4-7% of a disintegrant, 4-7% of a binder, and 0.7-1.2% of a lubricant, the remainder being a filler. The film coating layer comprises a gastric-soluble type and an enteric-soluble type. The processing of the tablet is simple, and the prepared tablet has good stability, dissolves rapidly, is convenient for oral administration to patients, can be taken outside of a hospital, and has increased safety.

Description

Remdesivir tablet and preparation method thereof Technical field

The invention belongs to the field of medicinal chemistry, and relates to a redecivir tablet and a preparation method thereof.

Background technique

Remdesivir (Remdesivir) is a drug under development by Gilead Sciences. Remdesivir is a nucleoside analog with antiviral activity. In HAE cells, the EC50 value to SARS-CoV and MERS-CoV is 74nM, and in delayed brain tumor cells, the EC50 value to murine hepatitis virus is 30nM.

On January 31, 2020, the authoritative medical journal "New England Journal of Medicine" (NEJM) published online papers on new coronavirus (COVID-19) cases, one of which introduced the diagnosis and treatment process of the first confirmed case in the United States As well as clinical manifestations, it shows that a drug called remdesivir has shown good efficacy against the new coronavirus, but its effectiveness has to go through large-scale clinical trials to be further verified. Remdesivir has not been approved for marketing in any country, and its safety and effectiveness have not been proven. On February 1, 2020, the global clinical trial database showed that the clinical trial of Gilead's research drug Remdesivir (Remdesivir) to treat the new coronavirus was launched on February 3 at Beijing China-Japan Friendship Hospital. Gilead also issued a statement announcing that it is cooperating with China's health department to carry out a randomized, controlled trial to determine whether the use of Remdesivir (Remdesivir) is safe and effective in the treatment of COVID-19 infections.

On February 4, 2020, the Wuhan Institute of Virology of the Chinese Academy of Sciences announced that important progress has been made in drug screening to inhibit the 2019 novel coronavirus (COVID-19). The relevant research results have been published in Cell Research. . They disclosed that studies have shown that on Vero E6 cells, the half effective concentration of Remdesivir (GS-5734) against COVID-19 is EC50 = 0.77uM (micromole per liter), and the selection index SI is greater than 129; This drug can effectively inhibit COVID-19 infection at the cellular level.

Gilead’s Remdesivir is a freeze-dried preparation for injection. Remdesivir lyophilized preparation for injection is a white to off-white or yellow lyophilized solid without preservatives. In addition to the active ingredients, the lyophilized preparation also contains the following inactive ingredients: water for injection, sulfobutyl beta cyclodextrin (SBECD) and hydrochloric acid and/or sodium hydroxide. The drug needs to be administered by injection under the guidance of professionals, and the form of administration is inconvenient, and the patient's compliance is poor.

At present, the company has developed a tablet of Remdesivir and its preparation method. It is convenient for patients to administer orally, and can be taken out of hospital to improve safety.

Summary of the invention

The purpose of the present invention is to provide a remdesivir tablet with simple process route, rapid dissolution and good stability and a preparation method thereof, so as to overcome the deficiencies of existing injections.

In order to achieve the above objectives, the present invention adopts the following technical solutions to achieve:

A remdesivir tablet, said tablet comprising a tablet core and a film coating layer, wherein the tablet core comprises the following components in mass fraction: remdesivir 55-65%, disintegrant 4-7%, Binder 4-7%, lubricant 0.7-1.2%, the balance is filler; the coating material of gastric-soluble film coating layer: hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose ( HPC), acrylic resin No. IV, polyvinylpyrrolidone (PVP), etc. Coating materials for enteric film coating layer: cellulose acetate phthalate (CAP), polyacrylol phthalate (PVAP), methacrylic acid copolymer, cellulose acetate trimellitate (CAT), hydroxyl Propylmethyl cellulose phthalate (HPMCP), acrylic resins, etc.

Further, the disintegrant is CMC-Na.

Further, the binder is hydroxypropyl methyl cellulose.

Further, the lubricant is magnesium stearate.

Further, the filler is microcrystalline cellulose, mannitol, lactose and the like.

Preferably, the tablet core includes the following components in mass fractions: Remdesivir 55-60%, hypromellose/polyvinylpyrrolidone 3-6%, CMC-Na3-5%, magnesium stearate 0.7-% 1.0%, the balance is microcrystalline cellulose.

More preferably, the tablet core includes the following components in mass fractions: Remdesivir 57%, polyvinylpyrrolidone 4%, CMC-Na 4%, magnesium stearate 0.8%, and the balance is microcrystalline cellulose.

The present invention also provides a method for preparing the aforementioned Redecivir tablet, which includes the following steps:

Step a, sieving Radixivir, disintegrant, filler, glidant and lubricant, and set aside;

Step b: Weigh the prescription amount of active drug remdesivir, and sieve and mix the filler, part of the disintegrant, glidant, and lubricant evenly;

Step c, placing the mixed powder in a dry granulation machine;

Step d, the prepared dry particles are uniformly mixed with the remaining amount of disintegrant, lubricant, and glidant;

Step e, placing the prepared particles in a high-speed rotary tablet press for compression;

Step f, film-coating the qualified tablets produced in the above.

Further, the gastric-soluble coating material: hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), acrylic resin No. IV, polyvinylpyrrolidone (PVP), etc. are prepared by dissolving in a corresponding solvent Coating solution; coating material of enteric coating layer: cellulose acetate phthalate (CAP), polyacrylol phthalate (PVAP), methacrylic acid copolymer, cellulose acetate trimellitate ( CAT), hypromellose phthalate (HPMCP), acrylic resins, etc. and auxiliary materials are dissolved in the corresponding solvent to make a coating liquid.

Further, the tablet core is preheated in a coating machine, the temperature of the tablet bed is controlled to be 30°C-37°C, the coating liquid is uniformly sprayed on the surface of the tablet core and fully dried to obtain the Redxivir film-coated tablet.

Compared with the prior art, the present invention has the following advantages: Gilead’s Remdesivir is a freeze-dried preparation for injection, and the drug needs to be injected under the guidance of professionals, the administration form is inconvenient, and patient compliance is poor. We have changed the freeze-dried preparation of Redecivir for injection into tablets, which is convenient for patients to administer orally, and can be taken outside the hospital to improve safety.

The tablet of the present invention includes a tablet core and a film coating layer, wherein the tablet core includes the following components in mass fraction: 55-65% of Redecive, 3-7% of disintegrant, 3-7% of disintegrant, Lubricant 0.7-1.2%, the remainder is filler; the coating material of the gastric-soluble film coating layer includes hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), acrylic resin No. IV, Polyvinylpyrrolidone (PVP) and so on. The coating material of the enteric film coating layer includes cellulose acetate phthalate (CAP), polyacrylol phthalate (PVAP), methacrylic acid copolymer, cellulose acetate trimellitate (CAT), hydroxyl Propylmethyl cellulose phthalate (HPMCP), acrylic resins, etc.

Experiments have proved that the disintegration time of the gastric-coated tablet of the present invention is within 3 minutes, and the dissolution exceeds 93% in 15 minutes. The stability is good; it can be stored for a long time; the enteric-coated tablet does not disintegrate within 2 hours in PH1-4. In PH5-7, the disintegration time is within 5 minutes, and the dissolution exceeds 93% in 15 minutes. It can be stored for a long time.

The technological operation of the tablet of the invention is simple and the yield is high.

Detailed ways

The present invention will be described in detail below in conjunction with specific embodiments.

Example 1

According to the following mass fractions, the raw materials are weighed to prepare the tablet core.

Remdesivir 57%, hypromellose 4%, CMC-Na 4%, magnesium stearate 0.8%, the balance is microcrystalline cellulose.

Example 2

According to the following mass fractions, the raw materials are weighed to prepare the tablet core.

Remdesivir 52%, hydroxypropyl methylcellulose 4%, CMC-Na 3%, magnesium stearate 1%, the balance is microcrystalline cellulose.

Example 3

According to the following mass fractions, the raw materials are weighed to prepare the tablet core.

Remdesivir 55%, polyvinylpyrrolidone 4%, CMC-Na 5%, magnesium stearate 1%, the balance is microcrystalline cellulose.

Example 4

According to the following mass fractions, the raw materials are weighed to prepare the tablet core.

Remdesivir 58%, polyvinylpyrrolidone 5%, CMC-Na 5%, magnesium stearate 1%, the balance is microcrystalline cellulose.

Example 5

According to the following mass fractions, the raw materials are weighed to prepare the tablet core.

Remdesivir 61%, polyvinylpyrrolidone 5%, CMC-Na 5%, magnesium stearate 1.2%, the balance is microcrystalline cellulose.

Example 6

According to the prescription amounts of the above examples 1-5, the preparation process is as follows:

(1) Sieve Remdesivir and auxiliary materials for use;

(2) Weigh the prescription amount of active drug Remdesivir, two-thirds of the filler, one-half of the binder, one-half of the disintegrant, and one-half of the lubricant to mix well;

(3) Place the mixed powder in the dry granulation machine;

(4) Mix the prepared dry particles with the remaining one-third filler, one-half binder, one-half disintegrant, and one-half lubricant;

(5) Place the obtained granules in a high-speed rotary tablet press for compression;

(6) Film-coating the qualified tablets prepared in the film, wherein the mass ratio of the film polyvinylpyrrolidone to polyethylene glycol is 1:1, and the coating materials polyvinylpyrrolidone and polyethylene glycol are dissolved in 85% ethanol Coating liquid is made in aqueous solution;

(7) The tablet core is preheated in a coating machine, the temperature of the tablet bed is controlled to be 30°-37°C, the coating liquid is evenly sprayed on the surface of the tablet core and fully dried to obtain Radixivir film-coated tablets.

Example 7

According to the prescription amounts of the above examples 1-5, the preparation process is as follows:

(1) Sieve Remdesivir and auxiliary materials for use;

Weigh the prescription amount of active drug Redecivir, two-thirds of the filler, one-half of the binder, and one-half of the disintegrant,

(2) One-half of the lubricant is evenly mixed;

(3) Place the mixed powder in the dry granulation machine;

(4) Mix the prepared dry particles with the remaining one-third filler, one-half binder, one-half disintegrant, and one-half lubricant;

(5) Place the obtained granules in a high-speed rotary tablet press for compression;

(6) Film-coating the qualified tablets obtained in the above, where the film material is Opadry film coating premix (gastric dissolving type)—85F92259 CN, and the coating material is dissolved in pure water to make a coating liquid ；

(7) The tablet core is preheated in a coating machine, the temperature of the tablet bed is controlled to be 30°-37°C, the coating liquid is evenly sprayed on the surface of the tablet core and fully dried to obtain Radixivir film-coated tablets.

Example 8

According to the prescription amounts of the above examples 1-5, the preparation process is as follows:

(1) Sieve Remdesivir and auxiliary materials for use;

(2) Weigh the prescription amount of active drug Remdesivir, two-thirds of the filler, one-half of the binder, one-half of the disintegrant, and one-half of the lubricant to mix well;

(3) Place the mixed powder in the dry granulation machine;

(4) Mix the prepared dry particles with the remaining one-third filler, one-half binder, one-half disintegrant, and one-half lubricant;

(5) Place the obtained granules in a high-speed rotary tablet press for compression;

(6) Coating the qualified tablets (enteric-coated type) obtained in the above, coating prescription: hypromellose phthalate 8%, titanium dioxide 0.4%, talc 1.4%, yellow iron oxide 0.1 %, 0.5% triethyl citrate, the coating material is dissolved in 85% ethanol aqueous solution to make a coating liquid;

(7) The tablet core is preheated in a coating machine, the tablet bed temperature is controlled to 36-37°C, the coating liquid is evenly sprayed on the surface of the tablet core and fully dried, to obtain Redcivir enteric film-coated tablets.

Example 9

According to the prescription amounts of the above examples 1-5, the preparation process is as follows:

(1) Sieve Remdesivir and auxiliary materials for use;

(2) Weigh the prescription amount of active drug Remdesivir, two-thirds of the filler, one-half of the binder, one-half of the disintegrant, and one-half of the lubricant to mix well;

(3) Place the mixed powder in the dry granulation machine;

(4) Mix the prepared dry particles with the remaining one-third filler, one-half binder, one-half disintegrant, and one-half lubricant;

(5) Place the obtained granules in a high-speed rotary tablet press for compression;

(6) Coating the qualified tablets obtained in the above (enteric type), coating material: Opadry film coating premix (enteric type)-93O18509-CN, the coating material is dissolved in pure aqueous solution Make a coating liquid;

(7) The tablet core is preheated in a coating machine, the tablet bed temperature is controlled to 36-37°C, the coating liquid is evenly sprayed on the surface of the tablet core and fully dried, to obtain Redcivir enteric film-coated tablets.

Experiments have proved that the tablets prepared in Examples 6 and 7 of the present invention disintegrate within 3 minutes in PH1-4, and dissolve more than 93% in 15 minutes. They have good stability and can be stored for a long time. The tablets prepared in Example 8 and Example 9 did not disintegrate within 2 hours in PH1-4, and in PH5-7, within 5 minutes, the dissolution exceeded 93% in 15 minutes. It has good stability and can be stored for a long time.

The tablet cores prepared in Example 1 were coated according to Example 7 and Example 9 to prepare corresponding gastric-coated and enteric-coated tablets with a dosage of 50-400 mg. The subjects were administered once orally, and the plasma concentration in the body was measured by Ultra Performance Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS/MS). We measured and calculated that the t _1/2 of the preparation drug was 0.903h, and the AUC _inf was 10-100h·ng. /mL. According to the early clinical trial report of Remdesivir released by the WHO in 2018, 150mg remdesivir was instilled for 30 minutes, AUC _inf was 1254.7h·ng/mL, and t _1/2 was 1.00h.

Through data analysis, we speculate that the preparation of gastric-coated tablets is better than enteric-coated tablets, and oral preparations can detect remdesivir in plasma; to achieve the blood concentration during intravenous infusion, the dose of oral gastric-coated tablets Theoretically, it needs to be increased; we can further formulate the formulation and optimize the process, including the use of materials that increase stability, such as cyclodextrin, to adjust the dissolution and disintegration time of the drug, and further increase the blood drug concentration.

Although the present invention has been disclosed as above in preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can use the methods and technical content disclosed above to improve the present invention without departing from the spirit and scope of the present invention. The technical solution makes possible changes and modifications. Therefore, any simple modification, equivalent change and modification made to the above embodiments according to the technical essence of the present invention without departing from the content of the technical solution of the present invention belong to the technical solution of the present invention. The scope of protection.

Claims (4)

A remdesivir tablet, characterized in that the tablet comprises a tablet core and a film coating layer, wherein the tablet core is composed of the following components in mass fraction: remdesivir 50-65%, disintegrant 4 7%, binder 4-7%, lubricant 0.7-1.2%, the balance is filler; the coating material of the gastric-soluble film coating layer includes: hydroxypropyl methylcellulose (HPMC), hydroxyl Propyl cellulose (HPC), acrylic resin No. IV, polyvinylpyrrolidone (PVP), etc. The coating materials of the enteric film coating layer include: cellulose acetate phthalate (CAP), polyacrylol phthalate (PVAP), methacrylic acid copolymer, cellulose acetate trimellitate (CAT), hypromellose phthalate (HPMCP), acrylic resins, etc. The method for preparing Redecivir tablets according to claim 1, characterized in that it comprises the following steps: Step a, sieving remdesivir, binder, disintegrant, filler, and lubricant for use. The binder is hydroxypropylmethyl cellulose, the disintegrant is CMCNa, and the filler is Microcrystalline cellulose, mannitol, lactose, etc., and the lubricant is magnesium stearate; Step b: Weigh the prescription amount of active drug Remdesivir, and sieve and mix it with some fillers, disintegrants, glidants, and lubricants; Step c, placing the mixed powder in a dry granulation machine; Step d, the prepared dry particles are uniformly mixed with the remaining amount of fillers, disintegrants, and lubricants; Step e, placing the prepared particles in a high-speed rotary tablet press for compression; Step f, film-coating the qualified tablets prepared therein. The method for preparing Redecivir tablets according to claim 2, wherein the gastric-soluble coating material: hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), Acrylic resin No. IV, polyvinylpyrrolidone (PVP), etc. are dissolved in a corresponding solvent to make a coating liquid; the coating material of the enteric coating layer: cellulose acetate phthalate (CAP), polyacryl alcohol Phthalate (PVAP), methacrylic acid copolymer, cellulose acetate trimellitate (CAT), hypromellose phthalate (HPMCP), acrylic resins, etc. and accessories are dissolved in corresponding solvents Coating liquid. The method for preparing Radixivir tablets according to claim 2, wherein the tablet core is preheated in a coating machine, the temperature of the tablet bed is controlled to be 30°C-37°C, and the coating liquid is uniformly sprayed onto the tablets. The surface of the core is fully dried to obtain Redecive film-coated tablets.