CN105982889B - The pharmaceutical composition and its application of resisiting influenza virus - Google Patents
The pharmaceutical composition and its application of resisiting influenza virus Download PDFInfo
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Abstract
The invention discloses a kind of pharmaceutical composition of resisiting influenza virus and its applications, belong to pharmaceutical technology field.The active constituent of the composition is made of Ah than flower or its pharmaceutically acceptable salt with Oseltamivir or its pharmaceutically acceptable salt according to weight part ratio for 1-10:1-5.Mutual cooperation by Ah than flower and Oseltamivir, different action target spots is acted on, synergistic effect is played, when catching a cold caused by influenza virus for treating and preventing, the dosage of Oseltamivir phosphate can be reduced, the generation of drug resistance and adverse reaction is reduced.
Description
Technical field
The present invention relates to pharmaceutical technology fields, more particularly to the pharmaceutical composition and its application of a kind of resisiting influenza virus.
Background technique
Influenza (influenza, abbreviation influenza) is acute respiratory infection caused by influenza virus, and a kind of
The disease that infectiousness is strong, spread speed is fast.It can make patient body weakness, cause multiple complications, it is sometimes desirable to be hospitalized for treatment
And may be lethal, for the old and frail weaker people of resistance, it is easy to which mutually infection causes a certain range of prevalence.
Annual influenza pandemic can cause 3 million to five million several cases, and cause 300,000-50 ten thousand people dead.Age is greater than 65
Year, less than the two years old poor people of immunity are the people at highest risk that serious illness and death possible occur.
The virus for causing influenza is influenza virus, and influenza virus is a kind of ribonucleic acid (RNA) virus, is divided into
First, second, the third three types, it is pathogenic mainly before amphitypy.Influenza A virus is according to surface protein hemagglutinin and neuraminidase
Structure and its genetic characteristics can be divided into many hypotypes (second, the third type do not have hypotype) again, so far it has been found that blood clotting be known as 16 Asias
Type (H1-16), 9 hypotypes (N1-9) of neuraminidase, the various combination of the two just form many hypotypes, such as popular in recent years
H1N1virus, H5N1 influenza virus and H7N9 influenza virus.
Influenza A virus also contains a kind of structure, referred to as M2 ion channel on coating.By target site, existing anti-current
Susceptible cytotoxic drug has two classes:
(1) M2 ion channel blocking agents are by preventing virus from sloughing shell, to stop reproduction process.But it is B-mode
The not no ionophorous protein of influenza virus, therefore such drug is only effective to Flu-A.Representing drug has amantadine and gold
Rigid ethamine.M2 ion channel blocking agents problem maximum at present is resistant rate height.The drug resistance of influenza A virus strain is supervised by foreign countries
Survey starts from 1991,1994-1995, and H3N2 virus is 0.4%, 2003-2004 to amantadine and Rimantadine resistant rate
Year increases to 12.3%.Studies in China shows that H3N2 virus 1989-1999 is without discovery drug resistance, drug resistance ratio in 2002
3.4%, 56.0% is risen within 2003, rises to 77.6% within 2005；Another research influenza virus in 2004 is to adamantane
Amine resistant rate is 73.8%.Serious problem is that drug resistant virus keeps good hereditary capacity, can passed between men
It broadcasts.
(2) neuraminidase inhibitor prevents virus by infected cell release and invasion adjacent cells, reduces virus and exist
Virus diffusion chain is cut off in the intracorporal duplication of host, active to first, influenza B virus.Representing drug has phosphoric acid Ao Sita
Wei, zanamivir and Peramivir etc..Wherein, Oseltamivir phosphate (Oseltamivir) trade name Tamiflu (Tamiflu),
Its structure is as follows:
Oseltamivir is the neuraminidase of the novel resisiting influenza virus by Gilead company and the exploitation listing of Roche company
Inhibitor, molecular formula C16H28N2O4·H3PO4, entitled -3 (the third oxygen of 1- ethyl of -5 amino of (3R, 4R, 5S) -4 acetamido of chemistry
Base) -1- cyclohexene -1- carboxylic acid, ethyl ester phosphate (Novel selective inhibitors of viral or
bacterial neuraminidases,WO9626933).Oseltamivir phosphate acts on influenza surface glycoprotein-nerve
Propylhomoserin enzyme (NA), so that suppressing virus replication and the propagation in respiratory tract, are a kind of highly selective influenza virus NA inhibitor.
Oseltamivir phosphate was listed in 1999 in Switzerland, for adult and 1 years old and 1 years old or more children A types and influenza B treatment
(Oseltamivir phosphate can effectively treat A type and influenza B, but the clinical application data of influenza B are still few).?
It can be used for adult and 13 years old and 13 years old or more teen-age A type and influenza B prevention.But with clinically applying
It promotes, virus continues to bring out (Influenza Neuraminidase Inhibitors as to its drug resistance phenomenon
Antiviral Agents.ANNUAL REPORTS IN MEDICINAL CHEMISTRY,2006(41):287-297；In
Vitro Generation of Neuraminidase Inhibitor Resistance in A(H5N1)Influenza
Viruses.Antimicrob.Agents Chemother., 2009 (53): 4433-4440), it will lead to control virus replication
And it is continuously increased dosage.Also, Oseltamivir phosphate also has certain adverse reaction, main adverse reaction are as follows: digestion
The discomfort in road, including nausea,vomiting,diarrhea, abdominal pain etc., the followed by adverse reaction of respiratory system, including bronchitis, cough
Deng in addition there are the adverse reactions of central nervous system, such as dizziness, headache, insomnia, fatigue.
Abiduoer (Arbidol) is a kind of antiviral drugs, molecular formula C22H25BrN2O3S, the entitled bromo- 5- of 6- of chemistry
Hydroxyl -1- methyl -4- ((dimethylamino) methyl) -2- (phenylthiomethyl) -1H- indole -3-carboxylic acid ethyl ester.Its structure is as follows
It is shown:
Abiduoer was approved to list in Russia first in 1993, in previous clinical application in 20 years, by its institute
The characteristics such as the curative for effect, Small side effects that have, patient should not generate drug resistance and medical expense is low are widely used in adult and 6
Year old or more pediatric population, the prevention and treatment drug of the bronchitis concurrent as influenza, influenza and pneumonia.Abiduoer is also
Be recommended as respectively by Russian Chinese Pharmacopoeia Commission and Russian Federation's health care and development division " adult and children's first,
The treatment and prevention medication of influenza B " and " prescription medicine of free medical rescue and the types of drugs of first aid organ indispensability ", and
" drug for the treatment of Influenza A H1N1 " is recommended as by ministry of Health of China in 2010.And the adverse reaction of Abiduoer is mainly
Nausea, diarrhea, dizziness and serum transaminase increase.
Although having several Tamiflu at present, an ideal drug that can effectively prevent in the flu outbreak phase still has
It is to be developed.Nearest one draws a conclusion to the meta-analysis of current curative effect of medication, and amantadine or Rimantadine are because it is aobvious
The side reaction of work and the rapid generation of virus drug resistance, it should not encourage to use.And neuraminidase inhibitor can then cause disease
Malicious drug resistance, and the price compared with Abiduoer costly.
Summary of the invention
Based on this, the purpose of the present invention is to provide a kind of pharmaceutical composition of resisiting influenza virus, in the composition Ah
Cooperate than Duo Er and Oseltamivir phosphate, act on different action target spots, play synergistic effect, for treating and
When flu caused by flu-prevention virus, the dosage of Oseltamivir phosphate can be reduced, reduces the hair of drug resistance and adverse reaction
It is raw.
To achieve the above object, the present invention takes following technical scheme:
A kind of pharmaceutical composition of resisiting influenza virus, the active constituent of the composition by compound of formula I or its pharmaceutically
Acceptable salt and Formula II compound or its pharmaceutically acceptable salt form:
Wherein, compound of formula I or its pharmaceutically acceptable salt and Formula II compound or its pharmaceutically acceptable salt
Weight part ratio is 1-10:1-5.
Pharmaceutical composition of the invention combines Oseltamivir shown in Abiduoer shown in Formulas I and Formula II,
In, Abiduoer specifically prevents influenza virus cyst membrane and host cell cell by activation 2,5- oligoadenylate synthetase
The contact of film is sticked and is merged, to block the duplication of influenza virus, and can penetrate the conjunction that nucleus directly inhibits viral RNA
At, also by the phagocytosis of the generation of inducing interferon and assistance macrophage, thus enhance cellular immune function, raising body
Body supports anti-infectious ability.Oseltamivir then acts on neuraminidase, inhibits the neuraminidase activity of virus, prevents virus
By infected cell release and invasion adjacent cells, virus is reduced in the intracorporal duplication of host, cuts off virus diffusion chain.The two phase
Mutually cooperation, acts on different action target spots, plays synergistic effect.
In one embodiment, the compound of formula I pharmaceutically acceptable salt is selected from: hydrochloride, hydrobromate, wine
Stone hydrochlorate, citrate, sulfate or acetate.
The compound of formula I pharmaceutically acceptable salt is hydrochloride in one of the embodiments,.
The Formula II compound pharmaceutically acceptable salt is phosphate in one of the embodiments,.
The phosphatic parts by weight of the hydrochloride of the compound of formula I and Formula II compound in one of the embodiments,
Than for 1-8:1-3.
The phosphatic parts by weight of the hydrochloride of the compound of formula I and Formula II compound in one of the embodiments,
Than for 4:1.
The invention also discloses a kind of pharmaceutical compositions of above-mentioned resisiting influenza virus to prevent and treat influenza in preparation
Application in drug.
When the pharmaceutical composition of above-mentioned resisiting influenza virus is used to catch a cold caused by preventing and treating influenza virus, A Biduo
Both you and Oseltamivir cooperate, and act on different action target spots, play synergistic effect, can reduce phosphoric acid
The dosage of Oseltamivir reduces the generation of drug resistance and adverse reaction.
The influenza is the stream as caused by influenza A virus or influenza B virus in one of the embodiments,
Sense.
The dosage form of the drug is oral solution, hard capsule, soft capsule, tablet, pill, drop in one of the embodiments,
Pill or granule.
Above-mentioned dosage form can be prepared according to the conventional production process of pharmaceutical field, for example, make active constituent with it is one or more
Pharmaceutically acceptable auxiliary material mixing, is then made into required dosage form.Wherein, pharmaceutically acceptable auxiliary material includes but not
Be limited to: diluent, disintegrating agent, wetting agent, adhesive, lubricant, corrigent, coating agent and other it is necessary commonly use it is medicinal auxiliary
Material etc..Diluent includes but is not limited to: starch, lactose, sucrose, microcrystalline cellulose, dextrin etc..Disintegrating agent includes but is not limited to:
Dried starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, croscarmellose sodium
Deng.Wetting agent or adhesive include but is not limited to: water, 30%-70% ethyl alcohol, sodium carboxymethylcellulose, hydroxypropyl cellulose etc..
Lubricant includes but is not limited to: magnesium stearate, superfine silica gel powder, talcum powder etc..Corrigent includes but is not limited to: sucrose, fructose, Ah
Take charge of Batan, stevioside etc..Coating agent includes but is not limited to: hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone, propylene
Acid resin etc..
Compared with prior art, the invention has the following advantages:
The pharmaceutical composition of resisiting influenza virus of the invention, by Abiduoer shown in Formulas I or its pharmaceutically acceptable salt
It combines with Oseltamivir shown in Formula II or its pharmaceutically acceptable salt, is cooperated by the two, act on difference
Action target spot, play synergistic effect, it is same reaching when catching a cold caused by influenza virus for treating and preventing
While therapeutic effect, the dosage of Oseltamivir phosphate can be reduced, reduces the generation of drug resistance and adverse reaction.
Detailed description of the invention
Fig. 1 is H274Y-PR8 virus infected mice survival rate figure in embodiment 6.
Specific embodiment
Below in conjunction with the drawings and specific embodiments, the present invention will be described in detail, but does not cause any restrictions to the present invention.
Embodiment 1
A kind of granule of resisiting influenza virus, prescription are as follows:
Preparation method: arbidol HCl and Oseltamivir phosphate are crushed in advance respectively, with lactose, stevioside and Gan Dian
Powder sieves with 100 mesh sieve uniformly mixed, soaks softwood processed with suitable quantity of water, crosses the granulation of 12 meshes, and 10 mesh sieves are crossed in 50 DEG C of drying, then
Fine powder is sifted out with 60 meshes, still soaks softwood processed with suitable quantity of water, crosses the granulation of 12 meshes, 10 mesh sieves are crossed in 50 DEG C of drying；Merge
Twice particle to get.
Embodiment 2
A kind of tablet of resisiting influenza virus, prescription are as follows:
Preparation method: arbidol HCl and Oseltamivir phosphate are crushed in advance respectively, with sucrose and 35g dried starch mistake
100 meshes are uniformly mixed, and with appropriate 30% ethanol wet softwood, cross the granulation of 18 meshes, and 16 mesh sieves are crossed in 45 DEG C of drying,
Fine powder is sifted out with 60 meshes again, still with appropriate 30% ethanol wet softwood, crosses the granulation of 18 meshes, 16 meshes are crossed in 45 DEG C of drying
Whole grain；Merge particle twice, be uniformly mixed with 15g dried starch and magnesium stearate, tabletting to get.
Embodiment 3
A kind of tablet of resisiting influenza virus, prescription are as follows:
Preparation method: arbidol HCl and Oseltamivir phosphate are crushed in advance respectively, with microcrystalline cellulose, sucrose and
10g low-substituted hydroxypropyl cellulose sieves with 100 mesh sieve uniformly mixed, soaks softwood processed with suitable quantity of water, crosses the granulation of 18 meshes, 55 DEG C of bakings
It is dry, 16 mesh sieves are crossed, then sift out fine powder with 60 meshes, still soak softwood processed with suitable quantity of water, crosses the granulation of 18 meshes, 55 DEG C of bakings
It is dry, cross 16 mesh sieves；Merge particle twice, is uniformly mixed with 5g low-substituted hydroxypropyl cellulose and magnesium stearate, tabletting, i.e.,
?.
Embodiment 4
A kind of tablet of resisiting influenza virus (coating tablet), prescription is as follows:
Preparation method: arbidol HCl and Oseltamivir phosphate are crushed in advance respectively, formed sediment with starch and 25g carboxymethyl
Powder sodium sieves with 100 mesh sieve uniformly mixed, with appropriate 70% ethanol wet softwood, crosses the granulation of 18 meshes, 16 meshes are crossed in 45 DEG C of drying
Whole grain, then fine powder is sifted out with 60 meshes, still with appropriate 70% ethanol wet softwood, the granulation of 18 meshes is crossed, 45 DEG C of drying cross 16
Mesh sieve；Merge particle twice, is uniformly mixed with 10g sodium carboxymethyl starch and talcum powder, tabletting.Above-mentioned tablet is set into coating
In pot, 45 DEG C are heated and kept, 15g hydroxypropyl methyl cellulose is made into the ethanol solution that concentration is 15%, is coated, i.e.,
?.
Embodiment 5
A kind of capsule of resisiting influenza virus, prescription are as follows:
Operation: arbidol HCl and Oseltamivir phosphate are crushed in advance respectively, with lactose and 10g low substituted hydroxy-propyl
Cellulose sieves with 100 mesh sieve uniformly mixed, with appropriate 70% ethanol wet softwood, crosses the granulation of 18 meshes, 16 mesh are crossed in 45 DEG C of drying
Whole grain is sieved, then sifts out fine powder with 60 meshes, still with appropriate 70% ethanol wet softwood, crosses the granulation of 18 meshes, 45 DEG C of drying, mistake
16 mesh sieves；Merge particle twice, be uniformly mixed with magnesium stearate, loading capsulae vacuus to get.
Embodiment 6
The present embodiment compares the arbidol hydrochloride and Oseltamivir phosphate composition (the i.e. present invention of different weight part ratio
Resisiting influenza virus pharmaceutical composition) be used alone arbidol hydrochloride and exclusive use Oseltamivir phosphate convection current it is susceptible
The inhibitory activity of poison is tested as follows:
One, experimental material
Influenza virus: A/PR8/8/34 (H1N1) (PR8), source: Guangzhou Inst. of Respiratory Diseases.
Arbidol hydrochloride (Arb), purity 97.5%, source: laboratory self-control, it is total through mass spectrum, infrared spectroscopy, nuclear-magnetism
The hydrogen that shakes is composed, carbon-13 nmr spectra carries out structural identification.
Oseltamivir phosphate (Osel), purity 98.0%, source: laboratory self-control, through mass spectrum, infrared spectroscopy, nuclear-magnetism
Resonate hydrogen spectrum, carbon-13 nmr spectra progress structural identification.
Mouse: 6-8 weeks, female, Balb/c, average weight 20g.
Two, viral infectious process
With PBS by PR8 viral dilution to 200pfu/40 μ l (2MLD50), mouse is after isoflurane is anaesthetized, with 100 μ l liquid reliefs
Device is drawn the PR8 virus that 40 μ l have diluted and is instilled in mouse nasal cavity through two sides nostril.
Three, experimental method
According to following table dosage, compound is dissolved in the PBS of 200 μ l pH7.2 and is administered, is grouped according to following table, every group 10
Mouse, wherein Viral interference control group only with virus infection, is not administered, and Normal group is neither with virus infection, also not
Administration, remaining each group gastric infusion, successive administration 5 days 2 times a day.Wherein, first administration is 4h before virus infection, is then spaced
12h administration (is administered) 2 times a day.
In an experiment, it weighs daily to mouse, observe the death rate.And it is calculated 10 days by the number of mice amount of survival in the 10th day
Survival rate.
1 dosage of table
Four, test result: result is as shown in Fig. 1 and table 2.
2 H274Y-PR8 virus infected mice survival condition of table
From the above results, Normal group mouse all survives, and Viral interference control group mice is all dead, says
Bright modeling success.
(Arb/Osel weight ratio is the 200 μ g of composition A group and administration of administration 20mg (Arb/Osel weight ratio be 4/1)
4/1) composition B group, D group, administration 2mg and the H that 200 μ g Oseltamivir phosphates are administered with administration 2mg arbidol HCl
Group is similar with I group, has same resisiting influenza virus effect, and 10 days survival rates are 100%.
But in B group, when the weight ratio of arbidol HCl and Oseltamivir phosphate is 4:1, i.e. hydrochloric acid in composition
The content of Abiduoer is 160 μ g, and the content of Oseltamivir phosphate is only 40 μ g, and 10 days survival rates are up to 100%, and when being administered
The full F group with 160 μ g arbidol HCls and the full J group with 40 μ g Oseltamivir phosphates, 10 days survival rates are respectively 40% He
40%, from the above results, two kinds of pharmaceutical compositions of Abiduoer and Oseltamivir are acted on using generated synergistic corrosion virus,
It is far longer than antiviral effect when same dose is used alone in the two.
And Arb/Osel weight ratio be 10:1 and 1:5 L group and M group, even if always dosage be 200 μ g, due to Ah
It is more different than the proportion between Duo Er and Oseltamivir, the B group that effect is 4:1 not as good as Arb/Osel weight ratio.
Therefore, Abiduoer and Oseltamivir are used in combination the present invention, reduce the dosage of Oseltamivir phosphate, are reaching
While to same therapeutic effect, treatment cost can be not only reduced, but also the generation of its adverse reaction can be reduced.
The embodiments described above only express several embodiments of the present invention, and the description thereof is more specific and detailed, but simultaneously
Limitations on the scope of the patent of the present invention therefore cannot be interpreted as.It should be pointed out that for those of ordinary skill in the art
For, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to guarantor of the invention
Protect range.Therefore, the scope of protection of the patent of the invention shall be subject to the appended claims.
Claims (10)
1. a kind of pharmaceutical composition of resisiting influenza virus, which is characterized in that the active constituent of the composition by compound of formula I or
Its pharmaceutically acceptable salt and Formula II compound or its pharmaceutically acceptable salt form:
Wherein, compound of formula I or the weight of its pharmaceutically acceptable salt and Formula II compound or its pharmaceutically acceptable salt
Part is than being 4:1.
2. the pharmaceutical composition of resisiting influenza virus according to claim 1, which is characterized in that the compound of formula I pharmacy
Upper acceptable salt is selected from: hydrochloride, hydrobromate, tartrate, citrate, sulfate or acetate.
3. the pharmaceutical composition of resisiting influenza virus according to claim 2, which is characterized in that the compound of formula I pharmacy
Upper acceptable salt is hydrochloride.
4. the pharmaceutical composition of resisiting influenza virus according to claim 1-3, which is characterized in that the Formula II
Conjunction object pharmaceutically acceptable salt is phosphate.
5. the drug that the pharmaceutical composition of the described in any item resisiting influenza virus of claim 1-4 prevents and treats influenza in preparation
In application；The influenza is the influenza as caused by influenza A virus.
6. application according to claim 5, which is characterized in that the dosage form of the drug is oral solution.
7. application according to claim 5, which is characterized in that the dosage form of the drug is hard capsule or soft capsule.
8. application according to claim 5, which is characterized in that the dosage form of the drug is tablet.
9. application according to claim 5, which is characterized in that the dosage form of the drug is pill or pill.
10. application according to claim 5, which is characterized in that the dosage form of the drug is granule.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102641266A (en) * | 2012-04-13 | 2012-08-22 | 石家庄中硕药业集团有限公司 | Medicament composite for treating viral influenza |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102641266A (en) * | 2012-04-13 | 2012-08-22 | 石家庄中硕药业集团有限公司 | Medicament composite for treating viral influenza |
Non-Patent Citations (3)
| Title |
|---|
| Antiviral and anti-inflammatory activity of arbidol hydrochloride in influenza A (H1N1) virus infection;Qiang LIU等;《Acta Pharmacologica Sinica》;20130617;第34卷(第8期);第1075-1083页 |
| 盐酸阿比朵尔体外抑制2009 新型流感病毒A (H1N1) 的作用;张兴权等;《中国医学科学院学报》;20120430;第34卷(第2期);第126-129页 |
| 盐酸阿比朵尔胶囊抗甲型H1N1流感病毒的体外实验研究;刘强等;《中国药学杂志》;20110131;第46卷(第2期);第108-112页 |
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