CN114502150A - Pharmaceutical composition for treating viral influenza and preparation thereof - Google Patents
Pharmaceutical composition for treating viral influenza and preparation thereof Download PDFInfo
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- CN114502150A CN114502150A CN202080062567.5A CN202080062567A CN114502150A CN 114502150 A CN114502150 A CN 114502150A CN 202080062567 A CN202080062567 A CN 202080062567A CN 114502150 A CN114502150 A CN 114502150A
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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
- A61K31/13—Amines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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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
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention provides a pharmaceutical composition and a preparation thereof, the pharmaceutical composition comprises two effective components with a mass ratio in a specific range, the pharmaceutical composition has an obviously better anti-influenza virus effect, and the pharmaceutical composition is considered to have a better patent medicine prospect after comprehensive evaluation.
Description
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition for treating viral influenza and a preparation containing the pharmaceutical composition.
Influenza virus, i.e., influenza virus (IFV), is a segmented, single-stranded, antisense RNA virus that can cause influenza in humans and animals. According to the World Health Organization (WHO) statistics, seasonal epidemics of influenza every year can cause 300 to 500 million cases of severe cases worldwide, 29 to 65 million cases die, and each influenza pandemic causes great damage to global public health and economy.
The current clinical scheme of influenza includes vaccination and chemotherapy and chemoprevention with antiviral drugs, wherein one of the important antiviral drugs is neuraminidase inhibitor, such as Oseltamivir (OSE), zanamivir (zanamivir), Peramivir (Peramivir), etc., which has significant effect on influenza a virus and is a common drug for treating viral influenza in clinic. However, similar to antibiotic products, the resulting drug resistance is becoming more severe with the long-term use of antiviral products. According to the monitoring data of the WHO western Pacific region, the following data are shown: the ratio of the oseltamivir drug-resistant strain of seasonal influenza A H1N1 virus in China 2008-2009 year reaches 28%, and the drug resistance of the influenza virus influences the treatment effect of the existing anti-influenza virus drugs.
Wherein, the oseltamivir is metabolized and converted into the active metabolite oseltamivir carboxylic acid after being orally taken to exert drug effect, and the process of releasing the virus from infected host cells is interfered by competitively combining with the active site of influenza virus neuraminidase, thereby reducing the spread of influenza A or B virus.
Patent WO2018041263 discloses a series of pyrimidine derivatives. In vitro activity data show that part of compounds show positive effects in the experiment of inhibiting influenza virus replication, and in further animal experiments, part of compounds also show remarkable treatment effects on influenza A virus H1N1 mouse infection models, wherein the comprehensive performance of the compound 1 (example 4, WX-216) is relatively outstanding, and the compound is considered to have better patent medicine prospects.
On the other hand, influenza viruses have the characteristics of high mutation rate, multiple virus recombination phenomena and the like, and although new structures and new mechanism active compounds are continuously discovered, in the long run, the defects that the virus concentration in the body cannot be effectively inhibited/reduced and the viral cold is cured by using a single antiviral drug may exist, and the corresponding use dosage increase and treatment time lengthening bring greater medication risk to patients. Finberg RW et al, J Infect Dis,2019 Mar 15; 219(7) 1026-.
Therefore, the search for a new solution to solve the drug resistance problem of new products with clinical prospects and reduce the occurrence probability of adverse drug reactions so as to meet the great demand of anti-influenza virus drugs which are not met clinically at present is a technical problem to be solved urgently in the prior art.
Disclosure of Invention
The first purpose of the present invention is to overcome at least one of the deficiencies of the prior art, and to provide a pharmaceutical composition for treating viral influenza, which utilizes the synergistic effect between the effective components to solve the technical problems of drug resistance of influenza virus, etc., and can effectively reduce the clinical medication risk, and after comprehensive evaluation, the pharmaceutical composition has a good prospect of patent medicine.
The purpose of the invention is realized by the following technical scheme:
a pharmaceutical composition comprising a first active ingredient and a second active ingredient, wherein the first active ingredient is compound 1, its corresponding ester, its corresponding salt, its corresponding ester salt, or a combination thereof; the second effective component is neuraminidase inhibitor; the mass ratio of the first effective component to the second effective component is 1-8: 1.
The first effective component refers to a mixture obtained by mixing one or more than two of compound 1, ester corresponding to compound 1, salt of compound 1 and salt of ester corresponding to compound 1 in any proportion.
The compound 1, the ester corresponding to the compound 1, the salt of the compound 1, and the salt of the ester corresponding to the compound 1 each include an anhydrate, a hydrate, and a solvate thereunder.
The ester corresponding to compound 1 refers to the ester formed by compound 1 and organic acid, including but not limited to methyl ester, ethyl ester, propyl ester, isopropyl ester, n-butyl ester, tert-butyl ester and the like of compound 1.
The salt of the compound 1 is a salt of the compound 1 with an organic acid and/or an inorganic acid, or a salt of the compound 1 with an organic base and/or an inorganic base, and includes, but is not limited to, a hydrochloride, a hydrobromide, a sulfate, a phosphate, a benzenesulfonate, a p-toluenesulfonate, a methanesulfonate, a tartrate, a camphorsulfonate, a lithium salt, a sodium salt, a potassium salt, a calcium salt, a magnesium salt, an aluminum salt, an ammonium salt, an ethylenediamine salt, a triethylamine salt, and the like of the compound 1.
The salt of the ester corresponding to compound 1 refers to the salt formed by the ester formed by the compound 1 and organic acid and organic base and/or inorganic base and/or organic acid and/or inorganic acid, and includes but is not limited to hydrochloride of compound 1 methyl ester, sulfate of compound 1 methyl ester, hydrochloride of compound 1 ethyl ester, sulfate of compound 1 ethyl ester and the like.
The neuraminidase inhibitor indicated by the second active ingredient is a mixture obtained by mixing one or more of Oseltamivir (Oseltamivir) or a derivative thereof, zanamivir (zanamivir) or a derivative thereof, Peramivir (Peramivir) or a derivative thereof and the like in any proportion; the derivatives of Oseltamivir (Oseltamivir), zanamivir (zanamivir) and Peramivir (Peramivir) are independently selected from acids and/or bases thereof, and may also be esters, amides formed by further hydrolysis of the compounds, or other derivatives of carboxylic acids and salts thereof obtained by hydrolysis, and each of the derivatives includes the following anhydrous compounds, solvates, hydrates and solvates, for example, Oseltamivir or its derivative may be selected from Oseltamivir free form, and may also be selected from Oseltamivir phosphate, Oseltamivir carboxylic acid, osemivir carboxylate, and the like.
The mass ratio of the first effective component to the second effective component is 1-8: 1, preferably, the mass ratio of the first effective component to the second effective component is 100-600: 75; specifically, the mass ratio of the first effective component to the second effective component is about 100:75,200:75,300:75,400:75,500:75,600: 75.
Unless otherwise specified, the mass of the salt in the present invention refers to the mass of the compound before metabolism (free base/acid equivalent), the mass of the hydrate/solvate refers to the mass of the compound on a dry basis (on an anhydrous basis), and the mass of the metabolite (e.g., carboxylic acid obtained by ester hydrolysis) refers to the mass of the compound before metabolism.
According to a preferable technical scheme of the invention, the first effective component in the pharmaceutical composition is compound 1, and the second effective component is oseltamivir phosphate; the mass ratio of the compound 1 to the oseltamivir phosphate in the pharmaceutical composition is 100-600: 75; specifically, the mass ratio of the compound 1 to the oseltamivir phosphate is about 100:75,200:75,300:75,400:75,500:75,600: 75.
According to a preferable technical scheme of the invention, the first effective component in the pharmaceutical composition is a sodium salt of the compound 1, and the second effective component is oseltamivir phosphate; the mass ratio of the sodium salt of the compound 1 to the oseltamivir phosphate in the pharmaceutical composition is 100-600: 75; specifically, the mass ratio of the sodium salt of the compound 1 to the oseltamivir phosphate is about 100:75,200:75,300:75,400:75,500:75,600: 75.
According to a preferable technical scheme of the invention, the first effective component in the pharmaceutical composition is hydrochloride of the compound 1, and the second effective component is oseltamivir phosphate; the mass ratio of the hydrochloride of the compound 1 to the oseltamivir phosphate in the pharmaceutical composition is 100-600: 75; specifically, the mass ratio of the hydrochloride of the compound 1 to the oseltamivir phosphate is about 100:75,200:75,300:75,400:75,500:75,600: 75.
According to a preferable technical scheme of the invention, the first effective component in the pharmaceutical composition is a potassium salt of the compound 1, and the second effective component is oseltamivir phosphate; the mass ratio of the potassium salt of the compound 1 to the oseltamivir phosphate in the pharmaceutical composition is 100-600: 75; specifically, the mass ratio of the potassium salt of the compound 1 to the oseltamivir phosphate is about 100:75,200:75,300:75,400:75,500:75,600: 75.
According to a preferable technical scheme of the invention, the first effective component in the pharmaceutical composition is a calcium salt of the compound 1, and the second effective component is oseltamivir phosphate; the mass ratio of the calcium salt of the compound 1 to the oseltamivir phosphate in the pharmaceutical composition is 100-600: 75; specifically, the mass ratio of the calcium salt of the compound 1 to the oseltamivir phosphate is about 100:75,200:75,300:75,400:75,500:75,600: 75.
According to a preferable technical scheme of the invention, the first effective component in the pharmaceutical composition is p-toluenesulfonate of the compound 1, and the second effective component is oseltamivir phosphate; the mass ratio of the p-toluenesulfonate of the compound 1 to the oseltamivir phosphate in the pharmaceutical composition is 100-600: 75; specifically, the mass ratio of the p-toluenesulfonate salt of the compound 1 to the oseltamivir phosphate salt is about 100:75,200:75,300:75,400:75,500:75,600: 75.
The inventors have surprisingly found in experiments that: when the mass ratio of the first active ingredient (compound 1, the corresponding ester thereof, the corresponding salt thereof, the corresponding ester salt thereof, or the combination thereof) and the second active ingredient (the neuraminidase inhibitor) is within a specific range, the pharmaceutical composition has a good pharmaceutical synergistic effect, and shows an effect against influenza virus which is significantly better than that of a single ingredient, and also shows an effect against influenza virus which is significantly better than that of a pharmaceutical composition having a mass ratio outside the specific range, and it is known that when the mass ratio of the first active ingredient and the second active ingredient in a unit preparation is within the specific range, the pharmaceutical composition has a better effect against influenza virus; after the evaluation of the properties (such as mixture stability, fluidity and the like) of other patent drugs is integrated, the pharmaceutical composition is considered to have better patent drug prospect.
Another objective of the present invention is to disclose a method for preparing the aforementioned pharmaceutical composition, which can ensure the stable preparation of the aforementioned pharmaceutical composition. Specifically, the preparation method adopts a mixing method which is conventional in the field; more specifically, the preparation method can be a direct mixing method, an equivalent incremental method and the like, the used mixing equipment can be mixing equipment which is common in the field according to the preparation scale, such as a V-shaped mixer, a double cone mixer, a rotary mixer and the like, and the preparation can also be realized in a manual mixing mode during small-scale preparation.
The third purpose of the invention is to disclose a preparation containing the pharmaceutical composition. Specifically, the preparation comprises the pharmaceutical composition and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier is selected from one or more than two of filler, adhesive, disintegrant, glidant, lubricant, flavoring agent and the like.
Specifically, the filler is selected from one or a mixture of two or more of calcium carbonate, magnesium carbonate, calcium phosphate, calcium sulfate, magnesium oxide, calcium carboxymethylcellulose, sodium carboxymethylcellulose, sucrose, lactose, fructose, xylitol, mannitol, starch or a derivative thereof, dextrin, microcrystalline cellulose, and the like, which are mixed at an arbitrary ratio.
Specifically, the binder is selected from one or a mixture of two or more of acacia, gelatin, tragacanth, dextrin, polyvinylpyrrolidone, starch and derivatives thereof, sodium alginate, sorbitol, syrup, hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, glucose, polymethacrylate, and the like, which are mixed at an arbitrary ratio.
Specifically, the disintegrating agent is selected from one or a mixture of two or more of starch, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylmethylcellulose, microcrystalline cellulose, and methylcellulose, which are mixed at an arbitrary ratio.
Specifically, the glidant is selected from one or a mixture of more than two of colloidal silicon dioxide, powdered cellulose, magnesium trisilicate, silicon dioxide, talcum powder and the like which are mixed in any proportion.
Specifically, the lubricant is selected from one or more of calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, microcrystalline cellulose, sodium benzoate, sodium chloride, sodium lauryl sulfate, sodium stearyl fumarate, talcum powder, zinc stearate, polyethylene glycol and the like, and is a mixture obtained by mixing the two or more of the calcium stearate, the glyceryl monostearate, the glyceryl palmitostearate, the magnesium stearate, the microcrystalline cellulose, the sodium benzoate, the sodium chloride, the sodium lauryl sulfate, the sodium stearyl fumarate, the talcum powder, the zinc stearate, the polyethylene glycol and the like in any proportion.
Specifically, the flavoring agent is selected from one or more than two of stevioside, aspartame, other essences and sweeteners commonly used in the field, and the like, which are mixed in any proportion.
The preparation containing the pharmaceutical composition is an oral preparation, and specifically can be powder, granules, pellets, capsules, tablets, solutions or lozenges.
Based on the beneficial effects of the aforementioned pharmaceutical compositions, such as: the preparation containing the pharmaceutical composition also has obviously better anti-influenza virus effect compared with the preparation containing single component, and also has obviously better anti-influenza virus effect compared with the preparation containing the pharmaceutical composition with mass ratio outside the specific range, thereby having better market prospect.
Compared with the prior art, the invention has the following outstanding advantages and beneficial effects:
1. the pharmaceutical composition comprises a first active ingredient (compound 1, a corresponding ester thereof, a corresponding salt thereof, a corresponding ester salt thereof or a combination thereof) and a second active ingredient (a neuraminidase inhibitor) in a specific mass ratio, and has a better pharmaceutical synergistic effect, wherein the neuraminidase inhibitor has the best effect on oseltamivir and/or oseltamivir salt and/or oseltamivir carboxylic acid or oseltamivir carboxylate obtained after hydrolysis of oseltamivir, and the pharmaceutical composition is considered to have better pharmaceutical prospects after comprehensive evaluation.
2. Provides a preparation method of the pharmaceutical composition, which can ensure the stable preparation of the pharmaceutical composition.
3. The preparation containing the pharmaceutical composition has a better anti-influenza virus effect than a preparation containing a single component, and has a better market prospect.
The present invention is attributed to the discovery that a combination of drugs in a specific range has a synergistic effect, and therefore, it will be understood by those skilled in the art that a combination of drugs in a unit dosage unit within the range of the present invention can be considered to be the subject of the present invention; in particular, the aforementioned unit dosage unit refers to the smallest unit for clinical use, such as: tablets per unit tablet, capsules per unit granule, oral liquid per unit bottle, granules per unit pack, and the like.
The present invention will be described in further detail with reference to examples, but the embodiments of the invention are not limited thereto.
The oseltamivir phosphate used in the examples is the bulk drug of the marketed preparation tamiflu, CAS: 204255-11-8, purity > 99%; the oseltamivir is a free product of a bulk drug of a commercially available preparation tamiflu, and the CAS: 196618-13-0, purity > 99%; oseltamivir carboxylic acid used was a commercially available intermediate, CAS: 187227-45-8, purity > 99%.
The zanamivir (CAS: 139110-80-8) and the peramivir (CAS: 229614-55-5) used in the examples are the bulk drugs of the commercial preparation, and the purity is more than 99%.
EXAMPLE 1 preparation of Compound 1
The compound 1 is prepared by adopting the method disclosed in example 4 of WO2018041263, and the structural characterization proves that the obtained product is the compound 1.
EXAMPLE 2 preparation of hydrochloride salt of Compound 1
5g of Compound 1 was charged into a 250mL eggplant-shaped bottle, THF (100mL) was added, 0.98mL of hydrochloric acid (concentrated hydrochloric acid dissolved in 9mL of THF) was added, and the mixture was stirred at 30 ℃ for 12 hours, and the solid was filtered, and the filter cake was dried under vacuum at 40 ℃ to obtain the hydrochloride of Compound 1.
EXAMPLE 3 preparation of p-Toluenesulfonic acid salt of Compound 1
5g of Compound 1 was put in a 250mL eggplant-shaped bottle, THF (100mL) was added, p-toluenesulfonic acid monohydrate (2.26g dissolved in 10mL of THF) was added, and the mixture was stirred at 30 ℃ for 12 hours, and the solid was filtered, and the filter cake was dried under vacuum at 40 ℃ to obtain a solid (0.425 g). This solid (0.101g) was added to acetone (2mL) and slurried for 12h to give the p-toluenesulfonate salt of Compound 1.
EXAMPLE 4 preparation of sodium salt of Compound 1
5g of Compound 1 was charged into a 250mL eggplant-shaped bottle, THF (100mL) was added, an aqueous NaOH solution (0.477g, dissolved in 1mL of water) was added, stirring was carried out at 30 ℃ for 12 hours, the solid was filtered, and the filter cake was vacuum-dried at 40 ℃ to obtain the sodium salt of Compound 1.
EXAMPLE 5 preparation of Potassium salt of Compound 1
2g of Compound 1 was weighed into a 100mL eggplant-shaped bottle, THF (35mL) was added, an aqueous KOH solution (0.255g, dissolved in 0.5mL of water and 5mL of THF) was added, and the mixture was stirred at 30 ℃ for 12 hours, followed by solid filtration, and the cake was dried under vacuum at 40 ℃ to obtain the potassium salt of Compound 1.
EXAMPLE 6 preparation of calcium salt of Compound 1
2g of compound 1 was put in a 100mL eggplant-shaped bottle, THF (35mL) was added, an aqueous calcium hydroxide solution (0.168g, dissolved in 0.5mL of water and 5mL of THF) was added, stirring was carried out at 25 ℃ for 12 hours, the solid was filtered, the cake was dried under vacuum at 40 ℃ to give a solid (1.440g), the solid (0.204g) was dissolved in a mixed solvent of ethanol and water (ethanol: water: 3:1) (4mL), slurried, stirred at 25 ℃ for 12 hours, the solid was filtered, and the cake was dried under vacuum at 40 ℃ to give a calcium salt of compound 1.
Example 7
200g of the compound 1 prepared in example 1 is taken and mixed with 75g of oseltamivir phosphate (calculated as oseltamivir) uniformly to obtain a pharmaceutical composition with the mass ratio of 200: 75.
Example 8
By the same method as in example 7, pharmaceutical compositions of compound 1 and oseltamivir phosphate in the mass ratios of 50:75, 100:75, 300:75,400:75,500:75,600:75 and 700:75 were prepared, respectively.
Using the same method as in example 7, the salt of compound 1 prepared in examples 2 to 6, and oseltamivir or oseltamivir phosphate, respectively, were used to prepare pharmaceutical compositions having mass ratios of 50:75, 100:75,200:75,300:75,400:75,500:75,600:75, and 700:75, respectively, both of which refer to the mass (free base/acid equivalent) in free form.
Example 9 comparative in vitro Activity experiment
1. Purpose of the experiment
The compound 1 and oseltamivir carboxylic acid (active metabolite) are taken as research objects, the synergistic inhibition effect of the compound 1 and oseltamivir (or oseltamivir carboxylic acid) on influenza A virus by combined administration at a certain proportion is analyzed, the plasma protein binding rate of the compound 1 and oseltamivir carboxylic acid is combined, and the in vivo combined effect is converted and predicted.
2. Experimental Material
Virus: A/Aichi/2/1968(H3N2), available from ATCC.
Cell: dog Kidney epithelial cell line (Madin-Darby Canine Kidney Cells, MDCK).
The drug dissolution method comprises the following steps: dissolving the compound 1 and an oseltamivir active metabolite (oseltamivir carboxylic acid, calculated as oseltamivir) by using dimethyl sulfoxide (DMSO), and preparing a 100mM/L mother solution for storage and later use; then diluted with the culture Medium Minimum Essential Medium (MEM) as a working solution (note: DMSO final concentration is 1%).
3. Experimental methods
MDCK cells were approximately 2.5X 10 per well4The cells were seeded in a 96-well plate, and after the cells grew into a monolayer (about 24 hours), the culture medium was discarded, and the cell surface was washed 2 times with PBS. Adding 100 μ L/well of virus dilution containing MOI 0.01, 37 deg.C, 5% CO2After incubation for 2h in the incubator, the virus solution was discarded, and 2-fold dilution containing compound 1 and oseltamivir carboxylic acid was added to the medium to obtain different concentrations and 0nM combination (i.e., 1, 0.5, 0.25, 0.125, 0.0625, 0.03125, 0.015625, 0nM for compound 1; 0.25, 0.125, 0.0625, 0.03125, 0. mu.M for oseltamivir carboxylic acid). Adding 100 μ L/well of the combined medicine into 96-well cells, setting 3 multiple wells for each concentration, and setting a normal cell group, a virus control group and a medicine control group; placing at 37 ℃ and 5% CO2After incubation in an incubator, the cytopathic condition was observed daily, and then the cell viability of each well was measured using MTT, and the results of virus inhibition after 72 hours of observation are shown in table 1 below.
TABLE 1 combination of Compound 1 with oseltamivir carboxylic acid anti-A/Aichi/2/1968 (H3N2) (% inhibition)
From the above data, when compound 1: the molar ratio of the oseltamivir carboxylic acid is 0.5nM to 0.03125 mu M to 0.015625
The synergistic effect on the tested influenza virus is shown when nM is between 0.25 mu M (1: 62.5-16000), and the virus inhibition rate after combined use is higher than that of single-drug virus; considering that after the compound 1 enters a human body, the binding rate of plasma protein can reach 99.9%, the compound 1 in a free state in the body accounts for about 0.1%, and the binding rate of oseltamivir carboxylic acid in the plasma protein of the human body is 0.3%, the oseltamivir carboxylic acid in the free state in the body accounts for about 99.7%; upon conversion, i.e. in vivo, the molar ratio of compound 1 to oseltamivir carboxylic acid should be in the range of about 1: 16 to 16: 1, namely the mass ratio of the compound 1 to the oseltamivir is about 1: 11.3 to 22.5: 1 (440: 4992 to 7040: 312) has good synergistic effect.
In subsequent experiments, the compound 1 has synergistic effect with oseltamivir, zanamivir and peramivir, but compared with other groups, the oseltamivir group has obviously better synergistic effect than other groups.
Example 10 in vivo Activity assay
Research on drug effect of PR8 influenza virus
1. Study of drug on death protection of PR8 influenza virus (PR 8 virus 2h in advance)
Influenza virus with higher titer was cultured, and BALB/C mice were infected with 2LD50 (lethal dose) by nasal drip.
Groups administered for 5 consecutive days: gavage was administered 2 times daily for 5 consecutive days 2h after infection, setting drug combination compound 1: 30mg/kg, compound 1: 20mg/kg, compound 1: 5mg/kg, compound 1: 1.5mg/kg, oseltamivir phosphate: 10mg/kg, oseltamivir phosphate + compound 1 ═ 10mg/kg +30mg/kg, oseltamivir phosphate + compound 1 ═ 10mg/kg +20mg/kg, oseltamivir phosphate + compound 1 ═ 10mg/kg +5mg/kg, oseltamivir phosphate + compound 1 ═ 10mg/kg +1.5 mg/kg; setting blank control groups and virus control groups, wherein each group contains 10 viruses; the observation is started from the first day of virus infection, the observation is continued for 14d, the weight change, the death condition and the like of the infected mice are observed and recorded every day, and the weight change, the death condition and the like are calculated according to the following formula:
mortality (%). percent number of dead mice in each group/total number before infection (one) × 100%
The results show that after the virus infection, the mice have symptoms of shortness of breath, rolling trembling, weight loss and the like, and have death; after continuous observation for 14d, the blank mice are in good state and have no death, and the death rate of the virus mice reaches 100 percent; compound 1: the 30mg/kg group has complete protection effect on infected mice, and the death rate of the group is 0 percent; compound 1: the 20mg/kg group has obvious protective effect on infected mice, and the death rate is 20%; compound 1: the mortality rate of mice in the 5mg/kg administration group was 80%; oseltamivir phosphate: 10mg/kg administration group and compound 1: the mortality rate of mice in the 1.5mg/kg administration group was 100%. After the compound 1 is combined with oseltamivir phosphate under the dosage of 5mg/kg and 20mg/kg, the death rate is obviously reduced, the synergistic effect is obvious, and the results are shown in table 2:
TABLE 2 mortality and survival rates of the groups of mice
It can be seen that 5mg/kg, 20mg/kg compound 1 and 10mg/kg oseltamivir phosphate in combination exhibit good synergistic antiviral effects in a mouse model of drug action. Based on the conversion of the pharmacokinetics test results of the compound 1 and the oseltamivir phosphate in different species (a mouse and a healthy person), the exposure of the compound 1 administered to the mouse at 5mg/kg and 20mg/kg is similar to the exposure of the compound 1 administered to a human body at 75mg and 600mg in vivo, and the exposure of the compound phosphate administered to the mouse at 10mg/kg is similar to the exposure of the active metabolite administered to the human body at 75mg in vivo, so that the combined drug effect of the compound 1 at 600mg and 75mg and the oseltamivir phosphate at 75mg is obvious, and the composition has better in vivo synergistic effect when the mass ratio of the compound 1 to the oseltamivir phosphate is 75-600: 75 (1-8: 1).
In conclusion, the synergistic effect of the composition of the invention has the situation of inconsistent in vivo and in vitro performances; specifically, the composition shows inconsistency between in vivo and in vitro in a range representing the drug synergy and a more optimal range, and specifically shows that the mass ratio of oseltamivir to compound 1 is about 1:22.5 to 11.3:1 in vivo by converting the range representing the drug synergy in vitro into a range representing the drug synergy in vivo, and an in vivo experiment shows that the range of the drug synergy is greatly reduced surprisingly, and the composition shows that the synergy is represented when the mass ratio of compound 1 to oseltamivir phosphate is 75-600: 75 (1-8: 1); further, the compound 1 and the oseltamivir phosphate have good in-vivo drug synergism when the mass ratio is 75:75, 100:75,200:75,300:75,400:75,500:75 and 600: 75;
further expanded experiments show that when the compound 1, the corresponding ester thereof, the corresponding salt thereof, the corresponding ester salt thereof or the combination thereof and oseltamivir or oseltamivir phosphate also show basically consistent performance, the pharmaceutical composition of the compound 1 and the oseltamivir phosphate and the pharmaceutical composition of the sodium salt of the compound 1 and the oseltamivir phosphate have the best effect, and have better in vivo drug synergism on a wider range of viruses within the protection scope of the patent claims, so the compound 1, the corresponding ester, the corresponding salt thereof, the corresponding ester salt thereof or the combination thereof is considered to have better clinical prospect.
Example 11
The pharmaceutical composition obtained in example 7 was mixed with an appropriate amount of a filler, a binder and a disintegrant and then directly compressed to prepare a tablet (200mg +75 mg).
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (13)
- A pharmaceutical composition characterized in that it comprises a first active ingredient and a second active ingredient, wherein the first active ingredient is compound 1, its corresponding ester, its corresponding salt, its corresponding ester salt or a combination thereof; the second effective component is neuraminidase inhibitor; the mass ratio of the first effective component to the second effective component is 1-8: 1
- The pharmaceutical composition according to claim 1, wherein the first active ingredient is a mixture obtained by mixing one or more of compound 1, an ester corresponding to compound 1, a salt of compound 1, and a salt of an ester corresponding to compound 1 in an arbitrary ratio.
- The pharmaceutical composition according to claim 2, wherein the ester corresponding to compound 1 refers to an ester formed by compound 1 and an organic acid, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl ester of compound 1; the salt of the compound 1 is a salt formed by the compound 1 and an organic acid and/or an inorganic acid, or a salt formed by the compound 1 and an organic base and/or an inorganic base, preferably hydrochloride, hydrobromide, sulfate, phosphate, benzene sulfonate, p-toluene sulfonate, methane sulfonate, tartrate, camphor sulfonate, lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, ammonium salt, ethylenediamine salt and triethylamine salt; the salt of the ester corresponding to compound 1 refers to the salt of the ester formed by compound 1 and organic acid and/or organic base and/or inorganic base and/or organic acid and/or inorganic acid, preferably hydrochloride, sulfate of compound 1 methyl ester, hydrochloride of compound 1 ethyl ester, and sulfate of compound 1 ethyl ester.
- The pharmaceutical composition according to any one of claims 1 to 3, wherein the neuraminidase inhibitor is a mixture obtained by mixing one or more of Oseltamivir (Oseltamivir) or a derivative thereof, zanamivir (zanamivir) or a derivative thereof, Peramivir (Peramivir) or a derivative thereof in any ratio; the derivatives of oseltamivir, zanamivir and peramivir are independently selected from acids and/or bases thereof, or esters and amides of the compounds, or carboxylic acids obtained after hydrolysis and salts thereof.
- The pharmaceutical composition according to any one of claims 1 to 4, wherein the second active ingredient is oseltamivir free form and/or oseltamivir phosphate and/or oseltamivir carboxylic acid and/or oseltamivir carboxylate.
- The pharmaceutical composition according to any one of claims 1 to 5, wherein the mass ratio of the first active ingredient to the second active ingredient is 100-600: 75.
- The pharmaceutical composition of any one of claims 1-6, wherein the mass ratio of the first active ingredient to the second active ingredient is about 100:75,200:75,300:75,400:75,500:75,600: 75.
- The pharmaceutical composition according to claim 1, wherein the first active ingredient is compound 1 and/or the sodium salt of compound 1 and/or the potassium salt of compound 1 and/or the hydrochloride salt of compound 1 and/or the calcium salt of compound 1 and/or the p-toluenesulfonate salt of compound 1; the second effective component is oseltamivir phosphate; the mass ratio of the compound 1 to the oseltamivir phosphate is 100-600: 75.
- The pharmaceutical composition according to claim 1, wherein the first effective component is compound 1 and/or a sodium salt of compound 1 and/or a potassium salt of compound 1 and/or a hydrochloride of compound 1 and/or a calcium salt of compound 1 and/or a p-toluenesulfonate of compound 1, the second effective component is oseltamivir phosphate, and the mass ratio of compound 1 to oseltamivir phosphate is 100:75,200:75,300:75,400:75,500:75,600: 75.
- A formulation comprising the pharmaceutical composition of any one of claims 1-9 and a pharmaceutically acceptable carrier.
- The preparation of claim 10, wherein the pharmaceutically acceptable carrier is selected from any one or more of fillers, binders, disintegrants, glidants, lubricants and flavoring agents.
- The preparation according to claim 11, wherein the filler is selected from the group consisting of calcium carbonate, magnesium carbonate, calcium phosphate, calcium sulfate, magnesium oxide, calcium carboxymethylcellulose, sodium carboxymethylcellulose, sucrose, lactose, fructose, xylitol, mannitol, starch or a derivative thereof, dextrin, microcrystalline cellulose, and the like, and a mixture obtained by mixing two or more thereof at an arbitrary ratio;the binder is selected from one or a mixture obtained by mixing more than two of acacia, gelatin, tragacanth, dextrin, polyvinylpyrrolidone, starch and derivatives thereof, sodium alginate, sorbitol, syrup, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, glucose and polymethacrylate in any proportion;the disintegrating agent is selected from one or more than two of starch, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospolyvinylpyrrolidone, low-substituted hydroxypropyl methylcellulose, microcrystalline cellulose and methylcellulose, and is mixed at any ratio;the glidant is selected from one or a mixture of more than two of colloidal silicon dioxide, powdered cellulose, magnesium trisilicate, silicon dioxide and talcum powder which are mixed in any proportion;the lubricant is selected from one or more than two of calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, microcrystalline cellulose, sodium benzoate, sodium chloride, sodium lauryl sulfate, sodium stearyl fumarate, talcum powder, zinc stearate and polyethylene glycol which are mixed in any proportion;the flavoring agent is selected from one or more than two of stevioside, aspartame and other essences and sweeteners commonly used in the field, and is mixed in any proportion.
- The formulation according to any one of claims 10 to 12, wherein the formulation is an oral formulation; preference is given to powders, granules, pellets, capsules, tablets, solutions or lozenges.
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| CN2019108517593 | 2019-09-10 | ||
| CN201910851759 | 2019-09-10 | ||
| PCT/CN2020/113105 WO2021047437A1 (en) | 2019-09-10 | 2020-09-02 | Pharmaceutical composition for treating viral influenza and preparation thereof |
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| WO2021047437A1 (en) | 2021-03-18 |
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