CN113521020A - Rudesivir solid dosage form containing water-soluble acid - Google Patents
Rudesivir solid dosage form containing water-soluble acid Download PDFInfo
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Abstract
The invention relates to a solid preparation of Rudexiwei containing water-soluble acid. Belongs to the technical field of pharmaceutical preparations. In particular to a solid dosage form which takes a compound with antiviral activity, namely Ruidexilvir, as an active ingredient and contains water-soluble acid. The preparation method of the solid preparation of the Rudexiluwei improves the dissolution rate and the bioavailability, is convenient for patients with mild or moderate degree to take, increases the compliance of the patients to take medicine, and has great clinical application value; in addition, the preparation method of the solid preparation of the Rudeseivir containing the water-soluble acid 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 preparation which takes a compound with antiviral activity, namely Reidesvir, as an active ingredient and contains water-soluble acid.
Background
The novel coronavirus (COVID-19) has close relationship with Severe Acute Respiratory Syndrome (SARS) coronavirus (SARS-CoV). Currently, there is no specific treatment for this new virus. Therefore, there is an urgent need to find effective antiviral drugs to combat this disease.
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 Reidesciclovir has thus early withdrawn the battle against Ebola.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). 5/7/2020, GiliddeScientifically announced that the Japan Ministry of labour and fat (MHLW) has passed through a special approval route, approved
(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 dosage form which is convenient to take and can increase the medication compliance of the patients 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. Therefore, the development of a ruidexiwei oral preparation with strong formula process operability, simple preparation process, high dissolution rate and high bioavailability for in vivo absorption is urgently needed.
The solid preparation of the ridciclovir contains water-soluble acid, and the medicament for reducing the gastric pH along with administration can change the solubility of the ridciclovir so as to improve the in-vivo absorption.
Disclosure of Invention
The invention provides a solid preparation of the Rudexiluwei containing water-soluble acid, which is convenient for mild and moderate patients to take, increases the medication compliance of the patients and has larger clinical application value; in addition, the oral preparation of the Rudexiluwei containing water-soluble acid prepared by the invention has stable and controllable quality and is convenient for industrial production.
Compared with the common tablet without water-soluble acid, the Rudexiluwei oral preparation containing water-soluble acid has the advantages of high dissolution rate, higher bioavailability by in vivo absorption and better clinical application prospect.
The invention provides a solid dosage form, which comprises the following components:
(i) the active ingredient is Reidesvir;
(ii) a water-soluble acid, or a hydrate or acid salt form of the above water-soluble acid; the water-soluble acid is selected from tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, ascorbic acid, glutamic acid or aspartic acid, and
(iii) other pharmaceutically acceptable auxiliary materials comprise a filling agent, a disintegrating agent and a lubricating agent.
In one embodiment, the water soluble acid is selected from tartaric acid, fumaric acid, succinic acid or citric acid. In another preferred embodiment, the water soluble acid is tartaric acid.
In one embodiment of the invention, the weight percentage of water-soluble acid in the solid dosage form of the invention is 5-70%. In a preferred embodiment, the weight percentage of water-soluble acid in the solid dosage form of the invention is 7-50%.
Other pharmaceutically acceptable auxiliary materials comprise a filling agent, a disintegrating agent and a lubricating agent. Wherein, the weight percentage of the filling agent in the solid dosage form is 10-90%. In a preferred embodiment, the weight percentage of the filler in the solid dosage form of the invention is 30-60%.
The bulking agent is selected from sugar alcohols, celluloses or starch. In a preferred embodiment, the sugar alcohol based bulking agent is selected from mannitol, maltitol, erythritol, lactitol, sorbitol or xylitol. In another preferred embodiment, the sugar alcohol based bulking agent is selected from spray dried mannitol. In a preferred embodiment, the cellulosic filler is selected from microcrystalline cellulose, powdered cellulose or silicified microcrystalline cellulose. In another preferred embodiment, the cellulose-based filler is selected from microcrystalline cellulose. In a preferred embodiment, the starch-based bulking agent is selected from the group consisting of corn starch, potato starch, or pregelatinized starch. In another preferred embodiment, the starch-based filler is selected from pregelatinized starch.
In a preferred embodiment, the bulking agent is mannitol. In another preferred embodiment, the filler is a mixture of mannitol and microcrystalline cellulose in a ratio of 1:1 to 4: 1.
In a preferred embodiment, the weight percentage of disintegrant in the solid dosage form of the invention is 1-15%.
The disintegrant is selected from one or more of crospovidone, croscarmellose sodium, low substituted hydroxypropyl cellulose, carboxymethyl starch sodium, corn starch or potato starch. In a preferred embodiment, the disintegrant is selected from crospovidone, croscarmellose sodium or sodium starch glycolate.
In a preferred embodiment, the lubricant is present in the solid dosage form of the invention in an amount of 0.5 to 5% by weight.
The lubricant is selected from one or more of magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oil, glyceryl behenate, stearic acid, and sodium stearyl fumarate. In a preferred embodiment, the lubricant is selected from magnesium stearate, glyceryl behenate or sodium stearyl fumarate.
In a preferred embodiment, the pharmaceutically acceptable further excipients according to the invention further comprise a binder, the weight percentage of binder in the solid dosage form according to the invention is 0-10%.
The adhesive is selected from one or more of hypromellose, hyprolose, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and polyvinylpyrrolidone. In a preferred embodiment, the binder is selected from hypromellose or hydroxypropyl cellulose.
In a preferred embodiment, the pharmaceutically acceptable further excipients according to the invention further comprise a solubilizer in an amount of 0 to 5% by weight of the solid dosage form.
The solubilizer is selected from one or more of sodium dodecyl sulfate, polysorbate 80, polyoxyethylene hydrogenated castor oil and poloxamer. In a preferred embodiment, the solubilizer is selected from sodium lauryl sulfate.
In a preferred embodiment, the pharmaceutically acceptable auxiliary materials of the present invention further comprise a glidant, wherein the weight percentage of the glidant in the solid dosage form is 0-2%.
The glidant is selected from colloidal silicon dioxide or talc.
In a preferred embodiment, the solid dosage form of the invention is in the form of a tablet. In another preferred embodiment, the solid dosage form of the invention is in the form of a bilayer tablet.
The solid dosage forms of the invention are optionally coated. The coating is carried out with the addition of conventional coating media and film formers (generally collectively referred to as coating materials) familiar to those skilled in the art, which may be selected from one or more of the following: hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymers (e.g. VA64, BASF), shellac, copolymers of acrylic and/or methacrylic esters and trimethylammonium methacrylate, copolymers of dimethylamino methacrylic acid and neutral methacrylic esters, polymers of methacrylic acid or methacrylic esters, ethyl acrylate-methyl methacrylate copolymers, methacrylic acid-methyl acrylate copolymers, propylene glycol, polyethylene glycol, triacetin, triethyl citrate and/or dye additives/pigments such as titanium dioxide, iron oxide, indigo or suitable lakes.
In a preferred embodiment of the present invention, the active ingredient, reed-ciclovir, is present in the solid dosage form of the invention in an amount of 10-50% by weight. In another preferred embodiment, the active ingredient, reed-ciclovir, is present in the solid dosage form of the invention in a weight percentage of 15-45%.
The invention provides a solid preparation of Rudeseivir containing water-soluble acid, wherein a preferred embodiment comprises the following components in percentage by weight:
wherein the acidulant is a water-soluble acid, or a hydrate or acid salt form of the water-soluble acid; the water-soluble acid is selected from tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, ascorbic acid, glutamic acid or aspartic acid.
Wherein the filler, binder, solubilizer, disintegrant, glidant, lubricant may be selected from the specific components described in the claims or elsewhere herein.
In a preferred embodiment of the present invention, a colorant may be added, such as to the acid-containing layer, to distinguish it from the active drug layer; the colorant may be selected from yellow iron oxide, red iron oxide, sunset yellow, carmine, and the like.
The invention provides a solid dosage form of ridciclovir containing a water-soluble acid, and a preferred embodiment, the solid dosage form comprises the following components in percentage by weight:
wherein the acidifying agent and fillers, binders, solubilizers, disintegrants, glidants, lubricants, colorants, etc. may be selected from the specific components set forth in the claims or elsewhere herein.
The invention provides a solid preparation of Rudeseivir containing water-soluble acid, which comprises the following components in percentage by weight in a preferred embodiment:
the invention provides a solid preparation of the RudeSewei containing water-soluble acid, which comprises the following components in percentage by weight in another preferred embodiment:
the invention provides a solid preparation of Rudeseivir containing water-soluble acid, which comprises the following components in percentage by weight in a further preferred embodiment:
the invention provides a solid preparation of Rudeseivir containing water-soluble acid, which comprises the following components in percentage by weight in a preferred embodiment:
the solid dosage form of the present invention, in a preferred embodiment, comprises the active ingredient reed-ciivir in an amount of 100mg to 400mg per unit dose of said solid dosage form; in some specific embodiments, the solid dosage form of the present invention comprises 100mg, 200mg, 300mg or 400mg of the active ingredient ridciclovir per unit dose.
The solid dosage form of the present invention, preferably a bilayer tablet, wherein one layer of the composition containing the acidifying agent (hereinafter referred to as the acid-containing layer) and the other layer of the drug containing the active ingredient (hereinafter referred to as the drug-containing layer) can be prepared by granulation and compression techniques commonly used for oral solid preparations, such as wet granulation, fluidized bed granulation, dry compression granulation, or direct mixing and compression. In the embodiment of the invention, the preparation process of direct mixed tabletting is adopted, the operation is simple, and the industrial production is convenient.
The solid dosage form of the invention, preferably in the form of a bilayer tablet; in the preparation of the bilayer tablet, the following steps are preferably employed:
the adjuvants except for acidifying agent (such as tartaric acid) and active substance Reidesvir are divided into two parts, and placed in the acid-containing layer and the medicine-containing layer respectively. In a preferred embodiment, the filler in the acid-containing layer: the content ratio of the filling agent in the medicine-containing layer is about 1:1-3: 1; the content ratio of the other adjuvants in the acid-containing layer and the medicine-containing layer is about 1: 1.
(1) And weighing the substances in the acid-containing layer and the substances in the medicine-containing layer according to the percentage content/proportion range.
(2) Uniformly mixing the filler and the acidifier in the acid-containing layer; uniformly mixing the filler in the medicine-containing layer and the Rudexiluwei; the mode of uniform mixing can be mixed by a mixer, and can also be one-step granulating and mixing by a wet granulator or a fluidized bed.
(3) Respectively adding a disintegrating agent, a binding agent and/or a solubilizer into the mixture of the acid-containing layer and the medicine-containing layer obtained in the step (2), and uniformly mixing or carrying out one-step granulation;
(4) sieving the lubricant with a 40-mesh sieve, respectively adding into the mixture containing the acid layer and the medicine layer obtained in the step (3), respectively mixing and uniformly mixing;
(5) and (4) tabletting the mixture of the acid-containing layer and the mixture of the medicine-containing layer obtained in the step (4) to prepare a double-layer tablet.
Compared with the prior art, the invention has the following advantages:
(1) the solid preparation of the Rudexiwei containing water-soluble acid is an oral preparation, and is convenient for patients to take.
(2) The solid preparation containing the water-soluble acid of the invention can increase 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) Compared with the common tablet, the solid preparation of the Rudexiluwei containing the water-soluble acid has high dissolution rate and higher bioavailability for in vivo absorption. Animal experiments prove that: the oral bioavailability of the present invention's ridciclovir bi-layer tablet containing water-soluble acid (example 1) is improved by about 24.1% over the conventional tablet containing no water-soluble acid (comparative example 1) in Beagle dogs.
(4) The solid preparation of the Rudexiluwei tablet containing the water-soluble acid has the advantages of simple preparation process, strong operability, high dissolution rate of the prepared Rudexiluwei tablet and good stability.
Drawings
FIG. 1 is a graph of the dissolution profiles of examples 1-4 and comparative example 1 in dissolution media at pH 1.0;
FIG. 2 is a graph showing the dissolution profiles of examples 1-4 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:
preparation of acid-containing layer:
(1) uniformly mixing tartaric acid and mannitol according to 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;
preparing a medicine-containing layer:
(4) uniformly mixing the Reidesciclovir and the mannitol according to the weight percentage;
(5) adding crospovidone, and uniformly mixing with the mixture obtained in the step (4);
(6) sieving magnesium stearate with a 40-mesh sieve, and mixing with the mixture obtained in the step (5) uniformly;
tabletting:
double-layer tablets are punched in an oval shape with the diameter of 16 multiplied by 6.3mm, the average weight difference is controlled to be +/-3 percent, and the hardness of the tablets is 6 kg-14 kg.
Example 2
The preparation method comprises the following steps:
preparation of acid-containing layer:
(1) uniformly mixing tartaric acid, mannitol and microcrystalline cellulose according to weight percentage;
(2) adding hydroxypropyl cellulose, crospovidone and red ferric oxide, 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;
preparing a medicine-containing layer:
(4) uniformly mixing the Reidesciclovir, the mannitol and the microcrystalline cellulose according to weight percentage;
(5) adding hydroxypropyl methylcellulose, crospovidone and colloidal silicon dioxide, and uniformly mixing with the mixture obtained in the step (4);
(6) sieving magnesium stearate with a 40-mesh sieve, and mixing with the mixture obtained in the step (5) uniformly;
tabletting:
double-layer tablets are punched in an oval shape with the diameter of 16 multiplied by 6.3mm, the average weight difference is controlled to be +/-3 percent, and the hardness of the tablets is 6 kg-14 kg.
Example 3
The preparation method comprises the following steps:
preparation of acid-containing layer:
(1) evenly mixing citric acid, mannitol and microcrystalline cellulose according to weight percentage;
(2) adding hydroxypropyl cellulose, croscarmellose sodium and red ferric oxide, 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;
preparing a medicine-containing layer:
(4) uniformly mixing the Reidesciclovir, the mannitol and the microcrystalline cellulose according to weight percentage;
(5) adding hydroxypropyl cellulose and croscarmellose sodium, and uniformly mixing with the mixture obtained in the step (4);
(6) sieving magnesium stearate with a 40-mesh sieve, and mixing with the mixture obtained in the step (5) uniformly;
tabletting:
double-layer tablets are punched in an oval shape with the diameter of 16 multiplied by 6.3mm, the average weight difference is controlled to be +/-3 percent, and the hardness of the tablets is 6 kg-14 kg.
Example 4
The preparation method comprises the following steps:
preparation of acid-containing layer:
(1) uniformly mixing succinic acid, mannitol and microcrystalline cellulose according to weight percentage;
(2) adding hydroxypropyl cellulose, carboxymethyl starch sodium and red ferric oxide, 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;
preparing a medicine-containing layer:
(4) uniformly mixing the Reidesciclovir, the mannitol and the microcrystalline cellulose according to weight percentage;
(5) adding hydroxypropyl cellulose and carboxymethyl starch sodium, and uniformly mixing with the mixture obtained in the step (4);
(6) sieving magnesium stearate with a 40-mesh sieve, and mixing with the mixture obtained in the step (5) uniformly;
tabletting:
double-layer tablets are punched in an oval shape with the diameter of 16 multiplied by 6.3mm, the average weight difference is controlled to be +/-3 percent, and the hardness of the tablets is 6 kg-14 kg.
Comparative example 1 (Ruidexiwei ordinary oral tablet without acidifier)
| Name of raw and auxiliary materials | Function of | Each tablet (mg) | Content (%) |
| Ruidexiwei (Ridexil) | Active ingredient | 100.00 | 29.85 |
| Mannitol | Filler | 211.55 | 63.15 |
| Cross-linked polyvidone | Disintegrating agent | 16.75 | 5.00 |
| Magnesium stearate | Lubricant agent | 6.70 | 2.00 |
| Tablet weight | - | 335.00 | 100.00 |
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), and controlling the average weight difference to be +/-3% by adopting a 10mm round punch, wherein the tabletting hardness is 4kg-12 kg.
Quality evaluation test of examples 1 to 4 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 dissolution profiles of the products obtained in examples 1 to 4 and comparative example 1 were determined in a hydrochloric acid solution at pH1.0 and purified water + 0.1% SDS, respectively. Taking appropriate amount of dissolution liquid 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 (0512 high performance liquid chromatography of the four headquarters in the 2015 edition), 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 μ l of each of the reference solution and the sample solution, respectively injecting into a liquid chromatograph, recording chromatogram, and calculating dissolution rate according to external standard method and peak area, and the results are shown in tables 1-2.
In vitro dissolution profiles of the ridciclovir tablets obtained in examples 1-4 of the present invention and comparative example 1 are shown in fig. 1-2.
Table 1 in vitro cumulative dissolution (%) -of the ruidexiwei tablets of examples 1 to 4 and comparative example 1 in a hydrochloric acid medium at ph1.0
Table 2 in vitro cumulative dissolution (%) -of the ruidexiwei tablets of examples 1 to 4 and comparative example 1 in purified water + 0.2% SDS medium
And (4) conclusion: from the above data, it can be seen that the reed-seivir tablets of examples 1-4 and comparative example 1 rapidly dissolved in hydrochloric acid having a ph of 1.0. In purified water + 0.2% SDS, the ridciclovir tablets of examples 1-4 dissolve out significantly faster and with higher dissolution rates than the ridciclovir tablets of comparative example 1. Therefore, compared with the common tablet (without the water-soluble acid), the oral solid dosage form of the Rudexiwei tablet containing the water-soluble acid has improved in-vitro dissolution rate.
2. Stability survey
In this study, the effect factor test was performed after the ruidexiwei tablets of examples 1 to 4 were packaged in oral high-density polyethylene bottles (specification 60ml) and 1 bag of solid medical paper and silica gel desiccant (specification 2.0g), 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 3:
table 3 stability results of the reed-seivir tablets of examples 1-4 under accelerated conditions
As a result: under the test conditions of the influence factors of high temperature of 40 ℃ and 60 ℃, the contents, related substances and dissolution rates of the RudeSewei tablets in the embodiments 1 to 4 have no obvious change, and the RudeSewei tablets meet the expected standards, thereby proving that the product is stable under the high temperature condition.
3. Bioavailability of
To study the bioavailability of oral solid dosage forms of ridciclovir, injection-administered ridciclovir (self-made, prepared in reference to patent WO 2019/014247), the ridciclovir tablets of example 1 and comparative example 1 were administered at doses of 2mg/kg, 100 mg/body, respectively, using a single-dose three-cycle parallel dosing design6 Beagle dogs (6 Beagle dogs tested were numbered P11, P12, P13, P14, P15, P16), plasma samples were collected and tested for their concentration of ridciclovir and the major metabolite, ridciclovir nucleoside (DHG), plotted against time of drug and pharmacokinetic parameters were calculated. The Reidcisvir is a prodrug and is quickly converted into DHG after being absorbed into blood, so the calculation of the pharmacokinetic parameters of the experiment is calculated according to the concentration of the DHG; AUC obtained after administration of injectable Reidesvir, Reidesvir tablets of example 1 and comparative example 1 was usedlastAfter dose normalization of the parameters, absolute bioavailability was calculated. The pharmacokinetic parameters of Beagle dogs after administration of injectable ridciclovir, the ridciclovir tablets of example 1 and comparative example 1 are listed in table 4 below:
TABLE 4 pharmacokinetic parameters of the major metabolite of Reidesvir, Reidesvir nucleoside (DHG)
And (4) conclusion: after 100 mg/dog Beagle dogs are administrated with the Reidesvir double-layer tablet containing water-soluble acid (example 1), the administration dosage is 8.83-15.63 mg/kg after conversion, the concentration point of the prototype drug which can be measured after drug administration is less, DHG is the main component which is measured, and the absolute bioavailability of the Reidesvir double-layer tablet calculated by the exposure amount of the DHG is 90.2 +/-29.8%.
After 100 mg/dog Beagle dogs are administered with the Rudexiliwei tablets (comparative example 1), the administration dosage is 8.61-15.34 mg/kg after being converted, the concentration point of prototype drug which can be measured after the administration is less, DHG is the main component, and the absolute bioavailability of the Rudexiliwei tablets calculated by the exposure amount of DHG is 66.1 +/-47.8%.
Oral absorption of the Reidesciclovir bilayer tablet containing water-soluble acid (example 1) is about 24.1% more bioavailable than the conventional tablet (containing no water-soluble acid).
Claims (10)
1. A solid dosage form comprising the following components:
(i) the active ingredient is Reidesvir;
(ii) a water-soluble acid, or a hydrate or acid salt form of the above water-soluble acid; the water-soluble acid is selected from tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, ascorbic acid, glutamic acid or aspartic acid, and
(iii) other pharmaceutically acceptable auxiliary materials comprise a filling agent, a disintegrating agent and a lubricating agent,
preferably wherein the water soluble acid is selected from tartaric acid, fumaric acid, succinic acid or citric acid;
more preferably, wherein the water-soluble acid is tartaric acid.
2. The solid dosage form according to claim 1, wherein the weight percentage of the water-soluble acid in the solid dosage form is 5-70%, preferably 7-50%.
3. The solid dosage form of claim 1, wherein the weight percentage of the filler in the solid dosage form is 10-90%, preferably 30-60%;
preferably, the filling agent is selected from one or more of sugar alcohols, celluloses or starches; wherein the sugar alcohol bulking agent is selected from mannitol, maltitol, erythritol, lactitol, sorbitol or xylitol, preferably spray-dried mannitol; wherein the cellulosic filler is selected from microcrystalline cellulose, powdered cellulose or silicified microcrystalline cellulose, preferably microcrystalline cellulose; wherein the starch-based filler is selected from corn starch, potato starch or pregelatinized starch, preferably pregelatinized starch;
further preferably wherein the filler is a mixture of mannitol and microcrystalline cellulose in a ratio of 1:1 to 4: 1.
4. The solid dosage form of claim 1, wherein the weight percentage of the disintegrant in the solid dosage form is 1-15%;
preferably, the disintegrating agent is selected from one or more of crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium starch glycolate, corn starch or potato starch; more preferably, the disintegrant is selected from crospovidone, croscarmellose sodium or sodium starch glycolate.
5. The solid dosage form of claim 1, wherein the weight percentage of the lubricant in the solid dosage form is 0.5-5%; preferably, the lubricant is selected from one or more of magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oil, glyceryl behenate, stearic acid and sodium stearyl fumarate; more preferably, the lubricant is selected from magnesium stearate, glyceryl behenate or sodium stearyl fumarate.
6. The solid dosage form of claim 1, wherein the pharmaceutically acceptable other excipients further comprise a binder, the weight percentage of the binder in the solid dosage form is 0-10%, the binder is selected from one or more of hypromellose, hyprolose, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, and polyvinylpyrrolidone; preferably, the binder is selected from hypromellose or hyprolose;
preferably, the pharmaceutically acceptable auxiliary materials further comprise a solubilizer, the solubilizer accounts for 0-5% of the solid dosage form, and the solubilizer is selected from one or more of sodium dodecyl sulfate, polysorbate 80, polyoxyethylene hydrogenated castor oil and poloxamer; preferably, the solubilizer is selected from sodium lauryl sulfate;
preferably, the pharmaceutically acceptable auxiliary materials further comprise a glidant, wherein the weight percentage of the glidant in the solid dosage form is 0-2%, and the glidant is selected from colloidal silicon dioxide or talcum powder.
7. The solid dosage form according to any of claims 1-6, which is in the form of a tablet, preferably a bilayer tablet.
8. The solid dosage form according to claim 1, wherein the weight percentage of the active ingredient ridciclovir in the solid dosage form is 10-50%, preferably 15-45%.
9. A solid dosage form of Rudesevir containing water-soluble acid comprises the following components by weight percent:
preferably, the weight percentages of the components are as follows:
wherein the acidulant is a water-soluble acid, or a hydrate or acid salt form of the water-soluble acid; the water-soluble acid is selected from tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, ascorbic acid, glutamic acid or aspartic acid.
10. A solid dosage form of Rudesevir containing water-soluble acid comprises the following components by weight percent:
or
Or
Or
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| CN112675143A (en) * | 2020-02-25 | 2021-04-20 | 顾世海 | Rudesiwei tablets and preparation method thereof |
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| CN112675143A (en) * | 2020-02-25 | 2021-04-20 | 顾世海 | Rudesiwei tablets and preparation method thereof |
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