CN103211826A - Antiviral pharmaceutical composition as well as preparation method and application thereof - Google Patents
Antiviral pharmaceutical composition as well as preparation method and application thereof Download PDFInfo
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- CN103211826A CN103211826A CN2013101762332A CN201310176233A CN103211826A CN 103211826 A CN103211826 A CN 103211826A CN 2013101762332 A CN2013101762332 A CN 2013101762332A CN 201310176233 A CN201310176233 A CN 201310176233A CN 103211826 A CN103211826 A CN 103211826A
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- tenofovir
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- pyrrole furan
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- ester
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- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 230000000840 anti-viral effect Effects 0.000 title abstract description 3
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to an antiviral pharmaceutical composition as well as a preparation method and an application thereof. The pharmaceutical composition comprises tenofovir dipivoxil or medicinal salt thereof and lamivudine. The invention also relates to a preparation method of the pharmaceutical composition and a new application thereof. The new application comprises prevention and treatment of various influenzas.
Description
Technical field
The pharmaceutical composition that the present invention relates to treat, it comprises tenofovir two pyrrole furan esters or its pharmaceutical salts and lamivudine, the invention still further relates to contain described preparation of drug combination method and new purposes thereof, comprises the purposes on the various influenzas of control.
Background technology
Fumaric acid tenofovir two pyrrole furan ester (fovir disoproxil fumarate, TDF), its chemistry is by name: 9-[(R)-two [[(isopropoxy carbonyl) oxygen base] methoxyl group] phosphinyls of 2-[[] methoxyl group]-propyl group] adenine fumarate (1: 1), its structure is as shown in the formula 1:
Formula 1
Fumaric acid tenofovir two pyrrole furan esters are by the research and development of U.S. Glead Scierices company, are to be used for the treatment of the ucleotides reverse transcription inhibitor that HIV infects.Aspect clinical practice, German scholar van Bommel etc. has reported after using lamivudine (LAM) drug resistance, use adefovir ester (ADV) instead and occur drug-fast 10 routine chronic hepatitis B patients once more, carried out surpassing the fumaric acid tenofovir two pyrrole furan ester single therapies of December.Research conclusion shows: fumaric acid tenofovir two pyrrole furan ester single therapies all have significant antivirus action to the relevant HBV-DNA that reaches the different drug resistance variant sites that merge of ADV.
The tenofovir two pyrrole furan ester officinal salts that gone on the market at present are fumarate, but other pharmaceutical salts of tenofovir two pyrrole furan esters also have same pharmaceutically active, and these salt comprise: tenofovir two pyrrole furan ester succinates, tenofovir two pyrrole furan ester L-tartrates, tenofovir two pyrrole furan ester oxalates, tenofovir two pyrrole furan ester saccharates, tenofovir two pyrrole furan ester citrates, tenofovir two pyrrole furan ester Salicylates, tenofovir two pyrrole furan ester phosphate etc.
Lamivudine (LAM), its chemistry is by name: (2R, 5S)-4-amino-1-(2-methylol-1,3-oxygen thia ring penta-5-yl)-1H-pyrimid-2-one, structure is as shown in the formula 2:
Formula 2
Lamivudine be in the clinical practice curative effect preferably, representative nucleoside analog.Its mechanism of action is for suppressing viral DNA polymerase and reverse transcriptase activity, and to the synthetic of viral DNA chain with prolong competitive inhibitory action, therefore is applicable to chronic hepatitis B.Serum HBV DNA detection result to most of hepatitis B patients shows that lamivudine can suppress hbv replication rapidly, and its inhibitory action continues in whole therapeutic process.Serum transaminase is reduced to normally, and prolonged application can significantly be improved the struvite change of hepatic necrosis and alleviate or stop the progress of hepatic fibrosis.
Yet so far, tenofovir two pyrrole furan esters or its pharmaceutical salts and lamivudine drug combination treatment chronic hepatitis B does not have report.
Therefore, the present invention is used in combination both, and the treatment chronic hepatitis B has been obtained excellent curative, and the present invention proposes The combined is prepared into a kind of compound medicinal formulation for this reason, takes to make things convenient for the patient.
The present invention finds unexpectedly, and The combined is prepared into compound medicinal formulation, makes serum transaminase reduce to normal effect, can suppress nucleotide reverse transcriptase simultaneously, so the two associating can be played better effect in whole therapeutic process.
Pharmaceutical composition of the present invention had both reduced the medicine cost, brought new Gospel to the patient in treatment.In process of the present invention, this pharmaceutical composition of also surprised discovery also has good effect in the influenza that control virus causes.
Summary of the invention
The purpose of this invention is to provide a kind of pharmaceutical composition that contains tenofovir two pyrrole furan esters or its pharmaceutical salts and two kinds of active constituents of medicine of lamivudine.
Another object of the present invention provides the preparation method of above-mentioned Pharmaceutical composition.
A further object of the invention provides the new purposes of this pharmaceutical composition.
Pharmaceutical composition of the present invention can be made the pharmaceutical preparation that oral administration is used, and also can be made into the pharmaceutical preparation of parenteral administration.
Pharmaceutical composition of the present invention when making peroral dosage form, contains tenofovir two pyrrole furan esters or its pharmaceutical salts 10～500mg, lamivudine 10～500mg in its pharmaceutical preparation.Preferred tenofovir two pyrrole furan esters or its pharmaceutical salts 50～300mg, lamivudine 50～300mg; Preferred especially tenofovir two pyrrole furan esters or its pharmaceutical salts 300mg, lamivudine 150mg.
Pharmaceutical composition of the present invention when making injection type, contains tenofovir two pyrrole furan esters or its pharmaceutical salts 10～300mg, lamivudine 10～150mg in its pharmaceutical preparation.Preferred tenofovir two pyrrole furan esters or its pharmaceutical salts 10～100mg, lamivudine 10～50mg; Preferred especially tenofovir two pyrrole furan esters or its pharmaceutical salts 50mg, lamivudine 25mg.
The content of the above tenofovir two pyrrole furan ester pharmaceutical salts when feeding intake all in the content of tenofovir two pyrrole furan esters, as tenofovir two pyrrole furan ester pharmaceutical salts the inventory content that is converted to tenofovir two pyrrole furan esters be 10-500mg, 50-300mg, 300mg, or, 10-300mg, 10-100mg, 50mg.
Pharmaceutical composition of the present invention as required, also can add the medicine acceptable carrier, and its percentage by weight that accounts for compositions can be 0.1%-99.9%.
Pharmaceutical composition of the present invention, wherein said tenofovir two pyrrole furan ester pharmaceutical salts are selected from: tenofovir two pyrrole furan ester succinates, tenofovir two pyrrole furan ester L-tartrates, tenofovir two pyrrole furan ester oxalates, tenofovir two pyrrole furan ester saccharates, tenofovir two pyrrole furan ester citrates, tenofovir two pyrrole furan ester Salicylates, tenofovir two pyrrole furan ester phosphate, fumaric acid tenofovir two pyrrole furan esters etc., the present invention is most preferred to be: fumaric acid tenofovir two pyrrole furan esters.
The present invention also further provides the application of described pharmaceutical composition in pharmaceutical preparation.Described preparation can be made into any pharmaceutically useful dosage form.These dosage forms comprise: tablet, sugar coated tablet, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral liquid, suck agent, granule, electuary, pill, powder, unguentum, sublimed preparation, suspensoid, powder, solution, injection, suppository, ointment, plaster, cream, spray, drop, patch.Preparation of the present invention is preferably peroral dosage form and injection.Wherein peroral dosage form particularly preferably is tablet, capsule, granule, oral liquid.Pharmaceutical composition of the present invention, can prepare according to the routine techniques of pharmaceutical preparation, as mixing with the medicine acceptable carrier again, by the system granule behind tenofovir two pyrrole furan esters and the lamivudine mixing, tablet, method such as encapsulated is prepared into oral drug preparation.
Preparing such formulations is the conventional method known of those skilled in that art normally.
Preferably, pharmaceutical composition of the present invention, contain in its prescription of per 1000 unit formulations:
This prescription obtains through screening, below is the stability data of screening experiment, respectively effective ingredient fumaric acid tenofovir two pyrrole furan esters and lamivudine in embodiment 1 tablet and embodiment 3 capsules is carried out study on the stability, and the result is as follows:
As seen from the above table, the effective ingredient of making behind tablet and the capsule does not have great variation, and corresponding effective ingredient do not influence each other and have influence on the stability of whole pharmaceutical composition, and other prescriptions of candidate do not have above-mentioned advantage, less stable, these prescriptions are disallowable for this reason.
Another purpose of the present invention provides the new purposes of this pharmaceutical composition.Promptly use pharmaceutical composition of the present invention to prevent and treat various influenzas.
According to the difference of virus antigen characteristic and genetic characteristics thereof, influenza virus is divided into the A(first), B(second), C(third) three types.Specifically be classified as follows:
A type (first type) influenza: A type influenza virus energy infected person, fowl, pig, horse, sea dog, whale and other animals, but wild birds is the natural host of this virus.A type influenza virus is always in continuous variation, is divided into different hypotypes according to two kinds of protein on viral top layer.These two kinds of protein are respectively hemagglutinin (HA) and neuraminic acid (NA).Wherein HA has 15 hypotypes, and NA has 9 hypotypes.Two kinds of protein of HA and NA may form multiple combination.Have only several A type influenza virus sub-strains in the crowd, generally to propagate (H1N1, H1N2 and H3N2) at present.Other subtype virus are mainly seen in various animals, the H7N7 and the H3N8 type virus that for example can cause herds of horses to infect.The title of A type influenza virus sub-strain is decided according to HA and two kinds of surface layer proteins of NA.For example, H5N1 type virus is made up of HA5 and two kinds of protein of NA1.
Type B (B-mode) influenza: the Type B influenza virus only sees human body usually.Different with A type influenza virus is that this virus can not make a variation rapidly, does not therefore have the hypotype classification.Though the Type B influenza virus can cause influenza in the crowd, this virus can not cause epidemic situation.
C type (third type) influenza: C type influenza virus only can cause human body slight condition of illness to occur, can not cause influenza disease or epidemic situation.C type influenza virus does not have the hypotype classification.
The concrete application in the various influenzas of control of this pharmaceutical composition is as follows:
1) is used for the treatment of the influenza that various street virus cause.B(second for example) type influenza and C(third) the type influenza.
2) be used for the treatment of special influenza, comprising the influenzas such as HN series in SARS, A (first) the type influenza, for example, HN series includes but not limited to H1N1, H1N2, and H2N2, H3N2, H3N8, H5N1, H7N7, H7N9, H9N2, or the like.
3) be used for the prevention of population infection influenzas such as easy infection crowd, high-risk group.Immunity degradation crowd for example, the crowds such as medical personnel that suffered from the family numbers of patients of influenza and contactee, treatment influenza, pharmaceutical composition of the present invention has the effect of prevention.
In addition, pharmaceutical composition of the present invention also has the application at control HIV.Wherein, tenofovir two pyrrole furan esters and other reverse transcriptase inhibitors are united and are used for the existing relevant report of treatment that HIV-1 infects.Pharmaceutical composition of the present invention is just in conjunction with the two, so it has certain effect at control HIV.
The specific embodiment
Further specify the present invention below by several specific embodiments, do not constitute the restriction of the claimed scope of the present invention for concrete data that relate among the embodiment and operation etc.
Embodiment 1(tablet)
Prescription:
Wherein feed intake if use tenofovir two pyrrole furan ester pharmaceutical salts, then consumption is in tenofovir two pyrrole furan esters.
Method for making: above-mentioned microcrystalline Cellulose, carboxymethyl starch sodium and magnesium stearate pulverize separately are crossed 100 orders; in 100 ℃ of drying under reduced pressure more than 10 hours; be chilled to room temperature; again with tenofovir two pyrrole furan esters or its pharmaceutical salts and lamivudine mix homogeneously; dry granulation mechanism grain; be pressed into 1000, promptly.
Embodiment 2(tablet)
Prescription:
Wherein feed intake if use tenofovir two pyrrole furan ester pharmaceutical salts, then consumption is in tenofovir two pyrrole furan esters.
Method for making: above-mentioned microcrystalline Cellulose, carboxymethyl starch sodium and magnesium stearate pulverize separately are crossed 100 orders; in 100 ℃ of drying under reduced pressure more than 10 hours; be chilled to room temperature; again with tenofovir two pyrrole furan esters or its pharmaceutical salts and lamivudine mix homogeneously; dry granulation mechanism grain; be pressed into 1000, promptly.
Embodiment 3(injection)
Prescription:
Method for making: fumaric acid tenofovir two pyrrole furan esters and lamivudine are dissolved among the Glycofurol75, add benzyl alcohol then, dissolving adds water to 3ml, after mixed liquor is filtered and is sealed in the 3ml ampoule glass bottle by sterile millipore filter.
Embodiment 4(capsule)
Prescription:
Method for making: the microcrystalline Cellulose in above-mentioned, carboxymethyl starch sodium pulverize separately are crossed 100 orders; in 100 ℃ of drying under reduced pressure more than 10 hours; be chilled to room temperature; with fumaric acid tenofovir two pyrrole furan esters and lamivudine mix homogeneously; dry granulation mechanism grain adds magnesium stearate, mixing; be filled in 1000 Capsuleses, promptly get described medicament composition capsule.
Embodiment 5(capsule)
Prescription:
Wherein feed intake if use tenofovir two pyrrole furan ester pharmaceutical salts, then consumption is in tenofovir two pyrrole furan esters.
Method for making: consistent with embodiment 3.
Embodiment 6(syrup)
Prescription:
Method for making: fumaric acid tenofovir two pyrrole furan esters and lamivudine are dissolved in the mixed liquor of glycerol and most of purified water, add sorbitol solution then, add xylitol at last, add purified water to volume required, and mixing, promptly.
Other dosage forms of embodiment 7()
Make other dosage forms according to the conventional method on the galenic pharmacy, dispersible tablet for example, is sucked agent, granule, electuary, sublimed preparation, pill, powder, powder, solution etc. at sugar coated tablet, film coated tablet, enteric coated tablet, oral liquid.
The application of the pharmaceutical composition of embodiment 8 embodiment 1-7 in the medicine of preparation treatment first type or influenza B.
Tablet among the embodiment 1 is respectively applied in first type H2N2 influenza virus, the Influenza B virus test, finds that first type H2N2 influenza virus, Influenza B virus all lose activity.
The application of the described pharmaceutical composition of embodiment 9 embodiment 1-7 in the medicine of preparation prevention first type or influenza B.
With the injection among the embodiment 2 be expelled in the experiment poultry with blank group poultry relatively, and contact same H1N1 influenza virus simultaneously, find only to infect the H1N1 influenza, and blank poultry group has 80% to infect the H1N1 influenza approximately less than 10% experiment poultry group.As seen, this pharmaceutical composition has the effect of prevention.
The application of the described pharmaceutical composition of embodiment 10 embodiment 1-7 in the medicine of preparation control HIV.
With the capsule of embodiment 3 give HIV patient by every day 600mg dosage edible, clinical data shows, HIV virus is controlled and descend to some extent.
Claims (10)
1. a pharmaceutical composition contains tenofovir two pyrrole furan esters or its pharmaceutical salts and lamivudine.
2. a pharmaceutical composition contains the tenofovir two pyrrole furan esters of 50～300mg or the lamivudine of its pharmaceutical salts and 50～300mg in the per unit preparation.
3. the described pharmaceutical composition of claim 1 or claim 2 is characterized in that described pharmaceutical composition is a peroral dosage form.
4. the described pharmaceutical composition of claim 1 or claim 2, it is characterized in that described tenofovir two pyrrole furan ester pharmaceutical salts are selected from: tenofovir two pyrrole furan ester succinates, tenofovir two pyrrole furan ester L-tartrates, tenofovir two pyrrole furan ester oxalates, tenofovir two pyrrole furan ester saccharates, tenofovir two pyrrole furan ester citrates, tenofovir two pyrrole furan ester Salicylates, tenofovir two pyrrole furan ester phosphate, tenofovir two pyrrole furan ester fumarates.
5. the described pharmaceutical composition of claim 4 is characterized in that described tenofovir two pyrrole furan ester pharmaceutical salts are fumaric acid tenofovir two pyrrole furan esters.
6. a pharmaceutical composition when making injection type, contains tenofovir two pyrrole furan esters or its pharmaceutical salts 10～300mg, lamivudine 10～300mg in the per unit preparation.
7. pharmaceutical composition, contain in its prescription of per 1000 unit formulations:
8. the application of any one pharmaceutical composition of claim 1-7 in the medicine of preparation treatment first type or influenza B.
9. the application of any one pharmaceutical composition of claim 1-7 in the medicine of preparation prevention first type or influenza B.
10. the application of any one pharmaceutical composition of claim 1-7 in the medicine of preparation control HIV.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2013101762332A CN103211826A (en) | 2013-05-14 | 2013-05-14 | Antiviral pharmaceutical composition as well as preparation method and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2013101762332A CN103211826A (en) | 2013-05-14 | 2013-05-14 | Antiviral pharmaceutical composition as well as preparation method and application thereof |
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| CN103211826A true CN103211826A (en) | 2013-07-24 |
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| CN2013101762332A Pending CN103211826A (en) | 2013-05-14 | 2013-05-14 | Antiviral pharmaceutical composition as well as preparation method and application thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104688747A (en) * | 2013-12-04 | 2015-06-10 | 重庆药友制药有限责任公司 | Pharmaceutical composition containing tenofovir disoproxil fumarate |
| CN108245536A (en) * | 2018-02-09 | 2018-07-06 | 福建广生堂药业股份有限公司 | Tenofovir and Lyopgized Nocardia rubra-cell Wall Skeleton double-layer tablets and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2007068934A2 (en) * | 2005-12-14 | 2007-06-21 | Cipla Limited | Pharmaceutical combination comprising nucleotide and nucleoside reverse transcriptase inhibitors (such as tenofovir and lamivudine) in different parts of the dosage unit |
| WO2008096369A2 (en) * | 2007-02-05 | 2008-08-14 | Matrix Laboratories Limited | Pharmaceutical formulation for use in hiv therapy |
| WO2009106954A1 (en) * | 2008-02-27 | 2009-09-03 | Aurobindo Pharma Limited | Stable dosage forms of lamivudine and tenofovir |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007068934A2 (en) * | 2005-12-14 | 2007-06-21 | Cipla Limited | Pharmaceutical combination comprising nucleotide and nucleoside reverse transcriptase inhibitors (such as tenofovir and lamivudine) in different parts of the dosage unit |
| WO2008096369A2 (en) * | 2007-02-05 | 2008-08-14 | Matrix Laboratories Limited | Pharmaceutical formulation for use in hiv therapy |
| WO2009106954A1 (en) * | 2008-02-27 | 2009-09-03 | Aurobindo Pharma Limited | Stable dosage forms of lamivudine and tenofovir |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104688747A (en) * | 2013-12-04 | 2015-06-10 | 重庆药友制药有限责任公司 | Pharmaceutical composition containing tenofovir disoproxil fumarate |
| CN108245536A (en) * | 2018-02-09 | 2018-07-06 | 福建广生堂药业股份有限公司 | Tenofovir and Lyopgized Nocardia rubra-cell Wall Skeleton double-layer tablets and preparation method thereof |
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