CN113521020B - A solid dosage form of adefovir containing water soluble acid - Google Patents
A solid dosage form of adefovir containing water soluble acid Download PDFInfo
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Abstract
The invention provides a adefovir dipivoxil solid dosage form containing water-soluble acid. Belongs to the technical field of pharmaceutical preparations. In particular to a solid dosage form which takes the compound adefovir with antiviral activity as an active ingredient and contains water-soluble acid. The prepared adefovir dipivoxil solid dosage form improves the dissolution rate and bioavailability, is convenient for patients with light and medium dose, increases the compliance of the patients for drug administration, and has larger clinical application value; in addition, the solid dosage form of the adefovir containing water-soluble acid 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 in particular relates to a solid dosage form containing water-soluble acid, wherein a compound Rede-ciclovir with antiviral activity is used as an active ingredient.
Background
Novel coronavirus (COVID-19) has a close relationship with Severe Acute Respiratory Syndrome (SARS) coronavirus (SARS-CoV). At present, there is no specific therapeutic method for this new virus. Thus, there is an urgent need to find effective antiviral drugs against this disease.
Remdesivir, a broad-spectrum antiviral drug developed by Jide corporation of the United states pharmaceutical industry, was originally designed to treat Ebola virus, and early cell and animal experiments have shown that it can produce good antiviral activity against SARS coronavirus and MERS coronavirus by inhibiting RNA polymerase. In 11 months 2018, in order to cope with ebola epidemic situation, congo (gold) initiated clinical control experiments under the initiative of the world and health organization, and tested the curative effects of 4 new drugs such as Remdesivir, MAb, REGN-EB3 and zmap. The race takes only 9 months to win or lose. Because the leading advantages of REGN-EB3 and mAb-114 are quite obvious, the committee decides to end the test in advance in month 8 of 2019, and the two medicines are promoted in a large scale. Adefovir thus exits the campaign against ebola early. However, during this period, gilid did not stop studying the role of adefovir in other areas, including coronaviruses, to "replicate" the buried vopen for this time.
It is worth mentioning that the prototype drug of adefovir GS-5734 is GS-441524, an FDA approved veterinary drug, which has been proposed for the treatment of infectious peritonitis in cats, which is rarely but deadly caused by feline coronavirus. Rad Wei Muqian is considered to be one of the most potential drugs most likely to achieve inhibition of new coronaviruses, among the most potential drugs for the treatment of new coronavirus pneumonia (covd-19). 5.7.2020, jilidean science announced that the Japanese Ministry of thick raw labor (MHLW) has been approved by a special approval route
(adefovir for injection) as a therapeutic agent for SARS-CoV-2 infection; the 10 month 8-day Jiled science published the three-phase clinical data of Ruidexivir for injection from the biological randomized, double-blind, placebo-controlled, phase 3 study conducted by the National Institute for Allergy and Infectious Diseases (NIAID), covering about 1060 hospitalized patients worldwide. The data show that average recovery time for hospitalized patients receiving injection of adefovir is five days faster, while patients with severe disease are seven days faster, and these severe patients account for 85% of the total study. The U.S. Food and Drug Administration (FDA) approved adefovir for injection in the gilid science for the treatment of patients in new corona discharge, the first formally available new corona treatment in the united states, 22 months 2020.
Ruidexivir is a nucleoside analogue with broad-spectrum antiviral activity, which can inhibit RNA-dependent RNA polymerase (RdRp), and the active ingredient GS-5734 is a phosphoramidate prodrug of 1' -cyano adenosine analogue, and is metabolized in cells to form active triphosphate form-NTP. Adefovir as a monophosphate prodrug can significantly increase the potency of the parent nucleoside by delivering 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. The cytolactonase (such as carboxylesterase-1 and cathepsin A) breaks down the ester into a carboxyl structure, then continues to break down into nucleoside monophosphates, and finally is phosphorylated to nucleoside triphosphates to exert antiviral effects.
Chemical name of adefovir: (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) propanoic acid 2-ethylbutyl ester, formula C 27 H 35 N 6 O 8 P, molecular weight 602.58. The structural formula is shown as the following formula I:
adefovir LogP is 2.2, pka is 3.1, and solubility in aqueous medium is poor. The dosage form of the Rede-Siwei which is clinically used at present is freeze-dried powder injection or injection with the specification of 100mg, and the Rede-Siwei is required to be infused and administrated by vein, has quick response and is suitable for critical patients with serious illness. Side effects that FDA suggests that adefovir may exist include: elevated levels of liver enzymes and allergic reactions include changes in blood pressure and heart rate, hypoxia, fever, shortness of breath, asthma, swelling (e.g. lips, periocular, subcutaneous), rash, nausea, sweating or trembling. For light and moderate patients, development of a dosage form for administration of rad Wei Kou, which is convenient to take and increases the medication compliance of patients, is urgently needed.
The presently clinically used rituximab for injection has the following disadvantages: 1. improper treatment is prone to systemic or localized infections; 2. excessive medicine or too fast instillation, adverse reaction is easy to generate, and even life is endangered; 3. sustained overdose, which is prone to overload of the cycle, or electrolyte imbalance; 4. the number of iatrogenic diseases increases. Therefore, there is an urgent need to develop an oral preparation of adefovir with strong operability of prescription process, simple preparation process, high dissolution and high bioavailability of in vivo absorption.
The prepared solid dosage form of the adefovir contains water-soluble acid, and the drug for reducing the pH of the stomach can change the solubility of the adefovir when being taken together with the drug, so that the in vivo absorption is improved.
Disclosure of Invention
The invention provides a adefovir dipivoxil solid dosage form containing water-soluble acid, which is convenient for light and medium patients to take, increases the medication compliance of the patients and has larger clinical application value; in addition, the prepared Ruidexi Wei Kou oral dosage form containing the water-soluble acid has stable and controllable quality and is convenient for industrial production.
The oral dosage form of the adefovir dipivoxil containing water-soluble acid has higher dissolution rate and higher in vivo absorption bioavailability than the common tablet without water-soluble acid, and has better clinical application prospect.
The invention provides a solid dosage form, which comprises the following components:
(i) Active ingredient adefovir;
(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, fumonic 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 lubricant.
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 present invention is 7-50%.
Other pharmaceutically acceptable auxiliary materials comprise a filling agent, a disintegrating agent and a lubricant. Wherein the filler is present in the solid dosage form of the invention in a weight percentage of 10-90%. In a preferred embodiment, the filler is present in the solid dosage form of the invention in a weight percentage of 30-60%.
The filler is one or more selected from sugar alcohols, celluloses or starches. In a preferred embodiment, the sugar alcohol filler is selected from mannitol, maltitol, erythritol, lactitol, sorbitol or xylitol. In another preferred embodiment, the sugar alcohol filler is selected from spray-dried mannitol. In a preferred embodiment, the cellulose-based filler is selected from microcrystalline cellulose, powdered cellulose or silicified microcrystalline cellulose. In another preferred embodiment, the cellulosic filler is selected from microcrystalline cellulose. In a preferred embodiment, the starch-based filler is selected from corn starch, potato starch or pregelatinized starch. In another preferred embodiment, the starch-based filler is selected from pregelatinized starches.
In a preferred embodiment, the filler is mannitol. In another preferred embodiment, the filler is a mixture of glycerol 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 forms of the present invention is 1-15%.
The disintegrating agent is one or more selected from 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 carboxymethyl starch.
In a preferred embodiment, the weight percentage of lubricant in the solid dosage form of the present invention is 0.5-5%.
The lubricant is one or more selected from 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 of the present invention further comprise a binder, the weight percentage of binder in the solid dosage form of the present invention being 0-10%.
The adhesive is one or more selected from hypromellose, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and polyvinylpyrrolidone. In a preferred embodiment, the binder is selected from hypromellose or hypromellose.
In a preferred embodiment, the pharmaceutically acceptable further excipients of the present invention further comprise a solubilizer in an amount of 0-5% by weight of the solid dosage form.
The solubilizer is one or more selected from sodium dodecyl sulfate, polysorbate 80, polyoxyethylene hydrogenated castor oil and poloxamer. In a preferred embodiment, the solubilizing agent is selected from sodium dodecyl sulfate.
In a preferred embodiment, the pharmaceutically acceptable further excipients of the present invention further comprise a glidant, the glidant being present in the solid dosage form in an amount of 0-2% by weight.
The glidant is selected from colloidal silicon dioxide or talcum powder.
In a preferred embodiment, the solid dosage form of the present invention is in the form of a tablet. In another preferred embodiment, the solid dosage form of the present invention is in the form of a bilayer tablet.
The solid dosage forms of the present invention are optionally coated. The coating is carried out with the addition of conventional coating media and film forming agents familiar to those skilled in the art (generally collectively referred to as coating materials), 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 acid esters and trimethylammonium methacrylate, copolymers of dimethylaminomethacrylic acid and neutral methacrylic acid esters, polymers of methacrylic acid or methacrylic acid esters, ethyl acrylate-methyl methacrylate copolymers, methacrylic acid-methyl acrylate copolymers, propylene glycol, polyethylene glycol, glyceryl triacetate, 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, adefovir, is present in the solid dosage form of the present invention in a weight percentage of 10 to 50%. In another preferred embodiment, the active ingredient, adefovir, is present in the solid dosage form of the invention in a weight percentage of 15 to 45%.
The invention provides a adefovir dipivoxil solid dosage form containing water-soluble acid, wherein one 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 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.
Wherein the filler, binder, solubilizer, disintegrant, glidant and lubricant may be selected from the specific components recited in the claims or elsewhere herein.
In a preferred embodiment of the present invention, a colorant, such as an acid-containing layer, may be added to distinguish from the active drug layer; the colorant may be selected from yellow iron oxide, red iron oxide, sunset yellow, carmine, etc.
The invention provides a adefovir dipivoxil solid dosage form containing water-soluble acid, and another preferred embodiment comprises the following components in percentage by weight:
wherein the acidulant, filler, binder, solubilizer, disintegrant, glidant, lubricant, colorant, and the like may all be selected from the specific components recited in the claims or elsewhere herein.
The invention provides a adefovir dipivoxil solid dosage form containing water-soluble acid, which comprises the following components in a preferred embodiment in percentage by weight:
the invention provides a adefovir dipivoxil solid dosage form containing water-soluble acid, and in another preferred embodiment, the adefovir dipivoxil solid dosage form comprises the following components in percentage by weight:
the invention provides a solid dosage form of adefovir containing water-soluble acid, in a further preferred embodiment comprising the following components in weight percent:
the invention provides a adefovir dipivoxil solid dosage form containing water-soluble acid, and in a further preferred embodiment, the adefovir dipivoxil solid dosage form comprises the following components in percentage by weight:
the solid dosage form of the present invention, in a preferred embodiment, comprises 100mg to 400mg of the active ingredient adefovir per unit dose of the 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 adefovir per unit dose.
The solid dosage forms of the present invention, preferably bilayer tablets, wherein one layer of the composition containing the acidulant (hereinafter referred to as acid-containing layer) and the other layer of the drug containing the active ingredient (hereinafter referred to as drug-containing layer) may be prepared by granulation tabletting techniques commonly used for oral solid formulations, such as wet granulation, fluid bed granulation, dry compression granulation, or direct blend tabletting. 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 bilayer tablets, the following steps are preferably employed:
the other auxiliary materials except for acidulant (such as tartaric acid and the like) and active substance adefovir are divided into two parts, and are respectively placed in an acid-containing layer and a drug-containing layer. In a preferred embodiment, the filler in the acid-containing layer: the content ratio of the filler in the medicine-containing layer is about 1:1-3:1; the content ratio of the rest auxiliary materials in the acid-containing layer and the medicine-containing layer is about 1:1.
(1) And weighing each substance in the acid-containing layer and each substance in the medicine-containing layer according to the percentage/proportion range.
(2) Uniformly mixing the filler and the acidulant in the acid-containing layer; uniformly mixing the filler in the medicine-containing layer with the Ruidexi Wei Hunge; the uniform mixing mode can be mixed by a mixer or one-step granulating and mixing by a wet granulator or a fluidized bed.
(3) Adding disintegrating agent, binder and/or solubilizer into the mixture containing acid layer and medicine layer obtained in step (2), mixing well or granulating in one step;
(4) Sieving the lubricant with a 40-mesh sieve, respectively adding the lubricant into the mixture of the acid-containing layer and the medicine-containing layer obtained in the step (3), and respectively mixing and uniformly mixing;
(5) Tabletting the mixture containing the acid layer obtained in the step (4) and the mixture containing the medicine layer, and preparing the bilayer tablet.
Compared with the prior art, the invention has the following advantages:
(1) The adefovir dipivoxil solid dosage form containing water-soluble acid is an oral dosage form, and is convenient for patients to take medicine.
(2) The adefovir dipivoxil solid dosage form containing water-soluble acid of the invention increases the medication compliance of patients for light and medium patients and can avoid the risk possibly brought by overdose of injection medication.
(3) The adefovir dipivoxil solid dosage form containing water-soluble acid has higher dissolution rate and higher bioavailability in vivo compared with common tablets. Animal experiments prove that: the adefovir dipivoxil bilayer tablet containing water-soluble acid of the invention (example 1) has about 24.1% improved oral bioavailability in Beagle dogs over the adefovir dipivoxil normal tablet without water-soluble acid (comparative example 1).
(4) The water-soluble acid-containing adefovir dipivoxil solid dosage form has the advantages of simple preparation process and strong operability, and the prepared adefovir dipivoxil tablet has high dissolution rate and good stability.
Drawings
FIG. 1 is a graph of dissolution of examples 1-4 and comparative example 1 in a dissolution medium at pH 1.0;
FIG. 2 is a graph of the dissolution 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 only given for illustrating the present invention, but not for limiting the present invention, and the simple improvements of the present invention on the premise of the technical solution of the present invention are all within the protection scope of the present invention.
Example 1
The preparation method comprises the following steps:
preparation of an acid-containing layer:
(1) Uniformly mixing tartaric acid and mannitol according to weight percentage;
(2) Adding crospovidone and uniformly mixing the mixture obtained in the step (1);
(3) Sieving magnesium stearate with a 40-mesh sieve, and uniformly mixing the magnesium stearate with the mixture obtained in the step (2);
preparation of a drug-containing layer:
(4) Uniformly mixing the adefovir and mannitol according to the weight percentage;
(5) Adding crospovidone and uniformly mixing the mixture obtained in the step (4);
(6) Sieving magnesium stearate with a 40-mesh sieve, and uniformly mixing the magnesium stearate with the mixture obtained in the step (5);
tabletting:
the double-layer tablet is punched by adopting an ellipse with the diameter of 16 multiplied by 6.3mm, the average weight difference is controlled to be +/-3 percent, and the tablet hardness is 6 kg-14 kg.
Example 2
The preparation method comprises the following steps:
preparation of an 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 uniformly mixing the magnesium stearate with the mixture obtained in the step (2);
preparation of a drug-containing layer:
(4) Uniformly mixing the adefovir, mannitol and microcrystalline cellulose according to the weight percentage;
(5) Adding hypromellose, 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 uniformly mixing the magnesium stearate with the mixture obtained in the step (5);
tabletting:
the double-layer tablet is punched by adopting an ellipse with the diameter of 16 multiplied by 6.3mm, the average weight difference is controlled to be +/-3 percent, and the tablet hardness is 6 kg-14 kg.
Example 3
The preparation method comprises the following steps:
preparation of an acid-containing layer:
(1) Uniformly 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 uniformly mixing the magnesium stearate with the mixture obtained in the step (2);
preparation of a drug-containing layer:
(4) Uniformly mixing the adefovir, mannitol and microcrystalline cellulose according to the 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 uniformly mixing the magnesium stearate with the mixture obtained in the step (5);
tabletting:
the double-layer tablet is punched by adopting an ellipse with the diameter of 16 multiplied by 6.3mm, the average weight difference is controlled to be +/-3 percent, and the tablet hardness is 6 kg-14 kg.
Example 4
The preparation method comprises the following steps:
preparation of an 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 uniformly mixing the magnesium stearate with the mixture obtained in the step (2);
preparation of a drug-containing layer:
(4) Uniformly mixing the adefovir, mannitol and microcrystalline cellulose according to the 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 uniformly mixing the magnesium stearate with the mixture obtained in the step (5);
tabletting:
the double-layer tablet is punched by adopting an ellipse with the diameter of 16 multiplied by 6.3mm, the average weight difference is controlled to be +/-3 percent, and the tablet hardness is 6 kg-14 kg.
Comparative example 1 (Rede Siwei general oral tablet without acidulant)
| Names of raw and auxiliary materials | Action | Each tablet (mg) | Content (%) |
| Rede Sivir | Active ingredient | 100.00 | 29.85 |
| Mannitol (mannitol) | Filler (B) | 211.55 | 63.15 |
| Crosslinked povidone | Disintegrating agent | 16.75 | 5.00 |
| Magnesium stearate | Lubricant | 6.70 | 2.00 |
| Plain tablet weight | - | 335.00 | 100.00 |
The preparation method comprises the following steps:
(1) Uniformly mixing the adefovir and mannitol according to the weight percentage;
(2) Adding crospovidone and uniformly mixing the mixture obtained in the step (1);
(3) Sieving magnesium stearate with a 40-mesh sieve, and uniformly mixing the magnesium stearate with the mixture obtained in the step (2);
(4) Tabletting the mixture obtained in the step (3), and controlling the average weight difference to +/-3% by adopting a 10mm round punch, wherein the tabletting hardness is 4kg-12kg.
Quality evaluation experiment of examples 1 to 4 and comparative example 1
1. In vitro dissolution experiments
The in vitro dissolution curve of the oral solid dosage form of the Ruidexiwei is determined by the following experimental method: the paddle method was used at a speed of 50 revolutions per minute, 900ml of dissolution medium. The dissolution profiles of the products obtained in examples 1 to 4 and comparative example 1 in a hydrochloric acid solution of pH1.0 and purified water+0.1% SDS, respectively, were determined. Taking a proper amount of the dissolution liquid at 5min, 10min, 20min, 30min, 45min and 60min respectively, filtering, and taking the subsequent filtrate as a sample solution; in addition, a proper amount of a Ruidexivir reference substance (prepared according to the prior art) is precisely weighed, dissolved in methanol, and diluted into a solution with the concentration of about 0.1mg/ml by a dissolution medium to be used as a reference substance solution. According to high performance liquid chromatography (China pharmacopoeia 2015 edition four general rules 0512 high performance liquid chromatography), octadecyl silica gel bonding silica gel is used as filler, 20mmol/L ammonium acetate (glacial acetic acid is used for regulating pH value to 4.6) -methanol (42:58) is used as mobile phase, detection wavelength is 245nm, column temperature is 50 ℃, and flow rate is 1.0ml/min. Precisely measuring 5 μl of each of the control solution and the sample solution, respectively injecting into a liquid chromatograph, recording the chromatograms, and calculating the dissolution according to the external standard method with peak area, wherein the results are shown in tables 1-2.
The in vitro dissolution profiles of the adefovir dipivoxil tablets obtained in examples 1-4 and comparative example 1 of the present invention are shown in fig. 1-2.
TABLE 1 in vitro cumulative dissolution (%)
TABLE 2 cumulative in vitro dissolution (%)
Conclusion: from the above data, it is clear that the adefovir dipivoxil tablets of examples 1-4 and comparative example 1 rapidly dissolve in hydrochloric acid at pH 1.0. The adefovir dipivoxil tablets of examples 1-4 significantly dissolved out faster and higher than the adefovir tablet of comparative example 1 in purified water +0.2% sds. Thus, the oral solid dosage form of the adefovir dipivoxil containing water-soluble acid has higher in-vitro dissolution rate compared with the common tablet (without water-soluble acid).
2. Stability investigation
In the study, the Redewei tablets of examples 1-4 are respectively packaged by adopting an oral high-density polyethylene bottle (with the specification of 60 ml) and 1 bag of solid medical paper bag silica gel desiccant (with the specification of 2.0 g) is added, and then the influence factor test is carried out, the influence on the content, the dissolution rate and related substances is examined after the tablets are placed for 5 days at the high temperature of 40 ℃ and 60 ℃, and the results are shown in the table 3:
table 3 stability results of the adefovir dipivoxil tablets of examples 1-4 under accelerated conditions
Results: the content, related substances and dissolution rate of the Ruidexiwei tablet of the examples 1-4 are not obviously changed under the condition of the influence factor test at the high temperature of 40 ℃ and 60 ℃, and the tablet meets the expected standard, and is proved to be stable under the high temperature condition.
3. Bioavailability of the active ingredients
To study the bioavailability of the oral solid dosage forms of adefovir, a single dose three-cycle parallel dosing design was used, adefovir for injection (prepared by self-made, see patent WO 2019/014247), adefovir tablet 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 doses of 2mg/kg, 100 mg/each, plasma samples were collected and the concentration of adefovir and the main metabolite adefovir Wei Hegan (DHG) therein were measured, and pharmacokinetic parameters were plotted and calculated. The Ruidexivir is used as a prodrug and is quickly converted into DHG after being absorbed into blood, so that the drug generation parameter calculation of the test is calculated by the concentration of the DHG; AUC obtained after administration of adefovir for injection, adefovir dipivoxil tablet of example 1 and comparative example 1 was used last After dose normalization of the parameters, absolute bioavailability was calculated. The pharmacokinetic parameters of Beagle dogs after administration of adefovir for injection, adefovir dipivoxil tablets of example 1 and comparative example 1 are listed in table 4 below:
TABLE 4 pharmacokinetic parameters of the major metabolite of Rede-Sivir, rede-Si Wei Hegan (DHG)
Conclusion: beagle dogs are given 100 mg/dose of adefovir dipivoxil double-layer tablet containing water-soluble acid (example 1), the dosage is converted to 8.83-15.63 mg/kg, the concentration point of the proto-drug which can be measured after drug administration is less, DHG is the main component measured, and the absolute bioavailability of the adefovir dipivoxil double-layer tablet is 90.2+/-29.8% according to the exposure amount of DHG.
After Beagle dogs are given 100 mg/dose of the adefovir dipivoxil tablet (comparative example 1), the dosage is converted to 8.61-15.34 mg/kg, the concentration point of the proto-drug which can be measured after the drug is less, DHG is the main component measured, and the absolute bioavailability of the adefovir tablet is 66.1+/-47.8% based on the exposure amount of DHG.
The adefovir dipivoxil bi-layer tablet containing water-soluble acid (example 1) has a bioavailability of about 24.1% higher than the normal tablet (without water-soluble acid).
Claims (1)
1. A double-layer tablet of Ruidexivir containing water-soluble acid comprises an acid-containing layer and a drug-containing layer, wherein the acid-containing layer comprises the following components in percentage by weight:
the medicine-containing layer comprises the following components in percentage by weight:
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